Pediatric neurology: principles & practice

1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899 PEDIATRIC NEUROLOGY: PRINCIPLES & PRACTICE

ISBN-13: 9780323033657 Volume 1: Part no. Volume 2: Part no. ISBN-10:

Copyright © 2006, 1999, 1994, 1989 by Mosby Inc All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Health Sciences Rights Department in Philadelphia, PA, USA: phone: (+1) 215 239 3804, fax: (+1) 215 239 3805, e-mail: [email protected]. You may also complete your request on-line via the Elsevier homepage (http://www.elsevier.com), by selecting ‘Customer Support’ and then ‘Obtaining Permissions.’ Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment, and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioners, relying on their own experience and knowledge of the patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Editors assume any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. The Publisher Library of Congress Cataloging-in-Publication Data Pediatric neurology : principles & practice / [edited by] Kenneth F. Swaiman, Stephen Ashwal, Donna M. Ferriero.—4th ed. p. ; cm. Includes bibliographical references and index. ISBN 0-323-03365-2 1. Pediatric neurology. I. Swaiman, Kenneth F., 1931– II. Ashwal, Stephen, 1945– III. Ferriero, Donna M. [DNLM: 1. Nervous System Diseases—Child. 2. Nervous System Diseases—Infant. WS 340 P3713 2006] RJ486.P336.2006 618.92′8—dc22 2005043798 Acquisitions Editor: Susan Pioli Developmental Editor: Jennifer Shreiner Publishing Services Manager: Frank Polizzano Project Manager: Lee Ann Draud Design Direction: Steve Stave Printed in the United States of America Last digit is the print number: 9 8 7 6 5 4 3 2 1

9996004716 9996004775 0-323-03365-2

DEDICATION

It is our pleasure to dedicate this book to our spouses, Phyllis Sher, Eileen Ashwal, and Thomas Rando, who made it possible for us to spend the enormous amount of time planning, reading, and editing that was necessary to bring this text to fruition. It is impossible to adequately describe the value of their encouragement and support. No dedication of a book embracing this field would be meaningful without a tribute to the courage and perserverance of neurologically impaired children and their caretakers.

CONTRIBUTORS

Anthony A. Amato, MD

Rose-Mary N. Boustany, MD

Associate Professor of Neurology, Harvard Medical School; ViceChairman, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts Inflammatory Myopathies

Professor of Pediatrics and Neurobiology, Duke University Medical Center, Durham, North Carolina; Professor of Pediatrics and Biochemistry and Head, Clinical and Basic Neuroscience, American University of Beirut, Beirut, Lebanon Degenerative Diseases Primarily of Gray Matter

Stephen Ashwal, MD Distinguished Professor of Pediatrics and Chief of the Division of Child Neurology, Loma Linda University School of Medicine, Loma Linda, California Pediatric Neuroimaging; Congenital Structural Defects; Impairment of Consciousness and Coma; Hypoxic-Ischemic Encephalopathy in Infants and Older Children; Determination of Brain Death in Infants and Children; Neurologic Manifestations of Rheumatic Disorders of Childhood; Inflammatory Neuropathies; Neurologic Disorders Associated with Gastrointestinal Diseases, Nutritional Deficiencies, and Fluid-Electrolyte Disorders

Carol S. Camfield, MD

James F. Bale, Jr., MD

Enrique Chaves-Carballo, MD

Associate Chair and Professor, Department of Pediatrics, University of Utah School of Medicine; Attending Physician, Department of Pediatrics, Primary Children’s Medical Group, Salt Lake City, Utah Viral Infections of the Nervous System

Clinical Professor, Departments of Pediatrics and History of Medicine, Kansas University Medical Center, Kansas City, Kansas Syncope and Paroxysmal Disorders Other than Epilepsy

Claudia A. Chiriboga, MD, MPH

Tallie Z. Baram, MD, PhD Professor of Pediatrics, Anatomy/Neurobiology, and Neurology, University of California, Irvine, School of Medicine, Irvine, California Myoclonus, Myoclonic Seizures, and Infantile Spasms

Associate Professor of Clinical Neurology and Pediatrics, Columbia University College of Physicians and Surgeons; Associate Attending Physician, Department of Neurology, Columbia University Medical Center, New York, New York Neurologic Complications of Immunization

Richard J. Barohn, MD

Raymond W. M. Chun, MD

Professor, Department of Pediatrics, Dalhousie University Faculty of Medicine; Pediatrician, IWK Health Centre, Halifax, Nova Scotia, Canada Pediatric Epilepsy: An Overview

Peter R. Camfield, MD Professor, Department of Pediatrics, Dalhousie University Faculty of Medicine; Pediatric Neurologist, IWK Health Centre, Halifax, Nova Scotia, Canada Pediatric Epilepsy: An Overview

Professor and Chair, Department of Neurology, University of Kansas Medical Center and University of Kansas Hospital, Kansas City, Kansas Diseases of the Neuromuscular Junction

Professor Emeritus of Neurology and Pediatrics, University of Wisconsin Medical School, Madison, Wisconsin Interrelationships between Renal and Neurologic Diseases and Therapies

Mark L. Batshaw, MD

Michael E. Cohen, MD

Associate Dean for Academic Affairs and Professor and Chair, Department of Pediatrics, George Washington University School of Medicine and Health Sciences; Chief Academic Officer, Children’s National Medical Center, Washington, DC Inborn Errors of Urea Synthesis

Professor of Neurology and Pediatrics, State University of New York at Buffalo School of Medicine and Biomedical Sciences; Attending Physician, Women and Children’s Hospital, Buffalo, New York Tumors of the Brain and Spinal Cord, Including Leukemic Involvement

Samuel F. Berkovic, MD

Anne M. Connolly, MD

Epilepsy Research Centre and Department of Medicine, University of Melbourne, Melbourne; Director, Comprehensive Epilepsy Program, Austin Health, Heidelberg, Victoria, Australia Genetics of Epilepsy

Associate Professor of Neurology and Pediatrics, Washington University School of Medicine; Attending Physician, St. Louis Children’s Hospital and Barnes Jewish Hospital, St. Louis, Missouri Anterior Horn Cell and Cranial Motor Neuron Disease

Angela K. Birnbaum, PhD

Jeannine M. Conway, PharmD, BCPS

Associate Professor of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis Minnesota Antiepileptic Drug Therapy in Children

Assistant Professor, Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota Antiepileptic Drug Therapy in Children

Contributors

David L. Coulter, MD

Patricia K. Duffner, MD

Associate Professor of Neurology, Harvard Medical School; Attending Neurologist, Children’s Hospital Boston, Boston, Massachusetts Ethical Issues in Child Neurology

Professor of Neurology and Pediatrics, State University of New York at Buffalo School of Medicine and Biomedical Sciences; Women and Children’s Hospital of Buffalo, Buffalo, New York Tumors of the Brain and Spinal Cord, Including Leukemic Involvement

Tina M. Cowan, PhD

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Associate Professor, Department of Pathology, Stanford University School of Medicine; Director, Biochemical Genetics Laboratory, Stanford University Medical Center, Stanford, California Aminoacidemias and Organic Acidemias

Ann-Christine Duhaime, MD

Natalie Z. Cvijanovich, MD

Adré J. du Plessis, MBChB, MPH

Clinical Assistant Professor, University of California, San Francisco, School of Medicine, San Francisco; Associate Physician, Critical Care, Children’s Hospital and Research Center at Oakland, Oakland, California Neonatal Brain Injury

Associate Professor of Neurology, Harvard Medical School; Senior Associate, Neurology, and Director, Fetal-Neonatal Neurology, Children’s Hospital Boston, Boston, Massachusetts Neurologic Disorders Associated with Cardiac Disease

Gregory M. Enns, MB, ChB

Soma Das, PhD

Assistant Professor of Pediatrics and Director, Biochemical Genetics Program, Stanford University School of Medicine; Attending Physician, Lucile Packard Children’s Hospital, Stanford, California Aminoacidemias and Organic Acidemias

Assistant Professor and Director, Clinical Molecular Genetics Laboratory, Department of Human Genetics, Pritzker School of Medicine at the University of Chicago, Chicago, Illinois Introduction to Genetics

Maria Descartes, MD Associate Professor, Department of Genetics and Department of Pediatrics, University of Alabama School of Medicine; Attending Physician, Children’s Hospital, Birmingham, Alabama Chromosomes and Chromosomal Abnormalities

Gabrielle Aline deVeber, MD, MHSc Associate Professor of Pediatrics, University of Toronto Faculty of Medicine; Staff Neurologist and Director, Children’s Stroke Program, The Hospital for Sick Children; Scientist, Population Health Sciences and Brain and Behavior Programs, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada Cerebrovascular Disease

Darryl C. De Vivo, MD Sidney Carter Professor of Neurology, Professor of Pediatrics, and Director Emeritus, Pediatric Neurology Division, Columbia University College of Physicians and Surgeons; Attending Neurologist and Attending Pediatrician, Columbia University Medical Center and New York–Presbyterian Hospital, New York, New York Mitochondrial Diseases

Salvatore DiMauro, MD Lucy G. Moses Professor of Neurology, Columbia University College of Physicians and Surgeons, New York, New York Mitochondrial Diseases

William B. Dobyns, MD Professor of Human Genetics, Neurology, and Pediatrics, Pritzker School of Medicine at the University of Chicago, Chicago, Illinois Congenital Structural Defects; Introduction to Genetics

Qing Dong, MD, PhD Adjunct Instructor, Department of Pediatrics, University of California, San Francisco, School of Medicine; Attending Physician, UCSF Children’s Hospital, San Francisco, California Endocrine Disorders of the Hypothalamus and Pituitary

Professor of Neurosurgery, Dartmouth Medical School, Hanover; Director, Pediatric Neurosurgery, Children’s Hospital at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire Inflicted Childhood Neurotrauma

Diana M. Escolar, MD Associate Professor of Neurology and Pediatrics, Department of Neurology, George Washington University School of Medicine and Health Sciences; Investigator, Research Center for Genetic Medicine, and Director, Neuromuscular Program, Children’s National Medical Center and Children’s Research Institute, Washington, DC Muscular Dystrophies

Owen B. Evans, Jr., MD Professor and Chairman, Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi Normal Muscle

Lydia Eviatar, MD Professor of Neurology and Pediatrics, Albert Einstein College of Medicine, Bronx; Chief Emeritus, Pediatric Neurology, Schneider Children’s Hospital of Long Island Jewish Medical Center Health System, New Hyde Park, New York Vertigo

Donna M. Ferriero, MD Professor, Departments of Neurology and Pediatrics; Division Chief, Child Neurology; and Director, Neonatal Brain Disorders Center, University of California, San Francisco, School of Medicine, San Francisco, California Pathophysiology of Neonatal Hypoxic-Ischemic Brain Injury; Neonatal Brain Injury

Pauline A. Filipek, MD Associate Professor of Clinical Pediatrics and Neurology, University of California, Irvine, School of Medicine, Irvine; Director, For OC Kids, University Children’s Hospital at UCI Medical Center, Orange, California Autistic Spectrum Disorders

Yitzchak Frank, MD Professor of Clinical Neurology and Pediatrics, Mount Sinai School of Medicine; Adjunct Professor of Neurology, New York University School of Medicine; Pediatric Neurologist, Mount Sinai Medical Center, New York, New York Neurologic Disorders Associated with Gastrointestinal Diseases, Nutritional Deficiencies, and Fluid-Electrolyte Disorders

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Contributors

Douglas Fredrick, MD

Alan Hill, MD, PhD

Associate Professor of Clinical Ophthalmology and Pediatrics, University of California, San Francisco, School of Medicine; Director of Pediatric Ophthalmology, University of California, San Francisco, Medical Center, San Francisco, California Vision Loss

Professor, Department of Pediatrics, Division of Neurology, University of British Columbia Faculty of Medicine; Division of Neurology, British Columbia Children’s Hospital, Vancouver, British Columbia, Canada Hypoxic-Ischemic Cerebral Injury in the Newborn

Hudson H. Freeze, PhD

Deborah G. Hirtz, MD

Adjunct Professor of Medicine, University of California, San Diego, School of Medicine; Professor and Director, Glycobiology and Carbohydrate Chemistry Program, The Burnham Institute, La Jolla, California Disorders of Glycosylation

Program Director, Clinical Trials, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland Autistic Spectrum Disorders

Bhuwan P. Garg, MB, BS

Professor of Medicine (Neurology) and Pediatrics, Dartmouth Medical School, Hanover; Chief, Section of Neurology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire Generalized Seizures

Professor of Neurology, Indiana University School of Medicine; Department of Child Neurology, James Whitcomb Riley Hospital for Children, Indianapolis, Indiana Disorders of Micturition and Defecation; Poisoning and DrugInduced Neurologic Diseases

Elizabeth E. Gilles, MD Assistant Professor of Pediatrics and Neurology, University of Minnesota Medical School, Minneapolis; Staff Child Neurologist, Gillette Children’s Specialty Healthcare, St. Paul, Minnesota Inflicted Childhood Neurotrauma

Christopher C. Giza, MD Assistant Professor, Divisions of Neurosurgery and Pediatric Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California Traumatic Brain Injury in Children

Carol A. Glaser, DVM, MD Associate Clinical Professor of Pediatrics, University of California, San Francisco, School of Medicine, San Francisco; Chief, Viral and Rickettsial Disease Laboratory, California Department of Health Services, Richmond, California Fungal, Rickettsial, and Parasitic Diseases of the Nervous System

Joseph G. Gleeson, MD Associate Professor of Neurosciences, University of California, San Diego, School of Medicine, La Jolla; Attending Physician, Children’s Hospital and Health Center, San Diego, California Congenital Structural Defects

Meredith Rose Golomb, MD, MSc

Gregory L. Holmes, MD

Barbara A. Holshouser, PhD Associate Professor of Radiology, Loma Linda University School of Medicine; Medical Physicist, Department of Radiology, Loma Linda University Medical Center, Loma Linda, California Pediatric Neuroimaging

Susan T. Iannaccone, MD Jimmy and Elizabeth Wescott Distinguished Chair in Pediatric Neurology and Professor of Neurology and Pediatrics, University of Texas Southwestern Medical Center at Dallas; Director of Child Neurology, Children’s Medical Center; Director of Neuromuscular Disease and Neurorehabilitation, Texas Scottish Rite Hospital for Children, Dallas, Texas Anterior Horn Cell and Cranial Motor Neuron Disease

Rebecca N. Ichord, MD Assistant Professor, Departments of Neurology and Pediatrics, University of Pennsylvania School of Medicine; Attending Physician, Department of Neurology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Perinatal Metabolic Encephalopathies

Edward M. Kaye, MD Consulting Neurologist, Children’s Hospital Boston, Boston; Vice President for Clinical Research, Genzyme Corporation, Cambridge, Massachusetts Disorders Primarily of White Matter

Assistant Professor, Indiana University School of Medicine; Attending Physician, Riley Hospital for Children, Indianapolis, Indiana Neonatal Brain Injury

John T. Kissel, MD

Cecil D. Hahn, MD, MPH

Ophir Klein, MD, PhD

Instructor, Department of Neurology, Harvard Medical School; Staff Physician, Department of Neurology, Children’s Hospital Boston, Boston, Massachusetts Neurologic Disorders Associated with Cardiac Disease

Clinical Fellow, Division of Genetics, Department of Pediatrics, University of California, San Francisco, School of Medicine, San Francisco, California Aminoacidemias and Organic Acidemias

Chellamani Harini, MD

Edwin H. Kolodny, MD

Fellow in Epilepsy and Clinical Neurophysiology, Children’s Hospital Boston, Boston, Massachusetts Spinal Cord Injury

Bernard A. and Charlotte Marden Professor and Chairman, Department of Neurology, New York University School of Medicine; Director, Department of Neurology, New York Medical Center, New York, New York Lysosomal Storage Diseases

Professor and Interim Chair, Department of Neurology, The Ohio State University, Columbus, Ohio Inflammatory Myopathies

Contributors

Bruce R. Korf, MD, PhD

David E. Mandelbaum, MD, PhD

Wayne H. and Sara Crews Finley Professor of Medical Genetics and Chair, Department of Genetics, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama Chromosomes and Chromosomal Abnormalities; Phakomatoses and Allied Conditions

Professor of Clinical Neurosciences and Pediatrics, Brown Medical School; Director, Division of Child Neurology, Rhode Island and Hasbro Children’s Hospitals, Providence, Rhode Island Attention-Deficit–Hyperactivity Disorder

Suresh Kotagal, MD

Stephen M. Maricich, PhD, MD

Professor, Department of Neurology, Mayo Clinic College of Medicine; Chair, Division of Child Neurology, and Consultant, Department of Child Neurology, Mayo Clinic, Rochester, Minnesota Sleep-Wake Disorders; Increased Intracranial Pressure

Fellow, Baylor College of Medicine; Fellow, Texas Children’s Hospital, Houston, Texas The Cerebellum and the Hereditary Ataxias

Robert L. Kriel, MD Professor, Departments of Neurology, Pediatrics, and College of Pharmacy, University of Minnesota Medical School; Pediatric Neurologist, Hennepin County Medical Center, Minneapolis, Minnesota Antiepileptic Drug Therapy in Children

Steven M. Leber, MD, PhD Professor of Pediatrics and Neurology, University of Michigan Medical School and C. S. Mott Children’s Hospital, Ann Arbor, Michigan The Internet and Its Resources for the Child Neurologist

Melissa Lee, MD Assistant Professor, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland Neuropsychopharmacology

Robert T. Leshner, MD Professor of Neurology and Pediatrics, George Washington University School of Medicine and Health Sciences; Attending Neurologist, Center for Genetic Medicine, Department of Neurology, Children’s National Medical Center, Washington, DC Muscular Dystrophies

Donald W. Lewis, MD Professor of Pediatrics and Neurology, Eastern Virginia Medical School; Pediatric Neurologist, Children’s Hospital of the King’s Daughters, Norfolk, Virginia Headaches in Infants and Children

Paul F. Lewis, MD Associate Professor of Pediatrics, Oregon Health and Science University; Public Health Physician, Acute and Communicable Disease Program, Oregon Department of Human Services, Portland, Oregon Fungal, Rickettsial, and Parasitic Diseases of the Nervous System

Uta Lichter-Konecki, MD, PhD Assistant Professor of Pediatrics, George Washington University School of Medicine and Health Sciences; Assistant Professor of Pediatrics, Children’s Research Institute, Children’s National Medical Center, Washington, DC Inborn Errors of Urea Synthesis

Kenneth J. Mack, MD, PhD Associate Professor of Neurology, Mayo Clinic, Rochester, Minnesota The Internet and Its Resources for the Child Neurologist

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Christopher J. Mathias, DPhil, DSc Professor of Neurovascular Medicine, National Hospital for Neurology and Neurosurgery, University College London; Professor of Neurovascular Medicine, Imperial College London at St. Mary’s Hospital, London, United Kingdom Disorders of the Autonomic Nervous System: Autonomic Dysfunction in Pediatric Practice

Claire McLean, MD Assistant Professor of Pediatrics, Keck School of Medicine of University of Southern California; Attending Physician, Children’s Hospital of Los Angeles, Los Angeles, California Pathophysiology of Neonatal Hypoxic-Ischemic Brain Injury

Julie A. Mennella, PhD Member and Director of Education Outreach, Monell Chemical Senses Center, Philadelphia, Pennsylvania Taste and Smell

Laura R. Ment, MD Professor, Departments of Pediatrics and Neurology, Yale University School of Medicine; Attending Physician, Yale–New Haven Hospital, New Haven, Connecticut Intraventricular Hemorrhage of the Preterm Neonate

David J. Michelson, MD Assistant Professor of Child Neurology, Loma Linda University School of Medicine, Loma Linda, California Spinal Fluid Examination; Cognitive and Motor Regression

Jonathan W. Mink, MD, PhD Associate Professor of Neurology, Neurobiology and Anatomy, and Pediatrics, University of Rochester Medical Center School of Medicine and Dentistry; Chief, Child Neurology, Golisano Children’s Hospital at Strong Memorial Hospital, Rochester, New York Movement Disorders

Wendy G. Mitchell, MD Professor of Neurology and Pediatrics, Keck School of Medicine of the University of Southern California; Director, Child Neurology Training Program, Children’s Hospital of Los Angeles, Los Angeles, California Behavioral, Cognitive, and Social Aspects of Childhood Epilepsy

Eli M. Mizrahi, MD Head, Peter Kellaway Section of Neurophysiology; Vice-Chairman, Department of Neurology; and Professor of Neurology and Pediatrics, Baylor College of Medicine; Chief, Neurophysiology Service, Methodist Hospital and St. Luke’s Episcopal Hospital; Chief, Clinical Neurophysiology Laboratory Services, Texas Children’s Hospital, Houston, Texas Neonatal Seizures

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Contributors

Lawrence D. Morton, MD

Marc C. Patterson, MD

Associate Professor of Neurology and Pediatrics, Medical College of Virginia Campus of Virginia Commonwealth University School of Medicine; Director, Clinical Neurophysiology, Virginia Commonwealth University Health Systems, Richmond, Virginia Status Epilepticus

Professor and Head, Division of Pediatric Neurology, Departments of Neurology and Pediatrics, Columbia University College of Physicians and Surgeons; Director of Pediatric Neurology, Morgan Stanley Children’s Hospital of New York–Presbyterian, New York, New York Diseases Associated with Primary Abnormalities in Carbohydrate Metabolism; Disorders of Glycosylation

Hugo W. Moser, MD Professor, Departments of Neurology and Pediatrics, Johns Hopkins University School of Medicine; Director, Neurogenetics Research Center, Kennedy Krieger Institute, Baltimore, Maryland Peroxisomal Disorders

Richard T. Moxley III, MD Professor of Neurology and Pediatrics, University of Rochester Medical Center School of Medicine and Dentistry; Director, Neuromuscular Disease Center, University of Rochester Medical Center, Rochester, New York Chanellopathies: Myotonic Disorders and Periodic Paralysis

SakkuBai Naidu, MD Professor, Department of Neurology, Johns Hopkins University School of Medicine; Director, Neurogenetics Unit, Kennedy Krieger Institute, Baltimore, Maryland Peroxisomal Disorders

Ruth Nass, MD Professor of Clinical Neurology, New York University School of Medicine, New York, New York Developmental Language Disorders

Douglas R. Nordli, Jr., MD Associate Professor of Pediatrics and Neurology, Feinberg School of Medicine, Northwestern University; Lorna S. and James P. Langdon Chair of Pediatric Epilepsy, Children’s Memorial Hospital, Chicago, Illinois Focal and Multifocal Seizures

Robert Ouvrier, MD Petre Foundation Professor of Paediatric Neurology, Department of Paediatrics, University of Sydney, Sydney; Attending Physician, Children’s Hospital at Westmead, Westmead, New South Wales, Australia Peripheral Neuropathies

Seymour Packman, MD Professor, Department of Pediatrics, and Director, Biochemical Genetics Service and Neurometabolic Program and Clinics, University of California, San Francisco, School of Medicine, San Francisco, California Aminoacidemias and Organic Acidemias

John Colin Partridge, MD, MPH Clinical Professor, Department of Pediatrics, University of California, San Francisco, School of Medicine; Attending Neonatologist, University of California, San Francisco, Medical Center and San Francisco General Hospital, San Francisco, California Pain Management and Palliative Care

John M. Pellock, MD Professor and Chairman, Division of Child Neurology, and Vice Chairman, Department of Neurology, Medical College of Virginia Campus of Virginia Commonwealth University School of Medicine, Richmond, Virginia Status Epilepticus

Ronald M. Perkin, MD, MA Professor and Chairman, Department of Pediatrics, Brody School of Medicine at East Carolina University; Medical Director, Children’s Hospital of Eastern North Carolina; Chief of Pediatrics, Pitt County Memorial Hospital, Greenville, North Carolina Hypoxic-Ischemic Encephalopathy in Infants and Older Children

Lauren Plawner, MD Assistant Clinical Professor, Departments of Pediatrics and Neurology, University of California, San Francisco, School of Medicine; Pediatric Neurologist, Department of Pediatrics, Kaiser Permanente Medical Center, San Francisco, California Congenital Structural Defects

Isabelle Rapin, MD Professor of Neurology and Pediatrics, Albert Einstein College of Medicine; Attending Neurologist and Child Neurologist, Jacobi Medical Center and Montefiore Medical Center, Bronx, New York Hearing Impairment

Gerald V. Raymond, MD Associate Professor, Department of Neurology, Johns Hopkins University School of Medicine; Neurologist, Neurogenetics Research Center, Kennedy Krieger Institute, Baltimore, Maryland Peroxisomal Disorders

Jong M. Rho, MD Associate Professor of Clinical Neurology, University of Arizona College of Medicine, Tucson; Associate Director of Child Neurology, Children’s Health Center, St. Joseph’s Hospital and Medical Center, Phoenix; Director of Pediatric Epilepsy Research, Barrow Neurological Institute, Phoenix, Arizona Neurophysiology of Epilepsy

Sarah M. Roddy, MD Associate Professor of Pediatrics and Neurology, Loma Linda University School of Medicine; Attending Physician, Loma Linda University Children’s Hospital, Loma Linda, California Breath-Holding Spells and Reflex Anoxic Seizures

Stephen M. Rosenthal, MD Professor of Pediatrics, University of California, San Francisco, School of Medicine, San Francisco, California Endocrine Disorders of the Hypothalamus and Pituitary

Gregory M. Pastores, MD

N. Paul Rosman, MD

Associate Professor of Neurology and Pediatrics, New York University School of Medicine; Director, Neurogenetics Laboratory, New York University Medical Center, New York, New York Lysosomal Storage Diseases

Professor of Pediatrics and Neurology, Boston University School of Medicine; Pediatric Neurologist, Boston Medical Center, Boston, Massachusetts Spinal Cord Injury

Contributors

Robert S. Rust, MD, MA

Elliott H. Sherr, MD, PhD

Worrell Professor of Epileptology and Neurology and Professor of Pediatrics, University of Virginia School of Medicine, Charlottesville, Virginia Interrelationships between Renal and Neurologic Diseases and Therapies

Assistant Professor of Neurology, University of California, San Francisco, School of Medicine; Attending Physician, UCSF Children’s Hospital, San Francisco, California Mental Retardation and Global Developmental Delay

Terence D. Sanger, MD, PhD Assistant Professor, Stanford University School of Medicine; Division of Child Neurology, Lucile Packard Children’s Hospital, Stanford, California Movement Disorders

Professor, Departments of Neurology/Neurosurgery and Pediatrics, McGill University Faculty of Medicine; Division of Pediatric Neurology, Montreal Children’s Hospital–McGill University Health Centre, Montreal, Quebec, Canada Mental Retardation and Global Developmental Delay

Urs B. Schaad, MD

Shlomo Shinnar, MD, PhD

Professor of Pediatrics, University of Basel; Medical Director and Chairman, Department of Pediatrics, University Children’s Hospital, Basel, Switzerland Bacterial Infections of the Nervous System

Professor of Neurology and Pediatrics and Hyman Climenko Professor of Neuroscience Research, Albert Einstein College of Medicine; Director, Comprehensive Epilepsy Management Center, Montefiore Medical Center, Bronx, New York Febrile Seizures

Ingrid E. Scheffer, MBBS, PhD

Michael I. Shevell, MD

Professor, Department of Medicine and Paediatrics, University of Melbourne, Melbourne; Paediatric Neurologist, Austin Health, Heidelberg; Paediatric Neurologist, Monash Medical Centre, Clayton, Victoria, Australia Genetics of Epilepsy

Stanford K. Shu, MD

Mark S. Scher, MD

Professor of Pediatrics and Neurology, University of Michigan Medical School, Ann Arbor, Michigan Pathophysiology of Neonatal Hypoxic-Ischemic Brain Injury

Professor of Pediatrics, Case Western Reserve University School of Medicine; Division Chief, Pediatric Neurology, and Director of Pediatric Sleep/Epilepsy and Fetal Neonatal Neurology Programs, Rainbow Babies and Children’s Hospital and University Hospitals of Cleveland, Cleveland, Ohio Pediatric Neurophysiologic Evaluation

Nina Felice Schor, MD, PhD Professor of Pediatrics, Neurology, and Pharmacology; Chief, Division of Child Neurology; Associate Dean for Medical Student Research, University of Pittsburgh School of Medicine; Carol Ann Craumer Chair of Pediatric Research and Director, Pediatric Center for Neuroscience, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania Neurologic Manifestations of Rheumatic Disorders of Childhood

Frederick L. Schuster, PhD Viral and Rickettsial Disease Laboratory, California Department of Health Services, Richmond, California Fungal, Rickettsial, and Parasitic Diseases of the Nervous System

Bennett A. Shaywitz, MD Professor of Pediatrics and Neurology, Yale University School of Medicine, New Haven, Connecticut Dyslexia

Sally E. Shaywitz, MD Professor of Pediatrics, Yale University School of Medicine, New Haven, Connecticut Dyslexia

Robert Sheets, MD Assistant Clinical Professor of Pediatrics, University of California, San Diego, School of Medicine, La Jolla; Pediatric Rheumatologist, Children’s Hospital of San Diego, San Diego, California Neurologic Manifestations of Rheumatic Disorders of Childhood

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Assistant Professor of Child Neurology, Loma Linda University School of Medicine, Loma Linda, California Cognitive and Motor Regression

Faye S. Silverstein, MD

Harvey S. Singer, MD Haller Professor of Pediatric Neurology, Johns Hopkins University School of Medicine; Director, Child Neurology, Johns Hopkins Hospital, Baltimore, Maryland Tourette Syndrome and Its Associated Neurobehavioral Problems

John T. Sladky, MD Professor of Pediatrics and Neurology, Emory University School of Medicine; Division Chief, Child Neurology, Children’s Healthcare of Atlanta; Division Chief, Child Neurology, Grady Health System, Atlanta, Georgia Inflammatory Neuropathies

Stephen A. Smith, MD Director, Neuromuscular Laboratory, Department of Pathology, Hennepin County Medical Center, Minneapolis, Minnesota; Director, Neuromuscular Program, Department of Neurology, Gillette Children’s Specialty Healthcare, St. Paul, Minnesota; Director, Neuromuscular Laboratory, Department of Pathology, Parkview Hospital, Pueblo, Colorado Peripheral Neuropathies

Carl E. Stafstrom, MD, PhD Professor of Neurology and Pediatrics, University of Wisconsin Medical School; Chief, Section of Pediatric Neurology, University of Wisconsin Hospital, Madison, Wisconsin Neurophysiology of Epilepsy

Jonathan B. Strober, MD Assistant Clinical Professor of Neurology and Pediatrics, University of California, San Francisco, School of Medicine, San Francisco, California Congenital Myopathies

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Contributors

Kenneth F. Swaiman, MD

Ann H. Tilton, MD

Director Emeritus, Division of Pediatric Neurology, and Professor Emeritus of Neurology and Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota General Aspects of the Patient’s Neurologic History; Neurologic Examination of the Older Child; Neurologic Examination after the Newborn Period until 2 Years of Age; Neurologic Examination of the Term and Preterm Infant; Muscular Tone and Gait Disturbances; Cerebral Palsy; Diseases Associated with Primary Abnormalities in Carbohydrate Metabolism

Professor and Section Chair of Child Neurology, Louisiana State University Health Sciences Center; Co-Director of Rehabilitation, Child Neurology, Children’s Hospital of New Orleans, New Orleans, Louisiana Pediatric Neurorehabilitation Medicine

Kathryn J. Swoboda, MD Associate Professor of Neurology and Adjunct Associate Professor of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah Diagnosis and Treatment of Neurotransmitter-Related Disorders

Ilona S. Szer, MD Professor of Clinical Pediatrics, University of California, San Diego, School of Medicine, La Jolla; Director, Pediatric Rheumatology, Children’s Hospital of San Diego, San Diego, California Neurologic Manifestations of Rheumatic Disorders of Childhood

Martin G. Täuber, MD Professor and Co-Director, Institute for Infectious Diseases, University of Bern; Director, Clinic and Policlinic for Infectious Diseases, University Hospital Insel, Bern, Switzerland Bacterial Infections of the Nervous System

Rabi Tawil, MD Associate Professor of Neurology, Pathology, and Laboratory Medicine, University of Rochester Medical Center School of Medicine and Dentistry; Co-Director; Neuromuscular Disease Clinic, University of Rochester Medical Center, Rochester, New York Chanellopathies: Myotonic Disorders and Periodic Paralysis

Donald A. Taylor, MD Director of Pediatric Clinical Neurophysiology, St. Mary’s Hospital, Richmond, Virginia Impairment of Consciousness and Coma

Ingrid Tein, MD, BSc Associate Professor of Pediatrics, Laboratory Medicine, and Pathobiology, University of Toronto Faculty of Medicine; Director, Neurometabolic Clinic and Research Laboratory, and Senior Scientist, The Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Metabolic Myopathies

Elizabeth A. Thiele, MD, PhD Associate Professor of Neurology, Harvard Medical School; Director, Carol and James Herscot Center for Tuberous Sclerosis Complex, Massachusetts General Hospital, Boston, Massachusetts Phakomatoses and Allied Conditions

Joseph R. Thompson, MD Professor of Radiology, Loma Linda University School of Medicine; Pediatric Neuroradiologist, Department of Radiology, Loma Linda University Medical Center, Loma Linda, California Pediatric Neuroimaging

Doris A. Trauner, MD Professor and Chief of Pediatric Neurology, University of California, San Diego, School of Medicine, La Jolla, California Developmental Language Disorders

Mendel Tuchman, MD Professor of Pediatrics, Biochemistry, and Molecular Biology, George Washington University School of Medicine and Health Sciences; Vice Chair for Research and Scientific Director, Children’s Research Institute, Children’s National Medical Center, Washington, DC Inborn Errors of Urea Synthesis

Roberto Tuchman, MD Associate Professor of Neurology, University of Miami Miller School of Medicine, Miami; Director, Developmental and Behavioral Neurology, Miami Children’s Hospital Dan Marino Center, Weston, Florida Epileptiform Disorders with Cognitive Systems

Marjo S. van der Knaap, MD, PhD Professor of Child Neurology, University Medical Center, Amsterdam, The Netherlands Disorders Primarily of White Matter

Michèle Van Hirtum-Das, MD Resident, Child Neurology, Children’s Hospital of Los Angeles, Los Angeles, California Behavioral, Cognitive, and Social Aspects of Childhood Epilepsy

V. Venkataraman Vedanarayanan, MD Professor of Neurology and Professor of Pediatrics, University of Mississippi School of Medicine; Attending Physician, University of Mississippi Medical Center, Jackson, Mississippi Normal Muscle

Ann Wagner, PhD Chief, Neurodevelopmental Disorders Branch, Division of Pediatric Translational Research and Treatment Development, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland Autistic Spectrum Disorders

John T. Walkup, MD Associate Professor, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine; Deputy Director, Division of Child and Adolescent Psychiatry, Johns Hopkins Hospital, Baltimore, Maryland Neuropsychopharmacology

Laurence E. Walsh, MD Assistant Professor of Clinical Neurology and Medical and Molecular Genetics, Indiana University School of Medicine; Director, Section of Child Neurology, James Whitcomb Riley Hospital for Children, Indianapolis, Indiana Poisoning and Drug-Induced Neurologic Diseases

Contributors

xiii

Maria B. Weimer, MD

Nathaniel D. Wycliffe, MD

Assistant Professor of Clinical Neurology, Louisiana State University Health Sciences Center; Staff Child Neurologist, Children’s Hospital, New Orleans, Louisiana Pediatric Neurorehabilitation Medicine

Assistant Professor of Radiology, Loma Linda University School of Medicine; Neuroradiologist and Director of Head and Neck Radiology, Department of Radiology, Loma Linda University Medical Center, Loma Linda, California Pediatric Neuroimaging

James W. Wheless, MD Professor of Neurology and Pediatrics and Director, Texas Comprehensive Epilepsy Program, University of Texas Health Science Center at Houston–Medical School; Director, Epilepsy Monitoring Unit, and Director, EEG and Clinical Neurophysiology, Memorial Hermann and Memorial Hermann Children’s Hospitals, Houston, Texas The Ketogenic Diet

Huda Y. Zoghbi, MD

Gil I. Wolfe, MD

Duke University Medical Center, Durham, North Carolina Degenerative Diseases Primarily of Gray Matter

Dr. Bob and Jean Smith Foundation Distinguished Chair in Neuromuscular Disease Research and Associate Professor, Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas Diseases of the Neuromuscular Junction

Yvonne Wu, MD, MPH Assistant Professor, Departments of Neurology and Pediatrics, University of California, San Francisco, School of Medicine, San Francisco, California Cerebral Palsy

Professor of Pediatrics, Molecular and Human Genetics, Neurology, and Neuroscience, Baylor College of Medicine; Investigator, Howard Hughes Medical Institute, Houston, Texas The Cerebellum and the Hereditary Ataxias

Adam Zucker, MD

Mary L. Zupanc, MD Professor, Departments of Neurology and Pediatrics, Medical College of Wisconsin; Director Comprehensive Epilepsy Center, Children’s Hospital of Wisconsin, Milwaukee, Wisconsin Epilepsy Surgery in the Pediatric Population

PREFACE TO THE FOURTH EDITION

S

ince publication in 1999 of the third edition of Pediatric Neurology: Principles & Practice, the discipline of child neurology has progressed and reached new levels of complexity. Advances in molecular biology and neuroimaging have fueled an explosion of knowledge that has translated into a richer understanding of nervous system development and function. Researchers and clinicians alike believe that, during the next decade, novel and targeted treatments will be the product of such fundamental advances in knowledge. Successful treatment of children with both common and rare neurologic disorders will be a reality. This fourth edition reflects the enormous growth and intricacy of the basic and clinical neurosciences. The entire text has been revised and reorganized. There are many new chapters that reflect areas of child neurology that are becoming increasingly relevant clinically (e.g., neurogenetics, neuropsychopharmacology, neurorehabilitation, ethics), as well as new chapters on diseases that were previously unrecognized (e.g., PNTD, CDG). Many chapters have new authors who bring to these discussions new insights into disease mechanisms. Also, the two senior editors are extremely fortunate to have Donna M. Ferriero join us to provide her expertise to ensure maintenance of the quality of this publication. The two volumes are divided into 16 parts, encompassing 95 chapters as outlined in the table of contents. Parts I and II contain information regarding selected aspects of the pediatric neurologic examination in a general sense, as well as the different motor and sensory systems, and these discussions are followed by a comprehensive review of the pertinent neurodiagnostic testing procedures and their clinical application. Part III covers important aspects of neonatal neurology and the long-term sequelae of acquired and developmental abnormalities that can result in chronic disorders, such as cerebral palsy, developmental delay, and epilepsy. Part IV documents the vast array of genetic and neurometabolic disorders that occur in infants and children; this section also provides many of the fundamental concepts of molecular biology and neurochemistry that constitute the scientific basis of these diseases. Part V describes the major neurobehavioral disorders of childhood and includes chapters on autism and the neuropsychiatric problems that accompany Tourette syndrome and a new chapter on neuropsychopharmacology. Part VI focuses on pediatric epilepsy and contains new chapters on the neurophysiology and neurogenetics of pediatric epilepsy. Also included are chapters on the various types of pediatric epilepsy, epileptiform disorders with cognitive symptomatology, the ketogenic diet, surgical treatment, and the learning and behavioral problems associated with epilepsy.

The second volume encompasses many of the serious and complex central and peripheral nervous system diseases that confront child neurologists and allied health professionals. Part VII reviews the nonepileptiform paroxysmal disorders, including headache, syncope, and sleep disorders. Parts VIII and IX deal with conditions that are degenerative in nature and cause severe loss of motor and mental function. These conditions include gray and white matter diseases that can cause ataxia, movement disorders, progressive spasticity, and dementia. Part X contains chapters on traumatic and nontraumatic brain injury in infants and older children. Because neurologists are frequently asked to provide consultation for many of these conditions, chapters on disorders of consciousness, nonaccidental trauma, anoxic brain injury, and traumatic brain and spinal cord injury are included, as well as a current review of the issues related to brain death determination. Parts XI (infection) and XII (tumors and cerebrovascular and vasculitic diseases) extensively cover the major diseases that directly or indirectly cause serious neurologic symptoms and are presented primarily from a clinical perspective. The neuromuscular diseases are reviewed in Part XIII, which contains chapters on the classic neuromuscular disorders including the anterior horn cell diseases, disorders of the peripheral nervous system, neuromuscular junction, inflammatory neuropathies, metabolic myopathies, and channelopathies. Parts XIV and XV include important chapters that review many pediatric systemic (e.g., endocrine, renal, cardiac, gastrointestinal) conditions that are known to cause neurologic symptoms, as well as chapters on poisonings, complications of immunizations, and autonomic nervous system disorders. This volume concludes with Part XVI, which has been revised extensively and includes new and revised chapters on pediatric neurorehabilitation, pain and palliative care management, ethical issues in child neurology, and an update on the Internet as it relates to child neurology. We hope that the reader will find this book a useful resource and that the information will benefit the many children who suffer from these conditions. It is our wish that the greater world community will increase support for the care of neurologically impaired children and the research necessary to provide further understanding of neurologic diseases. This support is necessary to facilitate discovery of new therapies that will improve the survival and quality of life of these unfortunate and brave children. Kenneth F. Swaiman Stephen Ashwal Donna M. Ferriero

PREFACE TO THE FIRST EDITION

I

t is concurrently tiring, humiliating, and intellectually revitalizing to compile a book containing the essence of the information that embraces one’s life work and professional preoccupation. For me, there is a certain mothto-the-flame phenomenon that cannot be resisted; therefore this new book has been produced. Pediatric neurology has come of age since my initial interest and subsequent immersion in the field. Concentrated attention to the details of brain development and function has brought much progress and understanding. Studies of disease processes by dedicated and intelligent individuals accompanied by a cascade of new technology (e.g., neuroimaging techniques, positron emission tomography, DNA probes, synthesis of gene products, sophisticated lipid chemistry) have propelled the field forward. The simultaneous increase of knowledge and capability of pediatric neurologists and others who diagnose and treat children with nervous system dysfunction has been extremely gratifying. Although once within the realm of honest delusion of a seemingly sane (but unrealistic) devotee of the field, it is no longer possible to believe that a single individual can fathom, much less explore, the innumerable rivulets that coalesce to form the river of knowledge that currently is pediatric neurology. Streams of information in certain areas sometimes peacefully meander for years; suddenly, when knowledge of previously obscure areas is advanced and the newly gained information becomes central to understanding basic pathophysiologic entities, a once small stream gains momentum and abruptly flows with torrential force.

This text is an attempt to gather the most important aspects of current pediatric neurology and display them in a comprehensible manner. The task, although consuming great energies and concentration, cannot be accomplished completely because new conditions are described daily. The advancement of the field necessitated that preparation of this text keep pace with current knowledge and present new and valuable techniques. My colleagues and I have made every effort to discharge this responsibility. Because of continuous scientific progress, controversies are extant in some areas for varying periods; wherever possible, these areas of conflict are indicated. This book is divided into four unequal parts. Part I contains a discussion of the historic and clinical examination. Part II contains information concerning laboratory examination. Chapters relating to the symptom complexes that often reflect the chief complaints of neurologically impaired children compose Part III. Part IV provides detailed discussion of various neurologic diseases that afflict children. Although every precaution has been taken to avoid error, bias, and prejudice, inevitably some of these demons have become embedded in the text. The editor assumes full responsibility for these indiscretions. It is my fervent hope that the reader will find this book informative and stimulating and that the contents will provide an introduction to the understanding of many of the conditions that remain mysterious and poorly explained. Kenneth F. Swaiman, MD Autumn 1988

ACKNOWLEDGMENTS

W

e wish to thank Arlene Carpenter, Diana Laulainen-Schein, Ann Elliott, and Kei Kaneshiro for their time and effort, which so efficiently affected manuscript flow, editing, and preparation, as well as the innumerable other tasks necessary to complete this book. We also wish to thank the librarians at the University of Minnesota Medical School and at the Coleman and Del Webb Libraries at Loma Linda University School of Medicine for

their help, advice, and willingness at any time to obtain information that we required. In addition, we wish to thank the editorial and publishing staff at Elsevier, especially Susan Pioli, Jennifer Shreiner, and Lee Ann Draud. Without their diligence, persistence, insight, and flexibility, we would have never been able to complete this project.

CHAPTER 1

General Aspects of the Patient’s Neurologic History Kenneth F. Swaiman

Modern technology does not and cannot substitute for skilled history taking. The crucial role of obtaining the patient’s neurologic history directly from the patient or a member of the patient’s family cannot be stressed enough. The history-taking procedure should elicit specific information and be directed so as to exclude or ensure inclusion of pertinent conditions in the differential diagnosis of the child’s condition. The information obtained during the history-taking session is critical during the subsequent analysis and synthesis of all patient data. The clinician should be involved in a dynamic diagnostic quest throughout the interview and during the review of previous medical and other relevant records. A systematic approach to the medical history is mandatory; however, the clinician must be alert to significant leads that may eventually prove essential to the diagnostic process. The history-taking session is not a netting operation with data to be subsequently sorted; rather, the data should be dynamically synthesized as they are collected and then used to alter the direction and depth of the questioning process. The process of identifying a differential diagnosis should begin at the outset of questioning. In a broad sense, certain umbrella categories encompass virtually all etiologic mechanisms that underlie the differential diagnosis. Inevitably, there is some overlap (e.g., vascular occlusion in MELAS, a metabolic condition; mass effect of a brain abscess, an infectious condition). The fundamental pathologic processes, simplistically identified, are infectious, traumatic, metabolic, endocrinologic, toxic (exogenous and endogenous), congenital structural malformations, vascular, neoplastic, degenerative (usually of unknown or obscure cause), and idiopathic. Each of these categories has many subsets with which the clinician who evaluates neurologic problems in children must be familiar. The likelihood that one of the broad umbrella classifications applies to the problem of the pediatric patient must be judged while the history is obtained, during which time some categories will gain in probability and some will become increasingly remote. The information gathered during the history-taking session may be vital in the process of literature and database searches that may subsequently prove necessary. The precise role of genetic determination (i.e., gene product formation and use) in all familial pathologic processes is exceedingly important now that the human genome has been mapped. Most chronic neurologic complaints are complex, and the neurologist’s involvement is often preceded by involvement of other professionals and agencies. If the parents are the primary caregivers, both the mother and father should be present if possible. When grandparents or other caregivers are involved in attending to the child, they should be present. Review of past medical and developmental histories is an essential component of a good history-taking session.

Information should be sought from records and from questioning the mother about health problems, including infertility, and diseases that occurred during pregnancy. With increasing data accumulating regarding adverse pediatric outcomes with assisted reproductive technologies [Jackson et al., 2004], it is important to ask whether conception was achieved naturally and, if not, what method of assisted reproductive technology was employed. Gestational information about infection, radiation, acute trauma, chronic illnesses such as diabetes mellitus, and toxins, including illicit drugs, tobacco, and alcohol, may prove invaluable. Further information about medications that the mother received, including over-the-counter preparations, should be probed. It is important to record the expected and actual dates of delivery. Review of birth records, including those of the mother, may reveal information concerning difficulties with pregnancy and problems in the perinatal period that are not known or remembered by the parents. Details of the intrapartum period, including associated hypertension, drugs administered, length of stages of delivery, occurrence of chorioamnionitis, and if possible, information concerning placental pathology and the general appearance of the newborn at time of birth, may prove enlightening. It is important to determine the status of the newborn infant. Information should be sought concerning Apgar scores, depression of activity, neonatal seizures, presence of hypotonia, and whether tracheal intubation and ventilatory support was needed. The patient’s caregivers should be questioned carefully about the nature and results of previously performed tests, including electrodiagnostic tests, brain-imaging studies, biochemical studies (e.g., quantitative assays of amino acids, organic acids, lactic acid, and lysosomal enzymes), biopsies, and chromosomal studies. The caregivers should also be asked about whether medication or other treatment has been administered or advised and about the result of such therapies. The primary problem of the child is embodied in the chief complaint. A combination of chief complaints may prove more specific and narrows the diagnostic spectrum (e.g., a 6-month-old male with delayed development and cataracts). The differential diagnosis initially is based on the chief complaint, which should therefore be documented as accurately as possible. The caregiver’s or patient’s description should be quoted verbatim, when possible. The period of onset and whether the symptoms began acutely or gradually should be carefully determined. The clinician should not substitute medical terminology in place of the terms used by the caregivers or patient when recording the chief complaint. Medical terms must be explained fully so that responses are complete and pertinent.

4

Clinical Evaluation / 1

1. 2. 3. 4.

Is the process acute or insidious? Is it focal or generalized? Is it progressive or static? At what age did the problem begin?

The order in which disease findings develop and the precise time of onset of symptoms and signs may be critical factors in the process of accurate diagnosis. The presence of repeated episodes or associated phenomena should be determined. Detailed questions should be asked of the caregivers and child to elucidate the facts.

Neurologic impairment

Vascular conditions

the history meaningful and complete may be the seemingly trivial information that is not readily recalled or divulged. The accomplished clinician can uncover this information by directed and specific inquiry. The chief complaint should trigger the process of differential diagnosis in the examiner’s thinking, which begins as a listing of the disease conditions that could cause the chief complaint at the child’s age. The following four specific questions should be answered, if possible, in taking the history of the current illness:

Toxic conditions

1 2 3 4 5 6 7 2 3 4 2 3 4 5 6 1 2 3 4 Days Weeks Months Years

1 2 3 4 5 6 7 2 3 4 2 3 4 5 6 1 2 3 4 Days Weeks Months Years

Infectious conditions

Degenerative and neoplastic conditions

Neurologic impairment

Neurologic impairment

Neurologic impairment

Notwithstanding these goals, the actual complaint may be imprecisely described because the caregivers’ memories, language, or observations may be inaccurate and because the child may be unable to provide detailed information. The clinician should make every attempt to question the child directly. Even a preschool-aged child may provide helpful information. Sometimes, adults who participate in the session may not be objective or capable of accuracy. Most commonly however, the observations and concerns of the caregiver should be given every consideration and essence of credibility. It is extremely unwise to disregard these components of the history when comments are somewhat unusual or incompatible with the clinician’s diagnostic bias. The features associated with the chief complaint compose the history of the present illness. The questioning should provide an incisive interaction between caregiver (or patient) and clinician and should be directed at formulating the differential diagnosis. This portion of the communication process requires skill and perseverance. An all-inclusive neurologic history is impossible; however, that which makes

Neurologic impairment

1 2 3 4 5 6 7 2 3 4 2 3 4 5 6 1 2 3 4 Days Weeks Months Years

1 2 3 4 5 6 7 2 3 4 2 3 4 5 6 1 2 3 4 Days Weeks Months Years

Metabolic conditions

1 2 3 4 5 6 7 2 3 4 2 3 4 5 6 1 2 3 4 Days Weeks Months Years FIGURE 1-1. Patterns of onset and courses of neurologic conditions. The arrow in each graph signifies the point of clinical recognition. (Adapted from Baker AB. Outline of clinical neurology. Dubuque, Iowa: William C Brown, 1958.)

Swaiman / General Aspects of the Patient’s Neurologic History

Sequelae of traumatic events develop over a period of minutes to a day (Fig. 1-1). Although the clinical manifestations of cerebrovascular events normally develop over minutes to hours, the underlying process may be longstanding; therefore, acute onset of vascular symptoms may be the result of a subacute or chronic process. Infectious processes, electrolyte imbalances, and toxic processes (endogenous or exogenous) usually reach their zenith within a day to several days. Degenerative diseases, inborn metabolic disorders, and neoplastic conditions usually progress insidiously over weeks or months.

5

Based on the chronologic aspects of the history, the clinician should ask questions related to the most likely pathologic processes. For example, when the history suggests a subacute process, the clinician should probe for characteristics associated with an infectious process (e.g., exposure to a known infectious source, recent infection, vomiting, diarrhea, fever) or with specific toxins (e.g., overthe-counter medications, prescribed medications, insecticides, other toxins found around the home). Evaluation of whether a condition is focal or generalized is embedded in the neurologic diagnostic process. A focal

FIGURE 1-2. Denver Developmental Screening Test (Denver II) directions. (From Frankenburg WK, Dodds JB, Archer P, et al. The Denver II: A major revision and restandardization of the Denver Developmental screening test. Pediatrics 1992;89:91.)

6

Clinical Evaluation / 1

FIGURE 1-2. cont’d.

Swaiman / General Aspects of the Patient’s Neurologic History

neurologic lesion is not necessarily one that causes focal manifestations but is one that can be related to dysfunction in a circumscribed neuroanatomic location. For example, a focal lesion in the brainstem may cause ipsilateral cranial nerve and contralateral corticospinal tract involvement. If the difficulties are not focal within this definition, they usually result from a generalized process or from several lesions (i.e., multifocal). Neoplastic and vascular diseases frequently result in focal processes; occasionally, trauma results in such abnormalities. Generalized or multifocal conditions are usually associated with degenerative, congenital, metabolic, or toxic abnormalities. The clinician must always attempt to determine whether the condition is progressive or static. A detailed developmental history is often the best means of substantiating whether a condition is progressive or static. The history should include a log of motor milestones and should contain specific information regarding motor, language, and adaptive-social behavior. Questions should be crafted to obtain evidence that the child is no longer capable of motor or intellectual activities that were previously performed. This information is essential to the diagnosis of progressive disease, which is usually preceded by a period of normal development. Occasionally, previous formal neurologic and psychometric evaluations may be available. Documentation may be forthcoming from family photographs, family video tapes, or baby books. In progressive conditions, documentation of increasing loss of normal function or an increase in any symptoms, including pain, is essential. Conditions that are static or improve spontaneously are usually the result of traumatic or anoxic episodes, congenital abnormalities, acute toxicity, or resolving infection. The Denver Developmental Screening Test (DDST) [Frankenburg and Dodds, 1967], the revised form [Frankenburg et al., 1981], the Denver II screening test (Fig. 1-2) [Frankenburg et al., 1992], or other developmental surveys allow a more precise approach to the determination of whether gains or losses of skills have occurred and aid in the decision about whether a process is progressive or static. The DDST has undergone a major revision and restandardization and is available as the Denver Developmental Screening Test II (DDST II, or Denver II). The DDST II has replaced the older versions of the DDST. Standardization testing for the Denver II included evaluating each item to determine if significant differences among different subpopulations existed. These subpopulations included gender, ethnic group (i.e., black, white, or Hispanic), maternal education (i.e., less than 12 grades completed or more than 12 grades completed), and place of residence (i.e., rural, semirural, or urban). The Denver II differs from the DDST in the selected items, test form, and interpretation. The total number of items has been increased from 105 to 125, and items that were judged as difficult to administer or interpret have been modified or eliminated. Most of the new items are in the language section. The technical manual should be consulted if a delay is identified because it may be caused by sociocultural differences. The DDST II has been modified for use in different language and cultural norms [Lejarraga et al., 2002; Lim et al., 1996]. The test form for the Denver II resembles the DDST in the vertical placement of items. Key Denver items have been

7

eliminated so that the age scale coincides with the American Academy of Pediatrics’ suggested schedule for health maintenance examinations to facilitate use of the Denver II during these visits. The norms for the distribution bars are in accordance with the new standardization data. A valuable addition to the front of the form is a checklist for documentation of the child’s behavior during testing. Scoring and interpretation changes have also been made. If a child is able to perform an item depicted to the right of the age line, the performance is designated as advanced. If a child fails or refuses an item that is depicted completely to the right of the age line, the score for the item is deemed normal. If the child passes, fails, or refuses an item on which the age line falls between the 25th and 75th percentile lines, performance is designated as normal. If the child refuses or fails an item on which the age line falls on or between the 75th and 90th percentile lines, performance is designated as a caution. If the child is unable to pass an item depicted entirely to the left of the age line, performance is designated as a delay. Sufficient items should be administered to establish basal and ceiling levels in each sector. To screen only for developmental delays, only items located completely to the left of the child’s age line should be administered. Retesting is recommended after 1 to 3 months for performance scored as a caution. Retesting for one or more delays, as well as refusals, should be performed within 2 weeks. It is essential that examiners, caregivers, and educational personnel recognize that the Denver II provides an evaluation of the child’s current developmental level and is not a predictor of the future rate of development or eventual maximum attainment. The test may be used for early identification of neurologic deficits [Hallioglu et al., 2001]. Abnormalities in more complex and abstract functioning may not be recognizable until a later age and will require more sophisticated testing vehicles. Alteration in the child’s biologic or environmental status may affect developmental rate and achievement and should be investigated and taken into account in the evaluation if appropriate. The clinician should ask specific questions regarding the age of attainment of developmental landmarks and should make every attempt to discern whether the child is delayed in many areas of development or has developed normally in some areas but not in others. Children who have normal motor development but also have hearing impairment may have delayed speech. However, the presence of neuromuscular disease may cause obvious retardation of motor development but may allow normal development of social and language skills. A specific form may be used by the examiner as a guideline to the history-taking procedure (Fig. 1-3). There are many systems for recording history and the subsequent examination. The form printed in this chapter may be modified to the specific needs of the patient and the clinician. The question of hyperactivity is often at the core of the caregiver’s complaint. A rating scale may be completed by teachers to aid the clinician in diagnosis (Fig. 1-4) [Connors, 1969]. The problem is discussed in more detail in Chapter 36. School behavior can also be assessed by caregivers, as shown in Box 1-1. Many children are involved in some planned day activity, day care, or school program after the age of 2 or 3 years. text continues on page 15

8

Clinical Evaluation / 1

GENERAL HISTORY FORM PREGNANCY Gestation data Birth date Expected date Birth weight Birth occipitofrontal circumference (from old records)

Medication taken by mother (check each one taken) Vitamins Iron Calcium Hormones Weight reduction medication Diuretics Contraceptives Sedatives, tranquilizers Antiepileptics Other Illnesses (record month of pregnancy in which illness occurred) Colds, flu, etc. Kidney, bladder infection Rubella (German measles) Rashes Other infectious diseases Exposures to infectious diseases Diabetes Kidney disease Surgery Radiographs Other (explain) Labor and delivery Breech or unusual presentation Forceps use Delay in respiration or cry (Apgar scores if available) Was oxygen administration necessary? Type of anesthesia employed for mother

Newborn period Jaundice Cyanosis Infection Seizures Anemia Other Medications administered Home from hospital in

days

DEVELOPMENT (indicate month skill attained) Smiled Laughed out loud First words Put words together (e.g., “Daddy, bye-bye”) Complete sentences Rolled over Sat without support Crawled Pulled to standing Walked around furniture Walked unassisted Rode tricycle ILLNESSES

Hospitalizations Age:

Reason:

Age:

Reason:

Age:

Reason:

Operations Age:

Reason:

Age:

Reason:

Injuries Age:

Reason:

Age:

Reason:

FIGURE 1-3. The general history form can be used for obtaining the medical history, developmental history, and family history of children with neurologic problems. (Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)

Swaiman / General Aspects of the Patient’s Neurologic History

GENERAL HISTORY FORM —cont’d

Has child ever been unconscious? Age: Reason: Age:

Describe: If child has had a convulsion, describe (first event, subsequent events, duration, warning, postconvulsion behavior, etc.)

Reason:

Has child ever been poisoned? Name of poison Has child ever had an electroencephalogram (EEG)? Age: SEIZURE HISTORY

Reason:

Ages: With fever Ages: Without fever Does child daydream often?:

Results:

MEDICATION Has child ever been treated with medication other than for colds and minor infections? If yes, please give age and reason and medication Has child ever taken any of the following medications? Drug Carbamazepine (Tegretol) Clonazepam (Klonopin) Ethosuximide (Zarontin) Gabapentin (Neurontin) Lamotrigine (Lamictal) Levcetiracetem (Keppra) Oxcarbazepine (Trileptal) Phenobarbital (Luminal) Phenytoin (Dilantin) Primidone (Mysoline) Tiabagine (Gabitril) Topiramate (Topamax)

FIGURE 1-3. cont’d.

Age/duration

Indicate age and reason below. Reason

Results

9

10

Clinical Evaluation / 1

GENERAL HISTORY FORM —cont’d Drug

Age/duration

Reason

Results

Valproic acid (Depakene/Depakote) Vigabatrin Zonisamide (Zonegran) Other antiepileptic drugs Amitriptyline (Elavil) Buproprion (Wellbutrin) Chlorpromazine (Thorazine) Dextroamphetamine (Dexedrine, Adderall) Diazepam (Valium) Fluoxetine (Prozac) Haloperidol (Haldol) Imipramine (Tofranil) Methylphenidate (Ritalin, Concerta) Paroxetine (Paxil) Pemoline (Cylert) Risperidone (Risperdal) Thioridazine (Mellaril) Sertraline (Zoloft) Other psychopharmacologic drugs FAMILY HISTORY Are there family members suffering or who have suffered from: Ataxia Blindness Cerebral palsy FIGURE 1-3. cont’d.

Deafness Dementia Mental retardation

Movement disorders Seizures Weakness

Swaiman / General Aspects of the Patient’s Neurologic History

11

Teacher Questionnaire—School Behavioral Assessment Date

Pupil’s name

Teacher: Please place a checkmark in the appropriate column for each item. Choose the degree of activity that best describes the child’s behavior. Degree of activity Observation

Not at all

Rarely

Fairly often

Very often

Classroom behavior Constantly fidgets Hums and makes other odd noises Demands must be met immediately—easily frustrated Coordination poor Restless or overactive Excitable, impulsive Inattentive, easily distracted Fails to finish things started—short attention span Overly sensitive Overly serious or sad Daydreams Sullen or sulky Cries often and easily Disturbs other children Quarrelsome Mood changes quickly and drastically Obnoxious behavior Destructive Steals Lies Temper outbursts, explosive and unpredictable behavior Childish and immature Easily frustrated in efforts Difficulty in learning

FIGURE 1-4. Teacher questionnaire for behavioral assessment. (Adapted from Conners CK. A teacher rating scale for use in drug studies with children. Am J Psychiatry 1967;126:884.)

12

Clinical Evaluation / 1 Teacher Questionnaire—School Behavioral Assessment–cont’d Date

Pupil’s name

Teacher: Please place a checkmark in the appropriate column for each item. Choose the degree of activity that best describes the child’s behavior. Degree of activity Observation Group participation Isolates self from other children Seems unaccepted by group Seems easily led No sense of fair play Seems to lack leadership Does not get along with opposite sex Does not get along with same sex Teases other children or interferes with their activities Denies mistakes and blames others Attitude toward authority Submissive Defiant Impudent Shy Fearful Excessive demands for teacher’s attention Stubborn Overly anxious to please Uncooperative Attendance problem FIGURE 1-4. cont’d.

Not at all

Rarely

Fairly often

Very often

Swaiman / General Aspects of the Patient’s Neurologic History

BOX 1-1

Parents/Caretaker Questionnaire—School Behavioral Assessment Pupil’s name

Date

School performance Have teachers expressed concern about your child’s learning? Yes No If yes, please list the grade at which concern was expressed and the subject(s) of concern.

Grade

Subject(s)

Have teachers expressed concern about your child’s behavior? Yes No If yes, please list the grade at which concern was expressed and the behavior of concern.

Grade

Behavior(s)

Have teachers expressed concern about your child’s relationships with other children? If yes, please list the grade at which concern was expressed and the behavior of concern.

Grade

Yes

No

Problem

Has your child repeated any grades? Yes No If yes, what grade(s) was repeated and what reason(s) was given?

Has your child received special education services? Yes No If yes, please list the grade and type of service provided. Services in schools include: Chapter 1 or Title 1 support; Learning Disabilities; Emotional Behavioral Disorder; Physical and Other Health Impairment; Mildly Mentally Handicapped, Trainable Mentally Handicapped; Adaptive Physical Education; Speech and Language; Occupational Therapy; and Physical Therapy.

Grade

Service

Courtesy Division of Pediatric Neurology, University of Minnesota Medical School.

13

14

Clinical Evaluation / 1

SCHOOL REPORT This report is confidential and for our use only I. Identifying information Grade Name Birthdate Address School School phone School address Teacher Principal Retention II. Child’s school history (please attach a transcript of grades, results of and achievement tests, including results of IQ tests, and previous psychologic and/or speech evaluations) III. Special characteristics (check all that apply under each category) Slightly Severe Reading level Above below difficulty Average grade Intense

Average

Indifferent

Resistant

Aggressive

Average

Shy

Withdrawn

Absorbed

Attentive

Needs urging

Easily distracted

Relationship to authority figures

Too deferent

Cooperative

Sometimes rebels

Defiant

Relationship with peers

Well liked by all

Normal

one or two friends

Isolated

Achievement

“Overachiever”

Up to ability

Sporadic

Severe problems

Never misses

Normal absence

Frequent absence

Extended absence

Normal

Questionable

Visual defect

Normal

Questionable

Hearing loss

Average for age

Poor

Handicapped (describe)

Minor difficulty

Severe difficulty

Motivation

Behavior Attention

Attendance

Eyesight

Hearing

Motor coordination Excellent Speech

No problem

FIGURE 1-5. School information form that can be used to obtain child’s school history from school, day care center, or day activity center. (Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)

Swaiman / General Aspects of the Patient’s Neurologic History

15

SCHOOL REPORT—cont’d Other health problems (specify)

Special help given

Remedial reading

Speech therapy

Special education

Tutoring

IV.

Briefly give your impression of the child’s behavior in school: any examples or anecdotes would be appreciated

V.

Attitude towards school

Other

Attitude towards peers Attitude towards self Attitude towards teacher VI.

Are there any problems that you think need special attention?

VII.

What do you like best about this child?

Yes

No

(please describe in detail)

What do his or her classmates like best? VIII.

What do you think can be done to help the child overcome his or her current difficulties? What resources are available in the school, school district, or community?

IX.

What is your impression of the home environment of the child (stimulating, average, detrimental)? Describe any specific features that you think may be important.

X.

What is the relationship between school personnel and the child’s parents?

Signature Title Date FIGURE 1-5. cont’d.

A questionnaire, as in Figure 1-5, can be devised that will allow supervisory personnel to record intellectual, motor, and emotional characteristics. It is essential that an adequate family history be recorded. Ages of siblings (including those who have died and those aborted), parents, grandparents, uncles, and aunts should be available. It is particularly helpful to gain health history details of deceased siblings and relatives, because familial conditions that might otherwise go undiscovered are often revealed. Questions concerning neurologic diseases initially should be specific; then more generalized questions should be asked because caregivers may not understand the more specific

approach. The presence of epilepsy, cerebral palsy, deafness, mental retardation, movement disorders, blindness, ataxia, weakness, or progressive intellectual and motor deterioration must be determined. Less sophisticated names, such as fainting spells, nervous breakdowns, strokes, and palsies, may strike a responsive chord. It is imperative that the clinician ask if any family members suffer from the same problems that affect the patient. Autosomal-dominant traits may be present in successive generations, although the degree of expressivity may vary. Autosomal-recessive traits often do not manifest in successive generations but may be present in siblings. Consanguinity must be considered when autosomal-recessive

16

Clinical Evaluation / 1

disease is part of the differential diagnosis. X-linked recessive conditions are manifest in male siblings, male first cousins, and maternal uncles. Careful questioning of the mother, if possible, is highly desirable. Although mitochondrial diseases may be inherited through transmission of maternal DNA, paternal inheritance patterns are also possible [Schwartz and Vissing, 2003]. If a genetic condition is suspected, it is wise to examine siblings, parents, and other family members to augment the history. REFERENCES Baker AB. Outline of clinical neurology. Dubuque, Iowa: William C Brown, 1958. Conners CK. A teacher rating scale for use in drug studies with children. Am J Psychiatry 1969;126:152. Frankenburg WK, Dodds JB. Denver developmental screening test. J Pediatr 1967;71:181. Frankenburg WK, Fandal AW, Sciarillo W, et al. The newly abbreviated and revised Denver Developmental Screening Test. J Pediatr 1981;99:995.

Frankenburg WK, Dodds JB, Archer P, et al. The Denver II: A major revision and restandardization of the Denver Developmental screening test. Pediatrics 1992;89:91. Hallioglu O, Topaloglu AK, Zenciroglu A, et al. Denver developmental screening test II for early identification of the infants who will develop major neurological deficit as a sequelae of hypoxic-ischemic encephalopathy. Pediatr Int 2001;43:400. Jackson R, Gibson KA, Wu YW, Croughan MS. Perinatal outcomes in singletons following in vitro fertilization: A meta-analysis. Obstet Gynecol 2004;103:551. Lim HC, Chan T, Yoong T. Standardisation and adaptation of the Denver Developmental Screening Test (DDST) and Denver II for use in Singapore children. Singapore Med J 1994;35:156. Lim HC, Ho LY, Goh LH, et al. The field testing of Denver Developmental Screening Test Singapore: A Singapore version of Denver II Developmental Screening Test. Ann Acad Med Singapore 1996;25:200. Lejarraga H, Pascucci MC, Krupitzky S, et al. Psychomotor development in Argentinean children aged 0-5 years. Paediatr Perinat Epidemiol 2002;16:47. Schwartz M, Vissing J. New patterns of inheritance in mitochondrial disease. Biochem Biophys Res Commun 2003;310:247.

CHAPTER 2

Neurologic Examination of the Older Child Kenneth F. Swaiman

The neurologic examination of children is described in this and the next two chapters. The material is organized on the basis of age for convenience of presentation; however, because it is usually feasible to perform a more rigorous examination of older children, detailed discussion of the conventional neurologic examination of children is provided in this chapter, including evaluation of the cranial nerves. Examination of a child older than 2 years should be as informal as possible while maintaining a basic flow pattern to permit complete evaluation. The older child has acquired a large repertory of skills since infancy (Box 2-1). For children between 2 and 5 years old, the Denver Developmental Screening Test II may be useful in evaluating various motor skills [Frankenburg et al., 1992] (see Chapter 1). Many neurologic functions of children between the ages of 2 and 4 years are examined in the same manner as those of children younger than 2 years. As is the case with younger children, some patients between 2 and 4 years old may be most comfortable sitting on a caregiver’s lap. The examining room should be equipped with small toys, dolls, and pictures with which to interest the child and provide for ease of interaction. Observation and play techniques are essential means of monitoring intellectual and motor function. Children may choose to move about the examining room and may be attracted to these various playthings. After 4 years of age, the components of the neurologic examination are more conventional and routine, and by adolescence, the examination is much the same as the adult examination.

OBSERVATION Much can be learned by observation during the historytaking session. Older children should sit in a chair or perform tasks, such as reading or drawing with crayons or colored pencils. If the child participates actively in the history-taking procedure, the child’s understanding and contribution to the session allow the examiner to make judgments about the child’s intellectual skills. The child’s language skills can be assessed. Stuttering, dysarthria, nasal speech, dysphonia, and problems of articulation are evident. This session also provides an additional opportunity to evaluate facial movements. Head nodding, lip twitching, eye blinking, and staring may be evidence of epilepsy. Movement disorders involving the face, such as chorea or tics, and other movement disorders involving the neck, limbs, and trunk (i.e., athetosis, chorea, dystonia, myoclonus, tics, and spasms) may be noticeable. This portion of the examination provides an opportunity to assess the child’s behavior. Impulsivity, short attention span, and relative dependence may be evident. The child may be

unable to sit or play quietly. Distractibility may be evident in response to minor external stimuli. The caregiver-child interaction may also be observed during this time. The caregiver may threaten or use physical force or obsequiously cajole the child. The child’s response may be inappropriate. The following questions must be answered. Does the child respond positively to the caregiver’s interaction? Does the child attempt to manipulate the caregiver? Is the response transient or persistent? Is the caregiver’s attitude one of caring or hostility?

SCREENING GROSS MOTOR FUNCTION Sometime between 4 and 6 years of age, most children of normal intelligence participate in a motor screening examination. A rapid screening component is advisable because the child may lose interest, become distractible, or become tired and oppositional. The child should stand before the examiner. Whenever possible during the entire the examination, the examiner should demonstrate each of the various motor acts with precision and good humor. A smiling examiner is much more likely to be accepted by the child. Then, for example, the examiner should ask the child to watch as he or she hops on either foot. The child should then be asked to hop in place on each foot (first one then the other) “just the way I did.” The same technique should then be used to have the child tandem walk forward and backward, toewalk, and heel-walk. The child should be asked to rise from a squatting position. The child should then be asked to stand with the feet close together, eyes closed, and arms and hands outstretched. This maneuver allows simultaneous assessment of Romberg’s sign and adventitious movements, particularly of the face, arms, and hands. The child should then be asked to perform finger-to-nose movements with the eyes closed and finger-to-finger-to-nose movements with the eyes open. After this rapid screening procedure, the examiner can begin a more detailed and systematic evaluation, bearing in mind any suggested abnormalities evident during the screening process.

PHYSICAL EXAMINATION Deep Tendon Reflexes Deep tendon reflexes (i.e., muscle stretch reflexes) are readily elicited by conventional means with a reflex hammer while the child is sitting quietly. In the case of the biceps reflex, it may be helpful for the examiner to place his or her thumb on the tendon and strike the positioned thumb to elicit the

18

Clinical Evaluation / 2

Box 2-1 EMERGING PATTERNS OF BEHAVIOR FROM 1 TO 5 YEARS OF AGE 15 Months Motor: Walks alone; crawls up stairs Adaptive: Makes tower of two cubes; makes a line with crayon; inserts pellet into bottle Language: Jargon; follows simple commands; may name a familiar object (ball) Social: Indicates some desires or needs by pointing; hugs parents 18 Months Motor: Runs stiffly; sits on small chair; walks up stairs with one hand held; explores drawers and waste baskets Adaptive: Piles three cubes; initiates scribbling; imitates vertical stroke; dumps pellet from bottle Language: 10 words (average); names pictures; identifies one or more parts of body Social: Feeds self; seeks help when in trouble; may complain when wet or soiled; kisses parents with pucker 24 Months Motor: Runs well; walks up and down stairs one step at a time; opens doors; climbs on furniture Adaptive: Makes tower of six cubes; circular scribbling; imitates horizontal strokes; folds paper once imitatively Language: Puts three words together (subject, verb, object) Social: Handles spoon well; tells immediate experiences; helps to undress; listens to stories with pictures 30 Months Motor: Jumps Adaptive: Makes tower of eight cubes; makes vertical and horizontal strokes but generally will not join them to make a cross; imitates circular stroke; forming closed figure Language: Refers to self by pronoun “I”; knows full name Social: Helps put things away; pretends in play 36 Months Motor: Goes up stairs altenating feet; rides tricycle; stands momentarily on one foot Adaptive: Makes tower of nine cubes; imitates construction of “bridge” of three cubes; copies a circle; imitates a cross Language: Knows age and gender; counts three objects correctly; repeats three numbers or a sentence of six syllables Social: Plays simple games (in “parallel” with other children); helps in dressing (unbuttons clothing and puts on shoes); washes hands 48 Months Motor: Hops on one foot; throws ball overhand; uses scissors to cut out pictures; climbs well Adaptive: Copies bridge from model; imitates construction of “gate” of five cubes; copies cross and square; draws a man with two to four parts besides head; names longer of two lines Language: Counts four pennies accurately; tells a story Social: Plays with several children with beginning of social interaction and role playing; goes to toilet alone 60 Months Motor: Skips Adaptive: Draws triangle from copy; names heavier of two weights Language: Names four colors; repeats sentences of 10 syllables; counts 10 pennies correctly Social: Dresses and undresses; asks questions about meanings of words; domestic role playing Adapted from Behrman RE, et al. Nelson textbook of pediatrics, 14th ed. Philadelphia: WB Saunders, 1992.

reflex. If the child is crying or overtly resists, the examiner should postpone this portion of the examination. The child may be reassured if the examiner taps the brachioradialis reflex of the caregiver before performing the same act on the child. Deep tendon reflexes customarily examined include the biceps, triceps, brachioradialis, patellar, and Achilles reflexes. Each tendon reflex is mediated at a specific spinal segmental level or levels (Table 2-1) [Haymaker and Woodhall, 1962; Hollinshead, 1969]. Hyperactive reflexes or clonic responses to tapping of the reflex result from corticospinal dysfunction. Hyperreflexia may also be indicated by an abnormal “spread”

of responses, which includes contraction of muscle groups that usually do not contract when a specific reflex is being elicited (i.e., crossed thigh adductor or finger flexor reflexes). Although a bilateral brisk reflex response may be normal, particularly when only one reflex is involved, unilateral hyperreflexia virtually always signals a pathologic process. Hyporeflexia may be associated with lower motor unit involvement (e.g., anterior horn cell disease, peripheral neuropathy, myopathy). However, hyporeflexia may occasionally be found with central depression, impaired central control of the gamma loop (central hypotonia), or involvement of

Swaiman / Neurologic Examination of the Older Child

TABLE 2-1 Muscle Stretch (Tendon) Reflexes REFLEX

NERVE

SEGMENTAL LEVEL

Biceps Brachioradialis Gastrocnemius and soleus (ankle jerk) Hamstring Jaw Quadriceps (knee jerk) Triceps

Musculocutaneous Radial Tibial

C5, C6 C5, C6 L5, S1, S2

Sciatic Trigeminal Femoral Radial

L4. L5, S1, S2 Pons L2-L4 C6, C8

the posterior root (intramedullary or extramedullary). With anterior horn cell involvement (e.g., infantile spinal muscular atrophy), the patellar reflexes are greatly diminished or absent early because the cells subserving the proximal muscles of the legs are profoundly involved first. Sensory involvement, particularly peripheral, is often detectable in patients with neuropathies. Similarly, the distal deep tendon reflexes tend to be involved earlier and to a greater degree. Reflexes may be normal early in the course of certain myopathies, including the muscular dystrophies, and may become absent later. Disease generally decreases muscle tone and may decrease tendon reflexes because of effects on the gamma loop. Enhancement of tendon reflex responses when reflexes are seemingly absent can be promoted by having the child squeeze an object such as a block or ball or perform the more traditional Jendrassik maneuver (i.e., hooking the fingers together while flexed and then attempting to pull them apart).

Other Reflexes A flexor (plantar) toe sign response is normal in children. Impairment of corticospinal tract function leads to extensor responses. The Babinski reflex is elicited by firm, steady, slow stroking from posterior to anterior of the lateral margin of the sole with an object such as a key or a tongue blade. The stimulus should not be painful. A positive response is a slow, tonic hyperextension of the great toe. This response is the constant and necessary feature of a positive response. The other four toes may also hyperextend, or they may slowly spread apart (i.e., fanning). Flicking the patient’s nail (second or third finger) downward with the examiner’s nail (i.e., the Hoffmann reflex) results in flexion of the distal phalanx of the thumb. No response or a muted response occur in normal children; a brisk or asymmetric response occurs in the presence of corticospinal tract involvement. Abdominal reflexes are obtained by stroking the abdomen from lateral to medial with strokes beginning just above the umbilicus, lateral to the umbilicus, and just below the umbilicus directed toward the umbilicus. Unilateral absence of the reflex usually is associated with acquired corticospinal tract dysfunction. The cremasteric reflex is elicited in males by stroking the inner aspects of the thigh in a caudal-rostral direction and observing the contraction of the scrotum. The reflex is normally present and symmetric. Absence or asymmetry may indicate corticospinal tract involvement.

19

Developmental reflexes are discussed in Chapter 3. The persistence of developmental reflexes beyond the expected age of extinction is usually an indication of corticospinal tract impairment [Zafeiriou, 2004].

Cerebellar Function Head tilt may be associated with tumors of the cerebellum. The tilt is usually ipsilateral to the involved cerebellar hemisphere, but exceptions are common. Herniation of the cerebellar tonsils through the foramen magnum resulting from increased intracranial pressure may cause head tilt; neoplasms that induce increased intracranial pressure, other than those of the cerebellum, may cause head tilt. Cerebellar function is also evaluated during testing of station and gait (see Chapter 5). Cerebellar dysfunction is usually associated with hypotonia. Tremor in cerebellar disease occurs with action (intention). Cerebellar function is assessed in a number of ways. Hand patting (i.e., alternating pronation and supination of the hand on the thigh while the other hand remains stationary on the other thigh) is a good method for assessing dysdiadochokinesis. The maneuver is repeated with each hand separately to assess the presence of mirror movements (i.e., synkinesis). Other tests that monitor cerebellar integrity include repetitive finger tapping (thumb to forefinger), foot tapping, and finger-to-nose, finger-to-finger (examiner’s)-to-nose, and heel-to-knee-to-shin stroking. These movements are an index of cerebellar function when limb strength and sensation are intact. Breaks in rhythm and nonfluidity of movement, as well as dysmetria, which is suggestive of cerebellar dysfunction, are evident during this phase of the examination.

Cranial Nerve Examination In older children, the cranial nerve examination may be performed in a systematic fashion, beginning with the first cranial nerve and testing through the twelfth. Examination of infants and younger children usually requires some modification of the sequence and may need some ingenious improvisation of the procedure, according to the degree of cooperation of the child. As is the case with all examinations of infants and young children, the less-threatening portions of the examination should be performed first.

Olfactory Nerve: Cranial Nerve I Olfactory nerve function is rarely impaired in childhood. Cranial nerve I can be evaluated by having the child smell pleasant aromas (e.g., chocolate, vanilla, peppermint) through each nostril while the other is manually occluded. Olfactory sensation is intact if the child appreciates a change in odor; precise identification is often impracticable. Anosmia occurs most commonly in children with upper respiratory infections or after head trauma, often occipital. Neoplasms in the inferior frontal lobe or cribriform plate regions can cause anosmia. Unilateral anosmia is more worrisome than bilateral anosmia because of the possibility of a unilateral neoplasm.

Optic Nerve: Cranial Nerve II Examination of cranial nerve II, the optic nerve, is one of the critical portions of the neurologic examination because of

20

Clinical Evaluation / 2

the long anterior-to-posterior span of the visual pathways within the brain. Formal visual acuity testing is possible with a Snellen chart or a “near card” in older children. Visual acuity and visual field testing should be performed in an appropriately lighted room. The visual test objects should be easily visible and without glare. Occasionally, when subtle changes are being investigated, it is efficacious to hold the visual field test object against a background of less contrast, increasing the difficulty of identification. Function can be difficult to evaluate in the very young child. Gross vision can be assessed in children younger than 3 or 4 years of age by their ability to recognize familiar items of various sizes, shapes, and colors. Beyond 4 years of age, the E test is useful. The child is taught to recognize the E and to discern the direction in which the three “arms” are pointing and point a finger accordingly. Most older children can be taught the essentials of the test in less than a minute. During the acuity evaluation, Es of different sizes, rotated in different directions, are presented to the child. For each eye, the visual field (range of vision) is assessed by confrontation with an object that is moved from a temporal to nasal direction along radii of the field. A small (3-mm), white or red test object or toy can be used. A modification of the same procedure can be used for double simultaneous testing by moving two test objects or penlights simultaneously from the temporal to the nasal fields and then from the superior and inferior portions of the temporal and nasal fields while the child looks directly at the examiner’s nose. Finger counting can be used if acuity is grossly distorted. In cases of extreme impairment, perception of a rapidly moving finger can be used. Visual acuity is rarely affected by papilledema until there is scarring of the optic nerve head. This lack of acuity change is in marked contrast to the early loss of visual activity that accompanies inflammation of the optic nerve.

The optic disc (i.e., optic nerve head) of the older child is sharply defined and often salmon colored, which differs from the pale gray color of the disc in an infant. In the presence of a deep cup in the optic disc, the color may appear pale, but the pallor is localized to the center of the disc. The pallor of optic atrophy occurs centrally and peripherally and is accompanied by a decreased number of arterioles in the disc margins. Most commonly, papilledema is associated with elevation of the optic disc, distended veins, and lack of venous pulsations. Hemorrhages may surround the disc. Before papilledema is obvious, there may be blurring of the nasal disc margins and hyperemia of the nerve head. Pupils should be observed in light that allows them to remain mildly mydriatic. The diameter, regularity of contour, and responsivity of the pupils to light should be examined. The upper lid is usually at the margin of the pupil. In Horner’s syndrome, impairment of the sympathetic pathway results in a miotic pupil, mild ptosis, and defective sweating over the ipsilateral side of the face (Fig. 2-1). Dragging a finger over the child’s forehead may aid in the recognition of anhidrosis. The fixed, dilated pupil usually is associated with other signs of oculomotor nerve dysfunction and may signify cerebral tonsillar herniation. The presence or absence of the pupillary light reflex differentiates between peripheral and cortical blindness. Lesions of the anterior visual pathway (i.e., retina to lateral geniculate body) result in the interruption of the afferent limb of the pupillary light reflex, producing an absent or decreased reflex. Anterior visual pathway interruption can cause amblyopia in one eye. In this situation, the pupil fails to constrict when stimulated with direct light; however, the consensual pupillary response (i.e., response when the other eye is illuminated) is intact. Various degrees of visual loss may modify this phenomenon so that the full response to direct stimulation is delayed, but the consensual reflex is brisk. The deficient pupillary reflex is revealed by alternately aiming a light source toward one eye and then the other. In the eye with decreased vision, consensual pupillary constriction is greater than the response to direct light stimulation (Marcus Gunn pupil); the pupil of the affected eye may dilate slightly during direct stimulation.

Oculomotor, Trochlear, and Abducens Nerves: Cranial Nerves III, IV, and VI

FIGURE 2-1. Bilateral oculomotor nerve paralysis. (Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)

The oculomotor, trochlear, and abducens cranial nerves control extraocular motor movements; these nerves must operate synchronously or diplopia ensues. Cranial nerve III innervates the superior, inferior, and medial recti; the inferior oblique; and the eyelid elevator (levator palpebra superioris). Cranial nerves IV and VI innervate the superior oblique muscle and the lateral rectus muscle, respectively. Unfortunately, for purposes of understanding, the function of extraocular muscles depends somewhat on the direction of gaze. The lateral and medial recti are abductors and adductors of the globe, respectively. The superior rectus and inferior oblique are elevators, and the inferior rectus and superior oblique are depressors. The oblique muscles act in the vertical plane while an eye is adducted. The recti muscles serve this function when an eye is abducted (Fig. 2-2). When directed forward (i.e., primary position), the oblique muscles effect

Swaiman / Neurologic Examination of the Older Child ELEVATION Superior rectus Inferior oblique

21

FIGURE 2-2. Extraocular muscle movement. A, In primary position. B, In abduction and adduction. (Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)

A

DEPRESSION Inferior rectus Superior oblique Superior rectus

Inferior oblique

A b d u c Lateral rectus

A b d u c

A d d u c Medial rectus

t i o n

Inferior rectus

t i o n

Superior rectus

Medial rectus

Superior oblique

torsion around the anteroposterior axis (rotation) of the globes [Cogan, 1966]. The eye position that results from paralysis of each eye muscle is listed in Table 2-2. In heterophorias, also called phorias, both globes are directed normally on near or far objects during fixation; however, one or both deviate when one eye is occluded TABLE 2-2 Extraocular Muscle Paralysis PARETIC MUSCLE

CRANIAL NERVE

EYE DEVIATION

Inferior oblique Inferior rectus Lateral rectus Medial rectus Superior oblique

III III VI III IV

Superior rectus

III

Down and out Up and in Medial Lateral Upward and outward (head tilted) Down and in

t i o n

Lateral rectus

B

Inferior rectus

while the other eye fixes. Forcing fixation of the uncovered eye by alternately covering each eye confirms the diagnosis of heterophorias. This predisposition may be evident when the child is febrile or fatigued. Exophoria is a predisposition to divergence, whereas esophoria is a predisposition to convergence. Eye deviations detectable during binocular vision are heterotropias, also called tropias. Adduction tropias are esotropias; abduction tropias are exotropias. Tropias are most often caused by compromised extraocular muscle innervation. Extraocular palsies can frequently be detected by observation of eye movements. A red glass is placed in front of an eye, and a focused, relatively intense white light is aimed at the eyes from various visual fields while the child fixes on the light. A merged, solitary, red-white image is perceived when extraocular movements are normal; however, when muscle paresis is present, the child reports a separation of the red and white images when looking in the direction of action of the affected muscle. The farthest peripheral image

22

Clinical Evaluation / 2

is the one perceived by the abnormal eye; this eye can be identified by the color of the image. Minimal extraocular muscle palsies may be heralded by delayed eye movement to the appropriate final position. Volitional turning of the head accompanies paresis of the lateral rectus muscle to forestall diplopia; the head is deviated toward the paretic muscle, and the eyes are directed ahead. In superior oblique or superior rectus muscle palsies, tilting of the head toward the shoulder opposite the side of the paretic eye muscle occurs. Extraocular muscle dysfunction is associated with many conditions that affect the brainstem, cranial nerves, neuromuscular junction, or muscles. Among the diseases are ophthalmoplegic migraine, cavernous sinus thrombosis, brainstem glioma, myasthenia gravis, and congenital myopathy. Cranial nerve VI function may be impaired by increased intracranial pressure, irrespective of cause. Squint, usually esotropia, often accompanies decreased visual acuity in infants and young children [Smith, 1967]. Ptosis and extraocular muscle paralysis accompany dysfunction of cranial nerve III. Ptosis resulting from oculomotor nerve compromise is usually more pronounced than is the malposition of the lid associated with Horner’s syndrome. This symptom is of great diagnostic aid because the lid does not significantly elevate when the patient is asked to look up. Complete oculomotor nerve paralysis, although uncommon, causes the eye to position downward and outward. Poor adduction and elevation are also evident (see Fig. 2-1). Version eye positioning may accompany irritative or destructive brainstem lesions and cerebral hemispheral lesions. In destructive brainstem conditions the conjugate eye movement (version) deviation is toward the opposite side. Destructive cerebral hemispheral lesions will cause the eyes to deviate toward the side of the lesion; conversely, an irritative cerebral hemispheral lesion causes the eyes to turn away from the side of the lesion. Eye-movement deviations of the binocular disconjugate (nonparallel) type caused by brainstem dysfunction also occur in children. Vertical gaze paresis results from dysfunction of the tectal area of the midbrain. Patients with a pineal tumor or hydrocephalus may be unable to elevate the eyes for upward gaze. Brainstem lesions, especially those in the midbrain or pons, may disrupt the medial longitudinal fasciculus. The resultant impairment of conjugate eye movement is referred to as an internuclear ophthalmoplegia. These lesions engender weakness of medial rectus muscle contraction of the adducting eye, which is accompanied by a monocular nystagmus in the abducting eye. Occasionally, paresis of lateral rectus muscle movement in the abducting eye may occur. Medial longitudinal fasciculus involvement may be unilateral or bilateral and may be associated with a number of brainstem conditions, including hemoglobinopathies, demyelinating disease, or brainstem vascular disease [Cogan, 1966]. Internal ophthalmoplegia consists of a fully dilated pupil that is unreactive to light or accommodation. Extraocular muscle function is normal when each muscle is tested separately. The oculomotor nerve, nucleus, or ciliary ganglion may be sites of involvement. External ophthalmoplegia results in ptosis and paralysis of all extraocular muscles. Pupillary reactivity is normal.

This pattern of involvement may accompany myasthenia gravis, hyperthyroidism, ocular myopathy, Möbius’ syndrome, tumors or vascular lesions of the brainstem, Wernicke’s disease, botulism, and lead intoxication. Opticokinetic nystagmus is a useful test in evaluating the eye movements of children. A drum or tape with stripes or figures is slowly rotated or drawn before the child’s eyes in horizontal and vertical directions. With fixation, the child should visually track the object in the direction the tape is being drawn, with a rapid, rhythmic movement (refixation) of the eyes in the reverse direction to enable fixation on the next figure or stripe. Absence of such a response may result from failure of fixation, amaurosis, or disturbed saccadic eye movements. The child who appears clinically blind because of a conversion reaction exhibits a normal opticokinetic nystagmus response. Children who manifest congenital nystagmus and have an opticokinetic nystagmus response in the vertical plane likely have adequate functional sight. Absence of opticokinetic nystagmus in the presence of congenital nystagmus heralds reduced visual acuity. If asymmetry of an opticokinetic nystagmus response is evident, lateral lesions in the posterior half of the cerebral hemisphere are likely present. The lesion is on the side that manifests reduced or absent opticokinetic nystagmus reactivity. The area of involvement is generally in the posterotemporal, parietal, or occipital areas. Hemianopic field defects may exist. Spontaneous nystagmus (i.e., involuntary oscillatory movements of the eye) may be horizontal, vertical, or rotary; a patient can exhibit all three types. The movements may consist of a slow and fast phase, giving rise to the term jerk nystagmus. However, the phases may be of equal duration and amplitude, appearing pendular. Nystagmus, especially vertical nystagmus, is most commonly induced by medications (e.g., barbiturates, phenytoin, carbamazepine, benzodiazepines). Such nystagmus often has a jerk component and is usually most prominent in the direction of gaze. Vertical nystagmus that is not associated with medications indicates brainstem dysfunction. A few beats of horizontal nystagmus with extreme lateral gaze is usually normal. Persistent horizontal nystagmus indicates dysfunction of the cerebellum or brainstem vestibular system components; the nystagmus is coarser (i.e., the amplitude of movements greater) when the direction of gaze is toward the side of the lesion. A rare condition, seesaw nystagmus, is characterized by disconjugate (alternating) movement of the eyes, which move upward and downward in a seesaw motion. This type of nystagmus accompanies lesions in the region of the optic chiasm (see Chapter 6).

Trigeminal Nerve: Cranial Nerve V Cranial nerve V, the trigeminal nerve, has motor and sensory functions. The motor division of the trigeminal nerve innervates the masticatory muscles: masseter, pterygoid, and temporalis. Temporalis muscle atrophy manifests as scalloping of the temporal fossa. The masseter muscle bulk may be assessed by palpation while the patient firmly closes the jaw. Pterygoid muscle strength is evaluated by having the patient open the mouth and “slide” the jaw from one side to the other while the examiner resists movements with the hand to assess muscle strength. The jaw reflex is elicited when the

Swaiman / Neurologic Examination of the Older Child

23

examiner places a finger on the patient’s chin while the mouth is slightly open and taps the finger to stretch the masticatory muscles. A rapid muscle contraction with closure of the mouth is the reflex response. This stretch reflex receives its afferent and efferent nerve control from cranial nerve V; the segmental level is located in the midpons. The expected reflex reaction is absent with motor nucleus and peripheral trigeminal nerve compromise. Conversely, this reflex is overactive in the presence of supranuclear lesions; rarely, jaw clonus may be evident. Because of weakness of the ipsilateral pterygoid muscles, unilateral impairment of the trigeminal nerve causes deviation of the jaw toward the side of the lesion. Cranial nerve V is also responsible for sensation involving the face and the anterior half of the scalp (Fig. 2-3). Brainstem compromise can effect clearly delineated laminar sensory deficits; however, mapping of such deficits is difficult in children. The corneal reflex, provided its sensory input by the trigeminal nerve, may be diminished or absent after trauma, in cerebellopontine angle tumors, in brainstem tumors, in cavernous sinus thrombosis, in Gradenigo’s syndrome, or in childhood collagen-vascular diseases.

Facial Nerve: Cranial Nerve VII Taste sensation over the anterior two thirds of the tongue, secretory fibers (parasympathetic) innervating the lacrimal and salivary glands, and innervation of all facial muscles are accomplished by cranial nerve VII. Complete motor dysfunction on one side of the face ensues when the cranial nerve VII pathway is disrupted in the nucleus, pons, or peripheral nerve. The patient is unable to move the forehead upward, close the eye forcefully, or elevate the corner of the mouth on the side of the affected nerve (Figs. 2-4 and 2-5). Central (supranuclear) facial nerve impairment produces only paresis of the muscles involving the lower face, with resultant drooping of the angle of the mouth, disappearance or diminution of the nasal labial fold, and widened palpebral fissure. The muscles of the forehead, which are innervated bilaterally, are unaffected. Cardiofacial syndrome is a congenital weakness that causes failure of depression of the angle of the mouth and is unrelated to facial nerve palsy.

FIGURE 2-4. Right facial paralysis of the peripheral type. (Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)

Ophth. C2 C2,3

Max.

Mand.

C2,3

FIGURE 2-3. Facial sensation supplied by the trigeminal nerve. (Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)

FIGURE 2-5. The Möbius syndrome is manifested by bilateral palsy of cranial nerves VI and VII.

Taste sensation in the anterior two thirds of the tongue is in part provided by the chorda tympani nerve, which traverses the path of the facial nerve for a short distance. Testing of taste sensation is difficult. Evaluation of taste requires that the patient extend the tongue and that the examiner hold the tip of the tongue with a piece of gauze and place salty, sweet, acidic, and sour and bitter materials, usually represented by salt, sugar, vinegar, and quinine, on the anterior portion of the tongue. The patient’s tongue must remain outside of the mouth

24

Clinical Evaluation / 2

until the test is completed. An older patient should be able to identify each substance.

Auditory Nerve: Cranial Nerve VIII Function and evaluation of cranial nerve VIII are discussed in detail in Chapters 7 and 8. Although cranial nerve VIII is known as the auditory nerve, it has auditory and vestibular functions. Gross auditory impairment may be suspected during the history-taking session while the child is in the room. The child may not respond directly to questions or to directions from the caregivers. More specific testing with whispered language, the ticking of a watch, a party noisemaker, or a tuning fork may be used to gain more information. Patients who fail to develop speech or who have slow speech development, as well as those who have difficulty with fluency and articulation, may have hearing impairment. Older children can cooperate with formal audiometric testing. Such testing may not be possible in younger infants, but brainstem auditory-evoked potentials may provide the necessary information concerning hearing impairment and the level of dysfunction within the nervous system. The clinical evaluation and caloric testing can be used for gross assessment of vestibular function. More complex evaluation should be undertaken if the screening tests or the complaint indicate a need for more detailed assessment. Complaints of nausea, ataxia, vertigo, or unexplained vomiting, singly or in combination, may indicate labyrinthine and vestibular pathologic origins. Caloric testing can be performed with relative ease. While the patient is in the supine position, the head is flexed at 30 degrees. Ice water (10 mL) is injected over 30 seconds into one external auditory canal at a time. The conscious patient develops coarse nystagmus toward the ipsilateral ear; no eye deviation occurs. If the patient has some degree of obtundation, there is a modification of the response. The eyes become tonically deviated ipsilaterally, with accompanying nystagmus occurring contralaterally. If the patient is comatose, cold water stimulation usually causes tonic deviation ipsilaterally and no nystagmus; if the coma is profound or the patient is brain dead, no eye changes occur.

absence of other findings. The integrity of cranial nerves IX and X is necessary for a gag response. Although the larynx can be studied under direct or indirect laryngoscopy, the presence of stridor, hoarseness, or dystonia suggests the need for more detailed examination of the brainstem and cranial nerve IX integrity.

Spinal Accessory Nerve: Cranial Nerve XI Cranial nerve XI provides innervation for the trapezius and sternocleidomastoid muscles. Cranial nerve XI comprises some fibers from C1 and C2 and some from the motor nucleus in the brainstem and is unique in combining brainstem and cervical cord origins. The trapezius muscles are assessed when the patient is asked to shrug the shoulders against resistance placed by the examiner. Atrophy of the muscle and drooping of the shoulder provide further information on the status of the trapezius. The sternocleidomastoid muscle is tested by exerting resistance against the child’s head while the child attempts rotation to one side. Weakness of the sternocleidomastoid muscle results in an inability to rotate the head to the contralateral side. Muscle bulk of the sternocleidomastoid muscle is readily palpable and is readily visible in the presence of moderate-to-severe atrophy. Congenital or acquired lesions in the area of the foramen magnum most commonly cause difficulties of cranial nerve XI.

Hypoglossal Nerve: Cranial Nerve XII The tongue muscle is the primary responsibility of cranial nerve XII. Atrophy and fasciculation of the tongue occur when the ipsilateral hypoglossal nucleus or hypoglossal nerve is involved. The protruded tongue deviates toward the involved side because contraction of the normally innervated tongue muscle causes protrusion and is unopposed. The child cannot push the tongue against the cheek of the unaffected side. Speech may be muffled or dysarthric. Bilateral involvement of hypoglossal nuclei or cranial nerve XII may be severely incapacitating. The tongue muscle may be markedly

Glossopharyngeal and Vagus Nerves: Cranial Nerves IX and X Examination of the larynx, pharynx, and palate provides most of the desired information concerning the function of cranial nerves IX and X. Unilateral paresis of the soft palate causes an ipsilateral droop, even when the patient is expelling air through the open mouth or gagging in response to a tongue blade. Bilateral involvement causes a flaccid, soft palate bilaterally. With bilateral paresis, the voice becomes nasal, and regurgitation of fluids occurs during drinking. During evaluation of swallowing, the child should be asked to swallow up to 10 times to determine the efficacy of swallowing and stamina. The examiner can evaluate the difficulty and the relative movements of the hyoid during swallowing. The gag reflex is mediated through cranial nerve IX and is elicited by touching the posterior pharyngeal mucosa with a tongue blade. Normal individuals may have absence or a seemingly disproportionately violent response; assessing the importance of changes in the gag reflex is difficult in the

FIGURE 2-6. Fasciculation of the tongue, especially of the right lateral border, in a patient with group 2 Werdnig-Hoffman disease. (Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)

Swaiman / Neurologic Examination of the Older Child

atrophied, and fasciculations of the tongue may be very prominent (Fig. 2-6). The patient may be unable to protrude the tongue beyond the lips, and there is marked dysarthria with unintelligibility of speech. Although chewing and swallowing are somewhat affected by unilateral tongue weakness, bilateral involvement results in gross difficulty. Cranial nerve XII dysfunction may result from supranuclear bulbar palsy from unilateral or bilateral corticobulbar tract involvement. Although the signs and symptoms may resemble those of involvement of the hypoglossal nucleus or nerve, lower motor unit signs such as fasciculations and atrophy are absent. Certain movement disorders, particularly dystonia, may interfere with normal tongue movements and confound the examiner.

Sensory System Cooperation of the pediatric patient is paramount to the success of the sensory examination. Vibration sense and joint and position sense are usually easily tested in all four limbs. Touch may be assessed by a single stimulus or by double simultaneous stimulation of two skin areas. The latter tests extinction of perception over an involved area. Testing should include areas of the face, trunk, and limbs. The ability to localize the area of contact of a tactile stimulus, topagnosis, is monitored by touching the patient, whose eyes are closed, on the face, arm, hand, leg, or foot with the examiner’s finger or a cotton swab; the child is asked to point to or verbally identify the area. The loss of ability to localize the stimulus is associated with parietal lobe dysfunction.

In a more sophisticated test, the patient is touched on two parts of the body simultaneously (i.e., double simultaneous stimulation test). Extinction is the term used to denote failure of the child to perceive both stimuli. The contralateral parietal lobe to the side on which the unidentified stimulus was applied is the site of dysfunction. Pain, as tested with pinprick, must be assessed gently, rapidly, and in a nonthreatening and playful manner. Testing for segmental sensory level during childhood is sometimes an essential portion of the examination. Because the patient must be attentive and cooperative, the examination often must be repeated for corroboration. Segmental sensory innervations of the arm and leg are illustrated in Figures 2-7, 2-8, and 2-9 [Keegan and Garrett, 1948]. The nipples are at approximately the T5 level and the umbilicus at the T10 level. Cortical sensory function can be tested in the older child. So-called cortical sensory functions require attentiveness and cooperation and involve complex processing. Because the tests are primarily of parietal lobe function, testing of these functions assumes and requires intact sensory neurologic pathways from the diverse cutaneous specialized nerve endings, muscles, and joints and subsequent connections with the parietal lobe. Stereognosis is the recognition of familiar objects by touch. After the patient closes the eyes, objects are placed by the examiner in one of the child’s hands and then the other. The patient should recognize the objects by size, texture, and form. Objects may include a button, safety pin, or key. Coins are particularly useful because older patients can be asked to differentiate among them. The patient must be able

FIGURE 2-7. Segmental sensory innervation of the arm. (Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School; adapted from Keegan JJ, Garrett FD. The segmental distribution of the cutaneous nerves in the limbs of man. Anat Rec 1948;102:409. Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.)

Ventral C3

C6

C4 C5 T1

C7 C8 C3 Dorsal C6

C7 C8

25

C4 C5 C6 C7 C8 T1

26

Clinical Evaluation / 2

Dorsal

ulation is determined. Normal findings have been reported for children 2 to 12 years old [Cope and Antony, 1992]. Testing of this modality is frequently performed over the fingertips. Differences in perception over homologous areas on both sides are sought. Absence or impairment of two-point discrimination results from parietal lobe dysfunction.

Ventral

L1 L2 L3 L4 L5 S1 S2 S3 S4 S5

Skeletal Muscles S2 L1

L2

L2

L3

L3 L5

Tone, bulk, and strength of the skeletal muscles should be determined during this portion of the examination. The segmental innervation patterns of the trunk muscles and the extremities and the motor functions of the spinal nerves are described in Tables 2-3, 2-4, and 2-5. The strength of limb muscles is assessed, when possible, by testing the child’s ability to counteract resistance imposed by the examiner on proximal and distal muscle groups or individual muscles. Norms cited for gross motor outcomes in young children with brain injury are useful in assessing children with apparent motor difficulties [Golumb et al., 2004].

S2

Muscle Testing S1 L4

L4 S1

L5 FIGURE 2-8. Segmental sensory innervation of the leg. (Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School, adapted from Keegan JJ, Garrett FD. The segmental distribution of the cutaneous nerves in the limbs of man. Anat Rec 1948;102:409. Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.)

to manipulate the objects freely with the fingers and palms. Absence of stereognosis is astereognosis. Astereognosis usually results from lesions of the parietal lobe. Graphesthesia is the ability to recognize numbers, letters, or other readily identifiable symbols traced on the skin. It is necessary to ascertain that the child is capable of identifying the symbols. This ability can be determined best by tracing the symbols in a preliminary trial while the child’s eyes are open. When the patient’s eyes are closed, the figures are traced over the palm or forearm. Failure to identify the symbols is called dysgraphesthesia. By 8 years of age, most children are able to correctly identify all single digits. The ability to distinguish between closely approximated stimulation at two points is two-point discrimination. The minimal distance between two simultaneous points of stim-

The skeletal muscles selected in the subsequent text are responsible for primary movements (Table 2-6). The material presented is adapted from Baker [1958]. Frequently, more than one muscle participates in the movement. For this reason, while testing the selected muscles, the examiner should observe and palpate surrounding muscles to detect any substitution of action of other muscles. The following scoring system is useful for recording muscle power*: 5: Normal power 4: Inability to maintain position against moderate resistance 3: Inability to maintain position against slight resistance or gravity 2: Active movement with gravity eliminated 1: Trace of contraction 0: No contraction While testing for muscle function, it is most convenient for the patient to maintain a fixed position against force. The examiner can assess the strength of various muscles by instituting the action of the antagonist. This strategy obviates the necessity of providing new directions for each muscle tested and simplifies the procedure for patient and examiner. The fixed positions depicted in Figure 2-10 are used routinely here and are referred to by the following letters: Position A: The arm is adducted, the forearm flexed at the elbow, and the wrist placed across the xiphoid process. Position B: The child lies on the back with the lower extremity flexed at 90 degrees at the hip and knee. The examiner should support the lower limb at the ankle. Position C: The child lies on the back with the leg and foot in normal extension. *Adapted from Medical Research Council. War memorandum, no. 7. Aids to the investigation of peripheral nerve injuries, 2nd ed. London, His Majesty’s Stationery Office, 1943 (reprinted 1960).

Swaiman / Neurologic Examination of the Older Child

27

C2

C3 C2 C4 C4 C5

T2 T3 T4

T2

T5 T6 T7 T8 T9 T10 T11 T12

C6 T1

C6

T1

C7

C5 T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12 L1 L2 S2 S3

C3 C5 T2

C6

C6

L1

L2

T1

T1

S4 S5

C7 L2

C8

C8

S3 S2

L3 L3

L5 L4

L5 L4

S1 S1 FIGURE 2-9. Radicular cutaneous fields.

When the weakness of any muscle group prevents the use of any of these positions, substitute positions should be improvised. Unfortunately, while examining young children, problems with cooperation or coordination may make it difficult to evaluate maximal strength; only gross testing may be possible, during which various functions are tested by using game playing or gross maneuvers, such as the “wheelbarrow” maneuver (i.e., walk on the hands while the examiner holds the child’s feet and moves slowly forward). Arm and shoulder strength can also be assessed by using functional operations. The child is asked to lean against a wall with the legs placed a foot or two from the wall edge and the arms outstretched with the palms against the wall. Strength of the shoulder girdle and arm extension can be evaluated. Winging of the scapulas also is evident. Alter-

natively, the child can be placed on the floor and asked to “wheelbarrow.” The child should be placed on the floor and asked to rise without aid. The normal child will spring erect. The child with weakness of the hip extensors will engage in Gowers’ maneuver and climb up the legs and push off into the erect position (Fig. 2-11). During examination of gait, the examiner must be aware of the presence of normal associated movements of the arms, circumduction of the legs, footdrop, unusual positions of the feet, and waddling (see Chapter 5). The presence of a limp may also be evident. Muscle bulk is evaluated by gentle palpation and observation. Abnormalities include atrophy and fasciculations that accompany anterior horn cell disease and muscle hypertrophy, particularly of the gastrocnemius and deltoid muscles associated with Duchenne’s muscular dystrophy and

28

Clinical Evaluation / 2

TABLE 2-3 Motor Functions of the Spinal Nerves NERVES

MUSCLES*

FUNCTION

Cervical plexus (C1–C4) Cervical Phrenic

Deep cervical Scalene Diaphragm

Flexion, extension, and rotation of the neck Elevation of the ribs (inspiration) Inspiration

Pectorales major and minor Serratus anterior Levator scapulae Rhomboid Supraspinatus Infraspinatus Lattisimus dorsi Teres major Subscapularis Deltoid Teres minor Biceps brachii Coracobrachialis Brachialis Flexor carpi radialis Palmaris longus Flexor digitorum sublimis Flexor pollicis longus Flexor digitorum profundus (radial half) Pronator quadratus Pronator teres Abductor pollicis brevis Flexor pollcis brevis Lumbricals I, II, III

Adduction and depression of the arm downward and medially Fixation of scapula on raising the arm Elevation of scapula Drawing the scapula upward and inward Outward rotation of the arm Elevation and outward rotation of the arm

Suprascapular Subscapular Axillary Musculocutaneous Median

Ulnar

⎧ ⎪ ⎨ ⎪ ⎩

Brachial plexus (C5–T1) Anterior Long thoracic Dorsal scapular

Opponens pollicis brevis Flexor carpi ulnaris Flexor digitorum profundus (ulnar half) Adductor pollicis Hypothenar Lumbricals III, IV

Extensor indicis proprius

Adduction of metacarpus I Abduction, opposition, flexion of the little finger Flexion of the first phalanx and extension of the other phalanges of fourth and fifth fingers Same action as preceding. Also spreading apart of fingers and bringing them together Extension of the forearm Flexion of the forearm Extension and radial flexion of the hand Extension of proximal phalanges of second through fifth fingers Extension of the proximal phalanx of the little finger Extension and ulnar deviation of the hand Supination of the forearm Abduction of metacarpus I Extension of the proximal phalanx of the thumb Abduction of first metacarpus and extension of the distal phalanges of the thumb Extension of the proximal phalanx of the index finger

Thoracic and abdominal

Elevation of the ribs, expiration, abdominal compression, etc.

Iliopsoas Sartorius Quadriceps femoris Pectineus ⎧ Adductor longus ⎪⎪ ⎪ Adductor brevis ⎨ Adductor magnus ⎪⎪⎪ ⎩ Gracilis Obturator externis

Flexion of the leg at the hip Inward rotation of the leg together with flexion of the upper and lower leg Extension of the lower leg

Gluteus medius Gluteus minimus Tensor fasciae latae Piriformis Gluteus maximus

Abduction and inward rotation of the leg, also under certain circumstances, an outward rotation Flexion of the leg at the hip Outward rotation of the leg Extension of the leg at the hip

Interossei Radial

Thoracic nerves Thoracic Lumbar plexus (T12–L4) Femoral Obturator

Sacral plexus (L5–S5) Superior gluteal

Inward rotation and abductiion of the arm toward the back Inward rotation of the arm Raising of arm to the horizontal Outward rotation of the arm Flexion and supination of the forearm Elevation and adduction of the arm Flexion of the forearm Flexion and radial deviation of the hand Flexion of the hand Flexion of the middle phalanges of second through fifth fingers Flexion of the distal phalanx of the thumb Flexion of the distal phalanges of second and third fingers Pronation Pronation Abduction of metacarpus I at right angles to palm Flexion of proximal phalanx of thumb Flexion of the proximal phalanges and extension of the other phalanges of first, second, and third fingers Opposition of metacarpus I Flexion and ulnar deviation of the hand Flexion of distal phalanges of fourth and fifth fingers

Triceps brachii Brachioradialis Extensor carpi radialis Extensor digitorum communis Extensor digit quinti propius Extensior carpi ulnaris Supinator Abductor pollicis longus Extensor pollicis brevis Extensor pollicis longus

Adduction of the leg Adduction and outward rotation of the leg

Swaiman / Neurologic Examination of the Older Child

29

TABLE 2-3 Motor Functions of the Spinal Nerves—cont’d

Inferior gluteal Sciatic

MUSCLES*

FUNCTION ⎧ ⎪ ⎨ ⎪ ⎩

NERVES

Obturator internus Gemelli Quadratus femoris Biceps femoris Semitendinosus Semimembranosus Tibialis anterior Extensor digitorum longus Extensor hallucis brevis Peroneus Gastrocnemius Soleus Tibialis posterior Flexor digitorum longus Flexor hallucis longus Flexor digitorum brevis Flexor hallucis brevis Plantar ⎧ ⎪ ⎨ ⎪ ⎩

Peroneal Deep Superficial Tibialis

Pudendal

Perineal anal sphincters

Outward rotation of the leg Flexion of the leg at the hip Dorsiflexion and supination of the foot Extension of the toes Extension of the great toe Pronation of the foot Plantar flexion of the foot Adduction of the foot Flexion of the distal phalanges II through V Flexion of distal phalanx I Flexion of middle phalanges II through V Flexion of middle phalanx I Spreading and bringing together and flexion of the proximal phalanges of the toes Closure of sphincters of the pelvic organs; participation in the sexual act; contraction of pelvic floor

*Various muscles may receive still other nerve supplies than those mentioned. The following are the principal accessory nerve supplies: the brachial muscle receives fibers from the radial nerve; the flexor digitorum sublimis, from the ulnar; the adductor pollicis, from the median; the pectineus, from the femoral; the adductor magnus, from the tibial. From Haymaker W. Bing’s local diagnosis in neurological diseases, 15th ed. St. Louis: Mosby, 1969.

Position A

Position B

Position C

FIGURE 2-10. Position of the limbs for muscle strength (see Table 2-6).

FIGURE 2-11. Gowers’ maneuver indicates weakness of truncal and proximal lower extremity muscles. (Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)

other dystrophies, as well as myotonia congenita. Muscle tenderness, nerve tenderness, and nerve hypertrophy can also be assessed by palpation. Myotonia can be elicited by tapping over the thenar eminence and deltoid muscles. Tapping the tongue should be performed at the end of the examination

30

Clinical Evaluation / 2 Table 2-4

Segmental Innervation of Muscles of Extremities THORACIC SEGMENTS

CERVICAL SEGMENTS 4

5

6

7

8

1

Supraspinatus

Shoulder

Teres minor Deltoid Infraspinatus Subscapular Teres major Biceps brachii

Arm

Brachialis Coracobrachialis Triceps brachii Anconeus Brachioradialis Supinator Extensor carpi radialis Pronator teres Flexor carpi radialis Flexor pollicis longus Abductor pollicis longus

Forearm

Extensor pollicis brevis Extensor pollicis longus Extensor digitorum communis Extensor indicis proprius Extensor carpi ulnaris Extensor digiti V proprius Flexor digitorum subimis Flexor digitorum profundus Pronator quadratus Flexor carpi ulnaris Palmaris longus From Haymaker W. Bing’s local diagnosis in neurological diseaes, 15th ed. St. Louis: Mosby, 1969.

Continued

Swaiman / Neurologic Examination of the Older Child

Table 2-4

Segmental Innervation of Muscles of Extremities—cont’d

THORACIC SEGMENTS 12

LUMBAR SEGMENTS 1

2

SACRAL SEGMENTS

3

4

5

1

2

Iliopsoas Tensor fasciae latae Gluteus medius Gluteus minimus Hip

Quadratus femoris Gemellus inferior Gemellus superior Gluteus maximus Obturator internus Piriformis Sartorius Pectineus Adductor longus Quadriceps femoris Gracilis

Thigh

Adductor brevis Obturator externus Adductor magnus Adductor minimus Articularis genu Semitendinosus Semimembranosus Biceps femoris Tibialis anterior Extensor hallucis longus

Leg

Popliteus Plantaris Extensor digitorum longus Soleus From Haymaker W. Bing’s local diagnosis in neurological diseaes, 15th ed. St. Louis: Mosby, 1969.

3

31

32

Clinical Evaluation / 2 Table 2-4

Segmental Innervation of Muscles of Extremities—cont’d CERVICAL SEGMENTS 4

5

THORACIC SEGMENTS 6

7

8

1

Abductor pollicis brevis Flexor pollicis brevis Opponens pollicis Flexor digiti V

Hand

Opponens digiti V Adductor pollicis Palmaris brevis Abductor digiti V Lumbricals Interossei THORACIC SEGMENTS 12

LUMBAR SEGMENTS 1

2

3

SACRAL SEGMENTS 4

5

1

2

Gastrocnemius Peroneus longus Peroneus brevis

Leg—cont’d

Tibialis posterior Flexor digitorum longus Flexor hallucis longus Extensor hallucis brevis Extensor digiti brevis Flexor digiti brevis Abductor hallucis Flexor hallucis brevis Lumbricals

Foot

Abductor hallucis Abductor digiti V Flexor digiti V brevis Opponens digiti V Quadratus plantae Interossei

3

Swaiman / Neurologic Examination of the Older Child

Table 2-5

Segmental Innervation of Trunk Muscles

CERVICAL SEGMENTS 1

2

3

33

4

5

6

7

LUMBAR SEGMENTS

THORACIC SEGMENTS 8

1

2

3

4

5

6

7

8

9

10 11 12

1

2

3

4

SACRAL SEMENTS 5

1

2

3

4

COCCYX 5

DEEP LONG MUSCLES OF THE BACK Short deep neck muscles

Splenius muscles

Levator, sphincter ani, perineal, and coccygeal

Serratus posterior inferior

Serratus posterior superior

Latissimus dorsi

Trapezius

Levator scapulae Rhomboids Longus capitis

Longus colli

Rectus abdominis External oblique, abdominal

Scalenes

Pectoralis major

Transverse abdominal

Pectoralis minor

Internal oblique, abdominal

Subclavius

Quadratus lumborum

Serratus anterior Diaphragm

Intercostal muscles

From Haymaker W. Bing’s local diagnosis in neurological diseaes, 15th ed. St. Louis: CV Mosby, 1969.

and only when other elements of the history or examination make this evaluation essential. Tapping individual muscles with the reflex hammer elicits the myotatic reflex, which may be useful in the detection of myopathy because the reflex is absent in myopathies. Muscle tone is evaluated when the child is relaxed so that resistance to passive movement can be monitored. Aside from passive movement of limbs at joints, the examiner also assesses the extensibility of muscles by shaking the limbs and determining the range of motion. Tone may be decreased in the presence of cerebellar disease and anterior horn cell disease. Tone may be increased because of the rigidity associated with basal ganglia disease and spasticity associated with corticospinal tract dysfunction.

GAIT EVALUATION The evaluation of gait is discussed in detail in Chapter 5, but a brief outline is presented here. The child should be asked to walk back and forth normally, preferably in a corridor, and up and down steps. The examiner should observe whether the gait is wide or narrow based, whether there are symmetric reciprocal movements of the arms, and whether the legs and feet move in a symmetric and normal fashion. The child should also be asked to run because running exaggerates neurologic impairment. Flexion or extension of an arm with subsequent athetosis not present during walking may be apparent during running.

34

Clinical Evaluation / 2

TABLE 2-6 Muscle Testing MUSCLE

INNERVATION

NORMAL FUNCTION

TEST*

Supraspinatus

C4–C5

Initiates arm abduction

Deltoid

C5–C6

Lower trapezius

C2–C4

Serratus

C5–C7

Infraspinatus Subscapularis and teres major Pectoral and latissimus dorsi Brachioradialis

C5 C5–C8 C5–C8 C5–C6 radial

Abduction of arm between 15 and 90 degrees Elevation of arm above shoulder Fixes the medial border of the scapula External rotation of the arm Internal rotation of the arm Adduction of the arm Flexion of elbow

Holding the patient at his or her side, have the patient attempt to abduct the limb Have the patient maintain abduction of arm at 45 degrees against resistance Have patient maintain elevation of arm above the shoulder against resistance Using position A, apply pressure in axis of the humerus

Biceps

Flexion of elbow

Triceps Pronators

C5–C6 musculocutaneous C7–C8 C6–C7

Supinators

C5–C6

Supinates forearm

Flexors of wrist

C7-median/ulnar

Extensors of wrist

C7-radial

Extensors of the digits

C7-radial

Flexors of fingers (grip) Adductor of thumb

C7-median/ulnar T1-ulnar

Opponens thumb

T1-median

Interossei

T1-ulnar

Extends forearm Pronates forearm

Extends fingers

Back muscles

Extends the back

Abdominal muscles

Contracts the abdominal wall

Intercostal muscles

Raises the rib cage

Diaphragm

C4

Iliopsoas

L2 femoral

Participates in respiration and facilitates coughing Flexion of hip on abdomen

Adductors of hip

L2–L3 obturator

Adducts leg at the hip

Gluteus medius and minimus

L4–L5

Abduction of leg at the hip

Quadriceps Hamstrings Tibialis anticus

L3 femoral S1–S2 sciatic L4 peroneal

Extension of the knee Flexors of the knee Dorsiflexion of the foot

Triceps surae

L5–S2 tibial

Plantar flexion of the foot

Posterior tibial

L4 tibial

Inverts the foot

Peroneals

L5 peroneal

Everts the foot

Dorsiflexors of toes

S1 peroneal

Plantar-flexors of toes

S2 tibial

Gluteus maximus

S1–S2

*Use this table in conjunction with Figure 2-10.

Extension of the leg at the hip

Using position A, apply downward pressure on forearm Using position A, pull the wrist away from the body Using position A, abduct the arm in the midaxillary line Using position A, (forearm must be pronated), push downward at the wrist Using position A but with forearm supinated, push downward at wrist Using position A, push upward at wrist Using position A, rotate forearm so the upper border of the hand turns outward Using position A, rotate the forearm so that the upper border of the hand turns inward Using position A but with hand supinated, push down on the palmar surface of the hand Using position A but with hand pronated, push down on the dorsal surface of the hand Using position A but with hand pronated, push down on the first phalanx of each digit Using position A, have patient squeeze hard Using position A, with thumb adducted, pull upward on the thumb Using position A with hand supinated, have patient resist the separation of the tip of the little finger from the tip of the extended thumb Using position A but with hand supinated and fingers spread apart, attempt to approximate the fingers Using position C, place hand beneath patient’s back and have the patient arch the back With patient in supine position, place hand on patient’s abdomen and have patient attempt to rise from a recumbent position With patient in supine position, observe action of intercostals on deep inspiration; observe excursion and observe for symmetry of excursion of chest Have patient cough and observe the epigastric impulse Using position B, place hand above knee and push downward Using position B, place hand on the medial surface of the thigh and push inward Using position B, place hand on outer aspect of the thigh and push outward Using position B, attempt to further flex the leg at the knee Using position B, attempt to extend the leg at the knee Using position C, place hand on the dorsal surface of the foot and push in a plantar direction Using position C, place hand on ball of foot and push in the direction of the patient Using position C, grasp the foot at the arch and rotate so that the plantar surface turns outward Using position C, grasp the foot at the arch and rotate so that the plantar surface turns inward Using position C, push in a plantar direction against the dorsal surface of the toes Using position C, place hand on the plantar surface of the toes and push in the direction of the patient With patient lying on the side and with the lower limbs maintained in normal extension, place hand on back of thigh and push forward

Swaiman / Neurologic Examination of the Older Child

Among the abnormal gaits are those that can be characterized as cerebellar, spastic, waddling, and steppage. These gait types are discussed further in Chapter 5. REFERENCES Baker AB. An outline of clinical neurology. Dubuque, Iowa: William C Brown, 1958. Cogan DG. Neurology of the ocular muscles. Springfield, Ill: Charles C Thomas, 1966. Cope EB, Antony JH. Normal values for two-point discrimination. Pediatr Neurol 1992;8:251. Frankenburg WK, Dodds JB, Archer P, et al. The Denver II: A major revision and restandardization of the Denver Developmental screening test. Pediatrics 1992;89:91. Golumb MR, Garg BP, Williams LS. Measuring gross motor recovery in young children with early brain injury. Pediatr Neurol 2004;31:311 Haymaker W. Bing’s local diagnosis in neurological diseases, 15th ed. St. Louis: CV Mosby, 1969. Haymaker W, Woodhall B. Peripheral nerve injuries. Philadelphia: WB Saunders, 1962. Hollinshead WH. Functional anatomy of the limbs and back. 3rd ed. Philadelphia: WB Saunders, 1969. Keegan JJ, Garrett FD. The segmental distribution of the cutaneous nerves in the limbs of man. Anat Rec 1948;102:409. Medical Research Council, War Memorandum No 7. Aids to the investigation of peripheral nerve injuries. 2nd ed. London: His Majesty’s Stationery Office, 1943. (Reprinted 1960.) Smith JL, ed. Neuro-ophthalmology: Symposium of the University of Miami and the Bascom Palmer Eye Institute, Vol. 3. St. Louis: CV Mosby, 1967. Zafeiriou DI. Primitive reflexes and postural reactions in the neurodevelopmental examination. Pediatr Neurol 2004;31:1.

SUGGESTED READING Brett EM. Normal development and neurological examination beyond the newborn period. In: Paediatric Neurology, 3rd ed. London: Churchill Livingstone, 1997.

35

Dekaban A. Examination. In: Dekaban A, ed. Neurology of early childhood. Baltimore: Williams & Wilkins, 1970. Dodge PR. Neurologic history and examination. In: Farmer TW, ed. Pediatric neurology. New York: Paul B Hoeber, 1964. Egan DF. Developmental examination of infants and preschool children. Clinics in developmental medicine, no. 112. Oxford: MacKeith Press, 1990. Fenichel GM. Clinical pediatric neurology: a signs and symptoms approach, 3rd ed. Philadelphia: WB Saunders, 1997. Fenichel GM. The neurological consultation. In: Fenichel GM, ed. Neonatal neurology, 3rd ed. New York: Churchill Livingstone, 1990. Haerer AF. Dejong’s the neurologic examination. Philadelphia: Lippincott, 1992. Illingworth RS. The development of the infant and young child, 9th ed. Baltimore: Williams & Wilkins, 1987. Kestenbaum A. Clinical methods of neuro-ophthalmologic examination. New York: Grune & Stratton, 1961. Menkes, JH, Sarnat HB. Textbook of Child Neurology, 6th ed. Baltimore: Williams & Wilkins, 2003. Nellhaus G. Composite international and interracial graphs. Pediatrics 1968;41:106. Paine RS. Neurologic examination of infants and children. Pediatr Clin North Am 1960;7:41. Paine RS. Neurologic conditions in the neonatal period: diagnosis and management. Pediatr Clin North Am 1961;8:577. Paine RS. The evolution of infantile postural reflexes in the presence of chronic brain syndromes. Dev Med Child Neurol 1964;6:345. Paine RS, Brazelton TB, Donovan DE, et al. Evolution of postural reflexes in normal infants and in the presence of chronic brain syndromes. Neurology 1964;14:1036. Paine RS, Oppe TE. Neurological examination of children. London: William Heinemann, 1966. Peiper A. Cerebral function in infancy and childhood. New York: Consultants Bureau Enterprises, 1963. Popich GA, Smith DW. Fontanels: Range of normal size. J Pediatr 1972;80:749. Sauer C, Levinsohn MW. Horner’s syndrome in childhood. Neurology 1976;26:216. Volpe JJ. The neurological examination: Normal and abnormal features. In: Volpe JJ, ed. Neurology of the newborn, 4th ed. Philadelphia: WB Saunders, 2001.

CHAPTER 3

Neurologic Examination after the Newborn Period until 2 Years of Age Kenneth F. Swaiman

Systematic acquisition of skills and responses results from maturation of physiologic processes and anatomic structures of the developing central and peripheral nervous systems. Adequate neurologic assessment depends on comparing the results of the infant’s examination with established norms (Table 3-1) [Gesell and Amatruda, 1956; Illingsworth, 1987; Zafeiriou, 2004]. Because it is critical that the infant remain calm and cooperative for the longest possible time during the examination, the least intrusive portions of the examination should be done first. A review of Chapter 2 can assist in understanding the material in this chapter.

APPROACH TO THE EVALUATION Experienced examiners develop individual approaches to and sequences for the evaluation [Brett, 1997]. Most schemes embody much of the following material. Although arbitrary, examination of the infant can be subdivided into stages. Observation occupies most of the first stage. Some observations are made during the history-taking session. Caregivers should undress the child except for the undershirt, underwear, plastic pants, or diaper. The child should

TABLE 3-1 Child Development from 2 Months through 2 Years 2 Months Keeps hands predominantly fisted Lifts head up for several seconds while prone Startles in response to loud noise Follows with eyes and head over 90-degree arc Smiles responsively Begins to vocalize single sounds 3 Months Occasionally holds hands fisted Lifts head up above body plane and holds position Holds an object briefly when placed in hand Turns head toward object, fixes and follows fully in all directions with eyes Smiles and vocalizes when talked to Watches own hands, stares at faces Laughs 4 Months Holds head steady while in sitting position Reaches for an object, grasps it, brings it to mouth Turns head in direction of sound Smiles spontaneously 5 to 6 Months Lifts head while supine Rolls from prone to supine Lifts head and chest up in prone position Exhibits no head lag Transfers object from hand to hand Babbles Sits with support Localizes direction of sound 7 to 8 Months Sits in tripod fashion without support Stands briefly with support Bangs object on table Reaches out for people Mouths all objects Says “da-da,” “ba-ba” Data from Frankenburg et al, 1981; Illingsworth RS, 1987; Knobloch H et al, 1980.

9 to 10 Months Sits well without support, pulls self to sit Stands holding on Waves “bye-bye” Drinks from cup with assistance Uses pincer grasp 11 to 12 Months Walks with assistance Uses two to four words with meaning Creeps well Assists in dressing Understands a few simple commands 13 to 15 Months Walks by self, falls easily Says several words, uses jargon Scribbles with crayon Points to things wanted 18 Months Climbs stairs with assistance, climbs up on chair Throws ball Builds two- to four-block tower Feeds self Takes off clothes Points to two or three body parts Uses many intelligible words 24 Months Runs, walks up and down stairs alone (both feet per step) Speaks in two- or three-word sentences Turns single pages of book Builds four- to six-block tower Kicks ball Uses pronouns “you,” “me,” and “I”

38

Clinical Evaluation / 3

remain on the caregiver’s lap. At first the clinician should continue questioning the caregivers about pertinent aspects of the history. Usually, the child becomes reassured that the clinician means well. Observation allows limited assessment of cranial nerve function, unusual facies, gross structural deformities (including those of the head and neck), symmetry of strength and movements of the extremities, and unusual posturing. At the beginning of the second stage, while the child remains on the caregiver’s lap, the head, deep tendon reflexes, muscle tone, superficial and deep sensation, gross response to sound, and visual fields can be evaluated. Examination of the plantar responses (e.g., Babinski’s reflex) also can be done. The caregiver is then asked to undress the child completely, and the child is placed on a table. During this segment of the examination, more interactive assessment of muscle function and further assessment of the developmental reflexes, traction response, parachute response, and sitting and standing abilities takes place. The sensory examination is best done at this time. The third stage may require help from a caregiver or assistant. At this time, examination of the abdomen, genitalia, back, and anal area is accomplished. Examination of the mouth, tongue, and sternocleidomastoid muscles should also be done. If previously deferred, measurement of the occipitofrontal circumference (OFC) is mandatory. The fundi and ears are examined. At the beginning of the fourth stage of the examination, the child is placed on the floor so that assessment of crawling, walking, and running can be accomplished.

EVALUATION OF THE PATIENT Stage 1 Stage 1 of the evaluation should be done with ease in the approach. The examiner should avoid quick movements or display of instruments that could be interpreted as threatening. Smiling at the infant and speaking in soft and reassuring tones are highly effective methods. The child should sit on the caregiver’s lap and face the examiner. It is preferable that the child be placed in this position during the history-taking session so that familiarity with the examiner and the room is developed. Observations made of the child while in this position during the initial conversation may provide much information to the skilled examiner. The sequence of examination should be flexible and should be determined by the child’s comfort and temperament and by the natural postures and positions assumed by the child. The examiner must be highly sensitive to the child’s mood and defer those parts of the examination that appear to upset the child until last. Flexibility on the part of the examiner may be the key to a successful session. Nevertheless, a reasonably complete examination should be done. The clinician must not lose sight of the need for all pertinent data to be collected. It is imperative that the clinician systematically conduct that portion of the examination related to the chief complaint. The clinician should make judgments concerning the facial and extraocular movements and the asymmetry and

character of limb movements. The child’s state of alertness, awareness of surroundings, and affect should be evident. The child’s vocalization should be age appropriate.

Head Examination of the head must be done systematically, and the examiner should observe for asymmetry, indentations, and protuberances. Evaluation of all the cranial sutures and associated fontanels can be carried out by gentle palpation. The dimensions of the anterior fontanel should be carefully recorded [Popich and Smith, 1972]. The examiner should determine by observation and palpation the presence of suture synostosis, suture separation, a bulging fontanel, frontal bossing, and unusual shapes of the head, including trigonocephaly, marked dolichocephaly or brachycephaly, and plagiocephaly. If the child is comfortable, the occipitofrontal circumference should be measured. If the child becomes agitated from placement of the tape measure, the measurement should be deferred until later (stage 3). The largest measured circumference should be recorded and plotted on a standardized graph of normative data. (When hydrocephalus is suspected in the early months of life, studies using ultrasonography, computed tomography [CT], or magnetic resonance imaging [MRI] should be obtained.) Simultaneously, unusual masses under the scalp and gross asymmetries of the skull should be sought. If possible, the tenseness of the anterior fontanel should be evaluated when the child is held in an upright position. The size of the anterior fontanel varies [Popich and Smith, 1972]. The anterior fontanel pulsates in unison with the heartbeat, becomes fuller or bulging when the child cries, and may be full in disease states in which there is increased intracranial pressure. The posterior fontanel usually admits only a finger at time of birth and usually is not palpable by the time the child is 2 months old. Other fontanels are usually difficult to palpate readily, except in pathologic states. Occasionally, accessory fontanels may be found along the sutures, particularly the sagittal suture. They usually are benign abnormalities. The cranium is auscultated for the presence of unusual intracranial bruits. However, intracranial bruits occur commonly in childhood, and cautious interpretation is advised. Asymmetric bruits and those that can be suppressed by carotid artery suppression are frequently pathologic. Vascular abnormalities, such as vein of Galen malformations, produce extremely loud bruits. The vein of Galen malformation is associated with increasing occipitofrontal circumference, high-output cardiac failure, and infant distress while in the supine position. The child also may have seizures. Ultrasound and CT examinations of the newborn brain may provide information about the presence of hemorrhage, ventricular size, and amplitude of cerebral pulsations. MRI evaluation is often feasible but may require sedation at this age. Sometimes, when more sophisticated methods are not readily available, the use of transillumination with a flashlight may suggest the presence of a fluid compartment within the brain or over the cortical mantle. Such findings are associated with hydranencephaly, porencephaly, subdural effusions, caput succedaneum, hydrocephalus, and infiltrated intravenous sites.

Swaiman / Neurologic Examination after the Newborn Period until 2 Years of Age

Cranial Nerves Examination of cranial nerve function can be done primarily through observation. More details concerning examination of each cranial nerve can be found in Chapter 2. Using bright objects facilitates the assessment of extraocular muscle movements. Nystagmus and strabismus may be detected during this portion of the examination. If the child appears uninterested in bright objects, the possibility of a visual defect or an underlying intellectual defect must be considered. Rolling movements of the eyes and dysconjugate gaze suggest gross visual impairment. Double simultaneous stimulation—bringing two bright objects into different visual fields (one in each temporal area) simultaneously—normally causes the child to look from one object to the other. Failure to take notice of one object may indicate homonymous hemianopsia. A tape with repetitive bars or objects should be drawn horizontally and then vertically across the child’s field of vision. Lack of opticokinetic response results from lack of visual fixation or from gross impairment of vision. Unusual transient deviations of the eyes may occur in the first year of life [Echenne and Rivier, 1992]. A beam from a small flashlight should be directed at each eye to allow evaluation of pupillary responses, anisocoria, and the red retinal reflex. The examiner should initially direct the light beam at the child’s hand or abdomen so that the child is aware of the safety of the procedure. The presence of abnormalities, such as symmetry of the palpebral fissures, the relative size of the two globes, the angulation of the eyes compared with other facial components and with the ears, cataracts, conjunctival telangiectases, colobomas of the iris, ptosis, proptosis, and malformed or eccentrically placed pupils, can be determined at this time. Hair color, patterning distribution, and texture should be assessed. During the entire examination, the examiner should observe the child’s facial movements closely. Smiling at the child, tickling the child, or making unusual noises or facial grimaces often causes the child to smile or laugh, allowing observation of the nasolabial folds. The presence of facial weakness from central or peripheral cranial nerve VII dysfunction should be determined. Widening of the ipsilateral palpebral fissure is indicative of facial nerve weakness. It is essential that the examiner distinguish between central and peripheral facial nerve palsies; the latter include involvement of the muscles of the forehead. In the younger infant, sucking and rooting reflexes can be obtained. Tongue thrusting, drooling, and unusual shapes of the lips should be evident. Sometimes, the child can be induced to protrude the tongue if the examiner urges the child to imitate the examiner’s tongue movements. Deformity, atrophy, or abnormal positioning of the tongue can be observed. Basic responses to rubbing together of the fingers, ringing a bell, or using a toy noisemaker that generates noise at a modest volume may provide much information. A tuning fork may also be used. The examiner must be careful not to confuse response to a visual cue (e.g., the movement needed to elicit noise from a toy) for response to the sound. The infant turns the head toward the sound, and there is arrest of motor activity. A child older than 6 months usually reaches for the noisemaker. If the child fails to perform

39

satisfactorily, formal audiometry and auditory-evoked response testing should be obtained.

Motor Evaluation Observation is the most efficacious approach in motor evaluation. The examiner should systematically observe the symmetry of movements of arms and legs and notice any gross discrepancies in muscle bulk or limb length. Definite hand preference before 24 months suggests a central or peripheral nervous system impairment of the opposite hand and arm. In this situation, leg movement and use should be carefully studied to detect the presence of hemiparesis. Most commonly, there is also a decrease in spontaneous movement of the affected limb. Unusual posturing of the limbs may indicate paresis or incipient extrapyramidal disease. Evaluation of muscle tone, the resistance of muscle to passive stretch, is an important facet of the motor examination. The muscle tone of the arms and legs can be assessed by the examiner gently shaking and moving the feet and hands while the child is relaxed. Tone and range of motion can be assessed by shaking the arms and hands about the various joints. Pronation and supination of the hands and forearms provide further information about range of motion and the possibility of spasticity or rigidity. Greater than normal resistance indicates increased tone, whereas less than normal resistance indicates decreased tone. This portion of the examination is most difficult for the novice because reasonable experience is required to make accurate judgments. Limitation of movement may also indicate joint contracture. During the examination, the infant may well resist attempts to move the arms, providing the examiner with some sense of muscle strength. Spontaneous muscle movements, particularly those against gravity, provide the most information concerning muscle strength. Upper motor neuron unit involvement, such as that in hemiparesis, may manifest by limited flexion of the arm at the elbow, decreased movement of the extremity, persistent fisting, and adduction of the thumb against the palm. Patients with brachial plexus injury of Erb’s type often hold the arm in a position of internal rotation and adduction at the shoulder. Interaction with the infant by using toys and other interesting objects may help to evaluate limb strength, range of motion, and coordination of limb movements. If the child is sufficiently cooperative, individual muscle testing, when appropriate, should be carried out. There is a normal sequence as the child becomes more adept at grasping objects with the hands. Grasping an object with both hands and holding the object before the face, transferring the object from hand to hand, and placing the object in the mouth all provide information concerning the infant’s motor control. The infant’s grasping skills are best demonstrated when progressively smaller objects are presented. When 4 to 5 months old, the child is able to grasp an object with the entire hand (Fig. 3-1); at 7 months, the grasp is done by the thumb and the neighboring two fingers (Fig. 3-2); and the pincer grasp, in which the thumb and forefinger are used, should be present by 9 to 11 months (Fig. 3-3). The palmar grasp reflex (i.e., obligate grasp reflex) should gradually diminish from 3 to 6 months of age. The persistence of the obligate grasp reflex beyond 6

40

Clinical Evaluation / 3 FIGURE 3-1. Entire hand grasp of 4-month-old infant. (Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)

FIGURE 3-2. Use of two fingers and thumb in the grasp of a 7-month-old infant. (Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)

months of age may signal corticospinal tract dysfunction. Observation of the child’s ability to raise the arms and to abduct and adduct the arms while reaching for a proffered object provides valuable information concerning proximal muscle strength. Simultaneously, the presence of intention tremor and of the avoidance response of early athetosis may be evident. Congenital malformations of the fingers and hands can be readily determined during this portion of the examination. Examination of the hips should include assessment of range of motion; decreased excursion may signify spasticity or subluxation of the hip joints. Subluxation may exist separately or as a result of spasticity. Initially, examination of the legs should consist of evaluation of muscle symmetry and mass. The presence and symmetry of spontaneous motor movements should be evaluated. Assessment of tone is similar to that done with the arms and hands. Gently shaking the feet and movements about the hip and knee joints are monitored. Tightness of the Achilles tendon should also be evaluated. Decreased range of motion and inability of the feet to readily dorsiflex beyond 90 degrees are abnormal. Deep tendon reflexes that are very brisk may indicate upper motor neuron unit disease. Asymmetry is particularly worrisome because of the association with pathologic

FIGURE 3-3. Pincer grasp with the thumb and forefinger of an 11-month-old infant. (Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)

conditions. Absent deep tendon reflexes are likely to be associated with anterior horn cell disease or peripheral neuropathy. The crossed adductor reflex is elicited when the patellar reflex is stimulated and resultant contraction of the adductor muscles occurs in the opposite leg. This response is normal until approximately 1 year of age. When this response persists, particularly unilaterally, it suggests the presence of corticospinal tract difficulty. Elicitation of the plantar response is as important in children as in adults. There is no consensus of opinion about the latest time at which an extensor response is detectable. At least in one report, an extensor response was obtained in 50% to 75% of 1-year-old infants [Dodge, 1964]. Using careful techniques, Hogan and Milligan [1971] found that the initial response is flexor in 93% of normal infants. In this study, the claim was made that the usual response in the newborn period is flexor in origin. This report contrasts with the experience of many examiners. In any event, asymmetric extensor toe signs or extensor toe signs that persist beyond the age of 1 year should be considered pathologic. Pathologic toe signs are indicative of upper motor neuron unit disease. Ankle clonus is often present in the neonatal period; it is rarely sustained. There are usually three to six beats of ankle clonus. Ankle clonus should disappear by 2 months of age. The persistence of ankle clonus and extensor toe signs suggests the possibility of upper motor neuron unit disease. Cerebellar function is difficult to assess and requires an interchange of objects between infant and examiner and observation of the infant during play to monitor tremor, dysmetria, truncal sway while sitting, and fine motor coordination. Titubation may be evident. Decreased tone may accompany cerebellar dysfunction but has many other causes.

Sensory Testing The patient should respond to stroking of the extremities by awareness and by withdrawal of the limbs. The infant should also acknowledge the sensory contact by eye deviation and facial responses. Using a tuning fork with contact over bony

Swaiman / Neurologic Examination after the Newborn Period until 2 Years of Age

41

FIGURE 3-4. Segmental distribution of the cutaneous nerves of an infant. (Modified from Fanaroff AA, Martin RJ. Neonatal-perinatal medicine: Diseases of the fetus and infant, 5th ed. St Louis: CV Mosby, 1992.)

C4 13 5 C5

C4 4 T2 6

C4 T2 C6

7 8 9

T1

11 C7

L1 L2

10

C6

12

C3 C4 C5 T3 5 7 T1 9 11 L1

4 6 8 10 12

L2

C8

C7

L1

C8 L2

S4 S5

C7 L2 S2

L3 L4

S3 L3 L2

L3 L4

L5

L5 L5

S1

S1

areas often causes arrest of motion and a wide-eyed look of wonder in the child who cannot otherwise describe the sensation. Proprioception cannot be directly evaluated at this age, but observations of sitting positions, gait, and posture may provide some clues about normality of function. Stroking of the skin may elicit a response and provide information about light touch perception (Fig. 3-4). Using a pin or gentle pinching for pain evaluation should be reserved until late in the examination; careless use of the pin can destroy rapport with the patient. The child may cry or make short, whimpering sounds. Decreased muscle bulk may not be appreciated because of the large amount of subcutaneous fat, and muscle atrophy may be undetected. The examiner should be careful to palpate muscle mass beneath the fat and not misinterpret the subcutaneous tissue as muscle. The skin of the infant is observed for obvious areas of abnormality that may suggest certain conditions, including neuroectodermal neurocutaneous disorders. Examination of the spine may indicate the presence of scoliosis, sinus tracts, scars, dimples, and hemangiomas. Unusual skin lesions or hair growth over the spine suggest the presence of an underlying mesodermal defect, including diastematomyelia. The spine should be palpated along its entire course for defects. Abdominal and cremasteric reflexes are present at birth. The abdominal reflex is elicited by stroking the skin of the upper, middle, and lower portions of the abdomen. Each stroke elicits a muscle contraction mediated by a different group of thoracic and lumbar nerves. The response results in the retraction of the umbilicus toward the stimulated side. The various spinal cord segmental levels involved in the reflex range from T8 to T12. The cremasteric reflex is elicited by stroking the inner thigh, beginning 3 to 5 cm below the inguinal crease. The cremasteric reflex results in an elevation of the testicles

S1

because of contraction of the overlying smooth muscles. Cremasteric reflexes are mediated by spinal nerves L1 and L2.

Stage 2 For stage 2 of the evaluation the child should be placed on a table with the caregiver standing close by for reassurance to the child and assistance, if necessary, to the examiner. Motor evaluation can be carried out on an examining table or on a larger, carpeted surface. By 3 months of age, an infant can hold the head and chest off the table while in the prone position. Good head control while sitting with support is evident by 4 months of age. The child should be able to sit without support and maintain adequate balance by 8 to 9 months of age. Unassisted assumption of the sitting position should occur by 10 months of age. The child should crawl by 10 months, pull to a standing position by 10 months, and creep by 11 months. The child should walk with support by 12 months and without support by 13 to 14 months. Lack of these abilities should be evaluated in concert with other findings. Trunk, shoulder, and pelvic girdle tone and strength should be evaluated further. The child is observed while held in vertical and horizontal suspension. A hypotonic child, when held in horizontal suspension, often droops over the examiner’s arm [Paine, 1960]. In vertical suspension, the child may slide through the examiner’s hands. The child may be unable to maintain a standing posture when the feet are placed on the table surface. Increased tone, or hypertonicity, usually the result of spasticity, may manifest by a backward curve of the extended head, neck, and back while in horizontal suspension. The legs may be extended and may “scissor” while the child is in vertical suspension, and the child may stand on the toes when the feet are allowed to touch the table (Fig. 3-5).

42

Clinical Evaluation / 3 FIGURE 3-5. Extended legs, scissoring, toe stance, and fisting in an infant with spastic quadriplegia. (Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)

TABLE 3-2 Most Commonly Used Motor Performance Tools Developmental Scales Amiel-Tison [Amiel-Tison, 1968] Amiel-Tison [Amiel-Tison, 2002] Bayley [Bayley, 1961] Brazelton [Brazelton and Nugent, 1995] Dubowitz [Dubowitz et al., 1999] Haataja [Haataja et al., 1999] Peabody [Reed, 1985] Prechtl [Prechtl and Beintema, 1964] Developmental Screening Tests Denver Developmental Screening Test (Denver II) [Frankenburg et al., 1992] Battelle Screening Test [Glascoe and Byrne, 1993] Clinical Adaptive Test (CAT)/Clinical Linguistic and Auditory Milestone Scale (CLAMS) [Leppert et al., 1998] Knobloch Revised Screening Inventory [Knobloch et al., 1980] General Movements (GMs) Assessment [Dargassies 1997; Prechtl 1997; Prechtl et al., 1997]

Motor Performance Instruments Through the years, several instruments have been devised that are useful for evaluating motor performance in relation to chronologic age. These instruments have provided norms for evaluating expected rate of motor development for a number of different assessments and maneuvers [Zafeiriou, 2004]. The instruments that are most commonly used are found in Table 3-2.

Motor Assessment Instruments Alberta Infant Motor Scale (AIMS) [Piper et al., 1992] Early Motor Pattern Profile (EMPP) [Morgan, 1988] Gross Motor Function Measure (GMFM) [Russell et al. 2002] Movement Assessment Inventory (MAI) [Kaye and Whitfield, 1988] Test of Infant Motor Performance (TIM) [Campbell et al., 1993] Adapted from Zafeiriou DI. Primitive reflexes and postural reactions in the neurodevelopmental examination. Pediatr Neurol 2004;31:1.

Developmental Reflexes Developmental reflexes are patterned responses that are achieved by certain ages. General development of the nervous system can be assessed by eliciting these reflexes. Occasionally, they may have localizing value, but usually, they do not. The abnormalities may be the continued presence of a reflex that should have dissipated, absence or poor manifestation of the expected response, or a response that is not symmetric. These reflexes and means of elicitation are listed in Tables 3-3 and 3-4 [Zafeiriou, 2004]. Although the Moro reflex may be demonstrated by several maneuvers, essentially, the position of the head in relation to the trunk must be altered in the supine position. Eliciting this reflex is correctly done while the child is in the supine position; the head is lifted off the padded examining table and then allowed to fall approximately 30 degrees in relation to the trunk [Parmelee, 1964]. The examiner should allow the head to fall onto his or her hand. The expected response is extension and abduction of the arms and extension of the fingers. This posturing is followed by adduction of the arms at the shoulder. The child often emits a cry (Fig. 3-6). An abnormality in the Moro reflex does not signify a specific area of involvement but rather a diffuse process, usually depression of the central nervous system (CNS). Generalized weakness or severe spasticity may also cause limitation of the Moro reflex. If the Moro reflex is asymmetric, motor abnormalities, such as Erb’s and Klumpke’s

FIGURE 3-6. The Moro response to rapid extension of the neck in a 2-dayold infant. The abduction phase of arm movement is illustrated. A cry usually accompanies the response, and the leg position varies.

brachial plexus palsies, or fractures of the humerus or clavicle should be considered [Dekaban, 1970]. Spastic hemiplegia may also result in an asymmetric Moro reflex. An exaggerated Moro reflex may indicate pathologic CNS irritability. Although the Moro reflex usually exists in children up to 5 or 6 months old, the manifestation of the reflex changes with maturation. When children are 2 months old, the Moro reflex is incomplete. The usual pattern is that the adduction phase is greatly attenuated. The tonic neck reflex reaches a peak when the child is 2 months old but may be detected in the neonatal period. The

Swaiman / Neurologic Examination after the Newborn Period until 2 Years of Age

43

TABLE 3-3 Eliciting Primitive Reflexes Reflex

Position

Method

Response

Age at Disappearance

Palmar grip Plantar grip

Supine Supine

Flexion of fingers, fist making Flexion of toes

6 months 15 months

Galant

Prone

Asymmetric tonic neck

Supine

Placing the index finger in the palm of the infant Pressing a thumb against the sole just behind the toes Scratching the skin of the infant’s back from the shoulder downward, 2-3 cm lateral to the spinous processes Rotation of the infant’s head to one side for 15 seconds

Suprapubic extensor

Supine

Pressing the skin over the pubic bone with the fingers

Crossed extensor

Supine

Passive total flexion of one lower extremity

Rossolimo

Supine

Heel

Supine

Moro

Supine

Babinski

Supine

Light tapping of toes 2 through 4 at their plantar surfaces Tapping on the heel with a hammer, with the infant’s hip and knee joints flexed and the ankle joint in neutral position Sudden head extension produced by a light drop of the head Striking along the lateral aspect of the sole, extending from the heel to the head of the fifth metatarsal

Incurvation of the trunk, with the concavity on the stimulated side

4 months

Extension of the extremities on the chin side and flexion of those on the occipital side Reflex extension of both lower extremities, with adduction and internal rotation into talipes equinus Extension of the other lower limb, with adduction and internal rotation into talipes equinus Tonic flexion of the toes at the first metacarpophalangeal joint Rapid reflex extension of the lower extremity in question

3 months

Abduction followed by adduction and flexion of upper extremities Combined extensor response: simultaneous dorsiflexion of the great toe and fanning of the remaining toes

6 months

4 weeks 6 weeks 4 weeks 3 weeks

Presence always abnormal

Data from Futagi et al., 1992; Vojta 1988; Zafeiriou DI, 2004; Zafeiriou et al., 1995; Zafeiriou et al., 1999a; Zafeiriou et al., 1999b; Zafeiriou et al., 2000.

TABLE 3-4 Eliciting Postural Reactions Reaction

Position

Method

Traction

Supine

Horizontal suspension

Prone

Vertical suspension

Vertical

Vojta response

Vertical

Collis horizontal suspension

Prone

Collis vertical suspension

Prone

Peiper-Isbert vertical suspension

Prone

Placing the examiner’s index finger in the infant’s hand and pulling the infant at a 45-degree angle to the examination bed Suspending the infant by placing the hands around the infant’s thorax without providing support for the head or legs Placing both hands in the axillae without grasping the thorax and lifting the infant straight up facing the examiner Suspension from the vertical to the horizontal position facing the examiner by placing both hands around the infant’s thorax Placing one hand around the upper arm and the other around the upper leg and suspending the infant in the horizontal position, parallel to the examination bed Placing one hand around the upper leg and suspending the infant in the vertical position with the head directed downward Placing the examiner’s hands around the upper leg of the infant and suspending the infant in the vertical position with the head directed downward

Data from Vojta, 1988; Zafeiriou et al., 1998; Zafeiriou, 2004.

reflex gradually diminishes and is absent in children 6 months of age and older. To elicit the reflex, the head is turned to one side while the child is supine and the shoulders fixed. The arm and leg on the side toward which the face is turned extend, and the arm and leg on the opposite side flex. The degree of response varies widely but is usually symmetric. In any event, a normal infant does not remain in the reflex position when the reflex is elicited. If the struggling infant does not escape the reflex response, the response is abnormal. The response should not exist beyond 6 months of age [Paine et al., 1964]. A unilateral reflex may indicate a lesion in the hemisphere opposite the direction in which the face is turned. The same consideration holds true if the response is

obligate or persists beyond the expected age. The weak child may also have an abnormal response secondary to central or peripheral motor unit involvement. Sitting or standing is impaired when the child has an overactive tonic neck reflex. Athetoid and spastic infants may also have an exaggerated response. An object or the examiner’s finger is placed in the palm of the infant’s hand to elicit the palmar grasp reflex. The child has an involuntary flexion response and grasps the object. This reflex subsides by 3 to 6 months of age, and voluntary grasping is evident. The obligatory involuntary grasp reflex may persist and often indicates infantile hemiplegia [Paine, 1964].

44

Clinical Evaluation / 3

To elicit the Landau reflex, the infant is held prone in horizontal suspension by the examiner. The examiner flexes the infant’s head. Flexion of the legs and trunk is the normal response. This response is present in most infants by 5 months of age and absent by 2 years of age [Cupps et al., 1976]. Virtually all normal infants have a positive Landau response by 10 months of age. When held in horizontal suspension, 55% of infants spontaneously elevate their heads above the horizontal plane by age 5 months and 95% by 6 months [Paine et al., 1964]. The placing reflex response can be demonstrated by holding the upright infant in a manner that causes the dorsal surface of the infant’s feet to touch the underside of a tabletop. The infant flexes the legs at the hips and knees so that contact with the underside of the surface ceases. One of the most useful maneuvers is the traction response. The response is elicited while the infant is lying supine. The examiner grasps each hand of the infant and pulls the infant gently and slowly, allowing the infant to assist, to a sitting position. Marked head lag with little resistance to the examiner’s pulling efforts is present in the newborn period (Fig. 3-7). After a month or so, when the child comes forward, the infant’s head comes forward with neck flexion and then transiently is extended at the neck. Usually by 3 to 5 months of age at the latest, the infant is able to pull against the examiner with arm flexion at the elbow, hold the head and trunk in a straight line, and otherwise actively participate while the examiner pulls the infant to the upright position. No head lag is observed, and little or no forward motion of the head occurs as the child reaches the upright position. Asymmetry signals a neurologic difficulty. A traction response, in which the infant is brought to a sitting position only transiently followed by rapid assumption of a standing position because the legs are extended at the hips and knees, suggests bilateral corticospinal tract difficulty. A valuable measure of vestibular function in the newborn can be obtained by holding the infant in a supine position; the feet are closest to the examiner. The examiner, with the infant lying on the arm, rotates in one direction and then reverses direction. The eyes of the infant deviate in the

FIGURE 3-7. The traction maneuver causes little response in a 2-day-old infant. There is little or no perceptible flexion of the neck or the arms at the elbows.

direction of rotation accompanied by intermittent nystagmus to the opposite side. Extraocular movements may also be assessed during this maneuver. It is essential that the examiner take into account the overall pattern of developmental responses. An abnormality of one reflex does not indicate significant neurologic abnormality. There are other developmental reflexes, but those discussed here appear to be the most often evaluated and the most useful.

Stage 3 Examination of the optic fundi should be carried out with the infant supine on the table, on the caregiver’s lap, or sometimes held over the caregiver’s shoulder with the infant’s head held tightly to the caregiver’s head. Abnormalities of the fundi, including vascular changes, abnormalities of the optic disc, retinal changes, and abnormalities of the lens and media, should be sought (see Chapter 6). Mydriatic agents are rarely needed, although both mydriatic agents and sedation occasionally are necessary. During the first few months of life, the optic discs may be somewhat gray. This normal finding should not be confused with optic atrophy. Changes in the retina include chorioretinitis and retinitis pigmentosa. The discs may be hypoplastic or swollen. The general portion of the examination follows. The presence of hepatosplenomegaly should be determined because many storage diseases, which also affect the brain, may be the cause of organ enlargement. The anal sphincter should be examined for tone and the presence of an anal cutaneous reflex. Congenital anomalies of the genitalia should be sought. The remainder of the general examination, particularly the intrusive aspects, such as evaluating the auditory meati, tympanic membranes, mouth, and teeth, should be done at this time.

Stage 4 If the child crawls, stands, or walks, the child should be placed on the floor. If the child crawls, the floor should be carpeted or a suitable pad should be provided. The child should be encouraged to crawl, walk, or run by rolling a ball across the room or sliding an object such as a block across the floor. Waddling, footdrop, limp, or ataxia may be evident. The manner in which the child stoops and bends to retrieve a ball or block may show premature hand dominance, athetosis, tremor, or weakness of the legs. The child should be observed when arising from the floor to a standing position to determine the presence of Gowers’ maneuver (see Fig. 2-11). The clinician should make every attempt to evaluate the child’s gait to determine the presence of hemiparesis or ataxia (see Chapter 5). Unlike in the examination of adults, the testing of individual muscle groups in infants is usually impracticable. Nevertheless, evaluation of spontaneous movements and use of some specific maneuvers (e.g., traction response, wheelbarrow maneuver, arising from the floor) can provide information about spasticity, weakness, and incoordination. As is the case at all stages of childhood, a comparison of the examination findings must be made with expected norms. Further examination of muscle strength can be accomplished by using the parachute response; the examiner holds

Swaiman / Neurologic Examination after the Newborn Period until 2 Years of Age

45

General Considerations

FIGURE 3-8. Abnormal parachute response. (Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)

the child in the prone position over an examining table and thrusts the patient toward the table surface. A fully developed response when the child is 8 months old consists of arm extension and extension of the wrists, allowing the palms of the hands to make contact with the table. The infant supports body weight with arms and shoulders. Each arm and shoulder can be tested individually if the opposite arm is pulled from the table by the examiner, forcing the child to support most of the body weight on one arm and shoulder. A somewhat older infant may be induced to “wheelbarrow” and move forward on the hands (Fig. 3-8), further demonstrating arm and shoulder strength (see Chapter 2). The child should then be invited to crawl. Formal individual muscle testing can be used in the older child whenever necessary. The sensory examination is difficult and is usually limited to rather gross evaluation of touch and pain; however, it can be accomplished with persistence and patience. Examination of touch, position sense, and vibration sense should be done first. When a tuning fork is placed on the appropriate bony prominence, a look of surprise—usually of bemusement—appears. Evaluation of pain should be done last and only after the examiner demonstrates to the child the method that will be used. The child should be asked to stand in one place with the feet together and then asked to close the eyes to be evaluated for Romberg’s sign. The examiner should observe the child for titubation of the head, nystagmus, and dysmetria while reaching for objects. Finger-to-nose and finger-to-fingerto-nose tests while the eyes are closed are frequently accomplished in children older than 3 years. The heel-toshin test is frequently not possible in children younger than 4 years. Depending on the maturity and abilities of the older infant, many of the maneuvers suggested in Chapter 2 for the older child are applicable. Assessment of the deep tendon reflexes is best carried out with the child in a caregiver’s or assistant’s lap. The biceps response in most infants is difficult to elicit, but the triceps and brachioradialis reflexes are usually detected. Patellar tendon and Achilles tendon responses are normally present and easy to elicit. Toe signs can be evaluated as in older children.

Throughout the examination, the clinician should evaluate the child’s alertness, interest in the surroundings, and ability to learn during the examination. The child’s speech pattern should also be assessed. By 15 months of age, the child should have spoken 2 to 6 words, and by 18 months, 2 to 20 words. Short phrases consisting of two or three words are usually part of the child’s repertoire by 21 to 24 months. By 2 years of age, most children have a vocabulary of up to 50 words. Using specific scales to evaluate intelligence and development levels is of some help but may not be reliable. It is therefore important that the examiner become proficient in informal means of assessing these characteristics. A new site, PediNeuroLogicExam (http://medstat.med.utah.edu/ pedineurologicexam/) provides text and movies demonstrating the changing examination as the child matures and the approach to examining the young patient. REFERENCES Amiel-Tison C. Neurological evaluation of the maturity of newborn infants. Arch Dis Child 1968;43:89. Amiel-Tison C. Update of the Amiel-Tison neurologic assessment for the term neonate or at 40 weeks’ corrected age. Pediatr Neurol 2002;27:196. Bayley N. The Bayley scales of infant development. New York: The Psychological Corporation 1969. Brazelton T, Nugent K. Neonatal Behavior Assessment Scale, 3rd ed. London: MacKeith Press, 1995. Brett EM. Normal development and neurological examination beyond the newborn period. In: Brett EM, ed. Paediatric Neurology, 3rd ed. London: Churchill Livingstone, 1997. Campbell S, Osten E, Kolobe T, et al. Development of the test of infant motor performance. Phys Med Rehabil Clin 1993;4:541. Cupps C, Plescia MG, Houser C. The Landau reaction: A clinical and electromyographic analysis. Dev Med Child Neurol 1976;18:41. Dargassies SS. Neurological development in the full term and premature neonate. New York: Excerpta Medica, 1997. Dekaban A. Examination. In: Dekaban A, ed. Neurology of Early Childhood. Baltimore: Williams & Wilkins, 1970. Dodge PR. Neurologic history and examination. In: Farmer TW, ed. Pediatric Neurology. New York: Paul B. Hoeber, Medical Book Department of Harper & Brothers, 1964. Dubowitz LMS, Dubowitz V, Mercuri E. The neurological assessment of the preterm and full-term infant, 2nd ed. London: MacKeith Press, 1999 Echenne B, Rivier E. Benign paroxysmal tonic upward gaze. Pediatr Neurol 1992;8:154. Fanaroff AA, Martin RJ. Neonatal-perinatal medicine: Diseases of the fetus and infant, 5th ed. St. Louis: CV Mosby, 1992. Frankenburg WK, Sciarillo W, Burgess D. The newly abbreviated and revised Denver Developmental Screening Test. J Pediatr 1981; 99:995. Frankenburg WK, Dodds J, Archer P, et al. The Denver II: A major revision and restandardization of the Denver Developmental Screening test. Pediatrics 1992;89:91. Futagi Y, Tagawa T, Otani K. Primitive reflex profiles in infants: Differences based on categories of neurological abnormality. Brain Dev 1992;14:294. Gesell A, Amatruda CS. Developmental diagnosis. New York: Paul B. Hoeber, Medical Books Department of Harper & Brothers, 1956. Glascoe F, Byrne KE. The usefulness of the Battelle Developmental Inventory Screening Test. Clin Pediatr 1993;32:237. Haataja L, Mercuri E, Regev R, et al. Optimality score for the neurological examination of the infant at 12 and 18 months of age. J Pediatr 1999;135:153. Hogan GR, Milligan JE. The plantar reflex of the newborn. N Engl J Med 1971;285:502. Illingsworth RS. The development of the infant and young child, 9th ed. Baltimore: Williams & Wilkins, 1987.

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Kaye L, Whitfield MF. The eighth month movement assessment of infants as a prediction of cerebral palsy in high-risk infants (Abstract). Dev Med Child Neurol 1988;30 (Suppl 57):11. Knobloch H, Stevens F, Malone A. The Revised Developmental Screening Inventory. Houston, Texas: Gesell Developmental Test Materials, 1980. Leppert MLO, Shank TP, Shapiro BK, et al. The Capute Scales: CAT/CLAMS—tool for the early detection of mental retardation and communicative disorders. Ment Retard Dev Disabl Res Rev 1998; 4:14. Morgan A. Early diagnosis of cerebral palsy using a profile of abnormal motor patterns. Dev Med Child Neurol 1988;30 (Suppl 57):12. Paine RS. Neurologic examination of infants and children. Pediatr Clin North Am 1960;7:41. Paine RS. The evolution of infantile postural reflexes in the presence of chronic brain syndromes. Dev Med Child Neurol 1964;6:345. Paine RS, Brazelton TB, Donovan DE. Evolution of postural reflexes in normal infants and in the presence of chronic brain syndromes. Neurology 1964;14:1036. Parmelee AH Jr. A critical evaluation of the Moro reflex. Pediatrics 1964;33:773. Piper MC, Pinnell LE, Darrah J, et al. Construction and validation of the Alberta Infant Motor Scale (AIMS). Can J Publ Health 1992; 83 (Suppl 2):46. Popich GA, Smith DW. Fontanels: Range of normal size. J Pediatr 1972;80:749. Prechtl H, Beintema D. Neurological examination of the full term infant. London: Heinemann, 1964. Prechtl HF. State of the art of a new functional assessment of the young nervous system. An early predictor of cerebral palsy. Early Hum Dev 1997;24:1. Prechtl HF, Eisenpieler C, Cioni G, et al. An early marker for neurological deficits after perinatal brain lesions. Lancet 1997;349:1361. Reed H. Review of Peabody developmental motor scales and activity cards. In: Mitchell J, ed. The ninth mental measurements yearbook. Lincoln: University of Nebraska Press, 1985:1119. Russell D, Rosenbaum PL, Avery LM, et al. Gross Motor Function Measure (GMFM-66 and GMFM-68). User’s manual. London: MacKeith Press, 2002. Vojta V. Die cerebralen Bewegungstoerungen im Kindesalter, 4te Auflage. Stuttgart: Ferdinand Enke Verlag, 1988. Zafeiriou DI. Plantar grasp reflex in high-risk infants at the first year of life. Pediatr Neurol 2000;22:75. Zafeiriou DI. Primitive reflexes and postural reactions in the neurodevelopmental examination. Pediatr Neurol 2004;31:1. Zafeiriou DI, Tsikoulas IG, Kremenopoulos GM. Prospective follow-up of primitive reflex profiles in high-risk infants: Clues to an early diagnosis of cerebral palsy. Pediatr Neurol 1995;13:148. Zafeiriou DI, Tsikoulas I, Kremenopoulos G, et al. Using postural reactions as a screening test to identify high-risk infants with cerebral palsy: A prospective study. Brain Dev 1998;20:307. Zafeiriou DI, Tsikoulas I, Kremenopoulos G, et al. Moro reflex profile in high-risk infants at the first year of life. Brain Dev 1999a; 21:216. Zafeiriou DI, Tsikoulas I, Kremenopoulos G, et al. Plantar response profile of high-risk infants at the first year of life. J Child Neurol 1999b;14:514.

SUGGESTED READING Dodge HW. Cephalic bruits in children. J Neurosurg 1956;13:527. Egan DF. Developmental examination of infants and preschool children. Clinical developmental medicine, No. 112. Oxford: MacKeith Press, 1990. Fenichel GM. Clinical pediatric neurology: A signs and symptoms approach, 3rd ed. Philadelphia: WB Saunders, 1997. Hack M, Mostow A, Miranda SB. Development of attention in preterm infants. Pediatrics 1976;58:669. Haymaker W. Bing’s local diagnosis in neurological diseases, 15th ed. St. Louis: CV Mosby, 1969. Kamin DF, Hepler RS, Foos RY. Optic nerve drusen. Arch Ophthalmol 1973;89:359. Keegan JJ, Garrett FD. The segmental distribution of the cutaneous nerves in the limbs of man. Anat Rec 1948;102:409. Kestenbaum A. Clinical methods of neuro-ophthalmologic examination. New York: Grune & Stratton, 1961. Knobloch H, Pasamanick B. Predicting intellectual potential in infancy. Am J Dis Child 1963;166:43. Korobkin R. The relationship between head circumference and the development of communicating hydrocephalus following intraventricular hemorrhage. Pediatrics 1975;56:74. Lubchenco LO, Hansman M, Boyd E. Intra-uterine growth in length and head circumference as estimated from live births at gestational ages from 26 to 42 weeks. Pediatrics 1966;37:403. Miller G, Heckmatt JZ, Dubowitz LMS, et al. Use of nerve conduction velocity to determine gestational age in infants at risk and in very-lowbirth-weight infants. J Pediatr 1983;103:109. Moosa A, Dubowitz V. Assessment of gestational age in newborn infants: Nerve conduction velocity versus maturity score. Dev Med Child Neurol 1972;14:290. Nellhaus G. Composite international and interracial graphs. Pediatrics 1968;41:106. Nelson KB, Eng GD. Congenital hypoplasia of depressor anguli oris muscle: Differentiation from congenital facial palsy. J Pediatr 1972;81:16. O’Neill E. Normal head growth and prediction of head size in infantile hydrocephalus. Arch Dis Child 1961;36:241. Paine RS. Neurologic conditions in the neonatal period: Diagnosis and management. Pediatr Clin North Am 1961;8:577. Paine RS, Oppe TE. Neurological examination of children. London: William Heinemann Medical Books, 1966. Peiper A. Cerebral function in infancy and childhood. New York: Consultants Bureau Enterprises, 1963. Prechtl HFR. The neurological examination of the full term newborn infant, 2nd ed. London: William Heinemann Medical Books, 1977. Robinson RJ. Assessment of gestational age by neurologic examination. Arch Dis Child 1966;41:437. Sauer C, Levinsohn MW. Horner’s syndrome in childhood. Neurology 1976;26:216. Scher MS, Barmada MA. Gestational age by electrographic, clinical, and anatomical criteria. Pediatr Neurol 1987;3:256. Sonksen PM. The assessment of vision in the preschool child. Arch Dis Child 1993;68:513. Volpe JJ. The neurological examination: normal and abnormal features. In: Volpe JJ, ed. Neurology of the newborn, 4th ed. Philadelphia: WB Saunders, 2001. Volpe JJ, Pasternak JF, Allan WC. Ventricular dilation preceding rapid head growth following neonatal intracranial hemorrhage. Am J Dis Child 1977;131:1212.

CHAPTER 4

Neurologic Examination of the Term and Preterm Infant Kenneth F. Swaiman

THE TERM INFANT Monitoring of the fetus routinely takes place during the intrapartum period through electronic fetal monitoring [Volpe, 2001a]. Alterations in fetal heart rate patterns prove to be valuable in assessing the fetus. The term infant is assessed immediately after birth. Apgar scores are routinely obtained for term infants at the time of birth. The categories for scoring are described in Table 4-1. Details of the scoring and the total scores often provide useful information concerning the newborn’s status for the examiner and subsequent health-care providers. Use of the Sarnat score is of value in assessing term infants who are encephalopathic at birth (Table 4-2) [Sarnat and Sarnat, 1976]. The neurologic examination of a term infant should be conducted in a quiet and evenly lighted area that is suitably warmed so that the infant remains comfortable after removal of clothing and covering. When the infant is in a stable condition, thorough examination during the first day is customary. If possible, another examination should be performed on the second or third day of life several hours after feeding so that the infant is optimally responsive. This examination is usually performed just before discharge. In emergent situations, the infant should be evaluated after stabilization has been achieved. It is often necessary to examine the infant on several occasions to confirm the presence and monitor the evolution of abnormal findings. Many protocols for the examination of the term infant (gestational age of 38 to 42 weeks) have been written [Ashwal, 1995; Brazelton, 1973; Dubowitz and Dubowitz, 1981; Paine, 1960; Peiper, 1963; Prechtl, 1977]; some investigators have addressed the subject as part of the discussion of neonatal neurology [Fenichel, 2001; Volpe, 2001b]. Estimation of gestational age is discussed in this chapter. It is essential that the examination of the term infant be conducted in a systematic manner. Examination of the sick neonate may be difficult because of the presence of monitoring wires, sensors, catheters, eye shields, and infusion lines; however, systematic order in the sequence and extent of examination must be maintained to provide optimal information. These sick infants often must be examined on multiple occasions for sequential monitoring purposes and to complete portions of the examination not possible at the first encounter.

Observation A proper examination begins with observation. The infant’s clothing should be removed slowly and gently, and the diaper should be opened only for the period in which the covered area is evaluated. The examiner should make no quick

moves. It is a common error to begin handling the infant before an adequate observation period. The examiner should delineate the presence of congenital abnormalities, including midline defects of the cranium, face, palate, and spine. Midline defects are often associated with abnormalities of the neural tube. Abnormalities of the trunk, limbs, and skin are readily observed. Skin pigmentation changes are important because of the shared ectodermal beginnings of the integument and the nervous system. In particular, the presence of abnormalities associated with neurocutaneous syndromes should be ascertained, even though manifestations may not be present in the newborn. Freckling in the axillary areas is highly suggestive of neurofibromatosis. Assessment of most cranial nerves can be accomplished in part through observation. The cranial nerves enabling eye movements and facial movements can be readily monitored. Gross motor abilities of the newborn infant can be partially evaluated by observation. The head is preferentially turned to the right for longer periods than to the left. Term infants have predominant flexor tone, with resultant flexion of the arms at the elbows and of the legs at the knees. Bilateral fisting of the hands, including adduction and infolding of the thumbs (i.e., cortical thumbs), is expected. Limb position and posturing should be roughly symmetric. While supine, the infant manifests spontaneous limb movements that are often asymmetric and have a rapidly jerking quality. Jitteriness or tremulousness of the hands or jaw is sometimes spontaneous. These movements may indicate hyperexcitability of the central nervous system (CNS). Causes of hyperexcitability are discussed later in this chapter. The examiner should mentally quantitate frequency and amplitude of limb movements. Diminished frequency or amplitudes of arm movements may indicate brachial plexus injury; involvement of an arm and ipsilateral leg may indicate hemiparesis. While prone, the infant normally maintains a flexed posture of the arms and legs, with resultant elevation of the pelvis and flexion of the hips and knees. The infant’s respiratory rhythm and chest movement should be observed to indicate adequate contraction of intercostal muscles. Although diaphragmatic breathing is normally accentuated in the newborn, the absence of intercostal muscle participation and a “sucking in” of the sternum may indicate anterior horn cell disease, neuromuscular junction disease, or spinal cord injury. The presence of a pectus excavatum deformity in the newborn should not be regarded as an isolated congenital deformity until neuromuscular conditions in which the diaphragm overpowers the intercostal muscles have been excluded. The level of alertness increases with CNS maturation. At 37 weeks’ gestation, crying is common during wakefulness. At term, the infant remains alert for reasonable periods and

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Clinical Evaluation / 4

TABLE 4-1 Apgar Scoring SIGN

0

1

2

1 MIN

5 MIN

10 MIN

Heart rate Respiratory effort Muscle tone Reflex response* Color Total Apgar rating

Absent Absent Limp No response Blue, pale

Slow, below 100 Slow, irregular Some flexion of extremities Grimace Body pink, extremities blue

Over 100 Good crying Active motion Cough or sneeze Completely pink

— — — — — —

— — — — — —

— — — — — —

*Catheter inserted in nostril. Adapted from Apgar V. A proposal for a new method of evaluation of the newborn infant. Curr Res Anesthesiol 1953;32:360.

TABLE 4-2 Distinguishing Features of the Three Clinical Stages of Postanoxic Encephalopathy in Term Newborns FEATURE

STAGE 1

STAGE 2

STAGE 3

Level of consciousness Neuromuscular control Muscle tone Posture Stretch reflexes Segmental myoclonus Complex reflexes Suck Moro Oculovestibular Tonic neck Autonomic function Pupils Heart rate Bronchial and salivary secretions Gastrointestinal motility Seizures Electroencephalographic findings

Hyperalert

Lethargic or obtunded

Stuporous

Normal Mild distal flexion Overactive Present

Mild hypotonia Strong distal flexion Overactive Present

Flaccid Intermittent decerebration Decreased or absent Absent

Weak Strong; low threshold Normal Slight Generalized sympathetic Mydriasis Tachycardia Sparse

Weak or absent Weak, incomplete, high threshold Overactive Strong Generalized parasympathetic Miosis Bradycardia Profuse

Absent Absent Weak or absent Weak or absent Both systems depressed Variable; often unequal; poor light reflex Variable Variable

Normal or decreased None Normal (awake)

Increased; diarrhea Common; focal or multifocal Early: low-voltage continuous delta and theta; later: periodic pattern (awake); seizures: focal 1-1.5 Hz spike and wave 2-14 days

Variable Uncommon (excluding decerebration) Early: periodic pattern with isopotential phases; later: totally isopotential

Duration

Less than 24 hours

Hours to weeks

From Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress: A clinical and electroencephalographic study. Arch Neurol 1876;33:696.

responds to visual, auditory, and tactile stimulation. Crying is often forceful. Sleep and wake periods are clearly delineated.

Cranial Vault Evaluation Among the most important facets of the examination is the measurement of the occipitofrontal (head) circumference. For the most part, this measurement is a reflection of brain growth. However, undue enlargement may be associated with cephalohematoma, subdural fluid collection, hydrocephalus, hydranencephaly, macrocephaly, or megalencephaly (Chapter 19). Serial measurements provide an index of brain growth in sick neonates. Microcephaly may be associated with many conditions, including intrauterine infection, hereditary abnormalities, maternal substance abuse, and poor nutrition. The shape of the head influences the measure of the circumference. The nearer the head shape approximates a perfect circle, the smaller is the head circumference com-

pared with the circumference of a noncircular head, despite the fact that the area of a plane through the maximal circumference and the brain volumes are the same. A similar relationship exists between a perfect sphere and the volume contained within it. The occipitofrontal circumference should be plotted on a graph standardized for gender, race, and gestational age to determine if the measurement falls within the normal range (i.e., two standard deviations above or below the mean) (Fig. 4-1) [Braun et al., 2004]. On the average, occipitofrontal circumference increases 2 cm during the first month of life, 6 cm during the first 4 months, 7 cm during the first 6 months, and 12 cm during the first 12 months of life [Fujimura and Seryu, 1977]. Infants delivered vaginally may have some deformity of the head because of scalp and subcutaneous edema with resulting caput succedaneum formation; vacuum extraction delivery often results in caput formation. Infants delivered by cesarean section usually have relatively round heads. The caput deformity, usually transient, produces an increased diameter and may confound accurate occipitofrontal circumference measurements. Ceph-

Swaiman / Neurologic Examination of the Term and Preterm Infant

49

FIGURE 4-1. Head circumference charts. (From Nellhaus G. Composite international and interracial graphs. Pediatrics 1968;41:106.)

alohematomas, which are delimited by the periosteum of the individual cranial bones, produce asymmetry of the head and increase the occipitofrontal circumference. Most occur over the parietal bones. A caput succedaneum, unlike a cephalohematoma, extends over two or more cranial bones and is

not restricted to the subperiosteal (subgaleal) space (see Chapter 17). The anterior fontanel, readily palpable at birth, is concave or flat in relation to the surrounding cranium. The fontanel should be assessed with the child held in the sitting position if there is any question of increased pressure. The

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Clinical Evaluation / 4

fontanel may bulge during crying or in the presence of pathologic increased intracranial pressure. Unfortunately, the presence of normal conformation of the fontanel does not guarantee normal pressure; conversely, a bulging anterior fontanel strongly suggests increased intracranial pressure. The anterior fontanel varies in size but usually ranges from 1 to 3 cm in its longest dimension [Popich and Smith, 1972]. The fontanel pulsates synchronously with the infant’s pulse. The posterior fontanel in the neonate usually is open but admits only a fingertip. The presence of an enlarged posterior fontanel suggests the possibility of intrauterine increased intracranial pressure. From time to time, particularly in the presence of wormian bones, auxiliary fontanels may be palpable. A detailed discussion of the infant skull can be found in Chapter 19. The cranial sutures (e.g., sagittal, metopic, lambdoidal, squamosal) are readily palpable in the newborn. Infants delivered vaginally may manifest overriding of the sutures that with normal head growth resolves during the first week of life. The sagittal and lambdoidal sutures are most frequently involved. The sutures are readily separated from one another with palpation. The abrupt steplike contour of the overriding bone at the suture interface distinguishes this condition from that of premature closure of the sutures. When a suture closes prematurely, growth continues along the line of apposition of the bones across the suture. For example, sagittal synostosis causes an increase in the anteroposterior diameter (i.e., scaphocephaly). Increased bitemporal diameter occurs in the presence of coronal synostosis (i.e., brachycephaly). Asymmetric suture closure may lead to grossly asymmetric head shape (i.e., plagiocephaly). Auscultation over the infant skull, particularly the anterior fontanel and neck vessels, usually reveals a venous hum in a number of locations. Rarely, systolic-diastolic bruits, particularly those that are focal and asymmetric, indicate the presence of an arteriovenous malformation [Dodge, 1956]; however, these bruits may be heard in normal infants. Cranial ultrasound, computed tomography (CT), and magnetic resonance imaging are often informative concerning subdural hematomas, cystic lesions, hemorrhages, and enlarged ventricles. Before more advanced methodology, the use of transillumination with a flashlight or more sophisticated light source often indicated the possibility of a subdural effusion, subdural hematoma, or cystic lesions [Dodge and Porter, 1961].

Developmental Reflexes Developmental reflexes are primitive reflexes with complex responses and largely reflect the integrity of the brainstem and spinal cord; the role of higher centers, although of importance, is not fully known. Many of these reflexes are present at birth and undergo modification during the first 6 months of life. Detailed discussion of these reflexes is presented in Chapter 3. Their persistence beyond the expected date of dissipation suggests maturational lag or impaired CNS function. This group includes the Moro, rooting, grasping, tonic neck, stepping, and placing reflexes. Generalized diminution of the manifestation of these reflexes suggests diffuse depression of brain function. Asymmetry indicates central or peripheral nervous system dysfunction that must be further localized.

Motor Function Gentle manipulation of the infant’s limbs allows for assessment of muscle tone and strength. Tone is defined as resistance to passive movement (see Chapter 5). Tone at each large joint should be evaluated while the infant is at rest. Spontaneous movements and resistance of the infant to limb and trunk movement provide a measure of muscle strength. The examiner should recall any clues from the observation period suggesting muscle weakness and corroborating changes in tone and strength at this time. The infant should be supine with the head in the midposition while tone is evaluated so that the tonic neck reflex does not augment tone unilaterally. The newborn infant should be held in the horizontal position while attitude and posture of the limbs and trunk are observed. The infant should then be held in vertical suspension again to determine whether the expected flexor tone of the limbs is present and symmetric. When held in the vertical position the hypotonic and weak infant tends to slide through the examiner’s hands. The infant’s arms are held loosely at the sides, and the expected configuration of the shoulder girdle is poorly maintained. In the horizontal position, the infant appears to be looped over the examiner’s arms. Infants with increased tone manifest an opisthotonic position in conjunction with obligate extension in both vertical and horizontal positions. Although it usually manifests in older infants, scissoring (i.e., crossing of the legs because of excessive, involuntary adductor magnus contraction) may be evident. The most common cause of generalized decreased tone is depression of CNS function, which may result from hypoxic-ischemic encephalopathy, neonatal sepsis, intraventricular hemorrhage, subdural hemorrhage, or metabolic abnormalities (e.g., hypoglycemia). Congenital malformations, including neuronal migration disorders, may be associated with hypotonia. Tone and strength may be decreased in a number of neuromuscular conditions, including spinal muscular atrophy, neonatal myasthenia gravis, congenital myopathies, and neonatal myotonic dystrophy. Muscle tone may be increased in a variety of conditions that cause a neonatal encephalopathy, including many metabolic disorders, hypoxic-ischemic encephalopathy, neonatal stroke, intrauterine infection, congenital malformations, and trauma. While the infant is being handled, stimulation may engender jittery or tremulous movements of the jaw or limbs. Such movements are arrhythmic and do not have a definite phasic composition. The movements usually terminate when stimulation ends, although noises or abrupt changes in light may trigger them. Sometimes, there may be spontaneous tremulousness. Crying enhances the frequency and range of the movements. Such tremulousness may indicate metabolic abnormalities (e.g., electrolyte imbalance), bleeding, congenital CNS defects (structural or functional), infections, or drug withdrawal syndromes. Exaggerated and persistent tremulousness may indicate relative irritability of the cerebral cortex and potential risk for subsequent, significant neurologic dysfunction including seizures. Deep tendon reflexes are elicited using a reflex hammer and are often brisk in the newborn, although they may be normally absent [Critchley, 1968]. They may be inordinately enhanced by upper motor neuron abnormalities and are further facilitated by crying. CNS depression may be asso-

Swaiman / Neurologic Examination of the Term and Preterm Infant

ciated with reduced deep tendon reflexes. The examiner should confirm that the deep tendon reflexes are symmetric, because asymmetry may indicate central or peripheral nervous system impairment. If previous examination has suggested the possibility of hemiparesis, deep tendon reflexes should be carefully evaluated for asymmetry; they are usually increased on the affected side. Deep tendon reflex asymmetry in the arms may be associated with upper motor neuron abnormality, but asymmetrically absent deep tendon reflexes suggest peripheral involvement, possibly the result of brachial plexus injury. Nerve conduction studies in newborns may provide an index of neurologic maturity [Dubowitz et al., 1968]. Controversy remains over the significance of the plantar response in the newborn period in term infants. Although some investigators have reported that the Babinski sign is flexor and symmetric in the newborn period [Hogan and Milligan, 1971], this is more likely caused by obtaining a plantar grasp than a Babinski response if only the sole of the foot is used to elicit the response. The plantar response is extensor for at least the first month of life and usually through the first year of life. However, at all times, the response should always be bilaterally symmetric. Persistence of extensor toesign responses beyond infancy suggests corticospinal tract impairment and may be associated with alterations in tone and other deep tendon reflex abnormalities. Ankle clonus is frequently elicited in the newborn; rarely are there more than eight beats in normal infants. The clonus is enhanced during crying and may be facilitated during hyperexcitable states, such as those associated with metabolic abnormalities, infection, and subarachnoid hemorrhage. Sustained ankle clonus has the same significance in term newborns as in later life and suggests dysfunction of the corticospinal tracts. A reflex akin to the plantar response has been described for the hand in term and preterm newborns. The examiner strokes the ulnar aspect of the infant’s palm with the thumb, beginning distally and stroking proximally from the small finger to the hypothenar eminence. The normal response is

51

gradual extension of the fingers, beginning with the small finger and continuing to the middle fingers [Modanlou, 1988]. Lack of response or gross alteration of response may be observed in the presence of corticospinal tract dysfunction.

Cranial Nerve Examination A more detailed discussion of the cranial nerve examination is found in Chapter 2. Cranial nerve I, the olfactory nerve, is infrequently tested but may be evaluated by the use of pleasant but definitive aromatic substances, such as cinnamon and cloves [Sarnat, 1978]. The infant usually manifests an arrest of activity, arousal, and sucking activity when exposed to these aromas. Virtually all neonates born after more than 32 weeks’ gestation respond [Sarnat, 1978]. Evaluation of cranial nerves II, III, IV, and VI involves assessment of the eyes. The pupils should be symmetric, and there should be an equal bilateral response to light. A bright light causes the infant to blink or hold the lids closed. The presence of ptosis or increased height of the palpebral fissure should be evaluated. The examiner should ascertain the presence of heterochromia, although it may not be evident until later. Examination of the optic fundi may be difficult but is necessary. Numerous changes, including chorioretinitis (i.e., salt-and-pepper pigmentary changes), may be observed. Hemorrhages are commonly detected after vaginal delivery, even in the absence of traumatic delivery. The optic nerve may be hypoplastic, as manifested by a small, pearl-colored optic disc. The color of the optic disc in the newborn infant is grayish white. Retinal hemorrhages may be found in a large percentage of otherwise normal infants who have no history of abnormal delivery and who later prove to be neurologically normal [Besio et al., 1979]. Further discussion of funduscopic characteristics is presented in Chapter 6. The newborn infant turns toward a light of moderate intensity and fixes on a bright object or the examiner’s face. Most often, the newborn’s eyes are symmetrically open or FIGURE 4-2. Horner’s syndrome (left eye). (Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)

52

Clinical Evaluation / 4

closed. If one eye is open and the other closed, there should be a shifting from one side to the other. Width of palpebral fissures should be equal; if not, the presence of ptosis should suggest an abnormality of cranial nerve III function, sympathetic innervation dysfunction, neuromuscular junction difficulty, weakness of the levator muscle of the lid, or abnormality of the lid connective tissue. Among the conditions to be considered are congenital myasthenia gravis, myotonic dystrophy, Horner’s syndrome (Fig. 4-2), Möbius’ syndrome, congenital myopathies, and Duane’s syndrome. Occasionally, central or peripheral seventh nerve paresis may result in asymmetry of the palpebral fissure. Extraocular movements should be monitored while a child is lying quietly. Slight lapses of conjugate gaze are common in the newborn period. Newborn visual acuity is difficult to assess, but black and white–patterned objects can be used. The examiner’s face is often the best “target.” The intended object of focus is moved slowly in the infant’s field of vision, less than a foot from the infant’s eyes. The infant slowly follows with eye movement, particularly in lateral directions. Prolonged gaze may occur in the newborn period [Brazelton et al., 1976]. Opticokinetic nystagmus may be elicited by using a striped, rotating drum or striped cloth strip, which is slowly pulled across the infant’s visual field in the vertical and horizontal directions. The response is the same as in older children (see Chapter 2). Although small-excursion, lateral-gaze nystagmus may be present in the newborn, the grosser to-and-fro pattern of congenital nystagmus, which is oscillatory in nature, is usually unmistakable. Although unusual, nystagmus associated with mild esotropia or exotropia may be evident in the newborn. Wild, jerky nystagmus of congenital opsoclonus is a startling and readily discernible finding suggesting midbrain involvement. Doll’s-eye movement is elicited by the examiner gently rotating the infant’s head from one side to the other when the infant is asleep. The eyes move conjugately in the direction opposite to the rotation of the head. Movement of the head in the vertical position (upward and downward) causes similar movements in the vertical plane. Failure of the eyes to move in the expected manner or direction indicates abnormalities of the cranial nerves or brainstem nuclei. Failure of abduction is associated with cranial nerve VI impairment or lateral rectus muscle impairment. Failure of normal movement in the medial direction implicates medial rectus muscle or cranial nerve III impairment. To gain further information, the infant may be held supine on the examiner’s arm as the examiner rotates and watches the infant’s eyes. This oculovestibular maneuver causes movement so that there is lateral conjugate deviation in the direction of the rotation. When the rotational movement is terminated abruptly, the eye movements reverse. It is possible to assess the integrity of cranial nerves III and VI with this maneuver. Cranial nerve VII involvement may be the result of the position of the infant in the maternal pelvis and delivery by pressure incurred during forceps delivery or by agenesis of the motor nucleus of cranial nerve VII. Facial movements are readily observed during crying; an asymmetry of mouth movement may indicate cranial nerve VII involvement. During crying, the angle of the mouth is depressed on the normal side. The syndrome referred to as asymmetric crying facies may manifest this way [Nelson and Eng, 1972]. This

syndrome results from weakness of the lower lip caused by hypoplasia of the depressor muscle of the mouth angle. This phenomenon is a congenital abnormality and does not signal cranial nerve VII involvement. This condition also may be associated with somatic atrophy, vertebral and rib abnormalities, renal dysgenesis, and most importantly, cardiac defects (i.e., atrial or ventricular septal defect) [Pape and Pickering, 1972]. Hearing in term infants has been evaluated by sophisticated testing techniques that indicate some ability to localize and discriminate. However, meaningful hearing evaluation during routine neurologic examination is difficult to accomplish because of simultaneous visual cues and variable responses. The use of brainstem auditory-evoked potential testing has greatly improved the ability to evaluate hearing response during the neonatal period. Vestibular function can be monitored by the oculovestibular maneuver described previously. Assessment of cranial nerves IX, X, and XII may be facilitated by evaluating the infant’s cry; however, impairment of crying may occur because of central rather than peripheral abnormalities. An infant with generally depressed CNS function often cries infrequently, and the cry is weak and may be high pitched. The volume and tone of the cry should be assessed. An irritable child with a hyperexcitable nervous system may have a high-pitched shriek, whereas unusual cries such as that associated with the cri du chat syndrome are similar to a cat’s cry. Observation of the infant during crying is a valuable adjunct to certain portions of the examination. During the lusty segments of crying, the infant’s tongue and palate may be readily inspected. Asymmetry or loss of tongue bulk may indicate abnormalities of cranial nerve XII or its nucleus. The presence of fasciculations may indicate spinal muscular atrophy. More complex forms of the Möbius syndrome may also involve the tongue. Tongue fasciculations must be identified when the child is quiet and not crying. The fasciculations occur along the lateral margins and underside of the tongue. Cranial nerves V, VII, IX, X, and XII are involved in sucking and swallowing. Swallowing dysfunction requires close scrutiny to determine which cranial nerve or nerves are involved. The gag reflex is present in term newborns and requires normal function of cranial nerves IX and X. Tests for pain and sensation are imprecise at this age, and the gross response of infants to stroking and pinprick with withdrawal, crying, and change in sucking rates may be the only information possible. More sophisticated testing can be devised during which heart and respiratory rates are monitored. If necessary, in the presence of olfactory, gustatory, visual, tactile, or auditory stimuli, sophisticated monitoring and scoring of body activity may be performed [Brazelton, 1976]. All such sensory stimuli produce habituation in the newborn [Lipsitt, 1977]. Lack of habituation or failure to respond to these stimuli is abnormal; however, the abnormality may be specific for the sensory mechanism or merely may be a reflection of generalized CNS depression.

THE PRETERM INFANT The neurologic evaluation of the preterm infant is a major challenge to the clinician. Much of the information in this

Swaiman / Neurologic Examination of the Term and Preterm Infant

chapter concerning the term infant is applicable to the preterm infant. The fragility of the patient, the changing developmental norms coupled with the uncertainty of the length of gestation, and the frequent need for life-support systems and associated paraphernalia, which interfere with the examination and the spontaneity of movement, all complicate the process. Modern imaging techniques permit correlation of clinical examination and image alterations never before available. The use of cranial ultrasound examination and, when feasible, CT has permitted the timely diagnosis of intraventricular and hemispheral hemorrhage and early hydrocephalus in preterm infants. The information provided is greater in quality and quantity than has been available previously. The designation of an infant as preterm is related primarily to length of gestation. Term gestation is 38 to 42 weeks from conception, and preterm therefore is any period less than 38 weeks, although most clinicians would not consider a baby preterm or premature between 36 and 38 weeks. Expected developmental milestones are based on gestation [Mercuri, 2003]. The clinician must estimate gestational age to facilitate interpretation of the observations and findings made during the neurologic examination. An infant whose birth weight is low compared with length of gestation (e.g., intrauterine growth retardation, small for gestational age) exhibits different growth patterns or neurologic findings than the infant whose weight is appropriate for gestational age. In a parallel fashion, preterm infants born of diabetic mothers may weigh more than 2500 g, but these infants manifest findings consistent with their preterm status during the neurologic evaluation. The designation of extremely low birth weight infants has been assigned to those infants who weigh less than 1000 g at birth [Doyle et al., 2004; Kilbride, 2004]. Most of these infants are at 28 weeks or less gestation. The very low birth weight infants are those who weigh less than 1500 g at birth. In the absence of intrauterine growth retardation, most infants of this birth weight are born after 31 to 32 weeks’ gestation [Lubchenco et al., 1966]. The neurologic examination of these infants is reviewed in this portion of the chapter; the expected results of the examination should be based on the gestational age as determined from the various tables and illustrations.

General Examination It is not possible with any great assurance to estimate gestational age from the date of the first day of the mother’s last menstrual period [Lubchenco, 1970]. Nevertheless, a number of physical findings evident during the examination can prove helpful in this evaluation [Farr et al., 1966a, 1966b; Lubchenco, 1970; Usher and McLean, 1969]. Among the most valuable findings are skin texture and color, quantity of breast tissue and ear cartilage, and the stage of development of the external genitalia. No single characteristic can determine the gestational age. The estimate should be based on the average of expected findings (Table 4-3). The combination of findings based on physical characteristics and neuro-

Box 4-1 SELECTED GESTATIONAL AGE–DEPENDENT ELECTROENCEPHALOGRAPHIC PATTERNS BASED ON CONVOLUTIONAL MEASUREMENTS Less than 28 Weeks Prominent occipital theta/alpha Prominent vertex-central delta brush Rhythmic occipital delta (<6 seconds)* Prominent bitemporal attenuation Diffuse theta/delta slowing Interburst intervals (<40 seconds) Brief continuous portions (<1 minute) 28 to 29 Weeks Prominent occipital delta (<10 seconds) Appearance of temporal delta brush Occasional temporal attenuation Diffuse theta/delta slowing Interburst intervals (<40 seconds) Continuous portions (>1 minute) 30 to 31 Weeks Prominent temporal theta bursts Prominent temporal delta brushes Prominent occipital delta brushes (>10 seconds) Interburst intervals (<30 seconds) Continuous portions (several minutes) *Parentheses contain observed duration of electroencephographic pattern. Adapted from Scher MS, Barmada MA. Estimation of gestational age by electrographic, clinical, and anatomic criteria. Pediatr Neurol 1987;3:256.

TABLE 4-3 External Characteristics Useful for Estimation of Gestational Age EXTERNAL CHARACTERISTICS

28 Weeks

Ear cartilage

Pinna soft, remains folded

Breast tissue Male external genitalia

None Testes undescended; smooth scrotum

Female external genitalia

Prominent clitoris; small, widely separated labia Smooth

Plantar surface

GESTATIONAL AGE 32 Weeks Pinna slightly harder but remains folded None Testes in inguinal canal; few scrotal rugae Prominent clitoris; larger separated labia One to two anterior creases

From Volpe JJ. Neurology of the newborn, 4th ed. Philadelphia: WB Saunders, 2001.

53

36 Weeks

40 Weeks

Pinna harder, springs back 1- to 2-mm nodule Testes high in scrotum; more scrotal rugae Clitoris less prominent; labia majora cover labia minora Two to three anterior creases

Pinna firm, stands erect from head 6- to 7-mm nodule Testes descended; pendulous scrotum covered with rugae Clitoris covered by labia majora Creases cover sole

54

Clinical Evaluation / 4 FIGURE 4-3. A, Scoring system for neurologic criteria.

A SCORE

Neurologic sign 0

1

2

3

4

5

Posture

Square window 90°

90°

45°

30°

0°

90°

75°

45°

20°

0°

110°

90°

Ankle dorsiflexion

Arm recoil 180°

90–180°

<90°

180°

90–180°

<90°

180°

160°

130°

Leg recoil

Popliteal angle <90°

Heel to ear

Scarf sign

Head lag

Ventral suspension

logic examination has proved of value in the estimation of gestational age [Dubowitz et al., 1970]. This method is discussed with the specifics of the neurologic examination.

Electrophysiologic Assessment Motor nerve conduction velocity studies of the ulnar and posterior tibial nerves may corroborate the clinical estimation of gestational age because nerve velocity becomes more rapid with maturation. Such studies also differentiate infants of short gestation from those with intrauterine growth retardation, including those at high risk and with very low birth weight [Dubowitz et al., 1968; Cruz-Martinez et al., 1983; Miller et al., 1983; Moosa and Dubowitz, 1972].

Electroencephalographic (EEG) patterns also appear to be a function of maturity. Comparison of EEG, anatomic, and clinical criteria provides one means of estimating gestational age [Scher and Barmada, 1987]. EEG correlates are listed in Box 4-1 [Scher and Barmada, 1987] and are further discussed in Chapter 12.

Neurologic Examination Although estimation of gestational age should be made as soon after birth as possible, the neurologic examination may be postponed for 1 to 2 days, depending on the condition of the infant and the need for physiologic support. The examination should be performed while the infant is awake and

Swaiman / Neurologic Examination of the Term and Preterm Infant

B SOME NOTES ON TECHNIQUES OF ASSESSMENT OF NEUROLOGIC CRITERIA POSTURE: Observed with infant quiet and in supine position. Score 0: Arms and legs extended; 1: Beginning of flexion of hips and knees, arms extended; 2: Stronger flexion of legs, arms extended, 3: Arms slightly flexed, legs flexed and abducted; 4: Full flexion of arms and legs.

55

FIGURE 4-3. B, Description of techniques used to assess neurologic signs. (A, From Dubowitz L, Dubowitz V, Goldberg C. Clinical assessment of gestational age in the newborn infant. J Pediatr 1970;77:1.)

SQUARE WINDOW: The hand is flexed on the forearm between the thumb and index finger of the examiner. Enough pressure is applied to get as full a flexion as possible, and the angle between the hypothenar eminence and the ventral aspect of the forearm is measured and graded according to diagram. (Care is taken not to rotate the infant’s wrist while doing this maneuver.) ANKLE DORSIFLEXION: The foot is dorsiflexed onto the anterior aspect of the leg, with the examiner’s thumb on the sole of the foot and other fingers behind the leg. Enough pressure is applied to get as full flexion as possible, and the angle between the dorsum of the foot and the anterior aspect of the leg is measured. ARM RECOIL: With the infant in the supine position the forearms are first flexed for 5 seconds, then fully extended by pulling on the hands, and the released. The sign is fully positive if the arms return briskly to full flexion (Score 2). If the arms return to incomplete flexion or the response is sluggish it is graded as Score 1. If they remain extended or are only followed by random movements the score is 0. LEG RECOIL: With the infant supine, the hips and knees are fully flexed for 5 seconds, then extended by traction on the feet, and released. A maximal response is one of full flexion of the hips and knees (Score 2). A partial flexion scores 1, and minimal or no movement scores 0. POPLITEAL ANGLE: With the infant supine and his pelvis flat on the examining couch, the thigh is held in the knee-chest position by the examiner’s left index finger and thumb supporting the knee. The leg is then extended by gentle pressure from the examiner’s right index finger behind the ankle and the popliteal angle is measured. HEEL TO EAR MANEUVER: With the infant supine, draw the infant’s foot as near to the head as it will go without forcing it. Observe the distance between the foot and the head as well as the degree of extension at the knee. Grade according to diagram. Note that the knee is left free and may draw down alongside the abdomen. SCARF SIGN: With the infant supine, take the infant’s hand and try to put it around the neck and as far posteriorly as possible around the opposite shoulder. Assist this maneuver by lifting the elbow across the body. See how far the elbow will go across and grade according to illustrations. Score 0: Elbow reaches opposite axillary line; 1: Elbow between midline and opposite axillary line; 2: Elbow reaches midline; 3: Elbow will not reach midline. HEAD LAG: With the infant lying supine, grasp the hands (or the arms if very small infant) and pull him slowly towards the sitting position. Observe the position of the head in relation to the trunk and grade accordingly. In a small infant the head may initially be supported by one hand. Score 0: Complete lag; 1: Partial head control; 2: Able to maintain head in line with body; 3: Brings head anterior to body. VENTRAL SUSPENSION: The infant is suspended in the prone position, with examiner’s hand under the infant’s chest (one hand in a small infant, two in a large infant). Observe the degree of extension of the back and the amount of flexion of the arms and legs. Also note the relation of the head to the trunk. Grade according to diagrams. If score differs on the two sides, take the mean.

approximately 1 hour before the next scheduled feeding. The child may become fussy shortly before a feeding and often becomes somnolent after a feeding, resulting in decreased muscle tone.

Environmental Interaction Periods of apparent wakefulness are rare before 28 weeks. Arousal by external stimulation is often necessary for the 28-week preterm infant [Illingworth, 1972]. Nevertheless, small preterm infants respond to environmental factors, such as temperature, light, and feeding. Periods of wakefulness

and somnolence are relatively brief and change swiftly in the preterm infant. The waking periods of preterm infants of 25 to 30 weeks’ gestation are short compared with those of term infants [Fenichel, 1978, 1985]. A readily recognizable level of alertness during wakeful stages occurs even in infants of 31 weeks’ gestation [Hack et al., 1976]. In infants of 32 weeks’ gestation, external stimulation is usually unnecessary. Responsiveness increases with CNS maturation; suck rate increases, and sucking persists for longer periods. In those born after 37 weeks’ gestation, crying is commonly present during wakefulness. By 40 weeks’ gestational age, the preterm infant continues to be alert for reasonable periods

56

Clinical Evaluation / 4 44

Formal Scale of Gestational Assessment

42

Using a systematic evaluation of body and neurologic characteristics, Dubowitz and colleagues [1970] were able to achieve a high correlation with gestational age, making this method of assessment most valuable. The evaluation was based on 10 neurologic and 11 external (e.g., skin texture, breast size, ear form) characteristics. The external evaluation was adapted from Farr and colleagues [1966a, 1966b]. The scoring scheme is detailed in Figures 4-3 and 4-4 and in Table 4-4 [Dubowitz et al., 1970].

y = 0.2642x + 24.595

Gestational age (wk)

40 38 36 34 32

Deep Tendon Reflex Assessment 30 28 26 10

0

20

30 40 Total score

50

60

70

FIGURE 4-4. Graph for reading gestational age from total score obtained from scores derived from Figure 4-3. (Redrawn from Dubowitz LMS, Dubowitz V, Goldberg C. J Pediatr 1970;77:1.)

and responds to visual, auditory, and tactile stimulation. Sleep and wakeful periods are easily identified. Sleep is discussed in detail in Chapter 56.

The assessment of deep tendon reflexes in preterm infants can be of value in the presence of many conditions, such as spinal cord anomalies, peripheral nerve injuries, congenital myopathies, and infantile spinal muscular atrophy. A standard method of deep tendon reflex examination for preterm infants has been proposed [Kuban et al., 1986]. The methods of elicitation are described in Table 4-5 and depicted in Figure 4-5 [Kuban et al., 1986]. Deep tendon reflexes differ in healthy and ill preterm infants of 33 weeks’ gestation; the elicitation rate and intensity of deep tendon reflexes vary with maturity (i.e., less than and greater than 33 weeks’ gestation) [Kuban et al., 1986]. In a study of preterm infants of more than 27 weeks’ postconceptional age, the pectoralis major reflex was elicited in all, regardless of maturity. In 98% of the infants of more than 33 weeks’ gestation, the

B

A

C

D

E

FIGURE 4-5. Elicitation of deep tendon reflexes in a preterm infant of 32 weeks’ gestation. A and B, Pectoralis major. C, Brachioradialis. D, Thigh adductors and crossed adductors. E, Achilles. (From Kuban KCK, Skouteli HN, Urion DK, et al. Deep tendon reflexes in premature infants. Pediatr Neurol 1986;2:266.)

Swaiman / Neurologic Examination of the Term and Preterm Infant

57

TABLE 4-4 Scoring System for External Criteria SCORE* EXTERNAL ASSESSMENT

0

1

2

Edema

No obvious edema of hands and feet; pitting over tibia Thin and smooth

No edema

Skin texture

Obvious edema of hands and feet; pitting over tibia Very thin, gelatinous

Skin color

Dark red

Uniformly pink

Pale pink; variable over body

Skin opacity (trunk)

Veins and tributaries seen

A few large vessels clearly seen over abdomen

Lanugo (over back)

Numerous veins and venules clearly seen, especially over abdomen No lanugo

Plantar creases

No skin creases

Abundant, long, and thick over whole back Faint red marks over anterior half of sole

Hair thinning Small amount of especially over lanugo and bald lower back areas Definite red marks over Indentations over more than anterior more than anterior half; indentations third over less than anterior third

Nipple formation

Nipple barely visible; no areola

Areola stippled, edge not raised, diameter <0.75 cm

Areola stippled, edge raised, diameter >0.75 cm

Breast size

No breast tissue palpable

Ear form

Pinna flat and shapeless, little or no incurving of edge Pinna soft, easily folded, no recoil

Nipple well defined; areola smooth and flat, diameter <0.75 cm Breast tissue on one or both sides <0.5 cm Incurving of part of edge of pinna

Breast tissue both sides; one or both 0.5-1.0 cm Partial incurving whole of upper pinna

Breast tissue both sides; one or both >1 cm Well-defined incurving whole of upper pinna

Pinna soft, easily folded, slow recoil

Cartilage to edge of pinna but soft in places, ready recoil At least one testis right down Labia majora completely cover labia minora

Pinna firm, cartilage to edge, instant recoil

Ear firmness Male genitals Female genitals (with hips half abducted)

Neither testis in scrotum Labia majora widely separated; labia minora protruding

At least one testis high in scrotum Labia majora almost cover labia minora

Smooth; medium thickness; rash or superficial peeling

3

4

Slight thickening; superficial cracking and peeling especially of hands and feet Pale; only pink over ears, lips, palms, or soles A few large vessels seen indistinctly over abdomen

Thick and parchment-like; superficial or deep cracking

No blood vessels seen

At least half of back devoid of lanugo Definite deep indentations over more than anterior third

*If score differs on two sides, take the mean. From Dubowitz LMS, Dubowitz V, Goldberg C. Clinical assessment of gestational age in the newborn infant. J Pediatr 1970;77:1.

Achilles, patellar, biceps, thigh adductor, and brachioradialis reflexes were obtained. Infants of less than 33 weeks’ gestation had decreased elicitation rates for patellar and biceps reflexes and had overall decreases in reflex intensity compared with their older counterparts. For all infants in the study, the following tendon reflexes were found to be present (in decreasing order): finger flexors, jaw, crossed adductors, and triceps. Contrary to conventional wisdom, head position had no effect on the reflexes [Kuban et al., 1986].

Body Attitude During maturation, preterm infants adopt typical postures that correspond to gestational age. These postures have been

charted and are very useful for evaluation of gestational age [Dubowitz et al., 1970; Dubowitz and Dubowitz, 1981].

Muscle Tone Assessment of muscle tone in the preterm infant is requisite to completion of a satisfactory neurologic evaluation [AmielTison, 1968, 2002; Saint-Anne Dargassies, 1966]. The muscle tone of small-for-gestational-age infants differs from that of infants with only a short gestation. At 26 to 28 weeks’ gestation, the infant is extremely hypotonic. When held by the examiner in vertical suspension, the infant does not extend the head, limbs, or trunk (Fig. 4-6). The change from the hypotonia of the preterm

58

Clinical Evaluation / 4

TABLE 4-5 Deep Tendon Reflexes Evaluated in Preterm Infants DEEP TENDON REFLEXES

INNERVATION

TECHNIQUE OF ELICITATION

Jaw

Cranial nerves V and VII

Pectoralis major

Brachioradialis

Predominantly C7 and C8, lateral pectoral nerve C5 and C6, musculocutaneous nerve C5, C6, radial nerve

Triceps

C7, C8, radial nerve

Finger flexors

C8, T1, median nerve

Patellar

L3, L4, femoral nerve

Thigh adductors and crossed adductors

L3, L4, obturator nerve

Achilles

L5, S1, tibial nerve

The point of the finger is placed over the chin so that the jaw is slightly open. The hammer strikes the index finger tip. The examiner’s index finger is firmly placed in a caudad (or cephalad) direction onto the axilla over the pectoralis major. The examiner’s index finger is placed onto the biceps tendon in the superomedial aspect of the antecubital fossa with the arm flexed at the elbow. The tendon of the muscle is struck directly over the distal third of the radius while slowly flexing and extending the arm. The examiner’s finger is placed over the triceps tendon at its distal aspect proximal to the elbow. The triceps tendon also may be struck directly while flexing and extending the arm. The examiner’s finger is placed horizontally across the base of the infant’s fingers to elicit a partial grasp. The examiner’s finger is then struck. The reflex hammer strikes examiner’s finger placed across the patellar tendon, or the latter is struck directly while flexing and extending the leg at the knee. The examiner’s index finger to be struck is placed diagonally across the medial aspect at the knee (thigh adductor) with the little finger placed on the contralateral leg to maintain a 45- to 60-degree angle (crossed adductor). The examiner’s finger to be struck is placed horizontally across the plantar aspect of the infant’s foot, which is partially dorsiflexed.

Biceps

From Kuban KCK, Skouteli HN, Urion DK, et al. Deep tendon reflexes in premature infants. Pediatr Neurol 1986;2:266.

FIGURE 4-6. Preterm baby, 26 to 28 weeks’ gestation. Notice the hypotonic posture with lack of extension of the spine and head and lack of flexion of the extremities.

infant to the flexion posture of the term infant manifests first in the legs and then in the arms and head. At 34 weeks’ gestation, the infant lies in the frogleg position while supine; the legs are flexed at the hip and knee, but the arms remain extended and relatively hypotonic (Fig. 4-7). Measurement of various limb angles offers some objective evidence for the degree of tone. The popliteal angle, measured by maximum extension of the leg at the knee with the hip fully flexed, decreases from 180 degrees at 28 weeks’ gestation (Fig. 4-8; see also Fig. 4-14) to less than 90 degrees at term [Kato et al., 2005]. Similarly, the adductor and dorsiflexion angle of the foot diminishes to almost 0 degrees at term (Fig. 4-9). During the traction maneuver, the head lags considerably, with little resistance until after 30 weeks’ gestation. The head extensors develop gradually, followed by the flexors. By 38 weeks, the head follows the trunk, is maintained

FIGURE 4-7. Two weeks after birth, the frogleg position of a preterm infant of 34 weeks’ gestation.

briefly, and then falls forward when the infant is pulled from a supine to a sitting position during the traction maneuver. In small preterm infants, the scarf sign, which is elicited by folding the arm across the chest toward the opposite shoulder, is present if the elbow reaches the opposite shoulder (Fig. 4-10). In term infants, the elbow cannot be brought beyond the midline. The extreme hypotonia of preterm infants permits the legs to be flexed at the hip so that the heel can be passively brought to the side of the face (i.e., heel-to-ear maneuver). Understandably, this positioning is restricted in the older infant because of increasing tone (Fig. 4-11).

Swaiman / Neurologic Examination of the Term and Preterm Infant

59

FIGURE 4-8. The popliteal angle is 180 degrees in a preterm infant of 28 weeks’ gestation.

FIGURE 4-10. An infant of 32 weeks’ gestation demonstrates the scarf sign, with the elbow approximating the opposite shoulder.

FIGURE 4-9. The adductor angle of the thighs is almost 180 degrees in a preterm infant of 30 weeks’ gestation.

Tone may also be monitored while postural and righting reflexes are assessed. During the stepping maneuver, the 28-week preterm infant will not support weight (Fig. 4-12). However, over the next few weeks, there is gradual support of weight, and by 34 weeks, a good supporting response is present. Tremors and even clonic movements manifest in the small preterm infant but are not normally discernible after 32 weeks’ gestation. Stretching movements of the limbs are common in small preterm infants while they are awake but somewhat less common during sleep. These movements may spread to include the trunk and head. Serial measurements may indicate the likelihood of developing spasticity. A “tight” (<120 degrees) angle was found at 4 months in infants with birth weights ranging from less than 999 g up to 1999 g. Infants who had birth weights ranging from 2000 to more than 2500 g had only an 8% incidence of tight popliteal angle (Table 4-6).

Cranial Nerves Some features of the preterm infant examination are different from features of the older infant’s examination. Head

FIGURE 4-11. Diminished tone in the very small preterm infant of 30 weeks’ gestation allows the heels to reach the head easily. The pelvis should be flat on the table.

position is unpredictable in the small preterm infant, but by 35 weeks’ gestation, there is a preference for the head to be held to the right. By 39 weeks’ gestation, the head is held to the right approximately 80% of the time while the infant is at rest [Gardner et al., 1977]. The small preterm infant may cry in response to provocation [Fenichel, 1978], but crying often occurs when the infant is unprovoked. By 36 to 37 weeks’ gestation, the cry is more vigorous, frequent, and persistent, and it is easily elicited by noxious stimuli.

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Clinical Evaluation / 4

TABLE 4-7 Neurologic Maturation FUNCTION

26 WEEKS

30 WEEKS

34 WEEKS

38 WEEKS

Resting posture

Flexion of arms Flexion or extension of legs Unable to maintain Absent Absent Absent

Flexion of arms Flexion or extension of legs Maintain briefly Long latency Long latency Variable

Flexion of all limbs

Flexion of all limbs

Remain awake Present Weak Present

Remain awake Present Vigorous Present

No response No response

Head lag

Mild head lag Complete

Arousal Rooting Sucking Pupillary reflex Traction Moro

No response Extension; no Adduction adduction variable Withdrawal Absent Withdrawal Crossed Crossed only extension extension FIGURE 4-12. Preterm infant of 28 weeks’ gestation supports his weight briefly. Toe-walking may be evident.

TABLE 4-6 The Rates of Infants with a Tight Popliteal Angle BIRTH WEIGHT ≤999 g 1000-1499 g 1500-1999 g 2000-2499 g ≥2500 g

1 Month

CORRECTED AGE 4 Months 8 Months

12 Months

11/19 (58%) 3/32 (48%) 11/36 (31%) 11/37 (30%) 21/52 (40%)

8/20 (40%) 10/36 (28%) 20/46 (43%) 2/40 (8%) 5/60 (8%)

0/20 0/37 0/46 0/40 0/61

0/20 2/37 (5%) 0/46 1/40 (3%) 0/61

From Kato T, Okumura A, Hayakawa F, et al. Popliteal angle of low birth weight infants during the first year of life. Pediatr Neurol 2004;30:244.

The pupillary light reflex is not fully mature before 29 to 30 weeks’ gestation, and in the resting state, the infant’s pupils are usually meiotic. The reflex becomes progressively evident and is mature by 32 weeks. Although they may forcefully close their eyes when a bright light is directed toward them, infants of 28 weeks’ gestation or less do not turn in the direction of the light. By using a large target (e.g., large, red ball; hoop; handful of yarn), visual fixation and even rudimentary scanning and tracking may be evident in infants of 31 to 32 weeks’ gestation [Hack et al., 1976]. Associated with this response, there may be widening of the palpebral fissure. By 36 to 38 weeks’ gestation, the infant rotates the head toward a light and closes the eyes forcefully when a strong light stimulus is presented. The doll’s-eye reflex is elicited in the 28- to 32-week preterm infant who has no compromise of consciousness. The ease of eliciting a response is enhanced because infants do not visually fixate. By 36 weeks’ gestation, this response is not elicited in the normal infant.

Developmental Reflexes Observation and description of the major reflex changes peculiar to the preterm infant have been undertaken by many

From Fenichel GM. The neurological consultation. In: Fenichel GM, ed. Neonatal neurology, 4th ed. New York: WB Saunders, 2001.

investigators (Table 4-7) [Amiel-Tison, 1968, 2002; Fenichel, 1985; Lubchenco, 1970; Saint-Anne Dargassies, 1966]. The rooting and sucking reflexes in small preterm infants are perfunctory but become vigorous in infants of 34 weeks’ gestation. The Moro reflex, first present in fragmentary form at 24 weeks, is well developed by 28 weeks, although it fatigues easily and lacks a complete adduction phase. Not until 38 weeks’ gestation is the entire response characteristic of the term infant observed. At 28 weeks’ gestation, the grasp reflex is evident just in the fingers, and by 32 weeks, the palm and fingers participate. Slightly later contraction of the muscles of the shoulder girdle and elbows occurs during the traction maneuver when the infant is pulled from a supine to a sitting position. The tonic reflex is elicited by turning of the head to one side. The arm on the side to which the head is turned extends, and the other arm flexes. The legs may follow suit, but the response is often absent or subtle. This “fencing” position often can be elicited in the 35-week preterm infant. The crossed-extensor reflex is obtained by stroking the sole of one foot while holding the leg firmly in extension. The response occurs in the opposite leg and comprises rapid flexion at the hips and knees with attendant withdrawal, followed by extension, adduction, and fanning of the toes. The complete response, elicited in infants of about 36 weeks’ gestation, is informative when asymmetric. Otherwise, it only establishes that some degree of primitive function is present. The stepping response (i.e., automatic walking) is usually present by 37 weeks’ gestation and can be induced by resting the infant’s soles on a mattress and rocking the infant gently from one foot to the other. This procedure usually initiates a walking sequence, which is facilitated by the examiner supporting the infant’s weight and tilting the infant forward. The preterm infant usually walks on his or her toes, whereas the term infant uses a heel-to-toe sequence. The response manifests at 32 to 34 weeks’ gestation. Ongoing neurologic examinations of the preterm infant are most important for the assessment of development and

Swaiman / Neurologic Examination of the Term and Preterm Infant

61

FIGURE 4-13. The hips are abducted, and the pelvis is low in a prone preterm infant of 32 weeks’ gestation.

neurologic status. When the preterm infant reaches the equivalent of 40 weeks’ gestation, the neurologic examination’s results are not the same as those of a term newborn [Illingworth, 1972]. Because after reaching 40 weeks’ gestation the preterm infant lies with relatively less elevation of the pelvis, the prone-body profile is flatter than that of the term newborn (Fig. 4-13). The preterm infant continues toewalking and, even at 40 weeks, manifests relative hypotonia, incomplete dorsiflexion of the foot, and a greater popliteal angle compared with the term newborn. Tone can also be evaluated by measurement of the popliteal angle in preterm infants. These data provide useful

FIGURE 4-14. Measurement of the popliteal angle in an infant who was 8 months old (corrected age). The popliteal angle is evaluated by bringing the infant’s knees to the chest and by extending the legs with the use of gentle pressure behind the ankles. The popliteal angle was approximately 180 degrees in this case. (From Kato T, Okumura A, Hayakawa F, et al. Popliteal angle of low birth weight infants during the first year of life. Pediatr Neurol 2004;30:244.)

Head circumference

cm

46

46 cm

44

44

42

42

40

cm 80

38

76

36

72

34

68

32

kg 64 11 60 10 56 9.0 52 8.0 48 7.0 44 6.0

30 28 26 24 22 cm

Length

GROWTH RECORD FOR INFANTS in relation to GESTATIONAL AGE AND FETAL AND INFANT NORMS (Combined sexes)

Weight

Length

40 36 32 kg 2.5 2.0 1.5 1.0

Mean ± 1 S.D.

5.0 4.5 4.0 3.5 3.0 2.5

± 2 S.D. 26 28

30

32

34 36

40 1 mo.

2

3

6

9

1 year

FIGURE 4-15. A fetal-infant growth graph for infants of various gestational ages can be used for plotting growth from birth until 1 year of age after term status has been reached. (From Babson SG, Benda GI. Growth graphs for the clinical assessment of infants of varying gestational age. J Pediatr 1976;89:814.)

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Clinical Evaluation / 4

Head circumference (CM)

GROWTH RECORD FOR PRETERM INFANTS

30 28

26 24 1

7

14

21

28

35

42

49

Days FIGURE 4-16. Head circumference growth record for preterm infants. (From Hall RT, Shaffer S. 1988.)

information in assessing tone (Kato et al., 2004). The angle is assessed as shown in Figure 4-14. Data documenting preterm infants and popliteal angle changes are found in Table 4-6.

Assessment of Head Growth Patterns It is essential to measure and plot growth data to facilitate early detection of abnormal patterns. The shape of the head changes markedly with growth in preterm infants. The ratio of anteroposterior diameter to biparietal diameter increases rapidly in preterm infants during the first few months of life [Baum and Searls, 1971]. There are known differences between the extrauterine body growth patterns of preterm infants and the extrauterine body growth patterns of the term infant [Babson et al., 1970; Gardner and Pearson, 1971; Lubchenco et al., 1966; Usher and McLean, 1969]. The occipitofrontal circumference of preterm infants often shrinks during the first few days of life. Expected patterns of extrauterine head growth are reasonably well documented, making diagnosis of hydrocephalus or microcephaly in the preterm infant possible. Frequent serial occipitofrontal circumference measurements should be obtained to allow early diagnosis. A standard plotting curve must be used to monitor head growth in the preterm infant. A useful standard plot is depicted in Figure 4-15 [Babson and Benda, 1976]. Conventional symptoms and signs of hydrocephalus are not immediately evident, even though the presence of ventricular dilatation is documented with imaging techniques [Korobkin, 1975; Volpe et al., 1977]. The presence of certain characteristics should alert the clinician to the presence of hydrocephalus [Sher, 1982], such as full fontanel with separation of the cranial sutures, abnormally high rate of occipitofrontal circumference increase, frontal bossing, scaphocephaly, and increased ratio of head size to body length. The preterm infant’s state of health is a major determinant of head growth [Sher and Brown, 1975a, 1975b]. Mean occipitofrontal circumferences for small and large, healthy, preterm infants and for sick infants are graphed [Sher and Brown, 1975a] for comparison with the data of O’Neill [1961]. Irrespective of gestational age, sick infants were designated as those who were maintained with mechanical ventilation and intravenous therapy for various periods up to 2 weeks [Sher and Brown, 1975a, 1975b]. Infants with easily

correctable metabolic abnormalities or minimal degrees of hyperbilirubinemia not requiring exchange transfusion were excluded from the sick group. On the basis of the study of Sher and Brown [1975a, 1975b], some conclusions are possible [Sher, 1982]. The rate of occipitofrontal circumference increase in the healthy preterm infant is approximately double (1.1 cm/week) that of the term infant in the first and second months after delivery (Fig. 4-16). The rate of increase of occipitofrontal circumference in the healthy preterm infant is approximately equal (0.5 cm/week) to that of the term infant in the third and fourth months. The average rate of occipitofrontal circumference for ill preterm infants is 0.25 cm/week for the first 3 months. Preterm infants with a short gestation have more rapid rates of occipitofrontal circumference increase than infants with a longer gestation. Preterm infants with rates of occipitofrontal circumference increase greater than the expected rate should be evaluated for the presence of hydrocephalus. Preterm infants who are healthy and who fail to achieve the least expected rate of occipitofrontal circumference increase may have intrinsic brain disease. When comparisons are made based on postconceptional age, the occipitofrontal circumference of preterm infants is greater than that of the term infant, at least for the first 5 postnatal months [Fujimura et al., 1977]. The maximum velocity of head growth in healthy, preterm infants with good caloric intake occurs shortly postpartum and decreases thereafter. In general, the prognosis for normal development of lowbirth-weight infants is much improved since the advent of focused obstetric practices related to the preterm infant and neonatal intensive care units [Hutson et al., 1986; Kitchen and Murton, 1985]; however, the increase in the number of very-low-birth-weight infants has resulted in an increase in the prevalence of cerebral palsy in this population [Hagberg et al., 1989; Pharoah et al., 1990]. The clinician must be cognizant of the normal, rapid rate of head growth and avoid unnecessary procedures designed to diagnose hydrocephalus. Caution should be exercised in placing undue emphasis on isolated neurologic findings that deviate from expected findings in preterm infants. Variations from infant to infant and from time to time in the same infant are common. The infant’s general pattern of responses should weigh heavily in the assessment of CNS integrity at any one moment.

Swaiman / Neurologic Examination of the Term and Preterm Infant

REFERENCES Amiel-Tison C. Neurologic evaluation of the maturity of newborn infants. Arch Dis Child 1968;43:89. Amiel-Tison C. Update of the Amiel-Tison neurologic assessment for the term neonate or at 40 weeks corrected age. Pediatr Neurol 2002;27:196. Apgar V. A proposal for a new method of evaluation of the newborn infant. Curr Res Anesthesiol 1953;32:360. Ashwal S. Historical aspects of the neonatal neurological examination: Why child neurologists are not “little adult neurologists.” J Hist Neurosci 1995;4:3. Babson SG, Behrman RE, Lessel R. Fetal growth: Liveborn birth weights for gestational age of white middle class infants. Pediatrics 1970;45:937. Babson SG, Benda GI. Growth graphs for the clinical assessment of infants of varying gestational age. J Pediatr 1976;89:814. Baum JD, Searls D. Head shape and size of newborn infants. Dev Med Child Neurol 1971;13:576. Besio R, Caballero C, Meerhoff E, et al. Neonatal retinal hemorrhages and influence of perinatal factors. Am J Ophthalmol 1979;87:74. Brazelton TB. Neonatal behavioral assessment scale. London: Spastics International Medical Publications, 1973. Brazelton TB, Parker WB, Zuckerman B. Importance of behavioral assessment of the neonate. Curr Probl Pediatr 1976;2:49. Braun L, Flynn D, Ko CW, et al. Gestational age-specific growth parameters for infants born at US military hospitals. Ambul Pediatr 2004;4:461. Critchley EM. The neurological examination of neonates. J Neurol Sci 1968;7:427. Cruz-Martinez A, Ferrer MT, Martin MJ. Motor conduction velocity and H-reflex in prematures with very short gestational age. Electromyogr Clin Neurophysiol 1983;23:13. Dodge HW. Cephalic bruits in children. J Neurosurg 1956;13:527. Dodge PR, Porter P. Demonstration of intracranial pathology by transillumination. Arch Neurol 1961;5:594. Doyle LW, for the Victorian Infant Collaborative Group. Changing availability of neonatal intensive care for extremely low birthweight infants in Victoria over two decades. Med J Aust 2004;181:136. Dubowitz L, Dubowitz V. The neurological assessment. In: Dubowitz L, Dubowitz V, eds. The neurological assessment of the preterm and full-term newborn infant. Clinics in developmental medicine, no. 79. London: William Heinemann Medical Books, 1981. Dubowitz L, Dubowitz V, Goldberg C. Clinical assessment of gestational age in the newborn infant. J Pediatr 1970;77:1. Dubowitz W, Whittaker GF, Brown BH, et al. Nerve conduction velocity: An index of neurologic maturity of the newborn infant. Dev Med Child Neurol 1968;10:741. Farr V, Kerridge DF, Mitchell RG. The value of some external characteristics in the assessment of gestational age at birth. Dev Med Child Neurol 1966a;8:657. Farr V, Mitchell RG, Neligan, GA, et al. The definition of some external characteristics used in the assessment of gestational age in the newborn infant. Dev Med Child Neurol 1966b;8:507. Fenichel GM. Neurological assessment of the 25 to 30 week premature infant. Ann Neurol 1978;4:92. Fenichel GM. The neurological consultation. In: Fenichel GM, ed. Neonatal neurology, 2nd ed. New York: Churchill Livingstone, 1985. Fenichel GM. Clinical pediatric neurology: A signs and symptoms approach, 4th ed. Philadelphia: WB Saunders, 2001. Fujimura M, Seryu JI. Velocity of head growth during the prenatal period. Arch Dis Child 1977;52:105. Gardner D, Pearson J. A growth chart for premature and other infants. Arch Dis Child 1971;46:783. Gardner J, Lewkowicz D, Turkewitz G. Development of postural asymmetry in premature human infants. Dev Psychobiol 1977;10:471. Hack M, Mostow A, Miranda SB. Development of attention in preterm infants. Pediatrics 1976;58:669. Hagberg B, Hagberg G, Olow I, et al. The changing panorama of cerebral palsy in Sweden. V. The birth year period 1979-82. Acta Paediatr Scand 1989;78:283. Hogan GR, Milligan JE. The plantar reflex of the newborn. N Engl J Med 1971;285:502. Hutson JM, Driscoll JM, Fox HE, et al. The effect of obstetric management on neonatal mortality and morbidity for infants weighing 700-1000 grams. Am J Perinatol 1986;3:255.

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Illingworth RS. The development of the infant and young child, 5th ed. Baltimore: Williams & Wilkins, 1972. Kato T, Okumura A, Hayakawa F, et al. Popliteal angle of low birth weight infants during the first year of life. Pediatr Neurol 2004;30:244. Kato T, Okumura A, Hayakawa F, et al. Popliteal angle in preterm infants with periventricular leukomalacia. Pediatr Neurol 2005;32:84. Kilbride HW. Effectiveness of neonatal intensive care for extremely low birth weight infants. Pediatrics 2004;114:1374. Kitchen WH, Murton LJ. Survival rates of infants with birth weights between 501 and 1,000 gm: Improvement by excluding certain categories of cases. Am J Dis Child 1985;139:470. Korobkin R. The relationship between head circumference and the development of communicating hydrocephalus following intraventricular hemorrhage. Pediatrics 1975;56:74. Kuban KCK, Skouteli HN, Urion DK, et al. Deep tendon reflexes in premature infants. Pediatr Neurol 1986;2:266. Lipsitt LP. The study of sensory and learning processes of the newborn. Clin Perinatol 1977;4:170. Lubchenco LO. Assessment of gestational age and development at birth. Pediatr Clin North Am 1970;17:125. Lubchenco LO, Hansman M, Boyd E. Intrauterine growth in length and head circumference as estimated from live births at gestational ages from 26 to 42 weeks. Pediatrics 1966;37:403. Mercuri E, Guzzetta A, Laroche S, et al. Neurologic examination of preterm infants at term age: Comparison with term infants. Pediatrics 2003;142:647. Miller G, Heckmatt JZ, Dubowitz, et al. Use of nerve conduction velocity to determine gestational age in infants at risk and in very-low-birth-weight infants. J Pediatr 1983;103:109. Modanlou H. Extension reflex of fingers in the newborn. Pediatr Neurol 1988;4:66. Moosa A, Dubowitz V. Assessment of gestational age in newborn infants: Nerve conduction velocity versus maturity score. Dev Med Child Neurol 1972;14:290. Nelson KB, Eng GD. Congenital hypoplasia of depressor anguli oris muscle: Differentiation from congenital facial palsy. J Pediatr 1972;81:16. O’Neill E. Normal head growth and prediction of head size in infantile hydrocephalus. Arch Dis Child 1961;36:241. Paine RS. Neurologic examination of infants and children. Pediatr Clin North Am 1960;7:41. Pape KE, Pickering D. Asymmetrical crying facies: Index of other congenital anomalies. J Pediatr 1972;81:21. Peiper A. Cerebral function in infancy and childhood. New York: Consultants Bureau Enterprises, 1963. Pharoah POD, Cooke T, Cooke RWI, et al. Birthweight specific trends in cerebral palsy. Arch Dis Child 1990;65:602. Popich GA, Smith DW. Fontanels: Range of normal size. J Pediatr 1972;80:749. Prechtl HFR. The neurological examination of the full term newborn infant, 2nd ed. London: William Heinemann Medical Books, 1977. Saint-Anne Dargassies S. Neurologic maturation of the premature infant of 28 to 41 weeks’ gestational age. In: Falkner F, ed. Human development. Philadelphia: WB Saunders, 1966. Sarnat HB. Olfactory reflexes in the newborn infant. J Pediatr 1978;92:624. Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. Arch Neurol 1976;33:696. Scher MS, Barmada MA. Estimation of gestational age by electrographic, clinical, and anatomic criteria. Pediatr Neurol 1987;3:256. Sher PK. Neurologic examination of the premature infant. In: Swaiman KF, Wright FS, eds. The practice of pediatric neurology. St. Louis: CV Mosby, 1982. Sher PK, Brown S. A longitudinal study of head growth in preterm infants. I. Normal rates of head growth. Dev Med Child Neurol 1975a;17:705. Sher PK, Brown S. A longitudinal study of head growth in preterm infants. II. Differentiation between “catch-up” head growth and early infantile hydrocephalus. Dev Med Child Neurol 1975b;17:711. Usher R, McLean F. Intrauterine growth of liveborn Caucasian infants at sea level: Standard obtained from infants born between 24 and 44 weeks’ gestation. J Pediatr 1969;74:901. Volpe JJ. Hypoxic-ischemic encephalopathy. In: Volpe JJ, ed. Neurology of the newborn, 4th ed. Philadelphia: WB Saunders, 2001a:285. Volpe JJ. The neurological examination: normal and abnormal features. In: Volpe JJ, ed. Neurology of the newborn, 4th ed. Philadelphia: WB Saunders, 2001b:103.

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Volpe JJ, Pasternak JF, Allan WC. Ventricular dilation preceding rapid head growth following neonatal intracranial hemorrhage. Am J Dis Child 1977;131:1212.

SUGGESTED READING Bacola E, Behrle FC, deSchweinitz L, et al. Perinatal and environmental factors in late neurogenic sequelae. I. Infants having birth weights under 1500 grams. Am J Dis Child 1966a;112:359. Bacola E, Behrle FC, deSchweinitz L, et al. Perinatal and environmental factors in late neurogenic sequelae. II. Infants having birth weights from 1500 to 2500 grams. Am J Dis Child 1966b;112:369. Beintema DJ. A neurological study of newborn infants. London: William Heinemann Medical Books, 1968. Crosse VM. The premature baby, 4th ed. London: J&A Churchill, 1957. Cruise MO. A longitudinal study of the growth of low birth weight infants. I. Velocity and distance growth, birth to 3 years. Pediatrics 1973;51:620. Dekaban A. Examination. In: Dekaban A, ed. Neurology of early childhood. Baltimore: Williams & Wilkins, 1970.

Dodge PR. Neurologic history and examination. In: Farmer TW, ed. Pediatric neurology. New York: Harper & Brothers, 1964. Knobloch H, Pasamanick B. Predicting intellectual potential in infancy. Am J Dis Child 1963;166:43. Paine RS. Neurologic conditions in the neonatal period: diagnosis and management. Pediatr Clin North Am 1961;8:577. Paine RS. The evolution of infantile postural reflexes in the presence of chronic brain syndromes. Dev Med Child Neurol 1964;6:345. Paine RS, Brazelton TB, Donovan DE, et al. Evolution of postural reflexes in normal infants and in the presence of chronic brain syndromes. Neurology 1964;14:1036. Rawlings G, Reynolds EOR, Stewart A, et al. Changing prognosis for infants of very low birth weight. Lancet 1971;1:516. Robinson RJ. Assessment of gestational age by neurologic examination. Arch Dis Child 1966;41:437. Saint-Anne Dargassies S. Long-term neurological follow-up study of 286 truly premature infants. Dev Med Child Neurol 1977;19:462. Volpe JJ. The neurological examination: Normal and abnormal features. In: Markowitz M, ed. Neurology of the newborn, 2nd ed. Major problems in clinical pediatrics, Vol. 22. Philadelphia: WB Saunders, 1987.

CHAPTER 5

Muscular Tone and Gait Disturbances Kenneth F. Swaiman

Muscular tone is conventionally separated into phasic and postural types. Phasic tone is the result of rapid stretching of a tendon, attached muscle, and most important, the muscle spindle. The response is rapid and short lived. Postural tone is the result of a steady, restrained stretch on tendons and attached muscles, with resultant protracted contraction of the involved muscle. Gravity is the most common stimulus for this response. Postural tone is the topic primarily discussed in this chapter, and it is referred to simply as tone. Tone is functionally defined as resistance to passive movement (i.e., resistance experienced by the examiner while the patient’s relaxed limbs are moved about the joints). Hypotonia is a decreased resistance to passive movement. Hyperextensibility is an abnormally increased range-of-joint movement. Hyperextensibility of the elbows, wrists, knees, and ankles usually accompanies hypotonia but is not pathognomonic. The combination of hypotonia and hyperextensibility allows an infant to adopt unusual and awkward-appearing postures. The term floppy is frequently used to describe hypotonic children. This term is useful only if the clinician does not believe that the “classification” constitutes a diagnosis rather than a shorthand description of clinical manifestations. Hypotonia must not be equated with hyporeflexia or muscle weakness. For example, patients with Down syndrome commonly have normal deep tendon reflexes and normal strength but are usually hypotonic. Conversely, patients with anterior horn cell disease are weak and manifest hypotonia and hyporeflexia.

PATHOLOGY The central and peripheral nervous systems modify tone, but intrinsic physical characteristics of the tendons, joints, and muscles and the anatomic interrelationships of these structures also contribute significantly to tone. In childhood central nervous system (CNS) dysfunction, upper motor neuron (unit) disease may cause increased or decreased muscle tone [Teddy et al., 1984]. Disease involving the lower motor neuron (unit) results in hypotonia and weakness. The final common pathway of upper or lower motor unit modification of tone is through the gamma loop (fusimotor) system [Gordon and Ghez, 1991; Granit, 1975]. Intimately involved with monitoring and effecting tone are the two stretch-sensitive muscle receptors—the muscle spindles and the Golgi tendon organs (Fig. 5-1). It also has become evident that nonreflex, mechanical mechanisms are involved in the maintenance of resting muscle tone. Spinal cord reflex responses depend on ongoing activity in interneurons [Davidoff, 1992].

Stationed in all areas of the skeletal muscle is the muscle spindle, a fusiform-shaped receptor structure (Fig. 5-2). The spindle is composed of contractile fibers at each end and a capsule covering a central fluid-filled dilation. Sensory endings wrap around the central sections of the intrafusal fibers and monitor the stretch of these fibers; they communicate through the afferent axons that are described later in this chapter. Through efferent axons, gamma neurons within the anterior horn of the spinal cord innervate the contractile muscle portions on each end of the intrafusal fiber and enhance the sensitivity of the sensory endings to stretch [Gordon and Ghez, 1991]. Gamma motor neurons that innervate muscle spindles comprise the fusimotor system. A further division of labor occurs; the intrafusal muscle fibers are divided into three types: nuclear chain fibers, dynamic nuclear bag fibers, and static nuclear bag fibers. These fibers derive their names from the configuration of their nuclei in the fiber center. Chain fibers have nuclei arranged in a single column, whereas bag fibers have nuclei aligned in rows of two or three. A solitary Ia afferent fiber provides primary sensory innervation for all three types of intrafusal fibers. A group II afferent fiber innervates chain and static bag fibers providing secondary sensory endings. The various

Alpha motor axon

Extrafusal muscle fiber Spindle afferents and efferents

Muscle spindle

Tendon organ afferent

Golgi tendon organ

FIGURE 5-1. Muscle spindles and Golgi tendon organs are encapsulated structures found in skeletal muscle. The main skeletal muscle fibers, or extrafusal fibers, are innervated by large-diameter alpha motor axons. The muscle spindle has a fusiform shape and is arranged in parallel with extrafusal fibers. It is innervated by afferent and efferent fibers. The Golgi tendon organ is found at the junction between a group of extrafusal fibers and the tendon; it is therefore in series with extrafusal fibers. Each tendon organ is innervated by a single afferent axon. (Adapted from Houck JC, Crago PE, Rymer WZ. Functional properties of the Golgi tendon organs. In: Desmedt JE, ed. Spinal and supraspinal mechanisms of voluntary motor control and locomotion. Progress in clinical neurophysiology, Vol. 8. Basel: Karger, 1980:33.)

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Clinical Evaluation / 5

A

Intrafusal muscle fibers

Capsule Sensory endings

Afferent axons

B

Dynamic nuclear bag fiber

Static nuclear bag fiber

Dynamic gamma motor axon

Static gamma motor axon

Afferent axons

Ia II

Nuclear chain fibers

Primary ending Secondary ending

Efferent axons

FIGURE 5-2. The main components of the muscle spindle are intrafusal fibers, sensory endings, and motor axons. A, The intrafusal fibers are specialized fibers; their central regions are not contractile. The sensory endings spiral around the central regions of the intrafusal fibers and are responsive to stretch of these fibers. Gamma motor neurons innervate the contractile polar regions of the intrafusal fibers. Contraction of the intrafusal fibers pulls on the central regions from both ends and increases the sensitivity of the sensory endings to stretch. B, The muscle spindle contains three types of intrafusal fibers: dynamic nuclear bag, static nuclear bag, and nuclear chain fibers. A single group Ia afferent fiber innervates all three types of intrafusal fiber, forming a primary ending. A group II afferent fiber innervates chain and static bag fibers, forming a secondary ending. Two types of efferent axons innervate different intrafusal fibers. Dynamic gamma motor axons innervate only dynamic bag fibers; static gamma motor axons innervate various combinations of chain and static bag fibers. (A, Adapted from Hullinger M. The mammalian muscle spindle and its central control. Rev Physiol Biochem Pharmacol 1984;101:1; B, Adapted from Boyd IA. The isolated mammalian muscle spindle. Trends Neurosci 1980;3:258. Reproduced with permission from Elsevier.)

Motor endings

1 mm

sensory endings on the different types of intrafusal fibers have different characteristics of sensitivity in regard to rate of change of length. Dynamic gamma motor axons innervate the contractile portions of dynamic nuclear bag fibers, and static gamma motor axons innervate the contractile portions of the static bag fibers [Gordon and Ghez, 1991]. This intricate system of muscle spindle innervation allows the muscle stretch receptors to monitor muscle tension, length, and velocity of stretch and provide input for maintenance of tone [Carew, 1985]. It is through their effect on the gamma motor neuron that portions of the CNS (i.e., motor cortex, thalamus, basal ganglia, vestibular nuclei, reticular formation, and cerebellum) modify tone, with ensuing hypotonia or hypertonia (i.e., spasticity) [Alexander and Delong, 1985; Brooks and Stoney, 1971; Carew, 1985; Ghez, 1985]. The Golgi tendon organs, unlike the muscle spindles, are found in series with the skeletal muscle fibers (Fig. 5-3) and are attached at one end to the muscle and at the other to the tendon. A number of individual skeletal muscle fibers enter a Golgi tendon organ through a constricted collar. The muscle fibers are attached to collagen fibers within the Golgi tendon organ. A single Ib axon enters each capsule and forms branches that are interlaced among the collagen fibers. The afferent axon branches are compressed when muscle contraction occurs and impulses are transmitted. Tendon organs are much more sensitive to muscle contraction than muscle spindles. Tendon organs appear to be less sensitive to stretch than muscle spindles. Each of these sensitivities has a different value during the performance of various motor tasks [Gordon and Ghez, 1991].

EVALUATION OF THE PATIENT History Because several conditions characterized by hypotonia are hereditary, a careful genetic history must be sought. Questioning of grandparents and parents may prove most valuable. The age at which hypotonia is first evident may be allimportant diagnostically. The presence of hypotonia at birth or shortly thereafter can help differentiate among a number of conditions [Brooke et al., 1979; Dubowitz, 1985]. Weak fetal movements or the change from apparently normal fetal movements to those of decreased amplitude and vigor should be determined. Hypotonia in the setting of polyhydramnios signals prenatal interference with swallowing.

Examination Observation and manipulation of fixed contractures of the limbs in the neonatal period may demonstrate that hypotonia is associated with an antenatal insult. Preterm infants, even when not ill, are normally hypotonic relative to a term newborn; their corrected ages should be considered when assessing preterm infants during the first few months of life. The tendency of the infant to assume unusual positions, including the “frog’s legs” configuration, in which the supine infant assumes a position with the lower limbs externally rotated and abducted, may indicate the presence of hypotonia. The hypotonic infant may have difficulties evident at birth. [Swaiman and Wright, 1979]. Weakness is often associated with hypotonia, with resultant poor suck, cry, and

Swaiman / Muscular Tone and Gait Disturbances

Muscle fibers

lb Afferent

Capsule

Axon Collagen fiber Tendon

250 ␮m FIGURE 5-3. Golgi tendon organs are specialized structures found at the junctions between muscle and tendon. Collagen fibers in the tendon organ attach to the muscle fibers. A single Ib afferent axon enters the capsule and branches into many unmyelinated endings that wrap around and between the collagen fibers. When the tendon organ is stretched (usually because of contraction of the muscle), the afferent axon is compressed by the collagen fibers (inset) and increases its rate of firing. (Adapted from Schmidt RF. Motor systems. In: Schmidt RF, Thews G, eds. Human physiology [Biederman-Thorson MA, translator]. Berlin: Springer, 1983:81; inset, Adapted from Swett JE, Schoultz TW. Mechanical transduction in the Golgi tendon organ: A hypothesis. Arch Ital Biol 1975;113:374.)

respiratory effort. There may be a paucity of spontaneous limb movements. Weakness should be suspected if the infant does not briskly withdraw a limb in response to painful stimuli. The infant may be unable to raise a limb or sustain the position of a raised limb. Tone should be assessed in the active state and passive resting state in the newborn, because it is different, with active tone normally higher than passive tone appendicularly. Passive pronation, supination, flexion, and extension of the limbs and gently shaking the hands and feet while grasping the wrists or ankles are common means of assessing tone. The hands move over a large amplitude when the arms are shaken gently at the wrists. Often, the elbows can be extended beyond their normal range. The scarf sign assessment involves wrapping the infant’s arm across the chest toward the neck on the contralateral side and is positive when the elbow can be readily moved beyond the midline. One of the best means of evaluating tone is use of the traction maneuver, during which head control, flexion of elbows during infant participation, and general body and back posture are observed (see Fig. 3-7). The hypotonic infant’s foot may be brought to the opposite ear, and extreme passive foot dorsiflexion may be possible when hypotonia is profound.

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The hypotonic infant will slip through the hands of the examiner when held by the axillae (i.e., vertical suspension maneuver). If the hypotonic infant is supported by the trunk in an outstretched prone position (i.e., horizontal suspension maneuver), gravity causes flexion, or droop of the head and extremities. The normal infant holds the head erect and flexes the limbs against gravity while holding the back straight. Facial weakness, weak suck, weakness of muscles of deglutition, and paresis of the elevators of the eyelid and the extraocular muscles are often associated with unusual myopathies. The tongue should be carefully examined for atrophy and fasciculations. Evaluation of muscle weakness can be facilitated with the traction maneuver and by ascertaining the withdrawal response to appropriate stimuli and the ability to resist gravity. Paucity of movement signals the likely presence of concomitant weakness. If limb weakness is present, localization of the weakness to the proximal or distal extremities should be attempted. Older children present with talipes planus, pronation at the ankles, and genu recurvatum. The pectus excavatum deformity and a bell-shaped chest may indicate predominate strength of the diaphragm over the intercostal muscles during respiratory efforts. Skeletal deformities and fixed contractures are often present in congenital myotonic dystrophy and some congenital myopathies. Fixed contractures of the limbs may signal the presence of arthrogryposis multiplex congenita, which may result from dysfunction at a number of lower motor neuron unit sites [Lebenthal et al., 1970; Yuill and Lynch, 1974] (see Chapter 75). Fasciculations of limb muscles are difficult to observe in infants because of the overlying, abundant, subcutaneous tissue. However, the experienced examiner can palpate the muscle beneath the fat and estimate the adequacy of muscle bulk. The deep tendon reflexes in the normal preterm and term newborn should always be elicited. These reflexes may be difficult to elicit in the triceps, variably obtainable at the biceps, easier to obtain at the pectoralis, and present at the patellar and Achilles tendons. In previously normal infants, the immediate onset of weakness and hypotonia that are progressive and profound suggests the possibility of infantile botulism [Infant botulism, 2003; Kao et al., 1976; Pickett et al., 1976; Ravid et al., 2000; Thompson et al., 1980]. There is accompanying constipation, poor feeding, and bulbar involvement. In addition to most of the previously mentioned characteristics, hypotonia in the ambulatory child may manifest with a waddling gait, genu recurvatum, and talipes planus. There may be pronation of the feet at the ankles. The presence of scoliosis suggests associated weakness and neuromuscular disease. In the older child, more formal and discrete muscle testing is possible as described in Chapter 2. Observation of gait may indicate weakness. Elicitation of the deep tendon reflexes, toe signs, and myotonic response to percussion and scrutiny of muscles for evidence of fasciculations are accomplished relatively easily. When the lower motor unit is involved, the deep tendon reflexes usually are hypoactive and sometimes are absent. The reflexes are absent in infantile spinal muscular atrophy [Bundey and Lovelace, 1975; Smith and Swaiman, 1983].

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When the upper motor unit is involved, the reflexes tend to be normal or increased. Further neurologic examination is necessary and should include the search for fasciculations, ptosis, squint, myotonia, and extensor toe signs. The presence of squint or ptosis suggests the possibility of congenital myopathies [Clancy et al., 1980; McComb et al., 1979; Riggs, et al., 2003], myotonic dystrophy, myasthenia gravis [Holmes et al., 1980; Namba et al., 1970], or mitochondrial myopathies (see Chapters 28 and 79). Knowledge about the congenital myopathies has grown considerably during the past decade, and the clinical and genetic complexities have become increasingly evident [Bruno and Minetti 2004; Kirschner and Bonnemann, 2004]. Specific laboratory studies may be essential in establishing the diagnosis. When lower motor unit diseases are considered, serum enzyme determinations, nerve conduc-

tion velocities, electromyography, and nerve or muscle biopsies may be of importance. When upper motor unit diseases are involved, a careful history, electroencephalographic and evoked-response testing, brain imaging, specific endocrine evaluations, and specific enzyme determinations may be required.

DIAGNOSIS For didactic purposes and simplification, the motor pathway from the motor neuron in the motor strip to the skeletal muscle fiber can be divided into upper and lower motor neuron units. The upper motor neuron (unit) includes the motor neuron in the motor strip and the myelinated nerve fiber, which traverses the corticospinal tract and eventually terminates in the internuncial pool in the spinal cord adja-

Box 5-1 SELECTED CONDITIONS ASSOCIATED WITH HYPOTONIA COMBINED CENTRAL AND PERIPHERAL NERVOUS SYSTEM DISEASE Adrenoleukodystrophy (neonatal) Cerebellothalamospinal degeneration Fukuyama’s muscular dystrophy and encephalopathy Infantile neuroaxonal dystrophy Krabbe’s disease (globoid cell leukodystrophy) Metachromatic leukodystrophy Prader-Willi syndrome Zellweger’s syndrome

Toxicity Bilirubin Magnesium Phenobarbital Phenytoin Sedative drugs Trauma Brain Cord

Upper Motor Unit Disease (Central Nervous System Diseases) Acute cerebral insult Cerebrovascular accident (e.g., hemorrhage, thrombosis, embolism) Hypoxic-ischemic encephalopathy Infection (e.g., viral, bacterial, fungal, parasitic) Chromosomal abnormality Angelman’s syndrome Down syndrome Prader-Willi syndrome Congenital motor disease (cerebral palsy) Ataxia Atonic diplegia or paraplegia (periventricular leukomalacia) Incontinentia pigmenti Metabolic disease Carnitine deficiency Cytochrome c oxidase deficiency Fucosidosis Gangliosidosis (GM1) Hyperammonemia Hypercalcemia Hyperglycinemia Hyperlysinemia Niemann-Pick disease Mannosidosis Oculocerebrorenal syndrome (Lowe’s syndrome) Organic acidemias Renal tubular acidosis Tay-Sachs disease (and other GM2 gangliosidoses)

Lower Motor Unit System Diseases Arthrogryposis multiplex congenita Carnitine deficiency Connective tissue disease, such as Ehlers-Danlos syndrome Anterior horn cell Infantile spinal muscular atrophy Kugelberg-Welander disease Poliomyelitis Peripheral nerve Familial dysautonomia Guillain-Barré syndrome Hereditary motor-sensory neuropathies Polyneuropathy Neuromuscular junction Botulism Myasthenia gravis Myasthenic syndrome Neonatal myasthenia gravis (immune- and nonimmune-mediated forms) Neonatal transient myasthenia gravis Muscle Congenital myopathies (e.g., central core disease, congenital fiber type disproportion, myotubular myopathy, nemaline myopathy) Glycogen storage disease (e.g., acid maltase deficiency, phosphofructose kinase deficiency, phosphorylase deficiency) Hypothyroidism Myotonic dystrophy Polymyositis

Swaiman / Muscular Tone and Gait Disturbances

cent to the anterior horn cell. The lower motor neuron (unit) consists of the anterior horn cell, peripheral nerve, neuromuscular junction, and muscle. Disorders affecting muscular tone are divided into upper and lower motor unit disorders. Combined disorders also occur. It cannot be overstressed that, in contradistinction to the usual residua in older children and adults, upper motor unit disease may result in increased or diminished muscle tone in infants and young children. Functional impairment of the lower motor unit causes hypotonia and weakness. Hyporeflexia, fasciculations, and muscle atrophy also result. Certain conditions (e.g., Krabbe’s disease) cause combined upper and lower motor unit impairment and produce hypotonia initially. The most common cause of hypotonia is inadequate brain control of the motor pathways, or central hypotonia. The presence of normoactive or brisk deep tendon reflexes suggests that the child is probably not suffering from lower motor unit impairment. The examiner should be alert for other signs of brain dysfunction, such as lethargy, unresponsiveness to the environment (i.e., visual and auditory stimuli), lack of development of social skills in the early months of life, and in older children, delayed development of language and reasoning skills. Diseases of the upper motor unit may be classified according to pathophysiologic cause (i.e., metabolic, degenerative, traumatic, congenital-structural, infectious, or toxic). A similar classification may be used for lower motor unit diseases; such diseases also may be categorized by the anatomic site of involvement. A number of specific diseases can be suggested by historic and physical findings. Marked arching of the back and irritability suggest Krabbe’s disease. Obesity with small male genitalia with profound hypotonia and poor feeding in the neonatal period suggests Prader-Willi syndrome. Down syndrome is often evident on clinical grounds alone, although confirmatory chromosomal studies are necessary. Visceromegaly, particularly hepatomegaly, is found with some diseases associated with hypotonia, including NiemannPick disease and cerebrohepatorenal syndrome. Blindness, seizure activity, and hyperacusis suggest Tay-Sachs disease. Muscle wasting and flexion contractures are characteristic of arthrogryposis multiplex congenita. The presence of hypothyroidism is suggested by decreased height and weight, a large tongue, and developmental delay. The conditions associated with hypotonia are listed in Box 5-1 and are discussed in detail elsewhere in this book.

CLINICAL LABORATORY STUDIES Conventional laboratory studies, such as hemogram, erythrocyte sedimentation rate, urinalysis, and serum electrolyte determinations, are usually not helpful in assessing hypotonia, although creatine kinase and thyroid hormone levels may be. Hypothyroidism can be diagnosed from conventional thyroid studies. Determination of activities of serum muscle enzymes (i.e., enzymes that have escaped the muscle cells and are detectable in serum) infrequently aids the diagnosis of hypotonia; however, activities are sometimes elevated in certain congenital muscular dystrophies and mito-

69

chondrial myopathies. The ease of obtaining serum creatine kinase activity makes such determinations worthwhile. Some conditions linked to hypotonia require special tests to yield a precise diagnosis. Pertinent portions of this text should be consulted to determine special laboratory testing requirements. Neuroimaging techniques using computed tomography or magnetic resonance imaging (MRI) may be helpful in the diagnosis of CNS abnormalities. MRI is of particular value in the diagnosis of white matter diseases, including leukodystrophies. Spinal fluid studies may demonstrate pleocytosis, increased levels of protein, or abnormal proteins, suggesting demyelinating conditions or peripheral neuropathy. Assessment for leukocyte enzyme activities associated with certain lipid storage diseases may provide definitive diagnoses for conditions that affect the brain alone, the brain and anterior horn cells, or the brain and peripheral nerves. Some of these conditions affect some non-neural organs. Some neuromuscular and mitochondrial diseases are associated with cardiomyopathies, and electrocardiography or echocardiography may be of aid in establishing a diagnosis. Electromyography differentiates neurogenic from myopathic conditions and should inspire more intense considerations of some diagnostic categories. Studies in infants and young children require patience and experience for optimal studies and interpretation. The conventional assessment of insertion potentials and potentials at rest and during movement is as essential in infants as it is in older children and adults. The diagnosis of peripheral neuropathy, particularly in conditions that involve the central and peripheral nervous systems, may be readily overlooked without the determination of nerve conduction velocities. Normative data are available for all age groups [Gamstorp, 1963]. The value of muscle biopsy is well established in the diagnosis of neuromuscular conditions and is discussed elsewhere in this book. It is virtually obligatory that biopsies, preparation of the muscle specimens, and light and ultramicroscopic studies be performed by individuals specially trained and experienced in these endeavors.

GAIT IMPAIRMENT Gait disturbances are a common manifestation of neurologic disease in children; however, the clinician must be cognizant that gait abnormalities may not be related to neurologic dysfunction. Congenital abnormalities, such as hamstring muscle and plantar foot flexor tightness, may result in difficulties with posture and back pain [Jozwiak et al., 1997]. Clinical indices are available for the evaluation of gait pathology in children [Romei et al., 2004]. Foot deformities are present in 4% of newborns, but the natural course of all congenital deformities, except clubfoot, is favorable [Widhe, 1997]. Gait is a demanding, complicated skill that requires integration of many functional components of the nervous system and is the result of a repetitive sequence of limb movements. Study of toddlers and older children indicate that in toddlers the walking pendulum mechanism differs from older children and adults and is not in place at the onset of unsupported locomotion. Evidence suggests that by 2 years of age mechanical energy data are similar for 2 year olds and adults

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[Ivanenko et al., 2004]; however, reliability of gait parameters in children younger than 2 years remains to be established [Marques-Bruna and Grimshaw, 2004]. Significant changes in plantar pressure of the foot during the first year of standing and walking occur and the age of development of a mature pattern is highly variable [Bertsch et al., 2004]. Sophisticated evaluation of foot kinetics during walking is useful in providing information about gait impairment [MacWilliams et al., 2003]. Care must be taken in developing data generated from children of different ages because of the need to take height and leg length into consideration [Stansfield et al., 2003]. Development of mature displacement of center of mass of the body during independent walking is a gradual neural process that evolves until age 7 years [Dierick et al., 2004]. Optimal gait requires the least expenditure of energy possible. Mechanical energy must be generated and then dissipated in a controlled fashion during each cycle [Gage et al., 1984; Õunpuu et al., 1991]. The encumbrance of additional weight can interfere with optimal walking posture; backpack load and walking distance do not affect stride, but a load of above 15% of body weight induces a significant increase in trunk inclination [Hong and Cheung, 2003]. During the gait cycle, posture and balance must be maintained, and the feet must clear the ground without scraping. Quantitive gait evaluation is increasingly precise and useful [Schwartz et al., 2004]. When comparing children with pathologic gait characteristics with characteristics of normal children, these data should be developed from the same walking speed [van der Linden et al., 2002]. Gait must be assessed when the patient’s chief complaint focuses on walking or running; however, assessment of gait allows the clinician rapid appraisal of a number of significant nervous system units when patient complaints are other than those relating to gait. Acquired idiopathic gait difficulties may

Initial contact

Loading response

Midstance

Terminal stance

occur with some frequency in children admitted to some children’s hospitals. Some acquired gait disorders have definite physical cause, and some are idiopathic [Wassmer et al., 2002]. Further data documenting the incidence of these disorders is needed to evaluate the economic and social impact.

PHYSIOLOGIC CONSIDERATIONS Skills required for standing must be synthesized into the walking procedure. The walking sequence requires that the non–weight-bearing leg moves forward while weight is shifted smoothly from leg to leg. The definitive components of support and forward movement require separate consideration; the rhythm and duration of each phase require monitoring [Gage and Õunpuu, 1989; Paine and Oppe, 1966]. Conventionally, the period from one heel-ground contact to the next heel-ground contact of one foot is one gait cycle; walking can be divided into stance and swing phases. The instant from which heel-ground contact occurs until the instant when contact terminates is the stance phase. The stance phase can be divided into four parts: initial contact, loading response, midstance, and terminal stance (Figs. 5-4 and 5-5). The period beginning immediately after the toe leaves the ground until the heel contacts the ground is the swing phase (see Figs. 5-4 and 5-5) [Burnett and Johnson, 1971a, 1971b; Norlin et al., 1981]. The swing phase can also be divided into four parts: preswing, initial swing, midswing, and terminal swing. Decreased knee flexion during the swing phase (i.e., stiff-knee gait) may be caused by overactivity of the rectus femoris [Piazza and Delp, 1996]. The stance phase occupies 60% of the duration of the cycle, and the swing phase occupies 40%.

Preswing

Initial swing

Midswing

Terminal swing

FIGURE 5-4. Schematic representation of various phases of a child walking. (Adapted from Õunpuu S, Gage JR, Davis RB. Three-dimensional lower extremity joint kinetics in normal pediatric gait. J Pediatr Orthop 1991;11:341.)

Double support (10%)

Double support (10%)

Stance (60%) 10% 30% 50% Loading Terminal response Midstance stance Preswing Initial contact

Stance (40%) 70% 85% Initial Terminal swing Midswing swing

Toe off Stride (100%)

Initial contact

FIGURE 5-5. Graphic representation of the phases of gait and their duration. (From Õunpuu S, Gage JR, Davis RB. Three-dimensional lower extremity joint kinetics in normal pediatric gait. J Pediatr Orthop 1991;11:341.)

Swaiman / Muscular Tone and Gait Disturbances

Elaborate methods for the assessment of phases of gait have been devised [Burnett and Johnson, 1971a; Õunpuu et al., 1991]. The center of gravity is affected by several factors during ambulation: pelvic rotation, pelvic tilt, knee flexion at midstance, foot and knee mechanics, and lateral displacement of the pelvis [Saunders et al., 1953]. The center of gravity in older children shifts approximately 4.5 cm during the gait cycle. Pelvic rotation and pelvic tilt are usually necessary for development of independent gait [Burnett and Johnson, 1971a, 1971b]. Children usually acquire adult patterns of walking within 55 weeks after independent gait is achieved [Burnett and Johnson, 1971a, 1971b]. Because walking is such a complex skill, the normal participation of many motor system parts is vital; these include the basal ganglia; sensory cortex; neck proprioceptors; visual receptors; cerebellum; spinal cord motor and sensory tracts, and gray matter masses; peripheral nerves; neuromuscular junctions; and muscles [Norlin et al., 1981; Winter, 1990]. The participation of various muscles varies greatly during each portion of the gait cycle (Fig. 5-6).

EVALUATION OF THE PATIENT Neurologic assessment should be directed at a number of target points. It is important to determine whether abnormalities are focal or diffuse. Alterations from normal include muscle tone deviations, weakness, nystagmus, titubation, and dysmetria. Extrapyramidal movements associated with basal ganglia dysfunction, including dystonia, chorea, and athetosis, may be evident. Extensor toe signs, usually Babinski’s sign, may also be present. Deep tendon reflexes can be assessed, with particular reference to the patient’s response to the tendon stretch elicited by a reflex hammer and to response asymmetry. The patient should be wearing only underwear during the examination. The child’s back should be carefully examined. In particular, the area directly over or just slightly lateral to the spine should be searched for lipomas, hair patches, hemangiomas, and dimples; these skin changes may accomInitial contact

% Gait cycle

Toe off

71

pany spine and cord deformities. Café au lait spots may signal the presence of neurofibromatosis. Scoliosis of the spine should be determined with proper technique. The child should bend from the waist while placing both feet together flat on the floor. The child should bend toward the examiner while the spine is examined. If scoliosis is suspected, the length from the anterior spine of the ilium to the midpoint of each medial malleolus should be measured to ascertain leg length discrepancy. The hip, knee, and ankle joints should be moved through their entire range of motion, and the presence of contractures determined. Any pain associated with joint movement should be evaluated. In infants, congenital dislocation or subluxation of the hip is often associated with skin fold asymmetry along the medial thigh. This abnormality is best seen posteriorly. Abnormal placement of the head of the femur may result in limited range of motion or, alternatively, spasticity may result in subluxation of the femoral head. Before observing the patient’s walk, the Romberg test should be performed. Walking should be assessed while the patient is barefoot and while wearing shoes. Patients who wear braces should be examined with and without braces. The child needs an explanation of the walking procedure, which entails walking down the hallway, turning abruptly, and returning. The clinician should systematically evaluate the components of the child’s gait and associated movements. Among the important characteristics are symmetry of gait from leg to leg; whether walking occurs on the balls of the feet, flatfooted, or on the heels; and the relative stability of the pelvis. Associated movements of the arms should be carefully observed. The fingers and hands may flex associated with infolding of the thumbs, indicating possible corticospinal tract dysfunction. The arms should move so that the contralateral arm swings forward synchronously with the swing phase of each leg (see Fig. 5-4). When the child runs, abnormal arm and hand postures and movements are frequently accentuated. It is important in gait evaluation to accurately measure leg length. Discrepancies of less than 3% are not

Initial contact

0 10 20 30 40 50 60 70 80 90 100

Iliopsoas Rectus femoris Adductor longus Adductor brevis Vastii Hamstrings Anterior tibialis Gastrocnemius Soleus Tensor fasciae latae Gluteus maximus

FIGURE 5-6. Graphic representation of the involvement of various muscles during the phases of gait. (From Õunpuu S, Gage JR, Davis RB. Three-dimensional lower extremity joint kinetics in normal pediatric gait. J Pediatr Orthop 1991;11:341.)

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associated with compensatory movements [Song et al., 1997]. An older child should be asked to tandem walk forward and backward (heel-to-toe); the examiner can facilitate compliance by demonstration. The child should be asked to pivot quickly when changing direction. The backward heelto-toe walk should also be executed. The child should walk on the toes and reverse direction, remaining on the toes. This process needs to be repeated on the heels. A child who exhibits impaired heel walking may have an Achilles tendon contracture, equinovarus deformity, or foot dorsiflexor weakness. The clinician should ask the child to circle the examiner, first in one direction and then in the other. If the child has hemispheric cerebellar disease, the child will tend to depart from the circular path toward the examiner or away from the examiner, depending on the side of the lesion. It is advantageous to have the child climb steps to observe pelvic strength and stamina. Hip girdle strength can be assessed when the child is asked to squat and then stand rapidly. Evidence of hip girdle weakness may also be gained by asking the child to lie down in the supine position and sit up by flexing at the hip. While the child walks and runs with shoes on, the examiner should listen and observe for evidence of scraping, scuffing, and slapping sounds. As described later, sensory ataxia and steppage gait are associated with “split” sounds. More precise methods of gait analysis are available. Three-dimensional bilateral kinematic data can be obtained for analysis of the various facets of gait in children. The child is studied from several aspects: sagittal (i.e., the subject is viewed and monitored from the side), coronal (i.e., the subject is viewed and monitored from the front), and transverse (i.e., the subject is viewed and monitored from above). Data are generated from the changes in relationships as measured in angles (degrees) of various skeletal parts during the gait cycle [Gage, 1991; Myers et al., 2004; Õunpuu et al., 1991; Schwartz et al., 2004]. Electromyographic patterns of extrinsic ankle muscles in healthy children between 4 and 11 years old demonstrate the significant effect of walking speed changes but are independent of growth over this age range. This information can be reduced to a nomograph [Detrembleur et al., 1997].

DIFFERENTIAL DIAGNOSIS Spastic Hemiplegic Gait Disruption of the corticospinal tract above the medulla results in a hemiplegic gait and abnormal posture on the contralateral side. Below the medulla, the ipsilateral side is involved. The leg is extended or only slightly flexed at the knee, and the natural swing at the knee and hip is impeded. Tone is often increased. The leg usually abducts, moves forward, and then swings back toward the midline in a circular movement. The pelvis is often tilted upward on the involved side to permit adequate circumduction. The patient scuffs the lateral sole and the toe of the shoe while dragging the foot. The heel-walking exercise is impaired. With gross involvement, the movements are markedly slow and require great effort. Some children with modest spasticity of the knee

may assume a position of mild flexion at the knee and hip and decrease the scuffing of the foot, which is often held in the equinovarus position. During ambulation, the affected leg bears weight for decidedly less time than the normal leg. Frequently, the arm is held in an awkward posture, usually close to the body, flexed at the elbow and wrist, and with a closed fist (i.e., cortical thumb posturing). The expected rhythmic reciprocal swing of the arm with the stance phase of the opposite leg is absent. If the arm is held behind the plane of the body on a routine basis, the possibility of dystonia should be considered. Frequently, the cause of hemiplegic gait is uncertain, but focal brain lesions, such as porencephalic cysts, subdural hematomas, cerebral masses, and cerebrovascular accidents, may lead to this gait pattern.

Spastic Paraplegic Gait Bilateral corticospinal tract dysfunction involves both legs. Toe-walking may be the only indication during the early years of spastic paraplegia. Nevertheless, toe-walking may be familial or unexplained and may not be pathologic during the first few years or relevant to future development. The clinician should establish the presence of other manifestations of upper motor neuron unit dysfunction before attributing pathologic significance to toe-walking [Kelly et al., 1997; Volpe, 1997]. Patients with spastic paraplegia often have spasticity with flexion in the hips and knees and weakness and limitation (or dorsiflexion) of both feet. The resultant posture resembles crouching. Occasionally, a child may manifest extreme spastic extension at the knees. The typical posture of the feet is equinovarus. Adduction of the thighs may cause the knees to brush one another during walking. Infants may have a scissoring gait in which the legs cross; the highly increased adductor tone forces them into this position. Each step is deliberate, and the walking process painfully slow. Steps are short, and the toes are scuffed with each forward movement. Weight must be deliberately shifted from foot to foot, and the patient’s balance is unstable. This sequence is further complicated by the equinovarus position of the foot and the subsequent weight bearing on the toes. Examination often reveals no cerebellar findings and no superficial or deep sensory impairment. The expected findings associated with corticospinal tract dysfunction include hyperactive deep tendon reflexes, ankle and knee clonus, extensor toe signs, and ankle contractures with resultant equinovarus positioning. Spastic paraplegia may result from hemispheral masses, porencephalic cysts, subdural hematomas, postmeningitic and postencephalitic states, and demyelinating diseases.

Cerebellar Gait The cerebellum is a unique brain component that serves as a coordinating motor center. Optimal functioning requires reception and synthesis of sensory information from the peripheral nerves, posterior columns of the spinal cord, and cortex. Patients with cerebellar gait have an unsteady, wide-based gait that sometimes appears to be lurching. Cerebellar hemi-

Swaiman / Muscular Tone and Gait Disturbances

spheral lesions result in lateral veering. When a child with a right cerebellar lesion is asked to circle the examiner with the right arm next to the examiner, the child will walk into the examiner after completing a few circles. The cerebellar gait is sometimes similar to the walking pattern of individuals under the influence of drugs or alcohol. Titubation, involuntary head bobbing, and sometimes truncal bobbing movements may occur in any direction but happen most frequently in the anteroposterior direction. These movements may be subtle or clearly evident. Nystagmus is an inconstant feature. The clinician may facilitate observation of the effects of cerebellar impairment. The child should be asked to rise from a chair, walk a straight line, and suddenly reverse direction. The child should be asked to stand with the feet close together, first with eyes open and then with eyes closed. The child with cerebellar difficulties will sway or fall toward the involved cerebellar hemisphere. If the patient has a stable stance with eyes open but becomes unstable with eyes closed, this positive response to the Romberg test is most commonly caused by posterior column dysfunction. Occasionally, a child with severe peripheral neuropathy manifests the same Romberg response. The child should be asked to tandem walk along a straight line to facilitate observation of ataxia. If the anterior lobe of the cerebellum or midline cerebellar structures are compromised, only gait may be involved, without abnormalities of the arms or hands. These abnormalities usually include action tremor with resultant difficulties with fine coordination. Compromise of the cerebellar hemisphere is associated with abnormal movement of the ipsilateral limbs. Myriad conditions affect the cerebellum. Among these conditions are congenital malformations, inherited cerebellar atrophies, aminoacidurias, mitochondrial diseases, lipid storage diseases, anoxic episodes, demyelinating diseases, posterior fossa tumors, hydrocephalus, and intoxication. Many hereditary cerebellar diseases have been described; these conditions often affect only a small number of pedigrees [Brown, 1980].

Acute Cerebellar Ataxia The sudden appearance of ataxia in children without obvious cause requires systematic evaluation. Commonly, the process is self-limiting; however, the differential diagnosis is broad and includes some serious conditions [Hayakawa and Katoh, 1995; Sunaga et al., 1995]. In most cases, the child has experienced an influenza-like syndrome within the previous few weeks. The patient is usually between 1 and 4 years old and most frequently between 1 and 2 years old [Weiss and Carter, 1959]. The attacks may be so severe that the patient is bedridden. At other times, severe truncal ataxia is present. Nystagmus is present in one half of these children [Cotton, 1957]. Other inconstant features are hypotonia, tremors, and scanning speech. Noncerebellar symptoms include headaches, photophobia, and lightheadedness. Full recovery may require 2 months, but some children return to normal within 10 days. If no improvement in the ataxia occurs after several weeks, the clinician should be alert to the possible existence of a serious underlying cause. Approximately 30% of children retain a neurologic deficit, including ataxia and

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speech impairment [Weiss and Carter, 1959]. The differential diagnosis of ataxia is found in Chapte 57. The diagnosis of a posterior fossa tumor should be excluded by neuroimaging. Papilledema is frequently associated with posterior fossa tumors that obstruct spinal fluid flow but is not present in brainstem gliomas until much later in the disease course. The latter condition is usually associated with cranial nerve dysfunction, particularly the nerves that subserve eye and facial movements. Lumbar puncture indicates normal pressure. Pleocytosis (up to 90 leukocytes/mm3) may be found [Cotton, 1957]. Although a slight increase in protein content may be evident after several weeks, protein concentration is usually normal in the early stages of ataxia. Acute cerebellar ataxia has been linked with numerous bacterial and viral infections, including diphtheria, pertussis, typhoid fever, rubella, mumps, varicella, coxsackievirus A9, echovirus 9, and poliomyelitis [King et al., 1958; Mendez-Cashion et al., 1962]. The clinician must remember that many drugs—illegal substances and those intended for medical use—may cause ataxia. The affected children are usually too young to provide an accurate history of intake and are prime subjects for accidental ingestion. Ataxias associated with myoclonus may result from a neuroblastoma. The combination of myoclonus and neuroblastoma is known as the myoclonic encephalopathy syndrome. Acute trauma may induce cerebellar edema and subsequent hemorrhage with resultant ataxia. Hartnup’s disease and maple syrup urine disease may cause transient episodic ataxia. Children with absence seizures may appear to be ataxic and confound the correct diagnosis.

Sensory Ataxia Ataxia results when the hemispheres and cerebellum are deprived of normal sensory input from various portions of the sensory system, including peripheral nerves, posterior roots, posterior columns, or connections leading from the posterior columns to the parietal lobes through the medial lemnisci. The patient experiences marked instability during standing and walking, and the gait is wide based. Muscle power does not decrease. The patient lacks the sensation of the feet touching the ground and avoids obstacles by raising the legs inordinately and stepping sharply downward, the heel striking the ground first. A fraction of a second later the toe makes contact and produces the second part of a split sound. The child flexes the body slightly forward, and the gait is marked by variability of stride length. The child often gazes at the ground during walking. Examination reveals no sensory abnormality unless ataxia is caused by an extremely incapacitating peripheral neuropathy. Position and vibratory sense in the feet and legs are abnormal. Romberg’s sign is positive. Although tabes dorsalis, a disease of adults, is the prototypic disease of posterior column involvement, children who have subacute combined degeneration, polyneuritis, demyelinating disease, and Friedreich’s ataxia manifest this gait.

Extrapyramidal Gait Patients with extrapyramidal gait usually have changes in the basal ganglia such as those in Parkinson’s disease,

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Hallervorden-Spatz syndrome, Wilson’s disease, postencephalitic syndromes, and drug toxicity. Extrapyramidal gait is identified by decreased automatic movements, rigidity, and bradykinesia. The patient tilts the trunk and head forward. The arms are flexed at the elbows and wrists and are held close to the body. The fingers are extended unlike the fisting in spastic paraplegia. The child fails to elevate the feet sufficiently so that each step is a shuffle. Steps are short and slow. The patient often extends the upper portion of the body forward, with a subsequent shift of the center of gravity forward. The resultant propulsion or festination of gait is characteristic. If the child loses control because the steps become more rapid and the center of gravity shifts unduly forward, the child will fall. This gait pattern may be present when the patient walks forward or backward. When the latter occurs, it is referred to as retropulsion. Characteristically, the patient may have difficulty with the initial step and may take a few short steps or actually hop and shuffle forward before the walking sequence is established. In addition to the gait difficulties, children with extrapyramidal involvement blink infrequently, are virtually devoid of facial expression, and seldom fold their arms or cross their legs.

Other Dyskinetic Gaits A number of other movement disorders cause unusual gait patterns. Athetosis, when profound, may be associated with overall stiffness and bizarre body postures. With this condition, the feet may be positioned in plantar flexion, requiring the patient to bear weight on the toes. Inversion and dorsiflexion of the foot occur. After a stride is initiated, the flexed hip is externally rotated, the knee is flexed, and the foot remains in the plantar flexed position. The walk may have an associated dancelike or prancing appearance and may be incorrectly diagnosed as a form of conversion reaction. This gait pattern is often associated with dystonia, particularly idiopathic torsion dystonia. The arms, hands, wrists, and fingers frequently move in deliberate, writhing movements about the long axis of the limb and then slowly reverse the rotational movement with irregular pace. Other uncommon gait manifestations may accompany torsion dystonia. The foot may be held in plantar flexion or inversion. During the stationary phase, the leg may be rigid and a shoulder elevated. During the stride, the patient may have lordosis of the trunk, and the pelvis may be tilted forward with resultant partial hip flexion. Flexion of the knees may accompany the dystonia and may intensify as the patient develops dromedary gait. Because this manifestation may fluctuate in intensity, the clinician should be careful not to diagnose a conversion reaction. Children with this condition walk better backward than forward, including during the tandem-walk examination. This pattern of walking better backward than forward also may be found in patients who have quadriceps muscle weakness. Chorea may also impair proximal hip muscle and trunk muscle action. The result is a rapidly shifting positioning of the trunk and body. The head may also move quickly along, with associated grimacing of the facial muscles, choreiform movements of the trunk and limbs, and irregular breathing patterns and sounds.

Steppage Gait Weakness of dorsiflexion of the feet and toes and fixed contracture in plantar flexion result in a steppage gait. The contracture most often accompanies weakness of the peroneal and anterior tibial muscles. To avoid stumbling, the child lifts the foot disproportionately high at the start of each stride. Flexion at the hip and knee is exaggerated, followed by a forward flinging of the foot. The toe precedes the heel or ball of the foot in hitting the ground, emitting the first portion of a split sound. This pattern of ground contact wears away the tips of shoes. The steps are similar to one another and rhythmic. This unusual gait may be isolated to one leg but is more often bilateral. This condition is most often associated with anterior horn cell disease or peripheral neuropathic involvement in disease processes such as progressive muscular atrophy, poliomyelitis, Charcot-Marie-Tooth disease, Guillain-Barré syndrome, and distal myopathy.

Hip Weakness Gait Severe weakness of the abductors and extensors of the hip leads to a pathologic gait. The child walks with a marked lordosis of the thoracolumbar spine, and the gait is “waddling.” The pelvis is unstable and the gait broad based. The pelvis markedly pivots and rotates sharply from side to side as weight shifts. The movement pattern allows balance to be maintained despite hip muscle weakness. Stability may be further compromised by accompanying equinovarus deformities. These deformities are frequently present in various muscular dystrophies, myositides, and spinal muscular atrophies, including Kugelberg-Welander disease.

Gait Apraxia Occasionally, severe frontal lobe problems result in gait disturbances. These patients have no direct motor or sensory impairment. Although the child may successfully complete certain simple and automatic movements with the legs, he or she is unable to implement more complex activities, such as tracing a circle with the feet, kicking an object, or attempting to walk in a prescribed pattern. The gait is deliberate. The patient may have difficulty initiating the walking process when already standing and have further problems with execution of the serial acts of rising, standing, or walking. Other characteristics, such as perseveration of leg movements and rigidity, are often present. A curious phenomenon in which a leg becomes rigid when the limbs are passively manipulated occurs during fluctuating resistance (i.e., gegenhalten). Other frontal lobe manifestations, such as dementia and reappearance of primitive grasp reflexes, rooting, and palmomental reflexes, may be present.

Antalgic Gait (Painful Gait) Pain can arise from any leg and foot structure, including nails, skin, joints, bone, and muscles. The associated limp is caused by a decreased weight support on the painful leg and increased duration of weight support on the unaffected leg [Chung, 1974]. The examiner may require prolonged ob-

Swaiman / Muscular Tone and Gait Disturbances

servation to determine the precise nature of the limp. The exact limp pattern is determined by the location of the pain [Hensinger, 1977].

Conversion Reaction Gait Conversion reaction may result in patterns that simulate ataxia, hemiplegia, monoplegia, and paraplegia. Children between 10 and 16 years old are most commonly affected. The gait pattern may vary from one moment to the next; this phenomenon should alert the examiner to the possible diagnosis of conversion reaction. The clinician will find no abnormalities of coordination, tone, or strength when the patient is sitting or lying down. The gaits may be outrageously intricate and may vary from time to time in the same child. Short periods of normal walking activity may occur. Tremulousness of the fingers and hands during standing or walking may be associated findings. Patients with conversion reaction resembling hemiplegia or monoplegia usually drag the foot along the floor or push it ahead in contradistinction to patients with corticospinal tract difficulty who elevate and circumduct the leg during each step. When both legs are involved, the patient may be bedridden or use crutches. On rare occasions, the child lurches out of control but does not fall, demonstrating remarkable coordination and strength. In patients with a positive Romberg sign, the swaying is often at the hips or higher trunk. Patients with conversion reactions occasionally do not separate their feet, whereas children with neurologic problems often separate their feet to maintain their balance because they tend to sway from the ankles. They may have associated rapid random movements of the head, hands, and hips. If the patient falls, there may be a dramatic aspect to the mishap. The patient may be able to run or walk backward without difficulty. However, patients with dystonia musculorum deformans may walk backward smoothly, although they have problems with forward ambulation. Patients with conversion reaction gait difficulties should never be thought to be malingering and require skillful intervention that is supportive and empathetic. Patients and parents must receive experienced and measured professional therapy and counseling.

REFERENCES Alexander G, Delong M. Organization of supraspinal motor systems. In: McKhann A, McDonald W, eds. Diseases of the nervous system: Clinical neurology. Philadelphia: WB Saunders, 1985. Bertsch C, Unger H, Winkelmann W, et al. Evaluation of early walking patterns from plantar pressure distribution measurements. First year results of 40 children. Gait Posture 2004;19:235. Boyd IA. The isolated mammalian muscle spindle. Trends Neurosci 1980;3:258. Brooke MH, Carroll JE, Ringel SP. Congenital hypotonia revisited [Review]. Muscle Nerve 1979;2:84. Brooks VB, Stoney SD. Motor mechanisms: The role of the pyramidal system in motor control. Annu Rev Physiol 1971;33:337. Brown JR. Diseases of the cerebellum. In: Baker AB, Baker LH, eds. Clinical neurology, 4th ed. Baltimore: Harper & Row, 1980. Bruno C, Minetti C. Congenital myopathies. Curr Neurol Neurosci Rep 2004;4:68. Bundey S, Lovelace RE. A clinical and genetic study of chronic proximal spinal muscular atrophy. Brain 1975;98:455. Burnett CN, Johnson EW. Development of gait in childhood. I. Method. Dev Med Child Neurol 1971a;13:196.

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Burnett CN, Johnson EW. Development of gait in childhood. II. Dev Med Child Neurol 1971b;13:207. Carew T. Posture and locomotion. In: Kandel E, Schwartz J, eds. Principles of neural science, 2nd ed. New York: Elsevier Science Publishing, 1985. Chung SM. Identifying the cause of acute limp in childhood: Some informal comments and observations. Clin Pediatr (Phila) 1974;13:769. Clancy RR, Kelts KA, Oehlert JW. Clinical variability in congenital fiber type disproportion. J Neurosci 1980;46:257. Cotton DG. Acute cerebellar ataxia. Arch Dis Child 1957;32:181. Davidoff RA. Skeletal muscle tone and the misunderstood stretch reflex. Neurology 1992;42:951. Detrembleur C, Willems P, Plaghki L. Does walking speed influence the time pattern of muscle activation in normal children? Dev Med Child Neurol 1997;39:803. Dierick F, Lefebvre C, van den Hecke A, et al. Development of displacement of center of mass during independent walking in children. Dev Med Child Neurol 2004;46:533. Dubowitz V. Evaluation and differential diagnosis of the hypotonic infant. Pediatr Rev 1985;6:237. Gage JR. Gait analysis in cerebral palsy. London: MacKeith Press, 1991. Gage JR, Fabian D, Hicks R, et al. Pre- and postoperative gait analysis in patients with spastic diplegia: A preliminary report. J Pediatr Orthop 1984;4:715. Gage JR, Õunpuu S. Gait analysis in clinical practice. Semin Orthop 1989;4:72. Gamstorp I. Normal conduction velocity of ulnar, median and peroneal nerves in infancy, childhood and adolescence. Acta Paediatr Scand 1963;146(Suppl):68. Ghez C. Introduction to the motor systems. In: Kandel E, Schwartz J, eds. Principles of neural science, 2nd ed. New York: Elsevier Science Publishing, 1985. Gordon J, Ghez C. Muscle receptors and spinal reflexes: The stretch reflex. In: Kandel E, Schwartz J, Jessell T, eds. Principles of neural science, 3rd ed. New York: Elsevier Science Publishing, 1991. Granit R. The functional role of the muscle spindles—facts and hypotheses. Brain 1975;98:531. Hayakawa H, Katoh, T. Severe cerebellar atrophy following acute cerebellitis. Pediatr Neurol1995;12:159. Hensinger RN. Limp. Pediatr Clin North Am 1977;24:723. Holmes LB, Driscoll SG, Bradley WG. Contractures in a newborn infant of a mother with myasthenia gravis. J Pediatr 1980;6:1067. Hong Y, Cheung CK. Gait and posture responses to backpack load during level walking in children. Gait Posture 2003;17:28. Houck JC, Crago PE, Rymer WZ. Functional properties of the Golgi tendon organs. In: Desmedt JE, ed. Spinal and supraspinal mechanisms of voluntary motor control and locomotion. Progress in clinical neurophysiology, Vol. 8. Basel: Karger, 1980. Hullinger M. The mammalian muscle spindle and its central control. Rev Physiol Biochem Pharmacol 1984;101:1. Infant botulism—New York City, 2001-2002. MMWR Morb Mortal Wkly Rep 2003;52:21. Ivanenko YP, Dominici N, Cappellini G, et al. Development of pendulum mechanism and kinematic coordination from the first unsupported steps in toddlers. J Exp Biol 2004;207:3797. Jozwiak M, Pietrzak S, Tobjasz F. The epidemiology and clinical manifestations of hamstring muscle and plantar foot flexor shortening. Dev Med Child Neurol 1997;39:481. Kao I, Drachman DB, Price DL. Botulinum toxin. Mechanism presynaptic blockade. Science 1976;193:1256. Kelly IP, Jenkinson A, Stephens M, et al. The kinematic patterns of toewalkers. J Pediatr Orthop 1997;17:478. King G, Schwarz GA, Slade HW. Acute cerebellar ataxia of childhood. Pediatrics 1958;21:731. Kirschner J, Bonnemann CG. The congenital and limb-girdle muscular dystrophies: Sharpening the focus, blurring the boundaries. Arch Neurol 2004;61;189. Lebenthal E, Shochet SB, Adam A, et al. Arthrogryposis multiplex congenita: Twenty-three cases in an Arab kindred. Pediatrics 1970;46:891. MacWilliams BA, Cowley M, Nicholson DE. Foot kinematics and kinetics during adolescent gait. Gait Posture 2004;17:214. Marques-Bruna P, Grimshaw P. Reliability of gait parameters in children under two years of age. Percept Mot Skills 2004;98:123. McComb RD, Markesbery WR, O’Connor WN. Fatal neonatal nemaline myopathy with multiple congenital anomalies. J Pediatr 1979;94:47.

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Mendez-Cashion D, Sanchez-Longo LP, Valcarcel M, et al. Acute cerebellar ataxia in children associated with infection by polio virus I. Pediatrics 1962;29:808. Myers KA, Wang M, Marks RM, et al. Validation of a multisegment foot and ankle kinematic model for pediatric gait. IEEE Trans Neural Syst Rehabil Eng 2004;12:122. Namba T, Brown SB, Grob D. Neonatal myasthenia gravis: Report on two cases and review of the literature. Pediatrics 1970;45:488. Norlin R, Odenrick P, Sandlund B. Development of gait in normal children. J Pediatr Orthop 1981;1:261. Õunpuu S, Gage JR, Davis RB. Three-dimensional lower extremity joint kinetics in normal pediatric gait. J Pediatr Orthop 1991;11:341. Paine R, Oppe T. Posture and gait. In: Paine R, Oppe T, eds. Neurological examination of children. London: William Heinemann Medical Books, 1966. Piazza SJ, Delp SL. The influence of muscles on knee flexion during the swing phase of gait. J Biomech 1996;29:723. Pickett J, Berg B, Chaplin E. Syndrome of botulism in infancy: Clinical and electrophysiologic study. N Engl J Med 1976;295:770. Ravid S, Maytal J, Eviatar L. Biphasic course of infant botulism. Pediatr Neurol 2000;23:338. Riggs JE, Bodensteiner JB, Schochet SS Jr. Congenital myopathies/ dystrophies. Neurol Clin 2003;21:779. Romei M, Galli M, Motta F, et al. Use of the normalcy index for the evaluation of gait pathology. Gait Posture 2004;19:85. Saunders JB, Inmann VT, Eberhart HD. The major determinants in normal and pathological gait. J Bone Joint Surg Am 1953;35:543. Schmidt RF. Motor systems. In: Schmidt RF, Thews G, eds. Human physiology [Biederman-Thorson MA, translator]. Berlin: Springer, 1983:81. Schwartz MH, Trost JP, Wervey RA. Measurement and management of errors in quantitative gait data. Gait Posture 2004;20:196.

Smith S, Swaiman K. Hypotonic infant. In: Moss A, ed. Pediatrics update. New York: Elsevier Biomedical, 1983. Song KM, Halliday SE, Little DG. The effect of limb-length discrepancy on gait. J Bone Joint surg Am 1997;79:1690. Stansfield BW, Hillman SJ, Hazlewood ME, et al. Normalisation of gait data in children. Gait Posture 2003;17:81. Sunaga Y, Kikima A, Ostuku T, Morikawa A. Acute cerebellar ataxia with abnormal MRI lesions after varicella vaccinations. Pediatr Neurol1995;13:340. Swaiman KF, Wright FS. Pediatric neuromuscular diseases. St. Louis: CV Mosby, 1979. Swett JE, Schoultz TW. Mechanical transduction in the Golgi tendon organ: A hypothesis. Arch Ital Biol 1975;113:374. Teddy PJ, Silver JR, Baker JH, et al. Traumatic cerebral flaccid paraplegia. Paraplegia 1984;22:320. Thompson JA, Glasgow LA, Warpinski JR, et al. Infant botulism: Clinical spectrum and epidemiology. Pediatrics 1980;66:936. van der Linden ML, Kerr AM, Hazlewood ME, et al. Kinematic and kinetic gait characteristics of normal children walking at a range of clinically relevant speeds. J Pediatr Orthop 2002;22:800. Volpe RG. Evaluation and management of in-toe gait in the neurologically intact child. Clin Pediatr Med Surg 1997;14:57. Wassmer E, Wright E, Rideout S, Whitehouse WP. Idiopathic gait disorder among in-patients with acquired gait disorders admitted to a children’s hospital. Pediatr Rehabil 2002;5:21. Weiss S, Carter S. Course and prognosis of acute cerebellar ataxia in children. Neurology 1959;9:711. Widhe T. Foot deformities at birth: A longitudinal prospective study over a 16-year period. J Pediatr Orthop 1997;17:20. Winter DA. The biomechanics and motor control of human gait, 2nd ed. Toronto: John Wiley & Sons, 1990. Yuill GM, Lynch PG. Congenital non-progressive peripheral neuropathy with arthrogryposis multiplex. J Neurol Neurosurg Psychiatry 1974;37:316.

CHAPTER 6

Vision Loss Douglas Fredrick

In children, the complaint of blurred vision or vision loss is often nonspecific and may be difficult to elicit. Although most causes of vision loss in children result from ocular problems, neurologic disorders may have vision loss as a characteristic and early-manifesting feature [Thompson and Kaufman, 2003]. The ability to determine the cause of vision loss frequently aids in the diagnosis of the underlying neurologic disorder, may help determine prognosis, and can be used to monitor treatment efficacy. A thorough understanding of the anatomy of the visual system, the normal stages of visual development in children, and the signs and symptoms of visual dysfunction in children can greatly aid clinicians in evaluating children with vision loss.

VISUAL DEVELOPMENT Of all the sensory systems, the visual system is perhaps the most immature at birth. It is structurally incapable of processing sensory stimuli to yield maximum visual acuity, and structural changes must occur in the first months of life if normal vision is to be achieved. Postnatal developmental reorganization of the retina takes place during the first several months of life with intercellular connections forming between the photoreceptors and inner retinal cells [Daw, 1994; Dubowitz et al., 1983, 1986]. Myelination of the optic radiations through the temporal, parietal, and occipital lobes occurs in the first year of life [Barkovich et al., 1992]. The most dramatic structural reorganization occurs in the striate cortex, where cortical cells responsible for the first stages of visual processing require normal focused visual input to develop in the correct orientation and to achieve maximum visual acuity. As described by Hubel and Wiesel [1962], visual deprivation leads to abnormal formation of the striate cortical cells and leads to amblyopia. For vision to develop normally, all of the anatomic components of the visual system must be properly formed during development. The sensory neurologic end organ for processing vision is the eye itself. The focusing components of the eye must be developing normally, with clear corneas, crystalline lenses, and optically transparent vitreous media. Properly focused light energy is converted to electrical signals in the photoreceptors that transmit this electrical information through a complex series of interactions through multiple layers of the retina to the ganglion cells, which send projections through the superficial layers of the retina to the optic nerve, finally synapsing in the lateral geniculate nucleus. At the level of the lateral geniculate nucleus, the first levels of cortical processing and organization take place. From the lateral geniculate nucleus, axons project along the optic radiations through the parietal and temporal lobes to synapse in the

striate cortex of the occipital lobe. Visual processing occurs in multiple locations in the occipital and temporal lobes in areas labeled V1 to V5 [Amedi et al., 2003]. Processing of information from these centers occurs in visual association cortical centers, linking vision with speech, cognition, and more complex, higher cortical functions. A structurally intact neurologic substrate must receive properly focused visual information consistently over the first several years of life if normal, maximal visual acuity is to be achieved [Boothe et al., 1985].

ASSESSMENT AND QUANTIFICATION OF VISUAL ACUITY Vision Assessment in Infancy At term, healthy infants display a wide range of visual behaviors, with some infants lying awake and alert and tracking faces from the first day of life, whereas others are seemingly disinterested in their visual world for the first several weeks. Several diagnostic methods can be used to determine whether an infant can see. Most infants can visually fix on a face and follow by 2 months of age. It is possible to assess vision before this time in the office with no special tools or techniques. The most important requisite for assessing visual acuity is the need for an infant to be fully awake. A sleepy infant or one who has just eaten often cannot easily be aroused, no matter what maneuver the clinician undertakes. For infants, light is usually an aversive stimulus, and turning on the lights or shining a light in the eye causes the infant to wince. This response is an indication that the child is experiencing some light stimuli. When infants have their eyes closed in a lighted room, they often open the eyes widely when the lights are turned off, almost in a startled fashion. This action allows the clinician to know that the infant at least can perceive light. The best stimulus to elicit visual behavior is the face of a parent or caretaker. Positional changes can also be used to the examiner’s advantage, because an infant who keeps his or her eyes closed often opens the eyes when held in the supine position and rotated gently about the observer. Another method is to grasp the infant under the arms and lift her or him above the observer’s head. The infant reflexively opens the eyes, allowing the observer to get the infant’s attention. Another method is to start with an auditory cue to get the infant’s attention. The infant is held still while the face is moved backward and forward with the auditory cue. Once the infant attends to the observer’s face, the observer becomes silent but continues to move the face to see if the infant fixes and follows. Brightly colored toys that also have an auditory cue

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are helpful in determining fixation behavior. Mylar materials are especially attractive to infants and are easily transportable. Because most infants fix and follow by 2 months of age, those who do not should be referred to an ophthalmologist. Although fixation behavior allows the clinician to determine whether the infant can see, it does not quantify visual acuity. Two techniques have been devised for this purpose. They are used clinically and for research purposes, and they have allowed estimation of visual acuity in visually immature infants [Droste et al., 1991; Fulton et al., 1981]. The visual evoked potential is an electrophysiologic test in which visual stimuli are presented to an alert and focused infant, and the cortical response to the visual stimulus is measured in a repeatable and quantifiable fashion [Iinuma et al., 1997] (see Chapter 12). Typically, the infant is placed in front of a computer monitor at a close distance and presented with a visually interesting pattern. The pattern may be an alternating checkerboard or horizontally or vertically aligned black and white stripes [McCulloch and Taylor, 1992; Sokol et al., 1983]. The size of the stripes or checkerboard are described as cycles per degree or cycles per centimeter, which can be correlated to standard methods of visual or decimal visual acuity. Large targets are initially used to confirm that a cortical signal is recorded by occipitally placed scalp electrodes.

A

The stimulus pattern is then slowly decreased in size until a recordable response can no longer be elicited. The limit of visual acuity is estimated when there is no longer a recordable electrical response to a viewed visual stimulus. The prerequisite for successfully completing this test is an attentive child who is paying attention to the monitor. Because a child who looks elsewhere will not give an appropriate response, the examination must be performed quickly by a trained tester who is skilled at getting the attention of young infants and maintaining their fixation [Good, 2001; Iinuma et al., 1997]. A second test used to quantify visual acuity is the forcedchoice preferential looking test (PLT) [Mayer and Fulton, 1985]. Instead of using a cortically recorded electrical response, visual stimuli are presented and the child’s ability to see is determined by the ability to move the eyes toward the visual stimulus. Vertically or horizontally aligned black and white stripes are presented to the child on a test card. One side of the card has the stimulus; the other side of the card has a homogeneous gray background (Fig. 6-1A). The infant is directed toward the test card in an apparatus where other visual stimuli are blocked from the infant’s view. When given a choice between a pattern background and a homogenous background, infants instinctively are interested in the pattern background and make an eye movement or saccade toward the black and white stripes. An observer who is watching through a peephole in the middle of the card records in a masked fashion whether he or she sees the infant make the saccade. When the observer reliably identifies the eye movements, the card is removed, and the procedure repeated with test cards using smaller stimuli to quantify visual acuity. Limitations of this test include having an infant who is not irritable, a trained observer, and the appropriate apparatus (see Fig. 6-1B) [Lewis and Maurer, 1986]. Both techniques have been validated in older children and are reliable and accurate methods to assess visual acuity. Using these techniques, it can be estimated that a neonate’s visual acuity is approximately 20/2000. By 2 months of age, acuity has improved to 20/200, and by 1 year of age, it is approximately 20/60. By 4 years of age, infants should see 20/25. At this age, more reliable tests of visual acuity can be used.

Vision Assessment in Children

B FIGURE 6-1. A, Forced-choice preferential looking test (PLT) card. One side of the card contains high-contrast black and white stripes of specific spatial frequency, and the other side has a homogeneous gray background. B, Apparatus for PLT vision assessment. The examiner sits on one side of the screen, presents the test card to the child, and observes to see if the child makes a saccadic eye movement toward the stripes.

Once a child becomes verbal but preliterate, matching tests can be used to quantify visual acuity (Fig. 6-2). In the past, the tumbling E has been used; the examiner asks the child to show the direction of the letter E as it is presented in numerous different positions. This test requires some visual spatial integration and visual spatial perception, which some children find difficult, and so may give falsely low estimates of visual acuity. These tests have been replaced by matching games such as HOTV cards and child recognition symbols or Lea symbols that ask a child to match test optotypes that are presented in progressively smaller sizes (see Fig. 6-2). These tests have been validated and are consistent with Snellen visual acuity, which is the gold standard for measurement of visual acuity in children and adults. Snellen visual acuity can be recorded in numerous forms using notations such as 20/20, decimal notation, or “logmar” notation, a method of quantification that allows more useful statistical analysis

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A

C

B when conducting studies of visual acuity in children and adults.

ASSESSMENT OF COLOR VISION Assessment of color vision can be useful in determining the cause of vision loss. Optic nerve injury often causes decreased color vision as its first presenting sign, even before distance visual acuity or the size of the visual field has been affected. The most useful tests for this purpose are the Harley-Rand-Ritter (HRR) test plates and the Ishihara color plates. The HRR plates are patterns of colored dots that create shapes that can be identified by preliterate children. The Ishihara color plates use numbers as well as trails of colored dots to assess whether or not a child can detect color. The combination of these techniques can separate those children who simply have red-green color deficiency from those with impaired color vision caused by optic nerve injury.

FIGURE 6-2. A, Tumbling E test card requires the child to be able to point the hand in same direction as the bars of the E. B, The HOTV test card requires the child to point to the appropriate letter on a response card placed on the child’s lap. C, Allen figures test requires the child to verbalize name of object.

Assessment of Visual Fields It is not possible to quantify small visual-field deficits in young children. It is possible to diagnose significant hemianopias in small infants using a two-person examination technique. With this technique, one examiner sits in front of the child, maintaining fixation through use of a toy or verbal stimulus. A second tester stands behind the child and introduces a toy or colored object silently in the periphery of the child’s vision. When the child sees the toy, he generates a saccade or a head movement toward the toy. In this fashion, hemianopias can be detected, aiding in the diagnosis of underlying neurologic problems and determining rehabilitation strategies for children with vision impairment associated with neurologic disease. Older patients can be tested with kinetic perimetry using the Goldmann perimeter or tangent screen testing. Using the Goldmann perimeter, the examiner can assure fixation as a test object is brought in from the peripheral visual field. This test is particularly useful for patients who are being monitored for visual-field changes associated with benign

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intracranial hypertension, low-grade gliomas, or midline tumors that, before treatment, may induce ocular or central nervous system (CNS) injury.

Assessments of Ocular Motility Assessment of ocular motility allows the examiner to assess function of cranial nerves III, IV, and VI (see Chapters 2 to 4). Ductions and versions can be tested using brightly colored toys and objects. It is important to first check the child binocularly before patching the infant’s eye because patching may be distracting and preclude acquiring useful information. Alignment should be checked using the alternate cover test where fixation is maintained and the visual axis of each eye is occluded alternately. Refixation of the eyes during alternate occlusion may indicate the presence of strabismus such as esotropia, exotropia, or hypertropia (Fig. 6-3).

CLINICAL FEATURES ASSOCIATED WITH VISION LOSS The three features that must be characterized in assessing vision loss are laterality of vision impairment, temporal na-

ture of vision loss, and associated ocular and neurologic abnormalities. Children with unilateral vision loss are frequently asymptomatic. It is rare for a child to complain of blurred vision in one eye. When they do realize that there is unilateral decreased visual acuity, it is usually because of the sudden discovery of this problem rather than its sudden onset. A child may develop conjunctivitis or get a foreign body in the “good” eye and only then notice the decreased visual acuity in the affected eye. Mild degrees of vision loss are not usually recognized by the child but usually are detected by a teacher or health-care provider at the time of a vision-screening examination. The rapidity of onset of the vision loss also depends on whether the loss is unilateral or bilateral; long-standing unilateral vision loss may not be noticed until the unaffected eye is covered. In contrast, bilateral sudden vision impairment, as can occur with compressive or rapidly demyelinating lesions, may be noticed by the child or caretaker immediately. Associated neurologic signs and symptoms often allow the clinician to localize the disease process before neuroimaging and help the neuroradiologist determine the best type of study to perform. Because symptoms are inconsistently reported, clinicians must be familiar with the physical signs of unilateral vision loss. During the newborn’s physical examination, pediatricians must look for the presence of a red pupillary reflex in each eye. The presence of a white pupil is called leukocoria (i.e., white body), and it is associated with poorly developed vision in one or both affected eyes in the infant (Fig. 6-4).

A

B FIGURE 6-3. A, Esotropia of the left eye causes the corneal light reflex to be temporally displaced. B, Exotropia of the right eye causes the corneal light reflex to be nasally displaced.

FIGURE 6-4. Leukocoria in a patient with retinoblastoma. See also Color Plate.

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The causes of leukocoria are variable, and at a minimum, the condition can cause loss of vision; in more serious situations, leukocoria can be associated with life-threatening conditions such as retinoblastoma. Poor vision in one eye from birth often leads to strabismus that is noticed by the caretaker. Nystagmus is common when there is decreased visual acuity in one or both eyes resulting from a structural anomaly or to a functional deficit preventing visual information from being transmitted from the eye to the cortex [Good, 2001, Hoyt and Fredrick 1998; Jan and Freeman, 1998]. A vision screening examination failed because of decreased visual acuity in one eye is one of the most common reasons that children are referred to their pediatrician and ophthalmologist. In an infant, bilateral vision loss is manifested by strabismus or nystagmus and visual inattention with poor fixation after 2 months of age. Older children with mild vision loss are usually asymptomatic and their problems are not detected until vision is screened by their pediatrician or family practitioner. Children who have progressive loss of visual acuity exhibit behaviors such as sitting extremely close to the television, being disinterested in distant objects or activities, and having difficulty with tasks that require fine visual acuity. Attempts should be made to assess the temporal course of the vision loss. When there is unilateral sudden vision loss, it is usually accompanied by a sudden discovery. Bilateral sudden onset of vision loss is usually noticed by the parents when marked behavioral changes occur in their infant or child. Most causes of chronic vision loss are slowly progressive and often noticed in retrospect. Attempts should be made to elicit the history of the vision loss from parents, siblings, and other caretakers and teachers who may provide insight as to the course of the vision loss. Associated ocular features of vision loss are important to confirm. Infants with poor vision often develop nystagmus by 2 months of age. They are visually inattentive and do not fix and follow well by this age, and they frequently manifest strabismus. Older children usually do not complain of vision problems but have strabismus or a “wandering eye.” They often close one eye or squint the eye in different lighting conditions, rub their eyes frequently, and occasionally complain of double vision when strabismus occurs suddenly. Children with significant vision loss have disrupted circadian rhythms and disturbed sleep-wake cycles [Leger et al., 1999, 2002; Okawa et al., 1987; Palm et al., 1997]. Other associated neurologic symptoms include headache, nausea, and vomiting. Children with profound vision loss demonstrate stereotyped behaviors such as body rocking, rhythmic head movement, and gazing at their fingers or hands as they are moved rapidly in front of their eyes and face [Fazzi et al., 1999].

EXAMINATION OF CHILD WITH VISION LOSS It is the role of the neurologist or the primary care physician to document decreased visual acuity in children who are suspected of having vision loss or found to have vision loss during a screening examination. Infants should have their visual acuity assessed by their fixation behavior. Extraocular movements should be tested to evaluate cranial nerve function and pupils should be tested to determine the response to

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light and presence or absence of an afferent pupillary defect. A direct ophthalmoscope should be used to check for a red reflex, because absence of the red reflex indicates a corneal or lenticular opacity or an intraocular tumor such as retinoblastoma. If the patient has any of these abnormalities, she or he should be seen by an ophthalmologist to assess for structural abnormalities and to recommend additional diagnostic tests. Older children can have their acuity assessed as described earlier. They should have a full motility examination, and an attempt should be made to examine the fundus. The neurologist should feel comfortable using dilating eye drops such as tropicamide (1% solution). This procedure facilitates examination of the optic nerve head and macula. Any child with abnormal visual acuity, motility, pupillary reflexes, or retinal examination should be referred to an ophthalmologist for further examination.

VISION LOSS IN INFANTS Clinical Manifestations Whereas most adults and older children with neurologic disease involving the visual pathways present with alterations in visual acuity or visual function, infants usually have problems resulting from failure of vision to develop normally after birth. Parents are concerned that their children fail to use their vision appropriately or never develop normal visual fixation behaviors. These children have no symptoms because they cannot articulate their complaints, but they manifest many signs that can be useful in diagnosing and localizing the cause of the decreased visual acuity. Signs of decreased visual acuity in an infant include failure to fix and follow an object by 2 months of age or visual inattention manifested by the complaint that the infant looks through the caretaker or indirectly at their face. The infant appears to be more interested in looking at windows or bright lights rather than objects or the caretaker. Strabismus is another common complaint in children and infants who have poor visual acuity. Strabismus early in life is not rare. Up to 30% of infants manifest intermittent deviations in the first 2 months of life, with exotropia occurring more commonly than esotropia [Nixon et al., 1985]. The deviation is usually intermittent and decreases in frequency over the first few months of life. Any child who has a strabismus lasting longer than a few months should be assessed for an underlying ocular anomaly. Constant deviations require close follow-up and early evaluation, particularly when there is constant exodeviation. Whereas infantile esotropia is readily apparent and quite frightening to the parents, this condition usually is not associated with an underlying neurologic abnormality. In contrast, constant exotropia should alert the practitioner that an underlying neurologic abnormality exists. If a constant esotropia is not associated with a sixth nerve palsy, it is usually not associated with neurologic problems. Nystagmus is commonly seen in children who have bilateral, structural anomalies, leading to abnormal visual development. Nystagmus rarely exists at birth. At birth, there may be other movements such as ocular flutter, square wave jerks, or saccadic intrusions that are short lived and become infrequent over time. In contrast, when a child has a structural anomaly such as

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bilateral optic nerve hypoplasia, lack of visual stimulation of the striate cortex leads to a sensory nystagmus. The amplitude of the nystagmus can be quite large between the ages of 2 and 6 months, with the amplitude decreasing and the frequency increasing with time. Infants with visual problems also often demonstrate behavioral mannerisms that help suggest the cause of the vision loss [Brown et al., 1997b; Good and Hoyt, 1989]. Children with retinal dysfunction from congenital dysfunction of the photoreceptors or from retinopathy of prematurity often press their eyes to generate some sort of photic stimulation [Sonksen and Dale, 2002]. Children with cortical visual impairment may demonstrate overlooking behavior, an eccentric fixation, to maximize visual function in the visual fields that are least damaged from the underlying cortical injury. Patients with achromatopsia or congenital glaucoma may be quite photosensitive and demonstrate behaviors to shield their eyes from the light to minimize the dysphoric sensation they receive from visual stimulation.

Differential Diagnosis of Vision Loss in Infants As with every physical sign and symptom, the history and general physical examination often determine the diagnosis even before ophthalmologic and neurologic examination. For example, a child who had a traumatic birth with significant hypoxia is at high risk for cortical visual impairment. A child whose parents and grandparents had cataracts at birth must be evaluated for vision loss caused by congenital cataracts. After vision loss is suspected by the pediatrician or family practitioner, the child should first be seen by an ophthalmologist before being seen by a neurologist. Most infants with vision loss have underlying ocular anomalies that can be diagnosed and obviate the need for expensive neuroimaging or genetic and metabolic testing. The ophthalmologist can direct the neurologist and geneticist in the direction of the most likely diagnosis to minimize the inconvenience, cost, and morbidity associated with diagnostic evaluation in children with vision loss resulting from neurologic disease.

Structural Anomalies

[Merin and Crawford, 1971]. In developed countries, the most common cause is autosomal-dominant cataracts, for which there is a clear history of congenital cataracts affecting multiple generations. These cataracts usually affect both eyes with characteristic morphologic features. Infectious cataracts are uncommon in developed countries but are a leading cause of blindness in developing nations [Bale and Murph, 1992]. Immunizations are effective in reducing the incidence of infectious cataracts, but other viral illnesses can cause cataracts, as can other malformations. Metabolic causes of cataracts include galactosemia, with which infants present with poor feeding and failure to thrive, and galactokinase deficiency, with which infants may be quite healthy. These two metabolic disorders can be distinguished by performing enzymatic assays of erythrocytes. Early detection and dietary treatment may prevent the neurologic sequelae of these disorders. Most developed countries have programs to identify children at risk for cataracts, but screening occasionally fails, and the clinician should be aware of the oil droplet morphology of these refractive types of cataracts. Early recognition and treatment can prevent loss of vision and may result in reversal of early cataracts in patients with galactosemia. Often, cataracts are idiopathic, with no previous family history of cataracts. Other neurometabolic conditions such as mitochondrial disorders can be associated with cataracts. Frequently, these are not present at birth but evolve in the first few years [Marcel, 1998; Sher et al., 1979]. For this reason, children with a suspected neurometabolic disorder should be followed to determine whether cataracts develop. Treatment involves prompt recognition, removal of visually significant cataracts, and visual rehabilitation with intraocular lens implantation, extendedwear soft contact lenses, or aphakic spectacles [Basti et al., 1996].

CORNEAL OPACITY Corneal opacities usually are easily detected by pediatricians or parents at birth when a white spot, or leukoma, is detected within the cornea. These opacities are associated with other structural anomalies, such as microphthalmos, or small eye, and anterior segment dysgenesis, which may also be associated with glaucoma or birth trauma (Fig. 6-5). These corneal opacities can cause significant vision impair-

RETINOPATHY OF PREMATURITY Retinopathy of prematurity remains a common cause of vision impairment in infants, causing blindness in more than 500 infants each year in the United States. Despite intensive efforts to screen and treat the early stages of retinopathy by neonatologists and ophthalmologists, the disease progresses in some children. These patients develop cicatricial changes in the retina leading to vision impairment [Pierce and Mukai, 1994].

CONGENITAL CATARACTS All infants should be screened for cataracts at birth by their pediatrician or family practitioner. The presence of a clear red reflex makes it unlikely that cataracts are present. An abnormal red reflex should prompt ophthalmologic evaluation to determine the location of the optical opacity. The causes of congenital cataracts vary throughout the world

FIGURE 6-5. Corneal edema caused by a forceps injury at the time of delivery. See also Color Plate.

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ment and are difficult to correct, because the success rate of corneal transplantation is poor in infants. Embryologically, the cornea and crystalline lens originate from surface ectoderm, and the iris, uvea, and ciliary body arise from neural crest and mesenchymal cells, with all of the structures forming the anterior segment of the eye. When development is abnormal, the condition is called anterior segment dysgenesis, which can be associated with congenital corneal and lens opacities and with glaucoma, all of which can lead to permanent vision impairment in infants. Patients with anterior segment dysgenesis often have other associated dysmorphic features that indicate the presence of a syndrome or sequence which if unrecognized can lead to profound morbidity of the affected child. One example of a form of abnormal anterior segment development is the absence or profound hypoplasia of the iris, a condition known as aniridia. Aniridia is associated with abnormal retinal development leading to nystagmus and vision impairment. It may occur in isolation, or it may occur as a feature of a syndrome characterized by Wilms’ tumor, genitourinary abnormalities, and mental retardation (WAGR) that is associated with deletion on the short arm of chromosome 11 (11p13). Anterior segment anomalies involving the cornea, lens, and iris are known as Peters’ anomaly, and if the child also has mental retardation, the diagnosis of Peters’ syndrome is made. Dysgenesis of the iris and peripheral cornea causing glaucoma is called Rieger’s anomaly, and if associated dental, cardiac, and cerebellar abnormalities are present, the term Rieger’s syndrome is used. Collaboration with a medical geneticist is helpful in identifying other dysmorphic features and determining appropriate genetic testing. In developing countries, a leading cause of blindness associated with corneal opacities is vitamin A deficiency and measles [Semba and Bloem, 2004].

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A

OCULAR COLOBOMA Coloboma, or absence of tissue, can affect vision profoundly. If the coloboma involves the iris but not deeper tissues, visual acuity can be normal (Fig. 6-6). However, when the coloboma involves the central retina, macula, or the optic nerve, vision can be severely impaired [Apple et al., 1982]. Children with bilateral colobomata are at high risk for underlying neurologic problems [Chestler and France, 1998, Russell-Eggitt et al., 1990]. Any child with bilateral colobomata should be evaluated for chromosomal trisomies and the CHARGE association (i.e., coloboma, heart defects, atresia choanae, retardation of growth and development, genitourinary problems, and ear anomalies). Aicardi’s syndrome should be considered in any female with a seizure disorder and ocular colobomata (Fig. 6-7). Patients with Aicardi’s syndrome have ectopic gray matter and other CNS malformations; the disorder is X-linked and lethal for males [Carney et al., 1993; Gloor et al., 1989].

CONGENITAL GLAUCOMA Congenital glaucoma occurs when the aqueous drainage pathways of the iris form abnormally, leading to increasing intraocular pressure, corneal edema, and optic nerve injury. Most cases of congenital glaucoma are not associated with specific syndromes or underlying neurologic disorders. The exception is Sturge-Weber syndrome, in which vascular ano-

B FIGURE 6-6. A, Coloboma of the iris due to developmental anomalies is usually located inferonasally. B, Coloboma of the choroid and sensory retina can be seen in isolation or as part of a syndrome such as the CHARGE association (i.e., coloboma, heart defects, atresia choanae, retardation of growth and development, genitourinary problems, and ear anomalies). Vision may be normal if the macula is not involved. See also Color Plate.

malies involving the eye lead to increased episcleral venous pressure and glaucoma (see Chapter 31). These patients typically have cerebrovascular malformations, epilepsy, and contralateral hemiplegia.

RETINAL DYSPLASIA Structural anomalies of the retina not associated with retinopathy of prematurity can lead to significant vision impairment. These forms of retinal dysplasia are frequently associated with a variety of neurologic malformations. An example is Walker-Warburg syndrome, in which congenital retinal dysplasia is associated with cerebral structural abnormalities such as hydrocephalus, agyria, and occasionally encephalocele (see Chapter 19). Muscle-eye-brain disease is another example of neurologic and retinal dysplasia resulting from abnormal glial development due to defective glyco-

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OPTIC NERVE HYPOPLASIA

FIGURE 6-7. Optic nerve hypoplasia and chorioretinal lacunas seen in patients with Aicardi’s syndrome. See also Color Plate.

sylation of α-dystroglycan. This results in profound CNS involvement and significant vision loss. Norrie’s disease is an X-linked condition in which retinal dysplasia is associated with mental retardation and deafness. In this condition, a genetic defect in the gene product norrin leads to abnormal endothelial cell migration and proliferation [Mintz-Hittner et al., 1996].

Failure of the optic nerves to form properly leads to a small dysfunctional optic nerve [Siatkowski et al., 1997]. In optic nerve hypoplasia, the nerve is small and its morphology abnormal (Fig. 6-8). Frequently, there is a double-ring sign; the scleral canal of the optic nerve is present, but the optic nerve tissues comprise only a small portion of the canal, leading to two distinct rings. Children with optic nerve hypoplasia frequently present with nystagmus. Children with optic nerve hypoplasia may have de Morsier’s syndrome, or septooptic dysplasia, characterized by midline structural defects of the CNS (e.g., absence of the septum pellucidum, agenesis of the corpus callosum) in addition to neuroendocrine dysfunction (see Chapter 84). All children with optic nerve hypoplasia should undergo neuroimaging, with particular attention to the septum pellucidum, corpus callosum, and pituitary body [Brodsky, et al., 1990]. The presence of an ectopic bright spot places the child at higher risk for neuroendocrine dysfunction. Patients suspected of having septo-optic dysplasia should have their growth and endocrine status monitored closely [Siatkowski et al., 1997; Skarf and Hoyt, 1984]. A child may have normal endocrine function early in life and later develop panhypopituitarism. There have been numerous cases of sudden death associated with septo-optic dysplasia, in which affected children develop a febrile illness that leads to rapid decompensation and death due to adrenal insufficiency [Brodsky et al., 1997]. This complication may occur in children who have or have not received corticosteroid therapy. Parents should be advised concerning these potential risks and treat all illnesses seriously. The cause of optic nerve hypoplasia is unknown, although there have been numerous case reports of optic nerve hypoplasia occurring in infants exposed prenatally to quinine, LSD, alcohol, and antiepileptic drugs [Lambert et al., 1987]. Some infants with optic nerve hypoplasia develop moderate visual function, and the clinician should be careful in prognosticating long-term visual function based on the appearance and size of the optic nerve.

ANIRIDIA Aniridia is a condition in which the iris fails to form completely. There is often a small rim of iris tissue, and children present with large pupils and nystagmus. Aniridia is associated with abnormal formation of the photoreceptors and foveal structure creating the condition of foveal hypoplasia. Visual acuity is usually in the range of 20/200. Up to 20% of patients with aniridia develop glaucoma within the first decade, as well as the early onset of cataracts. A subset of patients with aniridia has an associated 11p13 chromosomal deletion placing the child at risk for Wilms’ tumor. Patients with aniridia require evaluation by a geneticist and periodic renal ultrasounds to determine whether Wilms’ tumor is present.

OCULAR OR OCULOCUTANEOUS ALBINISM

FIGURE 6-8. Optic nerve hypoplasia can be diagnosed by comparing the size of the nerve head with the caliber of the retinal vessels. See also Color Plate.

Normal pigment formation is essential for normal ocular development and normal function of the retinal pigment epithelium [Brodsky et al., 1993]. Albinism may involve the eye and skin (oculocutaneous albinism) or only the eye (ocular albinism); both forms are associated with decreased visual acuity. Patients with oculocutaneous albinism are more

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severely affected, with visual acuity in the 20/200 range, whereas those with ocular albinism have acuity in the range of 20/60 to 20/80. Both conditions manifest with nystagmus early in life. The diagnosis of ocular albinism is made by documenting transillumination defects in the iris during slit-lamp examination. This test can be performed in infants, and it obviates the need for further evaluation. Patients with oculocutaneous albinism should be assessed for systemic disease such as ChediakHigashi syndrome, which is associated with white blood cell dysfunction and recurrent infections, and Hermansky-Pudlak syndrome, which increases the risk for rheologic abnormalities and clotting disorders [Carden et al., 1998].

and Steirn-Kranjc, 1999; Fulton et al., 1981]. Infants present with large-amplitude, slow-frequency, roving nystagmus. They frequently begin to press on their eyes by 2 to 3 months of age [Lambert et al., 1997; Sullivan et al., 1994], and they may have a completely normal ophthalmoscopic examination with normal-appearing optic nerve and retina. The diagnosis is established by electroretinography [Weleber, 2002]. In this test, the electrical amplitude of the retina is measured using a contact lens placed on the eye that is stimulated by bright lights to elicit a cone response and dim lights to stimulate a rod response (Fig. 6-9). In congenital amaurosis, both rod and cone responses are extinguished [al-Salem, 1997, Heher et al., 1992].

LEBER’S CONGENITAL AMAUROSIS

Vision Loss Due to Cortical Visual Impairment

Leber’s congenital amaurosis is a disorder of the photoreceptors and the retinal pigment epithelium in which photoreceptor function is extinguished [Babel et al., 1989; Brecelj

In developed countries, decreased vision caused by cortical or cerebral visual impairment is the leading cause of vision impairment in infants [Blohme and Tornquist, 2000; Gilbert,

FIGURE 6-9. Electroretinogram for a normal child (left) and child with Leber’s congenital amaurosis (right). Different light stimuli can be used to localize abnormal function to rods or cones, or both.

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2003; Gilbert et al., 1999; Huo, et al. 1999; Mervis et al., 2000]. Damage to the visually immature brain impedes normal visual development and leads to lifelong subnormal vision [Brodsky et al., 2002; Hoyt, 2003]. The most common causes of cortical visual impairment in developed countries are neonatal encephalopathies [Casteels et al., 1997; Flanagan et al., 2003; Lanzi, et al., 1998] (see Chapter 14). The second most common cause of cortical visual impairment is periventricular leukomalacia [Afshari et al., 2001; Hoyt and Fredrick, 1998; Huo et al., 1999] (see Chapter 16). Injury and ischemia lead to damage in the periventricular white matter and frequently affect visual development. The location of periventricular leukomalacia determines the form of cortical visual impairment. Lesions involving the anterior visual pathways (e.g., anterior corpus callosum) frequently result in oculomotor anomalies such as apraxia, saccadic paresis, and strabismus. These infants often have difficulty generating saccades and have poor visual fixation. Visual acuity in affected infants may be good but not useful because of the patient’s inability to move the eyes. Damage to the posterior visual pathways (e.g., parieto-occipital white matter, striate cortex) is usually associated with more severe vision loss, poor acuity, and a poor prognosis for recovery [Dutton and Jacobson, 2001; Hoyt and Fredrick, 1998; Jacobson et al., 1998; Sonksen and Dale, 2002]. Clinical features of cortical visual impairment are those of an infant who fails to develop visual fixation behavior after 2 to 3 months of age [Afshari et al., 2001]. These children are often neurologically impaired and have delayed motor milestones and abnormal findings for the neurologic examination [Levtzion-Korach et al., 2000; Whiting et al., 1985]. Magnetic resonance imaging in affected children usually provides evidence of leukoencephalopathy [Casteels et al., 1997]. Infants with cortical visual impairment do not fix or follow and appear to be visually disinterested in the environment [Dutton and Jacobson, 2001; Good et al., 1994]. Often, the first stimulus of interest to the infant is a bright light or shiny object. Patients often keep their eyes elevated, looking upward to see the light in an overhanging light fixture or a window near the infant’s crib. Infants commonly demonstrate off and on visual behavior, during which there are moments of what appears to be normal visual fixation interspersed with longer periods of visual inattention. Infants respond well to high-contrast targets such as black and white toys and large pattern images. Children with profound cortical visual impairment early in infancy can demonstrate a progressive increase in visual function over several years and may become quite visually proficient [Marcel, 1998]. It is important to refer children with cortical visual impairment for low-vision services that can provide sensory stimulation exercises, which improve the visual performance of infants and provide emotional, social, and educational support for parents [Amedi et al., 2003; Ashmead et al., 1998; Levtzion-Korach et al., 2000; Zihl, 1980].

Structural Cerebral Anomalies Causing Cortical Visual Impairment HYDROCEPHALUS Ophthalmic signs of hydrocephalus and increased intracranial pressure include the setting sun sign, which describes the infant’s gaze held in a downward fixed position, with the

eyelids retracted and the infant unable to elevate the eyes willfully. Because the cranial sutures are not closed, papilledema usually does not occur early in infancy. After the cranial vault is closed, papilledema can occur as with any child with increased intracranial pressure (see Chapter 65). Children with hydrocephalus require surgical relief of their obstruction by ventriculostomy or ventriculoperitoneal shunt placement. An ophthalmologic examination should be obtained to document the presence of normal optic nerves or the absence of optic atrophy. Many older children with chronic hydrocephalus present with optic atrophy that precludes future useful information about the presence of intracranial pressure because atrophic optic nerves do not swell and cannot reflect increased intracranial pressure. Other ocular signs of increased intracranial pressure include cranial nerve VI paresis, often manifesting as new-onset esotropia. Some children with hydrocephalus are at risk for superior oblique muscle dysfunction (cranial nerve IV) leading to strabismus, in which the esotropia is worse in upward gaze.

STRUCTURAL BRAIN ANOMALIES Children with schizencephaly frequently have decreased visual acuity due to damage to the optic radiations and pathways. Contralateral hemianopias and epilepsy are common clinical manifestations. Visual function in children with large schizencephalic clefts, as well as those with porencephaly or hydrocephalus, may improve despite a very abnormal appearance on neuroimaging once the patient is shunted and the cortex reexpands. [Summers and MacDonald, 1990]. There are numerous congenital disorders associated with brain malformations, such as the Walker-Warburg syndrome, Dandy-Walker syndrome, and muscle-eye-brain disease, in which structural brain anomalies (see Chapter 19) are accompanied by decreased visual function due to striate cortex involvement or associated ocular anomalies such as retinal dysplasia [Liu et al., 2000; Yamamoto et al., 2004].

VISION LOSS DUE TO EPILEPSY Children with epilepsy frequently have poor visual function. When the seizure disorder results from a structural abnormality, there is often concomitant strabismus, nystagmus, and developmental delay. Patients with seizures may develop visual auras before the seizure (see Chapter 44), and functional blindness during the postictal period [Bauer et al., 1991]. Children with frequent seizures throughout the day often have poor visual fixation development. Abnormal electrical activity can interfere with the development of useful vision [Trevathan et al., 1997]. The use of antiepileptic drugs may sedate the child to the point where general development is delayed, and this can affect development of visual acuity [Remler et al., 1990]. Optimizing antiepileptic drug therapy should be encouraged, because visual acuity can markedly improve when seizures are well controlled [Shahar and Barak, 2003]. Certain antiepileptic drugs such as vigabatrin may be associated with specific retinal or ophthalmic abnormalities (see Chapter 49).

DELAYED VISUAL MATURATION Occasionally, a healthy infant older than 2 months is referred because of failure of development of visual fixation behaviors.

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Results of ophthalmologic and neurologic examinations may be completely normal. Such infants may have the condition of delayed visual maturation, a diagnosis of exclusion in which visual development is delayed, but eventually becomes normal. Often, the onset of visual fixation is dramatic and usually occurs by 6 months of age. Three types of delayed visual maturation have been described [Fielder et al., 1991]. In type I, the child is healthy and has normal vision within 1 year of age. In type II, the child has associated neurologic or systemic disease, and in type III, ocular anomalies occur. Most ophthalmologists reserve the diagnosis of delayed visual maturation for children who have the type I form [Hoyt et al., 1983].

Diagnostic Evaluation of Infants with Poor Vision An infant who fails to develop visual fixation should first be referred to an ophthalmologist [Kivlin et al., 1990]. Examination by an ophthalmologist most often uncovers the causes of decreased vision, which may be caused by any of the congenital structural anomalies described previously. If examination findings are completely normal, the next considerations are a neurologic examination and possibly neuroimaging. Certain neurologic signs and symptoms may suggest a specific neurologic diagnosis [Backhouse et al., 1999]. Magnetic resonance imaging is preferred to computed tomography for evaluating structural anomalies. Neurometabolic testing should be performed to exclude reversible and potetially treatable inborn errors of metabolism involving carbohydrate or urea cycle metabolism or mitochondrial disorders [Cooper et al., 2002; Goebel, 1995; Hansen et al., 1979; Santavuori et al., 1993]. These conditions are decribed in detail in various chapters in this textbook. In an infant with poor visual function but normal neurologic examination results and normal neuroimaging findings, electroretinography may be used to determine the presence of photoreceptor dysfunction. Such patients usually demonstrate signs of retinal disease including nystagmus and eye-pressing behavior. An electroretinogram is obtained by placement of contact lens attached to electrodes on the surface of the cornea. Lights are used to stimulate the retina and the electrical responses are recorded. Depending on the light stimulus, determination can be made whether there is rod-related (affecting night vision) or cone-related dysfunction that affects central vision or color, or both (see Fig. 6-9). Assessing prognosis of central visual acuity should be made with caution in children. Normative values for electroretinographic latencies in infants vary but changes in the electroretinogram can be recorded serially as children mature.

VISION LOSS IN CHILDREN The disease processes leading to vision loss in children are quite different from those affecting infants. Children often demonstrate different signs of vision loss and are often able to complain of symptoms associated with vision loss aiding in the evaluation and guiding diagnostic strategies.

Symptoms and Signs of Vision Loss Children with vision loss frequently do not complain about vision loss unless it is bilateral. Children often do not use the term blurred vision, but a child may say “I can’t see,”

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“things are fuzzy,” or “things are double.” Signs of vision loss are much more helpful. The first sign of vision loss is squinting behavior. When the child squints the eyelids closed, the pinhole effect helps focus out-of-focus light. This behavior is common in children with refractive errors. Children also rub their eyes in attempt to clear their vision. Children with acute bilateral loss of vision will sit close to the television or become disinterested in activities occurring at a distance. They may hold objects very close to their faces to see them clearly. Children with new-onset strabismus associated with vision loss frequently close one eye to avoid diplopia. They may be sensitive to sunlight and shield their eyes because bright light may markedly decrease their visual acuity, especially when there is associated retinal dysfunction. Children may also tilt their heads when vision is reduced in one eye [Nucci and Rosenbaum, 2002].

Differential Diagnosis of Vision Loss in Children Refractive errors are the most common cause of vision loss in children. This form of vision loss is usually detected by a pediatrician who does a vision screening examination in the office or by the school district that mandates vision checks in kindergarten or first grade. Vision loss may be unilateral or bilateral. Three types of refractive errors can occur. In myopia or nearsightedness, distant images are out of focus, and diverging lenses placed over the eyes allow the patient to see clearly at a distance and at a close range. Hyperopia, or farsightedness, is associated with an optical system that requires constant accommodation, which requires distant and near sight. Hyperopic children frequently complain of fatigue and strain when reading as their hyperopia requires extra effort for near activities. These children often are prescribed glasses to be used when reading or doing other activities that require near vision. In astigmatism, irregular curvature of the cornea can lead to a decrease in distant and near visual acuity, and spectacles can be helpful for both distances. When vision loss is caused by refractive error, correcting the refractive error yields 20/20 vision in each eye.

Amblyopia Amblyopia is decreased visual acuity caused by abnormal cortical stimulation of the developing visual system. There are three causes of amblyopia in children. Deprivation amblyopia occurs when an optical visual impediment in the eye prevents focused light from being received on the retina and transmitted to the developing occipital striate cortex. Conditions such as congenital cataract, infantile vitreous hemorrhage, or complete ptosis can lead to deprivation amblyopia. To treat this form of amblyopia, the visual impediment needs to be removed (e.g., cataract surgery in infants), and focused vision is restored. In strabismic amblyopia, a misalignment to the visual axis does not lead to diplopia in young children because the child quickly develops a fixation preference in one eye over the other leading to amblyopia in the deviated eye. In anisometropia, unequal refractive errors between the two eyes leads to unequal, unfocused visual stimuli from one eye compared with the other that results in decreased visual acuity. Amblyopia is a functional and structural condition wherein an abnormal visual stimulus leads to abnormal development of cortical visual processing cells with smaller cell size and

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abnormal intercellular connections [Hubel and Wiesel, 1962]. These structural changes are reversible if detected early in life and treated with occlusion therapy. By removing the visual impairment, straightening the eye or by focusing the vision through spectacles and then patching the unaffected eye to stimulate the immature visual system, amblyopia can be reversed. Whether or not vision can be restored depends on the age of detection. Success in reversing amblyopia lies in the underlying causative factor and the amount of compliance with occlusion therapy. Visual deprivation amblyopia is the most profound and must be reversed within the first few months of age whereas anisometropic amblyopia can be reversed even in the second decade of life with aggressive patching therapy. As a rule, most children with amblyopia should be detected and treated by the age of 6 months for the best visual prognosis.

Ocular Anomalies Causing Vision Loss In an infant with vision loss, it is helpful to systematically approach the eye from an external to an internal point to evaluate for causes of vision impairment.

EYELID ABNORMALITIES: PTOSIS Ptosis can be a cause of vision loss and a localizing sign of underlying impairment. Ptosis most commonly occurs as a congenital anomaly of the development of the levator muscle of the upper eyelid. During development, fatty infiltration may occur with abnormal muscle formation. Ptosis may be unilateral or bilateral. Ptosis may be so profound that it occludes the visual axis, leading to deprivation amblyopia. The eyelid may rest over the cornea and be associated with significant astigmatism that can lead to anisometropic amblyopia. Other forms of congenital ptosis include congenital third nerve palsy and the congenital fibrosis syndrome, which are associated with abnormalities of all extraocular muscles with very abnormal eye movements. Neurologic causes of ptosis in children include infant botulism, congenital Horner’s syndrome (associated with congenital neuroblastoma), or Marcus Gunn jaw wink syndrome, a synkinesis with eyelid bobbing occurring during masseter muscle function and chewing due to synkinesis of cranial nerves V and III.

CORNEAL ANOMALIES Although most corneal anomalies are structural anomalies seen in infants such as Peters’ syndrome or scleralization of the cornea, acquired corneal dystrophies and degenerations can lead to vision loss. Keratoconus is a condition in which the cornea achieves extreme corneal curvature associated with peripheral corneal thinning. This anomaly is detectable by refractive changes and with slit-lamp examination. Some metabolic diseases manifest with corneal changes leading to vision loss. These include the mucopolysaccharidoses such as Hurler syndrome, which is associated with corneal clouding, and Fabry’s disease, which can lead to deposition of material in the cornea, decreasing visual acuity.

OCULAR ANOMALIES: IRIS Inflammation of the pigmented tissues of the eyes is a condition called uveitis. The most common cause of uveitis in

children is found in conjunction with juvenile rheumatoid arthritis, especially in girls with pauciarticular, antinuclear antibody–positive juvenile rheumatoid arthritis. Up to 70% of these children may develop recurring iritis during the course of their disease. This form of iritis usually is not related to visual or ocular symptoms, because inflammation may not cause decreased visual acuity, pain, or redness, signs that are usually present in association with iritis when it occurs in adults. Iritis can cause decreased vision because it may develop in association with glaucoma or cataracts.

ANOMALIES OF THE RETINA Degenerative diseases of the retina can cause gradual loss of visual acuity and may be extremely difficult to diagnose in young children (Table 6-1). Unlike congenital retinal dysfunction that leads to large-amplitude nystagmus, marked vision impairment, and clear-cut electroretinographic findings, retinal degeneration in older children may be insidious in onset, unaccompanied by significant visual symptoms and with equivocal findings on electroretinography. One of the most common causes of visual dysfunction due to retinal dysfunction is Stargardt’s disease [Weleber et al., 1984; Weleber, 2002], also known as fundus flavimaculatus. This disease is a degenerative condition of the retinal pigment epithelium leading to photoreceptor dysfunction [Szlyk et al., 1998]. There is a defect in flipase (ABCA4), with different mutations causing different presentations [Weber, TABLE 6-1 Neurologic Disease Associated with Vision Loss and Retinal Abnormalities CONDITION Neuronal ceroid lipofuscinosis Abetalipoproteinemia Refsum’s disease Cockayne’s syndrome Bardet-Biedl syndrome Kearns-Sayre syndrome Hallervorden-Spatz syndrome Aicardi’s syndrome Alström’s syndrome Gangliosidoses Tay-Sachs disease Sandhoff’s disease Mucopolysaccharidoses Hunter’s syndrome Hurler syndrome Sanfilippo’s syndrome Scheie’s syndrome Zellweger’s syndrome Friedreich’s ataxia Niemann-Pick disease Sialidosis Farber’s syndrome Metachromatic leukodystrophy Spinocerebellar ataxia Gaucher’s disease Adrenoleukodystrophy +, Positive association.

CHERRY-RED MACULAR SPOT DYSTROPHY +

PIGMENTARY CHANGES + + + + + + + + +

+ +

+

+ + + + + +

+

+

+ + + + + +

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funduscopic appearance, and ophthalmoscopic examination coupled with electrophysiologic testing can help diagnose these children who present with seizures and progressive dementia [Cotlier, 1971]. Retinal dysfunction occurs in inherited mitochondrial cytopathies such as Kearns-Sayre syndrome, in which a pigmentary retinopathy is associated with decreased visual acuity, external ophthalmoplegia, and cardiac conduction defects. Retinitis is an unusual cause of vision loss in children, but it can occur in patients with cytomegalovirus infection, herpes simplex or zoster infection, cat-scratch disease, and Lyme disease [Clarke et al., 2001; Dreyer et al., 1984; Purdy et al., 2003]. A history of immune suppression or recent systemic illness also can suggest the appropriate diagnosis.

FIGURE 6-10. Children with degenerative retinal disease often present with pigmentary changes in the retinal pigment epithelium, such as this granular- and mottled-appearing peripheral retina. See also Color Plate.

2003]. Children present with slowly decreasing visual acuity. There are characteristic changes on funduscopic examination, and diagnostic tests such as fluorescein angiography, visualfield testing, and electroretinography can help confirm the diagnosis (Fig. 6-10). Mutations of the gene involved in phototransduction have been identified and characterized in some families with this condition [Zack et al., 1999].

RETINITIS PIGMENTOSA In retinitis pigmentosa, abnormalities of the retinal pigment epithelium can lead to photoreceptor dysfunction and death. Retinitis pigmentosa typically affects rods before affecting cones [Foxman et al., 1985; Heidemann and Beck, 1987]. This process leads to initial symptoms of night blindness and constriction of the peripheral visual field, eventually affecting cones and central visual acuity. A typical “bone spicule” pattern of the retinal pigment epithelium is diagnostic. Electrodiagnostic tests such as electroretinography may be helpful. Retinitis pigmentosa has been characterized as involving rods or cones or both. All modes of inheritance patterns have been described, and there may be variations of phenotypic expression within families. Although some investigators feel that vitamin supplementation may delay disease progression, there have been no studies proving any benefit of any treatment intervention for retinitis pigmentosa in children [Szlyk et al., 1998].

Optic Nerve Disorders PAPILLEDEMA The presence of increased intracranial pressure leads to edema of the optic nerve (i.e., papilledema). The borders of the optic nerve are indistinct, and the vessels are swollen; the nerve itself is elevated, with surrounding hemorrhage or exudates (Fig. 6-11). Papilledema in children can be caused by obstruction of the ventricular system, craniosynostosis [Fishman et al., 1971; Stavrou et al., 1997], or communicating hydrocephalus. Whereas early papilledema in adults rarely causes visual symptoms, papilledema can be chronic in children, with slow onset and relatively late discovery of disease, and decreased visual acuity can be a presenting complaint. Usually, this does not occur unless the increase in intracranial pressure is rapid and significant in onset or has been of long duration, leading to chronic axonal compression and edema formation in the retina and causing decreased visual acuity or cell death and incipient optic atrophy. For papilledema in children, mandatory neuroimaging should be followed by lumbar puncture [Brodsky and Glasier, 1995]. Papilledema also occurs in children with malignant hypertension leading to permanent vision loss if not corrected [Browning et al., 2001]. Pseudotumor cerebri or benign intracranial hypertension is not an infrequent

NEUROMETABOLIC RETINAL DYSFUNCTION Several neurometabolic disorders have been associated with retinal dysfunction and secondary vision loss [Collins et al., 1990]. In neuronal ceroid lipofuscinosis, abnormal accumulation of neurotoxic products within the retina leads to cell dysfunction and death [Backhouse et al., 1999; Bohra et al., 2000; Brown et al., 1993; Fulton et al., 1985; Spalton et al., 1980] (see Chapter 59). There are multiple forms of neuronal ceroid lipofuscinosis occurring in different age groups. Characteristic of all forms of neuronal ceroid lipofuscinosis is the development of decreased visual acuity resulting from poor retinal function [Bohra et al., 2000]. Degeneration of the ganglion cell layer results in a typical

FIGURE 6-11. Severe papilledema in a patient with idiopathic intracranial hypertension. Notice the swollen and elevated nerve, peripapillary hemorrhage and engorged retinal veins, and blurring of the disc margins. See also Color Plate.

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cause of papilledema in overweight children [Baker et al., 1985, 1989]. The diagnosis is made after neuroimaging excludes an obstructive lesion and lumbar puncture reveals increased intracranial pressure and no abnormal cytology. Occasionally, pseudotumor cerebri may be associated with sinovenous thrombosis that can be detected with magnetic resonance venography. Because many drugs can cause benign intracranial hypertension, the treatment is withdrawing inciting agents such as tetracycline and its derivatives and vitamin A analogs. Improvement is also seen with substantial weight loss. Visual dysfunction associated with possible secondary ischemic optic neuropathic changes should prompt consideration for optic nerve sheath fenestration or lumbar or ventriculoperitoneal shunting to relieve pressure to prevent permanent loss of visual acuity [Brodsky and Rettele, 1998].

PSEUDOPAPILLEDEMA In pseudopapilledema, the optic nerve appears to be elevated, but there is a lack of edema surrounding the nerve, which is seen with true papilledema (Fig. 6-12). Pseudopapilledema can be seen with optic nerve head drusen. Optic nerve drusen are extracellular deposits of material within the nerve fiber layer that cause a lumpy elevation of the optic nerve. Later in childhood, the material develops a glistening calcific appearance and can be easily detected by autofluorescence angiography or by ultrasonography [Bec et al., 1984; Friedman et al., 1977]. In earlier stages of the disease, the bright signal intensity and reflective characteristics are not as evident, making the diagnosis one of exclusion considered only after lumbar puncture and neuroimaging have eliminated more dangerous conditions [Savage et al., 1985]. Pseudopapilledema can also be seen in hyperopia, in which the nerve head may look elevated. The absence of hemorrhages and of blurred disc margins suggests that pseudopapilledema is more likely to be present. Serial examinations and documentation by photography can help differentiate true papilledema from pseudopapilledema [Mustonen, 1983].

OPTIC NEURITIS Whereas adults with optic neuritis usually present with unilateral disease, bilateral presentation is more common in

FIGURE 6-13. Frosted angiitis in an immunosuppressed patient with cytomegalovirus retinitis and neuritis. See also Color Plate.

children [Kennedy and Carol, 1960]. Children rarely complain of decreased vision in one eye. This phenomenon of failure to detect the unilateral disease may lead to the higher reported incidence of bilaterality and may be artifactual. Optic neuritis in children frequently follows viral illnesses and is most commonly associated with inflammation and swelling of the optic nerve head, and it may be accompanied by vasculitis (Fig. 6-13) [Bar et al., 1990; Chrousos et al., 1990; Winterkorn, 1990]. In children, there is usually edema of the optic nerve associated with loss of vision and an afferent pupillary defect, whereas in adults, most cases of optic neuropathy are retrobulbar with no visible changes on ophthalmoscopy [Sato et al., 1998]. Any demyelinating episode may be the first sign of multiple sclerosis, and the risk of a pediatric patient eventually developing multiple sclerosis varies from 7% to 56% [Bye et al., 1985]. A particular form of optic neuritis that occurs more frequently in children than adults is acute disseminated encephalomyelitis (ADEM), as described in Chapter 60 [Brodsky and Beck, 1994]. This can lead to peripheral neurologic changes, central visual loss, and decreased visual acuity. ADEM is usually responsive to corticosteroid or interferon treatment, but relapses can occur, and patients may be followed with magnetic resonance imaging and careful observation of vision, assessment of color vision, and examination of the pupils [Sato et al., 1998].

OPTIC ATROPHY

FIGURE 6-12. Optic disc drusen cause elevation of the optic nerve without obscuration of capillaries at the disc margin. The circumpapillary light reflex is intact, and there is no venous congestion. See also Color Plate.

In children, optic atrophy is often not diagnosed until both eyes are affected (Table 6-2). The most worrisome cause of optic atrophy is compressive disease of the optic nerve [Liu, 2001; Varma et al., 2003]. Atrophy may occur from increased intracranial pressure due to obstructive intracranial lesions or from compression of the optic nerve from orbital processes or intrinsic tumors of the optic nerve leading to optic atrophy (e.g., optic nerve gliomas) [Belgaumi et al., 1997; Fletcher et al., 1986]. Children with optic atrophy should undergo neuroimaging to establish a specific diagnosis. When neuroimaging fails to demonstrate compressive lesions, hereditary optic atrophy should be considered [Brown, 1990; Eliott et al., 1993; Vinkler et al., 2003]. Kjer’s optic atrophy is transmitted in an autosomal-dominant pattern and

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TABLE 6-2 Neurologic Disease Associated with Vision Loss and Optic Atrophy CATEGORY

DISEASE OR SYNDROME

Developmental anomalies

Optic nerve hypoplasia Septo-optic dysplasia or de Morsier’s syndrome Prenatal or perinatal ischemia Infarction Periventricular leukomalacia White matter disease of prematurity Cerebral structural anomalies Hydrocephalus Schizencephaly Walker-Warburg syndrome Encephalocele Holoprosencephaly

Degenerative disease

Leukodystrophies Adrenoleukodystrophy Krabbe’s leukodystrophy Pelizaeus-Merzbacher disease Alexander’s disease Canavan’s disease Leigh’s syndrome Lysosomal disorders Gangliosidoses GM1 and GM2 Mucopolysaccharidoses Niemann-Pick disease Ataxias Friedreich’s ataxia Charcot-Marie-Tooth disease Miscellaneous conditions Neuronal ceroid lipofuscinosis Wolfram’s syndrome Zellweger’s syndrome

Inflammatory conditions

Infectious diseases Collagen-vascular disease Autoimmune disorders

Ischemic conditions

Renal disease Sickle cell disease Moyamoya disease

Trauma

Direct Indirect

Demyelinating conditions

Optic neuritis Acute disseminated encephalomyelopathy Multiple sclerosis Leigh’s disease

Compressive conditions

Pituitary tumor Hypothalamic tumor Craniopharyngioma Optic nerve glioma Optic nerve meningioma Rhabdomyosarcoma Papilledema Idiopathic intracranial hypertension Craniosynostosis or craniofacial dysostosis

Hereditary conditions

Kjer’s optic atrophy Leber’s congenital amaurosis Mitochondrial cytopathy

Toxicities

Lead Copper Streptomycin Hydroxyquinolones Methanol Ethambutol

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presents with slow onset of visual acuity loss, first in a 20/80 to 20/100 range and then stabilizing in the 20/400 range. Kjer’s optic atrophy has been mapped to OPA1 on chromosome 3 [Egan and Kerrison, 2003]. Wolfram’s disease includes optic atrophy as one of its clinical features (i.e., diabetes insipidus, diabetes mellitus, optic atrophy deafness [DIDMOAD]), and this autosomal-recessive condition maps to WFS1 on chromosome 4p (Egan and Kerrison, 2003). Examination of parents, siblings, and other relatives can be helpful in the diagnosis of hereditary optic neuropathies [Brown et al., 1997a; Kline and Glasier, 1979]. Neurometabolic diseases may cause optic atrophy and are usually diagnosed by the constellation of neurologic and physical findings associated with the disease [Huber, 1994]. Ischemic optic neuropathy has been described in children with underlying renal insufficiency in which the patient develops sudden changes in blood pressure because of illness or blood loss [Bates et al., 1999; Browning et al., 2001; Thomas et al., 2003]. When children sustain damage to the CNS prenatally or perinatally, damage to the occipital cortex and radiations can lead to death of the ganglion cells by transsynaptic degeneration across the lateral geniculate nucleus [Miller and Newman, 1981]. This damage is most commonly seen in preterm infants with periventricular leukomalacia in which optic atrophy may be accompanied by extensive optic cupping due to death of the ganglion cell. Neuroimaging demonstrates periventricular leukomalacia or other white matter injury, and it can help confirm the diagnosis when suspected because of premature birth or birth accompanied by hypoxic-ischemic encephalopathy [Uggetti et al., 1997]. Toxic optic neuropathies can occur with exposure or ingestion of heavy metals, disorders of mineral metabolism, and poisoning from methanol or medications such as ethambutol (see Chapter 87). Another group of disorders that can lead to optic atrophy are the mitochondrial encephalopathies (see Chapter 28). Patients with maternally transmitted Leber’s hereditary optic neuropathy present with loss of visual acuity in the second decade of life [Acaroglu et al., 2001; Newman, 1993]. This is associated with characteristic unilateral changes in the optic nerve head and telangiectatic changes in the optic nerve head vessels. Bilateral involvement frequently develops within months. There have been numerous genetic polymorphisms described in patients with Leber’s optic atrophy, and molecular DNA testing is available [Johns et al., 1992, 1993]. Included in this group of disorders is Kearns-Sayre syndrome, mitochondrial encephalomyopathy with lactic acidosis and strokelike syndrome (MELAS) [Rummelt et al., 1993], and myoclonic epilepsy with ragged red fiber disease (MERRF) (see Chapter 28).

CEREBRAL VISION IMPAIRMENT Whereas cerebral vision impairment in infants results from ischemic encephalopathy or white matter disease, impairment in older children usually is traumatic in nature [Billingsley et al., 2002]. An ischemic episode such as a near drowning, meningitis, or stroke can also cause cortical vision impairment. Toxic cortical blindness can be caused by vincristine, cyclosporine, and tacrolimus. Therapy should

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be discontinued in the children receiving these agents to reverse the symptoms [Jarosz et al., 1997; Schouten et al., 2003]. Visual acuity can be profoundly affected and show slow, progressive improvement over 1 to 2 years. The diagnosis is made by a combination of history, neuroimaging, and normal ocular examination findings.

NYSTAGMUS IN INFANCY Like the visual system, the ocular motor system is immature at birth. Abnormal eye movement such as ocular flutter, bobbing, saccadic intrusions, or saccadic paresis may be transient in the first few weeks of life, but they usually resolve completely. Nystagmus, or oscillation of the eyes in a stereotypic fashion, is rarely seen at birth but usually develops by 2 months of age. There are three primary causes of nystagmus in infancy, each having different visual consequences and health considerations [Lambert et al., 1989].

Nystagmus Caused by Visual Deprivation Any condition that causes failure of a formed visual image to be perceived by the striate cortex can lead to bilateral nystagmus (Table 6-3). The most common causes are bilateral congenital cataracts, bilateral optic nerve hypoplasia, aniridia, albinism, and retinal anomalies. When the visual acuity is less than 20/200, nystagmus can be large in amplitude and slow in frequency at birth, but it usually becomes more rapid with a lower amplitude later in life. Depending on TABLE 6-3 Causes of Bilateral Infantile Vision Impairment Manifesting with Nystagmus by Age 2 Months CATEGORY

CAUSE OF IMPAIRMENT

Disorders of corneal clarity

Developmental anomalies Peters’ syndrome Rieger’s syndrome Sclerocornea Congenital glaucoma Forceps birth trauma

Crystalline lens opacity

Congenital cataract

Uveal anomalies

Aniridia Oculocutaneous or ocular albinism

Vitreous anomalies

Vitreous hemorrhage Persistent hyperplastic primary vitreous

Retinal anomalies

Leber’s congenital amaurosis Achromatopsia or monochromatopsia Retinopathy of prematurity Retinal dysplasia Chorioretinal scarring Congenital toxoplasmosis Chorioretinal coloboma

Optic nerve anomalies

Optic nerve hypoplasia Optic nerve atrophy Optic nerve coloboma Morning glory disc

interventions to clear the visual axis and improve visual acuity, nystagmus may decrease, and visual acuity may be quite good if the condition is detected and treated early [Jan et al., 1990]. If the structural anomaly is in the optic nerve or in the retina, surgical or optical interventions are usually not helpful in significantly improving visual acuity. The presence of an ocular anomaly usually obviates the need for additional neuroimaging and assessment.

Nystagmus Due to Cerebral Disease Brain tumors can cause nystagmus. The nystagmus may be monocular or binocular and can occur in any pattern. Intracranial lesions can cause abnormal eye movements but are usually associated with other neurologic signs and symptoms associated with obstructive hydrocephalus or developmental anomalies. Differentiating children with intracranial pathologies from those with ocular anomalies usually is based on results of the ophthalmic and neurologic examinations. Neuroimaging may be needed to determine whether an underlying neurologic process is causing the patient’s abnormal eye movements.

Congenital Motor Nystagmus Congenital motor nystagmus is a diagnosis of exclusion. If ocular examination has revealed no abnormality, electroretinography has found normal retinal function, and neuroimaging has demonstrated no abnormal structural or functional anomalies of the brain, the diagnosis of congenital motor nystagmus can be considered. Often, the diagnosis can be made without electrophysiologic testing or neuroimaging. There is frequently a family history of nystagmus occurring in siblings, parents, or grandparents. The nystagmus often is similar to that observed in other family members. It is coarse at onset, with a slow frequency and high amplitude, and becomes more rapid but smaller in magnitude with maturation. Between the ages of 2 to 4 years, children develop good head and neck control that allows the child to move in certain positions to dampen the frequency and the amplitude of the nystagmus. This condition is called the null point; patients gaze or hold their heads in positions so that the eyes demonstrate minimal movement, which affords them the best visual acuity possible. It is important to explain to parents that children with nystagmus do not experience oscillopsia and that their visual acuity is decreased because they do not process the visual information when the eyes are not aligned toward the object of regard. By placing the eyes in the null point, the amount of time spent not looking at the object of regard decreases, and visual acuity increases. When testing children with nystagmus, it is important to test monocularly and binocularly because occlusion of one eye can greatly increase the amplitude and frequency of nystagmus and result in decreased visual acuity measurements. Although congenital motor nystagmus is presumed to arise from a neurologic abnormality of fixation, it is not known whether the molecular defect is located in the eye or in the brain. It may be inherited as an autosomal-dominant, autosomal-recessive, or X-linked disease. Congenital motor nystagmus has been linked to Xq26-q27 [Kerrison et al., 1999].

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TRANSIENT EPISODIC VISION LOSS IN CHILDREN To hear a child complain about occasional abnormal vision is not a rare phenomenon. School-age children frequently complain about blurred vision after prolonged distance or near-visual tasks such as reading, taking tests, or taking notes from the white board. These symptoms are usually brief and resolve after a short period of rest. Complaints of more profound transient and episodic visual loss or blindness should make the clinician consider three causes: intracranial hypertension, migraine, and functional vision loss. Increased intracranial pressure can cause transient obscuration of vision, especially when children change position from supine to standing. They may also complain of positive scotoma and “black-out spells.” Migraines in children do not usually manifest as classic migraines but frequently have an atypical presentation with vision loss, frequent episodes of abdominal pain, and absence of headache [Barlow, 1994; Ehyai and Fenichel, 1978]. Obtaining a family history of migraines and excluding intracranial pathology is important in establishing this frequently missed diagnosis [Hockaday, 1979; Tomsak and Jergens, 1987]. A child may complain about decreased visual acuity but have normal vision without ocular pathology. This form of functional visual loss has a variety of causes and may be difficult to diagnose and detect [Schwartz and Vahgei, 1998]. Children most often complain about bilateral vision loss and initially report visual acuity in the 20/400 range. Their symptoms may be exaggerated, but the children rarely bump into objects when entering a room despite reports of markedly diminished visual acuity. This is a diagnosis of exclusion, and children should be carefully examined perhaps on repeated occasions before the diagnosis is made. The ophthalmologist can use certain techniques to uncover functional visual loss, including placing the child behind the phoropter and surreptitiously and purposefully blurring the vision using high plus lenses and then uncovering one eye or the other and monitoring visual acuity as the vision is being cleared. Often, patients with functional vision loss have miraculous improvement of vision when given a pair of glasses with very low refractive power. These children simply want a pair of glasses and are pretending to have poor visual acuity. Other children who are feigning vision loss to seek attention may be more difficult to diagnosis. An inconsistency between near visual acuity and distance visual acuity, the presence of stereovision when tested with polarized lenses, and nonphysiologic visual fields should cause the examiner to suspect functional visual loss [Mewasingh et al., 2002]. Functional visual loss is a diagnosis of exclusion only after the patient has had a thorough ophthalmic examination and more than one measurement of visual acuity. Occasionally, the practitioner must resort to neuroimaging and or electrophysiologic retinal testing before becoming confident in diagnosing functional vision loss. After the diagnosis is made, supportive reassurance for the child and the family that vision will return and that the child will be able to see usually leads to rapid clearing of the visual “impairment.” Special consideration should be given to children, because there have been numerous cases of sexual abuse occurring in children who present with decreased visual acuity [Kathol et al., 1983].

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Brodsky MC, Glasier CM, Pollock SC, et al. Optic nerve hypoplasia. Identification by magnetic resonance imaging. Arch Ophthalmol 1990;108:1562. Brodsky MC, Rettele GA. Protracted postsurgical blindness with visual recovery following optic nerve sheath fenestration. Arch Ophthalmol 1998;116:107. Brown AM. Development of visual sensitivity to light and color vision in human infants: A critical review. Vision Res 1990;30:1159. Brown FR 3rd, Voigt R, Singh AK, et al. Peroxisomal disorders. Neurodevelopmental and biochemical aspects. Am J Dis Child 1993;147:617. Brown J Jr, Fingert JH, Taylor CM, et al. Clinical and genetic analysis of a family affected with dominant optic atrophy (OPA1). Arch Ophthalmol 1997a;115:95. Brown R, Hobson RP, Lee A, et al. Are there “autistic-like” features in congenitally blind children? J Child Psychol Psychiatry 1997b;38:693. Browning AC, Mengher LS, Gregson RM, et al. Visual outcome of malignant hypertension in young people. Arch Dis Child 2001;85:401. Bye AM, Kendall B, Wilson J. Multiple sclerosis in childhood: A new look. Dev Med Child Neurol 1985;27:215. Carden SM, Boissy RE, Schoettker PJ, et al. Albinism: Modern molecular diagnosis. Br J Ophthalmol 1998;82:189. Carney SH, Brodsky MC, Good WV, et al. Aicardi syndrome: More than meets the eye. Surv Ophthalmol 1993;37:419. Casteels I, Demaerel P, Spileers W, et al. Cortical visual impairment following perinatal hypoxia: Clinicoradiologic correlation using magnetic resonance imaging. J Pediatr Ophthalmol Strabismus 1997;34:297. Chestler RJ, France TD. Ocular findings in CHARGE syndrome. Six case reports and a review. Ophthalmology 1988;95:1613. Chrousos GA, Drack AV, Young M, et al. Neuroretinitis in cat scratch disease. J Clin Neuroophthalmol 1990;10:92. Clarke WN, Vomiero G, Leonard BC. Bilateral simultaneous retinal arteriolar obstruction in a child with hemoglobin SS sickle cell disease. J AAPOS 2001;5:126. Collins ML, Traboulsi EI, Maumenee IH. Optic nerve head swelling and optic atrophy in the systemic mucopolysaccharidoses. Ophthalmology 1990;97:1445. Cooper LL, Hansen RM, Darras BT, et al. Rod photoreceptor function in children with mitochondrial disorders. Arch Ophthalmol 2002;120:1055. Cotlier E. Tay-Sachs’ retina. Deficiency of acetyl hexosaminidase A. Arch Ophthalmol 1971;86:352. Daw NW. Mechanisms of plasticity in the visual cortex. The Friedenwald Lecture. Invest Ophthalmol Vis Sci 1994;35:4168. Dreyer RF, Hopen G, Gass JD, et al. Leber’s idiopathic stellate neuroretinitis. Arch Ophthalmol 1984;102:1140. Droste PJ, Archer SM, Helveston EM. Measurement of low vision in children and infants. Ophthalmology 1991;98:1513. Dubowitz LM, Mushin J, De Vries L, et al. Visual function in the newborn infant: Is it cortically mediated? Lancet 1986;1:1139. Dubowitz LM, Mushin J, Morante A, et al. The maturation of visual acuity in neurologically normal and abnormal newborn infants. Behav Brain Res 1983;10:39. Dutton GN, Jacobson LK. Cerebral visual impairment in children. Semin Neonatol 2001;6:477. Ehyai A, Fenichel GM. The natural history of acute confusional migraine. Arch Neurol 1978;35:368. Egan RA, Kerrison JB. Survey of genetic neuro-ophthalmic disorders. Ophthalmol Clin North Am 2003;16:595. Eliott D, Traboulsi EI, Maumenee IH. Visual prognosis in autosomal dominant optic atrophy (Kjer type). Am J Ophthalmol 1993;115:360. Fazzi E, Lanners J, Danova S, et al. Stereotyped behaviours in blind children. Brain Dev 1999;21:522. Fielder AR, Mayer DL, Fulton AB. Delayed visual maturation. Lancet 1991;337:1350. Fishman MA, Hogan GR, Dodge PR. The concurrence of hydrocephalus and craniosynostosis. J Neurosurg 1971;34:621. Flanagan NM, Jackson AJ, Hill AE. Visual impairment in childhood: Insights from a community-based survey. Child Care Health Dev 2003;29:493. Fletcher WA, Imes RK, Hoyt WF. Chiasmal gliomas: Appearance and long-term changes demonstrated by computerized tomography. J Neurosurg 1986;65:154.

Foxman SG, Heckenlively JR, Bateman JB, et al. Classification of congenital and early onset retinitis pigmentosa. Arch Ophthalmol 1985;103:1502. Friedman AH, Beckerman B, Gold DH, et al. Drusen of the optic disc. Surv Ophthalmol 1977;21:373. Fulton AB, Hansen RM, Harris SJ. Retinal degenerations and brain abnormalities in infants and young children. Doc Ophthalmol 1985;60:133. Fulton AB, Hansen RM, Manning KA. Measuring visual acuity in infants. Surv Ophthalmol 1981;25:325. Gilbert C, Awan H. Blindness in children. BMJ 2003;327:760. Gilbert CE, Anderton L, Dandona L, et al. Prevalence of visual impairment in children: A review of available data. Ophthalmic Epidemiol 1999;6:73. Gloor P, Pulido JS, Judisch GF. Magnetic resonance imaging and fundus findings in a patient with Aicardi’s syndrome. Arch Ophthalmol 1989;107:922. Goebel HH. The neuronal ceroid-lipofuscinoses. J Child Neurol 1995;10:424. Good WV. Development of a quantitative method to measure vision in children with chronic cortical visual impairment. Trans Am Ophthalmol Soc 2001;99:253. Good WV, Hoyt CS. Behavioral correlates of poor vision in children. Int Ophthalmol Clin 1989;29:57. Good WV, Jan JE, DeSa L, et al. Cortical visual impairment in children. Surv Ophthalmol 1994;38:351. Hansen E, Bachen NI, Flage T. Refsum’s disease. Eye manifestations in a patient treated with low phytol low phytanic acid diet. Acta Ophthalmol (Copenh) 1979;57:899. Heher KL, Traboulsi EI, Maumenee IH. The natural history of Leber’s congenital amaurosis. Age-related findings in 35 patients. Ophthalmology 1992;99:241. Heidemann DG, Beck RW. Retinitis pigmentosa. A mimic of neurologic disease. Surv Ophthalmol 1987;32:45. Hockaday JM. Basilar migraine in childhood. Dev Med Child Neurol 1979;21:455. Hoyt CS. Visual function in the brain-damaged child. Eye 2003;17:369. Hoyt CS, Fredrick DR. Cortically visually impaired children: A need for more study. Br J Ophthalmol 1998;82:1225. Hoyt CS, Jastrzebski G, Marg E. Delayed visual maturation in infancy. Br J Ophthalmol 1983;67:127. Hubel DN, Wiesel TN. Receptive fields, binocular interactions and functional architecture in the cats visual cortex. J Physiol 1962;160:106. Huber A. Genetic diseases of vision. Curr Opin Neurol 1994;7:65. Huo R, Burden SK, Hoyt CS, et al. Chronic cortical visual impairment in children: Aetiology, prognosis, and associated neurological deficits. Br J Ophthalmol 1999;83:670. Iinuma K, Lombroso CT, Matsumiya Y. Prognostic value of visual evoked potentials (VEP) in infants with visual inattentiveness. Electroencephalogr Clin Neurophysiol 1997;104:165. Jacobson L, Lundin S, Flodmark O, et al. Periventricular leukomalacia causes visual impairment in preterm children. A study on the aetiologies of visual impairment in a population-based group of preterm children born 1989-95 in the county of Varmland, Sweden. Acta Ophthalmol Scand 1998;76:593. Jan JE, Freeman RD. Who is a visually impaired child? Dev Med Child Neurol 1998;40:65. Jan JE, Groenveld M, Connolly MB. Head shaking by visually impaired children: A voluntary neurovisual adaptation which can be confused with spasmus nutans. Dev Med Child Neurol 1990;32:1061. Jarosz JM, Howlett DC, Cox TC, et al. Cyclosporine-related reversible posterior leukoencephalopathy: MRI. Neuroradiology 1997;39:711. Johns DR, Smith KH, Miller NR. Leber’s hereditary optic neuropathy. Clinical manifestations of the 3460 mutation. Arch Ophthalmol 1992;110:1577. Johns DR, Smith KH, Savino PJ, et al. Leber’s hereditary optic neuropathy. Clinical manifestations of the 15257 mutation. Ophthalmology 1993;100:981. Kathol RG, Cox TA, Corbett JJ, et al. Functional visual loss: II. Psychiatric aspects in 42 patients followed for 4 years. Psychol Med 1983;13:315. Kennedy C, Carroll FD. Optic neuritis in children. Arch Ophthalmol 1960;63:747.

Fredrick / Vision Loss Kerrison JB, Vagefi MR, Barmada MM, et al. Congenital motor nystagmus linked to Xq26-q27. Am J Hum Genet 1999;64:600. Kivlin JD, Bodnar A, Ralston CW, et al. The visually inattentive preterm infant. J Pediatr Ophthalmol Strabismus 1990;27:190. Kline LB, Glasier JS. Dominant optic atrophy. The clinical profile. Arch Ophthalmol 1979;97:1680. Lambert SR, Hoyt CS, Narahara MH. Optic nerve hypoplasia. Surv Ophthalmol 1987;32:1. Lambert SR, Kriss A, Taylor D. Vision in patients with Leber congenital amaurosis. Arch Ophthalmol 1997;115:293. Lambert SR, Taylor D, Kriss A. The infant with nystagmus, normal appearing fundi, but an abnormal ERG. Surv Ophthalmol 1989;34:173. Lanzi G, Fazzi E, Uggetti C, et al. Cerebral visual impairment in periventricular leukomalacia. Neuropediatrics 1998;29:145. Leger D, Guilleminault C, Santos C, et al. Sleep/wake cycles in the dark: Sleep recorded by polysomnography in 26 totally blind subjects compared to controls. Clin Neurophysiol 2002;113:1607. Leger D, Prevot E, Philip P, et al. Sleep disorders in children with blindness. Ann Neurol 1999;46:648. Levtzion-Korach O, Tennenbaum A, Schnitzer R, et al. Early motor development of blind children. J Paediatr Child Health 2000;36:226. Lewis TL, Maurer D. Preferential looking as a measure of visual resolution in infants and toddlers: A comparison of psychophysical methods. Child Dev 1986;57:1062. Liu GT, Hunter J, Miki A, et al. Functional MRI in children with congenital structural abnormalities of the occipital cortex. Neuropediatrics 2000;31:13. Liu GT. Visual loss in childhood. Surv Ophthalmol 2001;46:35. Marcel AJ. Blindsight and shape perception: Deficit of visual consciousness or of visual function? Brain 1998;121(Pt 8):1565. Mayer DL, Fulton AB. Preferential looking grating acuities of infants at risk of amblyopia. Trans Ophthalmol Soc U K 1985;104(Pt 8):903. Mayer DL, Fulton AB, Hansen RM. Visual acuity of infants and children with retinal degenerations. Ophthalmic Paediatr Genet 1985;5:51. McCulloch DL, Taylor MJ. Cortical blindness in children: Utility of flash VEPs. Pediatr Neurol 1992;8:156. Merin S, Crawford JS. The etiology of congenital cataracts. A survey of 386 cases. Can J Ophthalmol 1971;6:178. Mervis CA, Yeargin-Allsopp M, Winter S, et al. Aetiology of childhood vision impairment, metropolitan Atlanta, 1991-93. Paediatr Perinat Epidemiol 2000;1 4:70. Mewasingh LD, Kornreich C, Christiaens F, et al. Pediatric phantom vision (Charles Bonnet) syndrome. Pediatr Neurol 2002;26:143. Miller NR, Newman SA. Transsynaptic degeneration. Arch Ophthalmol 1981;99:1654. Mintz-Hittner HA, Ferrell RE, Sims KB, et al. Peripheral retinopathy in offspring of carriers of Norrie disease gene mutations. Possible transplacental effect of abnormal Norrin. Ophthalmology 1996;103:2128. Mustonen E. Pseudopapilloedema with and without verified optic disc drusen. A clinical analysis I. Acta Ophthalmol (Copenh) 1983;61:1037. Newman NJ. Leber’s hereditary optic neuropathy. New genetic considerations. Arch Neurol 1993;50:540. Nixon RB, Helveston EM, Miller K, et al. Incidence of strabismus in neonates. Am J Ophthalmol 1985;100:798. Nucci P, Rosenbaum A. Acquired anomalous head posture following loss of vision in one eye. Acta Ophthalmol Scand 2002;80:109. Okawa M, Nanami T, Wada S, et al. Four congenitally blind children with circadian sleep-wake rhythm disorder. Sleep 1987;10:101. Palm L, Blennow G, Wetterberg L. Long-term melatonin treatment in blind children and young adults with circadian sleep-wake disturbances. Dev Med Child Neurol 1997;39:319. Pierce EA, Mukai S. Controversies in the management of retinopathy of prematurity. Int Ophthalmol Clin 1994;34:121. Purdy KW, Heckenlively JR, Church JA, et al. Progressive outer retinal necrosis caused by varicella-zoster virus in children with acquired immunodeficiency syndrome. Pediatr Infect Dis J 2003;22:384. Remler BF, Leigh RJ, Osorio I, et al. The characteristics and mechanisms of visual disturbance associated with anticonvulsant therapy. Neurology 1990;40:791. Rummelt V, Folberg R, Ionasescu V, et al. Ocular pathology of MELAS syndrome with mitochondrial DNA nucleotide 3243 point mutation. Ophthalmology 1993;100:1757. Russell-Eggitt IM, Blake KD, Taylor DS, et al. The eye in the CHARGE

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association. Br J Ophthalmol 1990;74:421. Santavuori P, Vanhanen SL, Sainio K, et al. Infantile neuronal ceroid-lipofuscinosis (INCL): Diagnostic criteria. J Inherit Metab Dis 1993;16:227. Sato K, Adachi-Usami E, Mizota A. Follow-up studies on pattern reversal visually evoked cortical potentials in a 2-year-old child with optic neuritis. J Neuroophthalmol 1998;18:21. Savage GL, Centaro A, Enoch JM, et al. Drusen of the optic nerve head—an important model. Ophthalmology 1985;92:793. Schouten D, de Graaf SS, Verrips A. Transient cortical blindness following vincristine therapy. Med Pediatr Oncol 2003;41:470. Schwartz TL, Vahgei L. Charles Bonnet syndrome in children. J AAPOS 1998;2:310. Semba RD, Bloem MW. Measles blindness. Surv Ophthalmol 2004;49:243. Shahar E, Barak S. Favorable outcome of epileptic blindness in children. J Child Neurol 2003;18:12. Sher NA, Letson RD, Desnick RJ. The ocular manifestations in Fabry’s disease. Arch Ophthalmol 1979;97:671. Siatkowski RM, Sanchez JC, Andrade R, et al. The clinical, neuroradiographic, and endocrinologic profile of patients with bilateral optic nerve hypoplasia. Ophthalmology 1997;104:493. Skarf B, Hoyt CS. Optic nerve hypoplasia in children. Association with anomalies of the endocrine and CNS. Arch Ophthalmol 1984;102:62. Sokol S, Hansen VC, Moskowitz A, et al. Evoked potential and preferential looking estimates of visual acuity in pediatric patients. Ophthalmology 1983;90:552. Sonksen PM, Dale N. Visual impairment in infancy: Impact on neurodevelopmental and neurobiological processes. Dev Med Child Neurol 2002;44:782. Spalton DJ, Taylor DS, Sanders MD. Juvenile Batten’s disease: An ophthalmological assessment of 26 patients. Br J Ophthalmol 1980;64:726. Stavrou P, Sgouros S, Willshaw HE, et al. Visual failure caused by raised intracranial pressure in craniosynostosis. Childs Nerv Syst 1997;13:64. Sullivan TJ, Heathcote JG, Brazel SM, et al. The ocular pathology in Leber’s congenital amaurosis. Aust N Z J Ophthalmol 1994;22:25. Summers CG, MacDonald JT. Vision despite tomographic absence of the occipital cortex. Surv Ophthalmol 1990;35:188. Szlyk JP, Fishman GA, Grover S, et al. Difficulty in performing everyday activities in patients with juvenile macular dystrophies: Comparison with patients with retinitis pigmentosa. Br J Ophthalmol 1998;82:1372. Thomas WJ, Sahney S, Siegel LM. Acute visual loss in a child with autosomal recessive polycystic kidney disease: Case report and review of the literature. J AAPOS 2003;7:217. Thompson L, Kaufman LM. The visually impaired child. Pediatr Clin North Am 2003;50:225. Tomsak RL, Jergens PB. Benign recurrent transient monocular blindness: A possible variant of acephalgic migraine. Headache 1987;27:66. Trevathan E, Murphy CC, Yeargin-Allsopp M. Prevalence and descriptive epidemiology of Lennox-Gastaut syndrome among Atlanta children. Epilepsia 1997;38:1283. Uggetti C, Egitto MG, Fazzi E, et al. Transsynaptic degeneration of lateral geniculate bodies in blind children: in vivo MR demonstration. AJNR Am J Neuroradiol 1997;18:233. Varma D, George N, Livingston J, et al. Acute visual loss as an early manifestation of metastatic neuroblastoma. Eye 2003;17:250. Vinkler C, Lev D, Kalish H, et al. Familial optic atrophy with white matter changes. Am J Med Genet 2003;121A:263. Weber RG. Treatment of retinal and choroidal degenerations and dystrophies: Current status and prospects for gene based therapy. Ophthalmol Clin North Am 2003;16:583. Weleber RG. Infantile and childhood retinal blindness: A molecular perspective. The Franceschetti Lecture. Ophthalmic Genet 2002;23:71. Weleber RG, Tongue AC, Kennaway NG, et al. Ophthalmic manifestations of infantile phytanic acid storage disease. Arch Ophthalmol 1984;102:1317. Whiting S, Jan JE, Wong PK, et al. Permanent cortical visual impairment in children. Dev Med Child Neurol 1985;27:730. Winterkorn JM. Lyme disease: Neurologic and ophthalmic manifestations. Surv Ophthalmol 1990;35:191. Yamamoto T, Kato Y, Karita M, et al. Expression of genes related to muscular dystrophy with lissencephaly. Pediatr Neurol 2004;31:183.

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CHAPTER 7

Hearing Impairment Isabelle Rapin

Hearing problems, frequent in childhood, often go unrecognized. Physicians may not inquire about hearing or routinely screen for hearing impairment. Overlooking the hearing loss of a young child may result in a lifetime of deleterious consequences [Furth, 1966; Rapin, 1979]. The prevalence of conductive impairment resulting from chronic middle ear effusion is high among preschoolers. Its effect on language acquisition and later scholastic achievement is controversial but not negligible, especially in the face of another medical or social handicap [Gravel and Wallace, 2000; Kavanagh, 1986; Roberts and Wallace, 1997; Ruben, 2003]. The prevalence of severe-to-profound hearing loss is at least 1 case per 1000 children. Prelingual hearing loss precludes language learning without highly specialized and intensive habilitation and special education, unless the child happens to be the child of deaf parents whose language is sign language. Even today, most severely hearing-impaired children learn the oral and written language of their culture inadequately. The severe informational deprivation these children suffer because of inadequate language skills prevents many from achieving their cognitive and vocational potential.

ANATOMY AND PHYSIOLOGY OF THE EAR AND AUDITORY SYSTEM The ear and cranial nerve VIII provide information about sound, the angular acceleration of the head, and its position with respect to the vertical plane. Although audition and vestibular function are distinct, the inner ear contains the sensory receptor organs for both of these systems, which share a common blood supply and fluid milieu. Some pathologic conditions, notably many genetic and biochemical defects, affect the receptor cells of one or the other organ selectively. Other disorders such as vascular or inflammatory diseases or trauma are likely to be unselective and to affect both systems. The clinical consequences of damage to the vestibule are discussed in Chapter 8. Many excellent reviews of the anatomy and physiology of the ear are available [Brodal, 1981; Katz, 2002; Pickles, 1997; Wright, 1997].

Embryology and Anatomy Except for the pinna, the entire ear is encased in the temporal bone. The external ear consists of the pinna, external ear canal, and external surface of the tympanic membrane. Their embryologic origins are the first and second branchial arches and first branchial groove. The external ear begins to develop at about 40 days’ gestation and is completed by the

fourth month. The middle ear cavity derives from the first pharyngeal pouch at about the same time. The middle ear comprises the tympanic cavity, which communicates with the mastoid air cells and, through the eustachian tube, with the nasopharynx. Pressure in the middle ear is equalized with atmospheric pressure whenever the eustachian tube opens during swallowing or yawning. This air-filled middle ear contains the ossicular chain. The eardrum, ossicular chain, and stapes footplate form a complex impedancematching transformer that amplifies the sound energy approximately 22-fold in transferring sound pressure from the lateral surface of the tympanic membrane to the perilymphatic fluid of the cochlea. Contraction of the tensor tympani muscle, innervated by a branch of the masticator root of cranial nerve V, and especially of the stapedius muscle, innervated by cranial nerve VII, damp loud sound transmission. These muscles contract just before the start of phonation and attenuate the perceived loudness of one’s own voice. The middle ear contains the chorda tympani, which carries taste fibers and travels along the inner surface of the tympanic membrane, and the geniculate ganglion and facial nerve, which are encased in a bony canal in the wall of the middle ear. The inner ear has two parts: the cochlea (ventral) and the vestibule (dorsal); the latter comprises the three semicircular canals, utricle, and saccule (Fig. 7-1). The inner ear arises from the otic vesicle; its development begins at the end of the first month of gestation and is essentially complete in 50 days. It is encased in the otic capsule or bony labyrinth, which is adult size at birth. The auditory and vestibular receptors are located within the membranous labyrinth that is filled with a high-potassium fluid, the endolymph. The membranous labyrinth is separated from the bony labyrinth by the perilymph, a high-sodium plasma ultrafiltrate connected to the cerebrospinal fluid through the cochlear aqueduct. Maintenance of these ionic gradients, which is an energy-consuming process dependent on the metabolically active stria vascularis, is essential for generating the electrical potentials resulting from the bending of the stereocilia on the endolabyrinthine surface of the vestibular and cochlear hair cells. There are three fluid-filled spaces in the cochlea: the perilymph-filled scala vestibuli and scala tympani, which communicate at the apex of the cochlea through the helicotrema, and the endolymph-filled scala media, which contains the organ of Corti. The footplate of the stapes is encased in the oval window of the scala vestibuli. The round window of the scala tympani is covered by a compliant membrane that bulges outward when the stapes footplate compresses the perilymph. The perilymphatic space of the scala tympani is continuous with the subarachnoid space of

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Membranous ampulla (superior)

FIGURE 7-1. The intricate relationship of the semicircular canals, vestibule, and cochlea is depicted. The membranous labyrinth contains endolymph and is separated from the bony labyrinth by perilymph. The ampullae at the terminus of each semicircular canal open into the vestibule. A crista is contained within each ampulla. The superior portion of the vestibule is the utricle. The inferior portion is the saccule. The stapes footplate fits in the oval window of the scala vestibuli. Direction of flow of perilymph is indicated by the arrows. (Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)

the posterior fossa through the cochlear aqueduct, which is patent in neonates but barely detected or undetected in adults. Patency of the cochlear aqueduct in early life may be a factor in the higher prevalence of purulent endolabyrinthitis—which results in profound deafness with vestibular impairment [Merchant and Gopen, 1996] —among young children than among adults. The endolymphatic duct leads from the utriculosaccular duct of the vestibule to the endolymphatic sac located within the dura on the dorsal surface of the petrous bone, close to the internal acoustic meatus. Meniere’s disease, which is uncommon in children, is characterized by episodes of severe vertigo and tinnitus and a fluctuating, later progressive sensorineural hearing loss. Its pathology is associated with hydrops of the endolymphatic spaces, including the endolymphatic sac. One approach to its treatment is drainage of the sac or the use of other surgical approaches to decompress the endolabyrinthic space [Huang, 2002]. The scala media has the cross-sectional shape of a rightangle triangle whose apex is directed medially toward the modiolus (axis) of the cochlea and whose vertical side, the stria vascularis, is apposed to the osseous outer wall of the cochlea (Fig. 7-2). The floor of the scala media is formed by the basilar membrane and osseous spiral lamina, which separate the scala media from the scala tympani. The roof of the scala media is formed by Reissner’s membrane, sep-

arating it from the scala vestibuli. The organ of Corti sits on the basilar membrane, a coiled, mobile, truncated triangular membrane whose stiffer, narrower end is located at the base of the cochlea and whose wider, more pliable end is located at the apex. The organ of Corti comprises the auditory receptor cells, consisting of a single row of inner hair cells, the main auditory receptors, and three rows of outer hair cells that modulate acoustic reception. Specialized supporting cells, including the pillar cells that form the tunnel of Corti filled by the cortilymph, surround the hair cells. Inner hair cells have a single row of stereocilia of various lengths on their endolymphatic surfaces, whereas outer hair cells have three rows arranged in a W shape. The cilia of the outer hair cells are embedded in the tectorial membrane, a gelatinous membrane attached to the medial limbus of the scala media, as well as to supporting cells of the organ of Corti. The base of each of the approximately 3500 inner hair cells synapses with the dendrites of about 20 spiral ganglion cells, whereas the dendrites of a single smaller spiral ganglion cell contact about 10 outer hair cells, of which there are about 12,000. Axons of the inhibitory efferent olivocochlear bundle divide widely, each synapsing with many outer hair cells with which they make direct contact, whereas they terminate sparingly on the dendrites that make contact with the inner hair cells [Hunter-Duvar and Harrison, 1988].

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Ductus cochlearis Stria vascularis

Bone

Outer hair cells

Scala vestibuli Tectorial membrane

Spiral ligament

Organ of Corti

Vestibular membrane (Reissner)

Basilar membrane Inner hair cells

Scala tympani

Spiral artery

Spiral ganglion Capsule of ganglion cell Myelin sheath

FIGURE 7-2. Structural components of the organ of Corti. The flow of the perilymph results in movement of the scala media (cochlear partition), which vibrates around its attachment to the modiolus and osseous spiral lamina. The complex traveling wave in the basilar membrane produces unequal shearing forces on the stereocilia of groups of hair cells, which are the transducers of sound. (Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)

The first-order neurons of the auditory system reside in the spiral ganglion of Corti, located in the modiolus of the cochlea. The first-order neurons of the vestibular system form the ganglion of Scarpa, which is located at the base of the internal auditory meatus. The meatus contains the cochlear and vestibular divisions of cranial nerve VIII, including the descending fibers of the inhibitory olivocochlear tract, and the facial nerve, chorda tympani, and internal auditory artery and vein. The myelinated axons of the spiral ganglion neurons project to the cochlear nuclei of the medulla. They are of quite uniform caliber, which means that their conduction velocities are uniform, which is presumably important for the conduction of sounds. Axons from the base of the cochlea, which carry high-frequency sounds, project to the ventral cochlear nucleus and ventral portion of the dorsal cochlear nucleus; those from the apex of the cochlea, which carry low-frequency sounds, project to the dorsal portion of the dorsal cochlear nucleus (Fig. 7-3). Each spiral ganglion neuron is connected to five different types of neurons in the cochlear nuclei. Most of the auditory fibers cross the midline, forming the acoustic striae on the floor of the fourth ventricle as they course through the trapezoid body to form

the ascending lateral lemniscus. Relays in the central auditory pathway include the cochlear nuclei, superior olivary complex, nucleus of the lateral lemniscus, inferior colliculus, and medial geniculate body of the thalamus, where all fibers synapse before reaching the primary and secondary auditory cortices (areas 41 and 42) of the superior temporal gyrus. There is tremendous multiplication of auditory neurons and connections in the central auditory pathway; the 30,000 first-order neurons project on about 10 million neurons in the medial geniculate body of the rhesus monkey. Neurons of the primary auditory cortex in the temporal operculum project to the secondary auditory cortex (area 42) situated behind it. The secondary auditory areas of the two hemispheres are connected through fibers traveling in the body of the corpus callosum. They are also widely connected to other cortical areas, including frontal and temporoparietal language areas, the cingulate gyrus, and frontolateral cortices.

Physiology The relevant dimensions of sound are intensity, which is expressed in decibels (dB) of pressure, and frequency, which

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Clinical Evaluation / 7 FIGURE 7-3. Peripheral and central auditory pathway, which is both crossed and uncrossed and projects to the horizontally oriented auditory cortex of the planum temporale. There are about 300 times more fibers in the central auditory pathway than in cranial nerve VIII, and there are extensive connections between the left and right brainstem relays. (Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)

Medial geniculate body

Brachia of inferior colliculi

Inferior colliculus

Midbrain level

Nuclei of lateral lemnisci

Dorsal cochlear nucleus

Lateral lemnisci

Ventral cochlear nucleus

Restiform body

Spiral ligament Apical turn of bony labyrinth Spiral ganglion Scala tympani

Superior olivary complex

Trapezoid body Medulla level

is measured in cycles per second or hertz (Hz) [Allen, 1988; Wright, 1997]. Units of intensity and frequency are logarithmic. The decibel scale displayed on audiograms appears to be linear, but the units themselves are logarithmic. An increase of about 10 dB results in approximately doubling of subjective loudness. Audiometers are calibrated so that audiometric 0 (i.e., normal sensitivity or hearing level, or 0 dB of hearing loss) corresponds to the internationally accepted threshold of normal hearing for each frequency. The ear is most sensitive at about 2000 Hz and very sensitive between 1000 to 4000 Hz, with sensitivity decreasing rapidly below 100 Hz and above 4000 Hz. At the extremes of the audible frequency band, more sound pressure is required to reach threshold than in the middle, resulting in a U-shaped threshold sensitivity curve across frequencies. Localization of sound in space is in part mediated by differences in intensity and lag in phase of sounds reaching each of the ears. Processing of sound frequency, intensity, location, and onset and cessation takes place largely in brainstem auditory relays.

The primary role of the pinna is in sound localization. The middle ear acts as a sound amplifier that compensates for loss of sound energy as it is transmitted from air to fluid because of the much greater area of the tympanic membrane than that of the oval window, the vibration pattern of the eardrum, and the leverage of the ossicular chain. Sound in air is also transmitted to the cochlea through the skull, but it occurs at threshold intensities that exceed air conduction by 40 to 60 dB. Bone conduction is used in audiometry to distinguish middle ear hearing loss from sensorineural hearing loss. At the bedside, the clinician tests for conductive hearing loss with the Weber test, by placing a vibrating tuning fork on top of the head, which is heard better in the ear with a conductive loss than in the opposite ear, and by the Rinne test, in which the sound of a vibrating tuning fork is heard better and longer when it is placed on the mastoid process of an ear with a conductive hearing loss than when it is held in front of that ear.

Rapin / Hearing Impairment

The piston action of the stapes footplate generates pressure waves in the perilymph that travel from the basal turn to the apex of the cochlea. These traveling waves induce complex radial and longitudinal displacements of the basilar membrane and organ of Corti, with the net result of bending of the stereocilia of particular subpopulations of hair cells. The frequency and intensity of the sound determine which areas of the basilar membrane sustain maximum displacement. The hair cells are the transducers from mechanical energy to sensory stimulation; their action depends on the ionic gradients of the various compartments of the cochlea. Frequency selectivity of the cochlea is the result of the following mechanisms: 1. Low-pitched sounds produce maximum displacement of the basilar membrane near the apex of the cochlea, whereas high-pitched sounds do so near the base. Sounds of different frequencies stimulate different groups of hair cells selectively. The outer hair cells and descending olivocochlear pathway contribute to enhancing frequency selectivity. 2. Firing of neurons of the spiral ganglion that respond to low-frequency stimuli follows the periodicity of lowpitched sounds; at frequencies greater than 1000 Hz,

A

C

20 +

+ 0.3 Pa

0 – – 0.3 Pa 4 ms

20 dB 0

6 kHz

B + 0.5 mPa

– 0.5 mPa 0

ms 10

20

FIGURE 7-4. Averaged transient evoked otoacoustic emission recording in an ear of a 7.5-year-old female with normal hearing. A, Amplitude scale to permit examination of the input (click) stimulus. The stimulus was an 83-dB sound pressure level and was presented repeatedly. B, Amplified view of the time course of the evoked otoacoustic emission recorded from the external ear canal, with the first 4 milliseconds of the trace blanking out the stimulus artifact. Two separate averages are superimposed to show the high level of reproducibility. C, Frequency spectrum of the response versus background noise in the ear canal (shaded black), demonstrating an excellent signal-to-noise ratio and therefore unequivocal outer hair cell function across all the frequencies up to 6 kHz. The output displays provided by clinical instruments include the number of stimuli that entered into the average, the number and percent of stimuli automatically rejected because of excessive noise, the reproducibility of the two recorded waves, and the elapsed test time. (From Durant JD. Physical and physiologic bases of hearing. In: Bluestone CD, Stool SE, Kenna MA, eds. Pediatric otolaryngology, 3rd ed. Philadelphia: WB Saunders, 1996.)

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groups of neurons fire in such a way that the group follows the periodicity of higher frequency stimuli. 3. The auditory system is tonotopically organized throughout. The basilar membrane is a highly sensitive and very sharply tuned resonator. Cells in the cochlea and in higher relays of the auditory system are also tuned narrowly; that is, they respond selectively to certain frequencies and only at much higher intensities or not at all to others. A number of electric potentials are generated in the cochlea [Hyde, 1988; Pickles, 1997]. The cochlear microphonic, reflecting activation of the hair cells is recorded optimally near the round window with averaging techniques and transtympanic electrodes. The cochlear microphonic follows the frequency and amplitude of the auditory stimulus. The summating potential, which can be measured by the transtympanic membrane electrode, is a direct current potential generated by the hair cells. There is an 80-mV endocochlear potential recorded in the scala media, which has no known clinical utility. A fourth potential is the cranial nerve VIII compound action potential generated from the spiral ganglion cells. The cochlea, an active mechanical processor of acoustic energy, emits narrow-band tones; these cochlear emissions, emitted spontaneously and in response to evoking click or tonal stimuli, can be measured in the external ear canal if the middle ear transducer is functional (Fig. 7-4) [Kemp, 1978; Whitehead et al., 1996]. These transient otoacoustic emissions (i.e., cochlear echoes) are generated by the outer hair cells, which are contractile and tightly coupled to the basilar membrane and tectorial membrane; their contraction increases sound-induced vibration of the basilar membrane, enhancing its frequency selectivity and its sensitivity to low-level sounds. Evoked cochlear emissions are highly reproducible over a wide frequency range, and they are easier and less invasive to record for clinical purposes than the cochlear microphonic and faster than the brainstem auditory-evoked responses (BAER). They are widely used for newborn screening and in the evaluation of children who are candidates for a cochlear implant [Norton et al., 2000b]. Averaging techniques enable the recording from the scalp of the negative compound action potential of the auditory nerve. It is called wave I of the BAER (Fig. 7-5) and occurs with an average latency of 1.5 msec at high intensity to 5.5 msec near threshold. The five waves of the BAER are attributed to activation of the auditory nerve, cochlear nucleus, superior olive, nucleus of the lateral lemniscus, and inferior colliculus or structures in their vicinity. Their latency ranges from a maximum of 1.9 msec for wave I to 5.9 msec for wave V in adults in response to high-intensity clicks. Latency is longer at low-intensity levels and in infants [Stapells and Oates, 1997]. Wave V is the largest. Increased latency (>4 msec) between waves III and V suggests a pathologic process in the brainstem, whereas absence of wave I signifies peripheral hearing loss. Absence of wave I with persistence of otoacoustic emissions and the cochlear microphonic indicates that the hearing loss results from damage in the spiral ganglion cells or auditory nerve with preservation of the hair cells [Rapin and Gravel, 2003]. Physiologic activation of higher relays of the central auditory pathway can be recorded (see Fig. 7-5) [Stein-

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VII I

II

VI 0.2 ␮V

III IV V

12.5 ms

Nb Na No

Po

0.4 ␮V Pa 50 ms

N2

N1

P1 0.2 ␮V P2

0.5 s

FIGURE 7-5. Components of the scalp-recorded averaged auditory-evoked responses to 1000 clicks presented at 60 dB above the subject’s threshold. Each panel contains four different trials superimposed to show the reliability of the responses. Notice the different time scales on the abscissas and different amplitude scales on the ordinates. The top panel shows the seven waves of the brainstem response, the middle panel shows the middle components, and the lower panel shows the early obligatory cortical waves. Negativity at the vertex electrode produces an upward deflection. (From Durant JD. Physical and physiologic bases of hearing. In: Bluestone CD, Stool SE, Kenna MA, eds. Pediatric otolaryngology, 3rd ed. Philadelphia: WB Saunders, 1996.)

schneider and Dunn, 2003]. The somewhat inconstant waves VI and VII of the brainstem response are believed to reflect activity in the vicinity of the medial geniculate body and auditory radiations. So-called middle potentials [Kraus and McGee, 1990], which have a latency of about 15 to 80 msec, may reflect activation of the acoustic radiations and initial activation of the auditory cortex. Later obligatory potentials originate in the primary and secondary auditory cortices; they are recorded with maximum amplitude at the vertex of the scalp because of the geometry of the auditory cortex, which lies horizontally in the sylvian fissure. The N1 wave, which has a latency of approximately 100 msec, reflects activation of primary auditory cortex. Its maximum amplitude at the vertex reflects the orientation of its generators in the horizontal planum temporale. The mismatch negativity,

a frontocentral potential with a latency range of 60 to 120 msec, is recorded when the average response to infrequent auditory stimuli interspersed unpredictably with frequent stimuli is subtracted from the response to the frequent stimuli. As the mismatch negativity does not require attention or the generation of a behavioral response, it may be suitable to test auditory discrimination in infants or uncooperative children [Steinschneider and Dunn, 2003]. Later components of auditory event–related potentials differ by their latencies and topography, and they are contingent on the cognitive processing of various aspects of the signal. Later components of auditory event–related potentials depend on what part of the language-processing cortical areas are activated when subjects are required to respond to various of the phonologic, syntactic, and semantic aspects of language [Steinschneider and Dunn, 2003]. For example, Steinschneider and Dunn [2003] recorded differences in evoked responses to voiced consonants such as d, compared with unvoiced consonants such as t, generated in auditory cortex in monkeys and humans. Neville and Mills [Mills and Neville, 1997; Neville and Mills, 1997] have studied electrophysiologic correlates of grammatical maturation by changes in a negative complex recorded over the anterior temporal or frontal cortex of the left hemisphere (including Broca’s area) in response to closed class words such as articles, prepositions, and conjunctions, and of semantic maturation by changes in a negativity recorded from temporoparietal derivations (including Wernicke’s area) in response to open class words such as nouns, verbs, and adjectives. They also used evoked responses to study the emergence of word comprehension in normal and languagedelayed toddlers. Dunn and colleagues [Dunn et al., 1999; Dunn and Bates, in press] were able to characterize differences in semantic processing (i.e., organization of the lexicon or repository of word meanings) in verbal children with autism compared with normal subjects. Together with imaging using functional magnetic resonance imaging (fMRI), positron emission tomography (PET), or single photon emission computed tomography (SPECT), these electrophysiologic techniques make it possible to identify the cortical and subcortical circuitry that participates in the various stages of auditory and language processing.

CLASSIFICATION AND CLINICAL FEATURES There are several overlapping ways to classify hearing losses: unilateral and bilateral; conductive, sensorineural and mixed; cochlear and retrocochlear, mild, moderate, severe, and profound; prelingual and postlingual; static and progressive.

Conductive Hearing Loss Conductive hearing losses result from pathologic conditions in the external ear canal, tympanic membrane, or middle ear (Box 7-1). Conductive hearing loss does not exceed 60 dB because sound is conducted to the cochlea through the skull (bone conduction) above that intensity. The most common causes of conductive hearing losses in young children are acute and chronic (secretory) otitis media resulting from eustachian tube dysfunction; they rarely produce hearing

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Box 7-1 CAUSES OF CHRONIC HEARING LOSS Conductive Hearing Loss Chronic middle ear effusion caused by eustachian tube malfunction Otitis media or mastoiditis Malformation of the external or middle ear Ossicular ankylosis, necrosis, traumatic disruption Cholesteatoma or other middle ear mass Sensorineural Hearing Loss Cochlear Genetic (many types) Cochlear malformation Perinatal problems (e.g., hyperbilirubinemia [?], anoxia, ototoxicity) Congenital infection (e.g., rubella, cytomegalovirus) Endolabyrinthitis, purulent (e.g., meningitis, mastoiditis) or viral Ototoxic, prenatal or postnatal Temporal bone fracture Sound trauma Retrocochlear Neuropathy of cranial nerve VIII Kernicterus (i.e., neonatal hyperbilirubinemia) Brainstem glioma, malformation, demyelination Leukodystrophy (e.g., mitochondrial cytopathy, adrenoleukodystrophy) Acoustic neurinoma, sporadic or genetic (e.g., neurofibromatosis type 2)

losses in excess of 40 dB. Congenital anomalies of the ear canal and middle ear and trauma account for most of the other cases.

Sensorineural Hearing Loss The term sensorineural hearing loss refers to hearing loss of highly variable severity and course due to damage or malfunction of the cochlea. If damage is limited to the hair cells, the ganglion cells may survive or undergo transneuronal degeneration, whereas if the spiral ganglion cells die, their axons in cranial nerve VIII inevitably undergo wallerian degeneration. The advent of cochlear prostheses has made it important to determine whether damage affects the hair cells or ganglion cells, or both, with physiologic tests of hearing such as otoacoustic emissions and brainstem-evoked responses [Rapin and Gravel, 2003]. The main causes of sensorineural hearing losses are genetics and infections, with malformations and other causes being less frequent. Unilateral sensorineural hearing losses are rarely genetic. Most are caused by prenatal infections, such as rubella and cytomegalovirus, or acquired viral infections, such as mumps. Sensorineural hearing losses may or may not be associated with vestibular dysfunction. Vestibular dysfunction was present in 41% of pupils in a Dutch school for the deaf and was most common in children with thresholds above 90 dB and those with exogenous hearing losses [Huygen et al., 1993]. It is also characteristic of type 1

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Usher’s syndrome [Ahmed et al., 2003; Sun et al., 2001] and of many children deafened by purulent meningitis [Hugosson et al., 1997; Nadol, 1997]. It is not clear how much awareness of the presence or absence of a vestibular deficit would help in the differential diagnosis because vestibular testing is not performed routinely in deaf children.

Retrocochlear Hearing Loss Hearing loss in children is infrequently retrocochlear. The audiologic community has come to apply the term auditory neuropathy to children with more severely impaired language learning than would have been predicted from their audiograms and who have recordable otoacoustic emissions with abnormal or absent BAERs [Sininger and Starr, 2001]. Unfortunately, many of the papers lump disorders of the spiral ganglion cells and cranial nerve VIII with those involving the central auditory pathway, without awareness of the differences in the biology of peripheral and central myelin and without awareness that the term neuropathy applies only to disorders of the peripheral nervous system [Rapin and Gravel 2003]. Auditory neuropathy is most clearly applicable to cases in which one of the many peripheral neuropathies is associated with a hearing loss, such as to some of the hereditary sensorimotor neuropathies, with or without cerebellar involvement, and to metabolic disorders like Refsum’s disease. It has been proposed that, as a group, retrocochlear hearing losses be called neural hearing losses, a more general term that does not imply that the process involves the spiral ganglion cells or cranial nerve VIII specifically [Rapin and Gravel, 2003]. Damage to the central auditory pathway rarely gives rise to total hearing loss because of the bilaterality of central acoustic projections. Kernicterus damages the relay nuclei of the central auditory and vestibular pathways and probably the cochlea as well. Rare causes of retrocochlear hearing losses, especially in children, are the bilateral acoustic tumors of neurofibromatosis type 2 [Martuza and Eldridge, 1988], sporadic acoustic tumors that start in the vestibular division of cranial nerve VIII early on and compress the cochlear division, and occasional brainstem gliomas [Yagi et al., 1980]. Cortical deafness, which implies bilateral pathology in the acoustic radiations or in the auditory cortex, is rare. Auditory sensitivity is preserved, but the recognition of the source of sounds and the decoding of the acoustic code of language (i.e., phonology) are impaired. Adrenoleukodystrophy is one of the main causes of central (neural) deafness in children [Kaga et al., 1980]. Acquired epileptic aphasia (i.e., Landau-Kleffner syndrome), a cause of insidious loss of language in young children with a paroxysmal electroencephalogram, with or without clinical seizures, usually reflects auditory agnosia or verbal auditory agnosia due to temporal lobe dysfunction [Kaga, 1999b; Klein et al., 1995; Lewine et al., 1999; Rapin et al., 1977].

Severity and Shape of the Hearing Loss Hearing loss can be classified by its severity (Table 7-1). Mild flat losses up to 40 dB do not preclude the acquisition of oral speech but may significantly impoverish it; the degree of handicap depends on the age of the child and the

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TABLE 7-1 Severity of Hearing Loss SEVERITY*

CONSEQUENCES†

MANAGEMENT

None: 0-20 Mild: 25-40

Normal speech and language Speech and language normal, mildly delayed, or slightly impaired in normal child, detrimental in multiply handicapped or socially deprived children Speech and language usually delayed and defective—consonants faulty; severe impairment in most children

None Repeated testing Preferential seating May need speech therapy and FM loop in school Hearing aid; FM loop in school Auditory training; speech and language therapy Normal school and resource room with teacher of the hard of hearing Hearing aid, FM loop, cochlear implant? Auditory training, sign language desirable; focus on written language Most do best in special school or class for the deaf, at least initially Hearing aid, cochlear implant? Auditory training, sign language mandatory (Total Communication or, better, American Sign Language); focus on written language Most do best in specialized programs for the deaf

Moderate: 45-60

Severe: 65-80

Speech and language usually severely defective; require intensive specialized training

Profound: 85 +

Most develop poor speech, even with early specialized training; language severely defective in most, who sign much better

*Severity is measured in decibels of hearing loss (dB HL)/pure tone average. Each category of severity is recorded in dB HL or decibels above the average normal hearing threshold. Pure tone average refers to the mean of thresholds at 500, 1000, and 2000 Hz. †Not all consequences of hearing losses of designated severities are listed. These characteristics vary among individual children within a category.

severity and configuration of the hearing loss [Gravel and Ruben, 1996]. If the loss is present from early infancy, it is likely to delay speech [Abraham et al., 1996], especially if the child is socially deprived or otherwise handicapped [Wallace et al., 1996]. Middle ear effusion in an older child with well-established verbal skills constitutes a minor handicap. Children with even mild sensorineural losses may benefit from amplification and preferential seating in school and from a mild-gain individual or classroom FM system. In most children, moderate loss of 45 to 60 dB interferes severely with, but does not preclude altogether, the acquisition of speech. Children with moderate (45 to 60 dB) and severe (65 to 80 dB) hearing losses gain the most from hearing aids [Nozza, 1996; Roeser and Downs, 1995]. Virtually all children with severe hearing losses require some type of special education to learn language. Profound losses (>85 dB) and total losses preclude the acquisition of language without intensive specialized education. Strictly speaking, the term deafness applies only to these two groups, but it is often used loosely in referring to all children who cannot learn language without special assistance. Children with very limited or no hearing benefit little from hearing aids except for the awareness that a sound has occurred. Most profoundly deaf adolescents and adults do not wear hearing aids; however, as children they should be encouraged to wear aids because it is difficult to predict who will benefit from wearing them. Children with profound but incomplete hearing losses gain more from their cochlear implants than those with pure tone average thresholds exceeding 100 dB [Pulsifer et al., 2003], and toddlers implanted early (by 18 months to 2 years) benefit much more from their implants than children implanted in middle childhood [Govaerts et al., 2002]. Another means of classifying hearing loss is by the shape of the audiometric threshold. The two most common types are the flat and sloping high-tone loss threshold curves. Ushaped and inverted U (dome)–shaped thresholds are less

frequent. The shape and the severity of the hearing loss determine the effects on language acquisition. Sloping hightone losses are particularly treacherous. They are common and often overlooked unless systematic testing across the entire frequency range is performed because the children may respond normally to environmental sounds and voices that contain energy in the low frequencies, which the children can hear.

Age at Onset According to the outstanding sociologic study of the deaf in the United States performed by Schein and Delk [1974], there are three main types of childhood hearing losses: congenital or prelingual, perilingual, and postlingual. Prelingual loss occurs before birth or in the first few months of life, and perilingual loss occurs during the age of language acquisition, when a normal child learns the main rules of oral language; this age has been arbitrarily set at 3 years. Children who lose their hearing after 3 years of age—those with postlingual deafness—retain some speech or at least have less difficulty reacquiring speech than children who never had hearing. Most of the prevocationally deaf—those whose deafness began before the age of 19 years, before they started working in a job or profession—are prelingually or perilingually deaf. The impact of cochlear implants and more active efforts to accommodate hearing-impaired students into mainstream higher education will no doubt change the conclusion of the 1974 Schein and Delk study, but how profoundly remains to be seen. Schein and Delk discuss the jobs that the prevocationally (most of them prelingually or perilingually) deaf were able to secure and their family and social circumstances. In general, because of their curtailed verbal skills, including in written language, these deaf adults encounter severe limitations to their vocational options. Most marry deaf partners and receive assistance in obtaining suitable employment by the community of deaf persons that

Rapin / Hearing Impairment

exists in every sizable city. What proportion of severely to profoundly prelingually or perilingually deaf persons cochlear implants will allow to be integrated into the society of the hearing remains to be seen. Experience suggests that 3 years of age is too young to designate as the division between the prelingually or perilingually and postlingually deaf. Most children who are deafened by meningitis before age 4 years do not retain much speech even if their parents and educators make a concerted effort to stimulate their speaking and they begin intensive auditory and language training lessons immediately. Per-

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haps these children do so poorly because they are likely to be totally deaf. Very young children need to hear to continue speaking. Rapid loss of speech is also typical of children with acquired epileptic aphasia with word deafness, even those older than 5 years who communicate through the visual-gestural channel or in writing. If electrophysiologic testing indicates that at least some of the spiral ganglion cells have survived, children deafened by meningitis may be candidates for early cochlear implants. Early implantation is important for another reason: The long-term sequelae of purulent endolabyrinthitis are ossification of the cochlea

TABLE 7-2 Genetic Deafness Syndromes SYNDROME

INHERITANCE

Nonsyndromic deafness, without associated anomalies Hearing loss [HL] may be mild, moderate, or severe; static or progressive; occasionally unilateral. Variability within families is less with recessive than with dominant genes. Usher syndrome Type I: severe congenital HL and vestibular impairment with later appearance of retinitis pigmentosa (RP) Type 2: less severe hearing loss, normal vestibular function, late onset RP Type 3: progressive hearing loss, variable onset RP Waardenburg syndrome (several variants) White forelock, heterochromia of iris, telecanthus, severity of HL variable HL with pigmentary abnormalities Albinism Piebaldism, multiple lentigines, and others HL with other skin and nail abnormalities Treacher Collins syndrome Microtia, coloboma of lower lid, midface hypoplasia, conductive HL Alport’s syndrome (several types) Glomerulonephritis, progressive HL, eye anomalies

Dominant or recessive or X-linked

Childhood HL and renal tubular acidosis Jervell and Lange-Nielsen syndrome Congenital HL with prolonged QT interval (K+ channelopathy) Pendred’s syndrome HL with goiter; frequent labyrinthine malformations Other thyroid diseases Susceptibility to aminoglycoside toxicity Hunter’s syndrome (mucopolysaccharidosis type II) Other mucopolysaccharidoses Refsum’s disease Progressive deafness, ataxia, neuropathy, retinitis pigmentosa, with storage of phytanic acid Other peroxisomal diseases Adrenoleukodystrophy Leukodystrophy with adrenal insufficiency (central hearing loss) Other leukodystrophies Sensorimotor neuropathies (demyelinating and axonal types) Friedreich’s ataxia Kearns-Sayre and other mitochondrial cytopathies Mitochondrial myopathy, encephalopathy, lactacidosis, stroke (MELAS syndrome), myoclonic epilepsy and ragged red fibers (MERFF syndrome), Leigh’s syndrome, and others Cockayne’s syndrome (several variants, some associated with xeroderma pigmentosum) Cachectic dwarfism, microcephaly, deafness, miosis, retinitis pigmentosa, spasticity, ataxia, joint contractures, and others Neurofibromatosis type 2 with bilateral acoustic neurinomas Norrie’s disease Congenital blindness with microphthalmia, progressive hearing loss in adolescence, autism, often mental deficiency Osteogenesis imperfecta tarda Osteopetrosis type I Otosclerosis Trisomies Other chromosomal anomalies

Recessive

Dominant X-linked Variable Dominant X-linked Recessive Dominant Recessive Recessive Recessive Variable Maternal mitochondrial X-linked Recessive Recessive X-linked Recessive X-linked Dominant Recessive Sporadic Maternal or recessive Recessive Dominant X-linked Dominant Recessive Dominant Sporadic Many sporadic

Data from Online Mendelian Inheritance in Man (OMIM) (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM and http://www.uia.ac.be/dnalab/hhh/ and from Nance WE. The genetics of deafness. Ment Retard Dev Disabil Res Rev 2003;9:109.

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and transsynaptic degeneration of the spiral ganglion neurons, which jeopardize implantation [Nadol, 1997].

Course Most of the severe sensorineural hearing losses are static, but about 10%, notably those caused by cytomegalovirus infection [Fowler et al., 1997] or a neurologic disease, such as an acoustic tumor, and a significant proportion of genetic hearing losses (Table 7-2) are progressive [Davis et al., 1995]. Hearing losses that worsen during infancy are unlikely to be diagnosed as progressive but may account for some of the children who pass neonatal screening and later turn out to be deaf. Genetic hearing losses that do not become apparent until later childhood or adult life are progressive by definition. Controversy exists over how much of the ubiquitous presbyacusis of old age is genetic and how much results from acoustic trauma and other acquired deleterious influences on the cochlea. Genetic information about progressive hearing losses is insufficient to predict the course of a child’s hearing loss unless the child belongs to a large family with many affected members who all have followed similar courses, or the child carries a mutation with a known course. The causes of this progression at the cellular level are not well understood. Other hearing losses, such as those caused by middle ear effusion, episodic acoustic trauma, salicylate intoxication, and Meniere’s disease, fluctuate. Fluctuation may occur under other circumstances that are not understood.

PATHOLOGY Conductive hearing loss may result from atresia of the external canal, usually associated with gross malformation of the pinna; malformation, dislocation, or destruction of the ossicular chain; fluid or a mass in the tympanic cavity; fixation of the stapes footplate; tympanosclerosis (i.e., fibrosis, scarring, or calcification of the tympanic membrane); destruction of the tympanic membrane; or a combination of these conditions. In young children, the most common cause of conductive hearing loss is middle ear effusion attributable to an incompetent eustachian tube, a condition that improves as the base of the skull grows. Complete destruction of the middle ear produces a hearing loss of at most 60 dB because the skull transmits sound above this level directly to the inner ear. Malformations may be part of a branchial arch malformation syndrome that also involves the face and, in some children, other organ systems such as the spine, the limbs, gastrointestinal tract, or genitourinary system [Cohen, 1997; Toriello et al., 2004]. These associated anomalies arise at the same time during gestation as the ear anomalies. Because the neural crest contributes to the formation of the ear and these other systems, the entire malformation complex may be regarded as a cristopathy. Ear anomalies may also be associated with anomalies of the posterior fossa, other cranial nerves, eyes, and brain [Wiznitzer et al., 1987]. Sensorineural hearing loss usually results from hair cell loss, with or without associated damage to the cells of the spiral ganglion [Dublin, 1976; Nadol et al., 1989]. The cells of the organ of Corti and spiral ganglion are end-state cells

that are incapable of cell division [Ruben, 1967], which explains the irreversibility of most sensorineural hearing losses. Loss of spiral ganglion cells leads to wallerian degeneration in the acoustic nerve and may result in delayed transneuronal degeneration in the central auditory pathway [Ruben and Rapin, 1980]. True nerve deafness or auditory neuropathy (i.e., deafness resulting from selective damage to the axons of cranial nerve VIII) is rare except in the context of an acoustic neurinoma or of infiltration of the leptomeninges by an infectious, granulomatous, or neoplastic process [Rapin and Gravel, 2003]. Infections, including bacterial meningitis, congenital rubella, and cytomegalovirus; trauma; and vascular disease are unselective and are likely to damage all elements of the cochlea and vestibule. Bacterial meningitis may deafen because of purulent endolabyrinthitis or by lymphocytic infiltration of the vestibule and cochlea and cellular apoptosis, suggesting an immune pathophysiology [Nadol, 1997]. Some viral infections are surprisingly selective, producing only a high-tone loss rather than total destruction of the cochlea. A pathologic study of 66 patients who were profoundly deaf revealed that those with presumptive postnatal viral and bacterial labyrinthitis, malformative, and genetic causes were less likely to have residual spiral ganglion cells than those in whom deafness resulted from aminoglycoside toxicity or sudden idiopathic hearing loss [Nadol et al., 1989]. Ototoxic drugs [Stavroulaki et al., 2001; Stavroulaki et al., 2002], some other toxins, and sound trauma [Salvi et al., 1986] are highly selective as to the cell type they destroy. This finding has been exploited in experimental studies of the physiology of the inner ear in animals. Genetic sensorineural hearing losses are more often the result of early death of cells in the cochlea than of their failure to form, although there are a number of cochlear malformations in which there is more or less complete lack of hair cells and other cell types in the cochlea [Westerhof et al., 2001]. Because of inaccessibility of the middle and inner ears, not enough is known about the cellular pathology of human deafness, compared with what is known about pathologic processes in all other organ systems. Studies of animal models of deafness, in particular those made possible by progress in genetics, have resulted in significant progress in understanding at the cellular and molecular levels. Examination of the ear requires sawing into the petrous bone, lengthy decalcification of the specimen, and serial sectioning. Because of the long interval between the diagnosis of hearing loss and the death of adult patients, physicians are unlikely to remember that they were hearing impaired. The ear is not removed at postmortem examination, even though there are a number of laboratories equipped to study the ear. Temporal bone banks have been established in some teaching institutions and at the Armed Forces Institute of Pathology. These laboratories often are willing to study specimens, provided they are accompanied by adequate information regarding the patient’s hearing and clinical status.

ETIOLOGY There are three etiologic categories of hearing loss: genetic, acquired, and unknown. The unknown category encompasses

Rapin / Hearing Impairment

genetic and acquired causes, with single cases of autosomal recessive or X-linked recessive causes and unsuspected intrauterine infections accounting for most. Although some malformation syndromes (e.g., Treacher Collins syndrome) are genetic and result from single-gene defects or various chromosomal anomalies, the cause of many malformation syndromes is unknown and presumed to be nongenetic. In counseling parents who are trying to understand why the hearing loss occurred in their particular child, the following points should be made: 1. An isolated hearing loss in a child born to a family without any other affected member may be genetic. It is possible to test today for some of the more prevalent genetic defects and provide parents with genetic counseling and, in some cases, information about their child’s probable course and the possibility of unsuspected problems in other organs such as the eyes, thyroid, or heart. 2. A negative genetic test does not exclude a genetic cause for the hearing loss because only a minority of deafness genes are tested today, a situation likely to change in the near future, and there are new mutations to be discovered. 3. Although many congenital causes of hearing loss are genetic, some are acquired (e.g., rubella and cytomegalovirus infections, ototoxic drugs such as thalidomide, nongenetic malformation syndromes). 4. Some genetic hearing losses do not appear until childhood or later. Even well-educated parents are unlikely to be familiar with straightforward mendelian genetics, let alone mitochondrial genetics. Genetic counseling requires time and expertise and, for in-depth information, the services of a professional genetic counselor.

Genetics Genetic hearing losses are generally bilateral but may be asymmetric and may be static or progressive; they may be syndromic (i.e., associated with abnormalities in other organ systems) or nonsyndromic (i.e., isolated). They may be dominant, relatively frequent and easy to spot such as Waardenburg’s syndrome, which is often associated with a white forelock and iris and other pigmentary changes, or Treacher Collins syndrome with its malformations of the external and middle ear and face, or they may be recessive, X-linked, or mitochondrial. In some cases, deafness is not the most prominent aspect of the disorder (e.g., progressive hearing loss in some of the spinocerebellar degenerations). The number of identified mutations responsible for sensorineural hearing losses associated and unassociated with other systemic signs is exploding. The comprehensive and regularly updated web site Hereditary Hearing Loss Homepage at http://www.uia.ac.be/dnalab/hhh/ lists known genes and loci associated with hearing loss. Considerable progress has been made toward understanding the function of some of these genes [Friedman and Griffith, 2003]. For example, some code for ion channels, critical to maintaining the ionic gradients in the fluids of the inner ear and in signal transduction by the hair cells; some for motor molecules such as myosin XV; and some for gap junctions, transcription

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factors, and extracellular matrix proteins [Steel and Bussoli, 1999; Steel and Kros, 2001]. As is true of most modern genetics, what was thought to be single, clinically defined diseases turns out to be several, often caused by more than one gene. Clinically distinct syndromes may be caused by allelic mutations with different consequences on gene function, and the same gene may produce dominant or recessive phenotypes because of variable degrees of inactivation depending on the position of the mutation or because of the influence of interacting genes. The phenotypes of mitochondrial diseases, whether encoded by mitochondrial or nuclear genes, are especially variable. These complexities mean that searching for the genes responsible for nonsyndromic recessive deafness is not yet clinically feasible unless the child carries one of the more common deficits such as the gap junction component connexin 26. Another example is the Jervell and Lange-Nielsen syndrome, for which prolonged QT interval on the electrocardiogram must be looked for in every child with apparently nonsyndromic congenital hearing loss because of the risk of sudden death. The genes for Usher’s syndrome constitute another example because the retinal degeneration is not apparent in early infancy unless electroretinography is performed; this is one of the deafness syndromes for which the indication for an early cochlear implant is least controversial because of the threat of deaf-blindness in later life. Whether it would be considered ethical to offer a prenatal diagnosis of deafness by DNA testing or linkage analysis is a matter of debate unless deafness is part of a devastating multiple-organ syndrome. Audiograms in all immediate family members are recommended to detect unsuspected hearing losses before offering genetic counseling to the parents of children with hearing loss of unknown origin. The proportion of genetic hearing losses due to new mutations, deletions, or other chromosomal anomalies is not known. Hearing loss is a symptom of several genetic neurologic diseases. Mucopolysaccharidoses, notably X-linked Hunter’s syndrome, regularly impair hearing. Hearing loss occurs in Charcot-Marie neuropathy type 1B; Refsum’s disease; some spinocerebellar degenerations and leukodystrophies, particularly Cockayne’s syndrome; and a number of the mitochondrial diseases in which deafness may appear many years before external ophthalmoplegia, pigmentary degeneration of the retina, myoclonus, ataxia, and other signs of central nervous system dysfunction. Some genetic deafness syndromes associated with mitochondrial diseases are maternally inherited, putting all of the mother’s children at risk. Recurrence risk is that of mendelian traits in mitochondrial hearing loss resulting from nuclear mutations and is absent when it arises from a de novo deletion of the mitochondrial DNA, such as in Kearns-Sayre syndrome. Every parent of a hearing-impaired child should be given genetic counseling at diagnosis. Clinicians can provide this service if they have genetic counseling experience and access to McKusick’s regularly updated inventory of known human genetic syndromes (Online Mendelian Inheritance in Man [OMIM]) on the Internet (http://www.ncbi.nlm.nih.gov/ entrez/query.fcgi?db=OMIM) or to the web site cited earlier (http://www.uia.ac.be/dnalab/hhh/). The probability of parents having a second hearing-impaired child if the cause of deafness in the older child is unknown is approximately 1 in 10, a composite of the risk of 1 in 4 when the deafness is

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genetic and recessive plus 1 in 2 when it is dominant but not expressed (or unrecognized) in the parent and 1 in 1000 when it is acquired. The empirically derived figure of 1 in 10 indicates that sporadic deafness is more likely to be genetic than acquired. Even at the height of the 1964 rubella epidemic, genetics probably still accounted for one half of the children with congenital deafness, and genetic defects are estimated to account for at least two thirds of current cases. Several hundred mutations are responsible for genetic hearing losses; one in four unaffected individuals carries one of these genes. Thirty years ago, Brown [1969] estimated the approximate contribution of various causes of childhood deafness by surveying the pupils at a school for the deaf in Massachusetts and found that 25% of the children were deaf as a result of an acquired cause and 57% were deaf because of a genetic trait (40% autosomal recessive, 15% autosomal dominant, and 2% X-linked recessive). In 18% a recognized factor or polygenic inheritance was likely. Brown’s figures are congruous with more recent statistics from the United States and other parts of the world [Das, 1988; Marazita et al., 1993; Pabla et al., 1991]. Brown assumed that most of the children with sporadic hearing losses of unknown cause were affected by an autosomal-recessive trait. This assumption is supported by the report that the prevalence of childhood deafness decreased in parallel with the diminishing rate of consanguinity in Jerusalem [Feinmesser et al., 1990]. Genetic counseling in cases with an unknown cause is particularly important because the risk of hearing parents having another affected child is high [Wang et al., 2003; Westerhof et al., 2001]. Parents should be told that

autosomal-recessive inheritance cannot be excluded when the cause of the hearing loss is unknown.

Malformations Malformations may be sporadic or genetic and involve one or several parts of the ear. Stenosis or atresia of the external ear canal, which is often associated with malformations of the pinna and ossicular chain, produces a severe conductive loss. This type of anomaly may occur in isolation or as part of a complex malformation syndrome, which may be nongenetic or genetic [Cohen, 1997; Gorlin et al., 2001]. Malformations of the cochlea are visible on ultrahigh-resolution computed tomography (CT) of the temporal bones, and cranial nerve VIII is visible by MRI, which is critical for deciding whether a child is a candidate for an implant [Wang et al., 2003; Westerhof et al., 2001]. Some cochlear anomalies are associated with fistulas into the middle ear, usually through the stapes footplate; they may produce fluctuating or progressive hearing losses and severe intermittent labyrinthine dysfunction with vertigo, nausea, or vomiting, and they may provide a path for a purulent endolabyrinthitis or meningitis [Reilly and Weber, 2003]. Table 7-3 lists some of the more common malformation syndromes, most of them of unknown cause, that are associated with hearing losses; see http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM or http://www.uia.ac.be/dnalab/hhh/ and Toriello and colleagues [2004] for extensive listings of syndromes associated with hearing loss. Eustachian tube dysfunction is present in virtually all children with cleft palate, midfacial malformation syndromes, choanal atresia, or Down syndrome.

TABLE 7-3 Syndromic Deafness: Deafness Associated with Congenital Malformations SYNDROME

PRESUMED CAUSE

Treacher Collins (mandibulofacial dysostosis) Ear anomaly, midface hypoplasia, coloboma lower lid, conductive hearing loss (HL) Goldenhar Hemifacial microsomia, microtia, preauricular tags, epibulbar dermoids, coloboma upper lid, spinal anomalies, conductive HL, and others Hemifacial microsomia Variant of Goldenhar (?); conductive HL Microtia/anotia Atresia and middle ear anomalies; conductive HL CHARGE association Coloboma, heart, choanal atresia, retarded growth and development, genital anomalies, ear anomalies (usually aplasia of the lower part of the pinna, often vestibular and cochlear malformation); various other anomalies and autism in some children Other ear anomalies and branchial arch syndromes (e.g., Vater association) Consider HL (conductive or sensorineural) and renal anomalies. Mondini and other malformations of the cochlea

Genetic, dominant

Cleft palate and other palatal anomalies (including bifid uvula) Almost always cause eustachian tube dysfunction and conductive HL Midface hypoplasia syndromes (eustachian tube dysfunction and conductive HL) Crouzon’s disease, Apert’s syndrome, and others Others, including Down syndrome Möbius and variants Multiple cranial nerve nuclear agenesis (usually VI and VII, but others, including VIII, may be involved) Wildervanck Deafness with Klippel-Feil and Duane syndromes; females almost exclusively affected

Genetic (?), mostly sporadic Sporadic Mostly sporadic, dominant Multifactorial (?), genetic (?)

Mostly sporadic, multifactorial (?) Genetic, sporadic, intrauterine cytomegalovirus infection Mostly sporadic, multifactorial, some genetic and syndromic Dominant Dominant Trisomy 21 Sporadic Rarely genetic dominant Polygenic with limitation or females

Data from Online Mendelian Inheritance in Man (OMIM) (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM and http://www.uia.ac.be/dnalab/hhh/ and from Toriello HV, Reardon W, Gorlin RJ. Hereditary hearing loss and its syndromes. New York: Oxford University Press, 2004; Gorlin RJ, Cohen MM Jr, Hennekam RC. Syndromes of the head and neck. New York: Oxford University Press, 2001; Cohen MM Jr. The child with multiple birth defects. New York: Oxford University Press, 1997.

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Acquired Causes Eustachian tube dysfunction, often caused by repeated upper respiratory infection or allergic rhinitis with adenoid hypertrophy and by malformation or immaturity of the tube, is the major cause of middle ear effusion (Table 7-4). Middle ear effusion produces a fluctuating hearing loss of variable duration and mild or at most moderate severity. Chronic middle ear effusion (“glue ear”) is often undetected and is responsible for conductive losses or mixed losses when granulation tissue involves the inner ear. Although the long-term consequences of middle ear effusion on language skills depend on whether there are associated handicaps [Ruben, 2003], it is important to detect middle ear effusion and treat it aggressively, including insertion of ventilating tubes if indicated [Handler, 1994], especially in children who have sensorineural hearing losses, because an additional 30 or 40 dB of hearing loss can transform a hard-of-hearing child into a deaf one. Ventilating tubes do not preclude the wearing of hearing aids. Congenital infections account for a variable proportion of childhood deafness. Toxoplasmosis is a rare cause of congenital hearing loss with vestibular impairment. Congenital syphilis does not cause hearing loss until later in childhood; prompt treatment may reverse or arrest the hearing loss. TABLE 7-4 Main Causes of Acquired Hearing Losses TYPE OF INSULT

TYPE OF INSULT

Infection

Congenital rubella, cytomegalovirus Bacterial meningitis Chronic purulent otitis media, mastoiditis, endolabyrinthitis Mumps, measles, scarlet fever* Congenital syphilis (childhood onset), toxoplasmosis Others Kernicterus (mainly central auditory and vestibular pathways) Prematurity† Severe anoxia Hyperbilirubinemia (especially in premature infants) Ototoxic drugs Aminoglycosides (e.g., streptomycin, dihydrostreptomycin, kanamycin, neomycin); mitochondrial genetic susceptibility through matrilineal inheritance Furosemide, ethacrynic acid Cisplatin Aspirin (transient) Thalidomide (prenatal exposure) Temporal bone fracture Hemorrhage into the middle ear or cochlea Ossicular dislocation Sound trauma Bilateral acoustic neurinoma (neurofibromatosis type 2) Other cerebellopontine tumor Tumor of the middle ear (e.g., rhabdomyosarcoma, glomus tumor)

Neonatal hyperbilirubinemia Perinatal insults

Ototoxic drugs

Trauma

Neoplasms

*These are rare causes of deafness and their etiologic importance has been exaggerated. † Perinatal insults and prematurity have additive effects; if hearing loss occurs, it is generally multidetermined.

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Besides retinopathy, hearing loss is the most common manifestation of congenital rubella [Chess et al., 1971], now rare because of immunization. Severity of the hearing loss varies from mild to profound, and it may be progressive because of viral persistence after birth. The hearing loss may be associated with vestibular impairment and with signs of central nervous system damage such as microcephaly, motor deficits, mental deficiency, autism, and learning disability. The most severely handicapped children are those in whom deafness is associated with marked visual impairment due to cataract and other pathologies or with autism. However, physicians should be conservative in predicting outcome in infants with congenital rubella because it is often more favorable than expected [Chess, 1977]. Congenital cytomegalovirus infection probably is a major cause of hearing loss in young children. Its severity varies. It occurred in 7% of 307 children who were asymptomatic at birth [Fowler et al., 1997]. One half of these children had progressive hearing losses; onset was delayed in 18% (in some cases, up to 5 years of age), and 23% had fluctuating losses. Children who were symptomatic at birth had a higher risk of neurologic sequelae and deafness. Imaging occasionally reveals a cochlear malformation in children who acquired the infection early in pregnancy; they are the ones who are most likely to have severe brain damage or malformations. Proving that sporadic, isolated hearing loss is caused by congenital cytomegalovirus infection is often impossible because postnatal infection is ubiquitous; this precludes diagnosis by serologic testing or by culturing the virus from the urine unless these tests are performed soon after birth. Otitis media, measles, scarlet fever, mumps (which may produce unilateral hearing loss), and other childhood illnesses are probably blamed more often than warranted for childhood deafness. Although herpes zoster causes Ramsay Hunt syndrome, which may be associated with unilateral hearing loss later in life, the varicella and herpes simplex viruses do not seem to cause deafness in early life. Purulent meningitis causes an endolabyrinthitis in 3% to 10% of patients [Dichgans et al., 1999; Dodge et al., 1984; Hugosson et al., 1997]. Early administration of dexamethasone together with antibiotics may prevent some cases of postmeningitic hearing loss in children [Chaudhuri, 2004], although the indication is not as clear in adults [van de Beek et al., 2003]. Hearing losses demonstrable within 6 hours of admission were often reversible within 2 days [Richardson et al., 1997]. Perhaps these favorable cases resulted from the “serous” labyrinthitis found by Merchant and Gopen [1996] in a third of the temporal bones of patients who died of purulent meningitis, the mechanisms of which may be immunologic; 49% had purulent endolabyrinthitis. The damage in purulent labyrinthitis usually is bilateral, severe, and unselective and results in a profound or total hearing loss with vestibular impairment. There are cases in which damage is less severe, asymmetric, or even improves and, rarely, cases in which hearing loss may progress months to years later [Silkes and Chabot, 1985]. All children with meningitis should have hearing tests before they leave the hospital because undetected hearing and vestibular losses may be misconstrued as brain damage in a child who is mute and temporarily unable to sit, stand, or walk. If deafness is documented, candidacy for prompt cochlear implantation needs to be determined with physiologic tests.

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Newborn hyperbilirubinemia is another cause of infantile hearing loss that has become infrequent because of preventive measures, such as the routine use of RhoGAM after the birth of an Rh-positive infant to an Rh-negative mother, phototherapy in all neonates whose bilirubin exceeds safe levels, and exchange transfusion in the few with high levels likely to cause development of kernicterus. Kernicterus may occur when levels of bilirubin are low in asphyxiated, acidotic, and premature infants or in patients who have various drugs competing with bilirubin for albumin-binding sites [Ostrow et al., 2003]. There was no correlation, however, between bilirubin levels and IQ or hearing loss in the Perinatal Collaborative Study [Newman and Klebanoff, 1993], and later studies in very-low-birth-weight infants stress that multiple variables besides peak bilirubin modulate outcome [Oh et al., 2003]. Kernicterus is named for bilirubin staining and damage to the nuclei of the central auditory and vestibular pathways, cerebellar nuclei, and basal ganglia. It is controversial whether the membranous labyrinth is also damaged because few informative cases have been studied pathologically, but BAER data suggest involvement of the cochlea and the brainstem [Vostanis et al., 1994]. Hyperbilirubinemia typically causes high-tone loss but may produce profound hearing loss in some patients. Because severe hyperbilirubinemia also causes athetosis and a severe dysarthria, affected children may be unable to communicate through gestures or speech and may be misdiagnosed as severely mentally deficient; unlike children whose athetosis is caused by diffuse anoxic brain damage, many kernicteric children without other complications are quite intelligent because the cerebral cortex is unaffected. Longitudinal studies of premature infants and other graduates of neonatal intensive care units invariably reveal a significant number of children with impaired hearing [Amatuzzi et al., 2001; Valkama et al., 2000]. In a cohort of British intensive care unit graduates born in the 1980s, Davis and Wood [1992] found that the risk was 10 times higher than in control infants. Prematurity per se is not responsible for hearing loss because the ear is fully developed at the end of the second trimester; hearing loss results from complications of prematurity such as ischemia, anoxia, acidosis, hyperbilirubinemia, meningitis, and administration of potentially ototoxic drugs such as aminoglycoside antibiotics [Van Camp and Smith, 2000]. It is rarely possible to attribute the hearing loss of an infant at risk to any one of these factors, which may have cumulative effects. Other pediatric ototoxic drugs, besides the aminoglycosides, include aspirin, cisplatin, furosemide, and ethacrynic acid in patients with renal failure [Garetz and Schacht, 1996]. Unlike the other drugs, salicylate produces a transient hearing loss. Risk for aminoglycoside toxicity is inherited as a maternally mediated specific mitochondrial mutation [Braverman et al., 1996]. Trauma can produce bleeding into the middle ear and can dislocate the ossicular chain, producing a conductive hearing loss. The loss may be mixed if it is associated with trauma to the cochlea. Fractures through the otic capsule often produce severe unilateral hearing losses associated with signs of acute labyrinthine dysfunction. Fractures occasionally create a communication between the middle ear and intracranial spaces and result in delayed meningitis. CT detects petrous fractures much more reliably than plain radio-

graphs of the skull. Because high-intensity sound can produce acoustic trauma with permanent hearing loss [Brookhouser, 1996], there is increasing concern about damage from the very loud music that some adolescents listen to constantly and about exposure to other high-intensity sounds. Neoplasms such as brainstem gliomas are exceptional causes of hearing loss in childhood. The bilateral acoustic neurinomas of neurofibromatosis type 2, caused by a mutation on chromosome 22, typically become symptomatic in adolescence or adulthood [Martuza and Eldridge, 1988], although childhood cases involving cranial nerve VIII or other cranial nerves are well documented [Nunes and MacCollin, 2003]. Tumors of the ear include glomus tumors and other rare neoplasms. Cholesteatomas of the ear and mastoid often arise in the presence of chronic middle ear disease associated with perforation of the drum at the limbus; intracranial cholesteatomas are idiopathic and may compromise hearing when located in the cerebellopontine angle.

CLINICAL EVALUATION AND LABORATORY TESTS Patient and Family Histories A detailed family history and pedigree should be integral parts of the evaluation of every newly identified hearingimpaired child. Parents should be questioned closely about consanguinity, infections during pregnancy, prematurity, perinatal insults, exposure to ototoxic drugs, prior meningitis, and any other event that might have resulted in impairment. It is better to obtain birth records of mother and child and records from any other hospital where the child might have been admitted for a serious illness than to rely on the parent’s memory, because parents are prone to blame deafness on some trauma, episode of transient anoxia, or bad ear infection that had nothing to do with the hearing loss. Most parents are unaware that unexplained sporadic hearing loss is more likely to be genetic and recessive than the sole evidence of a perinatal incident.

Physical and Otolaryngologic Evaluation In addition to examining the child for pathologic conditions of the external ear and tympanic membrane, such as a malformed pinna, middle ear effusion, tympanic perforation, fistula, or palatal anomaly such as a submucosal cleft (all of which may be responsible for eustachian tube dysfunction), it is essential to look for evidence of associated anomalies in other organ systems. The many genetic and nongenetic syndromes associated with hearing loss are detailed in other sources [Cohen, 1997; Gorlin et al., 2001; Toriello et al., 2004] and web sites (http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?db=OMIM; http://www.uia.ac.be/dnalab/hhh/). Pigmentation disorders of the skin and iris, unusual facial features, anhidrosis, hyperkeratosis, and anomalies of the fingers or nails are some of the integumentary conditions that can provide clues to a specific diagnosis. Syndromic hearing losses may be associated with retinal pathology, congenital heart disease, spinal anomalies, and genitourinary and gastrointestinal malformations. A neurologic evaluation is indicated. Malformations of the ear are often associated with malformations of some of the

Rapin / Hearing Impairment

structures of the posterior fossa, notably nuclear agenesis [Wiznitzer et al., 1987]. Hypotonic hearing-impaired children with or without delayed motor milestones require neurologic assessment to decide whether vestibular impairment is responsible for the hypotonicity or the child has cerebellar, lower motor neuron, or muscle involvement. Intrauterine infections, prematurity, meningitis, kernicterus, and some genetic syndromes may affect the brain and the ear. Assessment of the child’s developmental level and mental status is essential. Awareness that a few deaf children may be mentally deficient or autistic and hearing impaired is critical to provide habilitation for both deficits [Jure et al., 1991]. In older deaf children, a review of academic skills is required because hearing-impaired children are no less prone to developmental problems, including mental deficiency, attention-deficit disorder, and learning disabilities, than children with normal hearing. No meaningful long-term prognosis can be offered without knowledge of the child’s neurologic and developmental status.

Assessments of Hearing, Vestibular Function, and Vision Universal neonatal screening of infants at birth or of graduates of neonatal intensive care units is commonplace. The most widely used methods are otoacoustic emissions, followed by brainstem-evoked responses in those who fail newborn screening [Norton et al., 2000b]. The problems are that some children do not return for follow-up, that there are many falsepositive test results, and that neonatal screening does not pick up children whose hearing deteriorates after birth. No child, including a neonate, is too young or too handicapped to undergo definitive quantitative assessment of the functional state of the middle ear and the sensitivity of the cochlea and auditory pathway. The mere suspicion of hearing loss at any age requires prompt, definitive assessment of hearing and middle-ear function with physiologic testing, without wasting time on repeated and unreliable behavioral tests in very young children or those with handicaps. Definitive hearing testing is also needed for any neonate who has a hearing-impaired member in the immediate family; who has a malformation of the external ear, face, or palate; who has Down syndrome or another syndromic condition known to be associated with hearing loss; or who manifests any other condition listed in the position paper of the Joint Committee on Infant Hearing [2000] (Box 7-2). Definitive hearing testing is also mandatory in all children with delayed acquisition of language, regardless of any other probable cause for inadequate or unintelligible speech. Children with sensorineural hearing losses should undergo vestibular testing, described in Chapter 8, to detect Usher’s syndrome and because lack of vestibular function may explain delayed gross motor milestones and stumbling in dim light [Kaga, 1999a]. Lack of vestibular function puts children at risk for drowning because the children may become disoriented under water in the absence of gravity. Detection of suboptimal vision is crucial because hearingimpaired children are exceptionally dependent on their eyes; yearly refraction of young, deaf children is recommended inasmuch as children who require glasses rarely complain of poor vision and most refractive errors arise in childhood. Examination of the retina is essential because it may yield

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Box 7-2 HIGH-RISK REGISTRY FOR DEAFNESS* A. Birth to 28 days 1. Family history positive for childhood deafness 2. Congenital perinatal TORCH infection (i.e., toxoplasmosis, rubella, cytomegalovirus [herpesvirus], syphilis) 3. Malformation of the pinna and ear canal, face, palate (e.g., cleft or submucous cleft, bifid uvula), Down syndrome, other syndromic or nonsyndromic dysmorphology 4. Low birth weight (<1500 g or 3.3 lb) 5. Hyperbilirubinemia plus other risk factors, exchange transfusion 6. Bacterial meningitis 7. Severe neonatal asphyxia with Apgar scores of 0 to 3; need for a ventilator 8. Use of ototoxic drugs, including but not limited to the aminoglycosides, used in multiple courses or in combination with loop diuretics 9. Apgar scores of 0-4 at 1 minute or 0-6 at 5 minutes 10. Mechanical ventilation lasting 5 days or longer 11. Stigmata or other findings associated with a syndrome known to include a sensorineural or conductive component, or both B. 29 days through 3 years: conditions requiring rescreening 1. Parent or caregiver concern regarding hearing, speech, language, or developmental delay 2. Bacterial meningitis and other infections associated with sensorineural hearing loss 3. Significant head trauma 4. Recurrent or persistent otitis media with effusion lasting at least 3 months 5. Conditions previously listed in section A C. 29 days through 3 years: conditions requiring periodic monitoring 1. Family history of hereditary childhood deafness 2. TORCH infection 3. Neurofibromatosis type 2 4. Neurodegenerative disorder *This list of indicators is meant to be used when universal hearing screening at birth is not available and to identify children in need of further audiometric testing beyond infancy. Adapted from Joint Committee on Infant Hearing. 1994 Position statement. Pediatrics 1995;95:152 and Joint Committee on Infant Hearing. Year 2000 position statement: Principles and guidelines for early hearing detection and intervention programs. Pediatrics 2000:106:798

crucial etiologic evidence, such as the chorioretinitis associated with an intrauterine infection or the retinitis pigmentosa of Usher’s syndrome. Children with vestibular dysfunction must be referred immediately to an ophthalmologist who is aware that the diagnosis of Usher’s syndrome is being considered because these children are candidates for early cochlear implantation. Electroretinography is more sensitive than ophthalmoscopy in the early stages of retinitis pigmentosa [Young et al., 1996]. Usher’s

Clinical Evaluation / 7

syndrome type 1, the most devastating genetic variant, causes tunnel vision and ultimately causes blindness in adulthood. Not all variants of Usher’s syndrome are associated with vestibular dysfunction [Ahmed et al., 2003].

Types of Hearing Tests There are two broad categories of hearing tests: tests that assess a patient’s subjective hearing experience and require a behavioral verbal or nonverbal response to indicate that an auditory stimulus was perceived and physiologic tests of the sensitivity of the auditory system.

BEHAVIORAL HEARING TESTS Screening Tests In a pediatric office setting, testing is limited to behavioral screening and tympanometry that assesses only the mechanical properties of the middle ear. At best, infant screening tests provide a gross estimate of normal function in children in whom there is no suspicion of auditory impairment. Lack of behavioral response to sound does not necessarily indicate a peripheral hearing loss in uncooperative, autistic, or severely retarded children, but the presence of another handicap must raise suspicion. Screening tests are inappropriate in multiply handicapped children, children with risk factors for deafness, or clinical suspicion of hearing loss, all of whom must be referred promptly for formal quantitative testing. Screening tests performed in the office have many pitfalls, and they cannot be relied on to exclude hearing losses. Speaking softly to a child without risk factors, even if the response is appropriate, may be misleading if it provides nonverbal tactile or visual cues or speaking is louder than intended; interpreting lack of response as unwillingness to cooperate rather than failure to hear or comprehend is a major error. Producing a loud sound out of an infant’s or toddler’s field of vision is uninformative because hand claps and dropped metal basins are likely to provide somatosensory as well as auditory cues that may falsely reassure physician and parents that the child hears. Broadband stimuli cannot pick up high-tone losses. Crumpling paper or ringing a small bell out of the child’s sight and observing whether the child turns the head and eyes promptly in the direction of the sound may exclude profound hearing loss but is not a reliable hearing test; a consistent head turn in the horizontal plane does not occur before 6 months of age and in the vertical plane until almost 1 year, and blind children do not turn toward a sound source. It is dangerous to rely on such subtle responses as eye widening and cessation of activity because they are subject to observer bias. There are screening instruments available, such as a 3000-Hz warbler of variable and calibrated intensity, but some of the same caveats pertain. As with all biologic measurements, a single observation does not suffice; a reproducible one is required, with the caveat that habituation occurs after a few presentations, as soon as the stimulus has lost its novelty and alerting properties. In children too young to speak and in those with handicaps, only formal audiometric testing is sufficient.

Formal Behavioral Audiometry Behavioral audiometry in a soundproof room, using carefully calibrated pure tones and other acoustic stimuli pre-

sented to each ear through earphones, is the gold standard against which all other tests are gauged. Air and bone conduction can be tested. Behavioral audiometry is quantitative and efficient in experienced hands. It ensures that sound has been perceived and processed because it has elicited a specific response. It does necessitate cooperation on the patient’s part and adequate motivation and attention. Pure-tone behavioral audiometry yields sensitive, reliable, and reproducible threshold curves. It may be applicable to some young and handicapped infants with such refinements as visually reinforced and play audiometry. Conditioned behavioral techniques are not clinically reliable in infants whose developmental age is less than 6 months [Gravel and Traquina, 1992], despite the fact that their hearing can be measured in the laboratory with experimental behavioral methods. In older children, standard audiometry enables the comparison of air with bone thresholds in the same way as in adults. In sensorineural hearing losses, air and bone thresholds are identical, whereas in conductive hearing losses, bone thresholds are better than air-conduction thresholds [Kruger, 1988]. Many children have mixed hearing losses, in which bone threshold is better than air threshold, but both are elevated. Fluctuating hearing losses, especially if associated with signs of vestibular dysfunction, suggest the possibility of cytomegalovirus infection or labyrinthine fistula. Diagnosing fistulas is important because surgical correction may prevent progressive loss and improve hearing in some cases. Many sensorineural hearing losses and most conductive hearing losses produce flat threshold curves (i.e., they impair hearing for sounds of all frequencies to more or less the same degree) (Fig. 7-6). The average profoundly deaf child has minimal or no functionally useful hearing (Fig. 7-7). Responses recorded to low frequencies may represent awareness of vibration rather than hearing. Sloping hearing losses (Fig. 7-8) are common and affect higher tones to a much greater degree than lower frequencies. This type of hearing loss is notoriously easy to Frequency in Hz Hearing threshold level in dB re ANSI–1969

112

125 –10 0

250

500

1,000 2,000 4,000 8,000

10 20 30 40 50 60 70 80 90 100 110

FIGURE 7-6. Pure tone air-conduction audiogram for moderate binaural flat hearing loss. If it had been a mixed hearing loss, the level of bone conduction would have been indicated in brackets. O, right ear; X, left ear.

Rapin / Hearing Impairment

Hearing threshold level in dB re ANSI–1969

Frequency in Hz 125 –10 0

250

500

1,000 2,000 4,000 8,000

10 20 30 40 50 60 70 80 90 110

FIGURE 7-7. Pure tone air-conduction audiogram for profound binaural loss at all frequencies, with slight residual hearing at 250, 500, and 1000 Hz. No response (arrows) occurs at 2000 and 4000 Hz in the left ear. O, right ear, X, left ear.

Hearing threshold level in dB re ANSI–1969

Frequency in Hz 250

500

1,000 2,000 4,000 8,000

10 20 30 40 50 60 70 80 90 100 110

amplify certain frequencies selectively. Some hearing aids transpose frequencies into a range where the child has better preserved hearing [Gravel and Chute, 1996]. Rarer types of audiometric threshold curves are U-shaped losses that involve the middle frequencies more than the high and low and inverted U-shaped or dome-shaped losses that involve the high and low frequencies more than the middle frequencies. Occasionally, patients have preserved hearing in the so-called ultrahigh frequencies, which are those above 8000 Hz [Collins et al., 1991]. Poor correlation between language ability and audiometric threshold is especially common in patients with neural rather than cochlear hearing losses [Sininger and Starr, 2001].

TESTS OF CENTRAL AUDITORY FUNCTION

100

125 –10 0

113

Z Z

Z

Large batteries of tests measuring more complex auditory skills than the detection of pure tones are often administered to children with learning disabilities and language disorders in an effort to understand the source of their problem [Hood and Berlin, 2003; Rapin and Gravel, 2003]. Speech audiometry measures the ability to detect speech sounds and to repeat phonetically balanced sounds. The ability to discriminate words that are distorted or presented against a noisy background is often impaired in children with hightone losses; it may be unilaterally impaired in patients with pathologic processes in the temporal lobe contralateral to the ear with the lower score [Segal et al., 2003]. Competing words or sounds may be presented simultaneously to both ears (i.e., dichotic test) to assess cerebral dominance for the processing of language. In virtually everyone, including most left-handed people, language is processed in the left hemisphere, whereas the right hemisphere is dominant for music, the intonation of speech (prosody), and environmental sounds. In dichotic testing, words presented to the right ear of individuals left dominant for language are somewhat more likely to be reported than those presented to the left ear. Dichotic testing is helpful for detecting pathologic lateralization of the auditory brain because stimuli presented to the ear contralateral to a damaged hemisphere may be not be reported [Hugdahl and Carlsson, 1994; Nass et al., 1992].

Z

ELECTROPHYSIOLOGIC HEARING TESTS FIGURE 7-8. Pure tone air-conduction audiogram for severe binaural sloping hearing loss. An acoustic reflex (Z) was present at 500 to 1000 Hz but absent (arrows) at 2000 and 4000 Hz, confirming the shape of the hearing loss. O, right ear; X, left ear.

overlook; hearing-impaired children respond to voices, especially male voices, and environmental noises, which always contain energy at the low end of the frequency spectrum, at nearly the same intensity as hearing children and therefore do not appear deaf. Lack of hearing in the high frequencies has particularly deleterious consequences for language learning because consonant sounds differ in their high-pitch components. Because consonants carry most of the linguistic message, children with sharply sloping hearing losses are more handicapped than hearing-impaired children with the same mean threshold but a flat loss. Children with sloping hearing losses and other irregular thresholds may benefit from and better tolerate hearing aids that

The advent of electrophysiologic tests of hearing has revolutionized pediatric audiometry. The Joint Committee on Infant Hearing [2000] recommends universal hearing screening at birth, or at least before 3 months of age, using cochlear emission or brainstem responses, tests that are widely available, with appropriate follow-up or referral of children who failed (see Box 7-2).

Acoustic Immittance Testing Aural acoustic immittance quantifies the compliance of the eardrum and middle ear and is useful for screening and in the diagnosis of middle ear effusions and other anomalies. Effusion is associated with negative middle ear pressure, lack of compliance of the tympanic membrane, and absence of the acoustic reflex [Katz, 2002; Nozza, 1996]. The acoustic reflex arises from the contraction of the stapedius muscle in response to a loud sound (usually 70 to 90 dB above hearing threshold). The presence of an acoustic reflex indicates

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that the middle ear transducer is intact, the middle ear is aerated, and the acoustic (cranial nerve VIII) to facial (cranial nerve VII) reflex arc is intact, including its relays in the brainstem; it is not a test of auditory sensitivity. The acoustic reflex is useful for localizing the site of pathologic processes in patients with Bell’s palsies. It is present when the pathologic process responsible for the facial palsy is distal to the middle ear, and it is absent when the process is proximal to the nerve to the stapedius muscle (e.g., brainstem tumors, leukemic meningeal infiltration).

Evoked Otoacoustic Emissions Otoacoustic emissions are considered a quick, easy, reliable, and relatively inexpensive universal screening test for neonatal hearing [Norton et al., 2000a]. The recommendation is to test twice because about 10% of results are false positives. Infants who demonstrate no emissions require retesting and assessment of middle ear function. If the infants fail again, brainstem-evoked responses are needed to confirm the hearing loss. Otoacoustic emissions are especially useful for detecting mild-to-moderate hearing losses, such as those caused by middle ear pathology, or for monitoring early signs of ototoxicity. Sedation is seldom required. Because otoacoustic emissions are a test of outer hair cell function, they enable localization of dysfunction as sensory or neural, as in children with brainstem pathology who may have absent or abnormal brainstem responses despite preserved cochlear function. They have largely supplanted transtympanic recording of the cochlear microphonic and compound nerve action potential (i.e., electrocochleography) because they do not require anesthesia, although the latter tests are important to assess spiral ganglion function in children being considered for a cochlear implant [Rapin and Gravel, 2003].

Brainstem Auditory Evoked Responses BAER testing [Stapells and Oates, 1997] does not require cooperation from the subject; it can be performed reliably whether the subject is awake, asleep, or anesthetized. It is an ideal technique to supplement behavioral audiometry in hard-to-test infants and children. Its disadvantage is that it often requires sedation. BAERs to clicks provide data on the response of cranial nerve VIII to sounds containing energy at frequencies of 100 to 8000 Hz and, tentatively, data on the sensitivity of each of the brainstem relays of the auditory pathway up to the level of the inferior colliculus. For audiometric applications where frequency-specific threshold estimates are required, it is important to also obtain BAERs to tones. For example, reproducible responses to 500 and 2000 Hz at intensities of 30 and 20 dB above normal hearing level for the stimuli used almost certainly indicate normal peripheral sensitivity [Stapells and Oates, 1997]. In infants with microtia or an extremely narrow canal or when it is crucial to determine that hearing loss is conductive rather than sensorineural, the stimuli can be presented through a bone oscillator. For neurologic purposes, transmission time between waves I and V of the BAER provides data on localization of pathology in the auditory pathway, wave I to III interval from the spiral ganglion cells to the cochlear nucleus, and waves III and V from the cochlear nucleus to the vicinity of the inferior colliculus [Rapin and Gravel, 2003]. Transmission time is prolonged in premature infants and newborns and decreases

with maturity as myelination advances. It is often prolonged transiently in stressed neonates and some young children, but prolonged transmission time alone is rarely predictive of future neurologic, auditory, or cognitive deficits. A demyelinating auditory neuropathy or compression of the acoustic nerve by an acoustic tumor may prolong or suppress waves I to III (and in that case, affect later waves). Spared wave I with later waves absent or the interwave interval prolonged suggests intrinsic brainstem pathology, such as by demyelination or a neoplasm. The consequences of prolonged latency and even absence of brainstem waves with spared otoacoustic emissions vary from apparently normal hearing to more severe impairment of hearing than predicted from the behavioral audiogram because of desynchronization rather than lack of auditory conduction in the brainstem.

Cortical Auditory Event–Related Potentials For clinical purposes, later cortical potentials are less useful gauges of hearing sensitivity than brainstem potentials, primarily because they are altered by changes in alertness and sleep phase. Some of their components provide physiologic correlates of the later stages of auditory perception and discrimination [Steinschneider and Dunn, 2003]. In the future, they may play a role in the clinical diagnosis of children with auditory processing disorders, dysphasia, autism, and learning disabilities. Interpretation of brainstem or late cortical-evoked responses as evidence for such disorders must be considered controversial, and this approach belongs in the experimental laboratory rather than the clinic.

Imaging of the Ear In neonates, the bony labyrinth is seen on transorbital view of a plain skull radiograph because the otic capsule is fully grown at birth and proportionately larger and better calcified than the remainder of the skull. High-resolution, thin-cut, and tridimensional CT and MRI have added an entirely new dimension to the imaging of the ear [Fisher et al., 1996; Westerhof et al., 2001]. The external canal, middle ear and ossicular chain, round and oval windows, eustachian tube, semicircular canals, utricle, saccule, cochlea, and cranial nerve VIII are depicted clearly. Fluid in the middle ear or mastoid air cells, mastoiditis, tumors, fistulas, cholesteatomas, and acoustic nerve tumors are detectable, and detailed study of malformations of any part of the ear is possible. Patients who have had purulent endolabyrinthitis as a complication of bacterial meningitis in the past often have ossified inner ears with a functionally dead, obliterated cochlea. Such a finding may jeopardize delayed implantation of a cochlear prosthesis because to be effective, the cochlear prosthesis requires functioning spiral ganglion cells [Nadol, 1997]. Prostheses applied to the brainstem may be effective in such cases [Grayeli et al., 2003]. Most children with isolated sensorineural hearing losses have normal middle and inner ears on imaging because premature cellular death by apoptosis rather than a gross malformation is the usual pathologic process. The yield of radiologic examination of the temporal bones is much higher when the hearing loss is mixed, conductive, or fluctuating and when there are malformations in other organ systems.

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Miscellaneous Urine, Blood, and Other Tests Early childhood deafness may result from an intrauterine infection. In neonates, high levels of immunoglobulin M suggest an active infection in the child, whereas high levels of immunoglobulin G are acquired passively from the mother. A deaf child who has a cataract or chorioretinitis almost certainly was infected with rubella or cytomegalovirus (of the other TORCH infections, toxoplasmosis rarely causes deafness and herpes simplex probably does not) [Boppana et al., 1997; Chess et al., 1971]. Many neonates are not visibly infected; later antibody titers are of limited value if the child was immunized or infected postnatally with cytomegalovirus. Rubella and cytomegalovirus in the urine indicate an active infection that may persist for many months and be responsible for a progressive hearing loss [Fowler et al., 1997]. Further epidemiologic studies are needed to assess the relative importance of cytomegalovirus infection as a cause of sporadic hearing loss. Children with anomalies of the external and middle ear require kidney sonograms because as many as 10% of these children may have serious genitourinary anomalies, including life-threatening hydronephrosis. Most of the several genetic variants of Alport’s syndrome, one of the more common causes of acquired deafness, are characterized by hematuria, deteriorating renal function, and progressive hearing loss and eye anomalies [Kashtan, 1999; Wester et al., 1995]. Renal tubular acidosis may be associated with profound childhood deafness [Caldas et al., 1992]. Hunter’s syndrome and some of the other mucopolysaccharidoses cause conductive or mixed hearing losses. Appropriate blood tests should be obtained when one of these disorders is suspected. Thyroid disease with goiter (e.g., cretinism) may be the cause of hearing loss [Squatrito et al., 1981], which is progressive or fluctuating in Pendred’s disease. Pendred’s disease can be diagnosed after thyroid function is blocked with perchlorate, but this is less reliable than genetic testing [Campbell et al., 2001] or imaging showing cochlear hypoplasia and widening of the vestibular aqueduct [Cremers et al., 1998]. Children with congenital rubella or ear anomalies may suffer from structural congenital heart disease. Children with the rare recessive Jervell and Lange-Nielsen syndrome [Neyroud et al., 1997] are congenitally hearing impaired and typically have syncopal episodes in early childhood. Electrocardiograms reveal a conduction defect (i.e., prolonged QT interval). It is important to consider the possibility of this condition, rather than that of a seizure disorder because many of these children have died suddenly and unexpectedly, and they might have been treated with a noradrenergic blocker or a pacemaker. It is important to consider the possibility of a syndromic hearing loss, even in children without obvious pathology in other organ systems, because genetic studies have taught us that the products of mutated genes are regularly found in many other tissues besides the cochlea where they may result in delayed pathology. Even more troubling is the knowledge that what was previously viewed as one disease, such as Alport’s disease, is clinically and genetically heterogeneous. A prevalent cause of nonsyndromic deafness found in approximately 50% of children with flat, severe-to-pro-

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found recessive prelingual hearing loss is mutation in the connexin 26 gene [Nance, 2003]. Molecular genetics makes it possible to offer genetic counseling, but revelation of the many new complexities makes it necessary to refer to centers specialized in the genetics of deafness families with all but the most straightforward conditions; even in such cases, clinicians must access updated databases before offering information to their patients (http://www.ncbi.nlm.nih.gov/ entrez/ query.fcgi?db=OMIM; http://www.uia.ac.be/dnalab/hhh/).

Psychologic Evaluation It might be assumed that deafness, which affects a peripheral receptor and not the brain, has no effect on cognitive competence; however, deprivation of input through one of the major sensory channels, especially during the development of language, alters brain structure and function. There is abundant anatomic and physiologic evidence for altered wiring from studies of a number of species and from electrophysiology, functional imaging, and psychologic studies of humans. Inputs from other sensory modalities occupy receptor sites in cortex deprived of its dominant sensory input [Roeder and Neville, 2003]. In the congenitally blind, somatosensory and auditory inputs occupy what would have been visual cortex, with resultant enhancement, especially with training, of tactile and auditory function, enabling efficient Braille reading and remarkable auditory memory and, in more than a few blind individuals, exceptional talent for music. Congenital deafness results in enhanced perception of movement in the peripheral visual fields [Bavelier et al., 2000]. There is evidence that one of the bases for crossmodal plasticity is the existence of projections of other sensory modalities to what will become, for example, auditory cortex; the presumption is that synaptic pruning or functional inhibition takes place postnatally in these projections from other modalities as a result of massive sensory stimulation in the primary modality, in this case audition. Decreased cross-modal function was demonstrated electrophysiologically by gradual shrinkage over the ensuing 2 years of the extent of cortical activity elicited by auditory stimuli over visual brain regions in normal 6-month-old infants [Neville and Bavelier, 2002]. These observations suggest that timing for optimal development of auditory cortex by the provision of an auditory prosthesis is limited. Better acquisition of speech after cochlear implantation in young versus older congenitally deaf children supports this [Govaerts et al., 2002], although some degree of plasticity remains even in adults, as demonstrated by reorganization of tonotopic projections to auditory cortex in acquired hightone loss [Dietrich et al., 2001]. At a minimum, deafness affects the life experience of the child (and family) profoundly, which has consequences for intelligence and personality [Mayberry, 2003; Rapin, 1979]. The most serious consequence of a lack of hearing is language deprivation. Deaf children of hearing parents, who represent more than 90% of severely hearing-impaired children, are much more seriously deprived than deaf children of deaf parents who use American Sign Language (ASL) as their primary language [Schlesinger and Meadow, 1972]. Deaf children of deaf parents learn ASL at the languagelearning age and are able to communicate normally with their parents. There are several reasons why normal com-

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munication with parents is unlikely to develop in the deaf child of hearing parents: Diagnosis of hearing loss is often delayed, lip reading is a grossly inefficient way to learn language, and many hearing parents of deaf children are reluctant to learn sign language, or if they do eventually learn it, they are not fluent. As a result, until they start school, many deaf children of hearing parents are likely to develop with the gestures that they and their parents have devised as the only language (“home sign”). To what degree early cochlear implants will enable deaf children to learn speech is promising but still uncertain, and this expensive methodology will not be available to most children with hearing losses in the world because it requires the surgical procedure, electronic technology, meticulous follow-up, and on-going, intensive training. Hearing speech is a major vehicle for incidental learning that is unavailable to deaf children. Even television has little meaning without sound. It takes most deaf children many years to learn to read fluently enough to read closed captions on TV or to read for pleasure or as an efficient means for gaining information; many deaf individuals never achieve this level of proficiency [Conrad, 1979; DiFrancesca, 1972]. School experience is likely to be much less enriching for deaf children than for hearing children, especially as much time is consumed, at least in the early grades, by learning language and later by attempting to catch up. Although they are bright, most deaf children suffer from severe experiential and cultural deprivation. They know and experience less than their hearing peers [Furth, 1966]. Lack of adequate language for thought assuredly alters their cognitive experience. Not surprisingly, most deaf children do dramatically less well than hearing children on verbal portions of intelligence test batteries; however, some of them inexplicably also do less well on nonverbal tests, perhaps because they have an unrelated learning disability or have been experientially deprived [Furth, 1966]. It is also possible that verbal ability is advantageous for carrying out ostensibly nonverbal memory or picture arrangement tasks. A few psychologic test batteries have been developed and standardized for deaf populations [Geers and Lane, 1984; Snijders and Snijders-Oomen, 1970]. At least one performance test can be administered verbally or nonverbally: the Hiskey-Nebraska Test of Learning Aptitude [Hiskey, 1966]; it has lower norms for deaf than for hearing children. The nonverbal Leiter Performance Scale–Revised [Royd and Miller, 1997] is another resource. Any definition of cognitive competence based on IQ scores is restricted despite its widespread acceptance. Its usefulness is debatable in atypical populations. Nonetheless, IQ scores do predict level of educational achievement, which even today is significantly lower for the deaf than the hearing. The fact that experiential deprivation rather than biologic inferiority accounts for the generally lower academic achievement of the deaf challenges current approaches to deaf education [Lane, 1992]. This is not to say that educational and professional achievements of some prelingually deaf persons have not matched those of hearing peers, but they are a small minority. It is still too early to evaluate to what extent cochlear implants will reverse this disparity in individuals fortunate enough to have been implanted early and to have received the intensive training required to profit optimally from these prostheses.

MANAGEMENT Amplification Because some genetic and nongenetic hearing losses, particularly those due to congenital cytomegalovirus infection, are progressive, audiograms must be obtained regularly throughout childhood. All infants and children with significant hearing losses must be fitted immediately with hearing aids [Chase and Gravel, 1996; Roeser and Downs, 1995]. Hearing aids are variable gain amplifiers inserted into the external ear canal. Behind-the-ear miniaturized hearing aids yield as much amplification as the body-worn aids of the past. Their smallness does have disadvantages: loss and damage. Previously, cochlear hearing losses due to hair cell damage made it difficult for some hard-of-hearing children to accept a hearing aid inasmuch as amplification made them perceive moderately intense sounds as intolerably loud (i.e., recruitment). Prescriptive fitting techniques, real ear measurement procedures, and wide dynamic range compression circuitry have allowed output limiting characteristics to be determined and verified instrumentally, even in very young children [Chase and Gravel, 1996]. It is essential to explain to parents that hearing aids do not restore hearing and only bring within the child’s narrowed hearing window sounds that would otherwise be below hearing threshold. The aids do so at the expense of distortion of amplitude and frequency and of loss of signal-to-noise ratio. Sound cannot be amplified to the point of acoustic trauma, which occurs at equal intensity in normal and impaired ears. However, profoundly deaf children may gain awareness of sound even though they have little discrimination. Amplification is especially effective for children with conductive losses who derive more benefit from amplification than children with sensorineural hearing losses do because their inner ear is normal and the purpose of the aid is to bypass the defective mechanical transducer. Children with atresia can be fitted with bone oscillators. Radio-frequency FM closed-loop listening systems are widely used in schools for the deaf, in mainstream educational settings, and by some parents. The advantage of such a system is that each child receives the amplified speech signal in his or her hearing aids, with much less amplification of background noise than with standard hearing aids, which amplify unselectively. The teacher can wear a transmitter and the child the FM receiver, enabling some severely hearing-impaired children to be mainstreamed into normal classrooms. To maximize the development of their residual auditory function, it is important to fit children with a hearing aid as early as possible after the hearing loss is detected. Schools for the deaf insist that all children wear them in school, at least during the elementary years. Many of the profoundly deaf adolescents and adults who derive little or no benefit from aids choose not to wear them. Binaural aids usually are prescribed so that children may have access to cues for sound localization and may benefit from better hearing in noisy backgrounds [Chase and Gravel, 1996]. It is generally recommended that children with unilateral losses also be provided with an aid, and because sound may come from any direction, it is preferred that they wear a mild-gain FM

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system and be placed in a classroom with an FM system [Updike, 1994]; this approach is taken because a significant proportion experience academic difficulties [Brookhouser et al., 1991]. Children with high-tone and other nonflat hearing losses require hearing aids with selective amplification of the frequencies they hear most poorly. Hearing aids should be fitted by trained pediatric audiologists who use objective prescriptive selection and evaluative procedures to fit optimal amplification devices [Chase and Gravel, 1996]. Preschool children with hearing aids must be examined every few months because their external canals grow and new molds need to be made frequently and because the child’s hearing must be monitored until it is ascertained that the loss is nonprogressive.

Cochlear Implants Implanted auditory prostheses are gaining in popularity, although a survey of pupils in schools for the deaf indicated that almost one half, especially of those implanted in middle childhood, were no longer using their prostheses [Rose et al., 1996]. Recent models, which provide better speech recognition, are multichannel and programmable, and the technology is still evolving. Most implants are intracochlear and lie against the basilar membrane within the scala tympani. The bony labyrinth must be patent and spiral ganglion cells alive if an intracochlear implant is contemplated, which may be a problem after meningitis. Consequently, detailed preoperative behavioral, electrophysiologic, and imaging assessments are essential to evaluate the anatomic integrity of the bony labyrinth and viability of the hair cells and neurons in the spiral ganglion. Complete loss of hair cells abolishes the cochlear microphonic, otoacoustic emissions, and wave I (and later waves) of the BAER to sound, but cochlear stimulation may result in a recordable response if the spiral ganglion cells and cranial nerve VIII are spared [Rapin and Gravel, 2003]. Implants that stimulate the central auditory pathway in the brainstem have also been attempted in a number of patients with bilateral acoustic tumors [Colletti et al., 2002] or completely ossified cochleas after meningitis [Schneider et al., 2001]. Part of the implant is a subcutaneous receiver-stimulator that is connected, usually through the skin, to an external receiver. Although miniaturized, the devices require a mastoid of reasonable size, making implants impractical for infants younger than about 1 year. There are reports of complications requiring removal or replacement of the prosthesis [Parisier et al., 1996] or damage to the cochlea, as well as reports of late meningitis [Reefhuis et al., 2003]. Unilateral implants are recommended to leave one cochlea untouched. Implanted children and adults need extensive postoperative training extending over several years to profit maximally from the implant [Tye-Murray et al., 1995]. Implants require an intensive commitment of their parents and many more hours of auditory and phonologic training than schools can provide. Speaking children with acquired hearing losses profit more from cochlear implants than older children with congenital hearing losses who have little or no experience of audition or speech. Several thousand prelingually deaf children have already been implanted

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worldwide, and age at implantation and intensity of postimplantation habilitation are major factors in enabling profoundly deaf children to be mainstreamed [Geers et al., 2003]. Speech intelligibility remains low for many months after implantation and comprehension limited except for words that have been taught specifically, but with continued intervention, progress continues for several years. Delay in the acquisition of useful language comprehension and production has raised the issue of whether to continue the use of sign language. Some educators are opposed to it, but others point out that continued exposure to sign language is helpful to children who had learned it while intensive auditory and speech training is taking place because sign language is much easier for them to acquire than speech and will render them bilingual. In Sweden, commitment of the parents to becoming proficient in sign language and continuing to use it is a prerequisite for implanting the child [Preisler et al., 1997]. Some members of the deaf community, especially deaf parents of deaf children, have mixed feelings about cochlear implants, fearing that the children will distance themselves and give up the rich cultural heritage of their community. Some are justifiably anxious about the short- and long-term demands and potential complications of implants [Christiansen and Leigh, 2004].

Reconstructive Surgery Reconstructive surgery for external and middle ear malformations is contraindicated in very young children because they are at high risk for middle ear infections. Even in older children, middle ear reconstruction carries with it the danger of adding a sensorineural component to the conductive loss, and unilateral surgery is usually performed. Hearing aids, particularly those anchored to the mastoid, invariably give good results in conductive losses, whereas the outcome of reconstructive surgery is somewhat problematic [Raveh et al., 2002]. Reconstruction of the pinna in middle childhood may be important for cosmetic reasons [Siegert, 2003].

Education Since the enactment of U.S. Public Law 94-142 in 1975, a variety of infant auditory training programs have become available to any infant or preschooler younger than 3 years who is identified as hearing impaired, and most states provide full-day special education for deaf children at age 3. Programs in different localities differ in detail. Most infant programs are at least partially home based, with an itinerant teacher of the deaf visiting the child’s home, working with parents, and providing auditory, speech, and language training. Most hard-of-hearing children can be mainstreamed into normal classes from the start, provided they have hearing aids, an FM system, speak reasonably intelligibly, and have access to a part-time special teacher for the hearing impaired to give them individual academic assistance and on-going speech and language therapy. Children with unilateral hearing losses are educated in normal classes with a hearing aid and FM system. How best to educate the deaf has been a subject of raging controversy for more than a century between the proponents

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of oralism and those who champion the use of sign language. One problem is that the hearing have prescribed education for the deaf [Lane, 1992]. It is too early to determine the impact of cochlear implants on this debate. Hearing parents would like their deaf children to be educated and speak well enough to blend into the normal population. Oralists recommend amplification, auditory training, lip reading, and cochlear implants. The most successful children taught lip reading and given auditory training and an implant will, at a minimum, be delayed in the acquisition of vocabulary and syntactic sophistication. Lip reading is an inefficient channel for language learning because many sounds are not visible on the lips. Before the advent of cochlear implants, only a minority of profoundly hearing-impaired children became proficient speakers and fully mastered the written language of their community with the oralist approach. Some parents view sign language as evidence of failure of oralism and a social stigma; they fear that nonoral children will be isolated from society. These parents need to understand that speech is only one form of language and that sign language is just as rich and viable a language as English, Arabic, or Chinese [Klima and Bellugi, 1979; Lane, 1984]. They also need to know how important it is for young children to acquire language at the normal age for language acquisition (i.e., infancy and early preschool years) by being exposed to fluent users of that language. Languages that are not learned at the biologically appropriate age for language acquisition have to be taught by a much less efficient process; taught languages are almost never acquired as well as a person’s native tongue. Because most deaf children taught with the oralist approach do not become fully proficient in English, it is unfair to delay exposing them to sign language until they have failed oralism. Deaf and hearing children of deaf parents who are exposed to the native language of the deaf community (i.e., American Sign Language [ASL] in the United States, French Sign Language in France, and equivalent forms of sign language in other countries) begin to express themselves in sign language at an earlier age than hearing children speak, presumably because gestures develop earlier than speech and producing signs requires less refined motor coordination than producing intelligible words [Mayberry, 2003; Schlesinger and Meadow, 1972]. Children whose native language is some form of sign acquire from early on syntactic devices such as question forms, verbs, and prepositions, and they understand that each person, thing, feeling, and action has a name; they possess from the start a fully adequate vehicle for self-expression. American Sign Language in not suitable for simultaneously speaking and signing because its syntax is encoded differently from that of English. Starting in the early 1970s, many deaf educators recommended the use of Signed Exact English for deaf education. Signed Exact English is a contrived language that transliterates English word for word into signs borrowed from American Sign Language; words are produced in their order of appearance in English, and there are signs for English grammatical markers. It enables speaking and signing to proceed simultaneously (i.e., Total Communication). It was hoped that this approach would provide deaf children with a channel to express themselves and would facilitate their learning of English. Although it was a step in the right direction, Signed Exact English is not

well suited for a visually coded language; consequently, there is movement toward a return to American Sign Language, which was banished from many schools for the deaf by well-meaning hearing teachers in the 1980s [Lane and Philip, 1984; Sacks, 1989]. There is no convincing evidence that learning sign language delays the acquisition of written English. Lane [1992] strongly urges the use of sign language with deaf children so that they have a language to serve as a foundation for learning English as a second language. English learning at school age can begin by concentrating on proficiency in written language and learning the auditory-alphabetical code. Currently, deaf children, even in schools that use sign language, spend much time in speech training, but most are grossly deficient in their knowledge of written and spoken English, to the detriment of their educational achievement and general cognitive proficiency [Conrad, 1979; DiFrancesca, 1972; Lane, 1992; Rapin, 1979]. Whether the hope that cochlear implants will drastically change this state of affairs will be fulfilled remains to be seen [Francis et al., 1999]. Deaf children who are sufficiently proficient in English and other subjects eventually can be mainstreamed into regular classrooms with appropriate assistance. It is debatable whether deaf children perform better in normal schools with deaf interpreters and individual tutoring than in schools for the deaf where everyone uses sign language. It is also uncertain which approach provides “the least restrictive environment’’ prescribed by U.S. Public Law 94-142. Boarding schools for the deaf are practical for children who live in small, isolated communities unable to provide special services for one deaf child. Residential placement is much more acceptable than in the past, because it is possible to have children go home for some or all weekends. Residential school placement offers the advantage of deaf peers, the consistent use of sign language, and the loss of the stigma of being considered handicapped. It may be the least restrictive environment for children from deprived backgrounds whose families are not motivated to learn sign language, cannot provide extensive auditory language training, and often do not speak English, the only language besides American Sign Language used in deaf education in this country. In day schools for the deaf, such children may have no opportunity to communicate with anyone except during the 6 hours of the 180 school days. Some deaf children have serious behavior problems because their parents may feel guilty over their child’s handicap and are reluctant to discipline them or may not be able to communicate adequately enough with their child to bring them under parental control. However, most deaf children do not have severe behavior problems. Deafness is not an adequate explanation for autistic behaviors.

OUTCOME The hearing-impaired child whose hearing loss was diagnosed early and who had the benefit of optimal habilitation and a supportive family does well cognitively, socially, and emotionally and may go on to higher education and a profession. However, with rare exceptions, the less privileged with minimal hearing are significantly or severely deficient in language skills, even if they have normal or superior non-

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verbal intelligence and no associated handicap. As a result, reading ability and other academic skills are severely curtailed, and as these children grow older, they typically fall further behind their hearing peers [Conrad, 1979; Schein and Delk, 1974]. Although inadequate knowledge of English and poor reading skills result in profound informational deprivation, many deaf people find a niche in the workplace and are not unduly penalized for these deficiencies. A much smaller proportion of the deaf than the hearing population is able to acquire a college education or profession, even though there are specialized universities for the deaf, such as Gallaudet in Washington, DC; the National Technical Institute for the Deaf at the Rochester Institute of Tecnology in Rochester, New York; and other smaller programs. The deaf are at risk for significant medical and emotional problems because there are few physicians, nurses, social workers, job counselors, psychiatrists, psychologists, and other health-care workers with whom they can communicate adequately. The profound jeopardy of even intelligent deafautistic, deaf-blind, and otherwise multiply handicapped deaf children is not being addressed adequately. There is a need for medical and other professionals who understand the particular problems of deaf individuals and who can communicate with them to evaluate and treat them competently. Despite these obstacles, most deaf adults are independent and self-supporting [Greenberg, 1970]. Deaf communities exist in most large cities and provide informal networks of social and practical assistance to their members [Schein and Delk, 1974]. Many deaf children are not diagnosed as early as desirable and grow up without the benefits of optimal habilitation. They may experience severe social deprivation and may have parents who are not able to communicate with them, except through a primitive gesture system, a few spoken nouns and verbs, and words such as “no.’’ However, even totally deprived deaf adults are capable of learning a language, provided they are intelligent, highly motivated, and are lucky enough to meet a truly dedicated teacher [Schaller, 1991]. ACKNOWLEDGMENTS The helpful suggestions of Judith S. Gravel, Michelle Dunn, and Robert J. Ruben are gratefully acknowledged. The author is also grateful to the principals and many teachers at St. Joseph’s School for the Deaf in the Bronx and at the Florida School for the Deaf and the Blind who discussed issues of deaf education with her over a span of more than 4 decades.

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Joint Committee on Infant Hearing. Year 2000 position statement: Principles and guidelines for early hearing detection and intervention programs. Pediatrics 2000;106:798. Jure R, Rapin I, Tuchman RF. Hearing-impaired autistic children. Dev Med Child Neurol 1991;33:1062. Kaga K. Vestibular compensation in infants and children with congenital and acquired vestibular loss in both ears. Int J Pediatr Otorhinolaryngol 1999a;49:215. Kaga K, Tokoro Y, Tanaka Y, Ushijima H. The progress of adrenoleukodystrophy as revealed by auditory brainstem evoked responses and brainstem histology. Arch Otorhinolaryngol 1980;228:17. Kaga M. Language disorders in Landau-Kleffner syndrome. J Child Neurol 1999b;14:118. Kashtan CE. Alport syndrome. An inherited disorder of renal, ocular, and cochlear basement membranes. Medicine (Baltimore) 1999;78:338. Katz J. Handbook of clinical audiology. Philadelphia: Lippincott Williams & Wilkins, 2002. Kavanagh JF. Otitis media and child development. Parkton, Md: York Press, 1986. Kemp DT. Stimulated acoustic emissions from within the human auditory system. J Acoust Soc Am 1978;64:1386. Klein SK, Kurtzberg D, Brattson A, et al. Electrophysiologic manifestations of impaired temporal lobe auditory processing in verbal auditory agnosia. Brain Lang 1995;51:383. Klima ES, Bellugi U. The signs of language. Cambridge: Harvard University Press, 1979. Kraus N, McGee T. Clinical applications of the middle latency response. J Am Acad Audiol 1990;1:130. Kruger B. Basic audiologic evaluation. In: Alberti PW, Ruben RJ, eds. Otologic medicine and surgery. New York: Churchill Livingstone, 1988:365. Lane H. When the mind hears: A history of the deaf. New York: Random House, 1984. Lane H. The mask of benevolence: Disabling the deaf community. New York: Alfred Knopf, 1992. Lane H, Philip FT. The deaf experience. Cambridge, MA: Harvard University Press,1984. Lewine JD, Andrews R, Chez M, et al. Magnetoencephalographic patterns of epileptiform activity in children with regressive autism spectrum disorders. Pediatrics 1999;104:405. Marazita ML, Ploughman LM, Rawlings B, et al. Genetic epidemiological studies of early-onset deafness in the U.S. school-age population. Am J Med Genet 1993;46:486. Martuza RL, Eldridge R. Neurofibromatosis 2 (bilateral acoustic neurofibromatosis). N Engl J Med 1988;318:684. Mayberry RI. Cognitive development in deaf children: the interface of language and perception in neuropsychology. In: Segalowitz S, Rapin I, eds. Child neuropsychology. In: Boller F, Grafman J, series eds. Handbook of neuropsychology, Vol. 8, part 2. 2nd ed. Amsterdam: Elsevier, 2003:487. Merchant SN, Gopen Q. A human temporal bone study of acute bacterial meningogenic labyrinthitis. Am J Otol 1996;17:375. Mills DL, Neville HJ. Electrophysiological studies of language and language impairment. Semin Pediatr Neurol 1997;4:125. Nadol JB Jr. Patterns of neural degeneration in the human cochlea and auditory nerve: Implications for cochlear implantation. Otolaryngol Head Neck Surg 1997;117:220. Nadol JB Jr, Young YS, Glynn RJ. Survival of spiral ganglion cells in profound sensorineural hearing loss: Implications for cochlear implantation. Ann Otol Rhinol Laryngol 1989;98:411. Nance WE. The genetics of deafness. Ment Retard Dev Disabil Res Rev 2003;9:109. Nass RD, Sadler AE, Sidtis JJ. Differential effect of congenital versus acquired unilateral brain injury on dichotic listening performance. Evidence for sparing and asymmetric crowding. Neurology 1992;42:1960. Neville H, Bavelier D. Human brain plasticity: Evidence from sensory deprivation and altered language experience. Prog Brain Res 2002;138:177. Neville HJ, Mills DL. Epigenesis of language. Ment Retard Dev Disabil Res Rev 1997;3:282. Newman TB, Klebanoff MA. Neonatal hyperbilirubinemia and long-term outcome: Another look at the Collaborative Perinatal Project. Pediatrics 1993;92:651. Neyroud N, Tesson F, Denjoy I, et al. A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nat Genet 1997;15:186.

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CHAPTER 8

Vertigo Lydia Eviatar

Vertigo and dizziness are often used interchangeably in the medical literature, although each term describes a different set of symptoms. In 1901, Gowers defined vertigo as “any movement or sense of movement, either in the individual himself or in external objects, that involves a defect, real or seeming, in the equilibrium of the body.” Dizziness is a less specific term and may imply a sensation of lightheadedness or an impending sensation of falling, which does not necessarily indicate vestibular dysfunction. The maintenance of equilibrium depends on proper sensory afferent input from the vestibular, visual, and proprioceptive systems that provide the information necessary to initiate appropriate postural reactions in response to changes in the center of gravity, controlled by the pyramidal, extrapyramidal, and cerebellar systems.

ANATOMY AND PHYSIOLOGY OF THE VESTIBULAR SYSTEM The vestibular organ, specifically the membranous labyrinth, is fully developed in the 30-mm human embryo [Dekaban, 1970]. Oculovestibular reflexes are first detected around the 12th week of gestation and are fully established by the 24th week [Gesell and Amatruda, 1945]. The vestibular nerve appears to be fully myelinated by the 16th week of gestation, and the vestibular receptors of the inner ear are fully activated by the 32nd week. A Moro reflex can be elicited by 32 weeks’ gestation and sometimes even earlier [Hamilton and Mossman, 1972]. Each of the paired organs of equilibrium—the labyrinths—consists of three semicircular canals, a utricle, and a saccule (see Fig. 7-1). The labyrinths monitor any changes in the position of head and body in space. The cristae in the ampules of the semicircular canals are primarily stimulated by angular acceleration of the head and body, whereas the macules of the utricle and saccule act as transducers that collect information from gravitational forces and from vertical acceleration. Information received by both labyrinths simultaneously is conveyed through the vestibular nerves to the vestibular nuclei. Impulses ascend in the medial longitudinal fasciculus to cranial nerves III, IV, and VI and contribute to the oculovestibular responses. Impulses from the vestibular nuclei descend in the medial and lateral vestibulospinal tracts and provide excitatory stimuli to the extensor muscles of the head, trunk, and extremities to counteract gravity and maintain the upright posture. The cerebellum receives afferent impulses from the vestibular nuclei and serves as a major center for integration of oculovestibular and postural responses. Efferent impulses from the flocculonodular lobe of the cerebellum are transmitted directly to the labyrinth and

vestibular nuclei and modulate their responses. Widespread, diffuse connections with the reticular activating system, thalamus, and subthalamic nuclei modulate vestibular responses. Cortical representation is at the level of the posterior temporal gyrus, adjacent and posterior to the Heschl gyrus. Penfield’s experiments documented that direct stimulation of this cortical area produces a definite vertiginous sensation [Carpenter, 1974]. The oculovestibular reflex permits ocular fixation on stationary objects while the head and body are in motion. Nystagmus can be induced by rotation (i.e., sinusoidal stimulation) and caloric stimulation of the labyrinths. The intensity of the induced nystagmus can be measured, recorded, and used as a parameter of vestibular function. During clockwise rotation, maximum stimulation of the horizontal canal, the endolymphatic fluid and cupula of the horizontal canal shift in the counterclockwise direction. As a result, labyrinthine impulses reach the ipsilateral abducens and the contralateral oculomotor nuclei and induce a slow eye deviation in the direction of motion of the endolymphatic fluid (i.e., counterclockwise). After maximal eye deviation is achieved, a quick conjugate ocular realignment back to the midposition takes place. The slow eye deviation, followed by a brisk realignment, is called nystagmus. The direction of nystagmus is designated in accordance with the direction of the fast component, which is controlled by paramedian pontine centers. It is the slow component of nystagmus, however, that represents the true oculovestibular response. Calculating the velocity of the slow component provides an estimate of the intensity of response to vestibular stimulation. During the early stages of rotation and during acceleration, the nystagmus and sensation of motion are in the direction of rotation, whereas during deceleration, they are opposite the direction of rotation. Another method of vestibular testing, which assesses responses from each labyrinth separately, uses caloric irrigation of the ear canal with water or air that is cooler or warmer than body temperature, causing a temperature gradient from the external auditory canal to the inner ear that is transmitted by convection. The horizontal semicircular canal develops the largest temperature gradient because it is closest to the source of temperature change. The response is best achieved with the patient in the supine position and the head tilted 30 degrees up, placing the horizontal canals in the vertical plane. When a warm caloric stimulus (44° C) is applied, the column of endolymph nearest the middle ear rises because of the decreased density. As a result, the cupula deviates toward the utricle (ampullipetal flow) and produces horizontal nystagmus, with the fast component directed toward the stimulated ear. A cold stimulus (33° C) produces the opposite effect, causing ampullifugal endolymphatic flow, with nystagmus directed away from the stimulated ear. This

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specific response to caloric stimulation is the most widely used clinical test of vestibular function and has the advantage of testing each labyrinth separately. Clinical testing of vestibular-induced nystagmus to assess pathology is constantly evolving and can be used to confirm a clinical impression without using expensive laboratory tests. However, the information obtained is of a qualitative nature and is not standardized for children. For detection of unilateral vestibular deficit, the headthrust sign, head-shaking nystagmus, and vibration-induced nystagmus can be used [Fife et al., 2000]. The head-thrust test is performed using horizontal high acceleration head thrusts while the patient maintains gaze fixated on the examiner. The examiner looks for “catch-up” saccades. These may occur when the head is rapidly turned toward the side of the vestibular lesion. Head-shaking nystagmus is performed while the head is vigorously turned back and forth horizontally, with eyes closed for 30 seconds, to “charge” the brainstem velocity storage system. On stopping the shaking maneuver, the patient opens the eyes, and a nystagmus away from the lesioned labyrinth can be observed (preferably using Frenzel lenses) in a patient with a unilateral lesion. Tapping the head over the mastoid or applying a 60-Hz vibration stimulus to the mastoid bone can also evoke horizontal nystagmus, beating away from the side of the vestibular lesion. For the detection of bilateral vestibular lesions, a dynamic visual acuity test can be performed. The test assesses visual acuity during head rotations from side to side with a velocity of at least 1 Hz. Worsening of visual acuity by at least three lines on the Snellen chart during this maneuver is pathologic. Abnormal findings usually correlate with clinical oscillopsia. All clinical tests are helpful in further supporting a clinical diagnosis but are not sufficiently accurate to be definitely conclusive. Because management and prognosis depend on accurate diagnosis, laboratory tests using electronystagmography are necessary when unilateral or bilateral vestibular lesions are suspected.

NEUROVESTIBULAR EXAMINATION The neurovestibular examination consists of the following components: 1. Detailed prenatal and perinatal history and a detailed description of the presenting complaint 2. General neurologic examination with special emphasis on cranial nerves, proprioception, pyramidal tract function, and cerebellar function 3. Specific neurovestibular testing adapted to the patient’s age, emphasizing postural reactions (i.e., age appropriate developmental reflexes or equilibrium reactions), electronystagmography (adapted to age level), and audiometry adapted to the patient’s age when hearing loss is suspected

History The examiner should inquire about the presence of perinatal asphyxia, hyperbilirubinemia, prenatal or perinatal exposure

to infections, such as toxoplasmosis, rubella, cytomegalovirus, herpes (TORCH); bacterial meningitis or viral meningitis; acquired immune deficiency syndrome (AIDS); or AIDS-related complex. Exposure to ototoxic drugs such as aminoglycosides, ethacrynic acid, furosemide (Lasix), isoniazid, quinine, or acetylsalicylic acid in large amounts should be determined. Diabetes and endocrine disorders (i.e., thyroid, parathyroid, and adrenal insufficiency) should be excluded. Head trauma causing temporal bone fracture, concussion, or a whiplash syndrome may also cause vestibular injury and vertigo or dizziness [Davies and Luxon, 1995; Eviatar et al., 1986]. A hypercoagulable state or increased platelet aggregation can result in vascular obstruction and impair the vascular supply to the labyrinth, leading to dizziness [Asakura et al., 1995]. Vertigo, described as a hallucination of motion of the individual or the environment, is the most common manifestation of vestibular dysfunction. Conversely, dizziness is a nonspecific symptom of lightheadedness that suggests a metabolic disorder, cardiovascular dysfunction, hyperventilation, or a psychiatric condition, such as anxiety or depression. Vertigo may begin acutely as a sudden impairment of equilibrium that is most frequently accompanied by autonomic symptoms, such as nausea, vomiting, and diaphoresis. Nystagmus is often present. This constellation of symptoms is suggestive of peripheral vestibular dysfunction (Box 8-1). The presence of hearing loss, tinnitus, or sensation of fullness in the ear further localizes the condition to the inner ear, where the cochlea and labyrinth are close and may be affected by the same inflammatory, metabolic, toxic, or vascular process. Vertigo that is strictly positional is usually a benign paroxysmal positional vertigo that occurs in about 17% of vertiginous patients [Anthony, 1996] and has been attributed to floating particles in the semicircular canals [De la Meilleure et al., 1996]. The vertigo is usually worse with the affected ear down. Many articles describe positioning maneuvers for treating the condition [Baloh, 1996; Beynon, 1997; Brandt et al., 1994; Hilton et al., 2002]. Chronic,

Box 8-1 SYMPTOMS AND SIGNS OF PERIPHERAL VESTIBULAR DISEASE Sudden onset of vertigo, no loss of consciousness Dysequilibrium, swaying, and falling toward affected side Nausea, vomiting, autonomic dysfunction Nystagmus ± Toward unaffected side Induced by changing head position (Bruns’ sign) Maximal with affected ear down Latency of onset: 3 to 10 seconds Duration : ≤ 60 seconds Fatigues with repeated positioning Inhibited by visual fixation Prefers supine position with affected ear up Sensation of tilt or body motion Head tilt Paroxysmal torticollis or tortipelvis in infants ± Present or absent.

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unremitting vertigo is more likely the result of central vestibular dysfunction and is often associated with cranial nerve deficits, pyramidal signs, and cerebellar signs.

Neurologic Examination Examination of the cranial nerves and visual fields and the observation of spontaneous or induced nystagmus are important. Hearing responses can be tested with tuning forks, and the Weber and Rinne tests help differentiate conductive from sensorineural hearing loss. When hearing loss is suspected, audiometry, adapted to the patient’s age, is indicated (see Chapter 7). Deep tendon reflexes, postural reflexes, and age-appropriate equilibrium reactions are assessed. Vestibular dysfunction results in the body’s inability to respond to abrupt changes in the center of gravity with appropriate postural reactions, causing loss of equilibrium and falling. Cerebellar testing is most important because the cerebellum participates in the modulation and integration of vestibular responses.

Clinical Evaluation of Nystagmus Physiologic nystagmus (i.e., end-point nystagmus) is observed in normal individuals, primarily at a 40-degree lateral deviation of the eyes. Pathologic nystagmus implies an underlying abnormality of peripheral or central oculovestibular controls. Visual fixation may inhibit mild pe-

Box 8-2 CLINICAL TESTING OF PERIPHERAL VESTIBULAR DISORDERS Nylen-Bárány positioning maneuver Nystagmus and vertigo with affected ear down Latency: about 10 seconds Duration: ≤ 60 seconds Fatigues with repeated procedures Stepping test 45-degree deviation toward affected side or 50-cm forward displacement Past pointing Points toward affected side Extended Romberg Falls toward affected side Tandem gait (blindfolded) Sways toward affected side Sharp turns Falls toward affected side Righting responses (6–24 mo)/equilibrium reaction (>24 mo) Absent response on affected side Doll’s eye responses or vertical acceleration in infants Absent or incomplete response

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Box 8-3 CENTRAL VESTIBULAR DYSFUNCTION Clinical Symptoms and Signs Unremitting dizziness or vertigo Nystagmus ± Not inhibited by fixation No change with head position No latency and no fatigue Cranial nerve deficits likely (nerves V, VI, and VII; cochlear nerve) Cerebellar and pyramidal signs common Clinical Testing Nylen-Bárány positioning maneuver (?) Nystagmus in all positions No change in intensity or direction All clinical test results positives with eyes open or closed ± Present or absent.

ripheral vestibular nystagmus. Using Frenzel glasses (+10 diopters) or recording the nystagmus in the dark with electronystagmography helps prevent fixation and its inhibitory effect. Clinical tests that can be done for the evaluation of peripheral and central vestibular disorders are provided in Boxes 8-2 and 8-3. Nystagmus of central origin is often found in conjunction with other brainstem signs and is not effectively inhibited by fixation. Positional nystagmus frequently occurs after traumatic or infectious damage to the labyrinth, after lesion of the otoliths, or when the specific gravity of the cupula is changed by structural or metabolic factors (i.e., alcohol or drug intoxication). Paroxysmal positional nystagmus, first described by Bárány and further characterized by Nylen and by Dix and Hallpike, is frequently seen in patients complaining of brief episodes of vertigo induced by abrupt changes in head position, abrupt turns, or sudden realignment of gaze. This type of vertigo is called benign paroxysmal positional vertigo. Patients often can identify the offending position, or the examiner can reproduce the symptoms by using the NylenBárány maneuver. The Nylen-Bárány positioning maneuver is used during the neurologic examination to elicit paroxysmal positional nystagmus and vertigo. The test is performed with the patient sitting on the examining table; the patient is rapidly moved from a sitting to a head-hanging position, with the head extended 45 degrees below horizontal. The patient is then returned to the sitting position for a few minutes until the sensation of vertigo subsides. The head is then turned 45 degrees laterally, and the patient is moved to the supine position, with the head below the horizontal position. This test is performed once with the head to the right and once with the head to the left, in an attempt to induce paroxysmal positional nystagmus and vertigo. Frenzel glasses can be used for inhibition of fixation and permit better observation of the nystagmus. Benign paroxysmal positional nystagmus is often a sequela of acute labyrinthitis, stapedectomy, perilymphatic fistula, traumatic labyrinthine injury that has displaced one of the otoliths, or vascular occlusion. Displacement of an otolith may occur spontaneously for unknown

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reasons. The nystagmus usually has a 3- to 10-second latency before onset and generally lasts less than 60 seconds. Benign paroxysmal positional nystagmus is most prominent in one of the tested head-hanging positions, has a rotatory component directed toward the unaffected ear, is associated with severe vertigo, and subsides with subsequent maneuvers. The severe positional vertigo initially experienced by the patient also subsides and becomes less intense with repeated positioning. When, in addition to benign paroxysmal positional nystagmus, unilateral decreased labyrinthine response to caloric stimulation is found on electronystagmography, the most likely diagnosis is vestibular endorgan disease. Positional nystagmus that is associated with brainstem or cerebellar disease is a persistent, nonfatiguing nystagmus that does not decrease in amplitude or duration with repeated positioning of the head. There is no obvious latency before its appearance, and it usually lasts longer than 60 seconds and sometimes for as long as the head position is maintained.

Clinical Evaluation of Postural and Equilibrium Reactions In infants, labyrinthine reactions consist of tonic neck reflexes. These reflexes are triggered by vestibular input from the labyrinths, proprioceptive input from the cervical vertebrae, and present as tonic reaction of the extremities, that depend on the integrity of the pyramidal tract system. A more specific vestibular test described by Eviatar and Eviatar [1978] is called the vertical acceleration test. The infant is held in the supine position at arm’s length with the head properly aligned with the body. Vertical acceleration is provided while the examiner abruptly descends to a semicrouched position. The normal response in all infants is abduction and extension of the upper extremities followed by an embrace. This maneuver tests the utricular response to gravitational and vertical acceleration. The doll’s-eye maneuver is an infantile oculovestibular reflex, in response to angular acceleration. The infant is maintained at arm’s length, head flexed at 30 degrees, and rotated around the examiner for 360 degrees several times. In newborn infants, the eyes deviate in the opposite direction of rotation. By 2 to 3 weeks of age, nystagmus is superimposed in the direction of rotation. By 6 months of age, righting responses appear and persist throughout life, although they are modified or inhibited voluntarily after the age of 2 years. A righting response is the ability of the child to right the head (i.e., align the horizontal semicircular canals parallel to the ground) and extend the upper extremities, as a propping reaction in the direction of tilt. Because optical and vestibular righting reactions are identical, labyrinthine tests should be performed with the infant blindfolded to eliminate optical righting responses. By the age of 4 years, equilibrium reactions can be tested with the help of a tilt board in the prone, supine, sitting, or kneeling position. After an acute labyrinthine injury, children will be unable to right their head or prop the upper extremities in the direction of tilt. Moreover, the child is likely to fall in the direction of tilt. In time, postural mechanisms develop that help compensate for the loss of labyrinthine function. Normal visual and proprioceptive cues are essential for this to occur.

After the age of 4 years, additional tests, such as blindfolded tandem gait, Romberg, and reinforced Romberg, can be performed with a cooperative child. In the presence of unilateral labyrinthine involvement the patient sways toward the side of the lesion while walking with closed eyes and falls toward it during the Romberg test. During reinforced Romberg testing, the patient is asked to stand in a tandem position with one foot in front of the other, arms folded, and eyes closed. Normal children are able to maintain this position for about 30 seconds. However, in the presence of a unilateral labyrinthine dysfunction, the patient falls toward the affected side. The stepping test is a modification of Fukuda’s original stepping test. The child is asked to take 60 steps with eyes closed at the 90-degree intersection of two straight lines. The examiner reports the angle of lateral displacement and the extent of forward or backward displacement. The test is performed with arms extended, parallel to the ground, and with eyes closed. There is a tendency to rotate at an angle greater than 45 degrees toward the affected side in a unilateral lesion. In patients with bilateral lesions, forward or backward displacement, generally greater than 20 inches from the starting position, may occur. A test of past pointing can be done. The patient is asked to sit in front of the examiner with eyes closed to eliminate visual cues. The patient’s and examiner’s arms are extended forward while the patient places an extended index finger on that of the examiner, closes the eyes, raises the extended arm and index finger to a vertical position, and attempts to return the index finger to touch the examiner’s finger. A consistent deviation to one side is called past pointing and suggests ipsilateral vestibular dysfunction.

Specific Neurovestibular Testing Several tests usually are done as part of a comprehensive neurotologic evaluation when there is suspicion of vestibular dysfunction.

Electronystagmography Electronystagmography permits eye movements to be recorded during positional testing, visual pursuit, and in response to vestibular stimulation by rotation or caloric irrigation (Box 8-4). Each optic globe acts as an electric dipole oriented in the direction of the long axis of the eyes, with the cornea being electropositive and the retina electronegative. The changes in the magnetic fields created around the orbit during ocular displacement can be recorded by placing two electrodes bitemporally and a reference ground electrode on the nasion (i.e., binocular recording). The difference in potential between the electrodes is amplified and used to control the displacement of a pen recorder that provides a permanent record of eye movements. The advantage of this technique is the availability of a permanent record that measures eye movements, which can be used for future reference. The recommended test battery is described in Box 8-4. Electronystagmography detects abnormalities of oculovestibular control during visual pursuit, abnormalities of optokinetic nystagmus, and abnormal saccades, in which the motion of the target and resulting eye movements can be simultaneously displayed. The nystagmus induced by

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Box 8-4 ELECTRONYSTAGMOGRAPHY: TECHNICAL ASPECTS AND CLINICAL APPLICATIONS Technical aspects of testing Record nystagmus on straight gaze, 30-degree lateral gaze up, gaze down, eyes open, and eyes closed Record positional nystagmus in darkness or with eyes closed Hennebert test for fistula Computerized rotatory vestibular test (RVT) (done with sinusoidal rotation at frequencies from 0.01 Hz to 0.16 Hz) amplitude of output slow component velocity Gain = = amplitude of input stimulus velocity Phase =

time of output output

CW – CCW Asymmetry = CW + CCW × 100 (>14%) Suppression of nystagmus with fixation Oculomotor function Saccades Smooth pursuit Opticokinetic nystagmus at 20 degrees/second and 40 degrees/second Visual/vestibular interaction RVT abnormalities with unilateral/bilateral peripheral vestibular lesions Unilateral peripheral lesions Acute Asymmetric response to rotational stimuli because of the following: 1. Direction changing bias resulting from spontaneous nystagmus 2. Difference in response to CW and CCW stimulation of the intact labyrinth Chronic Direction changing bias gradually disappears. 1. Gain asymmetry between CW and CCW decreases; remains most pronounced at high frequencies; 0.16 Hz and 0.32 Hz 2. Decreased gain and increased phase lead at low frequencies of sinusoidal stimulation, 0.01 Hz and 0.02 Hz Bilateral peripheral lesions 1. Decreased but recordable responses to high-frequency stimulation 2. Decreased gain and increase phase lead at low frequencies 3. Early damage detected at low frequencies less than 0.05 Hz Bithermal caloric testing Labyrinthine preponderance (RW + RC) – (LW + RC) RW + RC + LW + LC × 100 (>14%) Directional preponderance (RW + RC) – (LW + RC) RW + RC + LW + LC × 100 (>18%) Ice-cold calorics are done in both ears in supine and prone positions in infants up to 36 months or in nonresponsive labyrinth. CCW, counterclockwise; LW, left cold; RC, right cold; RW; right warm.

sinusoidal chair rotation at frequencies ranging from 0.01 to 0.32 Hz can also be recorded simultaneously with the recording of the chair motion and is referred to as perrotatory nystagmus. The maximum slow-component

velocity of nystagmus elicited by sinusoidal stimulation increases linearly with the log of stimulus intensity. Unfortunately, there is variability in the oculovestibular reflex function measured in normal subjects that depends on stress,

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fatigue, level of mental alertness, and habituation. The intrasubject variability is much less than intersubject variability. To compare the response of clockwise (CW) and counterclockwise (CCW) stimulations, the following formula is used: (CW + CCW)/(CW − CCW) × 100. The mean value for the normalized difference between clockwise and counterclockwise responses is approximately zero at each stimulus. A difference greater than 20% indicates a directional preponderance of nystagmus, the significance of which is similar to the directional preponderance obtained from bithermal caloric testing. The ratio of the total amplitude of the eye movement excursion to the total chair rotation excursion, known as gain, can be measured. Gain can also be defined as the peak slow-phase eye velocity divided by the peak stimulus velocity. Phase describes the temporal relationship between the input and output. If there is proper timing of compensatory eye movements to the chair rotation during a sinusoidal rotation test, the eye movement will be 180 degrees out of phase with head movement or, by convention, will be said to have zero phase level.

Perrotatory and Caloric Stimulation Perrotatory stimulation and ice-cold caloric (see Box 8-4) stimulation are performed on patients younger than 3 years because young children cannot tolerate the lengthy bithermal caloric procedure. The perrotatory test induces bilateral labyrinthine stimulation during sinusoidal rotation, whereas the ice-cold caloric test stimulates each labyrinth individually. Normative data for torsion swing and ice-cold caloric stimulation are available for all age groups [Eviatar and Eviatar, 1989]. Normative data for the computerized rotary chair–induced nystagmus in children are available from Staller and associates [1986] and Cyr and colleagues [1985]. Best results are obtained when the infant is seated in the parent’s lap during the rotary stimulation. From 60 days to 10 months, reliable responses were obtained at 0.16-Hz rotation. Subsequently, responses were also obtained at the lowest frequencies, such as 0.01 Hz.(i.e., subliminal stimulation), suggesting a maturational trend with age. After 36 months of age, bithermal caloric irrigation can be performed instead of ice-cold caloric stimulation (see Box 8-4). Directional preponderance on bithermal caloric irrigation usually suggests a central vestibular dysfunction. Labyrinthine preponderance is indicative of a peripheral labyrinthine disorder or a hypoactive labyrinth.

Neurotologic Examination The neurotologic examination is important in the evaluation of a child with vertigo and is usually best performed by an otorhinolaryngologist, who can exclude pathology of the middle and inner ear. In addition to visualizing the eardrums and determining that no infection or cholesteatoma is present, it is important to perform a fistula sign, or Hennebert’s sign, by inducing negative pressure in the ear with the help of the pneumatic otoscope. The positive sign consists of ocular deviation toward or away from the affected ear, followed by a few beats of nystagmus. The patient usually experiences severe vertigo when the test is positive. A posi-

tive Hennebert sign may occur with a perforated tympanic membrane or an erosion of the bony labyrinth secondary to chronic infection, trauma, or surgery. In the presence of an intact tympanic membrane, conditions such as congenital syphilis, Meniere’s syndrome, and perilymphatic fistula should be considered. Neurologists and pediatricians can learn to use a pneumatic otoscope and perform the Hennebert test in the office.

DIAGNOSIS AND MANAGEMENT Guided by a detailed account of the history and the results of the neurologic and neurovestibular examination, the physician can consider the differential diagnosis in a rational manner. The diagnostic algorithm (Box 8-5 and Table 8-1) helps to establish the most likely cause on the basis of specific symptoms and clinical examination findings (Fig. 8-1). In our study that reviewed records of 62 patients with vertigo, the algorithm-derived diagnosis matched the medical record–derived diagnosis in 84%. The questionnaire-derived diagnosis was identical to the medical record–derived diagnosis in 92% of cases. When both tools combined provide a clear-cut diagnosis, no further evaluation is necessary [Ravid et al., 2003]. The following discussion reviews some of the major clinical situations and disorders associated with vertigo that can occur in infants and children.

Acute Paroxysmal Vertigo with Hearing Loss Labyrinthitis A history of infection before the onset of vertigo and the presence of hearing impairment suggest the diagnosis of labyrinthitis. The autonomic symptoms in this condition are significant, as are the instability of gait and personal discomfort. Spontaneous nystagmus with the fast component directed toward the normal ear is often found on exam-

Box 8-5 DIAGNOSTIC TESTING OF PATIENT WITH VERTIGO Pediatric and neurologic examinations Neurologic examination to exclude infection, malformation, cholesteatoma, and fistula Hearing test adapted to patient’s age Brainstem auditory-evoked response in infants Electronystagmography Electroencephalogram (with loss of consciousness) Metabolic evaluation: complete blood cell count with sickle cell preparation, glucose tolerance test, determinations of electrolytes (e.g., Ca, P, Mg) and thyroid hormones (i.e., T3, T4, and TSH) Computed tomography of the brain with thin cuts through the temporal bones (exclude congenital anomaly of inner ear) Magnetic resonance imaging plus gadolinium when tumor or degenerative disease is suspected; magnetic resonance angiography when vascular malformation is suspected

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TABLE 8-1 Approach to the Patient with Vertigo SYMPTOM COMPLEX

DIAGNOSIS

Acute-Onset Vertigo with Hearing Loss With no loss of consciousness (all ages) Fever, +; infection, +; toxin, + Fever, −; tinnitus, +; ear pressure, +; vomiting, + Head trauma, barotrauma, +; exertion, + None of the above

Labyrinthitis Meniere’s disease Perilymphatic fistula Vascular occlusion

Recurrent Paroxysmal Vertigo without Hearing Loss With no loss of consciousness (16 months to 4 or 5 years old) Nystagmus, ±; EEG, nl; ENG, ± Torticollis, +; GER, ±; EEG, nl; ENG, ±

Benign paroxysmal vertigo Benign paroxysmal torticollis

With no loss of consciousness (older children and adolescents) Postinfection, +; vomiting, +; EEG, nl; ENG, +

Vestibular neuronitis

With no loss of consciousness (any age group) Head trauma, +; vomiting, +; EEG, nl; ENG, +; PPN, + Positional only: vomiting, ±; EEG, nl; ENG, + With head motion: vomiting, −; EEG, −; ENG, + Headache, +; vomiting, +; EEG, nl; ENG ±

Labyrinthine concussion Paroxysmal positional vertigo Oscillopsia Migraine

With loss of consciousness (any age group) Headache, +; vomiting, +; EEG, slowing; ENG, ± Headache, ±; vomiting, ±; EEG, +; ENG, ± Headache, ±, vomiting, −; EEG, nl; ENG, nl

Basilar artery migraine Seizures Hyperventilation

Chronic Unremitting Vertigo Neurologic evaluation, + Cranial nerve deficits, +; pyramidal signs, +; cerebellar signs, +; CT/MRI scan, +

Neurologic evaluation, Metabolic evaluation, + Hemoglobin electrophoresis, + Metabolic evaluation, −

CPA tumor (neurofibromatosis type 2), posterior fossa tumor, Arnold-Chiari type I malformation, multiple sclerosis, degenerative disorders (cerebellar ataxia type 2, Refsum’s disease, ataxia telangiectasia, adrenoleukodystrophy, juvenile Huntington’s disease, neuroacanthocytosis, GM2 gangliosidosis), vascular anomalies (arteriovenous malformation, brainstem telangiectasia, vertebrobasilar aneurysm) Metabolic disorder Sickle cell disease, Cooley’s anemia Panic or anxiety disorder, conversion reaction, depression

*Metabolic evaluation includes ascertaining levels of fasting blood glucose, electrolytes such as calcium and magnesium, T3, T4, and thyroid stimulating hormone. CN, cranial nerve; CPA, cerebellopontine angle tumor; EEG, electroencephalogram; ENG, electronystagmography; GER, gastroesophageal reflux; nl, normal; PPN, paroxysmal positional nystagmus; +, present or positive; –, absent or negative; ±, present or absent.

ination. The patient’s most comfortable position is lying on the unaffected side. Any attempt to move causes severe vertigo, nausea, and vomiting. After a few days the acute symptoms generally subside. Acute otitis media in children may cause labyrinthitis, and in the practice of otorhinolaryngology, this entity is found to be the most common cause of vertigo in children [Bower and Cotton, 1995]. Bacterial labyrinthitis requires prompt and vigorous antibiotic treatment to prevent damage to the labyrinth. Childhood viral diseases (i.e., chickenpox, mumps, and measles) may also cause labyrinthitis [Comacchio et al., 1996]. Electronystagmography, performed shortly after the acute episode, generally demonstrates a poorly reactive labyrinth and the presence of positional nystagmus. Although hypoactivity of the labyrinth may subside, the positional nystagmus is likely to remain for a long time. Treatment of labyrinthitis is primarily directed toward control of the underlying disease, namely, antibiotics in

bacterial infections and symptomatic treatment of vertigo in viral infections or toxic conditions. Administration of meclizine and prochlorperazine alleviate symptoms.

Meniere’s Syndrome Meniere’s syndrome is not very common in children and consists of the well-described tetrad of vertigo, fluctuating hearing loss, pressure in the ear, and tinnitus. Meniere’s syndrome is usually the result of cochlear hydrops that can be of toxic, allergic, or metabolic origin. Recurrent episodes are common, with progressive hearing loss found after each episode. The treatment is similar to that described for labyrinthitis. Conventional diuretics (i.e., furosemide or thiazide) are given to reduce the endolymphatic pressure [Brookes, 1996; Davies and Luxon, 1995]. Sedatives and antiemetics alleviate the symptoms. Successful treatment with corticosteroids and plasma electrophoresis lends support to an auto-

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Clinical Evaluation / 8 NATURE OF SYMPTOM Acute/Vertigo

Chronic/Dizziness

Hearing loss?

Hearing loss? Yes

No

Yes

Fever? Yes

Labyrinthitis

Age? 5 Yr ≤

No

Head trauma?

Concussion or fistula

Yes

Ototoxic drugs? Yes

Ototoxicity

No

Yes

Headache? CP Angle tumor

No

Yes

Neuro deficits? > 5 Yr

BPV

Meniere’s

No

Vasc. event

No

Yes

Cholesteatoma, autoimmune

Posterior fossa tumor, degenerative dis Yes

Positional? Yes

No

Vomiting? Psychogenic Migraine Vomiting? Yes

Neuro deficits?

No

Anxiety? Yes

No

Yes

Neuronitis

No

Chronic headache r/o depression

No

Headache, stress? No

Systemic dis (endocrine metabolic)

LOC? Yes

PPV/ Orthostatic

No

Sz/ Syncope

No

Panic attack

FIGURE 8-1. Computer algorithm for the differential diagnosis of dizziness in children. BPV, benign paroxysmal vertigo; CP, cerebellopontine; dis, disease; LOC, loss of consciousness; Neuro, neurologic; Post, posterior; PPV, paroxysmal positional vertigo; r/o, rule out; Sz, seizure; Vasc, vascular. (Modified from Ravid S, Bienkowski R, Eviatar L. A simplified diagnostic approach to dizziness in children. Pediatr Neurol 2003;29:317.)

immune mechanism for endolymphatic hydrops [Schessel et al., 1993].

Perilymphatic Fistula Head trauma or abrupt change in barometric pressure (i.e., decompression syndrome) can cause the sudden onset of hearing loss and vertigo resulting from a ruptured round or oval window into the vestibule, creating a perilymphatic fistula. In children, the condition is far more common than initially suspected and is often caused by minor trauma that may be forgotten by parents and patients. A positive fistula sign is diagnostic and a high index of suspicion should be maintained. Such patients should be referred immediately to otorhinolaryngologists because surgery may restore some hearing and cause cessation of vertigo [Poe and Botrill, 1994; Supance and Bluestone, 1983].

the disease. There is no hearing loss, and the episodes are self-limited but tend to recur periodically with lesser intensity with each recurrence. The neurologic, neurotologic, and audiologic evaluations are normal between attacks; the only positive findings may be electronystagmography that demonstrates positional nystagmus, a hypoactive labyrinth on bithermal caloric stimulation, and an asymmetric response to sinusoidal rotation. Single or combination use of intravenous diazepam, meclizine, or diphenhydramine during the acute stage is helpful [Eviatar and Eviatar, 1977; Lindsay 1967]. Significant individual variations in the clinical findings suggest variability in the pathophysiology of this condition [Ishikawa et al., 1993; Kazuo et al., 1993]. The natural history and long-term follow-up of vestibular neuronitis in children was reviewed by Taborelli and colleagues [2000].

Benign Paroxysmal Vertigo

Paroxysmal Vertigo without Hearing Loss Vestibular Neuronitis Vestibular neuronitis primarily occurs in adolescents after a history of respiratory infection. Onset is acute, and vertigo, nausea, vomiting, and postural instability are hallmarks of

First described by Basser [1969] and subsequently by Koenigsberger and colleagues [1970], benign paroxysmal vertigo is a condition of early childhood that first appears at about 16 months to 2 years of age and occurs at intervals of weeks or months, subsiding spontaneously by the age of 4 to 6 years. With benign paroxysmal vertigo, there is no hearing

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impairment, and the neurologic examination between episodes is normal. During an episode the child is extremely unsteady and sometimes unable to maintain an upright position. There is often arrest of motor activity and a search for immediate support by crouching, kneeling, or holding onto the parent; nystagmus is frequently present during the attacks. However, vomiting and diaphoresis are uncommon. Although fearful and anxious during the episode, the child remains mentally lucid and fully cognitive of the environment, which helps differentiate this condition from partial complex seizures of childhood. An electroencephalogram (EEG) is essential because it eliminates the possibility of a seizure disorder, and electronystagmography is sometimes helpful because it may reveal the presence of a hypoactive labyrinth [Lanska and Remler, 1997]. Long-term follow-up of patients with benign paroxysmal vertigo indicates that migraine headaches develop later in life in a significant proportion of children [Calder, 1994]. A strong family history of migraine is common, and benign paroxysmal vertigo is considered by most physicians as a migraine equivalent [Holguin and Fenichel, 1967; Kayan et al., 1984; Lanzi et al., 1994].

Paroxysmal Torticollis, Retrocollis, and Tortipelvis Paroxysmal torticollis is a condition seen in infants and children that usually begins between 2 and 8 months of age and consists of episodes of head tilt that may be associated with pallor, vomiting, agitation, and ataxia [Snyder, 1969]. Truncal posturing (i.e., retrocollis and tortipelvis) is an added feature in some cases [Chutorian, 1974]. The episodes may last 10 minutes to 14 days, recur two or three times each month, and involve either side (see Chapter 50). There are several causes conducive to paroxysmal torticollis in infants and children. Before 1 year of age, the condition may be accompanied by vomiting and gastroesophageal reflux and is known as Sandifer’s syndrome [Kinsbourne, 1964]. Vestibular studies performed on 20 infants with paroxysmal torticollis disclosed a vestibular imbalance in most children [Eviatar, 1994]. Gastroesophageal reflux was also documented in many of these infants. Snyder [1969] described 12 infants with paroxysmal torticollis and vomiting; 9 had abnormal vestibular responses, and 4 had hearing loss. Because no gastroesophageal studies were performed in Snyder’s patients, it is unknown whether they suffered from reflux. Deonna and Martin [1981] described five children with paroxysmal torticollis without hearing loss or vestibular abnormalities. In three infants, typical migraine developed by early childhood; all three had family histories positive for migraine. Chutorian [1974] summarized his experience with nine patients (eight females) who were seen early in infancy with paroxysmal torticollis and postprandial vomiting. None had hearing loss, and in only one patient was a caloric abnormality demonstrated (Chutorian, 1974). The episodes ceased by 1 or 2 years of age in most children. Ataxia developed in those who had persisting episodes until the age of 3 years. With our current understanding, it is possible that the children who developed ataxia were suffering from a nonsense mutation of the gene encoding the alpha-1a voltage-dependent calcium channel subunit CACNA1A (i.e., episodic ataxia 2) [Pulst et al., 1996].

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Labyrinthine Concussion Head trauma, with or without temporal bone fracture, may result in a labyrinthine concussion [Davies and Luxon, 1995; Eviatar et al., 1986]. The condition is marked by dysequilibrium, vertigo, and falling toward the affected side. Symptoms are typical of acute peripheral organ disease, and the neurovestibular examination elicits the same signs. The presence of paroxysmal positional nystagmus induced during the Nylen-Bárány maneuver is characteristic and may persist for weeks or months after injury. Symptoms subside gradually over a period of 3 to 6 weeks but occasionally may last longer. Whiplash injuries to the head and neck may also cause vestibular symptoms, and electronystagmography will record positional nystagmus. Symptomatic treatment of such patients with a cervical collar to prevent excessive mobility of the head over the neck may alleviate the acute symptoms. Exercises to develop habituation and tolerance to abrupt changes in head position are helpful in the long-term rehabilitation of patients with head injuries and labyrinthine concussions [Herdman, 1994; Johnson, 1998; McCabe et al., 1972]. In the initial stages of the disease, dimenhydrinate and meclizine can be used, as can as diazepam, which has a sedative and a specific effect at the level of the brainstem by inhibiting excessive discharges from the vestibular nuclei.

Paroxysmal Vertigo without Hearing Loss Basilar Artery Migraine The most common cause of acute paroxysmal vertigo without hearing loss in adolescents is migraine [Abu Arafeh and Russell, 1995]. The most striking association between headache and vertigo occurs in patients with basilar artery migraine. Symptoms include bilateral scintillating scotomas or visual obscuration; paresthesias around the mouth and acroparesthesias; tinnitus; occasional drop attacks, with or without loss of consciousness; and a pounding headache that often follows the first four symptoms. Basilar artery migraine was first described by Bickerstaff [1961]. Symptoms are the result of impaired flow within the vertebrobasilar distribution, causing ischemia of the occipital lobes and brainstem. Visual obscuration may last minutes to hours and is extremely frightening to the patient. Confusion can also accompany the episode. Although the patient appears very ill during the migraine attack and may have positive neurologic findings, all of these symptoms disappear as the episode subsides [Aragones et al., 1993]. An EEG obtained shortly after the attack may reveal bilateral posterior slowing [Lapkin et al., 1977]. Cranial computed tomography with contrast or magnetic resonance imaging (MRI) or magnetic resonance angiography (MRA) is usually obtained to exclude the possibility of a vascular malformation in the posterior circulation. In cases of basilar artery migraine, it is always normal. The results of electronystagmography in vertiginous migraine vary, depending on the territory most affected by the vasoconstriction and the resulting ischemia [Eviatar, 1981]. The major symptom of migraine (i.e., associated dizziness) was studied by Cutrer and Baloh [1992] in 91 patients referred to a neurotology clinic. Thirty-one patients had an

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abnormal electronystagmography, and 20.9% of these had a hypoactive labyrinth. Nine of 91 patients had dizziness with a temporal relationship to the headache consistent with a migrainous aura. Three patients started having complaints at the age of 9 years consistent with the symptoms of benign paroxysmal vertigo. More than one half the patients had episodes lasting up to 6 hours and not always temporally associated with headache, similar to the patient described by Slater [1979]. Others described episodes of vertigo lasting more than 24 hours and best described as prolonged episodes of motion sickness. Cutrer and Baloh’s [1992] study of adolescent patients and our personal experience suggest that vertiginous migraine, in its various forms, is one of the most common causes of vertigo without hearing loss in adolescents; other frequent causes are anxiety and panic attacks. Treatment of the basilar artery syndrome is similar to that of migraine in general. After excluding vascular malformations or space-occupying lesions with neuroimaging studies such as MRI or MRA, reassurance is needed and becomes an important factor in the therapeutic management. Nonsteroidal anti-inflammatory agents are helpful, and the use of cyproheptadine (Periactin) is beneficial in small children. Frequent, recurrent episodes of basilar artery migraine are best controlled with the prophylactic use of beta-blockers (e.g., propranolol). When propanolol fails, use of a tricyclic drug such as amitriptyline or nortriptyline can be effective. Sodium valproate as prophylaxis for migraine is gaining wide recognition and was reported to decrease by 50% the incidence of headaches in 75% of the children studied. Other antiepileptic drugs such as topiramate, lamotrigine, levetiracetam, and gabapentin may also be used for prophylaxis of migraine [Miller, 2004]. Use of an ergot preparation or of sumatriptan in basilar artery migraine is controversial because these drugs may increase ischemia in the brainstem and prolong or potentially worsen symptoms [Hershey and Powers, 2001].

Vertiginous Seizures Vertigo may be the aura preceding a generalized seizure, and this is a fairly common occurrence in patients with epilepsy. However, vertigo can be the manifestation of an ictal phenomenon and represent a form of partial complex seizures [Alpers, 1960; Fujino et al., 1996]. The patient may have only a slight impairment of cognitive function during or after the sensation of vertigo or may experience complete lack of awareness. In either situation the diagnosis can be firmly established with the help of a sleep-deprived EEG or prolonged electroencephalographic telemetry that documents the presence of spike-wave discharges during a vertiginous episode. Epileptogenic foci in the temporoparietal area or posterior temporal area may have a vertiginous correlate. MRI is indicated in such patients to eliminate the possibility of a structural anomaly or space-occupying lesion. Electronystagmography reveals directional preponderance on bithermal caloric stimulation in the majority of cases [Eviatar and Eviatar, 1977].

Vestibulogenic Seizures Vestibulogenic seizures are rare and constitute a form of sensory epilepsy, with symptoms of vertigo or dizziness

triggered by a stimulus generated in an abnormal or deafferentated labyrinth [Behrman and Wyke, 1958]. This stimulus may generate paroxysmal discharges in the reticular activating system of the brainstem and become secondarily generalized through the thalamocortical pathways. Cantor [1971] was the first to describe vestibulogenic seizures in a patient with missile wounds affecting the temporal bone. Testing by simultaneous cold-caloric irrigation of the ear canals and EEG recording from the temporoparietal cortex elicits paroxysmal discharges in this condition. Vertiginous and vestibulogenic seizures respond to antiepileptic medication used in partial complex seizures, such as carbamazepine, oxycarbamazepine, or phenytoin.

Unremitting Vertigo or Dizziness with Neurologic Signs Complaints of unremitting, protracted vertigo or dizziness accompanied by cranial nerve deficits, pyramidal tract signs, or cerebellar abnormalities are suggestive of a spaceoccupying lesion in the brainstem or cerebellum (e.g., medulloblastoma, astrocytoma, ependymoma) or cerebellopontine angle (e.g., vestibular schwannoma). Bilateral vestibular schwannoma is a manifestation of neurofibromatosis type 2 , an autosomal-dominant disease caused by a mutation of the tumor suppressor gene, schwannomin, at chromosomal locus 22q12. It is associated with propensity of multiple intracranial tumors, notably bilateral schwannomas and meningiomas. A genetic basis for the development of unilateral schwannoma has been suggested by Bikhazi and colleagues [1997]. A posterior fossa congenital anomaly, such as an Arnold-Chiari type I malformation, may also cause dizziness or vertigo often precipitated by exertion [Albers and Ingels, 1997]. MRI usually reveals a structural abnormality within the cerebellum, brainstem, or cerebellopontine angle. Computed tomography with thin-cut scans through the temporal bone help detect an intracanalicular vestibular schwannoma; however, MRI better demonstrates the pathology in the internal auditory canal and in the cerebellopontine angle or in the posterior fossa [Casselman et al., 1994]. MRI is particularly helpful in detecting demyelinating diseases, such as multiple sclerosis, or inflammatory conditions, such as central nervous system Lyme disease, that can present with vertigo. Lumbar puncture may demonstrate elevation of cerebrospinal fluid protein levels, immunoglobulins, and oligoclonal bands, or it may detect an elevated antibody titer to Lyme confirming the diagnosis of Lyme disease. Abnormal visual-evoked responses and abnormal brainstem auditoryevoked responses are common in multiple sclerosis [Ghezzi et al., 1997]. Electronystagmography in patients with multiple sclerosis may demonstrate a hypoactive labyrinth suggestive of a demyelinating vestibulopathy. Unremitting vertigo accompanied by progressive intellectual deterioration and neurologic findings is suggestive of a degenerative brain disease. A combination of peripheral neuropathies, ichthyosis, ataxia, and retinitis pigmentosa is characteristic of Refsum’s disease and can be diagnosed by an increased level of phytanic acid in the blood. Dizziness related to vestibular dysfunction is often present in Friedreich’s ataxia and in many spinocerebellar degenerative disorders. Dizziness resulting from a vestibulopathy is common in ataxia-telangiectasia. Abnormalities of visual

Eviatar / Vertigo

pursuit, abnormal saccades, and poor visual inhibition of perrotatory nystagmus are often recorded in cerebellar diseases. An autosomal dominant form of vestibulocerebellar ataxia mapped to chromosome 19p has been described [Vehedi et al., 1995], and responds favorably to treatment with acetazolamide.

Unremitting Vertigo without Neurologic Abnormalities Metabolic disorders, such as diabetes or latent diabetes, endocrine abnormalities, blood dyscrasias, dysgammaglobulinemias, and sickle cell disease, may cause dizziness and sometimes cause vertigo [Rybak, 1995]. Labile hypertension and cardiovascular conditions causing intermittent vertebrobasilar insufficiency may cause dizziness or vertigo. The subclavian steal syndrome should also be excluded. Ototoxic drugs, particularly aminoglycosides, phenytoin, quinine, acetylsalicylic acid, and ethacrynic acid, may cause a progressive peripheral vestibular neuropathy manifested by unremitting dizziness and, rarely, by true vertigo. Hearing loss is often present after ingestion of these drugs. Absence of metabolic disorders, lack of hematologic or cardiovascular abnormalities, and normal laboratory test results suggest the diagnosis of a psychosomatic disorder. The complaint of nonspecific dizziness is frequently the first symptom of a depression or a psychosomatic disorder of adolescence. Anxiety syndrome or panic attacks can also present episodes of vertigo mixed with underlying constant dizziness. The patient who continues to complain despite a normal neurologic examination and negative laboratory test results requires a psychiatric evaluation and ongoing psychologic treatment [Furman and Jacob, 1997].

SUMMARY The differential diagnosis of vertigo in children and adolescents is complex and requires a systematic review of systems and careful evaluation of the patient’s complaint. Because of the many possible causes, a dizziness questionnaire and diagnostic algorithm that take into account patient’s age, specific complaints, and associated clinical and laboratory findings, greatly simplify the process of reaching an accurate diagnosis. The success of treatment ultimately depends on the clinician’s ability to establish the cause of the condition. REFERENCES Abu Arafeh I, Russell G. Paroxysmal vertigo as a migraine equivalent in children: A population based study. Cephalalgia 1995;15:22. Albers FW, Ingels KJ. Otoneurological manifestations in Chiari-I malformation. J Laryngol Otolaryngol 1997;107:441. Alpers BJ. Vertiginous epilepsy. Laryngoscope 1960;70:631. Anthony PF. Utricular ablation for benign positional vertigo. Ear Nose Throat J 1996;75:416. Aragones JM, Fortes Rego J, Fuste J, et al. Migraine: An alternative in the diagnosis of unclassified vertigo. Headache 1993;33:125. Asakura M, Kato L, Tahashi K, et al. Increased platelet aggregability in patients with vertigo, sudden deafness, and facial palsy. Acta Otolaryngol Suppl Stockh 1995;520:399. Baloh RW. Vestibular and auditory disorders. Curr Opin Neurol 1996;9:32.

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Basser LS. Benign paroxysmal vertigo and vestibular neuronitis. Brain 1969;87:141. Behrman S, Wyke BD. Vestibulogenic seizures. Brain 1958;81:529. Beynon GJ. A review of management of benign paroxysmal positional vertigo by exercise therapy and by repositioning manoeuvres. Br J Audiol 1997;3:11. Bickerstaff ER. Basilar artery migraine. Lancet 1961;1:15. Bikhazi NB, Slattery WH III, Lalwani AK, et al. Familial occurrence of unilateral vestibular schwannoma. Laryngoscope 1997;107:1176. Bower CM, Cotton RT. The spectrum of vertigo in children. Arch Otolaryngol Head Neck Surg 1995;121:911. Brandt T, Steddin S, Daroff RB. Therapy for benign paroxysmal positioning vertigo, revisited. Neurology 1994;44:796. Brookes GB. The pharmacological treatment of Meniere’s disease. Clin Otolaryngol 1996;21:3. Calder J. Benign paroxysmal vertigo of childhood: A long-term followup. Cephalalgia 1994;14:395. Cantor FK. Vestibular-temporal lobe connections demonstrated by induced seizures. Neurology 1971;21:507. Carpenter MB. Core text of neuroanatomy. Baltimore: Williams & Wilkins, 1974:347. Casselman JW, Kuhweide R, Dehaene L, et al. Magnetic resonance examination of the inner ear and cerebellopontine angle in patients with vertigo and/or abnormal findings at vestibular testing. Acta Otolaryngol Suppl Stockh 1994;513:15. Chutorian AM. Benign paroxysmal torticollis, tortipelvis, retropelvis and retrocollis of infancy. Neurology 1974;24:366. Comacchio F, D’Eredita R, Marchiori C. MRI evidence of labyrinthine and eighth-nerve bundle involvement in mumps virus sudden deafness and vertigo. Otorhinolaryngol Relat Spac 1996;58;295. Cutrer MF, Baloh RW. Migraine-associated dizziness. Headache 1992;32:300. Cyr GD, Brookhouser PE, Valente M, et al. Vestibular evaluation of infants and preschool children. Otolaryngol Head Neck Surg 1985;93:463. Davies RA, Luxon LM. Dizziness following head injury: A neuro-otological study. J Neurol 1995;242:242. Dekaban A. Neurology of early childhood. Baltimore: Williams & Wilkins, 1970. De la Meilleure G, Dehaene I, Depondt M, et al. Benign positional vertigo of the horizontal canal. J Neurol Neurosurg Psychiatry 1996;60:68. Deonna T, Martin D. Benign paroxysmal torticollis in infancy. Arch Dis Child 1981;56:956. Eviatar L. Vestibular testing in basilar artery migraine. Ann Neurol 1981;9:126. Eviatar L. Dizziness in children. Otolaryngol Clin North Am 1994;27:557. Eviatar L, Bergtraum M, Malat Randel R. Post-traumatic vertigo in children: A diagnostic approach. Pediatr Neurol 1986;2:61. Eviatar L, Eviatar A. Vertigo in children, differential diagnosis and treatment. Pediatrics 1977;59:833. Eviatar L, Eviatar A. Neurovestibular examination of infants and children. Adv Otorhinolaryngol 1978;23:169. Eviatar L, Eviatar A. The normal nystagmic response of infants to caloric and perrotatory stimulation. Laryngoscope 1989;89:1036. Fujino O, Hashimoto K, Enokido H, et al. Epileptic vertiginous seizure in a Japanese boy: A case report. No To Hattatsu 1996;28:515. Furman JM, Jacob RG. Psychiatric dizziness. Neurology 1997;48:1161. Fife TD, Tusa RJ, Furman JM, et al. Assessment: Vestibular testing techniques in adults and children. Neurology 2000;55:1431. Gesell A, Amatruda CS. The embryology of behavior: The beginning of the human mind. New York: Harper & Row, 1945. Ghezzi A, Deplano V, Faroni J, et al. Multiple sclerosis in childhood: Clinical features of 149 cases. Mult Scler 1997;3:43.yy Gowers WR. Epilepsy and other chronic convulsive disorders: Their causes, symptoms and treatment, 2nd ed. London: J & A Churchill, 1901. Hamilton WJ, Mossman HW. Human embryology: Prenatal development of form and function, 4th ed. Cambridge, Mass: Hoffer, 1972. Hershey AD, Powers SW. Abortive therapy for migraine. In: Maria BL, ed. Current management in child neurology, 2nd ed. Hamilton, Ontario: BC Decker, 2001:67. Herdman SJ. Vetibular rehabilitation. Philadelphia: FA Davis, 1994:392. Hilton M, Pinder D. The Epley manoeuver for benign paroxysmal

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positional vertigo—a systematic review. Clin Otolaryngol Allied Sci 2002;27:440. Holguin J, Fenichel G. Migraine. J Pediatr 1967;70:290. Ishikawa K, Edo M, Terada N, et al. Gait analysis in patients with vertigo. Eur Arch Otorhinolaryngol 1993;250:229. Johnson GD. Medical management of migraine–related dizziness and vertigo. Otolaryngol Head Neck Surg 1987;96:239. Kayan A, Hood JD. Neuro-otological manifestations of migraine. Brain 1974;107:1123. Kazuo I, Masataka E, Kiyoshi T. Clinical observation of 32 cases of vestibular neuronitis. Acta Otolaryngol Suppl Stockh 1993;503:13. Kinsbourne M. Hiatus hernia with contortions of the neck. Lancet 1964;1:1058. Koenigsberger MR, Chutorian AM, Gold AP, et al. Paroxysmal vertigo of childhood. Neurology 1970;20:1108. Lanska DJ, Remler B. Benign paroxysmal positioning vertigo: Classic descriptions, origins of the provocative positioning technique and conceptual developments. Neurology 1997;48:1167. Lanzi G, Balottin U, Fazzi E, et al. Benign paroxysmal vertigo of childhood: A long-term follow-up. Cephalalgia 1994;14:458. Lapkin ML, French JH, Golden GS, et al. The EEG in childhood basilar artery migraine. Neurology 1977;27:583. Lindsay JR. Paroxysmal postural vertigo and vestibular neuronitis. Arch Otolaryngol 1967;85:544. McCabe BF, Ryn JH, Sekitani T. Further experiments on vestibular compensation. Laryngoscope 1972;82:381. Miller GS. Efficacy and safety of levetiracetam in pediatric migraine. Headache 2004:44:238.

Poe DS, Botrill ID. Comparison of endoscopic and surgical exploration for perilymphatic fistulas. Am J Otol 1994;15:735. Pulst SM, Nechiporuk A, Nechiporuk T, et al. Moderate expansion of a normally biallelic trinucleotide repeat on spinocerebellar ataxia type 2. Nat Genet 1996;14:269. Rybak LP. Metabolic disorders of the vestibular system. Otolaryngol Head Neck Surg 1995;112:128. Ravid S, Bienkowski R, Eviatar L. A simplified diagnostic approach to dizziness in children. Pediatr Neurol 2003;29:317. Schessel DA, Nedzelski JA. Meniere disease and other peripheral vestibular disorders. In: Cummings CW, ed. Otolaryngology head and neck surgery. St. Louis: Mosby–Year Book, 1993;3152. Snyder CH. Paroxysmal torticollis in infancy. Am J Dis Child 1969;117:458. Slater R. Benign recurrent vertigo. J Neurol Neurosurg Psychiatry 1979;42:363. Staller SJ, Goin DW, Hildebrandt M. Pediatric vestibular evaluation with harmonic acceleration. Otolaryngol Head Neck Surg 1986; 95:471. Supance JS, Bluestone CD. Perilymphatic fistulas in infants and children. Otolaryngol Head Neck Surg 1983;91:663. Taborelli G, Melagrana A, D’Agostino R. Vestibular neuronitis in children: Study of medium and long term follow up. Int J Pediatr Otolaryngol 2000:54:117. Vehedi K, Joutel A,Van Bogart, et al. A gene for hereditary paroxysmal cerebellar ataxia maps to chromosome 19p. Ann Neurol 1995;37:289.

CHAPTER 9

Taste and Smell Julie A. Mennella

CHEMICAL SENSES The chemical senses of taste, smell, and chemical irritation convey a range of information, warning us of environmental hazards and determining the flavor of ingested foods and beverages. The literature reviewed in this chapter suggests that human infants have functioning gustatory and olfactory

systems that modulate their feeding and expressive behaviors. Although responsiveness is evident early in development, infants are not merely miniature adults, because these chemosensory systems mature postnatally and are influenced by experiences. Because little is known about the infants’ perception of chemical irritation (e.g., sensations of burn, viscosity, and temperature resulting from stimulation

FIGURE 9-1. Taste innervation is supplied by cranial nerves VII, IX, and X. Filiform, fungiform, and circumvallate papillae are present, with most taste sensation originating from the fungiform and circumvallate papillae. The anterior two thirds of the tongue are innervated by the chorda tympani, a branch of cranial nerve VII, whereas the posterior one third of the tongue and palate is innervated by cranial nerves IX and X. Central connections of the pathways of the cranial nerves in the nucleus solitarius ascend through the thalamus to the parietal operculum. S.S.P.N., small superficial petrosal nerve.

Arcuate nucleus of thalamus ? Solitary tract and nucleus

V Great superficial petrosal nerve

Sphenopalatine ganglion Vidian nerve

.N S.S.P

Lingual nerve

Otic ganglion

Chorda tympani Circumvallate papillae

.

VII IX

X

Lower medulla oblongata

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of nerve endings in the soft membranes of the buccal and nasal cavities), the discussion focuses on the senses of taste and smell but acknowledges that this other chemical senses may play an important role in the behavior of infants.

Taste, Smell, and Flavor Taste or gustation refers to the sensation that occurs when chemicals stimulate taste receptors located on a large portion of the tongue’s dorsum and other parts of the oropharynx, such as the larynx, pharynx, and epiglottis. Taste receptors are localized in taste buds and are innervated by branches of three cranial nerves: facial (VII), glossopharyngeal (IX), and vagal (X) nerves (Figs. 9-1 and 9-2). The taste stimuli that interact with these receptors are often separated into a small number of primary tastes, which include sweet, salty, bitter, sour, and umami tastes that can be perceived in all areas of the tongue [Bartoshuk and Beauchamp, 1994]. Advances in genetic research have led to the discovery of a family of taste receptor genes that mediate

Nervus intermedius

bitter taste perception (TAS2R) and the TAS1R gene family that mediate sweet (TAS1R2 and TAS1R3) and umami (TAS1R1 and TAS1R3) taste perception; this topic is reviewed by Kim and colleagues [2004]. Salty and sour tastes are still poorly characterized in genetic terms [Kim et al., 2004]. Smell or olfaction occurs when chemicals stimulate olfactory receptors located on a relatively small patch of tissue high in the nasal cavity (Fig. 9-3). There are several other noteworthy differences between taste and smell. First, unlike the gustatory receptors, the olfactory neurons are the actual receptor cells and are uniquely exposed to the external environment. Second, the olfactory receptors are served by only a single cranial nerve (I). Third, there may be many different classes of odor stimuli as suggested by the identification of a large family of genes that apparently code for a large number of receptor proteins located on membranes of the cilia of olfactory neurons [Buck and Axel, 1991]. The olfactory receptor genes are encoded by the largest mammalian gene superfamily of more than 1000 genes; however, more than 60% are pseudogenes in humans [Gilad et al., 2003]. Fourth,

Greater superficial petrosal nerve

VIII V

VII Lesser superficial petrosal nerve

Geniculate ganglion

Anastomotic nerve

Tympanic nerve plexus

Tympanic nerve (Jacobsen)

Facial nerve

Otic ganglion Auriculotemporal nerve Chorda tympani

Parotid gland

IX Branches to eustachian tube, tonsil, uvula, posterior third of tongue, and epiglottis

Internal maxillary artery Lingual nerve Submaxillary ganglion

Nerve to digastric muscle Anastomotic nerve Superior cervical sympathetic ganglion and internal carotid artery

Sublingual gland

External carotid artery Preganglionic sympathetic fiber

Langley ganglion

Submaxillary gland

FIGURE 9-2. Lateral depiction of the innervation of cranial nerves VII, IX, and X in the tongue and their relation to major vascular and other soft tissue structures.

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137

Subcallosal gyrus Olfactory portion of anterior commissure

Paraolfactory area (Broca)

Cribriform of ethmoid Olfactory epithelium

Medial olfactory stria Uncus

Lateral olfactory stria

Hippocampal gyrus

FIGURE 9-3. The sagittal section demonstrates the major structures involved in olfaction. The olfactory cells lie within the olfactory epithelium and mucosa, where they are stimulated by different odors. The cells give rise to filaments that traverse the cribriform plate of the ethmoid bone and synapse in the olfactory bulb. Each cell synapses with a number of glomeruli within the bulb, which are composed of dendrites from other cells within the bulb and the mitral and tufted cells. Axons from these cells form the olfactory tract, which projects into five regions: the anterior olfactory nucleus, the piriform cortex, the olfactory tubercle, the corticomedial amygdala, and the entorhinal cortex.

odor stimuli can reach the olfactory receptors in two ways; they can enter the nostrils during inhalation (i.e., orthonasal route), or they can travel from the back of the nasopharynx toward the roof of the nasal cavity (i.e., retronasal route) during chewing and swallowing in older children and adults and during suckling in infants. Flavor, as an attribute of foods and beverages, is defined as the integration of multiple sensory inputs of the taste, retronasal olfaction, and irritation of a substance in the oral and nasal cavities. However, the perceptions arising from the taste and smell senses are often confused and misappropriated [Rozin, 1982], with sensations such as vanilla, fish, chocolate, and coffee being erroneously attributed only to the taste system although much of the sensory input results from retronasal olfaction. Holding the nose while eating interrupts retronasal olfaction and thereby eliminates many of the subtleties of food, leaving the taste components remaining. Another example of the importance of olfaction in flavor perception is the inability to discriminate common foods when olfactory receptors are blocked by a head cold.

Clinical Disorders of Taste and Smell The common confusion between taste and retronasal olfaction is highlighted because many patients, young and old, report they cannot taste when they suffer only from olfactory loss [Cowart et al., 1997; Deems et al., 1991; Pribitkin et al., 2003]. The sense of smell appears to be more

vulnerable than that of taste, in part because of the differences described earlier. Approximately two thirds of patients who present to specialized chemosensory clinics complained of taste loss, but most patients were diagnosed with a measurable smell dysfunction, rather than gustatory dysfunction, as the basis of their “taste” complaint [Cowart et al., 1997]. A retrospective review of the 1176 patients evaluated for chemosensory dysfunction complaints at the Monell-Jefferson Chemosensory Clinical Research Center in Philadelphia revealed that severe, generalized taste deficit (i.e., complete or nearly complete taste loss) does occur but is extremely rare (<1% of patients), whereas profound olfactory deficit is more common (32% of patients) [Pribitkin et al., 2003]. A complete listing of the National Institute on Deafness and Other Communication Disorders (NIDCD)– funded clinics that specialize in the assessment and treatment of chemosensory problems, along with information about the NIDCD Clearinghouse, a national resource center for information about hearing, balance, smell, taste, voice, speech, and language for health professionals, patients, industry, and the public can be found in Box 9-1. Although complete taste loss is rare, clinical disorders that influence taste and smell perception are more common. The confusion between taste and retronasal olfaction underscores the need for careful sensory evaluation of these causes and helps explain why patients’ description of the complaint are often inaccurate. Moreover, clinical disorders that influence taste perception involve multiple organ sys-

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Box 9-1 CLINICS SPECIALIZING IN DISORDERS OF TASTE AND SMELL The following medical centers are supported by the National Institute on Deafness and Other Communication Disorders (NIDCD)* and specialize in developing a better understanding of the chemical senses in health and disease: Connecticut Chemosensory Clinical Research Center University of Connecticut Health Center Farmington, CT 06032 (860) 679–2459 Monell-Jefferson Taste and Smell Clinic Jefferson Medical College Department of Otolaryngology, Head and Neck Surgery 925 Chestnut Street, Sixth Floor Philadelphia, PA 19107 (215) 955–5652 Rocky Mountain Taste and Smell Center University of Colorado Health Science Center, Department of Otolaryngology 4200 East 9th Avenue Denver, CO 80262 (303) 315–5650 San Diego Nasal Dysfunction Clinic UCSD Medical Center 9350 Campus Point Drive La Jolla, CA 92037 (619) 543–3893 or (619) 657–8594 University of Pennsylvania Smell and Taste Center Hospital of the University of Pennsylvania 3400 Spruce Street, G1 Philadelphia, PA 19104 (215) 662–6580 Wake Forest University Smell and Taste Center Department of Otolaryngology Wake Forest University School of Medicine Medical Center Boulevard Winston-Salem, NC 27006 (336) 716–4100 *The NIDCD also supports the NIDCD Information Clearinghouse, a national resource center that provides information about hearing, balance, smell, taste, voice, speech, and language for health professionals, patients, industry, and the public. The Clearinghouse can be reached by calling (800) 241-1044 (voice) or (800) 241-1055 (TTY), 8:30 AM to 5:00 PM (EST), or through the web site ([email protected]).

tems and require a multidisciplinary approach for appropriate diagnosis and management [Bromley and Doty, 2003]. Particular attention should be paid to the history of problems with speech articulation, salivation, chewing, swallowing, oral pain or burn, otitis media, mouth dryness, periodontal disease, foul breath odor, recent dental pro-

cedures and surgeries, recent radiation exposure, medications, bruxism, and dietary changes. Questions about hearing, tinnitus, and balance may reveal useful information because the vestibulocochlear nerve travels near the facial nerve and is susceptible to similar conditions [Bromley and Doty, 2003]. The neurologic examination should pay particular attention to the first (olfactory), fifth (trigeminal), seventh (facial), ninth (glossopharyngeal), and tenth (vagus) cranial nerves and their central connections. Frontal lobe function and signs of increased intracranial pressure, such as papilledema and abducens nerve palsies, should be assessed [Barwick, 1989]. The oral cavity should be checked for dryness, inflammation, infections, and suspicious lesions. The tongue should be palpated to detect masses, neoplastic lesions, or collections in the tongue’s musculature, and its color, presence of plaque, and degree of salivation should be evaluated. Of particular importance are the appearance of teeth, gums, and taste papillae and the color of the dorsal surface of the tongue (i.e., white, brown, or red [atrophic]) [Spielman, 1998]. For some gustatory disorders, a detailed dental history may be helpful. The nasal cavity and sinuses should be checked because the color of the mucosa, purulent discharge, edema, and atrophy may indicate a condition that can affect olfactory functioning [Snow et al., 1991]. Newer endoscopes (e.g., Storz) may assist in visualizing the olfactory epithelium. Sinus radiographs may be useful when evaluating ethmoid or diffuse sinus disease, whereas computed tomographic (CT) scans may be indicated if intracranial or sinus disease is suspected. However, no significant relationship has been found between the size of the nasal and sinus structures as assessed by CT scans and smell ability in adults [Hong et al., 1998]. Magnetic resonance imaging (MRI), the method of choice for soft tissue anatomy and central nervous system structures, has been used to evaluate sites of injury in patients with post-traumatic olfactory deficits [Yousem et al., 1996]. MRI of the oropharynx and neck should be conducted for patients presenting with ageusia to exclude hematoma or abscess of the tongue and surrounding tissues [Pribitkin et al., 2003]. Gustatory dysfunction has been related to MRI-established ischemia, hemorrhage, or demyelination plaques in the brainstem and higher cortical areas in some patients which chronic dysgeusia [Bromley and Doty, 2003]. In addition to a careful medical history and otolaryngologic examination, the assessment of a smell or taste complaint should involve standardized testing using a variety of psychophysical techniques (e.g., detection thresholds, magnitude estimates, quality identification) in a clinical setting [Cowart et al., 1997; Frank et al., 2003; Pribitkin et al., 2003]. For example, patients are often asked to identify the taste quality (i.e., sweet, sour, bitter, salty) of a solution that is sipped or to identify an odor that is smelled. Retronasal olfactory function also should be assessed [Heilmann et al., 2002; Pierce and Halpern, 1996]. For younger pediatric populations, age-appropriate odorants (i.e., baby powder, bubble gum, candy cane, licorice, and peach) are recommended [Richman et al., 1995]. A commercially available scratchand-smell test, The University of Pennsylvania Smell Identification Test (Sensonics, Inc., Haddon Heights, NJ; www.sensonics.com), has found widespread acceptance because of its relative ease of administration. In addition to identification, detection thresholds and intensity functions

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can be determined by having patients signify, usually verbally, the presence, absence, or intensity of a taste or smell stimulus presented at various concentrations [Bartoshuk et al., 1987; Frank et al., 2003]. A variety of methods have been applied to the clinical assessment of adolescents and children 5 years old or older. However, their use in the younger child is problematic [Richman et al., 1995]. As shown in Boxes 9-2 and 9-3, disorders of taste and smell in adults (and presumably in younger patients) can arise from a variety of sources, including medications, radiation therapy, nutritional deficiencies, metabolic changes, head trauma, chronic disorders of the nasal epithelia, neurologic disorders such as tumors, viral infections, endocrine imbalances, aging, and environmental exposure [Cowart et al., 1997; Doty, 2003; Doty et al., 2003; Mott and Leopold, 1991; Murphy et al., 2003; Schiffman, 1983; Spielman, 1998]. However, many of the conditions listed are based on adult patients’ reports and not on standardized test assessments of chemosensory functioning or controlled clinical trials.

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Despite advances in our understanding of the mechanisms and functions of the chemical senses, treatment options for taste and smell disorders remain limited. Olfactory dysfunctions resulting from impairment of odor access to the olfactory receptors may be treated. For example, patients may experience improvements in olfactory ability after adenoidectomy [Ghorbanian et al., 1983] or surgical management of nasal polyps because of the reestablishment of nasal airflow (but see Doty and Mishra [2001]). However, those whose source of deficit lies within the olfactory neuroepithelium or central olfactory or cortical pathways typically have no treatment options available other than time and possible spontaneous recovery. Similarly, the prognosis for severe taste loss is mixed, and delayed, gradual recovery was the most common pattern observed in such patients [Pribitkin et al., 2003]. Although zinc supplementation has received considerable attention as a treatment for taste loss, two double-blind studies failed to determine a benefit compared with placebo [Henkin et al., 1976; Yoshida et al., 1991].

Box 9-2 CONDITIONS ASSOCIATED WITH DISTURBANCES OF TASTE Congenital Conditions Familial dysautonomia Turner’s syndrome Endocrine, Metabolic, and Autoimmune Conditions Adrenal insufficiency Diabetes mellitus Hypothyroidism Hyperthyroidism Pseudohypoparathyroidism Gastrointestinal and liver diseases Acute hepatitis Chronic liver disease Cronkhite-Canada syndrome Lupus erythematosus Obstructive jaundice Primary amyloidosis (affecting tongue) Reiter’s syndrome Scleroderma Sjögren’s syndrome

Ulcerative lesions (e.g., gonorrhea, herpes simplex virus infection, mycoses, syphilis, varicella-zoster infection) Local Processes Hansen’s disease Submandibular gland carcinoma Sjögren’s syndrome Parotid infection or tumor Glossitis Oral mycosis Otitis media Neurologic Conditions Bell’s palsy Brain tumor Guillain-Barre syndrome Head trauma High-altitude syndrome Migraine Multiple sclerosis Seizure disorders

Hypertension Iatrogenic Conditions Acoustic tumor removal After hypophysectomy After laryngectomy Cerebellopontine angle meningioma removal Chorda tympani injury or stretching Radiation or chemotherapy Temporal lobectomy Infectious Conditions After upper respiratory tract infection Candidiasis

Psychiatric Conditions Bulimia Uremia or Dialysis Miscellaneous Conditions Acquired immunodeficiency syndrome (AIDS)–related periodontitis Cancer Dental caries Gingivitis (acute and chronic) Occupational exposure Gastric reflex disease

Data from Mott AE, Leopold DA. Disorders in taste and smell. Med Clin North Am 1991;75:1321 and from Bromley SM, Dory RL. Clinical disorders affecting taste: Evaluation and management. In: Dory RL, ed. Handbook of olfaction and gustation, 2nd ed. New York: Marcel Dekker, 2003:935.

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Box 9-3 CONDITIONS ASSOCIATED WITH DISTURBANCES OF OLFACTION Congenital Conditions Cleft palate (males) Down syndrome Familial dysautonomia Kallmann’s syndrome Turner’s syndrome Endocrine or Metabolic Conditions Adrenal insufficiency Diabetes mellitus Hypothyroidism Pseudohypoparathyroidism Iatrogenic Conditions After laryngectomy Ethmoidectomy Hypertelorism procedures Orbitofrontal lobectomy Radiotherapy Rhinoplasty Submucous resection, nasal septum Temporal lobectomy Infectious Conditions Herpes simplex meningoencephalitis Human immunodeficiency virus (HIV) infection Upper respiratory tract, viral Liver Disease Acute viral hepatitis Cirrhosis

Local Processes Hansen’s disease Nasal obstruction (adenoid hypertrophy, large inferior turbinates) Polyposis Sjögren’s syndrome Tumors Neurologic Conditions Alzheimer’s disease Head trauma Huntington’s disease Korsakoff’s syndrome Multiple sclerosis Meningiomas Migraines Parkinson’s disease Seizure disorders Temporal lobe tumors Psychiatric Conditions Hypochondriasis Major depression Post-traumatic stress disorder Schizophrenia Uremia or Dialysis Miscellaneous Conditions Cystic fibrosis Giant cell arteritis Occupational exposure Sarcoidosis

Adapted from Mott AE, Leopold DA. Disorders in taste and smell. Med Clin North Am 1991;75:1321.

ONTOGENY OF TASTE PERCEPTION AND PREFERENCES The following sections focus on research on infants, children, and adolescents. The study of the chemical senses is possible throughout the lifespan and includes many variables, such as age, genetics, and feeding history, that can influence their responses. Conditions associated with disturbances of taste or smell, or both, in pediatric populations are also discussed.

Fetus and Preterm Infants Although amniotic fluid and embryonic membranes provide a series of barriers that protect the fetus from outside world disturbances, the fetus is nevertheless exposed to a variety of chemosensory stimuli in utero. The composition of amniotic fluid varies over the course of gestation, particularly as the fetus begins to urinate, so that by term, the human fetus is actively swallowing almost a liter per day and has been exposed to a variety of substances, including glucose, fructose, lactic acid, pyruvic acid, fatty acids, phospholipids, creati-

nine, urea, uric acid, amino acids, proteins, and salts [Liley, 1972]. The taste system is well developed before birth. The apparatus needed to detect taste stimuli, the taste buds, makes its first appearance around 7 or 8 weeks’ gestation, and by 13 to 15 weeks, the taste bud begins to morphologically resemble the adult bud, except for the cornification overlying the papilla [Bradley, 1972]. Taste pores, which provide the access for taste stimuli to interact with taste receptor cells, are present in fetal fungiform papillae before the end of the fourth month [Bradley, 1972; Hersch and Ganchrow, 1980; Witt and Reutter, 1997]. There is some evidence, albeit weak and indirect, for preferential responding to taste stimuli in the human fetus. Clinical observations of differential fetal swallowing after the injection of sweet or bitter substances into the amniotic fluid suggest that the fetus prefers sweet and rejects bitter, but these observations are inconclusive because of the methodologic limitations in measuring fetal responses [DeSnoo, 1937; Liley, 1972]. Another approach used in determining whether taste perception and preferences are present before birth is to study preterm infants. Such studies reported increased salivation in response to oral presentations of a drop of pure lemon

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juice, diminished suckling in response to quinine solutions, and enhanced suckling in response to glucose compared with water [Tatzer et al., 1985]. Because premature infants are at risk for aspirating fluids because of immature suckswallow coordination, a method was developed that did not necessitate the delivery of any fluids while administering a taste. The taste substance was embedded in a nipple-shaped gelatin medium that released small amounts of the substance when it was mouthed or sucked. Infants, born preterm and tested between 33 and 40 weeks after conception, produced more frequent, stronger sucking responses when offered a sucrose-sweetened nipple compared with a nonsweet latex nipple [Maone et al., 1990]. In conclusion, studies on premature infants support the hypothesis that preference for sweet taste is evidenced before birth. These data also suggest that taste buds are capable of conveying gustatory information to the central nervous system by the third trimester of pregnancy, and this information is available to systems organizing changes in sucking, facial expressions, and other affective behaviors; Ganchrow and Mennella [2003] have reviewed this topic.

Newborns, Infants, and Young Children In some of the earliest investigations on human taste development, facial expressions suggestive of contentment and liking or discomfort and rejection were used to assess the newborn’s responsiveness to taste stimuli. This testing revealed that during the first few hours of life, infants display relatively consistent, quality-specific facial expressions when the sweet taste of sugars, the sour taste of concentrated citric acid, and the bitter taste of concentrated quinine and urea are presented into the oral cavity [Ganchrow et al., 1983; Rosenstein and Oster, 1990; Steiner, 1977]. No distinct facial response has been reported for stimulation with salt taste [Rosenstein and Oster, 1990; Steiner, 1977]. Although infants beyond the neonatal period (1 to 24 months) have been most neglected in studies of taste development, a few findings suggest that changes in responses to each of the five basic tastes—sweet, umami, sour, bitter, and salty— occur during development (Table 9-1).

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Sweet Taste Consistent with the findings on premature infants’ response to sweets, newborns exhibit a strong acceptance of sweettasting sugars. Infants can detect even dilute sweet solutions, and they differentiate various degrees of sweetness and different kinds of sugars [Desor et al., 1977]. The preference for sweet taste remains heightened during childhood and adolescence and declines during late adolescence to the level observed in adulthood [Desor et al., 1977]. Infants, children, and teenagers are living in their own sensory worlds. One of the most predominant taste qualities of the first food of all mammals, mother’s milk, is its sweetness. It has been suggested that the innate preference for sweet tastes evolved to help us solve the basic nutritional problem of attracting us to mothers’ milk and then to other sources of high energy. The strong sweet preference displayed by infants may also reflect the physiologic effects of sugars. A small amount of a sweet-tasting liquid placed on the tongue of a crying newborn exerts a rapid, calming effect that persists for several minutes [Barr et al., 1994; Blass and Hoffmeyer, 1991]. The rapid onset of analgesia, which has been observed during painful procedures such as blood sampling and circumcision, suggests that afferent signals from the mouth are responsible for such effects. Because noncaloric sweet substances (e.g., aspartame) mimic the analgesic effects produced by sucrose [Barr et al., 1999] and because the administration of sucrose by nasogastric tube is not effective in reducing crying in newborns [Ramenghi et al., 1999], afferent signals from the mouth, rather than gastric or metabolic changes, appear to be responsible for the analgesic properties of sweet tastes. Sucrose continues to have analgesic properties in 8- to 11-year-old children undergoing a cold pressor test [Miller et al., 1994]. Whether the analgesic effect of sweet taste was induced by the sweetness per se or by the pleasantness or palatability of the stimulus remains unknown. The use of sucrose in mediating analgesia is intriguing because of its natural simplicity, viability, and efficacy. However, more research is needed to determine its efficacy in reducing pain

TABLE 9-1 Developmental Changes in Response to Tastes PRIMARY TASTES

TASTE EXAMPLES

FETUSES AND PREMATURE INFANTS

NEWBORNS

OLDER INFANTS (1-24 mo)

CHILDREN

Sweet Sour Bitter

Sugars Citric acid Quinine Urea

Preference*,† Not known Not known Not known

Preference*,† Rejection* Not known Rejection

Preference*,† Preference*,† Rejection*

Salty

NaCl

Not known

MSG

Not known

Indifference Preference*,¶ Preference||

Preference*,†

Umami

Preference*,† Rejection* Rejection* Indifference* Rejection‡ Indifference* Rejection§ Preference||

*Responses to various taste solutions relative to water or diluent. † Heightened preference when compared with adults. ‡ Facial expressions suggest rejection, whereas intake studies suggest indifference. § Sucking measures suggest rejection, whereas intake and facial expression studies suggest indifference. || Preference seen only when monosodium glutamate (MSG) is mixed with soup; MSG solution alone is rejected relative to plain water. ¶ Preference emerges at approximately 4 months of age; before that, indifference or rejection occurs, depending on the methods used.

Not known

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after repeated administrations [Barr et al., 1994; Johnston et al., 1999; Masters-Harte and Abdel-Rahman, 2001]. Until more is known, we should proceed with caution.

Umami Taste Although there is no English word for it, umami (a Japanese term) is a savory taste exemplified by glutamate and 5′nucleotides that occurs naturally in many foods such as tomatoes, Parmesan cheese, cured ham, sun-dried tomatoes, seaweed, fish, and meats. Although the taste of umami itself is subtle, it blends well with other tastes to expand and round out flavors. Developmental research has revealed that infants display distinct positive facial expressions similar to those observed with sweetness (i.e., facial relaxation, followed by positive mouth gaping) when tasting soup to which monosodium glutamate (MSG) has been added compared with the soup diluent alone [Beauchamp and Pearson, 1991; Steiner, 1987; Vazquez et al., 1982]. MSG alone does not appear to elicit those facial responses, however, raising the question of exactly what it is about the MSG-flavored soup that is preferred. The glutamate content of human milk is substantially higher than that found in cow’s milk or some formulas [Harzer et al., 1984]. The long-term effects that such experience has on food choice and preferences remain unknown.

Sour Taste In contrast to the innate preference for sweet and umami tastes, newborns reject the sour taste of citric acid as evidence by facial grimacing [Steiner, 1977] and reduced intake [Desor et al., 1975]. Little is known about the ontogeny of sour taste preferences because of the paucity of scientific research in this area. However, one study demonstrated that preference for sour tastes is heightened during childhood [Liem and Mennella, 2003]. One third of the 5- to 9- year-old children tested, but none of the adults, preferred extremely sour tastes in a food matrix. Moreover, the children’s preferences for sour tastes generalized to other foods, such as candies and lemons. One explanation for such findings is that there are ontogenic changes in taste perception, independent of experiences, that underlie the heightened sour preferences in some children. Another explanation for individual difference in level of preferred sour taste lies in the child’s previous experiences. For example, children who were fed a formula that has a sour and bitter flavor component (i.e., protein hydrolysate formulas) during their infancy preferred higher levels of citric acid in juice and were less likely to make negative facial expressions during the taste tests compared with children who were fed milkbased formulas [Liem and Mennella, 2002; Mennella and Beauchamp, 2002].

Bitter Taste Conclusions regarding the newborn’s responses to bitter tastes are more problematic. Although newborns respond with highly negative facial expressions to concentrated quinine and urea [Ganchrow et al., 1983], they do not reject moderate concentrations of urea, which adults identify as unpleasantly bitter [Desor et al., 1977]. That the infant’s

sensitivity to some bitter taste develops postnatally is suggested by the finding that the rejection of relatively low concentrations of urea was not evident until infants were older than 2 weeks [Kajuira et al., 1992]. Although these data are consistent with the hypothesis that there is an early developmental change in the perception of this particular bitter taste, they could instead reflect changes in the ability of the infant to regulate the intake of bitter solutions. Some bitter tastes may involve several different transduction pathways, depending on the bitter substance tasted [Spielman et al., 1994; Yan et al., 2001]. The newborn infant may be differentially sensitive to bitter taste because of different rates of maturation of these transductive sequences. As a practical matter, this may explain why older infants reject bitter-tasting medicines and foods such as green vegetables. A common culinary method to reduce the unpleasantness of bitter taste is the addition of salt. Sodium salts impart a desirably salty taste to foods, and they are effective in reducing the bitterness and increasing the acceptance of some bitter compounds by adults [Breslin and Beauchamp, 1995] and children [Mennella et al., 2003]. Because children preferred salted solutions more than adults did, these findings suggested that the use of sodium salts might be an especially effective strategy for reducing the bitterness of some medicines and facilitating compliance among pediatric populations. However, based on sodium’s differential ability to inhibit bitterness, each food or drug of interest must be evaluated separately [Mennella et al., 2003].

Salty Taste Infant response to salt taste provides the clearest example of a developmental change to a taste stimulus that occurs postnatally [Beauchamp and Cowart, 1993]. Consistent with the absence of a facial response to salt taste in the newborn, preferential ingestion of and differential sucking to salt water relative to plain water are absent in the very young infant and do not emerge until approximately 4 to 6 months of age [Beauchamp et al., 1986, 1994]. Experience with salty tastes does not appear to play a major role in this shift from indifference or rejection of salt at birth to acceptance in later infancy. This developmental change instead may reflect postnatal maturation of central or peripheral mechanisms underlying salt taste perception, as has been demonstrated in animal model studies [Hill and Mistretta, 1990]. The preference that emerges at 4 months appears to be largely unlearned. Research has revealed that young children undergo another developmental shift in their preference for salt taste. By 18 months of age, children begin rejecting salted water. Like adults, they do not choose to consume salt water, but they begin exhibiting robust preferences for salt in soup and other foods such as carrots or pretzels [Beauchamp and Moran, 1984]. In other words, the same level of saltiness may elicit a positive or negative response, depending on the medium in which salt is presented to the child, underlying the importance of sensory context in its perceived pleasantness and preference. Similar to the heightened preferences observed for sweet taste, preschoolers and teenagers prefer greater saltiness than adults do [Beauchamp et al., 1986]. The adult pattern for salt taste preference does not emerge until late adolescence.

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Early Experiences and Preferences for Salt Taste during Childhood and Adolescence A series of animal-model experiments testing the development of salt (NaCl) sensitivity demonstrated that rat pups whose mothers were severely salt restricted during an early period of gestation have altered sensitivity, behaviorally and electrophysiologically, when tested at various times after birth [Stewart et al., 1997]. The mechanism by which the deprivation results in this reduced salt sensitivity remains elusive, but the fact that there is a sensitive period for this effect has been established. Similarly, variation in salt intake between conception and 30 days of age in rats led to persistent difference in preference in adulthood [Contreras and Kosten, 1983]. These data are consistent with the hypothesis that high salt intake of the mother and young infant leads to high salt intake later in life. In other animal-model studies of salt preferences, it was found that rat pups given one or several experiences of sodium depletion exhibit heightened preference for salt as adults [Frankmann et al., 1986]. Evidence suggests that early exposures are more effective than later ones in establishing this heightened preference, leading the investigators to propose that the hormonal changes consequent to sodium depletion (i.e., increases in angiotensin and aldosterone) permanently alter structures in the brain that are responsible for modulating salt intake. A series of studies in humans have suggested a parallel phenomenon. The adult offspring (college students) of mothers who experienced considerable morning sickness during their pregnancies had greater salt preferences compared with students whose mothers suffered little or no morning sickness [Crystal and Bernstein, 1995]. The proposed mechanism is that morning sickness leads to transient fluid and sodium depletion in a manner analogous to that reported in animal-model studies. Consistent with these findings, 12- to 14-year-old children who had been exposed to a chloride-deficient formula during early development had heightened preferences for salty (but not sweet) foods relative to their unexposed control siblings [Stein et al., 1996]. Because chloride deficiency mimics sodium deficiency in some ways (e.g., altered hormonal profile), this finding is consistent with other rat and human studies. With regard to taste, the sensory world of the infant is different from that of the adult because sensitivity to several different taste stimuli develops at different times postnatally (see Table 9-1). Specifically, responses to sweet tastes are evident prenatally, and major changes are not known to occur postnatally. The rejection of sour tastes is evidenced from birth onward. In contrast, salt and bitter sensitivities change postnatally, with salt sensitivity providing the clearest example. The developmental changes in salt preferences may reflect changes in sensitivity independent of experience or may be a consequence of specific experiences, or both.

Clinical Significance Taste dysfunctions are described by several terms. Ageusia refers to a complete loss of gustatory function, whereas hypogeusia refers to diminished sensitivity to detect a specific taste quality or class of compounds (e.g., phenylthiocarbamide). Dysgeusia and phantogeusia refer to the

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distortion in the perceived qualities of a taste stimulus and the experience of a taste sensation in the apparent absence of a gustatory stimulus, respectively [Cowart et al., 1997]. The study of clinical abnormalities in taste perception in pediatric populations has received little scientific attention, in part because the clinical assessment of taste is not well developed [Cowart et al., 1997]. However, some reports in pediatric populations, albeit limited, are highlighted here, and Box 9-2 lists conditions that sometimes are associated with taste disorders in adults. A few disorders with neurologic symptoms have been associated with taste disturbances in pediatric populations. Familial dysautonomia, a hereditary autonomic and sensory neuropathy that affects almost exclusively Jewish children of Ashkenazi extraction, is caused by a defect localized to the chromosome 9 q31-q33 [Blumenfeld et al., 1993]. Features of this disorder include corneal abrasions, lack of tearing, erythematous blotching of the skin, paroxysmal hypertension, emotional lability, increased sweating, cold hands and feet, drooling, scoliosis, and the absence of fungiform papillae on the tongue. Patients with this disorder could detect but failed to correctly label salty, bitter, sweet, and water stimuli compared with control children and adults [Gadoth et al., 1997]. Sour taste and the sense of smell was preserved in these dysautonomic patients. Another congenital disorder that may affect taste perception but does not manifest until later childhood is Melkersson-Rosenthal syndrome. Features of this syndrome include chronic facial swelling, relapsing peripheral unilateral or bilateral facial palsy, and in some cases, lingua plicata (i.e., “scrotal” tongue). A report of a patient with clinical features of this syndrome suggests that the gene is located at 9p11 [Smeets et al., 1994]. Of interest is the report that this patient, who had no facial palsy, complained of taste loss in the anterior part of the tongue. Surgical procedures of the head or neck may sometimes result in taste loss or dysgeusia. For example, tonsillectomy has been associated with taste dysfunction, perhaps because of damage of the lingual branch of the glossopharyngeal nerve [Reider, 1981], whereas surgical procedures that involve the middle ear may damage the chorda tympani nerve (branch of cranial nerve VII), which mediates taste perception on the anterior tongue [Della Fera et al., 1995; Duffy et al., 2003]. Damage to or anesthesia of the chorda tympani nerve can increase taste sensations (particularly bitter) from the other taste nerves (i.e., glossopharyngeal branch of cranial nerve IX and cranial nerve X) and blunt retronasal olfactory sensations from cranial nerve I [Duffy et al., 2003]. Likewise, middle ear infections or oral infections that reach the middle ear through the eustachian tubes may affect the chorda tympani nerve as it passes between the malleus and incus and affect taste perception. Studies by Duffy and colleagues [2003] suggest that insults to chorda tympani nerve function may explain some taste disruptions in children. In particular, exposure to otitis media during childhood was associated with losses of bitter taste on the tip of the tongue and, when severe, reduction in the perception of sweetness throughout the mouth [Duffy et al., 2003; Williams, 1995], which was associated with a higher risk for obesity [Snyder et al., 2003]. Endocrine, metabolic, and nutritional disorders causing loss of taste are rare in adults and presumably in pediatric

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populations. Children with chronic renal failure exhibited reduced preference for sweet-tasting foods, which was unrelated to plasma zinc levels [Bellisle et al., 1995], whereas infants and children diagnosed as suffering from secondand third-degree protein-energy malnutrition preferred soup to which casein hydrolysate had been added over soup alone [Beauchamp et al., 1987; Vazquez et al., 1982]. Wellnourished control infants and malnourished infants who had recovered exhibited the opposite response, suggesting that protein-energy status affects taste preferences [Beauchamp et al., 1987; Vazquez et al., 1982]. Both the well-nourished and malnourished infants preferred the sweet-tasting liquids and rejected bitter-tasting (urea) and sour-tasting (citric acid) liquids. Such findings provide information that may be useful for clinicians in planning palatable diets for these patients. Although the most common etiologic factor contributing to taste disturbances in adults appears to be medication use, there are few reports regarding similar effects in pediatric populations [Ahonen et al., 2004]. Not all individuals taking a particular drug are affected, and the mechanisms by which these medications alter chemosensory function are not well understood. Nevertheless, a variety of medications has been reported to sometimes cause taste (and smell) dysfunction in adults (Table 9-2) [Abdollahi and Radhar, 2003; Ackerman and Kasbekar, 1997; Mott et al., 1993; Murphy et al., 2003; Schiffman, 1983; Spielman, 1998].

THE ONTOGENY OF OLFACTORY AND FLAVOR PERCEPTION Relative to studies on taste perception, less is known about the ontogeny of olfactory and flavor perception. However, the research discussed in the following sections demonstrates that infants are able to detect and discriminate between a wide variety of odors shortly after birth. They hedonically respond to differences in odor quality [Mennella and Beauchamp, 1991a, 1998a; Soussignan et al., 1997], appear to be as sensitive to odors as adults (if not more so), and are capable of retaining complex olfactory and flavor memories [Mennella et al., 2001; Schaal et al., 2000; Sullivan et al., 1991).

Fetus Although the olfactory system is well developed before birth, it is not known whether the human fetus responds to olfactory stimuli [Arey, 1930; Bossey, 1980; Nakashima et al., 1984]. However, the environment in which the fetus lives— the amnion—can be odorous. In addition to certain disease states, such as maple syrup disease [Menkes et al., 1954], phenylketonuria [Partington, 1961], and trimethylaminuria [Lee et al., 1976], the odor of amniotic fluid reflects the foods eaten by the pregnant mother [Mace et al., 1976;

TABLE 9-2 Drugs Associated with Taste and Smell Dysfunction CLASS OF MEDICATION

SPECIFIC DRUGS*

CHEMOSENSORY DYSFUNCTION

Anesthetic

Benzocaine Lidocaine Cocaine HCl Tetracaine HCl Procaine penicillin Metronidazole HCl Tetracycline Doxycycline Carbamazepine Tegretol Biguanide Amphotericin B Phenylbutazone Azelastine 5-Fluorouracil Methotrexate Cisplatin Allopurinol Penicillamine Methylthiouracil Captopril Diltiazem Nifedipine Chlorhexidine Hexidine Sodium lauryl sulfate Baclofen Codeine Morphine Amphetamines Chlormezanone

Loss of taste Loss of smell Loss of smell Loss of taste Metallic dysgeusia Metallic dysgeusia Metallic dysgeusia Anosmia, parosmia Hypogeusia Hypogeusia Metallic dysgeusia Hypogeusia Ageusia Bitter, metallic dysgeusia Sour, bitter dysgeusia Sour, metallic dysgeusia; ageusia Ageusia Metallic dysgeusia Metallic dysgeusia Taste and smell loss Increased taste thresholds Hypogeusia, hyposomia Taste and smell distortions Ageusia, loss of salty taste, persistent aftertaste Altered taste Loss of sweet and salty taste; taste disturbance Ageusia, hypogeusia Olfactory depression Olfactory depression Bitter dysgeusia; olfactory dysfunction Ageusia; metallic and bitter dysgeusia

Antibacterial

Antiepileptic Antidiabetic Antifungal Anti-inflammatory Immunosuppressive/antineoplastic Antirheumatic Antithyroid Cardiovascular Dental products Muscle relaxant Opiate Sympathomimetic Tranquilizers

*This is a partial listing of the medications associated with taste and smell disturbances in adults. Not all individuals taking a particular drug are affected, and the mechanisms by which these medications alter chemosensory function are not well understood. Adapted from Ackerman and Kasbekar, 1997; Mott et al., 1993; Murphy et al., 2003; Schiffman, 1983; Spielman, 1998.

Mennella / Taste and Smell

Mennella et al., 1995, 2001; Schaal et al., 2000]. That the amniotic fluid and the newborn’s body can acquire the odor of a spicy meal ingested by the mother before giving birth suggests that odorous compounds in the mother’s diet can be transferred to amniotic fluid [Hauser et al., 1985]. This phenomenon has been experimentally demonstrated in a study in which amniotic fluid samples were obtained from pregnant women who were undergoing routine amniocentesis and who ingested garlic or placebo capsules approximately 45 minutes before the procedure [Mennella et al., 1995]. The odor of the amniotic fluid obtained from the women who ingested the garlic, as determined by adult human evaluators, was judged to be stronger or more like garlic than amniotic fluid from the control women who did not consume garlic. Because the normal fetus has open airway passages that are bathed in amniotic fluid and it swallows significant amounts of amniotic fluid during the latter stages of gestation, inhaling more than twice the volume it swallows, the fetus may be exposed to a unique olfactory environment before birth [Pritchard, 1965; Schaffer, 1910]. As discussed later, this secretion represents the first exposure to flavors (odors and tastes) that will subsequently be provided by mother’s milk and then the foods of the table. Studies on other animals reveal that certain odors experienced in utero were preferred postnatally [Hepper, 1987, 1988].

Newborn Shortly after birth, human infants can detect a wide variety of volatile chemicals, and they appear to be as sensitive to odors as adults, if not more so. Research has shown that they can detect and discriminate among many qualitatively distinct odorants as evidenced by changes in their facial responses, body movements, and heart and respiratory rates, and anatomic studies on human fetuses suggest that their olfactory neuroepithelium has a higher ratio of olfactory to respiratory epithelium compared with normal adults with no history of infection or exposure to toxins [Engen, 1982; Nakashima et al., 1984; Rovee, 1972]. Research on neonates revealed that the odor of amniotic fluid could calm the infant during the first days of life. Infants who were separated from their mothers cried significantly less when they were exposed to amniotic fluid [Varendi et al., 1998]. This finding is consistent with previous reports stating that newborns can detect the odor of amniotic fluid and that they prefer the odor of their own amniotic fluid relative to a control stimulus or unfamiliar amniotic fluid for at least the first few days of life. This topic has been reviewed by Porter and Schaal [2003]. Breast-fed infants acquire preferences for the odor of breast milk relative to the odor of their own amniotic fluid by the fourth day of life [Marlier et al., 1998]. Although amniotic fluid or its volatile components are initially particularly attractive to all newborns, this attraction appears to be relatively transient as infants gain experience with breast-feeding [Varendi et al., 1997]. Perhaps the most salient of odors for the newborn are those originating from the mother [Macfarlane, 1975]. Within hours after birth, mothers and infants can recognize each other through the sense of smell alone [Schaal, 1988]. Breast-fed infants spent more time orienting toward a breast

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pad previously worn by their lactating mothers than one worn by an unfamiliar lactating woman, and they move their heads and arms less and suck more when they are exposed to their mothers’ odors, suggesting that the odor of the mother may have a calming effect on the infant [Schaal, 1986, 1988]. This ability of breast-fed infants to discriminate the odors of their mothers from those of other lactating women is not limited to odors emanating from the breast region because they can also discriminate odors originating from their mothers’ underarms and neck [Cernoch and Porter, 1985; Schaal, 1986]. Like other mammalian young, this recognition of and preference for maternal odors may play a role in guiding the infant to the nipple area and facilitating early nipple attachment and suckling. This conclusion is supported by the finding that newborns preferred their mothers’ breasts unwashed compared with the same breasts that had been thoroughly washed and were therefore less odorous [Varendi et al., 1994].

Infants and Retronasal Perception of Flavors Considerable research indicates that the amniotic fluid and mothers’ milk is rich in flavor and that the flavors directly reflect the foods and beverages eaten (e.g., carrot, garlic, mint, alcohol, vanilla, tobacco, anise) or substances inhaled (e.g., tobacco) by the mother [Mennella and Beauchamp, 1991b, 1991c, 1993, 1996, 1998b; Mennella et al., 2001; Schaal et al., 2000]. The retronasal perception of odors in mother’s milk provides the infant with the potential for a rich source of various chemosensory experiences and a possible route for the development of preference for a diet similar to the mother, because the context in which the flavor is experienced, with the mother and during feeding, consists of a variety of elements (e.g., tactile stimulation, warmth, milk, mother’s voice) that are reinforcers for early learning. The transition from a diet exclusively of human milk to a mixed diet may be facilitated by providing the infant with bridges of familiarity, such that the infant experiences a commonality of flavors in the two feeding situations. For example, breast-fed infants who had been fed cereal mixed in water for approximately 2 weeks readily accepted the cereal when it was subsequently prepared with mother’s milk [Mennella and Beauchamp, 1997]. They consumed more of the cereal, and they displayed a series of behaviors signaling their preferences. Because the infant’s first flavor experience may occur even before birth in amniotic fluid, breast milk may bridge the experiences of flavors in utero to those in solid foods. Moreover, experience with a particular flavor in amniotic fluid or mothers’ milk biases the infants’ preferences for that flavor during breast-feeding [Mennella and Beauchamp, 1993, 1996] and weaning [Mennella et al., 2001]. Because the chemical senses are functional during infancy and change during development, breast-fed infants may have the opportunity to learn about the flavor of the foods of their culture long before solids are introduced. Unlike the bottle-fed infant, who experiences a constant set of flavors from standard formulas, the breast-fed infant’s sensory world is extremely rich and varied. As a result of this extensive exposure, breast-fed infants are more willing to accept a novel vegetable on first presentation than are

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formula-fed infants [Sullivan and Birch, 1994]. They are also less likely to become picky eaters if they have been breast-fed for at least 6 months [Galloway et al., 2003]. Diverse flavor experiences reduce neophobia by pre-exposing the infant to flavors that will later be presented at weaning and increase their readiness to accept completely unfamiliar flavors, thereby facilitating diet diversity throughout development. There are indications that infants are also learning about the flavor profile of the formula, although monotonous, they are consuming [Mennella and Beauchamp, in press] and that the effects of these early experiences may be long lived. For example, some work demonstrated that experience with the sour and bitter flavors of protein hydrolysate formulas programmed later acceptance of these flavors during infancy [Mennella et al., 2004] and elicited more positive responses to sensory attributes associated with formulas (e.g., sour taste, aroma) in 4- to 5-year-old children [Mennella and Beauchamp, 2002].

Young Children The few published studies that have focused on olfactory preferences in verbal children indicate that they have likes and dislikes to a range of odors but that their hedonic experience may be different from that of adults. Because children younger than 5 years old appear to respond positively to some odors, such as the odor of synthetic sweat and feces, some investigators have concluded that they do not have aversions to odors that adults and older children find offensive and are generally more tolerant of odors than are adults [Engen, 1982; Stein et al., 1958]. Some of the discrepancies about when olfactory preferences and aversions arise can be traced to methodologic and technical difficulties in testing young children. For example, children younger than 6 years tend to answer a positively phrased question in the affirmative, and they have a shorter attention span than older children [Engen, 1974]. Their responses may be biased and not reflect their actual reaction to the odor. By using methods that are sensitive to these behavioral limitations and that embed the olfactory task in the context of a game, research has demonstrated that olfactory preferences and aversions are evidenced in children as young as 3 years [Schmidt and Beauchamp, 1988, Mennella and Garcia, 2000]. Like adults, children preferred the odor of C16 aldehyde (i.e., strawberry), phenylethyl-methylethyl carbinol (i.e., floral), L-carvone (i.e., spearmint), and methyl salicylate (i.e., wintergreen), but they disliked the odor of butyric acid (i.e., strong cheese or vomit) and pyridine (i.e., spoiled milk). Of special interest was the reported difference between children and adults in their affective judgments of the odor of androstenone; 92% of the children and 59% of the adults rated this odor as bad. Androstenone is an interesting odor because it can be perceived as smelling urinous, sweaty, musky, like sandalwood, or having no smell; twin studies revealed that genetic differences between individuals contribute to these differences in the perception of androstenone [Wysocki and Beauchamp, 1989]. Approximately one half of the adult population has a specific anosmia to this odor. A high percentage of children rated this odor as bad, suggesting that most or perhaps all 3-year-old children can detect this odor. A developmental shift in the perception of andro-

stenone occurs at or near adolescence when approximately 50% of individuals lose the ability to smell this odor. The mechanisms underlying this change in perception remain unknown.

Clinical Significance The terminology used to describe olfactory dysfunction parallels that used for taste disorders. Anosmia refers to the complete absence of olfactory functioning, whereas hyposmia refers to diminished olfactory functioning. In some cases, patients may have a deficit in the perception of only a specific odorous compound (e.g., androsterone) or a class of compound; this condition is commonly referred to as specific anosmia. Hyperosmia refers to an increased sensitivity to smell, dysosmia or parosmia refers to conditions in which there are distortions in the perceived qualities of the odor stimulus in the presence of an odor, and phantosmia often refers to the perception of an odor when there is no odor present [Cowart et al., 1997]. Box 9-3 lists several conditions that are associated with olfactory disorders in adults. Nasal and paranasal sinus disease, prior upper respiratory tract infection, and head trauma account for the majority of adult cases of olfactory dysfunction [Mott and Leopold, 1991; Cowart et al., 1997]. In children, the loss of smell (and hearing) is less common after head trauma compared with adults [Jacobi et al., 1986]. Common causes associated with impaired olfactory sensitivity in children include nasal obstruction; allergic, chronic, or hypertrophic rhinitis; and nasal polyps (frequently seen in children suffering from cystic fibrosis) [Ghorbanian et al., 1983]. Olfactory functioning improves after adenoidectomy in children with nasal obstruction caused by adenoid hypertrophy [Ghorbanian et al., 1983]. Evaluation of a child with partial or complete loss of smell may require referral to an otorhinolaryngologist to determine whether there are any local pathologic findings (e.g., foreign body, nasal polyp). As discussed in Chapters 62 and 63, shearing of the olfactory nerves, hemorrhage into the olfactory bulb, fractures of the cribriform plate, and frontal lobe contusions have all been reported in children, but their impact on chemosensory functions remains unknown. Like the sense of taste, little is known about genetic and congenital disorders of smell perception in pediatric populations. The principal genetic syndrome associated with alterations in smell perception, Kallmann’s syndrome, is characterized by the coexistence of hypogonadotropic hypogonadism and permanent anosmia. MRI of the olfactory bulbs and sulcus revealed no evidence of morphologic changes in these areas [Ghadami et al., 2004]. In part, these symptoms appear to be the result of the failure of neurons producing gonadotropin-releasing hormone to migrate from the olfactory placode to the brain during embryonic development and the lack of synaptic connections between olfactory neurons and the olfactory bulbs [Kallmann et al., 1944; Rawson et al., 1995]. Patients with this syndrome, which appears to be X-linked recessive (Xp22.3) in some families [Meitinger et al., 1990] and autosomal recessive in others, may also have renal agenesis, mirror movements of the hands, pes cavus, high-arched palate, and cerebellar ataxia [Hardelin et al., 1992]. Down syndrome is another congenital condition associated with decreased ability to smell in adult patients; however, olfactory dysfunction is not evident

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during young adolescence and presumably during childhood [McKeown et al., 1996; Murphy and Jinich, 1996]. Like the sense of taste, a variety of medications can sometimes affect olfactory perception in adults (see Table 9-2). Moreover, certain metals (e.g., cadmium, zinc), tobacco products, and a variety of industrial substances cause olfactory loss or distortion [Schiffman and Nagle, 1992].

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Steiner JE. Facial expressions of the neonate infant indicating the hedonics of food-related chemical stimuli. In Weiffenbach JM, ed. Taste and development: The genesis of sweet preference. Washington, DC: US Government Printing Office, 1977:173. Steiner JE. What the neonate can tell us about umami. In: Kawamura Y, Kare MR, eds. Umami: A basic taste. New York: Marcel Dekker, 1987:97. Stewart RE, DeSimone JA, Hill DL. New perspectives in gustatory physiology: Transduction, development and plasticity. Am J Physiol 1997;272:C1. Sullivan RM, Taborsky-Barba S, Mendoza BS, et al. Olfactory classical conditioning in neonates. Pediatrics 1991;87:511. Sullivan S, Birch LL. Infant dietary experience and acceptance of solid foods. Pediatrics 1994;93:271. Tatzer E, Schubert MT, Timischl W, et al. Discrimination of taste and preference for sweet in premature babies. Early Human Dev 1985;12:23. Varendi H, Christensson K, Porter RH, Winberg J. Soothing effect of amniotic fluid smell in newborn infants. Early Hum Dev 1998;51:47. Varendi H, Porter RH, Winberg J. Does the newborn baby find the nipple by smell? Lancet 1994;334:989. Varendi H, Porter, RH, Winberg J. Natural odour preferences of newborn infants change over time. Acta Paediatr 1997;86:985. Vazquez M, Pearson PB, Beauchamp GK. Flavor preferences in malnourished Mexican infants. Physiol Behav 1982;28:513. Williams A. Effects of otitis media on taste in children [Thesis]. New Haven, Conn: Yale University School of Medicine, 1995. Witt M, Reutter K. Scanning electron microscopical studies of developing gustatory papillae in humans. Chem Senses 1997;22:601. Wysocki CJ, Beauchamp GK. Ability to smell androstenone is genetically determined. Proc Natl Acad Sci 1989;86:7976. Yan W, Sunavala G, Rosenzweig S, et al. Bitter taste transduced by PLC-beta(2)–dependent rise in IP(3) and alpha-gustducin–dependent fall in cyclic nucleotides. Am J Physiol Cell Physiol 2001;280:C742. Yoshida S, Endo S, Tomita H. A double-blind study of the therapeutic efficacy of zinc gluconate on taste disorder. Auris Nasas Larynx 1991;18:153. Yousem DM, Geckle RJ, Bilker WB, et al. Posttraumatic olfactory dysfunction: MR and clinical evaluation. Am J Neuroradiol 1996;17:1171.

CHAPTER 10

Spinal Fluid Examination David J. Michelson

Since the turn of the 20th century, lumbar puncture and the examination of the cerebrospinal fluid (CSF) have been vitally important in the diagnosis and management of neurologic diseases. Without question, these tests remain indispensable in the identification and treatment of central nervous system infections. Further refinements in CSF analysis promise to lead to revelations about the pathophysiology of neurologic diseases, improved diagnostic tests, and innovative therapeutic approaches. This chapter reviews CSF physiology and diagnostic testing.

HISTORY Although known of since ancient times, presence of fluid within the cavities of the brain was for many millennia thought to be pathologic. The Edwin Smith Surgical Papyrus, written around the 17th century BC, is considered the earliest record of the existence of CSF. In the 4th century BC, the Hippocratic writings mention removing CSF from the ventricles of a patient with hydrocephalus. Even with the detailed descriptions of the cerebral ventricles provided by Galen in the 2nd century AD, the function of the CSF remained almost unknown until the advent of more modern scientific techniques. Richard Lower, an English physician, first suggested in 1669 that the “watery humor” could be reabsorbed by the venous system. In 1757, Pacchioni postulated that the CSF was secreted by, rather than absorbed by, the arachnoid granulations that now bear his name. In 1764, Cotugno performed careful dissections of the brain and spinal cord before decapitation, allowing him to be the first to describe the presence of CSF within the subarachnoid space. It was Magendie, in 1825, who provided the first comprehensive description of the CSF pathways. He detailed the communication between the ventricles and the subarachnoid spaces of the brain and spinal cord and was the first to describe the fluid as cerebrospinal. Although this was correct, he mistakenly concluded that the CSF was secreted by the piaarachnoid and flowed toward the ventricles. The observations of Monro in 1783 and those of Kellie in 1824 drew attention to the nearly fixed volume of the cranial contents, although it was Burton who reported in 1846 that the blood, brain, and CSF volumes could undergo reciprocal changes, a concept now referred to as the Monro-Kellie doctrine. Definitive anatomic studies of the CSF pathways by Weed in 1935 built on the influential work done by Key and Retzius in 1875 and were the first to suggest that CSF was derived from the choroid plexus and the interstitial fluid of the brain. In 1891, Wynter first reported the use of lumbar puncture as a therapeutic measure after using the technique in a

patient with tuberculous meningitis. The diagnostic value of lumbar puncture was first recognized and described by Quincke in 1891. His innovations included using a percutaneous needle with a stylet, a manometer to record the opening pressure, and measurements of CSF cell counts, protein concentration, and sugar content. The technique quickly gained acceptance and had become a routine part of medical care by the turn of the 20th century. Several authors have summarized this early history [Torack, 1982; Vandam, 1989]. Numerous subsequent investigators have contributed to an ever-expanding understanding of the value of CSF analysis in various neurologic diseases [Fishman, 1992].

CEREBROSPINAL FLUID FORMATION, FLOW, AND ABSORPTION CSF is principally formed by secretion from the choroid plexus, villous invaginations of the walls of the lateral, third, and fourth ventricles lined by a ciliated epithelium and richly vascularized (Fig. 10-1). The choroid plexus in each of the lateral ventricles is continuous through the foramina of Monro with the choroid plexus of the roof of the third ventricle. The arterial supply to this portion of the choroid plexus originates from the anterior choroidal arteries, which branch off of the internal carotid artery, and from the posterior choroidal arteries, which are branches of the posterior cerebral arteries. The plexus within the fourth ventricle, which sends extensions through the lateral foramina of Luschka, is usually supplied by the posterior inferior cerebellar artery. In studies of rats, blood flow to choroidal vessels is almost 10 times greater than that to the cerebral cortex [Szmydynger-Chodobska et al., 1994]. Nerves derived from several sources, including the cervical sympathetic chain, the neural plexus of the internal carotid and posterior cerebral arteries, and the vagal nuclei, provide extensive adrenergic, cholinergic, and peptidergic innervation of the choroid plexus. These nerves innervate the surrounding blood vessels and the epithelial cells and influence the rate of CSF production that is in part independent of vasomotor change [Lindvall and Owman, 1981]. The capillaries of the choroid plexus, unlike those found in most other areas of the brain, have large fenestrations that offer little resistance to the passage of fluid, ions, and small macromolecules [Segal, 1993]. Passage of blood past these capillaries probably does create an ultrafiltrate of plasma within the interstitial space. However, analysis of the ionic composition of CSF relative to plasma (Table 10-1) reveals that this interstitial fluid is modified considerably before it reaches the ventricular system and strongly supports CSF formation being a secretory process [Davson et al., 1987].

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TABLE 10-1 Solute Concentrations in Plasma and Lumbar Cerebrospinal Fluid

A

Ventricle

Ependymal cells

Secretory Cells

SUBSTANCE

SOLUTE CONCENTRATIONS (mEq/L) Plasma CSF

Sodium Potassium Magnesium Calcium Bicarbonate Amino acids Osmolality

150 4.6 1.6 4.7 99 2.6 289 mOsm/L

147 2.9 2.2 2.3 113 0.7 289 mOsm/L

RATIO 1.0 0.6 1.4 0.5 1.1 0.3 1.0

basolateral membranes of the choroid plexus epithelial cells. Water follows the flow of sodium and chloride ions from the interstitial fluid into the CSF. Carbonic anhydrase within the epithelial cells catalyzes the formation of carbonic acid from water and carbon dioxide. Carbon dioxide diffuses freely, but the dissociation products of carbonic acid, bicarbonate, and hydrogen are transported across the basolateral membrane by specific proteins in exchange for sodium and chloride, favoring the passive diffusion of water into the cells [Speake et al., 2001]. Sodium transport out of the cells is principally mediated by sodium-potassium ATPases on the apical membrane, with selectively permeable apical chloride and potassium channels rounding out the complement of transporters thought to be most important to the net flow of water into the CSF (Fig. 10-2). Other specific active transport proteins present along the basolateral membrane allow transport into the CSF of essenblood

CSF Na+, HCO3–,CI– & H2O

K+ 3Na+

CI– 2K+

HCO3– Na+

BVs

Na+ 2CI–

H+ CT Core

B FIGURE 10-1. Structure of the choroid plexus. A, Light microscopy of a section through the choroid plexus and ventricle from the brain of a dog (Luxol fast blue and hematoxylin stain, ×200). B, A similar view of the choroid plexus in diagrammatic form. BV, blood vessel; CT, connnective tissue. (A, Courtesy of Dr. Thomas Caceci, Virginia-Maryland College of Veterinary Medicine; B, adapted from a drawing by Dr. Samir El-Shafey, Virginia-Maryland College of Veterinary Medicine.)

Additional studies have found that CSF secretion depends highly on active transport proteins that, as with other secretory epithelia, are differentially localized on the apical and

K+ C.A CO2 + H2O → H+ + HCO3–

HCO3–

H2O FIGURE 10-2. Major processes involved in cerebrospinal fluid (CSF) secretion. 1, Carbonic anhydrase catalyses the production of bicarbonate ions and protons from carbon dioxide. 2, Bicarbonate is exchanged for chloride across the basolateral membrane. 3, Bicarbonate and chloride flow into the CSF through anion channels, down an electrochemical gradient, and through sodium-potassium-chloride cotransport. 4, Sodium is exchanged for protons across the basolateral membrane and for potassium across the apical membrane. 5, Water follows the osmotic gradient created by the combined secretion of sodium, chloride, and bicarbonate into the CSF. (From Brown PD, Davies SL, Speake T, et al. Molecular mechanisms of cerebrospinal fluid production. Neuroscience 2004;129:957–970.)

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tial hydrophilic micronutrients, including glucose, amino acids, purines, nucleosides, and vitamins. Transport proteins along the apical membrane work to clear the CSF of potentially toxic metabolites, such as organic acids and bases [Spector and Johanson, 1989]. Although there is evidence to suggest additional formation of CSF though transependymal or transpial absorption of interstitial fluid, the actual contribution of these extrachoroidal mechanisms is unknown [Davson et al., 1987; Milhorat, 1987]. Tight junctions link the choroid plexus epithelial cells, limiting the free diffusion of ionic molecules and creating the blood-CSF barrier. Although protein diffusion is largely restricted, most of the small amount of protein found in the CSF is nevertheless of plasma origin. Maintenance of a relatively stable CSF composition, despite wide variation in the composition of the plasma, reflects the integrity of the blood-CSF barrier and the work of active transporters against concentration gradients [Fishman, 1992]. Various methods of investigation have found that the rate of CSF formation in healthy adults averages 0.35 mL per minute, or roughly 500 mL each day. Children produce proportionally less CSF, depending on their height and weight, with as little as 25 mL produced per day in newborns. Postmortem studies have provided estimates that total CSF volume ranges from 50 mL in term neonates to 150 mL in adults, with only a small percentage contained within normal-sized ventricles. The total volume of the CSF undergoes complete replacement three to four times each day. Choroid plexus epithelial cells express a wide range of receptors for hormones and neurotransmitters [Nilsson et al., 1992], but the rate of CSF formation appears to remain fairly constant under most conditions. Many factors have been found to influence the rate of CSF production in animal models, including cholera toxin, norepinephrine, hyperosmolality, hypothermia, atrial natriuretic hormone, vasopressin, serotonin, and dopamine [Rosenberg, 1990]. Cholera toxin and norepinephrine increase CSF production through an increase in cyclic AMP formation, which has been linked to increased bicarbonate transport [Epstein et al., 1977; Nathanson, 1983; Saito and Wright, 1984]. Greatly reduced CSF production has been seen after experimental administration of the sodium-potassium ATPase inhibitor ouabain [Vates et al., 1964]. Carbonic anhydrase inhibitors, such as acetazolamide, can reduce the choroidal production of CSF in rats by 50% to 100% [Fishman, 1992; Vogh et al., 1987]. Of the seven mammalian isoforms of carbonic anhydrase, however, the CAIII isoform that is most abundant in the human choroid plexus is insensitive to acetazolamide [Nogradi et al., 1993], explaining the somewhat limited clinical effectiveness of this medication [Cowan and Whitelaw, 1991]. Furosemide and other loop diuretics weakly inhibit carbonic anhydrase activity but are thought to reduce CSF production through inhibition of sodium, potassium, and chloride cotransporters [Johanson et al., 1994]. Endogenous vasopressin release and V1 receptor activation appears to mediate some of the reduction in choroidal blood flow and CSF formation that occurs with hypoxia or with increased intracranial pressure [Faraci et al., 1994]. Elevated CSF vasopressin levels have been found in some patients with the syndrome of idiopathic intracranial hypertension [Sorensen et al., 1982].

Lateral ventricle

Choroid plexus

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Subarachnoid space Arachnoid villi Sagittal sinus

Third ventricle Aqueduct of Sylvius

Fourth ventricle

Spinal nerves FIGURE 10-3. The diagram shows the ventricles, foramina, and major cisterns. Arrows indicate the direction of cerebrospinal fluid circulation.

Figure 10-3 illustrates the pathway taken by the CSF. Fluid is secreted into the lateral ventricles, passes through the foramina of Monro into the third ventricle, and flows through the aqueduct of Sylvius into the fourth ventricle. CSF exits the ventricular system through the lateral foramina of Luschka to enter the prepontine cistern and cerebellopontine angles. Alternatively, CSF can leave the fourth ventricle through the midline foramen of Magendie, entering the cisterna magna, from which it can flow upward over the cerebellar hemispheres or downward into the spinal subarachnoid space and around the brainstem into the basal cisterns, including the interpeduncular cistern. CSF flows predominantly downward posterior to the spinal cord and upward anterior to the cord, leading the fluid to eventually reach the basal cisterns, from which flow is mainly upward over the brain convexity. In the steady state, the rate of CSF absorption is equal to that of its production. Most CSF is absorbed into the venous sinuses across the arachnoid villi and granulations, arachnoid membrane invaginations through the dural lining of the sinuses that are concentrated near the sagittal sinus. Some absorption also occurs across the capillaries, veins, and lymphatics of the spinal cord and spinal roots [Guyton, 1971]. Absorption across the arachnoid villi occurs by vesicular transport. This action demonstrates a dependence on the hydrostatic pressure gradient across the villous surface such that the villi act as oneway pressure valves that open above a threshold pressure, usually 20 to 50 mm H20 [Welch and Friedman, 1960]. Studies using radionuclide cisternography and cardiac-gated magnetic resonance imaging (MRI) suggest that CSF absorption across brain capillaries may be more important than previously thought [Greitz and Hannerz, 1996].

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CEREBROSPINAL FLUID FUNCTION The CSF provides buoyancy and physical protection to the brain, absorbing the stretching and compressive forces generated by normal head movement and lessening the impact of the deceleration and rotational forces created by head trauma. A second protective function derives from the ability of the CSF to redistribute in response to acute changes in other intracranial contents, helping to maintain normal intracranial pressures. The CSF is also thought to serve as a route for the transport of centrally acting hormones, such as for the diffusion of hypothalamic releasing factors across the third ventricle [Kozlowski, 1982]. The CSF aids in the excretion of metabolites through bulk absorption of the interstitial fluid of the brain and spinal cord, with which it is in close communication [Go, 1997], prompting speculation that the CSF pathways are analogous in function to the lymphatic channels that these tissues lack [Cserr et al., 1977]. This “sink action,” along with the various mechanisms by which the CSF composition is maintained, suggests that the CSF plays a significant role in normal physiology and in the compensatory response to pathologic situations [Hochwald, 1984].

DIAGNOSTIC SAMPLING OF CEREBROSPINAL FLUID Indications Changes in the composition of the CSF have been associated with a wide variety of neurologic conditions. Sampling of the CSF is considered helpful in the diagnosis and management of several such conditions in children and may be most useful in cases of suspected meningitis, encephalitis, subarachnoid hemorrhage, intracranial hypertension (as in pseudotumor cerebri), leptomeningeal carcinomatosis, pediatric neurotransmitter diseases, and neurodegenerative diseases. In each case, the potential benefits of the information that can be obtained should be weighed against the risks of the procedures used for CSF sampling. Families should be involved as much as possible in the decision-making process to allow them to provide truly informed consent.

Contraindications and Cautions The presence of infection over the spinal canal in the lumbar region, such as a spinal epidural abscess or subdural em-

A

pyema, is an absolute contraindication to lumbar puncture. An increased bleeding tendency is also a contraindication, because this may incur a greater risk of epidural, subdural, or subarachnoid bleeding [Adler et al., 2001]. However, coagulopathy may be correctable by stopping an anticoagulant medication or by giving an appropriate transfusion of platelets or clotting factors. Before performing a lumbar puncture, it is believed that the patient should have a platelet count greater than 50,000 and an international normalized ratio less than 1.5. Anticoagulation therapy should probably be delayed for at least 2 hours after a lumbar puncture [Sadjadpour, 1977]. There is considerable and understandable fear that lumbar puncture in patients with a CSF obstruction can unbalance the pressure across the area of obstruction and contribute to cerebral herniation or spinal cord compression. Neuroimaging, usually with cranial computed tomography (CT), is often performed before lumbar puncture, especially in patients who appear ill. Patients are considered to be at an increased risk for cerebral herniation if neuroimaging reveals a focal mass lesion or obliteration of the fourth ventricle or quadrigeminal cistern. In adults with suspected meningitis, patients without clinical signs of increased intracranial pressure (i.e., papilledema or altered level of consciousness) or focal neurologic deficits are very unlikely to have an abnormal CT scan or to herniate after lumbar puncture [Hasbun et al., 2001]. However, herniation has been reported after normal neuroimaging, leading many to continue to debate the appropriate use of neuroimaging before lumbar puncture [Oliver et al., 2003]. Because it is considered essential that antibiotics not be delayed when meningitis is suspected, especially with meningococcal disease, current recommendations are to start antibiotics as soon as possible, before lumbar puncture if necessary [Wilks and Lever, 1996].

Procedure The success of a lumbar puncture is determined by the correct positioning of the needle and the patient and depends almost as much on the relaxation of the patient and on the skill and experience of the assistants as it does on that of the needle-wielding physician. Local analgesia, with or without the use of additional anxiolytics, may be sufficient for cooperative older children, but moderate-to-deep sedation is often necessary for younger children. Although aggressive assistants can easily overpower neonates and young infants,

B

FIGURE 10-4. Proper positioning of the patient. In the lateral recumbent position, the neck and hips are flexed without introducing spinal rotation (A), and the L3-4 interspace is found along a line between the superior iliac crests (B). (From Roos KL. Lumbar puncture. Semin Neurol 2003;23:105–114.)

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obviating the need for sedation, they must take care not to cause airway compromise. The lower end of the spinal cord, the conus medullaris, is found by MRI to be at the L1-2 vertebral interspace in most subjects and safely above the L3 vertebral body in all subjects without spinal deformity [Saifuddin et al., 1998]. To avoid damaging the conus, only the interspaces below L3 are used for lumbar puncture. With a patient lying in the lateral recumbent position, the L3-4 interspace can be found at the level of the superior iliac crests. This area should be carefully palpated and marked to ensure that it can be identified after the patient is cleaned and draped. Having the patient curl with the neck and hips flexed can maximize the size of the interspace. Whether the patient is placed in a lateral recumbent or seated position, care should be taken to maintain the alignment of the shoulders and hips, avoiding rotation of the spine. Having the patient’s back near the edge of the bed and at a proper height can aid in the comfort and success of the physician. The recommended positioning is shown in Figure 10-4. The patient’s skin should be prepared using a microbicidal agent, such as a 10% solution of povidone-iodine. The skin should be given time to dry and then wiped clean and draped with sterile towels. A local anesthetic, such as a 1% solution of lidocaine, can be injected into the area to minimize the pain of repeated needlesticks. Anaesthesia provides little benefit when the lumbar puncture can be accomplished with a single needlestick, because the pain of the anesthetic injection often equals or exceeds that of the spinal needle insertion. A reasonable alternative is the use of a topical analgesic cream, such as the 5% emulsion of lidocaine and prilocaine commonly referred to as eutectic mixture of local anesthetics (EMLA). EMLA requires 20 to 30 minutes of application but has been associated with a decreased pain response, even in neonates [Kaur et al., 2003]. The most commonly used spinal needles are 2.5- or 5-cm-long, 20- or 22-gauge Quincke needles, which are beveled and fitted with a stylet. The sharply beveled tip of the Quincke needle should be turned to face the patient’s side so that its cutting edge can push through, rather than

Quincke

Whitacre

Sprotte

FIGURE 10-5. The Quincke, Whitacre, and Sprotte needles. The arrow indicates the sharp edge of the beveled tip of the Quincke needle. (From Roos KL. Lumbar puncture. Semin Neurol 2003;23:105–114.)

157

cut, the longitudinal fibers of the dura. Atraumatic needles, such as the Whitacre and Sprotte needles, have duller tips that make dural injury less likely (Fig. 10-5). These needles are also more flexible, encounter more tissue resistance, and require the use of an introducer, making them more difficult to position. Using a needle without a stylet is discouraged because this is thought to increase the risk of introducing a plug of epidermal tissue into the subarachnoid space that may later form an epidermoid tumor [Ziv et al., 2004]. The needle is gradually advanced, the ligamentum flavum and dura are pierced, and a slight popping sensation is felt as the subarachnoid space is entered. The stylet is removed to allow CSF to drain to the needle hub. If no fluid appears, the needle should be rotated a quarter turn in case a nerve rootlet or strand of arachnoid is obstructing the opening. If this does not initiate CSF flow, the needle can be introduced a few millimeters more, sometimes resulting in a second popping sensation. If there is still no CSF, the stylet should be replaced and the needle slowly withdrawn for redirection of the needle toward the same interspace or for selection of another interspace [Roos, 2003]. After CSF is flowing from the needle, a stopcock and manometer should be attached to the needle hub. The opening pressure should be measured with the child relaxed and in the lateral decubitus position. There should be no direct pressure on the abdomen and little or no flexion of the legs or hips during the measurement. Slow CSF flow may be caused by partial needle obstruction or by low CSF pressure. One way to ensure that a low manometry reading is a true reflection of the CSF pressure is to apply firm pressure to the patient’s abdomen. In the absence of an outflow obstruction or disconnection between the needle and manometer, there should be a rapid rise in the manometer reading, followed by a rapid fall as abdominal pressure is released. An accurate manometry reading should also be accompanied by small fluctuations in the height of the fluid column with the pulse and respirations. The Queckenstedt test, which measures the effect on manometric pressures of jugular venous obstruction, was previously used to identify CSF obstruction. This test was somewhat dangerous and has been overtaken in sensitivity and specificity by current neuroimaging techniques, making it of historical interest only. Normal opening pressures in adults and older children generally range from 120 to 200 mm H2O. Pressures as high as 250 mm H2O in obese adults are also considered normal [Corbett and Mehta, 1983]. In a young, relaxed child, the pressure normally ranges from 60 to 180 mm H2O [Clark, 1969]. Normal pressures in newborns vary between 90 and 120 mm H2O [Levinson, 1928; Munroe, 1928; Volpe, 2001]. Pathologic elevations of the CSF pressure are discussed in Chapter 65. After the opening pressure has been recorded, CSF can be collected for analysis. Abdominal pressure or Valsalva maneuvers can be used to increase slow flow. In the case of very slow flow, gentle aspiration with a syringe may be attempted, although this may increase the risk of pulling a nerve rootlet or strand of arachnoid into the needle. At least 5 mL of CSF should be collected; the first three tubes of 1 to 2 mL are sufficient for routine studies: Gram stain, bacterial culture, cell count and differential, and glucose and protein concentrations. If the first tubes are grossly bloody, a fourth tube of at least 2 mL should be collected to aid in

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the differentiation of subarachnoid hemorrhage from a traumatic tap. This tube can also be held in reserve for additional studies such as special microbiologic, immunologic, or metabolic tests. Most cases of traumatic tap are obvious to the physician because blood is seen to enter previously clear CSF after a change in the needle position or to clear with continued collection. Transfer of the tubes of CSF to the laboratory should be expedited, because sitting for 2 hours at room temperature can cause lysis of up to 40% of white blood cells. Replacing the stylet before withdrawing the spinal needle is recommended to avoid pulling a strand of arachnoid through the dura, creating a channel for continued CSF leakage, and increasing the risk of post-procedural headache [Strupp et al., 1998]. The clinician should carefully document the details of the lumbar puncture in the medical record. In special situations, CSF can be obtained by ventricular or cisternal puncture. Patients with ventricular shunts may need to have their CSF sampled directly from the device. These procedures are best performed by neurosurgeons. For children who require repeated withdrawal of CSF or repeated intraventricular delivery of medications, a reservoir can be implanted that allows safer and more convenient access.

Complications Transient complications during the procedure include pain and paresthesias in the distribution of a lumbar nerve root resulting from contact with the needle. The discomfort should subside with repositioning of the needle toward the midline, and permanent nerve injury is highly unlikely. More serious complications of lumbar punctures do occur, although rarely [Evans, 1998; McHale and O’Donovan, 1997; Tobias, 1994; Wang and Schmidt, 1997]. These mainly involve subarachnoid, subdural, and epidural hematomas resulting from a breach of the epidural venous plexus, radicular arteries, or radicular veins [Vos et al., 1991]. Patients commonly have signs and symptoms of meningeal irritation or local pain. Severe symptoms, such as sensory, motor, or sphincter dysfunction, suggest the need for surgical hematoma evacuation [Kirkpatrick and Goodman, 1975]. Infectious complications, including meningitis, epidural abscess, and osteomyelitis, can result from the use of incompletely aseptic technique. Experiments have confirmed that lumbar puncture in bacteremic animals can cause meningitis but only with high colony counts and before the administration of antibiotics [Carp and Bailey, 1992]. Concern that patients with acute leukemia may have malignant cells introduced into the CSF by lumbar puncture has not been supported by experimental or clinical evidence. Neither of these theoretical hazards should cause lumbar puncture to be withheld from patients with suspected meningitis (Shinefield, 1975). The most common complications of lumbar puncture are back pain and post-procedural headache. This headache may occur within 72 hours of the puncture, may be worsened by an upright position and relieved by recumbency (orthostatic), and may be associated with neck stiffness, nausea, vomiting, and cranial nerve palsies. Symptoms usually resolve spontaneously after a few days, but protracted and complicated cases occasionally are reported. Post-procedural headache is thought to be caused by ongoing CSF leakage

FIGURE 10-6. Intracranial hypotension. Axial T1-weighted magnetic resonance imaging of the brain after intravenous gadolinium contrast injection shows diffuse, thick enhancement of the dura and enlargement of the sagittal venous sinus (arrow). (From Nakshi R, Mechtler LL, Kamran S, et al. MRI findings in lumbar puncture headache syndrome. Clin Imaging 1999;23:73–76.)

through a tear in the dura, low intracranial pressure, and downward displacement of pain-sensitive intracranial structures. MRI can demonstrate loss of intracranial CSF volume 24 hours after lumbar puncture. Very large reductions are associated with headache, but many patients are symptomatic despite having neither visible change in CSF volume nor measurable change in brain position [Grant et al., 1991]. MRI studies reveal diffuse meningeal and dural venous sinus contrast enhancement (Fig. 10-6), suggesting that a low CSF volume induces a painful compensatory venous sinus engorgement [Hannerz et al., 1999]. Pain may also result from a loss of brain buoyancy, downward displacement of the brain, and traction on the pain-sensitive meninges and vessels [Ferrante et al., 2004]. An identical clinical and radiologic picture is occasionally seen in patients with a documented low CSF pressure (<60 mm H2O) and no history of a lumbar puncture or other known source of a dural tear, such as head trauma or surgery. Patients with this syndrome of spontaneous intracranial hypotension are often found to have developed a spontaneous CSF leak, documented by CT myelography, radioisotope cisternography, or spinal MRI. Spontaneous intracranial hypotension sometimes occurs in patients with the features of Marfan’s syndrome or other connective tissue disorders [Mokri et al., 2002]. Symptomatic CSF leakage and hypovolemia has been associated with normal CSF pressures [Miyazawa et al., 2003]. Spontaneous intracranial hypotension is often confused with other chronic headache disorders, delaying effective therapy [Schievink, 2003]. Although CSF hypovolemia usually runs a benign course, rare, life-threatening complications have been reported, including diencephalic compression and subdural hematomas [Pleasure et al., 1998; Whiteley et al., 2003]. When

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bed rest is ineffective, treatment options include epidural injection of autologous blood or fibrin glue, continuous epidural saline infusion, and direct surgical repair of an identified site of leakage [Cousins et al., 2004; Inamasu et al., 2004; Schievink et al., 2004]. Several technical aspects and patient factors appear to lessen the incidence and severity of post-procedural headache in adults, including the use of small-diameter needles [Tourtellotte et al., 1972] or atraumatic needles [Strupp et al., 2001], low body mass index, male gender, and lack of a prior history of headache [Evans, 1998]. Bed rest after lumbar puncture has not been found to prevent headache, but it is effective in reducing pain after it has developed [Ebinger et al., 2004]. Similarly, prophylactic epidural blood patches do not prevent headaches but are very successful in the treatment of refractory post-procedural headaches [Berrettini et al., 1987; Tarkkila et al., 1989]. The efficacy of other treatments for headache, including intravenous fluids and caffeine, continues to be controversial [Lin and Geiderman, 2002].

CEREBROSPINAL FLUID ANALYSIS Appearance The appearance of the CSF should be studied and recorded. Normal CSF is clear and colorless, indistinguishable from water when held up to white light in identical tubes. The presence of cells can be assessed by looking for Tyndall’s effect, a snowy scattering of direct sunlight when the tube is held against a dark background and the bottom is flicked with a finger [Simon and Abele, 1978]. This test can be positive with cell counts of less than 50 cells/mm3. Higher cell counts (i.e., more than 200 leukocytes/mm3 or 400 red blood cells/mm3) are readily perceived, but the eye cannot easily distinguish between the contribution of leukocytes and red blood cells, and this test cannot replace laboratory analysis. With red blood cell counts between 500 to 6000 cells/mm3, the CSF color becomes pink or xanthochromic. Xanthochromia, a yellowish discoloration of the CSF, is seen with the presence of red blood cell breakdown products such as oxyhemoglobin, bilirubin, and methemoglobin, each of which can be quantified by spectrophotometry. In the context of acute subarachnoid hemorrhage, bilirubin has traditionally been thought to first appear after 10 hours, reach a maximum at 48 hours, and persist for up to 2 to 4 weeks [Walton, 1956]. Later in vitro studies have added further caution to the interpretation of xanthochromia, suggesting that it can develop in less than 2 hours with the addition to CSF of less than 10,000 red blood cells/mm3 and can develop immediately with the addition of 30,000 red blood cells/mm3 or more [Graves and Sidman, 2004]. An elevated bilirubin level in the CSF may result from elevations of the plasma bilirubin to levels above 10 to 15 mg/dL. A protein concentration above 150 mg/dL can also give CSF a mildly yellowish tint. Other causes of orange to brown discoloration of the CSF include hypercarotenemia, malignant meningeal melanomatosis, and the use of rifampin.

Cells Counting chambers are used for quantitation of red blood cells and white blood cells within the CSF. Such automated

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TABLE 10-2 Total White Blood Cell Counts in the Cerebrospinal Fluid of Children without Central Nervous System Disease AGE Neonate Premature (28-37 wk GA) Term (38-42 wk GA) Infant <6 weeks 6 weeks to 3 months 3 to 6 months 6 to 12 months Child Juvenile and adult*

N

WBC COUNT*

38 25

5.1 ± 5.8 4.5 ± 3.6

64 67 84 75 81

3.7 ± 3.4 2.9 ± 2.9 1.9 ± 2.0 2.6 ± 2.5 1.9 ± 2.7 2.6 ± 1.7

*White blood cell counts (cells/mm3) are reported as means ± standard deviations. The juvenile and adult level is provided for comparison. WBC, white blood cell; wk GA, weeks’ gestational age.

devices can also provide fairly accurate differentials for the types of white blood cells present, but a pathologist should review a stained slide to provide confirmation. A small number of red blood cells can be found in the fluid of normal older children and adults, even in the absence of a traumatic puncture. Even higher numbers of red blood cells can be found in normal newborns, with a mean of 120 red blood cells/mm3. Infants without proven central nervous system pathology have also been found to have a higher number of total white blood cells and a higher percentage of polymorphonuclear cells than is found in older children [Nascimento-Carvalho and Moreno-Carvalho, 1998l; Portnoy and Olsen, 1985]. Older children have normal values similar to those of adults [Dyken and Mulina, 1973]. The normal values determined by these studies are shown in Table 10-2. Centrifugation and staining of the CSF is suitable for most clinical cytology, but filtration and sedimentation techniques better preserve cell morphology and are preferred for the precise identification of abnormal cells, particularly tumor cells [Herndon and Brumback, 1989]. The white blood cells found in normal CSF are typically 70% lymphocytes and 30% monocytes. An elevated white blood cell count or more than a few polymorphonuclear cells may indicate inflammation or infection within the central nervous system, but counts are not specific enough to allow ready differentiation, for example, of bacterial from viral meningitis. This point is examined in detail in Chapters 68 and 69 on infections of the nervous system. Finding an elevated polymorphonuclear cell count despite a normal white blood cell count was common among children who had systemic infections without apparent central nervous system involvement [Naqvi et al., 1983]. Reports differ about whether seizures are associated with elevated white blood cell and polymorphonuclear cell counts [Portnoy and Olson, 1985; Woody et al., 1988]. Neoplastic cells, plasma cells, stem cells, and eosinophils within the CSF are always considered abnormal. However, because cytologic analysis has such a low sensitivity, CSF testing for leptomeningeal metastasis of a systemic malignancy should be repeated multiple times and should employ large collection volumes [DeAngelis and Cairncross, 2002]. Excessive red cells in CSF can be diagnostic of subarachnoid hemorrhage but can also occur with a traumatic

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lumbar puncture. Clot formation within the tube of CSF is quite unusual after subarachnoid hemorrhage but is common after traumatic puncture. Analysis of the supernatant fluid of centrifuged CSF for xanthochromia, if sufficient time has passed to allow for red blood cell breakdown, can help in differentiating the two possibilities, with additional attention paid to the red blood cell concentration. There is some validity to comparing red blood cell counts in serial tubes, because the counts always decrease in cases of traumatic puncture. This analysis must be informed by a realization that traumatic puncture can and does occur in patients with true subarachnoid hemorrhage. The possibility of subarachnoid hemorrhage should not be considered excluded by this method unless the later tubes have a red blood cell count approaching zero [Shah and Edlow, 2002]. A formula for the correction of the white blood cell count in patients with suspected traumatic lumbar puncture is widely used. The expected number of white blood cells is calculated based on the assumption that the red blood cell count is purely a reflection of peripheral blood contamination. In patients with a concurrently normal hemogram, this assumption predicts 1 white blood cell/mm3 (CSF) for every 700 red blood cell/mm3 (CSF). In patients with an abnormal hemogram, the direct calculation is corrected by the observed plasma ratio, predicting white blood cell (CSF) = red blood cell (CSF) × [white blood cell (plasma)/red blood cell (plasma)]. Although the rigid application of this method has been justifiably questioned [Novak, 1984], children with meningitis and a traumatic puncture are unlikely to be misdiagnosed through overcorrection as their white blood cell counts frequently are more than 10 times that predicted by this formula. The children usually have other clinical or CSF findings that suggest meningitis [Bonadio et al., 1990; Mayefsky and Roghmann, 1987].

Microorganisms The first 1 to 2 mL of CSF, even if contaminated with blood from a traumatic puncture, should be stained and cultured for microorganisms. Gram staining allows for an early bacteriologic diagnosis, and results may influence the choice of antibiotic treatment. Outside of a strong clinical suspicion, there is probably no benefit to the routine use of acid-fast stains and mycobacterial cultures, India ink preparations and fungal cultures, or viral cultures. Bacterial cultures should be tested in broth and on solid culture media. The pathogenic bacteria that are most commonly responsible for meningitis are usually successfully cultured on chocolate agar in a carbon dioxide atmosphere at 35° C to 37° C. Additional studies that are available for the rapid identification of microorganisms include counterimmunoelectrophoresis, latex agglutination, and limulus lysate assays. Adjunctive bacterial antigen detection tests, especially the more accurate latex agglutination test, have had diagnostic value in patients who had been treated with antibiotics before lumbar puncture for suspected meningitis [Bhisitkul et al., 1994; Mirdha et al., 1991]. Other studies have strongly questioned the value of such tests, finding high falsepositive rates, low sensitivity, or no added benefit over Gram staining and culture [Nigrovic et al., 2004; Tarafdar et al., 2001]. Tests to distinguish pyogenic from viral infections, including C-reactive protein [Putto et al., 1986] and lactate

[Jordan et al., 1983], demonstrate some specificity but not enough for their clinical application. Immunologic tests for antigens and antibodies and the polymerase chain reaction tests for DNA and RNA can greatly aid in the identification of organisms that are difficult to culture [Greenlee, 1990]. These techniques can be applied to cases of bacterial meningitis but are particularly useful in the evaluation of immunocompromised hosts, encephalitis, and chronic meningitis, when viral, fungal, rickettsial, and other unusual organisms are more likely to be identified.

Glucose Facilitated transporters on the membranes of capillary endothelial cells allow glucose to enter the interstitial fluid of the brain [Fishman, 1964]. With normal plasma glucose concentrations between 70 and 120 mg/dL, normal CSF glucose concentrations range between 45 and 80 mg/dL, or about two thirds of the plasma glucose concentration. Glucose readily equilibrates between the CSF and interstitial fluid, and the decline from plasma levels is thought to be a sign of the high cerebral metabolic rate for glucose. A CSF glucose concentration below 40 mg/dL (i.e., hypoglycorrhachia) or a ratio of less than two thirds of the plasma glucose level is considered abnormal. Very low CSF glucose values, sometimes below the limits of laboratory detection, are most characteristic of acute bacterial meningitis but mildly to moderately low values are commonly seen in fungal, parasitic, protozoal, spirochetal, and tuberculous meningitis. A low CSF glucose level is uncommon in viral meningitis but has been reported in association with mumps, herpes simplex, and herpes zoster infections [Donald et al., 1987; Mommeja-Marin et al., 2003]. Besides plasma hypoglycemia, there are other noninfectious causes of low CSF glucose, including meningeal carcinomatosis, sarcoidosis, chemical meningitis, and subarachnoid hemorrhage. In diverse causes of meningeal inflammation, a low CSF glucose level probably results from a combination of increased glucose use by the brain and spinal cord adjacent to the CSF; from glucose use by leukocytes within the CSF, especially polymorphonuclear cells; and from inhibition of glucose transport into the CSF. In the setting of plasma hyperglycemia, the saturability of the endothelial glucose transporters allows for only a partial parallel increase in the CSF glucose concentration. Diabetic patients without signs of meningitis can have CSF-toplasma glucose ratios of less than one third (Powers, 1981). Acute changes in the plasma glucose concentration are maximally reflected in the CSF concentration after 2 hours, with equilibration after a transient change requiring up to 4 hours. Optimal interpretation of the CSF glucose level therefore requires a simultaneous plasma glucose measurement, after the patient fasts for 4 hours. Defective transport of glucose across the blood-brain barrier was initially proposed as a novel mechanism of disease in two infants with low CSF glucose concentrations, low CSF lactate levels, and epileptic encephalopathy [De Vivo et al., 1991]. This theory was borne out by discovery of mutations in the SLC2A1 gene (formerly designated GLUT1) for the cerebral endothelial glucose transporter [Seidner et al., 1998]. Defects in SLC2A1 have since been found in children and adults with a variety of neurologic

Michelson / Spinal Fluid Examination

Protein The total protein content of the CSF normally varies with age. It is highest at birth and falls over the first year of life before gradually climbing toward its adult value [Widell, 1958]. The protein concentrations obtained by lumbar puncture in healthy subjects are displayed in Table 10-3 and Figure 10-7. Protein levels also vary by the anatomic area from which the CSF is sampled. In normal infants and adults, the CSF protein concentration is 6 to 15 mg/dL in the ventricles, 15 to 25 mg/dL in the cisterna magna, and 20 to TABLE 10-3 Total Protein Content in the Cerebrospinal Fluid of Healthy Children AGE

N

PROTEIN*

0-6 days 7-13 days 14-27 days 28-41 days 42-59 days 2-4 months 5-8 months 9-11 months 12-23 months 2-7 years 8-13 years

11 7 13 10 11 9 7 5 8 21 19

80.9 ± 20.8 70.4 ± 23.6 53.9 ± 17.8 46.5 ± 15.4 45.6 ± 14.2 34.8 ± 12 20.4 ± 2.4 16.6 ± 2.6 16.8 ± 2.7 17.7 ± 3.1 20.8 ± 4.1

Protein concentrations (mg/dL) are reported as means ± standard deviations.

Total CSF Protein vs. Age 120 100 Protein mg/dL

symptoms. In the classic phenotype, seizures begin within the first 4 months of life in previously healthy and normal infants. Other paroxysmal events may be observed over time, including apneic episodes, opsoclonus, ataxia, confusion, lethargy, alternating hemiparesis, total body paralysis, abnormal movements or postures, sleep disturbances, and headaches. Deceleration of head growth, with acquired microcephaly in most patients, and cognitive impairment ranging from learning disabilities to severe mental retardation have also been described. The paroxysmal events may be exacerbated by fasting and fatigue and may respond poorly to conventional antiepileptic drugs. In vitro tests have revealed aggravation of the SLC2A1 transport defect by barbiturates and methylxanthines, suggesting that phenobarbital and caffeinated foods be avoided. The ketogenic diet is highly effective in controlling seizures but does not appear to improve the neurobehavioral outcome of this condition. Nonclassic phenotypes include patients without clinical seizures who have predominant symptoms of mental retardation, ataxia, spasticity, choreoathetosis, or dystonia. A low CSF glucose level (<40 mg/dL) and a low-normal or low CSF lactate concentration (<1.4 nM) in the absence of systemic hypoglycemia are virtually diagnostic. Positron emission tomography (PET) scans have demonstrated very characteristic patterns of global reductions in glucose uptake, with more severe hypometabolism found in the medial temporal lobes and thalamic nuclei. Measurement of the glucose uptake into erythrocytes, which depends on the same SLC2A1 transporter, provides further confirmatory testing. Genetic testing with fluorescence in situ hybridization for microdeletions has a low sensitivity and must be followed by full genomic analysis [Pascual et al., 2004].

161

80 60 40 20 0

0

1

10

100 Age (d)

1000

FIGURE 10-7. Age-related concentrations of cerebrospinal fluid (CSF) protein. Total CSF protein levels (mg/dL) in healthy children are plotted as means ± standard deviation versus logarithmic age (days).

50 mg/dL in the lumbar sac [Merritt and Fremont-Smith, 1938]. This concentration gradient results from regional differences in the permeability of the blood-CSF barrier. A slight increase in lumbar CSF protein content, between 45 mg/dL and 75 mg/dL in older infants and adults, occurs with multiple neurologic conditions associated with bloodbrain barrier breakdown, a process often visualized on neuroimaging as contrast enhancement and vasogenic cerebral edema. Higher CSF protein concentrations (>500 mg/dL) occur in patients with meningitis and subarachnoid hemorrhage, and these levels may decrease the rate of protein absorption from the CSF, leading to further elevation of protein levels [Prockop and Fishman, 1968]. With a spinal cord tumor, arachnoiditis, and other reasons for complete spinal CSF obstruction, very high CSF protein levels are caused by poor CSF outflow and local breakdown of the blood-brain barrier. A loculated CSF collection with sufficient fibrinogen content to allow clot formation, frequently seen when the total protein concentration rises above 1 gram/dL, is known as Froin’s syndrome. Table 10-4 shows the elevations in CSF protein content found in adults with various neurologic disorders [Merritt and Fremont-Smith, 1938]. Electrophoresis separates plasma and CSF proteins into groups of similar molecular weight and electrical charge, classically defined as the prealbumin, albumin, and globulin (alpha1, alpha2, beta1, beta2, tau, and gamma) fractions. Such testing demonstrates that, compared with plasma, normal CSF has relatively higher prealbumin (transthyretin) and tau globulin fractions and a lower gamma globulin fraction [Werner, 1969]. This CSF-specific electrophoresis pattern has been exploited for the identification of CSF otorrhea and rhinorrhea [Porter et al., 1992]. Transthyretin is made by the choroid plexus, which accounts for its increased concentration in the CSF [Herbert et al., 1986]. Changes in the CSF concentrations of a number of specific proteins can accompany brain injury from inflammatory, traumatic, cerebrovascular, epileptic, and neurodegenerative disorders. Several such markers of brain injury have been investigated, including the 72-kDa heat shock

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TABLE 10-4 Total Lumbar Cerebrospinal Fluid Protein in Adults with Neurologic Disease DIAGNOSIS

N

NORMAL <45 mg/dL

MILD TO 45-100 mg/dL

HIGH 100-500 mg/dL

VERY HIGH >500 mg/dL

Spinal cord tumor Bacterial meningitis Cerebral hemorrhage Polyneuritis Head trauma Tuberculous meningitis Brain tumor Aseptic meningitis Brain abscess Myxedema Idiopathic epilepsy

36 157 247 211 474 253 182 81 33 51 793

5 (14)* 3 (2) 34 (14) 107 (51) 255 (54) 2 (1) 56 (31) 37 (46) 9 (27) 12 (24) 710 (90)

7 (19) 19 (12) 73 (30) 50 (24) 127 (27) 67 (26) 67 (37) 27 (33) 18 (54) 31 (61) 82 (10)

14 (39) 100 (64) 95 (39) 44 (21) 73 (15) 172 (73) 57 (31) 17 (21) 6 (18) 8 (16) 1

10 (28) 35 (22) 45 (18) 10 (5) 19 (4) 12 (5) 2 (1) 0 0 0 0

Immunologic Analysis Increases in CSF immunoglobulins, particularly immunoblobulin G, are seen with many inflammatory, infectious, and neoplastic conditions of the central nervous system. This increase is in large part a reflection of the impaired blood-CSF barrier, permitting increased entry into the CSF of all proteins, including albumin. Specific intrathecal production of immunoglobulin G may also occur in these conditions and can often be demonstrated qualitatively with tests for oligoclonal banding and quantitatively with calculations such as the immunoglobulin G index. Testing for oligoclonal bands uses isoelectric focusing and immunolabeling to look for discrete separation of the CSF immunoglobulin G. This separation occurs when clonal expansion of activated B cells leads to the production of immunoglobulin G antibodies against a small set of antigens. In normal test subjects, immunoglobulin G is homogeneously distributed, or it forms a monoclonal band [Wurster, 2004]. The presence of more than two clonal bands suggests an active humoral immune response. If oligoclonal bands are seen in the CSF but not in a simultaneously collected plasma sample, the immune response is considered to be of intrathecal origin [Siemes et al., 1981]. An example of a positive test result for intrathecal oligoclonal bands is provided in Figure 10-8.

Gamma

Beta

Alpha 2

Alpha 1

Albumin

protein (HSP70) [Lai et al., 2004], aggregated beta amyloid [Olsson et al., 2004], neuron-specific enolase [Lima et al., 2004], S-100β [Hayakata et al., 2004], tau protein [Franz et al., 2003], vascular endothelial growth factor [Shore et al., 2004], glial fibrillary acidic protein [Gurnett et al., 2003], brain-derived growth factor and nerve growth factor [Chiaretti et al., 2003], apolipoprotein E [Kay et al., 2003], interleukin-6 [Singhal et al., 2002], soluble FAS receptor [Lenzlinger et al., 2002], and BCL2 [Clark et al., 2000]. Other chemicals altered in patients with significant brain injury include free fatty acids [Pilitsis et al., 2003], the lipid peroxidation marker F2-isoprostane [Varma et al., 2003], and the excitatory neurotransmitters glutamate and glycine [Zhang et al., 2001]. Such detailed CSF analysis has added to our understanding of the pathophysiology of brain injury and holds great potential for future clinical use in diagnosis and prognosis [Siman et al., 2004].

⫹

*Data are reported as number (percentage). Adapted from Merritt and Fremont-Smith, 1938.

⫺

Plasma

CSF

FIGURE 10-8. Cerebrospinal fluid (CSF) protein oligoclonal bands. Protein isoelectric focusing of the plasma demonstrates a normally distributed scattering of gamma globulins, whereas isoelectric focusing of the CSF produces two discrete clonal groups (arrowheads) in the gamma globulin fraction. (Courtesy of Dr. Mark Braun, Indiana University School of Medicine, accessed at http://medsci.indiana.edu/c602web/602/start.htm.)

The immunoglobulin G index and immunoglobulin G synthesis rate compare simultaneous measurements of plasma and CSF immunoglobulin G and albumin concentrations to estimate the amount of intrathecal immunoglobulin G production [Link and Tibbling, 1977; Tourtellotte et al., 1980]. The immunoglobulin G index calculation is simple: ([IgG]CSF / [IgG]plasma) / ([Alb]CSF / [Alb]plasma) More complex is the formula for calculating the immunoglobulin G synthesis rate, an estimate of the daily production of intrathecal immunoglobulin G (expressed as milligrams per day), which incorporates several constants derived from the study of normal subjects: 0.5 × {[IgGCSF] − ([IgGS]/369) − {([AlbCSF] − ([AlbS]/230)) × ([IgGS]/[AlbS]) × 0.43}} Among patients with clinically definite multiple sclerosis, for example, up to 95% have intrathecal oligoclonal bands, and more than 70% have an elevated immunoglobulin G index. Such tests are highly sensitive and highly predictive of multiple sclerosis when supported by appropriate clinical and radiologic findings. However, they are nonspecific in isolation. Positive intrathecal oligoclonal bands are demon-

Michelson / Spinal Fluid Examination

strated for patients with postinfectious encephalomyelitis, subacute sclerosing panencephalitis, progressive multifocal leukoencephalopathy, human immunodeficiency virus encephalitis, Lyme disease, and other disorders from which multiple sclerosis must sometimes be differentiated [Olsson, 1994]. Some reports suggest that more detailed analysis of CSF immunoglobulins, such as measuring the kappa-tolambda ratio of immunoglobulin free light chains, may be useful in the diagnosis and prognosis of multiple sclerosis [Jenkins et al., 2001]. Specific antineuronal antibodies may be found in a wide range of neurologic conditions but most commonly are associated with paraneoplastic diseases [Vianello et al., 2004].

Neurometabolic Studies The usual laboratory evaluation of a child with unexplained encephalopathy consists of plasma, urine, and radiologic studies. When CSF is collected as a part of the evaluation, metabolic tests can be done, including lactate, pyruvate, and quantitative amino acid measurement [Hoffmann et al., 1998]. Proper collection and handling of the CSF is even more important in this context to avoid spurious test results. Some syndromic presentations suggest additional CSF tests. For example, organic acid analysis of the CSF is indicated when a child has a presentation suggesting an organic aciduria but has had repeatedly normal plasma and urine test results. Suspected early-onset nonketotic hyperglycinemia is confirmed by an elevated CSF glycine concentration or CSF-to-plasma glycine ratio on a quantitative test for CSF amino acids [Applegarth and Toone, 2001]. Patients with neuroimaging features of the Aicardi-Goutieres syndrome, a leukoencephalopathy of infantile onset with progressive basal ganglia calcification, can be tested for CSF interferon-α elevation and lymphocytosis [Lanzi et al., 2003]. Pediatric neurotransmitter diseases (see Chapter 30) may be suspected in patients with unexplained seizures, encephalopathy, dysautonomia, extrapyramidal symptoms, or intermittent ocular abnormalities, such as oculogyric crises or convergence spasms [Hyland, 2003]. Defects have been recognized in most of the enzymes involved in monoamine neurotransmitter synthesis, including tryptophan hydroxylase, which converts tryptophan to 5-hydroxytryptophan (5-HT); tyrosine hydroxylase, which converts tyrosine to L-hydroxyphenylalanine (L-dopa); and aromatic L-amino acid decarboxylase, which converts 5-HT to serotonin and L-dopa to dopamine. Tetrahydrobiopterin (BH4) is a crucial cofactor for the tryptophan and tyrosine hydroxylases, and neurotransmitter disorders may arise from defective BH4 synthesis from neopterin, as occurs in guanosine triphosphate-cyclohydrolase I deficiency (i.e., Segawa’s disease), or from defective recycling of dihydrobiopterin (BH2), as with dihydropteridine reductase deficiency. These disorders can usually be distinguished using clinically available CSF tests for BH4, neopterin, and the neurotransmitter metabolites 5hydroxyindolacetic acid (5-HIAA, derived from serotonin), homovanillic acid (derived from dopamine), and orthomethyldopa (derived from L-dopa). CSF samples for these tests must be carefully collected into specially treated tubes and snap frozen at the bedside in dry ice or liquid nitrogen. Disordered γ-aminobutyric acid (GABA) synthesis may result from succinic semialdehyde dehydrogenase defi-

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ciency, which can be diagnosed through careful urine or CSF testing for GABA hydroxybutyrate. The diagnosis of less common GABA disorders, such as GABA transaminase deficiency and homocarnosinosis, primarily depends on CSF testing [Pearl and Gibson, 2004]. Details about the indications for and interpretation of these and other metabolic tests are discussed in later chapters of this textbook. REFERENCES Adler MD, Comi AE, Walker AR. Acute hemorrhagic complication of diagnostic lumbar puncture. Pediatr Emerg Care 2001;17:184. Applegarth DA, Toone JR. Nonketotic hyperglycinemia (glycine encephalopathy): Laboratory diagnosis. Mol Genet Metab 2001;74:139. Berrettini WH, Simmons-Alling S, Nurnberger JI Jr. Epidural blood patch does not prevent headache after lumbar puncture. Lancet 1987;8537:856. Bhisitkul DM, Hogan AE, Tanz RR. The role of bacterial antigen detection tests in the diagnosis of bacterial meningitis. Pediatr Emerg Care 1994;10:67. Bonadio WA, Smith DS, Goddard S, et al. Distinguishing cerebrospinal fluid abnormalities in children with bacterial meningitis and traumatic lumbar puncture. J Infect Dis 1990;162:251. Carp H, Bailey S. The association between meningitis and dural puncture in bacteremic rats. Anesthesiology 1992;76:739. Chiaretti A, Piastra M, Polidori G, et al. Correlation between neurotrophic factor expression and outcome of children with severe traumatic brain injury. Intensive Care Med 2003;29:1329. Clark D. Lumbar puncture. In: Nelson W, ed. Textbook of pediatrics, 9th ed. Philadelphia: WB Saunders, 1969. Clark RS, Kochanek PM, Adelson PD, et al. Increases in bcl-2 protein in cerebrospinal fluid and evidence for programmed cell death in infants and children after severe traumatic brain injury. J Pediatr 2000;137:197. Corbett JJ, Mehta MP. Cerebrospinal fluid pressure in normal obese subjects and patients with pseudotumor cerebri. Neurology 1983;33:1386. Cousins MJ, Brazier D, Cook R. Intracranial hypotension caused by cervical cerebrospinal fluid leak: Treatment with epidural blood patch. Anesth Analg 2004;98:1794. Cowan F, Whitelaw A. Acute effects of acetazolamide on cerebral blood flow velocity and PCO2 in the newborn infant. Acta Pediatr Scand 1991;80:22. Cserr HF, Cooper DN, Milhorat TH. Flow of cerebral interstitial fluid as indicated by the removal of extracellular markers from rat caudate nucleus. In: Bito L, Davson H, eds. The ocular and cerebrospinal fluids. New York: Academic Press, 1977. Davson H, Welch K, Segal HB. The physiology and pathophysiology of the cerebrospinal fluid. New York: Churchill Livingstone, 1987. De Vivo DC, Trifiletti RR, Jacobson RI, et al. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N Engl J Med 1991;325:703. DeAngelis LM, Cairncross JG. A better way to find tumor in the CSF? Neurology 2002;58:339. Donald PR, Burger PJ, Becker WB. Mumps meningo-encephalitis. S Afr Med J 1987;71:283. Dyken PR, Mulina JL. The normal cellular population of the cerebrospinal fluid by sedimentation-flocculation techniques at various ages. Proc Child Neurol Soc 1973;2:26. Ebinger F, Kosel C, Pietz J, Rating D. Strict bed rest following lumbar puncture in children and adolescents is of no benefit. Neurology 2004;62:1003. Epstein MH, Feldman AM, Brusilow SW. Cerebrospinal fluid production: Stimulation by cholera toxin. Science 1977;196:1012. Evans RW. Complications of lumbar puncture. Neurol Clin 1998;16:83. Faraci FM, Kinzenbaw D, Heistad DD. Effect of endogenous vasopressin on blood flow to choroid plexus during hypoxia and intracranial hypertension. Am J Physiol 1994;266:H393. Ferrante E, Savino A, Sances G, Nappi G. Spontaneous intracranial hypotension syndrome: Report of twelve cases. Headache 2004;44:615. Fishman RA. Cerebrospinal fluid in diseases of the nervous system, 2nd ed. Philadelphia: WB Saunders, 1992. Fishman RA. Carrier transport of glucose between blood and the cerebrospinal fluid. Am J Physiol 1964;206:836.

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Franz G, Beer R, Kampfl A, et al. Amyloid beta 1-42 and tau in cerebrospinal fluid after severe traumatic brain injury. Neurology 2003;60:1457. Go KG. The normal and pathological physiology of brain water. Adv Tech Stand Neurosurg 1997;23:47. Grant R, Condon B, Hart I, et al. Changes in intracranial CSF volume after lumbar puncture and their relationship to post-LP headache. J Neurol Neurosurg Psychiatry 1991;54:440. Graves P, Sidman R. Xanthochromia is not pathognomonic for subarachnoid hemorrhage. Acad Emerg Med 2004;11:131. Greenlee JE. Approach to diagnosis of meningitis: Cerebrospinal fluid evaluation. Infect Dis Clin North Am 1990;4:583. Greitz D, Hannerz J. A proposed model of cerebrospinal fluid circulation: Observations with radionuclide cisternography. Am J Neuroradiol 1996;17:431. Gurnett CA, Landt M, Wong M. Analysis of cerebrospinal fluid glial fibrillary acidic protein after seizures in children. Epilepsia 2003;44:1455. Guyton AC. The cerebrospinal fluid system. In: Guyton AC, ed. Textbook of medical physiology, 4th ed. Philadelphia: WB Saunders, 1971. Hannerz J, Ericson K, Bro Skejo HP. MR imaging with gadolinium in patients with and without post-lumbar puncture headache. Acta Radiol 1999;40:135. Hasbun R, Abrahams J, Jekel J, et al. Computed tomography of the head before lumbar puncture in adults with suspected meningitis. N Engl J Med 2001;345:1727. Hayakata T, Shiozaki T, Tasaki O, et al. Changes in CSF S100B and cytokine concentrations in early-phase severe traumatic brain injury. Shock 2004;22:102. Herbert J, Wilcox JN, Kim-Thu C, et al. Transthyretin. A choroid plexus-specific transport protein in human brain. Neurology 1986;36:900. Herndon RM and Brumback RA. The cerebrospinal fluid. Boston: Kluwer Academic Publishers, 1989. Hochwald GM. Cerebrospinal fluid. In: Baker AB, Baker LH, eds. Clinical neurology. New York: Harper & Row, 1984. Hoffman GF, Surtees RA, Wevers RA. Cerebrospinal fluid investigations for neurometabolic disorders. Neuropediatrics 1998;29:59. Hyland K. The lumbar puncture for diagnosis of pediatric neurotransmitter diseases. Ann Neurol 2003;54:S13. Inamasu J, Nakamura Y, Orii M, et al. Treatment of spontaneous intracranial hypotension secondary to C-2 meningeal cyst by surgical packing—case report. Neurol Med Chir (Tokyo) 2004;44:326. Jenkins MA, Cheng L, Ratnaike S. Multiple sclerosis: Use of light-chain typing to assist diagnosis. Ann Clin Biochem 2001;38:235. Johanson CE, Palm DE, Dyas ML, et al. Microdialysis analysis of effects of loop diuretics and acetazolamide on chloride transport from blood to CSF. Brain Res 1994;641:121. Jordan GW, Statland B, Halsted C. CSF lactate in diseases of the CNS. Arch Intern Med 1983;143:85. Kaur G, Gupta P, Kumar A. A randomized trial of eutectic mixture of local anesthetics during lumbar puncture in newborns. Arch Pediatr Adolesc Med 2003;157:1065. Kay AD, Petzold A, Kerr M, et al. Cerebrospinal fluid apolipoprotein E concentration decreases after traumatic brain injury. J Neurotrauma 2003;20:243. Kirkpatrick D, Goodman SJ. Combined sub-arachnoid and subdural spinal hematoma following spinal puncture. Surg Neurol 1975;3:109. Kozlowski GP. Ventricular route hypothesis and peptide-containing structures of the cerebroventricular system. Front Horm Res 1982;9:105. Lai Y, Kochanek PM, Adelson PD, et al. Induction of the stress response after inflicted and non-inflicted traumatic brain injury in infants and children. J Neurotrauma 2004;21:229. Lanzi G, D’Arrigo S, Drumbl G, et al. Aicardi-Goutieres syndrome: Differential diagnosis and aetiopathogenesis. Funct Neurol 2003;18:71. Lenzlinger PM, Marx A, Trentz O, et al. Prolonged intrathecal release of soluble Fas following severe traumatic brain injury in humans. J Neuroimmunol 2002;122:167. Levinson A. Cerebral spinal fluid in infants and children. Am J Dis Child 1928;36:799. Lima JE, Takayanagui OM, Garcia LV, et al. Use of neuron-specific enolase for assessing the severity and outcome in patients with neurological disorders. Braz J Med Biol Res 2004;37:19. Lin W, Geiderman J. Myth: Fluids, bed rest, and caffeine are effective in preventing and treating patients with post-lumbar puncture headache. West J Med 2002;176:69.

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CHAPTER 11

Pediatric Neuroimaging Nathaniel D. Wycliffe, Joseph R. Thompson, Barbara A. Holshouser, and Stephen Ashwal

A clear understanding of various clinical signs and symptoms of neurologic diseases in children and knowledge of normal neuroanatomy and its alterations in various disease processes are prerequisites for the correct performance and interpretation of the many powerful neuroimaging techniques that are available. Different modalities of neuroimaging continue to evolve, with better resolution in two-dimensional and threedimensional depiction of anatomy and its aberrations in disease processes in the field of pediatric ultrasound (sonography), computed tomography (CT), and magnetic resonance imaging (MRI). Even though these remain the mainstay of pediatric neuroimaging, the techniques, interpretation, and usefulness of functional neuroimaging have been improved by development of other methods, including diffusionweighted imaging, perfusion-weighted imaging, MR spectroscopy, single-photon emission computed tomography (SPECT), positron emission tomography (PET), and blood oxygen level-dependent functional MRI (fMRI). These advanced imaging techniques are becoming increasingly available to the clinicians for evaluation of pediatric neurologic diseases. Ultrasonography is used extensively for prenatal evaluation of the unborn child and in the neonatal period for evaluation of suspected intraventricular hemorrhage, hydrocephalus, and other developmental anomalies, with CT or MRI used to clarify uncertain findings. During late infancy, childhood, and adolescence, when ultrasound is no longer practical, CT is used in the emergency setting for the evaluation of trauma, stroke, and raised intracranial pressure and for examination after placements of ventricular shunts. CT is still the examination of choice for the detection of acute hemorrhage and lesions containing calcium. In most centers, CT is used as the initial examination for evaluation of closed-head or spine injury because of its superior ability to demonstrate acute hemorrhage or osseous injury. CT is more commonly used than MRI as the initial method for evaluating children presenting with seizures in the emergency department. MRI can be used when the results of CT are uninformative or used for better delineation of lesions identified on CT; however, for children, MRI requires more extensive monitoring, sedation, or general anesthesia. MRI is superior to other available imaging modalities for the detection of hypoxic-ischemic insults, white matter abnormalities, subacute and chronic central nervous system hemorrhages, lesions causing seizures including mesial temporal sclerosis, migrational anomalies, and other developmental malformations. For the evaluation and follow-up of central nervous system neoplasms, MRI is the examination of choice. An overview of the strength and weaknesses of pediatric ultrasound, CT, and MRI is provided in this chapter. A

discussion of the neuroimaging changes associated with normal brain development is beyond the scope of this chapter, but several excellent monographs are available [Ball, 1997; Barkovich, 2005; Siegel, 2001].

CRANIAL ULTRASOUND In the perinatal period, the real-time sonogram is probably the most frequently used radiologic modality for neuroimaging. Sonography is portable, fast, and multiplanar, and it can be performed at the bedside of sick newborns. To produce a sonogram, pulses of nonionizing ultrasound at a frequency of 3.5 to 10 MHz are applied by a transducer to the area of interest. The ultrasound waves are reflected at different amplitudes from organ and tissue interfaces. A reflected sound wave or echo is represented as a dot, with the gray shade or brightness of the dot proportional to the strength of the returning echo and the location of the dot related to the depth of the reflecting structure. B-mode scanning (i.e., brightness mode), which has been largely supplanted by real-time ultrasound, is done by moving the transducer over an area of interest while data are collected and summated over time to produce a twodimensional, gray-scale image. Real-time instruments that

FIGURE 11-1. A 1600-gram newborn at 31 weeks’ estimated gestational age. The ultrasound scan of the head was obtained at 1 day of age and demonstrates a large, subdural hemorrhage in the occipital region. This left parasagittal image demonstrates the superior portion of the subdural hemorrhage, shown as a sonolucent fluid collection with the dependent portion containing cellular debris (white arrow), which has inhomogeneous echogenicity similar to the brain parenchyma. Parasagittal anatomy of the cerebral hemisphere (curved white arrow), left lateral ventricle (curved black arrow), tentorium (open white arrow), and the cerebellum (black arrow) can be seen.

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FIGURE 11-2. Ultrasound scan of the head of a 1-day-old infant born at 31 weeks’ estimated gestational age. Coronal ultrasound demonstrates a grade III intraventricular hemorrhage, revealing highly echogenic material that is consistent with hemorrhage within the lateral ventricles and the third ventricle extending through the foramina of Monro (arrows). The lateral ventricles and the third ventricle are enlarged.

FIGURE 11-3. Ultrasound scan of the head of a 3-day-old newborn at 25 weeks’ estimated gestational age. Coronal ultrasound demonstrates highly echogenic material within the ventricles that are dilated (arrows). This finding defines a grade III intraventricular hemorrhage; however, the patient also had an intraparenchymal hemorrhage, indicating that this is a grade IV hemorrhage.

FIGURE 11-4. Ultrasound scan of the head of an 8-day-old newborn of 26 weeks’ estimated gestational age reveals a grade III, castlike hemorrhage in the lateral ventricle, including the atrium and the temporal horn (arrowheads) on the left parasagittal image. The enlarged ventricle is almost completely filled with the clot.

FIGURE 11-5. Follow-up ultrasound scan of the head of a 3-month-old infant born at 24 weeks’ estimated gestational age with a birth weight of 596 grams. The infant had a grade IV intraventricular hemorrhage in the newborn period. This right parasagittal image shows persistent dilation of the lateral ventricle and a retracting clot in the occipital horn of the right lateral ventricle (arrow).

produce several images per second when displayed rapidly give the impression of constant motion and are more commonly used and referred to as real-time, gray-scale sonography. Another method, duplex Doppler sonography, is a powerful tool for the evaluation of vascular flow. Another improvement, color Doppler ultrasonography, can provide real-time imaging of tissue morphology in gray scale like duplex Doppler, while simultaneously displaying color-coded vascular flow to provide flow direction and velocity information. Sonography is used extensively for the prenatal evaluation of the fetus, taking advantage of the nonionizing character of sound waves. In newborns, the open anterior fontanel provides an excellent window for the evaluation of the infant brain. No contrast agent is needed for the evaluation of the central nervous system with sonography, and sedation is not required in most instances. The real-time nature of the examination is of great help in obtaining

images from patients who cannot sustain breath holding, are uncooperative, or are crying. The images are available immediately for interpretation. Real-time sonography can display echogenic (bright) structures, such as choroid plexus, hemorrhage (Figs. 11-1 to 11-5), some tumors, and focal areas of cerebritis, and sonolucent structures, such as cerebrospinal fluid in the ventricles (Fig. 11-6), subarachnoid spaces, cysts (Figs. 11-7 and 11-8), and cystic lesions (Fig. 11-9) [Siegel, 2001]. Normal brain gives rise to fairly uniform echogenicity. Several limitations in the use of ultrasound exist. The technique is operator dependent, but this dependency can be less of a drawback when the experience and efficiency of the sonographer improves. Ultrasound requires a soft tissue–transducer interface and a sonographic window that is not blocked by bone or air because the sound waves are

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FIGURE 11-6. Coronal ultrasound scan of the head of a 1-day-old infant born at 37 weeks’ estimated gestational age by cesarean section with a birth weight of 2986 grams. The infant had hydrocephalus prenatally, and this examination demonstrates massively dilated lateral ventricles (arrows). The fourth ventricle was not enlarged, and follow-up magnetic resonance imaging revealed aqueductal stenosis.

FIGURE 11-8. Right parasagittal ultrasound scan of the head of a 2-month-old infant of 25 weeks’ estimated gestational age demonstrates a cystic area in the peritrigonal region (arrow) that is consistent with periventricular leukomalacia.

unable to penetrate these barriers. Despite these limitations, ultrasound can be used with great advantage in infants up to approximately 1 year of age who have open fontanels and cartilaginous laminae and in older children through a craniotomy or laminectomy. Detection of fetal central nervous system anomalies has significantly increased in the last 10 to 15 years because of the availability of high-resolution ultrasound equipment and the improvement in scanning techniques [Angtuaco et al., 1994]. Transabdominal and endovaginal ultrasound can document early first trimester development and compare it with known embryologic landmarks. The wide array of central nervous system pathology detected by prenatal sonography includes fetal seizures [Abrams and Balducci, 1996], holoprosencephaly [Stagiannis et al., 1995], encephalocele [Budorick et al., 1995], schizencephaly [Klingensmith and Cioffi-Ragan, 1986], lissencephaly and hydrocephaly (see

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FIGURE 11-7. Coronal ultrasound scan of the head of a 4-week-old infant, who was born by cesarean section after fetal distress with the cord around the neck, reveals septate cystic areas in the periventricular white matter (arrows) in the left parietal lobe that are consistent with periventricular leukomalacia.

FIGURE 11-9. Midline sagittal ultrasound scan of a newborn female shows a large posterior fossa cyst (solid arrows) consistent with a Dandy-Walker variant. The lateral (curved arrow) and the third ventricles (open arrow) are enlarged.

Fig. 11-6) [Holzgreve et al., 1993; Roume et al., 1990], Dandy-Walker malformation (see Fig. 11-9) [Cowles et al., 1993], spina bifida [Thiagarajah et al., 1990], and congenital astrocytoma [Heckel et al., 1995]. Postnatally, sonography is very helpful in the evaluation of hypoxic-ischemic encephalopathy [Anand et al., 1994], including complications of hemorrhage into the germinal matrix, ventricles, or surrounding parenchyma [Volpe, 1989]. For all infants of younger than 30 weeks’ gestation, routine cranial ultrasonography screening should be performed once between 7 and 14 days of age and should be repeated optimally between 36 and 40 weeks’ postmenstrual age [Ment et al., 2002]. This strategy detects lesions such as intraventricular hemorrhage, which influences clinical care, and those such as periventricular leukomalacia and ventriculomegaly, which provide information about long-term neurodevelopmental outcome [Ment et al., 2002]. Ultrasound can also screen for developmental malformations and for intrauterine infections and to determine the cause of an enlarging

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or enlarged head [Smith et al., 1998]. Ischemic white matter injury, periventricular leukomalacia (see Figs. 11-7 and 11-8), and cystic encephalomalacias are assessed by ultrasound [Rodriguez et al., 1990], but this approach may not reveal the full extent of injury [Huppi, 2004; Inder et al., 2003; Miller et al., 2003]. Progression or resolution of intracranial hemorrhage and some of its sequelae, such as hydrocephalus, can be monitored using sonography (see Fig. 11-5). Lesions containing cerebrospinal fluid or cerebrospinal fluid–like contents are well delineated because of the echo lucency of water [Chuang and Harwood-Nash, 1986]. Examples include ventriculomegaly (see Fig. 11-6), porencephaly, Dandy-Walker syndrome (see Fig. 11-9), arachnoid cyst, and encephalocele. Vascular malformations, especially aneurysms of the vein of Galen, can be well demonstrated with color Doppler ultrasound. Subtle differences between certain types of lesions, such as differentiation of hydranencephaly from severe hydrocephalus, may not be detected by ultrasound. Major migrational anomalies, such as agyriapachygyria and lissencephaly, may be delineated by ultrasound; however, smaller heterotopias or other subcortical dysplasias may be overlooked [Trounce et al., 1986]. Ultrasound is helpful in the evaluation of a newborn suspected of having tuberous sclerosis as it can detect the intracranial hamartomas or subependymal nodules seen in this condition [Tatsuno et al., 1993]. Sonography can be used to screen for myelodysplasia in early infancy, to demonstrate the level of the conus medullaris, and to evaluate newborns suspected of having closed spinal dysraphism (see Chapter 19 for ultrasound examples) [Toma and Rossi, 2001]. It can also reveal the presence or absence of cord pulsations, a sign of tethering, when viewed through the cartilaginous spinal laminae and the infraspinous gaps, which act as sonographic windows. Other dysraphic lesions, such as meningocele, lipoma, hydromyelia, Arnold-Chiari II malformation [DiPietro et al., 1987], diastematomyelia, and lipomyelomeningocele, also can be delineated. Occasionally, sonography is necessary postoperatively to determine the absence of cord pulsations, a finding that suggests cord retethering. Intraoperative sonography is an important modality for the safe and specific guidance of neurosurgical biopsy or lesion resection by separating the lesion from the surrounding edema. It also is used for the accurate placement of ventricular shunts [Kellnar et al., 1989], drainage of intraparenchymal fluid collections, localization of brain or cord tumors, drainage of hydrosyringomyelias, or the delineation of posttraumatic intraspinal bone fragments. Doppler sonography is used intraoperatively for monitoring resection of arteriovenous malformations during surgery and at the bedside or in the clinic to evaluate arterial patency, direction, and volume of flow and to calculate a resistive index [Lindegaard et al., 1993; Manchola et al., 1993]. Doppler sonography is used to evaluate the intracranial circulation during or after extracorporeal membrane oxygenation to detect ischemic or hemorrhagic injury. In patients with subarachnoid hemorrhage, transcranial Doppler ultrasound can be used to detect vasospasm before the patient suffers ischemic neurologic deficit or infarct [Topceuoglu et al., 2002]. It is a standard technique to determine the absence of cerebral blood flow in patients for whom the diagnosis of brain death is suspected.

COMPUTED TOMOGRAPHY CT has been available since the 1970s for clinical use in children. Ionizing radiation due to x-ray CT is effectively restricted to the immediate body part of interest by the tight collimation used to create the thin fan beam used for scanning. Considerable technical developments have taken place with CT in the past 3 decades. Several generations of scanners are available, including the helical CT introduced in the early 1990s and the multidetector or multislice scanner. This availability has resulted in an increased number of computed tomographic scans of children, increasing the potential for inappropriate use and excessive radiation dosing [Frush et al., 2003]. Some data indicate that low-dose radiation, similar to the amount received with CT, may be associated with a significant risk of cancer, especially in young children. Children have a longer lifetime in which to manifest radiation-related cancer, and the cancer risk from CT is cumulative over a lifetime. Each computed tomographic examination contributes to the lifetime exposure. It is necessary to limit radiation from CT in children and follow the ALARA (“as low as reasonably achievable”) principle. Several strategies can be followed toward this goal, including performing only necessary examinations, considering alternative imaging modalities such as ultrasonography and MRI when possible, limiting the region of coverage, and adjusting individual imaging parameters, depending on indication, region imaged, and size of the child [Frush et al., 2003]. The digital tomographic image is composed of a matrix of voxels (i.e., pixels with volume resulting from the finite thickness of the tomogram). Each voxel is assigned a numeric value called a CT number, which is related to the tissue density. Most systems express CT numbers in Hounsfield units, with water used as a reference and assigned a value of zero. Fatty tissues with densities less than water have negative CT numbers, whereas positive CT numbers indicate a tissue density greater than water. Most soft tissue elements have positive CT numbers. Calcium, mineralized bone, concentrated blood elements, and iodine in contrast-enhanced structures have CT numbers higher than most soft tissues. CT has good soft tissue resolution and is especially useful along high-contrast interfaces, such as air-water, fat-water, and bone-water in the orbits, sinuses, and temporal bones. CT is limited by streaking artifacts in areas adjacent to thick bone or metallic objects such as dental fillings and gunshot wound pellets. These Hounsfield artifacts are particularly troublesome in the posterior fossa because of the dense temporal petrous bones. CT scanners are fast and widely available for emergencies and for medically unstable patients. Direct scanning is routinely performed in the axial plane. Provided the child can cooperate for neck-extension positioning, computed tomographic scanning can be done in the coronal plane for evaluation of specific disorders. Multiplanar reformatting of axial image data can be accomplished with the software available for most scanners; however, reformatted images have less resolution. Direct coronal computed tomographic examinations can be obtained for the enhanced evaluation of the orbits, sinuses, temporal bones, and temporomandibular joints. Coronal plane images can be used to evaluate patients for

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intrasellar, skull-based, midline, or vertex intracranial lesions. Three-dimensional reconstructions using a surface-rendering algorithm for bone have been useful for surgical planning of craniofacial reconstructions. Abnormalities can be characterized with CT as having low density, isodensity, or high density in relation to the brain. Lesions that appear lower in density include edema, necrosis, infarction (Fig. 11-10), neoplasms, leukodystrophies, inflammation, and cysts. Loss of gray-white matter differentiation may be seen with diffuse brain edema after hypoxic-ischemic injury or a demyelinating process. Fatcontaining lesions usually appear less dense than water or of mixed density, as in patients with a teratodermoid type of

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FIGURE 11-10. A, Non–contrast-enhanced, axial computed tomography of a 19-month-old male who accidentally rammed a pencil into the back of his throat. The child was somnolent and not moving the left side of his body. A large infarct is seen as an area of low attenuation with a mass effect in the right cerebral hemisphere (arrows), primarily in the right middle cerebral artery distribution. B, A lower image demonstrates a hyperdense right middle cerebral artery (arrow) consistent with thrombosis. C, T2-weighted, axial magnetic resonance imaging also demonstrates a large infarct in the right middle cerebral artery distribution. D, A lower image demonstrates a normal flow void in the left middle cerebral artery (white arrow); however, lack of flow void is seen in the right middle cerebral artery (black arrow), which is consistent with thrombosis. E, Lateral projection of the right common carotid artery (arrow) on a contrast-enhanced angiogram demonstrates total occlusion of the right internal carotid artery at its origin. Only branches of the external carotid artery are visualized.

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infarction, or the sequelae of perinatal asphyxia [Erdem et al., 1994]. Hypercellular neoplasms with high nuclear-tocytoplasmic ratios (e.g., medulloblastomas, other primitive neuroectodermal tumors, germinomas, lymphomas) may also appear as high-density lesions on computed tomographic examination. CT in young children usually requires sedation and occasionally enhancement using intravenous

contrast material. CT myelography and CT cisternography can be accomplished with intrathecal contrast material introduced into the subarachnoid space. Computed tomographic imaging can be used for precise localization during needle-biopsy procedures or volumetric resection of pediatric brain tumors [Kelly, 1991]. In the evaluation of neonatal disorders, a non–contrast-enhanced computed tomographic

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FIGURE 11-11. A, Non–contrast-enhanced, axial computed tomography (CT) of the head of a 3-month-old child, who had a head circumference greater than the 99th percentile and a history of apneic spells, reveals a denser-than-brain mass (arrow) in the region of the posterior aspect of the body of the left lateral ventricle, with massive enlargement of the left lateral ventricle and mild enlargement of the right lateral ventricle. The hyperdensity of the mass lesion is caused by calcification. B, After administration of intravenous contrast, there is intense homogeneous enhancement of the mass lesion (arrow) on CT. Excisional biopsy revealed a choroid plexus papilloma. C, After contrast, T1-weighted, axial magnetic resonance imaging (MRI) demonstrates homogeneous, intense enhancement of the lesion (arrow) in a pattern similar that shown by CT. D, After contrast, T1-weighted MRI demonstrates the lesion in the sagittal plane (arrow) with excellent depiction of the surrounding anatomy, which is helpful for surgical planning.

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FIGURE 11-12. Non–contrast-enhanced, axial computed tomography of a 5-day-old male with hemophilia demonstrates a large, right-sided, panhemispheric subdural hemorrhage (white arrows) with diffuse edema (black arrows) in the right cerebral hemisphere, a mass effect, and midline shift.

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Iodinated contrast enhancement is normally seen as a high-density area within the brain and other normal tissues, including vascular and dural structures, pituitary gland, infundibulum, pineal gland, and choroid plexus, but normal parenchymal enhancement usually is too subtle to appreciate. Mechanisms of contrast enhancement include bloodbrain barrier disruption, extravasation of intravascular contrast material, or accumulation of contrast material in areas of hyperperfusion. Rarely, contrast enhancement is nonspecific, and the mechanism of this phenomenon remains poorly understood. Contrast-enhanced CT is helpful in the evaluation of suspected or known vascular malformation, neoplasms (see Fig. 11-11B), abscesses, and empyemas. In infants and children with chronic subdural hematomas, contrast enhancement may reveal an enhancing membrane. Contrastenhanced CT also can be used to differentiate infarction from neoplasm or abscess. Follow-up computed tomographic studies may help distinguish developing infarction from neoplasm. Contrast-only CT may be obtained for serial evaluations of patients with neoplasms, vascular malformations, or suppurative collections. In patients with suspected metastases or seeding of neoplasms, contrast-only CT scan may be sufficient. However, in all the clinical situations previously described, MRI is considered more definitive.

MAGNETIC RESONANCE IMAGING examination after ultrasound is helpful in the evaluation of acute hemorrhage (Figs. 11-12 and 11-13), developmental anomalies (Figs. 11-14 and 11-15), acute trauma (Figs. 11-16 and 11-17), suspected infarction (see Fig. 11-10A), and hydrocephalus or to demonstrate atrophy and mineralization. In neurodegenerative diseases of childhood, CT may reveal decreased attenuation in the basal ganglia and cerebral white matter or focal or generalized cerebral atrophy [Mirowitz et al., 1991]. Non–contrast-enhanced CT can be helpful in evaluating neurocutaneous syndromes to detect calcifications as in tuberous sclerosis (see Fig. 11-15) and for the evaluation of the patient with acute onset of seizures. After closed-head injury, CT without contrast material is usually optimal for evaluation of the skull, intracranial hemorrhage, orbits, sinuses, facial or temporal bones, and osseous spine for fractures or other types of injuries. Evaluation of these regions is of particular importance in the evaluation of young children who are victims of nonaccidental trauma. Non–contrastenhanced CT of the head can rapidly evaluate possible skull fracture and intracranial hemorrhage [Dashti et al., 1999]. Imaging patterns of intracranial hemorrhage in children younger than 3 years have been reported to predict whether the injury was intentional [Wells et al., 2002]. These patterns include subdural hemorrhage located over the cerebral convexities, hemorrhage within the interhemispheric subdural space, hygroma (i.e., nonhemic subdural fluid) with intracranial hemorrhage, and absence of a skull fracture with intracranial hemorrhage [Wells et al., 2002]. If there is a high-risk mechanism of injury, a normal neurologic examination result and maintenance of consciousness do not preclude significant intracranial injury in a pediatric trauma patient. A liberal policy of computed tomographic scanning is warranted for such patients [Simon et al., 2001].

MRI is being recognized increasingly as the most powerful neuroimaging modality for adults and children. It involves no ionizing radiation as in CT and no acoustic window that restricts cranial ultrasound to the period of infancy before the fontanels close. MRI provides multiplanar imaging with excellent resolution without repositioning of the patient or the machine. Bone does not interfere with soft tissue resolution; however, metallic objects often produce signal void or field distortion artifacts. Some ferromagnetic or electronic devices, such as aneurysm clips and pacemakers, contraindicate the use of MRI. MRI has less tolerance for patient movement than CT or ultrasound, and sedation is required for most young children. Sedated and intubated patients require magnetic-compatible monitoring of vital signs and ventilator support. MRI is generally more expensive than CT; however, it is less expensive than more invasive procedures such as angiography, CT myelography, or cisternography, all of which require anesthesia in young children. MRI uses magnetic fields and radiofrequency pulses to obtain high-resolution images of the body. Hydrogen nuclei (protons) are used to generate detectable signals in MRI. MR images are created by sending radiofrequency pulses into a patient lying in an external magnetic field, thereby perturbing hydrogen nuclei into producing signals of various intensities from different body tissues. As in CT, in MRI the resulting signals are mapped onto a gray-scale digital image. However, the intensity of the signals produced in MRI are determined by several factors, such as the proton density, the mobility of the protons within the molecular lattice (T1 relaxation), and the effect of local magnetic fields produced by magnetic nuclei within the tissue (T2 relaxation). Programmed sequences, such as spin echo (SE), inversion

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FIGURE 11-13. A, Non–contrast-enhanced, axial computed tomography (CT) of a 6-year-old male with acute lymphoblastic leukemia who presented at the emergency room with acute onset of lethargy and aphasia. CT demonstrates a hemorrhagic infarct in the left frontal lobe, showing high-density hemorrhage (arrow) and surrounding low attenuation from the edema with a local mass effect. Notice that the lesion extends to the cortical margin. B, Higher cuts demonstrate increased density in the superior sagittal sinus (arrow) that is consistent with superior sagittal sinus thrombosis. C, The two-dimensional, time-of-flight sagittal magnetic resonance venogram demonstrates absent flow (arrows) in the superior sagittal sinus, which is consistent with superior sagittal sinus thrombosis.

C recovery (IR), and gradient-recalled echo (GRE), use a sequence of radiofrequency and gradient magnetic field pulses to acquire images weighted with one of the aforementioned factors. Typically, tissues with short T1 relaxation times, such as fat and intracellular and extracellular methemoglobin, produce a high signal intensity (i.e., bright or hyperintense) on T1-weighted images. Cerebrospinal fluid, muscle, deoxyhemoglobin, and hemosiderin, tissues or substances with long T1 relaxation times, appear dark on T1-weighted images. Tissues or structures with long T2 relaxation times, such as cerebrospinal fluid, edema, many tumors, extracellular methemoglobin, infarcts, and multiple sclerosis plaques, are bright on T2-weighted images, whereas tissues or substances such as muscle, cortical bone, deoxyhemoglobin, and hemosiderin are dark as a result of short T2 relaxation times (see Figs. 11-20, 11-23, and 11-25). Routinely, T1- and T2-weighted images in various planes are obtained and followed by T1-weighted images with contrast if needed. The most commonly used contrast agent

for MRI contains gadolinium. Tissues that take up gadolinium contrast agent produce a bright or hyperintense signal on T1-weighted images. Magnetic resonance angiography (MRA) sequences, which are programmed to show moving protons as bright, are often added to image the vasculature. Faster imaging sequences using advanced systems allow acquisition during breath holding and during functional MRI and diffusion-weighted imaging (described later). MRI should be used as the primary imaging modality for screening patients in whom neurologic disease is suspected because it is generally the most sensitive and specific of the imaging techniques. MRI is the only modality that provides accurate assessment of brain myelination [Bird et al., 1989; Harbord et al., 1990]. Contrast-enhanced MRI is also more sensitive than contrast-enhanced CT for detection of encephalitis [Koelfen et al., 1996], brain abscess (Fig. 11-18), ventriculitis, or small foci of leptomeningeal involvement. MRI is often better than CT in demonstrating traumatic

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injuries, particularly diffuse axonal shearing injury [Mittle et al., 1994], posttraumatic olfactory dysfunction [Yousem et al., 1996], brainstem contusion [Gentry et al., 1988], subacute hemorrhage, encephalomalacia, and gliosis. Certain pathologies including migrational anomalies, such as graymatter heterotopias, closed-lip schizencephaly, lissencephaly,

pachygyria (Fig. 11-19), and hemimeganencephaly [Osborn et al., 1988], and neurocutaneous disorders, such as neurofibromatosis [Es et al., 1996], that are not seen well on CT are better demonstrated with MRI. In children with severe head injury who are comatose, the presence of traumatic brainstem lesions seen on MRI have a high correlation with outcome. CT fails to demonstrate these lesions [Woischneck et al., 2003]. MRI is useful in the evaluation of patients with movement disorders such as Wilson’s disease [King et al., 1996; Magalhaes et al., 1994] because it demonstrates abnormal T2 signal in the basal ganglia, especially the outer rim of the putamen and in the substantia nigra and in juvenile Huntington’s disease revealing atrophy of the caudate nuclei and increased T2 signal in atrophic caudate nuclei [Ho et al., 1995]. In pantothenate kinase deficiency (formerly designated as Hallervorden-Spatz syndrome), MRI demonstrates areas of symmetric low signal intensity in T2-weighted images with high signal intensity in the anteromedial aspect of the globus pallidus, the so-called eye of the tiger sign [Ou et al., 1994; Savoiardo et al., 1993]. MRI shows multifocal cortical infarctions and the presence of lactate peaks in proton MR spectroscopy in mitochondrial disorders, such as MELAS syndrome (i.e., mitochondrial encephalopathy with lactic acidosis and strokelike episodes) [Castillo et al., 1995; Barkovich et al., 1993; Kim et al., 1996; Wycliffe and Skeen, 1997]. In other mitochondrial disorders, such as MERRF syndrome (i.e., myoclonus, epilepsy, and red ragged fibers), Kearns-Sayre syndrome, Leigh’s syndrome, Alpers’ disease, and Menkes’ disease, symmetric white matter T2 hyperintensities with involvement of deep cerebral nuclei are observed on MRI. Patients with Menkes’ disease demonstrate rapidly progressive atrophy accompanied by large subdural hematomas [Barkovich et al., 1993].

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FIGURE 11-14. Non–contrast-enhanced, axial computed tomography of the head of a 2-year-old female with Arnold-Chiari II malformation reveals beaking of the midbrain tectum (arrow).

FIGURE 11-15. A, Non–contrast-enhanced, axial computed tomography of a 7-year-old female with a history of tuberous sclerosis and seizures demonstrates a hyperdense subependymal nodule (arrow) on the wall of the right lateral ventricle. B, A more inferior section of the same patient demonstrates multiple hyperdense subependymal nodules along the walls of the frontal horns of the lateral ventricles (arrows). These are subependymal tubers or hamartomas, which occur in patients with tuberous sclerosis.

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FIGURE 11-17. Non–contrast-enhanced, axial computed tomography of a 15-month-old infant, who was the victim of nonaccidental trauma and was unresponsive at the time of arrival at the emergency room, demonstrates diffuse cerebral edema as depicted by loss of gray and white matter differentiation and by diffuse low attenuation in both cerebral hemispheres. Increased density is delineated along the posterior aspect of the falx (arrow), consistent with intradural hemorrhage along the falx. This kind of hemorrhage can be seen with shaken-infant syndrome.

For focal (Fig. 11-20) and diffuse white matter disease, T2-weighted MRI is more sensitive than CT in demonstrating lesions. MRI should preferentially be used to evaluate children with acute disseminated encephalomyelitis (Fig. 11-21) [Lee et al., 1996], human immunodeficiency virus (HIV) encephalitis, sickle cell disease, vasculitis such

as systemic lupus erythematosus, Lyme disease [Oksi et al., 1996], progressive multifocal leukoencephalopathy, and multiple sclerosis [Guilhoto et al., 1995]. Recognizable patterns of white matter involvement can be seen with MRI in certain inherited leukodystrophies. For example, early, diffuse involvement of the peripheral subcortical white matter is seen in Pelizaeus-Merzbacher disease [Andre et al., 1990], Canavan’s disease, and Alexander’s disease. In Canavan’s disease, patients have macrocephaly, and on proton MR spectroscopy, a larger than normal N-acetyl-aspartate peak is produced. In Alexander’s disease, there is predilection for T2 lengthening in frontal white matter and enhancement after contrast administration. A predilection for occipital white matter involvement is seen with adrenoleukodystrophy. Follow-up MRI examinations have been used for patients with adrenoleukodystrophy to monitor progression of disease symptoms [Loes et al., 1994]. In globoid cell leukodystrophy (i.e., Krabbe’s disease), T2 hyperintensity can be seen in the cerebellum and deep cerebral white matter [Sasaki et al., 1991], whereas the thalami and basal ganglia may be hypointense [Osborn and Tong, 1996]. MRI can demonstrate mesial temporal sclerosis (Fig. 11-22) in seizure patients [Kuzniecky et al., 1996] and can reveal small tumors in the aqueduct, sella turcica [Kelly et al., 1988], or brainstem (Fig. 11-23) even when the CT is normal. Children with mesial temporal sclerosis may have dual pathology with mild to moderate cortical dysplasia and with hippocampal sclerosis that can be visualized with MRI [Mohamed et al., 2001]. Continuing technical advances are reported using four-coil, phased-surface-array MRI that can help obtain high-resolution images of the brain capable of detecting lesions not identified with standard MRI, including hippocampal dysplasia, hippocampal atrophy, and dual pathology with cortical dysplasia. These high-resolution MRI scans are improving the diagnosis of patients who are candidates for surgical treatment for refractory epilepsy [Goyal et al., 2004]. MRI is also the preferred procedure when

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FIGURE 11-18. A, T1-weighted sagittal magnetic resonance imaging (MRI) with contrast of a 22-day-old male with gram-negative meningitis from Citrobacter infection. A large, rim-enhancing abscess cavity ( arrow) is revealed in the left frontal lobe. B, After contrast, T1-weighted axial MRI demonstrates two rim-enhancing abscess cavities (arrows) in the frontal lobes. MRI is an integral part of the evaluation of central nervous system infections, including meningitis, encephalitis, ventriculitis, brain abscess, and opportunistic infections in patients infected with human immunodeficiency virus.

FIGURE 11-19. T1-weighted, sagittal magnetic resonance imaging (MRI) of a 1-day-old male born at 28 weeks’ gestational age with a birth weight of 1270 grams. Evidence of migrational anomaly is depicted by a lack of expected sulcation of the cerebral cortex, which is consistent with pachygyria. MRI is superior to other imaging modalities for evaluation of migrational anomalies.

children present with symptoms and signs that suggest a central nervous system tumor (Fig. 11-24; see Figs. 11-11 and 11-23). In the evaluation of pediatric head and neck lesions, MRI provides valuable additional information

concerning lesions that are difficult to resolve with CT, and it is essential for assessment of possible intracranial extension of disease [Jones and Koch, 1999]. For vascular and hemorrhagic lesions, MRI is more specific than CT or ultrasound. MRA has added a new dimension to the evaluation of pediatric cerebrovascular disease. This noninvasive imaging technique can be used to evaluate vascular malformations, vaso-occlusive disease (see Figs. 11-13C and 11-20B), and vascular neoplasms. MRA may demonstrate occlusions or stenoses of the supraclinoid internal carotid arteries, the proximal anterior and middle cerebral arteries, collateral vessels, and parenchymal lesions in moyamoya disease [Yamada et al., 1995], as well as proximal large vessel stenotic lesions in children with sickle cell disease [Wiznitzer et al., 1990]. MRI may detect silent infarctions in children with Kawasaki’s disease [Fujiwara et al., 1992] or sickle cell disease. In cases of childhood migraine and in sickle cell disease (see Fig. 11-20), MRI may demonstrate small white matter and basal ganglia infarctions not seen on CT. MRI is more specific than CT in the identification and staging of hemorrhage and clot formation as a function of the evolution of hemoglobin breakdown products (Fig. 11-25). MRI can differentiate arterial from venous occlusive disease. Sinovenous thrombosis in children primarily affects neonates and is a serious condition that can result in neurologic impairment or death in approximately half the patients [deVeber and Andrew, 2001]. The presence of a venous infarct or dural sinus thrombosis seen with MR venography predicts a poor outcome. In evaluating intracranial hemorrhage caused by angiographically occult lesions such as cavernous angiomas (see Fig. 11-25), MRI is the procedure of choice. MRI can help to differentiate between various

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FIGURE 11-20. A, T2-weighted, axial magnetic resonance imaging of a 3-year-old male with sickle cell anemia. Multiple focal hyperintensities (arrows) are revealed in the deep white matter of both cerebral hemispheres, indicating small white matter infarcts. B, Three-dimensional, axially oriented, time-offlight angiogram of the circle of Willis demonstrates marked luminal irregularities showing multiple segmental narrowings involving the proximal middle cerebral artery on both sides (arrows), proximal A1 segment of the left anterior cerebral artery (curved arrow), and the P2 segment of the left posterior cerebral artery (open arrow). Lack of flow is revealed in the distal branches of the left middle cerebral artery. A magnetic resonance angiogram is a noninvasive means of evaluating vasculopathies in children.

infantile extra-axial fluid collections and may distinguish effusions and hygromas from subdural hematomas, as in child abuse. Special MRI sequences are available that can differentiate cerebrospinal fluid-containing lesions (e.g., arachnoid cysts) from other lesions (e.g., epidermoid tumors) that are often difficult to visualize on CT. Sagittal MRI images have better resolution than ultrasound and also cannot be obtained using CT. MRI is excellent in delineating midline abnormalities including lesions in the sella, aqueduct, foramen magnum, and pineal region (Fig. 11-26) [Edwards et al., 1988]. Absence of T1 hyperintensity in the posterior pituitary on a sagittal MR image is diagnostic of central diabetes insipidus in children [Maghnie et al., 2000]. For evaluation of hypopituitarism in children, MRI of the head is critical [Geffner, 2002]. Hydrocephalus in children, unexplained by ultrasound and CT, may be evaluated satisfactorily with MRI examination (Fig. 11-27). Likewise, in patients with central nervous system tumors and cerebrospinal fluid seeding, MRI with gadolinium enhancement is more sensitive than a CT examination. MRI is also being used for planning surgery, radiotherapy, and chemotherapy, as well as for treatment follow-up. Contrast enhancement adds to the usefulness of MRI in these settings.

MAGNETIC RESONANCE SPECTROSCOPY MR spectroscopy is a clinically useful, noninvasive tool for identifying the biochemical state of the central nervous system [Novotny et al., 1998]. MR spectroscopy can provide information noninvasively about certain metabolites in normal and pathologic conditions [Ross and Michaelis, 1994].

Certain atomic nuclei such as 1H (protons) are magnetic, and when exposed to a strong magnetic field, they align in a particular orientation until equilibrium is reached [Prichard, 1993]. If the nuclei are then excited by a radiofrequency pulse at their resonant frequency, they produce a detectable signal during relaxation back to equilibrium. During relaxation, because of their local chemical environment, each proton produces a signal at a slightly different frequency, called a chemical shift. After a Fourier transform analysis, the plots of the resulting nuclear magnetic resonance spectra appear as peaks of signal intensity versus signal frequency or chemical shift. Peaks at a particular chemical shift represent signal from protons of a particular metabolite or biochemical compound. MRI uses the strong signals from 1H nuclei of water and their spatial location to reconstruct anatomic images. In contrast, proton MR spectroscopy is interested in the much weaker signals from nonwater protons to obtain quantitative information about biologic molecules within tissue. Special techniques, such as chemical shift selective saturation (CHESS), are used to suppress the overwhelming signal produced because of the large concentration of water. Small concentrations of metabolites, such as creatine, choline, N-acetyl-aspartate, lactate, and many amino acids, can be detected using acquisition sequences, such as stimulatedecho acquisition mode and point-resolved spectroscopy. The principles underlying this spectral editing are quite complex and are discussed in several reviews [Bolinger and Insko, 1996; Novotny et al., 1998; Ross and Michaelis, 1994]. Initial studies in children used phosphorus (31P) MR spectroscopy and investigated spectral changes seen after neonatal asphyxia [Azzopardi et al., 1989; Martin et al.,

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FIGURE 11-21. A, T2-weighted, axial magnetic resonance imaging (MRI) of a 3-year-old female who presented with acute onset of cranial nerve VI palsy. A focal area of hyperintensity is seen in the brainstem in the lower midbrain (arrow). B, A lower image demonstrates another focus of T2 hyperintensity in the left middle cerebellar peduncle and adjacent cerebellum (arrow). C, Follow-up examination approximately 2 months later demonstrates resolution of the signal abnormality from the brainstem. D, A lower image demonstrates reduction of the previously described signal abnormality in the left middle cerebellar peduncle and adjacent cerebellum. At the follow-up examination, the patient had recovered from the cranial nerve VI palsy. The initial signal abnormality was caused by acute disseminated encephalomyelitis. The patient had a febrile illness preceding her initial presentation. Diffuse and focal white matter lesions are well delineated by MRI examination.

1996]. Reduced phosphocreatine to inorganic phosphate (PCr/Pi) ratios suggested that impairment of energy metabolism occurred late rather than early after asphyxia, and this ratio correlated with poor neurologic outcome, as did the presence of lactate in other studies [Groenendaal et al., 1994; Martin et al., 1996].

Spectral Metabolites Using Proton Magnetic Resonance Spectroscopy Proton MR spectroscopy (1H-MR spectroscopy) is being used to investigate a wide range of neurologic disorders. Metabolites measured with 1H-MR spectroscopy include N-acetyl-aspartate, a neuronal marker; creatine composed

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tate, which accumulates in response to tissue damage or anaerobic glycolysis; and glutamate and immediately formed glutamine and myoinositol, an osmolyte and astrocyte marker [Birken and Oldendorf, 1989; Prichard, 1991; Sappey et al., 1992; Tunggal et al., 1990]. During normal maturation of the brain, N-acetyl-aspartate, creatine, and glutamate/glutamine levels increase, and Cho and myoinositol levels decrease [Kreis et al., 1993; Ross et al., 1992]. (Fig. 11-28). The newborn brain has a high water content, and the high Cho and myoinositol levels decline as myelination progresses [Kreis et al., 1993]. It is not uncommon to detect small lactate peaks in spectra from normal newborn brain, but if lactate levels are high or appear after the neonatal period, it may indicate possible hypoxic-ischemic injury [Holshouser et al., 1997], a metabolic disorder, or infection.

Diseases Studied with Proton Magnetic Resonance Spectroscopy

of phosphocreatine and its precursor creatine, which are bioenergetic metabolites; choline-containing compounds (Cho), including free choline and phosphoryl and glycerophosphoryl choline that are released during membrane disruption; lac-

Characteristic proton spectra in adults have been described in stroke, hepatic encephalopathy, dementia, diabetic ketoacidosis, tumor, multiple sclerosis, acquired immunodeficiency syndrome–related leukodystrophies, and trauma [Ross and Michaelis, 1994]. In children, abnormalities on 1 H-MR spectroscopy have been observed in a variety of metabolic [Chabrol et al., 1995; Kruse et al., 1994] and mitochondrial encephalopathies [Abe et al., 2004], brain tumors [Arle et al., 1997; Byrd et al., 1996; Sutton et al., 1992; Taylor et al., 1998; Warren et al., 2000], and certain neurodegenerative conditions [van der Knapp et al., 1992; Wang et al., 1996].

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FIGURE 11-22. T2-weighted, coronal image through the hippocampus in a child with temporal lobe seizures. T2 hyperintensity is demonstrated in the right hippocampus (arrow) in this patient with mesial temporal sclerosis. Magnetic resonance imaging is the examination of choice for evaluation of seizures.

FIGURE 11-23. A, T1-weighted, midsagittal magnetic resonance imaging (MRI) of a 5-year-old male with brainstem glioma (arrows) demonstrates involvement of the brainstem. The lesion shows low signal intensity in relation to the normal brain parenchyma and enlargement of the pons. B, T2-weighted, axial MRI through the level of the pons demonstrates marked, homogeneous high signal intensity (arrow), typical for brainstem gliomas. Many of these patients are treated with radiation therapy and chemotherapy after MRI without tissue diagnosis.

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FIGURE 11-24. T1-weighted, axial magnetic resonance imaging (MRI) of a 3-year-old male who presented with headache and ataxia of 1 month’s duration. A large, cystic mass is demonstrated in the right side of the cerebellum with an intensely enhancing mural nodule (arrow) and an enhancing septum extending from the neural nodule to the wall of the cyst. This is a pilocytic-type juvenile cerebellar astrocytoma. MRI is superior to computed tomography (CT) in the evaluation of lesions in the posterior fossa, because CT examination is somewhat limited by beam hardening artifact from the petrous pyramids.

Proton MR spectroscopy has been used after acute traumatic and nontraumatic injuries. Adult patients with severe closed-head injuries or stroke with long-term neurologic sequelae demonstrate elevated lactate peaks, reduced Nacetyl-aspartate peaks, and reduced N-acetyl-aspartate/ creatine ratios [Choe et al., 1995; Matthews et al., 1995]. After closed-head injury in children, lactate has been reported in regions of contusion and infarction but not in areas of diffuse axonal injury [Sutton et al., 1995]; lactate elevation is more common in children with nonaccidental trauma. Other researchers have found that reduced occipital Nacetyl-aspartate/creatine ratios or the presence of cerebral lactate correlated with poor outcomes [Ashwal et al., 2000; Shu et al., 1997]. Increased N-acetyl-aspartate/ Cho and reduced Cho/creatine ratios correlate with impaired neuropsychologic functioning after traumatic brain injury [Brenner et al., 2003]. Spectral sampling in areas of brain that did not appear to be visibly injured has shown altered metabolite ratios that suggested definite injury. Later studies have examined the role of myoinositol, a marker for posttraumatic astrogliosis or disturbed osmotic regulation, using quantitative short echo time MR spectroscopy and have found that occipital gray matter myoinositol levels are increased after traumatic brain injury and correlate with poor outcomes [Ashwal et al., 2004]. The glutamine and

B FIGURE 11-25. A, T1-weighted, sagittal magnetic resonance imaging (MRI) of a 3-year-old male with a history of new-onset seizures shows a hemorrhagic lesion in the right frontal lobe with a multilobulated appearance (arrow). B, T2-weighted, axial MRI demonstrates the presence of methemoglobin, which produces a bright signal on T1- and T2-weighted images (arrow), with a peripheral rim of hemosiderin seen as low signal intensity on the T2-weighted image (open arrow), indicating subacute and chronic hemorrhage. This example illustrates a typical appearance of hemorrhage from a cavernous hemangioma. MRI may be helpful in determining the age of hemorrhage.

Cho levels are elevated for all traumatic brain injury patients compared with control subjects, whereas N-acetyl-aspartate was not [Ashwal et al., in press]. The time interval before MR spectroscopy acquisition after injury and location of sample within the brain might affect findings. Overall, these

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FIGURE 11-26. A, T2-weighted, axial magnetic resonance imaging (MRI) of a 16-year-old female who developed 2 months of blurred vision and was found to have bilateral papilledema. A large, irregular mass lesion is demonstrated in the pineal region (arrow) that is isodense to gray matter and hypointense to cerebrospinal fluid (CSF). Hydrocephalus and transependymal CSF migration is demonstrated by high signal intensity in the periventricular white matter. B, Midsagittal, T1-weighted MRI shows the lesion with excellent reference to surrounding structures in the sagittal plane, causing compression of the aqueduct (small black arrow) and enlargement of the lateral (curved arrow) and third (white arrow) ventricles but no enlargement of the fourth ventricle. Biopsy revealed pinealoblastoma. MRI is superior to other available imaging methods for the delineation of midline lesions.

studies suggest the strong potential for using MR spectroscopy to provide accurate estimates of long-term neurologic and neuropsychologic function after traumatic brain injury in infants and children. MR spectroscopy with diffusion-weighted imaging is routinely used to evaluate children with stroke and hypoxicischemic injury. Confirmation of the death of tissue is provided on proton spectroscopy by a rise in lactate from anaerobic glycolysis and a loss of N-acetyl-aspartate from neuronal death [Zimmerman et al., 2000]. The combination of MRI and MR spectroscopy can provide prognostic information in children with hypoxic-ischemic injury, such as after near-drowning [Dubowitz et al., 1998]. MRI and MR spectroscopy have been found particularly useful in the evaluation of neonates with perinatal encephalopathy. Reduced N-acetyl-aspartate–derived metabolite ratios, elevated choline, or myoinositol, as well as abnormalities on diffusionweighted imaging, have been shown to reflect the severity of injury and to correlate with long-term developmental and neurologic outcomes [Bartha et al., 2004; Cady et al., 1997; Robertson et al., 2001; Zarifi et al., 2002]. Patients with elevated brain lactate levels and decreased N-acetylaspartate/creatine ratios have been significantly more likely to have a poor outcome compared with age-matched control subjects (Fig. 11-29) [Holshouser et al., 1997]. Proton MR spectroscopy combined with MRI is useful in screening patients for metabolic and mitochondrial disorders based on the detection of increased cerebral lactate or the presence of other elevated metabolite peaks [Ashwal et al., 1997; Barkovich et al., 1993; Chabrol et al., 1995; Cross et al., 1993; Matthews et al., 1993]. Abnormalities

have been reported in patients with glutaric aciduria type 2 [Shevell et al., 1995]; pyruvate dehydrogenase deficiency [Cross et al., 1994]; Leigh’s syndrome [Krageloh et al., 1993]; X-linked adrenoleukodystrophy [Kruse et al., 1994], MELAS [Abe et al., 2004; Kaufmann et al., 2004], and a variety of other conditions. In phenylketonuria, elevated phenylalanine levels can be seen with MR spectroscopy of the brain [Osborn and Tong, 1996]. In Canavan’s disease, MR spectroscopy shows marked elevation of the N-acetylaspartate peaks [Osborn and Tong, 1996]. In addition to an elevated N-acetyl-aspartate peak, patients with Canavan’s disease have abnormally increased N-acetyl-aspartate/creatine and N-acetyl-aspartate/Cho ratios [Barker et al., 1992]. In Leigh’s disease, as in other mitochondrial or metabolic disorders, MR spectroscopy reveals an abnormally high lactate peak and a decreased N-acetyl-aspartate peak in the basal ganglia [Osborn and Tong, 1996]. In some children with metabolic diseases, lactate is present during the acute illness, and with improvement, serial spectra can demonstrate its resolution [Kreis et al., 1995]. Elevated cerebral lactate has also been detected when blood lactate levels have been normal in symptomatic patients [Krageloh et al., 1993]. Proton MR spectroscopy has also been used in the evaluation of children with epilepsy [Duncan, 1996; Jackson, 1994; Kuzniecky, 2004; Novotny, 1995; Suhy et al., 2002]. Studies using localized proton MR spectroscopy have indicated decreased N-acetyl-aspartate, increased choline, and increased lactate levels in epileptic foci compared with nonictal or contralateral regions [Connelly et al., 1994]. Proton spectroscopic imaging studies have demonstrated similar metabolite changes, but with the added capability of

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FIGURE 11-27. A, T1-weighted, parasagittal image of a 1-day-old newborn with extreme hydrocephalus diagnosed by prenatal and neonatal ultrasound scans of the head. Massive dilation of the lateral ventricle is demonstrated with intraventricular hemorrhage seen as a fluid-fluid level (arrow) in the posterior, dependent portion. B, Proton-weighted, axial image at the level of the midbrain demonstrates the lack of a cerebrospinal fluid pulsatile flow void in the aqueduct (arrow). C, T1-weighted, midsagittal image demonstrates marked enlargement of the third and lateral ventricles and normal size of the fourth ventricle. No expected tubular signal void is seen at the level of the expected aqueduct (arrow), which is consistent with aqueductal stenosis.

C spatially defining the regions with metabolite abnormalities [Hetherington et al., 1995; Hugg et al., 1993]. Over the next decade, it is likely that additional studies will demonstrate a role for proton MR spectroscopy in the evaluation and selection of patients with intractable seizures for surgery. The use of proton MR spectroscopy has been examined in children and adults with central nervous system tumors [Byrd et al., 1996; Kinoshita et al., 1994; Negendank et al., 1996; Sutton et al., 1992; Tzika et al., 1997; Wang et al., 1995; Warren, 2004]. Malignant pediatric brain tumors are characterized by an increase in Cho/N-acetyl-aspartate ratio and a decrease in N-acetyl-aspartate/creatine ratio [Sutton et al., 1992], a general decrease in the N-acetyl-aspartate and

creatine peaks, and an increase in Cho [Byrd et al., 1996; Tzika et al., 1997]. In one study, the pretreatment total Cho peak was the most reliable indicator of malignancy [Taylor et al., 1998]. In another multicenter study, Cho signal intensities were highest in astrocytomas and anaplastic astrocytomas, and creatine signal intensities were lowest in glioblastomas [Negendank et al., 1996]. However, tumoral metabolic characteristics exhibited large variations within each subtype of glial tumor, precluding diagnostic accuracy of MR spectroscopy in differentiating low- and high-grade tumors. In children, it has been suggested that proton MR spectroscopy may be useful in differentiating various types of cerebellar tumors, such as primitive neuroectodermal

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tumors, low-grade astrocytomas, and ependymomas [Wang et al., 1995]. In one report, a computer-based neural network that combined MRI, MR spectroscopy, and clinical data to predict tumor histology in pediatric patients with posterior fossa tumors was able to correctly identify 95% of tumors in 33 children [Arle et al., 1997]. Other spectroscopy features reported include increased lactate and lipids, particularly in high-grade tumors [Byrd et al., 1996]. An acquisition technique commonly used to evaluate central nervous system tumors is MR spectroscopic imaging or chemical shift imaging because it allows simultaneous acquisition of multiple spectra within a single imaging plane (two-dimensional MR spectroscopic imaging) or in multiple planes to cover the entire brain (three-dimensional MR spectroscopic imaging). This technique allows evaluation of the entire tumor volume and surrounding brain to more accurately determine the extent of involvement outside an enhancing area or spectroscopic differences in a nonhomogeneous tumor. An example of an MR spectroscopic imaging acquisition in a pediatric tumor patient is shown in Figure 11-30. MR spectroscopy is useful in differentiating tumor recurrence from radiation necrosis. Patients with post-irradiation necrosis are more likely to have reduced N-acetyl-aspartate but preserved Cho peaks compared with patients with tumor recurrence in which Cho is increased [Usenius et al., 1995]. MR spectroscopy has prognostic significance in predicting outcome in children with relevant primary brain tumors. Patients with a Cho/N-acetyl-aspartate ratio greater than 4.5

were found to have a higher mortality rate [Warren et al., 2000]. In adults, proton MR spectroscopy has been used to determine whether metastatic central nervous system tumors from distal primary sites are present [Sijens et al., 1995]. However, MR spectroscopy data cannot be used alone because of significant overlap and nonspecificity of the results. It is difficult to distinguish non-neoplastic lesions such as hamartomas, histiocytic lesions, or dysplastic lesions from low-grade neoplasms by MR spectroscopy [Cecil et al., 2001].

DIFFUSION-WEIGHTED IMAGING Diffusion-weighted imaging is a technique that uses MRI to measure the diffusion of water through tissues [Ashwal and Holshouser, 1997; Buxton et al., 1996; Fisher et al., 1992; Warach, 1996]. Random displacements of water molecules (i.e., diffusion) are modified by structural and physiologic factors in a medium. In a medium in which diffusion of water molecules is identical in all directions the process is called isotropic diffusion. When the process depends on direction, it is called anisotropic diffusion [Ito et al., 2002]. In brain white matter, diffusivity of water molecules is not the same in all directions of three-dimensional space and is anisotropic at an imaging voxel scale because of its characteristic microscopic and macroscopic features such as myelin sheath, axon, and fiber tract [Klingberg et al., 1999]. Diffusion-weighted imaging has been used to investigate stroke and hypoxic-ischemic injury in children [Barkovich

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FIGURE 11-29. A, T2-weighted, axial magnetic resonance imaging (MRI) of a 13-month-old male after cardiac arrest after a near-drowning incident. Diffuse T2 hyperintensities occur in both cerebral hemispheres involving gray matter and gray-white matter junctions extending into the deep white matter (arrows), which is consistent with diffuse cytotoxic edema from prolonged ischemic or anoxic insult. B, Single-voxel proton MR spectrum (TR = 3000 msec, TE = 20 msec, stimulated-echo acquisition mode [STEAM]) from occipital gray matter obtained 2 days after injury reveals a prominent lactate (Lac) peak and a markedly reduced N-acetylaspartate/creatine (NAA/Cre) ratio compared with age-matched controls (see Fig. 11-28A to D). C, Proton MR spectrum (TR = 3000 msec, TE = 270 msec, point-resolved spectroscopy [PRESS]) of the same voxel area obtained immediately after the spectrum depicted in B also reveals a prominent lactate peak and a markedly reduced NAA peak, both of which indicate a poor prognosis. This patient was discharged in a vegetative state and died later.

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et al., 2001; Hunter, 2002; Phillips et al., 1999], to differentiate solid (e.g., epidermoid tumors) [Chen et al., 2001] from cystic central nervous system lesions and to evaluate patients with demyelinating disease. As more experience is gained with this technology and as it becomes more widely available, many additional applications are likely to be realized particularly in the area of traumatic and ischemic brain injury, as well as other acute metabolic and hypoxic-ischemic encephalopathies.

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Diffusion-weighted imaging is based on the ability to detect subtle changes in the diffusion of water molecules. Diffusion-weighted imaging measures the apparent diffusion of water (i.e., the self-diffusion of water among other water molecules within tissues) [Buxton et al., 1996; Warach, 1996]. The degree of diffusion depends on many factors, but those demonstrated to be most important include tissue and fluid viscosity, membrane barriers to the free movement of water, chemical interaction of water with macromolecules,

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FIGURE 11-30. Three-year-old male with histologically confirmed pilocytic astrocytoma. A, Magnetic resonance spectroscopic imaging was acquired in the posterior fossa with a 10-mm-thick slab, using 2 cc per voxel. B, Spectrum from long-echo-time acquisition (TR/TE = 3000/144 msec, point-resolved spectroscopy [PRESS]) demonstrates decreased N-acetyl-aspartate (NAA) (2.0 ppm) and creatine (3.0 ppm) and markedly elevated choline (3.2 ppm). Lactate is present as an inverted doublet (1.33 ppm). C, Spectrum from short-echo-time acquisition (TR/TE = 3000/40 msec, PRESS) with similar findings.

C and local tissue temperature. MRI can be used to measure this apparent diffusion by using an additional pair of strong gradient pulses to the standard pulse sequence such that the first pulse dephases and the second pulse completely rephases, spinning protons. Such data are used to calculate the apparent diffusion coefficient. The apparent diffusion coefficient of water protons is greater in regions of unimpeded water molecular motion, such as that from cerebrospinal fluid from the ventricular system or cystic brain lesions. In normal brain parenchyma, where diffusion of water molecules is relatively restricted, the apparent diffusion coefficient is lower. Regions of restricted or slower molecular motion appear hyperintense.

For example, with ischemic injury, water accumulates intracellularly and is reflected as hyperintense regions on diffusionweighted imaging. The hyperacute decrease in apparent diffusion coefficient seen during ischemia is related to the development of cytotoxic edema associated with an increase in intracellular volume because of sodium and water influx. Clinical applications of diffusion-weighted imaging began to appear in the mid 1980s, particularly in reference to disorders affecting the nervous system. Diffusion-weighted imaging is useful in differentiating cystic brain lesions (high apparent diffusion coefficient) from epidermoid tumors (lower apparent diffusion coefficient). In high-grade cerebral gliomas, diffusion-weighted imaging can differentiate com-

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ponents of the tumor and distinguish areas of nonenhancing tumor from areas of peritumoral edema. Because diffusion is also affected by axonal orientation, diffusion-weighted imaging has been used to study aspects of myelination [Nomura et al., 1994]. In white matter, diffusion has been found to be anisotropic; there is greater water mobility along myelinated fiber tracts than perpendicular to them. By measuring these differences, diffusionweighted imaging allows investigation of myelin orientation and development. This finding may be of particular interest in evaluating children with closed-head injuries. In one report, diffusion-weighted imaging was found to have increased utility in detection of brain injury in children with nonaccidental trauma [Suh et al., 2001]. In this study, diffusionweighted imaging revealed more extensive brain injury than was demonstrated on conventional MRI sequences. Diffusionweighted imaging may also identify evidence of corpus callosal and subcortical white matter injury. Diffusionweighted imaging should be obtained in children in whom nonaccidental trauma is suspected even if acquired several days after the insult [Chan et al., 2003]. During early brain myelination, anisotropy in diffusionweighted imaging precedes myelination changes and is helpful in evaluating the normal progression of myelination in infants [Engelbrecht et al., 2002]. Diffusion-weighted imaging obtained during the acute phase of periventricular leukomalacia is more sensitive than conventional MRI and ultrasound in detecting hyperintensities that evolve to damaging lesions at follow-up MRI and ultrasound studies [Bozzao et al., 2003]. Diffusion tensor imaging measures the proton diffusivity and preferential orientation of the diffusion tensor. In white matter, the free movement of water molecules is strongly limited by the axonal membrane and the presence of the cholesterol-laden myelin lipid bilayers of the myelin sheaths. Consequently, the molecular movement in white matter of the brain and spinal cord is preferentially higher along the fibers than across them. Diffusion tensor imaging is based on the real three-dimensional motional behavior of diffusion. Tractography depicts macroscopic three-dimensional architecture of the fiber tracts [Basser and Pierpaoli, 1996; Basser et al., 2000]. In X-linked adrenoleukodystrophy, significant abnormalities with diffusion tensor imaging that are not seen on conventional MRI are reported and are consistent with demyelination [Schneider et al., 2003]. In a case of vitamin B12–deficiency leukoencephalopathy, reduced anisotropy occurred within white matter lesions with T2 abnormalities and normal-appearing adjacent white matter [Kealey et al., 2002]. Diffusion-weighted imaging can detect larger areas of involvement than conventional MRI in this demyelinating process. In osmotic myelinolysis, cytotoxic [Chu et al., 2001] and extracellular [Chua et al., 2002] edema is reported with diffusion-weighted imaging, sometimes before abnormal signals are seen with conventional MRI [Ruzek et al., 2004]. In neonates, diffusion-weighted imaging is useful in evaluation of acute ischemic brain injury and seizures. In the acute setting, diffusion-weighted imaging provides information not available with CT and conventional MRI [Krishnamoorthy et al., 2000]. In children younger than 2 years, diffusionweighted imaging is useful for evaluating acute ischemic injuries, metabolic disorders, and leukodystrophies [Gelal et al., 2001]. In patients with sickle cell disease and an acute

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central nervous system event, diffusion-weighted imaging is an essential part of the investigation [Kirkham et al., 2004]. Diffusion-weighted imaging is helpful for earlier identification of the changes in acute carbon monoxide poisoning [Teksam et al., 2002]. In infants and children with dural sinus thrombosis, diffusion-weighted imaging shows both increased and decreased apparent diffusion coefficient mapping of nonhemorrhagic edema, consistent with extracellular and cytotoxic edema. Areas of increased apparent diffusion coefficient may return to normal [Keller et al., 1999], whereas areas with normal or decreased apparent diffusion coefficient occasionally show imaging sequelae [Ducreux et al., 2001]. Venous infarcts are frequently hemorrhagic. In patients with posterior reversible encephalopathy syndrome, diffusion-weighted imaging shows reversible vasogenic edema and, in severe cases, its conversion to cytotoxic edema, which is associated with a poorer outcome. Areas of hyperintensities on diffusionweighted imaging can progress to infarction [Covarrubias et al., 2002]. Children with new-onset prolonged seizures can develop unilateral hippocampal sclerosis. The presence of diffusion restriction in the affected hippocampal region can herald subsequent development of mesial temporal sclerosis [Farina et al., 2004]. Diffusion-weighted imaging can be helpful in evaluation of central nervous system tumors. It may show diffusion restriction in solid portions of primitive neuroectodermal tumors, a finding that is unusual in nonprimitive neuroectodermal tumor lesions [Erdem et al., 2001]. Glioblastomas are relatively uncommon in children, and they can be difficult to differentiate from other brain tumors such as primitive neuroectodermal tumors, ependymomas, or cystic astrocytomas. However, diffusion-weighted imaging hyperintensity has been observed in solid portions of glioblastomas, and in combination with spectroscopy, it may be helpful in determining an appropriate site for biopsy and in evaluating tumor recurrence [Chang et al., 2003]. Hyperintensity can be seen in lymphomas on diffusionweighted imaging [Stadnik et al., 2001]. Diffusion-weighted imaging is useful for evaluating children with intracranial infection. Cerebral abscesses, tuberculomas, subdural empyemas, and epidural abscesses demonstrate hyperintensity with diffusion-weighted imaging [Lim et al., 2003]. Neurocysticercosis cysts and encephalitis appear hyperintense on diffusion-weighted imaging, whereas toxoplasmosis lesions produce variable signal intensity. Diffusionweighted imaging hyperintensity is observed in neonates with brain abscesses [Sener, 2004]. Diffusion-weighted imaging may differentiate abscesses from necrotic tumors, although both appear as ring-enhancing lesions on MRI [Leuthardt et al., 2002]. In pyogenic ventriculitis, diffusion-weighted imaging shows signal intensity in dependent intraventricular fluid [Pezzullo et al., 2003]. Diffusion-weighted imaging may be of some prognostic value in children with herpes simplex encephalitis [Sener, 2001]. These lesions can exhibit low or high signal intensity indicating vasogenic or cytotoxic edema. Patients with cytotoxic edema have fulminating disease and are more likely to have a complicated clinical course and poorer outcome. Patients with vasogenic edema are less seriously ill and more likely to have a good outcome with prompt therapy [Sener, 2001]. In children who undergo middle ear and mastoid surgery for cholesteatomas, a combination of MRI and diffusion-weighted imaging can detect recurrent or

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FIGURE 11-31. A, T2-weighted, axial magnetic resonance imaging (MRI) of a 2-day-old male who had a normal term delivery and experienced right-sided seizures. There is T2 lengthening along the left frontal and parietal cortical margins (arrows) with loss of normal gyral outlines, which is consistent with edema from acute infarction and a local mass effect with sulcal effacement that are in the left middle cerebral artery distribution. B, T2-weighted coronal image shows the entire craniocaudal extent of the infarct, including the left temporal lobe in the left middle cerebral artery territory (arrows). C, Diffusion-weighted image demonstrates diffusion restriction in the left middle cerebral artery territory that conforms to the acute infarct. A susceptibility-weighted image was negative for hemorrhage in this infarct. D, Three-dimensional, time-of-flight MR angiogram demonstrates normal internal carotid arteries, vertebral arteries, basilar artery, and the intracranial major vessels, including the left middle cerebral artery and its branches.

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for early detection of potentially reversible ischemic injury. Future outcome studies will determine whether resolution of diffusion-weighted imaging lesions corresponds with clinical recovery or persistence of deficits.

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E FIGURE 11-31. cont’d. E, Two-dimensional, time-of-flight MR venogram show patent dural sinuses without evidence of sinovenous thrombosis.

residual cholesteatomas if they are more than 5 mm in diameter [Aikele et al., 2003]. Diffusion-weighted imaging has assumed an important role in the early evaluation of patients with stroke [Fisher et al., 1992; Lutsep et al., 1997; Warach et al., 1995]. Diffusion-weighted imaging reveals hyperintensity in an acute infarct soon after the onset of ischemia. Significant diffusion-weighted imaging lesions have been associated with little clinical recovery, with follow-up MRI scans demonstrating fixed lesions. In almost all previous reports of adults with stroke, regions with early diffusion-weighted imaging hyperintensity eventually demonstrated infarction. Diffusionweighted imaging also has been evaluated in pediatric stroke patients [Connelly et al., 1997]. In some patients, regions of diffusion-weighted imaging hyperintensity did not uniformly progress to infarction as determined by serial MRI studies, and this suggests that in children, diffusion-weighted imaging can demonstrate tissue that is compromised but not to the point of irreversibility. Stroke in children is an unexpected event, and the causes are more diverse than in older populations. Imaging plays an important role in the evaluation and management of children with stroke. The combination of MRI, diffusion-weighted imaging, diffusion tensor imaging, perfusion-weighted imaging, MRA, and MR venography, as clinically indicated, offers the best sensitivity for the detection of the lesion, determination of its extent, and evaluation of the degree of underlying vascular compromise [Uggetti, 2003]. In neonates, diffusionweighted imaging is helpful for the early diagnosis of stroke, and findings may be more pronounced than findings on MRI. It is not unusual in the evaluation of neonatal strokes to have positive findings on diffusion-weighted imaging and MRI but negative findings on MRA on MR venography (Fig. 11-31). Stroke in the newborn may be hemorrhagic rather than ischemic (Fig. 11-32). Performance of diffusion-weighted imaging as soon as possible after the onset of ischemic or traumatic symptoms holds promise

Perfusion-weighted imaging is an extension of MR technology that allows evaluation of blood volume, blood transit time, and blood flow as relative measures [Warach, 1996]. Perfusion-weighted imaging is primarily being investigated for its use in the evaluation of patients early after the onset of symptoms of cerebral ischemia, although other clinical applications are being investigated [Ashwal and Holshouser, 1997; Dunst et al., 2001; Tanner et al., 2003; Warach et al., 1996]. Two techniques have been developed to accomplish perfusion-weighted imaging on the basis of the magnetic susceptibility effect of gadolinium-containing contrast agents on the brain and the noninvasive magnetic labeling of arterial blood [Buxton et al., 1996; Warach, 1996]. The first, referred to as dynamic contrast-enhanced susceptibilityweighted perfusion imaging, can be used to image relative differences in blood volume over time. Paramagnetic compounds such as gadolinium (Gd-DTPA), which are used as MRI contrast agents, possess strong magnetic susceptibility. The susceptibility differences between the contrast agent and the surrounding tissue create local magnetic field gradients that can be used to acquire images after contrast injection. Images can be viewed dynamically to assess entry and clearance of the contrast through the tissue, and the transit time can be calculated. Cerebral blood volume can be estimated as can cerebral blood flow from the ratio of the cerebral blood volume and mean transit time through the brain. The second method involves blood flow imaging by magnetically labeled protons of the arterial inflow using a radiofrequency pulse and following the label through the brain’s circulation. Deoxyhemoglobin contained within erythrocytes is paramagnetic, and on deoxygenation, the magnetic susceptibility of deoxyhemoglobin is increased and creates local field gradients around these cells. The blood oxygen level–dependent technique takes advantage of this phenomenon to quantify cerebral blood flow [Patel et al., 1995]. Perfusion-weighted imaging can demonstrate regions of acute ischemia before lesions are detectable by MRI. Such studies can be done rapidly, and they do not involve contrast injection. Several studies have suggested that perfusion-weighted imaging, like diffusion-weighted imaging, can aid the evaluation of patients with acute ischemic injury, particularly by determining which patients have the potential for recovery and which may benefit from thrombolytic therapy [Ahmed and Masaryk, 2004; Grandin, 2003; Rowley and Roberts, 2004; Warach et al., 1995, 1996]. In patients with sickle cell disease, abnormalities on perfusion MRI are associated with neurologic symptoms although the areas of abnormality may not be seen in conventional MRI, MR angiography, or transcranial Doppler examination. Perfusion imaging is helpful in guiding management in such patients [Kirkham et al., 2001]. Perfusion imaging has also been used to

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Neurodiagnostic Testing / 11 FIGURE 11-32. A, T1-weighted, sagittal magnetic resonance imaging (MRI) of a 24-day-old male who underwent extracorporeal membranous oxygenation (ECMO) for pulmonary hypertension, respiratory failure, and cytomegalovirus sepsis. This image was obtained slightly to the right of the midline and shows a large, well-circumscribed area of increased signal intensity (arrow) in the right side of the cerebellum that is consistent with a subacute hematoma containing methemoglobin. B, T1-weighted, axial MRI through the posterior fossa demonstrates a large, well-circumscribed hematoma producing a bright signal (arrow) in the right cerebellar hemisphere and giving rise to a large mass effect, with compression of the brainstem and fourth ventricle. C, T2-weighted coronal image shows the craniocaudal and transverse extent of the large hematoma in the right side of the cerebellum (arrow), with compression of the fourth ventricle. The lateral ventricles are slightly enlarged. This patient underwent surgical decompression of the hematoma.

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differentiate tumor types. In one study of adult and pediatric patients using relative cerebral blood volume maps calculated for assessment of tumor vascularity, differences were observed in patients with glioblastomas, anaplastic gliomas, and low-grade gliomas [Lee at al., 2001]. Combined with

spectroscopy, perfusion-imaging findings can help differentiate progression from stable tumors [Tzika et al., 2004]. Another area of interest for diffusion-weighted imaging and perfusion-weighted imaging is in children with acute disseminated encephalomyelitis [Bernarding et al., 2002]. In

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children with cerebral arteriovenous malformation and other proliferative angiopathies, perfusion-weighted imaging may be helpful in determining areas of hyperperfusion, hypoperfusion, or venous congestion adjacent to the lesion [Ducreux et al., 2004].

SUSCEPTIBILITY-WEIGHTED IMAGING A sequence using a high-spatial-resolution, three-dimensional, fast, low-angle MRI technique that is extremely sensitive to susceptibility has been described. This sequence, which can be performed on conventional scanners, was originally designed for MR venography using the paramagnetic property of intravascular deoxyhemoglobin [Lee et al., 1999a, Reichenbach et al., 1997]. This technique, known as susceptibility-weighted imaging, has been very useful in detecting hemorrhagic lesions associated with diffuse axonal injury, and it has depicted significantly more small hemorrhagic lesions than conventional T2*-weighted, gradient-echo techniques [Tong et al., 2003a]. In children with traumatic brain injury and diffuse axonal injury, the number and volume of hemorrhagic lesions detected with susceptibility-weighted imaging have correlated with the initial severity of injury as measured by the Glasgow Coma Scale scores and duration of coma and with long-term outcome [Tong et al., 2004]. Susceptibilityweighted imaging can also be used to categorize tissue as normal appearing or with nonhemorrhagic or hemorrhagic injury [Holshouser et al., in press]. Using proton MR spectroscopic imaging, voxels with visibly injured (hemorrhagic) brain may demonstrate a significant decrease in N-acetylaspartate/creatine and increase in Cho/creatine compared with voxels with normal-appearing brain. Metabolite ratios from normal-appearing brain better predicted outcome than using ratios from visibly injured brain. Neonatal strokes, which are sometimes related to dural sinus thrombosis, are often hemorrhagic (see Chapter 17). Susceptibility-weighted imaging is more sensitive than CT or conventional MRI sequences (e.g., GRE T2*) in detecting hemorrhage in patients with acute strokes [Wycliffe et al., 2004]. This blood-sensitive sequence has been found to be extremely valuable in detection of hemorrhage in children with accidental or nonaccidental trauma [Tong et al., 2004], infarctions [Wycliffe et al., 2004], tumors [Barth et al., 2003], proliferative angiopathies, and vascular malformations [Essig et al., 1999], including Sturge-Weber syndrome [Tong et al., 2003b], cavernous angioma [Lee et al., 1999a] (Fig. 11-33), and in patients with hypertensive encephalopathy (Fig. 11-34). In the examples of susceptibility-weighted imaging (see Figs. 11-33 and 11-34), both cases exhibit a markedly increased number and more intense abnormal signal on susceptibilityweighted imaging than with other MRI sequences.

FUNCTIONAL MAGNETIC RESONANCE IMAGING Functional MRI is a technique that measures changes in tissue perfusion based on changes in blood oxygenation. It is used to study regional brain activity in response to sensory, motor, and cognitive stimulation [Ashwal and Holshouser, 1997; Rivkin, 2000; Strainer et al., 1997; Warach,

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1996]. Functional MRI can be used to study the distribution of cerebral hemodynamic changes associated with various sensory stimuli, including vision [Fox and Raichle, 1986; Zeki et al., 1991], sensorimotor [Rao et al., 1993], olfactory [Zatorre et al., 1992b], and auditory function [Binder et al., 1994; Lauter et al., 1985; Zatorre, 1997]. Functional MRI has been used to investigate complex cognitive functions, such as speech and language processing and reading [Klein et al., 1995; McCarthy et al., 1993; Zatore et al., 1992a, 1996] (see Chapter 35). Functional MRI allows investigators to study human cerebral activity in vivo as a function of perceptual or psychologic variables. Echo-planar functional MRI combined with appreciation of the blood oxygen level–dependent contrast mechanism can be used to image cortical responses to peripheral stimuli or cognitive task performance [Kwong, 1995; Ogawa and Lee, 1990; Ogawa et al., 1990a, 1990b]. The blood oxygen level–dependent contrast mechanism relies on the fact that an increase in regional cortical blood flow occurs in response to task performance or stimulation but that this is not accompanied by a concomitant increase in local tissue oxygen extraction [Fox et al., 1986, 1988; Kwong, 1995]. The presence of any substance in a magnetic field alters that field to some degree [Mosley and Glover, 1995]. Certain metal elements are stronger in altering the surrounding magnetic field. Products of reduced hemoglobin, such as deoxyhemoglobin, are stronger in altering the surrounding magnetic field than oxyhemoglobin. Cortical activation causes local vasodilation with increased regional blood flow and oxyhemoglobin. Because of this inflow of oxyhemoglobin, the amount of deoxyhemoglobin in the stimulated cortex does not significantly increase. This regional imbalance of oxyhemoglobin and deoxyhemoglobin reduces the net “susceptibility effect” of deoxyhemoglobin, which can be detected by magnetic susceptibility–sensitive imaging techniques using gradient-recalled echo methods. MRI scanners equipped with echoplanar imaging can obtain gradient images of the stimulated cortex within seconds after stimulation and display increased signal in the stimulated cortex. More-detailed technical descriptions and applications of this technique are beyond the scope of this chapter, but several sources provide excellent reviews of this emerging technology [Ashwal and Holshouser, 1997; Buxton et al., 1996; Fisher et al., 1992; Kwong, 1995; Mosley and Glover, 1995; Rivkin, 2000; Warach, 1996]. MR spectroscopy can be used for functional imaging to detect lactate in eloquent brain cortex (i.e., cortex controlling sensorimotor, language, and visual function) during activation after a stimulus. Increase in lactate concentration has been observed in the occipital and auditory cortex after stimulation [Prichard, 1991; Sappey et al., 1992; Singh, 1992]. One publication implied that lactate is the preferred substrate for the tricarboxylic acid cycle in neurons [Tsacopoulos and Magistretti, 1996]. Using a model of metabolic compartmentalization, these investigators describe glucose as being taken up by astrocytes and converted to lactate, which is then released into the extracellular space and used by neurons. Functional MR spectroscopy of the auditory cortex may be helpful in the detection of stimulus-induced and stable-biochemical spectroscopic changes in patients with hearing loss and may be useful in assessing disease activity [Richards et al., 1997].

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FIGURE 11-33. A, T1-weighted, sagittal magnetic resonance imaging (MRI) was obtained slightly to the right of the midline in this 2-year, 8-month-old male, who presented with sudden onset of headache, nausea, and vomiting and who rapidly deteriorated and developed multiple generalized seizures. Computed tomography from an outside institution showed hemorrhage in the right basal ganglia. This image shows a well-circumscribed area of hemorrhage (arrow) in the hypothalamic region with areas of hyperintensity consistent with the presence of methemoglobin. There is mild lateral ventricular enlargement. B, T2-weighted, axial image shows hemorrhage in the right basal ganglia and thalamus (arrows) with a fluid-fluid level. The area of low signal intensity seen posteriorly contains deoxyhemoglobin within the sedimentation of red cells. Increased signal intensity occurring superiorly is from supernatant fluid containing extracellular methemoglobin. C, Axial, susceptibility-weighted image (SWI) reveals the previously described lesion as low signal intensity (straight arrows). There are multiple additional lesions (curved arrows) scattered in both cerebral hemispheres that were not seen in other conventional MRI sequences. The large hemorrhagic lesion is characteristic of a cavernoma in conventional images and the SWI image, but additional smaller lesions in the brain are seen only in the SWI image, which was helpful in the diagnosis of cavernous angiomatosis. D, Axial, SWI image obtained at a slightly higher level demonstrates multiple other lesions seen as low signal intensity (straight arrows) because of the presence of blood products. The smaller lesions (curved arrows) were not seen in the conventional MRI sequences.

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A

B

FIGURE 11-34. A, T1-weighted, axial magnetic resonance imaging (MRI) of a 26-day-old female who has history of coarctation of the aorta and cardiopulmonary arrest at 3 days of age and who developed seizures after resuscitation. The T1-weighted image demonstrates several foci of signal hyperintensity in the periventricular white matter (arrows) that are consistent with the presence of methemoglobin. B, T2-weighted, axial image shows several foci of low signal intensity (arrows) in the periventricular and subcortical white matter that are consistent with the presence of hemorrhage (i.e., deoxyhemoglobin). C, Axial, susceptibility-weighted image (SWI) demonstrates a marked increase in the number and degree of low-intensity signals (arrows) in the periventricular and subcortical lesions. The multiple periventricular hemorrhagic foci in this patient are thought to result from coarctation of the aorta and its sequela, intracranial hypertension.

C Neuronal structures underlying specific perceptual and cognitive processes can be delineated by functional MRI. With the aid of functional MRI, the development of brain function can be followed, and deviation from the normal pattern can be established [Billingsley-Marshall et al., 2004]. Early diagnosis of functional deficits has the potential to reduce residual deficits because of the earlier implementation of cognitive or other forms of rehabilitation [Martin et al., 2001]. Acquisition of functional MRI data from children is associated with a number of methodologic challenges, primarily compliance and head motion; however, good data can be obtained. Conditioning and personal interactions can improve compliance, and motion reduction

techniques can successfully reduce artifacts resulting from movement [Poldrack et al., 2002]. Functional MRI is being used in patients with various neurologic diseases, including medically refractory epilepsy and brain tumors [Hunter et al., 1996; Lin et al., 1997]. Preoperative evaluation of such patients includes MRI, scalp, subdural, or depth electrode electroencephalography and often includes endovascular amobarbital testing to determine which cerebral hemisphere is dominant (Wada test) [Brassel et al., 1996]. In epilepsy surgery candidates or patients with tumors, preoperative functional MRI [Garcia et al., 1995] has been used to determine the feasibility of a proposed surgical resection and to select patients for invasive surgical functional mapping

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[Lee et al., 1999b]. Functional MRI appears to be as sensitive and specific as the Wada test for speech localization and preoperative memory lateralization and intraoperative cortical mapping [Lin et al., 1997; Sabbah et al., 2003]. Functional MRI performed immediately before surgery can help determine the location of neighboring eloquent functional area of concern in reference to a targeted lesion [Liu et al., 2003]. Information provided by functional MRI has contributed significantly in making optimal surgical decisions before craniotomy. In the future, functional MRI may replace the Wada test because it is much less invasive.

MAGNETIC SOURCE IMAGING Magnetic source imaging uses magnetoencephalography (MEG). When source localizations modeled from the magnetoencephalographic signal are registered with highresolution MRI, the resulting magnetic source images display

functional information in an anatomic context [Darcey et al., 1980; Gallen et al., 1993; Roberts et al., 1995]. In functional mapping of the sensorimotor cortex a combination of magnetic source imaging and functional MRI allows improved sensitivity, fewer false-positive results, and high spatial and temporal resolution [Roberts and Rowley, 1997]. One of the important clinical applications of functional brain imaging is pretreatment mapping to allow definition of eloquent cortex in relation to mass lesions that may be surgically resected or treated with focused irradiation (e.g., gamma knife, protons) or combinations of irradiation and chemotherapy. Magnetic source imaging may also have future applications in studying developmental plasticity after injury. Functional reorganization (i.e., functional plasticity) of the brain can occur after unilateral brain infarction [Lewine et al., 1994], and a similar phenomenon is also found in patients with tumors [Takashi et al., 1997] and arteriovenous malformations [Hasson et al.,1997]. Magnetoencephalography is a powerful and accurate tool for the presurgical evaluation of children with refractory epilFIGURE 11-35. T1-weighted, sagittal magnetic resonance imaging (MRI) of the lumbar spine in a 10-year-old female with a history of spinal dysraphism who underwent repair of myelomeningocele defect at birth. During this follow-up evaluation, she complained of increasing weakness of her lower extremities. A, MRI reveals a closed meningocele defect at the L5, S1, and S2 levels (black arrow); prolonged cord reaching to the level of S1; and a lipoma at the distal end of the dysplastic cord (white arrow). B, The full extent of the lipoma (white arrow) is delineated at the distal end of the cord at the L5, S1, and S2 levels (black arrow).

A

B

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epsy [Chuang et al., 1995; Minassian et al., 1999; Stefan et al., 2000]. Magnetoencephalography is also helpful in evaluating patients with dyslexia. Studies have demonstrated aberrant activation maps consisting of reduced activity in left temporoparietal areas (including the posterior part of the superotemporal, angular, and supratemporal gyri) and increased activity in homologous cortex from the right hemisphere [Simos et al., 2000]. Studies using magnetoencephalography in patients with normal MRI scans who had acquired aphasia and suspected Landau-Kleffner syndrome have demonstrated unilateral and bilateral perisylvian magnetoencephalography spikes, as well as spikes from nonsylvian regions [Sobel et al., 2000]. Magnetoencephalography was considered helpful for diagnosis and preoperative localization of epileptiform activity [Sobel et al., 2000]. Magnetoencephalography also has been used in patients with tumors and provides additional information regarding the spatial relation between brain lesions and functional cortex [Alberstone et al., 2000; Taniguchi et al., 1998]. Magnetoencephalography is also being used in association with three-dimensional MRI in neuronavigational systems. The method of incorporating functional data into neuronavigational systems is a promising tool that can potentially be used in more extensive surgical procedures to lessen injury to eloquent brain areas [Ganslandt et al., 1999]. Among the advantages of functional MRI, magnetic source imaging (magnetoencephalography), and MR spectroscopy are noninvasiveness, absence of ionizing radiation, and superior spatial resolution. Functional MRI is also complementary to anatomic MRI because functional imaging takes into account normal individual variations in the functional topography of the brain. It can detect altered topography or functional plasticity, which may present because of functional reorganization in patients with various forms of cerebral injury [Weiller et al., 1992]. Magnetoencephalography provides noninvasive localization data that are not otherwise available with MRI or conventional scalp ictal electroencephalography [Knowlton et al., 1997].

SPINAL IMAGING Initial assessment of spinal abnormalities in children includes plain films or, in the very young child, ultrasound. CT is usually indicated for acute spine injuries to determine whether a fracture, dislocation, or spondylolysis is present. CT is also helpful for the evaluation of benign tumors or vertebral body anomalies. For most infants and children, MRI has replaced myelography and CT myelography as the definitive procedure for spinal neuroaxis imaging, including spinal dysraphism, other developmental anomalies of the spine (Fig. 11-35), and acquired processes, such as neoplasms. CT myelography may have an advantage over MRI in patients with spinal dysraphism for demonstrating the location of cord tethering and for demonstrating nerve root avulsions after trauma. In the evaluation of the spinal bone marrow for metastatic disease, MRI is the procedure of choice (Fig. 11-36). Detailed information on spine imaging of children is beyond the scope of this chapter, but two excellent reviews are available [Castillo and Mukherji, 1996; Modic et al., 1994].

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FIGURE 11-36. Postcontrast, T1-weighted, sagittal magnetic resonance imaging (MRI) of the lumbar spine in a 7-year-old female with a history of medulloblastoma of the posterior fossa. After surgical resection, she developed leptomeningeal spread of the tumor. The MRI scan demonstrates extensive, enhancing leptomeningeal lesions that are consistent with drop metastases. Arrows mark the larger enhancing foci.

ANGIOGRAPHY The role of angiography has diminished since the emergence of CT, MRI, and MRA in pediatric neuroimaging. Contrast angiography in children requires sedation and anesthesia and may have complications such as death, stroke, and thrombosis of the femoral artery. It is usually restricted to the evaluation of vascular malformations, vasculitis, vasoocclusive disease (see Fig. 11-10E), and occasionally to central nervous system tumors.

SINGLE-PHOTON EMISSION COMPUTED TOMOGRAPHY AND POSITRON EMISSION TOMOGRAPHY Significant advances in single-photon brain imaging radiopharmaceuticals have occurred in the past decade. Technecium 99m ethylene cysteinate dimer, a radiopharmaceutical used for brain perfusion, and Tc 99m hexamethylpropyleneamine oxime are the main radiotracers used for clinical brain SPECT imaging. These radiotracers have the advantage of a Tc 99m label with its optimal imaging characteristics. There is widespread availability of multidetector SPECT. SPECT and PET scans are displayed in a similar fashion, analogous to MRI, in all three orthogonal planes: transverse, coronal, and sagittal. The oblique transverse or temporal lobe view is a useful adjunctive display, particularly in the presence of temporal lobe pathology. The indications for brain SPECT imaging in children [Gordon, 1998] include planning for epilepsy surgery [Cross, 2002], evaluation of brain death, acute neurologic

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loss (including stroke), language disorders, hypertension resulting from renal vascular disease, traumatic brain injury, and migraine. Pediatric psychologic conditions in which regional cerebral blood flow studies are occasionally obtained include anorexia nervosa, autism, Gilles de la Tourette syndrome, and attention-deficit–hyperactivity disorder [Gordon, 1998]. Considerable research is taking place in neuroreceptor imaging using iodinated- and technetium-labeled neuroligands to measure certain critical components of neurotransmission. Ongoing research is using SPECT and PET in the study of psychiatric disorders such as schizophrenia, anxiety disorders, depression [Frankle and Laruelle, 2002; Smith et al., 2003], eating disorders [Frank et al., 2004], and stress and mood disorders [Kennedy et al., 2004]. Iodine131-labeled metaiodobenzylguanidine localizes in adrenergic neurons. In one study, it was used to evaluate the uptake of this radiopharmaceutical in the cerebral tissue in patients with neural crest tumors who had no evidence of central nervous system disease [Bomanji et al., 1991]. Focal uptake was seen in the cerebellum, basal nuclei, and thalamic region. SPECT with radiolabeled metaiodobenzylguanidine may prove to be useful for mapping the adrenergic receptors in the human brain [Bomanji et al., 1991]. Increased uptake of MIBG by the brain is reported, especially in cerebellum after therapeutic iodine 131 metaiodobenzylguanidine in patients with pheochromocytoma [Dwamena et al., 1998]. Metaiodobenzylguanidine scans are used to evaluate and monitor children with neuroblastoma, along with CT or MRI scans, bone scans, bone marrow examination, and urine catecholamine measurements [Kushner, 2004]. Studies using PET scanning have made major contributions during the past decade to understanding the developmental neurobiology of the nervous system particularly in reference to cerebral and cerebellar glucose and oxidative metabolism and blood flow [Chugani et al., 1987; Shamoto et al., 1996]. However, because of its limited availability, a comprehensive review of the technology and its clinical applications is not included; several good sources are available [Chugani, 1992; Mohan et al., 1999; Neil, 1993; Phelps et al., 1986; Shulkin, 1997]. PET has been used to study patients with many different pediatric neurologic disorders, including various forms of epilepsy [Zupanc, 1996]; Rasmussen’s encephalitis [Caplan et al., 1996]; autism [Schifter et al., 1994]; language disorders [Semrud-Clikeman, 1997]; attention deficit disorders [Chabot and Serfontein, 1996]; movement disorders [Anouti and Koller, 1996]; neonatal hypoxic-ischemic encephalopathy [Chugani, 1992]; moyamoya disease [Ikezaki et al., 1994]; tuberous sclerosis [Rintahaka and Chugani, 1997]; Langerhans cell histiocytosis [Calming et al., 2002]; and central nervous system tumors [Hoffman et al., 1992]. The most common clinical application is for cases of pediatric epilepsy, particularly for patients who have not responded to pharmacologic management or the ketogenic diet. Such patients frequently have infantile spasms, focal ictal abnormalities in the frontal or temporal regions, or central nervous system malformations. These conditions are reviewed in greater detail in the chapters on epilepsy, particularly Chapter 51, on surgical evaluation and treatment. PET is most useful for patients who have normal neuroimaging studies but clinically and electrographically

have a focal seizure disorder or a generalized seizure disorder with significant asymmetries of activity [Chugani et al., 1994; Ferrie et al., 1996; Holopainen et al., 1997; Kramer et al., 1997; Sankar et al., 1995]. Interictal PET studies demonstrate areas of hypometabolic glucose metabolism using 2-deoxy[18F] fluoro-D-glucose in areas considered epileptogenic. Ictal PET scans demonstrate more variable metabolic changes. Chugani and colleagues [1994] reported three major metabolic ictal PET patterns based on the degree and type of subcortical involvement: asymmetric activity in the striatum and thalamus, unilateral cortical hypermetabolism that always involved frontal cortex, and symmetric striatal and thalamic metabolic abnormalities, accompanied by hippocampal or insular cortex hypermetabolism, diffuse neocortical hypometabolism, and absence of any cerebellar abnormality. In patients with refractory partial complex seizures, temporal lobe abnormalities can frequently be detected with PET [Adelson et al., 1992]. Studies have indicated congruence between focal temporal electroencephalographic (EEG) abnormalities, hippocampal atrophy on MRI, hypometabolism in corresponding interictal regions with PET, and reductions in the metabolite ratios using proton MR spectroscopy [Holopainen et al., 1997]. Patients with infantile spasms may also have significant EEG and PET cortical or subcortical asymmetries that have been shown useful in the evaluation for epilepsy surgery [Chugani, 1993; Kramer et al., 1997]. PET may reveal lateralized or localized regions of hypometabolic glucose use that corresponds to localized EEG abnormalities and cortical dysplasias or other structural abnormalities on neuropathologic examination. Surgical resection of regions with one hypometabolic area usually results in improved seizure control; patients with multiple hypometabolic regions are unlikely to benefit from such treatment. PET has also been of particular value in children with intractable seizures who have subtle or major central nervous system malformations. These cases include children with tuberous sclerosis [Rintahaka and Chugani, 1997], Sturge-Weber syndrome [Chugani et al., 1989], hemimeganencephaly [Rintahaka et al., 1993], and focal cortical dysplasias and other migrational disorders [Chugani, 1992; Kim et al., 2000; Sankar et al., 1995; Zupanc, 1996]. Identification of such areas of hypometabolic activity in conjunction with EEG and clinical correlates usually provides sufficient evidence to consider surgical resection. PET imaging of children with central nervous system tumors is useful [Wegner et al., 2004]. Brain tumors can be histologically heterogeneous and stereotactic biopsies may lead to inaccurate diagnosis or grading. Increased uptake with fluoro-D-glucose–PET may represent more malignant or aggressive tumors [Etzl et al., 2002]. By combining PET and MRI in the planning of a stereotactic brain biopsy, it may be possible to improve the diagnostic yield and reduce sampling from high-risk or functional areas [Massager et al., 2000; Pirotte et al., 2003]. ACKNOWLEDGEMENT Imaging figures in this chapter were provided by Dr. Nathaniel D. Wycliffe and spectra by Dr. Barbara Holshouser from the Department of Radiology, Division of Neuroradiology, Loma Linda University School of Medicine, Loma Linda, California.

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CHAPTER 12

Pediatric Neurophysiologic Evaluation Mark S. Scher

Pediatric neurophysiologic studies are an integral part of the diagnostic evaluation of the infant or child with suspected brain dysfunction; electroencephalography, polysomnography, and computerized electroencephalographic (EEG) analyses comprise three general diagnostic modalities. Pediatric neurologists must apply proper instrumentation and recording techniques to obtain reliable pediatric neurophysiologic studies in an EEG laboratory or at a child’s bedside. With proper knowledge of these techniques, the clinician can better appreciate the clinical relevance of these studies. In the first section of this discussion, techniques of recording unique to children are introduced. As outlined in the second section, maturational changes in arousal states of children are emphasized in considering normal or age-specific patterns. Third, abnormal EEG patterns are discussed in the context of common pediatric neurologic disorders [Blume, 2002; Ebersole et al., 2003; Niedermeyer et al., 2005]. A fourth section is devoted to computer applications of spontaneous EEG and evoked-potential studies. The neurologist should consistently follow analytic steps in the interpretation of neurophysiologic studies. Proper interpretative skills ultimately require two essential didactic elements that are beyond the scope of this discussion: presentation of multiple examples of the same neurophysiologic phenomena and use of typical and atypical clinical situations in which common and complex neurophysiologic patterns are observed. Several excellent reviews supplement this discussion and can assist the physician with the evaluation of children who exhibit these phenomena [Binnie et al., 2003; Blume, 2002; Cracco and Bodis-Wollner, 1986; Daube, 2002; Ebersole et al., 2003; Mizrahi et al., 2003; Niedermeyer et al., 2005; Scher, 2005; Spehlman, 2001; Weiner et al., 1991]. Use of neurophysiologic studies necessitates an understanding of their limitations and benefits. Such tests should only supplement proper history taking and physical examination techniques, which comprise the clinical diagnostic process. Overinterpretation of laboratory data without consideration of the clinical situation must be avoided; the neurologist should always rely on clinical judgment for each patient, rather than rely solely on the results of any laboratory test.

UTILITY OF PEDIATRIC ELECTROENCEPHALOGRAPHY The EEG results can assist in the diagnosis and prognosis of specific neurologic conditions. Understanding the specific situations in which the EEG findings are helpful allows efficient and effective use of this comparatively low-cost and safe tool [Drazkowski, 2003]. However, there is little

advanced evidence-based medicine in the literature on the subject of electroencephalography. In a review published by Medline and Cochrane [Fowle and Binnie, 2000], there is a lack of evidence concerning the usefulness of EEG findings. Only retrospective studies have assessed the efficacy of EEG results in the evaluation of neurologic conditions for children, uniformly reporting that interictal EEG findings may be overused during the evaluation of various pediatric brain disorders [Aydin et al., 2003], whereas normal EEG findings are highly predictable in children with nonepileptic conditions [Jan, 2002]. Although the physician should not ignore multivariable analyses in which EEG is used to differentiate risks, diagnostic decision-making still rests on clinical effectiveness data, rather than EEG diagnoses [Gilbert et al., 2000]. The physician also must consider the clinical settings of the emergency department or intensive care unit in which the indications and diagnostic yield of the electroencephalogram will vary [Alehan et al., 2001; Varelas et al., 2003] based on the selection bias of the pediatric groups chosen for study.

TRAINING IN CLINICAL NEUROPHYSIOLOGY Although the neurology trainee receives basic clinical neurophysiology instruction during residency training, there is a recognition that neurologists with more training and experience in clinical neurophysiology are needed, in part because of the increased complexity of the specialty and the demand for high-quality care for people with complex neurologic diseases. Accredited training programs in clinical neurophysiology and individual certification with the subspecialty of clinical neurophysiology have been available since 1993 [Burns et al., 2000]. An adequate duration of training with appropriate curriculum requirments is described. Future opportunities for the clinical neurophysiology subspecialist will lead to modifications of the subjects taught, such as for fields of sleep medicine and neurointensive care. Pediatric neurologists must satisfy these training requirements, with special emphasis on the unique aspects of developmental clinical neurophysiology for the office and hospital settings, including neonatal and pediatric intensive care units. In addition to the more thorough training requirements for pediatric neurologists, practice parameters have been more rigorously enumerated to develop strategies for patient management that are based on analysis of evidence. Such parameters include the use of EEG results more selectively, such as for children with development delays, cerebral palsy, or headache [Ashwal et al., 2004; Lewis et al., 2002; Shevell et al., 2003]. Such guidelines require comparisons with those specifically developed to improve the use of EEG

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methodology, such as for the diagnosis of epilepsy [Flink et al., 2002].

INSTRUMENTATION AND RECORDING TECHNIQUES Each EEG channel measures the electropotential difference between two points on the scalp under the assigned electrodes. Ten electrodes are required as a minimum number for adequate EEG recordings [American Electroencephalographic Society, 1986]. A greater area of cerebral activity can be measured with more EEG channels. EEG laboratories devoted to pediatric studies should use 16 to 24 channels. In the neonate, it may be more practical to apply fewer electrodes, as discussed later in this chapter. The International 10-20 System of electrode placement is the standard method of electrode application, and it routinely requires the placement of 22 electrodes on the head. The basis of the 10-20 system is the measurement of four standard points on the head: nasion, inion, and left and right preauricular points [Holmes, 1987; Niedermeyer et al., 2005]. Electrodes are spaced at 10% or 20% of the total distance between pairs of skull landmarks; scalp locations correspond to anatomic landmarks. Electrode names correspond to the underlying brain regions over which they are positioned. Electrodes with odd numbers correspond to regions in the left hemisphere, and even numbers refer to areas in the right hemisphere. Midline electrodes have a zero (z) as a suffix. Additional electrodes may be used to localize electrical activity. Readjustment of the electrode placements may be required for preterm neonates and for patients with skull deformities. Silver–silver chloride electrodes are most commonly used; application to the scalp is achieved with paste or collodion. Needle electrodes are no longer recommended. A qualified electroneurodiagnostic technologist is critical to ensure proper electrode application, particularly in children. Careful and rapid placement of electrodes is helpful to the success of each study. Electrode arrays, or montages, refer to the combination of electrodes examined at any particular point in time. There are two principal types of channel relationships. Bipolar recordings measure electrocortical activity between two active brain areas. Referential recordings compare a reference electrode, or neutral electrode, with an active electrode. The neutral electrode is usually placed on the ear or mastoid. Another referential montage is the average referential recording; activity from all active electrodes is averaged and compared with activity at any one electrode. There are advantages and disadvantages with each recording technique. Bipolar recordings permit better localization of electrographic phenomena, whereas referential recordings better display EEG patterns that have widespread distribution. The technologist should perform each recording using a variety of montages. Important maturational patterns and abnormal features in pediatric electroencephalography can be best displayed using multiple montage displays.

Polarity Localization Proper electrode placement and montage choices allow accurate comparisons between homologous brain regions. In

this way, the neurologist can localize EEG data on an anatomic basis and can standardize regional or hemispheric findings over multiple EEG recordings. An understanding of the principles of polarity is essential in using the localization technique. Inputs for two electrodes for one EEG channel are generated by two differential amplifiers, called input terminal one and input terminal two. With a differential amplifier, the output is proportional to the voltage difference between these two input terminals. The direction of the pen deflection depends on differences in polarity of this voltage difference. By convention, when input terminal one is relatively more negative, there is an upward deflection. Other possibilities include a downward deflection if input terminal one is relatively more positive. The reverse situation pertains to input terminal two; when input terminal two is relatively more negative, there is a downward deflection [Cooper et al., 1980]. An EEG waveform recorded on the scalp surface is assumed to arise from an electrical dipole within the brain. This hypothetic dipole arises from a group of neurons whose dendritic processes are oriented perpendicular to the scalp. An electrical field is represented on the scalp, with the maximum voltage potential near the center and decreasing levels of voltage denoted by concentric rings that successively enlarge from this central point. Most abnormal electrographic potentials are represented by a dipole with the negative end toward the surface and the positive end inward. Depending on the particular orientation of the dipole in relation to the surface, its field representation on the scalp has different shapes. Occasionally, surface positive waveforms are observed, such as positive sharp waves in newborn recordings and dipoles represented on the scalp in patients with rolandic epilepsy. Given the common practice of comparing groups of electrodes in a linear fashion, the amplitude and polarity expressed for each electrode in a bipolar recording may demonstrate a phase reversal in adjacent electrodes. This reversal is represented by a simultaneous pen deflection in opposite directions in two adjacent bipolar channels. By this technique, the electroencephalographer can localize focal EEG phenomena as long as sources of artifact are not suspected. For accurate localization, two linear electrode arrays at right angles to each other should intersect through the region to be examined. This technique can effectively localize most waveforms that are considered to have vertical dipoles in relation to the scalp.

Instrumental Control Settings Each EEG recording must clearly indicate all instrumental settings at the beginning of the study. Any adjustments in sensitivity, paper speed, or filter settings must be marked. Calibration signals should begin and conclude the recording to demonstrate to the electroencephalographer how the amplifier and pen-writing apparatus respond at all instrumental settings.

Sensitivity Settings Sensitivity settings should begin with the standard 7-μV/mm position and be adjusted accordingly throughout the record. Lower sensitivities (i.e., 10 μV/mm) are used for higher

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amplitude signals in which the pens block and do not reflect maximum amplitude. Higher sensitivities (2 to 5 μV/mm) are needed when lower amplitude signals do not cause sufficient pen deflection.

Filter Settings High- and low-frequency filters are required to allow accurate representation of the appropriate range of frequency-specific waveforms of cerebral origin. Adjustment of these filters should be made judiciously so that genuine brain-generated activities are not eliminated along with undesirable, noncerebral artifactual signals. High-frequency filters are set at a standard 70 Hz so as not to blunt the appearance of fast frequencies, including abnormal spikes and sharp waves. Occasionally, lower settings may be needed when excessive fastfrequency artifacts exist, such as 60-cycle interference from other electrical devices. Low-frequency limits, commonly referred to as time constants, routinely vary between 0.3 and 0.1 seconds. For situations when slow-frequency waveforms need to be analyzed or eliminated, longer or shorter time constants, respectively, can be chosen. This procedure is particularly important in EEG recordings of neonates and young infants in whom slower frequency activities need to be clearly represented.

Paper Speed The conventional 30-mm/sec paper speed is selected unless specific clinical situations require that the paper record

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be compressed or elongated to examine specific electrical phenomena. Slower speeds are recommended for newborn recordings and polysomnographic sessions in which slowly occurring activity can be compressed for easier analysis. Faster speeds can assist occasionally in identifying 60-cycle interference and in distinguishing muscle potentials from spikes of cerebral origin.

Physiologic Noncerebral Channels Important information can be derived from recording muscle movement, respiratory activity, eye movement, and cardiac activity. These monitors can assist in defining specific portions of the sleep cycle. Noncerebral physiologic observations, such as respiratory pauses or cardiac arrhythmias, may have relevance for the clinical problem that prompted the request for an EEG study. Sleep state-dependent apnea and congenital heart block are two clinical situations in which noncerebral physiologic monitoring can be crucial to the diagnosis. Important sources of artifact can be more readily identified and eliminated by using noncerebral monitors; cerebral activity can be more accurately displayed.

Artifact Recognition As with adults [Brenner, 1981; Richey and Norman, 1976], physiologic and nonphysiologic artifacts must be properly identified in pediatric recordings, because either may interfere with the interpretation of cerebral activity. Three basic forms of artifacts have been classified: instrumental, external,

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FP1–F7 F7–T3 T3–T5 T5–O1 FP2–F8 F8–T4 T4–T6 Right pinnae jerking T6–O2 T6–O2 FP1–F3 F3–C3 C3–P3 P3–O1 FP2–F4 F4–C4 C4–P4 P4–O2 FZ–CZ CZ–PZ EKG. OFF. OFF.

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1 sec.

FIGURE 12-1. A, Electroencephalogram (EEG) of an infant of 40 weeks’ gestation 1 day after birth. The infant had severe asphyxia caused by a ruptured vilamentous cord with exsanguination. Background activity is markedly suppressed with superimposed physiologic artifact from excessive tremulousness. Readjustment of the patient’s head lessened this artifact. B, An 11-year-old female with brainstem encephalitis. On neurologic examination, the right pinnae displayed myoclonic movements. Myogenic potentials on the EEG (in the region of the right temporal area [T4]) represent the segmental myoclonus noted on examination.(A, From Scher MS. Physiologic artifacts in neonatal electroencephalography. Am J EEG Technol 1985;25:257; B, Courtesy of Dr. P. Crumrine, Children’s Hospital, Pittsburgh.)

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and physiologic. Accurate descriptions by the technologist can assist the neurologist in the diagnosis of a neurologic disorder in adults [Klass and Reiher, 1965], children [Blume, 2002], and neonates [Scher, 1985] (Fig. 12-1). Such artifacts may help define normal and abnormal sleep and waking behaviors. The technologist should try to identify the source of any artifacts, initially to reproduce them and subsequently to eliminate artifacts that were identified during the recording.

Recording Setting The pediatric EEG laboratory should be within easy access to inpatients and outpatients. Technologists must also be able to travel rapidly to areas within the medical facility to perform portable EEG studies in the emergency department, intensive care units, or patients’ hospital rooms. To obtain quality recordings, effort must be made to elicit the child’s most cooperative behavior. A well-illuminated, neatly organized room with a friendly decor assists in preparing the child. Ample time should be arranged for proper electrode application and recording. Obtaining unmedicated, awake, drowsy, and natural sleep recordings on all children is highly recommended. Despite the special challenge provided by the infant and young toddler, it is possible to obtain quality tracings without the use of sedative medications. A minority of children may require sedation. The need for sedation can be substantially reduced by adequate preparation of the child, including the creation of a lessthreatening environment in which to perform the study. One report described a decreased proportion (32% to 2%) of 513 children who needed sedation over a 4-year period when appropriate preparation was provided [Olson et al., 2001]. Chloral hydrate (50 to 80 mg/kg; maximum dose, 2 grams) is most commonly used for sedation, and it should be administered only to a child who has not been recently fed. Rectal administration may be advantageous for the encephalopathic or extremely uncooperative child who requires the study [Thoresen et al., 1997]. Psychotropic or sedative drugs should be avoided because they produce more profound behavioral and EEG effects. Infant recordings should be obtained around a scheduled feeding or nap. At least 90 minutes should be scheduled for electrode application, EEG recording, and clean-up. With some exceptions, the parents’ presence during the recording session should be discouraged. A child-life specialist or similarly trained individual can provide developmentally appropriate and child-friendly support. The technologist should accurately record the pertinent clinical evaluation of the child that explains the reason for obtaining the EEG study. Information from parents or the medical record should include the child’s age; gestational and postconceptional ages should be included for neonates. The physician who ordered the study should be identified, and the written request for an EEG study should clearly state the clinical problem that prompted the EEG request. Notations by the technologist of the recording conditions must include the state of arousal and cooperation of the patient. Skull defects, vital signs, pertinent laboratory studies, and medications should be listed, because each may affect the technical recording and clinical correlation of the EEG recording. For instance, cephalohematomas, hypothermic

states, or barbiturate overdosage may attenuate the EEG activity on a regional or bihemispheric distribution, but they have dramatically different clinical interpretations. Frequent and accurate annotations by the technologist must describe changes in state throughout the spontaneous and activation portions of the record. Passive or active eye opening and closure are essential, and repositioning of the patient may be required to eliminate or minimize artifacts. Consensual validation of suspicious cerebral activity with an encephalographer must always be a high priority. Monitoring within the pediatric or neonatal intensive care settings requires special considerations, because of the need to obtain quality recordings in the hostile electronic and physical environment. Nursing personnel and physicians assigned to the intensive care unit teams should receive appropriate instructions on the documentation of events in question and on rudimentary pattern recognition to identify major bihemispheric ictal patterns and how to differentiate them from artifact.

NEUROPHYSIOLOGIC BASIS FOR ELECTROENCEPHALOGRAPHY Electrical activity generated by the brain can be classified in three broad categories. Spontaneous and evoked electrical activity detected on the scalp as oscillatory potentials are discussed primarily in this section. Electrical potentials generated by single neurons recorded by microelectrodes are briefly mentioned in the context of the neurophysiologic basis of EEG studies. Informative reviews of the neurophysics of cerebral electrical fields are available in other sources [Ebersole et al., 2003; Niedermeyer et al., 2005; Nunez, 1981]. The central problem for the neurologist is how to relate scalp potentials to underlying physiologic processes. It is an empiric observation that scalp potentials are expressed as a mixture of frequency-dependent waveforms that have temporal and spatial characteristics. The potentials depend on the nature and location of current sources within the brain that have electrical and geometric properties specific to the size and shape of the scalp, skull, and underlying brain substance. This concept is crucial to understanding maturational patterns and appreciating the neurophysiologic substrate of central nervous system (CNS) dysfunction in children. The major source of these oscillating potentials measured on the scalp is synaptic activity. A more limited contribution to the scalp-derived potential comes from the action potential of the neuron itself. To fully appreciate how synaptic potentials are generated on the scalp, the neurologist must acquire an understanding of the intracellular and extracellular ionic environment of the neuron. Neurons contain fluid restricted by a cylindric membrane that limits the movement of ions in and out of the cell. Because the axon and dendrites are connected to the cell body, the same ionic flux pertains to these structures. Restriction in ionic movement results in a resting voltage potential difference, with a high concentration of sodium and chloride outside of the cell and with potassium concentrated within the neuron. A sodium-potassium pumping system maintains these concentration gradients, with a resting potential of approximately 70 μV.

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With the production of an action potential, a rapid depolarization of the membrane occurs with a transient increase in sodium permeability, matched by an equal but opposite outflow of potassium. The gradual decrease in sodium conduction and the outflow of potassium lead to repolarization. The depolarization, or action potential, travels down the axon to synaptic clefts, where chemical transmitters are released. Presynaptic membrane release of neurotransmitters begins the process of cell-to-cell communication, with activation of the postsynaptic membrane by depolarization or hyperpolarization. Depolarization by specific neurotransmitters causes an inward flux of sodium, creating a voltage gradient that is called the excitatory postsynaptic potential. Hyperpolarization by other neurotransmitters causes an outward flow of sodium, contributing to an inhibitory postsynaptic potential. Summation of excitatory postsynaptic potentials and inhibitory postsynaptic potentials within a region involving a number of synapses determines the degree of postsynaptic membrane depolarization or hyperpolarization. If excitatory postsynaptic potentials predominate, depolarization will lead to an action potential. If inhibitory postsynaptic potentials predominate, hyperpolarization will follow, preventing the occurrence of an action potential. Although synaptic potentials are of lower voltage than action potentials, their longer time course and larger membrane surface area contribute primarily to scalp-detected EEG activity. During the excitatory postsynaptic potential or inhibitory postsynaptic potential, there is a current flow in a loop orientation with opposite polarities at each end of the cell’s axonal or dendritic processes of the cell. Because most neurons are oriented radially to the cortical surface, these current flows follow a radial direction in and out, as detected by surface electrodes. The polarity, as recorded on the surface, reflects an excitatory or inhibitory current flow, depending on the nature of the summated synaptic potentials and on the site of the synapse. Virtually all electrical activity recorded on the scalp is generated by current flow across the synaptic membranes of cortical neurons. Subcortical activity does not substantially contribute to the generation of current flow and electric fields. Instead, diencephalic structures, such as the thalamus, exert a modulatory effect on cortical rhythms, such as the regulation of the dominant alpha rhythm, and on the appearance and rhythmicity of sleep spindles. Glial cells consist of a soma and fibers. Glial cells intermingle with the neuronal structures and are electrically coupled, building up an extended functional network. Glial cells also exhibit a membrane potential. Unlike neurons, glial cells do not generate postsynaptic action potentials. Their resting potential is exclusively based on potassium-outward current through leakage channels. The membrane potential value is close to the potassium equilibrium potential. With a decrease in extracellular potassium concentration, glial cells depolarize and repolarize, respectively. Glial cells are functionally linked by way of the extracellular potassium concentration. Neuronal action potentials are associated with an outflow of potassium ions. With an increase in the repetition rate of neuronal action potentials, exocellular potassium concentration increases, resulting in depolarization of glial cells adjacent to active neurons [Somjen and Trachtenbers, 1979].

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Potential Fields and Neuronal Networks A variety of neuronal elements contributes to the extracellular currents that generate field potentials recorded at the surface of CNS structures. Spatial arrangements of neuronal elements and the position of recording electrodes play an essential role in establishing and detecting extracellular potential fields. There are two principal types of neuronal arrangements. The first is a parallel type in which the somata are in one layer and dendrites in the opposite layer. The second type consists of the somata in the center of a pool and dendrites extending to its periphery; the first type of organization is found in the cortex, and the second is observed in brainstem nuclei. Each neuronal arrangement generates opened and closed fields. In open fields, one electrode largely integrates potentials of the neuronal population, whereas the other electrode sees only the positive or negative field, permitting the recording of the field potential. In a closed field, external electrodes do not appear to see potential differences because currents within the pool compensate for each other [Niedermeyer et al., 2005]. Several types of field potentials can be differentiated, depending on the time constant of the amplifying recording device. Amplified EEG recordings at a time constant of 1 second or less can be contrasted with an infinite time constant using a direct current (DC) amplifier, permitting additional recording of baseline shifts and wavelike potentials. On conventional EEG studies, the generation of a wavelike potential consists of summated excitatory postsynaptic potentials, which occur in the dendrite. With sustained, regular activity, a depolarization shift of the membrane potential appears, and changes in the membrane potential in the upper dendritic layers lead to an action potential. When amplifiers with a finite time constant, such as on conventional EEG recordings, are used, fluctuations in field potential are recorded without recording shifts in membrane potentials. In contrast, baseline shifts or EEG/DC potentials reflect sustained values of the membrane potential of neuronal elements that are being recorded. Using a sufficiently high upper-frequency limit, DC recordings comprise conventional EEG waves and slow potential deviations. Glial cells are involved in the generation of baseline shifts, as are neuronal cells because of the functional coupling between neurons and glial cells. However, field potential changes are thought to be generated primarily by neuronal structures.

Neurophysiologic Basis of Abnormal Electrical Patterns Several electrical patterns appear to correlate with specific clinicopathologic situations in adults and children. In general, epileptiform and nonepileptiform abnormalities are subdivided because of presumably different neurophysiologic or neuropathologic substrates. The following discussion outlines selected experimental findings that help explain certain abnormal patterns relevant to pediatric and adult EEG studies, which are addressed in a later section. Interictal spike discharges, the hallmark of the epileptic neuron in experimental models of epilepsy, involve a specific type of membrane depolarization, referred to as a paroxysmal depolarization shift. There are general sim-

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ilarities between the neuronal events underlying this interictal epileptogenetic process [Jeffreys, 1990]. In hippocampal and neocortical slice recordings taken after penicillin application [Ayala et al., 1973], high-voltage discharges appear in the EEG recording and are associated with an intracellularly recorded paroxysmal depolarization shift. These phenomena appear in intracellular recordings of experimental animals and human cortices. The depolarization is of relatively high voltage (10 to 15 μV) and long duration (100 to 200 msec), and it is associated with a burst of spike discharges. The event produces a train of action potentials that conduct away from the neuron along the axon. The interictal paroxysmal depolarization shift is followed by a period of hyperpolarization. Over time, this depolarization can summate to form a prolonged depolarization with a persistent loss of hyperpolarization, which is recorded on the surface as continuous spike discharges coinciding with the tonic phase of a generated tonic-clonic seizure. Subsequently, large inhibitory potentials alternate with recurrent rhythmic depolarization, which coincides with the clonic phase of the seizure. Despite the higher threshold necessary to achieve depolarization and the longer refractory period observed in immature animals [Prince and Gutnick, 1972], an understanding of paroxysmal depolarization shift is crucial to an appreciation of maturational aspects of epileptogenesis. Based on these experimental observations, several hypotheses have been advanced to explain the mechanism by which normal neuronal activities convert to those of abnormal interictal discharges [Prince, 1985]. One mechanism A

involves intrinsic membrane abnormalities that promote burstgenerating properties in individual neurons by an imbalance of calcium and sodium ion movements [Schwartzkroin and Prince, 1978]. Another mechanism involves the loss of inhibition by a group of neurons because of the absence of the inhibitory neurotransmitter, γ-aminobutyric acid (GABA) [Prince, 1985]. A third mechanism of summated excitatory postsynaptic potentials helps explain how large groups of neurons generate depolarization shifts [Prince, 1978]. These proposed mechanisms unfortunately do not necessarily explain the transformation from an interictal to an ictal event. Other mechanisms have been proposed based on additional experimental studies, including changes in the ionic microenvironment that result in enhanced neuronal excitability, axonal burst generation, and cholinergic alteration of neuronal properties [Prince, 1985]. Metabolic factors related to glucose or electrolyte imbalance or noncerebral factors, such as trauma or fever, may facilitate the onset of seizures, particularly in children. Additional biochemical and anatomic alterations within a seizure focus may further promote seizure generation by neuronal destruction or glial proliferation [Aird et al., 1984].

Abnormal Suppression or Slowing of Electroencephalographic Activity In addition to the presence of spike or sharp-wave discharges for the diagnoses of seizure disorders, other types of abnormal EEG patterns coincide with different neuroB

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FIGURE 12-2. A, Electroencephalogram (EEG) of a 2-year-old female with marked attenuation in the right hemisphere occurring above and below the sylvian fissure demonstrates an absence of vertex waves and suppression of sleep spindles. Extensive, right hemispheric encephalomalacia is documented on imaging studies. B, EEG of a 9-year-old female with slowing in the left posterior quadrant demonstrates an arteriovenous malformation in the left hemisphere, which was depicted on imaging studies.

Scher / Pediatric Neurophysiologic Evaluation

pathologic substrates [Ebersole et al., 2003]. Unfortunately, little information exists that has correlated altered neuronal properties, such as the mechanisms discussed for epileptogenesis with specific neuropathologic entities. Instead, clinical interpretations of the following EEG patterns are mostly empirically based on correlative neuropathology. Local suppression or absence of background rhythmic activity is a strong indication of brain dysfunction, irrespective of age or location in the brain. Complete absence of activity usually implies cortical necrosis that is close to the surface [Goldensohn, 1979a, 1979b]. However, incomplete depression of background activity is the more common situation. Asymmetric suppression of frontal beta activity, central rhythms, dominant alpha activity, or sleep spindles in association with polymorphic delta waves strongly indicates a destructive process in the brain underlying those electrodes (Fig. 12-2A) [Arfel and Fischgold, 1961]. EEG recordings of neonates showing asymmetric background activities usually suggest that the brain lesion is in the attenuated location [Scher and Tharp, 1982]. Continuous polymorphic delta waves constitute a category of EEG abnormality that may suggest a structural brain lesion on an acquired or congenital basis (see Fig. 12-2B). Irregular delta waves between 0.5 and 2.5 Hz do not react to eye opening, arousal, or sleep. Correlations with brain lesions in animals [Gloor et al., 1968] and in humans at postmortem examination have been described [Rhee et al., 1975]. Focal slowing may imply focal destructive lesions of white matter by a congenital, vascular, neoplastic, or infectious process. Polymorphic delta waves can commonly appear imme-

A

diately after a seizure of focal onset and with reversible conditions, such as migraine [Hockaday and Whitty, 1969]; both are common occurrences in children. The combination of bilateral, synchronous rhythmic discharges and polymorphic delta waves occurs in diffuse encephalopathies involving white and gray matter. Certain brain regions, such as the frontal, temporal, and occipital areas, are more likely to express polymorphic delta waves. The association of background rhythm depression and polymorphic delta waves increases the likelihood of destructive lesions, especially tumors. Parasagittal and parietal lesions often are associated with attenuation of rhythms or prominent theta rhythms. Intermittent rhythmic delta activity is another category of nonepileptiform abnormality with a variety of neuropathologic correlates. Runs of sinusoidal 2.5 Hz are generally reactive to eye opening, hyperventilation, or arousal. Two distinct distributions of rhythmic delta activity over the scalp have been identified. Frontal intermittent delta activity (Fig. 12-3A) and occipital rhythmic delta activity (see Fig. 12-3B) generally indicate modification of cortically generated EEG activity by midline subcortical structures. The thalamus, reticular-activating system, and midbrain can contribute to the dysfunction between subcortical gray matter and cortical neurons [Daly, 1974]. These two types of rhythmic delta activity are largely age related. Frontal intermittent delta activity usually occurs in adult patients, whereas occipital rhythmic delta activity is found mainly in children. Intermittent rhythmic delta activity does not necessarily indicate that the major pathologic condition is in that region. Occipital rhythmic delta activity and frontal intermittent

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FIGURE 12-3. A, Electroencephalogram (EEG) of a 21/2-year-old male with frontal intermittent delta activity indicative of a diffuse encephalopathy on a hypoxic-ischemic basis. B, EEG recording of a 12-year-old male with a predominantly occipital intermittent rhythmic delta activity indicative of a diffuse encephalopathy on a metabolic basis.

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delta activity have been documented in 53% of 145 children with posterior fossa tumors [Martinius et al., 1968]. As a rule, it has little localizing value for supratentorial masses, although it may be accentuated on the side of the tumor [Hess, 1975]. Intermittent rhythmic delta activity is nonspecific and may be observed with systemic metabolic disorders, increased intracranial pressure, encephalitis, and trauma. However, a later report of frontal intermittent delta activity described this pattern as rare for children, observed in only 20 of 1500 EEG studies of children between 18 months and 17 years old. Most patients were awake, showed no encephalopathic signs, but were cognitively impaired. Another 50% had a history of epilepsy, with epileptiform activity occurring in 55% of the cohort [Watemberg et al., 2003]. Epileptiform discharges can be found in combination with slowing as an indication of a structural process. Focal discharges during a seizure have better localizing value than interictal spikes [Hess, 1975]. In general, slow-growing neoplasms, such as oligodendrogliomas or astrocytomas, produce more epileptiform activity than rapidly growing tumors [Kershmann et al., 1949]. Spike discharges are more common after surgery, such as for meningiomas, but neurologists are advised to exercise extreme caution concerning spike discharges as reliable guides to localization of destructive lesions. Imaging studies are far more reliable laboratory guides.

SIGNIFICANCE OF NORMAL VARIATION IN ELECTROENCEPHALOGRAPHY: MATURATIONAL PATTERNS Guidelines for Interpretation EEG analysis requires a systematic, orderly process in which a series of steps are followed to reach a proper interpretation [Ebersole et al., 2003]. The rhythmicity of spontaneous EEG signals gives a continuous admixture of scalp-generated oscillatory potentials. EEG frequencies are classified as four band ranges: Delta activity is less than 4 Hz; theta activity is 4 to 8 Hz; alpha activity is 8 to 13 Hz; and beta activity is greater than 13 Hz. In general, the amplitude of EEG activity is inversely proportional to frequency. For pediatric EEG studies, the amount of slow activity decreases with increasing age, and the persistence and frequency of slow activity vary in different brain regions. It is important to appreciate the presence and degree of expression of frequencies in various regions at different ages, and other parameters, such as waveform, manner of occurrence (e.g., random, continuous), and amplitude, are essential to visual analysis. By means of this cumulative analysis, using a list of parameters of EEG activity [Ebersole et al., 2003; Kellaway and Crawley, 1964; Lombroso, 1980], the neurologist can attempt to assign normal or abnormal clinical significance to the EEG pattern. Critical information regarding age and state of the patient affects the ability of the neurologist to judge normality in the EEG record. It may require several EEG recordings and the persistence or resolution of abnormal electrical activity relative to the state of the patient to assess normality properly. Several recordings allow an appreciation of the

ontogeny, or evolution, of significant age-specific EEG patterns. These guidelines must be repeatedly emphasized as the pediatric neurologist acquires an appreciation of the rich diversity of normal maturational patterns.

Newborn Electroencephalographic Patterns Neonatal EEG studies have been reported for almost 60 years [Okamato and Kirikae, 1951]. Pioneering investigations by several independent researchers have all contributed information concerning the developmental neurophysiology of the immature brain. Some of these studies predate the development of the tertiary-care neonatal intensive care unit, and the neurologist using EEG recordings had an understandably limited role in the diagnostic assessment and clinical care of the sick neonate. Improvements in recording equipment and standardization of the recording techniques are available in modern neonatal intensive care units. An internationally accepted system of electrode placement, adapted for the neonate and young infant, permits standardization of recordings between laboratories [American EEG Society, 1986]. Development of 16-channel and 21-channel EEG machines with improved filtering systems and electrode construction minimizes environmental and physiologic sources of artifacts. Synchronized video-EEG studies permit more accurate comparison between electrographic and behavioral changes in the assessment of seizures, movement disorders, and sleep cycles [Dyken et al., 1997; Scher, 1987]. Several fundamental principles for neonatal EEG studies serve as an introduction to an understanding of its chief clinical application. There are expected changes in the scalp-generated EEG patterns for neonates of different gestational ages. The experienced encephalographer can approximate the electrical maturity within 2 weeks of the gestational age. Changing electrical patterns reflect the postconceptional age of the neonate independent of birth weight. Maturation of the neonate’s sleep-wake behavior follows maturation of the CNS and is independent of the birth weight [Schulte et al., 1971]. Preterm neonates, when corrected to term postconceptional age, should have EEG patterns and sleep behavior similar to those of term, appropriate-for-gestational-age newborns. Detailed electrographic and anatomic correlations that compare sulcal-gyral development with evolving electrical patterns have been correlated with clinical information concerning gestational maturity [Scher and AhdabBarmada, 1987] (Figs. 12-4 and 12-5). Of 25 infants, 23 had maturational agreement within 2 weeks between electrical patterns and sulcal-gyral measurements of the inferior frontal, superior temporal, and calcarine gyri and between the cytoarchitecture of various brain regions. Regional changes in electrical activity clearly occur in the EEG of the premature neonate when recordings are obtained after 24 to 25 weeks’ estimated gestational age and at weekly intervals [Dreyfus-Brisac, 1979; Mizrahi et al., 2003; Tharp et al., 1981; Torres and Anderson, 1985; Scher 2005] (Fig. 12-6). Sleep-wake behavior cannot be distinguished for patients younger than 30 weeks of age, but other hemispheric or regional patterns demonstrate predictable, evolving characteristics.

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FIGURE 12-4. A, Two age-appropriate electroencephalographic tracings of a 26-week-gestation, 3-day-old female. Generalized theta and delta slowing is demonstrated, and vertex central slow activity is prominent (top left frame). Notice the bitemporal attenuation. Synchronous interburst intervals of less than 40 seconds’ duration and delta brush patterns in the vertex region are demonstrated (right frame). B, Lateral view of the brain of the patient in A. Underdeveloped frontal and temporal lobes with insulas are visible and indicate an immature sulcation pattern, especially of the rolandic, calcarine, and superior temporal sulci. (From Scher MS, Ahdab-Barmada M. Gestational age by electrographic, clinical and anatomical criteria. Pediatr Neurol 1987;3:256.)

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FIGURE 12-5. A, Two samples of an electroencephalogram of a 30-week-gestation, 9-day-old female. A greater degree of spontaneous, continuous electroencephalographic activity is demonstrated (top left frame), including temporal delta and delta brush patterns. The occipital delta and delta brush patterns are shown (right frame). B, Lateral view of the brain for the patient described in A. There is a greater degree of sulcation evident. Observe the more complete elaboration of the rolandic, superior temporal, and calcarine sulci. (From Scher MS, Ahdab-Barmada M. Gestational age by electrographic, clinical and anatomical criteria. Pediatr Neurol 1987;3:256.).

Scher / Pediatric Neurophysiologic Evaluation

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FIGURE 12-6. A, Relatively continuous background of slow and fast frequencies are shown for a 26-week-gestation, 5-day-old female. Rhythmic central delta occurs with superimposed delta brushes in the same region. Asymmetric or asynchronous occipital delta activity is demonstrated, and temporal attenuation is prominent. Myoclonic movement is indicated (arrow). B, For a 26-week-gestation, 1-day-old male, discontinuous background activity consiss of central and vertex delta slow activity with superimposed delta brushes. Diffuse theta bursts occur with occasional occipital theta bursts. C, For a 28-week-gestation, 11-day-old female (postconceptional age of 29.5 weeks), background activity is largely continuous with predominant delta slowing. More active temporal activity includes prominent temporal theta bursts. Delta brushes also are seen in the occipital and vertex regions. D, For a 28-week-gestation, 7-day-old male (postconceptional age of 29 weeks), rhythmic occipital delta signals occur in different head regions with prominent temporal delta brushes. Periodic breathing is evident in the respiratory channel. Continued

Ontogeny of Electroencephalographic Features The evolving EEG sleep patterns in the asymptomatic, presumably healthy preterm infant has been the subject of many

excellent reviews [Ebersole et al., 2003; Lombroso, 1985; Pope et al., 1992; Scher, 1993a, 1993b, 2005; Torres and Anderson, 1985]. Improvements in neonatal intensive care,

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FIGURE 12-6, cont’d. E, For a 28-week-gestation, 51-day-old male (postconceptional age of 35 weeks), continuous background activity is appropriately of lower amplitude for the corrected age. This activity consists of fast frequencies with delta brushes in multiple head regions. An isolated frontal sharp wave and rapid eye movements are present. F, For a 34-week-gestation, 8-day-old female (postconceptional age of 35 weeks), a discontinuous background is demonstrated with age-appropriate, short interburst intervals. Rhythmic occipital delta activity occurs with good interhemispheric synchrony. Periodic breathing is evident in the respiratory channel. G, For a 39-week-gestation, 2-day-old female, a high-voltage slow wave (HVS) pattern of quiet sleep with scattered sharp waves is present, particularly in the temporal regions. Regular respirations with no movements are demonstrated in the polygraphic channels. H, For a 39-week-gestation, 2-day-old female, a tracé alternant pattern of quiet sleep is demonstrated with synchronous high-amplitude bursts; age-appropriate, brief interburst intervals; and a well-developed background.

however, require periodic revisions to include more preterm infants [Mizrahi et al., 2003; Scher, 2005]. These revisions are particularly relevant for preterm infants younger than 32 weeks’ gestation, for whom substantial improvement in

survival rates has occurred over the past decade. It is always important to verify which EEG-sleep patterns are within the range of normal only after systematic neurodevelopmental assessment of such children.

Scher / Pediatric Neurophysiologic Evaluation

In the following discussion, regional and hemispheric EEG patterns for preterm and term neonates are arbitrarily assigned within specific gestational age ranges. Temporal, spatial, and state organization of the EEG recordings of cerebral activity during each age range are highlighted with appropriate illustrations.

Gestational Age of Younger than 28 Weeks Neonates with a gestational age younger than 28 weeks who fall below the limits of viability may not survive long enough to have even one EEG recording. However, useful information is available to characterize the neurophysiologic profile of preterm infants who do survive. An undifferentiated EEG sleep profile is typically observed, with no distinctive features obvious between wakefulness and sleep. The record is largely discontinuous, with short periods of continuous EEG activity that may last for as long as 1 minute. Patterns of motility alternate between segmental myoclonic movements of the face or body to more generalized myoclonic and tonic posturing in an axial or appendicular distribution. A pattern of alternating active and sleep periods in preterm infants is characterized as discontinuity, or tracé discontinu [Dreyfus-Brisac, 1955, 1968; Ellingson, 1964; Tharp et al., 1981]. Anderson and colleagues [1985] found that 60% of EEG recordings consisted of discontinuity. These same investigators found that the average interburst interval for this age range was 8 to 16 seconds, with the longest interburst intervals occurring between 15 and 88 seconds. Similar ranges for the duration of interburst intervals have been found by other investigators [Benda et al., 1989; Connell et al., 1987; Eyre et al., 1988; Hughes et al., 1983a, 1983b, 1987]. This finding sharply contrasts with earlier descriptions of interburst intervals as long as 2 minutes [Lombroso, 1985]. Such differences may be related to the medical condition of the neonate at the time of the recording or the lack of information concerning long-term follow-up. In this age group, EEG activity predominates in the vertex, central, and occipital regions. Bitemporal attenuation is common and may reflect intrahemispheric asynchrony [Scher et al., 1987]. Underdevelopment of the inferior frontal and superior temporal gyri may also help explain the relative quiescence of activity in this brain region. EEG activity consists of mixed frequencies, dominated by delta activity in the parasagittal and occipital regions. Occipital delta activity is isolated to one or two waveforms and rarely lasts longer than 5 to 6 seconds. Faster frequencies in the theta, alpha, and beta ranges are intermixed in multiple brain regions. Diffuse theta bursts are common during continuous or discontinuous periods. Beta/delta complexes are transient patterns that identify preterm infants of various conceptional ages. Random or briefly rhythmic 0.3- to 1.5-Hz delta activity of 50 to 250 μV has superimposed bursts of low to moderate amplitude, faster frequencies, with a frequency range of 10 to 20 Hz [Ebersole et al., 2003]. The amplitude of such activity on bipolar recordings rarely exceeds 60 to 75 μV. Historically, various terms have been applied to such complexes, including spindle delta bursts, brushes, spindle-like fast waves, and ripples of prematurity. These complexes can be seen as early as 24 to 26 weeks, largely in the central and midline regions, as well as in the occipital regions.

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Runs of monorhythmic alpha or theta activities are independent of delta brushes principally occurring in the occipital regions in the neonate younger than 28 weeks’ gestation. This transient pattern has been described in more detail and can last for 6 to 10 seconds in an asynchronous or asymmetric manner [Hughes et al., 1990]. Such activity should be distinguished from the more diffuse bursts of moderate- to high-amplitude theta activity that commonly exists at this degree of prematurity (see Fig. 12-5). Intrahemispheric synchrony and interhemispheric synchrony have been variably described by different investigators. Lombroso described synchronous bursts as morphologically similar bursts of activity appearing within 1.5 seconds. He estimated that synchronous periods ranged from only 50% of all periods of activity at 31 to 32 weeks’ postconceptional age to 100% at 40 to 43 weeks’ postconceptional age, with a midpoint of 70% to 85% at 35 to 36 weeks’ postconceptional age [Lombroso, 1985, 1989]. This finding is in sharp contrast to Anderson’s observations that interhemispheric synchrony had a mean of 93% for 1-minute epochs at 27 weeks’ postconceptional age, with a mean of 94% at 29 to 32 weeks’ postconceptional age [Anderson et al., 1985]. A high degree of intrahemispheric synchrony already exists in the preterm infant younger than 30 weeks’ gestation. However, it is also reasonable to consider that more epochs of asynchrony occur as the distance from the midline increases, given the rapid brain growth beyond 30 weeks’ postconceptional age. Rapid growth of temporal and parietal structures in particular may contribute to more frequent episodes of asynchrony [Scher, 2005]. Measures of asynchrony must include information about postconceptional age and about the EEG state. Asynchrony should be assessed for all background rhythms [Scher, 2005], not just for bursts during discontinuous epochs [Anderson et al., 1985; Lombroso, 1985].

Gestational Age of 28 to 31 Weeks Cyclic organization of state remains largely undifferentiated in infants with a gestational age of 28 to 31 weeks [Lombroso, 1985, 1989]. However, periods of body and eye movements are more distinctively associated with irregular respirations during continuous periods of the EEG. Discontinuous epochs still predominate but decrease in duration compared with the premature neonate younger than 28 weeks’ postconceptional age. Interbursts become progressively briefer with a dramatic increase in low-to-moderate amplitude faster rhythms primarily in the theta range. By 32 weeks’ postconceptional age, the degree of discontinuity has decreased to 45% of the record [Anderson et al., 1985]. Dreyfus-Brisac [1970] found an alternating pattern in 24% of records at 32 to 34 weeks’ gestation. The average interburst intervals at 29 to 31 weeks’ postconceptional age ranged between 5 and 14 and between 4 and 11 seconds, respectively, with means of 9 and 7 seconds; whereas the longest interburst periods for these two postconceptional age groups were found to be between 16 to 57 and 6 to 41 seconds with means of 36 and 20 seconds, respectively. Monorhythmic occipital delta patterns with durations of more than 30 seconds are quite abundant at 28 to 31 weeks. Delta brush patterns continue to be abundant, involving the

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vertex and central regions along with the occipital and temporal regions [Watanabe and Iwase, 1972]. Sometimes, it may be difficult to differentiate delta brushes in the temporal region, particularly because of superimposition with temporal theta bursts. Another useful developmental marker is the appearance of rhythmic, 4.5- to 6-Hz activity occurring independently and synchronously in each midtemporal region. Although this activity is occasionally observed in neonates younger than 28 weeks’ postconceptional age, it is expressed maximally between 28 and 32 weeks. In the past, this feature has been described as “temporal sawtooth waves” [Scher, 2005]. Amplitudes range from about 20 to 200 μV; with maturation, these bursts may reach the alpha frequency. In a study of 436 infants, a parabolic polynomial function described the age incidence of temporal theta activity, strongly reflecting the pattern as a maturational landmark [Hughes et al., 1987]. Temporal theta activity can obtain a maximum incidence of 36% at 29 to 30 weeks, after which it diminishes rapidly. At 32 weeks, only 12% of the record exhibits this pattern [Anderson et al., 1985]. This rhythmic theta activity should be distinguished from repetitive, sharp activity in the theta range seen at near-term and term ages in the midline and rolandic regions, particularly during quiet sleep. The clinical significance of sharp-wave transients in healthy, preterm infants has been poorly documented at early preterm ages. Regional patterns associated with maturation must be considered before assigning spike or sharp-wave criteria to a transient waveform. Sharply contoured delta brushes and temporal or occipital theta bursts may appear epileptiform without clearly satisfying morphologic criteria of an epileptiform discharge (see Fig. 12-9A). Sporadic multifocal spikes and sharp waves can be seen at any gestational age [Ellingson, 1964; Harris and Tizard, 1970; Monod et al., 1960; Parmelee et al., 1968; Samson-Dollfus, 1955; Scher, 2005; Torres and Anderson, 1985], but few studies include preterm infants younger than 32 weeks’ estimated gestational age. Anderson and associates [1985] studied the incidence and location of spikes and sharp waves in 33 preterm infants of 27 to 32 weeks’ estimated gestational age. Both features were uncommon, with spikes less common than sharp waves. Both morphologies were most abundant in frontal and temporal regions, with the frequency increasing from 27 to 32 weeks. Central sharp waves decreased in number over this period, whereas occipital and vertex discharges had the lowest incidence. Unfortunately, only 55% of infants were verified as normal on follow-up at 6 to 8 months of age. Larger preterm populations with longer periods of neurodevelopmental follow-up are needed before assigning clinical significance to sharp waves in asymptomatic preterm infants.

Gestational Age of 32 to 34 Weeks At a gestational age of 32 to 34 weeks, body and eye movements take on a more phasic than random pattern, with greater coincidence with continuous EEG segments than quiet or non–rapid eye movement (REM) sleep. Fewer movements, such as buccolingual movements and occasional myoclonic jerks [Curzi-Dascalova et al., 1988], occur during the more discontinuous segments. Variable respirations persist, but short periods of regular respirations are expressed during discontinuous portions of the recording.

The EEG background in these infants is more continuous with cyclic periods of tracé discontinu. Synchronous delta frequencies of various amplitudes still predominate, interrupted by random, low-amplitude, inactive periods. Faster frequencies of variable amplitudes are also present and are usually associated with the delta brush pattern. Regional patterns (i.e., brushes, theta bursts) predominate in the rolandic, occipital, temporal, and midline regions. The most characteristic feature at this age range is the notable increase in multifocal sharp waves and the appearance of reactivity to stimulation; these microarousals are characterized by transient periods of background attenuation that are physiologically different from the quiescent epochs during tracé discontinu. Sharply contoured activities predominate in the temporal and central regions, with positive temporal sharp waves frequently occurring synchronously or independently. Sharp activities in the central regions of negative polarity are distinguished from physiologic artifacts resulting from fontanel pulsations or ventilatory excursions. Positive temporal sharp waves need to be differentiated from rolandic and vertex positive sharp waves; the latter are observed in the sick neonate with intraventricular hemorrhage or periventricular leukomalacia [Scher, 1991]. Reactivity to stimulation appears during this gestational age range. Nonspecific EEG changes are induced by tactile or painful stimulation, usually with an abrupt attenuation or desynchronization of background, which can be difficult to distinguish from low-amplitude quiescent periods until later in gestation, when the examiner can more readily distinguish between active and quiet sleep. Uncommonly, bursts of higher amplitude delta activities may characterize the reactivity periods. It is unknown whether these are the precursors of more discrete arousal patterns, such as K complexes and hypersynchronous delta, which occur at older ages. Reactivity to photic stimulation has been studied systematically [Anderson et al., 1985]. Responses to photic stimulation clearly are seen in the EEG of the early preterm infant [Ellingson, 1958]. Responses to isolated flashes have a prominent, negative wave component. Ellingson described a later-occurring positive component at older ages, with decreasing latency in proportion to increasing postconceptional age [Ellingson, 1958, 1960]. In contrast to isolated flashes, repetitive flashes or photic driving has been investigated by several investigators, but such responses are difficult to detect in the EEG of the neonate [Ellingson, 1960, 1964]. About 5% of preterm and term infants exhibit photic driving with a wide range of flicker frequencies. Anderson and colleagues [1985] found that preterm infants between 27 and 32 weeks’ gestation may exhibit driving responses; 64% of 34 neonates showed this response with frequencies limited to 2 to 10 flashes per second. Some investigators have claimed that these driving responses are more readily seen in the preterm infant because of the more continuous, higher amplitude mixture of background frequencies [Monod and Tharp, 1977]. Responses to auditory or painful stimulation have been the subject of less attention in the preterm and term infant. Monod and Garma [1971] investigated behavioral and physiologic responses to auditory clicks and found vertex spikes in response to auditory clicks in neonates at 32 to 34 weeks’

Scher / Pediatric Neurophysiologic Evaluation

postconceptional age, which contrasts with the less distinctive response seen in older infants. Sudden, loud auditory stimuli more effectively produce EEG changes than visual [Ellingson, 1958] or tactile [Dreyfus-Brisac et al., 1957] stimuli. Such periods of desynchronization are thought to be associated with habituation and may represent electrographic representation of perceptual memory and discriminatory functions of the neonate [Anderson et al., 1985].

Gestational Age of 34 to 37 Weeks Cyclic alterations between wakefulness and sleep, as well as longer continuous periods of EEG activity, predominate in infants whose gestational age is 34 to 37 weeks. More concordant segments between cerebral and noncerebral signals resemble active and quiet sleep of the term infant. For instance, motility patterns take on a distinctive phasic quality that predominates during active sleep. Absence of motility except for generalized myoclonic and facial movements is seen during quiet sleep. Myogenic activity measured at the chin characteristically remains low during active sleep; higher and more phasic activities occur during quiet sleep. The cyclic nature of active and quiet sleep periods still lacks the well-defined 30- to 70-minute cycle seen in the term infant. Electrographic components of the EEG sleep cycle in this age group show a predominance of continuous EEG activity composed of mixed delta and theta activities that are usually lower in amplitude (20 to 100 μV) than at younger gestational ages. Low-amplitude, faster rhythms of alpha and beta activities are more prominent, with the remaining delta brushes present mainly in the temporal and occipital regions. Brushes also more commonly appear during quiet than active sleep. Frontal sharp transients of 50 to 150 μV are observed at 34 to 35 weeks’ gestation but may be seen earlier. Historically, these waveforms were called encoches pointes frontales [Monod et al., 1960] and were popularly identified as frontal sharp transients [Hrachovy et al., 1990] and pointes lents diphasiques frontales [Arfel et al., 1977; Monod et al., 1960]. These sharp waves usually have an initial surface positive component followed by a negative component but are also associated with rhythmic, sharply contoured, frontal delta activity and can occasionally be high amplitude (250 μV) [Goldie et al., 1971]. In contrast, fewer multifocal sharp transients occur and are sometimes difficult to distinguish from the intermixed background theta or beta background frequencies, as with more preterm neonates. The discontinuous quality of the sleep tracing during this postconceptional age range indicates the appearance of a tracé alternant rather than a tracé discontinu pattern seen in younger infants. Quiescent periods consist of more activity that exceeds 15 μV, with a greater mixture of low-amplitude, faster rhythms.

Gestational Age of 38 to 42 Weeks Electrographic and polygraphic patterns are fully elaborated for infants with a gestational age of 38 to 42 weeks. Alternating periods of wakefulness and sleep, as well as cyclic changes between four segments of sleep state, can be identified. Two active sleep and two quiet EEG patterns constitute

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this cycle, with a length varying from 30 to 70 minutes. The patterns are associated with the presence or absence of rapid eye movements, body movements, autonomic signs, and arousal episodes. Although conventional wisdom dictates that only term and near-term infants possess such an organized EEG sleep cycle, concordance among specific EEG and polygraphic parameters has been described in the preterm infant as early as 30 weeks’ gestation [Curzi-Dascalova et al., 1988]. A developmental match between cerebral and noncerebral physiologic parameters fundamentally reflects the coordination of specific neural and non-neural systems. There may be a more established order of state in the premature infant that has not been readily recognized by visual analysis techniques. A rudimentary cycle may be more easily detected in the premature neonate by more quantitative techniques [Scher et al., 1990b]. The EEG sleep organization of the term neonate has traditionally been considered similar for a premature infant who has matured to term and for the appropriatefor-gestational-age term neonate. Two active sleep segments occupy 50% of sleep time of the term infant and are composed of a mixed-frequency pattern and a low-voltage irregular pattern that begin and end the sleep cycle. Quiet sleep segments are situated in between, consist of highvoltage slow and tracé alternant segments, and make up 35% to 40% of the cycle. Transitional or indeterminate segments during which discordance between EEG and polygraphic criteria of sleep state is defined make up 10% to 15% of the cycle. The mixed-frequency active sleep pattern comprises moderate-amplitude delta and lower-amplitude theta, alpha, and beta activities. This EEG background also can be identified in the waking neonate. The low-voltage irregular pattern is characterized by continuous, low-amplitude admixture of frequencies (15 to 30 μV), mostly in the theta and beta ranges. Considerable alpha activity is intermixed posteriorly and anteriorly. This pattern can be seen during wakefulness and active sleep. Two quiet sleep segments, high-voltage slow and tracé alternant, occupy the second and third positions in this idealized EEG sleep cycle. The high-voltage slow pattern comprises diffuse, continuous, high-amplitude, 50- to 150-μV delta activity intermixed with theta- and beta-range activity of lower amplitude. The high-voltage slow segment is quite brief (4% to 6% of the cycle) and is rapidly replaced by the tracé alternant pattern. The tracé alternant segment comprises a discontinuous tracing of high-amplitude bursts of slow activity in the delta and theta ranges, alternating with lower amplitude faster frequencies and sharp waves seen synchronously over both hemispheres. Frontal sharp waves may be abundant, especially during quiet sleep. These waveforms are bilateral and synchronous but also can be asymmetric. Frontal sharp waves occur less often during active and indeterminate sleep segments and are least likely to occur during low-voltage irregular active sleep [Arfel et al., 1977; Statz et al., 1982]. During sleep, frontal sharp transients are observed until the beginning of the second month of life [Ellingson et al., 1980; Weiner et al., 1991]. As with preterm infants, the clinical significance of spikes and sharp waves in asymptomatic term neonatal populations remains controversial. Most studies do not have adequate

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follow-up, or entry criteria were based on a clinical rather than an EEG diagnosis. Clancy and associates [1985] identified 69 healthy infants who had acute, life-threatening events (i.e., near-miss sudden infant death syndrome). Analyses of 10 minutes of active sleep documented more frequent sharp waves in near-term than in term infants. Temporal sharp waves were more abundant than centrally located discharges, persisting until 45 weeks’ postconceptional age and disappearing by 50 weeks’ postconceptional age. Karbowski and Nencka [1980] studied 1-hour sleep recordings in 82 term, healthy newborns without subsequent follow-up. They found that 81% had predominantly right centrotemporal sharp waves, with an average interval of 3 minutes and 47 seconds. Only 12% had predominately left central waves, with an average interval of 15 minutes. All discharges were evident primarily in indeterminate sleep. Statz and colleagues [1982] evaluated 24 term, healthy infants 9 to 12 months of age after obtaining a neonatal sleep recording. They observed sporadic, multifocal, nonrepetitive discharges during quiet sleep in all infants; only 25% of infants had discharges during active sleep. The parietal region had the most abundant discharges, with intervals between 38 seconds and 25 minutes. The clinical significance of spikes and sharp waves that appear in preterm and term neonatal recordings needs further investigation. Sporadic sharp waves may be normal or abnormal, depending on the clinical context, the EEG background activity, location, morphology, and postconceptional age emphasized [Karbowski and Nencka, 1980]. Unless discharges are repetitive, periodic, or positive in polarity, pathologic significance should be cautiously assigned. Central sharp-wave transients and rhythmic, sharply contoured theta are found in the parasagittal and vertex regions. This midline pattern is rhythmic and has a spindle-like appearance [Hayakawa et al., 1987]. It is unknown whether this rhythmic activity is rudimentary sleep-spindle activity that will appear at 2 to 4 months of age. Delta brush patterns are occasionally observed during the quiet sleep segment, but they are rare and isolated primarily to the temporal and occipital regions. Synchrony should be 100% during sleep of the term neonate. Transient asymmetries, mainly in the temporal regions, can be observed, particularly during the initial minutes of quiet sleep [Challamel et al., 1984; O’Brien et al., 1987]. Ontogeny of EEG sleep by the end of the neonatal period (i.e., 28 days after a term birth) has been systematically investigated by only a few researchers [Beckwith and Parmelee, 1986; Ellingson et al., 1980; Lombroso et al., 1979]. Gradual disappearance of tracé alternant by 3 to 6 weeks after a term birth has been described. Change from active sleep to quiet sleep-onset on falling asleep has also been described. Sleep spindles commonly observed at 2 to 4 months of age also may be seen as early as 4 to 6 weeks of age. Frontal sharp waves persist to 3 to 4 weeks after birth. Although no significant differences can be distinguished between the maturational criteria at 1 month in preterm compared with term infants, some subtle differences have been observed in the elements of sleep architecture. Longer bursts during tracé alternant, early sleep-spindle appearance, more immature patterns at term, better phase stability, and specific frequency bands are described [Joseph et al., 1976]. Behavioral criteria of sleep are also different between the

two groups, suggesting that sleep organization of the preterm neonate to term and beyond is not entirely equivalent to the term newborn [Watt and Strongman, 1985]. On polygraphic recordings, differences between preterm and term cohorts at matched postconceptional term ages have been described. The sleep cycle in the preterm at postconceptional term age is one-third longer than that of the term infant and has a greater percentage of quiet sleep. These neonates had fewer movements, fewer and shorter arousals, higher mean rectal temperatures, less cardiorespiratory regularity during quiet sleep, and lower spectral EEG energies during specific sleep-state segments than term infants. Although subtle, each of these differences reflects conditions of prematurity on brain maturation for a specific neuronal system that subserves sleep. Adaptation of brain function of the preterm infant as expressed on EEG sleep studies may reflect physiologic dysmaturity to biologic and environmental stresses that may occur by intrauterine and extrauterine factors [Amiel-Tison and Pettigrew, 1991; Scher and Barabas, 1996; Scher et al, 1992, 1994a, 1994b, 1994c, 2003].

Normal Electroencephalographic Patterns in Infancy through Adolescence Waking Patterns Although sleep patterns predominate for the newborn, state development during infancy prepares the child for sustained periods of wakefulness. Waking EEG patterns are the first part of the discussion of normal EEG patterns in childhood. Emphasis is placed on specific patterns that have relevance for clinical applications. One of the fundamental characteristics of the waking EEG pattern is the dominant background activity. Berger [1931] initially described how the dominant frequency increased as ages advanced during childhood. By 3 to 4 months of age, a discernible occipitoparietal rhythm of 3 to 4 Hz is observed (Fig. 12-7A). The activity approximates 5 Hz by 6 months and increases to 6 to 7 Hz by 9 to 18 months of age (see Fig. 12-7B). The 6- to 7-Hz frequency remains fairly stable until 2 years of age, when it varies between 7 and 8 Hz. By 3 years of age, the dominant waking rhythm of childhood is within the alpha range in 82% of children [Eeg-Oloffsson, 1971; Peterson and Eeg-Oloffsson, 1971] (see Fig. 12-7C). The mean frequency is 9 Hz by 7 years of age and 10 Hz by 15 years of age (see Fig. 12-7D). Certain modifications in the waking dominant activity have been observed under different conditions. Passive eye closure causes the dominant rhythm to become better developed, whereas eye opening clearly attenuates the activity. This phenomenon becomes initially apparent at 5 to 6 months of age [Kellaway and Peterson, 1964]. The dominant rhythm may slow by 1 to 2 Hz during the drowsy state, sometimes accompanied by a lessening of associated muscle artifact. The amplitude, asymmetry, and locus of the dominant rhythm also change with increasing age. Higher amplitudes are seen at younger ages, with maximum amplitudes at 6 to 9 years that subsequently decline during adolescence. Asymmetries of this activity can be expected with higher amplitude on the right in 20% of children, although differences of 50% or greater must be considered with suspicion. No correlation to hand dominance has been demonstrated. About

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FIGURE 12-7. Posterior dominant rhythms (line markings) at four different ages during childhood while the patient was awake with eyes closed. A, A 4-Hz dominant rhythm at 4 months of age. B, Dominant rhythm of 6 to 7 Hz at 16 months of age. C, Dominant rhythm of 9 Hz at 3 years of age. D, Dominant rhythm of 10 to 12 Hz that is well regulated in a 16-year-old adolescent.

70% of adults and 95% of children have an occipital location to the dominant rhythm, but at least three independent alpha rhythms can be recorded over the scalp—occipital, temporal, and central regions—which may differ in frequency as much as 2 Hz [Kellaway, 1979]. More anterior expression of the dominant rhythm becomes evident during adulthood.

Mu Rhythm The mu, or central, rhythm commonly is 9 to 10 Hz and should not be confused with the central dominant rhythm of 7 to 9 Hz in infants. Although the mu rhythm is observed in less than 5% of children younger than 4 years, it can be observed in 18% of children between 8 and 16 years of age and occurs somewhat more frequently in females. It can be blocked by movement of the opposite limb rather than eye opening. Although the mu rhythm may frequently appear asymmetrically and alternately in either hemisphere, a persistent asymmetry suggests a structural lesion on the attenuated side or irritation on the predominant side (e.g., after head injury).

Beta Activity Three distinctive band ranges are described for beta frequencies in waking EEG recordings of children [Ebersole et al., 2003]. Limited diagnostic use can be applied to the overall description of fast activity. Beta activity in the range of 18 to 25 Hz is most commonly encountered, with ranges of 14 to 16 Hz and 35 to 40 Hz observed less frequently. Symmetric distribution over each anterior head region is

usually observed. Asymmetries of as much as 30% to 40% can be encountered without the presence of a structural lesion. Important diagnostic conclusions can be assigned if beta activity is reduced by more than 50%, especially when associated with delta or theta slowing in the same head region. Prominent scalp edema can also attenuate the highfrequency EEG signals in the absence of cerebral pathologic conditions. Symmetric prominence of beta activity is commonly encountered with the administration of certain sedative medications, especially barbiturates or benzodiazepines. Skull defects can contribute to an asymmetric exaggeration of beta activity over the bony defect, although it usually has little clinical relevance [Cobb et al., 1979].

Theta and Delta Slowing Theta rhythms are commonly encountered in the frontocentral regions and are usually related to drowsiness or heightened emotional states. In the past, theta rhythms were associated with a variety of clinical conditions, including epilepsy, but their common occurrence is now better appreciated as a normal variant [Hrachovy et al., 1990]. Posterior slow waves located in the parieto-occipital regions, commonly referred to as posterior slow waves of youth, constitute the most frequently observed normal delta slow activity in the waking EEG record of children (Fig. 12-8). Commonly located in the occipitoparietal or occipitotemporal regions is a 2.5- to 4.5-Hz monorhythmic or polymorphic delta wave with an amplitude less than 100 μV [Aird and Gastaut, 1959]. Superimposed alpha activities are also observed with these delta waves, which can have symmetric or asymmetric occurrences. The neurologist should view an

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asymmetry greater than 50% between regions with suspicion. It will block with eye opening and disappear with the alpha rhythm during drowsiness. Rarely seen before 2 years of age, it has maximum expression between 8 and 14 years, especially in females. Approximately 25% of normal children have this pattern [Eeg-Oloffsson, 1971]. The distinction between this pattern and other abnormal slow-wave activity should be based on complexity of the waveform, persistence, symmetry, and amplitude, all in the context of closedhead injury, hypoxia, or other encephalitides.

Lambda Waves Lambda waves can be observed in normal patients while they are viewing a well-illuminated picture of complex design. Sharply contoured occipital transients with a prominent surface-positive phase lasting 75 to 150 msec are described, although an extremely sharp appearance may cause suspicion of an abnormality. Eye closure or darkening of the room eliminates lambda waves, whereas occipital spike discharges persist. These transients are observed in young infants and can be observed occasionally in neonates [Tharp, 1986].

Hyperventilatory Response In the past, a response to hyperventilation was considered evidence of a brain abnormality in children [Lindsley and Cutts, 1940]. However, it has become commonplace to observe prominent high-amplitude slowing in normal children, with maximum expression between 8 and 12 years that persists as a less significant electrographic change into adulthood [Peterson and Eeg-Olofsson, 1971]. A greater degree

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FIGURE 12-9. A, Electroencephalogram (EEG) of an 8-year-old female during hyperventilation. Arrow indicates notching of the high-amplitude slow activity in the absence of epileptiform discharges. B, EEG of a 3-year-old female during drowsy, light sleep. Notched, high-amplitude delta activity occurs (arrow) in the absence of epileptiform discharges.

of response has been associated with lower blood glucose or carbon dioxide concentrations [Konish, 1987]. Standardization of hyperventilation is necessary for the clinician to best judge the EEG slowing relative to age differences reported for children [Konishi, 1987a, 1987b]. Proper testing procedure requires 3 to 5 minutes of overbreathing by the child to elicit the response. Careful notation of artifact and an anticipation of spikelike, high-amplitude sharp waves are emphasized [Ebersole et al., 2003]. Superimposed faster frequencies that may appear to be spike discharges are followed by slow waves during hyperventilation and are commonly overinterpreted as an abnormal finding (Fig. 12-9A). Only the appearance of clearly defined generalized or focal spike complexes or focal, lateralizing slow waves are to be potentially interpreted as abnormal. Studies are needed that incorporate analysis of evidence to ascertain the role of hyperventilation in routine clinical EEG studies in children. Although this activating maneuver frequently assists in temporally correlating interictal or ictal spike-and-wave discharges of generalized or focal distribution for specific populations of children with absence of localization related epilepsies, nonepileptic automatisms are common in children exhibiting hyperventilation-induced, high-amplitude rhythmic slowing and absence seizures. Yawning, smiling, fidgeting, and, less often, eye opening and fluttering mimic seizures and can be distinguished reliably only by EEG or preferably by synchronized video-EEG [Lum et al., 2002]. In a study of an epileptic population (92% were older than 18 years), patients with localization-related or generalized epilepsies were relatively resistant to routine hyperventilation. Only 21 of 433 patients had interictal discharges or rarely seizures during the

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procedure [Holmes et al., 2004]. Comparable pediatric guidelines are still needed.

distinguished by their waveform, field, symmetry, and persistence relative to the start and end of the flash of light. The abnormal photoparoxysmal response (see Fig. 12-10B and C) is discussed in a subsequent section, including its relationship to epilepsy and withdrawal states.

Photic Stimulation Photic stimulation may produce a variety of electrographic phenomena that can be useful to the neurologist. It is suggested that a strobe light be used with 500,000-foot to 2,000,000-foot candles of intensity at a distance of 12 inches from the face and at multiple flash frequencies. Both occipital and parietal channels should be included, with one channel recording the output signal from the light source. Two artifacts should be anticipated. The photoelectric effect usually appears in the frontopolar electrodes and is caused by high resistance or defective grounding of these electrodes. Simply shielding these electrodes from the light source may be sufficient to determine if it is present. A second artifact results from the photomyoclonic effect. Muscle contractions, usually around the anterotemporal, frontal, and frontopolar electrodes, are recorded in response to the light flashes. Taking these possible sources of artifact into consideration, the normal phenomenon is a sharp surface-positive waveform, maximal in the parietal and occipital electrodes, which matches the flash frequency (Fig. 12-10A). Photic stimulation might induce drowsiness, including a normal sharp-wave phenomenon known as posterior occipital sharp transients (see Fig. 12-12C). Slower flash frequencies result in more prominent responses in younger children. However, the spike discharges in these posterior leads diffusely can be

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A drowsy state represents a transition from wakefulness associated with the disappearance of the occipital alpha rhythm and the emergence of central-parietal theta activities. Pendular eye movements may be detected in the anterior, temporal, or frontopolar channels. EEG changes may precede behavioral evidence of sleepiness, especially in the younger child. This period of successively greater amounts of rhythmic and paroxysmal slow activity has been called hypnagogic hypersynchrony and may be overinterpreted by the inexperienced clinician [Kellaway and Fox, 1952]. Similar to the notched, sharp-wave activity during hyperventilation, superimposed activity may be seen during drowsiness and misinterpreted as abnormal spike or sharp-wave discharges (see Fig. 12-9B). The EEG recording should be obtained continuously from wakefulness through drowsiness into sleep so that the complete succession of changes in background activities can be observed. A slowing in the alpha rhythm with an increase in amplitude already described can be seen in a diffuse distribution or regionally over the anterior or posterior scalp areas in association with more prominent beta activity.

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FIGURE 12-10. A, Electroencephalogram (EEG) of an 8-month-old male with prominent driving in a slow-flash frequency in the occipital regions. B, EEG of a 12-year-old male with a photoparoxysmal response confined within the duration of the stimulus at six flashes per second. C, EEG of an 11-year-old female with suppression of driving in the left hemisphere and with intermixed slowing in the same head region. Encephalomalacia in the left posterior quadrant was demonstrated on imaging studies. (A, Courtesy of Dr. P. Crumrine, Children’s Hospital, Pittsburgh.)

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The first and more common pattern is rhythmic beta activities over the central or frontocentral region of approximately 200 μV. It is most pronounced between 3 months and 4 years of age and is not encountered after 7 years of age. Typically the frequency of this rhythmic pattern will increase to 6 Hz with age. A second pattern consists of prominent bisynchronous bursts of 2 to 5 Hz greater than 350 μV from 6 months to 5 years of age. This pattern is commonly misinterpreted as spike-and-wave discharges because of the superimposition of the faster frequencies.

Sleep-Activation Procedures Based on an extensive review of the subject of sleep and sleep deprivation [Bechinger et al., 1976; Ellingson et al., 1984], there is general agreement that sleep and sleep deprivation have a substantial activating effect on the occurrence of interictal epileptiform discharges. A recent update addressed the activating effect of sleep deprivation over and above the effect of only sleep [Mendez et al., 2001]. However, most published guidelines and interviewed epileptologists do not recommend sleep deprivation for the initial study because of the burden to the patient [Glick, 2002]. The pediatric patient presents specific challenges to obtaining the EEG study, particularly when the parents are asked to sleep-deprive their child in order to induce sleep, and presumably to better assess for epilepsy risk. The inclusion of sleep as part of the child’s study ensures the activation of specific epileptiform features associated with specific epileptic syndromes such as benign rolandic epilepsy of childhood and Landau-Kleffner syndrome. Children with generalized or localization-related epilepsies may not have the diagnostic yield improved by obtaining sleep with or without sleep deprivation. Similar to the situation for adults, evidencebased medicine does yet not meet the highest standards for children. One study assessed the value of partial sleep deprivation as a routine measure in pediatric EEG and reported that the procedure was well tolerated, with greater proportion of sleep achieved with than without deprivation [Liamsuwan et al., 2000]. However, diagnostic efficacy was not evaluated. Future studies must delineate the subgroup of epilepsies that have significant sensitivity to sleep and sleep-deprivation effects. Apart from the previously mentioned controversy, pediatric neurologists must recognize the reciprocal relationships between sleep and epilepsy and the management of sleep complaints in the patient with epilepsy [Vaughn and D’Cruz, 2004]. There can be the disruption of sleep brought on by seizures, disturbing the sleep-wake cycle. The physician must anticipate the effects of antiepileptic medications on sleep, including the vagal nerve stimulator. Patients with epilepsy have a greater prevalence for sleep disturbances than normal subjects, exemplified by sleep disorders such as obstructive sleep apnea, restless legs syndrome, and periodic limb movement syndrome. Sleep complaints centering on excessive daytime sleepiness or difficulties initiating or maintaining sleep must also be addressed.

SLEEP PATTERNS This discussion introduces major EEG features observed during sleep. Detailed descriptions of polysomnographic analysis of sleep architecture are addressed elsewhere.

Electroencephalographic Neonatal Sleep as an Ultradian Rhythm During the last several decades, extensive information has been published with respect to the existence and functional significance of ultradian rhythms (i.e., any rhythm less than 24 hours) in humans [Schulz and Labie, 1985]. Durations of ultradian rhythms between 30 minutes and 24 hours may represent an important portion of the spectrum of human biologic rhythms [Hildebrandt, 1986]. The human sleep cycle fits into a longer ultradian period of 75 to 90 minutes; individual EEG frequencies that are composed of oscillatory activity with much shorter periods last only milliseconds. Two biorhythmic processes define the temporal organization of sleep in the neonate: a weak circadian sleep-wake rhythm and a stronger ultradian REM–non-REM rhythm [Glotzbach et al., 1995]. Both biorhythms evolve over increasing ages. Internal “biologic clocks” become better organized around environmental cues, such as the light-dark cycle, temperature, noise, and social interaction [Anders et al., 1995]. In normal term newborns, sleep alternates with waking states over a 3- to 4-hour cycle at night and during the day. Within the first month or two of life after birth for the term infant, sleep-wake state organization begins to adapt to the light and dark cycles, as well as regularly recurring social cues. Circadian rhythmicity of body temperature and heart rate occurs in approximately 50% of preterm infants at 29 to 35 weeks’ conceptional age [Mirimiran and Kok, 1991]. However, longer-run ultradian rhythms of 3 to 4 hours’ duration correspond to feeding and social interventions [Glotzbach et al., 1995]. Increases in body movement activity and heart rate and decreases in rectal skin temperature are present during interventions, reflecting changes in the infant’s microenvironment and the infant-caretaker interactions. Even the ultradian EEG sleep cycle length of the preterm infant as defined by changes in EEG discontinuity shows a positive correlation of cycle length and increasing postconceptional age [Scher et al., 1994d, 1994e]. By postconceptional term age, the ultradian EEG sleep cycle is longer for the preterm than for the term infant [Scher et al., 1992]. Regardless of the cycle length, the architecture remains the same between preterm and term groups composed of active sleep segments interrupted by transitional or indeterminate sleep segments. Reactivity or arousal periods punctuate within and between sleep segments. Indeterminate sleep and arousal phenomena represent important expressions of sleep continuity (Fig. 12-11). The neonatal ultradian EEG sleep cycle is approximately 30 to 70 minutes [Dreyfus-Brisac, 1970; Parmelee et al., 1969; Weiner et al., 1991]. The sleep segments that constitute this cycle include two active and two quiet sleep segments, usually beginning as an active sleep portion on falling asleep. Transitional sleep segments within and between active sleep segments are commonly called indeterminate sleep segments. Reactivity or arousal periods also punctuate within and between sleep segments. Indeterminate sleep and arousal phenomena represent important expressions of sleep continuity. Mathematical relationships among sleep components better define the development of this ultradian neonatal sleep cycle in the infant [Harper et al., 1981]. Sleep parameters, including EEG sleep state, motility, REM, and arousal, can be better expressed quantitatively in terms of

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FIGURE 12-11. A, Electroencephalogram (EEG) of a 1-year-old female shows symmetric sleep spindles that also were produced in the vertex region. A well-developed frequency amplitude gradient also is demonstrated. B, EEG of a 31/3-year-old female with developmental delay and cerebral palsy during sleep shows “extreme” spindling in the absence of a frequency amplitude gradient.

period length, amplitude, and phase. For a particular gestational age range, specific period, phase, and amplitude, relationships may better define ontogeny of the EEG sleep cycle. With maturation of the CNS, relationships solidify among these parameters. Longitudinal studies of the EEG sleep cycle of the preterm infant maturing to term explore how this ultradian rhythm develops within the neonatal intensive care unit environment. Comparisons of EEG sleep organization in the preterm infant at a corrected term age with term infants can then highlight how preterm infants adapt to this extrauterine environment, reflecting brain altered maturation. It then follows that comparisons of preterm sleep patterns can be made with fetal state patterns. Differences between intrauterineand extrauterine-reared groups reflect differences in CNS maturation that in part reflect the maternal circadian influence on fetal development, which is replaced by other environmental influences in children born prematurely. Although ontogenetic studies of ultradian physiologic rhythms in the term neonate and young infant have been reviewed [Dittrichova et al., 1972; Parmelee, 1967; Stratton, 1982], specific studies of preterm EEG sleep parameters involving quantitative techniques have not yet been compared with term infant data. There may be interesting EEG relations among sleep, REM, and motility patterns in single studies or in studies of maturation across different gestational ages. Although circadian influence may not be established until sometime after birth [Hellbrugge, 1960, 1968], important periodic, phasic, and amplitude relationships may exist as ultradian rhythms during the preterm neonatal or fetal periods.

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A brief discussion of specific noncerebral components within the EEG sleep rhythm highlights the importance of correlating such parameters with the electrographic portion of the sleep rhythm during maturation. Rapid eye movement represents one of the principal features of active sleep. Active sleep constitutes about 50% of the neonatal sleep cycle at term; however, REM appears to be time-locked to continuous EEG activity as early as 31 to 32 weeks’ gestation [Curzi-Dascalova et al., 1988]. Rapid eye movement activity is not a random rhythm [Prechtl and Lenard, 1967] and may have predictable intervals of occurrence [Dittrichova et al., 1972]. Different classes of REM may exist at different times of the sleep cycle, and the numbers and types of REM increase with maturation [Evsyukova, 1980; Lynch and Aserinsky, 1986]. This feature also can be measured during fetal life and is associated with continuous EEG activity in preterm neonates as early as 30 weeks’ estimated gestational age [Prechtl et al., 1979]. Closer identification of REM occurrence, as well as quantification during different EEG states, is needed to better understand this important developing ultradian rhythm. REM occurrence during active sleep segments constitutes an important maturational milestone of the immature brain; it may have significance as a biologic marker, and it may be assessed in clinical situations. Motility patterns are an integral part of the neonatal sleep cycle [Anders et al., 1971]. Different motility patterns appear at successively older neonatal ages up to the term infant. Their ontogenic patterns are seen in extrauterine-reared neonates and fetuses [Robertson, 1982, 1987]. Myoclonic and entire body movements predominate in the preterm infant [Fukumoto et al., 1981; Prechtl et al., 1979], whereas smaller, slower body movements are seen in the term neonate. Attention to specific segments of the EEG sleep cycle of the neonate is important because motility patterns may differ during different segments of the cycle [Hayakawa et al., 1987]. Although similar motility patterns in the fetus reflect in utero maturational changes in motor pathways, as documented by fetal ultrasonography [Prechtl, 1984; Robertson, 1982, 1987], differences in motility behavior in preterm infants may signify altered brain development in an extrauterine environment. Maturational trends in cardiorespiratory behavior have also been studied in preterm infants using spectral analyses. Decreased variability of cardiorespiratory behavior is seen with increasing postconceptional age [Scher, 1995]. However, spectral EEG measures appear to be stronger indicators of functional brain maturity compared with noncerebral measures, such as cardiorespiratory behavior. Periodic breathing and respiratory pauses are physiologic events that commonly occur in preterm infants [Glotzbach et al., 1989; Martin et al., 1986]. Cardiorespiratory measures and motility and temperature changes do not correlate with changes in EEG continuity, rapid eye movements, or spectral EEG energies of the preterm infant or at any specific postconceptional age [Scher et al., 1997].

Infant and Childhood Sleep The infant’s ultradian sleep cycle lengthens with maturation to 75 to 90 minutes. The idealized sleep architecture after sleep onset consists of one REM sleep segment that follows

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four non-REM (or quiet sleep) segments. Regional EEG patterns are identified during these sleep segments, which assists in the assessment of sleep organization.

Vertex Waves and Sleep Spindles The transitional state of drowsiness is sometimes referred to as stage 1 of sleep and may include sharp-wave discharges that are maximal in amplitude over the vertex and central regions. Commonly, symmetric central diphasic waveforms become better expressed and more abundant during stage 2 sleep, which coincides with the appearance of sleep spindles. These waveforms usually have an initial surface-negative wave, followed by a surface-positive phase. The onset of vertex waves can be between 2 and 5 months of age and can appear asymmetric, particularly at younger ages. If this asymmetry exceeds 20%, the neurologist must consider the presence of a lesion on the attenuated side (see Fig. 12-2A). Excessively asynchronous appearance of vertex waves has been associated with increased intracranial pressure or structural midline defects, such as agenesis of the corpus callosum [Kellaway, 1979]. Sleep spindles primarily define stage 2 of sleep and are not clearly expressed until 3 to 4 months of age. Synchrony is gradually achieved with increasing age, and most spindles are bilaterally synchronous by 18 months (see Fig. 12-11A). The waveform morphology of sleep spindles in infants differs from that of older patients. The duration of spindles is 1.5 to 1.8 seconds at 4 to 6 months. At this age, they

A FP1–A1

frequently reach 4 to 6 seconds, which subsequently shortens to 0.5 second by 25 to 54 months [Tanguay et al., 1975]. Spindles lasting as long as 4 to 6 seconds are frequently observed in infants younger than 1 year, but “extreme” spindles have been described in neurologically abnormal children of older ages (see Fig. 12-11B). The common frequency range is 13 to 14 Hz, but slower spindle frequencies of 10 to 12 Hz are also documented in about 5% of children older than 5 years. Spindle density is highest at 3 to 9 months and at a minimum at 27 to 54 months [Kellaway, 1952]. Faster bursts of 18 to 22 Hz may resemble spindles but are usually associated with medications, such as benzodiazepines and barbiturates.

Occipital Sharp Transients Two types of sharp transients can occur in the occipital region during sleep. Posterior sharp transients of sleep are surface-positive, checkmark-like waveforms, which usually occur in runs of 4 to 5 Hz but may occur singly. Although appearing asymmetrically, these waveforms are bilaterally synchronous. Although posterior sharp transients of sleep can appear between 4 and 5 years of age, they are most commonly encountered during the early sleep of young adults 15 to 35 years of age (Fig. 12-12) [Vignaendra et al., 1974]. The other form of occipital transients in children also appears during drowsiness. It has a cone-shaped con-

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FIGURE 12-12. A, Electroencephalogram (EEG) of a 5-year-old male during drowsiness with a 14- and 6-positive sharp-wave pattern in the bilateral temporal regions. B, EEG of a 17-year-old male during drowsiness with a six-per-second, phantom spike-wave pattern over the left hemisphere. C, A 16-year-old female with bioccipital posterior occipital sharp transients occurring during drowsiness. (B, Courtesy of Dr. P. Crumrine, Children’s Hospital, Pittsburgh.)

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figuration or a diphasic sharp wave resembling a vertex transient [Kellaway, 1979].

motor variant patterns also are described in as many normal, asymptomatic individuals as in study patients.

Frequency Distribution during Sleep

ABNORMAL ELECTROENCEPHALOGRAPHIC PATTERNS

More pronounced beta activity can accompany drowsiness. As stage 2 sleep emerges, a definite frequency and amplitude gradient can be appreciated between the anterior and posterior head regions. Higher frequency, lower amplitude activity predominates in anterior head regions, with the converse situation occurring in posterior head regions. With deeper sleep, this gradient is less well defined. Its absence or poor organization has been observed in children with developmental delays (see Fig. 12-11B) [Slater, 1979].

Arousal Patterns Infants younger than 2 months of age have only a diminution of background amplitude with arousal. By 2 to 3 months of age, diphasic slow waves accompany this desynchronization and may merge with delta waves by 5 months of age. With further arousal, 4- to 8-Hz rhythmic waveforms appear diffusely or in the frontocentral regions, last for several seconds, and disappear by 4 years of age. More monorhythmic 4- to 5-Hz activity may persist into young adulthood and can be seen in 40% of children 10 to 14 years old [Gibbs and Gibbs, 1950]. Postarousal hypersynchrony of 2.5 to 3.5 Hz generally appears frontally but may also be expressed posteriorly with further arousals. Such electrographic changes cease at any time, with the recording reverting back to the previous sleep pattern.

Patterns of Uncertain Significance This discussion of normal EEG concludes with a consideration of patterns that can be readily confused with epileptiform phenomena. The neurologist should anticipate the appearance of these normal patterns and appreciate the historical significance of their proposed association with various medical conditions. The most commonly encountered pattern is the 14- and 6- positive spike discharge (see Fig. 12-12A). Although initially assigned clinical significance, this pattern subsequently has been identified in several control populations [Lombroso et al., 1966]. These surface-positive waveforms appear in the posterotemporal regions or adjacent areas during sleep, with a 60- to 70-μV, comb-shaped configuration that may last as long as 3 seconds. It is best demonstrated with a referential montage and has a peak incidence during adolescence. The 6-Hz spike-wave complexes are less common waveforms, having maximal amplitude in the centroparietal regions. Historically considered clinically important in patients with headache and autonomic symptoms, it can be seen in normal control subjects, especially adolescents [Gibbs and Gibbs, 1964]. These complexes can be induced by diphenhydramine in 30% of normal volunteers (see Fig. 12-12B) [Tharp, 1966]. Small, sharp spikes and psychomotor variants are uncommonly observed in young children but rarely have a relationship with clinical syndromes. Small, sharp spikes occur more frequently in a normal rather than a patient population [Gibbs et al., 1963; White et al., 1977]. Psycho-

In this section, an arbitrary categorization of abnormal EEG patterns begins with a separate discussion of abnormal neonatal EEG activities because this age group demands unique interpretative skills. This discussion is followed by a presentation of epileptiform patterns that occur during childhood because of the importance of EEG in the diagnosis of seizure disorders. Subsequently, nonepileptiform abnormalities are briefly discussed and a discussion of EEG patterns associated with common clinical problems relevant to pediatric populations concludes this section.

Abnormal Neonatal Electroencephalographic Patterns Numerous medical complications can contribute to an encephalopathic state in the sick neonate, consisting of diffuse, multifocal, or focal brain dysfunction (Mizrahi et al., 2003; Scher, 2005). Many times, focal and diffuse processes exist simultaneously, creating a more difficult interpretative situation. EEG findings can substantially add to clinical assessments, given the limited clinical repertoire of the immature infant and the practical limitations of a sick neonate who is confined by catheters, intubation, pharmacologic paralysis, and an isolette. Comparison of the neonate’s EEG background activity with that expected for a particular gestational or postconceptional age can rapidly estimate the severity of an encephalopathy. Four general guidelines must be recognized before applying EEG analysis to the assessment of the newborn with suspected CNS dysfunction. First, neonatal EEG abnormalities are nonspecific; a specific diagnosis is only infrequently associated with a particular EEG pattern. Second, it is difficult to determine by a single EEG study if the observed EEG abnormalities are reflective of a transient or more permanent encephalopathy. Third, EEG abnormalities alone cannot be interpreted by the clinician with respect to the timing of the brain insult. Fourth, despite the degree of severity regarding EEG patterns, abnormalities usually disappear rapidly over time. This “normalization” of EEG disturbances can occur even in infants who suffer severe neurologic sequelae [Lombroso, 1985; Tharp et al., 1981]. Obtaining several EEG studies is recommended for all highrisk infants, beginning during the acute phase of the illness and repeated judiciously over the first days of life and during the second week until normal studies are obtained.

Assessment of Prognosis Serial EEG studies during the neonatal period offer more information than can be obtained from an isolated recording. Nonetheless, some reports emphasize the prognostic significance of single recordings with severely abnormal features [Harris and Tizard, 1970; Schulte et al., 1971; Watanabe, 1980], whereas other reports suggest that serial studies provide the clinician with a sensitive prognostic indication of neurodevelopmental outcome [Monod et al., 1972; Tharp

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FIGURE 12-13. Electroencephalogram of a 42-week-gestation, 2-day-old male demonstrates a burst-suppression (paroxysmal) pattern after a severe hypoxic-ischemic insult.

et al., 1981]. Monod and colleagues [1972] analyzed 691 neonatal EEG studies of 270 children whose clinical conditions were documented from 3 to 14 years. Certain EEG abnormalities were related to neurologic sequelae. Exam-

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FIGURE 12-14. Electroencephalogram (EEG) of a 36-week-gestation, 1-day-old male with hypoxic-ischemic encephalopathy demonstrates an isoelectric pattern.

ples of suppression-burst (paroxysmal), isoelectric, multifocal sharp wave patterns, and an invariant pattern are shown in Figures 12-13 to 12-16. Tharp and colleagues [1981] subsequently adapted these abnormalities to preterm neonates. From a retrospective analysis of 184 neonatal FIGURE 12-15. Electroencephalogram of a 42-week-gestation, 2-day-old male demonstrates multifocal sharp waves and marked asynchrony, as well as attenuation in the right hemisphere, after a severe hypoxic-ischemic insult.

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Scher / Pediatric Neurophysiologic Evaluation 40 wk

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EEG studies of 81 infants born at or before 36 weeks’ gestation, and subsequent clinical assessment of 64 survivors, a severely abnormal pattern was of prognostic value. Table 12-1 summarizes the major EEG abnormalities dis-

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Major Electroencephalographic Abnormalities

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ABNORMALITIES

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Inactive‡ Burst suppression Slow Low voltage§ Monorhythmic No spatial/temporal organization Asymmetry Interhemispheric asynchrony Abnormal superimposed patterns Focal spikes Seizures

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Head on right Ventilator

RESP. EKG. 50 ␮V 2 sec.

FIGURE 12-16. Electroencephalogram of a 40-week-gestation, 8-day-old female who has an atypical, low-to-moderate-voltage invariant pattern that occurred after severe intracranial hemorrhage.

NEAR-TERM AND PRETERM TERM INFANTS* INFANTS† (36 to 41+ weeks) (30 to 36 weeks) X X X X X X X X X X X

X X X

X (>50%) X X X

*Data from Monod N, Pajot N, Guidasci S. The neonatal EEG. Statistical studies and prognostic value in full-term and preterm babies. Electroencephalogr Clin Neurophysiol 1972;32:529. † Data from Tharp BR, Cukier F, Monod N. The prognostic value of the electroencephalogram in premature infants. Electroencephalogr Clin Neurophysiol 1981;51:219. ‡ Below 5 mV or isoelectric, 0.5 to 1 Hz. § Maximal at 25 mV. Adapted from Scher MS. Cerebral neurophysiological assessment of the high-risk neonate. In: Guthrie RD, ed. Recent advances in neonatal care. Clinics in critical care medicine. New York: Churchill Livingstone, 1987.

A 27 wk

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FIGURE 12-17. A, Electroencephalogram of a 27-week-gestation, 8-day-old female who has a prominent, midline (C2), surface-positive sharp wave, also seen in an adjacent electrode (C1). B, Cranial ultrasound of the same patient demonstrates prominent periventricular echodensities (arrows). (From Scher MS. Midline electrographic abnormalities and cerebral lesions in the newborn brain. J Child Neurol 1988;3:135.)

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cussed in these two studies. Severe EEG disturbances help establish a reference point for the neonatologist. Improving or worsening trends may have important prognostic implications in the context of the neonate’s evolving clinical condition. Further descriptions of various diffuse encephalopathic abnormalities in preterm and term neonates are available [Barabas et al., 1993; Scher, 1993a, 1993b].

Focal Abnormalities Neonatal EEG patterns have only recently been shown to be helpful in the evaluation of focal, regional, or hemispheric brain abnormalities [Aso, 1989; Mizrahi et al., 2003; Scher, 2005]. Parasagittal and lateralized EEG abnormalities (central or midline regions) have been correlated with a variety of brain lesions. In a population of 60 neonates with midline EEG abnormalities and cerebral lesions identified with neuroimaging or neuropathologic studies, intraventricular hemorrhage was the most common hemorrhagic lesion, whereas periventricular leukomalacia and cerebral infarction were the most common ischemic lesions associated with parasagittal abnormal patterns [Scher, 1987]. Midline EEG abnormalities include amplitude attenuation, positive sharp waves, seizures, and discharges associated with myoclonus. Other studies have also demonstrated the association of positive vertex sharp waves with intraventricular hemorrhage [Clancy and Tharp, 1984; Cukier et al., 1972; Lombroso, 1982; Novotny et al., 1986, 1987] (Fig. 12-17), or periventricular leukomalacia [Novotny et al, 1986], and the association of midline electrographic seizures with infarction [Clancy and Fischer, 1984; Scher, 1987].

Lateralized EEG abnormalities, including neonatal seizures, have been associated with congenital or acquired brain lesions (Fig. 12-18). After the seizure, the prominent abnormality is an attenuation of background frequencies or amplitude. In one report describing 271 EEG studies of 58 neonates (28 preterm, 30 term), almost 90% of infants with hemorrhage or infarctions had the maximum EEG abnormality on the side of the injury [Scher and Tharp, 1982]. The attenuation disappeared in 20% of these EEG recordings within 3 weeks, without asymmetry in subsequent records, whereas increased slowing of the background developed in the same region or hemisphere on subsequent records for other patients. Because of the association of cerebral lesions with these lateralized or parasagittal EEG abnormalities, the clinician is advised to obtain cranial imaging studies for accurate anatomic localization. Aso and associates [1989] found that hemispheric asymmetry or focal attenuation was associated with significant brain pathology in term and preterm patients. Transient asymmetries have also been described in asymptomatic neonates during the initial portion of quiet sleep [Challamel et al., 1984; O’Brien et al., 1987]. Judgment must be used before proceeding to imaging procedures to assess such patients for structural lesions.

Neonatal Seizures Despite the need to promptly diagnose neonatal seizures, unique clinical and electrographic features may delay timely recognition and treatment. The varied and less organized clinical expression of neonatal seizures makes the diagnosis

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FIGURE 12-18. A, Electroencephalogram of a 43-week-gestation, 1-day-old male who has stimulus-induced electrographic seizures (X) with the onset in the right temporal occipital region (arrow). B, Computed tomographic scan of same patient at 1 day of age documents a large hemorrhagic infarction involving the right temporal, parietal, and occipital regions. (From Klesh K, Murphy TF, Scher MS, et al. Cerebral infarction in persistent pulmonary hypertension of the newborn. Am J Dis Child 1987;141:852.)

Scher / Pediatric Neurophysiologic Evaluation

more difficult [Dreyfus-Brisac and Monod, 1964; Harris and Tizard, 1970; Rose and Lombroso, 1970; Volpe, 2001]. Accepted clinical criteria may not always distinguish seizure movements from pathologic nonseizure movements [Volpe, 2001]. Classifications have been developed that have improved the clinical accuracy of the observer [Mizrahi and Kellaway, 1984b]. Technologies using prolonged EEG or synchronized video EEG-monitoring sessions will likely prove more valuable in diagnosing clinical and electrographic seizures [Mizrahi and Kellaway, 1984b, 1998; Scher et al., 1989].

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Neonates may have seizures that are not detected unless an EEG is performed. Some of these patients are pharmacologically paralyzed for ventilatory care [Tharp and Laboyrie, 1983], whereas others fail to demonstrate clinical seizures despite the appearance of electrographic seizures in the absence of a paralytic agent [Coen et al., 1982]. Electroclinical uncoupling after antiepileptic use can suppress clinical signs associated with seizures [Scher et al., 2003]. EEG seizures are recognized by the electroencephalographer based on the evolution of discharges that can be clearly distinguished from the background and are not

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FIGURE 12-19. A, Electroencephalogram (EEG) of a 41-week-gestation, 1-day-old male who has an electroclinical seizure characterized by rhythmic clonic movements of the left foot and bihemispheric electrographic discharges with higher amplitude in the right hemisphere. B, A 25-week-gestation, 4-day-old female has a clinical seizure and no electrographic accompaniments. C, A 40-week-gestation, 6-day-old female has stereotypic arm flexion in the absence of electrographic seizures. Muscle artifact is prominent.

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related to artifact. The frequency of these discharges is usually in the slow range, with a variety of waveforms. The evolution of discharges implies a gradual change in the locus, amplitude, waveform, or distribution. The arbitrary definition for the minimum duration of a seizure is 10 seconds, with the average duration being 2 to 5 minutes for term or preterm neonates, unless status epilepticus occurs [Clancy and Legielo, 1987; Scher et al., 1993b]. Clinical ictal activity may accompany the electrical seizure (Fig. 12-19A and B). Only a few patterns are associated with a particular clinical presentation. For example, alpha-range rhythms have been associated with respiratory disturbances, such as apnea, as the clinical correlate appearing with an electrographic seizure [Watanabe et al., 1977]. Five categories of clinical seizure types have been described and may be associated with any number of EEG seizure patterns [Volpe, 2001]. These five categories are subtle, focal clonic, multifocal clonic, tonic, and myoclonic. Focal or multifocal EEG seizures can be observed, and generalized discharges are seen rarely. The infrequent occurrence of a clinical seizure without a coincident EEG accompaniment has been described (see Fig. 12-19C) [Watanabe et al., 1977]. Although one explanation is that there is a nonseizure movement disorder originating from a subcortical location [Mizrahi and Kellaway, 1984b, 1998, 2003; Scher, 2005], the possibility of a subcortical seizure focus may exist [Weiner et al., 1991]. The incidence of neonatal seizures and the prognostic implications of this condition have been described. The incidence of clinical seizures is suggested to be 1% to 1.2% of live births [Keen and Lee, 1973]. Similarly, the incidence of electrographic seizures has been estimated to be 0.2% of livebirths [Scher, 1987]. These figures may be higher for preterm or outborn infants after a seizure disorder has been diagnosed; however, the interictal EEG patterns can better access prognostic risk [Tharp et al., 1981]. A worse prog-

nosis is likely for patients demonstrating isoelectric, paroxysmal, multifocal spike discharges or unresponsive, slow background patterns [Lombroso, 1979; Monod et al., 1972; Scher, 2005]. An EEG diagnosis of seizures correlates significantly with high morbidity and mortality rates, based partly on the cause of the underlying brain injury [Scher, 2003]. Of neonates with seizures in one center over a 3-year period, 90% had brain lesions documented by cranial computed tomography (CT) or neuropathologic analysis [Scher, 1993a, 1993b; Scher et al., 1989]. Cerebral infarction is associated with a significant proportion of patients with seizures [Clancy et al., 1985; Levy et al., 1985; Scher, 1987]. High mortality rates have been reported for neonates with seizures, especially those who are preterm [Ment et al., 1982; Scher et al., 1989]. Close neurodevelopmental follow-up is necessary because of the risk of neurologic sequelae in many survivors. Subsequent estimates for the risk of epilepsy range from 20% to 56% [Legido et al., 1991; Scher et al., 1992].

Focal Periodic Patterns Focal and multifocal periodic abnormalities have been described in neonatal recordings. These discharges do not have an acceptable evolution in EEG features to be identified as an electrographic seizure. Instead, stereotypic, repetitive discharges at slow frequencies are observed, and they are usually brief (Fig. 12-20). More prolonged and lateralized periodic discharges have also been described, specifically for neonates with asphyxia [McCutchen et al., 1985] and herpes encephalitis [Mizrahi and Tharp, 1982]. Short runs of periodic discharges are more commonly observed [Scher and Beggarly, 1986]. Parasagittal discharges occur in preterm and temporal patterns in term neonates, and they are associated with EEG seizures and brain lesions, FIGURE 12-20. Electroencephalogram of a 35-week-gestation, 1-day-old female demonstrates holoprosencephaly with periodic discharges seen in the vertex region after an electroclinical seizure. (From Scher MS. Physiologic artifacts in neonatal electroencephalography. Am J EEG Technol 1985;25:241.)

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such as infarction [Scher et al., 1993]. This association of periodic patterns with brain lesions is reminiscent of the association between periodic lateralized discharges and brain lesions in adults and children [Chatrian et al., 1964; PeBenito and Cracco, 1979]. Repetitive EEG patterns, such as periodic discharges, do not satisfy arbitrarily defined descriptions of electrographic seizures but may have important relationships to clinically observed seizures [Shewmon, 1990].

Spikes and Sharp Waves In most situations, the electroencephalographer has difficulty assigning clinical significance to sporadic epileptiform features on neonatal recordings. These epileptiform characteristics may be seen in asymptomatic, apparently healthy infants. Several features, however, may help distinguish normal from abnormal spike or sharp waves. Epileptiform discharges that are frequent and multifocal and persistently occur throughout sleep may have pathologic significance. Several investigators have proposed that five spike or sharpwave discharges per hour suggest an abnormality [Rowe et al., 1985; Weiner et al., 1991]. Other features, such as positive sharp waves, periodic discharges, and midline discharges, commonly reflect CNS insults [Scher, 1991]. Spike and sharp-wave discharges have been described in specific neonatal populations based on serious medical disorders, principally seizures. Hughes and colleagues [1983a, 1983b] described spike and sharp-wave discharges in 236 neonates whose postconceptional age ranged from 24 to 48 weeks. Approximately 55% had recordings because of a clinical suspicion of neonatal seizures. Sporadic sharp waves, more frequent in the right hemisphere, were found primarily in the centrotemporal regions in 85% of the total population. An additional 15% had positive sharp waves or repetitive sharp waves. No control group in which epileptiform discharges were observed was included nor was follow-up reported. Rowe and associates [1985] documented sharp wave discharges in 51% of 74 neonates. These infants were followed up to 33 months of age and the presence of sharp waves on the neonatal EEG correlated with early developmental outcome. However, the investigators stress that EEG background abnormalities were more predictive than isolated epileptiform features. Spike discharges rarely occur in the neonate at any gestational age [Scher et al., 1993]. Sharp-wave discharges are, however, common in frontopolar, right temporal, and left central regions in otherwise asymptomatic neonates. Sharp waves in occipital midline locations are rarely seen in healthy neonates and may have greater clinical significance [Scher et al., 1993].

Epileptiform Abnormalities Beyond the neonatal period, epilepsy is primarily a clinical diagnosis. EEG studies indirectly confirm such a clinical impression by the documentation of interictal epileptiform abnormalities. Because it is uncommon to witness a clinical seizure or confirm electrical seizures during the EEG recording, the neurologist must primarily rely on an accurate historical description of the event. There are instances, however, when the history is unclear and one or multiple EEG studies may be helpful.

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EEG remains the principal investigation for children with epilepsy. However, the technique has been historically accepted, without strict reliability assessments [Camfield et al., 1995]. The clinician’s classification of a child’s seizure disorder, as well as possible diagnostic and therapeutic decisions, is based on interictal EEG results. The neurologist relies on interictal EEG recordings performed particularly close in time to the occurrence of the seizure event. However, demonstration of epileptiform abnormalities in the EEG patterns of patients with seizures does not occur in approximately 50% of the first routine interictal EEG recording [Shinnar et al., 1994]. Repeated EEG recordings may increase the diagnostic yield. A retrospective study of adults with the diagnosis of epilepsy found the chance of detecting interictal epileptiform activities to be approximately 20% for the second electroencephalogram and less than 10% after the fourth negative repeat EEG recording [Salinsky et al., 1987]. In a study of children between the ages of 1 month and 16 years, with one or more idiopathic or symptomatic newly diagnosed seizures, a repeat electroencephalogram was obtained in children who expressed no epileptiform activity on their initial EEG recording. Of 552 children studied, 56% had epileptiform activity on the initial electroencephalogram; for the overall group who had a repeat EEG recording, 30% had epileptiform activity when the initial EEG pattern was normal. Epileptiform activities were more likely if the repeat electroencephalogram included sleep [Carpay et al., 1997]. These findings are in accord with earlier reports in the literature on repeat EEG recordings after sleep deprivation in children with suspected epilepsy; between 32% and 75% of children had epileptiform activity on repeat electroencephalograms after sleep deprivation [Degen 1980; Ellingson et al., 1984; Geller et al., 1969]. Other reports warn against obtaining a repeat electroencephalogram, which may yield different and sometimes conflicting information for the clinician in children with absence seizures or generalized motor seizures [Camfield et al., 1995]. These investigators describe repeat EEG recordings in 159 infants, with a 40% to 70% discordance for the type of abnormality on the second electroencephalogram compared with the first. Among a variety of abnormal EEG patterns, certain features have been associated in patients with seizure disorders and are commonly referred to as epileptiform [Zivin and Ajmone-Marsan, 1968]. Epileptiform waveforms include spikes, sharp waves, spikes and waves, sharp and slow waves, and multiple spikes. The sharp wave has a waveform that is characteristically negative in polarity, with a duration of 70 to 200 msec. This finding is contrasted with the spike morphology, which is of shorter duration (20 to 70 msec) and sharper morphology. The slow-wave complex that may accompany either waveform generally is between 1 and 5 Hz (i.e., 200 to 1000 msec) [Kooi, 1966; Maulsby, 1971]. Epileptiform features are not necessarily associated with clinical seizures. One study found that 2.7% of 743 normal children had epileptiform EEG activity. This percentage increased to 8.7% during sleep [Eeg-Oloffsson, 1971]. In certain forms of genetic epilepsy, family members are asymptomatic but have abnormal EEG discharges [Doose et al., 1969]. Conversely, patients with well-documented seizures may have normal EEG studies, particularly children younger

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than 2 years [Scher, 1986]. Only 56% of patients with seizures in one study had epileptiform activity on the first EEG recording [Ajmone-Marsan and Zivin, 1970]. Epileptiform discharges not accompanied by obvious clinical events usually are regarded as subclinical or interictal. However, careful observation with psychometric testing can reveal brief episodes of impaired cognitive function during such discharges. This feature has been observed in 50% of patients who exhibit discharges during testing, and it may contribute to behavioral and cognitive deficits. Limited evidence-based analyses suggest that suppression of discharges is associated with improved psychosocial function [Binnie, 2003]. Specific pediatric epileptic syndromes may have a greater association with such deficits [Aldenkamp and Arends, 2004]. After a patient with recurrent epileptic seizures is treated with antiepileptic medication and becomes seizure free for some period, the clinician is eventually challenged with the decision about whether treatment should be continued. In making this decision, the neurologist must weigh the risk of side effects of antiepileptic drugs against the risk of seizure relapse. Certain indicators of prognosis continue to be of important clinical value. The EEG study has remained one predictor of outcome after withdrawal of treatment, but many children who become seizure free during drug treatment continue to manifest epileptiform activity in their EEG recordings. Correlations between EEG findings and clinical

outcome after discontinuation of treatment have been reported in many studies, as reviewed by Andersson and colleagues [1997], but there is a lack of unanimity, given the fact that different EEG variables have been assigned prognostic importance. Children whose last electroencephalogram before discontinuation of treatment displays generalized irregular spike-and-wave activity relapse more often than other children; 67% of children with such activity in their final EEG studies relapsed, compared with a relapse rate of 33% for children without epileptiform activity or with other epileptiform abnormalities. Children who were treated for only 1 year and in whom irregular, generalized spike-and-wave activities were present in one or more recordings had a high relapse rate. Apart from treatment of children with irregular, generalized spike-and-wave activity, most physicians discontinue treatment after 6 months to 2 years of seizure control. The presence of epileptiform activity does not necessarily influence the prognosis for the recurrence of seizures, with the exception of certain types of abnormal epileptiform activity or patient groups. For example, in a cohort of children with cryptogenic localizationrelated epilepsy who were followed for more than 5 years after drug withdrawal, 8 (9.8%) of 82 experienced seizure recurrence. Two independent risk factors were 6 years of age or older at seizure onset and 5 years or more from the start of drug therapy [Ohta et al., 2004]. Another report of children with cryptogenic partial epilepsy recommended EEG

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studies during drug withdrawal, even with a previously normal EEG study, because the presence of EEG abnormalities was associated with a high probability of seizures [Verrotti et al., 2000].

Generalized Epileptiform Patterns Spike-and-Wave Patterns The most frequently encountered spike-and-wave pattern is a bilaterally synchronous, single or polyspike discharge, followed in frequency by rhythmic slow waves (Fig. 12-21A). Both features are surface negative, and these discharges can be 100 to 200 msec long. Discharges in certain regions (e.g., frontal) appear slightly before the generalized burst or are maximally expressed in one particular location. The examiner may see fragments of the spike-and-wave pattern, depending on the montage or sensitivity setting because of cancellation effects of bipolar recordings or the low amplitude of the complexes. The fastest frequency of the discharges (3 to 6 Hz) is at the onset of seizures, with slowing to 2.5 to 4 Hz during the electrographic seizure. Augmentation of the discharges can be seen with hyperventilation [Dalby, 1969] or non-REM sleep, although the spike-and-wave pattern can become slower and more complex in morphology during sleep. Two nonspecific phenomena are often associated with a generalized spike-and-wave pattern and consist of bursts of 2- to 4-Hz, rhythmic slow waves or a more monorhythmic, occipital delta activity. The most significant clinical correlation is that patients with this pattern have a strong association with a generalized seizure disorder. Although this pattern can be observed in patients without clinical seizures, most patients demonstrate a history of generalized motor or absence seizures. Generalized, 3-Hz, spike-and-wave discharges with absence seizures account for 10% of all patients with clinical absence spells [Penry et al., 1975]. A motor accompaniment is identified in 90% of patients [Doose et al., 1973; Penry et al., 1975], and 14% have myoclonic seizures [Dalby, 1969]. The reaction time to an auditory stimulus is slowed during the occurrence of the spike-and-wave complex [Browne et al., 1974]. Patients can “outgrow” these discharges, as evidenced by longitudinal studies between 5 and 14 years that suggest age penetrance of the clinical seizure with or without the EEG abnormality [Metrakos and Metrakos, 1974]. Up to 50% of adolescents with the 3-Hz, spike and slow-wave pattern develop generalized motor seizures. If spike-and-wave discharge is the only abnormality on the EEG, the incidence of other neurologic deficits is low. Photic stimulation may elicit a spike-and-wave discharge (see Fig. 12-10B) but only can support the evidence for seizures suggested by the clinical evaluation. This pattern also appears in 3.4% of normal control subjects [Doose, 1969] and in 20% of siblings of patients with photoparoxysmal seizures who have never had clinical seizures. Only 10% of these siblings had clinical seizures. A prolonged response that outlasts the stimulus may be a stronger indication that a seizure disorder is present [Reilly and Peters, 1973], but there is also an age-dependent expression of this abnormal pattern between 5 and 15 years. Even self-limited photoparoxysmal responses that do not outlast the stimulus can be

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highly correlated with epilepsy [Nagarajan et al., 2003]. This pattern is most easily elicited with a frequency of 10 to 16 flashes per second. Clinicians must anticipate that children with photosensitive epilepsy can still have an excellent prognosis that is independent of the persistence or disappearance of photosensitivity on the EEG study [Verrotti et al., 2004]. Patients on dialysis, with electrolyte disturbances, or exhibiting withdrawal from drugs such as barbiturates and alcohol are more susceptible to photoparoxysmal responses with or without clinical accompaniment. Even for the nonepileptic pediatric patient, photoparoxysmal responses may be present in the absence of acute encephalopathies, with persistence for as long as 6 years after the initial documentation [Verrotti et al., 2002].

Sharp-Wave and Slow-Wave Complexes The sharp-wave and slow-wave complex pattern consists of a sharp wave of negative polarity lasting 100 to 200 msec and slow waves lasting 350 to 400 msec at a frequency of 1 to 2 Hz (see Fig. 12-21B). Although diffusely distributed over the scalp in most patients, it may be asymmetric or confined to anterior or posterior quadrants. This waveform is augmented only during sleep and can be associated with sudden desynchronization of the record, which is associated with a burst of beta activity called an electrodecremental response. Although the highest incidence of sharp-wave and slow-wave complexes occurs between 1 and 5 years of age, they are also evident well into adulthood. Hypsarrhythmia can precede the sharp-wave and slow-wave complex during the first year of life. Of clinical seizures with sharp-wave and slow-wave complexes, 90% are tonic [Blume et al., 1973], and these seizures are resistant to therapy, persisting at least 15 years after beginning treatment [Markand, 1977]. Other types of clinical seizures can also occur, depending on the age of onset: tonic seizures at 16 months, absence seizures at 32 months, myoclonic seizures at 39 months, and tonic-clonic seizures after 43 months [Chevrie and Aicardi, 1972]. Mental subnormality is identified in 30% of patients at diagnosis. When seizures are present before 2 years of age and are caused by CNS disease, the child will more likely exhibit delayed development. The clinical and EEG syndrome that includes the three features of seizures, mental subnormality, and sharp-wave and slow-wave complexes is called the Lennox-Gastaut syndrome [Gastaut et al., 1966; Lennox, 1945].

Hypsarrhythmia Hypsarrhythmia is the most common interictal EEG pattern associated with infantile spasms. The most common clinical description is a sudden, symmetric, tonic muscle contraction producing flexion/extension of the trunk and extremities although a variety of movement patterns have been described [Hrachovy et al., 1990]. The EEG pattern is a chaotic mixture of high-amplitude slow waves, multifocal spikes, and intrahemispheric-interhemispheric asynchrony (Fig. 12-22). This EEG pattern usually is observed in children 3 months to 5 years old, and it can be preceded by a burst-suppression or low-voltage invariant pattern in the newborn period.

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uation for the surgical treatment of epilepsies. Such an approach attempts to excise the principal epileptic focus in a patient refractory to antiepileptic drug therapy alone. The Amytal or Metrazol test may abolish bilateral discharges if a carotid injection is performed into the hemisphere responsible for generating the primary discharge [Gloor et al., 1976]. In children an intravenous pentobarbital injection has been alternately suggested [Lombroso and Erba, 1970]. Surgical excision of this abnormal tissue will presumably abolish most or all of the bilateral discharges and allow improved or complete control with antiepileptic drugs.

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FIGURE 12-22. Electroencephalogram of a 7-month-old female with infantile spasms demonstrates a hypsarrhythmic pattern consisting of high-amplitude disorganized slow activity, intermixed spike and slow-wave discharges, and an electrodecremental response.

Hypsarrhythmia can also be preceded by a normal EEG pattern [Jeavons and Bower, 1974]. During a spasm, an electrodecremental response interrupts the high-amplitude slowing by a sudden diminution of all activity with a duration of 1 second to 1 minute. The role of EEG is limited to diagnosis only, with no reliable correlation with cause, course, or prognosis, including mental development.

Generalized Periodic Discharges Generalized periodic discharges are distinguished from bilateral synchronous spike-and-wave discharges by the broader waveforms in the context of a periodic quality. This pattern has been historically identified with two clinical situations: Creutzfeldt-Jakob disease in adults and subacute sclerosing panencephalitis in children. The periodic complexes in subacute sclerosing panencephalitis appear at 1- to 3-second intervals but have no relation with the clinical progression of the disease [Celesia, 1973]. Similarly, there is no relation between the myoclonic movements and these discharges. The periodic discharges may first arise from a normal background and may initially be observed only during sleep.

Secondary Bilateral Synchrony Penfield and Jasper [1946] originally described bilateral discharges that resulted from the initial excitation of postulated subcortical or unilateral discharges. This concept has been adopted in the diagnostic procedures related to the eval-

The incidence of focal-spike discharges in the normal population (1.5% of 1000 children) has already been stressed [Peterson and Eeg-Olofsson, 1971]. Spike discharges in symptomatic patients should be correlated with the clinical context in which the discharges are observed. Focal spikes are identified in children with cerebral palsy in the absence of clinical seizures; however, the presence of focal spikes in children younger than 2 years of age implies severe neurologic impairment. Spike foci on a single EEG examination are not a reliable indicator of structural brain lesions because the location of the spike discharges on subsequent EEG studies may be shifted to different foci [Trojaborg, 1968]. However, the absence or rare occurrence of a spike discharge on a routine EEG usually predicts better outcome, compared with more frequent spikes in any head region associated with EEG background slowing [Hughes et al., 2004]. With these caveats in mind, the neurologist should consider certain electroclinical syndromes associated with focal or multifocal spike foci in children. These have been reviewed [Duchowny et al., 1996] and are discussed in more detail in the chapters on epilepsy.

Rolandic Spikes Rolandic spikes are associated with the most common genetic epilepsy of childhood. High-amplitude spike and slow waves are prominently observed singly or in runs in the central and midtemporal regions (Fig. 12-23A). Shifting laterality occurs in the same or subsequent EEG studies, and these focal discharges may be associated with generalized spike-and-wave discharges in 5% of children. The EEG background activity is otherwise normal, and certain patients have rolandic spikes that appear only during sleep, commonly during non-REM sleep [Beaumanoir et al., 1974; Dalla Bernardina and Beghini, 1976]. An unusual polarity relationship is associated with the discharges, consisting of a simultaneous negative and positive phase-reversal in two different locations of the spike discharge. This polarity may represent a horizontal rather than the more common vertical dipole and is associated with abnormal EEG activity. This genetic epilepsy is clinically expressed in an agedependent manner between 3 and 14 years of age; it rarely occurs beyond adolescence. Commonly, a nocturnal seizure is observed, with focal motor phenomena usually involving the face; buccolingual involvement and salivation are evident. Generalized seizures also frequently occur. An interesting feature of this genetic epilepsy is that 13% of family members demonstrated rolandic spikes without

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FIGURE 12-23. A, Electroencephalogram (EEG) of a 7-year-old male with rolandic epilepsy of childhood demonstrates a horizontal dipole of sharp-wave discharges. Notice the upward, negative deflection simultaneous to the positive, downward deflection of the discharge. B, EEG of a 14-year-old male with complex partial seizures demonstrates frequent, repetitive temporal spikes. C, A 40-week-gestation, 8-day-old male who experienced photic-induced occipital spikes at slow-flash frequencies after a hypoxic-ischemic insult.

clinical seizures [Heijel et al., 1975]. A proportion of children with typical benign partial epilepsy demonstrated transitory cognitive impairments during the course of their epilepsy, probably related to the association with the paroxysmal EEG activity [Deonna et al., 2000].

Besides the benign occipital epilepsy syndrome, a greater proportion of children with occipital discharges have symptomatic epilepsy, and the EEG study can assist in predicting better outcome based on the presence of generalized spikeand-wave discharges or normal EEG background rhythms [Libenson et al., 1999].

Occipital Spikes Benign childhood epilepsy with occipital paroxysms (benign occipital epilepsy) typically presents between 4 and 12 years of age. One study by Panayiotopoulos [1989] suggests that this is a common form of epilepsy in children. Of 94 patients, 18 (or 20%) fulfilled the criteria for benign epilepsy of childhood with occipital paroxysms. The clinical presentation may be visual phenomena in older children with simple or complex hallucinations or distortions with preservation of consciousness. In younger children, seizures are less frequent and are often nocturnal but may be dramatic with periods of prolonged unresponsiveness. The EEG patterns for both clinical presentations are composed of repetitive occipital spike discharges on eye closure. It has been debated whether this syndrome is related to the reflex epilepsies in which generalized seizures and EEG abnormalities can be initiated by video games and other visual stimuli. However, the presence of occipital epileptiform EEG abnormalities may be associated with children with migraine headaches with or without accompanying epilepsy. Specific electroclinical features help distinguish these two groups [Brinciotti et al., 2000].

OTHER IDIOPATHIC PARTIAL EPILEPSIES OF CHILDHOOD Some clinical entities are not universally recognized: benign frontal epilepsy; benign epilepsy with affective symptoms (i.e., benign psychomotor epilepsy); benign partial epilepsy of adolescence; benign partial epilepsy with midline spikes; and benign partial epilepsy with extreme somatosensoryevoked potentials. Because these clinical entities are best described under the general topic of partial epilepsies of childhood, they are discussed in Chapter 44.

Temporal Spikes and Sharp Waves Although not associated with a distinctive epileptic syndrome, temporal spike discharges must be distinguished from the spikes associated with rolandic epilepsy. The electroencephalographer can ascertain a difference by determining whether there is a more limited temporal location to the spike discharge without expression of a dipole as described previously (see Fig. 12-23B). According to a study by Eeg-

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Oloffsson [1971], temporal spikes are rarely seen in normal children (2 of 743 patients) but are frequently seen in epileptic patients (92% of 666), including children with complex partial seizures [Currie et al., 1971]. Complex partial seizures commonly begin during childhood [Falconer, 1971; Ounsted et al., 1966], and anatomic abnormalities have been detected in some of these patients. Static lesions, such as mesial temporal sclerosis, hippocampal herniation, or hamartoma, have all been described [Earle et al., 1953; Falconer and Taylor, 1968], and several of these patients also demonstrate homonymous hemianopsia or quadrantanopsia on visual field testing, presumably because of perinatal occlusion of the posterior cerebral artery [Remillard et al., 1974].

Multiple Independent Spike Foci Patients with spike discharges in at least three noncontiguous electrode positions are considered to have multiple independent spike foci (Fig. 12-24). No patients in a normal population have this pattern, whereas 63 of 1500 patients with seizures and EEG recordings demonstrate this pattern [Blume, 1978; Eeg-Oloffsson, 1971]. Of patients with multiple independent spike foci, 90% had clinical seizures, most of which were generalized motor seizures. Although 66% of patients had subnormal intelligence, normal cognitive abilities were more likely if there were few spike discharges and a normal EEG background. Sleep can augment spikes and activate new foci, but hyperventilation or photic stimulation cannot. Of these patients, 25% had previous EEG studies with hypsarrhythmia or sharp-wave and slow-wave complexes. Etiologic possibilities for this pattern include perinatal insults, CNS infections, neurocutaneous syndromes, degenerative diseases, trauma, and anoxia. In 29% of patients with multiple independent spikes a specific cause cannot be assigned [Noriega-Sanchez and Markand, 1976].

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Three types of neurologic conditions are associated with spike foci: acquired aphasia of childhood, motor dysfunction, and visual perceptual difficulties. Temporal or centroparietal spike-and-wave discharges have been reported in some children with expressive and receptive aphasia. This condition develops in previously normal children between 3 and 8 years of age [Shoumaker et al., 1974; Worster-Drought, 1971]. The aphasia can precede the onset of seizures by several years [Landau and Kleffner, 1957]. Long-term follow-up studies have also documented resolution of the seizures and partial or complete resolution of the aphasia over a period of years in most patients [Mantovani and Landau, 1980]. Evaluation and treatment of this condition remain controversial and are further discussed in the chapter on epileptiform disorders with cognitive symptoms. Some children have demonstrated evidence of motor difficulties with central spike discharges on EEG without clinical seizure manifestations [Lairy and Harrison, 1968]. Subsequent reports have corroborated and supplemented these earlier findings [Shewmon et al., 1988]. Occipital spikes have been observed in children with visuoperceptual and oculomotor abnormalities [Kellaway et al., 1955] (see Fig. 12-23C). Seizures have been reported in 54% of 318 children with occipital spikes [Smith and Kellaway, 1964]. Most seizures occurred before the age of 1 year. Generalized motor seizures are the most common type, and only 9% of studies reported ictal manifestations that were visual in nature. Only 34% of patients with ocular difficulties and occipital spikes have clinical seizures, but only 2 of 743 normal children have occipital foci [Eeg-Oloffsson, 1971].

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Generalized periodic discharges and neonatal periodic patterns have already been discussed. The present description pertains to the EEG phenomenon that consists of repetitive stereotypic focal discharges that remain lateralized with a duration of at least 10 minutes, or 20% of the recording time. Waveform morphologies can be varied and are collectively referred to as periodic lateralized epileptiform discharges [Chatrian et al., 1964]. This phenomenon represents an acute or a subacute process in adults or children. Usually, a brain lesion, such as infarction, contusion, or cerebritis, can be identified. Periodic discharges in the temporal region may suggest an encephalitic process caused by a herpetic infection [Elian, 1975]. Biphasic or polyphasic discharges of 100 to 200 msec and 100 to 200 μV have a frequency of 1 to 2 Hz (Fig. 12-25). These discharges persist for a limited number of days or weeks in adults and are replaced by focal polymorphic delta slowing. Multifocal periodic patterns can also occur [Dela Paz and Brenner, 1981]. In children, more subacute or chronic processes have been associated with focal or multfocal periodic lateralized epileptiform discharges [PeBenito and Cracco, 1979]. Similar to adults, periodic lateralized epileptiform discharges can also be seen in acutely encephalo-

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eralized delta slowing, or suppression of all EEG activity. The slower the frequency, the more severe the abnormality. An asymmetry of slowing or focal slowing superimposed on diffuse bihemispheric slowing indicates more localized disturbances in addition to diffuse abnormalities. Polymorphic rhythmic slowing unreactive to afferent stimuli indicates severe cerebral dysfunction. An intermittent rhythmic slowing that attenuates with eye opening or arousal suggests a projected rhythm from diencephalic or subcortical structures.

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ROLE OF PEDIATRIC ELECTROENCEPHALOGRAPHY IN SPECIFIC NEUROLOGIC SITUATIONS

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This concluding section on pediatric EEG consists of a general overview of EEG patterns associated with specific neurologic conditions encountered during childhood (also see chapters that discuss individual topics). Nonepileptiform abnormalities are frequently associated with a diverse group of clinical diagnoses and can assist in the diagnosis or prognosis of a dynamic disease process.

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FIGURE 12-25. A 3-month-old male with prominent periodic discharges in the right parietal region had an ischemic cerebrovascular lesion in the distribution of the posterior cerebral artery.

pathic children from infection or toxin exposure, and are highly associated with seizures [Yoshikawa and Abe, 2003]. Stimulus-induced rhythmic, periodic, or ictal discharges can be documented in older patients undergoing continuous EEG monitoring in the intensive care setting, which need to be distinguished from spontaneous seizures [Hirsch et al., 2004]. Stimulus-evoked seizures have been described for neonates [Scher, 1997], but older pediatric populations have not been systematically identified. In adults, 90% exhibit a depressed level of consciousness, whereas 70% demonstrate focal neurologic defects. Periodic discharges are commonly observed after a seizure, particularly if it is focal in onset; about 80% of these patients have frequent seizures [Sternberg et al., 1972]. An unusual seizure disorder in children has been described, consisting of agitation and confusion, in which periodic discharges in the frontal regions are observed when the patient is awake or asleep [Tharp, 1972].

Abnormal Nonepileptiform Patterns Besides the value of the EEG in the diagnosis of epilepsy and focal cerebral disease, it can be used to evaluate patients with medical conditions that directly or indirectly disturb cerebral function. This diagnostic category includes diffuse encephalopathies, which usually correlate with alterations in a patient’s mentation or level of consciousness. In general, an EEG is obtained as an indicator of cerebral dysfunction and as a measure of severity of the disturbance. The most common change consists of slowing of the background rhythms, with various degrees of severity, which will range from slowing of the dominant rhythm to gen-

Depending on the timing of the EEG relative to a seizure during a febrile illness, abnormalities can be recorded. These findings, however, are unlikely to have clinical value if observed within hours or days of the febrile seizure. Situations when an EEG can be useful during this early period include a suspected focal brain lesion or a continuing subclinical seizure in a patient who has failed to fully regain consciousness within an expected interval [Blume, 1982; Thorne, 1982]. In a sequential study of patients with uncomplicated febrile seizures, 33% have prominent delta activity diffusely or over the posterior head regions. This activity resolves within 2 weeks and has no prognostic significance [Frantzen et al., 1968]. Of 218 patients studied, documentation of 42 patients with bisynchronous spike-and-wave discharges and 19 patients with focal spikes also failed to predict recurrence of febrile seizures or occurrence of later nonfebrile seizures. Only crucial historical information of antecedent neurologic difficulties, such as a focal seizure, prolonged duration (i.e., greater than 15 minutes), abnormal examination findings, or family history of seizures, has predictive value for later epilepsy [Nelson and Ellenberg, 1983]. However, consensus opinion adopted by the Academy of Pediatrics suggests that an EEG may have more predictive benefit when obtained beyond a month after the febrile seizure [Practice parameter, 1996]. Even studies that included children with complex febrile seizures or those with preexisting neurologic disease have not shown early EEG studies to be predictive of the development of epilepsy. Given the high rate of simple febrile seizures and the low rate of subsequent afebrile seizures, obtaining routine EEG studies would require a large number of tests to identify a small number of children who will later develop seizures [Practice parameter, 1996]. In one report the risk of seizure recurrence in 170 children with initial normal-appearing EEG patterns compared with 99 children with initial paroxysmal EEG patterns was the same. Increase in recurrence risk

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was determined by younger age. The EEG did not add information regarding the likelihood of recurrence of febrile seizures [Nelson, 1997].

Head Trauma As with adults, the degree of EEG abnormalities in children after blunt head trauma is proportional to the severity of the insult. However, the magnitude of EEG abnormalities in children may exceed the clinical severity more often than in adults. The most striking acute change is in the posterior delta rhythm [Silverman, 1962]. Persistence of abnormalities, such as posterior slowing, may suggest subsequent functional difficulties [Mizrahi and Kellaway, 1984a]. Brain injury has become an increasing problem in the United States, with an estimated incidence of 2 million cases per year, of which almost 500,000 are admitted to the hospital [Hernandez and Naritoku, 1997]. Post-traumatic epilepsy and functional disability constitute the major sequelae and impose a high cost to society and individual survivors. Mild traumatic brain injury is generally not accompanied by significant EEG changes [DeVivo and Dodge, 1971]. At 1 year after injury, approximately 15% of patients with mild traumatic brain injury are persistently symptomatic with disabling symptoms [Alexander, 1995]. In patients with more severe head injury, EEG recordings have an important prognostic role. For example, 24 children were studied 8 to 36 months after severe head injury. EEG patterns recorded after the third day of trauma provided the most reliable information on brain damage-induced changes. A slow, monotonous EEG pattern in comatose patients indicated a poorer prognosis. Conversely, reactive patterns that were considered “prewake” patterns predicted the onset of complete clinical awakening. Slow, monotonous EEG patterns also were associated with impaired longterm intellectual or motor recovery in 50% of patients, whereas other EEG patterns predicted a more satisfactory and normal recovery [Dusser et al., 1989]. Another study found that EEG reactivity alone was an excellent predictor of long-term outcome compared with somatosensoryevoked responses or the Glasgow Coma Scale [Gutling et al., 1995]. No comprehensive studies of closed head injury in pediatric populations have used serial EEG recordings to assess prediction for posttraumatic epilepsy. Because the time to start antiepileptic therapy in persons with acute traumatic brain injury remains problematic, such prospective studies using serial EEG recordings may identify subsets of patients who are at high risk for post-traumatic epilepsy.

Prognosis after Hypoxic-Ischemic Insults With hypoxia or ischemia, progressive EEG changes begin with slowing of the dominant rhythm, followed by emergence of theta and delta slowing and suppression of all background activity. This information can be useful, particularly when provided by serial studies in the comatose patient. Two studies indicate how serial EEG evaluations can be an adjunct to clinical assessment. Pampiglione and Harden [1968] and Seshia and associates [1979] found that specific EEG findings help predict outcome. Normal EEG activities suggest a favorable outlook, whereas delta slowing requires follow-up studies before prognostic statements can be affirmed. Low-voltage, invariant EEG background activity, suppression-burst activity, or electrocerebral silence suggest an unfavorable outcome. Less frequently, diffusely distributed monorhythmic activities (i.e., alpha or spindle waveforms) also suggest poor prognosis for clinical recovery in patients with altered levels of consciousness.

Determination of Brain Death Unlike adults, the current criteria for brain death do not easily apply to all ages of children. Published guidelines [Task Force, 1987] suggest clinical and laboratory examination procedures for the child. As with adults, this report emphasizes clinical evaluation and physical examination criteria. Several age-dependent observation periods are recommended, at which times clinical examination and EEG studies can be obtained. Because the EEG may not always agree with the clinical assessment of irreversible coma, EEG is only a confirmatory study. With complete absence of brainstem function, residual low-amplitude EEG activity may persist on rare occasions. Electrocortical silence more likely will result on subsequent EEG recordings, or the patient will deteriorate progressively and then die as a result of cardiopulmonary failure [Ashwal and Schneider, 1987]. Other ancillary studies evaluating cerebral blood flow may be helpful. These difficulties can be compounded by hypothermia or sedative medication, situations that can erroneously contribute to a low-amplitude or isoelectric tracing. In neonates, an isoelectric EEG pattern does not closely correlate with the absence of brainstem function [Scher et al., 1996], but it can be associated with acute and chronic brain insults [Scher et al., 1993]. The neurologist must carefully adhere to the EEG guidelines for the confirmation of brain death [American Electroencephalographic Society Guidelines, 1986] to avoid potential interpretive error.

Headaches

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By comparison, clinical judgment is more reliable than EEG to determine the cause of a headache syndrome in children. However, a high percentage of EEG abnormalities in children with headache are associated with migraine syndromes [Prensky and Sommer, 1979] or seizure disorders. Focal delta waves have been described with complicated migraine and hemiplegia [Slatter, 1968]. Epileptiform abnormalities together with headache complaints occur in a substantial number of children with a prodromal or ictal headache component associated with a seizure disorder.

With an encephalitic process, EEG changes consist of principally rhythmic or arrhythmic slowing. For herpes encephalitis or other encephalitides, focal or lateralizing findings may also be seen. EEG can also help monitor for seizures that are subtle or only electrographic. In general, EEG is always abnormal in viral encephalitis. During the acute phase a degree of slowing usually parallels the severity of clinical findings [Ebersole et al., 2003]. The rate of EEG improvement also has some prognostic value. Normalization within 4 to 5 weeks indicates a more favorable outcome. In general,

Scher / Pediatric Neurophysiologic Evaluation

EEG changes in sporadic encephalitis caused by neurotropic viruses (such as equine, mumps, or St. Louis) are characteristically less severe than those resulting from postinfectious syndromes with demyelination (such as measles, rubella, vaccinia, or after vaccination). Residual brain damage is often associated with persistent EEG abnormalities, including epileptiform discharges. Excessive slow activity also occurs during acute infection with measles, mumps, rubella, and scarlet fever, even without overt CNS involvement [Ebersole et al., 2003]. The most striking EEG changes occur in herpes simplex encephalitis as described by Upton and Gumpert [1970]. Although not pathognomonic, focal or lateralized arrhythmic delta activity or pseudoperiodic complexes can appear 2 to 15 days after the onset of the illness. This pattern is to be contrasted with the typical EEG pattern seen in subacute sclerosing panencephalitis (SSPE) in which the EEG contains periodic complexes that are bilaterally symmetric and synchronous and have high-voltage 250-μV bursts of polyphasic stereotypic delta waves [Binnie et al., 2003; Daube 2002; Ebersole et al., 2003]. Human immunodeficiency virus (HIV) may be associated with EEG findings that are usually nonspecific, with diffuse background slowing, often accompanied by loss of faster frequencies and reduced complexity of EEG patterns. Reports by Enzensberger and colleagues [1985] found that 50% of acquired immunodeficiency syndrome (AIDS) patients had nonspecific EEG changes without clinical neurologic deficits. Rasmussen’s encephalitis is a rare childhood syndrome of unilateral brain dysfunction and focal seizures. Unihemispheric dysfunction progresses relentlessly in severity of degree over months to decades, culminating in hemiparesis and dementia. Seizures occur that are refractory to antiepileptic medications. Neuroimaging reveals progressive atrophy of the affected hemisphere. Neuropathology characteristically demonstrates perivascular lymphocytic cuffing and proliferation of microglial nodules in the cortex of the affected hemisphere. Serial EEG studies in these patients may include interictal epileptiform activity that is localized to the affected hemisphere. As the disease progresses, increasingly frequent bilateral synchronous and contralateral epileptiform activity emerges [Andrews et al., 1997]. Autoantibodies to glutamate receptor GluR3 have been isolated in rabbit brains, as well as the sera of human subjects with this condition, implicating an autoimmune process in its pathogenesis [Rogers et al., 1994]. With meningitis, acute EEG changes resemble those occurring with encephalitis. Given the different neuropathologic complications of meningitis, such as subdural effusion, empyema, or cerebritis, EEG may suggest the presence of focal lesions with the appearance of lateralizing EEG findings. The value of neurophysiologic studies in the management of bacterial meningitis is not clear. In one study of 41 children with acute bacterial meningitis, neither electrophysiologic data using EEG, brainstem auditory-evoked responses, nor computed tomography scans were better indicators of neurologic prognosis than the clinical examination [Pike et al., 1990]. EEG studies may reflect the pathophysiology of bacterial meningitis; neuronal injury may develop as a result of the release of vasoactive substances or alteration of blood-brain barrier permeability. Greater emphasis on the measurement of increased intracranial pressure and decreased cerebral perfusion pressure highlights neuroimaging changes that reflect

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pathologic lesions associated with children who suffer bacterial meningitis [Ashwal et al., 1992]. Further research is needed to understand the relation between local and regional cerebral blood flow changes that occur as a result of release of neurotoxic substances as reflected on neuroimaging and electrophysiologic monitoring. Concern for children with bacterial meningitis should be contrasted with those who experience enteroviral meningitis. Although EEG recordings were not included in a particular study of 45 patients in whom enteroviral meningitis developed between 4 days and 12 months, the neurologic or psychologic language and academic outcome was favorable in the entire cohort; none of the survivors had major adverse neurologic sequelae [Bergman et al., 1987].

Degenerative Diseases Most degenerative diseases diffusely affect cerebral function and cause generalized changes on EEG studies. Various electrographic abnormalities may help narrow the diagnostic possibilities, given the child’s age, symptoms, course, and neurologic findings. In general, diseases affecting gray matter show bilaterally synchronous paroxysmal abnormalities, presumably referable to cortical or subcortical gray matter regions. White matter disease alternatively has been associated with diffuse, high-amplitude slowing in an intermittent or continuous pattern. Occasionally, the EEG abnormality may facilitate the suspicion of a diagnostic category of degenerative disease in an otherwise healthy patient [Blume, 1982]. In certain instances, specific EEG patterns are associated with various degenerative diseases. Patients with neuronal ceroid lipofuscinosis may first exhibit high-amplitude poly-

FP3–T3 T3–O1 FP4–T4 T4–O2 FP3–C3 C3–O1 FP4–C4 C4–O2 T3–C3 C3–CZ CZ–C4 C4–T4 FZ–CZ CZ–PZ T3–CZ T4–CZ OFF LOC ROC RESP. EKG.

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FIGURE 12-26. Electroencephalogram of a 38-week-gestation, 2-day-old male with glycine encephalopathy. The stimulus-induced electroclinical seizure (X) occurred with clonic movement of the right lower extremity and coincident electrographic seizures primarily in the vertex region. (From Scher MS, Bergman I, Ahdab-Barmada M, Fria T. Neurophysiological and anatomical correlations in neonatal nonketotic hyperglycinemia. Neuropediatrics 1986;17:137.)

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spikes over the posterior head region in response to slow rates of flash stimuli [Pampiglione and Harden, 1973], or alternatively a quasiperiodic EEG pattern during the early stages of the disease [Veneselli et al., 2001]. GM2 gangliosidosis in certain patients may be associated with stimulus-sensitive myoclonus with periodic or multifocal sharp waves [Morrell and Torres, 1960], as can be seen on EEG recordings of newborns with a variety of inherited metabolic diseases [Mises et al., 1977], such as glycine encephalopathy (Fig. 12-26). Conditions in older patients in which stimulus-sensitive myoclonus can be associated with EEG abnormalities include familial myoclonic epilepsy [Blume, 1982] and cherry-red spot myoclonus syndrome [Engel et al., 1977]. EEG findings with subacute sclerosing panencephalitis have already been discussed. The classic clinical features of Rett’s syndrome and Angelman’s syndrome are not yet apparent during infancy. The most frequent EEG finding in Angelman’s syndrome was a 2- to 3-Hz rhythmic activity of high amplitude in the frontal areas, not influenced by eye closure or intermittent photic stimulation [Laan et al., 1998]. In contrast, females with Rett’s syndrome exhibited spike discharges in the central or centrotemporal regions. This may be helpful in situations where the biochemical marker for Rett’s syndrome was negative [Laan et al., 1998].

Reye’s Syndrome Although deeper stages of coma in patients with Reye’s syndrome tend to correlate with worsening EEG abnormalities, some patients may improve while their EEG results remain abnormal [Aoki and Lombroso, 1973]. However, given the increasing use of pharmacologic paralysis for ventilatory care, EEG results remain useful as a guide to the level of encephalopathy related to increased intracranial pressure [Kindt et al., 1975] or to short-chain fatty acid levels [Trauner et al., 1977].

Nonepileptic Paroxysmal Disorders Several clinical situations exemplify how the EEG can support this category of paroxysmal disorders. Syncope and, more specifically, breath-holding episodes may resemble clinical seizures. The absence of epileptiform activity while the episode is precipitated during a recording session supports this diagnosis. The associated electrocardiographic changes coincident with the episode may allow further subclassification of the type of episode [Gastaut, 1968]. Concerning daytime suspicious behaviors for seizures versus nonepileptic phenomena, video-EEG monitoring is frequently considered helpful [Paolicchi, 2002]. In one study of 143 patients 5 months to 43 years old, 79 patients exhibited staring with epileptiform findings. Forty-six patients had partial seizures, and 33 had atypical absence spells. Thirty-five had behavioral staring, 8 had psychogenic seizures, and 19 had migraine equivalent, and in 20, no staring spells were recorded. Video-EEG monitoring can be used to adjust treatment or to exclude epileptic events in patients with refractory staring spells [Carmant et al., 1996]. Rhythmic movement disorders during sleep are difficult to diagnose by history alone. In one report, seven children 1 to 12 years old were evaluated for violent nocturnal behaviors, six of whom were suspected of seizures; 37 periods of

dyssomnias were documented without epileptiform activity detected. Video-EEG monitoring during sleep can also help differentiate ictal from nonictal behaviors. Psychogenic seizures should be suspected if there is no diffuse slowing or alteration of background disturbances when an electroencephalogram is obtained within 24 hours after a suspected, generalized motor seizure. The occurrence of repetitive behavioral changes in the absence of epileptiform activity strongly suggests (although it does not prove) that psychogenic seizures may be present even in patients with a well-established seizure disorder. However, interictal EEG changes may be seen in patients with psychogenic nonepileptic seizures, given that many of these children also suffer from organic brain disease [Reuber et al., 2002]. Concomitant epilepsy with nonepileptic events can occur in preschool, school-age, and adolescent patients [Kotagal et al., 2002].

MONITORING STRATEGIES AND COMPUTER ANALYSIS OF ELECTROGRAPHIC DATA Using computers, automated analyses of electrographic information can assist in the interpretation of analog or digital EEG recordings [Scher, 1990b; Scher et al, 2005]. Although traditional methods of visual analysis are qualitative and subjective, computer analyses can more efficiently and quantitatively process larger amounts of information. Prolonged studies over many hours to days can be performed with little loss in accuracy. The presentation of electrographic data to the electroencephalographer is more efficient using computer display methods [Gotman, 1990]. Computer analyses can never replace the decision-making strengths of an experienced electroencephalographer, especially with respect to artifact identification and pattern recognition. Computers can be an important adjunct to the visual analysis process. However, although digital EEG techniques have grown in popularity, the clinical role of quantitative EEG analysis techniques remains controversial [Nuwer, 1997]. There are no universally accepted clinical applications of these technologies without analysis of the accompanying EEG. The use of EEG brain mapping and other advanced quantitative EEG techniques should only be used by neurophysiologists highly skilled in clinical EEG and only as an adjunct to traditional EEG interpretation. Additional sources should be consulted to obtain an understanding of the basic methods of computer EEG analysis, including spectral analysis, digital filtering, transient pattern detection, multiple channel analysis, and signal averaging [Abarbanel, 1996; Gotman, 1990; Neidermeyer et al., 2005; Weitkunat, 1991]. Computer techniques to assess short-term, spontaneous EEG recordings; long-term, synchronized videoEEG monitoring; neurointensive care monitoring; EEG-linked neuroimaging; sleep recordings; and evoked-potential analyses are discussed in the remaining sections of this chapter as examples of how computer technology can be applied to clinical neurophysiologic consultations.

Synchronized Video-Electroencephalographic Recordings The clinical utility of monitoring neonates, infants, and children with synchronized video-EEG recordings is based

Scher / Pediatric Neurophysiologic Evaluation

on the full range of normal and abnormal epileptic and nonepileptic events that may occur in this age group [Mizrahi, 1999]. For the outpatient, ambulatory recordings with portable digital devices which synchronize video and EEG signals may help document nocturnal and early morning arousal phenomena. Older technologies using cassette-tape storage [Foley et al., 2000] have been replaced with digital storage of video and EEG signals, although the obstacles to accurate documentation remain with respect to excessive artifact and inadequate equipment functioning. Short-duration outpatient video-EEG monitoring in the hospital setting was judged successful or informative in 73 (83%) of 87 of children, even with children who exhibited a low baseline frequency of clinical events [Del Giudice et al., 2002], and was also found to aid in the proper classification of epileptic seizures and nonepileptic events [Valente et al., 2003]. Longer term monitoring in epilepsy monitoring units [Lawson et al., 2002] or the pediatric intensive care setting [Ross et al., 1999] have reported good efficacy in the diagnosis of intractable seizures or status epilepticus, including patients being evaluated for epilepsy surgery and encephalopathic children who are critically ill.

Pediatric Neurointensive Care Neurologic disease states can be difficult to assess in the critically ill neonate, infant, and child within the intensive care environment. Rapid changes in brain or systemic illnesses alter the child’s neurologic structure and function. Physical and pharmacologic manipulations of the intensive care unit patient further complicate the neurologist’s assessment of the underlying disease process that is responsible for the child’s condition. The diagnostic and prognostic value of clinical neurophysiologic tools have been emphasized within the context of sound clinical judgment by nurses and physicians [DeNicola et al., 2001]. In the context of more sophisticated neuroimaging using magnetic resonance imaging (MRI) studies, neurophysiologic recordings still provide the critical temporal resolution for the investigation of ictal and nonictal encephalopathic processes [Blume, 2001]. Assessment of prognosis using multimodal neurophysiologic studies of EEG and evoked potentials can assist in outcome prediction in children with nontraumatic asphyxial-induced coma [Mewasingh et al., 2003]. More limited bedside monitoring devices that use trending algorithms of digital EEG frequency-amplitude changes can assist in assessing seizure and encephalopathic states in the neonate [Hellstrom-Westas, 1992] and the older child [Murdoch-Eaton et al., 2001].

Electroencephalography and Functional Neuroimaging Advances in noninvasive brain imaging techniques, have improved the neurologist’s ability to link specific brain functions to changes in brain structure and function in healthy or sick children. Various methods using electrophysiologic and functional MRI (fMRI) can advance our understanding of brain-behavior relations [Thomas, 2003]. EEG-linked fMRI and epilepsy have coupled subtle changes in blood flow on fMRI related to neuronal activity with EEG documentation of seizure discharges triggered to these images. This technique purports to allow dynamic imaging

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of interictal and ictal epileptic activity [Jackson et al., 1994].

Magnetoencephalography Because magnetic signals are far less distorted by intervening tissues than electrical signals, magnetoencephalography provides a better spatial resolution of signals than does conventional EEG [Baumgartner et al., 2000]. Some data illustrate the usefulness of this technique in mapping activity of sensory and motor areas and in studying the spatiotemporal patterns of brain activation specific to somatosensory function. Magnetoencephalography can localize epileptic activity. Magnetic source imaging refers to the superimposition of magnetoencephalographic signals with MRI to improve spatial resolution compared with surface electroencephalography. For children with localizationrelated epilepsies, this technique may aid in the accurate selection of epileptic children for epilepsy surgery [Verrotti et al., 2003].

Computer Strategies for Electroencephalographic Sleep Analyses Computer analyses of EEG during sleep better define the complicated relations between cerebral and noncerebral physiologic activity. Automated techniques for such analyses have been applied to adults and children and only recently to neonates. Most techniques rely on conventional methods of spectral analysis that assume consistency of neurophysiologic signals (i.e., a predictable sine-cosine wave to represent physiologic data). Nonstationarity characterizes many neurophysiologic phenomena, and algorithms are available for appropriate investigation [Abarbanel 1996; Kantz, 1997; Weinkunat, 1991]. Ideally, a computer system is needed that can compare behavioral and electrographic components of sleep in a manner that preserves the integrity of continuous signals over time while simultaneously investigating the timeand frequency-dependent relations among signals that compose the rhythmicity of EEG sleep cycles [Scher et al., 1990b, in press]. Through graphic displays of the digitized data of EEG and polygraphic signals (Fig. 12-27), it is possible to detect patterns of sleep organization, as expressed by spectral content of EEG and cardiorespiratory autonomic behavior, or discrete events such as REM and motility during specific states of sleep, compared with the visual score of sleep.

Evoked Potential Analysis As with spontaneous EEG and polygraphic signals, evoked potential analyses use computer-generated waveforms appropriate for neurologic assessment. An evoked potential is the electrographic response of the brain to an environmental stimulus [Gilmore, 1988]. Each evoked potential is represented by a sequence of waves, the amplitudes and latencies of which represent conduction and neuronal processing of sensory information through the CNS. Stimulus-evoked potentials have been used to assess auditory, visual, and somatosensory functions. These techniques involve computer averaging of the electrical potentials evoked by auditory, visual, or somatosensory stimuli. Scalp-recorded evoked potentials are much less apparent on paper records than are

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spontaneous EEG signals, and the computer averaging technique allows the summation of numerous evoked potentials to be time-locked to the sensory stimuli. All random activity that is not stimulus related cancels itself over time. Individual component waves are identified by polarity convention, usually depicted by upward negativity, and their peak latency in milliseconds after the stimulus or their numeric order in the evoked-potential complex. Computer analyses of spontaneous or evoked-potential EEG signals provide a methodology to assess brain development and dysfunction. The combined use of computerized neurophysiologic techniques with fMRI methods can advance the understanding of brain-behavior relations and help identify the role that specific interventions play in long-term developmental outcomes during childhood [Thomas, 2003]. Computerized neurophysiologic analyses highlight the role that these techniques play in evaluating a wide range of childhood brain disorders. The role of neurophysiologic techniques for clinical assessment include neonatal neurointensive

care [Scher et al., 2005], pediatric neurointensive care [Goh et al., 2004; Mewasingh et al., 2003], surgery management [Sala et al., 2002], epileptic populations [Boyd and Dan, 2001; Turkdogan et al., 2003], and a variety of specific clinical entities ranging from spinal muscular atrophy [ChelioutHeraut et al., 2003] to Wilson’s disease [Hsu et al., 2003]. The major portion of the following sections pertains to descriptions of the early components of the evoked potential that occur within the first 50 msec after the stimulus. Intermediate and late components (including event-related potentials) are then briefly discussed. More detailed descriptions are also available [Cracco and Cracco, 1986; Spehlmann, 2001; Mizrahi and Dorfman, 1980; Dorfman et al., 1980; Thomas, 2003].

Auditory-Evoked Potentials Since the demonstration by Jewett and Romano [1972] that brainstem activity can be reproducibly recorded from the scalp, subsequent studies have solidified the concept that the

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Scher / Pediatric Neurophysiologic Evaluation

series of waves constituting the auditory-brainstem response is localized primarily in anatomically separate areas along the auditory pathway primarily in the brainstem, as well as within the auditory cortex. Auditory-evoked potentials can be elicited by brief click stimuli delivered to each ear at a rate of 5 to 30 per second, and the responses are recorded with a single pair of scalp electrodes, often on the vertex. Seven positive waveforms are postulated to be generated from these stimuli. The first wave corresponds to the auditory nerve itself, although the fifth positive wave is the most easily measurable response, generated at or near the inferior colliculus (Fig. 12-28, top). Attempts have been made to define maturational changes in brainstem responsivity in terms of the auditory-evoked potential [Despland, 1985]. The following generalizations are suggested:

1. The waveform and amplitude of components depend on chronologic age, with increasing amplitudes over time. 2. Although the peripheral transmission reflected by wave 1 matures before the subsequent waves representing central transmission, latencies do not reach adult values until 12 to 18 months. 3. The threshold for auditory responsivity is lower than that obtained by auditory cortical events or behavioral testing and is similar to that in adults. 4. Different waveform components become more distinct at slower rates of stimulation, until 1 month of age. A comparable maturational trajectory has been traced for the human auditory cortex, identifying three developmental periods. Each period is characterized by a different axonal

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FIGURE 12-28. An auditory brainstem response to 70-dB Hl click stimuli for a normal, 38-week-gestation newborn (top) and a newborn with glycine encephalopathy (bottom) who was also tested at 38 weeks’ gestation. Dashed lines denote the difference in component wave latencies of the two infants (see Fig. 12-26, depicting the electroencephalogram of a patient with glycine encephalopathy.) dB Hl is the intensity in decibels based on the hearing level. (From Scher MS, Bergman I, Ahdab-Barmada M, Fria T. Neurophysiological and anatomical correlations in neonatal nonketotic hyperglycinemia. Neuropediatrics 1986;17:137.)

system [Moore, 2002]. During the perinatal period (third trimester to the fourth postnatal month), neurofilament expression occurs only in the axons of the marginal layer. These axons drive the structural and functional development of cells in the deeper cortical layers, but do not relay external stimuli. In early childhood (6 months to 5 years), maturing thalamocortical afferents to the deeper cortical layers are the first source of input to the auditory cortex from lower brainstem levels of the auditory system. During later childhood (5 to 12 years), maturation of commissural and association axons in the superficial cortical layers allow communication between subdivisions of the auditory cortex, forming a basis for more complex cortical processing of auditory stimuli. Auditory-evoked potentials also provide a measure of neural plasticity in children and adults. Cortical auditory-evoked potentials after cochlear implantations and after auditory training document improvements in speech perception ability which are associated with changes in the central auditory system, particularly at the cortical level [Purdy et al., 2001]. Given these maturational guidelines, clinical applications of auditory-evoked potentials can be judiciously applied to the evaluation of children suspected of hearing impairment or neurologic dysfunction. A report of the Joint Committee on Infant Hearing adopted by the American Academy of Pediatrics [Salamy, 1984] has identified newborns at risk for hearing loss. Diagnostic test procedures used to define hearing capability of infants and young children involve evokedpotential studies, supplemented by behavioral audiometric measures at older ages [Widen and Keener, 2003]. Principal

clinical situations include asphyxia, hyperbilirubinemia, intracranial hemorrhage, and developmental disorders. Such infants require close auditory and neurodevelopmental follow-up care [Fuess et al., 2002; Jansson-Verkasalo et al., 2004]. Auditory-evoked potentials can be a powerful tool for testing the integrity of the brainstem, especially in the comatose neonate or in the infant receiving neuromuscular blockade [Majnemer and Rosenblatt, 1996]. One example demonstrates prolonged intra-axial latencies for the auditory-evoked potentials in a comatose infant with nonketotic hyperglycinemia (see Fig. 12-28). Spongy leukodystrophy, found on gross and microscopic examinations of the brain, involved all myelinated traits, including structures serving the auditory pathway [Scher et al., 1986]. Auditory-evoked potentials are most useful throughout childhood for the diagnosis of demyelinating diseases, extramedullary and intramedullary brainstem tumors, coma caused by metabolic or structural lesions, and corroboration in suspected brain death. A clinical interpretation of abnormal auditory-evoked potentials is suggested by Spehlmann [2001]. This classification can be adapted to pediatric diseases of unknown cause involving the brainstem, including degenerative disorders. In addition to CNS dysfunction, audiologic studies use auditory-evoked potentials to determine the type and severity of hearing defects in children who cannot be examined with conventional audiometric tests. Brainstem auditory-evoked potentials reflect maturational changes in the interpeak latencies I to V, with adult values reached by about 3 years of age [Brivio et al., 1993]. Cortical auditory processing and communication in children with autism can be assessed by combined neurophysiologic and behavioral measures. Developmental reorganization of left-right hemispheric functions in autistic children highlight aberrant neural plasticity, with preferential activation of the right hemisphere for functions usually allocated to the left hemisphere [Bruneau et al., 2003].

Visual-Evoked Responses Assessment of visual function constitutes another important aspect of neurologic evaluation of the child. Besides the specific information concerning the integrity of the visual pathway, visual function can help to predict maturation and intellectual performance [Brecelj et al., 2002; Kriss and Thomson, 1997]. Three techniques can be used to assess visual processing: behavioral testing, pattern-preference testing, and visual-evoked responses. Visual-evoked responses can be elicited by a stimulus of light delivered as a flash from a stroboscope or by a checkerboard. The responses are recorded from the occipital regions of the scalp near the primary visual cortex. The latter stimulus requires maintenance of fixation during testing; flash responses therefore have been applied to infants younger than 3 months of age. The earliest response to flash visual-evoked responses is at 24 weeks’ gestation, and maturational changes in the visual-evoked responses waveforms have been described [Brecelj, 2003; Umezaki and Morrell, 1970; Watanabe et al., 1972]. The earliest waveform is initially surface negative, and only after 35 weeks’ gestational age is it preceded by a positive wave. The most stable and readily identifiable component of the neonatal visual-evoked response is a major positive wave-

Scher / Pediatric Neurophysiologic Evaluation

form with a latency of approximately 190 msec. The P2 peak latency rapidly decreases by 2 months after term, followed by slower changes throughout childhood (Fig. 12-29). Waking and sleep states may alter the latency of visualevoked responses, and it is generally recommended that the testing be obtained during non-REM (quiet) sleep in newborns. Latencies are expected to be 50 msec shorter during the waking state [Harden, 1982]. Abnormal visual-evoked responses can be encountered in diseases such as neurodegenerative disorders, tumors, and demyelinating and developmental disorders [Apkarian, 1994; Balachandran et al., 2004; Weiss and Kelly, 2003; Zgorzalewicz et al., 2003] that involve the visual system [Harden and Pampiglione, 1977] and more commonly occur in patients with brain injury resulting from asphyxia or trauma. In general, high-risk neonates with severe respiratory disease can demonstrate abnormal visual-evoked responses [Graziani et al., 1972]. Specific ischemic cerebrovascular disorders, such as cavitary periventricular leukomalacia, may also result in abnormal visual-evoked responses [DeVries et al., 1986]. In such clinical circumstances, crude correlations have been suggested between the severity of visual-evoked response disruption and long-term neurodevelopmental outcome. Unfortunately, normal flash visual-evoked response results can be seen in patients with abnormal visual function. It is therefore generally recommended to reevaluate a patient at risk with pattern visualevoked response testing at an older age when visual acuity and attention have matured. Pattern visual-evoked response testing can be performed reliably as early as 3 months of age. Visual inattention in infancy does not directly mean blindness. Well-formed waveforms over one or both hemispheres suggest favorable prognosis [Iinuma et al., 1997]. In conjunction with careful ophthalmologic evaluation (see Chapter 6), visual-evoked responses can be helpful throughout childhood in the investigation of prechiasmatic, chiasmatic, and postchiasmatic lesions [Spehlmann, 2001].

Small check (25')

4 months 8 months

18 months

+ 10 ␮V

– 100 msec

This anatomic distinction may require using pattern-reversal, half-field stimulation in the older child. Monocular full-field stimulation may be preferable for the young child with a decreased level of cooperation. Less specific but helpful information can be obtained by using full-field testing in the evaluation of lesions within the visual pathways, especially demyelination. Although full-field studies can provide sufficient evidence for prechiasmatic lesions, if the visual-evoked response abnormality is clearly monocular, lesions of the chiasm and postchiasmatic portions must be considered with abnormal full-field visual-evoked responses. Further investigation with half-field stimulation is recommended in the cooperative child. For children who cannot sufficiently communicate their responses during these studies because of age or disease, monocular visual-evoked responses can be useful in the evaluation of visual acuity and refraction.

Electroretinography Obtaining an electroretinogram is an electrophysiologic procedure that can assist in the evaluation of retinal maturation and disease, in concert with the evaluation of visual pathways by the visual-evoked response. As with the visualevoked response, the electroretinogram can be obtained using unstructured flashes of light or patterned stimuli. The electroretinogram is an electrical response of the retina that is a consequence of light energy-stimulating retinal photoreceptors [Sherman, 1986]. After the stimulus, three major deflections occur in this evoked response (Fig. 12-30). An initial negative deflection called the A wave corresponds to photoreceptor activity. The second wave is a positive deflection called the B wave, which reflects activity presumably from the inner nuclear layer (i.e., Müller cells). The final C wave is a second positive deflection that apparently has its cellular origins in the retinal pigment epithelium. Given that the flash electroretinogram only represents overall retinal activity, diseases limited to the

FIGURE 12-29. Series of visual-evoked responses at increasing ages for small- and large-pattern checkerboard images. Decreasing latencies and morphologies of the major positive waveforms are demonstrated. (Courtesy of Dr. K. Aso, Department of Pediatrics, Nagoya University School of Medicine, Nagoya, Japan.)

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significant visual-evoked response abnormalities [Sokol, 1986]. The combination of these two studies therefore can aid the neurologist in the assessment of the visual system when considering static or progressive diseases of the nervous system that may involve the visual pathways or retina [Kelly et al., 2003].

B

Left eye

Somatosensory-Evoked Potentials A

Right eye

B

A

FIGURE 12-30. An electroretinogram (ERG) of a 22-month-old male with right eye estropia. Monocular ERG tracings demonstrate diminished amplitude of the A/B wave in the right eye, suggestive of right optic atrophy. The ERG of the left eye is normal. (Courtesy of Dr. R. Sclabassi, Developmental Neurophysiology Laboratory, Magee-Womens Hospital, Pittsburgh.)

macular region may not be detected by only a flash electroretinogram procedure. Such flash procedures may be useful, however, with widespread retinal abnormalities, such as retinitis pigmentosa. Patterned stimuli on electroretinography and visual-evoked potentials can better detect the 1% of total retinal area containing the macula, which may be important to evaluate patients with suspected macular degeneration, particularly the detection of cone loss [Kelly et al., 2003]. During childhood, the visual system including the retina continues to develop. Rod and cone components, which constitute the electroretinogram signal, are functionally present in the infant but electrographically are lower in amplitude and longer in latency than the adult electroretinogram [Armington, 1974]. The A and B waves are present at birth; however, amplitude increases considerably over the first 15 years of life. Decreases in latency are significant only for the B wave during the first 6 months of life [Flores-Guevara et al., 1996]. By 1 year of age, pediatric electroretinogram amplitudes are comparable with adult amplitudes, although continued pattern electroretinographic changes can be observed throughout childhood [Brecelj et al., 2002, 2003]. In combination, the electroretinogram and visual-evoked potential can be valuable diagnostic tools in the evaluation of a child’s visual system. However, the pattern electroretinogram has not yet been aggressively applied to pediatric populations because of the technical difficulties with applying the contact lens electrode in an uncooperative, awake patient. However, certain pathologic conditions that affect middle and far peripheral retinal function (i.e., retinitis pigmentosa) have a greater effect on the electroretinogram than the visual-evoked response. However, abnormalities of foveal function, such as amblyopia and maculopathy, manifest in near-normal electroretinogram patterns, despite

Somatosensory-evoked potentials are elicited by percutaneous electrical stimulation of the peripheral nerves. The median nerve is principally used, with cerebral recording over the contralateral parietal somatosensory cortex. A complex sequence of waveforms results, with significant changes in the early components between groups of different gestational ages, reflecting the postnatal myelination of the sensory fibers of the central somatosensory pathway. Peripheral conduction velocities are largely within the adult range by 3 years of age, whereas spinal cord velocities do not attain adult values until 5 years of age [Cracco et al., 1975; Spehlman et al., 2001]. Somatosensory-evoked potential studies in neonates and infants indicate that the first negative waveform, with a peak latency of 20 msec, is remarkably consistent in its changes over 8 years into the adult pattern. Techniques and results can vary between investigators, but short-latency somatosensory-evoked potentials in infants appear to be easily recorded and well tolerated. Somatosensory-evoked potentials may assist in the localization of brain dysfunction by testing the integrity of the dorsal column mediolemniscal system. Abnormal somatosensory-evoked potentials may suggest impairment, which carries a less favorable prognosis for specific highrisk groups, such as children at risk for hemiplegia [Ferri et al., 2001; Willis et al., 1984] or preterm neonates surviving periventricular hemorrhage [Laget et al., 1976]. Somatosensory-evoked potential abnormalities associated with lesions in the spinal cord, brain lesions caused by ischemia, malformation [Dorfman et al., 1980; Duckworth et al., 1976; Kalita et al., 2003], acute encephalopathies [Mandel et al., 2002; Robinson et al., 2003; Tomita et al., 2003], or neurodegenerative disease [Dorfman et al., 1978] may prove helpful in formulating a prognostic statement. Somatosensory-evoked potential types consist of arm or leg electrical stimulation (Fig. 12-31). Recording these potentials in children of various ages provides helpful information concerning maturation of the brain and somatosensory-evoked potential abnormalities associated with focal and diffuse neurologic deficits. Different types of spinal and scalp somatosensory-evoked potential abnormalities have been found in children with various spinal cord diseases, including those of traumatic, degenerative, and inflammatory causes [Cracco and Cracco, 1986]. As with auditory- and visualevoked potentials, somatosensory-evoked potentials have a role in the evaluation of patients with diffuse cerebral disorders with reduced consciousness or altered mental status. Reports on the prognostic utility of evoked potentials in comatose patients using all modalities have disclosed strong correlations with outcome, for a range of functional deficits, including neonates [Beca et al., 1995; Majnemer and Rosenblatt, 1996]. Multimodality monitoring during surgery is also recommended [DiCindio et al., 2003; Strahm et al., 2003; Wiedemayer et al., 2004].

Scher / Pediatric Neurophysiologic Evaluation Right median

+

P3 – Fz

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FIGURE 12-31. Somatosensory-evoked potential with stimulation of the right medial nerve as recorded at Erb’s point, the cervical vertebrae, and the somatosensory area of the cortex. (Courtesy of Dr. R. Sclabassi, Developmental Neurophysiology Laboratory, Magee-Women’s Hospital, Pittsburgh.)

–

CV7 – Fz +

–

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Erb’s 1+/ Fz

– 5 uv/mm Band width .3 1000 HZ

Event-Related Potentials Event-related potentials refer to evoked potentials and other types of potentials that are the result of cognitive processes after a stimulus. Such potentials occur substantially later than the standard evoked potential. However, these potentials depend on cognitive processes rather than on the physical characteristics of the stimuli, and can even be used during infancy to assess vigilance and visual processing [de Haan et al., 2003; Goldman et al., 2004]. For instance, measurement of the most commonly studied event-related potential is the positive peak, which occurs 300 msec after an unexpected stimulus (P300). Attempts have been made to relate abnormalities of the P300 to the condition of altered cognitive functioning in a variety of conditions occurring during childhood, such as learning disabilities [Ollo and Squires, 1986], attentional disorders [Hoeksma et al., 2004; Mangina et al., 2004; Potgieter et al., 2003], infantile autism [Novick et al., 1980], elevated lead levels [Otto et al., 1982], and iron deficiency [Otero et al., 2004]. Although a number of interesting findings have been reported concerning eventrelated potentials of children, the data have neither illuminated the nature of the process nor been diagnostically useful for clinical purposes. Greater attention to maturational studies of infants and children is needed [Davies et al., 2004; Lewis et al., 2004]. Whereas event-related potentials can be elicited in infants as young as 4 to 6 months of age, amplitude and latency differences distinguish infant from

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CHAPTER 13

Neonatal Seizures Eli M. Mizrahi

Neonatal seizures may be the first, and perhaps the only, clinical sign of a central nervous system (CNS) disorder in the neonate. The occurrence of seizures raises a number of hypothetical and practical concerns critical to the long-term outcome of newborns who experience seizures. For many years, the understanding of epileptogenesis in the developing brain was based on the notion that the immature brain was more likely to generate seizures in response to injury than the more mature brain. It was thought that the immature brain was not susceptible, or at least less susceptible, to seizure-induced injury. Although experimental data continue to support the idea of relative enhanced epileptogenesis of the immature brain, emerging experimental data suggest that seizureinduced injury may be a more significant problem in the developing brain than previously thought. Although neonatal seizures have been the topic of basic and clinical research over many years, there remain considerable gaps in knowledge in areas that relate to diagnosis, pathophysiology, cause, therapy, and prognosis. As research continues, the clinician is left with the task of developing strategies in diagnosis and management with limited scientifically confirmed data. The following discussion is based on the best available data and on considerations grounded in clinical practice when more scientifically derived data are unavailable. Although controversies related to the characterization and classification of neonatal seizures have for the most part been resolved, data relating to treatment and prognosis remain significantly limited. The debate continues in the basic neuroscience literature about whether and how seizures cause significant injury in the developing brain, and there is even less information concerning whether these findings are applicable to human newborns and whether the degree of injury is clinically significant. Resolution of these issues will ultimately guide antiepileptic drug therapy in neonates and more clearly define factors that predict long-term outcome. The more practical approach is to consider the notion that the overriding determinant of outcome is the origin of the seizure. Seizure occurrence may indicate the presence of a potentially treatable cause and should prompt an immediate search for this cause and institution of appropriate therapy. Seizures themselves may require emergent therapy because they may directly or indirectly disrupt the infant’s homeostasis or contribute to additional brain injury. Seizure occurrence and the type of seizures may have predictive value in determination of outcome. The approach to the clinical management of an infant thought to have experienced a seizure is defined by the orderly consideration of issues that can improve long-term outcome: accurate seizure characterization and classification; maintenance of infant homeostasis; urgent search

for a treatable cause; appropriate application of electroencephalography; institution of etiologic-specific treatment; thoughtful consideration of acute and chronic antiepileptic drug treatment; and consideration of risk factors that predict outcome to plan for long-term care.

INCIDENCE AND OCCURRENCE The first 28 days of life (defining the neonatal period) represents the period of greatest seizure hazard during the human life span. The incidence of seizure occurrence is greatest in childhood [Kellaway and Hrachovy, 1983; Tharp, 2002]. Reported incidence rates of seizures range from 1.5 to 5.5 in 1000 neonates [Bergman et al., 1983; Eriksson and Zetterström, 1979; Lanska et al., 1995; Ronen and Penney, 1995; Saliba et al., 1996; Spellacy et al., 1987], depending on various methodologies and the populations being studied. Most seizures occur within the first week of life [Lanska et al., 1995]. It has also been suggested that seizure incidence varies with specific risk factors such as birth weight, degree of illness, and possible cause. Lanska and colleagues [1995] reported seizure occurrence to be greatest in preterm or lowbirth-weight infants compared with term infants. They found an incidence of seizures in all neonates to be 3.5 in 1000 but 57.5 in 1000 in very-low-birth-weight (<1500 grams) infants, 4.4 in 1000 in low birth weight (1500 to 2499 grams) infants, 2.8 in 1000 in normal-birth-weight (2500 to 3999 grams) infants. Scher and colleagues [1993a, 1993b] reported that seizures occurred in 3.9% of neonates younger than 30 weeks’ conceptional age and in 1.5% of neonates older than 30 weeks’ conceptional age. Similarly, Kohelet and colleagues [2004] found an overall incidence of seizures in a cohort of very-lowbirth-weight infants to be 5.6%. Using the terminology of the International League Against Epilepsy, most neonatal seizures are considered to be acute reactive or symptomatic. Although seizures in this category are relatively frequent, the occurrence of specific neonatal epileptic syndromes, as defined by the International League against Epilepsy, is rare. These International League against Epilepsy–designated syndromes include benign neonatal convulsions, benign familial neonatal convulsions, early myoclonic encephalopathy, and early infantile epileptic encephalopathy [Commission, 1989; Aicardi,1994; Mizrahi and Clancy, 2000; Tharp, 2002].

CLINICAL CHARACTERIZATION AND CLASSIFICATION Seizures in the neonate have clinical features that are unique compared with those occurring in older infants and

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children. This has sometimes led to confusion and mischaracterizations of the observed paroxysmal clinical events. Differences in the clinical events in neonates compared with older children include fragmentation, disorganization, unusual patterns of spread, and simultaneous, but asynchronous, multiple regions of involvement. Some of these differences are based on mechanisms of epilepto-genesis and the state of early development in the immature brain. Other differences are based on the relative importance of non-epileptic mechanism of seizure generation in this age group. There are also similarities between neonatal seizures and those of older infants and children. These include the types of movements that characterize the events such as clonic, tonic, and myoclonic activity. Neonatal seizures have been classified according to clinical manifestations, the relation between clinical seizures and electrical seizure activity on the electroencephalogram, seizure pathophysiology, and type of epilepsy syndrome. Each classification has some clinical utility.

TABLE 13-1 Clinical Characteristics, Classification, and Presumed Pathophysiology of Neonatal Seizures CLASSIFICATION

CHARACTERIZATION

Focal clonic

Repetitive, rhythmic contracts of muscle groups of the limbs, face, or trunk May be unifocal or multifocal May occur synchronously or asynchronously in muscle groups on one side of the body May occur simultaneously but asynchronously on both sides Cannot be suppressed by restraint Pathophysiology: epileptic Sustained posturing of single limbs Sustained asymmetric posturing of the trunk Sustained eye deviation Cannot be provoked by stimulation or suppressed by restraint Pathophysiology: epileptic Sustained symmetric posturing of limbs, trunk, and neck May be flexor, extensor, or mixed extensor and flexor May be provoked or intensified by stimulation May be suppressed by restraint or repositioning Presumed pathophysiology: non-epileptic Random, single, rapid contractions of muscle groups of the limbs, face, or trunk Typically not repetitive or may recur at a slow rate May be generalized, focal or fragmentary May be provoked by stimulation Presumed pathophysiology: may be epileptic or non-epileptic May be flexor, extensor, or mixed extensor and flexor May occur in clusters Cannot be provoked by stimulation or suppressed by restraint Pathophysiology: epileptic

Focal tonic

Generalized tonic

Clinical Classification Efforts over the years to characterize and classify neonatal seizures [Dreyfus-Brisac and Monod, 1964; Lombroso, 1974; Mizrahi and Kellaway, 1987; Rose and Lombroso, 1970; Scher, 2003; Volpe, 1973, 1989; Watanabe et al., 1977] demonstrate an evolution of thought and underscore the importance of the groundbreaking work of French investigators reported more than 40 years ago [DreyfusBrisac and Monod, 1964]. Early classification schemes focused on the differences between neonatal seizures and those of older children; neonatal seizures were reported to be clonic or tonic, not tonic-clonic, and when the seizures were focal, they were characterized as unifocal or multifocal. Later classifications included myoclonus [Rose and Lombroso, 1970]. Early investigators also identified clinical events that had less of a traditional organization of motor activity, considered an important distinction between seizures of the neonate and older children [Dreyfus-Brisac and Monod, 1964; Minkowski et al., 1955; Sainte-Anne-Dargassies et al., 1953]. They were initially characterized as anarchic [Dreyfus-Brisac and Monod, 1964] and later as subtle [Volpe, 1973] or minimal [Lombroso, 1974]. These descriptions included events of oralbuccal-lingual movements, such as sucking and chewing; movements of progression, such as bicycling of the legs and swimming movements of the arms; and random eye movements. Although these events were initially considered epileptic in origin, others later suggested that they were exaggerated reflex behaviors and referred to them as “brainstem release phenomena” or “motor automatisms” [Mizrahi and Kellaway, 1987]. Table 13-1 lists the clinical characteristics of neonatal seizures according to a current classification scheme [Mizrahi and Kellaway, 1998]. This scheme can be applied through clinical observation of the neonate. The basic classification includes seizures characterized as focal clonic, focal tonic, myoclonic, spasms, generalized tonic, and motor automatisms (i.e., subtle seizures). Paroxysmal changes related to the autonomic nervous system have also been reported to be manifestations of seizures. These events include alterations in heart rate, res-

Myoclonic

Spasms

Motor automatisms Ocular signs Random and roving eye movements or nystagmus (distinct from tonic eye deviation) May be provoked or intensified by tactile stimulation Presumed pathophysiology: non-epileptic Oral-buccalSucking, chewing, tongue protrusions lingual May be provoked or intensified by stimulation movements Presumed pathophysiology: non-epileptic Progression Rowing or swimming movements movements Pedaling or bicycling movements of the legs May be provoked or intensified by stimulation May be suppressed by restraint or repositioning Complex Sudden arousal with transient, increased purposeless random activity of limbs movements May be provoked or intensified by stimulation Presumed pathophysiology: non-epileptic From Mizrahi EM, Kellaway P. Diagnosis and management of neonatal seizures. Philadelphia: Lippincott-Raven, 1998:21.

piration, and blood pressure, as well as flushing, salivation, and pupillary dilation [Goldberg et al., 1982; Lou and Friis-Hansen, 1979; Watanabe et al., 1977]. Any one of these findings occurring as an isolated epileptic event is rare. When they do occur, they do so most consistently in association with other clinical manifestations of seizures [Mizrahi and Kellaway, 1987].

Mizrahi / Neonatal Seizures

Classification According to Temporal Relation to Electrical Seizure Activity Although the clinical classification described earlier is based on the clinical characteristics of the seizures, other classification schemes consider the temporal relation of clinical events to the occurrence of electrical seizure activity on the electroencephalogram. An electroclinical seizure occurs when the clinical event overlaps in time with electrographic seizure activity. A clinical seizure is referred to as clinical only when the event occurs in the absence of any electroencephalographic (EEG) seizure activity. Electrical seizures may occur in the absence of any clinical events and are referred to as electrical-only seizures.

Classification According to Pathophysiology Seizures may also be classified according to their pathophysiology: epileptic or non-epileptic in origin (Box 13-1). This notion has been debated since Mizrahi and Kellaway

BOX 13-1 CLASSIFICATION OF NEONATAL SEIZURES BASED ON ELECTROCLINICAL FINDINGS Clinical seizures with a consistent electrocortical signature (pathophysiology: epileptic) Focal clonic Unifocal Multifocal Hemiconvulsive Axial Focal tonic Asymmetric truncal posturing Limb posturing Sustained eye deviation Myoclonic Generalized Focal Spasms Flexor Extensor Mixed extensor and flexor Clinical seizures without a consistent electrocortical signature (pathophysiology: presumed non-epileptic) Myoclonic Generalized Focal Fragmentary Generalized tonic Flexor Extensor Mixed extensor and flexor Motor automatisms Oral-buccal-lingual movements Ocular signs Progression movements Complex purposeless movements Electrical seizures without clinical seizure activity From Mizrahi EM, Kellaway P. Diagnosis and management of neonatal seizures. Philadelphia: Lippincott-Raven, 1998:23.

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[1987] reported their findings of neonates who experienced seizures during EEG-video monitoring. They presented a classification of neonatal seizures based on clinical characteristics, the relation between EEG and clinical events, and presumed pathophysiology. They suggested that a group of behaviors previously referred to as subtle seizures had features more consistent with reflex phenomena rather than epileptic seizures. These investigators demonstrated that the paroxysmal clinical events could be provoked by tactile stimulation of the infant; that the intensity of the response could be proportional to the intensity of the stimulus (in terms of intensity at a single site of stimulation or consistent intensity with increasing sites of stimulation); that the response could spread to regions of the body distant from the site of stimulation; and that the clinical events could be suppressed by restraint of the infant. These were considered features of reflex behaviors. When the concept of non-epileptic seizures is discussed in the literature by others, there is an emphasis on the finding of the absence of electrical seizure activity during clinical seizure activity [Volpe, 2001]. These discussions suggest that electrical discharges can be generated in deeper cortical or subcortical regions and not be recorded by scalp electroencephalography. Data from human adults and mature animal studies are provided to support this concept. Although this possibility cannot be discounted in human neonates, there is no supportive evidence in human neonates. Ictal singlephoton emission computed tomography (SPECT) performed in neonates with so-called non-epileptic events (i.e., brainstem release phenomenon) has failed to demonstrate the hyperperfusion that is characteristic of epileptic seizures [Alfonso et al., 2000]. The lack of associated EEG seizure activity is not the essential finding that suggests a nonepileptic pathophysiology; rather, the similarity of the events to the experimental models of reflex behaviors provides the most compelling data (Table 13-2). TABLE 13-2 Reflex Physiology Demonstrated in Animal Models Compared with Generalized Tonic Seizures and Motor Automatisms* in Human Neonates ANIMAL MODELS

NEONATES

Decortication

Cortical depression, obtundation, or coma Electroencephalographic background depressed and undifferentiated or electrocerebral silence Spontaneous or elicited movements Motor automatisms Tonic posturing Response to stimulation Temporal summation Spatial summation Irradiation of the response Response to restraint Arrest of behavior

Reflex movements Progression Posturing Response to stimulation Temporal summation Spatial summation Irradiation of the response Response to restraint Arrest of behavior

*So-called non-epileptic seizures. Based on data from Lindsley et al., 1949; Sherrington et al., 1932; Sprague and Chambers, 1954; Starzl et al., 1951. From Mizrahi EM, Kellaway P. Diagnosis and management of neonatal seizures. Philadelphia: Lippincott-Raven, 1998:23.

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Seizures of Epileptic Origin

TABLE 13-3

Some seizures clearly have an epileptic origin. They are closely associated with seizure activity on the electroencephalogram, and the clinical event cannot be provoked by stimulation nor suppressed by restraint of the infant. Certain properties of the developing brain enhance seizure initiation, maintenance, and propagation. These properties include enhanced cellular excitation, enhanced synaptic excitation, and a tendency to promote propagation of an epileptic discharge [Hablitz et al., 1992; Holmes, 1997; Moshé, 1993; Prince, 1993; Schwartzkroin, 1995; Swann, 1995]. The clinical events that are most clearly epileptic in origin are focal clonic, focal tonic, some types of myoclonic seizures, and spasms (see Table 13-1 and Box 13-1). These seizre types can be recognized and characterized at the bedside. During the event, the clinician can attempt to suppress the motor behavior by holding the affected limb; a continuation of rhythmic muscle contractions indicates the epileptic basis of the event. When the electroencephalogram is used, seizures characterized as electrical-only seizures are also considered epileptic in origin.

Comparison of Early Myoclonic Encephalopathy and Early Infantile Epileptic Encephalopathy

Seizures of Non-epileptic Origin Other seizures are best considered as non-epileptic in origin [Kellaway and Hrachovy, 1983; Mizrahi and Kellaway, 1987]. These events occur in the absence of electrical seizure activity, but more importantly, they have clinical characteristics similar to reflex behaviors. These clinical events can be provoked by stimulation of the infant. Both the provoked and spontaneous events can be suppressed by restraint or by repositioning the infant during the event. The clinical events may increase in intensity with the increase in the repetition rate of stimulation (i.e., temporal summation) or the sites of simultaneous stimulation (i.e., spatial summation). Clinical events classified as non-epileptic in origin include some types of myoclonic events, generalized tonic posturing, and motor automatisms such as oral-buccal-lingual movements, movements of progression, and some ocular signs (see Table 13-1 and Box 13-1).

Syndromic Classification The application of a syndromic classification of neonatal seizures is somewhat limited when considered in light of the classification of the International League against Epilepsy [Commission, 1989]. Almost all neonatal seizures are thought to be symptomatic—occurring as a consequence of a specific cause [Mizrahi and Watanabe, 2002]. Four specific syndromes identified by the International League against Epilepsy occur in the neonatal period. Benign neonatal convulsions and benign familial neonatal convulsions are discussed later in “Etiology and Clinical Manifestations” (see also Chapter 40). The features of early myoclonic encephalopathy [Aicardi and Goutiéres, 1978] and early epileptic encephalopathy [Ohtahara et al., 1992] are compared in Table 13-3. They are forms of catastrophic epilepsy with onset in the neonatal period, and they have characteristic seizure types, EEG findings, and causes (see Chapter 46). The syndromes of neonatal seizures are discussed later.

Based on data from Aicardi, 1997; Ohtahara et al., 1992. From Mizrahi EM, Clancy RR. Neonatal seizures: Early-onset seizure syndromes and their consequences for development. Ment Retard Dev Disabil Res Rev 2000; 6:229.

THE ELECTROENCEPHALOGRAM AND NEONATAL SEIZURES Although clinical observation is critical to the diagnosis of neonatal seizures, the electroencephalogram is the most important laboratory examination to assist in diagnosis. The neonatal electroencephalogram is discussed in detail in Chapter 12, but some aspects as it relates to neonatal seizures are reviewed here.

Interictal Background Electroencephalogram The degree of abnormality of the interictal background activity may provide information concerning the extent and type of CNS dysfunction associated with seizures. The nature of the interictal background activity may also suggest the risk individual infants have in experiencing a seizure [Laroia et al., 1998]; infants with normal background activity are less likely to eventually experience seizures than those with persistent diffuse background abnormalities. The degree, evolution, and rate of resolution (if any) of background EEG abnormalities may provide important information concerning prognosis. An electroencephalogram with normal background activity recording within the first 24 hours of life suggests a good outcome [Holmes and Lombroso, 1993], and EEG background activity with abnormal features that persist or that resolve slowly suggests a poorer outcome [Hrachovy et al., 1990].

Mizrahi / Neonatal Seizures

Interictal Focal Abnormalities The most frequent interictal focal abnormality identified on the neonatal electroencephalogram is sharp-wave activity. Some focal sharp waves that are normal findings include normal developmental elements such as frontal sharp transients and temporal sharp waves that occur randomly, are low or moderate in voltage, and are present in transitional or

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light sleep [Mizrahi et al., 2003]. Focal sharp waves that are persistent, high in amplitude, present in wakefulness and sleep, and have complex morphology suggest focal injury. Multifocal sharp waves may suggest diffuse dysfunction. Focal spikes may suggest focal injury or may have uncertain diagnostic significance [Hrachovy et al., 1990]. In the neonate, interictal focal sharp waves and spikes are not considered indicators of epileptogenesis in the same way that

F1C3 F2C4 C3O1 C4O2 F1T3 F2T4 T3C3 C3Cz CzC4 C4T4 FzCz CzPz 1 sec 50 ␮V

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A F1C3 F2C4 C3O1 C4O2 F1T3 F2T4 T3C3 C3Cz CzC4 C4T4 FzCz CzPz EOG

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B FIGURE 13-1. Electrical seizure activity can vary in frequency, morphology, voltage, and onset. A, Rhythmic sharp waves in the left central region that remain confined to that region (2-week-old infant, 40 weeks’ gestational age). B, Rhythmic sharp and slow-wave activity in the left occipital region (6-day-old infant, 40 weeks’ gestational age). continued on page 262

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they are in older children and adults. Although the finding of focal sharp waves or spikes suggests focal brain dysfunction in the neonate, it does not necessarily suggest a potentially epileptic process. Focal interictal EEG abnormalities may therefore not be as useful in predicting which neonates had or may eventually experience seizures.

Electrical Seizure Activity Electrical seizure activity in neonates is rare before 34 to 35 weeks. When electrical seizure activity is recorded, its manifestations can vary [Mizrahi et al., 2003; Patrizi et al., 2003]. The frequency, voltage, and morphology of the seiz-

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resp

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D FIGURE 13-1. cont’d. C, High-voltage, repetitive, slow, sharp waves arising in the right frontal region that later appear as faster and sharper activity spreading to the right central region (3-day-old infant, 40 weeks’ gestational age). D, Initial rhythmic, moderate-voltage, sharp-wave activity arising in the right central temporal region remains unchanged as another seizure arises independently from the left temporal region with a complex morphology (2-day old infant, 39 weeks’ gestational age). (From Mizrahi EM, Kellaway P. Diagnosis and management of neonatal seizures. Philadelphia: Lippincott-Raven, 1998.)

Mizrahi / Neonatal Seizures

ure discharges may change within an individual seizure, between seizures in an individual infant, or vary among infants (Fig. 13-1). The minimum duration is designated as 10 seconds [Clancy and Legido, 1987], although the duration of seizure discharges may also vary. The electrical events are most often focal and well circumscribed, and they frequently arise from the central or centrotemporal region of one hemisphere and less commonly in the occipital, frontal, or midline central regions (see Fig. 13-1). Seizures may arise focally and remain confined to that region, or they may spread to other regions (Fig. 13-2). This spread may be seen as a gradual widening of the focal area by an abrupt change from a small regional focus to involvement of the entire hemisphere (a finding that characterizes a hemiconvulsive seizure). The spread may also be characterized by migration of the electrical seizure from one area of a hemisphere to another or from one hemisphere to another [Mizrahi and Kellaway, 1998].

Electrical Seizures of the Depressed Brain Some ictal patterns are unique to the neonatal period; they are typically associated with severe encephalopathies and their associated abnormal background EEG patterns. Seizure discharges of the depressed brain are typically low in voltage, long in duration, and highly localized (Fig. 13-3) [Kellaway and Hrachovy, 1983]. They may be unifocal or multifocal and demonstrate little tendency to spread or modulate. They are typically not associated with clinical seizures. They occur when the EEG background is depressed and undifferentiated, and they suggest a poor prognosis.

Alpha Seizure Activity Alpha seizure activity is characterized by a sudden but transient appearance of rhythmic activity of the alpha frequency (8 to 12 Hz), typically occurring in the temporal or central region [Knauss and Carlson, 1978; Watanabe et al., 1982; Willis and Gould, 1980]. This pattern may evolve from the more typical seizure discharges or may appear de novo. As with seizure discharges of the depressed brain, clinical events usually do not occur with alpha seizure discharges. The presence of an alpha seizure discharge usually indicates the presence of a severe encephalopathy and signifies a poor prognosis (Fig. 13-4).

Electroencephalographic-Video Monitoring Electroencephalographic-video (EEG-video) monitoring is a powerful tool in the diagnosis and management of neonatal seizures. Initially, this technique had been the basis of clinical investigations that addressed seizure classification, therapy, and prognosis [Boylan et al., 2002; Bye et al., 1997; Clancy et al., 2003; Mizrahi, 1995; Mizrahi and Kellaway, 1987]. Although it is not available at many centers for routine use, EEG-video monitoring is gradually becoming more widely used. However, its increasing popularity should not detract from the fact that an attended electroencephalogram can provide important clinical information when the recorded infant is observed by a trained electroneurodiagnostic technologist who can carefully observe an infant’s behavior and characterize the events.

F1C3 F2C4 C3O1 C4O2 F1T3 F2T4 T3C3 C3Cz CzC4 C4T4 FzCz CzPz EOG EMG

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1 sec

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EKG resp FIGURE 13-2. Migration of electrical seizure activity that begins in the midline region (CZ) and shifts to the left central region (C3) as the CZ region becomes less involved. This electroencephalogram was recorded from a 4-day-old (40 weeks’ gestation) female infant with hypoxic-ischemic encephalopathy and suppression-burst electroencephalographic background. No clinical seizures occurred during the electrical seizure activity. (From Mizrahi EM, Kellaway P. Diagnosis and management of neonatal seizures. Philadelphia: Lippincott-Raven, 1998:132.)

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F1C3 F2C4 C3O1 C4O2 F1T3 F2T4 T3C3 C3Cz CzC4 C4T4 FzCz CzPz EOG

1 sec

50 ␮V

EMG EKG resp FIGURE 13-3. Seizure discharge of the depressed brain in the left temporal region occurring on the electroencephalogram of a 2-day-old (38 weeks’ gestation) female infant with hypoxic-ischemic encephalopathy. The electroencephalographic background is depressed and undifferentiated. No clinical seizures accompanied the electrical seizure activity. (From Mizrahi EM, Kellaway P. Diagnosis and management of neonatal seizures. Philadelphia: Lippincott-Raven, 1998:134.)

Computer-Assisted Electroencephalographic Analysis of Neonatal Seizures Computer-assisted analysis of the electroencephalogram to detect and quantify electrical seizure activity has been used

reliably in long-term EEG monitoring of older children and adults in epilepsy monitoring units. EEG seizure detection in neonates is more challenging because of variability of the electrographic events. Such programs have been developed and may provide reliable data, particularly if the recordings

F1C3 F2C4 C3O1 C4O2 F1T3 F2T4 T3C3 C3Cz CzC4 C4T4 FzCz

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CzPz EOG EMG EKG resp FIGURE 13-4. Alpha seizure discharge in the left temporal region is characterized by sinusoidal 10- to 11-Hz rhythmic activity that evolved from rhythmic sharp-wave activity. There is also an independent, repetitive, slow, sharp transient in the left occipital region. The electroencephalographic background activity is depressed and undifferentiated. This electroencephalogram was recorded from a 4-week-old (38 weeks’ gestation) male infant with pneumococcal meningitis. No clinical seizures occurred with these electrical seizure discharges. (From Mizrahi EM, Kellaway P. Diagnosis and management of neonatal seizures. Philadelphia: Lippincott-Raven, 1998:135.)

Mizrahi / Neonatal Seizures

are attended by a trained electroneurodiagnostic technologist [Gotman et al., 1996; Mukherejee et al., 2004]. There has also been renewed interest in the use of cerebral function monitors to detect neonatal seizures [Toet et al., 2003]. This technique is limited in terms of its ability to provide data from all brain regions and its reliance on nonexpert health care professionals. One study reported that up to 50% of neonatal seizures were misclassified or unrecognized when using cerebral function monitors [Rennie et al., 2004].

ETIOLOGY AND CLINICAL MANIFESTATIONS Neonatal seizures indicate the presence of CNS disease and prompt a thorough evaluation for the cause and specific treatment. In addition to the broad range of causes of neonatal seizures, predisposition of the immature brain toward epileptogenesis may account for the high incidence of seizres in the neonate. Although the list of potential causes is extensive [Mizrahi and Kellaway, 1998], most can be broadly categorized as hypoxia-ischemia, metabolic disturbances, CNS or systemic infections, and structural brain lesions. Box 13-2 lists the most frequently identified causes of neonatal seizures in the order of their relative occurrence.

Symptomatic Neonatal Seizures The diagnosis of hypoxic-ischemic encephalopathy can be difficult to establish because criteria have not been uniformly established. Some criteria may be so restrictive that infants with encephalopathy may not meet them but still

Box 13-2 MOST FREQUENT CAUSES OF NEONATAL SEIZURES* Hypoxia-ischemia Intracranial hemorrhage Intraventricular Intracerebral Subdural Subarachnoid Infection, central nervous system Meningitis Encephalitis Intrauterine Infarction Metabolic disorders Hypoglycemia Hypocalcemia Hypomagnesemia Chromosomal anomalies Congenital abnormalities of the brain Neurodegenerative disorders Inborn errors of metabolism Benign neonatal convulsions Benign familial neonatal convulsions Drug withdrawal or intoxication *Listed in order of frequency. Not listed is “unknown etiology,” which is encountered in approximately 10% of cases, although some of these cases in this category may be benign neonatal convulsions. From Mizrahi EM, Kellaway P. Diagnosis and management of neonatal seizures. Philadelphia: Lippincott-Raven, 1998:49.

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carry the diagnosis as “suspect,” or the criteria may not predict the occurrence of long-term neurologic sequelae [Nelson and Leviton, 1991; Paneth, 1993] (see Chapters 14 and 15). The American College of Obstetricians and Gynecologists in association with the American Academy of Pediatrics have provided guidelines for the diagnosis of hypoxicischemic encephalopathy [Committee, 1996]. At some centers, practice is directed toward identification of measures of asphyxia that have predictive value in the occurrence of long-term sequelae [Perlman, 1997] and that have less restrictive criteria for hypoxic-ischemic encephalopathy. Both approaches, however, include the tabulation of delivery room Apgar scores and the need for resuscitation, recognition of clinical aspects of encephalopathy, and confirmation of multisystem involvement. There is also an emerging discussion about the use of computer-assisted analysis of the electroencephalogram to aid in diagnosis [Shalak et al., 2003] such as amplitude-integrated electroencephalography, although this is still considered investigational. Metabolic disturbances ranging from electrolyte imbalances to inborn errors of metabolism may also be associated with neonatal seizures and represent an important group of potentially treatable causes. These include hypocalcemia, hypomagnesemia, and hypoglycemia. Much less common is the finding of an inborn error of metabolism such as aminoaciduria, urea cycle defect, or organic aciduria (see Chapter 23). Other rare causes of medically refractory neonatal seizures that are potentially treatable include pyridoxine deficiency and biotinidase deficiency. Bacterial and viral agents can cause CNS infections in the neonate that are associated with seizures, and their treatments are discussed elsewhere in this text (see Chapter 67). Prenatal infections can be risk factors for seizures. Structural brain lesions associated with neonatal seizures include hemorrhage (e.g., intracerebral, subarachnoid, intraventricular), infarctions, and congenital anomalies of the brain. Brain malformations may range from highly localized focal dysplasias to catastrophic defects—some of these malformations are associated with specific genetic disorders such as lissencephaly and are discuss in detail in Chapter 19. There are also special circumstances in which neonates may be at risk for seizures, providing opportunities for increased surveillance and development of preventative therapies. Clancy and colleagues [2003] prospectively studied neonates undergoing cardiac surgery who required hypothermic circulatory arrest. They found that 19% of all infants with nonhypoplastic left heart syndrome experienced a postoperative acute neurologic event, including seizures and coma.

Epileptic Syndromes Seizure syndromes are characterized by clinical signs, symptoms, and laboratory findings. These features include seizure type, age of onset, cause, anatomy (including neuroimaging findings), precipitating factors, severity, ictal and interictal EEG patterns, duration of the seizure disorder, associated clinical features, chronicity, diurnal and circadian cycling, response to antiepileptic drugs, and prognosis [Dreifuss, 1993]. In its classification of epilepsies and epileptic syndromes, the International League against Epilepsy designated only a few syndromes in the neonatal period [Com-

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mission, 1985; Wolfe, 1997], although their recognition in clinical practice is important. These syndromes are benign neonatal convulsions, benign neonatal familial convulsions, early myoclonic encephalopathy, and early infantile epileptic encephalopathy. They have been reviewed by Mizrahi and Clancy [2000]. The first two types are associated with a relatively good prognosis, whereas the others suggest a poor outcome and have been referred to as catastrophic neonatal epilepsy syndromes [LaJoie and Moshe, 1999]. The International League against Epilepsy also recognized a group of disorders considered acute and reactive, and their prognosis varies with the cause. Because most neonatal seizures are short-lived and self-limited and usually do not herald a chronic convulsive disorder, the term epilepsy is rarely applied to this age group [Aicardi, 1997] and in this context is used only in special circumstances. These are considered as a group in “Etiology and Clinical Manifestations.” However, because all of the seizure types that characterize the neonatal seizure syndromes have an epileptic pathophysiologic basis, they can be considered epileptic neonatal seizures.

Benign Neonatal Convulsions The syndrome of benign neonatal convulsions has also been referred to as benign idiopathic neonatal convulsions because of the lack of an identifiable cause [Plouin, 1990] and as fifth day fits because of their timing of onset [Dehan et al., 1977]. This syndrome is characterized by focal clonic seizures or, rarely, by focal tonic seizures in an otherwise normal neonate. The reported incidence has ranged from 4% to 38% of neonatal seizures, although most investigators suggest it occurs in 2% to 7% of neonates with seizures [Plouin and Anderson, 2002]. There is no family history of neonatal seizures. Infants are typically born at term after an uncomplicated, normal pregnancy, labor, and delivery. Ninety percent of seizures occur between the fourth and sixth day of life; 100% occur within the first 7 days of life. The clinical seizures are usually unifocal clonic and may be associated with apnea. Seizures are typically brief (1 to 3 minutes), although they rarely can be prolonged, and there have been reports of evolution to status epilepticus. The seizure disorder is self-limited. Seizures may recur during a 24- to 48-hour period after onset, although this period rarely may also be prolonged. The infants are neurologically normal before, between, and after the occurrence of seizures [Plouin, 1992; Plouin and Anderson, 2002]. The ictal electroencephalogram is characterized by focal, rhythmic, recurrent sharp-wave or spike activity that is closely correlated with the clinical seizures. The background electroencephalogram is typically normal, although it has also been reported that in up to 60% of neonates with this syndrome, the interictal EEG pattern referred to as theta pointu alternant may occur [Plouin, 1992]. This pattern is characterized as nonreactive, focal, rhythmic activity in the theta frequency (4 to 7 Hz), which may be mixed with sharp waves. This activity is discontinuous and may alternate between hemispheres. This pattern is no longer considered diagnostic for this disorder [Plouin and Anderson, 2002]. Although the clinical seizures may spontaneously resolve within a short period, the theta pointu alternant EEG pattern

may persist for up to 2 weeks. The ictal electroencephalogram is characterized by rhythmic spikes and sharp waves that are focal in onset—features not unique to this syndrome of neonatal seizures. A critical feature for diagnosis is that no cause for the seizures can be identified. In the past, this disorder was associated with a finding of rotavirus in the stool but not in cerebrospinal fluid [Herrmann et al., 1993] and with acute zinc deficiency in cerebrospinal fluid [Goldberg and Sheehy, 1982], although these findings are now considered of uncertain diagnostic relevance. Because initial clinical presentation may be similar in infants with symptomatic focal clonic seizures, this is a diagnosis of exclusion. Plouin [Plouin, 1992; Plouin and Anderson, 2002] proposed the following diagnostic criteria for this disorder: normal pregnancy and delivery; full-term gestation; appropriate for gestational age birth weight; Apgar score greater than 7 at 1 minute; typical interval between birth and seizure onset (4 to 6 days); normal neurologic examination results before and between seizures; normal laboratory findings (including metabolic studies, neuroimaging, and lumbar puncture); and no family history of neonatal seizures or post-neonatal epilepsy. Although the seizures are typically treated with phenobarbital, initiation of treatment is controversial. Because the seizures tend to be brief and infrequent, it may be argued that antiepileptic drug therapy may not be needed. If antiepileptic drugs are used, they are typically discontinued when the risk of seizures is thought to subside. The prognosis for infants with benign neonatal convulsions is generally good [Plouin, 1997]. However, some investigators have found transient psychomotor delays in infants [Dehan et al., 1977] or neurodevelopmental deficits at 2 years of age in 50% of those with this syndrome. The incidence of post-neonatal epilepsy (0.5% of patients) is slightly higher than in the population of those without neonatal seizures [Plouin, 1997]. Plouin and Anderson [2002], in a review of all published series, reported that approximately 15% of infants with this disorder were abnormal at follow-up (6 months to 6 years), although the abnormalities were somewhat nonspecific, including transient psychomotor delay, simple febrile seizure, and seizures without fever or spike foci on the electroencephalogram.

Benign Neonatal Familial Convulsions Benign neonatal familial convulsions is a syndrome characterized by early-onset focal clonic or focal tonic seizures in a neonate with a family history of neonatal seizures and with no other neurologic findings [Bye, 1994; Hirsch et al., 1993; Miles and Holmes, 1990; Pettit and Fenichel, 1980]. The reported incidence is 14.4 per 100,000 live births [Ronen et al., 1999]. Between 1964 and 1994, 44 families have been described in the literature [Plouin and Anderson, 2002]. There is an autosomal-dominant pattern of inheritance with incomplete penetrance [Cunniff et al., 1988] with two known chromosomal loci: one on chromosome 20q13 [Leppert et al., 1989] and one on chromosome 8q [Lewis et al., 1993; Ryan et al., 1991; Steinlein et al., 1995]. All of the families with benign neonatal familial convulsions provide sufficient data for linkage to chromosome 20q; only one family has provided data for linkage to chromosome 8q. The genes for this disorder have been identified. They are potassium channel

Mizrahi / Neonatal Seizures

genes referred to as KCNQ2 for the chromosome 20q gene [Biervert et al., 1998; Singh et al., 1998] and KCNQ3 for the chromosome 8q gene [Charlier et al., 1998; Steinlein et al., 1995]. It has been suggested that the KCNQ2/3 channels might be the molecular correlate of the M-current, a slowly activating and slowly deactivating potassium conductance that may play a critical role in determining the subthreshold electrical excitability of neurons [Biervert et al., 1998; Wang et al., 1998]. Only a slight loss of channel activity can lead to neuronal hyperexcitability and resultant seizures [Wang et al., 1998]. This disorder is considered one of several epileptic disorders characterized as a channelopathy [Leppert, 2000; Noebels, 2001]. Later studies revealed that KCNQ2 mutations can also occur in neonates with seizures with no family history of seizures and suggested that the mutations can arise de novo [Claes et al., 2004]. There are also reports of phenotypic variability associated with novel mutations in KCNQ2 found in pedigrees revealing some infants with only seizures and others with seizures and severe epileptic encephalopathy or focal seizures and mental retardation [Borgatti et al., 2004]. Seizure onset occurs between the first few days and 1 week of life [Quattlebaum, 1979] although there have been reports of onset as late as the second month of life. The various ages of onset may be developmentally determined, because infants who are born prematurely with this disorder have seizure onset at an older chronologic age than the infants born at term. The seizures are typically brief. The disorder is self-limiting, with most seizures recurring during the initial week after onset. However, isolated seizures can recur for several weeks before the disorder remits spontaneously. The seizures occur predominantly in term infants who are neurologically normal. The clinical seizures are best characterized as focal clonic or focal tonic, although several investigators have characterized the seizures in detail through observation or EEG-video monitoring [Bye et al., 1994; Hirsch et al., 1993; Ronen et al., 1993]. A typical sequence of behaviors has been described: asymmetric tonic posturing with autonomic features such as apnea or tachypnea, followed by other asymmetric motor behaviors, including focal clonic activity. A typical electrographic sequence is associated with the clinical seizures [Hirsch et al., 1993]. There is initial generalized voltage attenuation associated with the clinical tonic seizure, followed by focal spike discharges that are associated with focal clonic activity. The interictal electroencephalogram is typically normal, although the theta pointu alternant pattern also may occur in these infants. The treatment strategies are those for neonatal seizures with the initiation and maintenance of phenobarbital. Duration of therapy is typically for 2 weeks past the last seizure. Some investigators use valproate as an alternative [Plouin, 1997]. Although the outcome is generally good, there is a higher incidence (11% to 16% ) of post-neonatal seizures in affected infants later in life [Plouin, 1992; Ronen et al., 1993].

Early Myoclonic Encephalopathy Early myoclonic encephalopathy is a relatively uncommon syndrome characterized by the onset of erratic, fragmentary

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myoclonus in the first month of life and with the eventual development of focal seizures (originally described as partial motor seizure) and infantile spasms [Aicardi, 1992; Aicardi and Goutiéres, 1978]. The associated electroencephalogram is characterized as a periodic, suppressionburst pattern [Maheshwari and Jeavons, 1975]. This syndrome has been referred to as early myoclonic encephalopathy [Lombroso, 1990], neonatal myoclonic encephalopathy [Vigevano et al., 1981], myoclonic encephalopathy with neonatal onset [Cavazzutti et al., 1978], neonatal epileptic encephalopathy with period EEG bursts [Martin et al., 1981], and early epileptic encephalopathy [Dalla Bernardina et al., 1982, 1983]. Aicardi [1992] described the associated seizure types, including fragmentary or partial erratic myoclonus; massive (or generalized) myoclonus; simple partial (or focal) seizures; and infantile spasms with a sustained tonic component. These clinical events were not all present at the onset of the disorder. Typically, the erratic myoclonus frequently appears within the first few hours of life. These movements may involve very circumscribed regions of the limbs or face, are typically repetitive or virtually continuous, may shift persistently from one body region to another in an anarchic and asynchronous manner, and may persist in sleep. Generalized myoclonus and partial seizures may develop with the onset of erratic myoclonus or shortly thereafter. The generalized myoclonus may involve all extremities synchronously and bilaterally or may involve only axial musculature. The partial seizures may appear as deviation of the eyes associated with limb or face clonic activity, or autonomic phenomena such as flushing or apnea. Infantile spasms typically develop later in the course of the disorder, usually between 3 and 4 months of age. EEG findings are important in the diagnosis of this syndrome. The background activity is a suppression-burst pattern. The bursts occur periodically and are characterized by generalized and multifocal, high-voltage spikes and sharpand slow-wave complexes. Although typical for early myoclonic encephalopathy, these findings are not diagnostic because there are other neonatal disorders in which a suppression-burst pattern may be observed. The pattern may occur during wakefulness and sleep. There are typically no EEG correlates to the fragmentary or erratic myoclonus, although generalized myoclonus may occur in association with the complexes during bursts on the electroencephalogram. When partial (or focal) seizures occur, their EEG correlates are no different from those described for infants with other focal neonatal seizures. When infantile spasms do occur, they may eventually be associated with high-voltage, slow, sharp transients or episodes of generalized voltage attenuation, or both. Over time, the suppression-burst pattern may take on features that allow it to be characterized as atypical or modified hypsarrhythmia. The neurologic status of infants with early myoclonic encephalopathy is always abnormal at birth or at the onset of clinical seizures [Aicardi, 1992]. Most often, the infants are hypotonic and poorly responsive—features consistent with the clinical diagnosis of an encephalopathy. This early onset of abnormal neurologic status makes further neurologic deterioration difficult to assess. When the syndrome is encountered, a metabolic origin is typically considered, including nonketotic hyperglycinemia,

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propionic acidemia, D-glyceric academia, hyperammonemia due to carbamyl phosphate synthetase deficiency, or methylmalonic acidemia [Brandt et al., 1974; Dalla Bernardino et al., 1979; Grandgeorge et al., 1980; Lombroso, 1990; Vigevano et al., 1982]. However, other causes have been reported, including familial, cryptogenic, and uncommonly, congenital malformations of the brain. Therapy is symptomatic, directed toward the specific inborn error of metabolism if present, and results are often discouraging. Antiepileptic drugs or hormonal therapy often is used for infantile spasms, although neither is particularly effective. The outcome for infants with early myoclonic encephalopathy has been reported as poor, consistent with cause. There is a high incidence of death within the first few years of life (approximately 50%, most often occurring in the first year). In survivors, the partial seizures tend to persist and become intractable to medical management, whereas the erratic myoclonus usually resolved within the first few weeks to months. Survivors have remained in a vegetative state or have had significant developmental delay. An ongoing debate concerns the course of neurologic impairment. Some suggest that there is a gradual deterioration or arrest of development with onset of the disorder [Dalla Bernardina et al., 1982, 1983], whereas others suggest that because of the severity of impairment at onset, subsequent development cannot be quantified [Aicardi, 1992]. Debate continues about the relation of early myoclonic encephalopathy and the syndrome of early infantile epileptic encephalopathy described by Ohtahara and colleagues [Ohtahara, 1978, 1984; Ohtahara et al., 1976], which is discussed later. Aicardi and Ohtahara [2002] suggest that the two syndromes have some features indicating they may represent different aspects of a single process. The two syndromes are compared in Table 13-3.

Early Infantile Epileptic Encephalopathy Ohtahara and co-workers [Ohtahara, 1978, 1984; Ohtahara et al., 1976, 1992] proposed the syndrome of early infantile epileptic encephalopathy as one of three so-called agedependent epileptic encephalopathy syndromes—a group that also included the West syndrome and Lennox-Gastaut syndromes [Ohtahara, 1977, 1978; Yamatogi and Ohtahara, 1981; Ohtahara and Yamatogi, 2003]. Early infantile epileptic encephalopathy is a rare syndrome, with less than 40 cases reported in the literature. Its characteristics include onset in early infancy (i.e., neonatal period through the first few months of life); tonic spasms (i.e., brief tonic seizures) as the predominant seizure type; suppression-burst EEG background; severe psychomotor retardation; medically intractable seizures; poor prognosis; no single cause that could be characteristic for the disorder; evolution to West’s syndrome (i.e., infantile spasms, retardation, and hypsarrhythmia on the electroencephalogram) [Ohtahara et al., 1992]. Affected infants are neurologically abnormal at seizure onset and have developmental delay, spasticity, and motor asymmetries. The predominant initial seizure type is tonic spasm, characterized as brief episodes of limb and axial stiffening; each event lasts longer than a general myoclonic event but is shorter than a tonic seizure. The tonic spasms may occur in clusters, but in some patients, they may be intermittent and

may occur in wakefulness and during sleep. In addition to tonic spasms, about one third of affected infants may experience other seizure types, including focal motor seizures, hemiconvulsions, alternating hemiconvulsions, and generalized seizures. The erratic myoclonus seen in infants with early myoclonic encephalopathy is not present, and myoclonic seizures in general are rare. The electroencephalogram is characterized by a suppression-burst pattern. This pattern is not modulated by wake-sleep cycles, a feature thought to distinguish it from other suppression-burst hypsarrhythmic patterns [Ohtahara, et al., 1992]. During a clinical spasm, the electroencephalogram is characterized by generalized voltage attenuation. Several etiologic factors are associated with this syndrome. In a series of 15 cases, Ohtahara and colleagues [1992] reported four patients with cryptogenic disorders and 11 patients with symptomatic disorders. Of the symptomatic patients, four were thought to have suffered “neonatal anoxia,” and two had Aicardi’s syndrome; the remainder had porencephaly or cerebral atrophy or dysgenesis. None had specific metabolic disorders. Treatment is usually with adrenocorticotropic hormone in a manner similar to that used for infants with West’s syndrome. However, this therapy is considered less effective for early infantile epileptic encephalopathy than for West’s syndrome. Other medications used, although with limited success, include clonazepam, nitrazepam, valproate, zonisamide, and pyridoxine [Ohtahara et al., 1992]. The prognosis for those with early infantile epileptic encephalopathy is poor with a high incidence of death (approximately 50%). In survivors (who may live into their teenage years), intractable seizures are common, as is severe neurologic impairment [Ohtahara et al., 1992]. The degree of mental and physical impairment remains static over time. In considering survivors, Ohtahara and colleagues [1992] proposed an interesting hypothesis concerning the evolution of seizure types and syndromes and their relation to brain development. For many surviving patients with early infantile epileptic encephalopathy, there is an evolution of the electroencephalogram from a suppression-burst pattern to a hypsarrhythmic pattern and then to that of diffuse slowspike and slow-wave activity. The investigators propose that this evolution follows brain development, with periods of transition characterized by the emerging pattern when the infant is awake and the resolving pattern persisting in sleep. Evolution of the EEG pattern is an objective marker of and parallels the sequential emergence of the age-dependent epileptic encephalopathies: early infantile epileptic encephalopathy (associated with suppression-burst activity), West’s syndrome (associated with hypsarrhythmia), and Lennox-Gastaut syndrome (associated with generalized slow-spike and slow-wave activity). In general, this evolution occurs in a very small number of infants, because the occurrence of early infantile epileptic encephalopathy is rare. Although this sequence may be common in those with early infantile epileptic encephalopathy, the converse is not true—most children with West’s syndrome or LennoxGastaut syndrome do not experience an antecedent early infantile epileptic encephalopathy. There are similarities and differences between early infantile epileptic encephalopathy and early myoclonic encephalopathy (see Table 13-3). Some investigators have

Mizrahi / Neonatal Seizures

suggested that the two syndromes may be considered one because of their similarities [Aicardi, 1992]. However, others consider the two distinct [Ohtahara et al., 1992, 1997; Schlumberger et al., 1992]. These syndromes are compared in Table 13-3. Both occur early in life and are associated with encephalopathy, seizures, and a suppression-burst electroencephalogram. It has been suggested that one distinguishing feature of early myoclonic encephalopathy is the occurrence of erratic myoclonus, although this may be absent in some cases of nonketotic hyperglycinemia. Similarly, it had been thought that partial seizures might only occur in early myoclonic encephalopathy, but it was later found to also occur in early infantile epileptic encephalopathy. Early myoclonic encephalopathy is most often associated with inborn errors of metabolism or a genetic defect, whereas early infantile epileptic encephalopathy is associated with cerebral dysgenesis. Although the prognosis for both syndromes is grave, those with early infantile epileptic encephalopathy die at a later age, and for survivors, impairment is typically very severe. Most likely, early myoclonic encephalopathy and early infantile epileptic encephalopathy represent a single clinical syndrome with a number of overlapping features and with some distinct features that may characterize subgroups.

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TABLE 13-4 Etiology-Specific Therapy for Neonatal Seizures of Metabolic Origin THERAPEUTIC AGENT*

ACUTE THERAPY

MAINTENANCE THERAPY

Glucose, 10% solution Calcium gluconate, 10% solution (9.4 mg of elemental Ca/mL) Magnesium sulfate, 50% solution (50 mg of elemental Mg/mL) Pyridoxine

2 mL/kg IV

Up to 8 mg/kg/min IV

2 mL/kg IV over 10 min (18 mg of elemental Ca/kg) 0.25 mL/kg IM

8 m/kg/day IV† (75 mg of elemental Ca/kg/day) 0.25 mL/kg IM, repeated every 12 hr until normomagnesemia

100 mg IV

*Diagnosis of hypoglycemia, hypocalcemia, and hypomagnesemia may vary between laboratories and depends on the neonate’s gestational age (i.e., preterm infants tend to tolerate lower physiologic levels). Administration of metabolic-correcting solutions requires careful monitoring of the infant’s systemic homeostasis, including electrocardiographic monitoring during the administration of calcium [Kalhan and Saker, 1997; Koo and Tsang, 1994]. † After restoration of normocalcemia, tapering the dosage may help to prevent rebound hypocalcemia. From Mizrahi EM, Kellaway P. Diagnosis and management of neonatal seizures. Philadelphia: Lippincott-Raven, 1998:64.

such as hypocalcemia, hypomagnesemia, and hypoglycemia. Etiologic-specific therapies for these disorders are described in Table 13-4. Although treatment of some causes may not immediately affect seizure occurrence, therapy is still critical because it may limit the degree of CNS injury.

THERAPY Initial Considerations The principles of management of the critically ill infant are also relevant to the comprehensive therapy for neonatal seizures because some seizures and the use of antiepileptic drugs may be associated with changes in respiration, heart rate, and blood pressure. Ensuring airway patency and access to the circulatory system are considered critical early in the course of treatment. Assessment of the cause of seizures is often conducted in parallel to the initial phase of antiepileptic drug therapy. If specific causes of seizures are identified for which there are specific treatments, this therapy is initiated. This approach may be essential in management because it may directly treat the underlying disorder and because some seizures may not be controlled effectively with antiepileptic drugs unless the underlying cause is treated. This is particularly evident when seizures are caused by metabolic disturbances

Decision to Initiate Antiepileptic Drug Therapy The decision to initiate antiepileptic drug therapy should be based on consideration of several factors. Because antiepileptic drugs are used to treat neonatal seizures of epileptic origin, initial considerations are given to the clinical and EEG features of the events. When clinical seizures are witnessed during the recording of the electroncephalogram, patients with electroclinical seizures and electrical-only seizures are most clearly candidates for antiepileptic drug therapy. When clinical observation alone is the basis for management, focal clonic seizures and focal tonic seizures are the seizure types best characterized as epileptic in origin, whereas the clinical events characterized as generalized tonic and motor automatisms (i.e., those provoked by

TABLE 13-5 Dosages of First-Line and Second-Line Antiepileptic Drugs in the Treatment of Neonatal Seizures DRUG

Diazepam Lorazepam Phenobarbital Phenytoin

DOSE Loading

Maintenance

0.25 mg/IV (bolus) 0.5 mg/kg (rectal) 0.05 mg/kg (IV) (over 2-5 min) 20 mg/kg IV (up to 40 mg) 20 mg/kg IV (over 30-45 min)

May be repeated one or two times

AVERAGE THERAPEUTIC RANGE

APPARENT HALF-LIFE

31-54 hr May be repeated 3-4 mg/kg in two doses

20-40 μg/L

31-54 hr 100 hr after day 5-7

3-4 mg/kg in two to four doses

15-25 μg/L

100 hr (range, 40-200)

Based on data from Aicardi, 1994; Fenichel, 1990; Volpe, 2001. From Mizrahi EM, Kellaway P. Diagnosis and management of neonatal seizures. Philadelphia: Lippincott-Raven, 1998:64.

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stimulation and suppressed by restraint) are considered nonepileptic in origin. There has been discussion concerning the need to treat all neonatal seizures of epileptic origin because some are brief, infrequent, and self-limited—occurring only in reaction to an acute CNS insult. In these instances, antiepileptic drug may not be warranted, and the infant need not be exposed to acute and chronic antiepileptic drug therapy. However, some neonatal epileptic seizures have long durations, occur frequently, and are not self-limited. These types of seizures should be treated acutely and vigorously with antiepileptic drugs. It is difficult to predict at the onset of seizures which infants will have self-limited, frequent, or prolonged events. Clinical difficulties arise in the management of infants whose seizures have characteristics that fall between these two extremes. In clinical practice, almost all neonatal epileptic seizures within this intermediate category are treated.

Initial Antiepileptic Drug Therapy for Acute Seizures First-line antiepileptic drugs and dosing schedules are listed in Table 13-5. The pharmacology of some of these drugs, particularly phenobarbital and phenytoin, has been well studied in neonates (see Chapter 49). However, few comprehensive clinical trials have been conducted that determined the most effective regimen for the treatment of neonatal seizures. The most established strategy is to treat seizures acutely with an antiepileptic drug that can be given subsequently as maintenance therapy; most often, this is phenobarbital. It is given first as a loading dose and then with additional boluses titrated to response until the maximum tolerated dose or serum levels in the high therapeutic range are reached. Boylan and colleagues [2002] prospectively assessed the efficacy of phenobarbital using EEG-video monitoring and found that only 4 of 14 infants responded, whereas the remainder experienced a reduction in electroclinical seizures but an increase in electrical seizures. After phenobarbital, phenytoin is the antiepileptic drug most often used. It is typically initiated with fosphenytoin because of reports of reduced adverse effects with acute administration [Pellock, 1998]. As with phenobarbital, phenytoin administration is increased to the maximum tolerated dose or high therapeutic serum level. Painter and colleagues [1994] compared the effectiveness of acute administration of phenobarbital and phenytoin in seizure control and found no significant difference between the two medications. However, neither proved as efficacious as generally believed. An alternative strategy of seizure management is acute administration of repeated doses of short-acting benzodiazepines (i.e., lorazepam or midazolam) until seizures are controlled. This approach avoids chronic antiepileptic drug therapy. When the clinician begins antiepileptic drug therapy, it should be accompanied by establishment of criteria to determine whether acute therapy has been successful. Control of the clinical and electrical seizures is ideal but often difficult to determine or unattainable. A typical response by electroclinical seizures to acute antiepileptic drug therapy is the initial control of the clinical seizures with the persistence of the electrical seizure activity, referred to as uncoupling

[Mizrahi and Kellaway, 1987]. With additional doses, the electrical seizures may be controlled [Scher et al., 2003]. However, in some instances, the EEG seizures cannot be controlled despite increasing doses of the initial antiepileptic drug and addition of other antiepileptic drugs. Current practice consists of acute antiepileptic drug therapy until clinical seizures are controlled. The first antiepileptic drug is given to serum levels in the high therapeutic range or maximum tolerated dose, followed by a second drug; benzodiazepines are also given as needed. If an electroencephalogram is used to monitor the patient, the same antiepileptic drug strategy is followed, although the antiepileptic drugs are only given to high therapeutic range. Because the electrical seizure discharges are most often resistant to further antiepileptic drug therapy, additional drugs are not given to avoid adverse effects without significant benefit. Some pharmacologic aspects of phenobarbital and phenytoin in the neonate are useful to consider in the treatment of neonatal seizures because pathologic conditions can alter the availability of active drug given at standard doses in sick neonates [DeLorenzo, 1995; Levy et al., 1995; MacDonald, 1995; Painter and Gaus, 1995]. Because phenobarbital is a weak acid and is protein bound, infants with acidosis may have less active antiepileptic drug available, and those with hypoalbuminemia may have greater unbound or active drug available. Both conditions may be found in sick neonates. Phenobarbital is eliminated by the liver and kidney, and infants with impaired hepatic or renal function, such as those with hypoxic ischemic encephalopathy, may have a reduced rate of elimination and therefore a potential for toxicity with standard dosing. The half-life of phenobarbital is longer in preterm than in term infants, and in term infants, it is reduced with chronologic age in the first month of life. In preterm infants, there is the potential for higher serum levels with standard doses and the potential for toxicity; as the infant becomes older, there is the potential for identical doses to result in lower serum levels, creating the potential for breakthrough seizures with no other change in the infant’s clinical condition. Overall, monitoring trends of serum levels rather than day-to-day fluctuations is more useful in management of phenobarbital therapy [Donn et al., 1985; Gal et al., 1982; Painter et al., 1978; Volpe, 1995]. Important pharmacologic characteristics of phenytoin include nonlinear pharmacokinetics [Bourgeois and Dodson, 1983; Dodson, 1984], a variable rate of hepatic metabolism, a decrease in elimination rates during the first weeks of life, and a variable bioavailability of the drug with various generic preparations. The antiepileptic drug is redistributed after the initial dose, resulting in a drop in brain concentrations after the first dose. These pharmacologic characteristics indicate that phenytoin use requires individualization of dosing after the initiation of therapy.

Adjuvant Antiepileptic Drug Therapy for Acute Seizures The use of second-line alternative or adjuvant antiepileptic drugs falls into two categories: agents used for control of acute seizures and those that are administered in an attempt to control otherwise medically refractory seizures. Agents in both classes have been used intravenously or orally with

Mizrahi / Neonatal Seizures

variable success. Drugs given intravenously and primarily as alternatives to acute therapy include clonazepam [André et al., 1986], lidocaine [Hellström-Westas et al., 1988], midazolam [Sheth et al., 1996], and paraldehyde (not available in the United States) [Koren et al., 1986]. One study reported success with continuous midazolam infusion in the treatment of otherwise uncontrolled neonatal seizures [Hu et al., 2003], although infants experienced treatment-related hypotension that was medically managed. Lidocaine is another medication that has been the topic of renewed interest. Boylan and colleagues [2004] reported limited success with lidocaine in refractory neonatal seizures. Another investigation reported that during the use of lidocaine (initial loading dose of 2 mg/kg over 10 minutes, followed by a continuous infusion of 6 mg/kg/hour), 4.8% of infants experienced a cardiac arrhythmia; all responded to lidocaine discontinuation [van Rooij et al., 2004]. Other agents given orally to control medically refractory seizures include carbamazepine [Mackintosh et al., 1987], primidone [Sapin et al., 1988], valproate [Gal et al., 1988], vigabatrin [Aicardi et al., 1996], and lamotrigine [Wheless, 1998]. The success of this latter group of antiepileptic drugs is difficult to assess because they have been used in conjunction with other antiepileptic drugs and well into the course of illness.

Chronic Antiepileptic Drug Therapy The use of chronic antiepileptic drug therapy for neonates after the acute seizures have been controlled is not well standardized. There are no well-defined criteria for maintenance antiepileptic drug treatment. When chronic therapy is considered, phenobarbital or phenytoin is given in maintenance doses of 3 to 5 mg/kg/day, and serum levels are monitored. There are also no well-established criteria for discontinuation of maintenance antiepileptic drug therapy. Reported schedules range from 1 week up to 12 months after the last seizure [Boer and Gal, 1982], although one successful schedule is to withdraw antiepileptic drugs 2 weeks after the infant’s last seizure [Fenichel, 1997]. At some centers, electroencephalography is also performed at the end of this 2-week period to assess for electrical seizure activity not associated with clinical seizures.

Potential Adverse Effects of Antiepileptic Drug Therapy There has been much concern about the potential adverse effects of antiepileptic drugs on the developing brain. Early animal experiments suggested alteration in cell growth and energy substrate use [Bergey et al., 1981; Diaz et al., 1977], although the applicability of these findings to humans has been called into question [Volpe, 2001]. There have been few studies of clinically significant adverse effects of acute antiepileptic drug therapy. However, vigorous acute antiepileptic drug administration can result in CNS depression, hypotension, bradycardia, and respiratory depression. Any of these clinical events represent a risk for secondary CNS hypoxia or ischemia. Bittigau and colleagues [2002] assessed the effect of phenytoin, phenobarbital, diazepam, clonazepam, vigabatrin, and valproate on apoptotic neurodegeneration in the developing rat brain in plasma concentrations relevant for

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seizure control in humans. The basis of their study was the consideration that antiepileptic drugs work by three mechanisms: limitation of sustained repetitive neuronal firing through blockade of voltage-dependent sodium channels, enhancement of γ-aminobutyric acid (GABA)–mediated inhibition, and blockade of glutamatergic excitatory neurotransmission. However, they hypothesized that these mechanisms that are blocked are also features of an endogenous neuroprotective system in the brain that is crucial for neuronal survival during development. They concluded that antiepileptic drugs might impair survival-promoting signals and create an imbalance between neuroprotective and neurodestructive mechanisms in the brain, promoting apoptotic neurodegeneration during the developmental period of ongoing programmed neuronal death. However, it is unclear whether these results can be extrapolated to humans. Later data from the same group suggest that another antiepileptic drug, topiramate, lacks the toxicity of some of the drugs previously mentioned [Glier et al., 2004].

PROGNOSIS In clinical practice, the long-term outcome of neonates with seizures is most likely determined by the cause underlying seizure onset. However, two specific issues frequently may arise in discussion of prognosis: the possibility that seizures harm the developing brain [Camfield, 1997; Wasterlain, 1997] and the possibility that antiepileptic drug administration may adversely affect the neonate. The potential adverse effects on the developing brain are considered here before discussion of the clinical data on the outcome of neonatal seizures.

Adverse Effects of Seizures on the Developing Brain For many years, it was believed that even though the immature brain was more likely to develop seizures in response to injury than the more mature brain, the immature brain was more resistant to seizure-induced injury or any seizure-related alterations were not clinically significant. Various research strategies have been undertaken to further understand this problem with variable results. Overall, emerging evidence suggests that seizures early in life can result in permanent behavior changes and enhanced epileptogenicity, although the mechanisms of some seizure-induced dysfunctions have not been clearly delineated [Holmes, 2004; Holmes et al., 2002; Swann and Hablitz, 2000]. A number of mechanisms of seizure-induced injury that have been investigated to determine whether seizures cause direct neuronal injury or impair brain growth, whether seizures enhance epileptogenesis by altering hippocampal development, and whether seizures alter animal learning and behavior or the development of normal brain pathways.

Seizures Causing Direct Neuronal Injury Prolonged seizures may result in a sustained release of the glutamate [Choi, 1988; Sloviter and Dempster, 1985]. Activated glutamate receptors allow an influx of Ca2+ ions into postsynaptic neurons. This influx initiates a sequence of intracellularly generated toxic metabolites that may lead to cell death and apoptosis [Sloviter et al., 1996]. This type of

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seizure-induced injury is age dependent; the immature brain is significantly less vulnerable to this type of injury than the mature brain [Stafstrom et al., 1992; Thurber et al., 1994]. Resistance to this type of injury by the developing brain may arise from its greater capacity in handling the metabolic stress imposed by anaerobic metabolism and the accumulation of glycolytic by-products that could lead to accumulation of lactate- and pyruvate-associated neurotoxicity in mature animals [Ackerman and Lear, 1989; Lado et al., 2000]. Although the otherwise healthy immature brain may be relatively resistant to this type of neuronal damage, seizures may cause a greater degree of neuronal damage in previously immature abnormal brains, raising the possibility that a recurrence of seizures after neonatal seizures may be associated with cell death [Germano et al., 1996; Yager et al., 2002].

Seizure-Induced Brain Growth Retardation There is some evidence to suggest that prolonged seizures may result in increased energy use and decreased energy supply that can eventually deplete energy stores. This state inhibits the initiation of protein synthesis, which dissociates polysomes, slows growth, and inhibits DNA synthesis. However, these findings appear to be transient, and their appearance is followed by a period of catch-up brain growth [Meldrum, 1978; Jensen et al., 1991; Lowenstein et al., 1991; Wasterlain, 1997].

Seizures Altering Hippocampal Development Seizures may have an adverse effect on the structure and function of the hippocampus—a brain region important in the generation of recurrent seizures later in life. Hippocampal injury may be associated with an increased susceptibility to seizures and perhaps with chronic epilepsy [Cavalheiro et al., 1982; Cavazos and Sutula, 1990]. It has been hypothesized that in mature animals, hippocampal damage caused by seizures is manifested by synaptic reorganization and selective cell death. Several theories have been proposed. The sprouting hypothesis is based on the findings that in the hippocampus the response to seizureinduced cell death is aberrant growth of axons and reorganization of excitatory synapses. This reorganization of neuronal circuits and synapses establishes a state of chronic excitability [Sutula, 1993]. Another possible explanation is the dormant interneuron hypothesis, based on the idea that seizures lead to dysfunction of GABA-containing cells, rendering them nonfunctional or dormant and contributing to a state of decreased inhibition [Sloviter, 1994]. Both are agedependent effects; the immature brain may be more resistant to these seizure-induced changes than the mature brain. However, later data suggest a confluence of processes initiated by seizures early in life that promote or cause chronic epilepsy later in life through mechanisms that reorganize hippocampal circuitry. These include alteration of synaptic connectivity during brain development, alteration of morphology of individual pyramidal cells, and alteration in ion channel subunit composition. These changes create environments at neuronal and circuit levels that promote hyperexcitability. Patterns of neuronal activity that occur during brain development are critical in refining synaptic connectivity [Constantine-Paston et al., 1990; Swann and Hablitz, 2000]. Abnormal paroxysmal synchronized dis-

charges that characterize early seizures may prevent expected axonal remodeling within hippocampus, initiating an immature pattern of axonal branching that can persist into adulthood. Another theory suggests that seizure-induced growth or sprouting of recurrent axons may also occur, giving rise to recurrent excitatory collaterals and producing greater excitation in local networks. Within recurrent excitatory networks, there may be a loss of less active synapses, allowing those that are more stable and more capable of generating larger excitatory potentials to mediate seizure activity [Thompson, 1985].

Seizure-Induced Alterations of Brain Pathways An issue related to seizure-induced alteration of hippocampal circuitry is the effect epileptic activity may have on the immature brain in the subsequent development of other CNS pathways. To achieve precise patterns of connections within the normal mature brain, axons must grow toward and establish synaptic contact with their appropriate target. This growth is thought to be achieved by the establishment of a relatively imprecise projection pattern, followed by a process of fine-tuning. This process of maintenance of appropriate projections and selective elimination of inappropriate projections depends on normal patterns of neuronal activity [Khazipov et al., 2004; Schwartzkroin, 1995; Shatz and Styker, 1988]. Grigoinis and Murphy [1994] investigated the effect in immature animals of epileptic activity on the visual system, including occipital cortex and associated corpus callosal projections. Epileptic activity in the occipital cortex early in life stabilized immature projections that were normally eliminated during development, suggesting that epileptic-induced maintenance of such immature projections in the eventually mature brain may interfere with normal cortical functions later in life.

Seizure-Induced Alteration of Animal Learning and Behavior Studies have found that seizures in immature animals do not result in significant alterations of learning, memory, or activity levels in the immediate post-seizure period. However, when animals that had been exposed to seizures early in life were compared with those exposed when mature, the immature animals demonstrated impairments and alterations in behavior [Holmes et al., 1993a, 1993b; Stafstrom et al., 1993]. Adverse effects of seizures are more apparent when animals exposed to prolonged seizures early in life are then exposed to seizures when mature [Koh et al., 1999; Sarkisian et al., 1997]. Lado and colleagues [2000] suggest that subtle age-specific changes exist after the initial bout of prolonged seizures but that manifestations of symptomatic damage and behavioral effects require a second insult for expression. Holmes and colleagues [Hoffmann et al., 2004; Holmes, 2004; Sogawa et al., 2001] found that prolonged seizures in immature animals result in minimal behavioral consequences when the animals are studied later in life and that they are associated with minimal morphologic changes. However, in describing the two-hit hypothesis, they report that early-onset seizures result in changes in the brain that make it more vulnerable to the development of cognitive impairment when animals are exposed to post-neonatal seizures.

Mizrahi / Neonatal Seizures

Clinical Considerations in Prognosis The goal of the management of neonates with seizures is a good neurologic outcome. Although there is consensus that neonates with seizures who survive are at risk for adverse outcomes, there is less agreement concerning the basis for this belief. The outcome of infants with neonatal seizures has been assessed in terms of survival, neurologic disability, developmental delay, and post-neonatal epilepsy. Ortibus and colleagues [1996] reported that 28% of those with neonatal seizures died, 22% of survivors were neurologically normal at an average of 17 months of age, 14% had mild abnormalities, and 36% had severe abnormalities. In a prospective study of term infants 2 years after neonatal seizures, Mizrahi and colleagues [2001] found that 28% died, and among survivors, 42.7% had abnormal neurologic examination findings, 55.2% had values on the Bayley Developmental Assessment of Mental Development Index of less than 80, 49.6% had a Bayley Developmental Assessment of Psychomotor Developmental Index value less than 80, and 26% had post-neonatal epilepsy [Mizrahi et al., 2001] (Table 13-6). Brunquell and colleagues [2002] found that 30% of those with neonatal seizures died and that 59% of survivors had abnormal neurologic examinations; 40% were mentally retarded, 43% had cerebral palsy, and 21% had post-neonatal epilepsy when followed up to a mean of 3.5 years. Ellenberg and colleagues [1984] studied post-neonatal epilepsy in more detail. They found that approximately 20% of those who survived neonatal seizures experienced one or more seizures before they were 7 years old and that almost two thirds occurred within the first 6 months of life. Similar rates of 17% to 30% were found by Scher and colleagues [1993a], 28% by Ortibus and colleagues [1996], 21% by Bye and associates [1997], 26% by Mizrahi and colleagues [2001], 21% by Brunquell and associates [2002], and 22% by Da Silva and co-workers [2004] at the 12-month followup and 33.8% within 48 months. Clancy and Legido [1991] found a higher rate of post-neonatal epilepsy (56%), although their study population had relatively high risk factors for CNS dysfunction and were studied in specialized care units. Seizures that characterize post-neonatal epilepsy include partial and generalized types. Watanabe and colleaTABLE 13-6 Outcomes at 24 Months of Term and Near-Term Neonates with Seizures

From Mizrahi EM, Clancy RR, Dunn JK, et al. Neurologic impairment, developmental delay and postnatal seizures 2 years after EEG-video documented seizures in near-term and term neonates: Report of the clinical research centers for neonatal seizures. Epilepsia 2001;42:102.

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gues [1999] considered in detail a selected population of infants with neonatal seizures that persisted beyond the neonatal period and that could be classified as epilepsy of neonatal onset. For most of those infants with severe encephalopathy syndromes such as early infantile epileptic encephalopathy and early myoclonic encephalopathy, their initial epileptic syndrome evolved to West’s syndrome, with a fewer number evolving to symptomatic localizationrelated epilepsy. The management of neonatal seizures includes an accurate diagnosis, expeditious determination of the cause, rapid administration of etiologic-specific therapy, and successful antiepileptic drug treatment. The goal is to improve longterm outcome and prevent adverse sequelae. However, it is not clear which of these management components is critical to achieving the goal of maximizing the prognosis. In this regard, clinical studies are more difficult to interpret to determine whether seizures adversely affect the developing brain when compared with basic science investigations. Seizure duration may appear to influence outcome because infants who experience brief and infrequent seizures may have relatively good long-term outcomes, but those with prolonged seizures may not fare as well. However, easily controlled seizures or self-limited seizures may be the result of transient, successfully treated, or benign CNS disorders of neonates, whereas medically refractory neonatal seizures may be the result of more sustained, less treatable, or more severe brain disorders. McBride and co-workers [2000] demonstrated that a relation exists in infants with perinatal asphyxia between a greater amount of electrographic seizure activity and subsequent relative increased mortality and morbidity. Other investigators, using proton magnetic resonance spectroscopy in neonates, found an association between seizure severity and impaired cerebral metabolism measured by lactate-to-choline ratios and compromised neuronal integrity measured by N-acetylaspartate-to-choline ratios and suggested this to be evidence of brain injury not limited to structural damage detected by magnetic resonance imaging [Miller et al., 2002]. It is thought that the dominant variable that predicts outcome may be the underlying cause of the seizures rather than the presence, duration, or degree of brain involvement of the seizures themselves. Mizrahi and Kellaway [1998] analyzed a number of clinical studies indicating that normal outcomes occurred with increasing frequency in association with the following causes: hypoxic-ischemic encephalopathy, infection, hemorrhage, hypoglycemia, and hypocalcemia [Bergman et al., 1983; Clancy et al., 1985; Lombroso, 1983; Kellaway and Mizrahi, 1987; Mannino and Trauner, 1983; McInerny and Schubert, 1969; Rose and Lombroso, 1970]. In discussing prognosis, Volpe [2001] emphasized the effects of gestational age and cause of seizures on outcome (Table 13-7). Mortality increases with the greater degree of prematurity, and specific causes are associated with various degrees of developmental delay. It has been suggested that seizure type might also predict outcome [Mizrahi and Kellaway, 1987]. However, this linkage may reflect the cause or the degree of associated brain dysfunction at the onset of seizures. It was found that focal clonic and focal tonic seizures were associated with a relatively good outcome primarily because these seizure types were typically associated with relatively confined,

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TABLE 13-7 Prognosis of Neonatal Seizures According to Neurologic Disorder NEUROLOGIC DISORDER Hypoxic-ischemic encephalopathy Intraventricular hemorrhage† Primary subarachnoid hemorrhage Hypocalcemia Early-onset Late-onset Hypoglycemia Bacterial meningitis Developmental brain defect

NORMAL DEVELOPMENT (%)* 50 10 90 50‡ 100 50 50 0

*Because the prognosis is given for those with the stated neurologic disease when seizures are a manifestation, the value usually differs from that of the overall prognosis. Values are rounded to the nearest 5%. † Severe intraventricular hemorrhage usually is associated with major periventricular hemorrhagic infarction. ‡ This value primarily represents the prognosis in cases of complicating illness; the prognosis approaches that of later-onset hypocalcemia if no or only minor neurologic illness is present. From Volpe JJ. Neonatal seizures. In: Neurology of the newborn. Philadelphia: WB Saunders, 1995:172.

nondiffuse brain injury and significantly spared CNS function. Generalized tonic posturing and motor automatisms are associated with a poor outcome because they are associated with diffuse CNS dysfunction. Brunquell and colleagues [2002] demonstrated similar findings in long-term studies. In multivariant analyses, factors that were considered as predictors of outcome included features of the interictal electroencephalogram from one or serial recordings, the ictal electroencephalogram, the neurologic examination at the time of seizures, the character or duration of the seizures, seizure cause, findings on neuroimaging, conceptional age, and birth weight. The use of multiple factors appears to be most accurate in predicting outcome. For example, Ortibus and colleagues [1996] found that the predicted outcome is less reliable when based solely on EEG variables from a single recording obtained at seizure onset than when based on a combination of imaging findings and clinical and EEG data. Pisani and colleagues [2004] also considered several different independent variables and found the character of the EEG background activity predictive of developmental outcome. However, in these studies, all variables related to a single factor, the degree of brain injury at the time of seizure occurrence, which was related to cause. ACKNOWLEDGMENTS This work was supported in part by Contract Number NS-0-1234, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, and the Peter Kellaway Research Endowment, Baylor College of Medicine, Houston, Texas.

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CHAPTER 14

Hypoxic-Ischemic Cerebral Injury in the Newborn Alan Hill

Despite the occurrence of major improvements in neonatal care and a decrease in perinatal mortality and morbidity in recent decades, hypoxic-ischemic cerebral injury in the newborn remains a significant cause of infant mortality and long-term morbidity, such as cerebral palsy, mental retardation, visual impairment, and epilepsy [Volpe, 2001a]. In this chapter, the clinical features, diagnostic investigations, management, and prognosis for hypoxic-ischemic cerebral injury in preterm and term newborns are reviewed. The pathogenesis of such brain injury from the perspective of underlying cellular and molecular mechanisms is addressed in Chapter 15.

DIAGNOSIS History The diagnosis of neonatal hypoxic-ischemic cerebral injury should be made only after confirmation of a preceding hypoxic-ischemic insult, followed by the identification of an early neonatal encephalopathy [Volpe, 2001a]. Accurate diagnosis requires a detailed review of events of pregnancy, labor, and delivery and a careful neurologic examination of the affected newborn. There is close correlation between the type of hypoxicischemic insult sustained by an infant and subsequent cerebral injury. The severity and extent of injury is determined in large part by the time of onset, severity, and duration of the insult. The maturity and physiologic status of the fetus or newborn when the insult occurs plays an important role. Hypoxicischemic insults can have an antepartum, intrapartum, or postnatal onset. This issue has been addressed by several large epidemiologic studies, such as those by the National Collaborative Perinatal Project [Nelson and Ellenberg, 1986; Nelson and Leviton, 1991], the Western Australian Cerebral Palsy Register [Badawi et al., 1998a, 1998b; Felix et al., 2000; Stanley et al., 2000], and the California Cerebral Palsy Project [Grether and Nelson, 1997; Nelson, 2003a]. These studies emphasized the importance of antepartum insults. Based on these epidemiologic data, it has been estimated that less than 20% of cerebral palsy cases can be attributed directly to intrapartum hypoxic-ischemic insult [Gaffney et al., 1994]. One study documents a decline in birth asphyxia, but the reasons for this are unclear [Wu, 2004]. In some instances, earlier prenatal factors such as cerebral dysgenesis or intrauterine growth retardation might have predisposed the fetus to a subsequent intrapartum hypoxic-ischemic insult. Some degree of fetal hypoxia-ischemia occurs during the process of normal labor and delivery. For example, there is temporary reduction of uterine blood flow during con-

tractions, which does not usually compromise the fetus unless there are significant preexisting fetal or placental abnormalities or the occurrence of intrapartum complications. A detailed review should be performed of maternal history including means of conception (assisted), presence of infection during pregnancy and especially during labor, and substance abuse or maternal ingestion of herbs or medications. The details of the labor and delivery are critical (e.g., abnormalities of fetal heart rate monitoring, acid-base status of the fetus, Apgar scores, presence of meconium, placental pathology, resuscitation measures) to establish risks for an intrapartum hypoxic-ischemic insult [Perlman, 1999]. These clinical parameters of fetal status can establish that an intrapartum hypoxic-ischemic insult has probably occurred and should not be considered predictive of brain injury or of poor long-term outcome [Nelson, 2003b]. A relation between the type of hypoxic-ischemic insult and cerebral injury has been demonstrated in experimental animal models involving primates [Myers, 1975] and fetal lambs [De Haan et al., 1997; Mallard et al., 1995]. Two major types of intrapartum hypoxic-ischemic insults correlate with specific topographic patterns of brain injury. After an acute, total insult in primates, major irreversible injury occurred after 10 to 11 minutes, and neuropathologic lesions were located predominantly in deep gray matter (i.e., thalamus, basal ganglia, and brainstem) with relative preservation of cerebral cortex. After a prolonged, partial hypoxic-ischemic insult (i.e., an insult that was less severe but occurred continuously or intermittently over a longer period of time, often more than 1 hour), injury involved predominantly the cortex and subcortical white matter with relative preservation of central structures. These two types of insult represent the extremes of a spectrum of injury, and in most instances, there are components of both types of injury with predominance of one or the other. Similar patterns of injury have been recognized in the human term newborn [Pasternak and Gorey, 1998; Roland et al., 1998], and they are discussed in more detail in later sections. In term newborns, most hypoxic-ischemic insults occur antenatally or during delivery. Significant postnatal insults also may occur, especially in preterm newborns, who often have multiple problems related to their prematurity, such as respiratory distress syndrome or apnea that may have detrimental effects on cardiopulmonary function and cerebral perfusion.

Neurologic Examination for Clinical Encephalopathy In term newborns who sustain an intrapartum hypoxicischemic insult of sufficient severity to result in long-term neurologic sequelae, there is invariably a recognizable enceph-

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Perinatal Acquired and Congenital Neurologic Disorders / 14

alopathy during the early neonatal period. Conversely, the absence of such encephalopathy argues against a significant intrapartum hypoxic-ischemic insult that is the cause of any future detected neurologic abnormalities. Although hypoxic-ischemic encephalopathy occurs in preterm newborns, the clinical features are often more difficult to recognize and observations must be interpreted in the context of gestational age and the stage of maturation of the brain at the time of insult [Niijima and Levene, 1989]. Infants exposed to hypoxic-ischemic insult earlier in pregnancy do not necessarily display abnormal clinical neurologic signs in the neonatal period. Although there is a spectrum of hypoxic-ischemic encephalopathy, it is often valuable for prognostic purposes to quantify the encephalopathy as mild, moderate, or severe [Cheung and Robertson, 2000; Miller et al., 2004; Robertson and Finer, 1993; Sarnat and Sarnat, 1976]. A classification of encephalopathy, modified from that reported by Sarnat and Sarnat [1976] is outlined in Table 14-1. Additional data have been reported, and the use of the newer classification has been validated in predicting the outcomes of these infants [Miller et al., 2004]. This new encephalopathy score adds the clinical parameter of feeding and respiratory efforts and, when quantified, can be used to accurately assist in outcome prediction. The time of onset of the acute encephalopathy after an asphyxial episode varies. Some infants appear overtly encephalopathic immediately after delivery, whereas others appear essentially normal for several hours before the encephalopathy becomes apparent; in one study, the mean age of onset of seizures was approximately 10 hours (range, 1 to 90 hours) [Ahn et al., 1998]. However, seizures may begin at any time within the first 24 hours of life. Difficulties in the recognition of neonatal seizures may have a major influence in this regard [Shewman, 1990; Volpe, 2001a]. In term newborns with severe hypoxic-ischemic encephalopathy, there is often a predictable progression of clinical neurologic abnormalities. During the first hours of life, there may be a decreased level of consciousness, with preservation of the ability to breathe spontaneously. Subsequently, there may be increased tone and onset of seizures, which are often subtle but which become frequent and have other seizure manifestations [Perlman and Risser, 1996].

This condition is usually followed by worsening hypotonia and unresponsiveness, with the seizures becoming refractory to anticonvulsant therapy. Signs of brainstem dysfunction (e.g., apnea, abnormal eye movements and motor responses) often worsen during the first 3 days of life and may culminate in respiratory arrest and death at about 72 hours of age. This temporal profile of events corresponds to the occurrence of maximal cerebral edema [Lupton et al., 1988]. Increased intracranial pressure is detectable clinically by palpation of the anterior fontanel. Extensive cerebral edema of sufficient magnitude to cause increased tension and bulging of the anterior fontanel occurs typically after severe prolonged, partial intrapartum hypoxic-ischemic insult and is considered to reflect extensive tissue necrosis [Mujsce et al., 1990]. In this context, the use of anti-edema agents is unlikely to have significant beneficial effect [Levene et al., 1987; Lupton et al., 1988]. Some infants with hypoxic-ischemic encephalopathy may develop a degree of cerebral edema as a consequence of inappropriate secretion of antidiuretic hormone, which requires careful monitoring of fluid balance. Specific patterns of abnormal motor signs may be recognized according to the topographic distribution of the brain lesions. For instance, newborns with parasagittal watershed lesions may exhibit weakness and hypotonia that involves the shoulder girdle musculature, unilateral weakness may be seen after focal cerebral infarction, and preterm newborns with periventricular white matter injury may exhibit abnormal tone that affects predominantly the lower extremities. With evolution of the encephalopathy, seizures often abate over 3 to 4 days, and gradual stabilization of the neurologic status occurs during subsequent weeks. Persistent brainstem dysfunction (i.e., facial diplegia and bulbar dysfunction) may be observed, especially after acute, neartotal asphyxia in which there is predominant injury to the thalami, basal ganglia, and brainstem. Severely affected infants who sustain this pattern of injury have persistent long-term neurologic abnormalities that include abnormal tone, feeding problems related to impaired sucking and swallowing, and altered level of alertness (e.g., excessive irritability or lethargy). The clinicopathologic correlations of specific patterns of injury are reviewed later.

TABLE 14-1 Correlation of Severity of Encephalopathy and Outcome SEVERITY OF ENCEPHALOPATHY CHARACTERISTIC

Mild

Moderate

Severe

Level of consciousness Seizures Tone Tendon reflexes Primitive reflexes Brainstem dysfunction Other features

Hyperalert – Normal or increased Increased Exaggerated – Jitteriness, sympathetic overactivity

Lethargy ± Decreased Increased or decreased Depressed ± ±

Outcome

Normal

20–40% abnormal

Coma + Decreased Decreased or absent Absent + Elevated intracranial pressure, autonomic dysfunction 100% abnormal or death

+, present; –, absent; ±, present or absent. Data from Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress: A clinical and electroencephalographic study. Arch Neurol 1976;33:969, and from Volpe JJ. Neurology of the newborn, 4th ed. Philadelphia: WB Saunders, 2001.

Hill / Hypoxic-Ischemic Cerebral Injury in the Newborn

281

Although the occurrence of an acute encephalopathy is a critical component of the diagnosis of acute hypoxicischemic brain injury, the clinical features themselves are nonspecific and may occur after other cerebral insults (e.g., infection, metabolic derangements). Accurate assessment of the severity of the encephalopathy may be obscured by iatrogenic muscle paralysis, sedative medications, or other intensive care measures. In such instances, documentation of injury to organs other than brain (e.g., kidneys, myocardium, liver) and the use of adjunctive investigations, especially neuroimaging, may provide important corroborative evidence that hypoxic-ischemic insult has occurred.

maternal hypoxemia, graded reduction of placental blood flow, and graded or repetitive reduction of uterine blood flow were associated with activation of the diving reflex, whereas abrupt complete arrest of uterine blood flow caused reduction of perfusion to brain alone [Jensen et al., 1999]. Similar observations were reported for 14 of 57 newborns with hypoxic-ischemic encephalopathy who had no evidence of multisystem involvement [Phelan et al., 1998]. However, some newborns in this group had evidence of brief periods of dysfunction of systemic organs (e.g., hematuria, proteinuria, hypotension) that did not meet criteria for significant organ injury. Injury to brain only also has been observed.

Evaluation of Injury to Organs Other Than Brain

Neuroimaging

It is not surprising that an intrapartum hypoxic-ischemic insult may result in injury to organs other than brain. However, the frequency of involvement of other organs is not precisely known. Although there may be direct hypoxic ischemic injury to these organs, this injury may be exacerbated by the diving reflex, a phenomenon in which an acute asphyxial episode results in redistribution of the fetal circulation to vital organs (e.g., brain, heart, adrenal glands) at the expense of other systemic organs, which may cause transient injury to these organs. The most commonly affected organs in the term newborn and the clinical features of such systemic involvement are summarized in Table 14-2. Attempts to establish the incidence of systemic hypoxicischemic involvement is difficult because the various published studies use different definitions of asphyxia and the diagnosis of organ dysfunction [Hankins et al., 2002; Martin-Ancel et al., 1995; Phelan et al., 1998; Shah et al., 2004a]. Because systemic injury is considered to result in part from redistribution of the fetal circulation, it is plausible that these protective mechanisms may be overwhelmed or ineffective in some instances of severe, acute asphyxia (e.g., uterine rupture, massive placental abruption), and that the brain may be the first to be injured [Pasternak and Gorey, 1998; Phelan et al., 1998]. This conjecture is supported by experimental animal studies, which have demonstrated that

Cranial Ultrasonography

TABLE 14-2 Effects of Systemic Hypoxic-Ischemic Injury ORGAN

EFFECTS

Kidneys

Acute renal failure, hematuria, oliguric proteinuria; increased blood urea nitrogen and creatinine levels Elevated levels of liver enzymes, hyperammonemia, coagulopathies, hypoglycemia Mucosal hemorrhage, sloughing of mucosa, necrotizing enterocolitis Decreased ventricular function, hypotension, arrhythmia, papillary muscle necrosis, tricuspid regurgitation, mitral regurgitation Respiratory distress or failure, pulmonary hemorrhage, meconium aspiration syndrome, persistent pulmonary hypertension Thrombocytopenia, coagulopathy

Liver Intestines Heart Lungs Hematologic system

In the preterm newborn, cranial ultrasonography is considered the technique of choice for screening for germinal matrix or intraventricular hemorrhage [Barnes, 2001; Ment et al., 2002; Perlman and Rollins, 2000]. After germinal matrix or intraventricular hemorrhage, serial ultrasound scans are of value for the documentation of progressive post-hemorrhagic hydrocephalus, a serious sequelae of intraventricular hemorrhage [Grasby et al., 2003; Taylor, 2001]. Cranial ultrasound scans are of limited value for identification of white matter injury. After severe white matter injury, serial scans may demonstrate a characteristic temporal profile, with transient increased echogenicity in periventricular regions in the first days of life followed by cystic cavitation after several weeks. The period from onset of injury to development of cavitations varies and is related to the severity of injury and the stage of maturation of the brain [Childs et al., 2001; Groenendaal and de Vries, 2001; Hope et al., 1988; Maalouf et al., 2001]. Cystic periventricular leukomalacia is declining in incidence, and perhaps more subtle lesions of white matter that are missed on cranial ultrasound may have more importance in determining neurodevelopmental outcome [Hamrick et al., 2004; Inder et al., 2003a; Miller et al., 2003]. However, it is important to recognize, based on correlative neuropathologic and radiologic studies, that approximately 50% to 70% of periventricular white matter injury remains undetected by ultrasonography and may not show the subsequent gray matter loss that occurs in this setting [Inder et al., 1999a, 2003b; Ment et al., 2002; Miller et al., 2003]. This observation has important implications for the counseling of parents of preterm newborns during the early weeks of life. Magnetic resonance imaging (MRI) studies have identified less severe white matter lesions [Childs et al., 2001; Inder et al., 2003b; Sie et al., 2000]. MRI performed later in infancy or childhood often demonstrates characteristic features (e.g., ventriculomegaly) caused largely by white matter atrophy and collapse of cystic lesions and deep cortical sulci, which may abut directly onto the ventricular wall in severe cases. It is important to distinguish this type of ventriculomegaly, which is caused by cerebral atrophy, from progressive posthemorrhagic hydrocephalus. However, when germinal matrix hemorrhage or intraventricular hemorrhage has oc-

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curred concomitantly with white matter injury, the resultant ventriculomegaly may represent a combination of atrophy and post-hemorrhagic transient or progressive ventriculomegaly [Kuban et al., 1999]. In the scientific literature, it has been suggested that routine screening with cranial ultrasonography is indicated for all infants younger than 30 weeks’ gestation between 7 and 14 days of age and that it ideally should be repeated between 36 and 40 weeks [Ment et al., 2002]. MRI may be necessary to address specific clinical concerns. Ultrasonography has an even more limited clinical application in the term newborn. A generalized increase in echogenicity and decreased size of lateral ventricles has been considered to indicate diffuse hypoxic-ischemic injury. As in the preterm brain, the relative subjectivity of interpretation of such diffuse patterns of cerebral injury may be identified with confidence only in severe cases [Barkovich and Hallam, 1997]. Focal ischemic lesions may appear as localized areas of increased echogenicity that may become cystic (i.e., porencephaly).

Computed Tomography In the preterm newborn, the role of computed tomography (CT) for assessment of acute hypoxic-ischemic brain injury is limited because of the normally high water content of the premature brain, which precludes the use of low tissue attenuation as an index of cerebral edema and brain injury. Intracranial hemorrhage (i.e., extradural, subdural, subarachnoid, or cortical hemorrhage over the cerebral convexities, which are often difficult to visualize with ultrasound) may be diagnosed with CT. In later infancy and childhood, CT can document the sequelae of hypoxicischemic cerebral injury (e.g., periventricular leukomalacia) in infants born prematurely. In the term newborn, parenchymal hypoxic-ischemic injury is recognized on CT as various degrees of low tissue attenuation. In this context, there is close correlation among decreased attenuation on CT performed approximately 2 to 5 days after the insult, the time of maximal cerebral edema, and poor neurologic outcome. It is important to use appropriate techniques, such as window and level settings. After severe hypoxic-ischemic insult, earlier recognition of the edema may be possible. Scans performed in later infancy often demonstrate atrophy and multicystic encephalomalacia. CT can identify specific patterns of injury, such as cortical or subcortical injury, parasagittal injury, central injury (involving predominantly thalami and basal ganglia), and focal infarction. However, these patterns are much more clearly identified with MRI. Advances in high-resolution computer technology have enhanced the role of CT angiography and venography, and multidetector CT technology permits ultrafast imaging, which has reduced the need for sedation. Nevertheless, in many instances, the role of CT is being redefined in the context of improved availability of MRI.

Magnetic Resonance Imaging MRI is increasingly used in the assessment of neonatal brain injury, principally because of its improved sensitivity and

specificity. In the preterm newborn, conventional MRI has the capability to demonstrate diffuse hypoxic-ischemic injury in white matter; white matter hemorrhage, including punctate lesions on T2-weighted images; and more numerous or more extensive cystic periventricular leukomalacia than other imaging modalities [Roelants-van Rijn et al., 2001; Sie et al., 2000]. Asymmetric myelination of the posterior limb of the internal capsule at 40 weeks’ gestational age after periventricular hemorrhagic infarction has been shown to be an early predictor of hemiplegia [de Vries et al., 1999]. A potential difficulty in the interpretation of MRI imaging is related to the normal high T2 signal of relatively unmyelinated white matter in neonates that may obscure signal abnormalities. T1 shortening (presumably due to lipid breakdown products of myelin) may be visualized during the first week of life, before obvious changes in T2 signal occur, and diffusion-weighted imaging therefore is preferred for the earliest detection of ischemic injury [Barkovich et al., 2001]. Several studies suggest that diffusion-weighted MRI and magnetic resonance spectroscopy may be more sensitive for the detection of hypoxic-ischemic lesions than conventional MRI in the first days of life [Barkovich et al., 2001; Soul et al., 2001; Wolf et al., 2001]. Ischemic lesions, identified as areas of restricted diffusion due to cytotoxic edema, are more conspicuous than on conventional MRI. False-negative results may occur or the magnitude of the lesion may be underestimated if studies are performed early (i.e., before 24 hours of age) [Rutherford et al., 2004]. Diffusion coefficients appear to be maximally decreased between days 1 and 3 after a hypoxic-ischemic insult [McKinstry et al., 2002; Robertson et al., 1999]. In the term newborn, conventional MRI performed between 8 and 10 days after acute hypoxic-ischemic insult may demonstrate an ischemic or hemorrhagic pattern of injury, such as watershed parasagittal injury, central injury to thalami and basal ganglia, and in some instances, injury to the hippocampus, dorsal brainstem, and perirolandic cortex [Khong et al., 2003, Miller et al., 2005]. Subsequent MRI evaluation at approximately 2 years of age often demonstrates persistent signal changes and multicystic encephalomalacia in severe cases [Sie et al., 2000]. Proton magnetic resonance spectroscopy and diffusion tensor imaging provide two quantitative measures of brain development and injury that can be applied serially in the first days of life. Proton magnetic resonance spectroscopy demonstrates a lactate peak in the first 24 hours after acute hypoxic-ischemic brain injury and a subsequent reduction in N-acetyl aspartate levels [Barkovich et al., 2001; Hanrahan et al., 1999]. Lesions in thalami and basal ganglia [Aida et al., 1998] and elevated lactate-to-choline ratios and lowered N-acetyl aspartate–to-choline ratios, especially in basal ganglia [Barkovich et al., 1999; Miller et al., 2002a; Zarifi et al., 2002], are associated with poor neurologic outcome. Diffusion tensor imaging as a technique to quantify the average diffusivity and anisotropy of brain water has proved very useful in identifying lesions in preterm and term newborns and may assist in predicting subsequent injury patterns and neurodevelopmental outcome [Counsell et al., 2003; Hunt et al., 2004; Huppi et al., 2001; Miller et al., 2002b; Rutherford et al., 2004]. Applied together, magnetic

Hill / Hypoxic-Ischemic Cerebral Injury in the Newborn

resonance spectroscopy and dipyridamole-thallium imaging have the potential for identifying neonatal brain injury in its earliest state (i.e., elevated lactate levels and reduced average diffusivity) and to determine the progression of injury over time (i.e., reduced N-acetyl aspartate levels and reduced anisotropy). Current recommendations are that term newborns with a history of birth trauma, encephalopathy, low hematocrit, or coagulopathy should be scanned with noncontrast CT to detect hemorrhagic lesions. In infants who sustained hypoxic-ischemic insult, CT after 3 to 5 days is considered optimal for detection of cerebral edema. If computed tomographic images are inconclusive, MRI should be performed between 2 and 8 days of age. Diffusion-weighted imaging and magnetic resonance spectroscopy may allow earlier detection of cerebral injury [Ment et al., 2002]. These recommendations may require modification as new imaging techniques develop.

Single-Photon Emission Computed Tomography and Positron Emission Tomography Neuroimaging Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) studies can provide sensitive and accurate measurement of cerebral perfusion in infants with hypoxic-ischemic encephalopathy [Azzarelli et al., 1996; D’Arceuil et al., 2000; Haddad et al., 1994; Volpe et al., 1983]. However, clinical application is limited by lack of portability, relatively prolonged scanning time, and poor spatial resolution of the technique.

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Yager et al., 2002]. The identification of status epilepticus on electroencephalograms carries an unfavorable prognosis. The EEG background activity may assist in assessment of the severity of cerebral dysfunction and for determination of prognosis (see Chapter 12). Severely depressed amplitude (i.e., voltage suppression) unexplained by anticonvulsant therapy or sedation, a burst-suppression pattern characterized by a discontinuous recording with marked voltage suppression interposed with bursts of high-voltage sharp and slow waves, or an isoelectric pattern indicates severe cerebral dysfunction and probably a poor prognosis [Sarnat and Sarnat, 1976; Volpe, 2001a]. In contrast, milder disturbances of background, especially if they normalize within the first week of life, are associated with a more favorable prognosis [Sher et al., 1989; Sinclair et al., 1999; Takeuchi and Watanabe, 1989]. The use of amplitude-integrated electroencephalograms, which simplify bedside interpretation of the background, performed within 3 to 6 hours after birth can assist in the recognition of infants who may benefit from interventional therapy [Shalak et al., 2003; Toet et al., 1999].

Evoked Potentials Brainstem [Stockard et al., 1983], somatosensory [Majnemer et al., 1990], and visual-evoked responses [Whyte et al., 1986] have all been used in the evaluation of the asphyxiated newborn. Although each of these investigations has some prognostic value, they are not performed routinely at many centers, and their clinical application is often limited by technical difficulties.

Biochemical Investigations Electrodiagnostic Techniques Electroencephalography The electroencephalogram may be performed at the bedside and may assist in the recognition of seizures, assessment of severity of encephalopathy, and determination of prognosis. Seizures occur less commonly in asphyxiated preterm newborns as a consequence of immaturity of neuronal interconnections which prevent seizure propagation. Positive rolandic sharp-wave transients, especially when frequent and persistent, have correlated with periventricular leukomalacia in preterm newborns [Baud et al., 1998; Novotny et al., 1987; Vecchierini-Blineau et al., 1996]. However, the sensitivity of such electroencephalographic (EEG) abnormalities for assessment of white matter injury is limited [Aso et al., 1993; Sher et al., 1993]. In the term newborn, the EEG pattern may be of value in that some movements may be difficult to differentiate from seizure activity on the basis of observation alone [Shewman, 1990]. Seizures may be masked by concomitant use of sedatives, anticonvulsant medications, or neuromuscular blocking agents. The observation of frequent electrographic seizures on serial electroencephalograms or on continuous EEG monitoring permits early intervention. Although it is not clear whether medical intervention is as beneficial for electrographic seizures without recognizable clinical accompaniments, experimental animal data suggest that electrographic seizure activity with or without clinical accompaniment poses a risk for brain injury [Wirrell et al., 2001;

Biochemical derangements caused by hypoxic-ischemic injury of organs other than brain, such as hypoglycemia, hypocalcemia, hyponatremia, hyperammonemia, or acidosis, may contribute to the encephalopathy [Volpe, 2001a]. Other more specific metabolic parameters (e.g., creatine brain isoenzyme, neuron-specific enolase, glutamate, glial fibrillary acidic protein in cerebrospinal fluid) may serve as markers of the magnitude of the insult [Blennow et al., 2001; Nagdyman et al., 2003]. Several biochemical parameters that may be measured in a routine clinical setting may assist in identification of hypoxic-ischemic injury. Plasma lactate levels and base deficit appear most promising in that regard [Da Silva et al., 2000; Shah et al., 2004b]. Similarly, it has been reported that the lactate-to-creatinine ratio, measured in urine collected within 6 hours of birth, correlates with the degree of encephalopathy and neurologic outcome at 1 year of age [Huang et al., 1999]. One study reported the value of concentrations of nitric oxide and carbon monoxide in plasma for the assessment of the severity of encephalopathy [Shi et al., 2000].

NEUROPATHOLOGIC PATTERNS OF INJURY AND THEIR CLINICAL CORRELATIONS The neuropathologic patterns of neonatal hypoxic-ischemic cerebral injury are determined principally by the type, magnitude, and duration of the insult and by the gestational age

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TABLE 14-3 Correlation of Hypoxic-Ischemic Insult with Patterns of Cerebral Injury in Term Newborns TYPE OF INSULT

PATTERN OF INJURY

Prolonged, partial

Cortical or subcortical Parasagittal (watershed) Ulegyria (watershed) Global, diffuse Thalami, basal ganglia Brainstem ± Hippocampi ± Perirolandic cortex ± White matter ± Cerebellar vermis Combined pattern Global injury Unclassifiable

Acute, near-total (profound)

Combined profound and prolonged, partial

of the infant. Because the patterns are significantly different in term and preterm newborns, they are discussed separately. Focal and multifocal brain injury (e.g., focal cerebral infarction), which may occur in preterm and term newborns, has a more diverse origin (e.g., thrombotic disorders, embolic disease) and is discussed in detail in Chapter 17.

Term Newborn With advanced neuroimaging, there is an increased recognition of the clinical antecedents and neurodevelopmental outcomes of the major patterns of brain injury in the term newborn. The major patterns of hypoxic ischemic injury in term newborns are summarized in Table 14-3.

Cortical or Subcortical Injury PATHOGENESIS Studies in experimental animals have demonstrated this pattern of injury after a partial hypoxic-ischemic insult, which

A

B

may be continuous or intermittent and which is prolonged, usually more than 60 minutes [Myers, 1975]. At the more severe end of the spectrum of injury after a prolonged, partial insult, there is widespread necrosis of cortex and subcortical white matter, often with relative sparing of central gray matter structures (e.g., thalami, basal ganglia, brainstem).

DIAGNOSIS Cerebral edema, which appears on CT as low attenuation and decreased gray-white matter differentiation, is usually maximal at approximately 3 days after the insult (Fig. 14-1A). However, the precise time of recognition of the low attenuation depends on the severity of injury. Conventional MRI may demonstrate T1 hypointensity with T2 hyperintensity at 12 to 48 hours after the insult, followed by T1 hyperintensity at approximately 3 days and T2 hypointensity usually after 6 days [Barnes, 2001]. Diffusion-weighted studies may demonstrate abnormalities earlier than conventional MRI. Chronic changes demonstrated on CT or MRI include cystic encephalomalacia, atrophy, and gliosis or mineralization (see Fig. 14-1B).

CLINICAL FEATURES Seizures, abnormalities of motor function, and decreased level of consciousness are the hallmarks of injury after a prolonged, partial type of insult. Seizures may be difficult to control during the first days of life. At the most severe end of the spectrum, there may be cerebral edema, which becomes maximal approximately 3 days after the insult and correlates closely with death or major long-term sequelae. If infants survive beyond the first week, the clinical features tend to stabilize, and there may be gradual improvement. Long-term sequelae include intellectual impairment, spastic cerebral palsy, and epilepsy.

FIGURE 14-1. A, Computed tomography (CT) of a severely asphyxiated term newborn at 3 days of age. Notice the generalized low attenuation with total loss of gray and white matter differentiation. B, Multicystic encephalomalacia on late CT of a 6-month-old infant who had severe perinatal hypoxic-ischemic encephalopathy.

Hill / Hypoxic-Ischemic Cerebral Injury in the Newborn

Parasagittal Injury Hypoxic-ischemic injury involving principally the parasagittal regions may be considered a subtype of the cortical or subcortical pattern, and it follows prolonged, partial insults of lesser severity [Erdogan, 2001]. Recognition of this pattern clinically or by neuroimaging may be difficult.

and difficult to recognize clinically. Long-term sequelae include spastic quadriparesis. Specific deficits of language and visual-spatial perception may be a consequence of more posterior located parasagittal injury.

Central Injury: Thalami, Basal Ganglia, and Brainstem PATHOGENESIS

PATHOGENESIS The parasagittal cortex and subcortical regions, located in the superomedial regions of the cerebral convexities, are watershed zones of blood supply located between the territories supplied by the anterior, middle, and posterior cerebral arteries in term newborns. These watershed regions are particularly vulnerable to hypoxic-ischemic insult, which may result from only minor reduction of overall cerebral perfusion. The lesions are usually bilateral and relatively symmetric, and they are often more marked posteriorly.

DIAGNOSIS Edema localized to parasagittal regions may be recognized occasionally on CT, but this pattern is recognized more clearly on MRI (Fig. 14-2). The evolution of injury is otherwise similar to that of the more diffuse cortical or subcortical pattern.

CLINICAL FEATURES Clinical features of parasagittal injury in the term newborn include hypotonia and weakness of the proximal limbs (arms more than legs), which correlates with the topography of the lesion. However, motor abnormalities may be subtle

A

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B

A pattern of injury that affects predominantly central gray matter (i.e., thalami, basal ganglia, and brainstem nuclei) with relative preservation of cortex has been demonstrated in experimental studies involving fetal primates [Myers, 1975]. The posterior putamen and ventrolateral nucleus of the thalamus are particularly involved, and there may be injury to caudate nucleus and globus pallidus. In the primate model, this pattern of injury occurred as a consequence of acute, total asphyxia lasting approximately 10 to 20 minutes. In the human fetus, such a total insult (as was produced in the experimental animal studies) does not occur. Certain intrapartum events (e.g., uterine rupture, umbilical cord prolapse, placental abruption) may approximate the experimental conditions and produce an acute, but near-total insult associated with a pattern of central injury. However, because the insult is only near-total, a somewhat more prolonged insult may be necessary to cause irreversible injury. A significant factor in the pathogenesis of this pattern of injury is the high metabolic activity in affected regions of the newborn brain, such as the rapid differentiation of neurons and the transient, extensive glutamatergic innervation of the basal ganglia [Johnston et al., 2001]. In some instances, there may be injury to hippocampus, perirolandic cortex, and cerebellum [Khong et al., 2003; Sargent et al., 2004; Sie et al., 2000]. There is some variation in this pattern

FIGURE 14-2. A, T1-weighted magnetic resonance image of a term newborn with hemorrhagic infarction in bilateral parasagittal regions. B, Parasagittal cerebral injury. Coronal section of the hemisphere of a 6-month-old infant who had sustained a hypoxic-ischemic insult at term. Notice the cortical atrophy (pale area) in parasagittal region.

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depending on gestational age. In preterm infants, thalamic involvement is more marked than injury to putamen, whereas putaminal, hippocampal, or paracentral injury is more common at term [Barnes, 2001].

DIAGNOSIS Cranial ultrasonography may demonstrate a symmetric increase in echogenicity in deep structures [Eken et al., 1994] (Fig. 14-3A and B). However, ultrasound studies are relatively insensitive, and CT or MRI is superior for the demonstration of evolving central injury in thalami and basal ganglia. MRI is essential for recognition of injury to hippocampi, perirolandic cortex, and cerebellum. Assessment of brainstem injury remains difficult. MRI, especially diffusion-weighted studies, may be superior for identifying the timing of injury such as intrapartum or prior antenatal insult (see Fig. 14-3C-E) [Cowan et al., 2003].

CLINICAL FEATURES Initially, it may be difficult to distinguish between the different patterns of brain injury. After an acute, near-total insult, a

A

B

C

D

major feature often is prominent brainstem dysfunction, such as facial diplegia, gaze abnormalities, impaired sucking and swallowing, and in some instances, tongue fasciculations. Infants with extensive brainstem injury may require prolonged ventilatory support and subsequently may exhibit poor feeding, prominent drooling, and recurrent aspiration. Multiorgan involvement is observed less frequently, which may be related to the decreased opportunity for shunting of blood from less vital organs (e.g., diving reflex) because of the shorter duration of the insult. However, in many instances, there is hypoxic-ischemic insult to other organs. The long-term sequelae include spastic and extrapyramidal cerebral palsy with choreoathetosis, dystonia, rigidity and axial hypotonia, and brainstem dysfunction with chewing, sucking, and swallowing difficulties (often requiring gastrostomy tube feeding). Seizures may occur that reflect concomitant, although lesser cortical injury. The extrapyramidal features may not become apparent for several years and may appear to worsen with time, which is an atypical feature of cerebral palsy. If extrapyramidal features emerge early in the first year of life and are associated with disorders of vertical gaze and sensorineural hearing loss, kernicterus should be considered.

FIGURE 14-3. A, Coronal section of the brain of a term infant who died on the first postnatal day. Notice the hemorrhagic infarction in the thalami and basal ganglia. B, Coronal cranial ultrasound at 1 day of age. Notice the increased echoes in the region of the thalami and basal ganglia. C, Axial computed tomography (CT) of a 3-day-old term infant who sustained acute, near-total hypoxic-ischemic insult. Notice the bilateral hypodensities in the thalami and basal ganglia. D, T1-weighted magnetic resonance image of the 10-day-old term newborn shown in Figure 14-3C. Notice the bilateral signal abnormalities in the thalami and basal ganglia. E, Axial CT of a 5-year-old child who sustained acute, near-total insult at term. Notice the cystic lesions and atrophy in the region of central gray matter.

E

Hill / Hypoxic-Ischemic Cerebral Injury in the Newborn

There is often brainstem dysfunction with severe dysphagia, drooling, and feeding difficulties, which in some instances may require placement of a gastrostomy tube. Head growth is often relatively preserved, although there may be some decrease in head growth. Microcephaly develops only in a minority of children, which presumably reflects the topography of injury [Basheer et al., 2004a]. Preliminary evidence suggests that the development of epilepsy in later childhood appears to correlate with evidence on MRI of injury to hippocampi or perirolandic cortex [Basheer et al., 2004b].

Premature Infant In addition to antenatal and intrapartum insult, the preterm newborn is at particular risk for postnatal hypoxic-ischemic insult because of the high incidence of cardiorespiratory problems, such as respiratory distress syndrome, patent ductus arteriosus, apnea, and bradycardia. These problems and their management often result in episodes of systemic hypotension or hypertension that in the context of ineffective cerebrovascular autoregulation most probably results in fluctuations in cerebral perfusion. The fragile vasculature of the subependymal germinal matrix, when exposed to such fluctuations of cerebral perfusion, places the preterm infant at high risk for germinal matrix or intraventricular hemorrhage and its complications. Decreases in cerebral perfusion may result in ischemic lesions, such as periventricular leukomalacia or, if more severe, diffuse injury. Germinal matrix or intraventricular hemorrhage is not a major focus of this chapter, but periventricular hemorrhagic infarction that is considered a consequence of venous hypertension is addressed in greater detail later together with periventricular leukomalacia. The major patterns of hypoxicischemic injury in preterm newborns are summarized in Table 14-4.

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frontal parietal and occipital regions. The incidence of periventricular hemorrhagic infarction correlates closely with gestational age; approximately one third of cases occur in infants with birth weights between 500 and 700 grams. Careful neuropathologic studies [Takashima et al., 1986], Doppler blood flow studies [Dean and Taylor, 1995; Taylor, 1995], and MRI [Counsell et al., 1999] have demonstrated that periventricular hemorrhagic infarction is not simply a direct extension of germinal matrix or intraventricular hemorrhage into adjacent parenchyma but rather represents a lesion caused by venous infarction resulting from obstruction of flow in the terminal vein by a large, ipsilateral germinal matrix hemorrhage. Because intraventricular hemorrhage into the germinal matrix plays a major role in the pathogenesis of periventricular hemorrhagic infarction, the major risk factors for germinal matrix intraventricular hemorrhage [Roland and Hill, 2003] are also relevant for periventricular hemorrhagic infarction. The infarction is located in the periventricular white matter, a region that is also at high risk for ischemic injury because of poor arterial perfusion (see “Periventricular Leukomalacia”). Injury in the periventricular regions may be a result of combined venous infarction and arterial ischemia. These lesions are best visualized on MRI.

DIAGNOSIS Periventricular hemorrhagic infarction may be visualized by cranial ultrasonography [Bass et al., 1999], CT, or MRI [De Vries et al., 1999] as a fan-shaped hemorrhagic lesion in periventricular white matter that usually is associated with a large germinal matrix hemorrhage. The lesion is often unilateral (Fig. 14-4). An infant may present with “congenital hemiplegia” and be found to have had a periventricular hemorrhagic infarction in the newborn period [Takanashi et al., 2003].

CLINICAL FEATURES

Periventricular Hemorrhagic Infarction PATHOGENESIS Preterm newborns who sustain large germinal matrix hemorrhage with or without intraventricular hemorrhage often develop unilateral ischemic hemorrhagic lesions in adjacent periventricular white matter. Such lesions often have a characteristic fan- or wedge-shaped appearance and may be localized in the dorsal and lateral regions adjacent to the frontal horns of the lateral ventricles or, if more extensive, to

The clinical correlates include hemiparesis (usually with more marked involvement of the lower extremities), or more commonly, asymmetric quadriparesis as a consequence of concomitant ischemic injury to the contralateral hemisphere as part of a more diffuse cerebral insult. Asymmetric myelination of the posterior limb of the internal capsule at term on MRI has been reported to be predictive of development of hemiplegia [De Vries et al., 1999]. Cognitive impairment is common, and the severity varies [Guzzetta et al., 1986; Volpe, 2001a].

TABLE 14-4 Patterns of Hypoxic-Ischemic Injury in Premature Infants: Clinicopathologic Correlations INJURY PATTERN Periventricular hemorrhagic infarction Periventricular leukomalacia

ANATOMIC TOPOGRAPHY Unilateral periventricular white matter, often with germinal matrix hemorrhage Bilateral periventricular white matter (motor, optic, and acoustic radiations)

NEUROLOGIC FEATURES Newborn

Long Term

Hypotonia

Hemiparesis, quadriplegia, intellectual deficits

Abnormal tone and weakness in lower limbs

Spastic diplegia, visual impairment, intellectual deficits

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In preterm newborns, there is a predilection for hypoxicischemic injury to the periventricular white matter, a border zone of arterial perfusion located between the ventriculofugal choroidal arteries and the ventriculopedal penetrating branches of the anterior, middle, and posterior cerebral arteries [Volpe, 2001a]. The most common locations for periventricular leukomalacia are the watershed zones in the posterior white matter, the occipital radiations at the trigones of the lateral ventricles, and the anterior white matter around the foramen of Monro and at the angles of the an-

terior horns of the lateral ventricles. Relative sparing of the cerebral cortex in the preterm newborn is considered to relate to the rich interarterial anastomoses between terminal branches of the anterior, middle, and posterior cerebral arteries in the preterm brain. However, MRI studies have demonstrated a reduced volume of cortex in association with periventricular leukomalacia [Inder et al., 1999a]. In addition to the effects of the immature periventricular vascular anatomy, there may be more diffuse white matter injury related principally to the intrinsic vulnerability of the differentiating immature oligodendrocytes in this region. The mechanism of oligodendroglial cell loss appears to involve necrosis and apoptosis [Back, 2001; Back et al., 2002; Kinney and Back, 1998]. Other factors that are considered important in the pathogenesis include ineffective cerebrovascular autoregulation of the preterm brain and the limited vasodilatory capacity within the periventricular white matter in response to hypoxic-ischemic insult [Volpe, 2001a]. Systemic hypotension, a common occurrence in the preterm newborn caused by cardiopulmonary dysfunction, results in decreased cerebral perfusion. Animal studies suggest a role for inflammatory mediators, such as endotoxins and cytokines [Bell et al., 2004; Nelson and Willoughby, 2000; Shalak et al., 2002]. Clinical studies and studies of placental pathology document an increased incidence of periventricular leukomalacia in infants born to mothers with chorioamnionitis [Jensen et al., 2003; Kadhim et al., 2003; Yoon et al., 2003] and support a pathogenetic role for inflammatory mediators. However, the precise mechanisms by which these inflammatory mediators contribute to brain injury are not understood. The long-term neuropathologic features of white matter injury include small foci of gliosis and reduction in myelin, which result in compensatory ventricular dilation and multicystic encephalomalacia when cerebral hypoperfusion is more extensive and result in injury to periventricular white matter and other structures. It is important to recognize that cystic periventricular leukomalacia is declining and that the true extent of white matter injury might have been under-

A

B

FIGURE 14-4. Periventricular hemorrhagic venous infarction is demonstrated by coronal ultrasound of a preterm newborn at 1 day of age. Notice the germinal matrix–intraventricular hemorrhage and unilateral fan-shaped area of increased echoes in the periventricular white matter.

Periventricular Leukomalacia PATHOGENESIS

FIGURE 14-5. A, Periventricular leukomalacia is demonstrated by parasagittal cranial ultrasound of a preterm infant at 1 day of age. Notice the increased echogenicity in the periventricular white matter adjacent to the trigone of lateral ventricle (arrows). B, In the scan obtained at 6 weeks of age, notice the cystic lesions in the regions of previously increased echoes.

Hill / Hypoxic-Ischemic Cerebral Injury in the Newborn

represented in the past by cranial ultrasound [Hamrick et al., 2004]. The clinical significance of this lies in the fact that even small foci of white matter abnormalities on MRI may disturb development of white matter tracts and result in abnormal neurodevelopment [Huppi et al., 2001; Miller et al., 2002b].

DIAGNOSIS In many instances, the diagnosis of severe periventricular leukomalacia may be accomplished with serial cranial ultrasonography. Initially, in the days after the insult, there may be increased (often transient) periventricular echogenicity adjacent to the superolateral aspects of the ventricles. After severe insult, cystic degeneration occurs over approximately 2 to 4 weeks. After 2 to 3 months, ventricular dilation often occurs as a consequence of collapse of the cysts and overall white matter atrophy, and in severe cases, there is irregular scalloping of the ventricular walls. However, even when severe cystic periventricular leukomalacia eventually occurs, there may be a normal sonographic appearance in the first week of life. The increased periventricular echogenicity often observed on early scans may not be seen on subsequent serial scans (Fig. 14-5). The role of CT and MRI for diagnosis of the early stages of periventricular leukomalacia in the preterm newborn has not been established in detail. Late stages of periventricular leukomalacia appear on CT as ventriculomegaly with irregular ventricular walls and deep sulci abutting directly onto the ependymal surface due to loss of interposed white matter (Fig. 14-6A). However, MRI is considered the technique of choice for the detection of periventricular leukomalacia after 2 to 4 months of age because it can demonstrate more diffuse, abnormal signals in white matter that may not be detectable by ultrasonography or CT (see Fig. 14-6B) [Inder et al., 2003a]. Diffusion-weighted MRI

A

B

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may demonstrate periventricular leukomalacia in the early days of life [Inder et al., 1999a].

CLINICAL FEATURES The neurologic manifestations of periventricular leukomalacia in the neonatal period vary, and their recognition depends on the ability to perform an adequate neurologic examination, which may be difficult in the presence of complex life-support apparatus. Brain injury is often multifactorial, such as a consequence of intraventricular hemorrhage, post-hemorrhagic hydrocephalus, periventricular hemorrhagic infarction, or hypoxic-ischemic insult to gray matter. When periventricular leukomalacia is the predominant lesion, abnormalities of tone and power in the lower extremities may be recognized, and long-term sequelae include motor dysfunction, usually spastic diplegia or quadriplegia, with more severe involvement of the lower limbs [Cioni et al., 1997]. These clinical abnormalities reflect the anatomic location of the lesion in that fibers from motor cortex that subserve lower limb function descend medially in the periventricular white matter in proximity to the lateral ventricles, a location which is most vulnerable to periventricular leukomalacia. Injury to the optic radiations may result in visual impairment [Cioni et al., 1996]. More diffuse white matter or cortical injury is associated with more widespread neurologic dysfunction, which often includes behavioral disturbances, intellectual deficits, and seizures. An additional mechanism by which periventricular white matter lesions contribute to overall brain dysfunction is through interference with the migration of subplate neurons from the subpial marginal zone to the cortex, thereby producing aberrant cortical synaptic connections that may explain in part the high incidence of cognitive and attention-deficit disorders observed in children born prematurely (Fig. 14-7) [Volpe, 1996].

FIGURE 14-6. A, Computed tomography of a 6-year-old child born prematurely who developed spastic diplegia and visual impairment. Notice the reduction in the quantity of periventricular white matter posteriorly (black arrows) and the deep prominent sulci (white arrow). B, T1-weighted magnetic resonance image of the patient shown in Figure 14-1A. Notice the decreased quantity of white matter posteriorly (arrows) and deep sulci.

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FIGURE14-7. Coronal ultrasound of a preterm infant after hypoxic-ischemic insult. Notice the resolving intraventricular hemorrhage (i.e., clot in right lateral ventricle) and ventriculomegaly, the right porencephalic cyst, and left-sided cystic periventricular leukomalacia.

MANAGEMENT Newborns with hypoxic-ischemic encephalopathy, especially when severe, frequently have transient dysfunction of multiple organs other than brain, such as the heart, lungs, kidneys, and liver. Although accurate diagnosis and specific management of these systemic problems is important, this section addresses only prevention and strategies to minimize ongoing brain injury.

Prevention In most newborns with neonatal hypoxic-ischemic encephalopathy, the major insult occurs during labor and delivery, which underscores the importance of close fetal surveillance and prompt recognition of maternal risk factors through monitoring of the high-risk fetus during pregnancy, labor, and delivery [Stevenson et al., 2003; Volpe, 2001a]. This important topic falls largely within the realm of obstetrics, but a consensus statement by the American College of Obstetricians and Gynecologists and Academy of Pediatrics (ACOG/AAP) addresses some of these issues [ACOG/AAP, 2003].

Supportive Care Maintenance of Adequate Ventilation Although the primary hypoxic-ischemic cerebral insult often occurs before delivery, aggressive resuscitation and prevention of ongoing hypoxic insult is important. Traditionally, ventilation with oxygen is part of resuscitation in the delivery room. However, the routine use of oxygen is undergoing review because of concerns about potential toxic effects, such as acute lung injury, bronchopulmonary dysplasia, and retinopathy of prematurity [Bloom and Yost, 2004; Niermeyer and Vento, 2004; Saugstad, 2004]. Some data suggest that resuscitation with room air may be as effective as 100% oxygen regarding the severity of sub-

sequent encephalopathy. In this context, preliminary data demonstrate reduced oxygen free radical formation in newborns resuscitated with room air [Saugstad, 2001; Vento et al., 2002]. However, comparison of long-term outcomes is required before significant changes in resuscitation techniques can be recommended [Saugstad et al., 2003, 2004]. Another aspect of ventilation worthy of consideration is the possible occurrence of hypocarbia or hypercarbia; both may affect cerebral perfusion. The effects of vigorous hyperventilation (e.g., hypocarbia) may be associated with reduction in cerebral blood flow, especially in the context of impaired cerebrovascular autoregulation in critically ill newborns. However, increased cerebral perfusion associated with hypercarbia may contribute to increased risk of intracranial hemorrhage. The effects of newer ventilation strategies (e.g., high-frequency ventilation, inspired nitric oxide) on cerebral injury have not been fully evaluated [Schreiber et al., 2003].

Maintenance of Adequate Cerebral Perfusion The occurrence of impaired cerebrovascular autoregulation in preterm newborns and in critically ill term newborns (i.e., the pressure-passive relationship between systemic blood pressure and cerebral perfusion) adds critical importance to the rapid restoration and maintenance of adequate cardiac output [Volpe, 2001a]. This issue is particularly important in the extended management of preterm newborns who may develop episodes of sepsis with hypotension, patent ductus arteriosus with possible steal from the cerebral circulation, and apneic episodes with bradycardia, all of which may adversely influence cerebral perfusion. It is equally important to avoid systemic hypertension, which increases the risk of intracranial hemorrhage, especially in preterm newborns.

Restoration of Metabolic Homeostasis Restoration of metabolic homeostasis involves the provision of various substances (e.g., oxygen, glucose) and the correction of abnormalities (e.g., acidosis) that impair the capacity of cells to use these substances. Debate continues concerning optimal blood glucose levels in newborns who have sustained hypoxic-ischemic insults. Some infants are at higher risk for hypoglycemia, such as infants with reduced hepatic glycogen stores, infants who are preterm, infants with intrauterine growth retardation, infants of diabetic mothers who have impaired glucose metabolism, and infants with hypothermia or hyperthermia or infection who have increased glucose consumption. Experimental studies have demonstrated that hypoglycemia is associated with a twofold to threefold increase in cerebral blood flow, thereby possibly increasing the risk for hemorrhagic injury [Chiu et al., 1998]. There may be a synergistic detrimental effect between hypoglycemia and hypoxia-ischemia. The recommendation is to maintain normoglycemia [Stevenson et al., 2003; Vannucci and Vannucci, 2001].

Control of Seizures Neonatal seizures are discussed in more detail in Chapter13. However, because seizures are a major feature of moderate

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or severe hypoxic-ischemic encephalopathy, a brief discussion of seizures is warranted. Seizures may compromise ventilation and result in increased blood pressure, which may cause increased cerebral blood flow and intracranial hemorrhage if cerebrovascular autoregulation is impaired. Persistent seizures may result in reduced cerebral glucose and high-energy phosphate substrates and accumulation of toxic excitatory amino acids [Miller et al., 2002c; Volpe, 2001a]. Aggressive treatment to control seizures is indicated to reduce the potential for additional brain injury. There is concern that the long-term use of antiepileptic drugs (e.g., phenobarbital) may have detrimental effects on subsequent behavior and learning, and they have been shown to cause neuronal apoptosis in animal models [Jevtovic-Todorovic et al., 2003]. Initial management must include the correction of hypoglycemia or other metabolic derangements, followed by antiepileptic drug treatment. Careful monitoring for respiratory failure, hypotension, and cardiac arrhythmias is essential. Studies on the efficacy of anticonvulsants for treatment of neonatal seizures suggest that phenobarbital and phenytoin are equally effective. However, seizures are controlled in less than 50% of neonates when either drug is administered alone, whereas control is achieved in approximately 60% with combined therapy [Painter and Alvin, 2001; Painter et al., 1999]. Fosphenytoin, a phosphorylated prodrug of phenytoin that has fewer cardiovascular and cutaneous side effects, has received some attention. Concern has been raised regarding the conversion of this prodrug to phenytoin in young infants, and doses may need to be individualized [Kriel and Cifuentes, 2001; Takeoka et al., 1998]. In refractory cases, intermittent doses of benzodiazepines (e.g., lorazepam) are often used, or continuous midazolam infusion may be helpful. Midazolam may produce a burst-suppression EEG pattern that must be considered when EEG monitoring is being used as a prognostic indicator in severe hypoxic-ischemic encephalopathy. Maintenance therapy with phenobarbital and possibly with phenytoin is usually individualized and guided by blood levels. The optimal duration of antiepileptic therapy is governed by the likelihood of seizure recurrence, which is often difficult to predict [Scher, 1997]. Factors that may assist with decisions concerning the duration of treatment include the severity of hypoxic-ischemic encephalopathy and the persistence of neurologic and EEG abnormalities. Concerns about potential deleterious effects of antiepileptic drugs make it important to aim for a brief duration of treatment when possible [Volpe, 2001a].

Neuroprotective Strategies

Control of Brain Swelling

Accurate prognosis after perinatal hypoxic-ischemic insult in the newborn is difficult to establish because of our inability to establish precisely the severity of the hypoxic-ischemic insult and the location and extent of cerebral injury [Allen and Sobel, 2004]. Traditionally, many parameters that have been used for intrapartum or early postpartum assessment, such as abnormalities of fetal heart-rate monitoring, Apgar scores, or cord blood gases, should be considered only as clinical indicators that a hypoxic-ischemic insult has occurred [Nelson, 2003b]. Abnormalities of these parameters alone should not be equated with cerebral injury.

Cerebral edema may be recognized on brain imaging or, if severe, by clinical examination, such as identification of a bulging anterior fontanel. In such instances, there is no convincing evidence that the control of cerebral edema improves the ultimate neurologic outcome of asphyxiated newborns if adequate cerebral perfusion is maintained. Many infants with hypoxic-ischemic encephalopathy have inappropriate secretion of antidiuretic hormone, and careful monitoring of fluid intake and output, body weight, and serum electrolytes is important to avoid fluid overload.

Several experimental methods of brain preservation have been proposed as potential treatment for newborns with hypoxic-ischemic encephalopathy. Some substances, such as calcium channel blockers, monosialogangliosides, and lazaroids (21-aminosteroids), are being studied, principally in laboratory animals. Among the excitatory amino acid receptor inhibitors [Johnston et al., 2001], magnesium sulfate has promise for reducing the severity of hypoxicischemic cerebral injury in immature animals. A multicenter study involving human newborns is in progress. Preliminary data on the use of oxygen free radical inhibitors in human newborns (e.g., allopurinol, oxypurinol) have shown encouraging results. The most promising approach to brain protection is hypothermia. Hypothermia during and after experimental cerebral ischemia is associated with potent, dose-related, long-lasting neuroprotection in adult and newborn animals, presumably by the reduction of harmful oxygen free radicals and excitatory neurotransmitters, by improving function of the blood-brain barrier, and by prevention of proteolysis [Laptook and Corbett, 2002; Volpe, 2001b]. Trials evaluating human newborns who have had neonatal encephalopathy have been completed and appear to demonstrate safety and relative efficacy [Gluckman et al., 2005; Inder et al., 2004; Shankaran et al., 2004]. In experimental animal studies, brief, mild-to-moderate hypothermia of 0.5 to 3 hours’ duration immediately after the insult had modest, inconsistent effects [Laptook et al., 1997, 1999], whereas prolonged cooling for up to 72 hours has been associated with more consistent protection, even when the onset of cooling was delayed [Compagnoni et al., 2002; Gunn et al., 1997]. It appears that hypothermia, when used soon after hypoxic-ischemic insult, may decrease delayed neuronal death, which may occur for several days after the insult. In addition to any direct benefit from cerebral cooling, this strategy may widen the window of opportunity for neuronal rescue by additional therapeutic interventions [Shankaran, 2002]. The parameters for optimal timing and depth of hypothermia to achieve successful neuroprotection in humans have not been established. Both whole body cooling and selective head cooling have relative benefits in preventing cortical injury, and they may prevent mortality and subsequent poor neurodevelopmental outcomes [Eicher et al., 2005a, 2005b; Gluckman et al., 2005; Inder et al., 2004; Jacobs et al., 2003].

PROGNOSIS

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After confirmation of a hypoxic-ischemic insult based on abnormalities of the parameters described previously, the most useful prognostic factors are the severity and duration of the acute neonatal encephalopathy and acute abnormalities identified on neuroimaging [Kaufman et al., 2003; Ment et al., 2002; Miller et al., 2004, 2005; Mercuri et al., 1999; Rutherford et al., 1998]. Infants who sustain acute, intrapartum hypoxic-ischemic insult of sufficient magnitude to result in long-term neurologic sequelae invariably exhibit an acute encephalopathy during the first days of life. One possible exception may occur after focal cerebral infarction, in which features of encephalopathy other than seizures are not always seen but can occur in up to 5% of cases [Ramaswamy et al., 2004; Sreenan et al., 2000]. Infants with mild encephalopathy usually do not develop long-term sequelae, whereas the most infants with severe encephalopathy die or develop major neurologic sequelae, such as spastic quadriparesis, mental retardation, epilepsy, cortical visual impairment, and hearing loss. Follow-up studies of infants with moderate neonatal encephalopathy who did not develop cerebral palsy have demonstrated that there was delay in school readiness at 5 years of age [Robertson et al., 1989]. The likelihood of neurologic sequelae is increased twofold to fivefold when there are neonatal seizures. Seizures that occur early or are difficult to control are generally associated with a poorer prognosis. Brain injury has been detected using magnetic resonance spectroscopy when seizures are profound [Miller et al., 2002c]. The duration of encephalopathy correlates with outcome in that infants whose neurologic examinations were normal at discharge generally had good outcomes. The degree of neonatal encephalopathy on the first day of life is a useful marker for outcome [Miller et al., 2004]. As an adjunct to careful clinical neurologic assessment, the EEG and neuroimaging techniques that permit visualization of the topography of injury and the newer MRI modalities of diffusion tensor imaging and spectroscopy in preterm and term newborns may assist with prognosis.

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Miller SP, Latal B, Clark H, et al. Clinical signs predict 30-month neurodevelopmental outcome after neonatal encephalopathy. Am J Obstet Gynecol 2004;190:93. Miller SP, Newton N, Ferriero D, et al. Predictors of 30-month outcome following perinatal depression: Role of proton MRS and socioeconomic factors. Pediatr Res 2002a;52:71. Miller SP, Ramaswamy V, Michelson D, et al. Patterns of brain injury in term neonatal encephalopathy. J Pediatr 2005;146:453. Miller SP, Vigneron DB, Henry RG, et al. Serial quantitative diffusion tensor MRI of the premature brain: Development in newborns with and without injury. J Magn Reson Imaging 2002b;16:621. Miller SP, Weiss J, Barnwell A, et al. Seizure-associated brain injury in term newborns with perinatal asphyxia. Neurology 2002c;58:542. Mujsce DJ, Christensen MA, Vannucci RC. Cerebral blood flow and edema in perinatal hypoxic-ischemic brain damage. Pediatr Res 1990;27:450. Myers RE. Four patterns of perinatal brain damage and their condition of occurrence in primates. In: Meldrum BS, Marsden CD, eds. Advances in neurology, Vol. 10. New York: Raven Press, 1975. Nagdyman N, Grimmer I, Scholz T, et al. Predictive value of brain-specific proteins in serum for neurodevelopmental outcome after birth asphyxia. Pediatr Res 2003;54:270. Nelson KB. Can we prevent cerebral palsy? N Engl J Med 2003a;349:1765. Nelson KB. Defining hypoxic-ischemic birth events. Dev Med Child Neurol 2003b;45:71. Nelson KB, Ellenberg JH. Antecedents of cerebral palsy. Multivariate analysis of risk. N Engl J Med 1986;315:81. Nelson KB, Leviton A. How much of neonatal encephalopathy is due to birth asphyxia? Am J Dis Child 1991;145:1325. Nelson KB, Willoughby RE. Infection, inflammation and the risk of cerebral palsy. Curr Opin Neurol 2000;13:133. Niermeyer S, Vento M. Is 100% oxygen necessary for the resuscitation of newborn infants? J Matern Fetal Neonatal Med 2004;15:75. Niijima S, Levene MI. Post-asphyxial encephalopathy in a preterm infant. Dev Med Child Neurol 1989;31:395. Novotny EJ Jr, Tharp BR, Coen JW, et al. Positive rolandic sharp waves in the EEG of the premature infant. Neurology 1987;37:1481. Painter MJ, Alvin J. Neonatal seizures. Curr Treat Options Neurol 2001;3:237. Painter MJ, Sher MS, Stein AD, et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med 1999;341:485. Pasternak JF, Gorey MT. The syndrome of acute near-total intrauterine asphyxia in the term infant. Pediatr Neurol 1998;18:391. Perlman JM. Markers of asphyxia and neonatal brain injury. N Engl J Med 1999;29:341. Perlman JM, Risser R. Can asphyxiated infants at risk for neonatal seizures be rapidly identified by current high-risk markers? Pediatrics 1996;97:456. Perlman JM, Rollins N. Surveillance protocol for the detection of intracranial abnormalities in premature newborns. Arch Pediatr Adolesc Med 2000:154:822. Phelan JP, Ahn MO, Korst L, et al. Intrapartum fetal asphyxial brain injury with absent multiorgan system dysfunction. J Matern Fetal Med 1998;7:19. Ramaswamy V, Miller SP, Barkovich AJ, et al. Perinatal stroke in term infants with neonatal encephalopathy. Neurology 2004;62:2088. Robertson CMT, Finer NN. Long-term follow-up of term neonates with perinatal asphyxia. Clin Perinatol 1993;20:483. Robertson CMT, Finer NN, Grace MGA. School performance of survivors of neonatal encephalopathy associated with birth asphyxia at term. J Pediatr 1989;114:753. Robertson RL, Ben-Sira L, Barnes PD, et al. MR line-scan diffusion-weighted imaging of term neonates with perinatal brain ischemia. AJNR Am J Neuroradiol 1999;20:1658. Roelants-van Rijn AM, Groenendaal F, Beek FJ, et al. Parenchymal brain injury in the preterm infant: Comparison of cranial ultrasound, MRI and neurodevelopmental outcome. Neuropediatrics 2001;32:80. Roland EH, Hill A. Germinal matrix-intraventricular hemorrhage in the premature newborn: Management and outcome. Neurol Clin 2003;21:833. Roland EH, Poskitt K, Rodriquez E, et al. Perinatal hypoxic-ischemic thalamic injury. Ann Neurol 1998;44:161. Rutherford M, Counsell S, Allsop J, et al. Diffusion-weighted magnetic resonance imaging in term perinatal brain injury: A comparison with site of lesion and time from birth. Pediatrics 2004;114:1004.

Rutherford MA, Pennock JM, Counsell SJ, et al. Abnormal magnetic resonance signal in the internal capsule predicts poor neurodevelopmental outcome in infants with hypoxic-ischemic encephalopathy. Pediatrics 1998;102:323. Sargent MA, Poskitt KJ, Roland EH, et al. Cerebellar vermian atrophy after neonatal hypoxic-ischemic encephalopathy. AJNR Am J Neuroradiol 2004;25:1008. Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress: A clinical and electroencephalographic study. Arch Neurol 1976;33:969. Saugstad OD. Resuscitation of newborn infants with room air or oxygen. Semin Neonatal 2001;6:233. Saugstad OD. The role of oxygen in neonatal resuscitation. Clin Perinatal 2004;31:431. Saugstad OD, Ramji S, Irani SF, et al. Resuscitation of newborn infants with 21% or 100% oxygen: Follow up at 18 to 24 months. Pediatrics 2003;112:296. Saugstad OD, Ramji S, Vento M. Resuscitation of depressed newborn infants with ambient air or pure oxygen: A meta-analysis. Biol Neonate 2004;87:27. Schreiber MD, Gin-Mestan K, Marks JD, et al. Inhaled nitric oxide in premature infants with the respiratory distress syndrome. N Engl J Med 2003;349:2099. Shah P, Riphagen S, Beyenne J, et al. Multiorgan dysfunction in infants with post-asphyxial hypoxic-ischemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 2004a;89:F152. Shah S, Tracy M, Smyth J. Postnatal lactate as an early predictor of short-term outcome after intrapartum asphyxia. J Perinatol 2004b;24:16. Shalak LF, Laptook AR, Jafri HS, et al. Clinical chorioamnionitis, elevated cytokines and brain injury in term infants. Pediatrics 2002;110:673. Shalak LF, Laptook AR, Velaphi SC, et al. Amplitude-integrated electroencephalography coupled with an early neurologic examination enhances prediction of term infants at risk for persistent encephalopathy. Pediatrics 2003;111:351. Shankaran S. The postnatal management of the asphyxiated term infant. Clin Perinatol 2002;29:675. Shankaran S, Laptook AR, Ehrenkranz RA, et al. Safety of whole body hypothermia for hypoxic-ischemic encephalopathy (HIE). Pediatr Res 2004;55:582A. Scher MS. Seizures in the newborn infant: Diagnosis, treatment and outcome. 1997;24:735. Scher MS, Aso K, Beggarly ME et al. Electrographic seizures in preterm and full-term neonates: Clinical correlates, associated brain lesions, and risk for neurologic sequelae. Pediatrics 1993;91:128. Scher MS, Painter MJ, Bergman I, et al. EEG diagnosis of neonatal seizures: Clinical correlations and outcome. Pediatr Neurol 1989;5:17. Shewman DA. What is a neonatal seizure? Problems in definition and quantification for investigation and clinical purposes. J Clin Neurophysiol 1990;7:315. Shi Y, Pan F, Li H, et al. Role of carbon monoxide and nitric oxide in newborn infants with postasphyxial hypoxic-ischemic encephalopathy. Pediatrics 2000;106:1447. Sie LT, van der Knapp MS, van Wezel-Meijler G, et al. Early MR features of hypoxic-ischemic brain injury in neonates with periventricular densities on sonograms. AJNR Am J Neuroradiol 2000;21:852. Sinclair DB, Campbell M, Byrne P, et al. EEG and long-term outcome of term infants with neonatal hypoxic-ischemic encephalopathy. Clin Neurophysiol 1999;110:655. Sreenan C, Bhargava R, Robertson CMT. Cerebral infarction in the term newborn: Clinical presentation and long-term outcomes. J Pediatr 2000: 137:351. Stanley E, Blair E, Albeman E. Clinics in Developmental Medicine, No. 151. Cerebral palsies: Epidemiology and causal pathways. London: MacKeith Press, 2000. Stevenson DK, Benitz WE, Sunshine P. Fetal and neonatal brain injury: Mechanisms, management and the risks of practice, 3rd ed. Cambridge: Cambridge University Press, 2003. Stockard JE, Stockard JJ, Kleinberg F, et al. Prognostic value of brainstem auditory evoked responses in neonates. Arch Neurol 1983;40:360. Takanashi J, Barkovich AJ, Ferriero DM, et al. Widening spectrum of congenital hemiplegia: Periventricular venous infarction in term neonates. Neurology 2003;61:531.

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CHAPTER 15

Pathophysiology of Neonatal Hypoxic-Ischemic Brain Injury Faye S. Silverstein, Claire McLean, and Donna M. Ferriero

In term infants with neonatal encephalopathy, hypoxiaischemia predominates as the major cause of subsequent neurologic disability. The pivotal initiating event in the pathogenesis of hypoxic-ischemic brain injury is a sustained profound reduction in cerebral blood flow. The adverse consequences of cerebral ischemia include deprivation of energy substrates and oxygen and an inability to clear accumulated, potentially toxic metabolites. Although linear flow charts cannot accurately convey the complex cascade of interrelated molecular pathways that lead to hypoxicischemic neurodegeneration, Figure 15-1 highlights some of the critical mechanisms. Classic physiologic studies of neonatal hypoxia-ischemia focused on understanding the factors that regulate cerebral

blood flow, particularly the maturational differences in the regulation of cerebral blood flow and metabolism and the ontogeny of cerebral energy metabolism. In the past 20 years, considerable information has emerged about the cellular and molecular consequences of cerebral hypoxia-ischemia and the molecular events that lead to neuronal cell death. The underlying rationale for this scientific focus is the hope that a better understanding of the basic molecular mechanisms of neurodegeneration may provide ways to modulate these events pharmacologically, to limit their adverse consequences, and to protect the brain from irreversible damage. A complementary focus that has emerged—and will likely become particularly important in the setting of neonatal brain injury—is the delineation of the intrinsic neuronal mech-

Hypoxic-ischemic insult

Decrease in ATP production Tissue acidosis Membrane depolarization

Release of neurotransmitters Suppression of glutamate re-uptake Increased synaptic glutamate

Mitochondrial stress Loss of Ca2+ buffering Pro-apoptotic signaling

EAA receptor activation

NMDA

AMPA

Metabotropic

Increased Na+, Ca2+ influx Release of Mg2+ block of ion channel

Membrane depolarization Inositol triphosphate release

Increased Ca2+ influx Release of sequestered Ca2+ Activation of multiple intracellular enzymes

Phospholipases

Nitric oxide synthases

NO production Generation of peroxynitrites Oxidative injury

Proteases

FIGURE 15-1. This diagram illustrates some of the key molecular mechanisms that contribute to hypoxic-ischemic neurodegeneration. AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; ATP, adenosine triphosphate; NMDA, N-methyl-D-aspartates; NO, nitric oxide.

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anisms of adaptation and repair after hypoxic-ischemic brain injury. This chapter provides an overview of the basic mechanisms of neurodegeneration that appear to be particularly important for understanding neonatal hypoxicischemic brain injury. A major rationale for studies in neonatal models of acute brain injury is that pathophysiologic mechanisms of injury and repair may differ substantially between the immature and the adult brain and that immature animal models may more closely replicate human neonatal neuropathology. Although basic mechanisms of neurodegeneration are shared across all age groups, there are many examples of agerelated differences in the pathophysiology of brain injury in clinical practice and in experimental animal models; these are highlighted throughout the chapter. Despite the traditional view of greater resistance to central nervous system (CNS) injury in the neonate because of lower metabolic demands and the greater plasticity of the developing CNS, at specific stages of brain maturation, susceptibility to hypoxia-ischemia may be amplified. Clinical and experimental data have demonstrated that specific brain structures and neural cells in the developing brain may be selectively vulnerable to hypoxic-ischemic injury [McQuillen and Ferriero, 2004]. One of the bestcharacterized examples is the increased vulnerability of immature oligodendroglia to hypoxic-ischemic injury, which is evident clinically in premature infants and which has been successfully demonstrated in fetal and neonatal animal models [Back et al., 2002]. Risk of injury to the immature brain may be heightened by certain therapeutic interventions; this risk stems from the complex roles that pivotal molecular mediators of hypoxicischemic injury (e.g., glutamate, calcium) play in brain development. For example, some studies have provided compelling experimental evidence of maturational stagedependent deleterious effects of several commonly used antiepileptic drugs [Bittigau et al., 2002]. In the neonatal rat brain, several antiepileptic drugs cause massive neuronal apoptosis—an adverse response restricted to a narrow postnatal developmental period. This chapter reviews information about the pathophysiology of hypoxic-ischemic brain injury, integrates data obtained from experimental and clinical studies, and highlights mechanisms that are particularly relevant to understanding perinatal brain injury and repair. It is challenging to include discussions of all aspects of this vast topic, and several reviews can provide complementary perspectives (Gluckman et al., 2001; Jensen, 2002; Johnston, 2001; Vannucci and Hagberg, 2004; Volpe, 2001).

ANIMAL MODELS Studies using animal models have yielded many insights about the pathogenesis of neonatal hypoxic-ischemic brain injury. A brief overview of the range of large and small animal models that are used to study perinatal hypoxic-ischemic brain injury is provided, and some of the strengths and weaknesses of these models are discussed. All of these animal models share limitations. The hypoxicischemic insult is applied to otherwise healthy animals in a controlled and predictable setting, and often, no effort is

made to resuscitate the sickest animals, which are then excluded from subsequent analysis. In general, to obtain reproducible experimental data, efforts are made to minimize sources of variability (e.g., genetic background, gender, nutritional status) that could influence outcome but that are important to understand in the context of clinical practice. Precise correspondence of the maturational stage of the immature animal brain with that of the human neonate is difficult to establish. Although there has been a trend to incorporate functional outcome measures in addition to neuropathologic outcome evaluation, the relevance of these functional measures to understanding human brain development remains uncertain.

Large Animal Models A major strength of studies in larger animals (e.g., primates, sheep, piglets) is that it is possible to replicate many features of fetal pathophysiology and neonatal intensive care unit interventions in these species. The major limitations in studying large animal models of neonatal asphyxia include the great expense and the brief post-insult survival periods that are feasible in established models. Although important studies delineating the neuropathologic consequences of partial and near-total perinatal asphyxia had been performed in primates [Myers, 1975], a variety of complex constraints limits widespread applicability of primate models of perinatal hypoxic-ischemic brain injury. The pioneering work of Gluckman and Gunn to develop reproducible fetal sheep asphyxia models has been an important contribution to studies of perinatal neuropathology [Gunn et al., 1997]. In this model, the fetus is removed from the ewe’s uterus, vertebral-occipital anastomoses are ligated to restrict collateral circulation, and inflatable occluder cuffs are placed around the carotid arteries. Electroencephalographic (EEG) electrodes, vascular catheters, and ultrasonic flow probes can be placed before returning the fetus to the uterus. After a recovery period, reversible cerebral ischemia is induced by inflating the carotid cuffs, and cerebral ischemia is confirmed by the onset of an isoelectric EEG signal. Using this model, these investigators demonstrated that prolonged head cooling (performed with a cooling coil placed over the fetal scalp) conferred marked neuroprotection after fetal cerebral ischemia. Thoresen and colleagues have established a complementary neonatal piglet asphyxia model [Tooley et al., 2003]. Animals (weighing about 1500 grams) are studied on the first day of life; they are anesthetized, intubated and mechanically ventilated, and paralyzed with pancuronium bromide. Arterial and venous access and EEG monitoring are incorporated. After a 60-minute stabilizing period, animals are subjected to a hypoxic-ischemic insult by reducing the inspired oxygen concentration to 4% to 6% for 45 minutes; the suppression of the EEG amplitude is used to confirm cerebral ischemia. Animals are resuscitated, and after anesthesia, the piglets breathe spontaneously and survive for up to 72 hours. A neurologic scoring system has been devised, and functional and neuropathologic outcomes at 72 hours after the insult have been described. The combination of anesthesia and prolonged (24 hours) induced hypothermia are neuroprotective in this hypoxia-ischemia model [Tooley et al., 2003].

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Small Animal Models Neonatal rodent hypoxia-ischemia models have gained wide acceptance because of several practical considerations, including their relative simplicity, lower costs, feasibility of long-term survival, and availability of a substantial body of scientific data about normal rodent CNS development on which to build. Vannucci and colleagues developed a rodent model that has been widely used to study the pathophysiology of neonatal hypoxic-ischemic brain injury [Rice et al., 1981]. They selected 7-day-old (P7) rats, and this convention has been widely accepted. This age fortuitously coincides with several developmental stage–specific trends relevant to mechanisms of brain injury and repair (e.g., peak susceptibility to N-methyl-D-aspartate (NMDA) receptor neurotoxicity [McDonald et al., 1988] and to antiepileptic drug–induced apoptosis [Bittigau et al., 2002]). To elicit unilateral forebrain hypoxic-ischemic brain injury, animals are anesthetized, one carotid artery is ligated, and after a brief recovery period, animals are exposed to 8% oxygen for up to 3 hours; the anesthetic agent and the duration of hypoxia vary among laboratories using this model. Only the combination of ligation and hypoxia results in forebrain ischemia and, if prolonged, infarction; the duration of hypoxia determines the severity of tissue damage. Normal cerebral blood flow is restored in room air (i.e., this is a model of ischemia-reperfusion injury). The distribution of neuronal injury differs from that observed in middle cerebral artery occlusion models. In addition to ipsilateral cortical and dorsolateral striatal infarction, there is widespread hippocampal and thalamic damage. The original description of histopathology emphasized the distinctive vulnerability of immature white matter to ischemia, and subsequent studies demonstrated marked disruption of myelin basic protein immunostaining after lesioning [Liu et al., 2002]. Although this model does not precisely replicate human neonatal neuropathology, it can be used to generate relevant information about developmental stage specific mechanisms. It has not been technically feasible to determine the incidence or frequency of post-ischemic seizures. Chemically induced seizures do not amplify ischemic damage [Towfighi et al., 1999], but it is unclear whether spontaneously generated seizures influence progression of hypoxic-ischemic injury. There is variability in pathologic outcome (as seen in clinical practice in infants with seemingly comparable hypoxicischemic insults); however, experimental interventions that modulate injury can be reliably tested, if the experimental design incorporates adequate sample size. A similar lesioning procedure results in ipsilateral forebrain injury in P7-P10 mice [Ferriero et al., 1996]. However, in neonatal mice, there are marked strain differences in susceptibility to hypoxia-ischemia (i.e., the same lesioning conditions result in markedly different outcomes in animals of different genetic backgrounds). Although the specific genetic factors that underlie differential vulnerability are unknown, this phenomenon highlights the potential impact of intrinsic genetic differences on susceptibility to hypoxicischemic brain injury in a clinical context. Understanding these mechanisms is a high priority for research efforts. One study in neonatal mice raised another important theme. Johnston [2001] and others found that treatment with

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minocycline, which was neuroprotective in 7-day-old rats, worsened hypoxic-ischemic injury in 7- to 8-day-old mice [Tsuji et al., 2004]; evidence of this major species difference highlights the importance of conservative extrapolation from animal data to clinical practice.

CEREBRAL BLOOD FLOW AND METABOLISM Cerebral Blood Flow Disruption of cerebrovascular autoregulation has been implicated as an important factor in the pathophysiology of neonatal hypoxic-ischemic brain injury [Lou et al., 1979]. It is widely accepted that preterm infants have a “pressurepassive” cerebral circulation; however, term infants may remain at risk for impairment of cerebrovascular autoregulation [Boylan et al., 2000] and susceptibility to cerebral ischemia with fluctuations in systemic pressure. Several basic physiologic mechanisms may contribute to impaired autoregulation in the neonate. Increased expression of inducible and neuronal isoforms of nitric oxide synthase (iNOS and nNOS) may narrow the autoregulatory window [Hardy et al., 1999], and downregulation of prostaglandin receptors in response to high circulating prostaglandin levels may blunt the prostaglandin-mediated vasoconstrictive response to hypertension and thereby contribute to inappropriately increased cerebral blood flow [Chemtob et al., 1996]. In encephalopathic human newborns, functional abnormalities on amplitude-integrated EEG patterns are associated with impaired autoregulation [Pryds et al., 1990]. After an ischemic insult has occurred, the neonate remains at high risk for further damage in the acute recovery phase, because neonatal encephalopathy is often associated with major blood pressure fluctuations.

Energy Metabolism The standard methods for modeling ischemic brain injury in vitro in brain slices or cell cultures include exposure to the combination of oxygen and glucose deprivation. An inadequate supply of glucose or alternate substrates plays a pivotal role in hypoxic-ischemic neuronal cell death. Although overall metabolic demands are lower in the neonatal than in the adult brain, during periods of rapid brain growth, particularly the perinatal period, metabolic needs rise. The pattern of injury after hypoxia-ischemia can be explained in part on the basis of this metabolic demand [Azzarelli et al., 1996]; brain regions most susceptible to hypoxic-ischemic injury in the term infant (e.g., basal ganglia, thalamus) are the same regions that are most vulnerable to mitochondrial toxins. Normal cerebral glucose metabolism is discussed in Chapter 25. Brain development is associated with a transition from the ability to use glucose and ketones as energy substrates in the neonate to an absolute requirement for glucose in the adult. The immature brain can use lactate as an alternate fuel source to some degree, and the deleterious effects of lactate accumulation after hypoxia-ischemia therefore may be attenuated in the neonate compared with the adult. These factors illustrate the importance of understanding the use of glucose, lactate, and ketones in the newborn brain under

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normal and pathologic conditions [Vannucci and Vannucci, 2000]. It is unclear whether supplemental glucose is protective for hypoxic-ischemic brain injury in neonates. Several experiments have addressed this important issue, but study outcomes have varied, perhaps because of specific details of the experimental designs.

CELLULAR AND MOLECULAR MECHANISMS Excitotoxicity The excitatory amino acid glutamate is the major excitatory neurotransmitter in mammalian brain. Glutamate can activate a variety of excitatory amino acid receptors that are broadly classified based on their selective responses to specific agonists (e.g., NMDA, α-amino-3-hydroxy-5-methyl4-isoxazole propionic acid [AMPA], kainate) or their signaling mechanisms (i.e., ionotropic [ligand-gated ion channel] or metabotropic [G-protein coupled]). Excitatory amino acid neurotransmission plays a pivotal role in brain development and in learning and memory. A substantial body of data has emerged over the past 20 years documenting that overactivation of excitatory amino acid receptors (i.e., excitotoxicity) contributes to neurodegeneration in a broad range of acute and chronic neurologic disorders [Choi, 1988]. Most information about mechanisms of excitotoxicity comes from experimental studies (in animals and in vitro),

but studies in the human neonate have provided some evidence to support the hypothesis that hypoxic-ischemic brain injury disrupts brain glutamate metabolism. Analysis using magnetic resonance spectroscopy has revealed that neuronal glutamate metabolism is tightly coupled to cerebral glucose oxidation [Sibson et al., 1998a, 1998b], indicating that the cycle of glutamate release, re-uptake, and resynthesis is a major metabolic pathway in the brain [Magistretti et al., 1999]. Elevated levels of cerebrospinal fluid glutamate have been documented (by direct cerebrospinal fluid measurements and by proton magnetic resonance spectroscopy) in infants with severe hypoxic-ischemic injury [Pu et al., 2000]; cerebrospinal fluid levels of excitatory amino acids are directly proportional to the severity of clinical encephalopathy [Hagberg et al., 1993; Riikonen et al., 1992]. Two closely linked mechanisms contribute to ischemiainduced increases in synaptic glutamate: increased efflux from presynaptic nerve terminals and impaired re-uptake by glia and neurons. The initial increase in efflux is mediated by a calcium-dependent process through activation of voltagedependent calcium channels; later, calcium-independent efflux is thought to be mediated primarily by functional reversal of glutamate transporters. Removal of glutamate from the synaptic cleft depends primarily on energy-dependent glutamate transporters, which are predominantly glial. Figure 15-2 illustrates the complex relationships between neurons and glia in regulating synaptic glutamate metabolism [Magistretti et al., 1999]. Any pathophysiologic process that depletes energy supply (e.g., hypoxia-ischemia, hypoglycemia, pro-

FIGURE 15-2. The glutamatergic synapse. A, Glutamate is released by presynaptic neurons by a synaptosomal mechanism on excitation. Synaptically, glutamate acts at postsynaptic receptors until removed by energy-requiring astrocytic pumps. The astrocyte converts glutamate to glutamine, which can be taken up by the presynaptic neuron and converted back to glutamate. B, The astrocyte requires ATP and glucose to perform these functions. During hypoxiaischemia, the mechanism of glutamate re-uptake and recycling is impaired, and glutamate remains in the synapse, resulting in excitotoxicity. (From Magistretti PJ, Pellerin L, Rothman DL, et al. Energy on demand. Science 1999;283:496.)

Silverstein, McLean, and Ferriero / Pathophysiology of Neonatal Hypoxic-ischemic Brain Injury

longed seizures) will disrupt these mechanisms and result in increased synaptic glutamate accumulation [Choi, 1988]. In neonatal and adult animal models, overactivation of NMDA- and AMPA-type excitatory amino acid receptors contributes to ischemic neuronal injury [Barks and Silverstein, 1992; Choi et al., 1988]. Evidence has emerged that glutamate contributes to hypoxic-ischemic oligodendroglial damage, particularly in the immature brain [Follett et al., 2004]. The structure and function of the NMDA receptor channel complex is developmentally regulated [Danysz and Parsons, 1998; Haberny et al., 2002]. The receptor possesses multiple functional sites within it that recognize glutamate, coagonists, modulatory molecules such as glycine, dissociative anesthetics, redox agents, steroids, zinc, magnesium (which blocks permeability to calcium), and a cation-selective ion channel that admits Na+, K+, and Ca2+. When the neurotransmitter recognition site is activated by glutamate, the ion channel allows influx of calcium and sodium. The resulting increase in intracellular calcium is the stimulus for a multitude of downstream events, including transcription factor modulation, cell cycle regulation, and DNA replication. The NMDA receptor is relatively overexpressed in the developing brain compared with the adult brain [Fox et al., 1996]; in postnatal day 6 to 14 rats (which approximates the term human neonate), the NMDA receptor is expressed at 150% to 200% of adult levels. In humans, receptor expression is significantly higher at term than in the adult [Represa et al., 1989]. The particular combination of subunits determines the NMDA receptor’s functional state, and the predominating combination in the perinatal period seems to favor a more prolonged and pronounced calcium influx. In the setting of hypoxia-ischemia, NMDA receptor overactivation leads to massive Na+ and water influx, cell swelling, elevated intracellular calcium and its associated mitochondrial dysfunction, increased nitric oxide production, increased phospholipid turnover and accumulation of potentially toxic free fatty acids, and cell death by apoptotic or necrotic mechanisms. However, ischemia and energy failure also result in cation influx by non-NMDA–mediated mechanisms. In experimental rodent models, there is compelling evidence that susceptibility to NMDA- and AMPA-mediated excitotoxicity peaks in the immature brain [McDonald et al., 1988, 1992] and that treatment with NMDA and AMPA receptor antagonists confers robust protection against neonatal hypoxic-ischemic brain injury [Hagberg et al., 1994; Johnston, 2001]. However, concerns have been raised that NMDA receptor antagonists might have specific risks in the immature brain; blockade of NMDA synaptic activity could disrupt critical neurodevelopmental processes. Whether AMPA antagonists, which can block neuronal and white matter hypoxic-ischemic damage in neonatal rodent models, have fewer potential risks in the immature brain than do NMDA antagonists is an important question for study [Follett et al., 2004]. There has been considerable interest in evaluating the neuroprotective efficacy of magnesium sulfate in experimental and clinical models of neonatal brain injury. This interest stems from the intrinsic potentially neuroprotective properties of Mg2+ (including blockade of NMDA receptor activation) and the many years of clinical experience in safe

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use of magnesium sulfate in obstetric practice. Experimental studies provide evidence that pretreatment with magnesium sulfate can limit subsequent neonatal hypoxic-ischemic injury, but treatment after hypoxia-ischemia is of limited benefit [Greenwood et al., 2000; Turkyilmaz et al., 2002]. Mg2+ has many modes of action, unrelated to NMDA receptor activation that could influence brain responses to hypoxicischemic injury. Whether prenatal maternal administration of magnesium sulfate can reduce perinatal brain injury in atrisk term infants remains to be determined; a study in which magnesium sulfate was administered to women in preterm labor (<30 weeks’ gestation) found that treatment improved neurologic outcome [Crowther et al., 2003].

Oxidative Stress Oxidative stress describes the alterations in cellular milieu that result from an increase in free radical production as a result of oxidative metabolism under pathologic conditions. In the brain injured by hypoxia-ischemia, excitotoxicity and oxidative stress are inextricably linked. In cells with normally functioning mitochondria, more than 80% of available oxygen is reduced to energy equivalents (ATP) by cytochrome oxidase. The rest is converted to superoxide anions that under physiologic conditions are reduced to water by enzymatic and nonenzymatic antioxidant mechanisms. An inevitable consequence of mitochondrial dysfunction is an accumulation of superoxide, and any process that depletes antioxidant defenses will result in the default conversion of superoxide to even more reactive species such as the hydroxyl radical [Ferriero, 2001]. The concept of ischemiareperfusion injury (i.e., progression of tissue injury with reoxygenation after ischemia) [Inder and Volpe, 2000] is fundamental to the understanding of oxidative stress. This mechanism is not limited to the brain, but excitotoxic mechanisms in the brain can amplify these processes. Excitotoxicity causes energy depletion, mitochondrial dysfunction, and cytosolic calcium accumulation, leading to the generation of free radicals such as superoxide, nitric oxide derivatives, and the highly reactive hydroxyl radical. With reoxygenation, mitochondrial oxidative phosphorylation is overwhelmed and reactive oxygen species accumulate. Intrinsic antioxidant defenses are depleted, and free radicals directly damage multiple cellular constituents (lipids, DNA, protein) and can activate pro-apoptotic pathways. The brain is particularly susceptible to free radical attack and lipid peroxidation, and vulnerability is magnified in the immature brain. Contributing factors include a high polyunsaturated fatty acid content, high level of lipid peroxidation (particularly in response to hypoxic stress), immaturity of antioxidant defense enzymes, and high free iron concentrations, compared with the adult brain [Ferriero, 2001; Khan and Black, 2003]. The level of free iron, which catalyzes the production of various reactive oxygen species, is increased in the plasma and cerebrospinal fluid of asphyxiated newborns [Ogihara et al., 2003; VanBel et al., 1994]. In the rat, brain regions with high iron content are more vulnerable to injury, and deferoxamine, an iron chelator, is protective against hypoxia-ischemia in animal models [Almli et al., 2001; Subbarao and Richardson, 1990]. The deleterious effects of abundant iron and immaturity of the enzymatic oxidant defenses of the immature brain

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2O2· + 2H+

Superoxide dismutase

Glutathione peroxidase H2O2 + O2

Fe++

H2O

Reduced glutathione Oxidized glutathione

Fe+++

OH· FIGURE 15-3. Illustration of the reduction of superoxide (OH.) to hydrogen peroxide (H2O2) by superoxide dismutase and the further reduction of hydrogen peroxide to water by glutathione peroxidase. In the setting of abundant free iron and inadequate glutathione peroxidase activity (or inadequate reduced glutathione stores), hydrogen peroxide is converted to the extremely reactive hydroxyl radical (OH.). The immature brain has immature antioxidant enzyme systems, relatively decreased stores of reduced glutathione, and abundant free iron, making it extremely vulnerable to oxidative attack. (From McLean C, Ferriero DM. Mechanisms of hypoxic-ischemic injury in the term infant. Semin Perinatol. In press.).

are tightly interrelated. Copper-zinc superoxide dismutase (SOD-1) is the cytosolic enzyme responsible for conversion of superoxide to hydrogen peroxide. Hydrogen peroxide is further reduced to water by glutathione peroxidase or catalase, or alternatively, it can be converted to the hydroxyl radical in the presence of ferrous iron (Fig. 15-3). Enhanced glutathione peroxidase is protective when immature neurons in vitro are exposed to hydrogen peroxide. An imbalance of enzymatic maturity can explain these maturational differences; lack of sufficient glutathione peroxidase activity in the immature brain can lead to accumulation of hydrogen peroxide and lipid peroxidation products [Fullerton et al., 1998]. Free radical scavengers (e.g., alpha-phenyl-n-tertbutyl-nitrone [PBN], a spin-trap agent that converts free radicals to stable adducts) and metal chelators (e.g., deferoxamine) can protect neurons from injury mediated by hydrogen peroxide in vitro and in vivo. These agents also protect neurons from NMDA-induced toxicity, providing complementary evidence of the pathophysiologic link between excitotoxicity and oxidative stress [Almli et al., 2001; Cao and Phillis, 1994]. Nitric oxide metabolism provides another critical link between excitotoxicity and oxidative injury in the hypoxiaischemia–injured brain. Nitric oxide is produced constitutively in endothelium, astrocytes, and neurons in response to an increase in intracellular calcium. Hypoxic-ischemic increases in nitric oxide production have multiple potential beneficial and detrimental effects. Nitric oxide regulates vascular tone, influences inflammatory responses to injury, and directly modulates NMDA receptor function [Sorrentino et al., 2004]. In neonatal rodent brain, striatal neurons that express nNOS are selectively resistant to hypoxia-ischemia injury, providing a source for NMDA receptor mediated regulation of nitric oxide production [Ferriero et al., 1988]. Disruption of the nNOS gene [Ferriero et al., 1996] and pharmacologic inhibition of nNOS [Ishida et al., 2001] ameliorate neonatal hypoxia-ischemia injury.

Inflammation Nelson and colleagues [1998] first reported a link between elevated neonatal blood levels of a broad range of serum pro-inflammatory cytokines and subsequent diagnosis of spastic diplegia. In this retrospective analysis, it was impossible to distinguish whether inflammation contributed to or was the result of the brain injury that subsequently manifested as cerebral palsy and whether the primary source of these mediators was the systemic circulation or the injured brain. This landmark study heightened awareness of preexisting inflammation (e.g., maternal infection) as a mechanism contributing directly to neonatal brain injury or underlying increased susceptibility to hypoxia-ischemia brain injury. The observed relationship between maternal infection and neonatal brain injury could be explained by diverse mechanisms. Experimental studies provide support for the hypothesis that a pro-inflammatory milieu increases the susceptibility of the neonate to hypoxic-ischemic brain injury. In fetal or neonatal models, maternal infection is commonly simulated by injecting the potent pro-inflammatory agent lipopolysaccharide (i.e., endotoxin derived from Escherichia coli). Systemically administered endotoxin amplifies neonatal hypoxic-ischemic brain injury in rodent and sheep models; some of these deleterious effects are mediated, at least in part, by systemic mechanisms (e.g., hypotension, hypoglycemia) [Eklind et al., 2001; Lehnardt et al., 2003]. Cytokines are polypeptides that act systemically and locally to mediate and regulate multiple components of inflammation. Cytokines that have been strongly implicated as mediators of brain inflammation in neonates include interleukin-1β, tumor necrosis factor-α, interleukin-6, and membrane cofactor protein-1 [Foster-Barber and Ferriero, 2002]. An unresolved issue is the primary source of serum cytokines. After an asphyxial episode, there are many potential sources of plasma cytokines, including injured endothelium and acutely injured organs, such as the brain by means of a disrupted blood-brain barrier. Measurements of cerebrospinal fluid and plasma levels of several cytokines in asphyxiated term infants suggest that the injured brain can be the source of acutely elevated cytokine levels [Silveira and Procianoy, 2003]. In neonatal rodent models, hypoxic-ischemic brain injury elicits an acute inflammatory response, characterized by increased expression of pro-inflammatory cytokines [Bona et al., 1999; Szaflarski et al., 1995] and a rapid microglialmonocyte response [Ivacko et al., 1996]. Some features of inflammation persist for at least 5 weeks [Bona et al., 1999]. Evidence that cytokines can amplify hypoxic-ischemic brain damage in this setting includes the finding that treatment with a specific antagonist of interleukin-1β is protective [Martin et al., 1994]. Excitement about the role of inflammation in the pathogenesis of a broad range of neurodegenerative disorders stems in part from the availability of potent and selective anti-inflammatory therapies and from the idea that there could be a relatively prolonged window of opportunity for administration of effective treatment after onset of injury. Several anti-inflammatory drugs, including specific cytokine antagonists that are clinically available, attenuate hypoxic-

Silverstein, McLean, and Ferriero / Pathophysiology of Neonatal Hypoxic-ischemic Brain Injury

ischemic brain injury experimentally, but only if these agents are administered before or very soon after the initiating insult. Multiple pathways link excitotoxicity, oxidative stress, and inflammation in the acutely injured brain. NMDA

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receptor activation is a potent stimulus for cytokine and chemokine signaling. Microglia, the resident brain macrophages, play a central role as effectors of local brain inflammation; activated microglia produce a broad range of factors that can contribute to tissue injury (e.g., free radicals), but

FIGURE 15-4. The continuum of cell death phenotypes is shown, with features of apoptosis and necrosis that are found in the striatum and thalamus within the first 24 hours after hypoxic-ischemic (HI)–induced injury in neonatal rat brain. These electron micrographs emphasize that the nuclear and cytoplasmic changes that evolve after acute HI injury occur along a continuum and not necessarily in concert with one another. To prepare these images, thin sections were stained with uranyl acetate, viewed with transmission electron microscopy, and photographed at 6500 × magnification. The upper row includes three panels from the lesioned striatum at 3 hours after HI injury; the middle row panels are from a thalamus at 24 hours, a thalamus at 24 hours, and striatum at 6 hours after HI injury; and the lower row panels are from a thalamus at 6 hours, striatum at 3 hours, and striatum at 6 hours after HI injury. (Courtesy of Frances Northington and Lee Martin, Johns Hopkins University).

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paradoxically, these cells also produce neurotrophic factors that can enhance repair after brain injury. Little is known about developmental stage–specific features of microglial regulation or signaling. Inflammation may have beneficial effects and contribute to recovery after acute brain injury [Stoll et al., 2002], and anti-inflammatory agents can disrupt specific endogenous repair mechanisms. Evidence that premature infants who were treated with steroids for chronic lung disease had worse longterm neurodevelopmental outcome at school age [Yeh et al., 2004] heightens awareness that anti-inflammatory therapy may have adverse effects on the developing brain. However, it remains to be determined whether the adverse effects of steroids in premature infants are directly related to anti-inflammatory mechanisms.

Apoptosis Earlier sections discussed factors that contributed to hypoxic-ischemic cell death but did not specifically address the mode of cell death. Acute hypoxic-ischemic injury can elicit neural and oligodendroglial apoptosis and necrosis. These modes of cell death are classically distinguished based on electron microscopic evaluation of nuclear morphology (particularly the distinctive condensation pattern of nuclear chromatin). Complementary methods that are used to identify apoptotic neuronal cell death include biochemical and immunologic methods to identify specific molecules that are effectors of apoptosis (e.g., cysteine protease caspase-3) and histochemical methods to detect specific patterns of DNA degradation (terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling [TUNEL] or in situ end labeling histochemistry), coupled with morphologic features of apoptosis at the light microscopy level. Some dying neurons cannot be classified as apoptotic or necrotic; there is a continuum with regard to neuronal cell death mechanisms (Fig. 15-4) [Martin et al., 1998]. Edwards and colleagues [1997] evaluated pathology in six infants who died after severe birth asphyxia with hypoxic-ischemic encephalopathy and six others who had abrupt in utero death at or close to term. Although the issue of access to “normal control” tissue samples at the same developmental stage represents an inherent limitation in analysis of perinatal neuropathology, these investigators were able to demonstrate, based on morphologic criteria and on assays to detect specific patterns of DNA fragmentation in apoptotic cells, that apoptosis contributes significantly to cerebral damage in the perinatal period. An intriguing developmental trend is the propensity for hypoxic-ischemic neuronal apoptosis in the neonate, whereas in the adult, hypoxic-ischemic neuronal necrosis is the predominant mode of ischemia-induced neurodegeneration [Hu et al., 2000]. The strongest evidence of these ontogenic trends comes from systematic studies of ischemia-induced caspase-3 activation in animals of different ages; in rodent brain, hypoxicischemic caspase-3 activation peaks in neonatal animals and declines markedly with maturation. It is attractive to speculate that apoptotic neuronal death is more prominent in the neonate because of the physiologic role of apoptosis in normal brain development. Treatment with a caspase inhibitor confers neuroprotection in a neonatal rat model of hypoxic-ischemic brain

injury, even if administration is delayed up to 3 hours after the insult [Cheng et al., 1998]. This observation is concordant with evidence that a substantial fraction of hypoxiaischemia neuronal damage in the neonate is relatively delayed after the initiating insult and that this late neuronal damage is predominantly apoptotic [Northington et al., 2001]. Although there may be unique opportunities for therapeutic intervention with caspase inhibitors, disruption of apoptotic mechanisms with such agents may also have unique developmental stage–specific risks.

NEUROPROTECTION Neuroprotective interventions consisting of pharmacologic antagonism of glutamate, free radicals, inflammatory mediators, and apoptosis have been suggested [Hamrick and Ferriero, 2003]. Each of these approaches has been successful to some degree in experimental neonatal and adult animal models of hypoxic-ischemic brain injury. However, none of these strategies has been successfully translated into clinical practice. Whether lack of efficacy primarily reflects drug delivery issues with respect to timing of administration and penetration into brain or more complex pathophysiologic factors is a pressing issue for investigators attempting to translate experimental data to clinical practice. Alternative strategies for minimizing the adverse effects of hypoxic-ischemic brain injury are discussed in the following sections.

Hypothermia There is excitement about the potential to attenuate the adverse effects of acute hypoxic-ischemic encephalopathy with head or body cooling. In experimental animal models, it is clear that intra-ischemic hypothermia protects the brain from injury and that hyperthermia exacerbates hypoxicischemic brain injury. Post-ischemic hypothermia can also attenuate hypoxic-ischemic injury in certain settings [Bona et al., 1998; Gunn et al., 1997; Tooley et al., 2003]. Variables that influence the efficacy of post-ischemic “cooling” include the experimental model (e.g., animal species and age; the time interval between the ischemic event and initiation of cooling; typically, efficacy declines with increased delay); the depth of cooling (i.e., mild hypothermia, typically defined as core or brain temperature reduction to 32° C to 33° C, can be effective); duration of cooling (i.e., longer cooling periods [>24 hours] are more effective); and whether additional therapeutic agents are administered in conjunction with cooling [Liu et al., 2004]. Although the beneficial effects of intra-ischemic hypothermia can be attributed to a reduction in metabolic demands, there is no convincing evidence that this mechanism contributes to the protective effects of post-ischemia cooling. Hypotheses invoked to explain the neuroprotective effects of post-ischemia hypothermia include less impairment of re-uptake of glutamate, reduced oxidative stress, inhibition of inflammation, and inhibition of apoptosis. All of these mechanisms contribute to amplification of ischemic brain damage, and inhibition of one or more of these molecular cascades may reduce brain injury. Results of the first multicenter, randomized hypothermia

Silverstein, McLean, and Ferriero / Pathophysiology of Neonatal Hypoxic-ischemic Brain Injury

study in term infants with neonatal encephalopathy, in which a proprietary device was applied for selective head cooling, suggested that neurodevelopmental outcome was improved at the 18-month follow-up evaluation of infants who had been classified as moderately encephalopathic, but treatment did not influence outcome in the most severely affected group [Gluckman et al., 2004]. These findings, although encouraging, indicate that additional interventions are required to improve outcome in the group with most severe injury. A practical limitation of hypothermic neuroprotection in asphyxiated neonates is the inevitable lag period before treatment can be started; in the study described, entry criteria permitted initiation of cooling for up to 6 hours after birth. Early administration of neuroprotective drugs may provide additive or synergistic benefits with delayed-onset cooling; later experimental data provide support for this approach [Liu et al., 2004]. In the neonatal rat model of hypoxia-ischemia described earlier, the combination of treatment with a single dose of topiramate, a drug with antiepileptic and AMPA-antagonist properties, within 15 minutes after the end of a hypoxia-ischemia insult, followed by a initiation of cooling 3 hours later, substantially attenuated brain injury and improved functional outcome; neither treatment alone was of benefit. Many additional combination approaches merit consideration, but it must be acknowledged that future clinical trials to evaluate these types of interventions will be extremely challenging to complete.

Endogenous Mechanisms of Neuroprotection and Repair An important concept that has emerged from neuroprotection studies is that the CNS has potent endogenous mechanisms of neuroprotection and repair. Simulating or stimulating these endogenous systems may yield safe and effective therapeutic interventions after hypoxic-ischemic brain injury. A prerequisite for refinement of such approaches for treatment of neonatal brain injury is understanding these mechanisms in the developing brain.

Preconditioning Preconditioning is a biologic phenomenon that may provide important clues for future therapeutic strategies. In experimental animals, certain forms of metabolic stress or drug therapy may increase resistance to subsequent hypoxiaischemia insults. Diverse stimuli can induce this tolerance. The phenomenon can be elicited in neonatal and adult animals and in other organs in addition to the brain. A remarkable example of this phenomenon is provided by experiments in perinatal rats. If 6-day-old animals are exposed to a brief period of hypoxia (3 hours of 8% oxygen), they are completely resistant to a cerebral hypoxiaischemia insult imposed 24 hours later. Treatment with a nonselective nitric oxide synthase inhibitor, L-nitroarginine, blocks hypoxia-induced preconditioning; this finding suggests that nitric oxide production plays a pivotal signaling role in mediating tolerance [Gidday et al., 1999]. Hypoxic preconditioning also increases expression of hypoxia-inducible factor-1, a transcription factor that regulates a variety of hypoxia-inducible genes, including eryth-

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ropoietin, some glucose transporters, the glycolytic enzymes, and vascular endothelial growth factor [Bergeron et al., 2000]. Treatment with drugs that stimulate hypoxiainducible factor-1 expression can also attenuate ischemic injury in the neonatal rodent. Whether such drugs could be administered prenatally during high-risk labor and confer resistance to hypoxic-ischemic encephalopathy is an important question for future research.

Neurotrophic Factors A major focus of research is the hunt for interventions that can enhance recovery after neonatal brain injury. Neurotrophic factors are attractive candidate molecules, and several of these proteins have potent protective effects in the injured neonatal brain. In addition to classic neurotrophic factors such as brain-derived neurotrophic factor, diverse trophic factors characterized in other tissues have demonstrated CNS-trophic effects (e.g., insulin-like growth factor-1, erythropoietin). Intraventricular administration of brain-derived neurotrophic factor attenuates hypoxic-ischemic brain injury in 7-day-old rats; this is a developmental stage–specific response that wanes rapidly in older animals [Cheng et al., 1997]. Insulin-like growth factor-1 treatment suppresses oligodendrocyte cell death and increases myelination after ischemia in near-term fetal sheep [Guan et al., 2001]. Erythropoietin, originally characterized as a kidneyderived protein that regulates red blood cell production, has potent CNS functional activity. Erythropoietin receptors are abundantly expressed in the developing mammalian brain, and erythropoietin is a neurotrophic and neuroprotective agent in a wide variety of experimental paradigms [Juul, 2004]. Erythropoietin has multiple mechanisms of action, including induction of neuronal anti-apoptotic factors, suppression of inflammation, and antioxidant effects [Grasso et al., 2004]. However, the doses that have been used experimentally to confer neuroprotection in animal models are much higher than the doses used in clinical practice to stimulate erythropoiesis, and whether these higher doses can be safely administered after neonatal hypoxic-ischemic brain injury remains to be determined.

Stem Cells Surprising evidence has emerged about another endogenous repair mechanism in the acutely injured brain—neural stem cell proliferation and differentiation into mature neurons and glia. Experimental data indicate that diverse forms of brain injury stimulate neural precursor proliferation in the adult rodent forebrain subventricular zone [Parent, 2003]. The subventricular zone, which is adjacent to the lateral ventricle overlying the striatum, is the physiologic source of olfactory bulb neurons. After focal ischemic injury in adult rat brain, cell proliferation and neurogenesis increase in the adjacent subventricular zone, and neural precursors migrate toward the striatal infarct core and differentiate into neurons and glia. Some of these new striatal neurons persist up to 5 weeks after the stroke [Parent et al., 2002]. Although it might have been predicted that the neonatal brain would provide an environment that was particularly conducive to the survival of newly generated neurons, this

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sequela of an asphyxial event. Understanding the factors that influence survival of newly generated neurons and glia in the injured neonatal brain is critically important.

FUTURE DIRECTIONS

FIGURE 15-5. Evidence of hypoxic-ischemic (HI) injury–induced cell proliferation (A) and neurogenesis (B) in the subventricular zone (SVZ) of a neonatal mouse. Tissue samples were obtained from 17-day-old mice 1 week after animals underwent right carotid artery ligation, followed by 45 minutes of 10% oxygen exposure to elicit HI injury. The thymidine analog bromodeoxyuridine (BrdU) was administered to label proliferating cells. A, Increased numbers of BrdU-labeled cells appear on the lesioned (right panel) compared with the contralateral SVZ (left panel). B, Doublecortin (DCx) immunostaining identifies newly generated immature neurons 1 week after HI injury. Compared with the contralateral SVZ (left panel, black arrows), the SVZ of the injured hemisphere (right panel, black arrows) is massively enlarged with extensive DCx expression, and DCx-immunoreactive cells are clustered in the striatum (white arrow). (From Plane JM, Liu R, Wang TW, et al. Neonatal hypoxic-ischemic injury increases forebrain subventricular zone neurogenesis in the mouse. Neurobiol Dis 2004;16:585. Reprinted with permission from Elsevier.)

In clinical practice, there is unexplained variation in the severity of acute encephalopathy and in the ultimate neurologic outcome among infants who have incurred apparently equivalent hypoxia-ischemia insults. It is attractive to speculate that genetic variation with respect to any of the mechanisms discussed in this chapter may account for these divergent outcomes. Experimental data provide compelling evidence that genetic factors influence susceptibility to hypoxic-ischemic brain injury; for example, in neonatal mice, there is wide interstrain variability in the severity of injury after the same hypoxia-ischemia insult [Sheldon et al., 1998]. Sources of genetic variation that contribute to differential susceptibility to a broad range of illnesses are a subject of intense investigation, and many specific examples are likely to emerge. Similarly, genetic variations in the metabolism and efficacy of neuroactive drugs will be important to delineate. A major challenge for future studies will be to establish meaningful links between experimental and clinical data and to identify clinically important developmental stage– specific risks and benefits of specific treatment modalities that emerge. Complementary investigations in neonatal animal models and in the neonatal intensive care unit should continue to provide insights about basic mechanisms of neurodegeneration and repair that are particularly important in the developing nervous system. REFERENCES

outcome has not proved to be true. In neonatal mice, hypoxic-ischemic injury, elicited by unilateral carotid artery ligation and exposure to moderate hypoxia, does stimulate stem cell proliferation and neurogenesis in the subventricular zone and peri-infarct striatum territory. Figure 15-5 illustrates these findings; BrdU labeling identifies newly generated cells, and doublecortin immunostaining identifies increased numbers of immature neurons in these regions [Plane et al., 2004]. However, very few newly generated striatal neurons survive 3 weeks after lesioning. These results suggest that the molecular milieu of the injured neonatal brain is less conducive to neuronal survival than is the injured adult brain; this unexpected finding represents another example of a developmental stage– determined difference in the pathophysiology of brain injury. Delineation of the molecular determinants that underlie these developmental differences could provide important clues about how to enhance recovery after neonatal brain injury. A corresponding study in neonatal rats demonstrated that hypoxia-ischemia lesioning stimulated gliogenesis and that new oligodendroglia survived for up to 4 weeks after injury [Zaidi et al., 2004] within and adjacent to the infarct core. This experimental finding may represent a model of a classic pattern of pediatric neuropathology, status marmoratus, which describes hypermyelination of basal ganglia as a

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Represa A, Tremblay E, Ben-Ari Y. Transient increase of NMDA-binding sites in human hippocampus during development. Neurosci Lett 1989;99:61. Rice JE 3rd, Vannucci RC, Brierley JB. The influence of immaturity on hypoxic-ischemic brain damage in the rat. Ann Neurol 1981;9:131. Riikonen RS, Kero PO, Simell OG. Excitatory amino acids in cerebrospinal fluid in neonatal asphyxia. Pediatr Neurol 1992;8:37. Sheldon RA, Sedik C, Ferriero DM. Strain-related brain injury in neonatal mice subjected to hypoxia-ischemia. Brain Res 1998;810:114. Sibson NR, Shen J, Mason GF, et al. Functional energy metabolism: In vivo 13C-NMR spectroscopy evidence for coupling of cerebral glucose consumption and glutamatergic neuronal activity. Dev Neurosci 1998a;20:321. Sibson NR, Dhankhar A, Mason GF, et al. Stoichiometric coupling of brain glucose metabolism and glutamatergic neuronal activity. Proc Natl Acad Sci U S A 1998b;95:316. Silveira RC, Procianoy RS. Interleukin-6 and tumor necrosis factor-alpha levels in plasma and cerebrospinal fluid of term newborn infants with hypoxic-ischemic encephalopathy. J Pediatr 2003;143:625. Sorrentino DF, Fritz KI, Haider SH, et al. Nitric oxide-mediated modification of the glycine binding site of the NMDA receptor during hypoxia in the cerebral cortex of the newborn piglet. Neurochem Res 2004;29:455. Stoll G, Jander S, Schroeter M. Detrimental and beneficial effects of injury-induced inflammation and cytokine expression in the nervous system. Adv Exp Med Biol 2002;513:87. Subbarao KV, Richardson JS: Iron-dependent peroxidation of rat brain: A regional study. J Neurosci Res 1990;26:224.

Szaflarski J, Burtrum D, Silverstein FS: Cerebral hypoxia-ischemia stimulates cytokine gene expression in perinatal rats. Stroke 1995;26:1093. Tooley JR, Satas S, Porter H, et al. Head cooling with mild systemic hypothermia in anesthetized piglets is neuroprotective. Ann Neurol 2003;53:65. Towfighi J, Housman C, Mauger D, et al. Effect of seizures on cerebral hypoxic-ischemic lesions in immature rats. Brain Res Dev Brain Res 1999;113:83. Tsuji M, Wilson MA, Lange MS, et al. Minocycline worsens hypoxic-ischemic brain injury in a neonatal mouse model. Exp Neurol 2004;189:58. Turkyilmaz C, Turkyilmaz Z, Atalay Y, et al. Magnesium pre-treatment reduces neuronal apoptosis in newborn rats in hypoxia-ischemia. Brain Res 2002;955:133. VanBel F, Dorrepaul C, Benders MJNL. Neurologic abnormalities in the first 24 hours following birth asphyxia are associated with increasing plasma levels of free iron and TBA-reactive species. Pediatr Res 1994;35:388A. Vannucci RC, Vannucci SJ: Glucose metabolism in the developing brain. Semin Perinatol 2000;24:107. Vannucci SJ, Hagberg H. Hypoxia-ischemia in the immature brain. J Exp Med 2004;207:3149. Volpe JJ. Perinatal brain injury: From pathogenesis to neuroprotection. Ment Retard Dev Disabil Res Rev 2001;7:56. Yeh TF, Lin YJ, Lin HC, et al. Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity. N Engl J Med 2004;350:1304. Zaidi AU, Bessert DA, Ong JE, et al. New oligodendrocytes are generated after neonatal hypoxic-ischemic brain injury in rodents. Glia 2004;46:380.

CHAPTER 16

Intraventricular Hemorrhage of the Preterm Neonate Laura R. Ment

Preterm birth is becoming an increasingly common event. In recent years, more than 1% of all live-birth infants in the United States weighed less than 1000 grams and had gestational periods of less than 30 weeks [Guyer et al., 1998, 1999, 2000]. Although 80% of all preterm infants in this birth weight range routinely survive the newborn period [Ehrenkranz and Wright, 2003; Fanaroff et al., 2003], the incidence of neurodevelopmental disability among the prematurely born survivors of newborn intensive care remains high [Anderson et al., 2003; Bhutta et al., 2002; Hack et al., 2000b, 2002; Saigal et al., 2003; Vohr et al., 2000; Wood et al., 2000]. At age 8 years, more than 50% of infants with birth weights less than 1000 grams require special assistance in the classroom, 20% are in special education, and 15% have repeated at least one grade in school. Between 10% and 20% have cerebral palsy [Aylward, 2003; Bhutta et al., 2002; Horwood et al., 1998; McCarton et al., 1997; McCormick et al., 1990, 1996; PintoMartin et al., 1999; Taylor et al., 2000b]. Several investigators have reported that preterm infants with very-lowbirth-weights experience structural delay in postnatal brain development compared with term neonates and that this delay may be attributable to those environmental perturbations associated with preterm birth [Huppi et al., 1996; Inder et al., 2002, 2003a, 2003b, 2003c; Maalouf et al., 1999, 2001; McKinstry et al., 2002; Peterson et al., 2003], but the pathophysiology of these changes and the relationship of magnetic resonance imaging (MRI) studies to neurodevelopmental outcome data remain poorly understood. These data suggest that strategies for identifying and preventing causes of disability in this population of patients are critically important to physicians and parents alike. Intraventricular hemorrhage, or hemorrhage into the germinal matrix tissues of the developing brain, represents a major cause of handicap in preterm neonates [Volpe, 2001]. Intraventricular hemorrhage is detected in approximately one fourth of preterm infants with birth weights of less than 1500 grams [Fanaroff et al., 2003], and data from several centers over the past decade indicate that approximately one half of all hemorrhages occur within the first 6 to 8 postnatal hours [Dolfin et al., 1983; Ment et al., 1993a; Perlman and Rollins, 2000; Perlman and Volpe, 1986; Shaver et al., 1992]. Many neonatal intensive care units perform routine head ultrasound screening of preterm neonates using the system developed by Papile and colleagues [1978] for grading intraventricular hemorrhage (Table 16-1). Using this nomenclature, grade 1, or germinal matrix hemorrhage, describes blood in the germinal matrix only. Grade 2 is blood filling the lateral ventricles without distention, grade 3 is blood filling and acutely distending the ventricular system, and grade 4 describes hemorrhages with

parenchymal involvement. When associated with grades 1 to 3 intraventricular hemorrhage, unilateral grade 4 hemorrhages are considered in many cases to represent venous infarction of the periventricular white matter [de Vries et al., 2001], and the nomenclature of Volpe [2001] (see Table 16-1) provides a more pathophysiologic approach to parenchymal events. In the newborn period, 5% to 10% of preterm infants with intraventricular hemorrhage suffer seizures, and as many as 50% of infants with grade 4 intraventricular hemorrhage experience post-hemorrhagic hydrocephalus; the mortality rate is also higher for infants with intraventricular hemorrhage. Although the long-term neurodevelopmental outcome for infants with lower grades of hemorrhage remains uncertain at this time, most observers agree that infants with parenchymal hemorrhage are at high risk for neurodevelopmental handicaps (Fig. 16-1) [Krishnamoorthy et al., 1979; Ment et al., 2003; Szymonowicz et al., 1986; Vohr et al., 1992; Whitaker et al., 1996].

PATHOPHYSIOLOGY Intraventricular hemorrhage has been attributed to alterations in cerebral blood flow to the immature germinal matrix microvascular network [Shalak and Perlman, 2002; Whitelaw, 2001b]. Because this lesion is unique to preterm infants, examination of the developmental, environmental, and genetic events that result in intraventricular hemorrhage is critical. These include anatomic, physiologic, and genetic factors.

Anatomic Factors Permissive of Intraventricular Hemorrhage The germinal matrix and adjacent ventricular germinal ventricular zone are the sites of proliferation of neuronal and glial precursors in the developing brain, and during the late second and early third trimesters, they give rise predominantly to glial and microneuronal cells [Alvarez-Buylla et al., 2000; Fujita and Kitamura, 1976; Smart, 1976]. By 25 weeks’ gestation, almost all of the developing cortical neurons have been generated [Kostovic, 1990; Kostovic and Rakic, 1990; Kostovic et al., 1989, 2002], the elaboration of axonal and dendritic arbors is at an active stage, and synaptic contacts are beginning to form [Huttenlocher and deCourten, 1987; Huttenlocher and Dabholkar, 1997; Huttenlocher et al., 1982]. The germinal matrix remains relatively robust through 32 to 34 weeks’ gestation but almost completely involutes by term [Donat and Kleinberg, 1978; Rorke, 1982; Whitelaw, 2001b].

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TABLE 16-1 Grading Systems for Germinal Matrix Intraventricular Hemorrhages PAPILE* Grade

Description

VOLPE† Grade

Grade 1

Germinal matrix hemorrhage

Grade I

Grade 2

Blood within but not distending the ventricular system Blood filling and distending the ventricular system Parenchymal involvement of hemorrhage

Grade II

Grade 3 Grade 4

Description Germinal matrix hemorrhage with no or minimal intraventricular hemorrhage Intraventricular hemorrhage (10-50% of ventricular area)

Grade III

Intraventricular hemorrhage (>50% of ventricular area; usually distends ventricle)

Severe + periventricular hemorrhagic infarction

Grade III IVH with periventricular hemorrhagic infarction

*Data from Papile LS, Burstein J, Burstein R. Incidence and evolution of the subependymal intraventricular hemorrhage: A study of infants with weights less than 1500 grams. J Pediatr 1978;92:529. † Data from Volpe JJ. Neurology of the newborn, 3rd ed. Philadelphia: WB Saunders, 1995:424-428.

rhagic venous infarction of the periventricular white matter [Gould et al., 1987; Takashima et al., 1986; Taylor, 1995; Volpe, 2001].

Clinical Studies Assessing Environmental Events

FIGURE 16-1. Coronal cross section of a 28-week preterm infant brain with intraventricular hemorrhage and marked ventricular enlargement. (From Ment LR, Schneider K. Intraventricular hemorrhage of the preterm infant. Semin Neurol 1993b;13:42.)

During the period of rapid cell genesis, the germinal matrix requires a rich blood supply, but its vessels are neuropathologically immature, with large diameters and few supporting structures [Gould and Howard, 1987]. Immunohistologic and electron microscopic examination of these microvessels demonstrates a paucity of type IV collagen, laminin, and fibronectin, as well as a relative lack of tight junctions and glial supporting structures—all components of the developing blood-brain barrier [Gould and Howard, 1987; Kamei et al., 1992; Wei et al., 2000]. Grunnet [1989] therefore hypothesized that these immature microvessels might permit greater pressure to be exerted on their walls, which might make them more susceptible to hemorrhagic disruption. The venous circulation of the preterm brain may also contribute to susceptibility to intraparenchymal hemorrhage. Venous blood from the periventricular white matter flows through a fan-shaped array of short and long medullary veins into the veins of the germinal matrix and subsequently flows into the terminal veins found inferior to the germinal matrix. The somewhat tortuous anatomy of these veins is permissive for venous stasis, with subsequent hemor-

The routine clinical application of cranial ultrasonography for screening purposes in neonatal intensive care units has demonstrated that 25% of infants with birth weights of less than 1500 grams suffer intraventricular hemorrhage [Fanaroff et al., 2003]. The incidence of hemorrhage is inversely related to gestational age, and parenchymal involvement by intraventricular hemorrhage is more common among infants with the lowest gestational ages [Volpe, 1990]. Data suggest that 25% of infants with birth weights of 501 to 750 grams and 13% of those with birth weights between 741 and 1000 grams develop parenchymal involvement, or grade 4 intraventricular hemorrhage [Darlow et al., 2003; Perlman and Rollins, 2000; Shalak and Perlman, 2002].

Timing of Germinal Matrix and Intraventricular Hemorrhages The risk period for intraventricular hemorrhage for all preterm infants is the first 4 to 5 postnatal days [Ment et al., 2002; Perlman and Rollins, 2000]. More than 50% of all hemorrhages are detectable within the first 6 postnatal hours, and the work of Shaver and colleagues [1992] suggests that almost all of these early hemorrhages are in fact detectable within the first postnatal hour. Less than 5% of hemorrhages occur after the fourth or fifth postnatal day (Fig. 16-2) [Ment et al., 1993a; Perlman and Rollins, 2000]. The risk period for intraventricular hemorrhage is independent of gestational age, and between 10% and 65% of infants experience progression or extension of their hemorrhages over the first several postnatal days [Whitelaw, 2001b]. Extension of intraventricular hemorrhage and development of high-grade intraventricular hemorrhage are twice as common in infants with the earliest onset of intraventricular hemorrhage [Ment et al., 1993a]. This progression of hemorrhage has been linked to known clinical events, such as pneumothoraces and seizures, which increase cerebral blood flow [Perlman et al., 1993].

Ment / Intraventricular Hemorrhage of the Preterm Neonate 45 Ment

40

McDonald

35

Dolfin

30

de Crespigny

N 25 20 15

311

Box 16-1 EVENTS ASSOCIATED WITH INCREASED CEREBRAL BLOOD FLOW Acute hypoxemia Acute hypercarbia Apnea Pneumothorax Rapid volume re-expansion Seizure Adapted from Volpe JJ. Brain injury in the premature infant. Pediatr Res 1990;27:S28.

10 5 0 <6

6-24

24-48 Hours

48-72

>72

FIGURE 16-2. Time of first detection of intraventricular hemorrhage in preterm infants with birth weights of less than 1500 grams undergoing serial cranial sonography. (Data from deCrespigny et al., 1982; Dolfin et al., 1983; McDonald et al., 1984; Ment et al., 1993a.)

Risk Factors for Hemorrhage: Cerebral Blood Flow Studies Risk factors for intraventricular hemorrhage (Table 16-2) appear to include perinatal and postnatal events. Leviton and colleagues [1991] suggested that the pathophysiology of early-onset intraventricular hemorrhage in the first 8 to 12 postnatal hours might differ from that of later postnatal onset of hemorrhage. Using xenon 133 carotid angiography, Lou and coworkers [1979] demonstrated that cerebral blood flow is pressure passive in asphyxiated preterm infants, and results of later neonatal animal studies suggested that the efficiency of cerebral autoregulation of blood flow increases with gestational age [Tuor and Grewal, 1994; Tuor et al., 1994]. The immature brain is susceptible to ischemia during hypotensive events and hyperemia (or hemorrhage) during hypertension. Several investigators have suggested that the vessels of the germinal matrix are unable to undergo cerebral autoregulation [Trommer et al., 1987]. Numerous studies have demonstrated that the clinical events thought to be associated with increases in cerebral blood flow in the preterm infant and the presumed postnatal TABLE 16-2 Risk Factors for Intraventricular Hemorrhage EARLY-ONSET

ONSET AFTER 6 TO 8 POSTNATAL HOURS

Low birth weight, low gestational age No antenatal steroid exposure No maternal preeclampsia No maternal tocolysis No tertiary care delivery

Pneumothoraces Rapid volume re-expansion Respiratory distress syndrome Seizures Sodium bicarbonate exposure

Adapted from Shankaran S, Bauer CR, Bain R, et al. Prenatal and perinatal risk and protective factors for neonatal intracranial hemorrhage. Arch Pediatr Adolesc Med 1996a;150:491 and from Leviton A, Pagano M, Kuban KC, et al. The epidemiology of germinal matrix hemorrhage during the first half-day of life. Dev Med Child Neurol 1991;33:138.

onset of intraventricular hemorrhage include respiratory distress syndrome, vigorous resuscitation, rapid volume reexpansion, recurrent suctioning, hypoxemia, hypercapnia, acidosis, low hematocrit, and the administration of sodium bicarbonate [Boylan et al., 2000; Gleissner et al., 2000; Linder et al., 2003b; Vohr and Ment, 1996] (Box 16-1). Routine screening by bedside cranial ultrasonography has demonstrated intraventricular hemorrhage after seizures and pneumothoraces in infants who were previously known to have no evidence of hemorrhage [Cooke, 1981; Hill and Volpe, 1981; Hill et al., 1982]. Cerebrovasoactive cytokines are released in response to sepsis, and there is a welldescribed association of chorioamnionitis, sepsis, and intraventricular hemorrhage in the preterm infant [Alexander et al., 1998; Hansen and Leviton, 1999; Linder et al., 2003b]. The increasing recognition that extension of intraventricular hemorrhage and neonatal death are more common in patients with the earliest onset of intraventricular hemorrhage has prompted several investigators to evaluate the perinatal risk factors associated with earlyonset intraventricular hemorrhage [Ment et al., 1995a; Perlman and Rollins, 2000]. These studies have suggested that infants with the earliest onset of intraventricular hemorrhage are more likely to have lower birth weights and gestational ages than infants without early-onset intraventricular hemorrhage. They are also more likely to be appropriate for gestational age and to experience fetal distress, as defined by fetal bradycardia (i.e., heart rate less than 100 beats per minute), late deceleration, cord compression pattern, or sinusoidal pattern on fetal heart monitor tracing. Infants with early-onset intraventricular hemorrhage are less likely to have had exposure to antenatal corticosteroids and tocolytic agents [Crowley, 2000; Leviton et al., 1999]. The presence of maternal preeclampsia or premature rupture of the membranes has been reported to be protective for intraventricular hemorrhage [Perlman et al., 1997b; Shankaran et al., 1996a]. Several non-randomized, retrospective studies suggest that infants with the earliest onset of intraventricular hemorrhage were more likely to have undergone vaginal delivery than their nonintraventricular hemorrhage peers [Anderson et al., 1988; Tejani et al., 1987]. Other factors associated with intraventricular hemorrhage include assisted reproduction, particularly in vitro fertilization [Linder et al., 2003a], and transport of the newly born preterm infant [Hohlagschwandtner et al., 2001]. Although the latter may be associated with adverse hypotensive and hypoxemic insult, the finding of increased

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Perinatal Acquired and Congenital Neurologic Disorders / 16

intraventricular hemorrhage in infants born after assisted reproductive technologies—even when controlled for gestational age—remains largely unexplained. The cortical gray matter volume triples during the last third of pregnancy. Of critical importance for the outcome of infants with intraventricular hemorrhage is the observation that cerebral blood flow is markedly diminished after hemorrhage [Del Toro, 1991; Volpe, 1997]. Both xenon 133 inhalation and positron emission tomography have demonstrated significant hypoperfusion for longer than the first postnatal week in preterm infants with intraventricular hemorrhage [Ment et al., 1984; Volpe et al., 1983]. The cerebral hypoxemia and ischemia that accompany this depression in flow may result in damage to the periventricular white matter and to the glial precursors still residing in the germinal matrix zone. Oligodendroglia are responsible for myelination of the developing white matter tracts and, through molecules such as myelin-associated glycoprotein and a protein inhibiting axonal regeneration (NOGO-A), for axonal sprouting and guidance in the developing brain [Weiss et al., 2004]. Oligodendroglia and their precursors are among the most sensitive cells in the developing cortex to hypoxia, and their loss is postulated to result in secondary alterations in corticogenesis in developing brain [Arzoumanian et al., 2003; Larroque et al., 2003; Nagy et al., 2003]. Consistent with this hypothesis is the report of significantly decreased cortical gray matter volumes at term equivalent in very-low-birth-weight preterm infants with grades 1 to 3 intraventricular hemorrhage compared with those with no evidence for intraventricular hemorrhage in the newborn period [Vasileiadis et al., 2004]. After neonatal intraventricular hemorrhage, prematurely born children between the ages of 8 and 15 years have had persistent, significant decreases in gray matter volume and corpus callosum area [Nosarti et al., 2004; Peterson et al., 2000; Reiss et al., 2004].

Genetic Studies of Intraventricular Hemorrhage Although the environmental risk factors for intraventricular hemorrhage have been well studied, not all infants of a given birth weight range or those who suffer a known hypoxemic event experience intraventricular hemorrhage. The incidence of intraventricular hemorrhage has not changed during the past 10 years despite due diligence in care (Table 16-3) [Fanaroff et al., 2003]. For these reasons, several investigators

TABLE 16-3 Perinatal Information from Three Epochs for Infants Born with Birth Weights of 1500 Grams or Less in the NICHD Neonatal Research Network BIRTH YEARS 1993-1994

DATA

1987-1988

1999-2000

Number of infants Antenatal steroids (%) Delivery by cesarean section (%) Grades 3 or 4 intraventricular hemorrhage (%) Death before discharge (%)

1765 16 47

4593 35 49

5848 79 57

18

11

12

23

17

14

Adapted from Fanaroff AA, Hack M, Walsh MC. The NICHD Neonatal Research Network: Changes in practice and outcomes during the first fifteen years. Semin Perinatol 2003;27:281.

have tested the hypothesis that the cause of intraventricular hemorrhage is multifactorial, involving environmental and genetic events. Intraventricular hemorrhage results from simple mechanical rupture of the immature germinal matrix microvessels that are unable to tolerate fluctuations in cerebral blood flow. Alternately, several investigators have suggested that stasis produced by venous obstruction and cerebral venous infarction result in the parenchymal involvement of hemorrhage, or grade 4 intraventricular hemorrhage. The relatively recent description of the thrombophilias associated with the factor V Leiden and prothrombin G2021A mutations and the implication of both abnormalities in fetal and neonatal stroke suggested to several investigators that they might also be candidate genes for intraventricular hemorrhage (Table 16-4). A point mutation in the factor V gene resulting in the arginine506 to glutamine substitution in factor V (Gln506FV) is known as the factor V Leiden mutation, which has been associated with thrombotic conditions in adult and pediatric populations. The G20210A polymorphism in the prothrombin gene has also been associated with thrombotic conditions, and factor V Leiden and prothrombin G20210A mutations have been reported in children and infants with ischemic stroke, porencephaly, and other thromboembolic events. Gopel and colleagues [2001] hypothesized that relative hypercoagulability would protect preterm neonates from

TABLE 16-4 Susceptibility Genes for Intraventricular Hemorrhage and Periventricular Leukomalacia STUDY

GENE

INJURY

RESULT

Gopel et al., 2001

Factor V Leiden and/or prothrombin G20210A

IVH

Petaja et al., 2001

Factor V Leiden, prothrombin G20210A, protein C deficiency

IVH

Aronis et al., 2002

Prothrombin G20210A

IVH

Adcock et al., 2003

TNFα-308 A allele

IVH

Protective for grades 2 to 4 IVH (OR = 0.11; 95% CI, 0.02-0.5; P = 0.023) Infants with grades 2 to 4 IVH had OR of 6.2 for being a carrier of factor V Leiden; thrombophilic abnormalities in 32% infants with IVH Trend for neonates with IVH to have prothrombin G2021A allele Increased risk of IVH (RR = 2.07; 95% CI, 1.02-4.18; P = 0.041)

CI, confidence interval; IVH, intraventricular hemorrhage; OR, odds ratio; RR, relative risk.

Ment / Intraventricular Hemorrhage of the Preterm Neonate

the extension of grade 1 intraventricular hemorrhage to higher grades of hemorrhage. In this study of 305 infants with birth weights less than 1500 grams, the factor V Leiden mutation was protective for grades 2 to 4 intraventricular hemorrhage. In contrast, Petaja and co-workers [2001] hypothesized that the hypercoagulable state associated with the factor V Leiden mutation would promote periventricular venous infarction and render the infant susceptible to parenchymal involvement by intraventricular hemorrhage; this study of 51 infants of less than 32 weeks’ gestational age suggested that factor V Leiden was associated with grade 4 intraventricular hemorrhage (OR = 5.9). Aronis and associates [2002] evaluated 55 preterm infants of less than 32 weeks’ gestational age for factor V Leiden and prothrombin mutations and found a trend for thrombophilias among infants with the latter mutation. Proinflammatory cytokines are believed to represent important mediators of perinatal brain injury, and tumor necrosis factor-α (TNF-α) is known to be a central mediator in the inflammatory cascade. The degree of TNF-α production may be in part genetically driven. A biallelic G to A polymorphism at position –308 in the TNF-α promoter region confers high (A) or low (G) gene transcription. Hypoxia and ischemia, both of which contribute to the pathogenesis of intraventricular hemorrhage, are associated with the upregulation of TNF-α, and Adcock and colleagues [2003] reported an increased incidence of intraventricular hemorrhage among preterm neonates with the A allele in 178 preterm neonates who were screened shortly after birth. Although the results have not yet been correlated with neonatal imaging studies, Nelson and colleagues [2005] reported that prematurely born children with cerebral palsy were more likely to be heterozygous for eNOS A(-922)G, factor 7 arg353gln, lymphotoxin A (LTA thr26asn), and plasminogen activator inhibitor-1 (PAI-1) 4G9-675)5G. In non-Hispanic children, β2-adrenergic receptor glyn27glu also increased the risk of cerebral palsy.

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A

B FIGURE 16-3. Electron microscopic representation of a germinal matrix microvessel from a newborn beagle pup on postnatal day 1. The typical vessel has attenuated endothelium, indistinct basement membrane (BM), incomplete investment by supporting cell processes, and straight, short interendothelial junctional complexes. A, Low-power final magnification (×16,750). B, High-power final magnification (×50,000) of the boxed area in A. The arrow indicates the junctional complex. (From Ment LR, Stewart WB, Ardito TA, et al. Germinal matrix microvascular maturation correlates inversely with the risk period for neonatal intraventricular hemorrhage. Brain Res Dev Brain Res 1995;84:144.)

Animal Model of Intraventricular Hemorrhage Although newborn lambs and piglets have served as good models for the study of neonatal cerebral blood flow, the newborn beagle pup has provided an excellent model for the study of neonatal intraventricular hemorrhage. Hemorrhages neuropathologically similar to those found in preterm infants may be produced by the clinically relevant models of acute hypertension, acute hypercarbia, or hemorrhagic hypotension followed by volume reexpansion [Goddard et al., 1980; Goddard-Finegold and Michael, 1984; Ment et al., 1982]. Pasternak and associates [1982] demonstrated that the germinal matrix is a “low-flow” zone in the newborn pup, and Goddard-Finegold and Michael [1984] found increased cortical flows during an insult for intraventricular hemorrhage and suggested that the germinal matrix of the newborn pup, similar to the human preterm neonate, may not experience autoregulation of blood flow. After hemorrhage, flow was depressed to cortical gray and periventricular white matter regions. Neuropathologic studies of the newborn pup have suggested that the germinal matrix microvascular maturation correlates inversely with the risk period for neonatal intraventricular hemorrhage [Leuschen et al., 1984; Trommer

et al., 1987]. In contrast to data for cortical gray and periventricular white matter regions, significant increases in basement membrane deposition, tight junction length, and glial end-foot apposition have all been demonstrated during the risk period for intraventricular hemorrhage in this model (Figs. 16-3 and 16-4) [Ment et al., 1991]. These data suggest that the risk period for hemorrhage is determined by development of the components of the blood-brain barrier in the germinal matrix microvasculature.

Summary of Intraventricular Hemorrhage Pathophysiology Studies in preterm infants and an animal model have suggested that, although intraventricular hemorrhage may be attributable to alterations in cerebral blood flow to the immature germinal matrix microvasculature of the preterm infant, a genetic predisposition to hemorrhage may exist. Doppler studies have demonstrated elevations in cerebral blood flow velocities in preterm infants before the onset of hemorrhage, and infants with the earliest onset of hemorrhage have had prolonged depression of cerebral blood flow.

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B

A

FIGURE 16-4. Electron microscopic representation of a germinal matrix microvessel from a beagle pup on postnatal day 4, the close of the risk period for intraventricular hemorrhage in this animal model. The typical vessel demonstrates robust endothelium, a morphologically distinct and continuous basement membrane (BM), almost complete investment by supporting cell processes, and long interendothelial cell junctional complexes. A, Low-power final magnification (×16,750). B, High-power final magnification (×50,000) of the boxed area in A. The arrow indicates the junctional complex. (From Ment LR, Stewart WB, Ardito TA, et al. Germinal matrix microvascular maturation correlates inversely with the risk period for neonatal intraventricular hemorrhage. Brain Res Dev Brain Res 1995;84:144.)

Twins are more likely to experience intraventricular hemorrhage, and the inherited thrombophilias have been implicated in this disorder [Perlman et al., 1997a]. Infants with high-grade hemorrhage are at greater risk for periventricular leukomalacia and low-pressure ventriculomegaly, both of which have been attributed to hypoxic or ischemic insult to preterm brain, and both are discussed later in this chapter. Intraventricular hemorrhage represents a marker for insults of various types to the developing brain. The developmental phase of the infant, the environment, and genetic susceptibility all contribute to the cause of this common problem of preterm infants. A model for intraventricular hemorrhage and its sequelae is found in Figure 16-5.

Increased CO2

Decreased Po2

NEUROPATHOLOGY More than 90% of all intraventricular hemorrhages in preterm infants originate in the germinal matrix tissues located between the caudate nucleus and the thalamus at the level of or slightly posterior to the foramen of Monro in the developing brain [Donat and Kleinberg, 1978; Volpe, 1997]. A small percentage of hemorrhages in preterm neonates may also originate from the choroid plexus, which is the most common site of intraventricular hemorrhage in term infants [Rorke, 1982]. Although it is often difficult to differentiate the neuropathologic findings that are directly attributable to intra-

Decreased pH

Increased cerebral blood flow

Immature germinal matrix vascular bed

Genetic factors

IVH

Decreased CBF

PVL

Ventriculomegaly

FIGURE 16-5. Model for the development of intraventricular hemorrhage in the preterm infant. CBF, cerebral blood flow; IVH, intraventricular hemorrhage; PVL, periventricular leukomalacia.

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ventricular hemorrhage from those that frequently accompany it, many investigators would agree that germinal matrix destruction, periventricular hemorrhagic infarction, and posthemorrhagic hydrocephalus are the direct neuropathologic consequences of intraventricular hemorrhage [Shalak and Perlman, 2002; Whitelaw, 2001b]. In contrast, periventricular leukomalacia and ventriculomegaly are more frequently detected in infants with intraventricular hemorrhage but are multifactorial in origin. Germinal matrix hemorrhage solely confined to the germinal layer occurs equally in both hemispheres and is bilateral in approximately one half of cases [Leech and Kohnen, 1974]. There may be multiple hemorrhages over one caudate nucleus, and injection techniques have demonstrated that all of the major vessels supplying the germinal matrix, including the artery of Heubner, the anterior choroidal artery, the lateral striate arteries, and the terminal vein, remain intact after an initial germinal matrix hemorrhage [Pape and Wigglesworth, 1979]. Such a hemorrhage is associated with destruction of the capillary bed, and secondary germinal matrix cyst formation is common [Hambleton and Wigglesworth, 1976]. After rupture of a germinal matrix hemorrhage, the spread of blood throughout the ventricular system varies. Sonograms may demonstrate clots attached to the site of rupture and to the choroid plexus and demonstrate variable spread of

FIGURE 16-6. Twenty-eight-week preterm brain with intraventricular hemorrhage and mass of a clot within the subarachnoid spaces at the base of the brain.

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blood throughout the entire ventricular system. A characteristic pathologic finding is a mass of clot within the subarachnoid spaces at the base of the brain (Fig. 16-6) and extension of blood through the subarachnoid pathways into the sylvian fissure and over the convexities of the developing hemispheres. Serial cranial sonograms suggest that as many as 10% to 20% of preterm infants with germinal matrix hemorrhage subsequently develop intraparenchymal abnormalities [Fanaroff et al., 2003]. Although the neuropathologic correlates of these abnormalities are most likely multiple, they are most easily understood as arising from the acute increase in intracranial pressure attributable to the germinal matrix hemorrhage itself and from the profound decreases in regional blood flow that may follow it. In 10% to 20% of infants with extensive germinal matrix hemorrhage the branches of the terminal vein that typically drain through the area of hemorrhage become grossly congested, and venous hemorrhagic infarction of the periventricular white matter and even cortical tissues may occur during the first several days after intraventricular hemorrhage [Pape and Wigglesworth, 1979]. Periventricular white matter infarctions are frequently called intraparenchymal echodensities when examined by cranial ultrasonography or MRI. Some investigators believe that the parenchymal involvement of intraventricular hemorrhage readily visible by cranial ultrasonography represents a direct pressure-mediated extension of hemorrhage from a massive germinal matrix hemorrhage or the ventricular system [Perlman et al., 1993; Rushton et al., 1985]. The close clinical association of ischemia and hemorrhage and the timing of the development of intraparenchymal echodense lesions on ultrasonography suggest that at least a portion of these lesions represent venous infarction of the periventricular white matter. These lesions are difficult to distinguish at the time of postmortem examination and have been variously named hemorrhagic intracerebral involvement, parenchymal involvement of hemorrhage, or grade 4 intraventricular hemorrhage [Takashima et al., 1986]. Post-hemorrhagic hydrocephalus represents the third common sequela of intraventricular hemorrhage [Whitelaw, 2001b]. The meninges are thickened and demonstrate infiltration by hemosiderin-laden macrophages [Deonna et al., 1975; Larroche, 1972]. These changes result in occlusion of the arachnoid villi, obstruction to flow of cerebrospinal fluid through the foramina of Luschka and Magendie, and impairment of flow through the tentorial notch. Occasionally, aqueductal obstruction is caused by an acute blood clot, ependymal disruption, or reactive gliosis [Whitelaw, 2001b]. Periventricular leukomalacia and low-pressure cerebral ventriculomegaly are two relatively common neuropathologic findings in patients with intraventricular hemorrhage. Cystic periventricular leukomalacia is a common neuroimaging finding in infants who subsequently develop the spastic diplegic form of cerebral palsy [Allan et al., 1997; Aziz et al., 1995; Olsen et al., 1997; Rivkin, 2000]. Periventricular leukomalacia has been reported in 25% to 50% of infants with intraventricular hemorrhage [du Plessis, 1998; Paneth et al., 1990, 1994; Perlman, 1998], and riskfactor studies implicate hypoxemic, hypotensive, inflammatory, and other ischemic events [Dammann and Leviton, 1997, 1999, 2000; Dammann et al., 2001a, 2001b, 2001c;

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Erickson et al., 2002; Leviton and Gilles, 1996; Perlman, 1998]. Neuropathologic studies reveal periventricular leukomalacia to be a generally symmetric ischemic injury to the deep periventricular white matter watershed zone [Banker and Larroche, 1962; Leech and Alvord, 1974; Paneth et al., 1994]. Low-pressure cerebral ventriculomegaly has been recognized as a significant neuropathologic finding in patients with intraventricular hemorrhage [Allan et al., 1997; du Plessis, 1998; Whitaker, 1996]. Neuropathologic studies include ischemic white matter lesions and evidence for the nonischemic generalized paucity of white matter tracts [Erickson et al., 2002; Leviton and Gilles, 1996; Perlman, 1998]. Similarly, risk-factor studies include high-grade intraventricular hemorrhage and chronic sublethal hypoxic insult [Ment et al., 1999; Paneth, 1999; Paneth et al., 1994].

(Fig. 16-8) have been identified within the first 6 postnatal hours, most infants initially experience low-grade hemorrhage, which can be seen to progress over the course of time by cranial ultrasonography. The most common sites for parenchymal involvement of hemorrhage are the frontal and parietal regions; approximately 50% of parenchymal hemorrhages occur bilaterally [Ment et al., 1993a; Paneth et al., 1994; Rumack et al., 1985].

NEUROIMAGING Intraventricular Hemorrhage Routine cranial ultrasonography of the anterior fontanel is performed in neonatal intensive and special care units throughout this country, and this modality represents the method of choice for the diagnosis and monitoring of intraventricular hemorrhage and its complications in preterm infants. Most nurseries use the standard grading system found in Table 16-1 [Papile et al., 1978]. Grade 1 intraventricular hemorrhage designates blood within the germinal matrix only (Fig. 16-7); grade 2 designates blood within the ventricular system; grade 3 designates blood filling and distending the ventricular system; and grade 4 intraventricular hemorrhage indicates parenchymal involvement of hemorrhage. Although grade 4 hemorrhages

FIGURE 16-8. Intraparenchymal intraventricular hemorrhage. Massive hemorrhage emanating from the right germinal matrix destroys the adjacent ventricular anatomy, dissects into the brain parenchyma, and causes a mass effect on the surrounding structures as seen in the coronal view. Notice the midline shift to the left.

A

B

FIGURE 16-7. Germinal matrix hemorrhage (GMH). A, Coronal view demonstrates a focus of increased echogenicity (arrow) between the caudate head and the thalamus in the caudothalamic groove. B, Parasagittal view shows the GMH (arrow) in its usual location along the posterior aspect of the caudothalamic groove; fresh hemorrhage has a high level of echogenicity, similar to that of the choroid plexus.

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A

B

C

FIGURE 16-9. Intraparenchymal echodensity. A sizable amount of blood has ruptured from both germinal matrices into the lateral ventricles and the third ventricle, creating acute hemorrhagic distention. A, Coronal view. B, Parasagittal view. C, Follow-up study demonstrates that in the deep peritrigonal white matter on the left side, a cavity with an echogenic rim has developed in the deep white matter as a result of secondary infarction. Residual clot in the trigone (arrow) has evolved in the typical way, demonstrated by a hypoechoic center surrounded by an echogenic rim.

Intraparenchymal Echodensities Cranial ultrasonography and MRI are used for the diagnoses of intraparenchymal echodensities, porencephaly, periventricular leukomalacia, and ventriculomegaly. An intraparenchymal echodensity has been described as an asymmetric white matter lesion that may accompany the onset of intraventricular hemorrhage or follow it. Rarely found without germinal matrix hemorrhage or intraventricular hemorrhage, an intraparenchymal echodensity is believed to represent hemorrhagic venous infarction of the periventricular white matter and generally occurs in infants of the youngest gestational ages during the first postnatal week [de Vries et al., 2001; Taylor, 1995]. The ultrasound appearance (Fig. 16-9) is an echogenic juxtaventricular white matter lesion superior and lateral to the lateral ventricle and extending toward the cortex in a flare pattern without evidence for mass effect on the surrounding brain. Most often, an intraparenchymal echodensity eventually cavitates or atrophies to form a porencephaly or adjacent ex vacuo ventriculomegaly. Less frequently, the intraparenchymal echodensities may be tran-

sient, leaving no residual changes detectable by sonographic scans [Gaisie et al., 1990]. Improvements in MRI technology and the use of special MRI-compatible incubators and ventilators have permitted imaging of hemorrhage in the developing brain [Counsell et al., 1999, 2003; Maalouf et al., 2001]. In the newborn period, MRI studies demonstrate a single hemorrhagic lesion adjacent to or communicating with the lateral ventricle in addition to intraventricular hemorrhage (Fig. 16-10).

Porencephaly Porencephalies (Greek for “holes in the brain”) are hemispheric cavitary lesions; in neonates, porencephalies follow grade 4 hemorrhages, intraparenchymal echodensities, or periventricular venous infarctions. Although most porencephalies are freely communicating with the ventricular system, a porencephaly may present as a fluid-filled cyst that causes increased intracranial pressure in the preterm infant. A typical porencephaly is shown by ultrasound in Figure 16-11 and by MRI in Figure 16-12.

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Periventricular Leukomalacia

FIGURE 16-10. Magnetic resonance imaging (MRI) of intraventricular hemorrhage (IVH). This 31-week-old male infant with a benign perinatal course was found to have parenchymal involvement of hemorrhage on routine ultrasound. This axial MRI, performed shortly thereafter, demonstrates parenchymal involvement of IVH with moderate ventricular dilatation. (Courtesy of Linda S. de Vries, M.D., Wilhelmina Children’s Hospital, UMC, Utrecht, The Netherlands.)

A

Periventricular leukomalacia is the term best applied to symmetric nonhemorrhagic echogenic lesions deep in the white matter. This ultrasound finding is based on confirmatory neuropathologic studies [Adcock et al., 1998], and its appearance in preterm infants before 5 to 7 days of age is an uncommon (and perhaps an in utero) event. Periventricular leukomalacia sometimes can be difficult to differentiate from the normal periventricular hyperechoic brain tissue of normal preterm infants, and its conclusive diagnosis depends on the ultimate detection of eventual cystic change or ventriculomegaly (i.e., periventricular leukomalacia complex). In the early diagnosis of periventricular leukomalacia, posterior fontanel scans aid the sonographer, because periventricular leukomalacia is absolutely echogenic from all approaches, whereas the normal anatomic echogenicity found in preterm infants diminishes from the posterior fontanel view [de Vries et al., 2001]. The cysts of periventricular leukomalacia are usually less than 5 mm in diameter, are located deep in the white matter, and most often occur bilaterally (Fig. 16-13) [Roelants-van Rijn et al., 2001]. MRI studies in the newborn period demonstrate widespread punctate white matter lesions and diffusionweighted imaging abnormalities; follow-up imaging reveals irregularly sculpted ventricular enlargement with diffuse periventricular gliotic changes [Inder et al., 1999a, 1999b]. Although periventricular leukomalacia and intraparenchymal echodensities are both echogenic lesions of white matter, they differ in timing of occurrence, in white matter location, and in subsequent sonographic findings. An intraparenchymal echodensity occurs within the first week, is located in the juxtaventricular white matter, and generally results in subsequent sonographic findings of porencephaly or ventriculomegaly. In contrast, the lesions of periventricular leukomalacia are usually symmetric, rarely are seen before 5 to 7 days, and are located within the deep white matter. Eventually, sonography may detect the multiple

B

FIGURE 16-11. Porencephaly. A, A 28-week-gestation, 1100-gram infant had bilateral intraventricular hemorrhage and a hemorrhagic white matter infarction on the left. B, A repeat cranial ultrasound on postnatal day 21 demonstrated resolution of the intraventricular blood bilaterally and a porencephalic lesion connected with the ventricular system in the left periventricular white matter. (From Ment LR, Schneider K. Intraventricular hemorrhage of the preterm infant. Semin Neurol 1993b;13:46.)

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A

319

B

FIGURE 16-12. Neuroradiologic demonstration of the development of a porencephaly. A, Coronal cranial ultrasound of a 26-week-gestation male triplet at 2 weeks of age demonstrates a large left-sided parenchymal hemorrhage. B, Axial magnetic resonance image at term equivalent shows a left-sided porencephaly with mild ventriculomegaly. At the corrected age of 18 months, this child has hemiplegia but normal cognitive function. (Courtesy of Linda S. de Vries, MD, Wilhelmina Children’s Hospital, UMC, Utrecht, The Netherlands.)

small cysts characteristic of periventricular leukomalacia, whereas the MRI findings are most commonly periventricular gliosis and low-pressure ventriculomegaly. The

two conditions as demonstrated on ultrasound and MRI studies are compared in Table 16-5.

Ventriculomegaly Ventriculomegaly, defined as at least one lateral ventricle greater than the 97th percentile for postconceptual age, is rarely a lesion of the newly born preterm infant. Rather, ventriculomegaly is seen after intraventricular hemorrhage, severe periventricular leukomalacia, or periventricular white matter necrosis. In some cases, ventriculomegaly may be associated with increased intracranial pressure after hemorrhage (i.e., post-hemorrhagic hydrocephalus). In these instances the ventricular borders are rounded. The neuroimaging findings in patients with low-pressure ventriculomegaly include enlarged lateral ventricles with no enlargement of the foramen of Monro or third ventricle [Kuban et al., 1999; Ment et al., 1999; Paneth et al., 1990].

Recommendations for Imaging the Preterm Neonate

FIGURE 16-13. Periventricular leukomalacia. Angled coronal view portrays the white matter just above the lateral ventricles (V) similar to the perspective of a computed tomographic slice. Increased echogenicity is interspersed with areas of cavitation (arrows) in this image obtained several weeks after an episode of respiratory distress and hypoxemia.

Current recommendations for imaging the preterm neonate suggest that screening cranial ultrasonography should be performed on all infants with gestational ages of less than 30 weeks at 7 to 14 days of age and should be repeated at 36 to 40 weeks’ postmenstrual age. This recommendation by the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society is designed to detect clinically unsuspected intraventricular hemorrhage, which may require additional clinical and radiologic monitoring and changes in

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TABLE 16-5 Imaging Differentiation of Intraparenchymal Echodensities and Periventricular Leukomalacia IMAGING MODALITY

INTRAPARENCHYMAL ECHODENSITY

PERIVENTRICULAR LEUKOMALACIA

HUS

Usually unilateral Moderate to large IVH Triangular Well-defined borders Porencephalic cyst develops Single lesion adjacent to or communicating with lateral ventricle Intraventricular blood

Usually bilateral IVH may or may not occur Irregular borders Cysts separate from ventricular wall May result in ventriculomegaly Widespread punctate white matter lesions IVH may or may not be present

MRI

HUS, head ultrasonography; IVH, intraventricular hemorrhage; MRI, magnetic resonance imaging.

management plans, and evidence for periventricular leukomalacia or ventriculomegaly, which is useful for prognosis and best seen when the infants are examined at term.

CLINICAL FINDINGS Clinical Manifestations The clinical manifestations of intraventricular hemorrhage vary, and in one large series of postmortem examinations, more than 75% of hemorrhages were clinically unrecognized [Papile et al., 1978; Volpe, 1997]. Nonetheless, as shown in Table 16-6, infants with large hemorrhages generally suffer a profound decrease in peripheral hematocrit and may experience coma, seizures, abnormal eye findings (including dilated and nonreactive pupils and loss of eye movements), and changes in tone and reflexes [Dubowitz et al., 1998]. Apneic and bradycardic spells may be attributable to increased intracranial pressure or changes in cerebral blood flow to brainstem respiratory control centers. Infants with even low-grade intraventricular hemorrhage may have significantly elevated serum glucose values and evidence for inappropriate secretion of antidiuretic hormone [Moylan et al., 1978; Shalak and Perlman, 2002]. Persistent, unremitting metabolic acidosis unresponsive to alkali therapy or pressor agents is the hallmark of high-grade hemorrhage.

TABLE 16-6 Clinical Symptoms of High-Grade Intraventricular Hemorrhage SYMPTOM

INCIDENCE

Decrease in hematocrit Seizures Changes in tone Abnormal eye signs Apnea/Bradycardia Hyperglycemia Hyponatremia Metabolic acidosis

75% 10% to 15% 75% to 90% 33% to 95% 50% to 75% >50% >50% >75%

Adapted from Cepeda et al., 1978; Dubowitz et al., 1981; Lazzara et al., 1980; Moylan et al., 1978; Ment unpublished data, NS27116 Randomized Indomethacin IVH Prevention Trial, 1997.

Cerebrospinal Fluid Studies Several investigators have demonstrated that examination of the cerebrospinal fluid in preterm infants undergoing unremarkable sepsis evaluations routinely reveals 0 to 20 white blood cells (predominantly lymphocytes and monocytes per high-power field), the absence of red blood cells, and protein values of 100 to 200 mg/dL. In patients with new-onset intraventricular hemorrhage, cerebrospinal fluid findings include large numbers of red blood cells, white cells in direct proportion to the ratio of peripheral red blood cells to white blood cells, elevations of protein, and low glucose values. Cerebrospinal fluid protein levels and red blood cell counts have been reported to correlate with the grade of intraventricular hemorrhage. Subjects with grades 3 or 4 intraventricular hemorrhage generally are found to have cerebrospinal fluid protein concentrations of 500 to 1000 mg/dL and red blood cell values in excess of 1,000,000/mm3. In contrast, patients with grade 2 intraventricular hemorrhage generally demonstrate cerebrospinal fluid protein values of less than 500 mg/dL and red blood cell values of 10,000 to 250,000/mm3. Patients with germinal matrix hemorrhage, or grade 1 intraventricular hemorrhage, generally have no evidence for red blood cells within the cerebrospinal fluid unless they have also experienced a subarachnoid bleed; similarly, infants with grade 1 intraventricular hemorrhage usually have normal cerebrospinal fluid protein levels. Profound hypoglycorrhachia, with cerebrospinal fluid glucose values below 10 mg/dL, may be found in infants with all grades of hemorrhage, although this is also more common in patients with high-grade hemorrhage. Days to weeks after the primary hemorrhage, examination of the cerebrospinal fluid demonstrates decreasing red blood cell numbers but elevated white blood cell counts in excess of 500 to 1000 white blood cells/mm3 and persistent hypoglycorrhachia. The latter two findings may lead the clinician to suspect bacterial meningitis, a diagnosis that can be determined only by cerebrospinal fluid culture studies.

OUTCOMES Although recent advances in neonatal intensive care have resulted in increased survival rates for many critically ill and very preterm neonates, the neurodevelopmental fate of verylow-birth-weight infants remains uncertain. Depending on the birth weight of the patient cohort and the years in which

Ment / Intraventricular Hemorrhage of the Preterm Neonate

they were born, the incidence of major neurodevelopmental handicaps ranges from 12% to 36%, and the prevalence of cerebral palsy is reported to be rising [Anderson et al., 2003; Bhutta et al., 2002; Hack et al., 2000b, 2002; Saigal et al., 2003; Vohr et al., 2000; Wood et al., 2000]. These groups of very-low-birth-weight infants have an increased incidence of more subtle intellectual and behavioral problems at school age [Aylward, 2003; Bhutta et al., 2002; Horwood et al., 1998; McCarton et al., 1997; McCormick et al., 1990, 1996; Pinto-Martin et al., 1999; Taylor et al., 2000b]. In the neonatal period, infants with intraventricular hemorrhage are at risk for the development of seizures and post-hemorrhagic hydrocephalus. Depending on the birth weights and gestational ages of the cohorts studied and the investigator’s method for determining seizures, the reported incidence of seizures in preterm infants with intraventricular hemorrhage was 5% to 10%. Similarly, the incidence of post-hemorrhagic hydrocephalus depends on the gestational age of the population reported, on the investigator’s diagnoses, and on the grade of intraventricular hemorrhage; as many as 25% to 50% of infants with grades 3 or 4 intraventricular hemorrhage may experience posthemorrhagic hydrocephalus [Whitelaw, 2001b]. The mortality rate is higher for infants with intraventricular hemorrhage compared with their gestational age–matched peers without hemorrhage. However, in most series in which the causes of death are given, infants with intraventricular hemorrhage are likely to succumb to other lesions believed attributable to changes in blood flow, such as necrotizing enterocolitis and bronchopulmonary dysplasia [Fanaroff et al., 2003; Schmidt and David, 2001]. Infants with intraventricular hemorrhage more commonly have abnormal cranial sonograms at 40 weeks’ conceptional age than infants with no evidence of intraventricular hemorrhage [Allan et al., 1997].

Post-hemorrhagic Hydrocephalus Post-hemorrhagic hydrocephalus is diagnosed in the infant who meets all of the following criteria: presence of intraventricular blood, increasing ventriculomegaly (most commonly diagnosed by cranial ultrasonography), and evidence for increased intracranial pressure (defined as an opening pressure of greater than 140 mm H2O by lumbar puncture or, if indicated, cerebral ventricular tap) [Whitelaw, 2001b]. In infants with post-hemorrhagic hydrocephalus, the ventricular width at the intraventricular foramen by sonographic measurement exceeds 4 mm over the 97th percentile for gestational age [Levene, 1981]. Post-hemorrhagic hydrocephalus is most common in infants with high grades of hemorrhage and less common in infants with the lowest gestational ages. It is rare to diagnose post-hemorrhagic hydrocephalus in an infant born after less than 26 weeks’ gestation, even in the presence of grade 4 intraventricular hemorrhage. In contrast, post-hemorrhagic hydrocephalus is routinely detected in infants of 30 to 34 weeks’ gestational age who have suffered only grade 2 hemorrhage. In most instances, the sequence of events resulting in post-hemorrhagic hydrocephalus begins with multiple small clots throughout the ventricles. Although post-hemorrhagic hydrocephalus is traditionally thought to represent a communicating hydrocephalus with obstruction to the passage

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of cerebrospinal fluid at the level of the arachnoid villi, it is also probable that the cerebrospinal fluid is reabsorbed across the ependyma into small penetrating vessels within the developing white matter. Obstruction to flow may also occur at the level of these vessels or, less commonly, at the foramina of Luschka and Magendie in the posterior fossa [Deonna et al., 1975; Whitelaw, 1997]. In the presence of a block in the normal cerebrospinal fluid flow pathways, ventriculomegaly develops, and periventricular white matter damage may ensue. Suggested mechanisms for periventricular white matter injury after post-hemorrhagic hydrocephalus include raised pressure and edema, damaging effects of the free iron released into the cerebrospinal fluid during clot lysis, and proinflammatory cytokines [Savman et al., 2001]. A small percentage of infants with intraventricular hemorrhage may develop acute obstruction at the level of the aqueduct because of clots obstructing cerebrospinal fluid flow; these infants present with signs of acutely increased intracranial pressure (i.e., apnea, bulging fontanel, split sutures, and lethargy or coma) and require immediate neurosurgical attention. There is some evidence that there is an endogenous attempt to lyse clots in the cerebrospinal fluid by the preterm brain, but levels of plasminogen are low, and those of plasminogen activator inhibitor-1 (PAI-1) high in newborn cerebrospinal fluid [Hansen et al., 1997; Whitelaw, 1993]. Transforming growth factor-β1 (TGF-β1) is released into the cerebrospinal fluid of preterm infants after intraventricular hemorrhage; TGF-β1 upregulates genes for extracellular matrix proteins such as fibronectin and laminin and is critical for wound healing. TGF-β1 is virtually undetectable in the cerebrospinal fluid of infants without intraventricular hemorrhage; those with the greatest frequency of developing post-hemorrhagic hydrocephalus have the highest levels of TGF-β1 [Whitelaw et al., 1999]. When treating infants with post-hemorrhagic hydrocephalus, the physician must protect the neonate from damage from increased intracranial pressure and avoid the need for permanent cerebrospinal fluid drainage procedures. Previously advocated therapies included repeated lumbar punctures or ventricular taps; inhibition of cerebrospinal fluid production by acetazolamide or furosemide, or both; and intraventricular fibrinolytic therapy for clot lysis, but they have all been found to lack effect. Similarly, external ventricular drains and subcutaneous ventricular reservoirs have not been examined in controlled trials and are associated with significant risk of infection [Pang et al., 1986; Whitelaw, 2000a, 2000b, 2001a]. For these reasons, conservative management of post-hemorrhagic hydrocephalus in the absence of symptoms of increased intracranial pressure is generally recommended. Infants with intraventricular or intraparenchymal hemorrhage should undergo frequent determinations of occipitofrontal circumference [Ehrenkranz et al., 1999] and ultrasonographic determinations of ventricular size [Whitelaw, 2001b]. Although progressive ventriculomegaly may develop as early as the fourth or fifth postnatal day (see Fig. 16-13), the occipitofrontal circumference of the preterm infant may not increase until many days later because of the adaptive response of the preterm brain to absorb those subarachnoid fluid collections typically found over the convexities before exhibiting the more classic signs of increasing pressure

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Perinatal Acquired and Congenital Neurologic Disorders / 16

A

B

FIGURE 16-14. Intraventricular hemorrhage leading to post-hemorrhagic hydrocephalus (PHH). A, Coronal view shows where the blood has ruptured beyond the ependyma to enter the lateral ventricles, filling but not distending them. B, PHH is shown on a subsequent ultrasound scan, which demonstrates the interval enlargement of the lateral ventricles, third ventricle, and foramina of Monro. The development of PHH does not alter the grading of the original intraventricular hemorrhage.

[Wigglesworth et al., 1976]. MRI studies of infants with ultrasound-diagnosed post-hemorrhagic hydrocephalus (Fig. 16-14) may reveal intraventricular hemorrhage, ventriculomegaly, and evidence for periventricular infarction (Fig. 16-15). Because prolonged increased intracranial pressure may result in poor feeding, lethargy, apnea, and ultimately in

optic atrophy, if ventricular size and occipitofrontal circumference determinations persistently increase, neurosurgical consultation for ventriculoperitoneal shunt or third ventriculostomy can be electively planned. Infants with acute signs of increased intracranial pressure and ventriculomegaly with blockage at the aqueduct require immediate neurosurgical intervention.

Cerebral Palsy

FIGURE 16-15. Magnetic resonance imaging (MRI) demonstrates posthemorrhagic hydrocephalus. Axial MRI of a preterm infant reveals a large, left-sided intraventricular hemorrhage; acute ventricular dilation; and parenchymal infarction. (Courtesy of Andrew Whitelaw, MD, Southmead Hospital, University of Bristol Medical School, Bristol, UK.)

Cerebral palsy is an important and well-established outcome for preterm infants that has been monitored in some centers for more than 40 years [Hagberg et al., 1996]. Data suggesting that the incidence of cerebral palsy is increasing in the United States have attributed this finding to the increasing survival rates of many preterm and very-low-birth-weight infants [Allen, 2000; Hutton et al., 2000]. Several investigators have demonstrated that the risk factors for spastic motor handicap in preterm infants include abnormal cranial ultrasound findings [Doyle, 2001; Hack et al., 2000b; Wood et al., 2000]. Cranial ultrasound findings repeatedly found to be associated with disabling cerebral palsy include parenchymal involvement of intraventricular hemorrhage, cystic periventricular leukomalacia, and ventriculomegaly [Allan et al., 1997; Bass et al., 1999; de Vries et al., 1998; de Vries et al., 2004; Hansen et al., 2004; Piecuch et al., 1997; PintoMartin et al., 1995, 1999; van de Bor et al., 1993]. The authors of these eight studies compared ultrasound findings with the incidence of cerebral palsy in more than 2500 verylow-birth-weight preterm children between the ages of 2 and 9 years. Significant associations for grade 4 intraventricular hemorrhage, periventricular leukomalacia, and ventriculomegaly with cerebral palsy were found in all. In the study of Pinto-Martin, grade 4 intraventricular hemorrhage was

Ment / Intraventricular Hemorrhage of the Preterm Neonate

Cognitive Outcome in Preterm Infants with Intraventricular Hemorrhage Numerous studies have demonstrated that school-aged children of low birth weight (<1500 grams), very low birth weight (<1250 grams), and extremely low birth weight (<750 grams) are at excess risk for mental retardation and borderline intelligence [Hack et al., 2000a, 2002; McCarton et al., 1997; Vohr et al., 2003; Vohr et al., 2000]. Even when neurologically intact, these children have been shown to perform more poorly on tests related to language, visual perceptual organization, and memory than their term peers [Taylor et al., 2000a]. Preterm infants with parenchymal involvement by intraventricular hemorrhage are believed to be at particular risk for cognitive disability. In the 18 years since Krishnamoorthy and colleagues [1979] first reported that two of three surviving low birth weight infants with grade 4 intraventricular hemorrhage suffered mental retardation, the incidence of major developmental sequelae of this insult among very-low-birth-weight infants has been reported to vary from 45% to 86%. Infants with parenchymal involvement of hemorrhage suffer high rates (45% to 86%)

TABLE 16-7 Pharmacologic Prevention of Intraventricular Hemorrhage DRUG

MECHANISM OF ACTION

Antenatal corticosteroids

Induces germinal matrix microvascular maturation Induces pulmonary maturity Inhibits prostaglandin production Prevents free radical formation Decreases cerebral blood flow Closes patent ductus arteriosus Stabilizes capillaries Inhibits prostaglandin production Prevents capillary bleeding

Indomethacin

Ethamsylate

Adapted from Wells JT, Ment LR. Prevention of intraventricular hemorrhage in preterm infants. Early Hum Dev 1995;42:209.

90 Percentage of children

associated with cerebral palsy (OR = 15.4; 95% CI, 7.6 to 31.1), and in that of Hansen, the odds ratio for cerebral palsy with grades 3 or 4 intraventricular hemorrhage was 19.9 (CI, 6.1 to 64.8) [Hansen et al., 2004; Pinto-Martin et al., 1999]. In Pinto-Martin’s study, any grade intraventricular hemorrhage alone was associated with cerebral palsy (OR = 3.14; 95% CI, 1.5 to 6.5). Although most investigators include the results of all scans performed during the infant’s hospitalization, Allan and co-workers [1997] reported that cerebral palsy can be predicted from postnatal day 3 onward in preterm infants in whom serial ultrasonography is performed. Although preterm infants with cerebral palsy have traditionally been found to suffer spastic diplegia, concomitant with the rising rate of disabling spastic motor handicap, several investigators have also observed that cerebral palsy among preterm infants is almost equally divided among the three classic forms: spastic diplegia, hemiplegia, and quadriplegia [Allan et al., 1997; Hagberg et al., 1996]. It is believed that this change in distribution reflects both more focal and diffuse central nervous system injuries producing proportional increases in hemiplegias and quadriplegia.

323

80

> 80

70

70–80

60

< 70

50 40 30 20 10 0 IVH Neg

Gr 1– 2

Gr 3–4

FIGURE 16-16. Cognitive outcomes at 12 years’ corrected age of 322 children with birth weights between 600 and 1250 grams who participated in the Multicenter Randomized Indomethacin Intraventricular Hemorrhage Prevention Trial (NS 27116).The graph demonstrates the percent of children with normal full-scale IQ scores (>80), borderline scores (70-80), and scores in the mentally retarded range (<70); P = 0.002 for differences among the groups. Gr, grade; IVH, intraventricular hemorrhage; Neg, negative.

of mental retardation and cerebral palsy [Krishnamoorthy et al., 1979; Szymonowicz et al., 1986; Vohr et al., 1992; Whitaker et al., 1996], and grade 4 intraventricular hemorrhage is strongly associated with mental retardation at 2 to 9 years, with odds ratios ranging from 6.2 to 19 [Hansen et al., 2004; Ment et al., 2002] (Fig. 16-16). Although most investigators agree that maternal education and infant’s gestational age are important predictors of outcome at school age, even children with low grade hemorrhages are at cognitive disability when compared with their non-intraventricular hemorrhage, gestational age–matched peers [Whitaker et al., 1996]. Whitaker and colleagues [1996] found that preterm infants with low-grade intraventricular hemorrhage were almost five times more likely to suffer mental retardation at school age than their nonintraventricular hemorrhage, gestational age–matched peers.

PREVENTION OF INTRAVENTRICULAR HEMORRHAGE Although the numerous pharmacologic measures outlined in Table 16-7 have been suggested for the prevention of intraventricular hemorrhage in the preterm infant, it must be stressed that the most efficacious means for preventing intraventricular hemorrhage is the prevention of preterm birth [Creasy, 1991; Vermeulen et al., 2001]. When preterm birth is certain, transport of the mother and fetus to a tertiary perinatal center specializing in high-risk obstetric care is mandatory; for more than 3 decades, neonatologists have recognized that infants who were “outborn” and required transport to the neonatal intensive care unit have consistently higher rates of intraventricular hemorrhage than “inborn” patients [Hohlagschwandtner et al., 2001; Wells and Ment, 1995].

Antenatal Corticosteroid Exposure Corticosteroids administered before preterm birth lower the incidence of respiratory distress syndrome and decrease neonatal mortality [Crowley, 2000]. The incidence of

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Perinatal Acquired and Congenital Neurologic Disorders / 16

intraventricular hemorrhage is also reported to be lower in infants with antenatal corticosteroid exposure, possibly because of the improvement in respiratory difficulties. In the Cochrane Review, corticosteroid therapy consisted of 24 mg of betamethasone, 24 mg of dexamethasone, or 2 grams of hydrocortisone. Only four trials in that review reported intraventricular hemorrhage outcomes, and antenatal steroid exposure was followed by a relative risk of intraventricular hemorrhage of 0.57 (CI, 0.41 to 0.78), with a risk difference of –0.114 (CI, –0.176 to –0.53). These benefits extend to a broad range of gestational ages and are not limited by gender or race. No adverse consequences of a single course of prophylactic corticosteroid for preterm birth have been reported, although the action and long-term consequences of multiple courses of antenatal steroid exposure are not yet known, and there are no data to support repeated courses of these agents [Crowley, 2003; Wright et al., 1995]. Unlike studies evaluating respiratory distress syndrome as the primary outcome, a decrease in the incidence of intraventricular hemorrhage by antenatal corticosteroid exposure did not appear to require a complete course of medication. Decreased incidence of intraventricular hemorrhage has been observed after only a single dose of dexamethasone— suggesting the mechanism of prevention of intraventricular hemorrhage by these agents is not simply attributable to the induction of pulmonary maturation [Salhab et al., 2003; Wright et al., 1995]. For all of these reasons, the National Institutes of Health Consensus Development Conference recommended the liberal use of antenatal steroids for all preterm infants and stated that the significant benefits of this therapy outweigh possible adverse outcomes [Crowley, 1994].

Delivery Mode The role of labor and delivery mode in the pathogenesis of intraventricular hemorrhage is best examined in the studies using early cranial ultrasonography. Conservative evaluation suggests that only the hemorrhages detected within the first 6 hours of life may be best attributed to perinatal events. Although review of some retrospective studies with early ultrasonography suggests that infants delivered by cesarean section have less early-onset intraventricular hemorrhage than do those delivered vaginally [Anderson et al., 1988; Ment et al., 1992; Shaver et al., 1992; Synnes et al., 2001; Tejani et al., 1987], others do not support these data [Paul et al., 2002; Salafia et al., 1995], and prospective data are not yet available to address this important care issue [Matthews et al., 2003]. Although most investigators agree that the length and stage of labor must be considered as risk factors for early-onset intraventricular hemorrhage, these data appear more difficult to assess.

Neonatal Care The risk factors for intraventricular hemorrhage have been well described [Roland and Hill, 2003; Shalak and Perlman, 2002; Synnes et al., 2001]. Abrupt increases in blood pressure by volume re-expansion or pharmacologic means result in the loss of cerebral autoregulation and increased cerebral blood flow and should be avoided. Blood pressure and transcutaneous oxygen pressure should be continuously monitored to prevent hypoxemia, hypotension, and secondary

acidosis. Similarly, hypocarbia with PaCO2 levels below 30 mm Hg have been significantly associated with severe intraventricular hemorrhage [Erickson et al., 2002]. Depending on the gestational age and the postnatal day, preterm infants are known to have a high incidence of patent ductus arteriosus, and previous studies have suggested that the pharmacologic closure of this lesion is less likely to be associated with abrupt changes in cerebral blood flow than the surgical approach [Weiss et al., 1995].

Pharmacologic Prevention Concern about the neurodevelopmental outcome of very-lowbirth-weight preterm infants has prompted multiple pharmacologic intervention trials to prevent intraventricular hemorrhage. The agents evaluated have included antenatal and postnatal phenobarbital, vitamin E, indomethacin, and ethamsylate. After more than 15 years of study, the first two agents have been found not to influence the incidence of intraventricular hemorrhage in preterm infants [Donn et al., 1981; Shankaran et al., 1996b]. Indomethacin, a potent inhibitor of the cyclooxygenase pathway of prostaglandin synthesis, has consistently been found to decrease the incidence and severity of intraventricular hemorrhage in very-low-birth-weight preterm infants [Ment et al., 1994; Schmidt and David, 2001; Yanowitz et al., 2003]. In Fowlie’s meta-analysis of 19 clinical trials of the postnatal use of indomethacin in 2872 infants, postnatal indomethacin treatment reduced the overall risk for intraventricular hemorrhage by almost 50% and was found to be most efficacious for prevention of intraventricular hemorrhage grades 3 or 4 (RR = 0.66; 95% confidence interval 0.53 to 0.82) [Fowlie and Davis, 2002, 2003]. The ability of indomethacin to decrease the incidence and severity of intraventricular hemorrhage did not depend on gestational age. A synthetic indole derivative with a half-life of 11 to 30 hours in preterm infants, indomethacin decreases cerebral blood flow and blood-flow velocity in animal and human studies [Hammerman et al., 1995; McCormick et al., 1993]. Experimental animal studies have demonstrated a reduction in the normal pattern of cerebral blood flow reactivity to episodes of asphyxia or hypertension, including reducing the normal hyperemia induced by asphyxia [Leffler et al., 1985, 1986; Van Bel et al., 1993]. Nonetheless, Fowlie’s meta-analysis demonstrated no evidence of difference in rates of necrotizing enterocolitis, excessive bleeding, or sepsis in treated infants compared with controls. An increased incidence of oliguria was seen with prophylactic indomethacin (RR = 1.90 [1.45, 2.47]), but there was no evidence for major renal impairment [Fowlie and Davis, 2002, 2003]. Current recommendations suggest that all infants with birth weights of 1250 grams or less who are clinically stable and lack contraindications for indomethacin treatment be treated with prophylactic indomethacin with a dose of 0.1 mg/kg per dose, beginning at 6 to 12 postnatal hours and with two additional doses 24 and 48 hours after the first administration. Indomethacin may be best administered after the administration of surfactant, when there is evidence for acceptable oxygenation and ventilation. Indomethacin should be infused slowly, preferably over 30 minutes or more [Bada, 1996; Clyman, 1996].

Ment / Intraventricular Hemorrhage of the Preterm Neonate

Ethamsylate is a water-soluble, nonsteroidal drug that has been used in Europe for several decades to reduce capillary bleeding during surgery. There is some evidence that it may increase platelet adhesiveness and capillary resistance by causing polymerization of hyaluronic acid in the capillary basement membrane and modifying prostaglandin biosynthesis [Vinazzer, 1980]. Several clinical studies have been performed in Europe to evaluate the efficacy of postnatally administered ethamsylate in preventing intraventricular hemorrhage [Benson et al., 1986; Morgan et al., 1981]. In these trials, ethamsylate reduced the overall risk of intraventricular hemorrhage without significant reduction in the rates of severe intraventricular hemorrhage, death, or neurologic abnormality. ACKNOWLEDGMENTS This work was supported by NS 27116 and NS 35476 of the National Institute of Neurologic Disorders and Stroke.

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CHAPTER 17

Neonatal Brain Injury Meredith Rose Golomb, Natalie Z. Cvijanovich, and Donna M. Ferriero

Neonatal brain injury encompasses a wide variety of conditions that result in damage to the newborn nervous system. This chapter focuses on only the conditions thought to be acquired at or near the time of birth—neonatal stroke and trauma—rather than diseases that can manifest at birth with similar clinical presentations (e.g., neonatal encephalopathy) but are caused by metabolic diseases, genetic malformations, or early in utero ischemic events. Although neonatal stroke and trauma are not uncommon, the risk factors, causes, and outcomes are still unknown because of a paucity of population-based studies. However, emerging data are changing previous concepts regarding pathophysiology, especially for neonatal stroke. In the past, outcomes for these conditions have been primarily focused on the major neurologic residua of cerebral palsy (see Chapter 20). However, data from the Canadian Pediatric Stroke Registry and the German Childhood Stroke Study Group [deVeber et al., 2000, 2003; Kurnik et al., 2003] suggest that cognitive outcomes without motor impairment, especially in language function [Trauner et al., 2001], are equally important neurologic disabilities in affected children. This chapter reviews what is known regarding the incidence, causes, risk factors, and outcome of stroke and traumatic brain injury, with attention to the clinical presentations and methods of diagnosis and management after these conditions occur. Pathophysiology is discussed in more detail in Chapters 14 and 15 because hypoxicischemic injury and focal ischemia-reperfusion injury in the setting of stroke are thought to have common pathogenetic mechanisms. However, pathophysiology of trauma in the newborn period is relatively unstudied, and only broad assumptions can be made for these conditions.

STROKE Definition and Epidemiology The most common form of neonatal brain injury is stroke. Neonatal stroke is a term broadly used to define all ischemic and hemorrhagic events that affect the arterial and venous distribution of blood supply from early gestation to the first month of life. The term perinatal arterial stroke has been used to define strokes that occur between 28 weeks’ gestation and the first 7 days of life, in which the stroke is caused by ischemia in an arterial distribution only [Nelson and Lynch, 2004]. Strokes occurring before 28 weeks have been described [Ozduman et al., 2004]. In the newborn period, stroke has an incidence (1 in 4000 live births) similar to that of stroke in the elderly [Lynch et al., 2002]. As neuroimaging helps physicians define the

pattern of injury of stroke in the newborn, definitions will be improved, and better classifications will emerge [Sebire et al., in press]. Fortunately, unlike stroke in the elderly or even in children, stroke in newborns rarely recurs [Kurnik et al., 2003]. It is difficult to establish the exact prevalence of perinatal stroke. Using studies of children with neonatal seizures, prevalence has been estimated to be roughly 12% of neonates older than 31 weeks’ gestation with seizures [Estan and Hope, 1997; Lynch et al., 2002]. This rate translates to a prevalence of perinatal stroke of 24.7 cases per 100,000 infants older than 31 weeks’ gestation, and it is similar to the estimated prevalence of 28.6 cases per 100,000 live births reported by Perlman and colleagues [1994]. Based on these estimates, perinatal stroke is recognized in approximately 1 in 4000 live births. However, there is a subgroup of neonates who do not present until late infancy because the neurologic examination is normal in the newborn period. These infants present later with pathologic early hand preference or seizures, or both [Golomb et al., 2001]. Stroke in newborns has a male predominance, and there is a tendency toward left-sided lesions [Golomb et al., 2004; Trauner et al., 1993]. It is unclear why there is a gender difference. The U.S. infant mortality rate for 1995 to 1998 due to stroke (ICD-9 CM 430-437) is 5.33 deaths per 100,000 per year, the perinatal mortality rate is 2.21 per 100,000, and the neonatal mortality rate is 3.49 per 100,000 live births per year [Lynch and Nelson, 2001]. The National Hospital Discharge Survey (1980 through 1998) determined that for infants younger than 30 days of age, the in-hospital mortality rate for neonatal stroke was 10.1%, or 2.67 deaths per 100,000 live births [Lynch and Nelson, 2001; Lynch et al., 2002].

Classification and Risk Factors Neonatal strokes more frequently result from arterial occlusion (Fig. 17-1), but venous infarction and sinovenous thrombosis in the term infant can also be considered stroke syndromes. Various types of studies of infants with neonatal stroke have found an association with cardiac disorders, blood disorders, infection, trauma, drugs, maternal and placental disorders, and perinatal asphyxia, depending on the classification of stroke and the type of study [Nelson and Lynch, 2004]. In some studies, the occurrence of multiple risk factors has been documented, especially blood disorders with asphyxial stress [Golomb et al., 2001; Wood et al., 2000; Wu et al., 2002].

Risk Factors for Arterial Ischemic Strokes Many maternal, fetal, and neonatal risk factors have been associated with neonatal arterial ischemic strokes. Hemato-

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Perinatal Acquired and Congenital Neurologic Disorders / 17 FIGURE 17-1. In a term newborn with focal seizures, magnetic resonance imaging (MRI) reveals the arterial ischemic stroke. A, Diffusionweighted image (b = 700) reveals arterial distribution of damage well before the standard MRI image that only suggests signal abnormality in that region. B, SE = 600/11.

A

B

logic factors, including factor V Leiden mutation, hyperhomocysteinemia, and elevated lipoprotein(a) levels, have emerged as important antecedents for this condition [Govaert et al., 2000; Hogeveen et al., 2002]. A population-based study of arterial ischemic stroke found that most patients presented acutely in the newborn period. Prepartum and intrapartum conditions were more common in these infants than in controls drawn from births in a managed care organization in Northern California. Univariate analysis revealed gestation longer than 41 weeks, prolonged rupture of membranes, chorioamnionitis, prolonged second stage of labor, fetal distress, emergent cesarean section, fertility treatment, and preeclampsia as major risk factors. However, the factors that emerged after multivariate analysis were prolonged second stage of labor (OR = 8.8; P = 0.001), preeclampsia (OR = 5.3; P = 0.04), and prolonged rupture of membranes (OR = 3.4; P = 0.05) [Lee et al., 2005; Wu et al., 2004a]. However, in a population of children with perinatal ischemic stroke identified by the fact that they had motor impairment, risk factors were preeclampsia (OR = 3.6; 95% CI, 1.1 to

11.4) and intrauterine growth restriction (OR = 5.3; 95% CI, 1.5 to 18.6) [Wu et al., 2004b].

Risk Factors for Cerebral Venous Thrombosis Sinovenous thrombosis is an important cause of stroke in the neonate (Fig. 17-2). This type of stroke is becoming increasingly recognized, likely reflecting the use of more sensitive neuroimaging techniques such as magnetic resonance (MR) venography. In a retrospective series of children with abnormal imaging studies suggestive of sinovenous thrombosis, 61% were neonates [Carvalho et al., 2001]. The Canadian Pediatric Ischemic Stroke Registry identified 0.67 cases per 100,000 per year, with neonates the most commonly affected (43%) [deVeber and Andrew, 2001]. Risk factors are similar to those for arterial ischemic stroke. Neonates with sinovenous thrombosis have acute systemic illnesses, including thrombophilias, asphyxial stress, dehydration, and infection [deVeber and Andrew, 2001]. Often, neonates have more than one risk factor [Wu et al., 2002]. FIGURE 17-2. In a 6-day-old neonate with focal seizures, magnetic resonance imaging reveals a venous infarct in the temporal lobe with a thrombosed left transverse sinus (arrow). A, SE = 500/15. B, SE = 3000/120.

A

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Clinical Presentation and Diagnosis

Evaluation

Arterial and venous strokes in the newborn often manifest with seizures. Whereas seizures associated with other forms of neonatal encephalopathy tend to be multifocal or myoclonic, seizures associated with arterial ischemic stroke tend to be persistently focal motor, often involving only one upper extremity. The head ultrasound scan may be normal if the stroke is superficial and ischemic, or it may reveal an intraventricular hemorrhage, but this is not the intraventricular hemorrhage of prematurity. Magnetic resonance imaging (MRI) imaging, MR angiography, and venography may reveal the site of the occlusion or venous thrombosis and may show other parenchymal abnormalities, such as thalamic hemorrhage in cases of venous thrombosis [Wu et al., 2002]. In a population-based study of perinatal arterial stroke in children with motor impairment, most of the children presented after 3 months of life with hemiparesis (first recognized as early hand preference) or seizures [Wu et al., 2004b].

If it has been determined by neuroimaging and neurologic evaluation that the newborn has had a stroke, a complete evaluation must be performed. This evaluation includes MR angiography and venography to evaluate the vascular system, transendocardial echography if the stroke is thought to be embolic in distribution on neuroimaging, and a complete hematologic evaluation (Box 17-1). At the time of the event, certain hematologic disorders cannot be diagnosed accurately, and the evaluation must be performed in phases. Many prothrombotic risk factors in the fetus and neonate have been associated with neonatal stroke and sinovenous thrombosis. These can be assessed through measuring the overall function of the clotting pathways, the presence of components of the clotting pathways, and the activity of these components and by checking for genetic mutations of components in the clotting pathways. The overall function of the clotting pathways can be assessed using prothrombin time with the international normalized ratio and partial thrombo-

Box 17-1 EVALUATION OF NEONATES WITH ARTERIAL ISCHEMIC STROKE OR CEREBRAL SINOVENOUS THROMBOSIS* Prothrombotic Risk Factors Probably useful Complete blood count with differential (to screen for polycythemia, anemia) Prothrombin time (PT) with international normalized ratio (INR) Partial thromboplastin time (PTT) Serum electrolytes (to screen for dehydration) Protein C activity, protein S activity, antithrombin III activity† Activated protein C resistance (APCR) screen Lipoprotein(a) Homocysteine Factor V Leiden mutation Prothrombin 20210 gene defect Methylene tetrahydrofolate reductase (MTHFR) C677T gene defect Possibly useful Antiphospholipid antibody screens (unclear which are most helpful; large volume of blood required for test) Factor VIIIc MTHFR A1298C gene defect Plasminogen activator inhibitor-1 gene 4G/5G polymorphism Cranial Imaging Head computed tomography (CT); CT angiography or venography as appropriate and available Magnetic resonance imaging (MRI); diffusion weighted imaging MR angiography or venography as appropriate and available Echocardiography Transthoracic echocardiography Possibly useful Follow-up transthoracic echocardiography with injection of agitated saline after 1 year of age; transesophageal echocardiography in rare cases to screen for patent foramen ovale (PFO) because all neonates will have a PFO detected if echocardiography is done too early *There are few studies in this area, and there are no universally accepted guidelines. † Normal levels (determined by antigen measurement and activity) for neonates are lower than for older children and adults. Levels may be temporarily low in the setting of acute illness; the significance of this is unclear. Data from Debus OM, Kosch A, Strater R, et al. The factor V G1691A mutation is a risk for porencephaly: A case-control study. Ann Neurol 2004;56:287.

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plastin time. Components of the clotting pathways that should be tested include protein C, protein S, and antithrombin III. Elevated factor VIIIc levels have been seen in the setting of stroke; whether these are more cause or effect is uncertain. Tests for protein C activity, activated protein C resistance screen, protein S activity, and antithrombin activity clarify function; although a test for the presence of protein C using protein C antigens may be normal, an abnormality in protein C function can lead to a prothrombotic state. Assays for genetic mutations of components in the clotting pathways include tests for the factor V Leiden mutation, the prothrombin 20210 gene defect, and the 4G/4G genotype of the plasminogen activator inhibitor-1. Some molecules that do not play a direct role in the clotting pathways do affect the endothelium or interact with components of the clotting pathways; homocysteine, lipoprotein(a), and antiphospholipid antibodies are examples of this process. Elevated levels of these molecules may promote thrombosis. Mutations in the methylene tetrahydrofolate reductase gene (MTHFR) have been associated with elevated homocysteine levels, and increased thrombosis risk. Variations in platelet activity may play a role in neonatal thrombosis, but this is an area still under study. There are no evidence-based guidelines about which tests are the most useful because there have been few studies on neonates with stroke. Guidelines are not clear about when, if ever, abnormalities in these prothrombotic risk profiles should be treated prophylactically [deVeber and Andrew, 2001; Golomb, 2001, 2003; Kurnik et al., 2003; Nowak-Gottl et al., 2003]. Prothrombotic risk factors are one piece of the puzzle; initial strokes and the rare recurrences often occur in the setting of other underlying diseases [deVeber and Andrew, 2001; Kurnik et al., 2003]. Maternal prothrombotic risk factors may also play a role in perinatal stroke, and this area requires further study (see Box 17-1) [Golomb, 2003].

Management Acute Period For all types of perinatal stroke, supportive care with particular attention to monitoring of intracranial pressure is essential. Regular assessment of fontanel and head circumference is usually sufficient for the stable neonate; the less stable neonate may require intracranial pressure monitoring. Thrombolytic therapy has been used to treat thrombi in the peripheral vasculature in neonates [Nowak-Gottl et al., 1999], but it has rarely been used in the treatment of neonatal stroke. We are unaware of any examples of successful use of thrombolytic agents for the treatment of neonatal arterial ischemic stroke. There are a few case reports of its use in sinovenous thrombosis [Higashida et al., 1989; Wong et al., 1987]. The use of heparin is also controversial. It is not generally used in neonates with arterial ischemic stroke; there are rare cases of neonates with severe prothrombotic disorders with multiple systemic thrombi who might benefit. Low-molecular-weight heparin has been used in a pilot study of neonates with sinovenous thrombosis with few problems [deVeber et al., 1998]; but there is no agreement about when it should be used. Case reports have described the use of antithrombin concentrate [Petaja et al., 1999; Shiozaki et al., 1993] and protein C

concentrate [Dreyfus et al., 1995] in neonates with congenital or iatrogenic factor deficiencies to prevent venous thrombosis. Children with intraparenchymal hemorrhage need close monitoring of intracranial pressure. If hemorrhage is caused by thrombocytopenia or a factor deficiency, the deficiency should be corrected by platelet transfusion immediately with close monitoring. Vitamin K deficiency is still a cause of intraparenchymal hemorrhage in areas of the world where vitamin K is not routinely administered [Chuansumrit et al., 1998], and it should be given in these cases. Vitamin K deficiency induced by maternal ingestion of Coumadin or antiepileptic drugs before delivery may be difficult to treat even when large doses of vitamin K are administered [Renzulli et al., 1998; Sutor et al., 1999]. Intraparenchymal and intraventricular hemorrhages may require surgical evacuation and shunting [Sandberg et al., 2001]. Small case studies have described the use of recombinant tissue plasminogen activator in preterm infants with intraventricular hemorrhage to prevent the development of hydrocephalus; although early studies appear promising, additional studies are needed in larger groups of preterm and term neonates to evaluate this potential treatment [Haines and Lapointe, 1999; Whitelaw et al., 1996].

Chronic Period Rehabilitation therapy is a key component of the long-term management of all children with perinatal stroke. There is some evidence that for children with hemiplegia, therapy using constraint of the normal arm to force use of the plegic arm is effective [Taub et al., 2004]. There are no evidence-based guidelines about when, if ever, children with neonatal stroke should be placed on long-term prophylactic therapies such as aspirin or lowmolecular-weight heparin. Children with prothrombotic risk factors who also have complex congenital heart disease or who develop an illness that leads to dehydration or prolonged bed rest may be at particularly high risk for recurrent thromboembolism [Kurnik et al., 2003]. It may be worth considering prophylactic therapy in some of these patients. It seems reasonable to ensure that children carrying the MTHFR polymorphism receive adequate folate in their diets and maintain normal homocysteine levels. Supplemental folate may be warranted. There are similar issues concerning the long-term treatment of children with neonatal sinovenous thrombosis. It is reasonable to try to prevent known precipitating factors of sinovenous thrombosis, such as dehydration or anemia [deVeber and Andrew, 2001]. Neonates with bleeding disorders precipitating intraparenchymal hemorrhage may require prophylactic replacement of coagulation factors [Myles et al., 2001] and may need to adjust their lifestyle to prevent trauma.

Outcomes Perinatal stroke in the term and near-term neonate may result in significant long-term morbidities, including cerebral palsy, cognitive delay, and epilepsy. Many variables, including the extent of injury and the presence of coexistent conditions, may help predict the eventual outcome.

Golomb, Cvijanovich, and Ferriero / Neonatal Brain Injury

Motor Effects Arterial ischemic stroke may lead to permanent motor impairment or cerebral palsy. Estimates of motor impairment after neonatal arterial ischemic stroke range from 9% to 88% [Clancy et al., 1985; deVeber et al., 2000; de Vries et al., 1997; Koelfen et al., 1995; Mercuri et al., 1999, 2004; Sran and Baumann, 1988; Trauner et al., 1993], and estimates of motor impairment after neonatal sinovenous thrombosis range from 6% to 28% [deVeber and Andrew, 2001; deVeber et al., 2000; Volpe, 2001]. There are few studies of term neonates with spontaneous intraparenchymal hemorrhage; one study [Sandberg et al., 2001] reviewed 40 years of neurosurgical patients at the Hospital for Sick Children in Toronto and found only 11 term neonates with spontaneous intraparenchymal hemorrhage. Four (36%) of these children developed a chronic hemiparesis, which was mild in two. Motor impairment after perinatal stroke may range from subtle hemiplegia to severe quadriplegia. Most children with ischemic stroke diagnosed in the neonatal period attain independent walking [Golomb et al., 2003a]. Small study numbers, variation in case selection and identification, and limited degree of follow-up account for some of this variability.

Sensory Effects There are few studies in the area of sensory effects, in part because it is difficult to assess sensory function in young children. Thalamic atrophy has been seen in children with neonatal middle cerebral artery infarct, but whether this atrophy has long-term implications for sensory perception or memory is unclear [Giroud et al., 1995]. In 4 of 12 children and young adults with unilateral perinatal stroke, abnormally high somatosensory evoked potentials were found over the nonaffected hemisphere, but these 4 were unable to cooperate or communicate enough to further evaluate sensory function [Ferri et al., 2001]. Six (28%) of 16 school-age children with perinatal stroke tested had impaired visual function [Mercuri et al., 2003]. Children with unilateral pre- or perinatal strokes have more difficulty with facial recognition [Ballantyne and Trauner, 1999] and other visuospatial tasks [Schatz et al., 2000; Stiles et al., 1996, 1997].

Cognitive Effects Estimates of cognitive impairment after perinatal stroke range from 0% to 55%. Most studies do not report cognitive outcomes in detail; in some studies, motor and cognitive outcomes are grouped together as “developmental delay,” making it difficult to determine which abilities are affected. In one study of 29 children with unilateral perinatal stroke, all children older than 2 years of age had IQ scores within normal range [Trauner et al., 1993]. Above-average academic performance is possible even in the setting of large middle cerebral artery strokes [Golomb et al., 2005]. However, the presence of neonatal encephalopathy may be a poor prognostic sign; at 30 months of age, 5 (83%) of the 6 children with perinatal stroke and neonatal encephalopathy had Bayley Developmental Index scores more than

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2 standard deviations below the mean [Ramaswamy et al., 2004]. Estimates of generalized developmental delay after neonatal sinovenous thrombosis have ranged from 28% [Volpe, 2001] to 58% [Carvalho et al., 2001]. In one study, 1 (5.3%) of the 19 children with neonatal sinovenous thrombosis had a learning disability [Carvalho et al., 2001]. Speech delay or cognitive delay was reported in 4 (33%) of 12 children with spontaneous intraparenchymal hemorrhage [Sandberg et al., 2001].

Epilepsy There are few studies looking at epilepsy after perinatal stroke and sinovenous thrombosis. Estimates of epilepsy after the neonatal period for arterial ischemic stroke range from 0% to 46% [Estan and Hope, 1997; Golomb et al., 2001; Sran and Baumann, 1988; Sreenan et al., 2000]. Only two studies with more than 15 patients reporting epilepsy outcomes after neonatal sinovenous thrombosis have been published. One reported seizures in 12 (20%) of 61 neonates with sinovenous thrombosis [deVeber and Andrew, 2001]. The other study described 17 neonates with sinovenous thrombosis. One had a single febrile seizure after the neonatal period, one had two isolated seizures before 3 months of age, and one had severe epilepsy [Shevell et al., 1989]. A subset of pediatric stroke patients develops severe epilepsy syndromes such as infantile spasms [Shields et al., 1992] and intractable epilepsy requiring surgical treatment [Di Rocco et al., 1993].

Recurrence One study followed 215 children with neonatal arterial ischemic stroke who presented in the neonatal period for a median of 3.5 years and found recurrent symptomatic thromboembolism in 7 (3.3%); 4 children had arterial ischemic stroke, 2 had sinovenous thrombosis, and 1 had deep venous thrombosis of the leg. Prothrombotic risk factors and the presence of additional morbidities such as complex congenital heart disease or dehydration were associated with an increased risk of recurrence [Kurnik et al., 2003]. There are little data on the risk of recurrent thromboembolism after neonatal sinovenous thrombosis. Two of the 11 children with intraparenchymal hemorrhage in one study had reaccumulation of blood that required repeat evacuation, but none had repeat hemorrhage during the mean follow-up period of 4.5 years [Sandberg et al., 2001]. Children with hemophilia A who also carry prothrombotic factors may be at decreased risk for presenting in the neonatal period with hemorrhage or having recurrent intracranial hemorrhage [Escuriola Ettingshausen et al., 2001].

Predictors of Outcomes VASCULAR TERRITORY The vascular territory that is infarcted aids in predicting outcome but is not highly accurate. One study of 24 children with perinatal stroke reported that concomitant involvement of cortex, basal ganglia, and internal capsule on MRI predicted hemiplegia more strongly than involvement of one

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of these territories [Mercuri et al., 1999]. A study of 23 preterm and term neonates with middle cerebral artery ischemic stroke found that involvement of the main branch territory was predictive of hemiplegia [de Vries et al., 1997]. A study of 40 preterm and term neonates (22 term) found that primary cortex involvement was predictive of later hemiplegia [Govaert et al., 2000]. However, ultrasound was the only imaging study performed in the neonatal period, and it is not sensitive enough to determine the presence or degree of infarction [Golomb et al., 2003b]. In a study of 62 children with neonatal arterial ischemic stroke, the presence of bilateral infarctions predicted a lower probability of walking [Golomb et al., 2003a]. One study of 46 children with neonatal arterial ischemic stroke did not find that the extent of damage in a particular region of vascular territories was a good predictor of outcome [Sreenan et al., 2000]. Among children with sinovenous thrombosis, neonates who do not progress to infarction have better outcomes [Barron et al., 1992; deVeber and Andrew, 2001; Golomb et al., 2003a].

NEONATAL SEIZURES AND EARLY ELECTROENCEPHALOGRAM In one study of 46 neonates with arterial ischemic stroke the presence of seizures in the neonatal period was predictive of one or more disabilities in the first years of life [Sreenan et al., 2000]. The presence of an abnormal background electroencephalographic pattern was a predictor of hemiplegia in one study [Mercuri et al., 1999].

REHABILITATION Although there are many studies examining the effect of rehabilitation on outcome in children with cerebral palsy [Awaad et al., 2003; Bottos et al., 2001; Fedrizzi et al., 2003; Limperopoulos et al., 1997; Reid, 2002; Sala and Grant, 1995], no studies have looked specifically at the effect of rehabilitation on the outcomes of perinatal arterial ischemic stroke or sinovenous thrombosis. The need for rehabilitation may be a predictor of poor outcome [deVeber et al., 2000].

ADDITIONAL FACTORS Several other risk factors have been mentioned in individual studies. Neonatal encephalopathy may be a predictor of poor outcome after arterial ischemic stroke [Ramaswamy et al., 2004]. Some children appear normal in the neonatal period but develop hand preference or seizures after 2 months of age, and they are diagnosed with what is presumed to be perinatal arterial ischemic stroke. These children may have a poorer prognosis than children who present during the neonatal period because the symptoms with which they present (i.e., hemiparesis or seizures) may be more likely to persist [Golomb et al., 2001]. The presence of a prothrombotic disorder may lead to poorer outcome after neonatal arterial ischemic stroke [Mercuri et al., 2001]. Term neonates with intraparenchymal or intraventricular hemorrhages without clear precipitating causes appear to have a better prognosis than children whose hemorrhages were precipitated by hypoxic-ischemic insults or trauma [Bergman et al., 1985].

PERINATAL TRAUMA Perinatal traumatic injuries were first reported almost 2 centuries ago. In 1819, the occurrence of subgaleal hematoma was described by Naegele [Amar et al., 2003]. Salmonsen described cranial birth injuries after normal spontaneous vaginal deliveries in 1928 [Pollina et al., 2001]. Perinatal spinal cord injury was reported as early as 1869, when Parrot described an infant with difficult delivery requiring significant traction to the head resulting in rupture of the spinal cord at C6-7. In the 1920s, several classic articles on spinal cord injury were published [Blount et al., 2004; Filippigh et al., 1994; Rossitch and Oakes, 1992]. With recognition of the risk of significant perinatal central nervous system injuries and improvements in obstetric technique, the incidence of such injuries has reportedly decreased, but they remain a significant cause of neonatal morbidity and mortality.

Definition and Epidemiology Although cranial birth injuries in newborn infants are rare, they are potentially life-threatening complications. Major birth trauma, defined as “any condition that affects the fetus adversely during delivery” [Hughes et al., 1999] occurs in approximately 3.2% of births. Mechanical forces and hypoxia can contribute to birth injury. Mechanical trauma can result in damage to the extracranial, cranial, or intracranial structures; spinal cord; or peripheral nerves. Most birth injuries are clavicular fractures, accounting for more than 94% of injuries [Medlock and Hanigan, 1997]. However, 2% of all neonatal deaths and 10% of all neonatal deaths of term infants are the result of birth injury [Hughes et al., 1999; Pollina et al., 2001]. Injury-related neonatal death can result from intracranial hemorrhage, massive blood loss as a result of subgaleal hemorrhage, or cervical spinal cord injury.

Risk Factors A variety of factors predisposing infants to birth trauma have been reported. These include fetal macrosomia, breech or footling presentation, shoulder dystocia, prolonged labor, primiparity, and forceps- or vacuum-assisted delivery [Hughes et al., 1999; Medlock and Hanigan, 1997; Perrin et al., 1997; Pollina et al., 2001]. There also have been reports of significant perinatal injury even in the setting of seemingly uncomplicated delivery [Chamnanvanakij et al., 2002; Medlock and Hanigan, 1997; Morota et al., 1992; Pollina et al., 2001]. During the normal birth process, the fetal head is subjected to significant pressure, ranging from 38 to 390 mm Hg, with an average of 158 mm Hg [Medlock and Hanigan, 1997]. These pressures can result in overriding sutures, which may cause direct cerebellar trauma, rupture or tearing of large venous channels, bridging veins, or tentorial leaflets [Chamnanvanakij et al., 2002; Hayashi et al., 1987b; Perrin et al., 1997]. Traction and torsion injuries may result in cervical spinal cord and brachial plexus injury [Filippigh et al., 1994; Menticoglou et al., 1995; Morota et al., 1992; Rehan and Seshia, 1993; van Ouwerkerk et al., 2000].

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There is controversy about the effect of mode of delivery on the incidence of significant neonatal injury. In a large study of 583,340 live-born singleton infants born to nulliparous women and weighing between 2500 and 4000 grams, Towner and co-workers [1999] found that the incidence of neonatal intracranial injury (including subdural, intracerebral, intraventricular, and subarachnoid hemorrhage) was significantly higher with vacuum extraction, forceps delivery, and cesarean delivery during labor compared with spontaneous vaginal delivery or cesarean section with no labor. The investigators concluded that the increased risk of injury resulted from abnormal labor requiring intervention, rather than vacuum extraction or forceps delivery [Towner et al., 1999]. In another study, Pollina and associates [2001] conducted a retrospective chart review of 41 children with cranial birth injuries (i.e., skull fracture, epidural or subdural subarachnoid intracerebral intraventricular hemorrhage, or intraparenchymal brain injury) over a 9-year period. They found that birth weight, Apgar scores, and mode of delivery were independently associated with cranial injury. However, in contrast with the previous study, these investigators found that the incidence of cranial trauma was only slightly higher with delivery by cesarean section compared with spontaneous vaginal delivery, whereas it was markedly higher for infants delivered by means of forceps- or vacuum-assisted delivery [Pollina et al., 2001].

Clinical Presentation and Management by Diagnosis The clinical presentation of neonatal traumatic central nervous system injury varies according to the type of injury. Most commonly, cranial birth injuries manifest with apnea and seizures [Pollina et al., 2001]. Clinical presentations of the different types of injuries are discussed in more detail in later sections. A neonate presenting with signs and symptoms of cranial birth injury should be evaluated for anemia, thrombocytopenia, and coagulopathy. Laboratory tests should include complete blood count, prothrombin time, partial thromboplastin time, fibrinogen, and blood typing in anticipation of possible transfusion in more severe cases. Because of the difficulty in distinguishing between neonatal sepsis and cranial trauma on presentation, blood and urine cultures and a lumbar puncture are often performed during the initial evaluation [Chamnanvanakij et al., 2002]. Results of these initial evaluations usually reveal predisposing factors, such as vitamin K deficiency, hemophilia, thrombocytopenia, sepsis, or disseminated intravascular coagulopathy [Haase et al., 2003]. Radiographic studies that should be considered depend on the presentation and suspected site of injury. Computed tomography (CT) scanning is a useful initial study that can reveal depressed skull fractures, large subgaleal hematomas, and intracranial hemorrhage. MRI can further elucidate parenchymal injury and underlying bony fractures revealed by CT.

site of insertion can become a site of infection or bleeding. Although generally benign, scalp electrodes are associated with infection in 1% of cases, and in rare cases (usually in preterm infants), they can cause severe bleeding leading to hypotension. Caput succedaneum refers to the soft tissue swelling that is often associated with bruising over the molded region. Although the condition is generally benign and resolves over time, abrasions over the area can become infected, and absorption of blood from bruising can result in hyperbilirubinemia. Cephalhematoma is the term for hemorrhage into the subperiosteum as a result of separation of the pericranium from the skull during birth. It does not cross suture lines and does not transilluminate (in contrast to caput succedaneum). The incidence ranges from 0.4% to 2.49% of live births [Hughes et al., 1999]. Ultrasound may distinguish between cephalhematomas and subgaleal hematomas and detect coexisting intracranial hemorrhage. Spontaneous resolution usually occurs, with calcification appearing as a rim of curvilinear new bone that resorbs within 2 to 8 weeks (Fig. 17-3). Rarely, a cephalhematoma may become infected [King and Boothroyd, 1998]. Skull fracture is associated with cephalhematoma in up to 25% of neonates [Hughes et al., 1999], and skull radiography or CT is indicated when a fracture is suspected. Significant cephalhematoma may result in symptomatic anemia or hyperbilirubinemia, or both. Aspiration of a cephalhematoma is indicated only in the presence of increasing size, increasing erythema, or suspected infection [Medlock and Hanigan, 1997]. Subgaleal hematoma results from bleeding into the loose tissue beneath the scalp aponeurosis, usually in association

Extracranial Injury Scalp electrode injury is a possible effect of monitoring. Use of scalp electrodes for fetal monitoring has increased along with fetal blood sampling for blood gas measurement. The

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FIGURE 17-3. Plain x-ray film depicts a calcified cephalhematoma in a 6-week-old infant.

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with forceps- or vacuum-assisted delivery. When shearing or traction forces are applied to this tissue during birth, the multiple emissary veins that connect the intradural sinuses with the superficial veins of the scalp can be torn. Alternatively, the interparietal synchondrosis may be torn, resulting in bleeding from the sagittal sinus into the subgaleal space. In contrast to cephalhematoma, subgaleal hematomas may cross suture lines and extend to the nape of the neck. There is potential for life-threatening blood loss into this space, with associated hemorrhagic shock and a mortality rate of 20% to 25%. The incidence of subgaleal hematomas ranges from 4 to 59 per 10,000 births and is associated with vacuum extraction, prematurity, male gender, African lineage, primiparity, macrosomia, positional dystocia, and hypoxia [Amar et al., 2003]. Neonates with subgaleal hematomas present initially with fluctuant scalp swelling that may progress to skin discoloration of the frontal and suboccipital areas and obscuration of the fontanel. In severe cases, signs and symptoms of hypovolemic shock may develop, including tachycardia and oliguria. Consumptive coagulopathy may result in bleeding involving other organs with epistaxis or melena. If the hematoma is large enough to cause cerebral injury, irritability, lethargy, poor feeding, and other signs of central nervous system depression may ensue [Amar et al., 2003]. Resorption of the blood may result in hyperbilirubinemia. Laboratory tests should include a complete blood count and coagulation studies. The bleeding may be brisk enough that the hematocrit is not reflective of the actual blood loss. Coagulation factors, including prothrombin time, partial thromboplastin time, fibrinogen, and D-dimers, should be checked and corrected as needed. Head CT should be performed to determine the extent of the subgaleal hematoma and to assess whether other intracranial conditions exist (Fig. 17-4). Most subgaleal hematomas are benign and do not require treatment [Medlock and Hanigan, 1997]. In some neonates in whom a massive subgaleal hematoma occurs, management consists of fluid resuscitation to maintain adequate circulating blood volume, correction of anemia and coagulopathy, and treatment of seizures and hyperbilirubinemia. A rough estimate of blood loss can made by equating a 1-cm

increase in head circumference to a 40-mL blood loss. If there is evidence of brain compression, neurosurgical intervention may be required [Amar et al., 2003].

Cranial Injuries Skull fractures should be suspected in any neonate with a cephalohematoma or subarachnoid hemorrhage. Skull fractures may be linear, most commonly involving the parietal bone, or depressed, resulting in the so-called ping-pong fracture. Although fractures due to fetal compression against the bones surrounding the birth canal may occur during normal delivery, they are often associated with application of forceps or other assisted deliveries [Hughes et al., 1999; Medlock and Hanigan, 1997; Papaefthymiou et al., 1996]. Isolated depressed skull fractures can be diagnosed on physical examination as a shallow depression, usually in the parietal region [Tavarez et al., 1989]. The presence of a concomitant caput, cephalohematoma, or subgaleal hematoma may mask the fracture, which can be diagnosed by radiographic imaging (see Fig. 17-4A). Depressed skull fractures should prompt neurosurgical evaluation, although not all fractures require elevation [Medlock and Hanigan, 1997; Tavarez et al., 1989]. Surgical intervention is indicated in the setting of associated complications, such as increased intracranial pressure, cortical compression, or underlying hematoma [Tavarez et al., 1989]. Other complications of depressed skull fractures include sagittal sinus thrombosis associated with occipital depressed skull fracture [Medlock and Hanigan, 1997], osteodiastasis (i.e., separation between the temporal squama and occipital bone at the lambdoid suture) associated with breech presentation and significant neck hyperextension [Pollina et al., 2001], and “growing skull fracture,” or leptomeningeal cyst. This latter entity occurs as a result of a dural tear allowing free communication of the subarachnoid space and herniation of the meninges through the bony defect accompanied by rapid growth of the brain. Neurologic symptoms such as seizures, behavioral disturbances, and motor weakness may appear months to years after the injury. Some investigators advocate close follow-up of conservatively managed fractures with serial radiographs and CT [Papaefthymiou et al., FIGURE 17-4. Computed tomographic scan of the brain of a term infant born by cesarean section because of fetal distress after the head was engaged in the birth canal. A, Subgaleal hematoma and skull fracture. B, Epidural hematoma underlying skull fracture.

A

B

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1996]. Ultrasound and MRI are also useful for evaluation of a leptomeningeal cyst [King and Boothroyd, 1998].

Intracranial Injuries Epidural hematoma in the neonate occurs only rarely, even in the setting of intracranial hemorrhage [Akiyama et al., 2001]. In one postmortem examination series, only 2% of neonatal intracranial hemorrhages were epidural in location. In a series of 41 patients with cranial injuries monitored over an 8-year period, no epidural hematomas were reported. The investigators postulate that this is because most epidural hematomas are asymptomatic and therefore unrecognized [Pollina et al., 2001]. Others have postulated that because the dura mater does not separate from the skull as easily in neonates and the middle meningeal artery has not yet developed, neonates are at lower risk for epidural hematoma. Unlike epidural hematoma in older children, associated skull fracture is often absent [Akiyama et al., 2001]. Clinical presentation can include increasing head circumference, altered level of consciousness, or focal neurologic signs. Evaluation consists of complete blood count, coagulation studies, and head CT (see Fig. 17-4B). Neurosurgical evacuation of symptomatic epidural hematoma is required by craniotomy or by ultrasound-guided needle aspiration [Vachharajani and Mathur, 2002]. Outcome for an isolated epidural hematoma treated in a timely manner is generally good [Akiyama et al., 2001]. Subdural hematoma is the most common intracranial birth injury, accounting for 73% of neonatal intracranial hemorrhage in one study [Pollina et al., 2001]. In a study of 583,340 live births of singleton newborns weighing between 2500 and 4000 grams and excluding breech presentation, the incidence of subdural or cerebral hemorrhage was 2.9 per 10,000 for spontaneous vaginal delivery, 4.1 per 10,000 for cesarean section without labor, 21.3 per 10,000 with combined vacuum- and forceps-assisted delivery, and 25.7 per 10,000 for cesarean section after failed vaginal delivery [Towner et al., 1999]. Antenatal subdural hematoma and subdural hematoma after normal spontaneous vaginal delivery have been described [Chamnanvanakij et al., 2002]. Risk factors include primiparity, vacuum- or forceps-assisted delivery, traumatic or breech delivery, asphyxia, shock, and coagulopathy [Chamnanvanakij et al., 2002; Haase et al., 2003; Hayashi et al., 1987b]. Neonatal subdural hematoma is thought to result from tearing of the falx and tentorium or bridging cortical veins due to stretching associated with labor. Hemorrhage is therefore most commonly seen in the tentorial or interhemispheric areas [Haase et al., 2003; Perrin et al., 1997; Pollina et al., 2001]. Rarely, subdural hematoma may be caused by cerebral infarction as a result of blood rupturing into the subdural space from a hemorrhagic infarct or from hemorrhage into the subdural space from the surface of the infarcted adjacent brain [Steinbok et al., 1995]. Intraventricular, subarachnoid, or intraparenchymal hemorrhage may occur [Chamnanvanakij et al., 2002; Medlock and Hanigan, 1997]. Clinical presentation may vary from asymptomatic to severe mass effect with neurologic symptoms. When symptomatic, patients may present with irritability, poor feeding, apnea, seizures, and bradycardia [Perrin et al., 1997]. In one series of 26 infants with subdural hematoma, 60% had

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respiratory symptoms (e.g., cyanotic episodes, apnea), and the remainder had neurologic symptoms, including seizures or hypotonia or both [Chamnanvanakij et al., 2002]. An overlying cephalhematoma, subgaleal hematoma, or skull fracture may be present. Other birth injuries such as a brachial plexopathy (e.g., Erb’s palsy) or clavicular fracture may be present and are indicative of a difficult labor and delivery [Perrin et al., 1997]. Rarely, an infant with subdural hematoma may present with signs of impending herniation or cerebral infarction [Govaert et al., 1992; Haase et al., 2003; Steinbok et al., 1995]. Appropriate laboratory evaluation includes a complete blood count and coagulation profile. Subdural hematoma may be diagnosed by head ultrasound, but definitive diagnosis, including the presence of intracerebral hemorrhage, cerebral edema, hydrocephalus, or cerebral infarction, is made by CT (Fig. 17-5) [Chamnanvanakij et al., 2002; Hayashi et al., 1987b; Perrin et al., 1997; Steinbok et al., 1995]. MRI or cerebral angiography may be considered as secondary imaging studies [Perrin et al., 1997]. MRI provides superior imaging of tears in the tentorium as well as structures of the posterior fossa [King and Boothroyd, 1998]. Management is generally supportive, with maintenance of circulating blood volume, correction of significant anemia and coagulopathy, and treatment of seizures. Most often, no neurosurgical intervention is necessary. If there are signs of transtentorial herniation, needle aspiration of the subdural hematoma may be attempted [Steinbok et al., 1995]. In one series of 26 neonates with subdural hematoma, only 1 required surgery for elevation of a depressed skull fracture [Chamnanvanakij et al., 2002]. Perrin and colleagues [1997] studied a series of 15 neonates with posterior fossa subdural hematoma for whom neurosurgical consultation was obtained. In this series, 8 of 15 patients underwent surgical evacuation. Indication for surgery was development of signs of progressive brainstem compression [Perrin et al., 1997]. In another case series of 48 neonates with subdural hema-

FIGURE 17-5. Computed tomographic scan demonstrates a posterior fossa subdural hematoma in a term infant who had a difficult breech delivery at home and who was apneic and unresponsive at birth.

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toma, 13 underwent neurosurgical intervention, consisting of burr holes, craniotomy, or placement of ventriculoperitoneal shunt. The investigators recommend surgical intervention for increased intracranial pressure, obstructive hydrocephalus, or subdural hematoma accompanied by intracerebral hemorrhage [Hayashi et al., 1987b]. Outcome after neonatal subdural hematoma is generally good, but it depends on the underlying cause, severity of bleeding, associated intraparenchymal injury, and timely diagnosis and intervention when required [Chamnanvanakij et al., 2002; Haase et al., 2003; Perrin et al., 1997; Steinbok et al., 1995]. Subarachnoid hemorrhage is a relatively common neonatal intracranial injury and occurs as a result of tearing of veins traversing the subarachnoid space [Hughes et al., 1999; King and Boothroyd, 1998]. With increased use of CT and MRI, clinically insignificant subarachnoid hemorrhage has been diagnosed with increasing frequency [Odita and Hebi, 1996]. In their study of 583,340 singleton live births, Towner and colleagues [1999] found the incidence of subarachnoid hemorrhage varied from 0.9 per 10,000 infants born by cesarean section to as high as 10.7 per 10,000 infants born by vacuum- and forceps-assisted delivery. In Pollina’s series of 41 infants with cranial birth injury, 20% had subarachnoid hemorrhage [Pollina et al., 2001]. Presenting symptoms include decreased level of consciousness, hypotonia, and seizures [Hughes et al., 1999]. Hydrocephalus may develop because of obstruction of the fourth ventricle by clot or subarachnoid adhesions [Hayashi et al., 1987b; King and Boothroyd, 1998]. Subarachnoid hemorrhage may cause cerebral vasospasm leading to infarction [Medlock and Hanigan, 1997]. Diagnosis is made by CT, but subarachnoid hemorrhage should be suspected when frank blood or blood-tinged fluid and an elevated cerebrospinal fluid protein level are obtained on lumbar puncture (Fig. 17-6). Unless there is evidence of hydrocephalus, no treatment is needed because the con-

FIGURE 17-6. Computed tomographic scan demonstrates intraparenchymal and subarachnoid hemorrhages in a term infant with oligohydramnios who had a delivery with shoulder presentation and onset of seizures on the second day of life.

dition generally resolves spontaneously. Outcome is related to associated conditions such as subdural hematoma or stroke. Intracerebral hemorrhage may occur in isolation or in association with other cranial birth injuries, including subdural hematoma or cerebral vascular injuries. Intracerebral hemorrhage occurs in 7% to 20% of full-term infants with intracranial hemorrhage [Hanigan et al., 1995; Hayashi et al., 1987a; Pollina et al., 2001]. In one report, 31% of infants had risk factors for intracerebral hemorrhage, including perinatal asphyxia, coagulopathy, complicated delivery, or hyperviscosity. However, up to 50% of neonates with intracerebral hemorrhage in this series did not have any identifiable risk factors [Hanigan et al., 1995]. The mechanism of injury has been postulated by several investigators and includes direct compression of the brain as a result of molding forcing the frontal bone under the parietal bone during passage through the birth canal, occipital osteodiastasis resulting in intracerebellar hemorrhage, asphyxia inducing hemorrhagic arterial infarct, or venous infarct due to sagittal sinus thrombosis [Castillo and Fordham, 1995; Govaert et al., 1992; Hayashi et al., 1987a, 1987b]. The most common presentation for intracerebral hemorrhage is seizure within 48 hours of birth [Govaert et al., 1992; Hanigan et al., 1995; Hayashi et al., 1987a; Medlock and Hanigan, 1997]. Ultrasonography is not useful in the setting of intracerebral hemorrhage. Diagnosis can be made by CT or MRI (see Fig. 17-6). MRI offers more details of cortical structure and determination of the age of the hemorrhage, and it may indicate antepartum injury [Hanigan et al., 1995]. Treatment consists of control of seizures. Neurosurgical consultation should be obtained but surgery is often not indicated [Hanigan et al., 1995; Pollina et al., 2001]. Outcome is related to the degree of asphyxia and associated risk factors [Hanigan et al., 1995]. There are few studies describing outcome of perinatal traumatic cranial injury. Infants who sustain extracranial injuries such as cephalhematoma and subgaleal hematoma generally have a good outcome. Both types of injuries may result in hyperbilirubinemia with its attendant risks. However, massive subgaleal hematomas have the potential to result in life-threatening hypovolemic shock or extracranial cerebral compression, and in this setting, mortality rates of 20% to 60% have been described [Amar et al., 2003]. Neonates with isolated epidural hematomas have a good prognosis. In a review of several case series, Akiyama and co-workers [2001] found that of 18 children with neonatal epidural hematoma, 5 (28%) died, and 3 of those who died had associated injuries, including subdural hematoma, intraventricular hemorrhage, or subarachnoid hemorrhage. The survivors all had good outcomes, with the exception of one child who had psychomotor delay. However, in this report the length of follow-up and method of developmental assessment were not enumerated. Neurologic sequelae after perinatal subdural hematoma depend on the location of the hematoma, associated cerebral injury, and timely diagnosis and management. In one study of 26 infants with subdural hematoma, 9 (34.6%) had an abnormal neurologic examination result at discharge, with 7 infants exhibiting mild hypotonia and 2 infants with Erb’s palsy. There were no deaths in this series [Chamnanvanakij

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et al., 2002]. In another series, Perrin and co-workers [1997] retrospectively reviewed charts of 15 children with perinatal subdural hematoma. Follow-up ranged from 2 to 10 years, with a mean of 4.5 years. There were no deaths in this series, but three were profoundly delayed, two were moderately delayed, three were mildly delayed, and seven were neurodevelopmentally normal. Hayashi and colleagues [1987b] found that 8 (17%) of 46 had some developmental abnormalities 6 months to 3 years after injury. Outcome of intracranial hemorrhage depends on the extent of hemorrhage and associated lesions. In one small series of four infants, three were developmentally normal at 0.75 to 6 years of age, and the fourth was severely delayed at 3 years of age [Hanigan et al., 1995]. There are no prospective studies of neurodevelopmental outcome of neonates with perinatal brain injury.

Cranial Nerve Injuries Acquired facial nerve palsy occurs in 1.8 to 7.5 per 1000 deliveries and is more common in males than females (2:1 in one study). Most cases are associated with forceps deliveries, but 33% occur after spontaneous delivery. The mechanism in either case is similar, with compression of the facial nerve at the stylomastoid foramen either by the posterior forceps blade or by compression against the maternal sacral promontory [Hughes et al., 1999; Medlock and Hanigan, 1997]. Signs and symptoms include difficulty in closing the eyelid on the affected side, loss of the nasolabial fold, and an asymmetric crying facies. Electromyography and auditory brainstem response testing are recommended for neonates in whom there is no improvement over 3 to 4 days. Surgical intervention usually is deferred until 1 to 2 years of age [Hughes et al., 1999]. Other cranial nerve injuries include abducens nerve palsies, hypoglossal nerve palsies, and recurrent laryngeal nerve palsies [Medlock and Hanigan, 1997].

Spinal Cord Injuries Cervical spinal cord injury is an important although rare cause of neonatal morbidity and mortality for which the diagnosis is often delayed or overlooked during the initial evaluation. The incidence is difficult to ascertain because examination of the spinal cord is not routinely done at postmortem examination. In one series, 45% of neonates undergoing postmortem examination had evidence of distortional trauma to the spinal cord [Yates, 1959]; in a second series, the incidence of significant spinal or brainstem injury was greater than 10% [Towbin, 1969]. In a Canadian study from 1993, the investigators cite an incidence of 1 case in 29,000 live births [Rehan and Seshia, 1993], whereas another study reported an incidence of upper cervical spinal cord injury of 1 in 80,000 [Menticoglou et al., 1995]. Spinal cord injury may occur as a result of longitudinal traction, hyperextension or hyperflexion of the neck, excessive rotational force, or ischemic damage to the spinal cord [Filippigh et al., 1994; Morota et al., 1992; Rossitch and Oakes, 1992]. Because the interspinous ligaments, posterior joint capsule, and cartilaginous end plates of the neonate are elastic and redundant, the spine is more deformable in the

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child than in the adult. The facet joints are more horizontally oriented and therefore less stable than in adults. These factors make the pediatric spine more susceptible to hyperextension injury. This type of injury may occur in utero and usually results in a high spinal cord lesion [Rossitch and Oakes, 1992]. The neonatal spinal column is quite elastic, but the spinal cord can be stretched only 0.25 inch before rupturing. This difference in elasticity can result in spinal cord injury without radiographic abnormality (SCIWORA) because the bony and ligamentous elements may remain intact even when the spinal cord has been ruptured. Forceful longitudinal traction during difficult breech delivery may cause this type of injury, and results in lower cervical to high thoracic spinal cord injury [Morgan and Newell, 2001; Rossitch and Oakes, 1992]. Torsional forces during instrumentation with forceps, with head rotation of 90 degrees or more may cause rotational injury during delivery with cephalic presentation [Medlock and Hanigan, 1997]. This type of injury typically results in high cervical cord lesions [Rossitch and Oakes, 1992]. Diagnosis of spinal cord injury is often delayed because of the variable presentation and frequent presence of confounding factors. There is often concomitant perinatal asphyxia, respiratory distress, and brachial plexus injury [Mills et al., 2001; Onal et al., 2002; Rossitch and Oakes, 1992]. Neonates with spinal cord injury are flaccid with absent spontaneous movements and absent deep tendon reflexes. Complex spinal reflexes may be present and misleading. Apnea may occur in high cervical spinal cord injury, requiring intubation and mechanical ventilation. A sensory level can be detected by lack of facial response to painful stimuli below the level of injury [Filippigh et al., 1994; MacKinnon et al., 1993; Rossitch and Oakes, 1992]. The differential diagnosis includes hypoxic-ischemic encephalopathy, spinal muscular atrophy, congenital myopathies, brachial plexus injury, congenital intraspinal tumors, myelodysplasia, and sepsis. Unaffected facial muscles and presence of a sensory level can distinguish spinal cord injury from spinal muscular atrophy and cerebral diplegia [Filippigh et al., 1994]. Radiographic evaluation can elucidate the cause in most neonates. A variety of radiographic tests can be useful in the setting of suspected spinal cord injury. Plain films of the spine are often normal because of the deformability of the neonatal spine [Rehan and Seshia, 1993; Rossitch and Oakes, 1992]. Ultrasonography is useful in initial evaluation as a noninvasive test that may be done at the bedside. Because of incomplete ossification of the vertebral arch in neonates, the spinal cord may be visualized, and edema, hematomyelia, extraspinal hematoma, and avulsion of a nerve root can be visualized [Filippigh et al., 1994; Rehan and Seshia, 1993; Simon et al., 1999]. CT delineates the spinal column better than the cord itself, but bony abnormalities are relatively uncommon. CT myelography is invasive and may lead to false-negative or falsepositive results [MacKinnon et al., 1993]. If the infant is stable enough for transport, MRI is the imaging modality of choice. It provides excellent soft tissue delineation and can distinguish edema from hemorrhage, infarction, vascular anomalies, or congenital anomalies [Blount et al., 2004; Mills et al., 2001; Onal et al., 2002; Rehan and Seshia, 1993]. Somatosensory– evoked potentials may provide additional useful information [Rehan and Seshia, 1993]. The long-term outcome of neonatal spinal cord injury depends on the location of the injury. Infants with a lesion

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Age: 1 day

Age: 14 days

FIGURE 17-7. Term infant with spinal cord injury caused by a traumatic delivery. Image obtained at day 1 (left) demonstrates slight hyperintensity at the craniocervical junction. Two images obtained at 14 days (middle and right) show volume loss and a little blood (hypointensity on T2-weighted images) caused by the injury.

above C4 who display recovery of breathing movements in the first day with continued rapid recovery generally have a good outcome [MacKinnon et al., 1993]. Perinatal spinal cord injury usually results in some degree of permanent neurologic deficit (Fig. 17-7). In one retrospective series of 22 patients, all had at least mild disability. Seven patients with upper cervical cord lesions died, and four with cervicothoracic or thoracolumbar injuries died [MacKinnon et al., 1993]. Postmortem examination of the spinal cord in three neonates with intracord hemorrhage revealed irreversible spinal cord trauma, whereas a fourth neonate in the same case series who had presented identically with quadriparesis had only cord edema without hemorrhage and made a complete recovery. Similar to adult spinal cord injury, edema of the spinal cord without intracord hemorrhage on MRI is associated with good outcome [Mills et al., 2001].

Brachial Plexus Injury Brachial plexus injury is a relatively common birth injury, occurring in 0.5 to 4.5 of 1000 births [McNeely and Drake, 2003; Medlock and Hanigan, 1997; van Ouwerkerk et al., 2000]. Despite improved perinatal care, the incidence of

brachial plexus injury has not declined, possibly because of increasing birth weights. Predisposing factors include macrosomia, breech presentation, shoulder dystocia, and assisted delivery with forceps or vacuum [McNeely and Drake, 2003; van Ouwerkerk et al., 2000]. The mechanism of injury is thought to be excessive traction on the brachial plexus caused by lateral flexion and traction on the head during difficult delivery with shoulder dystocia. In cases of breech presentation, bilateral injury may exist [van Ouwerkerk et al., 2000]. Four types of injury have been described: neuropraxia, or temporary conduction block; axonotmesis, in which the axon is severed but surrounding neural elements are intact; neurotmesis, or complete postganglionic disruption of a nerve; and avulsion, or preganglionic disconnection from the spinal cord [van Ouwerkerk et al., 2000]. Brachial plexus injury may also be classified as complete, upper, or lower palsies [Medlock and Hanigan, 1997]. Diagnosis is generally made by noticing an asymmetric Moro reflex. Erb’s palsy is characterized by injury to C5 and C6, resulting in paralysis of the deltoid, biceps, brachioradialis, and supinator muscles. Grasp is preserved, and the arm is held in the “waiter’s tip” position. This accounts for

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90% of brachial plexus injuries. Klumpke’s paralysis involves C7 and results in loss of the grasp reflex in addition to the previously described symptoms. With involvement of the sympathetic fibers from the first thoracic root, Horner’s syndrome may be identified [Hughes et al., 1999]. Complete plexus injury results in atonic “flail limb” and Horner’s sign. Differential diagnosis includes arthrogryposis, sepsis of the shoulder joint, fractures of the humerus or clavicle, cerebral palsy, and spinal cord injury [van Ouwerkerk et al., 2000]. Electromyography and nerve conduction studies may be considered to assess degree of injury and to guide therapy for future management [Hughes et al., 1999; Medlock and Hanigan, 1997]. MRI can delineate the extent of injury and distinguish between brachial plexus injury and spinal cord injury or congenital anomalies [Medlock and Hanigan, 1997]. Management is controversial. Most injuries resolve spontaneously and require only supportive care with physical therapy and application of dynamic splints [Hughes et al., 1999]. In a systematic review of brachial plexus surgery, McNeely and Drake [2003] conclude that there is no definitive advantage to surgery over conservative management. Results of surgical intervention were variable, and patients frequently did not regain normal function. They recommend waiting at least 3 to 6 months before proceeding with surgical intervention. Brachial plexus injuries often resolve spontaneously, but in 5% to 25% of children, there is residual extremity weakess [Hughes et al., 1999; McNeely and Drake, 2003; van Ouwerkerk et al., 2000]. In a prospective observation of the natural history of brachial plexus injuries, Noetzel and colleagues [2001] found that for infants who had not recovered antigravity movement at the shoulder at 2 weeks of age, the degree of residual weakness at 6 months was highly predictive of eventual recovery. Permanent weakness or disability was highly likely in those children who had less than antigravity strength in the biceps, triceps, and deltoids or absence of active wrist extension. REFERENCES Akiyama Y, Moritake K, Maruyama N, et al. Acute epidural hematoma related to cesarean section in a neonate with Chiari II malformation. Childs Nerv Syst 2001;17:290. Amar AP, Aryan HE, Meltzer HS, et al. Neonatal subgaleal hematoma causing brain compression: Report of two cases and review of the literature. Neurosurgery 2003;52:1470. Awaad Y, Tayem H, Munoz S, et al. Functional assessment following intrathecal baclofen therapy in children with spastic cerebral palsy. J Child Neurol 2003;18:26. Ballantyne AO, Trauner DA. Facial recognition in children after perinatal stroke. Neuropsychiatry Neuropsychol Behav Neurol 1999;12:82. Barron TF, Gusnard DA, Zimmerman RA, et al. Cerebral venous thrombosis in neonates and children. Pediatr Neurol 1992;8:112. Bergman I, Bauer RE, Barmada MA, et al. Intracerebral hemorrhage in the full-term neonatal infant. Pediatrics 1985;75:488. Blount J, Doughty K, Tubbs RS, et al. In utero spontaneous cervical thoracic epidural hematoma imitating spinal cord birth injury. Pediatr Neurosurg 2004;40:23. Bottos M, Feliciangeli A, Sciuto L, et al. Functional status of adults with cerebral palsy and implications for treatment of children. Dev Med Child Neurol 2001;43:516. Carvalho KS, Bodensteiner JB, Connolly PJ, et al. Cerebral venous thrombosis in children. J Child Neurol 2001;16:574. Castillo M, Fordham LA. MR of neurologically symptomatic newborns after vacuum extraction delivery. AJNR Am J Neuroradiol 1995;16:816. Chamnanvanakij S, Rollins N, Perlman JM. Subdural hematoma in term infants. Pediatr Neurol 2002;26:301.

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Hayashi T, Harada K, Honda E, et al. Rare neonatal intracerebral hemorrhage. Two cases in full-term infants. Childs Nerv Syst 1987a;3:161. Hayashi T, Hashimoto T, Fukuda S, et al. Neonatal subdural hematoma secondary to birth injury. Clinical analysis of 48 survivors. Childs Nerv Syst 1987b;3:23. Higashida RT, Helmer E, Halbach VV, et al. Direct thrombolytic therapy for superior sagittal sinus thrombosis. AJNR Am J Neuroradiol 1989;10:S4. Hogeveen M, Blom HJ, Van Amerongen M, et al. Hyperhomocysteinemia as risk factor for ischemic and hemorrhagic stroke in newborn infants. J Pediatr 2002;141:429. Hughes CA, Harley EH, Milmoe G, et al. Birth trauma in the head and neck. Arch Otolaryngol Head Neck Surg 1999;125:193. King SJ, Boothroyd AE. Cranial trauma following birth in term infants. Br J Radiol 1998;71:233. Koelfen W, Freund M, Varnholt V. Neonatal stroke involving the middle cerebral artery in term infants: Clinical presentation, EEG and imaging studies, and outcome. Dev Med Child Neurol 1995;37:204. Kurnik K, Kosch A, Strater R, et al. Recurrent thromboembolism in infants and children suffering from symptomatic neonatal arterial stroke: A prospective follow-up study. Stroke 2003;34:2887. Lee J, Croen LA, Backstrand KH, et al. Maternal and infant characteristics associated with perinatal arterial stroke in the infant. JAMA 2005 293:723. Limperopoulos C, Majnemer A, Rosenblatt B, et al. Agreement between the neonatal neurological examination and a standardized assessment of neurobehavioural performance in a group of high-risk newborns. Pediatr Rehabil 1997;1:9. Lynch JK, Hirtz DG, DeVeber G, et al. Report of the National Institute of Neurological Disorders and Stroke workshop on perinatal and childhood stroke. Pediatrics 2002;109:116. Lynch JK, Nelson KB. Epidemiology of perinatal stroke. Curr Opin Pediatr 2001;13:499. MacKinnon JA, Perlman M, Kirpalani H, et al. Spinal cord injury at birth: Diagnostic and prognostic data in twenty-two patients. J Pediatr 1993;122:431. McNeely PD, Drake JM. A systematic review of brachial plexus surgery for birth-related brachial plexus injury. Pediatr Neurosurg 2003;38:57. Medlock MD, Hanigan WC. Neurologic birth trauma. Intracranial, spinal cord, and brachial plexus injury. Clin Perinatol 1997;24:845. Menticoglou SM, Perlman M, Manning FA. High cervical spinal cord injury in neonates delivered with forceps: Report of 15 cases. Obstet Gynecol 1995;86:589. Mercuri E, Anker S, Guzzetta A, et al. Neonatal cerebral infarction and visual function at school age. Arch Dis Child Fetal Neonatal Ed 2003;88:F487. Mercuri E, Barnett A, Rutherford M, et al. Neonatal cerebral infarction and neuromotor outcome at school age. Pediatrics 2004;113:95. Mercuri E, Cowan F, Gupte G, et al. Prothrombotic disorders and abnormal neurodevelopmental outcome in infants with neonatal cerebral infarction. Pediatrics 2001;107:1400. Mercuri E, Rutherford M, Cowan F, et al. Early prognostic indicators of outcome in infants with neonatal cerebral infarction: A clinical, electroencephalogram, and magnetic resonance imaging study. Pediatrics 1999;103:39. Mills JF, Dargaville PA, Coleman LT, et al. Upper cervical spinal cord injury in neonates: The use of magnetic resonance imaging. J Pediatr 2001;138:105. Morgan C, Newell SJ. Cervical spinal cord injury following cephalic presentation and delivery by Caesarean section. Dev Med Child Neurol 2001;43:274. Morota N, Sakamoto K, Kobayashi N. Traumatic cervical syringomyelia related to birth injury. Childs Nerv Syst 1992;8:234. Myles LM, Massicotte P, Drake J. Intracranial hemorrhage in neonates with unrecognized hemophilia A: A persisting problem. Pediatr Neurosurg 2001;34:94. Nelson KB, Lynch JK. Stroke in newborn infants. Lancet Neurol 2004;3:150. Noetzel MJ, Park TS, Robinson S, et al. Prospective study of recovery following neonatal brachial plexus injury. J Child Neurol 2001;16:488. Nowak-Gottl U, Auberger K, Halimeh S, et al. Thrombolysis in newborns and infants. Thromb Haemost 1999;82 (Suppl 1):112. Nowak-Gottl U, Gunther G, Kurnik K, et al. Arterial ischemic stroke in neonates, infants, and children: An overview of underlying conditions, imaging methods, and treatment modalities. Semin Thromb Hemost 2003;29:405.

Odita JC, Hebi S. CT and MRI characteristics of intracranial hemorrhage complicating breech and vacuum delivery. Pediatr Radiol 1996;26:782. Onal C, Yakinci C, Kocak A, et al. Cervical hematomyelia: A rare entity in a neonate with cesarean section and surgical recovery. Pediatr Neurosurg 2002;36:90. Ozduman K, Pober BR, Barnes P, et al. Fetal stroke. Pediatr Neurol 2004;30:151. Papaefthymiou G, Oberbauer R, Pendl G. Craniocerebral birth trauma caused by vacuum extraction: A case of growing skull fracture as a perinatal complication. Childs Nerv Syst 1996;12:117. Perlman JM, Rollins NK, Evans D. Neonatal stroke: Clinical characteristics and cerebral blood flow velocity measurements. Pediatr Neurol 1994;11:281. Perrin RG, Rutka JT, Drake JM, et al. Management and outcomes of posterior fossa subdural hematomas in neonates. Neurosurgery 1997;40:1190. Petaja J, Peltola K, Rautiainen P. Disappearance of symptomatic venous thrombosis after neonatal cardiac operations during antithrombin III substitution. J Thorac Cardiovasc Surg 1999;118:955. Pollina J, Dias MS, Li V, et al. Cranial birth injuries in term newborn infants. Pediatr Neurosurg 2001;35:113. Ramaswamy V, Miller SP, Barkovich AJ, et al. Perinatal stroke in term infants with neonatal encephalopathy. Neurology 2004;62:2088. Rehan VK, Seshia MM. Spinal cord birth injury—diagnostic difficulties. Arch Dis Child 1993;69:92. Reid DT. Benefits of a virtual play rehabilitation environment for children with cerebral palsy on perceptions of self-efficacy: A pilot study. Pediatr Rehabil 2002;5:141. Renzulli P, Tuchschmid P, Eich G, et al. Early vitamin K deficiency bleeding after maternal phenobarbital intake: Management of massive intracranial haemorrhage by minimal surgical intervention. Eur J Pediatr 1998;157:663. Rossitch E Jr, Oakes WJ. Perinatal spinal cord injury: Clinical, radiographic and pathologic features. Pediatr Neurosurg 1992;18:149. Sala DA, Grant AD. Prognosis for ambulation in cerebral palsy. Dev Med Child Neurol 1995;37:1020. Sandberg DI, Lamberti-Pasculli M, Drake JM, et al. Spontaneous intraparenchymal hemorrhage in full-term neonates. Neurosurgery 2001;48:1042. Schatz AM, Ballantyne AO, Trauner DA. A hierarchical analysis of block design errors in children with early focal brain damage. Dev Neuropsychol 2000;17:75. Sebire G, Rious E, Fullerton HJ, et al. Toward the definition of cerebrovascular diseases in childhood. Curr Opin Pediatr. In press. Shevell MI, Silver K, O’Gorman AM, et al. Neonatal dural sinus thrombosis. Pediatr Neurol 1989;5:161. Shields WD, Shewmon DA, Chugani HT, et al. Treatment of infantile spasms: Medical or surgical? Epilepsia 1992;33 (Suppl 4):S26. Shiozaki A, Arai T, Izumi R, et al. Congenital antithrombin III deficient neonate treated with antithrombin III concentrates. Thromb Res 1993;70:211. Simon L, Perreaux F, Devictor D, et al. Clinical and radiological diagnosis of spinal cord birth injury. Arch Dis Child Fetal Neonatal Ed 1999;81:F235. Sran SK, Baumann RJ. Outcome of neonatal strokes. Am J Dis Child 1988;142:1086. Sreenan C, Bhargava R, Robertson CM. Cerebral infarction in the term newborn: Clinical presentation and long-term outcome. J Pediatr 2000;137:351. Steinbok P, Haw CS, Cochrane DD, et al. Acute subdural hematoma associated with cerebral infarction in the full-term neonate. Pediatr Neurosurg 1995;23:206. Stiles J, Stern C, Trauner D, et al. Developmental change in spatial grouping activity among children with early focal brain injury: Evidence from a modeling task. Brain Cogn 1996;31:46. Stiles J, Trauner D, Engel M, et al. The development of drawing in children with congenital focal brain injury: Evidence for limited functional recovery. Neuropsychologia 1997;35:299. Sutor AH, von Kries R, Cornelissen EA, et al. Vitamin K deficiency bleeding (VKDB) in infancy. ISTH Pediatric/Perinatal Subcommittee, International Society on Thrombosis and Haemostasis. Thromb Haemost 1999;81:456. Taub E, Ramey SL, DeLuca S, et al. Efficacy of constraint-induced movement therapy for children with cerebral palsy with asymmetric motor impairment. Pediatrics 2004;113:305.

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Whitelaw A, Saliba E, Fellman V, et al. Phase I study of intraventricular recombinant tissue plasminogen activator for treatment of posthaemorrhagic hydrocephalus. Arch Dis Child Fetal Neonatal Ed 1996;75:F20. Wong VK, LeMesurier J, Franceschini R, et al. Cerebral venous thrombosis as a cause of neonatal seizures. Pediatr Neurol 1987;3:235. Wood NS, Marlow N, Costeloe K, et al. Neurologic and developmental disability after extremely preterm birth. EPICure Study Group. N Engl J Med 2000;343:378. Wu YW, Croen LA, Lee J, et al. Risk factors for perinatal stroke: Population-based study. Ann Neurol 2004a;56 (Suppl 8):S88. Wu YW, March WM, Croen LA, et al. Perinatal stroke in children with motor impairment: A population-based study. Pediatrics 2004b;114:612. Wu YW, Miller SP, Chin K, et al. Multiple risk factors in neonatal sinovenous thrombosis. Neurology 2002;59:438. Yates PO. Birth trauma to the vertebral arteries. Arch Dis Child 1959;34:436.

CHAPTER 18

Perinatal Metabolic Encephalopathies Rebecca N. Ichord

Neurologic disease in the newborn poses great peril and great opportunity. Knowledge of the pathophysiologic basis for neurologic disease of metabolic origin in newborns has grown rapidly as a result of applying advanced molecular biologic approaches to these conditions. Improved availability of specific metabolic testing provides the means to institute specific treatments that can be lifesaving and can protect the developing brain. For the many diseases for which specific curative treatments are not available, knowledge of underlying molecular and cellular defects provides a starting point for further evaluation of the links between molecular defect and clinical syndrome. This chapter surveys metabolic encephalopathies in the newborn, which are divided into two broad categories: correctable disturbances in glucose metabolism and ion balance that accompany other illnesses and genetically determined inborn errors of metabolism. Genetically determined metabolic diseases are grouped according to predominant type and tempo of clinical symptoms into four categories: acute fulminant illnesses with metabolic crisis, epileptic encephalopathies, chronic encephalopathies with multiorgan involvement, and chronic encephalopathies without multiorgan involvement (Table 18-1). A brief synopsis of each condition is provided, with emphasis on distinctive clinical features, diagnostic approach, and management. Comprehensive discussion of the molecular biology, pathophysiology, and genetics of these disorders may be found in excellent reviews by Scriver and co-workers [2001] and by Saudubray and colleagues [2002].

GENERAL APPROACH TO THE PATIENT Metabolic disease should be considered in the differential diagnosis of any newborn demonstrating symptoms or signs of encephalopathy, which are summarized in Table 18-2. Although none of these abnormalities is specific to metabolic disease, the temporal pattern and specific constellation of symptoms taken together often suggest a metabolic disease. Encephalopathies caused by acute correctable metabolic perturbations, such as in hypoglycemic encephalopathy, typically follow a monophasic course, which resolves in proportion to the timeliness of correction of the metabolic perturbation. The tempo of metabolic disease is more variable than acquired acute injury such as hypoxia or trauma. It often has a delayed or subacute presentation with an unexplained decline in the state of arousal or neonatal behaviors, such as feeding or visual attentiveness, or with the emergence of myoclonic seizures or a movement disorder. Chronic encephalopathies that initially manifest in the newborn period are increasingly being linked to genetically deter-

mined metabolic disease. These disorders may have no features that distinguish them as metabolic, manifesting with nonspecific signs such as hypotonia, depressed neonatal behaviors, or poor feeding. Nervous system manifestations of metabolic disease are diffuse in nature, with depression of consciousness or irritability. Motor abnormalities and brainstem dysfunction parallel the severity of disturbed consciousness in a nonlocalizing manner. Suspicion of an inborn error of metabolism should be elevated by any of the following patterns: involvement of multiple components of the nervous system (e.g., brain, special senses, peripheral nerves, skeletal muscle, autonomic system); involvement of multiple organ systems outside of the nervous system; or systemic symptoms such as prominent unexplained vomiting, hyperpnea in the absence of lung disease, or unusual odors. After a metabolic encephalopathy is suspected, further evaluation should proceed urgently to determine its cause. The most common causes of acute encephalopathy not due to metabolic diseases can usually be identified based on history, known risk factors, and results of first-stage laboatory and imaging studies. These include hypoxic-ischemic injury, intracranial hemorrhage, trauma, stroke, venous thrombosis, central nervous system infection, and intoxication with a variety of drugs. Many neonates with encephalopathy are assumed incorrectly to have suffered “asphyxia” when they have a static disease of prenatal origin or a metabolic disease that decompensated in the face of the metabolic stress of birth. A diagnosis of perinatal hypoxicischemic encephalopathy should be made with certainty only when there is unequivocal evidence of severe compromise of circulation and gas exchange in the peripartum period, such as in the case of uterine rupture, placental separation, or fetal or neonatal circulatory arrest. In the absence of such certainty, the differential diagnosis should remain broad until a comprehensive evaluation is complete. Diagnosis is further delineated by appropriate-stage laboratory studies, as shown in Table 18-3. The aim of the initial evaluation is to simultaneously narrow down the differential diagnosis and treat potentially life-threatening or handicapping conditions as quickly as possible. Results of first-stage studies will reveal abnormalities requiring immediate correction such as hypoglycemia, hyponatremia, hypocalcemia, or hypoxia. They will further define other organ involvement, such as renal or hepatocellular dysfunction. A constellation of abnormalities on the initial screen may suggest a particular inborn error of metabolism (Fig. 18-1). If the results of first-stage assessment combined with clinical history, examination, and neuroimaging do not provide a specific diagnosis, they should provide the rationale for choosing appropriate second-stage studies. These

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TABLE 18-1 Presenting Clinical Features of Neonates with Genetic Metabolic Disorders ACUTE FULMINANT METABOLIC CRISIS

SUBACUTE PROGRESSIVE EPILEPTIC ENCEPHALOPATHY

CHRONIC ENCEPHALOPATHY WITH MULTIPLE ORGAN INVOLVEMENT

CHRONIC ENCEPHALOPATHY WITHOUT MULTIPLE ORGAN INVOLVEMENT

Urea cycle defects MSUD Organic acidopathies Electron chain defects OxPhos defects CPT II MTP defects

Glycine cleavage defects Pyridoxine dependency, deficiency Sulf Ox/Mb cofactor Folinic acid responsive defects Menkes’ disease COX deficiency L-AAD deficiency MECP2 GLUT1 DS AICAR/SAICAR Serine biosynthesis defects

Mitochondrial disorders CDG Peroxisomal disorders Cholesterol biosynthesis defects

L-AAD deficiency Glutaric aciduria GTP cyclohydrolase deficiency PKU SSADH deficiency

AICAR/SAICAR, 5-amino-4-imidazolecarboxamide ribosiduria and succinyl-5-amino-4-imidazolecarboxamide ribosiduria; CDG, congenital defects of glycosylation; COX, cytochrome oxidase; CPT II, carnitine palmitoyltransferase deficiency type II; GLUT1 DS, glucose transporter type 1 deficiency syndrome; L-AAD, L-amino acid decarboxylase; MECP2, methyl-CpG-binding protein-2; MSUD, maple syrup urine disease; MTP, mitochondrial trifunctional protein deficiency; OxPhos, oxidative phosphorylation; PKU, phenylketonuria; SSADH, succinic semialdehyde dehydrogenase; Sulf Ox/Mb, sulfite oxidase and molybdenum cofactor deficiency.

TABLE 18-2 Neurologic Signs and Symptoms of Neonatal Metabolic Disease NEUROLOGIC DISORDER Alterations in consciousness Mild Moderate Severe Brainstem dysfunction

Cortical special senses Tone and movement abnormalities

Reflex abnormalities Seizures Neuromuscular abnormalities Autonomic dysfunction

SIGNS AND SYMPTOMS Excessively irritable or somnolent but awakens with light stimulation Unarousable but withdraws purposefully Comatose, responds to pain only by posturing or not at all Pupillary abnormalities Oculomotor deficits Depressed or disordered suck and swallow function Disordered control of breathing (e.g., hyperpnea, apnea) High-pitched (“cerebral”) cry No arousal to sound, poor or absent visual fixation Generalized hypotonia or hypertonia Non-epileptic myoclonus Dystonia, rigidity, opisthotonus Oculogyric crises Exaggerated deep tendon reflexes Disturbed neonatal reflex behaviors (e.g., Moro, grasp) Myoclonic, clonic, tonic, subtle, apnea Diffusely absent tendon reflexes, bilateral symmetric facial or limb weakness, respiratory insufficiency Temperature instability, gastrointestinal dysmotility

are aimed at identifying the category of metabolic defect, and in some cases, they provide a probable specific diagnosis that can be verified in third-stage studies, in which DNA or tissue sampling provides material for enzyme quantification or genetic analysis. A careful family history should be obtained to ascertain consanguinity, known inherited metabolic disease, excess fetal loss, or infant demise in a sibling under similar circumstances. Neuroimaging should be obtained early in the course of diagnostic evaluation. Although head computed tomography (CT) can provide clues and is sensitive to hemorrhage and major malformations, magnetic resonance imaging (MRI) is the preferred modality. For example, occipital T2 signal abnormalities can be seen with hypoglycemic encephalopathy, bilateral basal ganglia T2 signal changes are evident in a variety of metabolic disorders, and there are characteristic MRI findings in peroxisomal and other inborn errors of metabolism (see Barkovich, 2005). Diffusion-weighted sequences

add sensitivity, and when combined with standard anatomic imaging sequences and vascular studies such as MR angiography or venography, they may provide a definitive diagnosis in many cases with nonspecific clinical findings.

CORRECTABLE DISTURBANCES OF GLUCOSE AND SALT BALANCE Hypoglycemia Hypoglycemia is common among critically ill newborns and is a frequent manifestation of inborn errors of metabolism. The definition of hypoglycemia is controversial. Early definitions of hypoglycemia assumed that a specific threshold of blood glucose concentration existed below which neurologic symptoms and lasting brain injury invariably occurred. Subsequent observations have shown that blood glucose

Ichord / Perinatal Metabolic Encephalopathies

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TABLE 18-3 Laboratory Evaluation of the Infant with Suspected Metabolic Encephalopathy FIRST STAGE: SURVEY AND SCREENING

SECOND STAGE: IDENTIFY CATEGORY OF METABOLIC DEFECT

THIRD STAGE: VERIFY ENZYME OR GENE DEFECT

Blood Blood glucose Electrolytes, including Mg2+, Ca2+, PO42− BUN, creatinine Liver enzymes CBC, platelets, PT, PTT Arterial blood gas Ammonia Lactate, pyruvate Urine Ketone bodies, reducing substances Protein, blood Cells

Blood Quantitative plasma amino acids Very-long-chain fatty acids Acyl-carnitine profile Isoelectric transferrin point Copper, ceruloplasmin levels Cholesterol Uric acid

Tissue biopsy (e.g., muscle, liver) for enzyme assay

Cerebrospinal fluid Glucose, protein Cell count Microbiology

Skin fibroblast culture for enzyme assay DNA studies and specific gene mutation probes Family studies

Urine Quantitative amino acids Organic acids Galactose Sulfites Xanthine, hypoxanthine Uric acid Ribosides Cerebrospinal fluid Quantitative amino acids Biopterin metabolites Lactate, pyruvate

BUN, blood urea nitrogen; CBC, complete blood cell count; PT, prothrombin time; PTT, partial thromboplastin time.

Acute (hrs) onset Severe encephalopathy Independent of feeding, fasting cycles

None or mild

No

Maple syrup urine disease

Yes

Urea cycle defects Fatty acid oxidation defects

Hyperammonemia?

Acidosis? Mitochondrial energy defects Severe Yes

Lactic acidosis? No

Mild

Ketosis?

Yes Acute or subacute (hrs, days) onset Moderate or severe encephalopathy May be diet- or fasting-induced Isolated hepatomegaly with ketotic hypoglycemia

Overwhelming hepatocellular dysfunction with incidental hypoglycemia

Minimal or no systemic metabolic abnormalities

Glutaric aciduria type II Carnitine palmitoyl transferase II def. Long-chain acyl CoA dehydrogenase def. HMG CoA lyase deficiency Organic acidurias MCD

Glycogen storage disease Fructose-1,6-diphosphatase def. Galactosemia Fructose intolerance Tyrosinemia Liver failure of nonmetabolic origin.

Glycine cleavage defects Pyridoxine dependency Sulfite oxidase/molybdenum cofactor Glucose transporter defect Purine, serine biosynthesis defects

FIGURE 18-1. Algorithm for the evaluation of suspected metabolic encephalopathy in neonates. def., deficiency; HMG-CoA, hydroxymethylglutaryl coenzyme A; MCD, multiple carboxylase deficiency.

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TABLE 18-4 Causes of Neonatal Hypoglycemia CATEGORY

SPECIFIC DISORDERS

Disorders of adaptation to extrauterine life Hyperinsulinism

Prematurity Intrauterine growth retardation Infants of diabetic mothers Nesidioblastosis Beckwith-Weidemann syndrome Maternal isoimmune disease Hypoxia Global ischemia Seizures Post–hypoxic-ischemic hepatocellular injury Infectious hepatitis Any cause of liver failure Hypopituitarism due to brain malformation Congenital adrenal insufficiency Adrenal hemorrhage Hypothyroidism See Table 18-5

Elevated glucose consumption Acquired or transient hepatic dysfunction Primary endocrine disorders

Inborn errors of metabolism

values reflect a dynamic balance between substrate availability and use, and they should be viewed as a risk factor, rather than a definitive predictor, of variable sensitivity and specificity for hypoglycemic brain injury. These observations led a number of investigators to propose that a blood glucose value of 2.5 mmol/liter (46 mg/dL) is a prudent threshold that should prompt further evaluation and treatment. This threshold may be modified up or down in individual cases, depending on clinical symptoms and factors likely to affect brain substrate demand, such as seizures or hypoxia, and alternative substrate availability, such as lactate and ketones [Cornblath and Ichord, 2000; Hawdon et al., 1994]. TABLE 18-5 Inborn Errors of Metabolism with Neonatal Hypoglycemia as a Common Symptom CATEGORY

SPECIFIC DISORDERS

Disorders of carbohydrate metabolism

Hereditary fructose intolerance Fructose-1,6-biphosphatase deficiency Glycogen storage diseases, especially types I and III Medium-chain and long-chain acyl-CoA dehydrogenase deficiencies Carnitine palmitoyltransferase II deficiency Hydroxymethylglutaryl-CoA lyase deficiency Holocarboxylase synthetase deficiency (multiple carboxylase deficiency) Pyruvate carboxylase deficiency Maple syrup urine disease Propionic acidemia Methylmalonic acidemia Isovaleric acidemia Ethylmalonic aciduria

Fatty acid oxidation defects

Defects in ketone body synthesis Gluconeogenesis defects

Disorders of branched-chain amino acid catabolism and related organic acidurias CoA, coenzyme A.

Disorders leading to neonatal hypoglycemia may be grouped into four broad categories: maladaptation to extrauterine life, hyperinsulinism, increased glucose consumption due to prior or intercurrent illness, and inborn errors of metabolism (Table 18-4). Maladaptation to extrauterine life affects premature infants and small-for-gestational age infants because of low stores of fat, protein, and glycogen; inefficient ketogenesis and gluconeogenesis; or diminished tolerance of feedings [Hawdon and Platt, 1993]. Hyperinsulinism is associated with maternal dia-betes, nesidioblastosis, and Beckwith-Weidemann syndrome, and it should be suspected when hypoglycemia (<2.6 mmol/liter) without ketonuria occurs in a well-nourished infant beyond the first 2 postnatal hours despite initiation of enteral feeds. Hypoglycemia from increased substrate utilization occurs during hypoxia or ischemia due to a shift from aerobic to anaerobic metabolism [Vannucci et al., 1980], sometimes compounded by decreased hepatic gluconeogenesis and ketogenesis [Hawdon et al., 1994]. Brain glucose consumption is dramatically increased by seizures from any cause, and it may exceed the capacity of cerebral energy metabolism in brain regions compromised by a recent ischemic insult [Young et al., 1987]. Inborn errors of metabolism may cause hypoglycemia resulting from enzyme deficiencies in glycogenolysis or gluconeogenesis or because of hepatocellular dysfunction. The neurologic manifestations in these cases represent combined effects of the hypoglycemia and the metabolic disorder. Table 18-5 lists inborn errors of metabolism commonly associated with neonatal hypoglycemia [Worthen et al., 1994]. Neonatal hypoglycemia may be associated with congenital endocrinopathies affecting the hypothalamic-pituitary-adrenal axis as a result of major brain malformations of the hypothalamic-pituitary region, congenital adrenal hypoplasia, or hypothyroidism. The clinical signs and symptoms of hypoglycemia in the neonate are variable and nonspecific, exemplified by infants with hyperinsulinism [Anderson et al., 1967]. Signs and symptoms in the early stages may be dominated by signs of elevated circulating catecholamines: tachycardia, pallor, diaphoresis, irritability, jitteriness or tremor, exaggerated tendon reflexes, and neonatal reflexes (e.g., Moro). Progressive depression of consciousness occurs as cerebral glucose stores are exhausted, associated with hypotonia, depressed reflexes, hypothermia, and often with seizures. At its worst, uncorrected hypoglycemia at levels of less than 1.0 mmol/liter in the absence of circulating ketone bodies will progress to coma, characterized by an isoelectric electroencephalographic (EEG) pattern, cerebral edema, flaccid unresponsiveness, apnea, loss of brainstem reflexes, and circulatory collapse. Mild and moderate degrees of symptoms are rapidly reversed with glucose administration, whereas severe encephalopathy reflecting irreversible neuronal injury is not. Hypoglycemic coma is associated with irreversible neuronal necrosis and lasting neurologic deficits, the severity of which depend on the duration of coma. Long-term sequelae may include microcephaly, cortical visual impairment, combined motor and cognitive handicap, and in some cases, epilepsy [al-Rabeeah et al., 1995]. The management of neonatal hypoglycemia has been a controversial subject [Aynsley-Green and Hawdon, 1997; Cornblath and Ichord, 2000]. High-risk infants should be screened for hypoglycemia and should be provided exog-

Ichord / Perinatal Metabolic Encephalopathies

Persistent or recurring hypoglycemia Hepatomegaly?

Isolated, without hepatocellular dysfunction

yes

yes Ketosis?

yes

Lactacidosis?

no no Metabolic acidosis?

yes

no Excess glucose requirement?

Glycogen storage disease Infectious Post-hypoxic Metabolic (galactosemia, fructose intolerance, tyrosinemia)

With hepatocellular dysfunction

no

349

Maple syrup urine disease Organic acidurias Prematurity Intrauterine growth retardation Adrenal insufficiency HMG CoA lyase deficiency

yes

Hyperinsulinism

no Growth hormone deficiency Cortisol deficiency Fatty acid oxidation defects

enous feeds, enteral or intravenous, at rates and concentrations sufficient to maintain blood glucose concentrations of more than 2.5 mmol/liter (>46 mg/dL). Bedside screening for low levels of blood glucose should be performed for any infant who develops signs and symptoms of acute encephalopathy. Symptomatic infants should be treated while the first-stage evaluation proceeds, as outlined in Table 18-3. If ketones are absent and the exogenous glucose requirement is high (>10 mg/kg/min), hyperinsulinism should be suspected and further evaluated by measuring insulin levels. A paradigm for assessment of hypoglycemia in neonates (Fig. 18-2) has been adapted from Saudubray and Charpentier [1995]. Treatment of acute symptomatic hypoglycemia should proceed immediately for any infant with a blood glucose level less than 2.5 mmol/liter (<46 mg/dL) using a minibolus of 10 mg/kg with 10% dextrose infused over 2 minutes, followed by continuous infusion of 10% dextrose starting at 8 mg/kg per minute and increasing as necessary to maintain stable blood glucose levels higher than 2.6 mmol/liter. Monitoring the effect of glucose administration on clinical symptoms, particularly level of consciousness, can help clarify the neurologic significance of the hypoglycemia and the need for evaluation for other causes of encephalopathy.

Disturbances of Sodium Balance The function of excitable membranes depends on the regulation of concentrations and fluxes of sodium, potassium, and calcium within narrow limits. Sodium plays a critical role in synaptic transmission as a co-transported ion in neurotransmitter reuptake systems for glutamate, γ-aminobutyric acid (GABA), glycine, and serotonin. Sodium accounts for more than 90% of body fluid osmoles and plays a critical role in regulating cell volume and water metabolism. Cell volume is largely determined by passive diffusion of water, which is determined by extracellular sodium and intracellular potassium concentrations. In the acute phase of the disorder, hypotonic sodium concentrations cause cell swell-

FIGURE 18-2. Algorithm for evaluation of hypoglycemia in neonates. HMG-CoA, hydroxymethylglutaryl coenzyme A.

ing, and hypertonic sodium concentrations cause cell shrinkage. Cell swelling compounds neurologic dysfunction by increasing intracranial pressure, which may lead to secondary ischemia. Cell swelling from hypotonic sodium concentrations provokes cellular counter-regulatory mechanisms to extrude potassium and amino acids, returning the osmoles and cell volume to normal levels.

Hyponatremia The clinical effects of hyponatremia depend on the rapidity of the change, the absolute level of abnormality, and the effectiveness of cellular counter-regulatory responses. Acute decreases in sodium, occurring over hours or days, can cause mild symptoms at serum concentrations between 120 and 130 mEq/liter and cause severe symptoms at concentrations of less than 120 mEq/liter. Mild symptoms include irritability, apathy, excessive somnolence, and hypotonia. As the abnormality progresses, seizures may occur, culminating in coma if uncorrected or if complicated by severe cerebral edema and intracranial hypertension. Osmotic demyelination, or central pontine myelinolysis, due to overly rapid correction of hyponatremia has not been described in neonates. It would be difficult to isolate osmotic demyelination as a cause of white matter injury in neonates, most notably premature infants, who are vulnerable to white matter injury from other causes. Hyponatremia occurs when sodium losses exceed sodium intake or water intake or reabsorption exceeds water excretion, or both. Hyponatremia is common in neonates who are sick because of immature or damaged renal mechanisms of salt and water balance or because of perturbations in the hypothalamic-pituitary mechanisms regulating volume and osmolar status. Hyponatremia during the first 1 to 2 weeks of life in sick neonates is most commonly caused by excess arginine vasopressin secretion in association with other diseases (e.g., lung disease), intracranial hemorrhage, pain, and surgical procedures [Rees et al., 1984]. These are summarized in Table 18-6.

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TABLE 18-6 Causes of Hyponatremia and Hypernatremia in Neonates CAUSES OF HYPONATREMIA

CAUSES OF HYPERNATREMIA

Disorders Causing Positive Water Balance Excessive arginine vasopressin (AVP) secretion Systemic hypoxia, ischemia Mechanical ventilation Pneumothorax Intracranial hemorrhage Septic shock Neonatal drug withdrawal Hypothyroidism Water intoxication Inappropriately dilute intravenous fluids Inappropriately dilute formula feedings

Disorders Causing Negative Water Balance Deficient AVP secretion (central diabetes insipidus) Meningitis, encephalitis Hypoxic-ischemic encephalopathy Midline central nervous system malformations with pituitary insufficiency Renal unresponsiveness to AVP Obstructive uropathy Renal dysplasia Drugs Excess water losses Extensive skin disease Osmotic diuresis

Disorders Causing Negative Sodium Balance Abnormal renal salt handling Chronic renal insufficiency Adrenal insufficiency Acute pyelonephritis Acute obstructive uropathy Urinary ascites Insufficient salt intake relative to losses High insensible fluid and electrolyte losses Vomiting, diarrhea Low-salt infant formulas

Disorders Causing Positive Sodium Balance Administration of hypertonic salt solutions Ingestion of hypertonic feedings

The management of hyponatremic encephalopathy in neonates depends on the cause, the chronicity, and the severity of the symptoms. Subacute or chronic (i.e., days to weeks) hyponatremia of mild degree (>120 mEq/liter) should be treated by determining and correcting the underlying cause. Controversy surrounds the treatment of acute severe hyponatremic encephalopathy, which is usually associated with serum sodium concentrations of less than 120 mEq/liter [Sterns, 1992]. In such cases, seizures are usually resistant to standard antiepileptic drugs, and the encephalopathy frequently depresses respiratory drive and airway protective reflexes, all of which constitute a degree of urgency in favor of rapid correction. Sarnaik and colleagues [1991] reported rapid correction of hyponatremic seizures in a series of infants and young children without neurologic complications by the use of 3% saline. The fact remains, however, that little is known about neurologic complications from rapid correction of acute symptomatic hyponatremia in premature infants and critically ill term neonates, who are already at high risk for neurologic injury from other causes. Until better data are available in this population, treatment should proceed with caution.

Hypernatremia Neurologic manifestations of hypernatremia arise from hypertonic dehydration of neurons and glia, and they may be compounded by secondary ischemic injury from hyperviscosity or intracranial hemorrhage. Mild symptoms accompany mild elevations of serum sodium, generally less than 160 mEq/liter, and severe encephalopathy usually occurs with elevations of more than 170 mEq/liter. The causes of hypernatremia are the inverse of those causing hyponatremia: excess sodium intake relative to sodium losses, or excess water losses relative to water intake or reabsorption, or both (see Table 18-6). Excess sodium intake occurs with administration

TABLE 18-7 Clinical Neurologic Features of Neonatal Genetic Metabolic Encephalopathies DISORDER

HYPOTONIA

SEIZURES

MICROCEPHALY

CPT II CDG COX Urea cycle Sulf Ox/Mb cofactor GTPC GLUT1 DS MECP2 L-AAD Glutaric aciduria I Glycine cleavage Mitochondrial disorders Methylmalonic aciduria MTP defects Serine biosynthesis SSADH Cholesterol biosynthesis Menkes’ disease AICAR/SAICAR

+ + +

+ + +

+

+ + + + + + + + + + + + + + +

++ + + +

MOVEMENT DISORDER

RETINA, OPTIC NERVE + +

± +

+

+ +

+ + + + +

+ +

NEUROPATHY

+ +

+ ++ + + +

MYOPATHY

+

+

+ + +

+ +

AICAR/SAICAR, 5-amino-4-imidazolecarboxamide ribosiduria and succinyl-5-amino-4-imidazolecarboxamide ribosiduria; CDG, congenital defects of glycosylation; COX, cytochrome oxidase deficiency; CPT II, carnitine palmitoyltransferase deficiency type II; GLUT1 DS, glucose transporter deficiency syndrome; GTPC, GTP cyclohydrolase defect; L-AAD, L-amino acid decarboxylase deficiency; MECP2, methyl-CpG-binding protein-2; MTP, mitochondrial trifunctional protein deficiency; SSADH, succinyl semialdehyde dehydrogenase defect; Sulf Ox/Mb cofactor, sulfite oxidase and molybdenum cofactor deficiency; +, present; ++, present and prominent; ±, present or absent.

Ichord / Perinatal Metabolic Encephalopathies

of hypertonic intravenous solutions or from hypertonic oral feedings. Negative water balance is the most common cause of hypernatremia, caused by excess losses of hypotonic body fluids, defective renal water absorption due to nephrogenic diabetes insipidus, or deficient pituitary secretion of arginine vasopressin. Hypothalamic-pituitary insufficiency is caused by acquired brain insults such as meningitis or hypoxicischemic encephalopathy and by midline brain malformations. Management of hypernatremia begins with assessment and correction of intravascular volume deficits with normotonic solutions or plasma expanders in sufficient amounts to restore perfusion to normal levels and to maintain urinary output. Precise strategies for correction of estimated total body volume and sodium abnormalities have been thoroughly discussed in other reviews [Gruskin and Sarnaik, 1992]. The guiding principle in these strategies is to prevent cerebral edema by correcting the hypernatremia over 48 to 72 hours, decreasing the serum sodium concentration at a rate not exceeding 10 to 15 mEq/liter per 24 hours.

351

INBORN ERRORS OF METABOLISM Neonatal encephalopathies due to genetically determined errors of metabolism constitute a rapidly growing class of diseases as the powerful tools of molecular biology are applied to the evaluation of infants with previously illdefined neurologic syndromes. The approach to diagnosis taken in this chapter is to classify diseases into one of four groups based on predominant clinical pattern and tempo of illness: acute fulminant illnesses with metabolic crisis, subacute epileptic encephalopathies, chronic encephalopathies with multiorgan involvement, and chronic encephalopathies without multiorgan involvement (see Table 18-1). Patterns of clinical features may be helpful in recognizing characteristic patterns associated with specific disorders (Tables 18-7 and 18-8). Specific diagnoses can be suspected on the basis of the predominant clinical features and results of first-stage assessments; they are then verified by definitive second- or

TABLE 18-8 Non-neurologic and Metabolic Abnormalities in Neonatal Genetic Metabolic Disorders DISORDER

OTHER ORGAN INVOLVEMENT

ASSOCIATED METABOLIC FINDINGS

CPT II

Heart, kidneys, liver

CDG

Heart failure, thrombophilia

COX deficiency Cholesterol biosynthesis

Heart Heart, kidneys, lungs, gastrointestinal tract, genital, digital anomalies

Hypoglycemia (nonketotic), metabolic acidosis Abnormal transferrin isoelectric focus point (may be delayed finding) Lactic acidosis Low serum cholesterol and high 7-dehydrocholesterol levels

Urea cycle defects Sulf Ox/Mb cofactor

Elevated plasma ammonia level Low serum uric acid, high urinary sulfite, and high urinary xanthine and hypoxanthine levels Hyperphenylalaninemia Hypoglycemia, high uric acid and riboside levels in urine Low CSF glucose level

GTPC AICAR/SAICAR GLUT1 DS MECP2 mutation (in males) L-AAD

Hypoglycemia, metabolic acidosis High glutaric acid level in urine Elevated CSF and plasma glycine level, high CSF/plasma ratio for glycine

Glutaric aciduria I Glycine cleavage defects Mitochondrial disorders Methylmalonic aciduria

Heart, muscle Bone marrow, liver

MTP deficiency

Heart, liver

Menkes’ disease Coarse, brittle hair; lax skin Serine biosynthesis defect SSADH defect

Lactic acidosis Metabolic acidosis, hyperammonemia, hypoglycemia Lactic acidosis, hypoketotic hypoglycemia, dicarboxylic aciduria, transaminitis, elevated creatine kinase level, hyperammonemia, hypocalcemia Low serum and CSF serine and glycine levels, low CSF 5-MTHF level High GABA levels in CSF and urine, high 4-hydroxybutyric acid level in urine

OTHER FEATURES

Inverted nipples, subcutaneous fat pads, growth failure Dysmorphic facies Dysmorphic facies, cleft palate

Dysmorphic facies, growth failure Apnea Polymicrogyria (bilateral perisylvian), central hypoventilation, growth failure Autonomic dysfunction Macrocephaly Rapidly progresses to coma, burst-suppression on electroencephalogram Growth failure Growth failure IUGR, hydrops

Hypothermia IUGR, hypogonadism, cataracts

CDG, congenital defects of glycosylation disorder; CSF, cerebrospinal fluid; COX, cytochrome oxidase deficiency; CPT II, carnitine palmitoyltransferase deficiency type II; CSF, cerebrospinal fluid; GABA, γ-aminobutyric acid; GLUT1 DS, glucose transporter type I deficiency syndrome; GTPC, GTP cyclohydrolase defect; IUGR, intrauterine growth retardation; L-ADD, L-amino acid decarboxylase deficiency; MECP2, methyl-CpG-binding protein-2; 5-MTHF, 5-methyltetrahydrofolate; MTP, mitochondrial trifunctional protein deficiency; SSADH, succinyl semialdehyde dehydrogenase; Sulf Ox/Mb cofactor, sulfite oxidase and molybdenum cofactor deficiency.

352

Perinatal Acquired and Congenital Neurologic Disorders / 18

TABLE 18-9 Magnetic Resonance Imaging Findings in Neonatal Genetic Metabolic Encephalopathies DISORDER

MALFORMATIVE ABNORMALITIES Cortical Cerebral Cerebellar Corpus Dysplasia Atrophy* Atrophy Callosum

DESTRUCTIVE ABNORMALITIES Cortex Basal White Brainstem Ganglia Matter

Sulf Ox/Mb cofactor

+

+

+

Urea cycle

+

+

+

+

+

+

+

+

MSUD Glycine cleavage defect

+D

Glutaric aciduria I

+ FT

COX deficiency PKU AICAR/SAICAR Menkes’ disease Cholesterol biosynthesis MMA Serine defects GLUT1 DS CPT II CDG MECP2 SSADH defect

+

+

+

+

+

+

+

OTHER FEATURES

Mimics hypoxic-ischemic injury; severe, diffuse cystic leukomalacia in chronic stage Diffuse cytotoxic edema, then atrophy or gliosis Reversible edema subcortical and brainstem nuclei Vacuolated degeneration of myelinated tracts in pyramidal tracts, cerebellar peduncles, dentate nuclei Communicating hydrocephalus, subdural hematoma, arachnoid cysts White matter lesions mimic periventricular leukomalacia Progressive dysmyelination

+D +F

+

+

+

+

Tortuous arteries Holoprosencephaly, microcephaly +

+ WM + + +

Microcephaly, hypomyelination Microcephaly

+D +

+ +

+

Dandy-Walker anomaly Bilateral perisylvian polymicrogyria +

*Regions affected by atrophy: diffuse (D), frontal (F), frontotemporal (FT), white matter (WM). AICAR/SAICAR, 5-amino-4-imidazolecarboxamide ribosiduria and succinyl-5-amino-4-imidazolecarboxamide ribosiduria; CDG, congenital defects of glycosylation; COX, cytochrome oxidase deficiency; CPT, carnitine palmitoyltransferase deficiency; GLUT1 glucose transporter deficiency; MECP2, methyl-CpG-binding protein-2; MMA, methyl malonic acidurias; MSUD, maple syrup urine disease; PKU, phenylketonuria; SSADH succinic semialdehyde dehydrogenase deficiency; Sulf Ox/Mb cofactor, sulfite oxidase and molybdenum cofactor deficiency, +, positive finding.

third-stage studies (see Table 18-3). Many of the subacute epileptic encephalopathies and chronic disorders are less common and less well characterized. The full range of phenotypic variation remains to be fully described in more recently described disorders. The widespread availability of MRI has provided new insights concerning the nature and anatomic distribution of brain abnormalities in these disorders and in more classic metabolic diseases. Some disorders, such as the cavitary leukomalacia seen in sulfite oxidase deficiency, are associated with distinctive MRI findings (Table 18-9). A brief summary follows for genetically determined metabolic encephalopathies, which manifest predominantly or in variant form in the neonatal period. Comprehensive discussions of inherited metabolic diseases are available in several excellent reviews [Saudubray et al., 2002; Scriver et al., 2001].

Acute Fulminant Metabolic Diseases Maple Syrup Urine Disease Maple syrup urine disease is an autosomal-recessive disorder resulting from deficient activity of branched-chain keto-acid dehydrogenase (BCKAD), which causes accumulation in plasma of leucine, isoleucine, and valine and their corresponding keto acids. Of the five clinical phenotypes, the severe neonatal form is the most common. After a

normal interval of 4 to 7 days after birth, affected infants develop progressive lethargy and hypotonia, evolving to coma and decerebrate posturing, sometimes with seizures. Cerebral edema, particularly involving white matter, appears in the early stages, giving rise to a distinctive pattern of abnormalities on MRI, with diffusion-weighted imaging demonstrating marked restriction of proton diffusion compatible with cytotoxic or intramyelinic sheath edema in the brainstem, basal ganglia, thalami, cerebellar and periventricular white matter, and the cerebral cortex [Jan et al., 2003]. Biochemical abnormalities include ketoacidosis, ketonuria, and hypoglycemia. Neuropathology consists of spongiform degeneration or delayed myelination of white matter with oligodendroglial cell loss and cerebellar granular cell necrosis [Silberman et al., 1961]. The pathophysiology of the neurologic manifestations is incompletely understood and is likely multifactorial related to the roles of branched-chain amino acids as glucose-sparing energy substrates and precursors of fatty acid and cholesterol synthetic pathways (Fig. 18-3). Deficiencies in transmitter pools of glutamate, aspartate, and GABA, along with deficient GABA receptors, have been demonstrated in an animal model [Dodd et al., 1992], and human neuropathologic analysis has revealed reduced myelin lipids in untreated patients. The EEG pattern during metabolic decompensation may reveal characteristic central sharp waves or diffuse slowing to burst suppression as the

Ichord / Perinatal Metabolic Encephalopathies Leucine

353

Valine

Isoleucine

Branched chain keto acids

1

1 2-methylbutyryl CoA

Isovaleryl CoA

2

CHOLESTEROL SYNTHESIS Acetoacetate

1

Threonine Methionine Odd-chain fatty acids Cholesterol

Isobutyryl CoA

3

Acetyl CoA

Propionyl CoA

4 FATTY ACID SYNTHESIS Krebs cycle GLUCONEOGENESIS

Methylm a lonyl C oA

6

5

Cobalamin

Succin yl CoA

Homocysteine

Methionine

OXIDATIVE PHOSPHORYLATION GLUTAMATE METABOLISM

symptoms progress [Trottier et al., 1975]. Diagnosis rests on the detection of marked elevations in plasma of leucine (up to 1000 to 5000 mM during acute decompensation), isoleucine, and valine. Detection of L-alloisoleucine in plasma is pathognomonic for this disorder. Urine organic acid profiles reveal elevated 3-hydroxyvaleric acid levels. BCKAD assay in cultured skin fibroblasts reveals activity less than 2% of normal levels and confirms the diagnosis. Treatment for acute, severe decompensation requires metabolite removal by peritoneal dialysis or hemodialysis, along with supportive and nutritional measures to induce an anabolic state. Long-term management consists of dietary restriction

FIGURE 18-3. Biochemical pathways are affected by defects in branched-chain amino acid and organic acid metabolism. Disorders and their corresponding enzyme defects: 1, maple syrup urine disease, branched-chain keto acid dehydrogenase (BCKAD); 2, isovaleric acidemia, isovaleryl-CoA dehydrogenase; 3, isoleucine defects, mitochondrial acetoacetyl-CoA thiolase; 4, propionic acidemia, propionyl-CoA carboxylase; 5, methylmalonic acidemia, methylmalonyl-CoA mutase or defective cobalamin metabolism (6).

of leucine, good nutritional support, and avoidance of catabolic stresses. Long-term outcome is related to the number and severity of metabolic decompensations.

Organic Acidopathies Branched-chain organic acidurias are autosomal-recessive disorders caused by defects in the catabolism of branchedchain amino acids, propionate and methyl malonate, and their cofactors, biotin and cobalamin (vitamin B12) (see Fig. 18-3). Defects in the degradation of branched-chain keto acids of leucine, valine, and isoleucine cause accu-

TABLE 18-10 Biochemical Diagnosis of Organic Acidopathies DISORDER

ENZYME DEFICIENCY

URINARY ORGANIC ACID PROFILE

ASSOCIATED BIOCHEMICAL ABNORMALITIES

Isovaleric acidemia

Isovaleryl-CoA dehydrogenase

Isovaleryl glycine 3-Hydroxyisovaleric acid 3-Hydroxybutyrate

Metabolic acidosis (ketones, lactate) Hyperammonemia Low plasma glycine level Pancytopenia

3-Hydroxy-3-methylglutaric aciduria

Hydroxymethylglutaric-CoA lyase

Severe hypoglycemia No ketosis Lactic acidosis

Isoleucine defects

Mitochondrial acetoacetyl- CoA thiolase

Propionic acidemia

Propionyl-CoA carboxylase

Methylmalonic acidemia

Methylmalonyl-CoA mutase Defective cobalamin metabolism

3-Hydroxy-3-methylglutaric acid 3-Methylglutaconic acid 3-Hydroxyisovaleric acid 3-Methylglutaric acid 2-Methyl-3-hydroxybutyric acid 2-Methylacetoacetic acid 2-Butanone Acetoacetic acid 3-Hydroxybutyric acid Propionic acid Methylcitrate β-Hydroxypropionic acid Tiglic acid Methylmalonic acid

CoA, coenzyme A.

Similar to that for isovaleric acid

Severe acidosis with ketosis Variable elevations of plasma branched-chain amino acids Hyperglycinemia Severe acidosis with ketosis Hyperammonemia Thrombocytopenia Pancytopenia

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Perinatal Acquired and Congenital Neurologic Disorders / 18

mulation of one or more branched-chain organic acid intermediates, which can be identified from specific patterns of urinary organic acid abnormalities arising from the breakdown of acyl–coenzyme A (acyl-CoA) thioester intermediates. Clinical symptoms first appear from the neonatal period to early infancy and include acute onset of severe metabolic acidosis with ketoacidosis, hypoglycemia, and hyperammonemia, which may progress to seizures and coma. Associated features may include growth failure, vomiting, diarrhea, hepatic dysfunction, circulatory collapse, neutropenia, and thrombocytopenia. Pathogenesis of clinical symptoms has been attributed to a combination of direct toxic effects of accumulated metabolites and compensatory responses (see Fig. 18-3). Energy metabolism may be compromised as a result of deficient substrates for gluconeogenesis and limited availability of free CoA for mitochondrial fatty acid oxidation. Accumulation of acyl-CoA intermediates inhibits the urea cycle, resulting in hyperammonemia. Diagnosis should be suspected when first-stage screening reveals prominent metabolic acidosis with variable combinations of ketosis, lactacidosis, hypoglycemia, and hyperammonemia. The diagnosis rests on specific urinary organic acid profiles, and it can be confirmed by enzyme assay in cultured skin fibroblasts (Table 18-10). Management consists of glucose administration, with insulin if necessary, to reverse catabolic states; protein restriction; and respiratory

and circulatory support. Carnitine and glycine supplementation may improve the clearance of toxic metabolites in isovaleric acidemia. Cofactor supplementation can be helpful in subgroups characterized by primary defects in the cofactor metabolism, using pharmacologic doses of cobalamin in some cases of methylmalonic acidemia or biotin in some cases of propionic acidemia. Long-term management includes protein-restricted, high-carbohydrate diets and avoidance of catabolic stresses. Long-term outcome can be normal if decompensations are minimized in frequency and treated aggressively when they occur.

Defects in Oxidative Phosphorylation Metabolic encephalopathy in neonates is associated with primary lactic acidosis in several groups of enzyme defects: pyruvate dehydrogenase complex, pyruvate carboxylase, respiratory chain defects, and hepatic glycogenolysis or gluconeogenesis. Figure 18-4 illustrates these pathways in relation to cellular energy and lactate metabolism. Secondary lactic acidosis is common in patients with hypoxia or ischemia and in those with other inborn errors of metabolism that affect energy metabolism, including organic acidopathies, urea cycle disorders, and fatty acid oxidation defects. Pyruvate dehydrogenase defects are the most common of the primary congenital lactic acidoses, and they include

Glycogen

Glucose

Fat

Glycolysis Gluconeogenesis

Free fatty acids

Glucose-6-P

G6P Pyruvate

lactate

Acyl-CoA synthetase

1 2

Carnitine 4

NADH + H +

␤-Oxidation

Acetyl Co A

␣-ketoglutarate

Acetyl CoA

HMGCoA Lyase

Respiratory Chain O2

H2O

Glutamate

MITOCHONDRION

Leucine

NADH+H+ 3

Aspartate

GABA

Ketogenesis

Krebs Cycle

Oxaloacetate

Urea Cycle

Lipolysis

Glycogenolysis, Glycogenosis

Acetoacetate

Ketones ADP

ATP

FIGURE 18-4. In the pathways of intermediate metabolism, selected disorders and their corresponding enzyme deficiencies are indicated as follows: Defects in oxidative phosphorylation: 1, pyruvate dehydrogenase; 2, pyruvate carboxylase; 3 respiratory chain. Fatty acid oxidation defects: 4, carnitine palmitoyl transferase (CPT). Acetyl-CoA, acetyl–coenzyme A; GABA, γ-aminobutyric acid; G6P, glucose-6-phosphate; HMG-CoA, hydroxymethylglutaryl–coenzyme A.

Ichord / Perinatal Metabolic Encephalopathies

multiple subtypes, depending on the component of this large enzyme complex that is affected. E1 component defects are the most common and are inherited as X-linked dominant traits. The most severe form manifests in newborns with permanent lactic acidosis, often more than 7 mM, which is maximal in the fed state, and with a fulminant severe encephalopathy progressing to death in the first months of life. Intrauterine growth retardation, subtle facial and limb anomalies, and signs of brain dysgenesis (e.g., absent corpus callosum) illustrate the fetal effects of this disorder. Postnatal evolution of the neurologic symptoms is associated with necrotic changes and cavitation in cortical white matter, basal ganglia, and brainstem nuclei. Treatment options are limited, although some success has been reported with institution of a ketogenic diet with thiamine and carnitine supplements. Pyruvate carboxylase is a critical enzyme in gluconeogenesis and plays an important role in the flux of citric acid cycle intermediates, thereby influencing energy metabolism and substrate supply for neurotransmitter pools of glutamate and GABA. Deficiency occurs with a spectrum of clinical manifestations. In the severe neonatal form, permanent severe lactic acidosis occurs along with citrullinemia and hyperammonemia. This finding has been attributed to the critical role of aspartate in the urea cycle and in transporting reducing equivalents between the cytosol and mitochondria. Postmortem examinations of these patients reveal widespread neuronal death and arrest of myelination, leading to cortical and white matter atrophy or cystic encephalomalacia. Highcarbohydrate diets have been used in these patients to avoid dependence on the defective gluconeogenic pathways. Respiratory chain defects constitute a large spectrum of disorders in oxidative phosphorylation, which have a highly variable and rapidly expanding phenotype. The phenotypic complexity arises in part from the fact that both nuclear and mitochondrial genes determine these structures. This group of disorders should be considered in infants with severe, intractable lactic acidosis or with a cardinal clinical feature with or without lactic acidosis. Cardinal clinical features include external ophthalmoplegia, myopathy, and cardiomyopathy, often with variable encephalopathy. Involvement of other organs is common, such as hepatic dysfunction, renal tubular abnormalities, or growth failure. When lactic acidosis occurs, the lactate-to-pyruvate ratio is increased (>25) in disorders of oxidative phosphorylation compared with pyruvate dehydrogenase complex disorders, in which the lactate-to-pyruvate ratio is usually normal. The clinical course may be benign in cases with only skeletal muscle involvement (e.g., benign infantile mitochondrial myopathy) or intractable and fatal in cases with intractable acidosis (e.g., lethal infantile mitochondrial disease). Diagnosis is difficult because of the extreme phenotypic and genotypic variability and because histologic and histochemical diagnostic techniques are difficult and not widely available. The limited treatment options generally have relied on supportive strategies to minimize catabolic stresses and on administration of carnitine and the respiratory chain cofactors nicotinamide and riboflavin.

Fructose Intolerance Fructose-1,6-biphosphatase (FDPase) deficiency is an autosomal-recessive disorder causing a profound defect in gluconeogenesis. It manifests as a severe, acute metabolic

355

encephalopathy in the first month of life, with marked, fasting-induced lactic acidosis, ketoacidosis, and hypoglycemia, usually without other organ involvement except for hepatomegaly. The characteristic clinical and biochemical features should suggest the diagnosis, but confirmation rests on enzyme assay of a liver biopsy specimen. Treatment is similar to that for type I glycogenosis and includes restriction of fructose and sucrose intake.

Fatty Acid Oxidation Defects Fatty acid oxidation defects represent a broad spectrum of disorders, most of which manifest beyond the neonatal period as acute encephalopathies with nonketotic hypoglycemia provoked by fasting or catabolic stress (see Chapter 23). In these disorders, one of several enzymes is deficient in the pathway for degradation of lipids to fatty acids to acetyl-CoA or ketone body production (see Fig. 18-4). Several of these disorders have been reported with prominent and distinctive presentations in neonates, including carnitine palmitoyl transferase II deficiency and mitochondrial trifunctional protein deficiency. Acyl-CoA dehydrogenase deficiencies (i.e., long-chain [LCAD], mediumchain [MCAD], or short-chain [SCAD] forms) more typically manifest beyond the neonatal period. These disorders share a constellation of clinical features that include the rapid onset of a fulminant metabolic encephalopathy with hypoglycemia, moderate hyperammonemia, low or moderate ketonuria (i.e., disproportionately low for the degree of hypoglycemia), and metabolic acidosis. Associated clinical features may include hepatomegaly, cardiomyopathy, and myopathy. The pathogenesis of neurologic symptoms has been attributed to the combined effects of direct toxicity from accumulated free fatty acids, insufficient glucose and ketones to fuel the Krebs cycle, and inhibition of mitochondrial energy production by the disturbed ratio of acyl-CoA to free CoA. The characteristic clinical features should suggest the diagnosis, which can be further supported by finding decreased levels of total plasma carnitine and specific patterns of elevated plasma levels of acylcarnitine intermediates as follows: C16 and C18 species in carnitine palmitoyl transferase II deficiency, C14 species in LCAD, C6 to C8 species in MCAD, and C4 species in SCAD. Definitive diagnosis rests on assay of enzyme activity from cultured skin fibroblasts. Treatment involves supportive measures, glucose administration, carnitine supplementation, and modification of feeding schedules to minimize fasting states. Creatine supplements have been suggested for patients with mitochondrial trifunctional protein deficiency. Recurrent decompensations can be minimized by early initiation of intravenous glucose during intercurrent illnesses and avoidance of fasting. Long-term outcome depends on the frequency and severity of decompensations. Mitochondrial trifunctional protein is distinguished among these disorders by the high proportion of cases (about 50%) presenting in the neonatal period [den Boer et al., 2003]. It has two types of presentations. The first is a neonatal presentation consisting of fulminant acute illness with rapid onset of depressed consciousness, heart failure, diffuse hypotonia, and weakness with absent tendon reflexes, severe lactic acidosis, and death of most from heart

356

Perinatal Acquired and Congenital Neurologic Disorders / 18

failure. The second is a subacute, infantile presentation with gradually progressive emergence of hypotonia, diffuse weakness, and cardiomyopathy. Multisystem involvement has been reported, including retinopathy, peripheral neuropathy, myopathy, cardiomyopathy, and liver disease. Carnitine palmitoyl transferase II deficiency has several phenotypes, with onset in adulthood, infancy, or the neonatal period. The latter is the least common and most severe form [Sigauke et al., 2003], and it is reported to be universally fatal. Affected infants often have prenatally detected cerebral lesions and malformations, including ventriculomegaly, agenesis of the corpus callosum, polymicrogyria, periventricular cystic leukomalacia, and subependymal hemorrhages. Neurologic symptoms that appear at birth or within the first few days of life include seizures, depressed consciousness, and hypotonia with myopathic features. Cardiomyopathy leading to circulatory failure is common. The metabolic findings are typical of fatty acid oxidation defects as described earlier. Management is supportive and symptomatic but ineffective in most cases. Definitive biochemical diagnosis is a prelude to genetic testing, which can provide a basis for family counseling and management of future pregnancies. A number of states have incorporated carnitine palmitoyl transferase II in neonatal metabolic screening programs in the hope of promoting early diagnosis.

former of acidosis, ketosis, or lactic acidosis and by specific metabolites in urinary organic acid profiles, as described earlier. Transient hyperammonemia of the newborn is a poorly understood disorder, characterized by severe transient hyperammonemia associated with respiratory distress syndromes or herpes simplex infection. It is distinguished from the genetically determined enzyme defects by its earlier onset (first 24 hours of life) and its association with prematurity and pulmonary disease. The pathophysiology of hyperammonemic encephalopathy is complex and is in part related to astrocyte swelling and dysfunction due to excessive glutamine accumulation [Takahashi et al., 1991]. Treatment of acute, severe hyperammonemic coma in the neonate is best achieved with hemodialysis to rapidly reduce plasma ammonia levels to at least three times the upper limit of normal. Use of pressors and volume to maintain adequate cerebral perfusion pressure is preferable to the use of hyperventilation or osmotic diuresis in managing intracranial hypertension. Careful protein restriction and administration of drugs to enhance excretion of excessive metabolites are tailored according to the specific enzyme defect and are thoroughly described elsewhere [Scriver et al., 2001]. Longterm outcome is variable. Motor and cognitive deficits depend on the severity and frequency of hyperammonemic decompensations.

Subacute Epileptic Encephalopathies

Urea Cycle Disorders Urea cycle defects manifesting in the neonate are characterized by the onset between 1 and 4 days of age of severe hyperammonemia with rapidly progressive lethargy and vomiting, progressing to coma with signs of cerebral edema. Associated features may include respiratory alkalosis and hypothermia. First-stage laboratory assessments reveal no other major abnormalities. A presumptive diagnosis can be made from results of plasma amino acid, urine organic acid, and urinary orotate excretion profiles (Fig. 18-5). Elevated plasma glutamine levels are common to all the urea cycle disorders. Organic acidopathies and congenital lactic acid disorders that may cause hyperammonemia can be distinguished from urea cycle disorders by the presence in the

Glycine Cleavage Defects Glycine cleavage defects are a group of autosomal-recessive disorders leading to accumulation of glycine (Fig. 18-6). The most common form is a neonatal-onset progressive encephalopathy with depressed consciousness and seizures, usually myoclonic, associated with an EEG pattern of burst suppression. Glycine toxicity appears to be maximal in the neonatal period, and it may spontaneously diminish after Glucose

3-Pglycerate Glutamate

Oxaloacetate 1

␣-ketoglutarate

D-Serine

Aspartate

2 1

L-Serine

Citrulline NH4

Argininosuccinate 3

4 Carbamyl phosphate

2

HCO3Orotate

Ornithine

Arginine

FIGURE 18-5. Urea cycle defects: 1, argininiosuccinate synthetase; 2, argnininosuccinase; 3, ornithine transcarbamylase; 4, carbamylphosphatate synthetase.

Glycolipids, myelin synthesis

Purine, pyrimidine biosynthesis

Glycine

3

MTHF

NH3 + CO 2

FIGURE 18-6. Disorders of serine and glycine metabolism: 1, 3-phosphoglycerate dehydrogenase; 2, serine hydroxymethyl transferase; 3, glycine cleavage system. MTHF, methylenetetrahydrofolate.

Ichord / Perinatal Metabolic Encephalopathies

1 month of age. Lifelong, severe cognitive and motor handicaps and intractable epilepsy are the rule among survivors, although there is considerable variability among survivors [Applegarth and Toone, 2004]. Factors that predict a poorer outcome include earlier age of symptom onset, presence of cerebral dysgenesis, and severity of glycine level elevation. Neurologic manifestations occur as a result of excessive stimulation of central nervous system glycine receptors, which are inhibitory in spinal cord and excitatory in brain by means of a co-agonist effect at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. Biochemical abnormalities are limited to the finding of elevated glycine levels in plasma (onefold to eightfold above normal) and cerebrospinal fluid (15-fold to 30-fold above normal). In cases with equivocal plasma elevations of glycine concentrations, the diagnosis can be made by finding a cerebrospinal fluid–to-plasma ratio above 0.08. Glycine cleavage defects can be distinguished from the hyperglycinemia that accompanies organic acidopathies by the presence of ketosis in the latter and by characteristic organic acid excretion profiles. There are no proven therapies. Attempts to reduce glycine levels by dietary restriction and benzoate administration have not ameliorated the neurologic abnormalities. Seizures generally have been resistant to standard antiepileptic drugs.

357

Treatment with dextromethorphan, an NMDA-receptor antagonist, has had limited success in a small number of reported cases [Hamosh et al., 1992].

Pyridoxine Deficiency or Dependency Pyridoxine dependency disorder results from a relative or absolute lack of GABA synthesis from presumed defective binding of glutamic acid decarboxylase with its cofactor pyridoxal-5-phosphate, resulting in GABA deficiency (Fig. 18-7). GABA is the major inhibitory neurotransmitter in mammalian brain, a deficiency of which readily accounts for the clinical manifestations of intractable seizures and severe cortical dysfunction. Affected infants have neonatalonset seizures or, in some cases, in utero–onset seizures with no other metabolic abnormalities. Seizures are usually unresponsive to standard antiepileptic drugs. In a group of six affected neonates, Mikati and colleagues [1991] observed a unique EEG pattern consisting of generalized bursts of 1- to 4-Hz, sharp- and slow-wave activity [Mikati et al., 1991]. Isolated reports have suggested that the diagnosis can be supported by the findings of decreased cerebrospinal fluid GABA and increased cerebrospinal fluid glutamate levels [Kurlemann et al., 1987], which normalize after treatment with pyridoxine. Definitive diagnosis rests on the demon-

NEURON ASTROCYTE

Glutamine Gutamine

Glucose Pyruvate

Lactate

Glutamate

Glutamate GABA

Glutamate GABA

MITOCHONDRION Acetyl-CoA

Krebs cycle 2 Succinate

Succinic semialdehyde

␣-ketoglutarate

Glutamine

Glutamate

Glutamine

Glutamate

GABA

Transmembrane transporter

1 Pyridoxine

GABA

FIGURE 18-7. Schematic of relationships between intermediate metabolism and the major neuronal neurotransmitters glutamate and γ-aminobutyric acid (GABA). Selected defects affecting GABA metabolism include pyridoxine dependency or deficiency (1) and succinic semialdehyde dehydrogenase deficiency (2).

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Perinatal Acquired and Congenital Neurologic Disorders / 18

stration of a normalized EEG pattern and control of seizures on intravenous administration of 50 to 100 mg of pyridoxine. Management requires lifelong pharmacologic doses of pyridoxine (10 to 100 mg/day).

Sulfite Oxidase and Molybdenum Cofactor Deficiency Molybdenum cofactor deficiency and isolated sulfite oxidase deficiency are closely related autosomal recessive diseases involving defects in xanthine metabolism and sulfite degradation pathways. Molybdenum cofactor is essential for the function of xanthine dehydrogenase and sulfite oxidase (Fig. 18-8). The mechanism of the brain injury is multifactorial, involving direct toxic effects of sulfite metabolites on cellular architecture, damage to mitochondria, thiamine degradation, and impaired mucopolysaccharide synthesis. These two distinct genetic defects share a similar clinical manifestation, consisting of acute or subacute evolution of a severe, neonatal-onset epileptic encephalopathy with diffuse, severe cavitary leukomalacia. Infants are usually born at term uneventfully, and they develop seizures in the first week of life that progress over the ensuing weeks in association with arrested development, acquired microcephaly, and early appearance of diffuse hypertonicity, evolving to severe, mixed motor and cognitive handicaps in survivors. Most children do not survive infancy. The clinical and radiographic features in the early stages mimic those seen in children with hypoxic-ischemic encephalopathy. The absence of a history of severe peripartum hypoxia or circulatory decompensation should prompt a search for other diagnoses. The severe cavitary leukomalacia seen in these patients is distinctive and is not typically seen after perinatal hypoxia-ischemia. It is more severe in cases of isolated sulfite oxidase deficiency than in cases with molybdenum cofactor deficiency [Dublin et al., 2002]. There are no associated malformative anomalies, systemic metabolic perturbations, or abnormalities affecting other organ systems. Diagnostic biochemical characteristics include increased urinary excretion of sulfites, thiosulfate, S-sulfocysteine, and taurine. Patients with molybdenum cofactor deficiency have low serum and urinary levels of uric acid and increased urinary levels of xanthine and hypoxanthine. These findings may vary according to protein intake and nutritional status. Patients with isolated sulfite oxidase deficiency have normal uric acid metabolite levels.

GMP

Guanosine sulfite

Amino acids

salts

Folinic Acid–Responsive Syndrome Hyland and Arnold [2002] have described a distinct syndrome of folinic acid–responsive seizures in a number of neonates who have refractory epileptic encephalopathies of unknown origin. Typically, the term neonates were born uneventfully, have no syndromic stigmata or other systemic disease, and develop refractory epilepsy in the first weeks or months of life. Analysis of cerebrospinal fluid for neurotransmitters by high-performance liquid chromatography reveals an unidentified peak. Treatment with folinic acid was found to be highly effective for controlling seizures in reported cases [Hyland and Arnold, 2002].

Menkes’ Disease Menkes’ disease is an X-linked recessive disorder that causes defective function of the intestinal copper transport protein, resulting in low tissue levels of copper and, secondarily, deficient function of numerous enzymes for which copper is a cofactor. The clinical phenotype invariably consists of severe neonatal-onset, chronic encephalopathy with refractory epilepsy. Infants typically have central hypotonia and developmental arrest with microcephaly. Distinguishing findings on examination, other than neurologic abnormalities, include redundant and hyperelastic skin; coarse, brittle hair; thin or absent eyebrows and eyelashes; and poor temperature stability. When examined under a microscope, hair fibers display the classic appearance of pili torti. Non-neurologic manifestations include vasculopathy with excess tortuosity and fragility, leading to thromboembolic stroke or subdural hemorrhage. This disease should be suspected in the setting of early infantile epileptic encephalopathy with the characteristic physical stigmata, and the diagnosis is supported by the biochemical findings of low levels of ceruloplasmin and serum copper. Treatment of patients with Menkes’ disease is supportive, with an emphasis on anticonvulsant management. Correction

IMP 3

Sulfur-containing

The diagnosis may be confirmed by enzyme assay of biopsied liver or cultured skin fibroblasts. Treatment is supportive, with an emphasis on optimizing anticonvulsant therapy. Dietary intervention with cysteine and thiamine supplementation and methionine restriction has been beneficial in isolated cases [Boles et al., 1993].

4 Guanine

3 Inosine 4 Hypoxanthine 5

2

1

MBD

Xanthine 5

Detoxification & degradation products

Uric acid

AMP 3 Adenosine 4 Adenine

FIGURE 18-8. Defects in purine metabolism caused by deficiencies in molybdenum cofactor deficiency (1) and isolated sulfite oxidase deficiency (2). Enzymes in purine metabolism are shown as 5’nucleotidase (3), purine nucleoside phosphorylase (4), and xanthine dehydrogenase(5), which requires molybdenum as a cofactor. AMP, adenosine monophosphate; GMP, guanosine monophosphate; IMP, inosine monophosphate; MBD, molybdenum.

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of serum copper levels with dietary supplements has been tried, with no beneficial effect on the neurologic manifestations of the disease.

limited benefit for the neurodevelopmental disability. Longterm outcome is variable, with most children affected by some degree of cognitive impairment.

Glucose Transporter Defects

Serine Biosynthesis Defects

DeVivo and associates [2002] characterized a deficiency syndrome arising from mutations in the neuronal glucose transporter GLUT1 (now designated SCL2A1). The disease manifests as early infantile-onset epileptic encephalopathy associated with a low cerebrospinal fluid concentration of glucose (mean, 30 mg/dL). The onset of seizures occurs between 4 weeks and 18 months of age, with a mean of 5 months. They include all clinical seizure types (i.e., focal, generalized, and myoclonic) and are resistant to antiepileptic drugs [Leary et al., 2003]. Affected infants have neurodevelopmental impairment of variable severity and acquired microcephaly. The cardinal biochemical feature is a decreased ratio of cerebrospinal fluid glucose relative to the plasma glucose concentration, typically less than 33%, which contrasts with the relatively high ratio of cerebrospinal fluid-to-blood glucose seen in term and premature newborns of 70% to 80% [Sarff et al., 1976], accompanied by low levels of the GLUT1 glucose transporter assayed in red blood cells. Conventional anatomic neuroimaging with CT or MRI is typically normal, whereas metabolic imaging with 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) reveals a distinctive pattern of hypometabolism in the thalami and mesial temporal regions [Pascual et al., 2002]. The ketogenic diet is the mainstay of treatment, resulting in good control of seizures in most patients, but it has

Defects in serine biosynthesis manifest as neonatal-onset, chronic encephalopathies with prominent refractory epilepsy [de Koning and Klomp, 2004]. Affected infants are neurologically abnormal at birth, with intrauterine growth retardation, congenital microcephaly, cataracts, seizures, and neurodevelopmental impairment. A distinctive pattern of leukoencephalopathy is seen on MRI, characterized by hypomyelination, vacuolar changes, and gliosis, which may improve after treatment with serine and glycine supplementation. The disease involves defective serine biosynthesis caused by 3-phosphyglycerate dehydrogenase deficiency (see Fig. 18-6). Clinical manifestations have been attributed to multiple mechanisms, including loss of neurotrophic effects of serine; impaired synthesis of glycine, which acts as a glutamate receptor co-agonist; and impaired synthesis of 5-methyltetrahydrofolate (5-MTHF), which is a cofactor for numerous brain enzyme pathways. Diagnosis can be made by finding low cerebrospinal fluid concentrations of serine, glycine, and 5-MTHF. In contrast to many inborn errors of metabolism, this disorder is potentially treatable by high-dose dietary supplementation of serine (200 to 600 mg/kg/day) and glycine (200 mg/kg/day).

SAICAR 1

SAICA riboside

AICAR 2 AICA riboside FAICR 2

S-Ado

S-AMP 1

GMP

IMP

AMP

Guanosine

Inosine

Adenosine

Guanine

Hypoxanthine

Adenine

Xanthine

Uric acid FIGURE 18-9. Defects in purine biosynthesis caused by deficiencies in adenylosuccinate lyase (1) and AICA riboside transformylase (2). AICA, 5-amino-4-imidazolecarboxamide riboside; AMP, adenosine monophosphate; FAICR, formyl-5-amino-4-imidazolecarboxamide riboside; GMP, GMP, guanosine monophosphate; IMP, inosine monophosphate; S-Ado, succinyladenosine; SAICA, succinyl-5- amino4-imidazolecarboxamide riboside.

Purine Biosynthesis Defects Defects of purine biosynthesis have been described with clinical manifestation in the neonatal period involving adenylosuccinate lyase or riboside transformylase enzyme deficiencies (Fig. 18-9) [Castro et al., 2002; Marie et al., 2004]. These infants are typically born uneventfully at term, manifest a severe neonatal encephalopathy with hypotonia and seizures, and have mildly dysmorphic facies. Neuroimaging may be normal initially, but over time may disclose diffuse atrophy. The long-term course is characterized by persistent, severe static encephalopathy with profound mental retardation, blindness due to optic atrophy, refractory epilepsy, and growth failure. The cardinal biochemical features include massive urinary excretion of the riboside metabolites 5-amino-4-imidazolecarboxamide ribosiduria (AICA) and succinyl-5-amino-4-imidazolecarboxamide ribosiduria (SAICA) in urine and cerebrospinal fluid. These metabolites give a positive result on the Bratton-Marshall test, which screens for high concentrations of succinyl purines. Diagnosis is confirmed by high-resolution thinlayer chromatography analysis of urine for succinyl purines. Affected infants may have disturbed glucose and lipid metabolism as a result of impaired hepatic gluconeogenesis, fatty acid, and cholesterol synthesis. Management is symptomatic and supportive because there is no definitive or curative treatment. L-Amino

Acid Decarboxylase Deficiency

L-Amino acid decarboxylase deficiency (L-ADD) is a defect of biogenic amine neurotransmitter metabolism, causing

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Perinatal Acquired and Congenital Neurologic Disorders / 18 Tyrosine

6 3-o-methyldopa

5

L-dopa

5-HT

2

2

Dopamine

Serotonin

GTP

3

4

BH4 2

5-HIAA

Phenylalanine 1

BH2

Tyrosine

3 Norepinephrine

VLA

tryptophan

1

HVA L-dopa

4 Epinephrine

VMA

FIGURE 18-10. Defects in biogenic amine neurotransmitter metabolism: 1, tyrosine hydroxylase + BH4; 2, aromatic L-amino acid decarboxylase + B6; 3, dopamine β-hydroxylase; 4, phenylethanolamine-N-methyltransferase; 5, tryptophan hydroxylase + BH4; 6, catechol-ortho-methyl transferase (COMT). Affected metabolites and cofactors include homovanillic acid (HVA), vanillylmandelic acid (VMA), vanillactic acid (VLA), 5-hydroxy-tryptamine (5-HT), 5-hydroxy-indole acetic acid (5-HIAA), tetrahydrobiopterin (BH4).

a combined deficiency of brain dopamine, serotonin, norepinephrine, and epinephrine (Fig. 18-10) [Swoboda et al., 2003]. Patients commonly present in the first weeks of life with a progressive disorder affecting multiple levels of the nervous system. Symptoms and signs include lethargy, hypotonia, suck and swallow dysfunction, and seizures, sometimes associated with hypoglycemia and acidosis. Autonomic dysfunction leads to ptosis, hypotension, gastric and intestinal dysmotility, and poor temperature regulation. With advancing age, a distinctive movement disorder appears, consisting of dystonia, athetosis, oculogyric crises, and nonepileptic myoclonus. Diagnosis rests on evaluation of cerebrospinal fluid neurotransmitter profiles, which demonstrate increased levels of the biogenic amine precursors L-dopa and 5-hydroxytryptamine and decreased levels of the neurotransmitter metabolites homovanillic acid (HVA) and 5hydroxy-indole acetic acid (5-HIAA). Similar profiles of neurotransmitter amino acids are measured in plasma and urine. A clue to this disorder is the finding on a urine organic acid profile of elevated vanillacetic acid, a breakdown product from an alternate degradative pathway for L-dopa. Management is symptomatic and supportive. Attempts to treat by replacing deficient neuroactive amines have been hindered by the lack of an effective targeted delivery system. Outcome is poor for most patients, who develop mixed, severe motor and cognitive disabilities and chronic movement disorders that are refractory to symptomatic treatment.

Chronic Encephalopathies without Multiorgan Involvement Hyperphenylalaninemia Hyperphenylalaninemia causes a chronic encephalopathy with neonatal onset due to one of several defects in the metabolism of phenylalanine. These include phenylalanine hydroxylase deficiency, tetrahydrobiopterin (BH4) synthesis deficiency, and guanosine triphosphate cyclohydrolase deficiency (Fig. 18-11). In classic phenylketonuria caused by phenylalanine hydroxylase deficiency, plasma phenylalanine concentrations exceed 1000 μM, and liver biopsy reveals that phenylalanine hydroxylase activity is severely deficient

Biogenic amines

Fumarate

Acetoacetate

Gluconeogenesis

Ketogenesis

FIGURE 18-11. Defects in amino acid metabolism leading to hyperphenylalaninemia: 1, phenylalanine hydroxylase; 2, dihydropterin reductase; 3, guanine triphosphate (GTP) cyclohydrolase; 4,6-pyruvyltetrabiopterin synthase. BH2, dihydrobiopterin; BH4, tetrahydrobiopterin.

(<1% of normal). In a milder form of the disease, designated nonphenylketonuria hyperphenylalaninemia, plasma phenylalanine concentrations are less than 1000 μM, and phenylalanine hydroxylase activity is less severely decreased (5% to 30% of normal). Clinical symptoms in untreated classic phenylketonuria consist of irritability, hyperkinesis, acquired microcephaly, and severe cognitive deficiency. Infants with GTP cyclohydrolase deficiency have neonatal-onset chronic encephalopathy with severe hypotonia, bulbar dysfunction, and sometimes seizures, which may evolve over time to a pattern of rigidity, hyperkinesia, and oculomotor abnormalities. Treatment with L-dopa has been beneficial in some patients [Nardocci et al., 2003]. Diagnosis is made by newborn metabolic screening in most countries. After identi-fication of newborns with hyperphenylalaninemia, further quantitation of plasma phenylalanine and tyrosine and of urinary and cerebrospinal fluid biopterin metabolites at baseline and after phenylalanine loading is necessary to distinguish classic phenylketonuria from BH4 and GTP cyclohydrolase disorders. Treatment consists of the use of a semisynthetic diet low in phenylalanine, which is carefully titrated according to plasma amino acid levels. Patients with BH4 disorders require folate and BH4 replacement. A trial of L-dopa and 5-hydroxytryptophan replacements to restore brain monoamine levels may help the dystonia and rigidity in some patients.

Succinic Semialdehyde Dehydrogenase Deficiency Succinic semialdehyde dehydrogenase deficiency is a defect of GABA degradation resulting in elevated levels of GABA in the brain (see Fig. 18-7). The clinical presentation varies [Pearl et al., 2003]. Some patients present in the neonatal period with a chronic encephalopathy with diffuse hypotonia and neurodevelopmental impairment, and some also have epilepsy. An important clue to the diagnosis in this otherwise nonspecific clinical pattern is the finding on brain MRI of T2 hyperintensity in the globus pallidus. Diagnosis rests on the finding of elevated levels of urinary 4-hydroxybutyric acid, which is associated with high levels of GABA

Ichord / Perinatal Metabolic Encephalopathies

in cerebrospinal fluid and urine. Treatment with vigabatrin, a selective inhibitor of GABA transaminase, has resulted in partial or equivocal benefit in reported cases.

Glutaric Aciduria Glutaric aciduria is an autosomal recessive defect in the degradation of 2-keto-adipic acid, a metabolite in the lysine and tryptophan degradation pathways. Neonatal and early infantile manifestation occurs with type I glutaric acidurias due to glutaryl-CoA dehydrogenase deficiency. Affected infants have a chronic, progressive encephalopathy of neonatal or early infantile onset, with macrocephaly, hypotonia evolving to rigidity and dystonia, developmental regression, and epilepsy in some cases. There may be episodic decompensations, with vomiting, ketotic hypoglycemia, acidosis, hyperammonemia, hepatomegaly, and depressed consciousness triggered by intercurrent illness. MRI abnormalities are distinguished by the finding of selective frontotemporal atrophy, especially involving subcortical white matter, with prominent extra-axial cerebrospinal fluid collections and, in some cases, subdural hemorrhage. Metabolic crises, which are associated with acute, bilaterally symmetric striatal necrosis in a large proportion of these patients, lead to permanent neuromotor disability [Strauss et al., 2003]. Diagnosis rests on the finding of elevated urinary levels of glutaric acid and 3-hydroxy-glutaric acid, and it is confirmed if needed in equivocal cases by enzyme assay in cultured fibroblasts. Treatment involves dietary protein restriction, particularly L-lysine and tryptophan, and supplementation with L-carnitine and riboflavin. Timely supportive care with intravenous fluids and dextrose during intercurrent illness can minimize the risk of metabolic decompensations and the attendant striatal necrosis.

Chronic Encephalopathies with Multiorgan Involvement Congenital Disorders of Glycosylation Congenital disorders of glycosylation comprise a group of genetically determined metabolic diseases characterized by abnormalities in protein glycosylation, which is a cotranslational modification step in the synthesis of most secretory and membrane-bound proteins (see Chapter 26). The nervous system is prominently affected, in association with abnormalities in multiple other organ systems, including liver, kidney, heart, and bone [Miossec-Chauvet et al., 2003]. Two main subgroups have been described. Type I involves defects in assembly of the oligosaccharide precursors, and type II involves processing of the oligosaccharide. Congenital disorder of glycosylation Ia is the most common and best-described disorder; it can manifest with a neurologic or multisystem pattern. The neurologic presentation is one of chronic, severe neurologic disability punctuated by episodic, acute deterioration resembling stroke. There is usually prominent cerebellar dysfunction with severe cerebellar atrophy detected on brain MRI. Usually normally grown at birth, some patients present with hypotonia and oculomotor abnormalities in the newborn period. Over time, patients display persistent ataxic-

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hypotonic motor impairment and severe cognitive deficiency, retinopathy, epilepsy, acquired microcephaly thromboembolic strokes, and weakness due to polyneuropathy. Associated non-neurologic findings include growth failure, protein-losing enteropathy, obstructive cardiomyopathy, nephrotic syndrome, and deficient antithrombin III or protein C or S. Inverted nipples and subcutaneous fat pads are distinctive physical stigmata of the disorder. Diagnosis is made by measuring transferrin isoelectric focus point, which may not become abnormal until the second or third week of life. Associated biochemical findings include elevated levels of liver transaminases, low levels of serum proteins, anemia, leukopenia, and low serum levels of cholesterol. Treatment with high-dose mannose supplementation has provided no clear neurologic benefit in patients with congenital disorders of glycosylation I.

Peroxisomal Disorders Peroxisomal disorders constitute a group of progressive neurologic diseases with variable age of onset and severity (see Chapter 29). Neonatal forms with prominent neurologic involvement include Zellweger’s syndrome and neonatal adrenoleukodystrophy, both of which appear to be autosomal-recessive disorders. Infants with the classic Zellweger syndrome have multiorgan involvement with typical facial dysmorphic features, ocular anomalies (e.g., cataract, glaucoma, pigmentary retinopathy), hepatic fibrosis, cystic kidney disease, subclinical adrenocortical insufficiency, and cardiac anomalies. Neurologic features include seizures, cranial nerve dysfunction, optic atrophy, and diffuse myopathic weakness. Survivors are multiply and profoundly handicapped. Neuroimaging and pathologic studies have revealed cortical and cerebellar migration abnormalities and a central white matter demyelinating process. Pathogenesis is related to near-complete failure of peroxisomal function as a result of defective transport of proteins into the peroxisomal matrix. This results in defective oxidation and abnormal accumulation of very-long-chain fatty acids, phytanic and pipecolic acids, and deficient synthesis of plasmalogens. The typical clinical features should suggest the diagnosis, which is supported by the finding of markedly elevated plasma levels of very-long-chain fatty acids and decreased plasmalogen levels. Neonatal adrenoleukodystrophy resembles Zellweger’s syndrome in many respects, but it is less severe. There are no proven definitive treatments. Trials are evaluating strategies aimed at modifying lipid and fatty acid composition of the diet.

Cholesterol Biosynthesis Defects: Smith-Lemli-Opitz Syndrome The molecular defect in Smith-Lemli-Opitz syndrome has been characterized as a disorder of cholesterol biosynthesis. This condition manifests in the neonatal period with a constellation of multiple congenital anomalies and a chronic static encephalopathy [Herman, 2003]. Infants typically present with microcephaly, abnormal facies with ptosis and micrognathia, genital anomalies, and growth retardation. Less frequent abnormalities include cataracts, congenital heart defects, digital anomalies, and cleft palate. Neurologic

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features include hypotonia, sensorineural deafness, feeding and swallowing dysfunction, and severe cognitive deficiency. Common cerebral malformations include holoprosencephaly, agenesis of the corpus callosum, frontal hypoplasia, and cerebellar hypoplasia. The serum cholesterol level is low in 90% of cases, but definitive diagnosis rests on finding elevated serum levels of 7- and 8-dehydrocholesterol measured by gas chromatography and mass spectrometry. Treatment is supportive and symptomatic. Enteral supplements of cholesterol may mitigate some of the symptoms [Haas et al., 2001].

REFERENCES al-Rabeeah A, al-Ashwal A, al-Herbish A, et al. Persistent hyperinsulinemic hypoglycemia of infancy: Experience with 28 cases. J Pediatr Surg 1995; 30:1119. Anderson JM, Milner RDG, Strich SJ. Effects of neonatal hypoglycaemia on the nervous system: A pathological study. J Neurol Neurosurg Psychiatry 1967; 30:295. Applegarth DA, Toone JR. Glycine encephalopathy (nonketotic hyperglycinaemia): Review and update. J Inherit Metab Dis 2004;27:417. Aynsley-Green A, Hawdon JM. Hypoglycemia in the neonate: Current controversies. Acta Paediatr Jpn 1997;39 (Suppl 1):S12. Barkovich, AJ, al-Ali F, Rowley HA, et al. Imaging patterns of neonatal hypoglycemia. AJNR Am J Neuroradiol 1998;19:523. Boles RG, Ment LR, Meyn MS, et al. Short-term response to dietary therapy in molybdenum cofactor deficiency. Ann Neurol 1993;34:742. Castro M, Perez-Cerda C, Merinero B, et al. Screening for adenylosuccinate lyase deficiency: Clinical, biochemical and molecular findings in four patients. Neuropediatrics 2002;33:186. Cornblath M, Ichord R. Hypoglycemia in the neonate. Semin Perinatol 2000;24:136. de Koning TJ, Klomp LW. Serine-deficiency syndromes. Curr Opin Neurol 2004;17:197. De Vivo DC, Wang D, Pascual JM, et al. Glucose transporter protein syndromes. Int Rev Neurobiol 2002;51:259. den Boer ME, Dionisi-Vici C, Chakrapani A, et al. Mitochondrial trifunctional protein deficiency: A severe fatty acid oxidation disorder with cardiac and neurologic involvement. J Pediatr 2003;142:684. Dodd PR, Williams SH, Gundlach AL, et al. Glutamate and GABA neurotransmitter systems in the acute phase of maple syrup urine disease and citrullinemia encephalopathies in newborn calves. J Neurochem 1992;59:582. Dublin AB, Hald JK, Wootton-Gorges SL. Isolated sulfite oxidase deficiency: MR imaging features. AJNR Am J Neuroradiol 2002;23:484. Gruskin AB, Sarnaik A. Hyponatremia: Pathophysiology and treatment, a pediatric perspective. Pediatr Nephrol 1992;6:280. Haas D, Kelley RI, Hoffmann GF. Inherited disorders of cholesterol biosynthesis. Neuropediatrics 2001;32:113. Hamosh A, McDonald JW, Valle D, et al. Dextromethorphan and highdose benzoate therapy for nonketotic hyperglycinemia in an infant. J Pediatr 1992;121:131. Hawdon JM, Ward Platt MP. Metabolic adaptation in small for gestational age infants. Arch Dis Child 1993;68:262. Hawdon JM, Ward Platt MP, Aynsley-Green A. Prevention and management of neonatal hypoglycaemia. Arch Dis Child Fetal Neonatal Ed 1994;70:F60, discussion F65. Herman GE. Disorders of cholesterol biosynthesis: Prototypic metabolic malformation syndromes. Hum Mol Genet 2003;12:R75. Hyland K, Arnold LA. Value of lumbar puncture in the diagnosis of infantile epilepsy and folinic acid-responsive seizures. J Child Neurol 2002;17 (Suppl 3):3S48. Jan W, Zimmerman RA, Wang ZJ, et al. MR diffusion imaging and MR spectroscopy of maple syrup urine disease during acute metabolic decompensation. Neuroradiology 2003;45:393. Kurlemann G, Loscher W, Dominick HC, et al. Disappearance of neonatal seizures and low CSF GABA levels after treatment with vitamin B6. Epilepsy Res 1987;1:152.

Leary LD, Wang D, Nordli DR Jr, et al. Seizure characterization and electroencephalographic features in Glut-1 deficiency syndrome. Epilepsia 2003;44:701. Marie S, Heron B, Bitoun P, et al. AICA-ribosiduria: A novel, neurologically devastating inborn error of purine biosynthesis caused by mutation of ATIC. Am J Hum Genet 2004;74:1276. Mikati MA, Trevathan E, Krishnamoorthy KS, et al. Pyridoxinedependent epilepsy: EEG investigations and long-term follow-up. Electroencephalogr Clin Neurophysiol 1991;78:215. Miossec-Chauvet E, Mikaeloff Y, Heron D, et al. Neurological presentation in pediatric patients with congenital disorders of glycosylation type Ia. Neuropediatrics 2003;34:1. Nardocci N, Zorzi G, Blau N, et al. Neonatal dopa-responsive extrapyramidal syndrome in twins with recessive GTPCH deficiency. Neurology 2003;60:335. Pascual JM, Van Heertum RL, Wang D, et al. Imaging the metabolic footprint of Glut1 deficiency on the brain. Ann Neurol 2002;52:458. Pearl PL, Novotny EJ, Acosta MT, et al. Succinic semialdehyde dehydrogenase deficiency in children and adults. Ann Neurol 2003;54 (Suppl 6):S73. Rees L, Shaw JC, Brook CG, et al. Hyponatraemia in the first week of life in preterm infants. Part II. Sodium and water balance. Arch Dis Child 1984;59:423. Sarff LD, Platt LH, McCracken GH Jr. Cerebrospinal fluid evaluation in neonates: Comparison of high-risk infants with and without meningitis. J Pediatr 1976;88:473. Sarnaik AP, Meert K, Hackbarth R, et al. Management of hyponatremic seizures in children with hypertonic saline: A safe and effective strategy. Crit Care Med 1991;19:758. Saudubray JM, Charpentier C. Clinical phenotypes: Diagnosis/algorithms. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill, 1995:327. Saudubray JM, Nassogne MC, de Lonlay P, et al. Clinical approach to inherited metabolic disorders in neonates: An overview. Semin Neonatol 2002;7:3. Scriver CR, Beaudet, Sly, et al. The metabolic and molecular bases of inherited disease. 8 ed. New York: McGraw-Hill, 2001. Sigauke E, Rakheja D, Kitson K, et al. Carnitine palmitoyltransferase II deficiency: A clinical, biochemical, and molecular review. Lab Invest 2003;83:1543. Silberman J, Dancis J, Feigin I. Neuropathologic observations in maple syrup urine disease. Arch Neurol 1961;5:351. Sterns RH. Severe hyponatremia: The case for conservative management. Crit Care Med 1992;20:534. Strauss KA, Puffenberger EG, Robinson DL, et al. Type I glutaric aciduria. Part 1. Natural history of 77 patients. Am J Med Genet C Semin Med Genet 2003;121:38. Swoboda KJ, Saul JP, McKenna CE, et al. Aromatic L-amino acid decarboxylase deficiency: Overview of clinical features and outcomes. Ann Neurol 2003;54 (Suppl 6):S49. Takahashi H, Koehler RC, Brusilow SW, et al. Inhibition of brain glutamine accumulation prevents cerebral edema in hyperammonemic rats. Am J Physiol 1991;26:H825. Trottier A, Metrakos K, Geoffroy G, et al. A characteristic EEG finding in newborns with maple syrup urine disease. Electroencephalogr Clin Neurophysiol 1975;38:108. Vannucci RC, Nardis EE, Vannucci SJ. Cerebral metabolism during hypoglycemia and asphyxia in newborn dogs. Biol Neonate 1980;38:276. Worthen HG, al Ashwal A, Ozand PT, et al. Comparative frequency and severity of hypoglycemia in selected organic acidemias, branched chain amino acidemia, and disorders of fructose metabolism. Brain Dev 1994;16 (Suppl):81. Young RS, Cowan BE, Petroff OA, et al. In vivo 31P and in vitro 1H nuclear magnetic resonance study of hypoglycemia during neonatal seizure. Ann Neurol 1987;22:622.

RESOURCES Web site for Online Mendelian Inheritance in Man (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM). Web site for Gene Clinics (http://www.geneclinics.org/).

CHAPTER 19

Congenital Structural Defects Joseph G. Gleeson, William B. Dobyns, Lauren Plawner, and Stephen Ashwal

Remarkable progress in our understanding of the genetic, molecular, and pathogenic mechanisms underlying congenital structural brain defects has paralleled progress in developmental and molecular neurobiology. The extraordinary information about the sequence of molecular and structural events controlling brain development, and, likewise, the effects of gene dysregulation in the pathogenesis of many well-recognized but poorly understood malformations, continues to emerge at an exciting pace. Two of the most important contributions that have advanced this knowledge are the capability to perform detailed neuroimaging in patients and the draft of the human genome sequence. Imaging has provided more refined correlations between clinical symptomatology, progression of disease, and molecular findings and has been critical in grouping patients together for detailed genetic studies. Availability of the human genome sequence has fueled genetic research, through identification of most human genes, human sequence variations, correlations with other species, and high-throughput genomics approaches that have greatly aided molecular studies in all areas of medicine. Some disorders discussed in this chapter represent welldefined clinical and genetic entities for which the molecular underpinnings have been elucidated and specific DNAbased diagnostic tests and prognosis are available. Other disorders have an ill-defined developmental etiology and unknown genetic causes. In most cases, recognition of a disorder of brain development portends a degree of developmental disability, and often a seizure disorder, which can be among the most difficult of pediatric epilepsies to treat. In addition, it now bears on the treating physician to recognize the radiologic pattern of these conditions and their genetic causes, and to properly advise patients and their families of the risks of recurrence or refer them to the proper specialist who can provide this information. This chapter focuses on the clinical presentation, natural history, diagnosis, prognosis, and treatment of developmental brain disorders in children. The scope of the discussion is limited to conditions with a primary brain defect; the chapter is not presented as a comprehensive treatise of all genetic conditions that can include a degree of brain impairment. Thus, defects of neural tube closure (dysraphisms) are included but not neural crest disorders (such as Hirschsprung’s disease). Also included are disorders of skull development and hydrocephalus. The reader is referred to several other sources for details on related topics, including neuropathology [Dickett, 1995], developmental genetics [Epstein et al., 2004], neonatal neurology [Volpe, 2001], neurobiology [Cowan et al., 1997], and neuroradiology [Ball, 1997; Barkovich, 2005].

OVERVIEW OF PATHOGENESIS Malformations of the brain and spinal cord occur during fetal nervous system development. Such malformations may result from a defect in one or more key developmental steps due to a genetic perturbation in the fetus. Malformations also may arise from extrinsic factors, such as teratogens or infections (Box 19-1), from a maternal biochemical defect, or from interactions between genetic and environmental factors. Although it is difficult to provide exact numbers, approximately 3% of newborns have malformations serious enough to require medical attention, and the risk is considerably higher in families with consanguinity [Jaber et al., 1994] or other environmental risk factors. Together, malformations account for approximately 500,000 deaths per year worldwide. Malformations are the leading cause of infant mortality in the United States [Petrini et al., 1997], accounting for 70% of fetal deaths and 40% of deaths within the first year of life [Caviness, 1989]. Malformations of the central nervous system (CNS) also account for approximately 13% of infant deaths [Petrini et al., 1997; Rosano et al., 2000]. Developmental abnormalities also are the single most commonly identified cause of intractable childhood epilepsy and constitute an important cause of developmental delay. Malformations represent an important contribution to the total disease burden seen in pediatric neurology. The etiology of CNS malformations is unknown in more than 60% of patients. Hereditary factors that cause nervous system malformations include autosomal and X-linked conditions and chromosome abnormalities. Single mutant genes may cause localized malformations or multisystem involvement, and it has been estimated that a specific genetic etiology has been identified in perhaps 50% of these conditions, with a genetic cause in the remaining 50% to be identified in the near future. These mutations tend to be among the most severe and include mutations predicted to truncate proteins, render them useless, or block a genetic or biochemical pathway through a dominant effect. Multigenic disorders, in which less severe mutations are encountered in several different genes, each contributing to the overall risk of disease, are more difficult to study, and few examples exist in which this has been conclusively demonstrated. In the future, however, as current understanding of the pathogenesis of each condition improves, the frequency with which these conditions are diagnosed molecularly will increase. At the other end of the spectrum are multifactorial inheritance disorders, in which gene-environment interactions play a role. Although clearly important in a majority of neurologic diseases, these conditions are likely to be among the hardest to understand at a genetic and environmental level.

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Box 19-1 ETIOLOGY OF HUMAN NERVOUS SYSTEM MALFORMATIONS Teratogens Fetal malpositioning or crowding Hyperthermia Physical agents in utero Radiation Trauma Infectious Agents In Utero Cytomegalovirus Herpesvirus types 1 and 2 Mumps virus Rubella virus Toxoplasma gondii Treponema pallidum Varicella virus Maternal Metabolic Derangement Antiepileptic drugs (phenytoin, trimethadione, valproic acid) Antimetabolites Carbon monoxide Cocaine; other substances of abuse Diabetes mellitus Ethyl alcohol Hypoxia Iodine deficiency Isotretinoin (Accutane) Malnutrition Maternal toxin and drug exposure Methyl mercury (Minamata disease) Phenylketonuria Toxemia of pregnancy Vitamin excess or deficiency Genetic Conditions Autosomal dominant Autosomal recessive Chromosomal abnormality Complex (polygenic) inheritance Single-gene inheritance X-linked Teratogens, such as trauma, hypoxia, hyperthermia, chemical toxins, drugs, infectious agents, and radiation, as well as maternal diabetes mellitus, phenylketonuria, and intrauterine conditions such as constricted fetal position or twin-mediated vascular catastrophe, account for approximately 5% of nervous system malformations in which the cause is apparent. Malformations associated with teratogens depend on the mechanism of action and specific time and duration of exposure during gestation. For example, isotretinoin (Accutane), a vitamin A analog used to treat acne, or vitamin A in a high oral intake (more than 10,000 IU per day), is a well-recognized human teratogen that acts during the first trimester [Alles and Sulik, 1992]. Valproic acid and phenytoin, when administered during gestation at therapeutic levels, also are associated with CNS disease with a genetic predisposition [Lundberg et al., 2004].

Fetal infections may lead to morphologic alterations, dysfunction with or without histologic changes, as can latent infection with subsequent abnormality. Toxoplasma gondii infection, rubella, herpes simplex, and cytomegalovirus infections all can cause malformations, as can fetal exposure to maternal human immunodeficiency virus infection [Bale, 2002; Griffith and Booss, 1994]. These infections are discussed in detail in Chapters 69 and 70.

NORMAL EMBRYONIC DEVELOPMENT Knowledge of nervous system embryology (Table 19-1) is vital for understanding and classifying developmental abnormalities. The genetics and signaling utilized in brain development are briefly reviewed to provide a framework for the understanding of human brain developmental disorders. Disorders of brain development are best understood in the context of normal brain development. Accordingly, this chapter is organized on the basis of the critical stages of mammalian brain development. Nervous system development begins with induction of the neural plate, which then undergoes a morphologic change toward the neural tube. Failure of neural tube closure along the neural axis gives rise to several disorders, including spina bifida and anencephaly, and may underlie other conditions such as encephaloceles and schizencephaly. Next, the neural tube is divided along the three major axes— rostral-caudal, dorsal-ventral, and medial-lateral—into what will later become specific brain regions. This process is referred to here as segmentation, specification, or regionalization. During this process, the unspecified nervous system tissue is specified with certain anatomic and cell-type specific identities. Transplantation studies in animal models of one brain region to another area have found that to some degree, this specification is reversible, meaning that the tissue is not committed to a specific fate, although in other instances the cell identify is committed at this stage. Examples of diseases resulting from such errors in specification TABLE 19-1 Simplified Scheme of Brain Development in Humans CRITICAL EVENT IN BRAIN DEVELOPMENT

DEVELOPMENTAL WINDOW (weeks of gestation)

EXAMPLE(S) OF MAJOR HUMAN DISEASE

Neural tube closure

3-6 weeks

Dorsal cleft formation Ventral specification

5-6 weeks

Schizencephaly, spina bifida Holoprosencephaly

Neuronal proliferation Neuronal migration onset Neuronal migration movement Cerebellar development Neuronal differentiation

5-6 weeks 8-16 weeks (in majority) 10-15 weeks 10-20 weeks 20-40 weeks and beyond 20-40 weeks and beyond

ACC, agenesis of the corpus callosum.

Septo-optic dysplasia, ACC Microcephaly Periventricular heterotopia Lissencephaly Dandy-Walker, Joubert’s syndromes Mental retardation

Gleeson, Dobyns, Plawner, and Ashwal / Congenital Structural Defects

are septo-optic dysplasia, Dandy-Walker malformation, and holoprosencephaly. The next step in brain development is neuronal proliferation, where massive amplification of neural progenitor cells gives rise to the billions of cells that will constitute the brain. Defects in neuronal proliferation likely underlie the disorder of microcephaly, in which brain volume is less than normal, and other syndromes in which regional hypoplasia is prominent. The next step in brain development is neuronal migration. A key feature of brain development is that neurons are not generated in the place where they will eventually reside. Instead, they arise from specialized proliferative zones along the cerebrospinal fluid–containing spaces and migrate great distances to achieve final positioning. Examples of disorders in which this process is defective are lissencephaly, polymicrogyria, and neural crest migration disorders. The final step is neuronal differentiation, whereby neurons that have achieved their final position make interneuronal synaptic connections that define brain circuitry. Although this is a simplified model for brain development, and although many of these steps occur more or less simultaneously, this is a helpful framework for considering the classification of brain malformation syndromes.

DEFECTS IN NEURAL TUBE FORMATION Neural Tube Closure After the second gestational week, all embryonic tissues— mesoderm, ectoderm, and endoderm—are present in the embryonic disk. Following the primary axis of the embryonic disk (Fig. 19-1), the nervous system emerges from ectoderm. During the first month of gestation, one germ layer has the potential of inducing a change in another (induction). During the first phase, organizer tissue adjacent to the presumptive neural plate functions as a neural inducer and later produces the notochord, which is required for

A

B

Neural plate

ventral patterning by the CNS. By 20 days of gestation, the neural plate is indented centrally and contains a groove flanked by ridges—the neural folds. Once elevation and hypertrophy occur, the neural folds become the neural tube after the lateral margins of the neural folds join and then fuse in the midline. Midline fusion of the neural folds, a process known as neurulation, is promulgated rostrally and caudally. A neural tube forms with apertures at each end at the anterior and posterior neuropores. The anterior neuropore, the region that will eventually give rise to the brain, is sealed at approximately day 26 of gestation. The posterior neuropore, the region that will give rise to the caudal spinal cord, closes at approximately day 29. As the neural tube develops, it moves from the original ectoderm. Specific cells at the edge of the neural folds are excluded from the neural tube; these cells form the neural crest, which is the anlage of the peripheral and autonomic nervous systems, the meninges, and portions of the skull and face. Work from frog and mouse has identified a host of factors that are necessary for proper neurulation and neural tube closure, and this evidence has direct implications for human disease because vertebrates display a conserved body plan. A key observation was that a small fragment of non-neural tissue (mesoderm), when transplanted, was capable of duplicating the neural tube, indicating that secreted factors from mesoderm are sufficient to induce neurulation. Thus, the factors necessary for neurulation are intrinsic to and are secreted from this mesodermal region. These factors include chordin, noggin, sonic hedgehog, and several others, which are both necessary and sufficient for proper neurulation and control of the amount and fate of the neuroectoderm [De Robertis and Kuroda, 2004]. In mammals, two distinct groups of non-neural cells appear to provide these early patterning signals: axial mesodermal cells of the notocord, which underlie the midline of the neural plate, and the cells of the epidermal ectoderm, which flank its lateral edges. The notocord is the source of ventralizing inductive factor, and the epidermal ectoderm is the source of dorsalizing factors.

C

Neural fold

D

Neural tube

R DRG

NC S

S S

Spinal cord

C

R

ECT N

S

F N

S

365

F N

M

I F N

FIGURE 19-1. Stages in the development of the embryonic spinal cord. A, The neural plate consists initially of a simple columnar epithelium. Cells at the midline of the neural plate are contacted directly by axial mesoderm cells of the notocord (N). More lateral regions of the neural plate overlie the segmental plate mesoderm, which gives rise to the somites (S), eventually giving rise to the limb buds. These are flanked by the epidermal ectoderm (ECT). B, During neurulation, the neural plate buckles at its midline to form the neural fold and a floor plate (F) at the midline. Contact between the midline of the neural plate and the notochord is maintained at this stage. C, The neural tube is formed when the dorsal tips of the neural folds fuse. Cells in this region of fusion form a specialized group of dorsal midline cells, the roof plate (R), and the neural crest cells (NC), which emigrate from the dorsal neural tube. D, After neural tube closure, neuroepithelial cells continue to proliferate and eventually differentiate into defined classes of neurons at different positions within the spinal cord and brain, including commissural (C), motor (M), and inter- (I) neurons. The NC cells eventually give rise to dorsal root ganglia (DRG) and other crest derivates. (From Cowan WM, Jessell TM, Zipursky SL, eds. Molecular and cellular approaches to neural development. New York: Oxford University Press, 1997. Copyright © 1997 by Oxford University Press. Used by permission of Oxford University Press, Inc.)

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Opposing actions of these two signals appear to be critical in establishing the identity and pattern of cell types generated along the dorsal-ventral axis of the neural tube. Differentiation of each of the cell types generated in the ventral half of the neural tube— notably, floor plate cells, motor neurons, and ventral interneurons—depends on signals provided by the axial mesodermal cells of the notochord [Placzek, 1995], whereas cells in the dorsal half of the neural tube depend on signals provided by the lateral epidermal ectoderm. The leading candidate for a mediator of notochord-derived ventralizing inductive signals is Sonic hedgehog (Shh), and for the dorsalizing inductive signal it is a family of bone morphogenetic proteins (BMPs)— BMP4 and BMP7. In this model, Shh released by the notochord diffuses toward the ventral neural tube and induces the differentiation of the floor plate. The floor plate then becomes capable of producing additional Shh, which diffuses and establishes a gradient along the dorsal-ventral axis of the neural tube. BMP4 and BMP7, released by the epidermal ectoderm, diffuses toward the dorsal neural tube and induces the differentiation of the roof plate. The roof plate then becomes capable of producing additional bone morphogenetic proteins, which diffuse and establish a gradient along the ventral-dorsal axis of the neural tube. These countering gradients are received by the cells in the spinal cord and lead to diverse cell fates. Regions of the spinal cord that are exposed to the highest concentrations of Shh and lowest concentrations of bone morphogenetic proteins give rise to cells of ventral fate such as motor neurons, whereas cells exposed to lowest Shh and highest bone morphogenetic protein concentrations give rise to cells of dorsal fate such as commissural projection neurons [Cowan et al., 1997]. Some of these genes exhibit altered DNA sequence among patients with neural tube defects [Felder et al., 2002].

Pathogenesis of Defects Neural tube defects are a result of a failure of the neural tube to close during embryogenesis and are among the most common, serious malformations of human structure. Because the neural tube in humans has multiple sites of closure, the ultimate morphologic defect plus resulting symptomatology is likely to depend on the specific site where failure of fusion occurs. The result of rostral defects is encephalocele or anencephaly, whereas caudal defects give rise to spinal bifida and related disorders. Each of these sites is likely to be controlled by distinctive genetic pathways, because clustering of a lesion site within single families has been observed in both humans and other species [Van Allen et al., 1993]. Lack of closure of the posterior neuropore, the terminal location of normal neural tube fusion, may explain why lumbosacral malformations frequently accompany spina bifida. Two critical regulators of neural tube closure are retinoic acid and folate, which have important implications for risk of these conditions. Retinoic acid is a well-known teratogen when administered to nonhuman embryos, in which one of its many effects is to induce neural tube defects including spina bifida, exencephaly, and anencephaly in several different species [Shenefelt, 1972; Tibbles and Wiley, 1988; Yasuda et al., 1989]. Furthermore, inactivation of retinoic acid–synthesizing enzyme genes or receptor genes in mice

leads to significantly increased rates of neural tube defects. High doses of retinoic acid (vitamin A) or retinoids are to be avoided during pregnancy, although direct evidence for a role in neural tube defects in humans is lacking. The important role of the folate pathway in the pathogenesis of neural tube defects cannot be overemphasized. Inadequate intake of natural folate before and during early pregnancy is associated with a two- to eightfold increased risk of spina bifida and anencephaly, as indicated by several series of case-controlled, randomized clinical trials and community-based interventions [Wald, 1993]. Moreover, the risk of having a child affected by a neural tube defect is indirectly related to both maternal folate intake and maternal folate level [Daly et al., 1995; Moore et al., 2003; Wald et al., 2001]. The mechanism underlying the association between neural tube defects and folate has not been established. It is known, however, that folate participates in two metabolic pathways that, if disrupted, could have an adverse effect on the development of the embryo. One of these pathways is important for nucleic acid synthesis, and the other for a range of methylation reactions, and DNA mutations in these constituents have been found among humans with neural tube defects [Doolin et al., 2002; van der Put et al., 1995]. Recently, studies have demonstrated that neural tube defects can occur in the offspring of pregnant women who had maternal autoantibodies against folate receptors [Rothenberg et al., 2004]. These autoantibodies blocked the binding of [3H]folic acid to folate receptors on placental membranes, presumably resulting in reduced levels of CNS folate that contributed to development of the neural tube defect.

Epidemiology and Etiology of Defects At birth, neural tube defects tends to be more common in females than in males. Additionally, the prevalence of spina TABLE 19-2 Risk Factors for Spina Bifida RISK FACTOR Established Risk Factors History of previous affected pregnancy with same partner Inadequate maternal intake of folic acid Pregestational maternal diabetes Valproic acid and carbamazepine Suspected Risk Factors Maternal vitamin B12 status Maternal obesity Maternal hyperthermia Maternal diarrhea Gestational diabetes Fumonisins Paternal exposure to Agent Orange Chlorination disinfection byproducts in drinking water Electromagnetic fields Hazardous waste sites Pesticides

RELATIVE RISK (-fold increase)

30 2-8 2-10 10-20 3 1.5-3.5 2 3-4 NE NE NE NE NE NE NE

NE, not established. From Mitchell LE, Scott Adzick N, Melchione J, et al. Spina bifida. Lancet 2004;364:1885–1895.

Gleeson, Dobyns, Plawner, and Ashwal / Congenital Structural Defects

bifida varies across time, by region, and by both race and ethnicity and approximates 0.26 to 2.9 cases per 100 live births, although these numbers do not reflect the decrease in incidence that has followed folic acid supplementation or the availability of prenatal diagnosis and the elective termination of some pregnancies with affected fetuses. The variables that have been implicated as risk factors for the nonsyndromic form of spina bifida are listed in Table 19-2. Most of the associations that have been reported are weak, however, and have not been replicated in subsequent studies. Consequently, only a few variables have been established or are strongly suspected to be risk factors for spina bifida. TERATOGENS

Many antiepileptic drugs are known teratogens. Different antiepileptic drugs, however, are associated with different constellations of malformations. An increased risk of spina bifida is associated with in utero exposure to valproic acid or carbamazepine alone, or in combination with each other or other antiepileptic drugs [Hernandez-Diaz et al., 2001; Lammer et al., 1987; Matalon et al., 2002]. In infants exposed to valproic acid or carbamazepine, the risk of spina bifida might be as high as 1% to 2% [Koren and Kennedy, 1999]. Women who use these drugs for indications other than epilepsy (e.g., bipolar disease, migraine, chronic pain) also are at increased risk of having a child with spina bifida if they become pregnant while taking these drugs. The mechanisms by which valproic acid and carbamazepine increase the risk of spina bifida have not been established, but these drugs may affect the folate pathway. Folate administration does not fully protect against the effects of valproic acid or carbamazepine on neural tube closure. FAMILY HISTORY

Although spina bifida aggregates within families, the reported familial recurrence patterns are unlikely to be attributable to the effects of a single genetic locus. Rather, spina bifida seems to be a complex trait determined by many genes and environmental factors that might affect susceptibility independently or through interactions. A family history of spina bifida or anencephaly is one of the strongest risk factors for these disorders. The risk for spina bifida or anencephaly, or both, in the siblings of affected persons ranges from 3% to 8% and is increased to at least 10% after the birth of two affected children. Recurrence risk for identical twins is only slightly higher than for nonidentical twins. The recurrence risk is consistently higher than that of the general population for second- or third-degree relatives of affected persons [Carter and Evans, 1973; Carter et al., 1968; Demenais et al., 1982; Hunter, 1984]. Neural tube defects have been reported in children with various karyotype abnormalities [Seller et al., 2004; Sepulveda and Dezerega, 2004], including trisomy 13 [Rodriguez et al., 1990] and trisomy 18 [Flannery and Kahler, 1986]. Because of the profound effect of folate on the risk of myelomeningocele, polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene were evaluated as a risk factor. Initial studies suggested a sevenfold increased risk associated with the 677C→T alteration, present in about 8% of the populations tested [Ou et al., 1996; van der Put et al., 1995, 1997]. Subsequent studies in other genetic populations, however, did not support the hypothesis that the

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polymorphism is a general risk factor [Koch et al., 1998]. For this reason, testing is not recommended as part of routine screening for risk of neural tube defects. No gene mutations have been directly implicated in the etiology of spina bifida in humans, but the genes identified from lower organisms make attractive candidates.

Spina Bifida Occulta Spina bifida occulta is defined as a defect in the posterior bony components of the vertebral column without involvement of the cord or meninges. It occurs in at least 5% of the population but most often is asymptomatic. This defect often is found incidentally on radiographic studies or is diagnosed because of a subtle clinical finding such as a tuft of hair or a cutaneous angioma or lipoma in the midline of the back marking the location of the defect. The presence of such a cutaneous lesion is associated with spina bifida occulta in only approximately 10% of cases, although the percentage increases to approximately 50% when two or more skin lesions are present [Guggisberg et al., 2004]. This defect is located most often in the lower lumbar area involving the lamina of L5 and S1. When associated neurologic involvement is present, the condition is occult spinal dysraphism. On rare occasions a sinus tract may communicate from the skin to the underlying dura.

OCCULT SPINAL DYSRAPHISM The spectrum of occult spinal dysraphism includes distortion of the spinal cord or roots by fibrous bands and adhesions, intraspinal lipomas, dermoid or epidermoid cysts, fibrolipomas, subcutaneous lipomas (lipomyelomeningoceles), tethered cord, and diastematomyelia [Anderson, 1975; Byrd et al., 1991; Kriss et al., 1995]. A tethered cord is the most common condition [Michelson and Ashwal, 2004]. Symptoms of occult spinal dysraphism may be absent, minimal, or severe, depending on the degree of neural involvement. The patient may exhibit static or slowly progressive weakness, spasticity, or sensory loss in the legs or feet, gait difficulty, and foot deformity. Bowel and bladder dysfunction, such as incontinence, repeated bladder infection, and enuresis, also may occur. Symptoms are caused by abnormally formed neural tissue or pressure on the spinal cord or nerve roots. Common findings include diminished Achilles tendon reflexes, contracted heel cords, high arches, equinovarus deformity of the feet, decreased rectal sphincter tone, unequal leg or foot length, scattered sensory loss, Babinski signs, and trophic ulcers. Because many of these patients have associated posterior fossa or cervical cord malformations, neurologic involvement of the upper extremities may occur in the form of partial paralysis or spasticity. Ophthalmologic complications, usually observed when hydrocephalus is present, also are common and require careful evaluation and follow-up. Ultrasonography and magnetic resonance imaging (MRI) have greatly facilitated the diagnosis and management of these occult lesions (Fig. 19-2). A tethered spinal cord, lipoma, or fatty filum terminale can be detected without invasive myelography. Ultrasonography can demonstrate a poorly pulsatile, low-lying, or thickened conus medullaris in infants. The decision to proceed to surgery is based on progressive symptomatology.

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ternal connections include midline dermal sinus; temporal bone fistula to the middle ear, eustachian tube, or nasopharynx; neurenteric fistula; and basal encephalocele or meningocele involving the cribriform plate, sphenoid bone, or clivus. Such dermal sinus tracts are seen in approximately 1 in 2500 live births [McIntosh et al., 1954]. A rapid test for whether clear discharge from a dermal pit is cerebrospinal fluid is to analyze the fluid for glucose; results will be positive with cerebrospinal fluid but negative with most other body fluids. An MRI scan should be obtained, followed by rapid surgical treatment to ablate this connection and remove the risk of meningitis.

Meningocele

FIGURE 19-2. Tethered spinal cord. T1-weighted magnetic resonance image shows the intradural spinal lipoma (black arrow) tethering the spinal cord at the level of L5 (white arrow), whereas normally the cord should terminate at T11-12. (Reprinted with permission from Marushima A, Matsumura A, Fujita K, et al. Adult tethered cord syndrome presenting with refractory diarrhoea. J Neurol Neurosurg Psychiatry 2003;74:1596– 1597. Reproduced by permission from BMJ Publishing Group.)

Recurrent meningitis from external contamination of cerebrospinal fluid may result from occult congenital malformations along the spinal canal and neuroaxis. These ex-

Meningocele, a protrusion of meninges without accompanying nervous tissue, is not associated with neurologic deficit. The mass usually is evident as a fluid-filled protrusion covered by skin or membrane in the midline. Membranous lesions are found rostrally, and skin-covered lesions are more evenly distributed along the neuroaxis. MRI analysis is helpful in determining the contents of a mass along the spine and in differentiating meningocele from meningomyelocele (Fig. 19-3). Very small subcutaneous lesions may remain undetected for prolonged periods and typically require no specific treatment, but must be differentiated from small encephaloceles. When careful examination of patients with suspected meningocele reveals significant neurologic abnormality (e.g., equinovarus deformity, gait disturbance, abnormal bladder function), the diagnosis of meningomyelocele is appropriate. These patients likely have entrapped nerve roots within the defect that can be identified during surgery. A meningocele in the cranial or high cervical area may coexist with aqueductal stenosis, hydromyelia, or a Chiari II malformation. Membrane-covered meningoceles are more likely to be accompanied by severe abnormalities; lesions covered with normal skin often are free of associated abnormalities. Elective surgical treatment is recommended, except for very small lesions [Feltes et al., 2004].

FIGURE 19-3. Lumbar meningocele in a newborn. A, External appearance of skin. B, Midline sagittal view from T2-weighted magnetic resonance imaging (MRI) study depicts a fluid-filled cystic lesion, measuring 5 cm by 5 cm. Note homogeneous water signal within the lesion, confirming the diagnosis of meningocele, rather than meningomyelocele. The spinal cord terminates appropriately at T1 (arrow). C, Axial view of lesion from T1-weighted MRI study. Note defect in posterior spinal process (arrows), with extrusion of contents into the cyst. (From http://www.neurocirugia.com/intervenciones/ meningocele/Meningocele.htm, with permission.)

Gleeson, Dobyns, Plawner, and Ashwal / Congenital Structural Defects

Myelomeningocele Myelomeningocele, the most complex of congenital spinal deformities, involves all underlying layers (i.e., spinal cord, nerve roots, meninges, vertebral bodies, skin). The spinal cord may be exposed because of complete failure of neural closure (myeloschisis) (Fig. 19-4) or may be covered by a membrane (Fig. 19-5). The birth prevalence rate for spina bifida, which has steadily declined because of improved methods of prenatal diagnosis, has been estimated to be 4.6 cases per 10,000 births [Lary and Edmonds, 1996].

Clinical Characteristics The mortality rate for myelomeningocele is approximately 50% in the absence of therapy; surgical intervention is required because death results from hydrocephalus, meningitis, and renal failure. The renal complications are induced by chronic urinary tract infections, abnormal urodynamic function, and genitourinary tract abnormalities, such as progressive hydronephrosis. Patients at particular risk are the subgroup with high pressure within the bladder [Snodgrass and Adams, 2004]. Myelomeningoceles may be situated at any longitudinal level of the neuroaxis. The location and extent of the defect

FIGURE 19-4. Myelomeningocele with myeloschisis. Note open neural tube with skin defect, resulting in exposure of underlying neural structures. (From http://www.vms.hr/atlas/pathology/ch_6/c6_5.html, with permission.)

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determine the nature and degree of neurologic impairment; rating scales have been developed in an attempt to standardize the evaluation of affected children [Oi and Matsumoto, 1992]. Lumbosacral involvement is most common. The protuberant and fluctuant lesion is readily observable and palpable. Thoracic defects are the most complex and frequently are associated with serious complications. Cervical cord involvement is different from myelomeningocele of the lower spine and can be differentiated into two types: (1) the myelocystocele herniating posteriorly into a meningocele and (2) a meningocele with or without an underlying split cord malformation [Steinbok, 1995; Steinbok and Cochrane, 1995]. Cervical lesions are clearly protuberant, covered at the base by full-thickness skin and covered on the dome by a thick epithelium. Neural tissue is not superficially exposed but usually is tethered to adjacent dural or intrasaccular tissues. These differences likely are responsible for the more favorable outcome in cervical lesions [MeyerHeim et al., 2003]. Varying degrees of paresis of the legs, usually profound, and sphincter dysfunction are the major clinical manifestations. Congenital dislocation of the hips or deformities of the feet such as clubbing may also occur. Severe sensory loss and accompanying trophic ulcers may complicate the condition. Occasionally, only sphincter disturbances are present. Radiographs reveal the primary defect of the vertebral arch. Hydrocephalus, a frequently associated defect, is the result of a Chiari II malformation. Other possible associated findings include aqueductal stenosis and syringomyelia. Hydrocephalus, present in about 70% to 85% of patients with myelomeningocele, occurs most frequently when the lesion is situated in the thoracolumbar area [Rintoul et al., 2002], which is the case in 90% of patients. Although hydrocephalus was believed to be present at birth in only 25% of patients, modern imaging techniques almost always reveal the lesion to be present at birth. Lesions located more rostrally than others produce less lower motor unit paralysis and sphincter involvement. Radiographic evidence of Chiari II malformations is present in most (greater than 75%) affected persons [Just et al., 1990]. Clinically symptomatic Chiari II malformations (e.g., apnea, swallowing difficulties, and stridor in the newborn; headache, quadriparesis, scoliosis, and balance and coordination difficulties in the older child) are present in up to a third of persons with the disorder. Most persons with spina bifida have normal intelligence, but specific cognitive disabilities and language difficulties are common and can adversely affect educational and occupational achievements and the ability to live independently [Northrup and Volcik, 2000; Vachha and Adams, 2003]. Caudal lesions in the neuroaxis typically are associated with bladder and sphincter involvement. The profound paralysis that accompanies caudal involvement often prevents patients from walking.

Prevention

FIGURE 19-5. Myelomeningocele with spinal contents covered by an epidermal membrane in a newborn.

Neural tube defects occur during early pregnancy, often before a woman knows she is pregnant; 50% to 70% of these defects can be prevented if a woman consumes sufficient folic acid daily before conception and throughout the first trimester of her pregnancy. Two landmark studies in the early 1990s found that administration of folic acid had a

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profound effect on the risk of neural tube defects [Medical Research Council Vitamin Study, 1991; Czeizel and Dudas, 1992]. In 1992, to reduce the number of cases of spina bifida and other neural tube defects, the U.S. Public Health Service recommended that all women capable of becoming pregnant consume 400 micrograms of folic acid daily. Because approximately 50% of pregnancies in the United States are unplanned and the neural tube develops before most women know they are pregnant, it was also recommended that women consume this amount of folic acid routinely. Three approaches to increase folic acid consumption were cited: (1) improve dietary habits, (2) fortify foods with folic acid, and (3) use dietary supplements containing folic acid. Mandatory fortification of cereal grain products went into effect in January 1998; during October 1998 to December 1999, the reported prevalence of spina bifida declined 31%, and the prevalence of anencephaly declined 16%. The estimated number of neural tube defect–affected pregnancies in the United States declined from 4000 in the period 1995 to 1996 to 3000 in 1999 to 2000 [Centers for Disease Control and Prevention, 2004]. This analysis controls for declines in live births with neural tube defects as a result of recently implemented screening programs. This decline in affected pregnancies highlights the partial success of the U.S. folic acid fortification program as a public health strategy, and other countries are identifying similar trends.

Antenatal Diagnosis Maternal serum alpha-fetoprotein determination and ultrasound examination are now routinely used to identify fetuses that have or are likely to have spina bifida or anencephaly [Drugan et al., 2001]. Positive findings from either of these two screening tests can be monitored with amniocentesis and detailed sonography. Alpha-fetoprotein is a component of fetal cerebrospinal fluid, and it may leak into the amniotic fluid from the open neural tube. Elevated amniotic alphafetoprotein concentrations correlate with the type of defect; closed lesions often do not lead to increased alphafetoprotein concentration. Detection of neural tube defects correlates with the magnitude of increase in the amniotic fluid alpha-fetoprotein level; neural tube defects are identified in a minority of pregnancies with mildly elevated alpha-fetoprotein levels, in a majority of those with moderately elevated levels, and overwhelmingly in those with very elevated alpha-fetoprotein levels [Canick et al., 2003]. In approximately 2% of unaffected pregnancies, 80% of open spina bifida pregnancies, and 95% of anencephalic pregnancies, a multiple of the median of 2.0 or higher is found. Elevations in amniotic fluid acetylcholinesterase, produced by the fetal nervous system, correlate with maternal serum or amniotic fluid alpha-fetoprotein and can provide additional specificity and sensitivity in this screening approach. When acetylcholinesterase is elevated, more than 95% of patients with moderately or very elevated alphafetoprotein levels had evidence of a neural tube defect. Thus, it can differentiate between open ventral wall defects (i.e., gastroschisis and omphalocele), which will have normal acetylcholinesterase, and open neural tube defects, which will have elevated acetylcholinesterase. Sonography also can be used to differentiate between ventral wall and neural tube defects [Lennon and Gray,

1999], and to identify additional structural malformations that are characteristic of fetuses with chromosomal abnormalities [Sepulveda and Dezerega, 2004]. When a diagnosis of spina bifida is confirmed, ultrasound examination is used to assess spontaneous leg and foot motion and to screen for leg and spine deformities, a Chiari II malformation, and other physical defects. Ultrasonography can detect or confirm the extent of the neural tube defects [Watson et al., 1991] and has had an enormous impact on the number of liveborn infants among populations in which termination of pregnancy is accepted [Zlotogora et al., 2002]. It is 60% accurate in low-risk pregnancies, which is equivalent to that of serum alpha-fetoprotein screening (64%), 89% accurate in high-risk pregnancies, and 100% accurate for women referred for confirmation of a suspected spina bifida by another ultrasonographer [Chan et al., 1993, 1995]. The data indicate that neither sonography nor alpha-fetoprotein screening alone provides sufficient sensitivity or specificity, but that when these studies are used together, the predictive value is much more powerful [Chan et al., 1995]. Prenatal MRI, with ultra-fast T2-weighted sequences, also can be used to characterize the Chiari II and other malformations. Such prenatal imaging studies might help to predict neurologic deficit [Cochrane et al., 1996] and ambulatory potential [Biggio et al., 2001]. Most fetuses with spina bifida that are not electively terminated receive no treatment until after birth. Several studies have investigated whether method of delivery influences the outcome for infants with the disorder. A study based on a review of this work concluded that, in general, conclusive evidence is lacking that relative to vaginal delivery, cesarean section improves the outcome in children with spina bifida [Anteby and Yagel, 2003]. Cesarean section, however, might be justified for large lesions, to reduce the risk of trauma, and is done after in utero treatment of spina bifida, because the forces of labor are likely to produce a wound dehiscence. Additionally, the fetal karyotype can be examined to rule out chromosomal anomalies. Cytogenetic analysis is justified in the setting of prenatally detected spina bifida based on the prevalence of chromosome abnormalities in 17% of fetuses (trisomy 18, trisomy 13, triploidy, and translocation).

Management Management of a child with a myelomeningocele requires the efforts of a multidisciplinary team involving many specialists. Treatment includes surgical reduction and other associated defects such as syringomyelia, prevention of infection, and covering of the myelomeningocele, control of hydrocephalus, management of urinary dysfunction, and treatment of the paralysis and abnormalities of the hips and feet.

Management during Pregnancy Animal studies, in which a model for spina bifida is created by laminectomy and exposure of the spinal cord to amniotic fluid, demostrate that function can be retained if the lesion is closed before birth [Meuli et al., 1995; Michejda and Bacher, 1985]. Other evidence indicates that the Chiari II malformation, which occurs in almost all persons with spina bifida, is acquired and could potentially be prevented by in utero closure [Osaka et al., 1978; Paek et al., 2000]. Hence, in utero treatment might lead to improved outcome for persons with spina bifida relative to conventional treatment strategies.

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Increasing evidence suggests that surgical treatment in utero can provide improved outcome. In 1998, in utero repair of spina bifida by hysterotomy was reported [Adzick et al., 1998; Tulipan and Bruner, 1998]. Early experience suggested that infants with spina bifida treated by hysterotomy had at least partial correction of hindbrain herniation [Tulipan et al., 1999a] and possibly a diminished need for shunting relative to infants who received postnatal reatment [Bruner et al., 1999]. Compared with historical controls, infants given treatment in utero have a lower incidence of moderate to severe hindbrain herniation and hydrocephalus requiring

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shunting [Tulipan et al., 1999b]. In a series of 50 spina bifida cases treated in utero, reversal of hindbrain herniation was reported in all cases, and the proportion requiring shunting was less than in historical control subjects (43% versus 85%) [Johnson et al., 2003]. A similar proportion requiring shunting (54%) also was noted in a second series of 116 spina bifida cases treated in utero at Vanderbilt University Medical Center [Bruner et al., 2004]. Comparisons between infants with spina bifida treated in utero and historical control subjects are, however, subject to substantial bias. The approach is being tested in prospective trials.

Management in the Newborn Period

FIGURE 19-6. Magnetic resonance imaging appearance of constellation of features seen in spina bifida in the newborn. Hydrocephalus can be appreciated (large black arrow) on the basis of distention of the lateral ventricles. The Chiari II malformation is observed (small white arrow) as cerebellar parenchyma herniation through the foramen magnum. A thoracic syrinx is noted (large white arrow) as fluid within the spinal cord. Also evident is herniation of the spinal cord into the lumbar spinal defect, with spinal cord tethering (small back arrow).

Optimal medical management should be provided at birth, including aseptic techniques. The mortality rate is extremely high (approximately 85%) in infants not given treatment by 1 year of age. Standard treatment includes closure of skin lesions overlying myelomeningoceles and treatment of hydrocephalus. Neonates with spina bifida should undergo baseline imaging studies of the CNS (Fig. 19-6) with subsequent serial head measurements to assess the velocity of head growth and the need for shunting. Orthopedic deformities also should be treated shortly after birth, and ultrasonography and urodynamic studies should be done to assess the status of the urinary tract and provide a baseline for continuing assessment. At this age, bowel function is usually not a substantial difficulty, because affected infants have the gastrocolic reflex and pass stools with most feedings. Medical care and monitoring of patients with spina bifida are best provided by regular assessments by a multidisciplinary team. This team should be under the direction of a skilled physician with training in the care of children who have multiple disabilities, and should include a coordinator who is responsible for patient follow-up. Additional team members should include a nurse specializing in the care of children with multiple handicaps, a pediatric neurosurgeon, a urologist, an orthopedic surgeon, a physical therapist, and a social worker. Other subspecialists should be available on an as-needed basis. Team members should be in direct communication with each other and with the patient’s primary care physician, who should provide routine medical care (e.g., immunizations) and continuing emotional support for the family. The value of immediate correction of the defect within 24 hours of birth is widely accepted. Even when cerebrospinal fluid leakage occurs, however, a delay in closure for up to 48 hours does not increase the risk of infection or worsen the neurologic deficit [McComb, 1997]. In such cases, the patient is given antibiotics, and the exposed placode is kept clean and moist. When primary closure is impossible because of the large cutaneous area involved, epithelialization must be encouraged, and surgery performed later. The decision for vigorous therapy for the most severely affected infants with myelomeningocele is beset by moral and medical considerations; restricted therapy often is associated with survival but poor outcome. Appropriate treatment of newborns with myelomeningocele increases the number of survivors and perhaps the quality of survival. Early surgical repair is appropriate for most newborns with myelodysplasia [McComb, 1997]. Each patient must be assessed individually in the context of advances in technology and medical care.

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Short-term and long-term survival of patients with spina bifida has increased with improvements in medical and surgical management. The most recent population-based data indicate that the 1-year survival rate is about 87%, and that roughly 78% of all persons with spina bifida survive to the age of 17 years [Wong and Paulozzi, 2001]. Unfortunately, these patients continue to be subject to excess morbidity and mortality into and throughout adulthood. [Bowman et al., 2001; Hunt, 1999; McDonnell and McCann, 2000; Singhal and Mathew, 1999]. Whether treated in utero or postnatally, patients with spina bifida are at substantial risk for leg weakness and paralysis, sensory loss, bowel and bladder dysfunction, and orthopedic abnormalities (e.g., clubfoot, contractures, hip dislocation, scoliosis, kyphosis). In general, the functional level of the defect corresponds to the anatomic level of the bony spinal defect as determined by radiologic studies. Patients with spina bifida are at risk for associated malformations of the nervous system, including hydrocephalus, syringomyelia, and Chiari II malformations. Almost all patients with thoracic level lesions require a ventricular shunt, whereas shunting is required in less than 70% of those with sacral level lesions [Rintoul et al., 2002]. Radiographic evidence of Chiari II malformations is present in more than 75% of affected persons [Just et al., 1990].

Associated Problems Central Nervous System Complications Routine measurements of head circumference should be taken, and patients should be monitored for symptoms of shunt malfunction and infection and other neurologic complications. Seizures have been reported in up to 17% of patients with meningomyelocele and almost always occur in those with shunted hydrocephalus [Talwar et al., 1995]. Electroencephalographic abnormalities are nonspecific. Additional CNS abnormalities seen in these patients are believed to explain the cause of seizures and include encephalomalacia, previous stroke, malformations, and intracranial calcifications. Seizures may be difficult to control, and frequently, exacerbation of seizures is associated with shunt malfunction or ventriculitis.

Bladder and Bowel Dysfunction Bladder dysfunction and urinary incontinence pose major management problems and may be present at birth in the form of hydronephrosis [Silveri et al., 1997; Stone et al., 1995]. Interruption of sacral nerve roots and fiber connections between the brainstem and sacral cord causes the dysfunction. Loss of sphincter tone, overflow incontinence, sacral and rectal loss of sensation, and loss of detrusor activity on cystometry are seen. In other patients with higher lesions, dyssynergia of reflex pathways results in irregular contractions of the bladder in conjunction with outlet obstruction. Normal bladder control occurs in 10% of children with myelomeningocele. Prevention of bladder infection requires intermittent catheterization to maintain low residual urine volumes and prophylactic antibacterial drugs [Buyse et al., 1995]. Vesicoureteral reflux often develops during the second and third years of life, and assessment for this problem must be ongoing. Reimplantation of the ureters into the bladder or external drainage of the ureters either directly or through an ileal conduit may be helpful. Transurethral

resection of the external sphincter has been recommended when ureteral dilation occurs. The use of prosthetic devices emulating sphincters has been useful in highly selected patients [Simeoni et al., 1996] as has selective sacral rhizotomy [Schneidau et al., 1995]. Constipation and fecal incontinence are common problems in children with spinal dysraphism and usually can be managed medically [Knab et al., 2001]. Dietary manipulation, oral and rectal laxatives, and manual evacuation are common treatments. Retrograde colonic enemas also may be successful.

Orthopedic Problems It is important to consider that the paralysis below the cord lesion associated with spina bifida will be hypotonic, which predicts the types of orthopedic problems. Orthopedic defects associated with paralysis, muscle imbalance, and regional spasticity may be severe and necessitate early intervention. Hip subluxation usually is treated with prosthetic splints or plaster casting [Heeg et al., 1998]. Sensory deficits of the casted skin areas frequently enhance the likelihood of skin ulcers. Severe foot deformities are seen in up to 80% of children and are treated with splinting or casting; neither age nor segmental level influences outcome of the foot deformity [Flynn et al., 2004]. Physical therapy may help to preserve and extend the range of motion of the joints [McDonald, 1995]. In infants and children, progressive leg or foot deformity, weakness, pain, or deterioration of gait or bladder function implies restricted growth or tethering of the spinal cord. Cord tethering may be found in many older children with spina bifida who are neurologically stable, however. Evidence of brainstem dysfunction may be recorded by means of respiratory pneumograms with a carbon dioxide challenge [Petersen et al., 1995] or by using brainstem auditoryevoked response testing [Docherty et al., 1987]. These signs and symptoms indicate the possibility of a Chiari II malformation or a tethered spinal cord. Considerations in the differential diagnosis of delayed deterioration in a child with repaired meningomyelocele include a malfunctioning or infected shunt, seizures, scoliosis, hydrocephalus, hydromyelia, and an undetected second lesion of occult spinal dysraphism, such as a dermoid, epidermoid, or arachnoid cyst. Of course, intercurrent illness or drug toxicity should be considered. Surgical repair of a worsening tethered spinal cord and shunting or fenestration of syringomyelia can prevent decline of function [Iskandar et al., 1994].

Outcome Virtually all infants and children born with neural tube defects are provided with surgical and medical treatment. Previous studies reported that the 5-year survival rate for children with sacral lesions was in the range of 80% to 90%, with increased mortality among children with lesions located more superiorly along the neuraxis [Honein et al., 2001]. Studies of the long-term outcome in children born with meningomyelocele have demonstrated an improved outcome that coincides with medical advances [Wong and Paulozzi, 2001]. Among 101 patients assessed at birth, the mortality rate was 18%; 53% were community ambulators,

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58% attended normal school and were grade-appropriate, 75% were socially continent of urine, and 86% were socially continent of stool. Hydrocephalus was present in 93 children, and 85 required shunting. The shunt revision rate in the first year of life was 50% and after 2 years decreased to 10% per year [Steinbok et al., 1992]. Of note, an increased risk of shunt infections follows new abdominal surgery for renal complications [Aldana et al., 2002].

Counseling Counseling is essential to ensure that parents understand the nature and severity of the deformities and the necessary surgical and long-term rehabilitative efforts [Liptak et al., 1988]. Parents also should be aware of the patient’s potential for intellectual and physical development. In addition, parents should be educated about the higher incidence of late medical complications that can arise and their warning signs, such as latex allergy, in children with spina bifida [Konz et al., 1995]. It is important to communicate these potential problems to family members and others involved in their care.

Diastematomyelia In diastematomyelia, a midline septum divides the spinal cord longitudinally into two usually unequal portions extending up to 10 thoracolumbar segments. The septum may span the entire width of the spinal canal and is anchored to the ventral dura mater on the posterior aspect of the vertebral bodies. It may be attached posteriorly to the vertebral arch or dura mater. The septum is derived from mesoderm and is composed of fibrous tissue, cartilage, or bone (Fig. 19-7). The etiology of diastematomyelia is currently unknown. Diastematomyelia can be divided into two different types. In type I, present in 50% of cases, a split spinal cord is surrounded by a normal undivided arachnoid-dural sleeve without a septum. In type II, present in the other 50%, each hemicord is invested by a separate dural sleeve, divided by a fibrous, cartilaginous, or bony septum [Pang et al., 1992]. The bony septum can be visualized on computed tomography (CT), which may be helpful if surgery is required. These conditions are differentiated from diplomyelia (see later on) on the basis of the integrity of the spinal cord; in

A

B

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diastematomyelia, only a single central canal that is split at or near the midline is present.

Clinical Characteristics Patients with diastematomyelia present with a congenital scoliosis, hydrocephalus, or cutaneous lesion such as hairy patch, dimple, hemangioma, subcutaneous mass, or teratoma [Kothari and Bauer, 1997]. A progressive myelopathy, with deformities of the feet, scoliosis, kyphosis, or discrepancy in leg length, also may develop. Resection of the spur frequently does not result in clinical improvement. The intervening mesenchymal elements appear to contribute to progressive neurologic, urologic, and orthopedic deterioration from spinal cord tethering. Resection of the spur should be performed in patients who have progressive neurologic manifestations; those without worsening symptoms should be observed until progression occurs and then resection performed [Miller et al., 1993]. Diastematomyelia can be detected prenatally by ultrasonography [Anderson et al., 1994; SonigoCohen et al., 2003]. MRI is the preferred neuroimaging study for the evaluation of patients suspected of having this condition. Although most lesions occur in the lumbosacral region, presentations involving the cervical cord are reported. Diastematomyelia also is much more common in females (female-to-male ratio of greater than 3:1) [Mathieu et al., 1982]. Urodynamic and electrophysiologic studies are abnormal in approximately 80% of patients [Kothari and Bauer, 1997].

Diplomyelia Diplomyelia is a side-by-side or anteroposterior duplication of the spinal cord [Dias and Pang, 1995]. It is differentiated from diastematomyelia by the presence of two central canals, each surrounded by gray and white matter arranged in the normal pattern. The two cords often are completely reunited caudally but may remain separated to the tip of the conus medullaris. A bony septum may partly intervene between the duplicated cords. The two cords are often unequal or may be side by side (the most common position), or one may be dorsal to the other. These malformations are compatible with normal function; deterioration suggests the presence of diastematomyelia or tethering. The etiology of this condition also remains unknown.

FIGURE 19-7. Diastematomyelia. The patient was a 12-year-old boy who presented with hydrocephalus and scoliosis. A, Split spinal cord (arrow) can be seen on this axial view from a T1-weighted magnetic resonance imaging study of the thoracic spine. B, Computed tomography image of cervical spinal cord demonstrates a septum of bone density that splits the spinal canal in half. (From http://www.uhrad.com/ mriarc/mri014.htm, with permission.)

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Sacral Agenesis Sacral agenesis is defined as congenital absence of the whole or part of the sacrum [Davidoff et al., 1991; Towfighi and Housman, 1991]. It has a heterogeneous etiology. In its classic form, often described as the caudal regression syndrome, malformations of most or all structures derived from the caudal region of the embryo, including the urogenital system, the hindgut, caudal spine, spinal cord, and the lower limbs, may be seen. Approximately 15% to 25% of mothers of these children have insulin-dependent diabetes mellitus. An autosomal-dominant form of sacral agenesis, sometimes described as a partial sacral dysgenesis, ASP (anal atresia, sacral anomalies, presacral mass) syndrome, or Currarino’s syndrome, also exists. Typical features include hemisacrum with preservation of the first sacral vertebrae [Lynch et al., 2000]. The defect usually takes the form of a sickle-shaped or crescent-shaped deformity of the sacrum; the hemisacrum or so-called scimitar sign is present in approximately 75% of patients (Fig. 19-8). In its most severe presentation, the hemisacrum is associated with a presacral mass (anterior meningocele, enteric cyst, and/or presacral teratoma) and anorectal stenosis. Autosomal dominant inheritance, localization to 7q36, and mutations in a homeobox gene, HLXB9, have been identified in several affected patients [Belloni et al., 2000; Ross et al., 1998]. Mutations in the coding sequence of HLXB9 have been identified in nearly all cases of familial Currarino’s syndrome and in approximately 30% of patients with sporadic Currarino’s syndrome.

FIGURE 19-8. Partial sacral dysgenesis, or Currarino’s syndrome. Note the scimitar sacrum (arrow) with a right-sided defect. (From Lynch SA, Wang Y, Strachan T, et al. Autosomal dominant sacral agenesis: Currarino syndrome. J Med Genet 2000;37:561-566. Reproduced by permission from BMJ Publishing Group.)

The neurologic findings are similar to those with myelomeningocele, ranging from a minimal deficit to equinovarus deformity of the feet to more extensive sensory and motor deficits of the lower extremities. The level of bone anomaly corresponds well with the level of weakness but not to sensory loss; sensation usually is preserved. The caudal spinal cord often is truncated, dysraphic, and tethered [Estin and Cohen, 1995]. Most patients have neurogenic urinary tract and bowel impairment, visceral abnormalities, flattened buttocks, and prominent iliac crests. Constipation and perianal sepsis are common complaints. Ascending infection resulting in bacterial meningitis also has been reported. Treatment is similar to that for patients with myelodysplasia, particularly for the problems of urinary incontinence, constipation, progressive urinary tract and renal dysfunction, and orthopedic abnormalities. Some patients experience progressive neurologic deficits, demonstrating that sacral agenesis is not always a static disability [O’Neill et al., 1995]. Slow deterioration of neurologic function may masquerade as an orthopedic or urologic problem unless the potential for progressive lesions is appreciated. Dural sac stenosis, tethered spinal cord, diastematomyelia, and cauda equina lipomas and dermoids also have been associated with sacral agenesis. Although plain radiographs demonstrate the degree of sacral agenesis, CT or MRI is necessary to delineate the underlying spinal cord

FIGURE 19-9. Partial absence of distal sacrum (black arrows) and abrupt wedge-shaped truncation of the tip of the conus (white arrows). No tethered cord is noted. These findings are consistent with caudal regression syndrome (also known as sacral agenesis). (From http://www.aiclancaster.com/nl/nl_0036.htm.)

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anomalies (Fig. 19-9). Surgical intervention is indicated in patients with progressive neurologic deficits associated with occult spinal cord lesions [Pang, 1993]. Sirenomelia is a typically condition characterized by fusion of the lower limbs, single umbilical artery, and severe malformations of the urogenital and lower gastrointestinal tract. Controversy exists in the literature regarding whether sirenomelia occurs as a separate entity or represents the extreme form of caudal regression syndrome. The presence of two umbilical arteries, nonlethal renal anomalies, nonfused lower limbs, abdominal wall defects, and abnormalities of tracheoesophageal tree, neural tube, and heart serves to differentiate caudal regression syndrome from sirenomelia, however. In addition, caudal regression syndrome is strongly associated with maternal diabetes, whereas sirenomelia is typically because of bilateral renal agenesis and associated severe pulmonary hypoplasia [Das et al., 2002].

Chiari II (Arnold-Chiari) Malformation Much confusion exists regarding the nomenclature and classification of a group of conditions known collectively as Chiari malformations. Chiari was among the first to recognize multiple hindbrain malformations associated with congenital hydrocephalus [Arnett, 2003]. Four types of Chiari malformation have been characterized. Chiari I malformation is a downward displacement of the cerebellum and TABLE 19-3 Classification of Chiari Malformations TYPE

ANATOMIC ABNORMALITIES

I

Downward displacement of the cerebellum and cerebellar tonsils, elongated brainstem fourth ventricle

NEUROLOGIC FINDINGS

Mild and delayed onset of headache and brainstem symptoms usually beginning in adolescence Symptoms secondary to hydrocephalus or syringomyelia II Downward displacement Associated with (Arnold-Chiari of the cerebellar vermis myelomeningocele malformation) and cerebellar tonsils; in more than 95% of thinned and elongated patients; symptoms medulla may actually resulting from be positioned side by progressive side with upper segments hydrocephalus and of the atrophic cervical secondary brainstem spinal cord dysfunction; feeding and respiratory complications are common including apnea III Encephalocervical Features as for Chiari meningocele with spina II, without the same bifida over the cervical degree of association area and protrusion of with cerebellum through myelomeningocele posterior encephalocele IV Hypoplasia of the Variable, ranging from cerebellum asymptomatic to classic cerebellar dysfunction Data from Friede, 1989; Norman et al., 1995; Sarnat, 1992.

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cerebellar tonsils. Chiari II malformation, also known as the Arnold-Chiari malformation, is a complex malformation that includes downward displacement of the cerebellar vermis and tonsils and is encountered in the vast majority of patients with myelomeningocele. Chiari III is an encephalocervical meningocele, and Chiari IV refers to hypoplasia of the cerebellum. The differentiating features are indicated in Table 19-3. Only Chiari II is discussed here; Chiari I and IV are included in the section on cerebellar malformations, and Chiari III is included in the following section on encephaloceles. The major features of the Chiari II malformation include (1) inferior displacement of the medulla and the fourth ventricle into the upper cervical canal, (2) elongation and thinning of the upper medulla and lower pons and persistence of the embryonic flexure of these structures, and the appearance of a “beaking” of the tectum, (3) inferior displacement of the lower cerebellum through the foramen magnum into the upper cervical regions, and (4) a variety of bone defects of the foramen magnum, occiput, and upper cervical vertebrae (Fig. 19-10). Nearly every case of thoracolumbar, lumbar, and lumbosacral myelomeningocele is accompanied by the Chiari II malformation. Hydrocephalus occurs in most patients as a result of aqueductal stenosis or obstruction to cerebrospinal fluid flow around the medulla. Hydromyelia and syringomyelia of the cervical spinal cord occur in 20% to 50% of patients [Breningstall et al., 1990]. Vascular lesions, including hemorrhage and infarction, often are present in the tegmentum of the medulla in children, with resultant altered respiratory control. Other CNS defects, such as small increased numbers of gyri, heterotopias, Klippel-Feil syndrome, craniolacunae, and bone anomalies at the base of the skull, also may accompany the Chiari II malformation.

Pathophysiology The precise mechanism causing Chiari II malformation is unknown. The most parsimonious theory is that the open neural tube fusion to the overlying skin produces downward traction on the neural axis, resulting in herniation of the brainstem and cerebellum through the foramen magnum.

FIGURE 19-10. Chiari II malformation. Note the thinning and elongation of the upper medulla and lower pons, and the persistence of the embryonic flexure of these structures (arrowhead). The “beaked” tectum is apparent on this image (arrow).

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This herniation results in obstructing of hindbrain cerebrospinal fluid outflow, which leads to hydrocephalus. This theory is in keeping with the observation that the Chiari II malformation precedes the development of hydrocephalus. Hydrocephalus associated with the Chiari II malformation probably results primarily from one or both of two basic causes. The first is the hindbrain malformation that blocks either the fourth ventricular outflow or the cerebrospinal fluid flow through the posterior fossa. The second is aqueductal stenosis or atresia that may be associated with the malformation in approximately 50% to 85% of cases [Bell et al., 1987; Peach, 1965; Stein and Schut, 1979]. Further insights into the pathogenesis of the Chiari II malformation will come from study of animal models of neural tube defects. It has been possible to examine the developmental progression of this constellation of malformations in the Splotch animal model of spina bifida due to mutations in the PAX3 gene [McLone and Dias, 2003].

Clinical Characteristics It may be difficult to differentiate between symptoms related to the hydrocephalus and those related to the Chiari II malformation, but several features are uniformly seen in this condition (Table 19-4). These symptoms are directly referable to cerebellar, brainstem, and cranial nerve dysfunction. Greater than one third of affected infants display feeding disturbances associated with reflux and aspiration. Approximately one half of the deaths among infants with myelomeningocele can be attributed to the hindbrain anomaly. Other features include vocal cord paralysis with stridor and abnormalities of ventilation, including both obstructive and central apnea. The causes of the clinical abnormalities of the brainstem function are primarily threefold. First, they relate in part to the brainstem malformation, which involves cranial nerves and other nuclei, and which are present in the large majority of cases [Gilbert et al., 1986]. Second, compression and traction of the anomalous caudal brainstem by hydrocephalus and increased intracranial pressure also may play a role, especially in the vagal nerve disturbance that results in the vocal cord paralysis and stridor. Third, ischemic TABLE 19-4 Clinical Manifestations of Chiari II Malformation

and hemorrhagic necrosis of the brainstem also often is present and may be secondary to the disturbed arterial architecture of the caudally displaced vertebrobasilar circulation [Charney et al., 1987].

Management Careful monitoring of infants with known Chiari II malformations is advocated [Cai and Oakes, 1997; Stevenson, 2004]. Evaluation with MRI is the procedure of choice [Rossi et al., 2004]. Controversy exists in the literature about whether the brainstem symptomatology may be due in part to increased intracranial pressure from hydrocephalus. Paramount in the treatment of myelomeningocele is shunting of the accompanying hydrocephalus. Before surgical decompression of the posterior fossa in symptomatic patients is considered, it is important to document physiologic intracranial pressure. A properly functioning ventricular shunt often can obviate the need for decompression of hindbrain herniation. Many patients will have resolution of brainstem symptomatology once shunt dynamics are corrected [Caldarelli et al., 1995]. Shunt patency studies, intracranial pressure monitoring, or ultimately shunt revision should be considered if questions arise in the setting of persistent or progressive brainstem dysfunction. Significant improvement in the size of the accompanying spinal syrinx may occur after ventriculoperitoneal shunting or shunt revision [Milhorat et al., 1992]. Consensus is lacking on surgical treatment for infants with the Chiari II malformation beyond ventricular shunting, if elevated pressure and hydrocephalus are identified. Suboccipital craniectomy to decompress the suboccipital and cervical areas may be warranted to reduce the progressive compression of neural and vascular structures. Studies have suggested that early surgical intervention to alleviate brainstem compression is associated with improved longterm neurologic outcome and a decreased need for tracheostomy or gastrostomy [Pollack et al., 1992, 1996]. Alleviation of fourth ventricle outflow obstruction by foraminal fenestration or shunting and occlusion of the communication between the spinal central canal and obex are most often done. In one series of 50 symptomatic Chiari II patients, surgical treatment resulted in complete relief of symptoms in 20%, improvement in 66%, stabilization in 8%, and worsening in 6% [Dyste et al., 1989]. Despite these data, no standards for treatment have yet been established, because the current neurosurgical literature is characterized by significant debate and variable results [Tubbs et al, 2004]. Resection of the cerebellar tonsils is not advocated.

Encephalocele

From McLone DG, Dias MS. The Chiari II malformation: Cause and impact. Childs Nerv Syst 2003;19:540-550.

An encephalocele is a herniation of intracranial contents through a midline skull defect. Also known as cephaloceles, these lesions are classified by their contents and location [David, 1993]. Cranial meningoceles contain only leptomeninges and cerebrospinal fluid, whereas encephaloceles also contain brain parenchyma. A ventriculocele is an encephalocele in which the herniated brain contents also contain portions of the ventricle. The incidence of cephaloceles is approximately 0.8 to 5 per 10,000 live births, with encephaloceles being the most common form [Siffel et al., 2003].

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Encephaloceles usually are located in the occipital (75%) or frontal areas (25%). Basal and transsphenoidal encephaloceles are rare; they may appear between the ethmoid and sphenoid bones and extend into the upper pharynx [Harley, 1991]. Encephaloceles that extend from the area of the orbit, nose, or forehead are termed sincipital encephaloceles; those in the occipital region are termed notencephaloceles. Exencephaly consists of a large outpouching of brain tissue with surrounding thick walls. This defect may involve the spinal cord, forming an encephalomyelocele. Cranial encephalocele may contain a combination of meninges, ventricles, and brain parenchyma [Wininger and Donnenfeld, 1994].

The etiology of encephaloceles is not known but likely is multifactorial, with implication of various environmental and genetic factors and involvement of multiple sites of anterior neural tube closure [Golden and Chernoff, 1995; Martinez-Lage et al., 1996; McComb, 1997; Van Allen et al., 1993]. Studies have indicated that consumption of folic acid during the periconceptional period can reduce the risk of anencephaly, as well as spina bifida [Botto et al., 1999; Honein et al., 2001]. A similar protective effect, however, has not been noted for encephalocele [Stevenson et al., TABLE 19-5 Selected Syndromes Associated with Encephaloceles SYNDROME

CLINICAL FEATURES

Walker-Warburg syndrome

Hydrocephalus, severe neurologic impairment, vermian agenesis, type II lissencephaly, autosomal recessive inheritance Polycystic kidney, sloping forehead, polydactyly, hepatobiliary fibrosis, cleft lip and palate, autosomal recessive inheritance Hydrocephalus, partial or complete absence of cerebellar vermis, posterior fossa cyst contiguous with fourth ventricle, cranial nerve palsies, nystagmus, truncal ataxia, sporadic occurrence Cerebellar vermian aplasia, episodic hyperpnea, abnormal eye movements, rhythmic protrusion of tongue, ataxia, retardation, coloboma, retinal dystrophy, renal cysts, autosomal recessive inheritance Orofacial abnormalities, preauricular tags, epibulbar dermoids, sporadic occurrence Vitreoretinal degeneration with retinal detachment, high myopia, and occipital encephalocele, normal intelligence, gene localized to 21q22.3 Anterior encephalocele, autosomal recessive inheritance Anterior encephalocele, autosomal dominant inheritance

Dandy-Walker syndrome

Joubert’s syndrome

Goldenhar-Gorlin syndrome Knobloch’s syndrome

Robert’s syndrome Median cleft face syndrome

2000], suggesting that efforts to increase folic acid conumption among women of reproductive age are not likely to have any influence on the incidence. Although some affected fetuses are stillborn, or some affected pregnancies are terminated as a consequence of increased prenatal diagnosis of neural tube defects, a substantial proportion of affected infants are live born [Allen et al., 1996]. Although the etiology in most cases likely is multifactorial, some cases display likely monogenetic causes [Van Esch et al., 2004] that are associated with well-defined syndromes (Table 19-5).

Clinical Characteristics

Etiology

Meckel-Gruber syndrome

377

Data from Online Mendelian Inheritance in Man (OMIM), 2005.

A fluctuant, round, balloon-like mass that protrudes from the cranium, usually posteriorly, is the most typical manifestation of encephaloceles. The mass may pulsate and be covered by an erythematous, translucent, or opaque membrane or by normal skin. The covering may not be uniform throughout its surface. The amount of compromised and deformed neural tissue and the degree of resultant microcephaly determine the extent of cerebral dysfunction [Lorber and Schofield, 1979], but otherwise little has been published about prognosis. Brain tissue not extending into the encephalocele (i.e., retained within the intracranial cavity) may be deformed and functionally impaired. Severe intellectual and motor delays typically occur in association with microcephaly; motor delay is accompanied by weakness and spasticity. Intellectual impairment is more prevalent in patients with posterior than in those with anterior encephaloceles [Hockley et al., 1990]. Some patients, however, may have fairly normal development. Occipital lobe destruction is associated with various degrees of visual impairment. When the deformity extends into the ventricle, hydrocephalus is almost inevitable. Because of increased intracranial pressure, the encephalocele may become stretched until the rim of neuronal tissue is infarcted, with resultant infection and rupture if the problem is not surgically corrected. Other malformations may accompany encephaloceles, including Dandy-Walker syndrome, Klippel-Feil syndrome, Arnold-Chiari malformation, porencephaly, agenesis of the corpus callosum, myelodysplasia, optic nerve dysplasia, cleft palate, and others [Aleksic et al., 1983; Cohen and Lemire, 1982; Fisher and Smith, 1981; Joy et al., 2001; Koenig et al., 1982; Lieblich et al., 1978; Mecke and Passarge, 1971; Pagon et al., 1978; Sertie et al., 1996; Van Esch et al., 2004; Wang et al., 1999; Waterson et al., 1985] (see Table 19-5). Although ultrasonography may be helpful, the clinical diagnosis is confirmed by CT or MRI (Fig. 19-11). Neuroendocrine disturbances occur, particularly with basal encephaloceles that involve the sella turcica or sphenoid sinus [Lieblich et al., 1978]. These conditions may be undetectable by gross inspection. Intranasal mass or endocrine dysfunction is the cardinal feature. Encephaloceles are seen with a variety of chromosomal disorders (e.g., trisomy 13 or 18; 13q or 16q deletion) and syndromes (see Table 19-5). Occipital encephalocele, microcephaly, cleft palate or lip, polydactyly, holoprosencephaly, and polycystic kidneys constitute Meckel-Gruber syndrome [Chao et al., 2005]. Retinal degeneration with detachment and occipital encephalocele (Knobloch’s syndrome) is another autosomal-recessive condition [Wilson et al., 1998].

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ultrasonography [Birnbacher et al., 2002], In the past 2 decades, prenatal screening with ultrasound examination during the first trimester, which is nearly 100% accurate, and maternal alpha-fetoprotein determinations have resulted in earlier detection of anencephaly [Aubry et al., 2003]. Earlier detection has resulted in a dramatic decrease in the average gestational age at birth, from 35.6 weeks in the 1970s to 19.6 weeks in 1988 to 1990, with virtually no term liveborn anencephalic infants born after 1990 in those pregnancies in which a prenatal diagnosis of anencephaly had been made [Drugan et al., 2001].

Pathogenesis

Nasal glioma, a congenital tumor, appears as a frontonasal mass that mimics an encephalocele [Rahbar et al., 2003]. The tumor is derived from herniated brain tissue that has lost its connection to the brain; this relation can be demonstrated by neuroimaging techniques.

Anencephaly follows failure of closure of the anterior neural tube. The critical period during which the neural tube closes is from approximately day 21 to day 26 of gestation; the embryonic defect probably occurs before closure of the anterior neuropore on day 26. Two mechanisms leading to anterior neural tube defects have been proposed: Anencephaly could result from failure of neural tube closure to occur at a discrete site or from a failure of two closure sites to meet. The causes of anencephaly remain unknown, but of importance, they mirror the causes of spina bidifa, and similarly, folate has reduced the incidence of disease significantly. Various agents have been associated, including perinatal infections, folic acid antagonists, drinking water minerals, maternal hyperthermia, and chromosomal abnormalities.

Management

Differential Diagnosis

Prenatal diagnosis of encephaloceles may be established with determination of increased amniotic alpha-fetoprotein content and ultrasound studies [Graham et al., 1982]. Surgical correction of all but the smallest encephaloceles is necessary. Accompanying hydrocephalus may require ventriculoperitoneal shunting. Associated systemic abnormalities are present in approximately half of the patients, depending on the syndromic nature of the condition. A full battery of endocrinologic screens should be performed to evaluate basal encephaloceles.

In anencephaly, the absence of the brain and calvaria can be total or partial. Acrania is defined as congenital partial or total absence of the skull. Craniorachischisis is characterized by anencephaly accompanied by a contiguous bony defect of the spine and exposure of neural tissue. In iniencephaly, dysraphia in the occipital region is accompanied by severe retroflexion of the neck and trunk, with three cardinal features: deficiency of the occipital bone, cervicothoracic spinal retroflexion, and rachischisis. Iniencephaly differs from anencephaly in that the cranial cavity is present and skin covers the head and retroflexed region. Severe retroflexion of the neck present on fetal ultrasound examination may suggest the diagnosis. A majority of the patients also have visceral and other severe CNS malformations. Another related condition is meroanencephaly. Meroanencephaly is a rare form of anencephaly characterized by malformed cranial bones and a median cranial defect through which protrudes the area cerebrovasculosa. In encephalocele, the brain and meninges herniate through a defect in the calvaria [Botto et al., 1999]

FIGURE 19-11. Occipital encephalocele. The patient was a primigravida at 18 weeks of pregnancy complicated by a large occipital meningoencephalocele (arrows). (From http://www.thefetus.net/ page.php?id=1159. © 2003 Gunjan Puri.)

Anencephaly Anencephaly is a congenital malformation in which both cerebral hemispheres are absent [Medical Taskforce on Anencephaly, 1990]. The cranial vault defect is an extensive cranioschisis. Most anencephalic infants are stillborn. Those infants born alive die shortly after birth [Walters et al., 1997]. Epidemiologic studies demonstrate a striking variation in prevalence rates. The highest incidence is in Great Britain and Ireland, and the lowest incidence is in Asia, Africa, and South America. Other countries have intermediate incidence rates. Anencephaly occurs six times more frequently in whites than in blacks. Female fetuses are more often affected than males. Antenatal diagnosis is possible using assays of alphafetoprotein or acetylcholinesterase, which are increased in maternal serum and amniotic fluid [Brock et al., 1985; Crandall and Chua, 1995; Loft et al., 1993; Wald et al., 1989]. Antenatal diagnosis also is feasible through the use of fetal

Pathology The cranial vault is defective over the vertex, exposing a soft, angiomatous mass of neural tissue covered by a thin membrane continuous with the skin. The cranial abnormality may extend inferiorly to the cervical region with formation of a complete spina bifida. The extremely thin and flattened spinal cord (craniorachischisis) is readily observed. The optic globes usually are protuberant because of inadequate bony orbits.

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tube). Disruption of this process leads to open neural tube defects such as exencephaly. Defects in neurulation can be caused by mutations in genes that are expressed in the neural ridge. At the rostral limit of the neural plate is a structure called the anterior neural ridge (Fig. 19-12), which probably gives rise to much of the telencephalon. A groove in the midline of the neural plate overlies the axial mesoendoderm (prechordal plate and notochord). This groove stops short of the anterior neural ridge. After neurulation, the deepest part of this groove will give rise to the floor plate, and the adjacent region will become the basal plate (i.e., the motor-related part of the mature CNS) (Fig. 19-13). The region between the prospective basal and roof plates represents the anlage of the alar plate (the sensory-related part of the mature CNS). The roof, alar, basal, and floor plates are the principal longitudinal or dorsoventral subdivisions of the CNS [Shimamura et al., 1995]. The left and right parts of the longitudinal domains are continuous across the rostral and caudal midlines, in the forebrain and tailbud, respectively. Abnormalities in the induction of these subdivisions give rise to holoprosencephaly. By neurulation, the CNS is divided into its major transverse parts: the spinal cord, rhombencephalon (hindbrain), mesencephalon (midbrain), and prosencephalon (forebrain) (see Fig. 19-13). The rhombencephalon consists of the myelencephalon, the most caudal of the brain vesicles, and the metencephalon, which extends from the pontine flexure to the rhombencephalic isthmus. The myelencephalon will give rise to the medulla oblongata, and the metencephalon gives rise to the cerebellum and pons. The alar and basal plates, which will give rise to the sensory and motor regions, are separated by the sulcus limitans, a rostrocaudal delineation that extends the length of the brainstem. The walls of

Clinical Considerations Anencephaly is a lethal condition, with no capacity for survival in these circumstances. No specific treatment is available. Neuroendocrine defects are frequent, with failure of endocrine end-organ development secondary to a hypoplastic pituitary gland. Adrenal insufficiency may be associated with adrenocortical hypoplasia. The posterior pituitary also is hypoplastic, which may lead to clinical diabetes insipidus. Controversy has existed about the rationale for harvesting organs from anencephalic infants. In some instances, healthy organs have been retrieved and used as life-saving transplants for other infants. The controversy has centered on the definition of “brain death” versus “death,” neither of which criteria are met by anencephalic newborns. These issues remain unresolved.

REGIONALIZATION AND SEGMENTATION DISORDERS Neural Tube Organization Concurrent with cleavage of the telencephalon, the neural tube becomes specified in an anteroposterior, or rostalcaudal direction, which gives rise to the major segmental brain regions, including cerebral cortex, midbrain, and cerebellum. As the neural plate folds into the neural tube (neurulation), fusion of the lateral edges creates the roof plate (dorsal midline) of the neural tube and separates the CNS from the surface ectoderm. Fusion occurs at loci in the midbrain and hindbrain. The last regions to close are the rostral and caudal neuropores (transient open portions of the neural

RP

AP

BP

FP

Eye AP

BP FP

ANR

RP

FP

AP

A

RP

BP AP

ANR

B

MP FP

RP AP

Eye BP

FP BP

Tel AP

C

379

ANR FP

BP

Eye

FIGURE 19-12. Representation of the neurulation (neural tube closure) viewed from the rostrolateral end of the brain. A, Neural plate stage; B, transition stage; C, neural tube stage. Non-neural structures are not shown. As the borders of the neural plate approach each other and fuse at the dorsal midline, the eye vesicles evaginate and the FB and MD gradually acquire their characteristic shape. The FP, which is adjacent to the notochord, and the RP formed at the area of neural tube closure, are the major dorsal-ventral organizers of the FB. The ANR at the very rostral end of the neural tube likely works as a secondary organizer for the FB. The ANR expresses HESX1 and SIX3 genes, whereas the eye primordium expresses PAX3 genes and the telencephalon expresses BP1, thus defining major brain regions. AP, alar plate; ANR, anterior neural ridge; BP, basal plate; FB, forebrain; FP, floor plate; MD, midbrain; RP, roof plate; Tel, telencephalic vesicle. (Adapted from Rubenstein JLR, Puelles L. Development of the nervous system. In: Epstein CJ, Erickson RP, WynshawBoris A, eds. Inborn errors of development. Oxford: Oxford University Press, 2004, p 75.)

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Perinatal Acquired and Congenital Neurologic Disorders / 19

A

Cephalic flexure

B Rhombencephalon (hindbrain)

Mesencephalon (midbrain)

Prosencephalon Cervical flexure Mesencephalon

Optical vesicle

Cranial and spinal sensory ganglia

Prosencephalon (forebrain)

Rhombencephalon Spinal cord

Lumen spinal cord

C

D Lateral ventricle

Rhombencephalic Pontine flexure isthmus Metencephalon Myelencephalon

Telencephalon

FIGURE 19-13. Neural tube specification. Lateral views (A, C) and luminal views (B, D) of brain vesicles and part of the spinal cord in 4-week-old (A, B) and 6-week-old (C, D) human embryos. After neurulation (closure of the neural tube), the neural axis begins to segment into major divisions under the influence of area-specific genes. This process is coincident with expansions and contractions of brain regions, and with the formation of major flexures that define anatomic boundaries. The rhombencephalon gives rise to the metencephalon and the myelencephalon, eventually forming the midbrain and hindbrain (cerebellum), respectively. The prosencephalon divides into two telencephalic hemispheres that will each give rise to one cerebral hemisphere. (From Sadler TW. Langman’s medical embryology. Baltimore: Williams & Wilkins, 1985, with permission.)

Interventricular foramen of Monro 3rd ventricle

Mesencephalon

Optic cup Future aqueduct of Sylvius

Diencephalon

Primitive cerebral hemisphere

Optic vesicle Telencephalon

4th ventricle

Central canal

these structures contain the three primary cellular layers of the brain—the ventricular, mantle, and marginal layers). The diencephalon will become the thalamus, hypothalamus, and optic vesicles. Lateral growth from the rostral portion of the prosencephalon develops into the telencephalon, which in turn is transformed into the cerebral hemispheres. At this stage, the caudal portion of the original prosencephalon becomes the diencephalon, parts of which subsequently give rise to the neural components of the optic nerves and retina and olfactory cortex. Subdivision of the prosencephalon occurs by day 36 of gestation. The dorsolateral parts of the alar plates bend medially and form the rhombic lips that will give rise to several cell populations within the brain, most notably the cerebellar granule neurons. The rhombic lips become compressed in the cephalocaudal direction at the pontine flexure to form the cerebellar plate. In the 12-gestational-week embryo, this plate shows a small midline portion, the vermis and two lateral portions, the cerebellar hemispheres. A transverse fissure soon separates the nodule from the vermis and the lateral flocculus from the hemispheres. The flocculonodular lobe is phylogenetically the most primitive part of the cerebellum.

Hindbrain Patterning At the completion of neural tube closure, bulges appear in the hindbrain regions that define distinct anatomic boundaries known as rhombomeres (Fig. 19-14). Rhombomeres partition from one another based on the cell-cell contactmediated attraction and repulsion, in a repeating manner. Thus, cells in rhombomere 1 will not integrate into rhombomere 2, 4, or 6 but can integrate into rhombomeres 3, 5, and 7. Consistent with an expected tendency of neighboring cell groups to separate, an enlarged intercellular space is the earliest specialization of rhombomere boundaries. Complementing this adhesive differential is an alternating periodicity to the expression domains of several classes of genes— of most importance, the Eph-like receptor tyrosine kinases and their ligands and the Hox gene family of transcription factors (Fig. 19-15). Perturbing function of the Eph genes results in failure to establish sharp inter-rhombomere boundaries; thus, these ligand-receptor partners may mediate repulsive interactions that serve to sharpen rhombomere borders. Perturbations of Hox genes lead to misidentification of rhombomeres. They also may provide a potential mechanism whereby cells in adjacent rhombomeres interact with each

Gleeson, Dobyns, Plawner, and Ashwal / Congenital Structural Defects r1

r1

r2

r2

r3

r3

r4

r4

r5

r5

r6

381

FIGURE 19-14. Hindbrain segmentation is dependent on regionally restricted gene expression. This diagram summarizes the correlation of gene expression with specific rhombomeres, compiled from analysis in mouse and chick embryos. Top, Odd- and even-numbered rhombomeres (r1 to r7) are indicated by repeating dark and light shades. The rodlike notochord and overlying floor plate in continuum with the rhombomeres are indicated by the blue bar. Bottom, The patterns of gene expression are depicted schematically, with the darkest colors indicating the highest levels of expression. Eph receptors for the Ephrin ligands are indicated; note the mutually exclusive patterns of expression. Kreisler and Krox are in the Eph family. Below them are the homeobox Hox genes; note that these are overlapping where the combinatorial expression is required for proper specification. (Courtesy of A. Lumsden.)

r7

r6 Kreisler Krox-20 EphA4 EphA2 EphB2 EphB3 EphA7 Ephrin-A2 Ephrin-B1 Ephrin-B2 Hoxa1 Hoxb1 Hoxa2 Hoxb2 Hoxa3 Hoxb3 Hoxd3 Hoxd4 Hoxb4 Hoxa4

r2

r3

r4

r5

r6

Fgf3 follistatin CRABP-1 RAR␣ RAR␤

other to establish additional cell states at the interrhombomeric boundaries. Furthermore, such perturbations severely affect the projection and trajectory of axons leaving the hindbrain. Rhombomere 1 is the same as the metencephalon. It gives rise to the cerebellar primordium, the locus ceruleus (the source of norepinephrine) and the raphe nuclei (the source of serotonin). After appearance of the pontine flexure at approximately the fifth gestational week, the fourth ventricle has a thin roof and laterally positioned dorsal (alar) plates. During the fifth gestational week, cellular proliferation within the alar plates and formation of the pontine flexure form the rhombic lips. The neuroepithelial zones in the roof of the fourth ventricle and the rhombic lips are locations of the germinal matrices where the cells of the cerebellum and many brainstem nuclei will form. Between 9 and 13 gestational weeks, the Purkinje cells of the cerebellar cortex and the neurons of the deep cerebellar nuclei migrate radially outward from this germinal matrix. The identity of the Pur-

kinje cells depends on the expression of multiple genes including Wnt3. By contrast, neurons of the granule layer of the cerebellar cortex migrate tangentially from the germinal zone of the rhombic lips, over the cerebellar surface, to form a transient external granular layer, which acts as a secondary germinal matrix.

Midbrain Patterning A clearly discernible midbrain vesicle arises from the developing anterior neural tube during the fifth week of gestation. Morphologically, the mesencephalon is delimited at its anterior end by the diencephalic vesicle and at its posterior end by the isthmic constriction, which separates it from the hindbrain or rhombencephalon. Development of the midbrain territory and of the anterior hindbrain is tightly linked and dependent on the midbrain-hindbrain organizer, one of the key structures that directs morphology of surrounding structures during development, through the production

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Perinatal Acquired and Congenital Neurologic Disorders / 19 TEL It

AH

Subpallium

OB

och Eye

AEP

rch NH

Pallium BH

Ped. area AH

Mam RM

zli

Nigral Tegm.

VTA

p3

Emt Prethal.

(VT)

p2 Pin

ETh

(DT)

Thalamus

p1 Sco

Pretectum

III

Tectum Mes

iorg

IV

Ped. pon.

r1

Pons

r2 r3

Isthmus

Cb

r4 r5 r6 r7

Pontobulb. Medulla Raphe

Prosencephalon Patterning Rhomb

Trig.

Basal plate

Vest.

and secretion of morphogens [Raible and Brand, 2004]. One of the most important cell populations to arise from the midbrain is the dopaminergic neurons of the substantia nigra. The mesencephalon (midbrain territory) is established in molecular terms even before morphologic subdivisions are apparent. The Otx2 expression domain defines the prospective forebrain and midbrain territory, whereas the Gbx2 expression field defines the prospective hindbrain region and spinal cord. The region at which the expression domains of both genes meet later becomes the midbrain-hindbrain boundary. Otx2 appears to be required for the specification and maintenance of anterior head structures—namely, the forebrain and midbrain [Acampora et al., 2001]. Conversely, genetic ablation of Gbx2 leads to a rostralization of the hindbrain—that is, the anterior hindbrain corresponding to rhombomeres 1 to 3 does not form, and the midbrain expands up to the rhombomere 3 to 4 boundary [Wassarman et al., 1997].

Acust

Alar plate

FIGURE 19-15. Prosomere model of brain development detailing fate of early neural plate structures. Specific rhombomeres (r1 to r7) give rise to the brainstem and trigeminal (Trig.), vestibular (Vest.), and acoustic (Acust.) nuclei, as well as cerebellum (cb). The mesencephalon gives rise to cranial nerve III and the tectum. Prosomeres p1 to p3 give rise to forebrain structures as indicted. AEP, anterior entopeduncular area; AH, alar hypothalamus; BH, basal hypothalamus; DT, dorsal thalamus; Emt, eminentia thalami; ETh, epithalamus; iorg, isthumus organizing center; lt, lamina terminalis; Mam, mammillary complex; Mes, mesencephalon; NH, neurohypophysis; Nigral Tegm, nigral tegmentum; OB, olfactory bulb; och, optic chiasma; Ped.area, peduncular area; Ped.pon., pedunculopontine region; Prethal., prethalamus; Pontobulb., pontobulbar area; rch, retrochiasmatic area; RM, retromammmillary area; Sco, superior colliculus; Tel, telencephalon; VT, ventral thalamus; VTA, ventral tegmental area; zli, zona limitans intrathalamica.

Prosencephalic development occurs by inductive interactions under the primary influence of the prechordal mesoderm. The peak time period is the second and third month of gestation, with the earliest prominent phases in the fifth and sixth weeks of gestation. The major inductive relationship of concern is between the notochord/prechordal mesoderm and the forebrain. This interaction occurs ventrally at the rostral end of the embryo, and thus the term ventral induction is sometimes used. The inductive interaction influences formation of much of the face and of the forebrain; accordingly, severe disorders of brain development at this time usually result in striking facial anomalies. Development of the prosencephalon is considered best in terms of three sequential events: prosencephalic formation, prosencephalic cleavage, and midline prosencephalic development (Fig. 19-16). Prosencephalic formation begins at the rostral end of the neural tube at the end of the first month and beginning of the second month. It consists of segmentation of the prosencephalon into three major domains, termed the prosomeres (P1 to P3). P1 gives rise to the

DORSAL Epiphysis Diencephalic roof Lamina terminalis

Commissural primordium ROSTRAL

CAUDAL Chiasmatic primordium

Olfactory bulb

Hypothalamus

Hypophysis Optic vesicle BASAL

FIGURE 19-16. Prosencephalic midline development. The prosencephalic midline is presented by a series of independent but closely related segments. Note particularly the commissural, chiasmatic, and hypothalamic primordia or plates. The proximity of these structures in the developing brain and their derivation from a common primordium explains the spectrum of midline defects associated with septo-optic dysplasia, which include optic nerve hypoplasia and hypothalamic and corpus callosum defects. (From Leech RW, Shuman RM. Holoprosencephaly and related midline cerebral anomalies: A review. J Child Neurol 1986;1:3.)

Gleeson, Dobyns, Plawner, and Ashwal / Congenital Structural Defects

pretectum, the region of brain just rostral to the midbrainderived tectum. P2 gives rise to the thalamus, and P3 gives rise to the prethalamus. More rostral brain regions, including the telencephalon, are also divided into prosomeric boundaries, the clearest of which are the anatomic boundaries of the developing basal ganglia, the medial and lateral basal ganglion, which arise as bulges along the ventrolateral telencephalon and express the markers Dlx and Arx. The neocortex itself exhibits regionally restricted gene expression. Manipulation of these expression patterns results in shifting of cellular identities of the neocortex (FGF8, EMX2). The evidence to date, however, argues against anatomically and regionally restricted boundaries, because cell lineage experiments demonstrate that sibling cells can occupy multiple nuclei throughout the anteroposterior axis.

Prosencephalic Cleavage Prosencephalic cleavage occurs most actively in the fifth and sixth weeks of gestation and includes three basic cleavages of the prosencephalon: (1) horizontal, to form the paired optic vesicles, olfactory bulbs and tracts; (2) transverse, to separate the telencephalon from the diencephalons; and (3) sagittal, to form the paired cerebral hemispheres, lateral ventricles and the basal ganglia from the telencephalon. Three crucial thickenings or plates of tissue become apparent around the end of the second month; these are the commissural, the chiasmatic, and the hypothalamic plates. These structures are important in the formation, respectively, of the corpus callosum and septum pellucidum, the optic nerve chiasma, and the hypothalamic structures. The most prominent of these developments is the formation of the corpus callosum, the earliest component of which appears at 9 weeks. Disorders associated with abnormal development of the prosencephalon are outlined in Table 19-6.

Regional Boundaries within the Telencephalon Clear anatomic and structural determinants are not apparent in the cerebral cortex. Clonal analysis demonstrates widespread movement of cells. Clear evidence of genetic determinants, however, is apparent in telencephalic development. By 3 months of gestation, the cerebral hemispheres are distinct and contain delineated subdivisions: the rhinencephalon (limbic system), striatal area (basal ganglia), and cerebral cortex. Sulcus differentiation originates in the third month in the area of the sylvian fissure. The primary fissures and the frontal, parietal, temporal, and occipital lobes are clearly identifiable between the fifth and sixth months of gestation. The prosencephalon divides into the telencephalon (two TABLE 19-6 Disorders of Midline Prosencephalic Development REGION AFFECTED

DISORDER

Commissural plate

Agenesis of the corpus callosum and/or septum pellucidum Septo-optic dysplasia

Commissural and chiasmatic plates Commissural, chiasmatic, and hypothalamic plates

Septo-optic–hypothalamic dysplasia

383

telencephalic vesicles) and diencephalon. The telencephalic vesicles will become the cerebral hemispheres. The diencephalic alar plate forms the thalamus, the hypothalamus, and the epithalamus, beginning in the fifth week. The thalamus and hypothalamus are visible as swellings on the inner surface of the diencephalic neural canal. The thalamus grows disproportionately after the seventh week and becomes the largest element of the diencephalons. The two thalami meet and fuse across the third ventricle at one or more points called the interthalamic adhesions. The anterior pituitary is formed from the diencephalons and fuses with tissue from Rathke’s pouch, which gives rise to the posterior pituitary gland. The thalamus and hypothalamus differentiate to form complexes of nuclei that serve a diverse range of functions. The thalamus acts as the primary relay center for the cerebral cortex. It receives all of the information that will be projected to the cerebral cortex. Additional diencephalon-derived structures are the pineal body and mammillary bodies. Regional specification or segmentation of the developing telencephalon is an important step in brain development and is under control of a number of genes that encode transcription regulators. In the fruit fly, Drosophila, these genes are involved in segmentation and define structures such as hairlike spiracles. Not surprisingly, the role of these genes in human brain development differs, yet it appears that the general role of these proteins is that of regional specification of clones of cells destined to form specific brain structures. Homeobox and other transcription genes encode some of these transcriptional regulators that “turn on” genes by binding to specific DNA sequences and thereby initiate genetic programs that lead to cell and tissue differentiation.

DISORDERS OF SEGMENTATION Schizencephaly Schizencephaly is a term used to describe a gray matter– lined cleft that extends from the lateral ventricle to the inner table of the skull. It likely represents a heterogeneous set of abnormalities of variable etiology. One theory holds that an early (first-trimester) destructive event disturbs subsequent formation of the cortex. Another theory is that segmental failure occurs in the formation of a portion of the germinal matrix or in the migration of primitive neuroblasts. Schizencephaly has been regarded by many investigators as a migration abnormality and as such also is discussed later in this chapter under that topic. Clinical manifestations vary, depending on the size of the defect and whether bilateral disease is present [Barkovich and Kjos, 1992a; Packard et al., 1997] (Table 19-7). The defect is termed open-lipped if the cleft walls are separated by cerebrospinal fluid, with gray matter lining the clefts that communicate with the subarachnoid space peripherally and the ventricle centrally. The defect is termed close-lipped if gray matter is apparent along the lining of the cleft that extends from the outer cortex. The outer cortex gray matter often is dysplastic and polymicrogyric. The original description of this condition was by Yakovlev and Wadsworth [1946a, 1946b], who described clefts lined by thick cellular layers of malformed gray matter that is often continuous with heterotopic gray matter de-

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Perinatal Acquired and Congenital Neurologic Disorders / 19

TABLE 19-7 Clinical Features of Schizencephaly TYPE OF SCHIZENCEPHALY

PERCENT OF PATIENTS AFFECTED Severe Neurodevelopmental Delays

Unilateral closed lip Bilateral closed lip Unilateral open lip Bilateral open lip

17% 33% 53% 92%

Epilepsy 67% 50% 47% 67%

Adapted from Packard AM, Miller VS, Delgado MR. Schizencephaly: Correlations of clinical and radiologic features. Neurology 1997;48:1427.

posited under the ependyma. The membranes roofing these defects consist of pia covered by normal arachnoid and fused centrally with thickened and stratified ependyma. The exact location of the pial-ependymal seam appears to be at the ventricular margin. The cleft itself is lined by pia and gray matter, even with the lips of the defects. Bilateral schizencephaly is associated with mental retardation and spastic cerebral palsy; affected patients often

are microcephalic. Unilateral closed-lip schizencephaly is associated with epilepsy but not necessarily with severe neurodevelopmental delay. Seizure type and onset may vary in this disorder. Epilepsy is estimated to occur in 50% to 70% of patients, in equal proportion with unilateral or bilateral clefts [Granata et al., 1996, 1997; Packard et al., 1997]. Patients may experience focal or generalized seizures, and some will present with infantile spasms. The onset varies, ranging from infancy to the early adult years. Seizures may be easily controlled or may be recalcitrant to standard antiepileptic therapy. Improvements in neuroimaging have enhanced the recognition of schizencephaly. The lesions may occur in isolation or may be associated with other anomalies of brain development such as septo-optic dysplasia (Fig. 19-17).

Septum Pellucidum Anomalies The septum pellucidum can be divided into two parts: the “true” septum, or septum verum, which is a nerve cell– containing area, and the septum pellucidum [Andy and Stephan, 1968]. The septum pellucidum is a thin translucent

FIGURE 19-17. Schizencephaly variants. A, Unilateral closed-lip schizencephaly associated with septo-optic dysplasia and absence of the septum pellucidum. Note the cleft from the cortical mantle extending to the lateral ventricle, with the edges nearly apposed. B, Unilateral open-lip schizencephaly, showing the splayed lips of the cleft. In schizencephaly, the cleft is lined with gray matter (arrow), which differentiates it from a porencephalic cleft.

A

B

A

B

C

FIGURE 19-18. Septum pellucidum defect. A, Normal brain, with fused leaflets of the septum pellucidum (long arrow). B, Cavum septum pellucidum (arrow) with cerebrospinal fluid between the two leaflets. C, Absence of the septum pellucidum. Note absence of midline structures (arrow) with continuum between the lateral and the third ventricles. (From Born CM, Meisenzahl EM, Frodl T, et al. The septum pellucidum and its variants. An MRI study. Eur Arch Psychiatry Clin Neurosci 2004;254:295; and Supprian T, Sian J, Heils A, et al. Isolated absence of the septum pellucidum. Neuroradiology 1999;41:563, with permission.)

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plate that forms the medial wall of the lateral ventricle. Its development is linked to the development of the corpus callosum, which accounts for the common association of the developmental anomalies of the two. The two major defects are absence of the septum pellucidum and of cavum septum pellucidum, which are easily differentiated on brain MRI (Fig. 19-18).

34 weeks of gestation. Nevertheless, a large cavum (more than 1 cm in diameter) in a term newborn should be viewed as suggestive of other brain malformations. In one series, all children with such findings had abnormal neurologic outcome [Bodensteiner and Schaefer, 1990].

ABSENCE OF THE SEPTUM PELLUCIDUM

Absence of the telencephalon and diencephalon characterizes the syndrome of aprosencephaly; in atelencephaly, only the telencephalon is absent. Atelencephalic aprosencephaly is characterized by the presence of at least a rudimentary diencephalon. Embryologically, aprosencephaly is

Absence of the septum pellucidum may be due to primary agenesis or to secondary mechanisms, such as hydrocephalus, with subsequent damage. The prevalence of absence or hypoplasia of the septum pellucidum has been estimated at 2 to 3 per 100,000 persons, although this is heavily biased by the reason for imaging and imaging technique detection rates. Absence nearly always is associated with other CNS anomalies, such as septo-optic dysplasia, schizencephaly, agenesis of the corpus callosum, hydrocephalus, or encephaloceles [Barkovich and Norman, 1989]. In the rare instance in which no other major CNS malformations are identified, then epilepsy and mental retardation are infrequently seen. Absence of the septum pellucidum occasionally is identified on prenatal ultrasound examination, when it may indicate a brain malformation. Most fetuses in which this feature is seen are later found to have a more severe brain malformation, including holoprosencephaly, hydrocephalus, and septo-optic dysplasia [Lepinard et al., 2004; Malinger et al., 2004].

CAVUM SEPTUM PELLUCIDUM Cavum septum pellucidum is identified in approximately 20% of normal control subjects [Born et al., 2004]. Controversy exists in the literature over whether this represents a true malformation or just a variant of normal. An elevated prevalence of cavum septum pellucidum has been reported in several psychiatric conditions, including schizophrenia and bipolar disorder. Widely separated pellucidum leaflets greater than 1 cm across occur much less commonly and may be a marker of disturbed brain development, when this finding takes on the same significance as absence of the septum pellucidum. This finding is clearly abnormal only after the neonatal period, because all premature infants exhibit an ultrasonographically demonstrable cavum at up to

A

B

Aprosencephaly

TABLE 19-8 Conditions Featuring Agenesis of the Corpus Callosum (ACC) GENE MUTATION OR LOCUS*

NAME

FEATURES

Andermann’s syndrome Spastic paraplegia type II FG syndrome

ACC, mental retardation, polyneuropathy ACC, spastic paraplegia

ACC, mental retardation, macrocephaly, imperforate anus Aicardi’s syndrome ACC, retinal lacunae, epilepsy Proud’s syndrome ACC, abnormal genitalia XLAG syndrome ACC, X-linked lissencephaly/ ambiguous genitalia Schinzel’s acrocallosal ACC, polydactyly, syndrome macrocephaly, mental retardation CRASH syndrome ACC, retardation, adducted thumbs, spastic paraplegia, and hydrocephalus Septo-optic dysplasia ACC, pituitary insufficiency, visual disturbance Orofacial-digital Facial/digital defects, syndrome type I renal cysts, ACC Joubert’s syndrome Absence of cerebellar type III vermis, polymicrogyria, ACC

SLC12A6 15q13 Xq12-q21.31 Xp22 ARX ARX GLI3 L1CAM

HESX1 CXORF5 AHI1

CRASH, corpus callosum agenesis, retardation, adducted thumbs, spastic paraparesis, hydrocephalus.

FIGURE 19-19. Agenesis of the corpus callosum without other associated CNS malformations. A, Coronal image shows Probst bundles (arrows) protruding toward the midline but failing to cross. These are bundles of axons destined to cross at the midline, running rostrocaudally. B, Sagittal image shows absence of the characteristic midline corpus callosum (arrows indicate normal location).

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thought to occur after the optic vesicles form but before the cerebral vesicles appear [Harris et al., 1994]. It is differentiated from ancencephaly by the closure of the neural tube and skin coverings of the brain. Facial features similar to those of holoprosencephaly may be present. Only a handful of cases have been reported, and the condition is not compatible with long-term survival.

Agenesis of the Corpus Callosum Agenesis (and dysgenesis) of the corpus callosum is a frequent anomaly that manifests with a spectrum of clinical features and exhibits variable findings when neurologic studies are performed (Fig. 19-19). Clinical signs and symptoms are the result of cerebral and extracerebral malformations associated with callosal dysgenesis. Callosal agenesis may be an isolated anomaly or may be syndromic as part of more extensive malformations or metabolic and genetic

disorders [Davila-Gutierrez, 2002]. Conditions in which agenesis of the corpus callosum is featured along with the genetic abnormalities are listed in Table 19-8. A more extensive list of conditions in which partial or complete callosal agenesis has been reported is presented in Box 19-2. Agenesis of the corpus callosum may be complete or partial. Partial agenesis may take one of two forms: either thinning of the entire structure or agenesis of the caudal portion. The rostral portion typically is retained in all patients except when complete absence of the corpus callosum occurs. Agenesis of the corpus callosum may be further subdivided on the basis of the presence or absence of Probst’s bundles. The superomedial aspects of the lateral ventricles are deformed by the fibers of the cerebral hemispheres that were destined to cross in the corpus callosum, and that, with agenesis, instead course longitudinally in a rostrocaudal direction as the bundles of Probst.

Box 19-2 CONDITIONS ASSOCIATED WITH ABNORMAL DEVELOPMENT OF THE CORPUS CALLOSUM Associations with Other Organ Involvement Asplenia, anophthalmia, coloboma Blepharophimosis, coloboma, hearing loss Congenital choanal atresia Hirschsprung’s disease Median cleft face syndrome Morning glory syndrome Ocular albinism Osseous lesions CNS Malformation Syndromes Arachnoid cysts Arnold-Chiari (Chiari II) malformation Cerebellar dysgenesis CRASH syndrome (X-linked hydrocephalus) Dandy-Walker malformation Hydrocephalus Interhemispheric cyst Intraventricular lipomas Lissencephaly Chromosomal/Genetic Disorders Aneuploidies (45,X; 47,XXY) Autosomal recessive Pseudotrisomy 13 Trisomies 8, 11q−, 13, 16, 18 X-linked Metabolic Disorders Carbohydrate-deficient glycoprotein syndrome Leprechaunism (insulin receptor defect) Mitochondrial disorders (e.g., Leigh’s syndrome) Nonketotic hyperglycemia Organic acidurias (3-OH-isobutyric aciduria) Pyruvate decarboxylase deficiency Zellweger’s syndrome (peroxisomal disorder)

Syndromes Acrocallosal syndrome Adams-Oliver syndrome Aicardi’s syndrome Andermann’s syndrome Apert’s syndrome Baller-Gerold syndrome Basal cell nevus syndrome Cerebrofaciothoracic dysplasia Coffin-Siris syndrome Cranioectodermal dysplasia DiGeorge’s syndrome Ectodermal dysplasia Edward’s microphthalmia Frontonasal dysplasia and polydactyly Fryns’ syndrome Goldenhar’s syndrome Hypohydrotic ectodermal dysplasia Jeune’s thoracic asphyxiating dystrophy Kallmann’s syndrome Marshall-Smith syndrome Meckel-Gruber syndrome Microcephalic osteodysplastic primordial dwarfism Neu-Laxova syndrome Oculocerebrocutaneous syndrome Orofacial-digital syndrome (type 1) Pena-Shokeir syndrome type II Rubinstein-Taybi syndrome Seckel’s syndrome Shapiro’s syndrome Shprintzen-Goldberg syndrome Smith-Lemli-Opitz syndrome Thanatophoric dwarfism Whistling face syndrome Teratogens Fetal alcohol syndrome Maternal valproate use Maternal phenylketonuria

CNS, central nervous system; CRASH, corpus callosum agenesis, retardation, adducted thumbs, spastic paraparesis, hydrocephalus. Data from Online Mendelian Inheritance in Man (OMIM), 2000; Norman et al., 1995; and Ball, 1997.

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Agenesis of the corpus callosum often is associated with other CNS malformations, most prominently the Chiari II malformation, and with disorders of neuronal migration. The association with disordered neuronal migration may relate to the fact that callosal development and neuronal migration occur concurrently in human brain development between weeks 10 and 20, or may reflect a common cellular requirement for key genes in neuronal movement and axon outgrowth. Agenesis of the corpus callosum without other recognized abnormalities of the CNS can be asymptomatic or may manifest with seizures or developmental delay. When it is associated with a specific syndrome, the other features may dominate the clinical course. Genetic studies are under way to determine the genotype for certain forms of agenesis of the corpus callosum. Prenatal ultrasound examination may identify agenesis of the corpus callosum beginning at 20 weeks of gestation [Vergani et al., 1994]. In approximately two thirds of cases, one of the syndromic forms can be diagnosed either during pregnancy or at the time of birth. In the remaining one third, it is present in its isolated form and is associated with a much better prognosis. Anophthalmia is a primary disorder of formation of the optic pit, meaning failure to specify the eye primordium. It is always present bilaterally, and consanguinity is not uncommon. It should be differentiated from microphthalmia (small eye) and cryptophthalmos (failure of eyelid opening). Mutations in the SOX2 gene are identified in approximately 11% of patients with this condition [Fantes et al., 2003].

Septo-optic Dysplasia Septo-optic dysplasia, also known as de Morsier’s syndrome, is a rare, highly heterogeneous condition characterized by the classical triad of optic nerve hypoplasia, midline neuroradiologic abnormalities, such as absence of the septum pellucidum or agenesis of the corpus callosum, and hypothalamic/pituitary hypoplasia with consequent pituitary hormone deficiency (Fig. 19-20) [Arslanian et al., 1984; Hoyt et al., 1970; Izenberg et al., 1984; Stanhope et al., 1984]. Some of the clinical features associated with septo-optic dysplasia are listed in Table 19-9.

387

TABLE 19-9 Clinical Features in Patients with Septo-optic Dysplasia FEATURE

SUBGROUP

PERCENT AFFECTED

Pituitary dysfunction

Single hormonal imbalance Multiple hormonal imbalances Bilateral Unilateral

40–50% 20% 70% 20% 75%

Optic nerve hypoplasia Mild/moderate neurologic disorder Electroencephalographic abnormalities

35%

Adapted from Riedl SW, Mullner-Eidenbock A, Prayer D, et al. Auxological, ophthalmological, neurological and MRI findings in 25 Austrian patients with septooptic dysplasia (SOD). Preliminary data. Horm Res 2002;58 (Suppl 3):16.

It is not infrequently associated with cortical malformations, including disorders of migration or schizencephaly, which is known as the schizencephaly–septo-optic dysplasia syndrome [Kuban et al., 1989]. “Septo-optic dysplasia plus” is another syndrome that may include an assortment of cortical malformations, including polymicrogyria or subependymal nodules [Miller et al., 2000]. An association between mutations in the HESX1 gene and septo-optic dysplasia has been identified in several families [Dattani et al., 1998; Tajima et al., 2003; Thomas et al., 2001], whereas heterozygous mutations in this gene may be associated with isolated developmental defects of the pituitary [Brickman et al., 2001]. Nevertheless, most patients with septo-optic dysplasia display sporadic disease, suggesting a more complex inheritance pattern in a majority of the cases. Because results of genetic testing for HESX1 mutations are negative in a majority of patients, routine testing for such mutations is not currently recommended.

Management Patients with segmentation disorders should undergo detailed brain imaging studies, careful evaluation of vision, and comprehensive evaluation of endocrinologic function [Riedl et al., 2002]. Genetic counseling may be appropriate.

CEREBELLAR MALFORMATIONS The classifications that have been proposed for brain malformations largely ignore the status of the cerebellum, in all likelihood because cerebral anomalies are generally considered to be more important in determining cognitive and neurologic outcome. This lack of attention to the cerebellum, however, has resulted in a notable lag in current understanding of cerebellar anomalies, as compared with understanding of cerebral anomalies. Moreover, it is becoming increasingly clear that the cerebellum is important in cognition and motor function.

Chiari I Malformation FIGURE 19-20. Septo-optic dysplasia. In this brain of a newborn, note corpus callosum thinning (short arrow), absent septum pellucidum (long arrow), hypothalamic hypoplasia (double arrows), and optic nerve hypoplasia (asterisk).

The Chiari I malformation is a disorder of uncertain origin that has been traditionally defined as downward herniation of the cerebellar tonsils of a distance of at least 3 to 5 mm

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through the foramen magnum [Dyste and Menezes, 1988; Dyste et al., 1989; Pillay et al., 1991] .The anomaly is a leading cause of syringomyelia [Banerji and Millar, 1974; Dyste et al., 1989; Milhorat et al., 1995] and occurs in association with osseous abnormalities at the craniovertebral junction. In contrast with other Chiari malformations, Chiari I malformation tends to manifest in the second or third decade of life and sometimes is referred to as the adult-type Chiari malformation. Chiari I malformation is distinguished from the more familiar Chiari II (Arnold-Chiari) malformation, which is present at birth and consists of downward herniation of the lower cerebellum and medulla into the spinal canal, in association with myelodysplasia and complex anomalies of the brain such as aqueductal forking and polymicrogyria. The comparatively rare Chiari III malformation also is present at birth and is defined as cerebellar herniation into a cervical encephalocele.

Pathophysiology From a developmental standpoint, Chiari malformations have been classified as neuroectodermal defects, and indeed, a high incidence of craniovertebral anomalies has been noted in affected patients. Accumulating evidence, however, suggests that tonsillar herniation in Chiari I malformation is attributable to overcrowding of the hindbrain by an underdeveloped posterior cranial fossa (PCF) [Badie et al., 1995; Friede and Roessmann, 1976; Marin-Padilla, 1979; Nishikawa et al., 1997; Schady et al., 1987]. An increased prevalence among affected family members has been suggested, and a complex inheritance pattern is likely. The genetic and environmental contributing factors are not known. Information is limited regarding the epidemiologic features of Chiari I malformation. Female patients greatly outnumber male patients [Levy et al., 1983; Nishikawa et al., 1997; Pillay et al., 1991].

Clinical Characteristics Current interest in Chiari I malformation can be attributed to MRI, which has revolutionized diagnosis and has led to the detection of cases that either were not recognized or were erroneously identified as other conditions. The resulting increase in the number of reported cases has emphasized the need for greater understanding of the pathogenesis and clinical manifestations of Chiari I malformation. The presenting features largely depend on whether syryingomyelia is present; this defect tends to dominate the clinical picture. In the absence of syringomyelia, the clinical syndrome consists of (1) headaches, (2) pseudotumor-like episodes, (3) a Meniere’s disease–like syndrome, (4) lower cranial nerve signs, and (5) spinal cord disturbances [Milhorat et al., 1999]. The headache in Chiari I malformation typically is suboccipital in location in greater than 80% of patients. It is described as a heavy, crushing, or pressure-like sensation at the back of the head that radiates to the vertex and behind the eyes and inferiorly to the neck and shoulders and lacks a pounding quality. The pain often is accentuated by physical exertion, Valsalva maneuvers, head dependency, and sudden changes in posture. These features may help distinguish Chiari I malformation from migraine. Additional

FIGURE 19-21. Chiari I malformation. This sagittal view from a T1-weighted magnetic resonance imaging study shows tonsillar ectopia. The patient was a 15-year-old girl who had a protracted course of benign intracranial hypertension subsequent to lateral sinus thrombosis. The tonsils are herniated approximately 2 cm through the foramen magnum (arrow). (From Boltshauser E. Cerebellum—small brain but large confusion: A review of selected cerebellar malformations and disruptions. Am J Med Genet A 2004;126:376. Reprinted with permission of WileyLiss, Inc., a subsidiary of John Wiley & Sons, Inc.)

clinical symptomatology includes ocular disturbances (pain, scotoma), otoneurologic disturbances (nystagmus, dizziness, tinnitus, oscillopsia), and brainstem or cerebellar disturbances (dysphagia, sleep apnea, dysarthria). MRI will demonstrate downward displacement of the cerebellar tonsils (Fig. 19-21). Additional findings include compression of the cerebellar cisterns and a lower overall volume of the posterior fossa [Stovner et al., 1993]. No clear correlation of the size of the posterior fossa with the presence of syringomyelia or clinical symptomatology has been possible [Christophe and Dan, 1999]. Symptomatology of syringomyelia associated with the Chiari I malformation is typical of syringomyelia and depends on its localization and size. Symptoms can occur as a result of stretching and distention of nervous tissue or dissection of central canal cavities into the parenchymal tissues of the spinal cord [Milhorat et al., 1995]. Although it was previously thought that syringomyelia was caused by the forceful diversion of cerebrospinal fluid from the fourth ventricle into the central canal, it is now known that most types of syrinx do not communicate with the fourth ventricle and are separated from it by an occluded or stenotic segment of the canal [Milhorat et al., 1994, 1995, 1999]. Current

Gleeson, Dobyns, Plawner, and Ashwal / Congenital Structural Defects

evidence suggests that syrinx formation is the result of an obstruction of cerebrospinal fluid flow at the foramen magnum, which exaggerates the pulsatile systolic pulse wave in the spinal subarachnoid space [Oldfield et al., 1994] and drives cerebrospinal fluid through anatomically continuous perivascular and interstitial spaces [Milhorat et al., 1993; Stoodley et al., 1997] into the central canal of the spinal cord. More severe obstruction of cerebrospinal fluid circulation occasionally causes hydrocephalus.

Management Surgical correction of the posterior fossa with decompression and duraplasty has been found to be helpful in relieving signs and symptoms seen in patients with Chiari I malformation [Nohria and Oakes, 1990]. The purpose of the operation is to enlarge the bone compartment housing the craniocervical junction and to expand the dura surrounding the brainstem. Generally, in patients with symptomatic Chiari I malformation, one must first exclude hydrocephalus and ventral compression of the hindbrain, because these are initially treated with ventriculoperitoneal shunting. In patients with a syrinx, a Chiari decompression surgery is performed. Surgery is similarly indicated in patients without a syrinx but with greater than 5 mm caudal descent of the hindbrain. In patients with caudal descent between 3 and 5 mm, clinical judgment is indicated in determining the value of surgery. In patients with less than 3 mm of descent, surgery is not indicated. Decompression of the posterior fossa alone often is sufficient to reduce the syringomyelia without directly shunting the fluid collection. In approximately 10% of patients, however, the syrinx will persist [Tubbs et al., 2004]. If it persists, shunting of the syrinx may be necessary. Plugging of the obex with muscle or placement of a Silastic stent into the fourth ventricle to improve cerebrospinal fluid outflow into the basal cisterns and subarachnoid space also may be performed but is controversial.

Cerebellar Hypoplasia Cerebellar hypoplasia likely is much more common than currently appreciated. Sporadic nonsyndromic cerebellar hypoplasia was identified specifically in 11 of 2500 (0.5%) of children brought to a pediatric neurologist for evaluation [Shevell and Majnemer, 1996], although the prevalence of cerebellar hypoplasia is approximately 5% in children presenting with developmental delay. The main clinical features of cerebellar hypoplasia are developmental or speech delay, autistic features, ataxia, hypotonia, and ocular signs [Wassmer et al., 2003]. The combination of speech delay, ataxia, hypotonia, autistic features, and ocular signs, specifically oculomotor apraxia or nystagmus, correctly predicts cerebellar hypoplasia in a majority of the patients. It is critical to differentiate cerebellar hypoplasia syndromes from cerebellar atrophy syndromes, the latter characterized by progressive loss of cerebellar volume and progressive ataxia. It is impossible to confidently differentiate between these entities in every case, but serial MRI studies that demonstrate the presence of additional brainstem findings, or symptoms consistent with one of the

389

TABLE 19-10 Conditions with Hemispheric Cerebellar Hypoplasia CONDITION

CLINICAL FEATURES

Cerebellar ataxia

Nonprogressive ataxia, mental retardation, dominant, recessive or X-linked Severe retardation, ataxia, elevated lipoprotein, mutations in reelin Severe retardation, congenital muscular dystrophy, retinal dysplasia Aplastic anemia, immunodeficiency, microcephaly, cerebellar hypoplasia, and growth retardation, Xq28 chromosomal locus Hypotonia, hyporeflexia, ataxia, growth retardation, obesity, inverted nipples, dysmorphisms Aniridia, ataxia, mental retardation

Lissencephaly with cerebellar hypoplasia Cobblestone lissencephaly syndromes Hoyeraal-Hreidarsson syndrome Congenital disorder of glycosylation Ia Gillespie’s syndrome

progressive syndromes (i.e., cutaneous telangiectasias in ataxia-telangiectasia syndrome, hypoalbuminemia in ataxiaoculomotor apraxia syndrome), are useful. Inborn metabolic disorders can affect the cerebellum in its development and maturation [Steinlin et al., 1998]. Cerebellar hypoplasia also occurs with a wide variety of genetic disorders, including nonprogressive autosomal-recessive disorders, as well as situations in which it is sporadic [Ramaekers et al., 1997]. In several progressive metabolic and genetic disorders, like congenital disorders of glycosylation, diffuse cerebellar hypoplasia is a characteristic feature. Conditions associated with hemispheric cerebellar hypoplasia are summarized in Table 19-10. A more extensive listing of disorders in which some degree of cerebellar hypoplasia (unilateral or bilateral) has been reported is presented in Box 19-3. TABLE 19-11 Syndromes with Cerebellar Vermis Hypoplasia SYNDROME

CLINICAL FEATURES

Joubert’s syndrome

Absent cerebellar vermis, molar tooth abnormality, ataxia, oculomotor apraxia, mental retardation Polycystic kidney disease, encephalocele, hepatic ductal dysplasia, polydactyly Agenesis of the corpus callosum, cutaneous hypopigmentation, cataracts, cleft lip, combined immunodeficiency syndrome, mental retardation, pigmentary retinopathy, polydactyly, obesity, hypogenitalism, diabetes Congenital blindness; autosomal recessive Brachycephaly, midface hypoplasia, prognathism, hoarse voice, and speech delay; hearing loss, psychomotor and growth retardation, and behavioral problems; chromosome 17 deletions Oculomotor apraxia, ataxia Pontocerebellar hypoplasia, hypotonia, dysmorphic facies, inverted nipples, lipodystrophy, hepatic fibrosis

Meckel’s syndrome Vici’s syndrome

Bardet-Biedl syndrome Leber’s congenital amaurosis Smith-Magenis syndrome

Cogan’s syndrome Congenital disorders of glycosylation

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Box 19-3 CONDITIONS ASSOCIATED WITH ABNORMAL CEREBELLAR DEVELOPMENT Associations with Other Organ Involvement Congenital hepatic fibrosis Congenital hip dislocation Congenital lymphedema Congenital retinal blindness (Leber’s amaurosis) Hirschsprung’s disease Hypogonadotropic hypogonadism Immunodeficiency syndromes Optic coloboma Progressive pancytopenia Tapetoretinal degeneration CNS/PNS Malformation Syndromes Arrhinencephaly Arnold-Chiari (Chiari II) malformation Cranial meningocele Dandy-Walker malformation Hydrocephalus Lissencephaly/pachygyria Microcephaly Occipital meningomyelocele Pontocerebellar hypoplasia (types 1 to 3) Porencephaly Posterior fossa arachnoid cyst Rhombencephalosynapsis Spinal dysraphism Tectocerebellar dysraphia Chromosomal/Genetic Disorders Autosomal dominant Autosomal recessive Down syndrome Chromosome 5 deletion (cri du chat syndrome) Trisomies 9, 13, 18 X-linked

Metabolic Disorders Congenital disorders of glycosylation Mitochondrial disorders Muscle phosphofructokinase deficiency

Syndromes CHARGE association COACH asociation Cornelia de Lange’s syndrome CRASH syndrome (X-linked hydrocephalus) Dekaban-Arima syndrome Down syndrome Fukuyama’s congenital muscular dystrophy Fryns’ syndrome Hoyeraal-Hreidarsson syndrome Joubert’s syndrome Marinesco-Sjögren syndrome Meckel-Gruber syndrome Menkes’ syndrome Muscle-eye-brain disease Neu-Laxova syndrome Neurocutaneous melanosis Orofacial-digital syndrome (type 6) Otopalatodigital syndrome Ritscher-Schinzel (3C) syndrome Senior-Loken syndrome Walker-Warburg syndrome Whistling face syndrome

Teratogens Fetal alcohol syndrome Maternal isotretinoin use

3C, cranio-cerebello-cardiac; CHARGE, coloboma of the eye, heart anomaly, choanal atresia, retardation of mental and somatic development, genital abnormalities (microphallus), ear abnormalities and/or deafness; COACH, cerebellar vermis hypoplasia, oligophrenia, congenital ataxia, coloboma, hepatic fibrocirrhosis; CRASH, corpus callosum agenesis, retardation, adducted thumbs, spastic paraparesis, hydrocephalus. Data from Online Mendelian Inheritance in Man (OMIM), 1998; Norman et al., 1995; and Ball, 1997.

Cerebellar Vermis Hypoplasia Associated with Molar Tooth Malformation of the Brainstem, Including Joubert’s Syndrome and Related Disorders Cerebellar vermis hypoplasia may be encountered in several conditions (Table 19-11), but additional brain malformations or systemic malformations may help differentiate among these various conditions. One of the most helpful signs is the molar tooth malformation of the midbrainhindbrain junction. The molar tooth malformation is a radiographic hallmark consisting of three key components that together result in a “molar tooth” appearance of the midbrainhindbrain junction on MRI axial images of the brain [Maria et al., 1999b]. These features include (1) cerebellar vermis hypoplasia (or aplasia/dysplasia) that produces enlargement of the fourth ventricle; (2) a deep interpeduncular fossa; and (3) upwardly rotated and malformed superior cerebellar peduncles (Fig. 19-22).

The molar tooth malformation is encountered in several conditions with overlapping clinical features (Table 19-12). Joubert’s syndrome is the best known and probably the most common syndrome associated with the molar tooth sign. Joubert’s syndrome is a disorder of autosomal recessive inheritance marked by agenesis or severe hypoplasia of the cerebellar vermis, by the molar tooth sign, and clinically by ataxia, hypotonia, oculomotor apraxia, neonatal breathing abnormalities, and mental retardation. Joubert’s syndrome is notable for both intrafamilial and interfamilial phenotypic variability. Even in the original pedigree of four affected siblings described by Joubert, two had hypoplasia of the posterior inferior cerebellar vermis, and two had complete agenesis of the cerebellar vermis [Joubert et al., 1968]. The breathing dysregulation associated with these conditions may be life-threatening. Affected neonates are identified on the basis of long pauses in respirations followed by panting respirations. Although some infants have died of apneic episodes, in general the breathing abnormalities

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391

FIGURE 19-22. Radiographic appearance of the brain in Joubert’s syndrome. A, Diminished volume of cerebellar vermis (short arrows) and horizontally oriented superior cerebellar peduncle (long arrow). B, Hypoplasia of the cerebellar vermis (arrow shows residual tissue). The midbrain-hindbrain junction takes the shape of a molar tooth (circle), giving rise to the name for this malformation.

A

B

subside with age and may completely disappear [Boltshauser and Isler, 1977; Maria et al., 1999a, 1999b]. Cognitive abilities are variable, ranging from severe mental retardation to normal intelligence, but most commonly children display moderate mental retardation. Seizures and behavioral problems are not uncommon. Many children display autistic features [Holroyd et al., 1991; Ozonoff et al., 1999] and require psychoactive medication for stabilization. The molar tooth malformation is always associated with the clinical features of Joubert’s syndrome, including ataxia, hypotonia, oculomotor apraxia, mental retardation, and neonatal breathing dysregulation. It occurs in at least eight clinically distinct conditions: (1) classic Joubert’s syndrome; (2) Leber’s congenital amaurosis (rod cone dystrophy) associated with congenital retinal blindness; (3) Dekaban-Arima syndrome, associated with renal cysts; (4) Senior-Loken syndrome, associated with progressive renal fibrosis (nephronophthisis) and congenital retinal blindness; (5) orofacialdigital syndrome type VI, associated with preaxial or mesaxial polydactyly, tongue hamartomas, and pituitary hamartomas; (6) occipital encephaloceles (so-called Malta syndrome); (7) an association with cortical polymicrogyria; and (8) COACH syndrome (cerebellar vermis hypoplasia, oligophrenia [i.e., mental retardation], ataxia, coloboma, hepatic fibrosis) [Gleeson et al., 2004]. TABLE 19-12 Variants of Joubert’s Syndrome (JS) Classical JS JS with cortical polymicrogyria JS with Leber’s congenital amaurosis JS with nephronophthisis (Senior-Loken syndrome) JS with polydactyly and tongue tumors (orofacial-digital syndrome 6, Varadi-Papp syndrome) JS with neuroepithelial cysts JS with hepatic fibrosis and coloboma (COACH) JS with encephalocele (Malta syndrome, may overlap with Meckel-Gruber syndrome) COACH, cerebellar vermis hypoplasia, oligophrenia, congenital ataxia, coloboma, hepatic fibrocirrhosis.

The genetic etiology of these conditions is not entirely understood, but they typically are inherited in an autosomalrecessive fashion. At least five distinct genetic forms of the entity Joubert’s syndrome and related disorders, as well as mutations in the gene AHI1, encoding the Jouberin protein [Dixon-Salazar et al., 2004], and in NPHP1, encoding nephrocystin [Parisi et al., 2004], have been identified in several families. Because of the low prevalence of mutations in individual families, genetic testing is recommended on a research basis only.

Management Patients identified in the neonatal intensive care unit should be monitored closely for apnea. Treatment with caffeine may help promote respiratory drive, and an apnea monitor may be required for the first year of life. Because of the heterogeneity of these conditions, it is recommended that patients be evaluated by a geneticist and undergo screening for coexisting medical problems, including brain MRI, polysomnogram, echocardiogram, careful dysmorphology and retinal evaluation, and yearly monitoring with liver function tests and renal ultrasound examinations [Parisi and Dobyns, 2003].

Dandy-Walker Malformation The Dandy-Walker malformation was first described in 1887 by Sutton [Sutton, 1887] and was further characterized by Dandy and Blackfan in 1914 and Taggart and Walker in 1942 [Dandy and Blackfan, 1914; Taggart and Walker, 1942]. The key components of this malformation include hypoplasia of the cerebellar vermis and cystic dilation of the fourth ventricle. The fourth ventricle communicates with a retrocerebellar cyst that may cause enlargement of the posterior fossa and elevation of the tentorium, seen on imaging studies as elevation of the torcula or confluence of the sinuses. A third, variable component of Dandy-Walker malformation is communicating hydrocephalus with enlarged lateral ventricles. Presentation of Dandy-Walker malformation can take many forms. It often manifests with macrocephaly in the

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Perinatal Acquired and Congenital Neurologic Disorders / 19 FIGURE 19-23. Dandy-Walker malformation. A, Note the presence of the cerebellar vermis (asterisk) that is rotated upward. A cystic dilation of the fourth ventricle replaces the site normally taken by the vermis. B, Axial image through the pons. The vermis is visible (white arrow), and no molar tooth malformation is evident (black arrows).

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neonatal period, and infants may come to medical attention because of hydrocephalus, developmental delay, or ataxia. It may be identified on prenatal ultrasound examination, when prenatal counseling takes on a critical role. It may be present in asymptomatic persons undergoing brain imaging for an unrelated reason. Dandy-Walker malformation is a relatively common malformation, occurring in at least 1 in 5000 liveborn infants [Parisi and Dobyns, 2003]. It has been reported in a wide variety of chromosomal anomalies, and in several different genetic syndromes [Bordarier and Aicardi, 1990; Chitayat et al., 1994; Murray et al., 1985]. Some of these syndromes, specifically Meckel-Gruber and Walker-Warburg syndromes, have complex midbrain-hindbrain malformations that are unlikely to represent the classic Dandy-Walker malformation. Some surveys suggest that environmental factors, including prenatal exposure to teratogens such as rubella or alcohol, are associated with Dandy-Walker malformation [Benke, 1984; Clarren et al., 1978].

scribed under the acronym PHACE (posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities) [Frieden et al., 1996; Poetke et al., 2002]. Conditions associated with the Dandy-Walker malformation are outlined in Table 19-13.

Variability of the Dandy-Walker Malformation At least four cerebellar malformations frequently are confused with Dandy-Walker malformation: cerebellar vermis hypoplasia/aplasia, retrocerebellar cyst, mega cisterna magna, and Blake’s pouch cyst (Fig. 19-24). Collectively, these have been grouped together as Dandy-Walker variants; as has become better appreciated, however, they have no direct relation to Dandy-Walker malformation and should be treated as distinct from this entity. The confusion initially arose when axial plane CT was the standard imaging modality [Archer et al., 1978], because these different malformations are best appreciated in the parasagittal plane. Cerebellar

Diagnostic Criteria and Associated Features The core criteria of Dandy-Walker malformation are (1) cerebellar vermis hypoplasia; (2) cystic enlargement of the fourth ventricle; and (3) elevation of the roof of the posterior fossa (the tentorium cerebelli and torcula [Parisi and Dobyns, 2003] (Fig. 19-23). In addition to these diagnostic criteria, enlargement of the posterior fossa, stenosis of the outflow tracts of the fourth ventricle, and hydrocephalus with increased intracranial pressure often are features. Associated malformations, generally CNS in origin (including occipital encephalocele, polymicrogyria, and heterotopia), are present in 25% to 50% of persons with Dandy-Walker malformation. A significant proportion (10% to 17%) display agenesis or dysgenesis of the corpus callosum [Ben Hamouda et al., 2001; Wilson et al., 1994]. Other non-CNS anomalies with an increased frequency in Dandy-Walker malformation include congenital heart disease, cleft lip and/or palate, and neural tube defects [Huong et al., 1975; Ritscher et al., 1987]. A recurring association of Dandy-Walker malformation with facial hemangiomas has been noted and de-

TABLE 19-13 Conditions Associated with Dandy-Walker Malformation CONDITION

CLINICAL FEATURES

Classic Dandy-Walker malformation

Vermis hypoplasia, upward vermis rotation, elevation of torcula, cystic dilation of fourth ventricle, variable hydrocephalus Less severe cerebellar hypoplasia, less notable or absent upward rotation of vermis, smaller fourth ventricle cysts Classic features of Dandy-Walker malformation, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, eye abnormalities

Dandy-Walker malformation variant PHACE syndrome

PHACE, posterior fossa malformations, large cervicofacial hemangioma, arterial anomalies of the head and neck, coarctation of the aorta and cardiac defects, eye anomalies and sternal cleft.

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FIGURE 19-24. Conditions to be distinguished from Dandy-Walker malformation. A, Cerebellar vermis hypoplasia/atrophy. Note normal size of posterior fossa and absence of hydrocephalus. B, Retrocerebellar cyst with shift of cerebellum anteriorly, which has resulted in obstruction of cerebrospinal fluid (CSF) outflow and resultant hydrocephalus. C, Mega cisterna magna. Note enlarged size of posterior fossa, but normal size of cerebellum. D, Blake’s pouch cyst. Note CSF collection in the fourth ventricle that is contiguous with a collection inferior to the cerebellum (asterisk). Small arrows show upward mass effect from fluid. In none of these conditions is the fourth ventricle significantly enlarged or upwardly rotated.

vermis hypoplasia/atrophy can be observed as an isolated finding or may be part of a metabolic or genetic defect, such as associated with congenital disorders of glycosylation [Worthington et al., 1997] or with mutations in the oligophrenin gene [des Portes et al., 2004]. Retrocerebellar cysts, mega cisterna magna, and Blake’s pouch cysts may be part of a continuum and cannot always be distinguished from one another, but each usually can be distinguished from DandyWalker malformation. A Blake’s pouch cyst is merely an extension of the fourth ventricle through the foramen of Magendie into the vallecula. It may be associated with mild vermian hypoplasia and may be a forme fruste of the DandyWalker malformation. Retrocerebellar cysts usually are arachnoid cysts that sit in the fairly dense subarachnoid space posterior to the vermis. They usually are more rostral and more dorsal than a Blake’s pouch cyst. Mega cisterna magna is applied to large retrocerebellar cerebrospinal fluid collections in patients who are asymptomatic or are symptomatic from other conditions. Often, these posterior fossa fluid collections are of no clinical significance [Boltshauser et al., 2002], unless associated with cerebellar parenchyma volume loss, cerebrospinal fluid fluid obstruction resulting in hydrocephalus, or cerebellar compression.

Clinical Course Dandy-Walker malformation often manifests in the neonatal period with macrocephaly, occipital encephaloceles, and/or hydrocephalus [Hirsch et al., 1984]. Among affected patients with severe obstructive hydrocephalus, multiple congenital anomalies, and/or other severe CNS anomalies such as porencephaly, the mortality rate is high. Apnea and seizures are seen in a significant proportion of children with Dandy-Walker malformation [Gerszten and Albright, 1995], although developmental delay and mental retardation are highly variable. These infants tend to have congenital hypotonia, and spasticity may develop later [Maria et al., 1987]. Ataxia and nystagmus are seen in many patients, but cerebellar signs are variable and may not be present. Many patients are diagnosed in infancy, on the basis of increasing head circumference and/or symptoms of elevated intracranial pressure such as lethargy, vomiting, and irritability; however, some will display normal intellect and essentially normal motor function [Maria et al., 1987]. Dandy-Walker

malformation has been diagnosed incidentally on cranial imaging studies performed for other indications [Lipton et al., 1978].

Treatment The treatment of Dandy-Walker malformation has been a subject of great controversy. In early series, based on the belief that hydrocephalus was due to obstruction of the foramina of Lushka and Magendie, surgery involved excision of the posterior fossa membranes to create unobstructed flow of cerebrospinal fluid, with resultant poor outcomes [Sawaya and McLaurin, 1981]. Treatment by either direct shunting of the lateral ventricles in the presence of hydrocephalus is typically required but has met with mixed success [Kumar et al., 2001]. Although it has been proposed that return of normal cerebellar architecture by shunting the cyst is associated with good functional outcome [Golden et al., 1987], some investigators suggest that the measured volume of cerebellum is not significantly changed by cyst shunting and advocate ventriculoperitoneal shunting as the best approach to relieve increased intracranial pressure [Gerszten and Albright, 1995]. Cognitive outcomes in Dandy-Walker malformation series vary widely and appear to fit a bimodal distribution, suggesting that factors other than the malformation itself contribute to the outcome [Parisi and Dobyns, 2003].

Pontocerebellar Hypoplasia Conditions described as pontocerebellar hypoplasia also are known as pontocerebellar atrophies because of the progressive atrophy of the brain that is observed on serial brain imaging. The major brain regions involved include the ventral pons and often the inferior olivary nuclei, cerebellar vermis, and cerebellar hemispheres. Supratentorial atrophic changes include enlargement of the ventricles and extra-axial cerebrospinal fluid spaces, widened cerebral sulci, and thinning of white matter and corpus callosum [Zelnik et al., 1996]. Clinically, children with pontocerebellar hypoplasia have prenatal onset of neurologic abnormalities; postnatal findings include severe developmental delay, mental retardation, and often a seemingly neurodegenerative course [Barth, 1993]. The progressive MRI changes may be more

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apparent than actual clinical regression [Parisi and Dobyns, 2003; Uhl et al., 1998]. The general clinical course reveals neonatal hypotonia, poor feeding, growth retardation, and failure to achieve any significant motor or cognitive milestones, resulting in severe-to-profound mental retardation, although exceptions are possible in mild cases [Zelnik et al., 1996]. These conditions need to be differentiated from infantile neuroaxonal dystrophy; mitochondrial defects; a syndrome of progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy; and congenital disorders of glycosylation. Although the term infantile olivopontocerebellar atrophy has been applied to this group of disorders, this leads to confusion with the adult-onset spinocerebellar ataxia conditions that also are known as olivopontocerebellar atrophy syndromes [Barth, 1993]. As with cerebellar vermis hypoplasia, the forms of pontocerebellar hypoplasia are individually very rare conditions, with fewer than 20 published cases. At least three forms have been defined on the basis of clinical and pathologic features

Pontocerebellar Hypoplasia Type 1 Pontocerebellar hypoplasia type 1 (pontocerebellar hypoplasia associated with spinal muscular atrophy) is characterized by neonatal respiratory insufficiency, often with ventilator dependency and congenital contractures (arthrogryposis). The clinical course is characterized by bulbar dysfunction, feeding and respiratory problems, and death generally within the first year of life [Barth, 1993, 2000; Chou, 1990; Norman, 1961; Rudnik-Schoneborn et al., 2003]. MRI findings include hypoplastic brainstem and cerebellum. Degeneration of the anterior horn cells of the spinal cord resembles spinal muscular atrophy histologically, and the muscle biopsy reveals grouped atrophy consistent with this pathogenesis. The disease is genetically distinct from spinal muscular atrophy, and the genetic causes are unknown.

Pontocerebellar Hypoplasia Type 2 In pontocerebellar hypoplasia type 2 (pontocerebellar hypoplasia with dyskinesia), the neonatal presentation is one of marked microcephaly and absence of normal swallow and feeding ability. The microcephaly is progressive, and generalized epilepsy with marked chorea that has its onset within the first few months of life and that evolves into dystonia in later childhood also is common [Barth et al., 1990, 1995]. Most affected children die within the first decade of life. Imaging reveals atrophy of the ventral pons and cerebellar hemispheres and vermis, with progressive subcortical atrophy. Spinal anterior horn cells are normal, differentiating this condition from the type 1 disorder. Several reports have described less severe variants, with the suggestion of heterogeneity in type 2. No genes have been mapped for this autosomal-recessive condition.

Other Forms of Pontocerebellar Hypoplasia Several other individual families with pontocerebellar hypoplasia have been described and exhibit evidence of genetic mapping to distinct loci, implying that there are several distinct genetic entities. These families display hypoplasia/ atrophy of the cerebellum, with a predilection for the cerebellar vermis, as well as pontine hypoplasia. Features of neither spinal muscular atrophy or dyskinesia are prominent. Mental retardation, optic atrophy, and skin anomalies often

are associated findings [Delague et al., 2001, 2002; Megarbane et al., 2001; Rajab et al., 2003; Straussberg et al., 2005].

Rhombencephalosynapsis Rhombencephalosynapsis is a rare congenital abnormality characterized by dorsal fusion of the cerebellar hemispheres, agenesis or hypogenesis of the vermis, and fusion of dentate nuclei and superior cerebellar peduncles [Toelle et al., 2002]. In this sense, it may be viewed as a condition with failure to form the midline structures of the cerebellum, akin to holoprosencephaly, which affects primarily the cerebral cortex. Common associated findings include cerebral cortical malformations, such as corpus callosum hypoplasia or cortical dysplasia [Mendonca et al., 2004], but major features of holoprosencephaly are not typically present. Clinical findings range from mild truncal ataxia and normal cognitive abilities to severe cerebral palsy and mental retardation. This broad spectrum may be a result of the frequent association with hydrocephalus. Pathologic studies have revealed defects that include fusion of the inferior colliculi and absence of dorsal olivary nuclei [Yachnis, 2002].

Lhermitte-Duclos Disease Lhermitte-Duclos disease is a rare dysplastic hamartomatous gangliocytoma of the cerebellar midline. It is believed to be a result of overgrowth of hypertrophic ganglion cells that replace the granular cell layer and Purkinje cells of the cerebellum, resulting in global thickening of the cerebellar folia [Albrecht et al., 1992; Ambler et al., 1969; Nowak and Trost, 2002]. Clinically, patients with Lhermitte-Duclos disease may present with ataxia, signs and symptoms of increased intracranial pressure, and seizures. Surgery may be required to relieve posterior fossa pressure or hydrocephalus [Tuli et al., 1997]. It also is critical to distinguish Lhermitte-Duclos disease from medulloblastoma, because they may appear similar on brain imaging studies [Chen et al., 2002]. Approximately half of the published cases of LhermitteDuclos disease include features of Cowden’s syndrome [Robinson and Cohen, 2000], an autosomal-dominant condition with age-related penetrance characterized by multiple hamartomas affecting derivatives of all three germ layers and by a high risk of breast, thyroid, and endometrial cancers [Eng, 2000; Marsh et al., 1997; Robinson and Cohen, 2000]. Germline mutations in the PTEN (phosphatase and tensin homolog) gene are a frequent cause of Cowden’s syndrome, and mutations in this gene have been identified in some patients with Lhermitte-Duclos disease [Liaw et al., 1997; Nelen et al., 1997], but the frequency of these mutations among these patients is unknown. Careful diagnosis is important, because recognition may lead to earlier diagnosis of systemic malignancies [Prabhu et al., 2004].

Vein of Galen Malformation Vein of Galen malformation is a rare congenital vascular malformation characterized by shunting of arterial flow into an enlarged cerebral vein dorsal to the tectum [Jones et al., 2002]. Most of these malformations present during infancy

Gleeson, Dobyns, Plawner, and Ashwal / Congenital Structural Defects

or early childhood, often causing congestive heart failure and failure to thrive. Children presenting during the neonatal period have a generally much worse prognosis than those presenting later in childhood. The malformation develops between weeks 6 and 11 of gestation, after development of the circle of Willis. It is thought to result from the development of an arteriovenous connection between primitive choroidal vessels and the median prosencephalic vein of Markowski. The abnormal flow through the connection retards the normal involution of this embryonic vein and prevents the normal development of the vein of Galen. The shunt is maintained through the remainder of brain development, with the persistent median vein draining into the sagittal sinus, often via a persistent falcine vein, with absence of the straight sinus. Other venous anomalies are commonly present in association, including anomalous dural sinuses and sinus stenoses [Lasjaunias et al., 1987; Raybaud et al., 1989]. The adequacy of these alternative pathways may be one of the most important factors in determining long-term prognosis, as treatment often requires obliteration of the aneurysm through vascular approaches [Brunelle, 1997].

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Disorders Associated with Prosencephalic Development Prosencephalon Cleavage A single prosencephalic vesicle forms at the end of the neural tube at about day 22 of gestation. The cells of the prosencephalic vesicle form the cerebral hemispheres and deep cerebral nuclei. By day 32, the areas that will form the telencephalon and diencephalon separate. Also at this time, the telencephalon separates into two cerebral hemispheres. These actions are induced by the notochord ventral to the developing nervous system. Specifically, the Sonic hedgehog protein (Shh), released from the prechordal plate, is one of the primary signals that result in the separation of the two cerebral hemispheres, and of the telencephalon from the diencephalon. Shh also interacts to define midline facial structures. Abnormalities of Shh or of components of the Shh pathway may result in midline brain or facial malformations. Delineation of these processes is under intense investigation (Roessler and Muenke, 2003).

Holoprosencephaly Description; Pathologic and Radiologic Features Holoprosencephaly is a disorder characterized by a failure of complete separation of the prosencephalon into two distinct cerebral hemispheres, and into a distinct telencephalon and diencephalon. The complex brain malformations typically are associated with midline facial anomalies. This so-called rare disorder also is considered a “common brain malformation,” because the incidence in aborti is 1:250 (Matsunaga and Shiota, 1977), but the incidence in live births is only approximately 1:10,000 (Bullen et al., 2001; Croen et al., 2000; Forrester and Merz, 2000; Rasmussen et al., 1996) because of the high rate of pregnancy loss. The incidence of 1:10,000 may be an underestimation as these studies were likely to have missed milder cases not identified until later in infancy.

FIGURE 19-25. Subtypes of holoprosencephaly (HPE). A, B, Alobar HPE on T1-weighted magnetic resonance imaging (MRI) study. The axial image (A) reveals the lack of separation of the cerebral hemispheres and deep gray nuclei, with large dorsal cyst (dc) posteriorly. The sagittal image (B) shows the midline monoventricle (mv) that communicates with the dorsal cyst. C, D, Semilobar HPE on T2-weighted MRI study. The axial image (C) demonstrates lack of separation of the cerebral hemispheres anteriorly, absence of the anterior horns of the lateral ventricles, and incomplete separation of the basal ganglia. The coronal image (D) reveals the absence of the interhemispheric fissure, and the presence of a monoventricle (mv). E, F, Lobar HPE on T1-weighted MRI study. The axial image (E) shows the presence of an interhemispheric fissure both anteriorly and posteriorly separating the cerebral hemispheres. There are rudimentary frontal horns of the lateral ventricles (arrowheads). The coronal image (F) shows the incomplete separation of the inferior frontal lobes near the midline. G, H, Middle interhemispheric variant on T1-weighted MRI study. The axial (G) and coronal (H) images demonstrate continuity of the gray matter in the posterior frontal lobes across the midline (arrows). (From Hahn JS, Plawner LL. Evaluation and management of children with holoprosencephaly. Pediatr Neurol 2004;31:79.)

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Holoprosencephaly typically is divided into three main types as delineated by DeMyer and co-workers (DeMyer and Zeman, 1963; DeMyer et al., 1964), distinguished by the degree of separation of the cerebral hemispheres (Fig. 19-25). In the most severe type, alobar holoprosencephaly, nearly complete lack of separation of the cerebral hemispheres is characteristic, with a single midline ventricle often communicating with a dorsal cyst. The interhemispheric fissure and corpus callosum are completely absent. In the intermediate form, semilobar holoprosencephaly, the anterior hemispheres are not separated, but some degree of separation of the posterior hemispheres is seen. Similarly, the genu and body of the corpus callosum are absent, but the splenium is present. The frontal horns of the lateral ventricles are not developed, but the posterior horns are present. The mildest form, lobar holoprosencephaly, is characterized by lack of separation of the most rostral and ventral aspects of the cerebral hemispheres. The splenium and body of the corpus callosum are present, but the genu is absent. Rudimentary frontal horns may be present. In addition to the often-emphasized nonseparation of the cerebral hemispheres, lack of separation also is common in the hypothalamic, caudate, lentiform, and thalamic nuclei. About a quarter of patients have some degree of nonseparation of the mesencephalon (Norman et al., 1995; Simon et al., 2000). Cytoarchitecturally, the brain often is normal; a brain abnormality might be due to secondary injury. Occasionally, isolated neuronal heterotopias are seen. The gyri often are normally developed, although the gyral pattern can be abnormal in alobar and semilobar holoprosencephaly (Golden, 1998). In addition to DeMyer’s classic holoprosencephaly subtypes, some authors have suggested a fourth holoprosencephaly subtype, middle interhemispheric variant (Simon et al., 2002). In this variant, the midportion of the cerebral hemispheres is continuous across the midline, with absence of the corpus callosum in this region only. There is separation of the anterior frontal lobes, basal forebrain and occipital lobes. Evidence for this malformation being a subtype of holoprosencephaly is bolstered by the finding that a mutation in the ZIC2 gene that has been implicated in causing the classic forms of holoprosencephaly, has been found in a patient with middle interhemispheric variant (Brown et al., 2001). Although holoprosencephaly is typically divided into these subtypes, the degree of malformation and brain regions involved occur along a spectrum, and individual patients frequently do not fall neatly into any one category. Historically, two thirds of children have been thought to have the most severe type, alobar holoprosencephaly, but with increasing use of MRI, milder cases are being increasingly identified.

Environmental and Genetic Causes Multiple environmental and genetic factors have been implicated in causing holoprosencephaly. Maternal diabetes (Barr et al., 1983), and exposures to alcohol (Sulik and Johnson, 1982) and retinoic acid (Croen et al., 2000) have the strongest evidence. Anecdotal reports also suggest viruses, low-calorie diet, hypocholesterolemia, salicylates, and contraceptives as possible causes.

It has been reported that up to 45% of live births with holoprosencephaly have chromosomal abnormalities (Croen et al., 1996), but this is probably an overestimation based on underreporting of milder cases. Holoprosencephaly can be seen in association with trisomy 13, trisomy 18 or triploidy. Holoprosencephaly can also be seen in several multiple malformation syndromes having normal karyotypes, such as Pallister-Hall syndrome, Rubinstein-Taybi syndrome and Smith-Lemli-Opitz syndrome (Siebert et al, 1990). In nonsyndromic holoprosencephaly, multiple pedigrees have been described that report various inheritance patterns, most commonly autosomal-dominant and autosomal-recessive inheritance. Eight genes have been associated with holoprosencephaly: SHH (7q36), ZIC2 (13q32), SIX3 (2p21), TGIF (18p11.3), PTCH (9q22), GLI2 (2q24), TDGF1 (3p21), and FAST1 (8q24). Mutations in these genes account for approximately 15% to 20% of the cases of holoprosencephaly (Dubourg et al., 2004; Ming and Muenke, 2002). SHH was the first identified and has been the most extensively studied (Belloni et al., 1996). The Shh protein is a secreted intercellular signaling molecule involved in establishing cell fates at several points during development. Shh is expressed early in development in the ventral forebrain and is critical for ventral patterning of the developing neural tube. It also is expressed in the ectoderm of the frontonasal and maxillary processes. Disruption of Shh signaling in several animal models produces the brain and facial malformations seen in holoprosencephaly. The Shh signaling network is the common pathway through which multiple environmental and genetic influences interact to cause holoprosencephaly. Several of the other holoprosencephaly genes are important components of the Shh signaling network; PTCH is a receptor for Shh, and GLI2 is a mediator of Shh target gene transcription. A wellstudied example of environmental influences acting through the Shh signaling network is the association of holoprosencephaly with various causes of hypocholesterolemia (Ming and Muenke, 2002). Shh is modified by cholesterol, which is felt to be essential for its proper functioning. Maternal hypocholesterolemia has been implicated in causing holoprosencephaly. The incidence of holoprosencephaly is also increased in Smith-Lemli-Opitz syndrome, which is due to a defect in 7-dehydrocholesterol reductase, the final step in cholesterol synthesis (Kelley et al., 1996). In addition, an outbreak of cyclopia (severe midline facial malformation) in flocks of sheep was believed to be caused by ingestion of plants containing cyclopamine and jervine, inhibitors of cholesterol (Keeler and Binns, 1968). Studies of genotype-phenotype correlation in mutations of SHH have found that the same mutation can result in extremely variable phenotypes. Even within the same family, an identical mutation in SHH may result in severe brain malformation, only a “mild sign” known as a microform (such as a single central incisor), or no phenotypic abnormality. It is estimated that among carriers of an abnormal gene, 37% will have holoprosencephaly, 27% will have a microform, and 36% will have no clinical abnormality (Cohen, 1989b). This observation of great variability in phenotype with the same genetic mutation has suggested that although holoprosencephaly is classically thought of as a single-gene disorder, it should be considered a multifactorial disorder, with the specific phenotype being the result of

Gleeson, Dobyns, Plawner, and Ashwal / Congenital Structural Defects

multiple genetic and environmental influences (Ming and Muenke, 2002). Indeed, in some cases, the phenotypically normal family members have mutations in SHH, and the affected child has this mutation in addition to a mutation in another holoprosencephaly gene (Nanni et al., 1999). Another hypothesis is that the timing of the exposure to a teratogen is critical to the specific resulting phenotype. An experimental model using cyclopamine, an inhibitor of cholesterol, has revealed that varying the time of exposure resulted in a continuum of midline facial malformation (Codero et al., 2004).

Clinical Characteristics Along with the midline brain malformation seen in holoprosencephaly, a corresponding midline facial malformation may be present. In its most severe and usually lethal form, cyclopia, with the presence of a single midline eye and a proboscis (rudimentary single-nostril nose) above the eye, can be present. The surviving patient, more likely to be encountered by a neurologist, may have hypotelorism, a flattened nasal bridge, median cleft lip and palate, and/or a single central incisor. The oft-quoted statement “the face predicts the brain” (DeMyer et al., 1964) refers to the observation that the degree of facial malformation frequently reflects the degree of brain malformation. This was amended later to “the face predicts the brain approximately 80% of the time,” in recognition of cases of lobar holoprosencephaly with normal facies and cases of milder brain malformation with abnormal facies (Cohen, 1989b). Early literature indicated that children with holoprosencephaly do not survive beyond early infancy. This finding may have been a function of identification of only the most severe cases. Early death is typical for most cytogenetically abnormal children and those with the most severe facial features (cyclopia or ethmocephaly) (Croen et al., 1996). In children without these risk factors, more recent research has indicated that long-term survival is not uncommon. Of cytogenetically normal patients with all types of holoprosencephaly, greater than 50% are alive at 12 months (Barr and Cohen, 1998; Olsen et al., 1997). In one large series of 104 holoprosencephaly patients seen at a referral center, the mean age was 4 years, and 15% were between 10 and 19 years of age (Hahn and Plawner, 2004). Even with the most severe brain malformation, alobar holoprosencephaly, children may survive. In a descriptive study of alobar holoprosencephaly, 30% were alive at 12 months, with long-term survival noted as well (Barr and Cohen, 1999). When death did occur in the alobar group, causes were noted to be brainstem dysfunction, pneumonia, dehydration from diabetes insipidus, and rarely, intractable seizures. Children with holoprosencephaly may experience a variety of medical and neurologic problems. A significant proportion develops hydrocephalus. The likelihood of requiring ventriculoperitoneal shunting is much more likely in alobar than in semilobar or lobar holoprosencephaly (60% versus 8%) (Plawner et al., 2002). The risk of developing hydrocephalus also is more likely when a dorsal cyst is present (Simon et al., 2001). The dorsal cyst is thought to form as a result of the thalami being fused across the midline, thereby blocking cerebrospinal fluid egress from the third ventricle and disrupting cerebrospinal fluid flow. Because most children with holoprosencephaly are micro-

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cephalic, normocephaly or macrocephaly is a potential indicator of hydrocephalus. As in children with other midline brain defects, endocrinologic problems are very common. Diabetes insipidus is particularly frequent. In one series of 68 children, three quarters had diabetes insipidus (Plawner et al., 2002). Diabetes insipidus can be insidious in presentation; serum sodium concentrations of 160 mEq/L or greater were occasionally detected on routine electrolyte evaluation and were not accompanied by any acute symptoms. Diabetes insipidus can have a waxing and waning course. Growth hormone deficiency, hypocortisolism, and hypothyroidism also may occur. It is unclear whether the abnormalities are related to pituitary or hypothalamic dysfunction. The degree of endocrinologic abnormality correlates with the degree of hypothalamic nonseparation but not pituitary abnormality on neuroimaging, indicating a potential hypothalamic etiology. Approximately half of the children with holoprosencephaly have seizures. The likelihood of seizures does not correlate with the severity of the brain malformation. The most common seizure type is complex partial seizures, with or without secondary generalization. Seizure type, however, can be variable, including generalized tonic-clonic, tonic, atonic, myoclonic seizures or infantile spasms (Hahn and Plawner, 2004). In 50% of these children, the seizures are relatively easy to control with antiepileptic medication. Having a concurrent area of cortical dysplasia is a risk factor for having difficult-to-control seizures (Plawner et al., 2002). Feeding problems and swallowing dysfunction are common in children with holoprosencephaly, and are correlated with the severity of the brain malformation. Two thirds of patients with alobar and semilobar holoprosencephaly require gastrostomy tubes (Plawner et al., 2002). Abnormalities of muscle tone are also very common in holoprosencephaly, and the severity correlates with the severity of the brain malformation. Many children have early hypotonia, followed by the development of upper limb and oromotor dystonia, and lower limb spasticity (Hahn and Plawner, 2004). Delayed development has been well described in holoprosencephaly. Severe developmental delay and mental retardation are common in alobar holoprosencephaly (Barr and Cohen, 1999). There is no reported case of a child with alobar holoprosencephaly who is able to sit independently. In lobar holoprosencephaly, approximately 50% of children ambulate (with or without assistance), use their hands functionally, and have some verbal communication (Plawner et al., 2002). Formal neuropsychologic evaluation in all types of holoprosencephaly demonstrates relative strengths in receptive language and socialization, and weaknesses in visual reasoning and nonverbal problem skills (Kovar et al., 2001). In the middle interhemispheric variant, the incidence of endocrinopathies is much lower than has been attributed to the more normally separated hypothalamus seen on MRI. The degree of motor complications (hypotonia and dystonia) and developmental dysfunction is similar to that seen in lobar holoprosencephaly. A high incidence of dorsal cysts has been attributed to the frequent occurrence of nonseparation of the thalami (Lewis et al., 2002).

Management Recent work has addressed specific management issues of children with holoprosencephaly. Children with alobar holo-

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prosencephaly, a dorsal cyst, or normo- or macrocephaly should be closely observed for the development of hydrocephalus. Most experts recommend ventriculoperitoneal shunting for hydrocephalus even in severe holoprosencephaly, because failure to institute this measure will lead to progressive head enlargement and greater difficulty in caring for the child (Barr and Cohen, 1999; Hahn and Plawner, 2004). Routine electrolyte screening should be performed to assess for the subacute development of diabetes insipidus. Screening for other endocrine abnormalities should be considered less frequently, with assays of cortisol, thyroidstimulating hormone (TSH), free thyroxine (T4), and insulinlike growth factor-1 (IGF-1). Because seizures may not develop in half of the children with holoprosencephaly, prophylactic antiepileptic drugs are not recommended. If seizures do develop, the possibility of acute reactive seizures should be entertained, and a serum sodium level checked. MRI also should be considered to evaluate for focal heterotopia. Gastrostomy tubes often are necessary to address the complex management issues of ensuring adequate calories related to feeding dysfunction and delivery of adequate free water necessary for management of diabetes insipidus. Motoric difficulties and dystonia may be partially responsive to tri-hexyphenidyl. This agent may improve upper extremity and oromotor function [Hahn and Plawner, 2004].

Prenatal Diagnosis and Genetic Counseling The recurrence risk of isolated holoprosencephaly is estimated to be 6% [Roach et al., 1975]. Special attention should be given to the family history, to identify “microforms” such as anosmia or a single central incisor. Such a finding would indicate a substantially higher recurrence risk. Commercial genetic testing for SIX3, SHH, TGIF, and ZIC2 is available (see http://www.genetests.org) and should be considered if familial holoprosencephaly is suspected. Prenatal testing is possible by means of amniocentesis or chorionic villus sampling. The sensitivity of first-trimester ultrasound examination in the detection of holoprosencephaly remains unclear. It can detect alobar holoprosencephaly [Filly et al., 1984; Sepulveda and Dezerega, 2004] but may be much less sensitive in detection of milder cases. In a study of 104 children with holoprosencephaly, although prenatal ultrasound examination was performed in greater than 90%, a prenatal diagnosis was made in only 22% [Stashinko et al., 2004]. Prenatal MRI can better characterize cerebral malformations, but its role in diagnosing holoprosencephaly has not yet been well studied.

MALFORMATIONS OF CORTICAL DEVELOPMENT Numerous malformations of the cerebral cortex and of elements of the cortex found in subcortical locations have been described and classified into three major groups based primarily on the major developmental process involved: those resulting from abnormalities of cell proliferation; those resulting from abnormalities of neuronal migration; and those resulting from abnormal cortical organization [Barkovich et al., 1996, 2001]. Causal data, especially genetic information, are used whenever possible, however. An understanding of the underlying embryology is essential to understanding the classification of these disorders.

Embryology The cerebral hemispheres are formed as diverticula of the embryonic forebrain, at first comprised of a single layer of pseudostratified columnar epithelium with frequent cell division. This layer remains adjacent to the ependyma as the ventricular zone, which is the primary germinal zone. Neuroblasts in the ventricular zone have highly mobile nuclei that move up and down within the cytoplasm of the cell, undergoing division when the nuclei were located near the ventricular surface. The second layer or marginal zone forms superficial to the ventricular zone by the fifth gestational week, initially as a cell-sparse zone comprised of cytoplasmic processes of cells in the ventricular zone. Rapidly proliferating precursor cells in the ventricular zone generate many postmitotic but immature neurons, which migrate outward from the ventricular zone by climbing up a scaffold formed by special cells known as radial glia that have processes extending all the way from the ventricular zone to the cortical surface (pial membrane). Neurons leave the ventricular zone in two major waves [Sidman and Rakic, 1982]. The first and smaller wave begins generating neurons in the 6th week that move outward into the marginal zone to form the preplate in the 7th week, and diminishes by the 10th week. After the preplate has formed, the neurons that follow them migrate into the middle of the preplate to form the early cortical plate, first visible at about 52 days, splitting the preplate into an upper marginal zone that contains the early-differentiating Cajal-Retzius cells and a lower zone that contains subplate neurons [O’Rahilly and Muller, 1994]. The Cajal-Retzius cells express reelin and other proteins that regulate neuronal migration, cortical lamination, and subsequent cortical organization [D’Arcangelo et al., 1995; Sarnat and Flores-Sarnat, 2002]. The upper part of the original marginal zone persists to form layer 1 of the mature cortex. The subplate neurons participate in forming synaptic connections in thalamocortical systems and corticocortical connections. They also express numerous regulatory protein receptors, neurotransmitter receptors such as GABA, and receptors for different types of growth factors before disappearing late in gestation [Del Rio et al., 2000; Sarnat and Flores-Sarnat, 2002]. Formation of the preplate and early cortical plate leaves a relatively cellsparse region between the preplate and marginal zone that is known as the intermediate zone. A second and larger wave begins generating neurons in the 10th week, which begin to move outward during the 11th week. It peaks during weeks 12 to 14 and gradually trails off over several weeks [Norman et al., 1995; Sidman and Rakic, 1982]. These cells form the major portion of layers 2 to 6 of the mature cortex. A secondary germinal zone known as the subventricular zone forms as the final layer of the developing cortex between the ventricular zone and the intermediate zone and contains proliferating cells including glioblasts that divide without the to-and-fro movement characteristic of neuroblasts in the ventricular zone [Norman et al., 1995]. Classic studies have demonstrated that the cerebral cortex is formed by an “inside-out” migration of ventricular zone cells, so that neurons that are generated early during cortical development and migrate to the cortical plate first will occupy deeper layers, while later generated and migrating neurons pass the earlier cells to progressively more superficial positions.

Gleeson, Dobyns, Plawner, and Ashwal / Congenital Structural Defects

On a cellular basis, the cerebral cortex is formed by a complex series of developmental steps that involve neuronogenesis and gliogenesis, cellular differentiation and migration, and development of complex interconnectivity. Until recently, the available data suggested that all cortical neurons were generated in the ventricular zone of the neocortex and climbed up the radial glia to the cortical plate. Recent data, however, have overturned several former theories. First, radial glial cells are now known to be primitive multipotential cells that function as neuroblasts in the ventricular zone, as well as forming the radial glia scaffold. Second, many neuroblasts divide to generate neurons away from the ventricular wall. Finally, the cortex is formed by significant contributions from both the dorsal neocortex and the ventral ganglionic eminence. These and other discoveries have led to a sea change in our understanding of this complex process. Despite its remarkable complexity, the cortex is composed of two primary populations of neurons [Marin and Rubenstein, 2001]. The first population consists of radially migrating neurons that originate in the ventricular zone or subventricular zone of the dorsal telencephalon and give rise to glutamatergic pyramidal neurons that constitute the major projection neurons of the nervous system. These cells are produced from two distinct types of progenitor cells. The first are radial glial cells, which have recently been recognized to have a second function as neuronal and glial progenitors [Heins et al., 2002; Malatesta et al., 2000; Miyata et al., 2001; Noctor et al., 2001]. The second are neuronal progenitor cells that divide away from the ventricular surface, and were thus designated intermediate progenitor cells, also known as non–surface-dividing cells or basal progenitors. This process is carefully regulated by expression of serial regulatory proteins. For example, recent studies have found that the radial glia and other ventricular zone neuroblasts express the paired class transcription factor Pax6, whereas intermediate progenitor cells express the T domain transcription factor Tbr2, and immature post-mitotic neurons the related Tbr1 gene, especially neurons of the preplate and early-generated neurons that reside in cortical layer 6 [Englund et al., 2005; Hevner et al., 2001]. Some of the intermediate progenitor cells in the subventricular zone may be interneurons, although the origin of these cells remains uncertain as they may belong to a second population of cells derived from the ventral telencephalon and are simply “passing through” the subventricular zone [Marin and Rubenstein, 2001]. This second population consists of neurons that originate in the ventricular zone of the ventral telencephalon, especially the medial ganglionic eminence, and migrate along nonradial pathways to the cortex (Fig. 19-26). These progenitors primarily give rise to inhibitory interneurons that express the neurotransmitter γ-aminobutyric acid (GABA) [Anderson et al., 1997, 2001; Lavdas et al., 1999; Letinic et al., 2002; Wichterle et al., 2001]. The latter constitute 20% to 30% of cortical neurons, and serve a vital role in modulating cortical output [Cherubini and Conti, 2001; Krimer and Goldman-Rakic, 2001]. They also regulate neuronal proliferation and migration later in corticogenesis [Owens and Kriegstein, 2002], and are important for the postnatal development of cortical circuits [Fagiolini and Hensch, 2000; Huang et al., 1999]. Several distinct subtypes of interneurons have been identified that differ by axonal and dendritic morphology [Lund and Lewis, 1993], chem-

399

CTX CTX Glu

HIP

HIP LGE MGE

STR

AEP POa

GP

GABA

ACh

BMC

FIGURE 19-26. Representation of a coronal section of the brain from an embryonic day 14 mouse (equivalent to a week 15 human embryo). Right half, The major subdivisions of the telencephalic proliferative zones, with the probable regions of origin of neurons expresssing specific neurotransmitters, including glutamate, GABA, and acetylcholine. Left half, The migration pathways followed by neurons from the various proliferative zones, with straight arrows representing radial migration in all three major zones and curved arrows representing nonradial or tangential migration. Most projection neurons follow radial migration, whereas most interneurons follow nonradial pathways. Ach, acetylcholine; AEP, anterior entopeduncular area; BMC, basal magnocellular complex; CTX, cortex; GABA, γ-aminobutyric acid; Glu, glutamate; GP, globus pallidus; HIP, hippocampus; LGE, lateral ganglionic eminence; MGE, medial ganglionic eminence; POa, anterior preoptic area; STR, striatum. See also Color Plate. (Modified from Wilson SW, Rubenstein JLR. Induction and dorsoventral patterning of the telencephalon. Neuron 2000;28:641-651. Reprinted with permission from Elsevier.)

ical markers [DeFelipe et al., 1993; Gonchar and Burkhalter, 1997], connectivity, and physiology [Cauli et al., 1997; Kawaguchi and Kubota, 1996]. The major subtypes of GABAergic interneurons identified by chemical markers include calbindin, calretinin, parvalbumin, somatostatin, neuropeptide Y, and nitric oxide synthase. By approximately 22 weeks, distinctive layers first appear in the cortex. Further maturation consists of additional synaptogenesis, retraction of early axonal collaterals that did not establish appropriate connections, neurotransmitter biosynthesis, and other processes. Most of these processes continue well beyond the perinatal period. The marginal zone of the fetal cortex matures to become layer 1, or the molecular layer of mature cortex. The pioneer Cajal-Retzius neurons disappear, leaving a zone of nerve fibers, dendrites, and synapses with only a few cells. The subplate is incorporated into the deep layers of the cerebral cortex. By 27 weeks of gestation, all six layers of the mature cortex are visible [Sarnat, 1992]. The positional pattern of neurons in the cortical plate is columnar or vertical, related to the radial (centrifugal) migration of the dominant cell types. As their final positions are reached, migrating neurons begin the process of differentiation into functional subtypes with the appearance of neuronal processes, the development of specific neuronal cell membrane properties, and a designation toward a specific type of cell-to-cell transmission. As part of this process, further morphologic differentiation occurs, as

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Perinatal Acquired and Congenital Neurologic Disorders / 19

does the process of more complex cell molecular and physiologic differentiation and the development of more complex synaptic interconnections [Cowan, 1992]. Throughout much of this period, glial cells are dividing and differentiating as well. At least three major types of glial cells are known, including oligodendrocytes, type 1 astrocytes, and type 2 astrocytes. The interactions among these cell types are complex but important in their later role in neuronal migration.

Epidemiology Although individually uncommon or rare, malformations of cortical development including disorders of proliferation, migration, and later cortical organization are collectively relatively common. When macrocephaly and microcephaly are defined as head size above or below 2 standard deviations (SD) from the mean, then by definition approximately 2.5% of the population must have abnormally small or large head size. No data are available, however, regarding the frequency of severe macrocephaly or microcephaly, defined as 3 SD above or below the mean. Data from metropolitan Atlanta from 1994 through 1999 show rates of 0.77 per 1000 for microcephaly as identified in medical discharge diagnoses in the first 6 years of life (personal communication with Birth Defects and Genetic Diseases Branch Personnel, Metropolitan Atlanta Congenital Defects Program, Centers for Disease Control and Prevention, Atlanta, 2002). Similarly, disorders of migration or later cortical organization appear to be common, because 15% of adults and 25% of children referred to epilepsy centers for intractable partialonset seizures have focal cortical dysplasia [Kuzniecky et al., 1991, 1995]. More severe cortical malformations are less common, but current estimates likely are too low, because most data predate MRI. A case ascertainment study of lissencephaly in The Netherlands reported a prevalence of 11.7 per 1 million births [de Rijk-van Andel et al., 1991]. Data from metropolitan Atlanta from 1994 through 1999 show rates of 0.04 per 1000 for lissencephaly and 0.01 per 1000 for polymicrogyria using data from the CDC as cited.

Malformations of Neuronal and Glial Proliferation Many different malformations associated with abnormal neuronal and glial proliferation have been described and can be classified into major groups: those with increased proliferation (or reduced apoptosis) of normal cell types, those with decreased proliferation (or increased apoptosis) of normal cell types, and those with abnormal, dysplastic cell types. Although progress has lagged behind other types of malformations, knowledge regarding this heterogeneous group has advanced with several megalencephaly syndromes described, the first genes causing severe microcephaly identified, and more variants with abnormal cell types delineated.

Congenital Microcephaly with Normal Cell Types Microcephaly usually is defined as occipitofrontal circumference more than 2 SD below the mean for the patient’s age and gender [Opitz and Holt, 1990], which is below the second percentile. Although not often used, the term microencephaly refers to an underweight brain that is similarly more than 2 SD below the mean. When congenital microcephaly is the only abnormality found, the disorder has been

designated primary microcephaly, or microcephalia vera [Opitz and Holt, 1990; Tolmie et al., 1987]. This definition, however, is not helpful, because it includes up to 2% of children, some of whom have normal intelligence. Several groups now define primary microcephaly to include children with birth occipitofrontal circumference below −3 SD [Barkovich et al., 1998; Dobyns et al., 1996a; Ross and Frias, 1977] or even below −4 SD [Jackson et al., 1998, 2002], again with no other abnormalities. Here we designate microcephaly with occipitofrontal circumference between −2 and −3 SD as borderline or mild microcephaly, and microcephaly with occipitofrontal circumference below −3 SD as severe microcephaly or primary microcephaly when no other anomalies are found. PATHOGENESIS

The causes of microcephaly are remarkably heterogeneous, and include developmental and destructive causes that may begin before or after birth. Developmental disorders are the primary concern, especially congenital disorders defined as present at the time of birth with birth occipitofrontal circumference at or below −3 SD. During pregnancy, maternal, fetal, and environmental factors may cause microcephaly. Most are sporadic, with no clear underlying cause found [Cohen et al., 1996]. Microcephaly also occurs with many other brain malformations, such as holoprosencephaly, lissencephaly, and polymicrogyria. They are considered in this section only if the birth occipitofrontal circumference is less than −3 SD, and otherwise are included in the discussion of the associated malformation. The vast majority of primary microcephaly and syndromic microcephaly with birth occipitofrontal circumference below −3 SD are genetic and presumably caused by reduced cellular proliferation or by excessive programmed cell death. Although most attention has been given to reduced proliferation, the concept of excessive apoptosis is supported by observation of rare types in which the brain is disproportionately small compared to skull size, as shown below. CLINICAL CHARACTERISTICS

The clinical manifestations associated with microcephaly are remarkably heterogeneous. In general, below-average intelligence is associated with the presence of microcephaly [Dolk, 1991; Nelson and Deutschberger, 1970]. However, mild microcephaly with occipitofrontal circumference between −2 and −3 SD is not inevitably linked with mental retardation; 7.5% of a large group of microcephalic children had normal intelligence [Martin, 1970; Sells, 1977]. However, some patients with mild microcephaly have severe or profound mental retardation. This mental retardation may be partly explained by associated brain abnormalities, whether developmental or destructive, as brain imaging frequently reveals additional abnormalities [Sugimoto et al., 1993] but also reflects the causal heterogeneity. Children with severe congenital microcephaly with birth occipitofrontal circumference less than −3 SD fall into several groups: those with microcephaly only, those with microcephaly and other malformations, and those with microcephaly and proportionate growth deficiency. The first group of patients has severe microcephaly that is disproportionately small compared with body size, which may also be mildly small, but no other congenital anomalies. This is the most common group, classified as primary microcephaly. The second group has similar

Gleeson, Dobyns, Plawner, and Ashwal / Congenital Structural Defects

disproportionate microcephaly but with associated birth defects of the brain or other parts of the body. The final group has severe microcephaly associated with proportionate growth deficiency and often other abnormalities especially involving the skeleton. Examination reveals obvious microcephaly, often with a low, sloping forehead and flat occiput. The face and ears may be of disproportionate normal size. Mental retardation is moderate in some types but severe to profound in others. In moderately affected patients, hyperactivity may dominate the patient’s behavior while tone is typically normal. In severely affected children, spasticity and epilepsy predominate. CLASSIFICATION

Mild Microcephaly Mild microcephaly has been associated with a variety of maternal and other prenatal disorders, prenatal and postnatal

brain injuries, familial forms, chromosome disorders, and numerous syndromes with either prenatal or postnatal-onset microcephaly. A selection of the more common causes is reviewed. The developing nervous system is highly vulnerable to infections, including toxoplasmosis, rubella, cytomegalovirus, herpes simplex, and group B coxsackievirus. Intrauterine infections with these can result in microcephaly [Evrard, 1992; Norman et al., 1995; Volpe, 2000]. Microcephaly also has been reported in infants of women exposed to ionizing radiation from the atomic bomb or radium implantation in the cervix during the first trimester [Dekaban, 1968; Wood et al., 1967]. Maternal metabolic disorders during pregnancy, such as diabetes mellitus, uremia, and undiagnosed or inadequately treated phenylketonuria may result in neonatal microcephaly [Levy et al., 1996; Rouse et al., 1997]. Malnutrition, hyper-

Box 19-4 COMMON CAUSES FOR MICROCEPHALY Infections Cytomegalovirus Herpes simplex Rubella Varicella Coxsackie B virus Acquired immunodeficiency syndrome Toxoplasmosis Syphilis Postmeningitis Drugs Alcohol Tobacco Marijuana Cocaine Heroin Anticancer Antiepileptic Prescription drugs Toluene Anoxia/Ischemia Generalized cerebral anoxia Post-status epilepticus Porencephaly/hydranencephaly Carbon monoxide poisoning Placental insufficiency Hereditary Normal variation in OFC, asymptomatic Mendelian pattern, symptomatic: autosomal-dominant, autosomal-recessive, or X-linked Craniosynostosis Heredofamilial degenerative diseases Pelizaeus-Merzbacher disease Neuronal ceroid lipofuscinosis (Batten’s disease) Aminoacidurias/organic acidurias Miscellaneous syndromes, frequently with dwarfism (achondroplastic type excluded) OFC, occipitofrontal circumference.

401

Smith-Lemli-Opitz syndrome Cornelia de Lange’s syndrome Rubinstein-Taybi syndrome Dubowitz’s syndrome Proportionate short stature syndromes Nijmegen’s immunodeficiency syndrome Chromosomal Abnormalities Down syndrome and other trisomies Ring chromosomes Deletions Sex chromosome aneuploidy Malformations Primary microcephaly (microcephalia vera) Atelencephaly (aprosencephaly) Holoprosencephaly Lissencephaly Polymicrogyria Encephalocele Trauma Birth trauma Battered child Perinatal Metabolic/Endocrine Imbalances Hypoglycemia Hypothyroidism Hypopituitarism Hypoadrenocorticism Other Factors Malnutrition Prenatal Maternal Illness or Pregnancy Factors Systemic illness Anemia Malnutrition Toxic exposures Small for gestational age/extreme prematurity

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Perinatal Acquired and Congenital Neurologic Disorders / 19

tension, and placental insufficiency may all result in intrauterine growth retardation and microcephaly. Maternal alcoholism during pregnancy has also been linked with microcephaly as part of the fetal alcohol syndrome [Clarren et al., 1978; Loebstein and Koren, 1997; Ouellette et al., 1977; Spohr et al., 1993]. The clinical features include growth and mental retardation, midfacial hypoplasia, short palpebral fissures, epicanthal folds, and behavioral disturbances. Neuropathologic findings include microcephaly, heterotopia, widespread cortical and white matter dysplasias, and defects of neuronal and glial migration [Wisniewski et al., 1983]. Microcephaly has also been reported with maternal exposure to cocaine [Loebstein and Koren, 1997]; some other reports are largely anecdotal, so the associations are often not proven. Familial (mild) microcephaly may have either complex (polygenic) or autosomal dominant inheritance. The autosomal recessive forms typically present with severe, primary microcephaly. Most reviews have not clearly separated patients with mild and severe microcephaly, making the clinical data difficult to interpret. The polygenic or autosomal dominant forms generally are associated with mild-to-moderate cognitive problems, however, and epilepsy is uncommon. The risk of recurrence in siblings may be as high as 50% with the assumption of autosomal-dominant inheritance but is probably lower considering that polygenic inheritance may be involved. No studies have been reported separating this group from those with severe microcephaly. Many chromosome disorders including the common trisomies (trisomies 13, 18, and 21) and many structural rearrangements such as the cri du chat syndrome (deletion 5p15) are associated with microcephaly (see Chapters 21 and 22). A search of Online Mendelian Inheritance in Man lists more than 400 syndromes with microcephaly, so that it is not a very useful search term. Some of the better known among these include Angelmann’s, Cornelia de Lange’s (Brachmann–de Lange), and Dubowitz’s syndromes [Opitz and Holt, 1990]. With potentially hundreds of causes of microcephaly, including prenatal and postnatal onset, as well as genetic and acquired etiologies, diagnostic evaluations may be complex (Box 19-4; see Box 19-7). Investigation of patients with microcephaly includes evaluation for prenatal exposure to teratogens, especially alcohol, drugs, and isotretinoin (a vitamin A analog), and assessment of the family history, birth history, and associated malformations. Laboratory studies should include titers for toxoplasmosis, syphilis, rubella virus, cytomegalovirus, and herpes simplex viruses; neuroimaging [Sugimoto et al., 1993]; evaluation for maternal and childhood metabolic disorders; and genetic testing, including chromosome analysis and testing for small deletions or duplications, which currently is performed by fluorescence in situ hybridization with subtelomeric probes [Knight et al., 2000]. Severe Microcephaly Patients with primary microcephaly tend to fall into two further, albeit somewhat heterogeneous, subgroups [Dobyns, 2002]. The first are children with severe microcephaly but only moderate neurologic problems, usually with moderate mental retardation and with no spasticity or epilepsy. The second subgroup consists of severe microcephaly with a

much more severe neurologic phenotype that consists of abnormal neonatal reflexes, generalized spasticity, and epilepsy [Barkovich et al., 1998; Dobyns, 2002; Sztriha et al., 1999; ten Donkelaar et al., 1999]. These children have poor feeding and recurrent vomiting leading to poor weight gain, profound mental retardation, and severe spastic quadriparesis. Most of them also have early onset intractable epilepsy. In most patients with primary microcephaly, brain imaging reveals characteristic abnormalities designated “microcephaly with simplified gyral pattern” [Barkovich et al., 1998; Dobyns and Barkovich, 1999]. This pattern consists of a reduced number of gyri separated by abnormally shallow sulci. Common associated abnormalities include foreshortened frontal lobes, mildly enlarged lateral ventricles, and sometimes a thin corpus callosum or even partial agenesis of the corpus callosum. On brain imaging studies, the brain image is typically expanded to “fill the box”; this practice obscures the small size of the brain. Brain imaging may in fact be normal in children with mild microcephaly or microcephaly at or just below −3 SD, so some care is needed in interpretation. In patients with severe microcephaly and relatively high function (moderate mental retardation), no other abnormalities are seen. In patients with very low function (severe mental retardation), brain imaging may look the same. However, additional abnormalities are common, including noticeably enlarged extraaxial spaces (despite the microcephaly), delayed myelination, or severe hypoplasia of the brainstem and cerebellum. A few patients also have co-existing malformations of neuronal migration or cortical organization including lissencephaly (then designated as microlissencephaly), periventricular nodular heterotopia, or polymicrogyria. The wide clinical spectrum suggests pathogenetically heterogeneous conditions, and several syndromes and genes have been identified (Tables 19-14 and 19-15).

TABLE 19-14 Genes Associated with Malformations of Neuronal and Glial Proliferation GENE

SYNDROME(S)

CLINICAL TESTING*

Syndromes with Severe Microcephaly (MIC) ASPM Primary MIC − MCPH1

Primary MIC with PCC

−

SLC25A19

Amish lethal MIC

−

ATR

Seckel’s syndrome

−

Syndromes with Abnormal Cell Types TSC1, TSC2 Tuberous sclerosis

+

REFERENCES

Bond et al., 2002, 2003 Jackson et al., 2002; Trimborn et al., 2004 Kelley et al., 2002; Rosenberg et al., 2002 Alderton et al., 2004; O’Driscoll et al., 2003 Dabora et al., 2001; Langkau et al., 2002; Niida et al., 1999

*Plus sign indicates that such testing is available; minus sign indicates that testing is unavailable. PCC, premature chromosome condensation.

Gleeson, Dobyns, Plawner, and Ashwal / Congenital Structural Defects

403

TABLE 19-15 Established and Suspected Megalocephalic and Microcephalic Syndrome Subtypes PHENOTYPE

INHERITANCE (Causative Genes)

Syndromes with Severe Microcephaly and Relatively Normal Stature Primary microcephaly with moderate AR (ASPM, MCPH1) phenotype Primary microcephaly with severe phenotype Amish lethal microcephaly

AR AR (SLC25A19)

Syndromes with Severe Microcephaly and Additional Malformations Microcephaly with periventricular AR (ARFGEF2) nodular heterotopia Microlissencephaly (group A) Sporadic* Barth’s microlissencephaly syndrome (group B) Microcephaly with diffuse polymicrogyria

AR

Bond et al., 2002, 2003; Jackson et al., 1998, 2002; Jamieson et al., 1999, 2000; Moynihan et al., 2000; Pattison et al., 2000; Roberts et al., 1999, 2002 Barkovich et al., 1998; Dobyns, 2002; Sztriha et al., 1999; ten Donkelaar et al., 1999 Kelley et al., 2002; Rosenberg et al., 2002 Sheen et al., 2003a, 2004 Dobyns and Barkovich, 1999; Dobyns et al., 1984; Norman et al., 1976 Barth et al., 1982; Dobyns and Barkovich, 1999; Kroon et al., 1996 Dobyns and Barkovich, 1999

Syndromes with Severe Microcephaly and Proportionate Short Stature Microcephalic osteodysplastic AR primordial dwarfism Seckel’s syndrome AR (ATR) Syndromes with Megalencephaly Megalencephaly, isolated Macrocephaly-CMTC syndrome Megalencephaly with mega–corpus callosum Megalencephaly-polymicrogyriapolydactyly-hydrocephalus

REFERENCE(S)

Sporadic* Sporadic* Sporadic*

Corsello and Giuffre, 1998; Hall et al., 2004; Majewski et al., 1982; Meinecke and Passarge, 1991 O’Driscoll et al., 2003 DeMyer, 1999 Giuliano et al., 2004; Moore et al., 1997 Gohlich-Ratmann et al., 1998 Unpublished data

Syndromes with Abnormal Neuronal and Glial Proliferation (Abnormal Cell Types) HMEG Sporadic* (mosaic?) Linear nevus sebaceus syndrome with HMEG Hypomelanosis of Ito with HMEG Klippel-Trenaunay syndrome with HMEG Neuromelanosis with HMEG Proteus syndrome with HMEG Tuberous sclerosis

Sporadic* (mosaic?) Sporadic* (mosaic?) Sporadic* (mosaic?) Sporadic* (mosaic?) Sporadic* (mosaic?) AD (TSC1, TSC2)

Focal cortical dysplasia with balloon cells Focal transmantle dysplasia

Sporadic* (mosaic?) Sporadic* (mosaic?)

Adamsbaum et al., 1998; Flores-Sarnat, 2002, 2003; Guerrini et al., 2003; Vigevano et al., 1989 Dodge and Dobyns, 1995; Pavone et al., 1991 Ross et al., 1982 Torregrosa et al., 2000 Wieselthaler et al., 2002 Ahmetoglu et al., 2003 Dabora et al., 2001; Jones et al., 1999; Langkau et al., 2002; Niida et al., 1999 Becker et al., 2002; Taylor et al., 1971; Wyllie et al., 1994 Barkovich et al., 1997

*Only isolated patients have been observed, so the pattern of inheritance is unknown. AD, autosomal-dominant; AR, autosomal-recessive; CMTC, cutis marmorata telangiectasia congenita; HMEG, hemimegalencephaly.

In clinical practice, misidentification of these patterns is common. The “simplified” gyral pattern often is misrecognized as “normal,” but of course it is not normal. In more severely affected children, the brain imaging pattern often is misinterpreted as “lissencephaly” because of the reduced number of gyri. This is especially likely when the image is expanded to “fill the box,” which makes individual gyri look larger than they really are (Fig. 19-27). The cortex is thin, however, and not thick as in true lissencephaly.

Primary Microcephaly When congenital microcephaly is the only abnormality on evaluation, the disorder has been designated primary microcephaly. As discussed previously, this designation becomes much more useful when restricted to children with birth occipitofrontal circumference below −3 SD. Most patients with primary microcephaly also have mild growth defi-

ciency with stature typically −2 to −3 SD, which may be part of the syndrome or partly nutritional. This deficiency is much less striking than their head size, which is typically −4 to −8 SD after early childhood. Most affected persons fall into one of two groups [Dobyns, 2002]. The first group is composed of children with extreme microcephaly but only moderate neurologic problems, usually with only moderate mental retardation without spasticity or epilepsy [Barkovich et al., 1998; Peiffer et al., 1999; Tolmie et al., 1987]. Their neonatal examinations are usually normal except for microcephaly, but many children have poor feeding and weight gain at first. They may have normal tone or mild distal spasticity but do not have moderate or severe spasticity. Seizures are uncommon in this group and are easily controlled when they occur. Febrile seizures occur and should be managed as in any other child. Their early development is delayed but only mildly, and many go on to walk between 1 and 2 years of age and develop limited

404

Perinatal Acquired and Congenital Neurologic Disorders / 19 FIGURE 19-27. Subtypes of serve congenital microcephaly. Midsagittal (left column), parasagittal (middle column), and axial (right column) magnetic resonance images in four patients with severe congenital microcephaly (MIC). A, The top row images are from a patient with primary MIC and a severely simplified gyral pattern that resembles agyria. Thickness of the cortex is normal, however, so this is primary MIC and not any form of lissencephaly. B, The second row images are from another patient with primary MIC, with a less severe but still simplified gyral pattern. The number of gyri is reduced, and the sulci are shallow. C, The third row images are from a patient with a severe congenital MIC but with markedly enlarged extra-axial space that suggests a different process from typical primary MIC. The cerebellum is mildly small even in proportion to the cerebral hemispheres. D, The bottom row images depict similar MIC, but the cortex is moderately thick, indicating a form of microlissencephaly. (Images from patients LP97-111 [A], LR01-171 [B], LR01-099 [C], and LR00-166 [D].)

A

B

C

D

language skills. Several genes have been identified from studies of patients with this disorder (see Table 19-14). The second subgroup consists of primary microcephaly with a severe neurologic phenotype that includes severe spasticity and epilepsy [Barkovich et al., 1998; Dobyns, 2002; Sztriha et al., 1999; ten Donkelaar et al., 1999; Tolmie et al., 1987]. Neonatal examinations demonstrate abnormal neonatal reflexes and generalized spasticity, and these children go on to have poor feeding and recurrent vomiting leading to poor weight gain, severe developmental delay, later profound mental retardation, and severe spastic

quadriparesis. Most of them have early onset intractable epilepsy. In addition to a simplified gyral pattern, brain MRI may demonstrate other abnormalities as summarized above (see Fig. 19-27). Children with Amish lethal microcephaly have this phenotype, except that hypotonia predominates rather than spasticity, and seizures are not prominent [Kelley et al., 2002; Rosenberg et al., 2002]. The term radial microbrain was introduced by Evrard to describe the brain in some patients with severe mental retardation, profound microcephaly and early death, describing an abnormally small brain that has a normal gyral

Gleeson, Dobyns, Plawner, and Ashwal / Congenital Structural Defects

pattern, normal cortical thickness, and normal cortical lamination although the number of cortical neurons was only 30% of normal [Evrard et al., 1989; Evrard, 1992]. He hypothesized that a decreased number of radial neuronalglial units was responsible for the microcephaly. This group fits into the lower functioning group of patients with primary microcephaly, rather than comprising an independent syndrome. However, multiple causes with different pathologic changes and clinical courses are likely to emerge from this group.

Severe Microcephaly with Cortical Malformation Although still incompletely delineated, several syndromes with severe congenital microcephaly and additional severe brain malformations are known. The combination of severe microcephaly and true lissencephaly (with an abnormally thick cortex) has been reported with at least three different patterns [Barth et al., 1982; Dobyns and Barkovich, 1999; Sztriha et al., 1998]. The most common of these very rare syndromes is probably the Barth microlissencephaly syndrome, which consists of severe microcephaly, diffuse complete agyria, and severe brainstem and cerebellar hypoplasia [Barth et al., 1982; Kroon et al., 1996]. Severe microcephaly with diffuse periventricular nodular heterotopia has been described, and clearly differs from other forms of heterotopia [Robain and Lyon, 1972; Sheen et al., 2003a]. Some patients with severe microcephaly have also had diffuse polymicrogyria [Dobyns and Barkovich, 1999].

Severe Microcephaly with Proportionate Growth Deficiency Several syndromes with severe intrauterine and postnatal growth deficiency and proportionate microcephaly have been described, although the head size does not keep up with even slow body growth, leading to disproportionate microcephaly in childhood and later. The best known of these are Seckel’s syndrome, Majewski’s syndrome, microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1), also known as Taybi-Linder syndrome and microcephalic osteodysplastic primordial dwarfism type 2 (MOPD2). Several other syndromes with severe growth deficiency and microcephaly have been described in a few patients, however, so that this is likely to become a large and complex group of syndromes. In some, the skeletal changes may be absent or less prominent than in Seckel’s syndrome or the MOPD syndromes. Seckel’s syndrome consists of severe intrauterine and postnatal growth deficiency and microcephaly, and abnormal facial features including large eyes, beaklike protrusion of the nose, narrow face, and receding lower jaw [Majewski and Goecke, 1982; Seckel, 1960]. All have severe mental retardation, although the severity varies considerably and some live to adulthood. Abnormalities of the brain seen on postmortem examination or brain imaging demonstrate pure microcephaly with deficient production of neurons and other cell types in some patients [Hori et al., 1987], whereas others had severe brain malformations including lissencephaly [Capovilla et al., 2001; Shanske et al., 1997; Sugio et al., 1993]. Some patients have had various types of myelodysplasia such as pancytopenia or acute myeloid leukemia [Butler et al., 1987; Hayani et al., 1994]. MOPD1, or Taybi-Linder syndrome, consists of similar severe intrauterine and postnatal growth deficiency and microcephaly, combined with abnormal body proportions and

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short limbs. Typical skeletal changes consist of a low and broad pelvis with poor formation of the acetabulum, short and bowed humerus and femur, dislocated hips and elbows, retarded epiphyseal maturation, cleft vertebral arches, platyspondyly, horizontal acetabular roofs, and short long bones with enlarged metaphyses. They may have skin abnormalities including hyperkeratosis and sparsity of hair and eyebrows [Meinecke et al., 1991; Sigaudy et al., 1998; Taybi, 1992]. Brain malformations in addition to the severe microcephaly appear to be common, including lissencephaly, heterotopia, callosal agenesis, and cerebellar vermis hypoplasia [Klinge et al., 2002; Sigaudy et al., 1998]. MOPD2 consists of similar severe intrauterine and postnatal growth deficiency, proportionate microcephaly at birth that progresses to disproportionate microcephaly, shortening of the middle and distal segments of the limbs, a progressive bony dysplasia, and abnormal facial appearance including prominent nose and malformed ears, and a high squeaky voice [Hall et al., 2004; Majewski and Goecke, 1998; Majewski et al., 1982]. They may have dilated arteries in the brain that resemble aneurysms or moya-moya disease [Kannu et al., 2004; Young et al., 2004]. Although all have severe microcephaly, no other brain malformations have been described [Fukuzawa et al., 2002]. Although these syndromes dominate the literature concerning intrauterine and postnatal growth deficiency and microcephaly, review of many reports suggests overall substantial causal heterogeneity, with probable confusion among these and other syndromes in this group. In support of this, several novel syndromes have been reported [Kantaputra, 2002; Okajima et al., 2002]. GENETICS

At least five loci for primary microcephaly with mild or moderate phenotype have been mapped to 1q31, 8p22-pter, 9q34, 15q, and 19q13.1-q13.2, and two of these loci (MCPH1 and ASPM) have now been cloned. Two genes causing severe microcephaly with severe phenotype have also been identified, those being the causal genes for Amish lethal microcephaly and microcephaly with periventricular nodular heterotopia. In Seckel’s syndrome, defects in DNA repair were suggested by chromosome instability with exposure to mitomycin C [Abou-Zahr et al., 1999; BobabillaMorales et al., 2003]. Subsequently, at least three loci for Seckel’s syndrome have been confirmed, mapped to chromosomes 3q22.1-q24 and 18p11.31-q11.2, and at least one additional unknown locus [Faivre et al., 2002]. Mutations of the ATR gene in 3q2 were recently identified [Alderton et al., 2004; O’Driscoll et al., 2003]. All of these genes are listed in Table 19-15 with references. Of interest, the two genes associated with microcephaly and mildmoderate phenotype both reveal an evolutionary signature of rapid evolution [Evans et al., 2004a; Evans et al., 2004b]. ANTENATAL DIAGNOSIS

Microcephaly can often but not always be diagnosed by second trimester fetal ultrasonography [Bromley and Benacerraf, 1995]. This likely is due to variable onset of the deceleration in head growth. When this occurs early, as it often does for severe microcephaly, ultrasound examination should be able to detect the abnormality but not when it begins in the late second or third trimester.

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COUNSELING

Megalencephaly with Normal Cell Types

Some older references cite a 6% risk of a family’s having a second microcephalic child, but these sources do not consistently address severity of the microcephaly. This figure may be useful for mild and borderline microcephaly with birth occipitofrontal circumference between −2 and −3 SD below the mean. On the basis of findings in many families with two or more affected siblings with primary microcephaly and other forms of severe microcephaly with birth occipitofrontal circumference below −3 SD, counseling for autosomal-recessive inheritance is clearly appropriate in this group. A few X-linked forms of microcephaly exist but appear to be very rare [Shrimpton et al., 2000].

Megalencephaly is defined as “an oversized and overweight brain that exceeds the mean by more than two SD for the patient’s age and gender, or is above the 98th percentile” [DeMyer, 1986]. DeMyer classified megalencephaly into anatomic and metabolic types. Malformations in the anatomic group are characterized by an increase in the number of neurons and glia, an increase in cell size, or both that result in an overall increase in brain size. Increased cell number could result from either increased proliferation or decreased apoptosis or programmed cell death. This definition includes patients with and without associated brain malformations, but only those with normal cell types are

FIGURE 19-28. Subtypes of megalencephaly and hemimegalencephaly. Right parasagittal (left column except midsagittal in D), left parasagittal (middle column), and axial (right column) magnetic resonance images from four patients with megalencephaly (MEG) or hemimegalencephaly (HMEG) variants. A, The top row images depict symmetric MEG and perisylvian polymicrogyria with normal white matter. The patient was a female with the recently described “megalencephaly-polymicrogyriapolydactyly-hydrocephalus” (MPPH) syndrome [Mirzaa et al., 2004]. The symmetry and normal white matter distinguish this malformation from HMEG. B, The second row images show partial HMEG, with enlargement of the posterior frontal, temporal, and parietal lobes on the right. The abnormal white matter typical of HMEG is seen circling the back of the right lateral ventricle. C, The third row images demonstrate severe HMEG involving the entire right hemisphere, but sparing the left. The central and deep white matter has diffusely bright signal, sparing only the superficial U fibers. D, The bottom row images show a very rare malformation consisting of bilateral HMEG that is more severe on the left side. The patient survived only a few months. (Courtesy of Dr. William B. Dobyns, The University of Chicago, Department of Human Genetics, Chicago, Illinois. Images from patients LR02-064 [A], LR03-049 [B], LR03-049 [C], and LR03-049 [D].)

Gleeson, Dobyns, Plawner, and Ashwal / Congenital Structural Defects

considered. In some patients, the enlargement may involve only part of the brain, most often limited to one side. These will be considered in a later section, because these are associated with abnormal cell types. Metabolic megalencephaly designates brain enlargement from edema or the

accumulation of a metabolic product, abnormal in type or quantity, without an increase in number in cells. This is not a true cortical malformation and will not be considered further.

Box 19-5 MOST COMMON CAUSES FOR MACROCEPHALY Hydrocephalus Noncommunicating Arnold-Chiari malformation Aqueductal stenosis Dandy-Walker malformation Galenic vein aneurysm Neoplasms, supratentorial and infratentorial Arachnoid cyst, infratentorial Holoprosencephaly with dorsal interhemispheric sac Vein of Galen malformation Communicating External or extraventricular obstructive hydrocephalus (dilated subarachnoid space) Arachnoid cyst, supratentorial Meningeal fibrosis/obstruction Postinflammatory Posthemorrhagic Neoplastic infiltration Vascular Arteriovenous malformation Intracranial hemorrhage Dural sinus thrombosis Choroid plexus papilloma Neurocutaneous syndrome Incontinentia pigmenti Destructive lesions Hydranencephaly Porencephaly Familial, autosomal dominant, autosomal recessive, X-linked Megalencephaly Bilateral Anatomic without extraneural malformations Asymptomatic familial anatomic megalencephaly (neurologically normal person with excessive brain weight; autosomal dominant transmission) Symptomatic familial anatomic megalencephaly (neurologically abnormal person with excessive brain weight in whom the findings do not match those of another syndrome; autosomal-dominant or autosomalrecessive transmission) Metabolic Lysosomal diseases (noncatalysis) Tay-Sachs disease Generalized gangliosidosis Mucopolysaccharidoses With gigantism Beckwith-Wiedemann syndrome Soto’s syndrome (cerebral gigantism) Pituitary Weaver-Smith syndrome CMTC, cutis marmorata telangiectasia congenita.

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With skeletal dysplasia Achondroplastia Apert’s syndrome Thanatophoric dwarf With neurocutaneous syndrome Neurofibromatosis Nevoid basal cell carcinoma CMTC-macrocephaly syndrome Cowden’s syndrome (Bannayan-Riley-Ruvalcaba syndrome) With spongy degeneration Canavan’s disease Alexander’s disease Hemimegalencephaly (see Table 19-15) Subdural Fluid Hematoma Hygroma Empyema Brain Edema (Toxic-Metabolic) Intoxication Lead Vitamin A Tetracycline Endocrine Hypoparathyroidism Hypoadrenocorticism Galactosemia Spongy degeneration of the brain Idiopathic (pseudotumor cerebri) Thick Skull or Scalp Familial variation Anemia Myotonia dystrophica Cranioskeletal dysplasia Rickets Osteopetrosis Osteogenesis imperfecta Orodigitofacial dysostosis Craniometaphyseal dysplasia of Pyle Cleidocranial dysostosis Hyperphosphatasemia Epiphyseal dysplasia Russell’s dwarfism Pyknodysostosis Leontiasis ossea Progressive diaphyseal dysplasia Bannayan-Riley-Ruvalcaba and Proteus syndromes

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PATHOGENESIS

Several mouse models of megalencephaly have been described. The first is a novel megalencephaly mutant in which several insulin-like growth factor–binding proteins (IGFBPs) and transforming growth factor-β1 (TGF-β1) are upregulated, whereas IGFBP-5 is downregulated [Donahue et al., 1996; Petersson et al., 1999b]. In another, transgenic mice expressing a stabilized β-catenin in neural precursors develop enlarged brains with increased cerebral cortical surface area and folds resembling sulci and gyri of higher mammals [Chenn and Walsh, 2002, 2003]. Brains from these animals have enlarged lateral ventricles lined with neuroepithelial precursor cells that are derived from an expanded precursor population. Compared with the wild type of precursors, a greater proportion of transgenic precursors reenter the cell cycle after mitosis, which suggests that β-catenin regulates cerebral cortical size by controlling the generation of neural precursor cells. CLINICAL CHARACTERISTICS AND OUTCOME

Megalencephaly occurs as a mild familial variant with normal brain structure, designated anatomic megalencephaly. The clinical findings associated with anatomic megalencephaly have been variable [DeMyer, 1972], but with normal function or mild handicaps predominating. However, many patients have had severe mental retardation and other neurologic abnormalities; most of these reports predated wide availability of modern brain imaging modalities. At least two large series of patients have been studied. In one series of 557 children with large heads, 109 had “primary megalencephaly,” defined similarly to DeMyer’s anatomic megalencephaly. Of these, seven had mental retardation and nine had epilepsy, including two with very large heads. In a recent study of 732 boys with primary megalencephaly, the large brain size was found to be significantly associated with mental retardation with an estimated odds ratio in megalencephaly cases to controls of 1.31, with a 95% confidence interval of 0.80 to 2.02 [Petersson et al., 1999a]. Further, an association between the mother’s and child’s birth head circumference was also found, supporting multifactorial inheritance of megalencephaly with moderate heritability. This suggests that some types of anatomic megalencephaly may represent one end of a quantitative trait locus rather than a mendelian trait. In another series, 25 of 31 patients were mentally retarded. Partial autopsy data from this group demonstrated cortical malformations such as pachygyria and polymicrogyria in at least 10 of these patients [Dekaban and Priestly, 1977]. In another group of 74 children with megalencephaly, 37 had developmental delay, at least 7 were mentally retarded, and 8 had seizures [Laubscher et al., 1990]. The methods of ascertainment were different between these groups, but still demonstrate that many patients with megalencephaly and mental retardation have additional brain malformations, especially malformations of the cortex that contribute to the poor outcome, and likely are underrecognized (see Table 19-15) (Fig. 19-28).

Syndromes with Megalencephaly Large head size may be caused by increase in any of the major tissues of the head including the scalp, skull, subdural space, brain tissue, or ventricular system, with abnormalities

of the ventricular system, especially hydrocephalus, being the most common (Box 19-5). The brain may be large due to a developmental defect or from edema. Here we consider developmental disorders associated with enlarged brain, or megalencephaly. Anatomic megalencephaly has been found in many different disorders including overgrowth syndromes such as Sotos or Weaver-Smith syndromes [Amir et al., 1984; Schaefer et al., 1997; Winship, 1985], and hemangiomatosis-overgrowth syndromes such as Bannayan-RileyRuvalcaba, Cowden’s, and Proteus syndromes [Biesecker et al., 1999; Fargnoli et al., 1996; Hanssen et al., 1993; Okumura et al., 1986; Turner et al., 2004]. Anatomic megalencephaly also occurs in neurofibromatosis [Cutting et al., 2002], and in several skeletal dysplasias such as achondroplasia, arachnodysplasia and thanatophoric dysplasia [Ho et al., 1984]. While only a few specific megalencephaly syndromes have been delineated, these serve as examples of the types of disorders likely to explain the combination of megalencephaly and poor neurologic outcome. As one example, three children were reported with megalencephaly, greatly hypertrophied corpus callosum, and complete lack of motor development [Gohlich-Ratmann et al., 1998]. The three children reported with this syndrome had clinically progressive macrocephaly and severe mental retardation. Cranial MRI demonstrated bilateral and symmetric megalencephaly, and areas of thick gray matter consistent with polymicrogyria. Another probable example of this syndrome was described in a 34-week-gestation fetus [Rypens et al., 1996]. MRI in this child showed an irregular gyral pattern characteristic of polymicrogyria, open sylvian fissures, periventricular nodular heterotopia, and an abnormally thick corpus callosum. The syndrome may thus be designated the megalencephaly–mega-corpus callosum–polymicrogyria (MCCP) syndrome. A similar syndrome, recently described in five children, consists of diffuse megalencephaly that is symmetric or mildly asymmetric, diffuse polymicrogyria most severe in the perisylvian regions, postaxial polydactyly, and hydrocephalus typically treated with a shunt [Mirzaa et al., 2004]. The megalencephaly and polymicrogyria affected all five children; the polydactyly occurred in three, and hydrocephalus requiring a shunt was reported in four of five patients (recently in five of five patients). Clinical characteristics included severe mental retardation in all five, diffuse hypotonia in four, seizures in three, and an epileptiform electroencephalogram (EEG) in one other patient. The birth occipitofrontal circumference was between +2 and +4 SD, and the largest recorded occipitofrontal circumference, +2 to +5 SD. The corpus callosum was normal or mildly thin in four of the five, and never enlarged. All had persistent cavum septi pellucidi with or without cavum vergae. This syndrome was designated the megalencephaly-polymicrogyriapolydactyly-hydrocephalus syndrome. GENETICS AND COUNSELING

Anatomic megalencephaly, especially with normal or near normal function, appears to be a relatively common familial trait, probably with autosomal dominant inheritance. Criteria for anatomic asymptomatic megalencephaly are outlined in Box 19-6. In contrast, megalencephaly with mental retardation and especially megalencephaly with other brain

Gleeson, Dobyns, Plawner, and Ashwal / Congenital Structural Defects

Box 19-6 DIAGNOSTIC CRITERIA FOR ASYMPTOMATIC (BENIGN) FAMILIAL ANATOMIC MEGALENCEPHALY 1. OFC more than two standard deviations above the mean or above the 98th percentile 2. No clinical evidence of increased intracranial pressure in the form of bulging fontanel, palpably split sutures, or persistent vomiting 3. Normal findings on developmental and neurologic examination 4. Absence of any neurocutaneous signs and craniofacial or somatic anomalies that might identify a specific syndrome 5. One or more of the parents or siblings has a large OFC but is neurologically normal, or the increased OFC can be traced through several generations. 6. Follow-up visits establish the normality of the patient’s developmental course, and the OFC curve commences to level off, and although it remains high, it begins to parallel the normal curve. 7. Radiographic demonstration of normal or only slightly enlarged ventricles in one of the family members with an enlarged OFC, establishing that the condition is megalencephaly, not arrested hydrocephalus or some other lesion 8. Negative results of chemical screening tests for metabolic disorders or lysosomal enzyme deficits in those patients lacking some of the other criteria OFC, occipitofrontal circumference. Modified from DeMyer W. Megalencephaly: Types, clinical syndromes, and management. Pediatr Neurol 1986;2:321.

malformations have rarely been observed to recur in families. No genetic tests for megalencephaly are available. When one or both parents themselves have megalencephaly and normal or relatively normal function, the risk of transmitting this disorder to the child is very high, but the child is likely to do well. When neither parent has an enlarged head and findings on the child’s examination are abnormal or the MRI demonstrates associated malformations, the outcome is likely to be poor. The genetic recurrence risk appears to be very low based on limited knowledge.

Malformations of Neuronal and Glial Proliferation with Abnormal Cell Types Malformations in this group are characterized by the presence of abnormal neurons and often glia as well. The cell number may be increased, further supporting abnormal proliferation beginning early in development. All of these are focal or lateralized malformations, and some have abnormal cell types that have been classified as neoplastic, although the malignant potential is typically low. The most common of these is tuberous sclerosis, which is reviewed in Chapter 31. PATHOGENESIS

The most dramatic and severe of these disorders is hemimegalencephaly, in which most of all of the hemisphere is enlarged with dysplastic tissue involving both cortex and white matter. Hemimegalencephaly has been observed in several neurocutaneous syndromes, including linear sebaceous

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nevus syndrome (also known as the epidermal nevus syndrome), hypomelanosis of Ito, Klippel-Trenaunay syndrome, neuromelanosis, and Proteus syndrome (see Table 19-15). These skin disorders are thought to constitute a sign of tissue mosaicism [Happle, 1993, 2002]. By extension, the brain malformations are likely to represent areas of somatic mosaicism in the brain. CLINICAL CHARACTERISTICS

The clinical presentation in patients with any of these malformations almost always includes seizures, which start early in life for the more extensive malformations such as hemimegalencephaly and often later in childhood for more restricted malformations. Seizures are typically partial, with secondary generalization, and often prove intractable to medical therapy. Infantile spasms and drop attacks may present in early childhood with more extensive malformations. Unilateral neurologic signs, such as hemiparesis and hemianopia, may also occur. Minimal neurologic dysfunction with normal cognitive abilities is common in patients with less extensive malformations [Vigevano et al., 1989]. SYNDROMES

Hemimegalencephaly As the term suggests, hemimegalencephaly typically consists of enlargement of one hemisphere of the brain with associated gyral malformations, cortical thickening with lack of lamination, blurred boundaries of the gray and white matter, white matter abnormalities, and abnormal cell types including large heterotopic neurons [Bosman et al., 1996; Flores-Sarnat, 2002; Flores-Sarnat et al., 2003; Guerrini et al., 2003]. However, careful review of brain imaging studies or neuropathology demonstrates wide variation in the extent of the malformation, with some patients having no more than half of a hemisphere involved, the so-called posterior quadrantic dysplasia (or hemi-hemimegalencephaly) [D’Agostino et al., 2004]. It is usually an isolated brain malformation but has been seen in several neurocutaneous syndromes (see Table 19-15). The clinical presentation in patients with hemimegalencephaly almost always includes seizures, which usually start within the first 6 months of life, typically arising from the enlarged and dysplastic hemisphere [Vigevano et al., 1989]. The seizures are typically partial, with secondary generalization, and often intractable to medical therapy. Infantile spasms and drop attacks may present in early childhood. Unilateral neurologic signs, such as hemiparesis and hemianopia, are common. Minimal neurologic dysfunction with normal cognitive abilities has been reported in some patients, typically when less than a full hemisphere is involved. Brain imaging that demonstrates enlargement of at least one lobe and may range from mild to severe is present in all patients. In more than one half of patients, the entire hemisphere appears to be enlarged, but sometimes the enlargement is localized to the frontal or temporoparietal regions. In rare patients, the dysplasia involves a full hemisphere and extends across the midline to involve part of the other hemisphere. The gyri are thick and broad, with flattened gyri and shallow sulci. The underlying white matter is usually abnormal, with abnormal signal characteristics and or alteration in the volume of white matter (increased or decreased)

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in some individuals. Heterotopia are common, and the lateral ventricle system is typically enlarged. Electroencephalographic abnormalities are extensive throughout the abnormal hemisphere. Severe hemiparesis, smooth cortical surface on MRI, and abnormal activity on the EEG suggests a poor outcome. Both the epilepsy and the cognitive deficits may be improved in selected patients by timely hemispherectomy [Devlin et al., 2003; Maher et al., 2003]. Focal Cortical Dysplasia with Abnormal but Non-neoplastic Cells and Transmantle Dysplasia Focal cortical dysplasia with balloon cells has been observed in patients with tuberous sclerosis and in those with no other anomalies [Guerrini and Carrozzo, 2002]. The balloon cells likely are the result of proliferation of abnormal cells in the germinal zone, rather than of local effects on migrating cells within the intermediate zone. The appearance is very similar to the changes in tuberous sclerosis, and a genetic relationship is possible [Becker et al., 2002]. Focal transmantle dysplasia consists of a streak or column of abnormal cells extending from the ependyma to the pial surface, but the pathologic appearance is identical to that of focal cortical dysplasia with balloon cells [Barkovich et al., 1996]. Focal cortical dysplasia likely is the most common form of focal developmental disorder diagnosed in patients with intractable focal epilepsy. The characteristic pathologic abnormalities of these lesions consist of disruption of cortical lamination with poorly differentiated glial cell elements. Since its original description, focal cortical dysplasia has been recognized to encompass a spectrum of pathologic changes. These range from mild cortical disruption, without apparent giant neurons, to the most severe forms, in which cortical dyslamination, large bizarre cells, and astrocytosis are present. The presence of balloon cells differentiates focal cortical dysplasia type I without balloon cells and focal cortical dysplasia type II with balloon cells [Crino et al., 2002; Hardiman et al., 1988; Kuzniecky et al., 1991; Taylor et al., 1971]. Focal cortical dysplasia with abnormal cell types also has been subdivided into cytoarchitectural dysplasia, Taylor’s focal cortical dysplasia without balloon cells, and Taylor’s focal cortical dysplasia with balloon cells; these entities probably represent a spectrum of severity of pathologic changes [Colombo et al., 2003b; Tassi et al., 2002]. The clinical manifestations are variable [Colombo et al., 2003b; Kuzniecky et al., 1995; Wyllie et al., 1994]. Seizures usually begin in the first or, less often, second decade of life, usually after 2 to 3 years, but sometimes shortly after birth. With improvement in current ability to recognize subtle focal cortical dysplasia on brain MRI, these lesions are even occasionaly diagnosed in epilepsy of adult onset. The seizures may be partial simple motor, partial complex, or secondary generalized. The location of the lesion often dictates the clinical presentation [Kuzniecky et al., 1991, 1995]. Most patients have extratemporal cortical dysplasia, with the frontal lobes being the most common site. Involvement of precentral and postcentral gyri may lead to cortical motor and sensory abnormalities. MRI findings include abnormal gyral thickening with underlying T2-weighted white matter changes (see Fig. 19-28) that often are circumscribed. Interictal EEG may exhibit frequent spikes or even localized subclinical EEG seizures. Focal cortical dysplasia of the temporal lobe also has been reported with involvement of

mesial and lateral neocortical structures [Hardiman et al., 1988; Kuzniecky et al., 1991]. The seizures and clinical course in these patients are similar to those in paients who have temporal lobe epilepsy due to hippocampal sclerosis, except that the EEG abnormalities usually are less circumscribed. MRI shows cortical thickening of temporal convolutions associated with poor differentiation of the gray-white junction. The association of hippocampal sclerosis with dysplastic cortex in the temporal lobe (dual pathology) is well known. Cortical Dysplasias with Neoplastic Changes Several low-grade primarily neuronal neoplasms have been associated with cortical dysplasia, including dysembryoplastic neuroepithelial tumors, ganglioglioma, and gangliocytoma. Controversy continues over the proper classification of these tumors. Their frequency in epilepsy surgical series is approximately 5% to 8%, and they occur most often in children or young adults. The tumors are most often located in the temporal lobes, where residual heterotopic neurons in the white matter are also common [Emery et al., 1997; Rojiani et al., 1996], but tumors can also be seen elsewhere. Patients usually present with partial seizures that are difficult to control with antiepileptic drugs. Surgical treatment is highly effective in most cases if the lesion is completely resected. GENETICS AND COUNSELING

All patients with hemimegalencephaly, transmantle dysplasia, or any form of focal cortical dysplasia with abnormal cell types, should be examined for possible signs of tuberous sclerosis. If any are found, a full diagnostic evaluation for tuberous sclerosis is indicated. The inheritance of tuberous sclerosis is autosomal dominant. When this disorder has been excluded, no familial recurrence of any of the other disorders has been reported.

Malformations of Neuronal Migration Many different malformations of the developing cerebral cortex have been described, often labeled as “disorders of neuronal migration.” Several of these appear to contain all neuronal types, however, and thus likely postdate neuronal migration. Therefore, it is appropriate to differentiate between true “malformations of neuronal migration” and later “malformations of cortical organization” such as polymicrogyria, schizencephaly, and focal cortical dysplasia. The three major categories of malformations with truly deficient neuronal migration are lissencephaly (including agyria, pachygyria, and subcortical band heterotopia), cobblestone complex malformations, and all types of heterotopia.

Lissencephaly and Subcortical Band Heterotopias Lissencephaly typically is a diffuse brain malformation manifested by a smooth cerebral surface, abnormally thick cortex with four abnormal layers that includes a deep zone of diffuse neuronal heterotopia and enlarged, dysplastic ventricles [Barkovich et al., 1991; Dobyns and Truwit, 1995; Norman et al., 1995]. It encompasses the pathologic terms agyria (absent gyri) and pachygyria (broad gyri) and merges with a lesser form known as subcortical band heterotopia. This latter condition consists of symmetric and circum-

Gleeson, Dobyns, Plawner, and Ashwal / Congenital Structural Defects

ferential bands of gray matter located just beneath the cortex and separated from it by a thin band of white matter. The inner margin of the band usually is smooth, whereas the outer margin may be smooth or follow interdigitations of the true cortex and white matter. This appearance led to the alternative although incorrect term “double cortex” for this malformation. The overlying cortex appears normal or mildly simplified as a result of abnormally shallow sulci [Barkovich, 2000; Barkovich et al., 1994; Dobyns et al., 1996a]. Several different types of lissencephaly have been described. In the most common or “classic” form (formerly designated “type 1”), the lissencephaly consists of a thick (12 to 20 mm) cortex composed of four layers: a marginal

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layer, a superficial cellular layer that corresponds to the cortical plate, a cell-sparse zone, and a deep cellular layer composed of heterotopic neurons. Less common pathologic forms of lissencephaly with three or two layers also have been described, as discussed later. In the classic four-layered forms, lissencephaly and subcortical band heterotopia comprise a single malformation spectrum based on observations of rare patients with areas of lissencephaly that merge into subcortical band heterotopia and of multiple families with X-linked lissencephaly in males and subcortical band heterotopia in females [des Portes et al., 1997; Dobyns et al., 1996a; Matell, 1893; Pilz et al., 1999; Ross et al., 1997]. Of importance, subcortical band heterotopia

FIGURE 19-29. Subtypes of lissencephaly (LIS) with ARX or DCX mutations. Midsagittal (left column), parasagittal (middle column), and axial (right column) magnetic resonance images from patients with four different forms of (LIS). A, ARX mutation. The top row images demonstrate diffuse pachgyria (grade 4 LIS), more severe posteriorly, only moderately thick (approximately 7 to 10 mm) cortex, diffuse abnormal signal of white matter, total agenesis of the corpus callosum, and normal cerebellum. The patient was a male with typical X-linked lissencephaly with abnormal genitalia (XLAG) and a truncation of ARX in exon 4: c.1187_1188insC and G397fs [Kato et al., 2004]. B, DCX (severe) mutation. The second row images depict severe, grade 1 LIS with diffuse agyria and no apparent gradient, very thick (15 to 20 mm) cortex, mildly enlarged lateral ventricles, intact corpus callosum that appears mildly flattened frontally, and normal brainstem and cerebellum. The patient was a male with isolated lissencephaly sequence (ILS) and a deletion of all coding exons of DCX. C, DCX (mild) mutation. The third row images show diffuse pachgyria (grade 4 LIS) more severe frontally, thick (15 to 20 mm) cortex, mildly enlarged lateral ventricles, and normal corpus callosum, brainstem, and cerebellum. The patient was a male with ILS and a missense mutation of DCX in exon 5: 587G>A and R196H [Demelas et al., 2001]. D, DCX (band) mutation. The bottom row images demonstrate diffuse, thick, subcortical band heterotopia with no apparent gradient. The patient was a female with a missense mutation of DCX in exon 5: 668G>T and G223V [Matsumoto et al., 2001]. (Courtesy of Dr. William B. Dobyns, The University of Chicago, Department of Human Genetics, Chicago, Illinois. Images from patients LR00185 [A], LR00-056 [B], LP97-140a1 [C], and LP94-049 [D].)

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does not occur with other types of lissencephaly to be described later. Less common types often are associated with intermediate-thickness (8 to 12 mm) cortex, agenesis of the corpus callosum, or severe cerebellar hypoplasia [Dobyns and Truwit, 1995; Dobyns et al., 1999a; Hourihane et al., 1993; Kato et al., 1999; Ross et al., 2001]. Lissencephaly and subcortical band heterotopia are distinguished by both the pattern and the severity of the malformation. The pattern or gradient can be anterior more severe than posterior (a > p), posterior more severe than anterior (p > a), or, least often seen, anterior similar to posterior (a = p). The patterns and grades of lissencephaly and subcortical band heterotopia have become very important in distinguishing the different syndromes and genes associated with lissencephaly and subcortical band heterotopia [Dobyns et al., 1999b; Kato and Dobyns, 2003; Pilz et al., 1998]. Examples of the patterns associated with each of the major LIS genes are shown in Figures 19-29 and 19-30. Of importance, lissencephaly is frequently confused with severe, primary microcephaly and with polymicrogyria. Differentiating these clinical entities is important, because management and counseling depend critically on the correct diagnosis. CLINICAL CHARACTERISTICS

Children with lissencephaly or severe subcortical band heterotopia typically appear normal as newborns, although a few demomstrate apnea, poor feeding, or hypotonia. With most types of lissencephaly, seizures are uncommon during the first days of life. The epileptic spectrum is homogeneous, often starting as nonspecific seizures between 3 and 6

months of age, occasionally later. These are quickly followed by infantile spasms with hypsarrhythmia in a majority of children. In many children, the infantile spasms respond at first to corticotropin or other antiepileptic drugs, but almost all affected children will go on to have frequent seizures and severe mental retardation. Typical seizure types include myoclonic, tonic, and tonic-clonic; many meet criteria for Lennox-Gastaut syndrome. Profound mental retardation, early hypotonia, mild spastic quadriplegia, and opisthotonus also are seen. Many patients require a gastrostomy because of poor nutrition and repeated episodes of aspiration pneumonia [Dobyns et al., 1992]. By contrast, most patients with subcortical band heterotopia and uncommon patients with partial lissencephaly have mild to moderate mental retardation, although both normal intelligence and severe mental retardation have been seen. Other clinical features are minimal pyramidal signs and dysarthria [Barkovich et al., 1994; D’Agostino et al., 2002; Dobyns et al., 1996a]. Seizures usually begin in childhood but may appear much later, and multiple types occur that may be difficult to control. Cognitive development may slow after onset of seizures. The frequency and severity vary greatly. EEG investigations usually demonstrate generalized spike-and-wave discharges or multifocal abnormalities [Battaglia, 1996; D’Agostino et al., 2002; Palmini et al., 1991a]. Neurologic outcome usually correlates with the thickness of the subcortical band heterotopia as seen on MRI. Children with X-linked lissencephaly with abnormal genitalia are almost all males and have even more severe clinical problems [Kato et al., 2004]. Frequent and sometimes continuous seizures typically are seen on the first day

TABLE 19-16 Genes Associated with Malformations of Neuronal Migration and Cortical Organization GENE(S)

SYNDROME(S)

CLINICAL TESTING

Syndromes with Lissencephaly and Subcortical Band Heterotopia ARX XLAG, ACC, ISS, MR + DCX ILS, SBH, MR + LIS1 ILS, SBH + LIS1 and 14-3-3ε MDS + RELN LCH group B –

REFERENCE(S)

Bienvenu et al., 2002; Kato et al., 2004; Stromme et al., 2002b Gleeson et al., 1998, 2000b; Matsumoto et al., 2001 Cardoso et al., 2000, 2002; Pilz et al., 1998 Cardoso et al., 2003 Hong et al., 2000

Syndromes with Cobblestone Malformation FCMD FCMD, WWS

–

FKRP

MEB, WWS

–

LARGE POMT1 POMGnT1

MEB WWS, MEB MEB

– – –

Beltran-Valero de Bernabe et al., 2003; Kobayashi et al., 1998; Kondo-Iida et al., 1999; Silan et al., 2003 Beltran-Valero de Bernabe et al., 2004; Louhichi et al., 2004; Topaloglu et al., 2003 Longman et al., 2003 Beltran-Valero de Bernabe et al., 2002; Currier et al., 2005 Diesen et al., 2004; Taniguchi et al., 2003; Yoshida et al., 2001

–

Fox et al., 1998; Sheen et al., 2001

–

Sheen et al., 2003a, 2004

–

Chang et al., 2003; Piao et al., 2004

Syndromes with Periventricular Nodular Heterotopia FLNA Periventricular nodular heterotopia ARFGEF2 Microcephaly with periventricular nodular heterotopia Syndromes with Polymicrogyria GRP56 BFPP

ACC, agenesis of the corpus callosum; BFPP, bilateral frontoparietal polymicrogyria; FCMD, Fukuyama’s congenital muscular dystrophy; ILS, isolated lissencephaly sequence; ISS, infantile spasms; LCH, lissencephaly with cerebellar hypoplasia; MDS, Miller-Dieker syndrome; MEB, muscle-eye-brain disease; MR, mental retardation; WWS, WalkerWarburg syndrome; XLAG, X-linked lissencephaly with abnormal genitalia.

Gleeson, Dobyns, Plawner, and Ashwal / Congenital Structural Defects

of life, often in the delivery room, and generally do not respond to any form of therapy. Affected children also commonly have persistent hypothermia, hypotonia, very poor feeding, chronic diarrhea, and ambiguous or severely hypoplastic genitalia. The feeding problems and diarrhea combine to lead to very poor nutrition. LISSENCEPHALY SYNDROMES

Several different lissencephaly syndromes have been delineated that correlate well with the four LIS genes and one modifier gene identified to date. The most common lissencephaly syndromes are Miller-Dieker syndrome, isolated

A

B

C

D

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lissencephaly sequence, subcortical band heterotopia, several types of lissencephaly with cerebellar hypoplasia, and X-linked lissencephaly with abnormal genitalia (XLAG). Most of these include the classic or four-layered (previously type 1) form of lissencephaly [Crome, 1956], whereas XLAG is characterized by a three-layered cortex [Bonneau et al., 2002], and one form of lissencephaly with cerebellar hypoplasia is associated with an unusual two-layered cortex [Kerner et al., 1999]. The syndromes associated with the cobblestone malformation (type 2 lissencephaly) are discussed in the next section. The different patterns of lissencephaly and associated genes are summarized in Table 19-16. FIGURE 19-30. Subtypes of lissencephaly (LIS) caused by LIS1 or unknown mutations. Midsagittal (left column), parasagittal (middle column), and axial (right column) magnetic resonance images from patients with four different forms of LIS. A, LIS1 (Miller-Dieker). The top row images depict severe, grade 1 LIS with diffuse agyria and no apparent gradient, very thick (15 to 20 mm) cortex, mildly enlarged lateral ventricles, intact corpus callosum that appears mildly flattened frontally, and normal brainstem and cerebellum. The patient was a female with MillerDieker syndrome with a large deletion of 17p13.3 extending from PAC95H6 to the telomere, with loss of LIS1, 14-3-3ε, and many other genes [Cardoso et al., 2003]. B, LIS1 (deletion). The second row images demonstrate grade 3 LIS with frontal pachgyria, posterior agyria, thick (15 to 20 mm) cortex, mildly enlarged lateral ventricles, the typical flattened corpus callosum, and normal brainstem and cerebellum. The patient was a female with typical ILS with mosaic deletion of PAC95H6 and LIS1 [Dobyns et al., 1999b]. C, LIS1 (missense). The third row images show mild frontal lobe hypoplasia, a transitional zone of thick cortex in the midfrontal region, and extensive posterior subcortical band heterotopia. The patient was an adult male with a missense mutation of LIS1 in exon 6: c.499T>C and S169P [Pilz et al., 1999]. D, LCH (no mutations identified). The bottom row images demonstrate severe, grade 1 LIS with diffuse agyria and no apparent gradient, very thick (15 to 20 mm) cortex, mildly enlarged lateral ventricles, intact corpus callosum that appears mildly small and flattened frontally, mild brainstem hypoplasia, moderate cerebellar vermis hypoplasia, and a large fluid collection beneath the cerebellum. The patient was a female in whom results of tests for LIS1 were negative. (Courtesy of Dr. William B. Dobyns, The University of Chicago, Department of Human Genetics, Chicago, Illinois. Images from patients LR01-167 [A], LP95132 [B], LP94-051 [C], and LP97041 [D].)

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Perinatal Acquired and Congenital Neurologic Disorders / 19

Miller-Dieker syndrome is a striking multiple-congenitalanomaly syndrome characterized by classic lissencephaly, typical facial appearance, and variable other birth defects such as heart malformations. The facial features include prominent forehead, bitemporal hollowing, short nose with upturned nares, protuberant upper lip with thin vermilion border, and small jaw. The brain malformation consists of severe lissencephaly with no apparent gradient (see Figs. 19-29 and 19-30), although rare patients may have the same p > a gradient seen in patients with isolated lissencephaly sequence with LIS1 mutations [Cardoso et al., 2003; Dobyns et al., 1991]. All patients with Miller-Dieker syndrome have large deletions of chromosomal region 17p13.3 that include LIS1, 14-3-3, and all intervening genes, which indicates that the 14-3-3 gene is an important modifying factor for lissencephaly [Cardoso et al., 2003; Dobyns et al., 1991]. The isolated lissencephaly sequence consists of classic lissencephaly with a normal facial appearance except for mild bitemporal hollowing and small jaw [Dobyns et al., 1984, 1992]. Different patterns of lissencephaly have been found with mutations of the two known causative genes, DCX and LIS1. Isolated lissencephaly sequence associated with mutations of the X-linked DCX gene is characterized by either severe lissencephaly with no apparent gradient or lissencephaly with a clear a > p gradient (see Fig. 19-29B, C), and normal facial appearance [Dobyns et al., 1999b; Pilz et al., 1998]. Isolated lissencephaly sequence associated with mutations or deletions of the LIS1 gene is characterized by lissencephaly with a p > a gradient or, very rarely, a = p gradient (see Fig. 19-29B). Facial appearance may be normal or have subtle dysmorphism similar to that in Miller-Dieker syndrome but much less severe [Cardoso et al., 2003; Dobyns et al., 1992]. Subcortical band heterotopia occurs as an isolated malformation with rare exceptions. Most patients are female, because the most common cause is heterozygous mutations of the DCX gene on the X chromosome [Dobyns et al., 1996a; Matsumoto et al., 2001]. This represents the “carrier” phenotype found in female relatives of males with DCX-related lissencephaly. Many affected males, however, also have been reported [D’Agostino et al., 2002]. Mutations of DCX and LIS1, the same two genes that cause isolated lissencephaly sequence, have been identified that result in somewhat different patterns of malformation. Subcortical band heterotopia associated with mutations of DCX gene is characterized by diffuse thick subcortical band heterotopia with no apparent gradient (see Fig. 19-29D), or by partial frontal thin subcortical band heterotopia with an obvious a > p gradient [Gleeson et al., 2000a; Matsumoto et al., 2001]. Subcortical band heterotopia associated with mutations or deletions of the LIS1 gene is characterized by partial posterior thin or intermediate bands with an obvious p > a gradient (see Fig. 19-30C). This is a rare cause of subcortical band heterotopia, and most patients have mosaic mutations of LIS1 [D’Agostino et al., 2002; Pilz et al., 1999; Sicca et al., 2003] or deletions of 17p13.3 (unpublished data). The rare Baraitser-Winter syndrome consists of facial dysmorphism, typically including trigonocephaly and shallow orbits, colobomas of both iris and retina, and lissencephaly with an a > p gradient [Baraitser and Winter, 1988; Ramer et al., 1995; Rossi et al., 2003]. The lissencephaly

usually is relatively mild, with pachygyria most severe in the mid-frontal region that undergoes transition posteriorly to subcortical band heterotopia and then to a more normal gyral pattern, thus resembling the DCX pattern. The cause and pattern of inheritance are unknown. Lissencephaly with cerebellar hypoplasia comprises a small percentage of patients with lissencephaly syndromes. The most common type, designated lissencephaly with cerebellar hypoplasia group a, resembles isolated lissencephaly sequence, but with the addition of mild or, rarely, moderate cerebellar vermis hypoplasia. Indeed, some of these patients have mutations of DCX or LIS1, although the frequency is much less than among patients with typical isolated lissencephaly sequence. Lissencephaly with cerebellar hypoplasia group b consists of pachgyria with a subtle a > p gradient, moderate (8 to 10 mm) cortical thickness, globular hippocampus and small, afoliar cerebellum. Some patients with this imaging appearance have had mutations of RELN. In most patients with lissencephaly with cerebellar hypoplasia, mutation analysis of DCX and LIS1 is normal. Lissencephaly with cerebellar hypoplasia group c was defined based only on fetal pathologic examinations, which now appear to resemble the changes in lissencephaly with cerebellar hypoplasia group f. Lissencephaly with cerebellar hypoplasia group d resembles isolated lissencephaly sequence except that the lissencephaly is severe, typically generalized agyria, and the cerebellar vermis and hemispheres are usually small (see Fig. 19-30D). Results of mutational analysis of DCX and LIS1 were normal in several patients in this group. Lissencephaly with cerebellar hypoplasia group e consists of frontal agyria with an abrupt transition to a mildly simplified or normal cortex posteriorly. Lissencephaly with cerebellar hypoplasia group f consists of lissencephaly with agenesis of the corpus callosum, severe cerebellar hypoplasia, and a rare two-layered cortex. A similar two-layered cortex was found in brains in both lissencephaly with cerebellar hypoplasia group c and group f, so these groups likely should be combined into a single group c/f pending further experience. XLAG consists of variant lissencephaly in genotypic males with p > a gradient and intermediate (8 to 10 mm) thickness of cortex, agenesis of the corpus callosum that is most often complete, abnormal basal ganglia that often are cavitated or indistinct, severe postnatal microcephaly, and abnormal genitalia that are ambiguous or severely hypoplastic. Affected children have profound mental retardation, hypothalamic dysfunction with poor temperature regulation, intractable epilepsy with onset typically on the first day of life, infancy-onset dyskinesia that may be difficult to distinguish from seizures, and chronic diarrhea [Dobyns et al., 1999a; Kato et al., 2004]. Female relatives, including some mothers, have isolated agenesis of the corpus callosum. Mutations of the ARX gene have been found in almost all patients [Kato et al., 2004; Kitamura et al., 2002]. Other syndromes with lissencephaly and agenesis of the corpus callosum exist but appear to be very rare. Of importance, less severe mutations of the same gene, ARX, have been found in boys with cryptogenic infantile spasms, infancy-onset dyskinesia, and some less specific mental retardation and epilepsy syndromes [Bienvenu et al., 2002; Kato et al., 2003; Scheffer et al., 2002; Stromme et al., 2002a, 2002b, 2003; Turner et al., 2002; Wellington, 2003].

Gleeson, Dobyns, Plawner, and Ashwal / Congenital Structural Defects

Studies in a mouse model have found that nonradial migration of inhibitory interneurons from the embryonic ganglionic eminence (the origin of the basal ganglia) to the neocortex is disrupted with loss of Arx [Kitamura et al., 2002]. A second X-linked gene associated with cryptogenic infantile spasms, CDKL5 or STK9, might have similar pathogenesis [Kalscheuer et al., 2003; Tao et al., 2004; Weaving et al., 2004]. GENETIC TESTING

All forms of lissencephaly and subcortical band heterotopia are genetic, and genetic testing is currently available for at least 80% of patients with lissencephaly or subcortical band heterotopia, although this varies with the specific phenotype. When lissencephaly or subcortical band heterotopia is suspected but the exact syndrome diagnosis is uncertain, the most productive order of testing is chromosome analysis and fluorescence in situ hybridization searching for deletions of chromosome 17p13.3 that include the LIS1 gene, followed by sequencing of LIS1, then DCX, and finally ARX. However, knowledge regarding the phenotype can be used by experienced specialists to change the order of tests, such as ordering testing of DCX first in females with subcortical band heterotopia or ARX first for males with lissencephaly and severe genital hypoplasia. Genetic testing for lissencephaly and subcortical band heterotopia is important, because several syndromes are associated with high risks of recurrence. This risk is especially great for parents who are carriers of a rearrangement of chromosome 17 and for mothers who carry ARX or DCX mutations. In Miller-Dieker syndrome, chromosome analysis identifies visible deletions of 17p13.3 in approximately 60% to 70% of patients, and fluorescence in situ hybridization detects deletions in the remaining patients. In approximately 30% of families, one parent is the carrier of a balanced chromosome rearrangement. The recurrence risk in these families is approximately 33% [Pollin et al., 1999]. For isolated lissencephaly sequence, the parents should be tested whenever mutations or small deletions of LIS1 have been found. When their results are normal, the recurrence risk is low, as we have not seen recurrence in more than 100 families. The possibility of recurrence exists with mosaicism in one parent, so the availability of prenatal diagnosis for future pregnancies is important. When mutations of DCX are found, the rules for X-linked inheritance apply [Dobyns et al., 2004]. Carrier testing in the mother is indicated, and fathers of female probands also are tested because such testing has identified one father who was a mosaic carrier of the mutation found in his affected daughter. The recurrence risk is 50% when the mother is found to be a carrier [Matsumoto et al., 2001], although this varies somewhat according to the phenotype in the affected child. The frequency of mosaicism among carrier mothers is high [Gleeson et al., 2000b; Matsumoto et al., 2001]. Recurrences in siblings in families when results of mutation analysis are negative have been described [Kuzniecky, 1994; Ramirez et al., 2004], and counseling is recommended for a 10% to 15% recurrence risk in this situation. When no testing has been done, counseling is more difficult. For subcortical band heterotopia, the same rules apply as for isolated lissencephaly sequence, except that the large majority of cases of subcortical band heterotopia are asso-

415

ciated with mutations of DCX, so most affected persons need counseling for X-linked inheritance. When mutations of LIS1 are found, these follow the same rules as for isolated lissencephaly sequence, except that mosaicism is more likely and would indicate a much lower risk of recurrence in siblings. When testing is negative, counseling is again recommended for a 10% to 15% recurrence risk, because both autosomal-dominant and autosomal-recessive forms of inheritance have been noted [Deconinck et al., 2003]. The inheritance of XLAG also is X-linked, and a large majority of patients with this phenotype have mutations of ARX. Thus, counseling for X-linked inheritance and testing for ARX mutations usually are indicated. Mothers often are carriers, some of whom have agenesis of the corpus callosum. The counseling for rare lissencephaly syndromes such as Baraitser-Winter syndrome and lissencephaly with cerebellar hypoplasia is less clear. Recurrence in several types of lissencephaly with cerebellar hypoplasia is possible, so counseling for autosomal-recessive inheritance is appropriate. Testing for RELN mutations is not available clinically. ANTENATAL DIAGNOSIS

Normal fetuses in the second and early third trimesters have a smooth brain surface with reduced number of gyri compared with the brain of a full-term child. Children with lissencephaly also have a reduced number of gyri. At present, it is not possible to differentiate lissencephaly from normal fetal brain reliably until the third trimester, usually between 32 and 36 weeks of gestation. Thus, fetal ultrasound examination and even fetal MRI performed before this time cannot reliably differentiate between normal and abnormal, and these tests should not be used. Successful prenatal diagnosis of lissencephaly has been performed by ultrasound late in the third trimester. When a chromosome abnormality or gene mutation has been identified in the affected child from a family, however, this result can be used for prenatal diagnosis for future pregnancies in that family. This has been used many times, as molecular diagnosis is now possible for a majority of patients with lissencephaly or subcortical band heterotopia. MANAGEMENT

Children with the most common lissencephaly syndromes, such as Miller-Dieker syndrome, isolated lissencephaly sequence, and subcortical band heterotopia, are often not recognized to have problems as newborns. A few children, especially those with Miller-Dieker syndrome, may have poor feeding and high bilirubin, but seizures are rare. By contrast, males with XLAG typically have severe seizures beginning on the first day of life and also have chronic hypothermia and diarrhea. Optimal management begins with early recognition and accurate counseling regarding the prognosis, because parents of children with the more severe forms may choose to limit life-sustaining interventions such as ventilation during severe illnesses. All or almost all children with lissencephaly or subcortical band heterotopia have seizures, often including infantile spasms, which may be difficult to treat. Early diagnosis and aggressive attempts to control seizures usually prove helpful in maintaining function. The epilepsy may consist of most types of seizures, and mixed types are common. Many children with lissencephaly go on

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Perinatal Acquired and Congenital Neurologic Disorders / 19

A

B

C

D FIGURE 19-31. Subtypes of cobblestone lissencephaly. Midsagittal (left column), parasagittal (middle column), and axial (right column) magnetic resonance images from patients with four different cobblestone malformation syndromes. A, FCMD mutation. The top row images demonstrate mild frontal pachygyria with 7- to 8-mm-thick cortex, normal to mildly simplified gyral pattern posteriorly, widely open sylvian fissures especially on the left, moderately enlarged lateral ventricles, intact but stretched corpus callosum, normal brainstem, and moderate cerebellar hypoplasia and atrophy. These images are from a Japanese child with Fukuyama’s congenital muscular dystrophy (FCMD), who most likely is homozygous for the Japanese founder mutation consisting of addition of a 3-kb retrotransposon into the 3′ untranslated region of the FCMD gene [Kobayashi, 1998]. B, POMGnT1 mutation. The second row images show moderate frontal pachgyria with an 8- to 12-mm-thick cortex that extends into the parietal lobe, patches of abnormal white matter with high T2 signal intensity, hypoplastic brainstem especially in the pons, moderate cerebellar hypoplasia, and a few small cysts in the high white matter. The patient was a male with muscle-eye-brain disease due to a homozygous mutation of POMGnT1 in exon 20: c.1813delC and H573fs (patient CC described by Yoshida and colleagues [2001] and Taniguchi and associates [2003]). C, FKRP mutation. The third row images demonstrate diffuse agyria with an irregular surface, diffusely abnormal white matter with high T2 signal intensity, moderately enlarged lateral ventricles, very thin corpus callosum, hypoplastic brainstem with a prominent tectum, severe hypoplasia of the cerebellar vermis, moderate hypoplasia of the cerebellar hemispheres, large posterior fossa fluid collection, and overall enlarged posterior fossa. The patient was a female with a form of Walker-Warburg syndrome intermediate between the classic syndrome and muscle-eye-brain disease—the kink of the upper brainstem typically seen in Walker-Warburg is not present. She has a missense mutation of FKRP: c.953C>T and C318Y (patient 2 described by Beltran-Valero de Bernabe and co-workers [2004]). D, No mutation identified. The bottom row images show diffuse agyria with an irregular surface, diffuse abnormal signal of white matter with very high T2 signal intensity, very thin and likely hypoplastic corpus callosum, moderate to severely enlarged lateral ventricles, severe hypoplasia of the brainstem with the typical Walker-Warburg kinking at the junction of the pons and midbrain, severe cerebellar hypoplasia, small fluid collection in the posterior fossa, and overall small posterior fossa. This female has Walker-Warburg syndrome with no known mutation, although only POMT1 has been tested. (Courtesy of Dr. William B. Dobyns, The University of Chicago, Department of Human Genetics, Chicago, Illinois. Images from patients LR01-058 [A], LP95-146 [B], LP97-123 [C], and LR00-181 [D].)

Gleeson, Dobyns, Plawner, and Ashwal / Congenital Structural Defects

417

to have the Lennox-Gastaut seizure syndrome, and their seizures may be managed as for those in patients with other causes for Lennox-Gastaut syndrome. They often have motor control problems (mixed hypotonia and spasticity), feeding problems, and gastroesophageal reflux, as in children with cerebral palsy, which may be managed similarly.

syndrome is the most severe, Fukuyama’s congenital muscular dystrophy the least severe, and muscle-eye-brain disease intermediate, and with the widest range of severity. This likely represents a semantic issue, because muscle-eyebrain disease is the diagnosis used for any intermediate phenotype.

OUTCOME

COBBLESTONE MALFORMATION SYNDROMES

Children with Miller-Dieker syndrome, severe isolated lissencephaly sequence (lissencephaly grades 1 to 3 and the more severely affected grade 4), most forms of lissencephaly with cerebellar hypoplasia, or XLAG have severe-toprofound mental retardation, mixed seizure types that often are intractable, chronic feeding problems that lead to recurrent pneumonia, and shortened lifespan. Most boys with XLAG die within the first several months of life, with a few living for 3 to 5 years. About half of all children with MillerDieker syndrome (defined as having large 17p13 deletions) pass away during the first 2 to 3 years of life, and few live past age 10 years. About half of the children with typical isolated lissencephaly sequence live for close to or beyond 10 years, but few live past 20 years. Most patients with mild isolated lissencephaly sequence (lissencephaly grade 4 that is not complete), lissencephaly with cerebellar hypoplasia group b, Baraitser-Winter syndrome, or subcortical band heterotopia live much longer.

Fukuyama’s congenital muscular dystrophy consists of relatively mild cobblestone complex, moderate-to-severe mental retardation and epilepsy, and severe congenital muscular dystrophy with progressive weakness, joint contractures, and elevated serum creatine kinase [Fukuyama and Osawa, 1984; Osawa et al., 1991]. The brain malformation is less severe than seen in either muscle-eye-brain disease or Walker-Warburg syndrome (see Fig. 19-31A). The causative FCMD gene was identified, as well as a common founder mutation, in the Japanese population [Kobayashi et al., 1998; Kondo-Iida et al., 1999]. This phenotype has not been associated with any other gene. Muscle-eye-brain disease consists of moderate cobblestone dysplasia with severe mental retardation, epilepsy, complex eye abnormalities, and congenital muscular dystrophy or myopathy with weakness, contractures, and elevated serum creatine kinase. The brain malformation typically is more severe frontally and is intermediate in severity between Fukuyama’s congenital muscular dystrophy and Walker-Warburg syndrome (see Fig. 19-31B). The white matter changes normalize somewhat over time, so in older patients this malformation can be confused with polymicrogyria, especially the frontoparietal type associated with mutations of GPR56 (see later). The brainstem and cerebellum are hypoplastic, but the brainstem lacks the distinctive kink at the midbrain-pons junction seen in most patients with Walker-Warburg syndrome. The eye anomalies consist of retinal and choroidal hypoplasia, optic nerve pallor, high-grade myopia, anterior chamber-angle abnormalities, glaucoma, iris hypoplasia, cataracts, and rare colobomas [Santavuori et al., 1989]. Although the most typical form of muscle-eye-brain disease occurs with mutations of POMGnT1, this syndrome has been associated with mutations of four different genes (see Table 19-16). Biochemical deficiency has been demonstrated in muscle [Zhang et al., 2003]. Walker-Warburg syndrome consists of severe cobblestone malformation leading to agyria (lissencephaly), as well as the most severe brainstem and cerebellar malformations of any of the cobblestone group of syndromes (see Fig. 19-31C, D). Most patients have hydrocephalus, and approximately 25% have occipital cephaloceles [Dobyns et al., 1985, 1989]. All patients with Walker-Warburg syndrome have profound mental retardation, epilepsy, eye abnormalities similar to those in muscle-eye-brain disease, and the same congenital muscular dystrophy or myopathy with elevated serum levels of creatine kinase and contractures as seen in muscle-eye-brain disease. Walker-Warburg syndrome has been associated with mutations of three different genes (see Table 19-16).

Cobblestone Complex Lissencephaly Cobblestone complex (previously “type 2 lissencephaly”), or cobblestone lissencephaly, is a severe brain malformation observed in three overlapping syndromes, all genetic with autosomal-recessive inheritance: Fukuyama’s congenital muscular dystrophy, muscle-eye-brain disease, and WalkerWarburg syndrome. The brain malformation consists of cobblestone cortex (a term first proposed by Haltia); abnormal white matter; enlarged ventricles, often with hydrocephalus; small brainstem; and small dysplastic cerebellum [Dobyns et al., 1985, 1989; Dubowitz, 1994; Haltia et al., 1997; Takada et al., 1988; Walker, 1942]. The abnormal cortex is severely disorganized with no recognizable layers and with disruption by abnormal vascular channels and fibroglial bands that extend into and often obstruct the subarachnoid space. The changes are widespread in the most severe syndrome (Walker-Warburg syndrome), which led to the term type 2 or cobblestone lissencephaly, but are less extensive in the other syndromes. The white matter is poorly myelinated with large numbers of heterotopic neurons. Associated brain abnormalities include obstructive hydrocephalus, brainstem hypoplasia, and cerebellar hypoplasia with cysts. The typical appearance of Fukuyama’s congenital muscular dystrophy, muscle-eye-brain disease, and Walker-Warburg syndrome on brain imaging is shown in Figure 19-31. In a few patients, absent septum pellucidum, absent corpus callosum, or occipital cephaloceles may be noted. The brain malformation frequently is associated with eye malformations and likely always associated with congenital muscular dystrophy. CLINICAL CHARACTERISTICS

The clinical course in all three syndromes consists of severe to profound mental retardation, severe hypotonia, mild distal spasticity, and typically poor vision. Walker-Warburg

GENETIC TESTING

All of the syndromes associated with the cobblestone malformation have definite autosomal-recessive inheritance.

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All of the known genes code for proteins known or suspected to be involved with glycosylation, particularly O-mannosylation of α-dystroglycan [Hewitt and Grewal, 2003; Ross, 2002]. Homozygous null mutations of αdystroglycan cause embryonic lethality in mice, but a brainspecific mouse knockout resulted in a brain malformation that closely resembles the cobblestone malformation [Moore et al., 2002]. Mutation analysis for these genes has been done in several research laboratories but is not available clinically. An enzymatic diagnostic test to assess function of POMGnt1 has been developed [Zhang et al., 2003], and testing for POMT1 may become available. ANTENATAL DIAGNOSIS

All or almost all patients with Walker-Warburg syndrome or muscle-eye-brain disease have greatly enlarged lateral ventricles, and many have frank hydrocephalus; many have a small cerebellum, and a few have gross microphthalmia. Each of these may be detected on prenatal ultrasound examination, usually in the mid- to late second trimester, and genetic ultrasound study has been used for prenatal diagnosis. Most affected fetuses should be detected, although no large series has been reported. Molecular genetic testing is possible only when a specific mutation has been identified in the proband. MANAGEMENT

Children with these syndromes have both the cobblestone brain malformation and congenital muscular dystrophy and so have a combination of hypotonia (from the brain and muscle disease) and spasticity (from the brain malformation). The muscle disease may be progressive, and the combination makes orthopedic and rehabilitation management more difficult. Although the causative genes may be the same, it is important to distinguish between these clinical syndromes as the prognosis and thus the management is different. Walker-Warburg syndrome is a very severe disorder associated with profound mental retardation and congenital hypotonia, and few children with true Walker-Warburg syndrome live past the age of 3 years. Some children who were reported to live longer than this might be better classified as having muscle-eye-brain disease. Once again, optimal management begins with early recognition and accurate counseling regarding the prognosis, because parents of children with Walker-Warburg syndrome may choose to limit life-sustaining interventions such as ventilation during severe illnesses. Seizures occur but are rarely as severe as those seen in patients with lissencephaly or subcortical band heterotopia. Careful seating is essential owing to severe hypotonia, and contractures need to be managed with physical therapy and splinting when needed. Congenital glaucoma and buphthalmos require care by an ophthalmologist. Treatment of other eye anomalies that can interfere with vision, such as retinal non-attachment or detachment, cataracts, and corneal opacity, should be considered on an individual basis, in view of the overall poor prognosis. The congenital muscular dystrophy probably progresses slowly over time, but this is not apparent clinically owing to the severe hypotonia and short survival period. Muscle-eye-brain disease and Fukuyama’s congenital muscular dystrophy are less severe, with survival into the teens and beyond; some patients have survived into their 40s. Seizures are common but less severe than in lissen-

cephaly or subcortical band heterotopia. The muscle disease slowly progresses, so that frequent evaluations to assess orthopedic, seating, and other rehabilitation needs are important. Children with Fukuyama’s congenital muscular dystrophy who learn to walk typically lose this skill several years later. Children with muscle-eye-brain disease have the same eye abnormalities as those found in Walker-Warburg syndrome, whereas children with Fukuyama’s congenital muscular dystrophy have only minor eye anomalies, if any. MANAGEMENT IN THE NEWBORN PERIOD

Most children with Walker-Warburg syndrome and some with muscle-eye-brain disease have congenital hydrocephalus, which usually requires a shunt. Children with Walker-Warburg syndrome and occipital cephaloceles usually do not have hydrocephalus at birth. Excision of the cephaloceles is frequently followed by hydrocephalus, however, so at the time of cephalocele removal, prophylactic shunt placement should be considered. Walker-Warburg syndrome is the most severe, with survival beyond 3 years rare. Fukuyama’s congenital muscular dystrophy is the least severe, with moderate-to-severe mental retardation, only minor eye abnormalities, and survival well into the second decade of life. Muscle-eye-brain disease is the most variable, with some cases almost as severe as Walker-Warburg syndrome and others associated with survival into the third or fourth decade. All children have severe (muscle-eye-brain disease and Fukuyama’s congenital muscular dystrophy) or profound (Walker-Warburg syndrome) mental retardation.

Neuronal Heterotopias Neuronal heterotopias consist of groups of neurons in an inappropriate location, typically either below or above the cerebral cortex although other abnormal locations are known. The most common type of heterotopia is located immediately adjacent to the lateral ventricles, known as periventricular or subependymal nodular heterotopia. Other types may be found in the subcortical white matter, throughout the thickness of the cerebral mantle, above the pia, or in several other locations. Examples of several types are shown in Figure 19-32. PERIVENTRICULAR NODULAR HETEROTOPIA

Periventricular nodular heterotopia consists of nodular masses of gray matter that line the ventricular walls and protrude into the lumen, resulting in an irregular outline (see Fig. 19-32A). Periventricular nodular heterotopia is a relatively common malformation that may be unilateral or bilateral, symmetric or asymmetric, and contiguous or noncontiguous [Dobyns et al., 1996a; Dubeau et al., 1995]. When the nodules are single or few in number, symptoms such as seizures may result, but such findings are unlikely to help with diagnosis. When the lesions are bilateral and numerous, a genetic basis is likely. Bilateral periventricular nodular heterotopia often is associated with hypoplasia of the corpus callosum or cerebellum, especially when the nodules are diffuse and contiguous, and have been associated with polymicrogyria. Pathology On gross examination, periventricular or subependymal heterotopia is seen as nodular masses of gray matter that line

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FIGURE 19-32. Subtypes of heterotopia. Midsagittal (left column), parasagittal (middle column), and axial (right column) magnetic resonance images from patients with three different types of heterotopia. A, The top row images depict bilateral, nearly contiguous periventricular nodular heterotopia (PNH), an overlying normal gyral pattern, and mild cerebellar vermis hypoplasia, with all other structures normal. This is the typical pattern associated with mutations of FLNA, although testing has not been performed in this adult female patient. B, The second row images demonstrate a large mass of nodular heterotopia in the left frontal lobe that compresses the left lateral ventricle and extends up to fill much of the subcortical white matter. The overlying cortex appears normal. The mass of heterotopia enlarges the left frontal lobe so that it pushes across the midline to compress the right frontal lobe. This is the characteristic appearance of (giant) subcortical nodular heterotopia. C, The single axial image shows a rare transmantle heterotopia, which consists of a column of heterotopic cells that extends from the ventricular surface to the cortex. The lack of a cleft differentiates this condition from schizencephaly. (Courtesy of Dr. William B. Dobyns, The University of Chicago, Department of Human Genetics, Chicago, Illinois. Images from patients LR01-357m, LR03-202, and LR04-420m.)

A

B

C the walls of the lateral ventricles. Microscopically, the abnormal tissue contains both neurons and glial cells and forms clusters of rounded, irregular nodules separated by layers of myelinated fibers. The individual heterotopia may have no apparent disorganization or rudimentary lamination. Periventricular nodular heterotopia can be induced in the developing rat by intraperitoneal injection of the cytotoxic agent methylazoxymethanol acetate at embryonic day 15. In this model, reciprocal connections between the periventricular nodular heterotopia and normal cortex have been found supporting the hypothesis that neurons in the periventricular nodular heterotopia were destined for the cortex before the interruption of their migration [Colacitti et al., 1999]. Additional evidence comes from a report describing an elderly patient with Alzheimer’s disease and periventricular nodular heterotopia who had amyloid plaques in both the cortex and the nodular masses [Joseph, 1997]. Clinical Characteristics The most frequent manifestation of periventricular nodular heterotopia is epilepsy, occurring in 80% to 90% of patients. The age at onset is variable, but onset often is delayed until early adulthood [Battaglia et al., 1997]. Most patients have one or more types of partial seizures, which often are intractable. The associated EEG abnormalities are not specific, consisting of infrequent interictal discharges that may be

generalized, multifocal or focal. Pseudotemporal lobe localization has also been reported [Battaglia et al., 1997; Sisodiya et al., 1999]. Studies using depth electrodes in patients with periventricular nodular heterotopia and epilepsy have found the nodules to be intrinsically epileptogenic [Kothare et al., 1998]. A few patients have had chronic headache or other incidental symptoms, whereas others discovered during family evaluations are asymptomatic. Most patients with periventricular nodular heterotopia, especially females, have normal intelligence, although the curve may be shifted slightly to the left, with an average intelligence quotient (IQ) of approximately 85. Affected males are more likely to have mental retardation, reflecting the high frequency of the X-linked form of periventricular nodular heterotopia, which has a relatively mild phenotype, and possibly the existence of other X-linked periventricular nodular heterotopia syndromes. A skewed gender ratio toward females has been observed among patients with bilateral periventricular nodular heterotopia. Periventricular Nodular Heterotopia Syndromes Unilateral periventricular nodular heterotopia is less common than the bilateral form. In one large series, 14 patients had bilateral compared with 6 with unilateral periventricular nodular heterotopia [Dubeau et al., 1995]. The clinical manifestations are similar, including some patients without

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epilepsy and some with mental retardation. As suggested by anecdotal experience, unilateral periventricular nodular heterotopia may occur as part of other malformation syndromes. X-linked periventricular nodular heterotopia due to mutations of the filamin-A (FLNA) gene is the most common heterotopia syndrome and was recognized on the basis of observations of a skewed gender ratio toward females among sporadic patients, and reports of several families with multiple affected females and a decrease in the number of sons born to affected women, which suggested prenatal lethality of affected males [Dobyns et al., 1996a; Huttenlocher et al., 1994]. The causative gene was mapped to Xq28, and mutations were identified in FLNA [Eksioglu et al., 1996; Fox et al., 1998]. Females with this syndrome usually have bilateral, contiguous periventricular nodular heterotopia, with normal intelligence or mild learning problems and seizures [Dobyns et al., 1996a; Poussaint et al., 2000]. The phenotype in males varies widely, ranging from the mild female phenotype to prenatal lethality [Dobyns et al., 1996a; Guerrini et al., 2004; Huttenlocher et al., 1994; Sheen et al., 2001]. Several other causative genes for typical periventricular nodular heterotopia probably exist, because mutations of FLNA are detected in only 80% of familial and 20% of sporadic patients [Sheen et al., 2001]. Several pedigrees consistent with autosomal-recessive inheritance have been reported [Sheen et al., 2003a], and periventricular nodular heterotopia has been observed with two different deletions of chromosome 5p [Sheen et al., 2003b]. A few females have had periventricular nodular heterotopia and Ehlers-Danlos syndrome [Cupo et al., 1981; Thomas et al., 1996]. A rare autosomal-recessive syndrome of severe congenital microcephaly with bilateral periventricular nodular heterotopia has been described, and the causative gene identified as ARFGEF2 [Sheen et al., 2004]. Several other syndromes with periventricular nodular heterotopia have been described predominantly in males, including periventricular nodular heterotopia with syndactyly and severe mental retardation [Dobyns et al., 1997], with frontonasal malformation and moderate mental retardation [Guerrini and Dobyns, 1998], with short gut that in retrospect suggests a mutation of FLNA [Evrard, 1992; Nezelof et al., 1976], with nephrosis [Palm et al., 1986], and possibly with agenesis of the corpus callosum [Vles et al., 1990, 1993]. Finally, periventricular nodular heterotopia associated with overlying polymicrogyria has been reported [Leeflang et al., 2003] and may be relatively common. Genetic Testing Mutation analysis of FLNA and ARFGEF2 has so far been performed only in specialized research laboratories. For FLNA, the limiting factor is primarily its large size, which makes sequencing expensive. The availability of less costly methods is likely to eventually make this more available. Antenatal Diagnosis Periventricular nodular heterotopia and other heterotopias cannot be visualized reliably at prenatal ultrasound examination, and fetal MRI has not been evaluated for this purpose. When mutations of FLNA or ARFGEF2 have been identified, currently available only in research laboratories, diagnostic testing for the specific mutation is possible. The large majority of females with mutations of FLNA have nor-

mal intelligence, however, so prenatal diagnosis would be used more often for male fetuses. Management All patients with periventricular nodular heterotopia are at high risk for seizures, which should be treated aggressively. Temporal lobe surgery for patients with periventricular nodular heterotopia and associated hippocampal sclerosis generally has not been successful [Li et al., 1997]. Outcome The outcome is remarkably variable. Most affected persons with a few nodular masses and no underlying syndrome, as well as almost all females with X-linked periventricular nodular heterotopia and some others with bilateral periventricular nodular heterotopia syndromes, have normal intelligence or only mild learning disabilities. Other syndromes, especially those in males, are associated with severe mental retardation. Most patients have seizures, although onset may not occur until adulthood, and the seizures may be intractable. OTHER TYPES OF HETEROTOPIA

Although much less common and less recognized, other types of heterotopia are known. Subcortical nodular heterotopia consists of a large mass of heterotopic tissue expanding a portion of one cerebral hemisphere (see Fig. 19-32B). This lesion is rarely if ever bilateral and often is associated with ipsilateral periventricular nodular heterotopia, agenesis of the corpus callosum, and cerebellar vermis hypoplasia. Overlying cortical dysplasia may be seen rarely [Barkovich, 2000; Barkovich and Kjos, 1992b]. Despite the large size of the heterotopia, development may be normal or nearnormal, and onset of seizures may not begin until the third decade of life. Some patients have overlying cortical dysplasia, which leads to more severe problems including mental retardation. Transmantle heterotopia consist of a column of gray matter without nodular features that extends from the ventricular wall up to the cortical surface, where it is surrounded by a typically small area of cortical dysplasia (see Fig. 19-32C). All cases reported to date have been sporadic. Periventricular laminar heterotopia is rare and differs from periventricular nodular heterotopia in lack of nodularity. Several types likely exist, with some heterotopias appearing smooth and others ribbon-like. Excessive white matter neurons have been reported in patients undergoing epilepsy surgery and in postmortem studies. These abnormalities most often are seen in the temporal lobe and occasionally are seen in the frontal lobes. Isolated heterotopic neurons in the white matter in normal brains also are most numerous in the temporal lobes [Emery et al., 1997; Rojiani et al., 1996]. The clinical correlates of the pathologic disorder are not well understood, although these neurons appear to be increased in patients undergoing temporal lobe resections for seizures [Hardiman et al., 1988]. MRI studies may reveal an abnormal white-gray matter junction if the number of ectopic cells is large. No familial recurrence or specific gender or racial predominance has been observed.

Malformations of Cortical Organization This group includes malformations in which most neurons reach the cortex but do not form normal cortical layers or

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intracortical connections, which suggests a later embryologic origin than the true neuronal migration malformations. The disorders in this group are characterized by an abnormal gyral pattern with moderately increased thickness of the cortex, typically 5 to 10 mm, in contrast with the normal thickness of 3 to 4 mm in most regions. The major malformations in this category include four-layered and unlayered polymicrogyria, schizencephaly, focal cortical dysplasia with normal cell types, and microdysgenesis.

Polymicrogyria and Schizencephaly Polymicrogyria is a cortical malformation characterized by abnormal cortical lamination, excessive cortical infolding

A

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resulting in many small gyri separated by shallow sulci, fusion of the cortical molecular layer, and variable associated abnormalities such as heterotopia and enlarged ventricles. Schizencephaly consists of a deep cleft lined by cortex that extends from the pial surface down to the ventricular wall, and polymicrogyria involving cortex of the cleft and surrounding brain surface. Polymicrogyria and schizencephaly must be considered together as rare patients have schizencephaly on one side of the brain and polymicrogyria without a cleft on the other. Pathologic examination of the cortex in both polymicrogyria and schizencephaly typically shows a simplified fourlayered cortex that consists of the marginal layer, a

FIGURE 19-33. Subtypes of polymicrogyria (PMG) and schizencephaly. Midsagittal (left column), parasagittal (middle column), and axial (right column) magnetic resonance images from patients with four different malformations with polymicrogyria. A, The top row images demonstrate bilateral frontoparietal PMG with extensive involvement of the frontal and parietal lobes, extended sylvian fissure, patches of very bright T2 signal of white matter (again more severe frontally), mildly enlarged lateral ventricles, thin corpus callosum, and hypoplasia of the brainstem and cerebellum. The patient was a female with a missense mutation of the GPR56 gene in exon 3: 112C3T and R38W [Piao et al., 2004]. B, The second row images show bilateral perisylvian PMG involving the entire perisylvian region, with extension into the posterior parietal region, extended sylvian fissures, and otherwise normal brain structure. The patient was a male with X-linked perisylvian PMG [Villard et al., 2002]. C, The third row images demonstrate bilateral mesial parietooccipital PMG with irregular and highly infolded cortex in the medial parietal and occipital regions and mildly enlarged lateral ventricles posteriorly. D, The bottom row images demonstrate bilateral open lip schizencephaly with a small occipital cleft on the right, a large parieto-occipital cleft on the left, enlarged and dysplastic lateral ventricles on the right, partial agenesis of the corpus callosum, and normal brainstem and cerebellum. (Courtesy of Dr. William B. Dobyns, The University of Chicago, Department of Human Genetics, Chicago, Illinois. Images from patients LP93-017a2 [A], LP99146a1 [B], LP98-090 [C], and LR00-029 [D].)

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superficial cellular zone continuous with normal layers II to IV, a thin cell-sparse zone, and a deeper cellular zone continuous with layers V and VI that merges imperceptibly into the white matter. The cortex is thinner than normal, but appears thickened due to infolding or festooning of the cortical ribbon, which in more severely affected areas may resemble columns [Crome, 1952; Ferrer, 1984; Levine et al., 1974]. The walls of the shallow sulci are fused in their deeper portions, and have small penetrating blood vessels. The small and tightly packed microgyri mimic the appearance of pachygyria, leading to frequent misdiagnosis by clinicians. Less often, these layers cannot be distinguished and the malformation is designated “unlayered” polymicrogyria. This distinction persists in the literature, although a careful review demonstrates that both the four-layered and unlayered types have been found in patients with similar forms of schizencephaly, lending some uncertainty to the validity of this separation. MRI in polymicrogyria demonstrates loss of the normal gyral pattern, an irregular or pebbled brain surface, increased numbers of small, approximately 2- to 5-mmwide gyri separated by very shallow sulci, and an irregular border between the cortex and underlying white matter (Fig. 19-33). The cortex is mildly to moderately thick, usually 5 to 10 mm, compared with the normal thickness of 3 to 4 mm. The underlying white matter often is thinner than usual, and in several rare polymicrogyria syndromes, additional striking white matter abnormalities are seen. Whenever the perisylvian region is involved, the sylvian fissures extend further posteriorly and upward than usual to merge with cortex of the parietal convexity. MRI in schizencephaly reveals the same cortical abnormalities plus the deep cleft, which can be open or closed; the sides of an open-lipped cleft are separated by cerebrospinal fluid, whereas the sides of closed-lip clefts are apposed and may appear as a column of gray matter [Barkovich and Kjos, 1992a].

mental delay and mental retardation, seizures, spasticity, and the associated musculoskeletal and feeding problems. These vary greatly in severity, so that predicting outcome in young infants may be difficult, but some general guidelines have emerged from clinical experience with many patients. The major prognostic factors across all types of polymicrogyria and schizencephaly include head size at birth, the localization and extent of polymicrogyria, and the motor examination. The most unfavorable prognostic factors are microcephaly, especially severe congenital microcephaly with birth head size more than 3 SD below the mean, involvement of extensive areas of the brain, especially the frontal lobes, and the presence of spastic quadriparesis. Involvement of the primary motor cortex is typically associated with spasticity. Patients with polymicrogyria restricted to the perisylvian region, especially the posterior perisylvian region, often have pseudobulbar palsy with the accompanying severe oromotor and speech apraxia. Patients with unilateral or very asymmetric polymicrogyria or schizencephaly, and those with relatively small regions of the brain affected, especially when the frontal lobes are spared, may have mild cognitive and motor deficits. Nevertheless, all are at high risk for seizures, which have been reported in more than 80% of patients, most with severe epilepsy. The seizures consist of atypical absences, tonic-atonic attacks, and generalized tonic-clonic seizures. EEG abnormalities include generalized spike-and-wave or multifocal abnormalities. A syndrome consisting of unilateral central polymicrogyria and transient nonconvulsive status epilepticus has been reported [Caraballo et al., 1999]. Many patients have epilepsy that remains relatively amenable to medical treatment until puberty, when seizures become intractable. They may improve again after puberty has passed. In many patients, the seizures remain under relatively good control during adult years and may abate with medication adjustments.

PATHOGENESIS

POLYMICROGYRIA AND SCHIZENCEPHALY SYNDROMES

For most but not all brain malformations, evidence supporting nongenetic causes such as teratogens or external agents is weak or does not exist. For polymicrogyria, recent experience again demonstrates several genetic causes but also supports extrinsic causes such as intrauterine viral infections and impaired vascular supply to the fetus. This possibility complicates diagnosis, genetic counseling, and research but must always be taken into consideration. The best-understood causes are reviewed along with other genetic syndromes. CLINICAL CHARACTERISTICS

Polymicrogyria and schizencephaly only rarely involve the entire brain, and the clinical presentations associated with these malformations vary according to head size and the localization and extent of the cortical malformation. When the correct interpretation of brain imaging studies as lissencephaly or polymicrogyria is in doubt, the clinical examination can be helpful. A large majority of patients with lissencephaly have diffuse hypotonia with no spasticity or minimal spasticity in the distal extremities, whereas most patients with polymicrogyria or schizencephaly have spasticity. The most common clinical problems found in patients with polymicrogyria or schizencephaly include develop-

The number of syndromes with polymicrogyria or schizencephaly has been expanding rapidly during the past decade, most with different regional patterns of polymicrogyria or different associated brain malformations. Based on a study of more than 200 patients still in progress, the perisylvian form of polymicrogyria appears to be by far the most common, accounting for about two thirds of patients [R.J. Leventer and W.B. Dobyns, unpublished data]. This and other forms are listed in Table 19-17. Seven of these have been reported at least once, whereas several others have been recognized but are not yet fully delineated. In addition, polymicrogyria occurs in numerous multiple congenital anomaly syndromes, including Adams-Oliver syndrome, Aicardi’s syndrome, homozygous PAX6 syndrome, micro syndrome, and thanatophoric dysplasia [Aicardi et al., 1965; Amor et al., 2000; Donnenfeld et al., 1989; Glaser et al., 1994; Graham et al., 2004; Hall-Craggs et al., 1990; Savarirayan et al., 1999; Shigematsu et al., 1985; Yamaguchi and Honma, 2001]. Bilateral Frontal Polymicrogyria Bilateral frontal polymicrogyria consists of bilateral and symmetric polymicrogyria of the frontal lobes extending back to the precentral sulcus posteriorly and the frontal

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TABLE 19-17 Polymicrogyria-Schizencephaly: Types and Syndromes SYNDROME

INHERITANCE (Causative Genes)

Established Syndromes with Polymicrogyria (PMG) Frontal PMG (only) AR, sporadic Frontoparietal PMG with brainstem AR (GPR56) and cerebellar hypoplasia Perisylvian PMG AD, AR, XL, chromosomal, sporadic Lateral parieto-occipital PMG Sporadic Mesial parieto-occipital PMG Sporadic Schizencephaly CMV, sporadic, vascular Septo-optic dysplasia with schizencephaly Suspected Syndromes with PMG* Diffuse PMG MIC with diffuse PMG MIC with diffuse PMG and PNH MIC with asymmetric PMG Familial schizencephaly Parasagittal PMG Perisylvian or diffuse PMG with diffusely abnormal white matter Perisylvian PMG with frontal PNH Posterior-temporal PMG and PNH

CMV, sporadic, vascular

AR, XL, sporadic Sporadic Sporadic AR, XL AR Sporadic Sporadic

REFERENCE(S)

Guerrini et al., 2000 Chang et al., 2003; Piao et al., 2004 Gropman et al., 1997; Guerreiro et al., 2000; Kuzniecky et al., 1993; Villard et al., 2002 Ferrie et al., 1995 Guerrini et al., 1997 Barkovich and Kjos, 1992a; Barkovich et al., 1989; Barth and van der Harten, 1985; Iannetti et al., 1998; Norman, 1980; Sener, 1998 Kuban et al., 1989; Miller et al., 2000; Sener, 1996

See legend

Sporadic Sporadic

AD, autosomal dominant; AR, autosomal recessive; CMV, cytomegalovirus; MIC, microcephaly (below −3 standard deviations at birth); PNH, periventricular nodular heterotopia; XL, X-linked. *The suspected syndromes have been identified by an informal PMG study group (A.J. Barkovich, W.B. Dobyns, R. Guerrini, R. Kuzniecky, and R. Leventer) but have not been fully delineated. Diffuse or generalized PMG has been reported [Chang et al., 2004], but the series was composed largely of patients we classify as having severe perisylvian PMG or Adams-Oliver syndrome.

operculum inferiorly. Most patients present with developmental delay and mild spastic quadriparesis and have variable mental retardation, language impairment, and epilepsy [Guerrini et al., 2000]. Bilateral Frontoparietal Polymicrogyria Bilateral frontoparietal polymicrogyria is a syndrome of autosomal recessive inheritance characterized by polymicrogyria involving the frontal and parietal lobes, with variable extension to the posterior temporal and occipital lobes (see Fig. 19-33A). Accompanying features include brainstem and cerebellar hypoplasia, patchy abnormal white matter signal changes, and enlarged ventricles [Chang et al., 2003]. No pathologic examinations have been reported, so the classification as polymicrogyria is based only on brain imaging. Clinical experience indicates that the microgyri tend to be less prominent than with other forms of polymicrogyria, so future pathologic studies might demonstrate a polymicrogyria variant or possibly a form of cobblestone malformation. The white matter signal changes and cerebellar hypoplasia resemble the abnormalities seen with the cobblestone malformation, with which it can easily be confused [Dobyns et al., 1996b]. Numerous patients have been reported, often classified as having other malformations, so it may prove to be a relatively common malformation [Dobyns et al., 1996b; Farah et al., 1997; Harbord et al., 1990; Straussberg et al., 1996; Sztriha and Nork, 2000]. The clinical features include global developmental delay and mental retardation of at least moderate severity, seizures, dysconjugate gaze, and bilateral pyramidal and cerebellar signs.

The locus for bilateral frontoparietal polymicrogyria was mapped to chromosomal region 16q12-q21, and the gene recently was identified as GPR56, an orphan G proteincoupled receptor with a large extracellular domain whose function is not yet understood [Piao et al., 2002, 2004]. Perisylvian Polymicrogyria Perisylvian polymicrogyria, also known as the congenital bilateral perisylvian syndrome, was first described in 1926 but has been widely recognized only in the past decade [Kuzniecky et al., 1993]. In the most typical form, patients present with prominent pseudobulbar paresis, in the form of swallowing difficulties and aspiration, inability to protrude the tongue, dysarthria and facial diplegia. They also have mild-to-severe mental retardation and seizures. At the mild end of severity, the syndrome certainly overlaps with congenital suprabulbar palsy, also known as Worster-Drought syndrome [Clark et al., 2000; Nevo et al., 2001]. It may manifest with much greater severity, however. For example, children may have developmental delay, poor palatal function, hypotonia, arthrogryposis, hemiparesis, apnea, motor deficits, micrognathia, and pectus excavatum [Gropman et al., 1997]. Seizures of varying types and severity have been reported in 58% to 87% of children [Gropman et al., 1997; Kuzniecky et al., 1994a, 1994b]. Brain imaging most often shows polymicrogyria that involves the sylvian fissures and surrounding opercular cortex [Kuzniecky and Andermann, 1994], but the extent and associated clinical findings vary greatly (see Fig. 19-33B). In the least severe form, perisylvian polymicrogyria may be restricted to a small region of the posterior sylvian fissure,

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whereas in the most severe form, it may involve the entire brain but appears most severe in the perisylvian regions and typically spares the mesial occipital regions (personal observation). Perisylvian polymicrogyria may be bilateral and symmetric, bilateral and highly asymmetric, or unilateral. In most cases, highly asymmetric or unilateral polymicrogyria has a perisylvian distribution. Perisylvian polymicrogyria usually is sporadic, although numerous families with multiple affected persons have been reported. Most studies have suggested X-linked inheritance, and a locus was mapped to Xq28, but data from other families suggest autosomal-dominant or autosomal-recessive inheritance [Bartolomei et al., 1999; Borgatti et al., 1999; Caraballo et al., 2000; Guerreiro et al., 2000; Villard et al., 2002]. It also has been associated with structural chromosome abnormalities. The most frequent of these is deletion 22q11.2, with approximately 10 patients reported [Bingham et al., 1998; Ehara et al., 2003; Ghariani et al., 2002; Kawame et al., 2000; Sztriha et al., 2004; Worthington et al., 2000], although other less common loci also have been described, such as deletion 1p36 [Shapira et al., 1999] and deletion 1q44 [Zollino et al., 2003]. Mesial Parieto-occipital Polymicrogyria Bilateral mesial or parasagittal parieto-occipital polymicrogyria is an uncommon subtype of polymicrogyria associated with epilepsy [Guerrini et al., 1997]. Brain imaging shows a very focal and typically symmetric malformation (see Fig. 19-33C). Although the location in watershed regions of the anterior and posterior cerebral arteries suggests postmigratory perfusion failure as a possible etiology, the consistent focal location suggests disruption of a developmental gene, so the cause is not known. No familial recurrence has been reported. The clinical presentation is related primarily to epilepsy, with mean age at onset of 9 years. Most patients have had partial seizures, with or without minor automatisms, that were typically intractable. Interictal EEG tracings show diffuse and bilateral parieto-occipital or temporal abnormalities. Intelligence and findings on the neurologic examination were normal in most patients, although some had mild mental retardation. Occipital Polymicrogyria Several patients with polymicrogyria restricted to the occipital lobes were reported along with other cortical pathologies such as focal cortical dysplasia [Kuzniecky et al., 1997]. Most presented with seizures, with mean age at onset of 8 years. Epileptic visual symptoms correlated well with the EEG abnormalities and the brain imaging findings. Most patients had normal results on visual field testing. Cortical resections resulted in good seizure control. Schizencephaly Schizencephaly, or “cleft brain,” is a relatively common brain malformation characterized by full-thickness clefts extending from the brain surface to the ventricular wall (see Fig. 19-33D). Most but not all of these clefts are located in the region of the sylvian fissures [Barkovich and Kjos, 1992a; Barkovich and Norman, 1988]. The clefts may be open and therefore filled with cerebrospinal fluid, or closed with the sides of the cleft touching. They are lined by dysplastic cortex that has the appearance of either four-layered or unlayered polymicrogyria, and polymicrogyria surrounds the sides of the cleft for variable distances [Crome, 1952; Norman et al., 1995]. It

usually has been considered to be due to an encephaloclastic process secondary to fetal ischemic injury, typically in the distribution of the middle cerebral artery, based on the pathologic appearance [Friede, 1989] and an association with twinning [Barth and van der Harten, 1985; Norman, 1980; Sugama and Kusano, 1994], congenital cytomegalovirus infections [Barkovich and Lindan, 1994; Hayward et al., 1991; Iannetti et al., 1998; Sener, 1998], and rarely other factors in which the fetal vascular supply is affected, such as maternal warfarin therapy [Barth, 1992; Levine et al., 1974; Pati and Helmbrecht, 1994]. Rare examples of familial schizencephaly have been reported, however, which supports causal heterogeneity [Hilburger et al., 1993; Robinson, 1991]. Schizencephaly usually occurs with no associated brain malformation other than polymicrogyria, but a syndrome of septooptic dysplasia (absent septum pellucidum and optic nerve hypoplasia) together with schizencephaly has been reported [Aicardi and Goutieres, 1981; Barkovich et al., 1989; Kuban et al., 1989; Sener, 1996] and some affected infants also have agenesis of the corpus callosum. A few patients with septooptic dysplasia have had polymicrogyria without clefts rather than schizencephaly, again demonstrating the relationship between these malformations [Miller et al., 2000]. Clinical experience suggests that in many if not most patients with typical schizencephaly, the septum pellucidum is absent or partially absent, so isolated schizencephaly and septo-optic dysplasia with schizencephaly may well be part of a single spectrum. Clefts are not seen in the well-defined regional polymicrogyria syndromes, however, implying that multiple causes may lead to polymicrogyria. The clinical manifestations in schizencephaly are related to the size and type of defect. Children with unilateral schizencephaly typically have mild or moderate impairments, whereas those with bilateral lesions usually have more severe mental retardation, epilepsy, and generalized spasticity [Barkovich and Kjos, 1992a; Granata et al., 1996; Packard et al., 1997]. Clinical findings usually are commensurate with the size of the lesion [Aniskiewicz et al., 1990; Barkovich and Kjos, 1992a]. Children with closed-lip schizencephaly may present with hemiparesis or motor delay, whereas those with open-lip schizencephaly are more likely to present with hydrocephalus or seizures. In one series, 57% of patients had seizures, 91% had associated cerebral developmental anomalies, and 45% had absent septum pellucidum [Packard et al., 1997]. In patients with larger clefts, seizures usually are focal and often intractable, but clinical variability is observed. Despite gross structural lesions, EEG localization often is regional rather than focal. The central location of the lesions and widespread areas of epileptogenic activity often render surgery impossible. Mutations of the EMX2 homeobox gene were reported in several patients with schizencephaly [Brunelli et al., 1996; Faiella et al., 1997]. The clinical findings in these patients were not described, however, and several of the sequence changes were intronic and open to alternative interpretations. This result has never been confirmed by further reports, and the proposed association likely is not true, although a definitive study has not appeared. Genetic Testing All patients with polymicrogyria should have chromosome analysis performed, as well as fluorescence in situ hybridization analysis for deletions of 22q11.2 (DiGeorge’s syn-

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drome region) and fluorescence in situ hybridization with a set of subtelomeric probes to pick up small deletions of 1p36, 1q44, and possibly other regions of interest. These tests are indicated even if the child does not look like he or she has DiGeorge’s or velocardiofacial syndrome. Sequencing of GPR56, the causative gene for bilateral frontoparietal polymicrogyria, is not available clinically, although testing on a research basis has been possible in some instances.

varying recurrence risks. Preliminary data suggest a recurrence risk of 5% to 10% for families with female probands and of 10% to 20% for families with affected male probands, which reflects a mild skewing of the gender ratio toward males and the known X-linked inheritance [Guerreiro et al., 2000]. The recurrence risk for schizencephaly, including septooptic dysplasia with schizencephaly is very low.

Antenatal Diagnosis As with lissencephaly and subcortical band heterotopia, it is not possible to differentiate polymicrogyria from normal fetal brain reliably until the third trimester, usually between 32 and 36 weeks of gestation. Thus, fetal ultrasound examination and even fetal MRI performed before this time cannot reliably differentiate between normal and abnormal and should not be used. The clefts in schizencephaly may be seen by imaging, but their time of origin is unclear; this is less important, because the recurrence risk for schizencephaly is extremely low. When a specific chromosome abnormality or gene mutation has been identified in the affected child from a family, this result can be used for prenatal diagnosis for future pregnancies in that family.

Focal cortical dysplasia without balloon cells or other abnormal cell types, also designated architectural dysplasia, is a mild cortical malformation characterized by abnormal cortical lamination and ectopic neurons in white matter [Colombo et al., 2003b; Palmini et al., 2004; Tassi et al., 2002]. Brain imaging demonstrates subtle lobar or gyral hypoplasia, mild atrophy of underlying white matter, moderately increased T2 and decreased T1 signal intensity of white matter, and sometimes mild blurring of the gray-white border and mildly increased thickness of the cortex [Colombo et al., 2003a, 2003b; Palmini et al., 1991b]. The distinction between pure focal cortical dysplasia (architectural dysplasia) and focal cortical dysplasia with abnormal cell types (cytoarchitectural dysplasia and Taylor-type dysplasia) is clear with histopathologic examination but is not always possible on brain imaging [Colombo et al., 2003b]. Microdysgenesis is a similar but microscopic malformation that consists of neurons in the marginal layer, subtle changes in laminar architecture, and excess neurons in white matter [Meencke and Janz, 1984; Thom et al., 2001]. No changes are seen on brain imaging. Both pure focal cortical dysplasia (architectural dysplasia) and microdysgenesis require histopathologic confirmation for diagnosis, typically obtained only after epilepsy surgery, and both may occur with hippocampal sclerosis, the so-called dual pathology.

Management Optimal management begins with early recognition and accurate counseling regarding the prognosis, because parents of children with the more severe forms may choose to limit lifesustaining interventions such as ventilation during severe illnesses. Many children with polymicrogyria have much less severe problems, however, and must be approached individually. A large majority of patients with polymicrogyria have seizures, which may prove difficult to treat. Early diagnosis and aggressive attempts to control seizures usually prove helpful in maintaining function. The epilepsy may consist of almost any type of seizures, and mixed types are common. Some children have severe seizures during puberty that become easier to control later on. Patients with polymicrogyria and schizencephaly often have motor control problems, especially spasticity, feeding problems, and gastroesophageal reflux, as in children with cerebral palsy or lissencephaly, which may be managed similarly. The orthopedic problems often are more severe than in lissencephaly and may be managed as for any child with spastic cerebral palsy. Outcome The outcome for patients with polymicrogyria or schizencephaly is highly variable and related to head size at birth, extent of brain involvement, and severity of changes on the neurologic examination. The most useful indicators for a poor outcome include congenital microcephaly (below −2 SD, and especially below −3 SD), bilateral involvement of large brain regions, and spastic quadriparesis. Counseling The recurrence risk for autosomal recessive forms of polymicrogyria is typically 25%, and persons with rare subtypes with unknown inheritance patterns should be counseled for the possibility of recessive inheritance and the accompanying 25% risk. Both perisylvian and the very rare true diffuse forms of polymicrogyria sometimes have X-linked inheritance. The most common perisylvian form of polymicrogyria has multiple potential genetic causes, with widely

Focal Cortical Dysplasia and Microdysgenesis

CLINICAL CHARACTERISTICS

Because confirmation of the diagnosis usually is obtained only in patients with severe epilepsy leading to surgical treatment, the full spectrum of clinical manifestations have not been well described. Cortical dysplasia without balloon cells and milder forms of microdysgenesis are usually reported in patients with epilepsy [Kuzniecky et al., 1991]. As for focal dysplasias associated with balloon cells, the clinical abnormalities correlate with location of the lesions. Both are found most frequent in the frontal lobes, followed by the temporal regions. In most individuals, the malformations do not follow any boundaries between various regions and usually involve more than a single gyrus or lobe. Familial recurrence has not been reported, and the causes are not known.

Management and Outcome Management primarily involves treatment of the epilepsy. The associated seizures are focal in origin, as would be expected from the pathology, and may become intractable. The outcome is related to the success of seizure management.

HYDROCEPHALUS Hydrocephalus results from obstruction of cerebrospinal fluid egress from the ventricular system, reduced absorption from arachnoid villi, or rarely, excess production of cerebro-

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spinal fluid within an abnormal choroid plexus [Aronyk, 1993]. The excess cerebrospinal fluid enlarges the cerebral ventricles and elevates intracranial pressure, which produces the clinical manifestations of hydrocephalus. Hydrocephalus is a common problem. It is estimated that approximately 125,000 persons are living with shunts and that 33,000 shunts are placed annually in the United States [Bondurant and Jimenez, 1995].

Pathophysiology Most of the cerebrospinal fluid (70%) is secreted by the choroid plexus within the cerebral ventricles. Extrachoroidal cerebrospinal fluid production in subarachnoid sites and by way of a transependymal route has been documented [Fishman, 1980]. About 20% or more of cerebrospinal fluid is derived from brain extracellular fluid created as a by-product of cerebral metabolism [Rekate, 1997]. Normally, rates of production (0.35 mL per minute) and absorption of cerebrospinal fluid are equal. Total cerebrospinal fluid volume is 65 to 140 mL in children and 90 to 150 mL in adults. The process of cerebrospinal fluid formation by the choroid plexus includes plasma ultrafiltration and secretion. Secretion, an energy-dependent process, is initiated by hydrostatic pressure in the choroidal capillaries and by active transport of sodium. The enzymes sodium-potassium ATPase and carbonic anhydrase partly regulate cerebrospinal fluid secretion [Fishman, 1980]. By contrast, the process of cerebrospinal fluid reabsorption is not an energy-dependent process [Rekate, 1997]. After formation, cerebrospinal fluid exits from the lateral ventricles through the foramen of Monro into the third ventricle (Fig. 19-34). Cerebrospinal fluid then traverses the aqueduct of Sylvius into the fourth ventricle and enters the

Superior cerebral vein

subarachnoid space through the foramina of Luschka and Magendie. Information gained from MRI analysis of cerebrospinal fluid movement demonstrates pulsatile toand-fro motion of cerebrospinal fluid within the lateral ventricles, produced from a brain-pumping motion that ejects the cerebrospinal fluid and causes a net downward flow [Feinberg and Mark, 1987]. Cerebrospinal fluid is absorbed into the vascular system through the arachnoid villi within the arachnoid granulations covering the brain and spinal cord leptomeninges [Alksne and Lovings, 1972; Welch, 1975]. A layer of endothelium within the arachnoid villi separates the subarachnoid cerebrospinal fluid space from the vascular system. Water and electrolytes pass freely across these arachnoid membranes. Larger proteins and macromolecules cannot pass through intercellular junctions but are selectively transported across the cytoplasm of endothelial cells by an active process involving micropinocytosis [Alksne and Lovings, 1972]. Cerebrospinal fluid also is absorbed by the choroid plexus, leptomeninges, ventricular ependyma, and lymphatics [Fishman, 1980]. Increased absorption through the arachnoid villi protects the brain from transient increases in intracranial pressure [Mann et al., 1978].

Classification Because many processes and structures affect cerebrospinal fluid dynamics [Davson, 1972], hydrocephalus results from multiple causes [Guiffre et al., 1995]. Inadequate absorption of cerebrospinal fluid is the prime mechanism producing hydrocephalus. A blockage of cerebrospinal fluid circulation at any point from the site of production to the site of absorption through the arachnoid villi enlarges the proximal cerebral ventricles because of excessive cerebrospinal fluid accumulation.

Arachnoidal granulation

Superior sagittal sinus Arachnoid Subarachnoid space Dura Choroid plexus of lateral ventricle

Foramen of Monro

Great cerebral vein Aqueduct of Sylvius Cisterna interpeduncularis Cisterna superior Foramen of Luschka Choroid plexus of fourth ventricle Foramen of Magendie Cisterna cerebellomedullaris

FIGURE 19-34. Cerebrospinal fluid circulation. The lightly stippled area indicates the position of the lateral ventricle.

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Hydrocephalus is classified as either noncommunicating (i.e., obstructive) or communicating. In the noncommunicating form, ventriculomegaly occurs rostral to the site of obstructed cerebrospinal fluid flow. Vulnerable blockage sites include the foramina of Monro, aqueduct of Sylvius, third and fourth ventricles, and the outflow foramina of the fourth ventricle. In communicating hydrocephalus, the cerebrospinal fluid flows from the enlarged ventricular system into the spinal and cranial subarachnoid space. In addition, cerebrospinal fluid accumulates as a result of impaired cerebrospinal fluid absorption by the pacchionian granulations or obstruction within the subarachnoid space over the cerebral hemispheres or around the incisura of the tentorium. Increased intracranial venous pressure from sinus thrombosis or bilateral jugular catheterization also may cause communicating hydrocephalus secondary to decreased cerebrospinal fluid absorption, especially in infants younger than 18 months of age [Rosman and Shands, 1978; Wu and Swaiman, 1982]. Rarely, excessive production of cerebrospinal fluid from a choroid plexus papilloma may cause hydrocephalus.

Pathologic Findings Acute hydrocephalus results from sudden obstruction of cerebrospinal fluid flow or absorption. The precise pathologic features of hydrocephalus vary depending on the age of onset, the rate of ventricular enlargement, and the degree of ventriculomegaly. Typically, elevated cerebrospinal fluid pressure initially enlarges the frontal horns of the lateral ventricles, followed by enlargement of the entire ventricular system above the site of obstruction. Ependymal cells are injured, and periventricular glial cells proliferate, resulting in a layer of reactive gliosis. The pathologic findings may be a result of reduction in blood flow to the white matter causing hypoxic injury, and/or toxicity to the white matter due to buildup of waste products not removed appropriately because of changes in the extracellular matrix [Del Bigio, 2004]. Separation of the ependymal lining of the ventricles enhances permeability, which increases the edema of adjacent white matter (transependymal fluid absorption). MRI may demonstrate periventricular edema. The expanding ventricles flatten the cerebral gyri and obliterate the sulci over the cortical surface. Unless the acute obstruction is relieved, the increasing pressure may hinder cerebral blood flow, cause cerebral herniation, and compromise brainstem function. Nonprogressive hydrocephalus occurs when cerebrospinal fluid absorption compensates for the excess cerebrospinal fluid accumulation, resulting in arrested hydrocephalus. However, ventricular enlargement may progress insidiously without clinical symptoms. In infants, continued ventricular dilation results in separation of cranial sutures and a progressive increase in head circumference. The increasing pressure and ventricular enlargement are associated with necrosis of brain parenchyma. White matter is more vulnerable to destruction than cerebral gray matter in the presence of progressive hydrocephalus [Rubin et al., 1972]. The corpus callosum may also be preferentially affected with evidence of transcallosal swelling, thickening, or demyelination [Spreer et al., 1996; Suh et al., 1997]. These effects do not appear to be associated with cognitive changes nor neuropsychologic evidence of callosal disconnection.

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Clinical Characteristics Rapid head enlargement, vomiting, lethargy, and irritability are the first signs of acute hydrocephalus in infants. Hydrocephalus may progress insidiously with only excessive head enlargement. Headache, lethargy, and vomiting are typical symptoms in children. Patients with arrested hydrocephalus may be asymptomatic but are at risk to develop symptoms of increased intracranial pressure when the hydrocephalus progresses. In preterm infants, ventricular enlargement may progress with a delay in concomitant excessive head enlargement [Volpe, 2000]. Evaluation of the patient with an enlarged head entails consideration of the many causes of macrocephaly, including hydrocephalus. Evaluation should include a history of trauma or CNS infection, which may obstruct cerebrospinal fluid drainage or impair absorption, leading to hydrocephalus. The family history may demonstrate X-linked hydrocephalus caused by stenosis of the aqueduct of Sylvius or may reveal familial megalencephaly. Besides hydrocephalus, causes of increasing head size include chronic subdural effusions or hematoma, pseudotumor cerebri, neurofibromatosis, metabolic abnormalities of bone or brain, cerebral gigantism (Soto’s syndrome), and benign familial forms (Box 19-7) [DeMyer, 1972]. Rapid head growth, enlarged subarachnoid space, and little or no ventricular enlargement define the entity of external hydrocephalus, which may be part of the clinical spectrum of benign familial macrocephaly [Alvarez et al., 1986]. External hydrocephalus is probably a benign condition that requires no treatment. Considerations in the differential diagnosis of hydrocephalus are listed in Box 19-7. Communicating hydrocephalus is the most common form; obstructive hydrocephalus is less frequent and is usually caused by a congenital defect such as aqueductal stenosis (Fig. 19-35). Subarachnoid or intraventricular hemorrhage, meningitis, intrauterine viral infections, elevated cerebrospinal fluid protein, and other conditions compromising cerebrospinal fluid absorption by the arachnoid granulations are typical causes of communicating hydrocephalus. Principal causes of obstructive hydrocephalus include tumors, congenital malformations, aqueductal stenosis, Arnold-Chiari malformation, DandyWalker syndrome, arteriovenous malformation involving the vein of Galen, intraventricular hemorrhage, and other vascular abnormalities. Hydrocephalus and pseudomeningocele may follow posterior fossa surgery. Hydrocephalus has been reported in association with endocardial fibroelastosis and cataracts (HEC syndrome) and may be due to intrauterine infection or a yet-to-be-determined genetic disorder [Devi et al., 1995]. Autosomal-recessive and X-linked recessive [Castro Gago et al., 1996] and X-linked dominant [Ferlini et al., 1995] forms of hydrocephalus are recognized. X-linked hydrocephalus can be part of the L1 spectrum of disorders, caused by mutations in the L1 cell adhesion molecule (CAM). L1CAM belongs to the immunoglobulin superfamily and is found on the membranes of axons and Schwann cells during development of the nervous system. It plays a role in cell adhesion, axon growth and path-finding, neuronal migration and myelination [Wong et al., 1995]. The L1 disorders initially were described as different entities: HSAS (X-linked hydrocephalus with stenosis of aqueduct of Sylvius,

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Box 19-7 DIFFERENTIAL DIAGNOSIS OF HYDROCEPHALUS Congenital Malformations Agenesis of the corpus callosum Autosomal-recessive aqueductal stenosis Aqueductal stenosis Arachnoid cyst Cerebellar agenesis Arnold-Chiari malformation Basilar impression Dandy-Walker malformation Encephalocele Peters’ anomaly Porencephaly Infectious Causes Congenital syphilis Cytomegalic inclusion disease Mumps Postmeningitis Postencephalitis Toxoplasmosis Miscellaneous Elevated cerebrospinal fluid protein content with endocardial fibroelastosis, cataracts Neoplasms Brainstem glioma Cerebellar astrocytoma Choroid plexus papilloma Colloid cyst of third ventricle Ependymoma Histiocytosis X Leukemia Lymphoma Medulloblastoma Neuroblastoma Pinealoma Syndromes Achondroplasia Agyria and retinal dysplasia

Apert’s syndrome Cockayne’s syndrome Coffin-Lowry syndrome Crouzon’s syndrome Biemond’s syndrome Fryns’ syndrome Hirschsprung’s disease Gaucher-like disease Glutaricaciduria type I Hurler syndrome Incontinentia pigmenti Larsen’s syndrome Klippel-Trenaunay-Weber syndrome Knobloch’s syndrome Krabbe’s disease Meckel-Gruber syndrome Mucopolysaccharidosis VI Muscle-eye-brain disease Myotubular myopathy Myotonic dystrophy Neurofibromatosis Osteopetrosis Ruvalcaba syndrome Thoracic dysplasia Shprintzen-Goldberg syndrome VACTERL association Walker-Warburg syndrome X-linked aqueductal stenosis (CRASH syndrome) Traumatic Causes Hemorrhage Hypoxic-ischemic encephalopathy Posterior fossa surgery Vascular Causes Arteriovenous malformation Jugular vein catheterization Vein of Galen malformation Venous sinus thrombosis

CRASH, corpus callosum agenesis, retardation, adducted thumbs, spastic paraparesis, hydrocephalus; VACTERL, vertebral anomalies, anal atresia, cardiac defect, tracheoesophageal fistula with esophageal atresia, renal abnormalities, limb abnormalities.

spastic paraparesis type 1, X-linked agenesis of the corpus callosum) and MASA (mental retardation, aphasia, shuffling gait, adducted thumbs) syndrome. Through the 1990s it became clear that these disorders all were the result of a mutation in a single gene, L1CAM [Fransen et al., 1995, 1997; Jouet et al., 1994; Vits et al., 1994]. Thus, some investigators have suggested that these separately named conditions all now be lumped into the acronym CRASH (corpus callosum agenesis, retardation, adducted thumbs, shuffling gait, and hydrocephalus), but others have objected to the negative implications of this name [Schrander-Stumpel, 1998; Schrander-Stumpel and Fryns, 1998]. The clinical phenotype is variable, even within a single family, but some genotypephenotype correlations can be made [Fransen et al., 1998]. Oversecretion of cerebrospinal fluid from choroid plexus papillomas produces hydrocephalus in children, a symp-

tom typically but not universally present before the age of 3 years [Carson et al., 1997; Hamilton, 1996]. The lateral ventricles in children and the fourth ventricle in adults are the most common sites for this tumor. Head circumference measurements provide evidence of an enlarged cranial vault and intracranial volume. Rapid growth evidenced by serial measurements of increasing head circumference is the most important indication of progressive hydrocephalus. The normal rate of head growth during infancy is 2 cm per month during the first 3 months of life, 1 cm per month during the second 3 months, and 0.5 cm per month until 1 year of age. Closure of the anterior fontanel occurs by age 18 months, but closure is delayed in patients with hydrocephalus. Abnormal head shape, particularly occipital prominence, often indicates the likely diagnosis. Severe cranial asym-

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A

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B

FIGURE 19-35. Hydrocephalus secondary to aqueductal obstruction in a 29-year-old female patient. A, Acquired aqueductal obstruction or stenosis with distended third ventricle and proximal aqueduct of Sylvius (arrow). Note enlarged frontal horns elevating thinned corpus callosum (arrowheads) on this image from a T1-weighted magnetic resonance imaging (MRI) study. B, Distended temporal and occipital horns are evident, as well as distended proximal aqueduct (arrow), on this axial image from a spin density–weighted MRI study. (Courtesy of Joseph R. Thompson, Department of Radiation Sciences, Loma Linda University School of Medicine, Loma Linda, Calif.)

metry suggests either a porencephalic cyst or a lateral ventricle dilated after stenosis of one foramen of Monro. Biparietal enlargement is often observed with bilateral subdural hematomas. Frontal bossing is common in uncomplicated hydrocephalus. A cranial bruit may indicate an arteriovenous malformation. Papilledema is rarely observed in the infant’s fundi because the cranial sutures spread in response to increased pressure; however, papilledema is common with onset in older children. Retinal hemorrhages associated with acute hydrocephalus may occur but are quite rare. Chronic hydrocephalus is associated with optic nerve atrophy, which is indicated by a pale optic disc and attenuated arterioles. Chorioretinitis suggests an infectious cause, including cytomegalic inclusion disease, lues, and toxoplasmosis. Cranial nerve abnormalities usually are present. The eyes may be rotated to an extreme downward position, producing a “setting sun” sign. This phenomenon may be intermittent and likely indicates a disturbance of the superior colliculus, such as that occurring in Parinaud’s syndrome. Upper eyelid retraction (Collier’s sign), which may occur with lesions of the rostral midbrain and third ventricle, also contributes to the setting sun phenomenon. Abducens nerve paralysis with attendant turning out of the affected eye often is present and constitutes a false localizing sign. Abnormal head movements described as like those of a “bobble-head doll” may be a sign of hydrocephalus,

especially when associated with a third ventricular cyst or aqueductal stenosis [Coker, 1986]. In some patients, the bobble-head doll syndrome may precede the signs and symptoms of increased intracranial pressure. Hyperreflexia, knee and/or ankle clonus, spasticity, and poor head control often are evident on examination. Cutaneous changes over the spine (e.g., bulge, dimple, hemangioma, hypertrichosis) may signal the presence of spina bifida. Skull radiographs may provide evidence of chronic, elevated intracranial pressure, such as excessive convolutional skull markings and separation of cranial sutures, which may occur until the age of 12 years. An enlarged posterior fossa is associated with Dandy-Walker syndrome; a small posterior fossa suggests Arnold-Chiari malformation. Periventricular calcifications accompany cytomegalic inclusion disease; disseminated calcification occurs with toxoplasmosis. Neuroimaging (e.g., CT, MRI, cranial ultrasonography) is essential in delineating the presence and etiology of hydrocephalus (Fig. 19-36). In complex anomalies, the site of obstruction can be documented using CT with contrast material (metrizamide) administered into the cerebrospinal fluid by lumbar or ventricular puncture. In utero diagnosis of fetal hydrocephalus with ultrasonography has potential therapeutic implications (Fig. 19-37). MRI also may be used to diagnose fetal hydrocephalus and may be helpful in determining long-term outcome based on the etiology and progression [Oi et al., 1998].

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FIGURE 19-36. Hydrocephalus. A, This computed tomography (CT) scan demonstrates enlarged lateral and third ventricles caused by obstruction of the aqueduct of Sylvius by a venous angioma. Note the lucency in the periventricular white matter indicating transependymal edema. B, This CT scan of the posterior fossa reveals a small fourth ventricle, which confirms the diagnosis of aqueductal stenosis in A. Note the vascular malformation. (Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School, Minneapolis, Minn.)

A

B

FIGURE 19-37. Hydrocephalus detected in utero. This fetal ultrasonogram demonstrates massive ventricular dilation during the third trimester of pregnancy. (Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School, Minneapolis, Minn.)

Proton MR spectroscopy may be useful in neurosurgical management to assist in differentiating patients with cerebral atrophy (reduced NAA/Cr levels; presence of lactate) from those with hydrocephalus [Bluml et al., 1997]. Functional MRI is being investigated for imaging of cerebrospinal fluid motion in patients with hydrocephalus. It may be useful in patients with newly diagnosed hydrocephalus or in those with suspected shunt malfunction [Feinberg, 1995]. Enlarged ventricles without elevated pressure may occur with cerebral atrophy (hydrocephalus ex vacuo), cerebral malformations (lissencephaly), and nonprogressive arrested hydrocephalus. Radiologic findings that suggest elevated pressure include compressed sulci and transependymal edema surrounding the frontal horns (see Fig. 19-36A).

Management Shunting of cerebrospinal fluid to facilitate absorption usually is required for progressive or symptomatic hydrocephalus [McLaurin et al., 1989; Portnoy et al., 1998; Rekate,

1997]. In the presence of noncommunicating hydrocephalus, removal of the obstruction is preferred. This situation occurs infrequently in comparison with communicating hydrocephalus. If no documented obstruction or operable lesion is present and the hydrocephalus is slight and slowly progressive, a trial period of observation or medical management may be indicated, especially in preterm infants. Hydrocephalus in the preterm infant presents a therapeutic dilemma [Volpe, 2000]. In such infants, hydrocephalus may develop as a result of intraventricular hemorrhage originating from the periventricular germinal matrix. The intraventricular hemorrhage may lead to hydrocephalus by occlusion of the arachnoid granulations by breakdown products of the hemorrhage, although this theory remains unproved. Shunting for these infants frequently is unnecessary and hazardous [Brockmeyer et al., 1989]. The course of the ventricular dilation is variable; patients may demonstrate an arrest or reduction in ventriculomegaly with no treatment. Complications of shunting in this age group include a collapsed cortical mantle, subdural hemorrhage, marked cerebral conformational changes, and extensive intraparenchymal hemorrhage [Bass et al., 1995]. In view of the high morbidity for shunt placement in premature infants, multiple other interventions have been used. Studying the effectiveness of these interventions is challenging because of the variable course of posthemorrhagic ventricular dilation and the multiple other insults that occur in these infants. Acetazolamide and furosemide have been used to reduce cerebrospinal fluid output. A small study found a nonsignificant trend toward reduced shunt rates with use of diuretic therapy [Libenson et al., 1999]. The results of a larger, multicenter, randomized controlled trial, however, did not support the use of diuretics [Kennedy et al., 2001]. Shunt placement or death, the primary outcome measures, were higher in the diuretic treatment group (with furosemide and acetazolamide) than in the standard therapy group, although not significantly so. The principal secondary outcome measure of death in the first year of life or neurodevelopmental disability was significantly higher in infants

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receiving diuretic therapy. In addition, nephrocalcinosis developed in 25% of infants in the diuretic treatment group. Repeated lumbar punctures to remove cerebrospinal fluid are a common method of attempting to prevent ventricular dilation after intraventricular hemorrhage, and as a therapy to manage symptomatic hydrocephalus. The theory is that removal of cerebrospinal fluid containing blood and protein might allow the normal resorption of cerebrospinal fluid to be restored. There have been two trials of repeated lumbar punctures in preventing the development of hydrocephalus [Anwar, et al., 1985; Mantovani, 1980], and two trials of infants with intraventricular hemorrhage and progressive ventricular dilation that examined the effect of lumbar punctures [Dykes, 1989] or lumbar punctures or ventricular tapping [Ventriculomegaly Trial Group, 1990]. In addition, a Cochrane review performed a meta-analysis on the foregoing four studies [Whitelaw, 2005]. None of the studies demonstrated that cerebrospinal fluid tapping decreased the need for a shunt or decreased the likelihood of death or disability. The Ventriculomegaly Trial found a higher incidence of cerebrospinal fluid infections in those infants who received cerebrospinal fluid taps. The Cochrane review concluded that cerebrospinal fluid tapping for infants at risk of or having developed post-hemorrhagic hydrocephalus could not be recommended. However, the reviewer additionally said that despite the lack of evidence, cerebrospinal fluid tapping should still be considered for symptomatic raised intracranial pressure. Likewise, despite the lack of evidence, some experts continue to recommend the use of cerebrospinal fluid tapping in specific situations. Volpe [2000] advocates its use in infants with persistent slowly progressive ventricular dilation after intraventricular hemorrhage. He stresses that a sufficient quantity of cerebrospinal fluid must be removed, approximately 10 to 15 mL/kg. Some studies have examined the use of intraventricular fibrinolytics to prevent the development of hydrocephalus after intraventricular hemorrhage. So far, it appears that this is ineffective [Whitelaw, 1997]. Another option in patients with rapidly progressive ventriculomegaly who are too small for ventriculoperitoneal shunt placement, is placement of a direct ventricular drainage system. This includes an external ventricular drain, a subgaleal ventricular reservoir, or a subgaleal shunt. These devices can be used until the infant is large enough for permanent shunt placement. In addition, 25% of patients with these devices have arrest of their hydrocephalus, and do not require permanent shunt placement [Garton and Piatt, 2004]. Most hydrocephalic patients require placement of an extracranial shunt. These shunts redirect cerebrospinal fluid flow or circulation into the peritoneal or pleural cavity. Refinements of the Holter, Pudenz, and Hakim valves continue to be developed [McLaurin et al., 1989; Rekate, 1997; Turner, 1995]. Shunts cause cerebrospinal fluid to flow unidirectionally under the aegis of a valve system. Pressures required to overcome valve resistance are preset and can be used in patients with different pressure requirements. Ventriculoperitoneal shunting is the most accepted initial procedure. Use of an antisiphon device developed in the 1970s improved the success rate of shunting by reducing overdrainage of cerebrospinal fluid but was also associated with complications [DaSilva and Drake, 1991]. Many new

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valve types have been used in the hopes that they would decrease the incidence of shunt malfunction. Orbis-Sigma valves or Delta valves have flow/pressure characteristics that reduce overdrainage [Drake and Kestle, 1996]. However, use of these did not reduce time to first shunt failure [Kestle et al., 2000; Rekate, 1997]. Programmable valves are an alternative system that allow multiple pressure settings; as the child grows, adjustments in flow can be made. Study of the time to shunt failure with these valves, however, did not show any difference from standard valves [Pollack et al., 1999]. Similarly, studies on varying ventricular catheter position and endoscope-assisted catheter placement have found no improvement in outcome [Bierbrauer et al., 1990; Kestle et al., 2003]. Endoscopic third ventriculostomy is an alternative to cerebrospinal fluid shunting in appropriate patients [Barlow and Ching, 1997; Jones et al., 1996]. This creates an outlet in the floor of the third ventricle. Ventriculostomy is particularly useful in patients with congenital aqueductal stenosis that requires cerebrospinal fluid diversion and in selected patients with intracranial cysts or loculated cystic ventricular cerebrospinal fluid collections [Drake, 1993]. The ventriculostomy remains patent in 70% of patients. The ventricles do not decrease in size to the degree they do with a ventriculoperitoneal shunt, so determining the function of a ventriculostomy by neuroimaging can be difficult [Kestle, 2003]. In selected patients, ventriculoatrial shunting can also be used. However, the number of repeat surgeries to adjust the length of the atrial catheter or to revise the distal end favors ventriculoperitoneal shunt placement [Vernet et al., 1995]. The overall failure rate of shunts is 40% in the first year after placement. Common reasons for failure are obstruction, infection, disconnection, overdrainage, and loculated ventricles. Shunt malfunction caused by disconnection, kinking, or obstruction of the tubing results in typical signs and symptoms of increased intracranial pressure. Fever may occur if infection is present. In one series of patients whose shunts were tapped, normal cerebrospinal fluid values correlated with an overall incidence of complications of 39.2%, whereas abnormal cerebrospinal fluid values were correlated with a complication rate of 90.9% [Caldarelli et al., 1996]. Rates of infective complications were 2.7% in the patients with normal cerebrospinal fluid and 77.3% in patients with abnormal cerebrospinal fluid. In patients being evaluated for shunt malfunction, continuous intracranial pressure monitoring may provide additional information to determine the need for shunt revision [Fouyas et al., 1996]. Other complications of ventriculoperitoneal shunts include peritonitis, cerebrospinal fluid ascites, inguinal hernia, intraabdominal cysts, intracranial granulomas, gastrointestinal obstruction, migration of the shunt within the peritoneal cavity, headache, and perforation of abdominal viscera [Borgbjerg et al., 1995; Caldarelli et al., 1996; Ersahin et al., 1996; Key et al., 1995a; Sgouros et al., 1995]. Abdominal pseudocysts manifest with nausea, vomiting, and abdominal distention and pain; abdominal ultrasonography may demonstrate the cysts [Hann et al., 1985-1986]. Thromboembolic phenomena, cardiac dysrhythmias, cardiovascular perforation, endocarditis, catheter embolization, pulmonary thromboembolism, and immune complex shunt nephritis are special complications of ventriculoatrial shunts [Borgbjerg et al.,

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1995; Lam et al., 1997; McLaurin et al., 1989; Sleigh et al., 1993]. Correction of long-standing hydrocephalus may cause subdural hematomas. Staphylococcus epidermidis and Staphylococcus aureus are the most common causes of shunt-related infection, which usually occurs within 2 months of shunt placement. The infection rate varies but typically is less than 5% [Quigley et al., 1989]. Infection rates of 1% or less have been reported and have been attributed to optimal surgical technique [Choux et al., 1992; Kanev et al., 2003]. Organisms that ordinarily are nonpathogenic may cause infection in the presence of shunt tubing in the ventricles, body cavities, or circulation. Whenever suppurative infection is suspected, appropriate blood and cerebrospinal fluid specimens for culture must be obtained, the organism isolated, and sensitivities determined to facilitate effective antimicrobial therapy. Most shunts can be tapped to obtain cerebrospinal fluid specimens and to assess cerebrospinal fluid dynamics. If infection leads to impairment of the shunt mechanism, removal and replacement usually are required; temporary insertion of an external ventriculostomy may be necessary until the infection is controlled. Prophylactic antibiotics during shunt placement have significantly reduced the incidence of early-onset shunt infections [Venes, 1976]; however, this conclusion is not universally accepted [Shurtleff et al., 1985-1986; Slight et al., 1985].

Fetal Ventriculomegaly and Hydrocephalus The frequent use of prenatal ultrasound examination has led to increasing identification of fetal ventriculomegaly. Neurologists and geneticists often are called on to counsel families regarding this finding. One difficulty is that ventriculomegaly has a myriad of potential causes. In addition, the differentiation of fetal ventriculomegaly due to a developmental or destructive process of the periventricular white matter from fetal hydrocephalus can be challenging and sometimes impossible on prenatal ultrasound studies. Most experts define fetal ventriculomegaly as a lateral ventricular atrial measurement of greater than 10 mm between 15 and 40 weeks of gestation [Cardoza et al., 1988]. Ventriculomegaly is said to be mild when the measurement is between 10 and 15 mm, and severe at greater than 15 mm. Fetal ventriculomegaly is associated with a variety of congenital anomalies, chromosomal abnormalities, and congenital infections; thus, evaluation typically consists of karyotyping, screening for TORCH infections (toxoplasmosis, other infections [e.g., hepatitis B, syphilis, herpes zoster], rubella, cytomegalovirus infection, herpes simplex), and detailed ultrasound examination. Ventriculomegaly with atrial enlargement to greater than 15 mm is associated with a greater chance of abnormal neurologic development [Graham et al., 2001]. Studies of outcome in fetuses with mild ventriculomegaly tend to be small and methodologically variable, so comparing results is difficult. Kelly and associates [2001] reviewed the literature; on combining the data, they found that of almost 500 patients with mild ventriculomegaly, the incidence of chromosomal abnormalities was 9%. If no other malformations were identified, the incidence of chromosomal abnormalities was 4%. The incidence of other abnormalities varied, ranging from 33% to 61%. Studies of neurologic outcome in children with isolated mild fetal ventriculomegaly are small,

use little standardized testing, and have short monitoring periods. In these studies, the incidence of developmental delay varies, ranging from 0% to 36% [Alagrappan et al., 1994; Arora et al., 1998; Bloom et al., 1997; Bromley et al., 1991; Goldstein et al., 1990; Patel et al., 1994; Pilu et al., 1999; Senat et al., 1999; Vergani et al,. 1998]. In view of the conflicting results, it is difficult to know how to counsel families. The role of prenatal MRI in providing additional information is still being clarified. In one study of MRI in 36 fetuses with isolated mild ventriculomegaly the MRI results aided management in five cases: In two cases, ventriculomegaly was ruled out (MRI was normal); in two cases, germinal matrix hemorrhages were found; and in one case, periventricular cystic lesions and abnormal sulcation were detected [Valsky et al., 2004]. Studies of fetal hydrocephalus are likewise fraught with the difficulty of distinguishing hydrocephalus from ventriculomegaly due to other causes. A subset of patients can be more clearly determined to have hydrocephalus—for example, those with aqueductal stenosis, Dandy-Walker syndrome, and Chiari II malformation. Patients with prenatally diagnosed hydrocephalus have a worse outcome than that in patients diagnosed at birth or in the neonatal period [von Koch et al., 2003]. This finding has led to various trials of fetal surgical management, including percutaneous cephalocentesis [Birnholz and Frigoletto, 1981], and ventriculoamniotic shunt placement [Clewell et al., 1982; Frigoletto et al., 1982; Manning et al., 1986]. Overall, patients did not fare well, possibly as a result of poor patient selection. Accordingly, a voluntary moratorium on fetal surgery for hydrocephalus is in place. Interest in fetal shunting may be renwed, however, given that advances in neuroimaging may improve patient selection and surgical technique has improved [von Koch et al., 2003].

Prognosis The neurologic and intellectual disabilities among patients with hydrocephalus depend on many factors, including etiology and degree of hydrocephalus, thickness of the cortical mantle and corpus callosum [Fletcher et al., 1992], requirement for a shunt, and presence of other brain anomalies [Dennis et al., 1981; Laurence, 1969]. Associated conditions such as intraventricular hemorrhage, CNS infection [McLone et al., 1982], and hypoxia may dictate the ultimate prognosis more than the hydrocephalus. The predictive value of cortical mantle thickness remains controversial [Hunt and Holmes, 1976]. A series of 233 patients with congenital hydrocephalus were evaluated for longer than 20 years; 13.7% died. The average number of shunt revisions was 2.7. In this series of 233 patients, of 115 who underwent psychological evaluation, approximately 63% showed normal performance, whereas 30% had mild retardation, and 7% had severe retardation [Lumenta and Skotarczak, 1995]. A more recent study of 155 children followed from 1978 to 1983 found that the children with congenital hydrocephalus were less likely to require special education placement (29%) than were those in whom hydrocephalus was due to meningitis (52%) or intraventricular hemorrhage (60%) [Casey et al., 1997]. Epilepsy also is more prevalent among patients with hydrocephalus, and complications of shunt surgery appear

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to play a relatively minor role in its development [Piatt and Carlson, 1996]. Intellectual sequelae include significant scatter among Wechsler Intelligence Scale for Children-Revised (WISC-R) subtest scores, often with greater impairment of performance and motor tasks, as well as of nonverbal compared with verbal skills [Brookshire et al., 1995; O’Brien and Harris, 1993]. Normal intellectual function is present in 40% to 65% of patients who receive appropriate treatment [Dennis et al., 1981]. The probability of normal intelligence is enhanced if shunts are placed early and proper function is maintained. A study of 99 children ranging in age from 6 to 13 years with shunted or arrested hydrocephalus demonstrated a close correlation between the area of the corpus callosum and nonverbal cognitive skills and motor abilities [Fletcher et al., 1996]. Behavioral problems also are more common in children with hydrocephalus, irrespective of etiology [Fletcher et al., 1995].

Aqueductal Stenosis Aqueductal stenosis leads to a form of noncommunicating hydrocephalus. Partial or complete obstruction of the aqueduct of Sylvius is associated with congenital structural malformations, hemorrhage, infection, neoplasms, and vascular malformations. Concomitant occlusion of the subarachnoid space may occur. Specific pathologic types of aqueductal stenosis, including congenital narrowing, aqueductal forking, septum formation, and aqueductal gliosis, are difficult to differentiate clinically [Drachman and Richardson, 1961]. The inflammatory process subsequent to neonatal meningitis and intraventricular hemorrhage can cause aqueductal gliosis. Hereditary aqueductal stenosis is transmitted as an X-linked recessive trait [Edwards, 1961]. Rare cases of autosomal recessive inheritance also are reported [Castro Gago et al., 1996]. Aqueductal stenosis as part of the MASA syndrome (X-linked hydrocephalus with stenosis of aqueduct of Sylvius) and the L1CAM spectrum of disorders is described earlier (in the section on clinical characteristics). Aqueductal stenosis may accompany Arnold-Chiari malformations, myelomeningocele, and neurofibromatosis. Aqueductal stenosis also may be secondary to an existing communicating hydrocephalus [Nugent et al., 1979]. In experimental animals, vitamin A excess, mumps encephalitis, and other viral infections cause aqueductal gliosis with associated aqueductal stenosis and hydrocephalus [Volpe, 2000]. In humans, mumps encephalitis has been associated with acquired aqueductal stenosis and hydrocephalus after a latent period of 3 months to 4 years [Spataro et al., 1976]. The pathogenesis in experimental animals and humans may be the propensity for selective infection of ependymal cells by the mumps virus [Volpe, 2000]. Patients with congenital aqueductal stenosis are hydrocephalic at birth. Cranial ultrasonography demonstrates enlarged lateral and third ventricles with a normal or small fourth ventricle. Other neuroimaging techniques may detect tumor, vascular malformation, and associated congenital anomalies (see Figs. 19-35 and 19-36). Remarkably, some patients with congenital and even earlyacquired aqueductal stenosis are asymptomatic until later childhood or early adult life; some remain free of symptoms. When they become apparent, manifestations include findings

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consistent with chronic increased intracranial pressure, such as an enlarged head, headache, seizures, gait disturbance, decreased visual acuity, dementia, and occasionally cerebrospinal fluid rhinorrhea [Little et al., 1975]. Hypothalamic-pituitary disturbance may occur, including precocious or delayed puberty, impotence, short stature, obesity, hypothyroidism, temperature instability, diabetes insipidus, and amenorrhea. Abnormalities of growth hormone, antidiuretic hormone, thyroid-stimulating hormone, gonadotropins, and gonadotropin-releasing hormone have been documented [Fiedler and Krieger, 1975; Hier and Wiehl, 1977]. Treatment is similar to that for progressive hydrocephalus. After shunting procedures, patients with hypothalamic-pituitary disturbance often improve.

INTRACRANIAL ARACHNOID CYSTS Intracranial arachnoid cysts are benign, nongenetic developmental cysts that contain spinal fluid and occur within the arachnoid membrane [Gosalakkal, 2002]. The mechanism of formation during embryogenesis is uncertain [Hirano and Hirano, 2004; Naidich et al., 1985-1986]. Several mechanisms could account for the enlargement of these cysts including secretion by the cells forming the cyst walls, a unidirectional valve, or liquid movements secondary to pulsations of the veins [Gosalakkal, 2002]. The cysts occur in proximity to arachnoid cisterns, most often in the sylvian fissure (Table 19-18). Common neurologic features are headache, seizures, hydrocephalus, focal enlargement of the skull, and signs and symptoms of elevated intracranial pressure and developmental delay, as well as specific signs or symptoms resulting from neural compression. Some arachnoid cysts remain asymptomatic [Mason et al., 1997]. Progressive enlargement and intracystic or subdural hemorrhage are potential complications. Suprasellar arachnoid cysts may produce neuroendocrine dysfunction, hydrocephalus, and optic nerve compression. Posterior fossa cysts are now more frequently recognized with the use of MRI and CT and frequently require surgical treatment [Domingo and Peter, 1996]. In a series of 61 children with arachnoid cysts, about 53% of cases were diagnosed before age 1 year, 42% were supratentorial, and 46% infratentorial [Pascual-Castroviejo et al., 1991]. Macrocephaly was the presenting symptom in 72%, and associated features included cranial asymmetry in 39%, aqueductal stenosis in 16%, and agenesis of the corpus TABLE 19-18 Distribution of Arachnoid Cysts LOCATION

PERCENT OF CYSTS

Sylvian fissure Cerebellopontine angle Quadrigeminal area Vermian area and sellar-suprasellar area Interhemispheric fissure Cerebral convexity Clival area

49% 11% 10% 9% 5% 4% 3%

Modified from Rengachary SS, Watanabe I. Ultrastructure and pathogenesis of intracranial cysts. J Neuropathol Exp Neurol 1981;40:61.

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A

B

FIGURE 19-38. Arachnoid cyst. A, A cystic mass with signal intensity suggestive of cerebrospinal fluid is seen to deform the right temporal lobe (arrows) on this parasagittal image from a T1-weighted magnetic resonance imaging (MRI) study. B, Note the eroded appearance of the greater sphenoid wing (arrows) from the arachnoid cyst on this axial image from a spin density–weighted MRI study. (Courtesy of Joseph R. Thompson, Department of Radiation Sciences, Loma Linda University School of Medicine, Loma Linda, Calif.).

callosum in 13%. Developmental delay was a common finding. Skull radiographs may suggest the diagnosis; CT or MRI is the definitive diagnostic procedure [Weiner et al., 1987] (Fig. 19-38). Injection of contrast medium into the cyst to document communication with the ventricular system is seldom necessary.

Clinical Presentations Symptoms vary depending on the size of the cyst and its location. Several common locations have been well described in the literature. Sylvian Fissure/Middle Cranial Fossa. Nearly two thirds of pediatric arachnoid cysts are located in the sylvian fissure/middle cranial fossa [Gosalakkal, 2002]. They may increase in volume, opening the fissure and exposing the middle cerebral artery. This exposure may result in compression and underdevelopment of the anterior superior surface of the temporal lobe. The origins of these cysts have been the subject of debate since they were first described. Controversy remains concerning whether they originate directly from the meninges adjacent to the temporal pole or whether partial agenesis of the temporal lobe favors secondary formation of the cyst. Headaches are the most common presenting symptom; proptosis, contralateral motor weakness, and seizures also may occur. In 10% of children, developmental delay may be present. Treatment, as discussed later, depends on clinical symptoms. Recent studies have suggested some cognitive improvement after surgical treatment [Raeder et al., 2005]. Children with bitemporal arachnoid cysts also should be evaluated for the possibility of glutaricaciduria type 1 [Lutcherath et al., 2000]. Bitemporal

arachnoid cysts also have been reported in children with neurofibromatosis [Martinez-Lage et al., 1993] Sellar Region Cysts. Both suprasellar and intrasellar cysts can occur in children. Suprasellar cysts can cause third ventricular obstructive hydrocephalus at the level of the foramen of Monro and may be associated with visual impairment and endocrine dysfunction [Mohn et al., 1999]. Progressive head enlargement, growth retardation, developmental delay, and bitemporal hemianopsia have all been described. [Gosalakkal, 2002]. A bobble-head doll syndrome with involuntary head movements secondary to increased pressure on the third ventricle and dorsomedial thalamic nuclei is responsible [Fioravanti et al., 2004]. Endoscopic surgical approaches are now preferred. Posterior Fossa Arachnoid Cysts. Arachnoid cysts of the posterior fossa are uncommon and must be differentiated from other cystic malformations of the posterior fossa such as the Dandy-Walker malformation [Gosalakkal, 2002]. Macrocrania and raised intracranial pressure are frequently observed. Cerebellar cysts demonstrate nystagmus and other cerebellar signs. Other rare manifestations reported include cervical spinal cord compression, which may improve after posterior fossa cystoperitoneal shunting or endoscopic surgery. In such patients, gait disturbances and headache are commonly seen. Posterior fossa cysts may be very large [Lancon and Ellis, 2004] and also can occur in families [Sinha and Brown, 2004].

Complications Several clinical complications are believed to be associated with arachnoid cysts, although the relation between cyst

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presence and development of symptoms remains controversial; thus, the decision to operate is difficult and must be made on a patient-by-patient basis. Surgery is indicated when the cyst is causing obstructive hydrocephalus or if neuroimaging demonstrates mass effect with compression of normal brain or brainstem structures. The relation between symptoms such as attention-deficit disorder, aphasia, or migraine-like headaches is uncertain, and correlation between cyst location and specific symptoms or congruent EEG abnormalities is necessary before symptoms can be attributed to the cyst. Epilepsy. Anecdotal studies suggest a relation between seizure reduction after removal of arachnoid cysts [D’Angelo et al., 1999]. The relation between the presence of arachnoid cysts and occurrence of seizures when the intracranial pressure is normal is uncertain, however, and differences in outcomes whether patients are managed medically or surgically are similar [Koch et al., 1995]. In addition, interictal and ictal EEG may not correspond to the site of the arachnoid cyst, raising the question of whether the presence of an EEG abnormality is incidental. Subdural Hematoma and Hygroma. Subdural hematomas and hygromas are infrequently encountered complications of arachnoid cysts of the middle cranial fossa and are particularly rare with cysts in other regions [Donaldson et al., 2000]. Minor head trauma has been suggested to be a precipitating factor. Arachnoid cysts of the middle cranial fossa were found in 2.43% of patients with chronic subdural hematomas or hygromas in one report [Parsch et al., 1997]. Neuropsychiatric Disorders. Attention-deficit–hyperactivity disorder, speech delay, and developmental delay have been found in association with arachnoid cysts, particularly in the temporal lobe, but a causal relation remains uncertain [Millichap, 1997]. Mental impairment and developmental delay have been associated with large arachnoid cysts [Gosalakkal, 2002], and the presence of cysts and developmental delay may be part of a common developmental process. Recent studies have suggested improvements in cognition after surgical treatment [Raeder et al., 2005]. The increased incidence of arachnoid cysts in conditions such as Down syndrome, mucopolysaccharidosis, schizencephaly, and neurofibromatosis suggests a higher incidence in children with underlying abnormalities of the brain [Gosalakkal, 2002]. Aphasia, including that of Landau-Kleffner syndrome, also has been associated with the presence of left sylvian arachnoid cysts. Even in patients in whom CT and MRI failed to reveal mass effect, positron emission tomography (PET) has demonstrated hypometabolism in speech areas. Postoperative improvement in PET studies corresponded to improvement in vocabulary [De Volder et al., 1994].

Management When symptoms warrant, surgical intervention to decompress the cyst, including endoscopic management or shunting procedures, is required [Abbott, 2004; Germano et al., 2003; Godano et al., 2004; Raffel and McComb, 1988]. Arachnoid cysts may occur with or without hydrocephalus. The success rate of fenestration is higher in those patients without hydrocephalus (i.e., 73% required no additional treatment) than in hydrocephalus patients (32%) [Fewel et al., 1996]. About

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12% of patients with hydrocephalus treated with fenestration alone may require a cystoperitoneal shunt. In general, cyst fenestration should be the primary procedure in patients without hydrocephalus. If hydrocephalus is present, cyst fenestration is still recommended, but a ventriculoperitoneal shunt should be placed if hydrocephalus is marked or after fenestration if the hydrocephalus is progressive [Fewel et al., 1996]. Congenital intraspinal cysts also can occur and require surgical evaluation [Chang, 2004]

CONGENITAL ABNORMALITIES OF THE SKULL Classification The congenital abnormalities of skull ossification listed in Box 19-8 include primary skull or bone disorders and skull abnormalities associated with CNS and systemic disorders. Neurologic features of these disorders may include abnormal head size and shape, hydrocephalus, localized scalp mass or skull deformity, headache, proptosis, pulsating exopthalmos, premature or delayed closure of the cranial sutures and fontanels, large or small fontanels, and progressive compression of neural and vascular structures leading to elevated intracranial pressure and cranial nerve or spinal cord injury [Lachman, 1997]. Many bone diseases that affect the skull cause or are associated with skeletal abnormalities. Other noteworthy features include short stature, syndactyly, polydactyly, and frequent fractures of long bones. Examination of the skull includes determination of the greatest head circumference; palpation to detect ridging or separation of sutures, size of the fontanels, and skull defects or softening; and assessment of skull configuration and symmetry. The head circumference should be recorded sequentially and compared with appropriate growth charts [National Center for Health Statistics, 2005; Nellhaus, 1968]. The skull radiograph often is diagnostic. Skull disorders can be classified into abnormalities of sutures or ossification. The terminology used to describe skull abnormalities [Burrows and Leeds, 1981] includes sclerosis (increased density), hyperostosis (increased thickness), erosion (thinning from pressure resorption), destruction (from infiltration), and deformity (misshapen skull).

Normal Development and Anatomy The skeletal system develops from the mesodermal germ layer during the third week of gestation [Beals and Joganic, 2004]. The mesenchyme or embryonic connective tissue, a mesodermal derivative, forms the fibroblasts, chondroblasts, and osteoblasts. The large surface bones of the skull ossify directly from the mesenchymal tissues (membranous ossification) to form the cranial vault, or membranocranium. The smaller bones of the base of the skull and part of the occipital bone change from mesenchyme to cartilage before ossification (endochondral ossification) and compose the chondrocranium. The cranial vault and chondrocranium encase the brain and are collectively called the neurocranium. The term viscerocranium refers to the remaining bones of the skull and face, which are derived partly from the neural crest cells in the head region. The base of the

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Box 19-8 CONGENITAL ABNORMALITIES OF OSSIFICATION OF THE SKULL Decreased Ossification Associated major neural defect Anencephaly Cranium bifidum Dandy-Walker syndrome Encephalocele Holoprosencephaly Hydranencephaly Hydrocephalus Porencephaly Bone disorder or variation Biparietal thinning Cleidocranial dysostosis Fibrous dysplasia (monostotic, polyostotic) Hypophosphatasia Large sinus grooves Metopic fontanel Neurofibromatosis (sphenoid bone and lambdoid suture defects) Osteogenesis imperfecta Pacchionian granulations Parietal foramina Persistent emissary foramina Persistent fontanels Pyknodysostosis Sinus pericranii Venous lakes Increased Density and/or Thickness of the Skull (Sclerosis, Hyperostosis) Craniotubular bone-modeling disorders Craniodiaphyseal dysplasia Craniometaphyseal dysplasia Dysosteosclerosis Osteopetrosis Sclerosteosis Van Buchem’s syndrome Aminopterin embryopathy Craniosynostosis Fibrous dysplasia (monostotic, polyostotic) Myotonia congenita (Thomsen’s disease) Myotonic dystrophy Neurofibromatosis Pyknodysostosis Thickened normal cranial vault Tuberous sclerosis Deformity of the Cranial Base Achondroplasia Basilar impression Osteogenesis imperfecta Skeletal dysplasia Modified from Jacobson RI. Neurol Clin 1985; 3:119.

skull, including the foramen magnum, is prone to developmental defects, probably as a result of the more complex intrinsic control of endochondral bone formation. The membranous skull bones are joined by connective tissue at the sagittal, coronal, lambdoidal, metopic, and squamosal sutures (Fig. 19-39). These sutures are easily palpated in neonates and may be overriding as a consequence of normal cranial molding during delivery. The anterior fontanel is the soft spot at the junction of the frontal and parietal bones, which is the intersection of the metopic, coronal, and sagittal sutures. Normal closure of the anterior fontanel occurs between 6 and 20 months with a fibrous suture union. The oblique diameter of the anterior fontanel in neonates ranges from 0.6 to 3.6 cm [Duc and Largo, 1986]. A large, persistent anterior fontanel may constitute a normal variation or a pathologic feature of many disorders (Box 19-9) [Tan, 1976]. The posterior fontanel located at the junction of the lambdoidal and sagittal sutures closes by the age of 3 months. A third fontanel, actually a defect in ossification, may occur 2 cm anterior to the posterior fontanel in 6.3% of normal preterm and term infants and is common in infants with Down syndrome and congenital rubella [Chemke and Robinson, 1969]. Mature suture closure occurs by age 12 years, but completion of bony fusion continues at least through the third decade of life. Elevated intracranial pressure may separate the sutures, especially the sagittal suture, until ages 10 to 12 years. The timing of closure of the sutures and fontanels are listed in Table 19-19. Many developmental skull variations exist. Wormian bones are small, multiple bones that occur in sutures, particularly in the lambdoidal suture. They may be a normal variation but often occur in hydrocephalus and other skull disorders (see Box 19-9). Parietal foramina are symmetric, full-thickness congenital defects in the parietal bones close to the midline. They often are familial and may have no pathologic significance.

Genetic Mechanisms of Craniofacial Development A number of gene families have been shown to play important roles in craniofacial development [Aleck, 2004; Cobourne, 2000]. These genes act as regulators of gene transcription and are intimately involved with the control of complex interactions between multiple downstream genes. In vertebrates, Hox genes pattern the hindbrain and branchial regions of the developing head up to and including structures derived from the second branchial arch. The first branchial arch and more rostral regions of the head are patterned by groups of homeobox genes more divergent than the original Hox clusters. These gene families include several classes of homeobox genes: paired class (Oxt, Goosecoid, and Ant/Hesx1), antennapedia class (Emx and Hex/ Prh), Lim class (Lim1), and winged class (Forkhead and Hnf3) [Cohen, 2002]. Later during development, these genes function in brain patterning and neurogenesis. More recent studies as outlined by Trainor and colleagues [2003] suggest that neural crest cells can respond and adapt to the environment in which they migrate and, furthermore, that the cranial mesoderm plays an important role in patterning the identity of the migrating neural crest cells. These results support a new model called the neural crest plasticity and

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A

B

independent gene regulation model as a mechanism for describing neural crest and craniofacial development.

The Neural Crest The neural crest plays an important role in facial and cranial development [Chambers and McGonnell, 2002; Cobourne, 2000]. The facial mesenchyme is derived principally from the neural crest and not the mesoderm of the embryonic third germ layer. Neural crest cells migrate extensively throughout the embryo, and in the developing head, the cephalic neural crest migrates from the posterior midbrain and hindbrain regions into the branchial arch system. The ectomesenchymal neural crest cells then interact with epithelial and mesodermal cell populations present within the arches, leading to the formation of craniofacial bones, cartilages, and connective tissues. It is the rhombencephalic-derived neural crest that will give rise to the majority of the branchial arch mesenchyme. Development of the mid- and lower regions of the craniofacial complex is associated with these branchial regions. Neural crest cells that migrate and form the bulk of the facial mesenchyme arise from the same axial level of neural tube as the rhombomeres whose neurons will ultimately innervate that mesenchyme. Neural crest cells destined for the first branchial arch migrate from rhombomeres 1 and 2, whereas those for the second and third arches migrate from rhombomeres 4 and 6. The even-numbered rhombomeres (2, 4, and 6) contain the exit points for cranial nerves V, VII, and IX, which will innervate branchial arches 1, 2, and 3 [Cobourne, 2000]. Members of the zinc-finger transcription factor family (e.g., Slug, Snail), as well as bone morphogenetic proteins, fibroblast growth factors (FGFs) and members of the Wnt signaling family are recognized for their roles in neural crest induction, differentiation, and development [Trainor et al., 2003].

Gene Regulatory Mechanisms A role for Hox genes in patterning regions of the developing head and neck has been suggested. Expression domains of

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FIGURE 19-39. A, Posteroanterior radiographic view of a 9-month-old infant’s skull. B, Lateral skull film from the same infant. 1, coronal suture; 2, lambdoidal suture; 3, sagittal suture; 4, mendosal suture; 5, squamosal suture; 6, metopic suture, partially fused; 7, occipital mastoid suture. (Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School, Minneapolis, Minn.)

certain of the Hox genes cluster, however, do not extend into the first branchial arch or more rostral head regions, indicating that Hox genes are not involved in specification of neural crest from these more anterior levels [Cobourne, 2000]. The ems (empty spiracle) and otd (orthodenticle) gene families also are expressed in the anterior regions of the developing head in Drosophila. In mice, it has been found that Otx-2 is essential for formation of the rostral head, and craniofacial malformations may include loss of the lower jaw structures and the eye. As described by Cobourne [2000], these defects are consistent with human otocephalic mutations. Other homeobox-containing genes are expressed in the maxillary and mandibular arches and developing facial primordia. These genes include Msx-1, Msx-2, Dlx1-6, and Barx-1. Msx-1 and Msx-2 are strongly expressed in the neural crest–derived mesenchyme of the developing facial prominences and participate in skull and face development [Ferguson, 2000]. Members of the Dlx gene family also are required for the development of neural crest–derived skeletal elements of the first and second branchial arches. Goosecoid is another homeobox-containing transcription factor that in the wild type of mice has been detected at later stages of development in the osteogenic mesenchyme of the developing mandible, tongue, and middle ear. Goosecoid mutants have been associated with development of a hypoplastic mandible, as well as other osseous defects including involvement of the maxillary, palatine, and pterygoid bones. The endothelin-1 gene (ET1) is another gene that has been associated with facial anomalies in mice. It normally encodes a vasoactive peptide expressed in vascular endothelial cells that plays a role in the regulation of blood pressure, but targeted disruption of ET1 in mice is associated with marked reduction in tongue size, micrognathia, and cleft palate [Kurihara et al., 1994] The Sonic hedgehog gene (SHH) is the vertebrate homolog of the Drosophila hedgehog segment polarity gene. In the vertebrate embryo, SHH encodes a signaling peptide that is involved in mediating long- and short-range patterning [Cobourne, 2000]. Mutations of SHH in the human [Belloni

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Box 19-9 DIFFERENTIAL DIAGNOSIS OF SKULL ABNORMALITIES IN INFANTS Conditions Associated with Skull Softening Cleidocranial dysostosis Craniotabes Lacunar skull Osteogenesis imperfecta Multiple wormian bones Rickets Conditions Associated with Delayed Closure of the Anterior Fontanel Achondroplasia Aminopterin embryopathy Cerebrohepatorenal syndrome (Zellweger’s syndrome) Cleidocranial dysostosis Congenital rubella Down syndrome Hallermann-Streiff syndrome Hypophosphatasia Hypothyroidism Increased intracranial pressure—hydrocephalus, pseudotumor cerebri Malnutrition Osteogenesis imperfecta Pyknodysostosis Rickets Trisomies 13 and 18 Conditions Associated with Wormian Bones No pathologic significance Cleidocranial dysostosis Hydrocephalus (chronic) Hypophosphatasia Hypothyroidism Kinky hair disease Osteogenesis imperfecta Pyknodysosteogenesis Rickets (healing phase) Data from Burrows EH, Leeds NE. Neuroradiology, vol 1. New York: Chuchill Livingstone, 1981; and Lemire RJ, Loeser JD, Leech RW, et al. Normal and abnormal development of the human nervous system. Hagerstown, MD: Harper & Row, 1975.

TABLE 19-19 Timing of Closure of Sutures and Fontanels SUTURE/FONTANEL

CLOSURE

SKULL SHAPE

Metopic suture Coronal suture

9 months to 2 years 40 years

Sagittal suture

40 years

Lambdoid suture

40 years

Trigonocephaly Unilateral harlequin deformity, plagiocephaly Scaphocephaly/ dolichocephaly Unilateral: plagiocephaly Bilateral: brachycephaly

Anterior fontanel Posterior fontanel Anterior-lateral fontanel (pterion) Anterior fontanel (asterion)

15–18 months 3–6 months 3 months 2 years

From Aviv RI, Rodger E, Hall CM. Craniosynostosis. Clin Radiol 2002;57:93–102.

appears to play an important role in development of the mesoderm. FGFRs belong to a subgroup of the receptor tyrosine kinase family of signal transduction molecules and serve as the major binding proteins for FGFs. FGFR1, FGFR2, and FGFR3 are expressed widely during embryogenesis. FGFR1 and FGFR2 expression is noted in cartilage and bone precursors, whereas FGFR3 is found in highest concentration in the developing CNS but also in bone precursors involved with endochondral bone formation [FloresSarnat, 2002]. A detailed discussion of this topic is beyond the scope of this chapter, and the reader is referred to several recent monographs [Francis-West et al., 2003; Sperber, 2001] and reviews [Cobourne, 2000; Cohen, 2002; Trainor et al., 2003; Wilkie and Morriss-Kay, 2001] of this rapidly expanding field. An excellent and very comprehensive publication, Inborn Errors of Development: The Molecular Basis of Morphogenesis, is highly recommended [Epstein et al., 2004]. A review of selected genetic malformations, their chromosomal locations, and the associated mutationbearing genes is provided in Table 19-20.

Deformational Plagiocephaly et al., 1996; Roessler et al., 1996] lead to significant craniofacial abnormalities such as holoprosencephaly and cyclopia. Later in development, Shh is expressed in the ectoderm of the frontonasal and maxillary processes and has been found to be essential for their normal development. Transient loss of Shh signaling in chick embryos in regions of the developing face can result in defects analogous to hypotelorism and cleft lip/palate, whereas excess Shh leads to mediolateral widening of the frontonasal process resulting in hypertelorism [Cobourne, 2000]. Identification of mutations in Twist and fibroblast growth factor receptors (FGFRs) in craniosynostosis demonstrates their importance as critical signaling molecules during normal cranial development [Flores-Sarnat, 2002]. Twist is a class II basic helix-loop-helix transcription factor originally identified in Drosophila that also is present in humans and

Deformational or positional plagiocephalies (from the Greek, meaning “oblique head”) are common in children and frequently are confused with craniosynostosis [Persing et al., 2003]. Deformational plagiocephalies have been referred to by many names, such as benign positional molding, posterior plagiocephaly, occipital plagiocephaly, frontal plagiocephaly, and plagiocephaly without synostosis [Huang et al., 1998]. The incidence of plagiocephaly has been estimated to be as low as 1 in 300 live births to as high as 48% of typical healthy infants younger than 1 year, depending on the sensitivity of the criteria used to make the diagnosis [Persing et al., 2003]. By contrast, the incidence of isolated lambdoid craniosynostosis is quite rare, estimated to be approximately 3 in 100,000 births (0.003%). Two forms of plagiocephaly are recognized: deformational frontal plagiocephaly if the front of the cranial vault

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TABLE 19-20 Selected Genetic Disorders with Craniofacial Anomalies DISORDER Achondrogenesis type 1B Achondrogenesis type 2 Achondroplasia Acromesomelic dysplasia Alagille’s syndrome Albright’s hereditary osteodystrophy Apert’s syndrome Atelosteogenesis type II Bannayan-Riley-Ruvalcaba/Cowden syndrome Beare-Stevenson cutis gyrata syndrome Bloom’s syndrome Boston-type craniosynostosis Branchio-otorenal syndrome Camptomelic dysplasia Chondrodysplasia punctata, X-linked dominant type Chondrodysplasia punctata, X-linked recessive type Chondrodysplasia, rhizomelic type Cleft lip/palate, ectodermal dysplasia (AR) Cleidocranial dysplasia Conradi-Hunermann type Crouzon’s disease Crouzonodermoskeletal syndrome Diastrophic dysplasia Ectrodactyly-ectodermal dysplasia–clefting (EEC) syndrome Ellis–van Creveld syndrome Familial adenomatous polyposis/Gardner’s syndrome FG syndrome Fibrous dysplasia Fragile X syndrome Greig’s cephalopolysyndactyly Hay-Wells syndrome Holoprosencephaly (all types)

Hypochondroplasia Hypodontia Hypodontia/clefting Hypohidrotic ectodermal dysplasia Jackson-Weiss syndrome Jansen’s metaphyseal chondrodysplasia Langer-Giedion syndrome Mandibuloacral dysplasia Marfan’s syndrome McCune-Albright syndrome Mucolipidosis II Mucolipidosis III Mucopolysaccharidosis IH Mucopolysaccharidosis II Mucopolysaccharidosis IIIA Mucopolysaccharidosis IIID Mucopolysaccharidosis IS Mucopolysaccharidosis IVA Mucopolysaccharidosis IVB Mucopolysaccharidosis VI Mucopolysaccharidosis VII Muenke’s syndrome Multiple endocrine neoplasia type 2B Neurofibromatosis type 1 Neurofibromatosis type 2 Nevoid basal cell carcinoma syndrome

CHROMOSOMAL LOCATION(S)

MUTATION-BEARING GENE(S)

5q31-q34 12q13.1-q13.3 4p16.3 20q11.2 20p12 20q13 10q25.3-q26 5q31-q34 10q23 10q25.3-q26 15q26.1 5q34-q35 8q13.3 17q24.3 Xp11.22-p11.23 Xp22.3 6q22-q24 11q23 6p21

DTDST COL2A1 FGFR3 CDMP1 JAG1 GNAS1 FGFR2 DTDST PTEN FGFR2 BLM MSX2 EYA1 SOX9 3β-Hydroxysterol ARSE PEX PVRL1 RUNX2 D7 isomerase FGFR2 FGFR3 DTDST TP63 EVC FAP-GS FGS1 GNAS1 FMR1 GLI3 TP63 SIX3 GLI2 CRIPTO SHH FAST1 PTCH ZIC2 TGIF FGFR3 PAX9 MSX1 EDA2 EDA3 EDA1 FGFR2 [PTH/PTHrP]R TRPS1 and EXT1 LMNA FBN1 GNAS1 GNPTA GNPTA IDA IDS HSS GNS IDA GALNS GLBI ARSB GUSB FGFR3 RET NF1 NF2 PTCH

10q25.3-q26 4p16.3 5q31-q34 3q27 4p16 5q21-q22 Xq12-q21.31 20q13 Xq27.3 7p13 3q27 2p21 2q14 3p21-p23 7q36 8q24.3 9q22.3 13q32 18p11.3 4p16.3 14q12-q13 4p16 2q11-q13 2q11-q13 Xq12.2-q13.1 10q25.3-q26 3p21.1-p22 8q24.11-q24.13 1q21 15q21 20q13 4q21-q23 4q21-q23 4p16.3 Xq27.3-q28 17q25.3 12q14 4p16.3 16q24.3 3p21.33 5q13.3 7q21.11 4p16.3 10q11.2 17q11.2 22q11.21-q13.1 9q22.3

continued

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TABLE 19-20, cont’d Selected Genetic Disorders with Craniofacial Anomalies DISORDER Opitz’s BBB/G syndrome Osteogenesis imperfecta Papillon-Lefevre syndrome Parietal foramina Peutz-Jeghers syndrome Pfeiffer’s syndrome Popliteal pterygium syndrome Pfeiffer’s syndrome Pyknodysostosis Rieger’s syndrome Rubinstein-Taybi syndrome SADDAN syndrome Saethre-Chotzen syndrome Septo-optic “dysplasia” Simpson-Golabi-Behmel syndrome Smith-Lemli-Opitz syndrome Soto’s syndrome Spondyloepiphyseal dysplasia congenita Stickler’s syndrome Thanatophoric dysplasia type 1 Thanatophoric dysplasia type 2 Townes-Brocks syndrome Treacher Collins syndrome Trichodento-osseous syndrome Trichorhinophalangeal syndrome Tuberous sclerosis Van der Woude’s syndrome Waardenburg’s syndrome type 1 Waardenburg’s syndrome type 2 Wiedemann-Beckwith syndrome

CHROMOSOMAL LOCATION(S)

MUTATION-BEARING GENE(S)

Xp22 7q22.1 17q21.31-q22.05 11q14 5q34-q35 11p11.2 19p13.3 8p11.2-p12 1q32-q41 10q25.3-q26 1q21 4q25-q27 16p13.3 4p16.3 7p21 3p21.1 Xq26 11q12-q13 5q35 12q13.1-q13.3 6p21 12q13.1-q13.3 4p16.3 4p16.3 16q12.1 5q33-q33.1 17q21 8q24.12 9q33-q34 16p13.3 1q32-q41 2q37 3p12-p14 11p15.5

MID1 COL1A2 COL1A1 CTSC MSX2 ALX4 STK11 FGFR1 IRF6 FGFR2 CTSK RIEG CBP FGFR3 TWIST HESX1 GPC3 DHCR7 NSD1 COL2A1 COL11A1 COL2A1 FGFR3 FGFR3 SALL1 TCOF1 DLX3 TRPS1 TSC1 TSC2 IRF6 PAX3 MITF IGF2, p57KIP2

SADDAN, severe achondroplasia with developmental delay and acanthosis nigricans. From Cohen MM Jr. Malformations of the craniofacial region: Evolutionary, embryonic, genetic, and clinical perspectives. Am J Med Genet 2002;115:245-268.

is involved [Hansen and Mulliken, 1994] and deformational posterior plagiocephaly when the posterior aspects of the skull are affected [Pollack et al., 1997]. In children with deformational frontal plagiocephaly, one side of the forehead is flat, sometimes the cheek and lower jaw are small, an ear is positioned farther back, and the eyelid opening may look smaller. All of these characteristics occur on the same side as the flattened forehead. About two thirds of infants with deformational frontal plagiocephaly have a head tilt toward the shoulder on the affected side as a result of torticollis. In children with deformational posterior plagiocephaly, the back of the head is flat on one side, the ear on that side is further forward than normal, and often, minor flattening of the forehead is seen on the opposite side. Deformational posterior plagiocephaly also can be bilateral, occurring on both sides. Table 19-21 summarizes features of deformational frontal plagiocephaly and deformational posterior plagiocephaly and compares clinical features of these entities with those in children with isolated coronal or lambdoid synostosis. Plagiocephaly typically is present at or shortly after birth and usually is due to in utero or intrapartum molding associated with uterine constraint, multiple births, birth injury from forceps or vacuum-assisted delivery, and prematurity [Persing et al., 2003]. In a majority of infants, plagiocephaly

resolves spontaneously during the first few months of life. In some infants who continue to rest their head asymmetrically on the flattened side of the occiput the deformity may persist. Before the 1990s, a majority of plagiocephalies involved the frontal regions, but this predilection has shifted, with deformational posterior plagiocephaly more common at present. Presumably this evolved because of the recommendations of the American Academy of Pediatrics and others that infants be placed on their backs for sleep [American Academy of Pediatrics, 1992], because prone and side sleeping during early infancy had been linked with sudden infant death syndrome.

Diagnosis and Treatment Confirmation of deformational frontal plagiocephaly or deformational posterior plagiocephaly requires skull radiographs or CT scanning that demonstrates the absence of synostosis [Glat et al., 1996]. Management of deformational plagiocephaly involves counseling of parents, mechanical adjustments, and exercises as reviewed in a clinical report from the American Academy of Pediatrics [Ellenbogen et al., 2000; Persing et al., 2003]. Parental assistance in

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TABLE 19-21 Distinctions between Common Synostoses and Deformational Plagiocephalies Unicoronal Synostosis versus Frontal Deformational Plagiocephaly ANATOMIC FEATURE

CORONAL SYNOSTOSIS

FRONTAL DEFORMATIONAL PLAGIOCEPHALY

Ipsilateral superior orbital rim Nasal root Ipsilateral cheek Chin deviation Ipsilateral palpebral fissure Anterior fontanel deviation

Up and high

Down

Ipsilateral Forward Contralateral Wide, low

Midline Backward Ipsilateral Narrow, high

Contralateral

None

Lambdoid Synostosis versus Occipital Deformational Plagiocephaly ANATOMIC FEATURE

LAMBDOID SYNOSTOSIS

OCCIPITAL DEFORMATIONAL PLAGIOCEPHALY

Posterior bossing

Contralateral occipitoparietal Contralateral Posterior and low Tilted

Contralateral occipital Ipsilateral Anterior No tilt

Frontal bossing Ipsilateral ear Skull base

From Aviv RI, Rodger E, Hall CM. Craniosynostosis. Clin Radiol 2002;57:93–102.

performing exercises is required, to reduce the likelihood of development of a severe deformity. Parents should be instructed when their infants are 2 to 4 weeks of age to place the child in the supine position for sleeping, alternating positions (i.e., left and right occiputs); when awake, the infant should be placed in the prone position. Infants should spend minimal time in car seats (when not a passenger in a vehicle) or other seating that maintains the supine position. Once deformational plagiocephaly has developed, these same preventive strategies may be used to reduce progression. It also is important to monitor head shape closely until the physician is certain that improvement will continue, usually when the infant is old enough to sit, crawl, or spend less time lying on the back. In children with neurologic disorders such as cerebral palsy, microcephaly, or global delay, this time frame is likely to be much longer than in children who are unaffected. Because torticollis can worsen plagiocephaly, neck rotation exercises should be implemented. As outlined in the American Academy of Pediatrics report, exercises to stretch the sternocleidomastoid muscle should be done with each diaper change [Persing et al., 2003]. One hand is placed on the child’s upper chest, and the other hand rotates the child’s head gently so that the chin touches the shoulder for approximately 10 seconds. The head is then rotated toward the opposite side for the same duration. A second exercise that stretches the trapezius muscle should then be done. The head is tilted so that the infant’s ear touches his or her shoulder for approximately 10 seconds and should be repeated contralaterally. Progression or lack of improvement warrants referral to a pediatric neurosurgeon, a general neurosurgeon with expertise in pediatrics, or a craniofacial surgeon or craniofacial team to establish the diagnosis and direct subsequent management, which may include molding helmets or surgery

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[Kaufman et al., 2004]. Referral to a physical therapist also should be considered if torticollis does not improve with neck-stretching exercises within 2 to 3 months. Skullmolding helmets, usually used in infants 4 to 12 months of age, may help correct atypical skull shapes, although repositioning of infants may be equally effective. Surgery may be necessary in approximately 10% of children with deformational plagiocephaly when the deformities are severe and resistant to nonsurgical measures [David and Menard, 2000; Littlefield, 2004; O’Broin et al., 1999; Rekate, 1998].

Craniosynostosis Although clinical descriptions of craniosynostosis date back to Hippocrates and Galen, the first modern scientific investigator to describe the anatomic structure of calvarial sutures and the results of their premature closure was Sommering in 1800 [Jimenez et al., 2002]. It was Virchow, however, who first coined the term craniostenosis, in 1851, and who proposed that bone growth occurs perpendicular to an open suture and that premature fusion of sutures results in calvarial deformities secondary to restrictive bone growth perpendicular to the closed suture and compensatory bone growth in directions parallel to the fused suture. Subsequently, the American surgeon Lane performed the first surgical procedure for craniosynostosis in a 9-monthold infant with microcephaly, and the French surgeon Lannelogue performed bilateral strip craniectomies for sagittal synostosis in 1890 [Jimenez et al., 2002]. In 1894 Jacobi reported his unsuccessful treatment of 33 microcephalic patients with presumed craniosynostosis, and this had the effect of dampening interest in the surgical treatment of craniosynostosis for the next 30 years. Surgical treatment for craniosynostosis to prevent blindness and other associated complications was reintroduced by Faber and Town in 1927. Their successful outcomes, combined with low morbidity and mortality, fostered wide acceptance of the concept of surgical correction for craniosynostosis; since then, many surgical techniques have been introduced.

Pathogenesis Primary craniosynostosis results from premature fusion of single or multiple cranial sutures that deforms the skull or face. The process of premature fusion begins in utero and can be detected in neonates. The primary pathologic bony defect restricts normal growth across the affected sutures and consequently may limit adequate brain growth, resulting in neurologic deficits. In other infants, postnatal onset of craniosynostosis may develop [Connolly et al., 2004]. Primary craniosynostosis occurs in up to 1 in 2000 to 1 in 2500 births. The shape and size of the skull depend on adequate brain growth without restriction. Inadequate brain growth, such as that occurring in microcephaly or after surgical shunting of severe hydrocephalus, may also result in premature closure of cranial sutures—secondary craniosynostosis. Secondary craniosynostosis does not further compromise the already impaired brain growth. The etiology of primary craniosynostosis may be a defect in the mesenchymal layer of the ossification centers within the skull. Pathologic examination reveals obliterated sutures

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that can be distinguished from normal suture closure [Albright and Byrd, 1981]. Evidence for a systemic disorder of mesenchymal tissue and ossification includes the craniosynostosis syndromes associated with facial and skeletal deformities [Cohen, 1988]. Mechanical factors also may cause craniosynostosis (e.g., experimental bony defects, such as a ridge placed across a suture, intrauterine compression, inadequate brain development) [Jones, 1997]. Another often-mentioned but controversial explanation ascribes craniosynostosis to a deformity of the cranial base that alters the tensile forces on the sutural sites of attachment of the dura mater [Albright and Byrd, 1981]. Failure of the bony microspicules that

normally bridge sutures to fracture, with the resultant sutural bony buildup, also has been suggested [Burke et al., 1995]. In infants and children, craniosynostosis may result from chromosomal disorders, hematologic disorders with bone marrow hyperplasia, endogenous or exogenous hyperthyroidism, and abnormal calcium and phosphorus metabolism, including that of rickets, hypercalcemia, and hypophosphatasia. Most patients have isolated craniosynostosis of unknown etiology, however. Over the past decade, the role of the dura in maintaining sutural patency has been extensively studied [Panchal and Uttchin, 2003]. The dura appears to initially play an induc-

TABLE 19-22 Major Craniosynostosis Syndromes SYNDROME

GENETICS

FGFR-Related Craniosynostosis Syndromes Apert’s syndrome (ACS1) AD 10q26 FGFR2 Crouzon’s disease (CFD1) Jackson-Weiss syndrome Pfeiffer’s syndrome (ACS5)

AD 10q26 FGFR2 AD FGFR2 AD 10q23-q2 FGFR2 8p12-p11.2 FGFR1

Muenke’s syndrome

4p16.3 FGFR3

Beare-Stevenson syndrome

10q26 FGFR2

TWIST-Related Craniosynostosis Syndromes Saethre-Chotzen syndrome 7p21 (ACS3) AD TWIST gene Baller-Gerold syndrome AR MSX-Related Craniosynostosis Syndromes Boston-type craniosynostosis AD 5q34-35 MSX2 gene

Fibrillin-Related Craniosynostosis Syndromes Shprintzen-Goldberg syndrome AD 15q21.1 Other Craniosynostosis Syndromes Antley-Bixler syndrome

7q11.2

Carpenter’s syndrome (ACS2)

AR

Hunter-McAlpine syndrome

AD 17q23-24

CLINICAL FEATURES

Multiple synostoses, with coronal most common, severe fusion syndactyly of hands and feet, hypertelorism, proptosis; downslanting palpebral fissures; mental retardation common Two subgroups: 1. Classic: above with mid-digital hand mass with single nail common to digits 2 through 4 2. Atypical: above but without mid-digital hand mass Coronal craniosynostosis, shallow orbits, proptosis, parrot-beaked nose, short upper lip, hypoplastic maxilla

Coronal and basal skull suture involvement, broad big toes, tarsal fusion, syndactyly, craniofacial abnormalities Coronal synostosis; broad, short thumbs and toes, polydactyly, syndactyly Three subgroups [Cohen, 1993]: 1. Classic type with broad, short thumbs and toes, polydactyly, normal neurologic outcome (AD) 2. Cloverleaf skull with Pfeiffer’s hands (sporadic) 3. Similar to 2 but without cloverleaf skull (AD) Coronal craniosynostosis, on radiograph abnormalities of hands and feet, including thimble-like middle phalanges, coned epiphyses, and carpal and tarsal fusions; hearing loss, developmental delay Craniosynostosis, ear defects, cutis gyrata, acanthosis nigricans, anogenital anomalies, skin tags, and prominent umbilical stump Asymmetric coronal synostosis with facial asymmetry, plagiocephaly, low-set frontal hairline, ptosis, brachydactyly, syndactyly, seizures, hearing loss, cervical spine fusion Multiple synostoses, radial aplasia, short stature, imperforate anus, rectovaginal fistula, mental retardation Four phenotypes described: 1. Fronto-orbital recession 2. Frontal bossing 3. Turribrachycephaly due to coronal craniosynostosis 4. Cloverleaf skull Synostosis of multiple sutures, mandibular and maxillary hypoplasia, multiple abdominal hernias, exophthalmos, mental retardation Craniosynostosis, severe midface hypoplasia, proptosis, choanal atresia/stenosis, frontal bossing, dysplastic ears, depressed nasal bridge, radiohumeral synostosis, long bone fractures and femoral bowing, and urogenital abnormalities Acrocephaly or turricephaly with brachydactyly, syndactyly, preaxial polydactyly, soft tissue syndactyly, obesity, hypogenitalism; mental retardation may occur Brachyphalangia, mental retardation, almond-shaped palpebral fissures, downturned or small mouth, short stature

ACS, acrocephalosyndactyly; AD, autosomal dominant; AR, autosomal recessive; CFD1, craniofacial dysostosis type 1. Data from Online Mendelian Inheritance in Man (OMIM), 2005.

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tive role; later, it assumes a permissive role in maintaining sutural patency through various signaling factors. Previous studies have documented an increased level of TGF-β and messenger RNA levels locally, indicating an interaction between the dura and overlying sutures at the time of closure [Most et al., 1998]. Other studies have demonstrated that dura mater transplanted from beneath normally patent sutures to sites of sutural fusion in a naturally occurring craniosynostotic rabbit model successfully kept these sites from re-obliterating [Mooney et al., 2001]. The interaction between the brain and patency of the overlying sutures has been amply proved by clinical evidence showing the premature closure of sutures in the presence of microcephaly and continuing patency in the presence of hydrocephalus [Panchal and Uttchin, 2003]. Secondary craniosynostosis also can develop after placement of a shunt in a child with hydrocephalus (shunt-induced craniosynostosis) because of a drop in intracranial pressure and diminution of neural thrust. The neural thrust and patency of the overlying sutures are closely integrated through the dura. The dura also serves as an intermediary source of signaling, which is mediated by transforming growth factor, FGFR, Twist, and MSX2. Many theories have been advanced to explain craniosynostosis; the vast array of clinical syndromes has defied a unifying hypothesis [Becker and Hinton, 1995; Cohen, 1988, 2000; Epstein et al., 2004; Flores-Sarnat, 2002]. The etiology of craniosynostosis must include contributions from developmental, mechanical, metabolic, and genetic factors that influence skull growth. More recently, several of the syndromic forms of craniosynostosis have been associated with identified

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deletions of genes (Table 19-22 and Fig. 19-40) that code for the FGFRs [De Moerlooze et al., 1997; Epstein et al., 2004; Muller et al., 1997; Mulliken and Warman, 1996]. Crouzon’s disease is associated with a deletion of the FGFR2 gene on chromosome 10 [Bresnick et al., 1995]. Specifically, lower levels of FGFR2 staining could be demonstrated from stenosed sutures removed at surgery. Children with nonsyndromic craniosynostoses did not demonstrate this abnormality. Members of the FGF family and their receptors play essential roles in regulating cellular proliferation, differentiation, and tissue patterning during vertebrate embryogenesis [Yamaguchi and Rossant, 1995]. A report including 61 persons from 20 unrelated families found coronal synostosis resulting from an amino acid substitution that results from a single point mutation in the FGFR3 gene on 4p [Muenke et al., 1997]. Other syndromic forms of craniosynostosis, including Pfeiffer’s, JacksonWeiss, and Apert’s syndromes, or autosomal-dominant nonsyndromic forms also are associated with mutations involving the FGFR2 gene [Muller et al., 1997; Steinberger et al., 1996]. In some cases of Crouzon’s disease and Pfeiffer’s syndrome, mutations of the FGFR1 and FGFR3 gene have been observed. Mutations of the transcriptional regulator gene MSX2 and TWIST genes have also been reported in patients with craniosynostosis [Wilkie, 1995]. In many of the disorders associated with these gene defects, highly variable phenotypes exist even within one family. Thus, the clinically distinct craniosynostotic syndromes are extremes of a spectrum of craniofacial abnormalities and not nosologic entities [Muller et al., 1997; Steinberger et al., 1996].

Greig: 7p, GLI-3 Stickler: 12q, COL2A1; : 6p, COL11A2 DiGeorge: 22q Velocardiofacial: 22q Van der Woude: 1q Treacher Collins: 5q Saethre-Chotzen: 7p Cleidocranial dysplasia: 6p

Waardenburg I: 2q, PAX3 II: 3p, MITF Boston type CS: 5q, MSX2 Apert: 10q, FGFR2 Crouzon: 10q, FGFR2 Pfeiffer: 8p, FGFR1 : 10q, FGFR2

Holoprosencephaly: 2p, 7q Jackson-Weiss; 10q, FGFR2 Adelaide type CS: 4p Achondroplasia: 4p, FGFR3 Thanatophoric dysplasia: 4p, FGFR3

FIGURE 19-40. Syndromes associated with craniofacial malformations and craniosynostosis (CS) and their respective genetic abnormalities. (Courtesy of Dr. John B. Mulliken. Updated from a figure in Mulliken and Warman, 1996; the engraving of the full-term infant skull was originally taken from JBM Bougery, Traité complet de L’Anatomie de l’Homme, vol. 1, plate 14, Paris, 1831.)

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Clinical Characteristics Normal skull growth occurs perpendicular to each suture. If one suture is fused before birth, compensatory growth during infancy occurs parallel to that fused suture or across the non-united sutures, producing a characteristic abnormal head shape. More complex abnormalities of head shape and size occur with multiple suture fusion, such as cloverleaf skull malformation (kleeblattschädel). The deformity of the skull may be mild at birth; during ensuing rapid head growth the abnormal shape is exaggerated. Craniosynostosis is usually sporadic and occurs without associated anomalies. The rate of prevalence is about 0.04% to 0.1%. Approximately 2% to 8% of patients with isolated craniosynostosis have a familial defect. Craniosynostosis is occasionally associated with various anomalies and genetic and sporadic craniofacial disorders, including Apert’s, Saethre-Chotzen, and Carpenter’s syndromes and Crouzon’s disease, which have extracranial manifestations such as syndactyly, polydactyly, dysmorphic facies, midfacial hypoplasia, beaklike nose, and proptosis [Cohen, 1988]. Bilateral coronal and basal skull synostoses are common with these genetic disorders. Neuropathologic findings occasionally associated with craniosynostosis include holoprosencephaly, agenesis of the corpus callosum, hydrocephalus, Arnold-Chiari malformation, and myelodysplasia [Friede, 1989]. Choanal atresia also may accompany craniosynostosis and requires early surgical intervention. Cosmetic defects, restriction of brain growth with elevated intracranial pressure, and associated maldevelopment of facial and orbital structures are the important clinical features and focus of evaluation. Hydrocephalus, mental retardation, and symptoms associated with spinal cord anomalies also may develop [Hemmer et al., 1987; Noetzel et al., 1985]. Obstructive sleep apnea may also occur [Tajima and Imai, 1994]. Clinical diagnostic features of craniosynostosis include abnormal asymmetric craniofacial appearance, sutural ridging, and early closure of the fontanels. A small fontanel also may result from hyperthyroidism, primary microcephaly, a wormian bone (anterior fontanel bone), and other normal variations. In a neonate, palpable ridging of a suture suggests premature synostosis. Positional or birth molding needs to be excluded. The sutures can be separated with gentle palpation in the cases of overriding sutures resulting from birth molding. Cloverleaf skull or kleeblattschädel usually occurs as a result of premature closure of the cranial sutures, with accompanying hydrocephalus, proptosis, visual loss, and cranial base and midfacial hypoplasia [Goh et al., 1997; Zuccaro et al., 1996]. This rare malformation is associated with various congenital syndromes. Plain skull radiographs are usually diagnostic of craniosynostosis; hyperostotic bony fusion and obliteration of the suture characterize primary craniosynostosis. Highresolution three-dimensional CT reconstruction scanning is the radiologic procedure of choice for determining the extent of premature bone fusion [Abrahams and Eklund, 1995; Benson et al., 1996; Vannier et al., 1994]. In secondary craniosynostosis resulting from microcephaly, complete bone fusion is usually not observed, and the skull typically is symmetric. MRI is particularly useful in identifying the wide variety of

primary and secondary CNS malformations described in patients with craniosynostoses [Tokumaru et al., 1996].

Classification Several overlapping classifications of the craniosynostoses are commonly used. The most common is based according TABLE 19-23 Classification of Craniosynostosis TYPE

DISORDER

Primary head shape syndrome

Scaphocephaly Brachycephaly Plagiocephaly

Associated conditions

SUTURE(S) AFFECTED

Sagittal Coronal Coronal, lambdoidal, or both (unilateral) Trigonocephaly Metopic Oxycephaly Multiple Apert’s syndrome Coronal and basal skull Carpenter’s syndrome Coronal and basal skull Crouzon’s disease Coronal and basal skull Chromosomal abnormality Endocrine: hyperthyroidism (endogenous and exogenous), hypophosphatasia, hypercalcemia, rickets Hematologic diseases with bone marrow hyperplasia Inadequate brain growth: microcephaly, post-shunted hydrocephalus

Modified from Jacobson RI. Neurol Clin 1985;3:117.

FIGURE 19-41. Sagittal synostosis. Plain skull film from a 6-week-old infant demonstrates premature fusion and sclerosis of the sagittal suture. Note the elongated skull—scaphocephaly. (Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School, Minneapolis, Minn.)

Gleeson, Dobyns, Plawner, and Ashwal / Congenital Structural Defects

FIGURE 19-42. Spiral computed tomography in craniosynostosis. The arrow on the ridged surface indicates the synostosis. The patient was a 6-month-old child. (From Binaghi S, Gudinchet F, Rilliet B. Three-dimensional spiral CT of craniofacial malformations in children. Pediatr Radiol 2000;30:856.)

to the abnormal shape of the skull produced by the prematurely closed suture or sutures [Cohen, 1988; McIntyre, 1997]. In practice, craniosynostosis is described by the involved suture or sutures (Table 19-23). Craniosynostoses are also classified as “primary” (idiopathic or genetic) or “secondary” (secondary to systemic or neurologic diseases). Other classifications have divided the craniosynostoses into “syndromic” and “nonsyndromic” groups. With the advent of determining the underlying molecular etiologies of craniosynostosis, genetic classification schemes are currently evolving [Epstein et al., 2004; Flores-Sarnat, 2002; Steinberger et al., 1996]. Sagittal Synostosis. Premature fusion of the sagittal suture (scaphocephaly) is the most common form of craniosynostosis, comprising approximately 60% of all types. Most patients are boys; the defect may be familial and is usually not syndromic. The anteroposterior diameter of the skull is elongated and the transverse diameter decreased (Figs. 19-41 and 19-42). This abnormal head shape is present at birth, with palpable ridging over the sagittal suture. The neurologic examination is normal in most patients [Boop et al., 1996a]. Scaphocephaly (dolichocephaly) in premature infants results from positional molding and not from premature suture closure. Coronal Synostosis. Bilateral coronal synostosis (brachycephaly) comprises about 20% of cases of craniosynostosis and is more common in females (Fig. 19-43). The skull is shorter in the anteroposterior diameter but is widened with a high vault; the occiput and forehead are flattened. The anterior fontanel is displaced anteriorly, and ridging may be palpated over the prematurely closed coronal sutures. Neurologic features, especially in untreated cases, include proptosis, strabismus, papilledema, and optic atrophy [Gupta et al., 1993]. The skull radiograph may document an elliptic orbit, or harlequin eye sign, on the side of the coronal synostosis (Fig. 19-44). Single Synostosis. Single synostosis, or plagiocephaly, describes the asymmetric skull without indicating which suture is involved. Unilateral closure of a coronal suture,

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FIGURE 19-43. Three-dimensional craniofacial shaded surface display. Study performed in a 2-day-old infant with compound craniosynostosis secondary to Crouzon’s syndrome demonstrates bilateral incomplete coronal synostosis associated with compensatory widening of the metopic (large arrow) and temporoparietal (small arrows) sutures. (From Binaghi S, Gudinchet F, Rilliet B. Three-dimensional spiral CT of craniofacial malformations in children. Pediatr Radiol 2000;30:856.)

lambdoidal suture, or both causes an asymmetric skull. In lambdoidal synostosis, the ipsilateral ear is displaced anteriorly, one frontal bone is larger than the other, and the occipital bones manifest a similar but contralateral asymmetry [Hinton et al., 1984]. The head shape is skewed to resemble a parallelogram. Both lambdoidal synostosis and deformational forces have been implicated as potentially causal in the pathogenesis of this deformity [Dias and Klein, 1996]. Enlarged subarachnoid spaces also have been observed in children with occipital plagiocephaly; this feature may increase the compliance and malleability of the calvaria and sutures and predispose the affected child to the development of a positional deformity [Sawin et al., 1996]. A similar head shape occurs in infants with congenital torticollis but without craniosynostosis. Congenital muscular torticollis, or congenital wryneck, consists of head tilt and unilateral shortening and contracture of the sternocleidomastoid muscle. During early infancy the head and face become progressively deformed, producing asymmetry of the head that may mimic plagiocephaly from craniosynostosis—that is, flat contralateral occiput and ipsilateral face and frontal area. Characteristic clinical features include head tilt towards the side of the affected muscle with the chin turned to the opposite side. By contrast, patients with coronal plagiocephaly have head tilt that is due to extraocular muscle dysfunction rather than to the skull deformity [Gosain et al., 1996]. Metopic Synostosis. Premature closure of the metopic suture (trigonocephaly) results in a pointed forehead with a prominent ridge in the midforehead area. The eyes are close together, the forehead is narrow, and the anterior skull appears triangular when viewed from above. Some patients may have related abnormalities, including mental retardation, cleft palate, coloboma, anomalies of the urinary tract, and holoprosencephaly. The incidence of metopic synostosis ranges from 1 in 7000 to 1 in 70,000 live births. It usually occurs as an isolated synostosis and several subtypes have

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A

B

C

D

FIGURE 19-44. Unilateral coronal synostosis in a 1-year-old male infant. A, Axial cut from a computed tomography (CT) study with bone windowing demonstrates “contraction” of skull base on the left side of the synostosis (arrows). B, Cut-away ventral view of inner calvaria from the same study as in A using CT with three-dimensional reconstructions. Note elevated left sphenoidal wing (arrow). C, Viewing skull from above, with the same threedimensional data, the sagittal suture (arrow) can be seen to be rotated away from the synostotic suture and the flattened contour of the skull around it. D, Flattened skull deformity is well demonstrated looking from below. (Courtesy of Joseph R. Thompson, Department of Radiation Sciences, Loma Linda University School of Medicine, Loma Linda, Calif.)

been categorized based on the severity of the skull base deformity. In 10% to 20% of patients, other sutures are involved, and in 2% to 5% of patients, the condition is familial. Intracranial hypertension has been observed in some patients but is never severe [Collmann et al., 1996]. Disorders of visual function, such as astigmatism and strabismus, can occur with trigonocephaly [Denis et al., 1994]. About one third of patients with metopic synostosis are found to have cognitive and behavioral abnormalities on long-term follow-up evaluation [Sidoti et al., 1996]. Agenesis of the corpus callosum may also be recognized in some patients with trigonocephaly. In children born with fetal

valproate syndrome, it is important to be aware of the possibility of metopic suture synostosis, which some authorities believe should be considered part of the syndrome. Early surgical intervention in such patients may improve cognitive outcome [Lajeunie, et al., 2001]. Multiple Synostosis. Premature closure of both coronal and sagittal sutures results in oxycephaly. This abnormality may cause increased intracranial pressure and significant neurologic sequelae. Examination often reveals optic atrophy or papilledema, exophthalmos, and choanal atresia. Auditory and vestibular disturbances result from narrowing of the internal auditory canal. Turricephaly involves synostoses of

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TABLE 19-24 Prevalence and Molecular Basis of FGFR-Related Craniosynostosis Syndromes

From http://www.geneclinics.org.

the coronal, sphenofrontal, and frontoethmoidal sutures with both shortening of the anteroposterior diameter of the skull, as well as the skull appearing excessively high and narrow. Both oxycephaly and turricephaly usually do not appear before the age of 2 years. Secondary turricephaly may occur after initial correction of coronal synostoses [Sonstein et al., 1996].

Nonsyndromic Craniosynostoses Nonsyndromic craniosynostoses usually can be identified by a combination of suture involvement and morphologic appearance. There remains a group of patients with nonsyndromic craniosynostoses who have been difficult to classify. A study of 53 such patients representing 3.6% of patients with craniosynostosis categorized these patients into the following two groups: (1) those with two-suture disease and (2) a “complex” group in which more than two sutures were affected [Chumas et al., 1997]. Group 1 patients (68%) demonstrated no progression over time, to suggest a more diffuse pansynostosis. The sagittal suture was the most commonly involved, and a trend for these patients to have a higher intelligence quotient was noted. Group 2 patients presented at a slightly earlier age (1 year) with severe morphologic changes and multiple suture involvement, with bilateral involvement of lambdoid and sagittal sutures being the most common.

Syndromic Craniosynostoses In the past decade, understanding of many of the classic craniosynostosis syndromes has changed dramatically because the genetic bases for these disorders are being determined (see Tables 19-20 and 19-22).

FGFR-RELATED CRANIOSYNOSTOSIS SYNDROMES Diagnosis of most of the FGFR-related craniosynostosis syndromes is based on the clinical findings of bilateral

coronal craniosynostosis or cloverleaf skull, characteristic facial features, and variable hand and foot abnormalities. The exception is Muenke’s syndrome, which may have unilateral coronal synostosis or megalencephaly without craniosynostosis; its diagnosis depends on identification of a mutation in the FGFR3 gene. A summary of the prevalence and molecular basis of FGFR-related craniosynostosis syndromes is given in Table 19-24.

Apert’s Syndrome First described in 1906, Apert’s syndrome (acrocephalosyndactyly type 1) is inherited as an autosomal dominant trait, occurs in approximately 1 in 65,000 births, and accounts for approximately 4.5% of all patients with craniosynostosis. Apert’s syndrome maps to chromosomal region 10q26 and is caused by a mutation of the FGFR2 gene; in nearly all cases in which the mutation has been identified, it occurs in one of two adjacent sites of the gene, either position 252 or position 253 [Anderson et al., 2004; Ibrahimi et al., 2005]. The 253 mutation appears to be associated with the more severe forms, with regard to the severity of syndactyly and to mental outcome [Lajeunie et al., 1999]. Unregulated FGF2 signaling caused by mutations in FGFR2 suggests increased constitutive receptor activity in Apert mutant osteoblasts and an autocrine loop involving the FGF2 pathway in modulation of Apert osteoblast behavior [Baroni et al., 2005]. In most patients, the mutant allele is paternal in origin. Paternal bias for point mutations is seen in other genetic conditions, but the skewing seen in Apert’s syndrome in favor of paternal mutations is considered unusual and possibly is related to a paternal age effect [Glaser et al., 2003]. Discovery of mutations in FGFR genes allows definitive antenatal diagnosis of Apert’s syndrome [Hansen et al., 2004]. Multiple sutures are involved, with the coronal most frequently affected [Renier et al., 2000]. These patients are readily recognized at birth because of the associated severe fusion syndactyly involving the hands and feet, hypertelorism, proptosis, and down-slanting palpebral fissures.

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Hydrocephalus is common. Radiologic investigation of the cervical spine is indicated in patients with Apert’s syndrome. Fusion of the cervical vertebrae, primarily at the C5 to C6 level, occurs in 68% (single fusion 37%; multiple fusions 31%) [Kreiborg et al., 1992]. Patients with Apert’s syndrome have “interrupted eyebrows,” presumably resulting from an underlying bony defect. In older children and adolescents, hyperhidrosis of the hands and acneiform lesions are common skin manifestations. Patients with Apert’s syndrome have varying degrees of mental retardation [Sarimski, 1997]. In one study of 29 patients, 48% had a normal or borderline IQ, 31% had mild mental retardation (IQ of 50 to 70), 14% were moderately retarded (IQ of 35 to 49), and 7% were severely retarded (IQ less than 35) [Patton et al., 1988]. Moderate-to-severe language impairment, relatively normal performance IQ, and difficulties with attention, speech and oral motor skills also have been reported [Shipster et al., 2002]. Other problems that have received attention are a higher incidence of autism [Artigas-Pallares et al., 2005], obstructive sleep apnea [Pijpers et al., 2004], visual loss without other symptoms of intracranial hypertension [Bartels, et al., 2004], and hearing loss [Huang et al., 2004]. The mean intracranial volume also is increased in persons with Apert’s syndrome irrespective of whether the genotype is 252 or 253 [Anderson, et al., 2004]. Early craniectomy does not appear to improve intellectual outcome. Cohen and Kreiborg [1990] observed that many patients with Apert’s syndrome had ventriculomegaly or CNS malformations that frequently involved the corpus callosum or limbic structures. Other malformations in previously reported cases included megalencephaly, gyral abnormalities, encephalocele, pyramidal tract abnormalities, hypoplasia of cerebral white matter, and heterotopic gray matter [Cohen and Kreiborg, 1990]. By contrast, Reiner and colleagues [1996] found an IQ greater than 70 in half the children who had corrective surgery before age 1 year versus only 7.1% of those operated on later. They also found that anomalies of the septum pellucidum correlated with IQ, whereas malformations of the corpus callosum and ventricular size did not. More recent studies involving 18 patients with Apert’s syndrome have reported the absence of CNS anomalies in 44% of patients [Yacubian-Fernandes, et al., 2004]. The remaining patients had ventricular enlargement, corpus callosum hypoplasia, septum pellucidum hypoplasia, cavum vergae and a posterior fossa arachnoid cyst. Herniation of the cerebellar tonsils may also occur [Fearon et al., 2001]. Abnormalities of venous drainage that particularly affect the sigmoid-jugular sinus complex can produce a state of venous hypertension that may cause raised intracranial pressure with resultant blindness [Taylor et al., 2001]. In such patients in whom this is suspected, cerebral angiography or MR venography is necessary.

Crouzon’s Disease Crouzon’s disease accounts for approximately 5% of patients with craniosynostosis at birth and is due to closure of the coronal and basal skull sutures. This disorder was first reported in 1912. An autosomal-dominant pattern of inheritance is recognized in about three fourths of patients; the remaining cases are sporadic. Crouzon’s disease maps to chromosome 10q26, and in some series, mutations in the

FGFR2 gene have been reported in about half of the patients [Glaser et al., 2000; Reardon et al., 1994]. Recent studies of patients with the Crouzon and Pfeiffer types of craniosynostosis have found that mutations in the FGFR2 cluster at two critical cysteine residues, 278 and 342 [Kress et al., 2000].The spectrum of mutations overlap the two syndromes and reflect the phenotypic similarities observed in both patient groups. Associated features include hypertelorism, shallow orbits, exophthalmos, external strabismus, parrot-beaked nose, short upper lip, hypoplastic maxilla, and relative mandibular prognathism. Mental function in patients with Crouzon’s disease varies from normal in some series to up to 26% of patients with mental retardation [Hunter and Rudd, 1977; Kapp-Simon et al., 1993; Noetzel et al., 1985]. In a more recent series, 12% of patients had evidence of decreased mental function [Proudman et al., 1995]. Hydrocephalus is common in patients with Crouzon’s disease and may evolve over time [Hoefkens et al., 2004]. About 28% require surgical treatment, and 73% of these patients have chronic tonsillar herniation [Cinalli et al., 1995; David et al., 2002]. Syringomyelia may also occur [Fujisawa et al., 2002]. Other CNS anomalies are reported in about 14% of patients [Proudman et al., 1995]. Obstructive sleep apnea may also develop in children with Crouzon’s syndrome [Mitsukawa et al., 2004]. A rare form of Crouzon’s disease with acanthosis nigricans has been reported and is associated with an FGFR3 mutation in all patients [Meyers et al., 1995].

Jackson-Weiss Syndrome Jackson-Weiss syndrome has been reported in a large Amish kindred with coronal and basal skull craniosynostosis, enlarged great toes, and craniofacial abnormalities. JacksonWeiss syndrome is an autosomal-dominant disorder and resembles Pfeiffer’s syndrome except for the absence of thumb abnormalities [Jackson et al., 1976]. Jackson-Weiss syndrome maps to the same region (10q23-q26) as for Crouzon’s disease [Li et al., 1994], and at least six different mutations in the FGFR2 gene have been demonstrated [Heike et al., 2001; Jabs et al., 1994]. The evolution of craniofacial deformities seen in patients with the Jackson-Weiss syndrome seems to parallel those described with Crouzon’s disease and suggests similar evaluation and management strategies [Stankovic et al., 1994].

Pfeiffer’s Syndrome Pfeiffer’s syndrome is a form of acrocephalopolysyndactyly (type 5a) that differs from Apert’s syndrome (type 1) because of the presence of polydactyly. Since Pfeiffer’s original description in 1964, three subtypes have been categorized (see Table 19-24) [Cohen, 1993, 2000]. Patients have synostosis of the coronal and basal skull sutures, broad, short thumbs, and big toes. The proximal phalanx of the thumb usually is either triangular or trapezoid and occasionally is fused with the distal phalanx so that the thumb points outward. Developmental outcomes of patients with Pfeiffer’s syndrome are variable; most patients with type 1 Pfeiffer’s syndrome have normal development and a generally favorable outcome [Cohen, 1993]. A more recent report of Pfeiffer’s syndrome in six children with types 2 and 3 found essentially normal development in three, mild delay in two, and moderate delay in one [Robin et al., 1998].

Gleeson, Dobyns, Plawner, and Ashwal / Congenital Structural Defects

The classic type of Pfeiffer’s syndrome (type 1) is an autosomal-dominant disorder that has been associated with deletions of either the FGFR2 gene that maps to chromosome 10 (the original family reported by Pfeiffer was of this type) or to the FGFR1 locus on chromosome 8 [Ibrahimi et al., 2004; Muenke et al., 1994; Schell et al., 1995]. Moderate-to-severe conductive hearing or mixed hearing loss is common in patients with Pfeiffer’s syndrome [Vallino-Napoli, 1996]. CT abnormalities include external auditory canal stenosis or atresia, or either hypoplasia or enlargement of the middle ear cavity and hypoplastic ossicles. Prenatal diagnosis has been reported in several cases based on ultrasound findings of craniosynostosis, hypertelorism, extreme proptosis, and broad thumbs [Nazzaro et al., 2004]. Elevated intracranial pressure may occur in patients with Pfeiffer’s syndrome and requires surgical intervention [Gosain, et al., 1996] The type 2 form consists of a cloverleaf skull deformity with Pfeiffer’s hands and feet and ankylosis of the elbows [Oyamada et al., 2003]. Most patients with the type 2 form have significant developmental lags, but normal development can occur [Soekarman et al., 1992]. Type 2 cases all have been sporadic, in all likelihood caused by new mutations in the FGFR2 gene or in another unidentified gene. Most patients die shortly after birth from severe pulmonary or CNS abnormalities (cloverleaf skull and hydrocephalus), prematurity, or postoperative complications [Plomp et al., 1998; Teebi et al., 2002]. Type 3 is similar to type 2 but without the cloverleaf skull deformity [Robin et al., 1998]. Ocular proptosis is severe, and the anterior cranial base is markedly short. Various visceral malformations have been found in patients with type 3. Early demise is also characteristic of type 3, which has only occurred sporadically [Cohen and Barone, 1994]. Although children with types 2 and 3 have an increased risk for neurodevelopmental difficulties, a favorable outcome can be achieved in some cases with aggressive medical and surgical management [Robin et al., 1998].

Muenke’s Craniosynostosis This new clinical syndrome, first reported in 1997, is known as FGFR3-associated coronal synostosis syndrome and maps to chromosomal region 4p16.3 [Muenke et al., 1997]. It may ultimately be determined to be one of the most common genetic causes of craniosynostosis. In addition to craniosynostosis, affected persons may have radiographic abnormalities of the hands and feet, including thimble-like middle phalanges, coned epiphyses, carpal and tarsal fusions, and brachydactyly [Graham et al., 1998]. In some reports, mental retardation is a common feature (44%) [Reardon et al., 1997]. Muenke’s craniosynostosis is caused by a point mutation (C749G) on the FGFR3 gene, resulting in a Pro250Arg substitution. This substitution usually occurs as a new mutation and manifests as one of the highest documented rates for any transversion in the human genome [RannanEliya et al., 2004]. The P250R mutation also has been reported in families with autosomal dominant congenital moderately severe bilateral sensorineural deafness in which some of the family members also had craniosynostosis [Holloway et al., 1998]. In more recent studies, the P250R mutation was identified in 20 probands from 27 unrelated families (74%), whereas only 6 of 35 sporadic cases (17%)

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were found to have this mutation, and in both the familial and the sporadic cases, females were more severely affected [Lajeunie et al., 1999]. EEG abnormalities with bitemporal discharges and poor gray-white matter differentiation, defective gyri, and abnormally shaped hippocampi have been reported in Muenke’s syndrome [Grosso et al., 2003]. It is likely that patients previously described as having the Adelaide form of craniosynostosis have Muenke’s craniosynostosis.

Beare-Stevenson Syndrome Fewer than 10 patients with this disorder, which is associated with FGFR2 [Przylepa et al., 1996] and FGFR3 mutations [Roscioli et al., 2001], have been described. The disorder is associated with craniosynostosis, ear defects, cutis gyrata, acanthosis nigricans, anogenital anomalies, skin tags, and a prominent umbilical stump.

TWIST-RELATED CRANIOSYNOSTOSIS SYNDROMES Saethre-Chotzen Syndrome Saethre-Chotzen syndrome is an autosomal-dominant disorder with coronal and basal skull synostosis. The coronal synostosis is frequently asymmetric, causing plagiocephaly and facial asymmetry. Partial soft tissue syndactyly of the second and third digits and third and fourth toes is common. The thumbs and big toes are normal. Strabismus, ptosis, low frontal hair line, a long, thin pointed nose, and unusually shaped ears with a prominent crus are common [Carter et al., 1982; von Gernet et al., 1996]. Torticollis, clinodactyly of the fourth and fifth toes, large halluxes, and sensorineural hearing loss and cervical vertebral body fusion may occur [Clauser et al., 2000; Legius et al., 1989]. In some patients with Saethre-Chotzen syndrome, delayed onset of development of craniosynostosis has been reported [De Heer et al., 2004b]. Obstructive sleep apnea has also been reported [Pijpers et al., 2004]. Neurologic manifestations of Saethre-Chotzen syndrome include seizures and abnormal EEGs in slightly less than half the patients and significant neuroimaging abnormalities [Elia et al., 1996]. Cervical spine fusion (primarily at the C2-3 level) that is progressive during childhood occurs in about half the patients [Anderson et al., 1997a]. Conductive hearing loss resulting from cranial bone involvement (stapes ankylosis, small or even absent mastoids), atresia of the ear canal, or chronic ear infections may occur [Ensink et al., 1996]. Saethre-Chotzen syndrome is caused by mutations in the TWIST gene on chromosome 7p21 [Gripp et al., 2000]. To date, more than 80 different mutations in TWIST have been reported [Brueton et al., 1992; De Heer et al., 2004a; El Ghouzzi et al., 1997; Howard et al., 1997]. The TWIST gene product is a transcription factor containing a basic helixloop-helix (b-HLH) domain, required in head mesenchyme for cranial neural tube morphogenesis in mice [El Ghouzzi et al., 1997]. The TWIST gene was selected as a candidate gene for patients with Saethre-Chotzen syndrome, because the expression pattern and mutant phenotypes in Drosophila and mouse were consistent with the human phenotype [Howard et al., 1997]. In one study of 37 patients with classic features of Saethre-Chotzen syndrome, the overall detection rate for TWIST mutations was 68%. The risk for developmental delay

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in patients with deletions involving the TWIST gene is approximately 90%, or eight times more common than in patients with intragenic mutations [Cai et al., 2003]. Other investigators have reported a mutation of the FGFR3 gene in a large family with autosomal-dominant craniosynostosis suggestive of Saethre-Chotzen syndrome, in which linkage to the Saethre-Chotzen syndrome loci on 7p had been excluded [Golla et al., 1997]. A recent study found that 82% of patients with the Saethre-Chotzen phenotype had detectable genetic changes in the TWIST gene or of FGFR3 and it was suggested that initial screening for the FGFR3 P250R mutation, followed by sequencing of TWIST and then fluorescence in situ hybridization for deletion detection of TWIST, is sufficient to detect mutations in greater than 80% of patients with the Saethre-Chotzen phenotype [Chun et al., 2002]. The overlap in clinical features and the presence, in the same genes, of mutations for more than one craniosynostotic condition—such as Saethre-Chotzen syndrome, Crouzon’s disease, and Pfeiffer’s and Muenke’s syndromes—support the hypothesis that TWIST and FGFR genes are components of the same molecular pathway involved in the modulation of craniofacial and limb development in humans [Paznekas et al., 1998]. Studies using human mutant calvaria osteoblastic cells from a child with Saethre-Chotzen syndrome with a TWIST mutation found increased cell growth, collagen expression, and osteogenic capability, but inhibition of osteocalcin gene expression. In part, this may explain the development of the premature cranial ossification in patients with SaethreChotzen syndrome [Yousfi et al., 2001].

Baller-Gerold Syndrome Baller-Gerold syndrome is a rare form of craniosynostosis described by Baller in 1950 and Gerold in 1959. Essential features include radial or thumb aplasia with craniosynostosis (coronal, lambdoid or metopic) resulting in acrocephaly. Fewer than 50 cases have been described, and some authorities question whether this should be considered a separate syndrome, because overlap with Saethre-Chotzen syndrome is well recognized [Cohen and Toriello, 1996; Gripp et al., 1999; Temtamy et al., 2003]. Although this initially was thought to be an autosomal-recessive disorder, recent studies suggest an autosomal-dominant pattern of inheritance associated with a nonsense mutation in TWIST, a gene associated with SaethreChotzen syndrome [Gripp et al., 1999; Seto et al., 2001]. Baller-Gerold syndrome after fetal exposure to sodium valproate also has recently been reported [de Oliveira et al., 2005]. Short stature, spine and pelvic skeletal anomalies, cardiac or urinary tract anomalies, imperforate anus, and rectovaginal fistulas are reported. Mental retardation, congenital hydrocephalus, polymicrogyria, and partial agenesis of the corpus callosum have been noted in some patients [Dunac et al., 1995; Gripp et al., 1999; Lewis et al., 1991; Rossbach et al., 1996]. Other cases of presumed Baller-Gerold syndrome have been rediagnosed as Roberts’ syndrome, Fanconi’s pancytopenia, Rothmund-Thomson syndrome, or VACTERL association (vertebral anomalies, anal atresia, cardiac defect [most often ventricular septal defect], tracheoesophageal fistula with esophageal atresia, renal abnormalities, limb abnormalities [most often radial dysplasia]) [Temtamy et al., 2003]. These reports have led to a narrowed redefinition of Baller-Gerold syndrome based on the exclusion of cytogenetic and hematopoetic abnormalities and the

absence of additional malformations in patients with craniosynostosis and preaxial upper limb abnormalities [Gripp et al., 1999].

MSX-RELATED CRANIOSYNOSTOSIS SYNDROMES Boston-Type Craniosynostosis Fewer than 30 patients with this form of craniosynsostosis have been reported; most have been from one family [Warman et al., 1993]. Four general phenotypes emerged: (1) fronto-orbital recession; (2) frontal bossing; (3) turribrachycephaly due to coronal craniosynostosis; and (4) cloverleaf skull. Short first metatarsals are present. Headaches, seizures, myopia, and visual deficits may occur. The gene for this disorder is located on 5q. Mutations in MSX2 are causative [Jabs et al., 1993]. Inheritance is autosomal dominant, with complete penetrance and variable expression.

FIBRILLIN-RELATED CRANIOSYNOSTOSIS SYNDROMES Shprintzen-Goldberg Syndrome Shprintzen-Goldberg syndrome is rare (fewer than 40 patients reported), is also known as the marfanoid craniosynostosis syndrome, and consists of multiple suture synostoses in association with severe exophthalmos, maxillary and mandibular hypoplasia, soft tissue hypertrophy of the palatal shelves, low-set ears with soft and pliable auricles, multiple abdominal hernias, arachnodactyly, and camptodactyly. Hypotonia, mental retardation, and obstructive apnea are common. Shprintzen-Goldberg syndrome, which maps to 15q21.1, is distinct from the velocardiofacial syndrome, also known as Shprintzen’s syndrome (22q11 deletion), that is characterized by cleft palate, cardiovascular anomalies, typical facies, and learning disorders [Carlson et al., 1997]. Skeletal abnormalities in patients with ShprintzenGoldberg syndrome include progressive bowing of long bones, metaphyseal flaring, large persistent anterior fontanel, 13 pairs of ribs, vertebral abnormalities that develop by the second year of life, and progressive osteopenia. Communicating hydrocephalus is common [Ades et al., 1995] and epilepsy has been reported [Tanaka et al., 1993]. Abnormalities of the first and second cervical vertebrae, dilation of the lateral ventricles, microcephaly, hypoplasia of the corpus callosum and Arnold-Chiari I malformations have also been documented [Greally et al., 1998; Hassed et al., 1997; Saal et al., 1995]. MR imaging abnormalities, osteopenia, and progressive hydrocephalus are also found in this disorder as well as ventriculomegaly and Chiari-I malformations [Greally et al., 1998; Hassed et al., 1997; Ohnuma et al., 1997]. Overlap with patients who have marfanoid features has also been recognized [Lacombe and Battin, 1993; Saal et al., 1995] and several investigators have found that ShprintzenGoldberg syndrome is associated with mutations of the same gene (fibrillin-1) that is involved in Marfan’s syndrome [Sood et al., 1996]. Fibrillins 1 and 2 are major components of extracellular microfibrils and are widely distributed in connective tissue throughout the body and are responsible for the biomechanical properties of most tissues and organs [Ramirez and Pereira, 1999]. Fibrillins are cysteine-rich glycoproteins made predominantly of multiple repeats homologous to the calcium-binding epidermal growth factor module. Fibrillins polymerize extracellularly as parallel bun-

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dles of head-to-tail monomers. Binding to calcium rigidifies the structure of the monomers. Mutations in the fibrillin-1 (FBN1) gene, at 15q21.1, have been found to cause Marfan’s syndrome, a dominantly inherited disorder characterized by clinically variable skeletal, ocular, and cardiovascular abnormalities. Fibrillin-1 mutations have been found not only in Shprintzen-Goldberg syndrome but also in several other related connective tissue disorders, such as severe neonatal Marfan’s syndrome, dominant ectopia lentis, familial ascending aortic aneurysm, and isolated skeletal features of Marfan’s syndrome [Hayward and Brock, 1997]. Fibrillin-2 alterations cause the overlapping phenotype of congenital contractural arachnodactyly.

acrocephaly or turricephaly (coronal and basal skull sutures), peculiar facies, brachydactyly and syndactyly of the hands and preaxial polydactyly and syndactyly of the toes, and congenital heart disease [Cohen et al., 1987]. Fewer than 50 persons with Carpenter’s syndrome have been described. Obesity, mental retardation, hypogonadism, cryptorchidism, umbilical hernia, and bone abnormalities occur. Hearing loss is a rare complication [Tarhan et al., 2004]. Craniosynostosis variants considered within the clinical spectrum of Carpenter’s syndrome include Summitt’s syndrome, Goodman’s syndrome, and Sakati-Nyhan syndrome. Dental abnormalities including prolonged retention of primary teeth and hypodontia have been reported [Blankenstein et al., 2001]. Mental retardation is not an invariable feature of this syndrome.

OTHER CRANIOSYNOSTOSIS SYNDROMES

Hunter-McAlpine Syndrome

Craniosynostosis can be a finding in greater than 150 genetic disorders [Cohen, 2000]. In addition to those disorders in which specific genetic abnormalities have been described, several other craniosynostosis syndromes have been described that have yet to have a specific gene abnormality determined. They are included here because they are more common and have features that suggest their diagnosis based on clinical criteria.

Hunter-McAlpine syndrome is a form of craniosynostosis that was first described by Hunter and Rudd [1977] and consists of brachyphalangia, mental retardation, and facial dysmorphism. Patients have a small or downturned mouth, almond-shaped palpebral fissures, short stature, and acralskeletal abnormalities. Fewer than 10 cases of this autosomal dominant disorder have been reported. Thomas and colleagues [1996] described a 9-year-old boy with this disorder in whom a deletion at 17q23.1-q24.2 was detected. Considerable phenotypic variability within families exists. More recently, the original family members with this disorder and another reported patient were found to have a duplication of 5q35-qter [Hunter et al., 2005]. Debate also exists regarding whether the Hunter-McAlpine syndrome is identical to the Ruvalcaba syndrome or represents a type of trichorhinophalangeal syndrome.

Antley-Bixler Syndrome Fewer than 50 cases of this autosomal-recessive disorder have been reported since its original description in 1975. Cardinal features include craniosynostosis, radiohumeral synostosis, multiple joint contractures, arachnodactyly, femoral bowing, severe midface hypoplasia, proptosis, choanal atresia/stenosis, frontal bossing, dysplastic ears, depressed nasal bridge, long bone fractures, ambiguous genitalia and urogenital abnormalities [Hassell and Butler, 1994]. Renal agenesis and imperforate anus may occur as well [LeHeup et al., 1995]. Early death, usually due to respiratory complications linked to upper airway obstruction, occurred in about half of the reported cases. Coronal and lambdoid sutures are affected, giving the head a trapezoidal shape (“trapezoidocephaly”). Approximately one third of patients have survived, many with normal intelligence; others have varying degrees of disability [Bottero et al., 1997; Hassell and Butler, 1994]. Hydrocephalus and the Arnold-Chiari malformation have been described in some children with Antley-Bixler syndrome [Lee et al., 2001]. Although mutations in the FGFR2 gene have been found in some patients with Antley-Bixler syndrome [Chun et al., 1998], genetic heterogeneity of this syndrome has been proposed. In addition, particularly in infants with ambiguous genitalia, unique abnormalities in steroidogenesis (apparent decreased activity of 17α-hydroxylase, 17,20-lyase, and 21-hydroxylase) have been reported [Adachi et al., 2004]. Some investigators have suggested that the skeletal findings and altered steroidogenesis are not associated with genes specific to individual sterol or steroid pathways but rather are related to NADPH cytochrome P-450 reductase or cytochrome b5, which is common to these pathways [Cragun et al., 2004; Fukami et al., 2005].

Carpenter’s Syndrome Carpenter’s syndrome (acrocephalopolysyndactyly type II) also is a rare autosomal-recessive form of craniosynostosis, originally described in 1909, with major features consisting of

Lowry-MacLean Syndrome Lowry-MacLean syndrome is a rare syndrome of presumed autosomal-dominant inheritance that consists of multiple congenital anomalies and mental retardation with cleft palate, eventration of the diaphragm, congenital heart disease, glaucoma, craniosynostosis (usually coronal), and growth failure [Kousseff et al., 1994; Lowry and MacLean, 1977]. Congenital glaucoma and a Crouzon-like facial appearance are recognized [Al-Torki et al., 1997].

Evaluation Evaluation and management of children with craniosynostosis require radiologic and neuroimaging confirmation, molecular genetic testing, and a team of specialists including neurosurgeons, craniofacial surgeons, anesthesiologists, otorhinolaryngologists, child neurologists, geneticists, speech pathologists, psychologists, and physical and occupational therapists. Although conventional skull radiographs are helpful and frequently diagnostic, most centers recommend threedimensional CT scans [Binaghi et al., 2000]. Some centers have questioned their need in the management of single-suture craniosynostosis, however [Cerovac et al., 2002]. Such scans can depict suture patency, extent of synostosis, and the degree of calvarial deformity and can differentiate true synostosis from deformational plagiocephaly [Flores-Sarnat, 2002; Panchal and Uttchin, 2003]. MRI also should be considered, because it may detect underlying brain malformations that may not be seen with three-dimensional CT scans, which are

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Apert’s syndrome

Crouzon’s and Pfeiffer’s syndromes

SaethreChotzen syndrome

Muenke’s syndrome

Unilateral coronal synostosis

FGFR2 (P252W S253R)

FGFR2 (IIIa, IIIc) sequence

TWIST sequence

FGFR3 (P250R)

FGFR3 (Pro250Arg) FGFR2 TWIST

Stop

Stop

–

+

+

–

Stop

FGFR3 (P250R)

FGFR3 (P250R)

focused on delineating the severity of the cranial vault dysplasia. In one report comprising 217 children with craniofacial anomalies, brain anomalies were present in 36%, absent in 36%, and undefined in 28%. Craniosynostosis occurred in 74% of these children, and a syndromic diagnosis was established in 50% [Okkerse et al., 2004]. CNS malformations reported in association with craniosynostosis include DandyWalker malformation, partial agenesis of the corpus callosum, holoprosencephaly, and the appearance of blunted gyri under the area of suture synostosis [Flores-Sarnat, 2002]. The yield from molecular testing of children with craniosynostosis likely will increase over the next decade as genetic abnormalities are identified. In one recent report, a molecular diagnosis was made in 51% of 99 patients who had one of the common bilateral coronal craniosynostosis syndromes [Chun et al., 2003]. The diagnostic yield in patients with unilateral coronal synostosis is lower, at 7% [Lajeunie et al., 1999], 11% [Gripp et al., 1998], and 17% [Mulliken et al., 2004] in reported series. Although the yield is lower for patients with unilateral coronal synostosis, screening is recommended by most investigators for the purpose of genetic counseling [Mulliken et al., 2004; Zackai et al., 2000]. An algorithm for this evaluation modified from the work of Chun and colleagues [2003] is presented in Figure 19-45. Several Web-based resources are available that provide current recommendations, laboratory sites, and contact information (http://www.geneclinics.org/ and http://rarediseases.info.nih. gov/html/resources/info_cntr.html).

Reconstructive Surgery Numerous approaches have been developed to treat the various forms of craniosynostosis [Posnick and Ruiz, 2000]. The goals of treatment of primary craniosynostosis are fourfold: (1) to ensure normal brain growth, (2) to prevent increased intracranial pressure, (3) to prevent compromise of visual and auditory function, and (4) to improve skull and facial appearance [Bruce, 1996; Keating, 1997; Thauvoy et al., 1995]. Patients with microcephaly or cerebral atrophy resulting in secondary craniosynostosis do not benefit from

FIGURE 19-45. Diagnostic strategy for molecular testing of craniosynostosis. Apert’s syndrome and Muenke’s syndrome patients are screened for recurrent mutations in FGFR2 and FGFR3, respectively. For Crouzon’s syndrome and Pfeiffer’s syndrome patients, FGFR2 exons IIIa and IIIc are initially sequenced, and for Saethre-Choutzen syndrome patients, TWIST is sequenced. If the sequencing is positive for a mutation, further screening is not necessary. If the sequencing is negative, patients are tested for the FGFR3 P250R mutation. (From Chun K, Teebi AS, Azimi C, et al. Screening of patients with craniosynostosis: Molecular strategy. Am J Med Genet A 2003;120:470. Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.)

surgery because the defect in skull growth is secondary to the already impaired brain growth. The general management of craniofacial syndromes can be summarized as follows [Panchal and Uttchin, 2003]: Step I: Correction of craniosynostosis between the ages of 3 and 6 months. Step II: Correction of syndactyly between the ages of 1 and 2 years. Step III: Correction of midface retrusion with distraction techniques by the age of 4 to 5 years. Timing and progress of the distraction may vary, depending on the severity of obstructive sleep apnea, malocclusion, and psychologic disturbance. Step IV: Correction of hypertelorism and turricephaly, if present, at age 4 to 6 years. This may be done in conjunction with, or separately from, step III. Step V: Await full maturity and perform Le Fort I or Le Fort III procedure in conjunction with mandibular osteotomy to normalize appearance and correct malocclusion. The ultimate configuration of the skull and face depends on the location and number of the prematurely fused sutures and the age of the patient. In sagittal suture synostosis, cosmetic improvement is the main indication for surgery although in some children raised intracranial pressure may be present and is the primary reason for treatment. With multiple suture synostosis or cases involving the coronal suture or sutures, early surgical correction is essential to prevent neurologic sequelae and to provide the best cosmetic result [Sgouros et al., 1996b]. Wide linear craniectomy to reopen the sutures is usually performed 1 to 3 months after birth and if possible always before 6 months of age [Boop et al., 1996b; Salkind et al., 1986]. A wide range of procedures have been attempted, ranging from partial morcellation to extensive calvarial remodeling, including total ablation of the cranial vault in some patients [Flores-Sarnat, 2002; Panchal and Uttchin, 2003; Posnick and Ruiz, 2000]. Absorbable plating systems, rather than

Gleeson, Dobyns, Plawner, and Ashwal / Congenital Structural Defects

those that are titanium based, have been of significant benefit by ensuring rigid fixation and a better outcome [Panchal and Uttchin, 2003]. Endoscopically assisted (minimally invasive) craniosynostosis repair is being used as an alternative to traditional open craniosynostosis repair [Jimenez et al., 2002]. Advantages included decreased blood loss, operative time, and hospital stay, while providing esthetic results and safety comparable with those associated with traditional open methods of repair. Nevertheless, the difficulties inherent in endoscopic visualization may result in complications such as development of dural tears or leptomeningeal cysts [Aryan et al., 2004]. Distraction osteogenesis has been applied to the craniofacial skeleton, as well as the long bones of the extremities [Matsumoto et al., 2003]. This technique does not require bone grafting and allows correction of craniofacial deformities with less invasion. The distraction procedures can expand the overlying soft tissues simultaneously. Hydroxyapatite also is commonly used after cranial vault remodeling for osseous defects that have failed to ossify or to augment the temporal hollowing and minor asymmetry that may occur after cranial vault remodeling. Suture separation may need to be repeated if the suture reunites prematurely; repeat surgery is more likely in cases of multiple synostosis in which more extensive remodeling is necessary [McLaurin et al., 1989]. Patients with severe facial deformities, such as in Crouzon’s disease, may need total calvarial vault reconstruction [Burstein et al., 1994; McCarthy et al., 1990]. Major surgical advances involve an intracranial approach to correct the major craniofacial deformities, and a team approach to the management of such patients is beneficial [David et al., 1982; Marchac and Renier, 1982; Renier et al., 2000]. This technique attempts to change the entire facial structure by detaching the facial and orbital bones from the cranium and moving them into a more normal configuration. Patients with craniosynostosis that is secondary, occurring after ventriculoperi-toneal shunting for hydrocephalus, may require modifications in surgical management to maintain the contour and prevent recurrent collapse of the cranial vault [Shuster et al., 1995]. In some patients, craniosynostosis appears later in childhood with the development of midfacial hypoplasia and hypertelorism. The skull shape is normal at birth and the sutures are open in infancy, but later, multiple-suture craniosynostosis develops that requires surgery. Although the patients initially do not display manifestations of craniosynostosis, increased intracranial pressure frequently develops subsequently, which can have devastating consequences. In one series, a majority of such persons were diagnosed as having Crouzon’s syndrome, and most had FGFR2 mutations [Connolly et al., 2004].

Increased Intracranial Pressure Children with complex and to a lesser extent isolated forms of craniosynostosis may have raised intracranial pressure before surgery that remits postoperatively [Bristol et al., 2004; David et al., 1996; Panchal and Uttchin, 2003]. In one study, raised intracranial pressure was present in 28/53 patients with syndromic craniofacial dysostosis and in 20/83 nonsyndromic patients [Thompson et al., 1995]. Another report found papilledema in 12% of 122 children with

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craniosynostosis [Tuite et al., 1996a]. In this study, papilledema was a specific (98%) indicator of raised intracranial pressure, but its sensitivity was age-dependent. It was 100% sensitive in children older than 8 years, but only 22% sensitive in younger children. A higher incidence of the classic “beaten copper” appearance on skull x-ray is found in those patients with increased intracranial pressure and craniosynostosis [Tuite et al., 1996b]. The cause of increased intracranial pressure in patients with craniosynostosis has been thought to be due to either decreased intracranial volume or impeded venous drainage. Premature fusion of skull sutures is assumed to restrict skull growth [Gault et al., 1992]. Obstruction of the sigmoid sinuses at the skull base resulting in venous sinus hypertension and increased intracranial pressure also has been reported [Saine-Rose et al., 1984]. Abnormal cerebrospinal fluid hydrodynamics occur in about 8% of patients with craniosynostosis and include progressive hydrocephalus, nonprogressive ventriculomegaly, and subarachnoid space dilation [Cinalli et al., 1998]. Hydrocephalus occurs much more frequently in patients with syndromic craniosynostosis (12%) than in those with isolated craniosynostosis (less than 1%). Patients with kleeblattschädel almost always have hydrocephalus. Patients with Crouzon’s disease also are more likely to have hydrocephalus than in other syndromes [Cinalli et al., 1998]. In one patient with Crouzon’s disease, hydrocephalus was thought to be due to increased intracranial venous pressure, secondary to bilateral jugular foraminal stenosis [Martinez Perez et al., 1996]. In Apert’s syndrome, nonprogressive ventriculomegaly without increased intracranial pressure occurs frequently. Patients with syndromic craniosynostosis are also likely to have venous sinus obstruction and/or chronic tonsillar herniation. Patients also require evaluation for anomalous intracranial venous drainage before corrective surgery [Anderson et al., 1997b]. Chronic tonsillar herniation is a common MRI finding in patients with Crouzon’s disease (73%), in contrast with patients with Apert’s syndrome (2%) [Cinalli et al., 1995]. This finding is not necessarily related to the presence of hydrocephalus and is believed to be due to the premature synostosis of the lambdoid suture in the first 24 months of age. Studies have suggested that the incidence of delayed, asymptomatic increases in intracranial pressure after initial cranioplasty in children with complex craniosynostosis is surprisingly high and ranges from 3% to 36% [Pollack et al., 1996; Siddiqi et al., 1995; Stavrou et al., 1997]. Reported findings include bulging fontanel, progressive frontal bone protrusion, intermittent headaches, irritability, vomiting, proptosis, papilledema, visual failure, optic atrophy, and progressive head enlargement. Repeat surgery to expand the cranial vault is necessary in these patients. In other patients, signs or symptoms of increased intracranial pressure may be clinically difficult to detect and require lumbar puncture and measurement of intracranial pressure [Campbell et al., 1995]. Prompt evaluation of neonates and young infants with suspected craniosynostosis offers the optimal choice of early intervention. Surgery results in substantial cosmetic improvement and prevents neurologic sequelae with minimal complications. Correction of complex malformations by correcting posterior skull defects may relieve pressure on

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anterior orbital and frontal structures and allow completion of the repair when the child is older [Sgouros et al., 1996a]. In some children, obstructive sleep apnea develops secondary to narrowing of the nasopharyngeal space, and surgical intervention to enlarge the nasopharyngeal space can reduce the severity of these symptoms [Edwards et al., 1992]. In some patients, skull-molding helmets can be used to correct abnormal skull shapes due to deformational plagiocephaly resulting from positional molding or due to craniosynostosis [Kane et al., 1996; Strohecker, 1996]. Guidelines to an approach to intracranial pressure evaluation and management in children with craniosynostosis have been suggested [Cohen and Persing, 1998; Mouradian, 1998]. In the absence of definitive data on the incidence of intracranial hypertension and the long-term outlook for children with single-suture synostosis, for children with confirmed sagittal, lambdoid, and metopic synostosis whose parents have chosen surgical intervention, intracranial pressure monitoring is unlikely to improve clinical management. For children whose parents wish to avoid intracranial surgery, measurement of intracranial pressure may provide a means of assessing potentially damaging consequences of the synostosis. Children presenting later than 1 year of age, particularly those with developmental delay or other signs of increased intracranial pressure, may be referred for intracranial pressure monitoring. All children with confirmed synostosis should be monitored closely by a craniofacial surgeon, a pediatric neurosurgeon, a pediatric ophthalmologist, and a neurodevelopmental specialist for signs and symptoms of increased intracranial pressure, and treatment should be planned accordingly.

Cognitive Outcomes Reported cognitive outcomes in children with craniosynostosis are variable. Depending on the suture involved, rates of global delay range from 0% to a high of 66% [Kapp-Simon, 1998; Kapp-Simon et al., 1993; Lekovic et al., 2004]. This variability has been attributed to whether or not the child has a syndromic form of synostosis, the presence of associated medical problems and issues related to case ascertainment, and the different populations studied. A majority of studies of children with single suture craniosynostosis have normal development during the first year of life [Kapp-Simon, 1998], although other investigations have demonstrated cognitive delays before any surgical interventions were performed [Panchal et al., 2001]. Early studies did not reveal a correlation between neurocognitive outcomes and chronic raised intracranial pressure [Renier et al., 1982]. Other studies also have not found that surgery improves neurodevelopmental outcome [Kapp-Simon, 1998; Kapp-Simon et al., 1993]. Correlation between intelligence and severity of the craniofacial deformity was demonstrated in some studies [Kapp-Simon et al., 1993] but not in others [Turtas et al., 1993]. Postoperative head circumference and volume measurements are reduced in patients with mental impairment. Speech and language disorders also may occur in children with craniosynostosis. In one study of children with isolated sagittal synostosis, 37% of children had impairment, and in most it was moderate to severe in severity [Shipster et al., 2003]. Raised intracranial pressure, perinatal risk factors, otitis media, and previous surgery were not associated with speech

impairment. Other studies have found evidence of reading or spelling disorders and learning disability in 50% of children with isolated sagittal synostosis [Magge et al., 2002].

Other Complications Other complications that can occur in children with craniosynostosis include cerebral salt wasting syndrome, developing after cranial vault remodeling [Lee et al., 2004; Levine et al., 2001]. This may be confused with the syndrome of inappropriate antidiuretic hormone release (SIADH), but cerebral salt wasting syndrome is associated with increased urine output and increased urine sodium concentration and volume contraction. Obstructive sleep apnea also is common in syndromic craniosynostosis, and in one study it was suspected from questionnaire results in 53% of patients [Pijpers et al., 2004]. Visual failure caused by raised intracranial pressure in craniosynostosis also can develop [Stavrou et al., 1997]. In some patients, monitoring visualevoked potentials is helpful, because abnormalities may develop before the appearance of papilledema or other signs of increased intracranial pressure [Mursch et al., 1999]. Corneal ulcers also may occur in some forms of craniosynostosis (e.g., Apert’s syndrome) [Ueeck et al., 2001].

Klippel-Feil Syndrome Although not a congenital malformation of the skull, the Klippel-Feil syndrome is included here because the primary abnormality relates to bone development. The cardinal feature of Klippel-Feil syndrome is a decreased number and partial or complete fusion of the cervical vertebrae [Ulmer et al., 1993]. The anomaly is the result of failure of segmentation of cervical vertebrae and mesodermal somites before the fourth week of gestation. It is a heterogeneous disorder in terms of both its clinical expression and its genetic basis. Klippel-Feil syndrome most often occurs sporadically. It also can be inherited as an autosomal-dominant disorder with variable expression and reduced penetrance, as an autosomal recessive disorder, or as an X-linked disorder (as part of Wildervanck’s syndrome). The specific genes involved in causing Klippel-Feil syndrome have not yet been identified, but several candidate genes and genetic foci have been suggested. In one report, autosomal dominant inheritance cosegregated with a pericentric inversion involving chromosome 8 (q22.2-q23.3) [Clarke et al., 1995]. This gene has been labeled SGM1 (segmental-1) and is associated with vertebral fusions and vocal impairment [Clarke et al., 1996]. A balanced translocation between 5q11.2 and 17q23 has also been reported in at least one Klippel-Feil syndrome patient [Fukushima et al., 1995]. Lowry and associates [2001] described a family in which an abnormality in the FGFR3 gene was associated with coronal craniosynostosis, Klippel-Feil syndrome, and Sprengel’s shoulder. Another group of investigators [McGaughran et al., 2003] screened 63 Klippel-Feil syndrome patients for mutations in the PAX1 gene, which is implicated in vertebral segmentation defects in mice. These workers found that 6 of the patients had mutations in the coding region. They suggested that PAX1, alone or in conjunction with other genetic or environmental factors, plays a role in the development of Klippel-Feil syndrome.

Gleeson, Dobyns, Plawner, and Ashwal / Congenital Structural Defects

Clinical Characteristics The classic triad of Klippel-Feil syndrome is a short neck, limitation of neck motion, and a low occipital hairline. The head appears to sit directly on the shoulders, without an intervening neck. Head and neck movements are limited except for some flexion and extension. The scapulae are elevated or discrepant in size. Less than 50% of patients have all three cardinal features, and there are many other reported associated features. These include facial asymmetry often associated with torticollis, fused and anomalous ribs including cervical ribs, hemivertebra, scoliosis or kyphosis, platybasia, Sprengel’s deformity, myelodysplasia, Arnold-Chiari malformation, diastematomyelia, syringomyelia, and hydrocephalus. The average age at clinical presentation in one series of patients was 9 years, with neurologic symptoms seen in about 40% of patients [Baba et al., 1995; Guille et al., 1995]. Additional abnormalities include cardiopulmonary, urogenital, and gastrointestinal anomalies; congenital deafness; absent ulna; and absent vagina [McKusick, 1994]. MRI scanning and CT myelography most commonly reveal cervical spondylosis, disk herniation, cervical dysraphism, or Arnold-Chiari malformations [Ulmer et al., 1993]. Klippel-Feil syndrome occurs as part of the Wildervanck syndrome in association with congenital perceptive deafness, abducens palsy, and Duane’s syndrome (cervico-oculoacoustic syndrome) [Gupte et al., 1992]. Wildervanck’s syndrome is almost completely limited to females and may be responsible for at least 1% of deafness among females. Otologic defects have been reported in about one third of patients with Klippel-Feil syndrome and are caused either by dysplasia of the labyrinth, internal auditory canal, or middle and outer ear [Dubey and Ghosh, 1993]. Deafness is usually sensorineural or mixed and is rarely conductive in nature. Three types of cervical vertebral fusion have been described [Baba et al., 1995]. In type 1, massive fusion of many cervical and upper thoracic vertebrae into bony blocks occurs. In type 2, fusion at only one or two interspaces is present, although hemivertebrae or occipitoatlantal fusion may be present. In type 3, both cervical fusion and lower thoracic or lumbar fusion are seen. A fourth type associated with sacral agenesis has also been reported [Raas-Rothschild et al., 1988]. Clarke and associates [1998] introduced a new KlippelFeil syndrome classification that attempted to integrate the clinical phenotype with the mode of inheritance. Fusions involving C1 were described as KF1, in which severe associated anomalies are present and inheritance is recessive. In KF2, C2-3 fusion is dominant and is the most rostral; the mode of inheritance is dominant. In KF3, C2-3 or C3-4 fusion is most rostral and often is a single isolated fusion; reduced penetrance inheritance is characteristic. KF4 is Wildervanck’s syndrome with presumed X-linked dominant inheritance. With regard to the neurologic symptoms, weakness and atrophy of arm muscles may be profound. Paraplegia may result from bony impingement on the spinal cord. Sympathetic dysfunction also may be prominent. Mirror movements (synkinesias) of the extremities, particularly the arms and hands, may be subtle or so overt that they are disabling. These movements have been ascribed to abnormalities of pyramidal decussation [Farmer et al., 1990]. Obstructive sleep apnea, bradypnea, and stridor have been reported in Klippel-Feil syn-

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drome patients in conjunction with the presence of hindbrain abnormalities [Rosen et al., 1993]. Patients with Klippel-Feil syndrome and hypermobility of the upper cervical segment are at risk for neurologic sequelae; those with alteration in motion of the lower cervical segment are predisposed to degenerative disease [Pizzutillo et al., 1994]. Another group of investigators found that the more numerous the occipito-C1 abnormalities, the more significant the neurologic risk [Rouvreau et al., 1998]. Occasionally, patients may present with an acute neurlogic syndrome (e.g., quadriplegia) after relatively minor neck trauma [Smith and Griffin, 1992].

Management Comprehensive evaluation of all patients with Klippel-Feil syndrome is indicated because of the varied possible associated anomalies. Appropriate radiologic imaging of the cervical spine is required to define the cervical abnormalities, and any potential for spinal cord or radicular compression. This may include MRI with lateral views in flexion and extension [Rouvreau et al., 1998]. Imaging of the thoracic and lumbosacral spine is needed to look for other spinal anomalies and to monitor for the development of scoliosis. Periodic neurologic examinations are necessary to assess for cranial nerve abnormalities, cervical radiculopathy or myelopathy, or symptoms of Chiari malformation or hydrocephalus. Cardiac evaluation, renal ultrasound, and audiologic testing are necessary due to possible associated problems in these systems [Tracy et al., 2004]. The precise nature of the cervical abnormality and other associated problems dictates the intervention for the particular patient. For some, modification of activity is all that is necessary; patients with progressive symptomatic segmental instability or neurologic compromise may require surgical stabilization (e.g., anterior or posterior arthrodeses or laminectomies). Neurosurgical treatment (posterior fossa decompression or ventricular shunting) may be indicated as may surgery for gastroesophageal reflux (fundoplication) [Baba et al., 1995; Guille et al., 1995; Johnson, 1992].

ABNORMALITIES OF OSSIFICATION: SCLEROSIS AND HYPEROSTOSIS Craniotubular Bone-Modeling Disorders These disorders (see Box 19-9) are caused by disequilibrium between the processes of bone formation and resorption that leads to defective modeling and remodeling of bone [Paterson, 1997]. Neurologic features often include cranial nerve deficits, brainstem compression, abnormal head shape, and elevated intracranial pressure [Stein et al., 1983]. Osteopetrosis is discussed as an example of these disorders, although distinct cellular and metabolic defects likely are responsible for each one.

Osteopetrosis Osteopetrosis, a disease of defective bone resorption, results in generalized bone sclerosis and fragility, constriction of cranial foramina, and bone marrow failure, which leads to anemia, thrombocytopenia, hepatosplenomegaly, and sus-

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ceptibility to infection [Kocher and Kasser, 2003]. Three clinically distinct forms of osteopetrosis are recognized— the infantile malignant autosomal-recessive form, the intermediate autosomal-recessive form, and the adult autosomaldominant form, which is characterized by sclerosis, predominantly involving the spine, the pelvis, and the skull base [Kocher and Kasser, 2003; Walpole et al., 1990]. The autosomal recessive, malignant infantile type is the only one with significant neurologic features. Carpal tunnel syndrome [Lachman, 1997] or syringomyelia [Sari and Demirci, 1996] may develop in patients with autosomaldominant osteopetrosis. An isolated case of severe neurologic involvement has been seen with the dominant form [Walpole et al., 1990].

Pathogenesis The basic defect in the process of endochondral ossification is impaired lysosomal function of osteoclasts and their precursor cells, monocytes. Bone formation by osteoblasts continues and becomes excessive without the dynamic remodeling and resorption of bone by the osteoclasts; thus, the marrow cavity becomes filled. The precursor monocytes also are defective, leading to susceptibility to infection. Localization of the gene for autosomal-dominant osteopetrosis to chromosomal region 1p21 has been reported [Van Hul et al., 1997]. Osteopetrosis may be due to intrinsic defects to either the osteoclast-monocyte lineage or the mesenchymal cells that constitute the microenvironment that supports osteoclast ontogeny and activation. Implicated factors include specific proto-oncogenes, growth factors, and immune regulators. In many patients, the disease is caused by defects in either the proton pump (the α3 subunit of vacuolar-type H+-ATPase, encoded by the gene variously termed ATP6i or TCIRG1) or the ClC-7 chloride channel (ClCN7 gene). These pumps are responsible for acidifying the bone surface beneath the osteoclast [Steward, 2003]. A subset of patients with the intermediate autosomal-recessive form has been characterized with carbonic anhydrase II isoenzyme deficiency [Borthwick et al., 2003]. Evidence of a defect in the gene for macrophage colony-stimulating factor (CSF1) in the osteopetrotic mouse (op/op) has been found [Yoshida et al., 1990]. Transplantation of normal bone marrow cells into the op/op mouse, however, has not resulted in resolution of the bone defect. In addition, no definite evidence indicates that a mutation in the CSF1 gene is responsible for osteopetrosis in humans [Orchard et al., 1992].

Clinical Characteristics Although the osteopetroses generally are thought of as bone diseases, the most serious consequences of these disorders are seen in the nervous system. Cranial nerves, blood vessels, and the spinal cord are compressed by either gradual occlusion or lack of growth of skull foramina [Steward, 2003]. The typical patient with osteopetrosis is an infant with poor vision, optic atrophy, anemia, hepatosplenomegaly, and immune dysfunction. The risk for developing visual or hematologic impairment in the first year of life is approximately 75%, and the probability of survival until the age of 6 years is approximately 30% [Gerritsen et al., 1994a]. Considerations in the differential diagnosis include

certain lysosomal storage diseases. Neurologic complications result from bleeding, infection, fractures, and encroachment on neural structures from overgrowth of the skull. Cranial nerves, the carotid arteries, and the jugular veins may be compressed by progressive obliteration of the cranial foramina. Typical neurologic symptoms and signs in infants include progressive blindness and deafness, anosmia, headaches, optic atrophy, proptosis, seizures, facial nerve paralysis, other cranial nerve palsies, macrocephaly with frontal and parietal bossing, hypotonia, spasticity, developmental delay, and sleep apnea [Ainsworth et al., 1993; Benecke, 1993; Carter et al., 1988; Steward, 2003]. Hypotonia results from CNS dysfunction; findings on electromyography and muscle histology are normal. Elevated intracranial pressure occurs secondary to hydrocephalus or pseudotumor cerebri, which may develop as a result of obstruction of venous drainage or intracranial hemorrhage [Rosman and Shands, 1978; Wu and Swaiman, 1982]. Visual impairment usually results from optic nerve compression. Some patients without evidence of optic nerve encroachment may have primary retinal degeneration with abnormalities on electroretinograms, primary optic nerve dysmyelination, or optic atrophy from increased intracranial pressure or compression of the retinal veins [Haines et al., 1988]. A neurodevelopmental follow-up study of 23 children with the severe autosomal recessive form of osteoporosis noted the following: (1) 8 patients were blind, 11 were visually impaired, and 4 had satisfactory vision; (2) 2 patients had hearing loss; (3) motor delay initially was mild and worsened to severe, followed by gradual improvement, so that by age 4 years, all but two children were ambulatory; and (4) language and intellectual function was variably impaired, with many patients having significant deficits [Charles and Key, 1998]. Useful diagnostic studies for osteopetrosis include skeletal radiography and bone biopsy. CT and MRI of the skull and brain and plain skull radiographs may demonstrate enlarged ventricles, cerebral atrophy, hydrocephalus, and thickened skull bones with narrow cranial foramina at the base of the skull [Cure et al., 2000; Herman and McAlister, 1991]. MRI also may demonstrate tonsillar herniation, proptosis, and dural venous sinus stenosis. Acquired cephaloceles can occur, and optic nerve atrophy and optic canal stenosis are present in a majority of patients. Middle ear fluid is present in greater than half of the patients. Petrous carotid canal and internal carotid or vertebral artery stenotic lesions in patients with malignant osteopetrosis with evidence of extramedullary hematopoiesis can be detected using CT scanning and MR angiography. Dandy-Walker syndrome and agenesis of the corpus callosum also have been associated with the severe autosomal-recessive form of osteopetrosis [Ben Hamouda et al., 2001]. Delayed myelination has been observed in some patients with developmental retardation. Prominent cerebrospinal fluid spaces over the frontal lobes may be present in normal patients [Elster et al., 1992]. Syringomyelia also may occur [Sari and Demirci, 1996]. Abnormal visual- and auditory-evoked potentials result from compression of optic and auditory nerves. Anemia, leukopenia, and thrombocytopenia secondary to marrow replacement by the thickened bone are common.

Gleeson, Dobyns, Plawner, and Ashwal / Congenital Structural Defects

A rare and poorly understood form of the neuronopathic osteopetrosis disease has been associated with infantile neuroaxonal dystrophy [Rees et al., 1995]. It causes rapid neurodegeneration and death within the first year. Although characterized by the finding of widespread axonal spheroids and accumulation of ceroid lipofuscin, the biochemical basis of this disease remains unknown [Steward, 2003]. In addition, a form of osteopetrosis associated with renal tubular acidosis has been described [Borthwick et al., 2003].

Management Management of patients with osteopetrosis requires a comprehensive approach to characteristic clinical problems including hematologic and metabolic abnormalities, fractures, deformity, back pain, bone pain, osteomyelitis, and neurologic sequelae [Kocher and Kasser, 2003]. Specific neurosurgical treatment should be considered early in the course of the disease, to prevent permanent sequelae. The possibility of elevated intracranial pressure should be investigated before any surgery. Progressive hydrocephalus can be managed with a shunting procedure; caution is advised in this decision because mild, nonprogressive hydrocephalus or ventricular enlargement from cerebral atrophy may occur in many patients and not require treatment. Patients should be evaluated for progressive loss of vision and hearing. Visual-evoked potentials are useful for monitoring the progression of optic nerve compromise, to determine the optimal timing and response to decompressive surgery. Neurosurgical procedures to unroof the optic foramina and decompress the encroached optic nerves can prevent further deterioration. In patients with either the recessive or the dominant forms of osteopetrosis, localized cervical or lumbar back pain may develop secondary to spondylolysis that usually can be managed with a lumbosacral corset or a thoracolumbosacral orthosis [Martin et al., 1997]. Until recently, congenital osteopetrosis was a fatal disease with progressive neurologic involvement. Complications from the bleeding diathesis and infection were the usual causes of death. Medical treatment of osteopetrosis is based on efforts to stimulate host osteoclasts or provide an alternative source of osteoclasts. Stimulation of host osteoclasts has been attempted with calcium restriction, calcitriol, steroids, parathyroid hormone, and interferon. Bone marrow transplantation has been used for infantile malignant osteopetrosis, with resultant cure [McMahon et al., 2001]. Because osteopetrosis likely represents a spectrum of underlying causative disorders resulting in osteoclast dysfunction, effective therapies most likely need to be individualized [Gerritsen et al., 1994b; Kocher and Kasser, 2003; Solh et al., 1995]. Bone marrow transplantation offers treatment when a suitable matched donor is available, with survival rates as high as 79% [Gerritsen et al., 1994b; Solh et al., 1995]. Neurologic deterioration may be halted, and some patients may experience improvement with respect to already existing neurologic abnormalities (usually vision); therefore, early diagnosis and referral are necessary to achieve the best neurologic outcome [Hwang et al., 2000]. Experimental treatment with calcitriol produces bone but not clinical improvement [Gerritsen et al., 1994b; Key et al., 1984]. Interferon-γ also has been used, with evidence to suggest neurologic

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improvement [Charles and Key, 1998; Key et al., 1995b]. Cord blood transplantation in one case report resulted in bone resorption without normalization of neurologic findings [Locatelli et al., 1997]. The brain isoenzyme of creatine kinase (BB-CK) is elevated in children with osteopetrosis but not in other sclerosing bone disorders [Whyte et al., 1996]. The reasons for this elevation remain unclear. Assay of BB-CK in fetal blood could potentially be used for prenatal diagnosis of malignant osteopetrosis but requires further investigation.

Fibrous Dysplasia of Bone Fibrous dysplasia is a developmental disorder of bone that can manifest in a monostotic or polyostotic form. Primarily affecting adolescents and young adults, it accounts for 7% of benign bone tumors [Ippolito et al., 2003; Parekh et al., 2004]. Localized areas of bone are replaced by dense fibrous tissue, causing slowly progressive erosion, hyperostosis, bone deformity, and frequent fractures of long bones. Fibrous dysplasia has been associated with multiple endocrine and nonendocrine disorders, and with McCune-Albright syndrome and Mazabraud’s syndrome (i.e., fibrous dysplasia with intramuscular or juxtamuscular myxomas). Manifestations of fibrous dysplasia and the McCuneAlbright syndrome appear to be due to increased activity of tissues regulated by the accumulation of cyclic adenosine monophosphate. Overproduction of cyclic adenosine monophosphate is mediated by activating mutations of the alpha stimulatory guanine nucleotide-binding protein (Gs alpha) [Perdigao et al., 2004; Spiegel, 1997]. Specifically, upregulation of the Gs alpha protein appears to be due to missense mutations of the Gs alpha gene [Weinstein et al., 1991]. During maturation, precursor osteogenic cells form normal osteoblasts; this pattern of expression is retained in fibrous dysplasia. Fibrotic areas consist of an excess of cells with features of preosteogenic cells, whereas the lesional bone formed within fibrotic areas represents the output of mature but abnormal osteoblasts [Riminucci et al., 1997]. Osteoblasts involved with the de novo deposition of lesional bone in fibrous dysplasia produce a bone matrix enriched in certain anti-adhesion molecules and poor in the pro-adhesive molecules. These findings are in contrast with the high levels of proadhesive proteins found in normal de novo bone. Fibrous dysplasia may thus be considered a disease of cells in the osteogenic lineage that is triggered by the effects of excess cyclic adenosine monophosphate on bone cell function [Riminucci et al., 1997]. Increased cell proliferation and inappropriate cell differentiation result in overproduction of a disorganized fibrotic bone matrix [Marie et al., 1997]. The monostotic form involves only one bone in each patient, often a rib or the skull. The fronto-orbital regions, including the frontal, maxillary, and sphenoid bones, the anterior base of the skull, and the orbit, are most often affected. The polyostotic form—McCune-Albright syndrome—involves multiple bones in a similar manner but also includes endocrine and dermatologic manifestations. Skull and facial bones are involved in 10% to 25% of cases of monostotic fibrous dysplasia and in 50% of the polyostotic variety [Brown et al., 1995]. The three major radiographic classifications of fibrous dysplasia are pagetoid, sclerotic, and cystic. The monostotic

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form affects both genders equally; the polyostotic form is more common in females, particularly with endocrine manifestations. In one recent series, the ethmoid bones were most commonly involved (71%), followed by the sphenoid (43%), frontal (33%), maxilla (29%), temporal (24%), parietal (14%), and occipital (5%) bones, and the most common presenting features included atypical facial pain and headache, complaints referable to the sinuses, proptosis and diplopia, hearing loss, and facial numbness [Lustig et al., 2001]. Clinical features manifest between ages 5 and 15 years. Progressive facial, orbital, and skull deformity and asymmetry become apparent during skeletal growth; the bone deformity often stabilizes after completion of puberty. A hard scalp mass and local pain often are the chief complaints. Complications of the skull dysplasia include cosmetic deformity and compression of neural foramina, especially the optic foramina, producing progressive visual loss, proptosis, and extraocular muscle weakness [Seiff, 1997]. In some patients, the gradual development of a small posterior fossa due to fibrous dysplasia of the occipital bone, with consequent tonsillar herniation resulting in syringomyelia, has been noted [Chandy, 1999]. Fibrous dysplasia also may manifest with conductive hearing loss resulting from stenosis of the external auditory canal [Morrissey et al., 1997]. Sensorineural hearing loss usually has been attributed to involvement of the otic capsule. Less common, long-term complications include (1) malignant transformation of the dysplastic bone into osteosarcomas, fibrosarcomas, or chondrosarcomas and (2) hemorrhage into the dysplastic bone. Both cause a rapidly enlarging scalp mass and local pain [Beuerlein et al., 1997; Graf and Perret, 1980; Rodenberg et al., 1996]. The risk of malignant transformation, which carries with it a poor prognosis, is 0.5%, with a predilection for the craniofacial region, the polyostotic form, and male gender [Ruggieri et al., 1994]. Swelling, local pain, and progressive radiographic changes suggest malignant transformation. Rare complications include the development of intramuscular myxomas [Limouzy et al., 1996] and spinal involvement with paraparesis [Przybylski et al., 1996]. Spinal lesions and scoliosis also may occur in patients with polyostotic fibrous dysplasia [Leet et al., 2004]. On rare occasions, epilepsy also has been reported as an initial manifestation of the polyostotic form [Soler et al., 1999]. The diagnosis of fibrous dysplasia can be suspected from the presence of typical facial features and, in the polyostotic form, from the associated extraskeletal manifestations. Skull radiographs demonstrate characteristic hyperostotic areas with a ground-glass opaque appearance in combination with radiolucent cysts, usually in the frontal or parietal bones. The base of the skull, particularly the sphenoid, sella turcica, roof of the orbit, and frontal bones, demonstrates diffuse sclerosis and thickening. CT and MRI also demonstrate cortical bone destruction [Sener, 1997a; Yao et al., 1994]. The alkaline phosphatase level may be elevated, but plasma phosphorus and calcium concentrations are normal. Bone biopsy is necessary for diagnosis in uncertain cases to exlude tumor or osteomyelitis, particularly in the monostotic form without confirmatory extraskeletal manifestations [Andrisano et al., 1991]. Surgical treatment is indicated for patients with progressive compression of neural structures or rapidly growing or painful lesions suggesting late complications such

as malignant transformation or hemorrhage [Bibby and McFadzean, 1994; Jan et al., 1994; Papay et al., 1995; Posnick et al., 1993]. Although encasement of the optic canal in fibrous dysplasia causes narrowing of the canal, subsequent visual loss is not invariable, and prophylactic decompression of the optic nerve may not necessarily be indicated on the basis of the presence of fibrous dysplasia on diagnostic images alone [Lee et al., 2002]. Local radiation is of no value as a primary treatment. Cosmetic surgery is best considered after the completion of puberty and skeletal maturation. In addition to orthopedic treatment, administration of bisphosphonate pamidronate intravenously every 6 months has been reported to reduce the severity of bone pain, the rate of bone turnover assessed by biochemical markers, and the size of the radiologic lesions [Chapurlat et al., 1997; Kos et al., 2004; Schoenau and Rauch, 2002]. Aminobisphosphonate, which is available in the United States, also has been used successfully [Weinstein, 1997].

MCCUNE-ALBRIGHT SYNDROME The McCune-Albright syndrome is characterized by polyostotic fibrous dysplasia, pigmentary patches of the skin (e.g., café au lait spots), and endocrinologic abnormalities, including precocious puberty, short stature, thyrotoxicosis, pituitary gigantism, and Cushing’s syndrome [de Sanctis et al., 1999; Hannon et al., 2003]. Asymmetric involvement of the skull and facial bones is a common and prominent feature of McCune-Albright syndrome. Deafness and blindness result from involvement of the cranial foramina [Bocca et al., 1998]. Pathologic fractures, bone deformities, and pseudoarthrosis are frequent presenting manifestations. A particularly characteristic area of bone involvement is the proximal femur, which results in the “shepherd’s crook” deformity. Severe craniofacial hyperostosis can occur [Viljoen et al., 1988]. Skin involvement consists primarily of large café au lait spots with irregular margins (i.e., “coast of Maine” configuration) as compared with the more regularly outlined “coast of California” lesions characteristic of neurofibromatosis. The café au lait spots usually are unilateral and on the same side as the bone lesions and usually do not cross the midline; the nape of the neck is a common site of involvement. Endocrine manifestations are common in McCuneAlbright syndrome [Hannon et al., 2003]. Precocious puberty, usually manifesting with vaginal bleeding, occurs in more than 50% of females and is the most common endocrinopathy [DiMeglio and Pescovitz, 1997]. Hyperthyroidism occurs in approximately 20% to 40% of patients. Gigantism (excessive growth hormone secretion), hyperprolactinemia, hyperadrenocorticism, and gynecomastia also occur. Nonendocrine manifestations of McCune-Albright syndrome include hypophosphatemia, hepatobiliary dysfunction, splenic and pancreatic hyperplasia, pancreatitis, intestinal polyps, abnormal cardiac muscle, and sudden death [DiMeglio and Pescovitz, 1997]. McCune-Albright syndrome should not be confused with Albright’s hereditary osteodystrophy, an autosomal dominant disorder also associated with defects in G proteins [Spiegel, 1997]. Patients with Albright’s hereditary osteodystrophy have characteristic physical features (short stature, obesity, round face, brachydactyly) and variable biochemical

Gleeson, Dobyns, Plawner, and Ashwal / Congenital Structural Defects

changes (pseudohypoparathyroidism or pseudopseudohypoparathyroidism). Most patients with Albright’s hereditary osteodystrophy have decreased activity of the guanine nucleotide-binding protein (Gs protein) that stimulates cyclic adenosine monophosphate [Phelan et al., 1995]. Loss of G alpha subunit function leads to tissue resistance to multiple hormones whose receptors couple to the G alpha subunit [Ringel et al., 1996]. Pamidronate treatment has been successfully used in patients with McCune-Albright syndrome [Matarazzo et al., 2002].

ABNORMALITIES OF OSSIFICATION: LYTIC LESIONS Lacunar Skull Lacunar skull is characterized by defects in the inner table of the cranial vault (membranous bone). This condition occurs in newborns and is associated with spina bifida and other major structural anomalies of the CNS and in some metabolic disorders [Cole, 2000]. Lacunar skull is not caused by elevated intracranial pressure and usually resolves over 6 months. Skull radiographs demonstrate a mixed pattern of decreased densities described as “soap bubble” rarefactions. Sinus pericranii is a parieto-occipital vascular scalp mass that is fluctuant and swells with elevated venous pressure and occurs with crying and the supine position [Wen et al., 2004]. Thus, the diagnosis can be confirmed during the physical examination. This lesion is a persistent connection between an intracranial dural sinus, usually the sagittal sinus, and the venous system of the scalp. Spontaneous partial thrombosis can occur; MRI and MR venography are particularly useful in detection of sinus pericranii and its complications [Azusawa et al., 2000; Carpenter et al., 2004]. Persistent emissary veins constitute a similar lesion but involve intracranial veins instead of a dural sinus. Both types erode the skull; the radiographic pattern may simulate parietal foramina, which constitutes a normal variation. Surgical treatment is elective and may not be necessary. In extensive or progressive lesions, treatment includes ligation of the anomalous connection. Traumatic scalp hemorrhage is a potential complication in untreated patients.

Cleidocranial Dysplasia Cleidocranial dysplasia is a congenital disorder of bone development characterized by persistently open or delayed closure of cranial sutures and wormian bones, hypoplastic and/or aplastic clavicles, wide pubic symphysis, dental anomalies, and short stature [Cooper et al., 2001; Mundlos, 1999]. Dental anomalies and delayed skeletal development are prominent features. Delayed ossification of membranous bones affects the frontal, parietal, and occipital bones. Cleidocranial dysplasia is inherited as an autosomal dominant trait, and the human CBFA1 gene has been identified as the responsible gene [Winer et al., 2003]. Autosomal-recessive inheritance also occurs [McKusick, 1994]. Chromosomal translocations, deletions, insertions, nonsense and splice-site mutations, as well as missense mutations of the RUNX2 gene which is an osteoblast transcription factor have been described in patients with cleidocranial

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dysplasia [Otto et al., 2002; Yoshida et al., 2003]. The runt box (Runx) is a highly conserved DNA-binding and protein-protein interaction domain that defines a family of heterodimeric transcription factors with essential roles in development [Coffman, 2003]. Runx proteins have essential functions in cell proliferation and differentiation, and in mammals they are both proto-oncogenes and tumor suppressors. Whereas Runx1 is essential for mature hematopoiesis and Runx2 for osteochondrogenesis, Runx3 has a function in the nervous system [Otto et al., 2003]. Physical examination reveals a broad head with a decreased anteroposterior diameter and frontal bossing. The sagittal suture and the large anterior and posterior fontanels remain open. Spasticity and mental retardation may occur. The shoulders can be closely adducted. Absence of the clavicles may result in injury to the unprotected brachial plexus and atrophy of the muscles of the hand. Short stature and multiple unerupted supernumerary teeth are common [Seow and Hertzberg, 1995]. Associated anomalies may include syringomyelia, partial agenesis of the corpus callosum, scoliosis, spina bifida, cervical ribs, and pelvic deformities [Vari et al., 1996]. Skull radiography demonstrates defective ossification, wide sutures, and multiple wormian bones; the chest x-ray examination reveals hypoplastic or absent clavicles. The only treatment available for cleidocranial dysplasia is to protect the brachial plexus from pressure injury to prevent pain and muscular atrophy. Hearing loss, as a presenting symptom of cleidocranial dysplasia, also has been reported [Dhooge et al., 2001]. In some patients with cleidocranial dysplasia, unilateral sensorineural hearing loss and ataxia has been a prominent feature [Scherer et al., 2001]. The combination of skull defects in the form of enlarged parietal foramina and deficient ossification of the clavicles is known as parietal foramina with cleidocranial dysplasia. It is considered to be distinct from classic cleidocranial dysplasia [Garcia-Minaur et al., 2003].

ABNORMALITIES OF THE CRANIAL BASE Achondroplasia Achondroplasia is a common form of human dwarfism with characteristically rhizomelic shortening of extremities, relative macrocephaly, short stature, dysmorphic features, congenital skeletal abnormalities, and neurologic involvement. It is transmitted in an autosomally dominant manner and about 80% of the cases result from sporadic mutations without a positive family history [Jones, 1997; McKusick, 1994; Su et al., 2004; Tanaka, 1997]. It is the most common skeletal dysplasia and occurs in about 1 in 15,000 to 40,000 live births. The basic defect is in endochondral bone formation, which explains the impaired growth of the base of the skull (endochondral bone), with a compensatory increase in growth of the normal membranous bones of the cranial vault. Achondroplasia is caused by mutation in the FGFR3 gene, which maps to chromosomal locus 4p16.3 [Rousseau et al., 1994; Shiang et al., 1994]. In 97% of the patients, a glycine-to-arginine substitution occurs at position 380 within the FGFR3 transmembrane domain, leading to receptor

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overactivation. This FGFR tyrosine kinase is expressed by chondrocytes in the growth plate of developing long bones and plays a crucial role in bone growth [Aviezer et al., 2003]. FGFR3 is expressed in developing bone, cochlea, brain, and spinal cord [Colvin et al., 1996]. Mutations in the FGFR3 gene enable abnormal cartilage growth plate differentiation and insufficient bone development [Su et al., 2004]. Prenatal detection for achondroplasia is available [Li et al., 2004]. The relation between the presence of brain FGFR3 transcripts and the increased occurrence of megalencephaly in patients with achondroplasia is being investigated. Prenatal screening for achondroplasia is available using polymerase chain reaction and chorionic villus sampling [Bellus et al., 1994; Shiang et al., 1994]. Screening has been recommended for pregnancies at risk for homozygous achondroplastic fetuses [Shiang et al., 1994].

Clinical Characteristics The diagnosis usually is readily apparent and is based on the physical examination findings of short-limbed dwarfism, prominent forehead, mid-facial hypoplasia, macrocephaly, exaggerated lumbar lordosis, limitation of elbow extension, genu varum, and a trident hand [Hall, 1988]. Although achondroplasia is an autosomal-dominant disorder, most cases (80%) represent a new mutation without a known family history. Skeletal radiographs demonstrate early fusion of the spheno-occipital synchondrosis at the base of the skull, short tubular bones, J-shaped sella turcica, and anterior beaking of the lumbar vertebrae. Symptoms and signs include dysphagia, poor head control, apnea, cyanotic episodes, hypotonia, delayed motor milestones, and weakness. Progressive obesity is a major problem and aggravates the morbidity associated with lumbar stenosis, joint problems, and early cardiovascular mortality. Most patients have normal intelligence and can lead a normal life, although some have mild deficits in visualspatial tasks or mild mental retardation associated with other neurologic or respiratory complications [Cohen et al., 1967; Hecht et al., 1991; Thompson et al., 1999]. Neurologic symptoms occur in approximately 20% to 47% of patients [Haga, 2004; Ruiz Garcia et al., 1997]. Neurologic and skeletal abnormalities include quadriparesis, paraplegia, macrocephaly, brachycephaly, hydrocephalus, true megalencephaly, platybasia, basilar impression, small foramen magnum, midfacial hypoplasia, lumbar lordosis, kyphosis, syringomyelia, diastematomyelia, Arnold-Chiari malformation, and stenosis of the spinal canal [Jones, 1997; Yamada et al., 1981; Yundt et al., 1996]. Conductive hearing loss is common and secondary to frequent otitis media. Temporal bone morphologic changes described in patients with achondroplasia (narrowing of the skull base, “towering” petrous ridges, abnormal orientation of inner and middle ear structures) do not appear to correlate with the degree of sensorineural or conductive hearing loss [Shohat et al., 1993]. Infants with achondroplasia are at risk for apnea and unexpected sudden death resulting from brainstem dysfunction and constriction of the cranial base [Bland and Emery, 1982; Pauli et al., 1984]. Polysomnographic studies during sleep frequently are abnormal [Zucconi and Bruni, 2001]. Abnormalities include upper airway obstruction with

obstructive apnea, central apnea, and abnormal electromyographic activity of accessory muscles of respiration. Correlation between somatosensory-evoked response abnormalities or foramen magnum size and polysomnographic abnormalities has not been observed [Waters et al., 1995]. Trigeminal neuralgia [Takada et al., 2001] and facial palsy [Cerqueiro-Mosquera et al., 2001] also may occur. Progressive neurologic deterioration involves brainstem, spinal cord, or nerve root compression and hydrocephalus secondary to spinal canal stenosis, vertebral subluxation, and impaired growth of the base of the skull (cartilaginous bone), which has a small deformed foramen magnum [Hamamci et al., 1993; Mueller et al., 1977; Wieting and Krach, 1994]. Cervicomedullary junction compression is a prominent finding in some patients and can cause pain, ataxia, incontinence, apnea, and respiratory arrest. One of the signs can be progressive quadriparesis, which can be a presenting symptom and may be caused by a vascular lesion, as well as by cord compression. Also, nerve root compression in the neural foramina can cause symptoms and signs in the limbs [Gordon, 2000; Pauli et al., 1995; Ryken and Menezes, 1994]. Stenosis of the spinal canal results from increased endochondral ossification with premature synostosis of the ossification centers of the vertebral body and the posterior arch, with thickening of the lamina, shortening of the pedicles, and reduced height of the vertebral bodies [Hamamci et al., 1993]. Prolapsed intervertebral disks, osteophytes, and progressive thoracolumbar kyphosis also contribute to the narrowing of the spinal canal. For patients with craniospinal junction compression, symptoms and treatment are similar to those for patients with basilar impression. Cauda equina compression resulting from lumbar stenosis may cause leg pain with exercise. Hydrocephalus, a narrow foramen magnum, spinal deformity, and spinal canal stenosis can cause neurologic problems leading to disabilities in locomotion, communication, and learning. Malfunctions of the otolaryngeal system such as otitis media, upper respiratory obstruction, deafness, speech delay, and malocclusion are interrelated and also can lead to disabilities in communication and learning [Haga, 2004]. Hydrocephalus likely is due to stenosis, compression of the fourth ventricle or medullary foramina, and increased intracranial venous pressure from bilateral jugular venous compression or stenosis [Erdincler et al., 1997; Gordon, 2000; Pierre-Kahn et al., 1980]. The development of hydrocephalus, which occurs in about 15% of patients, can be monitored more effectively by using head circumference charts normalized for children with achondroplasia and by performing cranial ultrasound examinations in infants [Horton et al., 1978]. Apart from the treatment for hydrocephalus, the most important decision often is the question of whether to surgically correct the cervical medullary compression [Ho et al., 2004]. Risk factors such as brisk reflexes, small foramen magnum, or central hypopnea can be an indication for surgery, but timing can be difficult, because the cord compression can resolve spontaneously [Gordon, 2000]. Pseudotumor cerebri may occur in some patients, perhaps as a result of obstruction of venous drainage [Rosman and Shands, 1978]. Using MRI, dynamic changes in brain morphometry and in cerebrospinal fluid dynamics in children with achondroplasia have been described [Bruhl et al., 2001; DiMario

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et al., 1995]. A rostral displacement of the brainstem and gradual compression of the frontal lobes resulting from enlargement of the ventricles are the most significant features. These changes occur in association with an increase in venous sinus distention and suggest that hydrocephalus in these patients may be related to chronic hydrostatic pressure changes. Interruption of cerebrospinal fluid flow due to narrowing of the craniocervical junction also has been demonstrated; this finding may be helpful in determining whether surgical decompression is warranted [Bruhl et al., 2001].

Management Recommendations for the management of achondroplasia previously have been reviewed [Horton and Hecht, 1993; Nicoletti et al., 1988]. Management of neurologic complications begins with careful and regular clinical assessment, especially in searching for symptoms and signs of elevated intracranial pressure; hearing loss; or brainstem, spinal cord, and nerve root compression. Serial measurements of growth and head circumference using growth curves standardized for achondroplasia are important. Many patients have enlarged ventricles, possibly representing atrophy or nonprogressive arrested hydrocephalus, which does not require specific treatment. Shunting procedures should be considered only in patients with evidence of progressive ventriculomegaly and in those with symptoms of elevated intracranial pressure associated with ventriculomegaly. Serial CT, MRI, somatosensory-evoked potentials, and polysomnography are important in the follow-up management of these patients. Surgical enlargement of the foramen magnum in patients with severe stenosis needs to be considered. The diagnosis of pseudotumor cerebri should be considered in symptomatic patients without enlarged ventricles; medical management is indicated. The large head of the achondroplastic fetus creates an increased risk of intracranial bleeding during delivery. Obstructive sleep apnea in infants and abnormal respiratory function require early recognition and management [Nelson et al., 1988]. Patients with achondroplasia are also at greater risk for sudden unexpected death in the first year of life presumably because of cervicomedullary junction compression [Pauli et al., 1995]. Lower limb hyperreflexia, central apnea or hypopnea detected with polysomnography, and reduced foramen magnum measurements are more common in those patients who develop symptoms of cervicomedullary compression [Pauli et al., 1995]. Because of this risk, early evaluation with MRI and consideration for early surgical intervention in those patients with cervicomedullary compression has been recommended [Keiper et al, 1999; Pauli et al., 1995; Yamada et al., 1996]. In some patients, papilledema secondary to increased intracranial pressure may become intractable and result in optic atrophy. Treatment with nerve unsheathing and shunting is required [Landau and Gloor, 1994]. Evaluation of progressive spinal cord and nerve root involvement includes spinal radiography, electromyography, MRI, and CT [Hamamci et al., 1993; Thomas et al., 1988; Wang et al., 1987]. Somatosensory-evoked potentials may provide a noninvasive method to monitor spinal cord function sequentially in these high-risk patients [Boor et al., 1999]. Lumbar puncture should be performed only after the absence of significant hydrocephalus is documented and the

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risks and benefits of the procedure are considered. Patients with progressive paraparesis; brainstem, spinal cord, or nerve root compression; or bowel and bladder dysfunction need immediate evaluation and possible decompressive laminectomy or suboccipital decompression [Nelson et al., 1988; Pauli et al., 1995; Reid et al., 1987; Ryken and Menezes, 1994]. Spinal cord infarction secondary to spinal stenosis may also occur [Wieting and Krach, 1994]. Spinal stenosis, which typically manifests in early adulthood, usually requires lumbar laminectomy. Recombinant human growth hormone has been used in children with achondroplasia, but the clinical indications, long-term effects, and duration of treatment require continued evaluation [Shohat et al., 1996; Stamoyannou et al., 1997]. Careful monitoring and control of weight to within 1 standard deviation of the mean weight-for-height curves also have been recommended [Hunter et al., 1996]. Waters and colleagues [1995] studied the results of treatment of obstructive sleep apnea in achondroplasia. Treatment included adenotonsillectomy, weight loss, and nasal mask continuous positive airway pressure. Patients with achondroplasia frequently require orthopedic intervention for spinal deformities and for limb lengthening [Ain et al., 2004; Aldegheri et al., 2001] and tethered cord release [Archibeck et al., 1997].

Basilar Impression Basilar impression (platybasia) is a congenital skeletal malformation that combines deformity of the osseous structures of the base of the skull with invagination of the foramen magnum and upper cervical spine into the posterior fossa [Bassi et al., 1992; Sawin and Menezes, 1997]. The foramen magnum is small and deformed. The floor of the posterior fossa and the odontoid process are displaced upward, further narrowing the foramen magnum and compressing the medulla and upper cervical spinal cord [McLaurin et al., 1989]. Metabolic bone disease such as osteomalacia, osteogenesis imperfecta, congenital hypothyroidism, rickets, and Paget’s disease may result in acquired basilar impression. The congenital condition is inherited as an autosomal-dominant trait with variable expression [McKusick, 1994].

Clinical Characteristics Neurologic symptoms most often begin after age 10 years. Neck stiffness, progressive spasticity and weakness of the legs, occipital headaches, and difficulty in walking are common complaints. Basilar impression should be considered in patients with progressive cerebellar ataxia or spastic paraparesis and brainstem or cervical cord syndromes, which might be mistaken for multiple sclerosis, spinal cord tumors, Arnold-Chiari malformation, and syringomyelia. Basilar impression may be associated with the Arnold-Chiari malformation and aqueductal stenosis; in such instances, hydrocephalus may be a feature. The progressive symptoms are attributed to pressure on the medulla and upper cervical spinal cord, similar to that in other craniocervical junction defects. Interference with the local blood supply and direct compression of neural structures have been postulated as pathogenic mechanisms. Physical examination reveals a short neck, low hairline, painful torticollis, restricted neck motion, and a loss of

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TABLE 19-25 Clinical Features of Osteogenesis Imperfecta Subtypes

From Steiner RD, Pepin, MG, Byers, PH. Osteogenesis imperfecta. See http://genetests.org and the review under “Osteogenesis Imperfecta”, 2005.

the normal cervical spine lordosis. Neurologic findings may include downbeat or periodic alternating nystagmus, fixed or intermittent cranial nerve impairment, bilateral corticospinal tract signs, ataxia, weakness, and sensory loss in the hands [Burrows, 1981]. The diagnosis is confirmed by a lateral radiograph of the skull. The odontoid process extends above a line drawn from the hard palate to the posterior edge of the foramen magnum (Chamberlain’s line). MRI and CT clearly define the existence of neural compression and should replace myelography [Koenigsberg et al., 2005].

Management Surgical decompression of the posterior fossa and the upper cervical cord is the treatment for symptomatic patients with congenital basilar impression [Harkey et al., 1990; McLaurin et al., 1989; Sawin and Menezes, 1997; Tuite et al., 1996b]. Decompressive surgery should be avoided in children with acquired basilar impression resulting from a metabolic bone disease because surgery may worsen the deformity.

Osteogenesis Imperfecta Osteogenesis imperfecta is a group of hereditary disorders of collagen manifested by bone fragility, fractures with minimal or absent trauma, short stature, dentinogenesis

imperfecta, blue sclerae, and postpubertal hearing loss [Rauch and Glorieux, 2004; Steiner et al., 2005]. Laxity of joints and skin and cardiovascular disease also may be features, depending on the type of osteogenesis imperfecta [Byers, 1993; Marini and Gerber, 1997; Tosi, 1997]. The clinical features of osteogenesis imperfecta represent a continuum ranging from perinatal lethality to a presentation with severe skeletal deformities, mobility impairments, and very short stature to a nearly asymptomatic presentation associated with a mild predisposition to fractures, normal stature, and normal lifespan. Fractures can occur in any bone but are most common in the extremities. Osteogenesis imperfecta is characterized by gray or brown teeth that may appear translucent and that wear down and break easily. Before the molecular basis of osteogenesis imperfecta was understood, this condition was classified into four types on the basis of mode of inheritance, clinical presentation, and radiographic findings. With detailed radiographic and bone morphologic studies and molecular genetic analyses, the classification has expanded to seven types (Table 19-25) [Steiner et al., 2005]. Osteogenesis imperfecta types I to V are inherited in an autosomal-dominant manner. Osteogenesis imperfecta type VII is inherited in an autosomal recessive manner, and the mode of inheritance of osteogenesis imperfecta type VI is not yet certain. The four well-recognized types of osteogenesis imperfecta are a dominant form with blue sclerae; a perinatal lethal form; a progressive deforming form

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with normal sclerae; and a dominant form with normal sclerae [Byers, 1993]. Joint motion, muscle strength, and functional ability vary, depending on the type of osteogenesis imperfecta present [Engelbert et al., 1997; Rauch and Glorieux, 2004; Wilkinson et al., 1997]. Type I patients characteristically have normal strength and generalized hypermobility of the joints without decreased joint motion. In type III patients, the lower and, to a lesser extent, the upper extremities have weak musculature and severe deformities, whereas in type IV patients, proximal muscles are weaker and the upper and lower extremities are equally affected. Bruck’s syndrome is a recessively inherited phenotypic disorder featuring the unusual combination of skeletal changes resembling osteogenesis imperfecta with congenital contractures of the large joints [Ha-Vinh et al., 2004]. The gene for this rare disorder has been localized to chromosomal region 17p12, and the underlying molecular defect is a deficiency of bone-specific telopeptide lysyl hydroxylase, which results in aberrant cross-linking of bone collagen. Molecular defects of type 1 collagen are the major cause of osteogenesis imperfecta types I to IV [Cole, 1997]. Osteogenesis imperfecta types V to VII are not due to COL1A mutations, and the defects for these three forms of osteogenesis imperfecta are not yet well established. For types I to IV, the proportion of cases caused by a de novo mutation in either COL1A1 or COL1A2 varies according to the severity of disease: Approximately 60% of persons with mild osteogenesis imperfecta have de novo mutations; virtually 100% of persons with lethal (type II) osteogenesis imperfecta and a smaller proportion of those with osteogenesis imperfecta type II have a de novo mutation. Whereas the milder forms are due to quantitative abnormalities of type 1 collagen, the more severe forms are due to both quantitative and qualitative type 1 collagen abnormalities. The mutant type 1 collagen molecules are susceptible to degradation with loss of normal and mutant collagen chains that severely impair the formation of the extracellular matrix and cause an abnormal architecture of dermis and bone. Prenatal diagnosis is available using analysis of collagen synthesized by cells cultured from chorionic villus biopsies or direct mutation identification or analysis of polymorphic restriction sites in the COL1A1 gene of type 1 collagen [Nuytinck et al., 1998; Pepin et al., 1997]. Treatment includes cesarean birth, if prenatal diagnosis is known, and immobilization of the neck postnatally [Pauli and Gilbert, 1986]. The value of surgery later in life is uncertain, although recent reports indicate clinical improvement in patients who have an associated Arnold-Chiari malformation or basilar impression [Harkey et al., 1990; Tominaga et al., 1991]. Extremity deformities also can be surgically corrected [Luhmann et al., 1998]. Because of the high incidence of progressive hearing loss, regular hearing evaluations after adolescence are recommended. Defective skull ossification, fractures, and neurologic complications develop in infants with the more severe and often lethal types II and III. Neurologic complications include intracranial hemorrhage [Sayre et al., 1987], basilar impression, upper cervical cord compression, hydrocephalus, and macrocephaly [Hayes et al., 1999; Sawin and Menezes, 1997], which may lead to respiratory insufficiency and death. Bone mineral density is decreased in osteogenesis imperfecta, especially of the lumbar spine [Reinus et

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al., 1998]. Pulmonary hypoplasia and chest wall constriction also may produce respiratory compromise. Conductive or mixed-type hearing loss occurs in about 50% of families, beginning in late childhood [Imani et al., 2003] or adolescence and progressing over time to profound deafness, tinnitus, and vertigo [Garretsen et al., 1997]. Reflex sympathetic dystrophy syndrome also may occur [Neri et al., 1997]. Deformities of the upper limbs have been reported in 37.1% of patients with osteogenesis imperfecta, with many showing significant functional impairments [Amako et al., 2004]. Other studies examining the natural history of osteogenesis imperfecta have found that total joint range of motion decreases significantly over time, especially in the lower extremities [Engelbert et al., 2004]. Although no significant changes in total muscle strength were found in this study, an increase in self-care needs and a decrease in mobility were reported. In addition to surgery, specific occupational and physical therapy programs are integral parts of the treatment of patients with osteogenesis imperfecta [Zeitlin et al., 2003]. Osteogenesis imperfecta type II has been shown to be associated with neuropathologic alterations, specifically perivenous microcalcifications, and impaired neuroblast migration. A recent study of nine osteogenesis imperfecta patients, a majority of whom had type II osteogenesis imperfecta, found hippocampal malrotation, agyria, abnormal neuronal lamination, migrational defects, diffuse hemorrhage, periventricular leukomalacia and calcifications, and white matter gliosis. These findings were interpreted as supporting the contention that collagen mutations might negatively impact CNS development [Emery et al., 1999]. Cerebrovascular abnormalities have been described in patients with osteogenesis imperfecta, presumably caused by the vascular fragility resulting from the collagen abnormality. These have included a cerebrovasculopathy of largecaliber intracranial vessels manifested by stenosis, thrombosis, and occlusion and a moya-moya pattern [Albayram et al., 2003]. Carotid and vertebral artery dissections also have been reported [Rouviere et al., 2004; Zuccoli et al., 2002]. Bisphosphonate treatment for moderate-to-severe forms of osteogenesis imperfecta also is now recommended [Licata, 2005]. Cyclic intravenous or oral administration of dimethylaminohydroxypropylidene bisphosphonate (pamidronate) in children with type I or III osteogenesis imperfecta has resulted in increased bone density and reductions in the frequency of new fractures [Astrom and Soderhall, 1998; Bembi et al., 1997; Fujiwara et al., 1998; Landsmeer-Beker et al., 1997]. Bisphosphonates were selected because of their ability to inhibit osteoclastic bone resorption and to increase bone density [Shaw, 1997]. At present, however, the best treatment regimen and the long-term outcomes of bisphosphonate therapy are unknown. Although this treatment does not constitute a cure, it constitutes a potentially beneficial adjunct to physiotherapy, rehabilitation, and orthopedic care. Gene-based therapy at present remains in the early stages of preclinical research [Niyibizi et al., 2004; Rauch and Glorieux, 2004]. Bisphosphonates usually are given intravenously, although oral forms have been tried, with no demonstrable decrease in fracture incidence compared with that in control subjects [Dimeglio et al., 2005]. When a child presents with one or more unexplained or recurrent fractures, nonaccidental trauma also must be considered [Chapman and Hall, 1997]. Conversely, osteo-

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TABLE 19-26 Selected Common Cleft Lip and Palate Disorders Associated with Major Neurologic Manifestations and Developmental Delay

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TABLE 19-26, cont’d Selected Common Cleft Lip and Palate Disorders Associated with Major Neurologic Manifestations and Developmental Delay

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TABLE 19-26, cont’d Selected Common Cleft Lip and Palate Disorders Associated with Major Neurologic Manifestations and Developmental Delay

From Steiner RD, Pepin MG, Byers PH. (Updated 1/28/05). Osteogenesis imperfecta. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2005. Available at http://www.genetests.org. Accessed 5/4/05.

genesis imperfecta could be mistaken for child abuse [Kruse et al., 1997]. Collagen analysis to exclude milder forms of osteogenesis imperfecta, especially type IV, is recommended only in cases in which the diagnosis of osteogenesis imperfecta remains in doubt [Ablin and Sane, 1997]. Cases in infancy of bilateral chronic subdural hematoma as the initial presentation of osteogenesis imperfecta type I have been reported and were considered to be due to impaired bone calcification, vascular fragility, and permanent friction between multiple bone fragments of the skull, although nonaccidental trauma could not be eliminated as a diagnostic possibility [Groninger et al., 2005]. Retinal hemorrhages in addition to subdural hematomas also have been reported in patients with type I osteogenesis imperfecta after minor trauma [Ganesh et al., 2004]. In a recent study using cultured fibroblasts from 262 children in whom nonaccidental trauma was suspected, 11 had alterations consistent with the diagnosis of osteogenesis imperfecta; in 11 others, the diagnosis could not be excluded [Marlowe et al., 2002]. Referring physicians correctly identified children with osteogenesis imperfecta in only 6 of the 11 instances and did not identify osteogenesis imperfecta by examination in 3. The authors of this study suggested that in view of the inability to identify all children with osteogenesis imperfecta by clinical examination in situations of suspected nonaccidental trauma, laboratory testing for osteogenesis imperfecta (and other genetic disorders that predispose for fractures) was valuable in discerning the basis for fractures [Marlowe et al., 2002].

DISORDERS ASSOCIATED WITH CLEFT LIP AND PALATE Clefts of the lip or palate, or both, are among the most common birth defects worldwide, with an incidence of between 1 in 600 and 1 in 1000 live births. It is the fourth most common congenital disorder in humans [Cobourn, 2004; Cox, 2004; Stanier and Moore, 2004]. The Online Mendelian Inheritance in Man catalog (http://www3.ncbi.nlm.nih.gov/ Omim) lists more than 400 single-gene causes of cleft lip/

palate. A majority (i.e., 70%) of cases of this disorder are nonsyndromic, in which cleft lip/palate occurs in isolation of other phenotypes. When one or more additional features are involved, clefts are referred to as syndromic. Collectively, cleft lip/palate has a major clinical impact requiring surgical, dental, orthodontic, speech, hearing, and psychologic treatments or therapies throughout childhood. The etiology of cleft lip/palate is complex and thought to involve both major and minor genetic influences, with variable interactions from environmental factors. Several monographs published in the past decade and more recently provide much information about these disorders and their evaluation and management [Berkowitz, 1996; Canady et al., 1999; Gorlin, 1990; Jones, 2000; Sperber, 2001; Turvey, 1996; Wyszynski, 2002]. Table 19-26 presents a selected list of the most common disorders in which neurologic involvement may be significant in children with cleft lip/palate.

Embryology The lip and palatal regions are developed from the embryonic primary and secondary palates [Wong and Hagg, 2004]. The primary palate contributes to the lip, anterior toothbearing alveolus, and the anterior palate up to the incisal foramen. The secondary palate contributes to the remaining hard and soft palates. During the fourth week of gestation, neural crest cells from the anterior neural tube migrate to form the facial primordia, from which the nasal and the lateral maxillary processes fuse to form the primary palate. The secondary palate begins to form in the sixth week of gestation. Palatal shelves initially appear as two downward extensions from the inner side of the left and right maxilla along the lateral surface of the tongue. In the ninth week, the two palatal shelves undergo a rapid horizontal transformation, by moving over the tongue and fusing with each other and with the nasal septum. Failure in the fusion of primary or secondary palates leads to clefts of the respective areas. Thus, the resultant defect appears commonly as cleft lip with or without cleft palate or isolated cleft palate.

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Genetic and Environmental Factors An in-depth review of the molecular basis of cleft lip/palate is beyond the scope of this chapter. Several recent reviews have summarized available data on this subject [Cobourn, 2004; Cox, 2004; Lidral and Murray, 2004; Wong and Hagg, 2004]. Overall, four categories of genes for which there are results suggestive of a genetic susceptibility to cleft lip/palate are (1) genes expressed in a particular area of the embryo or in a particular period of palatal arch development, such as TGF-α, TGF-β2, and TGF-β3; (2) genes having biologic activities linked to pathogenesis of cleft lip/palate without direct involvement (e.g., the retinoic acid receptor, the methylenetetrahydrofolate reductase receptor and the folic acid receptor; (3) genes or loci identified in experimental animals as the homeotic genes MSX1 and MSX2; (4) genes involved in the interaction with the xenobiotic metabolism, such as those in the P-450 cytochrome system [Bianchi et al., 2000].

Recently Discovered Genes Causing Syndromic Cleft Lip or Palate Some of the more important recently discovered genes are summarized next and in Table 19-27. T-Box Transcription Factor-22 Gene. X-linked cleft palate is characterized by isolated cleft palate and “tonguetie” (ankyloglossia), and the gene has been localized to chromosomal region Xq21. Mutations of the T-box transcription factor-22 gene (TBX22) were demonstrated in a large Icelandic family with X-linked cleft palate and in several other families [Braybrook et al., 2001]. Animal experiments have found that expression of TBX22 is highly restricted to the palatal shelves and the base of the tongue corresponding to the frenulum. Involvement of TBX22 in nonsyndromic cleft lip/palate has recently been suggested. Poliovirus Receptor–Like-1 Gene. Cleft lip/palateectodermal dysplasia syndrome, inherited as an autosomal recessive trait, is characterized by cleft lip with or without cleft palate, hidrotic ectodermal dysplasia, syndactyly, and occasionally mental retardation. Mutations of the poliovirus receptor–like-1 gene (PVRL1) have been demonstrated in families with this dosorder. Now known as nectin, the protein product of PVRL1 was initially identified as poliovirus receptor-related protein that functioned as a CAM [Takahashi et al., 1999]. TABLE 19-27 Candidate Genes or Loci Involved in Nonsyndromic Cleft Lip and Palate

From Wong FK, Hagg U. An update on the aetiology of orofacial clefts. Hong Kong Med J 2004;10:331.

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Interferon Regulatory Factor-6 Gene. Van der Woude’s syndrome is the most common form of syndromic cleft lip/ palate and accounts for 2% of all cases of cleft lip/palate. This syndrome is characterized by cleft lip with or without cleft palate, isolated cleft palate, pits or mucous cysts on the lower lip, and hypodontia. Popliteal pterygium syndrome includes all of the features of Van der Woude’s syndrome plus popliteal pterygium, syngnathia, distinct toenail abnormality, syndactyly, and genitourinary malformations. In families with Van der Woude’s syndrome and popliteal pterygium syndrome, localization to chromosomal region 1q32-q41 has been demonstrated, and mutations in the interferon regulatory factor-6 gene (IRF6) have been described [Kondo et al., 2002]

Candidate Genes for Nonsyndromic Cleft Lip or Palate Transforming Growth Factor-α Gene. The gene encoding transforming growth factor-α (TGFA) has been associated with nonsyndromic cleft lip/palate. The combined effects of TGFA mutations and environmental influences in this disorder have suggested that the presence of the rare TGFA variant (TaqI C2 allele) associated with maternal smoking results in a six- to eightfold increase in the risk of cleft palate and a twofold increase in the risk of cleft lip with or without cleft palate [Hwang et al., 1995; Shaw et al., 1996]. In addition, lack of multivitamin use during the first trimester of pregnancy in infants with the TGFA TaqI C2 allele appears to increase the relative risk for cleft lip with or without cleft palate three- to eightfold [Shaw et al., 1998]. Drosophila Msh Homeobox Homolog-1 Gene. MSX1 (Drosophila msh homeobox homolog-1 gene) mutations cause an autosomal dominant form of tooth agenesis and more recently have been identified in patients with cleft lip with or without cleft palate [Jezewski et al., 2003]. It is suggested that MSX1 mutations contributed to 2% of all cases of nonsyndromic cleft lip/palate. A recent study showed that the combined genetic background of rare variants of TGFA and MSX1 could increase the risk of cleft palate up to 9.7 times, demonstrating the significance of gene-gene interaction in the etiology of nonsyndromic cleft lip/palate [Jugessur et al., 2003a]. 5,10-Methylenetetrahydrofolate Reductase Gene. The association between folic acid deficiency and neural tube defects is well established (see also Chapter 90). 5,10-Methylenetetrahydrofolate reductase (MTHFR) is the enzyme responsible for catalyzing the conversion of 5,10-methylenetetrahydrofolate into 5-methyl-tetrahydrofolate. The MTHFR C677T genotype is a risk factor for neural tube defects. In nonsyndromic cleft lip/palate, the MTHFR C677T genotype in the mother conferred a risk of cleft lip/palate in offspring that was increased 4.6-fold [Prescott et al., 2002]. In association with folate deficiency during pregnancy, the MTHFR thermally labile variant could lead to a 10-fold increased risk of cleft lip/palate [van Rooij et al., 2003]. Transforming Growth Factor-b3 Gene. Mice lacking the gene encoding TGF-β3 (TGFB3) have cleft palate because of defective adhesion of opposing palatal shelves. In humans, TGFB3 has been associated with nonsyndromic cleft lip/palate [Jugessur et al., 2003a]. Other Genes and Loci. Numerous other genes and proteins have been associated with cleft lip/palate. Table 19-27 summarizes some of these factors.

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Environmental Factors Smoking. The relation between maternal smoking and cleft lip/palate is not strong but is significant [Wong and Hagg, 2004]. Several studies have consistently yielded a relative risk of about 1.3 to 1.5 [Wyszynski and Wu, 2002]. The combined effect of maternal smoking and certain maternal or fetal genotypes may further increase the risk of cleft lip/palate. Maternal glutathione S-transferase θ-1 (GSTT1) genotype, combined with smoking, increases the risk of cleft lip/palate by a factor of 4.9, and maternal smoking plus infant MSX1 genotypes increases the risk by 7.16. Alcohol Use. Heavy maternal drinking, in addition to causing fetal alcohol syndrome, increases the risk of cleft lip/palate by 1.5 to 4.7 in a dose-dependent manner [Munger et al., 1996]. Investigators have found that mothers who have more than five drinks per occasion increase the risk of cleft lip/palate in their offspring by a factor of 3.4 [Shaw and Lammer, 1999]. Low-level alcohol consumption, however, does not appear to increase the risk of cleft lip/palate, and the relation between alcohol use and genotypes on the risk of cleft lip/palate has yet to be determined [Wong and Hagg, 2004]. Use of Folic Acid and Multivitamins. The relation of folate to cleft lip/palate is discussed in an earlier section. Folate deficiency with the background of the TGFA TaqI C2 genotype also has been found to increase the risk of cleft lip/palate [Jugessur et al., 2003b]. Defective maternal vitamin-dependent homocysteine metabolism also is a risk factor for cleft lip/palate in offspring. As reviewed by Wong and Hagg [2004], the role of folic acid supplementation in the prevention of cleft lip/palate has been investigated in several studies. Low-dose folate supplementation by fortifying cereal grain products did not protect against cleft lip/ palate; only high-dose supplementation (e.g., 10 mg daily) was effective.

Associated Neurologic, Neurocognitive, and Speech and Language Impairments A majority of the patients with nonsyndromic cleft lip/palate have normal neurologic function and do not have any longterm neurologic, neuropsychologic, or neurobehavioral problems. Persons with syndromic clefting are more likely to encounter difficulties in these domains. The literature on these coexistent conditions is small, but in the past decade, new interest aimed at a better understanding of these associated problems has developed. Of interest, some very-long-term clinical studies spanning more than 5 decades that examined aspects of quality of life in patients with cleft lip/ palate have been published [Christensen and Mortensen, 2002].

Speech and Language Functioning Children with cleft lip/palate are at risk for speech and language disorders, which can be identified during infancy [Kapp-Simon and Krueckeberg, 2000]. These include limitations in phonemic repertoire, poor intelligibility, and delays in expressive and receptive language skills [KappSimon and Krueckeberg, 2000; Scherer and D’Antonio, 1995]. Conventional audiologic evaluations such as pure tone audiometry, word discrimination audiometry, and acoustic immittance measures may find abnormalities in

these children, as well as evidence of auditory processing disorders [Minardi et al., 2004; Schnitt et al., 2004]. A study of 54 children with cleft lip/palate found normal intelligibility in 53%, mild hypernasality in 23.5%, and mild hyponasality in 29% [Timmons et al., 2001]. Dysphonia was present in 41% of patients with cleft lip/palate.

Neurologic Involvement Very little information is available concerning brain morphology or neurologic function in children with cleft lip/ palate. In one study of adult males with nonsyndromic clefting, MRI found enlarged anterior regions of the cerebrum, and decreased volumes of the posterior cerebrum and cerebellum compared to age matched controls [Nopoulos et al., 2002a]. The most severely affected region was the left temporal lobe. Structural abnormalities also were believed to be directly related to cognitive dysfunction. A second study from the same group of investigators found evidence of an enlarged cavum septum pellucidum in 8% of adults with cleft lip/palate and also demonstrated an inverse relation between IQ and presence of the cavum [Nopoulos et al., 2001]. Similar studies have not been performed in children.

Neurocognitive and Neurobehavioral Disorders Studies of cognitive function in children are complicated by the heterogeneous sampling described in most studies. In one report of 84 patients, 46% of children with cleft lip/ palate had a learning disability, 47% had deficient educational progress, and 27% had repeated a grade [Broder et al., 1998]. Male patients with cleft palate only had a significantly higher rate of learning disorders. A longitudinal study of 16 children with cleft lip/palate using the Bayley Scales of Infant Development found that the children had lower scores on the mental and motor scales of the Bayley Scales of Infant Development, and on tests of language comprehension and expression, than corresponding scores of control subjects [Jocelyn et al., 1996]. Early studies that have been recently confirmed found that cognitive and motor development based on Bayley Scales of Infant Development scores was in the average range during the first year of life but then regressed during the second year [Kapp-Simon and Krueckeberg, 2000]. A third study of 148 children with all types of cleft lip/palate found Bayley Scales of Infant Development scores in the normal range; however, the presence of systemic congenital malformations was associated with lower scores [Swanenburg de Veye et al., 2003]. Reading problems in children with cleft lip/palate also have been evaluated. Children with nonsyndromic cleft lip/ palate show symptoms similar to a naming-memory deficit model of developmental dyslexia. Reading treatment should therefore avoid sight word approaches and focus on oral phonics [Richman et al., 2003]. Mental retardation does occur in patients with cleft lip/ palate, but its prevalence is unknown. One study of 56 persons with cleft lip/palate and mental retardation found that 46.8% had an isolated cleft palate and that 46.3% had multiple anomalies, syndromes, or associated medical findings [Strauss and Broder, 1993]. Common findings included cardiopulmonary defects, seizures, and deviations in head size. Adults with nonsyndromic cleft lip/palate have lower full scale IQ, performance IQ, and verbal IQ scores than corresponding scores in control subjects with specific deficits in verbal fluency [Nopoulos et al., 2002b].

Gleeson, Dobyns, Plawner, and Ashwal / Congenital Structural Defects

Psychiatric problems of children and adults with cleft lip/palate have been investigated to a very limited degree. In one 1978 study of 10 children, problems with excessive dependency, mental retardation, and developmental deviations were noted [Simonds and Heimburger, 1978]. Through the Danish Facial Cleft Database, 6462 patients with cleft lip/ palate born between 1936 and 1987 were evaluated over time. The risk of hospitalization for mental disorders was increased in patients with cerebral palsy, but not to any substantial degree in patients with cleft lip/palate. Both groups had an increased risk of mental retardation and substance abuse, but the risk for schizophrenia or bipolar illness was not increased compared with that in the background population. Also, no evidence indicates that the psychosocial stressors associated with cleft lip/palate and its treatment had any impact on the risk for mental illness requiring hospitalization [Christensen and Mortensen, 2002].

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CHAPTER 20

Cerebral Palsy Kenneth F. Swaiman and Yvonne Wu

DEFINITION AND CLINICAL CHARACTERIZATION Cerebral palsy is a nonspecific, descriptive term pertaining to disordered motor function that is evident in early infancy and is characterized by changes in muscle tone (typically spasticity or rigidity), muscle weakness, involuntary movements, ataxia, or a combination of these abnormalities. The condition is the result of brain dysfunction and is not episodic or progressive. Although tone and postural abnormalities may become more pronounced during early childhood, qualitative changes are uncommon. The full extent of motor disability may not be evident until the age of 3 or 4 years. Intellectual, sensory, and/or behavioral difficulties may accompany cerebral palsy; however, they are not included in the diagnostic criteria. For the most part, these accompanying difficulties can be managed with conventional approaches to each entity [Gross-Tsur, 2002]. Children with cerebral palsy often exhibit other neurologic impairments including mental retardation (52%), hearing impairment (12%), and speech and language disorders (38%) [Ashwal et al., 2004]. Epilepsy occurs in 34% to 94% of children with cerebral palsy, depending on the study population. Cerebral palsy encompasses a wide range of brain disorders associated with impaired motor function. As a result, the definition of cerebral palsy varies depending on the purpose for which the term is being used [Badawi et al., 1998c]. Consensus is lacking on whether a child with a known underlying pathologic condition (e.g., neuronal migrational defect, metabolic disease) should be included under the rubric of cerebral palsy, or whether the degree of disability also should be taken into account. The prevalence of the condition will clearly depend on how it is defined and on the age at diagnosis, because children with mild impairment may experience substantial improvement or dissolution of abnormal findings during maturation [Nelson and Ellenberg, 1982]. Nevertheless, the designation of cerebral palsy as an entity, irrespective of underlying conditions, is valuable, because afflicted children commonly have similar medical care, rehabilitation, and social services needs.

EPIDEMIOLOGY Cerebral palsy occurs in 1.2 to 2.5 children per 1000 live births. Despite the lack of a consistent definition, population prevalence rates from four continents have remained relatively constant over several decades. Numerous cerebral palsy registries exist throughout the world [Cans et al., 2004]. In the United States, the prevalence of cerebral palsy increased slightly from 1.7 to 2.0 per 1000 live births between the mid-1970s and late 1980s [Winter et al., 2002]. As estimated from these rates, 8000 children with cerebral palsy are born annually in the United States.

Prematurity is the single most important risk factor for cerebral palsy. The risk of cerebral palsy in very-low-birthweight infants is as high as 8% to 10%, whereas the risk in term infants is only 1.0 to 1.5 per 1000 live births [Grether et al., 1992; Hagberg et al., 2001; Topp et al., 2001; Wu et al., 2003]. An increase in the rate of cerebral palsy among preterm infants during the mid-1980s was attributed to increased survival of low-birth-weight infants [Colver et al., 2000; Pharoah et al., 1990; Topp et al., 2001]. Subsequent longitudinal studies of cerebral palsy in the late 1980s and 1990s, however, suggest that the rate of cerebral palsy among preterm infants has remained constant or even decreased during this more recent period [Clark and Hankins, 2003; Hagberg et al., 2001; O’Shea et al, 1998; Winter et al., 2002]. Nevertheless, preterm infants still constitute 50% to 60% of all infants with cerebral palsy. The prevalence of cerebral palsy among term infants has not diminished over the past 3 decades, despite the introduction of electronic fetal monitoring during the 1970s and the subsequent sharp rise in births by cesarean section [Clark and Hankins, 2003; Colver et al., 2000; Topp et al., 2001; Winter et al., 2002]. The unchanged prevalence is disappointing in view of the fact that perinatal deaths, stillbirths, and birth asphyxia as measured by low Apgar scores all have dropped dramatically in recent decades. Longitudinal data in the United States suggest that a slight increase in cerebral palsy prevalence among infants with normal birth weight is responsible for the significant increase in total cerebral palsy prevalence reported over a 15-year period [Winter et al., 2002]. Although the severity of cerebral palsy within an Australian population increased during this period [Blair, 2001], suggesting that perhaps more infants who would have died in previous times are being saved, workers in England have described a decrease in severity of cerebral palsy among term infants over a similar (18-year) period [Colver et al., 2000]. An infant who is the product of a multiple gestation carries a higher risk for cerebral palsy. Twins, who constitute 2% of the population, contributed 10% to the prevalence of cerebral palsy in one U.S. study [Grether et al., 1992]. The increased risk of cerebral palsy among infants of multiple gestation is partly due to the higher rate of prematurity. Twins born at term, however, also exhibit an increased risk for cerebral palsy [Petterson et al., 1993; Pharoah, 2001]. Death in utero of a co-twin, such as from twin-twin transfusion, places the surviving twin at particularly high risk for neurologic and other complications [Grether et al., 1993; Szymonowicz et al., 1986]. Blacks have an increased risk of cerebral palsy when compared with whites [Murphy et al., 1993]. This finding is due in part to an increased rate of prematurity. The risk of cerebral palsy among black infants born at term, however,

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also is elevated, for reasons that are poorly understood [Wu et al., 2003]. Life expectancy of patients with cerebral palsy is related to the type of involvement and the severity of motor disability. Severe quadriplegia has been associated with a shortened life expectancy. Other significant variables include associated disabilities and availability of quality medical care. The risk of death is highest in the first 5 years of life [Blair et al., 2001]. As mortality data have become available, it has become clear that with reasonable medical attention, a majority of affected persons will survive into adult life [Evans et al., 1990; Eyman et al., 1990; Hutton et al., 1994; Plioplys, 2003; Plioplys et al., 1998; Strauss et al., 1998].

ETIOLOGY A wide range of causative disorders and risk factors have been identified for cerebral palsy. Table 20-1 lists some of the more common etiologic categories and risk factors broadly classified into the following groups: perinatal brain injury, brain injury related to prematurity, developmental abnormalities, prenatal risk factors, and postnatal brain injury. These factors may co-exist and interact with each other in contributing to the pathogenesis of brain injury resulting in cerebral palsy.

Perinatal Brain Injury Intrapartum hypoxia-ischemia is a well-described cause of cerebral palsy, especially in the setting of an acute intra-

TABLE 20-1 Selected Etiologic Disorders and Risk Factors in Cerebral Palsy* Perinatal Brain Injury Hypoxia-ischemia Neonatal stroke (arterial and venous) Traumatic brain injury Intracranial hemorrhage Brain Injury Related to Prematurity Periventricular leukomalacia Intraventricular hemorrhage Developmental Abnormality Brain malformation Genetic abnormality Metabolic abnormality Postnatal Brain Injury Kernicterus Central nervous system infection Prenatal Risk Factors Maternal chorioamnionitis Intrauterine growth retardation Toxin exposure Congenital TORCH infections *Note that many of these conditions may coexist in a child with cerebral palsy. TORCH, toxoplasmosis, other infections, rubella, cytomegalovirus infection, herpes simplex.

partum event such as uterine rupture, placental abruption, or cord prolapse. The extent to which hypoxic-ischemic brain injury is responsible for cerebral palsy, however, has been a major source of controversy. Epidemiologic studies suggest that in a minority (between 6% and 28%) of affected children, cerebral palsy is due to perinatal asphyxia [Hagberg et al., 2001; Nelson and Grether 1998]. The form of cerebral palsy most often associated with hypoxic-ischemic brain injury is spastic quadriparesis. The term perinatal asphyxia is confusing and deserves further clarification. Traditionally, this term has been defined by clinical signs and symptoms including low Apgar scores, meconium-stained amniotic fluid, and low cord pH. Yet the clinical findings used to define this term are not specific for hypoxic-ischemic brain injury [Blair, 1993]. Although various groups of investigators have defined specific criteria that can be used to establish intrapartum hypoxiaischemia as the underlying cause of cerebral palsy [MacLennan, 1999], still lacking is a widely accepted evidencebased standard for determining when cerebral palsy is due to hypoxia-ischemia. Neonatal encephalopathy has emerged as the preferred term to describe the clinical syndrome traditionally called perinatal asphyxia, because it is an all-embracing term that does not imply a single underlying etiologic disorder [Leviton and Nelson, 1992]. Signs and symptoms of brain dysfunction that constitute neonatal encephalopathy include low Apgar scores, failure to initiate and/or maintain respiration, depressed consciousness, abnormal tone (usually flaccidity), depression of developmental reflexes, and seizures during the first 48 hours of life. The clinical syndrome of neonatal encephalopathy may be preceded by a variety of prenatal and intrapartum risk factors [Badawi et al., 1998b] and usually is associated with acute brain injury occurring around the time of birth [Cowan et al., 2003]. Signs and symptoms of neonatal encephalopathy are strongly predictive of cerebral palsy in the child. For instance, term infants whose immediate postpartum course comprises of a 5-minute Apgar score of 5 or less, continuing neurologic abnormalities, and seizures in the first days of life constitute a group at high risk for chronic motor disability (55%) and for death or disability combined (70%) [Ellenberg and Nelson, 1988]. The risk of cerebral palsy is increased 30-fold in infants with a 5-minute Apgar score of less than 7, and 80-fold in infants with a 5-minute Apgar score of 3 or less [Moster et al., 2001; Thorngren-Jerneck and Herbst, 2001; Wu et al., 2003]. Perinatal arterial ischemic infarction, commonly referred to as neonatal stroke, may be responsible for greater than half of all cases of hemiplegic cerebral palsy in term infants [Humphreys et al., 2000; Uvebrant, 1988; Wu et al., 2003]. Among children with cerebral palsy who are referred for neuroimaging, 13% to 37% are diagnosed with a neonatal stroke [Ashwal et al., 2004]. Although the term perinatal implies an event that occurs before the age of 7 days the term is not clearly defined, whereas neonatal refers to an event within 28 days of life [Lynch and Nelson, 2001], the two entities are often lumped together under the single category of “neonatal stroke.” Newborns with arterial ischemic infarction either may present acutely during the neonatal period, with neurologic symptoms such as seizures, or may be clinically asymptomatic until several months of age, when pathologic handed-

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ness or seizures are first noted [Golomb et al., 2001]. The risk of cerebral palsy after perinatal arterial stroke is especially high among infants with delayed presentation; this finding is not surprising given that hemiparesis is the most common presenting symptom in this group [Golomb et al., 2001; Wu et al., 2004]. Involvement of the internal capsule also portends a poorer motor outcome after perinatal arterial stroke [Mercuri et al., 1999; Wu et al., 2004]. Other cerebrovascular conditions, such neonatal sinovenous thrombosis, also can lead to cerebral palsy. In a population-based study of pediatric stroke in Canada, 43% of all cases of sinovenous thrombosis occurred during the neonatal period [deVeber and Andrew, 2001]. Risk factors for neonatal sinovenous thrombosis include systemic illness, polycythemia, coagulation abnormalities and extracorporeal membrane oxygen (ECMO) therapy, and motor sequelae such as cerebral palsy were more common if sinovenous thrombosis led to development of venous infarction [deVeber and Andrew, 2001; Wu et al., 2002]. Periventricular venous infarction [Takanashi et al., 2003], intraparenchymal hemorrhage, and birth trauma also may lead to cerebral palsy (please refer to Chapter 17 for further discussion of birth trauma).

Brain Injury Related to Prematurity Preterm infants have a disproportionate share of the cases of spastic diplegia but can manifest any cerebral palsy subtype. Both intraventricular hemorrhage and white matter necrosis may occur before or after birth. Cystic periventricular leukomalacia is the strongest risk factor for cerebral palsy among preterm infants and is reviewed in Chapter 14. The extent to which hypoxia-ischemia is a contributor to cerebral palsy in the very-low-birth-weight infant is not well established. Defects in autoregulation of cerebral blood flow may be important, as well as postnatal risk factors such as lung disease and hypotension. Recent evidence suggests that inflammation also contributes to the pathogenesis of white matter injury in preterm infants [Dammann and Leviton, 1997; Wu and Colford, 2000]. Periventricular leukomalacia and intraventricular hemorrhage are reviewed in Chapter 14.

Developmental Abnormalities Brain malformations originating from intrauterine maldevelopment may underlie the neurologic impairment seen in children with cerebral palsy. As a group, children with cerebral palsy have a higher incidence of congenital malformations both within and outside of the brain. Populationbased studies of cerebral palsy suggest that 9% to 14% of affected children have a brain malformation [Croen et al., 2001; Wu et al., 2003]. The most common malformations in term children are cortical dysplasia/polymicrogyria, schizencephaly, and pachygyria/lissencephaly; complex brain malformations are the most frequent category among preterm infants with cerebral palsy [Ashwal et al., 2004]. A genetic or metabolic disorder may be associated with a specific brain malformation that causes cerebral palsy. For instance, children with Zellweger’s syndrome typically have polymicrogyria and other cortical malformations. MillerDieker syndrome also is a known cause of lissencephaly. Glutaricaciduria type I may masquerade as dyskinetic cerebral palsy [Hauser and Peters, 1998], and arginase deficiency

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mimics diplegic cerebral palsy [Prasad et al., 1997]. Children with cerebral palsy who demonstrate either progressive decline or atypical features such as dysmorphisms, macrocephaly, or a strong family history should be tested for an underlying genetic or metabolic disorder.

Prenatal Risk Factors A number of maternal conditions have been associated with an increased risk of cerebral palsy in the offspring. Intrauterine inflammation, or chorioamnionitis, has received increasing attention as a potential risk factor [Grether and Nelson, 1997; Leviton et al., 1999; Wu and Colford, 2000]. Epidemiologic studies suggest that maternal intrapartum fever, a clinical or histologic diagnosis of chorioamnionitis, and serologic markers of inflammation in the fetus all confer an increased risk of cerebral palsy. In term infants, chorioamnionitis, often diagnosed by the presence of intrapartum maternal fever, is a particularly strong risk factor for spastic quadriplegia [Grether and Nelson, 1997; Wu et al., 2003]. Maternal fever during labor also increases the chance that the neonate will have low Apgar scores and characteristics of neonatal encephalopathy [Badawi et al., 1998a; Lieberman et al., 2000]. It is hypothesized that the fetal inflammatory response that occurs in the setting of an inflammatory intrauterine environment is responsible for brain injury leading to cerebral palsy [Dammann et al., 2002; Nelson et al., 1998]. Yet the mechanism by which intrauterine inflammation might cause cerebral palsy remains controversial and unexplained. Furthermore, the manner in which inflammation may interact with hypoxia-ischemia to injure the newborn brain also is unknown. Intrauterine growth restriction is associated with an increased risk of cerebral palsy, especially in term infants [Jarvis et al., 2003; Topp et al., 1996]. Infants who are large for gestational age also have been reported to be at higher risk [Uvebrant and Hagberg, 1992]. Prothrombotic abnormalities, including factor V Leiden mutation and presence of anticardiolipin antibodies, have been found with increased frequency among infants with perinatal arterial infarction and may contribute to the pathogenesis of cerebral palsy [Gunther et al., 2000; Hagstrom et al., 1998]. A history of infertility also has been found to be associated with an increased risk of neonatal encephalopathy, developmental delay, and cerebral palsy [Badawi et al., 1998b; Ericson et al., 2002; Stromberg et al., 2002]. A number of toxins have been described to cause cerebral palsy, such as benzyl alcohol preservative and in utero alcohol exposure [Benda et al., 1986; Burd et al., 2003]. Ingestion of methyl mercury by pregnant women in the Minamata Bay disaster resulted in the birth of children who were spastic, microcephalic, and mentally retarded. Congenital infections, often referred to as TORCH infections (toxoplasmosis, rubella, cytomegalovirus, and herpes simplex infection), also can infect the fetus and produce serious encephalitides with motor sequelae [Sever, 1985]. The pathogenesis of cerebral palsy is complex and multifactorial. Among infants with thromboembolic stroke in the newborn period, multiple risk factors often are observed [Gunther et al., 2000; Wu et al., 2002]. When signs of hypoxia-ischemia and markers of infection both are present in a newborn, the risk for cerebral palsy is markedly heightened [Nelson and Grether, 1998]. Similarly, chorio-

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amnionitis is a particularly strong risk factor for cerebral palsy among term infants who are found on head imaging to have suffered hypoxic-ischemic brain injury [Wu et al., 2003]. Studies of placental abnormalities in cerebral palsy also suggest that a combination of both thrombotic and inflammatory findings confers the highest risk of adverse neurologic outcome [Redline and O’Riordan, 2000].

Postnatal Brain Injury Cerebral palsy may result from brain injury occurring during the neonatal period. For instance, neonatal meningitis from group B streptococcal and other infections may cause brain damage leading to cerebral palsy. Other types of postnatal brain injury including hypoxia-ischemia and traumatic brain injury from nonaccidental trauma also may cause cerebral palsy. Bilirubin toxicity continues to be a significant problem in spite of recent progress in management of hyperbilirubinemic neonates [Shapiro, 2003]. Although bilirubin levels below 25 mg/dL may be associated with kernicterus [SooraniLunsing et al., 2001], more commonly bilirubin levels greater than 25 to 30 mg/dL lead to kernicterus, a wellknown cause of dyskinetic cerebral palsy. Symptoms of kernicterus in a jaundiced newborn usually are present by the second or third day of life. The child becomes listless and sucks poorly. Fever may be present, and crying becomes weak. The Moro and deep tendon reflexes become difficult to elicit, and general muscle tone becomes decreased. After several weeks, tone increases, and the infant manifests extension of the back with opisthotonos and marked extension of the extremities [Van Praagh, 1961]. The full clinical pattern of kernicterus infrequently is present in a single affected patient. Signs and symptoms consist of choreoathetosis, dystonia, tremors, and rigidity. Upward gaze and, on rare occasion, horizontal gaze may be impaired. Sensorineural hearing loss is common. Mental retardation, microcephaly, and spasticity may be present. A clinical score for assessing bilirubin-induced dysfunction in newborns has been recommended [Johnson et al., 1999]. Unconjugated bilirubin damages mitochondria and is toxic to neurons and to astrocytes [Ostrow et al., 2004]. Microscopic examination reveals yellow granules that are found not only in the nerve cells but also in the interstitial tissue. These changes occur in the first few days of involvement. Neurons are grossly pyknotic, and in children who live for longer periods, large areas of cell loss, gliosis, and demyelination are evident.

GENERAL PATHOLOGIC FEATURES Subependymal and intraventricular hemorrhages, sometimes associated with hypoxia-ischemia, may result in chronic motor impairment in preterm infants. Severe cystic changes in white matter in preterm infants often are accompanied by motor dysfunction [Bejar et al., 1986; de Vries et al., 1987]. Diminished blood flow in distal vessels to periventricular white matter, metabolic disturbances, and infection may precede white matter destruction [Leviton and Gilles, 1984]. In term, asphyxiated infants, an impairment of the blood flow in parasagittal areas has been documented by positron emission tomography [Volpe et al., 1985].

In studies of patients with documented motor disabilities, clinical neuropathologic correlative studies have been unsystematic, variously selective, and valuable in methods of evaluation, description, and interpretation. Use of current quantitative techniques of neuropathologic stains for cell processes has been minimal, and examination of fine structure in brains not demonstrating obvious perinatal destructive lesions has been limited as well [Nelson et al., 1994]. The presence of microcephaly at birth, dysmorphic features, and congenital anomalies outside the nervous system suggests early developmental defects.

CLINICAL FEATURES AND DIAGNOSIS Delay in attaining developmental milestones is the most distinctive presenting complaint in children with cerebral palsy. A detailed history and thorough physical and neurologic examinations are crucial in the diagnostic process. Records of the mother’s pregnancy and delivery and of the infant’s early neonatal period may be invaluable. Video recordings may be helpful. Physical and neurologic abnormalities may be subtle. The clinician should be cautious about diagnostic pronouncements unless the findings are unequivocal. Prognostic statements generally are not appropriate until after several serial examinations and history review sessions. The clinical findings often change with maturation; both severity and distribution may be altered. A child with cerebral palsy who has been hypotonic may become hypertonic. A number of infants with mild abnormalities subsequently demonstrate a decrease or, in some instances, a disappearance of motor dysfunction [Nelson and Ellenberg, 1982]. The clinical picture should not include evidence of progressive disease or loss of skills previously acquired. Any suggestion of progression of disability should result in expansion of the differential diagnosis to explain the progression. The history should focus on an attempt to identify a specific cause and should especially investigate familial or metabolic disease that might have implications for treatment or family counseling [Barabas and Taft, 1986]. The neurologic evaluation of the infant depends on the assessment of infantile developmental reflexes, muscle tone, deep tendon reflexes, and plantar responses. The use of standard developmental screening tests (e.g., the Denver Developmental Screening Test II) may provide quantitative evidence of motor delay, as well as evidence of delay in acquisition of other skills. Other constituents of the neurologic examination also are important and should be carefully documented by the examiner. Several approaches to evaluating infants have been well described [Capute et al., 1984; Ellison, 1984; Paine, 1964] (see Chapter 4). Although no one plan can suffice to establish the diagnosis of cerebral palsy, an algorithm for evaluation of the child with cerebral palsy has been published (Fig. 20-1) [Ashwal et al., 2004]. This algorithm provides an approach that should prove to be useful.

Further Diagnostic Evaluation The diagnosis of cerebral palsy often is indicated by delayed developmental milestones, the persistence of developmental reflexes, the presence of pathologic reflexes, and the failure to

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FIGURE 20-1. Algorithm for the evaluation of the child with cerebral palsy (CP). Screening for associated conditions (mental retardation, vision/hearing impairments, speech and language delays, oral motor dysfunction, and epilepsy) is recommended. Neuroimaging (magnetic resonance imaging [MRI] is preferred to computed tomography [CT]) is recommended for further evaluation if the etiology has not been previously determined. In some children, additional metabolic or genetic testing may be indicated. EEG, electroencephalogram. (From Ashwal S, Russman BS, Blasco PA, et al. Practice parameter: Diagnostic assessment of the child with cerebral palsy: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2004;62:851-863.)

develop maturational reflexes in a timely fashion, such as the traction response and the parachute response (see Chapter 4). Diagnostic tests designed to establish the etiology of cerebral palsy have been recently reviewed as part of a practice parameter [Ashwal et al., 2004]. An abnormality is documented on head magnetic resonance imaging (MRI) (in 89% of cases) or computed tomography (CT) (in 77%) in a large percentage of patients; therefore, all children with cerebral palsy should undergo a neuroimaging study, preferably MRI [Accardo et al., 2004]. Because of the reported low incidence of metabolic and genetic disorders among children with cerebral palsy, testing for these disorders is indicated only in children in whom the history or clinical examination includes atypical features or if a specific diagnosis is not established with neuroimaging. Children with a brain malformation also warrant consideration for further

testing to determine if an underlying genetic or metabolic disorder is present. The high incidence rates for mental retardation (52%), epilepsy (45%), ophthalmologic defects (28%), speech and language disorders (38%), and hearing impairment (12%) [Ashwal et al., 2004] make it imperative that all children with cerebral palsy be screened for mental retardation, ophthalmologic and hearing impairments, and speech and language disorders; nutrition, growth, and swallowing also should be closely monitored.

CLASSIFICATION The nosology applied to cerebral palsy is often varied and sometimes confusing. Agreement among clinical observers concerning a specific patient may be lacking [Blair and

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Stanley, 1985]. The classification of cerebral palsy patients remains somewhat unsettled and continues to require revision [Shapiro, 2004]. The use of conventional neurologic terms in descriptions of patients in recent years has made classification somewhat more understandable.

Functional Classification The Gross Motor Function Classification System (GMFCS) has become increasingly accepted for characterizing children with cerebral palsy. Selection of 85 items in this classification system was based on literature review and clinical judgment [Russell et al., 1989]. The scale was further refined, and the number of items was reduced to 66 (GMFM-66) [Russell et al., 2002]. The validated Gross Motor Function Classification System (GMFCS) provides an easy and straightforward way to classify severity of motor impairment into one of the five levels [Palisano et al., 1997]. The GMFCS scale has been found to predict GMFM scores [Palisano et al., 2000] and is simpler to use. Some evidence suggests that family reporting may be utilized to enhance the use of the GMFCS [Morris et al., 2004]. In recent years, the GMFCS has been applied to develop five distinct motor development curves for use in prognostication [Rosenbaum et al., 2002]. Many other scales and inventories are in use, however [Shapiro, 2004]. These include the modified Ashworth scale, passive Range of Motion measurements, Selective Motor Control scale, and the Pediatric Evaluation of Disability Inventory [Ostensjo et al., 2004]. Adequacy of performance of everyday activities is best predicted by the child’s ability to perform gross motor tasks [Ostensjo et al., 2004].

SPECIFIC CEREBRAL PALSY SYNDROMES Cerebral palsy can be classified by the predominant type of motor abnormality—spasticity, choreoathetotic, dystonic, hypotonic, ataxic, or mixed—as well as by the distribution of limb involvement—hemiplegia, quadriplegia, or diplegia. The most common clinical cerebral palsy syndromes are discussed next.

Spastic Hemiplegia Clinical Findings Although children may manifest obvious hemiplegia in the second year of life, specific difficulties may not be observed during the first 3 to 5 months of life. After a perinatal stroke, an infant may be neurologically normal until the development of pathologic handedness at approximately 4 to 6 months of age. For unexplained reasons, the left hemisphere (right side) is affected in two thirds of patients, and perinatal stroke is more common on the left than on the right [Crothers and Paine, 1959; Nelson and Lynch, 2004]. During the examination, the child exhibits impaired gross and fine motor coordination, has difficulty moving the hand quickly, and frequently is unable to grasp small items with a pincer grasp. The obligate palmar grasp reflex, which usually is absent by age 6 months and frequently rudimentary

after age 4 months, may be obligate. Weakness of the wrist and forearm often is associated with limitation of range of motion of supination. The range of elbow extension may be restricted. Attempts at reaching for objects may be accompanied by athetotic posturing with flexion of the wrist and hyperextension of the fingers (avoidance reaction). Facial involvement is unusual. Only 10% of affected patients, including those with extensive hemiplegia, have homonymous hemianopia [Black, 1988]. Children with hemiparesis have a circumductive gait with a variable degree of abnormality. Most commonly the child walks on the toes and swings the affected leg over a nearly semicircular arc during the course of each step. In contrast with the leg, the affected arm usually moves less than normal and does not participate in normal reciprocal motion during ambulation. An equinovarus positioning of the foot is seen; weakness and lack of full range of motion of dorsiflexion often are present. Further evidence of upper motor neuron involvement on the hemiplegic side includes hyperreflexia of the deep tendon reflexes, ankle clonus, and extensor toe signs. Such children usually have intact cremasteric and abdominal reflexes. Growth retardation of the abnormal side, usually more prominent in the distal arm and hand or distal leg and foot, may be manifest. An indication of the presence of growth impairment may be obtained when the thumb and thumbnail of the affected side are compared with their normal opposite members and found to be smaller. Growth discrepancy of the leg may result in significant difficulties during walking, leading to orthopedic problems involving the proximal leg and the lower spinal vertebrae. Although frequently overlooked, corticosensory impairment and hemineglect of the affected side are common. Examination for the integrity of stereognosis and graphesthesia usually reveals varying degrees of compromise [Brown et al., 1987; Skatvedt, 1960]. Perlstein and Hood [1955] reported that approximately 28% of patients with infantile hemiplegia have some degree of mental retardation. Seizures occur in approximately one third of patients who have spastic hemiplegia. Mental retardation is highly correlated with epilepsy in hemiplegic patients [Aicardi, 1990; Uvebrant, 1988]. Prognosis is difficult to establish in patients with hemiplegic cerebral palsy. Review of birth history and findings on EEG and CT scans in 52 children was performed by Cohen and Duffner [1981]. They concluded that the birth history was of little value in judging prognosis. EEG and neuroimaging findings provide a better correlation with the development of seizures and mental impairment. Furthermore, if anatomic abnormalities of the cerebral cortex, commissural pathways, or association pathways are present, these children are more likely to experience seizures and mental retardation.

Pathologic Findings Because various underlying conditions may lead to spastic hemiplegia, the neuropathologic findings also vary. Development of infarction with subsequent cystic formation in the distribution of the middle cerebral artery frequently is observed. The pathogenesis of the thromboembolic infarction is infrequently determined, although potential embolic sources include the placenta, the heart, and an intracranial or extra-

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cranial vessel [Guzetta et al., 1986; Nelson and Lynch, 2004; Uvebrant, 1988]. The vascular insult may be prenatal [Asindi et al., 1988] or perinatal [Baumann et al., 1987; Wiklund et al., 1991]. The degree of involvement varies. In an extreme form, the white and gray matter overlying the lateral ventricle may be so greatly thinned that the ventricle may extend into the area, with the development of a porencephalic cyst. Examination of the brain demonstrates generalized atrophy in the affected hemisphere. Although the affected areas may be small and few in number, large areas of gross cortical thinning, with loss of underlying white matter and extensive dilation of the adjoining lateral ventricle, may be seen. Microscopic examination confirms disruption of the neuronal laminar pattern, neuronal loss, and associated gliosis of variable extent. In preterm infants, asymmetric periventricular leukomalacia with resultant loss of white matter and ventricular dilation may be present [Uvebrant, 1988; Wiklund et al., 1991]. In one report on use of CT scanning in 111 children with hemiplegia, findings were normal in 29%. Periventricular atrophy was present in 42%, maldevelopment in 17%, and cortical-subcortical atrophy in 12%; miscellaneous abnormalities were noted in 3% [Wiklund et al., 1991].

pneumonia during the first years of life. Almost 50% of children with spastic quadriplegia experience generalized tonic-clonic seizures [Ingram, 1964]. In addition, a large but indeterminate number of these children are grossly developmentally delayed [Crothers and Paine, 1959]. Neurologic examination demonstrates marked spasticity and accompanying signs of corticospinal tract involvement, including hyperactive deep tendon reflexes, ankle clonus, and extensor toe signs. Weakness of dorsiflexion of the feet associated with equinovarus deformities is common. Marked spasticity of the hip muscles may lead to subluxation of the femur and associated acetabular pathologic conditions. Radiographs may be necessary to exclude the abnormal positioning of the head of the femur. Flexion contractures of the wrists and elbows of various degrees and spasticity of the arm muscles are readily apparent. Ophthalmologic evaluation of children with spastic quadriplegia more commonly reveals visual impairment in these children than in children with athetoid cerebral palsy [Preakey et al., 1974]. The incidence of auditory, visual, motor, and learning disability is much higher in children with spastic quadriplegia than in children with spastic hemiplegia, spastic diplegia, and ataxic cerebral palsy [Robinson, 1973].

Spastic Quadriplegia

Pathologic Findings

Clinical Findings

Neuropathologic changes in children with spastic quadriplegia include cystic degeneration as the final outcome of softening, necrosis, and edema of the central white matter, as well as cyst formation. Although cortical abnormalities are almost always present, involvement is not as extensive as that found in white matter. Multicystic encephalomalacia and brain malformations commonly are present [Benda, 1952; Chutorian et al., 1979]. Studies using diffusion-tensor imaging of central white matter pathways suggest disruption of connections to sensory cortex in these children [Hoon et al., 2002]. Mantle sclerosis may be found in patients with mild-tomoderate quadriplegia. Necrosis of the subcortical white matter is accompanied by degeneration of the overlying cortical laminar pattern. Underlying status spongiosus may be the end stage of a grouping of numerous small subcortical cysts. Gliosis is prominent in the area usually occupied by neurons, and the meninges are grossly thickened. The extent of the lesions varies, with involvement ranging from an entire hemisphere to an entire lobe to portions of one lobe. Mantle sclerosis may be bilateral but is almost always more profound in one hemisphere. Alterations in brainstem structure also are commonly present [Wilson et al., 1982].

Little [1861] first described cerebral palsy. He used the term spastic rigidity in place of the modern term spasticity. As part of his original treatise, he wrote: Spastic cerebral palsy has the characteristics of upper motor unit involvement, such as hyperreflexia and increased tone, often with ankle clonus, crossed adductor reflexes, and extensor toe signs. Both lower extremities are more or less generally involved. Sometimes the affection of one limb only is observed by the parent, but examination usually shows a smaller degree of affection in the limb supposed to be sound. The contraction in the hips, knees, and ankles is often considerable. The flexors and adductors of thighs, the flexors of knees, and the gastrocnemii, preponderate. In most cases, after a time, owing to structural shortening of the muscles and of the articular ligaments, and perhaps to some changes of form of articular surface, the thighs cannot be completely abducted or extended, the knees cannot be straightened, nor can the heels be properly applied to the ground. The upper extremities are sometimes held down by preponderating action of pectorals, teres major and teres minor, and latissimus dorsi; the elbows are semiflexed, the wrists partially flexed, pronated, and the fingers incapable of perfect voluntary direction. Sometimes the upper extremities appear unaffected with spasm or want of volition, sometimes a mere awkwardness in using them exists.

Spastic quadriplegia is characterized by a generalized increase in muscle tone. The legs are involved more than the arms, and paucity of limb movement is characteristic. Opisthotonic posturing may be evident in early infancy and may persist through the first year of life. Movement of the head often initiates forced extension of the arms and legs, resulting in a position similar to that in decerebrate rigidity. Accompanying supranuclear bulbar palsy, the result of bilateral corticobulbar tract impairment, may produce difficulties with swallowing and articulation. The incoordination of the oropharyngeal muscles may predispose the patient to recurrent

Spastic Diplegia Clinical Findings Spastic diplegia is characterized by bilateral leg involvement and commonly some degree of upper extremity impairment. Preterm infants are particularly prone to spastic diplegia. Approximately 80% of preterm infants who manifest motor abnormalities have spastic diplegia [McDonald, 1963]. In recent years, the survival of very small preterm infants has resulted in a larger group of more severely neurologically impaired survivors [Hagberg et al., 1989a, 1989b].

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Some infants with spastic diplegia manifest ataxia after further maturation. These infants have a great increase of tone of the leg muscles and accompanying difficulties in coordination and strength. Impairment may be asymmetric. When a small child is held in the vertical position by the examiner and the plantar surfaces of the feet are lightly bounced on the examining table, adduction of the legs (scissoring) and obligatory extension (extensor thrust) are seen. The feet also are kept in an equinovarus posture. Further examination reveals weakness of dorsiflexion of the feet. In older children, this same spasticity causes them to toe-walk. As expected, signs of upper motor unit involvement are easily demonstrable in the legs (e.g., hyperactive deep tendon reflexes, bilateral ankle clonus, extensor toe signs). Striking spasticity of the hip muscles may lead to subluxation of the femur and associated acetabular pathologic conditions and further restriction of motion. Radiographs may be necessary to exclude the abnormal positioning of the femoral head. The arms may be affected but usually only to a mild degree. The child may hold the arms in unusual fixed postures, either extended or flexed during walking, and may have clumsy, reciprocating, swinging arm movements or hold both arms flexed at the elbows. Affected children may extend their arms, pronate their hands, and clench their fists during running. Associated athetosis makes this latter posturing more likely. Vasomotor instability, often manifested by cold extremities and variable and sometimes unpredictable patterns of sweating, may prove troublesome for the patient. After a variable period, usually 18 months to 2 years in children with moderate involvement, spasticity is increasingly accompanied by contractures that maintain the hips in flexion, knees in flexion, and the feet in an equinovarus position. For reasons that are unclear—either disuse or probably hemispheric (parietal) lobe dysfunction—marked retardation of growth of leg length may be a feature.

subcortical gray matter regions can be uniformly associated with the individual movement abnormality or specific combination of these movements. Patients are unable to smoothly perform meaningful movements because of interfering movements and involvement of inappropriate agonist and antagonist muscles (see Chapter 58). Extrapyramidal cerebral palsy involves defects of posture and involuntary movement (e.g., athetosis, ballismus, chorea, dystonia); increased tone usually is associated with these conditions and is of the “lead pipe” or rigid variety. Extrapyramidal cerebral palsy can be divided arbitrarily into two primary clinical subtypes—choreoathetotic and dystonic. Each may be accompanied by other extrapyramidal movements. Other classifications and subdivisions have been proposed [Kyllerman, 1983]. No classification is fundamentally satisfactory.

CHOREOATHETOTIC CEREBRAL PALSY

Examination of the brain of infants with spastic diplegia may reveal porencephalic cysts and abnormalities of gyral size (microgyria). Periventricular leukomalacia in the path of fibers coursing through the internal capsule that subserve leg function explain the clinical symptoms in many of these infants [Benda, 1952; Christensen and Melchior, 1967]. Preterm infants are particularly susceptible to these germinal matrix periventricular lesions, although the pathologic and clinical patterns also may develop in term infants [Hagberg et al., 1975a, 1975b]. CT or preferably MRI confirms the presence of periventricular leukomalacia and various degrees of ventricular dilation. The presence of atrophy, abnormal gray matter configuration, and marked leukomalacia is correlated with severe impairment [Yokochi et al., 1990]. MRI studies appear to be more sensitive than CT studies and correlate well with clinical impairment [Yokochi et al., 1990].

Choreoathetotic cerebral palsy is characterized by largeamplitude, involuntary movements. The most obvious and dominating movement component is athetosis. Chorea is present in variable degree. Tremor, myoclonus, and even some element of dystonia also may be evident. Athetosis usually involves the distal limbs. Athetosis results in slow, writhing involuntary movements. Other common features are finger and toe extension and rotation of the limb and its long axis. The resultant pattern of these movements culminates in bizarre transient positions of the limbs. Chorea may involve the face, limbs, and rarely the trunk. The choreiform movements can be characterized as asymmetric, fleeting, incoordinated, involuntary contractions of individual muscle groups. The combination of athetoid and choreiform movements results in a pattern of distal extremity movement, ongoing hypertonia, and rotary writhing movements of the limbs. Athetotic posturing may be evident in the first year of life when the child begins to reach for objects. The movements, as generally is true of most involuntary movements, are not present during sleep. Movements are more prominent during stress or illness, and their intensity changes from day to day. As expected from the pathologic findings, evidence of upper motor neuron unit impairment (e.g., hyperactive deep tendon reflexes, ankle clonus, positive extensor toe signs), as well as seizures, spasticity, and mental retardation, may be present. Children with choreoathetosis may have marked difficulty with speech that is characterized by great variability in rate and explosive changes in volume. Ballismus, a movement disorder in which the arms and legs are violently flung about, may be an extreme form of choreoathetotic cerebral palsy. Most of the activity takes place at the shoulders and hips. Although patients with ballismus are said to have a shortened life expectancy and do not survive beyond the second decade, few data are available, and clinicopathologic correlation is undefined.

Extrapyramidal Cerebral Palsy

DYSTONIC CEREBRAL PALSY

The extrapyramidal cerebral palsy classification is rather broad based, but for all practical purposes, little in the way of pathogenetic lesions or specific involvement of cortical or

The dystonic form of cerebral palsy is uncommon. The extrapyramidal form of cerebral palsy is often, but not always, preceded by hypoxic-ischemic brain injury or kernicterus.

Pathologic Findings

Swaiman and Wu / Cerebral Palsy

Requirement for respiratory support and hypoxic-ischemic encephalopathy at birth usually is documented in the patient history. The dystonic movements are not unlike those in other conditions associated with dystonia. The trunk muscles and proximal portions of the limbs are predominantly affected. Movements may be slow and persistent, particularly of the head and neck, which may be pulled to one side or the other, or retrocollis may be present. At times the movements may consist of rapid and repetitive retractions of the head. The trunk may be literally twisted into many fixed positions that may appear bizarre. Corticospinal tract findings may be evident in children who have choreoathetosis. On pathologic examination, the brains of these children may reveal large areas of patchy necrosis of the cortical laminar pattern, venous congestion in the cortex, ventricular dilation, and accompanying white matter loss that may be related to demyelination and central necrosis. Fibrosis in the meninges also may be present. Both cortex and basal ganglia may be jointly involved in these patients. Cortical lesions associated with necrosis in areas adjacent to the ventricles may be the result of occlusion of the vein of Galen. Obstruction of this major vessel triggers a chain of events, including rupture of blood vessels, primarily veins, with ensuing multiple hemorrhages in the areas served by the branches of the internal cerebral veins. The hemorrhages result in subependymal necrosis and subsequent pathologic dilation of the lateral ventricles and associated atrophy of the basal ganglia. If obstruction is extremely widespread, the internal capsule may be involved, and further symptoms and signs of corticospinal tract involvement arise. In one report, patients with severe athetoid cerebral palsy originating perinatally were divided into two groups neuropathologically: the “globo-Luysian group” and the “thalamoputaminal group.” The major abnormal sites in the globo-Luysian group were the pallidum and subthalamic nucleus, and in the thalamoputaminal group, the thalamus and putamen. The causative pathologic condition in the globo-Luysian group was primarily perinatal severe jaundice, and the cause in the thalamoputaminal group was predominantly neonatal asphyxia. The patients in the thalamoputaminal group demonstrated lower mental ability and suffered from more intractable convulsions than those in the globo-Luysian group. In the globo-Luysian group, rigidity and spasticity were frequently demonstrated, with fluctuation of athetoid movements, whereas in the thalamoputaminal group, various abnormalities of muscle tone and rather restricted athetosis were observed [Hayashi et al., 1991]. MRI studies in 22 children with athetotic cerebral palsy frequently revealed high-intensity areas in the thalamus and putamen in T2-weighted images. Of 16 children with known perinatal asphyxia, 14 had lesions in the basal ganglia, thalamus, and/or cerebral white matter. MRI findings were normal in 7 of the 22 children [Yokochi et al., 1991].

Hypotonic (Atonic) Cerebral Palsy Infants with hypotonic cerebral palsy almost always have associated leg weakness. Although hypotonic, the arms may manifest near-normal strength and coordination. In the past, this combination of clinical findings led to the use of the term atonic diplegia to describe such children.

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Diagnosis is difficult because of the plethora of possibilities. Most children with generalized hypotonia have so-called central hypotonia (see Chapter 5), resulting from inadequate control of the motor pathways and subsequent disruption of gamma loop function. Others, with absent or hypoactive deep tendon reflexes, may have involvement of the lower motor neuron unit (i.e., anterior horn cell, peripheral nerve, neuromuscular junction, muscle). Extrapyramidal (choreoathetotic and dystonic) cerebral palsy may be preceded by a hypotonic phase. Atonic cerebral palsy is relatively uncommon compared with other forms of cerebral palsy; it often is associated with slow attainment of motor milestones and the presence of normal or hyperactive deep tendon reflexes. Children with atonic cerebral palsy, when suspended while held under the arms, flex both legs at the hips (Förster’s sign). Although in the past it has been thought that muscle tone almost always increases with maturation in this form of cerebral palsy [Ingram, 1964], experience has taught that in a sizable number of cases, spasticity does not develop, but the child remains hypotonic. The causes leading to this condition and the associated anatomic location of brain involvement are unknown. It is through their effect on the gamma motor neuron that portions of the central nervous system (e.g., motor cortex, thalamus, basal ganglia, vestibular nuclei, reticular formation, cerebellum) modify tone, with ensuing hypotonia.

Ataxic Cerebral Palsy The last common form of cerebral palsy is the ataxic form. It sometimes coexists with spastic diplegia [Hagberg et al., 1975b]. This form usually is associated with other motor abnormalities; however, the diagnosis is applied only when the predominant manifestation is cerebellar dysfunction. Patients with ataxic cerebral palsy may have impairment of intellectual ability, but they are rarely grossly delayed [Clement et al., 1984]. Motor difficulties often are not apparent until late in the first year of life. Early manifestations include hypotonia, truncal ataxia with sitting, dysmetria, and gross incoordination. The motor involvement results in delayed attainment of motor skills; independent walking may not occur until age 3 or 4 years and then may be performed only with great difficulty and frequent falling. Compromise of writing skills and other skills that demand good fine motor coordination often adversely affects educational endeavors. Examination often reveals nystagmus, dysmetria, hypotonia, and a wide-based gait. The result on Romberg testing with the eyes open is positive. Likely sites of involvement are the cerebellum and adjacent brainstem. Because of the large number of conditions associated with ataxia, the clinician must exclude conditions in which ataxia predominates in early childhood (see Chapter 57). Ataxia, especially if accompanied by mental retardation, may not be properly included among cerebral palsy conditions but may be the result of one of many inherited conditions [Hagberg et al., 1984]. The pathologic features of ataxic cerebral palsy are poorly defined and inconstant. Discussion of these features is confounded by the fact that total absence of the vermis may not give rise to cerebellar symptoms in certain congenital

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conditions, whereas aplasia of the vermis may be associated with nonprogressive ataxia [Bordarier and Aicardi, 1990]. Cerebellar hemispheric lesions may or may not be present in patients with ataxic cerebral palsy. The lack of correlation of evident structural changes with functional impairment is emphasized by CT studies. In one report, CT evaluation of patients with ataxic cerebral palsy revealed that the posterior fossa was normal in 38% and abnormal in 28%. By contrast, the cerebral hemispheres were abnormal in 55% of the patients [Miller and Cala, 1989].

Mixed Cerebral Palsy Mixed cerebral palsy includes manifestations of both spastic and extrapyramidal types; often an ataxic component is present. Patients with predominantly spastic quadriplegia may have a mild-to-marked degree of choreoathetosis. Conversely, frequently patients in whom choreoathetosis predominates also may manifest upper motor neuron unit involvement. These patterns of motor impairment are the result of compromise of large areas of the brain with sequelae of basal ganglia, cortex, and subcortical disruption. Characteristics of these patients are discussed in the sections describing individual types. Most patients can be categorized into the types discussed on the basis of predominant manifestations.

GENERAL PROGNOSIS FOR MOTOR FUNCTION A number of factors affect the prognosis of the child with cerebral palsy: the clinical type of cerebral palsy; the degree of delay in meeting milestones noted at evaluation; the pathologic reflexes present, and the degree of associated deficits in intelligence, sensation, and emotional adjustment [Sala and Grant, 1995]. Cognitive level is difficult to assess in the young child with motor impairments but can be gauged even in the severely affected child [McCarty et al., 1986]. It is necessary to consider the cognitive level despite the challenges posed in assessment, because the level of mental function may be the factor that really determines the quality of life the child will enjoy. Children with hemiplegia but with no other major problems almost always walk by the age of approximately 2 years; some benefit from use of a short leg brace, often needed only for temporary assistance. The presence of a small hand on the hemiplegic side, with a thumbnail that is narrower than that of the other thumb, may be associated with sensory dysfunction of parietal origin, and the sensory defect may limit the development of fine motor skills in that hand. About 25% of children with hemiplegias have hemianopsia; recognition of this deficit allows the clinician to advise placing the affected child in an area of the classroom that maximizes useful vision. Because most daily activities can be accomplished with only one hand, using the affected hand only as a “helper,” with small adaptations, such as shoes that do not require lacing and tying, hemiplegic children of reasonable intelligence can be expected to achieve independence in daily living. Seizures may be a problem in children with hemiplegia. More than 50% of children with spastic diplegia learn to walk, commonly by the age of approximately 3 years, but gait often is abnormal, and some children require assistance

devices such as crutches. Hand activities commonly are involved to some degree, although the impairment may be subtle. Abnormalities of extraocular movement are relatively common. Of children with spastic quadriplegia, 25% require total care; approximately 33% walk, usually after the age of 3 years. Intellectual function often is the most life-limiting concomitant problem, and involvement of the bulbar musculature may add further difficulties. Marked truncal hypotonia with pathologic reflexes or persisting rigidity is associated with an unfavorable outlook. A majority of such children have grave intellectual limitations. The prognosis for walking has been evaluated recently in large populations of children with cerebral palsy. The validated GMFCS can help predict whether the child will eventually achieve the ability to walk 10 steps unsupported. [Rosenbaum et al., 2002]. Furthermore, a child’s motor function at age 2 years can be used to evaluate the prognosis for future ambulation at three levels of competency, with the help of ambulation charts reflecting the combined experience of greater than 5000 children with cerebral palsy (Fig. 20-2) [Wu et al., 2004].

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FIGURE 20-2. Ambulation charts showing the probabilities of four levels of ambulation over time. The graphs combine the data for 5366 children with cerebral palsy who were nonambulatory at age 2 years, 3152 of whom were monitored past age 6 years. Separate charts are provided for those with different levels of motor function at age 2 years. Rolling refers to the ability to roll over from front to back or from back to front. Sitting refers to the ability to maintain a sitting position without support or the ability to achieve a sitting position without assistance. (From Wu YW, Day SM, Strauss DJ, Shavelle RM. Prognosis for ambulation in cerebral palsy: A population-based study. Pediatrics 2004;114:1264-1271.

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Crothers B, Paine RS. The natural history of cerebral palsy. Cambridge: Harvard University Press, 1959. Dammann O, Kuban KC, Leviton A. Perinatal infection, fetal inflammatory response, white matter damage, and cognitive limitations in children born preterm. Ment Retard Dev Disabil Res Rev 2002;8:46. Dammann O, Leviton A. Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn. Pediatr Res 1997;42:1. de Vries LS, Connell JA, Dubowitz LMS, et al. Neurological, electrophysiological and MRI abnormalities in infants with extensive cystic leukomalacia. Neuropediatrics 1987;18:61. deVeber G, Andrew M. Cerebral sinovenous thrombosis in children. Canadian Pediatric Ischemic Stroke Study Group. N Engl J Med 2001;345:417. Ellenberg JH, Nelson KB. Cluster of perinatal events identifying infants at high risk for death or disability. J Pediatr 1988;113:546. Ellison PH. Neurologic development of the high-risk infant. Clin Perinatol 1984;11:41. Ericson A, Nygren KG, Olausson PO, et al. Hospital care utilization of infants born after IVF. Hum Reprod 2002;17:929. Evans PM, Evans SJW, Alberman E. Cerebral palsy: Why we must plan for survival. Arch Dis Child 1990;65:1329. Eyman RK, Grossman HJ, Chaney RH, et al. The life expectancy of profoundly handicapped people with mental retardation. N Engl J Med 1990;323:584. Golomb MR, MacGregor DL, Domi T, et al. Presumed pre- or perinatal arterial ischemic stroke: Risk factors and outcomes. Ann Neurol 2001;50:163. Grether JK, Cummins SK, Nelson KB. The California Cerebral Palsy Project. Paediatr Perinat Epidemiol 1992;6:339. Grether JK, Nelson KB, Cummins SK. Twinning and cerebral palsy: Experience in four northern California counties, births 1983 through 1985. Pediatrics 1993;92:854. Grether JK, Nelson KB. Maternal infection and cerebral palsy in infants of normal birth weight [published erratum appears in JAMA 1998;279:118]. JAMA 1997;278:207. Gross-Tsur V, Shalev RS, Badihi N, et al. Efficacy of methylphenidate in patients with cerebral palsy and attention-deficit hyperactivity disorder (ADHD). J Child Neurol 2002;17:863. Gunther G, Junker R, Strater R, et al. Symptomatic ischemic stroke in full-term neonates: Role of acquired and genetic prothrombotic risk factors. Stroke 2000;31:2437. Guzzetta F, Shackelford GD, Volpe S, et al. Periventricular intraparenchymal echodensities in the premature newborn: Critical determinant of neurologic outcome. Pediatrics 1986;78:995. Hagberg B, Hagberg G, Beckung E, et al. Changing panorama of cerebral palsy in Sweden. VIII. Prevalence and origin in the birth year period 1991-94. Acta Paediatr 2001;90:271. Hagberg B, Hagberg G, Olow I. The changing panorama of cerebral palsy in Sweden 1954-1970. I. Analysis of the general changes. Acta Paediatr Scand 1975a;64:187. Hagberg B, Hagberg G, Olow I. The changing panorama of cerebral palsy in Sweden 1954-1970. II. Analysis of the various syndromes. Acta Paediatr Scand 1975b;64:193. Hagberg B, Hagberg G, Olow I. The changing panorama of cerebral palsy in Sweden: IV. Epidemiological trends 1959-78. Acta Paediatr Scand 1984;73:433. Hagberg B, Hagberg G, Olow I, et al. The changing panorama of cerebral palsy in Sweden: V. The birth year period 1979-52. Acta Paediatr Scand 1989a;78:283. Hagberg B, Hagberg G, Zetterstrom R. Decreasing perinatal mortality— increase in cerebral palsy morbidity? Acta Paediatr Scand 1989b;78:664. Hagstrom JN, Walter J, Bluebond-Langner R, et al. Prevalence of the factor V Leiden mutation in children and neonates with thromboembolic disease. J Pediatr 1998;133:777. Hauser SE, Peters H. Glutaric aciduria type 1: An underdiagnosed cause of encephalopathy and dystonia-dyskinesia syndrome in children. J Paediatr Child Health 1998;34:302. Hayashi M, Satoh J, Sakamoto K, et al. Clinical and neuropathological findings in severe athetoid cerebral palsy: A comparative study of globo-Luysian and thalamo-putaminal groups. Brain Dev 1991;13:47. Hoon AH Jr, Lawrie WT Jr, Melhem ER, et al. Diffusion tensor imaging of periventricular leukomalacia shows affected sensory cortex white matter pathways. Neurology 2002;59:752.

Humphreys P, Whiting S, Pham B. Hemiparetic cerebral palsy: Clinical pattern and imaging in prediction of outcome. Can J Neurol Sci 2000;27:210. Hutton JL, Cooke T, Pharoah POD. Life expectancy in children with cerebral palsy. BMJ 1994;309:431. Ingram TTS. Paediatric aspects of cerebral palsy. Edinburgh: ChurchillLivingstone, 1964. Jarvis S, Glinianaia SV, Torrioli MG, et al. Cerebral palsy and intrauterine growth in single births: European collaborative study. Lancet 2003;362:1106. Johnson L, Brown AK, Bhutania VK. BIND—a clinical score for bilirubin induced neurologic dysfunction in newborns. Pediatrics 1999;104:746. Johnston MV. Clinical disorders of brain plasticity. Brain Dev 2004;26:73. Koman LA, Smith BP, Shilt JS. Cerebral palsy. Lancet 2004;364:28. Kyllerman M. Reduced optimality in pre- and perinatal conditions in dyskinetic cerebral palsy. Distribution and comparison to controls. Neuropediatrics 1983;14:29. Leviton A, Gilles FH. Acquired perinatal leukoencephalopathy. Ann Neurol 1984;16:1. Leviton A, Nelson KB. Problems with definitions and classifications of newborn encephalopathy. Pediatr Neurol 1992;8:85. Leviton A, Paneth N, Reuss ML, et al. Maternal infection, fetal inflammatory response, and brain damage in very low birth weight infants. Developmental Epidemiology Network Investigators. Pediatr Res 1999;46:566. Lieberman E, Lang J, Richardson DK, et al. Intrapartum maternal fever and neonatal outcome. Pediatrics 2000;105:8. Little WJ. On the influence of abnormal parturition, difficult labours, premature birth, and asphyxia neonatorum on the mental and physical condition of the child, especially in relation to deformities. Trans Obstet Soc London 1861;3:293. Lynch JK, Nelson KB. Epidemiology of perinatal stroke. Curr Opin Pediatr 2001;13:499. MacLennan A. A template for defining a causal relation between acute intrapartum events and cerebral palsy: International consensus statement. BMJ 1999;319:1054. McCarty SM, St. James P, Berninger VW, et al. Assessment of intellectual functioning span in severe cerebral palsy. Dev Med Child Neurol 1986;28:364. McDonald AD. Cerebral palsy in children of very low birth weight. Arch Dis Child 1963;38:579. Mercuri E, Rutherford M, Cowan F, et al. Early prognostic indicators of outcome in infants with neonatal cerebral infarction: A clinical, electroencephalogram, and magnetic resonance imaging study. Pediatrics 1999;103:39. Miller G, Cala LA. Ataxic cerebral palsy—clinico-radiologic correlations. Neuropediatrics 1989;20:84. Minear WL. A classification of cerebral palsy. Pediarics 1956;18:841–852. Moster D, Lie RT, Irgens LM, et al. The association of Apgar score with subsequent death and cerebral palsy: A population-based study in term infants. J Pediatr 2001;138:798. Murphy CC, Yeargin-Allsopp M, Decoufle P, et al. Prevalence of cerebral palsy among ten-year-old children in metropolitan Atlanta, 1985 through 1987. J Pediatr 1993;123:S13. Nelson KB, Dambrosia JM, Grether JK, et al. Neonatal cytokines and coagulation factors in children with cerebral palsy. Ann Neurol 1998;44:665. Nelson KB, Ellenberg JH. Children who “outgrew” cerebral palsy. Pediatrics 1982;69:529. Nelson KB, Grether JK. Potentially asphyxiating conditions and spastic cerebral palsy in infants of normal birth weight. Am J Obstet Gynecol 1998;179:507. Nelson KB, Lynch JK. Stroke in newborn infants. Lancet Neurol 2004;3:150–158. Nelson KB, Swaiman KF, Russman BS. Cerebral palsy. In: Swaiman KF, ed. Pediatric neurology: Principles and practice. St Louis: Mosby, 1994. Oeffinger DJ, Tylkowski CM, Rayens MK, et al. Gross Motor Function Classification System and outcome tools for assessing ambulatory cerebral palsy: A multicenter study. Dev Med Child Neurol 2004;46:311. O’Shea TM, Preisser JS, Klinepeter KL, et al. Trends in mortality and cerebral palsy in a geographically based cohort of very low birth weight neonates born between 1982 to 1994. Pediatrics 1998;101:642.

Swaiman and Wu / Cerebral Palsy Ostensjo S, Carlberg EB, Vollestad NK. Motor impairments in young children with cerebral palsy: Relationship to gross motor function and everyday activities. Dev Med Child Neurol 2004;46:580. Ostrow JD. Pascolo L, Brites D, Tribelli C. Molecular basis of bilirubininduced neurotoxicity. Trends Mol Med 2004;10:65–70. Paine RS. The evolution of infantile postural reflexes in the presence of chronic brain syndromes. Dev Med Child Neurol 1964;6:345. Palisano RJ, Hanna SE, Rosenbaum PL, et al. Validation of a model of gross motor function for children with cerebral palsy. Phys Ther 2000;80:974–985. Palisano R, Rosenbaum P, Walter S, et al. Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol 1997;39:214–223. Perlstein M, Hood P. Infantile spastic hemiplegia. Am J Med 1955;34:391. Petterson B, Nelson KB, Watson L, et al. Twins, triplets, and cerebral palsy in births in Western Australia in the 1980s. BMJ 1993;307:1239. Pharoah PO. Twins and cerebral palsy. Acta Paediatr Suppl 2001;90:6. Pharoah PO, Cooke T, Cooke RW, et al. Birthweight specific trends in cerebral palsy. Arch Dis Child 1990;65:602. Plioplys AV. Survival rates of children with severe neurologic disabilities: A review. Semin Pediatr Neurol 2003;10:120. Plioplys AV, Kasnicka I, Lewis S, et al. Survival rates among children with severe neurologic disabilities. South Med J 1998;91:161. Prasad AN, Breen JC, Ampola MG, et al. Argininemia: A treatable genetic cause of progressive spastic diplegia simulating cerebral palsy: Case reports and literature review. J Child Neurol 1997;12:301. Preakey A, Wilson J, Wilson B. Sensory and perceptual function in the cerebral palsied; perceptual relationships. J Nerv Ment Dis 1974;158:70. Redline RW, O’Riordan MA. Placental lesions associated with cerebral palsy and neurologic impairment following term birth. Arch Pathol Lab Med 2000;124:1785. Robinson R. The frequency of other handicaps in children with cerebral palsy. Dev Med Child Neurol 1973;15:305. Rosenbaum PL, Walter SD, Hanna SE, et al. Prognosis for gross motor function in cerebral palsy: Creation of motor development curves. JAMA 2002;288:1357. Russell DJ, Avery LM, Rosenbaum PL, et al. Improved scaling of the gross motor function measure for children with cerebral palsy: Evidence of reliability and validity. Phys Ther 2000;80:873. Russell DJ, Rosenbaum PL, Avery LM, et al. Gross Motor Function Measure (GMFM-66 and GMFM-88) user’s manual. London: Mac Keith Press, 2002. Russell DJ, Rosenbaum PL, Cadman DT, et al. The Gross Motor Function Measure: A means to evaluate the effects of physical therapy. Dev Med Child Neurol 1989;31:341. Sala DA, Grant AD. Prognosis for ambulation in cerebral palsy. Dev Med Child Neurol 1995;37:1020. Scheidt PC, Bryla DA, Nelson KB, et al. NICHD phototherapy clinical trial: Six year follow-up. Pediatrics 1990;85:455. Sever JL. TORCH tests and what they mean. Am J Obstet Gynecol 1985;152:495. Shapiro BK. Cerebral palsy: A reconceptualization of the spectrum. J Pediatr 2004;145 (2 Suppl):S3. Shapiro SM. Bilirubin toxicity in the developing nervous system. Pediatr Neurol 2003;29:410. Skatvedt M. Sensory, perceptual and other non-motor defects in cerebral palsy. Little Club Clin Dev Med 1960;1:115. Soorani-Lunsing I, Woltil HA, Hadders-Algra M. Are moderate degrees of hyperbilirubinemia in healthy term neonates really safe for the brain? Pediatr Res 2001;50:701. Steer PJ. Premature labour. Arch Dis Child 1991;66:1167. Strauss DJ, Shavelle RM, Anderson TW. Life expectancy of children with cerebral palsy. Pediatr Neurol 1998;18:143. Stromberg B, Dahlquist G, Ericson A, et al. Neurological sequelae in children born after in-vitro fertilisation: A population-based study. Lancet 2002;359:461. Szymonowicz W, Preston H, Yu VY. The surviving monozygotic twin. Arch Dis Child 1986;61:454. Takanashi J, Barkovich AJ, Ferriero DM, et al. Widening spectrum of congenital hemiplegia: Periventricular venous infarction in term neonates. Neurology 2003;61:531. Thorngren-Jerneck K, Herbst A. Low 5-minute Apgar score: A population-based register study of 1 million term births. Obstet Gynecol 2001;98:65.

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Topp M, Langhoff-Roos J, Uldall P, et al. Intrauterine growth and gestational age in preterm infants with cerebral palsy. Early Hum Dev 1996;44:27. Topp M, Uldall P, Greisen G. Cerebral palsy births in eastern Denmark, 1987-90: Implications for neonatal care. Paediatr Perinat Epidemiol 2001;15:271. Uvebrant P. Hemiplegic cerebral palsy. Aetiology and outcome. Acta Paediatr Scand Suppl 1988;345 (Suppl):1. Uvebrant P, Hagberg G. Intrauterine growth in children with cerebral palsy. Acta Paediatr 1992;81:407. Van Praagh R. Diagnosis of kernicterus in the neonatal period. Pediatrics 1961;28:870. Volpe JJ. Neurology of the newborn, 4th ed. Philadelphia: WB Saunders, 2001. Volpe JJ, Herscovitch P, Perlman JM, et al. Positron emission tomography in the asphyxiated term newborn: Parasagittal impairment of cerebral blood flow. Ann Neurol 1985;17:287. Wiklund LM, Uvebrant P, Flodmark O. Computed tomography as an adjunct in etiological analysis of hemiplegic cerebral palsy. I: Children born preterm. Neuropediatrics 1991;22:50. Wilson ER, Mirra S, Schwartz JF. Congenital diencephalic and brain stem damage: Neuropathologic study of three cases. Acta Neuropathol 1982;57:70. Winter S, Autry A, Boyle C, et al. Trends in the prevalence of cerebral palsy in a population-based study. Pediatrics 2002;110:1220. Wu YW, Colford JM. Chorioamnionitis as a risk factor for cerebral palsy: A meta-analysis. JAMA 2000;284:1417. Wu YW, Day SM, Strauss DJ, et al. Prognosis for ambulation in cerebral palsy: A population-based study. Pediatrics 2004;114:1264. Wu YW, Escobar GJ, Grether JK, et al. Chorioamnionitis and cerebral palsy in term and near-term infants. JAMA 2003;290:2677. Wu YW, March WM, Croen LA, et al. Perinatal stroke in children with motor impairment: A population-based study. Pediatrics 2004;114:612. Wu YW, Miller SP, Chin K, et al. Multiple risk factors in neonatal sinovenous thrombosis. Neurology 2002;59:438. Yokochi K, Aiba K, Kodama M, et al. Magnetic resonance imaging in athetotic cerebral palsied children. Acta Paediatr Scand 1991;80:818. Yokochi K, Hosoe A, Shimabukuro S, et al. Gross motor patterns in children with cerebral palsy and spastic diplegia. Pediatr Neurol 1990;6:245.

SUGGESTED READINGS Bleck EE. Orthopaedic management in cerebral palsy. Clinics in Developmental Medicine No. 99. Philadelphia: Lippincott-Raven, 1987. Bobath K. Neurophysiological basis for the treatment of cerebral palsy. Clinics in Developmental Medicine No. 75. Philadelphia: LippincottRaven, 1991. Broggi G, Angelini L, Bono R, et al. Long-term results of stereotactic thalmotomy for cerebral palsy. Neurosurgery 1983;12:195. Burke JP, O’Keefe M, Bowell R. Optic nerve hypoplasia, encephalopathy, and neurodevelopmental handicap. Br J Ophthalmol 1991;75:236. Colditz PB, Henderson-Smart DJ. Electronic fetal heart rate monitoring during labour: Does it prevent perinatal asphyxia and cerebral palsy? Med J Aust 1990;153:88. Cooper IS, Riklan M, Amin I, et al. Chronic cerebellar stimulation in cerebral palsy. Neurology 1976;26:744. Crofts BJ, King R, Johnson A. The contribution of low birth weight to severe vision loss in a geographically defined population. Br J Ophthalmol 1998;82:9. Davidoff RA. Antispasticity drugs: Mechanism of action. Ann Neurol 1985;17:107. Dennis J, Johnson MA, Mutch LMM, et al. Acid-base status at birth in term infants and outcome at 4.5 years. Am J Obstet Gynecol 1989;161:213. Dinnage R. The child with cerebral palsy. National Children’s Bureau Bibliographies 2. Albany, NY: Delmar, 1986. Faust D, Ziskin J. The expert witness in psychology. Science 1988;239:31. Fenichel GM, Lane DA, Livengood JR, et al. Adverse events following immunization: Assessing probability of causation. Pediatr Neurol 1989;5:287. Gahm NH, Russman BS, Cerciello RL, et al. Chronic cerebellar stimulation for cerebral palsy: A double-blind study. Neurology 1981;31:87.

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Galjaard H, Prechtl HFR, Velickovic M. Early detection and management of cerebral palsy. Topics in the Neurosciences. Norwell, Mass: Kluwer Academic Press, 1988. Geralis E. Children with cerebral palsy: A parents’ guide. New York: Cambridge University Press, 1992. Gorter JW, Rosenbaum PL, Hanna SE, et al. Limb distribution, motor impairment, and functional classification of cerebral palsy. Dev Med Child Neurol 2004;46:461. Gross H, Jellinger K, Kaltenback E, et al. Infantile cerebral disorders: Clinical neuropathological correlations to elucidate the aetiological factors. J Neurol Sci 1968;7:551. Hoyme HE, Higginbottom MC, Jones KL. Vascular etiology of disruptive structure defects in monozygotic twins. Pediatrics 1981;67:288. Ingram T. A study of cerebral palsy in the childhood population of Edinburgh. Arch Dis Child 1955;117:395. Koeda T, Suganuma I, Kohno Y, et al. MR imaging of spastic diplegia: Comparative study between preterm and term infants. Neuroradiology 1990;32:187. Krageloh-Mann I, Hagberg B, Petersen D, et al. Bilateral spastic cerebral palsy—pathogenetic aspects from MRI. Neuropediatrics 1992;23:46. Landau WM, Hunt CC. Dorsal rhizotomy, a treatment of unproven efficacy. J Child Neurol 1990;5:174. Leviton A, Paneth N. White matter damage in preterm newborns—an epidemiologic perspective. Early Hum Dev 1990;24:1. Malamud N, Itabashi HH, Castor J, et al. An etiologic and diagnostic study of cerebral palsy. J Pediatr 1964;65:270. Melone PJ, Ernest JM, O’Shea MD, et al. Appropriateness of intrapartum fetal heart rate management and risk of cerebral palsy. Am J Obstet Gynecol 1991;165:272. Meyer BA, Dickinson JE, Chambers C, et al. The effect of fetal sepsis on umbilical cord blood gases. Am J Obstet Gynecol 1992;166:612. Miller F, Bachrach SJ. Cerebral palsy: A complete guide for caregiving. In: Johns Hopkins Press Health Book. Baltimore: Johns Hopkins University Press, 1998. Miller G, Clark CD. The cerebral palsies: Causes, consequences, and management. Boston: Butterworth-Heinemann, 1998. Morris C, Bartlett D. Gross Motor Function Classification System: Impact and utility. Dev Med Child Neurol 2004;46:60. Morris C, Galuppi BE, Rosenbaum PL. Reliability of family report for the Gross Motor Function Classification System. Dev Med Child Neurol 2004;46:455. Narayan RK, Loubser PG, Jankovic J, et al. Intrathecal Baclofen for intractable axial dystonia. Neurology 1991;41:1141. Nelson KB, Ellenberg JH. Apgar scores as predictors of chronic neurologic disability. Pediatrics 1981;68:36.

Nelson KB, Ellenberg JH. Cerebral palsy. 1. Univariate analysis of risks. Am J Dis Child 1985a;139:1031. Nelson KB, Ellenberg JH. Predictors of low and very low birth weight and the relation of these to cerebral palsy. JAMA 1985b;254:1473. Nelson KB, Leviton A. How much of neonatal encephalopathy is due to birth asphyxia? Am J Dis Child 1991;145:1325. Nelson KB. Prenatal origin of hemiparetic cerebral palsy: How often and why? Pediatrics 1991;88:1059. Paludetto R. Neonatal complications specific to twin (multiple) births (twins transfusion syndrome, intrauterine death of cotwin). J Perinat Med 1991;19 (Suppl 1):246. Peacock W, Staudt LA. Spasticity in cerebral palsy and the selective posterior rhizotomy procedure. J Child Neurol 1990;5:179. Perlman JM, Tack ED. Renal injury in the asphyxiated newborn infant: Relationship to neurologic outcome. J Pediatr 1988;113:875. Phelan JP, Ock Ahn M, Korst L, et al. Intrapartum fetal asphyxial brain injury with absent multiorgan system dysfunction. J Matern Fetal Med 1998;7:19. Scrutton D. Management of the motor disorders of children with cerebral palsy. Clinics in Developmental Medicine No. 90. New York: Cambridge University Press, 1991. Seidman DS, Paz I, Laor A, et al. Apgar scores and cognitive performance at 17 years of age. Obstet Gynecol 1991;77:875. Stanley F. Epidemiology of the cerebral palsies. Clinics in Developmental Medicine No. 87. Philadelphia: Lippincott-Raven, 1991. Sussman MD. The use of casts as an adjunct to physical therapy management of cerebral palsy patients. Proceedings: Orthopedic Aspects of Developmental Disabilities. University of North Carolina School of Medicine, Chapel Hill, 1978:47. Vogt C, Vogt O. Zur psychiatrischen Wurdingung der anatonschen Entdekung und Wertung des Status marmoratus striat. J Psychol Neurol 1928;37:387. Volpe JJ. Value of MR in definition of the neuropathology of cerebral palsy in vivo. Am J Neuroradiol 1992;13:79. Volpe JJ. Neurology of the newborn, 3rd ed. Philadelphia: WB Saunders, 1995. Watt J, Sims D, Harchom F. A controlled study of inhibition casting as an adjunct to physiotherapy for cerebral-palsied children. Dev Med Child Neurol 1986;28:480. Wiley ME, Damiano DL. Lower-extremity strength profiles in spastic cerebral palsy. Dev Med Child Neurol 1998;40:100. Young RR. Physiologic and pharmacologic approaches to spasticity. Neurol Clin 1987;5:529.

CHAPTER 21

Introduction to Genetics William B. Dobyns and Soma Das

In the broadest sense, genes are simply units of hereditary information; the genome is the totality of all the hereditary information in a cell or organism; and genetics may be defined as the study of genes and genomes. With the advent of modern molecular biology and the Human Genome Project, all aspects of genetics have come to play a more prominent role in the day-to-day evaluation and management of children with neurologic diseases, most of which have a genetic basis. This chapter presents a brief synopsis of the most important principles of genetics, to serve as background for information presented elsewhere in this text. More detailed information on genetics is available in many excellent textbooks, such as Genetics in Medicine [Nussbaum et al., 2001], Genes VIII [Lewin, 2003], and Human Molecular Genetics [Strachan and Read, 1999]. The last is availble online, along with several other relevant publications, at the National Center for Biotechnology Information web site (Table 21-1).

MOLECULAR BASIS OF HEREDITY Modern theories of molecular biology hold that all information needed for function of cells and organisms is contained in macromolecules composed of simple repeating units. The flow of genetic information is (almost) exclusively unidirectional: DNA → RNA → protein. That is, the sequence of deoxyribonucleic acid (DNA) specifies the syn-

thesis and sequence of ribonucleic acid (RNA) by a process known as transcription. Messenger RNA in turn specifies the synthesis and sequence of polypeptides, which are the building blocks of proteins, by a process known as translation. Other forms of RNA function independently. This theory is the central dogma of molecular biology. Accordingly, this chapter begins with a review of the structure and function of these three macromolecules. Several of the processes involved in gene (and protein) expression, including gene structure and organization, RNA processing, and epigenetics, are then reviewed. Epigenetics refers to modification of genes other than changes in the DNA sequence, especially addition of methyl groups to the DNA, which alter gene expression. The two most important epigenetic changes found to be relevant to clinical disorders to date are imprinting and X-inactivation.

Structure and Function of DNA DNA is a large polymer or macromolecule composed of linear sequences of simple repeating units. The specific sequence of these units contains all of the genetic information of an individual cell or organism. The structure of DNA in its native state was deduced by Watson and Crick in 1953 [Watson and Crick, 1953]. The basic repeating unit of DNA is the nucleotide, which consists of a five-carbon sugar known as deoxyribose; a phosphate group; and a nitrogencontaining base, which may be either a purine or a pyri-

TABLE 21-1 Genetic Information Sites Available on the Internet SITE

*

INTERNET ADDRESS

Disease-Oriented Web Sites GeneTests, GeneReviews* OMIM† via NCBI and direct

http://www.genestar.org/ or http://www.genereviews.org/ or http://www.genetests.org/ http://www.ncbi:.nlm.nih.gov/ or http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

Genome Data Web Sites Ensemble‡ HUGO§ Human Genome Project|| NCBI homepage (Entrez)¶ NCBI SNP database (dbSNP) UCSC Genome browser**

http://www.ensembl.org/Homo_sapiens/ http://www.gene.ucl.ac.uk/nomenclature/ http://www.ornl.gov/sci/techresources/Human_Genome/home.shtml http://www.ncbi.nlm.nih.gov/ http://www.ncbi.nlm.nih.gov/projects/SNP/ http://genome.ucsc.edu/

The disease summaries in GeneReviews all are authored by experts and peer reviewed, so they typically are highly accurate and up to date. OMIM, Online Mendelian Inheritance in Man. The disease summaries in OMIM typically are done by staff with oversight and contain both dated and new data, so the information typically is confirmed from a second source. ‡ Ensemble Human Genome Browser. § Human Gene Nomenclature web site. || Human Genome Project Information maintained by the U.S. Department of Energy Office of Science. ¶ National Center for Biotechnology Information. ** University of California–Santa Clara Genome Bioinformatics site. †

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midine (Fig. 21-1A). In DNA, the purine base may be either adenine (A) or guanine (G), and the pyrimidine base may be either thymine (T) or cytosine (C). Nucleotides polymerize into long chains by formation of phosphodiester bonds between the 5′ carbon position of one deoxyribose molecule and the 3′ carbon of the preceding deoxyribose molecule (see Fig. 21-1B). Each DNA molecule consists of two strands of nucleotides that are held together by weak hydrogen bonds between pairs of bases: A pairs only with T, and G pairs only with C. These paired units are known as base pairs (bp). In the native state, the two strands wind around each other to form a double helix that resembles a right-hand spiral staircase with two unequal grooves known as the major and minor grooves (Fig. 21-2). A single turn of the helix measures 3.4 nm and contains 10 nucleotides. Each strand has a directionality imparted by the deoxyribose sugar backbone. Adjacent nucleotides are linked by phosphodiester bonds between the 5′ and 3′ carbon atoms of the sugar residues, so that one end of the DNA strand has an unlinked 5′ carbon (the 5′ end) and the other end of the strand has an unlinked 3′ carbon atom (the 3′ end). The two strands are antiparallel— that is, they run in opposite directions so that the 5′ end of one strand is paired with the 3′ end of the other. Within living cells, DNA is associated with proteins and supercoiled into more complex structures known as chromosomes, which are described later in the chapter.

Thus, when the sequence of one DNA strand is known, the sequence of the opposite or complementary strand may be predicted. Thus, precise replication of DNA is possible, a process that involves initiation, elongation, and termination stages. The process begins with recognition of an “origin of replication.” Such points of origin are specific DNA sequences recognized by a protein complex known as the primosome that occur every 50 to 300 kilobases (kb) of DNA; the unit kb (kilobases) refers to 1000 sequential nucleotides. The two parental DNA strands must first be separated by helicase, an enzyme that unwinds the supercoiled DNA helix to create a replication fork. The process of elongation occurs at the site of the replication fork or replisome. Synthesis of new strands begins with the addition of approximately 10 RNA bases by a protein complex known as primase and then continues with chain elongation using the original strands as templates. This process is known as semiconservative replication. Both initiation or RNA priming and chain elongation involve large protein complexes that include several DNA polymerases. Five distinct DNA polymerases have been isolated in mammalian systems including human cell cultures (Table 21-2). They are able to copy DNA only by adding nucleotides to the 3′ end of the growing chain, so DNA can elongate only in the 5′ to 3′ direction. Thus, the template DNA can be read only in the reverse or 3′ to 5′ direction. As DNA is unwound, the replication fork necessarily unwinds one strand in the

5'

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FIGURE 21-1. A, The chemical structure of DNA depicts the four bases of DNA. B, The chemical structure of the sugar-phosphate backbone and 3′-5′ phosphodiester bonds.

O

Dobyns and Das / Introduction to Genetics

A. Double

B. Nucleosome fiber

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~10 nm

~30 nm

FIGURE 21-2. Several levels of protein packaging of DNA provide the structural support for chromosomes. A and B, The right-handed double helix of DNA wraps around a histone core to form nucleosomes. C and D, The nucleosomes are packed into a solenoid structure, and loops of solenoids compose an interphase chromosome. (Modified from Thompson MR, McInnes RR, Willard F, et al. Genetics in medicine, 5th ed. Philadelphia: WB Saunders, 1991.)

TABLE 21-2 DNA Polymerases in Mammalian Systems POLYMERASE

LOCATION

FUNCTION

3′ TO 5′ EXONUCLEASE

α(I) β γ δ(III) ε(II)

Nuclear Nuclear Mitochondrial Nuclear Nuclear

Priming, especially of lagging strand DNA repair Replicates mitochondrial DNA Synthesis or elongation DNA repair

No No Yes Yes Yes

3′ to 5′ direction and the other in the 5′ to 3′ direction. The 3′ to 5′ or leading strand is replicated in a continuous fashion at the replication fork by DNA polymerases α(I), which primes the reaction, and δ(III), which synthesizes the DNA chain. The new strand is complementary and so elongates in the opposite or 5′ to 3′ direction. The 5′ to 3′ or lagging strand cannot be copied continuously because this would require synthesis of the complementary new strand in a 3′ to 5′ direction, which is not possible, because DNA polymerases are able to synthesize DNA only in the 5′ to 3′ direction. Thus, the lagging strand is copied by DNA polymerases α(I) and δ(III) in small segments of 100 to 1000 base pairs in the opposite direction from the replication fork. These are known as Okazaki fragments. DNA replication is described as semidiscontinuous because of the continuous replication of the leading strand and the discontinuous replication of the lagging strand. The Okazaki fragments are then joined by another enzyme, DNA ligase. DNA replication is a long process, requiring about 8 hours in most human cells in culture. Thus, the function of DNA is to reliably encode and store the genetic information needed for the cell and organism to function. It has no direct

functions itself but rather acts by directing synthesis of both RNA and protein.

Structure and Function of RNA RNA differs chemically from DNA in the substitution of ribose for deoxyribose in the sugar backbone of the molecule and of uridine (U) for thymine as one of the pyrimidine bases. Also, RNA normally exists as a single-stranded rather than double-stranded molecule. Recent advances have demonstrated far more diverse functions for RNA than was previously appreciated, particularly involving genes that produce functional RNA products that do not code for proteins. These probably represent at least 5% of all human genes as suggested by current knowledge [Strachan and Read, 1999]. Several distinct classes of RNA molecules have been recognized, most of which are involved with regulating or assisting gene expression. Ribosomal RNA. Ribosomal RNAs (rRNAs) are functional RNA transcripts that constitute one of the main components of cytoplasmic ribosomes. The genes coding for the major form of cytoplasmic rRNA are located in multiple

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Genetic, Metabolic, and Neurocutaneous Disorders / 21

TABLE 21-3 Classification of Amino Acids by Side Chain AMINO ACID

CODE

Neutral and Hydrophobic Alanine Isoleucine Leucine Methionine Phenylalanine Proline Tryptophan Valine

ala ile leu met phe pro trp val

A I L M F P W V

Acidic Aspartic acid Glutamic acid

asp glu

D E

AMINO ACID

CODE

Neutral and Polar Asparagine Cysteine Glutamine Glycine Serine Threonine Tyrosine

asn cys glu gly ser thr tyr

N C Q G S T Y

Basic Arginine Histidine Lysine

arg his lys

R H K

copies on the short arms of the acrocentric chromosomes (13, 14, 15, 21, 22); these genes produce a single large 45S primary transcript that is cleaved into 28S, 18S, and 5.8S rRNA classes, designated by their separation in centrifugation gradients and by several associated proteins. Multiple copies of another gene on chromosome 1 produce 5S rRNA. Transfer RNA. Transfer RNAs (tRNAs) are small RNA transcripts that bind specific amino acids and transport them to ribosomes for use during protein synthesis. More than 40 subfamilies of tRNA genes are known, dispersed across the genome. Messenger RNA. Messenger RNAs (mRNAs) are the RNA transcripts of all genes that encode polypeptides and some other genes that encode the unprocessed forms of functional RNAs. Messenger RNA molecules are large. All mRNA transcripts undergo further processing, including excision of large segments of noncoding RNA known as introns, the addition of 7-methylguanosine to the first 5′ nucleotide, forming a CAP structure, cleavage of the 3′ end at a specific point downstream from the end of the coding sequence, and addition of the polyA tail at a site specified in part by the sequence AAUAAA, which is located in the 3′ untranslated region (3′ UTR) of the gene. The polyA tail appears to increase the stability of mRNA. The fully processed mRNA is transported to the cytoplasm where translation occurs. Small Nuclear RNA. Small nuclear RNA (snRNA) transcripts are small, uridine-rich RNA transcripts that associate with specific proteins to form ribonucleoprotein particles (RNPs). Some of them function in RNA splicing (removing introns from mRNA). They comprise a large family of genes dispersed across the genome. Small Nucleolar RNA. Small nucleolar RNAs (snoRNAs) are small RNA transcripts that are present in the nucleolus and have important roles in specific cleavage reactions and base-specific modifications during maturation of ribosomal RNA. About 200 snoRNA genes have been identified. MicroRNA. MicroRNAs (miRNAs) are another class of small noncoding genes that regulate the expression of proteinencoding genes at the post-transcriptional RNA level [Denli et al., 2004]. The process begins with transcription (synthesis) of primary RNA transcripts that range in size from several hundred to several thousand kb. These transcripts are recognized

and cut into precursor miRNAs in the nucleus by a protein known as Dicer, moved to the cytoplasm, and processed into mature miRNAs. The mature miRNAs join the RNA-induced silencing complex (RISC) that recognizes and cleaves (or otherwise silences) a target gene. This process has been demonstrated in many organisms, including mammals, and appears likely to play a key role in regulation of many genes.

Structure and Function of Polypeptides and Proteins Proteins are composed of one or more polypeptide chains. Polypeptides are large polymers or macromolecules composed of linear sequences of repeating units known as amino acids, which are more complex than the repeating units of DNA or RNA. Amino acids consist of a three-carbon backbone with an amino group attached to carbon 1 and a carboxyl group to carbon 3. They differ in the composition of a side chain attached to carbon 2. With rare exceptions, all polypeptides and proteins in nature are built from different sequences of 20 amino acids (Table 21-3). The side chains may be neutral and hydrophobic, neutral and polar, basic, or acidic. The simplest amino acid is valine, which has a hydrogen ion as the side chain. The process of information transfer from RNA polypeptides and proteins is known as translation. It is based on the genetic code, the system by which the base sequence of mRNA specifies the amino acid sequence of a polypeptide chain. In this nearly universal code, each set of three adjacent bases in the mRNA transcript constitutes a codon, and different combinations of bases within the codon specify the individual amino acids (Table 21-4). The small tRNA molecules serve as the molecular link between mRNA codons and amino acids. One segment of each tRNA transcript contains a three-base anticodon that is complementary to a specific codon on the mRNA, whereas another segment contains a binding site for one of the 20 amino acids. With a total of only 20 amino acids and only 64 possible codons, most amino acids are specified by more than one codon. For some of the different amino acids, the base in the third position in the triplet may be either of the purines, either of the pyrimidines, or sometimes any of the four bases. For this reason, the third position in the codon sometimes is called the

Dobyns and Das / Introduction to Genetics

TABLE 21-4 The Nuclear Genetic Code U U

C

A

G

UUU UUC UUA UUG CUU CUC CUA CUG AUU AUC AUA AUG GUU GUC GUA GUG

C phe phe leu leu leu leu leu leu ile ile ile met val val val val

UCU UCC UCA UCG CCU CCC CCA CCG ACU ACC ACA ACG GCU GCC GCA GCG

A ser ser ser ser pro pro pro pro thr thr thr thr ala ala ala ala

UAU UAC UAA UAG CAU CAC CAA CAG AAU AAC AAA AAG GAU GAC GAA GAG

G tyr tyr stop stop his his gln gln asn asn lys lys asp asp glu glu

UGU UGC UGA UGG CGU CGC CGA CGG AGU AGC AGA AGG GGU GGC GGA GGG

cys cys stop trp arg arg arg arg ser ser arg arg gly gly gly gly

wobble position. Arginine and leucine are each specified by six codons, whereas only methionine and tryptophan are specified by a single codon. Three codons signal termination of translation and accordingly are called stop codons.

Transcription The process of information transfer from DNA to RNA is known as transcription. Synthesis of RNA begins at a specific transcription start site and continues in a 5′ to 3′ direction with regard to the RNA product. The DNA strand that corresponds to the RNA sequence is known as the coding or sense strand. This strand, however, is not used as the template for synthesis of an RNA molecule. Rather, the complementary DNA strand, known as the noncoding or antisense strand, actually serves as the template and is read in the 3′ to 5′ direction. The RNA product is known as a transcript.

Translation The process of information transfer from RNA to polypeptide or protein is known as translation. This process takes place in the cytoplasm on small structures known as ribosomes, macromolecules composed of the four species of rRNA noted earlier. They function like small migrating factories that travel along an mRNA template engaging in rapid cycles of peptide bond synthesis. The process consists of initiation, elongation, and termination stages. The ribosome contains a large site that binds about 35 bp of mRNA and two adjacent sites for binding the smaller aminoacyl-tRNA molecules. The first is the acceptor or A site, which holds the incoming aminoacyl-tRNA. The second is the donor or P site, which is occupied by a tRNA carrying the growing polypeptide chain. Translation begins with mRNA binding to the ribosome at the site of the first AUG base triplet, which specifies the amino acid methionine, and also serves as the start signal for synthesis of the polypeptide chain and establishes the reading frame of the mRNA. The mRNA and tRNA then move in the same direction along the ribosome, with the tRNA moving from the A site to the P site, and the mRNA sliding over three bases, allowing recognition of the next codon. Bonding between the mRNA codon and tRNA anticodon brings the appropriate amino acid into position on the ribosome to form a new pep-

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tide bond to the carboxyl end of the growing polypeptide chain. As part of this reaction, the polypeptide chain is released from the tRNA at the P site but remains bonded to the tRNA at the A site. The tRNA and mRNA then move another three base pairs along the chain, and the process is repeated. This reaction continues until one of the stop codons is reached. Thus proteins are synthesized from the amino to the carboxyl terminus, which corresponds to translation from the 5′ to the 3′ end of the mRNA molecule, and methionine is always the first amino acid of each polypeptide chain, although it usually is removed before protein synthesis is completed.

Gene Structure and Organization As noted earlier, a gene has been traditionally defined as a unit of genetic information. This concept has gradually progressed to a more useful definition, which states that a gene is a sequence of chromosomal DNA that is required for production of a functional product, whether the product is RNA or protein [Nussbaum et al., 2001]. By convention, genetic information is always read in the 5′ to 3′ direction, whether encoded in DNA or RNA—in an upstream to downstream direction. The nomenclature regarding the 5′ and 3′ positions of the sugar backbone can be confusing. The 5′ carbon of the first nucleotide of a sequence is joined by a phosphodiester bond to a nucleotide not involved in the sequence, whereas its 3′ carbon is joined to the 5′ carbon of the second nucleotide, and so on. The last nucleotide of the sequence has a 3′ carbon, which joins another uninvolved nucleotide.

Genes Genes are composed of a continuous length of DNA with predominantly definable starts and end points, which include the sequence that codes for the RNA or polypeptide product. This part of the gene is known as the coding region. It has become clear, however, that the structure of a gene is complex and includes much more than the coding sequence of the protein. All genes include additional sequences on either end of the coding region—the 5′ and 3′ UTRs—that do not code for an RNA product or polypeptide. These regions function to regulate transcription and RNA stability. The gene is considered to include the entire sequence represented in the RNA product because some mutations within noncoding regions can impair gene function. A model of a typical human gene is shown in Figure 21-3. Promoter sequences required for regulation and initiation of RNA transcription are present at the 5′ end of the gene, such as the CAT and TATA boxes whose sequences are tightly conserved among many different genes and species. Downstream from the promoter sequences is a specific sequence that signals the start of transcription. Even further downstream is an initiator codon, AUG, which codes for methionine. This triplet signals the start of the actual coding sequence for the polypeptide product, as discussed in an earlier section. The region between the transcription and translation start sites is the 5′ UTR. The next segment of the gene is the coding region. The coding regions of most genes in prokaryotes and lower eukaryotes are colinear, which means that the coding sequence corresponds exactly to the sequence of amino acids

512

Genetic, Metabolic, and Neurocutaneous Disorders / 21 Introns 5' UTR

Highly-conserved regions

3' UTR

Transcription start site (RNA)

Exons

Translation start site (protein)

Translation end site (protein) Transcription end site (RNA)

FIGURE 21-3. The structure of a typical human gene.

in the polypeptide. By contrast, most higher eukaryotic genes including human genes contain additional sequences that lie within the coding region, interrupting the sequence that represents the polypeptide. The regions that code for the final polypeptide (or functional RNA) product are known as exons, whereas the regions that are missing from the final mRNA product are introns. The removal of introns from the final mRNA product is known as splicing and is regulated by a large complex of proteins and functional RNA transcripts. The coding sequence ends at one of three specific stop codons: UAA, UAG, or UGA. The last segment of the gene is the 3′ UTR, which contains a polyadenylation signal and presumably a signal to end transcription, although no transcription stop sequence has been identified. The length of a gene may vary, ranging from less than 1 kb to several hundred kb. The longest gene known, which codes for dystrophin, spans more than 2000 kb of genomic sequence, although this is not the largest protein produced in the cell.

modified in several ways to become functional, especially for mRNA. The first modification to mRNA is the addition of a CAP structure to the 5′ end and is followed by the removal or splicing of introns. The mechanism of mRNA splicing depends on the specific nucleotide sequences at the exon/intron boundaries called splice junctions (Fig. 21-4). The most important of these is the GT-AG rule: Introns almost always start with GT (actually GU, because this occurs in RNA), which is therefore called the splice donor site, and end with AG, which is called the splice acceptor site. Several additional specific sequences are also needed, including sequences within the intron just after the GT splice donor site, at a highly conserved branch site located about 40 bp before the end of the intron and just before the AG splice acceptor site. The splicing mechanism produces the following: (1) cleavage at the 5′ donor site splice junction just before the invariant G, (2) nucleolytic attack by the terminal G of the splice donor site at the invariant A of the branch site to form a “lariat”-shaped structure, and (3) cleavage at the 3′ splice acceptor site at the 3′ splice junction, leading to release of the intronic RNA as a lariat or loop, and splicing of the two exons. These reactions are catalyzed by large complexes composed of snRNA and specific proteins. The snRNAs involved have specific sequences that allow binding with conserved intronic sequences or the recognition sites of other snRNAs. The snRNA–protein–target RNA complexes form large particles known as spliceosomes. Once a 5′ splice site is recognized, the complex scans the RNA sequence until it encounters a branch site, which aids in identifying the nearby 3′ splice acceptor site. This process does not necessarily happen in linear order along the RNA. Rather, the order likely is determined by the vagaries of RNA folding. The last steps involve

Regulatory Regions Many genes have highly conserved sequences either upstream or downstream of the transcribed gene that are involved in regulating expression. These elements seem to be particularly common for genes involved with RNA processing and transcriptional control [Bejerano et al., 2004]. Current understanding of these regions, however, remains limited.

RNA Processing Transcription of DNA gives rise to a precursor RNA that corresponds exactly to the genome sequence but must be

Splice donor site

5'

C A AG GT AGT A G

Exon

Branch site

T C T A C N A C T CG T Intron

Splice acceptor site

CCCCCCCCCCC C G N AG 3' TTTTTTTTTTT T A Exon

FIGURE 21-4. Consensus sequences at the splice-donor, branch, and splice-acceptor sites in introns of higher eukaryotes. The GT at the start of the intron, the A near the end of the branch site, and the AG that ends the intron are essentially invariant, whereas most others represent the majority nucleotide. When two nucleotides are depicted at a single position, no preference is signified regarding which is listed on the top or or on the bottom. A, adenine; C, cytosine; G, guanine; N, any nucleotide; T, thymine. (Modified from Strachan T, Read AP. Human molecular genetics. New York: Wiley-Liss, 1996.)

Dobyns and Das / Introduction to Genetics

cleavage of part of the 3′ UTR, which occurs at a specific point downstream from the end of the coding sequence, and addition of a long sequence of adenosine nucleotides that is called the polyA tail. The site of the polyA tail is specified in part by the sequence AAUAAA, which is located within the 3′ UTR.

Imprinting and X-Inactivation Several regions of the genome are subject to inactivation under special circumstances, with no changes to the DNA sequence. The processes involved thus represent a form of “epigenetic” modification. The two processes reviewed here, imprinting and X chromosome inactivation, both can result in a phenotype when disrupted.

Imprinting The process by which certain genes in specific chromosomal regions are expressed from only one chromosome, depending on the parental origin of the chromosome, is known as “imprinting.” Although the mechanism remains unknown, a key component involves allele-specific DNA methylation, found predominantly at the carbon 5 position of about 80% of all cytosines that are part of symmetrical CpG dinucleotides [Jiang et al., 2004; Strachan and Read, 1999; Weksberg et al., 2003]. This process is controlled by regulatory imprinting “centers” located nearby on the same chromosome as that of the silenced or “imprinted” gene. In effect, then, two alleles of the same gene that are identical in nucleotide sequence but derived from opposite parents are regulated differently in the same nucleus. This process is reversible, so that the silent, imprinted allele can be reactivated and the active allele silenced when passed through the germ line of the opposite-sex parent. Most imprinted genes are found in large clusters of greater than 1 Mb (megabase pairs) in length. Imprinted clusters have been identified in chromosomes 6q24, 7p11.2, 11p15.5, 14q32, 15q11-q13, and 20q13.2, and others may exist as well [Cavaille et al., 2002; Gardner et al., 2000; Hall, 1990; Jiang et al., 2004; Weksberg et al., 2003; Wylie et al., 2000]. Imprinted regions all share several common characteristics including differential DNA methylation, allele-specific RNA transcription, antisense transcripts, histone modifications, and differences in timing of replication.

X-Inactivation In cells with two (or more) X chromosomes, all but one undergo extensive gene silencing by methylation. This phenomenon, known as X chromosome inactivation (Xi), causes one of the two X chromosomes in cells of female mammals to become transcriptionally inactive early in embryonic development [Lyon, 1961, 2002]. In mutant cells with more than two X chromosomes, all but one becomes inactivated. This has the effect of balancing gene dosage of X-linked genes between male and female cells. The process of Xi is random, so that on average the maternally and paternally derived X chromosomes each are inactivated in approximately 50% of cells. Alterations from this pattern are seen in female carriers of some X-linked diseases, resulting in skewing of Xi. This alteration can be favorable, with decreased severity of the phenotype, or unfavorable, with increased severity of the phenotype.

513

CELL CYCLE AND CHROMOSOMAL BASIS OF HEREDITY Current knowledge regarding the chromosomal basis of heredity and that concerning the cell cycle are inextricably linked, because the intracellular structures now known as chromosomes were first seen in cells undergoing cell division. The existence of chromosomes was foreshadowed by some of Gregor Mendel’s work. For years after he described independent sorting of genetic traits, occasional exceptions to Mendel’s law of segregation were discovered. Certain traits were found that were typically inherited as a group. These observations were eventually explained by the discovery of chromosomes. The nuclear material of a cell, or chromatin, appears relatively homogeneous during most of the cell cycle but condenses into a number of distinct rodshaped organelles during cell division. These tiny structures were called chromosomes because they stain darkly with various biologic dyes.

Cell Cycle Humans begin life as a single diploid cell or zygote that gives rise to all of the cells of the body by a combination of cell growth and cell division, with the latter including both asexual (mitosis) and sexual (meiosis) cell division. The life cycle of somatic cells is divided into four stages. After cell division, the cell enters the G1 (gap 1) resting phase, during which DNA synthesis does not occur. Some differentiated cells, such as neurons, stop growth in a modified G1 phase known as G0. Late in G1, the cell passes a critical point after which it proceeds through the rest of the cell cycle at a standard rate. G1 is followed by the S phase, during which DNA synthesis or replication occurs. The genetic material is duplicated in the form of two chromatids (future chromosomes) joined by attachment to a single centromere. The cell then enters the G2 (gap 2) resting phase, which is much shorter than G1. The G1, S, and G2 phases together constitute interphase.

Mitosis Somatic cell division, or mitosis, is an elaborate mechanism that distributes one chromatid of each duplicated chromosome to each of the two daughter cells. The process is continuous but has been divided into the following five stages: prophase, prometaphase, metaphase, anaphase, and telophase (Fig. 21-5). In prophase, the chromatin begins to condense, the nucleolus disappears, and the mitotic spindle begins to form. Prophase is followed by prometaphase, during which the nuclear membrane disappears, allowing the chromosomes to disperse in the cell and attach to the spindle by paired kinetochores located at the centromere. In metaphase, the chromosomes are maximally contracted and arranged at the equatorial plane of the cell. In anaphase, the replicated chromosomes separate at the centromere, allowing the two chromatids to become daughter chromosomes, which move to opposite ends of the cell. In telophase, the chromosomes decondense, the nuclear membrane re-forms, and the nucleus returns to the interphase appearance. Shortly afterward, the cytoplasm divides to form two daughter cells. For routine studies, chromosomes are examined during metaphase. For

514

Genetic, Metabolic, and Neurocutaneous Disorders / 21 FIGURE 21-5. Diagram of mitosis demonstrating two chromosome pairs.

Interphase Prophase

Prometaphase

MITOSIS

Metaphase

Anaphase

Telophase

Interphase

high-resolution studies, they are examined before the point of maximal contraction, during prophase or prometaphase.

Meiosis Reproductive cell division, or meiosis, is an even more complex mechanism in which two successive cell divisions, known as meiosis 1 and meiosis 2, give rise to the haploid germ cells (Fig. 21-6). Meiosis is of critical importance in understanding many of the methods of modern molecular genetics and the pathogenesis of many genetic diseases. In meiosis 1, the chromosome number is reduced from the diploid to the haploid number. The key step consists of close pairing of homologous chromosomes during prophase 1, which is further divided into several stages. During leptotene,

the chromosomes first become visible, with homologs located close together. During zygotene, the homologs begin to pair closely along their entire length, held together by a thin protein-containing structure known as a synaptonemal complex. During pachytene, synapsis or pairing is completed, and the homologs appear as a bivalent. Pachytene is the stage during which exchange of homologous segments between nonsister chromatids occurs, which is known as recombination or crossing over. The remaining steps are similar to mitosis, except that it is the paired homologs that are pulled apart rather than the centromeres. In meiosis 2, which closely resembles mitosis, the chromatids separate at the centromere to form daughter chromosomes. Ova and sperm have remarkably different timing, but the sequence of meiosis is the same.

Dobyns and Das / Introduction to Genetics

515

Interphase Prophase 1 (crossing over) Prometaphase 1

Metaphase 1

Anaphase 1

MEIOSIS

Telophase 1

Metaphase 2

Anaphase 2

Gametes FIGURE 21-6. Diagram of meiosis depicting two chromosome pairs.

Chromosomal Basis of Heredity Chromosome Structure The nuclear DNA is dispersed among 23 or 24 separate linear structures—the chromosomes, each of which consists of a single, uninterrupted double helix that contains 50 to 250 Mb of DNA—and a group of associated proteins that

form the support structure or scaffolding. The scaffolding consists of five basic proteins called histones and several more acidic nonhistone proteins. Two copies of each of four histones—H2A, H2B, H3, and H4—join to form an octamer. The DNA double helix wraps almost twice around the octamer, which involves about 140 bp. Adjacent octamers are separated by a short spacer segment of 20 to 60 bp that

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Genetic, Metabolic, and Neurocutaneous Disorders / 21

is associated with histone H1. The complex of DNA and core histones is known as a nucleosome (see Fig. 21-2). Strings of nucleosomes are further compacted into a secondary helical structure known as a solenoid. These structures have a diameter of about 30 nm (see Fig. 21-2) and contain six nucleosomes per turn. The solenoids are packed into large loops of 10 to 100 kb of DNA, which are attached to a nonhistone protein scaffolding. These loops pack together loosely to form interphase chromosomes. During early prophase, they pack together more closely to form knoblike thickenings known as chromomeres, which then coalesce further to form the bands observed in prometaphase and metaphase chromosomes when stained with appropriate dyes. The alternating light and dark bands that characterize all nuclear chromosomes with a variety of staining methods likely reflect the compartmentalization of the genome into isochores, defined as large regions with variation in base composition or variable spacing of scaffold attachment regions. The dark bands observed with Giemsa staining are AT rich, replicate late in the DNA synthesis phase of the cell cycle, and contain relatively few genes. The light bands observed with Giemsa are GC rich, replicate early, and contain many genes. Some are greatly enriched for GC and contain high concentrations of genes. Most, although not all, such bands are located near the ends or telomeres of chromosomes and therefore are known as T bands.

Specialized Regions All nuclear chromosomes have specialized regions that are required for chromosome integrity and function, including centromeres, telomeres, and origins of replication. Centromeres are DNA sequences that act in cis. That is, they act on the same chromosome on which they are located and are responsible for the segregation of chromosomes during cell division. Centromeres contain extensive repeats of an approximately 171-bp unit known as alpha-satellite DNA, the sequence of which differs slightly between each chromosome. Fragments of chromosomes that lack a centromere, known as acentric fragments, are lost during cell division. The two ends of a chromosome are called telomeres and also are required for chromosome stability. In humans, they consist of long arrays of tandem repeats of the sequence TTAGGG, which extend about 5 to 20 kb. DNA polymerases are unable to replicate the telomeres because of the lack of a template. This problem is resolved by the enzyme telomerase, which contains an RNA component to serve as a template to prime further synthesis on the leading strand. Further extension of the leading strand provides the needed template for the lagging strand. Origins of replication are specialized sequences where DNA replication begins and thus are important in maintaining chromosome number and integrity. They consist of autonomously replicating sequence (ARS) elements that contain a core consensus sequence and some imperfect copies of the core sequence and extend about 50 bp. A human consensus ARS has been identified [Strachan and Read, 1999]. Regions of variable staining known as heterochromatin consist of long arrays of repeat sequences as short as 5 bp. These regions are located primarily in the pericentromeric regions of chromosomes 1, 9, and 16, and in distal Yq. The

five human acrocentric chromosomes have small satellites attached to the short arm by short stalks or secondary constrictions that contain the rRNA genes.

Chromosome Number Each human somatic cell contains 46 chromosomes that consist of 22 matched pairs known as autosomes and two sex chromosomes: XX in females and XY in males (Fig. 21-7). By contrast, human germ cells contain only 23 chromosomes, consisting of one of each kind of autosome and a single sex chromosome. The former is known as the diploid or 2n number, and the latter is known as the haploid or 1n number. The autosomes are numbered according to length, with chromosome 1 being the longest and chromosome 21 the shortest. Although chromosome 21 is slightly shorter than chromosome 22, the numbers were retained for historical reasons. The two members of each pair of autosomes and the two X chromosomes in females carry the same genes and are known as homologous chromosomes, or homologs. Although they appear similar under the microscope, homologs are not strictly identical. They contain essentially the same genes, but the nucleotide sequence differs at thousands of positions.

Chromosome Identification Individual chromosomes may be seen only when tightly contracted during cell division. Each chromosome consists of two chromatids, which are joined at the primary constriction, or centromere. In standard cytogenetic nomenclature, the centromere divides the chromosome into two arms, designated the p or short arm and the q or long arm. The tip of each arm is the telomere. Human chromosomes are classified into the following three types according to the position of the centromere: (1) metacentric, in which the centromere is centrally placed and the two arms are of about equal length; (2) submetacentric, in which the centromere is off center and the arms are of unequal length; and (3) acrocentric, in which the centromere is near one end.

ORGANIZATION OF THE HUMAN GENOME The human genome comprises the total of all genetic information in the cell. It is divided into two separate compartments—a complex nuclear genome and a much simpler mitochondrial genome. The mitochondrial genome consists of a single circular DNA molecule that is present in many copies in each mitochondrion, and the nuclear genome is distributed among 23 (in females) or 24 (in males) linear structures known as chromosomes. The available data regarding the genome have become much more extensive and accurate with completion of the Human Genome Project. A few of the most useful Human Genome Project–related web sites are listed in Table 21-1.

The Nuclear Genome The human nuclear genome consists of approximately 3 × 109 base pairs (bp), or 3000 Mb of DNA. About 75% of this represents unique or single-copy DNA, which includes genes and some important regulatory elements; the remaining 25% consists of several classes of repetitive DNA

Dobyns and Das / Introduction to Genetics 36.3– 36.2– 36.1– 35– 34.3– 34.2– 34.1– 33– 32–

25– 24– 23– 22– 21– 16– 15– 14– 13– 12– 11.2– 11.1– 11.1– 11.2– 12– 13– 14.1– 14.2– 14.3– 21–

31– 22– 21– 13– 12– 11– 11– 12– 21– 22– 23– 24– 25–

22–

31–

32–

26– 25– 24– 23– 22–

14– 13–

33– 34– 35– 36–

41– 42– 43– 44–

37–

1 25– 24– 23– 22–

2

13– 12– 11– 11.1– 11.2– 12– 13–

21– 22– 23– 24– 25– 26– 27–

21– 22– 23– 24– 25– 26.1– 26.2– 26.3– 27– 28– 29–

31–

15.3– 15.2– 15.1– 14–

13–

12– 11.1– 11.1– 11.2– 12– 13.1– 13.2– 13.3–

24–

32–

16– 15.3– 15.2– 15.1– 14– 13– 12– 11– 11– 12–

21–

23–

517

14– 15– 21– 22–

28–

23–

31.1– 31.2– 31.3– 32– 33– 34– 35–

31–

3

32– 33– 34– 35–

4

5

22– 21–

21.3– 21.2– 21.1– 12– 11.2– 11.1– 11– 12– 13– 14– 15– 16–

23– 22– 21– 12– 11.2– 11.1– 11.1– 11.2– 12– 13–

11.2– 11.1– 11.1– 11.2– 21–

21–

22–

21.1– 21.2– 21.3–

31–

22–

32– 33– 34– 35– 36–

23–

22– 23– 24– 25– 26– 27–

6 13– 12– 11.2– 11.1– 11– 12– 13– 14–

13– 12– 11.2– 11.1– 11.1– 11.2– 12– 13–

22– 31– 32– 33– 34–

32–

13 13.3– 13.2– 13.1– 12– 11– 11– 12– 13.1– 13.2– 13.3– 13.4–

14 13– 12– 11.2– 11.1– 11.1– 11.2– 12– 13.1– 13.2– 13.3–

19

20

11.2– 11.1– 11.1– 11.2–

13–

21–

15–

14– 21– 22–

23– 24– 25–

23–

34–

26–

24– 25–

9

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FIGURE 21-7. Standardized diagram or idiogram of human chromosomes at the 400-band stage.

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[Lander et al., 2001; Nussbaum et al., 2001; Venter et al., 2001].

Genes and Conserved Noncoding DNA Somewhat surprisingly, recent estimates predict that the human genome contains only 30,000 to 40,000 genes, far fewer than earlier estimates, which account for only about 1.2% of nuclear DNA [Lander et al., 2001; Venter et al., 2001]. Another 5% of the human genome is more conserved than would be expected from estimates of neutral evolution, which suggests that many of these regions have specific, regulatory functions [Chiaromonte et al., 2003; Waterston et al., 2002]. Studies of these highly conserved regions of DNA have used different thresholds, such as stretches of more than 100 bp with 70% to 80% conservation between mouse and human. Some of these regions have been found to contain important noncoding elements [Dermitzakis et al., 2002, 2003; Frazer et al., 2004; Hardison, 2000]. More stringent analysis demonstrates that the human genome contains 481 sequences of 200 or more bp that are 100% conserved among human, mouse, and rat [Bejerano et al., 2004]. These segments were designated “ultra-conserved elements” and are preferentially located near genes involved in RNA processing or regulation of transcription and development. Similarly, about 5000 sequences of 100 bp or more are conserved among these three species, which emphasizes that noncoding sequences are common and important.

Repetitive DNA Repetitive DNA in the human genome consists of several classes of DNA whose nucleotide sequence is repeated, either exactly or with minor variations, hundreds to millions of times. Some classes are clustered, whereas others are dispersed throughout the genome. Clustered, repeated sequences constitute 10% to 15% of the genome and are collectively called satellite DNA because of their separation from other DNA on density centrifugation. Satellite DNA consists of head-to-tail or tandem arrayed repeat sequences that can extend for several thousand kb. Dispersed, repeat sequences constitute 6% to 10% of the genome and belong to several different classes. Minisatellite or variable number of tandem repeat (VNTR) sequences are dispersed, intermediatelength (15 to 65 bp) repeats that usually span only several kb. The Alu family of DNA repeats includes about 500,000 related sequences that are each about 300 bp in length and together make up about 3% of the genome. The L1 family of repeats includes about 10,000 related sequences that extend up to 6 kb in length and make up another 3% of the genome. The cytosine-adenine (CA) repeat family includes 50,000 to 100,000 sequences consisting of short tandem repeats of the cytosine-adenine dinucleotide (or guanine-thymine on the complementary strand). Although the origin of these sequences is not known, no functions have been identified, and it appears likely that they simply exploit cellular processes to propagate themselves. Several classes have been useful as polymorphic DNA markers.

Low Copy Repeats Segmental duplications known as low copy repeats (LCRs) are DNA sequences of 10 to 250 kb present in multiple copies with greater than 95% sequence identity that

make up approximately 5% of the human genome [Babcock et al., 2003; Bailey et al., 2002; Cheung et al., 2001; Stankiewicz and Lupski, 2002]. LCRs are dynamic regions of the genome because specific repeats tend to cluster within the same genomic regions, where they mediate unequal nonhomologous recombination events producing segmental deletions and duplications. Several of these have been associated with well-known developmental disorders in humans such as Williams’ syndrome in 7q11.23, Angelman’s syndrome and Prader-Willi syndrome in 15q12, hereditary neuropathy with predisposition to pressure palsies and Charcot-Marie-Tooth neuropathy type 1A in 17p12, SmithMagenis syndrome in 17p11.2, and DiGeorge’s syndrome in 22q11.2 [Babcock et al., 2003].

Polymorphisms A mutation is a permanent change in the DNA of an individual organism, specifically a change in the nucleotide sequence anywhere in the genome [Nussbaum et al., 2001]. Genetic diseases and many cancers are caused by mutations that adversely affect function of one or more genes, although most mutations have little or no effect on gene function and therefore do not change the survival or reproductive fitness of an individual. Some of these persist in the population as morphologic variants known as polymorphisms. Sequence changes that have frequencies of less than 1% are known as rare variants, whereas those with frequencies of 1% or more are known as polymorphisms. By convention, a genetic polymorphism is defined as the occurrence of two or more variants or alleles in a region of DNA where at least two alleles appear with frequencies greater than 1%. Several different classes of polymorphisms occur in the genome, and several methods in molecular biology take advantage of the normal variation between individuals.

Minisatellites One of the most useful classes of polymorphisms in the genome is that of the minisatellite or VNTR DNA sequences. These are intermediate-length (15 to 65 bp) DNA sequences that are repeated one to several dozen times in tandem and usually span several kb in total length. They are highly polymorphic, and their extreme polymorphic nature coupled with the complexity of multilocus minisatellites makes them valuable for DNA fingerprinting applications such as forensic, paternity, and zygosity testing and linkage mapping. They also are inherently unstable and susceptible to mutation at a higher rate than observed for other sequences of DNA.

Microsatellites Microsatellites, also known as satellite DNA or short tandem repeats, are segments of DNA two to five nucleotides in length (dinucleotide, trinucleotide, tetranucleotide, or pentanucleotide repeats) that are scattered throughout the genome in noncoding regions between genes or within genes (in introns). They often are used as markers for linkage analysis because of the naturally occurring high variability in repeat number between individuals. These regions are inherently unstable and susceptible to mutations. The most common class of microsatellites is CA repeats (also called GT repeats), which consist of short tandem repeats

Dobyns and Das / Introduction to Genetics

of the dinucleotide CA on one strand and GT on the complementary strand. They thus take the form (CA)n/(GT)n, with n in the range of 6 to 30 [Weber and May, 1989]. The number of repeats within a (CA)n block varies greatly among different members of a species, producing a set of alleles that always differ in size by multiples of two bases. About 70% of the human population is heterozygous at any given (CA)n repeat locus, making these highly polymorphic. The human genome contains about 50,000 to 100,000 interspersed (CA)n blocks, which is enough to place 1 block every 30 to 60 kb if evenly spaced. For both VNTR and CA repeat sequences, the combination of high frequency in the genome and a high rate of polymorphism has made them very useful for gene mapping studies. Some microsatellite repeats, most often trinucleotide repeats, present within coding regions of genes or, less often, the 5′ or 3′ UTR, can expand to an abnormal length and are the basis of triplet repeat diseases such as Huntington’s disease, spinocerebellar ataxias, and fragile X syndrome.

Single-Nucleotide Polymorphisms Single-nucleotide polymorphisms (SNPs, pronounced “snips”) are DNA sequence variations that occur when a single nucleotide (A, T, C, or G) in the genome sequence is changed. For example, a SNP might change the DNA sequence TCACG to TTACG. The most common sequence change involves replacement of cytosine (C) with thymidine (T), accounting for about two thirds of all SNPs. As with other types of sequence variation, a SNP must occur in at least 1% of the population to be classified as a polymorphism. SNPs occur in both unique-sequence (coding and noncoding) and repetitive DNA and are responsible for about 90% of all human genetic variation. SNPs are found on average approximately every 100 to 300 bases along the entire human genome. Although most SNPs likely have no function, some are known to influence disease predisposition or responses to drugs and thus are proving to be very valuable in studying the causes of common human diseases. The current inventory of known SNPs can be found in the Human SNP database (dbSNP) on the NCBI Entrez web site (see Table 21-1). SNPs can affect restriction enzyme sites in the genome and are the basis of restriction enzyme fragment length polymorphisms (RFLPs). Restriction enzyme sites comprise specific DNA sequences scattered within the genome that are recognized and cleaved by bacterial restriction enzymes/ endonucleases (discussed in more detail later). Depending on the location of restriction enzyme sites, specific DNA fragment lengths are obtained on digestion with restriction endonucleases. The presence of a SNP at one of these restriction enzyme sites will affect cleavage by restriction enzymes, resulting in a different-sized DNA fragment that is the RFLP. RFLPs also can be produced by any change that alters the size of the DNA fragment on which the restriction site is located, such as deletions or duplications. RFLPs are a measure of naturally occurring variations or polymorphisms of normal DNA and are inherited according to mendelian principles. RFLPs have been useful for gene mapping.

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Mitochondrial Genome Mitochondria are cellular organelles that are primarily responsible for cellular respiration and production of adenosine triphosphate. Each cell contains numerous mitochondria, and each mitochondrion contains many copies of a small 16.5-kb circular chromosome, adding up to thousands per cell. The mitochondrial chromosome contains 37 genes that code for two types of rRNA, 22 types of tRNA, and 13 polypeptides. The two DNA strands differ significantly in base composition, with a heavy strand rich in guanines that codes for 28 genes and a light strand rich in cytosines that codes for 9 genes. It is very densely packed, with 93% comprising coding sequence [Strachan and Read, 1999]. All of the genes coded by the mitochondrial chromosome are expressed only in the mitochondria. The rRNA genes differ in size from those in nuclear DNA. The genetic code by which tRNAs decipher mRNAs differs slightly from nuclear DNA. The 13 polypeptides function as subunits of the mitochondrial oxidative phosphorylation system. The nuclear genome encodes the remaining 80 or more subunits and also encodes all mitochondrial ribosomal proteins and many other essential genes, such as mitochondrial DNA and RNA polymerases.

Human Genome Project The importance of DNA, including both genes and noncoding regions, became increasingly apparent during the 1970s and 1980s, leading to one of the most ambitious scientific research projects ever undertaken—a plan to sequence the entire human genome. This project, which was begun in 1990, came to be known as the Human Genome Project. The goals of the project, as taken from the Human Genome Project web site (see Table 21-1), were as follows: • To identify all of the approximately 20,000 to 25,000 genes in human DNA • To determine the sequences of the 3 billion chemical bp that make up human DNA • To store this information in databases • To improve tools for data analysis • To transfer related technologies to the private sector • To address the ethical, legal, and social issues (ELSIs) that may arise from the project The successful completion of the Human Genome Project has had the effect of changing genetic research from “bottom up” to “top down” research. That is, a major goal of research before completion of the Human Genome Project was to determine the nucleotide sequence of genes associated with the disease under study. Following completion of the project, research now typically begins with the nucleotide sequence. Although the Human Genome Project has been officially completed, numerous difficult regions of duplicated DNA remain to be sequenced correctly, and data analysis of the entire project is ongoing. The latter will certainly continue for many years. The effects of the Human Genome Project, however, have been enormous. Research projects that once required several years now can be done in several weeks or months.

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TECHNOLOGY OF CYTOGENETICS The modern field of cytogenetics began when methods for arresting cells during mitosis were developed, when chromosomes were contracted and could be visualized under the microscope with various stains. The human diploid chromosome number of 46 was discovered, and many different defects in chromosome number and structure were found, such as Down syndrome. The field has expanded with development of new computerized image recognition systems for chromosome identification and a variety of methods that make use of molecular genetics methodologies. Thus, the distinction between cytogenetics and molecular genetics has become blurred. In general, cytogenetics tests examine large regions of the genome, such as chromosomes or regions of chromosomes, whereas standard molecular genetics methods focus on much smaller regions of the genome, from single nucleotides to genes and gene regions.

Chromosome Analysis When methods for examining chromosomes under the microscope were first developed, individual chromosomes could not be identified because of solid staining. Instead, they were separated into seven groups (A to G) based on their length and centromere position. It is now possible to individually identify all 24 human chromosomes using several different staining techniques that take advantage of differences in chromatin structure and composition to produce a recognizable pattern of bands, as diagrammed in Figure 21-7. These methods are now used to examine the entire chromosome complement of an individual patient, which is known as the karyotype. The same term is used to describe the normal chromosome complement of a species. The three most commonly used staining methods are G-banding, R-banding, and Q-banding. For G-banding, the chromosomes are treated with trypsin and then Giemsa stain to produce the alternating light and dark bands known as G bands. For R-banding, the chromosomes are pretreated with heat and then stained with Giemsa. The resulting R bands are the exact reverse of those produced by G-banding. For Q-banding, the chromosomes are stained with quinacrine mustard and examined under fluorescent light. A specific pattern of bright and dim Q bands is seen, with the bright Q bands corresponding to the dark G bands. For standard chromosome analysis, cell division is arrested in metaphase, when 400 to 550 bands per haploid set can be seen. Analysis should be performed on cells with at least 550-band resolution. For high-resolution chromosome analysis, cell division is arrested in prophase before full contraction has occurred, when 550 to 850 bands per haploid set can be seen. This technique is labor intensive but may be useful for finding very small chromosome rearrangements. A uniform system of human chromosome classification and nomenclature was developed at a series of international conferences and most recently was revised in 1995 [ISCN, 1995]. In this system, chromosomes are separated into regions and subregions based on the banding pattern. For example, band 17p13.3 (read as “17-p-one-three-pointthree”) is found near the telomere of the short arm of chromosome 17.

During the past decade, computer image analysis systems have been developed that can locate chromosome spreads on the slide, recognize and automatically sort chromosomes, and help with analysis. Review by trained cytogenetic technicians is still required, however.

Fluorescence In Situ Hybridization Fluorescence in situ hybridization (FISH) is a technique used to detect specific chromosomes or chromosomal regions through hybridization (attachment) of fluorescently labeled DNA probes to denatured chromosomal DNA. Examination under fluorescent lighting detects the presence or absence of the hybridized fluorescent signal (and hence presence or absence of the chromosome material). This study usually is performed on metaphase chromosomes (Fig. 21-8) but also can be used on cells in interphase. Interphase FISH often is used for rapid detection of specific types of aneuploidy in fetal cells and for detection of certain deletions, duplications, and other abnormalities in tumor cells. In contrast with metaphase FISH, interphase FISH does not permit visualization of the actual chromosomes, so that most types of structural rearrangements cannot be detected. FISH can be used to examine a small set of chromosomal regions at once, usually 1 or 2, although study of 8 to 10 is possible

FIGURE 21-8. Fluorescence in situ hybridization (FISH) of a standard metaphase spread using a set of three overlapping cosmids at D17S379. The top arrow points to two D17S379 probe signals on the two chromatids of one chromosome 17 homolog. The bottom arrow points to the tip of the other chromosome 17 homolog, which lacks the normal signal and is thus deleted for this probe. The chromosome 17 centromeres are marked by a larger signal just below (top) or above (bottom) the arrows. Different colors are used for the D17S379 and 17 centromere probes so that they can be differentiated easily under the microscope. (Courtesy of David H. Ledbetter, Emory University, Atlanta, GA.)

Dobyns and Das / Introduction to Genetics

with special fluorescent markers. Telomere-specific FISH analysis is an example of hybridization with multiple probes simultaneously. Telomere-specific probes that correspond to the telomeres of all of the chromosomes are hybridized to metaphase chromosomes in groups and used to detect abnormalities at the ends of chromosomes that are not visible by routine chromosome analysis.

Comparative Genomic Hybridization Comparative genomic hybridization (CGH) is a molecular cytogenetics method developed to detect changes in copy number between two genomes, typically those of a control and an experimental subject. The alterations are classified as DNA gains and losses and reveal a characteristic pattern that includes mutations at chromosomal and subchromosomal levels. Equal amounts of DNA from two different sources (control and experimental) are labeled with two different fluorescent labels and hybridized to normal metaphase chromosome spreads. For example, control DNA may be labeled with red, and experimental subject DNA with green. When the control and the subject samples both contain a DNA fragment of interest, both labels are seen; this produces yellow fluorescence on the metaphase chromosome spread. When a given DNA fragment is deleted in the experimental subject, only the red control label is seen. When a given DNA fragment is duplicated in the subject, only the green subject label is seen. Array formats for CGH have been developed that have increased the resolution of this technique for detecting smaller deletions and duplications. Instead of hybridizing onto metaphase chromosome spreads, a set of DNA probes across the entire genome is used. The probes are placed on microarrays that can detect DNA fragments with the same sequence as for the probe. Several different methods have been developed using different probes such as bacterial artificial chromosome (BAC) DNA, complementary DNA (cDNA), or DNA fragments produced by cleavage of genomic DNA by the restriction enzyme BglII [Ishkanian et al., 2004; Lucito et al., 2003; Sebat et al., 2004]. These offer different resolution, with probes every approximately 15 to 100 kb. CGH technology has numerous advantages over FISH, including coverage of the entire genome, finer resolution, and lower cost per probe tested. Thus, clinical tests based on CGH technology are likely to replace FISH technology during the next few years.

TECHNOLOGY OF MOLECULAR GENETICS Molecular genetics is that branch of genetics concerned with the structure and function of genes at the molecular DNA level. The rapid gains in this field during the past decade have resulted from discovery of several new techniques that have made detailed analysis of both normal and abnormal genes possible. These discoveries have in turn led to better understanding of many important biologic processes, as well as the molecular basis for many genetic diseases. Several of these methods have proved to be of particular importance and are commonly used in research studies. Some familiarity with these procedures is helpful in understanding the nature and significance of new discoveries in this area.

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This section presents a brief introduction to some of the more important procedures. More detailed information can be found in several laboratory manuals, especially Current Protocols in Human Genetics [Dracopoli et al., 1997].

DNA Clones A vector is a DNA molecule that can replicate itself in a host cell, such as a bacterium or yeast. Integration of DNA fragments into the vector with restriction endonucleases and DNA ligase results in propagation of the DNA fragment along with the vector, producing large quantities of the fragment of interest. Vectors with inserted recombinant DNA fragments of interest are known as clones, and the methods used to generate them are collectively known as cloning. Clones are chosen at random from clone libraries, which are large collections of clones originating from a specific source, such as the total genomic DNA or chromosome-specific DNA of a human or other organism. Several common types of vectors have been used including phage (bacterial virus) (up to 20-kb insert DNA), plasmids (accessory circular bacterial chromosomes, used to clone several kb of DNA), cosmids (approximately 35 to 45 kb), BACs (approximately 100 to 150 kb) and PACs (P1 plasmid artificial chromosomes) (approximately 100 to 150 kb), and YACs (yeast artificial chromosomes) (up to 1000 kb). The most commonly used at present are BACs and PACs [Stein, 1997], which have proved to be useful for FISH, CGH, and many other technologies. Creation of chromosome-specific DNA libraries by cloning followed by mapping and sequencing is the basis of the information obtained through the efforts of the Human Genome Project.

Restriction Enzymes Restriction enzymes or endonucleases are bacterial enzymes that recognize short, double-stranded DNA sequences and cut the DNA molecule at or near the recognition site [Lewin, 2003]. When a mutation occurs that changes as few as one of the base pairs in the sequence, it is no longer recognized and cut by the enzyme. Several hundred restriction endonucleases have been isolated. Most of the recognition sites are palindromes, which means that they read the same in the 5′ to 3′ direction on both strands, and most of the enzymes leave short overhangs of singlestranded DNA that are known as sticky ends. For example, the enzyme BamHI recognizes the sequence GGATCC and cuts it between the two G bases, leaving the following fourbase overhang: 5′–GGATCC–3′ → 5′–G 3′–CCTAGG–5′ → 3′–CCTAG

GATCC–3′ G–5′

Restriction endonucleases have several important uses in molecular biology. First, they are used to cut or “digest” large DNA molecules into a reproducible collection of a million or more smaller and more manageable DNA fragments that can be identified on the basis of their size. Second, a mutation at any of the recognition sites that changes the sequence or a mutation elsewhere that creates a new recognition site can potentially be detected. Finally, DNA molecules cut with the same restriction endonuclease all have the same sticky ends and may be joined using the enzyme DNA ligase. This condition allows specific DNA sequences of interest to be inserted into vectors and

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introduced into cells such as the bacterium Escherichia coli or the yeast Saccharomyces cerevisiae (common bakers’ yeast), which then can be propagated to produce large amounts of the sequence of interest. DNA sequences inserted into a vector are known as recombinant DNA. This is the basis of DNA cloning.

Polymerase Chain Reaction The polymerase chain reaction (PCR) technique has revolutionized the field of molecular genetics. It is a simple but elegant method to amplify a small amount of DNA greater than a million-fold within a matter of hours. PCR results in the enrichment and amplification of a particular DNA region of interest from the total genome, making it more amenable to study, without the use of cloning or Southern blots (described later on). The region of DNA with known base sequence to be amplified, such as part of a gene, is selected, and two short DNA sequences flanking the region of interest are synthesized to serve as primers for amplification. To construct the primers, a short sequence of about 20 to 25 bp just upstream or 5′ of the target sequence on the DNA “sense” strand is chosen as a starting site, and an oligonucleotide (or primer) that is complementary to this short upstream sequence is synthesized. Another short sequence upstream or 5′ of the target sequence on the complementary (or “antisense”) strand also is chosen, and a

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FIGURE 21-9. The polymerase chain reaction. Depiction of the cycling process of denaturation, annealing, and extension that results in the exponential amplification of DNA.

second complementary oligonucleotide is synthesized. The two primers thus flank the region of interest on opposite strands. The DNA is denatured to separate the strands, after which the oligonucleotides are hybridized to the complementary sequences. The short oligonucleotides then serve as primers for synthesis of a complete complementary DNA strand with appropriate deoxynucleotide triphosphate molecules (adenosine, cytosine, guanosine, and thymidine triphosphate [dATP, dCTP, dGTP, and dTTP]) being added, and is mediated by the enzyme DNA polymerase. Because both strands are copied, one round of amplification results in a complete second copy of the original target sequence. Repeated cycles of heat denaturation, hybridization of the primers, and DNA synthesis result in the exponential amplification of the target sequence. Within a few hours, more than a million copies of the sequence may be made (Fig. 21-9).

Methods of General Mutation Detection DNA Sequence Analysis DNA sequence analysis is the most sensitive and direct method for mutation detection. The most widely used method of DNA sequencing is the Sanger method, also known as dideoxy sequencing or chain termination. It is based on the use of synthetic nucleotide analogs—2,3-dideoxynucleoside triphosphates (ddNTPs). Dideoxy NTPs differ from nucleotides found in DNA in that they lack the 3′-hydroxyl group and, when integrated into a sequence, prevent the addition of further nucleotides. Because a phosphodiester bond cannot form between a dideoxynucleotide and the next incoming nucleotide, the DNA chain is terminated. DNA sequencing most commonly is performed by the method of cycle sequencing, in which the DNA region to be sequenced (which is first generated by PCR) is denatured and a short oligonucleotide is annealed to one of the template strands. DNA synthesis occurs in the presence of DNA polymerase, ddNTPs and nucleotides and starts from the 3′ end of the annealed oligonucleotide. As the DNA is synthesized, nucleotides are added onto the growing chain by the DNA polymerase; however, on occasion, a ddNTP is incorporated into the chain in place of a normal nucleotide, resulting in a chain-terminating event. At the end of the sequencing reaction multiple DNA molecules are present at such that at each nucleotide position, a proportion of molecules are terminated owing to the incorporation of a ddNTP. These products are separated by size on capillary or polyacrylamide gel electrophoresis systems, and the fluorescently labeled ddNTPs are detected. Each ddNTP is labeled with a different fluorophore. Shorter DNA molecules migrate faster than longer molecules on electrophoresis, and by analyzing the different fluorescent signal of all of the different-sized molecules, the DNA sequence can be determined. For example, ddCTP is labeled with a blue fluorophore. Everywhere a G residue exists in the template DNA, either a dCTP or a ddCTP will be incorporated into the synthesized strand. For every G residue in the template DNA, a proportion of molecules with a ddCTP at that site will be present. Each of these molecules will be of a different size, depending on where a G residue resides in the sequence, and will be distinguished by electrophoresis. The same applies for the other ddNTPs.

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Specialized DNA sequencing software exist that can convert the different fluorescent signal to different-color peaks that constitute a DNA sequence chromatogram.

Mutation Scanning Mutation scanning refers to methods used to determine the presence of a sequence change in a region of DNA (such as an exon of a gene). These methods need to be followed up by DNA sequencing, however, to determine the exact nature of the sequence change. Mutation scanning generally is less labor intensive, faster, and more cost-effective to perform than DNA sequencing and may be the method of choice when a large gene needs to be analyzed for the presence of mutations. The exons of the entire gene are subjected to mutation scanning, and only those exons that demonstrate the presence of a sequence change need to be sequenced to determine the precise nature of the sequence change. Various methods of mutation scanning exist that differ in their sensitivities of mutation detection [Cotton, 1997; Eng and Vijg, 1997; Grompe, 1993]. The general basis of most mutation scanning methods is the abnormal migration of a DNA fragment that contains a sequence change from a normal “wild-type” sequence. All are PCR-based methods—the DNA region to be studied is amplified by PCR before the different mutation scanning methods are performed. Single-Stranded Conformational Polymorphism. With the single-stranded conformational polymorphism (SSCP) technique, DNA fragments are denatured and made singlestranded. The single-stranded DNA takes on a specific conformation, depending on its sequence. A change in the DNA sequence will result in a change in the single-stranded conformation structure. Denatured fragments are separated on polyacrylamide gels under a series of differing conditions, and fragments with different conformation structures will migrate differently and can be detected. This method has an approximate sensitivity of 80% for detecting DNA sequence changes. Denaturing Gradient Gel Electrophoresis. With denaturing gradient gel electrophoresis (DGGE), DNA fragments are denatured and allowed to reanneal slowly. In the absence of a sequence change, the only DNA molecules that will be formed are homoduplexes (i.e., with no mismatch of DNA sequence between the complementary strands). In the presence of a sequence change, molecules representing both homoduplexes and heteroduplexes (i.e., a normalsense strand binds to a mutant antisense strand, or vice versa, to create a mismatch of DNA sequence at the position of the mutation) will be formed. These products are allowed to migrate on a polyacrylamide gel with an increasing gradient, and at a particular gradient, the structure of the heteroduplex molecules changes significantly and affects its migration, compared with that of the homoduplex molecules. For this technique it is important to have specialized GC clamps at the ends of the DNA fragment that enhance the difference between the heteroduplex and homoduplex molecules, and these are included in the PCR primers used to generate the DNA fragment. This method has a high sensitivity, approximately 98% to 100%. Denaturing High-Performance Liquid Chromatography. Denaturing high-performance liquid chromatography (DHPLC) also is based on the separation of DNA homoduplex from heteroduplex molecules. The

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medium of separation is a column composed of a polystyrenedivinylbenzene copolymer to which DNA binds and gets released through interaction with specific buffers. At increased temperatures, heteroduplex molecules get released from the column faster than do homoduplex molecules and therefore can be detected. This method does not require the sophisticated GC clamps of DGGE and has a high sensitivity, close to 100%. Protein Truncation Test. As the name suggests, the protein truncation test (PTT) is used for the detection of mutations that result in a protein truncation, such as a frameshift or nonsense mutation. The starting material is generally RNA that is converted to cDNA by reverse transcription PCR. In vitro transcription and translation are performed, and the protein products are labeled and separated by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis. A DNA fragment that contains a truncation mutation will result in a protein product that will be shorter in length than a normal product and therefore can be detected. This technique will not detect mutations that do not result in protein truncation, such as missense mutations.

Southern Blot Analysis Southern blot analysis, named after its inventor, E.M. Southern, has been used extensively for DNA analysis, particularly for the detection of DNA abnormalities. With the advent of PCR techniques, the use of this analytic method is decreasing. It still remains useful, however, for the detection of large deletions or duplications that affect a part or the whole of a gene. Genomic DNA is digested with a restriction enzyme, which results in the production of different-sized DNA fragments that are separated on an agarose gel by electrophoresis. The separated DNA fragments are made singlestranded by treatment with an acid and then transferred and fixed onto a nylon membrane. The single-stranded fixed DNA is hybridized with a radioactively labeled probe specific for a certain gene. A probe can be a cloned fragment of a gene or a PCR product of a gene. The probe will hybridize to that region of the DNA where it finds its complementary sequence. Excess probe is washed off, and the nylon membrane is exposed to an x-ray film to reveal where the probe has bonded. When a large deletion, duplication, or other form of DNA rearrangement occurs, either deletion or creation of restriction enzyme sites can result. Using a probe that binds to the deleted, duplicated, or rearranged area will reveal a different pattern of hybridization based on what restriction enzymes have been affected. The presence of a different hybridization pattern compared with a normal control is indicative of a change in the DNA structure.

Methods for Detecting Specific Sequence Changes (Genotyping) Different methods exist for the detection of specific mutations in genes, especially point mutations or insertions and deletions of a few bp. These methods are useful for the detection of the common mutations present in diseases such as sickle cell anemia, cystic fibrosis, and hereditary hemochromatosis. These techniques are possible only when the base sequence and precise point mutation responsible for the disease phenotype are known.

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Allele-Specific Oligonucleotide Hybridization For allele-specific oligonucleotide (ASO) hybridization, separate ASO probes complementary to either the normal or a specific mutant allele are synthesized. The probes consist of the point mutation or its normal counterpart and 9 to 12 base pairs flanking it on either side, for a total length of 19 to 25 base pairs. The probes then are hybridized to the DNA source under stringent conditions. Because the probes are short, they are highly sensitive to sequence changes at even a single nucleotide. A probe complementary to the normal allele will hybridize to the normal allele but not to the mutant allele, and vice versa. Thus, DNA from a person homozygous for the normal gene will hybridize to the ASO probe complementary to the normal DNA sequence but not to the probe complementary to the point mutation. DNA from persons homozygous for the mutation will hybridize to the ASO probe complementary to the mutation but not to the normal probe. Only DNA from heterozygotes will hybridize to both probes. It is important to remember that DNA from persons who are heterozygous for different mutations in the same gene—compound heterozygotes—also will hybridize to the normal probe. Several different formats have been developed to detect ASO probes ranging from radioactivity to chemiluminescence to fluorescence and can be performed in both solid and liquid phases.

Single-Base Extension Oligonucleotide primers of approximately 20 bp are designed to hybridize just upstream or downstream of the nucleotide to be genotyped, and an extension reaction— more specifically, a single-base extension (SBE) reaction— is performed in the presence of ddNTPs. In the case of a normal sequence, a ddNTP corresponding to the complementary normal nucleotide is added to the primer; in the case of a mutation, a ddNTP corresponding to the complementary mutant nucleotide is added to the primer. The ddNTPs generally are labeled with different fluorochromes, allowing their detection. In a person homozygous for a normal gene, extension will occur only with the ddNTP corresponding to the normal allele, whereas in a person homozygous for a mutated gene, extension will occur only with the ddNTP corresponding to the mutated allele. A heterozygous person will have both normal and mutated extension products. Several different formats have been developed to detect SBE products and can be performed in both solid and liquid phases.

DNA Arrays In DNA arrays, hundreds to thousands of DNA targets are arranged (arrayed) on a solid medium such as a glass slide or microchip. DNA arrays are of two main types—genotyping arrays and sequencing arrays. Genotyping arrays consist of hundreds to thousands of different ASO probes or SBE primers arrayed on a chip that allows the genotyping of a large number of different loci simultaneously. DNA sequencing arrays consist of a series of hundreds of thousands of approximately 20-bp oligonucleotides, spanning the length of a gene, that are arranged in a tiling fashion. For each nucleotide to be sequenced, four oligonucleotides are present that differ only at the central position and have an A, C, G, or T. Digested DNA is fluorescently labeled and hybridized to the tiled oligonucleotide chip under stringent con-

ditions. DNA hybridizes to those oligonucleotides that correspond to the correct sequence and the fluorescent signal read from which the DNA sequence is deciphered. DNA sequencing and genotyping arrays are available for several genes and are still largely used for research, although some clinical applications have been initiated. Expression arrays are different and refer to cDNA arrays to which RNA is hybridized and are used to determine the expression profile of hundreds of genes simultaneously. This technique is currently used only in the research setting.

Restriction Enzyme Analysis Some mutations result in the destruction or creation of a restriction enzyme site in the DNA sequence. PCR amplification of the region of interest, followed by digestion of the genomic DNA with the appropriate restriction enzyme and gel electrophoresis, can be performed to determine the presence or absence of a mutation that affects a restriction enzyme site. Destruction or creation of a restriction enzyme site will result in a different-sized DNA fragment compared with a normal control fragment. The sickle cell anemia mutation and the hereditary hemochromatosis mutation both affect restriction enzyme sites.

DNA Methylation Analysis DNA methylation analysis can be performed for the detection of abnormalities in imprinted genes. Of the two alleles of an imprinted gene, one allele is methylated at the promoter (silenced allele), and the other is unmethylated (expressed). Any aberration that affects the imprinting status (e.g., deletion or uniparental disomy) will affect the methylation pattern. Methylation can be assayed with the use of methylationsensitive restriction enzymes followed by Southern blot analysis or by methylation-specific PCR techniques. For methylation-specific PCR assays, genomic DNA is treated with the chemical sodium bisulfite that converts all cytosine molecules to thymidine, except if methylated. The methylated cytosine molecules are left unchanged. As a result, a methylated sequence will be changed in its nucleotide content, as compared with an unmethylated sequence after bisulfite treatment, and can be distinguished by the use of specific PCR primers. Genes subject to X-inactivation also are methylated and can be detected using the same method.

CLINICAL CYTOGENETICS Chromosome abnormalities may involve either the number or the structure of chromosomes. The former are considered genome mutations and the latter, chromosome mutations. The mechanisms involved in the two major types of mutations are quite different, but both may result in loss or gain of DNA in the nucleus. Both types may involve all of the cells of an organism or only a proportion. When only a proportion of cells are involved, the abnormality is termed mosaic, discussed in detail later in this section.

Abnormalities of Chromosome Number For germ and somatic cells, the normal chromosome complement consists of the haploid and the diploid number,

Dobyns and Das / Introduction to Genetics

Aneuploidy Aneuploidy is defined as any chromosome complement that deviates from a multiple of the haploid number. In most cases, it consists of either monosomy, which is defined as loss of an entire chromosome, or trisomy, which refers to gain of an entire chromosome. Aneuploidy is the most common and clinically significant type of chromosome disorder, occurring in 3% to 4% of all recognized pregnancies. Both monosomy and trisomy of autosomes are lethal during early pregnancy in a large majority of affected fetuses. Autosomal monosomy is uniformly lethal except for a few reports of liveborn children with monosomy 21. Monosomy X is prenatally lethal in most affected fetuses, but many survive and will have the phenotype of Turner’s syndrome. The effects of trisomy vary depending on the chromosome involved. Trisomy 16 is the most frequent autosomal trisomy at conception but is uniformly lethal before birth. The most common type of trisomy in liveborn infants is trisomy 21, which is the chromosome abnormality observed in 95% of children with Down syndrome. The only other autosomal trisomies observed at appreciable frequencies are trisomy 13 and trisomy 18, although trisomy 8 may be observed in mosaic form. The most common mechanism is nondisjunction, which is the failure of a pair of chromosomes to separate correctly during one of the two stages of meiosis, usually meiosis 1. The consequences of nondisjunction during meiosis 1 and 2 are somewhat different. If the error occurs during meiosis 1, the unbalanced gamete with 24 chromosomes contains both the maternal and the paternal members of the pair. If the error occurs during meiosis 2, the unbalanced gamete will contain either the maternally or the paternally derived chromosome but not both.

Mechanisms Some progress has been made recently in current understanding of the mechanisms causing or at least predisposing to structural chromosome rearrangements. Many appear to occur randomly, with no evidence of recurrent breakpoints. For example, no consistent breakpoints have been found for the interstitial deletions and reciprocal translocations involving chromosome band 17p13.3 [Cardoso et al., 2003]. In many other locations, the small duplicated regions known as LCRs can mediate several different types of rearrangements. These were first identified as the cause of common deletion or microdeletion syndromes, such as deletion (del) 2q13 with juvenile nephronophthisis and Joubert’s syndrome–related disorder [Parisi et al., 2004; Saunier et al., 2000], 7q11.23 in Williams’ syndrome [Osborne et al., 2001; Urban et al., 1996], del 15q11.2-q13

Site of crossover

Normal

Occasionally, fetuses with three or four times the normal haploid number of chromosomes have been observed. These abnormal chromosome complements are called triploidy (3n) and tetraploidy (4n). The few children who are liveborn survive only briefly after birth, unless the abnormality is mosaic (i.e., involves only a proportion of their cells). Failure of a maturational division in either egg or sperm results in triploidy, whereas failure of completion of an early division of the zygote causes tetraploidy.

Del Dup

Triploidy and Tetraploidy

gain of DNA sequence. The phenotypic effects often are severe. The chromosomes involved in the reconfiguration are known as derivative chromosomes. Many different types of rearrangements have been reported, as described in the following sections. Only those derivative chromosomes that contain a functioning centromere and telomeres, however, are stable and capable of being transmitted unaltered to daughter cells during mitosis or meiosis. Derivatives lacking a centromere or telomere are unstable and are lost during cell division. Some regions of the genome, such as 8p, contain a noncentromeric sequence that is sufficiently similar to function as a “neocentromere” during cell division [Giglio et al., 2001].

Normal

respectively. Any deviation from these numbers is associated with significant abnormalities. The most common types result from abnormal segregation of chromosomes in germ cells; epidemiologic studies have estimated a rate of abnormal segregation of approximately 1 per 25 to 50 meiotic cell divisions.

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Abnormalities of Chromosome Structure Structural chromosome rearrangements consist of loss, gain, or altered position of segments of chromosomes, and many different types have been recognized. The estimated frequency is about 1 per 1700 cell divisions, making them much less frequent than aneuploidy. Rearrangements are termed balanced if the chromosome complement has a normal amount of genetic information, regardless of its location. They are termed unbalanced if there has been either loss or

FIGURE 21-10. Drawing of a recombination event between homologs resulting from mispaired low copy repeats (LCRs) during meiosis 1. On the left side of the drawing, the far right and far left chromatids have paired correctly, and the middle two chromatids have paired incorrectly. A crossover within the mispaired region results in one daughter chromosome with a duplication and another with a deletion (depicted on the right side of the drawing). The dark squares represent the LCRs.

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in Angelman’s syndrome and Prader-Willi syndrome [AmosLandgraf et al., 1999], del17p12 in hereditary neuropathy with predisposition to pressure palsies [Chance et al., 1994], del17p11.2 in Smith-Magenis syndrome [Chen et al., 1997], and del22q11.2 in DiGeorge’s syndrome/ velocardiofacial syndrome [McDermid and Morrow, 2002]. The same LCRs are associated with duplications of the same regions, including duplication 15q11.2-q13 [Mohandas et al., 1999], 17p12 [Pentao et al., 1992], and 17p11.2 [Potocki et al., 2000]. A simple diagram of this mechanism is shown in Figure 21-10. Many of the LCRs are inverted with respect to each other, which can lead to very complex combinations of deletions and duplications. This can occur for LCRs on the same chromosome, as seen with Williams’ syndrome and some X chromosome rearrangements [Giglio et al., 2000; Osborne et al., 2001], or between homologous chromosomes. The latter appears to be more common when two matching LCRs on homologous chromosomes are inverted with respect to each other, a novel type of polymorphism [Giglio et al., 2001]. Similar mechanisms also can predispose to structural rearrangements between completely different chromosomes involving either an LCR or a gene cluster such as olfactory receptor clusters [Giglio et al., 2002; Spiteri et al., 2003].

Balanced and Unbalanced Chromosomal Rearrangements As noted previously, structural chromosome rearrangements that result in no net loss or gain of genomic sequence are balanced, whereas those that do result in a net loss or gain of material are unbalanced. Persons with balanced rearrangements usually are normal, unless one of the chromosomal breaks disrupts an important gene. More recent studies, however, have found that chromosome rearrangements that appear balanced often have submicroscopic loss or gain of material and so are actually unbalanced [Astbury et al., 2004b], and some chromosome rearrangements are more complex than standard chromosome analysis suggests [Astbury et al., 2004a]. A

Specific Types of Chromosome Rearrangements The most common structural rearrangements include terminal and interstitial deletions and duplications, reciprocal and robertsonian translocations, inversions, and rings. Examples of most of these are shown in Figure 21-11.

Deletions and Duplications A deletion consists of loss or gain of a chromosome segment. Deletions may be either interstitial or terminal, with terminal deletions including the telomere (see Figs. 21-8 and 21-11D), whereas most duplications are interstitial. Most interstitial deletions and duplications result from unequal crossing over in LCRs (see Fig. 21-10). Terminal deletions are more likely to result from simple chromosome breakage, although some apparently terminal deletions prove to be interstitial deletions in which one breakpoint happens to be close to the telomere. Any carrier of a deletion is hemizygous for the information on the corresponding segment of the normal homolog. Thus, small but cytogenetically visible deletions involving critical genes occasionally produce single-gene phenotypes such as lissencephaly or retinoblastoma. Duplicated segments usually are adjacent to each other and may be in the same orientation (direct dup), or inverted (inverted dup) with respect to one another. In general, the phenotypic effects of duplications are less severe than the effects of deletion of a similar segment. Small duplications also can result in single-gene phenotypes such as CharcotMarie-Tooth neuropathy [Chance et al., 1994], although this is recognized less often than with deletions.

Inversions Inversions are segments within a chromosome that are inverted with respect to the normal orientation and result from crossovers within existing duplicated segments (LCRs) or from two breaks within a single chromosome, followed by

B

C

D

E

FIGURE 21-11. Partial karyotypes of structural chromosome rearrangements. A, Pericentric inversion: 46,XX,inv(1)(p36.1q32). The pair on the left are stained for G bands, and the pair on the right, for C bands (centromere bands). B, Reciprocal translocation: 46,XX,t(2;4)(p22.2;q35.2). C, Robertsonian translocation: 45,XX,t(13q14q). D, Interstitial deletion: 46,XY,del(13)(q21.3q31). E, Ring: 46,XY,r(17)(p13.3q25.3). (Karyotypes in A from Johnson DD, Dobyns WB, Gordon H, et al. Hum Genet 1988;78:315; those in B, C, and D courtesy of B.A. Hirsch, Department of Laboratory Medicine and Pathology, University of Minnesota Medical School; karyotype in E from Dobyns WB, Stratton RF, Parke JT, et al. J Pediatr 1983;102:552.)

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inversion of the intervening segment and repair of the breaks. When the inverted segment includes the centrosome, the rearrangement is described as a pericentric inversion (see Fig. 21-11A), whereas rearrangements in which the inverted segment does not include the centrosome are designated as paracentric inversions. Both types of inversions may result in production of unbalanced gametes because of the effects of recombination within the inverted segment. With pericentric inversions, a loop is formed between the inverted chromosome and its homolog during meiosis 1 (Fig. 21-12). Recombination is somewhat but not completely suppressed within inversion loops, so crossovers are common in larger loops.

3

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4 5

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FIGURE 21-12. The effect of recombination within the loop of a pericentric inversion. A, A normal chromosome is depicted on the right, with loci 1 to 7 in order and the centromere located between loci 3 and 4. A pericentric inversion is depicted on the left, with the segment containing loci 3 to 5 and the centromere inverted. B, Pairing of the normal and inverted chromosomes during meiosis 1, with a crossover occurring within the inversion loop in the middle two chromatids. C, The four types of gametes produced after completion of meiosis include a normal chromosome, a derivative chromosome with duplication of the distal short arm and deletion of the distal long arm (dup p), the reverse derivative chromosome with duplication of the distal long arm and deletion of the distal short arm (dup q), and a balanced pericentric inversion.

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Recombination within a pericentric inversion loop produces derivative chromosomes in which segments distal to the breaks are either duplicated or deleted (see Fig. 21-12C). The effects on the phenotype are inversely proportional to the size of the inversion. Thus, the distal segments typically are large with small pericentric inversions, and most unbalanced offspring are spontaneously aborted. Liveborn children with birth defects are more likely with larger inversions that lead to relatively small distal segments. Crossovers within a paracentric inversion loop, which commonly result from crossovers within LCRs, result in acentric or dicentric chromosomes. Acrocentric chromosomes

Inversion

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Dup q

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C 4

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1 2 6 7

B

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are quickly lost during subsequent rounds of cell division. Dicentric chromosomes inactivate one of the two centromeres and are retained. For both, the loss or gain of chromosomal material and genes is so great that almost all affected embryos are spontaneously aborted, unless a large part of the derivative chromosome happens to break off and become lost. This mechanism has been proved and may be more common than appreciated [Giglio et al., 2002].

Reciprocal Translocations Reciprocal translocations consist of breaks in nonhomologous chromosomes, with a reciprocal exchange of the broken segments (see Fig. 21-11B). Usually only two chromosomes are involved, but complex translocations involving three or more chromosomes have been described and likely are more common than standard chromosome analysis has suggested [Astbury et al., 2004a]. Population studies have

Normal

Carrier t(3;6) Alternate

detected reciprocal or robertsonian translocations in about 1 in 500 newborns. Reciprocal translocations often result in the production of unbalanced gametes. During meiosis 1, the derivative chromosomes and their normal homologs form a quadriradial shape that may separate into pairs in one of three ways: alternate, adjacent 1, and adjacent 2 segregation. Alternate segregation produces balanced gametes that have either normal chromosomes or both derivatives, which are therefore balanced. Adjacent 1 segregation produces unbalanced gametes in which homologous centromeres separate into different daughter cells. It results in duplication of the distal segment of one derivative chromosome and deletion of the distal tip of the other. In most translocation carriers, alternate and adjacent 1 segregation account for a large majority of the gametes (Fig. 21-13). Adjacent 2 segregation also produces unbalanced gametes. In this uncommon

der(6)

der(3) Adjacent 1

FIGURE 21-13. Diagram of the alternative types of segregation and gametes produced in the carrier of a reciprocal translocation between the short arms of chromosomes 3 (solid black) and 6 (hatched). The top line represents the parental chromosome pairs, the middle line represents the four types of gametes produced by the father, and the bottom line represents four possible chromosome combinations that may be observed in offspring. Alternate segregation (depicted on the left) produces offspring with either normal chromosomes or the balanced translocation. Adjacent 1 segregation (depicted on the right) produces offspring with unbalanced karyotypes. Children with the derivative 6 karyotype [der(6)] have deletion of the distal segment of 6p and duplication of the distal segment of 3p. Children with the derivative 3 karyotype [der(3)] have deletion of 3p and duplication of 6p. In both alternate and adjacent 1 segregation, homologous centromeres pass to different daughter cells. In adjacent 2 segregation (not depicted), homologous centromeres pass to the same daughter cells, leading to even greater chromosomal imbalance.

Dobyns and Das / Introduction to Genetics

mechanism, homologous centromeres pass to the same daughter cell. The resulting nondisjunction produces 3:1 and even a 4:0 segregation. Reciprocal translocations often are detected in normal adults evaluated because of repeat fetal loss or after the birth of a child with multiple congenital anomalies caused by transmission of the translocation in unbalanced form. Apparently balanced reciprocal translocations sometimes are found in children with birth defects or abnormal development. In these instances, the abnormal phenotype usually results from either submicroscopic loss of genetic material or disruption of a gene at one of the breakpoints [Astbury et al., 2004b].

Robertsonian Translocations Robertsonian translocations involve two acrocentric chromosomes that fuse in or near the centromere region, with loss of the short arms (see Fig. 21-11C). Because the short arms contain repetitive DNA elements, especially rRNA, no phenotypic effects result. Carriers of a robertsonian translocation on chromosome 21 have a high risk of producing a child with translocation Down syndrome.

Insertions Insertions occur when a small segment of a chromosome is removed and inserted into a different region on the same or another chromosome. If the segment is inserted with the same orientation with respect to the centromere, it is known as a direct insertion. If it is inserted with the reverse TABLE 21-5 Examples of Chromosomal Abnormalities Using Standard Nomenclature (Short System) Rearrangement

Karyotype

Genome Mutations Triploidy Monosomy Trisomy

69,XXX 45,X (Turner’s syndrome) 47,XX,+21 (Down syndrome)

Deletion Terminal Interstitial

46,XY,del(8)(p21.1) 46,XX,del(17)(p11.2p11.2)

Duplication Direct Inverted

46,XY,dir dup (2)(p14p23) 46,XX,inv dup (11)(p12p15)

Paracentric Inversion Balanced Unbalanced

46,XX,inv(1)(p32p36.1) 46,XX, dup q, inv(1)(p32p36.1)

Pericentric Inversion Balanced Unbalanced

46,XX,inv(1)(p36.1q32) 46,XY,dup(q),inv(1)(p36.1q32)mat

Reciprocal Translocation Balanced 46,XY,t(–17,+der(17),t(7;17)(p22.3;p13.3)pat Ring 46,XY,r(17)(p13.3q22.3) Robertsonian Translocation Balanced 46,XX,rob(13;21) Unbalanced 46,XY,–13,+der(13),rob(13;21)mat del, deletion; der, derivative; dir, direct; dup, duplication; inv, inversion; mat, maternal; pat, paternal; r, ring; rob, robertsonian translocation; t, translocation.

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orientation, it is called an inverted insertion. Insertions are rare because three separate chromosomal breaks are required. Segregation during meiosis can produce either abnormal offspring, with duplication or deletion of the inserted segment, or normal offspring and balanced carriers.

Rings Rings—ring chromosomes—are formed when a chromosome undergoes two breaks, usually one in each arm, and the broken ends are rejoined (see Fig. 21-11E). The two segments distal to the breaks are lost, resulting in deletion of both telomeres and adjacent regions of both the short and the long arms of the chromosome. Rings may not segregate properly during mitosis and meiosis, especially if a crossover occurs. Crossover often results in breakage followed by fusion, which may produce larger or smaller rings.

Isochromosomes and Dicentrics Isochromosomes are chromosomes in which one arm is missing and the other is duplicated as the result of misdivision of the centromere during meiosis 2. Isochromosomes also can result from translocation of an entire arm to its homolog with a breakpoint adjacent to the centromere. The most commonly observed isochromosome involves Xq. Dicentrics are rare chromosomes in which two segments, each containing a centromere, fuse end to end. They tend to break during mitosis because of the double centromeres.

Cytogenetic Nomenclature Detailed rules regarding nomenclature of chromosomes and chromosomal abnormalities have been published [ISCN, 1995]. Examples of most of the major types of abnormalities are listed in Table 21-5 using standard nomenclature. Note that breakpoints on the same chromosome are not separated by any punctuation, whereas breakpoints on different chromosomes are separated by a semicolon.

MUTATIONS AND GENETIC DISEASES The number of genetic changes causing disease, including neurologic disorders, is far too great to cover here, although many of these are reviewed in other chapters in this book. Here we review the general mechanisms that lead to genetic diseases, starting with a definition of mutation. As a very basic definition, a mutation is simply a permanent change in the DNA of an individual. The change most often is a change in the nucleotide sequence anywhere in the genome, although some chemical modifications of DNA can result in mutations as well. Such modifications are known as epigenetic mechanisms. Genetic diseases are caused by mutations that adversely affect function of one or more genes. The same is true for many types of cancer.

Classes of Mutations Mutations have been subdivided into three main types: genome, chromosome, and gene mutations. They may occur in either somatic or germ cells, although only germ cell mutations can be transmitted to offspring. All three occur often enough for affected individuals to be observed in clinical practice.

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Genome and Chromosome Mutations Abnormalities of chromosome number, including triploidy, tetraploidy, and aneuploidy, are classified as genome mutations. Similarly, structural rearrangements are classified as chromosome mutations. Both of these were reviewed in the preceding section. Genome and chromosome mutations are rarely perpetuated to the next generation because most result in spontaneous abortions. Thus, the frequencies cited are probably underestimates.

Gene Mutations Gene mutations differ from genome and chromosome mutations because the segment of DNA involved is much smaller and the mechanisms are different. The most common types are base pair substitutions and small deletions or insertions that can be caused by an error during DNA replication or by base changes induced by extrinsic agents referred to as mutagens. Because genome and chromosome mutations usually are lethal, most significant heritable mutations are gene mutations.

DNA Replication Errors DNA replication normally is an accurate process. The DNA polymerases (see Table 21-2) insert an incorrect base only once in every 10 million bp. A series of DNA repair enzymes exist that are able to recognize and replace noncomplementary bases, correcting more than 99.9% of errors. The overall mutation rate is therefore only 10−10 per base pair per cell division. The human genome consists of about 6 × 109 base pairs, so this mutation rate results in less than 1 bp mutation per cell division. Nevertheless, an estimated 1015 cell divisions occur during the lifetime of an adult human. Thus, thousands of new mutations occur at virtually every position in the genome. Not surprisingly, inherited defects in DNA replication and repair enzymes lead to a striking increase in the frequencies of all types of mutations. Most of the mutations occur in somatic cells, where they may cause cancer or a genetic disease affecting only part of the body, such as segmental neurofibromatosis. Fewer mutations occur in germ cells. During oogenesis, female germ cells undergo mitosis approximately 22 times and begin meiosis only once during fetal life. The cells are suspended in meiosis from fetal life till shortly before ovulation during the reproductive years. Spermatogenesis consists of approximately 30 mitoses from conception until puberty and approximately 20 to 25 per year thereafter. Thus, the opportunity for mutations is expected to be far greater for sperm than for ova. This phenomenon has been confirmed in several genetic disorders, such as neurofibromatosis type 1, achondroplasia, and hemophilia A. It has been estimated that as many as 1 in 10 sperm in healthy males may carry a new deleterious mutation. Most are recessive or lethal and therefore not apparent in liveborn children.

Mutation Rate The mutation rate for any given gene or other DNA segment depends on both its size and its location. The location may be important because certain areas of the genome are known to be “hot spots” for recombination. The average mutation rate is about 1 × 10−6 mutation per locus per generation, but the rate varies by more than a thousand-fold for different genes. For example, the number of new mutations

per 106 gametes is 40 to 100 for Duchenne muscular dystrophy and neurofibromatosis 1, but only 2 to 5 for aniridia and hemophilia B. These statistics include only mutations causing genetic diseases. The rate of change of protein polymorphisms suggests a rate as high as 6 × 10−6 per locus per generation (a locus is the position of a gene on a chromosome).

Specific Types of Gene Mutations The development and widespread use of modern molecular techniques have led to the discovery of specific mutations at many different loci. From among these, many different types of mutations have been recognized, all of which have the potential for causing genetic diseases. They may be divided by size into single and multiple base changes. The latter may involve only one or a few bases or may involve millions of base pairs. In any specific gene, mutations are almost always heterogeneous, although some types may be more common than others. Thus, the specific mutations in unrelated persons with the same genetic disease often are different. A few notable exceptions to this rule have been identified, such as achondroplasia, which almost always is caused by a specific single base change in the fibroblast growth factor receptor 3 gene [Bellus et al., 1995].

Nucleotide Substitutions Point mutations or single-base substitutions represent one of the most common types of mutation. Most are related to an error in DNA synthesis by the enzyme DNA polymerase that was not corrected by DNA repair enzymes. Some combinations of nucleotides are mutation prone, however. More than 30% of point mutations found in some genetic diseases are the result of cytosine-to-thymine transitions, which are caused by methylation of cytosine residues to 5-methylcytosine, especially cytosine residues occurring as the first base in a 5′-CG-3′ dinucleotide pair. The latter then undergoes spontaneous deamination to thymidine. Thus, the 5′-CG-3′ doublet represents a “hot spot” for mutation in the human genome.

Deletions, Duplications, and Insertions The remainder of mutations consist of loss or gain of nucleotide bases somewhere in the genome; a variety of mechanisms for such changes are known. A deletion consists of any loss of DNA sequence, whereas a duplication consists of a second copy of a DNA sequence that is usually located immediately adjacent to the first copy. An insertion consists of a DNA sequence that has been removed or copied from one location and moved to a nonhomologous region elsewhere on the same chromosome or to a different chromosome. Deletions, duplications, and insertions that involve one or a few base pairs can be detected only by nucleotide sequencing. Larger deletions and duplications may be detected by several of the methods described earlier including direct sequencing, Southern blot analysis, FISH, and CGH.

Effects of Mutations on Gene Function The effect of mutations on gene function depends as much or more on the specific location of the mutation as on the size. Mutations that occur in DNA outside functioning genes

Dobyns and Das / Introduction to Genetics

usually have no consequences. Mutations within the boundaries of a gene may inactivate it or have little or no effect, depending on the nature of the change.

Missense Mutations A point mutation within the coding region of a gene can alter the genetic code by changing the nucleotide triplet and cause the replacement of one amino acid by another in the gene product, thus altering function of the gene product. Such mutations are called missense mutations and do not change the reading frame of the DNA sequence. The bestknown example is the A-to-T substitution in the sixth codon of the β-globin gene, which causes sickle cell anemia, by substituting valine for glutamic acid in the β-globin protein chain. Not all mutations within coding regions of a gene result in a missense mutation, however. All but 2 of the 20 amino acids are specified by more than one codon, most often differing in the third or “wobble” position of the triplet. The gene product will be identical if the new triplet codes for the same amino acid.

Nonsense (Chain Termination) Mutations Mutations that generate one of the three stop codons result in premature termination of translation, whereas those that alter a stop codon allow translation to continue until the next stop codon is reached. Those mutations that result in a premature stop codon are called nonsense mutations. In general, these mutations have no effect on transcription (DNA to RNA), but the shortened polypeptide may have lost critical functional domains of the protein, or the mRNA may be so unstable that it is rapidly degraded in the cell. The latter process is known as nonsense-mediated mRNA decay, a process by which mRNA species containing premature termination codons are recognized and degraded before translation, although this typically spares truncation mutations in the last coding exon [Frischmeyer and Dietz, 1999]. Both base substitutions and nucleotide loss or gain mutations may result in nonsense mutations.

RNA Splicing Mutations The sequence surrounding intron splice sites is highly conserved, and mutations of key nucleotides frequently prevent or reduce efficiency of splicing. The key nucleotide sequences at most splice junctions are shown in Figure 21-4. Splicing mutations may either inactivate existing splice sites or create new ones. In the first type, the mutation alters the splice donor, branch, or splice acceptor site, resulting in failure to correctly splice the intron at that site. This failure results in a large insertion of nucleotides that normally are not translated into the processed mRNA. This insertion is almost certain to introduce a stop codon within the next hundred or so codons, because 3 of the possible 64 triplet combinations are stop codons. In the second type, mutations within the intron create alternative splice donor or acceptor sites that compete with the normal splice sites during mRNA processing. Thus, a proportion of the mature mRNA will contain incorrectly spliced intron sequences. Both base substitutions and nucleotide loss-or-gain mutations may result in splicing mutations. One example of the first type is a G-to-C transition in the first position of the intron at the donor splice site in the

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hexosaminidase A gene found in many Ashkenazi Jewish patients with Tay-Sachs disease [Nussbaum et al., 2001], as shown here: Normal allele: Tay-Sachs allele:

5′–CCAGGCTCTGgtaagggt–3′ 5′–CCAGGCTCTGctaagggt–3′

In this example, the bases in the exon are capitalized, whereas those in the intron are not, and the mutation is underlined.

Frameshift Mutations Small nucleotide loss-or-gain mutations may alter the reading frame of the mRNA product from the point of the mutation on, which results in a completely different amino acid sequence at the carboxyl end of the protein product or premature chain termination if a stop codon is encountered in the new reading frame. Any loss-or-gain mutation that involves a multiple of three bases maintains the reading frame, whereas a mutation that does not involve a multiple of three nucleotides changes the reading frame. Larger deletions that include one or more introns also may cause a frameshift mutation, because exon/intron splice sites may occur at any point in the reading frame, thereby splitting codons. If the exon just downstream from the deletion normally begins at a different position in the triplet than the deleted intron, the reading frame will be changed. By contrast, base substitutions do not cause frameshift mutations. Deletions and insertions cause dysfunction of the gene more often than point mutations because of the possibility of a frameshift. One of the best-known frameshift mutations is a single base deletion in the ABO blood group locus that results in the nonfunctional O allele. The deletion alters the reading frame at codon 86 until a premature stop codon is reached 30 codons later. The stop codon is normally out of frame and is therefore not read. With some intermediate-size deletions of approximately 1 kb to 1 Mb, one or more exons of a gene may be duplicated or deleted. About two thirds of these will change the reading frame and result in a frameshift mutation. Those that maintain the reading frame produce truncated products that may or may not retain function. These relatively small deletions and duplications are too small to be seen with chromosome analysis or FISH and cannot be found by sequencing, which is not sensitive to dosage (recall that all autosomal genes and X-linked genes in females have two copies of each gene). These may be rare or common mechanisms of mutation. For example, small deletions and duplications are the most common mutational types for Duchenne muscular dystrophy and Becker muscular dystrophy, both caused by mutations of the dystrophin or DMD gene. These are simple to detect for X-linked diseases in males, because only one gene copy is present. When any autosome of the X chromosome in a female is involved, the mutation can be detected by other methods, such as quantitative PCR assay.

Transcriptional Control Mutations Mutations involving promoter sequences in the 5′ UTR or other regulatory sequences in the 3′ UTR of a gene may result in a significant decrease in the amount of mature, processed mRNA produced. Both base substitutions and

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nucleotide loss-or-gain mutations may result in transcriptional control abnormalities.

single allele or a pair of alleles. Only a single allele is present for most genes on the X chromosome in males, who have only one X chromosome. A pair of alleles is present for all genes on the autosomes, and for a subset of genes on the X chromosome located in “pseudoautosomal” regions, which have functional homologs on the Y chromosome. The observable expression of the genotype is the phenotype. Penetrance has been defined as the percentage of persons with a particular genotype who have the expected phenotype; this is an all-or-none phenomenon. Expressivity is defined as the extent to which a genetic trait or disease is expressed and may vary greatly between affected persons. The proband is the affected family member through whom a family is identified; the consultand is the person in the family who seeks advice, regardless of whether affected or not. A pedigree is a diagram of the family history that shows the family members, their relationships to the proband, and their status with regard to the hereditary condition. Some of the symbols used for pedigrees in medical genetics are illustrated in Figure 21-14. A more detailed standardized nomenclature has been proposed for publication of pedigrees [Bennet et al., 1995]. The most widely recognized patterns of inheritance are single-gene or “mendelian” patterns, which include autosomal-dominant, autosomal-recessive, and X-linked modes of inheritance; example pedigrees are shown in Figure 21-15. All of these result from mutations in a single gene. The disorder or trait is autosomal if located on human chromosomes 1 to 22 and X-linked when located on the X chromosome. The only true Y-linked trait is male sex determination (the SRY gene). Autosomal traits are considered dominant when expressed in both heterozygotes and homozygotes, and recessive when expressed only in homozygotes; neither of these terms really fits with X-linked

PRINCIPLES OF MEDICAL GENETICS Several principles of genetics derived from the chromosomal and molecular basis of heredity form the basis for the different patterns of inheritance observed in genetic diseases. A working understanding of the principles of inheritance is important for understanding the genetic diseases encountered in pediatric neurology clinics, for formulating an optimal management approach to patients with these diseases, and for providing accurate genetic counseling. The simplest and best-known patterns of inheritance involve mutations of single genes; however, more complex patterns of inheritance likely are more common. Here we review some of these principles and examine the basis for genetic counseling.

Patterns of Inheritance A discussion of inheritance requires familiarity with a special vocabulary. As reviewed previously, a gene is a sequence of DNA that is required for production of a functional product. The position of a gene on a chromosome is known as its locus. The alternative forms of a gene that may occupy a given locus are known as alleles. Different alleles typically result from one or more minor differences in nucleotide sequence. When both alleles at a given locus are identical, the person is said to be homozygous for that trait. When the alleles are different, the person is described as heterozygous. When only one allele is present, the person is hemizygous. The genetic constitution of an individual is the genotype. At any given locus, the normal genotype consists of either a

4

2

Male

Marriage

Female

Extramarital mating

Sex unspecified

Divorce

Number of children of sex indicated

Consanguineous mating

Affected Monozygotic twins

Heterozygotes for autosomal trait Carrier of X-linked recessive trait

Dizygotic twins

Proband ? Twins of unknown zygosity

Deceased individual Prenatal death

1

I

2

Miscarriage Adopted into a family II

1

2

Numbering individuals in pedigrees 3

Proband is II-2

Adopted out of a family No offspring

FIGURE 21-14. Common symbols used in pedigrees.

Dobyns and Das / Introduction to Genetics AD

AR

Heterozygous affected

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XL

Carrier of X-linked disorder

Homozygous or hemizygous affected FIGURE 21-15. Examples of autosomal-dominant (AD), autosomal-recessive (AR), and X-linked (XL) pedigrees.

inheritance, as reviewed later on. The pattern of single-gene inheritance is modified in special cases in which mutations involve genes subject to imprinting or X inactivation, or involve only a proportion of cells in the body or affected tissue. Finally, many diseases have more complicated inheritance.

Autosomal-Dominant Inheritance The most important attributes of autosomal-dominant inheritance are expression of the trait in heterozygotes and male-to-male transmission (Fig. 21-15). The autosomaldominant pattern may be recognized because (1) the trait or disease typically appears in every generation, except that it may arise by new mutation in the first affected family member, (2) any child of an affected person has a 50% risk of inheriting the trait, (3) the offspring of unaffected family members also are unaffected, and (4) the trait may be transmitted by a parent of either sex to a child of either sex, and specifically may be transmitted from father to son, which distinguishes it from X-linked inheritance. Autosomal dominant inheritance is readily identified in most families but may be difficult to discern in others. When the disease occurs as a result of a new mutation, no relatives are affected. With reduced penetrance, low expressivity, and late age at onset, other affected family members may go unrecognized. Among the best examples for each of these characteristics are myotonic dystrophy and Huntington’s disease. Finally, incorrect information regarding family relationships, such as false paternity, may complicate interpretation of the pedigree. Most persons affected by a disorder of autosomaldominant inheritance are heterozygous, but rarely a homozygous person is encountered. Generally, the phenotype in homozygous persons is significantly more severe than in heterozygous persons. For example, one child born to parents who each had hereditary motor and sensory neuropathy type I had a much more severe neuropathy consistent with Dejerine-Sottas disease, or hereditary motor and sensory neuropathy type III [Killian and Kloepfer, 1979]. The best-known exception to this rule is Huntington’s disease, in which persons heterozygous for this trait cannot be distinguished from homozygotes.

Autosomal-Recessive Inheritance The most important attributes of autosomal-recessive inheritance are expression in homozygotes and equal gender distribution (see Fig. 21-15). This pattern may be recognized by the following four characteristics: (1) the trait or disease may affect multiple siblings but not parents, children, or other relatives, except in highly inbred populations, (2) each full sibling of an affected person has a 25% chance of inheriting the trait, (3) the parents are more likely than usual to be related, and (4) with rare exceptions, males and females are equally likely to be affected. In Western societies, a child with a disorder of autosomal-recessive inheritance may be the only affected person in the family owing to small family size and a tendency for parents of affected children to have fewer children after birth of a child with a genetic disease. This practice does not hold true in many other cultures, especially those with inbred populations. When the frequency of a rare recessive allele is relatively high within a family or population, the disease may appear in more than one generation. This pattern is known as pseudodominant inheritance. Some genes on the X chromosome have functional homologs on the Y chromosome, and traits or diseases associated with these genes will behave in the same manner as for autosomal loci. This pattern is known as pseudoautosomal inheritance. The risk of bearing a child with an autosomal-recessive disease or trait is increased when the parents are consanguineous or related by descent. More formally, the probability that a homozygote has received both alleles of a pair from an identical ancestral source is known as the coefficient of inbreeding. It also is the proportion of loci at which a person is homozygous by descent. For example, any child born to first cousins is homozygous at 1/16 of all loci. Although the relative risk of abnormal offspring is higher for first cousins than for unrelated parents, it is still low, at about 5%.

X-Linked Inheritance The inheritance of diseases and traits associated with genes located on the X chromosome differs markedly from autosomal forms of inheritance, becauses females have two X chromosomes whereas males have only one. Thus, when

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mutations of an X-linked gene occur in males, no genetic “backup” is available. The situation in heterozygous (carrier) females is more complicated, owing to the phenomenon of X chromosome inactivation (Xi), which ensures that dosage for X-linked genes is the same in male and in female cells. Because Xi is random in most females, the maternally derived and paternally derived X chromosomes usually are active in about half of the cells in a female organism. Thus, mutation of one gene should cause no more than a 50% loss of function of the protein or other gene product. With this background, several mechanisms have been described that lead to disease expression in female carriers of X-linked mutations. First, some genes are dosage sensitive, so that 50% expression is not enough for normal function. Next, by chance or because of cell selection (usually favoring the normal allele), some females have skewing of X-inactivation such that one X chromosome is inactivated in a high proportion (80% to 100%) of cells. Unfavorable skewing will cause or worsen disease, whereas favorable skewing will prevent or reduce disease expression. Finally, skewing of X-inactivation also may result from mutations of the genes that actually control inactivation, especially the XIST gene, which is responsible for inactivation of one of the two X chromosomes. Not surprisingly, affected females usually have a less severe phenotype than that seen in affected males. The important characteristics of X-linked inheritance result from differential segregation of the X and Y chromosomes in males and females, and the differences in gene dosage. The most consistent characteristics include more severe phenotype in males than in females, transmission of disease through carrier females who are unaffected or less affected than males, and lack of male-to-male transmission (see Fig. 21-15). The last is explained by transmission of the Y chromosome from fathers to sons, whereas the disease genes TABLE 21-6 Rules for X-Linked Inheritance in Humans Rules Related to Segregation of the X and Y Chromosomes Hemizygous males transmit X chromosomes to daughters and Y chromosomes to sons. • Male-to-male transmission of X-linked disorders cannot occur. • Sons of hemizygous males never inherit the disorder. • Daughters of affected males all are heterozygous (carriers or affected). • All affected males in a family are related through heterozygous females. Heterozygous females transmit X chromosomes to both sons and daughters. • Fifty percent of sons of heterozygous females will be hemizygous males. • Fifty percent of daughters of heterozygous females also will be heterozygous females. Rules Related to Penetrance, Expressivity, and Sex Ratio Penetrance and Expressivity • In general, penetrance is higher and expressivity more severe in hemizygous males than in heterozygous females. Sex Ratio of Affected Persons • Males are predominantly affected when female penetrance is low. • Female-to-male ratio is close to 2:1 when female penetrance and male survival are high. • Females are predominantly affected, with prenatal lethality in males.

are located on the X chromosome. X-linked disorders traditionally have been divided into dominant and recessive subtypes, just as for autosomal single-gene disorders. This distinction was first made in fruit flies under experimental conditions but has never worked very well for human disorders. In a recent survey of more than 30 X-linked diseases, a remarkably wide range of penetrance, with many disorders intermediate between so-called X-linked dominant and recessive patterns, were found [Dobyns et al., 2004]. On the basis of these and other arguments, use of these subtypes should be discontinued. The rules for X-linked inheritance have been modified to reflect this change (Table 21-6). In many instances, children with X-linked diseases present primarily or frequently to pediatric neurologists, including those with adrenoleukodystrophy, the Duchenne and Becker forms of muscular dystrophy, fragile X syndrome, many X-linked mental retardation syndromes, two forms of X-linked lissencephaly, and many others. These diseases all result in more severe phenotypes in males than in females. Another class of X-linked disorders are “X-linked, male lethal” have proved to be particularly important in pediatric neurology. These diseases are observed almost exclusively in females and are thought to cause prenatal lethality in males or to cause a much more severe phenotype that is not recognized as the same disorder. Examples are Aicardi’s, Goltz’s, and Rett’s syndromes and orofaciodigital syndrome type I.

Genomic Imprinting In most single-gene disorders, the expression of a trait or disease is expected to be the same regardless of whether the gene was inherited from the mother or the father. Significant differences in expression based on the gender of the transmitting parent, however, have been observed in several disorders. This phenomenon is known as imprinting and reflects differences in the state of the maternal and paternal contributions to the genome, especially differential methylation of the maternally and paternally derived chromosomes. An imprinted gene can be imprinted or differentially methylated (i.e., differentially silenced) in all cells of the body, or only in selected tissues, such as brain. This differential silencing means that imprinted genes will be expressed from the maternally derived gene or from the paternally derived gene, but not from both. So if the functioning copy of an imprinted gene is lost owing to a deletion or mutation, the affected person is left with no functioning gene, and a disease phenotype will result. The underlying mechanisms are under study but still are not well understood [Hall, 1990; Jiang et al., 2004]. Imprinting disorders result from deletions or other types of mutations of genes within imprinted regions (or in the imprinting control regions). The most common of these result in infantile developmental disorders relevant for pediatric neurologists, such as BeckwithWiedemann syndrome due to defects of imprinted genes on 11p15.5 [Weksberg et al., 2003] and Angelman’s syndrome and Prader-Willi syndrome due to defects of imprinted genes on 15q11.2-q13 [Amos-Landgraf et al., 1999]. These disorders are reviewed elsewhere in this book.

Uniparental Disomy Defects of imprinted genes also may result from a rare mutation type known as uniparental disomy (UPD). UPD is

Dobyns and Das / Introduction to Genetics

defined as the presence of a diploid cell line containing two chromosome homologs inherited from the same parent. It is believed to result from nondisjunction, which produces trisomy for a particular chromosome. Trisomy is followed by loss of one of the three homologs, reducing the chromosome number back to normal. This mutation is known as uniparental isodisomy when the two homologs are identical and uniparental heterodisomy when they are different (as a result of crossing over, different regions of the affected chromosomes usually are involved). When UPD involves a chromosome with an imprinted region, problems occur. For example, a child may inherit two paternally derived chromosomes, in which case no maternally derived chromosome will be present. Any genes that are normally expressed only from the maternally derived gene will not be expressed at all. This is one cause of Angelman syndrome. The same type of problem occurs in reverse if the child inherits two maternally inherited chromosomes. No paternally derived genes will be present, and a disease will occur. This is one cause of Prader-Willi syndrome [Amos-Landgraf et al., 1999]. Very rarely, UPD can result in a genetic disease by causing homozygosity of a recessive disease gene. Because the two chromosomes are identical, they are homologous at all loci. If the involved chromosome contains any recessive disease loci, the person with the mutation will be homozygous and therefore affected.

Mosaicism Mosaic is a term used to refer to an individual organism or tissue that contains two or more cell lines that differ in DNA sequence, although they are derived from a single zygote. All organisms begin with a specific DNA sequence in the cell of origin or zygote. As cell division proceeds, some mutations occur that produce small differences among different cell lines. The presence of two or more cell lines differing in their DNA sequence but derived from a single zygote is known as mosaicism. Mosaicism is clinically important in many disorders and probably explains some unusual diseases in which only part of the body appears to be affected with a birth defect or genetic disease. A good example is segmental neurofibromatosis. This phenomenon can involve any tissue or group of tissues in the body. When mosaicism is found in lymphocytes, fibroblasts, or other somatic cells of the body, it is designated somatic mosaicism. The mosaic individual typically demonstrates at least mild signs of disease. When mosaicism is found only in germ cells (egg, sperm), it is known as gonadal mosaicism. The mosaic individual usually is identified as the parent of two or more children with a genetic disease, despite having no signs of the disease clinically or on mutation analysis. Mosaicism may begin with a somatic mutation in the germline of the affected person, which then persists in the clonal descendants of that cell, including a proportion of the ova or sperm. When the mutation exists only in the germline, the parent has no signs of the disease but may conceive multiple affected children. This phenomenon has been seen frequently in Duchenne muscular dystrophy due to mutations of the DMD gene, the autosomal-dominant form of osteogenesis imperfecta associated with mutations of the COL1A1 or COL1A2 gene, and X-linked lissencephaly due to mutations of the DCX

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gene. The distinction between somatic and germline mosaicism is most likely artificial, however, because standard evaluations examine very few tissues.

Complex Inheritance The most important attributes of complex or multifactorial inheritance are lack of a clear pattern of inheritance in single families, although more than one relative may be affected, and a relatively low risk to first-degree relatives (approximately the square root of the population risk), typically in the range of 1% to 5%. This form of inheritance results from variation at two or more loci with two or more alleles each, often with a prominent environmental influence. This pattern also is referred to as polygenic (we prefer oligogenic) or multifactorial inheritance. Examples of traits inherited in this pattern are head circumference, autism, neural tube defects, and common forms of epilepsy. Some are continuous traits that can be measured, such as head circumference, whereas others fall into non-overlapping groups, such as autism and epilepsy. For continuous traits such as head circumference, children are likely to be intermediate between their parents, or closer to the mean than either parent (so-called regression to the mean).

Mitochondrial Inheritance Mitochondria are the cellular organelles that are primarily responsible for cellular respiration and production of adenosine triphosphate, both essential for cellular energy management. Each mitochondrion contains multiple copies of a small 16.5-kb circular chromosome that codes for 13 proteins and many rRNA and tRNA genes that differ in sequence from the nuclear rRNA and tRNA genes. The proteins all are components of the respiratory chain, and the remainder of the respiratory pathway enzymes are encoded by nuclear genes. The mitochondria in any one person are derived almost exclusively from the mother through the ovum. Each ovum contains hundreds of mitochondria, and each mitochondrion contains many copies of the circular mitochondrial chromosome. Sperm contain a few mitochondria, most of which are degraded rapidly by the proteasome-dependent protein degradation pathway of the ubiquitin system within the ovum after fertilization [Sutovsky et al., 2003]. A small paternal contribution of mitochondria, however, has been demonstrated in several species, such as sheep [Zhao et al., 2004]. The same likely is true for humans, as suggested by one example of paternal inheritance of a mitochondrial disorder [Schwartz and Vissing, 2002]. This must be very rare, however, owing to the small proportion of paternal compared with maternal mitochondria, and as indicated by studies in humans with mitochondrial diseases [Filosto et al., 2003; Zhao et al., 2004]. In patients with mutations of mitochondrial genes, a variable proportion of the mitochondrial chromosomes carry the mutation. Thus, diseases caused by mutations in mitochondrial DNA exhibit strict maternal inheritance (with very rare exceptions) and usually will exhibit phenotypic variation within a family owing to variation in the proportion of mutant and normal mitochondria between individuals [Zeviani et al., 1989]. Maternal inheritance may be recognized because (1) the incidence of the disease is equal in males and females, (2) the disease is transmitted from mother to offspring

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of both genders but never from father to offspring, and (3) variable expression is common. These criteria have been met for several diseases associated with mitochondrial DNA mutations, including Kearns-Sayre syndrome, Leber’s hereditary optic neuropathy, MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes), and MERRF (myoclonic epilepsy with ragged-red fibers).

Genetic Counseling Medical genetics differs from other specialties because family members other than the patient may be at high risk for a disease first recognized in the patient, who then becomes the proband. The person or persons actually seeking advice may not themselves be affected. Ideally, the patient or the parents or guardians of minor children or incompetent adults, and all other family members at risk, should be made aware of both the clinical and the reproductive consequences of a genetic disease. Genetic counseling is the process of providing this information. Although any physician may provide genetic counseling as part of

overall patient management, it is more commonly conducted in genetics clinics.

Standard of Care All physicians have a professional responsibility to make certain that genetic counseling has been provided in appropriate situations and to ensure that the counseling meets current standards of practice [ASHG/ACMG report, 1995]. Failure to provide this information may have tragic results. Perhaps the best example for pediatric neurologists is the birth of a second or even a third male with Duchenne muscular dystrophy in a family. Courts have upheld the principle of physician responsibility to provide accurate counseling on several occasions. For example, the parents of a child with Down syndrome claimed negligence because the mother had not been referred for prenatal diagnosis. In another case, parents who were tested for Tay-Sachs disease carrier status both were told that they were not carriers. They later had an affected child and filed a claim. Cases of this type are known as wrongful life claims.

TABLE 21-7 Recurrence Risks in Siblings for Selected Neurologic Disorders of Childhood DISORDER

EMPIRICAL RISK

REFERENCE(S)

Brain Malformations Agenesis of the corpus callosum Cerebellar vermis hypoplasia (variant)‡ Dandy-Walker malformation (true)§ Molar tooth malformation (Joubert’s syndrome)|| Holoprosencephaly (literature) Holoprosencephaly (author) Hydrocephalus Male sibling of male hydrocephalus proband Lissencephaly with all test results normal Lissencephaly with no testing done Neural tube defects

Low,* XL† 5–25%,* XL ~1% 25% 6% 10–15% 1–4%, XL 12%, XL 5–10%,* XL 1–33%,* XL 2–3%

Baraitser, 1997 Philip et al., 2003 Murray et al., 1985 Satran et al., 1999 Roach et al., 1975 Baraitser, 1997 Burton, 1979 Authors’ experience Authors’ experience Koch and Fuhrmann, 1985

Developmental Disorders Autism Cerebral palsy, spastic and symmetric Cerebral palsy, spastic and asymmetric Mental retardation (MR) Male sibling of male patient with MR Microcephaly Microcephaly (below ~3 SD at birth) Microcephaly, multiple congenital disorders

4–5% 10% 1–2% 4–5%, XL 6–12%, XL 12% 25% 6%

Jorde et al., 1991 Baraitser, 1997 Baraitser, 1997 Herbst and Baird, 1982 Herbst and Baird, 1982 Baraitser, 1997 Authors’ experience Baraitser, 1997

Seizure Disorders Benign rolandic epilepsy Febrile seizures Partial epilepsy Primary generalized epilepsy

8–24% 15% 5% 4–13%

Heijbel et al., 1975 Hauser et al., 1985; Tsuboi, 1987 Andermann, 1982 Metrakos and Metrakos, 1961

Other Neurologic Disorders Migraine

12–27%

Baraitser, 1997

*These figures are estimates based on the personal experience of one of us (WBD) and a conservative approach to risk counseling. Note that several figures are higher than published data, which we attribute to less complete ascertainment of affected siblings in older published studies. †X-linked inheritance has clearly been observed for certain disorders and needs to be taken into account for risk counseling. ‡ Cerebellar vermis hypoplasia sometimes is called a Dandy-Walker “variant.” § In typical DWM, the vermis is small and rotated well upward, with an enlarged, cystic fourth ventricle. || This includes several Joubert’s syndrome–related disorders such as Arima, COACH, Senior-Loken, and Varadi syndromes. COACH, cerebellar vermis hypoplasia, oligophrenia, congenital ataxia, coloboma, hepatic fibrocirrhosis; DWM, Dandy-Walker malformation; SD, standard deviation; XL, X-linked.

Dobyns and Das / Introduction to Genetics

Responsibility to Relatives The responsibility to provide genetic counseling does not formally extend beyond the consultand, or person seeking genetic advice. People with genetic disorders are entitled to the same confidentiality as for persons with any other type of disease. Nevertheless, the need for confidentiality does not mean that no effort should be made to inform relatives of a common risk. Whenever the genetic evaluation suggests that other family members or their future children may be at risk, the consultand should be encouraged to contact those persons or ask the physician (or designee) to contact them and advise them to seek genetic evaluation. A majority of people act responsibly in this regard, but exceptions do arise that may present an ethical dilemma for health-care practitioners providing the counseling.

Relevance for Pediatric Neurology The obligation to provide accurate genetic counseling is particularly important for pediatric neurologists. Many neurologic and neuromuscular diseases in children have a genetic basis or a genetic component, including some of the most common problems seen in clinics. For disorders such as Duchenne muscular dystrophy, neurofibromatosis type 1, and tuberous sclerosis, the genetic basis and need for genetic counseling are well known. For others, the genetic basis or contribution is not widely recognized. Febrile seizures, benign rolandic epilepsy, and some types of primary generalized epilepsy may affect many persons in a family and appear to have autosomal-dominant inheritance, although penetrance is not complete. Mental retardation, microcephaly, and cerebral palsy have a significant genetic component, with recurrence risks of 5% to 10%. Most brain malformations are sporadic, but familial recurrence of almost every known type of brain malformation has been described. Because of the possibility of recurrence in relatives, pediatric neurologists should take a genetic history and advise patients and parents of their genetic risks. Referrals from pediatric neurology clinics to genetics clinics should occur frequently. Even for single-gene disorders with a known risk of recurrence, referral usually is needed to provide an accurate presentation of methods of prevention such as prenatal diagnosis when this is available, artificial insemination by donor, contraception, sterilization, and adoption. If the parents decide to terminate a pregnancy, continued professional support is an appropriate and important part of genetic counseling.

Genetic Risk One of the most crucial steps in offering accurate genetic counseling is to estimate the risk of recurrence of a genetic disorder in other family members. Estimation is not difficult for most diseases with a single-gene pattern of inheritance, but even these may be complex because of late age at onset or incomplete penetrance. For many other disorders, empirical recurrence risk estimates are used. These risk figures are derived from previous experience with the same disorder. Although such figures generally are accurate, exceptions occur because of causal heterogeneity and lack of knowledge regarding many rare disorders. The recurrence risks for some of the more common diseases seen in pediatric neurology clinics are listed in Table 21-7. In any given family, the recurrence risk may be different; consultation

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with a geneticist or genetic counselor may be helpful in providing this information.

Prenatal Diagnosis Prenatal diagnosis can now be performed for hundreds of genetic disorders, including many of those discussed in this chapter. The major methods used include chromosome analysis, enzyme assays and other biochemical tests, molecular genetic tests, and direct examination of the fetus by ultrasonography. The last is a far more rigorous procedure than routine prenatal ultrasonography and usually is referred to as high-resolution, level 2, or genetic ultrasonography. The purposes of prenatal diagnosis are to provide (1) a range of informed choices for parents at risk for having a child with an abnormality, (2) reassurance to reduce anxiety, especially among parents at high risk, and (3) an opportunity for parents, who otherwise would choose not to have children, to conceive and bear healthy children. The results of prenatal tests are normal in more than 98% of pregnancies evaluated, and parents are reassured that the infant will be unaffected by the condition in question. Of course, the infant remains at risk for other disorders, just as do children born to any other parents. In a small proportion of cases, the fetus is indeed found to have a serious defect. Because effective prenatal therapy is not possible for most disorders, the parents then have the option of terminating the pregnancy.

Genetics and Medicine Genetics has become one of the most rapidly expanding fields in all of biology, and it is likely that this trend will continue. The past few years have seen completion of the Human Genome Project and identification of many genes relevant to neurologic disorders of childhood. The next few years will see the isolation of new genes responsible for common and complex diseases and many more single-gene disorders. REFERENCES Amos-Landgraf JM, Ji Y, Gottlieb W, et al. Chromosome breakage in the Prader-Willi and Angelman syndromes involves recombination between large, transcribed repeats at proximal and distal breakpoints. Am J Hum Genet 1999;65:370. Andermann NE. Multifactorial inheritance of generalized and focal epilepsy. In: Anderson VE, Hauser WA, Penry VK, et al., eds. Genetic basis of the epilepsies. New York: Raven Press, 1982:355. ASHG/ACMG report. Points to consider: Ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Am J Hum Genet 1995;57:1233. Astbury C, Christ LA, Aughton DJ, et al. Delineation of complex chromosomal rearrangements: Evidence for increased complexity. Hum Genet 2004a;114:448. Astbury C, Christ LA, Aughton DJ, et al. Detection of deletions in de novo “balanced” chromosome rearrangements: Further evidence for their role in phenotypic abnormalities. Genet Med 2004b;6:81. Babcock M, Pavlicek A, Spiteri E, et al. Shuffling of genes within low-copy repeats on 22q11 (lcr22) by Alu-mediated recombination events during evolution. Genome Res 2003;13:2519. Bailey JA, Gu Z, Clark RA, et al. Recent segmental duplications in the human genome. Science 2002;297:1003. Baraitser M. The genetics of neurological disorders, 3rd ed. Oxford: Oxford University Press, 1997. Bejerano G, Pheasant M, Makunin I, et al. Ultraconserved elements in the human genome. Science 2004;304:1321.

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CHAPTER 22

Chromosomes and Chromosomal Abnormalities Maria Descartes and Bruce R. Korf

The development of the human organism is directed by an estimated 30,000 genes, consisting of some 3 billion base pairs (bp) of DNA. These genes encode the structure of both proteins and noncoding RNAs, which together are responsible for the orderly unfolding of human development beginning from the fertilized egg (zygote), and for the maintenance of body structure and function. The entire pool of genetic information must be replicated with each cell division and a complete set of information apportioned to the two daughter cells. In addition, the full complement of genes must be transmitted from generation to generation through the germ cells. Genes do not exist as isolated entities within the cell nucleus but rather are arranged on structural units called chromosomes. Each chromosome contains hundreds or thousands of genes arranged in a linear order. This order is reproducible from cell to cell within an individual organism and from individual to individual in the population. The normal human chromosome complement consists of 46 chromosomes, including 22 pairs of nonsex chromosomes (autosomes) and either two X chromosomes in females or an X and a Y in males. Each of these chromosomes has a characteristic structure and includes a specific set of genes arranged in a specific order. The chromosomes are units that ensure the orderly distribution of a complete set of genetic information during cell division. Chromosome number and structure are tightly regulated, and deviations from the norm usually are associated with clinical problems. Multiple genes are simultaneously disrupted as a consequence of chromosomal abnormalities; accordingly, the phenotypic consequences usually are complex. Because of the complexity of the nervous system and its dependence on multiple genes, neurologic problems accompany most of the chromosomal disorders. Chromosomal abnormalities were among the first genetic disorders to be studied in the laboratory. Beginning in the late 1950s, with the advent of reliable techniques for chromosomal analysis, a set of syndromes resulting from changes in chromosome number or structure were described. Initially these were syndromes associated with loss or gain of entire chromosomes or large chromosome segments, such as Down syndrome, resulting from trisomy 21. Refinements in analytic technology have gradually improved the resolution of chromosomal analysis, permitting progressively smaller changes to be detected. Current techniques are beginning to bridge the gap between chromosomal anomalies visible with the light microscope and changes in individual genes at a submicroscopic level. At the same time, techniques have been developed that permit chromosomal analysis in nondividing cells and in various tissues that can be sampled prenatally. This chapter focuses on the approach to chromosomal disorders in pediatric neurology. The basic principles of

chromosome structure and function are considered, followed by a description of methods of chromosomal analysis. The various types of chromosomal abnormalities are then considered. This discussion is followed by an overview of the clinical approach to chromosomal abnormalities and then a brief clinical description of major chromosomal syndromes. The chapter closes with a look at future prospects for improving the power of cytogenetic analysis.

CHROMOSOME STRUCTURE AND FUNCTION The DNA double helix is a thread about 2 nm wide; if stretched, the DNA that makes up the entire genome would be approximately 2 meters in length. Within the nucleus, DNA is complexed with protein and folded into a highly organized structure. The basic unit of organization is known as the nucleosome [Turner, 1993]. Two copies each of the four histones—H2A, H2B, H3, and H4—bind with about 146 bases of DNA to form a globular structure (Fig. 22-1). Adjacent nucleosomes are separated by a variable length of DNA of up to 80 bases to form a structure resembling beads on a string. This string is the form in which DNA is transcribed to make messenger RNA (mRNA). Inactive chromatin is further folded into a more compact structure with histone H1 and nonhistone proteins. The most highly compacted state of chromatin occurs during the process of cell division. After DNA replicates, during the prophase stage of mitosis, chromatin condenses into the familiar structure of the mitotic chromosome [Boy de la Tour and Laemmli, 1988; Felsenfeld, 1996; Manuelidis and Chen, 1990]. The smallest chromosome segment resolvable with the light microscope may contain 105 to 106 bp, potentially including dozens of genes. Chromosome structure is best appreciated during this highly condensed phase (Fig. 22-2). The two chromatids represent replicated copies of the chromosome, each consisting of a single continuous double helix of DNA complexed with proteins as described. The chromatids remain joined at the centromere until anaphase, when the chromatids disjoin to the two daughter cells. The centromere divides the chromosome into a short arm (designated p, for petit) and a long arm (designated q). The ends of the chromosome consist of a specialized DNA sequence referred to as the telomere. Telomeres form a kind of cap necessary for chromosome replication [Cech, 2004]; maintenance of the telomere is thought to play a role in aging and also in malignancy. Although the basic role of DNA is to encode the amino acid sequence of proteins, much of the DNA does not serve a coding function. This noncoding DNA includes introns

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Genetic, Metabolic, and Neurocutaneous Disorders / 22

DNA double helix

2 nm

“Beads-on-a-string” form of chromatin

11 nm

Chromatin fiber of packed nucleosomes

30 nm

Extended section of chromosome

300 nm

Condensed section of chromosome

700 nm

FIGURE 22-1. Schematic representation of DNA and chromosome organization. A, Orders of chromatin packing at metaphase. Width expressed in nanometers (nm). B, Relative size of chromosome band, the β-globin cluster of genes, and the β-globin gene, expressed in length of DNA (μm) and in the number of base pairs (bp) (1000 bp = 1 kilobase [kb]). (Modified from Albert B, Bray D, Lewis J, et al. Molecular biology of the cell. New York: Garland Publishing, 1983; Schmickel, 1986.)

A

*7800 ␮m 15.5 15.4 15.3 15.2 15.1

14.3

14.2 14.1 13

12

11.2 11.12 11.11 17 12.1 12.2 12.3 13.1 13.2 13.3 13.4 13.5

14.1

14.2 14.3 21 22.1 22.2 22.3 23.1 23.2

23.3 24.1 24.2 24.3 25

700 nm

B

Chromatid of chromosome I I at prometaphase

5000 kb

*1700 ␮m 60 kb ␤

␦

G␥

␺␤1 A␥

⑀

1600 kb

*22 ␮m ␤-like globin gene cluster *0.5 ␮m ␤-globin gene

*Total length of DNA

that separate parts of genes and are spliced out of the transcript to form the mature messenger RNA (mRNA), as well as DNA that forms the space between genes [Long et al., 1995]. In addition, stretches of DNA sequences that are repeated hundreds or thousands of times seem to serve a structural role. Large blocks of such repeated sequences occur near the centromeres [Willard, 1990]. These tend to remain highly condensed with protein throughout the cell cycle and are referred to as heterochromatin. The exact size and sequence composition of heterochromatic segments may not be highly conserved. Structural variants in these regions therefore may not be clinically significant.

The past decade saw a major worldwide effort to map the human genome and identify all of the genes. The Human Genome Project has resulted in delineation of an essentially complete human genome sequence and has produced major insights into the structure and function of the genome [Lander et al., 2001; Venter et al., 2001]. Although the exact number of genes is not known, it is estimated to be in the range of 30,000. It is clear that sequences that encode protein constitute a relatively small proportion of the genome. Many of the transcripts include RNAs that have functions other than serving as a template for proteins, and other parts of the genome include repeated sequences of unknown function.

Descartes and Korf / Chromosomes and Chromosomal Abnormalities Mid-metaphase banding

Prophase and prometaphase banding Band

1p35 Telomere

Band

6 3

P

Short arm

543

1p35.3 1p35.2 1p35.1

5 4 3 2 1

Negative or pale staining Q and G bands Positive R bands

Positive Q and G bands Negative R bands Sub-band

2 2 1 1

Variable bands

3 21

Centromere

1

Long arm Region

1

2

2

1 2 3 4 5

q

3

Band

4

1 2 21 3 4

Telomere Sister chromatids

CHROMOSOME

A

B FIGURE 22-2. A, Schematic anatomy of chromosome 1. B, An idiogram at different stages of condensation: R-banding. (Courtesy M.G. Mattei, Marseilles, France.)

METHODS OF CHROMOSOME ANALYSIS The history of clinical cytogenetics can be characterized as a series of technical advances each of which has led to the

recognition of new clinical syndromes resulting from chromosomal abnormalities. The modern era in human cytogenetics began with the discovery of methods to permit individual chromosomes to be identified in dividing cells.

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The key breakthrough was the use of hypotonic treatment to spread apart the chromosomes, thereby avoiding overlaps [Hsu and Pomerat, 1953; Hughes, 1952]. This advance led, in 1956, to the discovery that the normal human chromosome number is 46, rather than 48 as had been previously thought [Tjio and Levan, 1956]. The second major advance was the discovery that the kidney bean extract phytohemagglutinin can stimulate lymphocytes to divide in culture, providing an easily obtained source of dividing cells for analysis [Nowell, 1960]. The first golden age of discovery of chromosomal abnormalities began with the recognition of trisomy 21 in persons with Down syndrome in 1959 [Lejeune and Gauthier, 1997] and continued through the early 1960s with the identification of other aneuploidy syndromes. Chromosome structure is most easily appreciated during mitosis, when the chromatin fiber is condensed and coiled into a characteristic structure. Spontaneously dividing cells are rarely available except in tumors or chorionic villus tissue used in prenatal diagnosis. Rather, cells are grown in short-term culture. For routine analysis, peripheral blood lymphocytes most commonly are used, although skin fibroblasts also may be cultured and analyzed. Phytohemagglutinin-stimulated peripheral blood usually is grown in culture for 3 days. Blocking the mitotic spindle with a drug such as colchicine leads to accumulation of dividing cells, which then are induced to swell by treatment with hypotonic saline, fixed, and spread onto a microscope slide. Chromosomes must be stained to be visualized with the light microscope. In the early days, cytogenetic stains that bound to either DNA or protein and that uniformly colored each chromosome were used. This practice made it difficult to identify chromosomes of similar size and shape and made it impossible to detect subtle rearrangements. Beginning in 1968, a number of stains were discovered that reveal a set of characteristic bands that permit precise identification of each chromosome and definition of chromosome regions [Caspersson et al., 1968]. Most laboratories use a form of G-banding, involving protease treatment of the chromosomes followed by Giemsa staining for routine analysis [Bickmore and Sumner, 1989]. The advent of chromosome banding stimulated a second wave of discovery of chromosomal syndromes during the 1970s. Subsequent developments in laboratory cytogenetics have gradually improved the resolution of chromosomal analysis. As the cell proceeds through mitosis, the chromosome gradually contracts, until anaphase, when the chromatids separate. If cells are collected during early prophase, chromosomes are highly extended, revealing a fine, highly detailed banding pattern [Yunis, 1976, 1981]. This banding pattern has facilitated recognition of subtle chromosome rearrangements involving small chromosome segments. Even with this approach, however, the resolution is limited to a few million bp of DNA, which may include dozens of genes. The gap between the light microscopic resolution of chromosome structure and the gene is being bridged by the technique of fluorescence in situ hybridization (FISH). This technique uses a fluorescently tagged segment of purified DNA corresponding to a specific gene or chromosome segment. Chromosomal DNA is separated into single strands on a microscope slide and incubated in a solution with single-stranded, fluorescently labeled DNA. Wherever this

FIGURE 22-3. Use of fluorescence in situ hybridization to detect submicroscopic deletions of chromosome 15. Each chromosome 15 is hybridized with two DNA probes, one for the region deleted in Prader-Willi and Angelman syndromes and one for a control region to mark chromosome 15. In this photograph, one copy of chromosome 15 demonstrates the normal two sets of hybridization signals, whereas the other demonstrates only one set, indicative of deletion. (Photograph courtesy of S. Weremowicz, Boston.)

“probe” DNA finds homologous DNA on the chromosome, a stable double helix forms. When this double helix is visualized with the light microscope, a bright spot is seen at the site on the chromosome that has bound to the probe (Fig. 22-3). FISH can be done using DNA probes isolated from single genes or with “cocktails” of multiple probes specific to a particular chromosome. Use of the latter lights up the entire chromosome, referred to as chromosome painting. FISH is used to detect deletions of small segments of DNA that cannot be visualized with the light microscope [Ligon et al., 1997] and has revealed a set of “microdeletion syndromes” resulting from deletions of contiguous genes. FISH also is helpful in the characterization of complex chromosome rearrangements or in the identification of chromosomal segments that participate in such rearrangements [Daniel et al., 1994]. Finally, FISH can permit visualization of chromosome regions in nondividing cells. This visualization can be used for rapid diagnosis of chromosome trisomies (if three fluorescent spots are seen to correspond with a particular chromosome, rather than the normal two) or for rapidly screening large numbers of nondividing cells for evidence of chromosomal mosaicism [Liehr et al., 1995; Lomax et al., 1994; Luquet et al., 2002]. FISH techniques also are being developed that stain each chromosome a different color, permitting “spectral karyotyping” with exceedingly high resolution and sensitivity for detection of subtle changes [Liehr et al., 2004]. Deletions and duplications are detected in most clinical laboratories by FISH. FISH focuses on only one region per analysis, so the technique is expensive and slow. New technologies are now available that allow genomewide screening. One of these methods is comparative genomic

Descartes and Korf / Chromosomes and Chromosomal Abnormalities

hybridization (CGH). In CGH, differentially labeled total genomic DNA from a test and reference genomic DNA are co-hybridized to normal DNA metaphase chromosomes and/or fragments immobilized to a matrix. Repetitive sequences are blocked, and the resulting differences in hybridization provide representation of DNA copy-number variation [Pinkel et al., 1998; Pollack et al., 1999]. CGH can target metaphase chromosomes, total genomic DNA, cDNA, genomic clones, defined DNA, and nuclei acid sequences [Solinas-Toldo et al., 1997]. The resolution is in the range of 1.5 Mb (megabases) [Kriek et al., 2004].

TABLE 22-1 Common Chromosome Heteromorphisms CHROMOSOME(S)

STAIN

HETEROMORPHISM

1

G or Q

3

Q

9

G

16

G or C

Variation in size of heterochromatin on long arm; may be inverted Bright fluorescence of pericentromeric region Variation in size of heterochromatin on long arm; may be inverted Variation in size of heterochromatin on long arm; may be inverted Variation in size and fluorescence intensity of satellite region

13, 14, 15, 21, 22 G or Q

HUMAN KARYOTYPE

545

C, C-banding; G, G-banding; Q, Q-banding.

The normal human karyotype is depicted in Figure 22-4. Although each chromosome has a characteristic size and shape, chromosome morphology varies somewhat from person to person. These chromosome variants tend to occur in regions of the genome that do not encode genetic information and therefore are clinically silent. They are referred to as heteromorphisms and must be distinguished from clinically important chromosomal abnormalities. Common heteromorphisms include variations in the sizes of blocks of darkly stained regions at the centromeres of certain chromosomes (heterochromatic regions), large satellites of acrocentric chromosomes, and certain inversions (Table 22-1). Some chromosomal regions are prone to breakage and are

referred to as fragile sites. Most are clinically insignificant. The one major exception, fragile X, is described in detail in a later section.

CHROMOSOMAL ABNORMALITIES Most chromosomal abnormalities exert their phenotypic effects by increasing or decreasing the quantity of genetic material. Abnormalities can range from complete extra or missing chromosomes to small deletions or duplications.

FIGURE 22-4. Normal human karyotype.

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With the discovery of genomic imprinting, it has become clear that inheritance of both copies of a chromosome from the same parent also can result in a phenotype. This section reviews the major classes of chromosomal abnormalities. Specific syndromes of neurologic interest are described later in the chapter.

Numeric Abnormalities The most straightforward of chromosomal abnormalities are alterations of chromosome number. Deviation from the normal diploid complement of 46 chromosomes is referred to as aneuploidy; an extra chromosome results in trisomy, whereas a missing chromosome constitutes monosomy. Although all of the possible chromosome trisomies have been observed in spontaneous abortions, trisomies 13, 18, and 21 are the only autosomal trisomies to be observed in a nonmosaic state in liveborns. All autosomal monosomies are lethal. The only viable monosomy involves the X chromosome (45,X, resulting in Turner’s syndrome). Aneuploidy results from an error in cell division referred to as nondisjunction, in which two copies of a chromosome go to the same daughter cell during meiosis or mitosis. Nondisjunction occurs most often in the first division of meiosis in the maternal germ line. Mitotic nondisjunction results in the presence of an aneuploid and a normal cell line—a condition referred to as mosaicism. The causes of nondisjunction are unknown. The only well-documented risk factor is maternal age. The term polyploidy refers to presence of a complete extra set of chromosomes: Triploidy represents three sets, with 69 chromosomes; tetraploidy represents four sets, or 92 chromosomes. Rarely, a triploid fetus will be liveborn, but in general, polyploidy is lethal. In a few instances, however, mosaicism for a diploid and a triploid cell line producing congenital anomalies has been compatible with long-term survival.

Deletions and Duplications Small deletions or duplications of chromosomal material result in increased or decreased gene “dosage.” Large deletions usually are lethal; monosomy for large chromosomal segments or entire chromosomes is not well tolerated. Application of FISH techniques has shown that a number of syndromes result from submicroscopic deletions. In these syndromes, groups of contiguous genes are thought to be removed, resulting in a defined set of congenital anomalies, as described later in this chapter. Deletion of genetic material from both ends of a chromosome can lead to fusion of the ends to form a ring-shaped structure. In addition to gene deletions, ring chromosomes tend to be unstable during cell division, resulting in some cells that lose the ring (and become monosomic for the chromosome) and others that have multiple copies of the ring.

Chromosome Inversions Inversions occur when there are two breaks in a chromosome and the intervening material flips 180 degrees. Inversions that span the centromere are referred to as pericentric, whereas those that do not are called paracentric.

Inversions generally do not result in added or lost genetic material and therefore usually are viewed as neutral changes. Disruption of a gene at one of the break points in the inversion, however, could upset function of that gene. Also, alteration of gene order at the borders of the inversion could affect the function of blocks of genes that are coordinately regulated (“position effect”). These considerations notwithstanding, usually chromosome inversions have no phenotypic effect. Crossing over within the inversion during meiosis may, however, result in deletions and duplications of chromosomal material. Although such an event in a paracentric inversion results in dicentric or acentric chromosomes that tend to be unstable, crossing over in a pericentric inversion can lead to genetically unbalanced but viable gametes.

Translocations Translocations involve the exchange of genetic material between chromosomes. In a balanced translocation the exchange is equal, with no loss or gain of genetic material. As with an inversion, it is possible for a gene to be disrupted at the point of exchange. Such a disruption has resulted, for example, in Duchenne muscular dystrophy in females with X-autosome translocations breaking the X within the dystrophin gene [Cockburn et al., 1992; Van Bakel et al., 1995]. More often, the carrier of a balanced reciprocal translocation is free of clinical signs or symptoms but is at risk for having offspring with unbalanced chromosomes. This risk is related to the nature of the products of segregation of the balanced translocation at meiosis. Aside from occasionally producing unbalanced gametes with 46 chromosomes, three of the four chromosomes involved in the meiotic configuration can segregate to the same germ cell (so-called 3:1 segregation), resulting after fertilization in 47 chromosomes including the rearranged chromosome. Some translocations involve three or more chromosomes. Chromosome painting can help identify the chromosomes that contribute to such a complex rearrangement. One specific type of translocation that is relatively common is the robertsonian translocation. This translocation results from a fusion of two acrocentric chromosomes (chromosomes 13, 14, 15, 21, or 22) at the centromeres. Carriers of a robertsonian translocation have 45 chromosomes and are clinically unaffected. The most common deleterious outcome is trisomy 21, in which a carrier for a robertsonian translocation involving chromosome 21 produces a gamete with both the translocation chromosome and a normal 21, resulting in trisomy 21 after fertilization. The risk for production of unbalanced gametes from a translocation carrier depends on the chromosomes involved, the specific break points of the translocation, and the gender of the carrier. Empirical data are available for some specific translocations [Daniel et al., 1989]. Risks include miscarriage and the birth of a liveborn child with congenital anomalies resulting from chromosome imbalance. The phenotype usually is a complex mixture of the results of loss or gain of at least two chromosome segments and therefore can be difficult to predict.

Marker Chromosomes A marker chromosome is defined as a chromosome with a centromere consisting of rearranged genetic material of

Descartes and Korf / Chromosomes and Chromosomal Abnormalities

unknown origin. The prenatal incidence of supernumerary marker chromosomes (SMCs) is approximately 1 in 2500 live births, and 30% to 50% originate from chromosome 15 [Gardner and Sutherland, 1996]. In some cases, a marker will be a small bit of chromosome material almost at the limit of light microscopic resolution. Two thirds of de novo marker chromosomes can be associated with an abnormal outcome, whereas inherited ones can be passed from generation to generation without apparent clinical effects [Li et al., 2000]. Larger markers with more genetically active material are more likely to be of clinical significance. With the advent of FISH, the composition of marker chromosomes is increasingly likely to be defined, allowing these chromosomes to be characterized as derivative chromosomes resulting from translocations or other rearrangements.

Genomic Imprinting Although an individual normally receives a complete copy of autosomal genes from each parent, some genes are not expressed equally from the maternal and paternal genetic contributions. These genes are said to be imprinted [Driscoll et al., 1993; Hall, 1990; Sapienza, 1995]. The full complement of imprinted genes is not yet known, but several regions of the genome are known to include imprinted genes of clinical significance. Approximately 16 imprinted regions, each containing 1 to 10 genes, have been located to date [Lercher and Hurst, 2003]. Deletion of the expressed copy of an imprinted gene results in phenotypic effects, whereas deletion of the nonexpressed copy has no impact on development. Aside from deletion, another mechanism for genetic abnormality involving imprinted genes is uniparental disomy [Ledbetter and Engel, 1995]. Uniparental disomy is defined

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as the inheritance of both copies of a chromosome from the same parent. Uniparental disomy likely results in most cases of “trisomy rescue,” in which a nondisjunction event occurs in a trisomic zygote, resulting in a return to a disomic karyotype. If the two retained chromosomes are from the same parent, the embryo, although having a normal chromosome number, will have uniparental disomy. Uniparental disomy also may occur in an embryo having trisomy because of a 3:1 disjunction of a balanced translocation. Major syndromes associated with imprinted genes are described in a later section of this chapter.

Cytogenetic Nomenclature Cytogeneticists describe findings of chromosomal analysis using a standardized system of nomenclature (International System of Cytogenetic Nomenclature). Detailed description of this system is beyond the scope of this chapter, but major terms used are listed in Table 22-2. The normal male karyotype is designated 46,XY, and the normal female karyotype is 46,XX. Any derivative chromosome is described after the sex chromosome constitution, and mosaic cell lines are separated by a slash (e.g., 46,XY/47,XY,+21 to designate mosaicism for trisomy 21).

CLINICAL APPROACH TO CHROMOSOMAL ABNORMALITIES Chromosomal analysis has been incorporated into the routine battery of tests available to the clinician. This section considers some of the more common indications for chromosomal analysis.

TABLE 22-2 Examples of Usage of Cytogenetic Nomenclature TERM

INTERPRETATION

46,XX 46,XY 47,XX,+21 46,XX/47,XX,+21 69,XXY 46,XY,inv(2)(p21q31)

Normal female karyotype Normal male karyotype Trisomy 21; “+” indicates additional chromosome, with specific chromosome identified Mosaic karyotype with normal and trisomy 21 cell line Triploid karyotype with XXY sex chromosome complement Male karyotype with inversion of chromosome 2, with break points at band p21 on short arm and band q31 on long arm (pericentric inversion) 46,XX,del(5)(p14) Male karyotype with deletion of short arm of chromosome 5, with break at band p14 46,XX,dup(1)(q22q25) Female karyotype with duplication of part of chromosome 1 between bands q22 and q25 on long arm 46,XX,r(7)(p22q36) Female karyotype with ring chromosome 7, with break points at p22 on the short arm and q36 on the long arm and fusion of the short and long arms into a ring structure 46,XY,t(2;5)(q21;q31) Male karyotype with balanced reciprocal translocation involving chromosomes 2 and 5, with break points at bands q21 and q31 on chromosomes 2 and 5, respectively 46,XX,der(1)(1;3)(p22;q13) Female karyotype with abnormal chromosome (“derivative chromosome”) with centromere of chromosome 1, resulting from segregation of a balanced translocation between chromosomes 1 and 3, with break points on 1 and 3 at bands p22 and q13, respectively 45,XX,der(13;21)(q10;q10) Female karyotype with robertsonian translocation representing fusion of chromosomes 13 and 21; balanced karyotype 46,XX,der(13;21)(q10;q10),+21 Female karyotype with robertsonian chromosome but with additional chromosome 21, resulting in trisomy 21 46,XX,add(19)(p13) Female karyotype with additional material of unknown origin attached to chromosome 19 at band p13 47,XY,+mar Male karyotype with additional chromosome of unknown origin (marker chromosome) 46,XX.ish del(22)(q11.2q11.2)(D22S75−) Female karyotype normal by standard cytogenetic analysis but with submicroscopic deletion at band 22q11.2 detected by FISH with probe D22S75 FISH, fluorescence in situ hybridization. Modified from Mitelman F, ed. An international system for cytogenetic nomenclature. Basel: S Karger, 1995.

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Incidence of Chromosomal Abnormalities Estimates of the incidence of chromosomal abnormalities vary with the mode of ascertainment and the technology used for chromosomal analysis. In general, the incidence falls from conception to birth and then decreases with age after birth. The highest rates have been observed among products of conception from first-trimester spontaneous abortions. Upward of half of these conceptions demonstrated chromosomal abnormalities, most often triploidy or aneuploidy [Boue et al., 1973]. Estimates of incidence in the second trimester, based on results of amniocentesis, are higher than those at birth [Hook et al., 1983]. Jacobs and colleagues [1992] have estimated the frequency of balanced and unbalanced structural abnormalities in newborns based on the study of prenatal samples from 14,677 women. The frequency of unbalanced rearrangements was 0.061% and of balanced rearrangements, 0.522%.

Multiple Congenital Anomalies Genetic imbalance resulting from a chromosomal abnormality usually results in aberrant embryonic development. Most commonly this abnormal development involves multiple tissues, including the brain. Many specific syndromes can be recognized from a constellation of dysmorphic physical features and specific congenital anomalies. The clinician should be familiar with the most common syndromes, especially those resulting from trisomies 13, 18, and 21, as well as the sex chromosome aneuploidies (47,XXX, 47,XXY, and 45,X). Phenotypes resulting from duplication or deletion of smaller amounts of genetic material can be more difficult to identify clinically. Some of the more important syndromes are described in the next section. Some clues to the occurrence of a chromosomal abnormality are provided in Box 22-1. As a rule, chromosomal studies should be performed in a patient who exhibits congenital anomalies involving two or more tissues in whom a specific alternative diagnosis cannot be established and if the anomalies are not related to one another as cause and effect (e.g., hydrocephalus resulting from spina bifida).

Box 22-1 COMMON CLUES NEEDED FOR CHROMOSOMAL ANALYSIS Family History • Recurrent miscarriage • Infertility • Family history of congenital anomalies • Family history of balanced chromosome rearrangement Clinical Factors • Low birth weight/congenital microcephaly/dysmorphic features • Multiple congenital anomalies • Hemihypertrophy/significant body asymmetry • Pigmentary dysplasia (streaky hyper/hypopigmentation) • Infertility/delayed puberty • Unexplained developmental impairment

5qter 5pter

del(5)(pter) 5qter

FIGURE 22-5. Deletion of subtelomeric region of chromosome 5 demonstrated by fluorescence in situ hybridization. (Courtesy of A. Carroll, Birmingham, AL.)

Developmental Impairment In some chromosomal abnormalities, the phenotype is primarily that of developmental delay, with few or no congenital anomalies. Sometimes minor dysmorphic features are present, but these often are not noticed on routine examination. Fragile X syndrome and the presence of a supernumerary inverted duplication of chromosome 15 are examples. Chromosomal analysis and fragile X testing therefore should be considered in the evaluation of a child with unexplained developmental delay. Mental retardation is a common disorder that affects 1% to 3% of the population, and the cause is established in only 50% of the cases [Anderlid et al., 2002; Kriek et al., 2004]. Subtelomeric regions, localized proximal to the telomeres, are gene-rich regions. These subtelomeric regions have been found to be susceptible to chromosome changes (Fig. 22-5). It has been proposed that approximately 6% of the patients with idiopathic mental retardation have subtelomeric deletions or duplications [Flint, 1995]. These rearrangements can be detected by FISH analysis using subtelomeric probes [Anderlid et al., 2002].

Recurrent Miscarriage Chromosomal imbalance most often leads to miscarriage rather than to live birth. Carriers of balanced rearrangements, including translocations or inversions, may therefore come to attention through recurrent miscarriage [Flint and Gibb, 1996; Hook et al., 1989]. It is recommended that couples who have experienced two or more unexplained first trimester miscarriages be offered chromosomal analysis. Finding a balanced rearrangement permits genetic counseling of the couple, including offering prenatal diagnosis for future pregnancies. Other members of the family also may carry the balanced rearrangement and should be offered counseling and testing.

Prenatal Diagnosis Chromosomal analysis of a developing fetus can be achieved through collection of fetal cells by chorionic villus biopsy

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(CVS), amniocentesis, or peripheral umbilical blood sampling (PUBS) [D’Alton and DeCherney, 1993]. CVS involves sampling part of the fetal placenta using a biopsy device either passed through the cervix or inserted by a needle through the mother’s abdomen [Pijpers et al., 1988; Smidt-Jensen and Hahnemann, 1988]. It is performed at 10 to 12 weeks of gestation. CVS offers the advantage of early testing, with results available before the pregnancy is obvious. Early testing provides more privacy to the couple if termination of pregnancy is elected, as well as resolution at an earlier point in the pregnancy. The complication rate is estimated at around 1%. There is evidence that performance of CVS before 10 weeks is associated with an increased risk of limb or orofacial anomalies [Froster and Jackson, 1996; Holmes, 1993]. Amniocentesis involves sampling amniotic fluid at 16 to 18 weeks of gestation. Fetal cells in the fluid are cultured and can be used for chromosomal analysis. The complication rate is approximately 0.5%. Some centers offer earlier testing at 14 weeks [Johnson et al., 1996; Wilson et al., 1997]. PUBS is offered after 20 weeks of gestation and involves sampling fetal blood by nicking the umbilical vein under ultrasound guidance. Single cell analysis also is possible using FISH, and has been applied to preimplantation diagnosis of trisomy or familial translocation [Sermon et al., 2004]. Indications for prenatal testing are listed in Box 22-2. General practice is to offer prenatal testing for pregnancies in which the risk of a chromosomal abnormality exceeds the risk of a complication of the procedure. For couples in which one partner carries a chromosome rearrangement, prenatal testing to detect unbalanced chromosomes can be offered. The actual risk of unbalanced chromosomes in the pregnancy depends on the nature of the rearrangement but generally is greater than 1%. The laboratory performing the prenatal testing must be informed of the details of the rearrangement, to ensure that subtle changes are detected. The recurrence risk for future trisomy for a couple who have had one pregnancy affected with trisomy is approximately 1% [Lister and Frota-Pessoa, 1980]. This risk is irrespective of the particular chromosome involved in the trisomy. The risk of trisomy rises with maternal age; it is standard to offer prenatal testing to women who will be 35 years of age or older at the time of delivery. Pregnancies are increasingly being monitored for fetal anomalies by ultrasound or maternal serum screening.

Box 22-2 COMMON INDICATIONS FOR PRENATAL CYTOGENETIC DIAGNOSIS • Parent is carrier of balanced chromosome rearrangement • Advanced maternal age (older than 35 years of age at time of delivery) • Abnormality on ultrasound examination • Congenital anomaly • Short femur/thickened nuchal skin (indications of trisomy 21) • Echogenic bowel • Maternal serum screen indicative of increased risk of trisomy 21 or 18

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Ultrasound studies may identify a congenital anomaly or a feature, such as thickening of nuchal folds or short femur, each of which tends to be associated with chromosomal abnormalities [Bahado-Singh et al., 1995; Nyberg et al., 1990]. Maternal serum screening for α-fetoprotein, human chorionic gonadotropin (hCG), and unconjugated estriol can determine increased risk for trisomy 21 or trisomy 18 [Canick, 1990; Kloza, 1990; Knight and Palomaki, 1990; Staples et al., 1991]. Although such screening tests have relatively high frequencies of false-negative and falsepositive results, they can identify pregnancies for which further prenatal testing may be helpful. Integrated first- and second-trimester screening that uses both ultrasound technology and extended serum screening has been developed; with this approach, the false-positive rate has decreased and the detection rate for Down syndrome has increased in comparison with rates with second-trimester analyte screening alone [Fergal et al., 2003].

Chromosomes and Malignancy Genetic studies have revealed that cancer cells acquire their abnormal properties through a series of changes in the genetic information. These changes include gene mutations and chromosome rearrangements. The chromosome rearrangements result in abnormal gene dosage because of deletion or duplication, or in juxtapositions of genetic material that alter gene regulation. Consideration of the various genes that are involved in malignancy, many of which constitute oncogenes, is beyond the scope of this chapter. In several instances, however, specific chromosomal rearrangements have been associated with particular cancers. Chromosomal analysis can be helpful in these disorders to provide diagnostic information, to assess appropriate treatment and prognosis, and to follow response to therapy.

SPECIFIC CYTOGENETIC SYNDROMES Polyploidy Cytogenetics Tetraploidy is an infrequent chromosomal abnormality, but triploidy occurs fairly often. Most triploid embryos miscarry in the first trimester. In approximately 20% of first-trimester spontaneous abortions the conceptus is found to have a triploid karyotype. Liveborn infants with triploidy exhibit multiple congenital anomalies and rarely survive the newborn period. Those that do usually are mosaics (sometimes referred to as mixoploids, because diploid and triploid cell lines may arise from separate fertilizations) for a diploid and a triploid cell line.

Clinical Features The triploid phenotype is distinct and easily recognized [Philipp et al., 2004; Wertelecki et al., 1978]. Polyhydramnios or preeclampsia may complicate the pregnancy. The placenta may be large, and hydatidiform changes may be seen. Birth weight usually is low. Syndactyly involving

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the third and fourth digits is characteristic. Craniofacial features include low-set, malformed ears, hypertelorism, and micrognathia. Cardiac, renal, and central nervous system malformations are common. Males may have dysplastic external genitalia. Recent studies of the parental origin of the three chromosome sets in triploidy have revealed that a majority of affected persons have two maternal sets, perhaps because of more frequent survival to term of triploid fetuses with two maternal sets of chromosomes (digynic triploids) [McFadden et al., 1993; Miny et al., 1995]. Long-term survivors often are mosaics and may have less obvious phenotypic features [Carakushansky et al., 1994]. Body asymmetry and pigmentary dysplasia may be clues to chromosomal mosaicism in general, including, in some cases, triploidy [Woods et al., 1994].

Management Most triploid fetuses are spontaneously aborted or are stillborn. Most liveborn infants with full triploidy die in the early days of life. Survivors require supportive care for their congenital anomalies and developmental impairment.

Aneuploidy Only a minority of aneuploid embryos survive to term; the rest miscarry, usually in the first trimester. Only the most common trisomy and monosomy syndromes compatible with live birth are considered in the following discussion.

Trisomy 13 (Patau’s Syndrome) Cytogenetics Trisomy 13 occurs in approximately 1 in 10,000 live births [Wyllie et al., 1994]. A majority of affected persons have 47 chromosomes, with an extra copy of chromosome 13. Approximately 25% have trisomy because of translocation between 13 and another acrocentric chromosome, usually chromosome 14 (robertsonian translocation). Mosaicism

occurs in a small proportion of cases and may ameliorate the phenotype. Duplication of part of chromosome 13 resulting from unbalanced translocation can result in abnormal phenotypic features, although not necessarily similar to those seen in full trisomy 13.

Clinical Features Trisomy 13 is associated with congenital anomalies involving most major organ systems (Fig. 22-6). Holoprosencephaly is the hallmark central nervous system anomaly [Moerman et al., 1988], occurring in about 80% of cases. Incomplete division of the cerebral hemispheres and basal ganglia may be present in various degrees. The optic nerves and chiasm may be hypoplastic. Olfactory bulbs usually are absent. The abnormalities may include cerebellar hypoplasia and Arnold-Chiari malformation. Infants with trisomy 13 who demonstrate holoprosencephaly usually have accompanying craniofacial anomalies. The eyes may be set closely together (hypotelorism) or even fused in a single orbit (cyclopia). Other ocular anomalies include microophthalmia, iris colobomata, cataracts, and retinal dysplasia. Premaxillary agenesis and cleft lip or palate also may be present. Ulcer-like defects in scalp skin (cutis aplasia) occur commonly. Limb anomalies include postaxial polydactyly in two thirds of patients and rocker-bottom foot. Congenital heart defects, especially ventricular septal defect (VSD), are common, as are renal anomalies, including cystic dysplasia. The phenotype overlaps to some degree with that of MeckelGruber syndrome (encephalocele, polydactyly, polycystic kidney), inherited as an autosomal-recessive trait. This overlap underlines the importance of confirming the clinical diagnosis of trisomy 13 by chromosomal analysis.

Management Few infants with trisomy 13 survive the newborn period, with apnea being the most common cause of death [Rasmussen et al., 2003; Wyllie et al., 1994]. Often the anomalies are too numerous and severe to be corrected. In

FIGURE 22-6. Newborn with trisomy 13. (Karyotype courtesy of M. Rochon, Sherbrooke, Quebec, Canada.)

Descartes and Korf / Chromosomes and Chromosomal Abnormalities

the absence of life-threatening malformations, however, long-term survival has been well documented, albeit with severely impaired cognitive function [Baty et al., 1994a, 1994b].

Trisomy 18 (Edwards’ Syndrome) Trisomy 18 affects approximately 1 in 8000 live births. It is virtually always associated with a 47-chromosome karyotype, although a small proportion of affected newborns have a mosaic karyotype. Segregation of a parental balanced translocation may result in trisomy for part of the short or long arm of chromosome 18. Molecular analysis has revealed that most nondisjunction events that lead to trisomy 18 occur in maternal meiosis [Kupke and Müller, 1989].

Clinical Features Infants with trisomy 18 have low birth weight and microcephaly [Marion et al., 1988]. Other common features include a prominent occiput, low-set “simple” ears, and a small mouth (Fig. 22-7). Hands usually are tightly clenched in a characteristic configuration, with the fourth and fifth fingers overlapping the first and second. Terminal phalanges often are hypoplastic, and rocker-bottom foot may be present. Congenital heart defects, particularly redundancy of valve leaflets, occur in most cases [Balderston et al., 1990; Van Praagh et al., 1989]. Renal anomalies also are common. Brain malformations include heterotopias, agenesis of the corpus callosum, Dandy-Walker malformation, and ArnoldChiari malformation [Moerman et al., 1982]. Infants commonly are jittery and hypertonic and have apnea and seizures. Pigmentary dysplasia has been described in persons with mosaic trisomy 18 [Ohashi et al., 1992].

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Management No definitive treatment exists for trisomy 18. Most affected infants die in the neonatal period [Embleton et al., 1996; Rasmussen et al., 2003]. Long-term survivors have developmental impairment and require supportive care [Root and Carey, 1994].

Trisomy 21 (Down Syndrome) Trisomy 21 is the most common and widely recognized of the autosomal trisomy syndromes. It occurs in approximately 1 in 700 live births, with a striking increase in frequency with advanced maternal age [Epstein, 1995; Hook and Cross, 1989]. The frequency of Down syndrome at birth may be lower in areas in which prenatal screening and testing are offered. Prenatal diagnosis is offered to women who will be older than 35 years of age at the time of delivery, and up to 60% of pregnancies at risk can be identified by second-trimester maternal serum screening. Full trisomy 21 occurs in about 95% of cases [Mutton et al., 1996]. Most of these result from nondisjunction in the first division of maternal meiosis [Antonarakis and Down Syndrome Collaborative Group, 1991]. Translocation, usually between chromosome 21 and another acrocentric chromosome, most often chromosome 14, is identified in approximately 4%. These are robertsonian translocations. A parent who carries such a translocation while having 45 chromosomes may be at risk for recurrence of Down syndrome in offspring. Rarely, patients with clinical Down syndrome have only a partial trisomy of 21. The analysis of these rare cases suggested the existence of a critical region for Down syndrome (21q22.1-q22.3). Another chromosomal region on proximal 21q also may be responsible for Down FIGURE 22-7. Patient with trisomy 18 at 7 years of age. (Karyotype courtesy of M. Rochon, Sherbrooke, Quebec, Canada.)

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syndrome features [Antonarakis, 1998]. The remaining 1% of affected persons have a mosaic karyotype. The pathogenesis of the features of Down syndrome is attributed to increased dosage of genes on chromosome 21. The levels of gene expression apparently are tightly regulated, with increased levels of expression leading to aberrant development. Efforts are under way to identify specific genes responsible for specific components of the Down syndrome phenotype. New evidence indicates that dysregulation of several neuronal genes occurs in Down syndrome [Bahn et al., 2002]. One gene, called minibrain, has been localized to a region of chromosome 21 and may be involved in the cognitive phenotype [Hammerle et al., 2003; Smith et al., 1997].

Clinical Features Down syndrome consists of a set of characteristic physical features and developmental impairment (Fig. 22-8) [Cooley and Graham, 1991; Jackson et al., 1976; Preus, 1977]. Short stature and brachycephaly are characteristic, and mild microcephaly may be noted. Down syndrome growth charts are available and should be used to monitor growth in affected children [Cronk et al., 1988]. Craniofacial features include upslanted palpebral fissures, epicanthal folds, flat facial profile, and small, low-set ears with narrow ear canals. White speckles (Brushfield spots) may be seen on the iris.

A common finding is redundant folds of nuchal skin, which is one of the markers used for prenatal diagnosis by ultrasound examination [Gray and Crane, 1994]. Fingers are short, with incurving of the fifth finger (clinodactyly) and, often, a single transverse palmar crease. A wide space between the first and second toes is a frequent finding. The hallmark neurologic feature of Down syndrome is hypotonia. No gross central nervous system (CNS) malformation is consistently seen, although lack of normal growth of the brain is typical [Lott, 1986; Lott and Richardson, 1981]. Microscopic analysis has revealed impaired myelination, reduced density of neurons, malformed dendritic trees and spines, defective lamination of the cortex, and abnormality of synaptic density [Golden et al., 1994; Wisniewski, 1990]. Impaired neurologic development is a universal feature, but the degree of impairment varies widely [Pueschel et al., 1987]. Children with Down syndrome benefit from early intervention, physical therapy, and being reared in a family setting [Gath, 1981, 1990; Gath and Gumley, 1984]. An increased frequency of psychiatric problems, such as depression and behavioral problems including hyperactivity, disruptive behaviors, and repetitive behaviors, has been documented [Gath and Gumley, 1986; Myers and Pueschel, 1991; Pueschel et al., 1991]. Linguistic ability may be impaired out of proportion to cognitive impairment [Kernan, 1990; Kernan and Sabsay, 1996]. Seizures, including infantile spasms, may be seen with increased frequency but often FIGURE 22-8. A, Newborn with trisomy 21 (Down syndrome). B, Boy with Down syndrome at 12 years of age. (Karyotype courtesy of M. Rochon, Sherbrooke, Quebec, Canada.)

A

B

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are related to medical complications or their treatment [Pueschel et al., 1991; Stafstrom et al., 1991]. An increased frequency of dementia, associated with pathologic changes of Alzheimer’s disease, has been described in patients with Down syndrome [Iwatsubo et al., 1995; Johannsen et al., 1996; Lai and Williams, 1989; Schupf et al., 1996]. This increased frequency may be accounted for, at least in part, by increased expression of the amyloid precursor protein, the locus for which is on chromosome 21 [Cataldo et al., 2003; Teller et al., 1996]. Congenital anomalies commonly associated with Down syndrome include heart and gastrointestinal defects. The most typical heart defect is common atrioventricular (AV) canal, although other anomalies, such as VSD or tetralogy of Fallot, may be seen [Marino et al., 1990]. Gastrointestinal malformations include duodenal atresia and Hirschsprung’s disease.

Nutritional supplementation has been recommended for children with Down syndrome, although the benefits are not clearly documented. Some encouraging results have been reported in clinical trials with the anticholinesterase inhibitor donepezil in management of dementia in patients with Down syndrome [Lott et al., 2002]. Parents of children with Down syndrome should be counseled regarding the natural history of the disorder, opportunities for intervention, and genetic recurrence risks and should be provided emotional support. Life expectancy for persons with Down syndrome has improved with advances in surgery and medical treatment of complications of the disorder. Survival into the seventh decade is not unusual [Baird and Sadovnick, 1989].

Management

The only other autosomal trisomy compatible with live birth is trisomy 8. Even this is lethal in utero, except as a mosaic karyotype [Kurtyka, 1988]. Phenotypic features include hypertelorism; camptodactyly and other joint contractures; long, slender habitus; absence of patellae; and deep creases of the palms and soles (Fig. 22-9). Asymmetric growth, presumably due to chromosomal mosaicism, also may be a feature.

The American Academy of Pediatrics has published guidelines for management of children with Down syndrome [American Academy of Pediatrics Committee on Genetics, 2001]. Children with Down syndrome frequently require surgery for correction of congenital anomalies, such as heart defects or gastrointestinal malformations. They have a markedly increased risk of respiratory infection, often requiring antibiotic treatment. The frequency of leukemia is increased in children with Down syndrome. Transient leukemoid reactions also may occur. Children with Down syndrome are at risk for atlantoaxial dislocation. Whether screening for dislocation should be offered for children with Down syndrome, particularly those who will participate in sports activities, has been the subject of controversy [American Academy of Pediatrics Committee on Sports Medicine and Fitness, 1995; Cremers et al., 1993; Morton et al., 1995; Risser et al., 1995]. All children with Down syndrome should be monitored for neurologic signs of cervical cord compression. The American Academy of Pediatrics recommends obtaining radiographs once during the preschool years for this purpose.

Trisomy 8

Turner’s Syndrome Cytogenetics Turner’s syndrome is associated with a 45,X karyotype, with a single X chromosome. Mosaicism is not uncommon, however, with a separate cell line containing either a normal 46,XX or XY karyotype, or 46 chromosomes including a structurally rearranged X or Y [Crocker, 1992; Hassold et al., 1988; Jacobs et al., 1990; Kuznetzova et al., 1995]. Unlike in other aneuploidy syndromes, the frequency of Turner’s syndrome does not increase with advancing maternal age [Warburton et al., 1997]. FIGURE 22-9. A and B, Patient with trisomy 8 at 18 months of age. C, Same patient with trisomy 8 at 18 years of age. Note the deep palmar and plantar creases that are commonly seen in these patients. (Karyotype courtesy of M. Rochon, Sherbrooke, Quebec, Canada.)

A

B

C

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Genetic, Metabolic, and Neurocutaneous Disorders / 22 FIGURE 22-10. Girl with Turner’s syndrome: A, at 9 years of age; B, at 1 month of age; and C, at birth. (Courtesy of K. Khoury; karyotype courtesy of M. Rochon, Sherbrooke, Quebec, Canada.)

B A

C

Clinical Features Patients with Turner’s syndrome typically have a female phenotype, although those with a cell line including a Y chromosome may have some degree of virilization, often with ambiguous genitalia. At birth, infants may manifest pedal edema or diffuse edema (Fig. 22-10). Facial features include small mandible, narrow maxilla, and epicanthal folds. In older children and adults with Turner’s syndrome, short stature and webbing of the neck commonly are seen. The thorax is broad, with increased distance between the nipples. Extremity findings include cubitus valgus, short fourth metacarpal and metatarsal bones, and narrow or hyperconvex nails. Often multiple pigmented nevi are present on the skin. Congenital anomalies include anomalies of the lymphatic system, cardiac defects, especially coarctation of the aorta and bicuspid aortic valve, and renal anomalies, such as horseshoe kidney. Although mental retardation is rare, delays in both gross and fine motor development are common in females with Turner’s syndrome [Bender et al., 1993; Nijhuis van der Sanden et al., 2003; Salbenblatt et al., 1989]. Some patients display cognitive problems, but difficulties with visuospatial perception are most common [Bender et al., 1984; Pennington et al., 1982]. Hearing impairment is common and children should be monitored for deficits or progression of impairment.

have demonstrated increased growth with administration of growth hormone [Cianfarani et al., 1994; Ranke, 1995; Rocchiccioli et al., 1995]. Turner’s syndrome typically is associated with the presence of a streak gonad, lack of secondary sexual development, and infertility. Referral to an endocrinologist for hormonal induction of puberty should be done at an appropriate age [Hanton et al., 2003]. Intraabdominal gonads in patients with Turner’s syndrome who have a Y chromosome are at risk of transformation into gonadoblastoma and therefore should be removed.

Management

The diagnosis of Klinefelter’s syndrome usually is not suspected at birth. Affected males tend to be tall, with long limbs (Fig. 22-11). They display hypogonadism, and virilization may be incomplete at puberty; gynecomastia develops in some patients. Azoospermia and infertility are characteristic [Yoshida et al., 1997]. As in Turner’s syndrome, mental retardation is not a typical feature of Klinefelter’s syndrome, but learning disabilities, neuromotor developmental delay [Salbenblatt et al., 1987], and behavioral

Recommendations for diagnosis and management of Turner’s syndrome have been published [Rosenfeld et al., 1994; Seashore et al., 1995]. Newborns should be evaluated for renal and cardiac defects and monitored if these are found. Thyroid autoimmunity may a feature, so monitoring of thyroid function is required. Although not all children with Turner’s syndrome are growth hormone deficient, some

Klinefelter’s Syndrome Cytogenetics Klinefelter’s syndrome occurs in about 1 in 3000 males and is associated with a 47,XXY karyotype. The incidence increases as a function of maternal age [Carothers and Filippi, 1988]. Rare patients may have multiple X chromosomes (e.g., 48,XXXY or 49,XXXXY). Usually the presence of multiple X chromosomes in such persons is associated with more severe cognitive impairment.

Clinical Features

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physical stigmata are absent. XYY is associated with a male phenotype and tall stature but no other physical features. Learning disabilities and neuromotor impairment occur commonly in 47,XXX females [Bender et al., 1983, 1989, 1993, 1995; Pennington et al., 1982; Salbenblatt et al., 1989]. The behavioral phenotype of XYY syndrome has been a source of some controversy because of reports associating the karyotype with criminal behavior. The frequency of learning disabilities and behavioral problems is increased among affected males, although a wide range of cognitive outcomes have been reported [Fryns et al., 1995; Robinson et al., 1979].

Structural Abnormalities

FIGURE 22-11. Boy with Klinefelter’s syndrome at age 13 years. (Courtesy of K. Khoury; karyotype courtesy of M. Rochon, Sherbrooke, Quebec, Canada.)

problems [Salbenblatt et al., 1981] are common. Receptive and expressive language problems also have been reported [Bender et al., 1983; Pennington et al., 1982].

Management Children with Klinefelter’s syndrome require support at home and school for learning and behavioral problems. Testosterone is administered, beginning in adolescence, to improve secondary sexual development.

Other Sex Chromosome Aneuploidies Two other major sex chromosome aneuploidies are 47,XXX and 47,XYY. The XXX aneuploidy is associated with a female phenotype and tall stature; usually other major

Structural abnormalties of chromosomes cause phenotypic effects resulting from deletions or duplications of genetic material. In some cases, these occur sporadically as a result of de novo chromosome rearrangements, whereas in others, they may be inherited as a consequence of segregation of a familial balanced translocation. Major structural abnormalities began to be recognized in the early days of clinical cytogenetics, with several syndromes identified between 1960 and 1970. The advent of chromosome banding led to a second wave of discovery of syndromes resulting from more subtle rearrangements. More recently, the application of FISH has further increased the resolution of cytogenetic analysis and revealed a chromosomal basis for a group of “microdeletion syndromes” [Dallapiccola et al., 1995]. Some small deletion or duplication syndromes are fairly well characterized in terms of phenotypic effects and may be recognized clinically. Clinical diagnosis often is complicated, however, by a number of factors. First, most of these syndromes are exceedingly rare and are much less common than the trisomy syndromes. Second, the exact extent of deleted or duplicated material may differ from one affected child to another, leading to subtle but important variation in clinical manifestations. Third, many of these syndromes are seen as a consequence of malsegregation of a familial balanced translocation. The usual consequence is imbalance of two or more

TABLE 22-3 Important Deletion/Duplication Syndromes ABNORMALITY

CLINICAL FEATURES

CNS INVOLVEMENT

REFERENCE

Deletion terminal short arm chromosome 1 Deletion 4p (Wolf-Hirschhorn syndrome) Deletion 5p (cri du chat syndrome)

Developmental delay, seizures

Shapira et al., 1997

Developmental delay, seizures

Estabrooks et al., 1995

Hypotonia, developmental delay

Overhauser et al., 1994

Developmental delay

Wilson et al., 1985

Hypertonia, developmental delay

Huret et al., 1988

Holoprosencephaly, developmental delay

Brown S, et al., 1993

Inverted duplicated 15

Minor dysmorphic features (hypertelorism, cleft lip) Cleft lip, hypertelorism, microcephaly, growth retardation Low birth weight, catlike cry, microcephaly, hypertelorism Growth retardation, microcephaly, hypertelorism, brachydactyly Metopic suture synostosis (trigonocephaly), upslanting palpebral fissures Microcephaly, high nasal bridge, hypertelorism; risk of retinoblastoma if q14 deleted No characteristic dysmorphism

Cheng et al., 1994

Deletion 18p

Growth retardation, hypertelorism

Deletion 18q

Growth retardation, midface hypoplasia, microcephaly

Developmental delay, autistic features Holoprosencephaly, developmental delay Developmental delay, behavioral problems

Trisomy 9p Deletion 9p Deletion 13q

CNS, central nervous system.

Schinzel et al., 1974 Kline et al., 1993

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Genetic, Metabolic, and Neurocutaneous Disorders / 22

TABLE 22-4 Major Microdeletion Syndromes SYNDROME

MAJOR FEATURES

CHROMOSOME REGION

REFERENCE(S)

Monosomy 1p36

Severe psychomotor retardation, microcephaly, seizures, facial anomalies, and visual impairment Low-set malformed ears, digital anomalies, congenital heart defects Pre- and postnatal onset of growth retardation, microcephaly, characteristic facial appearance, seizures, unusual palmar creases, developmental delay Characteristic facies, supravalvar aortic stenosis, developmental impairment Exostoses, abnormal facies, developmental delay

1p36

Zenker et al., 2002

2q23q24.3

Mass et al., 2000

4p16

Clemens et al., 1998

7q11.23 elastin locus

Lowery et al., 1995

8q24.1 11p11.2

Prader-Willi syndrome

Multiple exostoses, biparietal foramina, minor craniofacial abnormalities, mental retardation Wilms’ tumor, aniridia, genitourinary dysplasia, mental retardation Retinoblastoma, mental retardation Hypotonia, blepharophimosis, ptosis, bulbous nose, long philtrum, upturned corners of mouth, mild developmental delay Hypotonia, developmental delay, obesity

Hou et al., 1995; Lüdecke et al., 1995 Hall et al., 2001

Angelman’s syndrome

Seizures, abnormal movements, mental retardation

15q12 UBE3A/E6-AP gene mutations

Interstitial 15q21 deletion

Mental retardation, growth retardation, beak-like nose with hypoplastic alae nasi, thin upper lip α-Thalassemia, mental retardation Microcephaly, characteristic facies, mental retardation Mental retardation, characteristic facies Lissencephaly, characteristic facies Peripheral neuropathy

15q21.1-q21.3

Knoll and Lalande, 1993 Kishino et al., 1997; Knoll and Lalande, 1993; Matsuura et al., 1997 Liehr et al., 2004

16p13.3 16p13.3 17p11.2 17p13.3 CMT: dup(17p12) HSPP: del(17p12)

Wilkie et al., 1990 Breuning et al., 1993 Greenberg et al., 1996 VanTuinen et al., 1988 Chance and Fischbeck, 1994

Intrahepatic biliary atresia, growth retardation, pulmonic stenosis, unusual facial features

20p11.2 Notched gene

Diamond-Blackfan anemia (DBA), mental retardation, skeletal malformations Cleft palate, conotruncal cardiac malformations, DiGeorge sequence (absent thymus, parathyroids), schizotypal and mood disorders Ichthyosis, anosmia

19q13.2

Li et al., 1997; Oda et al., 1997; Rand et al., 1995 Tentler et al., 2000

Ocular abnormalities, pathognomonic linear skin defects Mixed conductive sensorineural deafness, atypical Mondini-like dysplasia, dilated petrous facial canal and auditory meatus, large cochlear canal, wide posterior bulbous labyrinth

Interstitial 2q23 deletion Pitt-Rogers-Danks syndrome

Williams’ syndrome Langer-Giedion syndrome Potocki-Shaffer syndrome WAGR syndrome Retinoblastoma/mental retardation 14q terminal deletion

α-Thalassemia/mental retardation Rubinstein-Taybi syndrome Smith-Magenis syndrome Miller-Dieker syndrome Charcot-Marie-Tooth disease (CMT) type IA/hereditary susceptibility to pressure palsies (HSPP) Alagille’s syndrome 19q13 microdeletion DiGeorge’s/velocardiofacial syndrome Steroid sulfatase deficiency/ Kallmann’s syndrome Xp deletion syndrome X-linked progressive mixed deafness

distinct chromosome regions, resulting in a set of anomalies that combine the phenotypic effects of both segments. Some of the more common or clinically important deletion or duplication syndromes are summarized in Table 22-3. The microdeletion syndromes constitute a relatively recent addition to the list of disorders caused by chromosomal imbalance (Table 22-4). Most had been previously recognized as clinical entities, usually occurring sporadically and of unknown cause. In general, standard chromosomal analysis in persons with these syndromes is unrevealing. In rare instances, however, a chromosome deletion or other rearrangement drew

11p13 13q14 14q32.31-qter 15q12

Gessler et al., 1989; Rose et al., 1990 Janson et al., 1990 van Karnebeek et al., 2002

22q11

Arnold et al., 2001; Lindsay et al., 1995

Xp22.3

Ballabio et al., 1989

Xp22.3 Xq21

Paulger et al., 1997 Piussan et al., 1995

attention to a specific chromosome region, which was then subjected to further study using molecular techniques, especially FISH. This process has revealed deletions of chromosomal material in other persons with the same disorders but with chromosomal defects below the limits of resolution of the light microscope [Gopal Rao et al., 1995]. The clinical phenotypes of microdeletion syndromes may be explained in two ways. First, many of these are “contiguous deletion syndromes.” That is, a cluster of closely linked genes are simultaneously deleted, leading to a complex phenotype that reflects the contributions of multiple genes.

Descartes and Korf / Chromosomes and Chromosomal Abnormalities

Specific components of the phenotype may be present or absent in any given case, depending on the extent of deletion. This mechanism is operative, for example, in the WAGR (Wilms’ tumor, aniridia, genitourinary dysplasia, and mental retardation) association, occurring with deletion of a region on the short arm of chromosome 11 [Gessler et al., 1989]. Depending on the extent of deletion, features may include Wilms’ tumor, aniridia, genitourinary anomalies, and developmental impairment, or some combination of these features. The second mechanism is that deletion results in altered or absent expression of one critical gene in the region that itself leads to a complex phenotype. Deletion is likely to be one of many mechanisms of mutation of the gene; thus, FISH analysis will not reveal the deletion in all affected persons. This mechanism accounts for Rubinstein-Taybi syndrome [Breuning et al., 1993], Angelman’s syndrome [Matsuura et al., 1997], and Alagille’s syndrome [Li et al., 1997; Oda et al., 1997; Rand et al., 1995]. These two mechanisms, of course, are not mutually exclusive. Deletion of a major gene may account for much of a particular phenotype, but deletion of contiguous genes may contribute additional phenotypic features in some patients.

Imprinting Disorders The recognition of the phenomenon of genomic imprinting has led to the discovery of a new class of genetic disorders

A

557

B

FIGURE 22-12. Boy with Prader-Willi syndrome: A, at 7 months of age; B, at 6 years of age. (Karyotype courtesy of M.G. Mattei, Marseilles, France.)

FIGURE 22-13. Boy with Angelman’s syndrome at 6 years of age. (Karyotype courtesy of M. Rochon, Sherbrooke, Quebec, Canada.)

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Genetic, Metabolic, and Neurocutaneous Disorders / 22

associated with aberrations of imprinted genes. The prototype disorders are Prader-Willi and Angelman’s syndromes (Figs. 22-12 and 22-13). The features of these syndromes are described in Table 22-5. Although distinct from one another clinically, both have been found to be associated with deletions of the same region of chromosome 15 in about two thirds to three fourths of cases [Knoll and Lalande, 1993]. How this could account for such different phenotypic effects was a mystery until it was found that deletions resulting in PraderWilli syndrome invariably are of the paternal copy of the chromosome region, whereas maternal deletions occur in Angelman’s syndrome [Donlon, 1988; Knoll et al., 1989]. Most patients with Prader-Willi syndrome who do not have deletions have uniparental disomy for chromosome 15, with two maternal copies and no paternal 15 [Woodage et al., 1994]. Either mechanism—deletion or uniparental disomy— leads to deficiency of a gene or genes on chromosome 15 that are expressed in the paternal but not the maternal chromosome. Paternal uniparental disomy accounts for a low percentage of cases of Angelman’s syndrome [Nicholls et al., 1992; Saitoh et al., 1994]. Mutations in the UBE3A/E6-AP gene, located at 15q11.2, have been found in some patients with Angelman’s syndrome [Kishino et al., 1997; Matsuura et al., 1997]. This gene is imprinted in the brain [Albrecht et al., 1997; Rougeulle et al., 1997] and is the gene responsible for the Angelman syndrome phenotype. No single gene has so far been implicated in the pathogenesis of Prader-Willi syndrome. A small proportion of patients with Prader-Willi or Angelman’s syndrome may have a small deletion or other mutation that leads to aberrant imprinting of the region [Buiting et al., 1995]. These findings have led to major advances in genetic diagnosis of Prader-Willi and Angelman’s syndromes.

Chromosome 15 deletions usually are submicroscopic but are easily detected by FISH [Bettio et al., 1995; Delach et al., 1994; Dewald et al., 1996; Smith et al., 1995]. Defects in imprinting or uniparental disomy can be identified by studies of patterns of DNA methylation in the region [Beuten et al., 1996; Buiting et al., 1994; Dittrich et al., 1996; GillessenKaesbach et al., 1995; Monaghan et al., 1997; Van den Ouweland et al., 1995; Zeschnigk et al., 1997]. One particular cloned segment of DNA is methylated in the maternal but not the paternal genome. Failure to identify the methylated or nonmethylated copy of the sequence is indicative of deletion, uniparental disomy, or a mutation that alters the imprinting mechanism. Although the full extent of imprinted genes is not yet known, a growing list of clinical disorders have been found to be associated with imprinted regions (Table 22-6) [Ledbetter and Engel, 1995]. TABLE 22-6 Chromosome Regions Known to Include Imprinted Genes and Disorders Associated with Deletions or Uniparental Disomy for These Regions Chromosome Region

Disorder

15q11-q13

Prader-Willi syndrome or Angelman’s syndrome (see Table 22-5) Beckwith-Wiedemann syndrome (macrosomia, omphalocele, macroglossia, hemihypertrophy) Short stature (Russell-Silver syndrome) Short stature, developmental delay

11p 7q 14

TABLE 22-5 Comparison of Features of Prader-Willi and Angelman’s Syndromes Feature

Prader-Willi Syndrome*

Angelman’s Syndrome†

Diagnostic criteria

Major clinical criteria Neonatal hypotonia Feeding problems in infancy Rapid weight gain between 1 and 6 years of age Characteristic facies Hypogonadism Developmental delay Hyperphagia Minor criteria Decreased fetal movement Characteristic behaviors Sleep disturbances Short stature Small hands Narrow hands Esotropia/myopia Thick, viscous saliva Speech articulation defects Skin picking Supportive findings High pain threshold Decreased vomiting 70% to 75% deletion 15q11-q13 paternal sequence 20% to 25% maternal disomy Unknown

Consistent features (100%) Developmental delay Speech impairment Movement disorder (ataxia of gait, tremulous movement of limbs) Behavioral features: frequent laughter or smiling, hand flapping Frequent features (80%) Acquired microcephaly Seizures (usually in patients younger than 3 years) Abnormal EEG (high-amplitude 2- to 3-Hz spike-wave discharges) Associated features (20% to 80%) Flat occiput, occipital groove Protruding tongue Prognathism Wide mouth and widely spaced teeth Drooling, chewing, mouthing movements Strabismus Hypopigmentation Brisk lower limb deep tendon reflexes Sleep disturbance

Cytogenetic Uniparental disomy Gene

*Data from Holm V, et al. Pediatr 1993;91:398. †Data from Williams CA, et al. Am J Med Genet 1995;56:237. EEG, electroencephalogram.

65% to 75% deletion 15q11-q13 maternal sequence 2% paternal disomy Mutations in UBE3/E6-AP on chromosome 15

Descartes and Korf / Chromosomes and Chromosomal Abnormalities

559

Fragile X Syndrome

TABLE 22-7

Fragile X syndrome often is considered along with chromosomal disorders, because fragility of the distal region of the X chromosome is a marker of the disorder. The condition is known to be the result of a mutation of a specific gene on the X chromosome, with the fragility of the X chromosome being a consequence of the nature of the mutation.

Number of CGG Repeats in Premutation Allele and Risk of Full Mutation*

Incidence The prevalence of fragile X syndrome has been estimated to be as high as 1 in 1000 males, making it one of the more common genetic causes of mental retardation. This estimate is based on the use of a chromosomal assay to diagnose fragile X syndrome. With use of a DNA-based assay, a recent study suggests that the true prevalence may be 1 in 2000 to 1 in 3000 [Morton et al., 1997].

Genetics The fragile X syndrome was identified as a unique entity that accounts for X-linked transmission of mental retardation when it was found that affected males exhibit fragility of the distal end of the X chromosome [Lubs, 1969]. This fragility is expressed at its highest frequency when cells for analysis are grown in culture medium deficient in thymidine, and the frequency is further increased by growth in the presence of 5-fluorodeoxyuridine, a thymidylate synthetase inhibitor [Sutherland, 1977]. For many years, growth of cells in special media followed by counting of the proportion that exhibited the fragile X phenotype was the mainstay of laboratory diagnosis [Dewald et al., 1992]. Fragile X syndrome exhibits the transmission pattern of X-linked inheritance, with no male-to-male transmission [Barbe et al., 1996; Barnes, 1989]. Unlike in classical Xlinked recessive traits, however, both males and females can be affected. Also, an unusual pattern of transmission was observed in large families, wherein the gene was transmitted from an unaffected male to an unaffected daughter, who then had affected children [Sherman et al., 1985]. This pattern of transmission is not expected for an X-linked trait, because males who carry the mutant gene should manifest the phenotype. This pattern came to be known as the Sherman paradox. The basis for both the Sherman paradox and the fragility of the X chromosome has come to light since the gene responsible for fragile X syndrome was cloned [Oberle et al., 1991; Verkerk et al., 1991; Yu et al., 1991]. The gene is designated FMR1 (fragile X mental retardation) and is expressed at high levels in neurons [Devys et al., 1993]. FMR1 includes a region near the promoter in which the triplet of bases CGG is repeated multiple times. The exact number of repeats is polymorphic, with repeat numbers ranging from 5 to 50 times in the general population [Kolehmainen, 1994]. Repeats within this range have no impact on the expression of FMR1 and have no phenotypic effect. Persons with fragile X syndrome, by contrast, have repeat numbers of more than 200, often substantially greater. This degree of expansion correlates with hypermethylation of the promoter region of the gene and lack of FMR1 expression.

No. of CGG Repeats

Risk of Expansion to Full Mutation

56 to 59 60 to 69 70 to 79 80 to 89 90 to 199

13.4% 20.6% 57.8% 72.9% 97.3%

*Risk that an FMR1 premutation allele in mother will expand to full mutation in offspring. Data from Nolin SL, et al. Am J Hum Genet 1996;59:1252.

The Sherman paradox is explained by the mechanism of transition from a wild type of allele to a mutant allele [Fu et al., 1991]. This transition occurs through an intermediate step known as premutation. Premutation alleles have repeat expansions in the range of approximately 50 to 200 repeats. These alleles tend to be unstable and may expand to full mutation in a subsequent generation. Nonmanifesting males, therefore, have premutations. Expansion to full mutation does not occur in males. The Sherman paradox is therefore explained by the passage of premutations from males to their daughters, who in turn pass full mutations to some of their offspring. The risk of expansion to full mutation is a function of the size of the premutation allele (Table 22-7) [Nolin et al., 1996; Turner et al., 1994]. Discovery of the molecular basis for fragile X syndrome has led to development of a robust DNA diagnostic test [Rousseau et al., 1991, 1994]. Most laboratories use a method based on Southern blot analysis, and a PCR-based assay can be used to precisely measure the size of permutation alleles [Brown et al., 1993; Kaplan et al., 1994]. Some patientss with fragile X have been found to be mosaics, having both a premutation and a full mutation allele [Cohen et al., 1996; Dobkin et al., 1996; Nolin et al., 1994]. Presumably these mutations arise by postzygotic expansion of a premutation. These patients may demonstrate the fragile X phenotype, although in some cases it may be milder than in a nonmosaic. Some persons with full mutations have some nonmethylated full mutation alleles, which also may ameliorate the phenotype [Hagerman et al., 1994]. The fragile X DNA assay has greatly improved both the sensitivity and the specificity of fragile X diagnosis. For patients tested in the past by cytogenetics alone, DNA testing should be offered either to confirm the fragile X diagnosis or to rule out a false-negative cytogenetic diagnosis. A separate fragile site has been identified on the X chromosome, designated fragile X type E (X-E) (distinguished from the classic fragile X, designated fragile X type A) [Holden et al., 1996]. Fragile X-E also is the result of a triplet repeat expansion in a different gene that is located near the fragile X-A gene. Fragile X-E also can be associated with X-linked mental retardation, although the full fragile X phenotype is not seen in affected persons. Fragile X-E apparently is rare compared with fragile X-A. Although expansion of the CGG repeat is the basis for fragile X syndrome in the vast majority of affected persons, other mutations also have been seen rarely [De Boulle et al., 1993]. In particular, several patients have been reported to

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Genetic, Metabolic, and Neurocutaneous Disorders / 22

have deletions in the FMR1 gene [Albright et al., 1994; De Graaff et al., 1996; Mannermaa et al., 1996; Meijer et al., 1994; Quan et al., 1995a, 1995b; Tarleton et al., 1993]. The pathogenesis of fragile X syndrome appears to be due to lack of expression of FMR1 in neurons, so any mutation that causes this defect will produce the fragile X phenotype. The protein is an RNA-binding protein and is thought to be involved in regulation of mRNA translation in neurons [Zalfa and Bagni, 2004].

Clinical Features The major phenotypic feature of fragile X syndrome is the occurrence of mental retardation [Prouty et al., 1988]. Developmental milestones are delayed, including gross motor and language. Intelligence quotient (IQ) scores for affected males generally are less than 70 [Morton et al., 1997; Prouty et al., 1988], and IQ may decline with age [Hagerman et al., 1989; Wright-Talamante et al., 1996]. Although males with fragile X syndrome may display autistic-like features [Malmgren et al., 1992], they do not fulfill criteria for autism [Einfeld et al., 1989], and cognitive and adaptive abilities may exceed those seen in children with pervasive developmental disorder [Fisch et al., 1994a]. Behavioral features include shyness and avoidance of eye contact [Einfeld et al., 1994]. Males with fragile X syndrome may display distinctive features that can aid in diagnosis. Birth weight usually is normal, but head circumference and height tend to be above average [De Vries et al., 1995; Prouty et al., 1988]. The face may be long, and ears tend to be large [Loesch and Wilson, 1989; Loesch et al., 1988]. Macro-orchidism can be an important clinical clue to the diagnosis of fragile X syndrome but may not be evident until after puberty [Lachiewicz and Dawson, 1994].

Females with fragile X full mutations also may display cognitive impairment [Cronister et al., 1991; Fisch et al., 1994b; Hagerman et al., 1992; Sobesky et al., 1996]. The frequency of cognitive problems in females with full mutation is approximately 50%, no doubt as a result of the phenomenon of X-chromosome inactivation. If the X chromosome bearing the fragile X mutation is inactivated preferentially, the phenotypic effects of the full mutation may be ameliorated or even eliminated. The clinical recognition of fragile X syndrome can be challenging. The presence of an IQ of less than 70, family history compatible with X-linkage, elongated face, large or prominent ears, and attention deficit- and autistic-like behaviors are useful predictors [Giangreco et al., 1996]. Children suspected of having fragile X syndrome often are found to have other chromosomal anomalies, so standard cytogenetic analysis should be performed along with fragile X testing. Numerous other syndromes are associated with X-linked mental retardation, many of which are difficult to diagnose using clinical or molecular tests [Sutherland et al., 1994]. Premutation carriers do not have mental retardation but may present with one (or more) of three distinct clinical disorders: mild cognitive and/or behavioral deficits on the fragile X spectrum; premature ovarian failure; and a more recently described neurodegenerative disorder of older adult carriers: fragile X–associated tremor/ataxia syndrome (FXTAS) [Hagerman et al., 2004]. Involvement in FXTAS consists of progressive intention tremor, gait ataxia, parkinsonism, and autonomic dysfunction, with associated features of peripheral neuropathy with decreased sensation and vibration sense in the distal lower extremities, as well as cognitive deficits involving loss of memory and executive function. Neuroimaging demonstrates symmetric hyperintensities on T2-weighted MR images of the middle cerebellar peduncles, and eosinophilic, intranuclear inclusions

TABLE 22-8 Major Syndromes Associated with Disorders of DNA Replication and Repair SYNDROME

FEATURES

GENETIC CAUSE

REFERENCE(S)

Ataxia-telangiectasia

Ataxia, telangiectasia, immune deficiency, lymphoma Short stature, photosensitive skin, risk of malignancy, increased frequency of sister chromatid exchange Short stature, premature aging, malignancy Congenital anomalies, aplastic anemia, chromosome breakage increased with alkylating agents or mitomycin C Photosensitive skin, freckling, skin cancer Abnormal skin and hair, short stature, developmental impairment

Mutations in ATM gene; cell cycle checkpoint for repair of DNA damage Mutations in helicase gene involved in DNA replication and recombination

Telatar et al., 1996

Bloom’s syndrome

Werner’s syndrome Fanconi’s anemia

Xeroderma pigmentosum Trichothiodystrophy Cockayne’s syndrome Nijmegen’s breakage syndrome

Photosensitive skin, white matter degeneration, cerebral calcification, dwarfism Progessive microcephaly, growth retardation, immunodeficiency, and cancer predisposition

Ellis and German, 1996; Ellis et al., 1996

Helicase gene mutations (distinct from Bloom’s syndrome gene) Genetically heterogeneous

Epstein and Motulsky, 1996; Yu et al., 1997 Tischkowitz and Hodgson, 2003

Defective excision repair of ultraviolet light–induced DNA damage Defective excision repair of ultraviolet light–induced DNA damage; possible effect on transcription Defective excision repair of ultraviolet light–induced DNA damage; possible effect on transcription Defective response to DNA douse-strand breaks

Tanaka and Wood, 1994 Chu and Mayne, 1996; Takayama et al., 1996 Van der Horst et al., 1997 Varon R et al., 1998

Descartes and Korf / Chromosomes and Chromosomal Abnormalities

have been found in neurons and astrocytes throughout the brain [Hagerman and Hagerman, 2004].

Management Guidelines for the care of patients with fragile X syndrome have been published [Desposito et al., 1996]. Children with fragile X syndrome should be provided with full developmental assessment and require supportive services to enhance developmental outcome. Medical issues include hyperextensibility of joints [Hagerman et al., 1984], which may lead to orthopedic problems, and an increased frequency of mitral valve prolapse [Crabbe et al., 1993]. Diagnosis of fragile X syndrome should prompt a discussion with the parents about the genetic risks, and carrier testing should be offered not only to the immediate family but also to more distant relatives who may be carriers of a premutation [McConkie-Rosell et al., 1997; Staley-Gane et al., 1996; Von Koskull et al., 1994].

Chromosome Breakage Syndromes It has long been recognized that certain inherited disorders are associated with an increased frequency of spontaneous chromosome breakage. Many of these disorders include a prominent neurologic component (Table 22-8), and most are known to represent disorders of DNA replication or repair. In general, routine cytogenetic studies are not the ideal approach to diagnosis of these disorders, although detection of an increased rate of sister chromatid exchange is still used to diagnose Bloom’s syndrome [Chaganti et al., 1974], and finding of cells with rearrangements of chromosomes 7 and 14 may support a diagnosis of ataxia-telangiectasia. The genes responsible for most of these syndromes have been identified, however, and genetic analysis is increasingly being used to evaluate the patient with a suspected clinical diagnosis.

FUTURE OF CLINICAL CYTOGENETICS Technical developments have driven advances in the diagnosis and management of disorders resulting from chromosomal imbalance. Over the past several decades we have moved from the discovery of conditions that are due to the presence of a complete extra chromosome to the recognition of syndromes resulting from deletions of tiny amounts of genetic material. In some cases, such microdeletions will result in mutations that affect single genes. Continuing technical advances are likely to further increase the resolution of cytogenetic analysis and potentially bridge the gap between the light microscopic detection of chromosomal changes and changes at the singlegene level. FISH has played a major role in this effort and is being applied to the study of submicroscopic deletions at the gene level. FISH also is being used to detect subtle chromosome rearrangements. The development of sets of FISH probes that distinguish each chromosome with a unique color (“spectral karyotyping”) provides a means of identifying rearrangements involving small chromosome regions, even in tumor cells that typically include multiple rearrangements. FISH also is providing reagents for studies of nondividing cells, permitting analysis of interphase nuclei for aneuploidy.

561

This procedure can result in more rapid diagnosis of trisomy or detection of low levels of trisomic cells in individuals with mosaicism. The sequencing of the human genome is providing a new set of tools likely to further bridge the gap between cytologic and molecular analysis. It has become clear that small deletions or duplications of genetic material can underlie developmental disorders, and establishing clinical diagnoses for each of these conditions will be difficult. The use of comparative genomic hybridization with microarrays of cloned segments of human DNA may provide a means for generalized screening of the genome for such changes. It is doubtful that the etiology of all chromosomal abnormalities will ever be fully understood, because many seem to be the result of random genetic events. Decades of research have not disclosed any definitive risk factors for nondisjunction other than advanced maternal age. More sensitive techniques for examination of chromosomal abnormalities in germ cells may permit more precise studies of the incidence and risk factors of nondisjunction. Similarly, as the mechanisms of control of DNA replication and cell division are better understood, both environmental and genetic factors that may predispose to chromosomal abnormalities may come to light. Improved methods of noninvasive prenatal cytogenetic investigation may play an increasing role in prenatal diagnosis. The true power of modern genetic analysis is best appreciated when the physician can incorporate genetic studies into day-to-day practice without being concerned about the underlying technical details. That time has not yet arrived in the application of clinical cytogenetics. The clinician must be alert to the possibility of microdeletion syndromes or fragile X, for example. Nevertheless, understanding of the basis of neurologic disease has expanded to include an appreciation of the prominent role of genetic factors in most neurologic disorders, and such factors increasingly are proving to be the key to diagnosis and understanding of basic pathogenesis. REFERENCES Albrecht U, Sutcliffe JS, Cattanach BM, et al. Imprinted expression of the murine Angelman syndrome gene, UBE3A, in hippocampal and Purkinje neurons. Nat Genet 1997;17:75. Albright SG, Lachiewicz AM, Tarleton JC, et al. Fragile X phenotype in a patient with a large de novo deletion in Xq27-q28. Am J Med Genet 1994;51:294. American Academy of Pediatrics Committee on Genetics. Health supervision for children with Down syndrome. Pediatrics 2001;107:442. American Academy of Pediatrics Committee on Sports Medicine and Fitness. Atlantoaxial instability in Down syndrome: Subject review. Pediatrics 1995;96:151. Antonarakis SE and Down Syndrome Collaborative Group. Parental origin of the extra chromosome in trisomy 21 as indicated by analysis of DNA polymorphisms. N Engl J Med 1991;324:872. Auerbach AD. Fanconi anemia. Dermatol Clin 1995;13:41. Bahado-Singh RO, Goldstein I, Uerpairojkit B, et al. Normal nuchal thickness in the midtrimester indicates reduced risk of Down syndrome in pregnancies with abnormal triple-screen results. Am J Obstet Gynecol 1995;173:1106. Baird PA, Sadovnick AD. Life tables for Down syndrome. Hum Genet 1989;82:291. Balderston SM, Shaffer EM, Washington RL, et al. Congenital polyvalvular disease in trisomy 18: Echocardiographic diagnosis. Pediatr Cardiol 1990;11:138.

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CHAPTER 23

Aminoacidemias and Organic Acidemias Gregory M. Enns, Tina M. Cowan, Ophir Klein, and Seymour Packman

Approximately 4% of individuals born in the United States have a genetic or partly genetic disorder. Inborn errors of metabolism contribute significantly to this total. Although individually rare, the aggregate incidence of metabolic disease is relatively high and may be greater than 1 in 1000 newborns. Newborn screening programs using tandem mass spectrometry, which can detect approximately 20 inborn errors of metabolism, typically have reported an incidence of 1 in 2000 to 1 in 4000. Because there are hundreds of known metabolic conditions, the aggregate estimate seems reasonable. Metabolic diseases infrequently produce symptoms immediately at birth, and they can manifest with slowly progressive encephalopathies. In this setting, histologic or biochemical abnormalities may be present in the fetal central nervous system by 4 to 5 months’ gestation. Inborn errors of metabolism also can manifest with rapid clinical deterioration in the newborn period or after an interval period of good health. Presenting clinical features are often nonspecific, and they may be misdiagnosed as infection, cardiovascular compromise, other causes of hypoxemia, trauma, primary brain anomalies, or the effects of a toxin. Recognition of patterns of clinical presentation and rapid implementation of laboratory investigations are essential for the initiation of appropriate therapy without delay. Unless appropriate therapy is initiated with dispatch, there is a high risk of morbidity or mortality, regardless of the cause of the acute illness. This chapter provides an overview of concepts of diagnosis and treatment for two categories of inborn errors: aminoacidopathies and organic acidemias. The general approaches described are broadly applicable to other heritable metabolic disorders, such as disorders of fatty acid oxidation, urea cycle disorders, and lactic acidosis syndromes. Descriptions of selected disorders of amino acid and organic acid metabolism are provided to illustrate and emphasize the approaches to diagnosis, treatment, and genetic counseling in this area of genetic medicine.

SIGNS AND SYMPTOMS Any infant, child, or adult who presents with neurodevelopmental delays, lethargy, feeding difficulties, vomiting, jaundice, failure to thrive, apnea or tachypnea, hypotonia or hypertonia, ataxia, movement disorders, seizures, or coma should be considered to suffer from diseases in one of two broad categories: disorders resulting from causes such as infection, cardiopulmonary dysfunction, other causes of hypoxemia, toxins, or trauma or from primary brain abnormalities or disorders caused by an inborn error of me-

tabolism. Because metabolic diseases are individually rare, there is a tendency to consider them only after excluding more common causes of acute or chronic illness or distress. However, the clinician must consider the possibility of an inborn error on initial presentation. In many cases, only rapid diagnosis and management can prevent death or significant morbidity. Appropriate laboratory investigations should be obtained immediately. Even conventional clinical laboratory tests such as those for blood gases, blood glucose, electrolytes, lactate, ammonia, liver function, hematologic counts and indices, and urinalysis (including pH, ketones, mellituria, and concentration) may provide valuable clues to the underlying diagnosis. The onset of symptoms of metabolic disease is generally postnatal, often appearing after an interval of apparent good health. This interval may be as short as a few hours or last several days to years. An affected individual may fare well until subjected to a catabolic insult (e.g., infection, fasting, dehydration) or an excessive protein or carbohydrate load, after which the infant, child, or adult may suddenly become strikingly ill. In a neonate, the absence of a normal period of apparent good health does not exclude an inborn error from diagnostic consideration. Neonatal distress from asphyxia or pregnancy complications may be the environmental stress that unmasks an underlying metabolic disease. Irritability and feeding difficulties may be associated with uncoordinated sucking or swallowing or with abnormal muscle tone. Persistent and severe vomiting and seizures may occur. In mildly affected patients, symptoms can disappear, only to recur in days or weeks. More severely affected infants and children have inexorable progression from lethargy to coma, episodic apnea, and death. More limited symptoms, often in the form of generalized or partial seizures, may occur in some instances. These can include staring spells, eye rolling or myoclonus, and various combinations of tone abnormalities, tremulousness, lethargy, and a weak cry. The electroencephalogram may suggest nonspecific, diffuse encephalopathy. Unless an inborn error is suspected, the child may be misdiagnosed as having hypoxic-ischemic encephalopathy, intraventricular hemorrhage, sepsis, heart failure, or gastrointestinal illness (e.g., pyloric stenosis, intestinal obstruction).

PHYSICAL FINDINGS A paucity of abnormal physical findings is the general rule in heritable metabolic diseases. Nevertheless, certain components of the physical examination should be emphasized. A detailed ocular examination is essential. Corneal clouding, cataracts, optic nerve abnormalities, and macular or

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retinal pigmentary changes may be helpful in establishing a diagnosis. Hepatomegaly can occur with organic acidemias that may have a Reye syndrome–like presentation. Alopecia, abnormal hair, or nonspecific eczematoid dermatitis may be seen in some aminoacidopathies and organic acidemias. An unusual odor of the child’s body or urine has been associated with several organic acidemias and disorders of amino acid metabolism. Ketosis accompanies many of these conditions, and ketone bodies in the urine cause its sweet odor. Although dysmorphic features suggest the diagnosis of a congenital developmental disorder rather than a heritable metabolic disorder, craniofacial and structural abnormalities of organ systems are being recognized in an increasing number of inborn errors of intermediary metabolism.

LABORATORY APPROACHES TO DIAGNOSIS Because the clinical presentation of patients with metabolic disorders is often nonspecific and suggests a wide variety of conditions, a rational and systematic laboratory approach is imperative for rapid and accurate diagnosis to implement early and appropriate treatment. It is rarely possible to base a precise diagnosis on clinical findings or results of routine laboratory tests. Laboratory testing for the symptomatic patient can proceed at many levels, including metabolic screening tests, quantitative metabolite profiles, specific enzyme or other functional assays, and DNA mutation analysis. The specific laboratory approach is often dictated by the clinical and family history and by results of routine laboratory investigations. An extensive description of diagnostic algorithms for the laboratory evaluation of patients suspected of having a metabolic disease has been published [Saudubray and Charpentier, 2001]. For the acutely ill patient, a comprehensive evaluation should include quantitative assessment of plasma amino acids, urine organic acid analyses, plasma carnitine (free and total) levels, and identification and quantitation of acylcarnitines in plasma or serum. These tests should be ordered in conjunction with other basic tests, including hematologic cell counts, electrolytes, blood glucose, blood gases, uric acid, liver transaminases, ammonia, and lactic and pyruvic acid levels. This approach can identify many cases of amino acid disorders and organic acidemias. The interpretation of metabolic tests is greatly enhanced when the laboratory is made aware of the clinical, medication, and dietary history of the patient because these factors can significantly influence results. Depending on the clinical evaluation and results of basic chemistry studies, additional testing may be warranted; these may include levels of urine orotic acid (e.g., elevated in certain urea cycle defects) (see Chapter 24), cerebrospinal fluid glycine (together with the plasma glycine level, which is elevated in glycine encephalopathy), cerebrospinal fluid neurotransmitters (see Chapter 30), and urine S-sulfocysteine (elevated in sulfite oxidase deficiency or molybdenum cofactor deficiency). Laboratory investigations are most useful when samples are collected during an acute episode, because metabolic abnormalities are most pronounced at that time. However, subtle abnormalities can often be appreciated even between episodes, particularly if the laboratory is made aware of the

clinical evaluation at the time of testing. However, normal results, particularly if obtained when the patient is well, do not exclude a metabolic disorder and should be followed by repeat testing of specimens obtained during an acute illness if possible. Metabolic screening tests in urine can be useful in certain situations, particularly in the assessment of older patients with a nonspecific history of developmental delay or mental retardation. Such testing includes qualitative amino acid screening by thin-layer chromatography or paper chromatography, the ferric chloride test for phenylketones (for identification of phenylketonuria and tyrosinemia), the cyanide-nitroprusside test for sulfur-containing amino acids (for identification of homocystinuria), and other colorimetric or flocculation tests. When taken in conjunction with clinical and other laboratory finding, these tests can give an inexpensive and rapid indication of an abnormality, and they can be useful in determining the direction of more specific testing. These tests are not appropriate in the evaluation of an acutely ill patient, for whom specific, quantitative metabolic studies are essential. Depending on the results of initial metabolic studies, confirmation of the diagnosis or delineation of specific disease subtypes may be established by specific enzyme assays. If the expression of enzyme activity is tissue specific, a biopsy (e.g., skin, muscle, liver) may be required. After a precise biochemical diagnosis has been established, molecular studies for the specific gene mutation may be possible. In many cases, delineation of the specific mutations can provide important prognostic information and can be used in the testing of other family members and in prenatal diagnosis.

TREATMENT For all inborn errors, acute symptoms must be treated immediately, regardless of the cause, and often before the results of screening and specialized laboratory tests become available. The success of treatment is a function of time; the longer the neurologic derangements persist before treatment, the poorer the prognosis. Because acidosis (or alkalosis) is observed in these disorders, acid-base status must be corrected immediately, along with necessary adjustments in electrolyte balance and hydration. Glucose infusions should be used as a source of calories and used to control hypoglycemia, if present. Hemodialysis can improve a number of disorders of amino acid and organic acid metabolism, and it should be instituted if the evidence suggests such a disorder. Selective avoidance of a particular nutrient or class of nutrients is specific and crucial. This generally means avoidance of one or more specific micronutrients that can accumulate proximal to the metabolic block. Protein should be avoided in the acute phase of treatment of any child presenting with neurologic dysfunction; continuation of dietary protein in a child with an aminoacidopathy or organic acidemia can be lethal. The response to protein avoidance may be of diagnostic help. When specific nutritional restrictions are instituted for a known or suspected inborn error, attention must be paid to adequate total caloric intake—by parenteral or oral administration—to prevent catabolism and to avoid iatrogenic nutritional deficiencies.

Enns, Cowan, Klein, and Packman / Aminoacidemias and Organic Acidemias

Specific supplements may be invaluable as treatment adjuncts under the general strategy designed to remove toxic metabolites by alternative or minor pathways. In selected disorders, glycine supplementation promotes the formation of rapidly excreted and nontoxic acylglycine conjugates. Carnitine administration favors the formation and excretion of acetylcarnitine and other acylcarnitines, thereby ameliorating ketosis and the accumulation of toxic organic acid metabolites in organic acidemias. A number of inborn errors respond favorably and, in some instances, dramatically to the administration of vitamins, which stabilize or otherwise increase the catalytic activity of incompletely defective enzymes. Vitamins such as cobalamin (B12), pyridoxine, thiamine, biotin, riboflavin, lipoate, folate, and niacin, administered in pharmacologic doses, may be lifesaving. In a child who is gravely ill and whose course has been one of inexorable decline, it is appropriate to administer a battery of rationally chosen cofactors and supplements in the hope that the child’s biochemical lesion will respond to one of the pharmacologic agents.

INHERITANCE AND GENETIC COUNSELING Treatment of heritable metabolic disorders involves considerations beyond the acute phase of the illness and even beyond the prognosis of the proband. Because of the importance of genetic counseling to the family, the physician has an obligation to try to arrive at a diagnosis, however poor the prognosis for the proband. Identifying a specific entity enables the family to be counseled about recurrence risks. Most inborn errors of metabolism are inherited as autosomal recessive traits. There are a few disorders, such as the urea cycle defect of ornithine transcarbamylase deficiency, that are inherited as X-linked disorders. In the case of an autosomal recessive condition, the affected relative is a sibling of either gender. In X-linked disorders, the affected relative may be a maternal uncle, a brother, or a mildly affected mother or other female relative. Some disorders are caused by mitochondrial DNA mutations (see Chapter 28), and maternal transmission to all children in a sibship is observed. In all circumstances, a detailed family history may reveal an affected relative who has a similar illness, and this can be of diagnostic importance. Special attention should be given to a family history of stillbirths, unexplained deaths, and neurologic diseases or delayed development of any degree or severity. The therapeutic repertory for inborn errors is expanding beyond nutritional manipulations and restrictions of micronutrient precursors proximal to a metabolic block. Modalities being used or clinically investigated include cofactors as pharmacologic agents in vitamin-responsive inborn errors; enzyme inhibitors to prevent the synthesis of a toxic metabolite; enzyme-stabilizing agents; organ transplantation (e.g., liver, bone marrow); enzyme replacement therapy; and gene therapy. Such therapies may be intrusive and expensive. Genetic counseling for inborn errors must include a discussion of recurrence risk and address issues related to therapeutic options, prognosis, prenatal management, and the emotional, psychologic, and financial burdens of the birth and long-term treatment of children with such chronic disorders. Many of the inborn errors discussed in this chap-

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ter and elsewhere can be diagnosed prenatally, giving families a number of reproductive options. The successful prenatal treatment of cofactor-responsive disorders and the expanding repertory of other novel postnatal treatment approaches augur an increasing focus on unique therapeutic opportunities in inborn errors.

AMINOACIDEMIAS Phenylketonuria Phenylketonuria, described by Asbørn Følling in 1934 [Følling, 1994], is caused by deficient activity of phenylalanine hydroxylase (PAH), a hepatic enzyme that converts phenylalanine to tyrosine (Fig. 23-1). The biochemical block results in the accumulation of phenylalanine, which is then converted to phenylpyruvic acid and phenyllactic acid, phenylketones that are excreted in the urine. Tetrahydrobiopterin is a necessary cofactor in the PAH reaction, and elevated phenylalanine levels rarely may be caused by inherited disorders of tetrahydrobiopterin synthesis, including guanosine triphosphate (GTP) cyclohydrolase I, 6-pyruvoyltetrahydrobiopterin synthase, pterin-4α-carbinolamine dehydratase, and dihydropteridine reductase deficiencies (see Fig. 23-1). Phenylalanine is neurotoxic, and untreated patients with classic phenylketonuria are typically mentally retarded. In the 1950s, a diet in which phenylalanine intake was restricted was shown to normalize plasma phenylalanine levels and stop urinary excretion of phenylpyruvic acid [Bickel et al., 1953]. Selective restriction of phenylalanine intake by using phenylalanine-free medical formulas and foods (and tyrosine supplementation), which provides enough additional protein and nutrients to support normal growth, remains the mainstay of phenylketonuria therapy. Mandatory population newborn screening for phenylketonuria, in combination with postnatal presymptomatic therapy, was begun in the 1960s using the Guthrie bacterial inhibition assay [Guthrie and Susi, 1963; Koch, 1997]. Modern newborn screening programs have switched to techniques that directly assay phenylalanine and tyrosine levels; the most recent innovation is tandem mass spectrometry. The presymptomatic institution of and continued adherence to specific dietary therapy prevents mental retardation. Phenylketonuria is a paradigmatic and landmark success story in biochemical genetics, and it is reviewed in some detail.

Classification A blood phenylalanine level above the normal range (30 to 110 μM) is referred to as hyperphenylalaninemia. Patients have been classified as having nonphenylketonuria hyperphenylalaninemia if their blood phenylalanine levels without dietary therapy are 360 to 600 μM. Classic phenylketonuria is characterized by untreated phenylalanine levels of more than 1000 μM [Scriver and Kaufman, 2001]. A range of reduced PAH-specific activity correlates broadly with the severity of the phenotype. When it has been measured directly (i.e., liver biopsy) or indirectly (i.e., 13 L-[1- C]phenylalanine breath test), residual liver PAHspecific activity is relatively high in milder hyperphenylal-

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Genetic, Metabolic, and Neurocutaneous Disorders / 23 Phenylanine

Tyrosine

Phenylalanine hydroxylase

(1) 4␣–Hydroxytetrahydrobiopterin (2)

7,8–Dihydrobiopterin (BH2)

6–Pyruvoyltetrahydropterin 6–Pyruvoyltetrahydropterin (5) synthase

Tetrahydrobiopterin (BH4) (6) Sepiapterin reductase

Dihydroneopterin GTP cyclohydrolase

Carbinolamine dehydratase

Dihydropteridine reductase

(4) GTP

(3) NAD⫹

NADH

FIGURE 23-1. Regulation of phenylalanine hydroxylase activity. Phenylalanine is converted to tyrosine (1) by the holoenzyme phenylalanine hydroxylase (PAH). PAH requires tetrahydrobiopterin (BH4) as an active cofactor and is recycled by the sequential actions of carbinolamine dehydratase (2) and dihydropteridine reductase (3). BH4 is synthesized in vivo through a complex series of steps that involve guanosine triphosphate (GTP) cyclohydrolase (4), 6-pyruvoyltetrathydropterin synthase (5), and sepiapterin reductase (6). Genetic defects at any of these steps may be associated with hyperphenylalaninemia. (From Wilcox WR, Cederbaum SD. Amino acid metabolism. In: Rimoin D, Connor J, Pyeritz R, Korf B, eds. Principles and practice of medical genetics, 4th ed. Philadelphia: Churchill Livingstone, 2002:2406.)

aninemic patients, whereas enzyme activity is zero-to-low in the more severe cases of classic phenylketonuria [Bartholome et al., 1975]. Measured PAH activity also correlates to some degree with tolerance for dietary protein [Güttler et al., 1996]. Patients with classic phenylketonuria can tolerate very little phenylalanine in the diet (<500 mg/day). The classification of phenylketonuria into subtypes based on blood phenylalanine levels is arbitrary, and some patients (i.e., mild, variant, or atypical phenylketonuria) fall between the two extreme biochemical phenotypes. Because environmental (phenylalanine intake) and genetic (modifier genes) factors alter the biochemical and neurodevelopmental phenotypes in this single-gene disorder, phenylketonuria in many ways behaves more like a complex trait than a monogenic disorder [Kayaalp et al., 1997].

Clinical Manifestations Profound mental retardation is the most significant clinical finding in untreated or poorly treated phenylketonuria. Acute metabolic encephalopathy, a common feature of many inborn errors of metabolism, does not occur in phenylketonuria. Children with phenylketonuria appear normal at birth and have normal early development, even if untreated. Neurologic manifestations appear insidiously and include reduced rate of growth of head circumference, developmental delay, abnormalities in muscle tone, and hyperactive deep tendon reflexes. Affected children may have lighter pigmentation than other family members (i.e., reduced melanin synthesis) and a musty odor attributed to phenylacetic acid. Eczema and decreased bone mineral density

may occur [Zeman et al., 1999]. Patients exposed to chronically elevated phenylalanine levels ultimately develop microcephaly, seizures (e.g., tonic-clonic, myoclonic, infantile spasms), tremors, athetosis, and spasticity, and they may be misdiagnosed as having cerebral palsy. Psychiatric and behavior problems, including autistic behavior and attention-deficit–hyperactivity disorder, are common [Pietz et al., 1997; Smith and Knowles, 2000]. Brain magnetic resonance imaging (MRI) may detect dysmyelination, especially T2 enhancement in the periventricular white matter, a finding that is potentially reversible with the initiation of dietary therapy [Cleary et al., 1995]. Abnormal areas of white matter demonstrate restricted diffusion of water, possibly indicating increased myelin turnover [Phillips et al., 2001]. In the past, most untreated phenylketonuria patients were institutionalized, and many born before universal newborn screening remain so. An eloquent and inspiring description of the life of a child with untreated phenylketonuria is given in a short monograph by Pearl S. Buck [Buck, 1950]. As a rule, well-treated classic phenylketonuria patients have normal IQs. Dietary control of the blood phenylalanine level appears to be the best predictor of ultimate IQ [Waisbren et al., 1987], but careful psychometric testing of welltreated individuals has detected instances and degrees of impairment in visual-motor skills, abstract reasoning, problem solving, specific aspects of executive control, attention, verbal memory, expressive naming, and verbal fluency [Fishler et al., 1987]. Such neuropsychologic impairments may be a consequence of mid-dorsolateral prefrontal cortex dysfunction caused by abnormal catecholamine levels

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[Huijbregts et al., 2002]. Abnormal electroencephalographic patterns, including general slowing and generalized paroxysmal activity with or without spikes, may be demonstrated for children with phenylketonuria, even if they are well treated [Pietz et al., 1988]. Emotional disorders (e.g., depression, anxiety, phobias) and hyperactive behavior are more frequently encountered in persons with classic phenylketonuria than in the general population [Smith and Knowles, 2000]. However, untreated mild hyperphenylalaninemic patients are not at risk for developing neuropsychologic impairment [Weglage et al., 1996].

Maternal Phenylketonuria Syndrome Elevated maternal blood phenylalanine levels can cross the placenta and cause fetal birth defects, including microcephaly, dysmorphic features, and congenital heart defects. Children with the maternal phenylketonuria syndrome are typically heterozygous for the mutant PAH allele, and they are not affected with phenylketonuria. More than 90% of children born to women with untreated classic phenylketonuria have mental retardation; 70% have microcephaly, 40% have intrauterine growth retardation, and 12% have congenital heart disease [Lenke and Levy, 1980]. The risk to the fetus is greatest with increasing phenylalanine levels in maternal blood. Dietary control should be achieved before conception, and mothers with phenylketonuria should be monitored carefully by an experienced center throughout pregnancy. Optimal birth outcomes occur when blood phenylalanine levels between 120 and 360 μM are achieved by 8 to 10 weeks’ gestation [Widaman and Azen, 2003]. Mothers with phenylketonuria can safely breast-feed their children.

Diagnosis The Guthrie bacterial inhibition assay was a technical breakthrough, allowing newborn screening of large populations. The growth inhibition of Bacillus subtilis by β-2-thienylalanine is prevented by phenylalanine, phenylpyruvic acid, and phenyllactic acid, and this forms the basis of the Guthrie test. Fluorometric assays or tandem mass spectrometry is used in screening and monitoring [Chace et al., 1993]. False-positive results may be seen in neonates with low birth weight or liver disease or in infants on parenteral alimentation. False-negative results may occur if the newborn screen is performed too early (especially less than 12 hours after birth) [Hanley et al., 1997]. Confirmation of the diagnosis is made by analysis of blood phenylalanine and tyrosine concentrations by means of high-performance liquid chromatography, fluorescent methods, or tandem mass spectrometry. Without the introduction of a phenylalaninerestricted diet, maximal elevation in plasma phenylalanine is typically reached within or soon after the first week of life in patients with classic phenylketonuria. Urine phenylpyruvic acid causes the appearance of a deep green color when ferric chloride is added. This ferric chloride test is sometimes performed as part of a metabolic screening panel for the evaluation of patients suspected of having an inborn error of metabolism, but it should not be used to confirm a diagnosis of phenylketonuria because of a lack of sensitivity and specificity. All patients with confirmed hyperphenylalaninemia must have urine pterins analyzed for defects

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in tetrahydrobiopterin metabolism. Phenylketonuria may be suspected in a child or adult and should reasonably be included in the differential diagnosis of a given patient of any age presenting with neurodevelopmental delay of unknown origin. In such settings, diagnostic testing for phenylketonuria (i.e., serum phenylalanine levels) must be done, even if there is a history or a record of a normal newborn screen.

Genetics Phenylketonuria is an autosomal recessive disorder with an incidence of 1 case per 10,000 people in the general white population of northern European ancestry [Eisensmith and Woo, 1994]. Phenylketonuria is more common in Turkey, Scotland, Czechoslovakia, and Arabic populations and among Yemenite Jews (1 case per 2500 to 5000 persons). It is relatively uncommon in Japan, Finland, and African Americans (1 case per 100,000 to 200,000 persons) [Scriver and Kaufman, 2001]. Nonphenylketonuria hyperphenylalaninemia has an overall incidence of 1 case per 50,000 persons. The PAH gene on chromosome 12q24.1 spans 90 kb and contains 13 exons [Kwok et al., 1985]. Almost 500 mutations have been reported throughout all exons and flanking sequences. A detailed account of PAH mutant alleles and other DNA variations is maintained at the PAH Mutation Analysis Consortium web site (http://www.pahdb.mcgill.ca/) [Waters and Scriver, 1998]. Most DNA alterations are missense mutations, although splice, nonsense, and frameshift mutations and large deletions and insertions have been identified. Most patients are compound heterozygotes, carrying a different mutant allele on each chromosome. Prevalences of specific mutant alleles differ from population to population [Eisensmith and Woo, 1994]. For example, R408W, IVS12nt1, and IVS10nt11 are severe mutations that account for about 50% of mutant alleles in Europeans, but they are rare in Asians. Conversely, mutant alleles R243Q, R413P, and Y204C are common in Asians, but they rare in Europeans [Eisensmith and Woo, 1994].

Pathogenesis Although PAH is a hepatic enzyme, the major effect of its deficiency is brain dysfunction. Elevated phenylalanine appears to be the cause of neurotoxicity. However, the precise cause of the mental retardation observed in untreated phenylketonuria is not understood. Defective brain myelination may be related to decreased biosynthesis of myelin proteins, because brain protein synthesis is inhibited by excessive phenylalanine [Huether et al., 1982]. Central nervous system effects may be ascribable to more global amino acid imbalances; elevated phenylalanine may affect the central nervous system concentrations of neutral amino acids by competitive inhibition of a shared amino acid transporter, with relative brain deprivation of tyrosine, tryptophan, and branched-chain amino acids [Huttenlocher, 2000]. Decreased brain tyrosine and tryptophan may lead to decreased neurotransmitter synthesis. The cause of abnormal brain myelination is also unclear. In a phenylketonuria mouse model (i.e., enu2 mouse), there is evidence that oligodendrocytes overexpress glial fibrillary acid protein

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Genetic, Metabolic, and Neurocutaneous Disorders / 23

and become nonmyelinating [Dyer et al., 1996]. Increased myelin turnover has also been observed in the enu2 mouse [Hommes and Moss, 1992]. In phenylketonuria patients studied by positron emission tomography (PET), brain protein synthesis appears to be impaired, which could also affect the myelination process [Paans et al., 1996]. Brain pathology in untreated classic phenylketonuria includes abnormalities in width of the cortical plate, cell density and organization, dendritic arborization and number of synaptic spines, and abnormal myelination [Bauman and Kemper, 1982].

Genotype-Phenotype Correlations Mutations in the PAH gene cause phenylketonuria and nonphenylketonuria hyperphenylalaninemia. However, the final biochemical phenotype (i.e., blood phenylalanine level and dietary phenylalanine tolerance) and clinical phenotype (i.e., IQ) depend on the severity of the mutations and are influenced by patient adherence to a strict diet, the effects of modifying genetic factors, and other environmental factors. Potential modifier genes may encode proteins mediating interindividual rates of protein synthesis (and phenylalanine use) or basal metabolism; synthesis and degradation of the PAH enzyme protein; gastrointestinal absorption of phenylalanine; hepatic uptake of circulating phenylalanine; metabolism of the tetrahydrobiopterin cofactor; and rate of phenylalanine transport across the blood-brain barrier [Dipple and McCabe, 2000; Treacy et al., 1997]. Because patients—including sibling patients—with identical mutations can have divergent neurodevelopmental progress, mutation identification may not predict the severity of the disease with certainty in a given patient [DiSilvestre et al., 1991; Enns et al., 1999b]. Genes encoding proteins responsible for transport of amino acids across the blood-brain barrier are especially attractive candidates for modifying factors in phenylketonuria. In a study of two siblings with identical genotypes but widely different IQ, in vivo nuclear magnetic resonance spectroscopy documented lower peak brain phenylalanine levels and more rapid decreases in brain phenylalanine concentration in the less severely affected sibling after a phenylalanine load [Weglage et al., 1998]. Subsequent studies have confirmed the wide interindividual variation of brain to blood phenylalanine concentrations in classic phenylketonuria patients with divergent cognitive phenotypes [Moller et al., 2003]. Despite these considerations, trends can be identified in whole populations. In general, individuals with classic phenylketonuria and poor dietary control have mental retardation, although exceptions exist. If patients with severe mutations are started on strict dietary therapy in the neonatal period and maintained on such treatment throughout life, cognition will be normal. Using in vitro expression analysis in cultured cells transfected with mutant cDNAs, specific mutant alleles (i.e., genotype) can be categorized as severe or mild; such categorization correlates with biochemical or clinical severity (i.e., phenotype) in most patients in relatively homogenous populations. In a study of German and Dutch subjects, the predicted level of PAH activity correlated strongly with neonatal pretreatment levels of blood phenylalanine and dietary phenylalanine tolerance in both populations [Okano

et al., 1991]. In relatively homogeneous German, Swedish, and southeastern U.S. populations, similar genotypephenotype correlations were observed [Eisensmith et al., 1996; Kayaalp et al., 1997; Trefz et al., 1993]. However, when populations with high ethnic diversity are studied in this way, a clear genotype-phenotype correlation may not be apparent [Enns et al., 1999b; Treacy et al., 1997], and the genotype-phenotype correlation is not straightforward in some patients. Although phenylketonuria is a single-gene mendelian disorder, the observed clinical spectrum is more in keeping with a complex multifactorial trait [Scriver and Waters, 1999].

Genetic Counseling After the diagnosis of phenylketonuria, a family is likely to be first seen by the medical care team after the newborn screening process has confirmed the diagnosis. The initial emphasis is on the institution of nutritional therapy, the support of the family, and the conveying of information on the broadly favorable prognosis. Genetic counseling in phenylketonuria cases is a continuing process. Understanding by parents and patients of the nature of the disorder, the genetics of the disorder, and the complexities of the phenotype and prognosis occurs over time during the course of multiple clinic visits. Mutation analysis, with characterization of both parental alleles, is possible, and it may facilitate detection of carrier status in other family members and subsequent prenatal diagnosis. Genotyping may eventually prove valuable in predicting a patient’s phenotype, helping to optimize therapy and aiding determination of long-term prognosis. However, because phenylketonuria behaves in many ways like a complex trait, care is needed when interpreting genotypic data. In the instance of a child with milder hyperphenylalaninemia or atypical phenylketonuria, recurrence risk counseling must consider the possibility that such mild hyperphenylalaninemia may not be the only outcome in a subsequent homozygous affected child. If one parent is a compound heterozygote for a mild and a severe mutation, but the other parent is a heterozygote for a severe mutation, their child may be born with classic phenylketonuria. Accordingly, after ascertainment of a child with milder hyperphenylalaninemia or atypical phenylketonuria, measuring the blood phenylalanine levels of the parents and characterizing both parents’ mutations are important studies to obtain. Patients who are diagnosed in the neonatal period and who adhere to the phenylalanine-restricted diet have normal intelligence. However, learning problems can occur in welltreated patients and include problems in basic spelling, reading, and mathematical calculation skills. Patients may also be more prone to depression, anxiety, phobic tendencies, and isolation from their peers [Smith and Knowles, 2000; Welsh et al., 1990]. Such potential adverse and unpredictable manifestations should be brought to the attention of parents and carefully explained, with care and support, during the ongoing genetic counseling process.

Treatment Medical nutrition therapy consists of using modified lowphenylalanine and low-protein products, supplemented by a

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small amount of natural protein to provide required amounts of phenylalanine. After an initial positive newborn screen, a confirmatory determination of blood phenylalanine level must be obtained without delay. Dietary restriction of phenylalanine is begun only after a diagnosis of phenylketonuria has been established or if the initial level is more than 600 μM as anticipatory management with the advice and collaboration of a metabolic center skilled in the management of phenylketonuria patients. Total elimination of phenylalanine from the diet is not done for longer than 1 to 2 days, because phenylalanine deficiency leads to tissue catabolism and rebound elevation of blood phenylalanine levels. It is important to screen for the presence of disorders affecting tetrahydrobiopterin metabolism if confirmatory testing corroborates persistent hyperphenylalaninemia. If the low-phenylalanine diet is initiated in the neonatal period (between 7 and 14 days) and maintained throughout life, the underlying biochemical toxicity is ameliorated, and mental retardation is prevented. In the neonatal period, breast-feeding is possible and should be encouraged in any mother who desires to do so. Breast milk contains a lower protein (and lower phenylalanine) concentration than commercial formulas, and it can be used in conjunction with the special phenylketonuria formulas required to provide the infant with appropriate calories, nutrients, and protein for sustained, normal growth. Significant restriction of dietary phenylalanine is required for treatment, but the exact level of daily phenylalanine intake varies from patient to patient and varies with age in an individual patient. Because phenylalanine is an essential amino acid, detrimental effects on growth and development may occur if restriction of phenylalanine intake is too severe, and the blood level drops to below normal. Although there is no worldwide consensus about optimal plasma phenylalanine levels, most clinics in the United States strive to maintain levels between 120 and 360 μM in children younger than 12 years and between 120 and 600 μM in individuals older than 12 years [Phenylketonuria, 2000]. Phenylalanine levels in unaffected individuals are usually below 120 μM. In general, phenylketonuria patients who harbor severe mutations require a greater limitation of phenylalanine intake to maintain acceptable blood phenylalanine levels. However, individual variations of phenylalanine tolerance may occur, even in patients with identical genotypes. Blood phenylalanine levels therefore are monitored frequently, especially in the first year of life, and the diet is adjusted with care for each individual patient. The regimen must be initiated and overseen by experts in phenylketonuria at a specialized center, and referral of the patient to such a specialized center is mandatory. An expert, coordinated team approach is clearly the most effective way of managing phenylketonuria; stricter management improves developmental outcome [Camfield et al., 2004]. In earlier therapeutic protocols, phenylalanine restriction was continued only through the first few years of life, theoretically corresponding to the age at which brain myelination is complete. As developmental data accumulated, it became evident that treatment throughout childhood and adolescence was the best course to preserve IQ [Smith et al., 1991]. In later studies, it has been found that characteristic periventricular T2 white matter signal abnormalities on conventional MRI, restricted white matter diffusion in

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diffusion-weighted imaging, and electrophysiologic testing abnormalities referable to the central nervous system are observed in adults who are on unrestricted phenylalanine intake or poorly compliant with dietary therapy [Phillips et al., 2001]. There is evidence that MRI changes in cases of phenylketonuria are at least partially reversible if patients return to a low-phenylalanine diet [Cleary et al., 1995]. Accordingly, it is reasonable to continue therapy into adulthood, and most centers recommend lifelong treatment. A variety of medical food products is available as special formulas for the treatment of phenylketonuria. These special formulas are low in phenylalanine or do not contain any phenylalanine, and they typically contain supplemental tyrosine and a balanced mixture of the additional amino acids, carbohydrates, essential fatty acids, vitamins, and minerals, including zinc, selenium, and molybdenum. The metabolic medical foods provide a variable amount of calories (up to 70% of daily requirement) in the form of starch (e.g., dextrose, cornstarch, dextromaltose, Polycose) and fat (i.e., corn or other oils), and they constitute a major source of nutrition for the lifetime of the patient. The special formula or medical food, containing no phenylalanine, is continued even after solid food is introduced. The special formula or medical food is ingested together with regular food during the same meal, providing the phenylalanine in food plus the amino acids, vitamins, and nutrients in the special formula in a complementary, beneficial manner. The medical and regular foods therefore should be given in a calculated proportion together in intervals throughout the day. Overall, the targeted total amino acid intake for children younger than 2 years is approximately 3 g/kg/day, and it is about 2 g/kg/day for older children [Cockburn and Clark, 1996]. If the medical food is ingested in a single sitting, the supply of amino acids may induce hyperinsulinism and hypoglycemia. Medical food products continue to be modified to increase palatability and optimize the treatment of phenylketonuria. Amino acid powders and gels with added carbohydrate and with or without fats, vitamins, and minerals are examples of commonly used protein substitutes. Newer protein substitutes include amino acid tablets and capsules, which do not contain carbohydrate, vitamins, or minerals. Special amino acid bars are also available. Phenylketonuria dietary research has focused on making the medical food products more palatable. Although lowphenylalanine flour, pastas, cookies, and nutrition bars are available, the phenylketonuria diet remains very bland, and poor dietary compliance can be a major problem, especially after childhood. Early efforts to make a more palatable amino acid mixture have met with preliminary success, with some patients preferring the new products to traditional medical foods. It is important to monitor periodically complete blood cell counts and serum vitamin B12 levels, because clinical and subclinical B12 deficiency has been reported in adolescents and adults with classic phenylketonuria, even in those poorly compliant with the restricted diet [Hanley et al., 1996]. In contrast to the strict dietary control required in the treatment of classic phenylketonuria, patients with nonphenylketonuria hyperphenylalaninemia (i.e., blood phenylalanine levels of 360 to 600 μM) are not placed on the special diet in most instances. These patients have normal

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Genetic, Metabolic, and Neurocutaneous Disorders / 23

intelligence, and they do not have the psychologic findings or head MRI changes that have been documented in classic phenylketonuria [Weglage et al., 1996]. Dietary therapy may be recommended in some instances for pregnant women with nonphenylketonuria hyperphenylalaninemia to minimize the risk of maternal phenylketonuria syndrome.

Additional and Novel Therapies A complementary therapeutic approach has received U.S. Food and Drug Administration approval: administration of dietary supplementation of large, neutral amino acids. Large, neutral anino acids compete with phenylalanine for transport across the blood-brain barrier by the L-type amino acid carrier and consequently decrease the level of phenylalanine in the central nervous system [Matalon et al., 2003]. In a study of six adult subjects with classic phenylketonuria, large, neutral amino acid supplementation resulted in increased blood concentrations of tyrosine and tryptophan (the respective precursors for dopamine and serotonin) and decreased brain phenylalanine concentration, as measured by 1H-magnetic resonance spectroscopy (MRS), toward the carrier range. All patients reported improvements in wellbeing and energy levels [Koch et al., 2003]. Deficiencies of carnitine and long-chain polyunsaturated fatty acids (i.e., arachidonic and docosahexaenoic acids) may contribute to central nervous system toxicity in uncontrolled phenylketonuria. Dietary supplementation of these fatty acids and of carnitine may benefit phenylketonuria patients who have low plasma levels of these essential metabolites [Infante and Huszagh, 2001]. Supplementation with omega-3, long-chain, polyunsaturated fatty acids resulted in improvement in visual-evoked potential latencies in 36 children with early-treated phenylketonuria [Beblo et al., 2001]. A novel therapeutic approach uses the nonmammalian enzyme phenylalanine lyase. This enzyme converts phenylalanine to trans-cinnamic acid, a harmless compound, and it has been found to reduce hyperphenylalaninemia in phenylketonuria rat and mouse models [Bourget and Chang, 1986; Sarkissian et al., 1999]. Enteral phenylalanine lyase therapy has the theoretic potential to substantially increase dietary phenylalanine tolerance, but significant practical hurdles need to be overcome; phenylalanine lyase is destroyed by gastric acidic pH and intestinal proteolysis. An alternative approach being considered uses polyethylene glycol derivatization to produce protected forms of PAH for potential enzyme replacement therapy [Gamez et al., 2004]. Oral administration of tetrahydrobiopterin, the naturally occurring cofactor for the PAH reaction, reduces serum phenylalanine concentrations, especially in patients with mild hyperphenylalaninemia [Muntau et al., 2002]. However, response to tetrahydrobiopterin has also been documented in patients with classic or variant phenylketonuria [Matalon et al., 2004]. These patients have mutations in the PAH gene, not in one of the genes encoding enzymes involved in tetrahydrobiopterin biosynthesis (see “Biopterin Disorders”). It has been suggested that the PAH mutations in such patients affect the structure of domains that are involved in the binding of tetrahydrobiopterin to the PAH enzyme. Tetrahydrobiopterin also may act as a

chemical chaperone, preventing the PAH enzyme from misfolding or protecting PAH from inactivation [Pey et al., 2004]. If these observations and hypotheses are borne out, it may be possible to define by mutation analysis a subset of patients who would predictably benefit from cofactor supplementation. Tetrahydrobiopterin may prove useful in the treatment of maternal phenylketonuria [Trefz and Blau, 2003].

Biopterin Disorders Neonatal hyperphenylalaninemia may rarely be caused by defects in the synthesis or recycling of tetrahydrobiopterin, an essential cofactor in the PAH reaction (see Fig. 23-1). Worldwide, it has been estimated that approximately 2% of patients with hyperphenylalaninemia have a defect in one of the four enzymes responsible for maintaining tetrahydrobiopterin levels [Blau et al., 1996]. Guanosine triphosphate cyclohydrolase (GTPCH) I and 6-pyruvoyltetrahydrobiopterin synthase (PTPS) are essential enzymes for tetrahydrobiopterin biosynthesis, whereas pterin-4αcarbinolamine dehydratase (PCD) and dihydropteridine reductase (DHPR) are responsible for tetrahydrobiopterin recycling [Blau et al., 2001]. All forms of tetrahydrobiopterin disorders that cause hyperphenylalaninemia are inherited as autosomal-recessive traits. An autosomal dominant form of GTPCH deficiency (e.g., dopa-responsive dystonia, Segawa’s disease, hereditary progressive dystonia) manifests with dystonia, but it is not associated with elevated phenylalanine levels (see Chapter 30). Because the tyrosine and tryptophan hydroxylases also require tetrahydrobiopterin for proper functioning, these disorders also result in deficiencies of the neurotransmitters L-dopa and 5-hydroxytryptophan. Hyperphenylalaninemia in association with neurotransmitter deficits causes the neurologic manifestations associated with the defects in tetrahydrobiopterin synthesis and recycling. More than 400 patients with tetrahydrobiopterin disorders have been identified (BIODEF database, http://www.bh4.org/). PTPS deficiency is the most common of these disorders, occurring in 59% of cases of reported tetrahydrobiopterin disorders. DHPR deficiency is seen in 32%, whereas PCD and GTPCH deficiencies are rare, reported in 5% and 4% of cases, respectively (BIODEF database, http://www.bh4.org/).

Clinical Manifestations Most patients with GTPCH, DHPR, and PTPS deficiencies have severe forms of disease, although mild forms of DHPR and PTPS deficiencies exist, and some forms of PTPS deficiency may be transient [Blau et al., 2001]. PCD deficiency is usually not associated with significant abnormalities other than transient tone abnormalities. Untreated patients with typical severe disorders of tetrahydrobiopterin synthesis or recycling usually develop neurologic manifestations by 4 months, although symptoms can appear in the neonatal period. Clinical manifestations include microcephaly, progressive neurologic deterioration, movement disorders, delayed motor development, seizures, tone disturbances, oculogyric spasms, swallowing difficulties, hypersalivation, and hyperthermia [Blau et al., 1996, 2001; Dhondt, 1993]. Diurnal fluctuation of dystonia may occur. The clinical course

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is similar in severe untreated tetrahydrobiopterin deficiency, regardless of the enzymatic defect. Head MRI findings have only rarely been reported [Pietz et al., 1996]. However, in DHPR deficiency, brain abnormalities such as diffuse demyelination, atrophy, spongy vacuolation of brainstem long tracts, and basal ganglia calcification may occur. Abnormal vascular proliferation in the cortex, white matter, and basal ganglia may also be detected [Gudinchet et al., 1992; Schmidt et al., 1988].

Diagnosis Patients with tetrahydrobiopterin defects are often identified by mandatory newborn screening programs because of hyperphenylalaninemia. All children with persistent hyperphenylalaninemia must be screened for aberrations in the levels of pterin metabolites (i.e., neopterin and biopterin). Patients with GTPCH deficiency have decreased urinary excretion of neopterin and biopterin. In PTPS deficiency, neopterin is increased and biopterin decreased, resulting in a greatly elevated neopterin to biopterin ratio (normally, the ratio is about 1:1). The neopterin to biopterin ratio in PCD deficiency is also increased but not to the same extent as in PTPS deficiency. In PCD deficiency, the characteristic feature is the presence of primapterin (7-biopterin) in the urine [Ayling et al., 2000]. In DHPR deficiency, the percentage of biopterin is elevated (>80% in most cases), but urine screening may miss it in some patients [Dhondt, 1984]. The measurement of DHPR activity in neonatal dried blood spots using a spectrophotometric assay is an effective method for diagnosis of DHPR deficiency. Urine pterin analysis and DHPR activity screening should be performed early in the management of a new patient with persistent hyperphenylalaninemia, or these disorders may be missed. Mutation analysis has yet to identify clear genotype-phenotype correlations [Blau et al., 1996].

Treatment The goals of therapy are to decrease the level of phenylalanine to an acceptable range (120 to 360 μM) and correct the neurotransmitter deficiencies with exogenous supplementation. The diet is similar to that used to treat classic phenylketonuria, but patients tend to have a higher phenylalanine tolerance (300 to 700 mg/day) [Blau et al., 2001]. Tetrahydrobiopterin supplementation (2 to 20 mg/kg/day) is also used to help control blood phenylalanine levels. Lower tetrahydrobiopterin doses (2 to 5 mg/kg/day) may be effective in GTPCH and PTPS deficiencies, whereas higher doses (up to 20 mg/kg/day) may be required in DHPR deficiency. L-Dopa and 5-hydroxytryptophan are administered in a dose of 1 to 10 mg/kg/day. Carbidopa, an inhibitor of peripheral aromatic amino acid decarboxylase, decreases the conversion rates of L-dopa to dopamine and 5-hydroxytryptophan to serotonin, allowing for the use of lower doses of these compounds; these therapeutic adjuncts may be especially helpful in severe forms of tetrahydrobiopterin deficiency. The optimal dose of each medication must be determined for each patient. Mild forms of disease may respond to tetrahydrobiopterin supplementation alone. Measuring levels of cerebrospinal fluid neurotransmitter metabolites (i.e., homovanillic acid and 5-hydroxyindolacetic acid) is useful in

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monitoring the efficacy of treatment [Blau et al., 2001; Shintaku, 2002]. Side effects of therapy include choreoathetosis, dystonia, and on-off phenomena, which are also features of the underlying disorders [Tanaka et al., 1989]. Tachycardia, diarrhea, and anorexia are associated with 5-hydroxytryptophan administration [Dhondt, 1993]. L-Deprenyl, a monoamine oxidase inhibitor, has been useful in decreasing catabolism of L-dopa and 5-hydroxytryptophan, allowing lower dosing [Schuler et al., 1995; Spada et al., 1995, 1996]. A low concentration of cerebrospinal fluid folate is typical in DHPR deficiency, and it is treated by folinic acid supplementation (10 to 20 mg/day) [Shintaku, 2002]. Trimethoprim-sulfamethoxazole and methotrexate are DHPR inhibitors, and they may cause serious side effects in patients with tetrahydrobiopterin deficiency [Millot et al., 1995; Woody and Brewster, 1990]. Neurologic function may improve with therapy, but the overall prognosis for these disorders is largely unknown.

Hepatorenal Tyrosinemia Hepatorenal tyrosinemia (i.e., tyrosinemia type I) is characterized principally by liver, kidney, and peripheral nerve involvement. The clinical spectrum ranges from severe hepatic failure in early infancy to later presentations of chronic liver disease and rickets in an older child. The overall incidence is 1 case per 100,000 births. In Quebec the incidence is quite high, at 1 in 16,700 births [Bergeron et al., 1974].

Pathophysiology Hepatorenal tyrosinemia is caused by a deficiency of fumarylacetoacetate hydrolase, a distal enzymatic step in the processing of the amino acid tyrosine (Fig. 23-2). Some investigations suggest that metabolites of tyrosine accumulating proximal to the blocked reaction step are toxic to liver and kidney, acting as alkylating agents or by disruption of Tyrosine

Protein synthesis, dopamine, melanin, thyroid hormones (1) p-OH-phenylacetic acid p-OH-phenylpyruvic acid

p-OH-phenyllactic acid

(2) Homogentisic acid (3) Maleylacetoacetic acid (4) Fumarylacetoacetic acid

Succinyl acetone

(5) Fumaric acid

Acetoacetic acid

FIGURE 23-2. The tyrosine metabolic pathway involves several enzymes: tyrosine aminotransferase (1); p-OH-phenylpyruvic acid dioxygenase (2); homogentisic acid oxidase (3); maleylacetoacetic acid isomerase (4); and fumarylacetoacetic acid hydrolase (5). (From Wilcox WR, Cederbaum SD. Amino acid metabolism. In: Rimoin D, Connor J, Pyeritz R, Korf B, eds. Principles and practice of medical genetics, 4th ed. Philadelphia: Churchill Livingstone, 2002:2411.)

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Genetic, Metabolic, and Neurocutaneous Disorders / 23

sulfhydryl metabolism [Russo et al., 2001]. One of the accumulating metabolites, succinylacetone, has been implicated in the peripheral neuropathy of tyrosinemia [Sassa and Kappas, 1983; Sassa et al., 1983].

Clinical Manifestations In states and countries that include tyrosinemia in newborn screening panels, infants are detected within the first weeks of life. Onset of disease manifestations may be sudden and may occur in the first month of life; a more gradual clinical course may also be seen. Children often manifest failure to thrive, and vomiting, diarrhea, and hepatosplenomegaly are common. Traditional classifications of acute and chronic disease have been replaced by assessment of disease status in target organs (e.g., peripheral nerve, liver, and kidney). Liver disease can include acute decompensations and cirrhosis. There is a high incidence of progression to hepatocellular carcinoma, likely caused by accumulation of mutagenic metabolites. Renal dysfunction ranges from mild tubular dysfunction to frank renal failure. Vitamin D–resistant renal rickets is a common feature. Neurologic involvement can include paresthesias, opisthotonic-like posture, bruxism and tongue biting, and in some cases, motor paralysis leading to respiratory failure and death [Mitchell et al., 1990]. Neurologic crises occur in up to 42% of individuals with tyrosinemia [Kvittingen, 1991]. These crises are biphasic, with an active period of pain, autonomic dysfunction, and sometimes paralysis lasting 1 to 7 days, followed by a period of recuperation. Succinylacetone blocks the heme biosynthetic pathway, and the neurologic crises—a major source of morbidity— therefore have a physiologic basis similar to those in porphyria [Russo et al., 2001].

Laboratory Tests Demonstration of increased serum amino acids in plasma or urine is pathognomonic. Variable hypertyrosinemia is nonspecific. Other findings include diminished serum phosphorus and elevated urinary excretion of phosphate, resulting from reduced tubular phosphorus reabsorption. Glucosuria and hyperaminoaciduria result from renal tubular impairment. Liver dysfunction results in hyperbilirubinemia and hypoproteinemia. Patients usually have leukopenia, anemia, and thrombocytopenia.

Management 2-[2-Nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione (NTBC) is an inhibitor of 4-hydroxyphenylpyruvate dioxygenase (4-HPD), a proximal step in tyrosine catabolism. Inhibition thereby prevents the synthesis of succinylacetone and related metabolites, which accumulate because of the enzymatic block at fumarylacetoacetate hydrolase, a distal step in the pathway. Treatment with this compound is effective within hours and dramatically reduces the risk of neurologic and hepatic crises [Holme and Lindstedt, 2000]. Dietary restriction of phenylalanine and tyrosine is used in combination with NTBC. Liver transplantation is curative for hepatic and nervous system disease, and it is used in those who are refractory to nonsurgical treatment.

Acute management of neurologic crises includes analgesia, glucose (which inhibits ALA synthetase), and symptomatic treatment of hypertension. Repletion of sodium, potassium, and phosphate is necessary. The use of barbiturates and other medications that aggravate porphyria should be avoided before stabilization on NTBC [Kang and Gerald, 1970].

Other Categories of Tyrosinemia Several causes of hypertyrosinemia exist in addition to fumarylacetoacetate hydrolase deficiency (see Fig. 23-2). Deficiency of tyrosine aminotransferase causes tyrosinemia type II (oculocutaneous tyrosinemia) [Hunziker, 1980]. In type II disease, developmental delay, corneal thickening, and hyperkeratosis of palms and soles occur, but there is usually no hepatorenal involvement. Type III disease is caused by deficiency of 4-HPD and has a spectrum of manifestations, ranging from clinically normal to severe mental retardation and neurologic anomalies, including ataxia [Cerone et al., 1997; Ruetschi et al., 2000]. A 4-HPD dysfunction can also cause Hawkinsinuria, a rare condition that can manifest with failure to thrive and metabolic acidosis, but it usually resolves as the patient’s metabolism matures [Borden et al., 1992]. Liver failure can lead to elevated tyrosine levels [Mitchell et al., 2001], as can postprandial testing and diseases such as vitamin C deficiency and hyperthyroidism. Premature infants may manifest transient tyrosinemia of the newborn because of temporary immaturity in the function of 4-HPD. This condition resolves spontaneously, but mild developmental delay has been reported [Nyhan, 1984].

Maple Syrup Urine Disease In 1954, Menkes and colleagues described four siblings who died in early infancy from a cerebral degenerative disease with onset occurring when they were 3 to 5 days old. Symptoms included feeding difficulty, irregular respiratory pattern, hypertonia, opisthotonus, and failure to thrive. All had urine with the smell of maple syrup [Menkes et al., 1954]. Soon thereafter, another patient with a similar history was found to have elevated levels of branched-chain amino acids in urine and blood, and the syndrome was initially referred to as maple sugar urine disease [Westall et al., 1957]. Maple syrup urine disease is caused by mitochondrial branched-chain α-ketoacid dehydrogenase complex deficiency (compared with the composite branched-chain amino acid pathways in Fig. 23-6). The enzymatic defect leads to accumulation of branched-chain amino acids and branched-chain α-ketoacids. Five forms of maple syrup urine disease (i.e., classic, intermediate, intermittent, thiamine-responsive, and dihydrolipoyl dehydrogenase [E3] deficiency) have been delineated based on clinical presentation, level of enzyme activity, and response to thiamine administration [Chuang and Shih, 2001].

Clinical Manifestations CLASSIC MAPLE SYRUP URINE DISEASE In the classic form, the clinical phenotype is one of severe neonatal encephalopathy, unless presymptomatic therapy is

Enns, Cowan, Klein, and Packman / Aminoacidemias and Organic Acidemias

initiated in areas where newborn screening for maple syrup urine disease is performed. Untreated neonates typically develop symptoms by the end of the first week of life. Feeding difficulties, alternating hypertonia and hypotonia, opisthotonic posturing, abnormal movements (“fencing” or “bicycling”) and seizures commonly occur. The characteristic urine smell develops on day 5 to 7 of life [Strauss and Morton, 2003a]. Unless an underlying inborn error of metabolism is suspected, affected children may be misdiagnosed as having sepsis and progress to coma and death. Ketosis is often found, and hypoglycemia may occur, but severe metabolic acidosis tends not to occur. Plasma amino acid analysis reveals elevated levels of branched-chain amino acids and the diagnostic presence of alloisoleucine in plasma [Schadewaldt et al., 1999]. Urine organic acid analysis demonstrates excretion of branched-chain α-ketoacids. Hyponatremia and cerebral edema are frequent sequelae during acute metabolic decompensation [Morton et al., 2002]. Other complications include pseudotumor cerebri, pancreatitis, and eye abnormalities [Burke et al., 1991; Kahler et al., 1994]. Ocular findings in untreated or late-diagnosed patients include optic atrophy, gray optic papilla, nystagmus, ophthalmoplegia, strabismus, and cortical blindness [Burke et al., 1991]. Children who survive the initial metabolic crisis typically have significant neurodevelopmental delays and spasticity [Chuang and Shih, 2001]. Although motor, visual, and learning deficits may occur, rapid identification of affected infants and careful institution of appropriate therapy can result in normal development [Kaplan et al., 1991; Morton et al., 2002]. Neuroimaging studies (Fig. 23-3) are typically abnormal in patients with untreated classic maple syrup urine disease who are in crisis. Computed tomographic (CT) scans appear normal in the first few days of life, but they reveal progression to marked generalized cerebral edema if the patient remains untreated [Brismar et al., 1990]. An unusual pattern of edema may occur, characterized by involvement of the cerebellar deep white matter, posterior brainstem, cerebral peduncles, posterior limb of the internal capsule, and posterior aspect of the centrum semiovale. Edema tends to subside in the second month of life [Brismar et al., 1990]. Patients with classic maple syrup urine disease in metabolic crisis with associated hyponatremia demonstrate a prominently increased T2 signal on brain MRI in the brainstem reticular formation, dentate nucleus, red nucleus, globus pallidus, hypothalamus, septal nuclei, and amygdala [Morton et al., 2002]. One report observed that brain MRI abnormalities were absent or only slight in sick patients with maple syrup urine disease in the absence of hyponatremia [Morton et al., 2002]. Cranial ultrasonography of neonates in acute metabolic crisis reveals symmetrically increased echogenicity of the periventricular white matter, basal ganglia, and thalami [Fariello et al., 1996]. Chronic changes, including hypomyelination of the cerebral hemispheres, cerebellum, and basal ganglia and cerebral atrophy, may supervene in poorly controlled patients. CT- and MRIdefined abnormalities and the clinical phenotype may improve after implementation of appropriate dietary therapy [Taccone et al., 1992]. Diffusion-weighted imaging and spectroscopy have also documented abnormalities during the acute phase of disease [Cavalleri et al., 2002]. Markedly restricted proton diffusion, suggestive of cytotoxic or intramyelinic sheath edema, was demonstrated in the brainstem,

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basal ganglia, thalami, cerebellar and periventricular white matter, and cerebral cortex in six patients with maple syrup urine disease. MRS demonstrated abnormal elevations of branched-chain amino acids, branched-chain α-ketoacids, and lactate in the four patients. All of these changes were reversed after the institution of appropriate nutritional and antibiotic therapy to treat intercurrent illness [Jan et al., 2003]. A characteristic comblike electroencephalographic pattern may be demonstrated for some patients with classic maple syrup urine disease between the second and third weeks of life [Tharp, 1992]. This unusual rhythm pattern resolves with the institution of dietary therapy [Tharp, 1992].

INTERMEDIATE MAPLE SYRUP URINE DISEASE Children who have the intermediate form of maple syrup urine disease do not present in the neonatal period, despite having persistently elevated plasma levels of branched-chain amino acids. Developmental delay and failure to thrive are common. Severe neurologic impairment is absent; episodes of metabolic decompensation may occur, although severe ketoacidosis episodes are variable [Gonzalez-Rios et al., 1985a]. These children have a higher tolerance for dietary protein than those who have the classic form [Gonzalez-Rios et al., 1985a]. Rarely, patients with intermediate-type maple syrup urine disease respond to thiamine administration.

INTERMITTENT MAPLE SYRUP URINE DISEASE Patients with intermittent maple syrup urine disease typically come to medical attention when they are 5 months to 2 years old and after stress induced by infection or highprotein intake; some have been detected as late as the fifth decade of life [Chuang and Shih, 2001]. The intermittent form of maple syrup urine disease can be particularly difficult to diagnose, because affected individuals have normal levels of branched-chain amino acids and no odor between episodes of metabolic decompensation. Episodic decompensation is characterized by ataxia, disorientation, and altered behavior, which may progress to seizures, coma, and even death unless therapy is instituted. Early development and intellect are usually normal.

THIAMINE-RESPONSIVE MAPLE SYRUP URINE DISEASE The clinical course of patients with the thiamine-responsive variant of maple syrup urine disease is similar to that of the intermediate form of disease. Plasma levels of branchedchain amino acid and urine excretion of branched-chain α-ketoacids decline days to weeks after thiamine administration (10 to 1000 mg/day) is started [Scriver and Kaufman, 2001]. Patients are also treated with nutritional regimens similar to those used in other forms of maple syrup urine disease. Developmental delay may be present, but normal intelligence has also been documented [Scriver et al., 1971].

DIHYDROLIPOYL DEHYDROGENASE–DEFICIENT MAPLE SYRUP URINE DISEASE The dihydrolipoyl dehydrogenase (E3)–deficient form of maple syrup urine disease is characterized by ketoacidotic crises in infancy. There is also lactic acidemia because the

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A

C

Genetic, Metabolic, and Neurocutaneous Disorders / 23

B

FIGURE 23-3. Maple syrup urine disease. A, Axial view, T2-weighted image shows edema in the internal capsules, lateral thalami, and globus pallidi. B, Axial view, calculated apparent diffusion coefficient image at the same level shows hypointensity, indicated by reduced water diffusion, in the affected areas. C, Proton magnetic resonance spectroscopy (echo time of 26 msec) shows a large peak at 0.9 ppm, believed to represent resonances of methyl protons from branched-chain amino acids and branched-chain αketoacids that accumulate as a result of defective oxidative decarboxylation of leucine, isoleucine, and valine. (Courtesy of Dr. A James Barkovich, University of California, San Francisco, CA.)

Enns, Cowan, Klein, and Packman / Aminoacidemias and Organic Acidemias

E3 subunit of the branched-chain α-ketoacid dehydrogenase complex is also required for catalytic function of pyruvate dehydrogenase and α-ketoglutarate dehydrogenase. In addition to the typical maple syrup urine disease metabolites, urine organic acid analysis reveals the presence of lactate, pyruvate, and α-ketoglutarate. The neonatal period is usually uneventful, but progressive neurologic deterioration, characterized by developmental delay, hypotonia or hypertonia, and dystonia, supervenes. Death in early childhood is common. Attempts at therapy have had limited success [Chuang and Shih, 2001; Sakaguchi et al., 1986].

Laboratory Tests Maple syrup urine disease can be detected easily and accurately by tandem mass spectrometry analysis of the newborn blood spot [Chace et al., 1995]. Although tandem mass spectrometry used in newborn screening is effective in diagnosing maple syrup urine disease, such screening is not yet universal. Urine screening tests for the presence of α-ketoacids (i.e., ferric chloride and 2,4-dinitrophenylhydrazine [DNPH]) may be positive, but the results are nonspecific and insensitive. Plasma amino acid analysis demonstrates elevations of leucine, isoleucine, and valine (5- to 10-fold greater than normal) [Strauss and Morton, 2003a]. Levels of branched-chain amino acids are greatly elevated in urine and cerebrospinal fluid [Chuang and Shih, 2001]. The detection of allo-isoleucine is diagnostic [Schadewaldt et al., 1999]. The branched-chain α-ketoacids 2-oxoisocaproic acid, 2-oxo-3-methylvaleric acid, and 2oxoisovaleric acid, derived from the branched-chain amino acids leucine, isoleucine, and valine, respectively, are found to be elevated on urine organic acid analysis during metabolic crises. Branched-chain amino acids levels and excretion of branched-chain α-ketoacids may be normal between episodes of decompensation in the intermittent form of disease. The branched-chain α-ketoacid dehydrogenase complex consists of three catalytic components—a thiamine pyrophosphate–dependent carboxylase [E1] with an α2β2 structure, a transacylase [E2], and a dehydrogenase [E3]— as well as two regulatory enzymes (a kinase and a phosphatase) [Chuang and Shih, 2001]. Deficient activity of this complex leads to the accumulation of leucine, isoleucine, and valine and their corresponding α-ketoacids. The decarboxylation activity can be measured in leukocytes, lymphoblasts, or fibroblasts, and it is loosely related to the clinical phenotype: 0% to 2% of normal activity in classic maple syrup urine disease and 3% to 30% activity in intermediate, 5% to 20% in intermittent, 2% to 40% in thiamine responsive, and 0% to 25% in E3 deficiency [Chuang and Shih, 2001; Scriver et al., 1971]. Because significant overlap exists between measured enzyme activity and clinical phenotype, enzymatic activity cannot be used to predict the clinical course with certainty.

Genetics Maple syrup urine disease is a pan-ethnic, autosomal-recessive condition that can be caused by mutations in any of the components of the mitochondrial branched-chain αketoacid dehydrogenase complex. In a study of 63 indi-

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viduals, E1β subunit mutations were most common (38%), followed by E1α (33%), and E2 (19%) mutations [Nellis and Danner, 2001]. Branched-chain α-ketoacid dehydrogenase phosphatase or kinase mutations are also predicted to cause maple syrup urine disease, but such abnormalities have not yet been detected. The overall incidence is approximately 1 case per 150,000 people in the general population, but maple syrup urine disease is more common in Old Order Mennonites in southeastern Pennsylvania (1 in 176 births) [Danner and Doering, 1998]. A novel founder mutation in the E1β subunit has been reported in the Ashkenazi Jewish population [Edelmann et al., 2001]. In general, increased residual branched-chain α-ketoacid dehydrogenase activity should convey some advantage, but there is a wide overlap between measured enzymatic activities and clinical outcome. Given the complexity of the molecular genetics, the potential for modifier gene and environmental interactions, and the multiple clinical phenotypes associated with maple syrup urine disease, a lack of definitive genotype-phenotype relationships is not surprising.

Treatment Chronic care of the child with maple syrup urine disease includes regular visits to an integrated metabolic clinic for medical and nutritional assessment. Adequate calories (100 to 120 kcal/kg/day) and protein (2 to 3 g/kg/day) are needed for growth. Chronic valine or isoleucine deficiency may cause an exfoliative dermatitis, and supplementation of these amino acids is often needed [Koch et al., 1993]. Thiamine supplementation is administered to patients with thiamine-responsive forms of maple syrup urine disease. Because patients on restricted diets are at risk for micronutrient and essential fatty acid deficiencies, patients should be periodically monitored for such deficits and supplementation given as needed. Because significant metabolic intoxication may occur rapidly, even in patients with apparently well-controlled disease, it is crucial to have carefully considered home and hospital emergency protocols in place for each child [Morton et al., 2002; Strauss and Morton, 2003a]. Acute metabolic decompensation (e.g., fasting or illness severe enough to cause catabolism) is a medical emergency that requires prompt intervention. Initial intervention is aimed at correcting dehydration, starting high-dose intravenous thiamine, and providing adequate calories (approximately 120 to 140 kcal/kg/day) to prevent further protein catabolism and higher rise in plasma leucine levels. To this end, high-dextrose intravenous fluids (to provide approximately 10 mg/kg/min) and intralipid are often administered. Branched-chain amino acid–free parenteral nutrition or enteral formula, delivered by continuous nasogastric drip, can also be used [Nyhan et al., 1998; Parini et al., 1993]. The rate of decrease of leucine is slowed in the face of valine and isoleucine levels inadequate to stimulate protein synthesis. Acute valine and isoleucine deficiency can be avoided by careful supplementation of these amino acids [Parini et al., 1993]. Leucine is reintroduced to the diet after therapeutic levels are achieved [Morton et al., 2002]. In a study of 36 maple syrup urine disease patients, plasma leucine levels fell to less than 400 μM 2 to 4 days after the initiation of therapy with enteral and parenteral nutrition. Initial leucine levels ranged from 233 to 778 μM

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in a group diagnosed on the first day of life (n = 18) and 1489 to 3359 μM in a group diagnosed between days 3 and 16 (n = 18). Over an 11-year period, neurologic examinations, gross motor development, and speech were normal in 34 of 36 children [Morton et al., 2002]. Enteral nutrition was also found to be beneficial when instituted within the first 20 days of life. Four patients receiving nasogastric drip feeding as the only treatment of neonatal classic maple syrup urine disease had normal development when 3 to 5 years old [Parini et al., 1993]. Hemodialysis and continuous venovenous extracorporeal removal therapies result in more rapid fall in plasma levels of branched-chain amino acids, but these modalities typically have been described in single case reports or small series with relatively short follow-up, and it is difficult to ascertain the long-term outcome of such intervention [Gouyon et al., 1996; Puliyanda et al., 2002]. Nevertheless, normal development has been reported for 8 of 12 children after continuous venovenous extracorporeal removal therapy [Jouvet et al., 2001]. Branched-chain amino acids levels often rebound after initial dialysis in cases of severe metabolic imbalance characterized by extremely high leucine levels, and dialysis may need to be repeated in such cases. Peritoneal dialysis is no longer routinely used; there is a tendency for leucine levels to plateau between 1000 and 1500 μM after 24 hours, limiting the utility of this therapeutic modality [Gortner et al., 1989]. Levels of branchedchain amino acids and branched-chain α-ketoacids tend to plateau with exchange transfusion therapy [Nyhan et al., 1998; Wendel et al., 1982]. Although enteral and intravenous therapy may be sufficient to manage many patients with maple syrup urine disease in acute crisis, various dialysis methods are commonly used and should be considered, especially when clearance of branched-chain amino acids by nutritional support is not effective or when other considerations such as life-threatening cerebral edema, renal imbalance, or cardiovascular abnormalities exist [Jouvet et al., 2001; Nyhan et al., 1998]. Liver transplantation has been performed rarely for maple syrup urine disease. Three patients who underwent successful transplantation were able to resume normal diets and were no longer at risk for metabolic deP

CHO ⫹ CH2⫺COOH

P

compensation [Wendel et al., 1999]. However, the inherent risks and expense of transplantation, when compared with the relative ease and success of nutritional therapy, make such invasive treatment the exception rather than the rule. Because hyponatremia and subsequent brain edema are serious and relatively common complications, it is important to monitor serum sodium and serum and urine osmolalities closely and replace urinary losses with saline [Morton et al., 2002]. Critical brain swelling and abnormal brainstem function may develop with only a moderate reduction in serum sodium level (by only 8 to 10 mEq/L) [Morton et al., 2002]. Low-dose diuretics may also be used to prevent water retention [Strauss and Morton, 2003a]. Mannitol is reserved for life-threatening episodes of increased intracranial pressure [Morton et al., 2002].

Glycine Encephalopathy Glycine encephalopathy, also known as nonketotic hyperglycinemia, is an autosomal-recessive disorder caused by defective function of the multimeric glycine cleavage enzyme system, leading to accumulation of glycine in all body tissues, including the central nervous system (Fig. 23-4). Gerritsen and colleagues [1965] described the initial patient in 1965. The glycine cleavage enzyme system has four components: the P protein (a pyridoxal phosphate–dependent glycine decarboxylase), the T protein (a tetrahydrofolatedependent protein), the H protein (a hydrogen carrier protein), and the L protein (lipoamide dehydrogenase). Infants with classic disease present in the first week of life with apnea, lethargy, severe hypotonia, and feeding difficulties [Hoover-Fong et al., 2004]. Respiratory failure, hiccups, and intractable seizures develop, and most infants die unless assisted ventilatory support is provided. Intermittent ophthalmoplegia is a relatively frequent finding [MacDonald and Sher, 1977]. The electroencephalogram commonly has a burst suppression pattern, but hypsarrhythmia has been reported rarely [Hoover-Fong et al., 2004]. Brain imaging results are normal for about one half of the neonatal-onset cases [Hoover-Fong et al., 2004]. Relatively common brain abnormalities include agenesis of the corpus

CH⫽N⫺CH2⫺COOH

NH2 S

glycine H

S

CO2

H

S⫺CH2⫺NH2 ⫹ P

P

CHO

CH⫽N⫺CH2⫺S

HS

H HS

T SH 5,10⫺CH2⫺THF ⫹ NH3 ⫹

L

H SH

NAD⫹

NAD⫹ ⫹ H⫹

FIGURE 23-4. The glycine cleavage system. Circles designate proteins with the active group shown. In the presence of P and H proteins, glycine is decarboxylated, and the remaining aminoethyl group binds to the reduced lipoic acid on the H protein. T protein is required to release ammonia and transfer the x carbon of glycine to tetrahydrofolate (THF), forming 5,10-CH2-THF. The L protein is necessary to regenerate the correct form of the H protein. (From Scriver C, Beudet A, Sly W, Valle D, eds. The metabolic and molecular basis of inherited disease, 8th ed. New York: McGraw-Hill, 2001:2066. Reprinted with permission from The McGraw-Hill Companies.)

Enns, Cowan, Klein, and Packman / Aminoacidemias and Organic Acidemias

callosum, progressive atrophy, and delayed myelination [Hoover-Fong et al., 2004]. Acute hydrocephalus, requiring shunting, may occur and is a poor prognostic sign [Van Hove et al., 2000]. 1H-MRS detects increased intracerebral levels of glycine, lactate, and creatine [Viola et al., 2002]. The lethal form of glycine encephalopathy appears to be associated with elevated levels of brain myo-inositol glycine, creatine, and N-acetylaspartate. Diffusion-weighted imaging has shown high-signal-intensity lesions in the pyramidal tracts, middle cerebellar pedicles, and dentate nuclei, likely reflecting myelin spongiosis [Sener, 2003]. Atypical and transient variants of glycine encephalopathy have also been reported in patients with cerebrospinal fluid–to-plasma glycine ratios of more than 0.08. Atypical forms manifest in infancy or early childhood after an uneventful pregnancy and neonatal period. Clinical features include seizures (in most cases) and relatively mild developmental delay. Atypical glycine encephalopathy documented by liver enzymology has also been reported in siblings with normal cerebrospinal fluid glycine levels and cerebrospinal fluid–to-plasma glycine ratios [Jackson et al., 1999]. Transient glycine encephalopathy is characterized by the same initial clinical and biochemical findings as the classic form, but it has only rarely been reported. In the transient form, cerebrospinal fluid and plasma glycine levels partially or completely resolve, and most patients have normal development [Aliefendioglu et al., 2003; Korman et al., 2004]. Transient elevations of cerebrospinal fluid glycine and the cerebrospinal fluid–to-plasma glycine ratio occurred in an asphyxiated patient with pyridoxine-dependent seizures [Maeda et al., 2000]. Diagnosis of glycine encephalopathy is established by detecting an elevated cerebrospinal fluid glycine concentration, typically 15 to 30 times normal, in association with an increased cerebrospinal fluid–to-plasma glycine ratio (normal < 0.02) [Applegarth and Toone, 2001; Hamosh and Johnston, 2001]. Classic neonatal-onset patients often have ratios higher than 0.2, whereas atypical patients have ratios of approximately 0.09 [Hamosh and Johnston, 2001]. A ratio higher than 0.08 is usually considered diagnostic for glycine encephalopathy. The plasma and cerebrospinal fluid samples should be obtained as closely as possible to one another, and the presence of blood in the cerebrospinal fluid invalidates the amino acid results [Applegarth and Toone, 2001]. Other causes of increased cerebrospinal fluid glycine levels include valproate therapy, brain trauma, and hypoxicischemic encephalopathy. Secondary elevations of plasma glycine, associated with ketosis, are often encountered in organic acidemias (e.g., methylmalonic, propionic, and isovaleric acidemias and β-ketothiolase deficiency) [Applegarth and Toone, 2001; Korman and Gutman, 2002]. Because sulfite oxidase deficiency (isolated or as part of molybdenum cofactor deficiency), folinic acid–responsive seizures, and disorders of neurotransmitters may have presentations similar to that of glycine encephalopathy, an aliquot of cerebrospinal fluid should also be frozen and saved for appropriate analyses in the event that the result of amino acid analysis is normal. Definitive confirmation of the diagnosis may be accomplished by assaying glycine cleavage enzyme in liver. Between 60% and 80% of patients with the classic neonatal form have defects in the P protein. T protein deficiency

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occurs in 5% to 20% of cases, whereas H protein and L protein defects are rarely reported [Tada and Kure, 1993]. Prenatal diagnosis by glycine cleavage enzyme system measurement in uncultured chorionic villus samples has resulted in false-negative and false-positive results in at least 1% of cases studied [Applegarth et al., 2000]. DNA analysis, when mutations are known, remains the most reliable form of prenatal diagnosis [Kure et al., 1999]. Comprehensive mutation analysis in 68 families with glycine encephalopathy detected GLDC (P protein gene) or AMT (T protein gene) mutations in 68% of neonatal and 60% of infantile types, respectively. No GCSH (H protein gene) mutations were identified [Kure et al., 2003]. The L protein is a component of pyruvate dehydrogenase and branched-chain ketoacid dehydrogenase, as well as the glycine cleavage enzyme system. However, L protein deficiency leads to a variant form of maple syrup urine disease or pyruvate dehydrogenase deficiency, rather than glycine encephalopathy [Applegarth and Toone, 2001]. Few glycine encephalopathy patients have been identified who carry the same mutations, making genotype-phenotype correlations problematic, although some possible correlations have been found [Applegarth and Toone, 2004]. Three of four patients with transient glycine encephalopathy and homozygosity for a novel GLDC mutation (A802V) had a normal outcome after intensive therapy as neonates. High residual activity of the mutant enzyme and therapeutic intervention during a critical period of brain sensitivity may have contributed to the good outcome in some cases of transient or mild glycine encephalopathy. The three-dimensional structures of the T protein, H protein, and L protein have been determined, which can aid in understanding the molecular mechanisms underlying the effects of missense mutations on glycine cleavage enzyme system activity [Lee et al., 2004]. In postmortem examination specimens from infants who died because of glycine encephalopathy, brain glycine concentrations are elevated twofold to eightfold [Perry et al., 1977]. Neuropathology has demonstrated deficient myelination, abnormal cortical neuron morphology, and spongiosis of the white matter with associated astrocytic gliosis [Brun et al., 1979]. Treatment of glycine encephalopathy has not improved the overall dismal prognosis in the classic form of disease [Chien et al., 2004]. Therapy is focused on controlling seizures with antiepileptic drugs, decreasing tissue glycine levels, and administering N-methyl-D-aspartate (NMDA) receptor antagonists to diminish glycine-induced neuronal excitotoxicity. Valproate is contraindicated because it can inhibit the glycine cleavage enzyme system, and it can cause hyperglycinemia in patients without glycine encephalopathy [Jaeken et al., 1977]. Sodium benzoate is given because of its ability to conjugate to glycine to form hippurate, which can then be excreted in the urine. A glycine-specific mitochondrial enzyme, benzoyl–coenzyme A (CoA):glycine acyltransferase, catalyzes the condensation of benzoate and glycine to form hippurate [Webster et al., 1976]. Sodium benzoate therapy can reduce plasma levels of glycine to the normal range and may have a mild effect on cerebrospinal fluid glycine levels, but it does not affect the dismal prognosis. Because high-dose sodium benzoate therapy can result in carnitine deficiency, plasma carnitine levels should be monitored closely and appropriate supplementation

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Genetic, Metabolic, and Neurocutaneous Disorders / 23

provided [Van Hove et al., 1995]. Dextromethorphan, an antagonist of the NMDA receptor, is also commonly used in therapy. Treatment with dextromethorphan may lead to improved seizure control and level of interaction in some patients. Ketamine has been used rarely, but it may provide benefit in controlling seizures and improving overall level of interaction [Boneh et al., 1996]. A low-protein diet has no proven efficacy and may result in severe protein malnutrition, micronutrient deficiency, and exfoliative dermatitis if not monitored carefully [Samady et al., 2000]. Sodium benzoate, alone or combined with imipramine, has been effective in improving clinical manifestations in milder forms of glycine encephalopathy [Neuberger et al., 2000; Wiltshire et al., 2000].

Cystathionine β-Synthase Deficiency Cystathionine β-synthase deficiency, the most common cause of homocystinuria, is characterized by multisystem involvement, including mental retardation, lens dislocations, occlusive vascular events, and skeletal deformities.

Pathophysiology The transsulfuration pathway converts methionine into cysteine. In cystathionine β-synthase deficiency, methionine, homocysteine, and homocystine accumulate in the blood and are excreted in large quantities in the urine [Christensen et al., 1991; Mudd et al., 1964]. Two major categories of β-synthase deficiency have been described, one responsive to pyridoxine and the other nonresponsive [Barber and Spaeth, 1969]. One half of patients with cystathionine βsynthase deficiency respond to pyridoxine therapy, and only modest restriction of methionine in their diet is required [Mudd et al., 1985]. Biochemical abnormalities in the central nervous system are thought to account for the occurrence of mental retardation and neurologic abnormalities. Synthesis of cystathionine, an important free amino acid in the brain [Brenton et al., 1965], is impaired, and this compound is virtually absent from the brain in affected individuals. Abnormalities in homocysteine, methionine, and other metabolites probably contribute to central nervous disease as well. Arterial and venous thromboses are prominent in many organs, including the brain. Large and medium-sized blood vessels (i.e., arteries, veins, and dural sinuses) are compromised. Fibrous thickening of the intima occurs, the vessel lumen may be compromised, and the media is also involved, with increased deposition of collagen and frayed,

Sulfur Amino Acid Metabolism and the Homocystinurias Homocysteine lies at a critical juncture between the transsulfuration and remethylation pathways of methionine metabolism, at which point homocysteine can be converted to cystathionine or methionine. The malfunctioning of three enzymes is known to cause homocystinuria: cystathionine β-synthase, methylene tetrahydrofolate reductase, and methionine synthase. The β-synthase enzyme is involved in the transsulfuration pathway (Fig. 23-5), and the latter two enzymes are involved in the sulfur conservation pathway. Several of the mutations that cause methylmalonic acidemia also cause homocystinuria, and these are discussed in the section on cobalamin complementation groups. A transport abnormality, selective intestinal malabsorption of vitamin B12, can also cause homocystinuria. The overall incidence of homocystinuria is approximately 1 case in 335,000 persons, but it varies from 1 in 65,000 in Ireland to 1 in 900,000 in Japan [Naughten et al., 1998].

Serine Methionine THF

Glycine (4)

(3) Methyl⫺B12

(2)

(6) β-adenosylmethionine

(5) Betaine

β-adenosylhomocysteine

N 5,10⫺methylene THF

Dimethylglycine

N5⫺methyl THF

Homocysteine Serine (1)

Homocystine

Cystathionine (7) Cysteine

Cystine

Cysteine sulphinic acid Pyruvate Sulfite (8) Sulfate

FIGURE 23-5. Abbreviated diagram for the transsulfuration pathway. The known genetic defects that cause homocystinuria are a deficiency of cystathionine β-synthase (1), N5,10methylenetetrahydrofolate reductase (2), methionine synthase or methionine synthase reductase (3), and deficient synthesis of methylcobalamin (4). Other defects in the pathway are cystathioninuria caused by γ-cystathionase deficiency (7), sulfite oxidase and molybdenum cofactor synthesis deficiencies (8), and hypermethioninemia from methionine adenosyltransferase deficiency (6). Betaine can be given therapeutically to treat homocystinuria by increasing remethylation of homocysteine by betaine-homocysteine methyltransferase (5). (From Wilcox WR, Cederbaum SD. Amino acid metabolism. In: Rimoin D, Connor J, Pyeritz R, Korf B, eds. Principles and practice of medical genetics, 4th ed. Philadelphia: Churchill Livingstone, 2002:2419.)

Enns, Cowan, Klein, and Packman / Aminoacidemias and Organic Acidemias

split smooth muscle fibers. A clotting diathesis is also involved [D’Angelo and Selhub, 1997]. An increased tendency of intravascular thrombosis may be related to abnormal adhesiveness of platelets. However, no single mechanism has been demonstrated to cause the vascular complications. Homocysteine elevation is an independent risk factor for arteriosclerotic vascular disease. This factor has been demonstrated for affected patients and for individuals in the general population who may have modest elevations in homocysteine concentrations. Degenerative changes in the fibers that hold the optic lens likely are caused by interference with fibrillin function [Sakai et al., 1986]. The bone disease likely results from abnormalities in connective tissue, such as defective fibrillin function or perhaps abnormal collagen cross-linking [Harris and Sjoerdsma, 1966].

Clinical Manifestations Four organ systems demonstrate major involvement: the central nervous, skeletal, ocular, and vascular systems [Mudd et al., 1985]. Other organs, such as the liver, hair, muscles, blood, and skin (e.g., hypopigmentation), may be involved. When the central nervous system is involved, the most frequent finding is mental retardation, which can manifest as developmental delay during the first year of life. There is a spectrum of cognitive function in untreated patients, with IQ scores ranging from 10 to 138. Intelligence in B6-responsive patients tends to be higher than in B6 nonresponders. Psychiatric disturbances are common, and seizures and extrapyramidal signs occasionally are seen. Focal neurologic signs point to a cerebrovascular occlusion. Patients identified on newborn screening who receive early treatment have normal cognitive function [Yap et al., 2001]. Skeletal abnormalities include osteoporosis, scoliosis, increased length of long bones, metaphyseal and epiphyseal anomalies, biconcave vertebrae, arachnodactyly, pes planus, and genu valgum. The skeletal and ocular findings may lead to confusion with Marfan’s syndrome. Involvement of the eye is manifested by ectopic lenses (i.e., dislocated downward) and myopia. Involvement occasionally is manifested by glaucoma, retinal changes, cataracts, and corneal changes. Thromboembolic events (arterial and venous), livedo reticularis, and malar flush are some of the vascular findings. Patients have suffered from pulmonary, cerebral, and renal infarction. Cerebral venous sinus thrombosis has been documented with scanning studies. An increased risk of myocardial infarction exists in patients with homocystinuria and in hyperhomocysteinemic members of the general population [Stampfer et al., 1992]. One half of patients will have a vascular event before age 30 years.

Laboratory Tests Homocystinuria occurs in all untreated patients [Isherwood, 1996], but this is not sufficient to establish the diagnosis, because it may occur in patients with other conditions. Serum amino acid analysis reveals elevated total homocysteine, low levels of cysteine, and elevated methionine. Direct assays are used to confirm the enzymatic deficiency,

583

and these can be performed on skin fibroblasts, liver, or leukocytes.

Treatment The goals of treatment are to reduce the severe hyperhomocysteinemia and other biochemical abnormalities. Supportive treatment of complications is essential. Treatment of patients who are B12 responsive consists of pyridoxine in combination with folic acid and vitamin B12 (Wilcken and Wilcken, 1997]. For vitamin B12 nonresponders, treatment is achieved with a methionine-restricted, cystine-supplemented diet (Komrower et al., 1966; Perry et al., 1966]. Pyridoxine, folic acid, and vitamin B12 have been used in pyridoxine nonresponders as cofactors of methionine metabolism to partially promote homocysteine conversions to other metabolites. Betaine, a methyl donor that remethylates homocysteine to methionine, is also an effective component of treatment [Wilcken et al., 1985].

Methionine Synthase Deficiency Methionine synthase lies at the intersection of folate, cobalamin, and sulfur-containing amino acid metabolism. Patients with defects in this enzyme have homocystinuria and low (or normal) methionine levels, but they do not have methylmalonic acidemia.

Pathophysiology Two complementation groups (CblE and CblG) have very similar clinical and laboratory presentations, and they are discussed together. These patients have isolated defects in methionine synthase function caused by mutations in the enzyme itself or abnormalities in the synthesis of the methylcobalamin cofactor.

Clinical Manifestations Most patients present in early infancy with poor feeding, emesis, lethargy, hypotonia, seizures, and developmental delay [Watkins and Rosenblatt, 1989]. There is usually a neurologic presentation, but this can vary and can include gait disturbances and multiple sclerosis-like features [Carmel et al., 1988]. There is a strong association with megaloblastic anemia.

Laboratory Tests Serum cobalamin and folate levels are normal or high, and methylmalonic aciduria is generally not seen [Tuchman et al., 1988]. Homocystinuria is a consistent feature, and CblE and CblG can be differentiated from other causes of homocystinuria by biochemical studies of cultured cells.

Treatment Administration of hydroxocobalamin in pharmacologic doses (with intramuscular administration at initial treatment stages) should begin as soon as the diagnosis is made. This typically leads to rapid biochemical improvement. Some patients also have improvement of anemia on folinic acid

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Genetic, Metabolic, and Neurocutaneous Disorders / 23

[Harding et al., 1997]. Prenatal therapy has been used for early diagnoses with success [Rosenblatt et al., 1985].

Methylene Tetrahydrofolate Reductase Deficiency In methylene tetrahydrofolate reductase deficiency, the degree of clinical severity varies with enzyme activity. In addition to the severe and moderate cases discussed later, the common 677C→T polymorphism—which can cause mild elevations in homocysteine levels—appears to be a risk factor for hypercoagulable states in the population at large.

Pathophysiology Major findings are demyelination and vascular changes such as those seen in cystathionine β-synthase deficiency [Beckman et al., 1987]. Other changes include dilated cerebral ventricles, hydrocephalus, and microgyria [Kanwar et al., 1976; Wong et al., 1977]. Methylene tetrahydrofolate reductase deficiency is thought to result in low levels of brain folate [Levitt et al., 1971].

Clinical Manifestations Clinical findings vary with enzyme function and include developmental delay, motor and gait abnormalities, seizures, and psychiatric disease such as psychosis and schizophrenia [Haan et al., 1985; Mudd et al., 1972]. Patients rarely have megaloblastic anemia. Severe disease is often lethal. Age at presentation ranges from birth in severe cases to adulthood in milder ones.

Laboratory Tests Moderate hyperhomocysteinemia and homocystinuria are seen, with low or normal methionine levels. The homocysteine excretion is significantly lower than in cystathionine β-synthase deficiency [Fowler and Jakobs, 1998].

Treatment Severe disease is refractory to treatment, and, although several treatments have been tried (i.e., folate, methionine, pyridoxine, cobalamin, and carnitine), none has been particularly effective [Fowler, 1998]. Betaine has somewhat improved the prognosis [Al Tawari et al., 2002; Sakura et al., 1998].

Sulfite Oxidase Deficiency Deficiency of sulfite oxidase function may occur as an isolated enzyme defect or as part of a combined deficiency (see Fig. 23-5). This rare disorder results in abnormalities of metabolism of sulfated amino acids. The cardinal feature of this condition is severe seizures in the neonatal period. Although some therapies lead to mild improvements, there is no effective treatment.

Pathophysiology The molybdenum cofactor is composed of the metal and a small pterin group [Johnson et al., 1980a]. This prosthetic

group is required for the function of three enzymes: sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase [Johnson et al., 1980b]. Most patients have mutations in one of several enzymes of the cofactor synthetic chain, whereas a minority has mutations in the sulfite oxidase gene. Postmortem examination of patients with sulfite oxidase or cofactor deficiencies have found encephalopathy with loss of neurons and myelin, attributable largely to deficiency of sulfite oxidase function and accumulation of sulfite in the brain [Roth et al., 1985]. Absence of sulfite oxidase leads to alternate metabolic pathways for sulfites, including formation of S-sulfocysteine and thiosulfate [Mudd et al., 1967]. S-sulfocysteine may substitute for cysteine in connective tissue, leading to ocular lens dislocation.

Clinical Manifestations The clinical picture includes severe neurologic abnormalities, dislocated ocular lenses, and mental retardation [Mudd et al., 1967]. This presentation is similar in isolated sulfite oxidase deficiency cases and in patients in whom the cofactor is absent. Although some variability is seen among patients, the key feature is neonatal seizures. It is recommended that all patients with neonatal seizures have metabolic testing. Other neurologic signs can include opisthotonus, axial hypotonia with peripheral hypertonia, regression, and loss of milestones. Ophthalmologic abnormalities can include nystagmus, coloboma, and cortical blindness [Lueder and Steiner, 1995]. Craniofacial dysmorphology includes bitemporal narrowing with deep-set eyes, long palpebral fissures, thick lips, elongated philtrum, and a small nose. Heterozygote carriers are unaffected.

Laboratory Tests Positive sulfite test results are usually observed on urine dipstick, although false-negative results can occur [van der Klei-van Moorsel et al., 1991]. Quantitative plasma and urine amino acids have the characteristic cysteine metabolite S-sulfocysteine [Johnson and Rajagopalan, 1995]. Low levels of urinary urothion, a degradation product of molybdopterin, are essentially diagnostic of molybdenum cofactor deficiency, and an elevated urinary thiosulfate level is diagnostic of sulfite oxidase deficiency or molybdenum cofactor deficiency.

Treatment Management for this condition is largely supportive because therapies are often ineffective. Molybdenum cofactor is too unstable to be used therapeutically. Patients with milder forms of isolated sulfite oxidase deficiency may respond to a diet low in sulfur-containing amino acids [Touati et al., 2000].

Hartnup’s Disease Hartnup’s disease is an aminoaciduria that is usually clinically silent, but it can manifest with episodes of cerebellar ataxia and a pellagra-like rash. Incidence has been estimated at 1 case in 33,000 persons [Wilcken et al., 1977].

Enns, Cowan, Klein, and Packman / Aminoacidemias and Organic Acidemias

Pathophysiology The metabolic aberration in Hartnup’s disease results from an error in the transport of monoamino-monocarboxylic (neutral) amino acids that affects renal tubular reabsorption and intestinal absorption [Baron et al., 1956; Mahon and Levy, 1986; Scriver et al., 1987]. There is deficient transport of neutral amino acids, including glutamine, histidine, valine, phenylalanine, tyrosine, tryptophan, alanine, asparagine, citrulline, isoleucine, leucine, serine, and threonine. Large amounts of the amino acids and of the amides of glutamate and aspartate are excreted in the urine [Bonetti and Dent, 1954]. Two tissue-specific forms of Hartnup’s disease are recognized: renal plus intestinal involvement and renal involvement alone. Amino acids such as tryptophan remain in the intestinal lumen [Milne et al., 1960], where they are converted to indolic compounds by bacteria and then absorbed [Asatoor et al., 1963]; these compounds are toxic to the central nervous system. Urinary excretion of large amounts of indican (a tryptophan metabolite) is characteristic of the disease. Large quantities of neutral amino acids are excreted in the feces [Scriver, 1965]. The lack of tryptophan absorption leads to niacin deficiency, which results in the pellagralike symptoms and photosensitivity.

Clinical Manifestations Patients detected on newborn screening usually are clinically normal, and Hartnup’s disease is usually benign [Scriver et al., 1987]. Nevertheless, some patients are affected, suggesting a monogenic trait with strong polygenic influence [Scriver, 1988]. The most prominent neurologic feature in affected individuals is attacks of cerebellar ataxia, which vary in intensity. These episodes may persist for as long as 2 weeks before improvement is evident. Less common neurologic disabilities include spasticity, wide-based gait, double vision, nystagmus, dystonia, and tremulousness. Psychiatric disturbances consisting of fear, anxiety, and mood swings may occur, as may constant headaches. Clinical involvement varies considerably among symptomatic individuals. Neurologic symptoms are often accompanied by a rash on areas of sun-exposed skin [Baron et al., 1956]. The skin is dry and reddened, resembling pellagra (i.e., nicotinamide deficiency). Sun exposure usually exacerbates the lesions, as does sulfonamide administration. Skin may become hyperpigmented.

Laboratory Tests Urine has strikingly elevated levels of neutral amino acids, but basic and acidic amino acids in urine are relatively normal [Tada et al., 1967]. Serum levels of amino acids are normal or low [Cusworth and Dent, 1960].

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tomatic patients should protect themselves from sunlight and other aggravating agents, such as photosensitizing drugs. Administration of nicotinic acid offsets deficiency in nicotinamide synthesis [Halvorsen and Halvorsen, 1963].

Histidinemia Histidinemia is benign in almost all affected individuals, although in rare cases, this condition may lead to central nervous system disease. The benign nature makes treatment unnecessary in almost all cases. Overall incidence has been estimated at between 1 in 8000 in Japan to 1 in 37,000 in Sweden [Virmani and Widhalm, 1993].

Pathophysiology Histidinemia results from deficiency of L-histidase (Lhistidine ammonia lyase) [Auerbach et al., 1962], resulting in accumulation of histidine and its metabolites in blood, urine, and cerebrospinal fluid and in a deficiency of urocanic acid [Levy et al., 1974]. Enzyme activity is essentially undetectable in liver and other tissues of patients but may be normal in skin [Woody et al., 1965].

Clinical Manifestations The initial patients identified with histidinemia were mentally retarded and had speech abnormalities; the group identified was likely a result of ascertainment bias. Prospective follow-up of newborns with histidinemia detected by newborn screening did not provide evidence of disease in affected individuals [Levy et al., 1974; Tada et al., 1982]. Although it is clear that histidinemia does not produce severe disease, there is still debate about possible minor effects on speech and intelligence.

Laboratory Tests The diagnosis is based on elevated plasma and urine levels of histidine.

Treatment Low-histidine diets have been successfully used to reduce blood histidine concentration; however, studies of mean IQ and general level of functioning revealed no statistical advantage of therapy. Therapy is not indicated for most patients who remain asymptomatic [Scriver and Levy, 1983]. If concern exists that elevated histidine is contributing to findings, consultation with a biochemical specialist is recommended.

ORGANIC ACIDEMIAS

Treatment

Propionic Acidemia

In the rare symptomatic patient, increasing amino acid intake in the form of a high-protein diet can overcome the deficient transport and loss of neutral amino acids [Scriver et al., 1987]. Conversely, poor nutrition can lead to attacks in patients who would otherwise be asymptomatic. Symp-

Propionic acidemia is caused by the deficiency of propionylCoA carboxylase (PCC), a biotin-requiring enzyme that catalyzes the conversion of propionyl-CoA to methylmalonylCoA in the metabolic pathways of valine, isoleucine, methionine, threonine, and odd-chain fatty acids (Fig. 23-6).

586

Genetic, Metabolic, and Neurocutaneous Disorders / 23 Extracellular space

bran e

Protein synthesis CH3

m em

CH3 CH

COOH CH3

NH2

CH3

CH

CH2

CH

COOH

CH3

CH

CH2

NH2

Valine

Cell Biotin

CH

CH3

CH

COOH

Cytosol

NH2

Isoleucine

Leucine Leucineisoleucinemia

Valinemia

(Dietary form) C N Protein

O Proteolytic degradation

2-Ketoisovaleric acid Maple syrup urine disease

Bioticyn

2-Keto-3-methylvaleric acid

Thiamine B1 Thiamine B1

Isobutyryl-CoA

Thiamine B1

2-Methylbutyryl-CoA

Isovaleryl-CoA Isovaleric acidemia

Biotinidase deficiency

Methacrylyl-CoA

Tiglyl-CoA

3-Methylcrotonyl-CoA CO2

ol

C

3–MethylcrotonylCoA carboxylase deficiency

Methylmalonyl-CoA semialdehyde

Biotin

2-Methylacetoacetyl-CoA

D-Methylmalonyl-CoA

3-Methylglutaconic aciduria

Propionyl-CoA Odd-chain fatty acids Threonine Methionine Methylcitric acidCholesterol

Propionic acidemia

Biotin

3-Methylglutaconyl-CoA

β-Ketothiolase deficiency

CO2

CO2

3-Hydroxy-3-methylglutaryl-CoA 3-Hydroxy-3-methylglutaric aciduria

L-Methylmalonyl-CoA

Acetoacetic acid + Acetyl-CoA cbIB

cbIA CbI1

Adenosyl CbI

Succinyl-CoA

3-Hydroxyisovaleric acid

3-Hydroxyisobutyryl-CoA 2-Methyl-3-hydroxybutyryl-CoA

s yto

Methylmalonic acidemia

2-Ketoisocaproic acid

Maple syrup urine disease

MMA

CbI2

cbIG CbI2 cbID

CO2 H2O

Acetone Mitochondria

Methyl Cbl

cbIE

cbIC

OHC3bl Cytosol

Methionine

Homocystin-II-uria

MMA

Homocysteine

MMAHCU

cbI F

OHC3bl

MM HC A U

Cell membrane

TCII

Lysosome OHCbl TCII

Extracellular space OHC3bl TCII

FIGURE 23-6. Pathways in the metabolism of the branched-chain amino acids, biotin, and vitamin B12 (cobalamin). Cbl, cobalamin; cbl, defect in metabolism of cobalamin; HCU, homocystinuria; MMA, methylmalonic academia; OHCbl, hydroxycobalamin; TC, transcobalamin. (From Rezvani I. Defects in metabolism of amino acids. In: Behrman R, Kliegman R, Jenson H, eds. Nelson textbook of pediatrics, 16th ed. Philadelphia: WB Saunders, 2000:355.)

This condition is estimated to occur in 1 of 50,000 to 100,000 livebirths. Propionyl-CoA carboxylase is a multimer consisting of six α subunits (PCCA) and six β subunits (PCCB), encoded by genes on chromosomes 13q22 and 3q21-q22, respectively. Biotin, the required cofactor, is bound to the α subunit to form the fully functional enzyme. More than 40 mutations in each of the PCC-subunit genes have been described in

propionic acidemia patients. There is growing evidence for genotype-phenotype correlations, with null mutations often associated with the most severe clinical outcomes [Clavero et al., 2002; Perez-Cerda et al., 2003]. A deficiency of PCC activity also results from mutations in two other genetic loci encoding enzymes in the biotin use and recycling pathway: holocarboxylase synthase and biotinidase. Primary defects in either enzyme lead to functional

Enns, Cowan, Klein, and Packman / Aminoacidemias and Organic Acidemias

deficiencies of all four biotin-requiring carboxylases, including PCC, and are discussed elsewhere in this chapter (see “Multiple Carboxylase Deficiencies”).

Clinical Manifestations The clinical presentation of propionic acidemia resembles that of the other so-called ketotic hyperglycinemias, including methylmalonic acidemia and isovaleric acidemia. More than 80% of propionic acidemia patients experience acute onset of symptoms within the first 3 months of life [Fenton et al., 2001; Sass et al., 2004a]. Symptoms of severe metabolic decompensation include vomiting, lethargy, and coma, accompanied by severe ketoacidosis, hyperammonemia, hyperglycinemia, and decreased serum carnitine. The disease is often fatal, particularly if diagnosis and implementation of treatment are delayed. Patients with onset in childhood or in adulthood have been described with episodes of neurologic decompensation associated with periods of ketoacidosis. Even for patients presenting later in life, the metabolic decompensation can be fatal [Lucke et al., 2004]. Patients with late-onset disease have been described with developmental delay or mental retardation but without a history of episodic ketoacidosis or hyperammonemia.

Diagnosis Urine organic acid analysis reveals a characteristic pattern of metabolite excretion, including 3-hydroxypropionic acid, propionylglycine, methylcitrate, and tiglylglycine. Samples collected during an acute episode can also have massive elevations of lactic, β-hydroxybutyric, and acetoacetic acids. Plasma acylcarnitine profile has markedly elevated propionylcarnitine, with elevations of acetylcarnitine in acute samples reflecting ketosis. There is often a significant deficiency of free and total carnitine, with an elevated ratio of acylcarnitine to free carnitine. The diagnosis is confirmed by demonstration of deficiency PCC activity in cultured fibroblasts. Assays of other carboxylases, including 3-methylcrotonyl-CoA carboxylase and pyruvate carboxylase, can be performed to exclude multiple carboxylase deficiency. Molecular studies for mutations in the PCCA and PCCB genes are available in a limited number of laboratories worldwide. Because abnormal elevations of propionylcarnitine are readily detected by tandem mass spectrometry, presymptomatic patients with propionic acidemia are identified in states in which expanded newborn screening by tandem mass spectrometry has been implemented. Early diagnosis of these patients, ideally before the onset of symptoms, allows initiation of specific therapies designed to reduce the risk of metabolic decompensation. Because expanded newborn screening has only recently been introduced to medical practice, the long-term outcome of propionic acidemia patients identified in this way has not been established [Leonard et al., 2003]. Some patients with propionic acidemia, particularly those with milder variant forms, have been missed by newborn screening. It is therefore important to maintain a high index of suspicion for patients presenting with symptoms compatible with this or any other organic acidemia, even in the face of normal newborn screening results.

587

Treatment Management of propionic acidemia patients during acute episodes is aimed at correcting the acidosis and hyperammonemia, and limiting catabolism of propionate precursors by restricting protein and providing fluids and glucose. If hyperammonemia is severe and persistent, dialysis and ammonia-scavenging medications (e.g., sodium benzoate, sodium phenylacetate) may be necessary. Long-term management of propionic acidemia consists of carnitine supplementation and a protein-restricted diet that includes supplementation with a special formula. Biotin supplementation has not been demonstrated to be effective [Fenton et al., 2001]. Liver transplantation has been performed in a small number of propionic acidemia patients, with preliminary results indicating a dramatic reduction in the risk for metabolic decompensation with less strict dietary restrictions. The long-term outcome of these patients is unknown [Yorifuji et al., 2004].

Methylmalonic Acidemias Several genetic defects can lead to methylmalonic acidemia, in which methylmalonic acid and its derivatives accumulate in physiologic fluids. These conditions are caused by deficiencies in transport and metabolism of vitamin B12, or cobalamin (Cbl), and by mutations in enzymes requiring this cofactor (see Fig. 23-6). Because of the variety of causative defects, this group of conditions has significant clinical heterogeneity and differences in response to therapy. Incidence is estimated at 1 case per 50,000 persons [Coulombe et al., 1981].

Pathophysiology The methylmalonic acidemias can be caused by defects in adenosylcobalamin-dependent methylmalonyl-CoA mutase, intracellular cobalamin metabolism, transcobalamin II deficiency, and intrinsic factor or by dietary cobalamin deficiency [Fowler, 1998]. Methylmalonyl-CoA mutase isomerizes methylmalonyl-CoA to succinyl-CoA, which then enters the tricarboxylic acid cycle and is converted to pyruvate. Methylmalonyl-CoA is a derivative of propionyl-CoA, which is a metabolite derived from isoleucine, valine, threonine, methionine, thymine, uracil, cholesterol, and odd-chain fatty acids. The major causes of methylmalonic academia are divided into several different complementation groups: mut0, mut–, CblA, CblB, CblC, CblD, CblF, and CblH [Rosenblatt and Cooper, 1990]. Mutase activity is completely and partially abolished in the mut0 and mut– groups, respectively. Defective adenosylcobalamin synthesis is responsible for CblA, CblB, and CblH. CblC and CblD cause methylmalonic acidemia and homocystinuria because of cobalamin reduction abnormalities that interfere with formation of adenosylcobalamin and methylcobalamin biosynthesis. Abnormal lysosomal transport of cobalamin leads to CblF disease, which also leads to combined methylmalonic acidemia and homocystinuria. CblE and CblG diseases involve defects in homocysteine metabolism; they are discussed in the section on homocystinuria (see “Sulfur Amino Acid Metabolism and the Homocystinurias”).

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Clinical Manifestations There is significant variability in presentation depending on the particular enzymatic deficiency, although several complementation groups share the general characteristics of failure to thrive, developmental delay, megaloblastic anemia, and neurologic dysfunction [Cooper and Rosenblatt, 1987]. Mut0, mut–, CblA, and CblB patients often present in the first few weeks of life with poor feeding, dehydration, increasing lethargy, emesis, and hypotonia [Lindblad et al., 1968; Matsui et al., 1983; Rosenberg et al., 1968]. These patients exhibit a short interval of apparent good health before presentation with symptoms. Metabolic acidosis may be catastrophic. Mild mut– or other forms of methylmalonic acidemia decompensate later in infancy or in childhood with hypoglycemia, acidosis, seizures, and lethargy. A CblC patient can present early in infancy or in later childhood with myopathy, lower extremity paresthesias, and thrombosis due to homocystinuria [Enns et al., 1999a]. Severely affected children with CblC methylmalonic acidemia can also have ocular abnormalities such as retinopathy, nystagmus, and worsening vision, as well as hydrocephalus and microcephaly [Rosenblatt et al., 1997]. Cranial imaging usually reveals pathology of the basal ganglia and white matter. The two initial cases reported with CblD presented in later childhood with mental retardation and behavioral problems, although subsequent reports have documented infantile onset with hypotonia and seizures and early childhood presentations with ataxia and gait abnormalities [Goodman et al., 1970; Suormala et al., 2004]. CblF patients have been reported to have minor facial anomalies and hematologic defects [Shih et al., 1989]. Transcobalamin II deficiency can manifest as failure to thrive in the first months of life with neurologic disease and mental retardation [Hall, 1992]. A benign form of methylmalonic acidemia has been reported in otherwise healthy children. [Ledley et al., 1984].

Laboratory Tests Methylmalonic acidemia can clinically resemble other organic acidemias, necessitating analysis of urine organic acids for diagnosis. This test reveals large amounts of methylmalonic acid, as well as methylcitrate, propionic acid, and 3-hydroxypropionic acid [Barness et al., 1963; Rosenberg et al., 1968]. Serum amino acids sometimes demonstrate elevation of glycine and hyperhomocysteinemia in the groups in which methylcobalamin metabolism is affected. Ketosis and hyperammonemia are common. Total plasma homocysteine levels are elevated in CblC, CblD, and CblF diseases. Total and free carnitine levels tend to be low, and acylcarnitine profiles reveal increased propionylcarnitine. The cobalamin transport deficiencies are assessed by measuring serum cobalamin levels and absorption by the Schilling test [Cooper and Rosenblatt, 1987]. Determination of complementation group is performed through analysis of fibroblasts.

Treatment During acute metabolic crises, treatment is directed toward limiting catabolism and restricting protein intake. The usual protein intake is stopped, and fluid and glucose are given

intravenously. Pharmacologic treatment includes carnitine, intramuscular hydroxocobalamin, metronidazole, or neomycin to decrease intestinal propionate production, betaine, and folate [Ogier de Baulny et al., 1998; Roe and Bohan, 1982; Rosenblatt and Cooper, 1987; Thompson et al., 1990]. Improved growth and enhanced nutrition status are seen in patients with methylmalonic acidemia fed an elemental medical food [Yannicelli et al., 2003]. Patients should consume a diet low in the micronutrient precursors proximal to the metabolic block and with adequate calories and total protein to enable growth. Plasma methylmalonic acid levels are followed for metabolic control [Nyhan et al., 1973]. Several transplantations of liver and kidneys in infants and children with methylmalonic acidemia have been reported. Although this approach seems to protect against metabolic crises, it does not lead to complete biochemical correction [Leonard et al., 2001].

Isovaleric Acidemia Isovaleric acidemia can manifest with early metabolic crises, often leading to coma, or it can result in a later, chronic condition. Patients are usually developmentally normal, but mild-to-severe mental retardation has been reported. Supportive care during crises and specific treatments such as glycine and carnitine have helped to improve outcomes. Overall incidence is estimated at less than 1 case per 200,000 persons.

Pathophysiology Deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase, part of the leucine catabolic pathway (see Fig. 23-6), leads to accumulation of several metabolites [Rhead and Tanaka, 1980]. Although the toxicity of individual metabolites is not well understood, isovaleric acid is an inhibitor of the tricarboxylic acid cycle and of hematopoiesis in cultured cells [Bergen et al., 1982; Hutchinson et al., 1985].

Clinical Manifestations Approximately one half of patients present with an acute neonatal metabolic crisis, and the remainder have chronic, intermittent illness. Both forms result from the same inborn error, and the differences in presentation may reflect the timing of catabolic insults or genetic background. The acute form occurs in infants who are clinically well at birth but who, within the first several days of life, begin to vomit, refuse feeding, and become listless, dehydrated, and lethargic [Mendiola et al., 1984]. They may have seizures, and the odor of sweaty feet often is detected. Untreated patients progress to coma and often to death, which can be caused by metabolic acidosis or attendant features such as infection [Wilson et al., 1984]. Patients who survive have the chronic, intermittent form of the disease, and they may have normal development. In the chronic form, the first episode occurs during the first year of life after a trigger such as a mild infection or protein load. Recurrent episodes involve vomiting, acidosis with ketonuria, lethargy that can progress to coma, and the cheesy or sweaty feet odor. Most patients with isovaleric acidemia who survive crises intact

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have normal development, but some have mild delay or even severe mental retardation.

Laboratory Tests Because clinical features of isovaleric academia can resemble several other conditions, analysis of urine organic acids is necessary. During crises, significant elevations of isovalerylglycine and 3-hydroxyisovaleric acid are seen in urine [Tanaka et al., 1968]. Other laboratory abnormalities include metabolic acidosis with mild to moderate ketonuria and lactic acidemia and sometimes include hyperammonemia. Hematologic abnormalities such as thrombocytopenia, neutropenia, and pancytopenia are common [Kelleher et al., 1980]. Hypocalcemia and hyperglycemia often occur.

Treatment During crises, treatment should be administered by a biochemical geneticist, and it is similar to that for other organic acidemias: protein restriction and glucose infusion to decrease protein catabolism. Management during intervening episodes includes protein restriction and supplementation with leucine-free foods. Two targeted treatment options, glycine and carnitine, conjugate with isovaleryl-CoA and lead to excretion of the nontoxic products [Cohn et al., 1978; Mayatepek et al., 1991].

3-Methylcrotonyl-CoA Carboxylase Deficiency 3-Methylcrotonyl-CoA carboxylase (MCC) deficiency, also known as 3-methylcrotonylglycinuria, is an autosomal recessive disorder in the catabolic pathway of leucine (see Fig. 23-6). MCC is a biotin-requiring enzyme consisting of two nonidentical subunits, α (MCCA) and β (MCCB), with the biotin-binding site located on the α subunit. Mutations have been identified in both subunits in patients with MCC deficiency, defining two complementation groups for this disorder [Baumgartner et al., 2001]. Although isolated MCC deficiency was once thought to be rare, an unexpectedly large number of patients have been identified in tandem mass spectrometry–based newborn screening programs, and the frequency is estimated at 1 case per 50,000 livebirths [Baumgartner et al., 2001]. Like propionyl-CoA carboxylase deficiency, MCC deficiency can arise from defects in the enzymes of the biotin use and recycling pathway: holocarboxylase synthase and biotinidase (see “Multiple Carboxylase Deficiencies”).

Clinical Manifestations The clinical presentation of MCC deficiency is highly variable and ranges from apparently benign to severe and life threatening. The classic presentation is in infancy or childhood, with rare cases occurring in the neonatal period [Bannwart et al., 1992]. Episodes are often associated with a mild infection or other stress, and they involve vomiting, feeding difficulties, lethargy, hypotonia, hyperreflexia, hypoglycemia, metabolic acidosis, and ketosis. Investigations of family members of affected patients have revealed a number of individuals with MCC deficiency with a normal clinical phenotype. MCC deficiency has been described in

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healthy mothers of infants identified by expanded newborn screening programs with elevated metabolites suggestive of MCC deficiency [Gibson et al., 1998]. Clinical severity, or lack thereof, is not predicted by the severity of MCC mutation or amount of residual MCC activity, in that most mutations identified in patients are associated with absent or severely diminished MCC activity [Desviat et al., 2003].

Diagnosis The diagnosis of MCC deficiency is established through studies of urine organic acids and plasma acylcarnitine profile, and enzyme assays for MCC in cultured fibroblasts. Abnormalities include the characteristic excretion of 3hydroxyisovaleric acid and methylcrotonylglycine in urine and elevation of 3-hydroxyisovalerylcarnitine in plasma. Free carnitine is often significantly decreased, with an elevated ratio of acylcarnitine to free carnitine. Urine acylglycine analysis also reveals elevated excretion of 3-methylcrotonylglycine and is a useful adjunct test. In addition to assaying MCC activity, assays of other carboxylases, including propionyl-CoA carboxylase and pyruvate carboxylase, can be performed to exclude multiple carboxylase deficiency. Asymptomatic or presymptomatic patients with MCC deficiency are also detected in expanded newborn screening programs as having elevated 3-hydroxyisovalerylcarnitine in dried blood spots [Koeberl et al., 2003]. This finding should be followed with urine organic acid and acylcarnitine studies for the patient and the mother [Gibson et al., 1998].

Treatment Treatment of acute episodes is aimed at restoring glucose homeostasis and correcting acidosis. Long-term treatment with carnitine supplementation and dietary restriction of leucine has been found to result in normal growth and development [Sweetman and Williams, 2001]. Responsiveness to biotin has been demonstrated in a small number of cases [Baumgartner et al., 2004].

Multiple Carboxylase Deficiencies The biotin-responsive multiple carboxylase deficiencies include at least two autosomal recessive disorders with somewhat distinct but overlapping clinical manifestations, referable to enzymopathies affecting the biotinylation of the four mammalian carboxylases. The carboxylases all require biotin for catalytic activity and include cytosolic acetyl-CoA carboxylase, the rate-limiting step for the de novo synthesis of fatty acids; mitochondrial pyruvate carboxylase, catalyzing the conversion of pyruvate to oxaloacetate, a tricarboxylic acid cycle intermediate and a precursor for gluconeogenesis; mitochondrial methylcrotonyl-CoA carboxylase, catalyzing an intermediate reaction step in leucine catabolism; and mitochondrial propionyl-CoA carboxylase, which catalyzes an intermediate step in the conversion of isoleucine, valine, and other precursors to succinic acid (see Fig. 23-6). In each of these enzymes, the biotin is linked to the epsilon amino group of a lysine residue, situated within the highly conserved amino acid sequence of the biotin-binding site. The clinical presentations and metabolic derangements in the multiple carboxylase deficiencies mirror those of primary

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deficiencies of each of the carboxylases and the clinical features of acquired nutritional biotin deficiency. The first patient was described in 1971 and was originally reported as having biotin-responsive β-methylcrotonylglycinuria [Gompertz et al., 1971]. A little more than a decade later, two different disorders—biotinidase deficiency, a defect in the recycling of biotin, and holocarboxylase synthase deficiency, a defect in the biotinylation of carboxylases— were characterized.

Biotinidase Deficiency CLINICAL MANIFESTATIONS Patients with biotinidase deficiency usually present in early to middle infancy, but they may come to medical attention in very early infancy or in later childhood. Because of the usual age of presentation, biotinidase deficiency was delineated as late-onset or infantile-onset multiple carboxylase deficiency [Packman et al., 1981b; Thoene et al., 1981]. Symptoms may be insidious or acute and can include lethargy, hypotonia, anorexia or vomiting, developmental delays, ataxia, seizures, and coma. Dermatologic manifestations are a frequent feature and can include alopecia, rashes, and mucocutaneous candidiasis. The rash bears resemblance to that seen in essential fatty acid deficiency or acrodermatitis enteropathica [Williams et al., 1983]. Hearing loss and optic atrophy can be significant long-term complications that do not uniformly respond to therapy. Patients presenting in later childhood or adolescence can come to medical attention because of motor weakness and spastic paresis or because of loss of visual acuity [Wolf, 2001]. When studied, neuropathologic findings in biotinidase deficiency have included changes suggestive of Leigh’s disease and Wernicke’s encephalopathy [Sander et al., 1980]. Such findings are consonant with the notion that neurologic sequelae may result from abnormal intracerebral lactate concentrations [Schurmann et al., 1997].

remaining bound to the lysine as a compound called biocytin. The release of biotin from biocytin requires the extracellular catalytic activity of biotinidase. In the absence of biotinidase, the cleavage of biocytin does not occur, and biotin is not released for reuse. Biotinidase may also be required for the release of biotin bound to dietary protein, resulting in reduced availability of dietary biotin. The failure to recycle biotin gradually leads to biotin deficiency, a secondary deficiency of biotin-dependent carboxylase activity, and the symptoms of biotinidase deficiency. Although the focus has been on the consequences of deficiency of the mitochondrial carboxylases, the contribution of acetyl-CoA carboxylase to the clinical manifestations also has been investigated [Gonzalez-Rios et al., 1985b; Packman et al., 1984, 1989; Proud et al., 1990]. Cells deficient in acetyl-CoA carboxylase cannot synthesize malonyl-CoA, required for de novo fatty acid synthesis and fatty acid elongation reactions. In such cells, the fatty acid pattern and composition of membranes and structural elements is abnormal, leading to speculation that such alterations may contribute to the dermatitis [Munnich et al., 1980], to the immunologic derangements reported in a number of patients [Cowan et al., 1979], and to some components of the neurologic manifestations.

DIAGNOSIS

The aberrant clinical chemistries include metabolic acidosis, with ketosis and lactic acidosis; hypoglycemia; hyperammonemia; and a distinct organic acid pattern that represents the combination of individual carboxylase deficiencies. The organic academia includes propionic acid, 3-hydroxypropionate, methylcitrate, and tiglylglycine, referable to propionyl-CoA carboxylase deficiency; lactic acid (and pyruvic acid and alanine), referable to pyruvate carboxylase deficiency; and 3-methylcrotonate, 3-methylcrotonylglycine, and 3-hydroxyisovaleric acid, referable to the derangement in the methylcrotonyl-CoA carboxylase step.

A small but significant fraction of cases ascertained because of clinical symptoms may not demonstrate the characteristic organic aciduria. Accordingly, serum biotinidase activity should be measured in any patient with features—especially cutaneous and neurologic features—that are consistent with biotinidase deficiency. Assay of serum biotinidase is a widely clinically available test. Enzyme activity can be measured in fibroblasts, peripheral blood leukocytes, and amniotic fluid or amniotic fluid cells if prenatal diagnosis is carried out. Many states have incorporated biotinidase testing on filter paper blood spots in state-sponsored newborn screening programs. Ascertainment of biotinidase deficiency in such newborn screening programs has led to the identification of two broad clinical cohorts of patients: those with profound biotinidase deficiency (less than 10% of control subjects) and children with partial biotinidase deficiency (10% to 30% of control subjects) [Wolf, 1991]. The combined incidence of profound and partial deficiency is estimated at 1 in 60,000, with the two forms each having approximately equal incidences. The natural history of partial deficiency is not entirely known. Because there are reports of patients with partial deficiency who have become symptomatic, it has been suggested that treatment for partial deficiency might be indicated [McVoy et al., 1990].

ETIOLOGY

TREATMENT

The defect in the infantile-onset form of biotin-responsive multiple carboxylase deficiency was determined by Wolf and colleagues [1983] to reside in a deficiency of biotinidase activity. Biotinidase is required in the recycling of biotin from carboxylases after the proteolytic degradative turnover of these enzymes (see Fig. 23-6). When a carboxylase is hydrolyzed, biotinyl lysine is released, with the biotin

Patients with biotinidase deficiency can be treated with pharmacologic dosages of biotin of 5 to 20 mg/day. Children with partial biotinidase deficiency have been treated with somewhat lower dosages of 1 to 5 mg/day. With treatment, the biochemical derangements (including the lactic acidosis) resolve, the dermatologic manifestations rapidly resolve, developmental delays are ameliorated or reversed, and there

LABORATORY TESTS

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is often resolution of seizures and ataxia. Hearing and visual loss may remain as long-term complications and be refractory to treatment.

Holocarboxylase Synthase Deficiency CLINICAL MANIFESTATIONS Children with holocarboxylase synthase deficiency generally present in the first several days or weeks of life with severe and life-threatening metabolic encephalopathy. The clinical course is variably marked by irritability, lethargy, feeding problems, vomiting, tachypnea, hypertonia or hypotonia, and progression to seizures and coma. The timing of the acute presentation led to the initial characterization of patients as representing a neonatal-onset form of multiple carboxylase deficiency [Packman et al., 1981a, 1984]. Patients with milder forms of holocarboxylase synthase deficiency present later or have a more protracted clinical course [Packman et al., 1984]. These children may have alopecia, rash, ataxia, and developmental delays, a clinical presentation that overlaps that of biotinidase deficiency.

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high- or low-biotin culture medium [Packman et al., 1984]. For prenatal diagnosis, both types of enzymatic assay approaches can be used [Packman et al., 1982]. As an adjunct to enzymatic assay and to achieve a rapid result, it is possible to measure the concentration of accumulating analytes (e.g., 3-hydroxyisovalerate, methylcitrate) in amniotic fluid, by stable isotope dilution analysis [Jakobs et al., 1984]. Prenatal diagnosis of holocarboxylase synthase deficiency has been performed [Packman et al., 1982]. In two pregnancies, prenatal treatment by administration of biotin to the mother during pregnancy [Packman et al., 1982; Roth et al., 1982) was successfully performed in paradigmatic studies of the application and efficacy of cofactor therapy in such settings.

TREATMENT

Abnormal clinical laboratory findings include metabolic acidosis (e.g., lactic acidosis, ketosis), hyperammonemia, evidence of the bone marrow toxicity of organic acidemias (e.g., thrombocytopenia), and the characteristic organic aciduria of multiple carboxylase deficiencies: 3-methylcrotonylglycine, 3-hydroxyisovalerate, lactate, 3-hydroxypropionate, methylcitrate, and tiglylglycine.

Patients respond well to oral biotin in pharmacologic doses. Generally, the starting dose is 10 mg/day. However, the KM for biotin can range from 3 to 70 times normal [Wolf, 2001]. Some patients may require a higher dose, because the mutant enzyme has a higher KM for biotin. There is also a suggestion that patients with mutant holocarboxylase synthase enzymes exhibiting a reduced Vmax may have a poorer response to biotin therapy than those with KM values for biotin mutations [Sakamoto et al., 1999]. Accordingly, careful monitoring of clinical status (including neurologic and cutaneous manifestations), of organic acid levels (including lactate), and of conventional clinical chemistries (i.e., ammonia, electrolytes, and ketones) is mandatory to arrive at optimal dosing of biotin. After treatment levels have been achieved, no dietary restrictions are required.

ETIOLOGY

3-Methylglutaconic Aciduria

The basic defect is in the activity of the enzyme holocarboxylase synthase [Burri et al., 1981], which catalyzes a two-step reaction that results in the covalent binding of biotin to apocarboxylases. All patients with deficient holocarboxylase synthase activity have shown detectable residual activity. Multiple mutations have been identified, with most resulting in the synthesis of an enzyme with an elevated Michaelis-Menten dissociation constant (KM) for biotin. Some patients have mutations that result in a normal KM for biotin but a reduced value for maximum velocity of enzymecatalyzed reactions (Vmax). These observations have led to speculation that a complete absence of holocarboxylase synthase activity might be lethal [Wolf, 2001].

At least four different conditions have the common feature of abnormal urinary excretion of 3-methylglutconic acid, and they are designated as 3-methyglutaconic aciduria types I, II, III, and IV. The metabolite 3-methylglutconic acid occurs in the leucine catabolic pathway and is converted by 3-methylglutaconyl-CoA hydratase to 3-hydroxy-3-methylglutaric acid, leading ultimately to ketone body formation and the production of cholesterol precursors. The clinical features, diagnosis, and treatment approaches for each type of 3-methylglutaconic aciduria are discussed in the following sections.

LABORATORY TESTS

DIAGNOSIS Holocarboxylase synthase assay can be performed in cultured fibroblasts or lymphocytes and in amniotic fluid cells [Packman et al., 1982]. An alternative enzymatic approach can be taken by measurements of individual carboxylase activities in fibroblasts cultured in low-biotin medium and in high-biotin medium. If grown in low-biotin medium, individual carboxylase activities will be low, but the activities will be normal or approach normal levels if the cells are grown in high-biotin medium. This assay result contrasts with that for biotinidase deficiency fibroblasts, which demonstrates normal activities whether grown in

Type I: Primary 3-Methylglutaconyl-CoA Hydratase Deficiency Primary 3-methylglutaconyl-CoA hydratase deficiency is a rare, autosomal recessive disorder caused by mutations in the 3-methylglutaconyl-CoA hydratase gene (AUH) and characterized by abnormal urinary excretion of 3-methylglutaconic and 3-hydroxyisovaleric acids. The 3-hydroxyisovaleric acid levels are not elevated in the other three types of 3-methylglutaconylaciduria. In the small number of patients reported with this disorder, the spectrum of clinical abnormalities ranges from mild to extremely severe. Although the presentation varies, many patients have had retardation, acidosis, hypoglycemia, hypotonia, and seizures. The diagnosis is suspected by the characteristic pattern of urine

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organic acid excretion, and it is confirmed by assays for the 3-methylglutaconyl-CoA hydratase activity in cultured fibroblasts. Molecular studies to identify mutations in the AUH gene are available in only a limited number of laboratories. Treatment with leucine restriction or Lcarnitine supplementation may be effective in some patients [Sweetman and Williams, 2001].

Type II: Barth’s Syndrome Barth’s syndrome, also known as X-linked cardioskeletal myopathy and neutropenia, is characterized by mitochondrial abnormalities and abnormal excretion of 3-methylglutaconic acid. Barth’s syndrome is caused by mutations in the G4.5 gene (TAZ), which produces through alternate splicing a class of proteins called the tafazzins. Tafazzins are mitochondrial proteins thought to play a role in the structure and function of cardiolipin, a membrane lipid required for proper functioning of the mitochondrial electron transport chain. Clinically, cardiomyopathy and skeletal muscle weakness are usually apparent in affected males in the first year of life. Neutropenia can vary from mild to severe, even within the same patient. Many patients die before they are 4 years old, although some reports suggest an improvement in survival rates due to increased awareness of the diagnosis and more aggressive management of cardiomyopathy and infections [Barth et al., 2004]. No specific symptoms have been identified in heterozygous females, and there is no effective treatment for Barth’s syndrome.

Type III: Costeff’s Optic Atrophy Syndrome Costeff’s syndrome is a rare, autosomal-recessive disorder characterized by early-onset bilateral optic atrophy and choreiform movement disorder and by variable later-onset spasticity and mental retardation. Excretion of 3-methylglutaconic and 3-methylglutaric acids is moderately elevated, and the activity of 3-methylglutaconyl-CoA hydratase is normal. This disorder was once thought to be confined to patients of Iraqi Jewish background, but it has been described in non-Iraqi Jews [Kleta et al., 2002]. Linkage studies of large Iraqi Jewish families have identified mutations in the OPA3 gene, which encodes a protein of unknown function, as being the underlying cause of the disorder [Anikster et al., 2001]. The diagnosis is suspected on clinical grounds and confirmed by urine organic acid analysis. No effective treatment is available [Sweetman and Williams, 2001].

Type IV: Unclassified The type IV 3-methyglutaconic acidurias constitute a heterogeneous group of disorders. Patients share the common features of abnormal excretion and normal 3-methylglutaconyl-CoA hydratase activity. The abnormal 3-methylglutaconic aciduria may result from a variety of causes possibly affecting energy metabolism. The varied clinical features include severe psychomotor retardation, cerebellar dysgenesis, neonatal hypotonia, absent reflexes, and optic atrophy. No specific treatment is available [Sweetman and Williams, 2001].

β-Ketothiolase Deficiency Inherited β-ketothiolase deficiency, also known as mitochondrial acetoacetyl-CoA thiolase deficiency, is a rare autosomal recessive disorder caused by defects in mitochondrial acetoacetyl-CoA thiolase, also known as βketothiolase, T2, or 3-oxothiolase (see Fig. 23-6). This enzyme participates in the pathways of ketone body and isoleucine metabolism. It is related to, but distinct from, four other β-ketothiolase enzymes that participate in reactions of mitochondrial β-oxidation of short- and medium-chain fatty acids, cholesterol synthesis, and peroxisomal β-oxidation. Numerous mutations in the mitochondrial acetoacetyl-CoA thiolase gene (ACAT1) have been described in patients, with some completely abolishing β-ketothiolase activity and others associated with significant residual activity. The degree of clinical severity does not appear to be associated with the molecular severity of mutation nor the degree of residual activity [Fukao et al., 2001, 2003].

Clinical Manifestations There is wide clinical variability associated with βketothiolase deficiency, with most patients presenting with acute ketoacidosis between 5 to 24 months. Attacks are often accompanied by moderate hyperammonemia and hyperglycinemia. Patients are typically well between episodes, with attacks often precipitated by an intercurrent illness or other stress. A small number of patients have been reported with dystonia, which reflects basal ganglia damage, and with mental retardation [Mitchell and Fukao, 2001]. A β-ketothiolase deficiency has been described in asymptomatic siblings of affected patients.

Diagnosis Urine organic acid analysis of patients with β-ketothiolase deficiency reveals a characteristic pattern of 2-methyl-3hydroxybutyric and 2-methylacetoacetic acids, with variable excretion of 2-butanone and tiglylglycine. The diagnosis is confirmed by assays for β-ketothiolase activity in lymphocytes or cultured fibroblasts [Mitchell and Fukao, 2001].

Treatment Treatment of acute episodes is aimed at correcting ketoacidosis with fluids, glucose, and carnitine supplementation and includes careful monitoring of plasma ammonia, glucose, and electrolytes. Patients are managed long term with normal or slightly reduced protein intake and with careful monitoring of urine ketones during mild intercurrent illnesses. With appropriate treatment, the long-term prognosis for patients is excellent for those in whom neurologic damage has not occurred before diagnosis [Mitchell and Fukao, 2001].

Canavan’s Disease Canavan’s disease, also known as spongy degeneration of the brain, is an autosomal-recessive disorder caused by a deficiency of aspartoacylase (or N-acyl-L-aspartate amidohydrolase). This enzyme catalyzes the hydrolysis of N-

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acetyl-L-aspartic acid (NAA) to aspartic acid and acetic acid, and it is particularly abundant in white matter of the brain. NAA itself is found only in the central nervous system, and its function is largely unknown [Beaudet, 2001]. Although the disorder is pan-ethnic, it occurs more frequently among patients of Ashkenazi Jewish descent, for whom the carrier frequency is estimated at 1 case per 40 persons. Two specific aspartoacylase mutations, E285A and Y231X, account for most of the disease alleles.

Clinical Manifestations Patients with Canavan’s disease are typically normal for the first 1 to 2 months of life, and they then develop hypotonia, poor head control, poor contact, and seizures, as well as macrocephaly and loss of early milestones. In most patients, neurologic abnormalities and macrocephaly are apparent by 6 months of age. Imaging studies demonstrate severe changes in the subcortical white matter and the lower layers of the gray matter, with relative sparing of the central white matter. Later features of the disorder may include spasticity, opisthotonus, and decerebrate or decorticate posturing. Most patients die within the first 3 years of life, although a small number of cases have been reported with later onset and a milder or more variable course [Beaudet, 2001].

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stration of abnormal excretion of NAA. Enzyme assays for aspartoacylase activity are available in only a small number of laboratories worldwide and are typically unnecessary to establish a diagnosis. Molecular analysis for common aspartoacylase mutations in the Jewish and European populations can be used for confirmation of the diagnosis and carrier testing of family members. Prenatal diagnosis can be performed by DNA analysis in cases where parental mutations are known. Prenatal diagnosis has also been performed through assays of aspartoacylase activity in chorionic villi or amniocytes or NAA levels in amniotic fluid, but these approaches have been shown to be unreliable in a number of cases [Beaudet, 2001].

Treatment There is no known treatment for Canavan’s disease. The American College of Obstetrics and Gynecology (ACOG) has recommended that molecular carrier testing for Canavan’s disease be offered to all Ashkenazi Jewish patients [American College of Obstetrics and Gynecology, 2004]. Such carrier screening programs are aimed at disease prevention through the identification of couples at risk of having an affected child. As with similar screening programs for Tay-Sachs disease, this is expected to dramatically reduce the occurrence of infants with Canavan’s disease born in this population.

Diagnosis

Glutaric Aciduria Type 1

The diagnosis of Canavan’s disease is suspected on the basis of clinical evaluation and neuroimaging studies (Fig. 23-7) and confirmed by urine organic acid analysis and the demon-

In 1975, Goodman and colleagues [1975] described glutaric acidemia and aciduria in siblings with a neurodegenerative disorder beginning in infancy and characterized by 100 NAA

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20 Ch

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ppm 4.5

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2.5

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FIGURE 23-7. Patient with Canavan’s disease. A, Axial view, T2-weighted image shows abnormal hyperintensity in the cerebral hemispheric white matter, globus pallidi, and thalami. B, Proton magnetic resonance spectroscopy (echo time of 288 msec) shows a markedly increased N-acetyl-L-aspartic acid (NAA) peak. (From Barkovich AJ. Pediatric neuroimaging, 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2005.)

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opisthotonus, dystonia, and athetosis. Glutaric acidemia type 1, also known as glutaryl-CoA dehydrogenase deficiency, is an autosomal-recessive condition caused by deficiency of glutaryl-CoA dehydrogenase activity and has an estimated prevalence of approximately 1 case per 100,000 persons [Lindner et al., 2004]. Glutaric acidemia type 1 is relatively common in the Old Order Amish in Lancaster County, Pennsylvania. Glutaric acidemia type 2 (i.e., multiple acyl-CoA dehydrogenase deficiency) is associated with defects in mitochondrial electron transfer flavoprotein or electron transfer flavoprotein dehydrogenase and is discussed further in Chapter 28. Glutaryl-CoA dehydrogenase is a key enzyme in the degradation pathway for lysine, hydroxylysine, and tryptophan. Deficiency results in accumulation of glutarate and, to a lesser extent, of 3hydroxyglutarate and glutaconate in body tissues, blood, cerebrospinal fluid, and urine. Glutaric acidemia type 1 is characterized by irreversible focal striatal necrosis after an acute illness, most often between the ages of 3 and 18 months. Affected children often have macrocephaly, dystonia, and dyskinesia [Strauss et al., 2003]. Macrocephaly may not be present at birth, but head growth velocity is increased [Hoffmann et al., 1996]. Intraretinal hemorrhages and subdural effusions may be mistaken for nonaccidental injury [Morris et al., 1999]. In some cases, the presentation is insidious, with gradual appearance of symptoms [Hoffmann et al., 1996]. Systemic manifestations typical of many other organic acidemias, such as pronounced metabolic ketoacidosis, hypoglycemia, and hyperammonemia, do not occur [Hoffmann et al., 1996; Kyllerman

et al., 2004; Strauss et al., 2003]. There appears to be a window of neurologic susceptibility to damage during the first years of life. Striatal injury is rarely encountered after age 3 years, although initial presentation as late as age 19 years has been described [Bahr et al., 2002; Strauss and Morton, 2003b]. The most characteristic head MRI finding in symptomatic children is symmetric widening of the sylvian fissure with poor operculization (“bat wing” appearance) caused by frontotemporal atrophy or hypoplasia (Fig. 23-8). Other features include basal ganglia injury, subdural effusions, ventriculomegaly, and delayed myelination [Neumaier-Probst et al., 2004]. Diffusion-weighted imaging may be more sensitive in demonstrating brain lesions than CT or MRI [Elster, 2004]. Urine organic acid analysis often documents highly elevated glutarate and lesser elevations of 3-hydroxyglutarate and glutaconate, but some children with a classic phenotype have low or undetectable levels of these metabolites (socalled low excretors) [Baric et al., 1999]. Newborn screening using tandem mass spectrometry has the potential for presymptomatic detection of glutaric acidemia type 1, although the existence of a low-excretor phenotype will undoubtedly result in missed cases [Lindner et al., 2004]. In a study of 215 patients, complete absence of glutaryl-CoA dehydrogenase activity was found in more than 50%, whereas 34% had a residual activity up to 5%, and a few had residual activity between 5% and 15% [Christensen et al., 2004]. Some correlations between severity of mutation and biochemical parameters have been established (e.g., patients

A

B

FIGURE 23-8. MRI in glutaric acidemia. A, Axial view, T2-weighted image shows markedly enlarged sylvian fissures bilaterally and abnormal hyperintensity of the central tegmental tract. B, Axial view, T2-weighted image at a slightly higher level shows abnormal hyperintensity of the lentiform nuclei bilaterally. (Courtesy of Dr. A. James Barkovich, University of California, San Francisco, CA.)

Enns, Cowan, Klein, and Packman / Aminoacidemias and Organic Acidemias

with at least one mild mutation frequently have a lowexcretor phenotype). However, no correlation between clinical outcome and genotype or biochemical phenotype has been established [Christensen et al., 2004]. Increased glutarate and 3-hydroxyglutarate levels may induce an imbalance in glutamatergic and GABAergic neurotransmission by inhibiting glutamate decarboxylase, the key enzyme in γ-aminobutyric acid (GABA) synthesis, or through direct damage to striatal GABAergic neurons [Kolker et al., 2004]. 3-Hydroxyglutarate may mimic the excitatory neurotransmitter glutamate and thereby cause excitotoxic cell damage mediated through activation of NMDA receptors [Kolker et al., 2004]. Glutarate inhibits synaptosomal uptake of glutamic acid and produces striatal lesions when injected directly into rat brain [Goodman, 2004]. Other potential contributors to neurotoxicity include cytokine-induced cell damage, mitochondrial dysfunction, increased production of reactive oxygen species, and production of toxic quinolinic acid, an intermediate in tryptophan metabolism in brain [Goodman, 2004; Strauss and Morton, 2003b]. Other reports have emphasized the relatively weak neurotoxicity of glutarate and 3-hydroxyglutarate in animal models and primary neuronal cell cultures. The pathogenesis of striatal necrosis and brain lesions in glutaric acidemia type 1 remains the subject of intensive investigation [Freudenberg et al., 2004; Lund et al., 2004]. Animal models may help resolve these conflicting results. Treatment of glutaric acidemia type 1 is based on restriction of protein and lysine intake, carnitine and riboflavin supplementation, and rapid intervention in times of intercurrent illness [Muhlhausen et al., 2004]. Antioxidants and creatine have theoretical therapeutic advantages, but such compounds are not routinely used [Muhlhausen et al., 2004; Strauss et al., 2003]. Despite early identification and aggressive management, permanent neurologic damage occurs in approximately one third of patients [Strauss and Morton, 2003b]. Anticholinergic drugs, such as trihexyphenidyl, and botulinum toxin are beneficial in treating generalized or focal dystonia in patients with glutaric acidemia type 1 [Burlina et al., 2004]. Stereotactic pallidotomy has been performed in three children, with one improving only slightly [Muhlhausen et al., 2004; Rakocevic et al., 2004].

5-Oxoprolinuria Glutathione (L-γ-glutamyl-L-cysteinylglycine) is a key component in cellular protection from oxidant damage. 5-Oxoprolinuria (i.e., pyroglutamic aciduria) may be caused by defects in enzymes involved in the synthesis and degradation of glutathione, including glutathione synthetase and 5-oxoprolinase, or as a secondary finding in a variety of conditions that are associated with glutathione depletion, including inborn errors of metabolism unrelated to the glutathione cycle (e.g., methylmalonic acidemia, propionic acidemia, urea cycle defects, hepatorenal tyrosinemia, mitochondrial disorders), certain medication exposure (e.g., vigabatrin, acetaminophen, antibiotics), severe burns, multiorgan failure, and malnutrition [Mayatepek, 1999]. Glutathione synthetase deficiency is an autosomalrecessive condition that features massive urine excretion of 5-oxoproline. Clinical manifestations include metabolic

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acidosis, mental retardation, ataxia, spasticity, seizures, psychiatric disturbances, recurrent bacterial infections, and hemolytic anemia [Ristoff et al., 2001]. Ophthalmologic findings, consisting of minor lens opacities, granular retinal hyperpigmentation, and abnormal electroretinography, were found in two sisters with glutathione synthetase deficiency [Larsson et al., 1985]. Head imaging may reveal brain atrophy [Al-Jishi et al., 1999]. Mild, moderate, and severe phenotypes have been described [Ristoff et al., 2001]. Postmortem examination has revealed generalized cerebellar atrophy, caused by a diffuse loss of granule cells, and ventriculomegaly, especially of the fourth ventricle [Skullerud et al., 1980]. Although patients with 5-oxoprolinase deficiency also excrete large amounts of 5-oxoproline, they are typically asymptomatic. The detection of developmental delay in some patients with 5-oxoprolinase deficiency may reflect ascertainment bias. The excessive urinary excretion of 5-oxoproline should be detected easily on urine organic acid analysis. 5-Oxoproline is derived from increased synthesis of γ-glutamylcysteine, and it is present in amounts that exceed the normal capacity of 5-oxoprolinase to convert it to glutamate [Wellner et al., 1974]. Definitive diagnosis is made by measuring erythrocyte glutathione synthetase activity or DNA analysis, or both. Varieties of missense and splice site mutations have been found in the GSS gene [Shi et al., 1996]. Treatment of glutathione synthetase deficiency includes correction of metabolic acidosis and high-dose supplementation with vitamins C and E [Ristoff et al., 2001]. Supplementation with N-acetylcysteine may also increase levels of plasma and leukocyte glutathione and may be of therapeutic benefit [Jain et al., 1994; Martensson et al., 1989]. Patients with glutathione synthetase deficiency should avoid medications associated with hemolytic crises in glucose-6-phosphate dehydrogenase deficiency.

Isobutyryl-CoA Dehydrogenase Deficiency Isobutyryl-CoA dehydrogenase deficiency is an autosomal recessive disorder of valine metabolism that was first described by Roe and colleagues [1998]. Defective enzyme activity results in impairment of the conversion of isobutyryl-CoA to methylacrylyl-CoA. The initial patient was a developmentally normal 2-year-old girl who developed a dilated cardiomyopathy at age 11 months. She had profound carnitine deficiency, and after carnitine supplementation, acylcarnitine analysis detected markedly increased levels of butyrylcarnitine and isobutyrylcarnitine. Urine organic acids were normal [Roe et al., 1998]. Mutations in the ACAD8 gene were later identified in this patient [Nguyen et al., 2002]. Tandem mass spectrometry newborn screening has identified asymptomatic children [Sass et al., 2004b]. It is uncertain whether children are at risk for serious clinical sequelae or whether therapy is needed.

3-Hydroxyisobutyric Aciduria 3-Hydroxyisobutyric aciduria is a rare autosomal-recessive disorder of valine metabolism, although the deficient enzyme has not been identified. The initial patient had repeated episodes of ketoacidosis, failure to thrive, and chronic lactic acidemia [Ko et al., 1991]. Microcephaly, dysmorphic facial

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features (i.e., short, sloped forehead; telecanthus; downslanting palpebral fissures; long, prominent philtrum; and micrognathia), seizures, cerebral dysgenesis, brain atrophy, focal white matter abnormalities, and intracerebral calcification have also been described [Chitayat et al., 1992; Sasaki et al., 2001]. This condition has been misdiagnosed as cerebral palsy [Sasaki et al., 2001]. Although most patients have had prominent mental retardation, mild disease and normal intelligence have been reported [Boulat et al., 1995]. Treatment with carnitine and dietary valine and protein restriction appear to be beneficial [Ko et al., 1991; Sasaki et al., 2001].

2-Methylbutyryl-CoA Dehydrogenase Deficiency 2-Methylbutyryl-CoA dehydrogenase, also known as shortor branched-chain acyl-CoA dehydrogenase deficiency, catalyzes the conversion of 2-methylbutyryl-CoA to tiglylCoA in the isoleucine degradative pathway. Deficiency of this enzyme leads to increased 2-methylbutyrylglycine and 2-methylbutyrlycarnitine in physiologic fluids. A neonate with metabolic acidosis, hypoglycemia, and apnea was the initial reported case. MRI demonstrates ischemic changes bilaterally in parietal and occipital lobes with increased signal intensity in the lentiform nuclei [Gibson et al., 2000]. Motor delay, strabismus, and generalized muscular atrophy developed during the second year of life in another patient [Andresen et al., 2000]. Tandem mass spectrometry newborn screening identified elevated 5-carbon-saturated acylcarnitine species in eight children of Hmong ancestry. All were treated with a low-protein diet and carnitine supplementation. All patients remained asymptomatic at ages 3 to 14 months, except for one who developed mild hypotonia [Matern et al., 2003].

Mevalonate Kinase Deficiency Deficiency of mevalonate kinase, an essential enzyme in cholesterol and nonsterol isoprenoid biosynthesis, leads to two distinct clinical phenotypes: (1) mevalonic aciduria and hyperimmunoglobulinemia D and (2) periodic fever syndrome (HIDS). Both disorders are inherited as autosomal-recessive traits. Because abnormal isoprenoid synthesis can lead to fever and inflammation, these conditions are classified as autoinflammatory disorders [Houten et al., 2003]. Mevalonic aciduria is characterized by psychomotor retardation, failure to thrive, dysmorphic features (i.e., dolichocephaly, frontal bossing, down-slanting palpebral fissures, and low-set, posteriorly rotated ears), and intercurrent episodes of crisis that feature high fever, vomiting, and diarrhea. Severe cerebellar atrophy and associated ataxia are common. Ocular involvement (e.g., cataracts, retinal dystrophy), hypotonia, mild hepatosplenomegaly, and cholestatic liver disease also occur [Hoffmann et al., 1993]. Recurrent febrile crises tend to decrease with advancing age and are not present in all cases. Patients with HIDS have lifelong recurrent febrile episodes, lymphadenopathy, splenomegaly, arthralgias, and rashes that begin in infancy. HIDS is not associated with neurologic impairment, and patients are typically asymptomatic in between episodes of fever. Because phenotypic overlap between mevalonic aciduria and HIDS exists, these

conditions most likely represent a continuous spectrum of disease, rather than two distinct entities [Simon et al., 2004]. Mevalonic aciduria is diagnosed by detecting elevated mevalonic acid on urine organic acid analysis. Standard clinical chemical investigations find normal or slightly reduced cholesterol and elevated creatine kinase levels, especially during crises [Hoffmann et al., 1993]. Although the level of serum immunoglobulin D may be elevated in mevalonic aciduria, this finding is not invariable. An elevated serum IgD level is a marker for HIDS. Mild elevations of urine mevalonic acid may occur in HIDS during attacks [Cuisset et al., 2001]. Analyzing mevalonate kinase activity in lymphoblasts or using direct DNA analysis can confirm of the diagnosis. Most patients are compound heterozygotes for mutant alleles. Some mutations are common to mevalonic aciduria and HIDS [Cuisset et al., 2001]. Treatment for both conditions is largely supportive. Oral cholesterol supplementation, alone or with various combinations of ursodeoxycholic acid, ubiquinone, and vitamin E, did not result in improvement of clinical or biochemical parameters. Lovastatin administration has resulted in the development of severe clinical crises, but some patients have responded dramatically to corticosteroid therapy during acute clinical crises [Hoffmann et al., 1993]. REFERENCES Aliefendioglu D, Tana Aslan A, Coskun T, et al. Transient nonketotic hyperglycinemia: Two case reports and literature review. Pediatr Neurol 2003;28:151. Al-Jishi E, Meyer BF, Rashed MS, et al. Clinical, biochemical, and molecular characterization of patients with glutathione synthetase deficiency. Clin Genet 1999;55:444. Al Tawari AA, Ramadan DG, Neubauer D, et al. An early onset form of methylenetetrahydrofolate reductase deficiency: A report of a family from Kuwait. Brain Dev 2002;24:304. American College of Obstetrics and Gynecology. The ACOG committee opinion, no. 298, August 2004: Prenatal and preconceptional carrier screening for genetic diseases in individuals of Eastern European Jewish descent. Obstet Gynecol 2004;104:425. Andresen BS, Christensen E, Corydon TJ, et al. Isolated 2methylbutyrylglycinuria caused by short/branched-chain acyl-CoA dehydrogenase deficiency: Identification of a new enzyme defect, resolution of its molecular basis, and evidence for distinct acyl-CoA dehydrogenases in isoleucine and valine metabolism. Am J Hum Genet 2000;67:1095. Anikster Y, Kleta R, Shaag A, et al. Type III 3-methylglutaconic aciduria (optic atrophy plus syndrome, or Costeff optic atrophy syndrome): Identification of the OPA3 gene and its founder mutation in Iraqi Jews. Am J Hum Genet 2001;69:1218. Applegarth DA, Toone JR. Nonketotic hyperglycinemia (glycine encephalopathy): Laboratory diagnosis. Mol Genet Metab 2001;74:139. Applegarth DA, Toone JR. Glycine encephalopathy (nonketotic hyperglycinaemia): Review and update. J Inherit Metab Dis 2004;27:417. Applegarth DA, Toone JR, Rolland MO, et al. Non-concordance of CVS and liver glycine cleavage enzyme in three families with non-ketotic hyperglycinaemia (NKH) leading to false negative prenatal diagnoses. Prenat Diagn 2000;20:367. Asatoor AM, Craske J, London DR, et al. Indole production in Hartnup disease. Lancet 1963;1:126. Auerbach VH, Digeorge AM, Baldridge RC, et al. Histidinemia. A deficiency in histidase resulting in the urinary excretion of histidine and of imidazolepyruvic acid. J Pediatr 1962;60:487. Ayling JE, Bailey SW, Boerth SR, et al. Hyperphenylalaninemia and 7-pterin excretion associated with mutations in 4a-hydroxytetrahydrobiopterin dehydratase/DCoH: Analysis of enzyme activity in intestinal biopsies. Mol Genet Metab 2000;70:179. Bahr O, Mader I, Zschocke J, et al. Adult onset glutaric aciduria type I presenting with a leukoencephalopathy. Neurology 2002;59:1802.

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CHAPTER 24

Inborn Errors of Urea Synthesis Mark L. Batshaw, Uta Lichter-Konecki, and Mendel Tuchman

Inherited urea cycle disorders represent a devastating group of inborn errors of metabolism that are associated with hyperammonemic encephalopathy and high mortality and morbidity rates. They comprise deficiencies in any of the six enzymes and two amino acid transporters involved in urea synthesis (Fig. 24-1). Accordingly, these disorders are named as follows (estimated prevalence rates are given) [Brusilow and Maestri, 1996; Tuchman, 1992; Yamanouchi et al., 2002]: • N-acetylglutamate synthase (NAGS) deficiency (prevalence unknown) • Carbamyl phosphate synthetase I (CPS I) deficiency (1 case per 62,000 population) • Ornithine transcarbamylase (OTC) deficiency (1 per 14,000) • Citrullinemia type II (mitochondrial aspartate/glutamate transport carrier [citrin] deficiency) (1 per 21,000 in Japan) • Argininosuccinate synthetase (ASS) deficiency (citrullinemia) (1 per 57,000) • Argininosuccinate lyase (ASL) deficiency (argininosuccinicaciduria) (1 per 70,000) • Arginase (ARG) deficiency (hyperargininemia) (1 per 353,000) • Hyperornithinemia-hyperammonemiahomocitrullinuria (HHH) syndrome (mitochondrial ornithine carrier deficiency) (prevalence unknown) These disorders are inherited as autosomal-recessive traits, except for ornithine transcarbamylase deficiency, which is X-linked. Because of the absence of mass newborn screening for these disorders, the true incidence of urea cycle disorders is unknown. Based on case reports and questionnaires about referred patients, the combined prevalence of all urea cycle disorders is estimated to be 1 per 8200 [Brusilow and Maestri, 1996]. Other than in arginase deficiency, infants with a complete deficiency of a urea cycle enzyme (N-acetylglutamate synthase, CPS I, ornithine transcarbamylase, argininosuccinate synthetase, or argininosuccinate lyase) commonly present in the newborn period with hyperammonemic coma. Despite aggressive treatment that relies primarily on hemodialysis, the mortality rate in infancy has been reported to approximate 50% [Maestri et al., 1999], and as demonstrated by our previous studies, virtually all of the survivors are left with developmental disabilities [Msall et al., 1984]. Patients with late-onset disease (those with partial enzyme deficiencies, including ornithine transcarbamylase–deficient female heterozygotes) may present at any age with hyperammonemic crises that carry a 10% mortality rate and a significant risk of developmental disabilities [Batshaw et al., 1986]. Even asymptomatic ornithine transcarbamylase–

deficient heterozygotes have been shown to have mild cognitive deficits [Batshaw et al., 1980; Gyato et al., 2004].

THE UREA CYCLE Dietary protein, on average, contains approximately 16% nitrogen. Greater than 90% of the nitrogen that is not used for anabolic processes normally is metabolized and excreted as urea. Therefore, substantial urea synthesis capacity (approximately 16 g per day in adults) is required [Linder, 1991]. With a deficiency of one of the urea cycle enzymes, an insufficient amount of urea will be formed, and nitrogen in the form of ammonia will accumulate. Accumulation in brain causes encephalopathic episodes. The urea cycle was proposed by Hans Krebs and Kurt Henseleit in 1932 and was the first cyclic pathway elucidated. Six enzymes and five cofactors or transporters are necessary for optimal urea cycle activity (see Fig. 24-1). The clinically most important cofactor is N-acetylglutamate, which is formed from acetyl coenzyme A (acetyl-CoA) and glutamate in a reaction catalyzed by N-acetylglutamate synthase. N-acetylglutamate synthase activates the first enzyme of the urea cycle, CPS I, which uses adenosine triphosphate and bicarbonate to synthesize carbamyl phosphate from ammonia, contributing the first atom of waste nitrogen to the cycle. CPS I is expressed in periportal hepatocytes and intestinal mucosa epithelial cells [Ryall et al., 1985]. It is the most abundant protein in liver mitochondria, accounting for 20% of the mitochondrial matrix protein [Lusty, 1978]. The enzyme consists of a single polypeptide with a molecular weight of 165,000 and approximately 1500 amino acid residues [Haraguchi et al., 1991]. The second enzyme in the urea cycle, ornithine transcarbamylase, like CPS I, is mitochondrial. Citrulline is formed by the action of ornithine transcarbamylase on carbamyl phosphate and ornithine. Once formed, citrulline is actively moved, by means of the ornithine transporter, out of the mitochondrion and into the cytosol, where it is conjugated with aspartate to form argininosuccinic acid by argininosuccinate synthetase. Here the second atom of waste nitrogen is contributed to the cycle by aspartate. A defect in argininosuccinate synthetase leads to citrullinemia, the accumulation of citrulline in blood. A second form of citrullinemia called type II or adult-onset citrullinemia is caused by deficient activity of the mitochondrial aspartate/glutamate transporter carrier, citrin. Argininosuccinic acid subsequently is cleaved to yield fumarate and arginine by the enzyme argininosuccinate lyase. A deficiency of this enzyme is called argininosuccinicaciduria, characterized by marked urinary excretion (and accumulation in blood) of argininosuccinic acid.

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Glutamate AcCoA NAGS CoASH N-acetylglutamate

ORNT1 Urea

Ornithine

Ornithine

CPS I CP OTC

ARG

Aspartate

Citrulline Arginine

CITR

ORNT1

Fumarate AL Argininosuccinate

NH3 HCO3– 2 ATP

FIGURE 24-1. The urea cycle. AcCoA, acetyl coenzyme A; AL, argininosuccinate lyase; ARG, arginase; AS, argininosuccinate synthetase; CITR, citrin; CoASH, uncombined acetyl coenzyme A; CPS I, carbamyl phosphate synthetase I; NAGS, N-acetylglutamate synthase; ORNT1, ornithine transporter 1; OTC, ornithine transcarbamylase.

Citrulline AS

Aspartate

The final step in the urea cycle involves cleavage of arginine to form urea and ornithine by arginase. A defect here is termed argininemia. Once formed, ornithine is transported back into the mitochondrion by the ornithine transporter. A defect in this transporter leads to the marked accumulation of ornithine in blood, resulting in hyperornithinemiahyperammonemia-homocitrullinuria syndrome. The complete urea cycle is found only in hepatocytes.

CLINICAL DESCRIPTION OF UREA CYCLE DISORDERS N-Acetylglutamate Synthase Deficiency Inherited N-acetylglutamate synthase deficiency leads to hyperammonemia by causing a secondary deficiency of CPS I. This disorder has been reported to date in approximately two dozen patients [Bachmann et al., 1982; Elpeleg et al., 2002] but is likely to be underdiagnosed because of the lack of specific

biochemical markers and the physiologically low abundance of N-acetylglutamate synthase in the liver. N-acetylglutamate synthase deficiency is inherited as an autosomal-recessive disorder and has a phenotype that is similar to that in CPS I deficiency. It is characterized by hyperammonemia in the newborn period or later in life and can be fatal or lead to mental retardation and other developmental disabilities. Plasma amino acid analysis usually demonstrates an increased level of glutamine and reduced or absent levels of citrulline. Urinary orotic acid level is normal or low. N-acetylglutamate synthase activity in the liver has a variable degree of deficiency (ranging from undetectable to normal residual activity) that is unresponsive to L-arginine. Because enzyme analysis requires large amounts of liver tissue and may not be entirely reliable, analysis of genomic DNA for mutations in the N-acetylglutamate synthase gene is the best diagnostic method [Morizono et al., 2004]. Treatment of N-acetylglutamate synthase deficiency currently consists of a low-protein diet and use of ammonia-scavenging drugs (Table 24-1). A more

TABLE 24-1 Long-Term Alternative Pathway Treatment of Urea Cycle Disorders (UCDs)* DISORDER

L-CITRULLINE

L-ARGININE FREE BASE

SODIUM PHENYLBUTYRATE

N-CARBAMYLGLUTAMATE

NAGS deficiency

—

—

—

CPS I or OTC deficiency

0.17 g/kg/d or 3.8 g/m2/d

—

Citrullinemia

—

0.40-0.50 g/kg/d or 8.8-11.0 g/m2/d

Argininosuccinic acidemia

—

Argininemia

—

0.40-0.70 g/kg/d or 8.8-15.4 g/m2/d —

0.45-0.60 g/kg if <25 kg; 9.9-13.0 g/m2/d in larger patients 0.45-0.60 g/kg if <25 kg; 9.9-13.0 g/m2/d in larger patients —

0.10 g/kg/d if <25 kg or 2.2 g/m2/d in larger patients —

HHH syndrome

0.17 g/kg/d if <25 kg; 3.8 g/m2/d in larger patients

—

0.45-0.60 g/kg/d if <25 kg; 9.9-13.0 g/m2/d in larger patients 0.45-0.60 g/kg/d if <25 kg; 9.9-13.0 g/m2/d in larger patients

— — — —

*Drugs and dose ranges are those commonly used in patients with UCD; however, doses can vary and need to be adjusted based on the severity of the disorder. While using doses at the upper recommended range or above, consideration should be given to increased risk of drug toxicity. CPS I, carbamyl phosphate synthetase I; HHH, hyperornithinemia-hyperammonemia-homocitrullinuria; NAGS, N-acetylglutamate synthase; OTC, ornithine transcarbamylase.

Batshaw, Lichter-Konecki, and Tuchman / Inborn Errors of Urea Synthesis

specific and promising therapy using N-carbamyl-L-glutamate is under investigation. N-carbamyl-L-glutamate is a stable structural analog of N-acetylglutamate and may substitute for it in the activation of CPS I.

Carbamyl Phosphate Synthetase I Deficiency CPS I deficiency was first reported in 1969 [Hommes et al., 1969]. This mitochondrial urea cycle enzyme should be distinguished from a similar, cytosolic enzyme, carbamyl phosphate synthetase 2, which is involved in de novo pyriidine synthesis. This disorder can manifest with hyperammonemic coma in the newborn period or later in childhood. Biochemically, the principal findings are hyperammonemia, an increased level of plasma glutamine, and reduced level or absence of citrulline on plasma amino acid analysis. Urinary orotic acid level is normal or low. Patients with neonatalonset disease generally demonstrate less than 5% normal CPS I activity in liver, whereas those with late-onset disease have higher residual activity [Qureshi et al., 1986]. Like most of the other urea cycle disorders, CPS I deficiency does not arise from a common mutation [Funghini et al., 2003; Summar, 1998]. Therapy consists of dialysis and/or intravenous alternate pathway therapy during severe hyperammonemic episodes, and low-protein diet and oral alternate pathway therapy for chronic treatment (see Table 24-1). Patients with the neonatal-onset form who survive the initial crisis generally require liver transplantation for long-term survival.

Ornithine Transcarbamylase Deficiency Ornithine transcarbamylase deficiency was first reported in 1962 in two girls, aged 20 months and 6 years, who were found to have hyperammonemia associated with episodic vomiting, delirium, stupor, failure to thrive, and mental retardation [Russell et al., 1962]. The mothers of the children were sisters, and both demonstrated evidence of a similar but less marked metabolic disorder. Both girls died before the age of 8 years. Several years later, this disorder also was identified in males. The delayed recognition in males was attributable to the almost total lack of enzyme activity and rare survival of affected males beyond the newborn period. The reason for this difference between males and females subsequently was determined to be related to its X-linked inheritance pattern, with the occurrence of symptomatic females explained by skewed X chromosome inactivation [Ricciuti et al., 1976]. The classic presentation of ornithine transcarbamylase deficiency in hemizygous males is as a catastrophic illness in the first week of life. This presentation accounts for approximately 60% of all cases [Matsuda et al., 1991]. In symptomatic female heterozygotes and in males with partial ornithine transcarbamylase deficiency, symptoms rarely present in the newborn period. Only one case of lethal ornithine transcarbamylase deficiency in a female neonate has been reported [Klosowski et al., 1998]. In partial deficiencies, age at presentation after the newborn period covers a wide spectrum, with development of hyperammonemic episodes in infancy in some patients, in later childhood in others, and not until adulthood in still others [Ahrens et al., 1996; Ausems et al., 1997; McCullough et al., 2000]. These patients generally have 5% to 30% of normal ornithine trans-

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carbamylase activity in liver on in vitro measurement. Biochemically, the principal findings are hyperammonemia, hyperglutaminemia, reduced levels or complete absence of citrulline in plasma, and increased urinary orotic acid level. More than 240 different mutations and polymorphisms have been found in ornithine transcarbamylase-deficient patients, and no mutations are prevalent [McCullough et al., 2000; Tuchman et al., 2002]. In greater than 80% of affected families, prenatal diagnosis using DNA techniques is possible [Grompe et al., 1991]. When the mutation in the family has been identified, carrier testing and prenatal diagnosis are straightforward. The identification of common intragenic polymorphisms allows tracking of the mutant allele even when the deleterious mutation is unknown [Plante and Tuchman, 1998]. Although most families have point mutations, 8% of families have large deletions of one or more exons, 10% have small deletions or insertions of one to five bases, and 18% have splice site mutations. Generally, mutations causing neonatal disease affect amino acid residues that are in the interior of the enzyme, especially around the active site, whereas those associated with late-onset and milder phenotypes tend to be located on the surface of the protein [Tuchman et al., 1998]. Of males with ornithine transcarbamylase deficiency, only 20% have been found to have spontaneous mutations, whereas approximately 80% of females with ornithine transcarbamylase deficiency have spontaneous mutations or inherited mutations from the father’s mutated sperm [McCullough et al., 2000]. Therefore, the chance of a mother’s having a second affected child depends on whether the first affected child was male or female [Tuchman et al., 1995]. Approximately 15% of ornithine transcarbamylase– deficient heterozygous females will become symptomatic during their lifetime [Batshaw et al., 1986]. (Heterozygotes for other urea cycle disorders are asymptomatic.) Heterozygote detection of ornithine transcarbamylase deficiency is important both to identify at-risk family members and to offer prenatal diagnosis. It can be accomplished by either molecular studies or provocative tests. The best provocative testing is with an allopurinol load [Hauser et al., 1990]. This has replaced the protein loading test, which can precipitate a hyperammonemic episode. The allopurinol load (300 mg given orally to adults) leads to increased excretion of orotic acid, reaching 10 to 20 times control values in 90% of ornithine transcarbamylase heterozygotes [Hauser et al., 1990]. Therapy for the neonatal-onset form of ornithine transcarbamylase deficiency consists of dialysis and administraion of intravenous ammonia scavenger drugs, followed by maintenance of a low-protein diet and long-term alternative pathway therapy (see Table 24-1). Patients with the neonatalonset form who survive the initial crisis generally require liver transplantation.

Citrullinemia Citrullinemia was first reported in 1962 [McMurray, 1962]. Its name derives from the marked elevation of citrulline in blood of affected persons. This disorder also has been called citrullinuria because of the increased excretion of citrulline in urine, and argininosuccinic acid (argininosuccinate) synthetase deficiency to denote its enzyme deficit. Heterogeneity is seen clinically, biochemically, and at the

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Genetic, Metabolic, and Neurocutaneous Disorders / 24

molecular level. Two distinct forms have been reported: types 1 and 3, neonatal childhood-onset citrullinemia (with diminished levels of argininosuccinate synthetase in all organs), and type 2, adult-onset citrullinemia and idiopathic neonatal cholestasis (associated with a defect in citrin) [Saheki et al., 1987]. Biochemically, the principal findings are hyperammonemia, citrullinemia, and citrullinuria. Citrulline levels generally are elevated 50-fold to 100-fold [normal levels less than 50 μmol/L] [Batshaw et al., 1981]. Urinary orotic acid levels also may be increased but less so than in ornithine transcarbamylase deficiency or argininemia. Citrullinemia is inherited as an autosomal-recessive trait. The gene has been localized to the q34 region of chromosome 9, and the nucleotide coding sequence and deduced amino acid sequence for the enzyme are known [Gao et al., 2003]. It is a cytoplasmic homotetramer with a subunit molecular weight of 46,400. A number of mutations have been identified in the argininosuccinate synthetase gene in cell lines derived from patients [Gao et al., 2003]. To date, greater than 50 mutations have been identified; some involve single base changes in the coding sequence, and others involve skipping of an exon in the messenger RNA (mRNA) due to abnormal splicing. Most patients appear to be compound heterozygotes of two different mutations. In neonatal-onset cases, argininosuccinate synthetase activity in liver is less than 5% of normal, whereas in childhood-onset cases, 10% to 25% residual activity is seen [Brusilow and Horwich, 2001]. Therapy for citrullinemia types 1 and 3 consists of dialysis during severe hyperammonemic crises, followed by lowprotein diet and long-term alternative pathway therapy (see Table 24-1). After the initial crisis, patients are in general more stable and easier to manage than patients with more proximal defects (CPS I and ornithine transcarbamylase deficiencies).

Citrullinemia Type 2 Citrullinemia type 2 was identified first in Japan and is caused by mutations in a gene encoding a previously unknown calcium-dependent mitochondrial membrane protein named citrin or aralar II (SLC25A13) [Kobayashi et al., 2003]. This inner mitochondrial membrane carrier transporter transports aspartate and glutamate [Palmieri et al., 2001]. Plasma ammonia levels are less severely elevated during acute episodes than in other urea cycle disorders, and citrulline levels are elevated up to 20-fold [Kobayashi et al., 1993]. It has been noted that serum pancreatic secretory trypsin inhibitor also is increased and may be useful as a diagnostic marker for the disorder [Kobayashi et al., 1993]. Citrullinemia type 2 manifests in adulthood with cyclical bizarre behavior patterns (aggression, irritability, hyperactivity), dysarthria, seizures, motor weakness, and coma. Dementia and hepatomegaly eventually develop. Cases of hepatocellular carcinoma also have been reported in affected persons [Hagiwara et al., 2003]. In retrospect, many of the patients have had symptoms since childhood that suggested hyperammonemia, including recurrent episodes of vomiting, lethargy, and irritability [Okeda et al., 1989]. Treatment generally relies on alternate pathway therapy (arginine and phenylbutyrate) [Imamura et al., 2003]; however, liver transplantation is becoming a more common practice in the

treatment of this disorder because of the possible liver complications [Ikeda et al., 2001; Yazaki et al., 2004]. More recently, a neonatal-onset form of citrin deficiency has been identified; this form is associated with intrahepatic cholestasis [Tamamori et al., 2002; Tazawa et al., 2001]. Affected infants have multiple metabolic abnormalities including aminoacidemia, galactosemia, hypoproteinemia, hypoglycemia, and cholestasis. Treatment usually is by nutritional manipulation, and symptoms often disappear within a year [Saheki et al., 2004]. A few children, however, have a severe form of the disorder with liver damage and tyrosinemia that necessitate liver transplantation. Hyperammonemia is not a major component of this disorder.

Argininosuccinicacidemia Argininosuccinicacidemia was first described in 1958 by Allan and colleagues [1958]. Its name derives from the marked elevation of argininosuccinic acid in blood of affected persons. This disorder also has been called argininosuccinicaciduria because of the increased excretion of argininosuccinic acid in urine, and argininosuccinate lyase deficiency to denote the underlying enzyme deficiency. In addition to hyperammonemic coma in the newborn period and recurrent hyperammonemic episodes later in childhood, a specific abnormality of the hair termed trichorrhexis nodosa develops in affected children. Nodules appear on the hair shaft, and the hair is friable. A generalized erythematous maculopapular skin rash also may appear in this disorder. Both conditions are associated with arginine deficiency and respond to arginine supplementation [Brusilow and Horwich, 2001]. Chronic marked hepatomegaly has been reported, both in patients managed with protein restriction and in those receiving arginine supplementation, but this finding is not universal. Pathologic examination reveals modest fatty infiltration and fibrosis. Results of liver function tests frequently are abnormal, especially during hyperammonemic crises, and a few cases of cirrhosis have been reported [Zimmermann et al., 1986]. The gene for argininosuccinate lyase has been localized to the long arm of chromosome 7 [Kleijer et al., 2002]. The deficient enzyme, a homotetramer of 50-kilodalton (kDa) subunits, is expressed in multiple tissues. Evidence of multiple allelic mutations and intragenic complementation, indicating extensive genetic heterogeneity, is characteristic of this disorder [Yu et al., 2001]. The frequency of some mutations, however, is higher than that of others; such mutations may occur at “hot spots” with higher susceptibility for alteration [Linnebank et al., 2002]. The multiple mutations may account for some of the observed heterogeneity in this disease at the clinical level. Biochemically, the principal findings are hyperammonemia, argininosuccinicacidemia, and argininosuccinicaciduria. The plasma argininosuccinic acid peak is large (normally it is undetectable) [Batshaw et al., 1981]. Of note, this peak may be missed, because it can overlie the peak for leucine or isoleucine. The presence of the two anhydrides of argininosuccinic acid, however, in areas of the chromatogram where homocystine and γ-aminobutyric acid normally are found, aids in the diagnosis. Markedly increased levels

Batshaw, Lichter-Konecki, and Tuchman / Inborn Errors of Urea Synthesis

of argininosuccinic acid also are readily identifiable in the urine. Additionally, levels of citrulline levels are increased 3- to 10-fold (to 100 to 300 μmol/L). The diagnosis can be confirmed by measuring argininosuccinate lyase in erythrocytes or fibroblasts, although this is rarely needed. In cerebrospinal fluid, elevated concentrations of argininosuccinic acid and its anhydrides, as well as pyrimidines (pseudouridine and uridine), have been found [Gerrits et al., 1993]. After the initial hyperammonemic crisis and establishment of the diagnosis, treatment for argininosuccinicacidemia currently consists of a low-protein diet and L-arginine supplementation (see Table 24-1).

Argininemia Argininemia, or hyperargininemia, was first described in 1969 by Terheggen and colleagues and is caused by a deficiency of arginase 1 [Terheggen et al., 1969]. Its name derives from the marked elevation of arginine in blood of affected persons. Argininemia presents differently from all of the other congenital urea cycle disorders. It usually appears as a progressive neurologic disorder, rather than as an acute encephalopathy [Cederbaum et al., 1979; Prasad et al., 1997]. Clinical symptoms do not classically start with hyperammonemic coma in infancy. In one report, however, a 2-month-old child with recurrent vomiting, persistent jaundice, and hepatomegaly (with associated cirrhosis) was diagnosed as having hyperargininemia [Braga et al., 1997]. Another patient presented with cerebral edema and growth retardation [Harrington et al., 2000]. More commonly, development for the first few years of life appears to be normal, although a detailed history often reveals evidence of protein aversion (often with anorexia, vomiting, and irritability) and some developmental delay. The disease runs an indolent course, but with acute episodes of ataxia, behavioral disturbances, vomiting, lethargy, and seizures. Such episodes often are precipitated by intercurrent viral illnesses [Grody et al., 1993]. Associated biochemical abnormalities usually include moderately elevated plasma ammonia levels of three to four times normal and plasma arginine levels of greater than five times normal, often exceeding 1000 μmol/L (normal is less than 120 μmol/L). The unique feature of this disorder is the development of progressive muscle weakness, tremor, and spasticity (diplegia or quadriplegia) [Prasad et al., 1997; Scheuerle et al., 1993]. Mental retardation and growth failure also commonly are evident by childhood, and glaucoma has been reported [Sacca et al., 1996]. Affected children generally do not succumb to hyperammonemic coma and therefore have a longer life span than those affected by proximal urea cycle disorders. Arginase 1 is found in liver and red blood cells. By contrast, renal arginase (arginase 2) is found in the mitochondrial matrix and differs from the liver type of enzyme in biochemical, molecular, and antigenic properties [Cederbaum et al., 2004]. Arginase 2 also is found in the small intestine and the brain, and its levels have been found to be elevated in patients with argininemia [Iyer et al., 1998]. It is possible that the presence of arginase 2 in hyperargininemia provides some degree of protection from nitrogen accumulation, resulting in less severe hyperammonemic episodes than in other urea cycle disorders. The gene for liver arginase has

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been localized to chromosome band 6q23 [Sparkes et al., 1986]. Available evidence suggests multiple point mutations and microdeletions in this disorder, indicating extensive genetic heterogeneity [Vockley et al., 1996], and many afected persons are compound heterozygotes. Correlation between the severity of the mutation and the degree of clinical symptoms has been shown [Uchino et al., 1998]. The principal biochemical finding is markedly elevated plasma levels of arginine. Arginine plus ornithine, aspartate, threonine, glycine, and methionine levels are elevated in cerebrospinal fluid [Cederbaum et al., 1982]. In addition, a generalized dibasic aminoaciduria (argininuria, lysinuria, cystinuria, ornithinuria) is present. Urinary excretion of orotic acid and guanidine compounds also is markedly increased [Marescau et al., 1990]. The diagnosis can be confirmed by measuring arginase 1 activity in erythrocytes. The mechanism responsible for the spasticity and cognitive deficits in argininemia is unknown but is unlikely to be the result of the generally moderate hyperammonemia. Arginine, its guanidine metabolites, and altered biogenic amines are candidate neurotoxins [Marescau et al., 1990]. Arginine is the substrate for nitric oxide synthetase, so overproduction of nitric oxide may play a role in neuropathology [Iyer et al., 1998]. It is theoretically possible that pharmacologic inhibitors of nitric oxide synthetase may be beneficial. Treatment with alternate pathway therapy appears to halt the progression of the spasticity, and botulinum toxin (Botox) and surgical tendon release may improve function.

Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome was first described in 1969 [Shih et al., 1969], and only about 50 cases have been reported in the literature, most being in the French-Canadian population in Quebec [Gjessing et al., 1986]. Clinical symptoms are similar to those in other urea cycle disorders but rarely develop in infancy [Zammarchi et al., 1997]. Spastic paraparesis also has been noted and occasionally coagulation disorders [Gallagher et al., 2001; Lemay et al., 1992; Salvi et al., 2001a, 2001b]. Plasma ornithine concentrations are elevated, ranging from 400 to 600 mmol/L. Plasma lysine level typically is low, and urinary excretion of homocitrulline is increased. The high blood levels and urinary excretion of homocitrulline likely are the result of conversion of lysine to homocitrulline by ornithine transcarbamylase, in the absence of ornithine in mitochondria. The etiology of hyperornithinemiahyperammonemia-homocitrullinuria syndrome begins with a mutation in the ornithine transporter gene, ORNT1, also called SLC25A15, whose product is a member of the solute mitrochondrial carrier protein family [Camacho et al., 1999]. This leads to decreased ornithine levels in mitochondria and secondary impairment of urea synthesis. The expression of ORNT2, an intronless gene or processed pseudogene, encoding a protein about 90% identical to OTNT 1, may explain the milder clinical signs and symptoms compared with those in CPS I and ornithine trancarbamylase deficiencies [Camacho et al., 2003]. Treatment of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome involves protein restriction, phenylbutyrate, and citrulline supplementation.

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Genetic, Metabolic, and Neurocutaneous Disorders / 24

COMMON CLINICAL PRESENTATIONS OF UREA CYCLE DISORDERS The classic presentation of a complete defect in the urea cycle (other than arginase) is as a catastrophic illness in the first week of life. This presentation accounts for approxmately 60% of all cases of urea cycle disorders [Matsuda et al., 1991]. Clinical manifestations appear between 24 and 72 hours of age, starting as a poor suck, hypotonia, vomiting, lethargy, and hyperventilation with rapid progression to coma and seizures. The electroencephalogram (EEG) pattern during hyperammonemic coma is one of low voltage with slow waves and asymmetric delta and theta waves. The tracing may demonstrate a burst suppression pattern, and the duration of the interburst interval may correlate with the height of ammonia levels [Clancy and Chung, 1991]. Neuroimaging studies reveal cerebral edema with small ventricles, flattening of cerebral gyri, and diffuse low density of white matter; evidence of intracranial hemorrhage also may be seen [Kendall et al., 1983]. Partial urea cycle enzyme deficiencies have a spectrum of presentations, with hyperammonemic episodes developing in infancy in some patients, in later childhood in others, and not until adulthood in still others. Symptoms may be delayed in onset with a mild deficiency or by dietary self-selection restriction—specifically, avoidance of meats, fish, eggs, milk, and other high-protein foods. Signs and symptoms in childhood include anorexia, ataxia, and behavioral abnormalities such as biting, self-injury, nocturnal restlessness, and hyperactivity [Rowe et al., 1986]. In adults, signs and symptoms may mimic those of psychiatric or neurologic disorders and include migraine-like headache, nausea, dysarthria, ataxia, confusion, hallucinations, and visual impairment (blurred vision, scotomas, lost vision) [Arn et al., 1990]. In a case report of lateonset ornithine transcarbamylase deficiency, the patient was a heterozygote who presented with a syndrome mimicking complex partial status epilepticus [Bogdanovic et al., 2000]. Neurologic findings may include increased deep tendon reflexes, papilledema, and decorticate/decerebrate posturing. Seizures generally are a late complication; the seizure episode typically is preceded by alteration in consciousness. In affected persons, hyperammonemic episodes have been precipitated by high-protein meals, infection, medication, trauma, surgery, and pregnancy/delivery. It is not uncommon for the initial hyperammonemic episode in a child with a partial deficiency to occur after weaning, when low-protein breast milk is replaced by higher-proteincontent formula or cow’s milk. The puerperium in ornithine transcarbamylase–deficient heterozygotes and valproate therapy in partial CPS, ornithine transcarbamylase, and argininosuccinate lyase deficiencies also have been associated with hyperammonemic crises [Arn et al., 1990; Batshaw et al., 1981; Honeycutt et al., 1992; Morgan et al., 1987]. The posited mechanism of valproate-induced hyperammonemia is through accumulation of the branched shortchain fatty acyl-CoA metabolites of valproate, which inhibit N-acetylglutamate formation and hence CPS I activity. This also has been the proposed explanation for hyperammonemia in the organic acidemias. In a case report of haloperidolinduced hyperammonemia in a patient with partial ornithine transcarbamylase deficiency, a similar mechanism is likely [Rubenstein et al., 1990].

ASSOCIATED MEDICAL CONDITIONS A number of medical conditions have been associated with urea cycle disorders. For example, it is recognized that chronic liver dysfunction develops in OTC-deficient patients with late-onset clinical disease (primarily female heterozygotes) and in patients with argininosuccinicacidemia. Other examples are anecdotal observations of a propensity for hypertension, electrolyte abnormalities (hypokalemia and hypomagnesemia), gastrointestinal abnormalities including anorexia, stunted growth, microcytic anemia, and nutritional deficiencies [Brusilow and Horwich, 2001]. Pancreatitis has also been described, although the etiology is unclear [Anadiotis et al., 2001]. In addition, metabolic strokes have been described in CPS and ornithine transcarbamylase deficiencies involving the caudate and putamen, with resultant extrapyramidal syndromes [Keegan et al., 2003].

HISTOPATHOLOGIC FEATURES OF UREA CYCLE DISORDERS Histopathologic examination of liver in urea cycle disorders may be normal but often demonstrates diffuse microvesicular steatosis, marked nuclear increased glycogen in periportal cells, and variable portal fibrosis [Badizadegan and Perez-Atayde, 1997]. Cirrhosis has been identified in certain cases of argininosuccinicaciduria, citrullinemia type II, and arginase deficiency [Zimmermann et al., 1986]. Neuropathologic findings in urea cycle disorders are similar to those following hepatic encephalopathy and hypoxic-ischemic insults. They depend both on the duration of hyperammonemic coma and on the interval between coma and death. Neonates dying in hyperammonemic coma have prominent cerebral edema and generalized neuronal cell loss on postmortem examination [Crome and France, 1971]. Histologically, astrocyte swelling was one of the first observations made in acute hyperammonemia. Swollen astrocytes may be the cellular correlate of the brain edema in acute hyperammonemia. The central role of astrocytes in hyperammonemic encephalopathy was further underscored by the finding of Alzheimer type II astrocytes in the brains of patients in whom the coma had taken an irreversible course. In survivors of prolonged coma, changes observed on neuroimaging studies obtained months later include ventriculomegaly with increased sulcal markings, bilateral symmetric low-density white matter defects, cystic degeneration, injury to the bilateral lentiform nuclei, and diffuse atrophy with sparing of the cerebellum [Kendall et al., 1983; Majoie et al., 2004; Takanashi et al., 2003; Yamanouchi et al., 2002]. Neuropathologic findings in those children who subsequently died were consistent with the neuroimaging findings and included ulegyria, cortical atrophy with ventriculomegaly, prominent cortical neuronal loss, gliosis (often with Alzheimer type II astrocytes), and spongiform changes at the gray-white matter interface and in the basal ganglia and thalamus [Dolman et al., 1988].

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(2) depleting intermediates of cell energy metabolism; (3) causing cytotoxic effects on microtubular aggregates; and (4) altering amino acid and neurotransmitter levels [Butterworth et al., 1987]. The combination of behavioral alterations during moderate hyperammonemia and brain damage after hyperammonemic coma has led to a recent focus on glutamate/excitotoxin hypothesis of brain injury in urea cycle disorders. Evidence supporting this hypothesis includes the correlation of prolonged episodes of

MECHANISM OF NEUROPATHOLOGY The mechanism of the ammonia-induced neuropathology remains unclear [Bachmann et al., 2004]. Ammonia normally is detoxified in astrocytes by glutamate dehydrogenase and glutamine synthetase. Accumulation of ammonia and glutamine in brain has a number of potentially toxic effects: (1) increasing blood-brain barrier permeability;

Hyperammonemia

Present

Prematurity, respiratory distress prior to 24 hr. of age

Absent

Transient hyperammonemia

Urinary organic acids (with acidosis and/or ketosis)

Inborn errors of metabolism

Abnormal

Normal

Inborn errors of ureagenesis

Plasma citrulline Congenital lactic acidosis

Organic acidemia

Fatty acid oxidation defects

• Pyruvate dehydrogenase deficiency • Pyruvate carboxylase deficiency • Mitochondrial disorders

• Propionic acidemia • Methylmalonic acidemia • Isovaleric acidemia • Multiple carboxylase deficiency • Glutaric acidemia • 3–MethyI-3-OHglutaryI CoA lyase deficiency

AcyI-CoA dehydrogenase deficiencies

Moderate elevation

Marked elevation

ASA in plasma and urine

Argininosuccinicaciduria

Citrullinemia

Normal or reduced Absent/trace Low/normal Urinary orotic acid

Plasma arginine Elevated

Normal

Elevated

CPS I deficiency NAGS deficiency

OTC deficiency

Elevated urinary lysine, ornithine, arginine

Elevated plasma ornithine, urinary homocitrulline Argininemia

LPI

HHH

FIGURE 24-2. Algorithm for differential diagnosis of hyperammonemia. Plasma amino acids, serum lactate, and urinary excretion of orotic acid and organic acids are measured. Acyl-CoA, acyl coenzyme A; ASA, argininosuccinic acid; CPS I, carbamyl phosphate synthetase I; HHH, hyperammonemiahyperornithinemia-homocitrullinuria syndrome; LPI, lysinuric protein intolerance; NAGS, N-acetylglutamate synthase; OTC, ornithine transcarbamylase.

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Genetic, Metabolic, and Neurocutaneous Disorders / 24

hyperammonemia with increasing cortical injury, leading to secondary time-influenced effects [Msall et al., 1984]. Magnetic resonance spectroscopy studies also have revealed elevations in the glutamine/glutamate concentration in brain [Takanashi et al., 2002]. Acutely, glutamine may function as an osmolyte within astrocytes, causing swelling. In addition, astrocytic glutamate transporters are downregulated [Desjardin et al., 2001], and extracellular glutamate is elevated in hyperammonemia [Felipo and Butterworth, 2002]. These changes likely contribute to excitotoxicity and encephalopathy, respectively. Furthermore, ammonia or glutamate-induced N-methyl-D-aspartate receptor activation leads to formation of nitric oxide, catalyzed by nitric oxide synthase. Nitric oxide not only serves as an antioxidant and regulates blood flow but also appears to inactivate glutamine synthase, possibly contributing to the elevation of glutamate levels [Marcaggi and Coles, 2001; Suarez et al., 2002]. Inhibition of glutamine synthase by methionine sulfoximine was reported to prevent astrocyte swelling in experimental hyperammonemia [Willard-Mack et al., 1996]. Besides glutamine, tryptophan and serotonin also are increased in the brain of the spf/Y mouse, an animal model for ornithine transcarbamylase deficiency, and in cerebrospinal fluid of children with urea cycle disorders [Bachmann et al., 1982; Batshaw et al., 1993; Inoue et al., 1987]. This finding led to the hypothesis that high glutamine levels also may cause other amino acid imbalances in the brain. Increased tryptophan levels result in increased levels of its metabolite quinolinate [Robinson et al., 1995], an excitotoxin at the N-methyl-D-aspartate receptor.

DIFFERENTIAL DIAGNOSIS In the newborn period, hyperammonemia is similar in presentation to a number of acquired conditions including sepsis, intracranial hemorrhage, and cardiorespiratory disorders. The measurement of plasma ammonia levels is critical to distinguish between these conditions. The acquired disorders generally are not associated with significant elevations in ammonia levels, whereas the inborn errors are. As a consequence, plasma ammonia levels should be measured as part of the routine evaluation for serious illness in the newborn period. Apart from urea cycle disorders, a number of other inborn errors of metabolism can cause hyperammonemia. These include organic acidemias, nonketotic hyperglycinemia, congenital lactic acidoses, lysinuric protein intolerance, and defects in fatty acid oxidation. An algorithm for distinguishing between these disorders is presented in Figure 24-2. In the organic acidemias (e.g., methylmalonicacidemia, propionicacidemia, isovalericacidemia, glutaricacidemia type II, multiple carboxylase deficiency), the usual findings include a marked metabolic acidosis, ketosis, and increased anion gap, although propionicacidemia can manifest without a metabolic acidosis in the newborn period [Ozand and Gascon, 1991]. Hypoglycemia and pancytopenia also may be present. Mass spectrometry of urine organic acids or acylcarnitine analysis in blood will make the specific diagnosis. In these disorders, plasma (but not cerebrospinal fluid) will have an elevated glycine level—from whence came the initial name ketotic hyperglycinemia. By contrast,

with nonketotic hyperglycinemia, ketosis is absent, glycine levels in both plasma and cerebrospinal fluid are markedly elevated, and cerebrospinal fluid glycine–to–plasma glycine ratio is increased [Tada and Hayasaka, 1987]. Fatty acid oxidation defects, caused by different-chainlength acyl-CoA dehydrogenase deficiencies, manifest with hypoglycemia, increased free fatty acids, and decreased ketones. Analysis of urinary organic acids shows a dicarboxylicaciduria; plasma carnitine levels are low; and abnormal acylcarnitine species are found [Roe and Ding, 2001]. Congenital lactic acidosis can be the result of a primary deficiency of pyruvate carboxylase or pyruvate dehydrogenase or secondary to a defect within the mitochondrial respiratory chain [McCormick et al., 1985]. The principal biochemical finding is lactic acidosis. In pyruvate dehydrogenase deficiency and mild pyruvate carboxylase deficiency, the ratio of lactate to pyruvate is maintained at 10:1 to 20:1. In severe pyruvate carboxylase deficiency, mitochondrial respiratory chain defects, and secondary lactic acidosis, however, this ratio is significantly increased [Zeviani et al., 1989]. In these oxidative phosphorylation defects and other mitochondrial diseases the 3-hydroxybutyrate–to–acetoacetate ratio also is elevated. These findings are in contrast with those in inborn errors of urea synthesis, in which the urinary organic acid profile is normal and plasma lactate level is normal or mildly increased. Although peak plasma ammonia levels generally are in the range of 150 to 500 μM (normal 15 to 40 μM) in these disorders, they are likely to be above 500 μM in neonatal-onset urea cycle disorders. Plasma amino acid patterns also are distinct in urea cycle disorders, with low levels of arginine and ornithine and either low or high levels of citrulline. Citrulline is the product of CPS I and ornithine transcarbamylase and the substrate for argininosuccinate synthetase and argininosuccinate lyase. Thus, it either is absent or is present only in trace amounts in N-acetylglutamate synthase, CPS I, and ornithine transcarbamylase deficiencies, and levels are markedly elevated in argininosuccinate synthetase and argininosuccinate lyase deficiencies [Hudak et al., 1985]. Differentiation of argininosuccinate synthetase from argininosuccinate lyase deficiencies depends on finding argininosuccinic acid in plasma and urine in argininosuccinate lyase deficiency. In hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, biochemical findings include accumulation of ornithine in blood and of homocitrulline in the urine. Differentiation of CPS I from ornithine transcarbamylase deficiency depends on detecting excessive urinary orotic acid excretion in ornithine transcarbamylase deficiency and decreased excretion in CPS I deficiency. A deficiency of Nacetylglutamate synthase is associated with low-normal orotic acid excretion. In summary, it is likely that measurement of ammonia, amino acids, and lactate in blood and of amino acids, organic acids, and orotic acid in urine will identify virtually all genetic causes of hyperammonemia. Confirmation of the diagnosis may require specific enzymatic or DNA analyses in a few instances (CPS I and N-acetylglutamate synthase deficiencies) but is not necessary to begin treatment. In older children and adults, identification of partialdefect urea cycle disorders often has been delayed by misdiagnoses that have included migraine, cyclical vomiting,

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viral encephalitis, stroke, Reye’s syndrome, drug toxicity, child abuse, psychosis, postpartum depression, seizure disorder, and cerebral palsy [Christodoulou et al., 1993; de Bruijn et al., 1976; DiMagno et al., 1986; Drogari and Leonard, 1988; Finkelstein et al., 1990]. Studies have found a mean delay of 8 to 16 months between the onset of symptoms and diagnosis of late-onset urea cycle disorders in children [Rowe et al., 1986]. During this time, progressive abnormalities in growth and cognitive/motor development may be noted. Diagnosis of late-onset urea cycle disorders may be less clearcut than in neonatal cases. Plasma ammonia levels may be in the range of 150 to 250 μM during symptomatic episodes and normal when the patient is clinically stable. Serum (blood) urea nitrogen, which clearly is subnormal in neonatal-onset deficiencies, may be normal. Plasma citrulline levels often are low-normal in partial ornithine transcarbamylase and CPS I deficiencies, rather than absent-trace as in complete defects. Yet, as noted previously, oroticaciduria can be provoked by an allopurinol load to detect partial ornithine transcarbamylase deficiencies, and marked elevations of argininosuccinic acid in blood and urine are characteristic in argininosuccinate lyase deficiency (up to 1500 μM in plasma, normally undetected), of citrulline in argininosuccinate synthetase deficiency (range 1000 to 5000 μM in plasma, normal 6 to 50 μM), and of arginine in arginase deficiency (up to 1500 μM, normal less than 100 μM) [Batshaw et al., 1981]. In hyperornithinemiahyperammonemia-homocitrullinuria syndrome, marked elevations of homocitrulline in urine and of ornithine in blood are seen. Apart from urea cycle disorders, other inborn errors of metabolism that manifest with symptomatic hyperammonemia in later childhood/adulthood include the organic acidemias and lysinuric protein intolerance [Simell et al., 1975]. These disorders can be distinguished by specific patterns of urinary organic acids, urinary amino acids, plasma amino acids and plasma carnitine/acylcarnitine levels. A number of acquired disorders also can manifest with hyperammonemia, including hepatic encephalopathy, Reye’s syndrome, drug toxicity, and hepatotoxins. The medical history, prothrombin time, a urinary toxin screen, and analysis of plasma amino acid pattern (low branchedchain amino acids, high aromatic amino acids in chronic liver disease, elevated lysine in Reye’s syndrome) should help differentiate these disorders.

TREATMENT Therapy of urea cycle disorders consisted of only protein restriction and dialysis during acute hyperammonemic crises until the advent of ammonia-scavenging agents— sodium benzoate, sodium phenylacetate, sodium phenylbutyrate, and L-arginine. In the United States, standardized medical treatment with sodium phenylbutyrate (Buphenyl, Ucyclyd Pharma, Scottsdale, AZ) became available in 1996. These scavenging compounds decrease ammonia levels by stimulating alternative pathways for waste nitrogen excretion. The long-term treatment of urea cycle disorders now consists of a low-protein diet combined with this alternative pathway therapy. Use of ammonia-scavenging drugs also is first-line

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therapy during hyperammonemic crisis in patients with urea cycle disorders. Liver transplantation is being used with increasing frequency for definitive treatment of severe cases. In the newborn period, treatment of urea cycle disorders may be reactive or anticipatory. In families who have had a previously affected child or in ornithine transcarbamylase– deficient kindreds, the birth of an at-risk or prenatally diagnosed infant provides the opportunity for prospective management. Within hours of birth, the child can be placed on oral alternate pathway therapy before the development of hyperammonemia (see Table 24-1). Of 15 infants with urea cycle disorders treated in this fashion, all but 3 survived the newborn period without hyperammonemic coma [Maestri et al., 1991].

Hemodialysis In infants who are diagnosed during hyperammonemic coma, hemodialysis should be started immediately [McBryde et al., 2004; Tuchman, 1992]. In addition, L-arginine HCl (except in hyperargininemia), sodium benzoate, and sodium phenylacetate (Ammonul, Ucyclyd Pharma) should be given intravenously at the same doses used to treat intercurrent hyperammonemia.

Liver Transplantation Long-term treatment of urea cycle disorders depends on the severity of the disease. For neonatal-onset CPS I and ornithine transcarbamylase deficiencies, current clinical guidelines recommend that liver transplantation be considered as a form of enzyme replacement therapy [Leonard and McKiernan, 2004]. This procedure usually is performed at 6 to 12 months of age, with use of alternate pathway therapy before surgery [Leonard and McKiernan, 2004; Saudubray et al., 1999]. More recently, and as a result of favorable outcome with liver transplantation, other neonatal-onset urea cycle and poorly controlled late-onset disorders also have been considered for this treatment. The United Network for Organ Sharing [McDiarmid, 2001] reports that a total of 25 liver transplantation procedures were performed in children with urea cycle disorders between 1998 and 2001 (most recent data), with a 12-month survival rate of 96%. According to the United Network for Organ Sharing report, a total of 45 children with urea cycle disorders received a liver transplant between 1988 and 2001, with an overall 12-month survival rate of 89% and a 5-year survival rate of 84%. Between 1996 and 2002, the ratio of cadaveric to living donor liver transplants was 10:1. A number of case reports have been published concerning the results of liver transplantation with regard to correction of the metabolic defects in urea cycle disorders [Leonard and McKiernan, 2004; Saudubray et al., 1999]. These reports suggest that transplantation corrects most of the metabolic abnormalities (although citrulline levels remain low in ornithine transcarbamylase and CPS I deficiencies) and prevents future hyperammonemic episodes. In terms of morbidity, concerns have included neurodevelopmental lags and frequent and prolonged hospitalizations for treatment of infections and regulation of immunosuppressing drugs. Overall, however, the reported quality of life has been much improved,

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with normalization of diet and a decreased frequency of hospital admissions [Leonard and McKiernan, 2004].

Protein Restriction In all urea cycle disorders other than citrullinemia type II, a protein-restricted diet should be combined with alternate pathway therapy unless liver transplantation has been performed. In general, using the minimum daily protein requirement for the child’s age is recommended. For neonatal-onset disease, this generally is given half as an essential amino acid supplement (e.g., Cyclinex, Ross Pharmeuticals) and half as natural protein. For mild late-onset disease, protein restriction alone may be sufficient. In children receiving sodium phenylbutryate, it also has been suggested to monitor branched-chain amino acid levels and supplement these as needed [Scaglia et al., 2004]. Additional calories can be provided via nonprotein formulas such as Prophree or MJ80056. The diet should be supplemented with vitamins, minerals, and trace elements. Also recommended is routine monitoring of weight, growth, hair, skin, nails, and biochemical indices of nutritional status.

Alternative Pathway Therapy For late-onset CPS I and ornithine transcarbamylase deficiencies, as well as for the other urea cycle disorders, long-term therapy generally involves nitrogen restriction combined with alternative pathway therapy (see Table 24-1) [Batshaw et al., 2001; Berry and Steiner, 2001]. Approaches to stimulating alternative pathways of waste nitrogen excretion vary with the site of the enzymatic block. In the case of argininosuccinate synthetase and argininosuccinate lyase deficiencies (including citrullinemia type II), arginine can stimulate waste nitrogen excretion through enhanced production and excretion of citrulline and argininosuccinic acid [Imamura et al., 2003]. In CPS I and ornithine transcarbamylase deficiencies, sodium phenylbutyrate has been used to provide an alternative pathway. It initially is converted to sodium phenylacetate, which then conjugates with glutamine to form phenylacetylglutamine, which is excreted by the kidney [Burlina et al., 2001; MacArthur et al., 2004]. Arginase deficiency has been managed with an argininerestricted diet supplemented with sodium phenylbutyrate.

N-Carbamyl-L-Glutamate In N-acetylglutamate synthase deficiency, administration of N-carbamyl-L-glutamate (Carbaglu, Orphan Europe, Paris, France) may be an effective therapy. N-carbamyl-L-glutamate is a stable structural analog of N-acetylglutamate and theoretically could substitute for it in the activation of CPS I [Hall et al., 1958]. Although the affinity of N-carbamyl-Lglutamate for CPS I is lower than that of N-acetylglutamate (Km = 2 and 0.15 mM, respectively) [Rubio and Grisolia, 1981], it is much more resistant to degradation by aminoacylase [Kim et al., 1972]. N-carbamyl-L-glutamate is therefore attractive for therapy of N-acetylglutamate synthase deficiency. Moreover, unlike N-acetylglutamate, N-carbamyl-L-glutamate can cross the mitochondrial membrane into the mitochondrion where N-acetylglutamate synthase resides [Kim et al., 1972]. Several patients with

N-acetylglutamate synthase deficiency have been reported to respond clinically to treatment with N-carbamyl-L-glutamate [Guffon et al., 1995; Hinnie et al., 1997; Morris et al., 1998; Schubiger et al., 1991]. One homozygous affected subject underwent a 15N-tracer study of ureagenesis rate before and after 3-day treatment with oral NCGL; it completely restored normal urea cycle function [Caldovic et al., 2003].

Management of Intercurrent Hyperammonemic Crises If vomiting occurs or if lethargy becomes evident, and ammonia levels are above three to five times normal, more aggressive treatment is needed. This approach involves hospitalization with temporary complete elimination of protein and institution of intravenous administration of sodium benzoate, sodium phenylacetate, and L-arginine (caution: arginine HCl may cause metabolic acidosis, and extravasation may lead to tissue necrosis). Although these medications are not associated with severe adverse events when they are given at therapeutic doses, severe toxicity and death have resulted from dosing errors [Praphanphoj et al., 2000]. Therefore, double-checking of drug administration orders is essential, and monitoring plasma levels is recommended. In the event that ammonia levels do not respond to this conservative management approach and biochemical abnormalities or clinical signs and symptoms worsen, hemodialysis should be initiated. The relative effectiveness of peritoneal dialysis, exchange transfusion, hemodialysis, and continuous arteriovenous hemofiltration has been the subject of some controversy. Yet nitrogen balance studies clearly demonstrate the advantage of hemodialysis, with continuous arteriovenous hemodiafiltration being second best if hemodialysis is unavailable [McBryde et al., 2004]. Hemodialysis should be continued until ammonia levels fall of less than five times of normal; peritoneal dialysis or continuous hemofiltration may then be initiated if needed. Hemodialysis using an extracorporeal membrane oxygenation pump has been reported to be effective for rapidly removing ammonia [Summar et al., 1996].

OUTCOME Before the development of alternative pathway therapy, few children with a complete urea cycle defect survived infancy [Shih, 1976]. Most died in the newborn period, and the remainder succumbed to intercurrent hyperammonemic episodes or protein malnutrition later in infancy or early childhood. Long-term survival, however, has improved with the introduction of alternative pathway therapy and liver transplantation [Brusilow and Horwich, 2001]. The mortality and morbidity rates currently cited for urea cycle disorders were obtained in the 1980s, when the index of suspicion for these disorders was low, leading to significant delays in diagnosis. In addition, no standardized treatment regimen was in use. At that time, the 5-year survival rate for a small prospective cohort of patients with neonatal-onset disease was reported to be approximately 25%, and the morbidity (e.g., mental retardation, seizure disorders, cerebral palsy) was found to be virtually universal for infants rescued from hyperammonemic coma [Batshaw et al., 1982; Msall et al., 1984]. In a retrospective study of

Batshaw, Lichter-Konecki, and Tuchman / Inborn Errors of Urea Synthesis

mortality among infants with neonatal-onset urea cycle disorders referred to one major metabolic center during that period [Maestri et al., 1999], 34 of 74 infants (46%) died during their neonatal hyperammonemic episode, and among the 40 infants surviving the initial hyperammonemic episode, the median survival period was 3.8 years. More recently, with the general availability of plasma ammonia assays at most hospitals, an increased index of suspicion for metabolic disorders, and standardized alternative pathway therapy, it is likely that the outcome has improved. Although mortality has decreased, morbidity remains high among survivors of neonatal hyperammonemic coma. Greater than three quarters of these children have mental retardation, and frequent comorbid conditions include cerebral palsy, seizure disorder, and visual deficits [Msall et al., 1984]. A correlation between intellectual function and duration of hyperammonemic coma has been noted. Children in coma for less than 3 days had a far better outcome than those in coma for longer periods [Msall et al., 1984]. Cognitive outcome also was better in infants with complete defects who received prospective treatment and in children with partial defects. Of interest, even ornithine transcarbamylase– deficient women with subtle clinical signs or symptoms (e.g., protein aversion) have been found to have mild cognitive impairments suggestive of a nonverbal learning disability [Gropman and Batshaw, 2004; Maestri et al., 1991; Nagata et al., 1991; Widhalm et al., 1992]. ACKNOWLEDGMENT Work on which this chapter is based was supported by the following NIH grants: 5P30HD040677, U54RR019453, and M01RR013297.

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CHAPTER 25

Diseases Associated with Primary Abnormalities in Carbohydrate Metabolism Marc C. Patterson and Kenneth F. Swaiman

ABNORMALITIES OF GALACTOSE METABOLISM Galactosemia Galactosemia describes a family of autosomal recessive disorders characterized by increased blood levels of galactose. The Leloir pathway that converts dietary β-D-galactose to galactose-1-phosphate requires the participation of four enzymes: galactose mutarotase, galactokinase, galactose1-phosphate uridyltransferase, and uridine diphosphogalactose-4-epimerase. Mutations in the GALK, GALT, and GALE genes that encode the last three enzymes, respectively, cause deficiency or absence of these enzymes, with consequent galactosemia [Holden et al., 2003; Petry and Reichardt, 1998]. Human galactose mutarotase deficiency has not been described. Clinical reports of the features of galactosemia and associated urinary excretion of galactose preceded the definitive report by Gorter [1951] that established galactosemia as an inborn error of metabolism. Galactose-1-phosphate storage in erythrocytes was later documented [Schwarz et al., 1956]. Each enzyme-deficient condition has a range of presentations, reflecting its allelic heterogeneity.

Galactose-1-Phosphate Uridyltransferase Deficiency Galactose-1-phosphate uridyltransferase deficiency is by far the most common cause of galactosemia. The incidence of galactosemia varies among populations but has been reported as 1 in 187,000 persons in Massachusetts and 1 in 72,000 in England [Shih et al., 1971]. Neonatal screening programs have found population incidence rates as high as 1 in 23,000 in Ireland [Badawi et al., 1996].

Pathology The precise link between the metabolic abnormality and the neuropathologic condition remains unknown. Galactose-1phosphate uridyltransferase is present in the brain in low concentrations. Studies of rat brain reveal no significant sitespecific differences in enzyme activity [Rogers et al., 1992]. Hypoglycemia may contribute significantly to the pathologic findings in many cases. The toxic effect of galactitol accumulation is not fully understood but is clearly relevant to adverse outcomes in the brain and lens. Great variety and widespread distribution of the accompanying lesions have been documented. Cortical neuronal degeneration depletes the neuronal population of the entire cerebral cortex, including Ammon’s horn, albeit to a variable extent and in different patterns. Spongiform changes are pronounced in some areas. Other

findings include mild pigmentary changes in the surviving neurons, perineuronal satellitosis, and mild, diffuse hypertrophy of microglial cells. Sclerotic and atrophic white matter are evident. Dense accumulations of iron-containing and non–iron-containing pigment material in the reticular zone of the substantia nigra and the globus pallidus are prominent. Histochemical staining demonstrates the presence of lipoprotein and polysaccharides in the pigment. Pigment accumulation is accompanied by neuronal degeneration in the substantia nigra and dysmyelination in the globus pallidus. Eosinophilic bodies resembling axonal spheroids are present in the thalamus. They are bright pink and hyalinelike and measure 30 to 150 μm in diameter. Pronounced astrocytic fibrosis in the dentate nuclei and diffuse Purkinje cell degeneration are accompanied by Alzheimer type II neuroglial reaction in many areas of the brainstem, cerebral gray matter, and cerebellum [Haberland et al., 1971].

Biochemistry The primary abnormality in galactosemia is the deficiency of activity of galactose-1-phosphate uridyltransferase (Fig. 25-1) that leads to accumulation of galactose-1-phosphate in red blood cells, liver, and brain [Isselbacher et al., 1956; Kalckar et al., 1956; Schwarz et al., 1956]. Galactose is metabolized through the following four possible pathways [Hill and Puck, 1973]: (1) the reduction of galactose to galactitol, (2) oxidation of galactose to galactono-γ-lactone, (3) the reaction of galactose-1phosphate with uridine triphosphate to form uridine diphosphate galactose and eventually glucose-1-phosphate, and (4) the reaction of galactose-1-phosphate with uridine diphosphate–glucose to form uridine diphosphate–galactose and glucose-1-phosphate. In classic galactosemia, the fourth pathway is obstructed; the other pathways function normally. Shih and colleagues assigned the GALT locus to 9p13 by gene dosage [Shih et al., 1982, 1984]. A number of mutations produce abnormal enzymes with little or no galactose1-phosphate uridyltransferase activity [Reichardt, 1991; Reichardt et al., 1992]. It is therefore not surprising that various genetic forms of galactosemia result from the presence of inefficient isoenzymes of galactose-1-phosphate uridyltransferase [Chacko et al., 1977; Kelly et al., 1973; Lang et al., 1980; Tedesco et al., 1975] (Table 25-1). Most patients are compound heterozygotes, not true molecular homozygotes [Elsas et al., 1995]. The isoenzymes are separated and identified by electrophoresis. Cross-reactivity patterns for the enzyme variants have been studied using rabbit antibodies to purify human placental galactose-1-phosphate uridyltransferase [Andersen

618

Genetic, Metabolic, and Neurocutaneous Disorders / 25 GALACTOSE +ATP Galactokinase

Galactitol

Galactokinase deficiency

Galactose-1-phosphate +UDP-Glucose Galactosemia

Galactose-1-phosphate uridyltransferase

UDP-Galactose +NAD

Epimerase deficiency UDP-Galactose-4epimerase UDP-Glucose +Pyrophosphate UDP-Glucose phosphorylase GLUCOSE-1-PHOSPHATE

FIGURE 25-1. Pathway of galactose metabolism depicting sites of metabolic block that lead to galactosemia. UDP, uridine diphosphate.

et al., 1984]. Transferase activity is absent in homozygous classic galactosemia (Q188R—accounting for 54% of alleles in the United States [Elsass, 2003]) and the Negro variant (S135L—accounting for 8.4% of U.S. cases [Segal et al., 1971], virtually absent in the Rennes variant [Schapira and Kaplan, 1969], and abnormally low in the Chicago, Indiana, and Duarte (N314D) variants [Beutler et al., 1965; Chacko et al., 1977; Lai et al., 1998; Levy et al., 1978]. Activity is normal in the Los Angeles variant (L218L) [Applegarth et al., 1976; Ng et al., 1973]. A screening method utilizing a standard

newborn screening blood spot has been described that detects the four most common GALT alleles (Q188R, S135L, K285N, and L195P) and the N314D Duarte variant with a turnaround time of less than 2 hours [Dobrowolski et al., 2003]. The precise mechanisms of central nervous system dysfunction and developmental aberrations remain unexplained. Hypoglycemia associated with galactosemia may be responsible for some of the neurologic (including higher cortical function) abnormalities observed in these patients, but the accumulation of unusual metabolites also may contribute to the pathogenesis of the disorder. Hypoglycemia may be the result of inhibition of phosphoglucomutase and accompanying failure of hepatic glycogenesis [Sauls and Ulstrom, 1967]. The high concentration of galactose may increase both insulin production and release, and the increased galactose also may compete with glucose for transport sites and carrier mechanisms across the blood-brain barrier. Galactose-1-phosphate accumulates in erythrocytes, liver, lenses, and kidneys and may be influential in disruption of both tissue structure and function, but galactitol accumulation likely is a more important factor in cataract development and perhaps other tissue disruptions [Dvornik et al., 1973; Gabbay, 1973] and cerebral dysfunction [Berry et al., 2001]. Galactokinase or transferase activity appears to be lower than expected in many women who give birth to nongalactosemic children with cataracts [Harley et al., 1974]. Because of the impairment of the transformation of galactose-1-phosphate to glucose-1-phosphate in galactosemic children, other pathways of galactose metabolism attain much more prominence, including the one in which galactose is oxidized to galactono-γ-lactone. Autoradiographic studies of cultured human galactosemic and nongalactosemic fibroblasts reveal that the addition of D-galactono-γ-lactone results in much greater inhibition of incorporation of labeled galactose into pathways that do not require galactose-1-phosphate uridyltransferase activity in the galactosemic patient [Hill and Puck, 1973].

Clinical Characteristics

TABLE 25-1 Biochemical Criteria for Assigning Phenotypes of Galactosemia* GALACTOSE-1-PHOSPHATE URIDYLTRANSFERASE Activity†

Mobility†

Phenotype

Zygosity

Normal Absent

Normal None

— Homozygous

Decreased Absent Decreased

Duarte (fast) None Normal

Decreased Much less Increased Decreased Decreased

Slower Slower Faster Fast Normal

Normal Galactosemic (classic form) Duarte variant “Negro” variant Galactosemic (classic form) Indiana variant Rennes variant Los Angeles variant Chicago variant Munster variant

*Characteristics of galactose-1-phosphate uridyltransferase. † Compared with normal.

Homozygous Homozygous Heterozygous Heterozygous Heterozygous Heterozygous Heterozygous Heterozygous

Infants usually are normal at birth, except for a slight decrease in birth weight [Hsia and Walker, 1961]. Symptoms become apparent when milk feedings begin. Jaundice usually develops between 4 and 10 days of age and persists for a longer period than does physiologic jaundice [Donnell et al., 1967]. Progressive hepatic involvement in the first several weeks causes edema, hepatomegaly, and hypoprothrombinemia. Renal dysfunction is accompanied by generalized aminoaciduria, proteinuria, and acidosis. Escherichia coli sepsis is a common complication [Levy et al., 1977]. Mild hypoglycemia also is common [Donnell et al., 1967]. Cataracts appear between 4 and 8 weeks [Isselbacher, 1966], reflecting the accumulation of galactose-1-phosphate [Gitzelmann et al., 1967] or galactitol. Recent studies in animals show that apoptosis of lens epithelial cells and cataract formation are directly related to galactitol accumulation and are prevented by aldose reductase inhibitors [Murata et al., 2001]. Apoptosis may be triggered by altered p53 expression secondary to the accumulating metabolites [Takamura et al., 2003].

Patterson and Swaiman / Diseases Associated with Primary Abnormalities in Carbohydrate Metabolism

Central nervous system impairment is manifested by lethargy and hypotonia, often associated with cerebral edema [Huttenlocher et al., 1970; Welch and Milligan, 1987] and may be documented by CT scanning [Belman et al., 1986]. Cerebral edema in an encephalopathic neonate with galactose-1phosphate uridyltransferase deficiency has been correlated with increased brain galactitol on magnetic resonance spectroscopy [Berry et al., 2001]. Therapy is not uniformly successful. Mental retardation, tremor, and ataxia developed in two siblings, although lactose was restricted in the neonatal period [Lo et al., 1984]. Unexplained progressive cerebellar and extrapyramidal motor disturbances appeared at the age of 12 years in female twins with classic galactosemia treated by conventional dietary means [Bohles et al., 1986]. After the appearance of neurologic symptoms, the patient may experience anorexia, vomiting, or diarrhea. Galactosemia may prove fatal at any time. Cirrhosis progresses inexorably in patients who do not receive treatment. If the disease progresses more slowly and therapy is not optimal, mild gastrointestinal symptoms and failure to thrive persist. Gonadal function in women with galactosemia is abnormal and usually manifests as primary ovarian failure. Both hypergonadotropic hypogonadism and abnormal response to gonadotropin-releasing hormone may be present. Prenatal accumulation of galactose-1-phosphate may be toxic to the developing ovary [Kaufman et al., 1986]. Rats exposed to high levels of galactose from day 3 of conception exhibited reduced primordial germ cell migration and reduced ovarian germ cell pools, supporting the role of high galactose activity concentrations in the genesis of premature ovarian failure [Bandyopadhyay et al., 2003a]. The mechanism also involves impairment of the hypothalamic-pituitary axis, as evidenced by hypergonadotropic hypogonadism [Bandyopadhyay et al., 2003b]. If treatment is not instituted, moderate-to-severe intellectual and motor retardation ensue in a majority of cases. Language impairment is prominent [Hansen et al., 1996], and takes the form of verbal dyspraxia in about 50% of patients with galactose-1-phosphate uridyltransferase deficiency [Webb et al., 2003]. The risk of dyspraxia is associated with elevated mean galactose-6-phosphate and urinary galactitol concentrations, and with impaired total body galactose metabolism as assessed by a carbon dioxide breath test [Hansen et al., 1996; Webb et al., 2003]. The characteristics of retardation resulting from untreated galactosemia are nonspecific. Pregnant women at risk to give birth to galactosemic infants require strict restriction of galactose intake and close metabolic monitoring to prevent congenital cataracts in offspring. Prenatal diagnosis is possible by means of galactose1-phosphate uridyltransferase assay using cultured amniotic fluid cells or chorionic villus biopsy specimens and by galactitol estimation in amniotic fluid supernatant [Holton et al., 1989]. When both mutations in an index case have been identified, direct molecular analysis is the preferred method of prenatal diagnosis [Elsas, 2001]. Occasional patients with genotypes and residual enzyme activity usually associated with severe phenotypes present with mild manifestations despite lack of dietary restriction. In one such case, the patient’s markedly reduced galactitol production, presumably reflecting limited aldose reductase

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activity, was identified as a major factor in preventing neurologic injury despite her classic Q188R missense mutations [Lee et al., 2003; Segal, 2004].

Clinical Laboratory Tests Biochemical tests for galactosemia document the deficiency of blood galactose-1-phosphate uridyltransferase activity [Isselbacher et al., 1956; Kalckar et al., 1956]. A fluorescent spot test for erythrocyte transferase activity (the Beutler test) is quite sensitive [Beutler and Baluda, 1966] but can yield false-negative results if the subject has received a blood transfusion up to 120 days earlier, because of residual galactose-1-phosphate uridyltransferase activity in the transfused blood. Enzyme activity is relatively low in heterozygous persons; this phenomenon aids in identifying carriers. Galactose tolerance testing is potentially dangerous and should be undertaken only for well-planned investigational purposes [Donnell et al., 1967]. Bedside urine testing is positive for reducing substances (Benedict’s test) but negative for glucose by the glucose oxidase method. Chromatography definitively identifies galactose as the abnormal metabolite. Antibiotics may interfere with neonatal screening [Clemens et al., 1986]. Urinary galactose may be present in neonates with hepatic dysfunction in disorders other than galactosemia. Repeated attempts at detecting the reducing substance must be made because galactosuria may be inconstant as a result of fluctuating galactose or lactose ingestion. Generalized aminoaciduria, proteinuria, and abnormalities on liver function tests are common. Screening tests that use E. coli bacteriophage assay of galactose and galactose-1-phosphate in dried blood samples are available and are useful for large-volume applications [Jinks et al., 1987; Schulpis et al., 1997]. Magnetic resonance imaging (MRI) in 67 transferasedeficient galactosemic patients revealed that 22 had mild cerebral atrophy, 8 had cerebellar atrophy, and 11 had multiple small hyperintense lesions in the cerebral white matter on T2-weighted images. The patients with classic galactosemia (those without measurable transferase activity) older than 1 year of age did not manifest the expected maturational decrease in peripheral white matter signal intensity on intermediate- and T2-weighted images. Interference with normal galactocerebroside formation may explain these findings [Nelson et al., 1992].

Management Galactose is a nonessential nutritional substance; therefore, exclusion from the diet is relatively easy and without complication. Milk, the primary galactose-containing fluid, can be avoided by the use of vegetable product substitutes [Hansen, 1969]. Unfortunately, certain fruits and vegetables contain relatively high concentrations of galactose, including bell peppers, dates, tomatoes, papaya, and watermelon [Gross and Acosta, 1991]. Appropriate diets are available. The widespread use of cow’s milk in the newborn diet makes early diagnosis essential. Intellectual and personality impairment is most successfully prevented with early treatment [Fishler et al., 1972]. Studies of the long-term outcome of

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Genetic, Metabolic, and Neurocutaneous Disorders / 25

therapy have been relatively disappointing, particularly in regard to central nervous system and ovarian dysfunction [Widhalm et al., 1997]. A report based on a German crosssectional study was more encouraging, suggesting that infants given appropriate treatment by 5 days of age achieved better outcomes than did those in whom treatment was begun later [Schweitzer-Kranz, 2003]. Most acute sequelae of the disease, including cirrhosis, are ameliorated with therapy, even if briefly delayed [Donnell et al., 1967]. Cataracts also may recede or disappear. Cataract formation in cultured lenses has been prevented when an inhibitor of aldose reductase was added during exposure of the tissue to high concentrations of galactose [Dvornik et al., 1973]. Signs or symptoms of sepsis should be investigated with blood, urine, and cerebrospinal fluid cultures to detect E. coli. Because dietary therapy does not uniformly alleviate many of the sequelae of the disease, new strategies for therapy are necessary. The use of folic acid may be a reasonable supplement to galactose restriction to enhance transferase activity [Segal and Rogers, 1990]. Uridine administration also has demonstrated some promise in enhancing galactose transformation [Holton, 1990]. A trial of oral uridine did not reveal any evidence of benefit to neurocognitive functioning in treated versus untreated cases [Manis et al., 1997]. Neurologic complications may occur as late as the fourth decade of life [Friedman et al., 1989]. Unfortunately, galactose-1-phosphate appears to accumulate in the galactosemic fetus in spite of maternal milk restriction [Irons et al., 1985].

mulation of galactose. As in galactosemia, galactitol, a reduction metabolite of galactose, is found in the urine and tissues [Egan and Wells, 1966]. The existence of two GALK genes is likely. The GALK1 gene is located at 17q24 [Bergsma et al., 1996]. GALK2 may reside on chromosome 15 [Lee et al., 1992]; its metabolic role is unknown, but it does not appear to be necessary for galactose metabolism. No mutations in GALK2 have been described. The molecular structure of galactokinase has been solved [Thoden and Holden, 2003], and functional analysis of GALK mutations has been studied in an E. coli expression system [Timson and Reece, 2003] Greater than 20 mutations in GALK1 have been described, most in compound heterozygotes for private mutations [Sangiuolo et al., 2004]. Only one common mutation, P28T, has been recognized in the Romany population [Kalaydjieva et al., 1999].

Uridine Diphosphogalactose Epimerase Deficiency

Clinical Characteristics

Five children have been recognized with generalized (severe) deficiency of uridine diphosphogalactose-4-epimerase (see Fig. 25-1) [Bowling et al., 1986; Garibaldi et al., 1986; Sardharwalla et al., 1988; Walter et al., 1999]. The presentations resemble those in classic galactosemia. Most survivors are dysmorphic and deaf. The GALE locus is at 1p36-p35; the human GALE gene is about 4 kilobases (kb) in length and contains 11 exons [Maceratesi et al., 1998]. The coding sequence of the GALE gene and screening for mutations in epimerase-deficient persons have been reported by the same investigators. The patients are either homozygotes or compound heterozygotes for mutations. Two forms of enzyme deficiency exist—one type benign (with expression restricted to the lens) and the other severe [Quimby et al., 1997]. In this condition, exogenous galactose is necessary for the synthesis of glycolipids and glycoproteins. Patients with the benign and severe forms of uridine diphosphogalactose-4-epimerase deficiency were described by Gitzelmann and colleagues [1972, 1976].

Pickering and Howell [1972] described abnormally low enzymatic activity of fibroblasts in a patient and decreased activity of galactokinase in fibroblasts from her parents. Other investigators have reported decreased erythrocyte galactokinase activity in family members [Monteleone et al., 1971]. Aside from hyperbilirubinemia, children with galactokinase deficiency have few obvious clinical manifestations in the first 2 months of life [Cook et al., 1971]. Mild and unexplained hepatic and splenic enlargement is a suggestive finding, particularly in association with cataract or the presence of positive urinary reducing substance. Cataracts, the only consistent manifestation of galactokinase deficiency, form in the first months of life. Cataract formation likely is related to the production and accumulation of the osmotically active sugar alcohol galactitol from galactose through the activity of aldose reductase (see earlier). In one patient, development was normal until the age of 17 years; then uncontrollable seizures developed, with subsequent profound and progressive intellectual deterioration. This outcome occurred despite the continuous administration of a diet relatively low in galactose, which had been instituted in the neonatal period [Pickering and Howell, 1972].

Galactokinase Deficiency Galactokinase deficiency was first detected in the Bulgarian gypsy (Romany) population. Its birth incidence varies, ranging from a high of 1 in 52,000 in Bulgaria to 1 in 2,200,000 in Switzerland [Kalaydjieva et al., 1999]. Deficiency of galactokinase activity causes a clinical condition similar to that in galactosemia [Gitzelmann, 1965; Gitzelmann et al., 1967]. Patients have cataracts and accu-

Biochemistry Galactokinase deficiency causes the accumulation of galactose, which eventually is metabolized to galactitol (see Fig. 25-1). Enzyme activity is reduced rather than absent in erythrocytes [Xu et al., 1989]. Galactose-1-phosphate does not accumulate. Large amounts of circulating galactose result in urinary excretion of galactose, which causes positive results on copper sulfate screening tests for urinary reducing substances. Specific assays for galactose-1phosphate or galactose-1-phosphate uridyltransferase are necessary to differentiate between deficiency of galactose-1phosphate uridyltransferase and deficiency of galactokinase.

Management Treatment consists of elimination of galactose from the diet, as for classic galactosemia.

Patterson and Swaiman / Diseases Associated with Primary Abnormalities in Carbohydrate Metabolism

ABNORMALITIES OF FRUCTOSE METABOLISM Hereditary Fructose Intolerance Biochemistry Hereditary fructose intolerance was first described by Chambers and Pratt [1956]. This condition results from a deficiency of hepatic fructose-1-phosphate aldolase B [Hers and Joassin, 1961]. (Isoenzyme A is found in muscle and kidney.) The gene encoding this enzyme maps to 9q22 [Henry et al., 1985]. Normal fructokinase activity results in the accumulation of large amounts of fructose-1-phosphate in the liver and kidneys. Fibroblasts from patients with hereditary fructose intolerance consume less glucose, produce less lactate, and contain less glycogen compared with control cells [Lemonnier et al., 1987]. A radioisotopic method for fructose-1-phosphate assay is available [Shin et al., 1983]. The enzyme deficiency is inherited as an autosomal-recessive trait and has a frequency of 1 in 20,000 in the population [Kaiser and Hegele, 1991]. Urinary fructose excretion also is present in a harmless metabolic variant resulting from fructokinase deficiency that should not be confused with hereditary fructose intolerance.

Clinical Characteristics and Differential Diagnosis Patients with hereditary fructose intolerance who ingest fructose experience nausea and vomiting; with continued exposure, weight gain is poor. Hypoglycemia begins immediately and reaches its low point 30 to 90 minutes after ingestion [Froesch et al., 1963]. Subsequent clinical and neuropathologic alterations result primarily from the hypoglycemia. Immoderate fructose feedings lead to albuminuria, jaundice, and a generalized aminoaciduria. Examination reveals jaundice and hepatomegaly. Neurologic impairment is relatively uncommon but may result from hypoglycemia, cardiovascular collapse, or liver failure. Central nervous system complications include seizures with subsequent epilepsy, increased intracranial pressure, mental retardation, quadriplegia, and deafness [Labrune et al., 1990; Rennert and Greer, 1970]. Imaging findings include cortical atrophy, hydrocephalus, and parenchymal hemorrhage [Labrune et al., 1990]. Microscopic examination of the brain demonstrates neuronal loss and decreased myelination, attributed to hypoglycemia. Cirrhosis of the liver usually is marked.

Clinical Laboratory Tests and Diagnosis The diagnosis may be corroborated by intravenous fructose challenge (0.1 to 0.2 g/kg, with adequate precautions to manage hypoglycemia). A positive response includes hypoglycemia, hypomagnesemia, hypouricemia, and hyperphosphatemia. Assay of of fructose-1-phosphate aldolase B in liver tissue permits definitive diagnosis, but liver biopsy may be avoided by direct genotyping in many patients. Although more than 20 mutations of the aldolase B gene have been described, two alleles (A149P and A174D) account for 70% or more of cases in western Europe and North America and may be readily detected in leukocytes by restriction fragment length polymorphism (RFLP) analysis [Kullborg-Lindh et al., 2002].

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Management Fructose elimination from the diet is accomplished by limited selection of vegetables and cereal products. Dietary counseling is required for proper therapy [Bell and Sherwood, 1987].

Fructose-1,6-Diphosphatase Deficiency Another inborn error of metabolism, fructose-1,6diphosphatase (i.e., fructose-1,6-bisphosphatase [FBPase]) deficiency, also is characterized by hypoglycemia after fructose ingestion [Baker and Winegrad, 1970; Hulsmann and Fernandes, 1971]. About half of the cases manifest in infants, with life-threatening episodes of hypoglycemia and metabolic acidosis. The causal relationship between the enzyme deficiency and hypoglycemia in this abnormality is not fully explained. Some data, however, suggest that α-glycerol phosphate, fructose-1-phosphate, and fructose1,6-diphosphate all inhibit phosphorylase-a activity [Kaufmann and Froesch, 1973]. This relationship may explain the hypoglycemic episodes in both hereditary fructose intolerance and fructose-1,6-diphosphatase deficiency. The role of the enzyme deficiency in glycolysis and gluconeogenesis requires further clarification [Adams et al., 1990]. The diagnosis can be established by measuring FBPase activity and mutational analysis in cultured monocytes, without the necessity for liver biopsy [Kikawa et al., 2002]. A retrospective study of Japanese patients with FBPase deficiency treated with intravenous glycerol, which contains fructose in Asian countries, found a relationship between the infusion of glycerol and the onset of cerebral edema in some patients [Hasegawa et al., 2003].

GLYCOGEN STORAGE DISEASES The biochemistry of the glycogen storage diseases offers an important lesson on the various effects of genetically determined enzymatic deficiencies along a single metabolic pathway. In spite of a few inconsistencies and a number of unexplained conditions, a logical approach to these diseases is practical. These conditions are classified among the lysosomal storage diseases. The first lysosomal storage disease defined as such was Pompe’s disease [Hers, 1963]. General characteristics of this disease family are discussed in Chapter 27. Clinical manifestations of glycogen storage disease often result from glucose deficiency, with ensuing hypoglycemia occurring separately or in association with increased glycogen storage. The location of the enzymatic block in the pathway determines whether the configuration of the glycogen is normal or abnormal. Patients have been described who accumulate glycogen in autophagic vacuoles but do not appear to have an enzymatic deficiency [Danon et al., 1981]. This phenotype, named Danon’s disease, is known to result from deficiency of lysosomal-associated membrane 2 [Nishino et al., 2000]. This X-linked dominant disorder has multisystem effects, most consistently involving the heart and skeletal muscle [Sugie et al., 2002].

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Genetic, Metabolic, and Neurocutaneous Disorders / 25

TABLE 25-2 Glycogen Storage Diseases (GSDs) NAME* 1. Glucose-6-phosphatase deficiency (von Gierke’s disease, Cori type I GSD) 2. Infantile acid maltase deficiency (Pompé’s disease, Cori type II GSD) 3. Late infantile acid maltase deficiency, adult acid maltase deficiency 4. Debrancher deficiency (Forbes’ limit dextrinosis, Cori type III GSD) 5. Brancher deficiency (Andersen’s disease, Cori type IV GSD) 6. Myophosphorylase deficiency (McArdle’s disease, Cori type IV GSD) 7. Hepatophosphorylase deficiency (Hers’ disease, Cori type VI GSD) 8. Phosphorylase kinase deficiency (also deficiency of activation sequence including loss of activity of 3′,5′-AMP–dependent kinase in muscle and probably liver) 9. Phosphoglucomutase deficiency 10. Phosphohexose isomerase deficiency 11. Phosphofructokinase deficiency plus other defects of terminal glucolysis, including deficiency of phosphoglycerate kinase and lactate dehydrogenase 12. Glycogen synthetase deficiency

CLINICAL MANIFESTATIONS

GLYCOGEN STRUCTURE

ENZYME DEFECT

Enlarged liver and kidneys; hyperlipidemia; hypoglycemia; ketoacidosis; seizures Cardiomegaly; death in infancy; progressive hypotonia and weakness; swallowing and respiratory difficulty Atonic anal sphincter; calf muscle hypertrophy; hip weakness (Gowers’ sign); slow or regressing motor development, contractures of Achilles tendons

Normal

Glucose-6-phosphate

Normal

Acid maltase

(?) Abnormal–short outer chains Abnormal–short outer chains, increased branch points

Acid maltase

Abnormal

Amylo-1,4→ 1,6-transglucosidase

Normal

Muscle phosphorylase

Growth retardation; hepatomegaly; hypoglycemia; mild ketosis

Normal

Muscle phosphorylase

Marked hepatomegaly, with glycogen storage; no hypoglycemia; no skeletal muscle disease; normal mental development

Normal

Phosphorylase kinase or 3′,5′-AMP–dependent kinase

Calf hypertrophy; mild generalized weakness; regression in motor development; toe-walking Late-onset myopathy; muscle cramps; poor stamina Similar to those in myophosphorylase deficiency

Normal

Phosphoglucomutase

Normal Normal

Phosphohexose isomerase Phosphofructokinase

Hypoglycemia; mental retardation; seizures

Normal

Glycogen synthetase

Hepatomegaly; hypoglycemia; late-onset weakness; mild growth failure; early, severe weakness with myopathy rare Cirrhosis; growth failure; hepatosplenomegaly; hypotonia; muscle wasting in lower extremities; slow motor development; weakness Atrophy in older patients; myoglobinuria; poor stamina; severe muscle cramps with exercise

Amylo-1,6-glucosidase

*The accompanying numerals identify these abnormalities in the pathway of glycogen metabolism shown in Figures 25-2 and 25-3.

Glycogen storage diseases result in the accumulation in various tissues of increased concentrations of glycogen of normal or abnormal configuration (Table 25-2). These diseases result from a deficiency or absence of specific enzyme activity in the metabolic pathway of glycogen. General agreement on the numbering system for these conditions obtains for up to type VI; thereafter, viewpoints diverge. The glucose molecule is the prime building block in the multistep synthesis of glycogen (Fig. 25-2) (see Table 25-2). Glycogen synthesis occurs in many tissues, predominantly in liver, kidney, and muscle. Glucose transported in the blood enters the cell, facilitated by a glucose transporter [Scheepers et al., 2004], is phosphorylated in a reaction catalyzed by the enzyme hexokinase, and becomes glucose6-phosphate. In the next step, the enzyme phosphoglucomutase mediates the transformation to glucose-1-phosphate. Glucose-1-phosphate, in association with uridine triphosphate, is transformed to uridine diphosphate–glucose with

the participation of uridine diphosphate glucose pyrophosphorylase. The glucose portion of this molecule is then attached by a 1,4 linkage to a terminal glucosyl unit. This reaction is facilitated by the active form of the enzyme glycogen synthase (uridine diphosphate–glucose-glycogen glucosyl transferase). When the glucosyl chain becomes 6 to 12 units long, this section is transferred and affixed to another glucosyl chain by a 1,6 linkage as a result of the action of the branching enzyme α-1,4-glucan:α-1,4-glucan6-glucosyl transferase. A 1,6 linkage constitutes the branch point, a final stage in glycogen formation. During the degradation process, the phosphorylase enzymes split the 1,4 linkages, which results in formation of free glucose-1-phosphate molecules. Both muscle and hepatic phosphorylase isoenzymes exist. Activation of phosphorylase takes place through a cascade of reactions ultimately involving phosphorylase b kinase (Fig. 25-3). As the cleavage of 1,4 bonds moves near the 1,6 branching point, “three-glucose” residues are removed in a block by

Patterson and Swaiman / Diseases Associated with Primary Abnormalities in Carbohydrate Metabolism

␣-1,4 Glucosidase (unknown pathway)

623

2,3

Glycogen Branching enzyme (amylo 1,4 1,6 transglucosidase)

5

6,7,8

Phosphorylase a* (acts on 1,4 linkages)

Glycogenesis

Limit dextrin Glycogen synthetase

12 4

Debranching enzyme (amylo-1,6 glucosidase cleaves 1,6 linkages)

7,8

Phosphorylase a* (acts on newly exposed 1,4 linkages after 1,6 linkages broken)

Uridine diphosphate glucose (activated glucose)

UDPG-Phosphorylase

Glycogenolysis

Glucosyl chain (1,4 linkages)

GLUCOSE-1-PHOSPHATE Phosphoglucomutase

Glycolysis (Embden-Meyerhof pathway)

Glucose + ATP

9

Hexokinase

Glucose-6-phosphatase GLUCOSE

Glucose-6-phosphate

Phosphohexose isomerase

10

1

Fructose-6-phosphate Phosphofructokinase Fructose

Fructokinase

11 Fructose-1,6-diphosphate

Aldolase Glyceraldehyde-3-phosphate

Dihydroxyacetone phosphate

**

Lactate Lactic acid dehydrogenase PYRUVATE FIGURE 25-2. Pathways of glycogen metabolism depicting sites of metabolic block that lead to glycogen storage disease. See Table 25-2 for description of abnormalities denoted by arabic numerals enclosed in boxes. * See Figure 25-3 for phosphorylase activation sequence. ** Other defects of terminal glycolysis.

oligo-1,4→1,4-glucan transferase, and the 1,6 linkage is disrupted by the debranching enzyme (amylo-1,6 glucosidase), with the resultant release of a free glucose molecule. Approximately 8% of glucose in glycogen is involved at 1,6 branch points and may be released in this free form. This process continues along the branches of the glycogen molecule. Therefore, both glucose-1-phosphate and free glucose molecules result from this series of degradation reactions. The glucose-1-phosphate molecules subsequently are converted to glucose-6-phosphate by the action of the enzyme

phosphoglucomutase. Phosphate is released from glucose-6phosphate in liver and kidney by glucose-6-phosphatase, and free glucose molecules result. (Glucose-6-phosphatase activity is absent in skeletal muscle.) The free glucose is transported by the circulation to other organs, where it is used. In other organs and in muscle the glucose-6-phosphate formed on entry is phosphorylated to fructose-1-6-diphosphate, which is transformed by the metabolic steps in the EmbdenMeyerhof pathway that leads eventually to the formation of pyruvic acid and lactic acid.

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Genetic, Metabolic, and Neurocutaneous Disorders / 25 FIGURE 25-3. Activation sequence of phosphorylase. See Table 25-2 for description of abnormalities denoted by the arabic numerals enclosed in boxes. ADP, adenosine diphosphate; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate. (Modified from Goldberg NB. Hosp Pract 1974;9:127.)

EPINEPHRINE, GLUCAGON, AND OTHERS Adenylate cyclase Inactive form

Adenylate cyclase Active form

*ATP Cyclic AMP

8 Protein kinase Inhibited form

Inhibitor ·· · cAMP Protein kinase Active form 8

*Phosphorylase kinase Inactive form

ATP

ADP

Phosphorylase kinase-phosphate Active form

8 ATP

ADP

*Phosphorylase b Inactive form Phosphorylase a-phosphate Active form

6,7

* Amplification effect at this step.

Glucose-6-Phosphatase Deficiency (Von Gierke’s Disease, Glycogen Storage Disease Type I, Hepatorenal Glycogenosis) Pathology In 1929, Von Gierke described the pathology of “hepatonephromegalia glycogenica,” and in 1952 the Coris described glucose-6-phosphatase deficiency as its cause (and established an enzyme deficiency as the cause of an inborn error of metabolism for the first time). Patients with Von Gierke’s disease, now known as glycogen storage disease type I, have

hepatomegaly and renomegaly. Light microscopy reveals enormous amounts of glycogen in liver cells and in the cells of the renal convoluted tubules. No increase in the concentration of glycogen is found in skeletal muscle, tongue, or heart. Best’s stain marks the presence of glycogen. Tissue must be fixed in a nonaqueous medium such as absolute alcohol; otherwise, the glycogen dissolves, and only vacuolar spaces will remain to mark the areas of deposit. Electron microscopy of glycogen storage disease type I liver reveals loss of microvilli of the membranes lining Disse’s

Patterson and Swaiman / Diseases Associated with Primary Abnormalities in Carbohydrate Metabolism

spaces and bile canaliculi. Changes in endoplasmic reticulum include the development of doubly contoured vesicles that appear to help ribosomes only on the innermost surface of the inner membrane. Glucose-6-phosphatase is located in or on the membranes of endoplasmic reticulum, and these findings parallel a disturbance of the phospholipid environment of the enzyme as a consequence of the mutation that affects enzyme activity [Spycher and Gitzelmann, 1971].

Biochemistry Two distinct subgroups of glycogen storage disease type I have been identified: those with primary glucose-6phosphatase deficiency (type Ia) and those phenocopies with additional features of immune impairment (neutropenia and neutrophil adherence defects), now designated as glycogen storage disease type I non-a. Glycogen storage disease type I non-a disorders originally were thought to result from defects in a multicomponent translocase system responsible for transporting glucose-6-phosphatase into microsomes [Annabi et al., 1998]. This model postulated three transport proteins, T1, T2, and T3, to chaperone glucose, glucose-6-phosphatase, phosphate, and pyrophosphate across the endoplasmic reticulum membrane. Cloning of the glucose-6-phosphatase translocase gene (G6PT) demonstrated that the previously proposed subtypes b, c, and d all were associated with mutations in G6PT, producing different kinetic variants [Matern et al., 2002; Moses and Parvari, 2002]. The G6PC gene that codes for glucose-6-phosphatase is located at 17q21 [Brody et al., 1995]. A number of allelic variants have been described. Glucose-6-phosphatase comprises at least five different polypeptides [Burchell and Waddell, 1991]. The G6PT locus is at 11q23 [Annabi et al., 1998]; several mutations have been characterized [Matern et al., 2002]. All forms share common clinical manifestations that are attributable to abnormal metabolism of glucose-6phosphate. In type Ia, glucose-6-phosphatase deficiency results in storage of glycogen of normal configuration in the liver and kidneys. The glycogen concentration usually exceeds 4% by weight. The enzyme activity frequently is absent or extremely low [Cori and Cori, 1952]. Glucose-6phosphatase is important in regulating the entry of free glucose into the circulation from the liver. Because of this pivotal role, deficiency of the enzyme produces hypoglycemia. Ethanol causes decreased blood lactate and pyruvate content, presumably by diverting carbon to triglyceride formation [Sadeghi-Nejad et al., 1975]. Insulin secretion was studied in five adult patients with glucose-6-phosphatase deficiency. Patients and controls ingested glucose alone or glucose plus protein or received arginine monochloride. The capacity of these patients to increase blood insulin was significantly less than normal. These data suggest that in addition to impaired glycogen metabolism, these patients had unexplained limitations in their ability to increase circulating insulin. As patients with this condition mature, they become normoglycemic and characteristically have abnormal glucose tolerance curves. These studies suggest that the increasing clinical stability noted with age and the associated tendency toward normoglycemia reflect a decrease in insulin responsiveness that may develop as an adaptive process [Lockwood et al., 1969].

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The intricacies of the glucose-6-phosphatase gene and protein and subsequent effects on glucose metabolism have been reviewed [Mithieux, 1997].

Clinical Characteristics Hypoglycemia causes much of the morbidity during the first year of life. Seizures are frequent and almost invariably the presenting complaint of affected children. Hypoglycemia may result in severe, chronic neurologic impairment, including hemiplegia [Fine et al., 1969]. Hepatomegaly and the failure-to-thrive syndrome are commonly present. An association with moyamoya disease has been described [Goutières et al., 1997]. A study of 19 patients with glycogen storage disease type I (median age 11 years) in one center found prevalence rates for epilepsy, deafness, and neuroradiologic abnormalities of 10.5%, 15%, and 57%, respectively, far in excess of the rates in the general population, or in children with other causes of neonatal hypoglycemia. MRI abnormalities included dilatation of occipital horns and/or hyperintensity of subcortical white matter in the occipital lobes in all patients [Melis et al., 2004]. Subcutaneous fat often is increased, especially over the buttocks, breasts, and cheeks. Xanthomas of the skin occur over the extensor surfaces of the limbs and at times over the buttocks [Field, 1966; van Creveld, 1939]. Affected children frequently have a protuberant abdomen because of massive enlargement of the liver. Hepatomegaly may be present at birth. The liver edge is hard and not tender. Careful palpation may reveal enlarged kidneys. Hepatic adenomas develop in between one half and three quarters of adults with glycogen storage disease I; about 10% undergo malignant transformation. Some data suggest that lower frequencies are associated with better dietary control [Lee, 2002]. Hepatocellular carcinoma has been reported complicating hepatic adenomas [Conti and Kemeny, 1992; Zangeneh et al., 1969]. Patients carrying mutations that cause relatively mild expression of the disease in childhood, often without hypoglycemia (such as 727 G>T), are associated with adult presentation of hepatocellular carcinoma [Matern et al., 2002]. Type I non-a patients typically have recurrent stomatitis, frequent infections, and chronic inflammatory bowel disease secondary to neutropenia and neutrophil dysfunction [de Parscau et al., 1988]. Seventy-five percent of 36 glycogen storage disease type I non-a patients had chronic gastrointestinal complaints, and 28% had proven inflammatory bowel disease. A further 22% had a highly suggestive history [Dieckgraefe et al., 2002].

Clinical Laboratory Tests The diagnosis can be made by assaying the enzyme activity in liver and peripheral white blood cells [Maire et al., 1991]. Severe hypoglycemia frequently occurs because of the failure of glucose formation from glucose-6-phosphate. Postprandial blood glucose concentration may be exceedingly high. Severe acidosis, which may vary in degree but usually is associated with lacticacidemia and pyruvicacidemia, and hyperuricemia is frequent. The presence of ketoacidosis has been unduly stressed. Hyperuricemia often has been documented but is poorly understood. Adenosine triphosphate depletion has been pos-

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Genetic, Metabolic, and Neurocutaneous Disorders / 25

tulated as a causative factor [Greene et al., 1978]. Ketoacidosis and hyperthermia during anesthesia in a child with glycogen storage disease type I has been described [Edelstein and Hirshman, 1980]. Blood cholesterol, fatty acids, and triglycerides are elevated; overt lipemia may be present. Decreased bone density documented by radiography may be related to chronic metabolic acidosis. Serum inorganic phosphate may be decreased in the presence of normal alkaline phosphatase activity. Provocation with epinephrine or glucagon demonstrates failure of the patient’s blood glucose concentration to increase within 10 to 20 minutes, although intracellular glucose-6phosphate is formed quickly after the induced activation of liver phosphorylase. Direct assay of hepatic glucose-6phosphatase activity in liver tissue remains the definitive diagnostic procedure but can be replaced by mutational analysis in many patients. Just five mutant alleles account for almost 70% of cases with glucose-6-phosphatase deficiency, so that mutation screening is a reasonable initial diagnostic approach, avoiding the risks and discomfort of liver biopsy [Matern et al., 2002].

Management Therapy provides small amounts of free glucose to allow maintenance of normal blood glucose concentration. Continuous nocturnal intragastric infusion of glucose has been relatively successful [Greene et al., 1976]. Subsequently the use of cornstarch suspensions given during the day obviated the need for nocturnal infusion in some children [Chen et al., 1984; Wolfsdorf et al., 1990]. The dietary carbohydrate must be monitored because excess glucose leads to glycogen storage in the liver and kidneys. Frequent small feedings of carbohydrates are provided. Severity of the disease reaches a plateau after the fourth or fifth year of life. Vigorous treatment is, therefore, worthwhile until the plateau is reached. A long-term study of 15 children with glycogen storage disease type I, beginning in infancy, found that careful metabolic control, aiming for high-normal plasma glucose levels and normal urine lactate, was associated with normal growth and lowering, but not normalization, of plasma lipids. Hepatic adenomas or renal impairment developed in none of the patients who reached adolescence [Daublin et al., 2002]. Dietary substitution of medium-chain triglycerides in glucose-6-phosphatase deficiency for long-chain triglycerides was attempted, to alter the hyperlipemic state by means of the unique absorptive and metabolic properties of medium-chain triglycerides. The results suggested that substitution of medium-chain triglycerides for long-chain triglycerides in the diet, along with normal carbohydrate consumption, leads to significant decrease in serum lipid levels, disappearance of eruptive xanthomas, and decrease in liver mass [Cuttino et al., 1970]. The hyperglycemic agent diazoxide has been beneficial [Rennert and Mukhopadhyay, 1968]. The drug’s action is not well understood, but normal blood glucose concentration has been maintained with this drug. Phenytoin also has been used [Jubiz and Rallison, 1974]. Surgical treatment for glucose-6-phosphatase deficiency involves creation of a portacaval shunt, which increases the peripheral blood glucose by allowing portal blood to bypass

the liver after absorption of glucose from the gut [Starzl et al., 1969]. The postoperative course has been complicated by severe hypoglycemia, hypocalcemia, acidosis, and respiratory impairment, the last primarily because of hepatomegaly. Preoperative intravenous hyperalimentation appears to eliminate these metabolic problems, reduce the size of the liver, and provide a smoother and shorter postoperative course [Folkman et al., 1972]. Liver transplantation was reported to produce beneficial results [Malatack et al., 1983]. More recent evaluation has found that this procedure, usually indicated for management of multiple hepatic adenomas, does not itself benefit metabolic control, and indeed, careful systemic management is essential to prevent graft complications [Labrune, 2002]. Chronic inflammatory bowel disease similar to Crohn’s disease has been associated with glycogen storage disease type I non-a. Initial studies suggested benefit from therapy with colony-stimulating factors [Roe et al., 1992]. A retrospective study of 57 patients with glycogen storage disease type I non-a found evidence of less frequent infections and diminished severity of inflammatory bowel disease in those who received granulocyte colonystimulating factor [Visser et al., 2002]. Splenomegaly was associated with granulocyte colony-stimulating factor therapy in this group. Renal disease also may ensue in older patients [Chen, 1991]. Brain abscess has been reported in a patient with type I non-a disease [Park et al., 1991]. Renal transplantation has been used for terminal renal failure, and occasionally, combined hepatic and renal grafting has been used. In both circumstances, meticulous systemic metabolic management is essential to successful outcome [Labrune, 2002].

Acid Maltase Deficiency, Infantile Type (Pompe’s Disease, Idiopathic Generalized Glycogenosis, Glycogen Storage Disease Type II) Pathology Infants with glycogen storage disease type II have a severe vacuolar myopathy, with accumulation of large amounts of periodic acid–Schiff–positive material within cardiac, skeletal, and smooth muscle fibers and in liver, renal tubules, lymphocytes, glial cells, anterior horn cells, and brainstem nuclei, in infantile cases. Storage in later-onset cases is largely restricted to skeletal muscle. Large amounts of metachromatic material are found within the muscle fibers in the infantile cases. Metachromasia is not seen as often in the adult cases. The metachromasia reflects glycolipid or glycoprotein accumulation. Glycogen also accumulates in anterior horn cells. Scattered, sparse, perivascular lymphocytic infiltrates are seen in the interstitial tissue [Hudgson and Fulthorpe, 1975].

Biochemistry Hers [1963] first reported the deficiency of activity of the lysosomal enzyme acid maltase (α-1,4-glucosidase). The locus for the gene that regulates synthesis of this enzyme is 17q25.2-q25.3 [Kuo et al., 1996; Martiniuk et al., 1985]. Glycogen structure has consistently been normal, and its

Patterson and Swaiman / Diseases Associated with Primary Abnormalities in Carbohydrate Metabolism

accumulation is restricted primarily to lysosomes, although lysosomal breakdown and cytoplasmic accumulation with disruption of muscle fibers occur in severe cases. Hypoglycemia is not a feature of this condition, but increased protein turnover with increased leucine flux and oxidation and increased resting energy expenditure has been found in late-onset cases [Bodamer et al., 2000]. Attempts have been made to differentiate biochemically among the infantile, late infantile, and adult-onset forms of acid maltase deficiency. Activity of α-1,4-glucosidase (acid maltase) at various pH values in infants, children, and adults with acid maltase deficiency has been studied. Only traces of neutral maltase are found in the heart, and significantly decreased neutral maltase activity was measured in the skeletal muscle and liver of an affected infant. In the late infantile form, neutral acid maltase activity is decreased only in the liver; in the adult form, neutral maltase is not deficient in any tissue. An absolute decrease of leukocyte acid maltase was found in four adults and a relative decrease in one of five adults with acid maltase deficiency. Decrease in the pH ratio of acid to neural maltase activity in leukocytes may be of diagnostic importance in adult acid maltase deficiency [Angelini and Engel, 1972]. A number of allelic variations have been described and may explain the differences in age at onset. The theoretical abnormalities that could result in a deficiency of α-glucosidase include synthesis of catalytically inactive protein, absence of messenger RNA (mRNA) for the enzyme, decreased synthesis of the precursor, lack of phosphorylation of the precursor, impaired conversion of the precursor to the mature enzyme, and synthesis of unstable precursor [Tager et al., 1987; Zhong et al., 1991]. In general, the location and nature of mutations predict the phenotype, but exceptional cases are described in which relatively mild phenotypes occur despite low levels of α-glucosidase expression in cultured cells and in the patient’s tissues [Hermans et al., 2004; Kroos et al., 2004]. Thus far, unidentified genetic modifiers and environmental factors are presumed to account for such variability. Unexplained storage of increased neutral lipid is coupled with low carnitine concentration and reduced β-hydroxyacylCoA dehydrogenase in muscle [Verity, 1991].

Clinical Characteristics Development usually is normal for several weeks to several months; then the affected infant presents with feeding difficulties, weakness, or respiratory impairment. The median age at presentation was 1.6 and 1.9 months, respectively, in 20 Dutch patients and 133 patients described in the literature [Van den Hout et al., 2003] (Fig. 25-4). Little spontaneous movement occurs, and the cry is short-lived and weak. Swallowing is grossly limited, and secretions pool in the posterior oropharynx. Respiratory difficulty reflects weakness of the accessory muscles of respiration [Tanaka et al., 1979]. Massive cardiomegaly develops, and a soft systolic murmur is often heard along the left sternal border [Pompe, 1932]. Obstruction to ventricular outflow and impairment of inflow may develop [Seifert et al., 1992], and serial echocardiography reveals progressive left venticular posterior wall diastolic thickening [Van den Hout et al., 2003]. Hepatomegaly is almost universally present. The liver has a sharp edge and a firm consistency on palpation. Subcutaneous fat over all areas of the body is sparse, and the muscles are

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FIGURE 25-4. This 8-month-old infant with infantile acid maltase deficiency (Pompé’s disease) is profoundly hypotonic and weak. The child is draped over the examiner’s hand while the infant’s arms and legs are immobile against gravity. (From Swaiman KF, Wright FS. Pediatric neuromuscular diseases. St. Louis: Mosby, 1979.)

small and firm. The tongue often is enlarged and may protrude. Intermittent cyanosis reflects respiratory and cardiac embarrassment. Deep tendon reflexes are lost by the age of 6 months. Affected infants undergo progressive debilitation, and most die, at median ages of 6 and 7.7 months in the literature cases and Dutch series, respectively. Fewer than 10% survive beyond 1 year; only two patients have been described who survived 18 months [Van den Hout et al., 2003], and almost all die by 2 years. A subgroup of children has been described who present later in infancy, with lesser degrees of weakness and cardiac impairment, who have survived for periods as long as 13 years with ventilatory and nutritional support [Slonim et al., 2000].

Clinical Laboratory Tests The quantity of glycogen storage and activity of the enzyme involved in glycogen metabolism can be monitored by using skin removed with a vacuum skin-blistering technique or fibroblasts grown from skin biopsy material. Among the enzymes in skin are phosphorylase, acid maltase, and the debranching enzyme amylo-1,6-glucosidase. No glucose6-phosphatase activity is present in skin. Both skin fibroblasts and amniotic fluid cells can be used for assay of acid maltase (α-1,4-glucosidase) activity [Butterworth and Broadhead, 1977; Leathwood and Ryman, 1971]. Prenatal diagnosis by biochemical study of uncultured amniotic fluid cells and chorionic villus biopsy material using maltose as a substrate have been reported [Hug et al., 1984; Park et al., 1992]. Mutational analysis has superseded these techniques in some cases, and complemented enzyme analysis and ultrasound examinations in others, as in a report of a fetus with this deficiency diagnosed in the second trimester, in which glycogen accumulation was detectable in muscle, as well as a visibly enlarged tongue on prenatal ultrasound examination [Chen et al., 2004].

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A simple differential immunoprecipitation assay of urinary acid and neutral α-glucosidases has been developed [Tsuji et al., 1987]. The chest x-ray film reveals massive cardiomegaly [Ruttenberg et al., 1964]. The electrocardiogram contains depressed ST segments, inverted T waves, and a shortened P-R interval. These changes may be confused with those of myocarditis. Electromyography (EMG) shows myopathic changes; polyphasic potentials and a reduced interference pattern with low voltage are the usual findings. Unusual high-frequency discharges, best described as myotonic-like, are very common [Gutman et al., 1967; Hogan et al., 1969]. Muscle and liver biopsy specimens contain large amounts of structurally normal glycogen when studied by both light and electron microscopy. Changes in peripheral nerve also have been reported [Araoz et al., 1974].

Genetics Acid maltase deficiency is inherited as an autosomal-recessive trait. The gene for human acid α-glucosidase is contained on chromosome 17 (segment q21-q23) [Martiniuk et al., 1986]. The structural gene for human acid α-glucosidase is undergoing intensive study; it is approximately 28 kb in length and contains 20 exons [Martiniuk et al., 1991]. Various mutations may result in the phenotype; missense mutations and failure of an allele to manifest mRNA expression have been reported [Zhong et al., 1991]. Prenatal diagnosis has been available since the 1970s [Hug et al., 1974]. The use of chorionic villus assay allows first-trimester diagnosis [Chowers et al., 1986]. Adult-onset and infantile glycogenosis type II has been detected in one family. Two types of mutant alleles were identified; one leads to complete deficiency of the enzyme, and the other results in reduced net production of active α-glucosidase, resulting in partial enzyme deficiency [Hoefsloot et al., 1990].

Earlier studies included the administration of specially prepared amyloglucosidase from Aspergillus foetidus, which produced decreased striated muscle glycogen content, lengthened P-R interval, and decreased ventricular electrical forces [Gillette et al., 1974]. Intravenous administration of the deficient enzyme to mice resulted in uptake of enzyme in skeletal muscle [Van der Ploeg et al., 1991]. Experimental attempts to introduce acid α-maltase into enzyme-deficient myoblasts also have enjoyed some success [Zaretsky et al., 1997].

Late Infantile Acid Maltase Deficiency A number of children have been reported who are deficient in acid maltase activity but without the phenotype of Pompé’s disease [Smith et al., 1966, 1967; Swaiman et al., 1968]. These children usually are asymptomatic during the first year of life and live beyond the age of 2 years. Most have slowly progressive weakness but no gross signs of overt deposits of glycogen in skeletal or heart muscle or in visceral organs. Symptoms and signs may mimic those of Duchenne’s muscular dystrophy. In this condition, the gastrocnemius and deltoid muscles may be firm and rubbery, with accompanying hypertrophy of the gastrocnemius muscle. Waddling gait, increased lumbar lordosis, and Gowers’ sign (Fig. 25-5) are frequently present. Achilles tendon contractures result in equinus gait. Cardiomegaly is absent, and an intermittent soft, systolic murmur may be heard. Two patients had a patulous anal sphincter.

Management Before the advent of enzyme replacement therapy (ERT), no practical treatment was available. Therapies previously studied included epinephrine administration, which reduced liver, but not muscle, glycogen content to normal [Hug, 1974]. Dietary supplementation with L-alanine, designed to reduce the elevated protein turnover characteristic of acid maltase deficiency, has apparently slowed progression of weakness and even reversed cardiomyopathy in some patients with late infantile and juvenile forms [Bodamer et al., 1997, 2000, 2002]. Attempts to replace the deficient enzyme date back to 1964, but effective ERT was not possible until suitable sources of receptor-targeted human recombinant acid glucosidase became available in the late 1990s. This was derived from both rabbit milk and Chinese hamster ovary (CHO) cells. The first clinical trial began in 1998, and by 2004, ERT for acid maltase deficiency was nearing approval in the United States [Reuser et al., 2002; Winkel et al., 2004]. Infants who received treatment early in the course of their illness demonstrated improved strength and cardiac function, with survival now extending over several years. The follow-up interval has been too short to determine if anterior horn cell and glial storage of glycogen will lead to chronic weakness and impairment of cerebral function in long-term survivors.

FIGURE 25-5. This 22-month-old child with late infantile acid maltase deficiency has increased lumbar lordosis, pseudohypertrophy of the calf muscles, and contractures of the Achilles tendons. (From Swaiman KF, Wright FS. Pediatric neuromuscular diseases. St. Louis: Mosby, 1979.)

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FIGURE 25-6. Infantile acid maltase deficiency. A, Ballooned muscle cells with dispersed myofibrils (arrow) resulting from glycogen appearing as clear areas. (Verhoeff–van Gieson stain; ×240.) B, Ultrastructure showing excessive glycogen beneath the sarcolemma and between myofibrillar bundles. (×15,000.) (A and B, Courtesy of Dr. Stephen A. Smith.)

A

B

Clinical Laboratory Tests Light and electron microscopy of muscle biopsy material displays moderate glycogen storage (Fig. 25-6). In muscles stained with hematoxylin and eosin, the glycogencontaining areas appear vacuolated. In one report, only type I fibers were involved [Papapetropoulos et al., 1984]. A few patients with glycogen storage in lysosomes have been described who appear to have normal acid maltase enzyme activity [Tachi et al., 1989]. Electron microscopy depicts monogranular and multigranular deposits of glycogen free in the sarcoplasm, as well as membrane bound in lysosomes. EMG documents polyphasic potentials and a reduced, low-voltage interference pattern. The bizarre, myotonic-type potentials described in early infantile acid maltase deficiency also occur in the late infantile form.

Biochemistry Aside from the accumulation of glycogen and its possible abnormal architecture, the most prominent abnormality de-

scribed is a deficiency of acid maltase activity. Quantitation of glycogen reveals increased content. The liver may or may not contain increased glycogen stores [Smith et al., 1966, 1967]. Two patients have been described who had glycogen of abnormal configuration because of shortened outer chains.

Management One child with late infantile acid maltase deficiency received epinephrine injections twice daily [Swaiman et al., 1968]. After 1 month of this treatment, the glycogen content of muscle was diminished. The relative success of this therapeutic method suggests that the conventional pathway for glycogen degradation is intact and can be normally stimulated by epinephrine. Attempts to manage patients by dietary means enjoyed modest success after initially disappointing results (see earlier) [Bodamer et al., 1997, 2000, 2002]. At present, enzyme replacement therapy appears to offer the best hope for definitive treatment in this group of patients [Reuser et al., 2002]. Investigational studies are ongoing.

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Juvenile and Adult Acid Maltase Deficiency A slowly progressive myopathy characterizes juvenile and adult acid maltase deficiency. Many patients were asymptomatic until adult life [DiMauro et al., 1978]. Findings include increased serum enzyme activity of creatine kinase, aspartate aminotransferase, and lactate dehydrogenase. Adult cases cannot be delineated from infantile and late infantile cases on the basis of muscle acid maltase activity. The enzymatic deficiency is demonstrable in adult patients [Wokke et al., 1995]. Neutral maltase activity appears to be normal in adult cases but may be decreased in infantile and late infantile cases. Glycogen content of muscles in adult patients does not differ from that in patients with deficiency of infantile and late infantile onset and ranges from 1.8% to 5.8% [Engel et al., 1973]. In both the juvenile and adult forms, weakness associated with acid maltase deficiency develops during the second through the sixth decades of life. Weakness is greater proximally than distally and is more prominent in the pelvis than in the shoulder girdle. Weakness varies from muscle to muscle. Intercostal and diaphragmatic muscles are involved in many patients. Adult patients do not have enlargement of the liver, heart, or tongue. Frequently, polymyositis and muscular dystrophy are the initial clinical diagnoses. In one series, 16 patients with adult-onset acid maltase deficiency were compound heterozygotes. Patients presented with proximal weakness of the legs or fatigue. The patients manifested progressive symptoms [Wokke et al., 1995]. Some diminution of α-glucosidase activity was identified in muscle [Wokke et al., 1995]. Electromyographic changes and histologic and electron microscopic findings in muscle biopsy specimens in adult cases are similar to changes in infantile and late infantile cases. In general, histologic findings in muscle biopsies also are the same in adults. Diastase digestion of fresh frozen sections confirms that the stored material is glycogen. Electron microscopy demonstrates no differences among infantile, late infantile, and adult cases. Epinephrine therapy in adult patients usually has not resulted in any increase in strength, but two adults who received this treatment for 3 and 1 years, respectively, appeared to gain some strength. One patient deteriorated during a 2-year treatment period, and four others were unchanged [Engel et al., 1973]. Replacement therapy with rabbit-derived recombinant human α-glucosidase in patients aged 11, 16, and 32 years over a 3-year period produced stabilization of pulmonary function and strength in the older patients, and sufficient improvement in strength that the youngest patient was able to dispense with his wheelchair and walk unassisted [Winkel et al., 2004].

Amylo-1,6-Glucosidase Deficiency (Debrancher Deficiency, Cori’s Disease, Forbes’ Disease, Limit Dextrinosis, Glycogen Storage Disease Type III) Pathology Electron microscopy of skeletal muscle of persons with glycogenoses has demonstrated glycogen deposits just inside the sarcolemmal membrane and between the filaments of the

I and A bands, as well as between the myofibrils. These abnormalities are not pathognomonic for this glycogenosis [Neustein, 1969], now classified as glycogen storage disease type III. Glycogen storage in liver is indistinguishable from glycogen storage in other glycogenoses that involve the liver.

Biochemistry A complementary DNA encoding the human muscle glycogen debranching enzyme (AGL) was used to localize the gene to 1p21 by somatic cell hybrid analysis and in situ hybridization [Yang-Feng et al., 1992]. The AGL gene was cloned and found to encode six isoforms that manifested tissue-specific distribution and two distinct functions, both as a debranching enzyme and as a transferase [Bao et al., 1996]. Polymorphic markers within the gene can be used for linkage analysis for prenatal diagnosis and carrier detection [Shen et al., 1997], although direct mutational analysis is frequently used. Glycogen storage disease type III has marked genetic heterogeneity, with almost 50 mutations described by 2004 [Lam et al., 2004]. Although genotypephenotype correlations are difficult in rare recessive phenotypes such as glycogen storage disease type III, in which most patients are compound heterozygotes for private mutations, it appears that glycogen storage disease type IIIa is associated with mutations downstream to exon 3, whereas glycogen storage disease type IIIb is associated with mutations in exon 3 [Lucchiari et al., 2002, 2003]. Several designated biochemical categories of type III glycogenosis have been identified. In type IIIa deficiency (both transferase and glucosidase deficiency), debranching enzyme activity is either absent or greatly reduced in liver and muscle. When the enzyme activity is deficient in liver alone, the condition is designated type IIIb. Type IIc patients have deficient glucosidase but not transferase activity. Some patients have the reverse—that is, isolated transferase deficiency with retention of glucosidase activity (type IIId disease) [Ding et al., 1990]. The likelihood of myopathy and cardiomyopathy can be determined from assay of debranching enzyme and debranching enzyme transferase activity [Coleman et al., 1992]. Approximately 70% of the patients have no activity in all tissues studied. In another 10% of patients, enzyme activity is absent in liver but present to a small degree in muscle tissue. In yet another group, some activity of the debranching enzyme is present in either or both liver and skeletal muscle. The use of skin fibroblasts for study of debrancher enzyme activity is the usual initial approach to enzyme studies [Brown et al., 1978]. Oligo-1,4→1,4-transglucosylase (transferase) activity may be present in muscle and liver of patients with type III glycogenosis but absent in their leukocytes. Electron microscopy of skin indicates glycogen storage in eccrine sweat glands [Sancho et al., 1990]. Characterization of the enzyme indicates immunochemical similarity of debranching enzyme in liver and in muscle. The evidence also suggests that deficiency of debranching enzyme activity in glycogen storage disease type III is the result of the absence of debrancher protein [Chen et al., 1987]. Assay of liver tissue of a patient with debrancher enzyme deficiency revealed increased activity of fructose-1,6diphosphatase. Lack of enzymatic activity limits the break-

Patterson and Swaiman / Diseases Associated with Primary Abnormalities in Carbohydrate Metabolism

down of glycogen, and during fasting, the release of glucose from the liver stems from gluconeogenesis. The increase in fructose-1,6-diphosphatase activity likely reflects increased gluconeogenesis. Administration of galactose [Hers, 1959], dihydroxyacetone [Brombacher et al., 1964], fructose [Hers, 1959], casein [Fernandes and van de Kamer, 1968], and glycerol [Senior and Loridan, 1968] has resulted in increased blood glucose concentrations; these findings support the critical compensatory role of gluconeogenesis in this condition [Sadeghi-Nejad et al., 1970]. In patients with deficient muscle enzyme activity, incorporation of uridine14 C-glucose into red cell glycogen is either very low or absent. Myogenic hyperuricemia is common in this condition but is not unique; hyperuricemia also accompanies glycogenosis type V and type VII [Mineo et al., 1987].

Clinical Characteristics INFANTILE TYPE Patients with debrancher enzyme deficiency may have muscle involvement, liver involvement, or both. The infantile type usually manifests in the first few months of life and is associated with hypoglycemia, failure to thrive, and hepatomegaly [Forbes, 1953]. Affected infants are hypotonic and weak and have poor head control. Glycogen deposition in cardiac muscle rarely is sufficient to create clinical disturbances; however, gross cardiac involvement with glycogen accumulation was reported in a 3-month-old patient, who died suddenly [Miller et al., 1972]. Association of debranching disease with profound cardiac muscle and skeletal muscle involvement accompanied by thyroid insufficiency also has been reported. The simultaneous presence of these two conditions is unexplained [Goutières and Aicardi, 1971]. The presence in infancy of hypoglycemia and hepatomegaly in this enzyme deficiency parallels abnormalities found in Von Gierke’s disease (glucose-6-phosphatase deficiency), but the abnormalities are less pronounced. One infant with both glycogen storage disease type IIIa and Costello’s syndrome has been described [Kaji et al., 2002]. The significance of this association is unclear.

CHILDHOOD TYPE Abnormal findings in a 7-year-old female with glycogen storage disease type III included exercise intolerance and heart failure. Cardiac and skeletal muscle contained increased stores of glycogen. Branching enzyme deficiency was confirmed with further studies [Servidei et al., 1987].

ADULT TYPE Debrancher enzyme deficiency also has been reported in older children and adults [Brunberg et al., 1971]. Adult patients with glycogen storage disease type III manifesting as chronic progressive myopathy in middle age have been described [DiMauro et al., 1978; Momoi et al., 1992]. Patients with debrancher deficiency should be monitored for cardiac involvement [Moses et al., 1989]. An adult with glycogen storage disease type IIIa presented with diabetes

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mellitus, complicating hepatic failure. He was successfully managed with an α-glucosidase inhibitor, which delays carbohydrate glycolysis in the gut, thus blunting postprandial hyperglycemia and the consequent risk of hypoglycemia [Oki et al., 2000]. Progressive cirrhosis may be more common in adult glycogen storage disease type III than was previously recognized and occasionally is complicated by hepatocellular carcinoma [Siciliano et al., 2000]. Debrancher deficiency has been associated with flaccidity, as reported in a 13-year-old patient [Forbes, 1953; Pearson, 1968], and with “weak tone,” described in a 3-year-old patient [van Creveld and Huijing, 1965]. A history of a protuberant abdomen during childhood often is present. Patients complain of muscle fatigue without tenderness, cramping, or associated hematuria. Persistent diffuse weakness is present, and wasting of the hand and forearm muscles with loss of body weight ensues. Sugar-containing foods are of no clinical benefit, and symptoms of hypoglycemia are absent. The family history may include death of siblings in late childhood from a similar illness.

Clinical Laboratory Tests Pseudomyotonic discharges are present on EMG. Serum creatine kinase activity may increase before and after exercise. Blood studies demonstrate mild fasting hypoglycemia, hyperlipidemia, fasting ketonuria, and diabetic glucose tolerance curves. Blood glucose concentration usually is not responsive to epinephrine or glucagon, but at times a mild response may occur. Results on galactose, fructose, and glycerol tolerance testing are normal. Blood lactic acid does not increase on ischemic exercise. Abnormally structured glycogen containing short outer chains has been demonstrated in liver, skeletal muscle, and red and white cells [Brandt and DeLuca, 1966; Van Hoof, 1967; Van Hoof and Hers, 1967].

Genetics Glycogen storage disease type III is inherited as an autosomal recessive trait. The use of cultured amniotic fluid cells and chorionic villus assay allows first-trimester diagnosis [Chowers et al., 1986; Yang et al., 1990]. Heterozygotes cannot be diagnosed with certainty using enzyme analysis [Cohn et al., 1975], but mutational analysis can accurately identify both affected persons and carriers when two mutant alleles have been detected in a proband.

Management Patients with growth failure and hepatic dysfunction, including hypoglycemia, appear to benefit from the administration of oral cornstarch [Borowitz and Greene, 1987; Gremse et al., 1990].

Amylo-1,4→1,6 Transglucosidase Deficiency (Brancher Enzyme Deficiency, Glycogen Storage Disease Type IV) Glycogen storage disease type IV (Andersen’s disease) results from a deficiency of glycogen branching enzyme (GBE), leading to the accumulation of abnormal glycogen

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resembling amylopectin in affected tissues. The reported phenotypes are highly varied but for the most part have been marked primarily by liver involvement. Glycogen storage disease type IV has been characterized as the most heterogeneous of the glycogen storage diseases [Moses and Parvari, 2002]. A few infants with severe congenital hypotonia and cardiomyopathy have been described [Nambu et al., 2003]. A mild, predominantly myopathic variant has been reported in older children [Reusche et al., 1992]. Adults with polyglucosan body disease who manifest late-onset pyramidal quadriparesis, micturition difficulties, peripheral neuropathy, and mild cognitive impairment have been described. Diagnosis in those cases was made initially by sural nerve biopsy. MRI revealed marked white matter alterations. Branching enzyme activity in leukocytes was about 15% of control values [Lossos et al., 1991], although some affected persons identified subsequently have normal enzyme activity. Five Jewish familes with adults with polyglucosan body disease have been described in which affected persons were homozygous for a Tyr329Ser mutation in GBE1. Not all such patients have recognized GBE mutations or impaired GBE activity, suggesting both phenotypic and genotypic heterogeneity [Klein et al., 2004].

Pathology Glycogen may accumulate disproportionately in the tongue and diaphragm in comparison with other striated muscle groups. The characteristic lesion is the polyglucosan body, a periodic acid–Schiff–positive inclusion that also is seen in phosphofructokinase deficiency, Lafora body disease, double athetosis (Bielschowsky bodies) and in aging (corpora amylacea) [Cavanagh, 1999]. Electron microscopy of the deposits reveals branched filaments, osmiophilic granules, and electron-dense amorphous material.

Biochemistry The first patient described with deficiency of brancher enzyme activity manifested cirrhosis of the liver and glycogen accumulation [Anderson, 1956], but patients with normal [Holleman et al., 1966] and decreased muscle glycogen concentrations [Sidbury et al., 1962] also have been described. Brancher enzyme deficiency results in the synthesis of unbranched glycogen composed of elongated chains of glucose molecules joined together in 1,4 linkages. As a result, the glycogen is composed of long outer chains, has few branch points, and resembles the pattern of starch also known as amylopectin. The glycogen brancher enzyme has been purified beyond 3000-fold from rabbit skeletal muscle. The enzyme appears to have a molecular weight of 92 to 103 kilodaltons (kDa), depending on the choice of reference protein. Amylopectin polysaccharide isolated from the liver of a patient with branching deficiency is branched in the presence of the purified enzyme and α-D-glucose-1-phosphate at pH 7 [Gibson et al., 1971]. Study of the fine structure of glycogen from a patient with brancher enzyme deficiency found that the similarity of abnormal glycogen to amylopectin is in some ways superficial. The abnormal glycogen contains a significant number of

short branches. This finding is consistent with the hypothesis that a normal debranching enzyme system in these patients can participate in a reverse reaction, with a resultant small degree of branching activity. The short chains are explained further by the supposition that the glycogen debranching enzyme system would form branch points by the apposition of 1→6 bonded α-glucose units by amylo1,6-glucosidase. Further elongation of this chain would occur by transfer of oligosaccharide by the oligo-1,4→1,4transferase component of the debranching system. The transferase favors transfer of maltotriosyl residue, which creates a four-unit branch. Brancher enzyme from muscle or liver ordinarily transfers glucose units containing seven glucose molecules. The shorter branches formed by a reversal of the debranching enzyme system are not as readily extended by glycogen synthetase. If the units are shorter than four glucose units, it may be impossible for them to be extended by synthetase [Mercier and Whelan, 1970]. The presence of short branches suggests that reversal of the debranching mechanism is operative.

Clinical Characteristics Manifestations of the disease usually appear in the first 6 months of life and are failure to thrive, hepatosplenomegaly, and liver failure with cirrhosis. Affected infants exhibit delayed motor and social development, hypotonia, weakness, and muscle atrophy, accompanied by absent or decreased deep tendon reflexes [McMaster et al., 1979; Zellweger et al., 1972]. A more benign form with clinical onset at the age of 2 years manifested as hepatomegaly and elevated liver enzyme activity. The patient had no neurologic abnormalities, and the liver disease was not progressive [Greene et al., 1988]. Another patient, a 3-year-old male, had mild glycogen storage, as well as dicarboxylicaciduria and secondary carnitine deficiency. Notable clinical improvement occurred with administration of oral L-carnitine [MaaswinkelMoody et al., 1987]. Yet another patient had mild clinical symptoms at 8 years of age despite profound deficiency of glycogen branching enzyme [Guerra et al., 1986]. Adult myopathic variants have been described [Bornemann et al., 1996].

Clinical Laboratory Tests Diagnosis of brancher deficiency by assay of peripheral white blood cells, skin fibroblasts, and amniotic cell activity is feasible [Howell et al., 1971]. Confirmation of the diagnosis by mutational analysis is now possible.

Genetics Early studies confirmed an autosomal recessive mode of inheritance [Legum and Nitowsky, 1969]. Enzyme activity in cultured fibroblasts is less than control levels in patients and both parents, corroborating the presence of an autosomal recessive mode of inheritance. Prenatal testing using cultured amniocytes and chorionic villi is feasible [Brown and Brown, 1989] but has been superseded by molecular analysis when available. The gene encoding brancher enzyme, GBE1, was identified in 1993 [Thon et al., 1993], and

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a variety of mutations have been recognized in all forms of GBE deficiency [Moses and Parvari, 2002]. 45

Management

McArdle’s Disease (Myophosphorylase Deficiency, Glycogen Storage Disease Type V) In 1951, McArdle reported a condition characterized by weakness, fatigue, and severe muscle cramping with pain after exercise. He subsequently noted the lack of normal lactate production in the affected muscles after ischemic work [McArdle, 1951; Pearson et al., 1961; Schmid and Mahler, 1959]. McArdle’s disease is classified as glycogen storage disease type V.

Pathology Light microscopic studies of muscle reveal moderately increased stores of glycogen beneath the sarcolemmal membrane. Electron microscopy demonstrates disorganization of the I band region and distortion of the myofibrils secondary to glycogen deposition [Rowland et al., 1963]. Histochemical study of muscle suggests the absence of myophosphorylase activity, but only quantitative biochemical studies are reliable to confirm the diagnosis. Critical and definitive diagnosis depends on assay for the enzymatic deficiency in the affected muscle tissue.

Biochemistry Glycogen breakdown to lactate begins with the initial disruption of the 1,4 linkage between glucosyl units. The enzyme myophosphorylase facilitates this reaction in skeletal muscle. After this linkage is cleaved, glucose-1phosphate is freed and metabolized to lactate through the Embden-Meyerhof pathway. The myophosphorylase enzyme is regenerated in a complex reaction involving a number of other enzymes, including phosphorylase kinase (see Fig. 25-3). Absence of myophosphorylase activity results in decreased glucose-1-phosphate production; as a result, lactic acid is not formed in exercised muscle, and serum lactic acid concentration is not appropriately elevated (Fig. 25-7). Structure of the excess glycogen stored is normal. Mitochondrial metabolism is normal [Argov et al., 1987]. Histochemical stains of fresh frozen sections of skeletal fibers demonstrate absence of phosphorylase. Studies of early multinucleated fibers and striated myofibers grown in vitro from these tissues reveal definite evidence of phosphorylase activity. Genetic coding for developing a form of myophosphorylase activity must be present in the precursor

Patient Control

40 Serum lactate concentration (mg/dl)

Treatment with a combination of zinc-glucagon and αglucosidase decreased liver glycogen concentration, but the infant died at 11 months of age from an infection [Fernandes and Huijing, 1968]. Liver transplantation has been successful in a number of patients [Selby et al., 1991]. Orthotopic liver transplantation has been attempted with varied success [Selby et al., 1991]. In one report, cardiac amylopectinosis occurred 9 months after successful transplantation [Sokal et al., 1992].

35 30 25 20 15 10 5 0 10 20 5 15 Time after exercise begun (minutes)

FIGURE 25-7. This line graph reflects the failure of increase in blood lactic acid concentration during ischemic exercise of the arm in a patient with McArdle’s disease.

cells of regenerating skeletal muscle. The observation suggests the presence of a mechanism for loss of activity during maturation of tissues. Feasible explanations include the following possibilities: muscle maturation may result in loss of an enzyme that maintains phosphorylase production, survival, or activity; an abnormal specific protease may develop with maturity and inactivate myophosphorylase; a normally repressed myophosphorylase repressor gene may be “derepressed”; and a normally present but inactive myophosphorylase-inhibiting or -destroying enzyme may be activated and inhibit myophosphorylase enzyme activity or survival [DiMauro et al., 1978; Roelofs et al., 1972]. Occasionally, patients are found to have no immunologic crossreactive material to normal myophosphorylase [Koster et al., 1979].

Clinical Characteristics Affected children have decreased stamina and tire easily. Fatigue may be mediated in part by ammonia accumulation [Coakley et al., 1992]. Severe cramping pain after minimal exercise is noted in the involved skeletal muscles and primarily affects distal muscles. Cardiac symptoms have not been reported, but cardiac muscle is involved [Ratinov et al., 1965]. Myoglobinuria occurs with moderate or strenuous exercise. In adolescence and adulthood, persistent weakness may develop, with moderate loss of muscle bulk [Schmid and Hammaker, 1961]. A “second wind” phenomenon has been described in which the patient appears to recover after a 15-minute period of weakness and fatigue [Braakhekke et al., 1986]. This phenomenon has been attributed to improved energy production when metabolic dependence

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switches from glycogen stores to blood-borne fuels, including glucose and fatty acids, and is consistently seen in glycogen storage disease type V but not in glycogen storage disease type VII, whose phenotype is otherwise indistinguishable [Haller and Vissing, 2004]. Prolonged or frequent repetitive episodes of myoglobinuria should be avoided because they may result in both acute and chronic renal failure. Renal failure occurs primarily in men, especially those who perform unusually vigorous exercise, thereby inducing myoglobinuria. These men generally are aware that they are exceeding their usual exercise tolerance. Acute renal failure may not be reversible in these patients [Bank et al., 1972]. One patient with recurrent myoglobinuria and renal failure was found to have had previously unrecognized convulsive seizures as the precipitating events for his episodes [Walker et al., 2003]. Onset usually is in childhood; neonatal onset has been reported [Milstein et al., 1989]. Adult-onset McArdle’s disease also has been reported. One patient had onset at 60 years of age [Felice et al., 1992]. Frequent ingestion of glucose or fructose has had little therapeutic effect. Muscle damage after prolonged exercise may be demonstrated by meams of radionuclide scanning techniques [Swift and Brown, 1978]. A 4-week-old female manifested diffuse, progressive muscle weakness and died at 13 weeks of age. She subsequently was demonstrated to have myophosphorylase deficiency and glycogen storage in the muscles. A female sibling died at 4 months of age from the same condition [DiMauro and Hartlage, 1978; Miranda et al., 1979]. A very severe phenotype, lethal in infancy, was reported in a child born to consanguineous parents with mutations in both PYGM and dGK, the gene encoding deoxyguanosine kinase, whose deficiency causes the hepatic form of mitochondrial depletion syndrome [Mancuso et al., 2003].

Clinical Laboratory Tests Exercise results in elevated serum creatine kinase activity and increase in activity of other serum enzymes released from muscle, ostensibly a result of loss of sarcolemmal membrane integrity. The electrocardiogram may demonstrate an increased QRS amplitude, a prolonged R-S interval, T wave inversion, and bradycardia [Ratinov et al., 1965]. Electromyographic study of contracted muscles after exercise reveals a decreased interference pattern; after ischemic exercise, the contracted muscles may demonstrate no electrical activity. Ischemic exercise effects may be studied using two blood pressure cuffs, one at the wrist and one just above the elbow (Fig. 25-8). The cuffs are inflated to above systolic pressure, and the pressure is maintained for 3 minutes. Blood is removed from the antecubital vein at 0, 3, 5, 10, 15, and 20 minutes. After the initial blood specimen is drawn (at time 0), the patient is asked to contract and extend the fingers over a rubber ball or rod while the cuff pressure is maintained. A patient with McArdle’s disease, or with any of the glycolytic abnormalities that interfere with lactate production, will experience severe contractures and complain bitterly of pain within 30 seconds after the initiation of ischemic exercise. The basis of the contracture phenomenon may be related to delayed reaccumulation of calcium ions in the sarcoplasmic reticulum [Gruener et al., 1968]. The exer-

FIGURE 25-8. Ischemic exercise testing is valuable in determination of McArdle’s disease and other conditions that feature a metabolic block in the Embden-Meyerhof pathway. The patient with McArdle’s disease manifests the contracture that becomes evident within a few seconds after beginning the test.

cise test may not identify patients with low levels of myophosphorylase, in contradistinction to those patients with absence of the enzyme [Taylor et al., 1987]. A test in which subjects cycle with moderate intensity for 15 minutes revealed a consistent decrease in heart rate from 7 to 15 minutes in glycogen storage disease type V patients, in contrast with an elevation in heart rate in control subjects and patients with other glycogen storage diseases. The test appears specific and sensitive in this population [Vissing and Haller, 2003a]. Relaxing factor (which controls accumulation of calcium ions by the sarcoplasmic reticulum) appears to be normal in patients with McArdle’s disease [Brody et al., 1970]. Spectroscopy studies are useful in the detection of excessive muscle glycogen [deKerviler et al., 1991; Jehensen et al., 1991].

Genetics The gene encoding synthesizing myophosphorylase, PYGM, is located at 11q13 [Lebo et al., 1990]. A number of mutations have been described [Vorgerd et al., 1998] but do not appear to explain the clinical heterogeneity of glycogen storage disease type V. A study of potential genetic modifiers found a strong association between angiotensinconverting enzyme genotype and clinical phenotype, suggesting that angiotensin-converting enzyme is a modifier of PYGM [Martinuzzi et al., 2003]. This condition is transmitted as an autosomal recessive trait and may manifest in a heterozygote [Schmidt et al., 1987]. Study of muscle biopsy material demonstrates molecular heterogeneity, including near-normal expression of phosphorylase mRNA concentration and size in some patients [McConchie et al., 1990].

Management A fat-rich diet was administered to a 21-year-old male patient; he subsequently had a shortened recovery period from the acute physical load and suffered no induration of the deltoid muscle after sustained abduction to 90 degrees.

Patterson and Swaiman / Diseases Associated with Primary Abnormalities in Carbohydrate Metabolism

Maximal strength does not appear to be improved by the fatrich diet, but tolerance of submaximal loads appears to be increased, and recovery from muscle discomfort appears to be accelerated [Viskoper et al., 1975]. The interrelationship of pyridoxal phosphate and glycogen phosphorylase may provide some hope for nutritional therapy [Beynon et al., 1996]. A controlled trial of oral sucrose loading showed improved exercise tolerance and stable glucose levels in 12 adults with glycogen storage disease type V [Vissing and Haller, 2003b]. Although not suitable for continuous use owing to its tendency to induce weight gain, this regimen, combined with aerobic conditioning, appears likely to be useful in improving performance under stressful conditions and may protect against acute rhabdomyolysis [Amato, 2003]. A review of published trials cited this study and one other in which oral creatine improved ischemic performance, suggesting these as the only therapies with evidence of benefit [Quinlivan and Benyon, 2004].

Hepatophosphorylase Deficiency (Hers’ Disease, Glycogen Storage Disease Type VI) Biochemistry Hers’ disease, described by Hers in 1959, now classified as glycogen storage disease type VI, is characterized by increased glycogen stores of normal configuration in the liver. Hepatic phosphorylase (hepatophosphorylase) activity is diminished or absent. Because of the possibility of abnormalities in the complex activating mechanism of hepatophosphorylase, systematic study of enzyme activity in suspected hepatophosphorylase deficiency is necessary to exclude phosphorylase kinase deficiency and other metabolic errors in the activating sequence. One patient had hepatomegaly with increased glycogen content and low activity of hepatophosphorylase. No abnormalities of muscle tissue enzymes or glycogen configuration were noted. A liver homogenate prepared from the patient’s biopsy specimen converted rabbit muscle phosphorylase-b to phosphorylase-a. Hepatic homogenate from the patient manifested no phosphorylase activity under the same conditions in which control human liver homogenate demonstrated phosphorylase activity through activation procedures. No activity was observed in the patient’s hepatic homogenate after the addition of phosphorylase kinase [Hug and Schubert, 1970]. The diagnosis of this glycogenosis could be made only from study of liver tissue [Hug et al., 1974] until the gene was identified. This identification was accomplished in a Mennonite kindred, whose affected members harbored a single base pair change in a splice donor site of intron 13 in the PYGL gene [Chang et al., 1998]. Six PYGL mutations had been identified by 2004. The technique is particularly helpful in distinguishing patients with relatively high residual enzyme activity from heterozygotes [Tang et al., 2003].

Clinical Characteristics The patients display various degrees of growth retardation, hypoglycemia, ketosis, and hepatomegaly. Specific neurologic findings are absent. Muscle and cardiovascular tissues are not primarily involved.

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Genetics The gene coding for the enzyme liver glycogen phosphorylase is located on chromosome 14 [Newgard et al., 1987] at 14q21-22. The condition is transmitted as an autosomalrecessive trait [Wallis et al., 1966].

Management Symptoms can be controlled with frequent small carbohydrate meals. No other forms of therapy have been necessary or recommended [Field, 1966].

Muscle Phosphofructokinase Deficiency (Tarui’s Disease, Glycogen Storage Disease Type VII) Biochemistry The enzyme phosphofructokinase transforms fructose-6phosphate to fructose-1,6-diphosphate. Decreased activity of this enzyme results in increased muscle glycogen stores of normal structure and increased concentration of glucose6-phosphate and fructose-6-phosphate [Layzer et al., 1967; Tarui et al., 1965; Thomson et al., 1963; Vora et al., 1987]. The history of glycogen storage disease type VII, since its discovery as the first enzymatic disorder of glycolysis in 1965, was reviewed [Nakajima et al., 2002]. Phosphofructokinase exists in five different isoforms with tissuespecific distribution. The gene consists of varying combinations of liver (L), muscle (M), and platelet (P) subunits. Muscle phosphofructokinase is a homotetramer of M subunits [Vora et al., 1980].

Clinical Characteristics Motor development is normal during the first decade. Nevertheless, patients experience decreased exercise tolerance and easy fatigability during childhood. They perform poorly in games requiring physical stamina and complain of muscle stiffness and weakness and occasionally of muscle cramps. Myoglobinuria may follow moderate-to-strenuous exercise and has precipitated acute renal failure [Exantus et al., 2004]. The clinical pattern is reminiscent of McArdle’s disease, except for the absence of a “second wind” phenomenon in glycogen storage disease type VII [Haller and Vissing, 2004]. One patient with hyperuricemia and gout has been described [Agamanolis et al., 1980]. An unusual infantile syndrome characterized by limb weakness, seizures, cortical blindness, and corneal opacifications has been reported. The infant died at 7 months of age. Microscopic studies of the brain revealed typical features of neuroaxonal dystrophy [Servidei et al., 1986]. Adult onset was reported in a 70-year-old male with progressive weakness of the legs [Vora et al., 1987]. An Ashkenazi kindred with glycogen storage disease type VII has been described whose members had clinical manifestations of diabetes in addition to abnormal results on glucose tolerance testing, confirming that PFKM mutations can cause impaired glucose responses to insulin [Ristow et al., 1997]. Affected persons in this family had first become symptomatic in childhood, with easy fatigability after exercise.

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A 66-year-old female with epilepsy and cardiac disease attributed to glycogen storage disease type VII manifested slow progression of symptoms over an 8-year period, but showed marked improvement after effective treatment of her seizures and cardiac disease [Finsterer et al., 2002]. This report emphasizes the importance of meticulously treating (or preferably preventing) complications, rather than adopting a nihilistic approach. Physical examination in patients with glycogen storage disease type VII is unremarkable except for variable weakness and loss of skeletal muscle bulk.

Clinical Laboratory Tests After exercise, serum creatine kinase and other serum enzymes released from muscle may be elevated. Electromyographic findings may be normal. Ischemic exercise testing, as described earlier for McArdle’s disease, results in muscle contracture and decreased lactic acid production. The definitive diagnosis is made by enzymatic assay of muscle tissue. Phosphofructokinase activity is about 50% of the expected value in the erythrocytes of these patients. A decrease from normal levels of activity also is noted in other patients [Sivakumar et al., 1996]. Immunologic study suggests that half of the total activity of erythrocyte phosphofructokinase is derived from an enzyme form identical to phosphofructokinase. One patient with phosphofructokinase deficiency was found to have (incidental) Gilbert’s syndrome (hepatic glucuronyltransferase deficiency) [Fogelfeld et al., 1990].

Genetics The phosphofructokinase gene (PFKM) is encoded at 12q13.3 [Howard et al., 1996]. Glycogen storage disease type VII is prevalent in Ashkenazim; 68% of mutant alleles in this population are accounted for by a splicing mutation in exon 5 [Raben and Sherman, 1995]. Fifteen diseasecausing mutations in PFKM have been described.

Hepatic Phosphorylase Kinase Deficiency and Activation Abnormalities (Glycogen Storage Disease Type VIII) Some patients with glycogen storage disease have defects in control of the phosphorylase system at the phosphorylase kinase level, rather than a deficiency of the phosphorylase enzyme (see Fig. 25-3). Although they appear to have hepatic phosphorylase deficiency disease, further studies identify the presence of the enzyme when activation cycle materials are added in vitro. These patients have glycogen storage disease type VIII. Hug and associates [1969] described five children with hepatomegaly and increased liver stores of glycogen of normal configuration. An additional three patients, who were siblings, had a mild form of the disease [Gray et al., 1983]. Hepatomegaly, attacks of ketonuria with fasting, and intermittent diarrhea may be prominent. Other patients with the same enzymatic deficiency have involvement of muscle with accompanying weakness [Madlom et al., 1989].

Phosphorylase kinase has a hexadecameric structure: (α, β, γ, δ)4. The α subunit is encoded by PHKA2 (at Xp22), the β subunit by PHKB, and the γ subunit by PHKG2. Mutations in all of these genes have been associated with phosphorylase kinase deficiency and a glycogen storage disease type VIII phenotype [Ban et al., 2003]. The analysis of the responsible genes confirms the prior clinical recognition of both autosomal recessive and X-linked inheritance [Huijing and Fernandes, 1969; Schimke et al., 1973]. One patient with deficiency of phosphorylase kinase activity had normal phosphorylase activity in leukocytes, with deficiency in liver. Three siblings with the condition exhibited a deficiency in red cell and leukocyte phosphorylase-b kinase. Specific therapy may not be necessary [Gray et al., 1983]. Treatment with diazoxide may be beneficial, because fasting hypoglycemia is curtailed. Diazoxide inhibits insulin release, increases adrenal medullary secretion of epinephrine, and inhibits the cyclic adenosine monophosphate phosphodiesterase activity. Together these actions should increase intracellular cyclic adenosine monophosphate. Neither insulin suppression nor associated decrease in hepatomegaly occurred in this patient [Ludwig et al., 1972]. In another patient, findings included evidence of central nervous system dysfunction and associated incomplete activation of brain phosphorylase [Hug et al., 1966]. Glucagon appeared to reverse the deficiency. Glucagon administration does not lead to clinical improvement in all patients with decreased hepatic phosphorylase kinase activity. Hug and Schubert [1970] described a 3-yearold child with marked hepatomegaly and no splenomegaly. A slight tendency to develop hypoglycemia without acidosis was noted. Mental development was normal. Administration of either glucagon or epinephrine did not stimulate phosphorylase activity. Phosphorylase activity was reinstituted by in vitro methods employing addition of cyclic adenosine monophosphate or its substituted derivatives. Reduced hepatophosphorylase activity may result from several separate defects in the phosphorylase activating system [Hug, 1972]. Hepatic tissue removed from a patient may fail to activate either endogenous or exogenous phosphorylase. Purified exogenous phosphorylase kinase may restore the phosphorylase activity, which establishes a deficiency of liver phosphorylase kinase. There may be no abnormalities in the cyclic adenosine monophosphate–dependent protein kinase cycle [Hug, 1972]. A 5-year-old male with glycogen storage disease type VIII manifested improved growth, stabilization of blood glucose, and improvement in laboratory measures with uncooked cornstarch supplementation [Nakai et al., 1994].

Phosphohexose Isomerase Deficiency (Satoyoshi’s Disease) Phosphohexose isomerase also is known as glucose phosphate isomerase and phosphoglucose isomerase. This enzyme catalyzes the interconversion of glucose-6-phosphate and fructose-6-phosphate in the Embden-Meyerhof pathway. Most reported cases of deficiency of this enzyme have been manifested as hemolytic anemia, but a few kindreds have been reported with skeletal muscle dysfunction. Satoyoshi and Kowa [1967] described a family whose members experienced muscle pain and stiffness with exer-

Patterson and Swaiman / Diseases Associated with Primary Abnormalities in Carbohydrate Metabolism

cise, beginning in childhood. The symptoms become more prominent in later life. Muscle contractures do not occur after ischemic exercise. Routine examination is normal. Heavy exercise leads to stiffness and tenderness of the muscles without apparent weakness. Lactic acid does not increase during ischemic exercise and serum creatine kinase is increased, but findings on EMG remain normal. Schroter and co-workers [1985] described a male with severe hemolytic anemia requiring splenectomy at 5 years. Eight years later he had mild hemolytic anemia, gallstones, and jaundice; neurologic findings included weakness, mixed sensory and cerebellar ataxia, and mental retardation. He was found to have a unique mutation (glucose phosphate isomerase Homburg) that produced severe enzyme deficiency. GPI has been assigned to 19cen-q12. It consists of 18 exons and is 40 kb in length [Walker et al., 1995]. The gene codes for two proteins in addition to hexosephosphate isomerase: neuroleukin, a chemokine, and autocrine motility factor [Niinaka et al., 1998]. Antibodies to glucose phosphate isomerase have been shown to sustain a rheumatoid arthritis–like condition in experimental animals [Schaller et al., 2001].

Phosphoglucomutase Deficiency (Thomson’s Disease) The phosphoglucomutases are a family of enzymes catalyzing the interconversion of glucose-1-phosphate and fructose-1phosphate. In early infancy, a male experienced numerous episodes of supraventricular tachycardia, requiring digitoxin treatment; development then proceeded normally until the age of 2 years, when he began to walk on his toes [Thomson et al., 1963]. Examination revealed mild weakness and poor muscle development. His calf muscles were bulky and firm, and shortening of the Achilles tendons was noted. No clinical history of exercise intolerance, muscle pain, or myoglobinuria was elicited. Serum enzyme activities, including creatine kinase, aldolase, glutamic-oxaloacetic transaminase, and glutamicpyruvic transaminase, were elevated. Examination by EMG suggested a myopathic process. In vitro study of biopsy tissue indicated a number of relative enzymatic deficiencies, but phosphoglucomutase deficiency was most pronounced. Glycogen structure appeared normal. Also evident was extensive replacement of muscle tissue by glycogen. Another patient, a 5-month-old male, presented with recurrent vomiting, lethargy, and poor weight gain. Metabolic acidosis was profound. In addition to the expected enzyme deficiency, he had decreased muscle and serum carnitine levels [Sugie et al., 1988]. The carnitine changes most likely were a secondary phenomenon. A 38-year-old male presented with a history of easy fatigability and exercise-induced weakness of the extremities since he was 20. He had weakness, wasting of extremities, bilateral clubbed fingers, and hypoesthesia of distal portion of extremities. Fasting plasma glucose was low (58 mg/dL), and no rise in lactate occurred after ischemic exercise. Phosphoglucomutase activity was 15% of control, and muscle biopsy depicted a small amount of glycogen storage [Nakashima et al., 1992].

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Other Defects of Glycolysis Causing Glycogen Storage Three enzyme defects affecting the terminal glycolysis pathway have been reported involving phosphoglycerate kinase, phosphoglycerate mutase, and lactate dehydrogenase [Bresolin et al., 1983; Tsujino et al., 1993]. Phosphoglycerate kinase deficiency is an X-linked disorder manifesting with hemolytic anemia, seizures, mental retardation, and exercise intolerance with myoglobinuria [Bresolin et al., 1984]. Two brothers subsequently were described with a glycogen storage disease type V phenotype [Aasly et al., 2000]. Phosphoglycerate mutase deficiency (PGAMD) has been associated in adults with myalgia, cramps, and myoglobinuria after exercise [Tonin et al., 1993]. A patient with PGAMD who experienced muscle cramps on forearm ischemic exercise test was protected from cramps by dantrolene, suggesting that cramps in this disease reflect excessive calcium release from the sarcoplasmic reticulum relative to calcium re-uptake capacity [Vissing et al., 1999]. The PGAMD gene has been cloned, and molecular diagnosis is feasible [Tsujino et al., 1993.] Lactate dehydrogenase M subunit deficiency has been reported in three families with exertional myoglobinuria [Kanno et al., 1998]. Additional cases have been identified, and a number of mutations identified in the responsible gene [Maekawa et al., 1994; Tsujino et al., 1994]. Successful pregnancy in an affected female has been described [Anai et al., 2002]. REFERENCES Aasly J, van Diggelen OP, Boer AM, Bronstad G. Phosphoglycerate kinase deficiency in two brothers with McArdle-like clinical symptoms. Eur J Neurol 2000;7:111. Adams A, Redden C, Menahem S. Characterization of human fructose 1,6-bisphosphatase in control and deficient tissues. J Inherit Metab Dis 1990;13:829. Agamanolis DP, Askari AD, DiMauro S, et al. Muscle phosphofructokinase deficiency: Two cases with unusual polysaccharide accumulation and immunologically active enzyme protein. Muscle Nerve 1980;3:456. Amato AA. Sweet success—a treatment for McArdle’s disease. N Engl J Med 2003;349:2481. Anai T, Urata K, Tanaka Y, Miyakawa I. Pregnancy complicated with lactate dehydrogenase M-subunit deficiency: The first case report. J Obstet Gynaecol Res 2002;28:108. Andersen MW, Williams VP, Sparkes MC, et al. Transferase-deficiency galactosemia: Immunochemical studies of the Duarte and Los Angeles variants. Hum Genet 1984;65:287. Anderson DH. Familial cirrhosis of the liver with storage of abnormal glycogen. Lab Invest 1956;5:11. Angelini C, Engel A. Comparative study of acid maltase deficiency. Arch Neurol 1972;26:344. Annabi B, Hiraiwa H, Mansfield BC, et al. The gene for glycogen-storage disease type 1b maps to chromosome 11q23. Am J Hum Genet 1998;62:400. Applegarth DA, Donnell GN, Mullinger M, et al. Study of a family with Los Angeles, Duarte, and classical galactosemia variants of galactose-1-phosphate uridyl transferase. Biochem Med 1976;15:206. Araoz C, Sun CN, Shenefelt R, et al. Glycogenosis type II (Pompe’s disease): Ultrastructure of peripheral nerves. Neurology 1974;24:739. Argov Z, Bank WJ, Maris J, et al. Muscle energy metabolism in McArdle’s syndrome by in vivo phosphorus magnetic resonance spectroscopy. Neurology 1987;37:1720. Badawi N, Cahalane SF, McDonald M, et al. Galactosaemia—a controversial disorder. Screening and outcome. Ireland 1972-1992. Ir Med J 1996;89:16.

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CHAPTER 26

Disorders of Glycosylation Hudson H. Freeze and Marc C. Patterson

Eukaryotic cells synthesize hundreds of types of sugar chains called glycans, which function within the cell, at the cell surface, and beyond. Within the cell, glycans influence protein folding, stability, turnover, and intracellular trafficking [Varki et al., 1999]. At the cell surface, they influence or determine cell-cell binding, receptor-ligand interactions, assembly of signaling complexes, binding to the extracellular matrix, tissue pattern formation, trafficking of lymphocytes, and much more [http://grtc.ucsd.edu]. The same glycan can function differently on different proteins or in different settings. This threedimensional complexity makes understanding the roles of glycans challenging but provides the body with an extraordinarily sensitive fine-tuning mechanism for many physiologic functions. It is not surprising that disrupting normal glycosylation causes moderate-to-severe pathology in multiple human organ systems. In the last decade, more than 20 rare inherited disorders of glycan biosynthesis have been identified [Jaeken, 2003; Jaeken and Carchon, 2004; Jaeken and Matthijs, 2001; Marquardt and Denecke, 2003]. Most of these are the newly defined congenital disorders of glycosylation (previously called carbohydrate-deficient glycoprotein syndrome and disialotransferrin developmental deficiency syndrome). Others, such as muscle-eye-brain disease and Walker-Warburg syndrome, were well known, but elucidation of their relation to glycosylation has provided new insights into their pathophysiology and opens possibilities for therapy.

extensively remodeled there, and later in the Golgi apparatus. All eukaryotic cells make a 14-sugar lipid-linked oligosaccharide in the endoplasmic reticulum membrane that is composed of Man, GlcNAc, and glucose (Glc). This entire chain is transferred to Asn within an Asn-X-Thr/Ser consensus sequence (X is any amino acid except proline) as newly made proteins emerge from the ribosome into the endoplasmic reticulum lumen. An estimated 30 to 40 genes are required to synthesize and transfer this glycan to proteins [Freeze, 2001b]. Extensive remodeling begins soon after sugar chain transfer. Up to two thirds of the original lipid-linked oligosaccharide glycan is discarded, and 6 to 15 other sugar units are added back to create a dazzling array of sugar chains. Why generate this complex process? The initial glycan helps the protein fold and also provides important checkpoints for monitoring of proper protein folding in the endoplasmic reticulum [Parodi, 2000]. The addition of more sugars in the Golgi usually imparts greater specificity to the sugar chain function. The congenital disorders of glycosylation defects are divided into group I and group II, and defects within each group are called types. Group I involves the biosynthesis and addition of the precursor sugar chain on proteins, and group II involves defects in the subsequent processing reactions [Marquardt and Denecke, 2003]. Understanding the biosynthetic pathways is important to be able to appreciate the nature of the defects.

Biosynthesis DEFINING TYPES OF GLYCOSYLATION Glycans are named according to their linkage to proteins, which defines the biosynthetic pathways, usual location in the cell, and typical functions they serve. Most of the congenital disorders of glycosylation defects occur in the N-linked pathway, which is defined by asparagine (Asn)-to-N-acetylglucosamine (GlcNAc) couplings. O-linked glycans come in several forms. Lesions in the biosynthesis of threonine/serine (Thr/Ser) to mannose (Man), or O-Man glycans, cause muscle-eye-brain disease and some cases of Walker-Warburg syndrome. A rare form of progeria results from defects in xylose (Xyl)-based glycans, O-Xyl, which initiates the synthesis of glycosaminoglycans such as chondroitin sulfate, dermatan sulfate, and heparan sulfate.

N-LINKED GLYCOSYLATION Overview Sugar chains are added to newly synthesized proteins in the lumen of the endoplasmic reticulum and are quickly and

Individual monosaccharides derived from the diet or salvaged from degraded glycans are activated to their nucleotide sugar derivatives [Freeze, 1999]. Figure 26-1 shows the known pathways. Note that phosphorylation of the monosaccharide is the first step, and some pathways interconvert phosphorylated forms, such as Man (mannose)-6-P→Man-1-P. Also, several alternative routes generate uridine diphosphate (UDP)GlcNAc, UDP-galactose (Gal), and guanosine diphosphate (GDP)-fucose (Fuc). For some types of glycosylation, the nucleotide sugar donates the sugar to a lipid-soluble carrier derived from the polyprenol dolichol phosphate (P-Dol) [Schenk et al., 2001]. These products include Man-P-Dol and Glc-P-Dol. Biosynthesis of the lipid precursor oligosaccharide involves a series of steps and enzymes that add sugars in specific linkages and in a specific order [Freeze, 2001a]. It begins with P-Dol + UDP-GlcNAc forming GlcNAc-P-PDol on the cytosolic face of the endoplasmic reticulum. Another UDP-GlcNAc donates a second GlcNAc using a different GlcNAc transferase, and this is followed by the addition of five Man units derived from GDP-Man. At this point, a “flippase” reorients the entire molecule from the

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FIGURE 26-1. Early steps in N-linked glycan synthesis: The biosynthesis and assembly of the lipid-linked oligosaccharide precursor (LLO), its transfer to Asn-X-Thr/Ser sequences in the endoplasmic reticulum (ER) lumen, and its early remodeling in the ER. The first steps involve the activation and interconversion of monosaccharides (sugars) to their donors, the nucleotide sugars or phosphoryldolichols, as shown symbolically in the upper left corner of the figure. Three types of congenital disorders of glycosylation (CDGs) result from defects (indicated by a circled “X”) in some of these steps. (The horizontal U in the lower half of the figure represents the ER membrane; a key to symbols is presented in the upper right.) Dolichol phosphate (extreme left of center) serves as the lipid carrier for the sugar chain, which is synthesized in a series of precisely ordered steps that involve addition of N-acetylglucosamine, mannose, and glucose. Nine CDG defects are caused by mutations in genes serving this portion of the pathway. Following transfer to proteins, oligosaccharide processing begins by removing all three glucose units and a mannose unit (bottom left). CMP, cytidine monophosphate; CTP, cytidine triphosphate; GDP, guanosine diphosphate; UDP, uridine diphosphate.

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cytosolic face into the endoplasmic reticulum lumen. A series of Man transferases use Man-P-Dol to add four more Man units, making a three-branched structure. Three glucosyltransferases sequentially add Glc from Glc-P-Dol to one branch to complete the sugar chain. This 14–sugar unit molecule is the optimal substrate for the 5-subunit oligosaccharyl transferase (OST) complex that recognizes the Asn-X-Thr/Ser consensus sequence on the protein and adds the sugar chain to Asn. Truncated glycans are poorly transferred and sometimes fail to occupy normal glycosylation sites. Following transfer, P-P-Dol is converted back to P-Dol and then to Dol. Recycling of the carriers is extensive. Within a few minutes of transfer to protein, the sugar chain is processed (Fig. 26-2; see also Fig. 26-1). A set of two glucosidases removes the Glc units. For some proteins, processing stops here, but for the great majority, a mannosidase in the endoplasmic reticulum removes a single Man unit. The proteins are carried to the Golgi, where another mannosidase called Golgi mannosidase I removes up to three more Man units. At this point, processing starts to add sugars. UDP-GlcNAc donates a GlcNAc to one branch, making the sugar chain an acceptable substrate for Golgi mannosidase II, which removes an additional two Man units. This process clears the way for the addition of a second GlcNAc to a Man on the remaining branch. Depending on the protein, up to three more GlcNAc transferases add GlcNAc units to the Man residues in a specific order to create up to five branches. These branches are then extended with Gal derived from UDP-Gal and sialic acid (Sia) derived from cytidine monophosphate (CMP)-Sia. In some cases, GDP-Fuc donates a Fuc to one or more of the branches or to the GlcNAc linked to the protein. In other cases, sulfates or phosphates or glucuronic acids are added to selected sugars. Individual branches may accumulate several repeating units of Gal-GlcNAc before being capped by Sia. These reactions occur in specific cisternae of the Golgi, and each nucleotide sugar donor must be translocated from its origin in the cytoplasm to the Golgi by a specific transporter [Gerardy-Schahn et al., 2001].

Enzymes and Cell Biology The sugar-activating enzymes reside in either the cytoplasm or the nucleus. The N-linked biosynthetic enzymes all are in the endoplasmic reticulum or Golgi, with their active sites situated in the expected orientation. Most of the glycosyltransferases used for building the lipid-linked oligosaccharide and the Golgi transporters span the membrane many times [Ishida and Kawakita, 2004]. Most enzymes participating in oligosaccharide processing are attached to the membrane by a single membrane span. The transferases and nucleotide sugar transporters are constantly recycled in the dynamic Golgi to maintain their correct relationship to the maturing glycoproteins as they pass through the Golgi. Therefore, correct trafficking of the biosynthetic machinery is essential for optimal function.

CONGENITAL DISORDERS OF GLYCOSYLATION Glycosylation is complex, and its disorders do not always lend themselves to phenotypic or symptomatic pigeon-

647

holing. Congenital disorders of glycosylation nomenclature is still evolving as attempts are made to design a systematic, clinically useful system based on biochemical origins. Congenital disorders of glycosylation resulting from defects in lipid-linked oligosaccharide biosynthesis and transfer to protein are defined as group I. The remaining congenital disorders of glycosylation that affect the biosynthesis and processing of the protein-bound sugar chains constitute group II. Nomenclature of group II is likely to be refined in the light of improved understanding. Individual disorders in group I or II are assigned lowercase letters (designating types, as noted earlier) when the genetic defect is proved. A set of outstanding reviews provide comprehensive and upto-date perspectives [Jaeken, 2003; Jaeken and Carchon, 2004; Jaeken and Matthijs, 2001; Marquardt and Denecke, 2003].

Diagnosis In most patients with congenital disorders of glycosylation the diagnosis is straightforward and is based on the analysis of serum transferrin isoforms. Several methods are suitable and commercially available. These include isoelectric focusing [Freeze, 2001a; Jaeken and Matthijs, 2001], mass spectrometry [Kleinert et al., 2003; Lacey et al., 2001], zone electrophoresis [Carchon et al., 2004], and high-pressure liquid chromatography [Helander et al., 2004]. Electrospray ionization–mass spectrometry is the most informative because it easily distinguishes the absence of entire sugar chains, which characterizes group I congenital disorders of glycosylation, from the absence of one or more individual monosaccharide units typical of group II congenital disorders of glycosylation. The predominant isoform in normal transferrin has two sugar chains, each containing two negatively charged Sia molecules, designated tetrasialotransferrin. In group I disorders, isoelectric focusing analysis demonstrates loss of one or both entire glycan chains, producing “disialotransferrin” or “asialotransferrin,” respectively, but clearly this is an incomplete description. By contrast, electrospray ionization–mass spectrometry demonstrates that the loss of one or two chains reduces the mass by about 2200 or 4400 mass units, respectively. In group II disorders, isoelectric focusing may distinguish among “tri-,” “di-,” “mono-,” and “asialo-” forms reflecting variable loss of Sia, whereas electrospray ionization–mass spectrometry can indicate specific loss of Sia alone or combinations of Sia with additional sugars. This distinction is essential for determining assignment to group I or group II and provides a signpost for specific identification of the defect. The singlestep electrospray ionization–mass spectrometry technique can be accomplished using less than 5 μL of blood in less than 30 minutes [Lacey et al., 2001]. This technique is therefore suitable for large-scale population screening for congenital disorders of glycosylation. Transferrin isoform analysis produces few false-positive results. Uncontrolled fructose and galactose intolerance and recent heavy alcohol consumption produce a pattern typical of group I disorders [Kleinert et al., 2003]. In apparently rare instances, patients with genetically confirmed congenital disorders of glycosylation exhibited normal transferrin isoelectric focusing profiles, and in some patients, previously abnormal patterns normalized in preadolescence

UDP-

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FIGURE 26-2. Processing of N-linked glycans in the Golgi membrane. Mannose trimming of the protein-bound sugar chains may stop or continue on, as shown at extreme left. Addition of a single Nacetylglucosamine or continued mannose trimming next leads to the buildup of sugar chains with two to five branches containing N-acetylglucosamine, galactose, and sialic acid. Fucose may be added to some chains, and sulfate may be attached to several other sugars using specific transferases. All of these reactions require delivery of the nucleotide sugar into the Golgi by specific transporters. Congenital disorder of glycosylation (CDG) defects (indicated by a circled “X”) occur in one of the trimming glycosidases, in a glycosyltransferase, and in two transporters. CMP, cytidine monophosphate; GDP, guanosine diphosphate; PAPS, 3′-phosphoadenosine–5′-phosphosulfate; UDP, uridine diphosphate.

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Mannose

N-acetylglucosamine

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648 Genetic, Metabolic, and Neurocutaneous Disorders / 26

Freeze and Patterson / Disorders of Glycosylation

[Dupre et al., 2001; Fletcher et al., 2000]. Thus, a normal transferrin pattern should not exclude follow-up testing. Healthy neonates sometimes have a slightly abnormal transferrin pattern, which normalizes within a few weeks. Suspicious results in neonates should be repeated. Specific diagnosis of the defect usually involves enzymatic, biochemical, and genetic analysis of the patient’s fibroblasts or leukocytes. Relatively few laboratories perform these analyses. Prenatal testing for the most common types of congenital disorders of glycosylation is available only for confirmed at-risk families [Matthijs et al., 1998, 2004]. Transferrin analysis of fetal material is not useful and produces false-negative results [Clayton et al., 1993].

649

Table 26-1 summarizes the known congenital disorders of glycosylation defects, including the mutated genes and major signs and symptoms. The known defects cover every aspect of the N-linked biosynthetic pathway. Activation or presentation of precursors (CDG-Ia, -Ib, -Ie, -If), glycosyltransferases for lipid-linked oligosaccharide biosynthesis (CDG-Ic, -Id, -Ig, -Ih, -Ii, -Ij, -Ik, -Il), glycosidases that trim the protein-bound sugar chain (CDG-IIb), Golgi-localized nucleotide sugar transporters (CDG-IIc and -IIf), and glycosyltransferases that extend the trimmed chain (CDG-IIa and -IId). One defect (CDG-IIe) alters the normal intracellular trafficking of multiple glycosyltransferases and nucleotide sugar transporters and secondarily impairs multiple pathways.

dysmorphism, abnormal fat distribution (supragluteal and vulval fat pads, focal lipoatrophy), inverted nipples, cryptorchidism, esotropia, recurrent infections, cardiomyopathy or pericardial effusions, coagulopathies, nephrotic syndrome, hypothyroidism, life-threatening episodes of hepatic failure, and unexplained coma. As many as 20% of infants with CDG-Ia succumb in this phase [Jaeken and Matthijs, 2001]. In the second phase (comprising the remainder of the first decade), children experience seizures and strokelike episodes, often precipitated by intercurrent infections. The third phase (in the second decade of life) is marked by slowly progressive cerebellar ataxia and limb wasting and by progressive visual loss secondary to pigmentary retinopathy. Adult survivors have moderate mental retardation with severe ataxia and hypogonadism, with or without skeletal deformities. Presentations are highly variable. In one girl with CDG-Ia, findings on computed tomography (CT) of the head were normal at 9 months, but subsequent imaging studies demonstrated progressive atrophy [Mader et al., 2002]. The investigators concluded that the cerebellar hypoplasia reported in infancy in most children with CDGIa likely reflects atrophy of antenatal onset, rather than hypoplasia. More extensive testing for congenital disorders of glycosylation has led to the identification of milder CDG-Ia phenotypes [Briones et al., 2002; de Lonlay et al., 2001; Grünewald et al., 2001]. The patients often have high residual levels of PMM2 activity [Drouin-Garraud et al., 2001; Grünewald et al., 2001; Westphal et al., 2001b]. Some patients have only borderline cognitive impairment, but strabismus persists in these very mild cases. Few adult CDG-Ia patients are employed. The carrier frequency of the most common mutant allele is about 1 in 70 in the northern European population [Schollen et al., 2000]. It is believed to be lethal in the homozygous state. Genotype-phenotype correlations have not been informative, but some evidence suggests that frequent polymorphisms in other glycosylation-related genes may influence the severity of the phenotype. No effective specific therapy for CDG-Ia exists. Experiments using CDG-Ia cells suggested that increasing dietary mannose might improve glycosylation in patients, but clinical trials demonstrated no benefit [Kjaergaard et al., 1998; Marquardt et al., 1997; Mayatepek et al., 1997]. Population studies find the risk of having a second child with CDG-Ia to be close to 1 in 3, rather than the expected mendelian ratio of 1 in 4, suggesting that reduced glycosylation may have some selective advantage [Schollen et al., 2004b]. At-risk couples should be counseled appropriately.

CDG-Ia

CDG-Ib

CDG-Ia is the best-known and most frequently recognized form of congenital disorders of glycosylation, first reported by Jaeken and co-workers in 1980 [Jaeken et al., 1980]. The defective gene was identified in 1995 as PMM2, which encodes phosphomannomutase (PMM) that converts Man-6-P → Man1-P. This defect results in insufficient production of lipid-linked oligosaccharide, leading to empty glycosylation sites. More than 400 patients are known worldwide, and greater than 60 mutations have been cataloged [Jaeken, 2003; Matthijs et al., 2000]. Hagberg and associates described four stages of the typical (severe) phenotype [Hagberg et al., 1993]. The first is the infantile phase, marked by various combinations of

CDG-Ib is caused by mutations in MPI, the gene encoding phosphomannose isomerase, which interconverts Man6-P and Fructose (Frc)-6-P. This reaction produces most of the mannose for glycoprotein synthesis [de Koning et al., 1998; Niehues et al., 1998]. Approximately 30 patients have been identified since its discovery in 1998. This phenotype is not associated with any primary neurologic symptoms. Gastrointestinal and hepatic pathology, with hypoglycemia, coagulopathy, and protein-losing enteropathy, are characteristic. CDG-Ib is unique in that simple dietary mannose therapy corrects the abnormalities, except for liver fibrosis [Durand

General Clinical Features Patients with congenital disorders of glycosylation have protean presentations mimicking mitochondrial (oxidative phosphorylation) disorders [Briones et al., 2001] but lack a history of maternal inheritance. An informal survey of congenital disorders of glycosylation-affected families indicated that earlier nonspecific diagnoses frequently included a metabolic defect or cerebral palsy. Most patients first present to pediatric neurology or metabolic clinics. They frequently have combinations of liver, gastrointestinal, and coagulation disturbances [Jaeken and Matthijs, 2001; Marquardt and Denecke, 2003]. The possibility of a congenital disorder of glycosylation should be investigated for any child presenting with developmental delay, seizures, or strabismus, particularly if any of these is accompanied by abnormal coagulation, liver dysfunction, or a gastrointestinal disorder. Most affected children are hypotonic and demonstrate failure to thrive.

Specific Disorders

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Genetic, Metabolic, and Neurocutaneous Disorders / 26

TABLE 26-1 Inherited Glycosylation Disorders DISORDER

GENE

ENZYME

OMIM No. KEY FEATURES

CDG-Ia

PMM2

Phosphomannomutase II

212065

CDG-Ib

MPI

Phosphomannose isomerase

602579

CDG-Ic

ALG6

603147

CDG-Id

ALG3

CDG-Ie

DPM1

CDG-If

MPDU1

Glucosyltransferase IGlc-P-Dol: Man9GlcNAc2-P-P-Dol glucosyltransferase Man-P-Dol:Man5GlcNAc2-P-P-Dol mannosyltransferase Man-P-Dol synthase I GDP-Man: Dol-P-mannosyltransferase MPDU1/Lec35

CDG-Ig

ALG12

Man-P-Dol:Man7GlcNAc2P-P-Dol mannosyltransferase

607143

CDG-Ih

ALG8

608104

CDG-Ii

ALG2

CDG-Ij

DPAGT1

CDG-Ik

ALG1

Glucosyltransferase II Glc-P-Dol:Glc1 Man9GlcNAc2-P-P-Dol glucosyltransferase Mannosyltransferase II GDP-Man: Man1GlcNAc2-P-P-Dol mannosyltransferase UDP-GlcNAc:dolichol phosphate N-acetylglucosamine 1-phosphate transferase Mannosyltransferase I GDP-Man: GlcNAc2-P-P-Dol mannosyltransferase

CDG-IL

ALG9

CDG-IIa CDG-IIb

MGAT2 GLS1

CDG-IIc

601110 603503 608799

607906 608093 608540

Mannosyltransferase Man-P-Dol:Man6 and Man8GlcNAc2-P-P-Dol mannosyltransferase GlcNAc-transferase 2 (GnT II) Glucosidase I

608776 212066 606056

GDP-fucose transporter

266265

CDG-IId

SLC35C1/ FUCT1 B4GALT1

β-1,4,-Galactosyltransferase

607091

CDG-IIe

COG7

Conserved oligomeric Golgi complex subunit 7

608779

CDG-IIf

SLC35A1

CMP-sialic acid transporter

—

Mucolipidoses II and III

GNPTA

UDP-GlcNAc: lysosomal enzyme, GlcNAc-1 phosphotransferase

252500

Walker-Warburg syndrome

POMT1

O-mannosyltransferase 1

236670

Muscle-eye-brain disease

POMTGNT1 O-mannosyl-β-1,2-N-acetylglucosaminyltransferase 1

253280

Fukuyama’s muscular dystrophy Ehlers-Danlos syndrome Hereditary multiple exostosis Chondrodysplasias

FCMD

Fukutin, a putative glycosyltransferase

253800

B4GALT7

β-1,4-Galactosyltransferase

130070

EXT1/EXT2

Glucuronyltransferase/ N-acetylglucosaminyltransferase

133700

DTDST/ SLC26A2

Sulfate anion transporter

222600 600972 256050

Mental retardation (MR), hypotonia, esotropia, lipodystrophy, cerebellar hypoplasia, strokelike episodes, seizures Hepatic fibrosis, protein-losing enteropathy, coagulopathy, hypoglycemia Moderate MR, hypotonia, esotropia, epilepsy Profound psychomotor delay, optic atrophy, acquired microcephaly, iris colobomas; hypsarrhythmia Severe MR, epilepsy, hypotonia, mild dysmorphism, coagulopathy Short stature, ichthyosis, psychomotor retardation, pigmentary retinopathy Hypotonia, facial dysmorphism, psychomotor retardation, acquired microcephaly Frequent infections Hepatomegaly, protein-losing enteropathy, renal failure, hypoalbuminemia, edema, ascites Normal at birth; mental retardation, hypomyelination, intractable seizures, iris colobomas, hepatomegaly, coagulopathy Severe MR, hypotonia, seizures, microcephaly, exotropia Severe psychomotor retardation, hypotonia, acquired microcephaly, intractable seizures, fever, coagulopathy, nephrotic syndrome, early death Severe microcephaly, hypotonia, seizures, hepatomegaly MR, dysmorphism, stereotypies, seizures Dysmorphism, hypotonia, seizures, hepatomegaly, hepatic fiborsis (death at 2.5 months) Recurrent infections, persistent neutrophilia, MR, microcephaly, hypotonia (normal Tf) Hypotonia (myopathy), spontaneous hemorrhage, Dandy-Walker malformation Fatal in early infancy; dysmorphism, hypotonia, intractable seizures, hepatomegaly, progressive jaundice, recurrent infections, cardiac failure Thrombocytopenia, no neurologic symptoms, normal Tf, abnormal platelet glycoproteins Coarsening, organomegaly, joint stiffness, dysostosis, median neuropathy at wrist; type III less severe than type II, which manifests in infancy Type II lissencephaly, cerebellar malformations, ventriculomegaly, anterior chamber malformations, severe delay; death in infancy Type II lissencephaly, progressive myopia, developmental delay, weakness, hypotonia; resembles but is less severe than Walker-Warburg syndrome Cortical dysgenesis, myopia, weakness and hypotonia; 40% have seizures Progeroid Ehlers-Danlos syndrome; macrocephaly, joint hyperextensibility Multiple exostoses (diaphyseal, juxtaepiphyseal) Diastrophic dysplasia: scoliosis, talipes equinovarus, “hitchhiker thumb,” malformed ears; airway collapse and early death in severe cases; adult survival reported Achondrogenesis Ib: short-limbed dwarfism, thin ribs with fractures and respiratory failure; usually stillborn or die in early infancy Atelosteogenesis II: severe skeletal malformations with small chest and pulmonary hypoplasia; typically fatal in infancy

CMP, cytidine monophosphate; GDP, guanosine diphosphate; GlcNAc, N-acetylglucosamine; Man, mannose; OMIM, Online Mendelian Inheritance in Man; P-Dol, dolichol phosphate; Tf, transferrin; UDP, uridine diphosphate.

Freeze and Patterson / Disorders of Glycosylation

et al., 2003; Niehues et al., 1998]. The dietary mannose is taken up through transporters and converted to Man-6-P, thereby bypassing the metabolic block. Mannose has no known side effects at the concentrations used. Nonenzymatic protein glycation occurs at high concentrations of mannose, which is considerably more reactive than glucose, and can raise hemoglobin A1c (HbA1c) levels [Harms et al., 2002]. Some patients have received such treatment for longer than 8 years without complications. Twenty percent of the patients who were subsequently confirmed to have phosphomannose isomerase deficiency, however, died before discovery of the disorder [Freeze, 2001a]. The potentially fatal outcome and availability of simple, effective treatment mandate investigation for congenital disorders of glycosylation in suspected cases. No adult patient with CDG-Ib currently requires mannose therapy, suggesting that it may not be required throughout life [Westphal et al., 2001a].

CDG-Ic CDG-Ic resembles but is less severe than CDG-Ia. It is characterized by moderate psychomotor retardation, hypotonia, esotropia, seizures, and ataxia. Nevertheless, at least five children have died of congenital disorders of glycosylationrelated complications [Marquardt and Denecke, 2003; Newell et al., 2003; Westphal et al., 2000]. The defect is in a glycosyltransferase, hALG6, that results in production of a truncated lipid-linked oligosaccharide sugar chain, which is inefficiently transferred to proteins. Patients sometimes experience life-threatening protein-losing enteropathy during bouts of gastroenteritis [Westphal et al., 2000]. This disorder was first identified in 1998 and subsequently has been diagnosed in 50 patients [Burda et al., 1998; Grunewald et al., 2000; Imbach et al., 2000a], making it the second most common form of congenital disorders of glycosylation.

CDG-Id, -Ie, and -If CDG-Id, -Ie, and -If all produce severe phenotypes. The defects all lead to impaired lipid-linked oligosaccharide synthesis beyond Man5GlcNAc2. CDG-Id. Patients with CDG-Id have mutations in ALG3, which encodes the mannosyltransferase used to synthesize Man6GlcNAc2 [Körner et al., 1999]. One patient has been described with microcephaly, optic nerve atrophy, iris colobomas, epilepsy, spastic quadriparesis, and profound psychomotor delay. Another patient had similar features plus Dandy-Walker malformation: agenesis of the cerebellar vermis and corpus callosum. She also had recurrent hypoglycemia, thrombocytopenia, hypoalbuminemia, and coagulopathy. CDG-Ie. CDG-Ie is responsible for another severe phenotype, characterized by psychomotor delay, profound hypotonia, microcephaly, cortical blindness, and intractable seizures [Imbach et al., 2000b; Kim et al., 2000]. Laboratory testing revealed elevated creatine kinase and depressed antithrombin III. Some children have dysmorphic features, including downslanting palpebral fissures, flat occiput and nasal bridge, hemangiomas of the occiput and sacrum, a high narrow palate, and mild limb shortening. Dolichol phosphate mannose synthase (DPM1) activity is markedly diminished in all reported cases. CDG-If. Three children with CDG-If have been described. Abnormalities included severe psychomotor retardation and variable features, including growth retard-

651

ation, optic nerve atrophy, icthyosis, dysmorphism (parietal bossing, thin lips), hypo- or hypertonia, enlarged subarachnoid spaces, thrombocytopenia, transient deficiency of growth hormone and insulin-like growth factor 1, and mild elevations of creatine kinase [Kranz et al., 2001]. All have mutations in MPUD1/Lec35, leading to deficient function of the Lec35 protein. Lec35 may act as a chaperone for P-Dol in the endoplasmic reticulum membrane, ensuring appropriate lateral spacing of Man-P-Dol and Glc-P-Dol. In the absence of such spacing, these compounds may form rafts that alter local concentration gradients, impairing synthesis of the lipid-linked oligosaccharide and its accessibility to the oligosaccharyltransferase complex.

CDG-Ig Five cases of CDG-Ig have been reported [Chantret et al., 2002; Grubenmann et al., 2002; Thiel et al., 2002]. The patients had typical congenital disorders of glycosylation abnormalities including hypotonia, generalized developmental delay, cerebellar hypoplasia, and decreased coagulation factors. Dysmorphic features included a long thin face, flat nasal bridge, and epicanthal folds. Frequent infections probably reflect reduced immunoglobulin G (IgG) concentrations. All three affected males had micropenis, a feature not reported in other types of congenital disorders of glycosylation. These patients have mutations in hALG12, which encodes dolichol-P-mannose: Man7GlcNAc2-PPdolichyl mannosyltransferase. Patients accumulate the truncated lipid-linked oligosaccharide, which is inefficiently transferred to proteins.

CDG-Ih Five patients have been described with CDG-Ih, caused by a deficiency in hALG8, the gene encoding the second glucosyltransferase in lipid-linked oligosaccharide synthesis [Chantret et al., 2003; Schollen et al., 2004a]. One patient had a mild clinical presentation, whereas the others all had severe multiorgan failure. Most died within a few months, but one patient survived a year before succumbing to renal failure with severe developmental delay. The others experienced hepatointestinal symptoms without neurologic complications.

CDG-Ii The only child with CDG-Ii recognized to date was normal at birth except for an iris coloboma. Seizures, hepatomegaly, and coagulation abnormalities emerged in the first year. Imaging studies revealed cerebral hypomyelination. Pathologic mutations were found in hALG2, the enzyme that adds the second mannose to the growing lipid-linked oligosaccharide sugar chain [Thiel et al., 2003].

CDG-Ij CDG-Ij is caused by a deficiency in UDP-GlcNAc: dolichol phosphate N-acetylglucosamine-1 phosphate transferase (GPT) activity encoded by DPAGT1. Two patients had severe hypotonia, intractable seizures, mental retardation, microcephaly, and exotropia [Wu et al., 2003].

CDG-Ik Four children with CDG-Ik have been described [Kranz et al., 2004; Schwarz et al., 2004]. Two had recurrent

652

Genetic, Metabolic, and Neurocutaneous Disorders / 26

intractable seizures, microcephaly, cerebral atrophy, and severe coagulation abnormalities. Progressive stupor led to death at 3 and 10 months in two children. The third patient had a similar presentation, but with normal findings on magnetic resonance imaging (MRI) of the brain. Ultrasound analysis of the fourth patient at 30 weeks of gestation found fetal hydrops and hepatosplenomegaly. Pregnancy was interrupted at week 35 because of bradycardia. The severely hydropic boy had normal cerebral structures, a large fontanel, hypertelorism, micrognathia, hypogonadism, contractures, areflexia, cardiomyopathy, and multifocal epileptic activity. He died 2 weeks later. Patients with CDG-Ik are deficient in GDP-Man:GlcNAc2-P-P-dolichol mannosyltransferase, encoded by the hALG1 gene, which adds the first Man to the lipid-linked oligosaccharide chain.

mental retardation, rhizomelic short stature, a broad flat nasal bridge, microcephaly, elevated leukocytes, frequent infections, persistent marked neutrophilia, and periodontitis. The disorder is caused by the mutations in the GDP-fucose transporter, which limits the synthesis of fucosylated glycans [Lübke et al., 2001; Lühn et al., 2001]. One of these is sialyl Lewis-X (sLeX), a glycan essential for leukocyte rolling before extravasation. Oral fucose supplements effectively reduced leukocytosis in two patients by allowing synthesis of sufficient sLeX [Hidalgo et al., 2003; Marquardt et al., 1999]. These patients also lack fucosylated H-antigen, the precursor for the ABO blood group. Fucose supplements have not provoked antigen synthesis or immunologic reactions. Transferrin glycosylation is normal in this type.

CDG-IL One patient with CDG-IL has been described. Abnormalities included severe microcephaly, central hypotonia, seizures, developmental delay, hepatomegaly, and bronchial asthma. This patient was found to carry a homozygous point mutation in human hALG9, whose product catalyzes the addition of both the seventh and ninth mannose units to the lipid-linked oligosaccharide chain [Frank et al., 2004].

A single patient with CDG-IId has been described. Abnormalities included psychomotor retardation, a DandyWalker malformation, progressive hydrocephalus, hypotonia, and myopathy [Hansske et al., 2002]. CDG-IId was caused by mutations in B4GALT1, encoding one of the isozymes that add β-1,4-galactose units to N-linked glycans during processing. The other isozymes do not compensate for this transferase deficiency.

CDG-IIa

CDG-IIe

Three children with CDG-IIa have been described [Cormier-Daire et al., 2000; Jaeken et al., 1994; Tan et al., 1996]. They were of Belgian, Iranian, and French descent, respectively, and all had severe psychomotor delay, acquired microcephaly and growth retardation, and variable combinations of hypotonia, ventricular septal defects, craniofacial dysmorphism (thin lips, hooked nose, large ears, hypertrophied gums, short neck), stereotypies, and coagulation defects. All were found to have impaired activity of the processing enzyme N-acetylglucosaminyltransferase II (MGAT2), which decreases the formation of multibranched N-linked glycans. A targeted disruption of this gene in the mouse faithfully recapitulates the human disorder [Wang et al., 2001].

Two siblings with CDG-IIe have been described. Abnormalities included perinatal asphyxia and dysmorphic features including low-set dysplastic ears, micrognathia, short neck, and loose wrinkled skin [Wu et al., 2004]. They had generalized hypotonia, hepatosplenomegaly, and progressive jaundice that appeared shortly after birth. A CT scan revealed an enlarged cisterna cerebelli superior in one patient; severe epilepsy developed in both. They both died by 10 weeks from recurrent infections and cardiac insufficiency. This type is unique because it is caused by a mutation in COG7, which encodes one of the eight subunits of the COG complex [Oka et al., 2004; Ungar et al., 2002]. This cytoplasmic complex associates with the cytoplasmic face of the Golgi and is involved in the shuttling of glycosyltransferases and nucleotide sugar transporters between the Golgi and other intracellular compartments. The mutation destabilizes the complex and slows the trafficking of these molecules, presumably leading to their degradation or mislocalization.

CDG-IIb Only one patient with CDG-IIb has been described [De Praeter et al., 2000]. Her parents were consanguineous. She had dysmorphic features, hypotonia, reduced nerve conduction velocity, seizures, and hepatomegaly with abnormal bile duct proliferation and fibrosis. The patient died at 2.5 months. This disorder was caused by mutations in α-glucosidase I, which trims the outermost glucose from oligosaccharides just after their transfer to nascent proteins. Although activity of the enzyme was severely decreased in this patient’s fibroblasts, transferrin glycosylation remained normal. This patient would be missed by the standard diagnostic assays. An endo-α-mannosidase apparently bypasses the glucosidase defect to permit normal oligosaccharide processing. Abnormal accumulation of fully glycosylated sugar chains may overwhelm the capacity of endoplasmic reticulum chaperone lectins.

CDG-IIc CDG-IIc originally was described as leukocyte adhesion deficiency II and is characterized by moderate to severe

CDG-IId

CDG-IIf The sole reported patient with CDG-IIf had severe thrombocytopenia and complete loss of the sialyl-Lewis-X antigen on leukocytes [Willig et al., 2001]. This disorder was associated with mutations in the gene encoding the Golgi cytidine monophosphate (CMP)-sialic acid transporter [Martinez-Duncker et al., 2004]. Although platelet membrane proteins exhibited altered glycosylation, transferrin and other serum glycoproteins were normal. This finding underscores the limitations of transferrin analysis.

When to Suspect and Test for Congenital Disorders of Glycosylation A congenital disorder of glycosylation should be suspected in any child presenting with an unexplained syndrome, particularly those characterized by developmental delay, hypo-

Freeze and Patterson / Disorders of Glycosylation

tonia, and seizures, especially in combination with abnormal liver or coagulation features. Testing for an abnormal transferrin should be considered. Patients with congenital disorders of glycosylation may have phenotypes resembling mitochondrial disorders, Joubert’s syndrome, or Dandy-Walker malformation. Using these broad criteria for testing, an informal survey suggests that abnormal transferrins are seen at a frequency of about 1 in 200 tests. Assays of phosphomannomutase and phosphomannose isomerase activity are readily available in most Western countries. In patients with a type I transferrin pattern, phosphomannomutase and phosphomannose isomerase activity should be assayed first. If results of these assays are negative, and genotyping either is not indicated or reveals no abnormality, direct collaboration with a research glycobiologist is necessary to identify the precise biochemical and genetic defect.

muscular dystrophy likely will be found to result from as yet unrecognized defects in this glycosylation pathway (Fig. 26-3).

Biosynthesis of O-Mannose Glycans POMT1 (protein-O-mannosyltransferase 1), and POMT2 (protein-O-mannosyltransferase 2), form a complex and use Man-P-Dol to form the Man-O-Ser/Thr linkage, presumably in the endoplasmic reticulum lumen. This linkage is extended by addition of β-1,2-GlcNAc through a pathwayspecific GlcNAc transferase (POMGnT1). Both POMT1/2 and POMGnT1 have proven enzymatic activities [Endo, 2004]. In α-dystroglycan, this disaccharide usually is extended with β-1,4-Gal and α-2,3-Sia, but the specific enzymes responsible have not yet been identified. More complex branched glycans with glucuronic acid (GlcA) or sulfate can be found in the brain, suggesting that this pathway is much more complex [Yuen et al., 1997]. Neither the protein that carries these glycans nor the function of these chains is known, however. About a third of all O-linked chains in the brain are built on O-Man.

GLYCOSYLATION-BASED MUSCULAR DYSTROPHIES Overview The dystrophin glycoprotein complex assembles on the sarcolemma of skeletal muscle cells. Mutations that affect the integrity of this complex cause congenital muscular dystrophies by compromising the integrity of the basement membrane [Martin, 2003]. α-Dystroglycan is a major component of this complex and contains O-linked glycans (i.e., those with an O linkage between Ser/Thr and mannose residues). Mutations in genes encoding enzymes involved in O-linked glycosylation cause a group of rare congenital muscular dystrophies with an autosomal-recessive inheritance pattern and a variable degree of brain involvement [Martin and Freeze, 2003]. Additional types of congenital

Sugars

Functional Defects Defects in this pathway are shown in Table 26-1. Deficiencies in POMT1 impair the addition of the linkage Man unit to the protein, preventing further elongations at that site. POMT1 mutations account for about 30% of the diagnosed cases of Walker-Warburg syndrome [Beltran-Valero de Bernabe et al., 2002; Muntoni et al., 2004]. No diseasecausing defects are known in POMT2. Defects in POMGNT1 impair addition of GlcNAc to Man and cause muscle-eye-brain disease [Zhang et al., 2003].

Transporters

Neu5Ac

653

Golgi Membrane

UDP-GlcNAc

N-acetylglucosamine Mannose

UDP-Gal

Defect

Galactose CMP-Neu5Ac

Walker-Warburg Syndrome S/T

Muscle-Eye-Brain Disease

S/T

S/T

S/T

S/T

+UDP-

+UDP-

+CMP-

UDP-

UDP-

CMP-

FIGURE 26-3. O-mannose glycan biosynthesis. Biosynthesis of O-mannose–linked glycans on molecules such as α-dystroglycan begins with the addition of mannose from Man-P-Dol in the lumen of the endoplasmic reticulum (ER). Defects in its addition are responsible for some cases of Walker-Warburg syndrome. An N-acetylglucosamine is added to the O-linked mannose using a specific transferase and a transporter-delivered UDP donor. Mutations in this transferase cause muscle-eye-brain disease. Extension by glactose and sialic acid requires transporter-delivered donors, but the transferases have not been defined. CMP, cytidine monophosphate; S/T, serine/threonine; UDP, uridine diphosphate.

654

Genetic, Metabolic, and Neurocutaneous Disorders / 26

Other congenital muscular dystrophies also have been linked to glycosylation abnormalities, but the specific molecular mechanisms are not known. These proteins include fukutin, fukutin-related protein, and LARGE. Mutations in FCMD cause Fukuyama’s congenital muscular dystrophy, common in Japan. Mutations in the fukutin-related protein gene, FKRP, cause CMD1C and limb-girdle muscular dystrophy [Muntoni et al., 2004]. The LARGE gene causes a form of murine muscular dystrophy, and mutations in its human homolog were found in a patient with a congenital muscular dystrophy and mental retardation [Longman et al., 2003]. The clinical presentations of congenital muscular dystrophies reflect the manifestations associated with specific mutations and may overlap. Mutations in POMT1, FKRP, and FCMD all have been associated with a Walker-Warburg syndrome phenotype [Muntoni et al., 2004]. FCMD, FKRP, and LARGE all have two glycosyltransferase-like domains and characteristic catalytic residues, but transferase activity has not been demonstrated. Sequence homologies usually are insufficient to predict the specific transferase reactions, because sugar-specific signatures are few, and the acceptor substrate may require both peptide and glycan recognition. Overexpression of LARGE can functionally bypass multiple glycosylation defects in α-dystroglycan, offering a potentially broad therapeutic approach [Barresi et al., 2004].

Clinical Features The European Neuromuscular Center has proposed a set of diagnostic criteria for congenital muscular dystrophies. These include hypotonia beginning in the first 6 months, early multiple contractures, diffuse weakness and muscular atrophy with sparing of extraocular muscles, normal mental development (in many), variable course, early elevation of serum creatine kinase, myopathic changes on electromyography (EMG), and necrotic-regenerative changes on muscle biopsy [Dubowitz, 1997]. The three forms of congenital muscular dystrophy associated with impaired O-glycosylation have considerable phenotypic overlap, as mentioned earlier. Fukuyama’s congenital muscular dystrophy is characterized by cortical dysgenesis and simple myopia. Affected children have global developmental delay, with regression in motor skills in the latter half of the first decade and death in adolescence. Almost all of the patients with Fukuyama’s congenital muscular dystrophy have seizures. Fukuyama’s congenital muscular dystrophy is the most common form of congenital muscular dystrophy in Japan, in contrast with Western populations, in which merosin deficiency predominates. Muscle-eye-brain disease is characterized by more severe pathologic changes than in Fukuyama’s congenital muscular dystrophy, including cobblestone lissencephaly, midline defects, and brainstem flattening associated with progressive myopia, retinal degeneration, and cataracts. Walker-Warburg syndrome also features type II lissencephaly, in combination with ventriculomegaly, cerebellar malformations, retinal and anterior chamber malformations, and congenital cataracts. Walker-Warburg syndrome represents the most severe congenital muscular dystrophy phenotype, with congenital blindness, hypotonia, profound developmental delay, and failure to thrive. Most affected children die in the first 6 months.

Biochemical and Genetic Tests Several monoclonal antibodies recognize the O-Man chain on α-dystroglycan, and their binding is greatly reduced or eliminated in these disorders [Michele et al., 2002]. Antibody against the peptide portion binds normally, but the loss of the glycan chains reduces the apparent size of the protein. A specific enzymatic assay can be used to diagnose muscle-eye-brain disease [Zhang et al., 2003], and it is likely that an enzymatic assay for POMT1 will be developed. Although both the antibodies and enzymatic assays should be useful, they are not yet available outside of specialized research laboratories. Sequencing is needed to positively identify mutations in the disease-specific genes.

DEFECTS IN GLYCOSAMINOGLYCAN SYNTHESIS Glycosaminoglycans are very large glycan chains that usually are built on selected core proteins [Esko, 1999]. These molecules are located in the extracellular matrix, where they provide mechanical support and help to organize the matrix. At the cell surface, they bind growth factors and act as signaling molecules that enhance or inhibit cell proliferation. They are the most diverse and complex glycans. The protein-bound glycosaminoglycan molecules include heparan sulfate, chondroitin sulfate, dermatan sulfate, and keratan sulfate. All but the last are linked to protein through O-xylose, which is extended with two galactose units and a glucuronic acid. Each of these glycosaminoglycan chains is extended by one of several alternating disaccharides composed of GlcNAc(α1,4)GlcA(β1,4) (heparan sulfate) or GalNAc(β1,3)GlcA(β1,3) (chondroitin sulfate and dermatan sulfate) or GlcNAc(β1,3)Gal(β1,4) (keratan sulfate). All of these glycosaminoglycans are partially sulfated. Hyaluronon, GlcNAc(β1,4)GlcA(β1,3), is the only glycosaminoglycan that exists as a free glycan chain and is not sulfated. Three known defects in glycosaminoglycan synthesis cause clinical disorders, but none have neurologic manifestations. Mutations in the gene XGPT1 cause abnormal synthesis of dermatan sulfate and are associated with the progeroid variant of Ehlers-Danlos syndrome [Quentin et al., 1990]. This gene encodes an enzyme that adds the first galactose residue to xylose in the core of glycosaminoglycan chains. The patient exhibited multiple abnormalities in connective tissue, leading to short stature, diffuse osteopenia, loose but elastic skin, hypermobile joints, and hypotonia. Cognitive impairment has not been reported. The condition multiple hereditary exostoses is inherited as an autosomal-dominant trait and characteristically affects the metaphyses of long bones [Zak et al., 2002]. Patients with multiple hereditary exostoses have mutations in the genes EXT1 and EXT2, both of which encode co-polymerase components that participate in the assembly of alternating residues of GlcNAc and GluA that form the backbone of the heparan sulfate glycosaminoglycan chains. Because heparan sulfate binds to many types of growth factors, a partial decrease in heparan sulfate is thought to upset the delicate regulation of chondrocyte proliferation. This situation in turn leads to enhanced chondrocyte growth and the formation of exostoses.

Freeze and Patterson / Disorders of Glycosylation

Macular corneal dystrophy (types I and II) is caused by a deficiency in a specific sulfotransferase (CHST6) called corneal N-acetylglucosamine-6-sulfotransferase (GlcNAc6ST), which is responsible for the sulfation of corneal keratan sulfate [Akama et al., 2000]. The unsulfated keratan chains are poorly soluble, and their eventual precipitation disrupts the collagen network, leading to thinning and loss of transparency of the corneal stroma. This progressive disorder manifests between ages 5 and 9 with very small, punctate corneal opacities. Erosions, painful photophobia, and sensation of an ocular foreign body develop subsequently.

DEFECTS IN O-N-ACETYLGALACTOSAMINE BIOSYNTHESIS The mucinous type of molecule is located at the surface of epithelial cells or in their secretions and typically subserve barrier functions [Marth, 1999]. They usually are composed of large clusters of O-galactose N-acetylglucosamine (OGalNAc)–linked sugar chains, each containing 2 to 10 sugars. Only a few are known to serve specific functions—for example, in lymphocyte recirculation and leukocyte extravasation [Lowe, 2003]. Few biosynthetic defects are known, and none have obvious neurologic manifestations.

SUMMARY Glycosylated molecules are present on the surface and in the interior of all cells. The biosynthesis of sugar chains is complex, with the potential to produce thousands of different structures at different times in response to endogenous and exogenous signals. At least 2% of the known genes encode proteins that either synthesize or bind to sugar chains, often with exquisite specificity. Disrupting glycan biosynthesis leads to a multitude of downstream effects that may involve every aspect of central nervous system development and function. The analysis of transferrin glycosylation status can point to glycosylation abnormalities in many patients. A few patients respond to simple dietary supplements of sugars. Although congenital disorders of glycosylation phenotypes are rare, their true frequency is unknown, and congenital disorders of glycosylation probably remain undiagnosed in many patients with mild or atypical manifestations. It is likely that many additional types of congenital disorders of glycosylation will be identified in the near future. REFERENCES Abou-Khalil BW, Siegel GJ, Sackellares JC, et al. Positron emission tomography studies of cerebral glucose metabolism in chronic partial epilepsy. Ann Neurol 1987;22:480. Akama TO, Nishida K, Nakayama J, et al. Macular corneal dystrophy type I and type II are caused by distinct mutations in a new sulphotransferase gene. Nat Genet 2000;26:237. Barresi R, Michele DE, Kanagawa M, et al. LARGE can functionally bypass alpha-dystroglycan glycosylation defects in distinct congenital muscular dystrophies. Nat Med 2004;10:696. Beltran-Valero de Bernabe D, Currier S, Steinbrecher A, et al. Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet 2002;71:1033.

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Grünewald S, Schollen E, Van Schaftingen E, et al. High residual activity of PMM2 in patients’ fibroblasts: Possible pitfall in the diagnosis of CDG-Ia (phosphomannomutase deficiency). Am J Hum Genet 2001;68:347. Hagberg BA, Blennow G, Kristiansson B, et al. Carbohydrate-deficient glycoprotein syndromes: Peculiar group of new disorders. Pediatr Neurol 1993;9:255. Hansske B, Thiel C, Lubke T, et al. Deficiency of UDP-galactose: N-acetylglucosamine beta-1,4-galactosyltransferase I causes the congenital disorder of glycosylation type IId. J Clin Invest 2002;109:725. Harms HK, Zimmer KP, Kurnik K, et al. Oral mannose therapy persistently corrects the severe clinical symptoms and biochemical abnormalities of phosphomannose isomerase deficiency. Acta Paediatr 2002;91:1065. Helander A, Bergstrom J, Freeze HH. Testing for congenital disorders of glycosylation by HPLC measurement of serum transferrin glycoforms. Clin Chem 2004;50:954. Hidalgo A, Ma S, Peired AJ, et al. Insights into leukocyte adhesion deficiency type 2 from a novel mutation in the GDP-fucose transporter gene. Blood 2003;101:1705. Imbach T, Grünewald S, Schenk B, et al. Multi-allelic origin of congenital disorder of glycosylation (CDG)-Ic. Hum Genet 2000a;106:538. Imbach T, Schenk B, Schollen E, et al. Deficiency of dolichol-phosphate-mannose synthase-1 causes congenital disorder of glycosylation type Ie. J Clin Invest 2000b;105:233. Ishida N, Kawakita M. Molecular physiology and pathology of the nucleotide sugar transporter family (SLC35). Pflugers Arch 2004;447:768. Jaeken J. Komrower Lecture. Congenital disorders of glycosylation (CDG): It’s all in it! J Inherit Metab Dis 2003;26:99. Jaeken J, Carchon H. Congenital disorders of glycosylation: A booming chapter of pediatrics. Curr Opin Pediatr 2004;16:434. Jaeken J, Matthijs G. Congenital disorders of glycosylation. Annu Rev Genomics Hum Genet 2001;2:129. Jaeken J, Schachter H, Carchon H, et al. Carbohydrate deficient glycoprotein syndrome type II: A deficiency in Golgi localised N-acetyl-glucosaminyltransferase II. Arch Dis Child 1994;71:123. Jaeken J, Vanderschueren-Lodewyckx M, Caeaer P, et al. Familial psychomotor retardation with markedly fluctuating serum prolactin, FSH and GH levels, partial TBG deficiency, increased serum arysulphatase A and increased CSF protein: A new syndrome? Pediatr Res 1980;14:179. Kim S, Westphal V, Srikrishna G, et al. Dolichol phosphate mannose synthase (DPM1) mutations define congenital disorder of glycosylation Ie (CDG-Ie). J Clin Invest 2000;105:191. Kjaergaard S, Kristiansson B, Stibler H, et al. Failure of short-term mannose therapy of patients with carbohydrate-deficient glycoprotein syndrome type 1A. Acta Paediatr 1998;87:884. Kleinert P, Kuster T, Durka S, et al. Mass spectrometric analysis of human transferrin in different body fluids. Clin Chem Lab Med 2003;41:1580. Körner C, Knauer R, Stephani U, et al. Carbohydrate deficient glycoprotein syndrome type IV: Deficiency of dolichyl-PMan:Man5GlcNAc2-PP-dolichyl mannosyltransferase. EMBO J 1999;18:6816. Kranz C, Denecke J, Lehle L, et al. Congenital disorder of glycosylation type Ik (CDG-Ik): A defect of mannosyltransferase I. Am J Hum Genet 2004;74:545. Kranz C, Denecke J, Lehrman MA, et al. A mutation in the human MPDU1 gene causes congenital disorder of glycosylation type If (CDG-If). J Clin Invest 2001;108:1613. Lacey JM, Bergen HR, Magera MJ, et al. Rapid determination of transferrin isoforms by immunoaffinity liquid chromatography and electrospray mass spectrometry. Clin Chem 2001;47:513. Longman C, Brockington M, Torelli S, et al. Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of alpha-dystroglycan. Hum Mol Genet 2003;12:2853. Lowe JB. Glycan-dependent leukocyte adhesion and recruitment in inflammation. Curr Opin Cell Biol 2003;15:531. Lübke T, Marquardt T, Etzioni A, et al. Complementation cloning identifies CDG-IIc, a new type of congenital disorders of glycosylation, as a GDP-fucose transporter deficiency. Nat Genet 2001;28:73.

Lühn K, Wild MK, Eckhardt M, et al. The gene defective in leukocyte adhesion deficiency II encodes a putative GDP-fucose transporter. Nat Genet 2001;28:69. Mader I, Dobler-Neumann M, Kuker W, et al. Congenital disorder of glycosylation type Ia: Benign clinical course in a new genetic variant. Childs Nerv Syst 2002;18:77. Marquardt T, Denecke J. Congenital disorders of glycosylation: Review of their molecular bases, clinical presentations and specific therapies. Eur J Pediatr 2003;162:359. Marquardt T, Hasilik M, Niehues R, et al. Mannose therapy in carbohydrate-deficient glycoprotein syndrome type I—first results of the German Multicenter Study. Amino Acids 1997;12:389. Marquardt T, Luhn K, Srikrishna G, et al. Correction of leukocyte adhesion deficiency type II with oral fucose. Blood 1999;94:3976. Marth JD. O-glycans. In: Varki A, Cummings R, Esko JD, et al., eds. Essentials of glycobiology. New York: Spring Harbor Laboratory Press, 1999. Martin PT. Dystroglycan glycosylation and its role in matrix binding in skeletal muscle. Glycobiology 2003;13:55R. Martin PT, Freeze HH. Glycobiology of neuromuscular disorders. Glycobiology 2003;13:67R. Martinez-Duncker I, Dupre T, Piller V, et al. Genetic complementation reveals a novel human congenital disorder of glycosylation of type II, due to inactivation of the Golgi CMP-sialic acid transporter. Blood 2004e: Dec 2. Matthijs G, Schollen E, Bjursell C, et al. Mutations in PMM2 that cause congenital disorders of glycosylation, type Ia (CDG-Ia). Hum Mutat 2000;16:386. Matthijs G, Schollen E, Cassiman JJ, et al. Prenatal diagnosis in CDG1 families: Beware of heterogeneity. Eur J Hum Genet 1998;6:99. Matthijs G, Schollen E, Van Schaftingen E. The prenatal diagnosis of congenital disorders of glycosylation (CDG). Prenat Diagn 2004;24:114. Mayatepek E, Schröder M, Kohlmuller D, et al. Continuous mannose infusion in carbohydrate-deficient glycoprotein syndrome type I. Acta Paediatr 1997;86:1138. Michele DE, Barresi R, Kanagawa M, et al. Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies. Nature 2002;418:417. Muntoni F, Brockington M, Torelli S, et al. Defective glycosylation in congenital muscular dystrophies. Curr Opin Neurol 2004;17:205. Newell JW, Seo NS, Enns GM, et al. Congenital disorder of glycosylation Ic in patients of Indian origin. Mol Genet Metab 2003;79:221. Niehues R, Hasilik M, Alton G, et al. Carbohydrate-deficient glycoprotein syndrome type Ib. Phosphomannose isomerase deficiency and mannose therapy. J Clin Invest 1998;101:1414. Oka T, Ungar D, Hughson FM, et al. The COG and COPI complexes interact to control the abundance of GEARs, a subset of Golgi integral membrane proteins. Mol Biol Cell 2004;15:2423. Parodi AJ. Protein glucosylation and its role in protein folding. Annu Rev Biochem 2000;69:69. Quentin E, Gladen A, Roden L, et al. A genetic defect in the biosynthesis of dermatan sulfate proteoglycan: Galactosyltransferase I deficiency in fibroblasts from a patient with a progeroid syndrome. Proc Natl Acad Sci U S A 1990;87:1342. Schenk B, Fernandez F, Waechter CJ. The ins(ide) and outs(ide) of dolichyl phosphate biosynthesis and recycling in the endoplasmic reticulum. Glycobiology 2001;11:61R. Schollen E, Frank CG, Keldermans L, et al. Clinical and molecular features of three patients with congenital disorders of glycosylation type Ih (CDG-Ih) (ALG8 deficiency). J Med Genet 2004a;41:550. Schollen E, Kjaergaard S, Legius E, et al. Lack of Hardy-Weinberg equilibrium for the most prevalent PMM2 mutation in CDG-Ia (congenital disorders of glycosylation type Ia). Eur J Hum Genet 2000;8:367. Schollen E, Kjaergaard S, Martinsson T, et al. Increased recurrence risk in congenital disorders of glycosylation type Ia (CDG-Ia) due to a transmission ratio distortion. J Med Genet 2004b;41:877. Schwarz M, Thiel C, Lubbehusen J, et al. Deficiency of GDPMan:GlcNAc2-PP-dolichol mannosyltransferase causes congenital disorder of glycosylation type Ik. Am J Hum Genet 2004;74:472. Tan J, Dunn J, Jaeken J, et al. Mutations in the MGAT2 gene controlling complex N-glycan synthesis cause carbohydrate-deficient glycoprotein syndrome type II, an autosomal recessive disease with defective brain development. Am J Hum Genet 1996;59:810.

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CHAPTER 27

Lysosomal Storage Diseases Gregory M. Pastores and Edwin H. Kolodny

OVERVIEW AND GENERAL CONCEPTS The lysosomal storage diseases are a clinically heterogeneous group of inborn errors of metabolism that have traditionally been classified according to the biochemical nature of the incompletely degraded macromolecules that accumulate in various tissues. The lysosomal storage diseases are represented by about 50 different clinical entities (Table 27-1). Most of the individual conditions also have an eponymous designation in recognition of the investigator who provided seminal descriptions of the typical manifestations and clinical course of specific variants, often before elucidation of their biochemical or molecular bases. As the terminal compartment in the endosomal-lysosomal pathway, the lysosome maintains an acidified milieu enriched with catabolic enzymes to facilitate the degradation of various byproducts of cellular turnover, which are mainly delivered to the lysosome through endocytosis. Phagocytosis and autophagy provide alternative points of substrate entry into the lysosome [Bishop, 2003]. These complex substrates may include sphingolipids, glycoproteins, and glycosaminoglycans (mucopolysaccharides). The particular metabolite that builds up (and the ensuing pattern and severity of the associated diseases) is primarily dependent on the substrate tissue-source and the relevant metabolic pathway and transport systems that are compromised. For instance, keratan sulfate is a major constituent of cartilage and the cornea; abnormalities in the turnover of keratan sulfate partly explain the characteristic features of skeletal dysplasia and the corneal opacities associated with the mucopolysaccharidoses [Wegrzyn et al., 2004]. The analysis (through a combination of immune quantification assays and tandem mass spectrometry) of the glycosphingolipid and oligosaccharide profiles in the blood and urine of affected patients may prove useful; as surrogate markers of disease activity, they may enable early diagnosis and the monitoring of clinical responses with directed therapies (such as enzyme replacement or substrate synthesis inhibition) [Meikle et al., 2004a]. The enzymes and transport or integral membrane proteins that are responsible for facilitating the intralysosomal metabolism of these substrates are formed within the endoplasmic reticulum and subsequently refined (through distinct post-translational mechanisms) by the Golgi apparatus [Eskelinen et al., 2003]. The uptake of newly synthesized enzymes by the lysosome, as opposed to other cellular organelles such as the peroxisome or mitochondria, is achieved largely through the mannose 6-phosphate receptor pathway. Thus, phosphorylation of the mannose residues of the complex carbohydrate side-chains of the various relevant proteins is an essential step in its maturational processing

[Urayama et al., 2004]. Elucidation of this pathway of lysosomal protein delivery, including uptake by the mannose receptors, was critical in the development of enzyme therapy for the lysosomal storage diseases [Grabowski and Hopkin, 2003]. Absent or defective hydrolytic activity within the lysosome, which can come about as a consequence of mutations within the specific encoding gene (for the functional enzyme or its activator or co-factor), is the most common cause of disease (Table 27-2) [Meikle et al., 2004a; Sadeghlar et al., 2003]. For example, deficient glucocerebrosidase activity as in Gaucher’s disease results in the accumulation of its substrate, the glycosphingolipid glucosylceramide. Sphingolipid co-factors called saposins facilitate the interaction between the water-soluble glycoprotein enzymes and their lipid-soluble substrates [Morimoto et al., 1990]. Mutation of the saposin C gene is associated with the incomplete metabolism of glucosylceramide in vivo and a rare condition that has clinical features that overlap with the chronic neuropathic form of Gaucher’s disease (type 3 disease). Other proteins (e.g., cathepsin A) serve as a component of a multienzyme complex and play a protective role, preventing the intralysosomal degradation of its component enzymes (i.e., β-galactosidase and sialidase). Deficiency of cathepsin A leads to the clinical entity known as galactosialidosis, which combines the clinical features encountered in the two different primary enzyme deficiency disorders, namely, GM1 gangliosidosis and sialidosis. Alternatively, a flaw in the processing of certain newly synthesized enzymes (e.g., because of a failure in generating mannose 6-phosphate residues) leads to their functional loss by keeping the enzyme from assuming its operational conformation or denying access to the lysosome. This flaw is one type of post-translational defect that can lead to the loss of activity of multiple lysosomal enzymes (as in mucolipidosis II and III). At present, there are no known defects of lysosome biogenesis, although there are lysosomal disorders that result from a defective protein involved in substrate transport (e.g., Niemann-Pick disease type C) or vesicle fusion (e.g., Danon’s disease) [Walkley, 2001]. Other defects of lysosomal transport (e.g., cystinosis, sialic acid storage disorders) involve a dysfunction of intracellular membrane transporters that mediate the movements of the hydrolyzed products outside of the lysosome for their final excretion [Mancini et al., 2000]. With respect to pathogenesis, cellular toxicity is hypothesized to occur when the lysosomal substrate burden has reached a critical threshold and presumptively triggers a cascade of downstream events that ultimately lead to cell death and the development of disease-specific com-

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Genetic, Metabolic, and Neurocutaneous Disorders / 27

TABLE 27-1 The Lysosomal Storage Disorders Classified According to Relevant Substrate Involved STORED SUBSTRATE Sphingolipids GM2 gangliosides, glycolipids, globoside oligosaccharides

GM1 gangliosides, oligosaccharides, keratan sulfate, glycolipids Sulfatides GM1 gangliosides, sphingomyelin, glycolipids, sulfatide Galactosylceramides α-Galactosylsphingolipids, oligosaccharides Glucosylceramide, globosides Glucosylceramide, globosides Ceramide Sphingomyelin Mucopolysaccharides (glycosaminoglycans) Dermatan sulfate and heparan sulfate Heparan sulfate

Keratan sulfate Dermatan sulfate Dermatan sulfate and heparan sulfate Hyaluronan Glycogen Glycogen

DISEASE

ENZYME/PROTEIN DEFICIENCY

GENE LOCUS

Tay-Sachs disease GM2 gangliosidosis (three types) Sandhoff’s disease GM2 gangliosidosis GM2 gangliosidosis, AB variant GM1 gangliosidosis (three types)*

α Subunit of β-hexosaminidase

15q23-24

β Subunit of β-hexosaminidase

5q13

GM2 activator β-Galactosidase

5q32-33 3p21-3pter

Metachromatic leukodystrophy Metachromatic leukodystrophy variant

Arylsulfatase A (galactose-3-sulfatase) Saposin B activator

22q13.31-qter 10q21

Krabbe’s disease Fabry’s disease

Galactocerebrosidase α-Galactosidase A

14q31 Xq22

Gaucher’s disease (three types)* Gaucher’s disease (variant) Farber’s disease (seven types) Niemann-Pick disease types A and B

β-Glucosidase Saposin C Acid ceramidase Sphingomyelinase

1q21 10q21 8p22-21.2 11p15.1-15.4

MPS I, Hurler-Scheie MPS II, Hunter MPS IIIA, Sanfilippo A MPS IIIB, Sanfilippo B MPS IIIC, Sanfilippo C

α-L-Iduronidase Iduronate-2-sulfatase Sulfamidase α-N-Acetylglucosaminidase Acetyl-CoA:α-glucosaminideN-acetyltransferase N-Acetylglucosamine-6-sulfatase Galactosamine-6-sulfatase β-D-Galactosidase N-Acetylgalactosamine-4-sulfatase Hyaluronidase β-D-Glucuronidase

4p16.3 Xq27.3-28 17q25.3 17q21.1 14 12q14 16q24.3 3p21.33 5q13-14 7q21.1-22 3p21.3

α-D-Glucosidase

17q25

Lysosomal associated membrane protein-2 (LAMP-2)

Xq24

MPS IIID, Sanfilippo D MPS IVA, Morquio A MPS IVB, Morquio B MPS VI, Maroteaux-Lamy MPS VII, Sly MPS IX

Glycogen

Pompe’s disease, glycogen storage disease type IIA Danon’s disease

Oligosaccharides/Glycopeptides α-Mannoside β-Mannoside α-Fucosides, glycolipids α-N-Acetylgalactosaminide Sialyloligosaccharides Aspartylglucosamine

α-Mannosidosis β-Mannosidosis α-Fucosidosis Schindler-Kanzaki disease Sialidosis Aspartylglucosaminuria

α-Mannosidase β-Mannosidase α-Fucosidase α-N-Acetylgalactosaminidase α-Neuraminidase Aspartylglucosaminidase

19p13.2-q12 4q22-25 1p34.1-36.1 22q13.1-13. 6p21.3 4q34-35

Mucolipidosis II (I-cell disease); mucolipidosis III (pseudo-Hurler polydystrophy)—three complementation groups

N-Acetylglucosamine-1-phosphotransferase

Galactosialidosis Multiple sulfatases

Protective protein/cathepsin A SUMF-1

4q21-q23 Mucolipidosis III subtype C: γ subunit mutations on 16p 20 3p26

Wolman’s disease, Cholesteryl ester storage disease Niemann-Pick disease type C

Acid lipase

10q23.2-q23.3

NPC1; HE1

18q11-12; 14q24.3

Sialin

6q14-15

Cystinosis

17p13

Multiple Enzyme Deficiencies Glycolipids, oligosaccharides

Sulfatides, glycolipids, glycosaminoglycans Lipids Cholesterol esters Cholesterol, sphingomyelin Monosaccharides/Amino Acid Monomers Sialic acid, glucuronic acid Cystine

Salla disease, infantile free sialic acid storage disease Cystinosis

Pastores and Kolodny / Lysosomal Storage Diseases

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TABLE 27-1, cont’d The Lysosomal Storage Disorders Classified According to Relevant Substrate Involved STORED SUBSTRATE

DISEASE

ENZYME DEFICIENCY

GENE LOCUS

Peptides Bone proteins

Pyknodysostosis

Cathepsin K

1q21

Infantile neuronal ceroid lipofuscinosis Late infantile neuronal ceroid lipofuscinosis

Palmitoyl-protein thioesterase Pepstatin-insensitive lysosomal peptidase

1p32 11p15

S-Acylated Proteins Palmitoylated proteins Pepstatin-insensitive lysosomal peptidase

*Three types imply infantile, childhood, and adulthood presentations.

TABLE 27-2 Illustrative List of Underlying Causes ETIOLOGY

DISEASE (EXAMPLES)

Single hydrolytic enzyme deficiency Single protease enzyme deficiency Co-factor/activator protein deficiency Multiple enzyme deficiencies

Gaucher’s disease, Tay-Sachs disease, Niemann-Pick disease Late infantile neuronal ceroid lipofuscinosis (pepinase) Gaucher’s disease variant (saposin); Tay-Sachs disease (GM2 activator) Galactosialidosis (protective protein/cathepsin A); multiple sulfatase deficiency (SUMF-1); I-cell disease (mucolipidosis II) Juvenile neuronal ceroid lipofuscinosis (battenin) Cystinosis; sialic acid storage disorders Mucolipidosis IV; Danon’s disease (LAMP-2); Niemann-Pick disease type C

Membrane protein defect Small-molecule transport protein Endocytosis, membrane-vesicle trafficking defect

plications. These consequent mechanisms of disease for most of the individual lysosomal storage diseases remain to be fully clarified. There is increasing recognition that besides mechanical forces, other pathologic factors (e.g., inflammation and apoptosis) may play contributory roles in the evolution of the disease phenotype. For instance, in the GM2 gangliosidoses, several markers of an inflammatory response have been found to be elevated and may partly explain the neurodegenerative features encountered in this group of diseases [Jeyakumar et al., 2002, 2003]. Studies have also suggested that certain lysosomal proteases may play active roles in the apoptotic execution process and can act as mediators of programmed cell death [Tardy et al., 2004]. The majority of genes that encode lysosomal proteins are ubiquitously expressed, and each of the various lysosomal storage disease subtypes is characterized by multisystemic involvement. There is wide heterogeneity in the clinical presentation of each entity among individually affected patients, and the concordance between genotype and phenotype is often imperfect even among siblings [Wilcox, 2004]. Disease manifestations may be evident prenatally or at any time from birth to adulthood. Certain lysosomal storage diseases present with nonimmune hydrops fetalis, and the failure to establish causality before the child’s death can lead to potential recurrence in future pregnancies among

couples at risk [Stone and Sidransky, 1999]. On the other hand, Gaucher’s and Fabry’s diseases may not be associated with prominent symptoms during childhood, and the diagnosis can be missed because the patients have either a mild or atypical course. This is true especially when the family history is uninformative. To some extent, the variable disease severity encountered between the individual patients has been attributed to different mutations that produce a protein with either no functional activity (in severe cases) or some residual enzyme activity (as observed in those with later onset of clinical expression). As most lysosomal storage diseases are autosomal-recessive disorders, heterozygotes (or carrier-individuals with a single defective gene copy) often have sufficient enzyme activity generated by their other (normal) allele. Carriers for these conditions do not exhibit evidence of tissue storage or suffer from the relevant disease that segregates in the family. There are at least three disorders, Fabry’s and Danon’s diseases and Hunter’s syndrome (MPS II), that are transmitted as X-linked traits. Although females who are carriers of the trait for Hunter’s syndrome do not appear to develop clinical problems related to the presence of a mutant protein, a proportion of females who are carriers of Fabry’s disease or Danon’s disease may experience disease-related complications, which in a few cases can be as severe as those found in classically affected males. The variable expression in these carrier females has been partly attributed to lyonization (i.e., the random inactivation during early embryogenesis of one of the two X chromosomes). Lyonization results in varying proportions of the mutant gene product in different organ systems [Opitz and Utkus, 2001]. Skewed lyonization may be seen in females with an X:autosome translocation. In these cases, there is inactivation of the intact X chromosome. If the X chromosome that is attached to an autosome remains functional and if it happens to bear a gene mutation, disease expression may be unmasked. In addition, rare cases have been reported of females with Hunter’s syndrome who also happen to have Turner’s syndrome (45,X), wherein the single X chromosome that is present also bears a mutation of the gene for the responsible enzyme (iduronate-2-sulfatase). Although the individual disorders are infrequent to rare and considered orphan disorders by drug regulatory agencies, the lysosomal storage diseases have a combined prevalence of about 1 in 5000 to 8000 [Meikle et al., 1999; Pinto et al., 2004]. This relatively high occurrence has prompted investigations of the feasibility of targeted screening [Meikle et al., 2003, 2004b]. The rationales given for these

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Genetic, Metabolic, and Neurocutaneous Disorders / 27

TABLE 27-3 Clinical Manifestations Reported in Patients with Lysosomal Storage Disorders Nonimmune hydrops fetalis Disseminated lipogranulomatosis (Farber’s disease) Galactosialidosis (neuraminidase deficiency) Gaucher’s disease GM1 gangliosidosis Infantile free sialic acid storage disease Mucolipidosis II (I-cell disease) MPS IV and VII Niemann-Pick disease type C Sialidosis type I Wolman’s disease

Cytopenia (anemia, thrombocytopenia) Gaucher’s disease Niemann-Pick disease Wolman’s disease (acanthocytosis) Vacuolated lymphocytes GM1 gangliosidosis (Landing’s disease) I-cell disease Multiple sulfatase deficiency (Austin’s disease) Neuronal ceroid lipofuscinosis Niemann-Pick disease Oligosaccharidosis (aspartylglucosaminuria, sialidosis) Pompe’s disease (glycogen storage disease type II)

Interstitial lung disease Gaucher’s disease Niemann-Pick disease Obstructive airway disease Fabry’s disease Mucopolysaccharidoses Cardiomyopathy Fabry’s disease (arrhythmia, conduction abnormalities) Mucopolysaccharidoses (valvular disease) Pompe’s disease (hypotonia)

Myoclonic seizures Galactosialidosis Gaucher’s disease type 3I GM2 gangliosidosis Neuronal ceroid lipofuscinosis Niemann-Pick C Oligosaccharidosis (α-N-acetylgalactosaminidase deficiency, fucosidosis, sialidosis type 1) Ataxia Galactosialidosis Gaucher’s disease type 3 GM1 gangliosidosis Late-onset GM2 gangliosidosis (cerebellar hypoplasia) Krabbe’s disease Metachromatic leukodystrophy Neuronal ceroid lipofuscinosis Niemann-Pick C Salla disease Extrapyramidal signs Gaucher’s disease type 3 GM1 gangliosidosis (adult form) Late-onset GM2 gangliosidosis Krabbe’s disease Niemann-Pick C Oligosaccharidosis Cortical atrophy Late stage of GM1 and GM2 gangliosidosis (cerebellar atrophy) Metachromatic leukodystrophy I-cell disease Neuronal ceroid lipofuscinosis

Cerebrovascular or strokelike episodes and other vascular events (e.g., Raynaud’s phenomenon) Fabry’s disease Dementia, psychosis Fabry’s disease Gaucher’s disease type 3 GM1 gangliosidosis Late-onset GM2 gangliosidosis Krabbe’s disease Metachromatic leukodystrophy MPS III (Sanfilippo’s disease) Neuronal ceroid lipofuscinosis Niemann-Pick C Macrocephaly Krabbe’s disease Tay-Sachs disease Sandhoff’s disease Peripheral neuropathy Krabbe’s disease Metachromatic leukodystrophy (spastic paraplegia) Multiple sulfatase deficiency Deafness‡ Fabry’s disease Galactosialidosis Gaucher’s disease type 2 I-cell disease MPS I, II, IV Oligosaccharidosis (α- and β-mannosidosis) Metachromatic leukodystrophy Infantile Pompe’s disease

Cherry-red spot,* optic atrophy, visual loss Galactosialidosis GM1 gangliosidosis Infantile free sialic acid storage disease Mucolipidosis II (I-cell disease) (MPS IV and MPS VII Neuronal ceroid lipofuscinosis Niemann-Pick disease type A Sialidosis type I Sandhoff’s disease Tay-Sachs disease Retinitis pigmentosa Neuronal ceroid lipofuscinosis Corneal opacities (clouding) I-cell disease (mucolipidosis II) Mucolipidosis IV MPS I, IV, VI Oligosaccharidosis (late-onset α-mannosidosis) Fabry’s disease Lenticular opacities (cataracts) Oligosaccharidosis (sialidosis, α-mannosidosis) Fabry’s disease Ophthalmoplegia (abnormal eye movements) Nystagmus Gaucher’s disease type 3 Niemann-Pick C and D

Hepatosplenomegaly Danon’s disease (8%–36% of cases) Gaucher’s disease Mucopolysaccharidoses Niemann-Pick disease A and B Niemann-Pick C (cholestatic jaundice) Oligosaccharidoses Pompe’s disease (hepatomegaly) Wolman’s disease and cholesteryl ester storage disease Nephrolithiasis Cystinuria Proteinuria Fabry’s disease Cystinosis (aminoaciduria, Fanconi’s syndrome) Osteopenia Gaucher’s disease I-cell disease Punctate epiphyseal calcifications β-Glucuronidase deficiency Degenerative arthritis, bone infarcts Fabry’s disease Farber’s disease Gaucher’s disease I-cell disease Mucolipidosis III MPS I Pain crises Gaucher’s disease types 1 and 3 (bone) Krabbe’s disease Metachromatic leukodystrophy Dysostosis multiplex† Mucopolysaccharidoses (coarse facies) Oligosaccharidoses Angiokeratoma Fabry’s disease Oligosaccharidoses (aspartylglucosaminuria, fucosidosis, galactosialidosis, β-mannosidosis, sialidosis)

*Describes the normal red macula surrounded by a pale retina, reflecting storage material in the perifoveal ganglion cells. † Refer to constellation of radiologic findings, including macrocephaly, thickened calvaria, J-shaped sella turcica, spatulate ribs, bullet-shaped phalanges that are shortened, rounding and anterior beaking of the vertebral bodies (especially in the lumbar region), and flaring of the iliac wings. ‡ Conductive, sensorineural, or a combination, with involvement of cochlear and CNS dysfunction.

programs include (1) the high frequency of certain disorders among a defined ethnic group (e.g., Tay-Sachs, Gaucher’s, and Niemann-Pick A diseases among the Ashkenazi Jewish population) [Slatkin, 2004]. (2) the potential to intervene before development of significant neurologic sequelae in cases that are diagnosed early and are potentially treatable (e.g., bone marrow transplantation for juvenile Krabbe’s disease [globoid cell leukodystrophy]), and (3) the opportunity for prevention during subsequent pregnancies in at-risk families (Table 27-3).

Several advances in the understanding of lysosomal storage diseases have resulted from investigations of animal disease models, which either have arisen spontaneously or have been generated by the application of recombinant genetic techniques (primarily involving mice) [Suzuki et al., 2003]. Numerous insights into the role of certain metabolites in embryonic and fetal development and their functions in various organs have been obtained from experiments involving these different animal models, which have also been useful in the development and preclinical testing of new putative

Pastores and Kolodny / Lysosomal Storage Diseases

therapies [Desmaris et al., 2004]. Although most mouse disease models are genetically authentic and mimic the human phenotype, several reproduce only some aspects or may have no clinical manifestations at all (e.g., the TaySachs disease knockout mouse) [Elsea and Lucas, 2002]. On the therapeutic front, industrial-scale production of recombinant human enzymes (through manipulation of mammalian cells in culture) has enabled the introduction of enzyme replacement therapy for several disorders, including Gaucher’s and Fabry’s diseases and the Hurler-Scheie syndrome (MPS I H/S) [Pastores, 2003; Schiffmann and Brady, 2002]. Studies to ascertain the safety and efficacy of enzyme replacement therapy in Pompe’s disease (glycogen storage disease II) and in the Hunter (MPS II) and Maroteaux-Lamy

(MPS VI) syndromes are also currently under way [Kakkis, 2002; Reuser et al, 2002]. In diseases primarily associated with central nervous system (CNS) degeneration (e.g., TaySachs disease and Niemann-Pick disease type C) and for which protein delivery across the blood-brain barrier represents a major obstacle, substrate reduction therapy is being explored [Butters et al., 2003]. The rationale for this approach is based on the following: in cases wherein mutant cells express residual enzyme activity, metabolic homeostasis may be restored or maintained by limiting the amount of intralysosomal substrate accumulation through inhibition of the amount of precursor material that is synthesized [Pastores and Barnett, 2003]. In Gaucher’s disease, substrate reduction therapy is feasible with the use of the imino sugar miglustat (which inhibits the activity of ceramide-specific

TABLE 27-4 Diagnosis and Therapeutic Options for the Lysosomal Storage Disorders

*

DISEASE*

DIAGNOSTIC METHOD†

TREATMENT‡

Tay-Sachs disease (B variant) GM2 gangliosidosis (three types) Sandhoff’s disease (O variant) GM2 gangliosidosis GM2 gangliosidosis, AB variant GM1 gangliosidosis (three types) Metachromatic leukodystrophy Metachromatic leukodystrophy variant (saposin B deficiency) Krabbe’s disease Fabry’s disease Gaucher’s disease types 1, 2, and 3 Gaucher’s disease (saposin C variant) Farber’s disease (seven types) Niemann-Pick disease types A and B MPS I, Hurler-Scheie MPS II, Hunter MPS IIIA-D, Sanfilippo A to D MPS IVA, Morquio A MPS IVB, Morquio B MPS VI, Maroteaux-Lamy MPS VII, Sly MPS IX Pompe’s disease, glycogen storage disease IIA Danon’s disease α-Mannosidosis β-Mannosidosis α-Fucosidosis Schindler-Kanzaki disease Sialidosis (mucolipidosis I) Aspartylglucosaminuria Mucolipidosis II (I-cell disease) Mucolipidosis IV Galactosialidosis (protective protein/cathepsin A deficiency) Multiple sulfatases Wolman’s disease, cholesteryl ester storage disease (acid lipase deficiency) Niemann-Pick disease type C Salla disease, infantile free sialic acid storage disease Cystinosis Pyknodysostosis Neuronal ceroid lipofuscinosis

Enz; Mol; Prenat (Enz/Mol)

SRT (in clinical trials)

Urine oligo; Enz; Mol; Prenat (Enz)

Palliative

Func; Mol; Prenat (Mol) Enz; Mol; Prenat (Enz) Enz; Mol; Prenat (Enz) Func/Subs; Mol; Prenat (Mol)

Palliative Palliative HSCT/BMT Palliative

Enz; Mol; Prenat (Enz) Enz/Subs; Mol; Prenat (Enz/Mol) Enz; Mol; Prenat (Enz) Func/Subs; Mol; Prenat (Mol) Enz; Mol; Prenat (Enz) Enz; Mol; Prenat (Enz) Urine GAG; Enz; Mol; Prenat (Enz) Urine GAG; Enz; Mol; Prenat (Enz) Urine GAG; Enz; Mol; Prenat (Enz) Urine GAG; Enz; Mol; Prenat (Enz) Urine GAG; Enz; Mol; Prenat (Enz) Urine GAG; Enz; Mol; Prenat (Enz) Urine GAG; Enz; Mol; Prenat (Enz) Enz; Mol; Prenat (none reported) Urine oligo; Enz; Mol; Prenat (Enz)

HSCT/BMT ERT ERT, primarily for types 1 and 3; SRT Palliative Palliative ERT (in clinical trials primarily for type B) ERT; HSCT/BMT ERT (in clinical trials) Palliative Palliative Palliative ERT (in clinical trials) Palliative Palliative ERT (in clinical trials)

Mol; Prenat (Mol) Urine oligo; Enz; Mol; Prenat (Subs) Urine oligo; Enz; Mol; Prenat (Enz) Mol; Prenat (Mol) Urine oligo; Enz; Mol; Prenat (Enz) Enz; Mol; Prenat (Enz) Urine oligo; Enz; Mol; Prenat (Enz) Urine oligo; Mul Enz; Mol; Prenat (Enz) Mol; Prenat (Mol) Urine oligo; Mul Enz; Mol; Prenat (Mul Enz)

Palliative HSCT/BMT HSCT/BMT HSCT/BMT Palliative Palliative Palliative Palliative; BMT (1 case) Palliative Palliative

Urine GAG; Mul Enz; Mol; Prenat (Enz) Enz; Mol; Prenat (Enz)

Palliative Palliative

Func/Subs; Mol; Prenat (Func/Subs) Subs; Mol; Prenat (Subs)

SRT (in clinical trials) Palliative

Func/Subs; Mol; Prenat (Func/Subs) Enz; Mol; Prenat (none reported) Enz; Mol; Prenat (Enz/Mol for certain subtypes)

Cysteamine Palliative Palliative

As listed in Table 27-1. Enz, enzyme assay; Func, functional assay (see text); GAG, glycosaminoglycans; Mol, molecular/DNA/gene defect analysis; Mul Enz, multiple enzyme in either cultured cells/amniotic fluid or serum media; Oligo, oligosaccharides; Prenat, prenatal diagnosis available; Subs, substrate analysis (see text). ‡ BMT, bone marrow transplantation; ERT, enzyme replacement therapy; HSCT, hematopoietic stem cell transplantation; SRT, substrate reduction therapy. †

663

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Genetic, Metabolic, and Neurocutaneous Disorders / 27

glucosyltransferase, the rate-limiting enzyme involved in the biosynthesis of glycosphingolipids). Before enzyme replacement therapy and substrate reduction therapy, bone marrow transplantation was undertaken in selected cases (Table 27-4) [Peters et al., 2003]. The high procedure-related morbidity and mortality risks associated with bone marrow transplantation (e.g., from graft-verushost disease, infections) preclude its general application, even in cases in which clear therapeutic gains could be established in the successfully engrafted patients. The use of hematopoietic or mesenchymal stem cells and less intensive (i.e., nonmyeloablative) conditioning regimens are being examined as a means to improve clinical outcome and to minimize procedural risks [Koc et al., 2002; Krivit, 2004]. Another novel approach, termed enzyme enhancement therapy, is also under investigation. Enzyme enhancement therapy is a potential treatment strategy for diseases resulting from a defective enzyme associated with a mutation that leads to its misfolding and rapid degradation [Desnick, 2004]. In these instances, the use of an agent that acts as a chaperone to stabilize the mutant enzyme may help restore its function. Proof of principle for this strategy has been demonstrated in Fabry’s disease, for which the regular intravenous administration of galactose has led to the resolution of cardiomyopathy and improvement in the associated hemodynamic changes in one patient [Frustaci et al., 2001]. Gene therapy is also being explored as an option, although most studies to date have only been with animal (primarily mouse) models, except for Gaucher’s disease, for which clinical trials have been performed [Caillaud and

Poenaru, 2000; Ellinwood et al., 2004; Eto et al., 2004; Gieselmann et al., 2003b; Shen et al., 2004; Sly and Vogler, 2002]. Unfortunately, gene therapy performed in the patients with Gaucher’s disease resulted in only transient expression of the functional enzyme [Cabrera-Salazar et al., 2002]. For most lysosomal storage diseases, the mainstay of treatment has been palliative or supportive care. Treatment of the secondary disabilities (e.g., seizures, sensory impairment, and behavioral, sleep-wake cycle, or communication problems) can have a positive impact on the patient’s quality of life and may help address some sources of parental frustration. Genetic counseling of affected individuals and their relatives is also an important component of comprehensive care of the patient and family.

SPHINGOLIPIDOSES The sphingolipidoses are several disorders characterized by abnormalities in the metabolism of multiple glycolipid substrates that form a component of myelin or of lipid rafts within membranes (Fig. 27-1). Most of the clinical variants in this group are associated with neurodegenerative features. The myelin sheath is an extended, modified plasma membrane that, in the CNS, represents an extension of oligodendroglial cell processes. Examination of normal myelin with polarized microscopy and radiographic diffraction has exhibited a protein-lipid-protein-lipid-protein structure. Chemical investigations have determined that the lipid layers are composed of a bimolecular layer of hydrocarbon

Galactose Glucose GM1

N–acetylgalactosamine N–acetylneuraminic acid

Cer

Cer

GM2

Sandhoff

Generalized Gangliosidosis

Cer Tay Sachs Cer Fabry

Cer Cer – P – Choline Cer SO4

Gaucher

MLD

Niemann – Pick A, B

Krabbe CH2OH

Cer Ceramide

Farber Sphingosine + Fatty Acid FIGURE 27-1. Metabolic pathway and the sites of disruption in sphingolipid catabolism. MLD, metachromatic leukodystrophy

Pastores and Kolodny / Lysosomal Storage Diseases

chains, cholesterol, phospholipids, and glycolipids (primarily galactocerebroside and sulfatide). The glycolipids are amphiphilic and have a hydrophobic ceramide moiety that acts as a membrane anchor and a hydrophilic, extracellularly oriented oligosaccharide chain. Rather than diffuse distribution in the cell membrane, current studies support the localization of glycosphingolipids, cholesterol, and certain proteins in specialized patches of membranes referred to as lipid rafts. Lipid rafts play key roles in intracellular transport, protein-sorting, and signal-transduction processes. Disturbed distribution of raft lipids and consequently protein subcellular localization due to a gridlock in the endocytic pathway, as seen in certain lysosomal storage diseases, is believed to lead to cell and organ functional impairments [Saravanan et al., 2004]. In addition, abnormalities of myelin membrane lipid composition result in the loss of membrane stability and its degeneration. The degradation of glycosphingolipids takes place in the lysosomes through a stepwise action of specific acid hydrolases. Several of these enzymes (such as β-glucosidase, βgalactocerebrosidase, arylsulfatase A, and acid ceramidase) also require the assistance of nonenzymatic glycoprotein cofactors, the so-called sphingolipid activator proteins (or saposins). Examination of tissue sections obtained from affected individuals with glycosphingolipid storage disease typically reveals membranous cytoplasmic bodies, which represent lipid material enclosed by the lysosomal membranes [Abramovich et al., 2001]. Studies in animal models for Sandhoff’s disease and Niemann-Pick disease type A revealed elevated levels of phosphatidylcholine surfactant in lung tissue [Buccoliero et al., 2004]. These observations suggest that changes in phospholipid levels and composition in lung surfactant might be a general feature of sphingolipid storage diseases and may in part be responsible for the increased susceptibility of these patients to respiratory infections and lung disease.

Gangliosidoses The gangliosides are complex lipids (with a ceramide backbone on which hexoses and sialic acids are attached); they are found predominantly in brain gray matter. Disorders of ganglioside metabolism are identified on the basis of the specific underlying enzyme deficiency and the resultant accumulation of its substrates (named by L. Svennerholm according to the presence of a sialic acid group [M, D, T, and Q] and their distinct chromatographic mobility [1, 2, and 3]). Within each disease category, there are several variants that are distinguished on the basis of the age at onset, including a classic (early or late) infantile and later onset (juvenile or adult) form. These delineations are artificial; in practice, most of the affected patients actually fall within the broad spectrum of disease expression, partly influenced by the absence or the presence of residual enzyme activity. Ganglioside (primarily GM2 and GM3) accumulation has also been found to occur secondarily in other disorders, such as the mucopolysaccharidoses [Walkley, 2004]. In the mucopolysaccharidoses, the primary storage of glycosaminoglycans is believed to lead to inhibition of the activity of several ganglioside-degrading lysosomal enzymes. In other disorders (e.g., Niemann-Pick disease type C), secondary gan-

665

glioside accumulation is believed to result from a disruption in retroendocytic movement of the substrate and does not appear to reflect simply the nonspecific changes in tissue cellularity (arising from neuronal loss and gliosis) [Walkley, 2004]. Neuronal cells that have GM2 ganglioside storage exhibit meganeurite formation (i.e., axonal hillock enlargement) and ectopic dendritogenesis (i.e., the sprouting of new synapse-covered dendritic neurites at the axon hillock) [Walkley, 2004]. Axonal spheroid formation (or neuroaxonal dystrophy) is also often noted. The spheroids occur as focal enlargements of various sizes scattered along myelinated and unmyelinated axons in the gray and white matter. In contrast to neuronal cell bodies, which contain characteristic storage material, spheroids consist of collections of multivesicular and dense bodies, mitochondria, and other organelles that would normally be found being transported along axons [Walkley, 2004]. These observations suggest that the development of spheroids may involve defective endocytic trafficking within axons.

GM1 Gangliosidoses Generalized gangliosidosis or GM1 gangliosidosis is associated with the neuronal storage of the monosialoganglioside GM1, which normally constitutes approximately 20% of all gangliosides found in the brain and 80% of ganglioside in myelin. This disorder results from a deficiency of the enzyme β-galactosidase, which is responsible for the cleavage of the terminal galactose of GM1. The same enzyme is also defective in another disorder, Morquio’s syndrome type B. Apart from mutations within its encoding gene, the activity of the enzyme β-galactosidase (combined with deficiency of sialidase [also known as neuraminidase]) can be compromised secondarily as a result of a deficiency of the protective protein/cathepsin A. This condition, called galactosialidosis, is a separate disorder. The gene encoding β-galactosidase also gives rise, after alternative splicing, to the elastin-binding protein that is involved in elastic fiber deposition. Deficient β-galactosidase activity leads to the incomplete metabolism of several other substrates, including galactosecontaining glycoproteins, N-acetylgalactosamine, lactose, and keratan sulfate (a glycosaminoglycan). Phenotypic differences likely result from varying activities of the mutant β-galactosidase enzyme against its various substrates, which may explain the dysmorphic facial features reminiscent of the mucopolysaccharidoses in the early infantile form of GM1 gangliosidosis and the predominance of skeletal disease in Morquio’s syndrome type B (due to allelic mutations) [Beck, 2001; Callahan, 1999]. Allelic mutations involve distinct sequence alterations of the same gene; the phenotype encountered may be different because the specific underlying gene defects involve distinct domains of the protein that subserve different functions. Studies in the mouse model of GM1 gangliosidosis have found that GM1 storage leads to several cellular changes (including activation of the unfolded protein response pathway), the upregulation of BiP and CHOP (C/EBP homologous transcription factor), and the activation of JNK2 and caspase 12, which lead to neuronal apoptosis [Tessitore et al., 2004].

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Genetic, Metabolic, and Neurocutaneous Disorders / 27

In the early infantile form, dysmorphic facial features (i.e., frontal bossing; wide, depressed nasal bridge; gingival hypertrophy or thickened alveolar ridges) may be present at birth or become more apparent with time. In the first few months of life, hepatosplenomegaly is also usually noted, and lateral spine radiographs reveal hypoplasia and anterior beaking of the thoracolumbar vertebrae. An additional skeletal radiographic finding is widening of the diaphysis (the midshaft) of long bones. These bone deformities (referred to as dysostosis multiplex) are similar to those found in the mucopolysaccharidoses. In affected individuals, the heart may be enlarged, and cardiac failure may develop as a consequence of endocardial fibroelastosis and valvular incompetence (secondary to thickening of the heart valves). The distinctive facies and visceromegaly observed in these patients are unusual characteristics for most of the other neurovisceral lipidoses. Hypotonia, feeding difficulties, and failure to thrive may be evident in the first weeks of life in patients with early infantile GM1 gangliosidosis. A macular cherry-red spot is found in about 50% of cases, and there is hyperacusis (or exaggerated acousticomotor response); these features are also typical of Tay-Sachs disease. In these diseases, substrate accumulation in the ganglion cells produces a white ring or halo of lipid-laden neurons encircling the red, ganglion cell–free region of the fovea, which is observed as the characteristic cherry-red spot. Ultimately, patients with infantile GM1 gangliosidosis develop spasticity, tonic spasms, and pyramidal signs. Affected infants who survive beyond 12 months usually exhibit decerebrate rigidity. Seizures can occur, generally during the later stages of disease. Death usually occurs by 2 years of age from respiratory failure and bronchopneumonia. Histologic examination of the brain of two infants with GM1 gangliosidosis revealed a marked decrease in the number of oligodendrocytes and myelin sheaths [van der Voorn et al., 2004]. An immunohistochemical decrease in proteolipid protein and a more profound deficiency of myelin basic protein were also found; these observations indicate that the brain lesions may not simply result from a delay or arrest in myelination but are due to a “dying-back” oligopathy. In addition, amyloid precursor protein–immunoreactive aggregates were observed in proximal axons and meganeurites, as well as in white matter axons. These data suggest that the myelin deficit results from a loss of oligodendrocytes and abnormal axoplasmic transport, consequent to the massive neuronal storage of GM1. The late infantile form (with onset usually between 12 and 18 months of life) often manifests with gait disturbances and frequent falls. There is usually no distinctive facial dysmorphism, and the liver and spleen are not enlarged. Skeletal deformities, such as hypoplasia of the acetabula and proximal deformity of the metacarpal bones, may be found on radiographic examination but are usually milder than those noted in the early infantile form of GM1 gangliosidosis. Patients develop seizures and spastic quadriparesis, with prominent pseudobulbar signs (i.e., drooling and dysphagia) (Fig. 27-2). Death is usual between the ages of 3 and 10 years. The absence of peripheral nerve involvement (i.e., normal conduction velocities) and normal cerebrospinal fluid findings help distinguish this condition from metachromatic leukodystrophy and Krabbe’s disease.

FIGURE 27-2. A 6-month-old girl with generalized GM1 gangliosidosis. The facies are dull, and there is nonpitting edema of the face. Hepatomegaly and less obvious splenomegaly are present.

In the juvenile or late-onset form, disease symptoms usually develop in late childhood or adolescence but may also occur as late as the third or fourth decade of life. Delayed onset is partly related to the presence of residual enzyme activity, which in one patient was reported to be associated with homozygosity for R521C mutation in the β-galactosidase gene [Silva et al., 1999]. This clinical variant has been observed in different ethnic groups but appears to be prevalent among the Japanese. Affected individuals have a protracted clinical course characterized by dysarthria and extrapyramidal signs (especially dystonia). Pathologic studies have revealed marked GM1 ganglioside storage in the basal ganglia. Intellectual impairment is slight to moderate. Laboratory findings in patients with GM1 gangliosidosis include vacuolization of peripheral blood lymphocytes and the presence of galactose-containing oligosaccharides and keratan sulfate in urine. These urinary findings help distinguish GM1 gangliosidosis from mucolipidosis II (I-cell disease), which is also associated with dysmorphic facial features and hepatosplenomegaly. For diagnostic purposes, deficient β-galactosidase activity can be demonstrated in peripheral blood leukocytes and cultured skin fibroblasts or prenatally by use of cultured chorionic villi or amniocytes. Mutation analyses have revealed broad heterogeneity, although certain gene defects tend to be common in

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particular subtypes. For instance, the R482H and R208C are often seen in infantile cases, R201C in the late infantile/juvenile patients, and I51T among rare adult/chronic cases [Callahan, 1999; Silva et al., 1999]. In contrast to the first two mutations, the last two defects are associated with moderate catalytic activity, consistent with expectations for the resultant phenotype. Only symptomatic treatment is available. In preclinical studies, administration of the imino sugar N-butyldeoxygalactonojirimycin to the β-galactosidase knockout mouse has been shown to significantly reduce total brain ganglioside and GM1 content, with no significant effect on viability, body weight, brain weight, or brain water content [Kasperzyk et al., 2004].

GM2 Gangliosidoses The GM2 gangliosidoses include several variants, all of which are associated with the neuronal storage of the monosialoganglioside GM2, resulting in the formation of meganeurites (i.e., distorted and ballooned neurons) and ectopic dendritogenesis. Primary accumulation of GM2 gangliosides occurs with mutations involving the genes encoding the α (Tay-Sachs disease) or β (Sandhoff’s disease) subunit of hexosaminidase A or the GM2 activator protein (in the AB variant) [Fernandes Filho and Shapiro, 2004]. The hexosaminidase A enzyme (with a molecular mass of approximately 100 kDa) is a trimer consisting of one α and two β subunits, encoded by structural genes on different chromosomes (see Table 27-1). Mutations of the β subunit also lead to deficiency of hexosaminidase B (a tetrameric homopolymer of β subunits). GM2 ganglioside storage is also seen in the so-called B1 variant, resulting from an altered substrate specificity of hexosaminidase A, wherein the mutated enzyme retains the ability to degrade the artificial substrate (used in most diagnostic assays) but not the sulfated or natural substrate in vivo. The highest incidence (approximately 3.1 per 100,000 live births) for the B1 variant of GM2 gangliosidoses has been described in Portugal, which has been suggested as the point of origin of a founder mutation (R178H) seen in Brazilian patients [Ribeiro et al., 1996; Tutor, 2004]. The “classic” infantile form of Tay-Sachs disease is named after a British ophthalmologist (Warren Tay) and an American neurologist (Bernard Sachs); both provided initial descriptions (in the 1880s) of the typical disease manifestations. Affected infants with Tay-Sachs disease have psychomotor deterioration and hyperacusis together with axial hypotonia, bilateral pyramidal signs, and blindness (associated with persistent pupillary responses) (Fig. 27-3). The macular cherry-red spot is a characteristic hallmark of the disease (Fig. 27-4). Head control is poor, and the size of the head increases markedly in the second year of life from enlargement of the brain (megalencephaly) and not because of tension hydrocephalus. Ultimately, with loss of the neurons and further gliosis, the ventricles may appear enlarged. Affected children become spastic and cachectic. Death usually occurs between 3 and 5 years of age. As patients approach the terminal stages, generalized tonic-clonic and minor motor seizures can occur. The patients do not have any of the following signs: dysmorphic features, visceromegaly, skeletal deformities, and signs of peripheral nerve

FIGURE 27-3. Patient with Tay-Sachs disease demonstrating a massive startle response to a relatively subtle sound stimulus. (From Swaiman KF. In: Baker AB, ed. Clinical Neurology. New York: Harper & Row, 1985.)

FIGURE 27-4. Macular cherry-red spot, a characteristic of Tay-Sachs disease and a few other lysosomal storage diseases. See also Color Plate.

involvement. These observations are useful in the delineation of Tay-Sachs disease from other lysosomal storage diseases associated with neurodegenerative features (see Table 27-3). In the general population, the incidence of Tay-Sachs disease has been estimated at 1 in 112,000 live births. TaySachs disease used to be prevalent (1 in 3900 live births) among Ashkenazi Jews, but this situation has been ad-

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dressed successfully through targeted screening programs. The success of targeted screening has prompted extension of the program to other disorders that are also common in Ashkenazi Jewish individuals, such as Gaucher’s disease, Niemann-Pick disease, and mucolipidosis IV. These particular disorders were chosen as part of the expanded screening program because they are found with increased carrier frequency among the Ashkenazi Jews, and causality has been attributed to a limited number of “common” mutations [Zhang B et al., 2004]. The later onset forms of GM2 gangliosidosis (referred to as LOTS, which stands for late-onset Tay-Sachs disease) can manifest in childhood, adolescence, or even adulthood. In contrast to the infantile-onset form, patients with juvenile or adult-onset disease follow a more protracted course and show no ethnic predilection. Affected individuals develop dysarthria and walking problems, primarily resulting from spastic paraparesis (in the childhood-onset form, between the ages of 3 and 6 years) or proximal muscle weakness (in the adult form, with symptom onset in the teens). Differences in the age at onset and disease course have led to distinction of the childhood-onset form (usually referred to as chronic GM2 gangliosidosis) from the adult-onset variant (or late-onset Tay-Sachs disease). The phenotype associated with the B1 variant is similar to that encountered in the childhood-onset form. Ataxia with cerebellar atrophy is also a prominent disease sign in the later onset forms. Tonic-clonic or myoclonic seizures are encountered in some children; psychiatric disturbances (i.e., bouts of psychosis and episodes of depression) are present and may be the initial manifestation of disease, particularly among adult-onset patients [Zaroff et al., 2004]. Consideration of late-onset GM2 gangliosidosis should be made in the differential diagnosis of patients with signs of lower motor neuron and spinocerebellar dysfunction. Vision is not impaired and optic fundi are normal, although intellectual deterioration is frequent. The rate of progression and disease severity usually correlate with the age at onset (presumably determined by the severity of the underlying mutation). Childhood-onset disease often leads to death by 15 years of age, preceded by a period characterized by progressive spasticity, rigidity, and dementia and ending in the vegetative state. Adult-onset patients may live into their 50s or early 60s. Mutation analyses performed in patients with late-onset Tay-Sachs disease have identified a high prevalence of the G269S gene defect, which is associated with residual hexosaminidase A activity, usually in combination with a null allele typical of classic Tay-Sachs disease [Paw et al., 1989]. The AB variant due to a deficiency of the GM2 activator, which is necessary for the hydrolysis of GM2 gangliosides by hexosaminidase A in vivo, has a clinical phenotype that is indistinguishable from the infantile form of Tay-Sachs disease [Li et al., 2003; Sakuraba et al., 1999]. It is a rare condition associated with normal laboratory test results in assays of hexosaminidase A and B enzyme activity with use of the artificial substrates. Diagnostic confirmation requires highly specialized methods, available only through a few laboratories. Sandhoff’s disease, due to mutations of the β subunit of hexosaminidase A, has an age at onset and clinical course characterized by neurologic and ophthalmologic findings

that are similar to Tay-Sachs disease. Sandhoff’s disease is a pan-ethnic disorder. A distinguishing feature is hepatosplenomegaly and the presence of N-acetylglucosamine– containing oligosaccharides in urine (as only hexosaminidase B, which is also deficient in Sandhoff’s disease but not in Tay-Sachs disease, is responsible for cleaving the Nacetylglucosamine moiety of globosides). Cardiomyopathy has also been noted occasionally. Death usually occurs between 2 and 4 years of age. There are extremely rare cases of patients with juvenile or late-onset Sandhoff’s disease [Hendriksz et al., 2004]. The enzymatic basis of GM2 gangliosidosis can be ascertained by assays of total hexosaminidase and hexosaminidase A activity, which can be measured in leukocytes and cultured skin fibroblasts. The biochemical tests can be complemented by analysis of the underlying hexosaminidase A gene mutations. Among the Ashkenazi Jewish population, two null hexosaminidase A mutations (a 4–base pair insertion [TATC1278] in exon 11 and a splice site gene defect [IVS12]) account for 96% of disease alleles among cases of Tay-Sachs disease [Frisch et al., 2004]. In this same population of patients, an allelic glycine to serine substitution at position 269 of the hexosaminidase A gene (G269S) represents the most common mutation among the adult-onset cases of GM2 gangliosidosis. Among non-Jewish patients, one mutation (IVS9) accounts for 14% of disease alleles [Cordeiro et al., 2000]. Pseudodeficiency for hexosaminidase A activity associated with decreased enzyme activity in vitro exists and can be clarified by DNA testing or analysis of enzyme activity with use of the natural rather than the artificial substrate. Two mutations (i.e., R247W and R249W) have been associated with pseudodeficient hexosaminidase A activity [Cao et al., 1997]. Investigations have proved that the infantile cases of TaySachs disease are usually due to a combination of severe deleterious mutations, whereas patients with the later onset forms often have a combination of one deleterious mutation and a second “milder” mutation associated with residual enzyme activity (based on in vitro mutagenesis and protein expression studies). The most frequent mutation responsible for the B1 variant of GM2 gangliosidosis is R178H [Matsuzawa et al., 2003]. Pathologic brain studies reveal widespread neuronal GM2 ganglioside storage throughout the cortex and central nuclear structures, the spinal cord, and the autonomic ganglia. Evidence of neuronal storage has been established in fetuses as early as 12 to 22 weeks of gestation. GM2 gangliosides are implicated in synaptogenesis, and it has been speculated that an altered pattern of cellular gangliosides may interfere with normal synaptic transmission [Zhao et al., 2004]. Lyso-derivatives of GM2 gangliosides, which are cytotoxic and may be responsible for inducing the neuronal degeneration, are found to be increased in tissues of patients with GM2 gangliosidoses. When they were initially described, the lysolipids were believed to exert their toxicity through inhibition of protein kinase C. More recently, studies in animal models have found that progressive CNS inflammation (as evident from the expression pattern of several inflammatory markers and cytokines) and an alteration in the integrity of the blood-brain barrier occurred coincidentally with the onset of clinical disease signs [Jeyakumar et al., 2003].

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Prenatal diagnosis for the various types of GM2 gangliosidoses is available through biochemical and molecular testing of cultured cells obtained by chorionic villus sampling or amniocentesis. Definitive therapy for GM2 gangliosidoses is not available. However, substrate reduction therapy is currently under investigation. This approach is based on the inhibition of glucosylceramide synthesis by the imino sugar miglustat and more recently by the galacto-derivative [Andersson et al., 2004]. Preclinical studies have found that animal models of GM2 gangliosidosis (primarily the Sandhoff mouse) given miglustat had a reduction in tissue storage of GM2 ganglioside, with delayed symptom onset and extended survival [Jeyakumar et al., 1999]. The inflammatory changes, a putative mechanism of disease in the untreated mice, and the resultant salutary changes noted in the animal models subjected to bone marrow transplantation have generated renewed interest in cellular approaches to treatment of the GM2 gangliosidoses [Norflus et al., 1998].

Fabry’s Disease Fabry’s disease is an X-linked disorder, first described independently in 1898 by J. Fabry (from Germany) and W. Anderson (from England). It is caused by a deficiency of the lysosomal hydrolase α-galactosidase A and the accumulation of glycosphingolipids (predominantly globotriaosylceramide [ceramide trihexoside] and galabiosylceramide) [Desnick and Brady, 2004]. As a consequence, lipid deposits can be found in the epithelial cells of the cornea, glomeruli and tubules of the kidneys, cardiac myocytes, and endothelial and smooth muscle cells of blood vessels. In the nervous system, lipid deposits are evident in ganglion cells of the dorsal root and autonomic nervous system and in specific cortical and brainstem structures. The distribution pattern of the storage material determines the associated clinical findings, including corneal and lenticular opacities, acroparesthesias, angiokeratomas, and anhidrosis or hypohidrosis (abnormal sweating) [MacDermot et al., 2001a]. Major morbidity in Fabry’s disease derives from renal, cardiac, and brain involvement. Although the disease primarily affects males, a significant proportion of females may also develop disease-related complications; however, onset among carrier females may be delayed [MacDermot et al., 2001b]. Disease incidence has been estimated at 1 in 117,000 males; however, this is likely an underestimate as certain patients may have atypical features (including later onset of cardiac complications) and not be properly identified. Most estimates also do not include females who may be missed because they remain asymptomatic. In the absence of a positive family history, the diagnosis of Fabry’s disease is often delayed (by as much as a decade). In late childhood or adolescence, affected individuals may experience recurrent attacks of burning or lancinating pains in the distal extremities (acroparesthesias), often associated temporally with physical activity and fever [MacDermot and MacDermot, 2001]. The pains may last for days or weeks, and edema of the hands and feet may occur. Physical examination often reveals angiokeratomas (telangiectatic skin lesions) distributed over the “bathing trunk” area between the nipple line and above the knees, in the um-

FIGURE 27-5. Angiokeratoma in a patient with Fabry’s disease.

bilical region, and, in males, over the penis and scrotum (Fig. 27-5). Corneal opacities, noted as a diffuse haze or in a verticillate or whorl-like pattern on slit-lamp examination, are typical; they are usually also seen among females and used to identify potential carriers before the availability of genetic test results. These eye findings do not interfere with vision, although central retinal artery occlusion can rarely occur and may lead to acute blindness [Orssaud et al., 2003]. Unilateral or bilateral hearing loss may develop [Germain et al., 2002]. Most patients also experience abdominal pains and bouts of diarrhea. The vasomotor, sweating, and gastrointestinal problems may reflect a dysfunction of the autonomic nervous system [Kolodny and Pastores, 2002]. In classically affected males, the condition leads to chronic renal insufficiency and eventually renal failure (usually between the ages of 35 and 45 years), often preceded by proteinuria (mostly in the non-nephrotic range) and hyposthenuria [Thadhani et al., 2002]. In early or middle adulthood, patients may develop cardiac conduction problems or

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arrhythmia together with hypertrophic cardiomyopathy and ultimately heart failure [Glass et al., 2004]. Obstructive airway disease may contribute to limitations in exercise tolerance. Patients are also at risk for transient ischemic events or stroke, related to ischemic or thrombotic events [Kolodny and Pastores, 2002]. Cerebral imaging and blood flow studies have paradoxically revealed hyperperfusion attributed to altered vascular reactivity rather than arterial occlusive disease [Moore et al., 2003]. There is increased tortuosity of the blood vessels (predominantly in the posterior circulation) and white matter signal abnormalities. Studies have also found that patients with Fabry’s disease have evidence of endothelial dysfunction and leukocyte activation consistent with a prothrombotic state, which may explain the risk for focal cerebral signs such as aphasia and hemiplegia [Altarescu et al., 2001]. Median cumulative survival in untreated males (50 years) and females (70 years) is reduced [MacDermot et al., 2001a and b]. The diagnosis of Fabry’s disease can be established in males (hemizygotes) on the basis of reduced α-galactosidase A activity in plasma or more reliably in leukocytes and cultured skin fibroblasts. A significant proportion of carrier females (heterozygotes) may have residual enzyme activity that overlaps with measurements obtained for the general population. Mutation analysis is a more reliable means for assignment of female carrier status, although this approach necessitates sequence characterization to identify the causal gene defect because most affected individuals tend to have a “private” mutation (i.e., unique or limited to few affected families). Lyonization may partly explain the wide variability in clinical presentation among carrier females. In addition, certain mutations may be associated with significant residual enzyme activity and may explain the delayed onset of symptoms or atypical disease course observed in some patients [Garman and Garboczi, 2002]. Affected individuals have elevated urinary excretion of ceramide trihexoside, although this requires demonstration with specialized testing (by high-performance liquid chromatography or tandem mass spectrometry). Biochemical or molecular genetic testing can be performed for prenatal diagnosis. Before the introduction of enzyme therapy with agalsidase alfa (Replagal) or agalsidase beta (Fabrazyme), treatment was primarily symptomatic. Analgesics and often opiate-type medications are given for acroparesthesia. The frequency and severity of the pain episodes may be reduced or eliminated by chronic low-dose phenytoin (Dilantin) or carbamazepine (Tegretol) treatment. Patients are usually also given low-dose aspirin or antiplatelet aggregating agents for stroke prophylaxis and angiotensin-converting enzyme inhibitors (e.g., enalapril [Vasotec]) for renal protection in those with proteinuria. Dialysis or kidney transplantation is introduced after renal failure, and patients may require a pacemaker or defibrillator for cardiac conduction abnormalities or arrhythmias. Patients with severe heart valve problems may need a mechanical or tissue heart valve replacement, and cardiac transplantation has been performed in patients with cardiomyopathy and heart failure [Cantor et al., 1998]. Enzyme therapy for Fabry’s disease is safe and effective in reducing the amount of tissue lipid storage. Associated benefits include the reduction of both pain episodes and the use of chronic pain medications, the stabilization or improvement of renal function in patients with normal or

mildly reduced kidney function (glomerular filtration rate of 60 mL/min or higher), and a reduction of excess cardiac mass among those so affected [Pastores and Thadhani, 2002]. Gastrointestinal complaints and abnormal sweating have also improved with enzyme therapy [Hoffmann et al., 2004; Schiffmann et al., 2003]. Cerebrovascular studies have demonstrated reversibility of the functional abnormalities with treatment, which may imply a reduction in risk for stroke [Moore et al., 2002]. Long-term studies will be required to ascertain the effectiveness of therapy in altering the natural history of the disease and improving survival. Additional studies will also be necessary to ascertain the determinants of therapeutic response, which is likely influenced by the presence of preexisting pathologic processes (e.g., glomerulosclerosis, calcified and stenotic heart valves). A significant proportion of enzyme-treated patients form antibodies against the administered protein, which results in neutralization of enzyme activity [Linthorst et al., 2004]. The long-term implications of antibody formation will need to be carefully assessed, although serial measurements indicate immunotolerance (i.e., a decrease in antibody titers over time) [Pastores, 2004]. Gene therapy experiments currently being undertaken in the mouse model of Fabry’s disease appear to suggest promising results [Ziegler et al., 2004].

Gaucher’s Disease The disease described by P. C. E. Gaucher (in 1882) as an epithelioma of the spleen is known to be a lipid storage disorder resulting from a deficiency of the lysosomal enzyme glucocerebrosidase (acid β-glucosidase) [Zhao and Grabowski, 2002]. The accumulation of its incompletely metabolized substrate, glucocerebroside (glucosylceramide), is confined to cells of monocyte-macrophage lineage. Glucocerebroside in the peripheral system is derived primarily from the breakdown of senescent red and white blood cell membranes. In the CNS, glucocerebroside is a byproduct of the catabolism of globosides and gangliosides. There are three major clinical subtypes, delineated on the basis of the presence or absence of neurologic involvement. Assignment of clinical subtype is based on observations of the age at onset, evolution of the disease, and, when it is present, the rate and severity of psychomotor deterioration [Goker-Alpan et al., 2003]. Type 1 Gaucher’s disease encompasses the non-neuropathic type associated with hepatosplenomegaly, anemia and thrombocytopenia, pulmonary involvement, and bone disease. Although type 1 Gaucher’s disease has been referred to as the adult type, this designation is misleading as onset of disease may be evident from childhood. There is wide heterogeneity in clinical presentation. A small proportion of patients remain asymptomatic for most of their adult lives; others may develop significant disease progression earlier. Although the patients do not have a primary neurodegenerative disease, there can be secondary neurologic complications (e.g., local nerve injury due to hemorrhage and entrapment or from spinal cord compression with collapse of a vertebral body) [Pastores et al., 2003]. There have also been reports of adult patients with type 1 Gaucher’s disease who have developed Parkinson’s disease, although it is not certain whether this observation represents an unfortunate coincidence [Lwin et al., 2004]. Neuropatho-

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A

B C

FIGURE 27-6. A, Hepatosplenomegaly in a child with Gaucher’s disease type 1, a presentation also typical for patients with Niemann-Pick disease type B. Examination of bone marrow cells demonstrates differences in the appearance of the storage material within histiocytes. B, Foamy histiocyte seen in patients with Niemann-Pick disease. C, Wrinkled silk appearance of the cytoplasm with eccentric nucleus in lipid-engorged histiocytes seen in a patient with Gaucher’s disease.

logic studies of brains obtained from patients with type 1 Gaucher’s disease have revealed focal regions of gliosis (especially in the hippocampal CA2-CA4 region and calcarine cortex) and the presence of α-synuclein–immunoreactive cortical and brainstem-type Lewy bodies [Wong et al., 2004]. These observations suggest a potential causal relationship that requires further investigation. Type 1 Gaucher’s disease is a pan-ethnic disorder that has been noted as prevalent among individuals of Ashkenazi Jewish descent (carrier frequency of approximately 1 in 20) [Colombo, 2000]. In most populations, type 1 Gaucher’s disease represents the most common lysosomal storage disorder with an estimated frequency of about 1 in 50,000 [Meikle et al., 1999]. The hematologic and visceral findings that typify type 1 Gaucher’s disease are also encountered in the neuropathic subtypes (Fig. 27-6). Type 2 Gaucher’s disease represents the acute neuropathic form, associated with disease onset before the age of 12 months. Patients develop spasticity with head retraction (opisthotonos), dysphagia, and a rapidly fatal course (with death usually between 2 and 3 years of age). Laryngeal stridor and trismus (due to bulbar spasticity) are added problems, and aspiration pneumonia is a frequent complication. Patients do not have dysmorphic features or the cherry-red spot that is typical of infantile Tay-Sachs disease and Niemann-Pick disease. However, the most severely affected patients can present with congenital ichthyosiform-collodion skin abnormalities or nonimmune hydrops fetalis [Burin et al., 2004]. The latter phenotype is characterized by an aggressive course, with death in the first few weeks of life. Similar findings were noted in the animal (mouse) model for Gaucher’s disease in association with an alteration of the glucocerebroside to ceramide ratio and a disruption in the lipid membranes at the level of the stratum corneum

[Sidransky et al., 1992]. Bone involvement, characteristically found in patients with types 1 and 3 Gaucher’s disease, is not seen in type 2 Gaucher’s disease, perhaps because there is insufficient time for the skeletal disease process to evolve. Type 3 Gaucher’s disease, which may manifest before the age of 2 years, is associated with chronic neurologic problems including tonic-clonic and myoclonic seizures, ataxia, and extrapyramidal rigidity, often complicated by severe pulmonary involvement (including interstitial lung disease) [Campbell et al., 2003]. Paralytic strabismus with oculomotor apraxia (i.e., saccadic initiation failure) is a characteristic finding in patients with primary neuropathic Gaucher’s disease. Brainstem auditory-evoked response testing often reveals diverse results, including prolonged peak and interpeak latencies for waves I to V and generally dysmorphic wave formation [Bamiou et al., 2001]. The clinical expression of type 3 Gaucher’s disease can be complex, but neurologic problems can occasionally be restricted to supranuclear horizontal gaze palsy despite significant extraneurologic systemic problems. An increased number of cases have been identified in the Norrbottnian region of Sweden, attributed to a founder effect (for the L444P mutation) [Dahl et al., 1993]. The founder effect refers to the phenomenon wherein the increased frequency of a certain gene defect within a defined population is explained by common ancestry (i.e., a shared identity by descent) [Slatkin, 2004]. The basis of primary neurologic involvement in certain Gaucher’s disease subtypes has not been fully elucidated. In contrast to the amount of lipid storage material measured in the liver and spleen, levels of glucocerebroside are not significantly elevated in brain tissue. Glucosylsphingosine (psychosine), an alternative metabolic byproduct of severely deficient glucocerebrosidase deficiency, is believed to play a contributory role [Schueler et al., 2003]. Evidence of

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FIGURE 27-7. This section of occipital cortex in an infant with Gaucher’s disease reveals marked neuronal loss and associated astrogliosis. Occasional neurons are distended with lipid. (Courtesy Joo Ho Sung, Minneapolis, MN.)

neuronal apoptosis has been demonstrated in type 2 Gaucher’s disease, and lipid-filled cells can be found in the perivascular Virchow-Robin spaces. Neuronophagic microglial nodules can also be found in several regions of the brain (e.g., cortex, thalamus, basal ganglia, brainstem, and cerebellum) and in the spinal cord (Fig. 27-7). Elevation of glucocerebroside in neurons, possibly involving endoplasmic reticulum membranes, leads to increased calcium stores (possibly secondary to modulation of the ryanodine receptors) [Lloyd-Evans et al., 2003]. These cellular changes may be added factors that promote neuropathic forms of Gaucher’s disease. Analysis of gene expression profiles in brains of the Gaucher’s disease mouse model revealed downregulation of the bcl-2 gene in the brainstem and cerebellum but not in cortex [Hong et al., 2004a]. In situ labeling of DNA fragmentation by the terminal transferase–mediated dUTP nick-end labeling (TUNEL) assay confirmed that apoptosis occurred at these sites. These observations suggest that the accumulation of either glucocerebroside or glucosylsphingosine affects the expression of apoptosis mediators and could be responsible for neuronal cell death. An atypical rare variant characterized predominantly by cardiac problems, such as aortic and mitral valve calcification, appears to be restricted to patients with a unique

genotype (i.e., homozygosity for the D409H mutation) [George et al., 2001]. These findings were first reported among the Arab patients with Gaucher’s disease from the Jenin area, but this phenotype has since been reported among other ethnic groups. Rare patients with evidence of glucocerebroside storage and normal glucocerebrosidase activity in vitro have been described; careful investigations have revealed a deficiency of saposin [Bradova et al., 1993]. Patients with saposin C or prosaposin deficiency usually present with symptoms characteristic of subacute neuropathic Gaucher’s disease (i.e., progressive horizontal ophthalmoplegia, pyramidal and cerebellar signs, myoclonic jerks, and generalized seizures). Saposin C, which is derived from the proteolytic cleavage of a precursor molecule (prosaposin), is a co-factor required by glucocerebrosidase in the hydrolysis of glucocerebroside. In biochemical assays to measure glucocerebrosidase activity, the role of saposin C is replaced by the use of detergents. This replacement explains the normal results obtained when the activity of glucocerebrosidase is measured in vitro. Prosaposin, through activation of mitogen- activated protein kinases, may act as an apoptosis suppressor [Misasi et al., 2004]. Thus, a prosaposin deficiency could promote neuronal cell loss. Several markers, readily measured in the plasma or serum of patients with Gaucher’s disease, are often elevated. Testing often reveals elevated measures of tartrate-resistant acid phosphatase, angiotensin-converting enzyme, ferritin, and chitotriosidase activity [Aerts and Hollak, 1997; Wajner et al., 2004]. These changes have not been associated with a specific pathologic mechanism and have been taken to reflect the systemic burden of disease. Polyclonal hypergammaglobulinemia is also a frequent finding, particularly in the elderly [Marti et al., 1998]. Bone involvement (e.g., severe osteopenia and osteonecrosis of major joints including the humeral and femoral heads) can be a major source of morbidity for patients with types 1 and 3 Gaucher’s disease. The indicators of bone turnover (e.g., osteocalcin, bone-specific alkaline phosphaase, N-telopeptides) have not been consistently abnormal, even when significant bone disease exists, suggesting the dominance of local (possibly vascular) over systemic factors [Ciana et al., 2003; Pastores and Meere, 2005; Zimran et al., 2004]. Cardiopulmonary complications can occur, and severe interstitial lung disease and alveolar consolidation have been described. Rare cases of patients with pulmonary hypertension, which has been found primarily among splenectomized adult patients, have also been reported [Mistry et al., 2002]. The diagnosis of Gaucher’s disease, regardless of clinical subtype, is based on deficient glucocerebrosidase activity, which can be measured in peripheral blood leukocytes or cultured skin fibroblasts. Prenatal diagnosis for Gaucher’s disease is based on analysis of glucocerebrosidase activity in cultured chorionic villi or amniocytes. Biochemical testing is often complemented by analysis of the common mutations (specifically, N370S, L444P, IVS2+1, 84insG, and R496H). Carrier assignment can also be performed more reliably through mutation analysis. The five gene defects noted account for approximately 96% of disease alleles among Ashkenazi Jewish individuals but

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for only about 40% to 60% of mutations among the nonJewish patients (wherein the 55–base pair deletion is frequent) [Wallerstein et al., 2001]. Correlation studies have revealed genotype-phenotype concordance to be imperfect, with isolated exceptions. For instance, the presence of at least one N370S (1226G) allele precludes development of primary CNS involvement. In general, patients homozygous for the N370S mutation tend to have milder disease compared with other patients who are compound heterozygotes for the other more deleterious alleles. Patients homozygous for the L444P mutation tend to have severe disease, often (but not invariably) associated with primary neurologic manifestations. Examination of bone marrow tissue (not the preferred method of diagnosis) reveals clumps of lipid-engorged macrophages (Gaucher cells). Magnetic resonance imaging (MRI) of the spine (sagittal views) and femurs (coronal views) has been useful in assessment of the degree of bone marrow infiltrative disease in Gaucher’s disease [Maas et al., 2003]. On occasion, Gaucher-like cells (or pseudo-Gaucher cells) in isolation may be detected in other disorders, such as chronic myelocytic leukemia, disease states associated with increased cell turnover [Stewart and Jones, 1999]. True Gaucher cells are periodic acid–Schiff positive, and their cytoplasm has an irregular wrinkled appearance (see Fig. 27-6B). Studies have revealed that Gaucher cells are alternative activated macrophage-like cells that express acid phosphatase, CD68, CD14, and HLA class II but not CD11b, CD40, or dendritic cell markers [Boven et al., 2004]. Furthermore, Gaucher cells exhibited infrequent immunoreactivity for mannose receptor and did not express proinflammatory cytokines such as tumor necrosis factor-α and monocyte chemoattractant protein 1, but they did express the markers CD163, CCL18, and interleukin-1 receptor antagonist. Before the introduction of enzyme therapy, the care of affected individuals was primarily palliative and included analgesics for bone pain, blood transfusions for severe anemia and thrombocytopenia, and splenectomy for severe hypersplenism. In addition, supplemental agents (such as bisphosphonates, calcium, and vitamin D) have been administered to patients (primarily adults) with Gaucher’s disease and severe osteopenia. Pregnancy in affected women requires careful monitoring and attention to risk reduction for bleeding and other problems, especially around labor and delivery in those who are severely thrombocytopenic [Elstein et al., 2004]. Enzyme replacement therapy is based on the regular intravenous administration of glucocerebrosidase, initially purified from human placenta (alglucerase [Ceredase]) and more recently by use of the recombinant enzyme (imiglucerase [Cerezyme]) and generated from overexpression in cultured mammalian cells [Grabowski et al., 1995]. The therapeutic protein is modified from its native form by sequential deglycosylation to expose the mannose residues necessary for targeted cellular uptake through the mannose receptor. Enzyme therapy reverses the hematologic and visceral manifestations of Gaucher’s disease and leads to the stabilization or improvement of bone involvement [Charrow et al., 2004; Weinreb et al., 2002]. Enzyme therapy does not influence the ultimate progression of neurologic complications in patients with type 2 Gaucher’s disease, and thus its use for

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this subgroup of patients is deemed inappropriate. Although intravenously administered enzyme does not lead to delivery of significant amounts of the protein across the blood-brain barrier, its use in patients with type 3 Gaucher’s disease leads to improved quality of life (as a consequence of the reversal of the extraneurologic disease manifestations). Abnormal brainstem auditory-evoked response findings noted at baseline in eight children with type 3 Gaucher’s disease continued to deteriorate with high-dose enzyme replacement therapy [Campbell et al., 2004]. Thus, patients with type 3 Gaucher’s disease and their parents should be counseled appropriately about long-term outcome and the possibility that certain aspects of the disease may continue to progress. Enzyme therapy alone also does not appear to improve bone density in patients with significant osteopenia, which has been demonstrated to respond to supplemental bisphosphonates [Wenstrup et al., 2004]. Substrate reduction therapy (with miglustat [Zavesca]) has been shown to lead to improvements in several key clinical features of Gaucher’s disease. This approach, when it is used alone (i.e., monotherapy), is based on the partial reduction of the synthesis of the substrate (to meet the metabolic capacity of the mutant enzyme) [Cox et al., 2000; Pastores and Barnett, 2003]. Studies have proved that a significant proportion of the orally administered agent (miglustat) can be found in cerebrospinal fluid [Platt and Butters, 2000]. Clinical trials with this drug in patients with type 3 Gaucher’s disease are currently under way to determine whether neurologic outcomes can be improved in treated patients when it is used in combination with enzyme replacement therapy. A minority of patients (about 10% to 15%) receiving enzyme replacement therapy have developed antibodies (primarily immunoglobulin G) against the infused glucocerebrosidase, although only a few have developed overt adverse events (mainly pruritus and hives) that respond readily to oral premedications (such as antihistamines) [Zhao et al., 2003]. This safety profile has led to consideration of enzyme therapy as the preferred treatment for patients with Gaucher’s disease, including those with the type 3 disease, pending the outcome of the clinical trials with miglustat. In patients with type 3 Gaucher’s disease and progressive CNS manifestations, bone marrow transplantation has been performed with favorable outcomes. However, the procedural risks associated with bone marrow transplantation and the prospect of graft-versus-host disease have limited its indication to carefully selected cases. The feasibility of gene therapy for Gaucher’s disease remains to be re-examined [Hong et al., 2004b].

Niemann-Pick Disease, Including Types A and B Niemann-Pick disease is the eponymous designation for the storage disorders characterized by a primary deficiency of acid sphingomyelinase, associated with the progressive storage of sphingomyelin (phosphorylcholine) in the reticuloendothelial system. Impaired formation of ceramide within the lysosome or in the plasma membrane and its role as an apoptosis inducer are being actively examined as a potential added mechanism of disease [Cock et al., 1998]. The original patient described by A. Niemann (1914), an 18-month-old girl with hepatosplenomegaly, presented with progressive intellectual and motor deterioration. These

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clinical features were reminiscent of type 2 Gaucher’s disease, but eventually L. Pick (1927) provided further clinical and pathologic descriptions that helped in the delineation of these two disorders. The causal enzyme defect was first isolated by R.O. Brady and colleagues at the National Institutes of Health (in 1966). Currently, Niemann-Pick disease types A and B are used to refer to the infantile neuropathic and later onset nonneuropathic forms of the disease, respectively. In actuality, both Niemann-Pick disease types A and B are allelic disorders (i.e., involving different mutations of the same gene) that result in primary deficiency of acid sphingomyelinase and represent the spectrum of phenotypes associated with mutations of the acid sphingomyelinase gene. Additional subtypes, referred to as Niemann-Pick disease types C and D in a classification scheme proposed by A. Crocker (1961), have clinical features that overlap with the classic NiemannPick disease types A and B. Eventually, Niemann-Pick disease types C and D were recognized as being associated with secondary and not primary acid sphingomyelinase deficiency. Indeed, a different cause for Niemann-Pick disease type C had been suggested by studies involving the fusion of cells (or formation of heterokaryons) from type A or B disease with type C cells. More recent investigations have found that Niemann-Pick disease types C and D are also allelic disorders due to mutations of one of two different genes (designated NPC1 and NPC2) leading to disruption in the trafficking or metabolism of cholesterol and sphingolipids [Walkley and Suzuki, 2004]. These various NiemannPick disease subtypes are all inherited as autosomalrecessive traits. Patients with early infantile Niemann-Pick disease (type A) present with failure to thrive and hepatomegaly in the first few weeks or months of life, usually before evident neurologic regression and the appearance of the macular cherry-red spot. The disorder is prevalent among individuals of Ashkenazi Jewish ancestry (carrier frequency of 1 in 90). In contrast to Gaucher’s disease, there is marked abdominal distention due to hepatosplenomegaly and liver dysfunction. Serum levels of acid phosphatase are normal. Affected infants do not have dysmorphic facial features or skeletal deformities. Respiratory problems develop, and chest radiographs often reveal a fine miliary infiltration of the lungs [Minai et al., 2000]. There is developmental delay, with head lag and the inability to sit, and eventual regression with reduction in spontaneous movements and loss of interest in the surroundings. Unlike in Tay-Sachs disease, an exaggerated acousticomotor response cannot be elicited, and head circumference is either normal or moderately reduced. With disease progression, there is rigidity and opisthotonos. The findings on cerebrospinal fluid examination are normal. Death occurs in the second or third year of life. Niemann-Pick disease type B is associated with visceral involvement (and by convention no neurologic problems) [Kolodny, 2000; Wasserstein et al., 2004]. The absence of significant brain involvement may be a consequence of the underlying mutation’s association with residual enzyme activity. Hepatosplenomegaly and pulmonary infiltrative disease may be detected in late infancy or early childhood. Progressive pulmonary infiltration is generally the major disease complication. On high-resolution chest computed tomography (CT), the main abnormalities consist of thick-

FIGURE 27-8. Ballooned anterior horn cells of the spinal cord in a 5-year-old boy with late infantile Niemann-Pick disease. Hematoxylin and eosin stain.

ening of the interlobular septa and patchy areas of groundglass attenuation [Minai et al., 2000]. These changes correspond to the reticular or reticulonodular pattern of abnormalities, involving mainly the lower lung zones, that can be seen on chest radiographs. Abnormal linear growth and delayed skeletal maturation are also common in children and adolescents with Niemann-Pick disease type B [Wasserstein et al., 2003]. An intermediate phenotype may be encountered, with retinal degeneration and other neurologic signs (including slowed nerve conduction velocities) appearing in late childhood, adolescence, or adulthood (Fig. 27-8). A study involving 45 patients (23 males and 22 females, ranging in age from 3 to 65 years) with Niemann-Pick disease type B revealed the presence of macular halos or cherry-red spots that incidentally were found not to be an absolute predictor of neurodegeneration [McGovern et al., 2004b]. The course of disease in patients with a phenotype intermediate between type A and type B is similar to that observed in type 3 Gaucher’s disease, although the latter condition is often characterized by oculomotor apraxia and the absence of the cherry-red spot. In addition, there are differences found in the levels of chitotriosidase activity between patients with Gaucher’s disease (600-fold increase) and those with Niemann-Pick disease (30-fold increase) [Wajner et al., 2004]. Investigations of lipid abnormalities in 10 patients with Niemann-Pick disease type A and 30 additional patients with Niemann-Pick disease type B revealed that all had low (<35 mg/dL) high-density lipoprotein cholesterol [McGovern et al., 2004a]. Also noted were hypertriglyceridemia and increased low-density lipoprotein cholesterol in 25 of 40 (62%) and 27 of 40 (67%) of the patients, respectively. Coronary artery calcium scores were positive (>1.0) in 10 of 18 type B patients studied, which suggests that Niemann-Pick

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disease may be associated with a risk for early atherosclerotic heart disease. The diagnosis of Niemann-Pick disease types A and B can be established on the basis of deficient acid sphingomyelinase activity, demonstrable in leukocytes or cultured skin fibroblasts. It has been reported that the biochemical assay to measure acid sphingomyelinase activity by use of the artificial substrate 2-N-(hexadecanoyl)-amino-4-nitrophenyl phosphorylcholine can occasionally lead to a missed diagnosis [Harzer et al., 2003]. In this particular study, four patients had the Q292K mutation on at least one allele. Thus, when the diagnosis of Niemann-Pick disease remains strongly suspected and a negative result is obtained on enzyme testing, it is important to determine whether the assay was performed with the artificial substrate (as is the custom in most laboratories). Another approach in these cases may entail examination of bone marrow (see Fig. 27-6A). Bone marrow examination (not the preferred initial means of diagnosis) reveals lipid-laden “foamy” histiocytes (with a soap bubble appearance), also evident in tissue sections obtained from the liver. The accumulated material is sudanophilic and periodic acid–Schiff negative. On occasion, the atypical storage cells in bone marrow have been designated sea-blue histiocytes [Candoni et al., 2001]. Three acid sphingomyelinase gene mutations (specifically, two missense defects, R496L and L302P, and one frameshift mutation, fsP330) represent the most common Niemann-Pick disease gene defects, accounting for approximately 95% of disease alleles among Ashkenazi Jewish patients with Niemann-Pick disease type A [Schuchman and Miranda, 1997]. Among Niemann-Pick disease type B cases from the North African region of Maghreb, a three-base inframe deletion of exon 6 (R608del) is frequent (87% of mutant alleles). This mutation was also found to be prevalent among patients with Niemann-Pick disease type B from the Grand Canary Islands of Spain, located on the northwest coast of Africa [Fernandez-Burriel et al., 2003]. Among patients with Niemann-Pick disease type B, homozygosity for the R608del mutation tends to be associated with a relatively milder phenotype compared with other combinations of acid sphingomyelinase gene mutations [Simonaro et al., 2002]. Several mutations in patients (primarily of Italian ancestry) with Niemann-Pick disease type B have been identified; in these studies, no correlation was found between onset of pulmonary symptoms and genotypes [Pittis et al., 2004]. Information about the causal mutation for specific families enables accurate carrier assignment. NiemannPick disease types A and B are pan-ethnic disorders, but the mutations that lead to disease outside of the populations just described tend to be private and require analysis of the acid sphingomyelinase gene sequence for identification. Prenatal diagnosis can be made by assay of acid sphingomyelinase activity in cultured chorionic villi or amniocytes [Vanier, 2002]. Preimplantation genetic diagnosis for Niemann-Pick disease type B has been reported [Hellani et al., 2004]. Only symptomatic treatment is available for NiemannPick disease types A and B, although enzyme therapy is under consideration for subtype B. Repeated subcutaneous implantation of amniotic epithelial cells has not been shown to influence the ultimate disease course in prior therapeutic studies [Bembi et al., 1992]. Niemann-Pick disease type A is not amenable to hematopoietic stem cell transplantation

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because of its rapid progression, but limited experience suggests that hematopoietic stem cell transplantation may have some beneficial effects for Niemann-Pick disease type B. Report of a 16-year follow-up of allogeneic bone marrow transplantation carried out on a 3-year old girl with NiemannPick disease type B revealed severe neurologic involvement (including bilateral cherry-red spots), despite normal findings on neurologic examination at the time of transplantation [Victor et al., 2003]. However, baseline pulmonary infiltration regressed after bone marrow transplantation, although there was no clinical evidence of pulmonary insufficiency. Her post-transplant course was complicated by severe graft-versus-host disease and respiratory arrest, factors that may have had an adverse influence on the neurologic outcome.

Niemann-Pick Disease, Including Types C and D Niemann-Pick disease type C is a neurovisceral lipid storage disorder associated with a wide spectrum of clinical phenotypes. It is characterized neuropathologically by the widespread appearance of axonal spheroids, an accumulation of intraneuronal cytoplasmic inclusions, and neuronal loss [Vanier and Millat, 2003]. The disease incidence has been estimated at 1 in 150,000. Approximately 95% of cases have mutations in a gene (designated NPC1) that encodes a large transmembrane glycoprotein, localized primarily in the endosomes [Sturley et al., 2004]. A smaller group of patients who are clinically and biochemically indistinguishable from individuals with NPC1 mutations have a defect of the NPC2 gene, which encodes a small soluble lysosomal protein with cholesterol-binding properties (previously identified as epididymal secretory glycoprotein 1 [HE1]) [Vanier and Millat, 2004]. It is likely that both protein products (i.e., NPC1 and NPC2) function in a coordinated fashion, as studies performed on skin fibroblasts obtained from patients with either mutation reveal the accumulation of unesterified cholesterol and glycolipids in the lysosome–late endosome. Furthermore, the mating of mice genetically deficient for each protein (i.e., NPC1 or NPC2) results in the generation of double-deficient mice that resemble the single-disease mutants [Pentchev, 2004]. The classically affected patients (accounting for 50% to 60% of cases) often have a benign, self-limited jaundice in early infancy and an unremarkable childhood [Vanier and Millat, 2003]. Eventually, between the ages of 3 and 8 years (less often after the 10th year of life), they are noted to be clumsy, have a tendency to fall, and develop ataxia. Hepatosplenomegaly may be noted, and supranuclear (vertical) gaze palsy, which may be accompanied by blinking or head thrusting, is evident on examination. With disease progression, patients experience dysarthria, dysphagia, and dementia. Additional neurologic manifestations include dystonia, choreoathetosis, and seizures (of the generalized tonic-clonic and myoclonic type). A proportion of patients with Niemann-Pick disease type C may present at birth with ascites or develop neonatal (cholestatic) jaundice and a rapidly fatal disease. Cataplexy also occurs late in the disease but rarely may be the presenting feature of Niemann-Pick disease type C [Vankova et al., 2003]. Typically, the loss of postural tone is evoked by a humorous stimulus (gelastic cataplexy). Examination of

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cerebrospinal fluid has revealed reduced hypocretin-1 levels in two patients with Niemann-Pick disease type C, which suggests that the storage abnormalities may have an impact on the hypothalamus and, more specifically, hypocretincontaining cells [Kanbayashi et al., 2003]. These changes may be partially responsible for the sleep abnormalities and cataplexy seen in these patients. Psychiatric disturbances including psychosis have been reported to occur in patients with Niemann-Pick disease type C, usually coinciding with the onset of puberty [Josephs et al., 2003]. Most patients develop spasticity and rigidity and die of pulmonary complications in their teens or early adulthood. Pertinent negative findings include the absence of retinal changes, visual failure, and signs of lower motor neuron disease; cerebrospinal fluid examination findings are also normal. In addition to neuronal storage, studies involving the mouse model of Niemann-Pick disease type C have revealed conspicuous hypomyelination in the cerebral white matter and corpus callosum. In brains from patients with NiemannPick disease type C, studies have found neuropathologic abnormalities (e.g., formation of tauopathies and neurofibrillary tangles) similar to those found in Alzheimer’s disease [Nixon, 2004]. Furthermore, the aggregated amyloid precursor protein cleavage product amyloid beta accumulates in late endosomes. In addition, presenilins (normally localized in late endosomes. In addition, presinilins (normally localized in the endoplasmic reticulum and endoplasmic reticulum–Golgi intermediate compartment) were distributed to late endosomes. These observations suggest that endosome dysfunction and the disruption of cholesterol homeostasis may promote mechanisms common to both Niemann-Pick disease type C and Alzheimer’s disease. In the mouse model, intracerebroventricular administration of two potent inhibitors (roscovitine and olomoucine) of the cyclin-dependent kinases attenuated the hyperphosphorylation of the neurofilament tau and mitotic proteins [Zhang et al., 2004]. These observations were associated with a reduction in the number of spheroids, the modulation of Purkinje neuron death, and the amelioration of the motor defects in these mice. Immunohistochemical studies involving the HE1/NPC2 protein revealed its localization in pyramidal or projection neurons in the cerebral cortex and amygdala and in the Purkinje neurons of the cerebellum [Ong et al., 2004]. This regional pattern of expression is similar to the findings with NPC1, with a low level of expression of both proteins in regions derived from the diencephalon (such as the thalamus and hypothalamus). In contrast to NPC1, which is found predominantly in astrocytes, HE1/NPC2 has been observed mainly in neurons. The HE1/NPC2 protein has also been found in the cytosol of dendrites and on postsynaptic densities. These results suggest that NPC1 and HE1/NPC2 are differentially enriched in astrocytes and neurons, respectively, and that HE1/NPC2 may function in supporting the integrity of the postsynaptic densities of neurons [Ong et al., 2004]. The diagnosis of Niemann-Pick disease type C is based on demonstration in cultured skin fibroblasts of impaired cholesterol esterification and intralysosomal storage of unesterified cholesterol (which gives off an intense perinuclear fluorescence with filipin staining) (Fig. 27-9). Identification of the causal NPC1 or NPC2 mutations requires specialized

FIGURE 27-9. Filipin-stained fibroblasts viewed under fluorescent light from a patient with Niemann-Pick disease type C. See also Color Plate.

studies because of the existence of genetic heterogeneity (i.e., similar clinical disorder or phenotype resulting from two different gene defects) and private mutations in most of the patients (outside defined populations). In one study involving 143 unrelated patients with Niemann-Pick disease type C, mutation analysis led to identification of 251 of 286 (88%) disease alleles [Park et al., 2003]. The most common NPC1 mutation, I1061T, was detected in 18% of NPC alleles. The designation Niemann-Pick disease type D was used to describe affected individuals among the French Acadians in Nova Scotia (Canada) [Greer et al., 1999]. In these patients, disease onset is usually between the ages of 2 and 4 years. After characterization of the NPC1 gene, studies revealed a common founder mutation (G309T) in this population of patients. Similarly, a specific gene defect (I106T) has been identified among Spanish American cases of Niemann-Pick disease type C in the Upper Rio Grande Valley (Colorado) attributed to a founder effect [Millat et al., 1999]. The management of patients with Niemann-Pick disease type C is primarily symptomatic. A therapeutic trial involving dietary restriction of cholesterol and the administration of cholesterol-lowering agents (i.e., statins) has resulted in the reduction of hepatic and plasma cholesterol levels but no effect on neurologic outcome [Patterson and Platt, 2004].

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The secondary accumulation of GM2 ganglioside in the brains of patients with Niemann-Pick disease type C, and as also shown in the mouse model, is believed to contribute to the neuronal degeneration. These observations have been used to justify clinical trials with miglustat, which are currently taking place. Preclinical studies in the knockout mouse model treated with miglustat have led to delayed onset of symptoms and increased survival. The outcome in the affected mice was enhanced when substrate reduction therapy was given in combination with bone marrow transplantation [Jeyakumar et al., 2001]. Miglustat given to one patient with Niemann-Pick disease type C reduced pathologic lipid storage, improved the endosomal uptake, and returned lipid trafficking to normal in peripheral blood B lymphocytes [Lachmann et al., 2004]. Demonstration that treatment with miglustat, which has no direct effect on cholesterol metabolism, corrects the abnormal lipid trafficking suggests that glycosphingolipid accumulation is the primary pathogenetic event.

Farber’s Disease (Lipogranulomatosis) Farber’s disease, initially described by S. Farber and colleagues (1957), is characterized by widespread granulomatous tissue infiltration by ceramide-containing foamy macrophages resulting from a deficiency of lysosomal acid ceramidase [Antonarakis et al., 1984]. Examination of the lysosomal deg-

FIGURE 27-10. Severely cachectic patient with Farber’s disease exhibiting multiple subcutaneous lymphogranulomas and periarticular swelling. (From Gellis S, Feingold M. Contributed by T.R.C. Sisson. Am J Dis Child 1971;122:573.)

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FIGURE 27-11. Section of spinal cord from a patient with Farber’s disease exhibiting swollen neurons, neuronophagia, and loss of neurons in the anterior horn area. (Courtesy Hugo W. Moser, Baltimore, MD.)

radation of sphingomyelin-derived ceramide in situ with use of the affected patient’s skin fibroblasts has found a significant correlation between the ceramide accumulation and the severity of Farber’s disease [Levade et al., 1995]. Clinical features include painful swollen and deformed joints and dysphonia (hoarse cry), with onset usually before the age of 4 months [Cartigny et al., 1985; Fujiwaki et al., 1992] (Fig. 27-10). Dyspnea due to infiltration of the peribronchial and perialveolar spaces is common. Firm subcutaneous nodules may be found on the fingers, wrist, elbows, and spine. Hand radiographs reveal destructive juxtaarticular bone lesions [Toppet et al., 1978]. Although lipid storage is present in neurons and glial cells (mainly in the brainstem nuclei, basal ganglia and ganglion cells of the retina, and anterior horn cells), neurologic signs are usually not prominent (Fig. 27-11). Formal evaluation of any developmental problem is complicated by the severe inanition and fixed joints [Jameson et al., 1987]. Some patients have progressive mental deterioration and visual loss. Cerebrospinal fluid protein levels are increased. Anorexia, vomiting, and swallowing difficulties lead to cachexia. Severe muscle atrophy, in part a consequence of immobilization of the joints, is also seen. Death generally occurs within the first 2 years of life, although there are rare cases of patients with an attenuated form of the disease and more prolonged clinical course [Pavone et al., 1980]. The diagnosis is often based on quantification of ceramide (a fatty acylsphingosine) accumulation in tissues or cultured skin fibroblasts [Mitsuo et al., 1988]. Analysis of ceramidase activity in vivo can also be performed on the same tissues; however, residual ceramidase activity has not been found to correlate with disease severity. Several mutations in the gene encoding lysosomal acid ceramidase have been identified [Bar et al., 2001]. There is no specific treatment, although affected individuals may obtain relief from joint pains with analgesics. Supportive care may be required for laryngeal and respiratory symptoms.

Krabbe’s Disease (Globoid Cell Leukodystrophy) In 1916, K. Krabbe, a Danish neurologist, described two siblings with an acute infantile diffuse “sclerosis” of the

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A

FIGURE 27-12. Clumps of globoid and epithelioid cells in cerebral white matter in Krabbe’s disease. The background area demonstrates demyelination and gliosis. (Courtesy Joo Ho Sung, Minneapolis, MN.)

brain (characterized by unusual cells in the white matter termed globoid cells by Collier and Greenfield) (Fig. 27-12). The condition has since been attributed to a deficiency of galactocerebroside β-galactosidase (β-galactosidase C, galactosylceramidase), which normally cleaves the bond between ceramide and the galactose moiety of galactosylceramide [Suzuki, 2003]. Disease incidence in the general population is estimated at 1 in 201,000, although an increased prevalence (1 in 25,000) of the early infantile form has been reported in Sweden [Arvidsson et al., 1995]. An authentic animal model (the twitcher mouse, which is galactosyceramidase deficient) has been described [Yagi et al., 2004]. The majority of cases are an early infantile form (with onset between 3 and 6 months of life) (Fig. 27-13). Patients demonstrate irritability and develop rapidly progressive generalized rigidity and tonic spasms [Korn-Lubetzki and Nevo, 2003]. Affected infants often have a clenched fist and develop myoclonic jerks. Blindness and optic atrophy appear later, along with pendular nystagmus. Abnormalities of the brainstem auditory-evoked responses are among the first objective indications of CNS disease; visual-evoked potential abnormalities also occur. Brain MRI shows signs of leukodystrophy, with symmetric signal abnormalities usually noted in the periventricular region of the posterior cerebral hemispheres. Fluorine 18–labeled 2-fluoro-2-deoxyglucose

B FIGURE 27-13. A, This female first manifested signs and symptoms of Krabbe’s disease at 2 years of age. She underwent a progressive course thereafter. There is fisting of the right hand, folding of the thumb, and spasticity of both legs. She experiences frequent episodes of myoclonic and generalized tonic-clonic seizures. B, A 9-month-old male with Krabbe’s disease manifesting opisthotonos, flexion of the arms, cortical thumb positioning, extension of the legs, spontaneous extensor toe signs, and extreme irritability.

positron emission tomography in one 21/2-year-old male revealed a marked decrease in the metabolism of the left cerebral cortex and no uptake in the caudate heads [Al-Essa et al., 2000]. However, normal glucose uptake was observed in the thalami, lentiform nuclei, and cerebellum. Cerebrospinal fluid protein is elevated in Krabbe’s disease, and examination of the peripheral nervous system reveals markedly reduced nerve conduction velocities [Husain et al., 2004]. There is no visceromegaly or skeletal abnormalities. Death, usually due to respiratory difficulties and bronchopneumonia, occurs between the ages of 1 and 2 years. In a small proportion (about 10% to 15%) of patients, onset is in the late infantile or juvenile period. Several such cases have been identified in southern Italy (and Sicily). These patients exhibit signs of progressive walking problems, spastic paraparesis, and cerebellar ataxia, mostly before the

Pastores and Kolodny / Lysosomal Storage Diseases

age of 5 years [Lyon et al., 1991]. With disease progression, patients may develop dystonia and visual failure (due to optic atrophy and demyelination of the optic radiation). In one report, a 48-year-old man presented with asymmetric upper and lower motor neuron signs initially attributed to a motor neuron disease [Henderson et al., 2003]. In this patient, nerve conduction studies and neuroimaging provided important signs leading to the correct diagnosis. In another report, which described three affected brothers with disease onset in the fifth decade, the neurologic examination found features of asymmetric peripheral neuropathy associated with pyramidal signs [Sabatelli et al., 2002]. Two of the patients in this family died at 59 and 61 years of age of respiratory failure. Other cases have been described with presentations consistent with spastic paraplegia [Bajaj et al., 2002]. Behavioral changes and intellectual impairment have also been reported, and these problems may be the initial complaints, particularly in juvenile-onset patients before recognition of the other features of Krabbe’s disease. A study examined the results of testing involving 26 children with Krabbe’s disease, 20 with the early infantile disease (range of ages at onset, 0.5 to 6 months) and 6 with the late-onset disease (range of ages at onset, 10 to 60 months) [Aldosari et al., 2004]. The results revealed that patients with early infantile disease had abnormal flash visual-evoked potentials (53%), abnormal brainstem auditory-evoked response (88%), and abnormal electroencephalograms (65%). Nerve conduction studies were abnormal in all of these patients. Among the lateonset patients, none had abnormal visual-evoked potentials, whereas brainstem auditory-evoked responses and electroencephalograms were abnormal in 40% and 33% of the children. Only 20% of the late-onset patients had abnormal nerve conduction studies. Abnormal neurophysiologic studies were found to correlate with more extensive disease as measured by MRI scans [Korn-Lubetzki et al., 2003]. Brain magnetic resonance spectroscopy performed in patients with infantile Krabbe’s disease has revealed elevation of myo-inositol and choline-containing compounds in affected white matter, consistent with demyelination and glial proliferation [Brockmann et al., 2003; Zarifi et al., 2001]. The accompanying decrease of N-acetylaspartate points to neuroaxonal loss. In juvenile-onset cases, magnetic resonance spectroscopy indicated astrocytosis with minor neuroaxonal damage in white matter [Farina et al., 2000]. Spinal involvement may be evident on MRI as abnormal contrast enhancement of the lumbosacral nerve roots [Given et al., 2001]. Pathologic studies of brains from patients with Krabbe’s disease reveal a rapid disappearance of myelin and myelinforming cells (i.e., oligodendrocytes in the CNS and Schwann cells in the peripheral nervous system). In addition, there is reactive astrocytic gliosis and tissue infiltration by multinucleated macrophages (globoid cells) filled with materials that are periodic acid–Schiff positive [Itoh M et al., 2002]. These findings are considered to reflect a reaction to psychosine (galactosylsphingosine), a toxic metabolite that accumulates in the tissues of patients with Krabbe’s disease [Haq et al., 2003]. Exposure of an immortalized human oligodendroglial cell line (MO3.13) to exogenous psychosine results in the concurrent upregulation of JNK AP-1 (a proapoptotic pathway mediator) and downregulation of the NF-kB pathway (an anti-apoptotic pathway factor) [Haq

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et al., 2003]. Another study, which examined a mousederived oligodendrocyte progenitor cell line (OLP-II), revealed that psychosine caused cytotoxic effects in a dosedependent manner [Zaka and Wenger, 2004]. Moreover, psychosine treatment resulted in the activation or cleavage of initiator caspases 8 and 9 and effector caspase 3. These results provide further support of a role for psychosine in cell death through an apoptotic mechanism. In a separate study that examined brain obtained from three patients with Krabbe’s disease, white matter lesions were found (in the corona radiata, corpus callosum, and cerebellar peduncles) in addition to the neuronal loss in the thalamus, cerebellum, and inferior olivary nucleus [Itoh M et al., 2002]. Ramified microglia was immunoreactive for ferritin and HLA-DR α chain, and both the small and large globoid cells exhibited immunoreactivity for ferritin KP-1 and neural cell adhesion molecule. T lymphocytes immunoreactive for leukocyte common antigen, ubiquitin carboxylterminal esterase L1, and CD3 were increased around the vessels in the white matter. These data suggest that immunoreactive changes may partly be involved in the myelin breakdown and glial pathologic changes in Krabbe’s disease. The diagnosis of Krabbe’s disease is based on demonstration of decreased galactosyceramidase activity in peripheral leukocytes or cultured skin fibroblasts [Randell et al., 2000]. Mutation analysis has led to identification of more than 40 gene defects responsible for Krabbe’s disease [Fu et al., 1999]. A deletion mutation (502del) has been reported as common, accounting for up to 40% of disease alleles. Homozygosity for this mutation is associated with the severe infantile form of the disease. Mutation analysis in a patient with late-onset disease revealed compound heterozygosity for the 809G→A (G270D) and 1609G→A (G537R) mutations [De Gasperi et al., 1999]. The relatively mild clinical phenotype observed in this patient was attributed to the 809G→A allele, based on the presence of residual galactosyceramidase activity in vitro. Indeed, this mutation has been found in several other patients with lateonset Krabbe’s disease. There is no specific treatment for the infantile form of Krabbe’s disease. However, the irritability encountered in the infantile form of Krabbe’s disease has been successfully controlled with low-dose morphine [Stewart et al., 2001]. Bone marrow transplantation with appropriate timing in the later onset forms has returned cerebrospinal fluid protein to normal levels and to stabilize the neurologic findings, neuropsychologic function, and extent of demyelination on MRI [Caniglia et al., 2002]. Newborn screening has been recommended for early detection and early intervention by hematopoietic stem cell transplantation to improve outcome [Galvin-Parton, 2003; Li et al., 2004]. Experimental studies in the twitcher mouse model with vascular endothelial growth factor, an endothelial cell mitogen and permeability factor, given intravenously at the time of birth led to increased blood-brain barrier permeability [Young et al., 2004]. Systemic treatment with vascular endothelial growth factor before bone marrow transplantation or the administration of recombinant lentivirus resulted in increased numbers of either donor cells or virus-transduced cells in the recipient brain. This approach may prove to be useful in future studies of cellular or enzyme replacement therapies for other lysosomal storage diseases with primary CNS involvement.

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Deficiency of saposin A was demonstrated to cause lateonset, slowly progressive globoid cell leukodystrophy in the mouse [Matsuda et al., 2001b]. The saposin A–null mouse developed slowly progressive hind limb paralysis, with onset at 2.5 months of age. Tremors and shaking, prominent in other myelin mutants, were not obvious until the terminal stage. Pathologic and analytic biochemistry revealed findings that were qualitatively identical to but generally much milder than those seen in the typical human infantile Krabbe’s disease. Interestingly, in affected female mice that became pregnant, neurologic symptoms greatly improved compared with affected nulliparous female mice or affected male mice. Immune-related gene (monocyte chemoattractant protein 1, tumor necrosis factor-α) expression was found to be significantly downregulated in the brain of pregnant saposin A–null mice. In addition, there was intense expression of the estrogen receptors (alpha and beta) on the globoid cells, activated astrocytes, and microglia in the demyelinating area [Matsuda et al., 2001a]. When these mice were subcutaneously implanted with timed-release 17β-estradiol pellets, the pathologic process was vastly improved. These findings suggest that the higher levels of estrogen during pregnancy may have a protective effect. Saposin A deficiency has not been described in human patients but might be anticipated as a cause of late-onset chronic leukodystrophy without primary galactosylceramidase deficiency.

leukodystrophy may lead to instability and myelin breakdown (Fig. 27-14). It has also been hypothesized that lysosulfatide (a deacylated form of sulfatide) may be cytotoxic and promote the dissolution of myelin [Toda et al., 1990]. The overall incidence of metachromatic leukodystrophy has been estimated at 1 in 121,000. The relatively high frequency (1 in 2520 live births, with an estimated carrier frequency of 1 in 25 to 1 in 50) in the Navajo Indians of the southwestern United States has been attributed to a “genetic bottleneck” that occurred in the mid-19th century [Holve et al., 2001]. Genetic bottleneck refers to an evolutionary event leading to a drastic reduction in population size. The same phenomenon explains the increased frequency (1 in 75 live births) of metachromatic leukodystrophy in a small Jewish community that lived in Habban (Yemen), isolated from the other Jewish populations [Zlotogora et al., 1995]. There have been rare patients with saposin B deficiency who are unable to catabolize sulfatide and other glycosphingolipids in vivo, leading to their accumulation and a neurodegenerative disease that is viewed as a variant of metachromatic leukodystrophy [Wrobe et al., 2000]. Saposin B (also known as sphingolipid activator protein 1) is a small glycoprotein that acts as an activator of arylsulfatase A and is required for the hydrolysis of galactosylsulfatide [Whitelegge et al., 2003]. Patients with saposin B deficiency have clinical features that overlap with the juvenile-onset form of metachromatic leukodystrophy [Wrobe et al., 2000].

Metachromatic Leukodystrophy (Sulfatide Lipidosis) Deficiency of arylsulfatase A activity leads to the accumulation of its incompletely metabolized substrate galactosylsulfatide (cerebroside sulfate) in the white matter of the central and peripheral nervous system [Gieselmann, 2003]. The associated clinical condition derives its name from the brownish or reddish birefringent (metachromatic) color of the sulfatide deposits, noted when involved tissues are stained with cresyl violet or toluidine blue [Gieselmann et al., 2003a]. Sulfatides are a component of myelin, and their increased concentration in tissues of the patients with metachromatic

FIGURE 27-14. Myelinated fiber obtained from the sural nerve. There is accumulation of lysosomal sulfatide in the Schwann cell cytoplasm of this 2-year-old child. L, lamellar inclusion; M, myelin; A, axon. (×132,000.) (Courtesy Stephen A. Smith, Minneapolis, MN.)

FIGURE 27-15. An 11-year-old boy with the juvenile form of metachromatic leukodystrophy. The patient is in a vegetative state. Marked spasticity and contractures are present. The patient has gross impairment of bulbar function and is fed through a gastric feeding tube.

Pastores and Kolodny / Lysosomal Storage Diseases

These individuals have evidence of tissue sulfatide storage with normal arylsulfatase A activity in vitro; their diagnosis can be confirmed by tests using specific antibodies against saposin B or identification of the causal saposin B gene mutation. Late infantile-onset metachromatic leukodystrophy represents the most common clinical form of the disease, accounting for 60% to 70% of all cases (Fig. 27-15). Later onset forms of the disease, developing in childhood or adolescence and even during adulthood, have been described. In late infantile metachromatic leukodystrophy, affected children usually present with progressive gait problems, manifesting between the ages of 14 and 16 months. Examination of the lower extremities may initially reveal a mixed picture, with flaccid paralysis or more commonly with pyramidal signs (e.g., spasticity and bilateral Babinski signs) and depressed or hyperactive deep tendon reflexes. Electrophysiologic testing reveals evidence of peripheral nerve involvement, with marked slowing of the motor and sensory nerve conduction velocities. The cerebrospinal fluid protein level is elevated. Brain MRI reveals leukodystrophy, with a hyperintense signal in the periventricular and central white matter on T2-weighted images, which may initially be limited to the parieto-occipital region [Sener, 2003]. In one 17-month-old male with metachromatic leukodystrophy, an echo-planar diffusion magnetic resonance sequence revealed a restricted diffusion pattern in the deep white matter [Sener, 2002]. Proton magnetic resonance spectroscopy revealed a marked decrease in choline, a metabolite related to myelin turnover [Sener, 2003]. These observations likely represent dysmyelination. The disease is progressive, and affected patients with metachromatic leukodystrophy are eventually unable to stand or sit up. Additional findings include dysarthria, drooling, and dysphagia. There may be visual failure. Seizures occur in a small proportion of patients in the terminal stages of their disease, by which time the children are rigid and assume decerebrate or decorticate postures [Cameron et al., 2004]. Deposition of sulfatides in the gallbladder can cause the formation of papillomatous changes and lead to cholecystitis [Vettoretto et al., 2001]. Death in patients with late infantile metachromatic leukodystrophy usually occurs between the ages of 3 and 7 years. Metachromatic leukodystrophy may manifest in later life, from early childhood (3 to 8 years of age) to adolescence or even adulthood. Behavioral abnormalities, cognitive deficits, and dementia may be more prominent in the later onset forms [Baumann et al., 2002; Black et al., 2003; Mihaljevic-Peles et al., 2001]. Abnormalities of nerve conduction and cerebrospinal fluid protein elevation may be minimal. Brain white matter alterations on MRI may also be less pronounced. The variability in clinical presentation can often lead to a missed diagnosis, and metachromatic leukodystrophy should be considered in cases characterized by deterioration in behavioral or mental capacities, a progressive disorder of gait or coordination, or a progressive polyneuropathy [Herska et al., 1987]. It is important to exclude arylsulfatase A pseudodeficiency in these patients. The course of disease in the late-onset forms of metachromatic leukodystrophy can be protracted, with survival of more than 5 to 10 years not unusual. However, disease may evolve more rapidly in some patients. Impaired cortical glucose metabolism (especially of the medial temporal and frontal cortices) was observed with

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positron emission tomography and fluorine 18–labeled fluorodeoxyglucose in a 41-year old male patient with lateonset metachromatic leukodystrophy [Johannsen et al., 2001]. In addition, brain MRI displayed confluent hyperintensities of periventricular and subcortical white matter. Neuropsychologic assessment demonstrated that he had mild amnesia, visuospatial dysfunction, and attention deficits with a slow psychomotor speed. The neuropsychologic deficits in this individual were related to the location of deficits in glucose metabolism. To a certain extent, the clinical course of metachromatic leukodystrophy is associated with the nature of the causal mutation. Patients with a combination of deleterious alleles for this autosomal-recessive condition have a late infantile onset, whereas those with a combination of a severe and mild mutation or two mild mutant alleles have delayed onset and follow a subacute or chronic disease course. Two gene defects, namely, 459+1G to A and 1277C to T (Pro426Leu), account for almost 50% of metachromatic leukodystrophy mutations; the remaining alleles are rare or private [Eng et al., 2003, 2004]. In a study of 12 adult metachromatic leukodystrophy patients with primary motor signs (pyramidal, cerebellar, and less often dystonia) and a peripheral neuropathy had the major adult arylsulfatase A mutation P426L in homozygosity [Lugowska et al., 2002]. In contrast, patients with the psychocognitive forms (associated with modifications of mood, peculiar social reactions, and a progressive mental deterioration) were often noted to be compound heterozygotes, with the I179S mutation on one allele [Lugowska et al., 2002]. In a separate study, screening for the mutations in 34 unrelated patients with metachromatic leukodystrophy from Poland revealed that the I179S mutation accounted for 17% of examined alleles (2 of 12) in adults and as much as 42% (5 of 12 alleles) in patients with late juvenile metachromatic leukodystrophy [Berger et al., 1997]. The I179S mutation has not been found in the late infantile or early juvenile cases. The diagnosis of metachromatic leukodystrophy is based on demonstration of deficient arylsulfatase A activity in leukocytes or cultured skin fibroblasts. Peripheral nerve biopsy, which is often unnecessary, reveals the typical prismatic and tuffstone inclusions in Schwann cells. Polymorphisms that give rise to arylsulfatase A pseudodeficiency (associated with decreased arylsulfatase A activity in vitro) are common in the general population (approximately 10%) [Rafi et al., 2003]. Biochemical assays for the enzyme with the artificial 4-methylumbelliferyl substrate may lead to an erroneous diagnosis of affected and carrier status in these individuals. Increased urinary sulfatide excretion (detected by thin-layer chromatography) is found only in affected patients with metachromatic leukodystrophy who have a true deficiency of arylsulfatase A activity [Whitfield et al., 2001]. Sulfatide loading tests performed with tissues in culture can help distinguish arylsulfatase A pseudodeficiency from a true carrier or affected status, but these methods require specialized expertise and have generally been replaced by a combination of biochemical and molecular assays. The sequence variation leading to arylsulfatase A deficiency has been characterized, and most laboratories offering the biochemical test can check for these mutations. In families in which the causal arylsulfatase A gene defects are known, true carrier status can be assigned reliably by mutation

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Genetic, Metabolic, and Neurocutaneous Disorders / 27

analysis. In families at risk for having an affected child, the presence of the arylsulfatase A pseudodeficiency allele should be ascertained in both parents to avoid mistakes in prenatal diagnosis. One study reported a higher incidence of evident or possible microorganic brain damage in metachromatic leukodystrophy–pseudodeficiency and metachromatic leukodystrophy heterozygotes, although none of these carriers had overt clinical problems [Tylki-Szymanska et al., 2002b]. On the other hand, there is a separate report that describes the neuropsychologic profiles and brain MRI findings of eight family members of a 7-year-old female with metachromatic leukodystrophy [Weber Byars et al., 2001]. All eight relatives were heterozygous carriers, including five who were also carriers of the arylsulfatase A pseudodeficiency gene. The patient’s younger sister had features of nonverbal learning disability despite a normal MRI study, whereas two members with minor white matter findings did not [Weber Byars et al., 2001]. Thus, the findings in this family do not support the concept of a syndrome of nonverbal learning disability in heterozygous carriers of the gene for metachromatic leukodystrophy, even in association with the metachromatic leukodystrophy pseudodeficiency gene. There is no effective treatment for metachromatic leukodystrophy. In a child with metachromatic leukodystrophy who required surgery for gastroesophageal reflux, general anesthesia was performed with a lumbar epidural technique [Hernandez-Palazon, 2003]. In this patient, the epidural catheter enabled the delivery of analgesia postoperatively, avoiding the risk of respiratory depression associated with the use of opioids in these high-risk patients. Bone marrow transplantation, when it is undertaken early, may slow or halt the progression of the disease, but not when neuropsychologic signs are advanced [Krivit et al., 1999]. Bone marrow transplantation may be a reasonable option for presymptomatic patients or while neuropsychologic function and independence in activities of daily living remain intact. Investigators are currently examining the role of mesenchymal stem cell infusion. In a study of four patients with metachromatic leukodystrophy, there were significant improvements in nerve conduction velocities after mesenchymal stem cell infusion [Koc et al., 2002]. Bone mineral density was either maintained or slightly improved in all the patients. However, there was no clinically apparent change in the patients’ overall health and mental and physical development after mesenchymal stem cell infusion. An arylsulfatase A–null mouse model of metachromatic leukodystrophy has been generated and found to have sulfatide accumulation in oligodendroglia and neurons [D’Hooge et al., 2001]. Neuronal sulfatide storage was most prominent in many nuclei of the medulla oblongata and pons and in several nuclei of the midbrain and forebrain. In the mouse studies, sulfatide storage did not affect the overall composition of most myelin proteins but specifically caused a severe reduction of myelin and lymphocyte protein (MAL), indicating the existence of a regulatory mechanism between lipid and myelin protein synthesis in oligodendrocytes [Wittke et al., 2004]. MAL is a myelin proteolipid protein with four transmembrane domains that tightly binds glycosphingo-

lipids with particular sulfatides. MAL is developmentally regulated in differentiated cultured oligodendrocytes, and its expression level peaks in the nervous system during myelin formation. The specific reduction and mistargeting of MAL protein may contribute to the pathogenic mechanisms in metachromatic leukodystrophy. Interestingly, there was no obvious sign of widespread demyelination in the arylsulfatase A–null mice, except for loss of neurons in two nuclei of the auditory pathway of aged mice, specifically in the ventral cochlear nucleus and nucleus of the trapezoid body. Several observations in the arylsulfatase A–null mice, such as hyperactivity, motor incoordination and slowing, and age-related learning and memory deficits, may relate to the decline of neuromotor and cognitive functions seen in patients with metachromatic leukodystrophy. These findings could be used as correlative or outcome measures in preclinical investigations of prospective therapies before their introduction in human trials.

Multiple Sulfatase Deficiency (Austin’s Disease) A defect of post-translational modification of several sulfatases leads to a neurovisceral disorder characterized by tissue accumulation of sulfatides, glycosaminoglycans (mucopolysaccharides), and cholesteryl sulfate [Eto et al., 1987]. The gene mutated in this disease is SUMF1, which encodes a protein, the human C(α)-formylglycine generating enzyme, involved in the processing of the catalytic site of all sulfatases; this step is required for the functional maturation of these enzymes [Cosma et al., 2003; Dierks et al., 2003]. The particular clinical picture encountered in the individual patient depends on the pattern of enzyme deficiencies [Macaulay et al., 1998]. The clinical features of multiple sulfatase deficiency represent a combination of the neurologic findings noted in patients with early infantile metachromatic leukodystrophy and the dysmorphic facial features and skeletal deformities (i.e., dysostosis multiplex) seen with mucopolysaccharidosis [Harbord et al., 1991]. Patients have ichthyosis (dry, scaly skin), usually evident in the first few weeks of life [Burk et al., 1984; Castano Suarez et al., 1997]. Inclusion (AlderReilly granules) may be seen in peripheral blood leukocytes [Soong et al., 1988]. Associated findings include retarded psychomotor development, hepatosplenomegaly, deafness, and peripheral neuropathy [Guerra et al., 1990]. Nerve conduction velocities are decreased, and cerebrospinal fluid protein is elevated. Urine analysis reveals increased excretion of sulfatides, heparan sulfate, and dermatan sulfate. Two unusual cases of multiple sulfatase deficiency with variable enzymatic deficiency of arylsulfatases A, B, and C have been reported. Both patients had ichthyosis, broad thumbs and index fingers, and an unusually slow progression of their neurologic symptoms [Blanco-Aguirre et al., 2001]. In addition, they lacked the hepatosplenomegaly that is typical of multiple sulfatase deficiency. Olivopontocerebellar atrophy was present, and one of the patients had a large retrocerebellar cyst. Mucopolysaccharides were not detected in the urine from either subject. Another patient has also been reported to develop early, severe visual impairment associated with prominent pigmentary retinopathy. Analysis of the lipid composition of the brain obtained from two patients with multiple sulfatase deficiency revealed

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sulfatide concentration in the white matter that was three to four times that of normal brains [Eto et al., 1976]. The ganglioside pattern in the gray and white matter was abnormal, with a higher proportion of GM3, GM2, and GD3 gangliosides. Increased amounts of glucocerebroside, ceramide lactoside, and ceramide trihexoside were also present. The fatty acid compositions of myelin sulfatide and sphingomyelin were almost normal, whereas the non-hydroxy fatty acids of cerebroside contained less long-chain fatty acids. A variant of multiple sulfatase deficiency described in Saudi Arabian children presented with corneal clouding, macrocephaly, and dysostosis multiplex [al Aqeel et al., 1992]. Ichthyosis was absent, and steroid sulfatase activity was normal. Mental retardation was reported to be mild. This Saudi variant of multiple sulfatase deficiency accounts for 5% of all lysosomal storage disease cases in the Cell Repository Registry of the Inborn Errors of Metabolism Laboratory at the King Faisal Specialist Hospital and Research Centre in Riyadh, Saudi Arabia. The diagnosis of multiple sulfatase deficiency can be made on the basis of characteristic clinical manifestations in conjunction with variable deficiencies of the arylsulfatases A, B (N-acetylgalactosamine-4-sulfate sulfatase), and C (steroid sulfatase) and four other sulfatases involved in the degradation of specific glycosaminoglycans [Mancini et al., 2001]. The identification of the responsible gene has led to characterization of several different mutations associated with variable clinical expression, including milder disease variants [Cosma et al., 2004]. There is no effective treatment. Simple emollients or those containing α-hydroxy acids (e.g., glycolic acid, lactic acid) or urea may be soothing and provide relief for ichthyosis.

WOLMAN’S DISEASE AND CHOLESTERYL ESTER STORAGE DISORDER The enzyme lysosomal acid lipase is normally involved in the hydrolysis of cholesteryl esters and triglycerides that have been internalized by receptor-mediated endocytosis of lipoprotein particles [Wolman, 1995]. Deficiency of lysosomal acid lipase leads to the massive accumulation of exogenous cholesteryl esters throughout most organ systems, giving rise to one of two phenotypes: the severe Wolman’s disease or the more benign cholesteryl ester storage disease. The observed differences in clinical disease course are likely due to expression of genetic mutations that either abolish lysosomal acid lipase enzyme activity in the more severe Wolman’s disease phenotype or lead to some residual activity as in cholesteryl ester storage disease [Pagani et al., 1998]. Wolman’s disease was first described in 1956 by Abramov and colleagues, who referred to it as a generalized xanthomatosis with calcified adrenals. The condition is clinically characterized by vomiting, diarrhea, malabsorption, and failure to thrive, with onset in infancy [Browne et al., 2003]. Patients are hypotonic and develop anemia and massive hepatosplenomegaly. Liver tissue sections reveal microsteatosis and macrosteatosis and cholesterol crystals in hepatocyte cytoplasm. The adrenal glands are enlarged and calcified, features detectable on CT scans. Bone marrow

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aspiration demonstrates a marked increase in foamy macrophages. Death occurs within the first year of life as a consequence of liver failure, coagulopathy, and pancytopenia. Cholesteryl ester storage disease has a more variable phenotype; it may be benign and remain undetected into adulthood [D’Agostino et al., 1988]. Lipid deposition is widespread, but hepatomegaly is the principal and sometimes the only sign of the disease, even when it is noted from birth or in early childhood. Patients develop early atherosclerosis and hepatic fibrosis, with possible evolution to cirrhosis. The diagnosis of Wolman’s disease and cholesteryl ester storage disease is based on demonstration of deficient lysosomal acid lipase activity in cultured skin fibroblasts and blood lymphocytes. Bone marrow transplantation has been reported to lead to normalization of peripheral leukocyte lysosomal acid lipase activity in a patient (6.5 months of age) with Wolman’s disease and to result in the resolution of diarrhea and return of liver function to normal [Krivit et al., 2000]. At the age of 4 years, the patient was noted to be gaining developmental milestones. Enzyme therapy and gene therapy experiments have been performed in the mouse model of Wolman’s disease [Du et al., 2002], establishing preclinical proof of concept for these therapeutic strategies.

MUCOPOLYSACCHARIDOSES The mucopolysaccharidoses are an etiologically heterogeneous group of disorders resulting from various individual deficiencies of the lysosomal enzymes (i.e., glycosidases and sulfatases) involved in the sequential degradation of glycosaminoglycans [Muenzer, 2004; Van Hoof and Hers, 1968] (Fig. 27-16). The glycosaminoglycans consist of polysaccharide chains that are attached to a polypeptide core through a xylose link; their incomplete hydrolysis leads to tissue deposition and increased urinary excretion of the substrates dermatan sulfate, heparan sulfate, keratan sulfate, and chondroitin sulfate. The pattern of substrate storage and corresponding urinary excretion profile are influenced by the specific underlying enzyme deficiency [Hochuli et al., 2003]. Tissue deposits, when they are examined under the electron microscope, reveal different types of intralysosomal inclusion bodies, the most characteristic of which have been designated zebra bodies. Testing for the presence and pattern of urinary glycosaminoglycan excretion is often used to screen for the diagnosis of mucopolysaccharidosis in suspected cases. However, this test often yields a falsenegative result [Mabe et al., 2004]. Definitive diagnosis of a particular mucopolysaccharidosis subtype is ultimately based on the specific assay for a particular enzyme with use of plasma, leukocytes, or cultured skin fibroblasts. The mucopolysaccharidoses are infrequent, with a collective incidence of about 1 in 25,000 to 1 in 50,000 [Nelson et al., 2003]. The individual disorders are assigned a number (based on the sequence of their historical description), and each has an eponymous designation. However, the former classification of MPS V and VIII as separate disorders has been dropped, after the recognition that these entities represent an attenuated form of other previously designated mucopolysaccharidosis subtypes. The relatively milder form

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Genetic, Metabolic, and Neurocutaneous Disorders / 27

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of disease expression in certain variants has been partly attributed to residual enzyme activity associated with less deleterious mutations. The absence of perfect concordance between residual enzyme activity and the clinical disease severity is hypothesized to result from the failure to account for the efficiency of substrate synthesis. Although each mucopolysaccharidosis subtype is due to a distinct enzyme deficiency, there is significant overlap in the non-neurologic manifestations across the individual diagnostic entities. The two most characteristic manifestations are coarse facial features and dysostosis multiplex. Coarsening of the facial features is a consequence of the storage of glycosamino-

glycans in the soft tissues of the orofacial region and the underlying facial bone dysostosis. The term dysostosis multiplex refers to the typical skeletal changes and constellation of radiographic findings (e.g., bullet-shaped phalanges, flattening of the vertebral bodies and their anterior beaking) (Fig. 27-17). These changes, in conjunction with deposition and thickening of the skin, lead to joint contractures and limitations in the range of neck and limb movements. Increased apoptosis has been described in chondrocytes from animals affected with MPS VI (Maroteaux-Lamy syndrome) and may be a common pathologic mechanism for this group of disorders [Simonaro et al., 2001].

Pastores and Kolodny / Lysosomal Storage Diseases

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FIGURE 27-17. Bone changes of dysostosis multiplex: widened tubular bones and expanded metacarpal bones (A) and beaking of vertebrae and widening of the ribs (B). (Courtesy Robert Gorlin, Minneapolis, MN.)

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B

Ophthalmologic complications, such as corneal stromal opacity, pigmentary retinal degeneration, optic nerve atrophy, and glaucoma, are also common in patients with mucopolysaccharidoses. Membrane-bound vacuoles in the nonpigmented epithelium of the ciliary processes have been observed by electron microscopy. Multiple iridociliary cysts have also been reported in patients with MPS I S (Scheie’s syndrome) and MPS VI [Sato et al., 2002]. Other abnormalities of diagnostic importance include deafness, hepatosplenomegaly, obstructive airway problems, and umbilical and inguinal hernia [Shih et al., 2002]. Recurrent upper respiratory tract and ear infections are prominent complaints in infancy, and cardiovascular abnormalities are frequent. In a study of 39 patients (aged 4 to 22 years) with various mucopolysaccharidoses, valvular lesions and different forms of cardiac involvement were detected [Mohan et al., 2002]. The most common finding, regardless of the mucopolysaccharidosis type, was thickening of the mitral valve with regurgitation or stenosis [Rigante and Segni, 2002]. Developmental regression is a feature of most but not all mucopolysaccharidosis subtypes, each of which constitutes a spectrum of disorders associated with variable expression of the skeletal and somatic anomalies noted before. The accumulation of heparan sulfate and the secondary storage of gangliosides in neurons may be partly responsible for the cerebral dysfunction. In one study, two patients with MPS IIIA with signs of CNS degeneration but only mild somatic features excreted a highly sulfated variant of heparan sulfate, whereas a patient with MPS I S and two patients with MPS II who presented primarily with coarse facial features, joint contractures, and skeletal deformities excreted a different type of heparan sulfate with lower sulfation [Perkins et al., 2001]. In the most severely involved cases, the storage problem can be compounded by tension hydrocephalus due to the deposition of glycosaminoglycans (which leads to

impairment of cerebrospinal fluid absorption) and the histiocytic infiltration and collagen proliferation in the meninges (pachymeningitis) [Paulson et al., 1974]. Progressive glycosaminoglycan storage at various sites may lead to compartment syndromes (e.g., carpal tunnel syndrome) and secondary focal neurologic deficits due to spinal cord or nerve root compression. Brain imaging studies involving 20 patients with different forms of mucopolysaccharidosis (with mental retardation in 11 individuals and normal cognitive function in 9) indicated a significant correlation between white matter alterations and mental retardation [Gabrielli et al., 2004]. The mucopolysaccharidoses are inherited in an autosomal recessive manner, with one exception (MPS II or Hunter’s syndrome, which is transmitted as an X-linked trait). Most forms are associated with significant morbidity as a consequence of skeletal and visceral complications; application of palliative care can have a positive influence on the patients’ health-related and functional quality of life [Dumas et al., 2004]. Attention to obstructive airway problems and consideration of continuous positive airway pressure or tracheostomy, when appropriate, can lead to significant relief [Khan and Khan, 2002; Shinhar et al., 2004]. Anterior instrumented correction and fusion of the spine is effective in treating the thoracolumbar kyphosis associated with mucopolysaccharidosis [Dalvie et al., 2001a]. Bone marrow transplantation has altered the course of disease in certain subtypes of mucopolysaccharidosis, and enzyme therapy has more recently been introduced for MPS I and currently is in clinical trials for MPS II and VI. There have also been several studies involving different animal models (of various mucopolysaccharidosis subtypes) that have examined the potential safety and effectiveness of gene therapy for these disorders [Bosch and Heard, 2003; Haskins et al., 2002]. The availability of enzyme therapy for MPS I, II, and VI and its consideration in the other mucopolysaccharidoses

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necessitate a sensitive and reliable method not only for early diagnosis but also for serial quantitative monitoring of therapeutic responses, if any [Kakkis, 2002]. In one study, examination of urine samples from 68 patients with mucopolysaccharidosis (by electrospray ionization–tandem mass spectrometry) led to identification of an oligosaccharide profile for each group of patients [Fuller et al., 2004; Ramsay et al., 2003]. Each of the urine oligosaccharide profiles enabled the identification of all patients and their subtypes, with the exception of MPS IIIB and IIIC. In three individuals who underwent bone marrow transplantation, a substantial reduction in the level of diagnostic oligosaccharides was observed after transplantation. These observations provide a disease-specific fingerprint that can be used in targeted screening and the biochemical monitoring of current and proposed therapies. Prenatal diagnosis is available for all mucopolysaccharidosis subtypes.

Mucopolysaccharidosis Type I (MPS I) This disorder is caused by a deficiency of α-L-iduronidase (IDUA) in association with the accumulation in tissues and increased urinary excretion of dermatan and heparan sulfate. The phenotypic spectrum has been arbitrarily divided into three clinical forms on the basis of the age at onset and severity of disease expression. The Hurler syndrome (MPS IH) is named after G. Hurler, who (in 1919) described infants with a gibbus deformity, corneal clouding, and mental retardation. This subtype constitutes the most severe end of the clinical spectrum. The Scheie syndrome (MPS IS), formerly classified under MPS V, includes patients initially described by Scheie and colleagues in 1962. Affected individuals with MPS IS have normal intelligence but suffer from restricted movements of their joints and develop the clawhand deformity. MPS IS may have normal or more often short stature. The intermediate form has been designated the Hurler-Scheie syndrome (MPS I H/S). Children with Hurler syndrome appear normal at birth but gradually develop a distinctive facies typical of the mucopolysaccharidoses (Fig. 27-18). Affected infants have a large scaphocephalic head, depressed nasal bridge, frontal bossing, and thickened skin, scalp hair, and eyebrows. These findings, including developmental delay, may not be apparent even to the parents until the age of 12 to 15 months, particularly when the affected infant is the first-born child. A review of the past medical history often reveals recurrent upper respiratory tract and ear infections. Additional clues to the diagnosis include the presence of clawhands with stubby digits, kyphosis, enlarged tongue, hepatosplenomegaly, umbilical and inguinal hernias, and corneal opacities. The eye findings may initially be mild and detectable only by slit-lamp examination. Body hair is also often increased, and the skin has a leathery (thickened) texture. Brain MRI in patients with MPS I reveals several abnormalities, including abnormal signal intensity in the white matter, widening of the cortical sulci and the size of the supratentorial ventricles, dilation of the perivascular spaces, and enlargement of the subarachnoid spaces. In one study of six patients with MPS I, no relationship was found between

FIGURE 27-18. This 18-month-old female with Hurler syndrome has a protuberant abdomen, umbilical hernia, and flexion contractures of the elbows and knees. There is a widened and flattened nasal bridge and thick eyebrows.

the brain MRI findings and clinical manifestations of the disease [Matheus et al., 2004]. Skeletal radiographs in a child with Hurler syndrome reveal a dolichocephalic skull with synostosis of the sutures, widening of the diaphyses of the metacarpals and long bones, and hypoplastic vertebrae with anterior beaking. Complications that often develop in affected children include upper airway obstruction, coronary artery occlusion, cardiomegaly, and heart valve problems. A study involving 99 patients (aged 1 to 24 years; median age, 10.3 years) with MPS I found that increasing age and abnormalities of the cardiac ejection fraction were significant risk factors for death [Mohan et al., 2002]. Pulmonary complications, such as sleep apnea, develop because of airway obstruction due to a combination of factors, including enlarged tonsils and adenoids, narrowing of the trachea, and thickening of the mucosal lining of the airways. These airway problems are aggravated by a small chest and an enlarged liver and spleen pushing up against the diaphragm. Increased intracranial pressure from communicating hydrocephalus can be a major source of morbidity if it is unrecognized. Neurosensory and conductive hearing difficulties develop as a consequence of recurrent middle ear infections, deformities of the ossicles, and narrowing of the skull foramina and pressure applied on the auditory nerve.

Pastores and Kolodny / Lysosomal Storage Diseases

Open-angle glaucoma, retinal pigmentary degeneration, and optic atrophy have been reported to lead to loss of vision. Death in patients with Hurler syndrome often ensues in the first decade of life. Children with the intermediate phenotype, Hurler-Scheie syndrome, have normal or nearly normal intellectual development. Disease manifestations, including the skeletal and other somatic features typical of Hurler syndrome, are usually evident later (between 3 and 8 years of age). However, the clinical findings are initially less severe, and the condition tends to progress at a slower rate. Some patients reach adulthood, often with several complications as described for the patients with Hurler syndrome, although the prognosis may be modified by the current availability of enzyme therapy. Individuals with the attenuated form, the Scheie syndrome, are often missed because they have normal intelligence and may achieve normal adult stature. Characteristic findings on close inspection may reveal corneal clouding, short neck, stiff joints, and cardiac valvular disease. In vivo confocal microscopy images of the cornea in a 13-year-old male with MPS I S revealed brighter intercellular spaces than those of normal corneas [Grupcheva et al., 2003]. Cicatrization of the anterior stroma was identified, and the keratocytes of the middle and posterior stroma exhibited markedly altered morphologic shape, often round or elliptic, and with clearly demarcated, hyporeflective centers. In addition, the nerve fibers of the sub-basal plexus were somewhat more irregular and difficult to distinguish, possibly because of underlying fibrosis. Radiographic studies in patients with MPS I S reveal subtle skeletal changes. These individuals often seek consultation with an orthopedic surgeon or rheumatologist because of increasing limitation in joint range of motion and development of the clawhand deformity or the carpal tunnel syndrome. As with other forms of MPS I, urinary glycosaminoglycan excretion is increased. Molecular characterization of MPS I patients has resulted in the identification of more than 70 distinct mutations in the IDUA gene [Matte et al., 2003; Yogalingam et al., 2004]. Mutation analyses have indicated that to a certain extent, the wide variability in clinical presentation of patients with MPS I is a reflection of the high degree of genetic heterogeneity [Terlato and Cox, 2003]. Two mutations, W402X and Q70X, that are prevalent among individuals of European extraction (and account for up to 70% of MPS I disease alleles) tend to be associated with the severe MPS I H when they are found in homozygosity or in combination with another deleterious allele. On the other hand, two other less common mutations, R89Q and R89W, tend to be found in patients with the attenuated phenotypes MPS I H/S and MPS I S [Hein et al., 2003]. Additional common mutations in the IDUA gene include P533R (among Moroccan and Sicilian Italian patients with MPS I) and R383H; these two mutations are associated with residual enzyme activity. In a survey of 29 Brazilian patients with MPS I, the frequency of common mutations identified was as follows: W402X, 37%; P533R, 11.6%; and R383H, 3.3% [Matte et al., 2003]. Palliative care, including measures to relieve signs of upper airway obstruction (e.g., continuous positive airway pressure, tracheostomy) and shunting for hydrocephalus (as indicated), is an important component of the overall management [Chan et al., 2003]. The patients also are at

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increased risk for complications during administration of anesthesia, and appropriate precautions must be taken before any elective surgical procedure [Walker et al., 1994, 2003b]. The routine follow-up care of affected individuals, including those with attenuated disease subtypes, must include a thorough neurologic examination because motor and sensory deficits (e.g., carpal tunnel syndrome, spinal cord compression) may develop, necessitating appropriate intervention to eliminate or to minimize long-term neurologic deficits. Carpal tunnel syndrome may be underrecognized because its onset is insidious and may be associated with few or none of the typical symptoms of numbness and tingling, except for thenar atrophy [Haddad et al., 1997]. The diagnosis of carpal tunnel syndrome often requires testing of nerve conduction velocities. Congenital umbilical hernias in MPS I are generally treated conservatively because complications such as incarceration or perforation are rare [Hulsebos et al., 2004]. Bone marrow transplantation in infants with Hurler syndrome, by providing an endogenous source of the enzyme, leads to clinical improvements such as the resolution of hepatosplenomegaly and obstructive airway disease [Souillet et al., 2003]. These positive changes mostly occur in the early years after bone marrow transplantation, and clinical benefit is greatest in the patients who received their transplant before the age of 2 years. Neuropsychologic responses to bone marrow transplantation are variable and related to the patient’s age and intellectual capacity at the time of engraftment [Staba et al., 2004]. Certain disease features, such as skeletal problems, have a much poorer response, likely because of the poor penetration of the enzyme into the relevant tissues [Weisstein et al., 2004]. Unfortunately, most children who successfully undergo transplantation ultimately require major orthopedic surgery for genu valgum, hip dysplasia, kyphoscoliosis, carpal tunnel syndrome, and trigger digits. Intellectual and developmental deterioration may occur, and cardiac valvular deformities persist. A proportion of patients undergoing transplantation also experience graft failure, and lifethreatening pulmonary hemorrhage has been encountered after the procedure [Gassas et al., 2003]. Enzyme therapy for MPS I has been approved on the basis of clinical trials primarily involving patients with the Hurler-Scheie phenotype. The studies proved that enzyme replacement therapy leads to improved pulmonary function (based on increased forced expiratory volume in 1 second) and increased exercise capacity (based on the 6-minute walk test, wherein distance traveled over time is measured) [Wraith et al., 2004]. Added observations noted in the treated patients include increased range of joint motion, reduction in sleep apnea or hypopnea, resolution of hepatosplenomegaly, and decreased urinary excretion of glycosaminoglycans. Weekly infusions of the recombinant enzyme (laronidase [Aldurazyme]) given to patients orally premedicated (with acetaminophen and diphenhydramine) were relatively well tolerated, despite the high incidence of antibody formation. Antibody formation was not associated with loss of therapeutic benefit, perhaps because of a decrease in antibody titers with time [Kakavanos et al., 2003]. In clinical practice, the recombinant enzyme formulation has also been prescribed to infants not subjected to or just before bone marrow transplantation and until engraftment has been established.

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The long-term benefit of enzyme therapy in these patients remains to be established. These efforts will necessitate careful follow-up of patients, including measures of physical performance. Reversal of somatic and visceral problems, commonly encountered in all clinical forms, is anticipated to improve the treated patient’s quality of life. Intrathecally administered recombinant human α-iduronidase given to MPS I–affected dogs penetrates the brain and reaches tissues in deep brain sections lacking cerebrospinal fluid contact [Kakkis et al., 2004]. These findings suggest that intrathecal enzyme administration may be an effective way to treat the CNS disease in MPS I.

Mucopolysaccharidosis Type II (MPS II) Deficiency of iduronate-2-sulfatase is the cause of MPS II (Hunter’s syndrome), the only X-linked disorder among the mucopolysaccharidoses. The clinical manifestations evident among affected males are akin to the findings in patients with MPS I, except for the absence of corneal opacities. Rarely, females with iduronate-2-sulfatase deficiency have been described, primarily carriers with inactivation of the X chromosome bearing the normal iduronate-2-sulfatase gene sequence, from nonrandom lyonization (in the presence of an X:autosome translocation) or the Turner (45,X) genotype wherein the extant X chromosome happens to bear a mutant iduronate-2-sulfatase gene.

There are two clinical MPS II variants that have similar somatic features but vary in degree. The MPS II subtypes are distinguished on the basis of intellectual development and rate of disease progression. In the severe form, there is mental retardation and neurologic involvement (as noted in patients with the Hurler syndrome) (Fig. 27-19). In the attenuated form, intelligence is preserved or mildly impaired. Chronic diarrhea is also a common problem in these patients, whose serial evaluations require careful attention to the potential for neurologic, pulmonary, and cardiac complications. Some patients have whitish macular skin lesions over the back, shoulders, and thighs; this is a distinctive dermatologic feature of Hunter’s syndrome and useful in its differential diagnosis. The diagnosis of MPS II is based on demonstration of deficient iduronate-2-sulfatase activity in leukocytes and cultured skin fibroblasts. Prenatal diagnosis is feasible on the basis of enzyme assay. A new method for diagnosis with a novel fluorigenic 4-methylumbelliferyl substrate has been described [Keulemans et al., 2002]. Mutation analyses in patients with MPS II indicate that most have unique gene defects [Froissart et al., 2002; Vafiadaki et al., 1998]. However, more than 35% of independent point mutations at the iduronate-2-sulfatase gene locus are found at CpG sites [Rathmann et al., 1996; Tomatsu et al., 2004b]. Large deletions of the gene encoding iduronate-2-sulfatase tend to correlate with more severe degrees of mental retardation. An Alu-mediated recombination has been implicated in a patient with MPS II who showed the skipping of exon 8 at the cDNA level and the generation of a new large rearrangement [Ricci et al., 2003]. Laboratory studies have revealed that evaluation of residual iduronate-2-sulfatase activity by gene analysis, expression studies, and transcript analysis does not always allow prediction of a patient’s phenotype. Enzyme therapy for MPS II is currently in clinical trials. Preliminary reports have described a marked decrease in urinary glycosaminoglycans as well as reduced glycosaminoglycan accumulation in several tissues [Muenzer et al., 2002]. Somatic gene therapy, with viral and nonviral (i.e., encapsulated heterologous cells and muscle electrogene transfer) approaches, are under investigation with use of MPS II primary fibroblasts [Tomanin et al., 2002].

Mucopolysaccharidosis Type III (MPS III)

FIGURE 27-19. This 16-month-old male with Hunter’s syndrome has many similarities with the patient in Figure 27-18. Flexion contractures of the knees and elbows are prominent. The facial features are also characteristic.

The Sanfilippo syndrome (or MPS III) includes a group of patients with a similar phenotype resulting from a defect of heparan sulfate degradation on account of four different enzyme deficiencies (see Table 27-1). Diagnosis of the individual subtypes is based on the specific enzyme deficiency as measured in biochemical assays performed on leukocytes or cultured skin fibroblasts. Each disorder is further classified by alphabetical letters into MPS III A, B, C, and D. MPS IIIA is the most common variant, and its expression tends to be more severe. Several mutations have been reported among patients with MPS IIIA and IIIB [Beesley et al., 1998; Di Natale et al., 1998; Schmidtchen et al., 1998; Yogalingam and Hopwood, 2001]; mutations in MPS IIID are just beginning to be identified [Beesley et al., 2003]. Unlike the other mucopolysaccharidosis subtypes that are associated with prominent skeletal and somatic features,

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consists of an irregular sleep-wake pattern, which at its onset might appear a disorder of initiating or maintaining sleep [Mariotti et al., 2003]. This finding could explain why some patients do not respond to conventional hypnotics. Therapies aimed at resynchronization (such as behavioral treatment, light therapy, or melatonin) have been recommended. Pathologic studies in the caprine (goat) model indicate that prenatal therapeutic intervention is likely to be necessary to prevent or to ameliorate substantive CNS and systemic lesions [Jones et al., 2004].

Mucopolysaccharidosis Type IV (MPS IV)

FIGURE 27-20. This patient with the Sanfilippo syndrome has coarse facial features, but they are not of the same degree as those seen in the Hunter and Hurler syndromes. (Courtesy Robert Gorlin, Minneapolis, MN.)

the Sanfilippo syndrome has clinical features dominated by early and marked behavioral problems (Fig. 27-20). Hyperactivity and aggressive behavior, which become apparent between the ages of 2 and 6 years, represent common initial concerns, followed by signs of arrest in intellectual development and speech delay. Altered sleep-wake cycles and insomnia are also frequent sources of parental frustration [Fraser et al., 2002]. The disease is progressive, and the patients become severely demented and often are bedridden by the end of the first decade. An exceptional report has described two sisters with MPS IIIC with adult-onset dementia and retinitis pigmentosa [Berger-Plantinga et al., 2004]. Another report also provides a description of an adult patient with MPS IIIA who presented at the age of 45 years with hypertension [Van Hove et al., 2003]. At the age of 53 years, she was found to have severe concentric hypertrophic nonobstructive cardiomyopathy. There was no coarsening of facial features. In addition, her neurologic function, skeleton, cornea, liver, and spleen were normal. As the somatic and skeletal features of MPS III may be subtle and the diagnosis often missed, inclusion of this disorder in the differential diagnosis of children presenting with behavioral problems is important. Studies of bone turnover and bone mineral density in three patients with MPS III revealed low serum vitamin D concentration and greatly reduced bone mineral density at lumbar and femoral sites [Rigante and Caradonna, 2004]. Screening for excessive urinary excretion of heparan sulfate may enable detection of MPS III. As testing of the urine alone may give falsenegative results, in circumstances when the diagnosis remains strongly suspected, analysis for the putative enzyme deficiency should be performed [Chih-Kuang et al., 2002]. There is no specific treatment for MPS III. Investigations suggest that the sleep disruption in patients with MPS III

This subtype, also referred to as Morquio’s syndrome, includes two genetically distinct enzyme deficiency disorders (identified as MPS IV A and B) [Haas, 2002]. Both subtypes are phenotypically similar or have overlapping clinical features. Intellect is usually normal, but secondary neurologic complications are frequent and related to the skeletal abnormalities and increased joint laxity [Ebara et al., 2003]. Affected patients have a high risk for cervical cord compression because of severe hypoplasia of the odontoid process and laxity of the cervical ligaments. The potential for atlantoaxial subluxation during anesthesia and while engaged in sports necessitates appropriate precautions [Dalvie et al., 2001b; Morgan et al., 2002]. In these patients, surgery to stabilize the cervical spine is usually necessary as a preventive measure. Lower leg paresis due to kyphoscoliosis was reported in a 65-year-old woman who developed compression of the spinal cord around T12 to L2 [Ebara et al., 2003]. With increased survival, there is a risk for respiratory failure secondary to abnormalities of the thoracic cage. Keratan sulfate is increased in urine among affected individuals with MPS IV from deficiency of either N-acetylgalactosamine-6-sulfate (MPS IVA) or β-galactosidase (MPS IVB). Mutation analysis performed on MPS IVA patients from Latin America revealed 12 different gene defects, with R386C accounting for 32.5% of the unrelated mutant alleles [Tomatsu et al., 2004a]. One mutation (R380S) was associated with an attenuated disease form. The underlying enzyme deficiencies for MPS IVB and GM1 gangliosidosis are identical; the variable disease expression has been attributed to distinct allelic mutations in the gene encoding β-galactosidase. An imbalanced substrate specificity of the mutant β-galactosidase that induces predominant accumulation of keratan sulfate has been demonstrated in skin fibroblasts of patients with MPS IVB and may be useful in differential diagnostic analysis and prognostication [Hinek et al., 2000]. Most mutations in MPS IVB are associated with homozygosity or heterozygosity for the W273L mutation, which expresses residual enzyme activity [Paschke et al., 2001]. There is no specific treatment. The anesthetic care of these patients, before any elective surgical procedures, should take into consideration increased risks resulting from the respiratory, craniofacial, cardiac, skeletal, ocular, and hepatic abnormalities [Walker et al., 2003a]. Because intellect is normal and skeletal deformities associated with the lysosomal storage diseases are not significantly modified by bone marrow transplantation, there is no role for this procedure in the management of patients with MPS IV A or B.

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Mucopolysaccharidosis Type VI (MPS VI)

Mucopolysaccharidosis Type VII (MPS VII)

Maroteaux-Lamy syndrome (MPS VI) results from a deficiency of N-acetylgalactosamine-4-sulfate (arylsulfatase B) in association with the excessive urinary excretion of dermatan sulfate. There is a wide variability in clinical expression, including mild and severe phenotypes, with skeletal and somatic features that are typical for the mucopolysaccharidoses. Corneal opacities result from deposition of keratan sulfate and other proteoglycans in lysosomes, causing the death of keratocytes and an abnormal build-up of proteoglycans in the stroma [Akhtar et al., 2002]. These changes are believed to be responsible for the lateral aggregation of collagen fibrils and impaired fibrillogenesis in MPS VI. Degenerate swollen keratocytes, together with gross changes in epithelial, stromal, and endothelial cells, would be expected to increase light scattering significantly in these involved corneas. Affected individuals with MPS VI usually have normal intelligence. Myelopathy secondary to thickening of the dura in the cervical region has been described. Hydrocephalus is another complication that, if unrecognized, may contribute to mental decline. The recognition of precocious excessive growth in two patients with MPS VI facilitated an early diagnosis [Heron et al., 2004]. A study involving Brazilian patients with MPS VI found no significant correlation between clinical manifestations and the levels of urinary glycosaminoglycans or the residual arylsulfatase B activity [Azevedo et al., 2004]. In this population of patients, a 23–base pair deletion causing a shift in reading frame has been found to be relatively common [Petry et al., 2003]. Molecular characterization of the gene encoding arylsulfatase B among other groups of patients has revealed broad heterogeneity in underlying gene defects [Isbrandt et al., 1994; Voskoboeva et al., 1994]. Bone marrow transplantation in patients with MPS VI has resulted in the resolution of hepatomegaly and splenomegaly, stabilization of cardiopulmonary function, and improvement of visual acuity and joint mobility. Corneal transplantation performed in a female who underwent bone marrow transplantation at the age of 13 years has been reported to help maintain clear corneal grafts [Ucakhan et al., 2001]. Enzyme therapy for MPS VI is currently in clinical trials, involving 39 patients ranging in age from 5 to 29 years. Preliminary reports indicate that treatment leads to improvements in several of the study end points, such as endurance, which is measured by the distance walked in 12 minutes and the number of steps taken during the 3-minute stair climb test [Harmatz et al., 2004]. In treated patients compared with patients receiving placebo, these findings were associated with significant reductions in urinary excretion of glycosaminoglycans. Infusions of the recombinant investigational enzyme (Aryplase [BioMarin Pharmaceutical Inc] at 1 mg/kg weekly) were generally well tolerated. Earlier phase I trials revealed an enzyme dosedependent reduction in urinary glycosaminoglycans. Enzyme therapy studies in the feline model indicate overall improvement in the disease (from a physical, neurologic, and skeletal perspective) that was most pronounced for cats treated from birth compared with those treated at a later age. These findings support the arguments for early intervention [Auclair et al., 2003].

Sly’s syndrome (MPS VII) results from a deficiency of βglucuronidase. There are about 40 cases reported in the medical literature. The disease is characterized by a wide spectrum of clinical manifestations. A severe neonatal form is associated with nonimmune hydrops fetalis [Cheng et al., 2003]. Craniovertebral instability and spinal cord compression have also been reported to occur in MPS VII [Dickerman et al., 2004]. Bone marrow transplantation has been performed in a 12-year-old female homozygous for the A619V mutation in the β-glucuronidase gene [Yamada et al., 1998]. The donor cells were obtained from an HLA-identical unrelated female donor. Reported improvements included almost normal βglucuronidase activity in circulating lymphocytes and greatly diminished urinary excretion of glycosaminoglycans. These observations were associated with improved motor function (including independent ambulation) and decreased frequency of upper respiratory tract and middle ear infections. Previous problems, such as dyspnea on exertion and vertigo, that the patient had experienced also improved. The diagnosis of MPS VII is based on demonstration of decreased β-glucuronidase activity. Several mutations have been described in the β-glucuronidase gene [Vervoort et al., 1997]. In the longest known survivor (a patient who died at the age of 37 years), mutation analysis revealed two novel missense mutations, K350N and R577L [Storch et al., 2003]. Expression studies revealed that the K350N gene defect was associated with residual enzyme activity, whereas the mutant protein resulting from the R577L transcript was rapidly degraded. Prenatal diagnosis for MPS VII can be made reliably by analysis of enzyme activity in amniotic fluid or cultured chorionic villi or amniocytes [Natowicz et al., 2003]. Several studies, including investigations of gene therapy, are taking place in the animal model of MPS VII [Sferra et al., 2004]. A report noted that peripheral administration of a recombinant adeno-associated virus type 2 vector in adult MPS VII mice led to transgene expression levels sufficient for improvements in both the peripheral and central manifestations of this disease [Sakurai et al., 2004]. These results correlate with findings in another study, which revealed that enzyme transport into brain parenchyma in early postnatal life in the mice was mediated by the mannose 6-phosphate/ insulin-like growth factor-2 receptor, which was not observed in the adult mice [Urayama et al., 2004]. The transplantation of genetically modified bone marrow stromal cells to the lateral ventricle of newborn MPS VII mice has been found to reduce the brain content of glycosaminoglycans, with marked improvement in cognitive function compared with the untreated mice [Shen et al., 2004]. In a separate study, βglucuronidase gene transfer led to a reversal of storage lesions in neurons that project to the gene expression site but not in nearby structures that would have been corrected if the effect had been mediated by diffusion [Frisella et al., 2001]. In addition, transduction of cells in the subventricular zone resulted in the uptake of β-glucuronidase by cells entering the rostral migratory stream. These findings suggest that gene transfer to specific neuronal circuits or cells in the migratory pathways may facilitate delivery to the global brain lesions found in these disorders [Shen et al., 2004].

Pastores and Kolodny / Lysosomal Storage Diseases

Mucopolysaccharidosis Type IX (MPS IX) The first patient subsequently classified as having MPS IX had a relatively mild phenotype (compared with patients with other forms of mucopolysaccharidosis). Clinical characteristics included periarticular soft tissue masses, mild short stature, and acetabular erosions of the joints [Natowicz et al., 1996]. The patient also did not have signs of neurologic or visceral involvement. Histologic examination of affected tissues revealed macrophages with hyaluronan-filled lysosomes. Serum hyaluronidase activity was noted to be deficient, and the concentration of hyaluronan in the serum was elevated 38to 90-fold above normal [Natowicz et al., 2003]. Hyaluronan is an important structural and functional component of the extracellular matrix. Changes in hyaluronan turnover have been associated with many processes involving cell proliferation, migration, and differentiation and with embryogenesis, inflammation, wound healing, and metastasis. Two mutations (as expected for an autosomal recessive trait) have been identified in the lysosomal hyaluronidase 1 gene. A 1412G to A mutation introduces a nonconservative amino acid substitution [Glu268Lys] in a putative active site residue [Triggs-Raine et al., 1999]. The second mutation is a complex intragenic rearrangement [1361del37ins14] that results in a premature termination codon. Subsequent studies have revealed that additional enzymes (hyaluronidase 2 and 3) are encoded by genes found to cluster on human chromosome 3p21.3 [Csoka et al., 2001]. The three enzymatic forms of hyaluronidase have markedly different tissue expression patterns, consistent with their differing roles in hyaluronan metabolism. There is no specific treatment.

GLYCOPROTEINOSES The glycoproteins are composed of oligosaccharide chains covalently attached to a peptide backbone. They consist of at least two forms, including the N-glycosidic asparaginelinked type, which serves as a substrate for several lysosomal enzymes. Most of the lysosomal enzymes involved in the hydrolysis of the glycoprotein carbohydrate side-chains are exoglycosidases, which sequentially remove terminal monosaccharides [Michalski and Klein, 1999]. Deficiencies involving these enzymes lead to disorders of glycoprotein degradation, referred to as the glycoproteinoses. These diseases are distinct from the carbohydrate-deficient glycoprotein syndromes associated with defective N-glycan synthesis and O-glycosylation [Marquardt and Denecke, 2003]. The clinical features of patients with a glycoproteinosis are similar to those found in the mucopolysaccharidoses, including the coarsening of facial features, some degree of dysostosis multiplex, and mental retardation. Other shared signs include hearing loss, macroglossia, and hepatosplenomegaly. Patients with glycoproteinoses have excessive urinary excretion of oligosaccharides, the pattern of which can be discerned by thin-layer chromatography. More recently, electrospray ionization–tandem mass spectrometry has been used to identify characteristic oligosaccharide profiles from small samples of urine, plasma, or whole blood spotted onto filter paper [Ramsay et al., 2003]. However, the diagnosis of

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the particular underlying enzyme deficiency still requires the performance of relevant biochemical assays on leukocytes or cultured skin fibroblasts.

Mannosidosis Mannosidosis results from a deficiency of either α- or βmannosidase. Two clinical forms of the α-mannosidosis have been distinguished, delineated on the basis of disease onset and severity [Sun and Wolfe, 2001]. The infantile form (type I) is associated with severe mental deterioration; facial dysmorphism, dysostosis multiplex, and hepatosplenomegaly are obvious features. Disease course in these patients is brief, with death occurring usually between the ages of 3 and 10 years. In the relatively milder form (type II), mental retardation may not be evident until 2 or 3 years of life. Speech is characteristically delayed and may remain imperfect. Motor performance is poor. The examination of the eyes reveals superficial corneal opacities and spokelike posterior lens opacities. This attenuated clinical subtype follows a protracted course, extending into adulthood. Additional features include deafness and subtle facial dysmorphism (with prominent jaw and gum hyperplasia) and skeletal abnormalities on radiographic examination. Hydrocephalus and spastic quadriplegia may develop. Brain MRI has revealed widening of the diploic space with underdevelopment of the sinuses, prominent periventricular Virchow-Robin spaces, and perioptic cerebrospinal fluid spaces [Patlas et al., 2001]. Storage of oligosaccharides in the joints can lead to their destruction in children and young adults [DeFriend et al., 2000; Gerards et al., 2004]. Prosthetic hip replacement might be successful in some of these patients, although diminished bone quality increases the risk of loosening of the prosthesis. A report delineates the phenotype in three siblings (aged 38 to 47 years) with the rare adult variant of α-mannosidosis [Gutschalk et al., 2004]. All had late-onset ataxia and retinal degeneration in addition to hearing loss, cognitive impairment, and dysostosis multiplex. One sibling also had psychosis. MRI revealed cerebellar atrophy and predominantly parieto-occipital white matter changes. Magnetic resonance spectroscopy revealed no evidence of demyelination. Mutation analysis involving 43 patients (from 39 families of European ancestry) revealed 21 novel α-mannosidase gene defects [Berg et al., 1999]. Most of the mutations identified were private or occurred in only two or three families, except for a missense mutation resulting in an R750W substitution, which was found in 13 patients and accounted for 21% of the disease alleles. There was no correlation between the types of mutations found and the observed clinical manifestations. Patients with β-mannosidosis develop severe psychomotor retardation, hearing loss, and seizures. Clinical manifestations can be widely variable, even among affected individuals from the same family [Bedilu et al., 2002; Kleijer et al., 1990]. Angiokeratoma and tortuosity of retinal vessels have been observed. Electron microscopic examination of skin biopsy specimens has demonstrated cytoplasmic vacuolization of lysosomes in the blood and lymph vessels, endothelial cells, fibroblasts, secretory portions of the eccrine sweat glands, neural cells, and basal keratinocytes in the epidermis. A few mutations in the ß-mannosidase gene have been described [Alkhayat et al.,

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1998; Uchino et al., 2003]. Disease presentation, even among patients with null mutations, can be variable, ranging from mild to severe. Several patients with α-mannosidosis have undergone bone marrow transplantation. The risk of pulmonary complications is increased during the first several months after the procedure. Follow-up studies suggest that neurocognitive and cardiopulmonary function is often preserved [Grewal et al., 2004]. In addition, improvements in adaptive skills and verbal memory have been reported, with improvement in hearing to normal or nearly normal for speech frequencies. Axonal polyneuropathy was reported to develop in a 23-year-old woman with juvenile-onset α-mannosidosis after bone marrow transplantation, complicated by chronic graft-versus-host disease [Mulrooney et al., 2003]. Progressive muscle weakness and paresthesias developed during at least 4 months and made her nonambulatory. In in vitro studies involving microglia derived from the feline model, there is significant secretion of α-mannosidase (compared with the other lysosomal enzymes) [Sun and Wolfe, 2001]. This observation may explain why the disease response to bone marrow transplantation has been comparably better. Enzyme therapy has also been administered to the mouse model for α-mannosidosis, resulting in the clearance of neutral oligosaccharide from the liver, kidney, and heart [Roces et al., 2004].

Fucosidosis Fucosidosis results from deficient α-fucosidase activity and the accumulation of fucose-containing oligosaccharides, glycopeptides, and glycolipids in tissues, with their excessive urinary excretion. The storage material consists largely of glycoasparagines (glycoproteins) and, to a lesser extent, oligosaccharides, mucopolysaccharides, and glycolipids. There is wide variability in clinical expression, but neurologic dysfunction is a prominent feature in all [Willems et al., 1991]. There is an early-onset form, with neurologic deterioration evident between 6 and 18 months of age and rapid progression to a state of decerebrate rigidity [Cragg et al., 1997]. In the later onset form, neurologic regression may not be appreciable until the second or third year of life, and the disease proceeds at a slower pace [Inui et al., 2000]. In both subtypes, death usually ensues between the ages of 4 and 6 years. A third group of patients may have signs of neurologic involvement in the first few years of life, but disease progression henceforth occurs slowly and extends into adolescence or adulthood [Fleming et al., 1998]. The presence of angiokeratoma can often serve as a clue to the diagnosis of fucosidosis, and examination of the eyes may reveal tortuosity of the conjunctival vessels and a pigmentary degeneration of the retina [Fleming et al., 1997]. The clinical distinction between the different forms of fucosidosis is artificial; the variable presentations result from allelic mutations of the gene encoding the enzyme αfucosidase [Cragg et al., 1997]. Indeed, clear-cut differentiation of subtypes may be complicated by their overlapping occurrence in members of the same family. A survey of 77 affected individuals revealed that most have a slower disease course; death before the age of 5 years was observed in only 7 (9%), whereas 36 patients (64%) reached the second

decade of life [Willems et al., 1991]. In this study, the investigators noted wide clinical heterogeneity that bore no relationship with either residual fucosidase activity or crossreacting immunoreactive material. Mutation analyses have revealed at least 22 gene defects, including four missense and 17 nonsense mutations consisting of seven stop codon mutations, six small and two large deletions, one duplication, one small insertion, and one splice site mutation [Willems et al., 1999]. All these mutations led to nearly absent enzyme activity and severely reduced cross-reacting immunoreactive material. Brain MRI in affected patients with fucosidosis indicates extensive and progressive changes in the signal intensity of the white matter, including the following areas: the corpus medullare; the periventricular, lobar, and subcortical supratentorial areas; the internal and external capsules; and the internal medullary laminae of the thalami [Galluzzi et al., 2001]. The globus pallidus and substantia nigra may demonstrate high signal intensity on T1-weighted images and low signal intensity on T2-weighted and FLAIR images. Cerebral and cerebellar atrophy have also been described in older patients with fucosidosis [Terespolsky et al., 1996]. The diagnosis is based on demonstration of decreased αfucosidase activity in leukocytes or cultured skin fibroblasts. Serum and plasma are not suitable for enzymatic diagnosis of fucosidosis because a proportion of individuals in the general population who are otherwise healthy may have markedly decreased enzyme activity in these body fluids. Thin-layer chromatography analysis of urine may reveal an excess amount of fucose-containing oligosaccharides and glycolipids. Analysis of urine may help with diagnostic confirmation as some patients may have a relatively high residual enzyme activity. Mutation analysis is available only on a research basis. Hematopoietic stem cell transplantation for fucosidosis has been reported in only a few patients [Sauer et al., 2004]. One report describes a 4-year post–hematopoietic stem cell transplantation follow-up in an asymptomatic female diagnosed at the age of 5 months as a result of family screening studies (performed after fucosidosis was detected in an older sister) [Miano et al., 2001]. The younger patient was 11 months old at the time of the transplant; clinical assessments a month earlier had revealed moderate hepatomegaly and mild psychomotor delay. Brain MRI revealed diffuse hypomyelination, and brainstem and somatosensory-evoked responses were altered. Thirty-two months after hematopoietic stem cell transplantation, the brain MRI revealed good myelination with small residual areas of hypomyelination and slight cerebellar atrophy. Follow-up brain scans at 38 and 46 months were reported to be nearly normal. Development was delayed but noted as comparably better than that of the untreated sibling (who died at the age of 7 years, after a long period of paraplegia and a vegetative state). At 42 months of age, evaluations (by the Brunet-Lezine test) revealed that the child who had undergone hematopoietic stem cell transplantation had the posture and coordination of a 27 month old and the social skills of a 24 month old. The child was also reported to walk independently starting at the age of 30 months.

Aspartylglycosaminuria Aspartylglycosaminuria results from a deficiency of aspartylglucosaminidase, which is normally responsible for cleaving

Pastores and Kolodny / Lysosomal Storage Diseases

the bond between asparagine and N-acetylglucosamine during the degradation of N-linked glycoproteins. The majority of cases have been found in Finland [Valkonen et al., 1999]. Randomized urine samples from 151 of 178 retarded children in eastern Finland identified three affected individuals with aspartylglycosaminuria (incidence of 1 in 3643), consistent with an estimated carrier frequency of 1 in 30 [Mononen et al., 1991]. In this study, aspartylglycosaminuria was, after trisomy 21 (n = 19) and the fragile X syndrome (n = 6), the most common genetic cause of mental retardation. Affected individuals with aspartylglycosaminuria have speech problems and severe behavioral abnormalities, with alternating periods of hyperactivity and apathy [Arvio and Arvio, 2002]. Recurrent infections and diarrhea may dominate the clinical picture in the early months and years of life. Gradual deterioration in motor and mental functions develops insidiously between the ages of 5 and 15 years. Mild coarsening of the facial features and skeletal abnormalities (i.e., deformities of the thoracolumbar vertebrae, periosteal thickening of the long bones, and thickening of the calvaria) are usually evident by adolescence [Arvio et al., 2002a]. An analysis of facial photographs of 76 patients with aspartylglycosaminuria revealed a consistent dysmorphic gestalt with hypertelorism, short and broad nose with round nares, simple and often small ears with small or missing lobule and modest folding of the helices, thick lips, and square-shaped face [Arvio et al., 2004]. Additional findings in affected individuals include short stature and joint laxity. In a 21-year-old man with aspartylglycosaminuria who had progressive severe gait disturbance with frequent falls and generalized epileptic seizures triggered by unexpected stimuli, treatment with a combination of clonazepam, valproate, and phenobarbital led to a dramatic improvement in his abnormal startle and seizures, enabling the patient to walk alone unaided [Labate et al., 2004]. This entity in aspartylglycosaminuria is important; progressive gait disorder with frequent falls could easily be misinterpreted as an additional irreversible manifestation of the anticipated ongoing neurologic deterioration (rather than poor seizure control). The diagnosis is based on demonstration of increased aspartylglucosamine in urine and decreased aspartylglucosaminidase activity in plasma, leukocytes, or cultured skin fibroblasts. Interestingly, examination of a group of 131 aspartylglycosaminuria carriers (the parents of patients) revealed that 3 (2.3%) had chronic arthritis and 17 (13%) were rheumatoid factor positive, higher than the percentages among Finns (in general, approximately 1.4% and 5%, respectively) [Arvio et al., 2002b]. Several aspartylglucosaminidase gene defects have been identified, including missense mutations (65%) and deletions (27%) [Saarela et al., 2001]. Many of these are predicted to interfere with the complex intracellular maturation and processing of the aspartylglucosaminidase polypeptide. Proper initial folding of aspartylglucosaminidase in the endoplasmic reticulum is dependent on intramolecular disulfide bridge formation and dimerization of two precursor polypeptides [Saarela et al., 2004]. One mutation, identified as the AGUFinn major, is responsible for 98% of disease alleles among Finnish patients; this observation permits facile screening of the population.

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Hematopoietic stem cell transplantation has been performed in two siblings with aspartylglycosaminuria with use of unrelated HLA A, B, and DR identical donors at the ages of 10 years 5 months and 5 years 10 months [Malm et al., 2004]. During a 5-year follow-up, no neuropsychologic or clinical deterioration was noted in the children, who had a stable enzyme expression. The spinal fluid concentration of Tau protein, a marker of neuronal and axonal degeneration and damage, peaked at approximately 12 months after hematopoietic stem cell transplantation and then declined to almost normal levels after 5 years. By MRI, an improvement of myelination in the younger sibling and an arrest of demyelination in the older one were observed [Autti et al., 1999]. Another study involving two patients who received transplants found them to be more severely mentally retarded than the patients with aspartylglycosaminuria who did not receive transplants after 7 and 5 years of follow-up [Arvio et al., 2001]. The poorer outcome in these patients may have been related to post-transplantation complications. Additional experience should clarify the appropriate counseling of families with affected children who may be deemed potential candidates for hematopoietic stem cell transplantation. Studies involving bone marrow transplantation in the mouse model showed improved clearance of the storage material in the brain by use of wild type compared with heterozygote donors [Laine et al., 2004]. This observation underscores the need for careful selection of potential bone marrow donors. Cellular gene therapy experiments incorporating the aspartylglucosaminidase promoter resulted in higher specific enzyme activity in glia than in neurons [Harkke et al., 2003]. The use of glial fibrillary acidic protein and neuron-specific enolase promoters also produced a clear overexpression of the enzyme in glial cells and neurons, respectively. The amount of exocytosed enzyme was significantly higher in glial cells than in neurons, and glial cells were also found to have a greater capacity to endocytose the enzyme. These data indicate the importance of glial cells in the expression and transport of aspartylglucosaminidase.

Sialidosis Deficiency of α-neuraminidase (sialidase) is associated with at least two clinical variants (known as sialidosis types I and II). Affected patients with either form have increased urinary excretion of sialyloligosaccharides. Human α-neuraminidase occurs in a high-molecular-mass complex with several other proteins, including cathepsin A and β-galactosidase [Achyuthan and Achyuthan, 2001]. Multiprotein complexation is important for the in vivo integrity and catalytic activity of α-neuraminidase [Lukong et al., 2000]. In sialidosis type I, progressive visual loss, polymyoclonus, and seizures develop in late childhood or adolescence [Naganawa et al., 2000]. Multiple, irregular myoclonic jerks may be precipitated by action (movement), sensory stimuli, and emotional upset and also by menstruation and smoking [Palmeri et al., 2000]. The clinical problems that affected patients experience are often progressive and can eventually interfere with their speech, walking, and feeding. Eye examination reveals a macular cherry-red spot and, in some patients, punctate lenticular opacities [Federico et al., 1991]. Blindness and optic atrophy occur, and there is

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intellectual deterioration. Cerebral and cerebellar atrophy are evident on brain CT or MRI scans. In one report, a brain CT scan performed at 21 years of age in one patient revealed enlargement of the fourth ventricle [Palmeri et al., 2000]. Brain MRI performed at the age of 40 years in the same patient found severe atrophy of the cerebellum and pontine region, cerebral hemispheres, and corpus callosum. Affected patients with sialidosis type I do not have dysmorphic facial features, bone and joint abnormalities, or hepatosplenomegaly. There is a report of an unusual case of α-neuraminidase deficiency associated with acute onset and fulminant nephrotic syndrome and complications that led to the patient’s death [Roth et al., 1988]. Pathologic examination of the kidneys revealed renal epithelial cell damage, most marked in the membranes of the glomeruli and proximal tubules. In sialidosis type II, there are neurologic, visceral, and skeletal abnormalities similar to those found in galactosialidosis (a distinct condition resulting from deficiency of cathepsin A). Sialidosis type II is also known as mucolipidosis type I. Affected individuals have dysostosis multiplex, Hurler-like phenotype, mental retardation, and hepatosplenomegaly. Occasional cases in newborns with hepatosplenomegaly and ascites have been described [Sergi et al., 1999]. Further details about this disorder can be found in the section on the mucolipidoses. The diagnosis is based on deficient α-neuraminidase activity in leukocytes and cultured skin fibroblasts (the preferred clinical material for enzyme testing). Analysis of α-neuraminidase gene mutations has revealed considerable heterogeneity [Bonten et al., 2000]. Patients who are compound heterozygotes, with a combination of a mild and severe mutation, usually have a milder disease [Itoh K et al., 2002]. Patients with the severe form mainly have frameshifts or other mutations resulting in premature protein truncation [Seyrantepe et al., 2003]. Some mutations may disrupt α-neuraminidase binding with lysosomal cathepsin A or β-galactosidase in the multienzyme lysosomal complex [Ostrowska et al., 2003]. There is no specific treatment. Airway assessment and management are particularly crucial in patients with sialidosis who require elective surgery [Tran et al., 2001]. Studies in the sialidase knockout mouse have revealed progressive deformity of the spine, high incidence of premature death, age-related extramedullary hematopoiesis, and lack of early degeneration of cerebellar Purkinje cells. These observations were unique to the sialidase knockout mice and not found in the galactosialidosis mouse model [de Geest et al., 2002].

Galactosialidosis Galactosialidosis results from the combined deficiency of α-neuraminidase and β-galactosidase, arising from defects of the protective protein/cathepsin A (PPCA). This multienzyme complex formation allows its correct compartmentalization in lysosomes and offers the protection required against rapid proteolytic degradation [Pshezhetsky and Ashmarina, 2001]. Studies also suggest that PPCA is present in a second complex, including the elastin-binding protein receptor, the major component of the non-integrin cell surface receptor that is involved in elastogenesis [Malvagia et al., 2004].

Galactosialidosis is clinically characterized by cerebellar ataxia, myoclonus, and visual failure, features that are usually evident in late childhood or adolescence [Friedhoff et al., 2003]. Additional findings include the cherry-red macular spot, dysmorphic facial features, hepatomegaly, and skeletal changes [Nobeyama et al., 2003]. Patients with juvenile onset may survive into adulthood. Early and late infantile forms have also been described. A report of a 14-year old male patient of Middle Eastern descent described cardiac valvular abnormalities (i.e., mitral regurgitation and aortic stenosis) similar to those found in patents with mucopolysaccharidoses [Bursi et al, 2003]. The majority of reported cases have been from Japan [Kawachi et al., 1998]. The diagnosis of galactosialidosis is based on demonstration of combined deficiency of α-neuraminidase and β-galactosidase activity in leukocytes or cultured skin fibroblasts or mutations in the gene encoding the PPCA. Electron microscopic examination of skin tissue reveals membranelimited vacuoles in the cytoplasm of the endothelial cells, pericytes, and fibroblasts. The material found in the cytoplasmic vacuoles appears to be glycoproteins with sialic acid, stained by the Limax flavus agglutinin (a lectin that binds specifically with sialic acid) [Nobeyama et al., 2003]. A few mutations in the gene encoding PPCA have been described. In an Italian patient with galactosialidosis and hydrops fetalis, two PPCA gene mutations, c60delG and IVS2+1G→T, were detected and found to lead to a frameshift and a premature stop codon, respectively [Groener et al., 2003]. The deleterious effect of such mutations was confirmed by the complete absence of the PPCA protein on Western blots. Molecular studies in two Dutch patients with the early infantile form revealed that one patient was a compound heterozygote, with a single missense mutation (Gly57Ser) and a single C insertion at nucleotide position 899, which gave rise to a frameshift and premature termination codon, respectively [Groener et al., 2003]. The second patient was found to be homozygous for the C899 insertion. Both patients presented with nonimmune hydrops fetalis. There is no specific treatment. In studies involving macrophages isolated from the PPCA-null (-/-) mouse, recombinant proteins (produced by baculovirus expression in insect cells) were readily taken up [Bonten et al., 2004]. Subsequently, intravenously injected recombinant PPCA given to affected mice has been shown to be efficiently internalized in resident macrophages of many organs and leads to clearance of the lysosomal storage deposits. These findings suggest that enzyme therapy may be an effective treatment for the extraneurologic manifestations of galactosialidosis. Bone marrow transplantation in mutant animals with use of transgenic bone marrow overexpressing the corrective enzyme in either erythroid cells or monocytes-macrophages is effective in modifying the phenotype [Leimig et al., 2002].

Schindler-Kanzaki Disease (␣-N-Acetylgalactosaminidase Deficiency) This rare condition is a form of neuroaxonal dystrophy that results from deficiency of the lysosomal enzyme αN-acetylgalactosaminidase, a glycosyl hydrolase [Herrmann

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et al., 1998]. The disorder was initially described by D. Schindler (1987) in two German brothers with progressive motor and mental deterioration who were bedridden by the age of 4 years. Additional findings included myoclonic seizures, pyramidal signs with hyperreflexia, hypotonia, and optic atrophy. Brain atrophy was noted on MRI. Cerebrospinal fluid protein level was not elevated, and nerve conduction velocity studies were normal. Subsequent investigations revealed that these patients had an E325K mutation in the gene encoding α-N-acetylgalactosaminidase (NAGA), which has also been found in two Moroccan siblings with αN-acetylgalactosaminidase deficiency. The index patient in the latter family was a 3-year-old male with congenital cataracts and slight motor retardation; however, his older sibling, who was also enzyme deficient, had no clinical or neurologic symptoms on examination at the age of 7 years [Bakker et al., 2001]. Positron emission tomography and administration of 2-[18F]fluoro-2-deoxy-D-glucose in another 4.8-year-old male with α-N-acetylgalactosaminidase deficiency revealed that overall cerebral glucose metabolism was reduced in proportion to the degree of cerebral atrophy [Rudolf et al., 1999]. In 1989, Kanzaki and colleagues described a group of adult Japanese patients without overt neurologic manifestations but who had diffuse angiokeratoma, α-N-acetylgalactosaminidase deficiency, and increased urinary excretion of several glycopeptides [Kanda et al., 2002]. Molecular studies revealed an R329W/Q mutation in the NAGA gene. Immunocytochemical analysis revealed that the main lysosomal storage material in cultured fibroblasts from these patients (whom they referred to as having Kanzaki’s disease) is the Tn antigen, a glycoprotein that forms the core of O-linked glycoconjugates and a substrate for α-N-acetylgalactosaminidase [Sakuraba et al., 2004]. In two other Japanese cases, analysis of the composition of the storage material by immunoelectron microscopy with mouse antibodies revealed GalNAc(α)1-O-Ser/Thr (Tn) in vacuolated lysosomes of vascular endothelial cells, eccrine sweat gland cells, fibroblasts, and pericytes [Kanda et al., 2002]. A more recent report presented another patient (aged 59 years) with α-N-acetylgalactosaminidase deficiency who developed sensory-motor polyneuropathy [Umehara et al., 2004]. The patient had mildly impaired intellectual function and suffered from repeated episodes of vertigo. Sural nerve biopsy revealed decreased density of myelinated fibers with axonal degeneration. Additional investigations revealed abnormal brain MRI findings (specifically, cerebral atrophy predominantly in the parieto-occipital region and highintensity areas in the posterior periventricular white matter and some high-intensity spots in the centrum semiovale on T2-weighted images) and sensorineural hearing impairment. Additional patients with Schindler-Kanzaki disease have since been described, including altogether 12 individuals from eight different families [Keulemans et al., 1996; Kodama et al., 2001]. Broad heterogeneity in clinical presentation and disease course has been noted [Chabas et al., 1994]. Investigations to date suggest that disease expression consistent with Kanzaki’s disease may be due to a single enzyme (αN-acetylgalactosaminidase) deficiency and that other factors (which remain to be defined) in addition to a defect of αN-acetylgalactosaminidase may contribute to the severe neurologic features encountered in Schindler’s disease. The corresponding NAGA gene in the mouse has been described [Wang

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et al., 1998]. Generation of a mouse model of α-N-acetylgalactosaminidase deficiency may further clarify the essential pathologic mechanisms leading to variable clinical expression in the Schindler-Kanzaki disease [Keulemans et al., 1996]. The diagnosis of Schindler-Kanzaki disease is based on demonstrated α-N-acetylgalactosaminidase deficiency in leukocytes and cultured skin fibroblasts [Prence et al., 1996]. Thin-layer chromatography can be performed to analyze abnormally excreted oligosaccharides in urine. Labeling the oligosaccharides with a tag, such as 8-aminonaphthalene-1,3,6-trisulfonic acid, also allows easy identification of the excreted compounds by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry [Horiuchi et al., 2002].

MUCOLIPIDOSES The mucolipidoses represent a cluster of disorders with clinical features that resemble those encountered in the mucopolysaccharidoses, except for the absence of increased urinary excretion of glycosaminoglycans [Spranger and Wiedemann, 1970]. Van Hoff and Hers and Spranger and Wiedemann were among the first to draw attention to the mucolipidoses. The name for the group is derived from the combined tissue storage of glycosaminoglycans and sphingolipids, noted as concentric membranous cytoplasmic bodies. The classification can actually be misleading because each of the clinical disorders that belong to the group displays considerable biochemical and clinical differences.

Mucolipidosis Type I (Sialidosis Type II) Affected patients have Hurler-like dysmorphic features and skeletal abnormalities. Clinical variants are delineated on the basis of age at onset. In the congenital form, nonimmune hydrops, hepatomegaly, and skeletal dysplasia are evident. Affected infants are usually stillborn or die within a few weeks [Godra et al., 2003]. In the early infantile form, hepatosplenomegaly and ascites may be evident in the neonatal period or may develop a few weeks later. The macular cherry-red spot and punctate lenticular opacities are usually demonstrable on eye examinations. Neurologic development is severely impaired, and death occurs in most patients after a few months or by the second year of life. Some children may live longer with severe mental retardation, seizures, and motor difficulties. A subgroup of patients manifests with severe renal dysfunction and proteinuria, with survival into adolescence [Toyooka et al., 1993; Tylki-Szymanska et al., 1996]. Pathologic examination of the kidneys reveals renal epithelial cell damage, most marked in the membranes of the glomeruli and proximal tubules, findings that are consistent with the high sialic acid content of the membrane in these areas of the nephron. Chemical analyses indicate that the bulk of the stored material is in the form of polar sialyloligosaccharides of high molecular weight. In the late infantile and juvenile forms, patients exhibit mild developmental delay and signs of dysmorphic facial features and dysostosis multiplex. Patients experience progressive problems, including seizures and myoclonus, and

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eventually become severely disabled. Death often occurs in the second or third decade. The diagnosis of mucolipidosis type I or sialidosis type II is based on increased urinary excretion of sialyloligosaccharides and decreased α-neuraminidase activity in leukocytes or cultured skin fibroblasts. The distinction between normal (unaffected) and affected ranges of enzyme activity in leukocytes can be quite small, and when the index of suspicion for this condition remains high, analysis of αneuraminidase activity in freshly cultured skin fibroblasts should be performed. In addition, the overlap in clinical expression with galactosialidosis necessitates the differentiation of this diagnosis from sialidosis type II based on the added demonstration of decreased β-galactosidase activity or mutations of the PPCA gene. Mutation analysis performed in three patients (including two siblings) with sialidosis type II revealed homozygosity for the C808T mutation in the neuraminidase gene [Rodriguez Criado et al., 2003]. The patients were from a small area to the east of the city of Seville (Spain), suggesting the existence of a founder mutation. Another study reported five novel gene defects, including four missense mutations and one nonsense mutation [Pattison et al., 2004]. None of the mutant alleles expressed significant enzyme activity, which likely explains the severe phenotypes of the patients.

Mucolipidosis Type II (I-Cell Disease) and Type III (Pseudo-Hurler Polydystrophy) These disorders result from an abnormality of the intracellular transport of newly synthesized enzymes to the lysosome and the associated deficiency in the metabolism of the relevant substrates. Defects in the synthesis of mannose 6-phosphate, the recognition marker for the lysosomal targeting of several enzymes, explain the underlying biochemical abnormalities. In mucolipidosis types II and III, UDP-Nacetylglucosamine-1-phosphotransferase (NAGPT) enzyme activity is defective. Studies involving patients with mucolipidosis type III have shown three complementation groups (namely, A, B, and C), suggesting genetic heterogeneity. Mutation analysis in patients with mucolipidosis type III subtype C has revealed defects in the NAGPT γ subunit gene located on chromosome 16p [Raas-Rothschild et al., 2004]. Patients with I-cell disease manifest with dysmorphic facial features, gingival hypertrophy, dysostosis multiplex, and progressive severe psychomotor retardation (Fig. 27-21). Impaired cathepsin-L activity has been suggested to have a key role in the establishment of the skin and gingival abnormalities in I-cell disease [Nishimura et al., 2002]. Renal proximal tubular dysfunction has also been documented and characterized by increased excretion of low-molecularweight proteins, aminoaciduria, hyperphosphaturia, and high or slightly increased urinary calcium concentration [Bocca and Monnens, 2003]. In these patients, the serum level of 1,25-dihydroxycalciferol is increased, and rickets is evident on skeletal radiographs. A case of I-cell disease with neonatal cholestasis has also been described [Hochman et al., 2001]. Death usually ensues by the age of 5 to 8 years, usually from congestive heart failure and recurrent pulmonary infections. The clinical observation made in human patients with I-cell disease is mimicked by the recently described feline model [Mazrier et al., 2003].

FIGURE 27-21. Coarse facial features of patient with I-cell disease reminiscent of Hurler disease along with the flattened bridge of the nose and widened alae nasi.

Patients with mucolipidosis type III have similar (but more variable severity of) clinical manifestations, including stiffness of the fingers (with the clawhand deformity) and shoulders, short stature, and scoliosis [Song et al., 2003] (Fig. 27-22). Mild coarsening of the face with corneal clouding, mild retinopathy, astigmatism, and cardiac valve involvement are also commonly seen [Pourjavan et al., 2002]. The condition can progress into adulthood. Bone involvement is slowly progressive, and bone pain and disability due to destruction of hip joints are the most frequent source of debilitation [Tylki-Szymanska et al., 2002a]. The diagnosis of mucolipidosis types II and III is based on a combination of biochemical studies involving plasma, leukocytes, and cultured skin fibroblasts. Affected individuals usually have markedly increased lysosomal enzyme activities (such as those of hexosaminidase and arylsulfatase A) in plasma; the corresponding activities in cultured skin fibroblasts are markedly decreased (except for β-glucosidase). Increased rates of lysosomal enzyme activities (found in the culture medium) are noted with increasing incubation time, usually to a greater extent among affected patients than in normal control subjects. Examination of peripheral blood lymphocytes obtained from affected individuals reveals vacuole-like inclusions that are negative for periodic acid–Schiff and Sudan black B staining [van der Meer et al., 2001].

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Mucolipidosis Type IV

FIGURE 27-22. This patient with I-cell disease has a characteristic contracture of the elbow. The widened hand with stubby, puffy fingers is also found in I-cell disease.

Prenatal diagnosis is feasible, using cultured chorionic villi or amniocytes and the same enzyme assays applied to cultured skin fibroblasts. Molecular analysis has also been performed, in a large Bedouin-Moslem family in which an affected individual was homozygous for the founder haplotype and the mutational single-stranded conformational polymorphism pattern of mucolipidosis type IIIC [FalikZaccai et al., 2003]. There is no specific treatment for mucolipidosis types II and III, although bone marrow transplantation performed in a 19-month-old female with I-cell disease revealed no new problems. Respiratory infections have diminished and cardiac function was noted to be normal at the age of 7 years (i.e., 5 years after transplantation) [Grewal et al., 2003]. The patient is also reported to continue to gain neurodevelopmental milestones, although at a very slow rate. However, musculoskeletal deformities have worsened despite bone marrow transplantation. In two siblings with mucolipidosis type III, intravenous pamidronate treatment given monthly for a year resulted in a reduction in bone pain and consequent improvement in mobility, despite the incomplete suppression of bone resorption as assessed by biochemical, radiographic, and histologic criteria [Robinson et al., 2002].

Mucolipidosis type IV is characterized by the combination of corneal clouding, retinal degeneration, and mental and motor retardation in the absence of dysmorphic facial features [Altarescu et al., 2002]. Patients with mucolipidosis type IV do not have signs of hepatosplenomegaly or skeletal abnormalities. The responsible gene (MCOLN1 mapped to chromosome 19p13.3-13.2) has been characterized and found to encode a protein called mucolipin, which normally functions as a calcium-permeable cation channel that is also involved in lysosomal biogenesis and membrane trafficking [LaPlante et al., 2002; Sun et al., 2000]. Fusion between late endosomes and lysosomes is a calcium-dependent process, related to signaling pathways involved in the regulation of intracellular calcium homeostasis [LaPlante et al., 2004; Raychowdhury et al., 2004]. Examination of cells from patients with mucolipidosis type IV reveals enlarged lysosomes, attributed to abnormal sorting and trafficking of these and related organelles. Affected individuals usually present with arrested neurologic development and visual impairment between 3 and 8 months of age. There also is severe impairment in motor development, and most patients eventually lose the ability to walk independently. Speech is generally lacking. Corneal opacity may be observed, and retinal degeneration with amblyopia and an “extinction” (electronegative) pattern on electroretinography is usually demonstrable [Pradhan et al., 2002]. Ophthalmologic findings in patients with mucolipidosis type IV have been extensively characterized [Smith et al., 2002]. In this study, all patients were found to have some degree of corneal epithelial haze, optic nerve pallor, retinal vascular attenuation, and retinal pigment epithelial changes. The eye findings were noted to be age related. Conjunctival cytologic studies reported characteristic lysosomal inclusions on light and electron microscopy. Variability in the clinical expression of mucolipidosis type IV has been described [Chitayat et al., 1991; Reis et al., 1993]. The disease usually runs a protracted course, extending well into adolescence and early adulthood. Correlation of the genotype with the neurologic handicap and corpus callosum dysplasia has been described [Frei et al., 1998]. Brain imaging studies involving 14 patients with mucolipidosis type IV (including 11 children and 3 adults) have revealed significant reductions in the ratios of N-acetylaspartate/creatine-phosphocreatine and N-acetylaspartate/choline-containing compounds [Bonavita et al., 2003]. No difference was found for the ratio of N-acetylaspartate/creatine-phosphocreatine between younger and older patients, suggesting that mucolipidosis type IV may be a largely static developmental encephalopathy associated with diffuse neuronal and axonal damage or dysfunction. The diagnosis of mucolipidosis type IV was previously based on demonstration by electron microscopy of lysosomal inclusions in conjunctival and skin biopsy specimens. In skin there are several types of lysosomal residual bodies, membrane-bound vacuoles, and avacuolar lamellar bodies resembling membranous cytoplasmic bodies, containing a diverse spectrum of lipopigments including curvilinear and fingerprint profiles [Bargal et al., 2002] (Fig. 27-23). For prenatal diagnosis, demonstration of the storage bodies in

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Genetic, Metabolic, and Neurocutaneous Disorders / 27

FIGURE 27-23. Biopsy specimen of skin from a patient with mucolipidosis type IV.

cultured amniocytes was used. These methods, which require considerable expertise, have been replaced by molecular genetic analysis. Mucolipidosis type IV is prevalent among individuals of Ashkenazi Jewish ancestry, but it has also been reported in other ethnic groups. The two most common mutations among the Ashkenazi Jewish patients are an A to G transition in the acceptor splice site of the third intron (IVS3-1A to G) and a partial gene deletion [Bargal et al., 2001]. Together, these two mutations account for approximately 95% of the Ashkenazi Jewish mucolipidosis type IV alleles, enabling targeted population screening to identify carrier couples at risk of having an affected child [Edelmann et al., 2002]. Non-Jewish patients with mucolipidosis type IV are usually compound heterozygotes for rare disease-causing alleles [Bargal et al., 2001]. There is no specific treatment for mucolipidosis type IV, although the corneal clouding can be decreased by the regular use of artificial tears.

GLYCOGEN STORAGE DISEASE TYPE II (POMPE’S DISEASE) This disorder of glycogen metabolism is due to a deficiency of the lysosomal hydrolase α-glucosidase (also known as acid maltase). There is a range of phenotypes resulting from α-glucosidase deficiency, from the most severe presentation known as classic infantile-onset Pompe’s disease to the later onset (proximal-type) myopathy [Kishnani and Howell, 2004]. In Pompe’s disease, affected infants usually present with cardiomegaly and hypotonia during the first 6 months of life, with death due to cardiorespiratory failure usually before 2 years of age. An age-related increase in the diastolic thickness of the left ventricular posterior wall and the cardiac weight (at postmortem examination) has been noted [van den Hout et al., 2003]. The physiologic effects of severe myocardial hypertrophy and existing or potential ventricular dysfunction in patients with glycogen storage disease type II necessitate careful

monitoring, attention to intravascular volume, and selection of appropriate anesthetic induction agents before any elective procedures requiring sedation [Ing et al., 2004]. Patients with the juvenile or adult-onset form develop progressive proximal myopathy and ultimately impairment in respiratory function. The adult form manifests itself at different ages but usually begins in the third or fourth decade as a myopathic disorder, resembling polymyositis or limb-girdle muscular dystrophy [Bosone et al., 2004]. Sarcoplasmic accumulation of sarcolemmal proteins, including dystrophin and sarcoglycans, has been demonstrated around some of the glycogen vacuoles and within nonvacuolated fibers. Utrophin has also been found to be upregulated and found at extrajunctional sarcolemmal locations of many fibers. These results demonstrate a close association of dystrophin and sarcoglycans during sarcoplasmic processing and may suggest a mechanism for the myopathy found in patients with α-glucosidase deficiency [Radojevic et al., 2003]. A combination of disuse atrophy and lipofusc in- mediated apoptosis of myocytes is also thought to contribute to the gradual loss of muscle mass. The presence of α-glucosidase deficiency has also been noted to affect the homeostasis of receptors (e.g., glucose transporter 4) cycling through the endosomes-lysosomes [Radojevic et al., 2003]. This disorder is further reviewed in Chapter 26. A few cases of acid maltase deficiency with onset in the sixth and seventh decade have been described [Swash et al., 1985]. In these later onset cases, deep tendon reflexes may be normal, diminished, or absent. Serum creatine kinase and liver transaminase levels may be moderately elevated (or even normal in the later onset cases). Electrocardiogram abnormalities and arrhythmias may be present, although cardiac enlargement generally does not occur in the juvenile or adult-onset form (in contrast to the infantile form). Intracranial aneurysms, especially of the basilar district, have also been reported as an associated feature. Electromyography in patients with glycogen storage disease type II reveals variable pseudomyotonic discharges and irritability. Muscle MRI has demonstrated a selective progressive pattern of muscle involvement, with a constant involvement of the adductor magnus and semimembranous muscles at the early stage of disease and a later fatty infiltration of the long head of the biceps femoris, semitendinosus, and anterior thigh muscles [Pichiecchio et al., 2004]. In advanced cases, a selective sparing of the sartorius, rectus, and gracilis muscles and peripheral portions of the vastus lateralis is also evident. Muscle strength and MRI findings are positively correlated, which suggests that muscle MRI may prove to be of value in the diagnosis and assessment of accurate muscle involvement in acid maltase deficiency and monitoring of the progression of the disorder or its response to therapy (if any). Sleep-disordered breathing and respiratory failure are major complications in patients with later onset glycogen storage disease type II, attributed to diaphragm weakness. Vital capacity correlates with respiratory muscle function [Mellies et al., 2001]. Sleep studies have demonstrated that respiratory insufficiency occurs most severely during rapid eye movement sleep. Patients have benefited clinically from the institution of nocturnal noninvasive bilevel positive airway pressure [Puruckherr et al., 2004].

Pastores and Kolodny / Lysosomal Storage Diseases

Assessment of the health-related quality of life of patients with late-onset Pompe’s disease has revealed scores that are markedly decreased for physical health domains [Hagemans et al., 2004]. However, scores for the mental health domains were only slightly lower than in the general population. Not surprisingly, the use of a wheelchair and artificial ventilation were both noted to be associated with lower physical and social functioning scores. The diagnosis of glycogen storage disease type II is based on demonstration of decreased α-glucosidase in lymphocytes and cultured skin fibroblasts (the preferred clinical material for analysis) [Whitaker et al., 2004]. Testing with use of rehydrated dried blood spots (on filter paper) incubated with the enzyme substrates is feasible [Chamoles et al., 2004]. In this assay, acarbose is used as an inhibitor of an interfering acid α-glucosidase present in neutrophils. This technique has been adapted for multiplex screening, with use of the relevant substrates for the diagnosis of the following additional lysosomal storage diseases: Gaucher’s disease, Niemann-Pick disease types A and B, Fabry’s disease, and Krabbe’s disease. Thus, this diagnostic approach may prove to be useful in targeted populations or newborn screening programs. In countries where the enzyme assay may not be available for prenatal diagnosis, electron microscopy for the detection of fibrocytes with the typical glycogen-filled vacuoles has been performed [Phupong et al., 2004]. Several mutations in the α-glucosidase gene have been identified, including missense, nonsense, and frameshift mutations [Fernandez-Hojas et al., 2002; Lam et al., 2003; Montalvo et al., 2004]. Patients with an attenuated phenotype usually have α-glucosidase gene mutations associated with residual enzyme activity [Hermans et al., 2004; Kroos et al., 2004]. Most adult-onset patients (up to 70%) share the same defect, namely, a splicing out of exon 2 caused by a 13 T to G transversion in intron 1 [Laforet et al., 2000]. Enzyme therapy for Pompe’s disease, which is still in clinical trials, decreases left ventricular mass and posterior wall thickness [Reuser et al., 2002]. Life span was also increased in the treated patients, beyond the expected length of survival for untreated patients. Improved skeletal muscle (i.e., gross motor) strength has been seen in some but not all patients [Van den Hout et al., 2004]. Relatively high doses of recombinant human α-glucosidase may be required to reduce the abnormal glycogen storage in cardiac and skeletal muscles because of the inefficient cation-independent mannose 6-phosphate receptor-mediated endocytosis of the enzyme by the affected target cells [Zhu et al., 2004]. The recombinant enzyme formulation that has been used in the different trials was isolated from Chinese hamster ovary cells in culture or the milk of transgenic rabbits. Reversible nephrotic syndrome during prolonged, highdose, experimental enzyme therapy with recombinant human α-glucosidase has been observed in one patient [Hunley et al., 2004]. Histologic evaluation of kidney tissue revealed glomerular deposition of immune complexes containing recombinant human α-glucosidase itself, in a pattern of membranous nephropathy. The nephrotic syndrome gradually resolved after the dose of recombinant human αglucosidase was decreased, indicating that decrease of the antigenic load can ameliorate glomerular immune complex

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deposition associated with enzyme replacement in a highly sensitized patient. In another report, a 30- to 90-dB hearing loss was discovered in four infants with Pompe’s disease who participated in a separate trial of enzyme therapy [Kamphoven et al., 2004]. Auditory brainstem response thresholds but not the interpeak latency times were increased, which pointed to a middle or inner ear disease rather than to involvement of the central auditory nervous system. The possible occurrence of cochlear disease was supported by the absence of otoacoustic emissions. Investigations in the mouse model revealed glycogen storage in the inner and outer hair cells of the cochlea, the supporting cells, the stria vascularis, and the spiral ganglion cells. These observations suggest that cochlear disease is the most likely cause of hearing loss, not an adverse reaction to the infused recombinant human α-glucosidase. Oral alanine supplementation in a patient with the late infantile form has been found to result in slower progression of the skeletal myopathy and almost complete resolution of the patient’s cardiomyopathy [Bodamer et al., 2002]. Gene therapy for Pompe’s disease is also under investigation. Hepatic targeting of a modified adenovirus vector expressing human α-glucosidase corrects the glycogen accumulation in multiple affected muscles in the αglucosidase knockout mice [Raben et al., 2002]. In experiments involving transgenic expression of human αglucosidase (in skeletal and cardiac muscle of α-glucosidase knockout mice) that could be turned on at different stages of disease progression by use of a tetracycline-controllable system, it has been demonstrated that α-glucosidase levels of approximately 20% to 30% of normal activity were sufficient to clear glycogen in the heart of the young mice but not in older mice with a considerably higher glycogen load [Xu et al., 2004]. However, in skeletal muscle, the induction of α-glucosidase expression in young mice to levels greatly exceeding wild-type values did not result in full phenotypic correction, and some muscle fibers exhibited little or no glycogen clearance. These results may have implications for the treatment of later onset cases of glycogen storage disease type II.

DANON’S DISEASE Danon’s disease (also termed X-linked vacuolar myopathy and cardiomyopathy) is due to a defect in LAMP-2, a lysosomal-associated membrane protein [Horvath et al., 2003]. LAMP-2 is thought to protect the lysosomal membrane from proteolytic digestion and to act as a receptor for proteins that are imported into the lysosome. Defects in endosomal-lysosomal trafficking and the accumulation of autophagic vacuoles have been described among affected patients [Nishino et al., 2000]. The reason for the primary involvement of muscle cells in this condition remains to be determined, but it may be partly explained by the predominant expression of one LAMP-2 isoform (LAMP-2b) in the heart and skeletal muscles. Affected individuals develop abnormalities of the heart (e.g., cardiomyopathy and conduction defects) and skeletal muscles (e.g., mild proximal limb and neck weakness) [Sugie et al., 2002]. Variable degrees of mental retardation

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Genetic, Metabolic, and Neurocutaneous Disorders / 27

also occur. Although it is an X-linked trait, carrier (heterozygous) females may develop disease-related symptoms. However, the incidence of disease complications is higher among affected male patients, with findings evident before the age of 20 years and in the majority during childhood (between 5 and 10 years of age) [Sugie et al., 2002]. Electrocardiography and echocardiography reveal hypertrophic or dilated cardiomyopathy and cardiac conduction problems, including the Wolff-Parkinson-White syndrome (seen in 35% of cases) [Charron et al., 2004]. In one survey, mean age at death from cardiac failure or sudden cardiac arrest was 19 years (range, 12 to 29 years) among males (N = 20) and 40 years (±7 years) among symptomatic females (N = 14) [Sugie et al., 2002]. Heart transplantation has been performed in patients with Danon’s disease who have developed cardiomyopathy and heart failure, and those with heart block have undergone pacemaker insertion [Dworzak et al., 1994]. The definitive diagnosis of Danon’s disease is based on demonstration of LAMP-2 deficiency through immunohistochemistry or Western blot analysis [Usuki et al., 1994]. Muscle biopsy reveals basophilic vacuoles filled with glycogen but normal α-glucosidase activity. Sarcolemmal proteins and basal lamina are associated with the vacuolar membranes. Serum levels of creatine kinase and aldolase are increased. Mutation analysis is available on a research basis only. In one report, a novel LAMP-2 mutation of the exon 8 splice acceptor site (IVS7-1G to A), which predicts abnormal splicing, has been identified; the two affected individuals presented solely with hypertrophic cardiomyopathy [Horvath et al., 2003]. In a population survey of 197 cases with cardiomyopathy, two different LAMP-2 mutations (leading to premature stop codons) were found in patients who evolved toward severe heart failure (<25 years old) [Charron et al., 2004]. Germline mosaicism in Danon’s disease has been identified in a family wherein a son and daughter were affected and carried the same mutation that was not detected in their mother’s peripheral blood or buccal cells [Takahashi et al., 2002]. This observation has important implications for genetic counseling.

SIALIC ACID STORAGE DISORDERS The sialic acid storage disorders include the allelic disorders infantile free sialic acid storage disease and Salla disease (or the Finnish variant). These disorders result from mutations of the sialin (SLC17A5) gene, which normally encodes a lysosomal membrane protein involved in the transport of sialic acid (N-acetylneuraminic acid), a negatively charged monosaccharide [Aula et al., 2002; Verheijen et al., 1999]. Investigation performed in the mouse model of sialic acid storage disorders revealed that sialin is predominantly expressed in neurons of the CNS, wherein it is suspected to play a role in the secretory processes of neuronal cells [Aula et al., 2004]. Another inborn error of metabolism named sialuria, which is a nonlysosomal disorder, has been described with increased sialic acid excretion [Enns et al., 2001]. In this condition, there is a defect in the feedback inhibition of

UDP-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase by the endproduct (CMP-NeuAc) of the sialic acid synthetic pathway. Recent evidence suggests that sialuria is an autosomal-dominant disorder. Only a few patients (<10) have been documented to have such an enzyme defect. A boy with sialuria monitored to age 11 years has been described. He had coarse features and massive hepatomegaly but showed normal growth and relatively normal development [Krasnewich et al., 1993]. The sialic acid storage disorders are autosomal-recessive traits. The severe infantile form (infantile free sialic acid storage disease) presents with nonimmune hydrops, hypertrophic cardiomyopathy, ascites, hepatosplenomegaly, and inguinal hernias [Kleta et al., 2003]. A protein-losing form of gastroenteropathy has also been described [Kirchner et al., 2003]. Coarse facies (large forehead, broad depressed nasal bridge, puffed eyelids, and long upper lip) and dysostosis multiplex may also be evident. Death often ensues within the first 2 years of life. The rare juvenile form is characterized by mild coarsening of the facial features, hepatomegaly, and psychomotor retardation [Strehle, 2003]. Lateral spine radiographs reveal mild beaking of the vertebrae. Developmental delays and growth retardation are seen in early childhood. A third phenotype called Salla disease is named after a region in northeastern Finland, where most of the cases can be found [Varho et al., 2002]. Affected children manifest with hypotonia, ataxia, and mental retardation during the first year of life. Exotropia (squint) and truncal ataxia are also frequently noted. Walking is delayed or never achieved, and speech is usually absent or reduced. There may be mild coarsening of the facial features, but there is no visceromegaly or skeletal abnormalities. Combined growth hormone and gonadotropin deficiencies of hypothalamic pituitary origin have been described [Grosso et al., 2001]. The life span of patients with Salla disease is nearly normal. Nerve conduction studies revealed abnormalities in nearly half of the patients with Salla disease (10 of 21) examined [Varho et al., 2000]. Four severely disabled patients and the oldest patient in the group had greatly reduced nerve conduction velocity and prolonged distal latencies compatible with demyelinating polyneuropathy. In addition, somatosensory-evoked potential was abnormal in the majority of the patients, but visual-evoked potential and brainstem auditory-evoked potential were abnormal in only a few cases. Brain magnetic resonance spectroscopy revealed higher N-acetyl and phosphocreatine concentrations in parietal white matter but lower concentrations of cholinecontaining compounds compared with the age-matched control subjects [Varho et al., 1999]. In this study, peripheral nervous system involvement was clearly associated with both the phenotypic severity and brain MRI findings. On the basis of neurologic and neurocognitive evaluation of patients with Salla disease (N = 41, ranging in age from 11 months to 63 years), the phenotype could be classified into two main categories [Alajoki et al., 2004]. The majority of patients (90%) with the so-called conventional phenotype have relatively mild symptoms. Their cognitive profile consisted of better verbal ability, especially speech comprehension, compared with nonverbal functioning. All but two patients with the conventional phenotype were homozygous for the Finnish founder mutation (R39C). Four patients (aged 15 to

Pastores and Kolodny / Lysosomal Storage Diseases

28 years) were severely disabled and profoundly mentally retarded, likely reflecting an underlying compound heterozygous genotype (with deleterious mutation) [Aula et al., 2000]. The diagnosis of sialic acid storage disorders is based on demonstration of increased amounts of free sialic acid in serum and urine [Kleta et al., 2004b]. The high-performance liquid chromatography–tandem mass spectrometry method for free sialic acid quantitation in urine is a rapid, accurate, sensitive, and selective test [Valianpour et al., 2004]. Intracellular accumulations of free sialic acid can also be demonstrated in cultured skin fibroblasts and several tissues, including the brain [Schleutker et al., 1995]. Ninety-five percent of the Finnish patients with Salla disease have a missense mutation (R39C) in the sialin gene [Aula et al., 2002]. The high prevalence of one founder mutation in this population enables targeted screening and appropriate counseling of carrier couples at risk for having an affected child. Prenatal diagnosis of sialic acid storage disorders can be performed through sialic acid assays and genetic linkage or mutation detection analyses with use of cultured chorionic villi or amniocytes [Salomaki et al., 2001]. Currently, only symptomatic therapy is available.

CYSTINOSIS Cystinosis is a lysosomal transport disorder characterized by an intralysosomal accumulation of cystine, the disulfide component of the amino acid cysteine. It is the most common inherited cause of the renal Fanconi syndrome, which manifests with acidosis, electrolyte imbalance, and hypophosphatemic rickets and failure to thrive in the first year of life. There are various clinical forms, including an infantile and juvenile variant, delineated on the basis of age at onset and severity of symptoms. Infantile nephropathic cystinosis is estimated to occur in approximately 1 per 100,000 to 200,000 live births [Middleton et al., 2003]. The major clinical manifestation is renal failure, which typically sets in between the ages of 9 and 10 years [Marx et al., 2004]. Affected individuals tend to have relatively fair (lighter) skin and hair pigmentation. Long-term complications that develop in a significant number of post-kidney transplant patients include retinal blindness and corneal erosions, diabetes mellitus, pancreatic insufficiency, and primary hypogonadism (in males) [Kalatzis and Antignac, 2003; Quinn et al., 2004]. Affected individuals have normal intelligence, but some adults have signs of neurologic deterioration, such as swallowing difficulties and distal myopathy [Geelen et al., 2002]. The causative gene, CTNS, encodes a novel seventransmembrane domain lysosomal protein called cystinosin, identified as an H+-driven cystine transporter [Kalatzis et al., 2004]. Approximately 40% of patients with cystinosis from northern Europe are homozygous for the 57-kilobase deletion [Mason et al., 2003]. Free (i.e., not protein bound) cystine accumulates and forms crystals within the lysosome of most tissues of affected patients. Cystinotic cells exhibit increased sensitivity to apoptosis that might be connected to their thiol-related redox status [Park et al., 2002]. In addition, cystinotic cell lines have been demonstrated to have

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decreased glutathione content during the exponential growth phase, resulting in increased solicitation of oxidative defenses of the cell as denoted by concurrent superoxide dismutase induction [Chol et al., 2004]. The diagnosis of cystinosis is based on demonstration of elevated cystine content in leukocytes or cultured fibroblasts. Serial measurement of cystine in peripheral mononuclear cells has been recommended for the monitoring of cysteamine treatment [Levtchenko et al., 2004]. Slit-lamp examination of the eyes reveals corneal crystals. Prenatal diagnosis can be done through measurement of cystine in cultured chorionic villi or amniocytes. The symptomatic management of cystinosis includes the initiation of dialysis or kidney transplantation after renal failure and hormone replacement therapy as needed for hypothyroidism, pancreatic insufficiency, and hypogonadism [Kleta et al., 2004a; Schneider, 2004]. The angiotensin-converting enzyme inhibitor enalapril given to patients with cystinosis diminishes albuminuria and thus may slow the progression of renal insufficiency attributed to proteinuria [Levtchenko et al., 2003]. Erythropoietin has also been given to anemic patients with renal failure. Cysteamine eye drops can dissolve corneal crystals [Dureau et al., 2003; Khan and Latimer, 2004]. Chronic oral administration of the aminothiol cysteamine significantly lowers leukocyte and tissue cystine levels, resulting in growth improvement and obviating the need for thyroid hormone replacement [Gahl, 2003]. Oral cysteamine, if it is given in the first 2 years of life, often enables an increase in glomerular filtration rate. Side effects of cysteamine include nausea and vomiting [Dohil et al., 2003]. The perioperative care of a cystinotic patient requires attention to potential problems related to renal insufficiency, the Fanconi syndrome, and photophobia [Ray and Tobias, 2004].

NEURONAL CEROID LIPOFUSCINOSES The neuronal ceroid lipofuscinoses are a group of neurodegenerative disorders characterized by the intralysosomal aggregation of proteinaceous material (i.e., ceroid and lipofuscin) [Cooper, 2003]. These so-called aging pigments have the unique property of autofluorescence by light microscopy [Sinha et al., 2004]. The term neuronal ceroid lipofuscinosis was coined by Zeman and colleagues to distinguish “familial cerebromacular degeneration” clinically and pathologically from the gangliosidoses. The nature of the responsible biochemical defect has been identified for several subtypes (Table 27-5). The abnormal products synthesized by the underlying causal genes have been demonstrated to be either a soluble lysosomal enzyme or a membrane protein that is localized to either the lysosome or endoplasmic reticulum; their functional role is not completely known [Mole, 2004a]. Studies in cultured fibroblasts have found that overexpression of human CLN3 (the mutant protein in Batten’s disease) induces the aggregation of another protein called Hook1, potentially by mediating its dissociation from the microtubules [Luiro et al., 2004]. An associated defect in receptor-mediated endocytosis and endocytic membrane trafficking has also been found. In a newly described variant referred to as NCL9, CLN9-deficient cells were found to have altered cell adhesion and apoptosis [Schulz et al.,

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TABLE 27-5 Neuronal Ceroid Lipofuscinosis CLINICAL FORM

GENE

LOCUS

GENE PRODUCT AND LOCALIZATION

Congenital Late infantile and juvenile variant Classic, late infantile and juvenile variant Late infantile, Finnish variant

? CLN1

Cathepsin D? 1p32

Lysosome Lysosomal palmitoyl-protein thioesterase

Granular osmiophilic deposits

CLN2

11p15

Lysosomal tripeptidyl peptidase

Curvilinear/mixed

CLN5

13q22

Late infantile, Costa Rican variant

CLN6

15q21-23

Novel 407 AA lysosomal membrane protein Novel 311 AA endosplasmic reticulum membrane protein

Fingerprint, curvilinear, rectilinear complex Curvilinear, fingerprint, rectilinear

Late infantile, Turkish variant Classic, juvenile Epilepsy with mental retardation, Northern epilepsy Juvenile variant Juvenile variant Kufs’ disease

CLN7 CLN3 CLN8

? 16p12.1 8p23

— Lysosomal membrane protein (438 AA) 286 AA endpoplasmic reticulum membrane protein

Fingerprint/mixed Fingerprint/mixed Curvilinear- or osmiophilic granular-like

CLN1 CLN2 CLN4

1p32 11p15 ?

— — —

2004]. Sphingolipid metabolism is also perturbed, and the cells have decreased levels of ceramide, sphingomyelin, lactosylceramide, ceramide trihexoside, and globoside, with an increased activity of serine palmitoyl transferase. The mechanism involved in cell death in the neuronal ceroid lipofuscinoses has not been conclusively determined. It has been hypothesized that the progressive neuronal loss may be related to augmented apoptosis, based on elevated concentrations of the pro-apoptotic lipid mediator ceramide in the brains of affected individuals [Mitchison et al., 2004]. Several mutations for each of the relevant genes have been identified. In the most frequently identified subtype, juvenile-onset neuronal ceroid lipofuscinosis (Batten’s disease), a 1-kilobase deletion in the CLN3 gene is the most common mutation (accounting for approximately 80% to 85% of disease alleles) [Rothberg et al., 2004]. Molecular genetic studies have also revealed that in a few cases, defects in the same gene (i.e., allelic mutations) may give rise to more than one subtype (e.g., CLN1 mutations may give rise to the infantile or juvenile forms) [Steinfeld et al., 2004]. As a group, the neuronal ceroid lipofuscinoses represent a common inherited neurodegenerative disorder in childhood, with a combined prevalence of approximately 1 in TABLE 27-6 Neuronal Ceroid Lipofuscinosis: Clinical Features CLINICAL FORM

ONSET AND TYPICAL PRESENTING FEATURES

LIFE EXPECTANCY

Infantile

<2 years of age; seizures and visual loss Between 2 and 4 years of age; seizures Between 4 and 10 years of age; visual loss Around 30 years of age; seizure or behavioral abnormalities

Usually between 8 and 11 years

Late infantile Juvenile Adult disease

6 to 30 years Late teens to the 30s Usually within a decade after onset of disease

ELECTRON MICROSCOPY OF STORAGE MATERIAL

12,500 births [Mole, 2004b]. There are eight major subtypes that are delineated on the basis of age at onset, clinical symptoms, neurophysiologic abnormalities, and pathologic findings. Characteristic features include seizures, myoclonus, ataxia, arrest of cognitive and motor development, and retinal degeneration leading to blindness (Table 27-6) [Santavuori et al., 2000]. The various subtypes of neuronal ceroid lipofuscinoses are further reviewed in Chapter 58. In a series of 620 patients with neuronal ceroid lipofuscinosis in the Batten Disease Registry at the Institute for Basic Research in Developmental Disabilities in New York, juvenile neuronal ceroid lipofuscinosis accounted for 43.2% of cases; late infantile disease represented 40.6%, infantile neuronal ceroid lipofuscinosis 7%, and Kufs’ disease 9.2% [Goebel and Wisniewski, 2004]. These various neuronal ceroid lipofuscinosis subtypes are inherited in an autosomalrecessive manner, except for some rare families with the adult form, in which the mode of inheritance appears to be autosomal dominant [Nijssen et al., 2003]. Patients with childhood or juvenile-onset disease experience premature death. Brain proton magnetic resonance spectroscopy performed in eight cases with the infantile form (CLN1) revealed cortical hypoperfusion and the loss of cortical benzodiazepine receptor ligand [Vanhanen et al., 2004]. Electroretinographic studies in patients with the infantile form of neuronal ceroid lipofuscinosis document normal scotopic bright flash a-wave amplitudes with severe loss of b wave (i.e., electronegative electroretinogram), indicating dysfunction at or proximal to the photoreceptor inner segments [Weleber et al., 2004]. Histopathologic studies revealed reduced cell numbers in all retinal layers, including the inner nuclear layer, and a central epiretinal membrane. Autofluorescent lipofuscin granules have been found in all neuronal cell types in the retina. Adult-onset (Kufs’) disease is distinguished from the other subtypes by the absence of visual failure and delayed disease onset (at around 30 years of age) [Vadlamudi et al., 2003]. Two siblings of Irish descent have been described, one of whom was a 38-year-old woman with intractable seizures, delusions, and hallucinations followed by ataxia,

Pastores and Kolodny / Lysosomal Storage Diseases

declining cognitive function, and death [Callagy et al., 2000]. At postmortem examination, there was widespread cerebral neuronal accumulation of autofluorescent pigment, in which fingerprint profiles were demonstrated. Systemic involvement was not demonstrated. In her older brother (aged 43 years) who developed slowly progressive cerebellar ataxia, similar neuronal autofluorescent pigment was found on brain biopsy [Callagy et al., 2000]. Electroencephalographic findings in five patients with biopsy-proven Kufs’ disease revealed that one patient had generalized atypical spike and slow-wave complexes and marked photoparoxysmal responses, particularly at low flash frequencies [Sinha et al., 2004]. Three patients had generalized slowing. One other patient had focal sharp and spike waves and quasi-periodic slow waves maximal over anterior regions of the head. The specificity of the various intralysosomal inclusions (described as osmiophilic granular deposits, curvilinear bodies, or fingerprint deposits) has been the subject of much discussion, particularly the justification of using them as markers of the different neuronal ceroid lipofuscinoses (see Table 27-5) [Topcu et al., 2004] (Fig. 27-24). Although the intralysosomal inclusions are somewhat pleomorphic, especially in older patients, one type of deposit predominates in each form of neuronal ceroid lipofuscinosis in biopsy specimens of skin cells, examined by electron microscopy [Goebel and Wisniewski et al., 2004]. Mitochondrial ATP synthase C protein is stored in neurons for most subtypes except NCL1, which is uniquely associated with the predominant accumulation of the sphingolipid activator proteins A and D. The storage material is widely distributed, but cell death appears to be specific to CNS neurons and the neural retina. Selective glial activation is also seen and may precede obvious neurodegeneration. There are no current specific therapies for the neuronal ceroid lipofuscinoses, but palliative care may be helpful. Long-term antioxidant supplementation with vitamin E and sodium selenite has been given to patients with the infantile-

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and juvenile-onset neuronal ceroid lipofuscinoses (BattenSpielmeyer-Vogt disease) with no clear improvement in the clinical course of the disease [Jarvela and Glueck, 2002; Santavuori et al., 1988]. Hematopoietic stem cell transplantation has been tried as a treatment for the infantile form of neuronal ceroid lipofuscinosis (PPT1 enzyme deficiency) with only transient amelioration of the classic symptoms of the disease [Lonnqvist et al., 2001]. Further studies are needed to better understand the function of the defective proteins underlying neuronal ceroid lipofuscinosis to establish the rationale for clinical drug trials. The management of patients with neuronal ceroid lipofuscinosis centers on seizure control and attention to other concerns, such as insomnia, malnutrition, gastroesophageal reflux, pneumonia, sialorrhea, hyperactivity and behavior problems, depression, spasticity, and dystonia [Mitchison and Mole, 2001]. Careful selection of antiepileptic drugs is important. Studies suggest that carbamazepine and phenytoin may increase seizure activity and lead to clinical deterioration [Aberg et al., 2000]. A significant proportion of patients with juvenile neuronal ceroid lipofuscinosis receiving valproic acid had sleep disturbances or excessive sedation; patients receiving clonazepam had increased salivation and respiratory secretions, which together with gastroesophageal reflux may increase the risk for pneumonia (particularly among bedridden individuals). Lamotrigine appears to be better tolerated and leads to relative seizure control. Low-dose risperidone, an atypical neuroleptic medication with usually few extrapyramidal side effects, given to a patient with juvenile neuronal ceroid lipofuscinosis for hallucinations triggered a neuroleptic malignant syndrome [Vercammen et al., 2003]. It has been hypothesized that the loss of dopaminergic neurons in this condition may make these patients more vulnerable to this severe adverse effect. Benzodiazepine, particularly clorazepate, improves weight and helps control myoclonus and spasticity. Trihexyphenidyl improves dystonia and sialorrhea. Doxepin improves sleep, mood, and gastric emptying. Careful monitoring of patients undergoing surgery and anesthesia is required, with particular emphasis given to avoidance of intraoperative hypothermia [Yamada et al., 2002]. The availability of murine animal models is enabling the investigations of directed therapeutic strategies, such as gene therapy and neuronal stem cell transplantation [Haskell et al., 2003; Zhong and Wisniewski, 2001]. In subtypes due to a soluble lysosomal protein deficiency, enzyme therapy may also prove to be an option, although there are potential limitations related to the presence of the blood-brain barrier and the paucity of mannose 6-phosphate receptors in neurons. Prenatal diagnosis for the neuronal ceroid lipofuscinoses may be considered in the subtypes in which the mutant gene or enzyme deficiency has been established [Young et al., 2001]. REFERENCES

FIGURE 27-24. Biopsy specimen of skin from a patient with neuronal ceroid lipofuscinosis.

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CHAPTER 28

Mitochondrial Diseases Darryl C. De Vivo and Salvatore DiMauro

Mitochondrial diseases represent one of the most exciting chapters of modern medicine. Knowledge of mitochondria and the relationship of mitochondrial dysfunction to human diseases has evolved during the past century, with an explosion of new information in the last decade [DiMauro and Bonilla, 2004]. During the last half of the 19th century, scientists gradually recognized the presence of subcellular organelles, and Benda coined the term mitochondrion in 1898 [Benda, 1898]. Benda was aware of threadlike granules within the cell that were barely detectable by existing methods. After this seminal observation, the metabolic role of mitochondria in cellular function was defined by a series of observations during the early part of the 20th century. The cytochrome system was described in 1925 [Keilin, 1925], and oxidation-reduction processes were described 4 years later [Warburg and Negelein, 1929]. The Krebs cycle was conceptualized in 1937, and later the phosphorylation of adenosine diphosphate to adenosine triphosphate was documented, together with the dependence of phosphorylation on oxygen consumption [Krebs and Kornberg, 1957]. By the middle of the 20th century, it was clear that the mitochondrion represented the intracellular domain for intermediary metabolism. In 1961, the chemiosmotic theory was proposed to explain the proton motive force that facilitates the synthesis of adenosine triphosphate [Mitchell, 1961]. In parallel with these biochemical observations, a series of studies described the ultrastructural characteristics of the mitochondrion [Palade, 1953]. The four components of the organelle were characterized, including the outer and inner membranes, the intermembranous space, and the inner matrix compartment. Subsequent studies have demonstrated that the inner mitochondrial membrane is largely impermeable to molecules of all sizes, and special adaptive mechanisms are necessary for the translocation of metabolites and proteins from the intermembranous space to the matrix. The protein importation process is energy dependent and requires the macromolecules to be unfolded before traversing the mitochondrial membranes and then refolded after entering the mitochondrial matrix [Curran and Koehler, 2004; Rapaport and Nargang, 2004]. Surprisingly, only a handful of mitochondrial diseases have been attributed to defects of mitochondrial protein importation, and possible reasons for this are described later in this chapter. Two important observations were made in 1963. Each observation is central to the understanding of mitochondrial diseases. The first observation recognized the presence of intramitochondrial fibers with DNA characteristics [Nass and Nass, 1963]. This observation was the first of many reports documenting DNA in mitochondria. It is realized that many human diseases are the result of mitochondrial DNA (mtDNA) mutations. The second observation was the

description of ragged-red fibers in biopsy specimens of skeletal muscle [Engel and Cunningham, 1963]. Because all mtDNA is derived from the ovum, mtDNA characteristics are inherited exclusively from the mother— hence the terms mitochondrial inheritance, maternal inheritance, and cytoplasmic inheritance [Fine, 1978; Giles et al., 1980]. These interchangeable terms describe a non-mendelian pattern of inheritance that characterizes human diseases resulting from mtDNA mutations. Each mitochondrion contains 2 to 10 copies of the mtDNA genome. Because cells have hundreds or thousands of mitochondria, more than 10,000 copies of mtDNA may exist in each cell. This genome is a small, double-stranded circular molecule containing 16,569 base pairs [Anderson et al., 1981]. The circular molecule contains a heavy and a light strand, and each strand contains its own origin of replication (Fig. 28-1). Clear differences exist between the mitochondrial genome and the nuclear genome (Table 28-1). The mitochondrial genome contains no introns. The only noncoding region in mtDNA is the displacement loop (D-loop). The D-loop region contains 1000 base pairs and is the site of origin for replication of the heavy strand and the promoter regions for both light and heavy strand transcription. Because the universal genetic code does not apply to mtDNA, the mitochondrial genome requires its own transcriptional and translational factors for synthesis of mitochondrial proteins. The mitochondrial genome contains 37 genes. Thirteen genes encode structural proteins in the respiratory chain. The mitochondrial genome also contains 22 genes for protein synthesis. These genes include 2 ribosomal RNAs and 22 transfer RNAs. The mtDNA genes code for 13 messenger RNAs, and all 13 gene products are located in the respiratory chain (Table 28-2). The mitochondrial genotype is homoplasmic if all mtDNA genomes are identical. Conversely, the genotype is heteroplasmic if the genomes represent a mixture of wild type and mutated type. The phenotype is determined by the proportion of mutated genomes; when this proportion exceeds a threshold, the biologic behavior of the cell, the tissue, and indeed the individual changes, reflecting the impaired energy state. The threshold effect is a relative concept influenced by several factors, such as the age of the patient and the energy demands of any specific tissue or organ. For example, brain and muscle cells have high energy demands, as do the tissues of the developing child. In these situations, the threshold for phenotypic expression of a pathogenic mutation is lower. The threshold may vary from 60% to 70% in chronic progressive external ophthalmoplegia due to single large-scale mtDNA deletions to 90% to 95% in the syndromes of mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes (MELAS) and myoclonus epilepsy and ragged-red fibers (MERRF).

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Genetic, Metabolic, and Neurocutaneous Disorders / 28 OH

Pvu II 12S

F

T

V

Cyt b 16S P E

L

ND6 ND1

ND5

I M

Q

L S H

OL ND2

AN C

FIGURE 28-1. Mitochondrial DNA contains 16,569 base pairs and 37 genes. These genes include 2 ribosomal RNA, 22 transfer RNA, and 13 structural reading frames. Digestion of human mtDNA with a single endonuclease (PvuII) cleaves the circular molecule in one place and produces a linearized version. CO, cytochrome-c oxidase; CYT, cytochrome; OL and OH, origin of replication for L and H strands; ND, NADH-CoQ reductase; PH1, PH2, primary transcripts of the H strand starting at H1, H2; PL, light (I-strand promoter). (From DeVivo DC. The expanding clinical spectrum of mitochondrial diseases. Elsevier Science Publishers, 1993.)

Y

ND4

W S

ND4L R

CO1

G ND3 D

CO3

OH

PH1 PH2 12 S 16 S

K 8

ATPase ND1

ND2

PL

CO1 CO2 8 6 CO3

6 ATPase

ND4L ND3

CO2

ND4

ND5

CYT B

OH

ND6

OL

TABLE 28-1

TABLE 28-2

Comparison of the Human Nuclear and Mitochondrial Genomes

Structural (Mit) Gene Products Encoded by Mitochondrial DNA

NUCLEAR DNA

MITOCHONDRIAL DNA

RESPIRATORY CHAIN COMPLEX

STRUCTURAL PROTEIN

Located in nucleus 3 × 109 bp/haploid genome Many introns Diploid in somatic cells 23 linear chromosomes 50,000 to 100,000 genes mRNAs encode all cellular functions Universal genetic code Exon/intron gene organization Many symmetric replication origins Monocistronic transcription

Located in cytoplasmic organelle 1.6 × 104 bp/genome No introns Polyploid in somatic cells One circular chromosome 37 genes (rRNAs, tRNAs, mRNAs) Only respiratory chain mRNAs

I II III IV V

1, 2, 3, 4, 4L, 5, 6 None Apocytochrome b I, II, III 6, 8

Modified genetic code No intron in any gene One asymmetric replication origin

theoretic explanations for the variable phenotypic expression of maternally transmitted human diseases.

Polycistronic transcription

INHERITANCE PATTERNS Replicative segregation is a biologic concept that refers to the stochastic redistribution of the mtDNA genomes during mitochondrial and cell divisions. The random segregation of the mitochondrial genomes during replication influences the oxidative capability of the cellular progeny. The concepts of threshold effect and replicative segregation have provided

One of the many exciting features of mitochondrial diseases is the pattern of inheritance of these diverse conditions. The unique dual influence of the nuclear and mitochondrial genomes on the respiratory chain has captivated students of mitochondrial diseases. A biochemical defect involving the respiratory chain may be transmitted either by mendelian or by nonmendelian patterns. The strictly maternal inheritance

De Vivo and DiMauro / Mitochondrial Diseases

717

FIGURE 28-2. Inheritance of a mitochondrial DNA HaeII polymorphism in a 33-member three-generation family. The typical mitochondrial DNA cleavage pattern is depicted in the open symbols, and the atypical cleavage pattern is depicted in the black symbols. NT, not tested. (From Giles RE, Blanc H, Cann HM, et al. Proc Natl Acad Sci USA 1980;77:6715.)

of mitochondria determines the pattern of vertical transmission of mtDNA mutations. Clinical conditions related to mtDNA point mutations are transmitted from the mother to all her male and female progeny, but only daughters pass the condition to succeeding generations (Fig. 28-2). This genetic profile is reminiscent of mendelian inheritance, including autosomal-dominant and X-linked patterns, but both genders are equally affected and there is no father-to-son transmission. Expression of the maternally inherited genetic defect is determined by replicative segregation and by the threshold effect. These biologic principles are demonstrated in several neurologic diseases associated with mtDNA mutations, including Leber’s hereditary optic neuropathy, MERRF, MELAS, and the syndrome of neuropathy, ataxia, retinitis pigmentosa/maternally inherited Leigh’s syndrome. Single deletions of mtDNA generally occur sporadically, as is the case with Kearns-Sayre syndrome, progressive external ophthalmoplegia, and Pearson’s syndrome. However, the pattern of inheritance for most mitochondrial diseases is not maternal. Rather, classic mendelian inheritance patterns apply to all disorders affecting biochemical pathways other than the respiratory chain, including defects of fatty acid oxidation, pyruvate utilization, and the Krebs cycle. Also, not surprisingly, several defects of the respiratory chain are inherited by mendelian inheritance because most subunits of respiratory chain complexes are encoded by nuclear DNA (nDNA) genes. Interestingly, many abnormalities of mtDNA are also due to mutations in nDNA genes; these mendelian diseases associated with mtDNA defects are due to faulty communications between the two genomes and are usually called defects of intergenomic signaling. For example, syndromes of progressive external ophthalmoplegia with multiple deletions of mtDNA are inherited as autosomal-dominant or, more rarely, autosomal-recessive traits. The nuclear gene defects in these cases apparently alter the biologic integrity of the mito-

chondrial genome and predispose the patient to multiple mtDNA deletions that characterize these clinical syndromes [Hirano and DiMauro, 2001]. Another defect of intergenomic sig-naling is due to a quantitative defect of mtDNA (mtDNA depletion). Syndromes due to mtDNA depletion may affect predominantly one tissue (infantile myopathy or hepatopathy) or multiple tissues (hepatocerebral syndrome) and are due to nuclear gene mutations impairing mtDNA replication [Hirano et al., 2004].

METABOLIC DISTURBANCES The principal function of mitochondria is the oxidation of substrates and the synthesis of adenosine triphosphate (ATP). The primary oxidizable substrates include pyruvate, fatty acids, ketone bodies, and amino acids. Mitochondria also play a role in the intracellular sequestration of calcium and in the detoxification of ammonia in the urea cycle. Biochemical defects involving these pathways are associated with distinctive metabolic disturbances. A biochemical defect altering pyruvate metabolism directly or indirectly causes an elevation of pyruvic acid. Pyruvate is in equilibrium with lactate and alanine. As a result, there is lactic acidosis that is proportionate or disproportionate to the elevation of pyruvate, depending on the associated effect of the biochemical defect on the oxidation-reduction potential. If the oxidation-reduction potential is unaffected by the biochemical defect, the lactate and pyruvate elevations are proportional and the lactate/pyruvate ratio is normal (<20). In contrast, if the oxidation-reduction potential is disturbed by a primary defect involving the respiratory chain, the lactate values are disproportionately elevated and the lactate/pyruvate ratio is increased (>20). Patients with pyruvate dehydrogenase deficiency typically have elevated lactate, pyruvate, and alanine concentrations and a normal

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Genetic, Metabolic, and Neurocutaneous Disorders / 28

lactate/pyruvate ratio. In contrast, patients with cytochrome-c oxidase deficiency have elevated lactate, pyruvate, and alanine concentrations, but the lactate/pyruvate ratio is increased. These metabolic observations serve as clues to the underlying biochemical defect and may be helpful when all other clinical and metabolic factors are considered simultaneously. Defects of fatty acid metabolism may be associated with elevated free fatty acids, hypoketonemia, hypocarnitinemia, and dicarboxylicaciduria. Patients with biochemical defects involving beta oxidation typically have hypoketotic hypoglycemia, dicarboxylicaciduria, and secondary carnitine deficiency. Medium-chain acyl coenzyme A dehydrogenase deficiency is the classic example. The hypocarnitinemia associated with defects of beta oxidation typically is accompanied by a disturbance of the ratio of free carnitine to esterified carnitine. The disproportionately high esterified carnitine fraction is characteristic of the secondary carnitine deficiency states [Tein, 1995, 2003]. Defects of the carnitine cycle produce a different metabolic profile. As with defects of beta oxidation, affected patients may have hypoketotic hypoglycemia during fasting. However, carnitine cycle defects are not associated with dicarboxylicaciduria as a rule. The disturbances of carnitine also are more variable. Defects of the membrane carnitine transporter system and the carnitineacylcarnitine translocase system are typically associated with low serum and tissue carnitine concentrations, whereas defects of carnitine palmitoyltransferase II (adult form) and carnitine palmitoyltransferase I are associated with normal or high serum and tissue carnitine concentrations. In contrast, the infantile multiorgan form of carnitine palmitoyltransferase II deficiency is associated with low serum and tissue carnitine concentrations [Tein, 2003]. Equally important observations can be made by measuring circulating ketone body concentrations. Ketone bodies normally are negligible in the fed state and elevated in the fasting state. Ketone bodies are formed primarily in the liver from the metabolism of fatty acids and are exported to extrahepatic tissues that are capable of metabolizing these substrates. Classically, hypoketotic hypoglycemia develops in patients with defects of fatty acid metabolism during fasting. Serum ketone body values also are helpful in distinguishing the biochemical defects associated with congenital lactic acidosis. The serum ketone body concentrations in these various defects reflect the intracellular concentration of acetyl coenzyme A. Acetyl coenzyme A is the pivotal metabolite in mitochondrial metabolism. Acetyl coenzyme A may be formed from the decarboxylation of pyruvate, fatty acids, or ketone bodies. A fraction of the acetyl coenzyme A pool may be shunted into the β-hydroxy-β-methylglutaryl coenzyme A cycle in the liver to form ketone bodies. Defects involving the pyruvate dehydrogenase complex prevent the conversion of pyruvate to acetyl coenzyme A. Therefore, ketone bodies cannot be formed, and the increased pyruvate concentrations are shunted disproportionately into the gluconeogenic pathway. As a result, patients with pyruvate dehydrogenase deficiency have elevated pyruvate, lactate, and alanine concentrations, relative resistance to hypoglycemia during fasting, and a disproportionately low serum ketone body concentration, particularly during fasting. In contrast, patients with pyruvate carboxylase deficiency fail to convert pyruvate to oxaloacetate. As a result, acetyl coenzyme A concentrations increase, and there is a

paradoxical formation of ketone bodies in the setting of the lactic acidosis. The deficiency of oxaloacetate and the secondary decrease in tissue aspartate concentrations also cause a paradoxical increase in the cytoplasmic oxidationreduction potential and a decrease in the intramitochondrial oxidation-reduction potential. Therefore, patients with pyruvate carboxylase deficiency have an increased lactate/ pyruvate ratio and a decreased β-hydroxybutyrate/ acetoacetate ratio [De Vivo et al., 1977]. This metabolic profile is distinctive for pyruvate carboxylase deficiency. Similar although less striking observations may be seen with defects of the Krebs cycle or the respiratory chain as it relates to the paradoxical presence of ketosis in the setting of lactic acidosis. Biochemical defects involving the urea cycle, specifically ornithine transcarbamoylase deficiency and carbamoyl phosphate synthetase deficiency, are associated with hyperammonemia. The urine orotic acid concentrations are increased in ornithine transcarbamoylase deficiency and decreased in carbamoyl phosphate synthetase deficiency. Combinations of metabolic abnormalities also may exist. For example, defects involving the metabolism of longchain fatty acids may be associated with the distinctive patterns of free fatty acidemia, dicarboxylicaciduria, hypocarnitinemia, hyperammonemia, and lactic acidosis. This profile is particularly evident in defects of the trifunctional enzyme protein and very-long-chain acyl coenzyme A dehydrogenase that are located in the inner membrane of the mitochondrion [Di Donato and Taroni, 2003]. These patients also have increased tissue concentrations of long-chain acylcarnitine, which may explain the organ toxicity associated with the defects of long-chain fatty acids.

HISTOPATHOLOGIC DISTURBANCES The tissue reactions in mitochondrial diseases may be informative and direct the clinician’s attention to the primary metabolic defect, or they may be modest or absent. A normal muscle biopsy result does not rule out a mitochondrial disease. The skeletal muscle biopsy specimen often looks normal in defects of pyruvate carboxylase, pyruvate dehydrogenase, the Krebs cycle, and the urea cycle. The biopsy tissue may appear normal with some defects involving fatty acid metabolism, including the adult form of carnitine palmitoyltransferase II, and several defects involving the respiratory chain. A lipid storage myopathy signifies a defect in fatty acid metabolism. Lipid accumulation is common in defects of beta oxidation, including glutaricaciduria type II and the infantile multiorgan form of carnitine palmitoyltransferase II deficiency. This tissue abnormality may be particularly striking in patients with the tissue-specific form of short-chain acyl coenzyme A dehydrogenase deficiency. In fact, several patients previously described with the myopathic carnitine deficiency syndrome [Engel and Angelini, 1973] later proved to have muscle-specific shortchain acyl coenzyme A dehydrogenase deficiency. Ragged-red fibers are present in many respiratory chain diseases, including many nDNA defects, except the subgroup associated with defects of intergenomic signaling. Ragged-red fibers represent the morphologic counterpart of large-scale rearrangements of mtDNA or point mutations affecting transfer RNA (tRNA) genes and some but not all protein-coding genes.

De Vivo and DiMauro / Mitochondrial Diseases

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FIGURE 28-3. Characteristic cranial abnormalities in mitochondrial encephalomyopathies on magnetic resonance imaging. The images represent T2-weighted images from four different patients. Upper left demonstrates bilateral putaminal hyperintensities in a child with cytochrome-c oxidase–associated Leigh’s syndrome; upper right demonstrates bilateral globus pallidus hyperintensities in a child with a familial Leigh syndrome phenotype; lower left demonstrates a left posterior cerebral hyperintensity in a child with MELAS; lower right demonstrates bilateral white matter hyperintensities in a child with Kearns-Sayre syndrome.

The pathologic process in the brain is distinctive in many mitochondrial diseases. Three patterns are common. The first is a widespread insult to the brain tissue with resulting microcephaly and ventricular dilation. This pattern is seen in defects of the urea cycle, several defects associated with congenital lactic acidosis, and some of the defects associated with fatty acid metabolism. Malformations also may be seen, including agenesis of the corpus callosum, ectopic displacement of the olivary nuclei, and cystic destruction of the basal ganglia. This pattern is particularly striking in infants with pyruvate dehydrogenase E1 α subunit deficiency. The second pattern is best typified by the neuropathologic changes

associated with Leigh’s syndrome [Leigh, 1951]. These patients have a symmetric subcortical distribution of tissue injury with a particular predilection for the basal ganglia, thalamus, brainstem, and cerebellar roof nuclei. Microscopic features include loss of brain cells, proportionate loss of myelin, reactive astrocytosis, and proliferation of the cerebral microvessels. In some patients, particularly those with MELAS, multifocal encephalomalacia develops. This pathologic condition typically is located in the posterior aspect of the cerebral hemisphere. The third pattern is a spongy encephalopathy with loosening and rarefaction of the neuropil. The spongy encephalopathy is the histo-

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Genetic, Metabolic, and Neurocutaneous Disorders / 28

pathologic counterpart of a defect in cerebral energy metabolism and is commonly seen in patients with Kearns-Sayre syndrome. Magnetic resonance imaging may reflect these patterns of brain tissue injury with a hyperintense signal of the central white matter on the T2-weighted image (Fig. 28-3). Strokelike lesions in the posterior cerebral hemisphere are typical of MELAS. Signal hyperintensities involving the putamen, globus pallidus, and caudate nuclei are characteristic of Leigh’s syndrome. A diffuse signal abnormality involving the central white matter is typical of Kearns-Sayre syndrome. Intracranial calcifications also are seen in these conditions. Basal ganglia calcifications are most commonly associated with Kearns-Sayre syndrome and MELAS.

BOX 28-1 BIOCHEMICAL GENETICS CLASSIFICATION OF MITOCHONDRIAL DISEASES Inherited conditions Nuclear DNA defects Defects of substrate transport Defects of substrate utilization Defects of the Krebs cycle Defects of oxidation-phosphorylation coupling Defects of the respiratory chain Defects of protein importation Defects of intergenomic signaling Mitochondrial DNA defects Sporadic large-scale rearrangements Transmitted large-scale rearrangements Point mutations affecting structural genes Point mutations affecting synthetic genes Acquired conditions Infectious (e.g., Reye’s syndrome) Toxic (e.g., MPTP) Drugs (e.g., zidovudine) Aging

CLASSIFICATION OF MITOCHONDRIAL DISEASES Several classification schemes of mitochondrial diseases are based on different criteria [DiMauro et al., 1985; Moraes et al., 1991; Shoffner et al., 1990]. The original attempts to classify mitochondrial diseases by clinical or morphologic criteria were unsatisfactory. The phenotypic heterogeneity of mitochondrial diseases complicated the clinical classification ␤-oxidation Cycle

Carnitine Cycle

O Carnitine TP

VLC

R

O

O

O

R AS

R

SCoA

O

CPT II R

LC

EH

B R

SCoA

LC

KT

R

SCoA

O

CPT I

O R

SCoA

R

KT O

Ocar R

AD LC

MC

SCoA

O

O

SC

C

SCoA

R

O R

SCoA

AS HO O

HD R

Plasma Outer membrane mitochondrial membrane

LC

HD SCoA

O

Ocar

SCoA

TL

A

Medium-chain fatty acids

R

SCoA O

AD Long-chain fatty acids

HO

Carnitine

Inner mitochondrial membrane

SCoA

EH

MATRIX

FIGURE 28-4. Schematic representation of fatty acid oxidation. This metabolic pathway is divided into the carnitine cycle (A), the inner mitochondrial membrane system (B), and the mitochondrial matrix system (C). The carnitine cycle includes the plasma membrane transporter, carnitine palmitoyltransferase I, carnitine-acylcarnitine translocase system, and carnitine palmitoyltransferase II. The inner mitochondrial membrane system includes the very-long-chain acyl-CoA dehydrogenase and the trifunctional protein with three catalytically active sites. Long-chain acylcarnitines enter the mitochondrial matrix by the action of the carnitine palmitoyltransferase II to yield long-chain acyl-CoAs. These thioesters undergo one or more cycles of chain shortening catalyzed by the membrane-bound system. Chain-shortened acyl-CoAs are degraded further by the matrix beta oxidation system. Medium-chain fatty acids enter the mitochondrial matrix directly and are activated to the medium-chain acyl-CoAs before degradation by the matrix beta oxidation system. TP, carnitine transporter; TL, carnitine-acylcarnitine translocase; LC, long chain; EH, 2-enoyl-CoA hydratase; CoA, coenzyme A; VLC, very long chain; AD, acyl-CoA dehydrogenase; HD, 3-hydroxyacyl-CoA dehydrogenase; CPT, carnitine palmitoyltransferase; KT, 3-ketoacyl-CoA thiolase; MC, medium chain; SC, short chain. (Modified from Pons R, De Vivo DC. J Child Neurol 1995;10:1. With the kind assistance of Dr. Horst Schulz.)

De Vivo and DiMauro / Mitochondrial Diseases

efforts. Similarly, the lack of histopathologic uniformity undermined the morphologic classification efforts. A biochemical classification of mitochondrial diseases was introduced in 1985 [DiMauro et al., 1985]. The clinical conditions were subclassified according to the primary site of the biochemical defect. In 1988, primary mutations of the mitochondrial genome were first recognized [Holt et al., 1988; Wallace et al., 1988]. These findings were particularly relevant to respiratory chain defects because this metabolic pathway is under the dual genetic influence of the mitochondrial and nuclear genomes. In recent times, the term mitochondrial diseases has been increasingly restricted to defects of one biochemical pathway, the respiratory chain [DiMauro and Schon, 2003], and further subgrouped as nuclear DNA defects and mtDNA defects (Box 28-1). However, in this review, the more general, biochemical classification for defects resulting from mutations in nuclear DNA is used, whereas for defects of the respiratory chain, a genetic classification is used.

CLINICAL FEATURES From the clinical perspective, mitochondrial diseases can be divided into the following three major categories: defects of fatty acid oxidation, defects of pyruvate metabolism, and defects of the respiratory chain. Most mitochondrial diseases can be subsumed under these major categories.

Defects of Fatty Acid Oxidation These conditions have specific clinical and metabolic signatures [Tein, 2003; DiDonato and Taroni, 2004]. Patients with defects of fatty acid oxidation experience metabolic decompensation during fasting. Organs that depend on fatty acid oxidation are primarily affected, including skeletal and cardiac musculature. Fatty acids accumulate in the liver in most of these defects and are shunted into auxiliary pathways, including omega oxidation. Omega oxidation occurs in the cytoplasm and accounts for the formation of dicarboxylic acids. Dicarboxylicaciduria is particularly evident in defects of beta-oxidation (see Fig. 28-4). Acylglycine and acylcarnitine esters also accumulate in patients with defects of beta oxidation, offsetting the sequestration of coenzyme A that occurs with accumulating acyl coenzyme A thioesters. Depletion of serum and tissue carnitine stores may result. Increased bound carnitine fractions are characteristic of mitochondrial beta-oxidation defects. Absolute decreases of free and total carnitine fractions are particularly distinctive in carnitine cycle defects (see Fig. 28-4). Defects of fatty acid oxidation result in the underproduction of acetyl coenzyme A and the resulting impairment of Krebs cycle activity and hepatic ketogenesis. As a result, many patients with defects of fatty acid oxidation have hypoketotic hypoglycemia. This metabolic state is associated with neurologic symptoms of altered consciousness. The precise mechanism of the cerebral dysfunction that is associated with defects of fatty acid oxidation is unknown. Decreased availability of ketone bodies and glucose deprives the brain of its two principal metabolic fuels. Fatty acids may enter the brain, but they are poorly metabolized. The accumulation of fatty acid intermediates in brain tissue also may have deleterious effects on cellular function.

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Many patients with specific defects of fatty acid oxidation have been described since 1973, when the adult form of carnitine palmitoyltransferase type II and the myopathic form of carnitine deficiency were described [DiMauro and DiMauro, 1973; Engel and Angelini, 1973]. About half of all cases involve medium-chain acyl coenzyme A dehydrogenase deficiency. In 1975, the first patient with systemic carnitine deficiency was described [Karpati et al., 1975]. Many patients with systemic carnitine deficiency have been restudied and found to have medium-chain acyl coenzyme A dehydrogenase deficiency [DiDonato and Taroni, 2004]. The fatty acid oxidation defects can be subdivided into defects of the carnitine cycle, defects of the inner mitochondrial membrane, and defects of beta oxidation (see Fig. 28-4). The specific clinical conditions are discussed later in this chapter.

Defects of Pyruvate Metabolism Pyruvate is the end product of glycolysis. This metabolite can be reduced to lactate or transaminated to alanine in the cytoplasm. Otherwise, pyruvate is translocated across the mitochondrial membrane (Fig. 28-5). In the mitochondrial matrix, pyruvate is carboxylated to oxaloacetate or decarboxylated and activated to acetyl coenzyme A. The first reaction is catalyzed by pyruvate carboxylase, and the second is catalyzed by the pyruvate dehydrogenase complex. The two reaction products—oxaloacetate and acetyl coenzyme A—condense to form citrate as the primary reactant in the Krebs cycle. Defects of pyruvate metabolism involve the pyruvate dehydrogenase complex, pyruvate carboxylase, or several enzymes in the Krebs cycle [De Meirleir, 2002; De Vivo et al., 2002]. These defects are associated with elevated serum and tissue concentrations of pyruvate, lactate, and alanine. The lactate/ pyruvate ratio is relatively preserved because the oxidationreduction potential is maintained. This generalization, although not absolute, is helpful in attempts to distinguish defects of pyruvate metabolism from defects of the respiratory chain (discussed later). The Krebs cycle is central to intermediary metabolism. Complete biochemical defects of this pathway are probably incompatible with life. Four partial defects of the Krebs cycle have been described and are discussed later in this chapter.

Defects of the Respiratory Chain The respiratory chain contains five functional units or complexes that are embedded in the inner mitochondrial membrane (see Fig. 28-5). The five complexes contain approximately 80 polypeptides, 13 of which are encoded by mtDNA (see Fig. 28-5 and Table 28-2). Complex II, unlike the other four complexes, is solely under the control of the nuclear genome. The function of the respiratory chain is the transfer of electrons from the reduced pyridine nucleotides and flavoproteins to molecular oxygen, with the resulting oxidation of reduced nicotinamide adenine dinucleotide phosphate and flavin adenine dinucleotide and the production of water. Biochemical defects of the respiratory chain are associated with lactic acidosis. However, unlike defects of pyruvate metabolism, respiratory chain defects are associated with a disturbed cellular oxidation-reduction potential manifested by an elevated lactate/pyruvate ratio (>20).

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Genetic, Metabolic, and Neurocutaneous Disorders / 28 Carbohydrates Glycolysis Pyruvate

Amino acids

PH1 PH2

Cytosol

Fatty acids

12s rRNA

OH 7S DNA

F

T

V

Cyt b

Transaminase Pyruvate Amino acids Fatty AcetyI CoA ␤-Oxidation acids

16s rRNA P E

L

ND6 ND1

ND5

Citrate

Oxaloacetate

I M

Q

␣-Ketoglotarate

Malate

Mitochondrion Fumarate Succinate

L S H

OL ND2

Succinyl Coenzyme A

AN C

Y

ND4

W S

ND4L R

CO I

G ND3 D

2H

2H

2H

2H

CO III CO II

K

FMN

FeS

FeS

FeS

FAD

FeS

FeS

Complex III (Cyt b)

FeS

CoQ

Complex II

6

ATPase

Complex I (ND 1, 2, 3, 4, 4L, 5, 6) NADH

8

FeS

Cyt bT

Cyt bK

FeS

Complex IV(CO I, II, III) Cyt c1

Cyt c

Cyt a

Cyt a3

O2

Complex V (ATPase 6, 8) ATP Synthase ADP Pi

ATP

FIGURE 28-5. A schematic overview of intermediary metabolism. Fatty acid oxidation is illustrated in detail in Figure 28-4. Pyruvate metabolism involves two reactions: pyruvate carboxylase and pyruvate dehydrogenase. Condensation of these two reaction products produces citrate at entry point of the Krebs cycle. Reducing equivalents are generated in the Krebs cycle and reoxidized by the respiratory chain. The five respiratory chain complexes contain approximately 80 polypeptides. Thirteen polypeptides are encoded by mitochondrial DNA illustrated in the upper right. The 13 mitochondrial DNA gene products are noted in parentheses above complexes I, III, IV, and V. (From De Vivo DC. The expanding clinical spectrum of mitochondrial diseases. Elsevier Science Publishers, 1993.)

CLINICAL FEATURES OF MITOCHONDRIAL DISEASES Clinical presentation of defects involving the respiratory chain should include failure of organs that have a high oxidative metabolic demand. This conclusion is confirmed by the frequent involvement of brain, muscle, heart, retina, renal tubule, and organ of Corti in these clinical syndromes. However, the expression of the biomolecular defect is modified by various factors, including selective alteration of tissue-specific isoforms and the degree of completeness of the generalized defect. Many of the earlier case reports describing patients with respiratory chain defects were published before the importance of mitochondrial genetics was understood. As a result, it is difficult to classify many of the earlier cases from the molecular point of view. Respiratory chain defects also are complicated by the diversity of clinical presentations. Some of the patients have neurologic or neuromuscular symptoms and are grouped together in the neurologic literature reports as examples of mitochondrial encephalomyopathies. Other patients may have non-neurologic symptoms, including dysfunction of the liver, heart, kidney, bone marrow, pancreas, or gastrointestinal tract. The specific clinical syndromes associated with the five respiratory chain complexes are discussed later in the chapter.

Inherited Conditions Associated with Nuclear DNA Defects DEFECTS OF SUBSTRATE TRANSPORT. Several genetically determined defects of substrate transport have been described. Perhaps the best examples are the defects involving the carnitine cycle. There are four such defects involving (1) the carnitine transporter, (2) carnitine palmitoyltransferase I, (3) the carnitine-acylcarnitine translocase, and (4) carnitine palmitoyltransferase II. The carnitine cycle is illustrated in Figure 28-4. Carnitine is actively transported from the blood across the plasma membrane. Approximately 90% of carnitine body stores reside in skeletal muscle, with skeletal muscle concentration of carnitine being about 60-fold higher than the plasma concentration. Long-chain fatty acids are translocated across the inner mitochondrial membrane as the carnitine ester. Medium-chain fatty acids enter the mitochondrial matrix directly before being activated to the thioester (see Fig. 28-4). A common defect in this cycle involves the carnitine transporter system [Tein, 2003]. This condition is inherited

De Vivo and DiMauro / Mitochondrial Diseases

as an autosomal-recessive trait and is clinically manifested in infancy or early childhood as a carnitine-responsive cardiomyopathy associated with hypotonia, weakness, failure to thrive, hypoketotic hypoglycemia, and altered consciousness or coma. The defect is generalized with involvement of skeletal muscle, heart, and kidney. Studies of cultured skin fibroblasts define the condition and identify the heterozygote asymptomatic carriers. Molecular genetic studies have identified pathogenic mutations in the gene (OCTN2) encoding the sodium-dependent, high-affinity carnitine transporter, OCN2. Oral carnitine supplementation is lifesaving with resolution of clinical symptoms and restoration of normal cardiac function. Carnitine palmitoyltransferase I deficiency is a clinical condition of infancy manifested by nonketotic hypoglycemic coma [DiDonato and Taroni, 2003; Tein, 2003]. The patients have marked hepatomegaly and hypertriglyceridemia even when they are clinically asymptomatic. The clinical syndrome mimics Reye’s syndrome, but dicarboxylicaciduria is absent and the serum carnitine values are normal or high. Hyperammonemia, disturbed liver function test results, and marked hepatomegaly are distinctive; persistent renal tubular acidosis may be present. Mediumchain triglycerides may be used to document a ketotic response and as treatment for this autosomal-recessive condition. Muscle from these patients has normal activities for both carnitine palmitoyltransferase I and carnitine palmitoyltransferase II, suggesting the existence of tissue-specific isoenzymes for carnitine palmitoyltransferase I. This finding has been confirmed by molecular studies demonstrating that there are two distinct genes for carnitine palmitoyltransferase I. One encodes the muscle-heart isoform; the other encodes the liver-fibroblast isoform. Several infants with carnitine-acylcarnitine translocase deficiency have been described, combining hypoketotic hypoglycemia, hepatomegaly, cardiomyopathy, seizures, lethargy, and coma [DiDonato and Taroni, 2003; Tein, 2003]. The gene for carnitine-acylcarnitine translocase is located on chromosome 3p21.31, and several mutations have been identified in patients. Carnitine palmitoyltransferase II was the first primary biochemical defect of fatty acid oxidation to be described [DiMauro and DiMauro, 1973]. The adult form is relatively benign and consistent with a normal life expectancy. A disproportionate number of affected males have been reported despite the fact that it is an autosomal-recessive trait. The clinical picture is that of a metabolic myopathy with recurrent muscle pain and myoglobinuria. Symptoms are provoked by fasting, prolonged exercise, cold exposure, infection, or emotional stress. Fixed limb weakness develops in about 10% of patients at an older age, and a similar percentage have evidence of a lipid storage myopathy [DiDonato and Taroni, 2003; Tein, 2003]. Carnitine concentrations are normal in this clinical syndrome. Several mutations compatible with some residual activity (“leaky mutations”) in the CPT2 gene have been associated with the myopathic form. A common mutation (Ser113Leu) has been identified in at least 50% of patients and may be used for diagnostic screening in genomic DNA isolated from blood. Carnitine palmitoyltransferase II deficiency in newborns is a generalized lethal disease with reduced enzyme activity in multiple organs and corresponding signs of liver failure,

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cardiomyopathy, hypoketotic hypoglycemia, and mild myopathy. There are reduced concentrations of free and total carnitine and increased concentrations of lipids and longchain acylcarnitines. It remains unclear what distinguishes the relatively benign adult, myopathic form of carnitine palmitoyltransferase II deficiency from the lethal infantile form. The residual enzyme activity is similar in these two phenotypes, but oxidation of long-chain fatty acids may be more severely impaired in the infantile form [DiDonato and Taroni, 2003]. Some patients with the mild form of multiple acyl coenzyme A dehydrogenase deficiency have a riboflavinresponsive syndrome, suggesting a genetic defect in flavin adenine nucleotide biosynthesis or transport [DiDonato and Taroni, 2003, 2004]. Riboflavin supplementation together with L-carnitine and a low-protein, low-fat diet represents effective treatment in this subgroup of patients with the glutaricaciduria type II phenotype. DEFECTS OF SUBSTRATE UTILIZATION. Pyruvate carboxylase deficiency, pyruvate dehydrogenase complex deficiency, and defects of beta oxidation are examples of substrate utilization defects. The sites of these biochemical defects are illustrated in Figure 28-4 (beta oxidation defects) and Figure 28-5. Classic pyruvate carboxylase deficiency, an autosomal recessive condition, is life-threatening in infancy and is associated with hypotonia, psychomotor retardation, failure to thrive, and metabolic acidosis [De Vivo et al., 1977]. Approximately 50 patients with pyruvate carboxylase deficiency have been described. The severe French phenotype is associated with absence of the enzyme protein. These patients die in early infancy and have lactic acidosis, ketoacidosis, citrullinemia, hyperlysinemia, hyperammonemia, and aspartate depletion. The less severe although equally fatal North American phenotype is associated with severe mental and motor developmental delay and death in late infancy or early childhood. A mutated protein is present in tissue with some residual enzyme activity. Three patients have had the laboratory features of the North American phenotype but were clinically spared, with normal mental and motor development between recurrent attacks of metabolic crisis. Biotin deficiency affects pyruvate carboxylase together with the other three biotin-dependent carboxylase reactions: propionyl–coenzyme A carboxylase, β-methylcrotonyl– coenzyme A carboxylase, and acetyl coenzyme A carboxylase. All carboxylation reactions occur in the mitochondria, except for the carboxylation of acetyl coenzyme A. Multiple carboxylase deficiency, an autosomal-recessive trait in all of its clinical presentations, is seen in early infancy as a result of holocarboxylase synthetase deficiency or later in infancy as the result of biotinidase deficiency. These patients may have irregular breathing patterns, failure to thrive, alopecia, rash, immunologic disturbances, optic atrophy, hearing loss, seizures, and metabolic acidosis; they respond to high-dose biotin supplementation, particularly if they are treated early in the disease course. Several hundred patients with defects involving the pyruvate dehydrogenase complex have been described [De Meirleir, 2002]. Most patients have a defect involving the E1 α subunit, and a male predominance is expected because the gene is located on the X chromosome. Two patients had

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Genetic, Metabolic, and Neurocutaneous Disorders / 28

mutations in the E1 β subunit, inherited as an autosomalrecessive trait [Brown et al., 2004]. The neonatal presentation includes hypotonia, episodic apnea, convulsions, weak suck, dysmorphic features, lethargy, low birth weight, failure to thrive, and coma. Dysmorphic features include broad nasal bridge, upturned nose, micrognathia, low-set and posteriorly rotated ears, short fingers, short arms, simian creases, hypospadias, and anteriorly placed anus. The infantile phenotype has been described in about 100 patients and usually is seen between 3 and 6 months of age with psychomotor retardation, hypotonia, convulsions, episodic apnea, ataxia, pyramidal tract signs, lethargy, dysmorphic features, deceleration of head growth, ophthalmoplegia, optic atrophy, peripheral neuropathy, ptosis, dysphagia, deceleration of somatic growth, extrapyramidal signs, and cranial nerve palsies. Postmortem examinations were performed in 21 cases of the infantile form; of these, 81% were consistent with Leigh’s syndrome [DeVivo and Van Coster, 1991]. Seven male children had a benign phenotype with fluctuating ataxia, post-exercise fatigue, transient paraparesis, and thiamine responsiveness. These children had normal mental and motor development between episodes. A high-fat diet has been recommended as an alternative source of acetyl coenzyme A in patients with pyruvate dehydrogenase deficiency [Wexler et al., 1997]. Thiamine, lipoic acid, and L-carnitine supplementation may be helpful in selected cases. Seven genetically determined conditions have been described involving enzyme deficiencies in the beta oxidation pathway (see Fig. 28-4) [DiDonato and Taroni, 2004; Tein, 2003]. All are transmitted as autosomalrecessive traits. Five of the genetic defects (deficiencies of medium-chain acyl coenzyme A, short-chain acyl coenzyme A, long-chain acyl coenzyme A, electron transfer flavoprotein, and electron transfer flavoprotein–coenzyme Q oxidoreductase) involve the first step in beta oxidation. The other two conditions (long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and short-chain 3-hydroxyacyl-CoA dehydrogease deficiency) involve the third step in beta oxidation. Two more enzyme defects involve the two membrane-bound enzymes of beta oxidation, very-longchain acyl-CoA dehydrogenase (VLCAD) and the trifunctional enzyme protein. VLCAD deficiency, as carnitine palmitoyltransferase II deficiency, can present in infancy with hypoketotic hypoglycemia, hepatopathy, and cardiomyopathy or in adult life as recurrent myoglobinuria [DiDonato and Taroni, 2003]. The gene (ACADVL) for VLCAD has been mapped to chromosome 17p12, and a relatively good genotype:phenotype relationship is emerging. The severe infantile form is associated with nonsense mutations, whereas the benign adult form is due to missense mutations compatible with some residual VLCAD activity. Trifunctional enzyme protein is a hetero-octamer composed of four α subunits catalyzing the long-chain L-3-hydroxyacyl-CoA dehydrogenase (LCHAD) and the long-chain 2-enoyl-CoA hydratase (LCEH) activities and four β subunits catalyzing the long-chain 3-ketoacyl-CoA thiolase (LCKT) activity. Trifunctional enzyme protein deficiency had been diagnosed as LCHAD deficiency until more careful biochemical analysis revealed combined defects of LCHAD, LCEH, and LCKT activities. In fact, most patients with mitochondrial trifunctional protein

deficiency have isolated LCHAD deficiency, with relative sparing of LCEH and LCKT activities. In infancy and early childhood, clinical features include recurrent attacks of hypoketotic hypoglycemia, cardiomyopathy, limb weakness, sensory neuropathy, pigmentary retinopathy, and hepatic dysfunction. Later in childhood, recurrent attacks of myoglobinuria are common. Two syndromes associated with LCHAD deficiency have been labeled HELLP (hemolysis, elevated liver enzymes, low platelets) and AFLP (acute fatty liver of pregnancy). The latter condition occurs in pregnant women carrying an affected fetus. A common mutation (G1528C) has been identified in the LCHAD domain of the a subunit. Full mitochondrial trifunctional protein deficiency, that is, combined severe deficiency of LCHAD, LCEH, and LCKT, is much rarer, and symptoms are similar but more severe than in isolated LCHAD deficiency. The molecular basis of full mitochondrial trifunctional protein deficiency is heterogeneous, with mutations in both α and β subunits. Mutations have been identified in the HADHA and the HADHB genes, both located on chromosome 2p23 [DiDonato and Taroni, 2003]. Medium-chain acyl coenzyme A dehydrogenase deficiency commonly develops before 2 years of age and represents about 50% of the described cases associated with beta oxidation defects [Roe and Coates, 1989]. The metabolic crisis in medium-chain acyl coenzyme A dehydrogenase deficiency is provoked by fasting or intercurrent infection. The classic picture is that of episodic vomiting, hypotonia, obtundation, or coma. The patient is healthy between attacks. This condition may masquerade as systemic carnitine deficiency, recurrent Reye’s syndrome, or sudden infant death syndrome. Developmental disabilities, chronic seizure disorder, and proximal limb weakness represent long-term consequences of this condition. The molecular defect involves a gene on chromosome 1p31. In multiple studies of white patients, one mutation, A985G, was found in 90% of mutant medium-chain acyl coenzyme A dehydrogenase alleles. This mutation alters protein stability and assembly of the subunits into the holoenzyme tetramer. The phenotypes of the other six defects resemble medium-chain acyl coenzyme A dehydrogenase deficiency, but there are some clinical caveats. Long-chain acyl coenzyme A dehydrogenase deficiency tends to be more severe in infancy, with a worse prognosis. Cardiac involvement is prominent, and patients may develop microcephaly, hypotonia, and pigmentary retinopathy. Limb weakness may be seen with all beta-oxidation defects except medium-chain acyl coenzyme A dehydrogenase deficiency. Short-chain acyl coenzyme A dehydrogenase deficiency may present in infancy with vomiting, hypoglycemia, developmental delay, limb weakness, muscle carnitine deficiency, and a lipid storage myopathy, or it may present in adulthood with progressive limb weakness and lipid storage myopathy [Turnbull et al., 1984]. Electron transfer flavoprotein or electron transfer flavoprotein–coenzyme Q oxidoreductase deficiency states may present the clinical picture of multiple acyl coenzyme A dehydrogenase deficiency (glutaricaciduria type II). The neonatal presentation may be associated with congenital anomalies, including facial dysmorphism with low-set ears, hypertelorism, high forehead, hypoplastic midface, rocker-bottom feet, muscle defects of the anterior abdominal wall, and anomalies of the external

De Vivo and DiMauro / Mitochondrial Diseases

genitalia. These patients usually die during the first week of life. The neonatal presentation may occur without congenital anomalies, and these patients have hypotonia, tachypnea, metabolic acidosis, hepatomegaly, hypoglycemia, and a peculiar odor reminiscent of isovaleric acidemia. An adult phenotype may exhibit episodic vomiting, hypoglycemia, hepatomegaly, and limb weakness. Some patients with the milder form of multiple acyl coenzyme A dehydrogenase deficiency respond to riboflavin. Patients with LCHAD deficiency have persistent hepatic dysfunction, low serum carnitine concentrations, and a neuropathy or myopathy with recurrent myoglobinuria [Dionisi-Vici et al., 1991]. The shortchain 3-hydroxyacyl-CoA dehydrogenase phenotype appears to be similar to the LCHAD phenotype, but only three cases have been described [Tein et al., 1991]. DEFECTS OF THE KREBS CYCLE. Several partial defects of this cycle have been described. The first patient, described with dihydrolipoyl dehydrogenase deficiency, died at the age of 6 months with persistent metabolic acidosis and progressive neurologic symptoms, including respiratory difficulties, lethargy, hypotonia alternating with irritability, optic atrophy, and hyperreflexia [Robinson et al., 1977]. The organic acid profile includes elevations of αketoglutarate, branched-chain α-keto acids, pyruvate, and lactate. A few cases of α-ketoglutarate dehydrogenase deficiency have been described [Bonnefont et al., 1992]. This condition is devastating in infancy. Fumarase deficiency is a progressive infantile encephalopathy with failure to thrive, hypotonia, microcephaly, and fumaric aciduria. This condition may be associated with enlarged cerebral ventricles and polyhydramnios in utero [De Meirleir, 2002; Zinn et al., 1986]. Succinate dehydrogenase is a critical step in the Krebs cycle and the first component of complex II in the respiratory chain (see Fig. 28-5). Before the molecular era, several patients were described with defects of complex II and progressive encephalomyopathy. A mutation in the flavoprotein subunit of succinate dehydrogenase was identified in two sisters with Leigh’s syndrome [Bourgeron et al., 1995], the first example of a nuclear DNA mutation resulting in a respiratory chain disorder. A few more cases of Leigh’s syndrome were later associated with mutations in the same gene [DiMauro and Bonilla, 2004]. DEFECTS OF OXIDATION-PHOSPHORYLATION COUPLING. Luft’s disease (nonthyroidal hypermetabolism) is

the singular example of a defect in this pathway. Only two cases have been reported, both sporadic and with negative family histories [Luft et al., 1962; DiMauro et al., 1976]. Onset is in adolescence with fever, heat intolerance, profuse perspiration, polyphagia, polydipsia, resting tachycardia, and exercise intolerance. Both women died in middle age. Numerous ragged-red fibers were present in skeletal muscle, but the underlying biochemical defect has not yet been elucidated. DEFECTS OF THE RESPIRATORY CHAIN. The respiratory chain contains five functional units or complexes that are embedded in the inner mitochondrial membrane (see Fig. 28-5). The respiratory chain is unique in that it is controlled by the nuclear and mitochondrial genomes. Complex II, unlike the other four complexes, is under the control of the nuclear genome only. As a result, any defects involving this complex are inherited as mendelian traits.

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Box 28-1 represents a molecular classification of defects of the respiratory chain. However, patients studied before the “molecular era” (1988) cannot be classified by these criteria. Classification is also complicated by the diversity of clinical presentations. Some patients with neurologic or neuromuscular symptoms are grouped together in the neurologic literature as examples of mitochondrial encephalomyopathies. Other patients have non-neurologic symptoms resulting from primary involvement of other organs, such as the liver, heart, kidney, bone marrow, pancreas, or gastrointestinal tract [DiMauro and Schon, 2003]. Complex I (reduced nicotinamide adenine dinucleotide phosphate–coenzyme Q reductase) is the largest complex of the respiratory chain, containing about 46 polypeptides and several nonprotein components. Seven of the polypeptides are encoded by mtDNA. Patients with complex I deficiency can be subclassified as examples of a myopathy or a multisystem disorder. The myopathy may develop in childhood or early adult life and is manifested by exercise intolerance and limb weakness. The weakness may become prevalent as the disease progresses. These patients are often sporadic and harbor “somatic mutations” in mtDNA-encoded genes of complex I, that is, spontaneous de novo mutations in the mitochondrial genome occurring in the oocyte or in the embryo but affecting myoblasts after germ-layer differentiation [DiMauro et al., 2003]. Patients with multisystem involvement of complex I deficiency can be subdivided into three clinical conditions. The first is manifested by a fatal infantile disorder with congenital lactic acidosis, weakness and hypotonia, developmental delay, and death resulting from cardiopulmonary failure [Hoppel et al., 1987; Moreadith et al., 1984; Robinson et al., 1986]. The molecular basis of this rapidly fatal infantile presentation is not known but may relate to mutations in nuclear genes (see later). The second presentation is associated with the clinical and neuroradiologic features of Leigh’s syndrome. In fact, complex I deficiency may be one of the major causes of Leigh’s syndrome, although it may be overlooked because of the difficulty of documenting the biochemical defect in frozen tissues. This concept seems confirmed by studies of nuclear genes, revealing a number of mutations in children with Leigh’s syndrome or leukodystrophy [Smeitink and van den Heuvel, 1999; Triepels et al., 2001]. Attention has recently been drawn to mutations in mtDNA-encoded complex I (ND) subunits, especially mutations in the ND5 gene, which appears to be a hotspot. These mutations have been associated with maternally inherited MELAS, MERRF, and Leigh’s syndrome phenotypes or various overlap syndromes of these phenotypes [Liolitsa et al., 2003; Naini et al., 2005]. Complex II (succinate–coenzyme Q reductase) contains only polypeptides encoded by the nuclear genome. There are few examples of complex II deficiency, and again, the clinical picture is that of an encephalomyopathy. Haller and colleagues [1991] and Schapira and associates [1990] described two patients with lack of succinate dehydrogenase stain in muscle biopsy specimens. One was a 22-year-old man with exercise intolerance and recurrent myoglobinuria; the other was a 14-year-old girl with exercise intolerance but no myoglobinuria. The complex II deficiency in these patients was accompanied by partial defects of complex I, complex III, and aconitase and was attributed to defective

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importation of nonheme iron-sulfur clusters into mitochondria. As mentioned before, a few patients with Leigh’s syndrome and complex II deficiency had mutations in the gene encoding the flavoprotein subunit of the complex [Bourgeron et al., 1995; Parfait et al., 2000; Taylor et al., 1996]. Coenzyme Q10 serves as an electron shuttle between complexes I and II and complex III. There are three clinical presentations of what appears to be primary, autosomalrecessive coenzyme Q10 deficiency. The myopathic form, first described in 1989 in two sisters [Ogasahara et al., 1989], has been reported in three more patients [DiGiovanni et al., 2001; Sobreira et al., 1997]. It is characterized by the triad (1) myopathy with recurrent myoglobinuria, (2) muscle biopsy with ragged red fibers and lipid storage, and (3) central nervous system dysfunction, with seizures, ataxia, or mental retardation. The ataxic form is dominated by cerebellar ataxia and cerebellar atrophy, inconsistently accompanied by seizures, pyramidal signs, and mental retardation [Gironi et al., 2004; Lamperti et al., 2003; Musumeci et al., 2001]. An infantile encephalomyopathic form was described in two families with severe brain involvement and renal disease [Rahman et al., 2001; Rötig et al., 2000]. These syndromes are important to be considered because all patients, but especially those with the myopathic and the infantile forms, respond dramatically to oral supplementation with coenzyme Q10. Complex III (coenzyme Q–cytochrome-c oxidoreductase) contains 11 subunits, one of which is encoded by mtDNA. Defects involving complex III are subdivided into a generalized multisystem disorder manifested by limb weakness, exercise intolerance, and various neurologic signs or a tissue-specific syndrome manifested either as a pure myopathy with onset in childhood or adolescence or as a pure cardiopathy (“histiocytoid cardiomyopathy”) manifested in early infancy. Some patients with the myopathic phenotype and without apparent maternal inheritance have mutations (“somatic” mutations; see earlier) in the cytochrome-b gene of mtDNA [Andreu et al., 1999; DiMauro and Bonilla, 2004]. A rapidly fatal infantile disorder observed in Finland and dubbed GRACILE (growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis, and early death) was associated with mutations in an assembly protein (BCS1L) needed for the correct synthesis and function of complex III [Visapaa et al., 2002]. Mutations in the same nuclear gene (BCS1L) have also been found in children with Leigh’s syndrome [de Lonlay et al., 2001]. Complex IV (cytochrome-c oxidase, COX) contains 13 subunits, three of which are encoded by mtDNA. In keeping with the clinical presentations of respiratory chain defects, complex IV deficiency can be divided into a myopathic form and a multisystemic form [DiMauro and Bonilla, 2004]. There are two infantile myopathic presentations, a fatal infantile syndrome and a benign infantile syndrome. The fatal infantile syndrome may be restricted to skeletal muscle and manifested by congenital lactic acidosis and progressive respiratory insufficiency [Bresolin et al., 1985]. These patients die before 1 year of age. Some of these patients may have kidney dysfunction with the de Toni-Fanconi syndrome, whereas others may have abnormalities of cardiac function. Benign infantile myopathy is virtually indistinguishable from the fatal infantile form in the newborn period

[DiMauro et al., 1983]. These patients also have respiratory insufficiency and severe lactic acidosis. Patients with the benign syndrome, however, spontaneously improve during subsequent months and are essentially normal by 1 to 3 years of age. Although it is assumed that these infantile myopathies are due to mutations in nuclear genes, the molecular bases of both conditions remain unknown. On the other hand, somatic mutations in mtDNA genes encoding COX I or COX III can cause exercise intolerance and recurrent myoglobinuria [Karadimas et al., 2000; Keightley et al., 1996]. The most common clinical presentation for the partial generalized defect of complex IV is Leigh’s syndrome [DiMauro and De Vivo, 1996; Van Coster et al., 1991]. These patients are clinically asymptomatic during early infancy. Somatic and neurologic symptoms subsequently develop after 6 months of age, and patients die around 4 to 5 years of age. This syndrome is inherited as an autosomalrecessive trait. Cytochrome-c oxidase-associated Leigh’s syndrome can be distinguished clinically from pyruvate dehydrogenase complex-associated Leigh’s syndrome and from maternally inherited Leigh’s syndrome due to mutations in the ATPase 6 gene of mtDNA [Santorelli et al., 1993]. Patients with cytochrome-c oxidase deficiency are clinically symptomatic in the neonatal or early infantile period and die within 6 to 12 months of life. Patients with pyruvate dehydrogenase complex–associated Leigh’s syndrome or maternally inherited Leigh’s syndrome commonly have seizures and recurrent apnea; in addition, patients with maternally inherited Leigh’s syndrome may have retinitis pigmentosa, which—when present—is pathognomonic. Patients with cytochrome-c oxidase–associated Leigh’s syndrome have a slower clinical course, deceleration of head growth, and peripheral neuropathy. Seizures are uncommon in patients with cytochrome-c oxidase– associated Leigh’s syndrome. In 1998, two groups discovered that most cases of cytochrome-c oxidase-associated Leigh’s syndrome were due to mutations in a cytochrome-c oxidase assembly gene, SURF1 [Tiranti et al., 1998; Zhu et al., 1998]. This finding has greatly improved genetic counseling and has made prenatal diagnosis possible. Mutations in several other ancillary proteins needed for cytochrome-c oxidase assembly have been found in children with Leighlike encephalopathy and involvement of one other tissue, liver, heart, or kidney. Thus, mutations in the SCO2 gene cause cardioencephalopathy [Papadopoulou et al., 1999]; in general, the cardiopathy predominates and causes early death, but a few cases presented as spinal muscular atrophy with cardiopathy [Salviati et al., 2001]. Mutations in COX15 also cause cardioencephalopathy [Antonicka et al., 2003], whereas mutations in SCO1 cause hepatoencephalopathy [Valnot et al., 1999], and mutations in COX10 cause nephroencephalopathy [Valnot et al., 2000]. The reasons for the selective involvement of specific tissues besides brain remain unclear. Alpers’ disease [Alpers, 1931] has been associated with complex IV deficiency, but these cases are not well characterized from the clinical and neuropathologic points of view. The similarity of Alpers’ disease to the hepatocerebral presentation of the mtDNA depletion syndrome supports evidence that many if not all cases of Alpers’ syndrome may be associated with mtDNA depletion, possibly due to muta-

De Vivo and DiMauro / Mitochondrial Diseases

tions in the POLG gene, which encodes the mitochondrial γ-polymerase [Naviaux et al., 1999]. Complex V (mitochondrial ATP synthase) is composed of 12 to 14 subunits, two of which are encoded by mtDNA. The most important causes of complex V deficiency seem to be mutations affecting the ATPase 6 gene of mtDNA. Two mutations at the same nucleotide, G8993T and G8993C, cause syndromes of different severity. Depending on the abundance of mutant mtDNAs (mutation load), the T8993G mutation can cause maternally inherited Leigh’s syndrome in infants (mutation load around 90%) or a milder encephalomyopathy called neuropathy, ataxia, and retinitis pigmentosa in young adults (the two conditions can coexist in the same family). The T8993C mutation causes milder symptoms in both children and adults, often associated with familial bilateral striatal necrosis. In accordance with the more severe presentation, there is biochemical evidence of severely impaired ATP production in cells harboring the T8993G mutation, whereas ATP production is essentially normal in cells harboring the T8993C mutation (whose pathogenic mechanism remains unclear) [Schon et al., 2002]. A few mutations elsewhere in the ATPase 6 gene have been associated with encephalomyopathy and familial bilateral striatal necrosis [DiMauro and Schon, 2003]. The first nuclear defect impairing complex V function has been described. It involves a gene (ATP12) encoding an assembly protein, and it is accompanied by congenital lactic acidosis and a fatal infantile multisystemic disease [De Meirleir et al., 2004]. DEFECTS OF PROTEIN IMPORTATION. The protein importation process is energy dependent and requires the proteins to be unfolded before traversing the mitochondrial membranes, then refolded before reaching their final destination. This process requires a complex machinery involving leader peptides, chaperonins, translocases in the outer and inner membranes, and proteases [Curran and Koehler, 2004; Rapaport and Nargang, 2004]. Relatively few human diseases have been attributed to dysfunction of mitochondrial protein import, possibly because of the devastating consequences that disruption of the general import machinery would have. Most of these mutations involve leader peptides. One affected the enzyme methylmalonyl-CoA mutase and accounted for one form of methylmalonicaciduria [Ledley et al., 1990]. Another affected the leader sequence of the E1 α subunit of the pyruvate dehydrogenase complex in a child with pyruvate dehydrogenase deficiency and Leigh’s syndrome [Takakubo et al., 1995]. One cause of primary hyperoxaluria type I was associated with the misdirecting of a mutated alanine glyoxylate aminotransferase enzyme protein to the mitochondrial matrix rather than to the peroxisome [Purdue et al., 1990]. The enzyme, although catalytically intact, was unable to perform its biologic function because it had been misdirected to the wrong intracellular compartment. Some defects of ornithine transcarbamoylase and carbamylphosphate synthetase I, the two urea cycle enzymes located in the mitochondrion, may be additional examples of mitochondrial protein importation defects. Two children have been described with a defect of heat-shock protein 60, a chaperonin needed for the correct folding and assembly of imported proteins. One infant female, the product of a consanguineous marriage, presented at birth with dys-

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morphic features, hypotonia, respiratory insufficiency, and severe lactic acidosis and died 2 days later [Agsteribbe et al., 1993]. The second child also had dysmorphic facial features, congenital hypotonia, and failure to thrive, and she died at 4.5 years of age [Briones et al., 1997]. The molecular bases of these biochemical defects were not established. However, two disorders have been associated with mutations in components of the transport machinery. The first is an Xlinked disease called deafness-dystonia syndrome (MohrTranebjaerg syndrome), characterized by neurosensory hearing loss, dystonia, cortical blindness, and psychiatric symptoms; it is due to mutations in the TIMM8A gene, which encodes the deafness-dystonia protein (DDP1), a component of the transport machinery [Roesch et al., 2002]. The second is an autosomal-dominant form of hereditary spastic paraplegia due to mutations in the chaperonin heatshock protein 60 [Hansen et al., 2002]. DEFECTS OF INTERGENOMIC SIGNALING. Two mtDNA-associated clinical syndromes result from a primary molecular defect involving the nuclear genome. Both conditions are inherited as mendelian autosomal traits. The first condition is associated with multiple deletions of mtDNA and was first described by Zeviani and colleagues [1989]. Patients with multiple mtDNA deletions have progressive external ophthalmoplegia, which can be the dominating feature or can be associated with multisystemic involvement. Patients with autosomal-dominant progressive external ophthalmoplegia usually become symptomatic in the third decade of life with ophthalmoplegia, progressive limb weakness, bilateral cataracts, depression, and precocious death. One form of autosomal-recessive progressive external ophthalmoplegia with onset in childhood is accompanied by severe cardiomyopathy requiring cardiac transplantation [Bohlega et al., 1996]. A special form of autosomalrecessive progressive external ophthalmoplegia is the mitochon-drial neurogastrointestinal encephalomyopathy syndrome, in which gastrointestinal dysfunction (chronic diarrhea, intestinal pseudo-obstruction), peripheral neuropathy, and leukodystrophy are prominent [Nishino et al., 2000]. In both conditions, there are ragged-red fibers in the muscle biopsy specimen. The molecular bases of these conditions are being understood at a rapid pace [Hirano and DiMauro, 2001]. Mutations in the gene for thymidine phosphorylase (TP) are responsible for mitochondrial neurogastrointestinal encephalomyopathy [Nishino et al., 1999]. Mutations in the gene encoding one isoform of the adenine nucleotide translocator (ANT1) were identified in some but not all patients with autosomal-dominant progressive external ophthalmoplegia [Kaukonen et al., 2000]. It is noteworthy that both types of mutations affect mitochondrial nucleotide pools and may have similar pathogenetic mechanisms. Mutations in a gene encoding Twinkle, a helicase, are associated with autosomaldominant progressive external ophthalmoplegia [Spelbrink et al., 2001], whereas mutations in the gene encoding polymerase γ (POLG) may cause either autosomal-dominant or autosomal-recessive progressive external ophthalmoplegia, often associated with psychiatric disease or parkinsonism [Van Goethen et al., 2001; Mancuso et al., 2004]. The second example of an intergenomic signaling defect is the mtDNA depletion syndrome with variable tissue expression. This condition was first described by Moraes and

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colleagues [1991] as an autosomal-recessive trait associated with a quantitative reduction of mtDNA copy number. Two major phenotypes have emerged, one dominated by myopathy, the other by liver and brain involvement. The myopathic form of mtDNA depletion syndrome may present as a congenital and rapidly fatal myopathy (generally associated with very low residual mtDNA in muscle) or as a childhood progressive myopathy (associated with higher residual amounts of mtDNA). The “hepatocerebral” form can present as fulminant hepatopathy of infancy or as a multisystem disorder affecting predominantly brain and liver (not unlike Alpers’ syndrome). However, symptoms overlap; for example, infants with the “myopathic” phenotype sometimes mimic spinal muscular atrophy, and mtDNA depletion should be considered in children with spinal muscular atrophy but without mutations in the SMN gene. Mutations in two genes, both involved in mitochondrial nucleotide homeostasis, have been associated with mtDNA depletion syndrome, although they do not explain all cases. Mutations in the gene encoding thymidine kinase (TK2) are more common in patients with the myopathic presentation [Saada et al., 2001], whereas mutations in the gene encoding deoxyguanosine kinase (dGK) predominate in patients with the hepatocerebral presentation [Mandel et al., 2001]. DEFECTS OF THE LIPID MILIEU OF THE INNER MITOCHONDRIAL MEMBRANE. This pathogenetic

mechanism is illustrated by Barth’s syndrome, an X-linked recessive disorder characterized by mitochondrial myopathy, cardiopathy, and leukopenia [Barth et al., 1999]. Mutations in the tafazzin (TAZ) gene are responsible for Barth’s syndrome, and TAZ encodes a family of proteins, named tafazzins, that are homologous to phospholipid acyltransferases [Bione et al., 1996]. Analysis of phospholipids in target tissues from patients with genetically proven Barth’s syndrome found markedly decreased levels of cardiolipin, as well as altered cardiolipin composition [Schlame et al., 2002, 2003]. Cardiolipin is the main phospholipid component of the inner mitochondrial membrane, where it not only functions as a “scaffold” but also interacts with respiratory chain complexes. Thus, alterations of cardiolipin amount and composition can affect respiratory function. DEFECTS OF MITOCHONDRIAL MOTILITY, FUSION, AND FISSION. Mitochondria are dynamic organelles

forming complex tubular structures in many cells, which requires constant fusion of the mitochondrial tubules, balanced by fission. Also, individual mitochondria move in the cell—sometimes covering considerable distances, as in axons—propelled by energy-requiring dynamins along cytoskeletal microtubular rails [Griparic et al., 2004]. Mutations in a gene (OPA1) encoding a dynamin-related guanosine triphosphatase have been associated with an autosomal-dominant form of optic atrophy resulting in young-onset blindness, similar to Leber’s hereditary optic neuropathy [Alexander et al., 2000; Delettre et al., 2002]. Mutations in the gene (MFN2) encoding mitofusin 2, an outer membrane fusion protein, cause Charcot-Marie-Tooth 2A, a severe and early-onset form of axonal neuropathy [Zuchner et al., 2004].

Inherited Conditions Associated with mtDNA Defects Since 1988, no less than 11 clinical syndromes have been associated with defects of the mitochondrial genome. These conditions can be subdivided into disorders associated with large-scale rearrangements of mtDNA, syndromes associated with point mutations affecting mtDNA genes, and syndromes associated with intergenomic signaling defects resulting from mutations of the nuclear genome. The last category is discussed in the section covering nuclear DNA defects. Large-scale rearrangements of mtDNA can be divided into sporadic syndromes and genetically transmitted syndromes. The sporadic syndromes include Kearns-Sayre syndrome, sporadic progressive external ophthalmoplegia, and Pearson’s syndrome [DiMauro and Bonilla, 2004; Schon et al., 2002]. A genetically transmitted condition is diabetes mellitus and deafness [Ballinger et al., 1992]. SPORADIC

LARGE-SCALE

REARRANGEMENTS.

Kearns-Sayre syndrome is the prototype of this group of diseases [Moraes et al., 1989; Zeviani et al., 1988]. Males and females are affected in roughly equal numbers, and there are no documented examples of familial Kearns-Sayre syndrome. The dominant clinical features include progressive eye signs, such as ptosis, restricted eye movements, and pigmentary retinopathy. Neurologic symptoms include cerebellar ataxia, mental retardation, and episodic coma. Seizures are infrequent and are usually associated with hypoparathyroidism. Complete heart block may lead to sudden death. Insertion of a pacemaker is lifesaving. Short stature and hearing loss are common. Endocrine disturbances include diabetes mellitus, hypoparathyroidism, and isolated growth hormone deficiency. Ragged-red fibers are found in almost all affected patients. Calcification of the basal ganglia usually occurs in the setting of hypoparathyroidism. The surprisingly rare incomplete forms of Kearns-Sayre syndrome demonstrate progressive external ophthalmoparesis as an invariant clinical sign. Some cases have unusual clinical presentations, such as renal tubular acidosis, whereas others may overlap with clinically distinct syndromes, such as MELAS [Eviatar et al., 1990; Zupanc et al., 1991]. Pearson’s syndrome is a non-neurologic disorder of infancy characterized by pancytopenia, disturbed pancreatic exocrine function, and liver abnormalities [Pearson et al., 1979; Rötig et al., 1990]. The few survivors of this infantile condition may later develop clinical features of KearnsSayre syndrome [Blaw and Mize, 1990; Larsson et al., 1990; McShane et al., 1991]. The phenotypic transformation from Pearson’s syndrome to Kearns-Sayre syndrome is an example of tissue-specific modifications of mitochondrial heteroplasmy (mitotic segregation). POINT MUTATIONS AFFECTING PROTEIN-CODING L GENES. There are six clinical conditions that are maternally

inherited and associated with point mutations in mtDNA protein-coding genes. Two of these, Leber’s hereditary optic neuropathy and the syndrome of neuropathy, ataxia, and retinitis pigmentosa, affect structural genes in the mitochondrial genome. Lactic acidosis is usually absent in Leber’s hereditary optic neuropathy and may be absent in the syndrome of neuropathy, ataxia, and retinitis pigmentosa; ragged-red fibers are conspicuously absent in the skeletal muscle biopsy specimens from patients with both conditions.

De Vivo and DiMauro / Mitochondrial Diseases

Leber’s hereditary optic neuropathy is dominated clinically by the sudden onset of visual loss in a young adult and is more common in men [Carelli, 2002]. The peak age at onset is between 20 and 24 years, although children as young as 5 years have been described. Visual loss is bilateral in the majority of cases, although the condition may first develop in one eye followed by involvement of the second eye in weeks or months. The presentation is that of a retrobulbar neuropathy, often associated with disc edema and subtle alterations of retinal vessels. The male predominance suggests an X-linked factor that modulates the expression of the mtDNA point mutation, but this remains to be documented. The condition is relatively static after the subacute visual loss. Other neurologic and psychiatric symptoms have been described in patients and their family members, signifying the global nature of the molecular defect. Variable findings have included hyperreflexia, Babinski signs, incoordination, peripheral neuropathy, and cardiac conduction abnormalities. Three mutations, all of them in genes encoding subunits of complex I (G3460A in ND1, G1178A in ND4, and T14484C in ND6) are considered “primary,” that is, capable of causing Leber’s hereditary optic neuropathy in and by themselves. The second point mutation affecting an mtDNA structural gene results in neuropathy, ataxia, and retinitis pigmentosa (see earlier). Holt and associates [1990] described four family members of three successive generations with a variable combination of retinitis pigmentosa, ataxia, developmental delay, dementia, seizures, proximal limb weakness, and sensory neuropathy. This maternally transmitted condition was associated with an mtDNA point mutation involving the gene for subunit 6 of mitochondrial H+-ATPase. The most severely affected member was 3 years old. She had exhibited reduced fetal movements. Development was delayed, and a pigmentary retinopathy was noted. She had increased limb tone, hyperreflexia, bilateral Babinski signs, and generalized ataxia. As already mentioned, the T8993G mutation in the ATPase 6 gene of mtDNA has been recognized as one important cause of Leigh’s syndrome [DiMauro and Schon, 2003]. Curiously, a different mutation at the very same nucleotide (T8993C) causes a milder clinical phenotype and a less severe impairment of ATP synthesis in mitochondria isolated from cultured fibroblasts [Santorelli et al., 1996]. Mutations in the ATPase 6 gene of mtDNA appear to be associated with various syndromes characterized by the neuroradiologic features of Leigh’s syndrome or bilateral striatal necrosis [DiMauro and Schon, 2003]. POINT MUTATIONS AFFECTING SYNTHETIC GENES.

There are more than 150 pathogenic point mutations but only two distinct and frequent clinical conditions that are maternally inherited and associated with mtDNA point mutations affecting transfer RNA genes. The two conditions are mitochondrial encephalopathy with lactic acidosis and strokelike episodes (MELAS) and myoclonus epilepsy and ragged-red fibers (MERRF). MELAS was first described in 1984 [Pavlakis et al., 1984] and appears to be the most common mtDNA-related disease. Most patients become symptomatic before the age of 40 years, and 90% to 100% of patients have normal early development followed by the onset of exercise intolerance, strokelike episodes, seizures, and dementia. Almost all patients have lactic acidosis and

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had ragged-red fibers in skeletal muscle biopsy specimens [Kaufmann et al., 2004]. Recurrent migraine-like headaches preceded by nausea and vomiting are common, as are hearing loss, short stature, learning difficulties, hemiparesis and hemianopia, and limb weakness. The cerebrospinal fluid protein concentration is normal in half of the patients and only mildly elevated in the other half. One third of patients have basal ganglia calcifications. Seizures are common and often precede the strokelike events. Progressive external ophthalmoparesis was noted in approximately 10% of cases. The A3243G mutation in the tRNAleu(uur) gene of mtDNA is responsible for about 80% of MELAS cases worldwide [Goto et al., 1990]. Several other mutations in the same gene have been associated with MELAS [Kaufmann et al., 2004], as well as increasing numbers of mutations in structural genes of mtDNA [Liolitsa et al., 2003; Manfredi et al., 1995; Naini et al., 2005; Santorelli et al., 1998]. MERRF was first described in 1980 [Fukuhara et al., 1980]. The major clinical features include cerebellar syndrome, generalized convulsions, myoclonus, dementia, hearing loss, impaired deep sensation, and a positive family history consistent with maternal inheritance. Other findings may include optic atrophy and short stature [DiMauro et al., 2002]. In 1990, Shoffner and colleagues [1990] described a point mutation (A8344G) involving the mtDNA gene for tRNAlys. Two more mutations in the same gene (T8356C and G8363A) are less frequent causes of typical MERRF. Only one mutation in a different gene (G611A in the tRNAPhe gene) has been reported to cause typical MERRF [Mancuso et al., 2004].

Acquired Conditions Associated with Mitochondrial Dysfunction The inherited conditions causing mitochondrial diseases have dominated medical news in recent years. However, a number of acquired conditions associated with mitochondrial dysfunction have emerged. Reye’s syndrome has been viewed as the prototype of an acquired illness associated with generalized mitochondrial dysfunction [De Vivo, 1978; Pranzatelli and De Vivo, 1987]. This clinical condition typically develops in the wake of a childhood infection, commonly influenza or varicella. The syndrome is dominated clinically by a diffuse encephalopathy with brain swelling. The laboratory abnormalities reflect a generalized disturbance of liver function with elevated serum transaminases, hyperammonemia, and a complex coagulopathy. A statistical association exists between the ingestion of aspirincontaining products and the development of Reye’s syndrome [Hurwitz et al., 1987]. The laboratory abnormalities can be explained entirely on the basis of a generalized disturbance of mitochondrial function. The nature of the mitochondrial injury is not known, but findings suggest the possibility that there is a transient disturbance in the mitochondrial protein import machinery [Van Coster et al., 1991]. Toxic mechanisms also have been implicated as a cause of acquired mitochondrial dysfunction. Exposure to 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine causes an impairment of brain complex I activity and results in a parkinsonian syndrome [Langston et al., 1983; Nicklas et al., 1985]. Parkinsonism, but not typical Parkinson’s disease, is seen in patients with multiple mtDNA deletions and mutations in

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the POLG gene. The best evidence of mitochondrial involvement in Parkinson’s disease comes from the documentation of mutations in a gene (PINK1) encoding a mitochondrial kinase (PTEN-induced kinase 1), which may phosphorylate—and protect—mitochondrial proteins in situations of stress [Valente et al., 2004]. Drug treatment also may produce mitochondrial dysfunction. Mitochondrial DNA depletion may be acquired by chronic exposure to zidovudine. The depletion in this setting is reversible when zidovudine is discontinued. Zidovudine is incorporated into mtDNA by polymerase g. As a result, this incorporation inhibits mtDNA replication [Arnaudo et al., 1991; Dalakas et al., 1990]. Another example of drug-induced mitochondrial damage is aminoglycoside-induced deafness, a form of deafness induced by aminoglycoside drugs, such as gentamicin, kanamycin, and streptomycin, in persons harboring a homoplasmic A1555G mutation in the 12s rRNA gene of mtDNA [Schon et al., 2002]. Finally, there is intriguing evidence to suggest that mtDNA damage may accumulate during oxidative stress. Mitochondrial DNA damage has been described in hypoxic hearts that were removed at transplantation [Corral-Debrinski et al., 1991]. Mitochondrial DNA deletions also have been described during the natural aging process, with particular predilection for the corpus striatum [DiMauro et al., 2002]. The clinical significance of these observations awaits further investigation.

SUMMARY The clinical manifestations of mitochondrial diseases result from dysfunction of organ systems that are highly dependent on aerobic metabolism. These systems include the brain, skeletal muscle, heart, liver, and kidney. Presentation in infancy causes a delay in psychomotor development. The rate of brain growth is compromised, with resulting deceleration of head growth and acquisition of microcephaly. Impairment of vision and hearing is common, and convulsions may occur. Peripheral neuropathy also may be present and has been described with defects of long-chain fatty acid metabolism, generalized cytochrome-c oxidase deficiency, and the neuropathy, ataxia, retinitis pigmentosa mutation. The respiratory pattern may be affected and cause central hypoventilation or apnea. Incoordination and hypotonia are common, and Babinski signs are present. Eye findings may include optic atrophy, retinal pigmentary degeneration, ptosis, and ophthalmoparesis. Limb weakness is common, and muscle atrophy frequently occurs. Cardiomyopathy develops in many patients with mitochondrial diseases. Conduction defects may coexist and predispose the patient to dysrhythmias or complete heart block. Kidney involvement produces tubular dysfunction with a generalized aminoaciduria, hypophosphaturia, and acidosis. This multisystemic involvement may be associated with somatic growth failure characterized by short stature and poor weight gain. Endocrinopathies are increasingly recognized in patients with mitochondrial diseases. Diabetes mellitus, hypothyroidism, hypoparathyroidism, and isolated growth hormone deficiency have been described. Distinctive laboratory abnormalities represent the metabolic signatures of mitochondrial diseases. The abnormal-

ities reflect the metabolic pathway that is disturbed. Lactate, pyruvate, and alanine concentrations typically are elevated in the blood, urine, and cerebrospinal fluid when the defect involves pyruvate metabolism, the Krebs cycle, or the respiratory chain. Elevated serum free fatty acids, hypoketonemia, primary or secondary carnitine deficiency, and dicarboxylicaciduria commonly are associated with fatty acid oxidation defects. Elevated ammonia concentrations are expected with urea cycle defects. Hypoglycemia results from defects involving gluconeogenesis or fatty acid oxidation. The lactate/pyruvate ratio may be normal when the oxidation-reduction potential is preserved or elevated when the primary defect involves the respiratory chain. Citric acid cycle intermediates, such as fumaric acid and α-ketoglutarate, may be elevated in the urine with specific biochemical defects involving the Krebs cycle. Effective treatment for mitochondrial diseases is limited. Biotin supplementation is of value in biotinidase deficiency and in the Km mutant of holocarboxylase synthetase deficiency. Thiamine and lipoic acid have been recommended in deficiencies affecting the pyruvate dehydrogenase complex. A ketogenic diet also may help patients with pyruvate dehydrogenase deficiency, and medium-chain triglycerides may bypass the fatty acid oxidation defect when the defect involves the metabolism of long-chain fatty acids. Treatment of the lactic acidosis has been relatively unsuccessful. Sodium bicarbonate may exacerbate the cerebral symptoms in patients with mitochondrial diseases. Dichloroacetate, an experimental agent, may prove to be beneficial by its direct action on the pyruvate dehydrogenase complex, lowering the serum lactate concentrations, but it causes disabling peripheral myopathy as a toxic side effect [Kaufmann et al., 2005]. Folic acid concentrations are low in the cerebrospinal fluid of patients with Kearns-Sayre syndrome, and oral replacement is recommended. Similarly, coenzyme Q10 has been recommended as a treatment for many mitochondrial diseases. L-Carnitine is also recommended because a secondary carnitine deficiency syndrome develops in many of these patients. L-Carnitine is lifesaving in patients with the primary carnitine-responsive cardiomyopathy of infancy. A cardiac pacemaker is important in Kearns-Sayre syndrome, and naltrexone may be helpful in treating some patients with central hypoventilation. Nutritional supplements, nasogastric tube feedings, and gastrostomies should be considered early in the management of infants and children with mitochondrial diseases to maintain adequate calorie intake. REFERENCES Agsteribbe E, Huckriede A, Veenhuis M, et al. A fatal, systematic mitochondrial disease with decreased mitochondrial enzyme activities, abnormal ultrastructure of the mitochondria and deficiency of heat shock protein 60. Biochem Biophys Res Comm 1993;193:146. Alexander C, Votruba M, Pesch UE, et al. OPA1, encoding a dynamin-related GTPase, is mutated in autosomal-dominant optic atrophy linked to chromosome 3q28. Nat Genet 2000;26:211. Alpers BJ. Diffuse progressive degeneration of the grey matter of the cerebrum. Arch Neurol Psychiatry 1931;25:469. Anderson S, Bankier AT, Barrell BG, et al. Sequence and organization of the human mitochondrial genome. Nature 1981;290:457. Andreu AL, Hanna MG, Reichmann H, et al. Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA. N Engl J Med 1999;341:1037.

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Tein I, De Vivo DC, Hale DE, et al. Short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency in muscle: A new cause for recurrent myoglobinuria and encephalopathy. Ann Neurol 1991;30:415. Tiranti V, Hoertnagel K, Carrozzo R, et al. Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency. Am J Hum Genet 1998;63:1609. Triepels RH, Van den Heuvel LP, Trijbels JM, Smeitink JA. Respiratory chain complex I deficiency. Am J Med Genet 2001;106:37. Turnbull DM, Bartlett K, Stevens DL, et al. Short-chain acyl-CoA dehydrogenase deficiency associated with a lipid-storage myopathy and secondary carnitine deficiency. N Engl J Med 1984;311:1232. Valente EM, Abou-Sleiman PM, Caputo V, et al. Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 2004;304:1158. Valnot I, Kassis J, Chretien D, et al. A mitochondrial cytochrome b mutation but no mutations of nuclearly encoded subunits in ubiquinol cytochrome c reductase (complex III) deficiency. Hum Genet 1999;104:460. Valnot I, von Kleist-Retzow J-C, Barrientos A, et al. A mutation in the human heme-A:farnesyltransferase gene (COX 10) causes cytochrome c oxidase deficiency. Hum Mol Genet 2000;9:1245. Van Coster R, Lombes A, DeVivo DC, et al. Cytochrome c oxidaseassociated Leigh syndrome: Phenotypic features and pathogenetic speculations. J Neurol Sci 1991;104:97. Van Goethem G, Dermaut B, Lofgren A, et al. Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nat Genet 2001;28:211. Visapaa I, Fellman V, Vesa J, et al. GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L. Am J Hum Genet 2002;71:863. Wallace DC, Singh G, Lott MT, et al. Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 1988;242:1427. Warburg O, Negelein E. Über das Absorptions Spektrum des Atmungsferent. Biochem Z 1929;214:64. Wexler ID, Hemalatha SG, McConnell J, et al. Outcome of pyruvate dehydrogenase deficiency treated with ketogenic diets: Studies in patients with identical mutations. Neurology 1997;49:1655. Zeviani M, Moraes CT, DiMauro S, et al. Deletions of mitochondrial DNA in Kearns-Sayre syndrome. Neurology 1988;38:1339. Zeviani M, Servidei S, Gellera C, et al. An autosomal-dominant disorder with multiple deletions of mitochondrial DNA starting at the D-loop region. Nature 1989;339:309. Zhu Z, Yao J, Johns T, et al. SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Nat Gen 1998;20:337. Zinn AB, Kerr D, Hoppel CL. Fumarase deficiency: A new cause of mitochondrial encephalomyopathy. N Engl J Med 1986;315:469. Zuchner S, Mersiyanova IV, Muglia M, et al. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet 2004;36:449. Zupanc ML, Moraes CT, Shanske S, et al. Deletion of mitochondrial DNA in patients with combined features of Kearns-Sayre and MELAS syndromes. Ann Neurol 1991;29:680.

CHAPTER 29

Peroxisomal Disorders Gerald V. Raymond, SakkuBai Naidu, and Hugo W. Moser

Disorders of the peroxisomes—organelles found in all eukaryotic cells—are characterized by alterations in their unique metabolic functions in the cell and tissues. The pervasive presence of the peroxisome leads to far-reaching consequences of these genetic disorders. Peroxisomal disorders are divided into two major categories. In the first, the organelle fails to develop normally, leading to disruption of multiple peroxisomal enzymes. The second category consists of those disorders in which the peroxisome structure is normal but functioning of a single peroxisomal enzyme is defective. Table 29-1 lists the known peroxisomal disorders; their combined incidence is estimated at 1 in 25,000 or higher [Heymans, 1984]. Because peroxisomal disorders are genetically determined, with a majority readily identifiable by biochemical means including prenatal testing, and nearly all affecting the nervous system, knowledge of these diseases is important. As the pathophysiology of these disorders is better understood, novel therapeutic strategies may be developed, which gives new hope for advances not only in the diagnosis but also in the management and outcome of peroxisomal disorders.

HISTORICAL OVERVIEW The organelle was identified in 1954 by Rhodin and named the “microbody” [Rhodin, 1954]. In 1960, it was found that this structure contained urate, D-amino acid oxidase, and catalase and was named the peroxisome by de Duve and Baudhuin [1966]. Recognition of its function in active cellular processes came with the demonstration of its role in the β-oxidation of fatty acids (Fig. 29-1) [Lazarow, 1978] and plasmalogen synthesis [Hajra and Bishop, 1982]. That change in peroxisome function results in disease was not evident until 1973, when Goldfischer and colleagues determined its absence in Zellweger’s syndrome [Goldfischer et al., 1973]. The link between peroxisomes and human disease was not made until that time, even though peroxisomal disorders had been described much earlier, including X-linked adrenoleukodystrophy in 1923 [Siemerling and Creutzfeldt, 1923], acatalasemia in 1948 [Takahara and Migamoto, 1948], and Zellweger’s syndrome in 1964 [Bowen et al., 1964]. From the initial three enzymes identified, more than 40 enzymes have been localized to the peroxisomes [Tolbert, 1981].

STRUCTURE AND INTRACELLULAR FUNCTION OF PEROXISOMES The peroxisome is bound by a single membrane and contains a fine granular matrix. Histologically, these organelles

are identified by the presence of catalase, are present in all human tissues except mature erythrocytes, and demonstrate variation in size and number. In liver and kidney, where they are abundant, the average diameter is 500 nm, whereas in the nervous system, fibroblasts, and amniocytes, they measure 100 to 250 nm [Hruban and Rechcigl, 1969]. They do not contain DNA and appear to be devoid of glycoproteins. The membrane is 6.5 to 7 nm thick and has a trilaminar appearance and a unique protein composition. Peroxisome membrane proteins with molecular masses of 22, 26, 27, 41, 57, 68, and 70 kDa have been identified [Hashimoto et al., 1986; Imanaka et al., 1991]. The peroxisomal membrane also contains four ATP binding cassette (ABC) proteins. Although the precise role of these proteins in the peroxisomal membrane is still under investigation, it is known that this family of proteins has important intracellular roles in transport and other functions. As discussed later on, the ABC protein, ABCD1, is defective in X-linked adrenoleukodystrophy, the most prevalent peroxisomal disorder [Guimaraes et al., 2004]. The process of peroxisomal biogenesis is highly conserved in all eukaryotic organisms, which has permitted the study of yeast to identify the cellular mechanism for the assembly of the organelle and targeting of proteins to the developing vesicle [Weller et al., 2003]. The early concept of peroxisome biogenesis by budding of the endoplasmic reticulum has undergone significant revision. Peroxisomal proteins are encoded by nuclear genes, synthesized on free polyribosomes, and discharged into the cytosol in the mature form. Work in yeast has identified greater than 20 genes labeled PEX whose products, peroxins, are required for the incorporation of peroxisome membrane proteins and matrix protein importation. Peroxins are required for the proper importation and have roles in receptor docking, stability, and translocation across the membrane [Weller et al., 2003]. Targeting information directing matrix proteins into the peroxisomes is inherent in the mature polypeptide. A majority of proteins destined for the peroxisome use peroxisome targeting sequence 1 (PTS1), which consists of a terminal tripeptide of serine-lysine-leucine (-SKL) that is recognized by the soluble receptor Pex5p [Gould et al., 1987, 1988, 1990; Keller et al., 1991; Miyazawa et al., 1989]. Not all matrix proteins contain the carboxyl-terminal PTS1 signal. Peroxisomal 3-ketoacyl–coenzyme A (CoA) thiolase and phytanoyl-CoA hydroxylase have a different peroxisomal targeting sequence (PTS2). PTS2 consists of a nine-residue signal located at the amino terminus. It directs the import of a smaller number of proteins using the soluble receptor Pex7p [Swinkels et al., 1991]. Both Pex5p and Pex7p receptors bind their targeted proteins in the cytoplasm outside the peroxisome. The

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TABLE 29-1 Peroxisomal Disorders Disorders of Peroxisome Biogenesis Zellweger’s spectrum Zellweger’s syndrome Neonatal adrenoleukodystrophy Infantile Refsum’s disease Rhizomelic chondrodysplasia punctata (RCDP) Refsum’s disease secondary to PEX7 mutation Disorders of Single Peroxisomal Enzymes X-linked adrenoleukodystrophy CADDS Acyl CoA-oxidase deficiency Bifunctional enzyme deficiency DHAP acyltransferase deficiency Alkyl DHAP synthase deficiency Hyperoxaluria type 1 Adult Refsum’s disease Acatalasemia Mulibrey nanism CADDS, contiguous ABCD1 DXS1357E deletion syndrome; CoA, coenzyme A; DHAP, dihydroxyacetone phosphate.

present model has the receptor-peptide complex dock at the peroxisome surface by means of membrane-associated complexes containing other peroxisome assembly proteins including Pex3p, Pex13p, Pex14p, and Pex17p. Other peroxins appear to function later in the process of translocation. Several are zinc-binding proteins acting downstream of the docking complex and are postulated to constitute the translocation complex involved in matrix protein import. Recent evidence has demonstrated that Pex5p is translocated into the peroxisome and is capable of returning to the cytoplasm—an extended shuttle model [Dammai and Subramani, 2001]. This import method has no parallel with any other organelle. Walton and colleagues demonstrated that peroxisome import allows the uptake of folded, oligomerized

proteins and even the import of non–PTS-containing substances, so long as it was with PTS-containing cargo [Walton et al., 1995]. This mechanism is in contrast with that in the mitochondria and lysosome, which have a translocon mechanism with structural modification occurring within the targeted organelle. In contrast with the proteins targeted for the matrix, the proteins used in the membrane utilize another mechanism. Jones and associates examined PMP34 and found that it contained at least two targeting regions. Examining another peroxisomal membrane protein, Pex13, these investigators again found that it had multiple nonoverlapping targeting signals [Jones et al., 2001]. These and other peroxisomal membrane proteins did not share targeting regions. Regions were relatively long and contained at least one membranespanning domain. Peroxisomal number and division appear to be under metabolic control. Hypolipidemic agents, such as clofibrate and industrial phthalate plasticizers, result in the proliferation of liver peroxisomes [Hess et al., 1965; Lazarow et al., 1985]. These agents induce a 20- to 30-fold increase in the activity of the fatty acid β-oxidation system by the rapid coordinated increase of peroxisomal acyl coenzyme A (acyl-CoA) oxidase and bifunctional enzyme [Reddy et al., 1986]. This effect is mediated by activation of peroxisome proliferator–activated receptor α (PPARα), a binding protein related to the steroid hormone receptor superfamily [Issemann and Green, 1990; Lalwani et al., 1987]. Activated PPARα heterodimerizes with a second member of the nuclear receptor superfamily, retinoid X receptor, to form an active transcription factor [Weller et al., 2003]. Peroxisomes also are induced by high-fat diets [Neat et al., 1980], by adrenocorticotropic hormone [Black and Russo, 1980], by thyroid hormone [Fringes and Reith, 1982], and by the agent 4-phenylbutyrate [Wei et al., 2000]. Peroxisomal function is therefore influenced by metabolic state, nutrition, and pharmaceutical agents.

PEROXISOMAL ␤-OXIDATION PATHWAYS L-SPECIFIC PATHWAY

Substrates: Straight, long chain, and very long chain fatty acids

D-SPECIFIC PATHWAY

Substrates: Branched-chain fatty acids

Substrates: Bile acid intermediates

Lignoceryl-CoA (C24) ↓ Acyl-CoA-oxidase

Methyl-palmitoyl-CoA ↓ BC-oxidase

Trihydroxy-coprostanoyl-CoA ↓ BC-oxidase

Lignocerenoyl-CoA ↓ MFP-1

Methy-hexadecanoyl-CoA ↓ MFP-2

Trihydroxy-coprostanoyl-CoA ↓ MFP-2

Hydroxy-lignoceryl-CoA ↓ thiolase

Hydroxy-methyl-palmitoyl-CoA ↓ SCPX

Varanoyl-CoA ↓ SCPX

C22-CoA + Acetyl-CoA MFP = multifunctional protein BC = branched chain SCP = sterol carrier protein Long chain acyl CoA-ligase and lignoceroyl-CoA ligase

Myristoyl-CoA + Propionyl-CoA

Choloyl-CoA + Propionyl-CoA

FIGURE 29-1. Activation and subsequent β-oxidation of very long chain fatty acids, branchedchain fatty acids, and bile acid intermediates by the L- and D-specific pathways in peroxisomes. CoA, coenzyme A.

Raymond, Naidu, and Moser / Peroxisomal Disorders

Reflecting this genetic and metabolic control, peroxisomes vary in tissues throughout the body and during development. In the nervous system of the rat, the peroxisomes are smaller, approximately 140 nm, and fewer than in the liver. They predominate in the first 2 weeks of life in the glia and neurons of the cerebrum, cerebellum, locus coeruleus, and spinal cord but are fewer in the neurons of adult animals [Nagase et al., 2004]. They are rare in oligodendrocytes in the neonatal or adult animals but become prominent during myelin formation and may lie adjacent to the outer lamellae that form the myelin sheath [Arnold and Holtzman, 1978]. The biochemical activities follow a similar pattern wherein the activities of catalase and peroxisomal acyl-CoA oxidase and oxidation of lignoceric acid in brain reach a peak at postnatal days 10 to 16 and then decline. This decline suggests that peroxisomes play a vital role during brain development and myelinogenesis, which may account for the severe brain abnormalities noted in the neonatal and infantile forms of these disorders, including neuronal migration defects.

Long-Chain Acyl-Coenzyme A Ligase and Lignoceroyl-Coenzyme A Ligase

METABOLIC FUNCTION OF PEROXISOMES

Acyl-Coenzyme A Oxidases

Peroxisomes were named for the presence of hydrogen peroxide and catalase, which decomposes the hydrogen peroxide. The seminal observation by Lazarow and de Duve in 1976 that rat liver peroxisomes oxidized palmityl-CoA, followed in 1978 by the demonstration of enzymes of βoxidation and production of acetyl-CoA by Lazarow and Fujiki [1985], led to the recognition of the importance of this organelle in biologic processes. It is now known that greater than 40 enzymatic functions are found in the peroxisome. Some peroxisomal activities, such as oxidation of fatty acids and cholesterol synthesis, can occur in other cellular compartments as well. Certain reactions, however, occur exclusively in the peroxisome. These reactions include oxidation of very long chain fatty acids and pipecolic acid and certain steps in the synthesis of plasmalogens and bile acids. These reactions are abnormal in many peroxisomal disorders. The composition of enzymes within the peroxisome varies among species and within tissues in a species, as well as with maturation, metabolic state, and environmental factors. The following discussion focuses on those metabolic pathways that are unique and are used as markers in diagnosis.

Peroxisomal Fatty Acid Oxidation Peroxisomal β-oxidation enzymes are distinct from their mitochondrial counterparts. The biochemical steps are similar, involving several distinct enzymes including an oxidase, multifunctional enzyme (displaying enoyl-CoA hydratase and 3-hydroxy acyl-CoA dehydrogenase activity), and 3-oxo acyl-CoA thiolase. It recently has become clear that several distinct oxidases, multifunctional proteins, and enzymes catalyzing the thiolytic cleavage exist. The two pathways, L- and D-specific, are depicted in Figure 29-1.

737

Initially it was thought that a single acyl-CoA ligase that activated long-chain (C10 to C18) fatty acids was involved in oxidation of fatty acids and that it was common to mitochondria, microsomes, and peroxisomes [Miyazawa et al., 1985]. This enzyme is localized to the cytoplasmic side of the peroxisomal membrane, unlike other peroxisomal enzymes, which are in the matrix [Mannaerts et al., 1982]. Subsequently, a series of investigations led to the recognition of a closely related but separate enzyme, which is a ligase for very long chain fatty acids and is referred to as lignoceryl-CoA ligase or synthetase [Singh et al., 1988]. This enzyme is active toward lignoceric acid (C24:0) and hexacosanoic acid (C26:0). Unlike long-chain ligase, very long chain fatty acid ligase is absent in mitochondria. Singh and co-workers [1984] demonstrated that lignoceric acid is oxidized exclusively in the peroxisome. It is unclear if the very long chain fatty acid ligase plays any role in the pathogenesis of peroxisomal disorders.

The straight-chain acyl-CoA oxidase is synthesized in the mature form containing the carboxyl-terminal PTS1 [Miyazawa et al., 1987]. The oxidase is most active toward saturated and unsaturated fatty acids with 12- to 18-carbon chain lengths. The oxidase for bile acid intermediates and branched-chain fatty acids is a separate enzyme in humans [Casteels et al., 1990; Ferdinandusse et al., 2003; Schepers et al., 1990].

Bifunctional or Multifunctional Enzymes In both peroxisomal β-oxidation systems, the hydration step (enoyl-CoA hydratase) and the dehydrogenation step (3-hydroxyacyl-CoA dehydrogenase) are catalyzed by multifunctional enzymes (MFEs). The originally identified “bifunctional enzyme,” known as either MFE1 or L-bifunctional protein (L-BP), is L-specific. Human deficiency of the D-specific enzyme, referred to as either MFE2 or D-bifunctional protein (D-BP), causes a failure in the oxidation of very long chain fatty acids and branched-chain fatty acids. MFE2 was found to be identical to 17hydroxysteroid dehydrogenase type 4 and has a domain at its carboxyl terminus that resembles sterol carrier protein 2 (SCP2), an important intracellular sterol and lipid-binding and transport protein [van Grunsven et al., 1999].

Thiolases 3-Ketoacyl-CoA thiolase is the enzyme for the L-specific pathway and was characterized and cloned first [Bout et al., 1988; Hashimoto, 1982]. Unlike other peroxisomal enzymes but similar to mitochondrial enzymes, it is synthesized as a precursor and converted to the mature form by cleavage of a leader sequence. The peroxisomal targeting sequence for thiolase is located at the amino-terminal end [Swinkels et al., 1991] and was the first protein in which the PTS2 signal was characterized.

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Genetic, Metabolic, and Neurocutaneous Disorders / 29

The thiolytic cleavage in the D-specific pathways is catalyzed by sterol carrier protein X (SCPX). This 58-kDa protein has an amino-terminal thiolase domain that is a phylogenetic equivalent of the mitochondrial and peroxisomal thiolases [Igual et al., 1992].

Plasmalogen Synthesis

Branched-chain fatty acids are channeled into the D-specific pathway. The relevant enzymes include branched-chain acylCoA oxidase, MFE2, and sterol carrier protein, which functions as thiolase (see Fig. 29-1). Phytanic acid has a β-methyl group that blocks β-oxidation and therefore must be αoxidized first. After activation to its CoA derivative, phytanic acid is α-hydroxylated by phytanoyl CoA α-hydroxylase, the enzyme defective in classic Refsum’s disease [Jansen et al., 1997; Mihalik et al., 1997]. The α-hydroxy phytanoyl CoA is then degraded by a lyase to pristanic acid and formate [Croes et al., 1997]. The pristanic acid then can enter β-oxidation through the branched-chain pathway.

Plasmalogens are ether phospholipids and constitute 5% to 20% of phospholipids in mammalian cell membranes [Snyder, 1972]. They are abundant in myelin, in which they constitute one third of the myelin phospholipids [Norton and Autilio, 1966]. Although the role of ether phospholipids is not fully elucidated, they appear to have important roles as antioxidants in membrane dynamics, storage of polyunsaturated fatty acids, and signal transduction [Brites et al., 2004]. Plasmalogen synthesis is initiated by the acylation of dihydroxyacetone phosphate by dihydroxyacetone phosphate acyltransferase. Experimental studies in cultured skin fibroblasts demonstrate that ATP is required to overcome the latency of dihydroxyacetone phosphate acyltransferase, a finding that is compatible with an ATP-linked translocation of the substrate across the peroxisomal membrane [Wolvetang et al., 1990]. The second enzyme, alkyl-dihydroxyacetone phosphate synthase, replaces the acyl group with a longchain alcohol [Hajra and Bishop, 1982]. Both enzymes involved in these initial steps of introducing the ether bond into ether phospholipids are located on the inner surface of peroxisome membranes. The third step is the reduction of the alkyl-dihydroxyacetone phosphate to 1-alkyl glycerol-3phosphate by the enzyme acyl/alkyl-dihydroxyacetone phosphate reductase, which is present in both peroxisomes and microsomes [Datta et al., 1990]. All subsequent steps of synthesis occur in the microsomes. A method developed by Roscher and co-workers [1985] determines the ratio of the activities in peroxisomal and microsomal components and has proved to be of value in the study of peroxisomal disorders, many of which feature a marked reduction in plasmalogen synthesis.

Bile Acid Synthesis

Prostaglandin Degradation

Cholesterol is converted in the liver to cholic acid and chenodeoxycholic acid by a series of enzymatic steps localized to several subcellular compartments. Pedersen and Gustafsson [1980] first demonstrated that the peroxisomal fraction of rat liver catalyzes the conversion of an intermediate product of this pathway, tri- or tetrahydroxy-5β-cholestanoic acid (trihydroxycholestanoic acid), to cholic acid. Subsequently, Kase and co-workers [1986] reported that the conversion of trihydroxycholestanoic acid to cholic acid and of dihydrocholestanoic acid to chenodeoxycholic acid also took place in peroxisomes and was deficient in patients with Zellweger’s syndrome. Shortening of the cholesterol side chain by β-oxidation resulting in the formation of bile acids is analogous to fatty acid oxidation and uses the enzymes of the D-specific peroxisomal β-oxidation pathway. The oxidase for trihydroxycholestanoic acid–CoA is separate from that of fatty acids and in humans also is believed to function as a branched-chain fatty acid oxidase (see Fig. 29-1). A cytochrome P-450 catalyzing the hydroxylation of the C26/27 carbon of cholesterol in bile acid synthesis and formation of taurine conjugates of bile acid also has been localized to peroxisomes [Gutierrez et al., 1988; Kase and Bjorkheim, 1989]. In peroxisomal disorders, an increase in plasma and urine bile acid intermediates can be used as a diagnostic criterion.

Peroxisomes are involved in the chain shortening of prostaglandins F2α [Diczfalusy and Alexson, 1988] and E2 [Schepers et al., 1986]. Tiffany and associates [1991] demonstrated that basal and interleukin-1–stimulated synthesis of prostaglandin E2 increased in a group of patients with X-linked adrenoleukodystrophy.

Oxidation of Unsaturated Fatty Acids Degradation of monounsaturated and polyunsaturated fatty acids has been demonstrated to occur in peroxisomes, in addition to chain shortening of long-chain dicarboxylic acids [Ferdinandusse et al., 2001; Hiltunen et al., 1986; Kolvraa and Gregersen, 1983; Schulz and Kunau, 1987]. An example of a polyunsaturated fatty acid that requires peroxisomal oxidation is docosahexaenoic acid, which has an important role in retina and brain development and is known to be deficient in certain peroxisomal disorders [Moser et al., 1999; Watkins et al., 2001].

Branched-Chain Fatty Acid Oxidation and Phytanic Acid a-Oxidation

Amino Acid Metabolism D-Amino

Acid Oxidase

D-Amino acid oxidase is a flavoprotein with stereospecific activity toward D-amino acids and greatest activity toward D-proline. The kidney has the highest level of activity,

although the enzyme is widely distributed in vertebral tissues. The role of D-amino acids as neurotransmitters has recently attracted attention [Angermuller, 1989; Schell, 2004; Vamecq, 1990].

Alanine-Glyoxalate Aminotransferase Alanine-glyoxalate aminotransferase is a pyridoxal phosphate–dependent enzyme that catalyzes the transamination of glyoxalate to glycine, with alanine serving as the amino group donor. The subcellular localization of alanineglyoxalate aminotransferase is species dependent; it is

Raymond, Naidu, and Moser / Peroxisomal Disorders

present in peroxisomes in humans, rabbits, guinea pigs, and macaques, whereas it is mitochondrial in humans and dogs. It is present in both organelles in the rat, mouse, and hamster. The complementary DNA (cDNA) sequence of alanine-glyoxalate aminotransferase has been determined, and the subcellular localization appears to be determined by the targeting signal at the amino terminus [Danpure, 1995; Noguchi and Takada, 1979; Noguchi et al., 1978]. Of great interest is the observation that the mitochondrial targeting signal active in the rat enzyme is not expressed in humans. In some patients with hyperoxaluria type 1, this is altered, resulting in targeting of the alanine-glyoxalate aminotransferase to mitochondria instead of to the peroxisomes [Purdue et al., 1990]. In hyperoxaluria, the defective alanine-glyoxalate aminotransferase results in the conversion of glyoxalate to oxalic acid, which causes oxaluria and nephrocalcinosis.

Pipecolic Acid Oxidase L-Pipecolic acid is a component of an alternate lysine degradation pathway and is oxidized by L-pipecolic acid oxidase to α-aminoadipic acid. This enzyme contains flavin, and its subcellular localization is species dependent. The major site of oxidation is peroxisomal in humans and monkeys and mitochondrial in rabbits [Mihalik and Rhead, 1989]. The enzyme has been identified in human liver and has been reported to be deficient in Zellweger’s syndrome [Mihalik et al., 1989; Wanders et al., 1988a]. The human enzyme most closely resembles the bacterial monomeric sarcosine oxidases [Dodt et al., 2000]. Isolated increases in pipecolic acid have been reported in normal adults and may be a benign trait [Vallat et al., 1996]. As suggested recently, pyridoxine-responsive seizures may involve pipecolic acid metabolism.

CLASSIFICATION OF PEROXISOMAL DISORDERS Peroxisomal disorders may be divided into two categories: (1) disorders of peroxisome assembly or biogenesis and (2) single-enzyme defects [Raymond, 2001]. In the first, the peroxisome fails to form, and abnormalities of multiple peroxisomal functions are present. It is understood that these disorders are defects in protein importation using the PTS1 and PTS2 targeting sequences or membrane incorporation. This group of biogenesis disorders can be further divided by their clinical and biochemical features into the Zellweger spectrum disorders and rhizomelic chondrodysplasia punctata. The second major group consists of a growing number of disorders in which a genetically determined abnormality of a single peroxisomal enzyme is present and peroxisomal structure is intact. All of these disorders are, in actuality, single-gene and ultimately single-protein deficiencies, but the downstream consequences of the first group affect more than one peroxisomal pathway, resulting in multiple diagnostic abnormalities. With the emergence of DNA-based diagnosis, the utility of this division may require reassessment. An overview of diagnostic evaluation of peroxisomal disorders is provided in Figure 29-2.

CONDITIONS RESULTING FROM DEFECTIVE PEROXISOME BIOGENESIS Conditions resulting from defective peroxisome biogenesis are listed in Table 29-1; Zellweger’s syndrome and rhizomelic chondrodysplasia punctata are the respective prototypes. Clinical and biochemical variation between these two

FIGURE 29-2. Diagnostic evaluation of peroxisomal disorders. Confirmatory genetic or biochemical testing may be required. ALD, adrenoleukodystrophy; RCDP, rhizomelic chondrodysplasia punctata; VLCFA, very long chain fatty acid.

Suspicion of Peroxisomal Disorder

VLCFA Abnormal

Normal

Plasmalogens

Plasmalogens

Abnormal

Normal

Abnormal

Zellweger spectrum disorder

ALD or other single-enzyme defect of beta oxidation

RCDP or other single-enzyme defect of plasmalogen synthesis

739

Normal

Phytanic acid Abnormal Adult Refsum’s disease

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Genetic, Metabolic, and Neurocutaneous Disorders / 29

types of assembly defects still makes it useful to discuss them separately, although it is important to recognize that these disorders were described on a clinical basis before details of the cell and molecular biology of peroxisomal disorders were known, and hence they were assigned names based on the clinical features, pathologic findings, or biochemical defects that identified them.

Molecular Etiology of Disorders of Peroxisome Assembly Cell complementation studies were instrumental in the early understanding of the genetics of peroxisomal assembly disorders. Identification of complementation groups provided cell lines that are homogeneous with respect to their gene defect. In conjunction with the use of other molecular biology tools, including the study of yeast and other cell types and the emergence of computerized genomic databases, a new understanding of the molecular underpinnings of the peroxisome assembly disorders has been attained [Lazarow, 1995]. These disorders result from defects in the PEX genes. A complex interaction of peroxins is necessary for the biogenesis of peroxisomes, and a defect in any of these proteins impairs the process. The final common pathway is peroxisomal dysfunction, with the respective clinical syndromes.

From the study of complementation groups, it was determined that peroxisomal disorders comprise up to 16 complementation groups [Moser et al., 1995]. A majority of the identified groups included persons with Zellweger’s syndrome and milder variations of that condition. One complementation group, however, contained all of the patients with rhizomelic chondrodysplasia punctata, and no overlap between this clinical group and the others was identified. It has subsequently been determined that Zellweger spectrum disorders are secondary to PTS1-mediated pathways including PEX5, and that rhizomelic chondrodysplasia punctata is secondary to mutations in PEX7, the receptor for PTS2 proteins. The most common causes of Zellweger spectrum disorders are mutations in either PEX1 or PEX6, although to date, 11 PEX genes have been identified as potential causes of these disorders (Table 29-2). PEX1 and PEX6 encode AAA ATPases. Their exact role in matrix protein importation is not certain, but evidently they can interact [Tamura et al., 2001]: Overexpression of PEX6 or PEX1 can correct mild deficiencies of the other [Germain-Lee et al., 1997; Reuber et al., 1997]. PEX1 defects account for greater than 65% of cases of such defects [Steinberg et al., 2003; Weller et al., 2003]. A degree of phenotype correlation with the causative mutation has been noted. A single base

TABLE 29-2 Disorders of Peroxisome Biogenesis GENE

COMPLEMENTATION GROUP

CHROMOSOME LOCALIZATION

PROTEIN NAME

PROTEIN FAMILY OR DOMAIN

PERCENTAGE OF PATIENTS WITH ZSD PHENOTYPE*

PEX1

1

7q21-22

AAA ATPase

68

PXR1 (PEX5)

2

12p13.3

C-terminus TPR domains N-terminal WxxxF/Y repeats

1.5

PEX12

3

17q21.1

C-terminal zinc binding RING

4.1

PEX6

4

6p21.1

AAA ATPase

10.7

PEX10

7

1p36.32

Peroxisome biogenesis factor 1 Peroxisomal targeting signal 1 receptor Peroxisome assembly protein 12 Peroxisome assembly factor-2 PAP 10

4.6

PEX26

8

22q11.2

PEX26 protein

PEX16

9

11p12-p11.2

PXMP3 (PEX2) PEX3

10

8q21.1

PMP PEX16 PAF-1

C-terminal zinc binding RING PMP, N terminal cytosolic, C-terminal peroxisomal Orphan C-terminal zinc binding RING

12

6q23

PAP PEX3

Orphan

1.5

PEX13

13

2p15

PMP PEX13

1.0

PXF (PEX19)

14

1q22

PEX14

—

1p36.2

Peroxisomal farnesylated protein PMP PEX14

C-terminal SRC homology domain Farnesylated at C-terminus

PEX7

11

6q21-q22.2

6.6 0.5 1.0

0.5

SH3-binding motif PxxP WD40 repeats containing protein

All PEX7 patients are rhizomelic chondrodysplasia punctata; other PEX genes express Zellweger spectrum disorder (ZSD). *Percentage of patients is adapted from the experience of the Kennedy Krieger Institute and Johns Hopkins Hospital DNA Diagnostic Laboratory (Steinberg et al., 2003). PMP, peroxisome membrane protein.

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A

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B

FIGURE 29-3. A, Cerebrohepatorenal syndrome of Zellweger. Note prominent forehead, large fontanel, hypertelorism, epicanthal folds, hypotonia, and hepatomegaly. B, Milder form of generalized peroxisomal disorder: 10-year-old boy with ataxia, significant mental retardation, visual loss secondary to retinitis pigmentosa, absence of speech, and sensorineural hearing loss. Liver biopsy showed micronodular cirrhosis and very few, abnormally small peroxisomes.

pair deletion results in a severe phenotype, and G843D allows a milder phenotype [Collins and Gould, 1999]. Because it is known that PEX1 and PEX6 interact, the mutation G843D affects this interaction [Weller et al., 2003]. Additional evidence indicates that this milder mutation is temperature sensitive and at lower temperatures results in some protein function and importation [Imamura et al., 1998, 2000].

Zellweger Spectrum Disorders Zellweger’s syndrome (cerebrohepatorenal syndrome) was first described by Bowen and associates [1964; Opitz, 1985]. Subsequently the disorders neonatal adrenoleukodystrophy and infantile Refsum’s disease were described as separate entities. Although classic Zellweger’s syndrome is the most severe form with a characteristic phenotype, clinical overlap exists between it and the other forms. All of the Zellweger spectrum disorders share morphologic and biochemical abnormalities, and genetic understanding of the underlying mutations has been obtained in many cases. In view of this overlap, it appears prudent at this time to retain a portion of this clinical nomenclature and refer to the group as Zellweger spectrum disorders.

Clinical and Pathologic Features ZELLWEGER’S SYNDROME Zellweger’s syndrome is a multiple congenital anomaly syndrome characterized by craniofacial abnormalities, eye abnormalities, neuronal migration defects, hepatomegaly, chondrodysplasia punctata, and near-complete absence of peroxisomes. The craniofacial features include a high forehead, hypoplastic supraorbital ridges, epicanthal folds, midface hypoplasia, and a large fontanel (Fig. 29-3). The head circumference usually is normal. Reported ocular abnormal-

ities include cataracts, glaucoma, corneal clouding, Brushfield spots, optic nerve hypoplasia, and pigmentary retinal abnormalities. Severe weakness and hypotonia manifest in the newborn period, often accompanied by seizures and apnea [Heymans, 1984; Wilson et al., 1986]. Most affected infants have oromotor dysfunction and require tube feeding. Little psychomotor development ensues, and the average life span has been reported to be 12.5 weeks [Wilson et al., 1986], although many affected children survive for 12 months. The facial appearance, Brushfield spots, and profound hypotonia may lead to a consideration of Down syndrome, although the chromosomal determination will eliminate that as a consideration. Striking abnormalities of neuronal migration unique to Zellweger’s syndrome are evident in the cerebral hemispheres as areas of pachygyria or polymicrogyria localized to the opercular region. In the cerebellum, the Purkinje cells form scattered heterotopias throughout the cortex and in the granule cell layer. Laminar discontinuities involving the olivary nucleus are noted, which also are unique to Zellweger’s syndrome [Evrard et al., 1978; Volpe and Adams, 1972]. Studies of PEX gene knockout mice have demonstrated similar neuropathologic changes [Baes et al., 1997; Faust, 2003; Faust et al., 2001; Gressens et al., 2000; Janssen et al., 2000, 2003]. N-methyl-D-aspartate (NMDA)-mediated abnormalities may contribute to the clinical findings seen in the most severely affected persons [Gressens et al., 2000]. Multiple other abnormalities have been reported. The eyes demonstrate loss of retinal ganglion cells and gliosis of the optic nerve [Cohen et al., 1983]. Retinal pigmentary degenerative changes are associated with absent electroretinograms [Hittner et al., 1981]. Hepatomegaly (present in 78% of patients) with periportal fibrosis may result in significant cholestasis (in 59%) and jaundice, micronodular cirrhosis (in 37%), and hypoprothrombinemia [Heymans, 1984]. Excessive iron deposition has been noted, which diminishes

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Genetic, Metabolic, and Neurocutaneous Disorders / 29

with age [Gilchrist et al., 1976]. Renal cortical cysts of varied sizes are present in 97% of patients studied pathologically but may be missed by ultrasound analyses [Bernstein et al., 1981; Heymans, 1984]. The adrenal gland demonstrates changes similar to those in X-linked adrenoleukodystrophy, with cytoplasmic lamellar inclusions consisting of cholesterol esterified with very long chain fatty acids [Goldfischer et al., 1983]. Skeletal abnormalities include clubfoot, thumb rotation, and stippled chondral calcification of the patella and acetabulum in 50% of patients [Heymans, 1984].

NEONATAL ADRENOLEUKODYSTROPHY AND INFANTILE REFSUM’S DISEASE The neonatal form of adrenoleukodystrophy was described by Ulrich and colleagues [1978] in a male infant with neonatal seizures and severe developmental delay. Postmortem examination at 18 months revealed adrenal atrophy and cytoplasmic inclusions typically seen in X-linked adrenoleukodystrophy; therefore, the disease was considered to be a connatal form of adrenoleukodystrophy. The multiple peroxisomal defects were first recognized in 1982 by Mobley and co-workers and substantiated later by others [Kelley et al., 1986; Partin and McAdams, 1983; Wanders et al., 1987]. Hyperpipecolicacidemia was described in 1968 by Gatfield and associates in a male infant with neurodegenerative disease and an enlarged liver who died at 27 months of age. A marked excess of pipecolic acid was noted in the tissues and body fluids. In 1975, Danks and colleagues demonstrated excess pipecolic acid in Zellweger’s syndrome, and in 1988, Wanders and associates described a generalized peroxisomal dysfunction in that disorder, including the original case of Gatfield and associates [Wanders et al., 1988c]. The term infantile phytanic acid storage disease, a possible variant of Refsum’s disease, was used by Scotto and co-workers [1982] to describe the disorder in three unrelated males aged 3 to 6 years with hepatomegaly, dysmorphism, mental retardation, sensorineural hearing loss, and retinitis pigmentosa. The investigators noted that the liver biopsy specimen contained inclusions similar to plant chloroplasts that included phytol, which led to the measurement and recognition of increased phytanic acid levels as in classic Refsum’s disease. The generalized peroxisomal dysfunction was documented by Poulos and colleagues [1984, 1986] and later by Poll-The and co-workers [1986a, 1986b] and Wanders and associates [1986b]. We now have a clear understanding that alteration in PEX genes may result in clinical phenotypes that are less severe than in Zellweger’s syndrome. Even in the milder forms, patients generally have mental retardation, retinal degeneration, and motor handicaps. Dysmorphism is less severe than in Zellweger’s syndrome; renal cysts may be absent, and no radiographic stippling of the cartilages is seen. Although neonatal adrenoleukodystrophy and infantile Refsum’s disease have in the past been split into distinct clinical presentations, this division can no longer be supported in light of more recent information on the genetic mechanism. This was already apparent from the clear clinical overlap between Zellweger’s syndrome and neonatal adrenoleukodystrophy and infantile Refsum’s disease. In addition, attempts to differentiate between these milder phenotypes either genetically or biochemically do not reliably predict the clinical course.

Patients with milder forms may present in the neonatal period with mild to moderate dysmorphism, hypotonia, poor feeding, and hepatomegaly with micronodular cirrhosis. Motor and cognitive development usually is delayed. Even with hypotonia, patients may be able to walk, although gait often is ataxic. Retinal pigmentary degeneration may not become evident until the age of 4 to 6 months and often results in visual loss in the first years of life. Electroretinograms show profound abnormalities in nearly all affected persons and do not correlate well with vision in this population. Sensorineural hearing loss is associated with limited language development [Aubourg et al., 1986; Boltshauser et al., 1982; Budden et al., 1986; Poll-The et al., 1987; Scotto et al., 1982; Torvik et al., 1988; Wanders et al., 1990a; Weleber et al., 1984]. Adrenal dysfunction may develop with age [Govaerts et al., 1989; Poll-The et al., 1987]. Liver dysfunction often is present and detectable by persistent elevation of liver enzymes. A bleeding diathesis that responds to vitamin K also may develop, and in several children, esophageal varices were observed, consistent with portal hypertension. Several investigators have reported postmortem studies in patients aged 8 months to 12 years [Challa et al., 1983; Chow et al., 1992; Powers and Moser, 1998; Torvik et al., 1988]. The liver demonstrated micronodular cirrhosis, and the adrenal glands were hypoplastic. Lipid-laden macrophages were present in the liver, lymph nodes, and certain areas of the cerebral white matter. The only cerebral malformation was a variable hypoplasia of the cerebellar granular layer and a migrational defect of the Purkinje cells. Retinal abnormalities include a loss of ganglion cells, gliosis of the nerve fiber layer, and bileaflet inclusions in the pigment epithelium and macrophages [Cohen et al., 1983]. Optic atrophy seen in patients with neonatal adrenoleukodystrophy/infantile Refsum’s disease has been confused with Leber’s optic atrophy [Ek et al., 1986], and the association of retinal pigmentary degeneration and sensorineural hearing loss has led to misdiagnosis as Usher’s syndrome [Kelley et al., 1986; Noetzel et al., 1983]. Lifespan is variable, and patients have survived to adulthood [Kelley et al., 1986; Poll-The et al., 1987]. Several older patients have now been described. All identified patients have been visually impaired, with sensorineural hearing loss. A progressive leukodystrophy, with variable age at onset, has been reported in a number of patients. This disorder results in loss of previously acquired skills and in most cases progresses to a vegetative state and death. Unlike in X-linked adrenoleukodystrophy, the rate of progression has been highly variable. Clinical recognition of these disorders may present some uncertainty because of nonspecific abnormalities and phenotypic variability. Disorders of peroxisome biogenesis commonly manifest in the neonatal period, and patients come to attention because of hypotonia, seizures, or liver disease. Evaluation appropriately focuses on a search for cytogenetic abnormalities, acute treatable metabolic disorders, and structural liver disease. Later in childhood, patients often are mistakenly diagnosed as having cerebral palsy, X-linked adrenoleukodystrophy, mitochondrial disease, or lysosomal disorders. The possibility of a disorder of peroxisome biogenesis should be considered in children with any of the following

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TABLE 29-3 Diagnostic Biochemical Plasma Profile of Peroxisomal Disorders

Zellweger spectrum disorder Rhizomelic chondrodysplasia punctata Adrenoleukodystrophy L-bifunctional enzyme deficiency Adult Refsum’s disease

Very Long Chain Fatty Acid

Red Blood Cell Plasmalogens

Pipecolic Acid*

Phytanic Acid*

↑↑ N1 ↑ ↑↑ N1

↓↓ ↓↓ N1 N1 N1

↓ N1 N1 N1 N1

↑ ↑ N1 ↑ ↑↑

N1, normal.

features: (1) psychomotor retardation; (2) dysmorphism; (3) hypotonia; (4) hepatomegaly; (5) seizures; (6) retinal pigmentary changes/absent electroretinogram; (7) sensorineural hearing loss; (8) renal cysts; (9) aberrant calcific stippling; and (10) adrenal insufficiency. After analyzing 40 cases, Theil and colleagues [1992] subdivided the clinical characteristics into major and minor features. They suggest that the combined presence of three major features (present in more than 75% of patients) and one or more minor features (present in 50% to 75%) warrants biochemical investigation for peroxisomal disease. Other investigators have pointed out that in view of the lack of specificity and ease of testing, strict screening criteria are not warranted, and the possibility of neonatal adrenoleukodystrophy and infantile Refsum’s disease should be considered in more children with previously undiagnosed developmental delay [Moser and Raymond, 1998]. All of the disorders in this group are inherited in an autosomal recessive fashion, so it is important for genetic counseling that an accurate diagnosis be arrived at expeditiously. Carrier detection is possible only by DNA analysis if the molecular defect has been identified in the index case [Shimozawa et al., 1992]. Carrier detection is not possible by biochemical determination in blood or fibroblasts.

Laboratory Diagnosis The diagnostic abnormalities present in patients with Zellweger spectrum disorders are listed in Table 29-3. A major diagnostic biochemical abnormality is the increased amount of very long chain fatty acids, which are fatty acids with carbon chains of greater than 22. They also are elevated in singleenzyme defects of peroxisomal β-oxidation, so their presence is nonspecific, and other studies are required for this diagnosis. Very long chain fatty acid accumulation here is due to the reduction of peroxisomal β-oxidation, which is greater in Zellweger’s syndrome than in milder forms. A virtual absence of peroxisomal acyl-CoA oxidase and bifunctional enzyme has been demonstrated in the liver of patients with Zellweger’s syndrome [Suzuki et al., 1986; Tager et al., 1985]. It should be noted, however, that very long chain fatty acids are not elevated in rhizomelic chondrodysplasia punctata and other peroxisomal disorders (e.g., acatalasemia) that do not involve lipid oxidation, and normal levels do not exclude all peroxisomal disorders. Because the first two steps of plasmalogen synthesis are peroxisomal functions, a reduction of plasmalogen levels is noted in patients with peroxisome biogenesis defects. Defi-

cient levels of dihydroxyacetone phosphate acyltransferase have been used for diagnostic purposes in skin fibroblasts, amniocytes, chorionic villus samples, red blood cells, leukocytes, and platelets [Besley and Broadhead, 1987; Datta et al., 1984; Schutgens et al., 1985; Wanders et al., 1985, 1986a]. Webber and colleagues [1987] have demonstrated that the Km values and other properties of the residual enzyme are normal, suggesting that the enzyme is not defective but is abnormally labile in the cytosol because of failure of transport into the peroxisome. Plasmalogens are reduced to 5% of control values in Zellweger’s syndrome [Heymans et al., 1984; Wanders et al., 1986a]. An age-related increase in the levels of phytanic acid occurs in all of the peroxisome biogenesis disorders including rhizomelic chondrodysplasia punctata, although not to the extent seen in classic adult Refsum’s disease. The accumulation of phytanic acid was demonstrated first in infantile Refsum’s disease [Scotto et al., 1982] and later in Zellweger’s syndrome [Poulos et al., 1984]. Poulos and associates [1988] demonstrated that pristanic acid is elevated in disorders of peroxisome biogenesis. This elevation was later confirmed to be due to an impaired capacity to oxidize pristanic acid [Singh et al., 1990]. These findings are unlike those in classic Refsum’s disease, in which the defect involves the conversion of phytanic acid to pristanic acid. Thus, oxidation of pristanic acid is a peroxisomal function that is disrupted in disorders of peroxisome biogenesis [Watkins et al., 1990]. Normally, bile acid intermediates, such as trihydroxycholestanoic acid and dihydroxycholestanoic acid, are absent or present in low concentrations. In Zellweger spectrum disorders, however, they constitute 30% to 50% of total plasma bile acids [Clayton et al., 1987; Eyssen et al., 1985; Gustafsson et al., 1983; Hanson et al., 1979; Mathis et al., 1980; Monnens et al., 1980; Poulos and Whiting, 1985]. Bile acid intermediates also may be abnormal in single-enzyme defects, such as peroxisomal bifunctional enzyme deficiency. The impaired activity of L-pipecolic acid oxidase results in increased accumulation of pipecolic acid in plasma and increased excretion of pipecolic acid in urine of patients with Zellweger spectrum disorders [Kelley and Moser, 1984; Mihalik et al., 1989; Wanders et al., 1988a]. Pipecolic acid levels in blood and urine are age dependent, but an excess can be demonstrated in all patients, irrespective of age [Dancis and Hutzler, 1986]. Medium- and long-chain dicarboxylic acids accumulate and are excreted in urine, suggestive of a partial block in the degradation of long-chain dicarboxylic acids [Bjorkheim et al., 1984; Rocchiccioli et al., 1986].

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Genetic, Metabolic, and Neurocutaneous Disorders / 29

In Zellweger’s syndrome, the number of catalasecontaining particles in liver or kidney biopsy specimens is reduced [Goldfischer et al., 1973; Small et al., 1988], although today biopsy rarely is needed for diagnosis. A reduction in the number of peroxisomes also occurs in neonatal adrenoleukodystrophy and infantile Refsum’s disease but, as expected, is less severe than in Zellweger’s syndrome. The catalase is cytosolic rather than particulate in catalase-containing particles. Although in the past, peroxisomes were considered absent, Santos and co-workers [1988] demonstrated membranous structures called peroxisomal ghosts that contain peroxisomal membrane proteins. This finding has been substantiated by other investigators who demonstrated the presence of major membrane proteins in skin fibroblasts from patients with Zellweger’s syndrome, some of which were quite abundant [Gaertner et al., 1991; Suzuki et al., 1989]. These ghosts lack the matrix enzyme catalase and some or all of the matrix proteins. Schram and colleagues [1986] have reported that peroxisomal βoxidation enzymes, which normally are located in the peroxisome matrix, are formed at a normal rate but are rapidly degraded in the cytosol. The mitochondrial abnormalities observed are considered secondary [Trijbels et al., 1983].

Prenatal Diagnosis Cultured amniocytes or chorionic villus cells can be used to diagnose all of the disorders of peroxisome biogenesis. A variety of biochemical strategies have been used and focus on the type and degree of biochemical abnormality. Two independent techniques, the measurement of very long chain fatty acid β-oxidation [Moser et al., 1984a; Solish et al., 1985] and plasmalogen synthesis [Roscher et al., 1985; Schutgens et al., 1985], have demonstrated accurate diagnosis when performed by laboratories experienced in these methodologies. Detection of elevated levels of very long chain fatty acids in amniotic fluid has yielded uncertain results [Jakobs et al., 1989]. Assay to detect increased levels of the bile acid intermediate trihydroxycholestanoic acid in amniotic fluid may be performed [Stellaard et al., 1988]. Molecular genetic techniques may be used in families in which the mutation has been identified.

Therapy Because many of the abnormalities are present in the affected fetus, potential for therapy is limited at present and likely to remain so. Treatment is primarily supportive, targeting, as appropriate, liver dysfunction with vitamin K for prothrombin deficiency, tube feeding, and antiepileptic medication. In the milder phenotypes, rehabilitative approaches including communication training and physical and occupational therapy are helpful. Attempts to normalize some of the biochemical abnormalities include oral ether lipid therapy [Holmes et al., 1987; Poulos et al., 1990; Wilson et al., 1986] and dietary restriction of very long chain fatty acids [Van Duyn et al., 1984] and phytanic acid [Greenberg et al., 1987; Steinberg, 1989]. These approaches may normalize plasma levels of very long chain fatty acids, phytanic acid, and red blood cell plasmalogens. The clinical effectiveness of these interventions, however, has yet to be demonstrated because of the

phenotypic variability of these disorders. Ursodeoxycholic acid can reduce levels of bile acid intermediates and has the potential to prevent liver damage [Colombo et al., 1990]. Dietary therapy with docosahexaenoic acid replaces low levels in plasma and red blood cells of patients with Zellweger’s syndrome, neonatal adrenoleukodystrophy, and infantile Refsum’s disease [Martinez et al., 1993, 1994]. Peroxisome proliferators, such as clofibrate, do not induce the formation of catalase-containing peroxisomes or improve clinical status [Lazarow et al., 1985].

RHIZOMELIC CHONDRODYSPLASIA PUNCTATA Rhizomelic chondrodysplasia punctata is characterized by severe shortening of limbs, mental retardation, and early death [Spranger et al., 1971]. A striking reduction in plasmalogen synthesis exceeding that seen in Zellweger’s syndrome led to the recognition of a peroxisomal defect in this disorder [Heymans et al., 1985, 1986]. Subsequent studies have revealed the following triad of biochemical defects: (1) marked reduction of plasmalogen levels resulting from impaired plasmalogen synthesis [Heymans et al., 1984]; (2) impaired oxidation of phytanic acid with increased plasma levels [Hoefler et al., 1988]; and (3) presence of 3-oxoacylCoA thiolase in the precursor form. The levels of very long chain fatty acids are normal, suggesting that the immature thiolase is catalytically active. Despite the presence of catalase in the particulate fraction, peroxisomal structure may not always be normal. Heymans and associates [1986] described two patients in whom peroxisomes were absent in some hepatocytes but large or irregularly shaped in others. The clinical features (Fig. 29-4A) include disproportionate shortening of the proximal portions of the extremities, short stature, microcephaly, dysmorphic facial appearance, cataracts, ichthyosis, and severe mental retardation. Radiologic highlights include shortening of the proximal limbs, metaphyseal cupping, and disturbed ossification with epiphyseal and extra-epiphyseal calcification (see Fig. 29-4B). Lateral views of the spine reveal coronal clefts of the vertebral bodies (see Fig. 29-4C). Epiphyseal stippling involves mainly the knee, hip, elbow, and shoulder and is uncommon in the vertebral column. The clinical features resemble those seen in warfarin embryopathy and should be differentiated from those of the milder autosomal-dominant form (ConradiHunermann type) and the X-linked forms of chondrodysplasia punctata, in which no biochemical abnormalities of peroxisomal function are detectable [Schutgens et al., 1988]. Rhizomelic chondrodysplasia punctata in a 9-month-old female with the classic triad of biochemical abnormalities, but with less severe disability, has been recognized. Her mentation and limb length were normal, despite radiographic evidence of chondrodysplasia punctata [Poll-The et al., 1991]. Other mildly affected patients have been identified, and many persons with an adult Refsum phenotype have alterations in PEX7 [Braverman et al., 2002; van den Brink et al., 2003]. The immature form of thiolase appears to be enzymatically active in patients with rhizomelic chondrodysplasia punctata because the levels of very long chain fatty acids are not increased and very long chain fatty acid oxidation is

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A

C

745

The diagnosis is confirmed by the impaired plasmalogen synthesis and elevated phytanic acid with reduced phytanic acid oxidation. Prenatal diagnosis using cultured amniocytes or chorionic villus samples is available. Duff and coworkers [1990] have reported on the prenatal diagnosis of rhizomelic chondrodysplasia punctata by ultrasound analysis. As suggested by the presence of the biochemical triad with normal intelligence and normal limb length reported by Poll-The and colleagues [1991], the phenotype of rhizomelic chondrodysplasia punctata is more varied than was previously recognized and cautions against the previous assumptions of these diagnostic criteria for prenatal diagnosis. Rhizomelic chondrodysplasia punctata is inherited in an autosomal-recessive manner. The disease results from a defect in PEX7, which encodes the receptor for PTS2. Several mutations have been noted in the PEX7 gene in patients with rhizomelic chondrodysplasia punctata; however, the L292ter found in greater than half of affected genes probably indicates a Northern European founder effect [Braverman et al., 2000, 2002]. Treatment is very limited and consists of palliative orthopedic care and cataract removal. Although dietary restriction of phytanic acid has been proposed, no evidence indicating that it affects outcome is available.

DEFECTS OF SINGLE PEROXISOMAL ENZYMES Defects of Single Peroxisomal ␤-Oxidation Enzymes Adrenoleukodystrophy

B FIGURE 29-4. A, Newborn with rhizomelic chondrodysplasia punctata showing midface hypoplasia, hypertelorism, severe shortening of proximal portions of limbs, and ichthyosis. B, Radiographic evidence of shortened proximal limbs, metaphyseal cupping, and stippling of the chondral epiphyses. C, Vertebrae show coronal clefts, which fused later. (A and B, Courtesy of Dr. B. McGillivary, Vancouver, British Columbia. C, Courtesy of Dr. J. Dorst, Johns Hopkins Hospital, Baltimore, Maryland.)

normal. Alternatively, small amounts of mature enzyme undetected by the immunoblot technique may be present. Balfe and colleagues [1990] reported that in rhizomelic chondrodysplasia punctata and in some cases of Zellweger’s syndrome, the immature thiolase is present in a subcellular particle with a lower density than in normal peroxisomes or mitochondria and speculated that this density difference may be related to peroxisome ghosts described by Santos and associates [1988].

The first clinical cases of what is known as X-linked adrenoleukodystrophy were described in 1923 by Siemerling and Creutzfeldt. The X-linked mode of inheritance was suggested by Fanconi and co-workers [1963]. A key observation of characteristic lamellar lipid-soluble cytoplasmic inclusions in the adrenal cortical cells and brain macrophages of patients with childhood adrenoleukodystrophy was made by Powers and colleagues [1980]. Similar inclusions were observed in men with Addison’s disease and spastic paraparesis by Budka and associates [1976] and Griffin and co-workers [1977], and the related condition was named adrenomyeloneuropathy. Similar histopathologic changes observed in a symptomatic child and an adult within a kindred strengthened the assertion that, despite the phenotypic variation, the same disease process was present. Igarashi and associates [1976] defined the biochemical defect by demonstrating that the inclusions in the adrenal cortex and cerebral white matter consisted of cholesterol esters with a striking excess of saturated unbranched fatty acids of 24- to 30-carbon chain length, of which C26:0 and C25:0 were the most abundant. This excess of very long chain fatty acids in cultured skin fibroblasts, plasma, or red blood cells is useful for diagnostic purposes [Kawamura et al., 1978; Moser et al., 1981; Tanaka et al., 1986, 1990; Tsuji et al., 1981].

Biochemical and Molecular Basis

The peroxisomal β-oxidation pathway consists of four enzymatic steps (as outlined in Fig. 29-1). Before the substrates can enter this pathway, the acyl residues require

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Genetic, Metabolic, and Neurocutaneous Disorders / 29

activation by transfer of a coenzyme A. For very long chain fatty acids entering the L-specific β-oxidation pathway, lignoceryl-CoA ligase (also referred to as lignoceryl-CoA synthetase) is the activating enzyme. Deficiency of this enzyme initially was implicated as the basis of the very long chain fatty acid accumulation in X-linked adrenoleukodystrophy. Singh and co-workers [1984] demonstrated that the capacity to oxidize the C24:0 and C26:0 fatty acids was reduced in patients with X-linked adrenoleukodystrophy. Studies by Lazo and colleagues [1988] and Wanders and associates [1988c] indicated that the defect involves the capacity to form the CoA derivative of very long chain fatty acid, because the capacity to oxidize lignoceryl-CoA is intact. It is known that the genetic basis for X-linked adrenoleukodystrophy is mutations of the ABCD1 gene, which encodes a PMP, an ATP-binding cassette protein [Mosser et al., 1993]. It remains unclear how mutations in this nonenzyme membrane protein affect the function of lignoceryl-CoA ligase. The ABCD1 gene is located on the X chromosome in the Xq28 region. The following other peroxisomal proteins with homology to ABCD1 have been described: (1) ALDR, adrenoleukodystrophy-related protein; (2) PMP70, PMP of 70 kDa [Kamijo et al., 1990]; and (3) PMP70R, PMP70-related protein. All of these proteins are located within the peroxisomal membrane and contain an ATP-binding cassette motif. It has been hypothesized that they are involved in the transport of other proteins or possibly substrates for peroxisomal pathways across the peroxisome membrane. Experimental data indicate that these proteins form homodimers and heterodimers [Valle and Gartner, 1993]. Multiple mutations in ABCD1 have been identified in patients with X-linked adrenoleukodystrophy, and no phenotype correlation has been identified [Kemp et al., 2001; Kok et al., 1995]. Several mouse models of X-linked adrenoleukodystrophy are now available [Lu et al., 1997].

Clinical and Pathologic Features of X-Linked Adrenoleukodystrophy and Adrenomyeloneuropathy Table 29-4 summarizes the different phenotypes of patients with X-linked adrenoleukodystrophy. These patients all demonstrate accumulation of very long chain fatty acid, and molecular studies have confirmed ABCD1 gene mutations. Various phenotypes have been recognized to oc-

TABLE 29-4 Phenotypes among X-Linked Adrenoleukodystrophy Hemizygotes TYPE

FREQUENCY (%)

Childhood cerebral Adolescent cerebral Adult cerebral AMN Addison’s only Asymptomatic

33–39 4–7 2–3 26–32 13–17 7–18

AMN, adrenomyeloneuropathy. Adapted from the North American data of the Kennedy Krieger Institute (Bezman and Moser, 1998).

cur within the same pedigree, so neither the genetic mutation nor the biochemical abnormality predicts the clinical presentation. Childhood Cerebral Form of Adrenoleukodystrophy. The childhood cerebral variant is the most common and fulminant form of X-linked adrenoleukodystrophy. Affected males are normal until 4 to 8 years of age, when they manifest behavior problems and failure in school as a result of rapid regression of auditory discrimination, spatial orientation, speech, and writing. Seizures occur in 30% of patients and in rare instances may be the initial sign. The magnetic resonance imaging (MRI) scan reveals parietooccipital white matter lesions (in 85% of patients) or frontal lesions (in 15%) at this stage, with contrast accumulation at the leading edge of the lesion [Duda and Huttenlocher, 1976; Eiben and DiChiro, 1977; Kumar et al., 1987] (Fig. 29-5). Rapid clinical deterioration leads to spastic quadriparesis, swallowing difficulty, and visual loss culminating in a vegetative state usually within 2 years of the initial signs and symptoms. Although males come to medical attention because of the neurologic deficits, impaired cortisol response can be identified by adrenocorticotropic hormone stimulation in 85% of this group [Moser et al., 1991b]. Adolescent Cerebral Form of Adrenoleukodystrophy. Patients with the adolescent cerebral form of adrenoleukodystrophy manifest signs and symptoms of cerebral involvement described previously between 10 and 21 years of age. Adult Cerebral Form of Adrenoleukodystrophy. In the adult cerebral form of adrenoleukodystrophy, dementia, psychiatric disturbances, seizures, and spastic paraparesis develop after age 21 [Bresnan and Richardson, 1979; Esiri et al., 1984; James et al., 1984; Kitchin et al., 1987; Sereni et al., 1987; Turpin et al., 1985]. Patients may be misdiagnosed as having multiple sclerosis, brain tumor, or schizophrenia and demonstrate rapid deterioration similar to that in the childhood cerebral form. Therefore, patients with these clinical presentations and adrenal insufficiency or leukodystrophy should be evaluated for a positive family history; in addition, measurement of plasma very long chain fatty acids is warranted. Adrenomyeloneuropathy. The neurologic manifestations of adrenomyeloneuropathy, an adult form of adrenoleukodystrophy, consist of an insidious onset and slow progression of spastic paraparesis, impaired vibratory sense in the lower extremity, and bladder or bowel dysfunction. Onset is typically in the third decade of life. The primary pathology involves the spinal cord with loss of myelinated axons in the corticospinal tracts, nucleus gracilis, and dorsal spinocerebellar tracts [Budka et al., 1983; Probst et al., 1980; Schaumburg et al., 1977]. Sural and peroneal nerves reveal a loss of large and small myelinated fibers. The development of cerebral demyelination has been seen in approximately 15% to 20% of men with adrenomyeloneuropathy [van Geel et al., 2001]. This pathologic change needs to be differentiated from long tract findings on MRI [Loes et al., 2003]. Cerebral disease is similar in time course to the childhood form of the disease and leads to dementia, spasticity, blindness, and death. Approximately half of patients with adrenomyeloneuropathy appear to have some degree of cerebral involvement, with mild to moderate abnormalities noted on MRI in 46% [Kumar et al., 1995] (see Fig. 29-5). These abnormalities consist most frequently

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A

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B FIGURE 29-5. Magnetic resonance imaging (MRI) studies in adrenoleukodystrophy. A, Typical alteration of the blood-brain barrier at the edge of the demyelinated lesion in childhood adrenoleukodystrophy demonstrated on gadolinium-enhanced MRI. B, The discrete but continuous auditory pathway involvement from the lateral lemniscus in the pons to the medial geniculate bodies at the midbrain level to the temporal cortex can be seen. MRI permits precise correlation between the location of the lesion and cognitive deficits; the findings may explain the early auditory comprehension deficiency seen in childhood adrenoleukodystrophy. C, MRI study of the spine in X-linked adrenoleukodystrophy. Views in axial (left) and lateral (right) planes demonstrate cord atrophy, particularly in the thoracic regions.

C of parietal-occipital white matter and optic radiation involvement. Adrenal insufficiency, or Addison’s disease, precedes the onset of neurologic symptoms in 42% of patients; in some, this may occur 3 to 35 years earlier. Adrenal insufficiency was evident in 67% of patients in our series. Serum testosterone levels were abnormally low in 22% of our patients, and early-onset sexual dysfunction occurred in one third. Adrenoleukodystrophy with Addison’s Disease Only. The diagnosis of adrenoleukodystrophy with Addison’s disease only includes the patients who have isolated Addison’s disease in the absence of neurologic signs and symptoms and is more common than was previously recognized. A study conducted in an endocrine clinic found that five of eight male Addisonian patients had the biochemical defect of adrenoleukodystrophy [Sadeghi-Nejad and Senior, 1990]. Recognition of these patients is vital for genetic counseling and to monitor for the development of adrenomyeloneuropathy or cerebral symptoms later on. Onset of adrenal dysfunction does not correlate with neurologic involvement. Asymptomatic Patients with the Biochemical Defect of Adrenoleukodystrophy. In asymptomatic patients with the biochemical defect of adrenoleukodystrophy, diagnosis may be accomplished by measurement of plasma very long chain fatty acids during screening tests of relatives of symptomatic patients. These persons may be of any age. The elevation of very long chain fatty acid levels in these males is

comparable with that in severely affected family members. At present, it is uncertain why the abnormal increase of very long chain fatty acids is not associated with disease in some patients. A 62-year-old man in this category whose brother died at the age of 48 years with the adult cerebral form of adrenoleukodystrophy has been identified. The unaffected brother had no evidence of adrenal insufficiency but, when reexamined by the same neurologist 4 years later, demonstrated signs of corticospinal tract involvement compatible with mild adrenomyeloneuropathy. Several asymptomatic men demonstrate an impaired cortisol response to adrenocorticotropic hormone stimulation, suggesting that they have adrenal involvement and are presumed to be at risk for developing adrenomyeloneuropathy. Symptomatic Heterozygotes. Between 10% and 20% of the women who are carriers for the adrenoleukodystrophy gene manifest myelopathy resembling that in adrenomyeloneuropathy between the third and fifth decades of life [Dooley and Wright, 1985; Heffungs et al., 1980; Morariu et al., 1982; Moser et al., 1980; Naidu et al., 1986; Noetzel et al., 1987; O’Neill et al., 1982, 1984; Penman, 1960; Pilz and Schiener, 1973]. Long tract signs and diminished vibration sense in the legs are present in two thirds of the patients, although only 25% complain of symptoms. Approximately 14% have severe spinal involvement requiring assistance with ambulation, and 5% have dementia [Naidu and Moser, 1990]. In contrast with males, adrenal insufficiency rarely occurs in these women [El-Deiry et al., 1997]. Elevation of very long chain fatty acids in plasma or skin fibroblasts allowed identification of 85% of obligate heterozygotes in one series [Moser et al., 1983]. The remaining cases can be identified by molecular analysis for the gene defect. Mutation analysis helps identify heterozygotes once

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the mutation in the index case is known [Boehm et al., 1999]. Migeon and co-workers [1981] studied fibroblast clones from heterozygotes and identified two types of cells; one had a normal fatty acid pattern, and the pattern in the other cell type was similar to that in affected males, reflecting X-inactivation status. To determine if differential X-inactivation accounts for the clinical variability in heterozygotes, an indirect immunofluorescence analysis of ALDP, the protein defective in X-linked adrenoleukodystrophy, has been applied to skin fibroblasts. Previous studies have reported that 70% of males with X-linked adrenoleukodystrophy lack immunoreactivity for ALDP. As a result of differential X-inactivation, heterozygotes from these informative families have a mixed population of normal and ALDP-deficient cells. Despite considerable variation, a positive correlation is noted between immunonegative cells and clinical severity. No correlation is seen between immunoreactivity and either very long chain fatty acid levels or age alone. When age is considered, however, the correlation between severity and ALDP immunoreactivity is strengthened. Thus, differences in patterns of X-inactivation appear, in part, to contribute to the variable severity of the disease seen in the X-linked adrenoleukodystrophy heterozygotes [Naidu et al., 1997].

Pathogenesis of Adrenoleukodystrophy The main biochemical defect is the striking excess of very long chain fatty acids, which accumulate in the cholesterol ester fraction, primarily in the adrenal gland and cerebral white matter. Theda and co-workers [1987] noted that in areas of brain where myelin was intact there was a 20-fold excess of C26:0 in the phosphatidylcholine fraction, whereas the cholesterol ester fraction had a normal fatty acid composition. The enrichment with C26:0 in the cholesterol ester fraction reported by earlier investigators [Brown et al., 1983; Igarashi et al., 1976; Menkes and Corbo, 1977; Molzer et al., 1981; Ramsey et al., 1979; Reinecke et al., 1985; Taketomi et al., 1987] was present only in zones undergoing active demyelination and to a lesser extent where myelin had been replaced by glial tissue. They concluded that increased very long chain fatty acids in phosphatidylcholine could be the primary event and that the excess in the cholesterol ester fraction is due to myelin breakdown. The accumulation of very long chain fatty acids in X-linked adrenoleukodystrophy is not as severe as in disorders of peroxisome biogenesis or single–peroxisomal β-oxidation enzyme defects. Red cell membrane microviscosity is increased in X-linked adrenoleukodystrophy [Knazek et al., 1983], which may impair functional capacity. This finding also is suggested by studies in human adrenal gland cultures, where the addition of C26:0 fatty acid to the culture medium resulted in an impaired cortisol response to adrenocorticotropic hormone [Whitcomb et al., 1988]. Cholesterol esterified with very long chain fatty acids is a poor substrate for cholesterol ester hydrolase, which may limit steroid production [Ogino and Suzuki, 1981]. The pathogenesis of the nervous system lesion has been more difficult to discern. It has been presumed that elevation of very long chain fatty acids results in the axonopathy seen in patients with adrenomyeloneuropathy and in women who are carriers. It is not clear, however, why rapid, inflammatory demyelination affecting the cerebral white matter tracts develops in certain persons. The levels of very long

chain fatty acids in plasma or skin fibroblasts or the capacity to metabolize very long chain fatty acids in cultured fibroblasts [Boles et al., 1991] do not differ in males with the childhood form from those in men with adrenomyeloneuropathy or other forms. No correlation exists between severity of the neurologic disease and levels of very long chain fatty acids. Antoku and colleagues [1991], however, reported that patients with childhood cerebral adrenoleukodystrophy had higher levels of very long chain fatty acids in mononuclear cells than did patients with adrenomyeloneuropathy, even though levels in plasma and erythrocytes demonstrated no difference. The inability to distinguish the various forms prospectively hampers genetic counseling and choice of therapeutic modalities. These observations have led to the conclusion that very long chain fatty acid excess alone is not sufficient to explain cerebral demyelination and that other factors must play a role in the phenotypic variability. The presence of the perivascular lymphocytic infiltration in the white matter of the cerebral forms provides evidence of immunologic involvement as one additional factor [Powers and Moser, 1998]. This is not seen in the adrenal gland or other leukodystrophies. Typing of the lymphocytic cells in brain from four patients with the cerebral form of adrenoleukodystrophy examined post mortem revealed 59% T cells, 34% T4 cells, 16% T8 cells, 24% B cells, and 11% monocytes [Griffin et al., 1985]. This pattern is similar to that found during a cellular immune response in the central nervous system. Bernheimer and co-workers [1983] reported increased levels of IgG and IgA in brain from patients with adrenoleukodystrophy, similar to that in patients with multiple sclerosis. Boutin and associates [1989] suggest that interleukin-2 plays an important role. McGuinness and colleagues [1995] demonstrated an elevation in tumor necrosis factor-α (TNF-α) in the leading edge of areas of active demyelination. The collective evidence implies that an immunologic mechanism contributes to the rapid progression of white matter lesions, possibly in response to the altered lipid composition in brain of patients with adrenoleukodystrophy. Segregation analyses suggest the existence of a modifier gene that potentially affects this immune response [Smith et al., 1991]. Further studies in this area may identify factors that contribute to the pathogenesis of the nervous system lesions.

Therapies for Adrenoleukodystrophy The two forms of therapy under intensive investigation are dietary restriction and bone marrow transplantation. Based on the observations of Kishimoto and co-workers [1980] that the very long chain fatty acids accumulating in the brain of patients with adrenoleukodystrophy were partly of dietary origin, a diet that restricted very long chain fatty acid intake was developed [Brown et al., 1982; Van Duyn et al., 1984]. This diet had no effect on the levels of plasma very long chain fatty acids or on the clinical course. Rizzo and associates [1986] reported that cultured skin fibroblasts synthesized saturated very long chain fatty acids including C26:0, and that the rate of this synthesis was reduced by the addition of monounsaturated fatty acids, such as oleic acid. As saturated and monounsaturated fatty acids are elongated to very long chain fatty acids by the same microsomal elongation system, presumably the addition of oleic acid reduces synthesis of saturated very long chain fatty acids by competing for the same enzyme system [Bourre et al., 1976].

Raymond, Naidu, and Moser / Peroxisomal Disorders

These findings led to clinical trials with oral glyceryl trioleate in combination with dietary restriction of very long chain fatty acids. This dual therapy achieved a 50% redution of the levels of saturated very long chain fatty acids in plasma, as well as a statistically significant improvement in peripheral nerve function in patients with adrenomyeloneuropathy [Moser et al., 1991a; Rizzo et al., 1987]. Subsequently, erucic acid (C22:1) was demonstrated to be more effective in reducing synthesis of saturated very long chain fatty acids; therefore, glyceryl trioleate was combined with glyceryl trierucate. A dramatic normalization of the level of C26:0 in plasma occurred within a month [Moser et al., 1995; Rizzo et al., 1989], and the microviscosity of the red cell membranes returned to normal [Knazek et al., 1983]. Unfortunately, this regimen does not alter the course of the childhood cerebral form of adrenoleukodystrophy [Uziel et al., 1990]. In open, uncontrolled studies, the effects on the clinical course of the adult form have been uncertain but generally unimpressive [Aubourg et al., 1993; Kaplan et al., 1995]. Further studies are planned in presymptomatic males; controlled studies, in men with adrenomyeloneuropathy. Symptomatic heterozygotes have been managed with glyceryl trioleate/ glyceryl trierucate and dietary restriction therapy without significant improvement, as in their male counterparts. Prophylactic treatment is not recommended for asymptomatic heterozygotes. The results of bone marrow transplantation in mildly affected patients are encouraging [Aubourg et al., 1990; Lockman et al., 1993; Loes et al., 1994; Peters et al., 2004]. In patients with more advanced disease, transplantation has not resulted in halting the course and may be associated with worsening of the neurologic status immediately after the procedure; therefore, this procedure is not advised [Moser et al., 1984b; Weinberg et al., 1988]. In patients with advanced disease, neither dietary therapy nor bone marrow transplantation is effective. Immunosuppression with cyclophosphamide did not arrest the rapid progression of the illness [Naidu et al., 1988a; Stumpf et al., 1981]. Males at risk for developing the childhood form of X-linked adrenoleukodystrophy (younger than 10 years of age) require appropriate monitoring. MRI should be performed on a yearly basis. Because MRI abnormalities become evident at least 12 months before onset of neurologic symptoms, periodic neurologic examination is not sufficient for monitoring these patients. Timely assessments are especially important because the best outcomes with bone marrow transplantation are in patients identified at an early stage of cerebral disease. Appropriate adrenal monitoring also is indicated in identified patients.

Contiguous Deletion of the XALD Gene Corzo and co-workers identified three males in the newborn period who demonstrated abnormalities suggestive of a defect of L-bifunctional enzyme [Corzo et al., 2002]. Very long chain fatty acids were elevated; other findings included hypotonia and liver disease. All three patients died in the first year of life. Further investigation demonstrated large deletions of ABCD1 including the promoter region, with extension of these 5′ deletions into contiguous genes including the DNA marker DXS1356E. The investigators proposed

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the name “contiguous ABCD1 DXS1357E deletion syndrome” (CADDS) for this phenotype. The specific role of the additional genetic areas is uncertain at present. Two of the mothers were determined to be carriers for these deletions, indicating the importance of correct diagnosis of single-enzyme defects of peroxisomal β-oxidation.

Acyl-CoA Oxidase Deficiency Two siblings and an unrelated female patient have been reported to have acyl-CoA oxidase deficiency [Kyllerman et al., 1990; Poll-The et al., 1988a]. A large deletion of the gene encoding this enzyme was reported in the siblings [Fournier et al., 1994]. Dysmorphism, hypotonia, feeding difficulties, and intractable neonatal seizures were the presenting features. Little motor or cognitive development occurred in the first 2 years of life. Ocular involvement with extinguished electroretinography and white matter involvement with abnormal contrast enhancement were present. Adrenal insufficiency was not evident, but elevated serum adrenocorticotropic hormone and low cortisol levels were present in one patient. No organomegaly was present. Although the clinical characteristics resembled those in the milder forms of peroxisome biogenesis disorders, the following two features distinguished it from the Zellweger spectrum disorders: (1) peroxisomes in the liver were abundant and appeared larger than normal; (2) except for increased levels of very long chain fatty acids in the range of values consistent with Zellweger’s syndrome, all other peroxisomal function studies, such as levels of phytanic acid, pipecolic acid, bile acid intermediates, and plasmalogen levels, were normal. Immunoblot studies revealed absence of acyl-CoA oxidase in the liver, and other peroxisomal β-oxidation enzymes were normal [PollThe et al., 1988a]. Cultured skin fibroblasts had a reduced capacity to oxidize lignoceric acid and peroxisomal palmitoylCoA oxidase. The first prenatal diagnosis of isolated acyl-CoA oxidase deficiency was made by Wanders and colleagues [1990b]. In amniotic fluid, measurements of very long chain fatty acids were significantly elevated, but levels of bile acid intermediates were normal. In amniocytes, very long chain fatty acids were markedly increased, but plasmalogen biosynthesis was normal. Immunoblot analysis of amniocytes and the aborted fetal liver tissues demonstrated that all components of acyl-CoA oxidase were absent, whereas the bifunctional protein and mature form of thiolase were normal.

Bifunctional Enzyme Deficiency Watkins and colleagues [1988] described a patient without dysmorphism or organomegaly who had significant hypotonia and neonatal seizures. Mental retardation was severe, and death occurred at 51/2 months. Neuropathologic abnormalities included polymicrogyria and focal cortical heterotopias, similar to those in peroxisome biogenesis disorders [Kaufmann et al., 1996; Naidu et al., 1988b]. The liver had normal-appearing peroxisomes. Biochemical studies revealed elevation of very long chain fatty acids and bile acid intermediates; all other peroxisomal functions were normal. Postmortem immunoblot studies of liver demonstrated the absence of the bifunctional protein; other peroxisomal β-oxidation enzymes were present. The mRNA for the bifunctional pro-

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tein was normal, indicating defective translation of the mRNA or abnormal post-translational processing, such as defective peroxisomal import mechanisms. Although bifunctional enzyme deficiency bears some clinical resemblance to the acyl-CoA deficiency with elevation of very long chain fatty acids, a significant difference is the additional accumulation of bile acid intermediates (trihydroxycholestanoic acid) as well [Watkins et al., 1995]. The reason for trihydroxycholestanoic acid accumulation is evident in Figure 29-1, which demonstrates that the initial oxidation step for bile acid intermediates and very long chain fatty acids occurs by separate enzymes, whereas the subsequent step at the level of the bifunctional enzyme is common to both systems. Another patient with similar clinical features was found to have a functionally inactive bifunctional protein, although immunologic studies revealed normal amounts of the enzyme [Wanders et al., 1990c]. This patient is presumed to have a different mutation from the one described previously.

3-Oxoacyl-CoA Thiolase Deficiency The entity 3-oxoacyl-CoA thiolase deficiency was first described by Goldfischer and co-workers in 1986 and called pseudo-Zellweger syndrome because of the presence of normal peroxisomes in the liver despite a clinical resemblance to Zellweger’s syndrome. Biochemically, the levels of very long chain fatty acids and bile acid intermediates were increased, but phytanic acid level was normal. A reexamination of material from one of these cases demonstrated that the infant in fact had a defect in bifunctional enzyme. The clinical existence of a thiolase deficiency is therefore not proved [Ferdinandusse et al., 2002].

Trihydroxycholestanoic Acid-CoA Oxidase Deficiency Christensen and associates [1990] described an unusual female patient who demonstrated normal development until 18 months of age, when she deteriorated, with clinical manifestations including ataxia, dysarthria, and dry skin. By 5 years of age, she was severely incapacitated, with hearing loss and mental retardation. She had at this stage normal findings on CT scan, absence of retinal degeneration, and normal liver function and nerve conduction velocities. Because the phytanic acid level was elevated, she was placed on a diet low in phytanate, after which she demonstrated significant improvement in gait, hearing, and speech. The most prominent biochemical abnormality, however, was an elevation in bile acid intermediates with normal very long chain fatty acid concentration, presumed to be secondary to a defect in trihydroxycholestanoic acid-CoA oxidase. Because phytanic acid oxidase levels were normal in cultured fibroblasts, the elevation in phytanic acid is believed to result from inhibition of phytanate oxidation by the accumulating bile acid intermediates.

Peroxisomal ␣-Methylacyl-CoA Racemase Defect Several patients with adult-onset neurologic findings including spasticity, sensory motor neuropathy, seizures, and retinitis pigmentosa have been described. Very long chain fatty acid

levels were normal, but elevations in C27 bile acid intermediates and pristanic acid were found. Phytanic acid was mildly elevated. Because pristanic acid β-oxidation was reduced, the activity of α-methylacyl-CoA racemase (AMACR) was examined and found to be deficient. AMACR is involved in the interconversion of (R)- and (S)-stereoisomers of αmethyl branched-chain fatty acyl-CoA esters, including pristanoyl-CoA, and the interconversion of the CoA esters of dihydroxycholestanoic acid and trihydroxycholestanoic acid. Its physiologic function is to produce the (S)-stereoisomers because only these serve as substrate for branchedchain acyl-CoA oxidase [Ferdinandusse et al., 2000].

Single-Enzyme Defects of Plasmalogen Synthesis Patients with defects in acyl-dihydroxyacetone phosphate transferase [Wanders et al., 1992] or alkyl-dihydroxyacetone phosphate synthase [Wanders et al., 1994] have a marked deficiency of plasmalogens. They differ from patients with defects of PEX7 because they metabolize phytanic acid and process thiolase normally. In most instances, however, the clinical picture resembles that in rhizomelic chondrodysplasia punctata. This similarity has led to the consideration that all of the clinical abnormalities in rhizomelic chondrodysplasia punctata are attributable to a deficiency of plasmalogens. Isolated dihydroxyacetone phosphate-AT deficiency also may manifest with a milder phenotype of rhizomelic chondrodysplasia punctata [Clayton et al., 1994].

Acatalasemia Acatalasemia demonstrates clinical heterogeneity, with presentations ranging from absence of symptoms (in the Swiss variant) to oral ulcers, presumed to be secondary to peroxidegenerating bacteria, in a severe Japanese variant. The Japanese patients have greatly reduced catalase activity; however, the electrophoretic mobility of the residual enzyme is normal. By contrast, the symptom-free patients with the Swiss variant have a large amount of catalase, but it demonstrates greaterthan-normal heat lability. Studies by Crawford and colleagues [1988] report that the Japanese variant involves a regulatory mutation in which the gene is not transcribed, whereas in the Swiss variant, a structural mutation renders the enzyme unstable. The human catalase gene has been localized to 11p13 and cloned [Junien et al., 1980; Quan et al., 1986].

Hyperoxaluria Type I Primary hyperoxaluria type I is inherited as an autosomalrecessive trait. Clinical onset is in childhood or adolescence. Patients present with urolithiasis and renal failure. Increased urinary excretion of oxalate (more than 50 mg/1.73 m2 of body surface per day), glycolate (more than 70 mg/1.73 m2 per day), and occasionally glyoxylate is diagnostic. In 1986, Danpure and Jennings demonstrated that the enzyme alanine-glyoxalate aminotransferase, which converts glyoxylate to glycine, is deficient in patients with this disorder [Danpure and Jennings, 1986]. Latta and Brodhel [1990] noted that this disorder accounted for 2% to 2.7% of children with end-stage renal disease. In human liver, this enzyme is peroxisomal [Danpure and Jennings, 1986], and the activity varies in affected patients, correlating with the sever-

Raymond, Naidu, and Moser / Peroxisomal Disorders

ity of the disease [Danpure and Jennings, 1988]. A milder pyridoxine-responsive form of the disease has a less severe reduction of the enzyme [Wanders et al., 1988b]. Liver biopsy establishes the enzyme defect, but peroxisomes are present and intact in the liver [Iancu and Danpure, 1969]. The functions of other peroxisomal enzymes are normal. Danpure and associates [1989a] and Cooper and co-workers [1988] noted that in one third of the patients with diminished but not absent alanine-glyoxalate aminotransferase, the enzyme is misdirected to the mitochondrion, instead of its normal localization in humans to the peroxisome. The alanine-glyoxalate aminotransferase cDNA has been sequenced from eight patients with hyperoxaluria type I in whom the alanineglyoxalate aminotransferase was localized to the mitochondrion, and three new mutations were identified. One of these encoded a glycine-to-arginine substitution at residue 170 and was unique to these patients, but the two other mutations also were present in 5% to 10% of the control population [Purdue et al., 1990]. Nishiyama and colleagues [1991] have reported a point mutation encoding a serine to proline mutation at residue 205 in a patient in whom alanine-glyoxalate aminotransferase activity was nearly absent and who thus differed from the other group. Diagnosis is established by the demonstration of deficient alanine-glyoxalate aminotransferase activity in a liver biopsy specimen [Danpure and Jennings 1986; Danpure et al., 1987]. Prenatal diagnosis has been achieved by second-trimester fetal liver biopsy [Danpure et al., 1989b] and, in the future, could be achieved by DNA analysis of amniocytes or chorionic villus sampling. The estimated incidence of this disorder is 1 in 5 million to 15 million children; family studies demonstrate an increased incidence of parental consanguinity [Latta and Brodhel, 1990]. An exciting therapeutic advance has been a combination of liver and kidney transplantation with extremely favorable results [McDonald et al., 1989; Morgan and Watts, 1989; Ruder et al., 1990; Watts et al., 1987]. Some of the mildly affected patients respond to pyridoxine [Wanders et al., 1988b; Watts et al., 1979]. MacCollin and associates [1991] have described a patient with normal intelligence, ataxia, peripheral neuropathy, and calcium oxalate stones. Peroxisomes were absent. A marked increase in very long chain fatty acid and pipecolic acid was documented, with catalase present in the cytosolic fraction. This patient’s case is the only recorded case of hyperoxaluria in association with abnormal peroxisome biogenesis and multiple peroxisomal enzyme involvement.

Peroxisomal Glutaryl-CoA Oxidase Deficiency The first patient with peroxisomal glutaryl-CoA oxidase deficiency was identified at 11 months, when the child was presented for failure to thrive and vomiting (in particular, postprandial vomiting), by Bennett and colleagues [1991]. Urinary glutaric acid level was 500 mmol per mole of creatinine, whereas the normal level is less than 2 mmol. The glutaricaciduria was responsive to riboflavin 200 mg given twice daily. At the age of 5 years 8 months, the patient was judged to be developmentally normal, although this outcome may have been attributable to the vitamin therapy. Detailed metabolic investigations ruled out glutaricaciduria types I and II. The activity of peroxisomal glutaryl-CoA oxidase was reduced to less than 10% of control values. Of

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interest, loading studies demonstrated that the glutaric acid was derived from lysine, presumably through the same pathway in which pipecolic acid is an intermediate. This case represents a peroxisomal cause of glutaricaciduria distinct from the well-known mitochondrial disorders resulting in glutaricaciduria types I and II.

Classic Refsum’s Disease Classic Refsum’s disease is a rare disorder, originally described by Refsum [1946], of autosomal-recessive inheritance characterized by retinitis pigmentosa, peripheral polyneuropathy, cerebellar ataxia, and increased cerebrospinal fluid protein. Biochemical identification is by the increased plasma levels of phytanic acid with normal pristanic acid. In this condition, the capacity for hydroxylation of phytanoylCoA has been lost. Low phytanic acid oxidation also is seen in human cells lacking PEX7, the receptor for PTS2, suggesting that the enzyme defective in Refsum’s disease is targeted to peroxisomes by a PTS2. The enzyme deficiency of phytanoyl-CoA hydroxylase A and the gene defect in this disease have been identified conclusively [Jansen et al., 1997; Mihalik et al., 1997] and is the primary cause of adult Refsum’s disease. The gene PAHX is localized to chromosome 10, and patients with Refsum’s disease are homozygous for inactivating mutations in PAHX. It must be emphasized, however, that a substantial number of adult patients with the same phenotypic features have now been identified as having mutations in PEX7 [Jansen et al., 1997], and mutational analysis is required for definitive diagnosis. Therapy consists of restriction of dietary phytanic acid and symptomatic treatment.

Mulibrey Nanism Mulibrey nanism is a rare disorder of autosomal-recessive inheritance that manifests with prenatal and postnatal growth failure, hepatomegaly, pericardial constriction, and characteristic facial features. Mulibrey stands for “muscle-liverbrain-eye,” and features of this disorder include yellow dots on the fundi, muscular weakness, enlarged cerebral ventricles, increased incidence of Wilms’ tumor, and cutaneous nevus flammeus [Kallijarvi et al., 2002; Lapunzina et al., 1995]. Patients have normal intelligence. It is more common in the Finnish population. Mulibrey nanism is due to defects in TRIM37 located on 17q22-q23. This gene encodes RING-B-box-coiled-coil protein which is localized to the peroxisome. Patients with TRIM37 mutations do have normal peroxisome morphology, and other PTS1-containing matrix proteins are not affected. No abnormality is seen in very long chain fatty acid concentration or other biochemical measures. TRIM37 apparently lacks a PTS1 signal, but uptake of this protein was lacking in cell lines defective for PEX1 and PEX5. The exact role in peroxisomal function is not known at present [Avela et al., 2000; Kallijarvi et al., 2002].

CURRENT AND FUTURE OUTLOOK With expanding clinical phenotypes, peroxisomal disorders are now included as standard considerations in the

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differential diagnosis for a variety of neurologic findings in infants, children, and adults. As new peroxisomal functions are being identified, they have provided insight into mechanisms involving biogenesis of the organelle and control of protein import. Their vital role encompassing neuronal migration in fetal brain development through membrane integrity in the axons in adults is being appreciated. All of the disorders can be recognized by noninvasive biochemical and genetic tests, providing valuable information for genetic counseling. These disorders may be severely debilitating or fatal, but therapeutic options are becoming available.

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CHAPTER 30

Diagnosis and Treatment of NeurotransmitterRelated Disorders Kathryn J. Swoboda

The term neurotransmitter disorders constitutes a broad and increasingly complex spectrum of neurologic conditions associated with defects in the production, transport, release, and re-uptake of a variety of chemical compounds involved in neurotransmission. This chapter provides an overview of such disorders, with an emphasis on those disorders associated with a dopamine or serotonin deficiency state. Neurologic symptoms associated with dopamine deficiency are broad and range from extremely mild and subtle alterations in mood or gait to a classic exercise-induced dystonic gait abnormality and an infantile-onset parkinsonism syndrome. In recessive inborn errors of dopamine metabolism associated with tetrahydrobiopterin (BH4) deficiencies, neurologic symptoms are often more severe and accompanied by hyperphenylalaninemia, which can be detected on newborn screening. Associated serotonin deficiency is present in most of these disorders. Even when these disorders are ascertained by newborn screening, repletion of neurotransmitter precursors may not be sufficient, resulting in global developmental impairment, fluctuating tone abnormalities, eye movement abnormalities, encephalopathy, ataxia, and seizures. Screening for this group of disorders occurs primarily by recognition of key neurologic symptoms. For example, symptoms such as exercise-induced dystonia and childhoodonset parkinsonism have a greater likelihood of an associated dopamine deficiency state. However, the wide spectrum of phenotypes associated with dopamine deficiency states and overlap with other disorders with shared features can make accurate identification and diagnosis of these disorders challenging. The routine availability of increasingly more sophisticated diagnostic tools, including cerebrospinal fluid neurotransmitter metabolite studies, cerebrospinal fluid and urine pterin studies, neuroimaging studies, phenylalanine loading studies, enzymatic assays in blood cells or skin fibroblasts, and molecular studies, has greatly increased our ability to accurately diagnose and treat patients in a timely fashion. For ease of classification, these disorders can be divided into four groups: (1) neurotransmitter deficiency states with hyperphenylalaninemia, (2) neurotransmitter deficiency states without hyperphenylalaninemia, (3) secondary neurotransmitter deficiency states, and (4) disorders of neurotransmitter metabolism (Table 30-1).

NEUROTRANSMITTER DEFICIENCY STATES WITH HYPERPHENYLALANINEMIA Overview The neurotransmitter deficiency in infants in this group arises as a result of defects in BH4 metabolism (Fig. 30-1).

Patients are usually identified by elevated phenylalanine levels on newborn screening, as BH4 is required for phenylalanine hydroxylation in the liver. The accompanying neurotransmitter deficiency results from the lack of BH4, an obligatory cofactor required for the synthesis of catecholamines and serotonin. Although most academic biochemical genetics clinics that monitor children with phenylketonuria systematically perform the additional studies required to diagnose this group of disorders, children occasionally are not identified until they have progressive neurologic symptoms or clear evidence of developmental delay despite a phenylalaninerestricted diet. In the past, these patients were referred to as atypical phenylketonurics. In some cases, such infants are missed because screening is performed before an adequate interval of protein intake, resulting in a false-negative result on newborn testing. Approximately 1% to 3% of patients with hyperphenylalaninemia have an associated BH4 deficiency state. It is critical to identify such children so that BH4 and neurotransmitter precursors can be supplemented as early as possible. The two most commonly identified disorders in children presenting with hyperphenylalaninemia in the newborn period are 6-pyruvoyltetrahydropterin synthase deficiency and dihydropteridine reductase deficiency. 6-Pyruvoyltetrahydropterin synthase deficiency results in inadequate BH4 synthesis; dihydropteridine reductase deficiency results in decreased regeneration of BH4 from dihydrobiopterin (see Fig. 30-1). Both are autosomal-recessive disorders in which hyperphenylalaninemia results from a deficiency of BH4. Because of the involvement of BH4 in catecholamine and serotonin synthesis, such infants also have a manifest deficiency of neurotransmitter metabolites in addition to hyperphenylalaninemia. Other conditions in this category include autosomal-recessive guanosine triphosphate cyclohydrolase deficiency and primapterinuria.

Role of BH4 in the Central Nervous System Because BH4 is required for the hydroxylation of aromatic amino acids, its importance in the CNS becomes immediately apparent. Tyrosine and tryptophan are required for the synthesis of catecholamines and serotonin. A BH4dependent process can be strongly suspected when plasma phenylalanine levels return to normal after BH4 supplementation. A dose of 5 mg/kg of BH4 is the usual recommended dose for correction of peripheral hyperphenylalaninemia. Because BH4 crosses the blood-brain barrier poorly, lifelong supplementation with the neurotransmitter precursors L-dopa and 5-hydroxytryptophan, along with carbidopa to enhance CNS delivery, is necessary in most of the disorders mentioned earlier. A much higher dose

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Genetic, Metabolic, and Neurocutaneous Disorders / 30

TABLE 30-1 Primary Neurotransmitter Deficiency Disorders DISORDER Elevated Plasma Phenylalanine 6-Pyruvoyltetrahydrobiopterin synthase deficiency* Dihydropteridine reductase deficiency* GTP cyclohydrolase deficiency* Primapterinuria

PHENOTYPIC FEATURES

LOCUS

INHERITANCE

Encephalopathy, dystonia, spasticity, axial hypotonia, autonomic symptoms, oculogyric crises, seizures

11q22.3-23.3

AR

4p15.31 14q22.1-22.2 10q22

AR AR AR

14q22.1-22.2

AD

7p11

AR

2p14p12

AR

11p15.5

AR

11p15.3

AR

9q34 Xp11.23

XR

6p22

AR

Benign hyperphenylalaninemia

Normal Plasma Phenylalanine GTP cyclohydrolase deficiency*

Exercise-induced dystonia, gait disorder, writer’s cramp, restless leg syndrome, tremor Dystonia, spasticity, torticollis, axial hypotonia, limb rigidity, autonomic symptoms, psychomotor retardation, oculogyric crises Parkinsonian symptoms, psychomotor retardation, behavioral disturbances Gait disturbance, infantile parkinsonism, dystonia, speech delay Ataxia, speech delay, hypotonia, psychomotor retardation Orthostatic hypotension, lethargy, ptosis Mild mental retardation, tendency for violent or aggressive behavior Psychomotor retardation, ataxia, seizures

Aromatic L-amino acid decarboxylase deficiency* Sepiapterin reductase deficiency* Tyrosine hydroxylase deficiency* Tryptophan hydroxylase deficiency* Dopamine β-hydroxylase deficiency* Monoamine oxidase A deficiency Succinic semialdehyde dehydrogenase deficiency

*Disorder associated with a dopamine deficiency state. AD, autosomal dominant; AR, autosomal recessive; GTP, guanosine triphosphate; XR, X-linked recessive.

GTP GTPCH Neopterin

Dihydroneopterin triphosphate PTS 6-pyruvoyltetrahydropterin SPR

Arginine

Tyrosine

Phenylalanine

NOS

PAH

cit + NO·

TH

Tyrosine

3-O-MD DBH

DHPR qBH2

TPH

L-DOPA

COMT

BH4

Tryptophan

PCD Pterin 4α-carbinolamine

5-HTP

AADC-B6 DOPAMINE MAO

NE

SEROTONIN

DOPAC

MAO

5-HIAA

HVA

MAO COMT EPI

Normetanephrine

DHPG

COMT

MHPG

VMA

FIGURE 30-1. Synthesis and catabolism of catecholamine and indoleamine neurotransmitters. AADC, aromatic L-amino acid decarboxylase; B6, pyridoxine; COMT, catechol O-methyltransferase; DBH, dopamine ß-hydroxylase; DHPR, dihydropteridine reductase; GTPCH, GTP cyclohydrolase; MAO, monoamine oxidase; NOS, nitric oxide synthase; PAH, phenylalanine hydroxylase; PCD, pterin-4α-carbinolamine dehydratase; PTS, 6-pyruvoyltetrahydropterin synthase; SPR, sepiapterin reductase; TH, tyrosine hydroxylase; TPH, tryptophan hydroxylase.

of BH4, approximately 20 mg/kg, can return BH4 levels in the cerebrospinal fluid to normal, but it remains prohibitively expensive, and no studies exist as to the possible additional benefit of such a regimen. The higher requirement of

tyrosine hydroxylase for BH4 in comparison with tryptophan hydroxylase may explain the more severe impairment in the catecholaminergic system compared with the serotonergic system.

Swoboda / Diagnosis and Treatment of Neurotransmitter-Related Disorders

Nitric oxide synthase is yet another enzyme with an absolute requirement for BH4 for the oxidation of arginine to nitric oxide. The inability to replete normal levels of BH4 in the CNS with oral administration in its currently used doses may be one reason that many children with BH4-deficient disorders develop lifelong cognitive and developmental impairments despite other treatments. Nitric oxide also plays a critical role in CNS neuroprotective mechanisms, and reduced efficiency of this enzyme may result in additional ongoing neuronal injury, cell death, and vascular dysregulation and injury.

6-Pyruvoyltetrahydropterin Synthase Deficiency 6-Pyruvoyltetrahydropterin synthase catalyzes the elimination of inorganic triphosphate from dihydroneopterin triphosphate to form 6-pyruvoyltetrahydropterin. Patients have elevated neopterin-to-biopterin ratios in urine and plasma. Reduced 6-pyruvoyltetrahydropterin synthase activity can be documented in red blood cells. In the classic form of the disorder, patients have reduced catecholamine and serotonin metabolites and an increased neopterin-to-biopterin level in cerebrospinal fluid. Patients are usually detected by newborn screening as phenylketonurics. They exhibit progressive signs of neurologic involvement in the first few months of life, including extrapyramidal signs, axial and truncal hypotonia, hypokinesia, feeding difficulties, choreoathetotic or dystonic limb movements, and autonomic symptoms. Many of these patients, despite early diagnosis and supplementation with BH4 and neurotransmitter precursors, continue to manifest delays in development [Dudesek et al., 2001]. A “peripheral” form of the disorder is characterized by normal central neurotransmitter levels and less significant or transient hyperphenylalaninemia [Niederwieser et al., 1987]. Patients with the peripheral form have an excellent prognosis for normal neurologic development, provided the hyperphenylalaninemia is corrected by diet or BH4 administration.

Dihydropteridine Reductase Deficiency Dihydropteridine reductase deficiency manifests in a variety of phenotypes, all with hyperphenylalaninemia. The clinical presentation is similar to that of 6-pyruvoyltetrahydropterin synthase deficiency. Without folinic acid to restore methyltetrahydrofolate status in the central nervous system (CNS), these patients can have progressive calcification of the basal ganglia and subcortical regions, despite treatment with BH4 and neurotransmitter precursors [Woody et al., 1989]. A juvenile variant has been reported in which siblings were developmentally normal until 6 years of age, at which time they developed progressive encephalopathy, epilepsy, and pyramidal, cerebellar, and extrapyramidal features on clinical examination [Larnaout et al., 1998]. Diagnosis can be confirmed by the pattern of urine pterins and documentation of abnormal dihydropteridine reductase activity in skin fibroblasts [Milstien et al., 1980]. Results of phenylalanine loading tests are abnormal, and phenylalanine status improves or returns to normal with BH4 supplementation. Cerebrospinal fluid neurotransmitter and pterin analysis reveals reduced concentrations of homovanillic acid and 5-hydroxyindoleacetic acid, decreased or normal BH4 levels, and elevated dihydrobiopterin levels.

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Autosomal-Recessive Guanosine Triphosphate Cyclohydrolase Deficiency Although most mutations in guanosine triphosphate cyclohydrolase to date have been documented in association with autosomal-dominant dopa-responsive dystonia, or Segawa’s disease, these patients do not have hyperphenylalaninemia on routine plasma screening studies. Patients with the autosomalrecessive form of guanosine triphosphate cyclohydrolase deficiency, however, present in a fashion similar to patients with dihydropteridine reductase deficiency and 6-pyruvoyltetrahydropterin synthase deficiency. Such patients have severe global developmental impairment, marked hypotonia of the trunk and axial muscles, eye movement abnormalities, limb hypertonia, and convulsions; autonomic symptoms include temperature dysregulation, excessive diaphoresis, and blood pressure lability caused by the associated catecholamine deficiency. They typically have absent guanosine triphosphate cyclohydrolase activity in blood cells, liver, and skin fibroblasts. By contrast, patients with autosomal-dominant doparesponsive dystonia have preservation of some guanosine triphosphate cyclohydrolase activity in liver because of their heterozygous status, enough to maintain normal phenylalanine levels under usual circumstances. Cerebrospinal fluid neurotransmitter metabolite analysis reveals low concentrations of homovanillic acid and 5-hydroxyindoleacetic acid and low neopterin and biopterin levels.

Pterin-4α-Carbinolamine Dehydratase Deficiency (Primapterinuria) Pterin-4α-carbinolamine dehydratase deficiency, or primapterinuria, is a cause of mild hyperphenylalaninemia [Blau et al., 1988; Adler et al., 1992]. These infants are usually identified on newborn screening but generally have a benign course with normal development. Phenylalanine hydroxylase catalyzes the conversion of phenylalanine to tyrosine, during which BH4 is converted to the unstable carbinolamine 4α-hydroxytetrahydrobiopterin [Citron et al., 1993]. Carbinolamine dehydratase catalyzes the dehydration of carbinolamine to quinonoid dihydropterin (qBH2). The decreased rate of dehydration is responsible for the production of 7-biopterin in some mildly hyperphenylalaninemic individuals [Thony et al., 1988]. Urine studies reveal an excess of 7-substituted pterins, reduced biopterin levels, and an increased neopterin-to-biopterin ratio.

NEUROTRANSMITTER DEFICIENCY STATES WITHOUT HYPERPHENYLALANINEMIA Overview Neurotransmitter deficiency disorders not associated with hyperphenylalaninemia span an increasingly complex spectrum of clinical phenotypes, ranging from ataxia and mental retardation to spastic diplegia to exercise-induced dystonia. The lack of ascertainment by way of newborn screening and increasingly broad phenotypic spectrum make these disorders as a group much more challenging to recognize. Other than autosomal-dominant dopa-responsive dystonia, the remaining disorders in this category are all inherited

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in an autosomal-recessive fashion with the exception of monoamine oxidase A deficiency, a rare X-linked recessive disorder. In general, heterozygous carriers for mutations in this group do not have a discernible phenotype, with rare exceptions in tyrosine hydroxylase deficiency and combined monoamine oxidase A and B deficiency.

Segawa’s Disease or Autosomal-Dominant Dopa-Responsive Dystonia The most well described and widely identified entity among this group of disorders is autosomal-dominant dopa-responsive dystonia caused by guanosine triphosphate cyclohydrolase deficiency, or Segawa’s disease [Segawa et al., 1976]. Identification and treatment of this disorder can be extremely rewarding because patients often benefit greatly with directed treatment of the associated dopamine deficiency state [Harwood et al., 1994]. Patients with a classic presentation of exercise-induced dystonia are not difficult to recognize. This diagnosis should also be considered in patients with spastic diplegia, especially when significant fluctuation in gait or worsening gait at the end of the day is noted, and in patients with more atypical presentations, including writer’s cramp, asymmetric limb dystonia, tremor, or restless leg type symptoms. In patients with a classic presentation, many clinicians can make the diagnosis on a presumptive basis, after observing remission of symptoms with a trial of L-dopa/carbidopa. Although inheritance is autosomal dominant, penetrance is incomplete, and variable expressivity among family members with the same mutation is well documented [Steinberger et al., 1998]. For instance, one might see spastic diplegia, writer’s cramp, restless leg syndrome, and more typical exercise-induced dystonia phenotypes among different members of the same family. The female-to-male ratio in sporadic cases is 4:1, and investigators have confirmed increased penetrance of guanosine triphosphate cyclohydrolase I gene mutations in females [Ichinose et al., 1994; Furukawa et al., 1998]. Not surprisingly, mood and sleep disorders appear to be unusually prevalent in families with the disorder, although these issues have not been systematically studied. Preliminary data in an ongoing study of prospectively ascertained family members support an increased burden of attentional difficulties, anxiety, dysphoria, depression, and sleep disorders. Cerebrospinal fluid neurotransmitter metabolite and pterin studies are helpful in confirming the diagnosis in these patients and can help characterize the degree of associated dopamine and serotonin deficiency. Phenylalanine loading is also valuable in confirming a suspected diagnosis but is not specific to the disorder, as phenylketonuria heterozygotes also manifest delayed phenylalanine clearance. Guanosine triphosphate cyclohydrolase activity can be measured directly in skin fibroblasts. Cerebrospinal fluid analysis should be performed before institution of a treatment trial of L-dopa/ carbidopa because treatment results in increased levels of homovanillic acid and 3-O-methyldopa. The typical pattern in cerebrospinal fluid in dopa-responsive dystonia resulting from guanosine triphosphate cyclohydrolase deficiency is a low homovanillic acid level, normal or low 5-hydroxyindoleacetic acid level, and reduced BH4 level. Patients who

are heterozygous for a guanosine triphosphate cyclohydrolase mutation, despite their normal blood phenylalanine levels on routine screening, have abnormal phenylalanine metabolism if they are stressed by administration of an oral phenylalanine load. If cytokinestimulated fibroblast enzyme analysis of biopterin metabolism is not feasible or patients decline a cerebrospinal fluid examination and have an otherwise typical presentation, an oral phenylalanine loading test may be helpful in supporting the diagnosis. Phenylalanine is administered orally to the fasting patient at a dose of 100 mg/kg. Serum phenylalanine and tyrosine levels are obtained at baseline and 1, 2, and 4 hours after loading. An elevated phenylalanine-to-tyrosine ratio and delayed clearance of phenylalanine are typical in patients with guanosine triphosphate cyclohydrolase deficiency because BH4 levels are typically reduced. Gene sequencing is available for confirmation of diagnosis and may be a valuable adjunct to biochemical diagnostic studies, but it will not always detect gene deletions, which are fairly frequent in this disorder. Treatment with L-dopa/carbidopa leads to significant benefit or resolution of motor symptoms in the majority of patients with Segawa’s disease within a few weeks. However, compound heterozygotes or patients with longstanding or more severe motor manifestations, such as parkinsonism or long-standing spastic paraparesis, may require more careful titration of dosing, with gradual adjustment during a period of several months. Mood manifestations, such as depression and anxiety, often respond to L-dopa treatment to some degree, but some patients have additional benefit from directed treatment of their associated serotonin deficiency, either with the serotonin precursor 5-hydroxytryptophan or with a serotonin reuptake inhibitor.

Aromatic L-Amino Acid Decarboxylase or DopaDecarboxylase Deficiency Aromatic L-amino acid decarboxylase is a pyridoxinedependent enzyme that decarboxylates L-dopa and 5hydroxytryptophan to make dopamine and serotonin, respectively. Patients with this disorder typically present in the first few months of life with dystonia or intermittent limb spasticity, axial and truncal hypotonia, oculogyric crises, autonomic symptoms, and ptosis [Hyland et al., 1992]. Neonatal symptoms, including poor suck and feeding difficulties, ptosis, lethargy, and hypothermia, are common. Neurologic signs and symptoms are clearly evident within the first few months of life in all patients described to date. These patients demonstrate multisystemic involvement with a wide array of neurologic difficulties including problems with sleep, attention, emotional regulation, and cognitive function that extend well beyond their motor difficulties. As they get older, gross motor delays with fluctuating tone, ataxia, and expressive speech impairment are prominent features, even in the patients with the best outcomes. The phenomenology of the movement disorder is remarkably similar among the cases and not surprisingly shares a number of features in common with children with BH4 deficiency disorders, such as 6-pyruvoyltetrahydropterin synthase deficiency and dihydropteridine reductase deficiency,

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FIGURE 30-2. Episodic neurologic manifestations in aromatic L-amino acid decarboxylase deficiency. A, Ocular convergence spasm, ptosis, and orofacial dystonia. B, Torticollis and limb dystonia. C, Torticollis and limb rigidity.

A

B

and the autosomal-recessive form of guanosine triphosphate cyclohydrolase deficiency. Intermittent oculogyric crises and limb dystonia, generalized athetosis, and an overall paucity of voluntary movement become evident between 1 and 6 months of age. Tongue thrusting, ocular convergence spasm (Fig. 30-2), myoclonic jerks, and episodes of sudden loss of head control or episodes resembling flexor spasms are common and frequently lead to a clinical diagnosis of epilepsy. Oculogyric crises, orofacial dystonia, torticollis, limb tremor with attempted voluntary movement, and blepharospasm are often the most compelling evidence supporting a defect in dopaminergic transmission. Breathholding or apneic spells, paroxysmal sweating, nasal congestion, sudden respiratory or cardiorespiratory arrest, unresponsiveness associated with hypoglycemia, intermittent hypothermia, and feeding and gastrointestinal issues are manifestations of the often profound autonomic dysfunction these patients demonstrate [Swoboda et al., 2003]. Cerebrospinal fluid neurotransmitter metabolites demonstrate a characteristic pattern: low homovanillic acid and 5-hydroxyindoleacetic acid levels; markedly elevated 3-O-methyldopa, 5-hydroxytryptophan, and L-dopa; and normal biopterin and neopterin levels. Plasma L-dopa is markedly elevated. Urine catecholamines may be reduced or elevated [Abeling et al., 1998, 2000]. Although some children benefit in terms of the underlying movement disorder, treatment is complex, and these patients are vulnerable to an array of medication-related side effects. Instead of replacement of neurotransmitter precursors, as in the BH4 deficiency-related disorders, the use of neurotransmitter receptor agonists or strategies to hinder re-uptake or metabolism of endogenously produced neurotransmitters is necessary. Reported benefit has been noted in a subset of patients with monoamine oxidase inhibitors, dopamine receptor agonists, anticholinergic agents, pyridoxine, and, in rare cases associated with a defect in the gene encoding aromatic L-amino acid decarboxylase at the dopa-binding site, L-dopa [Swoboda et al., 1999]. However, in spite of a variety of treatment interventions directed at ameliorating the effects of the associated neurotransmitter deficiency state, overall clinical outcomes in aromatic L-amino acid decarboxylase deficiency remain poor. All patients have had some degree of cognitive impairment, and there is increasing evidence of a gender-dependent discrepancy in severity, with females demonstrating the most severe phenotypes [Pons et al., 2004].

C

Sepiapterin Reductase Deficiency Sepiapterin reductase catalyzes the (NADP) reduction of carbonyl derivatives, including pteridines, and plays an important role in BH4 biosynthesis. Somewhat surprisingly, the first identified cases had normal plasma phenylalanine and urine pterin levels [Bonafe et al., 2001]. Blau and colleagues have hypothesized that peripheral tissues can use alternative carbonyl, aldose, and dihydrofolate reductases to perform the last two steps in BH4 biosynthesis. Therefore, BH4 levels in the liver are likely to be normal, probably explaining the absence of hyperphenylalaninemia in these patients. In addition, it is likely that low dihydrofolate reductase activity in the brain allows accumulation of dihydrobiopterin that inhibits tyrosine and tryptophan hydroxylases and uncouples neuronal nitric oxide synthase, leading to neurotransmitter deficiency and neuronal cell death. Thus, identification of low cerebrospinal fluid neurotransmitter levels and the presence of elevated cerebrospinal fluid dihydrobiopterin is crucial for making the diagnosis in these patients. Few patients have been described to date [Blau et al., 2001; Bonafe et al., 2001]. Dystonic posturing, oculogyric crises, spasticity, tremor, and ataxia with recurrent falls were reported in one 9-year-old boy. He also had a depressed affect, aggressive behavior, and psychomotor retardation. Another child had psychomotor retardation, microcephaly, growth deficiency, spasticity, and dystonia. Blau and colleagues [2001] confirmed this diagnosis in a 22-year-old woman, with “cerebral palsy” and lifelong cognitive impairment and a gait disorder, who had been having increasing difficulties with head control, excessive fatigue, and dystonia with associated parkinsonian features (gait instability, hypophonia, and palilalia). She had significant diurnal variation of symptoms, with symptoms much worse in the evenings. She benefited greatly with supplemental 5-hydroxytryptophan and L-dopa/carbidopa but later discontinued both because of side effects. She continues to receive treatment with selegiline, a monoamine oxidase B inhibitor that prolongs the half-life of dopamine at the synapse. Cerebrospinal fluid neurotransmitter metabolite and pterin analysis reveals low levels of homovanillic acid and 5-hydroxyindoleacetic acid and high levels of biopterin and dihydrobiopterin. Diagnosis can be confirmed by documenting low sepiapterin reductase activity in skin fibroblast cultures.

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Tyrosine Hydroxylase Deficiency or AutosomalRecessive Dopa-Responsive Dystonia Tyrosine hydroxylase deficiency, sometimes referred to as autosomal-recessive Segawa’s disease, displays a diverse phenotype ranging from exercise-induced dystonia to progressive gait disturbance and tremor in childhood to severe infantile parkinsonism [Bodeau-Pean et al., 1999; De Lonlay et al., 2000; de Rijk–Van Andel et al., 2000]. A wide range of symptoms can be associated with tyrosine hydroxylase deficiency, with mild, moderate, and severe phenotypes. In the mildest cases, walking or running may be clumsy, but little else may be noticed, at least initially. Abnormal posturing may be evident when the child is stressed or later in the day. These symptoms may progress slowly as the child gets older. Sometimes, one side of the body may seem weaker, or the child may begin to toe-walk because of hamstring or heel-cord tightness. Sometimes these children are diagnosed with cerebral palsy; other times, they are simply considered clumsy or uncoordinated. Some children demonstrate attentional difficulties or mild articulation disorders. Essentially all children with mild symptoms are readily treated with medication. In moderately affected cases, children demonstrate an abnormal gait. Children may demonstrate dystonic posturing while walking or with attempts to walk on their heels or toes. Some children are ataxic or have significant spasticity. Speech delay may be present. Many of these children are diagnosed with cerebral palsy. Some demonstrate involuntary eye movement problems, characterized either by brief upward eye-rolling movements when they are fatigued or stressed or by frank oculogyric crises. The majority of these children have an excellent response to treatment, but full benefit may take many months. In the most severe cases, children are severely disabled and affected from early infancy. This is referred to as the infantile Parkinson’s disease variant. Infants may demonstrate muscle tightness and rigidity, arching, tremor and poor muscle control, and involuntary eye movements. They may have ptosis. They usually have speech delay and often demonstrate difficulties in feeding, chewing, or swallowing. Constipation is common. Whereas most children tend toward increased muscle tone and even rigidity, there are children who have generalized low muscle tone, with poor head control and inability to sit unsupported. They often demonstrate torticollis. They may have difficulty directing their hands to a toy, generating a flinging hand motion. Occasional children suffer from intermittent color changes, unexplained low body temperature or fevers, low blood glucose level, and difficulty regulating blood pressure. These symptoms are more likely to occur during another illness the child may be experiencing. Children in the more severely affected group of patients are more difficult to treat, and several medications may be needed to modulate symptoms. They are unusually vulnerable to side effects of dopaminergic agonists or precursors, which can result in excessive movement and irritability. Response may be slow, with some continued benefit during months to years, but it may not result in the complete resolution of all symptoms. Some children have had persistent mental retardation, encephalopathy, and motor disability in spite of directed treatment of their underlying dopamine deficiency state.

Low tyrosine hydroxylase activity results in significant cerebrospinal fluid catecholamine deficiency as demonstrated by low homovanillic acid concentrations; cerebrospinal fluid concentrations of 5-hydroxyindoleacetic acid, neopterin, and biopterin are normal. It is more difficult to distinguish these children from secondary neurotransmitter deficiency states because phenylalanine loading studies are normal, and enzymatic assays for confirmation of a suspected diagnosis are not presently available. Confirmation by molecular testing is extremely helpful, particularly in providing adequate counseling for parents about recurrence risks with future pregnancies. Children have a paucity of autonomic features, suggesting a compensatory peripheral mechanism, except in children with the severe infantile parkinsonism variant. In four patients whom the author has observed, including one patient with the severe infantile parkinsonism variant, peripheral plasma catecholamine levels have been normal, although reduced urine homovanillic acid levels have been noted. Caution should be taken to monitor blood glucose concentration in the setting of prolonged fasting, such as before a magnetic resonance imaging study. Patients variably respond to L-dopa/carbidopa, and some have complete reversal of symptoms. The exception to this is the patient with the severe infantile parkinsonism form. These patients sometimes tolerate L-dopa poorly, with excessive dyskinesia, irritability, and reflux, or have incomplete or inadequate response with regard to their motor manifestations of the disorder [Brautigam et al., 1999; Dionisi-Vici et al., 2000]. When diagnosis occurs late in such patients, motor development must be recapitulated, and continued slow improvement during months is to be expected. Typical features in infants affected by the severe infantile parkinsonism variant include rigidity, tremor, bradykinesia, oculogyric crises, and severe psychomotor delay. Treatment with L-dopa/carbidopa alone may lead to severe dyskinesias with marked on-off effects in such patients. Addition of dopamine agonists such as selegiline or anticholinergic agents like trihexyphenidyl can provide significant benefit and help promote the gradual ongoing attainment of motor skills and ability to ambulate independently, but such achievements may occur during years, rather than months or weeks, in the most severely affected patients. Whereas more mildly affected patients may tolerate 1 to 3 mg/kg of L-dopa per dose, two to four times per day, severely affected infants and younger children require L-dopa quantities as low as 0.2 mg/kg/dose. Breaking standard formulations of L-dopa/carbidopa into more than two doses per tablet is not advisable because the amount of carbidopa will then be insufficient to help enhance transport of L-dopa across the blood-brain barrier and to minimize peripheral side effects, such as nausea, reflux, decreased appetite, and vomiting. Carbidopa should be maintained at a minimum of approximately 1 mg/kg/dose up to 25 mg per dose, no matter the L-dopa requirement. Slow institution of small, compounded doses of L-dopa/carbidopa, along with selegiline (monoamine oxidase B inhibitor) and an anticholinergic agent such as trihexyphenidyl, may be more beneficial than L-dopa/carbidopa alone [Haussler et al., 2001]. Selegiline doses may also require compounding because low-dose formulations are not available for use in

Swoboda / Diagnosis and Treatment of Neurotransmitter-Related Disorders

infants. Frequent side effects of excessive dosing include eating disorders, nightmares, and insomnia. Dosing should be started in the range of 0.1 mg/kg and increased as tolerated. Patients with a mild form of the disorder, such as an isolated gait disorder or exercise-induced dystonia, respond well to monotherapy with L-dopa/carbidopa and rarely develop dyskinesia. Although inheritance to date in most families seems to be recessive, at least one family has been described in which the father of the affected proband had mild exercise-induced dystonia responsive to therapy, raising the possibility that tyrosine hydroxylase deficiency could present in an autosomal-dominant fashion in some families with a milder phenotype [Furukawa et al., 2001].

Tryptophan Hydroxylase Deficiency Tryptophan hydroxylase catalyzes the BH4-dependent hydroxylation of tryptophan to 5-hydroxytryptophan, which is then decarboxylated to form serotonin. Tryptophan hydroxylase expression is limited to certain cells in the CNS and periphery, including raphe neurons, pinealocytes, mast cells, mononuclear leukocytes, beta cells of the islets of Langerhans, and enterochromaffin cells of the gut. Patients with presumed tryptophan hydroxylase deficiency have been described, although it is not yet certain that their symptoms result from tryptophan hydroxylase deficiency [Raemaekers et al., 2001]. Clinical features, consisting of ataxia, speech delay, mild psychomotor retardation, and hypotonia, are nonspecific. Cerebrospinal fluid neurotransmitter metabolite and pterin studies demonstrate the expected low 5-hydroxyindoleacetic acid with normal homovanillic acid, neopterin, and biopterin levels. Mutations in the gene encoding tryptophan hydroxylase have not yet been identified.

Dopamine β-Hydroxylase Deficiency Dopamine β-hydroxylase is the enzyme that converts dopamine to norepinephrine. Presenting symptoms of this disorder have been largely attributed to the importance of this enzyme in postganglionic sympathetic neurons [Robertson et al., 1986]. Patients with severe deficiency of this enzyme, however, cannot synthesize norepinephrine, epinephrine, and octopamine in CNS or peripheral autonomic neurons. Dopamine acts as a false neurotransmitter for noradrenergic neurons. Neonates with dopamine βhydroxylase deficiency can have episodic hypothermia, hypoglycemia, and hypotension leading to early death. Survivors do fairly well until late childhood, when overwhelming orthostatic hypotension profoundly limits their activities. The hypotension can be so severe as to lead to convulsive syncope with recurrent clonic seizures [Robertson et al., 1991]. Most patients have been identified as young adults. Observation of severe orthostatic hypotension in a patient whose plasma norepinephrine/dopamine ratio is much less than 1 supports the diagnosis. Orthostatic hypotension, particularly after exercise, and ptosis are constant features. General lethargy and lassitude improve dramatically and blood pressure becomes normal with treatment with D,Lthreo-dihydroxyphenylserine, a synthetic amino acid that is converted to norepinephrine by aromatic L-amino acid

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decarboxylase. Whether these patients suffer from attention problems or other subtle cognitive deficits has not been adequately studied. Patients may undergo personality change, becoming more “aggressive” with treatment.

Monoamine Oxidase Deficiency Monoamine oxidase is a mitochondrial enzyme involved in the catabolism of biogenic amines. Monoamine oxidase A, the primary type in fibroblasts, preferentially degrades serotonin and norepinephrine. Monoamine oxidase B, the primary type in platelets and in the brain, preferentially degrades phenylethylamine and benzylamine. These enzymes are critical in the neuronal metabolism of catecholamine and indoleamine neurotransmitters. The genes are closely linked on the X chromosome, near the Norrie disease locus, and only affected boys have been identified to date [Schuback et al., 1999]. Comparisons of the neurochemical characteristics of previously described patients with combined monoamine oxidase A and B deficiency and selective monoamine oxidase A deficiency have led to an improved understanding of the roles of monoamine oxidase A and monoamine oxidase B in the metabolic degradation of catecholamines and other biogenic amines, including serotonin and the trace amines.

Monoamine Oxidase A Deficiency Brunner described a family with an X-linked nondysmorphic mild mental retardation and a tendency to aggressive or violent behavior including arson, attempted rape, exhibitionism, and attempted suicide [Brunner et al., 1993]. Urine studies revealed marked disturbance of monoamine metabolism. Normal platelet monoamine oxidase B activity suggested that the unusual behavior pattern in this family might be caused by isolated monoamine oxidase A deficiency, which was later confirmed by identification in all affected males of a point mutation leading to premature termination of the protein [Brunner et al., 1993]. Measurement of 3-methoxy-4-hydroxyphenylglycol, a metabolite of norepinephrine, in plasma is the most sensitive index of monoamine oxidase A activity in humans and can be used to screen potential cases. Monoamine oxidase A enzyme activity can be measured directly from fibroblasts. The inability to identify additional patients despite screening of at-risk males with mental retardation or a behavioral phenotype makes it likely that this disorder is rare [Segawa et al., 1976]. Interestingly, a high-activity monoamine oxidase A promoter allele has been found with increased frequency in women with panic disorder [Deckert et al., 1999]. A possible association of decreased enzyme activity in women with bipolar disorder has also been reported [Preisig et al., 2000].

Monoamine Oxidase B Deficiency Isolated monoamine oxidase B deficiency has not yet been reported in a patient. Two brothers with a microdeletion including the Norrie locus and monoamine oxidase B, however, had features consistent with Norrie’s disease alone, with congenital blindness and progressive hearing loss caused by cochlear degeneration in adolescence. These patients had

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neither abnormal behavior nor mental retardation, leading the authors to conclude that monoamine oxidase A plays a more significant role than does monoamine oxidase B in the metabolism of biogenic amines, and monoamine oxidase B deficiency alone may have a primarily neurochemical phenotype: that of increased phenylethylamine in urine [Lenders et al., 1996].

Monoamine Oxidase A and B Deficiency Conclusions about the phenotype of individuals with combined deficiency of monoamine oxidase A and monoamine oxidase B come primarily from a study of a single boy with a microdeletion at Xp14 involving the Norrie locus and documented severe deficiency of monoamine oxidase A and B activity [Collins et al., 1992]. He was severely mentally retarded and blind, and he had other neurologic features including myoclonus and tendency for motor stereotypies. Because Norrie’s disease is an X-linked recessive disorder, obligate carriers would not be expected to have symptoms. In this family, two obligate carriers had normal intelligence. The proband’s mother had psychiatric symptoms characterized by “chronic hypomania and schizotypal features,” however, and both carriers had low monoamine oxidase activity.

Succinic Semialdehyde Dehydrogenase Deficiency Succinic semialdehyde dehydrogenase deficiency is an autosomal-recessive inborn error of metabolism associated with a defect in the metabolism of γ-aminobutyric acid [Gibson et al., 1998]. Phenotypic features range from nonspecific global developmental delay and hypotonia to ataxia, severe mental retardation, visual impairment, and seizures. Urine organic acid screening to detect elevated 4-hydroxybutyric acid is the most easily available screening strategy, but γ-aminobutyric acid levels in cerebrospinal fluid and urine are also elevated. Improvement of seizures in a mouse model of the disorder was demonstrated with treatment with vigabatrin or a γ-aminobutyric acid B receptor antagonist [Hogema et al., 2001]. The relevance of these findings to treatment of patients, if any, is not yet known.

SECONDARY NEUROTRANSMITTER DEFICIENCY STATES Menkes’ disease is an X-linked recessive disorder in which affected males have progressive encephalopathy, spasticity, seizures, and sparse, brittle hair. The primary defect is reduced or absent function of the copper-transporting ATPase ATP7A. Multiple copper-dependent enzymes can be secondarily affected, including dopamine β-hydroxylase, leading to secondary autonomic involvement and norepinephrine deficiency. Hyperekplexia, or “startle disease,” is a heterogeneous disorder caused by defects in the a1 subunit of the glycine receptor [Shiang et al., 1993]. The disorder occurs in autosomal-dominant and autosomal-recessive forms and is characterized predominantly by stimulus-sensitive myoclonus. Transient hypertonia and hypokinesia in infancy in some families with the disorder has led to the designation “stiff baby syndrome.” Dubowitz and colleagues [1992] described

an infant with classic startle disease in whom the cerebrospinal fluid concentrations of γ-aminobutyric acid were substantially lower than normal during the first weeks of life. Infants with hyperekplexia have higher than expected rates of sudden infant death syndrome. Later in life, patients develop involuntary myoclonus, markedly hyperactive brainstem reflexes, and a momentary generalized jerking on falling asleep. An exaggerated startle response persists throughout life; sudden, unexpected acoustic or tactile stimuli can precipitate a brief attack of intense rigidity with falling. Congenital dislocation of the hip and inguinal and abdominal hernias, presumably caused by increased intra-abdominal pressure, are more frequent in affected families. Dramatic improvement of symptoms occurs in most patients with clonazepam. Neurodegenerative disorders associated with ongoing cell loss are sometimes associated with reductions in neurotransmitter metabolites. Such abnormalities have been seen in patients with leukodystrophy and progressive encephalopathy phenotypes in which a primary defect in neurotransmitter or pterin metabolism could not be identified. Certain patients may still benefit from directed treatment of the underlying neurotransmitter deficiency. For example, in one young patient with an otherwise undefined leukodystrophy, supplementation with L-dopa/carbidopa markedly ameliorated his lower limb spasticity. Nonetheless, he continued to have progressive neurologic involvement with time. Periods of hypoxia or ischemia can lead to secondary deficiencies of serotonin and dopamine as demonstrated by low levels of homovanillic acid and 5-hydroxyindoleacetic acid in cerebrospinal fluid. In addition, BH4 levels are low and neopterin levels can be elevated. This presents a confusing pattern that mimics the metabolite profile observed in 6-pyruvoyltetrahydropterin synthase deficiency. The absence of hyperphenylalaninemia and the presence of signal abnormalities in the basal ganglia, thalamus, and cortex consistent with hypoxic-ischemic encephalopathy allow differentiation.

UNDEFINED NEUROTRANSMITTER DEFICIENCY STATES Increasingly, with more widespread testing of cerebrospinal fluid neurotransmitter metabolites, patients are being identified with documented neurotransmitter deficiency states that do not fit easily into any of the preceding diagnostic categories, and the nature of their underlying defects remains unknown. These include patients with a wide variety of movement disorder phenotypes, encephalopathy, or seizures. Additional studies are needed to determine the precise defects affecting neurotransmitter levels and to ascertain whether they are primary or secondary. In addition to neurotransmitter deficiency, excess levels of neurotransmitter metabolites have also been seen in some cases. The etiology in these patients remains uncertain at this time, but it may imply an underlying receptor defect, with secondary upregulation. A careful history of medications or herbal supplements is important because some agents, such as serotonin re-uptake inhibitors, could theoretically increase serotonin metabolite levels. Overall, cerebrospinal fluid neurotransmitter metab-

Swoboda / Diagnosis and Treatment of Neurotransmitter-Related Disorders

olite and pterin assays provide powerful tools to help better characterize patients with otherwise undefined or poorly defined neurologic disorders.

APPROACH TO TREATMENT IN PATIENTS WITH NEUROTRANSMITTER DEFICIENCY STATES Because patients with neurotransmitter deficiency disorders caused by tyrosine hydroxylase or BH4 deficiency have been deficient for prolonged periods before treatment, they can be extremely sensitive to initiation of neurotransmitter precursors. Starting with extremely conservative dosages, increasing the dosage slowly during weeks or months, and ensuring that peripheral aromatic L-amino acid decarboxylase is fully blocked by providing ample carbidopa can make the transition to treatment much easier. The rate or degree to which children respond depends on a variety of factors, including age at diagnosis, specific disorder and mutation, presence or absence of associated hyperphenylalaninemia, and presence or absence of central BH4 deficiency. In general, optimism about improvement is warranted. Institution of neurotransmitter precursor treatment may lead to new problems, such as intermittent dyskinesia related to a peak dose effect, changes in appetite, gastroesophageal reflux, diarrhea, and constipation. These problems, greatest in the first few weeks of institution of treatment, tend to improve with time. With regard to replacement of L-dopa, use of a slow-release form of the medication may theoretically be ideal. However, such formulations are dosed not for use in children but for use in adults with Parkinson’s disease. In addition, dividing standard dosage forms marketed for adults makes adequate dosing in infants and young children a significant challenge. Thus, ideal dosage forms may need to be formulated in compounded preparations, rather than through commercially marketed dosage preparations. Support for parents and children during this often difficult period of transition from initiation of treatment to adjustment of medications is critical because these patients will likely require neurotransmitter precursor replacement throughout their lifetimes. In a disorder such as aromatic L-amino acid decarboxylase deficiency, in which direct receptor agonists may be indicated, only adult formulations of these often potent medications are available, making the use of compounding necessary. Giving more frequent and lower doses throughout the day may be necessary in some children. Although patients with primary neurotransmitter deficiency states are more likely to respond optimally to treatment, patients with secondary neurotransmitter deficiency may have some symptomatic benefit from directed treatment of their underlying neurotransmitter deficiency state.

NEUROLOGIC DISORDERS CHARACTERIZED BY EXCESS NEUROTRANSMITTER LEVELS Nonketotic Hyperglycinemia Nonketotic hyperglycinemia or “glycine encephalopathy” is a heterogeneous disorder associated with insufficient activity of various components of the mitochondrial glycine

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cleavage system. The enzyme system for cleavage of glycine is composed of four protein components: P protein, a pyridoxal phosphate–dependent glycine decarboxylase; H protein, a lipoic acid–containing protein; T protein, a tetrahydrofolate-requiring enzyme; and L protein, a lipoamide dehydrogenase. Nonketotic hyperglycinemia may be caused by a defect in any one of these enzymes. It is an autosomalrecessive disorder with several reported phenotypes, including the classic severe neonatal form, an infantile variant, a mild-episodic childhood variant, a late-onset form, and a benign reversible form [Hamosh and Johnston, 2001]. Most patients described to date have the neonatal and most severe phenotype, likely because it is the most distinctive phenotype. These patients present shortly after birth with lethargy, encephalopathy, hypotonia, myoclonic jerks, and apnea. Electroencephalography generally reveals a burst-suppression pattern. Those who survive the neonatal period generally develop intractable seizures and profound mental retardation. Patients with the infantile form have seizures and variable cognitive impairment after a short period of apparently normal development. In the mildepisodic form, patients typically present sometime after infancy with mild psychomotor retardation and may manifest episodes of delirium, chorea, and vertical gaze palsy during febrile illness. In the late-onset form, children present with progressive spastic diplegia and optic atrophy. They generally do not have seizures, and intellectual function is preserved. Diagnosis is best made by documenting an increased cerebrospinal fluid–to-plasma glycine ratio [Applegarth and Toone, 2001]. In the neonatal form of nonketotic hyperglycinemia, cerebrospinal fluid glycine level can be 30 times normal. Plasma glycine level is also typically high, but it can be in the normal range. A cerebrospinal fluid–to-plasma ratio above 0.08 is usually considered diagnostic, but mildly affected cases can have ratios of 0.04 to 0.1 [Applegarth and Toone, 2001]. (In rare cases, cerebrospinal fluid–to-plasma ratios are normal, and only elevations in plasma glycine occur [Jackson et al., 1999].) Confirmation of diagnosis requires enzyme analysis in liver or transformed lymphoblasts [Christodoulou et al., 1993]. Treatment with dextromethorphan and sodium benzoate has led to variable improvement in seizure control and behavioral problems in some patients [Boneh et al., 1996; Hamosh et al., 1998].

Leukoencephalopathy with Vanishing White Matter Leukoencephalopathy with vanishing white matter (also known as childhood ataxia with central white matter hypomyelinization) is a recently identified leukodystrophy [van der Knaap et al., 1997]. It is a heterogeneous autosomalrecessive disorder characterized by progressive ataxia, motor impairment, and encephalopathy in which episodic deterioration is associated with infection or minor head trauma. A wide range of onset has been reported in the dozen patients described to date. Cerebrospinal fluid glycine is elevated and can be helpful in confirming the diagnosis [van der Knaap et al., 1999]. At least two genes have been noted to have mutations in patients with this disorder, EIF2B5 and EIF2B2, the first translation initiation factors implicated in human disease [Leegwater et al., 2001]. This disorder is described in more detail in Chapter 60.

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REFERENCES Abeling NG, Brautigam C, Hoffmann GF, et al. Pathobiochemical implications of hyperdopaminuria in patients with aromatic L-amino acid decarboxylase deficiency. J Inherit Metab Dis 2000;23:325. Abeling NG, van Gennip AH, Barth PG, et al. Aromatic L-amino acid decarboxylase deficiency: A new case with a mild clinical presentation and unexpected laboratory findings. J Inherit Metab Dis 1998;21:240. Adler C, Ghisla S, Rebrin I, et al. Suspected pterin-4α-carbinolamine dehydratase deficiency: Hyperphenylalaninaemia due to inhibition of phenylalanine hydroxylase by tetrahydro-7-biopterin. J Inherit Metab Dis 1992;15:405. Applegarth DA, Toone JR. Nonketotic hyperglycinemia (glycine encephalopathy): Laboratory diagnosis. Mol Genet Metab 2001;74:139. Blau N, Bonafe L, Thony B. Tetrahydrobiopterin deficiencies without hyperphenylalaninemia: Diagnosis and genetics of dopa-responsive dystonia and sepiapterin reductase deficiency. Mol Genet Metab 2001;74:172. Blau N, Dhondt JL, Guibaud P, et al. New variant of hyperphenylalaninaemia with excretion of 7-substituted pterins [Letter]. Eur J Pediatr 1988;148:176. Bodeau-Pean S, Ravassard P, Neuner-Jehle M, et al. A human tyrosine hydroxylase isoform associated with progressive supranuclear palsy shows altered enzymatic activity. J Biol Chem 1999;274:3469. Bonafe L, Blau N, Burlina AP, et al. Treatable neurotransmitter deficiency in mild phenylketonuria. Neurology 2001;57:908. Bonafe L, Thony B, Penzien JM, et al. Mutations in the sepiapterin reductase gene cause a novel tetrahydrobiopterin-dependent monoamine-neurotransmitter deficiency without hyperphenylalaninemia. Am J Hum Genet 2001;69:269. Boneh A, Degani Y, Harari M. Prognostic clues and outcome of early treatment of nonketotic hyperglycinemia. Pediatr Neurol 1996;15:137. Brautigam C, Steenbergen-Spanjers GC, Hoffmann GF, et al. Biochemical and molecular genetic characteristics of the severe form of tyrosine hydroxylase deficiency. Clin Chem 1999;45:2073. Brunner HG, Nelen M, Breakefield XO, et al. Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science 1993;262:578. Brunner HG, Nelen MR, van Zandvoort P, et al. X-linked borderline mental retardation with prominent behavioral disturbance: Phenotype, genetic localization, and evidence for disturbed monoamine metabolism. Am J Hum Genet 1993;52:1032. Christodoulou J, Kure S, Hayasaka K, Clarke JT. Atypical nonketotic hyperglycinemia confirmed by assay of the glycine in lymphoblasts. J Pediatr 1993;123:100. Citron BA, Kaufman S, Milstien S, et al. Mutation in the 4αcarbinolamine dehydratase gene leads to mild hyperphenylalaninemia with defective cofactor metabolism. Am J Hum Genet 1993;53:768. Collins FA, Murphy DL, Reiss AL, et al. Clinical, biochemical, and neuropsychiatric evaluation of a patient with a contiguous gene syndrome due to a microdeletion Xp11.3 including the Norrie disease locus and monoamine oxidase (MAOA and MAOB) genes. Am J Med Genet 1992;42:127. Deckert J, Catalano M, Syagailo YV, et al. Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder. Hum Mol Genet 1999;8:621. De Lonlay P, Nassogne MC, van Gennip AH, et al. Tyrosine hydroxylase deficiency unresponsive to L-dopa treatment with unusual clinical and biochemical presentation. J Inherit Metab Dis 2000;23:819. de Rijk–Van Andel JF, Gabreels FJ, Geurtz B, et al. L-Dopa-responsive infantile hypokinetic rigid parkinsonism due to tyrosine hydroxylase deficiency. Neurology 2000;55:1926. Dionisi-Vici C, Hoffmann GF, Leuzzi V, et al. Tyrosine hydroxylase deficiency with severe clinical course: Clinical and biochemical investigations and optimization of therapy. J Pediatr 2000;136:560. Dubowitz LM, Bouza H, Hird MF, Jaeken J. Low cerebrospinal fluid concentration of free gamma-aminobutyric acid in startle disease. Lancet 1992;340:80. Dudesek A, Roschinger W, Muntau AC, et al. Molecular analysis and long-term follow-up of patients with different forms of 6-pyruvoyl-tetrahydropterin synthase deficiency. Eur J Pediatr 2001;160:267. Furukawa Y, Graf WD, Wong H, et al. Dopa-responsive dystonia simulating spastic paraplegia due to tyrosine hydroxylase (TH) gene mutations. Neurology 2001;56:260.

Furukawa Y, Lang AE, Trugman JM, et al. Gender-related penetrance and de novo GTP-cyclohydrolase I gene mutations in dopa-responsive dystonia. Neurology 1998;50:1015. Gibson KM, Hoffmann GF, Hodson AK, et al. 4-Hydroxybutyric acid and the clinical phenotype of succinic semialdehyde dehydrogenase deficiency, an inborn error of GABA metabolism. Neuropediatrics 1998;29:14. Hamosh A, Johnston MV. Nonketotic hyperglycinemia. New York: McGraw-Hill, 2001:2065. Hamosh A, Maher JF, Bellus GA, et al. Long-term use of high-dose benzoate and dextromethorphan for the treatment of nonketotic hyperglycinemia. J Pediatr 1998;132:709. Harwood G, Hierons R, Fletcher NA, Marsden CD. Lessons from a remarkable family with dopa-responsive dystonia. J Neurol Neurosurg Psychiatry 1994;57:460. Haussler M, Hoffmann GF, Wevers RA. L-Dopa and selegiline for tyrosine hydroxylase deficiency. J Pediatr 2001;138:451. Hogema BM, Gupta M, Senephansiri H, et al. Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase. Nat Genet 2001;29:212. Hyland K, Surtees RA, Rodeck C, Clayton PT. Aromatic L-amino acid decarboxylase deficiency: Clinical features, diagnosis, and treatment of a new inborn error of neurotransmitter amine synthesis. Neurology 1992;42:1980. Ichinose H, Ohye T, Takahashi E, et al. Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nat Genet 1994;8:236. Jackson AH, Applegarth DA, Toone JR, et al. Atypical nonketotic hyperglycinemia with normal cerebrospinal fluid to plasma glycine ratio. J Child Neurol 1999;14:464. Larnaout A, Belal S, Miladi N, et al. Juvenile form of dihydropteridine reductase deficiency in 2 Tunisian patients. Neuropediatrics 1998;29:322. Leegwater PA, Vermeulen G, Konst AA, et al. Subunits of the translation initiation factor eiF2B are mutant in leukoencephalopathy with vanishing white matter. Nat Genet 2001;29:383. Lenders JW, Eisenhofer G, Abeling NG, et al. Specific genetic deficiencies of the A and B isoenzymes of monoamine oxidase are characterized by distinct neurochemical and clinical phenotypes. J Clin Invest 1996;97:1010. Milstien S, Kaufman S, Summer GK. Hyperphenylalaninemia due to dihydropteridine reductase deficiency: Diagnosed by measurement of oxidized and reduced pterins in urine. Pediatrics 1980;65:806. Niederwieser A, Shintaku H, Leimbacher W, et al. Peripheral tetrahydrobiopterin deficiency with hyperphenylalaninaemia due to incomplete 6-pyruvoyl tetrahydropterin synthase deficiency or heterozygosity. Eur J Pediatr 1987;146:228. Pons R, Ford B, Chiriboga CA, et al. Aromatic L-amino acid decarboxylase deficiency: Clinical features, treatment, and prognosis. Neurology 2004 13;62:1058. Preisig M, Bellivier F, Fenton BT, et al. An association between bipolar disorder and monoamine A gene polymorphisms: Results of a multicenter study. Am J Psychiatry 2000;157:948. Raemaekers VT, Senderek J, Hausler M, et al. A novel neurodevelopmental syndrome responsive to 5-hydroxytryptophan and carbidopa. Mol Genet Metab 2001;73:179. Robertson D, Goldberg MR, Onrot J, et al. Isolated failure of autonomic noradrenergic neurotransmission: Evidence for impaired beta-hydroxylation of dopamine. N Engl J Med 1986;314:1494. Robertson D, Haile V, Perry SE, et al. Dopamine beta-hydroxylase deficiency. A genetic disorder of cardiovascular regulation. Hypertension 1991;18:1. Schuback DE, Mulligan EL, Sims KB, et al. Screen for MAOA mutations in target human groups. Am J Med Genet 1999;88:25. Segawa M, Hosaka A, Miyagawa F, et al. Hereditary progressive dystonia with marked diurnal fluctuation. Adv Neurol 1976;14:215. Shiang R, Ryan SG, Zhu Y-Z, et al. Point mutations in the gene encoding the alpha-1 subunit of the inhibitory glycine receptor cause the dominant neurologic disorder, hyperekplexia. Nat Genet 1993;5:351. Steinberger D, Weber Y, Korinthenberg R, et al. High penetrance and pronounced variation in expressivity of GCH1 mutations in five families with dopa-responsive dystonia. Ann Neurol 1998;43:634. Swoboda KJ, Hyland K, Goldstein DS, et al. Clinical and therapeutic observations in aromatic L-amino acid decarboxylase deficiency. Neurology 1999;53:1205.

Swoboda / Diagnosis and Treatment of Neurotransmitter-Related Disorders Swoboda KJ, Saul JP, McKenna CE, et al. Aromatic L-amino acid decarboxylase deficiency: Overview of clinical features and outcomes. Ann Neurol 2003;54(Suppl 6):S49. Thony B, Neuheiser F, Kierat L, et al. Hyperphenylalaninemia with high levels of 7-biopterin is associated with mutations in the PCBD gene encoding the bifunctional protein pterin-4α-carbinolamine dehydratase and transcriptional coactivator (DCoH). Am J Hum Genet 1998;62:1302. van der Knaap MS, Barth PG, Gabreels FJM, et al. A new leukoencephalopathy with vanishing white matter. Neurology 1997;48:845.

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van der Knaap MS, Wevers RA, Kure S, et al. Increased cerebrospinal fluid glycine: A biochemical marker for a leukoencephalopathy with vanishing white matter. J Child Neurol 1999;14:728. Woody RC, Brewster MA, Glasier C. Progressive intracranial calcification in dihydropteridine reductase deficiency prior to folinic acid therapy. Neurology 1989;39:673.

CHAPTER 31

Phakomatoses and Allied Conditions Elizabeth A. Thiele and Bruce R. Korf

The disorders referred to as phakomatoses are notable for their dysplastic nature and tendency to form tumors in various organs, particularly the nervous system. Bielschowsky [1914, 1919] observed these characteristic features in neurofibromatosis and tuberous sclerosis complex, and Van Der Hoeve [1923] called particular attention to these disorders and named the disease category the “phakomatoses” (Greek phakos, “lentil; mole or birthmark”). Von Hippel-Lindau disease and Sturge-Weber syndrome were thought to belong to this category of diseases [Van Der Hoeve, 1932, 1933], and Louis-Bar [1941] identified a syndrome, ataxia-telangiectasia, that she believed also had the typical clinical characteristics of the phakomatoses. Some of these conditions have been referred to as neurocutaneous disorders because of the frequent involvement of the skin in addition to the nervous system. Cutaneous features are not present in all phakomatoses, however (e.g., von Hippel-Lindau syndrome), and many include features outside the skin and nervous system, so the term can be misleading. Table 31-1 lists disorders associated with specific cutaneous findings; Table 31-2 summarizes the clinical features of the phakomatoses. This chapter surveys the clinical features of the three major phakomatoses: neurofibromatosis, tuberous sclerosis complex, and von Hippel-Lindau syndrome. As discussed later on, neurofibromatosis has been found to consist of at least three distinct disorders: neurofibromatosis types 1 and

2 (NF1 and NF2) and schwannomatosis. Also included in this chapter are a number of additional disorders that are commonly considered along with the phakomatoses, TABLE 31-1 Neurocutaneous Disorders: Specific Cutaneous Abnormalities and Associated Disorders Hyperpigmented Lesions Neurofibromatosis Epidermal nevus syndrome Neurocutaneous melanosis Incontinentia pigmenti Hypopigmented Lesions Tuberous sclerosis complex Incontinentia pigmenti achromians Angiomatous Lesions Sturge-Weber syndrome Maffucci’s syndrome Osler-Weber-Rendu syndrome Hemiatrophy/Hemihypertrophy Klippel-Trénaunay-Weber syndrome Retinal Involvement Von Hippel-Lindau disease Wyburn-Mason syndrome

TABLE 31-2 Phakomatoses and Their Clinical Features SYNDROME

CLASSIC FEATURES

COMMON NEUROLOGIC FEATURES

Neurofibromatosis type 1 Neurofibromatosis type 2 Schwannomatosis Tuberous sclerosis complex

Café-au-lait spots, neurofibromas Bilateral vestibular schwannomas Cranial nerve schwannomas except vestibular nerve Cortical tubers, hypopigmented macules, angiofibroma, renal angiomyolipoma Port-wine stain, ipsilateral leptomeningeal angioma Retinal, cerebellar, and spinal hemangioblastomas Multiple enchondromas Patchy cutaneous hamartomatous lesions Facial hemiatrophy Abnormally pigmented cutaneous areas; leptomeningeal melanoma Unilateral limb hypertrophy, subcutaneous hemangiomas

Optic gliomas, learning difficulties Hearing loss, tinnitus Painful neuropathies Seizures, cognitive impairment, autism

Sturge-Weber syndrome von Hippel-Lindau disease Maffucci’s syndrome Epidermal nevus syndrome Parry-Romberg syndrome Neurocutaneous melanosis Klippel-Trénaunay-Weber syndrome Incontinentia pigmenti Incontinentia pigmenti achromians Wyburn-Mason syndrome

Females only; hyperpigmented skin lesions; abnormalities of CNS, eyes, hair, teeth, and bone Hypopigmented skin lesions; associated CNS/PNS abnormalities Extensive retinal and ipsilateral cerebral arteriovenous malformations

CNS, central nervous system; PNS, peripheral nervous system.

Seizures, glaucoma, cognitive impairment, hemiparesis CNS abnormalities, seizures

Macrocephaly, hydrocephalus

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including Sturge-Weber syndrome, incontinentia pigmenti, and several other rare disorders. Ataxia-telangiectasia is considered in detail in Chapter 57 on the inherited ataxias.

NEUROFIBROMATOSIS TYPE 1 Neurofibromatosis is transmitted as an autosomal-dominant trait and is notable for its great variability of expression. It can involve not only the peripheral and central nervous systems but also many other systems, including the skin, bone,

endocrine, gastrointestinal, and vascular systems. Although von Recklinghausen is credited with the initial clinical and pathologic account of this disease in 1882, he cited Tilesius [1793] for the first description of a patient with multiple fibrous skin tumors. Wishart [1822] and Smith [1849] also provided clinical accounts of the disease before the report of von Recklinghausen [Fulton, 1929], although early reports failed to recognize the distinction between the disorders known as NF1 and NF2. Diagnostic criteria for NF1 are presented in Table 31-3.

Clinical Characteristics TABLE 31-3 Diagnostic Criteria for Neurofibromatosis 1 Six or more café-au-lait macules more than 5 mm in greatest diameter in prepubertal children and more than 15 mm in greatest diameter in postpubertal children Two or more neurofibromas of any type or one plexiform neuroma Freckling in the axillary or inguinal regions Optic pathway glioma Two or more Lisch nodules (iris hamartomas) A distinctive osseous lesion, such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudarthrosis Diagnosis of neurofibromatosis 1 in a first-degree relative (parent, sibling, or offspring) according to foregoing criteria Data from Gutmann DH, Aylsworth A, Carey JC, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 1997;278:51; and Stumpf DA, Alksne JF, Annegers JF, et al. Neurofibromatosis. Arch Neurol 1988;45:575.

FIGURE 31-1. Multiple café-au-lait spots.

In NF1, the usual presenting signs are cutaneous manifestations. These skin changes include café-au-lait spots, cutaneous neurofibromas, hypopigmented spots, patchy and diffuse areas of hyperpigmentation, juvenile xanthogranulomas, and angiomas. Café-au-lait spots usually are present at birth and range in size from a few millimeters to centimeters [Crowe et al., 1956] (Fig. 31-1). They do not significantly increase in number after the first 2 years of life. Six or more café-au-lait spots measuring at least 5 mm across before puberty or 15 mm after puberty constitute one diagnostic criterion for NF1 [Stumpf et al., 1988]. Rare persons with variant forms of neurofibromatosis, such as spinal neurofibromatosis [Messiaen et al., 2003], may lack café-au-lait spots, and families with autosomal-dominant transmission

FIGURE 31-2. Axillary freckling.

Thiele and Korf / Phakomatoses and Allied Conditions

of café-au-lait spots, without other signs of neurofibromatosis, have been identified [Charrow et al., 1993]. Nevertheless, in a majority of children who present with six or more café-au-lait spots and do not have an alternative diagnosis, signs of NF1 eventually develop [Korf, 1992]. Usually the second sign to appear is skin fold freckling [Crowe, 1964; Korf, 1992] (Fig. 31-2). Freckles begin in the groin in children at 3 to 4 years of age and eventually appear in the axillae, at the base of the neck, and in the inframammary region in females. Areas of freckling also can be found over the trunk and extremities. Diffuse, patchy areas of hyperpigmentation also may appear, sometimes overlying plexiform neuromas. Areas of hypopigmentation, although common, are frequently overlooked and can be similar to the hypopigmented macules observed in tuberous sclerosis complex [Westerhof and Konrad, 1982]. Smaller hypopigmented macules, localized areas of hypoplasia, and angiomas also are commonly found in neurofibromatosis and can be present in early life, becoming more apparent with time. Juvenile xanthogranulomas are said to occur in up to 10% of affected patients with NF1; they usually appear during the first decade and then commonly disappear within several years. It has been suggested that the lesions can be associated with juvenile chronic myelogenous leukemia [Quesnel et al., 1994; Shannon et al., 1994], but this association has not been confirmed. Cutaneous neurofibromas are a prominent finding in NF1 and are located in the dermis or adjacent to it (Fig. 31-3). They are discrete, soft or firm papules, ranging in size from a few millimeters to several centimeters, and can be flat, sessile, or pedunculated and can be readily impressed into the skin below. Neurofibromas can develop at any time and in any location and may affect any component of the nervous system, from the dorsal root ganglion to the terminal nerve twigs. Plexiform neuromas represent tumors that involve a longitudinal section

FIGURE 31-3. Multiple cutaneous neurofibromas.

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FIGURE 31-4. Truncal plexiform neurofibroma with overlying hyperpigmentation.

of nerve and can involve multiple branches of a major nerve [Korf, 1999]. Near the surface of the body, they can invade skin and cause thickening and hypertrophy of the skin and soft tissues (Fig. 31-4). They may occur deeper in the body and be detected only by imaging [Tonsgard, 1998]. Tumors of the orbit or limbs can cause major physical deformity. Plexiform neurofibromas can be congenital lesions, which often grow rapidly in the early months of life, and then may remain quiescent for long periods of time, or grow unpredictably. Neurofibromas may originate at the dorsal roots and grow in a dumbbell shape invading the spinal canal (Fig. 31-5), sometimes causing spinal cord compression. The gastrointestinal tract can also be affected by growth of either neurofibromas or ganglioneuromas that can cause displacement of the lamina propria of the colonic mucosa, underlying muscularis propria, and the basal lamina. In one study, 10% of patients had neurofibromatous involvement of the gastrointestinal tract [Hochberg et al., 1974]. Gastrointestinal neurofibromas can cause intestinal obstruction or bleeding.

FIGURE 31-5. Magnetic resonance imaging scan showing bilateral spinal tumors, with displacement of the cord by the larger tumor on the right side of the photo.

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FIGURE 31-7. Sagittal magnetic resonance imaging scan of brain showing glioma of optic chiasm (arrow).

FIGURE 31-6. Congenital glaucoma (buphthalmos) associated with orbital plexiform neurofibroma.

Ophthalmologic features of NF1 include Lisch nodules, glaucoma, and optic glioma. Iris Lisch nodules are melanocytic hamartomas that are highly specific to NF1 [Lisch, 1937]. Their appearance is age dependent, usually beginning at the age of approximately 6 years. Lisch nodules occur in approximately 95% of adults with the disorder [Lubs et al., 1991] and are therefore helpful in diagnosis. Congenital glaucoma can be a manifestation of neurofibromatosis and usually occurs when the neurofibroma also involves the lid (Fig. 31-6). Grant and Walton [1968] reported that buphthalmos could be secondary to infiltration of the angle by a neurofibroma, to the stretching and enlarging of the cornea from increased intraocular pressure, or to the synechiae that close the angle by forming fibrovascular tissue within it. Pulsating exophthalmos and endophthalmos have been reported [Walsh and Hoyt, 1969] and result from deficiency of the posterior wall of the orbit. Optic pathway gliomas are found in approximately 15% of patients. Most are asymptomatic, but these tumors can manifest with symptoms of decreased visual acuity, visual field defects, or precocious puberty [Listernick et al., 1994, 1997]. The glioma can involve the optic nerves, chiasm, optic radiations, and hypothalamus (Fig. 31-7); it rarely manifests as the diencephalic syndrome of infancy or precocious puberty [Adornato and Berg, 1977; Holt, 1978; Saxena, 1970]. Optic gliomas are pilocytic astrocytomas but often are indolent and slowly growing [Gould et al., 1987; Hoyt and Baghdassarian, 1969; Imes and Hoyt, 1986; Listernick et al., 1994]. Aside from optic gliomas, astrocytomas of the cerebrum, brainstem, and cerebellum are the most common intracranial tumors encountered in NF1 [Malloy et al., 1995;

Pollack et al., 1996; Korf, 2000]. Malignant peripheral nerve sheath tumor occurs in upwards of 10% of affected persons [Evans et al., 2002]. These tumors manifest with pain or sudden growth, usually within a preexisting plexiform neurofibroma. Various other neoplastic disorders occur more frequently in patients with NF1 than in the general population, including leukemia, especially juvenile myelomonocytic leukemia [Side et al., 1997], and pheochromocytoma [Walther et al., 1999]. Macrocephaly and short stature are common in neurofibromatosis, and scoliosis has been reported to occur in 10% to 40% of patients [Crawford et al., 2000]. Scoliosis usually does not develop before the age of 6 years and most commonly involves the thoracic spine. Bowing of the tibia, fibula, and other long bones can be present in early life, with occurrence of spontaneous fractures at the junction of the middle and distal thirds of the bone shaft, resulting in pseudarthrosis [Crawford and Schorry, 1999; Stevenson et al., 1999]. Approximately 50% of patients have learning disabilities, with no specific pattern occurring uniquely in those with NF1 [North et al., 1997, 2002]. Both verbal and nonverbal disabilities occur, as well as attention-deficit disorder [Mautner et al., 2002], and hypotonia. Less than 10% have mental retardation, and most of these patients have large deletions of the NF1 gene [Kayes et al., 1994]. Seizures occur in approximately 6% to 10% of patients [Korf et al., 1993]. The pathogenesis of the cognitive phenotype is not known. Abnormal cortical architecture and heterotopias have been reported in the brains of some patients with severe cognitive deficits [Rosman and Pearce, 1967]. More recently, it has been suggested that the areas of enhanced T2 signal intensity characteristically seen in the brains of children with NF1 (Fig. 31-8) may be associated with learning disabilities [Denckla et al., 1996; North et al., 1994]. These lesions occur in the basal ganglia, brainstem, cerebellum, and internal capsule; tend to disappear with age [Ferner et al., 1993; Hyman et al., 2003]; and are characterized by increased myelin water content and gliosis [DiPaolo et al., 1995]. Vascular anomalies in NF1 include regions of intimal proliferation and fibromuscular changes in small arteries [Friedman et al., 2002]. Renal artery stenosis can lead to

Thiele and Korf / Phakomatoses and Allied Conditions

FIGURE 31-8. Area of enhanced T2 signal intensity in cerebellum (arrow).

hypertension in children [Fossali et al., 2000; Schurch et al., 1975] and involvement of other vessels can cause vascular insufficiency or hemorrhage as a result of arterial wall dissection. Stenosis of the internal carotid artery can lead to moyamoya disease and stroke. The stenotic changes can arise spontaneously in children with NF1 but frequently develop after radiation therapy for brain tumors in young children [Kestle et al., 1993].

Pathology Neurofibromatosis has been considered to be a neurocristopathy; however, although many of the tissues involved are of neural crest origin, tissues derived from other embryonal layers are also involved (e.g., bone). The core pathologic feature is the neurofibroma. Neurofibromas consist of a mixture of cell types, including Schwann cells, fibroblasts, perineurial cells, and mast cells. They are polyclonal, but genetic studies (see later on) have confirmed that the “tumor cell” is the Schwann cell [Sherman et al., 2000; Zhu et al., 2003]. The other cell types present in the lesion apparently proliferate as a secondary phenomenon, perhaps in response to stimulation by cytokines [Yang et al., 2003]. Mast cells are present in large numbers and have been suspected of being a source of cytokines [Carr and Warren, 1993; Riccardi, 1981]. In plexiform neurofibromas, the pathologic process extends across multiple nerve fascicles instead of just occurring at a focal site in a nerve, and may extend across branches of a larger nerve. Malignant peripheral nerve sheath tumor manifests as a malignant tumor of Schwann cell origin, although sometimes rhabdoid elements are present in such tumors. Most, if not all, of these neoplasms arise from preexisting tumors, usually plexiform neurofibromas. The pathology of other NF1associated lesions is less well understood than that of the neurofibroma. Lesions such as café-au-lait macules, bone dysplasias, and cerebral abnormalities are more likely to be dysplastic than proliferative in nature.

Genetics NF1, inherited as an autosomal-dominant trait, has an estimated prevalence of 1 in 4000, about half of which are new mutations. The NF1 gene is located at 17q11.2

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[Seizinger et al., 1987b; Skolnick et al., 1987] and encodes a 3818-amino-acid protein referred to as neurofibromin [Cawthon et al., 1990; Wallace et al., 1990; Viskochil et al., 1990]. Neurofibromin is expressed in multiple cell types but is highly expressed in Schwann cells, oligodendrocytes, and neurons [Daston et al., 1992]. The protein includes a functional GTPase-activating protein (GAP) domain that regulates conversion of Ras–guanosine triphosphate (GTP) to Ras-guanosine diphosphate (GDP) [Ballester et al., 1990; Xu et al., 1990]. Ras is a membrane-bound intracellular signaling molecule that is activated by complexing with GDP on ligand binding to membrane receptor tyrosine kinases. GAP proteins regulate this process by stimulating a GTPase activity that is intrinsic to Ras [Bernards, 2003]. Neurofibromin functions as a tumor suppressor gene with respect to neurofibroma formation [Cichowski and Jacks, 2001; Sherman et al., 2000; Zhu et al., 2003]. The germline mutation of one NF1 allele constitutes the first “hit”; the second hit is a somatic mutation in a Schwann cell that causes that cell to proliferate and attract other cells, such as mast cells, fibroblasts, and perineurial cells, which also proliferate. These cells, being heterozygous for the NF1 mutation, may be hypersensitive to cytokine stimulation. Transformation to malignancy requires additional genetic changes, such as loss of p53 [Legius et al., 1994]. It is unclear whether dysplastic lesions also occur as a result of a tumor suppressor mechanism, or whether haploinsufficiency of neurofibromin expression itself causes these lesions. NF1 exhibits a wide range of variability of expression and complete penetrance. Mutations are widely scattered across the gene and include a wide variety of mutational mechanisms [Messiaen et al., 2000]. Most of the mutations lead to decreased level of expression of neurofibromin or complete lack of expression. Few genotype-phenotype correlations have been established. Large deletions that include the NF1 gene and multiple contiguous genes over a 1.5-Mb region tend to lead to a particularly severe form of NF1, with mental retardation, early onset of large numbers of neurofibromas, facial dysmorphism, and increased risk of cancer [de Raedt et al., 2003; Kayes et al., 1994; Wu et al., 1995]. Another variant form of neurofibromatosis, familial spinal neurofibromatosis, may represent an additional genotypephenotype correlation. Persons with this disorder have multiple spinal neurofibromas and subcutaneous tumors but lack café-au-lait macules and dermal tumors [Ars et al., 1998; Kluwe et al., 2003]. These patients tend to have missense mutations or splicing mutations [Messiaen et al., 2003] that may result in hypomorphic but not totally inactivated alleles. Approximately 50% of cases of NF1 occur sporadically, as a result of a new mutation of the NF1 gene. Because of the high penetrance of the disorder, unaffected parents of a sporadically affected child have a low risk of recurrence, barring the rare instance of germline mosaicism [Lazaro et al., 1994]. Somatic mosaicism for NF1 has been reported, in some cases manifesting with segmental distribution of features [Tinschert et al., 2000]. Genetic testing for diagnosis of NF1 was difficult to develop, owing to the large size of the gene and wide diversity of mutations, but is available on a clinical basis. It is used to confirm a diagnosis in patients who fulfill only a single diagnostic criterion, to characterize patients with unusual clinical presentations, and to enable prenatal testing.

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Management

Clinical Characteristics and Pathology

Treatment of patients with neurofibromatosis is symptomatic. Affected persons should be followed on a regular basis by a physician who is familiar with the disorder, to recognize treatable complications early and to provide anticipatory guidance and counseling. Genetic counseling should also be provided. Controversy surrounds the use of imaging, especially magnetic resonance imaging (MRI), in screening patients with NF1. Most of the lesions that will be identified are not amenable to treatment, so such testing may create needless anxiety, and in children the procedure carries the risks associated with sedation. The value of the “baseline” examination is questionable, because most of the lesions of NF1 are slow-growing and will be followed both clinically and by imaging once they come to attention. Current consensus guidelines do not recommend routine imaging [Gutmann et al., 1997; Stumpf et al., 1988], although care should be individualized by clinicians for specific clinical needs. Neurofibromas of the peripheral nerves generally are indolent lesions and need not be removed unless they are subject to repeated irritation and trauma or develop malignant change. Some plexiform neuromas can be removed for cosmetic reasons, although complete resection is difficult and regrowth is common [Needle et al., 1997]. Malignant tumors are managed with appropriate neurosurgical measures, radiation therapy, and chemotherapeutic methods. Optic gliomas tend to behave in an indolent manner and therefore are followed clinically without treatment in asymptomatic children [Listernick et al., 1997]. Symptomatic tumors most often are treated with chemotherapy [Packer, 2000]. Malignant peripheral nerve sheath tumors tend to be highly malignant, so early diagnosis is essential. Patients with unexplained pain or growth of a neurofibroma should be evaluated, with consideration of biopsy. Some evidence indicates that positron emission tomography (PET) scanning can distinguish a peripheral nerve sheath tumor from plexiform neurofibroma, although more data are needed to address this issue [Ferner et al., 2000]. Clinical trials of candidate drugs to treat specific complications, especially growing plexiform neurofibromas (www.nf.org/clinical_trials), are ongoing.

Diagnostic criteria for NF2 are presented in Table 31-4 [Gutmann et al., 1998; Stumpf et al., 1988]. The defining feature of NF2 is the occurrence of bilateral vestibular schwannomas. Age at onset is highly variable, ranging from early childhood to the seventh decade and beyond. In view of this variability in age at onset of vestibular tumors, NF2 also should be considered in patients with early onset of associated tumors or those with combinations of associated tumors (see Table 31-4 and the review by Baser and colleagues [2002]). Vestibular tumors commonly manifest with tinnitus and/or hearing loss and may cause problems with balance [Evans, 1999]. Audiology and auditory brainstem–evoked response testing can be helpful, but definitive diagnosis is based on MRI findings (Fig. 31-9). Early tumors may be confined to the internal auditory canal and require careful search with thin MRI slices to be detected. Schwannomas can occur along any other cranial nerve, the fifth being most common after the eighth. Schwannomas also may occur along spinal nerves, with the potential for causing radiculopathy or cord compression, or along peripheral nerves. In some patients, a polyneuropathy develops as a result of Schwann cell proliferation around peripheral nerves [Gijtenbeek et al., 2001; Hagel et al., 2002]. Dermal schwannomas appear as plaquelike lesions, often with associated hair growth. Caféau-lait macules are not a reliable indicator of NF2, unlike in NF1. Other major central nervous system tumors associated with NF2 are meningiomas and ependymomas. Multiple meningiomas may not be surgically resectable and can be responsible for significant morbidity. By contrast, spinal ependymomas often are asymptomatic. Virtually the entire TABLE 31-4 Diagnostic Criteria for Neurofibromatosis 2 (NF2) Confirmed NF2 Bilateral vestibular schwannomas OR In a first-degree relative: NF2 and unilateral vestibular schwannoma before age 30 years or any two of: meningioma, schwannoma, gliomas, juvenile lens opacity Presumptive NF2 Unilateral vestibular schwannoma before age 30 years and at least one of: meningioma, schwannoma, gliomas, juvenile lens opacity OR

NEUROFIBROMATOSIS TYPE 2 It was only with the report of Young and associates [1970] that the distinction between a peripheral and a central form of neurofibromatosis came to be recognized. The classification was formalized by the National Institutes of Health (NIH) Consensus Development Conference in 1987 [Stumpf et al., 1988], with the peripheral form of neurofibromatosis referred to as NF1 and the central form, the hallmark of which is bilateral vestibular schwannomas, called NF2. The distinction between the disorders was subsequently verified when the two genes were found to be distinct, first by mapping and later by cloning. More recently, a third disorder, referred to as schwannomatosis, has been split out. This disorder is characterized by the development of multiple schwannomas of cranial nerves except the vestibular nerve, and of spinal and peripheral nerves.

Two or more meningiomas and unilateral vestibular schwannoma before age 30 years or at least one of: meningioma, schwannoma, gliomas, juvenile lens opacity Manchester Criteria* Bilateral vestibular schwannomas OR In a first-degree relative: NF2 and unilateral vestibular schwannoma or any two of: meningioma, schwannoma, gliomas, neurofibroma, posterior subcapsular lenticular opacity OR Unilateral vestibular schwannoma and any two of: meningioma, schwannoma, gliomas, neurofibroma, posterior subcapsular lenticular opacity OR Two or more meningiomas and unilateral vestibular schwannoma or any two of: meningioma, schwannoma, gliomas, neurofibroma, posterior subcapsular lenticular opacity *Data from Baser ME, Friedman JM, Wallace AJ, et al. Evaluation of clinical diagnostic criteria for neurofibromatosis 2. Neurology 2002;59:1759. Data from Gutmann DH, Aylsworth A, Carey JC, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 1997;278:51; and Stumpf DA, Alksne JF, Annegers JF, et al. Neurofibromatosis. Arch Neurol 1988;45:575.

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Management Persons with NF2 or schwannomatosis should be managed by a physician who is experienced with the disorder [Evans et al., 1993]. Those with NF2 should be monitored for the development of vestibular schwannoma using audiometry and periodic MRI. Symptomatic tumors usually are treated surgically, although stereotactic radiosurgery also has been used [Moffatt et al., 2003; Rowe et al., 2003]. Timing of surgery requires careful planning, taking into account the likelihood of preservation of hearing and whether the tumors are bilateral. Schwannomas of other cranial or peripheral nerves are treated surgically if symptomatic. Meningioma treatment also is currently limited to surgery. FIGURE 31-9. Magnetic resonance imaging scan of brain from person with NF2 showing meningioma (arrow 1) and two vestibular schwannomas (arrows 2 and 3). The tumor indicated by arrow 3 has been partially resected.

NF2 phenotype is characterized by proliferative lesions; the one exception is the occurrence of posterior subcapsular cataracts or cortical wedge opacities [Pearson-Webb et al., 1986].

Genetics NF2 is transmitted as an autosomal dominant trait with complete penetrance and variable expression. Approximately half of cases occur sporadically as a result of new mutation. The NF2 gene was mapped to chromosome 22 [Rouleau et al., 1987], and the responsible gene was identified by two groups in 1993 [Rouleau et al., 1993; Trofatter et al., 1993]. The protein is variously referred to as schwannomin or merlin (the latter an acronym for moeisin, ezrin, and radixin-like protein). Merlin is a cytoskeletal protein that appears to play a role in the control of cell growth in tissues [Xiao et al., 2002]. Schwannomas are clonal tumors, and the NF2 gene acts as a tumor suppressor in formation of these tumors, as well as other NF2-associated tumors [Seizinger et al., 1987a]. Genetic testing for NF2 is possible in some cases for diagnostic purposes. Some genotypephenotype correlations have been identified; specifically, missense or splicing mutations tend to predict milder disease than do mutations that lead to protein truncation [Parry et al., 1996; Ruttledge et al., 1996]. Somatic mosaicism for NF2 mutation may produce localized disease or ameliorate disease severity [Baser et al., 2000].

SCHWANNOMATOSIS Schwannomatosis is a more recently recognized entity [Evans et al., 1997; MacCollin et al., 1996; Purcell and Dixon, 1989] characterized only by the occurrence of schwannomas on cranial and spinal nerves other than the vestibular nerve. It often manifests with pain or nerve compression. Schwannomatosis is most commonly sporadic, but familial cases have been observed, in which case inheritance is autosomal dominant with incomplete penetrance. The gene has been mapped to chromosome 22 near the NF2 locus but appears to be distinct from that locus [MacCollin et al., 2003].

TUBEROUS SCLEROSIS COMPLEX Tuberous sclerosis complex is a disorder of autosomaldominant inheritance that affects multiple organ systems, resulting in manifold clinical expressions. Tuberous sclerosis complex is currently recognized as one of the most common single-gene disorders seen in children and adults, with an estimated incidence of 1 in 5800 live births (Osbourne et al., 1991). The first description of tuberous sclerosis complex was by von Recklinghausen [1862], who described a newborn who had died of respiratory distress and was found at postmortem examination to have multiple cardiac tumors and a “great number of cerebral scleroses.” Bourneville [1880] usually is credited with the first detailed description of the cerebral manifestations of the disease, describing “sclerose tubereuse,” indicating the superficial resemblance of the lesions of a potato. He attached no significance to the facial skin rash of his first patient, calling it acne rosacea, but he and Brissaud [1881, 1900] believed that the renal tumors and cerebral scleroses were associated findings. Facial angiofibromas were independently described in several reports, but Vogt [1908] emphasized the association of adenoma sebaceum and the cerebral scleroses described by Bourneville. He also described a “classic” triad of clinical features comprising mental retardation, intractable epilepsy, and adenoma sebaceum, which is now known to be present in less than one third of patients with tuberous sclerosis complex.

Clinical Characteristics Diagnostic criteria are provided in Table 31-5. The clinical presentation of tuberous sclerosis complex depends on the age of the patient, the organs involved, and the severity of involvement. Of importance, both the brain and the skin have more than one major criterion for diagnosis; therefore, a diagnosis of definite tuberous sclerosis complex can be based on skin findings alone, or on neuroimaging findings alone. Epilepsy is the most common presenting symptom in tuberous sclerosis complex and also is the most common medical disorder. In up to 80% to 90% of persons with tuberous sclerosis complex, seizures will develop during their lifetime, with the onset most frequently in childhood [Gomez, 1999; Thiele, 2004]. A majority of children with

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TABLE 31-5 Diagnostic Criteria for Tuberous Sclerosis Complex (TSC) Major Features Facial angiofibromas or forehead plaque Nontraumatic ungual or periungual fibroma Hypopigmented macules (more than 3) Shagreen patch (connective tissue nevus) Cortical tuber Subependymal nodule Subependymal giant cell astrocytoma Multiple retinal nodular hamartomas Cardiac rhabdomyoma, single or multiple Lymphangiomyomatosis Renal angiomyolipoma Minor Features Dental pits (more than 14), randomly distributed Hamartomatous rectal polyps Bone cysts Cerebral white matter radial migration lines Gingival fibromas Nonrenal hamartomas Retinal achromic patch “Confetti” skin lesions Multiple renal cysts Diagnostic Certainty Criteria Definite TSC 2 major features OR 1 major feature + 2 minor features Probable TSC 1 major feature + 1 minor feature

The electroencephalogram (EEG) in infantile spasms associated with tuberous sclerosis complex often demonstrates hypsarrhythmia or modified hypsarrhythmia. It is important to realize, however, that the EEG, although usually abnormal, frequently does not have the features of hypsarrhythmia; in some series, up to 70% of children with tuberous sclerosis complex and infantile spasms did not have the characteristics of hypsarrhythmia [Curatolo et al., 2001]. Several reports have characterized the EEG patterns of persons with tuberous sclerosis complex and have found a high incidence of abnormalities, including diffuse slowing and epileptiform features [Ganji and Hellman, 1985; Westmoreland, 1999]. Tuberous sclerosis complex is associated with a wide range of cognitive and behavioral manifestations. Approximately one half of persons with tuberous sclerosis complex have normal intelligence, whereas the other half have some degree of cognitive impairment, ranging from mild learning disabilities to severe mental retardation. A bimodal distribution of cognitive abilities is evident, with a majority of affected persons falling into a severely cognitively impaired group or a group with normal intelligence [Gillberg et al., 1994; Prather and deVries, 2004]. Persons with tuberous sclerosis complex, particularly those with cognitive impairment, also are at high risk for developmental disorders. Autistic spectrum disorders affect up to 50% of persons with tuberous sclerosis complex [Curatolo et al., 2001; Smalley 1998; Wiznitzer, 2004], and attention-deficit–hyperactivity

Possible TSC 1 major feature OR 2 or more minor features From Roach ES, Gomez MR, Northrup H. Tuberous Sclerosis Complex Consensus Conference: Revised clinical diagnostic criteria. J Child Neurol 1998;13:624.

tuberous sclerosis complex have the onset of seizures during the first year of life, and infantile spasms will develop in up to one third of children with tuberous sclerosis complex. Almost all seizure types can be seen in persons with tuberous sclerosis complex, including tonic, clonic, tonic-clonic, atonic, myoclonic, atypical absence, partial, and complex partial. Only “pure” absence seizures are not observed. Infantile spasms will develop in approximately one third of children with tuberous sclerosis complex, although some reports suggest an incidence as high as 75% [Riikonen and Simell, 1990; Fukushima et al., 1998; Hamano et al., 2003; Husain et al., 2000], with a likely strong association between increasing tuber load and presence of infantile spasms [Hamano et al., 2003]. Tuberous sclerosis complex is thought to be the most common single cause of infantile spasms, and in some series, 25% of symptomatic infantile spasms are secondary to tuberous sclerosis complex. Partial complex seizures precede infantile spasms in approximately one third of patients with tuberous sclerosis complex in whom infantile spasms develop [Curatolo et al., 2001, 2002]. A strong association between the presence of infantile spasms in tuberous sclerosis complex and subsequent developmental impairment has been noted, although children with tuberous sclerosis complex and infantile spasms can have a normal cognitive outcome [Thiele, 2004; Yamamoto et al., 1987].

FIGURE 31-10. Typical angiofibroma in an adult with tuberous sclerosis complex. (Courtesy of Dr. T. N. Darling, Uniformed Services University of Health Sciences, Bethesda, MD.)

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and related disorders also are common, affecting approximately 50% of the patients [Prather and deVries, 2004]. During adolescence and adulthood, anxiety disorders, depression, or mood disorders develop in a significant number of patients with tuberous sclerosis complex. Cutaneous manifestations are found in up to 96% of patients with tuberous sclerosis complex [Gomez, 1987]. Angiofibroma, the skin manifestation initially described in the disorder as adenoma sebaceum, typically appears between the ages of 1 and 4 years and can progress through childhood and adolescence [Gomez, 1987; Pampiglioni and Moynihan, 1976]. These lesions typically are pink or red papules that appear in patches or in a butterfly distribution on or about the nose, cheeks, and chin (Fig. 31-10). Hypopigmented, oval, or leaf-shaped spots, ranging from a few millimeters to several centimeters in length and scattered over the trunk and limbs, are commonly seen [Gomez, 1987; Fitzpatrick, 1991]. The lesions often are apparent at birth and can appear more prominent during the first several years of life as the child’s body size and surface area increase. Visualization of these hypopigmented spots is facilitated by using a Wood light, an ultraviolet light that accentuates the hypopigmented spots [Fitzpatrick et al.,

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1967, 1968; Roth and Epstein, 1971]. At least three types of white spots probably occur: Polygonal (similar to a thumbprint) is the most frequent shape (0.5 to 2 cm); an ash leaf–shaped hypopigmented macule is characteristic but is not the most common shape (1 to 12 cm); and the third common type is a confetti-shaped arrangement of multiple, tiny white macules (1 to 3 mm) [Fitzpatrick, 1991] (Fig. 31-11). Histologic assessment of the hypopigmented spots usually demonstrates a normal number of melanocytes, and on electron microscopy a reduction in the number, diameter and melanization of melanosomes in the melanocytes from the white macule is seen [Jozwiak and Schwartz, 2003]. If the scalp is involved, the affected person will have poliosis, or a patch of gray or white hair [McWilliam and Stephenson, 1978]. Another skin manifestation currently considered a major criterion for clinical diagnosis of tuberous sclerosis complex is the shagreen patch, a connective tissue hamartoma that is distributed asymmetrically on the dorsal body surfaces, particularly on the lumbosacral skin (Fig. 31-12). In a majority of the cases, the shagreen patch is characterized by multiple and small areas of connective tissue hamartoma, ranging in size from a few millimeters to 1 cm. Subungual or periungual fibromas (Koenen’s tumors) are present in about 20% of patients and usually first appear during adolescence, involving the toes more often than the fingers [Barroeta and Grinspan-Bozza, 1962; Jozwiak and Schwartz, 2003] (Fig. 31-13). Oral fibromas or papillomas occur in about 10% of patients and usually are found on the anterior aspect of the gingiva [Panpanyothou and Verzirtzi, 1975]. Dental enamel pits have been found in all adult patients with tuberous sclerosis complex, compared with 7% of controls [Hoff et al., 1975; Mlynarczyk, 1991; Weits-Binnerts et al., 1982].

FIGURE 31-11. Hypopigmented macule in a child with tuberous sclerosis complex. (Courtesy of Dr. T. N. Darling, Uniformed Services University of Health Sciences, Bethesda, MD.)

FIGURE 31-12. Shagreen patch (arrows) over the lumbosacral region of an adolescent with tuberous sclerosis complex. (Courtesy of Dr. T. N. Darling, Uniformed Services University of Health Sciences, Bethesda, MD.)

FIGURE 31-13. Periungual fibroma on finger of a patient with tuberous sclerosis complex. (Courtesy of Dr. T. N. Darling, Uniformed Services University of Health Sciences, Bethesda, MD.)

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The kidneys frequently are affected in persons with tuberous sclerosis complex, and after neurologic manifestations, renal involvement is the most common cause of morbidity and mortality [Franz, 2004]. The two main types of renal lesions are angiomyolipoma and renal cysts. Angiomyolipoma are present in up to 80% of patients with tuberous sclerosis complex and can develop in either childhood or adulthood [Franz, 2004; Neumann et al., 1998]. Persons with tuberous sclerosis complex can have multiple small angiomyolipomas on the surface of the kidneys, throughout the kidney, or one or more larger lesions. The larger lesions are considered to be at greater risk to become symptomatic, particularly when they reach 4 to 6 cm in size. They can produce nonspecific complaints such as flank pain, but they also carry a risk of potentially life-threatening hemorrhage from rupture of dysplastic, aneurysmal blood vessels in the angiomyolipoma. Renal cysts are seen in less than 20% of persons with tuberous sclerosis complex and are rarely if ever symptomatic. Polycystic kidney disease occurs in 3% to 5% of patients with tuberous sclerosis complex and, when present, reflects a contiguous gene syndrome, because the polycystic kidney disease gene is adjacent to the TSC2-tuberin gene on chromosome 16 [Brook-Carter et al., 1984]. The cardiac manifestation, rhabdomyoma, is seen in 50% to 60% of persons with tuberous sclerosis complex. Typically, rhabdomyomas, which can frequently be detected prenatally, are maximal at birth and early childhood and undergo spontaneous regression during the first few years of life. If symptomatic, they result in outflow tract obstruction or valvular dysfunction. If the lesions involve the cardiac conduction system, they can predispose the patient to dysrhythmias not only in infancy and childhood but throughout life. Pulmonary involvement is thought to occur exclusively in women with tuberous sclerosis complex and can include lymphangioleiomyomatosis, multifocal micronodular pneumocyte hyperplasia, and pulmonary cysts. Athough pul=monary abnormalities were once thought to be quite rare, affecting less than 1% of women, recent studies have found such abnormalities in up to 40% of women with tuberous sclerosis complex, many of whom are asymptomatic [Moss et al., 2001] Although complaints of impaired vision are infrequent, retinal hamartomas are relatively common, affecting at least 50% of patients. A nodular (mulberry) tumor can be seen on or about the optic nerve head, and round or oval gray-yellow glial patches can be central or peripheral. The large retinal tumors can be cystic [Messinger and Clarke, 1937; Walsh and Hoyt, 1969]. Other ophthalmic findings include iridic pigmentary changes and colobomas. Papilledema is not present except in those patients with an intracranial mass lesion that obstructs the normal circulation of the cerebrospinal fluid, resulting in increased intracranial pressure [Kapp et al., 1967]. Hamartomas also can be found in other organ systems, including stomach, intestine, colon, pancreas, and liver. Hepatic angiomyolipoma and cysts have been reported in up to 24% of persons with tuberous sclerosis complex and are typically asymptomatic and nonprogressive. Sclerotic and hypertrophic lesions of bone often can be seen, although these typically are not symptomatic.

Clinical Laboratory Testing As a result of the multiorgan involvement in tuberous sclerosis complex, a variety of clinical testing is recommended both at time of diagnosis and subsequently, to monitor for involvement and allow appropriate intervention (Table 31-6). Neuroimaging studies, including MRI and computed tomography (CT), are important in confirming the diagnosis of tuberous sclerosis complex, demonstrating cortical tubers, subependymal nodules (Fig. 31-14), and subependymal giant cell tumors (Fig. 31-15). Brain MRI is the preferred imaging modality, because it allows better delineation of cortical tubers and other cortical abnormalities such as radial migration lines. The imaging characteristics of tubers change with the age of the patient, which is thought to be related to myelination. In neonates, tubers appear hyperintense on T1 sequences and hypointense on T2. With increasing age, tubers appear isointense on T1 and hyperintense on T2. In addition to T1- and T2-weighted MRI sequences, fluid-attenuated inversion recovery (FLAIR) sequences appear most useful for identifying tubers and other cortical and subcortical abnormalities. Both CT and MRI can identify subependymal nodules; calcification of the nodules is readily apparent on CT scan. In view of the risk of development of subependymal nodules into subependymal giant cell tumors, which occurs in 5% to 10% of persons with tuberous sclerosis complex, follow-up neuroimaging is recommended annually if possible until the age of 20 years [Goh et al., 2004; Roach et al., 1999].

Pathology Tuberous sclerosis complex is a multisystem disorder of cellular migration, proliferation, and differentiation, resulting in the development of hamartias and hamartomas. The major pathologic features in the brain include cortical tubers, subependymal nodules, and subependymal giant cell tumors. Cortical tubers are found in the cortex and subcortical white matter, typically located at the gray-white junction. They vary widely in size and distribution among patients TABLE 31-6 Diagnostic and Follow-up Management in Tuberous Sclerosis Complex EVALUATION

INITIAL TESTING

FOLLOW-UP TESTING

Neuroimaging

At diagnosis

Neuropsychologic testing Electroencephalogram Ophthalmologic examination Echocardiogram, electrocardiogram Renal ultrasound examination Chest computed tomography (high resolution)

At diagnosis If seizures occur At diagnosis

Every 1–3 years until age 20 At school entry and as indicated As indicated As indicated

At diagnosis

As indicated

At diagnosis

Every 1–3 years, more frequently as indicated As indicated

At onset of adulthood (women only)

From Roach ES, DiMario FJ, Kandt RS, et al. Tuberous Sclerosis Consensus Conference: Recommendations for diagnostic evaluation. J Child Neurol 1999;14:401.

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abnormal glial and neural elements, with glia-derived cells and astrocytes predominating. A distinguishing feature of cortical tubers is the giant cell—an enlarged, bizarre-appearing neuron—or large cells with both neuronal and glial characteristics. As noted previously, many children with tuberous sclerosis complex may experience learning difficulties, as a result of mental retardation or autistic spectrum disorders. Risk factors include early seizure onset, infantile spasms, and an intractable seizure disorder. Correlation between the severity of cognitive deficits and epilepsy with tuber number and location is thought probable, although the data are limited. Distinct from cortical tubers, subependymal nodules do have growth potential and are located around the wall of the lateral ventricle, consisting of astrocytes arising from the subependymal zone and protruding into the ventricles. Subependymal nodules most commonly occur at the caudothalamic groove in the vicinity of the foramen of Monro, and it is thought that they arise from remnants of the germinal matrix in that region. Although these nodules generally are asymptomatic, in 5% to 10% of persons with tuberous sclerosis complex, subependymal nodules develop into subependymal giant cell tumors, which can manifest clinically with evidence of increased intracranial pressure or with changes in behavior or seizure control. FIGURE 31-14. Magnetic resonance imaging scan of brain in tuberous sclerosis complex, showing cortical tubers (black arrows) and subependymal nodules (white arrows).

FIGURE 31-15. Computed tomography scan of brain in tuberous sclerosis complex, showing subependymal giant cell tumor.

with tuberous sclerosis complex and may extend centrally in a linear or wedge-shaped zone spanning the full thickness from the ventricular wall to the cortical surface. Histologically, tubers consist of dysplastic, hypomyelinated aggregates of

Genetics Tuberous sclerosis complex is transmitted as an autosomaldominant trait with variable penetrance and an estimated incidence of 1 in 5800 live births worldwide [Gomez, 1999]. Wide phenotypic variability of clinical manifestations and severity has been noted, even within families having the same mutation. Currently, no known effect of paternal or maternal age or of birth order on disease phenotype has been recognized. Approximately two thirds of cases are sporadic and the result of apparent spontaneous mutations. Both somatic and germline mosaicism have been described in many patients [Kwiatkowski et al., 2003]. Two genes, TSC1 and TSC2, have been identified, for tuberous sclerosis complex. A mutation in one of these two genes can be identified in approximately 85% of persons with definite tuberous sclerosis complex according to current criteria [Kwiatkowski et al., 2003]. TSC1 was linked to chromosomal location 9q34, the gene was cloned in 1997, and the protein product, hamartin, was identified and characterized [Connor and Sampson, 1991; Haines et al., 1991; Sampson et al., 1989; Smith et al., 1990; Van Slegtenhorst et al., 1997]. The TSC2 gene is located on 16p13 [European Chromosome 16 Tuberous Sclerosis Consortium, 1993a, 1993b; Kandt et al., 1992]. The gene product is tuberin [European Chromosome 16 Tuberous Sclerosis Consortium, 1993a, 1993b]. Tuberin and hamartin are known to interact with each other, and to function as tumor suppressor molecules. Loss of heterozygosity has been identified in hamartomas from persons with TSC1 and TSC2 mutations, particularly in kidney and lung tissue, but less commonly in cortical tubers or subependymal giant cell astrocytomas [Henske et al., 1994]. Tuberin has GTPase-activating properties, similar to the NF1 protein product. TSC1 and TSC2 protein products participate in the 3-kinase–Akt-S6 kinase pathway to regulate cell size [Gao,

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2001; Manning et al., 2002; Potter et al., 2001; Tayon et al., 2001]. In vivo, it appears that tuberin can be phosphorylated by Akt, thereby regulating its activity. In normal cells, the TSC1/TSC2 complex acts as an inhibitor of a protein downstream in the pathway of mTOR (mammalian target of rapamycin). On growth factor stimulation or other stimuli, however, tuberin is phosphorylated by Akt, which leads to the inactivation of inhibitory activity of TSC1/TSC2 and resultant cell growth. In cells containing mutations affecting the function of TSC1 or TSC2, mTOR and S6 kinase activities are significantly increased, and cell growth is no longer regulated by the PI3-kinase–TSC1/TSC2 signaling pathway, which is thought to lead to the development of hamartoma.

Management Tuberous sclerosis complex affects most organ systems, and management and treatment recommendations vary according to organ manifestations (see Table 31-6). Affected persons should be managed with regular follow-up evaluations by a physician who is familiar with tuberous sclerosis complex, to recognize treatable manifestations early and to provide anticipatory guidance and counseling. With regard to neurologic manifestations, management focuses on treatment of epilepsy and behavioral disorders and on identification of learning disabilities. Treatment of epilepsy in tuberous sclerosis complex is similar to that for epilepsy resulting from other causes and includes antiepileptic medications, the vagus nerve stimulator, and the ketogenic diet [Thiele, 2004]. Vigabatrin is particularly effective in treating infantile spasms in patients with tuberous sclerosis complex. Epilepsy surgery has a very important role in the management of patients who have pharmacoresistant epilepsy [Weiner et al., 2004]. Currently, treatments are available for many of the manifestations, and with improved understanding of pathophysiologic mechanisms, it is hoped that specific pharmacologic treatments will be available in the future. These current treatment options are reviewed in detail in two monographs on this disorder [Curatolo, 2003; Gomez et al., 1999].

intracranial calcification was later described by Weber [1929, 1955].

Clinical Characteristics Sturge-Weber syndrome is characterized by angiomas involving the leptomeninges and ipsilateral skin of the face, typically in the ophthalmic (V1) and maxillary (V2) distributions of the trigeminal nerve. It can extend to other facial areas including the lips, gingiva, palate, tongue, pharynx, and larynx. The neck, trunk, and extremities also can be involved, either ipsilaterally or contralaterally to the facial angioma. The angioma also can involve the nasopharynx, mucous membrane, and ocular choroidal membrane, resulting in glaucoma in approximately 25% of patients (Fig. 31-16). Additional ocular findings include iridic heterochromia, strabismus, optic atrophy, and dilated retinal veins. In the brain, the associated ipsilateral leptomeningeal angioma most commonly involves the parietal and occipital regions but also may involve the temporal region and, on occasion, can affect both hemispheres. Dimitri [1923] reported that these patients had intracranial calcifications observed on the skull radiographs and described the typical serpentine “tram-track sign” of calcific intracranial densities. SturgeWeber syndrome, although inappropriately believed to be the “fourth phakomatosis” by Van Der Hoeve [1937], is included in this category of neurocutaneous disorders. No clear pattern of inheritance exists [Debicka and Adamczak, 1979]. Neurologic manifestations vary and depend on location and extent of the leptomeningeal angioma. Seizures occur in 75% to 90% of patients with Sturge-Weber syndrome and

STURGE-WEBER SYNDROME (ENCEPHALOFACIAL ANGIOMATOSIS) Sturge-Weber syndrome is characterized by presence of a facial angioma (port-wine stain, or nevus flammeus) and an ipsilateral leptomeningeal angioma, with an incidence currently estimated at 1 case in 50,000 persons [Thomas-Sohl et al., 2004]. Schirmer [1860] initially described a patient with a facial vascular nevus who had associated buphthalmos, but he did not mention the central nervous system lesion. Sturge [1879] initially described this syndrome by providing the clinical findings of a 6-year-old girl with a facial nevus who also had angiomas of the lips, gingiva, palate, floor of the mouth, uvula, and pharynx. The child had buphthalmos and was hemiparetic, and Sturge suggested that she had a similar vascular nevus of the underlying brain. Not until 1897, however, did Kalischer perform the first neuropathologic study of a patient with similar findings, demonstrating that Sturge’s initial contention of cerebral involvement by vascular nevus was correct. Associated

FIGURE 31-16. A 20-month-old girl with Sturge-Weber syndrome. Note facial angioma affecting primarily the upper face. In addition, she had a contralateral hemiparesis and hemiatrophy.

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may be refractory to treatment [Bebin and Gomez, 1998; Riviello, 2001]. It is hypothesized that the seizure activity results from cortical irritability caused by the leptomeningeal angioma, resulting in regional hypoxia, ischemia, and gliosis, although associated cortical dysgenesis also may be involved. Seizure manifestations are primarily partial motor (40%), although some patients can have primary or secondary generalized tonic-clonic (20%) and both partial and generalized seizures (40%) [Bebin and Gomez, 1988; Chao, 1959]. Other types of seizure activity occur less frequently. Unfortunately, refractory epilepsy develops in a significant number of patients with Sturge-Weber syndrome, ranging in series from 11% to 83% [Riviello, 2001]. Surgical procedures including focal cortical resection, hemispherectomy and corpus callosotomy should be considered if seizure activity proves medically intractable. Persons with Sturge-Weber syndrome also are at risk for hemiparesis contralateral to the leptomeningeal angioma, which is seen in approximately 33% of the patients. The hemiparesis can result from ischemia with venous occlusion and thrombosis due in part to venous congestion resulting from failure of cortical vein development [Alexander, 1972; Chamberlain et al., 1989; Chao, 1959; Hebold, 1913]. Transient weakness also may result from seizure activity and may become more severe and less transient with recurrent seizure activity. Leptomeningeal venous angiomas can arise in the absence of any facial angioma; although secondary cerebral signs and symptoms similar to those of Sturge-Weber syndrome can occur, these patients are more appropriately considered to have leptomeningeal angiomatosis [Jacobs and Walton, 1976]. Persons with Sturge-Weber syndrome also are at risk for developmental delay and mental retardation, which occur in 50% to 60% of the patients and are more likely in those with bilateral leptomeningeal involvement [Bebin and Gomez, 1988]. Headaches also are common, occurring in up to 60% of affected persons, and are thought to be secondary to the vascular abnormalities, giving symptoms consistent with migraine [Maria, 1998]. EEG studies document decreased amplitude and frequency of electrocerebral activity over the affected hemisphere. Diffuse, multiple, and independent spike foci commonly are present [Aminoff, 1992; Sassower et al., 1994]. Hemianopsia in young patients also is difficult to determine but is believed to occur in about one fourth to one half of patients. About one third of patients have glaucoma, and approximately half of these have buphthalmos ipsilateral to the facial angioma. Glaucoma can be unilateral or bilateral, regardless of whether the facial angioma is bilateral. Intracranial calcification is evident on radiographs in 90% of adult patients. Calcifications uncommonly are present at birth but are manifest in virtually all patients by the end of the second decade of life [Nellhaus et al., 1967]. The intracranial calcifications typically assume a linear, parallel configuration (“tram-track sign”) or a convolutional pattern most commonly seen in the parietal or parieto-occipital regions [Ozonoff, 1974; Taveras and Wood, 1964; Thomas-Sohl et al., 2004] (Fig. 31-17). Cranial CT and MRI scans are complementary in evaluating the cerebral changes of Sturge-Weber syndrome, in that the MRI demonstrates thickened cortex, decreased convolutions, and abnormal white matter, whereas cranial CT scans demonstrate more definitively the charac-

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FIGURE 31-17. Lateral skull radiograph from a young child with Sturge-Weber syndrome, demonstrating parallel linear calcifications (the “tram-track sign”).

teristic calcification. Cranial MRI scans (T2-weighted images) reveal smaller, nonspecific foci of hypointense signal [Chamberlain et al., 1989; Thomas-Sohl et al., 2004]. Gadolinium enhancement may reveal pial angioma, thereby allowing early diagnosis of Sturge-Weber syndrome before calcification [Sugama et al., 1997]. Cerebral angiography discloses decreased cerebral venous drainage with dilatation of the deep cerebral veins. Various other vascular abnormalities have been demonstrated in approximately one third of patients and include thrombotic lesions, dural venous sinus abnormalities, and arteriovenous malformations [Bentson et al., 1957]. PET provides a sensitive measure of the extent of cerebral metabolic impairment. Serial PET scans in children with Sturge-Weber syndrome can be useful and, when used with other neuroimaging studies, document the progression of the disease [Chugani et al., 1989].

Pathology Sturge-Weber syndrome is thought to be caused by the presence of residual embryonal blood vessels and their secondary effects on surrounding tissues. During development, a vascular plexus develops around the cephalic portion of the neural tube, under the ectoderm that subsequently becomes facial skin. This plexus forms during the sixth week of gestation and regresses at approximately the ninth week. It is thought that failure of this regression results in residual vascular tissue, subsequently forming the angiomata of the leptomeninges, face, and ipsilateral eye. Neuropathologic studies have demonstrated thickened, hypervascularized leptomeninges that involve the occipital, parietal, or temporoparietal region primarily (Fig. 31-18). These meningeal vessels generally are small and tortuous and rarely enter the

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Fuchs [1882] posited that the retinal lesions were arteriovenous malformations, and Collins [1894] believed that the retinal lesions were hemangioblastomas. Von Hippel [1911] believed that the retinal lesions were hemangioblastomas but labeled them as angiomatosis retinae. The postmortem examination in one patient with retinal lesions reported by von Hippel [1911] revealed cerebellar tumor, hypernephroma, and cystic lesions of the pancreas, kidney, and epididymis. Lindau [1926] recognized the similarity of the tissue type of the retinal lesions and some cerebellar tumors and also observed that the same type of tumor occasionally was found in the medulla and spinal cord. FIGURE 31-18. Coronal section of the brain in Sturge-Weber syndrome. There is an extensive leptomeningeal angioma, with notable underlying brain atrophy affecting primarily the parietal and occipital lobes. (Courtesy of Dr. Nathan Malamud, University of California Medical Center, San Francisco, CA.)

underlying brain substance. Calcific deposits are present in the walls of some small cerebral vessels but more commonly are found in the outer pyramidal and molecular cortical layers. Biochemical assays have demonstrated increased calcium content of the gray and white matter, with normal iron content. The pathophysiology of the deposition of intracerebral calcium is not well understood [Thomas-Sohl et al., 2004; Tingey, 1956; Wachswulth and Lowenthal, 1979; Weber, 1929].

Management Treatment for the neurologic manifestations of SturgeWeber syndrome includes management of seizure activity and headaches. Approximately 50% of children with seizures achieve control with administration of appropriate antiepileptic drugs. Those patients with seizure disorders refractory to medical treatment should be carefully considered for epilepsy surgery with resection of the affected lobe(s) or hemispherectomy. Rochkind and colleagues [1990] reported that seizure control after surgery was better in those patients who received antiepileptic drugs. Treatment options for the facial angioma include laser therapy using various pulsed-dye lasers, as well as pulsed-light sources, and other laser therapies. The current recommendation is to begin treatment as early as possible; infants have received treatment during the first week of life. Treatment of glaucoma, if present, consists of control of intraocular pressure, to prevent optic nerve injury, by medical or surgical intervention. The management of patients with Sturge-Weber syndrome requires the skill of an attentive physician, psychologist, and social worker.

VON HIPPEL-LINDAU DISEASE Von Hippel-Lindau disease is inherited as an autosomaldominant trait and is characterized by associated retinal, cerebellar, and spinal hemangioblastomas cystic tumors of the pancreas, kidney, and epididymis, renal cell carcinoma, and, in some families, pheochromocytoma. The basic pathologic lesion is a capillary hemangioblastoma. The retinal lesions, originally described by Panas and Remy [1879], were not recognized as hemangioblastomas.

Clinical Characteristics Retinal hemangioblastoma is one of the earliest manifestations of the disease, and although it has been reported in early childhood [Ridley et al., 1986; Webster et al., 1999], it usually is first observed during the third decade of life (Fig. 31-19A). The early retinal lesion has the appearance of an aneurysmal dilatation of a peripheral retinal vessel; typically, tortuous vessels later manifest, with an arteriovenous pair leading to small, elevated retinal lesions [MacMichael, 1970]. These lesions commonly are located in the retinal periphery and can easily be overlooked unless careful ophthalmoscopy is performed. Fluorescein angiography is helpful in demonstrating the lesion [Atuk et al., 1979; Augsburger et al., 1981; Greenwald and Weiss, 1984]. An accumulation of fluid beneath the retina can occur, and retinal detachment with progressive visual loss commonly is observed as the first manifestation of retinal abnormality [Goldberg and Duke, 1968; Hardwig and Robertson, 1984; Kupersmith and Berenstein, 1981; Palmer, 1972; Webster et al., 1999]. Although they usually affect the cerebellum, central nervous system hemangioblastomas sometimes are found in the medulla and spinal cord and rarely occur in the cerebral hemispheres. The tumor usually is found in patients after the third decade of life but has been reported to occur rarely in children; initial symptoms and signs are those of a spaceoccupying lesion of the posterior fossa. Symptoms and signs tend to be associated with tumors that display a cystic component [Slater et al., 2003]. Hemangioblastomas of the medulla or spinal cord are associated with syringomyelia in approximately 80% of patients [Salazar and Lamiell, 1980]. The tumor rarely is found in the supratentorial region and can occur in the pituitary gland, third ventricle, or cerebral hemispheres (i.e., frontal, temporal, parietal, and parietooccipital lobes). A variety of renal lesions has been found in von HippelLindau disease, including benign cysts, hemangiomas, adenomas, and malignant hypernephromas. Cystic lesions vary in size, ranging from a few millimeters to several centimeters across, and, although they can occur unilaterally, these lesions are more often bilateral and multiple [Melmon and Rosen, 1964]. The cystic lesions can be so extensive that they mimic polycystic kidney disease. A prominent cause of morbidity and mortality is renal cell carcinoma, occurring with a frequency next to that of the retinal and cerebellar hemangioblastoma [Christenson et al., 1982; Fill et al., 1979; Horton et al., 1976; Ludmere and Kissane, 1981, Neumann et al., 1998].

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which can be elevated in patients with cerebellar hemangioblastoma or malignant hypernephroma because of the increased erythropoietin activity of the cyst fluid. The absence of polycythemia, however, does not exclude the diagnosis of the tumor. Patients with central nervous system tumors commonly have increased protein concentration of the cerebrospinal fluid. A urine assay for epinephrine, norepinephrine, and vanillylmandelic acid should be performed to screen for the presence of pheochromocytoma [Jeffrys, 1975; Scully et al., 1978]. Genetic testing of the von HippelLindau gene is clinically available [Glasker, 2005].

Pathology

A

The tumors usually are well circumscribed, can be solid or cystic, and usually are found in the paramedial aspect of the cerebellar cortex (see Fig. 31-19B). Characteristic microscopic features include large numbers of thin-walled closely packed blood vessels lined by plump endothelial cells; the cells are separated by large, pale cells and incorporated in the elaborate network of reticulin fibers [Rubenstein, 1972; Russell and Rubenstein, 1977].

Genetics

B FIGURE 31-19. Von Hippel-Lindau disease. A, Typical round, elevated, whitish-red retinal lesion. These retinal angiomatous hamartomas can be located centrally near the optic disc or peripherally. (Courtesy of Dr. Creig Hoyt, University of California Medical Center, San Francisco, CA) B, Cerebellar hemangioblastoma. Note the typical paramedial and superficial location of the tumor.

Cystic lesions can also occur in the pancreas, adrenal gland, and epididymis. Other organs less commonly affected with cystic changes include the liver, spleen, and lung. Endolymphatic sac tumors associated with von Hippel-Lindau disease can cause hearing loss [Manski et al., 1997]. Pheochromocytomas occur more often in patients with von Hippel-Lindau disease than in the general population, with an incidence reported to range from 3.5% to 17% of patients [Atuk et al., 1979], and tend to cluster in certain families. The retinal hemangioblastoma diagnosis usually is established by careful ophthalmoscopy with fluorescein retinal angiography, revealing the vascular characteristics of the lesions. Cranial MRI scans demonstrate the cerebellar hemangioblastoma or those tumors affecting the medulla and spinal cord. Intra-abdominal cystic lesions can be visualized by CT, MRI, or ultrasonography. Other laboratory studies that can assist in diagnosis include erythrocyte count and hematocrit determination,

Von Hippel-Lindau disease is inherited as an autosomaldominant trait. It is estimated to affect about 1 in 36,000 persons [Maher et al., 1991]. Penetrance is found to be nearly complete on careful evaluation [Christoferson et al., 1961; Silver, 1954]. The gene is located on 3p25-26 [Latif et al., 1993] and encodes a protein that regulates a cellular system that senses and responds to hypoxia [Kaelin, 2003]. The von Hippel-Lindau gene functions as a tumor suppressor; hence, homozygous mutation occurs in tumors, leading to loss of function and constitutive activation of the hypoxia-sensing pathway. Genetic testing is available and has revealed that specific mutations tend to be found in families with von Hippel-Lindau disease associated with pheochromocytoma [Chen et al., 1995; Freidrich, 2001].

Management Posterior fossa hemangioblastomas are treated by surgical removal of the cystic structure and mural nodule. Retinal hemangioblastomas should be carefully followed by serial ophthalmologic evaluations when the lesion is small. If, however, visual loss or retinal detachment occurs, the lesions can be treated by either laser photocoagulation or cryocoagulation [Augsburger, 1981; Webster et al., 1999].

MAFFUCCI’S SYNDROME Maffucci’s syndrome is a rare congenital disease characterized by multiple enchondromas with secondary hemangiomas, phlebolithiasis, and malformations of bone. Occasionally, associated skin changes, including patches of vitiligo, café-aulait spots, and other hyperpigmented patches and nevi, are seen. The reported cases are sporadic, and no gender predilection exists. A related disorder, Ollier’s disease, is characterized by multiple endochondromas without hemangiomas. Hopyan and colleagues [2002] have identified mutations in the

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gene encoding the parathyroid hormone/parathyroid hormone– related protein (PTH/PTHrp) type I receptor in persons with endochondromatosis, suggesting that the disorder is inherited as autosomal dominant with most cases due to new mutation. The initial report of this syndrome by Maffucci [1881] described a 40-year-old woman who had multiple enchondromas, some of which had undergone sarcomatous changes. Her four children had no stigmata of the disease. Kast, von Recklinghausen, and others published case reports, but a complete clinical description of this syndrome was not available until 1948; the authors named it Maffucci’s syndrome in recognition of the previous publication [Carleton et al., 1948]. The enchondromas affect the small bones of the hands and feet or any bone preformed in cartilage; they are apparent during the first few years of life. Initially, a small, firm nodule 1 to 2 cm in diameter usually is found on digital bone; the nodule is readily palpable. Additional, similar nodules appear shortly thereafter. They are unilateral in about 40% of patients and, if bilateral, are strikingly asymmetric [Bean, 1955, 1958]. During childhood, the enchondromas increase in size, ultimately resulting in malformations of the limbs and trunk (Fig. 31-20). Patients generally are of small stature and have a distinctive appearance resulting from their deformities. Of all patients, about 20% to 30% have enchondromas that undergo sarcomatous changes [Albregts and Rapini, 1995; Ramina et al., 1997; Schwartz et al., 1977]. Cutaneous hemangiomas become apparent during the first decade of life and are not necessarily found in the areas of enchondromas. They can be superficial or deep, and they may affect the lips, tongue, palate, or cheeks. Visceral hemangiomas involving the esophagus, ileum, and anal mucosa have been reported. Patients have cavernous hemangiomas and lymphangiomas. Neurologic complications of Maffucci’s syndrome likely are more common than recognized. The signs and symptoms depend on the location and size of the tumor mass and are secondary to cerebral encroachment by either cranial osteochondromas or a primary brain tumor [Ramina et al., 1997]. Individual case reports of patients with this syndrome include those who had pituitary or brainstem tumors and other gliomas; one patient had a brain tumor not histologically identified. Associated angiofibromas, hemangiomas, hemangioendotheliomas, teratomas, thecomas, and pancreatic adenocarcinomas have been reported [McDermott et al., 2001].

No single treatment plan exists, because each patient must be individually managed. Some bone deformities can be corrected, to a variable degree, by orthopedic procedures. Patients with neurologic signs and symptoms secondary to an intracranial osteoenchondroma can benefit from surgical excision. Primary brain tumors are treated by appropriate neurosurgical measures, which can be followed by radiation therapy, chemotherapy, or both. The partial or complete removal of hemangiomas or lymphangiomas can be accomplished by reconstructive surgical procedures or by dermatologic methods, including laser techniques. Finally, the physician must provide realistic supportive care to the patient and family, recognizing the notable limitations of any palliative surgical procedure.

EPIDERMAL NEVUS SYNDROME Epidermal nevus syndrome is a heterogeneous group of disorders characterized by patchy cutaneous hamartomatous lesions, central nervous system abnormalities, and various other manifestations (Table 31-7). Most of these disorders occur sporadically and are highly variable in their presentation [Happle, 1991; Solomon et al., 1968; Vidaurri-de la Cruz et al., 2004]. Nevi can take various forms, including verrucous, sebaceous, and lentiginous, and may evolve over the years [Mehregan and Pinkus, 1965]. They tend to follow the lines of Blaschko and manifest early in life. Central nervous system manifestations include unilateral lissencephaly, a paucity of white matter, excessive and heterotopic gray matter, apparent schizencephaly, unilateral colpocephaly, and megalencephaly [Hager et al., 1991; Patrizi et al., 1989]. Associated neurologic abnormalities include mental retardation and convulsive disorders, occurring in approximately 60% of patients; ocular abnormalities in up to 50% of patients; and corticospinal tract dysfunction in a smaller number of patients [Holden and Dekaban, 1972; Kurokawa et al., 1981]. Cortical resection has been helpful in some instances [Maher et al., 2003], but no other definitive treatment exists. The patchy manifestations of these disorders have suggested the possibility that they result from somatic mosaicism; this has been demonstrated in some instances of Proteus’ syndrome, where mosaicism for PTEN has been found [Zhou et al., 2000], and in cells of a sebaceous nevus, where loss of heterozygosity for the PTCH gene has been reported [Xin et al., 1999].

PARRY-ROMBERG SYNDROME (FACIAL HEMIATROPHY)

FIGURE 31-20. Multiple enchondromas of the digits, typically observed in Maffucci’s syndrome.

Parry-Romberg syndrome, usually apparent in early childhood and rarely manifesting shortly after birth, is characterized by a progressive loss of facial soft tissue, cartilage, and bone. This tissue loss usually begins about the cheek and nose but affects most of the ipsilateral face during the ensuing years. The eyelashes, eyebrows, and hair on the involved side can be affected, and ipsilateral blanching of the hair or alopecia can occur (Fig. 31-21). Progression of this atrophic process generally is believed to cease by the end of the second or beginning of the third decade of life

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TABLE 31-7 Classification of Epidermal Nevus Syndrome DISORDER

FEATURES

GENETICS

Sebaceous nevus syndrome (Schimmelpenning’s syndrome) Nevus comedonicus syndrome

Congenital sebaceous nevus, neurologic dysfunction, skeletal, ocular anomalies Congenital hyperkeratotic papules of follicular origin on face, neck, chest, abdomen, arms; ipsilateral eye and skeletal defects; seizures, mental retardation Hyperpigmented plaque associated with hair growth; may have smooth muscle hyperplasia; occasional rib defects, breast hypoplasia Sebaceous and speckled lentiginous nevus; ipsilateral weakness, hypohidrosis; seizures, mental retardation Epidermal nevi; asymmetrical overgrowth of soft tissues and bone Ichthyosiform nevus; skeletal aplasia or hypoplasia; abnormalities in brain, lung, heart, kidneys

Sporadic

Becker nevus syndrome Phakomatosis pigmentokeratotica Proteus syndrome Congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD)

Sporadic

Sporadic; more common in males Sporadic Sporadic; some with PTEN mutations X-linked dominant; mutations in 3β-hydroxysteroid dehydrogenase gene

For additional information, see Happle R. How many epidermal nevus syndromes exist? A clinicogenetic classification. J Am Acad Dermatol 1991;25:550; and Vidaurri-de la Cruz H, Tamayo-Sanchez L, Duran-McKinster C, et al. Epidermal nevus syndromes: Clinical findings in 35 patients. Pediatr Dermatol 2004;21:432.

NEUROCUTANEOUS MELANOSIS

FIGURE 31-21. Hemifacial atrophy as manifested in Parry-Romberg syndrome.

[Rischbieth, 1976; Stone, 2003; Wartenberg, 1945; Wolf and Verity, 1974]. In addition to atrophy of the facial tissues, various other neurologic deficits have been reported, including recurrent headaches, ipsilateral Horner’s syndrome, contralateral partial seizures, and hemiparesis [Stone, 2003]. Moreover, an unusual association of the syndrome with multiple benign tumors has been described. Scleroderma and lipodystrophy must be clinically differentiated from this disease. Cranial CT can be normal or document cerebral atrophy; contralateral intracerebral calcification has been described [Asher and Berg, 1982]. No typical or consistent neuropathologic findings have been reported. No specific treatment for the syndrome exists; however, various reconstructive surgical procedures can result in reasonably good cosmetic results [Garcher, 1990; Hintringer et al., 1991; Mayro et al., 1991].

Neurocutaneous melanosis is a rare, nonfamilial condition characterized by abnormally pigmented cutaneous areas (e.g., giant hairy pigmented nevi, multiple hyperpigmented cutaneous nevi, large congenital melanocytic nevi) and leptomeningeal melanoma [DiRocco et al., 2004]. Von Virchow [1859] first reported the topographic distribution of melanotic cells in the arachnoid, but Rokitansky [1861] provided the initial clinical description of this condition with his report of a 14-year-old mentally retarded, hydrocephalic girl who had a giant pigmented nevus over her back and multiple hyperpigmented skin lesions. At postmortem examination, a brown-black pigmentation of the pia overlying the cerebral cortex was noted. Van Bogaert [1948] named this condition neurocutaneous melanosis, and Fanconi [1956], who regarded the condition as an ectodermal dysplasia and believed it to be one of the phakomatoses, described two additional patients. Infants and children younger than 2 years of age are primarily affected; however, the condition is present at birth. No gender predilection exists. All patients have areas of abnormal skin hyperpigmentation, the most common pattern of which is one of multiple giant hairy pigmented nevi. Giant hairy nevi usually have a “bathing suit” or capeshaped distribution. A less common form is characterized by multiple hyperpigmented cutaneous nevi that, although large, cannot justifiably be classified as giant nevi [Reed et al., 1965]. In one series of 289 patients with large congenital melanocytic nevi, 33 had manifest central nervous system melanosis wherein the nevi were present in the posterior axial location on the head, neck, back, and/or buttocks. “Satellite” nevi were present in 31 of the 33 patients [DeDavid et al., 1996]. Melanoblasts, normally present in the pia mater, are manifested by small brown-black pigmented flecks in the leptomeninges that are most frequently distributed over the ventral aspect of the lower medulla. These cells are the

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presumed source of melanoma originating in the central nervous system [Rokitansky, 1861]. The leptomeninges are thickened and infiltrated by melanin-containing cells that are diffuse or arranged in sheets. Regions in which the leptomeninges are particularly involved include the brainstem, cerebral peduncles, and basilar aspects of the cerebrum and cerebellum. Leptomeninges of the upper cervical cord are affected in 20% of patients. Localized areas of intracerebral brown-black pigmentation are relatively common and most often are found in the cerebellar cortex. The clinical presentation of neurocutaneous melanosis depends on the location and extent of involvement of this leptomeningeal lesion. Hydrocephalus is commonly encountered because of cerebrospinal fluid pathway obstruction in the basilar cisterns, the arachnoid villi over the cerebral hemispheric convexities, or both, and intraspinal melanotic arachnoid cyst, lipoma, and intraspinal lipoma have been described as obstructed [Kasantikul et al., 1989; Van Heuzen et al., 1989]. Behavioral abnormalities and recurring seizures are reported to occur. Findings on cerebrospinal fluid examination can be normal; however, the protein level usually is elevated, and glucose concentration is decreased. Cytologic examination usually reveals abnormal melanincontaining cells [Fox, 1972; Hoffman and Freeman, 1967]. In one study of MRI scans of seven patients with neurocutaneous melanosis, five had regions of T1 shortening in the cerebellum, three of whom also had T2 shortening. Five patients had regions of T1 shortening in the anterior temporal lobes. Other areas of involvement included the pia mater over the cerebellum, pons, medulla, and left parietal lobe. Only two lesions demonstrated enhancement, edema, or necrosis, and both lesions were found to be malignant melanomas at biopsy [Barkovich et al., 1994]. Attempts to treat hydrocephalus by a shunting procedure are only palliative. The prognosis for neurocutaneous melanosis generally is poor, regardless of the variety of treatment methods used, which include radiation therapy, chemotherapy, or both, and patients rarely live beyond the age of 20 years.

KLIPPEL-TRÉNAUNAY-WEBER SYNDROME Klippel-Trénaunay-Weber syndrome initially was believed to be characterized only by cutaneous and/or subcutaneous hemangiomas, varicosities, and hypertrophy of the soft tissues and bone of a limb. Additional associated anomalies later recognized included macrocephaly; hydrocephalus; lymphangiomas; hemangiomas of the trunk, intestine, and bladder; and abnormalities of the digits [Klippel and Trénaunay, 1900; Lian and Alhomme, 1945; Meine et al., 1997; Parkes-Weber, 1907]. Klippel-Trénaunay-Weber syndrome usually occurs sporadically but has been found at least in some patients to be due to mutations in the VG5Q gene, which encodes a protein involved in angiogenesis [Tian et al., 2004]. Typical skin lesions usually are present at birth but may not be recognized until several years later. They can be single or multiple and affect the face, trunk, and limbs. Prenatal diagnosis has been made by ultrasonography [Hatiis et al., 1981; Howlett et al., 1994; Warhit et al., 1983]. One series of 22 patients with this syndrome comprised 9 with cutaneous hemangiomas of the head, trunk, and limbs;

another 9 with cutaneous hemangiomas of the trunk and limbs; 2 patients with hemangiomas of the trunk; and 2 patients with hemangiomas of a limb [BD Hall, unpublished data, 1983]. The vascular lesions are variable and include capillary hemangiomas, nevus flammeus, telangiectasias, varicosities, phlebectasias, and arteriovenous fistulae; lymphangiectasis also can be present. Vascular lesions usually are found in areas of limb hypertrophy. Rarely, patients with large vascular lesions have a bleeding diathesis; thrombophlebitis can occur, as well as thromboembolic phenomena. Varicosities of various sizes commonly are present and, although usually found in the lower limbs, also can be found on the scalp, chest, and torso [Hall, 1983; Incemen and Tangun, 1969]. The most common finding in this syndrome is unilateral limb hypertrophy, which usually is apparent at birth. Lymphedema can be present. An inordinately progressive growth of the affected body part eventually occurs, leading to the development of various other abnormalities. Abnormal growth of one leg, for example, can result in a pelvic tilt and scoliosis, but the patient’s overall height is not significantly changed [Lindenauer, 1965]. The legs are affected more commonly than the arms. Additional abnormalities include megalocornea, glaucoma, iridic heterochromia, syndactyly, polydactyly, macrodactyly, and clinodactyly. Hemangiomas of the tongue, pharynx, larynx, and bladder have been described, and labial and scrotal lesions are common. Macrocephaly often is present, and seizures and mental retardation have been reported. Less frequently, associated abnormalities include congenital heart malformations and imperforate anus [Banhayan, 1971; Hall, 1971, 1983; Lindenauer, 1965]. Any treatment plan for these patients must be individualized. Arteriography and, less commonly, venography can be performed if any vascular surgical procedure is contemplated. MRI scanning has been of value in delineating soft tissue abnormalities, particularly of the abdomen. Some vascular lesions can be treated with cryotherapy or laser therapy, whereas others can be surgically removed. An osteotomy or epiphyseal stapling procedure can occasionally benefit patients with limb hypertrophy, but limb amputations may be required in others.

INCONTINENTIA PIGMENTI (BLOCH-SULZBERGER SYNDROME) Incontinentia pigmenti is transmitted as an X-linked dominant trait, affecting only females [Carney, 1976; Lenz, 1961; Lucas, 1974]. Hemizygous males apparently die in utero. The gene has been identified, is referred to as NEMO, and encodes a protein that participates in the nuclear factor kappa B (NF-κB) signaling pathway [Smahi et al., 2000]. The syndrome is characterized by various hyperpigmented skin lesions that can be apparent at birth and commonly associated abnormalities involving the central nervous system, eyes, hair, teeth, and bone. Garrod [1906] likely provided the first description of this syndrome with his report of the case of a 2-year-old mentally retarded, spastic diplegic girl who had a whorled pattern of brown skin pigmentation on her trunk and limbs.

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Bardach [1925], however, is most often credited with the first clinical description of the syndrome in twin sisters; Bloch [1926], Sulzberger [1930], and Sieman [1929] each later defined the syndrome more clearly. Bloch [1926] introduced the term incontinentia pigmenti, which is still used. The skin manifestations have been described as having three stages: The first stage typically is characterized by vesiculobullous lesions present at birth or during the first several weeks of life. These lesions appear in groups or in a linear distribution over the trunk and limbs following the lines of Blaschko. A preponderance of eosinophils is found in the vesicular fluid, and the peripheral blood also can exhibit an eosinophilia. The lesions rupture, resulting in oozing and crusting, and can persist for months. The second stage is characterized by evolution into verrucous lesions beginning after the sixth week of life. The third stage typically is characterized by hyperpigmented brown or graybrown macular lesions that have a “splashed-on” appearance. These pigmented skin lesions usually become more prominent during the first few years of life and then gradually fade. The decrease of abnormal pigmentation may continue throughout adolescence, and in some patients the pigmentation can completely disappear [Carney, 1976]. One third to one half of patients have symptoms and signs of neurologic abnormalities manifested by developmental retardation, corticospinal tract dysfunction, and seizures. Microcephaly and hydrocephaly have been reported. Recurrent encephalomyelitis also has been reported [Brunquell, 1987]. Approximately one third of patients have ocular abnormalities, including optic atrophy, papillitis, abnormal retinal pigmentation, nystagmus, strabismus, and cataracts. Visual loss occurs in about 8% of patients. The most common ocular abnormalities are retinal detachment and a fibrovascular retrolental membrane [Heathcote et al., 1991]. Associated abnormalities of hair can result in atrophic scarring and alopecia, and nails can be flat and thin, commonly with transverse ridges [Carney, 1976]. Reported skeletal abnormalities include spina bifida, hemivertebrae, accessory ribs, and syndactyly [Francois, 1984]. Delayed dentition, pegged teeth, and abnormal crown formation have been described [Carney, 1976]. Skin biopsy specimens obtained early in the course of the disease demonstrate a perivascular inflammatory infiltrate composed principally of eosinophils. The verrucous stage is characterized by hyperkeratosis and epidermal hyperplasia, and the third stage is notable for hyperpigmentation, with numerous melanophages found within the dermis. Electron microscopic examination of these lesions documents defects of the basement membrane, with melanocytic dendritic processes containing melanosomes and melanin granules extending into the dermis. Few neuropathologic studies are available. Some reports have described micropolygyria, cortical atrophy, and small areas of leukomalacia; however, these findings can be nonspecific and unrelated to the disease process [Banker and Larroche, 1962; Hauw et al., 1977; O’Doherty and Normal, 1968]. MRI studies suggest that the underlying cerebral pathology may be microvascular infarcts associated with the occlusion of small vessels [Hennel et al., 2003; Lee et al., 1995]. No specific therapeutic measures exist, and treatment remains symptomatic and supportive.

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INCONTINENTIA PIGMENTI ACHROMIANS (HYPOMELANOSIS OF ITO) Incontinentia pigmenti achromians initially was described by Ito [1951] and has been known as systemic achromic nevus and hypomelanosis of Ito. Typical skin changes occur as hypopigmented lesions on any part of the head, trunk, or limbs, either unilaterally or bilaterally. The configuration of the hypopigmented lesions may manifest as linear streaks or whorls of hypopigmentation that follow the lines of Blashko. The skin lesions are congenital. Multiple associated anomalies are common and can involve the central nervous system or the peripheral nervous system, eyes, and bone [Hamada et al., 1967, 1979; Takematsu et al., 1983]. Common central nervous system abnormalities include mental retardation, language disabilities, seizures, and motor system dysfunction. Ocular abnormalities include strabismus, epicanthic folds, myopia, optic nerve hypoplasia, and hypopigmentation of the fundus; rarely, corneal asymmetry, pannus, and atrophic irides with irregular pupillary margins have been reported. Cataracts and retinal detachments also have been reported. Visual loss has not been reported in patients with incontinentia pigmenti achromians [Takematsu et al., 1983; Weaver et al., 1991]. Characteristic histologic features of skin biopsy specimens include dyskeratosis, increased dermal mastocytes, and pilosebaceous abnormalities. Electron microscopy reveals few melanosomes, sparsely dendritic melanocytes, and a reduction in the number of melanosomes in keratinocytes [Schwartz et al., 1977]. In one study, MRI was performed in 13 affected patients, and anomalies of the white matter were observed in 7. Abnormal signals in white matter were located primarily in the parietal, periventricular, and subcortical regions of both hemispheres, and asymmetry of the cerebral and cerebellar hemispheres was observed in each of two patients. A correlation between the white matter changes and neurologic symptoms and signs was noted [Ruggieri et al., 1996]. Hypomelanosis of Ito occurs sporadically and in many cases has been found to be associated with mosaicism for chromosomal abnormalities. The abnormal cells may be confined to the skin lesions and therefore are detected only by cytogenetic analysis of cultured fibroblasts obtained by skin biopsy. No single chromosome abnormality accounts for all cases; rather, it appears that the streaky hypopigmentation associated with the disorder, or sometimes patches of hyperpigmentation following Blaschko’s lines, are the cutaneous manifestation of mosaicism for various genes or chromosomal regions [Flannery, 1990; Ritter et al., 1990; Taibjee et al., 2004; Zajac et al., 1997].

WYBURN-MASON SYNDROME (RETINOCEPHALIC ANGIOMATOSIS) Magnus [1874] described a retinal vascular formation as a medical curiosity. Yates and Paine [1930] reported an extensive retinal and ipsilateral cerebral arteriovenous malformation in a patient who died from cerebral hemorrhage, but the association of a unilateral arteriovenous malformation of the retina, brain, and parts of the face and head

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initially was described in a postmortem examination report by Brock and Dyke [1932]. Bonnet and co-workers [1937] emphasized the importance of a coexisting tortuous angioma of the fundus in patients with intracranial arteriovenous malformations. In 1943, Wyburn-Mason described the clinical syndrome in detail. Although known as Bonnet-DechaumBlanc syndrome in Europe and as Wyburn-Mason syndrome in England and the United States, the condition is more appropriately called a retinocephalic vascular malformation [Bonnet et al., 1937; Wyburn-Mason, 1943]. Wyburn-Mason [1943] reviewed reports of 27 patients with retinal angiomas and found signs of intracranial arteriovenous malformations in 22 patients. He later surveyed reports of 20 other patients with midbrain arteriovenous malformations and found 14 of those with associated retinal arteriovenous malformations. He then suggested that the syndrome was more common than had been suspected and that patients with vascular malformations of the retina or brain were likely to have other organs similarly affected. Because many of his patients had not been studied with cerebral angiography and only two patients had neuropathologic confirmation of the lesion, his suggestions were criticized, and the syndrome has been considered rare [Bech and Jensen, 1958]. Four patients with Wyburn-Mason syndrome have been reported to have unilateral optic atrophy and intraorbital and suprasellar arteriovenous malformations but not retinal arteriovenous malformations [Ponce et al., 2001]. One patient had a vascular malformation of the ipsilateral maxilla and mandible, and another had an ipsilateral facial vascular lesion. The retinal lesions are unilateral and readily observed by ophthalmoscopy. The vascular malformation affects one or all retinal vessels, which are notably dilated and tortuous. Ocular enlargement, conjunctival hyperemia, and proptosis usually occur; a cranial bruit is commonly present. Visual function of the involved eye is rarely normal, and the visual loss varies according to the severity of the vascular malformation. The retrobulbar soft tissue and optic nerve commonly are affected by the malformed vessels [Hoyt and Cameron, 1968; Reck et al., 2005]. The intracranial vascular malformation usually is deep within the brain substance and can involve the mesencephalon, diencephalon, and basal ganglia, extending to the visual pathways and chiasm. Variable involvement of the cranial nerves occurs, including the third, sixth, seventh, and eighth nerves; nystagmus and Parinaud’s syndrome have been reported. Corticospinal tract dysfunction can be unilateral or bilateral, and some patients are ataxic [Hoyt and Cameron, 1968; Theron et al., 1974]. Approximately one half of patients have vascular malformations that affect the palate, oral mucosa, maxilla, and mandible. Cutaneous lesions also can occur, manifesting as angiomas or punctate erythematous lesions. The diagnosis of this syndrome is initially considered when the retinal vascular lesion is observed. Cranial CT and MRI scans clearly demonstrate arteriovenous malformation, but only cerebral angiography reliably delineates the extent of the lesion [Fujita et al., 1989; Hopen et al., 1983]. No beneficial treatment method is currently available for this syndrome. The surgical removal of part or all of the extensive vascular malformation cannot be performed with any practical success, and the use of rigorous radiologic interventional techniques has been unsuccessful.

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CHAPTER 32

Mental Retardation and Global Developmental Delay Elliott H. Sherr and Michael I. Shevell

DEFINITIONS Mental retardation and global developmental delay are related, complementary, non-synonymous terms featuring common and distinctive characteristics. In a manner analogous to cerebral palsy, each is a symptom complex highlighting a clinically recognizable entity that is etiologically heterogeneous and that mandates a particular evaluation, management, and intervention approach. Both can be conceptualized as developmental disabilities that can be defined as early-onset, chronic disorders that share the essential feature of a predominant disturbance in the acquisition of cognitive, motor, language, or social skills, which has a significant and continuing impact on the developmental progress of an individual [APA, 1994]. The consensus definition put forward in 2002 by the American Association on Mental Retardation (AAMR) defines mental retardation as “a disability characterized by a significant limitation both in intellectual functioning and in adaptive behavior as expressed in conceptual, social, practical, and adaptive skills.” This disability originates before the age of 18 [AAMR, 2002] and manifests with severe problems in the individual’s capacity to perform (i.e., impairment), the ability to perform (i.e., activity limitations), and the opportunity to function (i.e., participation restrictions) [WHO, 2001]. Correct and consistent application of the AAMR definition requires an awareness of five inherent contextual assumptions: Limitations in current functioning are to be considered within the context of an individual’s typical community environments; valid assessments must consider, reflect, and be sensitive to linguistic and cultural diversity; limitations coexist with strengths; by describing limitations, a profile of needed supports can be conceptualized; and with appropriate sustained support, the life function of an individual with mental retardation can often be improved. Objectifying limitations in intellectual functioning requires defining and consistently measuring intelligence. This has proved problematic in the child younger than 5 years, an age below which widely used measures of intelligence are not generally standardized or considered reliable [Gould, 1981]. The young child is rapidly progressing concurrently through various developmental domains [Simeonsson and Sharp, 1992]. Limitations and delay in the widespread acquisition of these skills may suggest a developmental disability that mandates evaluation and intervention and that may be a harbinger of later mental retardation. For the young child, the term global developmental delay has emerged to describe a disturbance across a variety of developmental domains [Batshaw and Shapiro, 1997; Fenichel, 2001; Kinsbourne and Graf, 2001; Majnemer and Shevell, 1995; Shevell et al.,

2000; Simeonsson and Simeonsson, 2001]. The latest consensus definition used by the American Academy of Neurology (AAN) practice parameter statement defines global developmental delay operationally as a significant delay in two or more developmental domains (e.g., gross/fine motor, cognitive, speech/language, personal/social, activities of daily living) [Shevell et al., 2003]. Mental retardation and global developmental delay are frequently diagnosed on the basis of experienced clinical judgment in advance of or as a substitute for detailed standardized assessments. The precise relationship between the diagnoses of mental retardation and global developmental delay must still be determined [Petersen and Kube, 1998; Yatchmink, 1996].

EPIDEMIOLOGY Much information has been ascertained regarding the prevalence and causes of mental retardation; however, interpretation of these data necessitates an understanding of the assumptions inherent in these analyses. The operational parameters for mental retardation usually include an intelligence quotient (IQ) value that is 2 standard deviations below the mean (IQ < 70), identification before the age of 18, and difficulties in adaptive functioning. Although definitions are arbitrary, they allow for agreement on standardization of measurement. Assuming a normal distribution of IQ scores, approximately 2.25% of individuals will have an IQ below 70. Many of these individuals (given the high correlation between scores on IQ tests and standardized adaptive functioning tests) will also have adaptive difficulties, meeting the definition of mental retardation. Early population-based studies seem to have confirmed this point. Hagberg and Kyllerman [1983] documented a rate of mental retardation of 2%; 1.5% had mild mental retardation (IQ of 50 to 70), and 0.5% had moderate or severe mental retardation (IQ of less than 50). The population studied and the instruments used can influence the rate of mild mental retardation, but they seem to have little effect on the rate of severe mental retardation. The prevalence rates for mild mental retardation in 15 subsequent studies varied from 5 to 80 cases per 1000 people, with an average prevalence of 35 per 1000. In contrast, in 37 studies the prevalence of severe mental retardation varied only between 2.5 and 7 per 1000, with an average of 3.6 per 1000 [Leonard and Wen, 2002]. Because the highest percentage of children with mental retardation are in the mild range, any change between measured populations in mental retardation definitions or in the type or severity of deleterious environmental exposures (e.g., poor education, nutrition, environmental toxins such

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as lead) can have a significant effect on the overall numbers of children with mild mental retardation. One of the more comprehensive investigations of mental retardation, the Metropolitan Atlanta Developmental Disabilities Study, identified a smaller than average rate for mild mental retardation (IQ of 50 to 70) of 8.4 per 1000, whereas that for severe mental retardation, at 3.6 per 1000, was consistent with the metaanalysis average [Boyle et al., 1996; Yeargin-Allsopp et al., 1997]. This study also documented two additional observations about the prevalence of mental retardation: race disparity and gender imbalance. The Atlanta study found that mental retardation was 50% more overrepresented among blacks than in the white population [Yeargin-Allsopp et al., 1995] and that the male-to-female ratio was 1.4:1.0. A California study reported a similar rate of racial disparity for all categories of mental retardation and found that there was a substantial increased risk associated with low birth weight and maternal age [Croen et al., 2001]. Additional maternal influences observed in this study that increase the risk for mental retardation include poor nutritional status, tobacco smoking, and alcohol consumption. Paternal smoking also increases the risk for having affected children. In almost every study, gender disparity is a consistent finding, with males accounting for 20% to 40% more of the cases than females. A significant component of this difference may be related to X chromosome disorders, but studies have shown that maternal smoking or low birth weight has a more direct effect on IQ in male infants, suggesting that this disparity has many causes [Leonard and Wen, 2002]. Although there is considerable variation in the numbers of individuals diagnosed with mental retardation, there is less disagreement about the known causes of mental retardation and the high percentage of cases with unknown causes. For classification purposes, mental retardation cases are often grouped by prenatal, perinatal, and postnatal causes. The prenatal group includes known genetic syndromes and chromosomal disorders, central nervous system malformations, and toxic or infectious causes. Perinatal conditions include birth asphyxia, stroke, and infection. Postnatal conditions include infection, toxins (e.g., lead), and injury, such as nonaccidental trauma. Using this classification, the metropolitan Atlanta study found that 87% of children with mild mental retardation and 57% of moderately to severely affected children did not have identified causes. A similar breakdown—77% for mild and 65% for severe cases—was found in the California study. Among the causes identified, chromosomal defects were the most common, accounting for 25% of all causes of mental retardation among more than 4.5 million live births in California; Down syndrome was the single most common known chromosomal cause. Other causes of retardation, including infection, central nervous system anomalies, and metabolic or endocrine causes, accounted for up to 8% of the total. In this analysis, low birth weight and other environmental exposures were not counted as biomedical causes, although they were associated with increased risk, as previously mentioned. Better focus on how these environmental influences affect ultimate IQ is essential for prevention and early intervention. Many individuals with severe or mild mental retardation are unable to become productive members of society and require institutionalized or group-home care. The economic

costs to society are substantial. In a Dutch study, mental retardation was the disease category with the largest health care costs, almost equal to the economic impact of stroke, heart disease, and cancer combined [Meerding et al., 1998]. An analysis by the U.S. Centers for Disease Control and Prevention (CDC) estimates lifetime costs of more than $1 million dollars per person with mental retardation, which is more than that for cerebral palsy, hearing loss, or vision impairment [CDC, 2004].

HISTORY AND ETHICS The first to draw a clear distinction between mental retardation and mental illness was the English philosopher John Locke, who wrote in his essay Concerning Human Understanding (1690), “Herein seems to lie the difference between idiots and madmen, that madmen put wrong ideas together and reason from them, but idiots make very few or no propositions and reason scarce at all.” The development of intelligence testing by Alfred Binet and Theodore Simon in 1905 ushered in an era of a more rigorous, scientific approach to defining mental retardation that became the basis for formulating an approach to its comprehensive management [Sherr and Ferriero, 2003]. Early 20th century definitions of mental retardation focused on its incurability with permanent predetermined limitations and consistent prevention of participation in society (e.g., “mental deficiency is a state of incomplete mental development of such a kind and degree that the individual is incapable of adapting himself to the normal environment of his fellows in such a way to maintain existence independently of supervision, control or external support”) [Tredgold, 1937]. In the middle of the 20th century, adaptive behavior limitations were added as criteria for diagnosing mental retardation [Heber, 1961]. This addition was meant to implement a reduction in rigid reliance on IQ scores and to better reflect the social characteristics of the disability that is attached to mental retardation. Adaptive behavior deficiency was conceptualized as problems in maturation, learning, or social adjustment that were based on difficulties in adjusting to ordinary demands. By 1973, the AAMR definition of mental retardation required concurrent manifested deficits in general intellectual function and adaptive behavior [Grossman, 1973]. A 1992 AAMR definition specified the adaptive skill areas affected and emphasized limitations in current functioning across the individual’s lifespan [Luckasson et al., 1992]. Evolution of the concept of mental retardation has been marked by an ongoing debate regarding the nature of intelligence and its measurement. Despite the changing nuances of its definition, the primary criterion for diagnosing mental retardation over time has always been a deficit in intellectual ability [Gottfredson, 1997]. Factor analysis of data obtained from administering cognitive tests to large groups of individuals permitted the objectification of a unifactorial latent trait (i.e., general intelligence) to account for the variance between cognitive scores [Spearman, 1927]. Within this framework, intelligence was conceptualized as general mental capability that includes the ability to reason, solve problems, think abstractly, plan, and learn from experience [Carroll, 1997]. In essence, it is a reflection of a person’s

Sherr and Shevell / Mental Retardation and Global Developmental Delay

ability to comprehend his or her surroundings. In contradistinction to the established unifactorial position of intelligence, several theoretical models of intelligence as a multidimensional construct have been put forward, with each intelligence component featuring distinctive developmental trajectories, problem-solving, and information processing capacities [Gardner, 1993]. Validation by standardized and quantifiable measures of these intriguing and intuitively appealing constructs of intelligence remains elusive. Historical controversy exists regarding the mechanisms by which intelligence can be measured and the social, cultural, and ethnic contexts of its measurement [Gould, 1981]. Establishing cutoff points for the labeling of “subaverage intellectual functioning” has also been problematic [MacMillan et al., 1995]. IQ scores have unfortunately been used at various historical points to further biologically determinist agendas and to potentially demonize minority groups. A survey of the past century reveals a remarkable trajectory in the treatment of those affected by mental retardation or global developmental delay in Western society. With the prominence of eugenics (i.e., science of the improvement of the human race by better breeding) in the first part of the 20th century, those with mental retardation were targeted for involuntary eugenic sterilization in many jurisdictions [Kevles, 1985]. Eugenically based, active euthanasia programs targeting children or adults with mental deficiency were implemented in Nazi Germany and resulted in the known deaths of almost 80,000 individuals in a prelude to the horrors of the Holocaust [Parent and Shevell, 1998; Proctor, 1988]. These biologic programs fit with the political philosophy of the Nazis to restore pan-German power by restoring the vigor of the Aryan race. These programs were proving grounds for much of the killing techniques to be implemented by the Nazis in their murderous reign across occupied Europe. The global emphasis after World War II on individual civil rights resulted in national and international mandates that provided for legislative and judicial protection for the intellectually disabled from active discrimination (e.g., Americans with Disabilities Act of 1990). Early educational, rehabilitation, and school programs financed by public funds for those at risk for developmental disability or affected by mental handicap (e.g., Early Intervention Amendments to the Education of the Handicapped Act, Education for All Handicapped Children Act) have been implemented. These mandates for discriminatory protection and service provision exist with broad community and political support, providing a level of class protection not previously encountered. The absence of the capacity for competence (defined as “the ability to understand the context of the decision, the choices available, the likely outcomes of the varying choices, and to rationally process this information to make a decision”) together with minority age (typically less than 18 years) renders the pediatric patient with global developmental delay or mental retardation doubly vulnerable with respect to ethical issues [Bernat, 2002]. The cornerstone of ethical modern medical practice is the respect for individual autonomy reflected in the primacy accorded to informed consent in all aspects of medical decision-making [Faden et al., 1986]. Unable to ever provide informed consent, a “best interest” model for decision-making must be implemented that mandates careful selection of responsible proxy

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decision-makers and consideration of the risks and benefits for intervention from the unique perspective of the affected individual [Shevell, 1998]. Consensus exists that cognitive disability alone should never be the only reason to withhold or withdraw care. Developmentally appropriate models of assent that respect the cognitive capacity of the intellectually disabled offer an alternative to enhance our ethical practice [AAP, 1995]. A determined effort must be made to not use the challenges faced in ethical practice with this population to abandon efforts through research to improve all aspects of care and outcome [Shevell, 2002].

DIAGNOSIS Definitions and Testing Accurate diagnosis of mental retardation or global developmental delay is an essential precondition to proper management and service provision. Accurate diagnosis serves many functions, including understanding the specific associated medical and psychiatric complications, eligibility for service and support provision and its specific attributes, family counseling, and legal recognition of disability. The diagnosis of mental retardation as defined requires demonstration of significant limitations in intellectual functioning and adaptive behavior [AAMR, 2002]. Intelligence, conceptualized as general mental capabilities, is best represented objectively by an IQ score obtained through proper application of an appropriate assessment measure [Hernstein and Murray, 1994]. Adaptive behavior refers to skills (i.e., conceptual, social, and practical) that a person learns to function within the context of everyday life. Definite limitations in these skills affect the ability to respond to changes and demands encountered affecting performance in daily life. Standardized, age-appropriate measures have been normed and validated on normal populations to assess adaptive behavior skills [Spreat, 1999]. For intellectual function and adaptive behavior, a significant limitation thought sufficient to trigger possible inclusion under the rubric of mental retardation is performance at least 2 standard deviations below the mean for an appropriate test [AAMR, 2002]. Some of the standardized measures for the evaluation of intellectual, neurodevelopmental, and behavioral testing are summarized in Table 32-1, and a qualitative description of IQ and index scores on Wechsler tests that categorize intelligence levels is provided in Table 32-2. If there is reliance on standardized tests for diagnosis, potential errors in measurement need to be considered. Variation in test performance can be expected based on a variety of identified or unidentified factors. This is reflected statistically in the concept of the standard error of measurement, which for widely used measures with the typical mean of 100 and a standard deviation of 15 is between 3 and 4 points. The score obtained on a single test is not a precise one, but rather is bounded by a range of confidence that has been called the zone of uncertainty [Reschly, 1987]. This uncertainty is reflected in the conceptual hesitation to apply a fixed cutoff point for inclusion and the explicitly recognized need to consider an instrument’s standard error of measurement in considering the construct of significant subaverage functioning intellectually or in adaptive behavior [AAMR,

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TABLE 32-1 Measures for Evaluation of Intellectual, Neurodevelopmental, and Behavioral Progress TEST NAME, AGE RANGE OF SUBJECTS, AND TEST PUBLICATION DATA Developmental Tests Bayley Scales of Infant Development, Second Edition (Bayley II) 16 days to 3 years 6 months 15 days Nancy Bayley, The Psychological Corporation, 1993, www.psychcorp.com (Bayley III due in fall 2005)

Bayley Infant Neurodevelopmental Screener (BINS) 3 months to 24 months Glen P. Aylward, The Psychological Corporation, 1995, www.psychcorp.com

Denver Developmental Screening Test II (Denver II) Birth to 6 years W. K. Frankenburg and J. B. Dodds, et al., Denver Developmental Materials, 1992, www.denverii.com

Intelligence or Cognitive Tests Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) 6 years 0 months 0 days to 16 years 11 months 30 days David Wechsler, The Psychological Corporation, 2003 (Spanish version, 2005), www.psychcorp.com Wechsler Preschool and Primary Scale of Intelligence, Third Edition (WPPSI-III) 2 years 6 months 0 days to 7 years 3 months 30 days Preschool level: 2 years 6 months 0 days to 3 years 11 months 30 days; Primary level: 4 years 0 months 0 days to 7 years 3 months 30 days

TEST DESCRIPTION

ADMINISTRATION AND SCORING INFORMATION

Standardized assessment of cognitive, motor, and behavioral development for children ages 1 through 42 months The Mental Scale has 178 items, the Psychomotor Scale has 111 items, and the Behavior Rating Scale has 30 items. Mental Scale yields a normalized standard score called the Mental Development Index, evaluating a variety of abilities, including sensory/perceptual acuities, learning, and problem solving; verbal communication; abstract thinking; and mathematical concept formation. Motor Scale assesses skills of degree of body control, large muscle coordination, finer manipulatory skills of the hands and fingers, dynamic movement, dynamic praxis, postural imitation, and stereognosis. Behavior Rating Scale assesses the child’s relevant test-taking behaviors and measures the following factors: attention/arousal, orientation/ engagement, emotional regulation, and motor quality. Screening test to identify infants who are developmentally delayed or have neurologic impairments Four domains: Neurological Functions/Intactness (N), Receptive Functions (R), Expressive Functions (E), and Cognitive Processes (C) The infant is administered 11 or 13 items and scored as optimal or non-optimal performance. Total scores can range from 0 to 11 or 13, with a higher score indicating better functioning. This screen can be used to prompt a more comprehensive evaluation. Surveillance and monitoring instrument to determine if a child’s development is within the normal range. Acquired skills are checked off on a chart, and results demonstrate in a graphic manner the child’s pattern of developmental skills compared with age-mates. It is not intended as a diagnostic tool and may be more appropriate as a developmental chart or inventory rather than as a screener. Four domains: Personal-Social, Language, Fine Motor-Adaptive, and Gross Motor; 125 items

Yields: Mental Development Index (MDI) and Psychomotor Development Index (PDI); and five behavior factors: Attention/Arousal, Orientation/Engagement, Emotional Regulation, Motor Quality, and Total Behavior Rating MDI and PDI means = 100, SD = 15 Behavior ratings as percentile ranks: Non-optimal: 1–10th Questionable: 11–25th Within normal limits: 26–99th

This test of intellectual or cognitive ability for school-age children is part of a series that includes the WPPSI-III (described later) for preschool and primary ages and the WAIS-III for adolescents and adults. It is the most commonly used intelligence test for school-age children. Ten core subtests and 5 optional subtests Test of young children’s intellectual ability Preschool: 4 core subtests and 1 optional subtest Primary: 7 core subtests and 7 optional subtests

Administration time: younger, about 30 minutes; older, about 60 minutes

Yields: A Total Score summing performance across the 4 domains Chart shows age-appropriate cut-off values for high, moderate, or low risk for developmental delay or neurologic impairments. Administration time: 10 minutes

If a child fails items that are successfully completed by 90% of younger children, delay may be suspected, and further evaluation may be needed.

Yields: Verbal Comprehension Index (VCI), Perceptual Reasoning Index (PRI), Working Memory Index (WMI), Processing Speed Index (PSI), and Full Scale Intelligence Quotient (FSIQ) Subtest means = 10, SD = 3 Index and IQ means = 100, SD = 15 Administration time: 65–80 minutes for core subtests Yields: Preschool: Verbal IQ (VIQ), Performance IQ (PIQ), and Full Scale IQ (FSIQ); and optional General Language Composite (GLC) Primary: Verbal IQ (VIQ), Performance IQ (PIQ), Processing Speed Quotient (PSQ), and Full Scale IQ (FSIQ); and optional General Language Composite (GLC) Subtest means = 10, SD = 3 IQ, PSQ, GLC means = 100, SD = 15

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TABLE 32-1, cont’d Measures for Evaluation of Intellectual, Neurodevelopmental, and Behavioral Progress TEST NAME, AGE RANGE OF SUBJECTS, AND TEST PUBLICATION DATA

TEST DESCRIPTION

David Wechsler, The Psychological Corporation, 2002, www.psychcorp.com Stanford-Binet Intelligence Scales, Fifth Edition (SB5) 2 years 0 months to 85 years+ Gale H. Roid, Riverside Publishing, 2003, www.riversidepublishing.com

Differential Ability Scales (DAS) 2 years 6 months to 17 years 11 months Preschool level: 2 years 6 months to 5 years 11 months School-age level: 6 years 0 months to 17 years 11 months Colin D. Elliott, The Psychological Corporation, 1990 (DAS-II due in spring of 2006), www.psychcorp.com

ADMINISTRATION AND SCORING INFORMATION Administration times: preschool, 35–40 minutes for all; primary, 40-50 minutes for core subtests

Assessment of intelligence and cognitive abilities Two domains: Verbal (V) and Nonverbal (NV) Each has 5 factors of cognitive ability: Fluid Reasoning (FR), Knowledge (KN), Quantitative Reasoning (QR), Visual-Spatial Processing (VS), and Working Memory (WM) Use of Change-Sensitive Score (CSS) makes it possible to compare changes in an individual’s scores over time if retested.

Yields: 10 subtest scores and 4 types of composite scores—5 factor indices, 2 domain scales (Verbal IQ and Nonverbal IQ), Abbreviated Battery IQ, and the Full Scale IQ of all 10 subtests Change-Sensitive Scores (CSS) are criterion referenced (rather than norm referenced) and therefore reference absolute levels of ability from the 2-year-old level to the adult level. Subtest score means = 10, SD = 3 Index and IQ means = 100, SD = 15 Change-Sensitive Scores range = 376-592, from 2-year-old level to adult (most fall in the range of 420 to 530); 500 is an average score for an individual 10 years 0 months old

Administration time: 50-60 minutes for all 10 subtests Test of cognitive ability and of basic academic Yields: Cognitive: General Conceptual Ability skills; includes 9 cognitive and 3 achievement (GCA) score and cluster scores of Verbal subtests Ability and Nonverbal Ability for Preschool For language-impaired and non–English-speaking level; Verbal Ability, Nonverbal Reasoning children, the examiner can obtain Special Ability, and Spatial Ability for school-age Nonverbal Composite. level Academic Achievement: Basic Number Skills, Spelling, and Word Reading scores Subtest T-score means = 50, SD = 10 General Conceptual Ability (GCA), Cluster, and Academic Achievement means = 100, SD = 15

Leiter International Performance Scale, Revised (Leiter-R) 2 years 0 months to 20 years 11 months Gale H. Roid and Lucy J. Miller, Stoelting Company, 1997, www.stoelting.com

Comprehensive Test of Nonverbal Intelligence (CTONI) 6 years to 90 years Donald D. Hammill, Nils A. Pearson, and J. Lee Wiederholt, The Psychological Corporation, 1997, www.psychcorp.com

Totally nonverbal test of intelligence and cognitive abilities Two domains: Visualization and Reasoning (VR) for measuring IQ, and Attention and Memory (AM) There are 10 subtests in each domain. Includes 4 social-emotional rating scales (by Examiner, Parent, Self-Rating, and Teacher) Nonverbal tasks, especially suited for children and adolescents who are nonverbal, do not speak English, or use English as second language (ESL); speech-hearing-motor impaired; attention-deficit–hyperactivity disorder (ADHD), autistic; delayed; disadvantaged; or traumatic brain injury (TBI) Test measures nonverbal reasoning abilities and estimates intelligence of individuals who experience undue difficulty in language (e.g., bilingual, language other than English, deaf) or fine-motor skills. It can be administered orally in English or in pantomime. No oral responses, reading, writing, or object manipulation are required; responses are made by pointing to alternative choices. Analogical Reasoning, Categorical Classifications, and Sequential Reasoning in two different contexts: pictures of familiar objects and geometric designs; and solving problems

Administration time: full cognitive battery, 45–60 minutes; academic achievement tests, 15–25 minutes Yields: 20 subtests 5 composite scores: Fluid Reasoning, Fundamental Visualization, Spatial Visualization, Attention, and Memory; and Brief IQ (based on 4 VR subtests) and Full Scale IQ scores Growth-scale scores for subtests and IQ in a metric that can track growth over time if retested Subtest score means = 10, SD = 3 Composite and IQ score means = 100, SD = 15 Administration time: VR, about 40 minutes; AM, about 35 minutes Yields: 3 composite scores—Nonverbal Intelligence Quotient, Pictorial Nonverbal Intelligence Quotient, and Geometric Intelligence Quotient—and an overall score Subtest means = 10, SD = 3 Composite and overall means = 100, SD = 15 Administration time: 1 hour

(continued)

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TABLE 32-1, cont’d Measures for Evaluation of Intellectual, Neurodevelopmental, and Behavioral Progress TEST NAME, AGE RANGE OF SUBJECTS, AND TEST PUBLICATION DATA

TEST DESCRIPTION

ADMINISTRATION AND SCORING INFORMATION

Six subtests: Pictorial Analogies, Pictorial Categories, Pictorial Sequences, Geometric Analogies, Geometric Categories, Geometric Sequences Neuropsychological Tests NEPSY (NE for neuro and PSY for psychology) 3 years 0 months to 12 years 11 months Younger: 3 years 0 months to 4 years 11 months Older: 5 years 0 months to 12 years 11 months Marit Korkman, Ursula Kirk, and Sally Kemp, The Psychological Corporation, 1997, www.psychcorp.com (NEPSY-II due in winter 2007)

Delis-Kaplan Executive Function System (D-KEFS) 8 years to 89 years Dean C. Delis, Edith Kaplan, and Joel H. Kramer, The Psychological Corporation, 2001, www.psychcorp.com Indirect Functional Ratings by Parent or Caregiver Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) 0 to 89 years (parents/caregivers) 3 to 21 years 11 months (teachers) Sara S. Sparrow, Domenic V. Cicchetti, and David A. Balla, American Guidance Service (AGS), 2004, www.agsnet.com

Infant Development Inventory Birth to 18 months Harold Ireton, Behavior Science Systems, 1994, www.childdevelopmentreview.com

Child Development Inventory 15 months to 6 years Harold Ireton and Edward J. Thwing, Behavior Science Systems, 2005, www.childdevelopmentreview.com

Test of neuropsychological development in preschool and early school-age children Subtests can be used in various combinations, according to the needs of the child. Five domains: Attention and Executive Functions, Language, Sensorimotor Functions, Visuospatial Processing, and Memory and Learning Younger, 11 core (and 1 extended) subtests; older, 14 core (and 5 extended) subtests

Test of executive function in older school-age children and adults evaluates component processes of tasks thought to be especially sensitive to frontal lobe dysfunction, such as flexibility of thinking, inhibition, problem solving, planning, impulse control, concept formation, abstract thinking, and creativity in verbal and spatial modalities. Nine stand-alone tests A measure of personal and social skills as reported by the parent or caregiver Four domains: Communication, Daily Living Skills, Socialization, and Motor Skills, with 11 subdomains The Survey Interview, Expanded Interview, and Parent/Caregiver Rating Forms contain an optional maladaptive behavior domain for pinpointing undesirable behaviors that may interfere with adaptive functioning. A measure of skills as reported by parent/ caregiver Five areas: Social, Self-Help, Gross Motor, Fine Motor, and Language The child’s level of development in each area is determined by asking the parent, “What’s your baby doing?” and by observing the infant. The questionnaire can be completed by the parent or done as an interview. The child’s level of development in each area is compared with the child’s actual age. A measure of skills as reported by the parent or caregiver Nine scales: Social, Self-Help, Gross Motor, Fine Motor, Expressive Language, Language Comprehension, Letters, Numbers, and an overall General Development On an inventory of the child’s observed developmental skills, parents answer “yes” (present or already acquired) or “no” (not yet). There are 270 statements about the child’s behavior and 30 problem items describing various symptoms and behavior problems.

Yields: subtest and 5 domain scores Subtest Scaled Score means = 10, SD = 3 Core Domain Score means = 100, SD = 15 Percentile ranks ≤2% well below expected level 3–10% below expected level 11–25% borderline 26–75% at expected level (most children in each age group) >75% above expected level Administration times Core: younger, 45 minutes; older, 65 minutes Full: younger, 1 hour; older, 2 hours Yields: 9 test scores Scaled score means = 10, SD = 3 Administration time: 90 minutes for all 9 tests

Yields: 11 subdomain scores and 4 domain scores and an overall Adaptive Behavior Composite Subdomain score means = 10, SD = 3 Domain and Adaptive Behavior Composite score means = 100, SD = 15 Administration Time: Survey Interview and Parent/Caregiver Rating Forms, 20–60 minutes Yields: a profile of development in the 5 areas compared with age norms of children from birth to 21 months Administration time: 10 minutes

Yields: profile of development in the 8 behavior domains and of the overall level of development compared with age norms of children between the ages of 1 year and 6.5 years The age level assigned to each behavior item was defined as the age at which at least 75% of parents answered “yes” to that statement. Administration time: 30-50 minutes

Courtesy of Rita J. Jeremy, Ph.D., Developmental Psychologist, Department of Pediatrics, University of California, San Francisco, CA.

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TABLE 32-2 Qualitative Description of IQ and Index Scores on Wechsler Tests SCORE

CLASSIFICATION

PERCENT INCLUDED IN THEORETICAL NORMAL CURVE

130 and above 120–129 110–119 90–109 80–89 70–79 69 and below

Very superior Superior High average Average Low average Borderline Extremely low

2.2 6.7 16.1 50.0 16.1 6.7 2.2

2002]. The potential implication of the standard error of measurement is greatest when the score obtained together with the standard error of measurement spans the point that is 2 standard deviations below the normed mean. The reliability and accuracy of a measure in an individual is enhanced by repeated measures over time [Batshaw, 1993]. Widely used measures for intelligence testing for children (5 to 16 years old) include the Wechsler Intelligence Scale for Children III (WISC-III) [Wechsler, 1991], the Cognitive Assessment System (CAS) [Naglieri and Das, 1997] and the Kaufman Assessment Battery for Children (K-ABC) [Kaufman and Kaufman, 1983]. For adults, the Wechsler Adult Intelligence Scale III (WAIS-III) is widely used [Wechsler, 1997]. The Stanford-Binet IV has applicability for children and adults [Thorndike, 1986]. The Wechsler Preschool and Primary Scale of Intelligence–Revised (WPPSI-R) [Wechsler, 1967] has been standardized for children as young as 3 years and has recognized limitations in interpretability [Sattler, 1982]. The standard for a systematic measurement of adaptive behavior from birth to adulthood has been the Vineland Adaptive Behavior Scale (VABS) [Sparrow et al., 1984], although acceptable alternatives exist, including the AAMR Adaptive Behavior Scale (ABS) [Lembert, 1993; Nihira, 1983], the Scales of Independent Behavior–Revised (SIB-R) [Bruininks, 1996], the Comprehensive Test of Adaptive Behavior–Revised (CTAB-R) [Adamo, 1999] and the Adaptive Behavior Assessment System (ABAS) [Harrison and Oakland, 2000]. For an accurate diagnosis of global developmental delay, careful attention must be paid to its underlying concept and operational definition [Shevell, 1998; Shevell et al., 2002, 2003]. A significant delay (i.e., greater than 2 standard deviations below the mean) needs to be demonstrated in two or more developmental domains exclusive of the qualitative impairment in language and social interaction that has been used to define an autistic spectrum disorder. Practically, delay in the child with global developmental delay is typically evident across all developmental domains. The practitioner must be aware of the psychometric properties of testing instruments and their potential sources of error and inherent standard error of measurement. Standardized tests for assessment of infant, toddler, or preschool child development exist and include the Bayley Scales of Infant Development (2nd edition) [Bayley, 1993], the Battelle Developmental Inventory [Newborg, 1984], and the Denver Developmental Screening Test (2nd edition) [Frankenburg et al., 1992]. Frequently, rather than using a

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broad developmental instrument, domain-specific measures are individually applied and an overall assessment arrived at. Examples of domain-specific developmental measures include the following groups: 1. Motor profile: Alberta Infant Motor Scale (AIMS) [Piper and Darrah, 1994], the Peabody Developmental Motor Scales (PDMS) [Folio and Dubose, 1974], the BruininksOseretsky Test of Motor Proficiency (BOTMP) [Bruininks, 1978] 2. Language skills: Peabody Picture Vocabulary Test– Revised (PPVT-R) [Dunn and Dunn, 1997], Expressive One Word Picture Vocabulary Test–Revised (EOWPVT-R) [Gardner, 1990], the Clinical Linguistic and Auditory Milestone Scales (CLAMS) [Capute and Accardo, 1991], the Clinical Evaluation of Language Function (CELF, 4th edition) [Semel et al., 2003], and the Slosson Intelligence Test (SIT) [Slosson, 1983] 3. Behavior and activities of daily living: Vineland Adaptive Behavior Scale (VABS) [Sparrow, 1984], Pediatric Evaluation of Disability Inventory (PEDI) [Haley et al., 1992], and the Pediatric Functional Independent Measure (WeeFIM) [Msall et al., 1994] Often, a diagnosis of mental retardation or global developmental delay may be initially formulated or, less frequently, entirely based on clinical judgment [AAMR, 2002]. To be valid, such clinical judgment must be based on extensive direct experience with individuals with mental retardation or global developmental delay. Typically, clinical judgment may be necessary because of various social, cultural, and linguistic contexts or because of unavailability, inappropriateness, or delay in the administration of standardized assessment procedures. Validation of clinical judgment is increased by direct observation, reliance on reliable third-party informants, and input from an interdisciplinary team skilled in multidimensional assessments.

Advances in Diagnostic Testing How does the clinician approach the diagnostic evaluation? The AAN practice parameter for global developmental delay [Shevell et al., 2003] provides a framework for such an evaluation (Fig. 32-1). The recommendations incorporate a combination of broad screening tools and disease-specific testing. Correctly applied, each has a reasonable pretest probability (1%) of diagnosis. General screens include head magnetic resonance imaging (MRI), high-resolution chromosome analysis, fragile X testing, lead screen, and metabolic and other testing that usually is covered in newborn screening, such as plasma amino acids for phenylalanine and thyroid-stimulating hormone for hypothyroidism. Newer approaches to diagnostic evaluation include subtelomeric probes, proton MR spectroscopy (MRS), and more genes specifically tested by direct DNA sequencing. Diagnostic approaches being explored in the laboratory that will likely be available to clinicians by the next edition of this text include genomic microarrays, proteomic analysis for mitochondrial disease, and MRI diffusion tractography.

Subtelomeric Probes Subtelomeric probe testing, based on fluorescent in situ hybridization (FISH), screens for loss, duplication, or balanced

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FIGURE 32-1. Algorithm from the American Academy of Neurology for evaluation of the child with developmental delay. Audiologic and ophthalmologic screening is recommended for all children with global developmental delay. Metabolic studies usually consist of obtaining a urine organic acid screen; quantitative analyses of serum amino acids, serum lactate, and ammonia levels; determination of capillary or arterial blood gas values, and thyroid function studies. CNS, central nervous system; CT, computed tomography; EEG, electroencephalogram; FraX, fragile X testing; GDD, global developmental delay; MRI, magnetic resonance imaging; T4, thyroxine. (From Shevell M, Ashwal S, Donley D, et al. Practice parameter: Evaluation of the child with global developmental delay. Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2003;60:367.)

translocation of the subtelomeric regions of chromosomes. These regions are gene rich and thought to be susceptible to high rates of mutation. Numerous studies have shown that 5% to 10% of children whose chromosomes were normal by classic cytogenetic analysis will demonstrate submicroscopic subtelomeric changes when they possess dysmorphic features and mental retardation [Wilkie, 1993]. As a group, this is as common a cause of mental retardation as Down syndrome. These children typically have moderate to severe mental retardation. For children with mental retardation without associated dysmorphic features, the rate of detection using this approach is only approximately 1.0% [Xu and Chen, 2003]. This type of terminal translocation fre-

quently is seen in severely affected children, and in 50% of cases, this represents the unbalanced inheritance of a balanced translocation from one parent [De Vries et al., 2003]. The parent harboring the balanced translocation is usually asymptomatic and has a 50% chance of passing either imbalanced form of the translocation to offspring. This test is therefore important for family-planning decisions. Many patients with shared subtelomeric deletions have shared phenotypes, suggesting a common mechanism for disease, analogous to deletions that cause Williams’ syndrome or velocardiofacial syndrome. For some chromosomal regions, these deletions are not associated with any significant clinical consequences, but for others, an an-

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ticipatory pattern has been observed in which the children are more severely impaired than the affected parent [Baker et al., 2002].

Genomic Microarray Genomic microarray technology is an evolving platform that arrays a representation of the human chromosome on a glass slide and hybridizes fluorescently labeled control and patient DNA to detect copy number changes in the genome. The first-generation chips had approximately 3000 elements spaced approximately every 1.0 Mb [Pinkel et al., 1998]. The arrayed elements are representations of genomic BAC clones, spanning approximately 100 kb of sequence per spot. Newer-generation chips are being developed that completely cover the genome (i.e., tiling arrays) or that use approximately 100,000-oligonucleotide spots to cover almost the whole genome [Ishkanian et al., 2004]. All of these platforms aim to identify interstitial copy number changes. This approach has been used very successfully to identify chromosomal regions (and genes) involved in cancer progression. Early studies suggest that this approach will likely find many additional regions that are implicated in mental retardation [Harada et al., 2004; Shaw-Smith et al., 2004], although only large-scale studies with carefully controlled groups can give clinicians information about the true prevalence of these changes in mental retardation. One additional challenge that must be overcome is distinguishing normal variation from disease-causing changes. Some studies have identified a number of regions in which there is considerable variation in copy number of genomic regions that contain large numbers of repeat elements or clusters of homologous genes [Sebat et al., 2004]. Determining which of these changes are consequential for cognition will require much more investigation.

Advances in Imaging High-quality MRI has significantly advanced the ability to detect many brain malformations. Certain studies suggest that MRI is useful for detecting abnormalities in up to 50% of children with developmental delay. In some cases, such as bifrontal polymicrogyria, lissencephaly, and bilateral periventricular nodular heterotopia, certain genes are known to cause these inherited syndromes [Gaitanis and Walsh, 2004]. For most cases, the genetic or other cause for the malformation has yet to be determined. Proton MRS measures the resonance of molecules in the brain. Given the unique resonance frequencies of many molecules, their abundance can be noninvasively measured. This approach has been useful for detecting changes in cerebral lactate in mitochondrial disorders and for observing the absence of creatine in the three disorders of creatine deficiency [Stromberger et al., 2003], another cause of potentially treatable nonsyndromic mental retardation [Schulze, 2003]. This technique also has been useful for the detection of abnormalities in succinic semialdehyde dehydrogenase deficiency [Ethofer et al., 2004] and for changes that precede the changes on conventional T2-weighted MRI for X-linked adrenoleukodystrophy patients [Eichler et al., 2002]. Another mode of MRI that holds promise for refinement of diagnostics is diffusion tensor imaging (DTI). Predicated

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on the assumption that water molecules most likely diffuse along the trajectory of axons within the white matter, DTI can measure this water diffusion and, by employing certain algorithms, can approximate the position and direction of the major white matter tracts in the cerebrum. This approach should refine the imaging results for mental retardation or autism in which no changes can be identified by conventional MRI [Barnea-Goraly et al., 2004].

Proteomics in Disease Analysis Practical and theoretical concerns limit exclusive reliance on genetic information to understand the causes of mental retardation (even including only those that are genetically based). Proteomics potentially offers a rapid means to screen individuals for many specific diseases within a general category, particularly when the proteins are expressed in the blood or other tissue that is readily available for analysis. For example, the true prevalence of mitochondrial dysfunction as a cause of mental retardation is unknown, but some studies suggest that mitochondrial abnormalities can be detected in a high percentage of patients with developmental delay, seizures, and hypotonia [Fillano et al., 2002; Marin-Garcia et al., 1999]. Mitochondrial genetics are too complex to be approached directly, because most patients are thought to have autosomal recessive mitochondrial disease, and hundreds of genes are necessary for proper mitochondrial function. In cases of maternal inheritance, this problem can be addressed by full sequencing of the mitochondrial genome in muscle samples of affected individuals. Given that the mitochondrial genome contains only 16,500 bp, this is a feasible goal in the short term. Investigators have begun to undertake whole mitochondrial proteomics approaches (i.e., combining immunocapture with mass spectrometry peptide fingerprinting) to determine the quantitative values for the specific polypeptides in these multiprotein complexes [Lib et al., 2003]. Missing subunits can be readily identified, and the post-translational modifications (e.g., phosphorylation) can be monitored [Schulenberg et al., 2004].

ETIOLOGY General Considerations The known specific causes of mental retardation are too numerous to be listed here. The term mental retardation returns more than 1200 entries in the Online Mendelian Inheritance in Man site alone, and this catalogs only identifiable genetic causes. Mental retardation usually is classified by prenatal, perinatal, postnatal, and undetermined causes (Table 32-3). In most studies, the largest category of known primary causes is genetic or chromosomal [Leonard and Wen, 2002]. Many of the environmental causes such as low birth weight and prematurity are measured as risk factors and do not rise to the level of actual biomedical causes. Just as the prevalence varies, the percentage of mental retardation resulting from each group of causes varies by location and by definitions. In a California epidemiologic study of mental retardation, 75% of the known cases of mental retardation were due to chromosomal aberrations, whereas

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TABLE 32-3 Categories and Causes of Mental Retardation CATEGORIES

CAUSES

Prenatal

Genetic Chromosomal (e.g., trisomy 21, Prader-Willi syndrome, Williams’ syndrome, translocations) Syndromic single gene (e.g., fragile X, Rubinstein-Taybi, Coffin-Lowry syndromes) Nonsyndromic single gene (e.g., oligophrenin [OPHN1], FMR2 mutation) Metabolic (e.g., phenylketonuria, galactosemia, Smith-Lemli-Opitz syndrome) Acquired Fetal alcohol syndrome Other maternal substance abuse Nutritional (e.g., maternal phenylketonuria, iodine deficiency) Infection (e.g., rubella, toxoplasmosis, cytomegalovirus, human immunodeficiency virus) Stroke Unknown causes (most likely genetic but can be acquired) Clinical syndromes without genetic diagnoses (e.g., Schinzel-Giedion, Marinesco-Sjögren, Marden-Walker syndromes) Multiple congenital anomaly and mental retardation Birth asphyxia Infection (herpes simplex virus encephalitis or group B Streptococcus meningitis) Stroke (embolic or hemorrhagic) Very low birth weight, extreme prematurity Metabolic (e.g. hypoglycemia, hyperbilirubinemia) Toxins (e.g., lead) Infection (e.g., Haemophilus influenza b meningitis, arbovirus encephalitis) Stroke Trauma (consider nonaccidental source) Poor nutrition Poverty Familial Nonfamilial

Perinatal

Postnatal-environmental

Undetermined

less than 3% were caused by any endocrine of metabolic abnormality [Croen et al., 2001]. In a Taiwanese study, 82% of all the chromosomal causes of mental retardation were a result of Down syndrome, but these data were collected before the clinical use of subtelomeric FISH probes [Hou et al., 1998]. In some regions of the world, cretinism from severe iodine deficiency occurs in up to 2% to 10% of the population of isolated communities [Delange et al., 2001]. Mild mental impairment from iodine deficiency occurs five times more frequently than cretinism, making iodine deficiency the most common preventable cause of mental retardation. Treatment during the first trimester has a significant effect on reducing the cases of cretinism [Cao et al., 1994]. In regions of mainland China with iodine deficiency, children score on average 10 IQ points less than cohorts in iodine-rich regions do. This link between iodine deficiency and mental retardation also has a strong genetic link, because specific alleles for the deiodinase type II gene and the ApoE4 allele confer a significantly greater risk of mental retardation when the pregnant mother is iodine deficient [Guo et al., 2004; Wang et al., 2000]. Despite the tremendous wealth of information about the causes of mental retardation, the cause remains unknown in most cases. Genetic and epidemiologic approaches likely will continue to make progress toward unraveling and treating these currently unelucidated causes.

Genetic Causes Some of the most significant advances in our understanding of the genetic causes of mental retardation have come from

work addressing X-linked mental retardation, including mental retardation due to the fragile X syndrome and due to other genes.

Fragile X Syndrome The fragile X syndrome, caused by inactivation of the FMR1 gene, has an estimated prevalence of 1 in 3000 males and is one of the most common causes of mental retardation [Crawford et al., 2001]. Expansion of the trinucleotide sequence CGG to greater than 200 copies, results in CpG methylation and inactivation of the FMR1 gene. Patients have narrow and elongated faces, large protruding ears, macroorchidism, and joint hyperlaxity. Up to 20% have epilepsy, and most have complex partial seizures [Willemsen et al., 2004]. Carrier females and males with somatic mutations have various levels of intellectual impairment; studies demonstrate that the amount of the residual FMR protein detected in hair roots correlates well with IQ [Willemsen et al., 2003]. Research on the FMR protein has shown that it participates in the transport of mRNA and the regulation of protein translation in neuronal dendrites [Zalfa et al., 2003]. This function perhaps explains the paucity of dendrites seen in autopsy series of these patients [Greenough et al., 2001]. Although previous studies suggested that premutation male carriers (55 to 200 repeats) were asymptomatic, later work from Hagerman and colleagues [1988] documented a progressive neurologic disorder, the fragile X-associated tremor/ataxia syndrome (FXTAS). After the age of 50, male patients present with intention tremor and cerebellar ataxia, and they may have cognitive decline

Sherr and Shevell / Mental Retardation and Global Developmental Delay

[Jacquemont et al., 2004]. This syndrome, which is unique to these permutation males, may result from an increase in expanded repeat FMR1 mRNA that is consistent with a toxic “gain of function” mechanism [Hagerman and Hagerman, 2004]. Because the level of FMR protein correlates with disease severity, a number of investigators have tried to identify demethylating or hyperacetylating drugs as a means to activate FMR1 transcription [Chiurazzi et al., 1998, 1999]. Although these methods do not offer treatment for patients, this approach is generating new agents that can be tested for their ability to activate FMR1 without associated toxicity.

Other X-Linked Mental Retardation Conditions The increased prevalence of mental retardation in males and the relative ease of detecting the familial transmission of X chromosome mutations have facilitated the effort to uncover the genes on the X chromosome that cause mental retardation. Many excellent reviews have detailed the syndromic and nonsyndromic forms of X-linked mental retardation [Chelly and Mandel, 2001; Gecz, 2004]. Since 1996, more than 15 genes have been identified as causes for nonsyndromic mental retardation without other associated organ involvement or significant dysmorphology (Table 32-4). An initial assumption had been that these genes would work directly at the level of the synapse. In certain cases, in vitro and animal model data confirm that idea. For example, the protein neuroligin on the postsynaptic membrane and its binding partner neurexin on the presynaptic side have been shown to promote synapse formation in vitro [Dean et al., 2003; Scheiffele et al., 2000]. Some reports have shown that two X-linked neuroligin genes (NLGN3 and NLGN4) are implicated in mental retardation and autism [Jamain et al., 2003; Laumonnier et al., 2004]. Similarly, multiple genes that participate in signaling through the small G protein RHO are mutated in many cases of X-linked mental retardation: GDI1, PAK3, OPHN1, and ARHGEF6 [Ramakers,

2002]. In a mouse gene deletion of oligophrenin (OPHN1), there were clear deficits in the formation of spines along dendrites, the critical subcellular structure on which central nervous system excitatory synapses form [Govek et al., 2004]. However, involvement in synapse formation does not preclude possibly important roles more generally in organ and body development. For example, further analysis showed that mutations in oligophrenin are also found in patients with epilepsy, profound cerebellar hypoplasia, and cerebral cortical atrophy [Bergmann et al., 2003; Philip et al., 2003]. The genes ARX and MECP2 can cause syndromic mental retardation (as in patients with X-linked lissencephaly with ambiguous genitalia [XLAG] and Rett’s syndrome) and nonsyndromic mental retardation, depending on the severity of the mutation [Gomot et al., 2003; Sherr, 2003]. These observations demonstrate the complexity of understanding how genetic alteration causes mental retardation, what form it takes, and how genotype may correlate with phenotype.

Nonsyndromic Autosomal Mental Retardation The inheritance pattern of X-linked diseases accelerates the discovery of genes. However, because nonsyndromic mental retardation is not clinically unique, it is difficult to link families together by common features to find causative genes. In the only autosomal recessive mental retardation gene identified, a single 4–base pair (bp) deletion was found in the synapse-localized serine protease neurotrypsin [Molinari et al., 2002]. Although this same 4-bp deletion was identified in another proband with mental retardation, no confirmatory mutations were identified. Investigators have used an inclusive approach, sequencing candidate genes in many dozens of mental retardation families that link to the X chromosome. Looking for additional autosomal recessive mental retardation genes by this approach will increase the complexity more than 20-fold.

TABLE 32-4 GENES IMPLICATED IN X-LINKED MENTAL RETARDATION GENE

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FUNCTION

Genes Primarily Implicated in Nonsyndromic Mental Retardation PAK3 P21 (CDKN1A)-activated kinase 3 GDI1 GTP dissociation inhibitor 1 IL1RAPL1 Interleukin 1 receptor accessory protein-like 1 ARHGEF6 Rac/Cdc42 guanine nucleotide exchange factor 6 SLC6A8 Creatine transporter 8 FACL4 Long-chain fatty acid–coenzyme A ligase 4 AGTR2 Angiotensin II receptor, type 2 FTSJ1 S-adenosylmethionine-binding protein DLG3 Synapse-associated protein 102 (anchoring protein) NLGN3 Neuroligin 3 (postsynaptic receptor) NLGN4 Neuroligin 4 (binds Neurexin) PQBP1 Polyglutamine binding protein 1 RPS6KA3 Serine/threonine kinase ZNF41 Zinc-finger protein involved in chromatin activation Genes Implicated in Syndromic and Nonsyndromic Mental Retardation OPHN Rho-GTPase activating protein (cerebellar hypoplasia) ARX Aristaless-related homeobox (X-linked lissencephaly with ambiguous genitalia [XLAG]) MECP2 Methyl-CpG binding protein 2 (Rett syndrome)

LOCUS

STUDY

Xq23 Xq28 Xp21.3 Xq26.3 Xq28 Xq23 Xq23 Xp11.23 Xq13.1 Xq13.1 Xp22.32 Xp11.23 Xp22.12 Xp11.3

Allen et al., 1998 D’Adamo et al., 1998 Jin et al., 2000 Kutsche et al., 2000 van der Knaap et al., 2000 Meloni et al., 2002 Vervoort et al., 2002 Freude et al., 2004 Tarpey et al., 2004 Jamain et al., 2003 Laumonnier et al., 2004 Kalscheuer et al., 2003 Chechlacz and Gleeson, 2003 Shoichet et al., 2003

Xq12 Xp22.11

Billuart et al., 1998 Sherr, 2003

Xq28

Gomot et al., 2003

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Other Etiologic Considerations Several questions arise when considering the causes of mental retardation that guide the clinician when evaluating patients and help the researcher focus on the underlying pathophysiology. What is the prevalence of any genetic cause for mental retardation and how many genes can cause mental retardation? Will cases of mild mental retardation be caused by less severe mutations in these same already discovered genes or in a completely different subset? How many cases of mental retardation will be found to be caused by genetic factors alone, environmental factors alone, or the interplay between the two, as has been demonstrated for iodine deficiency?

EVALUATION OF THE PATIENT History The assessment of a child with suspected mental retardation or global developmental delay begins with a detailed history, and much time and effort should be directed to this evaluation [Shevell, 1998, 2002]. Fundamental to this process is obtaining a careful family history, searching for other affected family members with similar or other neurologic impairments. The possible presence of early postnatal deaths should be questioned. Parental or intrafamilial consanguinity needs to be ascertained along with the ethnic heritage of the parents. Clues to consanguinity (which may not be willingly acknowledged by the parents) include origin from the same village or sharing of the same last name within the family tree. The mother’s prior gestational history and pregnancy with the affected child must be carefully probed, seeking evidence for adverse events or toxin exposures and clues to intrauterine difficulties. Timing and mode of delivery should be determined, and the reason for any forceps application or cesarean section must be identified. Birth weight, Apgar scores, head circumference measurement at birth, and duration of postnatal hospital stay are important objective markers of newborn health status. Difficulties in the newborn nursery, especially pertaining to possible clues for a neonatal encephalopathy, must be searched for and carefully documented. Box 32-1 lists commonly accepted risk factors for later developmental disability that can be apparent on maternal, gestational, or neonatal history taking. The timing of developmental milestones should be determined for the affected child. Observant parents can usually and reliably recall motor skills in the first year of life, such as when their child rolled over, sat, crawled, cruised, and took the first steps. Parental recall of meaningful speech and language milestones is often not as certain [Majnemer and Rosenblatt, 1994]. The timing of initial parental concern regarding the child’s development is important to determine, as is the possibility of any loss or regression of previously acquired developmental skills that would mandate a different and more urgent approach to etiologic evaluation and follow-up. Current skill level in the various developmental domains and the degree of independence in activities of daily living must be ascertained. For the school-age child, important points include scholastic history, with special reference to actual school and classroom placement and identification of the provision of any supplemental educational resources.

Box 32-1 FACTORS THAT INCREASE THE RISK OF NEONATAL MORTALITY AND MENTAL RETARDATION Maternal Factors Complications of pregnancy Perinatal factors Neonatal factors Age younger than 16 or older than 40 years (>35 years for a primigravida) Cervical abnormalities (e.g., incompetence, tumor) Consanguinity Contracted pelvis Women statistically at higher risk: unmarried, short, thin, malnourished, uneducated, nonwhite, low income Other diseases and disorders Bacteriuria Diabetes mellitus Drug addiction Malnutrition Nephritis Phlebitis Proteinuria Renal hypertension Thyroid disease History of abortion, stillbirth, neonatal death, live or stillborn infants weighing less than 1500 grams, abruptio placentae, circumvallate placenta Hemorrhagic shock Polyhydramnios Vaginal bleeding in the second or third trimester Cesarean section after trial of labor Conditions at Birth Cyanosis Need for resuscitation Poor Apgar score Presence of respiratory distress Gestational age of less than 30 weeks Hypoxic-ischemic encephalopathy Intrauterine hypoxia associated with prolapsed umbilical cord, abruptio placentae, or toxemia of pregnancy Midforceps delivery or breech presentation Abnormal sucking, feeding, or crying Anomalies Asymmetry of face and extremities Hyperbilirubinemia Hypotonia Injuries Need for an incubator or oxygen Poor weight gain or malnutrition Seizures Vomiting and fever Data from Denhoff E. Cerebral palsy, the preschool years. Springfield, IL: Charles C Thomas, 1967, and from Pearson PH. The physician’s role in diagnosis and management of the mentally retarded. Pediatr Clin North Am 1968; 15:835.

Coexisting medical problems, with particular reference to possible seizure disorders or feeding difficulties, should be questioned. Sleeping and problematic behaviors (i.e., ag-

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gressive, inappropriate, or self-injurious) may be particular concerns of the parents. The past medical history, including possible chronic medical conditions, prior hospital admissions, or surgical procedures, should be documented. Past and current medications prescribed, their indications, and effects (beneficial or deleterious) must be assessed. The current social situation of the child and family must be carefully probed with reference to items such as socioeconomic status, parental educational attainment, marital status and home living arrangements, custody, and existing support services. The examiner must determine whether the patient has access to appropriate rehabilitation services (e.g., occupational therapy, physiotherapy, speech therapy, special education, psychology) and whether previous relevant evaluations or laboratory investigations have been conducted. By the end of the history taking, the clinician should have clear ideas regarding evidence of a static or progressive encephalopathy; an approximate idea of the developmental and functional level of the affected child; the possible timing of an underlying cause; the possibility of an underlying genetic cause; the social or rehabilitation status of the affected child; and the possibility of associated and relevant medical or behavioral condition.

Physical Examination Ideally, the physical examination begins with careful observation of the child as the history is being taken. The delayed or retarded child often presents a challenge to the clinician with respect to the formal examination because of inherent features, such as short attention span and limitations in understanding and cooperation. The availability of a play area with appropriate toys, including paper and crayons, that is amenable to observation by the examiner may allow for a nonintrusive and noninvasive assessment of developmental skills, dexterity, inquisitiveness, behavior, and interaction with the surroundings. Much of the neurodevelopmental examination can take place during extended history taking by observation alone. The general physical examination should ascertain possible dysmorphology, hepatosplenomegaly, and cutaneous markers of the phakomatoses. The spine should be carefully inspected, including the sacral region to look for dermal sinuses, hair tufts, or other subtle signs of spinal dysraphism. Height and weight should be plotted. Genetic catalogs are indispensable for an accurate recognition of specific syndromes. Current and previous occipitofrontal circumference should be obtained and plotted, with particular attention directed at microcephalic or macrocephalic measurements or changing percentile values over time. In cases of microcephaly or macrocephaly, the parental occipitofrontal circumferences also should be obtained and plotted. The head shape and status of the anterior and posterior fontanels in the infant, together with the sutures, should be observed. Determination of the presence of any focal neurologic findings is the primary objective of the formal neurologic examination. Careful evaluation of vision, in addition to aiding in a definitive diagnostic process, is indicated to minimize the contribution of potentially correctable visual impairment to the burden of disability. Similarly, this approach applies to gross auditory impairments.

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Within the clinical office setting, several test instruments exist for use as objective screening assessments of development during the first years of life (i.e., Denver Developmental Screening Test [Frankenburg, 1967], the Denver II [Frankenburg et al., 1992] and the CAT/CLAMS [Accardo and Capute, 1991], which focuses on language and nonlanguage-based reasoning abilities). These may be supplemented or complemented by the use of parent-based questionnaires (e.g., Child Developmental Inventory [Ireton, 1992], and Ages and Stages Questionnaire [Bricher and Squires, 1999]). Observed signs and symptoms and their association with various diagnostic entities that can result in global developmental delay or mental retardation are summarized in Boxes 32-2 to 32-10. Definitive diagnosis of these associated entities often requires specific laboratory testing.

Laboratory Testing Laboratory testing is directed at establishing the possible cause of the individual’s delay or retardation [Schaefer and Bodensteiner, 1992]. This testing may be confirmatory, directed at a suggested cause from the history and or physical examination, or it may be undertaken on a screening basis, directed at finding a previously unsuspected cause. Few data exist on the diagnostic yield of various laboratory investigations of community-derived samples of children with global developmental delay or mental retardation, with most series restricted to more severe variants of institutionalized individuals [Hagberg and Kyllermann, 1983; Hunter et al., 1980; McLaren and Bryson, 1987]. Controversy exists regarding the extent to which diagnostic investigations should be undertaken for a developmentally delayed or retarded child. However, consensus does exist that an all-inclusive “shotgun” approach is not warranted or feasible from medical, personal, or economic viewpoints [Shevell et al., 2003]. Laboratory testing is undertaken with the spirit that although yield may be lower than in other clinical situations, the potential value of a definitive etiologic diagnosis may be substantial. Technologic advances, especially in the domains of genetic testing and neuroimaging, have resulted in improved diagnostic yield and precision. This is reflected in improved etiologic yield in community samples studied retrospectively and prospectively [Majnemer and Shevell, 1995; Shevell et al., 2000]. Aiding the formulation of a rational approach to laboratory investigations in this clinical population is the AAN practice parameter (see Fig. 32-1) [Shevell, 2003] and the American College of Medical Genetics [Curry et al., 1997] formulation on this topic. Routine metabolic testing for an extensive list of potential inborn errors of metabolism cannot be justified [Carson and Neill, 1962; Henderson et al., 1981; Reinecke et al., 1983]. However, diagnostic vigilance needs to be maintained for these disorders given the implication for treatment, prognosis, and recurrent risk [Papavasiliou et al., 2000]. Clinical situations suggesting a possible inborn error of metabolism that should prompt careful and detailed metabolic testing include family history, parental consanguinity, documented developmental regression, suggestive dysmorphology, involvement of non-ectodermal organ systems, and possible white matter involvement.

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Box 32-2 EYE ABNORMALITIES

Box 32-3 SEIZURES

Cataracts Cerebrotendinous xanthomatosis Cockayne’s syndrome Cretinism Down syndrome Galactosemia Lowe’s syndrome Marinesco-Sjögren syndrome Myotonic dystrophy Pseudohypoparathyroidism Rubella (gestational) Trichothiodystrophy Cherry-red spot in macular area GM1 gangliosidosis (generalized) Neuraminidase deficiency Niemann-Pick disease type A Tay-Sachs disease Chorioretinitis Clouding of cornea Congenital lues Cytomegalic inclusion body disease Hunter’s syndrome Hurler syndrome Lowe’s syndrome Prenatal rubella (gestational) Corneal ulcers Familial dysautonomia Dislocated lenses Homocystinuria Sulfite oxidase deficiency Glaucoma Lowe’s syndrome Rubinstein-Taybi syndrome Sturge-Weber syndrome Nystagmus Hyperpipecolatemia Hypervalinemia Joubert’s syndrome Photophobia Cockayne’s syndrome Hartnup’s disease Homocystinuria Retinitis pigmentosa Ataxia-telangiectasia Cockayne’s syndrome Hallervorden-Spatz syndrome Hyperpipecolatemia Kearns-Sayre syndrome Laurence-Moon-Biedl syndrome Mitochondrial encephalomyopathies Neuronal ceroid lipofuscinosis Scleral telangiectasia Vertical supranuclear gaze palsy Niemann-Pick disease type C Tauopathy dementia (progressive supranuclear palsy)

Generalized tonic-clonic seizures Argininosuccinic aciduria Neuronal ceroid lipofuscinosis Citrullinemia Glycogen synthetase deficiency Hyper-beta-alaninemia Hyperammonemia Hyperlysinemia Hyperornithinemia-hyperammonemia and homocitrullinuria hyperprolinemia I Hypoglycemia, particularly associated with glycogen storage diseases I, III, IV, and VII and idiopathic hypoglycemia of infancy Joseph’s disease Ketotic hypoglycemia Kinky hair disease (Menkes’ disease) Lactic acidosis Lysine intolerance with periodic ammonia intoxication Maple syrup urine disease Methionine malabsorption syndrome Mitochondrial encephalomyopathies (e.g., MERRF [now MT-TK], MELAS defects) Nonketotic hyperglycinemia Phenylketonuria Severe myoclonic epilepsy of infancy (SCN1A defect) Tay-Sachs disease X-linked infantile spasm syndrome (ARX [also called ISSX] mutation) Seizures in the neonatal period Argininosuccinic aciduria Hyperammonemia I and II Hyperprolinemia I Hypoglycorrhachia (GLUT1 [now designated SCL2A1] deficiency syndrome) Hypoxic-ischemic encephalopathy Isovaleric acidemia Joseph’s disease Lactic acidosis Maple syrup urine disease Mitochondrial encephalomyopathy Methylmalonic acidemia Propionic acidemia

For the globally delayed or retarded child without an apparent cause after history and physical examination, a high-resolution banding karyotype (including subtelomeric

probes), fragile X mental retardation (FMR1) molecular genotype, and neuroimaging studies should be undertaken to screen for possible causes [Shevell et al., 2003]. Technologic improvements (e.g., FISH) in cytogenetics [Graham and Selikowitz, 1993] can aid routine and specific syndrome- directed studies [Joyce et al., 2001]. Yield should increase in the future, as newer techniques such as comparative genomic hybridization are introduced into general practice [Colleux et al., 2001; Sismani et al., 2001]. Cytogenetic studies have an etiologic yield even in the absence of traditionally recognized dysmorphic features on physical examination [Shevell et al., 2000]. Neuroimaging has greatly enhanced the clinical practice of neurology and improved etiologic yields. Although largely of little additional value in early reported studies [Lingham,

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Box 32-4 SKIN ABNORMALITIES Café au lait spots Ataxia-telangiectasia Bloom’s syndrome Neurofibromatosis Tuberous sclerosis Depigmented nevi Tuberous sclerosis Eczema Phenylketonuria Linear nevus Linear sebaceous nevus of Jadassohn Malar flush Homocystinuria Photosensitivity Hartnup’s disease Tryptophanuria Rash Biotinidase deficiency Holocarboxylase synthetase deficiency Synophrys Cornelia de Lange syndrome Cretinism

Box 32-5 HEARING ABNORMALITIES Conduction deafness Hunter’s syndrome Hurler syndrome Hyperacusis GM1 gangliosidosis (generalized) Krabbe’s disease Subacute sclerosing panencephalitis Sulfite oxidase deficiency Tay-Sachs disease Sensorineural deafness CHARGE syndrome (i.e., coloboma, heart defects, atresia choanae, retardation of growth and development, genitourinary problems, and ear anomalies) [Menenzes and Coker, 1990] Kearns-Sayre syndrome MELAS syndrome (i.e., mitochondrial myopathy, encephalopathy, lactacidosis, and stroke) MERRF syndrome (i.e., myoclonus epilepsy associated with ragged-red fibers) Refsum’s disease

Box 32-6 VOMITING Hyperammonemia (all types) Hyperglycinemia Hyperlysinemia Hypervalinemia Increased intracranial pressure Lactic acidosis Maple syrup urine disease MELAS syndrome (i.e., mitochondrial myopathy, encephalopathy, lactacidosis, and stroke)

813

Box 32-7 HAIR ABNORMALITIES Fine hair Homocystinuria Hypothyroidism Friable and tufted hair (trichorrhexis nodosa) Argininosuccinic aciduria Kinky hair disease (Menkes’ disease) Loss of scalp hair Familial lactic acidosis with necrotizing encephalopathy Premature gray hair Ataxia-telangiectasia Progressive cerebral hemisphere atrophy [Gomez and Moore, 1974] White hair (patches) Methionine malabsorption syndrome Tuberous sclerosis

Box 32-8 HEPATOSPLENOMEGALY Argininosuccinic aciduria Gaucher’s disease GM1 gangliosidosis (generalized) Glycogen storage disease types I and III Hydroxykynureninuria Hyperpipecolatemia Mucopolysaccharidoses Neuronal ceroid lipofuscinosis Niemann-Pick disease

Box 32-9 METABOLIC ACIDOSIS Ketotic hypoglycemia Lactic acidosis Maple syrup urine disease Methionine malabsorption syndrome Methylmalonic acidemia Mitochondrial encephalomyopathy 5-Oxoprolinuria (pyroglutamic aciduria) Propionic acidemia 1982; Moeschler et al., 1981], later studies have emphasized the added value of neuroimaging in detecting cerebral dysgenesis, acquired injury of various causes, or disturbances in white matter maturation [Bouhadiba et al., 2000; VanBogaert et al., 1992]. The superiority of MRI over computed tomography (CT) has made it the imaging modality of choice contingent on availability and sedation restrictions. Similar to metabolic studies, electrophysiologic studies such as electroencephalography should be undertaken only in the situation of a suspected coexisting paroxysmal disorder or evidence of language regression or behavioral abnormalities suggestive of an epilepsy syndrome such as Landau-Kleffner or electrical status epilepticus during slow-wave sleep [Sheth, 1998]. Visual and auditory evoked

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Box 32-10 OTHER ABNORMALITIES Anterior horn cell disease (includes electrodiagnostic evidence of normal nerve conduction time in the presence of muscular denervation potentials) Neuroaxonal dystrophy Beta-methyl-crotonyl CoA decarboxylase deficiency Ataxia (partial representative list) Argininosuccinic aciduria Ataxia-telangiectasia Cockayne’s syndrome GTP cyclohydrolase deficiency (dopa-responsive dystonia) Hartnup’s disease Hyperammonemia from any cause Joubert’s syndrome Kearns-Sayre syndrome L-2-α-hydroxyglutaric aciduria Marinesco-Sjögren syndrome Metachromatic leukodystrophy Mitochondrial disorders Neuronal ceroid lipofuscinosis 5-Oxoprolinuria (pyroglutamic aciduria) Partington’s syndrome (ARX defect) Pyruvate decarboxylase deficiency Tryptophanuria Broad thumbs and toes Rubinstein-Taybi syndrome [Rubinstein and Taybi, 1963] Choreoathetosis Dentatorubral pallidoluysian atrophy Glutaricaciduria type I Huntington’s chorea Joseph’s disease Lesch-Nyhan disease Pantothenate kinase–associated neurodegeneration (PKAN) Phenylketonuria Dystonia Alexander’s disease Canavan’s disease Enlarged head GM2 gangliosidosis (generalized) GTP cyclohydrolase deficiency (dopa-responsive dystonia) potentials are of use in assessing the integrity of the visual and auditory system in the young, uncooperative child. The presence of certain clinical features predicts the success or failure of the etiologic search. Documented neonatal difficulties, microcephaly, focal neurologic findings, and positive family history all suggest an enhanced possibility of success. Coexisting autistic features are a negative predictor of detecting an underlying cause [Shevell et al., 2000].

Consultation and Follow-up Concerns about the developmental and functional patterns highlighted at the time of specialty evaluation should prompt referrals to other health professionals with different, but

Histiocytosis X Hydrocephalus Mitochondrial disorders Mucopolysaccharidoses Pelizaeus-Merzbacher disease PKAN Sandhoff’s disease Spongy degeneration Subdural effusion Subdural hematoma Tay-Sachs disease Wilson’s disease Fat pad distribution, abnormal Congenital disorders of glycosylation Micromelia Cornelia de Lange syndrome Odors Isovaleric acidemia Maple syrup urine disease Methionine malabsorption syndrome Phenylketonuria Peripheral neuropathy (includes electrodiagnostic evidence of decreased conduction time) Cockayne’s syndrome Krabbe’s syndrome Metachromatic leukodystrophy Niemann-Pick disease Short stature Bird-headed dwarf (Seckel type) Cockayne’s syndrome Cornelia de Lange syndrome Cretinism Leprechaunism [Dekaban, 1965] Mucolipidoses Mucopolysaccharidoses Prader-Willi syndrome Rubinstein-Taybi syndrome Tremor Citrullinemia Hartnup’s disease Hyperpipecolatemia Hypersarcosinemia

complementary expertise, permitting a multidisciplinary, comprehensive evaluation of the affected individual [Shevell, 2002]. These professionals, in addition to objectively documenting various deficits in a standardized way, usually assume responsibility for implementing goal-directed therapeutic interventions and serve as conduits to appropriate community-based, long-term rehabilitation and educational resources. These health professionals represent occupational therapy (e.g., fine motor, activities of daily living, feeding), physical therapy (i.e., gross motor), speech and language pathology (i.e., language), and psychology (e.g., cognition, social, behavioral). Specific care needs such as tube feeding, respite care, or financial difficulties may prompt nursing or social service intervention. Vision and auditory screening are important because of the high frequency of potentially

Sherr and Shevell / Mental Retardation and Global Developmental Delay

correctable primary sensory impairments in this population, and results should prompt ophthalmologic and audiologic evaluations [Kwok, 1996; Menacker, 1993; Warburg, 1994]. Concerns regarding a possible genetic cause or specific behavioral issues may require the expertise and intervention of genetic or psychiatric services. A key part of the evaluation of the delayed or retarded individual is a second visit. This second visit is needed to review the results of laboratory investigations, integrate the reports of the various health professionals consulted, characterize the type and level of developmental disability, ascertain the provision of rehabilitation or relevant educational services, counsel the family appropriately, and by ascertaining developmental progress, exclude a progressive encephalopathy or neurodegenerative process. Frequently, the opportunity exists to consider the diagnostic evaluation over a longer period because the child neurologist participates directly in the ongoing care of the patient with mental retardation or developmental delay.

MEDICAL MANAGEMENT OF COEXISTENT CONDITIONS With a greater drive to incorporate mentally retarded individuals into the community comes a better awareness of their unique profile of medical issues and how best to optimize their treatment.

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Treatment of Psychiatric Disorders Several studies support medical therapies for the treatment of psychiatric conditions in the mental retardation population. The newer neuroleptics (especially risperidone) have been effective for behavioral disorders, particularly aggression and impulsivity, in patients with mental retardation or autism, or both [Snyder et al., 2002]. However, side effects can include intolerable weight gain, particularly at higher doses [Cohen et al., 2001]. Other antipsychotic agents such as quetiapine and aripiprazole have less effect on weight and may be effective for aggressive and aberrant behavior [Sajatovic, 2003; Stigler et al., 2004]. Clonidine has been effective for hyperactivity, hypersensitivity, and the less aggressive impulsive behaviors [Agarwal et al., 2001]. Clonidine can be quite helpful for sleep disorders, but the sedative effects can also be problematic. Methylphenidate has been effective for many patients with mental retardation [Aman et al., 2003; Pearson et al., 2004a, 2004b] and is the most common class of medications used for fragile X syndrome males, in which up to 67% showed a positive response in a controlled study [Hagerman et al., 1988]. Anxiety, compulsive, and perseverative behaviors and mood symptoms can be managed with selective serotonin reuptake inhibitors (SSRIs). In particular, SSRIs have been shown to be helpful for the treatment of social anxiety and withdrawal [Santosh and Baird, 1999]. Chapter 39 reviews the psychopharmacologic agents that can be used for the treatment of some of these disorders.

Psychiatric Disorders in the Mentally Retarded

Treatment of Epilepsy

The prevalence of coexistent psychiatric conditions is higher among patients with mental retardation than among people in the general population. These conditions are generally under-recognized and undertreated. In one population-based study, 40% of mental retardation patients had a Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) diagnosis, one fourth of this group had more than one diagnosis, and these disorders caused severe impairment in everyday functioning for more than one half of patients. Of these mental retardation patients, 22% had anxiety disorders, 5% had mood disorders, and 25% had disruptive disorders. The most common diagnoses were specific phobias (17.5%), attention-deficit–hyperactivity disorder (14.8%), and oppositional defiant disorder (13.9%). However, of all the children with a DSM-IV diagnosis, only 27% were receiving help for these problems [Dekker and Koot, 2003]. For those whose diagnoses caused severe impairment, only 41% received professional help. In light of this high percentage of mental retardation patients with DSM-IV diagnoses, a decision should be considered to refer all mental retardation patients for psychiatric evaluation. Most studies point to the ability to use the same criteria to arrive at a diagnosis for the mental retardation community as for those with higher verbal and cognitive functions [Szymanski and King, 1999]. As is the case for the diagnosis of mental illness in children generally, eliciting a careful history from the parents or caretakers is essential to the diagnosis and to the evaluation of treatment efficacy. Based on reasonable clinical inference, some modifications in specific diagnostic criteria are occasionally necessary.

Approximately 15% to 20% of mentally retarded patients also have epilepsy, 10 times higher than the general population [Kelly et al., 2004; Mayville and Matson, 2004]. Many of these patients have intractable epilepsy and constitute a considerable percentage of a clinician’s practice. When treating seizures, the same guidelines apply as for patients without mental retardation: minimize side effects while eliminating or substantially reducing the number of seizures. Because many patients with mental retardation will be unable to express verbally their response to the medication, the physician must be alert to other means of assessing side effects and seizure reduction. In the case of young children living at home, their parents or other primary caretakers can provide reasonable estimates of these parameters. In the case of multiple caretakers or of patients residing in assisted living environments, special care must be taken to ensure accuracy and reliability of reporting between different observers. Clarification of which seizure types to record and maintaining a seizure diary before introduction and after introduction of medication can help achieve this goal. In some instances, use of standardized instruments such as the Glasgow epilepsy outcome measure may be helpful [Espie et al., 2001]. Drug treatment should be guided primarily by the type of epilepsy. Patients with Lennox-Gastaut syndrome have responded well to lamotrigine, infantile spasms to vigabatrin, and nonsyndromic generalized seizures to valproic acid. In general, avoidance of barbiturates and benzodiazepines is preferable because of the propensity for sedation and impairment of cognition [Coulter, 1997].

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Sleep Disorders The most common sleep problem in the general population and among the developmentally impaired is insufficient sleep [Didde and Sigafoos, 2001]. Preadolescents sleep 9 to 10 hours per night, with sleep latencies of 20 minutes or more. Seizures during sleep are a frequent cause of sleep disruption. For generalized seizure disorders, one study determined that 34% of seizures occurred from arousal, 45% occurred only in sleep, and 21% occurred diurnally and nocturnally. Specific sleep epilepsy disorders such as electrical status epilepticus of sleep and nocturnal frontal lobe epilepsy should be considered [Lancioni et al., 1999]. Many patients with mental retardation also have hypotonia or extensive central nervous system abnormalities, or both, and central and obstructive sleep apnea is a common complication. Obstruction can occur at the pharyngeal level because of corticobulbar and bulbar weakness or because of the inability of the muscles of respiration to overcome the normal change in airway resistance produced by progression from waking to non–rapid eye movement sleep to rapid eye movement sleep. This problem is exacerbated by the loss of muscle tone seen in rapid eye movement sleep. Because the circadian clock (within the suprachiasmatic nucleus) requires light input from the retina to entrain a rhythm, patients who are blind or who have had profound brain injury may suffer from disorganized sleep architecture. In patients with a sleep problem, obtaining an accurate sleep history that includes sleep hygiene, nighttime awakenings, and daytime behavior is essential. If this approach is not informative, a formal sleep study with polysomnography is indicated [Harvey and Kennedy, 2002]. Melatonin has been particularly useful for this population and has been effective for patients with global developmental delay and sleep disturbance in general [Coppola et al., 2004].

Pharmacologic Treatment of Cognitive Impairment Pharmacologic treatment of cognitive impairment is a prominent goal of clinicians and researchers. There are tantalizing studies in animal models and some preliminary data from studies of patients. Unfortunately, there is not yet solid evidence supporting a role for pharmacologic enhancement of cognition in the mental retardation population as a whole. The animal model for the Rubinstein-Taybi syndrome exemplifies the potential of this approach [Bourtchouladze et al., 2003]. Rubinstein-Taybi syndrome, which manifests with mental retardation and characteristic physical findings (i.e., broad thumbs and toes, short stature, and craniofacial anomalies), occurs in approximately 1 in 125,000 births and is caused by mutations in the cAMP-responsive element binding protein (CREB)–binding protein (CBP). Many patients with Rubinstein-Taybi syndrome are heterozygous for de novo CBP truncation mutations or deletions involving the gene, implying that the phenotype is expressed in an autosomal dominant fashion. Analogously, CBP heterozygous knockout (+/-) mice share features with Rubinstein-Taybi syndrome patients, whereas the CBP homozygous knockout (-/-) pattern in mice is embryonically lethal. In one study, treatment with inhibitors of phosphodiesterase-4 resulted in an improvement in cognitive performance for the CBP +/mice [Bourtchouladze et al., 2003]. A similar improvement

in cognition was demonstrated in the mouse model of neurofibromatosis type 1. Neurofibromatosis type 1 results from an autosomal dominant heterozygous mutation in neurofibromin [Costa and Silva, 2002]. Additional experimental data suggest that overactivation of the small GTP protein RAS by the mutant neurofibromin is the cause of cognitive dysfunction. Inhibition of RAS through pharmacologic manipulation (i.e., farnesyl transferase inhibitors) or by genetic modification increases cognitive performance in neurofibromatosis type 1 mice and improves physiologic correlates for learning [Costa et al., 2002], such as long-term potentiation. Successful changes in cognitive function in patients have been much more limited, and most reports are uncontrolled and anecdotal. One open-label study with these methodologic limitations suggested that donepezil (a cholinesterase inhibitor) improved language performance in patients with Down syndrome [Heller et al., 2003].

OUTCOME AND PROGNOSIS Most developmentally delayed or retarded children remain at home with the best caregivers possible—a loving, supportive, and nurturing family. This represents a dramatic historical shift from the previous standard of segregated institutionalization. However, the child’s family should not be taken for granted, nor should the burden placed on the family be underestimated. Supportive counseling is often necessary to help family members accept the diagnosis, plan realistically for the future, and deal with any feelings of anger, guilt, loneliness, or even shame often regrettably but understandably experienced. The emotional states experienced by parents of a delayed or retarded child resemble those experienced during bereavement [Batshaw 1993; Kübler-Ross, 1969]. Support to lessen the family burden, especially in the context of severe delay or retardation, such as short-term respite care frequently needs to be sought and made available to ensure family health and well-being. Siblings of the delayed or retarded child are often overlooked and are prone to more frequent peer and behavior problems [Bagenholm and Gillberg, 1991]. Longitudinal studies suggest continued intellectual development in those with mild or moderate mental retardation [Eyman and Widaman, 1987; Hogg et al., 1988] and the absence of such improvement in those with severe or profound mental retardation. Functional attainment for the child with severe neurodevelopmental disability by age 6 typically represents the functional attainment for the lifespan [Strauss et al., 1997]. Greater developmental progress has occurred in those provided home or foster care rather than institutional or residential care [Eyman and Widaman, 1987]. In the United States, federal law mandates with public funds the provision of early educational and rehabilitation services to the preschool child with a developmental disability and appropriate educational services to the schoolage child, regardless of mental handicap. The long-term benefits of early intervention remains speculative in the absence of definitive longitudinal studies, but a beneficial trend for sustained intervention in a programmatic approach with targeted screening and intervention at key points in the lifespan is suggested [Majnemer, 1988].

Sherr and Shevell / Mental Retardation and Global Developmental Delay

Pragmatically, the focus should be on short-term achievable goals that assist in improving functional capacity, especially with respect to obtaining independence in activities of daily living. Life skills and vocational training are viable and important objectives for those with mild or moderate mental retardation and appear to be integral to achieving a sense of self-worth and self-esteem. Clinical judgment suggests that continued progress implies the potential for even further future progress and remains a good prognostic sign in contradistinction to a long-term plateau in developmental skills. The transition to adult life can be challenging for the retarded individual and the family members. It involves issues related to living situations, limited access to entitlements and opportunities for participation, sexuality, and employment [Batshaw, 1993]. Deterioration in ability or adaptive function has not been manifested in cohorts followed through this transitional phase [Eyman and Widaman, 1987]. Severe childhood mental retardation can predict later adult dependence and disability, but investigators are only now experiencing the transition to adulthood of populations raised in era after segregation to institutions [Clarke and Clarke, 1988]. Family involvement in transition planning and an individual’s prior work experience and educational attainment have been key factors in successful adjustment to adult life [Reiter and Palnizky, 1996]. Individuals with mild to moderate mental retardation have had higher unemployment rates than the general population and a tendency for placement in segregated (i.e., sheltered) environments [Kraemer and Blacher, 2001]. Periodic, ongoing support often has been a necessary precondition for continued employment. Because employment has been linked to a better quality of life, it should be sought for the individual patient or collectively for the class of individuals affected [Kraemer et al., 2003]. Psychiatric and behavioral disorders occur with increased frequency in delayed or retarded individuals, resulting in an additional barrier to social inclusion and a challenge to psychiatric service provision [O’Brien, 2000]. The life expectancy of a child with mild to moderate mental retardation who is in good general health without evidence for cardiorespiratory disease or severe epilepsy can be considered similar to that of a healthy child. Significant mobility limitations (e.g., quadriplegia with inability to independently roll or sit), lack of functional hand use, and feeding dependency (especially placement of a gastrostomy tube) have been associated with limitations in life expectancy. Other important variables include the nature of associated disabilities and medical conditions together with the availability of quality medical care. However, a temporal trend is evident, with life expectancy improving overall for those with delay and mental retardation, even for the most severely affected individuals [Eyman et al., 1990; Piloplys et al., 1998; Strauss et al., 1997]. ACKNOWLEDGMENTS The authors wish to thank Rita J. Jeremy, Ph.D., Developmental Psychologist, Department of Pediatrics, University of California, San Francisco for her assistance in preparation of the tables containing information on measures for evaluation of intellectual, neurodevelopmental, and behavioral progress.

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CHAPTER 33

Cognitive and Motor Regression David J. Michelson and Stanford K. Shu

In considering a child with a suspected developmental problem, even one in whom cognitive and motor skills appear to have been lost, it is important to distinguish between static and progressive disorders. A similar variety of acquired central nervous system injuries can cause cerebral palsy and developmental delay when suffered early in childhood and cause a static form of regression when occurring later. Truly progressive neurodegenerative disorders of childhood are more likely to be inherited and therefore to be metabolic, to carry a prognosis of continued functional decline and death, and to be at least theoretically amenable to specific therapies. These disorders are individually rare, however, and the importance of recognizing them can be matched by the difficulty of doing so. The manner in which neurodegeneration manifests depends on many factors, including the age of onset, the nervous system and other organ system functions that are most prominently affected, and the speed with which changes occur. Progressive loss of intellectual and motor function is most easily recognized when it occurs rapidly in an older child after a period of normal development. Many of the classic descriptions of childhood neurodegenerative diseases are based on such presentations. As insight into the molecular and genetic basis of these disorders has increased, so too has the awareness of the variety of phenotypes with which they can manifest. Many disorders previously recognized in only a few forms are now known to manifest in forms that vary from acute metabolic crisis in the newborn period to subtly progressive symptoms in adolescence or adulthood. For patients with rapidly progressive phenotypes, presenting symptoms can include an altered level of consciousness and seizures, mimicking a wide variety of acquired insults. Younger children with more slowly progressive symptoms may present with the loss of previously acquired skills (i.e., developmental regression) or with increasingly slow acquisition of new skills (i.e., developmental plateau). Older children can present with specific cognitive disturbances or with even more subtle changes in personality, behavior, judgment, or overall academic performance.

COGNITION The normal cortex is organized into areas with primary motor and sensory functions (i.e., unimodal) and areas that associate the primary functions to one another (i.e., heteromodal), giving rise to the so-called higher cortical functions such as language and reasoning. For example, the visual system involves sequential processing of input by increasingly complex networks of neurons, ultimately resulting in the conscious perception, recognition, and association of images, symbols, and concepts [Ringach, 2004].

Disturbances of higher cortical function are well characterized and localized in adult patients with acquired and degenerative disorders, including amnesia (i.e., disturbed ability to form new memories or to recall previously learned information), aphasia (i.e., difficulty with the expression or comprehension of language), apraxia (i.e., difficulty carrying out learned motor tasks not caused by weakness or incoordination), agnosia (i.e., difficulty recognizing or identifying objects or sounds not caused by sensory loss), and disturbed executive functioning (i.e., poor planning, organizing, sequencing, and abstracting). The American Psychiatric Association’s criteria for the diagnosis of dementia, impaired social and occupational functioning caused by the loss of higher cortical function, are often met by children with neurodegenerative disease, although the term is rarely applied to children in the United States [APA, 2000]. The definitions and localizations of the most commonly encountered cognitive disturbances are listed in Table 33-1. Compared with adults, specific cognitive disturbances are more difficult to diagnose in young children, in whom complex cognitive abilities are still developing. Localization of these abilities may also be less certain or fixed. Some functional imaging studies of healthy children suggest that cortical tasks such as language processing are as well localized in very young children as they are in adults [DehaeneLambertz et al., 2002]. However, the correlation between focal cortical injuries and specific neurologic deficits is weaker for very young children, suggesting a greater potential of the immature brain for reorganizing functions that are critical to survival [Ewing-Cobbs et al., 2003]. Primary motor and sensory functions are readily assessed by the screening neurologic examination, even in uncooperative children, but higher cortical functions are far more difficult to grade at the bedside. Tests used routinely to screen for dementia in adults, such as the Folstein Mini-Mental Status Examination, are easily administered to verbal, cooperative children, but interpretation of scores is limited by the lack of age-adjusted normative data. The collective observations of clinicians, parents, and teachers who suspect subtle cognitive decline should be supplemented by those of a child psychologist who is trained to administer age-specific tests and to appropriately assess the impact of potential confounders such as primary sensory and motor deficits, inattentiveness, shyness, behavior problems, and cultural and language differences [Sparrow and Davis, 2000].

EPIDEMIOLOGY Although the causes of neurodegeneration are individually rare, their incidence has been estimated to be as high as 1 in

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TABLE 33-1 Cortical Localization of Cognitive Impairments SYMPTOM Aphasia Sensory aphasia (Wernicke’s aphasia)

Motor aphasia (Broca’s aphasia) Conduction aphasia Alexia with agraphia Dysprosody (sensory, motor, conduction) Agnosia Visual Tactile Auditory Spatial Apraxia Ideational Ideomotor Limb-kinetic Gerstmann’s syndrome

FEATURES

LOCALIZATION

Altered discrimination of individual sounds (phonetic errors), substitution of sounds or syllables (phonemic errors or literal paraphasias), words or phrases (verbal paraphasias) Disturbed speech production with loss of fluency and sentence organization Poor repetition despite normal speech fluency and comprehension Isolated deficits in reading and writing language Impaired discrimination of, production of, or repetition of the intonation, melody, or phrasing of language

Dominant posterosuperior temporal gyrus

Impaired recognition of colors (achromatopsia), object classes (visual object agnosia), or specific objects (prosopagnosia) Decreased perception of object shape (astereognosis), weight, and texture. Inability to recognize verbal (word deafness) or nonverbal (amusia) sounds Inattention toward one side of the world or self that is partial (extinction) or complete (neglect) Inability to perform or recognize learned motor skills resulting from loss of mechanical knowledge Inability to copy gestures or use tools without errors in positioning, orientation, movement, and timing Loss of finger dexterity Impairments in writing (dysgraphia), performing arithmetic calculations (dyscalculia), distinguishing right from left, and identifying fingers (finger agnosia)

2000 live births [Surtees, 2002]. Much of what has been published regarding these disorders has been retrospective and focused on individual conditions, providing little basis for a discussion of their collective epidemiology. A few studies have been notable exceptions. An examination of 10 years of experience at two large academic centers in the United States found that of 1218 admissions to their child neurology services, 341 patients were diagnosed with 1 of more than 50 causes of developmental regression [Dyken and Krawiecki, 1983]. They classified more than 300 progressive neurologic disorders, based on their predominant localizations, as polioencephalopathies (i.e., cortical gray matter), leukoencephalopathies (i.e., subcortical white matter), corencephalopathies (i.e., subcortical gray matter), spinocerebellopathies (i.e., spinal cord and cerebellum), and diffuse encephalopathies. Table 33-2 shows the results of their analysis of the relative frequency of the various diagnoses. Forty-seven percent of the patients had one of the seven most common diagnoses: lysosomal storage disease (largely neuronal ceroid lipofuscinosis), hypoxic cerebral injury, subacute sclerosing panencephalitis, acute disseminated encephalomyelitis, spinal muscular atrophy, hereditary spastic paraplegia, and tuberous sclerosis. Although genetic-metabolic defects were implicated in 72% of cases, a significant number were attributed to acquired injuries due to infection, immunologic disorders, refractory epilepsy, chronic environmental insults,

Dominant inferior frontal gyrus Dominant arcuate fasciculus Dominant supramarginal and angular gyri Nondominant perisylvian cortex, with homology with the corresponding aphasia in the dominant hemisphere Bilateral occipitotemporal visual association cortex Contralateral parietal cortex Bilateral temporoparietal cortex Nondominant parietal cortex Dominant inferior parietal cortex Contralateral and dominant premotor and supplementary motor cortex Contralateral motor cortex Dominant angular gyrus of the parietal lobe

nutritional deficiencies, and iatrogenic factors. Two prospective surveys for dementia in childhood were undertaken in the United Kingdom [Devereux et al., 2004] and Australia [Nunn et al., 2002] as part of nationwide efforts to identify cases of new variant Creutzfeldt-Jakob disease. Although these studies relied on reports from pediatricians and were unable to provide absolute incidence or prevalence figures, they did reflect relative prevalences within their reporting areas. The UK study collected and analyzed 798 cases of childhood dementia over a 5-year span, of which 577 had a confirmed diagnosis, 6 had definite or probable new variant Creutzfeldt-Jakob disease, 51 had no clear cause, and 164 were still undergoing investigation. Among the 99 different confirmed diagnoses, more than one fourth of the cases were accounted for by the five most common: mucopolysaccharidosis type III (i.e., Sanfilippo’s syndrome) in 41 cases, adrenoleukodystrophy in 32 cases, late infantile neuronal ceroid lipofuscinosis in 31 cases, mitochondrial cytopathy in 30 cases, and Rett’s syndrome in 29 cases. Higher rates of prevalence and of consanguinity were found among residents of South Asian origin. The Australian study identified 230 cases of childhood dementia in a 2-year period, with 134 ascribed to Rett’s syndrome and 80 diagnosed with other progressive neurologic disorders. Of the 63 cases with a definite diagnosis other than Rett’s syndrome, there were 20 cases with a lyso-

Michelson and Shu / Cognitive and Motor Regression

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TABLE 33-2 Classification and Relative Frequency of 340 Cases of Childhood Neurodegeneration POLIODYSTROPHIES

N*

CORENCEPHALOPATHIES

N

SPINOCEREBELLOPATHIES

N

Lysosomal storage disorders Hypoxic poliodystrophy Idiopathic poliodystrophy West’s syndrome Lennox-Gastaut syndrome Metabolic poliodystrophy Toxoplasmosis Post-vaccine poliodystrophy Lowe’s syndrome

39 29 24 17 9 4 3 3 1

Total

129

Idiopathic corencephalopathy Huntington’s disease Mitochondrial disorders Dystonia musculorum deformans Hallervorden-Spatz syndrome Ataxia-telangiectasia Congenital indifference to pain Infantile neuroaxonal dystrophy Riley-Day syndrome Wilson’s disease Total

8 5 4 2 2 1 1 1 1 1 26

Spinal muscular atrophy Hereditary spastic paraplegia Acute cerebellar ataxia Infantile polymyoclonus Charcot-Marie-Tooth disease Friedreich’s ataxia Marinesco-Sjögren syndrome OPCA Spinocerebellar degeneration Refsum’s disease Total

19 12 8 4 2 2 1 1 1 1 51

LEUKODYSTROPHIES

DIFFUSE ENCEPHALOPATHIES

SSPE ADEM and MS Adrenoleukodystrophy Metachromatic leukodystrophy Pelizaeus-Merzbacher disease Krabbe’s disease Phenylketonuria Cockayne’s syndrome Canavan’s disease Alexander’s disease Maple syrup urine disease

26 17 8 5 4 4 2 2 1 1 1

Total

71

Tuberous sclerosis Idiopathic encephalopathy Hyperammonemic disorders Mitochondrial disorders Neurofibromatosis Achondroplasia Organic acidurias Letterer-Siwe disease Sturge-Weber syndrome Zellweger’s syndrome Homocystinuria Incontinentia pigmenti Sjögren-Larsson syndrome Total

19 17 6 4 4 2 2 2 2 2 1 1 1 63

*Examination of 10 years’ experience at two large academic centers in the United States found that of 1218 admissions to their child neurology services, 341 patients were diagnosed with one of more than 50 causes of developmental regression. Based on their predominant localizations, more than 300 progressive neurologic disorders were classified as polioencephalopathies, leukoencephalopathies, corencephalopathies, spinocerebellopathies, and diffuse encephalopathies. ADEM, acute disseminated encephalomyelitis; MS, multiple sclerosis; OPCA, olivopontocerebellar atrophy; SSPE, subacute sclerosing panencephalitis. Adapted from Dyken P and Krawiecki N. Neurodegenerative diseases of infancy and childhood. Ann Neurol 1983;13:351.

somal storage disorder, 16 cases with a leukodystrophy, 15 cases with a mitochondrial cytopathy, and 12 cases resulting from other causes.

DIAGNOSTIC EVALUATION There are few published studies regarding the evaluation of children with a suspected neurodegenerative disease, making it difficult to speak of evidence-based rules for such an evaluation. The recommendations provided here are based on our interpretation of multiple case reports, case series, retrospective studies, and review articles, but they have not been subjected to prospective testing. Every child with a suspected developmental disorder should be subjected to a thorough evaluation that includes a detailed history, family history, review of systems, and physical examination. Repeated examinations over a prolonged period may be necessary to uncover more subtle regression. A variety of metabolic and genetic conditions have been diagnosed in children initially thought to have cerebral palsy due to static encephalopathy, including those listed in Table 33-3. This experience suggests that children with a diagnosis of cerebral palsy should undergo further evaluation for neurodegenerative disorders when any of the following conditions is identified: no definite history of a

preceding injury, a family history of neurologic symptoms, a history of parental consanguinity, or inadequately explained oculomotor abnormalities, involuntary movements, ataxia, muscle atrophy, or sensory loss [Gupta and Appleton, 2001]. Children with recurrent, unexplained episodes of altered mental status, vomiting, or abnormal movements should be strongly suspected of having an inborn error of metabolism, such as a mitochondrial cytopathy, aminoacidopathy, organic aciduria, or urea cycle enzyme defect. Conversely, children who do not have a neurodegenerative disease can undergo clinical deterioration resulting from medication side effects, intercurrent medical or psychiatric illnesses, or the evolution of existing hydrocephalus, spasticity, dystonia, or seizures. When neurodegeneration is suspected, a timely evaluation that results in a specific diagnosis can be of great value. Although specific treatments are available for only a minority of diseases, information regarding prognosis and recurrence risk is desired by most families. Diagnoses can be categorized by their cause or by their prominent signs and symptoms. Tables 33-4 and 33-5 list the most commonly encountered causes of cognitive and motor regression by etiologic category and describes their common presenting features, the suggested diagnostic tests, and the chapter in this book in which greater detail can be found. Another approach to laboratory testing is outlined in Table 33-6, which lists the initial screening tests recom-

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TABLE 33-3 Progressive Disorders Misdiagnosed as Cerebral Palsy CEREBRAL PALSY DIAGNOSIS

UNDERLYING DISORDER

STUDY

Hypotonic

Duchenne muscular dystrophy Infantile neuroaxonal dystrophy Mitochondrial disorder 3-methylcrotonyl CoA carboxylase deficiency 3-methylglutaconic aciduria Dopa-responsive dystonia Glutaric aciduria type I Juvenile dystonic lipidosis Juvenile neuronal ceroid lipofuscinosis Leigh’s disease Lesch-Nyhan syndrome Pelizaeus-Merzbacher disease Rett’s syndrome Adrenoleukodystrophy and adrenomyeloneuropathy Arginase deficiency Hereditary progressive spastic paraplegia Holocarboxylase synthetase deficiency Metachromatic leukodystrophy Cervical tumor Angelman’s syndrome Ataxia telangiectasia GM1 gangliosidosis Neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome Niemann-Pick disease type C Pontocerebellar atrophy or hypoplasia (with carbohydrate-deficient glycoprotein syndrome) Posterior fossa tumor X-linked spinocerebellar ataxia

Mohamed et al., 2000 Ramaekers et al., 1987 Tsao et al., 1994 Murayama et al., 1997 Pantaleoni et al, 2000 Fletcher et al, 1993 Hoffmann et al., 1996 Meek et al., 1984 Naidu, 1993 Lissens et al., 1999 Christie et al, 1982 Carod-Artal et al., 1995 Naidu, 1997 Moser et al., 1984 Prasad et al., 1997 McDermott et al., 2000 Livne et al., 1994 Lyon et al., 1996 Giuffre et al., 1981 Clayton-Smith, 1992 Cabana et al., 1998 Nyhan and Ozand, 1998 Fryer et al., 1994

Dystonic

Spastic

Ataxic

Patterson, 2003 Barth, 1993 O’Brien et al., 2001 Apak et al., 1989

Adapted from Gupta R, Appleton RE. Cerebral palsy: Not always what it seems. Arch Dis Child 2001;85:356.

mended for children without suggestive signs and symptoms, as well as subsequent studies for infectious, toxic, endocrinologic, genetic, neoplastic, metabolic, autoimmune, dysautonomic, and nutritional disorders that may be suspected on the basis of the history or the results of the initial screening tests. Symptoms that suggest specific disorders are listed in additional tables on the basis of the presence of abnormal movements, including ataxia, tremor, chorea, dystonia, and myoclonus (Table 33-7), head size abnormalities, including as macrocephaly and microcephaly (Table 33-8); hepatomegaly (Table 33-9); skin abnormalities, including hyperpigmentation, hypopigmentation, eczema and other rashes, photosensitivity, lax or redundant skin, and angiokeratoma (Table 33-10); hair abnormalities, including sparse hair or alopecia, synophrys, fine or brittle hair, and hirsutism or hypertrichosis (Table 33-11); hearing abnormalities, including sensorineural deafness, conductive deafness, and hyperacusis (Table 33-12); ophthalmologic abnormalities, including cataracts, cherry-red macula, corneal clouding, coloboma,

and retinitis pigmentosa (Table 33-13); MRI abnormalities, including leukodystrophic changes, basal ganglia calcification, basal ganglia T2 hyperintensity, lissencephaly, gray matter heterotopias, polymicrogyria, schizencephaly, holoprosencephaly, and hemimegalencephaly (Table 33-14); lower motor neuron abnormalities, including myopathy and peripheral neuropathy (Table 33-15); and other abnormalities, including cryptorchidism, macro-orchidism, and abnormal urine odor (Table 33-16). Each syndrome that is listed is followed by laboratory tests that can help to confirm the diagnosis. Some of the genes listed in the tables are being analyzed only on a research basis, making testing dependent on direct communication and cooperation between the clinician and the research scientist. Up-to-date information about syndromes, tests, and their availability is available through the Online Mendelian Inheritance in Man catalog, maintained by the United States National Institutes of Health (www.ncbi.nlm.nih.gov), and through links to the Gene Tests catalog, maintained by the University of Washington at Seattle (www.genetests.org).

Michelson and Shu / Cognitive and Motor Regression

TABLE 33-4 Causes of Intellectual and Motor Regression in Childhood CATEGORY

DISORDERS

DIAGNOSTIC TESTS

CHAPTER

Endocrine

Addison’s disease Hashimoto’s encephalopathy Hypothyroidism Panhypopituitarism Doose’s syndrome Landau-Kleffner syndrome Lennox-Gastaut syndrome Ohtahara’s syndrome Progressive myoclonic epilepsy (e.g., Lafora body disease) West’s syndrome Meningitis Viral encephalitis Subacute sclerosing panencephalitis HIV encephalitis Variant Creutzfeldt-Jakob disease Post-infectious hydrocephalus Multiple sclerosis Chediak-Higashi syndrome

Serum TSH, T4, anti-thyroid antibodies, cortisol, glucose

84

Routine or prolonged EEG monitoring Skin biopsy for Lafora bodies, genetic testing

45

Neuroimaging CSF and serum tests for DNA, antigens, and antibodies EEG for periodic sharp waves

68, 69, and 70

Neuroimaging White blood cell analysis (neutropenia, defective NKC function) See Table 33-5 Neuroimaging Repeated CSF cytology Exposure history

59 and 60

Neuroimaging Repeated skin examinations Serum AFP (ataxia-telangiectasia) and genetic studies

31

Dietary history Serum B12, thiamin, vitamins E and A, albumin, and prealbumin Symptom rating scales MECP2 gene test

90

Epileptic

Infectious

Immunologic Metabolic Neoplastic

Neurocutaneous

Nutritional PDDs

Psychiatric Toxic Traumatic

Vascular

See Table 33-5 Primary and metastatic brain tumor Meningeal carcinomatosis Radiation necrosis Chemotherapeutic toxicity Paraneoplastic syndrome Ataxia-telangiectasia Incontinentia pigmenti Neurofibromatosis Sturge-Weber syndrome Tuberous sclerosis complex Vitamin deficiency Caloric starvation Protein deprivation (kwashiorkor) Autism Childhood disintegrative disorder PDD not otherwise specified Rett’s syndrome Thought disorder (schizophrenia) Severe mood disorder (depression) Environmental toxins Medications Illicit drug use Diffuse axonal injury Intracranial hemorrhage Post-concussion syndrome Post-traumatic hydrocephalus Arterial and venous stroke Congenital heart disease Systemic lupus erythematosus Moyamoya disease Sickle cell disease Vasculitis

71

38

Symptom rating scales

39

Exposure history Serum and urine toxicology screens

87

Neuroimaging Cognitive testing

62, 63, and 64

Neuroimaging with angiography Serum tests for thrombophilia, autoimmune disease Echocardiogram

72

AFP, α-fetoprotein; CSF, cerebrospinal fluid; EEG, electroencephalogram; HIV, human immunodeficiency virus; NKC, natural killer cell; PDD, pervasive developmental disorder; T4, thyroxine; TSH, thyroid-stimulating hormone.

825

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TABLE 33-5 Inherited Metabolic Causes of Intellectual and Motor Regression in Childhood CATEGORY

EXAMPLES

FEATURES

DIAGNOSTIC TESTS

CHAPTER

Peroxisomal biogenesis defects

Zellweger’s syndrome Neonatal adrenoleukodystrophy Infantile Refsum’s disease Rhizomelic chondrodysplasia punctata Adrenoleukodystrophy Refsum’s disease Bifunctional enzyme defect

Dysmorphism, hepatic insufficiency, hypotonia, seizures, calcification of cartilage

Neuroimaging Serum VLCFA, phytanic acid, red cell plasmalogens Skeletal survey

29

Increased pigmentation, adrenal insufficiency, spasticity, sensorineural deafness, behavioral disturbances, peripheral neuropathy, retinitis pigmentosa, ataxia Short stature, sensorineural hearing loss, retinitis pigmentosa, ataxia, seizures, ophthalmoplegia, peripheral neuropathy, myopathy, vomiting, migraine headaches, strokelike episodes, basal ganglia degeneration and calcification, hepatic insufficiency, renal tubular insufficiency, diabetes mellitus, diabetes insipidus Coarse facies, short stature, dysostosis, contractures, dystonia, spasticity, hyperacusis, hearing loss, seizures, megalencephaly, hepatosplenomegaly Blindness associated with cherry-red macula, cataracts, or optic atrophy Angiokeratoma corporis diffusum in mucolipidosis type I (Fabry’s disease)

Serum VLCFA, phytanic acid, cortisol

29

Neuroimaging Serum lactate, pyruvate Mitochondrial DNA Urine organic acids CSF lactate Muscle biopsy

28

Tissue biopsy and electron microscopy for nonspecific intracellular inclusions Specific leukocyte enzyme analysis or gene testing

27

Failure to thrive, seizures, lethargy, vomiting, chorea, hypopigmentation, aversion to high-protein diet

CSF and/or serum quantitative amino acids

23

Metabolic acidosis, lethargy, vomiting, ataxia, seizures, spasticity, chorea, optic atrophy, pancytopenia

Urine organic acids

23

Episodic altered consciousness, ataxia, vomiting, seizures, aversion to high-protein diet

Urine organic acids

24

Hypoglycemia, failure to thrive, generalized aminoaciduria, albuminuria, jaundice, hepatomegaly Jaundice, cataracts, hypoglycemic seizures, hepatosplenomegaly, sepsis with Escherichia coli Hypoglycemia, hepatomegaly, cardiomegaly, weakness Dysmorphism, failure to thrive, lipodystrophy, hepatomegaly, diarrhea, ataxia, spasticity, seizures, peripheral neuropathy Seizures, acquired microcephaly Hepatomegaly, tubular nephropathy

Urine reducing substances, organic acids Enzyme activity Urine reducing substances Enzyme activity

25

Peroxisomal enzyme defects

Mitochondrial disorders

Alpers’ syndrome Kearns-Sayre syndrome Leber optic atrophy Leigh’s syndrome MERRF syndrome MELAS syndrome NARP syndrome Wolfram’s syndrome

Lysosomal storage disorders

Fucosidosis Gaucher I-III GM1 gangliosidosis GM2 gangliosidosis I–II Krabbe’s disease Mannosidosis A-B Mucolipidosis I–IV Mucopolysaccharidosis I–VIII Niemann-Pick A–C Neuronal ceroid lipofuscinosis 1–8 Sialidosis I–II Wolman’s syndrome Hyperhomocysteinemia Phenylketonuria Maple syrup urine disease Nonketotic hyperglycinemia Glutaric academia type I Methylmalonic acidemia Propionic aciduria 3-α-Methylglutaconic aciduria Argininemia Arginosuccinic aciduria Citrullinemia Ornithine transcarbamylase deficiency Fructose intolerance

Amino acidopathies

Organic acidopathies

Urea cycle enzyme disorders

Carbohydrate disorders

Galactosemia Glycogen storage diseases Congenital disorders of glycosylation DeVivo’s syndrome Fanconi-Bickel syndrome Heavy metal disorders

Pantothenate kinase associated Chorea, dysarthria, dystonia, spasticity, neurodegeneration retinitis pigmentosa, optic atrophy, Other forms of Hallervorden-Spatz seizures, axonal neuropathy Neuroaxonal dystrophy Wilson’s disease

Hepatic failure, hyperbilirubinemia, dystonia, choreoathetosis, Kayser-Fleischer rings

Serum glucose Liver or muscle biopsy Sialotransferrin isoelectric focusing CSF to serum glucose ratio Gene test for GLUT1 and GLUT2 mutations* Neuroimaging Gene testing for PANK2 mutations Nerve biopsy for axonal spheroids Serum ceruloplasmin Urine 24-hour copper assay Liver biopsy

26

10 and 18 59 and 90

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TABLE 33-5, cont’d Inherited Metabolic Causes of Intellectual and Motor Regression in Childhood CATEGORY

Leukodystrophies

Poliodystrophies

Other

EXAMPLES

FEATURES

DIAGNOSTIC TESTS

CHAPTER

Menkes’ disease

Failure to thrive, hypopigmentation, kinky hair, spontaneous hemorrhages, spasticity, seizures Spasticity, ataxia, optic atrophy Macrocephaly (Alexander’s disease and Canavan’s disease) Neuropathy (metachromatic leukodystrophy and Krabbe’s disease) Ichthyosis (Sjögren-Larsson syndrome)

Serum ceruloplasmin Urine 24-hour copper assay

59

Seizures, chorea, dystonia, spasticity Ataxia, spasticity, peripheral neuropathy, optic atrophy, ophthalmoplegia Spastic paraparesis, peripheral neuropathy Dystonia, myoclonus Ataxia, retinopathy, steatorrhea, peripheral neuropathy Progeria, dysarthria, ataxia, peripheral neuropathy, seizures Spasticity, parkinsonism, athetosis, optic atrophy, retinitis pigmentosa

Neuroimaging Gene tests

58 and 59

Blood smear, serum cholesterol, and LDL Tests of cellular sensitivity to ultraviolet light Neuroimaging

58 and 59

Aicardi-Goutiéres syndrome Adrenoleukodystrophy Alexander’s disease Canavan’s disease Cerebrotendinous xanthomatosis Krabbe’s disease Metachromatic leukodystrophy Multifocal leukoencephalopathy with subcortical cysts Pelizaeus-Merzbacher disease Sjögren-Larsson syndrome CASH/VWM syndrome Huntington’s disease Spinocerebellar ataxias Hereditary spastic paraplegias Familial dystonia Abetalipoproteinemia Cockayne’s syndrome Fahr’s disease

Neuroimaging with contrast 60 CSF cytology and interferon-α Serum VLCFA and cholesterol Urine NAA Gene tests for EIF2B1 to EIF2B5, GFAP, MLC1, and PLP1

*The GLUT1 gene symbol has been renamed SLC2A1 and GLUT2 has been designated SLC2A2 in the International System of Gene Nomenclature. CASH/VWM, childhood ataxia with diffuse central hypomyelination/vanishing white matter; CSF, cerebrospinal fluid; LDL, low-density lipoprotein; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke; MERRF, myoclonus epilepsy associated with ragged-red fibers; NAA, N-acetyl-aspartate; NARP, neuropathy, ataxia, and retinitis pigmentosa; VLCFA, very-long-chain fatty acids.

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TABLE 33-6 Evaluation for Neurodegenerative Disorders Based on Signs and Symptoms EVALUATION Normal Findings Initial evaluation

Additional Screening Tests Autoimmune disorder Autonomic disorder Endocrinopathy Genetic disorder

DIAGNOSTIC TESTS

Neuroimaging (MRI with and without contrast) Electroencephalogram Comprehensive metabolic panel Complete blood count Ophthalmologic examination (by specialist if possible)

Nutritional disorder

Serum sedimentation rate (Westergren), antinuclear antibody titer, complement levels Histamine skin test, sweat testing, CSF neurotransmitter metabolite levels Serum T4, TSH, ACTH, and cortisol Karyotype FISH for expanded fragile X region MECP2 mutation screening Subtelomeric rearrangement studies CSF cell count, glucose, protein CSF bacterial, fungal, and viral cultures CSF HIV and HSV by polymerase chain reaction CSF fungal antigens CSF test for prion proteins CSF for viral antibodies (measles, mumps) Serum lead and thin layer chromatography Urine screen for drugs of abuse Serum amino acids, lactate, pyruvate, ammonia, carnitine profile Urine organic acids, metabolic screen, porphyrins CSF lactate, amino acids, and neurotransmitter metabolites CSF for cytologic analysis CSF and serum for paraneoplastic antibodies Serum niacin, thiamin, pyridoxine, cobalamine, homocysteine, and methylmalonic acid

Signs and Symptoms Abnormal movements Abnormal head size Hepatomegaly Abnormal skin Abnormal hair Abnormal hearing Ophthalmologic abnormalities MRI abnormalities Lower motor neuron abnormalities Other abnormalities

See Table 33-7 See Table 33-8 See Table 33-9 See Table 33-10 See Table 33-11 See Table 33-12 See Table 33-13 See Table 33-14 See Table 33-15 See Table 33-16

Infection

Intoxication Metabolic disorder Neoplastic disorder

ACTH, adrenocorticotropin hormone; CSF, cerebrospinal fluid; FISH, fluorescence in situ hybridization; HIV, human immunodeficiency virus; HSV, herpes simplex virus; MRI, magnetic resonance imaging; T4, thyroxine; TSH, thyroid-stimulating hormone.

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TABLE 33-7 Developmental Disorders Associated with Abnormal Movements DISORDER

DIAGNOSTIC TESTS

Aicardi-Goutiéres syndrome Abetalipoproteinemia Alexander’s disease Aminoacidopathies and organic acidurias Angelman’s syndrome Anoxia or carbon monoxide inhalation Ataxia-oculomotor apraxia syndrome Ataxia telangiectasia CNS malformation, injury, or mass lesion CNS vasculitis Cockayne’s syndrome Endocrinopathy Fragile X syndrome De Barsy’s syndrome Friedreich’s ataxia GM1 gangliosidosis GM2 gangliosidosis Hallermann-Streiff syndrome Hallervorden-Spatz syndrome Huntington’s disease Infectious and post-infectious encephalitis Kernicterus Krabbe’s disease Lafora body disease Lesch-Nyhan syndrome Marinesco-Sjögren syndrome

Serum and CSF interferon-α Serum lipid profile, blood smear for acanthocytes GFAP mutation analysis, brain MRI Serum amino acids and urine organic acids 15q11-13 mutation analysis, uniparental disomy, methylation Brain imaging, serum carboxyhemoglobin, CBC APTX mutation analysis α-Fetoprotein, ATM mutation analysis Brain and spinal cord imaging Cerebral and renal angiography, ESR, C3, C4, CH50, ANA Brain CT for calcifications, DNA repair studies, ERCC6 and ERCC8 mutation analysis Serum T4, TSH, cortisol, and parathyroid hormone FMR1 expansion Skin biopsy for elastin staining EMG, ECHO, FRDA expansion Leukocyte β-galactosidase activity Leukocyte hexosaminidase A and B activity Clinical diagnosis Brain MRI for iron deposition, PANK2 mutation Huntington’s disease gene expansion CSF studies Brain MRI, history of hyperbilirubinemia Leukocyte β-galactosylcerebrosidase activity Skin biopsy; EPM2A, EPM2B, and NHLRC1 mutation analysis Serum uric acid, urine urate-to-creatine ratio, HPRT activity, HPRT1 mutation analysis Brain imaging for cerebellar hypoplasia, serum creatine kinase, lymphocytes for electron microscopy Serum ceruloplasmin, 24-hour urine copper assay, hair microscopy, ATP7A mutation analysis Serum lactate and pyruvate, urine organic acids, acylcarnitine profile, mitochondrial DNA studies, CSF lactate level, muscle biopsy Electroencephalography, clinical diagnosis Conjunctival biopsy for electron microscopy, enzyme studies, genetic studies CSF studies for neurotransmitter and tetrahydrobiopterin metabolites Fibroblast filipin staining and cholesterol esterification tests, NPC1 and NPC2 mutation analysis CBC, serum protein, vitamin E, thiamine, cobalamin, pyridoxal phosphate CBC and bone marrow biopsy (lymphoid tumors), abdominal imaging, urine catecholamines (neuroblastoma) PLP1 mutation analysis Serum very-long-chain fatty acids, phytanic acid, erythrocyte plasmalogens Urine porphyrins Serum lactate and pyruvate, leukocyte pyruvate carboxylase activity Comprehensive metabolic panel Urine sialyloligosaccharides, fibroblast neuraminidase activity Urine sulfite, fibroblast sulfite oxidase activity, SUOX mutation analysis Brain MRI for cerebellar and brainstem atrophy, genetic panel for spinocerebellar ataxias Serum ASO and anti-DNase titers, CBC, and ESR TOR1A mutation analysis Serum lead, urine screen for drugs of abuse and thin layer chromatography Brain MRI, TSC1 and TSC2 mutation analysis, renal ultrasound CSTB mutation analysis Brain and spinal imaging for hemangioblastomas, VHL mutation analysis DNA repair studies Serum ceruloplasmin, 24-hour urine copper assay, ATP7B mutation analysis WFS1 and WFS2 mutation analysis

Menkes’ disease Mitochondrial disease Idiopathic epileptic encephalopathy Neuronal ceroid lipofuscinosis Neurotransmitter deficiency Niemann-Pick disease type C Nutritional deficiency Paraneoplastic syndromes Pelizaeus-Merzbacher disease Peroxisomal disorders Porphyria Pyruvate carboxylase deficiency Renal or hepatic failure Sialidosis Sulfocysteinuria Spinocerebellar ataxias Sydenham’s chorea (and other PANDAS) Torsion dystonia Toxins Tuberous sclerosis Myoclonic epilepsy of Unverricht and Lundborg Von Hippel-Lindau syndrome Xeroderma pigmentosa Wilson’s disease Wolfram’s syndrome

ANA, antinuclear antibodies; CBC, complete blood cell count; CNS, central nervous system; CSF, cerebrospinal fluid; CT, computed tomography; ECHO, echocardiography; EMG, electromyography; ESR, erythrocyte sedimentation rate; MRI, magnetic resonance imaging; PANDAS, pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections; T4, thyroxine; TSH, thyroid-stimulating hormone.

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TABLE 33-8 Developmental Disorders Associated with Abnormal Head Size DISORDER

DIAGNOSTIC TESTS

Macrocephaly Acromegaly Alexander’s disease Aminoacidopathies Bannayan-Zonana syndrome, Cowden’s syndrome Canavan’s disease Central nervous system mass lesion, injury, or malformation Costello’s syndrome FG syndrome (i.e., Opitz-Kaveggia syndrome) Fragile X syndrome Galactosemia GM1 gangliosidosis GM2 gangliosidosis Histiocytosis X Hydrocephalus, MASA syndrome Hypoadrenocorticism Hypomelanosis of Ito Hypoparathyroidism Incontinentia pigmenti Jacobsen’s syndrome Metachromatic leukodystrophy Mucopolysaccharidoses Neonatal progeroid syndrome Neurofibromatosis 1 Peters-plus syndrome Peroxisomal disorders Progeroid form of Ehlers-Danlos Proteus syndrome Rett’s syndrome Robinow’s syndrome Sebaceous nevus of Jadassohn Simpson-Golabi-Behmel syndrome Sotos’ syndrome Sturge-Weber syndrome Shwachman-Bodian-Diamond syndrome Toxins Tuberous sclerosis complex Weaver’s syndrome

Serum growth hormone Brain MRI, GFAP mutation analysis Serum amino acids PTEN mutation analysis Urine NAA, fibroblast aspartoacylase activity, ASPA mutation analysis Brain MRI, angiography, and venography Clinical diagnosis Clinical diagnosis FMR1 expansion Erythrocyte GALT activity, GALT mutation analysis Lymphocyte β-galactosidase activity Lymphocyte hexosaminidase A and B activity Brain MRI, tissue biopsy Brain MRI, L1CAM mutation analysis Serum cortisol, ACTH Skin biopsy for chromosomal mosaicism Serum calcium, phosphate, and parathyroid hormone levels IKBKG mutation analysis Karyotype, FISH for subtelomeric deletion of 11q23 Brain MRI, leukocyte arylsulfatase A activity Urine mucopolysaccharides, enzyme analysis, genetic testing Clinical diagnosis Clinical diagnosis, neurofibromin protein truncation analysis Clinical diagnosis Serum very-long-chain fatty acids, phytanic acid, erythrocyte plasmalogens Fibroblast galactosyltransferase I activity, B4GALT7 mutation analysis Chromosomal mosaicism, PTEN mutation analysis MECP2 mutation analysis ROR2 mutation analysis Clinical diagnosis, brain MRI GPC3 mutation analysis NSD1 mutation analysis Brain MRI CBC, serum trypsinogen, SBDS mutation analysis Serum lead, vitamin A Brain MRI, TSC1 and TSC2 mutation analysis NSD1 mutation analysis

Microcephaly Adams-Oliver syndrome Aicardi-Goutiéres syndrome Aicardi’s syndrome α-Thalassemia mental retardation syndrome Aminoacidopathies and organic acidurias Angelman’s syndrome Aspartylglucosaminuria Bloom’s syndrome Börjeson’s syndrome Chromsomal disorders CNS malformation, injury, infection Cockayne’s syndrome Coffin-Lowry syndrome Cohen’s syndrome Congenital disorders of glycosylation Cornelia de Lange syndrome Craniosynostosis Dubowitz’s syndrome Fanconi’s anemia Hallermann-Streiff syndrome Hereditary epidermolysis bullosa Hypoadrenocorticism Hypomelanosis of Ito Hypothyroidism Incontinentia pigmenti Insulin-like growth factor 1 deficiency Jacobsen’s syndrome Langer-Giedion syndrome Menkes’ disease

Clinical diagnosis Serum and CSF interferon-α Clinical diagnosis, brain MRI CBC, hemoglobin electrophoresis, ATRX mutation analysis Serum amino acids, urine organic acids 15q11-13 mutation analysis, uniparental disomy, methylation Urine aspartylglucosamine, fibroblast aspartylglucosaminidase activity RECQL3 mutation analysis PHF6 mutation analysis Karyotype, subtelomeric deletions Brain MRI, serum and CSF studies for infection, serum studies for thrombophilia Fibroblast DNA repair assay, ERCC8 and ERCC6 mutation analysis, head CT RPS6KA3 mutation analysis COH1 mutation analysis Serum transferrin isoelectric focusing NIPBL mutation analysis Head XR, CT with reconstruction Clinical diagnosis CBC, chromosomal breakage studies Clinical diagnosis Clinical diagnosis AM and PM cortisol levels Skin biopsy for chromosomal mosaicism T4, TSH IKBKG mutation analysis Serum IGF1, growth hormone, IGF1 mutation analysis Karyotype, FISH for subtelomeric deletion of 11q23 FISH for 18q24.11 to 18q24.13 deletion including LGCR region Serum ceruloplasmin, 24-hour urine copper level, hair microscopy, ATP7A mutation analysis

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TABLE 33-8, cont’d Developmental Disorders Associated with Abnormal Head Size DISORDER

DIAGNOSTIC TESTS

Miller-Dieker syndrome Mitochondrial disease

Karyotype, FISH for 17p13.3 deletion including MDS region Serum lactate and pyruvate, urine organic acids, acylcarnitine profile, mitochondrial DNA studies, CSF lactate, muscle biopsy SMADIP1 mutation analysis DNA instability testing, NBS1 mutation analysis Conjunctival biopsy for electron microscopy, enzyme studies, genetic studies GJA1 mutation analysis Clinical diagnosis Head MRI, PLP1 mutation analysis ERCC2 and ERCC6 mutation analysis Clinical diagnosis Clinical history MECP2 mutation analysis Serum phytanic acid, erythrocyte plasmalogens, PEX7 mutation analysis Clinical diagnosis Karyotype, CREBBP mutation analysis ATR mutation analysis Urine phospholipids, fibroblast electron microscopy, MCOLN1 mutation analysis Serum cholesterol, 7-dehydrocholesterol, DHCR7 mutation analysis Clinical diagnosis Hair analysis for cysteine-rich matrix proteins, nucleotide excision-repair analysis Clinical diagnosis Clinical diagnosis WFS1 and WFS2 mutation analysis Skin biopsy for elastin staining DNA repair studies

Mowat-Wilson syndrome Nijmigen breakage syndrome Neuronal ceroid lipofuscinosis Oculodentodigital dysplasia Opitz trigonocephaly syndrome Pelizaeus-Merzbacher disease Pena-Shokeir syndrome Peters-plus syndrome Prenatal or postnatal toxins or malnutrition Rett’s syndrome Rhizomelic chondrodysplasia punctata Roberts’ syndrome Rubenstein-Taybi syndrome Seckel’s syndrome Sialolipidosis Smith-Lemli-Opitz syndrome Spastic paraplegia type 23 Trichothiodystrophy Trichorrhexis nodosa syndrome Warburg’s micro syndrome Wolfram’s syndrome Wrinkly skin syndrome Xeroderma pigmentosa

ACTH, adrenocorticotropin hormone; CSF, cerebrospinal fluid; CT, computed tomography; FISH, fluorescence in situ hybridization; GALT, galactose-1-phosphate uridylyltransferase; IGF1, insulin-like growth factor-1; MASA, mental retardation, aphasia, shuffling gait, and adducted thumbs; MDS, myelodysplasia syndrome; MRI, magnetic resonance imaging; NAA, N-acetyl-aspartate; T4, thyroxine; TSH, thyroid-stimulating hormone; XR, radiography.

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TABLE 33-9 Developmental Disorders Associated with Hepatomegaly DISORDER

DIAGNOSTIC TESTS

3-Hydroxy-3-methylglutaryl cofactor A (HMG-CoA) lyase deficiency Aicardi-Goutiéres syndrome Aldolase A deficiency Aminoacidopathies and organic acidurias Argininemia Arginosuccinic aciduria Aspartylglucosaminuria Beckwith-Weidemann syndrome Chediak-Higashi syndrome Cockayne’s syndrome

Urine organic acids Serum and CSF interferon-α Muscle aldolase activity, ALDOA mutation analysis Serum amino acids, urine organic acids Serum ammonia, urine organic acids, erythrocyte arginase activity Serum ammonia, urine organic acids, fibroblast arginosuccinate lyase activity Urine aspartylglucosamine, fibroblast aspartylglucosaminidase activity NSD1 and CDKN1C mutation analysis, FISH for 11p15.5 mutation CBC, blood smear for peroxidase staining, CHS1 mutation analysis Fibroblast DNA repair assay, ERCC8 and ERCC6 mutation analysis, head CT for calcifications Serum transferrin isoelectric focusing Serum leptin, BSCL2 mutation analysis Clinical diagnosis Fasting glucose, serum and urine phosphate, GLUT2 mutation analysis* Urine ceramide, leukocyte N-laurylsphingosine deaminase activity Urine oligosaccharides, leukocyte α-fucosidase activity Erythrocyte GALT, GALK, and GALE activity Leukocyte glucosylceramidase activity Muscle or liver biopsy Leukocyte acid β-galactosidase activity Leukocyte hexosaminidase A and B activity Serum ammonia, urine organic acids Serum lactate and pyruvate, urine organic acids, acylcarnitine profile, mitochondrial DNA studies, CSF lactate, muscle biopsy Urine sialyloligosaccharides, fibroblast neuraminidase activity Urine oligosaccharides, fibroblast heparin sulfaminidase activity Urine mucopolysaccharides, enzyme analysis, genetic testing Serum ammonia, urine organic acids, serum biotinidase activity Conjunctival biopsy for electron microscopy, enzyme studies, genetic studies Leukocyte acid sphingomyelinase activity Fibroblast filipin staining and cholesterol esterification tests NPC1 and NPC2 mutation analysis Clinical diagnosis CA2 mutation analysis Serum very-long-chain fatty acids, phytanic acid, erythrocyte plasmalogens Serum lactate and pyruvate, leukocyte pyruvate carboxylase activity Urinary sialic acid, SLC17A5 mutation analysis GPC3 mutation analysis Serum ceruloplasmin, 24-hour urine copper assay, ATP7B mutation analysis

Congenital disorders of glycosylation Congenital lipodystrophy type 2 Desmons’ syndrome Fanconi-Bickel syndrome Farber’s lipogranulomatosis Fucosidosis Galactosemia types 1, 2, and 3 Gaucher’s disease Glycogen storage disease I, IIb, and III GM1 gangliosidosis GM2 gangliosidosis Lysinurgic protein intolerance Mitochondrial disease Mucolipidoses Mannosidosis Mucopolysaccharidoses Multiple carboxylase deficiency Neuronal ceroid lipofuscinosis Niemann-Pick disease type A Niemann-Pick disease type C Opitz trigonocephaly syndrome Osteopetrosis with renal tubular acidosis Peroxisomal disorders Pyruvate carboxylase deficiency Sialuria Simpson-Golabi-Behmel syndrome Wilson’s disease

*The GLUT2 gene symbol has been renamed SLC2A2 in the International System of Gene Nomenclature. CSF, cerebrospinal fluid; FISH, fluorescence in situ hybridization; GALE, UDP-galactose-4-epimerase; GALK, galactokinase; GALT, galactose-1-phosphate uridylyltransferase.

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TABLE 33-10 Developmental Disorders Associated with Abnormal Skin DISORDER

DIAGNOSTIC TESTS

Hyperpigmented Skin Adrenoleukodystrophy Ataxia-telangiectasia Bannayan-Zonana syndrome Bloom’s syndrome Costello’s syndrome Dyskeratosis congenita Fanconi’s anemia GM1 gangliosidosis Hereditary epidermolysis bullosa Incontinentia pigmenti Johnson’s neuroectodermal syndrome Kabuki syndrome Klippel-Trenaunay-Weber syndrome LEOPARD syndrome Linear sebaceous nevus of Jadassohn Mucopolysaccharidoses Neurofibromatosis 1 Nijmigen breakage syndrome Pallister-Killian syndrome Rubenstein-Taybi syndrome Seckel’s syndrome Silver-Russell syndrome Spastic paraplegia type 23 Sturge-Weber syndrome Tuberous sclerosis complex Xeroderma pigmentosa

Serum very-long-chain fatty acids Serum α-fetoprotein, ATM mutation analysis PTEN mutation analysis RECQL3 mutation analysis Clinical diagnosis DKC1 mutation analysis CBC, chromosomal breakage studies Leukocyte acid β-galactosidase activity Clinical diagnosis IKBKG mutation analysis Clinical diagnosis Clinical diagnosis Clinical diagnosis PTPN11 mutation analysis Clinical diagnosis Urine mucopolysaccharides, enzyme analysis, genetic testing Neurofibromin protein truncation analysis DNA instability testing, NBS1 mutation analysis Fibroblast karyotype for mosaicism CREBBP mutation analysis ATR mutation analysis Karyotype, uniparental disomy of chromosome 7 Clinical diagnosis Clinical diagnosis Brain MRI, renal ultrasound, TSC1 and TSC2 mutation analysis DNA repair studies

Hypopigmented Skin or Hair Angelman’s syndrome Ataxia telangiectasia Bloom’s syndrome Chediak-Higashi syndrome Dyskeratosis congenita Griscelli’s syndrome Hereditary epidermolysis bullosa Hypomelanosis of Ito Incontinentia pigmenti Methionine malabsorption syndrome Neurofibromatosis 1 Nijmigen breakage syndrome Pallister-Killian syndrome Phenylketonuria Sialuria Smith-Lemli-Opitz syndrome Spastic paraplegia type 23 Tuberous sclerosis complex Waardenburg’s syndrome Waardenburg-Shah syndrome Xeroderma pigmentosa

15q11-13 mutation analysis, uniparental disomy, methylation Serum α-fetoprotein, ATM mutation analysis RECQL3 mutation analysis CBC, blood smear for peroxidase staining, CHS1 mutation analysis DKC1 mutation analysis MYO5A mutation analysis Clinical diagnosis Leukocyte or fibroblast karyotype for mosaicism IKBKG mutation analysis Serum amino acids Neurofibromin protein truncation analysis DNA instability testing, NBS1 mutation analysis Fibroblast karyotype for mosaicism Serum amino acids Urinary sialic acid, SLC17A5 mutation analysis Serum cholesterol, 7-dehydrocholesterol, DHCR7 mutation analysis Clinical diagnosis Brain MRI, renal ultrasound, TSC1 and TSC2 mutation analysis PAX3 and MITF mutation analysis EDNRB, EDN3, and SOX10 mutation analysis DNA repair studies

Eczema or Other Rash Aicardi-Goutiéres syndrome Albright’s hereditary osteodystrophy Chondrodysplasia punctata 2 CINCA syndrome Costello’s syndrome Dubowitz’s syndrome Incontinentia pigmenti Multiple carboxylase deficiency Phenylketonuria Prolidase deficiency Rhizomelic chondrodysplasia punctata 3-Methylcrotonylglycinuria type 2 Rothmund-Thomson syndrome Smith-Lemli-Opitz syndrome Sponastrime dysplasia Sulfocysteinuria Trichothiodystrophy Trichorrhexis nodosa syndrome

Serum and CSF interferon-α Serum calcium, phosphate, parathyroid hormone Serum 8-dehydrocholesterol, EBP mutation analysis Serum CD10, CIAS1 mutation analysis Clinical diagnosis Clinical diagnosis IKBKG mutation analysis Serum ammonia, urine organic acids, serum biotinidase activity Serum amino acids Urine imidopeptides, fibroblast prolidase activity Serum phytanic acid, erythrocyte plasmalogens, PEX7 mutation analysis Urine organic acids REQL4 mutation analysis Serum cholesterol, 7-dehydrocholesterol, DHCR7 mutation analysis Clinical diagnosis Urine sulfite, fibroblast sulfite oxidase activity, SUOX mutation analysis Hair analysis for cysteine-rich matrix proteins, nucleotide excision-repair analysis Clinical diagnosis (continued)

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TABLE 33-10, cont’d Developmental Disorders Associated with Abnormal Skin DISORDER

DIAGNOSTIC TESTS

Photosensitivity Bloom’s syndrome Cockayne’s syndrome Ehlers-Danlos syndrome (progeroid form of) Hartnup’s disease Rothmund-Thomson syndrome Smith-Lemli-Opitz syndrome Trichothiodystrophy Trichorrhexis nodosa syndrome Tryptophanuria Xeroderma pigmentosa

RECQL3 mutation analysis Fibroblast DNA repair assay, ERCC8 and ERCC6 mutation analysis Fibroblast galactosyltransferase I activity, B4GALT7 mutation analysis Serum amino acids REQL4 mutation analysis Serum cholesterol, 7-dehydrocholesterol, DHCR7 mutation analysis Hair analysis for cysteine-rich matrix proteins, nucleotide excision-repair analysis Clinical diagnosis Serum amino acids DNA repair studies

Lax or Redundant Skin Ablepharon-macrostomia syndrome Aspartylglucosaminuria Cardiofaciocutaneous syndrome Coffin-Lowry syndrome Costello’s syndrome De Barsy’s syndrome Langer-Giedion syndrome Opitz trigonocephaly syndrome Progeroid form of Ehlers-Danlos Wrinkly skin syndrome

Clinical diagnosis Urine aspartylglucosamine, fibroblast aspartylglucosaminidase activity Clinical diagnosis RPS6KA3 mutation analysis Clinical diagnosis Skin biopsy for elastin staining FISH for 18q24.11 to 18q24.13 deletion including LGCR region Clinical diagnosis Fibroblast galactosyltransferase I activity, B4GALT7 mutation analysis Skin biopsy for elastin staining

Angiokeratoma Aspartylglucosaminuria GM1 gangliosidosis Fabry’s disease Mannosidosis Bannayan-Zonana syndrome, Cowden’s syndrome Fucosidosis Kanzaki’s disease

Urine aspartylglucosamine, fibroblast aspartylglucosaminidase activity Leukocyte β-galactosidase activity Leukocyte α-galactosidase A activity Urine oligosaccharides, fibroblast heparin sulfaminidase activity PTEN mutation analysis Urine oligosaccharides, leukocyte L-fucosidase activity Urine oligosaccharides, leukocyte α-acetylgalactosaminidase activity

CBC, complete blood cell count; CINCA, chronic infantile neurologic, cutaneous, and articular syndrome; CSF, cerebrospinal fluid; ECHO, echocardiography; FISH, fluorescence in situ hybridization; LEOPARD, lentigines, electrocardiogram abnormalities, ocular hypertelorism, pulmonary stenosis, genitalia abnormalities, retardation of growth, deafness; MRI, magnetic resonance imaging.

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TABLE 33-11 Developmental Disorders Associated with Abnormal Hair DISORDER

DIAGNOSTIC TESTS

Sparse Hair or Alopecia 3-Methylcrotonylglycinuria type 2 Adams-Oliver syndrome Alström’s syndrome Cardiofaciocutaneous syndrome Chondrodysplasia punctata type 2 Costello’s syndrome Desmons’ syndrome Dubowitz’s syndrome Ectrodactyly ectodermal dysplasia Fibrodysplasia ossificans progressiva Hallermann-Streiff syndrome Hereditary epidermolysis bullosa C Hypomelanosis of Ito Incontinentia pigmenti Johnson’s neuroectodermal syndrome Langer-Giedion syndrome Menkes’ disease Multiple carboxylase deficiency Neonatal progeroid syndrome Oculodentodigital dysplasia Orofacial digital syndrome type 1 Pachonychia congenita Pallister-Killian syndrome Progeroid form of Ehlers-Danlos Rhizomelic chondrodysplasia punctata Roberts’ syndrome Rothmund-Thomson syndrome Rubenstein-Taybi syndrome Sotos’ syndrome, Weaver’s syndrome

Urine organic acids Clinical diagnosis Serum TSH, T4, IGF1, insulin, glucose, sodium Clinical diagnosis Serum 8-dehydrocholesterol, EBP mutation analysis Clinical diagnosis Clinical diagnosis Clinical diagnosis EEC1, EEC2, EEC3, and TP63 mutation analysis Clinical diagnosis Clinical diagnosis Clinical diagnosis Clinical diagnosis, skin biopsy for chromosomal mosaicism IKBKG mutation analysis Clinical diagnosis FISH for 18q24.11 to 18q24.13 deletion including LGCR region Serum ceruloplasmin level, 24-hour urine copper analysis, ATP7A mutation analysis Serum ammonia, urine organic acids, serum biotinidase activity Clinical diagnosis GJA1 mutation analysis OFD1 mutation analysis Clinical diagnosis Fibroblast karyotype for mosaicism Fibroblast galactosyltransferase I activity, B4GALT7 mutation analysis Serum phytanic acid, erythrocyte plasmalogens, PEX7 mutation analysis Clinical diagnosis REQL4 mutation analysis CREBBP mutation analysis NSD1 mutation analysis

Synophrys Cohen’s syndrome Congenital hypothyroidism Cornelia de Lange syndrome Mucopolysaccharidoses Proud syndrome

COH1 mutation analysis Thyroid studies NIPBL mutation analysis Urine mucopolysaccharides, enzyme analysis, genetic testing ARX mutation analysis

Fine or Brittle Hair Arginosuccinic aciduria FG syndrome Homocystinuria Hypothyroidism Menkes’ disease Oculodentodigital dysplasia Sulfocysteinuria Trichothiodystrophy

Serum ammonia, urine organic acids, fibroblast arginosuccinate lyase activity Clinical diagnosis Urine and serum amino acids Serum TSH and T4 Serum ceruloplasmin level, 24-hour urine copper assay, ATP7A mutation analysis GJA1 mutation analysis Urine sulfite, fibroblast sulfite oxidase activity, SUOX mutation analysis Hair analysis for cysteine-rich matrix proteins, nucleotide excision-repair testing

Hirsutism or Hypertrichosis Congenital lipodystrophy type 2 Cornelia de Lange syndrome GM1 gangliosidosis Hennekam’s syndrome Kabuki syndrome Mucopolysaccharidoses Pena-Shokeir syndrome Rubenstein-Taybi syndrome Schwartz-Jampel syndrome Warburg’s micro syndrome

Serum leptin, BSCL2 mutation analysis NIPBL mutation analysis Leukocyte acid β-galactosidase activity Clinical diagnosis Clinical diagnosis Urine mucopolysaccharides, enzyme analysis, genetic testing ERCC2 and ERCC6 mutation analysis CREBBP mutation analysis HSPG2 mutation analysis Clinical diagnosis

IGF1, insulin-like growth factor 1; T4, thyroxine; TSH, thyroid-stimulating hormone.

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TABLE 33-12 Developmental Disorders Associated with Abnormal Hearing DISORDER Conductive Hearing Loss CHARGE syndrome Cockayne’s syndrome Crouzon’s syndrome Down syndrome Ectrodactyly ectodermal dysplasia Fibrodysplasia ossificans progressiva Frontonasal dysplasia Hemifacial microsomia Hennekam’s syndrome Hereditary motor and sensory neuropathies Johnson’s neuroectodermal syndrome LEOPARD syndrome Mitochondrial disease

CLINICAL TESTS

Mucopolysaccharidoses Orofaciodigital syndrome type 6 Oculodentodigital dysplasia Oropalatodigital syndrome Pfeiffer’s syndrome Smith-Magenis syndrome Sotos’ syndrome Spastic paraplegia 3 Velocardiofacial syndrome

FISH for 8q12.1 deletion involving CHD7 region DNA repair studies FGFR2 and FGFR3 mutation analysis Karyotype EEC1, EEC2, EEC3, and TP63 mutation analysis Clinical diagnosis Clinical diagnosis Clinical diagnosis Clinical diagnosis EMG with nerve conduction studies Clinical diagnosis PTPN11 mutation analysis Serum lactate and pyruvate, urine organic acids, acylcarnitine profile, mitochondrial DNA studies, CSF lactate, muscle biopsy Urine mucopolysaccharides, enzyme analysis, genetic testing Clinical diagnosis GJA1 mutation analysis FLNA mutation analysis FGFR1 and FGFR2 mutation analysis FISH for deletion of 17p11.2 involving SMCR NSD1 mutation analysis Mutation analysis FSP1 gene (also called SPG3A) FISH for 22q11 deletion

Hyperacusis Autistic spectrum disorders GM1 gangliosidosis GM2 gangliosidoses Sulfocysteinuria Williams-Beuren syndrome

Clinical diagnosis Leukocyte acid β-galactosidase activity Leukocyte hexosaminidase A and B activity Urine sulfite, fibroblast sulfite oxidase activity, SUOX mutation analysis Serum calcium, FISH for deletion of 7q11.23 involving ELN

Sensorineural Hearing Loss Aminoacidopathies Canavan’s leukodystrophy Cardiofaciocutaneous syndrome CHARGE syndrome Chondrodysplasia punctata 2 Cockayne’s syndrome Coffin-Lowry syndrome Cowden’s syndrome Craniosynostosis syndromes Desmons’ syndrome Dyskeratosis congenita Fanconi’s anemia FG syndrome Fibrodysplasia ossificans progressiva Galactosemia type 3 Hennekam’s syndrome Hereditary motor and sensory neuropathies Insulin-like growth factor 1 deficiency Kallmann’s syndrome Keratitis-ichthyosis-deafness syndrome Langer-Giedion Syndrome Mannosidosis MIDAS syndrome Mitochondrial disease Möbius syndrome Mucopolysaccharidoses Multiple carboxylase deficiency Multiple sulfatase deficiency Myoclonic epilepsy of Unverricht and Lundborg Noonan’s syndrome, LEOPARD syndrome Norrie’s disease Pendred’s syndrome Peroxisomal disorders Rothmund-Thomson syndrome Smith-Magenis syndrome Spinocerebellar ataxias

Serum amino acids Urine NAA, fibroblast aspartoacylase activity, ASPA mutation analysis Clinical diagnosis FISH for 8q12.1 deletion involving CHD7 region Serum 8-dehydrocholesterol, EBP mutation analysis Fibroblast DNA repair assay, ERCC8 and ERCC6 mutation analysis, brain CT for calcifications RPS6KA3 mutation analysis PTEN mutation analysis Head CT reconstruction, FGFR1, FGFR2, FGFR3 mutation analysis Clinical diagnosis DKC1 mutation analysis CBC, chromosomal breakage studies Clinical diagnosis Clinical diagnosis Erythrocyte GALE activity Clinical diagnosis EMG with nerve conduction studies Serum IGF1, growth hormone, IGF1 mutation analysis FGFR1 mutation analysis GJB2 mutation analysis FISH for 18q24.11 to 18q24.13 deletion including LGCR region Urine oligosaccharides, fibroblast heparin sulfaminidase activity FISH for Xp22.3 monosomy Serum lactate and pyruvate, urine organic acids Acylcarnitine profile, mitochondrial DNA studies, CSF lactate, muscle biopsy MBS1 mutation analysis Urine mucopolysaccharides, enzyme analysis, genetic testing Serum ammonia, urine organic acids, serum biotinidase activity Leukocyte arylsulfatase A, B, and C activity, urine mucopolysaccharides CSTB mutation analysis PTPN11 mutation analysis NDP mutation analysis SLC26A4 mutation analysis Serum very-long-chain fatty acids, phytanic acid, erythrocyte plasmalogens REQL4 mutation analysis FISH for deletion of 17p11.2 involving SMCR region Genetic panel for SCA mutation analysis

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TABLE 33-12, cont’d Developmental Disorders Associated with Abnormal Hearing DISORDER

CLINICAL TESTS

Usher’s syndrome type 1 Velocardiofacial syndrome, DiGeorge’s syndrome Wolf-Hirschhorn syndrome Wolfram’s syndrome Xeroderma pigmentosa

MYO7A mutation analysis FISH for 22q11 deletion involving VCF, DGCR, and DGCR2 regions Karyotype, FISH for 4p16 deletion WFS1 and WFS2 mutation analysis DNA repair studies

CBC, complete blood cell count; CHARGE, coloboma, heart defects, atresia choanae, retardation of growth and development, genitourinary problems, and ear anomalies; CSF, cerebrospinal fluid; CT, computed tomography; EMG, electromyography; FISH, fluorescence in situ hybridization; IGF1, insulin-like growth factor 1; LEOPARD, lentigines, electrocardiogram abnormalities, ocular hypertelorism, pulmonary stenosis, genitalia abnormalities, retardation of growth, deafness; MIDAS, microphthalmia, dermal aplasia, and sclerocornea; NAA, N-acetyl-aspartate.

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TABLE 33-13 Developmental Disorders Associated with Ophthalmologic Abnormalities DISORDER Cataracts Aicardi’s syndrome Albright’s hereditary osteodystrophy Aspartylglucosaminuria Bardet-Biedl syndrome Cerebrotendinous xanthomatosis Cockayne’s syndrome Congenital cataracts, facial dysmorphism, and neuropathy syndrome Congenital disorders of glycosylation Congenital hypothyroidism Congenital muscular dystrophies Cowden’s syndrome De Barsy’s syndrome Down syndrome Frontonasal dysplasia Galactosemia types 1, 2, and 3 Glutaric acidemia II Hallermann-Streiff syndrome Hypomelanosis of Ito Incontinentia pigmenti Larsen’s syndrome Lowe’s syndrome Marinesco-Sjögren syndrome Mevalonate kinase deficiency MIDAS syndrome Miller-Dieker syndrome Myotonic dystrophy types 1 and 2 Norrie’s disease Oculodentodigital dysplasia Pallister-Killian syndrome Pena-Shokeir syndrome Peroxisomal disorders Peters-plus syndrome Phenylketonuria Pseudohypoparathyroidism Roberts’ syndrome Rothmund-Thomson syndrome Rubenstein-Taybi syndrome Smith-Lemli-Opitz syndrome Schwartz-Jampel syndrome Trichorrhexis nodosa syndrome Usher’s syndrome type 1 WAGR syndrome Cherry-Red Macula Farber’s lipogranulomatosis GM1 gangliosidosis GM2 gangliosidoses Goldberg’s syndrome Niemann-Pick disease type A Sialidosis Corneal Clouding Cockayne’s syndrome Congenital syphilis De Barsy’s syndrome Fryns’ syndrome Goldberg’s syndrome Mucolipidosis IIIA Mucopolysaccharidoses Peroxisomal disorders Phosphofructokinase deficiency Roberts’ syndrome Sialuria

DIAGNOSTIC TESTS

Clinical diagnosis Serum calcium, phosphate, parathyroid hormone Urine aspartylglucosamine, fibroblast aspartylglucosaminidase activity BBS1, BBS2, BBS4, and MKKS mutation analysis Serum lipids, cholestanol Fibroblast DNA repair assay, ERCC8 and ERCC6 mutation analysis CDTP1 mutation analysis Serum transferrin isoelectric focusing TSH, T4 (serum) Muscle biopsy, POMGNT1 and POMT1 mutation analysis, FCMD testing PTEN mutation analysis Skin biopsy for elastin staining Karyotype Clinical diagnosis Erythrocyte GALT, GALK, and GALE activity Urine organic acids Clinical diagnosis Skin biopsy for chromosomal mosaicism IKBKG mutation analysis FLNB mutation analysis Fibroblast Ptd(4,5)P(2)-5-phosphatase activity, OCRL mutation analysis Brain imaging for cerebellar hypoplasia, serum creatine kinase, lymphocytes for electron microscopy Urine organic acids, lymphocyte mevalonate kinase activity FISH for Xp22.3 monosomy Karyotype, FISH for 17p13.3 deletion including MDS region DMPK and DMPK2 mutation analysis NDP mutation analysis GJA1 mutation analysis Fibroblast karyotype for mosaicism ERCC2 and ERCC6 mutation analysis Serum very-long-chain fatty acids, phytanic acid, erythrocyte plasmalogens Clinical diagnosis Serum amino acids Serum calcium Clinical diagnosis REQL4 mutation analysis CREBBP mutation analysis Serum cholesterol, 7-dehydrocholesterol, DHCR7 mutation analysis HSPG2 mutation analysis Clinical diagnosis MYO7A mutation analysis FISH for 11p13 deletion and PAX6 and WT1 mutation analysis Urine ceramide, leukocyte N-laurylsphingosine deaminase activity Fibroblast acid β-galactosidase activity Leukocytes hexosaminidase A and B activity Urine sialyloligosaccharides, fibroblast neuraminidase and galactosidase activity Fibroblast sphingomyelinase activity Urine sialyloligosaccharides, fibroblast α-neuraminidase activity Fibroblast DNA repair assay, ERCC8 and ERCC6 mutation analysis Hutchinson teeth, condyloma lata, saddle nose, sniffles, saber shins, radiographs, brainstem auditory-evoked responses, FTA-ABS fluorescent antibody Skin biopsy for elastin staining Clinical diagnosis Urine sialyloligosaccharides, fibroblast neuraminidase and galactosidase activity Urine mucopolysaccharides, fibroblast GNPTA activity Urine mucopolysaccharides, enzyme analysis, genetic testing Serum very-long-chain fatty acids, phytanic acid, erythrocyte plasmalogens Urine organic acids, muscle biopsy Clinical diagnosis Urine sialic acid, SLC17A5 mutation analysis

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TABLE 33-13, cont’d Developmental Disorders Associated with Ophthalmologic Abnormalities DISORDER

DIAGNOSTIC TESTS

Sialolipidosis Walker-Warburg syndrome

Urine phospholipids, fibroblast electron microscopy, MCOLN1 mutation analysis Head MRI, POMT1 gene analysis

Coloboma Aicardi’s syndrome CHARGE syndrome COACH syndrome, Joubert’s syndrome Congenital disorders of glycosylation Congenital muscular dystrophies Dubowitz’s syndrome Frontonasal dysplasia Hallermann-Streiff syndrome Hypomelanosis of Ito Incontinentia pigmenti Jacobsen’s syndrome Kabuki syndrome Linear sebaceous nevus of Jadassohn MIDAS syndrome Mowat-Wilson syndrome Peters-plus syndrome Rubenstein-Taybi syndrome Seckel’s syndrome Wolf-Hirschhorn syndrome

Clinical diagnosis FISH for 8q12.1 deletion involving CHD7 region Brain MRI for cerebellar vermis hypoplasia Serum transferrin isoelectric focusing Muscle biopsy, FCMD, POMGNT1, and POMT1 mutation analysis Clinical diagnosis Clinical diagnosis Clinical diagnosis Skin biopsy for chromosomal mosaicism IKBKG mutation analysis Karyotype, FISH for subtelomeric deletion of 11q23 Clinical diagnosis Clinical diagnosis FISH for Xp22.3 monosomy SMADIP1 mutation analysis Clinical diagnosis CREBBP mutation analysis ATR mutation analysis Karyotype, FISH for 4p16 deletion

Retinitis Pigmentosa Bardet-Biedl syndrome Cockayne’s syndrome Cohen’s syndrome Congenital disorders of glycosylation Fahr’s disease Hallervorden-Spatz syndrome Laurence-Moon syndrome MIDAS syndrome Mitochondrial disease Neuronal ceroid lipofuscinosis Peroxisomal disorders Usher’s syndrome type 1 Wolfram’s syndrome

BBS1, BBS2, BBS4, and MKKS mutation analysis Fibroblast DNA repair assay, ERCC8 and ERCC6 mutation analysis COH1 mutation analysis Serum transferrin isoelectric focusing Brain CT for basal ganglia calcification Brain MRI for iron deposition, PANK2 mutation analysis Clinical diagnosis FISH for Xp22.3 monosomy Serum lactate and pyruvate, urine organic acids, acylcarnitine profile, mitochondrial DNA studies, CSF lactate, muscle biopsy Conjunctival biopsy for electron microscopy, enzyme analysis, genetic testing Serum very-long-chain fatty acids, phytanic acid, erythrocyte plasmalogens MYO7A mutation analysis WFS1 and WFS2 mutation analysis

CHARGE, coloboma, heart defects, atresia choanae, retardation of growth and development, genitourinary problems, and ear anomalies; COACH, cerebellar vermis hypo/aplasia, oligophrenia, congenital ataxia, ocular coloboma, and hepatic fibrosis; CSF, cerebrospinal fluid; CT, computed tomography; FISH, fluorescence in situ hybridization; MIDAS, microphthalmia, dermal aplasia, and sclerocornea; MRI, magnetic resonance imaging; T4, thyroxine; TSH, thyroid-stimulating hormone; WAGR, Wilms’ tumor, aniridia, genitourinary abnormalities, and mental retardation.

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TABLE 33-14 Developmental Disorders Associated with Magnetic Resonance Imaging Abnormalities DISORDER Leukodystrophic Changes Aicardi-Goutiéres syndrome Alexander’s disease Amino acidopathies and organic acidurias Canavan’s disease Cockayne’s syndrome Krabbe’s disease Megaloencephalic leukoencephalopathy with subcortical cysts Metachromatic leukodystrophy Mitochondrial disease Multiple sulfatase deficiency Pelizaeus-Merzbacher disease Peroxisomal disorders Postinfectious demyelination Solvent inhalation, heavy metal poisoning Vanishing white matter disease Waardenburg-Shah syndrome Basal Ganglia Calcifications Aicardi-Goutiéres syndrome Albright hereditary osteodystrophy Anoxia or carbon monoxide inhalation Down syndrome Dyskeratosis congenita Fahr’s disease GM1 gangliosidosis Hypoparathyroidism or hyperparathyroidism Encephalitis Cockayne’s syndrome Oculodentodigital dysplasia Osteopetrosis with renal tubular acidosis Phenylketonuria type 2 Methotrexate or radiation toxicity Mitochondrial disease Sulfocysteinuria Tuberous sclerosis complex Velocardiofacial syndrome, DiGeorge’s syndrome Basal Ganglia T2 Hyperintensity Alexander’s disease Anoxia or carbon monoxide inhalation Infectious and post-infectious encephalitis Glutaric acidemia I Hallervorden-Spatz syndrome Huntington’s disease Methylmalonic aciduria Mitochondrial disease

DIAGNOSTIC TESTS

Serum and CSF interferon-α GFAP mutation analysis Serum amino acids and urine organic acids Urine NAA, fibroblast aspartoacylase activity, ASPA mutation analysis Fibroblast DNA repair assay, ERCC8 and ERCC6 mutation analysis Leukocyte galactocerebrosidase activity MLC1 mutation analysis Leukocyte arylsulfatase A activity Serum lactate and pyruvate, urine organic acids, acylcarnitine profile, mitochondrial DNA studies, CSF lactate, muscle biopsy Leukocyte arylsulfatase A, B, and C activity, urine mucopolysaccharides PLP1 mutation analysis Serum very-long-chain fatty acids, phytanic acid, erythrocyte plasmalogens Cerebrospinal myelin basic protein, oligoclonal bands, IgG index Urine thin-layer chromatography and heavy metal screen, serum hippuric acid and toluene levels EIF2B(1-5) mutation analysis EDNRB, EDN3, and SOX10 mutation analysis Serum and CSF interferon-α Serum calcium, phosphate, parathyroid hormone Brain imaging, serum carboxyhemoglobin, CBC Karyotype DKC1 mutation analysis Brain CT Fibroblast β-galactosidase activity Serum calcium, phosphate, parathyroid hormone Serum titers for toxoplasmosis and rubella, PCR for HIV, urine CMV culture Fibroblast DNA repair assay, ERCC8 and ERCC6 mutation analysis GJA1 mutation analysis CA2 mutation analysis Serum amino acids, fibroblast dihydropteridine reductase activity Clinical diagnosis Serum lactate and pyruvate, urine organic acids Acylcarnitine profile, mitochondrial DNA studies, CSF lactate, muscle biopsy Urine sulfite, fibroblast sulfite oxidase activity, SUOX mutation analysis Brain MRI, TSC1 and TSC2 mutation analysis FISH for 22q11 deletion involving VCF, DGCR, and DGCR2 regions

Pyruvate dehydrogenase deficiency Pyruvate carboxylase deficiency Wilson’s disease

GFAP mutation analysis Brain imaging, serum carboxyhemoglobin, CBC CSF studies Urine organic acids, serum acylcarnitine profile Brain MRI for iron deposition, PANK2 mutation Huntingtin mutation analysis Urine organic acids, serum acylcarnitine profile Serum lactate and pyruvate, urine organic acids, acylcarnitine profile, mitochondrial DNA studies, CSF lactate, muscle biopsy Serum lactate and pyruvate, leukocyte pyruvate dehydrogenase activity Serum lactate and pyruvate, leukocyte pyruvate carboxylase activity Serum ceruloplasmin, 24-hour urine copper assay

Lissencephaly, Pachygyria, or Gray Matter Heterotopia Bilateral frontal polymicrogyria Classic lissencephaly Congenital muscular dystrophies FG syndrome Kabuki syndrome Lissencephaly and ambiguous genitalia Lissencephaly and corpus callosum agenesis Miller-Dieker syndrome Norman-Roberts lissencephaly Periventricular nodular heterotopia 1 and 2 Peroxisome biogenesis disorders

GPR56 mutation analysis LIS1 mutation analysis Muscle biopsy, FCMD, POMGNT1, and POMT1 mutation analysis Clinical diagnosis Clinical diagnosis ARX mutation analysis XLIS (also called DCX) mutation analysis Karyotype, FISH for 17p13.3 deletion including MDS region RELN mutation analysis FLNA and ARFGEF2 mutation analysis Serum very-long-chain fatty acids, phytanic acid, erythrocyte plasmalogens

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TABLE 33-14, cont’d Developmental Disorders Associated with Magnetic Resonance Imaging Abnormalities DISORDER

DIAGNOSTIC TESTS

Other Cortical Malformations Bilateral perisylvian polymicrogyria Schizencephaly

Clinical diagnosis, linked to Xq28 EMX2 mutation analysis

Holoprosencephaly Kallmann’s syndrome Nonsyndromic holoprosencephaly Pseudotrisomy 13 syndrome Rubenstein-Taybi syndrome Smith-Lemli-Opitz syndrome

FGFR1 mutation analysis SIX3, SHH, TGIF, ZIC2, and PTCH mutation analysis Clinical diagnosis CREBBP mutation analysis Serum cholesterol, 7-dehydrocholesterol, DHCR7 mutation analysis

Hemimegalencephaly Hypomelanosis of Ito Linear sebaceous nevus syndrome Neurofibromatosis 1 Proteus syndrome

Skin biopsy for chromosomal mosaicism Clinical diagnosis Clinical diagnosis, neurofibromin protein truncation analysis Chromosomal mosaicism, PTEN mutation analysis

CBC, complete blood cell count; CMV, cytomegalovirus; CSF, cerebrospinal fluid; CT, computed tomography; FISH, fluorescence in situ hybridization; HIV, human immunodeficiency virus; MRI, magnetic resonance imaging; NAA, N-acetyl-aspartate; PCR, polymerase chain reaction.

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TABLE 33-15 Developmental Disorders Associated with Lower Motor Neuron Abnormalities DISORDER Myopathy Aldolase A deficiency Allan-Herndon-Dudley syndrome Congenital disorders of glycosylation Congenital muscular dystrophies Congenital myopathies Cowden’s syndrome Dystrophin muscular dystrophies Glycogen storage disease IIb Hyperglycerolemia Infantile fascioscapulohumeral dystrophy Marinesco-Sjögren syndrome Mitochondrial disease Myotonic dystrophy 1 and 2 Peroxisomal disorders Schwartz-Jampel syndrome Williams-Beuren syndrome Peripheral Neuropathy Alacrima-achalasia-addisonianism syndrome Andermann’s syndrome Ataxia-oculomotor apraxia syndrome Behr’s syndrome Cerebrotendinous xanthomatosis Chediak-Higashi syndrome Cockayne’s syndrome Congenital cataracts, facial dysmorphism, and neuropathy syndrome Congenital disorders of glycosylation Fragile X syndrome Fucosidosis GM2 gangliosidoses Keratitis-ichthyosis-deafness syndrome Krabbe’s disease Mannosidosis Merosin deficient congenital muscular dystrophy Metachromatic leukodystrophy Mitochondrial disease Möbius syndrome Neuroaxonal dystrophy Niemann-Pick disease type A Ornithine transcarbamylase deficiency Peroxisomal disorders Smith-Magenis syndrome Spastic paraplegia types 11 and 23 Spinocerebellar ataxias Tyrosinemia Waardenburg-Shah syndrome Xeroderma pigmentosa X-linked Charcot-Marie-Tooth type 2

DIAGNOSTIC TESTS

Muscle aldolase activity, ALDOA mutation analysis Clinical diagnosis Serum transferrin isoelectric focusing Muscle biopsy, FCMD, POMGNT1, and POMT1 mutation analysis Muscle biopsy PTEN mutation analysis DMD mutation analysis Muscle biopsy with glycogen storage and autophagy Serum glycerol, fibroblast glycerol kinase activity, GK mutation analysis Muscle biopsy Brain imaging for cerebellar hypoplasia, serum creatine kinase, lymphocytes for electron microscopy Serum lactate and pyruvate, urine organic acids, acylcarnitine profile, mitochondrial DNA studies, CSF lactate, muscle biopsy DMA and DMPK mutation analysis Serum very-long-chain fatty acids, phytanic acid, erythrocyte plasmalogens HSPG2 mutation analysis Serum calcium, FISH for deletion of 7q11.23 involving ELN Serum cortisol, ACTH, AAAS mutation analysis Brain MRI for absent corpus callosum, SLC12A6 mutation analysis APTX mutation analysis Brain MRI for cerebellar atrophy Serum lipids, cholestanol CBC, blood smear for peroxidase staining, CHS1 mutation analysis Fibroblast DNA repair assay, ERCC8 and ERCC6 mutation analysis CDTP1 mutation analysis Serum transferrin isoelectric focusing FMR1 mutation analysis Urine oligosaccharides, leukocyte α-L-fucosidase activity Leukocyte hexosaminidase A and B activity GJB2 mutation analysis Leukocyte β-galactocerebrosidase activity Urine oligosaccharides, fibroblast heparin sulfamidase activity Brain MRI, muscle biopsy Leukocyte arylsulfatase A activity Serum lactate and pyruvate, urine organic acids, acylcarnitine profile, mitochondrial DNA studies, CSF lactate, muscle biopsy MBS1 mutation analysis Nerve biopsy for spheroids Fibroblast sphingomyelinase activity Serum ammonia, amino acids Serum very-long-chain fatty acids, phytanic acid, erythrocyte plasmalogens FISH for deletion of 17p11.2 involving SMCR Clinical diagnosis Genetic panel for SCA mutation analysis Serum amino acids EDNRB, EDN3, and SOX10 mutation analysis DNA repair studies Clinical diagnosis

ACTH, adrenocorticotropin hormone; CBC, complete blood cell count; CSF, cerebrospinal fluid; FISH, fluorescence in situ hybridization; MRI, magnetic resonance imaging.

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TABLE 33-16 Developmental Disorders Associated with Other Abnormalities DISORDER

DIAGNOSTIC TEST

Cryptorchidism Aarskog-Scott syndrome α-Thalassemia mental retardation syndrome Apert’s syndrome Bardet-Biedl syndrome Beckwith-Weidemann syndrome Bloom’s syndrome Börjeson’s syndrome CHARGE syndrome Cockayne’s syndrome Congenital disorders of glycosylation Cornelia de Lange syndrome Dubowitz’s syndrome Ectrodactyly ectodermal dysplasia Ellis–van Creveld syndrome Fanconi’s anemia FG syndrome Fryns’ syndrome Hallermann-Streiff syndrome Jacobsen’s syndrome Kabuki syndrome Kallmann’s syndrome Larsen’s syndrome LEOPARD syndrome Lowe’s syndrome Miller-Dieker syndrome Noonan’s syndrome Norrie’s disease Oropalatodigital syndrome Opitz syndrome Opitz trigonocephaly syndrome Pallister-Killian syndrome Peroxisomal disorders Peters-plus syndrome Prader-Willi syndrome Roberts’ syndrome Robinow’s syndrome Rothmund-Thompson syndrome Rubenstein-Taybi syndrome Simpson-Golabi-Behmel syndrome Shprintzen-Goldberg craniosynostosis WAGR syndrome Warburg’s micro syndrome Weaver’s syndrome Wolf-Hirschhorn syndrome

FGD1 mutation analysis CBC, hemoglobin electrophoresis, ATRX mutation analysis FGFR2 mutation analysis BBS1, BBS2, BBS4, and MKKS mutation analysis NSD1 and CDKN1C mutation analysis, FISH for 11p15.5 mutation RECQL3 mutation analysis PHF6 mutation analysis FISH for 8q12.1 deletion involving CHD7 region Fibroblast DNA repair assay, ERCC8 and ERCC6 mutation analysis Serum transferrin isoelectric focusing NIPBL mutation analysis Clinical diagnosis EEC1, EEC2, EEC3, and TP63 mutation analysis EVC mutation analysis CBC, chromosomal breakage studies Clinical diagnosis Clinical diagnosis Clinical diagnosis Karyotype, FISH for subtelomeric deletion of 11q23 Clinical diagnosis FGFR1 mutation analysis FLNB mutation analysis PTPN11 mutation analysis Fibroblast Ptd(4,5)P(2)-5-phosphatase activity, OCRL mutation analysis Karyotype, FISH for 17p13.3 deletion including MDS region PTPN11 mutation analysis NDP mutation analysis FLNA mutation analysis MID1 mutation analysis Clinical diagnosis Fibroblast karyotype for mosaicism Serum very-long-chain fatty acids, phytanic acid, erythrocyte plasmalogens Clinical diagnosis FISH for 15p11-13 deletion, uniparental disomy, methylation Clinical diagnosis ROR2 mutation analysis REQL4 mutation analysis CREBBP mutation analysis GPC3 mutation analysis FBN1 mutation analysis FISH for 11p13 deletion, PAX6 and WT1 mutation analysis Clinical diagnosis NSD1 mutation analysis Karyotype, FISH for 4p16 deletion

Macro-orchidism Aspartylglucosaminuria Fragile X syndrome PPMX syndrome

Urine aspartylglucosamine, fibroblast aspartylglucosaminidase activity FMR1 mutation analysis MECP2 mutation analysis

Abnormal Urine Odor 3-Hydroxy-3-methylglutaryl cofactor A (HMG-CoA) lyase deficiency (cat urine) Maple syrup urine disease (maple syrup) Phenylketonuria (mousy) Methionine malabsorption syndrome (hops) Isovaleric academia (sweaty feet) Glutaric aciduria II (sweaty feet)

Urine organic acids Urine organic acids Serum amino acids Serum amino acids Urine organic acids Urine organic acids

CBC, complete blood cell count; CHARGE, coloboma, heart defects, atresia choanae, retardation of growth and development, genitourinary problems, and ear anomalies; FISH, fluorescence in situ hybridization; LEOPARD, lentigines, electrocardiogram abnormalities, ocular hypertelorism, pulmonary stenosis, genitalia abnormalities, retardation of growth, deafness; PPMX, psychosis, pyramidal signs and macroorchidism; WAGR, Wilms’ tumor, aniridia, genitourinary abnormalities, and mental retardation.

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REFERENCES American Psychiatric Association (APA). Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Association, 2000. Apak S, Yuksel M, Ozmen M, et al. Heterogeneity of X-linked recessive (spino)cerebellar ataxia with or without spastic diplegia. Am J Med Genet 1989;34:155. Barth PG. Pontocerebellar hypoplasias: An overview of a group of inherited neurodegenerative disorders with fetal onset. Brain Dev 1993;15:411. Cabana MD, Crawford TO, Winkelstein JA, et al. Consequences of the delayed diagnosis of ataxia-telangiectasia. Pediatrics 1998;102:98. Carod-Artal J, Prats Vinas JM, Garaizar Axpe C, et al. Congenital Pelizaeus-Merzbacher disease simulating infantile spastic cerebral palsy. Neurologia 1995;10:57. Christie R, Bay C, Kaufman IA, et al. Lesch-Nyhan disease: Clinical experience with nineteen patients. Dev Med Child Neurol 1982;24:293. Clayton-Smith J. Angelman’s syndrome. Arch Dis Child 1992;67:889. Dehaene-Lambertz G, Dehaene S, Hertz-Pannier L. Functional neuroimaging of speech perception in infants. Science 2002;298:2013. Devereux G, Stellitano L, Verity CM, et al. Variations in neurodegenerative disease across the UK: Findings from the national study of Progressive Intellectual and Neurological Deterioration (PIND). Arch Dis Child 2004;89:8. Dyken P, Krawiecki N. Neurodegenerative diseases of infancy and childhood. Ann Neurol 1983;13:351. Ewing-Cobbs L, Barnes MA, Fletcher JM. Early brain injury in children: Development and reorganization of cognitive function. Dev Neuropsychol 2003;24:669. Fletcher NA, Thompson PD, Scadding JW, et al. Successful treatment of childhood onset symptomatic dystonia with levodopa. J Neurol Neurosurg Psychiatry 1993;56:865. Fryer A, Appleton R, Sweeney MG, et al. Mitochondrial DNA 8993 (NARP) mutation presenting with a heterogeneous phenotype including “cerebral palsy.” Arch Dis Child 1994;71:419. Giuffre R, Di Lorenzo N, Fortuna A. Cervical tumors of infancy and childhood. J Neurosurg Sci 1981;25:259. Gupta R, Appleton RE. Cerebral palsy: Not always what it seems. Arch Dis Child 2001;85:356. Hoffmann GF, Athanassopoulos S, Burlina AB, et al. Clinical course, early diagnosis, treatment, and prevention of disease in glutaryl-CoA dehydrogenase deficiency. Neuropediatrics 1996;27:115. Lissens W, Vreken P, Barth PG, et al. Cerebral palsy and pyruvate dehydrogenase deficiency: Identification of two new mutations in the E1 gene. Eur J Paediatr 1999;158:853.

Livne M, Gibson KM, Amir N, et al. Holocarboxylase synthetase deficiency: A treatable metabolic disorder masquerading as cerebral palsy. J Child Neurol 1994;9:170. Lyon G, Adams RD, Kolodny EH. Neurology of hereditary metabolic diseases of children, 2nd ed. New York: McGraw-Hill, 1996. McDermott C, White K, Bushby K, et al. Hereditary spastic paraparesis: A review of new developments. J Neurol Neurosurg Psychiatry 2000;69:150. Meek D, Wolfe LS, Andermann E, et al. Juvenile progressive dystonia: A new phenotype of GM2 gangliosidosis. Ann Neurol 1984;15:348. Mohamed K, Appleton R, Nicolaides P. Delayed diagnosis of Duchenne muscular dystrophy. Eur J Paediatr Neurol 2000;4:219. Moser H, Moser AE, Singh I, et al. Adrenoleucodystrophy: Survey of 303 cases: Biochemistry, diagnosis and therapy. Ann Neurol 1984;16:628. Murayama K, Kimura M, Yamaguchi S, et al. Isolated 3-methylcrotonyl-CoA carboxylase deficiency in a 15-year-old girl. Brain Dev 1997;19:303. Naidu S. Movement disorders in neuronal ceroid-lipofuscinoses. J Inherit Metab Dis 1993;16:256. Naidu S. Rett syndrome: A disorder affecting early brain growth. Ann Neurol 1997;42:3. Nunn K, Williams K, Ouvrier R. The Australian Childhood Dementia Study. Eur Child Adolesc Psychiatry 2002;11:63. Nyhan WL, Ozand PT. Atlas of metabolic diseases. London: Chapman and Hall, 1998. O’Brien DF, Caird J, Kennedy M, et al. Posterior fossa tumours in childhood evaluation of presenting clinical features. Ir Med J 2001;94:52. Pantaleoni C, D’Arrigo S, D’Incerti L, et al. A case of 3-methylglutaconic aciduria misdiagnosed as cerebral palsy. Pediatr Neurol 2000;23:442. Patterson MC. A riddle wrapped in a mystery: Understanding Niemann-Pick disease, type C. Neurologist 2003;9:301. Prasad AN, Breen JC, Ampola MG, et al. Argininemia: A treatable genetic cause of progressive spastic diplegia simulating cerebral palsy: Case reports and literature review. J Child Neurol 1997;12:301. Ramaekers VT, Lake BD, Harding B, et al. Diagnostic difficulties in infantile neuroaxonal dystrophy. Neuropediatrics 1987;18:170. Ringach DL. Mapping receptive fields in primary visual cortex. J Physiol 2004;558:717. Sparrow SS, Davis SM. Recent advances in the assessment of intelligence and cognition. J Child Psychol Psychiatry 2000;41:117. Surtees R. Understanding neurodegenerative disorders. Curr Paediatr 2002;12:191. Tsao CY, Wright FS, Boesel CP, Luquette M. Partial NADH dehydrogenase defect presenting as spastic cerebral palsy. Brain Dev 1994;16:393.

CHAPTER 34

Developmental Language Disorders Ruth Nass and Doris A. Trauner

Developmental language disorders are behaviorally defined conditions in which there is a delay or abnormality in expressive or receptive language skills in the absence of global cognitive disability, autism, hearing loss, or identifiable neurologic or psychiatric disorders (Box 34-1). Children with developmental language disorders are believed to function normally in areas other than language. Many studies of developmental language impairment have defined this condition in part by the absence of other identifiable neurologic diagnoses. These children often are characterized as neurologically normal, although there have been few systematic studies of neurologic function in children with developmental language disorder. A glossary of some of the terms used in this chapter is provided in Box 34-2. It remains unclear as to what constitutes a delay in receptive or expressive language. It is well documented that there is a wide range of normal language development [Bates et al., 1994, 2003]. Box 34-3 summarizes some important early language milestones and the typical time of onset. However, the large degree of individual variability in the rate of language acquisition [Bishop and Leonard, 2000; Morley, 1965; Toppelberg and Shapiro, 2000; Verhoeven and van Balkom, 2003] sometimes makes it difficult to distinguish children with developmental language disorder from those with initial idiosyncratic delay who catch up and ultimately have normal language skills [Dale et al., 2003]. Such transient language delay is more likely to be environmental than genetic [Bishop et al., 2003]. For example, in a group of approximately l000 ultimately normal British children, first word acquisition occurred between 6 and 30 months of age, and phrase acquisition occurred between l0 and 44 months (Fig. 34-1) [Morley, l965]. The variability in normal acquisition accounts in part for the wide range in the reported prevalence of developmental language disorders (1% to 25%) among preschool children [Dale et al., 2003; Horwitz et al., 2003]. The prevalence of speech delay among 6-year-old children is about 4%, with a 2:1 male-to-female ratio [Shriberg et al., 1999]. Prevalence of early language delay in the toddler years also varies by ethnic groups [Achenbach and Rescorla 2000; Rescorla and Achenbach 2002], with non-Latino, white, 18- to 35-monthold children having a lower rate of language delay (4%) than blacks and “other” (e.g., Hispanics, Asians, Native Americans, South Asians, mixed) groups (24% to 29%). However, comprehensive studies of typical language development in diverse ethnic groups are lacking, and such data are difficult to interpret in terms of long-term outcome. Despite the wide range of normal language acquisition, early indicators of language delay or communication disorders can alert the physician that the child may need further attention [Rapin, 1996]. These indicators include lack of babbling (i.e., consonant-vowel utterances) by 10 months of age, lack of

pointing by 18 months, a vocabulary of less than 50 words by 2 years, or no two-word combinations by 2 years. Other indicators of potential language disorders are listed in Box 34-4. Many conditions are associated with a higher than expected incidence of language impairment. The differential diagnosis of a child with language delay is summarized in Box 34-5. Determining the prevalence of expressive language delays at 24 months based on a cut-off level of fewer than 50 words or no multiword combinations at 24 months yields a range of 10% to 20%, with boys having higher rates of delay than girls [Klee et al., 1998; Rescorla, 1989; Rescorla and Alley, 2001; Rescorla et al., 1993]. Varieties of specific criteria have been used to diagnose developmental language disorders that contrast nonverbal intelligence and language capabilities [Aram et al., 1992; Klee et al., 2000]. Using discrepancy criteria contrasting the Stanford Binet nonverbal IQ [Thorndike et al., 1986] and the Test of Language Development scores [Hammill and Newcomer, 1996a, 1996b], only 40% to 60% of children clinically deemed to have a developmental language disorder were identified. A Performance IQ–specific language test performance discrepancy criterion of one standard deviation (i.e., Wechsler Performance IQ [Wechsler, 1989, 1991] versus the Peabody Picture Vocabulary Test [Dunn and Dunn, 1981], Token Test [DiSimoni and Mucha, 1982], Rapid Automatized Naming [Denckla and Rudel, 1976], and Sentences Repetition subtest of the Clinical Evaluation of Language Fundamentals– III [Semel et al., 1995] identified 34% of very-low-birthweight 7-year-old children and 45% of controls as having a developmental language disorder. A discrepancy of two standard deviations yielded frequencies of 14% and 19% in the two groups, respectively [Aram et al., 1992]. A developmental language disorder diagnosis at age 2 years may not be reliable. In one study, only about 40% of children retained the diagnosis at ages 3 and 4 years [Dale et al., 2003)]. Some children, especially boys, whose expressive language is late despite normal receptive language development, eventually develop normal expressive language skills, but they may have trouble at school age with languagebased reading and writing skills [Bishop and Clarkson 2003; Rescorla, 2002]. Underdiagnosis and overdiagnosis of developmental language disorders occur with the best available criteria. Nonetheless, erring on the side of overdiagnosis in the young child and initiating therapy is probably better than underdiagnosis [Whitehurst and Fischel, 1994].

ETIOLOGY Some of the known conditions associated with developmental language disorder are listed in Box 34-6. Risk factors

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BOX 34-1 DEVELOPMENTAL LANGUAGE DISORDERS

BOX 34-2 GLOSSARY OF TERMS USED IN DESCRIBING LINGUISTIC FUNCTIONS

Articulation and Expressive Fluency Disorders Pure articulation disorders Stuttering and cluttering Phonologic programming disorder Verbal dyspraxia

Functors: small words of the language, such as prepositions and conjunctions. They also are called closed class words because they are limited in number. Lexicon: words in a language, the dictionary of word meanings. Mean length of utterance (MLU): number of morphemes per utterance. Morpheme: the smallest meaningful unit in a language occurring in a word or as a word. A compound word such as compounding is made up of three morphemes, com-pound-ing. Prefixes, suffixes, and inflected endings such as -ed, -s, and -ly are also morphemes. Phoneme: a distinct sound unit in a language. In English, there are 46, including 9 vowels and 37 consonants. Phonology: the rules a speaker follows when combining speech sounds. Pragmatics: the communicative intent of speech rather than its content (e.g., asking a question at the right time and in the right way). Prosody: the melody of language, the tone of voice used to ask questions, for example, or show emotion. Semantics: the meaning of words, their definition. Syntax: the grammar of a language, the acceptable relationship between words in a sentence.

Disorders of Receptive and Expressive Language Phonologic syntactic syndrome Verbal auditory agnosia Disorders of Expressive Language Verbal dyspraxia Phonologic programming Higher-Order Language Disorders Semantic pragmatic syndrome Lexical syntactic syndrome

BOX 34-3 NORMAL LANGUAGE MILESTONES Receptive Some words understood by 9 months of age Follows one-step commands by 12 months without being cued by a gesture Expressive Cooing: 2 months Babbling: 6 months Variable babble: 8 months One word other than dada and mama: 12 months 10 to 50 words used meaningfully: 16 to 20 months Two-word phrases: 20 to 24 months Points to at least one body part and to named objects and people on command: 20 months Vocabulary of more than 200 words: 2 years Two-word combinations: 2 years Follows two-part commands: 2 years Sentences of three or four words: 3 years Compound and complex sentences: 4 years Passive voice: 6 years

for developmental language disorder include low birth weight, prematurity, parental mental retardation, low socioeconomic status, frequent episodes of otitis media [Roberts et al., 2004; Shriberg et al., 2000], and a family history of developmental language disorders [Campbell et al., 2003; Lassman et al., 1980]. The incidence in families with a history of developmental language disorder is estimated at approximately 20% to 40%, whereas in the general population, it is about 4% [Choudhury and Benasich, 2003]. The increased concordance between monozygotic compared with dizygotic twins indicates that heredity, not just shared environment, is causal in family clustering of cases [Bartlett et al., 2002]. For males and females, heritability appears to be greater for

Percentage of children

100 80 60 40 Words Phrases Intelligible speech

20

6 8 101214 16 18

24

30 36 Age in months

42

48

54

80

FIGURE 34-1. The variability in normal language development is clear from this plot of early milestones. In a group of approximately l000 ultimately normal British children, first word acquisition occurred between 6 and 30 months of age, and phrase acquisition occurred between l0 and 44 months. (From Morley ME. The development and disorders of speech in childhood, 2nd ed. Baltimore: Williams & Wilkins, 1965.)

Nass and Trauner / Developmental Language Disorders

BOX 34-4 WARNING SIGNS OF A DEVELOPMENTAL LANGUAGE DISORDER

BOX 34-5 DIFFERENTIAL DIAGNOSIS OF LANGUAGE DELAY OR DISORDER

Limitations in expressive language • Has feeding problems related to sucking, swallowing, and chewing • Fails to vocalize in response to social stimuli and fails to vocalize two syllables at 8 months of age • Produces few or no creative utterances of three words or more by age 3 years

Hearing loss Mental retardation Severe oral motor dysfunction Autistic spectrum disorders Developmental language impairment

Limitations in vocabulary • Has small repertoire of words understood or used and acquires new words slowly or with difficulty

BOX 34-6 DISORDERS ASSOCIATED WITH LANGUAGE DELAY OR IMPAIRMENT

Limitations in comprehending language • Relies too much on contextual cues to understand language

Congenital and Developmental Disorders Congenital rubella syndrome Neuronal migration defects

Limitations in social interaction • Rarely interacts socially, except to have needs met

Epileptic Syndromes Infantile spasms Lennox-Gastaut syndrome Landau-Kleffner syndrome

Limitations in play • Has not developed symbolic, imaginative play by age 3 years • Does not play interactively with peers Limitations in learning speech • Expressive speech contains numerous articulation errors or is unintelligible to unfamiliar listeners Limitations in using strategies for language learning • Uses unusual or inappropriate strategies for age level (e.g., overuses imitation [echolalia], does not imitate verbalizations of others [dyspraxia], does not use questions for learning [“why” questions]) Limitations in attention for language activities • Shows little interest in book reading, talking, or communicating with peers

Genetic Disorders Fragile X syndrome Klinefelter’s syndrome Prader-Willi syndrome Angelman’s syndrome Williams’ syndrome Homocystinuria Tuberous sclerosis Isodicentric chromosome 15 Mitochondrial encephalopathies Fatty acid oxidation defects Amino acidopathies (e.g., Hartnup’s disease, phenylketonuria)

Data from Nelson NW. Childhood language disorders in context: Infancy through adolescence. New York: Macmillan, 1993, and from Hall N. Developmental language disorders. Semin Pediatr Neurol 1997;4:77.

TABLE 34-1 Subtypes of Developmental Language Disorders RECEPTIVE-EXPRESSIVE Verbal Auditory Phonologic Agnosia Syntactic Comprehension-Receptive Phonology ↓↓ Syntax ↓↓ Semantics ↓↓

↓ ↓ ?

Production-Expressive Semantics (lexical) ↓↓ Syntax ↓↓ Phonology ↓↓ Repetition ↓↓ Fluency ↓↓ Pragmatics N1 or ↓

↓↓ ↓↓ ↓ ↓ N1 or ↓

EXPRESSIVE Verbal Dyspraxia

Phonologic Programming

HIGHER ORDER Semantic Lexical Pragmatic Syntactic

↓↓

? ↓↓ ↓ N1 or ↓

? ↓ N1 or ↓

↓ ↓

↓↓

↓ ↓

↑ N1 or ↑ ↓↓

↓ ↓ ↓

Nl, normal; ↓, mild to moderate deficit; ↓↓, moderate to severe deficit; ?, unknown. Adapted from Nass R, Ross G. Disorders of higher cortical function in the preschooler. In: David R, ed. Child and adolescent neurology. St Louis: Mosby, 1997, and from Rapin I. Preschool children with inadequate communication. London: McKeith Press, 1996.

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Neurobehavioral Disorders / 34 ARTICULATION

10

11 Normal 42 II

Relapsing articulation

III 4

II

III

20

I

I II III 43 4 1

Normal 64

22

Normal 95

27 I 9

9

3 12 Years

4 12 Years

1

6 2 Years

Classification in following groups I Defective [th] &/or [r] only II Intelligible speech, but defects of articulation III Unintelligible speech % of children in group of 114 children

more severe language impairment, indicating stronger influence of genes at the lower end of language ability [Spinath et al., 2004; Viding et al., 2004]. Several gene loci for severe language impairment have been implicated, including 13q, 16q, and 19q [Bishop, 2002a, 2002b; Harasty and Hodges, 2002; SLI Consortium, 2002; Stein et al., 2004]. The most well-studied genetic language disorder is the three-generation KE family, in which one half of the members are affected with a severe speech and language disorder that is transmitted as an autosomaldominant monogenic trait—the FOXP2 forkhead-domain gene [Lai et al., 2001; Watkins et al., 2002b]. However, affected family members have other neurologic problems, including oral motor apraxia, motor incoordination, and cognitive deficits. This phenotype is not typical of most individuals with developmental language disorder; results of a screening of 270 4-year-old children with developmental language disorder were negative for the FOXP2 mutation [Meaburn et al., 2002].

SUBTYPES OF DEVELOPMENTAL LANGUAGE DISORDERS Depending on subtype, developmental language disorders vary in their characteristic features, causes, prognoses, and treatment responses. The subtypes listed in Table 34-1 focus on psycholinguistic features (see Box 34-2) that most closely approximate the adult aphasias.

Articulation and Expressive Fluency Disorders Pure Articulation Disorders Articulatory skills improve with age, and as with language development, the variability among normal children is considerable (Fig. 34-2) [Morley, 1965]. Most children (70%) speak intelligibly by age 2 years. Unintelligible speech is the exception at age 3 years (15%). However, almost 50% of children at age 4 years still have articulation difficulties. A common problem is defective use of th or r. At kindergarten entry, one third of children still have minor to mild articulation defects, but speech is unintelligible in less than 5%.

FIGURE 34-2. The range of articulation skills at different ages demonstrate that articulation improves at different rates in normally developing children. (From Morley ME: The development and disorders of speech in childhood. Edinburgh: Churchill Livingstone, 1965;55.)

Stuttering and Cluttering Stuttering is a disorder in the rhythm of speech. The speaker knows what to say but is unable to say it because of an involuntary, repetitive prolongation or cessation of a sound. Some degree of dysfluency is common as language skills evolve during the preschool years, particularly as the mean length of utterance reaches six to eight words between 3 and 4 years of age. In contrast to developmental dysfluency, stuttering is probably a linguistic disorder (i.e., errors occur at grammatically important points in the sentence) [Karniol, 1995] and a motor planning problem [Logan, 2003]. Stuttering is often a genetic trait. Although the cause of developmental stuttering is unknown, the main theories posit anomalous dominance and abnormalities of interhemispheric connections [Foundas et al., 2001]. Stuttering occurs more frequently in children with other developmental language disorders and with mental retardation [Blood et al., 2003; Gordon, 2002]. Cluttering, as occurs in children with fragile X syndrome, is characterized by incomplete sentences and short outbursts of two- to three-word phrases, along with echolalia, palilalia (i.e., compulsive repetition reiterated with increasing rapidity and decreasing volume), perseveration, poor articulation, and stuttering.

Phonologic Programming Disorder Children with the phonologic programming disorder have fluent speech, and the mean length of utterance approaches normal. Despite initially poor intelligibility, serviceable speech is expected. Language comprehension is relatively preserved. Most such children demonstrate delayed rather than deviant phonology, and they demonstrate improvement when evaluated 1 and 7 years after their preschool diagnosis. However, some children with expressive phonologic delays demonstrate significantly poorer phonemic perception and phonologic awareness skills at age 4 years than their normally developing peers [Rvachew et al., 2003]. Whether this disorder is a severe articulation problem or a mild form of verbal dyspraxia is debated [Shriberg and Kwiatkowski, 1994]. The fact that children with a phonologic programming disorder have more difficulty learning manual signs than control children supports an association

Nass and Trauner / Developmental Language Disorders

with dyspraxia [Bishop, 2002a; Bradford and Dodd, 1994]. A pre-remediation paired associate learning task may help select the best remediation method because some children are better with symbols, whereas other children are better with signs [Pearce et al., 1987]. An adult aphasia equivalent does not exist.

Verbal Dyspraxia The speech of children with verbal dyspraxia [Nevo et al., 2001; Shriberg et al., 1977a, b], also called dilapidated speech [Critchley, 1970; Ferry et al., 1975], is extremely dysfluent. Utterances are short and laboriously produced. Phonology is impaired and includes inconsistent omissions, substitutions, and distortions of speech sounds. Syntactic skills are difficult to assess in the face of dysfluency. Language comprehension is relatively preserved. Many require speech and language therapy for prolonged periods. Children with verbal dyspraxia who do not have intelligible speech by age 6 years are unlikely to acquire it later. The frequency with which nonverbal praxis deficits—buccal-lingual dyspraxia (e.g., positioning muscles of articulation) and generalized dyspraxia or clumsiness— coexist with verbal dyspraxia is unknown. The presence of a more diffuse disorder of praxis has significant therapeutic implications, because children with verbal dyspraxia may have to depend on signing and writing skills for communication [Shriberg et al., 1977a, b]. The cause of verbal dyspraxia is unknown. The excess of males and a familial tendency support a genetic basis [Lee et al., 2002]. Postmortem and structural imaging studies suggest peri-opercular pathology. Although often accompanied by other neurologic symptoms, isolated verbal dyspraxia most resembles the adult aphasia called aphemia.

Disorders of Receptive and Expressive Language Phonologic Syntactic Syndrome Syntax is considered by many to be the core component that distinguishes language from other forms of communication [Chomsky, 2000; Pinker, 1994]. Syntactic skills are affected in many children with developmental language disorders [Bishop, et al., 2000; Norbury and Bishop, 2003; Norbury et al., 2002]. Phonologic syntactic syndrome (also referred to as mixed receptive-expressive disorder, expressive disorder, or nonspecific formulation-repetition deficit) is probably the most common developmental language disorder [Aram and Nation, 1982; Korkman and Hakkinen-Rihu, 1994; Wilson and Risucci, 1986]. The phonologic disturbances consist of omissions, substitutions, and distortions of consonants and consonant clusters in all word positions. The production of unpredictable and unrecognizable sounds makes speech impossible to understand. The syntactic deficits include a lack of functor words (i.e., words that serve a grammatical purpose) and an absence of appropriately inflected endings. Grammar is atypical, not merely delayed. Whereas a normal young child may say “baby cry” or “a baby crying,” children with phonologic syntactic syndrome produce deviant constructions, such as “the baby is cry” [Rapin, 1996]. Telegraphic speech is common. The presence or absence of difficulties in other language areas is variable. Overall, comprehension is relatively spared. Semantic skills tend to be intact. Repetition,

849

pragmatics, and prosody may be normal. Autistic children with this developmental language disorder subtype produce a significant amount of jargon. Neurologic dysfunction is especially common in children with the phonologic syntactic syndrome. Feeding problems due to sucking, swallowing, and chewing difficulties are common, and drooling is often persistent. The neurologic examination may reveal signs of pseudobulbar palsy, oromotor apraxia, hypertonia, and incoordination. A single patient with the phonologic syntactic syndrome and oromotor apraxia had an atypical asymmetry of the planum region and a dysplastic gyrus in the left frontal cortex. Bilateral anterior and posterior perisylvian hypoperfusion has been demonstrated in a few children with this disorder. This developmental language disorder subtype most resembles Broca’s aphasia in adults.

Verbal Auditory Agnosia Children with verbal auditory agnosia (also called generalized low performance and global dysfunction in other developmental language disorder nosologies–classification systems) are unable to understand language despite the fact that they can hear. They appear to be deaf because they do not, for example, respond to their names or to verbal requests. Verbal auditory agnosia may occur on a developmental basis and as an acquired disorder, the Landau-Kleffner syndrome [Klein et al., 2000; Tuchman, 1997]. Verbal auditory agnosia is common in low-functioning children with autism. Verbal auditory agnosia best supports the theory that developmental language disorders result from difficulty with processing basic sensory information entering the nervous system in rapid succession [Tallal and Benasich, 2002; Tallal et al., 1993]. The long-term outcome for acquisition of language by children with the developmental form of verbal auditory agnosia is generally poor. The outcome for the acquired disorder is better in approximately one third of patients. Verbal auditory agnosia is seen in adults with acquired bitemporal lesions.

Higher-Order Language Disorders Semantic Pragmatic Syndrome Children with the semantic pragmatic syndrome (also called repetition strength and comprehension deficit or language without cognition in other developmental language disorder classification systems) are fluent speakers, even verbose. The term cocktail party syndrome has been used to describe the semantic pragmatic syndrome in children with hydrocephalus. Vocabulary is often large and somewhat formal. Parents are often encouraged by the child’s sizable vocabulary, only to find later that the verbosity did not indicate superior cognitive skills. Many children have trouble making meaningful conversation and exchanging ideas with another person. They talk to talk. Pragmatic skills are lacking. Children with semantic pragmatic syndrome often demonstrate deficits in prosody; their speech has a monotonous, mechanical, or singsong quality. They cannot convey the additional pragmatic intentions that prosody affords, such as speaking with proper emotion or indicating by the tone of their voice that they are asking a question. Com-

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prehension may be impaired. Phonologic and syntactic skills are generally intact [Rapin and Allen, 1988]. Semantic pragmatic syndrome is often seen in higher-functioning autistic children [Bishop, 2002c]. The neuroanatomic basis of this disorder is unknown. It is reported in patients with agenesis of the corpus callosum and those with hydrocephalus, particularly in children who have meningomyeloceles. These clinical associations suggest that this disorder is localized in the subcortex and its connections or that it is possibly a disconnection effect. Repetition strength in the setting of fluent speech with impaired comprehension characterizes the adult aphasia syndrome of transcortical sensory aphasia. Difficulties with prosody and pragmatics suggest dysfunction of the right hemisphere.

Lexical Syntactic Syndrome The lexical syntactic syndrome is relatively common and occurs in approximately 15% of children with developmental language disorders [Rapin, 1996; Wilson and Risucci, 1986; Wolfus et al., 1980]. Speech is generally dysfluent, even to the point of stuttering, because of word-finding difficulties and poor syntactic skills, with many hesitancies and false starts. Both literal and semantic paraphasias are common. Syntax is immature, not deviant. Phonology is spared, and speech therefore is intelligible. Repetition usually is better than spontaneous speech. In conversation, idiom use is better than spontaneous speech. Pragmatics may be impaired, particularly when this syndrome occurs in autistic children. Comprehension is generally acceptable, although complex questions and other linguistic forms taxing higher-level receptive syntactic skills are often deficient. The neuroanatomic basis of this disorder is unknown. No clear counterpart for the lexical syntactic syndrome exists among the acquired aphasias of adulthood, despite overlap with anomic aphasia, conduction aphasia, and transcortical aphasia.

OUTCOMES OF DEVELOPMENTAL LANGUAGE DISORDERS The occurrence of a developmental language disorder, even when it appears to resolve, may affect later social and emotional adjustment, educational achievement, and vocational choices. Short- and long-term behavioral, socialemotional, and psychiatric problems are associated with early language problems [Conti-Ramsden and Botting, 2004; Irwin et al., 2002; Jerome et al., 2002]. These problems include substance abuse and delinquency [Beitchman et al., 1999; Bryan, 2004]. In school-age children with speech and language problems, the frequency of attention-deficit– hyperactivity disorder is 30% to 49%, and the frequency of behavioral and emotional problems is 10% to 50% [Beitchman et al., l996a; 2001; Cantwell and Baker, 1987]. Children with early language impairment have higher rates of anxiety disorder (particularly social phobia) and antisocial personality disorder in young adulthood compared with nonimpaired children [Beitchman et al., 2001]. In some studies, the primary differentiating factor between those with and without a psychiatric diagnosis is the degree of language deficit [Beitchman et al., 2001; Cantwell and Baker, 1987].

In the National Collaborative Perinatal Project [Lassman et al., 1980], children with receptive and expressive language problems at age 3 years were at significantly increased risk for one of the three study-defined minimal brain dysfunction syndromes—hyperkinesis, soft signs, and learning disabilities—at age 7 years [Nichols and Chen, l98l]. In preschool children with developmental language disorder, nonverbal intelligence is an important predictor of overall long-term outcome, and severity of language problems is a key predictor of later language skills [Plomin et al., 2002]. Preschool language skills are the best single predictor of later reading ability and disability [Aram and Nation, 1980; Beitchman et al., 1996b; Carroll and Snowling, 2004]. Even children with good receptive skills who speak late may be at risk for continuing subtle language difficulties [Bishop et al., 2003; Rescorla and Roberts, 1997] and later reading and language-based academic difficulties [Rescorla, 2002]. In elementary school–age children, narrative story-telling skills and expressive syntax at age 7 years predicted the overall prognosis at age 11 years [Botting et al., 2001]. Language problems, although often subtle, persisting through childhood [Tomblin et al., 1997], into adolescence [Qualls et al., 2004], and beyond have been reported in up to 90% of these patients [Conti-Ramsden et al., 2001; Rescorla, 2002]. Communication problems, often subtle, may continue into adult life in 50% to 70% [Young et al., 2002]. Written language problems may also be a late marker of early language problems [Bishop and Clarkson, 2003].

EVALUATION OF THE CHILD WITH SUSPECTED LANGUAGE DELAY OR IMPAIRMENT Evaluation of the child with a developmental language disorder (Box 34-7) must include an assessment of hearing and an assessment of the overall level of cognitive functioning. An electroencephalogram (EEG), including a sleep record, is also appropriate in evaluating some children with isolated language delay to exclude subclinical seizures [Galanopoulou et al., 2002; Tuchman, 1997]. Overnight sleep recordings increase the yield considerably (see Chapter 45). Major risk factors for epilepsy and epileptiform EEGs are mental retardation, cerebral palsy, language regression, and the verbal auditory agnosia language disorder subtype. Perisylvian abnormalities are associated with language disorders, particularly in children with verbal dyspraxia or phonologic syntactic syndromes. Complete opercular agenesis is associated with suprabulbar palsy (i.e., WorsterDrought syndrome). Polymicrogyria has also been reported in the perisylvian region [Clark et al., 2000]. Patients with the most extensive pathology have the greatest language impairments, whereas those with posterior parietal polymicrogyria have milder symptoms [Guerreiro et al., 2002; Nevo et al., 2001; Nisipeanu et al., 1997]. Semantic pragmatic syndrome has been reported in patients with agenesis of the corpus callosum and with hydrocephalus [Fabbro et al., 2002]. Some children and adults with developmental language disorder (as well as relatives of developmental language disorder probands) do not have the typical planum temporale asymmetry pattern (i.e., left larger than right). The absence of the typical planum asymmetry may be the result of aberrant neurogenesis in the perisylvian

Nass and Trauner / Developmental Language Disorders

BOX 34-7 EVALUATION OF A CHILD WITH SUSPECTED LANGUAGE DISORDER Complete neurodevelopmental and family history and neurologic examination (including social interaction and communicative behaviors) Hearing test Office developmental screen (e.g., Denver Developmental Test [Frankenburg et al., 1992], McArthur Communicative Development Inventory [Fenson et al., 1993]; Children’s Communication Checklist [Norbury et al., 2004]; Peabody Picture Vocabulary Test [Dunn and Dunn, 1981]; Preschool language scale [Zimmerman et al., 1992]; Early Language Milestones [Coplan et al., 1982]) may be helpful. Psychometric testing is used to establish general cognitive function. A nonverbal intelligence test such as the Leiter International Performance Scale-Revised [Leiter, 1997] or the Test of Nonverbal Intelligence–P:3 or –I:3 (TONI-P:3, TONI-I:3) [Hammill and Newcomer, 1996a, 1996b] is most appropriate for a language-impaired child. Sleep electroencephalogram Depending on history and examination, other tests to consider: MRI of brain Karyotype, fragile X chromosome or DNA study, fluorescence in situ hybridization (FISH) probes Metabolic screen (e.g., urine organic acids, blood amino acids) Overnight video electroencephalographic monitoring regions. Callosal size is decreased in some children with developmental language disorder [Preis et al., 2000]. An extra sulcus in the inferior frontal gyrus was statistically associated with a history of developmental language disorder in a group of 41 neurologically normal adults [Clark and Plante, 1998]. In one series, one third of 35 children with developmental language disorder had nonspecific magnetic resonance imaging abnormalities, including ventricular enlargement (5), central volume loss (3), and white matter abnormalities (4) [Trauner et al., 2000]. Rare reports document abnormalities of the right hemisphere in the developmental language disorder child, suggesting a right hemispheric contribution to language acquisition [Plante et al., 2001]. In the KE family, the caudate nucleus and inferior frontal gyrus are reduced in size bilaterally, whereas the left frontal opercular region (i.e., pars triangularis and anterior insular cortex) and the putamen bilaterally have a greater volume of gray matter [Watkins et al., 2002a]. An insufficient dosage of a critical forkhead transcription factor during embryogenesis may lead to maldevelopment of brain speech and language regions [Lai et al., 2001]. Metabolic imaging of individuals with developmental language disorder suggests abnormalities in the left temporal region that may vary by developmental language disorder subtype [Hugdahl et al., 2004; Lee et al., 2002; Semrud-Clikeman, 1997]. In some children with developmental language disorder, the right hemisphere may be language dominant [Bernat and Altman, 2003]. Despite these

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research results, there is no reason to image the typical child with a developmental language disorder in clinical practice, unless focal abnormalities are suspected by history (e.g., a nonfamilial, early-declaring left-hander) or on examination.

TREATMENT Whether intensive early therapy changes the long-term outcome to an appreciable degree remains to be determined [Forrest, 2002; Tyler, 2002]. Treatment of language-disordered preschool children varies according to the kind of language impairment and its degree of severity. Children with moderateto-severe language impairment, who suffer associated social, cognitive, and behavioral difficulties, are best treated in a therapeutic nursery. Mildly impaired children often fare well in a regular nursery program combined with individual speech-language therapy. Play materials are used by the speech-language therapist with the preschool child in a directive way. Every activity becomes a language activity in that the child’s actions are given words by the therapist. Play activities are a helpful way to engage children with severe expressive difficulties. Pleasurable activities involving the mouth, such as blowing bubbles or initiating mouth movements and sounds, and nonvocal imitative games, such as hand clapping, foster language acquisition. Formal language work typically begins at the phonologic level involving repetition of sounds and sound sequences to encourage fluency. Treatment of receptive disorders often necessitates the use of visual modalities such as signs and gesture. Less severe disorders of comprehension are addressed through practiced structuring of conversations with the child. Developmental language disorder children with severe comprehension deficits rarely progress with treatment, as well as children with primary expressive disorders. Another approach to language remediation is driven by different theoretic frameworks [Dunn, 1997]. One approach involves identifying specific linguistic deficits (e.g., problems with morphology) and targeting them for remediation. Another involves identifying specific developmental language disorder subtypes and addressing them in remediation. This approach means, for example, that a child’s level of comprehension is taken into account in selecting a strategy for improving language production. A third approach aims to detect a core cognitive processing deficit to be targeted for intervention. A fourth approach emphasizes the neuropsychologic profile. In contrast to the other approaches, which are deficit centered, the neuropsychologic approach defines and uses children’s strengths to remediate their weaknesses; it also takes into account the child’s temperament and neurodevelopmental status to determine learning styles and develop optimal methods for remediating targeted deficits. No formal study has compared the efficacy of these approaches. REFERENCES Achenbach TM, Rescorla LA. Manual for the ASEBA preschool forms and profiles. Burlington, VT: University of Vermont Department of Psychiatry, 2000. Aram DM, Morris R, Hall NE. The validity of discrepancy criteria for identifying children with developmental language disorders. J Learn Disord 1992;25:549.

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CHAPTER 35

Dyslexia Sally E. Shaywitz and Bennett A. Shaywitz

Developmental dyslexia is characterized by unexpected difficulty in reading by children and adults who otherwise possess the intelligence and motivation considered necessary for accurate and fluent reading. “Dyslexia is a specific learning disability that is neurobiologic in origin. It is characterized by difficulties with accurate and/or fluent word recognition and by poor spelling and decoding abilities. These difficulties typically result from a deficit in the phonologic component of language that is often unexpected in relation to other cognitive abilities and the provision of effective classroom instruction” [Lyon et al., 2003]. Dyslexia (or specific reading disability) is the most common and most carefully studied of the learning disabilities, affecting 80% of all individuals identified as learning disabled. Although the diagnosis and implications of dyslexia were often uncertain in the past, advances in our knowledge of the epidemiologic, neurobiologic, genetic, and cognitive influences on the disorder allow it to be approached within the framework of a traditional medical model. This chapter reviews these advances and their implications for the approach to patients presenting with a possible reading disability. Historically, dyslexia in adults was first observed in the latter half of the 19th century, and developmental dyslexia in children was first reported in 1896 [Morgan, 1896]. Our understanding of the neural systems for reading began as early as 1891, when Dejerine [1891] suggested that a portion of the posterior brain region (which includes the angular gyrus and supramarginal gyrus in the inferior parietal lobule and the posterior aspect of the superior temporal gyrus) is critical for reading. Another posterior brain region, one more ventral in the occipitotemporal area, was also described by Dejerine [1892] as critical in reading.

EPIDEMIOLOGY Epidemiologic data indicate that, like hypertension and obesity, dyslexia fits a dimensional model. Within the population, reading ability and reading disability occur along a continuum, with reading disability representing the lower tail of a normal distribution of reading ability [Gilger et al., 1996; Shaywitz et al., 1992a]. Dyslexia is perhaps the most common neurobehavioral disorder affecting children, with prevalence rates ranging from 5% to 17.5% [Interagency Committee on Learning Disabilities, 1987; Shaywitz, 1998]. Longitudinal studies, prospective [Francis et al., 1996; Shaywitz et al., 1995a] and retrospective [Bruck, 1992; Felton et al, 1990; Scarborough, 1990], indicate that dyslexia is a persistent, chronic condition; it does not represent a transient developmental lag (Fig. 35-1). Over time, poor readers and

good readers tend to maintain their relative positions along the spectrum of reading ability [Francis et al., 1996; Shaywitz et al., 1995b].

ETIOLOGY Dyslexia is both familial and heritable [Pennington and Gilger, 1996]. Family history is one of the most important risk factors, with 23% to 65% of children who have a parent with dyslexia reported to have the disorder [Scarborough, 1990]. A rate among siblings of affected persons of approximately 40% and among parents of 27% to 49% [Pennington and Gilger, 1996] provides opportunities for early identification of affected siblings and often for delayed but helpful identification of affected adults. Replicated linkage studies of dyslexia implicate loci on chromosomes 2, 3, 6, 15, and 18 [Fisher and DeFries, 2002]. Whether the differences in the genetic loci represent polygenic inheritance, different cognitive paths to the same phenotype, or different types of dyslexia is not clear. Reading difficulties are commonly observed in children with known genetic abnormalities, particularly those involving sex chromosomes. Reading difficulties occur in 50% to 75% of boys with Klinefelter’s syndrome [Geschwind et al., 2000]. Neuropsychologic deficits in neurofibromatosis type 1 were originally believed to affect nonverbal domains, but later evidence indicates that problems in reading are observed in more than one half of affected children [Cutting et al, 2000; Mazzocco et al., 1995]. Individual word reading by girls with Turner’s syndrome is usually normal, although one report of difficulties in oral fluency suggests that reading fluency should be examined in this group of children [Temple, 2002]. Reading difficulties may be associated with a range of insults, although these associations usually occur in only a very small proportion of children presenting with reading disability. Data are strongest for the association between exposure to lead and a decline in academic functioning, including reading. Some data support the belief that what had been considered relatively safe blood levels (i.e., lead levels below 10 μg/dl) are associated with reading problems. Every 1-μg increase in blood lead concentration was associated with a 1-point decrement in mean reading scores [Bellinger, 2004; Bellinger et al., 1992; Lanphear et al., 2000]. Academic difficulties, including reading problems, are frequently reported in children with congenital heart disease, particularly cyanotic congenital heart disease [Ellerbeck et al., 1998; O’Dougherty et al., 1983; Wright and Nolan, 1994]. Bellinger and associates [2003], using a randomized clinical trial of two methods of vital organ support within a

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COGNITIVE INFLUENCES: THEORIES OF DEVELOPMENTAL DYSLEXIA

FIGURE 35-1. Trajectory of reading skills over time in nonimpaired and dyslexic readers. Numbers on the ordinate are Rasch scores (W scores) from the Woodcock-Johnson reading test [Woodcock and Johnson, 1989], and numbers on the abscissa are ages in years. Dyslexic and nonimpaired readers improve their reading scores as they get older, but the gap between the dyslexic and nonimpaired readers remains. Dyslexia is a deficit, not a developmental lag. (From Shaywitz S. Overcoming dyslexia: A new and complete science-based program for reading problems at any level. New York: Alfred A Knopf, 2003.)

longitudinal prospective design, examined the neurodevelopmental consequences of one type of cyanotic congenital heart disease, transposition of the great vessels. Follow-up at 8 years of age indicated that the most prominent deficits affected motor function and visuospatial skills, although academic difficulties, including reading problems, were observed in many children, particularly in their reading fluency. Cognitive problems, including problems in academic achievement such as reading, are reported more frequently in children with epilepsy than in nonimpaired groups, although the prevalence of reading problems in different types of epilepsy is not known. Studies have not differentiated the relative contributions of the underlying disorder, seizures, or contributions of the antiepileptic agents used to treat seizures in children with epilepsy [Meador, 2002]. Because most children with seizure disorders are receiving antiepileptic medications, any cognitive or behavioral difficulties attributed to the seizure disorder could as easily be attributed to medication effects. These questions are difficult to resolve. Farwell and colleagues [1990] suggested that phenobarbital used to prevent febrile seizures might lower intelligence quotients in 2- to 3-year-old children. Such findings lend support to the suggestion that long-term phenobarbital therapy to prevent seizures should be used judiciously [Freeman, 1990]. Report of a study that followed children exposed to phenobarbital in utero was reassuring in indicating normal reading at age 7 years compared with controls receiving placebo [Thorp et al., 2003]. Although the relation between epilepsy and reading difficulties remains a difficult one, the question of whether chronic otitis media with effusion results in reading problems appears to have been resolved. Using a prospective, longitudinal design, Roberts and associates [2002] demonstrated that there was no significant relation between a history of early otitis media with effusion and later reading problems.

Several theories of dyslexia have been proposed, including the phonologic theory [Liberman et al., 1989; Ramus et al., 2003]; the rapid auditory processing theory [Tallal, 1980, 2000; Tallal et al., 1993]; the visual theory [Livingstone et al., 1991; Lovegrove et al., 1980]; the cerebellar theory [Nicolson and Fawcett, 1990; Nicolson et al, 2001]; and the magnocellular theory [Galaburda et al., 1994; Livingstone et al., 1991; Stein, 2003; Stein and Walsh, 1997]. Ramus and associates [2003] have reviewed and critiqued the current literature on this topic. Among investigators in the field, there is a strong consensus supporting the phonologic theory. This theory recognizes that speech is natural and inherent but that reading is acquired and must be taught. To read, the beginning reader must recognize that the letters and letter strings (i.e., the orthography) represent the sounds of spoken language. To read, a child has to develop the insight that spoken words can be pulled apart into the elemental particles of speech (i.e., phonemes) and that the letters in a written word represent these sounds [Shaywitz, 2003]; such awareness is largely missing in dyslexic children and adults [Bruck, 1992; Fletcher et al., 1994; Liberman and Shankweiler, 1991; Shankweiler et al., 1979; Shaywitz, 2003; Torgesen and Wagner, 1995; Wagner and Torgesen, 1987]. Results from large and well-studied populations with reading disability confirm that in young school-age children [Fletcher et al., 1994; Stanovich and Siegel, 1994] and in adolescents [Shaywitz et al., 1999], a deficit in phonology represents the most robust and specific correlate of reading disability [Morris et al., 1998; Ramus et al., 2003]. Such findings form the basis for the most successful and evidence-based interventions designed to improve reading [National Reading Panel, 2000].

Implications of the Phonologic Model of Dyslexia Reading comprises two main processes: decoding and comprehension [Gough and Tunmer, 1986]. In dyslexia, a deficit at the level of the phonologic module impairs the ability to segment the written word into its underlying phonologic elements. As a result, the reader experiences difficulty, first in decoding the word and then in identifying it. The phonologic deficit is domain specific; that is, it is independent of other, nonphonologic abilities. In particular, the higher-order cognitive and linguistic functions involved in comprehension, such as general intelligence and reasoning, vocabulary [Share and Stanovich, 1995], and syntax [Shankweiler et al., 1995], are generally intact. This pattern—a deficit in phonologic analysis contrasted with intact higher-order cognitive abilities—offers an explanation for the paradox of otherwise intelligent, often gifted people who experience great difficulty in reading [Shaywitz, 1996, 2003]. According to the model, a circumscribed deficit in a lower-order linguistic function (i.e., phonology) blocks access to higher-order processes and to the ability to draw meaning from text. The problem is that the affected reader cannot use his or her higher-order linguistic skills to access the meaning until the printed word has first been decoded

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and identified. Suppose, for example, an individual knows the precise meaning of the spoken word apparition. That person will not be able to use knowledge of the meaning of the word until the printed word on the page can be decoded and identified, and it will appear that the individual does not know the word’s meaning.

Neurobiologic Studies To a large degree, advances in understanding the cognitive basis of dyslexia have informed and facilitated studies examining the neurobiologic underpinnings of reading and dyslexia. A range of neurobiologic investigations using postmortem brain specimens [Galaburda et al., 1985], brain morphometry [Brown et al., 2001; Eliez et al., 2000; Filipek, 1996], and diffusion tensor magnetic resonance imaging (MRI) [Klingberg et al., 2000] suggests that there are differences in the temporal-parietal-occipital brain regions between dyslexic and nonimpaired readers.

Functional Brain Imaging Rather than being limited to examining the brain in a postmortem examination specimen or measuring the size of brain regions using static morphometric indices based on computed tomographic scanning or MRI, functional imaging offers the possibility of examining brain function during performance of a cognitive task. The term functional imaging is used to refer to technologies that measure changes in metabolic activity and blood flow in specific brain regions while subjects are engaged in cognitive tasks. The term functional imaging has also been applied to the technology of magnetic source imaging using magnetoencephalography, an electrophysiologic method with strengths in resolving the chronometric properties of cognitive processes [Papanicolaou et al., 2003]. In principle, functional brain imaging is a straightforward process. When an individual is asked to perform a discrete cognitive task, that task places processing demands on particular neural systems in the brain. To meet those demands requires activation of neural systems in specific brain regions, and those changes in neural activity are reflected by changes in brain metabolic activity, which are reflected, for example, by changes in cerebral blood flow and in the cerebral use of metabolic substrates such as glucose.

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on an aurally presented semantic judgment task [Rumsey et al., 1994]. Paulesu and co-workers [1996], using a visually presented single letter rhyming task, reported a disconnection between the anterior and posterior language regions, a theory supported by their finding of underactivation in the insula in a small group of compensated dyslexic university students. Rumsey and colleagues [1997] found that dyslexic readers demonstrated reduced blood flow in temporal cortex and inferior parietal cortex, especially on the left, during pronunciation and decision-making tasks.

Functional Magnetic Resonance Imaging Functional magnetic resonance imaging (fMRI) promises to supplant other methods because of its ability to map the individual brain’s response to specific cognitive stimuli. Because it is noninvasive and safe, it can be used repeatedly, properties that make it ideal for studying humans, especially children. In principle, the signal used to construct MRI images changes by a small amount (typically 1% to 5 %) in regions that are activated by a stimulus or task. The increase in signal results from the combined effects of increases in the tissue blood flow, volume, and oxygenation, although the precise contribution of each of these is still somewhat uncertain. MR image intensity increases when deoxygenated blood is replaced by oxygenated blood. A variety of methods can be used to record the changes that occur, but one preferred approach makes use of ultrafast imaging, such as echo planar imaging, in which complete images are acquired in times substantially shorter than a second. Echo planar imaging can provide images at a rate fast enough to capture the time course of the hemodynamic response to neural activation and to permit a wide variety of imaging paradigms over large volumes of the brain. Details of fMRI are reviewed by Anderson and Gore [1997], Frackowiak and colleagues [2004], and Jezzard and co-workers [2001].

BRAIN ORGANIZATION FOR READING STUDIED BY FUNCTIONAL MAGNETIC RESONANCE IMAGING Functional MRI has proved to be a powerful tool for understanding the brain organization for reading. Studies have examined a number of domains, each of which is detailed in the following sections.

Positron Emission Tomography Studies Some of the first functional imaging studies of dyslexia used positron emission tomography (PET) [Gross-Glenn et al., 1991; Hagman et al., 1992]. In practice, PET requires intraarterial or intravenous administration of a radioactive isotope to the subject so that cerebral blood flow or cerebral glucose use can be determined while the subject is performing the task. Positron-emitting isotopes of nuclei of biologic interest have very short biologic half-lives and are synthesized in a cyclotron immediately before testing, a factor that mandates that the time course of the experiment conform to the short half-life of the radioisotope. Rumsey and colleagues [1992] found that adult dyslexic readers failed to activate the left parietal and left middle temporal regions in response to an aurally presented rhyming task; no differences were found between dyslexic and control adult readers

Identification and Localization of Specific Systems and Their Differences in Good and Poor Readers Several research groups, including ours, have used fMRI to examine the functional organization of the brain for reading in nonimpaired and dyslexic readers. In previous studies, we [Shaywitz et al., 1998] studied 61 right-handed adult subjects, 29 dyslexic readers (14 men, 15 women, ages 16 to 54 years), and 32 nonimpaired readers (16 men, 16 women, ages 18 to 63 years), focusing on the brain regions that previous research had implicated in reading and language [Demonet et al., 1994; Henderson, 1986; Petersen et al., 1990]. Significant differences in brain activation patterns were found between dyslexic and nonimpaired readers, differences that emerged during tasks that made progressive de-

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mands on phonologic analysis. During nonword rhyming by dyslexic readers, a disruption in a posterior region involving the superior temporal gyrus and angular gyrus with a concomitant increase in activation in the anterior inferior frontal gyrus was demonstrated. When studying adults with dyslexia, there is always the concern that the findings may represent the consequences of a lifetime of poor reading, and it is important to study children to examine the neural systems for reading during acquisition of literacy. Functional MRI was used to study 144

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FIGURE 35-2. Composite maps demonstrate brain activation in nonimpaired (NI) and dyslexic (DYS) readers as they determined whether two pseudowords rhymed (i.e., nonword rhyme [NWR]), and composite contrast maps compare directly the brain activation of the two groups. The four rows of images from top to bottom correspond to z = +23, +14, +5, and -5 in the Talairach atlas [Talairach and Tournoux, 1988]. Brain activation occurs in the following regions: 1, middle frontal gyrus; 2, inferior frontal gyrus; 3, anterior cingulate gyrus; 4, supramarginal gyrus; 5, cuneus; 6, basal ganglia; 7, superior temporal gyrus; 8, superior temporal sulcus and posterior aspect of the superior and middle temporal gyri; 9, lingual gyrus; 10, middle occipital gyrus; 11, anterior aspect of superior temporal gyrus; 12, medial orbital gyrus; 13, inferior occipital gyrus; 14, posterior aspect of middle temporal gyrus and anterior aspect of middle occipital gyrus. (From Shaywitz B, Shaywitz S, Pugh K, et al. Disruption of posterior brain systems for reading in children with developmental dyslexia. Biol Psychiatry 2002;52:101.)

right-handed children—70 dyslexic readers (21 girls and 49 boys, ages 7 to 18 years; mean age, 13.3 years) and 74 nonimpaired readers (31 girls and 43 boys, ages 7 to 17 years; mean age, 10.9 years)—as they read pseudowords and real words [Shaywitz et al., 2002]. This study was designed to minimize some of the problems encountered in previous studies. A large sample was examined particularly for a functional imaging study. It included boys and girls and a broad age range, and it found significant differences in brain activation patterns during phonologic analysis in nonimpaired compared with dyslexic children. Specifically, nonimpaired children demonstrated significantly greater activation than did dyslexic children in predominantly left hemisphere sites (including the inferior frontal, superior temporal, parietotemporal, and middle temporal–middle occipital gyri) and a few right hemisphere sites (including an anterior site around the inferior frontal gyrus and two posterior sites, one in the parietotemporal region and the other in the occipitotemporal region) (Fig. 35-2). These data converge with reports from many investigators using functional imaging that reveal a failure of left hemisphere posterior brain systems to function properly during reading [Brunswick et al., 1999; Helenius et al., 1999; Horwitz et al., 1998; Paulesu et al., 2001; Rumsey et al., 1992; Salmelin et al., 1996; Seki et al., 2001; Shaywitz et al., 2002, 2003; Temple et al., 2000] and during nonreading visual processing tasks [Demb et al., 1998; Eden et al., 1996]. The findings indicate that dysfunction in left hemisphere posterior reading circuits is already present in dyslexic children and cannot be ascribed to a lifetime of poor reading.

Compensatory Systems in Dyslexic Readers The previously described study design also allowed examination of compensatory systems that develop in dyslexic readers. Two kinds of information were helpful in examining this issue. One involved the relation between brain activation and age. During the most difficult and specific phonologic task (i.e., nonword rhyming), older compared with younger dyslexic readers engaged the left and right inferior frontal gyrus, in contrast to nonimpaired readers, for whom few differences emerged between older and younger readers. Another clue to compensatory systems comes from the findings of the relation between reading skill and brain activation. A significant positive correlation was observed between reading skill and activation in the left occipitotemporal word-form area. A negative correlation was found between brain activation and reading skill in the right occipitotemporal region; that is, the poorer the reader, the greater the activation in the right occipitotemporal region. Compensatory systems seem to involve areas around the inferior frontal gyrus in both hemispheres and perhaps the right hemisphere homolog of the left occipitotemporal word-form area as well.

Computational Roles of the Component Systems Data from laboratories around the world indicate that there are a number of interrelated neural systems used in reading, at least two in posterior brain regions, as well as distinct and related systems in anterior regions. The two posterior systems appear to parallel the two systems proposed by Logan [Logan, 1988, 1997] as critical in the development of skilled,

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FIGURE 35-3. As reading skill increases, brain activation increases. Correlation map between reading skill as measured by the Word Attack reading test [Woodcock and Johnson, 1989] performed out of the magnet during two activation tasks, judging whether two pseudowords rhymed (i.e., nonword rhyme [NWR]) and judging whether two real words were in the same category (CAT). At each voxel, a Pearson correlation coefficient (r) was calculated with age included as a covariate; a normal distribution test was used [Hays, 1988]. The four rows of images from top to bottom correspond to z = +23, +14, +5, and -5 of the Talairach atlas. Strong correlation was found in the inferior aspect of the temporal occipital region (fourth row), in the more superior aspect of the temporal occipital regions (second and third rows), and in the parietal regions (top row). (From Shaywitz B, Shaywitz S, Pugh K, et al. Disruption of posterior brain systems for reading in children with developmental dyslexia. Biol Psychiatry 2002;52:101.)

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automatic reading. One system involves word analysis, operates on individual units of words such as phonemes, requires attentional resources, and processes relatively slowly. It is reasonable to propose that this system involves the parietotemporal posterior reading system. As early as 1891, Dejerine suggested that a portion of the posterior brain region (which includes the angular gyrus and supramarginal gyrus in the inferior parietal lobule, and the posterior aspect of the superior temporal gyrus) is critical for reading. Since then, a large body of literature on acquired inability to read (i.e., acquired alexia) has described neuroanatomic lesions most prominently centered about the angular gyrus as a region considered pivotal in mapping the visual percept of the print onto the phonologic structures of the language system [Damasio and Damasio, 1983; Friedman et al., 1993; Geschwind, 1965]. It is reasonable to suggest that this temporoparietal reading system may be critical for analyzing the written word (i.e., transforming the orthography into the underlying linguistic structures). Perhaps of even more importance to reading is the second system proposed by Logan [Logan, 1988, 1997], a system that operates on the whole word (word form), an obligatory system that does not require attention and one that processes very rapidly. This system has historical roots that were described by Dejerine [1892]; the system is located in another posterior brain region, the occipitotemporal area. Converging evidence from a number of lines of investigation indicates that the left occipitotemporal area is critical for the development of skilled reading and functions as an automatic, instant word recognition system, the visual wordform area [Cohen et al., 2000, 2002; McCandliss et al., 2003]. Brain activation in this region increases as reading skill increases (Fig. 35-3) [Shaywitz et al., 2002]; this region also responds preferentially to rapidly presented stimuli [Price et al., 1996], responds within 150 milliseconds after presentation of a stimulus [Salmelin et al., 1996], and is engaged even when the word has not been consciously perceived [Dehaene et al., 2001]. Another reading-related neural circuit involves an anterior system in the inferior frontal gyrus (i.e., Broca’s area), a region that has long been associated with articulation and that serves an important function in silent reading and naming [Fiez and Peterson, 1998; Frackowiak et al., 2004].

Plasticity of Neural Systems for Reading Given the converging evidence of a disruption of posterior reading systems in dyslexia, the next step is to determine the plasticity of these neural systems—whether they are malleable and can be changed by an effective reading intervention. One report [Shaywitz et al., 2004] hypothesized that the provision of an evidence-based, phonologically mediated reading intervention would improve reading fluency and the development of the fast-paced occipitotemporal systems serving skilled reading. The experimental intervention was structured to help children gain phonologic knowledge (i.e., develop an awareness of the internal structure of spoken words) and at the same time develop their understanding of how the orthography represents the phonology [Blachman et al., 1994]. Children in the community intervention received a variety of interventions within the school setting.

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Seventy-seven right-handed children between the ages 6.1 and 9.4 years were recruited for three experimental groups: experimental intervention (n = 37), community intervention (n = 12), and community controls (n = 28), who were nonimpaired readers. Children in the community intervention group met criteria for reading disability and received a variety of interventions commonly provided within the school; specific, systematic, explicit phonologically based interventions comparable to the experimental intervention were not used in school programs that were provided to the community group. The experimental intervention provided second and third grade poor readers with 50 minutes of daily, individual tutoring that was explicit, systematic, and focused on helping children understand the alphabetic principle (i.e., how letters and combinations of letters represent the small segments of speech known as phonemes) and provided many opportunities to practice applying the letter-sound linkages taught. Children were imaged on three occasions: before intervention, immediately after intervention, and 1 year after the intervention was complete. Children who received the experimental intervention improved their reading accuracy, reading fluency, and reading comprehension. Compared with the community intervention group, the community control and experimental intervention groups demonstrated increased activation in left hemisphere regions, including the inferior frontal gyrus and the posterior aspect of the middle temporal gyrus. One year after the experimental intervention ended (Fig. 35-4), compared with preintervention images, experimental interventions were activating bilateral inferior frontal gyri, left superior temporal sulcus, the occipitotemporal region involving the posterior aspects of the middle and inferior temporal gyri and the anterior aspect of the middle occipital gyrus, the inferior occipital gyrus, and the lingual gyrus. These findings indicate that the nature of the remedial educational intervention is critical to successful outcomes in children with reading disabilities and that the use of an evidence-based reading intervention facilitates the development of those fast-paced neural systems that underlie skilled reading. Findings indicate that a phonologically based reading intervention leads to the development of neural systems in anterior (inferior frontal gyrus) and posterior (middle temporal gyrus) brain regions. This is the first imaging study of a reading intervention in children or adults that reports its effects on reading fluency, a critical but often neglected reading skill [National Reading Panel, 2000]. It is also the largest imaging study of a reading intervention and the first report of the effects of a reading intervention on fMRI in children that examined readingdisabled children who received an experimental reading intervention and reading-disabled children who did not receive such an intervention. Previous studies on the effects of a reading intervention on neural systems in reading disability were informative but limited to smaller studies in adults and magnetoencephalography and magnetic resonance spectroscopy in children and an fMRI study in solely readingdisabled children without a nonexperimental comparison group. Two studies from the same investigative group have used fMRI to examine the effects of a commercial reading program (Fast Forword), first in adults and then in children with dyslexia. The first study examined three adults with dyslexia who received Fast Forword training during a task

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requiring that subjects respond to a high-pitched stimulus [Temple et al., 2000]. After 33 training days, two of the three subjects demonstrated greater activation in the left prefrontal cortex after training compared with before training. These two adults also demonstrated improvement on rapid auditory processing and auditory language comprehension after training; the one adult who did not demonstrate a change in fMRI after training failed to exhibit behavioral changes. In a later study, immediate short-term improvement in reading accuracy and brain activation changes were observed in 20 children with dyslexia, changes that included the areas observed in our study, as well as changes in the right hemisphere and cingulate cortex [Temple et al., 2003]. Richards and colleagues [2000] used proton MR spectroscopy to measure brain lactate concentrations at two time points, 1 year apart, in eight dyslexic and seven control boys before and after 3 weeks of a phonologically based reading intervention. Before treatment, dylexic boys demonstrated increased lactate concentration (compared with controls) in the left anterior quadrant during a phonologic task. After treatment, brain lactate concentrations were no different in the dyslexic and control boys, and reading improved after treatment. This same group reported fMRI changes in areas similar to those reported here after 28 hours of an intensive phonologic and morphologic reading intervention [Aylward et al., 2003]. Simos and colleagues [2002] used magnetoencephalography (MEG) in eight children with dyslexia and eight controls before and after 8 weeks of a phonologically based reading intervention. Before intervention, the dyslexic readers demonstrated little or no activation of the posterior portion of the superior temporal gyrus. After intervention, reading improved, and activation increased in the left superior temporal gyrus. These findings of a reading intervention suggesting plasticity of the neural systems for reading in children parallel those observed after a variety of therapies in individuals with stroke [Carey et al., 2002] and after surgical removal of a hemisphere in a child with Rasmussen’s syndrome [HertzPennier et al., 2002]. It is reasonable to suppose that these differences in plasticity reflect Gilbert’s view [Gilbert et al., 2001] that the “ability of a given brain structure to participate in alteration of topography depends on a preexisting framework of connections” and that this framework changes with maturation. The effects of the experimental intervention on promoting skilled reading and on the activation of the occipitotemporal word-form area shown to be critical for skilled reading [Shaywitz et al., 2002] are similar to the co-occurrence of visuospatial proficiency and cortical specialization reported in adults. Gauthier and associates [Gauthier, 2000; Gauthier et al., 2000] demonstrated a progressive increase of activation of the right hemisphere fusiform face area and right lateral occipital cortex with increasing proficiency in identifying novel facelike stimuli they called Greebles. Findings suggest that, as in recognition of Greebles, an intervention that improved proficiency in reading was the most important element in functional reorganization of the neural systems for reading. Such findings have important implications for understanding the effect on neural systems of phonologically based reading programs for young children that have been demonstrated to be effective in the educational equivalent of clinical trials [National Reading Panel, 2000].

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In summary, these data demonstrate that an intensive, evidence-based reading intervention brings about significant and durable changes in brain organization such that brain activation patterns resemble those of typical readers with the appearance of the left occipitotemporal area and improvement in reading fluency. These data have important implications for public policy regarding teaching children to read: The provision of an evidence-based reading intervention at an early age improves reading fluency and facilitates the development of neural systems that underlie skilled reading.

Types of Reading Disability Using data from participants in a longitudinal epidemiologic study, the neural systems for reading were examined in two groups of young adults who were poor readers as children— a relatively compensated group and a group with persistent reading difficulties—and compared them with nonimpaired readers [Shaywitz et al., 2003]. These studies also determined whether there were factors distinguishing the compensated from persistently poor readers that might account for their different outcomes. The availability of a cohort who are participants in the Connecticut Longitudinal Study, a representative sample of now young adults who have been prospectively followed since 1983, when they were 5 years old, and who have had their reading performance assessed yearly throughout their primary and secondary schooling was used in these studies [Shaywitz et al., 1990, 1992a, 1999]. Three groups of young adults, between the ages 18.5 and 22.5 years, were classified as follows: 1. Persistently poor readers (n = 24) if they met criteria for poor reading in second or fourth grade and again in grade 9 or 10 2. Accuracy (but not fluency) improved (compensated) readers (n = 19) if the subject satisfied criteria for poor reading in second or fourth grade and not in grade 9 or 10 3. Nonimpaired readers (n = 27) were selected on the basis of not meeting the criteria for poor reading in any of the grades 2 to 10; having a reading standard score higher than 94 (i.e., above the 40th percentile) to prevent overlap with the persistently poor readers and accuracy-improved readers; and having average full-scale IQ lower than 130 to avoid a supernormal control group. Findings during pseudoword rhyming in both groups of poor readers were similar to those observed in previous studies; relative underactivation occurred in posterior neural systems located in the superior temporal and the occipitotemporal regions. However, when reading real words, findings were quite surprising. Brain activation patterns in the accuracy-improved readers and persistently poor readers diverged. As they had for the nonword rhyme reading task, compared with nonimpaired subjects, the accuracy-improved readers demonstrated relative underactivation in left posterior regions (Fig. 35-5, AIR). In contrast, during real word reading, persistently poor readers activated posterior systems (see Fig. 35-5, PPR); there was comparable activation in nonimpaired and persistently poor readers in the posterior reading systems, findings that were new and unexpected. Despite the significantly better reading

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Reading real words FIGURE 35-5. Composite maps demonstrate brain activation in nonimpaired (NI), accuracy-improved (AIR), and persistently poor (PPR) readers during the real word reading task. The slice locations correspond to z levels of –4 in the Talairach and Tournoux atlases [Talairach and Tournoux, 1988]. After standard magnetic resonance imaging nomenclature, the right side of the axial slice corresponds to the left hemisphere. Brain activation occurs in the following regions: 1, inferior frontal gyrus; 2, precentral gyrus; 3, insula; 4, superior temporal gyrus and superior temporal sulcus; 5, middle temporal gyrus and superior temporal sulcus; 6, cuneus; 7, middle occipital gyrus; 8, anterior cingulate sulcus and adjacent aspects of the cingulate gyrus and superior frontal gyrus; 9, posterior middle temporal gyrus and anterior middle occipital gyrus; 10, anterior aspect of the superior temporal gyrus; 11, inferior occipital gyrus; 12, middle temporal gyrus; 13, superior frontal gyrus; 14, posterior cingulate gyrus; 15, lingual gyrus; 16, medial occipital temporal gyrus (parahippocampal region); 17, basal ganglia. (Adapted from Shaywitz S, Shaywitz B, Fulbright R, et al. Neural systems for compensation and persistence: Young adult outcome of childhood reading disability. Biol Psychiatry 2003;54:25. Copyright 2003. Reprinted with permission from the Society of Biological Psychiatry.)

performance by nonimpaired readers compared with persistently poor readers on every reading task administered, left posterior reading systems were activated during reading real words in nonimpaired subjects and persistently poor readers. It was hypothesized that the persistently poor readers were reading real words very differently from nonimpaired readers, reading the very simple real words primarily by memory. Support for this belief came from their performance on a word pronunciation task when not undergoing fMRI studies. Persistently poor readers were accurate while

reading high-frequency words, but they were far less accurate when reading low-frequency and unfamiliar words. Further support for this hypothesis comes from a functional connectivity analysis. This strategy involves interrogating a “seed voxel” (in this case, a voxel in the left occipitotemporal region) and determining the regions most functionally related to the seed voxel [McIntosh et al., 1996, 1997]. It was hypothesized that in nonimpaired readers the occipitotemporal region processes print in a linguistically structured manner and should interact with other areas implicated in orthographic and phonologic processing. It was

FIGURE 35-6. Group connectivity profiles between the “seed voxel” in the left occipitotemporal region (Talairach coordinates -55, -36, -5) and other brain regions during the real word reading task. The images correspond to z = +24 in Talairach space. In the nonimpaired (NI) readers (left), a strong positive correlation is observed between the left occipitotemporal region and the left inferior frontal gyrus (i.e., Broca’s area), a traditional language region. In contrast, for persistently poor readers, the occipitotemporal region correlates with regions in the right superior, middle, and inferior frontal gyri, brain regions believed to play a role in attention and memory. (From Shaywitz S. Overcoming dyslexia: A new and complete science-based program for reading problems at any level. New York: Alfred A Knopf, 2003.)

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further hypothesized that in persistently poor readers, the occipitotemporal area serves as a visually based memory system and should interact with other areas implicated in memory retrieval. Results indicated that nonimpaired readers demonstrated connectivity between the left occipitotemporal seed region and the left inferior frontal gyrus, a traditional language region (Fig. 35-6, NL). In contrast, persistently poor readers (see Fig. 35-6, PPR) demonstrated functional connectivity between the seed region and right prefrontal areas often associated with working memory and memory retrieval [Fletcher et al., 1997; MacLeod et al., 1998], a finding consistent with the hypothesis that in persistently poor readers, the occipitotemporal area functions as a component of a memory network. Insight into some of the factors responsible for compensation on the one hand and persistence on the other comes from an examination of the early childhood measures. The two groups of disabled readers (i.e., accuracy-improved readers and persistently poor readers) began school with comparable reading skills but with persistently poor readers compared with accuracy-improved readers having poorer cognitive ability. There was a trend for persistently poor readers to come from families with lower socioeconomic status and to attend more disadvantaged schools. These findings suggest that the persistently poor readers may be doubly disadvantaged in perhaps being exposed to a less rich language environment at home [Hart and Risley, 1995] and then having less effective reading instruction at school. In contrast, the presence of compensatory factors such as stronger cognitive ability allowed the accuracy-improved readers to minimize in part the consequences of their phonologic deficit so that as adults, accuracy-improved readers were indistinguishable from nonimpaired readers on a measure of reading comprehension and a measure of prose literacy. These findings are consonant with a large body of evidence indicating that the impact of dyslexia can be modified by the availability of compensatory resources, such as semantic knowledge [Snowling, 2000], use of context [Frith and Snowling, 1983; Nation and Snowling, 1997], and verbal ability [Torgesen et al., 2001], to compensate for phonologic deficits. In adults, verbal abilities, as measured by verbal IQ, directly predict reading accuracy, with phonologic factors influencing reading indirectly through their effects on verbal IQ [Berninger et al., 2001]. Study findings demonstrate that childhood cognitive ability may be an important influence on the development of reading skills in later childhood and into adult life. Beginning reading is most related to phonologic skills, and within a few years, other language skills, such as semantic knowledge, gain in importance. The findings suggest that greater cognitive abilities may provide some degree of compensation for a reading difficulty; intuitively, this supposition makes sense because a larger vocabulary and better reasoning skills are helpful when struggling readers are trying to decipher unknown words. If the word is in their spoken language vocabulary, the beginning readers may recognize the words even if they can only partially sound them out. Strong reasoning abilities also help the reader to use the context around an unknown word to figure out its meaning. The imaging findings described earlier that demonstrate a greater number of ancillary systems in accuracy-improved readers compared with persistently poor readers may represent the neural correlates of this compensation.

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For the first time, results from functional brain imaging studies have distinguished two potential types of reading disability. These types are consistent with Olson’s suggestion of two possible causes for childhood reading disability: a primarily genetic type with IQ scores above 100 and a more environmentally influenced type with IQs below 100 [Olson, 1999; Olson et al., 1999; Wadsworth et al., 2000]. Although genetic and environmental factors play a role in reading in all children, it is intriguing to speculate that the accuracy-improved readers may represent a predominantly genetic type and that the persistently poor readers, with significantly lower IQ and a trend to come from lower socioeconomic status families and to attend more disadvantaged schools, may represent a more environmentally influenced type of dyslexic reader. It is possible that in young adults, the neural system differences between these groups may not have been recognized before, because previous functional imaging studies have generally focused on the compensated dyslexics who, with appropriate accommodations, are more successful academically and are able to enter university [Brunswick et al., 1999; Paulesu et al., 2001], whereas the environmentally influenced poor readers rarely attend university and may not readily come to the attention of investigators. These findings have important educational implications and are of special relevance for teaching children to read. Consistent with our knowledge of the components of reading, children need to be able to sound out words to decode them accurately, and then they need to know the meaning of the word to help decode and comprehend the printed message. The sounds and the meanings of words must be taught. These findings suggest that it may be beneficial to provide early interventions aimed at stimulating phonologic and verbal abilities in children at risk for reading difficulties associated with disadvantage.

DIAGNOSIS At all ages, dyslexia is a clinical diagnosis. The clinician seeks to determine through history, observation, and psychometric assessment if there are unexpected difficulties in reading (i.e., difficulties in reading that are unexpected for the person’s age, intelligence, or level of education or professional status) and associated linguistic problems at the level of phonologic processing. There is no one single test score that is pathognomonic of dyslexia. As with any other medical diagnosis, the diagnosis of dyslexia should reflect a thoughtful synthesis of all the clinical data available. Dyslexia is distinguished from other disorders that may prominently feature reading difficulties by the unique, circumscribed nature of the phonologic deficit, one not intruding into other linguistic or cognitive domains. In the preschool child, a history of language delay or of not attending to the sounds of words (e.g., trouble learning nursery rhymes or playing rhyming games with words, confusing words that sound alike, mispronouncing words) and trouble learning to recognize the letters of the alphabet, along with a positive family history, represent important risk factors for dyslexia. In the school-aged child, presenting complaints most commonly center about school performance,

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“she’s not doing well in school,” and often parents (and teachers) do not appreciate that the reason is a reading difficulty. A typical picture is that of a child who may have had a delay in speaking, does not learn letters by kindergarten, has not begun to learn to read by first grade, and has difficulty consistently sounding out words. The child progressively falls behind, with teachers and parents puzzled about why such an intelligent child may have difficulty learning to read. The reading difficulty is unexpected with respect to the child’s ability, age, or grade. Even after acquiring decoding skills, the child usually remains a slow reader. Bright dyslexic children may laboriously learn how to read words accurately, but they do not become fluent readers because they do not recognize words rapidly and automatically. Dysgraphia and spelling difficulties are often present and accompanied by laborious note taking. Selfesteem is frequently affected, particularly if the disorder has gone undetected for a long period (Box 35-1) [Shaywitz, 2003]. In an accomplished adolescent or young adult, dyslexia is often reflected by slowness in reading or choppy reading aloud that is unexpected in relation to the level of education or professional status, such as graduation from a competitive college or completion of medical school and a residency. In bright adolescents and young adults, a history of phonologically based reading difficulties, requirements for extra time on tests, and current slow and effortful reading (i.e., signs of a lack of automaticity in reading) are the sine qua non of a diagnosis of dyslexia. In summary, at all ages, a history of difficulties getting to the basic sounds of spoken language, of laborious and slow reading and writing, of poor spelling, and of requiring additional time in reading and in taking tests provides indisputable evidence of a deficiency in

Box 35-1 CLUES TO DYSLEXIA BEGINNING IN SECOND GRADE

From Shaywitz S. Overcoming dyslexia. New York: Alfred A Knopf, 2003:123–124.

phonologic processing, which serves as the basis for and the signature of a reading disability.

Assessment of Pre-reading and Reading Even before the time a child is expected to read, a child’s readiness to read may be assessed by measurement of the skills, especially phonologic, related to reading success. After a predictable developmental pathway, children’s phonologic abilities can be evaluated beginning at about age 4 years. Such tests mainly are centered on a child’s ability to focus on phonemes, the basic particles of spoken language. Initial tests typically ask what word rhymes with another or what spoken word begins (or ends) with the same sound as another. At more advanced levels, tests ask children to pronounce a spoken word after a sound is removed, such as “can you say steak without the t sound” (sake)” or “can you count the number of sounds you hear in man” (three sounds). In general, as a child develops, he or she gains the ability to notice and to manipulate smaller and smaller parts of spoken words. Tests of phonologic capabilities and reading readiness are becoming increasingly available; one such test is the Comprehensive Test of Phonological Processing in Reading (CTOPR, PRO-ED), which is nationally standardized for age 5 through adult years. In addition to phonology, knowledge of letter names and sounds are the strongest predictors of a child’s readiness to read. An appropriate battery of tests for the early recognition of reading problems includes tests of phonology, letter names and sounds, vocabulary, print conventions, and listening comprehension. Tests of reading are also useful because they allow comparison of a child’s reading skills with his peers at a time when he should be beginning to read [Shaywitz, 2003]. Tests of intelligence are relatively poor predictors of later reading difficulties or of response to reading interventions. The importance of such early assessments is that they can identify at-risk children early on so that these boys and girls can be provided with the highly effective, evidence-based reading interventions now available. Reading is assessed by measuring decoding (i.e., accuracy), fluency, and comprehension. In the school-age child, one important element of the evaluation is how accurately the child can decode words (i.e., read single words in isolation). This element is measured with standardized tests of single real word and pseudoword reading such as the Woodcock-Johnson III (Riverside) and the Woodcock Reading Mastery Tests (American Guidance Service). Pseudoword reading, measuring the ability to decode nonsense or made-up words, is a particularly useful test. Because the words are made-up, the child has not seen them before and therefore could not have memorized the words, each nonsense word must be sounded out. Tests of nonsense word reading are referred to as word attack. Silent reading comprehension may be assessed by the Woodcock test. Reading fluency, the ability to read accurately, rapidly, and with good intonation, is a critical but often overlooked component of reading. The ability to read words fluently is an indication that these words are read automatically, without the need to apply attentional resources. Fluency is generally assessed by asking the child to read aloud using the Gray Oral Reading Test (GORT, American Guidance Service). This test consists of 13 increasingly difficult passages, each followed by five

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comprehension questions; scores for accuracy, rate, fluency, and comprehension are provided. Such tests of oral reading are particularly helpful in identifying a child who is dyslexic; by its nature, oral reading forces a child to pronounce each word. Listening to a struggling reader attempt to pronounce each word leaves no doubt about the child’s reading difficulty. In addition to reading passages aloud, single-word reading efficiency may be assessed using the Test of Word Reading Efficiency (TOWRE, PRO-ED), a test of speeded oral reading of individual words. Children who struggle with reading often have trouble spelling. In reading, the written word is decoded into its constituent sounds; in spelling, sounds in a spoken word are encoded into letters. The Wide Range Achievement Test, Revised (WRAT-R, Wide Range) and the Test of Written Spelling-4 (PRO-ED) are among the tests that measure spelling. The role of intelligence testing in dyslexia is controversial. The traditional IQ-achievement discrepancy is referred to as a wait to fail model; that is, it typically takes a child 3 years to develop a large enough discrepancy to qualify for school services and thereby serves to delay early identification and effective reading intervention. Measures of intelligence can be helpful as one component of a comprehensive assessment. They often demonstrate areas of strength, particularly in areas of abstract thinking and reasoning, which are reassuring to parents and especially to the child. They also indicate that the reading difficulty is isolated and not reflective of a general lack of learning ability. With our current increased understanding of the phonologic basis of dyslexia, it is inappropriate to wait for a large IQ-reading discrepancy before providing a child with reading intervention. If the clinical picture, including history of spoken language difficulties, difficulties getting to the sounds of written words, problems reading or spelling words, despite good intelligence, motivation, and appropriate reading instruction converge with indications of reading and phonologic weaknesses in a school-age child, she or he should be eligible to receive school-based reading interventions. For informal screening by primary care physicians in an office setting, it is recommended that the physician listen to the child read aloud from his own grade-level reader. Keeping a set of graded readers available in the office serves the purpose and does not require children to bring their own schoolbooks. Oral reading is a very sensitive measure of reading accuracy and reading fluency. A set of read-aloud paragraphs appropriate for children in the primary grades can be found in Appendix 35-1. The most consistent and telling sign of a reading disability in an accomplished young adult is slow and laborious reading and writing. Failure to recognize or to measure the lack of automaticity in reading may be the most common error in the diagnosis of dyslexia in older children and in accomplished young adults. Simple word identification tasks cannot detect a dyslexic accomplished enough to be in honors high school classes or to graduate from college and attend law, medical, or any other graduate-degree school. Tests relying on the accuracy of word identification alone are inappropriate to use to diagnose dyslexia in accomplished young adults; tests of word identification reveal little or nothing of his struggles to read. It is important to recognize that, because they assess reading accuracy but not automaticity (speed), the kinds of reading tests commonly

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APPENDIX 35-1 Three reading samples are provided [Hiebert, 2003]. They can be photocopied and given to young patients as reading tests for informal screening of dyslexia during an office visit. The superscripted numbers indicate word counts.

Reading Sample for Children Beginning Second Grade OFFICE JOBS There are many kinds of offices. However, most people who work in offices spend their time inside. One kind of office is a25 bank. People keep their money in banks. Another kind of office is a doctor’s office. People go to doctors’ offices when they are sick. People50 who work in offices often work in teams. In banks, teams keep the money safe. In doctors’ offices, teams make sure that sick people get75 the help they need. In offices, everyone on a team works together to get the job done.92

Reading Sample for Children in Second Grade JOBS THAT HELP YOU There are many people who do jobs that help you. You see and talk to some of these people, such as25 your teacher or doctor. Teachers help you learn. Doctors help you stay well. You don’t see all the people who do jobs that help you.50 You are not likely to see the people who built your school or the writers of the books you read. You are not likely to75 see the people who make the pens you use to write or the paper on which you write. Around the world, many people are doing jobs that help you.104

Reading Sample for Children in Third Grade SELLING THINGS Many companies don’t sell their bikes to people. They sell their bikes to stores. Then these stores sell the bikes to people. Store25 owners need to have money to pay a company for the bikes. Store owners also need a place to sell the bikes. They need sales50 people to help people choose a bike. Store owners need to pay their sales people, too. Store owners also need to set the price of75 a bike. This price should be more than the store owner paid for it. However, the bike should cost the same as or less than100 bikes in other stores. After all, many people compare different stores’ prices.112 From Hiebert, 2003. ©2003 by Pearson Education, Inc. Used by permission.

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used for school-age children may provide misleading data on bright adolescents and young adults. The most critical tests are those that are timed; they are the most sensitive to a phonologic deficit in a bright adult. However, there are very few standardized tests for young adult readers that are administered under timed and untimed conditions; the Nelson-Denny Reading Test represents an exception. Any scores obtained on testing must be considered relative to peers with the same degree of education or professional training.

Physical and Neurologic Examination and Laboratory Tests A general physical examination has a very limited role in the evaluation of individuals with dyslexia. Primary sensory impairments should be ruled out, particularly in young children. In specific instances, examination for the features of sexlinked genetic disorders such as Klinefelter’s syndrome that may be associated with language and reading problems may also be productive. Otherwise, the examination should be governed by any nondyslexic symptoms that indicate specific areas of concern. Results of the routine neurologic examination are usually normal for children who are dyslexic. Laboratory measures such as imaging studies, electroencephalograms, or chromosome studies are ordered only if there are specific clinical indications. Functional imaging is currently restricted to research studies and is not to be used for clinical diagnosis.

OUTCOME: PHONOLOGIC DEFICIT IN ADOLESCENCE AND ADULT LIFE Deficits in phonologic coding continue to characterize dyslexic readers even in adolescence; performance on phonologic processing measures contributes most to discriminating between dyslexic and average adolescent readers and average and superior adolescent readers as well [Shaywitz et al., 1999]. Dyslexia does not spontaneously remit, nor do these children demonstrate a lag mechanism for “catching up” in the development of reading skills. However, many dyslexic readers can become quite proficient in reading a finite domain of words that recur in their area of special interest, usually words that are important for their careers. For example, an individual who is dyslexic in childhood may in adult life become interested in molecular biology and learn to decode words that form a minivocabulary important in molecular biology. Such an individual, although able to decode words in this domain, still exhibits evidence of his early reading problems when reading unfamiliar words, which then are read accurately but not fluently and automatically [Ben- Dror et al., 1991; Bruck, 1992, 1994; Lefly and Pennington, 1991; Shaywitz et al., 1999]. Because they are able to read words accurately (albeit very slowly), dyslexic adolescents and young adults may mistakenly be assumed to have “outgrown” their dyslexia. Data from studies of children with dyslexia who have been followed prospectively support the notion that in adolescents, the rate of reading and the facility with spelling may be most useful clinically in differentiating average from poor readers in students in secondary school, college, and even graduate school. These older dyslexic students may be similar to their unimpaired peers on untimed

measures of word recognition but continue to suffer from the phonologic deficit that makes reading less automatic, more effortful, and slow. For these readers with dyslexia, the provision of extra time is an essential accommodation; it allows them the time to decode each word and to apply their unimpaired higher-order cognitive and linguistic skills to the surrounding context to get at the meaning of words that they cannot entirely or rapidly decode. Other accommodations useful to adolescents with reading difficulties include the use of note-takers, taping classroom lectures, using Recordings for the Blind to access texts and other books they have difficulty reading, and the opportunity to take tests in alternate formats, such as short essays or even orally [Shaywitz, 2003].

TREATMENT The management of dyslexia demands a life-span perspective. Early on, the focus is on remediation of the reading problem. As a child matures and enters the more timedemanding setting of secondary school, the emphasis shifts to incorporate the important role of providing accommodations. Effective intervention programs provide children with systematic instruction in each of the critical components of reading and practice that is aligned with that instruction. The goal is for children to develop the skills that will allow them to read and understand the meaning of familiar and unfamiliar words they may encounter. As in other areas of medicine, knowledge is being accrued to inform the practice of evidence-based education. In 1998, the U.S. Congress, concerned about what appeared to be an epidemic of poor reading nationally, mandated that a National Reading Panel be formed. A major goal was to review the literature on teaching reading and to identify which specific methods and approaches are most effective. In April, 2000, the National Reading Panel issued its Report of the National Reading Panel—Teaching Children to Read: An Evidencebased Assessment of the Scientific Research Literature on Reading and Its Implications for Reading Instruction [National Reading Panel, 2000]. Based on a prior consensus report from the National Research Council [Snow et al., 1998] and on the results of its own analysis, the National Reading Panel reported that five critical elements were necessary to effectively teach reading: phonemic awareness (i.e., ability to focus on and manipulate phonemes, speech sounds, in spoken syllables and words); phonics (i.e., understanding how letters are linked to sounds to form lettersound correspondences and spelling patterns); fluency; vocabulary; and comprehension strategies. The National Reading Panel emphasized that these elements must be taught systematically and explicitly, rather than in a more casual, fragmented, or implicit manner. Such systematic phonics instruction is more effective than “whole word” instruction, which teaches little or no phonics or teaches phonics haphazardly or in a “by-the-way” approach. Fluency is of critical importance because it allows for the automatic, attention-free recognition of words, permitting these attentional resources to be directed to comprehension. Although it is generally recognized that fluency is an important component of skilled reading, it is often neglected in the classroom. The most effective method to build reading

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fluency is a procedure referred to as guided repeated oral reading. The teacher models reading a passage aloud, and the student rereads the passage repeatedly to the teacher, another adult, or a peer, receiving feedback until he or she is able to read the passage correctly. The evidence indicates that guided repeated oral reading has a clear and positive impact on word recognition, fluency, and comprehension at a variety of grade levels and applies to all students—good readers and those experiencing reading difficulties. The evidence is less secure for programs for struggling readers that encourage large amounts of independent reading (i.e., silent reading without any feedback to the student). Even though independent silent reading is intuitively appealing, the evidence is insufficient to support the notion that reading fluency improves in struggling readers. No doubt there is a correlation between being a good reader and reading large amounts; however, there is a paucity of evidence indicating that there is a causal relationship such that poor readers who read more will become more fluent. In contrast to teaching phonemic awareness, phonics, and fluency, interventions for reading comprehension are not as well established. In large measure, this reflects the nature of the very complex processes influencing reading comprehension. The limited evidence indicates that the most effective methods to teach reading comprehension involve teaching vocabulary and strategies that encourage an active interaction between reader and text. Large-scale studies have focused on younger children, and there are few or no data available on the effect of these training programs on older children. The data on younger children are extremely encouraging, indicating that using evidence-based methods can remediate and even prevent reading difficulties in primary school–aged children [Foorman et al., 2003; Shaywitz, 2003; Torgesen et al., 1999]. An essential component of the management of dyslexia in students in secondary school, college, and graduate school incorporates the provision of accommodations. High school and college students with a history of childhood dyslexia often present a paradoxical picture; they are similar to their unimpaired peers on measures of word recognition and comprehension, but they continue to suffer from the phonologic deficit that makes reading less automatic, more effortful, and slow. Neurobiologic data provide strong evidence for the necessity of extra time for readers with dyslexia. Functional MRI data demonstrate a disruption in the word-form area, the region supporting rapid reading. Readers compensate by developing anterior systems bilaterally and the right homolog of the left word-form area. Such compensation allows for accurate reading, but it does not support fluent or rapid reading [Shaywitz et al., 2002]. For these readers with dyslexia, the provision of extra time is an essential accommodation; it allows them the time to decode each word and to apply their unimpaired higher-order cognitive and linguistic skills to the surrounding context to get at the meaning of words that they cannot entirely or rapidly decode. Although providing extra time for reading is by far the most common accommodation for people with dyslexia, other helpful accommodations include allowing the use of lap-top computers with spelling checkers, tape recorders in the classroom, and recorded books (materials are available from Recording for the Blind and Dyslexic, 800-221-4792) and

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providing access to syllabi and lecture notes, tutors to “talk through” and review the content of reading material, alternatives to multiple-choice tests (e.g., reports or orally administered tests), and a separate, quiet room for taking tests [Shaywitz, 2003]. With such accommodations, many students with dyslexia are successfully completing studies in a range of disciplines, including medicine. It is important to appreciate that phonologic difficulties in dyslexia are independent of intelligence. Many highly intelligent boys and girls have reading problems that are often overlooked and even ascribed to “lack of motivation.” In counseling their patients who are dyslexic, physicians should bear in mind that many outstanding writers, lawyers, physicians, and scientists, including at least two Nobel laureates (Niels Bohr in physics and Baruj Benacerraf in physiology or medicine), were dyslexic [Shaywitz, 2003]. People with dyslexia and their families frequently consult their physicians about unconventional approaches to the remediation of reading difficulties; there are very few credible data to support the claims made for these treatments, such as optometric training, medication for vestibular dysfunction, chiropractic manipulation, and dietary supplementation. Physicians should be aware that there is no one program that remediates reading difficulties; a number of programs following the guidelines provided earlier have proved to be highly effective in teaching struggling children to read.

CONCLUSIONS AND IMPLICATIONS Within the last 2 decades, overwhelming evidence from many laboratories has converged to indicate the cognitive basis for dyslexia. Dyslexia represents a disorder within the language system and, more specifically, within a particular subcomponent of that system, phonologic processing. Advances in imaging technology and the development of tasks that sharply isolate the subcomponent processes of reading allow the localization of phonologic processing in brain and provide for the first time the potential for elucidating a biologic signature for reading and reading disability. Results from laboratories using functional brain imaging indicate a disruption of left hemisphere posterior brain systems in childhood and adult dyslexic readers while performing reading tasks with an additional suggestion for an associated increased reliance on ancillary systems, such as those in the frontal lobes and right hemisphere posterior circuits. The discovery of neural systems serving reading has significant implications. At the most fundamental level, it is possible to investigate specific hypotheses regarding the neural substrate of dyslexia and to verify, reject, or modify suggested cognitive models. From a clinical perspective, the identification of neural systems for reading offers the promise for more precise identification and diagnosis of the problem and for better targeted and more effective treatment of dyslexia in children, adolescents, and adults. ACKNOWLEDGMENTS The work described in this chapter was supported by grants from the National Institute of Child Health and Human Development (PO1 HD 21888 and P50 HD25802). The authors thank Chaz

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Hyseni for his help in preparing this chapter, portions of which appeared in or are similar to other reviews by us [Shaywitz, 1998, 2003; Shaywitz and Shaywitz, 2003, 2004a, 2004b, 2004c].

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CHAPTER 36

Attention-Deficit–Hyperactivity Disorder David E. Mandelbaum

Attention-deficit–hyperactivity disorder (ADHD) has been described as the most common neurobehavioral disorder in childhood [Cantwell, 1996]. Prevailing opinion characterizes ADHD as a disorder of executive function attributable to abnormal dopamine transmission in the frontal lobes and frontostriatal circuitry. In large part, this concept is based on the clinical efficacy of medications affecting catecholamine transmission in these regions. The first reference to behavior now associated with ADHD was by George Still in 1902, who referred to a deficit of “moral control.” Within the context of this broad concept, he made the following observation: “A notable feature in many of these cases of moral deficit without general impairment of intellect is a quite abnormal incapacity for sustained attention” [Still, 1902]. Strauss and Lehtinen [1947] used the term minimal brain damage syndrome to describe children with cognitive and behavioral deficits. In 1962, Clements and Peters coined the term minimal brain dysfunction to describe functional abnormalities in children in whom brain damage could not be demonstrated. Although widely accepted, this concept came under immediate challenge as including too heterogeneous a group of children [MacKeith, 1963]. The subsequent emphasis on attention and its neurologic substrate, the frontal lobe and frontostriatal circuitry, represents a refinement of the definition of the condition.

DIAGNOSIS OF ATTENTION-DEFICIT–HYPERACTIVITY DISORDER ADHD is a clinical diagnosis based on criteria in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (Box 36-1). Criteria are divided into two lists of symptoms, one for inattention and another for hyperactive-impulsive behavior. Based on the number of items identified, there are three classifications: ADHD/I (primarily inattentive type), ADHD/HI (primarily hyperactive-impulsive type), and ADHD/C (combined type). The revised diagnostic criteria of DSM-IV, with the inclusion of the three subtypes, increased the number of females, preschoolers, and adults with ADHD [Lahey et al., 1994]. Increased numbers in these groups resulted in an increase in the prevalence of ADHD from 3% to 5% with the DSM-III-R to about 12%; ADHD/I alone has been estimated to have a prevalence between 5.4% and 9% [Baumgaertel et al., 1995; Wolraich et al., 1996]. It has been proposed that the core deficit in ADHD is impairment of behavioral inhibition, which leads to the other symptoms of ADHD (Fig. 36-1). This model of impaired behavioral inhibition is limited to ADHD/HI and ADHD/C (i.e., those with hyperactive or impulsive symptoms) and excludes from this model children with ADHD/I (i.e., those

with inattention only) [Barkley, 1997]. The observation that overflow movements was the most discriminating finding between hyperactive boys (without learning disabilities) and normal control subjects seems to support the concept of impaired behavioral inhibition [Denckla and Rudel, 1978]. If this formulation is widely accepted, future classifications may call for separate diagnostic entities, such as attentiondeficit disorder and behavioral-inhibition disorder. Some investigators have proposed that all three ADHD subtypes can be explained as disorders of attention or executive function (other than response inhibition), with symptoms of hyperactivity and impulsivity resulting from these impairments [Brown, 2000; Chhabildas et al., 2001; Weiss and Weiss, 2002]. Others also distinguish ADHD/HI and ADHD/C from ADHD/I, but they posit that the symptoms of hyperactivity and impulsivity can result from poor inhibitory control or differences in motivational style characterized by delay aversion [Sonuga-Barke, 2002]. The use of the word often in the list of symptoms, coupled with the qualification “to a degree that is maladaptive and inconsistent with developmental level,” lends an element of subjectivity to this diagnostic schema. Symptom rating scales for parents and teachers have been developed to assist in the ascertainment of diagnostic criteria [Connors, 1997]. The use of broader rating scales, such as the Child Behavior Checklist, provides information regarding the presence of other disorders, such as conduct disorder, oppositional defiant disorder (ODD), and anxiety disorder [Achenbach, 1991; Vaughn et al., 2000], which may warrant diagnoses other than ADHD [Jensen et al., 1997]. The Yale Children’s Inventory was developed to ascertain the presence of attentional deficits and learning disabilities [Shaywitz et al., 1986]. A comprehensive review of evaluation issues in ADHD concluded that no single test can be used to make the diagnosis and that it is up to the clinician “to choose a battery of measures that satisfies what is, to some degree, an individually determined level of diagnostic certainty” [Nass, 2005]. The American Academy of Pediatrics has endorsed the Vanderbilt ADHD rating scales for parents and teachers [Wolraich et al., 2003a, 2003b] and has provided a complete “tool kit,” including a cover letter to teachers and scoring information, on the internet [www.nichq.org/resources/toolkit]. Developmental variability in the presentation of ADHD and the inconsistency of behavior of children with ADHD in different settings and at different times in the same setting add to the diagnostic confusion. In preschool children, in particular, the prevalence of ADHD-type symptoms [Blackman, 1999; Palfrey et al., 1985] and the transient nature of such symptoms in many cases [Barkley, 1998] make this a difficult diagnosis. Efforts have been made to provide a more objective basis for the diagnosis of

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Box 36-1 DIAGNOSTIC CRITERIA FOR ATTENTION-DEFICIT–HYPERACTIVITY DISORDER

From Diagnostic and Statistical Manual (DSM-IV). American Psychiatric Association, 1994.

ADHD, such as computerized continuous performance tests [Conners, 1985] or tests of variables of attention [Greenberg, 1993]. However, the correlation of these measures of attention with the behavioral disorder is not sufficient for them to be used as replacements for the behavioral criteria of DSM-IV [Barkley, 1991]. The motor examination may help distinguish between children with a learning disorder and those with ADHD; it is best to evaluate a child between the ages of 5 years and the onset of puberty, a period of rapid change in motor development, when quantitative examination of the motor system, such as the Physical and Neurological Examination for Soft Signs (PANESS) [Denckla, 1985], may demonstrate evidence of motor disinhibition (Denckla, 2003).

CONTROVERSIES IN THE DIAGNOSIS OF ATTENTION-DEFICIT–HYPERACTIVITY DISORDER The DSM-IV clinical criteria for diagnosing ADHD (see Box 36-1) indicate a number of qualifications that are too often ignored, resulting in an incorrect diagnosis [American Psychiatric Association, 1994]. The text explicitly states that the findings need to be present “to a degree that is maladaptive and inconsistent with developmental level.” Behavior that may not be typical but is not maladaptive does not warrant a diagnosis of ADHD. Similarly, unreasonable expectations of a child at a young age may result in a false diagnosis. The diagnostic criteria are followed by a number of statements regarding the context of the symptoms. Item C states, “Some impairment from the symptoms is present

Internalization of speech Description and reflection Rule-governed behavior (instruction) Problem solving/selfquestioning Generation of rules and meta-rules Moral reasoning

Motor control/fluency/syntax Inhibiting task-irrelevant responses Executing goal-directed responses Execution of novel/complex motor sequences Goal-directed persistence Sensitivity to response feedback Task re-engagement following disruption Control of behavior by internally represented information

Self-regulation of affect/ motivation/arousal Emotional self-control Objectivity/social perspective-taking Self-regulation of drive and motivation Regulation of arousal in the service of goal-directed action

Reconstitution Analysis and synthesis of behavior Verbal fluency/behavioral fluency Goal-directed behavioral creativity Behavioral simulations Syntax of behavior

FIGURE 36-1. A schematic configuration of a conceptual model that links behavioral inhibition with the performance of the four executive functions that bring motor control, fluency, and syntax under the control of internally represented information. (From Barkley RA. Behavioral inhibition, sustained attention, and executive functions: Constructing a unifying theory of ADHD. Psychol Bull 1997;121:73. Copyright © 1997 by the American Psychological Association. Reprinted with permission.)

Working memory Holding events in mind Manipulating or acting on the events Imitation of complex behavior sequences Retrospective function (hindsight) Prospective function (forethought) Anticipatory set Sense of time Cross-temporal organization of behavior

Behavioral inhibition Inhibit prepotent response Stop an ongoing response Interference control

Mandelbaum / Attention-Deficit–Hyperactivity Disorder 873

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in two or more settings (e.g., at school [or work] and at home).” This provision allows for the possibility that a child in an inadequate school environment, perhaps with excessive class size, hostile peers, or inexperienced teachers, may present with findings that are unique to that setting rather than represent a disorder of attention. Similarly a chaotic home environment may explain the child’s presentation. Item D reiterates that “there must be clear evidence of clinically significant impairment in social, academic or occupational function.” Perhaps most important is item E, which states, “The symptoms do not occur exclusively during the course of a Pervasive Developmental Disorder, Schizophrenia, or other Psychotic Disorder and are not better accounted for by another mental disorder [e.g., Mood Disorder, Anxiety Disorder, Dissociative Disorder, or a Personality Disorder].” If a child has symptoms that meet the diagnostic criteria for ADHD in the context of these other disorders, treatment should be directed at these other conditions before concluding the child has a disorder of attention. Not addressed in item E of the DSM-IV criteria are studies that have demonstrated that children with specific neurologic disorders can present with symptoms that meet criteria for ADHD but are attributable to the neurologic disorder rather than a primary disorder of attention. A study by Walters and colleagues [2000] demonstrated symptoms of impaired attention and hyperactivity in children diagnosed with restless leg syndrome; treatment of the sleep disturbance resolved the socalled ADHD symptoms. Disordered breathing during sleep has also been found to manifest with symptoms consistent with ADHD [Gottlieb et al., 2003]. There are reports of children with focal epileptic discharges having symptoms suggestive of ADHD that resolved when the spike activity was suppressed with antiepileptic drugs [Holtmann et al., 2003; Laporte et al., 2002]. It seems reasonable that future versions of the DSM add neurologic disorders (e.g., sleep disorders, epilepsy) to the list of conditions in item E that should be excluded before ADHD is diagnosed. The question of conditions coexisting with ADHD is quite complex. Should a diagnosis of ADHD be reserved for individuals with an isolated disorder of attention, hyperactivity or impulsivity, with an alternative classification used to describe children who meet DSM-IV criteria for ADHD in the context of other neurodevelopmental problems? Denckla [2003] used the term pseudo-ADHD to describe children with comorbidities or confounding factors. In a paper describing a father and son both with orbitofrontal epilepsy and associated attention difficulties and hyperactivity, the term attention-deficit–hyperactivity syndrome was used to make a distinction from the specific disorder of ADHD [Powell et al., 1997], analogous to the distinction between Parkinson’s disease and parkinsonism. It has been proposed that ADHD be divided into subgroups based on the patterns of comorbidity [Biederman et al., 1991]. The presumption that a response to psychostimulant medication indicates that the underlying problem is ADHD can lead to an erroneous diagnosis. Psychostimulant medications can ameliorate depression [Janowsky, 2003], chronic fatigue syndrome [Turkington et al., 2004], and daytime somnolence caused by sleep disorders [Happe, 2003; Ivanenko et al., 2003] and enhance normal individuals’ cognitive functioning and behavior [Rapoport et al., 1978]. A positive response to psychostimulants has no diagnostic significance.

NEUROBIOLOGY OF ATTENTIONDEFICIT–HYPERACTIVITY DISORDER Advances in structural and functional imaging, clinical neurophysiologic techniques, and molecular genetics have been applied to the evaluation of children with ADHD and have provided important insights into this condition. However, inconsistency in the inclusion and exclusion criteria among studies, particularly related to comorbidity, limits comparisons between studies and their conclusions.

Structural Imaging Cortical Structures Reports of reductions in volume of prefrontal regions, more so in the right than left hemisphere, have been described in children with ADHD [Castellanos et al., 1996; Filipek et al., 1997]. A later study further localized involvement to prefrontal and premotor areas [Mostofsky et al., 2002]. In this study of 12 males with ADHD, children with conduct, mood, and anxiety disorders were excluded, but 3 children with coexistent ODD were included. A study involving other brain regions reported reductions in total cerebral volume with a negative correlation between gray matter volumes and symptom severity [Castellanos et al., 2002]. However, the impact of coexisting conditions on anatomic findings was not considered or described (i.e., it was unclear if there was an association between severity of symptoms and coexisting conditions). Serial examinations found that most volume differences between ADHD and control subjects remained stable; however, the size of the caudate nucleus, which initially was smaller in the ADHD group, became comparable with that in the control group during adolescence. This finding reflected a greater rate of reduction in caudate size in the normal than in the ADHD group. Normalization of the caudate nucleus in adolescents with ADHD may relate to the observation that ratings for hyperactivity and impulsivity are decreased in that age group compared with those in younger children [Hart et al., 1995].

Subcortical Structures Findings in the basal ganglia have been inconsistent, with reports of volume reductions in the right caudate nucleus and globus pallidus [Castellanos et al., 1996] or in the left caudate [Filipek et al., 1997]. The study by Castellanos and colleagues [1996] included children with “mild-moderate” conduct disorder (CD), ODD, anxiety disorder, and reading disorders. However, reanalysis of the data by excluding the children who had CD or ODD found a more robust correlation between volume reductions in the right prefrontal, caudate, and globus pallidus and ADHD. In the study by Filipek and co-investigators [1997], children with coexistent conditions were excluded. In addition to the anatomic differences between children with ADHD and control subjects, this study revealed differences in structural abnormalities between children with ADHD who were considered responders to psychostimulants and those who were not. A study of monozygotic twins discordant for ADHD [Castellanos et al., 2003] revealed reduced caudate volume in the affected

Mandelbaum / Attention-Deficit–Hyperactivity Disorder

twin. In another report on twins discordant for ADHD [Sharp et al., 2003], fathers of twins discordant for ADHD had lower ADHD scores than fathers of ADHD singletons. The rate of breech presentation was greater in affected twins than affected singletons. The data suggested that the discordant twins represented nongenetic instances of ADHD, possibly caused by injury in utero, and that the caudate abnormalities in these individuals might not be pertinent to ADHD that is genetic in nature. No abnormalities have been reported in the putamen, and there have been few studies of the globus pallidus in children with ADHD [Durston et al., 2003].

Cerebellum Reductions in total cerebellar volume [Castellanos et al., 1996, 2002] and in volume reductions limited to the cerebellar vermis in ADHD compared with control subjects have been described [Castellanos et al., 2001; Mostofsky et al., 1998]. These differences could have been caused by different methods for serially measuring volume, making comparisons between studies difficult. These studies included children who had a high percentage of coexistent conditions, such as ODD, CD, and learning, mood and anxiety disorders, but the decreased volume of the cerebellar vermis in the ADHD group remained when children with disruptive behavioral disorders were removed from the analysis. However, the subgroup with ADHD and coexisting mood or anxiety disorders had the smallest vermis volumes.

Functional Imaging The clinical benefit from medications affecting catecholamine levels has led to a focus on frontostriatal circuitry and dopamine pathways in ADHD. Functional magnetic resonance imaging (fMRI) studies have demonstrated abnormal activation of frontostriatal regions in children with ADHD. In normal children, maturation is associated with increased activation of the ventral frontostriatal regions and improved inhibitory control [Durston et al., 2002]. A comparison of ADHD with normal control subjects demonstrated greater frontal activation and lower striatal activation during response inhibition in 10 children with ADHD (8 ADHD/C, 2 ADHD/I; children with high comorbidity scores were excluded). Administration of methylphenidate also resulted in improved performance in a test of response inhibition, associated with increased frontal activation in ADHD children and control subjects and increased striatal activation in the children with ADHD [Vaidya et al., 1998]. Single-photon emission computed tomography (SPECT) has been used to study children with ADHD. One study compared 8 adolescents with “pure” ADHD versus 11 with ADHD and coexistent conditions during a test of variables of attention (TOVA) [Lorberboym et al., 2004]. Children with coexistent conditions (e.g., ODD, CD, mood disorders, learning disorder alone or in combination) had decreased temporal lobe perfusion in response to the TOVA compared with the pure ADHD children, who had some but not statistically significant decreases in frontal lobe perfusion. Regional differences in perfusion between the two groups may explain the better rate of response to stimulants in the pure ADHD group and suggests that different treatments for the two groups may be warranted.

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Untreated adults with ADHD (with no psychiatric comorbidity) have increased striatal dopamine transporter (DAT) levels compared with normal control subjects (as measured by binding to technetium 99m TRODAT-1, the first 99mTc-labeled ligand identified by SPECT that specifically binds DAT), which decreased after 4 weeks of methylphenidate treatment [Krause et al., 2000]. This finding, along with increased striatal activity on positron emission tomographic (PET) scanning in adolescents with ADHD compared with normal control subjects [Ernst et al., 1999], suggests a role for excess dopaminergic activity in striatum or nucleus accumbens in persons with ADHD [Solanto, 2002]. Proton magnetic resonance spectroscopy has also been used to study children with ADHD [Sparkes et al., 2004]. N-acetyl-aspartate (NAA), glutamate/glutamine/γ-aminobutyric acid (Glx), choline, and creatine (Cre) levels in the right prefrontal cortex and left striatum during a test of response inhibition were compared between ADHD children and a control group. A negative correlation between the NAA/Cre ratio and reaction time in the ADHD group was found, compared with a positive correlation in the control group. Children with ADHD with NAA/Cre levels more comparable with those in controls also had much longer reaction times. These findings were thought to reflect preferential use of the prefrontal cortex by children with ADHD during tasks of response inhibition. Of the eight children with ADHD in this study, five had ODD, and one had a generalized anxiety disorder; the interpretation of these results as they apply to ADHD compared with other disorders is unclear.

Clinical Neurophysiology Event-related potential (ERP) studies in ADHD children suggest a lack of frontal lobe inhibitory processes, particularly in pathways involving the anterior cingulate cortex. In one study using a Go/NoGo task designed to assess inhibition, no significant performance differences were found between children with ADHD and normal control subjects [Smith et al., 2003]. However, children with ADHD had larger ERPs than the control group to a warning stimulus that provided no information helpful for task performance, suggesting a lack of inhibition to an irrelevant stimulus in the ADHD group. A second study found shorter-latency and higher-amplitude ERPs that were thought to reflect an inhibitory process in the ADHD group [Falkenstein et al., 1999]. These findings suggested that children with ADHD need to trigger inhibition processes earlier and more strongly to achieve the same behavioral performance as control subjects. Individuals in this study likely did not represent a pure ADHD group because they had higher scores in oppositional, delinquent, and aggressive behaviors and social problems. A third study found that the children with ADHD and without coexisting conditions had significantly longer reaction times to target stimuli and made significantly more omission errors than the control group but did not differ in the number of commission errors [Fallgater et al., 2004]. The ERP data indicated diminished activation of the anterior cingulate cortex in the Go/NoGo trials in the ADHD group, suggesting deficits in prefrontal response control. This deficit in prefrontal response control was distinguished from deficits in response inhibition. Because the latter study excluded ADHD children with comorbidity, it more strongly suggests that abnormalities in

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activation of the anterior cingulate cortex may be specific to ADHD.

Genetic Studies The knowledge that ADHD is an inherited condition [Thapar et al., 1999] and evidence of dopaminergic involvement have led to molecular genetic studies of dopamine transporter and receptor genes [Kent, 2004]. Pursuit of the DAT gene (SLC6A3, formerly designated DAT1) was in part caused by the fact that psychostimulant medications inhibit activity of DAT. An association between ADHD and the 480 base pair alleles at a variable number tandem repeat (VNTR) in SLC6A3 has been reported [Cook et al., 1995]. A subsequent study confirmed these findings and demonstrated a significant relation between SLC6A3 high-risk alleles and the number of hyperactive-impulsive symptoms but not inattentive symptoms [Waldman et al., 1998]. The study involved 117 probands, all but one of whom met criteria for ADHD; the remaining child had ODD. Most children with ADHD frequently had symptoms of or were diagnosed with ODD, CD, and depression or dysthymia. Two subsequent studies, one with a similar rate of coexisting conditions [Palmer et al., 1999] and one with a much lower rate [Swanson et al., 2000], failed to replicate the association between SLC6A3 and ADHD. The dopamine D4 receptor gene (DRD4) has also been associated with ADHD. A 48–base pair VNTR in the third exon of DRD4, also referred to as the DRD4 7-repeat allele, was suggested based on a review of previous studies [Faraone et al., 200l]. Children with ADHD who had the 7-repeat allele had a greater degree of impulsivity (i.e., faster and less accurate responses), were significantly more active (based on Actigraph measures), and had greater total ADHD symptoms scores than those without the allele. However, no differences were seen using measures of attention or response inhibition. The ADHD children with the 7-repeat allele also had higher rates of ODD and CD. A third dopamine receptor gene, DRD5, has been linked to ADHD. One study that examined a number of candidate genes, including DRD3, DRD4, DRD5, and genes for four enzymes involved in dopamine metabolism, found no significant association between the children with ADHD and genetic polymorphisms [Payton et al., 2001]. However, the 138 ADHD children in this study frequently had coexisting conditions, including ODD (57.5%), CD (11.6%), and tic (12.3%), anxiety (2.7%), and depressive (1.4%) disorders. Another study also included children with coexistent conditions (Tourette’s syndrome or tics in 34%, CD or ODD in 25%, anxiety or depression in 8%), and linkage to DRD5 only reached significance when restricted to the children who had a response to methylphenidate [Tahir et al., 2000]. Information was not provided about whether the methylphenidate responders had fewer coexisting conditions. Linkage of the DRD4 gene to methylphenidate responders was also observed. However, this study found an inverse relationship between DRD4 and DSM scores and comorbidity ratings.

Other Potential Causes of AttentionDeficit–Hyperactivity Disorder Data reported from the National Longitudinal Survey of Youth [NLSY, 1979] associated hours of television watched

per day at ages 1 and 3 years with parental reports of attentional problems at age 7 [Christakis et al., 2004]. The children did not necessarily have clinically diagnosed ADHD; rather, they were scored as having attentional problems by the parents. Although the interaction between environmental influences and genetic endowment is well accepted, such preliminary data suggest the need for further investigation because of issues of cause and effect, limitations in adjusting for confounders, potential for biased reporting, and selective recall.

COEXISTING CONDITIONS Many children who present with symptoms suggestive of ADHD have neurologic or psychiatric conditions that are the cause of those symptoms (e.g., depression, sleep disorders, epilepsy). There are other instances when multiple conditions coexist. The implications for management are significant. Just as correction of a sleep disorder may resolve the symptoms of inattention, hyperactivity, or impulsivity, addressing a child’s previously undiagnosed learning disability may resolve these symptoms. Alternatively, a child may have both problems, and remediation of the learning disability may still leave him or her with inattention, hyperactivity, or impulsivity that must be independently addressed. It has been proposed that ADHD be divided into subgroups based on the patterns of comorbidity [Biederman et al., 1991]. ADHD and CD have been posited to be distinct disorders [Schachar and Tannock, 1995]. From a practical standpoint, most studies of children with ADHD and coexisting CD treated with psychostimulants demonstrated a reduction in physical and nonphysical aggression and had improvement of ADHD symptoms [Spencer et al., 1996]. Antidepressants also reduced symptoms of aggression and ADHD in these children. Anxiety disorder has been shown to be transmitted independently from ADHD in families [Perrin and Last, 1996], suggesting that these two conditions are distinct disorders. Most studies of children with ADHD and coexisting anxiety or depression found a reduced response in ADHD symptoms when treated with psychostimulants compared with children only with ADHD [Spencer et al., 1996]. Reading disability and ADHD are two distinct disorders that may occur together [Shaywitz et al., 1995]. There is evidence of genetic linkage for ADHD and reading disability to the same region on the short arm of chromosome 6. This connection may represent a pleiotropic effect (i.e., the same gene increasing susceptibility to more than one disorder) [Willcutt et al., 2002]. A survey of audiologists and pediatricians found that although auditory processing disorder and ADHD/I have symptoms in common, there were features that allowed them to be distinguished from each other [Chermak et al., 2002].

DIAGNOSTIC EVALUATION ADHD is a clinical diagnosis; there are no diagnostic laboratory or cognitive tests [Nichols and Waschbusch, 2004]. A child presenting with symptoms suggestive of ADHD should undergo hearing and vision screening, potentially treatable problems that may be mistaken for ADHD. If the child’s difficulties are predominantly in the

Mandelbaum / Attention-Deficit–Hyperactivity Disorder

school setting, an evaluation for learning disabilities should be pursued, with educational remediation if problems are identified. Social stressors may also be a significant factor [Biederman et al., 2002], which may justify intervention by social services agencies. In general, routine diagnostic testing is not needed in the evaluation of a child for ADHD [American Academy of Pediatrics, 2000]. However, specific testing may be indicated in some circumstances.

Laboratory Studies Features in the history or on examination may lead to specific tests for disorders manifesting as or coexisting with ADHD, such as hypothyroidism [Rovet, 2002], hyperthyroidism [Suresh et al., 1999], or phenylketonuria [Antshel and Waisbren, 2003]. Reports of an association between lead exposure and ADHD have been inconsistent [Eppright et al., 1997; Tuthill, 1996]. Depending on the results of such laboratory studies, therapy targeting the specific condition may be initiated. An uncontrolled study reported improvement in the parents’ but not the teachers’ Connors Rating Scales scores in children with ADHD treated with iron supplementation, even though they were not iron deficient [Sever et al., 1997]. Better studies are needed before concluding that routine testing of or supplementation with iron or screening for iron deficiency is advisable.

Electroencephalography Studies reporting an increased frequency of epileptiform discharges in children with ADHD [Duane et al., 2003; Holtmann et al., 2003; Richer et al., 2002] and reports of ADHD-type symptoms resolving when spike activity was suppressed with antiepileptic drugs [Holtmann et al., 2003; Laporte et al., 2002] have led to proposed guidelines for obtaining an electroencephalogram (EEG). These include a history of clinical events suggesting a seizure (even if only nocturnal or febrile), perinatal stress, head trauma, fluctuating behavioral manifestations, or a family history of epilepsy [Duane, 1996].

Sleep Studies A sleep history should be obtained. If the results suggest a diagnosis of a sleep disorder or if there is a strong family history of sleep disorders, a sleep study should be considered [Gottlieb et al., 2003; Thunstrom, 2002; Walters et al., 2000].

Imaging Studies There are few clinical indications for imaging studies in children with ADHD. ADHD has been reported in association with head trauma [Gerring et al., 2000; Wassenberg et al., 2004], prematurity [Foulder-Hughes and Cooke, 2003], perinatal injury [Toft, 1999], and neurofibromatosis [Rosser and Packer, 2003]. However, if the child is clinically stable, the presence of ADHD symptoms does not call for imaging studies beyond those indicated for the primary condition.

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TREATMENT Pharmacologic Therapy In the 1930s, Charles Bradley administered benzedrine (an amphetamine) to children with a history of neurologic and behavioral problems in whom he had done a lumbar puncture, in an attempt to stimulate secretion of cerebrospinal fluid by the choroid plexus and diminish headaches after lumbar puncture. Although not affecting the incidence of headaches, the children’s teachers reported major improvement in learning and behavior in a number of children that lasted the entire time they were treated [Gross et al., 1995]. A subsequent open trial of benzedrine in children with neurologic and behavioral problems who had normal intelligence resulted in improvement in learning, a greater interest in and higher quality of their school work, behavioral and social improvements, and increased voluntary control [Bradley, 1937]. However, the use of medication in children was viewed unfavorably in the medical and educational community, and it was not until the 1960s, when methylphenidate was found to be effective in treatment of attention disorders, that stimulant use was accepted by physicians and parents [Clements and Peters, 1962]. Between 1990 and 1998, there was a 3.7-fold increase in the diagnosis of ADHD, and prescription of stimulants for children 5 to 18 years old increased from 11.5 to 42 per 1000 [Robison et al., 2002]. Table 36-1, derived from a review of pharmacotherapy in ADHD [Biederman et al., 2004], summarizes information regarding drug class, dose range, dosing schedule, indications, common adverse effects, and comments by the investigators.

Stimulant Medications Stimulant drugs, sympathomimetic agents structurally similar to endogenous catecholamines, act centrally and peripherally by enhancing dopaminergic and noradrenergic transmission. Stimulants have been demonstrated to improve cognitive ability, school performance, and behavior [Barkley et al., 1977; Famularo et al., 1987; Rapport et al., 1988]. A study of children with ADHD with a high degree of comorbidity (ODD, 10%; CD, 30%; anxiety disorder, 17%; dyslexia, 32%) found differential effects of methylphenidate on various attentional functions at different doses [Konrad et al., 2004]. Specifically, alertness and focused and sustained attention improved in a linear fashion with increasing dose, inhibition and set-shifting were enhanced at a low dose but worsened at a moderate dose, and divided attention did not change at all. The different dose-response relationships for various cognitive and behavioral functions were explained by differential effects of these agents in different brain regions [Solanto, 2002]. The positive effects of methylphenidate on cognitive functions were caused by facilitation of dopaminergic activity in some brain regions, whereas improvement in hyperactivity and impulsivity was mediated by reduction in dopaminergic stimulation in other brain regions. This study did not uncover any differences in the response to methylphenidate between children with ADHD/C versus ADHD/I, nor was there any effect of comorbidity. Such data suggest that a single measure of response to stimulant treatment may be

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TABLE 36-1 Major Drug Classes Used in the Pharmacotherapy of Attention-Deficit–Hyperactivity Disorder DRUG

TOTAL DAILY DOSE (mg/kg)*

DAILY DOSAGE SCHEDULE

MAIN INDICATIONS

COMMON ADVERSE EFFECTS AND COMMENTS

Stimulants Dextroamphetamine Dexedrine

0.3-1.0

2 or 3 times

ADHD

Insomnia, decreased appetite Depression, psychosis (rare, with very high doses) Increased heart rate and blood pressure (mild) Possible growth reduction with long-term use Withdrawal effects and rebound phenomena

Mixed salts of L- and D-amphetamine Adderall

0.5-1.5

1 or 2 times

1.0-2.0 1.0-2.0 0.5-1.0

2 or 3 times 2 or 3 times 2 or 3 times

1.0-2.5

1 or 2 times

Associated with rare, serious hepatotoxicity and requires monitoring of liver function tests

1.0-2.0

1 or 2 times

Ritalin LA

1.0-2.0

1 or 2 times

Metadate CD

1.0-2.0

1 or 2 times

Ascending profile, OROS technology Capsules with IR and DR beads 10-12 hr duration of behavioral effect 50:50 ratio (IR:DR) 8-9 hr duration of behavioral effect 30:70 ratio (IR:DR) 8-9 hr duration of behavioral effect

0.5-1.5

1 or 2 times

0.5-1.4

1 or 2 times

Methylphenidate Ritalin Methylin Focalin Magnesium pemoline Cylert Long-Acting Stimulants Methylphenidate Concerta

Mixed salts of LD-amphetamine

Has 6-hr action

and

Adderall XR

NSRIs Atomoxetine

Antidepressants Tricyclics

Tertiary amines Imipramine Amitriptyline Clomipramine Secondary amines Desipramine Nortriptyline MAOIs

2.0-5.0† 2.0-5.0† 2.0-5.0†

1 or 2 times 1 or 2 times 1 or 2 times

2.0-5.0† 1.0-3.0†

1 or 2 times 1 or 2 times

Capsules with IR and DR beads 50:50 ratio (IR:DR) 10-12 hr duration of behavioral effect ADHD ± comorbidity Enuresis (?) Tic disorder (?) Depression/anxiety disorders (?)

Mechanism of action: noradrenergic-specific reuptake inhibitor Mild or moderate appetite depression Gastrointestinal symptoms Mild initial weight loss Mild increase in blood pressure, pulse No ECG conduction or repolarization delays Not abusable

ADHD Enuresis Tic disorder Anxiety disorders (?) OCD (clomipramine)

Mixed mechanism of action (noradrenergic/serotonergic) Secondary amines more noradrenergic Clomipramine primarily serotonergic Narrow therapeutic index Overdoses can be fatal Anticholinergic effects: dry mouth, constipation, blurred vision Weight loss Mild increase in diastolic blood pressure and ECG conduction parameters with daily doses > 3.5 mg/kg

Atypical depression Treatment-refractory depression

Difficult medicines to use in juveniles Reserved for refractory cases Severe dietary restrictions (i.e., high-tyramine foods) Drug-drug interactions

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TABLE 36-1, cont’d Major Drug Classes Used in the Pharmacotherapy of Attention-Deficit–Hyperactivity Disorder DRUG

TOTAL DAILY DOSE (mg/kg)*

DAILY DOSAGE SCHEDULE

MAIN INDICATIONS

COMMON ADVERSE EFFECTS AND COMMENTS Hypertensive crisis with dietetic transgression or with certain drugs Weight gain Drowsiness Changes in blood pressure Insomnia Liver toxicity (remote)

Phenelzine Tranylcypromine Selegiline

0.5-1.0 0.5-1.0 0.5-1.0

2 or 3 times 2 or 3 times 2 or 3 times

Other Antidepressants SSRIs

MD, dysthymia OCD Anxiety disorders Eating disorders PTSD (?)

Serotonergic mechanism of action Large margin of safety No cardiovascular effects Irritability Insomnia Gastrointestinal symptoms Headaches Sexual dysfunction Withdrawal symptoms more common with short-acting drugs Potential drug-drug interactions (cytochrome P-450)

ADHD MD Smoking cessation Anti-craving effects (?)

Mixed mechanism of action (dopaminergic/noradrenergic) Irritability Insomnia Drug-induced seizures at doses > 6 mg/kg Contraindicated in bulimics Mixed mechanism of action (serotonergic/noradrenergic) Similar to SSRIs Irritability Insomnia Gastrointestinal symptoms Headaches Potential withdrawal symptoms Blood pressure symptoms Mixed mechanism of action (serotonergic/noradrenergic) Dizziness Nausea Potential interactions with nonsedating antihistamines, cisapride (cytochrome P-450) Rare, serious hepatotoxicity Less manicogenic (?) Mixed mechanism of action (serotonergic/noradrenergic) Sedation Weight gain Dizziness Less manicogenic (?)

Fluoxetine Paroxetine Citalopram Sertraline Fluvoxamine Bupropion (SR)

0.3-0.9 0.3-0.9 0.3-0.9 1.5-3.0 1.5-4.5 3-6

1 time, in arm 1 time, in arm 1 time, in arm 1 time, in arm 1 time, in arm 2 times

Venlafaxine (XR)

1-3

1 time

Bipolar depression (?) MD Anxiety disorders ADHD (?) OCD (?)

Nefazodone

4-8

1 time

MD Anxiety disorders OCD (?) Bipolar depression (?)

Mirtazapine

0.2-0.9

1 time, in the afternoon

MD Anxiety disorders Stimulant-induced insomnia (?) Bipolar depression (?)

Noradrenergic Modulators α2-Agonists Clonidine

0.003-0.010

2 or 3 times

Tourette disorder ADHD Aggression/self-abuse Severe agitation Withdrawal symptoms

Sedation (frequent) Hypotension (rare) Dry mouth Confusion (with high dose) Depression Rebound hypertension Localized irritation with transdermal preparation (continued)

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TABLE 36-1, cont’d Major Drug Classes Used in the Pharmacotherapy of Attention-Deficit–Hyperactivity Disorder DRUG Guanfacine β-Blockers Propranolol

TOTAL DAILY DOSE (mg/kg)*

DAILY DOSAGE SCHEDULE

0.015-0.05

1 or 2 times

1-7

2 times

MAIN INDICATIONS

COMMON ADVERSE EFFECTS AND COMMENTS Same as clonidine Less sedation, hypotension

Aggression/self-abuse Severe agitation Akathisia

Risk for bradycardia and hypotension (dose dependent) and rebound hypertension Bronchospasm (contraindicated in asthmatics) Rebound hypertension on abrupt withdrawal

*Doses are general guidelines and must be individualized with appropriate monitoring. Weight-corrected doses are less appropriate for obese children. When high doses are used, serum levels may be obtained to avoid toxicity. † Dose adjusted according to serum levels (therapeutic window for nortriptyline). ADHD, attention-deficit–hyperactivity disorder; DR, delayed release; ECG, electrocardiographic; IR, immediate release; MAOIs, monoamine oxidase inhibitors; MD, mood disorder; MR, mental retardation; NSRIs, norepinephrine-specific reuptake inhibitors; OCD, obsessive-compulsive disorder; OROS, oral osmotic; PTSD, post-traumatic stress disorder; SR, sustained release; SSRIs, selective serotonin reuptake inhibitors; XR, extended release. Adapted from Biederman J, Spencer T, Wilens T. Evidence-based pharmacotherapy for attention-deficit hyperactivity disorder. Int J Neuropsychopharmacol 2004;7:77.

insufficient, because different doses may be necessary to improve particular functions. The response to methylphenidate in a group of 28 preschoolers (3 to 5 years old), as measured by behavioral ratings by teachers and parents, documented improvement, with 82% rated as having normal behavior after treatment, higher than the rate generally achieved in older children [Short et al., 2004]. With the exception of decreased appetite, there were no adverse side effects. The investigators speculate that the higher normalization rate for preschoolers than elementary school children may be a function of fewer demands placed on the preschooler (e.g., shorter school day, no homework). The most commonly reported side effects of stimulants include appetite suppression and sleep disturbance. Absorption of stimulant medications is not notably affected when taken with or after meals, which may ameliorate appetite suppression [Green, 2001]. Insomnia can be a side effect from the medication but may also be caused by a rebound effect as the medication effect subsides. This distinction is important because in the latter situation, a late afternoon or evening dose of stimulant medication may ease falling asleep [Chatoor et al., 1983]. Uncommonly, there have been reports of mood disturbances and lethargy after stimulant use [Wilens and Biederman, 1992]. Stimulants may also affect heart rate and blood pressure, but in healthy children, this change is unlikely to have clinical significance [Brown et al., 1984; Short et al., 2004]. There have been reports of psychostimulants inducing or exacerbating tic disorders, but subsequent studies have not found this to be a universal problem [Spencer et al., 1999]. Although this possibility should be discussed with children and their families, the presence of tics in a child with ADHD or a family history of tics is not an absolute contraindication to the use of psychostimulants. Concerns are often expressed regarding an increased risk of substance abuse in children treated with psychostimulants [Biederman et al., 1995], but there is no supporting evidence. One study found that pharmacologic treatment for ADHD actually decreased the risk of subsequent substance abuse [Biederman et al., 1999]. There have also been reports of a decrease in the height of children taking stimulant medications [Safer et al., 1972],

but other studies indicated no effect [Gross et al., 1976]. The reported decrease in height may reflect a transient maturational delay associated with ADHD, rather than a growth-stunting effect of medication [Spencer et al., 1998]. A longitudinal study [MTA Cooperative Group, 2004] revealed that children treated with medication had a reduced height gain compared with those who were not treated. Growth suppression was still evident during the second year of treatment in the group treated continuously, indicating that this was a persistent effect. The observation that there was less growth suppression in the children who were not treated continuously suggests that interrupting treatment with stimulant medication may limit growth suppression, supporting the concept of drug holidays to address this side effect. However, there have been reports of behavioral deterioration when stimulant medications are abruptly discontinued [Biederman et al., 2004]. The most commonly used drugs in the stimulant class include methylphenidate, dextroamphetamine, and mixed salts of L- and D-amphetamine. Although in the same class, these drugs have slightly different mechanisms of action, and patients may respond differently to each of them [Greenhill et al., 1998]. Failure of one drug does not preclude success with another drug in the same class. A number of these agents are available in short- and long-acting formulations. The results of studies comparing short- and long-acting preparations have been inconsistent [Fitzpatrick et al., 1992; Pelham et al., 1987, 1990], making the choice of formulation an empirical one.

Methylphenidate Methylphenidate has fewer side effects than amphetamine [Efron et al., 1997]. In the standard formulation, methylphenidate reaches peak concentrations between 1 and 3 hours after oral intake. It is rapidly and extensively metabolized by nonmicrosomal hydrolytic esterases in liver and other tissues, with an average half-life of 3 hours. In children, the starting dose is 0.3 mg/kg in the morning, rounded to the nearest 5-mg tablet [Drugdex Drug Evaluations, 2004]. It can be useful to have teachers complete a behavior checklist before and after initiation of treatment (preferably without being aware exactly when the medication is started) to assess

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efficacy. If, after 1 to 2 weeks, there is inadequate benefit, the dose can be increased to 0.6 mg/kg. With an average half-life of 3 hours, a morning dose does not persist through the afternoon. Increasing the morning dose may increase the duration of the effect. Alternatively, a second dose 3 to 4 hours after the initial dose may be necessary. A dose in the middle to late afternoon to facilitate completion of homework may also be warranted. Alternatives to multiple daily doses are the longacting formulations of methylphenidate. These formulations reach peak concentration 6 to 8 hours after oral intake, obviating the need for a midday dose. When using the longeracting formulations, the entire daily dose is given in the morning. If there is no significant improvement in symptoms at a total daily dose of 1 to 2 mg/kg, alternate medication should be considered. The regular formulation of methylphenidate is available in 5-, 10-, and 20-mg tablets (Ritalin). There are multiple extended-release formulations that use different mechanisms to achieve their sustained-release effect; they are available in 10- and 20-mg tablets (Metadate ER); 10-, 20-, and 30-mg capsules (Metadate CD); 20-, 30-, and 40-mg capsules (Ritalin LA); and 18-, 27-, 36-, and 54-mg tablets (Concerta).

Dexmethylphenidate Dexmethylphenidate is the D-threo-enantiomer of methylphenidate. A PET study found specific binding of the Denantiomer to dopamine transporter in the basal ganglia, whereas the L-enantiomer had widespread, nonspecific binding [Ding et al., 1995]. Studies comparing dexmethylphenidate and methylphenidate have concluded both to be effective in ADHD, but dexmethylphenidate has a longer duration [Keating and Figgitt, 2002]. The time to peak concentrations after oral intake is similar to methylphenidate, between 1 and 3 hours, and like methylphenidate, it is rapidly and extensively metabolized by nonmicrosomal hydrolytic esterases in liver and other tissues, with an average half-life of about 2 hours. In children the starting dose of dexmethylphenidate is one half of the methylphenidate dose (0.15 mg/ kg in the morning, rounded to the nearest 2.5-mg tablet) [Drugdex Drug Evaluations, 2004]. If, after 1 to 2 weeks, there is inadequate benefit, the dose can be increased in 2.5-mg increments, to a maximum of 20 mg/day. The report of longer clinical efficacy than methylphenidate (despite the similar half-life) may eliminate the need for a midday dose, depending on the clinical response. There is no evidence that giving the D-isomer (dexmethylphenidate) at one half of the dose of the D,L-enantiomer (methylphenidate) confers any clinical advantage. Dexmethylphenidate is available in 2.5-, 5-, and 10-mg tablets (Focalin).

Dextroamphetamine Dextroamphetamine has a time to peak concentration of 60 to 160 minutes and is metabolized in the liver. The average halflife of dextroamphetamine is 10 to 12 hours, but this varies considerably with urinary pH; at a urine pH less than 6.6, more than two thirds of unmetabolized drug is excreted in the urine, whereas at a urine pH greater than 6.7, it is less than one half. The initial dose of dextroamphetamine is 0.15 to 0.3 mg/kg (rounded to the nearest 5 mg) [Drugdex Drug Evaluations, 2004]. This dose can be gradually increased to

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desired effect up to a peak dose of approximately 1 mg/kg/ day. Dextroamphetamine’s longer half-life compared with methylphenidate may obviate the need for a midday dose. An extended-release preparation of dextroamphetamine eliminates the need for midday dosing. The regular formulation of dextroamphetamine is available in 5-mg tablets (Dexedrine); the extended-release formulation is available in 5-, 10-, and 15-mg capsules (Dexedrine Spansules). Adderall is a combination of four amphetamine salts (D-amphetamine saccharate, D-amphetamine sulfate, D,Lamphetamine sulfate, and D,L-amphetamine aspartate), with a 3:1 ratio of D-isomer to L-isomer. The time to peak concentration and half-life are similar to those for dextroamphetamine. The initial dose of Adderall is 2.5 or 5 mg, with weekly increments based on the response to a maximum dose of 1.5 mg/kg/day, up to about 40 mg. The half-life of Adderall is such that a midday dose may or may not be necessary. Adderall is available in 5-, 7.5-, 10-, 12.5-, 15-, 20-, and 30-mg tablets. Adderall XR capsules, with one half of the contents in a delayed-release formulation, eliminates the need for midday dosing; the entire daily dose is given in the morning. Adderall XR is available in 5-, 10-, 15-, 20-, 25-, and 30-mg capsules.

Noradrenergic Potentiation Atomoxetine Atomoxetine (Strattera) is a norepinephrine-specific reuptake inhibitor that is effective in the treatment of children with ADHD. In a study comparing atomoxetine to methylphenidate and placebo, the response rate to atomoxetine and methylphenidate was essentially identical, and both were better than placebo. Appetite suppression was somewhat lower in atomoxetine compared with methylphenidate (22% versus 32%), and there was significantly less insomnia on atomoxetine (7% versus 27%) [Spencer et al., 2002]. Atomoxetine is metabolized by the cytochrome P-450 (CYP) 2D6 pathway. Peak plasma concentrations of atomoxetine occur 1 to 2 hours after oral administration. In extensive metabolizers (most patients), atomoxetine halflife is 4 to 5 hours. Substantial decreases in clearance and prolongation of the half-life are seen in poor metabolizers. The starting dose is 0.5 mg/kg/day, with gradual increase to a target dose of 1.2 mg/kg/day. In poor metabolizers (about 7% of the population), the half-life is substantially longer, and the dose requirement may be much lower. Depending on the response, midday dosing may be required for extensive metabolizers. Food does not affect absorption [Drugdex Drug Evaluations, 2004]. Because atomoxetine is not a controlled substance in the United States, prescriptions with multiple refills can be provided, and renewals can be done over the phone, in contrast to the procedures for stimulant medications. Atomoxetine is available in 10-, 18-, 25-, 40-, and 60-mg capsules. In December 2004 the Food and Drug Administration (FDA) asked the manufacturer to add a bolded warning about severe liver injury to the labeling, indicating that the medication should be discontinued in patients who develop jaundice or laboratory evidence of liver injury. In September 2005 the FDA directed the manufacturer to further revise the labeling to include a boxed warning regarding an increased risk of suicidal thinking in children and adolescents being treated with this drug.

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Nonstimulant Medications It is estimated that at least 30% of children diagnosed with ADHD do not respond to or tolerate stimulant medications [Spencer et al., 1996]. Most studies have reported a reduced rate of response to psychostimulants in children with ADHD and anxiety or depression [Spencer et al., 1996]. The failure to respond to psychostimulants suggests the possibility of an incorrect diagnosis. However, genetic studies have suggested that children with ADHD respond differently to methylphenidate, depending on whether they were homozygous or heterozygous for the 10-repeat allele at dopamine transporter gene SLC6A3 [Loo et al., 2003; Rhode et al., 2003; Winsberg and Comings, 1999].

Tricyclic Antidepressants Other agents found to be effective in the treatment of ADHD include tricyclic antidepressants (TCAs). In one study, comorbidity with conduct disorder, depression, or anxiety or a family history of ADHD did not result in a differential response to desipramine [Biederman et al., 1989]. In studies comparing TCAs with stimulants, TCAs appear to more consistently improve behavioral symptoms rather than cognitive function [Rapport et al., 1993].

Desipramine Desipramine, a TCA, is metabolized in the liver by the CYP-2D6 pathway, with an average half-life of 17.1 hours. For the 7% of the population with decreased activity of this enzyme, the half-life may be as long as 77 hours [Drugdex Drug Evaluations, 2004]. The effective dose of desipramine is lower and onset of action sooner for ADHD than for depression [Green, 1991]. The starting dose of desipramine is 1 mg/kg/day, with gradual increments to a maximum of 5 mg/kg/day. This medication may be given once daily or in divided doses, depending on the response. For slow metabolizers, the dose requirement is much lower, and oncedaily dosing should be sufficient. There have been case reports of sudden death in children treated with desipramine [Riddle et al., 1991]. Although a subsequent epidemiologic study did not find greater risk of sudden death with desipramine [Biederman et al., 1995], it has been suggested that a baseline ECG be obtained before initiating treatment and that serial ECGs be obtained after significant dose increments and periodically during treatment [Biederman et al., 2004].

Alpha-Adrenergic Agonists The α-adrenergic agents clonidine and guanfacine have been widely used for treatment of ADHD despite few clinical studies. The success of these agents for Tourette syndrome and other tic disorders [Leckman et al., 1991] has made them especially useful in children with ADHD and tic disorders, particularly if a trial of stimulant medication resulted in exacerbation of tics. Reports of three deaths of children taking a combination of methylphenidate and clonidine prompted reviews that found no evidence of an adverse methylphenidate-clonidine interaction [Fenichel, 1995; Popper, 1995]. Nevertheless, if planning to

prescribe this combination, a review of this literature and discussion of risks and benefits with the parents is advisable. Guanfacine appears to have an advantage over clonidine because it has a longer half-life and is less sedating [Hunt et al., 1995]. Guanfacine reaches a peak concentration after oral intake in 1 to 4 hours and is metabolized in the liver, with an average half-life of 17 hours [Drugdex Drug Evaluations, 2004]. The starting dose is 0.015 mg/kg/day (to the nearest 0.5 mg), with a gradual increase to a maximum of 0.05 mg/kg or 4 mg/day, based on the clinical response [Biederman et al., 2004; Green, 1995]. The half-life of guanfacine should allow for once-daily dosing, although in clinical studies it was administered in two to four divided doses [Chappell et al., 1995; Hunt et al., 1995]. Guanfacine is available in 1- and 2mg tablets (Tenex). Other agents reported to be effective in ADHD are reviewed in Table 36-1.

Nonpharmacologic Therapies Children with ADHD need a work environment with minimal distractions and with seating that is somewhat isolated and close to the front of the room in front of the teacher [Shaywitz and Shaywitz, 1984]. The setting should be fairly structured with organizational techniques such as checklists and homework assignment pads, and an uncluttered desk at home devoted exclusively to school work. A multicenter clinical trial of various treatment strategies for ADHD [MTA Cooperative Group, 1999] concluded that stimulants were more effective than behavioral therapies for ADHD symptoms. The combination of stimulants and behavioral therapy resulted in improved social skills but did not significantly improve ADHD symptoms over stimulants alone. A review of treatment modalities of children diagnosed with ADHD in the period from 1995 to 1999 found that among children diagnosed with ADHD, 24% also had mental illness. The most frequent treatments were stimulant medication alone (42%), stimulant medication combined with psychotherapy or mental health counseling (32%), and psychotherapy or mental health counseling alone (10.8%). Fifteen percent of children received no treatment other than office visits for initial and follow-up medical care. The percentage of children receiving psychotherapy or mental health counseling alone or in combination with stimulant medication increased with age, and males were more likely than females to receive treatment [Robison et al., 2004].

Biofeedback Programs Various forms of computerized training programs have been studied in treating children with ADHD. Computerized working memory training improved working memory capacity in children with ADHD and adults without ADHD. Improvement generalized to nonpracticed tasks involving prefrontal cortex and associated with improvement in working memory was a decrease in head movements in ADHD children [Klingberg et al., 2002]. Children with ADHD trained to modify their slow cortical potentials also have an increase in contingent negative variation (CNV) during a continuous performance task compared with those who did not receive training. Associated with this electrophysiologic phenomenon were fewer impulsivity errors on the continuous performance task, suggesting that the

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CNV increase represented a neurophysiologic correlate of improved self-regulatory capabilities [Heinrich et al., 2004]. Use of an EEG biofeedback program has been compared with the effectiveness of methylphenidate [Fuchs et al., 2003]. Children were trained to increase the power of the sensory motor rhythm (12 to 15 hertz) and low beta activity (15 to 18 hertz). Assignment to the biofeedback versus methylphenidate group was based on parental preference. Two thirds of parents chose the biofeedback training program, raising issues of selection bias, and there was no placebo arm in this study. After 3 months of the program, both groups had significant improvements in all four subscales on the TOVA and on improvement on a behavior rating scale. Changes in the EEG as a result of biofeedback were not monitored in this study. A previous study using biofeedback reported greater improvement on the TOVA in participants with significant EEG changes than in those without changes (although there were improvements in both groups) [Lubar et al., 1995]. There was no correlation between behavioral changes reported by the parents and changes in the EEG. This study did not include a control group. A study of EEG biofeedback that used a control group (i.e., association between EEG patterns and feedback to the participants was random) found no benefit from EEG biofeedback [Heywood and Beale, 2003]. The investigators observed that an analysis of the data that failed to control for overall behavioral trends unrelated to training and that also excluded dropouts would have led to the spurious conclusion that the treatment was effective.

Complementary and Alternative Medications A survey of parents of children referred for evaluation of ADHD reported that 54% of the parents used complementary and alternative medicine (e.g., acupuncture, nutritional supplements) for the child’s ADHD symptoms in the prior year [Chan et al., 2003]. Only 11% of the parents discussed using such interventions with their child’s physician. A review of the literature on the role of nutritional factors in ADHD, including food additives, sugars, food allergies or sensitivities, and essential fatty acids, identified methodologic problems with negative studies without similar discussion of problems with positive studies, possibly revealing bias of the authors [Schnoll et al., 2003]. Nevertheless, the summary statement is reasonably cautious: “There is increasing evidence that there is a subset of children with behavioral problems who are sensitive to one or more food components that may precipitate or contribute to their hyperactive behavior. Research indicates that it is futile to try to identify a specific food or substance that will precipitate negative behavior in all hyperactive children.”

OUTCOME ADHD persists into adulthood. The symptoms of ADHD may be less obvious after the individual is older [Hart et al., 1995]. The incidence of ADHD in adults depends on diagnostic criteria and whether historical data are obtained from the patients or their parents [Weiss et al., 2002]. The finding that adolescents and young adults with ADHD had more car accidents with bodily injuries indicates that this is a serious problem even in older children and adults [Barkley et al., 1993].

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CONCLUSIONS Study of higher cortical function is inherently complex. Advances in neuroscience have brought new methods to this endeavor. There is still much research required for achieving an understanding of ADHD, not least of which is agreeing on a precise definition so that studies can be compared. Available evidence suggests that there may be value in distinguishing ADHD/I from ADHD/HI and ADHD/C and in separating cases with comorbidity, because these groups have different characteristics and different responses to treatment. A crucial role for the physician assessing a child for the possibility of ADHD is recognizing features in the presentation that suggest alternative diagnoses. Although much remains to be done, substantial advances in the neurobiology, diagnosis, and management of this condition have been made, and the prospect for significant enhancement of the lives of children with ADHD continues to improve. REFERENCES Achenbach TM. Child behavior checklist for ages 4-18. Burlington, Vt: University of Vermont Department of Psychiatry, 1991. American Academy of Pediatrics. Committee on quality improvement and subcommittee on attention-deficit/hyperactivity disorder clinical practice guideline: Diagnosis and evaluation of the child with attention-deficit/hyperactivity disorder. Pediatrics 2000;105:1158. American Psychiatric Association. Diagnostic Statistical Manual of Mental Disorders, 4th ed. Washington, DC, American Psychiatric Press, 1994. Antshel KM, Waisbren SE. Timing is everything: Executive functions in children exposed to elevated levels of phenylalanine. Neuropsychology 2003;17:458. Barkley RA. The ecological validity of laboratory and analogue assessment methods of ADHD symptoms. J Abnorml Child Psychol 1991;19:149. Barkley RA. Behavioral inhibition, sustained attention, and executive functions: Constructing a unifying theory of ADHD. Psychol Bull 1997;121:65. Barkley RA. Attention-deficit hyperactivity disorder: A handbook for diagnosis and treatment, 2nd ed. New York: Guilford Press, 1998. Barkley RA, Guevremont DC, Anastopoulos AD. Driving related risks and outcome of ADHD in adolescents and young adults: A 3-5 year follow-up survey. Pediatrics 1993;92:212. Barkley RA, Jackson Tl Jr. Hyperkinesis, autonomic nervous system activity and stimulant drug effects. J Child Psychol Psychiatry 1977;18:347. Baumgaertel A, Wolraich ML, Dietrich M. Comparison of diagnostic criteria for attention deficit disorders in a German elementary school sample. J Am Acad Child Adolesc Psychiatry 1995;34:629. Biederman J, Baldessarini RJ, Wright V, et al. A double-blind placebo controlled study of desipramine in the treatment of ADD. I. Efficacy. J Am Acad Child Adolesc Psychiatry 1989;28:777. Biederman J, Faraone SV, Monuteaux MC. Differential effect of environmental adversity by gender: Rutter’s index of adversity in a group of boys and girls with and without ADHD. Am J Psychiatry 2002;159:1556. Biederman J, Newcorn J, Sprich S. Comorbidity of attention deficit hyperactivity disorder with conduct depressive anxiety and other disorders. Am J Psychiatry 1991;148:564. Biederman J, Spencer T, Wilens T. Evidence-based pharmacotherapy for attention-deficit hyperactivity disorder. Int J Neuropsychopharmacol 2004;7:77. Biederman J, Thisted RA, Greenhill LL, et al. Estimation of the association between desipramine and the risk for sudden death in 5-to 14-year old children. J Clin Psychiatry 1995;56:87. Biederman J, Wilens T, Mick E, et al. Psychoactive substance use disorder in adults with attention deficit hyperactivity disorder (ADHD): Effects of ADHD and psychiatric co-morbidity. Am J Psychiatry 1995;152:1652.

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Tuthill RW. Hair lead levels related to children’s classroom attentiondeficit behavior. Arch Environ Health 1996;51:214. Vaidya CJ, Austin G, Kirkorian G, et al. Selective effects of methylphenidate in attention deficit hyperactivity disorder: A functional magnetic resonance study. Proc Natl Acad Sci U S A 1998;95:14494. Vaughn ML, Riccio CA, Hynd GW, et al. Diagnosing ADHD (predominantly inattentive and combined type subtypes): Discriminant validity of the behavior assessment system for children and the Achenbach Parent and Teacher Rating Scales. J Clin Child Psychol 2000;26:349. Waldman ID, Rowe DC, Abramowitz A, et al. Association and linkage of the dopamine transporter gene and attention-deficit hyperactivity disorder in children: Heterogeneity owing to diagnostic subtype and severity. Am J Hum Genet 1998;63:1767. Walters AS, Mandelbaum DE, Lewin DS, et al. Dopaminergic therapy in children with restless legs/periodic limb movements in sleep and ADHD. Pediatr Neurol 2000;22:182. Wassenberg R, Max JE, Lindgren SD, et al. Sustained attention in children and adolescents after traumatic brain injury: Relation to severity of injury, adaptive functioning, ADHD and social background. Brain Injury 2004;18:751. Weiss M, Weiss G. Attention deficit hyperactivity disorder. In: Lewis M, ed. Child and adolescent psychiatry: A comprehensive textbook. Philadelphia: Lippincott Williams & Wilkins, 2002. Wilens T, Biederman J. The stimulants. Psychiatr Clin North Am. 1992;15:191. Willcutt EG, Pennington BF, Smith SD, et al. Quantitative trait locus for reading disability on chromosome 6p is pleiotropic for attentiondeficit/hyperactivity disorder. Am J Med Genet 2002;114:260. Winsberg BG, Comings DE. Association of the dopamine transporter gene (DAT1) with poor methylphenidate response. J Am Acad Child Adolesc Psychiatry 1999;38:1474. Wolraich ML, Hannah JN, Pinnock TY, et al. Comparison of diagnostic criteria for attention-deficit hyperactivity disorder in a county-wide sample. J Am Acad Child Adolesc Psychiatry 1996;35:319. Wolraich ML, Lambert W, Doffing MA, et al. Psychometric properties of the Vanderbilt ADHD Diagnostic Parent Rating Scale in a referred population. J Pediatr Psychol 2003a;28:559. Wolraich ML, Lambert W, Baumgaertel A, et al. Teachers’ screening for attention deficit/hypeactivity disorder: Comparing multinational samples on teacher ratings of ADHD. J Abnorm Child Psychol 2003b;31:445.

CHAPTER 37

Tourette Syndrome and Its Associated Neurobehavioral Problems Harvey S. Singer

Gilles de la Tourette syndrome (TS) is a chronic neuropsychiatric disorder characterized by the presence of involuntary motor and phonic tics that wax and wane [Singer 2000, 2005b]. Once considered a rare disorder, the prevalence of TS is estimated to be up to 1% of children and adolescents. In his late 19th century description, Georges Gilles de la Tourette suggested a familial pattern and a psychogenic origin. Since then, there is further evidence for a genetic inheritance pattern, but accumulating data support a neurobiologic rather than emotional basis. In addition to tics, children with TS often suffer from a variety of concomitant psychopathologies, including obsessive-compulsive disorder, attention-deficit– hyperactivity disorder, mood disorders, episodic outbursts, learning difficulties, sleep abnormalities, and other behavioral problems. Although the presence of neurobehavioral problems is not required for the diagnosis of TS, they are very common, and their clinical impact on the affected patient is often more significant than the impact of the tics themselves. The physician caring for a child with tics and complex psychopathologies must be able to recognize the various problems, understand their individual complexities, and develop an appropriate treatment plan.

TICS Tics, the hallmark feature of TS, are readily observed but difficult to appreciate from a written description. They are involuntary, sudden, rapid, repetitive, nonrhythmic, stereotyped movements or phonic productions. Because almost any movement, noise, or vocalization can emerge as a potential tic, the range of tic symptoms is almost limitless [Leckman, 2003]. They manifest in a variety of forms, have different durations, degrees of complexity, and severity, and no two patients have exactly the same presentation. Motor tics range from brief, rapid, meaningless motor fragments that often involve only one muscle group (i.e., simple tics) to a more coordinated sequence of movements that last longer and appear as a nonpurposeful or more goal-directed action (i.e., complex tics). Examples of simple motor tics include an eye blink, head or neck jerk, and shoulder shrug, whereas complex motor tics include nonpurposeful facial or body contortions or more purposeful-appearing ones that actually serve no purpose—actions such as touching, smelling, jumping, and obscene gestures. Complex motor tics should be differentiated from stereotypes and compulsions. Stereotypic movements, such as arm flapping, head nodding, and body rocking, tend to occur at an earlier age, appear fixed in their presentation, last longer, are provoked by absorbing activities, and aborted by distraction [Mahone et al., 2004]. Actions such as touching, tapping, and picking

of the skin may be tics or compulsive symptoms. The latter, however, usually occur in association with other obsessivecompulsive symptoms, tend to be preceded by a conscious need to perform the action to avoid an unwanted circumstance or a feeling, and include features such as performing the activity a fixed number of times until it feels “just right” or is equal on both sides of the body. Simple phonic tics are brief meaningless sounds or noises such as grunts, barks, sniffs, yelps, squeaks, and throat clearing. Complex vocalizations are diverse and may include syllables, words or phrases, alterations in speech pattern, echolalia (i.e., repeating other people’s words), palilalia (i.e., repeating one’s own words), or coprolalia (i.e., obscene words). Tics have several characteristics that can be helpful in assisting the clinician to differentiate them from other disorders. The typical course is one of waxing and waning number, frequency, intensity, and complexity. The precise mechanism underlying the fluctuation of tics remains undetermined, but it may involve environmental (e.g., psychosocial stress, adversity, infection) and biologic factors. Tics are exacerbated by anxiety, excitement, anger, or fatigue, and they are reduced by absorbing activities or sleep. They can be briefly suppressed, but this is often associated with a build-up of inner tension. Tics may be preceded by an urge, impulse, tension, pressure, itch, or tingle (i.e., premonitory urge) that is often localized to a discrete anatomic region [Kurlan, et al., 1989; Leckman, 2003]. This tic-prompting sensation occurs more frequently in adults than children [Banaschewski et al., 2003b; Kwak et al., 2003a]. Physician reliance on strictly historical data, rather than direct observation of symptoms, can lead to inaccurate reports; 21% of children followed because of a positive family history were reported to be unaffected, although they met the criteria for a tic disorder [McMahon et al., 2003], and 50% of adults with childhood tics who considered themselves to be tic free had tics evident from direct observation [Pappert et al., 2003]. Misdiagnoses are common. For example, eye-blinking tics are thought to stem from ophthalmologic problems, ocular tics are confused with opsoclonus, throat-clearing and coughlike tics are thought to be caused by sinusitis or allergic conditions, and involuntary sniffing frequently results in referral to an allergist. Severe tics can lead to physical injury, such as myelopathy [Dobbs and Berger, 2003; Muroi et al., 2002] and bilateral retinal detachment [Lim et al., 2004a], and iatrogenic eye injury has occurred during ocular examinations [Margo, 2002].

TIC DISORDERS Tic disorders represent a clinical spectrum ranging from a mild transient form to TS. A classification endorsed by the

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Tourette Syndrome Association [The Tourette Syndrome Classification Study Group, 1993] defines tics as transient (i.e., present for less than 12 months) or chronic (i.e., present for more than 12 months). Diagnoses are often retrospective, because there is no accurate way to predict whether an individual’s tics will resolve within months, others will be added, or persistent tics will become chronic. Transient tic disorder is the mildest and most common tic disorder, with duration of tics for less than 1 year. The prevalence of tics in childhood is about 6% to 12% (range, 4% to 24%) [Gadow et al., 2002; Kurlan et al., 2001; Snider et al., 2002; Wang and Kuo, 2003]. Chronic tic disorder (i.e., motor or phonic) requires tics be present for more than 1 year, and affected individuals have entirely motor or, less commonly, solely vocal tics. Several studies have documented that chronic multiple tic disorder represents a mild form of TS, and both are transmitted as inherited traits in the same family [Spencer et al., 1995]. TS criteria include the presence of multiple motor and at least one vocal tic (not necessarily concurrently); a waxing and waning course with tics evolving in a progressive manner; the presence of tic symptoms for at least 1 year; the onset of symptoms before age 21; the absence of a precipitating illness (e.g., encephalitis, stroke, or degenerative disease) or medication; and the observation of tics by a knowledgeable individual. Adult-onset tic disorders have been reported and are often associated with potential environmental triggers, more severe symptoms, greater social morbidity, and a poorer response to medications than in childhood-onset disorders [Eapen et al., 2002]. TS was once considered a rare disorder, but it has an estimated prevalence of about 1 to 10 cases per 1000 children and adolescents [Jin et al., 2004; Kurlan et al., 2001; Khalifa and von Knorring, 2003; Lanzi et al., 2004; Robertson, 2003; Stefanoff and Mazurek, 2003]. TS is more common in males than females (>3:1), and the mean age of onset is typically between 6 and 7 years, with most patients developing tics before adolescence. There is no diagnostic laboratory test or requirement for the presence of coexistent disorders. Neurologic examination and neuroradiographic studies are typically normal. “Soft” signs, including abnormalities of coordination and fine motor performance, synkinesis, and motor restlessness, are often observed in affected children, especially those with concomitant attentiondeficit–hyperactivity disorder. Although TS was originally proposed to be a lifelong disorder, its course may be quite variable, with some patients having a spontaneous remission or marked improvement independent of the use of tic-suppressing medication [Erenberg et al., 1987; Leckman et al., 1998; Pappert et al., 2003]. Investigators using a mathematical model to assess the time course of tic severity over the first 2 decades have suggested that maximum tic severity occurs between the ages of 8 and 12 years and that this period is followed by a steady decline in symptoms [Leckman et al., 1998]. A follow-up study of 58 teenagers and young adults found that tics virtually disappeared in 26%, diminished considerably in 46%, remained stable in 14%, and increased in 14% [Erenberg et al., 1987]. Comparison of videotapes and assessments that were obtained from individuals in childhood and as adults indicates that tic severity and disability diminish in adulthood, but 90% still have tics. Reported improvement was not related to the use of medications [Pappert et al., 2003]. Early tic severity is not a

good predictor of later tic severity [Leckman et al., 1998], and tic outcome does not equate with global well-being or with social and educational functional capabilities in adulthood. Tourette-like disorder (i.e., tourettism or secondary TS) comprises tic syndromes that do not meet the criteria for TS, such as those associated with a variety of acute and chronic neurologic disorders, including head trauma [Krauss and Jankovic, 1997; Majumdar and Appleton, 2002; Singer et al., 1989], stroke [Kwak and Jankovic, 2002], toxins [Ko et al., 2004], cardiac surgery with bypass and hypothermia [Singer et al., 1997], temporal lobectomy [Chemali and Bromfield, 2003], and infectious disease [Dale et al., 2003; Matarazzo, 1992; Northam and Singer, 1991; Riedel et al., 1998; Wohlfart et al., 1961]. The category also includes degenerative disorders, such as neuroacanthocytosis, Huntington’s disease, HallervordenSpatz syndrome, and Creutzfeldt-Jakob disease [Carod-Artal et al., 2004; Jankovic and Ashizawa, 1995; Romstad et al., 2003; Sacks, 1982; Scarano et al., 2002; Stone and Jankovic, 1991]. Tardive tourettism is the de novo appearance of motor and vocal tics in patients during withdrawal from chronic neuroleptic treatment [Klawans et al., 1978].

COMMON PROBLEMS IN TOURETTE SYNDROME The general principle that individuals solely with chronic tics (TS only) are less impaired than those with coexisting neuropsychiatric issues is supported by numerous studies [Channon et al., 2003a; Sukhodolsky et al., 2003]. Factors that had the greatest impact on altering the quality of life in adult TS patients were employment status, obsessive-compulsive behavior, anxiety, depression, and tic severity [Elstner et al., 2001]. Issues highly predictive of hospitalization of children and adolescents with TS are major depressive disorder and bipolar disorder; tic severity itself has only a minimal influence [Coffey et al., 2000]. Children with TS–attention-deficit–hyperactivity disorder have more coexistent disorders overall and lower psychosocial function than those with attention-deficit–hyperactivity disorder only [Spencer et al., 1998]. The severity of attentiondeficit–hyperactivity disorder, rather than tic severity, was the main predictor of associated behavioral and social problems [Hoekstra et al., 2004c]. Comorbidities, however, are not the only cause for social and nonsocial functional difficulties in TS. In a cohort of subjects without comorbidities, the ability to solve problems or to select an appropriate final answer after viewing videos containing interpersonal problem scenarios was below that of a matched control group [Channon et al., 2003a]. The presence of a child with TS in the home, especially one with behavioral comorbidity, can have a significant negative effect on the parents. In a study measuring psychologic morbidity and caregiver burden, parents of children with TS were at significantly greater risk for developing these difficulties than were parents of children with asthma [Cooper et al., 2003].

Neuropsychiatric Issues Obsessive-Compulsive Behaviors Obsessive-compulsive behaviors are common in individuals with TS, and there is evidence for a genetic association

Singer / Tourette Syndrome and Its Associated Neurobehavioral Problems

between obsessive-compulsive disorder and TS [Pauls et al., 1991; Robertson, 1995]. Family studies have identified a higher rate of obsessive-compulsive disorder in close relatives of TS probands [Eapen et al., 1993; Pauls et al., 1991], and segregation analyses of affected families suggest that tics and obsessive-compulsive disorder represent variable expressions of the same genetic trait [Pauls and Leckman, 1986]. A study of obsessive-compulsive behavior dimensions in affected sibling pairs with TS suggests that familial factors contribute significantly to the pattern of symptom phenotype [Leckman et al., 2003]. Nevertheless, obsessivecompulsive disorder is etiologically heterogeneous, and not all cases are associated with a chronic tic disorder [Pauls et al., 1995]. It has been suggested that simple tics, complex tics, and compulsions represent a clinical spectrum of symptoms in TS, with complex tics and compulsions sharing many overlapping features. For example, they are both repetitive, intrusive motor activities that wax and wane, are exacerbated by physical and psychologic stress, are variably suppressible, and are preceded by premonitory urges. It may be difficult to distinguish between complex tics and compulsions (e.g., touching, picking) in patients with TS, and the two may be interwoven (e.g., performing a tic a specific number of times or until it feels “just right”) [Leckman et al., 1994]. Obsessions are defined as recurrent ideas, thoughts, images, or impulsions that intrude on conscious thought and that are persistent and unwelcome. Typical obsessive symptoms include feelings of incompleteness or of a need for symmetry; fears or images of family being harmed, of contamination with dirt or germs, or of being responsible for the misfortune of others; or doubt that an act has been performed even though reason indicates that it has been done. Compulsions are repetitive, purposeful behaviors that are usually performed in response to an obsession, according to certain rules, or in a stereotyped fashion [Como, 1995]. Common compulsive symptoms include ordering and arranging habits, frequent counting, checking (locks, door, stove switches, or under the bed), and repeated hand-washing. Obsessive-compulsive behavior becomes obsessivecompulsive disorder when activities are sufficiently severe to cause marked distress, take up more than 1 hour of the day, or have a significant impact on normal routine, function, social activities, or relationships. The incidence of obsessive-compulsive features in TS is typically reported to be in the range of 20% to 60%, although some studies report higher frequencies [Grad et al., 1987; Robertson, 1995]. Differences in frequency are caused by a variety of factors, including evaluation methods, diagnostic criteria, and the population studied. In studies that used structured interviews and the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, third edition (DSM-III) criteria, the incidence of obsessivecompulsive disorder in TS is in the range of 28% to 62% [Leonard et al., 1992; Pigott et al., 1994]. In a communitybased sample of school children with tics, the observed rate for obsessive-compulsive disorder was 10.9% [Kurlan et al., 2002]. Obsessive-compulsive behaviors generally emerge several years after the onset of tics, usually during early adolescence [Holzer et al., 1994; Pitman et al., 1987]. Several investigators have proposed two subtypes of obsessive-compulsive disorder based on differences in

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prevalence in age groups and implied etiologic relationships: a juvenile subtype and one related to tics [RosarioCampos et al., 2001; Scahill et al., 2003a]. For example, the childhood-onset form is more common in boys and frequently associated with motor tics, whereas a juvenile-onset form occurs in the second decade, is more common in girls, and responds well to therapy. Preceding triggers for compulsive behaviors differ between groups. In patients with tics, a feeling of escalating tension or mental sensation of discomfort, rather than anxiety or cognitive phenomena (i.e., thoughts, ideas, and images) precedes the behavior. In a study comparing symptom profiles in children with obsessive-compulsive disorder with or without tics, the absence of tics was associated with an increased frequency of contamination and washing rituals and repetitive requests for reassurance. The presence of tics was associated with an increased frequency of repetitive behaviors that were unrelated to avoidance of harm [Scahill et al., 2003a]. When tics and obsessive-compulsive behavior coexist, fluctuations in symptoms tended to covary, remaining synchronous across time [Lin et al., 2002b]. Obsessive-compulsive behavioral symptoms in adults with TS are associated with the presence of attention-deficit–hyperactivity disorder and self-injurious behaviors [Eapen et al., 2004], whereas in children with TS, they are associated with impulsive and aggressive behavior, depression, and anxiety [Banaschewski et al., 2003a]. Most evidence, albeit indirect, suggests that obsessivecompulsive disorder is associated with a dysfunction in cortical-striatal-thalamic-cortical circuits and involves the neurotransmitter serotonin. Functional imaging studies reveal increased metabolic activity in the caudate nucleus, cingulate gyrus, and orbitofrontal cortex [Fitzgerald et al., 1999]. Symptoms respond to selective serotonergic reuptake inhibitors, and there is a controversial association with reductions in platelet serotonin levels or cerebrospinal fluid levels of a serotonin metabolite, 5-hydroxyindoleacetic acid [Dolberg et al., 1996; Flament et al., 1987; Thoren et al., 1980]. The finding that patients with obsessive-compulsive disorder and tics responded better to a combination of a dopamine antagonist and a selective serotonergic reuptake inhibitor compared with obsessive-compulsive disorder patients without tics [McDougle et al., 1994] suggests that there may be subtypes of obsessive-compulsive disorder with somewhat different pathophysiologic mechanisms. A possible subgroup of obsessive-compulsive disorder patients whose symptoms are triggered by an autoimmune mechanism after a streptococcal infection has been proposed [Swedo et al., 1998].

Attention-Deficit–Hyperactivity Disorder Attention-deficit–hyperactivity disorder is characterized by impulsivity, hyperactivity, and a decreased ability to maintain attention. The disorder is divided into three distinct forms: inattentive, hyperactive or impulsive, and combined (see Chapter 36). The disorder is common in TS probands and is reported to affect about 50% to 70% of referred TS cases [Comings and Comings, 1985, 1987b]. Attentiondeficit–hyperactivity disorder typically begins about age 4 to 5 years, and in TS patients, it usually precedes the onset of tics by 2 to 3 years. Its appearance is not associated with the concurrent severity of tics, although attention-deficit–

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hyperactivity disorder is common in those with more severe tic symptoms [Robertson et al., 1988]. Whether a genetic relationship exists between TS and attention-deficit– hyperactivity disorder remains controversial. Whereas some investigators have maintained that children with attentiondeficit–hyperactivity disorder are more likely to have a family history and increased incidence of tics [Comings and Comings, 1987b; Knell and Comings, 1993], other studies suggest that attention-deficit– hyperactivity disorder is not genetically related to tics [Pauls and Leckman, 1986; Pauls et al., 1993]. Some investigators have suggested that there may be two distinct populations of TS patients with coexistent attention-deficit–hyperactivity disorder: those with onset of attention-deficit–hyperactivity disorder before the onset of tics and those, possibly genetically associated, with onset after or in concert with the onset of tics [Pauls et al., 1993]. Attention-deficit– hyperactivity disorder was the only psychopathology that occurred significantly more frequently in school-aged children with tics evaluated in special educational and regular classroom settings [Kurlan et al., 2002]. Whether attention-deficit–hyperactivity disorder symptoms identified in children with TS differ from those in attention-deficit–hyperactivity disorder-only cohorts remains unclear. In preliminary studies, those with primary attention-deficit–hyperactivity disorder were significantly more impaired on tests that measure visual search and mental flexibility, had slower reaction times, and made fewer correct responses on simple and choice reaction time tasks [Silverstein et al., 1995]. The presence of attention-deficit–hyperactivity disorder in children with a tic disorder has a distinct impact on cognitive functioning, neuropsychologic capabilities, neuromotor function, behavior, and social and emotional adjustments. Neuropsychologic studies have demonstrated significantly higher full-scale IQ scores in children with TS only compared with children with TS–attention-deficit– hyperactivity disorder [Faraone et al., 1993; Schuerholz et al., 1996], leading investigators to suggest that there may be a lowering of full-scale IQ that is related to attentiondeficit–hyperactivity disorder [Faraone et al., 1993]. Children with attention-deficit–hyperactivity disorder only and TS–attention-deficit–hyperactivity disorder, but not those with TS only, were slow to complete items on the Physical and Neurologic Examination of Subtle Signs battery [Schuerholz et al., 1996]. Children with TS only had less impairment in executive functioning and higher perceptual organizational scores than did groups with TS–attentiondeficit–hyperactivity disorder and attention-deficit–hyperactivity disorder only [Schuerholz et al., 1996]. In patients with tics, the addition of attention-deficit–hyperactivity disorder symptoms correlates with increased psychosocial problems, disruptive behavior, and functional impairment [Carter et al., 2000; Spencer et al., 2001; Stephens and Sandor, 1999; Sukhodolsky et al., 2003]. Scores on the Behavior Rating of Executive Rating Scale for cohorts with attention-deficit– hyperactivity disorder and TS–attention-deficit–hyperactivity disorder, but not TS only, demonstrated impairment on five primary indexes [Mahone et al., 2001, 2002]. In a study evaluating parent-completed questionnaires, results suggested that the severity of attention-deficit–hyperactivity disorder, rather than tics or obsessive-compulsive disorder, determined the magnitude of many behavioral subscale

problems [Hoekstra et al., 2004c]. Others have demonstrated that although the school performance of a child with TS may be impaired by various problems, associated attentiondeficit–hyperactivity disorder appears to be the most important contributing factor [Abwender et al., 1996; Park et al., 1993]. The contribution of attention-deficit– hyperactivity disorder symptoms to social and behavioral problems varies by subtype, with the hyperactive or impulsive subtype having a greater influence than the inattentive form [Hoekstra et al., 2004c].

Anxiety, Depression, and Bipolar Affective Disorder In his original descriptions, Gilles de la Tourette observed that fears and phobias were common in TS. This has been further confirmed by documentation of increased rates of trait anxiety, phobias, panic attacks, and generalized anxiety disorder [Comings and Comings, 1987a; Pitman et al., 1987; Robertson et al., 1997]. Because non–obsessivecompulsive disorder anxiety disorders, especially separation anxiety disorder, are highly associated with tic severity, it has been suggested that severe tics may be anxiety mediated [Coffey et al., 2000]. In a variety of uncontrolled studies, the prevalence of depression in TS patients has ranged from 13% to 76%. In a search for possible associations, higher scores on depression indexes have been associated with the presence of unemployment, coprophenomena, echophenomena, selfinjurious behaviors, social problems, and prior history of depression and with rating scores for obsessive-compulsive behavior, aggression, and self-injurious behavior [Eapen et al., 2004]. Several controlled studies for depression in children all found a higher incidence of depression as compared with controls [Carter et al., 2000; Findley et al., 2003; Sukhodolsky et al., 2003; Wodrich et al., 1997]. In an epidemiologic study of tics in school-aged children with use of the Diagnostic Interview Schedule for Children, the frequency of mania was 1.9%, and the rate of major depressive disorder was 9.7% [Kurlan et al., 2002]. Because TS can be a chronic, socially disabling, and stigmatizing disorder that is associated with obsessivecompulsive disorder and attention-deficit–hyperactivity disorder, the specific causes for depression in TS remain unknown. Genetic studies have demonstrated that major depressive disorder is inherited, but TS and this disorder have been shown to be unrelated [Pauls et al., 1994]. Bipolar affective disorder, characterized by recurrent episodes of altered mood and activity, is also more common in people with TS [Coffey et al., 2000]. Similar to depression, the cause for bipolar affective disorder may be multifactorial.

Episodic Rage and Self-Injurious Behaviors Episodic outbursts (i.e., rage) are defined as discrete episodes of failure to resist aggressive impulses, resulting in serious acts of assault or destruction of property, a degree of aggression out of proportion to the provocation or stress, and aggressive episodes that are not caused by direct effects of a substance, other mental disorder, or general medical condition (according to the DSM-IV). Rage attacks are

Singer / Tourette Syndrome and Its Associated Neurobehavioral Problems

differentiated from temper tantrums by their occurrence in older children, their severe magnitude and resultant damage, and the lack of an obvious or trivial precipitant or stressor. In general, events cannot be interrupted or diverted, they are followed by exhaustion, and most patients are remorseful. Rage attacks and difficulty with aggression have been described in patients with TS [Budman et al., 1998, 2000, 2003; Santangelo et al., 1994]. In a study comparing 37 children with TS and rage attacks with 31 children without this symptom, those with rage were more likely to have attention-deficit–hyperactivity disorder, obsessivecompulsive disorder, and oppositional defiant disorder [Budman et al., 2000]. In children with TS, episodic rage has stereotypic features, represents a nonspecific symptom, and likely has environmental and neurobiologic factors [Budman et al., 2003]. Paroxetine has been used to treat episodic rages in individuals with TS [Budman et al., 1998]. Self-injurious behavior is the deliberate, nonaccidental, repetitive infliction of self-harm without suicidal intent. Self-injurious behavior has been reported in up to 60% of TS patients, although the incidence depends on the definition [Mathews et al., 2004]. In his original report, Gilles de la Tourette described two individuals, 24 and 14 years of age, who continuously injured themselves by biting their tongues or lips [Tourette, 1885]. Subsequent reports have included accounts of head-banging, body-punching, or body-slapping—banging oneself against a hard object, poking sharp objects into the body, scratching body parts, or putting hands through a window. In two separate cohorts, Robertson and colleagues reported a 33% (30 of 90) and 44% (22 of 50) incidence of self-injurious behavior among TS subjects [Robertson et al., 1989; Robertson and Yakeley, 1993]. In both studies, head-banging was most common, followed by hitting and lacerating oneself and biting. It is unclear whether these behaviors are caused by the presence of other disruptive psychopathology, such as obsessions, compulsions, attention-deficit–hyperactivity disorder–related impulsivity, risk-taking, rage, or affective disorders, or by motor stereotypies and tics. In study of 300 TS subjects investigated in the United States and Costa Rica for genetic studies, 27% had mild or moderate self-injurious behavior, and 4% had severe self-injurious behavior (i.e., self-cutting with sharp instruments, harmful poking in eyes, sewing fingers together, deliberate head-banging resulting in concussion) [Mathews et al., 2004]. The most important predictor variables for mild self-injurious behavior were related to obsessive-compulsive behavior and did not correlate with impulse or affect dysregulation, whereas severe selfinjurious behavior predictors were related to lack of impulse control (i.e., rages and risk-taking behaviors) and tic severity but not to obsessive-compulsive behavior. On the basis of these data, assuming that mild self-injurious behavior in TS is caused by compulsions, suggested treatment is like that for obsessive-compulsive disorder, including serotonin reuptake inhibitors, perhaps in conjunction with neuroleptics, and cognitive behavioral therapy.

Other Psychopathologies Other behavioral and emotional problems have been identified in patients with TS. In studies based on the Child Behavior Checklist, up to two thirds of TS subjects had

891

abnormal scores, with clinical problems including obsessivecompulsive behaviors, aggressiveness, hyperactivity, immaturity, withdrawal, and somatic complaints [Hoekstra et al., 2004c; Kurlan et al., 2002; Singer and Rosenberg, 1989; Walkup et al., 1992]. Other investigators have confirmed that somatic complaints are common, but it remains unclear whether these are symptoms of TS or are secondary to anxiety reaction [Frank et al., 1991]. On the basis of parent-completed questionnaires, it has been suggested that attention-deficit–hyperactivity disorder, anxiety, obsessivecompulsive disorder, conduct disorders, depression, discipline problems, dyslexia, mania, panic attacks, phobias, and stuttering occur 5 to 20 times more commonly in clinically referred TS patients than in controls [Comings, 1987].

Tic Severity and Psychopathology The association between psychopathologic behaviors and the severity of tics is controversial and results may be influenced by the use of pharmacotherapy [Rosenberg et al., 1995]. A linear relationship between tic severity and behavioral adjustment has been suggested [Rosenberg et al., 1984], but children with mild or moderate tics are also withdrawn, aggressive, and less popular [Stokes et al., 1991]. Additional studies have concluded that tic severity is not a linear predictor of behavioral disturbance [Hoekstra et al., 2004a; Singer and Rosenberg, 1989] and that results are influenced by the presence of patients without significant behavioral problems despite severe tics (i.e., resilient patients) and patients with poor adjustment despite a mild tic disorder (i.e., vulnerable patients) [Rosenberg et al., 1995].

Academic Difficulties Children with TS often have difficulties in school and many require special attention. In a California school district, 28% of children in special education classes had a tic disorder, with 12% having TS [Comings et al., 1990]. Similar findings have also been reported in Monroe County, New York, where examination of a randomly selected sample of fulltime special education students identified 26% with definite or probable tics [Kurlan et al., 2001]. Some investigators have reported that, depending on the academic skill tested, 16% to 68% of children with TS function below educational expectancy [Hagin and Kugler, 1988]. In a study of 200 children and adolescents with TS, 36% had learning problems, including learning disabilities (22%), poor grades (18%), the need to repeat a grade (12%), and attendance in full-time (8%) or part-time (12%) special education classes [Erenberg et al., 1986]. A variety of factors, including severe tics, medications, attention-deficit–hyperactivity disorder, obsessive-compulsive disorder, learning disabilities, and psychosocial problems, can result in poor school performance in children with school difficulties [Singer et al., 1995c]. In an individual with tics, it is essential to identify and assess each of these individual elements. Motor tics may interfere with handwriting and note taking, whereas vocal tics can interrupt a patient’s speech and result in blockage or hesitation and in embarrassment. Pharmacotherapeutic agents (i.e., clonidine and especially neuroleptic agents) used to suppress tics may further exacerbate existing learning and academic difficul-

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ties by causing sedation, dysphoria, apathy, depression, school phobia, separation anxiety, and cognitive impairment [Bruun, 1988]. Academic achievement may also be affected by the presence of obsessive-compulsive disorder, attentiondeficit–hyperactivity disorder, or other psychopathologies, such as anxiety, depression, or conduct disorders. Although formal psychoeducational evaluations have indicated normal levels of general intellectual functioning, there may be a discrepancy between performance and verbal IQ, impaired visual-perceptual achievement, and decreased visual-motor skills [Bornstein, 1990; Brookshire et al., 1994; Golden, 1984]. The incidence of learning difficulties, including reading, reading comprehension, spelling, and especially math, is increased in children with TS [Brookshire et al., 1994; Burd and Kerbeshian, 1992; Hagin and Kugler, 1988]. In a study defining learning disabilities as a discrepancy of 1.5 standard deviations between IQ and achievement in a group of 42 children with TS, 50% had a learning disability in one academic area, 21% had two areas of disability, and 11% had learning disabilities in three academic areas [Burd and Kerbeshian, 1992]. Discrepancy-based learning difficulties were absent, however, in a group of 21 males with TS but present in 32% of a strictly defined TS–attention-deficit–hyperactivity disorder group [Schuerholz et al., 1996, 1997]. These data suggest that coexistent attention-deficit–hyperactivity disorder may account for the increased incidence of learning difficulties in TS.

Executive Dysfunction Executive function refers to a domain of cognitive abilities (e.g., self-regulation, set maintenance, selective inhibition of responding, cognitive flexibility, planning, prioritizing, organizing time and space) that provides support for organization, anticipation, inhibition, working memory, and control and autoregulation of behavior. Anatomically, these functions are mediated by prefrontal regions of the brain and their interconnecting pathways. Neuropsychologic and executive function testing in children with TS, with and without attentiondeficit–hyperactivity disorder, revealed that those without attention-deficit–hyperactivity disorder performed significantly better on tests of executive function and perceptual organization [Brand et al., 2002; Channon et al., 2003b; Harris et al., 1995; Schuerholz et al., 1996]. These data emphasize that many of the psychologic deficits described in TS may be attributable to coexistent problems. Children with TS only, however, were not free of test abnormalities. For example, TS only patients displayed accurate but slow responses on measures of executive function, particularly those that were timed (e.g., Test of Variables of Attention) [Schuerholz et al., 1996] or on an executive measure involving inhibition and strategy generation [Channon et al., 2003b]. Most notable among these findings, regardless of gender, was a slowed performance on the Letter Word Fluency Test, a timed task involving verbal fluency and an efficient memory search. These findings have led to the hypothesis that patients with TS have a linguistic executive dysfunction involving the speed and efficiency of memory search. It has further been suggested that the abnormal Letter Word Fluency Test result may be a sign of frontostriatal inefficiency [Schuerholz et al., 1996], because there was no impairment on the Semantic Word Fluency Test (which identifies deficits in the posterior

language system), and performance under timed conditions, verbal fluency, and access to memory search systems are mediated by left frontal lobe circuitry [Miceli et al., 1981; Perret, 1974]. Patients with TS and obsessive-compulsive disorder also have deficits in executive function, predominantly in the areas of response inhibition, action monitoring, and error detection [Muller et al., 2003].

Other Problems Migraine Migraine questionnaires indicate that 25% of TS patients have migraine, several-fold higher than the general estimates of 10% to 13% for adults and 2% to 10% for children [Kwak et al., 2003b]. Although the incidence of obsessivecompulsive disorder did not differ between subjects with and without migraine (of interest because of a potential common serotoninergic mechanism), it remains unknown whether the presence of other comorbidities may be important factors.

Sleep Disorders Problems associated with sleep have been reported in about 20% to 50% of children and young adults with TS; the most common issues are difficulties falling and staying asleep and parasomnias. Polysomnographic studies have demonstrated disturbed sleep quality with increased sleep latency, reduced sleep efficiency, prolonged wakefulness after sleep onset, larger sleep stage changes, and altered slow-wave sleep. Disturbed sleep is accompanied by tics in all sleep stages, frequent arousals, periodic limb movements, parasomnias, and sleep apnea [Cohrs et al., 2001; Kostanecka-Endress et al., 2003; Rothenberger et al., 2001; Voderholzer et al., 1997]. Associated comorbidities, including attentiondeficit–hyperactivity disorder; anxiety, including separation anxiety; mood disorders; and obsessive-compulsive disorder, can contribute to the sleep deficits [Allen et al., 1992].

Restless Legs Syndrome TS and restless legs syndrome patients have a desire to move the limbs in association with a preceding urge or sensation, which typically worsens at the end of the day; have periodic limb movements in sleep; and share proposed pathologic associations with dopamine and frontal-striatal-cortical circuits [Lesperance et al., 2004; Muller et al., 1994; Voderholzer et al., 1997]. Restless legs syndrome was reported in 10% of TS probands within a French-Canadian population [Lesperance et al., 2004]. Although restless legs syndrome has not been considered a common comorbidity in TS patients, some investigators believe this diagnosis has been underestimated, in part because of confusion with attentiondeficit–hyperactivity disorder, complex tics, and compulsions [Lesperance et al., 2004].

GENETICS Strong support for TS being an inherited disorder is provided by studies of twins and by follow-up investigations of

Singer / Tourette Syndrome and Its Associated Neurobehavioral Problems

at-risk children [Hyde et al., 1992; McMahon et al., 2003; Price et al., 1985]. Monozygotic twins have an 86% concordance rate for chronic tic disorders, compared with a 20% rate for dizygotic twins [Price et al., 1985]. The search for a genetic site is being pursued by the use of several approaches, including genetic linkage, cytogenetics, candidate gene studies, and molecular genetic studies [Hyde et al., 1992]. Despite extensive evaluations, the precise pattern of transmission and the identification of the genes remain elusive [Pauls, 2003]. Linkage analyses have suggested several chromosomal locations (e.g., 2, 4, 5, 8, 10, 11, 13, 19) but without a clear reproducible locus or convergence of findings [Barr et al., 1999; Curtis et al., 2004; Merette et al., 2000; Simonic et al., 2001; TSAICG 1999]. Possible reasons for these discrepancies include problems defining the phenotype, inaccurate diagnostic assessment, improper ascertainment methods, and difficulties with genetic modeling and data analysis [Heutink et al., 1995; Sadovnick and Kurlan, 1997]. Attempts to link candidate genes with specific synaptic neurochemical markers have produced negative or equivocal results [Barr et al., 1997, 1999; Brett et al., 1997; Devor et al., 1998; Hebebrand et al., 1997; Stober et al., 1999; Thompson et al., 1998]. Gene polymorphism studies have demonstrated variable excess transmission of the 7-repeat allele of the DRD4 variable number tandem repeat [Diaz-Anzaldua et al., 2004; Huang et al., 2002] and heterozygote advantage for GA alleles of the dopamine transporter gene (DAT) del polymorphisms [Yoon et al., 2005]. Earlier proposals suggesting a sex-influenced autosomal-dominant role of inheritance with variable expressivity as TS, chronic tic disorder, or obsessive-compulsive disorder [Pauls and Leckman, 1986] have been seriously questioned. Other investigators have proposed the presence of a single major locus in combination with a multifactorial background (i.e., additional genes with different effect size or environmental factors) [Walkup et al., 1996]. Evaluation of extended families, obtained through the TS proband and use of a data-modeling computer program, suggested that transmission of TS is not consistent with mendelian inheritance [Seuchter et al., 2000]. The possible effects of genomic imprinting, bilineal transmission, epigenetic factors, and geneenvironment interactions further complicate our understanding of TS genetics [Burd et al., 1999; Comings et al., 1989; Eapen et al., 1997; Furtado and Suchowersky, 1994; Hanna et al., 1999; Kurlan et al., 1994; Lichter et al., 1995, 1999; McMahon et al., 1996].

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PANDAS involves an immune-mediated mechanism with molecular mimicry. Antibodies produced against GABHS cross-react with neuronal tissue in specific brain regions, resulting in tic or behavioral symptoms, or both. The existence of this entity, however, remains controversial [Kurlan and Kaplan, 2004; Singer, 2004a; Singer and Loiselle, 2003; Swedo et al., 2004]. For example, concerns continue to be raised about diagnostic criteria, epidemiologic factors, confirmation of infection, and the presence of antineuronal antibodies [Church et al., 2004; Hong et al., 2004b; Kurlan, 1998; Kurlan and Kaplan, 2004; Loiselle et al., 2004; Singer and Loiselle, 2003; Singer et al., 2004]. The proposed post-streptococcal autoimmune disorder PANDAS deserves careful study, but its validity remains unproven. Clinicians considering making this diagnosis should adhere strictly to the formal published criteria [Swedo et al., 1998, 2004] and recognize that the diagnosis requires longitudinal assessments, that a single measurement of antistreptococcal antibodies has limited value, and that treatment with prophylactic antibiotics or immunomodulatory therapies is controversial and associated with potentially serious side effects.

NEUROANATOMIC LOCALIZATION A series of parallel frontal subcortical circuits that link specific regions of the frontal cortex to subcortical structures Motor SMA ACA

Limbic

MOFC Oculomotor

SEF DLPC FEF LOFC

PMC

MC

Prefrontal

NEUROIMMUNOLOGY In 1998, it was proposed that a subset of children with tic disorders or obsessive-compulsive disorder, or both, had symptoms that were temporally associated with a streptococcal infection [Swedo et al., 1998]. Labeled as pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS), essential criteria included prepubertal onset, presence of a tic disorder or obsessivecompulsive disorder, acute fulminant onset or recurrences, association with group A β-hemolytic streptococcal infection (GABHS), and association with neurologic abnormalities. Based on the model proposed for Sydenham’s chorea, it was further hypothesized that the underlying pathology in

CD THAL

PU GP na ot

FIGURE 37-1. Frontal-subcortical circuits. Specific frontal lobe regions serve as sites of origin and thalamocortical targets for five structurally and functionally separate circuits. ACA, anterior cingulated area; CD, caudate; DLPC, dorsolateral prefrontal cortex; MC, primary motor cortex; MOFC, medial orbitofrontal cortex; na, nucleus accumbens; ot, olfactory tubercle; PMC, premotor cortex; PU, putamen; SEF, supplementary eye field; SMA, supplementary motor area; THAL, thalamus.

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[Alexander et al., 1986; Alexander and Crutcher, 1990; Cummings, 1993] provides a unifying framework for understanding the interconnected neurobiologic relationships that exist between TS and its multiple coexistent problems (Fig. 37-1). In brief, the striatum is distinguished by containing several structurally and functionally distinct subcortical and cortical circuits that are shared by the frontal lobe, globus pallidus, and thalamus. Each of these circuits has been associated with a behavioral abnormality seen in TS. The motor circuit, proposed to be abnormal in the production of tic symptoms, originates primarily from the supplementary motor cortex and projects to the putamen in a somatotopic distribution. The oculomotor circuit, possibly influencing ocular tics, begins principally in the frontal eye fields and connects to the central region of the caudate. The dorsolateral prefrontal circuit links Brodmann’s area 9 and 10 with the dorsolateral head of the caudate and appears to be involved with executive functions (i.e., flexibility, organization, constructional strategy, verbal and design fluency) and motor planning (i.e., sequential and alternating-reciprocal motor tasks). It is hypothesized that an abnormality of this circuit could explain problems of a slow memory search and attention-deficit–hyperactivity disorder. The lateral orbitofrontal circuit originates in the inferior lateral prefrontal cortex (area 10) and projects to the ventral medial caudate. Injury to this circuit is associated with obsessivecompulsive disorder, personality changes, mania, disinhibition, and irritability. The anterior cingulate circuit arises in the cingulate gyrus (area 24) and projects to the ventral striatum, which also receives input from the amygdala, hippocampus, and entorhinal and perirhinal cortex. A variety of behavioral problems may be linked with this circuit. Convincing evidence indicates that cortical-striatalthalamic-cortical pathways are involved in the expression of TS and its accompanying neuropsychiatric problems [Berardelli et al., 2003; Singer, 1997; Singer and Minzer, 2003]. In brief, direct evidence for pathophysiologic involvement of cortical-striatal-thalamic-cortical circuits in TS is provided by neurophysiologic studies (absence of Bereitschaft potentials [Obeso et al., 1981]); deficient prepulse inhibition of the startle reflex [Silvestri et al., 1990]; transcranial magnetic stimulation [Ziemann et al., 1997]; abnormal modulation of event-related brain potentials [Howells et al., 1998; Johannes et al., 2001, 2002; Oades et al., 1996]; functional imaging of glucose metabolism [Baxter et al., 1990; Stoetter et al., 1992] and blood flow [Chiu et al., 2001; Diler et al., 2002; Riddle et al., 1992]; volumetric magnetic resonance imaging (MRI) studies [Fredericksen et al., 2002; Hyde et al., 1995; Mostofsky et al., 1999; Peterson et al., 2001, 2003; Stern et al., 2000; Zimmerman et al., 2002]; area measurements of the corpus callosum [Baumgardner et al., 1996; Moriarty et al., 1997; Peterson et al., 1994], functional MRI imaging [Biswal et al., 1998; Gates et al., 2004; Kates et al., 2002]; and examination of ocular movements [Mostofsky et al., 2001; Narita et al., 1997; Serrien et al., 2002b]. Inferred evidence includes the induction or ablation of stereotypic behaviors after micro-injection of dopaminergic agents into rodent striatum [Delfs et al., 1990; Graybiel et al., 2000]; neuroradiographic findings in individuals with secondary tics [Singer, 1997]; neuropsychologic testing abnormalities of executive dysfunction [Harris et al., 1995; Mahone et al.,

2001; Muller et al., 2003; Schuerholz et al., 1996], motortask and visuospatial attention deficits [Mei Yoke Goh et al., 2002; Serrien et al., 2002b; Sheppard et al., 2000]; and tic suppression after neurosurgical treatments that disrupt cortical-striatal-thalamic-cortical circuitry (e.g., deep brain stimulation, leucotomies, and thalamotomies) [Rauch et al., 1995; Visser-Vandewalle et al., 2003]. Although there is general consensus about a cortical-striatal-thalamic-cortical circuit abnormality in TS, the precise pathophysiologic locations remain speculative. Many investigators have focused primarily on the striatal component, whereas others suggest that TS is a cortical dysfunction. The presence of dopaminergic, glutamatergic, GABAergic, serotoninergic, cholinergic, noradrenergic, and opioid systems within cortical-striatal-thalamic-cortical circuits raises the possibility that a variety of transmitters may be involved in the pathobiology of TS [Singer, 1997; Singer and Minzer, 2003]. Because many transmitter systems are interrelated in the production of complex actions, it is possible, if not probable, that imbalances exist within several transmitter systems (Fig. 37-2). Nevertheless, the possibility of a dopaminergic abnormality in TS continues to receive strong consideration because of a therapeutic response to neuroleptics and results from a variety of nuclear imaging protocols [Serra-Mestres et al., 2004; Singer et al., 2002; Wong et al., 1997], CSF [Singer et al., 1982] and postmortem studies [Anderson, et al., 1992; Minzer et al., 2004; Singer et al., 1991, 1995b]. Most available striatal data suggest that there are variable increases in the number of dopamine receptors, elevated levels of dopamine transporters (not associated with dopamine hyperinnervation except possibly in the ventral striatum), and increased intrasynaptic dopamine release. Another possibility, in keeping with evidence suggesting a role for cortical dysfunction, is a prefrontal-dopaminergic abnormality. A semiquantitative immunoblotting investigation demonstrated that the prefrontal area BA9 has increased levels of D2 dopamine receptors, dopamine transporter, vesicular monoamine transporter type 2, and α-adrenergic receptors [Minzer et al., 2004]. It has been postulated that the tonic-phasic model of dopamine release [Singer et al., 2002] might provide a unifying hypothesis; that is, a reduction in tonic (basal) dopamine, postulated to be caused by an overactive dopamine transporter system, could result in a system with elevated levels of dopamine receptors and an increased phasic release of dopamine [Grace, 1993]. A microarray analysis evaluating gene expression pattern in postmortem putamen of patients with TS showed several genes to be upregulated or downregulated, including those that affect synaptic neurotransmission [Hong et al., 2004a].

TREATMENT The decision to treat an individual patient should be based on an initial comprehensive evaluation, including analysis of tics, documentation of coexistent conditions, assessment of problem severity, and determination of resulting impairment. The treatment of various symptoms should be prioritized and individualized with respect to functional impairment by tics and coexistent illnesses, sources of support, capac-

Singer / Tourette Syndrome and Its Associated Neurobehavioral Problems

GABA –

895

FIGURE 37-2. Schematic diagram of cortical-striatalthalamic-cortical circuit illustrates neurochemical pathways. DA, dopamine; GABA, γ-aminobutyric acid; GLU, glutamate; GPe, globus pallidus externa; GPi, globus pallidus interna; LC, locus ceruleus; MR, median raphe; NE, norepinephrine; S, serotonin; SNpc, substantia nigra pars compacta; STN, subthalamic nucleus; VTA, ventral tegmental area.

GABA –

GLU + Striatum GLU + STN GPe

Thalamus

GABA – GLU +

GABA – GPi SNpc DA DA VTA NE

LC

S

MR

ities for coping, and challenges associated with various stages of development [Peterson and Cohen, 1998].

Tics Drug therapy for tics is reserved for patients with tics that are functionally disabling. None of the available pharmacotherapies for tics is curative, and all are associated with potential side effects. Physicians considering behavioral or pharmacologic treatment should be aware of the natural variability and the waxing and waning of tics, a large placebo response, and the influence of coexistent psychopathologies on outcome.

Nonpharmacologic Treatments A variety of nonpharmacologic behavioral treatments (i.e., conditioning techniques, massed negative practice, awareness training, habit reversal, relaxation training, biofeedback, and hypnosis) have been proposed as alternative therapeutic approaches, but few have been

Excitatory Inhibitory

adequately evaluated. In a small study comparing relaxation therapy and minimal therapy (control) groups, there was a greater reduction of tics in the relaxation treatment group at the end of a 6-week training period, but values failed to reach statistical significance [Bergin et al., 1998]. At a 3month evaluation, no differences between therapy groups were apparent. On the basis of this pilot study, relaxation therapy appears to have a limited role in the treatment of tics in TS. Habit reversal training significantly improved tics compared with a supportive therapy group, and the beneficial effect persisted to the time of a 10-month followup evaluation [Wilhelm et al., 2003]. In a small cohort, habit reversal therapy reduced the severity of vocal tics [Woods et al., 2003]. Acupuncture as used in traditional Chinese medicine has been suggested for tic suppression [Wu et al., 1996], although it has not received much attention in the scientific literature. There is little or no supporting scientific evidence for the use of alternative dietary therapies, such as vitamins, protein supplementation, or elimination diets.

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Pharmacotherapy There is no cure for tics, and all pharmacotherapy must be considered symptomatic therapy. If tic-suppressing medication is indicated, a two-tiered approach is recommended: non-neuroleptic drugs for milder tics and typical or atypical neuroleptic drugs for more severe tics (Table 37-1). The goal of treatment is not complete suppression of all motor and phonic tics but reducing them to a level at which they no longer cause significant psychosocial disturbance. Tier 1 medications include clonidine [Gaffney et al., 2002; Leckman et al., 1991], guanfacine [Scahill et al., 2001], baclofen [Singer et al., 2001], and clonazepam [Gonce and Barbeau, 1977]. Several antiepileptic medications, such as topiramate, levetiracetam, and gabapentin, are being investigated as tic-suppressing agents. Among tier 2 medications, classic neuroleptics, dopamine type 2 (D2) receptor antagonists, are effective ticsuppressing agents, but side effects may limit their usefulness. Some investigators prefer pimozide or fluphenazine to haloperidol, because the observed frequency of side effects is reduced [Kossoff and Singer, 2001]. Sulpiride and tiapride, which are substituted benzamides, have been beneficial in Europe, but neither drug is available in the United States. Several studies have confirmed that tetrabenazine, a benzoquinolizine derivative that depletes the presynaptic stores of catecholamines and blocks postsynaptic dopamine receptors, is effective [Jankovic and Orman, 1988]. Newer atypical neuroleptics (e.g., risperidone, olanzapine, ziprasidone, quetiapine) are charac-

terized by a relatively greater affinity for serotonin type 2 (5hydroxytryptamine [5HT2]) receptors than for D2 receptors and the potential for fewer extrapyramidal side effects than occur with typical neuroleptics. Substantial variations in receptor affinity profiles for subtypes of dopamine, serotonin, and adrenergic receptors exist among each of these atypical neuroleptic agents, suggesting that there may be important differences in clinical effects. In this group, risperidone has been studied most extensively. In two randomized, double-blind, placebocontrolled trials, risperidone in a mean or median daily dose of 2.5 mg/day produced a significant reduction of tics compared with placebo controls [Dion et al., 2002; Scahill et al., 2003b]. When compared with other medications, risperidone was equally as effective as clonidine [Gaffney et al., 2002] and appeared superior to pimozide in suppressing tics [Gilbert et al., 2004]. Reported side effects include weight gain [Gilbert et al., 2004], acute social phobia [Scahill et al., 2003b], major depressive disorder and dysphoria [Margolese et al., 2002], sedation [Gaffney et al., 2002], and suspected drug interaction with the human immunodeficiency virus medications ritonavir and indinavir [Kelly et al., 2002]. Several small studies have confirmed the clinical effectiveness of olanzapine [Budman et al., 2001; Stephens et al., 2004], ziprasidone [Sallee et al., 2000, 2003], and quetiapine [Mukaddes and Abali, 2003; Schaller and Behar, 2002]. Because results with the atypical neuroleptic clozapine have been inconsistent, the combination of 5HT2 and D2 receptor antagonist is not always successful in suppressing tics [Caine et al., 1979; Schmider and Hoff, 1998].

TABLE 37-1 Treatment of Tics, Attention-Deficit–Hyperactivity Disorder, and Obsessive-Compulsive Disorder TIC SUPPRESSION

ADHD THERAPY

OCD THERAPY

Tier 1 medications Clonidine Guanfacine Baclofen Clonazepam Gabapentin* Topiramate* Levetiracetam* Tier 2 medications Pimozide Fluphenazine Risperidone Olanzapine Haloperidol Aripiprazole Ziprasidone Quetiapine Tetrabenazine Trifluoperazine Pergolide Donepezil Botulinum toxin† Nicotine patch† Delta-9-tetrahydrocannabinol† Experimental methods Transcranial magnetic stimulation Deep brain stimulation

Common medications Methylphenidate Dextroamphetamine Clonidine Atomoxetine

Fluoxetine Sertraline Paroxetine Fluvoxamine Clomipramine

Other medications Guanfacine Desipramine Nortriptyline Imipramine Bupropion Deprenyl

*Under investigation. † Used in selected situations. ADHD, attention-deficit–hyperactivity disorder; OCD, obsessive-compulsive disorder.

Singer / Tourette Syndrome and Its Associated Neurobehavioral Problems

Other medications include the dopamine agonists pergolide and ropinirole, which have reduced tics when used at much lower doses than prescribed in treating Parkinson’s disease [Anca et al., 2004; Gilbert et al., 2003]. The mechanism of action is thought to involve presynaptic rather then postsynaptic striatal or cortical dopamine receptors. Apparently, not all dopamine agonists produce similar therapeutic effects, because talipexole treatment of adults with TS failed to benefit tics [Goetz et al., 1994]. The distribution and interaction of classic neurotransmitters within frontal subcortical structures make it possible for a variety of neurotransmitters, in addition to dopamine, to be involved in the pathobiology of TS. It is therefore not surprising that multiple nondopaminergic therapies have been proposed for the treatment of tic disorders. Several clinical trials support a beneficial response of TS to delta-9-tetrahydrocannabinol, the major psychoactive ingredient of marijuana [Muller-Vahl et al., 2002, 2003]. Nicotine has a variety of potential mechanisms of action in the central nervous system [Dursun and Kutcher, 1999], and there are reports indicating improved tic control when nicotine gum or a skin patch is used in conjunction with a neuroleptic drug [Sanberg et al., 1989, 1997]. Donepezil, a noncompetitive inhibitor of acetylcholinesterase, has diminished tics in a small number of patients [Hoopes, 1999]. Intravenous immunoglobulin (1 g/kg on 2 consecutive days) was not significantly better than placebo in suppressing tics [Hoekstra et al., 2004b]. Botulinum toxin has been successfully used in treating motor and vocal tics [Awaad, 1999; Trimble et al., 1998]. In 30 patients who received 2.5 IU of botulinum toxin-A in both vocal cords, phonic tics were reduced in 37%, and 50% were tic free [Porta et al., 2004]. The main response time was 5.8 days, and duration was 102 days. Hypophonia was a common side effect.

Surgical Therapy Multiple neurosurgical approaches with diverse target sites, including the frontal lobe (i.e., bimedial frontal leucotomy and prefrontal lobotomy), the limbic system (i.e., anterior cingulotomy and limbic leucotomy), the cerebellum, and thalamus, have been tried in attempts to reduce severe tics [Temel and Visser-Vandewalle, 2004]. Deep brain stimulation, a modern stereotactic treatment proposed for use in other movement disorders, has also been suggested as a potential therapy for the control of tics [Vandewalle et al., 1999]. In published cases, the selected target coordinates of the centromedian nucleus (part of the intralaminar thalamic nuclei), the substantia periventricularis (part of the midline thalamic nuclei), and the ventro-oralis internus were chosen on the basis of lesioning studies [Hassler and Dieckmann, 1970]. Although this technique has several advantages over other neurosurgical approaches (e.g., lack of permanent complications often associated with lesioning procedures, access to less surgically accessible brain regions, simultaneous bilateral stimulation), a cautious approach is recommended pending determination of patient selection criteria and the outcome of carefully controlled clinical trials.

Attention-Deficit–Hyperactivity Disorder Although psychostimulant medications are generally regarded as the treatment of choice for attention-deficit–

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hyperactivity disorder, their use in children with TS has been controversial. Early reports suggested that stimulant medications were associated with the potential to provoke or intensify tics and that tics might persist even when the medication was withdrawn [Barkley et al., 1990; Borcherding et al., 1990; Pollack et al., 1977]. Other investigators countered that patients receiving stimulants did not have a clinically significant worsening of tics [Law and Schachar, 1999; Nolan et al., 1999; Palumbo et al., 2004; TSSG, 2002] or that exacerbations occurred only with lower (starting) [Gadow et al., 1995] or higher doses of medication [Castellanos et al., 1997]. Investigators also suggested that methylphenidate was better tolerated than dextroamphetamine; exacerbations decreased with time even with continued administration of methylphenidate, whereas with dextroamphetamine, fewer exacerbations diminished over the long term [Castellanos et al., 1997]. In summary, there is increasing evidence that stimulants are beneficial for attention-deficit–hyperactivity disorder symptoms in children with a tic disorder and that methylphenidate therapy does not significantly induce or exacerbate tics. Alternative medications available for the treatment of attention-deficit–hyperactivity disorder symptoms in children with TS include clonidine [Tourette’s Syndrome Study Group, 2002], guanfacine [Cohn and Caliendo, 1997], desipramine [Singer et al., 1995a; Spencer et al., 2002], and deprenyl [Feigin et al., 1996].

Obsessive-Compulsive Disorder For TS patients with disabling obsessive-compulsive symptoms, pharmacologic and cognitive-behavioral therapy should be considered. Selective serotonergic reuptake inhibitors and serotonin reuptake inhibitors are the first line of treatment for patients with tic disorders and obsessivecompulsive disorder. Selective serotonergic reuptake inhibitors and serotonin reuptake inhibitors labeled for use in pediatric obsessive-compulsive disorder include fluvoxamine, fluoxetine, sertraline, and clomipramine. Common side effects include activation, sedation, and gastrointestinal problems. Black box warnings have been issued by the U.S. Food and Drug Administration about selective serotonergic reuptake inhibitors causing increased suicide ideation. Suggestions that patients with TS and obsessive-compulsive disorder responded less well to selective serotonergic reuptake inhibitors than obsessive-compulsive disorder–only patients are controversial [Jenike, 2001].

Other Behavioral Disorders Argumentiveness, disruptive behavior, temper tantrums, conduct disorder, anxiety-depression, episodic rage, and selfinjurious behaviors are relatively common problems encountered in patients with TS. In many individuals, these difficulties are comingled with attention-deficit–hyperactivity disorder and obsessive-compulsive disorder, providing a significant challenge for the family and physician. In complex cases, it is essential that the child receive proper evaluation and therapy by a multidisciplinary team capable of providing appropriate diagnostic testing, educational intervention, behavior modification, counseling for the family unit, and pharmacotherapy.

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CONCLUSIONS Neurobehavioral and psychoeducational problems in TS may be related to the putative genetic abnormality, a direct consequence of having a stressful stigmatizing disorder, or coexistent problems, or the difficulties may result from ticsuppressing medications. Whatever the cause, these problems may have serious consequences in the lives of patients with TS. It is therefore essential that evaluations include a careful assessment for difficulties beyond tics and that treatment programs provide comprehensive multidisciplinary approaches. REFERENCES Abwender DA, Como PG, Kurlan R, et al. School problems in Tourette syndrome. Arch Neurol 1996;53:509. Alexander GE, Crutcher MD. Functional architecture of basal ganglia circuits: Neural substrates of parallel processing. Trends Neurosci 1990;13:266. Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 1986;9:357. Allen RP, Singer HS, Brown JE, et al. Sleep disorders in Tourette syndrome: A primary or unrelated problem? Pediatr Neurol 1992;8:275. Anca MH, Giladi N, Korczyn AD. Ropinirole in Gilles de la Tourette syndrome. Neurology 2004;62:1626. Anderson GM, Pollak ES, Chatterjee D, et al. Postmortem analysis of subcortical monoamines and amino acids in Tourette syndrome. Adv Neurol 1992;58:123. Awaad Y. Tics in Tourette syndrome: New treatment options. J Child Neurol 1999;14:316. Banaschewski T, Siniatchkin M, Uebel H, et al. Compulsive phenomena in children with tic disorder and attention deficit-hyperactive disorder. Z Kinder Jugendpsychiatr Psychother 2003a;31:203. Banaschewski T, Woerner W, Rothenberger A. Premonitory sensory phenomena and suppressibility of tics in Tourette syndrome: Developmental aspects in children and adolescents. Dev Med Child Neurol 2003b;45:700. Barkley RA, McMurray MB, Edelbrock CS, et al. Side effects of methylphenidate in children with attention deficit hyperactivity disorder: A systemic, placebo-controlled evaluation. Pediatrics 1990;86:184. Barr CL, Wigg KG, Pakstis AJ, et al. Genome scan for linkage to Gilles de la Tourette syndrome. Am J Med Genet 1999;88:437. Barr CL, Wigg KG, Zovko E, et al. Linkage study of the dopamine D5 receptor gene and Gilles de la Tourette syndrome. Am J Med Genet 1997;74:58. Baumgardner TL, Singer HS, Denckla MB, et al. Corpus callosum morphology in children with Tourette syndrome and attention deficit hyperactivity disorder. Neurology 1996;47:477. Baxter LR Jr, Schwartz JM, Guze BH, et al. PET imaging in obsessivecompulsive disorder with and without depression. J Clin Psychiatry 1990;51 (Suppl):61; discussion 70. Berardelli A, Curra A, Fabbrini G, et al. Pathophysiology of tics and Tourette syndrome. J Neurol 2003;250:781. Bergin A, Waranch HR, Brown J, et al. Relaxation therapy in Tourette syndrome: A pilot study. Pediatr Neurol 1998;18:136. Biswal B, Ulmer JL, Krippendorf RL, et al. Abnormal cerebral activation associated with a motor task in Tourette syndrome. AJNR Am J Neuroradiol 1998;19:1509. Borcherding BG, Keysor CS, Rapoport JL, et al. Motor/vocal tics and compulsive behaviors on stimulant drugs: Is there a common vulnerability? Psychiatry Res 1990;33:83. Bornstein RA. Neuropsychological performance in children with Tourette’s syndrome. Psychiatry Res 1990;33:73. Brand N, Geenen R, Oudenhoven M, et al. Brief report: Cognitive functioning in children with Tourette’s syndrome with and without comorbid ADHD. J Pediatr Psychol 2002;27:203. Brett PM, Curtis D, Robertson MM, et al. Neuroreceptor subunit genes and the genetic susceptibility to Gilles de la Tourette syndrome. Biol Psychiatry 1997;42:941.

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CHAPTER 38

Autistic Spectrum Disorders Deborah G. Hirtz, Ann Wagner, and Pauline A. Filipek

The terms autistic spectrum and pervasive developmental disorders represent a wide continuum of associated cognitive and neurobehavioral disorders, including the following three core defining features: deficits in socialization, deficits in verbal and nonverbal communication, and restricted and repetitive patterns of behaviors [American Psychiatric Association, 1994]. The terms autism, autistic, and autistic spectrum disorders are used interchangeably throughout this chapter and refer to the broader umbrella of pervasive developmental disorders, whereas the term autistic disorder is used in reference to the more restricted disorder as defined by the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV and DSMIV-TR) criteria [American Psychiatric Association, 1994, 2000].

HISTORICAL PERSPECTIVE Kanner [1943] first described a syndrome of “autistic disturbances” with case histories of 11 children who presented between the ages of 2 and 8 years and who shared “unique” and previously unreported patterns of behavior, including social remoteness, obsessiveness, stereotypy, and echolalia. After its initial description, autism was poorly discerned during subsequent decades of the 20th century. The first set of diagnostic criteria for this disorder was formulated by the 1970s [Ritvo and Freeman, 1978; Rutter and Hersov, 1977]. In the DSM-III, the term pervasive developmental disorders was first used to describe “… disorders … characterized by distortions in the development of multiple basic psychologic functions that are involved in the development of social skills and language, such as attention, perception, reality testing, and motor movement” [American Psychiatric Association, 1980, p. 86]. Under this new umbrella of pervasive developmental disorders, the possible diagnoses included the terms infantile autism (onset before age 30 months) and childhood-onset pervasive developmental disorder (onset after age 30 months), with each further subclassified as full syndrome present or residual state, and atypical pervasive developmental disorder. In the DSM-III [American Psychiatric Association, 1980], autism was clearly differentiated from childhood schizophrenia and other psychoses for the first time, and the absence of psychotic symptoms, such as delusions and hallucinations, became one of the six diagnostic criteria. The term infantile autism referred to the more severe signs and symptoms manifesting before 30 months of age. The DSM-IIIR [American Psychiatric Association, 1987] broadened the spectrum of pervasive developmental disorders and narrowed the specific diagnoses to two: autistic disorder and pervasive developmental disorder–not otherwise specified (PDD-NOS). The

DSM-IV (1994) and DSMIV-IR (2000) include five possible diagnoses under the umbrella of pervasive developmental disorders (Table 38-1), which have some concordance with the categories in the World Health Organization’s International Classification of Disease, 10th edition, used primarily abroad [ICD-10, 1992]. Diagnostic criteria are listed in Box 38-1; because many of the criteria include behavior that may not be seen before the age of 3 years, modified DSM criteria have been established for this age range (Table 38-2).

BROADER PHENOTYPE DSM-IV criteria define a range of deficits rather than the absolute presence or absence of a particular behavior as sufficient to meet a criterion for diagnosis. The broader phenotype is called autistic spectrum or pervasive developmental disorder, and it includes children with milder, but definitive social, linguistic, and cognitive deficits. The correct diagnosis is often delayed or missed altogether. Many high-functioning autistic children are diagnosed after presentation to clinics specializing in learning disabilities or attention-deficit–hyperactivity disorder [Porter et al., 1992]. Almost 15% of previously undiagnosed children receiving special education services met criteria for DSM-IIIR autistic disorder in one series [Deb and Prasad, 1994, 2000]. Questionnaires devised to specifically diagnose attention-deficit– hyperactivity disorder do not identify autistic symptoms, and 74% of children with high-functioning autism in another series had been erroneously diagnosed with attention-deficit– hyperactivity disorder despite clear differences in their social competence and cognitive development [Jensen et al., 1997]. The correct diagnosis cannot be made unless the appropriate history is elicited.

CLINICAL FEATURES AND DIAGNOSTIC CRITERIA All children on the autistic spectrum demonstrate the deficits in reciprocal social interactions and verbal and nonverbal communication, with restricted and repetitive behaviors or interests [American Psychiatric Association, 1994, 2000]. There is, nonetheless, marked variability in the severity of symptoms among patients, and cognitive function can range from profound mental retardation through the superior range on conventional IQ tests. Symptoms and signs are discussed in detail in the DSM-IV, in the monograph edited by Rapin [1996a], in the Wing Autistic Disorders Interview Checklist–Revised [Wing, 1996], and in numerous additional publications [Allen, 1988, 1991; Allen and Rapin, 1992; Rapin, 1997].

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TABLE 38-1 The Pervasive Developmental (Autistic Spectrum) Disorders DSM-IV DIAGNOSES*

ICD-10 DIAGNOSES†

Autistic disorder Asperger’s disorder Childhood disintegrative disorder Rett’s disorder PDD-NOS

Childhood autism Asperger’s syndrome Other childhood disintegrative disorder Rett’s syndrome Atypical autism Other PDD PDD, unspecified Overactive disorder With mental retardation With stereotyped movements

No corresponding DSM-IV diagnosis

NOS, not otherwise specified; PDD, pervasive developmental disorder. *From American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Association, 1994. † From World Health Organization. The ICD-10 classification of mental and behavioral disorders: Clinical descriptors and diagnostic guidelines. Geneva: World Health Organization, 1992, 1993.

TABLE 38-2 Autism Characteristics Observable in Children Younger than 3 Years Decreased use of nonverbal behavior (e.g., eye-to-eye gaze, facial expression, body posture, gestures) Lack of social or emotional reciprocity Lack of seeking to share enjoyment, interests, or achievements with other people (i.e., absent showing or pointing) Delayed or absent language skills

Autistic Disorder Qualitative Impairment in Social Interactions (A1). The criteria for qualitative impairment in social interactions (A1) refer to a qualitative impairment in reciprocal social interactions, not to the absolute lack of social behaviors. Behaviors range from total lack of awareness of another person to the presence of eye contact that is not used to modulate social interactions. Marked Impairment in the Use of Multiple Nonverbal Behaviors, such as Eye-to-Eye Gaze, Facial Expression, Body Posture, and Gestures, to Regulate Social Interaction (1a). As infants, some autistic children do not lift up their arms or change posture in anticipation of being held. They may or may not cuddle or stiffen when held and often do not look or smile when making a social approach. Some children do make eye contact, often only in brief glances, but the eye contact is usually not used to get someone’s attention. Other children make inappropriate eye contact by turning someone else’s head to gaze into their eyes. Autistic children often ignore a familiar or unfamiliar person because of a lack of social interest. Some children do make social approaches, although their conversational turn-taking or modulation of eye contact is often grossly impaired. At the opposite extreme of social interactions, some children may make indiscriminate approaches to strangers (e.g., climb into the

Box 38-1 DIAGNOSTIC CRITERIA FOR 299.00 AUTISTIC DISORDER A. A total of six (or more) items from 1, 2, and 3, with two from 1 and at least one each from 2 and 3: 1. Qualitative impairment in social interaction, manifested by at least two of the following: a. Marked impairment in the use of multiple nonverbal behaviors, such as eye-to-eye gaze, facial expression, body postures, and gestures, to regulate social interaction b. Failure to develop peer relationships appropriate to developmental level c. Lack of spontaneous seeking to share enjoyment, interests, or achievements with other people (e.g., by lack of showing, bringing, or pointing out objects of interest) d. Lack of social or emotional reciprocity 2. Qualitative impairment in communication, as manifested by at least one of the following: a. Delay in or total lack of the development of spoken language (not accompanied by an attempt to compensate through alternative modes of communication, such as gesture or mime) b. In individuals with adequate speech, marked impairment in the ability to initiate or sustain a conversation with others c. Stereotyped and repetitive use of language or idiosyncratic language d. Lack of varied, spontaneous make-believe or social imitative play appropriate to developmental level 3. Restrictive repetitive and stereotypic patterns of behavior, interests, and activities, as manifested by at least one of the following: a. Encompassing preoccupation with one or more stereotyped and restricted patterns of interest that is abnormal in intensity or focus b. Apparently inflexible adherence to specific nonfunctional routines or rituals c. Stereotyped and repetitive motor mannerisms (e.g., hand or finger flapping, twisting or complex entire-body movements) d. Persistent preoccupation with parts of objects B. Delays or abnormal functioning occurs in at least one of the following areas, with onset before age 3 years: (1) social interaction, (2) language as used in social communication, or (3) symbolic or imaginative play. C. The disturbance is not better accounted for by Rett’s disorder or childhood disintegrative disorder. From American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Association, 1994.

examiner’s lap before the parent has entered the room, be unaware of psychologic barriers, be described as a child that continuously and inappropriately “gets in your face”). Failure to Develop Peer Relationships Appropriate to Developmental Level (1b). Some autistic children have no age-appropriate friends, and older children often are teased or bullied. A child may want “friends” but usually does not

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TABLE 38-3 Linguistic Terminology TERM Receptive Language Phonology Syntax Semantics Verbal pragmatics Nonverbal pragmatics Expressive Language Fluency Prosody Phonology Syntax Semantics Verbal pragmatics Nonverbal pragmatics

DEFINITION

EXAMPLE*

Decoding of speech sounds Comprehension of grammatical sentence structure

Can the child discriminate between, for example, pa, ta, and da? Is there noncompliance with commands? Do the answers miss the point? Does the child understand humor, jokes, nuances, irony, and sarcasm?

Comprehension of the meaning of words, sentences, or phrases Comprehension of the communicative intent of others Comprehension of gestures and body language Rate, amount, and ease of speech Melody and rhythm of speech Intelligibility of speech Complexity and grammatical accuracy of sentence structure Encoding of meaningful utterances Language use with an appropriate intent to communicate Use of nonverbal communication

Does the child respond appropriately to a gesture?

Is the speech too fast or too slow, or is it labored? Is the intonation unusual (i.e., monotonic or sing-song)? Can a stranger understand at least one half of what the child is saying by 3 years? Are sentences grammatically correct (e.g., “The boy bit the dog.” versus “The dog bit the boy.”)? Are the child’s word choices appropriate? Is there any immediate or delayed echolalia or “rehearsed scripts”? Does the child use language to communicate spontaneously? Does the child appropriately use gestures and conversational turn-taking to punctuate social communication?

*These examples may not apply universally to all children at every developmental level.

understand the concept of the reciprocity and sharing of interests and ideas inherent in friendship. They may refer to all classmates, for example, as friends. One telling example is the child who said, “Oh, I have many, many, 29 friends, but none of them likes me.” Verbal children may have one friend, but the relationship may be limited or may focus only on a similar circumscribed interest, such as a particular computer game. Often, children gravitate to older peers, in which case they play the role of followers, or to much younger peers, in which case they become the leaders. Lack of Spontaneous Seeking to Share Enjoyment, Interests, or Achievements with Other People (e.g., by a Lack of Showing, Bringing, or Pointing Out Objects of Interest) (1c). The characteristic give-and-take in lap play that is typical for developing children by the end of the first year is often missing. Older children often do not point things out or use eye contact to share the pleasure of seeing something with another person, which is called joint attention or social referencing. Lack of Social or Emotional Reciprocity (1d). Some children with autism indicate no interest in other children or adults and prefer to play alone, away from others. Others play with adults nearby or sit on the outskirts of other children’s play and engage in parallel play or simply watch the other children. Some children involve other children in designated, often repetitive play, but often only as “assistants,” without heeding any suggestions from the other children. Some prefer to serve in the passive role in other children’s play, such as the infant in a game of house, and follow others’ directions. Other children may seek out one specific child with whom there is a limited solitary interest that dominates the entire relationship. Qualitative Impairment in Communication (A2). The communication deficits seen in the autistic spectrum are far

more complex than presumed by simple speech delay, and they are similar to the deficits seen in children with developmental language disorders or specific language impairments [Allen and Rapin, 1992]. Expressive language function across the autistic spectrum ranges from complete mutism to verbal fluency, although fluency is often accompanied by many semantic (i.e., word meaning) and verbal pragmatic (i.e., use of language to communicate) errors (Table 38-3). Some mute autistic children do not respond to their names, and often, they are initially presumed to be severely hearing impaired. This syndrome, verbal auditory agnosia, is similar to adult-onset acquired word deafness, with one important exception: Adults with acquired word deafness remain fluent, whereas children with developmental verbal auditory agnosia or verbal auditory agnosia acquired with epileptiform aphasia usually are mute [Rapin and Allen, 1988]. Delay in or Total Lack of the Development of Spoken Language (Not Accompanied by an Attempt to Compensate through Alternative Modes of Communication such as Gesture or Mime) (2a). In early infancy, some children with autistic spectrum disorders do not babble or use any other communicative vocalizations, and they are described as quiet babies. Some children have absolutely no spoken language when speech should be developing, and they fail to compensate with facial expressions or gestures. A typically developing infant or toddler may pull his or her mother over to a desired object and then will clearly point to the object. In contrast, a characteristic behavior of many autistic children is to mechanically use another person’s hand to point to the desired object, an action called hand-over-hand pointing. Other “independent” children make no demands or requests of the parents but learn to climb at a young age and acquire the desired object for themselves.

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In Individuals with Adequate Speech, Marked Impairment in the Ability to Initiate or Sustain a Conversation with Others (2b). Some autistic children speak relatively fluently but are unable to engage in a conversation, defined as two or more parties communicating in a give-and-take fashion on a mutually agreed on topic. A hallmark of verbally fluent autistic children is their inability to initiate or sustain a conversation, although they may be able to respond relatively well to or ask a myriad of questions or talk “at” another person. Stereotyped and Repetitive Use of Language or Idiosyncratic Language (2c). A hallmark of autistic speech is immediate or delayed echolalia. Immediate echolalia refers to immediate noncommunicative repetition of words or phrases spoken by another—the child is simply repeating exactly what was heard without synthesizing the intrinsic language. This ability is a crucial aspect of normal language development in infants under the age of 2 years, but it becomes pathologic when it is still present as the sole and predominant expressive language after the age of about 24 months. Delayed echolalia or scripts refer to the use of highly ritualized phrases that have been memorized, such as from videos, television, commercials, or overheard conversations. The origin of this stereotypic language does not necessarily have to be clearly identifiable. Many older autistic children incorporate the scripts in appropriate conversational context, which can give much of their speech a rehearsed and often more fluent quality relative to the rest of their spoken language. Children also demonstrate difficulties with pronouns or other words that change in meaning with context, and they often reverse pronouns or refer to themselves in the third person or by name. Others may use literal idiosyncratic phrases or neologisms. Verbal autistic children may speak in detailed and grammatically correct phrases, which are nonetheless repetitive, concrete, and pedantic. If a child’s answers to questions seem to miss the point, further history and conversation with the child should be elicited, because this is also a hallmark of autistic language deficits. Lack of Varied, Spontaneous Make-Believe or Social Imitative Play Appropriate to Developmental Level (2d). Some autistic children do not appropriately use miniature objects, animals, or dolls in pretend play. Others use the miniatures in a repetitive, mechanical fashion without evidence of representational play. Some highly verbal children may invent a fantasy world that becomes the sole focus of repetitive play. A classic example of the lack of appropriate play is the fluent autistic preschooler who “plays” by repeatedly reciting a soliloquy of the old witch scene verbatim from Beauty and the Beast while manipulating dollhouse characters in sequence precisely according to the script. When given the same miniature figures and dollhouse but instructed to play something other than Beauty and the Beast, the same child is incapable of synthesizing any other play scenario. Restricted, Repetitive, and Stereotypic Patterns of Behaviors, Interests, and Activities (A3). This category of stereotyped behaviors and interests follows the qualitative multiformity seen with the previous criteria. Encompassing Preoccupation with One or More Stereotypic and Restricted Patterns of Interest That Is Abnormal in Intensity or Focus (3a). Some verbal autistic children ask the same question repeatedly, regardless of what reply is given, or they engage in highly repetitive, perseverative play.

Others are preoccupied with special interests that are highly unusual. For example, many children are fascinated with dinosaurs, but autistic children may amass exhaustive facts about every conceivable type of dinosaur and about which museums house which particular fossils; these children often repeatedly “share” their knowledge with others, regardless of the others’ interest or suggestions to the contrary. Apparently Inflexible Adherence to Specific Nonfunctional Routines or Rituals (3b). Many autistic children are so preoccupied with “sameness” in their home and school environments or routines that little can be changed without prompting a tantrum or other emotional disturbance. For example, some insist that all home furnishings remain in the same position, that all clothing is a particular color, or that only one specific set of favored sheets is on the bed. Others may eat only from a specific plate when sitting in a specific chair in a specific room, which may not necessarily be the kitchen or dining room. Some children may insist on being naked while in the home but insist on wearing shoes to the dinner table. This inflexibility may also pertain to familiar routines, such as taking only a certain route to school, entering the grocery store only by one specific door, or never stopping or turning around after the car starts moving. Many parents may not be aware that they are following certain rituals to avoid the emotional upheaval, or they may be aware but are too embarrassed to volunteer such information. Within this context, some children have distinct behavioral repertoires that they use to sustain sameness, even when not imposed externally. By adulthood, many of these rituals may evolve to more classic obsessive-compulsive symptoms. Stereotyped and Repetitive Motor Mannerisms (e.g., Hand or Finger Flapping or Twisting or Complex EntireBody Movements) (3c). Some children have obvious stereotypical movements, such as florid hand clapping or arm flapping whenever excited or upset, which is pathologic if it occurs after the age of about 2 years. Running aimlessly, rocking, spinning, bruxism, toe-walking, or other odd postures are commonly seen in autistic children. Others may repetitively tap the back of the hand in a less obtrusive manner or touch or smell items. In higher-functioning youngsters, the stereotypic movements may become “miniaturized” as they get older into more socially acceptable behaviors, such as pill rolling [Bauman, 1992; Rapin, 1996a]. Persistent Preoccupation with Parts of Objects (3d). Many children demonstrate the classic behavior of lining up toys, videotapes, or other favored objects, but others may simply collect things for no apparent purpose. Many are preoccupied with repetitive actions, such as opening and closing doors, drawers, or flip-top trash cans or turning light switches repetitively off and on. Others repetitively flick string, elastic bands, measuring tapes, or electric cords. Younger autistic children are often particularly fascinated with water, and they especially enjoy transferring water repetitively from one vessel into another. Others love spinning objects or themselves.

Asperger’s Disorder Unbeknownst to each other, the year after Kanner’s [1943] first description of autism, a pediatrician named Hans Asperger [1991] also reported four children with “autistic psychopathy” who had presumably milder autistic behaviors

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and normal IQ. The diagnostic term was included for the first time in DSM-IV (1994), and the criteria for the qualitative impairments in social interaction and restrictive and repetitive patterns of behaviors and activities are identical to those for autistic disorder. In sharp contrast to the autistic disorder criteria, which include deficits in verbal and nonverbal communication and play, Asperger’s criteria state that there is no evidence of “clinically significant” language delay, such that the child uses single words by age 2 years and communicative phrases by age 3 years. Normal or near-normal cognitive function is also the rule, including self-help skills, “adaptive behavior (other than in social interaction), and curiosity about the environment in childhood” [American Psychiatric Association, 1994, p. 77]. The apparent lack of language deviance is required for diagnosis, and high verbal skills are the rule in Asperger’s disorder. This situation usually leads to later clinical recognition than with other autistic spectrum disorders [Volkmar and Cohen, 1991]. In addition to the lack of deviant language development, Szatmari and colleagues [1995] further define this disorder by the complete lack of delayed echolalia, pronoun reversal, or neologisms in language production. The language in Asperger’s disorder is clearly not typical or normal. For example, there usually is pedantic and poorly intoned speech, poor nonverbal pragmatic or communication skills, and intense preoccupation with circumscribed topics, such as the weather or railway timetables [Ghaziuddin and Gerstein, 1996; Klin et al., 1995; Wing, 1981]. These patients often exhibit deficits in the semantics and verbal pragmatics of language, resulting in concrete and literal speech. Their answers often miss the point. Socially, individuals with Asperger’s disorder are usually unable to form friendships. Because of their naive, inappropriate, one-sided social interactions and lack of empathy, they may be ridiculed by their peers. Often, they cease their attempts to develop friendships because of the cruel ridicule and then remain extremely socially isolated. However, they honestly desire success in interpersonal relationships and are often quite puzzled when they do not succeed [Bonnet and Gao, 1996]. Fine and gross motor deficits have been described, including clumsy and uncoordinated movements and odd postures [Asperger, 1991; Klin et al., 1995; Wing, 1981]. However, motor apraxia is an inconsistent finding. Some studies have attempted to distinguish Asperger’s disorder from high-functioning autism on the basis of neuropsychologic constructs. In a study of high-functioning autistic children and children with Asperger’s disorder with similar full-scale IQ measures, the children with Asperger’s disorder had a significantly higher verbal IQ, with a verbal-nonverbal IQ discrepancy of 24 ± 14 points, whereas the autistic patients had similar verbal and performance IQ scores [Eisenmajer et al., 1996; Klin et al., 1995]. Deficits in fine and gross motor skills, visual-motor integration, visual-spatial perception, nonverbal concept formation, and visual memory were more typical of the Asperger subjects, whereas deficits in articulation, verbal output, auditory perception, vocabulary, and verbal memory were more predictive of the autistic subjects [Klin et al., 1995]. The validity of Asperger’s disorder as a definitive diagnostic entity separate from high-functioning (verbal) children with autism remains controversial [Kurita, 1997; Lord et al., 2000a; Schopler, 1996]. Clinically, the diagnosis of

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Asperger’s disorder is often given as an alternative, more acceptable, “A-word” to high-functioning autistic children [Bishop, 1989]. The similarity and overlap of signs and symptoms of Asperger’s disorder with nonverbal learning disabilities additionally expand the spectrum of these developmental disorders [Harnadek and Rourke, 1994; Klin et al., 1995; Rourke, 1989].

Childhood Disintegrative Disorder Childhood disintegrative disorder refers to the rare phenomenon of normal early development until at least age 24 months, followed by a neurodevelopmental regression that results most often in autistic symptoms. Childhood disintegrative disorder, previously called Heller’s syndrome, dementia infantalis, or disintegrative psychosis, usually occurs between 36 and 48 months of age but may occur up to 10 years of age. There have been only about 100 reports of childhood disintegrative disorder in the literature [Volkmar et al., 1997]. The hallmark signs include the loss of previously normal language, social, play, or motor skills and frequently include the onset of restrictive repetitive behaviors, all typical of autism (Box 38-2) [American Psychiatric Association, 1994]. Childhood disintegrative disorder is usually associated with more severe autistic symptoms than is early-onset autism, including profound loss of cognitive skills resulting in mental retardation [Evans-Jones and Rosenbloom, 1978; Tuchman and Rapin, 1997; Volkmar and Rutter, 1995]. There is a 4:1 male predominance and a mean age of onset of 29 ± 16 months; more than 95% demonstrate symptoms of speech loss, social disturbances, stereotyped behaviors, resistance to change, anxiety, and deterioration of self-help skills [Volkmar, 1994].

Atypical Autism or Pervasive Developmental Disorder—Not Otherwise Specified The diagnoses of atypical autism or PDD-NOS are used when clinically significant autistic symptoms are present involving reciprocal social interactions, verbal or nonverbal communication, or stereotyped behavior, interests, and activities but criteria are not met for a specific diagnostic category under the umbrella of autistic spectrum or pervasive developmental disorders (e.g., a child who does not meet the required 6 of 12 criteria for the diagnosis of autistic disorder). Children whose symptoms are atypical or not as severe are coded under this diagnosis. With the acceptance of the broader phenotype of autistic spectrum disorders, the use of these terms will probably decline appropriately.

Rett’s Syndrome Rett’s syndrome is a neurodegenerative disorder occurring mainly in females with the onset of specific deficits after a period of normal development after birth. Although it was first described in 1966 by Rett [1966], clinical awareness of the syndrome did not occur until Hagberg and associates [1983] reported 35 additional cases. The prevalence was 1 case per 10,000 children in Sweden [Hagberg, 1985] and 1 per 23,000 in a Texas population-based registry [Kosinetz et al., 1993]. Females with Rett’s syndrome have a reduced life expectancy; approximately 70% survive to age 35 years

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BOX 38-2 DIAGNOSTIC CRITERIA FOR 299.10 CHILDHOOD DISINTEGRATIVE DISORDER

Box 38-3 DIAGNOSTIC CRITERIA FOR 299.80 RETT’S DISORDER

From American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Association, 1994.

From American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Association, 1994.

[Naidu, 1997]. The initial clinical presentation occurs between the ages of 6 and 18 months with loss of cognitive, motor, and social or communicative skills (Box 38-3). Head circumference is normal at birth, but microcephaly develops later. Neuropathologic examination does not reveal degeneration but does identify small, closely packed neurons with reduced dendritic spines [Armstrong, 1997]. Distinctive stereotypic hand movements, such as wringing or washing, and poor truncal or gait coordination develop, with loss of social engagement and severely disordered receptive and expressive language development and cognitive skills. Abnormal sleep patterns are also characteristic [Armstrong, 1997; Hagberg, 1983; Naidu, 2003; Percy et al., 1990]. Although the loss of function that is apparent in the first few years of life is devastating, symptoms become relatively static thereafter [Naidu, 1997]. The initial loss of function is accompanied by inconsolable crying, screaming, agitation, breathing irregularities, food refusal, and in some cases, seizures [Armstrong, 1997]. Common breathing dysfunctions include periodic apnea during wakefulness; intermittent hyperventilation; electroencephalographic (EEG) abnormalities, including a slow waking background with intermittent rhythmic slowing; and epileptiform discharges

with or without clinical seizures. Almost all patients have abnormal EEG patterns with slow background activity and spikes, but clinical seizures occur in about one third of cases [Naidu, 1997]. Scoliosis, growth retardation, and small feet are common [Armstrong, 1997; Percy et al., 1990]. Some patients exhibit an incomplete phenotype, and they may retain hand use or develop symptoms more slowly. Rett’s syndrome is the first pervasive developmental disorder to be associated with a single-gene mutation [Amir et al., 1999; Neul and Zoghbi, 2004]. Between 80% and 96% of cases are caused by mutations in the gene encoding MECP2. Almost all mutations are of paternal orgin. MECP2, located at the tip of the long arm of chromosome 8, binds methylated DNA and regulates gene expression. Clinical phenotypes within Rett’s syndrome are related to location of the mutations relative to the nuclear localization sequences [Neul and Zoghbi, 2004]. Animal models that carry a mutation similar to that of MECP2 in humans demonstrate impaired nesting behavior and social regulation [Moretti et al., 2005]. MECP2-knockout mice develop symptoms after reaching maturity, which is analogous to the fate of girls with Rett’s syndrome who develop normally until 6 to 18 months of age. The gene is expressed after a certain period of apparently normal brain development. The phenotypic spectrum of MECP2 mutations is broader than initially expected; uncommon clinical variants may include Rett’s syndrome variants, mentally retarded males, and autistic children. Familial cases of Rett’s syndrome suggested an X-linked gene with male lethality, but boys have been identified with mutations in MECP2 that produce three phenotypes: those with severe epileptic encephalopathy; those with XXY karyotype and classic Rett’s syndrome (i.e., with one normal copy of MECP2); and those

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with mental retardation [Neul and Zoghbi, 2004]. A mutation in MECP2 has been found in a few girls with classic autistic disorder [Carney et al., 2003; Zappella et al., 2003].

Autistic Regression Approximately 25% to 35% of autistic children appear to develop normally until about 12 to 24 months, but their language and social skills then regress [Tuchman and Rapin, 1997]. Parents report that children are responsive, smile, wave bye-bye, and say some words, but they then suddenly or gradually stop speaking and seem to withdraw completely. One difficulty hindering a better understanding of autistic regression involves the disentangling of age at onset from age at recognition [Volkmar et al., 1985]. Many children thought by parents to be normal in the first 18 months may show signs or symptoms on retrospective evaluation of home movies and videotapes by as early as 12 months of age [Adrien et al., 1992; Bailey et al., 1996; Osterling and Dawson, 1994]. Parents of autistic children with or without a history of language regression demonstrate similar rates of features of the broader autism phenotype (about 30%), which may indicate that the genetic susceptibility is not different in children that do or do not demonstrate regression [Lainhart et al., 2002].

THEORIES OF COGNITIVE IMPAIRMENT Three overlapping models of the cognitive and behavioral underpinnings of the manifestations of autism have been proposed: theory of mind, weak central coherence, and executive dysfunction [Volkmar et al., 2004]. The theory of mind, proposed by Baron-Cohen [1991], suggests that social dysfunction results from the inability to understand or distinguish between one’s own or other people’s mental states, including beliefs, desires, and motivation. This dysfunction results in an inability to understand or predict behavior, focusing on the literal meaning of language and acts, and it interferes with the ability to communicate [Baron-Cohen, 1995; Kleinman et al., 2001; Leslie, 1987]. The basis of the weak central coherence theory is that the autistic individual has great difficulty making use of context, tends to pay attention to the parts rather than the whole, and cannot distinguish meaningful information from random and meaningless stimuli [Happé and Frith, 1996]. The autistic individual is unable to synthesize multiple pieces of information into higher-order concepts that help guide behavior [Briskman et al., 2001; Jolliffe and Baron-Cohen 2000], resulting in selective deficits of complex information processing and cognitive inflexibility. Processing of central coherence involves activation of both frontal lobes anterior to the motor strip, but many of these activities may involve much more widespread brain activation and may occur automatically [Deuel, 2002]. The executive dysfunction hypothesis is based on problems in a wide array of cognitive processes that require planning and organization. The autistic individual has difficulty in shifting attention and in perseveration, difficulty with change, reduced ability to plan, and ineffective problemsolving skills [Hughes et al., 1994; Ozonoff, 1997; Pennington and Ozonoff, 1996]. The areas involved are the dorsolateral

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prefrontal cortex and the basal ganglia, hippocampus, amygdala, and thalamus [Goldman-Rakic, 1999]. Multiple deficits are seen in complex abilities across multiple domains. Neuropsychologic testing of 33 autistic subjects with IQs higher than 80 suggested selective impairments in complex information processing within and across different domains compared with that of controls [Minshew et al., 1997]. Functional magnetic resonance imaging (fMRI) studies by Minshew and colleagues [1999] demonstrated that higherorder cognitive and neocortical dysfunction can be seen in tasks requiring higher cognitive control of visual saccades. Bachevalier [1994] hypothesizes that structures in the medial temporal lobes, and specifically the amygdala, that are involved in the regulation of emotional reactions and memory are implicated in the etiology of autism. Future studies of functional imaging in very early childhood stages of crosssectional and longitudinal autistic spectrum disorders will help illuminate the dynamic evolution of cognitive processes deficient in autism. These three theories are overlapping, not mutually exclusive, and not necessarily exclusive to autism. Baron-Cohen and colleagues [2001] suggested all three may be operative and may sometimes confer an advantage leading to specific strengths. It has been suggested that the rare savant skills in autistic individuals may result from the effect of increased processing within specific modules at the expense of intermodular processing or feedback [Deuel, 2002; Scheuffgen et al., 2000]. Consistent with these theories are three deficits that can be identified at an early age and are key to mediating later social development in the normal child: joint attention skills, or an inability to share a common focus of attention with another person [Mundy, 2003], which is most related to theory of mind; imitation, a key component in social learning [Rogers, 1999]; and interpersonal relatedness, or preferential orientation to social stimuli [Dawson et al., 1998; Klin, 1991; Mundy and Neal, 2001].

EPIDEMIOLOGY Until recently, autism was thought to be rare [Fombonne, 2001, 2003a, 2003b]. For many years after autism was first described in the 1940s, prevalence was considered to be 2 to 4 cases per 10,000 children [Wing and Potter, 2002]. Fombonne [2003a] reviewed 16 studies published from 1966 to 1991; the median prevalence was 4.4 per 10,000; for the 16 studies published from 1997 to 2001, the median was 12.7 per 1000. Definitions used, screening methods, diagnostic criteria, and completeness of sampling varied in these studies; all have methodologic issues affecting prevalence results. A study by the Centers for Disease Control and Prevention (CDC) examined children in metropolitan Atlanta, Georgia, who were 3 to 10 years old in 1996 and found a prevalence of children who were diagnosed with an autistic spectrum disorder (i.e., autistic disorder, PDD-NOS, or Asperger’s disorder) of 3.4 per 1000 (CI, 3.0 to 3.7) [Yeargin-Allsopp et al., 2003]. Prevalence was comparable for black and white children. This study did not include full population screening for case ascertainment but did use multiple ascertainment sources. European and U.S. studies using multiple sources based on repeated screening, standardized diagnostic measures,

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and community surveys to determine the prevalence of autism indicate, for children born in or later than 1985, the prevalence of autistic spectrum disorder is about 3 to 6 cases per 1000 children, and for Asperger’s disorder, the rate is 1 to 4 cases per 1000 children [Baird et al., 2001; Bertrand et al., 2001; Chakrabarti and Fombonne, 2001; Kadesjö et al., 1999; Kielinen et al., 2000; Magnússon and Saemundsen, 2001]. The reported prevalence of autism has dramatically increased, and some have called it an epidemic. A number of factors contribute to the apparent increase. Diagnostic criteria have evolved and broadened; the concept of autism is now defined as autistic disorder plus the broader autistic spectrum disorders, including Asperger’s syndrome and PDD-NOS; the growing public awareness among parents and teachers has led to earlier and more accurate diagnoses; the increased availability of services may influence the frequency of diagnosis; and children earlier diagnosed as mentally retarded may have met current criteria for autism [Prior, 2003]. Case ascertainment methodology in recent studies is also key, because using multiple sources and broad population screening increases the number of cases found. Although all these factors contribute to the increase, it is not known to what extent. Existing epidemiologic data are inadequate to determine whether autism has truly increased. It is important for etiologic reasons and for public health and educational planning to ascertain whether the rise in cases is genuine, if it is continuing, and to what degree. The CDC is monitoring over time the prevalence of autism in a number of U.S. sites using consistently applied ascertainment and diagnostic protocols [Croen et al., 2002; Fombonne, 2003a]. If most of the increase reflects more complete and accurate diagnosis in children at a younger age than previously, the rates should level off as the number of previously overlooked children decreases [Fombonne, 2003a]. The state of California, because of a huge increase in the demand for services for autistic children, has closely followed the prevalence of autism. Birth year prevalence rates have shown large increases, which may be influenced by many factors. In 1970, the prevalence based on children receiving services was 0.4 cases per 1000 children; the rate in 2002 for children with autistic disorder born in 1997 was 3.1 per 1000. In the 4 years from 1998 to 2002, the population receiving services doubled, and that number did not include those with the broader autism spectrum, those not yet diagnosed, or those younger than 3 years old [California Department of Developmental Services, 2003]. Of children diagnosed with autistic disorder, approximately 30% do not have intellectual impairment, 30% have mild-to-moderate cognitive impairment, and 30% to 40% are severely impaired. The mean male-to-female ratio is 4:1 or greater for the milder forms, but as severity of cognitive impairment increases, the male-to-female ratio decreases to 1.3 to 1 [Yeargin-Allsopp et al., 2003]. The rate of PDDNOS is approximately 1.5 times that of autistic disorder; the rate of Asperger’s disorder is one fourth that of autistic disorder. Childhood disintegrative disorder and Rett’s syndrome are rare. Children with autistic disorder and a measurable IQ of less than 50 are more likely than those who are high functioning to be female and to have minor physical anomalies, neuroimaging abnormalities, microcephaly, and epilepsy [Nicholson and Szatmari, 2003]. Those with specific, known inherited conditions such as tuberous sclerosis or phenyl-

ketonuria are likely to be more severely cognitively impaired [Rutter et al., 1994]. Studies previously suggesting an association between autism and social class were conducted before 1980, and results might have reflected selective case findings [Fombonne, 2003a]. Some of the current data do not confirm this [Fombonne, 2003a; Magnússon and Saemundsen, 2001]. Other data from California indicate that in a large population born between 1989 and 1994, women older than 35 years were three times more likely to have an autistic child than women younger than 20 years. Women with a postgraduate education were twice as likely to have an autistic child as women with less than a high school education. Risk was also increased in multiple births (RR = 1.7; 95% CI, 1.4 to 2.0) and in black children (RR = 1.6, 95%; CI, 1.5 to 1.8) [Croen et al., 2002].

DIAGNOSTIC EVALUATION AND SCREENING Autistic spectrum disorders can be reliably diagnosed in children as young as 2 years [Lord, 1995; Moore and Goodson, 2003], and early intervention is beneficial [Lord, 1995; National Research Council, 2001]. However, the average age of diagnosis is reported as 3 to 6 years [Howlin and Moore, 1997; Mandell et al., 2002], and it has remained fairly stable over the past decade. There is evidence that age of diagnosis varies as a function of ethnicity and socioeconomic status [Mandell et al., 2002]. Parents often report concerns about their child’s social and communication skills, and they seek medical assistance long before a formal diagnosis is obtained. The American Academy of Pediatrics and the CDC launched an awareness campaign to sensitize pediatricians and parents to the early symptoms of autism, to encourage caregivers to listen to parents’ concerns, and to encourage parents to be assertive in making sure that their concerns are addressed. The campaign includes evaluating strategies for screening and developing resources and tools for physicians. Clinicians involved with the care of children should become knowledgeable about the risk factors, early warning signs, and diagnostic procedures for autistic spectrum disorders (see “Resources for Families”). They should also be aware of and have available information about appropriate local services to which they can refer families for diagnosis and treatment.

Screening and Diagnostic Instruments Symptoms of autistic spectrum disorder vary with characteristics of the child, including the child’s age, IQ, and temperament. Although all children with autistic spectrum disorder share core features, there is great heterogeneity within this population. Some characteristics, such as repetitive behavior, are more common at certain ages and levels of cognitive functioning. This heterogeneity poses challenges to recognition during typical medical appointments. The Child Neurology Society and American Academy of Neurology published a “Practice Parameter for the Screening and Diagnosis of Autism” [Filipek et al., 1999, 2000]. A two-level approach is recommended. Level 1 involves developmental screening as part of routine well-child care, fol-

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lowed by an autistic spectrum disorder–specific screen for children identified with developmental delay. Level 2 involves formal diagnostic procedures to determine whether the child has autistic spectrum disorder. This level of diagnostic evaluation is conducted by an experienced clinician, and it uses information gleaned from the medical history, neurologic evaluation, and developmental testing to determine the child’s developmental profile.

Instruments for Autistic Spectrum Disorders Screening “Red flags” for language development can be easily recognized and should engender prompt referral (Box 38-4). Screening instruments for autistic spectrum disorder are in various stages of development. Presented here are those that have reported good psychometric properties (although they all need further development and psychometric evaluation) and that are available for use by clinicians. These instruments are most sensitive when they follow general developmental screening and are applied when a child has already been identified with delayed or atypical development. Some of these instruments are also being validated for use in the general population as a first-step screening, which would be desirable in many settings. However, administration of autistic spectrum disorder– specific screening tools after screening for and identification of atypical development is the method with the most sensitivity (i.e., probability of correctly identifying a child with autistic spectrum disorder) and specificity (i.e., proportion of non– autistic spectrum disorder cases correctly identified). The Checklist for Autism in Toddlers [Baird et al., 2000, 2001] was developed in Great Britain, and it is most useful in screening children 18 to 24 months old. It was designed for use in the general population and to be administered in the home by a medical caregiver. The Checklist for Autism in Toddlers is intended to be cost-effective and sensitive to early signs of autistic spectrum disorder. Parents respond to nine items asking about their child’s social orienting behaviors, such as pretend play, joint attention, and pointing. The clinician completes five items after observing the child. Unfortunately, when administered in the general population, the sensitivity has been disappointing, with high rates of false-negative results. The developers recommend a screen-rescreen procedure (at 18 and again at 19 months), which increases specificity to within acceptable limits [Charman et al., 2002].

Box 38-4 RED FLAGS FOR LANGUAGE DEVELOPMENT Prompt referral should be made for any of the following: No vocalizations by 6 months No polysyllabic babbling by 12 months No spontaneous (not echoed) single words by 18 months No spontaneous phrases by 24 months No spontaneous sentences by 36 months Any loss of babbling, single words or phrases, at any age Any loss of comprehension, including responding to name, at any age

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Scambler and colleagues [2001] conducted a small study in which they demonstrated better sensitivity (65%) and specificity (100%) when using the Checklist for Autism in Toddlers to distinguish children with autism from among a group already identified with developmental problems. They improved on this further by developing their own criteria (i.e., Denver Criteria) for defining risk status. The Checklist for Autism in Toddlers worked best with children whose developmental level was within the 18- to 24-month range despite being older in chronologic age. The sample size was small, and the Denver Criteria were developed ad hoc. Although the Checklist for Autism in Toddlers looks promising for this type of use, more validation is needed. Development of the Checklist for Autism in Toddlers is ongoing, and there are attempts at modifications to improve sensitivity and specificity within the general population. The Modified Checklist for Autism in Toddlers (M-CHAT) [Robins, 2001] relies only on parent report, and it is undergoing testing in a population of 24-month-old children. Preliminary data are encouraging for being able to accurately detect autistic spectrum disorder with few false-positive or false-negative results in a mixed sample, including high-risk and general pediatric populations. Its usefulness as a screening tool in a general population is not yet determined. The Screening Tool for Autism in Two-Year-Olds [Stone et al., 2000] is composed of interactive items administered by a clinician to children 24 to 35 months old. It is designed to identify children with autistic disorders (not the full range of autistic spectrum disorder) from a population of children identified with developmental delays. The Screening Tool for Autism in Two-Year-Olds quantifies behaviors in four domains: Play, Requesting, Directing Attention, and Motor Imitation. The instrument requires training in administration and scoring, and it takes about 20 minutes to complete. Strong psychometric properties are reported, although they are derived from small samples, and there is need for further development (e.g., evaluation of usefulness with the full range of autistic spectrum disorder) [Stone et al., 2004]. The investigators suggest that the qualitative information obtained during the screening can be used to inform intervention goals for individual children. In some settings, this may outweigh the inconvenience of the need for training and the relatively longer administration time. The Pervasive Developmental Disorders Screening Test, version II (PDDST-II) [Siegel, 2004] is a parent-completed questionnaire for children younger than 6 years (Box 38-5). Different versions are available for use in a primary care setting, use at the point of entry to developmental services (e.g., Child Find, Early Start), and use in autism specialty clinics to differentiate autism from other developmental disorders. Normative data are derived from more than 500 children with autistic spectrum disorder and from comparison groups with other neurologic disorders or high-risk status (e.g., very low birth weight). Excellent sensitivity and specificity are reported in the manual for the primary care version, and moderate sensitivity and specificity are reported for the other two versions. Further development with larger samples and peer-reviewed publication of the results is needed. The screening instruments previously described are designed for early diagnosis. Unfortunately, not all children are diagnosed early, and a neurology practice is likely to encounter undiagnosed children. The Social Communication

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Box 38-5 PERVASIVE DEVELOPMENTAL DISORDERS SCREENING TEST: STAGE TWO—DEVELOPMENTAL DISORDERS CLINIC SCREENING Name of child Today’s date Age in months Sex (M/F)

_______________________________________________________________________ _______________________________________________________________________ _______________________________________________________________________ _______________________________________________________________________

Directions: In the following form, fill in answers to indicate any difficulty you may have experienced with your child. Answer the questions to show what is most often true about your child, not “best” or “worst.” Usually True Yes

Question

Usually False No

Did your infant only sleep for short bouts or demonstrate a great deal of unpredictability in sleep patterns? Did your infant sometimes stare or tune out, making it hard to get his or her attention? Did your infant ignore toys most of the time or play almost all the time with one or two things? Did your infant’s mood sometimes change suddenly for no real reason? Did your infant seem uninterested in learning to talk? Did your infant usually enjoy being tickled or being chased but did not usually enjoy playing patty-cake or peek-a-boo? Did your infant cry when you left but seemed not to notice when you returned? Did your child often seem to understand only part of what was just said to him or her? (For example, was it hard to tell if he or she was disobeying or just not understanding you?) Did your child like things he or she could play with the same way, over and over, such as a See ‘n Say pull-the-string toy or toys with buttons to push (e.g., a toy telephone, typewriter)? Did your child seem exceptionally independent, coming to get you only if there was something he or she wanted and could not get for himself or herself? Had you worried that your child did not seem too interested in other children? Did your child seem unusually interested in mechanical things, such as light switches, door latches, locks, fans, vacuums, or clocks? Was your child mostly uninterested in watching television or only liked things a child his or her age would not watch, such as adult music videos, certain game shows, or certain commercials? Did your child not yet imagine make-believe people and actions when playing? Had you ever worried that your child could not see well because he or she held things close to his or her eyes and looked at them closely for a long time? Does your child seem very tuned in to order and neatness when playing? (For example, does he or she like to line things up, sort things by category over and over, or insist on putting things away when finished?) When excited, does your child flap his or her hands or fingers? Courtesy of Dr. B. Siegel. The Pervasive Developmental Disorders Screening Test (PDDST) is available from Bryna Siegel, PDD Clinics and Laboratory, Langley Porter Psychiatric Institute, Box CAS, University of California, San Francisco, CA 94143-0984; phone: (415) 476-7385; fax: (415) 476-7160.

Questionnaire [Berument et al., 1999; Rutter et al., 2003] was developed to identify older, higher-functioning individuals with autistic spectrum disorder. It is a 40-item, parent-

completed questionnaire for children 4 years old and older. In a large sample of children referred for possible autistic spectrum disorder diagnoses, the instrument performed well

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when differentiating autistic spectrum disorder from other diagnoses. Further development and testing of psychometric properties is ongoing.

be undertaken by clinicians with extensive training and experience in the diagnosis of autistic spectrum disorder.

Instruments for Autistic Spectrum Disorders Diagnosis

THE MEDICAL EVALUATION IN AUTISM

The Childhood Autism Rating Scale is a clinician-rated diagnostic instrument for use with children older than 2 years [Schopler et al., 1986, 2000]. It should be administered by a clinician who is experienced with autistic spectrum disorder. The clinician should view a training videotape before using this rating scale. It takes 30 to 45 minutes to administer. The Childhood Autism Rating Scale is widely recognized and used in clinical settings. Psychometric properties are good to excellent, although in some of these reports, the sample population is not well described. Because the Childhood Autism Rating Scale was developed before publication of the DSM-IV [American Psychiatric Association, 1994] and ICD-10 [World Health Organization, 1992], it is less helpful in distinguishing between subgroups within the broader category of autistic spectrum disorder or pervasive developmental disorders. The Autism Diagnostic Interview–Revised [LeCouteur et al., 2003; Lord et al., 1997; ], a structured parent interview, and the Autism Diagnostic Observation Schedule–General [Lord et al., 2000b] are considered the gold standards for the diagnosis of autistic disorder. These instruments differentiate between autistic disorder and PDD-NOS with definitive thresholds. They were developed for use in research, but both have become commercially available for clinical use. However, the procedures are time consuming and costly, and they require extensive training. As a result, they are most likely to be used in research or specialty clinics for autistic spectrum disorder and are not widely used in general clinical practice. The Autism Diagnostic Interview–Revised is a comprehensive interview with a parent or caregiver that probes for autistic symptoms in the spheres of social relatedness, communication, and ritualistic or perseverative behaviors. It asks about current behavior and about behavior in early childhood, when the classic symptoms of autism are most likely to be observed. The interview takes at least 1.5 hours to complete. The Autism Diagnostic Observation Schedule–General (available commercially as the Autism Diagnostic Observation Schedule) is a semistructured, observational assessment that includes investigator-directed activities to evaluate communication, reciprocal social interaction, play, stereotypic behavior, restricted interests, and other abnormal behaviors. The procedure takes about 45 minutes to complete. Four modules are available, each corresponding to a developmental level, so the instrument can be used with individuals of all ages and all levels of functional impairment. The Autism Diagnostic Observation Schedule is an observation of current behavior, and it must be combined with a clinical interview to obtain historical information. The reliability of a diagnosis is always increased when multiple sources of information are obtained and synthesized. When using more than one standardized instrument, there is always a possibility of obtaining conflicting results, with the same individual meeting a threshold cut-off on one instrument but not another. For this reason, diagnoses should

Physical Examination Most investigators report that a small proportion of autistic children have frank macrocephaly or megalencephaly. The distribution of head size is clearly shifted upward, with the mean approximately at the 75th percentile [Bailey et al., 1995; Bolton et al., 1994; Courchesne et al., 2003; Davidovitch et al., 1996; Lainhart, 2003; Woodhouse et al., 1996]. Some investigators have observed that a large head circumference correlates with higher IQ and tends to be a familial trait [Filipek et al., 1992b; Miles et al., 2000]. The large head circumference is not usually present at birth, but it may appear in early to middle childhood with increased rates of growth [Courchesne et al., 2001; Lainhart et al., 1997; Mason-Brothers et al., 1990]. Head circumference is generally normal by adolescence and adulthood [Aylward et al., 2002], as is postmortem brain weight by adulthood [Bauman and Kemper, 1997]. Microcephaly is more common in autistic subjects than in controls, and it is associated with abnormal physical morphology, medical disorders, lower IQ, and seizures [Fombonne et al., 1999; Miles et al., 2000]. Abnormalities in the neurologic examination may include hypotonia, which was observed in about 25% of 176 autistic children and in 33% of 110 nonautistic, mentally retarded children. Spasticity was found in less than 5% of either group (exclusionary criteria for this sample included the presence of lateralizing gross motor findings) [Rapin, 1996b]. Motor apraxia was identified in almost 30% of autistic children with normal cognitive function; in 75% of retarded, autistic children; and in 56% of a nonautistic, retarded control group [Mari et al., 2003; Rapin, 1996b; Williams et al., 2004]. Characteristic motor abnormalities include motor stereotypies, which occurred in more than 40% of autistic children but in only 13% of the nonautistic control group [Rapin, 1996b]. Hand or finger mannerisms, body rocking, and unusual posturing are reported in 37% to 95% of individuals, and they often manifest during the preschool years [Lord, 1995; Rapin, 1996b; Rogers et al., 2000].

Clinical Testing Hearing Testing Many children diagnosed with autism are first described by parents as acting “as if deaf.” However, most children with autism have normal hearing function. Rosenhall and colleagues [1999] performed audiologic evaluations on 199 children and adolescents with autism and found that pronounced to profound bilateral hearing loss or deafness was present in 3.5% of all cases, a prevalence greater than that for the general population but similar to the rate for individuals with mental retardation. However, the rate of hearing loss in this study was equivalent across all levels of cognitive functioning. In contrast, hyperacusis was commonly found; it affected almost 20% of the autistic sample.

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Audiologic evaluation or brainstem auditory-evoked potential testing should be performed in all children with autism so that, if indicated, appropriate referrals can be made for aural habilitation [Filipek et al., 1999, 2000]. If there is a receptive language deficit, a definitive hearing test should be performed early in the differential diagnostic process and include a battery of tests, including behavioral audiometric measures, assessment of middle ear function, and electrophysiologic procedures [American Speech-Language-Hearing Association, 1991].

Lead Level Children with developmental delays who spend an extended period in the oral-motor stage of play (when everything “goes into their mouths”) are at increased risk for lead toxicity, especially in certain environments [Filipek, 2005]. The prevalence of pica in this group can result in high rates of substantial and often recurrent exposures to lead and other metals [Shannon and Graef, 1997]. All children with delays or who are at risk for autism should have a periodic lead screen until the pica disappears [Centers for Disease Control and Prevention, 1997; Shannon and Graef, 1997].

tron emission tomography (PET) and single-photon emission computed tomography (SPECT) are used only as research tools and are not indicated in the diagnostic evaluation of autism [Filipek, 2005].

Tests of Unproven Value Unsupported claims have led a number of parents to subject their children to various tests in the hope of finding a treatable cause of autism. There is inadequate evidence to support routine clinical testing of individuals with autism for hair analysis for trace elements [Gentile et al., 1983; Shearer et al., 1982; Wecker et al., 1985], celiac antibodies [Pavone et al., 1997], allergies (particularly food allergies caused by gluten, casein, and Candida and other molds) [Lucarelli et al., 1995], immunologic or neurochemical abnormalities [Cook et al., 1993; Singh et al., 1997; Yuwiler et al., 1992], micronutrients such as vitamin levels [Findling et al., 1997; LaPerchia, 1987; Tolbert et al., 1993], intestinal permeability [D’Eufemia et al., 1996], stool analysis, urinary peptides [LeCouteur et al., 1988], thyroid function [Cohen et al., 1980; Hashimoto et al., 1991], or erythrocyte glutathione peroxidase [Michelson, 1998].

Metabolic Testing The reported co-occurrence of autistic-like symptoms in individuals with inborn errors of metabolism has led to consideration of screening tests as part of the assessment of patients with severe developmental impairment [Steffenburg, 1991]. However, the percentage of children with autism who prove to have an identifiable metabolic disorder is probably less than 5% [Dykens and Volkmar, 1997; Rutter et al., 1994, 1997]. Most of the biochemical analyses are useful only as research tools in the ongoing effort to understand the biology of autism, but metabolic testing clearly is indicated by a history of lethargy, cyclic vomiting, early seizures, dysmorphic or coarse features, and mental retardation [Filipek, 2005]. If mental retardation cannot be excluded, questionable newborn screening or birth outside of the United States should prompt biochemical testing because of the potential absence of newborn screening and maternal public health measures. Selective metabolic testing should be initiated only in the presence of suggestive clinical and physical findings [Curry et al., 1997; Filipek et al., 1999, 2000]. These findings may ultimately lead to future recommendations for screenings of lactate, pyruvate, ammonia, and free and total carnitine levels [Filipek et al., 2004].

Neuroimaging Studies Routine neuroimaging to evaluate a child with autism and macrocephaly is not warranted unless there is evidence of lateralizing signs on neurologic examination. A review of neuroimaging reports for children with autism found a very low prevalence of focal lesions or other abnormalities, none of which localized consistently to be more than coincidental findings [Filipek et al., 1992a, 1992b]. However, cortical migration malformations, including polymicrogyria, schizencephaly, and macrogyria, have been reported on MRI in a small number of high-functioning autistic or Asperger’s subjects without preference for a particular lobe or hemisphere [Berthier, 1994; Berthier et al., 1990; Piven et al., 1990]. Posi-

COEXISTENT MEDICAL CONDITIONS Feeding Disturbances and Gastrointestinal Problems Feeding habits and food preferences of children with autism typically are unconventional. Although there have been reports of gastrointestinal complaints in children with autism dating back more than 30 years [Goodwin et al., 1971; Walker-Smith and Andrews, 1972], the gastrointestinal tract only recently has become a significant focus of study [Filipek, 2005]. Lightdale and colleagues [2001] surveyed 500 parents of autistic children; almost 50% reported loose stools or frequent diarrhea. In an epidemiologic study, Fombonne and Chakrabarti [2001] found that 19% of children with autism reported gastrointestinal symptoms, with constipation identified in 9%. Molloy and Manning-Courtney [2003] found that of 137 children with autism, 24% had history of at least one chronic gastrointestinal symptom, and 17% had diarrhea; they found no association between gastrointestinal symptoms and autistic regression. Kuddo and Nelson [2003] found that the frequency of gastrointestinal symptoms in autistic children is not as common as the literature from gastroenterology clinics might suggest. Taylor and colleagues [2002] found an 8% rate of chronic constipation, which is similar to that estimated for the general childhood population [Loening-Baucke, 1998]. Black and associates [2002] performed a nested case-control study in the United Kingdom and found that 9% of children with autism and 9% of children without autism had a history of gastrointestinal complaints. Peltola and colleagues [1998] also found no association of autistic spectrum disorder and gastrointestinal symptoms over a 14-year period in Finland. DeFelice and colleagues [2003] found no relationship between autism and gastrointestinal immune dysregulation by investigating intestinal cytokines; intestinal levels of interleukin (IL)-6 and IL-8 were lower in patients with autistic spectrum disorder than in age-matched controls.

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Sleep Disturbances Sleep disturbances have been a recognized feature of autism, particularly abnormalities in sleep-wake cycles [Didde and Sigafoos, 2001; Ornitz, 1985]. Most autistic children studied have sleep problems, which are often severe and usually involve extreme sleep latencies, lengthy nighttime awakenings, shortened night sleep, and early morning awakenings [Honomichl et al., 2002; Patzold et al., 1998; Schreck and Mulick, 2000; Wiggs and Stores, 2004]. Children with autism also have more unusual and obligatory bedtime routines.

Epilepsy Epilepsy occurs frequently in children with autism; approximately one third will develop epilepsy by adulthood, and all seizure types occur [Volkmar and Nelson, 1990]. There is a bimodal distribution of age of onset, with peaks occurring at younger than 5 years and during adolescence [Tuchman and Rapin, 2002]. The rate of epilepsy is increased among those with mental retardation and those with severe behavioral disorders [Olsson et al., 1988]. The presence of cerebral palsy or focal motor findings also increases risk. Tuchman and colleagues [1991] found a prevalence of epilepsy of 14% among 314 autistic children, but many were younger than adolescent age; in autistic children with normal or near-normal cognitive function, the risk of epilepsy was less than 10% by age 10 years. The rate was 27% in the presence of severe mental retardation and 67% for those with severe mental retardation and a motor deficit. In a subgroup of 160 children with autistic spectrum disorder, normal intelligence, no associated cause, and no family history, the cumulative probability of epilepsy was 6%, similar to a rate of 8% for children with developmental language disorders. About 90% of those with Rett’s syndrome have epilepsy [Steffenberg et al., 2001]. In childhood disintegrative disorder, the risk of epilepsy may be as high as 70% [Mouridsen et al., 1999]. In contrast, the risk of epilepsy in children with Asperger’s disorder and PDD-NOS is less than 10%. Autism may follow infantile spasms [Riikonen and Amnell, 1981]. Chugani and co-workers [1996] found that among children with infantile spasms, those with bitemporal glucose hypometabolism were likely to manifest autism with severe language impairment and mental retardation. There are several genes relevant to epilepsy in the region of chromosome 15 that is a site of frequent duplications and inversions in autistic subjects, but no genetic subtype correlating with phenotypic epilepsy has yet been identified [Tuchman and Rapin, 2002]. Of children with autistic regression, 12% have epilepsy, but 25% have epileptiform EEG patterns [Tuchman and Rapin 1997]. Similarities have been identified between a subgroup of children with autistic regression and an epileptiform EEG pattern and children with Landau-Kleffner syndrome. LandauKleffner syndrome is an acquired aphasia with onset typically after age 3 years with clinical seizures or an epileptiform EEG pattern, whereas children with autism have behavioral and developmental impairments and an onset of symptoms usually first observed between 18 and 24 months. The EEG pattern of Landau-Kleffner syndrome tends to show frequent temporoparietal spikes, and is activated by slow-wave sleep. In autistic regression, the most common EEG abnormality is centro-

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temporal spikes, which can be infrequent and intermittent [Hirsch et al., 1990; Mantovani, 2000]. Long-duration video electroencephalograms of children with Asperger’s disorder, a history of regression, and no clinical seizures demonstrated epileptiform abnormalities in 46%; in comparison, 20% of all children with autism have an epileptiform EEG pattern [Tuchman and Rapin, 1997]. Landau-Kleffner syndrome has been treated with antiepileptic drugs, steroids, and immunoglobulins, but there are no controlled treatment trials, and it is not known whether there is benefit in similar treatment for children with autistic regression, abnormal epileptiform EEG patterns, but no seizures. No prospective, controlled trials are available to provide evidence for any treatment recommendations, and the question of whether subclinical epilepsy in children with autism could have adverse effects on cognition, language, or behavior has not been answered. Seizures in children with autism should be treated as they would be in children without autism, with even more attention than usual paid to the possible behavioral and cognitive side effects of antiepileptic drugs. Occasionally, it may be difficult to distinguish repetitive and stereotypic behaviors from symptoms of temporal lobe seizures, and inattention from absence seizures may be construed as abnormal autistic behavior. It is often necessary to use sedation to obtain electroencephalograms for children with autism; success may be more readily obtained with oral clonidine (0.05 to 0.2 mg) than with chloral hydrate [Mehta et al., 2004].

Mitochondrial Disorders Mitochondrial diseases are probably a rare and insignificant cause of pure autism, but evidence is accumulating that mitochondrial disorders can manifest with autistic features. [Filipek et al., 2004; Lerman-Sagie et al., 2004]. Coleman and Blass [1985] first reported an association of lactic acidosis with autism, which was also observed by Laszlo and coworkers [1994]. Graf and colleagues [2000] reported a family with a group of neurologic disorders associated with the mitochondrial DNA G8363A transfer ribonucleic acid (RNA) Lys mutation; of four family members affected, one child was also severely autistic. Ramoz and colleagues [2004] reported linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism. In 12 children presenting with hypotonia, intractable epilepsy, autism, and developmental delay (HEADD syndrome), there were reduced levels of specific mitochondrial respiratory chain functions encoded by mitochondrial DNA, with most also having mitochondrial structural abnormalities [Filiano et al., 2002]. Pons and associates [2004] reported five patients with autism who also had concurrent A3243G mitochondrial (mt) DNA mutations and mtDNA depletion syndromes. This mutation typically causes mitochondrial encephalopathy, lactic acidosis, seizures, hearing loss, and strokes (MELAS syndrome) with ragged red fibers in skeletal muscle. Four of these five patients were ascertained because a maternal relative was identified with the mutation, not because they presented with symptoms consistent with a mitochondrial disorder. Filipek and colleagues [2004, 2005] reported that free and total carnitine and pyruvate levels were significantly reduced, whereas ammonia, lactate, and alanine levels were considerably elevated in 100 autistic children. The relative carnitine deficiency in these patients, accompanied by slight elevations in lactate and significant

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elevations in alanine and ammonia levels, suggests mild mitochondrial dysfunction, and the investigators hypothesized that a mitochondrial defect might be the origin of the carnitine deficiency in these autistic children.

Phenylketonuria Autism has been associated with several inborn errors of metabolism, primarily phenylketonuria [Folstein and Rutter, 1988; Friedman, 1969; Miladi et al., 1992; Williams et al., 1980]. In a sample of individuals with autism, finding undiagnosed and untreated phenylketonuria is rare; however, in a sample of individuals with phenylketonuria, up to 5% may be autistic [Filipek, 2005]. In a study by Lowe and associates [1980], autistic symptoms in untreated children with phenylketonuria improved after initiation of dietary therapy.

GENETICS Although Bettelheim [1967] espoused the theory that autism was caused by parental behavior, ( the “refrigerator mother”), it has become clear that autism is a complex genetic disorder. Twin studies provide strong evidence that autism is genetic, involving multiple genes and variable expression. The concordance rate for classic Asperger’s disorder in monozygotic twins has been reported as 36% to 90% [Bailey et al., 1995; Folstein and Rutter, 1977; Ritvo et al., 1989; Steffenburg et al., 1989], compared with 0% to 23% in dizygotic twins [Bailey et al., 1995]. However, when twin pairs are evaluated for a broader autistic phenotype that includes communication and social disorders and stereotypic behaviors, the concordance rate is 92% for monozygotic twins and 10% for dizygotic twin pairs. This suggests an interaction among multiple genes, but environmental modifiers may affect the expression of autistic traits [Muhle et al., 2004]. In families of children with autism, characteristics known as the broader autism phenotype are more common than in controls [Fombonne et al., 1997; Pickles et al., 2000]. These characteristics include difficulty with communication and language, including delayed onset [Folstein et al., 1999], social reticence or phobias, and preference for routine and difficulty with change [Pickles et al., 2000; Piven et al., 1991a] or obsessive-compulsive traits [Hollander et al., 2003]. These traits are not usually associated with difficulties in function [Folstein and Rosen-Sheidley, 2001]. Milder impairments in social and communicative skills also occur in siblings and relatives of probands more often than in controls [Bailey et al., 1998; Szatmari et al., 2000]. Relatives are more likely to have traits within the broader autism phenotype if a proband is higher rather than lower functioning [Nicolson and Szatmari, 2003] and if there are multiple probands with autism [Spence, 2004]. Family members are more likely to have an increased level of platelet serotonin [Cook and Leventhal, 1996] and increased head circumference [Lainhart et al., 1997]. The risk of autistic spectrum disorder in a sibling is 3% to 8% when there is one affected child, compared with a rate of 3 to 6 cases per 1000 children in the general population [Chakrabarti and Fombonne, 2001], and the risk is 25% for the next child if there are two siblings with autistic spectrum disorder [Folstein and Rosen-Sheidley, 2001]. Rates of mental

retardation without autism are not increased in families with autistic spectrum disorder, suggesting the mental retardation is part of the autistic disorder, not a separate condition.

Known Genetic and Other Conditions Associated with Autism Bolton and associates [1991] and Rutter and colleagues [1993] conducted evaluations on 151 individuals with autism and found that 8.1% of these cases had specific associated medical conditions, including fragile X syndrome, bilateral deafness, cerebral palsy, multiple congenital abnormalities, and identified chromosomal anomalies. About 3.8% had other medical concerns that were less likely to be associated with etiologic factors. Medical conditions are more common in persons with severe mental retardation [Ritvo et al., 1990; Rutter et al., 1994]. The possibility of finding any associated medical condition rises with increasing degrees of mental retardation—approaching 50% among persons at the severe and profound levels of cognitive dysfunction [Scott, 1994]. In a survey of multiple studies, the fraction of patients with autism who have an associated medical condition of potential etiologic significance was 0% to 17%, with a mean of 6% [Fombonne, 2003a].

Fragile X Syndrome Fragile X syndrome is second only to Down syndrome in terms of a known chromosomal cause of mental retardation. Fragile X syndrome is characterized by macro-orchidism, large protruding ears, and moderate-to-severe mental retardation. In more than 99% of the cases, this syndrome is caused by an unstable amplification (i.e., excessive triplet repetition) of cytosine (C) and guanine (G) within the FMR1 gene on the X chromosome [Verkerk et al., 1991]. Between 7% and 30% of boys with fragile X syndrome are on the autistic spectrum [Rogers et al., 2001], and 0% to 6% of autism populations have fragile X syndrome (median of six studies 0.75%) [Fombonne et al., 1997]. Summarizing data across 40 studies, Fisch [1992] found virtually identical pooled proportions of fragile X syndrome in autistic males and in mentally retarded males. These studies suggested that autism and fragile X syndrome may occur together, but the prevalence of these cases is much lower than originally thought, and that fragile X syndrome is not a major etiologic factor in autism.

Tuberous Sclerosis Complex Tuberous sclerosis complex has been strongly associated with autism and identified more frequently in individuals with mental retardation and most commonly in those with epilepsy [Gutierrez et al., 1998; Kandt, 2003]. Approximately 25% of children with tuberous sclerosis complex are autistic, and up to 40% to 45% meet the criteria for autism or pervasive developmental disorder [Smalley, 1998]. The incidence of autistic individuals with tuberous sclerosis complex has been estimated between 0.4% and 4% in epidemiologic studies [Chudley et al., 1998; Fombonne et al., 1997; Ritvo et al., 1990; Smalley, 1998]. This rate increases to 8% to 14% for autistic individuals with epilepsy [Gillberg, 1991]. PET studies of children with tuberous sclerosis complex and autism have revealed changes in the deep cerebellar

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nuclei and caudate nuclei that were not seen in nonautistic tuberous sclerosis complex subjects [Asano et al., 2001], but the presence of cortical tubers in the temporal lobes did not increase the risk for autism.

Other Disorders Other genetic disorders that are less frequently associated with autism include neurofibromatosis [Folstein and Rutter, 1988], Prader-Willi syndrome, and Angelman’s syndrome [Steffenburg et al., 1996]. Smith-Lemli-Opitz syndrome, resulting from a defect in cholesterol synthesis, has some association with autistic spectrum disorder that may be related to abnormalities in development of serotonin pathways [Waage-Baudet et al., 2003]. Although Down syndrome and autism can occur together, large-scale studies that screened samples of patients with Down syndrome for autism found relatively low rates of autism, ranging from 1.0% to 2.2%. Comorbidity is no higher than would be expected by chance after the effects of mental retardation are taken into account [Fombonne, 2003a]. For autistic spectrum disorders other than Rett’s syndrome, known single-gene defects and diagnosed medical conditions account for about 10% of cases of autism [Chakrabarti and Fombonne, 2001; Fombonne, 2002]. In a Canadian study of 91 children with pervasive developmental disorders, 15% had a recognizable syndrome or genetic disorder, of which 9% were thought to be causally related to pervasive developmental disorder [Chudley et al., 1998].

METHODS FOR GENETIC STUDIES Entire-Genome Screening Studies Three interrelated methodologies have been used to study the genetics of autism: entire-genome screens or linkage studies in multiplex families (i.e., two or more affected members within the autistic spectrum) or sibling pairs; cytogenetic studies that investigate chromosomal abnormalities in affected individuals using karyotyping and fluorescence in situ hybridization (FISH); and screening for candidate gene associations [Muhle et al., 2004; Veenstra-VanderWeele and Cook, 2004]. Using entire-genome screens in families with more than one affected member, autism or autistic traits can be linked to shared genetic markers that are regions of interest inherited by affected persons more frequently than would be expected by chance. These regions can be linked with microsatellite markers whose location is known. Studies have used linkage-analysis techniques to identify 10 or more regions of interest [Muhle et al., 2004; Nicolson and Szatman, 2003; Risch et al., 1999; Yonan et al., 2003]. It is estimated that up to 20 or more genes interacting with one another contribute to autism. The exact mode of inheritance may depend on the presence of multiple loci, with small independent effects and additive effects from environmental factors influencing expression [Risch et al., 1999]. A number of significant genetic linkages have been identified, but how these influence brain development is not understood. A region of interest on chromosome 7q has been identified that is associated with developmental language disorder; because a core feature of autism is a communication disorder,

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it is possible that autism and severe language impairment could share a gene in this region [Ashley-Koch et al., 1999; Badner and Gershon, 2002; Folstein and Rosen-Sheidley, 2001; IMGSAC, 1998, 2001a]. Additional chromosomes identified include 2q, 3q, 13q, 16p, and 17q [Auranen et al., 2002; Buxbaum et al., 2001; Collaborative Linkage Study of Autism, 1999; IMGSAC, 2001b; Philippe et al., 1999; Rabionet et al., 2004; Risch et al., 1999; Shao et al., 2002; Yonan et al., 2003]. Liu and associates [2001] report finding possible autism markers on chromosomes 4, 5, 8, 11, 17, and 19. The multipoint logarithm of the odds score (MLS) reflects the likelihood that the marker and the autism locus are linked. The critical value thought to demonstrate significant evidence for linkage to simple, monogenic diseases with unambiguous phenotypes and established modes of transmission is three autosomal loci. Multiple alleles within a single gene may contribute to polygenetic susceptibility, and when a cluster of these alleles reaches a certain threshold, the phenotype of Asperger’s disorder results. If the number of high-risk alleles is less, characteristics of the broader autism phenotype may be expressed [Pickles et al., 2000; Piven and Palmer, 1999]. In further refinements of linkage studies, investigators have tried to identify phenotypes or traits and link them to risk alleles. The most replicated example is the phenotypic subgroup with phrase speech delay, which is linked to 2q [Buxbaum et al., 2001; IMGSAC, 2001a, 2001b; Shao et al., 2002] and to 7q [Ashley-Koch et al., 1999; Bradford et al., 2001; Yu et al., 2002]. Bartlett and colleagues [2004] used separate Canadian and U.S. samples selected for selective language impairment and confirmed linkage at chromosome 13q21. Studies have been relatively small, usually enrolling less than 400 multiplex families. Much larger samples of sibling pairs (>1000) are needed to reliably detect linkage to regions with modest effect sizes [Veenstra-VanderWeele and Cook, 2004]. As a result of collaborations of multiple independent groups of researchers and pooling of government and private financial resources, extremely large studies are being conducted that should increase knowledge about phenotypicgenotypic relationships.

Cytogenetic Studies Cytogenetic studies are done to identify relevant inherited or de novo mutations in affected individuals and families. The results of these studies are combined with results of entire-genome screens in affected multiplex families and are then narrowed by linkage disequilibrium studies. Linkage disequilibrium results in inheritance of a particular allele more often than would be expected. Broad linkage studies are refined and followed by association studies and mutation screening.

Candidate Genes Candidate genes are selected for study often through known genetic disorders or animal models, because they are known to affect developmental processes that may be involved in the pathogenesis of autism. Subjects are compared with controls with regard to presence of polymorphisms (i.e., mutations in the gene sequence) or with regard to the levels of expressed protein. Complementary studies may be done through targeted gene disruption in animals, which are then

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examined for symptoms analogous to autistic characteristics. For example, mu opioid receptor–knockout mouse pups do not respond to their mothers’ cues, and they demonstrate deficits in attachment behavior [Moles et al., 2004]. A number of candidate genes have been examined. WNT2 is a developmental gene in the 7q region [Wassink et al., 2001]. This gene encodes the same signaling pathways as DVL1. A mouse model lacking DVL1 has abnormal social interaction and sensory function [Lijam et al., 1997]. The 7q region also contains a gene called RELN that codes for a protein thought to help neurons migrate to their proper location. This mutated gene has been found in human autosomal recessive lissencephaly [Hong et al., 2000]. Studies of serotonin transporter genes have been conflicting [Betancur et al., 2002; Kim et al., 2002; Klauck et al., 1997; Maestrini et al., 1999; Persico et al., 2000; Tordjman et al., 2001; Yirmiya et al., 2001]. Glutamate transporter genes were found to be upregulated in postmortem studies [Purcell et al., 2001], and the glutamate receptor-6 gene (GRIK2, formerly designated GLUR6) was expressed in brain regions involving learning and memory [Jamain et al., 2002]. Neuroglins are important in excitatory synapses and synaptogenesis; defects may affect cognitive development and communication. A large French family with nonspecific X-linked mental retardation with and without autism spectrum disorder had 2-base pair deletions in the neuroligin-4 gene (NLGN4X) on X p22.33 [Laumonnier et al., 2004]. Other neuroligin genes involved in synaptogenesis are at the Xq13-q21 region [Jamain et al., 2003; Liu et al., 2001; Shao et al., 2002]. Association and linkage studies are needed to see whether this gene has a role in other families with autism. A locus frequently identified with high levels of repetitive movements or stereotypic behaviors is on 15q11-q13. The chromosome 15q11-13 region is the source of a duplication syndrome associated with autistic spectrum disorder [Nurmi et al., 2003]. Maternal duplications associated with autistic spectrum disorder in this region are the converse of the deletions in the same region in Prader-Willi or Angleman’s syndrome and contain a variant of the γ-aminobutyric acid (GABA) receptor gene complex [Buxbaum et al., 2002]. The HOXA1 gene is part of a family of genes that determines pattern formation within the central nervous system [Ingram et al., 2000a], but this association has not been confirmed in larger studies [Devlin et al., 2002; Gallagher et al., 2004; Li et al., 2002]. Another candidate gene involves oxytocin. Oxytocin levels affect social behavior, and two genome-wide screens have found linkage to a locus containing the oxytocin receptor gene [Auranen et al., 2002; Shao et al., 2002].

Epigenetics Hereditary exogenous factors can modify the control of gene expression. Epigenetics refers to the stable and heritable or potentially heritable changes in gene expression that do not involve a change in DNA sequence [Jiang et al., 2004]. Epigenetic mechanisms may help to explain the onset of symptoms in autism after a period of apparently normal development and may play a role in how the environment affects phenotypic expression. Chromosomes originating from one parent may have an abnormal epigenotype that leads to modulation of DNA methylation that causes gene silencing [Bjornsson et al., 2004].

Genomic imprinting is form of epigenetic modification in which allele silencing is parent-of-origin specific. This occurs in Angleman’s syndrome, caused by molecular abnormalities that include deletion of a maternally derived copy of the 15q11-q13 chromosomal region. Children with Angleman’s syndrome have many overlapping features of autism [Peters et al., 2004]. Two types of imprinting defects may cause Angleman’s syndrome: inherited deletions of the imprinting center, which are primarily genetic but also have secondary epigenetic effects, and imprinting defects that have no identifiable DNA sequence abnormality [Jiang et al., 2004].

Genetic Counseling There is no prenatal test to identify autism, but it is important to look for physical features in the identified autistic child that may suggest a diagnosable genetic condition such as fragile X syndrome [Miles and Hillman, 2000] or tuberous sclerosis complex. Karyotyping and DNA analysis for fragile X syndrome in children with autism should be done if there is mental retardation or the possibility cannot be excluded, if there is a family history of fragile X syndrome or mental retardation, or if the child has dysmorphic features [Filipek et al., 2000]. When there are implications of a cytogenetic or molecular diagnosis for other family members, especially when another pregnancy may be a possibility, their inclusion in the diagnostic evaluation of a child with autism is recommended [American College of Medical Genetics, 1994]. For the higher-functioning children with no dysmorphic features and minimal cognitive impairment, tests for new genetic conditions are of little or no benefit [Filipek et al., 2000; Skjeldal et al., 1998]. The risk of recurrence of autism in a subsequently born sibling is 3% to 8% [Chakrabarti and Fombonne, 2001; Folstein and Rosen-Sheidley, 2001; Ritvo et al., 1989], and the risk for a third child is 25% if there are already two affected siblings in a family; these are important statistics to discuss with parents contemplating another pregnancy. Even if no genetic condition is revealed, genetic counseling should include a discussion of the risks of recurrence of autistic spectrum disorder or Asperger’s disorder in a subsequent child and the lack of ability to diagnose them prenatally [Folstein and Rosen-Sheidley, 2001]. The goal of counseling is to provide as much information as possible but to leave decision-making and interpretation of the genetic information to the families. Additional studies are needed to understand the role of genetics and environmental influences in autism. Questions can be answered only with increasingly large and varied populations and by advances in phenotypic characterization. Collaborations to increase sample sizes of multiplex populations are in progress, and it is important to encourage families, particularly those with multiple affected members, to participate in clinical research.

PATHOPHYSIOLOGY AND ETIOLOGY Risk Factors Prenatal and perinatal factors have been studied to investigate a link with autism [Finegan and Quarrington, 1979]. Increased maternal age [Gillberg and Gillberg, 1983; Tsai and Stewart,

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1983], lower birth weight, “uterine stress,” depression, longer labor [Wilkerson et al., 2002], daily smoking early in pregnancy, being small for gestational age, or having an Apgar score at 5 minutes of less than 7 [Hultman et al., 2002] have all been associated in various studies with increased risk for autism. However, for most factors, when more than one study was examined, no consistency of risk factors was identified [Zwaigenbaum et al., 2002], and there is no one single complication that is clearly a risk factor for autism [Juul-Dam et al., 2001]. When composite measures of perinatal risk factors are used, affected children tend to have more complications than unaffected siblings [Lord et al., 1991; Piven et al., 1993]. Children with a history of perinatal problems were likely to also have had preceding prenatal problems [Gillberg and Gillberg, 1983]. Minor obstetric complications are likely to be epiphenomena rather than to have an etiologic role, with perinatal problems occurring with a higher frequency among genetically predisposed fetuses [Zwaigenbaum et al., 2002]. Some researchers have hypothesized that neuroimmune factors may play a role in the pathophysiology of autism. The frequency of autoimmune disorders in families of children with pervasive developmental disorder is increased compared with families of control subjects [Comi et al., 1999; Sweeten et al., 2003]. Several small studies have found the presence of various anti-brain antibodies in the blood of autistic patients. Not all autistic patients have these antibodies, which were also often found in their first-degree relatives [Connolly et al., 1999; Korvatska et al., 2002].

Animal Models No single animal models exists for autism, but several animal models that exhibit some of the major features of autism have provided an opportunity to understand the neural substrates of functional impairments. In the macaque monkey, social behavior is mediated by the amygdala, temporal cortex, orbitofrontal cortex, and superior temporal gyrus [Lord et al., 2000b]. Bilateral removal of the medial temporal lobe in a rhesus monkey model leads to abnormal social behavior during maturation that resolves in adults [Bachevalier and Merjanian, 1994; Machado and Bachevalier, 2003]. Symptoms include abnormal social interaction, absence of facial and body expression, and stereotypic behaviors. Social anxiety and fear have been studied in primates [Amaral, 2002] and in rats [Wolterink et al., 2001] and are related to amygdaloid circuitry. A behavioral syndrome in Lewis rats with analogies to autism is the result of Borna disease virus infection in neonates [Pletnikov et al., 2003; Weissenbock et al., 2000]. Neonatal infection produces specific behavioral abnormalities, with disturbances in sensorineural development, play, and social communication. Expression of some of the sensory motor abnormalities may be delayed. Tests requiring use of hindlimbs and balance were abnormal. Pathologically, Borna disease virus induces regional neuronal loss in the cerebellum. This model provides some insights into mechanisms of preand perinatal infection causing damage to the developing brain, but it does not indicate that Borna disease virus is an etiologic agent in autism. Other animal models have been developed by knocking out different candidate genes [Lijam et al., 1997], by oxytocin and vasopressin administration [Insel et al., 1999],

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and by exposing embryos to teratogens such as valproic acid [Ingram et al., 2000a]. Behavioral studies have focused on social interaction and memory deficits.

Neuropathology Abnormalities in major cortical and subcortical brain structures have been found through postmortem and MRI studies of autistic subjects. Comprehensive examination of nine autistic postmortem brains was carried out by Kemper and Bauman [1998]. They described three major findings: curtailment of normal development in forebrain neurons, which were smaller and more densely distributed than normal; an apparent congenital decrease in the number of Purkinje cells; and age-related changes in cell size and the number of neurons in the diagonal band of Broca, the cerebellar nuclei, and the inferior olive. These neuropathologic findings may account for many clinical features of autism. Perinatally acquired lesions in limbic system structures could lead to disruption in memory processes involved in the ability to learn new information. In contrast, striatal and cortical areas involved in habitual memory were spared, potentially relating to the need for sameness, narrow interests, and capacity for rote memory. Disruption of cerebellar function may lead to a number of motor and sensory system deficiencies, including mental imagery, anticipatory planning, and timing and integration of sensory and motor information [Kemper and Bauman, 1998]. Continued research into the neuropathologic underpinnings of autism is crucial, and it is being facilitated by a brain tissue bank [Pickett, 2001]. Use of quantitative volume analysis using MRI has provided information that the outer layers of white matter are enlarged in autistic subjects compared with controls. Herbert and co-workers [2004] compared 13 subjects with highfunctioning autism, 14 subjects with developmental language disorder, and 14 controls. The inner zones of white matter were not different in autistic subjects from those in controls, but the outer zone of white matter was larger than controls in autistic individuals and subjects with developmental language disorder. In the autistic group, frontal lobe enlargement was proportionally greater than other areas, but not in the developmental language disorder sample. These areas myelinate relatively late, beginning in the second half of the first year and continuing into the second year of life and later, which is consistent with the timing of increased head circumference seen in autistic subjects. By the time autistic children are 2 to 4 years old, 90% have above-average brain volume, and 37% have developmental macrocephaly, defined as brain volume exceeding 2 standard deviations above the normal mean for age [Courchesne et al., 2001]. This finding suggests an ongoing postnatal process that primarily affects interhemispheric and cortical connections. In other studies, children with autistic spectrum disorder were found to have significantly increased cerebral volumes compared with normal and with developmentally delayed children, and white matter enlargement was seen [Sparks et al., 2002]. There was greater enlargement of the frontal cortex [Carper et al., 2002] compared with other lobes and reduced amygdala volume [Aylward et al., 1999]. In a series of MRI studies, Courchesne and co-workers [2003] have found specific neuroanatomic abnormalities,

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increased cerebellar and cerebral white matter, and cerebral cortical gray matter in 2- to 3-year-old children compared with controls but not in older children or adolescents with autism. In this study, frontal lobes were most affected with greatest involvement in the dorsolateral and medial prefrontal cortex. A widely debated finding in the MRI literature is reduction in size of one or another subregion of the cerebellar vermis [Courchesne et al., 2001; Hashimoto et al., 1995]. Other investigations have failed to replicate these findings [Filipek, 1995; Hardan et al., 2001; Keleiman et al., 1992; Piven et al., 1995]. Another approach to determining the neuropathologic underpinnings of autism has been suggested by Rodier [2002]. She found that children exposed to thalidomide in the first trimester developed autism at an increased rate, supporting the idea that the brain abnormality originates at the time of closure of the neural tube [Rodier et al., 1996]. This finding was corroborated by postmortem examination of a brain from a subject with autism showing near-complete absence of the facial nucleus and superior olive and narrowing of the brainstem between the trapezoid body and inferior olive. This deficit was reproduced in an HOXA1-knockout mouse model and by exposing rat embryos to valproic acid on the day of neural tube closure [Ingram et al., 2000b]. The investigators concluded that central nervous system injuries occurring during or just after neural tube closure can lead to selective loss of neurons derived from the basal plate of the rhombencephalon, and this finding may indicate that the initiating injury in some cases of autism takes place around the time of neural tube closure. Additional supporting evidence for this theory comes from a Nova Scotia cohort of 61 autistic children [Rodier et al., 1997]. Forty-two percent of these children with autism had posterior rotation of the external ears, compared with 18% of controls. They postulated that these could have been associated with a disruption of optic disc formation in the fourth week of embryonic life and that ear anomalies found in some children with autism could possibly be a marker for initiating events in utero. An important additional neuropathologic finding described by Casanova and associates [2002] is abnormality in the structure of minicolumns in the brain of autistic individuals. Minicolumns consist of 80 to 100 neurons, and they are believed to be the smallest unit of functional organization in the cortex. In autistic individuals, the minicolumns were described as more numerous but smaller than those of controls and with less space in between. This structural difference may cause the firing of too many processing units at once and prohibit the units from coherently responding to signals. Overarousal or underarousal could easily result. This abnormality could also be responsible for the increased incidence of seizures in individuals with autism. Autistic children have profound deficits in face-recognition tasks [Klin et al., 1999]. Newer technologies involving the use of eye-tracking devices and fMRI have yielded important information regarding the pathways for face recognition in autism. The fusiform face area (on the lateral aspect of the fusiform gyrus) is hypoactive as seen by fMRI, and the degree of hypoactivation strongly correlates with the degree of disability [Critchley et al., 2000; Kanwisher et al., 1997; Pierce et al., 2001; Schultz et al., 2000]. Hubl and colleagues [2003] saw lower blood oxygen–level dependent

signals in 10 autistic subjects during face processing than in controls, and they observed higher activation in the medial occipital gyrus, an area related to processing objects. Schultz and colleagues [2000] also found lower activation in autistic subjects in the right fusiform gyrus, but they identified higher activity in the right inferior temporal gyrus.

Serotonin Elevated blood levels of serotonin (5-hydroxytryptamine [5HT]) in autistic subjects, first reported in 1961 [Schain and Freedman, 1961], are caused by an elevation within circulating platelets, an increase in the serotonin transporter concentration, and a decrease in 5HT2 receptor binding [Cook and Leventhal, 1996]. Elevated concentrations of a low-molecularweight peptide that increases the uptake of 5HT into platelets [Pedersen et al., 1999] was demonstrated in autistic subjects. Elevation of platelet serotonin levels has been well studied and generally replicated. Measurements of 5HT levels must be controlled for the effects of race and status before and after puberty [McBride et al., 1998]. It has been hypothesized that if siblings of children with autism have higher platelet 5HT levels, it may indicate a higher familial risk [Piven et al., 1991b]. A familial pattern of hyperserotonemia was confirmed by Leboyer and coworkers [1999] in a sample of 62 autistic subjects and 122 first-degree relatives. Levels of whole-blood 5HT did not change with age in subjects with autism but did change in controls. There does not seem to be a correlation between 5HT levels and specific defined phenotypes [Kuperman et al., 1987]. However, Leboyer and colleagues [1999] suggested that the level of 5HT in blood could be considered an intermediate or surrogate phenotype that could be correlated with DNA polymorphisms in the 5HT transporter gene. Serotonergic disturbances including defects in 5HT transporter expression and decreases in plasma tryptophan may play a role in the pathophysiology of autism [Croonenberghs et al., 2000; Marazziti et al., 2000]. 5HT has an important role in central nervous system development, affecting social behavior, sleep, aggression, anxiety, and affective regulation, and it plays a role in the modulation of synaptogenesis [Chugani, 2002]. It may have a role in the development of neuropathologic abnormalities in the hippocampus, amygdala, and cerebellum [Bauman and Kemper, 1994] and in thalamocortical connections. Depletion of 5HT in critical developmental periods may also cause a decrease in growth of dendritic spines [Yan et al., 1997]. Using PET scans, Chugani and associates [1997] found alterations of 5HT synthesis in the frontal and thalamic pathways that are important for language production and sensory integration. About one half of the patients with Smith-Lemli-Opitz syndrome, a malformation syndrome with mental retardation that is caused by an inborn error in cholesterol biosynthesis [Opitz et al., 2002], exhibit autistic behavior. A mouse model of the Smith-Lemli-Opitz syndrome was created by eliminating DHCR7, which encodes 7-dehydrocholesterol reductase, the terminal enzyme required for cholesterol biosynthesis [Waage-Baudet et al., 2003]. These knockout mice have a 300% increase in 5HT immunoreactivity in hindbrains compared with control mice, and 5HTimmunoreactive cells are present in unusual locations and

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represent an increase in the total number of 5HT neurons and fibers. These observations provide a basis for the autistic phenotype seen in Smith-Lemli-Opitz syndrome, and they support the focus of therapeutic interventions aimed at modulation of the serotonergic system.

Vaccines There has been public concern about a potential relation between autism and vaccines, undermining the confidence of some parents in accepting the recommended vaccinations. Symptoms of autism generally first are noticed in the second year of life, although they may be recognized only in retrospect, and this is when the measles-mumps-rubella vaccine is given. Targets of concern have been the measlesmumps-rubella vaccine itself and thimerosal, the mercurycontaining preservative that was used in childhood vaccines until its removal between 1999 and 2002. Six epidemiologic studies concluded that there was no increase in risk of autistic disorder with exposure to the measles-mumps-rubella vaccine [Chen et al., 2004; Dales et al., 2001; Fombonne and Chakrabarti, 2001; Kaye et al., 2001; Madsen et al., 2003; Taylor et al., 1999]. Additional data derived from passive surveillance systems also consistently failed to detect an association [Patja et al., 2000; Peltola et al., 1998a, 1998b; Plesner et al., 2000]. There has been no evidence that the incidence of regressive autism has increased after administration of the measles-mumps-rubella vaccine. The measles-mumps-rubella vaccine has been given at a constant rate since 1979 in the United States, 1982 in Finland, and 1998 in the United Kingdom and Denmark, but rates of autism have steadily risen [Klein and Diehl, 2004]. The Immunization Safety Review Committee of the Institute of Medicine of the National Academies (IOM) [Stratton et al., 2001] concluded that there was consistent evidence of no causal association between administration of the measlesmumps-rubella vaccine and autism. However, the IOM report did not think there was sufficient evidence to accept or reject a causal association between exposure to thimerosal and autism [McCormick, 2003]. Exposure to thimerosal is a concern because mercury is a known neurotoxin, and there are claims of abnormal levels of mercury in autistic children who respond to chelation therapy. There are no studies involving low doses, and the pharmacokinetics of ethyl mercury in human infants is unknown. Almost all studies available regarding mercury toxicity are related to exposure to methyl rather than ethyl mercury [Nelson and Bauman, 2003]. Analysis of data from California, Sweden, and Denmark [Stehr-Green et al., 2003] found that although thimerosal exposure from vaccines was eliminated in Sweden and Denmark by the early 1990s, the incidence of autism was accelerated. This finding was confirmed by a retrospective cohort study [Verstraeten et al., 2003]. Hornig and associates [2004] supported a biologic plausibility for a possible association by demonstrating that, in a genetically susceptible strain of mice, thimerosal caused behavioral abnormalities that could be analogous to those of autism and neuropathologic changes of densely packed, hyperchromic hippocampal neurons with altered glutamate receptors. Although these findings suggest that a genetic susceptibility may confer a vulnerability to thimerosal toxicity, no human analogy has been identified, and the propor-

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tion of cases accounted for by this genetic susceptibility would have to be very small in view of the overwhelming epidemiologic findings of no association. A claim has been made that persistent measles virus found in the gastrointestinal tract of 10 children with autism and bowel symptoms was causally related to their autism [Wakefield et al., 1998]. Kawashima and co-workers [2000] found that the strains of measles in these children were consistent with vaccine strains. Wakefield’s hypothesis is that measles-mumps-rubella vaccine is a risk factor for children with regressive autism. However, there was no clear clinical description of the subjects, there were no controls, and the history and timing of regression was determined years later retrospectively. Most of the other authors have since rescinded the conclusions of this study [Murch et al., 2004]. This hypothesis was examined by Taylor and colleagues [1999], who found 6.6% of children with autism had regression and bowel symptoms, but the onset of symptoms was not associated with the measles-mumps-rubella vaccine. Another prospective report [Fombonne and Chakrabarti, 2001] did not find any association in a large, prospective sample. Evidence for a potential biologic mechanism, based on findings of measles particles in the gut of a referred sample of children with uncertain clinical phenotype, was not supported by these studies.

PHARMACOLOGIC THERAPY The goal of pharmacologic treatment for children with autism is to improve symptoms and specific behaviors. Target symptoms include anxiety, repetitive motor behaviors, obsessive-compulsive symptoms, impulsivity, depression, mood swings, agitation, hyperactivity, aggression, and self-injurious behavior. Although no medications directly impact cognitive impairment, controlling these symptoms should allow the child to maximize benefit from educational and behavioral treatments that are more directed toward the core impairments. Almost all of these medications are prescribed off-label, and there have been few randomized, prospective, double-blind, placebo-controlled trials and almost no long-term follow-up. Dosing should start at low levels and be slowly escalated with careful attention to possible side effects, the most common of which is activation, defined as overactivity, agitation, or emotional lability. Target symptoms should be clearly defined, and new drugs should be tried for a sufficient amount of time to determine their usefulness. One caution to keep in mind is that sedation in response to pharmacotherapy may be mistaken for a positive response [Volkmar and Pauls, 2003]. It is important to work with teachers and families to monitor a therapy’s effectiveness and side effects. Drug treatment should be one facet of a comprehensive multidisciplinary treatment approach that includes structured special educational techniques, behavior modification, and family counseling.

Neuroleptic Agents Neuroleptics that block dopamine receptors, such as haloperidol, thioridazine, and trifluoperazine, were used until the development of drugs that were more effective in blocking

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serotonin receptors. Haloperidol decreased motor stereotypies, hyperactivity, withdrawal, and negativism in children with autism [Anderson et al., 1989]. Tardive dyskinesia has not been reported, but these drugs have not been in use long enough to determine the risk for this rare complication. Common side effects are sedation and weight gain [Campbell et al., 1997]. The newer atypical neuroleptics include risperidone, clozapine, olanzapine, and quetiapine. They modulate dopamine (D2) and serotonin (5HT2) receptors [Buitelaar and Willemsen-Swinkels, 2000]. Risperidone is the only one that has been studied with a multisite, prospective, doubleblind, randomized design in children and adults with autistic disorder [McCracken et al., 2002; McDougle et al., 1998, 2000]. Risperidone benefitted severe behavioral problems and symptoms of aggression and self-injurious behavior. Side effects were increased appetite and sedation, with a very low incidence of acute extrapyramidal symptoms. The maximum dose was 2.5 mg/day for children weighing less than 45 kg and 3.5 mg/day for children weighing more than 45 kg. Other atypical neuroleptics studied with good results include olanzapine and ziprasidone, although they were assessed only in open trials [Malone et al., 2001].

Opiate Antagonists Several published trials used naltrexone, a long-acting opiate antagonist that can be taken orally. The hypothesis for benefit in autism is that autism is associated with hypersecretion of brain opioids, including β-endorphins, and that many symptoms of autism are similar to those induced by opiate administration, such as decreased socialization, repetitive stereotypic movements, and motor hyperactivity [Feldman et al., 1999]. Naltrexone in doses of 1.0 mg/kg daily in 23 autistic children decreased restlessness and hyperactivity [Campbell et al., 1993] in a parallel study design. Side effects were mild gastrointestinal symptoms, appetite decrease, and drowsiness. In a randomized, double-blind, crossover design, naltrexone was associated with modest improvement of behavior in 11 of 24 children, but no improvement in learning occurred [Kolmen et al., 1997]. In a separate, similarly designed study that looked specifically at communication skills, no benefit was seen [Feldman et al., 1999]. Studies by Willemsen-Swinkels and colleagues [1995, 1996, 1999] also failed to prove any benefit, and in some children, stereotypic behaviors were increased.

Serotonin Transporter Inhibitors Symptoms causing major disruption in autism, such as anxiety and repetitive and ritualized behaviors, can impair learning. Serotonin is thought to be involved in sensory perception, motor function, learning, memory, and sleep [Moore et al., 2004]. Treatment of children with autism with serotonin transporter inhibitors decreases ritualistic behavior and aggression [Cook and Leventhal, 1996]. Results have been encouraging for behavioral rigidity, obsessive-compulsive disorder symptoms, rituals, and stereotypies, especially when accompanied by aggression and increased anxiety [Buitelaar and Willemsen-Swinkels, 2000]. Pharmacologic agents acting as 5HT receptor agonists (e.g., risperidone) or serotonin-

depleting agents (e.g., fenfluramine) benefit repetitive and ritualistic behaviors. Serotonin transporter inhibitors such as clomipramine, fluoxetine, sertraline, fluvoxamine, and paroxetine [Gordon et al., 1993; McDougle et al., 1996] improve social interaction, aggression, and irritability [Aman and Langworthy, 2000; August et al., 1984; McDougle et al., 1998, 2000]. The evidence for possible developmentally sensitive altered regulation of serotonin synthesis in autistic children supports a rationale for giving serotonergic drugs to very young autistic children. The goal is to improve synaptic plasticity during periods of brain development. Clinical trials enrolling young children are difficult to undertake but are being planned. A randomized, double-blind, placebo-controlled trial enrolling adults, but not children, with autism found improvement in one half of the fluvoxamine-treated patients compared with placebo, with reduction of repetitive thoughts and behavior, maladaptive behavior, language, social relatedness, and aggression [McDougle et al., 1996]. There were few side effects at a mean dose of 270 mg/day. A study enrolling autistic children did not find a similar treatment response and did demonstrate behavioral activation [McDougle et al., 1998]. However, low-dose liquid fluoxetine (mean dose of 10 mg/day) was superior to placebo in reducing repetitive behaviors in children and adolescents with autism in a randomized, crossover trial [Hollander et al., 2005]. A crossover trial of six adults using the selective serotonin reuptake inhibitor fluoxetine demonstrated significant improvement in obsessive behaviors and anxiety, and PET scans demonstrated fluoxetine-elevated metabolic rates in the right frontal lobes [Buchsbaum et al., 2001]. Some benefit of fluoxetine has been seen in open-label studies [Fatemi et al., 1998]. In the largest of these, in an observational study of 129 children 2 to 8 years old on 8 to 40 mg/day, 67% had a good to excellent response [Delong et al., 2002]. Of 23 subjects with autistic disorder who were 7 to 28 years old and given 20 mg every other day to 80 mg/day of fluoxetine over a mean follow-up time of 6 months, 15 improved in measures of overall clinical severity [Cook et al., 1992]. The limiting side effects were behavioral activation, irritability, and agitation. A third selective serotonin reuptake inhibitor, sertraline, improved global clinical severity ratings in eight of nine mentally retarded adults, five of whom also had a diagnosis of Asperger’s disorder and all of whom had target behaviors of self-injury and aggression. One patient experienced agitation and worsening self-injurious behaviors [Hellings et al., 1996]. In an open-label case series of nine children with Asperger’s disorder, eight of nine improved with regard to anxiety and behavioral difficulties on sertraline [Steingard et al., 1997]. In a 12-week trial enrolling adults with pervasive developmental disorder, 68% responded based on the Clinical Global Impressions scale [McDougle et al., 1998]. A retrospective review of 15 children with pervasive developmental disorder treated with another selective serotonin reuptake inhibitor, citalopram [Namerow et al., 2003], found that most children improved in the Clinical Global Impressions categories of repetitive behaviors and mood lability and aggression. Side effects included headaches and sedation. Clomipramine, a tricyclic antidepressant and an SRI, reduced compulsions in one pediatric study (n = 5) [Brasic et al., 1994]. However, in another open trial (n = 8), six children

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were worse on global rating scales, and one child developed urinary retention [Sanchez et al., 1996]. Ratings done by videotape by the same investigators did not detect a treatment effect [Sanchez et al., 1995]. In a double-blind comparison study of 24 subjects 6 to 23 years old, with 12 children assigned to clomipramine or placebo and 12 to clomipramine or desipramine, clomipramine was superior to placebo and to desipramine on ratings of stereotypies, anger, and compulsive, ritualized behaviors. Side effects were minor; maximum dosage was 5 mg/kg/day or 250 mg/day maximum [Gordon et al., 1993]. One child had a prolonged QT interval, and another had severe tachycardia; both effects resolved with a decrease in dosage. Another subject with no previous history had a seizure during the second week on clomipramine therapy. Although effective, clomipramine is not a first-line drug because of the potential side effects [Gordon, 2003]. Before selective serotonin reuptake inhibitors were available, fenfluramine, which decreases blood serotonin levels by promoting its release and blocking its reuptake and which also blocks dopamine receptors, was studied in autistic and severely retarded individuals, but most studies were not controlled [Ekman and Miranda-Linné, 1989]. This compound was withdrawn from the market by the U.S. Food and Drug Administration in 1997. Another SRI, venlafaxine, which inhibits serotonin, norepinephrine, and dopamine reuptake, was effective in an open-label study of 6 of 10 autistic subjects between the ages of 3 and 21 years in improving compulsive and repetitive behaviors and associated features of attention-deficit–hyperactivity disorder, as well as ratings on the Clinical Global Impressions scale, in a dose of 6 to 50 mg/day [Hollander, 2000]. Side effects were mild and included persistent signs of behavioral activation in five subjects and transitory signs in an additional three individuals. In summary, SRIs, selective serotonin reuptake inhibitors, and other medications affecting serotonin and dopamine levels can reduce specific symptoms of autism, such as ritualized behaviors, stereotypies, rigid behaviors, aggression, and anxiety. They have generally been found to be safe; children may be particularly sensitive to the possible behavioral activation of these drugs [Buitelaar and Willemsen-Swinkels, 2000]. There has been concern about reports of an association of fluoxetine and possibly other selective serotonin reuptake inhibitors with suicidal ideation in depressed children, and the Food and Drug Administration has recommended that children on these medications should be very carefully monitored. The implications for treatment of behavioral symptoms in children with autistic spectrum disorders are not clear, and the potential benefits may be great.

Stimulants and Drugs to Treat Hyperactivity Hyperactivity is an important target symptom that can be potentially improved with medication, but it has not been well studied. Some reduction in symptoms has been seen with antipsychotics, psychostimulants, and naltrexone. The greatest success has been with a reduction in overactivity, rather than in distractibility [Aman and Langworthy, 2000]. The number of studies and subjects involved in studies of stimulant drugs is small. In 13 children between the ages of 5 and 11 years with Asperger’s disorder and attentiondeficit–hyperactivity disorder, in a double-blind, placebocontrolled, crossover design, methylphenidate in a dose of

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0.3 to 0.6 mg/kg caused withdrawal and irritability in some children, although hyperactivity decreased in 8 children [Handen et al., 2000]. In a double-blind, crossover study of 10 children, those on methylphenidate improved compared with those on placebo [Quintana et al., 1995]. In a small trial involving eight children with Asperger’s disorder, clonidine, an adrenergic receptor agonist, had some effect in decreasing irritability and hyperactivity [Jaselskis et al., 1992]. In antipsychotic drug studies with haloperidol [Locascio et al., 1991] and in a crossover design with risperidone [McDougle et al., 1997; Nicholson et al., 1998; Perry et al., 1997], the outcome of reducing hyperactivity was best achieved with risperidone. There is little evidence for any beneficial effect on hyperactivity using the selective serotonin reuptake inhibitors. Naltrexone, however, has improved hyperactivity [Campbell et al., 1993; Kolmen et al., 1997; Willemsen-Swinkels et al., 1995, 1996, 1999]. Several antiepileptic drugs have been used for behavioral manifestations of autism, particularly for treating intense rapid mood shifts. In an open-label study, levetiracetam in 12 patients 4 to 18 years old was well tolerated, and it somewhat improved impulsivity and mood instability [Rugino and Samsock, 2002]. An open-label pilot study of divalproex sodium in 14 patients demonstrated improvement in 10 (71%) [Hollander et al., 2001]. Lamotrigine was found to be a benefit in parent rating scales but in no other measures [Belsito et al., 2001] in a randomized, placebo-controlled trial of 28 children. In summary, a number of medications, particularly SRIs and atypical neuroleptics, can help decrease specific symptoms of autism such as behavioral outbursts, stereotypic or compulsive behaviors, aggression, anxiety, inattention, and oppositional behavior (Table 38-4). Reduction in these behaviors can improve quality of life and promote better opportunities for learning. However, there is no pharmacologic treatment to address language and cognitive deficits or social understanding.

Complementary and Alternative Medicine A significant number of families seek complementary or alternative medicine treatments, few of which have been studied in well-designed trials. Examples are vitamin B6, antifungal agents, hormones, high-dose vitamin A, chelation therapy, and immunoglobulins. A review by Pfeiffer [1995] of vitamin B6 and magnesium studies indicates a favorable effect demonstrated in studies with imprecise outcome measures, small samples, repeated use of subjects in multiple studies, no follow-up, and no statistical adjustment of measures. A double-blind, placebo-controlled study [Findling, 1997] of pyridoxine and magnesium in 10 patients found no benefit but no significant side effects. In 20 autistic children, synthetic adrenocorticotropic hormone was used in a blinded, controlled trial [Buitelaar et al., 1992]. Some benefit was seen in play behavior and social interaction. Side effects were increased liability of mood and “inner tension” as rated by parents and teachers. Another popular treatment for autistic spectrum disorder is a gluten-free, casein-free diet. The first controlled, blinded, randomized trial of this therapy was begun in 2004, and results are not yet available. Immunoglobulin has been administered intravenously in open trials [DelGiudice-Asch et al., 1999; Plioplys, 1998]

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TABLE 38-4 Pharmacologic Therapy for Target Symptoms DRUG TYPE

DRUG

TRIALS*

DOSE

TARGET SYMPTOMS

POTENTIAL SIDE EFFECTS

Neuroleptic

Haloperidol

No

0.5-3.0 mg/day

Hyperactivity, negativism, stereotypies, withdrawal

Atypical neuroleptic

Risperidone

Yes

2.5 mg/d < 45 kg 3.5 mg/d > 45 kg

Olanzapine

No

5-20 mg/day

Opiate antagonist

Naltrexone

Yes

0.5-1.5 mg/kg/day

Disruptive behaviors; SIB, aggression; hyperactivity, irritability Hyperactivity, social relatedness; SIB, aggression, anxiety, irritability, depression Aggression, SIB, agitation, restlessness, hyperactivity

Risk of tardive dyskinesia and acute dystonic reactions, sedation, weight gain Increased appetite, weight gain, mild sedation, tremor, hypersalivation Increased appetite, weight gain, sedation, tremor

α2 Adrenergic agonist

Clonidine

Yes

0.15-0.2 mg/day

Hyperactivity, irritability, stereotypies, inappropriate speech, oppositional behavior, aggression

Tricyclic antidepressant/SRI

Clomipramine

Yes

25-75 mg/day, max 5 mg/kg/day

Stereotypies, anger, compulsive behaviors, social interaction, irritability

SSRIs

Fluoxetine

Yes

20-80 mg/day

Citalopram

No

2.5-20 mg/day

Sertraline

No

12.5-50 mg/day

Venlafaxine

No

6-50 mg/day

Anxiety, depression, repetitive thoughts and behaviors, irritability Repetitive behaviors, mood swings, aggression, irritability Anxiety, behavioral problems, social interaction, aggression Compulsions, repetitive behavior, hyperactivity Hyperactivity, irritability Affective instability, impulsivity, aggression, repetitive behavior Impulsivity, mood instability

SRI/NE reuptake inhibitor Stimulant Antiepileptic drugs

Methylphenidate Yes Divalproex Yes sodium Levetiracetam Yes

0.3-0.6 mg/kg/day 20-40 mg/kg/day 125-500 mg bid.

Mild gastrointestinal symptoms, decreased appetite, drowsiness Bradycardia

Urinary retention, hyperactivity, sleep disturbances, dry mouth, dizziness, seizure threshold and ECG changes Behavioral activation, aggression Headache, sedation, agitation, aggressiveness, dyskinesia Activation, insomnia, gastrointestinal side effects Behavioral activation Withdrawal, irritability Mood lability, fatigue, insomnia, diarrhea, weight gain Disinhibition

*Indicates whether controlled pediatric trials have been conducted for the drug. CGI, Clinical Global Impressions scale; ECG, electrocardiographic; HA, hyperactivity; NE, norepinephrine; SIB, self-injurious behavior; SRI, serotonin reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.

and not found to be useful. Dimethylglycine, which is closely related to the inhibitory transmitter glycine, has been proposed [Rimland, 1990] as helpful for autistic children and adults, but it was ineffective in a 3-month, double-blind, placebo-controlled trial of its use in eight subjects [Bolman and Richmond, 1999]. One survey [Levy et al., 2003] found that 32% of 284 children at a Pennsylvania regional autism center were using complementary and alternative medicine. The investigators suggested that it is important to respect the parents’ belief if the complementary medicine is not toxic, but if the treatment is potentially harmful, negotiating a safer replacement practice should be attempted. Reported dramatic improvement after the administration of secretin as part of endoscopy in three autistic children led to widespread use by parents. Subsequent blinded, randomized trials did not substantiate its efficacy [Chez et al., 2000; Coniglio et al., 2001; Dunn-Geier et al., 2000; Roberts et al., 2001; Sandler et al., 1999]. These trials included single- and repeated-dose protocols. It is challenging to perform clinical trials enrolling children with autism, but without well-designed, blinded studies, safe and effective therapies cannot be determined. Problems include standardization of diagnoses, heterogeneity of target problem behaviors, and lack of cooperation of subjects. Many

outcome measures are available, including global measures (Clinical Global Impression of Severity) and others targeted to specific symptoms. The National Institutes of Healthsponsored multicenter networks are planning and currently performing clinical trials (i.e., The Autism Research Units on Pediatric Psychopharmacology, The Studies to Advance Autism Research and Treatment Centers, and the Collaborative Programs of Excellence in Autism). Whenever feasible, parents should be encouraged to participate in clinical trials to make progress in validating new pharmacologic and behavioral therapies.

EDUCATIONAL AND BEHAVIORAL INTERVENTIONS The primary source of intervention for most children with autistic spectrum disorder is through the educational system. The Individual with Disabilities Education Act ensures a “free and appropriate” public education to “children” between the ages of 3 and 21 who have been diagnosed with learning disabilities. This act specifically covers autistic disorder, but whether the full range of autistic spectrum disorder is covered depends on the particular state’s definition of disabilities. The quality and extent of services that are

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provided vary from one community to another, even within a particular school district. The core deficits associated with autism affect all aspects of the individual’s life, necessitating a comprehensive approach to intervention [Lord and Bailey, 2002; Lord et al., in press; Wetherby et al., 1997]. Numerous comprehensive early intervention programs for children with autistic spectrum disorder have been developed and described [Dawson and Osterling, 1997; National Research Council, 2001; Rogers, 1998]. The National Research Council [2001] provides descriptions of 10 model programs considered representative of well-described, comprehensive treatment programs with at least some empiric support. None of these programs has been rigorously evaluated with regard to optimal time of initiation, mode of delivery, intensity, or duration. Given the great heterogeneity in the population with autistic spectrum disorders, intervention programs must be tailored to the needs of the individual. The National Research Council [2001] report describes the common elements of successful early intervention programs and makes several recommendations: • Intervention should begin early (as soon as an autistic spectrum disorder diagnosis is seriously considered). • Intervention should include active engagement in instructional programming for at least 25 hours per week, with full-year programming. • Intervention should include repeated, planned teaching opportunities that are one-to-one designs or delivered in a very small group, with individualized goals. • Intervention should include family support and parent training. • Intervention programs should have low student-toteacher ratios. • Program evaluation and assessment of the child’s progress should be ongoing. • Six kinds of intervention should have priority: communication, social skills, play skills, cognitive development, strategies to address problem behaviors, and functional academics. Methods based on applied behavior analysis for teaching skills and facilitating more appropriate and adaptive behaviors have been extensively tested for their effectiveness in children and adults with autism and other developmental disabilities [Dunlap and Fox, 2001; Lovaas, 1987; McEachin et al., 1993; Sheinkopf and Siegel, 1998; Smith et al., 2000]. Applied behavior analysis and comprehensive programs based on applied behavioral analysis are established on principles of behavior modification. By carefully analyzing the causes and consequences of a particular behavior, identifying an opposite, competing behavior (i.e., desired behavior) and consistently altering the consequences so that the desired behavior is rewarded, the instructor can teach new skills or transform inappropriate behaviors into more acceptable ones. This relatively simple principle has been developed into techniques that have been highly effective for teaching new skills, increasing the frequency of appropriate or adaptive behaviors, and decreasing the frequency of inappropriate or maladaptive behaviors. Behavioral techniques can be used to work on very specific social behaviors, such as making appropriate greetings and appropriate modes of expressing affection, sharing,

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and playing interactively. Behaviors that have the potential to generalize to other settings should be taught. For instance, teaching a child to make eye contact with a speech therapist is of limited use unless the child also makes eye contact when conversing with parents, peers, and others. One way to increase generalization is to help parents reinforce and apply the behavioral techniques at home and in the community. For this reason, good behavioral programs always contain a parent-training component. When parents are taught how to apply behavioral techniques, with ongoing coaching, they can be effective in smoothing out interactions between the individual with autistic spectrum disorder and other family members. Parents are most likely to learn applied behavior analysis techniques when enrolling their children in a comprehensive treatment program. As these comprehensive treatment programs have evolved, there have been trends toward teaching parents to implement the programs, toward using the behaviormanagement techniques in settings that are more naturalistic and during typical activities, and toward developing goals based on the child’s unique developmental profile [Ingersoll et al., 2001]. There is also a trend, at least when applied to programs for children and adults with developmental disabilities, away from emphasizing the consequences of a behavior and toward an emphasis on understanding the triggers of a behavior, proactively providing cues or rehearsal of the appropriate behavior, making changes in the environment to avoid or minimize those triggers, and teaching more adaptive or appropriate responses when the triggers cannot be avoided. Some comprehensive treatment programs derive strategies from a developmental theoretical framework. For instance, the Denver Model [Rogers et al., 2000] emphasizes the need to establish interpersonal relationships as a foundation to achieving other developmental milestones. The Developmental Intervention Model [Greenspan and Wieder, 1997] is based on an assumption that social problems in autistic spectrum disorders are caused by abnormal or atypical processing of sensory information and difficulties with emotional regulation. The focus is on addressing sensory processing irregularities and establishment of emotional contact. Both programs emphasize improving parent-child relationships. Although most of these programs have not been extensively evaluated using rigorous scientific trials, there are theoretical reasons and some preliminary scientific evidence that they can be useful for many children with autistic spectrum disorders [National Research Council, 2001; Rogers, 1998]. Many well-established programs combine elements of behavioral and developmental orientations [Marcus et al., 2000; McGee et al., 2000]. Some have specifically evaluated the effectiveness of the parent-training components of their programs. Parent-training models that are promising based on evidence provided by their developers include the Learning Experiences Alternative Program for Preschoolers and Their Parents [Strain and Cordisco, 2000], the Denver Model [Rogers et al., 2000], the Individualized Support Program at the University of South Florida [Dunlap, 1999], the Pivotal Response Training Model [Koegel et al., 1999], and the Douglas Developmental Center Program [Harris et al., 2000]. Whatever the theoretical underpinning, well-established and effective programs always include an emphasis on parentchild relationships and overall family support [Dawson and Osterling, 1997]. There is evidence that parents can learn to use these methods and that doing so helps them feel better in

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general and more satisfied and confident in their parenting role [Koegel et al., 1996; Ozonoff and Cathcart, 1998; Schreibman, 1997; Sofronoff and Farbotko, 2002]. There is much less evidence when considering intervention programs or treatment options for older children, adolescents, and adults with autistic spectrum disorder. There is growing recognition that although the needs of individuals with autism spectrum disorder change over time, there is need for lifelong support. In particular, transitions (e.g., to high school, to higher education or vocational training, to independent or assisted living) are critical periods during which supports already in place may be lost because of changes in eligibility or funding sources.

RESOURCES FOR FAMILIES An enormous amount of information is available to families on the Internet; they often need specific counseling regarding evaluation of treatments that are espoused without adequate scientific study. The American Academy of Pediatrics has a useful web site (http://www.aap.org/healthtopics/ autism.cfm). The National Institutes of Health web site (www.nih.gov) can be searched for current research, as can those of specific institutes, including the National Institute of Neurological Disorders and Stroke (www.ninds.nih.gov), National Institute of Child Health and Human Development (www.nichd.nih.gov), and the National Institute of Mental Health (www.nimh.nih.gov). The CDC’s National Center for Birth Defects and Developmental Disabilities has a web site (www.cdc.gov/ncbddd/dd/ddautism.htm) devoted to providing evidence-based information on autistic spectrum disorder and its treatment, including links to resources. The National Dissemination Center for Children with Disabilities (www.nichcy.org) has information on special education laws and on educational practices. Another effort, the First Signs program, is developing methods to inform physicians about the importance of early identification of autism, and it provides resources, including screening tools and referral guidelines. The First Signs web site (http://www.firstsigns.org) includes recommendations and information about obtaining autism screening instruments. Educational tools for families can be found on the Exploring Autism web site (http://www.exploringautism.com). An organization for autism research has a useful parent’s guide to understanding research on autism (www.researchautism.org). For practitioners, the AAN/CNS practice parameter for evaluation of children with autism and the detailed background paper can be found on the For OC Kids web site (http://www.forockids.org/en/forockids.php). A comprehensive review of the literature on treatment using applied behavior analysis and practical guidance for implementation is contained in Positive Behavioral Support: Including People with Difficult Behavior in the Community [Koegel et al., 1996]. DISCLAIMER The views expressed in this chapter are those of the authors and do not necessarily reflect the official position of the National Institute of Mental Health, the National Institute of Neurological Diseases and Stroke, the National Institutes of Health, or any other part of the U.S. Department of Health and Human Services.

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CHAPTER 39

Neuropsychopharmacology Melissa Lee and John T. Walkup

The practice of pediatric neuropsychopharmacology has grown increasingly complex in the past 2 decades. There have been dramatic increases in use of psychotropic medications despite limited empiric support and increasing concerns about the safety of these medications and their impact on growth and development. Historically, very few safe and effective medications were available to treat pediatric neuropsychiatric disorders, and children received no treatment or treatment that emphasized psychologic or behavioral interventions. With the rising availability of more tolerable and effective psychotropic medications and growing clinician comfort with prescribing for children, psychopharmacology has become standard practice for many neuropsychiatric disorders, resulting in increased use of medications in children [Zito et al., 2003] and more practitioners outside of child psychiatry prescribing psychotropic medications [Olfson et al., 2002]. The database for the safety and efficacy of psychotropic medications in children has increased dramatically in the past decade, although much remains to be done. There is support for the short-term efficacy of many commonly prescribed psychotropics, but there are few data on the longterm efficacy and safety of medication combinations commonly used in clinical practice, the comparative efficacy of modern psychologic treatments and psychopharmacology, and the proper sequence for staging psychologic and pharmacologic interventions. For example, there are excellent efficacy and safety data for the short-term treatment of attention-deficit–hyperactivity disorder (ADHD) with stimulants [Jensen et al., 2001], the treatment of anxiety disorders [Birmaher et al., 2003; RUPP, 2001; Rynn et al., 2001], treatment of obsessive-compulsive disorder [DeVeaugh-Geiss et al., 1992; Geller et al., 2001; March et al., 1998; Riddle et al., 2001], treatment of depression with antidepressants (e.g., the selective serotonin re-uptake inhibitors) [Emslie et al., 1997, 2002], and the use of atypical neuroleptics for affective disorders and behavioral problems in children [Findling et al., 2000]. However, there are few data on the short-term efficacy of mood stabilizers (e.g., lithium, anticonvulsants) for neuropsychiatric disorders. There is little information on the long-term usefulness of any psychotropic medication but increasing concerns about the long-term effects of psychotropic drugs on growth and development [MTA, 2004; Nilsson et al., 2004; Weintrob et al., 2002]. Medication combinations commonly used to treat children with multiple neuropsychiatric disorders (e.g., stimulants and selective serotonin re-uptake inhibitors for ADHD and anxiety or depression) have not been studied at all. An additional challenge for clinicians is the lack of correspondence between U.S. Food and Drug Administration

labeling for particular medications and data supporting safety and efficacy. Only a handful of psychotropic medications have Food and Drug Administration approval for use in the treatment of psychiatric conditions in children (Table 39-1). However, a number of studies supporting the safety and efficacy of psychotropic medication are not reflected in current labeling, leaving clinicians in an awkward position. As a result, most psychotropic medications prescribed for children are prescribed off-label. Off-label use of medications increased in the past 2 decades for a variety of indications, including stimulants for children younger than 5 years, selective serotonin re-uptake inhibitors for depression and anxiety, and atypical neuroleptics for mood disorders and aggression. Increased off-label use of these medications resulted from downward extension of a current indication to a younger age group (e.g., stimulants in children younger than 5 years, antidepressants in teens and children) and the availability of newer medications with a reduced potential for serious side effects compared with their predecessors. Sometimes, the benefit of off-label use has been extremely helpful (e.g., selective serotonin re-uptake inhibitors for anxiety disorders), but off-label prescribing of medications in advance of their achieving a good track record in clinical practice or the demonstration of efficacy in clinical trials may not be helpful. For example, based on its low sideeffect profile, a few positive case reports and open trials, and an aggressive marketing campaign, gabapentin was prescribed for the treatment of bipolar affective disorder; however, subsequent controlled trials have not supported its efficacy [Frye et al., 2000]. There has been a dramatic shift in the perceived safety of commonly prescribed psychotropic agents in children. Data suggest that longer-term use of stimulants may be associated with growth suppression [MTA, 2004], antidepressants for depression in children and adolescents may increase the risk for suicidal ideation or behavior early in the course of treatment [Hammad, 2004], and weight gain and risk for a metabolic syndrome are associated with neuroleptics [Allison and Casey, 2001; Lindenmayer et al., 2003; Wirshing et al., 1999] and some mood stabilizers [Yatham et al., 2002]. There is increasing public concern about the use of medications, particularly about the use of medications in vulnerable populations such as children. The decision about whether to use pharmacologic interventions mandates careful consideration of the benefits and the risks of treatment. To justify the use of medications, the child must first have a disorder or target symptoms with the potential for pharmacologic responsiveness. Second, the child’s level of impairment must cross a threshold of severity such that the lack of pharmacologic treatment, given all the potential risks, would cause more harm. Third, the

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TABLE 39-1 Labeled and Off-Labeled Use of Neuropsychopharmacologic Agents in Children and Adolescents DRUG Stimulants Amphetamine, mixed salts Atomoxetine (nonstimulant) Dextroamphetamine Methylphenidate Pemoline Clonidine Guanfacine Tricyclic antidepressants Clomipramine Imipramine Nortriptyline Bupropion

LABELED USE

OFF-LABEL USE/CLINICAL PRACTICE

Narcolepsy (methylphenidate, dextroamphetamine)

None Enuresis (imipramine) Depression in adolescents (imipramine, nortriptyline) OCD (clomipramine in children > 10 yr) None

Venlafaxine

None

Mirtazapine

None

Serotonin re-uptake inhibitors Citalopram HBr Clomipramine Fluoxetine Fluvoxamine Paroxetine HCl Sertraline Lithium

OCD (fluoxetine, fluvoxamine, sertraline) Depressive disorders (fluoxetine)

Anticonvulsants Carbamazepine Gabapentin Lamotrigine Topiramate Valproate Typical neuroleptics Haloperidol Pimozide Atypical neuroleptics Aripiprazole Olanzapine Quetiapine Risperidone Ziprasidone

Seizure disorders

None

ADHD Aggression Depression in children Anxiety disorders ADHD Depression ADHD Depression Anxiety disorders ADHD Depression Anxiety disorders Depression Anxiety disorders

Bipolar affective disorder Aggression Bipolar affective disorder Aggression

Vocal or motor tics Severe behavioral disturbances

Psychotic disorders

None

Psychotic disorders Tourette’s syndrome Bipolar affective disorder Aggression

ADHD, attention-deficit–hyperactivity disorder; OCD, obsessive-compulsive disorder.

child’s symptoms must not have improved with nonpharmacologic interventions or these interventions are not readily available in the community. Fourth, the clinician must have the time available to adequately monitor patients for both common and rare, but significant, adverse events (e.g., suicidal ideation or behavior). Safe prescribing of medications for children also requires detailed documentation of the decision-making process and an active monitoring plan for outcome and adverse events. The likelihood of a child with a neuropsychiatric disorder presenting to a pediatric neurology practice is high. To treat these children effectively, the pediatric neurologist must have the ability to collect and integrate information from multiple sources (i.e., child, family, school, and other agencies) and to make a diagnostic formulation and treatment plan that addresses the neuropsychiatric symptoms and psychosocial factors that affect the delivery of care and the

assessment of outcome. Given the rapidly changing nature and increasing complexity of modern clinical care, pediatric neurologists need to define their comfort level in assessing and treating neuropsychiatric disorders and to determine how this may influence the scope of their practice. For neurologists who treat neuropsychiatric disorders, it is critical to keep abreast of this evolving field, especially new safety data that influence the standard of care. It may require a team of colleagues, including psychologists and psychiatrists, who can be involved in the assessment and treatment of these children with complex medical profiles. This chapter provides an overview of the major classes of medications used in pediatric neuropsychopharmacology, including stimulant medications, antidepressants, mood stabilizers, anxiolytics, and α2-agonists. In-depth discussions regarding comprehensive psychiatric assessments and multimodal treatments can be found in the basic textbooks in

Lee and Walkup / Neuropsychopharmacology

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TABLE 39-2 Stimulant and Nonstimulant Medications for Attention-Deficit–Hyperactivity Disorder: Preparations, Pharmacology, and Dosing DRUG

PREPARATION

PHARMACOLOGY

DOSING

Methylphenidate, immediate release

Ritalin (5- and 10-mg tablets)

Time to peak plasma conc = 1-2 hr Half-life = 2-3 hr

Age ≥ 6 yr: 5 mg qd or bid; increase dose by 5 to 10 mg weekly; maximum dose of 60 mg/day Optimum dose between 0.3 and 0.7 mg/kg/dose, given bid or tid (total dose = 0.6 to 2.1 mg/kg/day) 8-hour dose of Rialin ER corresponds to titrated 8-hour dosage of immediate-release methylphenidate 8-hour dose of Methylin ER corresponds to titrated 8-hour dosage of immediate-release methylphenidate 8-hour dose of Metadate ER corresponds to titrated 8-hour dosage of immediate-release methylphenidate Once-daily dosing; may be opened and sprinkled on food

Methylin (5-, 10-, and 20-mg tablets) Methylphenidate, sustained release

Ritalin SR (20-mg tablets)

Time to peak plasma conc = 4-5 hr Duration of action = 8 hr

Methylphenidate, extended release

Methylin ER (10- and 20-mg tablets)

Time to peak plasma conc = 4.7 hr Duration of action = 8 hr

Metadate ER (10- and 20-mg tablets)

Time to peak plasma conc = 4-5 hr Duration of action = 8 hr

Metadate CD (10-, 20-, and 30-mg capsules)

Bimodal release of methylphenidate Time to first peak plasma conc = 1.5 hr Time to second peak plasma conc = 4.5 hr Bimodal release of Once-daily dosing; may be opened and methylphenidate sprinkled on food Time to first peak plasma conc = 1-3 hr Time to second peak plasma conc = 5-7 hr Bimodal release of 18 mg per day; increase gradually until methylphenidate clinical response achieved or maximum Time to first peak plasma conc = 1-2 hr daily dose of 54 mg (maximum daily Time to second peak plasma conc = 6-8 hr dose of 72 mg in adolescents) Time to peak plasma conc = 60-90 min Initial dose of 2.5 mg daily; increase Half-life = 2.2 hr gradually until clinical response achieved or maximum daily dose of 20 mg, given bid Time to peak plasma conc = 2-3 hr Ages 3-5 yr: 2.5 mg/day; increase by Half-life = 12 hr 2.5 mg once or twice weekly Age > 6yr: initial dose of 5 mg/day; increase by 5 mg once or twice weekly; maximum of 40 mg/day Optimum dose: 0.15 to 0.5 mg/kg/dose given bid or tid (total dose = 0.3 to 1.5 mg/kg/day) Time to peak plasma conc = 8 hr Once-daily dosing Dosing same as immediate-release form Time to peak plasma conc = 3 hr Age 3-5 yr: 2.5 mg/day; increase by Half-life = 7-8 hr 2.5 mg once or twice weekly Time to peak conc = 7 hr Age > 6 yr: initial dose of 5 mg/day; increase by 5 mg once or twice weekly; maximum of 40 mg/day Optimum dose: 0.15 to 0.5 mg/kg/dose given bid or tid (total dose = 0.3 to 1.5 mg/kg/day) Time to peak plasma conc = 2-4 hr Age ≥ 6 yr: initial dose of 37.5 mg/day; Half-life = 12 hr increase by 18.75 mg/week until clinical response or maximum of 112.5 mg/day. Half-life = 5.2 hr Children and adolescents < 70 kg: initial dose of 0.5 mg/kg/day qd or bid; starting with bid dosing may lessen gastrointestinal side effects; increase gradually to 1.2 mg/kg/day. Children, adolescents, or adults > 70 kg: initial dose of 40 mg/day; increase gradually to 80 mg; if less than optimal response by 3-4 wk, may increase to 100 mg if tolerated

Ritalin LA (20-, 30-, and 40-mg capsules) Methylphenidate, extended release, core Trilayer core tablets Dexmethylphenidate

Concerta (18-, 27-, 36-, 45-, and 54-mg tablets) Focalin (2.5-, 5-, and 10-mg tablets)

Dextroamphetamine, immediate release

Dexedrine (5-mg tablets)

Dextroamphetamine, sustained release Amphetamine, mixed salts

Dexedrine (5-, 10-, and 15-mg spansules) Adderall (5-, 10-, 20-, and 30-mgtablets) Adderall XR (10-, 20-, and 30-mg tablets)

Pemoline

Cylert (18.75-, 37.5-, and 75-mg tablets)

Atomoxetine

Strattera (10-, 18-, 25-, 40-, and 60-mg tablets)

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child psychiatry. The American Academy of Child and Adolescent Psychiatry (AACAP) and the American Psychiatric Association (APA) have developed and published practice guidelines that summarize current thinking about the assessment and treatment of pediatric neuropsychiatric disorders.

STIMULANTS This section briefly describes the use stimulants in the treatment of ADHD (Table 39-2). A discussion of atomoxetine (Strattera), a nonstimulant medication approved for the treatment of ADHD in children and adults, is also included. Chapter 36 provides a detailed discussion of the diagnostic assessment and other modalities of treatment of ADHD.

Clinical Applications Stimulants have been in clinical use since 1937, when it was observed that a group of children in residential treatment showed marked improvement in their behavior with Benzedrine (D- and L-amphetamine) [Weiss and Weiss, 2002]. Since then, the criteria for ADHD have been refined, and other stimulant medications have been evaluated and demonstrated efficacy in numerous placebo-controlled studies [Jensen et al., 2001]. Approximately 70% to 80% of patients with ADHD have a positive response to stimulant medication. Stimulants, with the exception of pemoline, are the first-line treatment for ADHD. Pemoline, although effective [Pelham et al., 1990], has been associated with acute liver failure (see “Adverse Effects”), and it is generally not considered unless alternative medications have failed. Atomoxetine, a nonstimulant medication, has been approved for the treatment of ADHD in children and adults [Strattera, 2003]. Stimulant medications have generally been viewed as ineffective or contraindicated for hyperactivity in children with autism and by extension other pervasive developmental disorders. However, stimulants can be useful for some children. A single test dose of stimulant may be useful to identify children for whom a longer stimulant trial is contraindicated. Children who experience a significant worsening of ADHD (e.g., hyperactivity and irritability) or pervasive developmental disorder symptoms (i.e., tics or stereotypies) with a single dose may be excluded from further stimulant treatment. For children who tolerate a test dose, it may be prudent to complete a full trial [Di Martino et al., 2004]. Despite substantial data supporting the efficacy of stimulants, their use in children is controversial because there are concerns about safety. The lay public and media have expressed concerns about the potential for overdiagnosis of ADHD and overuse of stimulant medications in children. According to the U.S. Surgeon General, most children with psychiatric disorders are not assessed or treated [Satcher, 2001]. Despite the dramatic increases in stimulant use in the past 10 years [Zito et al., 2003], the ratio of stimulant use to prevalence of ADHD is less than 1:1, suggesting that undertreatment is a more prevalent and important issue [Jensen et al., 1999]. Stimulant medications have come under public fire because of their reported associations with tics, growth suppression, and addiction. This connection has caused some to question their safety in short- and long-term use (see

“Adverse Effects”). Overall, it is difficult to make causal links between stimulants and any but the most common adverse events, because most clinical trials for efficacy are not fully powered to detect rare or unexpected adverse events. Some studies suggest that children with ADHD who are treated early in life have a lower risk of abuse than children with ADHD who are not treated [Katusic et al., 2003; Wilens et al., 2003]. Prudent practice therefore necessitates use of the lowest possible doses with close monitoring in addition to nonpharmacologic intervention when available and appropriate. During the titration phase, children often are monitored monthly for symptoms, side effects, blood pressure, pulse, height, and weight. After a maintenance dose is achieved, visits every 3 to 4 months should suffice. The data show that medication alone is more beneficial than behavioral therapy alone in children 5 years of age and older. The combination is specifically helpful for oppositional behavior and familial tension. Detailed discussion with the family and teachers with full documentation in the medical record is essential.

Pharmacology Stimulants are sympathomimetic drugs that directly stimulate α- and β-adrenergic receptors. They also stimulate the release of dopamine from presynaptic nerve terminals and inhibit their re-uptake. The exact mechanism for efficacy on attention and hyperactivity in ADHD is unknown. Stimulant medications are available in immediate-release and sustained-release preparations (see Table 39-2).

Clinical Management Assessment A neuropsychiatric assessment of inattention, impulsivity, and hyperactivity involves gathering information from multiple sources, including the child, parents, teacher, therapist, or other individuals involved with the child (e.g., day care providers and coaches). Information can be gathered through clinical interview; patient, parent, and teacher rating scales; neuropsychologic testing; and medical evaluation, including laboratory screening [AACAP, 1997b]. The diagnostic criteria for ADHD are detailed in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) [APA, 1994]. A thorough neuropsychiatric assessment is necessary because inattention, impulsivity, and hyperactivity can be complications of medical conditions, and they are commonly caused by other neuropsychiatric disorders. Children with ADHD often have co-occurring neuropsychiatric disorders, which can make it difficult to accurately determine whether ADHD symptoms are attributable to ADHD or to the co-occurring conditions. Medical and developmental problems in the differential include vision or hearing deficits, seizures, chronic medical illnesses, sleep deprivation, and poor nutrition [AACAP, 1997c]. Children who have unidentified intellectual deficits, learning disabilities, speech and language problems, or substance abuse may appear to exhibit ADHD symptoms. Neuropsychiatric conditions such as anxiety disorders, depressive disorders, and bipolar disorder have disturbances in attention, impulse control, and

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activity level that can be especially difficult to distinguish from ADHD. Identification of co-occurring conditions and risk factors for adverse effects is essential, because some medications may be contraindicated or medication management may require dosing modification or closer monitoring. For example, a patient with co-occurring ADHD and anxiety or depression may prompt the clinician to initiate treatment with an antidepressant first rather than a stimulant, depending on which of the two conditions is more impairing. A child with a pervasive developmental disorder may appear unresponsive to stimulants but may have an adverse behavioral reaction that can be severe. Similarly, a patient with a personal or family history of tic disorders may develop tics de novo or experience a worsening of existing tics during an initial stimulant trial, but evidence suggests that stimulants are unlikely to increase tic emergence relative to placebo [Kurlan, 2003]. A medical evaluation before initiating most psychotropic medications, including stimulants, is prudent to medically “clear” a child. The evaluation should include a recent medical history and a physical examination completed by the primary care provider. Any significant change in health during treatment requires repeat evaluation. Choice of laboratory screening procedures and imaging studies is guided by the medical history and findings on physical or neurologic examination. These may include lead level, thyroid function tests, genetic screening, metabolic studies, magnetic resonance imaging, and electroencephalography. Other assessments may be indicated, including occupational therapy, physical therapy, speech and language evaluation, and neuropsychology [AACAP, 1997b]. For stimulant medications, baseline height, weight, and family or personal history of a tic disorder are also important. Completing a baseline sexual history is often overlooked by physicians when treating adolescents because of the clinician’s lack of training or experience or because of discomfort with the topic. Monitoring for sexual side effects after medication initiation is essential because psychotropic medications can have a significant impact on sexual functioning and may affect the patients’ physical and mental health. Sexual side effects can be the cause of otherwise unexplained medication nonadherence. Some neuropharmacologic agents can interact with oral contraceptives, rendering them ineffective, and psychotropic medications may have teratogenic effects.

Medication Initiation and Titration Pharmacotherapy is only one component in the treatment of children and adolescents with ADHD. Patients and families should be informed of the benefits and limitations of medications and the importance of nonpharmacologic interventions in maximizing the benefits of treatment, including an appropriate school placement, behavior management training for parents, and consistency and structure at home and at school. Practitioners may not have the full range of skills necessary for the management of all aspects of ADHD, and the prescribing physician may wish to develop a treatment team to meet the often complex needs of children with ADHD. The starting dose of methylphenidate is 5 mg, given twice daily and dispensed after breakfast and lunch to minimize appetite-suppressant effects. The dose is increased at weekly

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intervals by increments of 5 to 10 mg until the therapeutic effect is achieved or side effects are encountered. The manufacturer recommends a maximum daily dose of 60 mg [Ritalin, 2004]; however, some clinicians exceed this dose if higher doses are necessary to control symptoms and the patient is not experiencing adverse effects. Detailed informed consent and adequate monitoring and documentation are essential for safe prescribing. Severity of symptoms, afterschool activities, or homework demands may warrant a late afternoon dose. An alternative method is to calculate the dose by weight [Duncan, 1990]. The target dose falls between 0.3 and 0.7 mg/kg, administered two to three times each day (total dose of 0.6 to 2.1 mg/kg/day). With D-amphetamine and mixed salts preparations, the starting dose for children between the ages of 3 and 5 years is 2.5 mg/day, with incremental increases of 2.5 mg weekly until a therapeutic response is achieved. For children 6 years old or older, the starting dose is 5 mg given once or twice each day, with weekly increases of 5 mg until a therapeutic response is achieved. The manufacturer does not recommend exceeding 40 mg/day [Adderall, 2004; Dexedrine, 2002]. As with methylphenidate, some clinicians use higher doses if clinically indicated. Dosing by weight, the optimum dose may fall between 0.15 and 0.5 mg/kg, administered twice or three times daily, with a maximum daily dose of 0.3 to 1.5 mg/kg/day [Duncan, 1990]. Sustained-release preparations are administered after breakfast. Whether sustained-release preparations are as effective as their immediate-release counterparts has been debated [Birmaher et al., 1989; Fitzpatrick et al., 1992; Pelham et al., 1987] but rarely studied. In clinical practice, many patients experience comparable or greater benefit from sustained-release preparations because of the convenience of once-daily dosing, avoiding dosing at school, increasing compliance, and reducing rebound effects. The physician can start with a long-acting preparation and turn to the immediate-release form if the long-acting formulation is not completely effective.

Monitoring Stimulants Ongoing monitoring of medication efficacy involves assessment of the patient’s level of functioning in school, family, community, and peer groups. Data are collected from behavioral observations during office visits, parent and teacher reports, and parent and teacher ADHD rating scales. Patients require monitoring of possible side effects that can occur with short-term and long-term stimulant use. Heart rate, blood pressure, weight, height, and emergence of or changes in tic severity should be assessed routinely. Some clinicians consider the use of “drug holidays” on weekends or during the summer to limit children’s exposure to stimulants and minimize possible long-term adverse effects such as low weight and growth suppression. However, the practice of drug holidays is controversial, because it usually results in the rapid return of symptoms and accompanying impairment. To identify patients who may do well with drug holidays, clinicians can review symptoms and impairment from times of the day when children are not benefiting from stimulants, such as early morning or later in the evening. If patients do well during these times, it may be reasonable to consider more extended time off stimulants.

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Drug holidays should be planned for times when there are no important school or social activities [AACAP, 1997c], and they should be reserved for patients whose families can provide adequate structure, behavior management, and supervision during these periods. Although hyperactive symptoms tend to improve as children mature, inattention and impulsivity often persist. Long-term stimulant treatment may be necessary as up to 80% of ADHD children continue to have symptoms into adolescence and 65% into adulthood [Barkley, 1996; Weiss and Hechtman, 1993].

Adverse Effects Although most children tolerate stimulant medications well, some do not. The most common side effects of stimulants are insomnia and nervousness [Ritalin, 2004]. Some children with ADHD experience sleep disturbance before exposure to stimulants. The child’s preexisting sleep history should be obtained, including other factors that may contribute to sleep disturbance (e.g., poor sleep hygiene, caffeine use, oppositional behavior, separation anxiety). Ironically, some children experience difficulty falling asleep related to hyperactivity, and they can benefit from a small dose of stimulant to help them stay in bed and fall asleep. In group comparisons, dosing three times daily with short-acting stimulants versus dosing two times daily was not found to increase sleep disturbance [Kent et al., 1995; Stein et al., 1996]; however, new-onset sleep delay after starting stimulants may be associated with a stimulant dose that is too high overall or with dosing stimulants too late in the day. Difficulty with falling asleep because of stimulants can be addressed with a combination of dose adjustment, improved sleep hygiene (i.e., straightforward ritual for falling asleep and removing distractions from the room such as televisions, video games, homework, and night lights), cooler room temperatures, roomdarkening shades, avoidance of late afternoon or evening doses of stimulants, switching to a different stimulant, or addition of a sedating medication with ADHD treatment effects such as clonidine [Brown and Gammon, 1992; Prince et al., 1996] or guanfacine. Statistically and clinically significant decreases in expected weight gain and even weight loss have been observed, and these effects appear to be dose related [MTA, 2004; Zeiner, 1995]. Because the impact on weight is mediated by stimulant-induced appetite suppression, administering stimulant doses immediately after meals [Swanson et al., 1983], allowing the child to eat later in the evening after the appetite suppressant effect of the stimulant has abated, or allowing drug holidays on weekends or evenings, may mitigate these effects. The possibility of growth suppression with long-term use of stimulants is a controversial topic. Studies have reported lower than expected heights in pre-adolescents with ADHD, but heights returned to normal by adulthood [Gittelman et al., 1985; Hechtman, 1985]. The apparent lack of impact on adult height was thought to result from the discontinuation of stimulants in adolescence. An alternative theory proposes that this pattern of growth was inherent in children with ADHD and not related to stimulant treatment. The dysregulation of several neurotransmitter systems associated with ADHD may alter neuroendocrine function, including those

involving growth [Spencer et al., 1998]. Adult height does not appear to be reduced after methylphenidate treatment in childhood [Klein and Mannuzza, 1988]. Follow-up of subjects in the Multimodal Treatment of ADHD (MTA) study suggests growth delay compared with a group that had growth above population norms from 14 to 24 months after starting medication. It is not clear whether growth suppression will continue and have a long-term impact, resolve with stimulant discontinuation, or resolve on its own [MTA, 2004]. Historically, stimulant treatment has been associated with the emergence of tics [Borcherding et al., 1990] or the exacerbation of preexisting tics [Law and Schachar, 1999]. Children at risk appeared to be those with a personal history or family history of tic disorders. However, the effect on tics is not absolute; only 25% to 30% of ADHD children with tics experienced significant worsening in some studies [Castellanos et al., 1997; Spencer et al., 1996]. In placebo-controlled trials, low to moderate doses of methylphenidate improve attention and behavior in children with chronic tic disorders without significantly worsening tics [Gadow et al., 1995, 1999]. In the Treatment of ADHD in Children with Tics (TACT) study, tic increases categorized as an adverse event occurred in nearly equal numbers of subjects on placebo (22%), clonidine (26%), and methylphenidate (20%). These data suggest that 20% to 26% of youngsters with tics will experience tic worsening shortly after initiation of any medication treatment, including placebo, lending support to the hypothesis that tic increases observed after starting stimulants reflect the natural waxing and waning of tic severity [TSSG, 2002]. Stimulants have been associated with nonsignificant increases in heart rate and blood pressure [Brown and Sexson, 1989; Tannock et al., 1995]. Although the product information for the stimulants warns of possible decreases in seizure threshold, no increase in seizure frequency was observed in children treated with stimulants who had co-occurring ADHD and seizure disorder [Feldman et al., 1989; Wroblewski et al., 1992]. There is no increased risk of addiction from appropriate treatment with stimulants for ADHD. Adolescents with ADHD treated with stimulants were less likely to abuse stimulants [Biederman, 2003; Faraone and Wilens, 2003; Hechtman, 1985]. Despite the impact on a broad range of ADHD symptoms, including irritability, stimulant medications can be associated with undesirable changes in mood and behavior [Gadow et al., 1992]. Some of these changes occur when the stimulant is reaching peak serum concentrations, or they may occur when serum concentrations are waning, so-called rebound effects. Effects associated with peak concentrations include dysphoria, anxiety, agitation, or the “zombie” effect (i.e., overfocused and passive). Rebound effects include overactivity, talkativeness, excitability, irritability, and insomnia [Rapoport et al., 1978; Zahn et al., 1980]. It is often difficult to determine whether such rebound symptoms are the reemergence of ADHD symptoms off stimulants or true withdrawal or rebound symptoms. These adverse behavioral effects can be managed in a variety of ways, including dose reduction or medication discontinuation and by improving late afternoon coverage by adding a low dose of immediate-release stimulant or by switching to a longacting stimulant [AACAP, 1997c]. Youngsters who experience these side effects on one of the stimulants do not necessarily have the same behavioral effects on another

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stimulant, and switching to another stimulant or alternative medication can be useful. Clinicians should be comfortable using all stimulant preparations to optimize treatment effects and minimize side effects. Pemoline (Cylert) has been associated with rare cases of acute hepatic failure. Since 1975, 15 cases have been reported to the Food and Drug Administration, and 12 of 15 cases resulted in death or necessitated liver transplantation. Although it is unclear whether the early detection of elevated liver enzyme levels can prevent progression of hepatic dysfunction, the manufacturer recommends obtaining baseline liver function tests and monitoring serum levels of alanine aminotransferase every 2 weeks during therapy. Alanine aminotransferase is considered significantly elevated if levels are more than twice the upper limit of normal [Cylert, 2004].

Drug Interactions If stimulant medications are administered concomitantly or within 2 weeks of receiving monoamine oxidase inhibitors, there is a significant risk of precipitating a hypertensive crisis. Methylphenidate may inhibit the metabolism of coumarin anticoagulants, some anticonvulsants (e.g., phenobarbital, phenytoin, carbamazepine, primidone), and tricyclic antidepressants (e.g., imipramine, desipramine, clomipramine). Foods and beverages with caffeine may increase both efficacy and adverse effects. Amphetamines inhibit adrenergic blockers. Gastrointestinal acidifying agents, including citrus juices, lower absorption of amphetamines. Urinary acidifying agents increase urinary excretion of methylphenidate. Both types of acidifying agents can lower blood levels and efficacy of amphetamines. Likewise, alkalinizing agents increase blood levels and potentiate the actions of amphetamines [Cylert, 2004]. The safety of combining stimulants, especially methylphenidate, with clonidine has been controversial. Clonidine has been helpful in managing sleep disturbance related to ADHD or stimulant treatment [Wilens et al., 1994]. The combination appears to help children with ADHD and co-occurring oppositional and conduct disorder [Hunt et al., 1990]. The combination also appears useful in the treatment of ADHD in children with tic disorders [TSSG, 2002]. Concerns about the interaction developed after the report of four deaths of children who apparently received clonidine and methylphenidate, as well as other medications in some cases [Fenichel, 1995]. Although the cases did not have a clear pattern of causality [Sallee et al., 2000a; Wilens et al., 1999], clinicians are more cautious about prescribing this combination. When combining clonidine and stimulants, careful screening is recommended for a personal and family history of cardiac abnormalities, arrhythmias, and non-vasovagal syncope, and a baseline and follow-up electrocardiogram (ECG) should be obtained.

NONSTIMULANT MEDICATION Atomoxetine Clinical Applications Atomoxetine is a nonstimulant medication that is approved for the treatment of ADHD in adults and children 6 years old

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or older. It is a selective norepinephrine re-uptake inhibitor that is structurally more similar to fluoxetine than to stimulant medications. Atomoxetine potentially offers several advantages over stimulant medications: longer duration of action, lower misuse or abuse potential, lower risk of rebound effects, lower risk of precipitating tics or psychosis, and ease of prescribing because duplicate or paper prescriptions are not required and multiple refills are possible. Effectiveness of atomoxetine in children has been supported by placebo-controlled trials [Kelsey et al., 2004; Spencer et al., 2002]. Atomoxetine doses of 1.2 and 1.8 mg/kg/day administered in divided doses were superior to placebo and atomoxetine in a dose of 0.5 mg/kg/day; there was no clear superiority of 1.8 versus 1.2 mg/kg/day. Early clinical trials have used twice-daily dosing, but once-daily dosing also appears effective [Michelson et al., 2004]. Long-term treatment (9 months) with atomoxetine appears to be safe and well tolerated [Michelson et al., 2004]. The therapeutic effects observed in short-term treatment were maintained in significantly more children compared with placebo, and the children attained superior psychosocial functioning [Kratochvil et al., 2002]. When compared with methylphenidate treatment, atomoxetine was associated with comparable therapeutic effects [Michelson et al., 2003]. Efficacy of atomoxetine in adults with ADHD was demonstrated at doses of 60 to 120 mg/day [Strattera, 2003].

Pharmacology Atomoxetine is well absorbed through the gastrointestinal tract and is metabolized by the liver, predominantly by cytochrome P-450 2D6 (CYP2D6). A small percentage of the population (approximately 7% of whites and 2% of African Americans) has reduced activity of the cytochrome P-450 isoenzyme system. These individuals are considered to be “poor metabolizers” of medications whose predominant method of metabolism is this isoenzyme. Poor metabolizers can be expected to achieve higher than expected plasma concentrations on a given dose and a prolonged half-life compared with those with normal CYP2D6 activity. The half-life of atomoxetine in poor metabolizers is 21.6 hours, compared with 5.2 hours in normal metabolizers. Atomoxetine is 98% bound to plasma proteins, primarily serum albumin [Strattera, 2003].

Clinical Management Children should undergo standard psychiatric and medical assessment for ADHD (see “Clinical Management of Stimulant Medication”). No laboratory screening is required, although consideration for obtaining baseline and follow-up liver function studies should be considered in view of reports of severe acute liver dysfunction (described later). Baseline values for weight, heart rate, and blood pressure should be obtained. Concomitant use of medications with cardiovascular effects and medications that inhibit cytochrome P-450 necessitates dosage adjustment. Although the determination of cytochrome P-450 metabolizer status is not routinely available, it appears to be unnecessary because regular dosing parameters provide the time for assessment of outcome and adverse events that may be experienced by poor metabolizers.

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In children, the usual starting dose of atomoxetine is 0.5 mg/kg/day, given in the morning or divided into morning and late afternoon doses. Starting with a split dosing regimen may decrease gastrointestinal side effects. The dose can be consolidated after a target dose is achieved. Decreasing side effects on initiation will ultimately lead to better compliance. The dose may be increased every 3 days to a target dose of 1.2 mg/kg/day. For adults or for children and adolescents weighing more than 70 kg, atomoxetine may be initiated at 40 mg/day. The dose may be increased gradually every 3 days to a maximum dose of 80 mg. If there is an inadequate response after a 2- to 4-week trial, the dose may be increased to 100 mg/day. Patients taking atomoxetine concomitantly with potent inhibitors of CYP2D6 should be maintained at the initial dose for at least 4 weeks before a dosage increase is considered. Dosage reduction is required in patients with hepatic impairment [Strattera, 2003]. In clinical practice, combination therapy may be used during initiation and titration of atomoxetine, especially in children with severe ADHD symptoms. The effectiveness and tolerability of combining atomoxetine with methylphenidate in children who have not responded to monotherapy have been reported in a few patients [Brown, 2004]. Discontinuation of atomoxetine does not require dose tapering. Abrupt discontinuation of atomoxetine has not been associated with an acute discontinuation syndrome [Wernicke et al., 2003].

Adverse Effects The most common side effects of atomoxetine in children and adolescents are upset stomach, decreased appetite, nausea, vomiting, dizziness, tiredness, and mood swings. Atomoxetine was associated with increases in heart rate of 6 beats per minute and increases in systolic and diastolic blood pressure of 1.5 mm Hg compared with placebo. In an analysis of short-term and long-term treatment with atomoxetine, increased systolic blood pressure was observed in adults, and increased diastolic blood pressure occurred in children and adolescents. Heart rate increased in both groups, and no prolongation of the QTc interval was observed [Strattera, 2003]. Seizures and prolonged QTc intervals were reported after an overdose with atomoxetine [Sawant and Daviss, 2004]. Two patients became severely ill from reversible liver failure while taking atomoxetine and other medications. Strattera labeling states that the medication should be discontinued when liver function test values are increased or when there is clinical evidence of jaundice. Use in patients with liver disease likely should be avoided.

Drug Interactions Inhibitors of CYP2D6 may increase serum concentrations of atomoxetine. Atomoxetine does not have significant effects on the cytochrome P-450 system. Combination with monoamine oxidase inhibitors may precipitate a hypertensive crisis. Atomoxetine has potential interactions with cardiovascular agents and adrenergic agonists. Albuterol’s tendency to increase heart rate and blood pressure may be potentiated by atomoxetine. No increase in the cardiovascular effects of methylphenidate was observed when atomoxetine was added, and no interactions between atomoxetine and other proteinbound medications were observed [Strattera, 2003].

ALPHA2-AGONISTS Clinical Applications Two α2-agonists, clonidine (Catapres) and guanfacine (Tenex), are prescribed in the treatment of ADHD, Tourette’s syndrome, aggressive or self-injurious behavior, and the physiologic symptoms of anxiety. The drugs are approved by the Food and Drug Administration for hypertension in adults. In clinical practice, clonidine is a second-line treatment for ADHD. Clonidine has been shown to improve behavior of children with ADHD; however, the degree of its effect in a meta-analysis was less than that of stimulants, and it was associated with many side effects [Connor et al., 1999]. Greater improvement was seen with hyperactivity and impulsivity [Hunt, 1987; Hunt et al., 1982] and frustration tolerance [Hunt, 1987] than with distractibility. Children have been maintained on clonidine for up to 5 years with continued benefit [Hunt et al., 1990, 1991]. The combination of clonidine and methylphenidate has been helpful in adolescents with co-occurring ADHD and oppositional or conduct disorder [Hunt et al., 1990]. This combination allowed the dose of methylphenidate to be reduced by 40% [Hunt et al., 1990]. In children with co-occurring ADHD and tic disorders, those treated with clonidine experienced improvements in both conditions [Steingard et al., 1993]. Clonidine has been used to treat sleep disturbances in children with ADHD [Wilens et al., 1994], and it appears to be helpful in managing severe aggression [Kemph et al., 1993]. Findings of studies looking at the use of clonidine in Tourette’s syndrome have been mixed [Leckman et al., 1982], but significant improvements in tics and behavior have been reported [Cohen et al., 1980; Comings, 1990; Leckman et al., 1991]. Limited data exist on guanfacine. One open trial demonstrated its effectiveness in ADHD [Hunt et al., 1995]. Findings for patients with ADHD and Tourette’s syndrome have been mixed [Chappell et al., 1995; Horrigan and Barnhill, 1995]. Results of more recent studies have been more promising [Scahill et al., 2001].

Pharmacology Clonidine and guanfacine are well absorbed from the gastrointestinal tract and reach peak plasma levels 1 to 3 hours after oral administration. The half-life of clonidine is 6 to 12 hours, and the half-life of guanfacine is 10 to 30 hours. Clonidine is also available in a transdermal patch. Clonidine and guanfacine exert agonist effects on presynaptic α2-adrenergic receptors in the sympathetic nuclei of the brain, resulting in decreased release of norepinephrine from presynaptic nerve terminals. In the central nervous system (CNS), clonidine and guanfacine are thought to regulate noradrenergic activity in the locus ceruleus [Catapres, 2004].

Clinical Management Before the initiation of clonidine or guanfacine, baseline ECG, heart rate, and blood pressure should be obtained. A history of syncope or cardiovascular disease is a relative contraindication. Heart rate and blood pressure should be monitored regularly during therapy for hypotension and bradycardia.

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Clonidine is initiated at 0.05-mg dose taken at bedtime, gradually titrating the dose over several weeks to 0.15 to 0.3 mg/day in divided doses. Clonidine is also available in a transdermal patch, which may have the advantage of increased medication compliance and more stable blood levels. After a therapeutic dose of oral clonidine is achieved, the equivalent patch can be substituted. The patch lasts 5 days in children and 7 days in adults [Catapres, 2004]. Guanfacine offers the advantage of a longer half-life and therefore less frequent dosing, and it may cause less sedation than clonidine [Hunt et al., 1995]. It is initiated at 0.5 mg at bedtime and is titrated up to a maximum of 3 mg/day.

Adverse Effects The most common side effects of clonidine and guanfacine include sedation, dizziness, fatigue, dry mouth and eyes, nausea, hypotension, and constipation [Catapres, 2004]. Catapres-TTS may be associated with contact dermatitis, which may be reduced by rotating its location on the body. Because of the risk of rebound hypertension with abrupt discontinuation, these medications should be prescribed only to patients with reliable medication compliance. Likewise, the dose should be tapered gradually when discontinuing the medication [Catapres, 2004]. One study retrospectively examined the effects of clonidine and clonidine plus stimulants on the ECGs of children and adolescents treated for ADHD or tic disorder. ECGs were examined before and after treatment, and no systematic electrocardiographic effect of clonidine was found [Kofoed et al., 1999].

Drug Interactions Clonidine may potentiate the CNS-depressant effects of alcohol and sedating medications. The manufacturer advises caution in combining clonidine with medications that affect cardiac conduction and sinus node function because of potential additive effects such as bradycardia and atrioventricular block [Catapres, 2004].

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ANTIDEPRESSANTS Tricyclic Antidepressants Clinical Applications Tricyclic antidepressants are approved for the treatment of depression in adults and adolescents (Table 39-3). Placebocontrolled studies have demonstrated the efficacy of tricyclic antidepressants in the treatment of depression in adults, but studies enrolling children and adolescents have yielded inconsistent results. Some open studies show no significant response to tricyclic antidepressants [Kashani et al., 1984; Kramer and Feiguine, 1981]. Others suggest efficacy of desipramine, imipramine, and nortriptyline [Boulos et al., 1991; Geller et al., 1986; Ryan et al., 1986]. Placebo-controlled studies, however, do not support efficacy [Geller et al., 1989, 1990; Puig-Antich et al., 1987]. The lack of efficacy in placebo-controlled trials may be related to methodologic problems, such as a small number of subjects, types of subjects enrolled (with depression that too mild or too severe), and the high placebo response rates in many studies. The use of tricyclic antidepressants for the treatment of depression in children and adolescents has declined because of their equivocal efficacy in this population and the availability of antidepressants with a more favorable side effect profile (e.g., selective serotonin re-uptake inhibitors). Clomipramine has been approved for use in children 10 years old or older for obsessive-compulsive disorder. A number of randomized, controlled trials have demonstrated short-term efficacy [DeVeaugh-Geiss et al., 1992] and efficacy in maintenance treatment [Leonard et al., 1991]. Clomipramine is less commonly used for obsessive-compulsive disorder than selective serotonin re-uptake inhibitors, in part because of the worse side-effect profile, but the drug should be considered for patients who do not tolerate selective serotonin re-uptake inhibitors for the treatment of obsessivecompulsive disorder. It is best to choose an antidepressant for which there is established efficacy for the primary or most impairing

TABLE 39-3 Representative Tricyclic Antidepressants Used in the Clinical Practice of Child Neuropsychopharmacology DRUG

PREPARATIONS

PHARMACOKINETICS

DOSING

Imipramine

Tofranil (imipramine hydrochloride) (10-, 25-, and 50-mg tablets) Tofranil-PM (imipramine pamoate) (75-, 100-, 125-, and 150-mg capsules)

Time to peak plasma conc = 1-2 hr Half-life = 8-16 hr

Nortriptyline hydrochloride

Pamelor (10-, 25-, 50-, and 75-mg capsules) Pamelor (10 mg/5 mL solution)

Time to peak plasma conc = 7-8.5 hr Half-life = 16-90 hr

Clomipramine hydrochloride

Anafranil (25-, 50-, and 75-mg capsules)

Time to peak plasma conc = 2-6 hr Half-life = 19-37 hr Time to steady state = 2-3 wk

Initiate at 25 mg/day and increase by 25 mg/day every 4-6 days while monitoring serum conc and electrocardiograms Therapeutic serum conc = combined serum concentration of imipramine and desipramine, 125 to 250 ng/mL Initiate at 10 mg/day and increase by 10 mg/day every 4-6 days while monitoring serum conc and electrocardiogram Therapeutic serum conc = 60-100 ng/mL Initiate at 25 mg/day and increase gradually while monitoring serum conc and electrocardiogram to a maximum dose of 3 mg/kg or 200 mg/day, whichever is lower

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condition. However, in patients with co-occurring conditions, it is not unusual for the prescriber to consider use of a single agent to treat both conditions. In the rare circumstance when there is proven efficacy of one medication for two conditions—the selective serotonin re-uptake inhibitors fluoxetine or sertraline for obsessive-compulsive disorder and depression—such a strategy is reasonable. Clinicians commonly use bupropion for depression and ADHD based on bupropion’s proven efficacy for depression in adults and its activity on norepinephrine or dopamine. This approach may ultimately be useful for an individual child, but is not likely to be as consistently effective as using an appropriate medication combination for two conditions (i.e., selective serotonin re-uptake inhibitor and a stimulant). Although amitriptyline is commonly used in neurologic settings, its side-effect profile in doses effective for the treatment of anxiety and depression is often prohibitive—sedation and weight gain. The primary metabolite of amitriptyline, nortriptyline, is often better tolerated at treatment doses. Because clinical trials do not support the efficacy of amitriptyline or nortriptyline for anxiety or depression, they should not be considered first-line treatments. For children who cannot tolerate the selective serotonin re-uptake inhibitors or atypical antidepressants, tricyclic antidepressants should be considered, and of the tricyclic antidepressants, nortriptyline likely has a better side-effect profile at treatment doses. Nortriptyline also has the benefit of a target blood level for efficacy that is unique among the tricyclic antidepressants. Tricyclic antidepressants have been prescribed as third-line treatments for patients with ADHD who have failed adequate trials of stimulants, who could not tolerate the adverse effects of stimulants, and who had co-occurring conditions such as depression, anxiety, tic disorders [Wilens et al., 1993], or enuresis. Studies have demonstrated significant improvement in ADHD symptoms with imipramine, nortriptyline [Saul, 1985; Wilens et al., 1993], and desipramine [Biederman et al., 1986, 1989; Gastfriend et al., 1984]. However, tricyclic antidepressants appear to be less efficacious than methylphenidate [Rapoport et al., 1974], and they have been associated with a large dropout rate over time due to loss of efficacy or side effects [Quinn and Rapoport, 1975]. Studies of imipramine in the treatment of separation anxiety disorder and school refusal have yielded inconsistent findings [Bernstein et al., 2000; Gittelman-Klein, 1971; Klein et al., 1992]. Imipramine plus a psychologic intervention increased school attendance significantly more than the psychologic intervention plus placebo. Case reports describe usefulness of tricyclic antidepressants in the treatment of panic disorder [Ballenger et al., 1989; Black and Robbins, 1990; Garland and Smith, 1990], but no placebo-controlled trials have been done. Imipramine appears to be effective in treating enuresis as an initial agent [Fritz et al., 1994; Poussaint and Ditman, 1965; Rapoport et al., 1980] and in children who have failed nonpharmacologic interventions and desmopressin [Gepertz and Neveus, 2004]. Efficacy appears to be correlated with serum concentration [Fritz et al., 1994]. Clomipramine is approved for the treatment of obsessivecompulsive disorder in adults and children older than 10 years. In short-term clinical trials, clomipramine has

demonstrated superiority over placebo [DeVeaugh-Geiss et al., 1992; Leonard et al., 1989] in reducing symptoms of obsessive-compulsive disorder and preventing relapse [Leonard et al., 1991]. Improvement in clomipramine-treated subjects was sustained during 1-year open treatment [DeVeaugh-Geiss et al., 1992].

Pharmacology Tricyclic antidepressants are divided into two groups based on the number of methyl groups bonded to the nitrogen atom of the side chain. Tertiary amines (i.e., imipramine, amitriptyline, clomipramine, trimipramine, and doxepin), which have two methyl groups, are metabolized into secondary amines. Several secondary amines, which have one methyl group, are marketed as independent entities, including desipramine (imipramine), nortriptyline (amitriptyline), and protriptyline (trimipramine). Tricyclic antidepressants differ from each other in their ability to block the re-uptake of norepinephrine and serotonin (5HT) and act as competitive antagonists at muscarinic, histaminic (H1), and adrenergic (α1, α2) receptors. Their therapeutic mechanism of action is thought to result from their effect on norepinephrine and serotonin systems in the CNS. Clomipramine distinguishes itself from other tricyclic antidepressants in its relatively potent inhibition of serotonin re-uptake in addition to its noradrenergic activity. Their central and peripheral activity at muscarinic, histaminic, and adrenergic receptors is not thought to be involved in the clinical response but rather is associated with side effects. Tricyclic antidepressants are well absorbed in the gastrointestinal tract. Tricyclic antidepressants are metabolized in the liver by the cytochrome P-450 system. Although multiple isoenzymes are involved in their metabolism (i.e., CYP1A2, CYP2D6, CYP3A4, and CYP2C), the CYP2D6 isoenzyme is of particular importance. About 7% of the population are poor metabolizers, with reduced activity of CYP2D6. This results in increased plasma concentrations of tricyclic antidepressants and other medications metabolized by CYP2D6 compared with most of the population. Several medications can inhibit or induce the activity of the cytochrome P-450 isoenzymes. Co-administration of the tricyclic antidepressants with medications that inhibit cytochrome P-450 can result in clinically significant interactions. These drug interactions may result in discernible changes in efficacy or exacerbation of common tricyclic antidepressant side effects, but coadministration of tricyclic antidepressants with medications that specifically inhibit the respective cytochrome P-450 pathway may result in elevated blood levels leading to silent but potentially significant impact on cardiac conduction (i.e., prolonged QTc interval). Electrocardiographic monitoring is required for patients taking such drug combinations.

Clinical Management ASSESSMENT As with ADHD, the assessment for anxiety disorders and depression requires gathering information from multiple

Lee and Walkup / Neuropsychopharmacology

sources, including the child, parents, school, therapist, and others involved with the child. Information can be gathered through clinical interview, other informants, self-reports, and medical evaluation, including laboratory screening [AACAP, 1997c]. Diagnostic criteria for anxiety disorders and depressive disorders are detailed in the DSM-IV [APA, 1994]. The diagnostic evaluation of children with depression and anxiety should also determine whether other coexisting conditions are present. Risk factors for adverse effects with tricyclic antidepressants should be identified: family and personal history of bipolar disorder; nonvasovagal syncope, history of cardiac disease (especially arrhythmias, conduction abnormalities, and sudden death); use of concomitant medications; hepatic disease; pregnancy; and narrow-angle glaucoma. A medical evaluation is required before initiating tricyclic antidepressants. A physical examination should have been completed within the past 1 year. A baseline ECG, orthostatic blood pressure and heart rate, complete blood cell count, electrolyte determination, renal and hepatic functions, thyroid function tests, and urinalysis should be performed [Green, 1995]. Other laboratory screening measures may be indicated based on findings in the history or physical examination.

INITIATION AND TITRATION OF TRICYCLICS Because there is large variability in plasma drug concentration with a given dose of imipramine among individuals, monitoring of serum concentration has been recommended [Biederman et al., 1989]. A combined serum concentration of imipramine and desipramine in the range of 125 to 250 ng/mL is considered therapeutic. Higher serum concentrations in this range have correlated with higher response rates compared with placebo in the treatment of pediatric depression. Serum concentrations greater than 250 ng/mL have not improved response rates and were associated with increased side effects [Preskorn et al., 1989]. Because of the risk of adverse cardiac effects, serial ECGs are recommended with the use of all tricyclic antidepressants. They should be obtained at baseline, at the middle point in titration, and at the final dose [Elliot and Popper, 1990/1991]. The following parameters have been suggested as safety parameters for cardiovascular monitoring: PR interval: no greater than 210 milliseconds QRS interval: widening no greater than 30% above baseline QTc interval: less than 450 milliseconds Heart rate: maximum of 130 beats per minute Systolic blood pressure: maximum of 130 mm Hg Diastolic blood pressure: maximum of 85 mm Hg Imipramine may be initiated at 25 mg and increased by 25 mg every 4 to 6 days while monitoring serum concentration and ECGs. Nortriptyline is not approved for use for any indication in children, but its use in limited studies did not appear to result in serious adverse effects [Geller et al., 1989, 1992]. Nortriptyline may be initiated at 10 mg/day and increased by 10 mg/day every 4 to 6 days. In adolescents, a total dose of 30 to 50 mg/day is recommended; however, there may

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be value in monitoring serum concentrations [Geller et al., 1986]. The therapeutic range for nortriptyline is 60 to 100 ng/mL [Geller and Carr, 1988; Geller et al., 1987]. ECGs should be obtained at baseline and after steady-state plasma levels are achieved [Geller et al., 1987]. Clomipramine may be initiated at 25 mg/day and increased gradually over the course of 2 weeks to a maximum dose of 100 mg/day or 3 mg/kg/day, whichever is less. After 2 weeks, the dose may be gradually increased to 200 mg/day or 3 mg/ kg/day, whichever is less. To allow tolerance to side effects and to avoid toxicity, slow titration is recommended after the first 2 weeks, because steady-state plasma concentrations may not be reached for 2 to 3 weeks. Total daily dosing above 3 mg/kg/day should be avoided because of the increased risk of seizures. ECGs should be obtained at baseline and when steady-state plasma levels are obtained.

Adverse Effects Side effects of tricyclic antidepressants include sedation, weight gain, orthostatic hypotension, and anticholinergic side effects (i.e., dry mouth, constipation, blurred vision, and urinary retention). Serious anticholinergic effects may occur, including paralytic ileus, exacerbation of narrowangle glaucoma, and the anticholinergic syndrome (“mad as a hatter, dry as a bone, blind as a bat, hotter than a hare”) [Sadock and Sadock, 2003]. Six sudden deaths have been reported for children taking antidepressant medications [Riddle et al., 1993; Zimnitzky, 1994]. Five were taking desipramine, and one was taking imipramine. Although the role of the tricyclic antidepressants in these tragic deaths is unclear, it has been speculated that the cause of death was cardiac in nature, most likely due to malignant arrhythmias. After the reports, child psychiatrists have become more cautious about prescribing tricyclics in general, carefully screening patients at risk for adverse effects and monitoring cardiac status with serial ECGs [Elliot and Popper, 1990/1991]. It is not clear whether the vulnerability to such medication effects can be determined from routine monitoring of cardiac function. Those who experience increased QTc above that which is considered safe while on tricyclic antidepressants should be monitored closely, and the dose should be adjusted downward until resolution of QTc prolongation. Behavioral side effects include early and acute increases in anxiety or depression. Tricyclic antidepressants may also induce manic episodes or rapid cycling in patients with a history of bipolar disorder. A family history of bipolar disorder may be a risk factor for this effect, but such a history is not a contraindication for the use of antidepressants. A discontinuation syndrome (e.g., flulike syndrome with nausea, headache, and malaise), hypomania, or mania may result from abrupt cessation of tricyclic antidepressants [Sadock and Sadock, 2003]. The Food and Drug Administration mandated a black box warning regarding increases in suicidal ideation for all antidepressants (see “Selective Serotonin Re-uptake Inhibitors”).

Drug Interactions Tricyclic antidepressants have multiple drug interactions. The product information for each of the tricyclic anti-

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depressants provides detailed information regarding specific drug interactions. A combination of tricyclic antidepressants and monoamine oxidase inhibitors can precipitate a hypertensive crisis requiring immediate medical treatment. Early signs and symptoms include headache, stiff neck, palpitations, sweating, nausea, and vomiting [Sadock and Sadock, 2003]. Medications that inhibit CYP2D6 activity such as fluoxetine, paroxetine, and haloperidol (refer to prescribing information for other inhibitors) result in increased serum concentrations of tricyclic antidepressants and increased risk for tricyclic antidepressant side effects. Decreased serum concentrations may be caused by cigarette smoking, lithium (Eskalith), ascorbic acid, ammonium chloride, barbiturates, and primidone. Oral contraceptives may induce hepatic enzymes and decrease tricyclic antidepressant serum concentrations. Tricyclic antidepressants may block the activity of antihypertensives (e.g., guanethidine, propranolol, clonidine). Tricyclic antidepressants may increase the sedative effects of other drugs such as over-the-counter cold medications, alcohol, opioids, anxiolytics, and hypnotics [Sadock and Sadock, 2003].

Selective Serotonin Re-uptake Inhibitors Clinical Applications The selective serotonin re-uptake inhibitors, including citalopram, escitalopram, fluvoxamine, fluoxetine, paroxetine, and sertraline, have Food and Drug Administration indications for a number of mood, anxiety, and eating disorders in adults (Table 39-4). In children, fluoxetine, fluvoxamine, and sertraline have a Food and Drug Administration indica-

tion for obsessive-compulsive disorder; fluoxetine also has a Food and Drug Administration indication for major depression. These indications are based on large-scale, randomized, controlled trials for obsessive-compulsive disorder [Geller et al., 2001; March et al., 1998; Riddle et al., 2001] and major depression [Emslie et al., 1997, 2002]. Other large, randomized, controlled trials of the agents have been completed, but not all have been published. Published trials demonstrating efficacy include citalopram for depression [Wagner et al., 2004]; fluoxetine [Birmaher et al., 2003] and fluvoxamine for separation, social, and generalized anxiety [RUPP, 2001]; sertraline for depression [Wagner et al., 2003] and generalized anxiety [Rynn et al., 2001]; and fluoxetine for stereotypies in children with autistic spectrum disorder [Hollander et al., 2001]. The use of the selective serotonin re-uptake inhibitors for depression and anxiety disorder has increased significantly over the past 10 years, with upward of 1% to 2% of teens currently taking these medications for all indications [Olfson et al., 2002]. Despite the marked increase in use, the prevalence of disorders in children and adolescents that are potentially responsive to the selective serotonin re-uptake inhibitors (e.g., depression and anxiety disorders) is much greater (minimum prevalence of 3% to 5%) than the number of children who are taking these medications (1% to 2%), suggesting overall undertreatment. However, this upward trend may be short lived. In response to finding an increased incidence of suicidal thoughts and behaviors in the large, controlled trails of antidepressants (including selective serotonin re-uptake inhibitors), the Food and Drug Administration began requiring a black box warning in the product information for

TABLE 39-4 Selective Serotonin Re-uptake Inhibitors DRUG

PREPARATIONS

PHARMACOKINETICS

DOSING

Citalopram

Celexa (20- and 40-mg scored tablets)

Initiate at 10 or 20 mg/day; titrate to maximum of 40 mg/day

Escitalopram

Lexapro (5-mg tablet; 10- and 20-mg scored tablets)

Fluoxetine

Prozac (10-mg scored tablet; 10-, 20-, and 40-mg pulvules; 20 mg/5 mL liquid)

Fluvoxamine

Luvox (50- and 100-mg scored tablets)

Paroxetine

Paxil (10- and 20-mg scored tablets; 30- and 40-mg tablets; 10 mg/5 mL suspension)

Time to peak conc = 4 hr Half-life = 35 hr Time to steady state = 1 wk Linear kinetics with dosage ↑ Time to peak conc = 5 hr Half-life = 27-32 hr Time to steady state = 1 wk Linear kinetics with dosage ↑ Time to peak conc = 6-8 hr Half-life (chronic administration) = 7 days (fluoxetine), = 16 days (norfluoxetine) Time to steady state = 4-6 wk Nonlinear kinetics with dosage ↑ Time to peak conc = 8 hr Half-life = 15 hr Time to steady state = 10-14 days Linear kinetics at low dose Nonlinear kinetics at high dose Time to peak conc = 5 hr Half-life = 21 hr Time to steady state = 10 days Nonlinear kinetics with dosage ↑

Sertraline

Zoloft (25-, 50-, and 100-mg scored tablets; 20 mg/mL concentrate)

Time to peak conc = 4-8 hr Half-life = 26 hr Time to steady state = 1 wk Linear kinetics with dosage ↑

No clinical trials in pediatric population Adult dosing: 10-20 mg/day, up to 30 mg/day in partial responders Initiate at 10 mg/day; after 1-2 wk, increase to 20 mg/day; increase to 30 mg or 40 mg/day at week 4-6 if indicated Initiate at 25 or 50 mg/day; increase by 50 mg weekly to maximum of 200 mg/day Average treatment dose in clinical trials = 150-200 mg/day Initiate at 5 mg/day Adult dosing: initiate at 20 mg/day; increase by 10 mg/day every 7-10 days; maximum dose = 50 mg/day Initiate at 25 or 50 mg/day; maximum dose = 200 mg/day

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all antidepressants as of January 28, 2005. They also mandated a change in how antidepressants are delivered from the pharmacy to the patient and required a medication guide to be delivered to consumers every time a prescription is picked up at the pharmacy. The black box warning describes the potential increased risk for suicidal ideation and behavior and the need for careful monitoring early in the course of treatment. No longer supplied in bulk to pharmacies, antidepressants instead are provided in unit packaging that contains a predetermined amount of medication. Inside each unit, a medication guide provides consumers with information regarding depression, suicide, the risk for suicidality early in the course of treatment, and strategies for monitoring worsening of depression or suicidal thoughts or behaviors.

Pharmacology PHARMACODYNAMICS The pharmacodynamic profiles of the selective serotonin reuptake inhibitors are very similar. Their beneficial effects are purported to be associated with their ability to block neuronal re-uptake of serotonin and the low side-effect profile is associated with their low affinity for other receptors. Although some individuals may do better on one selective serotonin re-uptake inhibitor than another, comparative treatment trials suggest similarity in efficacy across all agents in this class. The selective serotonin re-uptake inhibitors may demonstrate benefit in as little as 1 week, with substantial benefit occurring in 8 to 12 weeks. Improvement may continue at a more gradual rate for up to 6 to 12 months. Despite the similarity in pharmacodynamics, the selective serotonin re-uptake inhibitors are very different in chemical structure and pharmacokinetics in ways that may impact their use. Very little is known about the pharmacodynamics or pharmacokinetics of the selective serotonin re-uptake inhibitors in children. The following information pertains to adults unless stated otherwise.

PHARMACOKINETICS Citalopram Peak blood levels of citalopram (Celexa) occur at about 4 hours, with a half-life of about 35 hours. Single- and multiple-dose pharmacokinetics of citalopram are linear throughout the standard dose range (10 to 60 mg/day). Steadystate plasma concentrations are reached in approximately 1 week. Citalopram is metabolized in the liver to a number of mostly inactive metabolites. Citalopram appears to have limited ability to inhibit cytochrome P-450 isoenzymes; inhibition of these isoenzymes is primarily responsible for the demethylation of citalopram. CYP3A4 and CYP2C19 do not appear to significantly affect citalopram blood levels or halflife. The (S)-enantiomer of citalopram is mostly responsible for the serotonin re-uptake [Celexa, 2004].

Escitalopram Escitalopram (Lexapro) is the (S)-enantiomer of a 50:50 racemic mixture of (R)- and (S)-enantiomers of citalopram. The (S)-enantiomer in escitalopram is approximately 100 times more potent at serotonin re-uptake inhibition than the (R)-enantiomer. The peak blood level of escitalopram is

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reached at about 5 hours; the half-life is 27 to 32 hours. Steady state is achieved in about 1 week. The pharmacokinetic profiles of escitalopram for single and multiple doses are linear in the range of doses used clinically (10 to 30 mg/day). Escitalopram is metabolized primarily in the liver by CYP3A4, CYP2C19, and other enzymes. The primary metabolites are found in lesser concentrations in the plasma than escitalopram and are not thought to be clinically active. Similar to citalopram, it is not anticipated that escitalopram will inhibit cytochrome P-450 or be inhibited by medication that inhibits the cytochrome P-450 system [Lexapro, 2004].

Fluoxetine Fluoxetine (Prozac) [Simeon et al., 1986] reaches peak plasma levels approximately 6 to 8 hours after oral administration and is almost completely protein bound. Fluoxetine is extensively metabolized in the liver to norfluoxetine (active metabolite) through a variety of isoenzymes of the cytochrome P-450 system. The kinetic profiles are generally nonlinear, with chronic plasma levels not directly linked to dose. With chronic administration, the half-life of fluoxetine and norfluoxetine increases to 7 days and up to 16 days, respectively. Steadystate concentrations are therefore delayed for up to 4 to 6 weeks. This long duration of activity can have potential benefits (e.g., ongoing medication exposure with occasional missed doses and single-dose weekly administration for the sustained-release fluoxetine) and some risks—side effects may emerge as the plasma level increases 4 to 6 weeks after initiation of treatment, and newly prescribed medications may interact with fluoxetine or norfluoxetine for up to 4 weeks after fluoxetine discontinuation. The prolonged half-life may be problematic for patients who do not tolerate the medication, develop manic reactions, or have other problematic behavioral side effects [Hoehn-Saric et al., 1990, 1991] when the need to discontinue and clear the medication from the body is critical.

Fluvoxamine Fluvoxamine (Luvox) reaches peak plasma levels in up to 8 hours after oral administration and up to 12 hours with the extended-release preparation. Pharmacokinetic profiles are nearly linear in the lower range of treatment doses, with a loss of linearity with higher doses. The half-life of fluvoxamine increases slightly from 15 hours to between 17 and 22 hours after single and multiple doses, respectively. Steady-state plasma levels are usually achieved within 10 to 14 days. Fluvoxamine undergoes extensive metabolism in the liver to a number of clinically inactive metabolites, but the specific cytochrome P-450 isoenzymes involved are unknown. Fluvoxamine does inhibit CYP1A2 and, to a lesser extent, CYP3A4 and CYP2D6, resulting in potentially significant drug interactions, including tertiary amine tricyclic antidepressants (e.g., imipramine, clomipramine), some benzodiazepines, propranolol, warfarin, and theophylline [van Harten, 1995]. Pharmacokinetic studies suggest that children, especially young girls, metabolize fluvoxamine more slowly and that they therefore may require lower treatment doses [Labellarte et al., 2004].

Paroxetine Paroxetine (Paxil) reaches peak plasma concentrations at approximately 5 hours, and the average terminal half-life is about 21 hours after chronic administration of 30 mg/day.

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Steady-state paroxetine plasma levels are reached after about 10 days. Pharmacokinetics were nonlinear for multiple dosing and approximately eight times what would be expected based on single-dose kinetics. A nonlinear kinetic profile results from the saturation of CYP2D6, which is primarily responsible for paroxetine metabolism. Paroxetine undergoes extensive first-pass metabolism to a number of metabolites, none of which appears to have any significant clinical activity. Paroxetine appears to be a strong inhibitor of cytochrome P-450, which suggests the potential for clinically meaningful drug-drug interactions. Pediatric data suggest that children metabolize paroxetine more quickly than adults but that oncedaily dosing is likely adequate [Findling et al., 1999].

Sertraline Sertraline (Zoloft) reaches peak plasma concentrations at approximately 4 to 8 hours after a 2-week period of oral administration, with an average terminal half-life of about 26 hours. Steady-state sertraline plasma levels are reached after about 1 week. Pharmacokinetic profiles were linear for single doses in the treatment range of 50 to 200 mg/day. Sertraline undergoes extensive first-pass metabolism by multiple cytochrome P-450 isoenzymes to N-desmethylsertraline, which is substantially less clinically active than sertraline. Sertraline appears not to be a strong inducer or inhibitor of cytochrome P-450; coupled with the fact that sertraline is metabolized by multiple isoenzymes, this suggests that few clinically meaningful drug-drug interactions should occur. Pediatric data suggest that although children metabolize sertraline more quickly than adults, they may require lower doses because of their lower body weight to avoid excessive plasma levels.

Clinical Management ASSESSMENT The assessment of mood and anxiety disorders before initiation of a selective serotonin re-uptake inhibitor is similar to that described earlier for the tricyclic antidepressants. Assessment requires gathering information from multiple sources, including the child, parents, school, therapist, or others involved with the child. Information can be gathered through clinical interview, other informants, self-reports, and medical evaluation, including laboratory screening [AACAP, 1997a]. Diagnostic criteria for anxiety disorders and depressive disorders are detailed in the DSM-IV [APA, 1994]. The diagnostic evaluation should pay particular attention to conditions that may coexist with depression, such as anxiety disorders and ADHD. Risk factors for adverse effects of selective serotonin re-uptake inhibitors should be identified and include a family and personal history of bipolar disorder, history of suicidal ideation or behavior, sensitivity to other selective serotonin re-uptake inhibitors, concurrent medications that could inhibit or could be inhibited by the selective serotonin re-uptake inhibitor, pregnancy, and hepatic or renal disease. No medical evaluation is required before initiating selective serotonin re-uptake inhibitor treatment, but it may be prudent to medically clear a child by means of a medical history and physical examination, including baseline height and weight and targeted laboratory examination as indicated by the history or physical examination findings.

INITIATION AND TITRATION OF DOSE For all of the selective serotonin re-uptake inhibitors, treatment usually is initiated with a low dose that is adjusted upward slowly at weekly intervals. Because the time-response pattern for the selective serotonin re-uptake inhibitors occurs over a minimum of weeks, aggressive titration often leads to early side effects and may result in early discontinuation of the medication and the need to start again with another medication. Starting low and slowly titrating may allow the patient time to develop some tolerance to some of the side effects. However, the risk of starting with low doses and proceeding slowly is going too slowly and leaving patients undertreated. Dosing of selective serotonin reuptake inhibitors is usually recommended in the morning because of activating side effects and in the evening for individuals who feel sedated on the medication.

Citalopram Citalopram comes in 20- and 40-mg scored tablets. Treatment doses range from 10 to 60 mg/day in adults. In industry-sponsored clinical trials of citalopram in children, patients were started on 20 mg/day, with the option for going up to 40 mg/day at week 6. Citalopram 20-mg tablets are scored, allowing beginning doses of 10 mg/day.

Escitalopram Escitalopram comes in 5-, 10-, and 20-mg tablets. The 10and 20-mg tablets are scored. There are no published controlled trials to guide dosing in children. Standard adult dosing is 10 to 20 mg/day, with higher doses (30 mg/day) used only in those who have had a partial response.

Fluoxetine Fluoxetine comes in 10-, 20-, and 40-mg pulvules; 10-mg scored tablets; and Prozac Weekly, which contains approximately 90 mg of fluoxetine in a time-released preparation. Fluoxetine is also available in a liquid (20 mg/5 mL). In most clinical trials of fluoxetine in children and adolescents, dosing began at 10 mg/day for 1 to 2 weeks, with a subsequent increase to 20 mg. The dose is often held at this level up to 4 to 6 weeks before going to 30 or 40 mg/day [TADS, 2004]. Doses as high as 60 mg/day have been used in clinical trials, but maximum doses are used only if this dose is reached after a patient has demonstrated partial benefit after 10 to 12 weeks of treatment [TADS, 2004].

Fluvoxamine Fluvoxamine comes in 25-, 50-, and 100-mg scored tablets. In clinical trials of fluvoxamine in children, dosing began at 25 or 50 mg/day and increased by 50 mg on a weekly basis to a maximum dose of up to 200 mg/day. Average therapeutic doses at the end of treatment were between 150 and 200 mg/day [Riddle et al., 2001]. This method of titration often leads to the highest safe dose rather than least effective dose. Aggressive titration may lead to increased side effects early in treatment. With slower dosage adjustment, it may be possible to establish benefit at lower doses. This is particularly true for prepubertal children (especially girls) who may metabolize fluvoxamine more slowly and have higher blood levels than teens and adults [Labellarte et al., 2004].

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Paroxetine Paroxetine comes in 10-, 20-, 30-, and 40-mg tablets. The 10- and 20-mg tablets are scored. Paroxetine is also available in a suspension of 10 mg/5 mL. In adults, initial treatment can begin with 20 mg, given once daily in the morning or evening. Doses are increased by 10 mg/day every 7 to 10 days to a maximum dose of 50 mg. In clinical trials, final doses for adults ranged from 20 to 50 mg/day. For children, dosing can start as low as 5 mg/day.

Sertraline Sertraline comes in 25-, 50-, and 100-mg scored pills or tablets and in a concentrate of 20 mg/mL. Generally, 50 mg/day given as a single dose appears to be as effective as other doses for most conditions. Dosing can begin at 25 or 50 mg/day. For those who do not respond or only partially respond, higher doses may be necessary. Clinical trials enrolling adults and children using sertraline have usually used doses up to 200 mg/day as tolerated. One clinical trial of sertraline in children demonstrated efficacy on a fixed dose of 50 mg/day [Rynn et al., 2001].

Adverse Effects COMMON EFFECTS The product information for each medication should be consulted for a comprehensive review of adverse events and warnings. Given the similar pharmacodynamic properties of the selective serotonin re-uptake inhibitors, it is not surprising that their side-effect profiles are also very similar. Although many side effects are reported to have occurred in placebocontrolled trials of the selective serotonin re-uptake inhibitors, a few side effects occurred significantly more often on active medication than on placebo. These include nausea or other gastrointestinal symptoms, insomnia, and anxiety or agitation. Other side effects that occur more often on active medication but are less common overall include apathy or somnolence, tremor, sweating, sexual dysfunction, and allergic reactions, including rash. The most common causes of medication discontinuation other than lack of efficacy are the behavioral or psychiatric side effects such as anxiety or agitation. Although clinicians usually think of side effects as physical changes such as dry mouth, constipation, and sedation, for selective serotonin re-uptake inhibitors, the behavioral and psychiatric side effects and their impact on growth and development are a greater concern and require review with the patient and parent before starting treatment [Walkup and Labellarte, 2001]. Perhaps the most important of these side effects is activation, which occurs in about 10% to 20% of patients [March et al., 1998; RUPP, 2001]. This activation syndrome (distinct from the mood improvement effects of the antidepressants) can result in a number of complaints, including anxiety, increased activity level or akathisia, increased impulsivity, and disinhibition. This activation is very similar to what some children experience when they take diphenhydramine. Activation effects usually appear very early in treatment or after a dose change. When mildmannered children present with an increased activity level, the reaction can be clinically significant and debilitating. Patients do not appear to develop tolerance to these symp-

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toms, but they resolve with dose reduction or discontinuation, which is consistent with the pharmacokinetics of the medication. Much less common but also serious are manic and hypomanic reactions. Manic reactions (1% to 2%) are much less common than activation, occur later in treatment after a period of improvement, do not always go away with dose reduction or discontinuation, and may require medical intervention to control. Core symptoms of mania include decreased need for sleep, euphoria, and grandiosity. It is critical to differentiate activation effects from manic reactions as activation effects likely have little prognostic significance beyond potential sensitivity to other selective serotonin reuptake inhibitors, whereas manic reaction may have prognostic significance for the later development of mania. Children with anxiety and mood disorders who benefit from selective serotonin re-uptake inhibitor treatment do not always have uniform outcomes. For most, symptom relief is associated with return to normal and appropriate function. However, some children, especially those with behavioral problems or those at risk for other behavioral problems (i.e., poor parental discipline and monitoring), may present with increasing behavior problems after successful treatment of anxiety and depression. For example, a child with severe oppositional behavior may have a reduction of such behavior during a depressive episode due to psychomotor slowing or social withdrawal but may actually have more behavioral difficulties with normalization of mood or decreased anxiety. Parents of youngsters at risk for or with a history of behavior problems need to be more active about structure and to limit settings to manage the behavioral difficulties that can complicate recovery. Children with anxiety and mood disorders also experience an evolution of symptoms over time. Children first presenting with separation anxiety at age 8 years may evolve into a generalized anxiety disorder or have periods of recurrent depression in their middle to late teens. Because this can occur during the course of treatment, parents may be confused about whether medication treatment actually causes these changes in the progression of symptoms. Educating the patient and family regarding the progression of symptoms and the course of illness and treatment is helpful so that changes in the clinical course are to some degree anticipated and can be dealt with more easily. The selective serotonin re-uptake inhibitors have also been reported to induce an apathy syndrome. Although it may manifest early in treatment, those with anxiety and depression may not be sensitive to this subtle medication effect until after a period of recovery. Awareness of the potential for apathy improves the likelihood that it will be recognized. Even though patients who have experienced apathy can readily differentiate it from depression or sedation, careful interviewing may be required to make these differentiations. Apathy responds to dose reduction; however, dose reductions required to eliminate apathy may lead to loss of symptom control. Patients who report loss of response, not feeling like themselves, or feeling better but numb or who appear to have lost interest in living without significant depressive symptoms should be interviewed closely to assess for apathy [Hoehn-Saric et al., 1990]. Sexual side effects are not commonly documented in clinical trials with children and adolescents, but in clinical

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practice, it is not uncommon for physicians to find that teens begin to spontaneously complain about sexual side effects when they become sexually active in high school or college. Awareness of sexual side effects can make it more likely that these effects are identified and managed and that that they will not lead to discontinuation and loss of treatment response. Dose reduction, changing to antidepressants with a lower risk for sexual side effects, or the addition of medication that may improve sexual function (i.e., bupropion or Viagra) have all been reported to be effective [Woodrum and Brown, 1998]. Although epistaxis is common in children and adolescents, some children experience increased rate or severity of epistaxis and increased bruising. Such changes appear to be an effect of the selective serotonin re-uptake inhibitors on platelet functions, not on coagulation factors [Lake et al., 2000]. Selective serotonin re-uptake inhibitors, specifically fluoxetine, have been associated with change in the rate of linear growth. This was first reported in a small case series and confirmed in a review of the large fluoxetine database. It appears that the deceleration of growth stopped with medication discontinuation and recurred in one case when the medication was restarted. It is not clear whether this is an effect of all the selective serotonin re-uptake inhibitors or specific to fluoxetine. It also appears that this effect is mediated by suppression of growth hormone and is not mediated by reduction in appetite, as can occur with the stimulants. It does not appear to uniformly affect all children. Because the follow-up period is relatively short, it is unclear whether children can catch up while on medication or whether medication discontinuation is required for children to obtain their optimal height [Weintrob et al., 2002]. Although there are no data to suggest that selective serotonin re-uptake inhibitor treatment leads to drug-seeking behavior (i.e., addictive), some individuals do appear to have a discontinuation syndrome with abrupt discontinuation [Ditto, 2003]. There are three complications to abrupt discontinuation. The first complication is a withdrawal reaction that includes flulike symptoms, such as malaise and gastrointestinal symptoms, but it may also include unusual symptoms such as sensory or psychologic disturbances. Some patients with abrupt discontinuation also experience an abrupt return of symptoms, including suicidal risk. Ironically, case reports suggest that abrupt discontinuation of antidepressants can be associated with hypomanic reactions. Such a patient may initially report feeling much better off of medication and be reluctant to resume medication treatment. Antidepressants with shorter half-lives appear to be more commonly associated with discontinuation syndromes than selective serotonin re-uptake inhibitors with longer halflives.

ANTIDEPRESSANTS AND SUICIDE RISK Antidepressants have long carried warnings in their product labeling regarding the increased risk for suicidal ideation and behavior (i.e., suicidality) early in the course of treatment. The mechanism of this effect has never been clear, but it is commonly attributed to the positive energizing effects of antidepressants outpacing the improvement in

mood and suicidality. For example, a patient with depression, psychomotor retardation, and suicidality when treated with antidepressants may experience increased energy and be capable of acting on suicidal impulses. After approximately 10 years of market exposure, concerns about the development of suicidality on antidepressants, especially the selective serotonin re-uptake inhibitors, prompted a complete review by the British Medical and Healthcare Product Regulatory Agency and the U.S. Food and Drug Administration and ultimately led to stronger warnings within the product information. In the United States, this means that all antidepressants must carry a black box warning regarding the risk for suicidality while on antidepressants early in the course of treatment and the need for close monitoring. In the United States, antidepressants are packaged in unit doses (i.e., month-supply bottles), and each unit includes a medication guide for the patient. The data on which these new warnings are based include more than 24 randomized, controlled clinical trials (>4000 subjects) of the newer non-tricyclic antidepressants completed for the purpose of extended exclusivity under the Food and Drug Administration Modernization Act [FDAMA, 1997]. Although a number of methodologic limitations plague the analysis of these studies, it appears that there is a small but significant increased risk for more suicidality adverse events on active medication (about four events per 100 patients) versus placebo (about two events per 100 patients). There does not appear to be a groupwise risk for emergence or worsening of suicidal behavior for the medications, but the data do support an association with activation syndrome. Although the risk appears to be small (number needed to harm is about 50), the fact that in these same studies there is marginal antidepressant efficacy suggests that more caution is required when considering the use of these medications. In contrast to the industrysponsored studies completed for exclusivity, NIH-funded studies of the treatment of depression and anxiety in children suggest significant benefit for the selective serotonin re-uptake inhibitors [Birmaher et al., 2003; Emslie et al., 1997; RUPP, 2001; TADS, 2004]. The big difference between industry-sponsored and NIH-sponsored clinical trials is the large placebo response rate in industrysponsored trials, with resulting smaller sizes of effect than those observed in NIH-funded trials. The increased risk for suicidality previously observed was principally seen in depressed patients, and its use for other indications such as anxiety or for the treatment of children with autism may not share this increased risk. This may be an important consideration for child neurologists, because they are more likely to use selective serotonin re-uptake inhibitors for such purposes. The risk for suicide is higher overall among teenagers and less so in younger children.

Drug Interactions The product information for each of the selective serotonin re-uptake inhibitors provides detailed information regarding specific drug interactions. Because the number of individual interactions is too high to describe here, general principles are discussed. Adverse drug-drug interactions occur most commonly with highly protein-bound medications and with medications that significantly inhibit or induce cytochrome

Lee and Walkup / Neuropsychopharmacology

P-450 isoenzymes. Drug-drug interactions can result in loss (e.g., anticonvulsant combinations) or increase in benefit (e.g., cyclosporine and ketoconazole), increase in noticeable side effects (e.g., sedation), and an increase in side effects that can only be identified with careful monitoring (e.g., QTc prolongation). As a class, the selective serotonin reuptake inhibitors have more and more frequent drug-drug interactions because most of the selective serotonin reuptake inhibitors inhibit cytochrome P-450 isoenzymes. Most result in increased benefit of the co-administered agent or increase in noticeable side effects. The caution with using the selective serotonin re-uptake inhibitors is when they are combined with medications that have silent side effects such as QTc prolongation effects. Ironically, medications used in neuropsychiatry such as the antipsychotics (e.g., pimozide) and tricyclic antidepressants (e.g., desipramine) have a potential for producing cardiac conduction effects. Caution is warranted and monitoring is indicated when using selective serotonin re-uptake inhibitors in combination with medication that may affect the QTc interval.

Other Antidepressants Bupropion CLINICAL APPLICATIONS Bupropion (Wellbutrin, Zyban) is approved for the treatment of depression, nicotine dependence, and smoking cessation in adults [Wellbutrin, 2002]. Off-label uses of bupropion include monotherapy in the treatment of depression in children and adolescents, augmentation of selective serotonin reuptake inhibitor therapy in the treatment of depression [Lam et al., 2004], management of selective serotonin re-uptake

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inhibitor–induced sexual side effects [Masand et al., 2001], and as a second-line agent in the treatment of ADHD. Bupropion appears to improve symptoms of ADHD in prepubertal children [Casat et al., 1989; Simeon et al., 1986]. Effect sizes of bupropion and placebo differences were smaller than for standard stimulant medications [Casat et al., 1989]. However, bupropion appeared to have comparable efficacy compared with methylphenidate in a double-blind, crossoverdesign study [Barrickman, 1995]. Adolescents with depression [Glod et al., 2003] and those with co-occurring ADHD with depression [Daviss et al., 2001] demonstrated improvement with bupropion.

PHARMACOLOGY Bupropion is available in immediate-release tablets (Wellbutrin, Zyban) and extended-release tablets (Wellbutrin SR, Wellbutrin XL). The mechanism of action in ameliorating depression is unknown. In animals, bupropion selectively inhibits noradrenergic neurons in the locus ceruleus and inhibits the re-uptake of dopamine, but it does not have significant activity at α-adrenergic, cholinergic, or histaminic receptors. Bupropion is well absorbed through the gastrointestinal tract, with a peak serum concentration attained in 2 to 3 hours and with a half-life of 14 to 21 hours. Steady-state concentrations are achieved in 8 days. Steady-state plasma levels achieved with the extended-release form were about 85% of the immediate-release preparation. Bupropion is 80% bound to serum albumin. It is metabolized by the liver (primarily by CYP2B6) and excreted in urine and feces. Although bupropion has been found to induce its own metabolism in animals, this has not been specifically studied in humans (Table 39-5) [Wellbutrin, 2002].

TABLE 39-5 Other Antidepressants Used in Clinical Practice of Child Neuropsychopharmacology DRUG

PREPARATION

PHARMACODYNAMIC ACTIONS

PHARMACOKINETIC PROPERTIES

Bupropion

Wellbutrin (75- and 100-mg tablets) Wellbutrin XR (100-, 150-, and 200-mg tablets) Wellbutrin XL (150- and 300-mg tablets)

Unclear effects on NE systems

Time to peak = 2-3 hr Half-life = 14-21 hr

Venlafaxine

Effexor (25-, 37.5-, 50-, 75-, and 100-mg tablets) Effexor XR (37.5-, 75-, and 150-mg extended-release capsules)

Mirtazapine

Remeron (15- and 30-mg scored tablets; 45-mg tablet) Remeron SolTab (15-, 30-, and 45-mg orally disintegrating tablets)

DA, dopamine; 5HT, serotonin; NE, norepinephrine

DOSING

Immediate release: initiate at 50 mg/day; increase by 50 mg/day weekly Optimum dose: 100-250 mg/day or 3-6 mg/kg/day, given bid at least 8 hr apart Maximum dose of 400 mg/day and 200 mg/dose (extended release); 450 mg/day and 150 mg/dose (immediate release) At low doses, inhibits 5HT Time to peak = 5.5 hr 1-3 mg/kg/day given in re-uptake (immediate release), = 9 hr divided doses bid or tid At high doses, inhibits 5HT (extended release) and NE uptake Half-life = 3.5 hr (immediate release), = 9 hr (extended release) Time to peak = 2 hr Initiate at 7.5 mg/day at Antagonism of 5HT2 and 5HT3 receptors Half-life = 20-40 hr bedtime; increase by Antagonism of α2-adrenergic 7.5 mg/day every 1-2 wk receptors, ↑ synaptic NE Maximum dose = 45 mg/day and 5HT levels

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CLINICAL MANAGEMENT In addition to the standard assessment for ADHD or depression, possible risk factors for adverse effects should be identified. The risk of seizures increases with conditions that lower the seizure threshold, such as preexisting seizure disorder, anorexia and bulimia, head trauma, CNS tumor, concomitant use of medications that lower seizure threshold, excessive use of alcohol, abrupt withdrawal of alcohol or sedatives. Conditions that could raise bupropion levels, such as hepatic cirrhosis, increase the risk of seizures. No specific laboratory tests are recommended by the manufacturer before initiation. To minimize the risk of seizures, the manufacturer recommends that clinicians titrate bupropion slowly and divide the dose three times per day (immediate release), with each single dose no greater than 150 mg to avoid large peak serum concentrations. The dose should not exceed 450 mg/day for immediate-release preparations and 400 mg/day for extended-release preparations [Wellbutrin, 2002]. Bupropion has not been approved for use in children or adolescents. Bupropion may be initiated at 50 mg/day and increased by 50 mg/day at weekly intervals [Simeon et al., 1986]. Optimal doses in studies have ranged from 100 mg to 250 mg/day in prepubertal children [Clay et al., 1988; Simeon et al., 1986] or 3 to 6 mg/kg/day [Conners et al., 1996]. No incidence of seizure was reported in these studies. Short-term studies of 6 to 8 weeks have observed improvement of ADHD and depressive symptoms [Conners et al., 1996; Daviss et al., 2001; Glod et al., 2003]. If symptoms fail to respond to therapeutic doses of bupropion over this period, the medication should be tapered slowly to avoid adverse effects.

ADVERSE EFFECTS Common adverse effects include agitation, dry mouth, insomnia, headache, nausea, vomiting, constipation, and tremor [Wellbutrin, 2002]. Neuropsychiatric side effects have been observed in some patients, including psychotic symptoms and confusion. In general, antidepressants carry a risk of inducing manic symptoms in patients with bipolar affective disorder. The risk of inducing mania with bupropion is thought to be less than with tricyclic antidepressants and selective serotonin re-uptake inhibitors [Sadock and Sadock, 2003]. Bupropion has been reported to exacerbate tics in children with co-occurring ADHD and Tourette’s syndrome [Spencer et al., 1993]. Bupropion has been associated with seizures in approximately 0.4% of patients treated at doses up to 450 mg/day. The risk of seizures appears to be strongly associated with peak serum concentrations and dose. The incidence of seizures appears to increase significantly above daily doses of 450 mg and with rapid dose titration [Wellbutrin, 2002].

DRUG INTERACTIONS Because bupropion is metabolized by CYP2B6, plasma concentrations may increase if it is given concomitantly with inhibitors of this enzyme (e.g., orphenadrine, cyclophosphamide). Bupropion inhibits CYP2D6 and potentially

increases the plasma concentrations of other medications metabolized by this isoenzyme. The combination of bupropion with monoamine oxidase inhibitors may precipitate a hypertensive crisis. Both Wellbutrin and Zyban contain bupropion, and this combination is contraindicated because of an increased risk of seizure. Concurrent use of L-dopa and bupropion has been associated with an increased rate of adverse effects [Wellbutrin, 2002].

Venlafaxine CLINICAL APPLICATIONS Venlafaxine (Effexor) is approved for the treatment of major depressive disorder, generalized anxiety disorder, and social phobia in adults. Venlafaxine has also shown promise in the treatment of ADHD in adults [Findling et al., 1996] and cooccurring major depressive disorder and ADHD in adults [Hornig-Rohan and Amsterdam, 2002]. Studies of venlafaxine in children and adolescents are limited, and results have not been as promising as for adults. Children and adolescents treated with venlafaxine for major depressive disorder did not appear to benefit from medication compared with placebo [Mandoki et al., 1997]. In a group of children and adolescents with ADHD, venlafaxine was associated with improvements of behavioral (7 of 16 subjects) but not cognitive symptoms of ADHD; however, 3 of 16 patients had worsening of hyperactivity that precipitated drug discontinuation [Olvera et al., 1996].

PHARMACOLOGY Venlafaxine is available in immediate-release tablets (Effexor) and extended-release capsules (Effexor XR). At doses less than 150 mg/day, it selectively inhibits serotonin re-uptake. At higher dose, it inhibits serotonin and norepinephrine re-uptake. Venlafaxine does not have significant activity at muscarinic, histaminic, or α-adrenergic receptors. Venlafaxine is well absorbed through the gastrointestinal tract and is metabolized by the liver and excreted in the urine. The serum half-lives of venlafaxine and its active metabolite are about 5 and 11 hours, respectively (see Table 39-5) [Effexor, 2003].

ADVERSE EFFECTS Common side effects associated with venlafaxine include asthenia, sweating, nausea, constipation, anorexia, vomiting, somnolence, dry mouth, dizziness, nervousness, anxiety, tremor, blurred vision, and sexual dysfunction. Venlafaxine has been associated with a mean increase in diastolic blood pressure of 7.2 mm Hg, an effect that is dose dependent [Effexor, 2003].

DRUG INTERACTIONS Venlafaxine may increase plasma levels of haloperidol. Although venlafaxine is metabolized by CYP2D6, the serum concentration of venlafaxine and its active metabolite was not altered by imipramine, a CYP2D6 inhibitor, or in poor metabolizers [Effexor, 2003].

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Mirtazapine CLINICAL APPLICATIONS Mirtazapine (Remeron) is available in tablets and orally disintegrating tablets. It is approved for the treatment of major depressive disorder in adults. In short-term studies, it appears to be more effective than placebo and comparable to amitriptyline in improving depressive symptoms [Bremner, 1995; Claghorn and Lesem, 1995]. No placebocontrolled studies support the use of this medication in children.

PHARMACOLOGY Mirtazapine increases synaptic levels of norepinephrine and serotonin through antagonism of α2-adrenergic receptors in the CNS. It is an antagonist at 5HT2 and 5HT3 receptors, increasing relative 5HT1 activity. Mirtazapine has antagonist activity at H1 histaminic, α1-adrenergic, and muscarinic receptors. Mirtazapine is well absorbed from the gastrointestinal tract. It reaches peak concentration in 2 hours, and its elimination half-life is in the range of 20 to 40 hours. Mirtazapine is metabolized by the liver and excreted in the urine. The isoenzymes CYP2D6, CYP1A2, and CYP3A4 are involved in its metabolism (see Table 39-5) [Remeron, 2002].

CLINICAL MANAGEMENT In clinical practice, the sedating and appetite-stimulating effects of mirtazapine may be useful for patients who suffer from insomnia, agitation, decreased appetite, or anxiety as part of their depressive syndrome. Patients may be started at 7.5 mg (orally disintegrating tablets cannot be split) to 15 mg at bedtime. The dose may be increased up to a maximum of 45 mg daily at intervals of 1 to 2 weeks [Remeron, 2002]. More rapid dose escalation may actually be associated with fewer side effects, especially sedation and increased appetite.

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ANXIOLYTICS Anxiety disorders are one of the most prevalent categories of childhood and adolescent psychopathology. Approximately 8.9% of prepubertal children [Costello, 1989] in a general pediatric sample and approximately 8.7% of an adolescent sample [Kashani and Orvaschel, 1988] met criteria for at least one anxiety disorder. Anxiety disorders in children tend to have a chronic course with low remission rates [Keller et al., 1992]. Co-occurring conditions, such as other anxiety disorders [Kashani and Orvaschel, 1990; Strauss and Last, 1993], depression [Bernstein, 1991; Kashani and Orvaschel, 1988; Strauss et al., 1988], and ADHD [Anderson et al., 1987; Last et al., 1987] are common. Treatment of anxiety disorders in children and adolescents is multimodal, including psychoeducation, cognitivebehavioral therapy, family therapy, school interventions, and pharmacotherapy [AACAP, 1997a]. Psychopharmacologic intervention may be used if warranted by the severity of anxiety symptoms and level of impairment [AACAP, 1997a]. Choices include tricyclic antidepressants, selective serotonin re-uptake inhibitors, benzodiazepines, and α2-agonists and β-blockers. Tricyclic antidepressants may be a reasonable choice for patients with co-occurring depression, ADHD, or enuresis. Selective serotonin re-uptake inhibitors may be the preferred choice for patients with co-occurring depression or obsessive-compulsive disorder, and they have a more favorable side-effect profile than alternatives. The role of benzodiazepines is limited to the short-term management of anxiety symptoms. In cases of severe anxiety, they may be added to tricyclic antidepressants or selective serotonin re-uptake inhibitors for acute management of anxiety symptoms until the therapeutic effects of the antidepressants emerge. In clinical practice, the use of benzodiazepines is limited by concerns about possible abuse or dependence, drug diversion, and adverse cognitive effects.

Benzodiazepines ADVERSE EFFECTS

Clinical Applications

Common side effects of mirtazapine include sedation, dizziness, nausea, increased appetite, weight gain, and increased serum levels of cholesterol. Effects on sedation and appetite decrease at higher doses of mirtazapine. Less common side effects include liver enzyme elevations (i.e., aspartate transaminase) greater than three times the upper limit of the normal range and induction of mania or hypomania. Mirtazapine has been associated with rare cases of neutropenia or agranulocytosis in premarketing clinical trials [Remeron, 2002].

Benzodiazepines are classified as sedative-hypnotic medications. They act as sedatives or anxiolytics at low doses and sleep-inducing hypnotics at high doses. Although rapidly effective in relieving symptoms, they carry a risk of tolerance, dependence, and withdrawal with long-term use. These effects may be avoided by using only moderate doses for short-term therapy (1 to 2 weeks) [Sadock and Sadock, 2003]. Benzodiazepines differ from each other with regard to relative potency and half-life. In contrast to long-half-life benzodiazepines, short-half-life benzodiazepines are associated with less daytime sedation, more frequent dosing, earlier and more severe withdrawal syndromes, rebound insomnia, and anterograde amnesia. Long-half-life benzodiazepines require less frequent dosing and have a less severe withdrawal syndrome, but high plasma concentrations of the drug may accumulate and cause signs of toxicity over time [Sadock and Sadock, 2003]. Case reports and small open trials indicate that clonazepam and alprazolam may be helpful in treating anxiety

DRUG INTERACTIONS Mirtazapine may have additive effects if combined with alcohol or other CNS depressants. Mirtazapine is not a potent inhibitor of CYP2D6, CYP1A2, or CYP3A4. Combination of mirtazapine and monoamine oxidase inhibitors may induce a hypertensive crisis [Remeron, 2002].

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disorders in children and adolescents [Biederman, 1987; Kutcher and MacKenzie, 1988; Simeon and Ferguson, 1987]. However, placebo-controlled studies have not supported their use [Graae et al., 1994; Simeon et al., 1992]. With the availability of more effective anxiolytics (e.g., selective serotonin re-uptake inhibitors, tricyclic antidepressants, buspirone), benzodiazepines are not considered first-line treatment for anxiety disorders in children and adolescents. However, benzodiazepines can be useful for the short-term management of specific anxiety-provoking situations, such as medical procedures, or as short-term adjunctive treatment with selective serotonin re-uptake inhibitors in the initial treatment of severe anxiety disorders. Chronic administration of benzodiazepines for anxiety should be undertaken only after patients have failed more effective treatments for anxiety, including other medications and behaviorally oriented psychotherapy.

Pharmacology Benzodiazepines are well absorbed from the gastrointestinal tract. They are extensively metabolized in the liver and excreted in urine. Benzodiazepine plasma concentrations are sensitive to medications that inhibit or induce cytochrome P-450 isoenzymes (see “Drug Interactions”). Benzodiazepines activate γ-aminobutyric acid (GABA)–benzodiazepine binding sites, which open chloride channels, resulting in a reduced rate of neuronal firing and muscle activity (Table 39-6) [Klonipin, 2004].

Clinical Management In considering benzodiazepine therapy for a patient, the clinician should inquire about any possible history of substance abuse, because this is a relative contraindication [DuPont and Saylor, 1992]. Family history of substance abuse may identify patients who are at risk for drug abuse or dependence, and household members with substance use histories may indicate a risk for drug diversion. Concomitant use of medications and co-occurring medical conditions that may affect the metabolism of benzodiazepines should be identified. The patient and family should be informed about the risks of tolerance, dependence, and withdrawal effects, as well as possible effects on cognitive and motor functioning. During treatment, the clinician must ensure that medications are not overused, abused, or diverted and monitor for possible adverse cognitive or behavioral side effects. After the treatment trial is complete, the medication should be tapered slowly because of the potential for withdrawal and rebound anxiety [Coffey, 1993; Kutcher et al., 1992].

Adverse Effects The most frequent adverse effects in children and adolescents are sedation, drowsiness, and decreased mental acuity [Biederman, 1991]. Benzodiazepines may cause paradoxic behavioral disinhibition, which manifests as increased agitation, aggression, and hyperactivity. This has been described with clonazepam in children [Graae et al., 1994]

TABLE 39-6 Benzodiazepines: Pharmacokinetic Properties, Dosing, and Drug Interactions DRUG

PREPARATIONS

DOSE EQUIV.

HALF-LIFE

DOSING

DRUG INTERACTIONS

Alprazolam

Xanax (0.25-, 0.5-, 1.0-, and 2.0-mg tablets) Xanax XR (0.5-, 1.0-, 2.0-, and 3.0-mg tablets)

0.25

6-20 hr

Initial dose (immediate release) of 0.25 mg/day if < 40 kg, or 0.5 mg/day if > 40 kg Maximum daily dose of 0.04 mg /kg/day in divided doses bid to qid [Simeon et al., 1992]

Clonazepam

Klonopin (0.5-, 1.0-, and 2.0-mg tablets)

0.5

>20 hr

Initial dose of 0.25 mg/day; increase by 0.25 mg every 3-4 days Maximum dose of 2 mg/day [Graae et al., 1994]

Diazepam

Valium (2-, 5-, and 10-mg tablets) Diazepam injection (5 mg/mL)

5

>20 hr

Initial oral dose of 1 to 2.5 mg tid or qid; increase gradually as needed and tolerated [PDR, 2004]

Lorazepam

Ativan (0.5-, 1.0-, and 2.0-mg tablets) Ativan injectable (2 mg/mL, 4 mg/mL)

1

6-20 hr

Usual daily dose of 1 to 6 mg/day [Green, 1995]

CNS depressants (additive effects) Inhibitors of cytochrome P-450 3A4 (↑ plasma concentration) Fluoxetine (↑ plasma concentration) Propoxyphene (↑ plasma conc) Oral contraceptives (↓ clearance) CNS depressants (additive effects) Inhibitors of cytochrome P-450 3A4 (↑ plasma concentration) Inducers of cytochrome P-450 (↓ plasma concentration) CNS depressants (additive effects) Inhibitors of cytochrome P-450 3A4 (↑ plasma concentration) CNS depressants (additive effects) Inhibitors of cytochrome P-450 3A4 (↑ plasma concentration)

Lee and Walkup / Neuropsychopharmacology

and adolescents [Reiter and Kutcher, 1991]. Anterograde amnesia also has been associated with benzodiazepines, particularly high-potency benzodiazepines [Sadock and Sadock, 2003]. Benzodiazepine therapy carries a risk of tolerance, dependence, and withdrawal effects. Abrupt discontinuation or rapid dose reduction has been associated with seizures, delirium, and withdrawal symptoms [Xanax, 2004].

Drug Interactions Additive CNS depression may occur when benzodiazepines are administered concomitantly with other CNS depressants, such as alcohol. Disulfiram may decrease the clearance of diazepam and chlordiazepoxide. Because benzodiazepines are metabolized by cytochrome P-450 isoenzymes, inhibitors and inducers of these isoenzymes can significantly alter the plasma concentration of benzodiazepines. Clonazepam and phenytoin decrease each other’s plasma concentrations. Valproate may increase plasma concentrations of lorazepam [Sadock and Sadock, 2003].

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antagonist at 5HT1A receptors, as an agonist at postsynaptic dopamine receptors, and as an antagonist at presynaptic autoreceptor and postsynaptic sites in the CNS. Buspirone is rapidly absorbed from the gastrointestinal tract. Only 4% of the dose reaches systemic circulation because of extensive first-pass metabolism. The onset of clinical response may appear within the first 2 weeks of therapy, but optimal therapeutic effect is usually delayed [Kutcher et al., 1992]. The elimination half-life is about 2 to 4 hours; it is prolonged by renal or hepatic impairment. Buspirone is metabolized in the liver, primarily by the CYP3A4 isoenzyme, and it is excreted in the urine and feces [BuSpar, 2002].

Clinical Management Laboratory screening is not required before prescribing buspirone. The typical starting dose is 5 mg taken three times daily, with gradual increases to 15 mg taken three times daily. Younger children may be started at 2.5 to 5 mg/day and gradually increased to a total dose of 20 to 30 mg/day, administered in divided doses three times daily [Scahill and Martin, 2002].

Buspirone

Adverse Effects

Clinical Applications

The most common adverse effects of buspirone are dizziness, headache, drowsiness, and lightheadedness [BuSpar, 2002]. Side effects appear to be dose related and to decrease over time [Feighner and Cohn, 1989]. CNS depression is less common than in benzodiazepines.

Buspirone (BuSpar) is approved for use in the treatment of anxiety disorders and for short-term relief of symptoms of anxiety [BuSpar, 2002]. It is typically used in the treatment of generalized anxiety disorder. Buspirone does not appear to be effective as monotherapy in other anxiety disorders, such as post-traumatic stress disorder, panic disorder [Sheehan et al., 1988], or social phobia [van Vliet et al., 1997]. Although randomized, controlled trials do not support the use of buspirone to augment selective serotonin re-uptake inhibitors in partial responders, some patients with depression [Dimitriou and Dimitriou, 1998] and obsessivecompulsive disorder [Jenike et al., 1991] may benefit. Adolescents with generalized anxiety disorder appeared to benefit from buspirone in an open trial [Kutcher et al., 1992]. Another open trial showed improvement in anxiety symptoms in a group of children and adolescents with varied anxiety disorders [Simeon, 1991]. Buspirone appeared to improve anxiety and irritability in children with pervasive developmental disorders [Buitelaar et al., 1998]. A very large industry-sponsored, randomized, controlled trial did not demonstrate benefit (http://www.fda.gov). Buspirone offers several benefits over benzodiazepines, including lack of euphoric effects, performance impairment, abuse potential, and withdrawal symptoms with discontinuation. Although buspirone appears to be as effective as benzodiazepines in decreasing psychic symptoms of anxiety, it appears to be less effective for somatic symptoms of anxiety, and the onset of therapeutic effect may be delayed 2 to 4 weeks [Kutcher et al., 1992].

Pharmacology Buspirone differs from benzodiazepines in that it has no activity at the GABA-benzodiazepine receptor complex. Buspirone acts as a partial agonist or mixed agonist/

Drug Interactions Combination of buspirone and monoamine oxidase inhibitors may result in a hypertensive crisis, requiring emergency medical attention. Because of reports of liver transaminase elevations with the concomitant use of buspirone and trazodone, the manufacturer recommends monitoring liver function when prescribing this combination. Because buspirone is highly protein bound, it may displace other medications, which are protein bound and increase their free plasma level. Inducers of CYP3A4 may decrease plasma levels of buspirone. Alternatively, inhibitors of CYP3A4 (e.g., erythromycin, itraconazole, grapefruit juice) may increase the serum concentration of buspirone. Increased serum concentrations of haloperidol have been reported when combined with buspirone [BuSpar, 2002].

MOOD STABILIZERS The term mood stabilizers refers to a group of medications used to treat bipolar affective disorder, which in adults is characterized by alternating episodes of depression, mania, and euthymia [APA, 2002]. The diagnosis of bipolar disorder in children has been controversial because it does not resemble bipolar disorder in adults, and its symptoms often overlap with other syndromes. Studies have indicated that juvenile bipolar disorder has been under-recognized, misdiagnosed as schizophrenia or disruptive behavior disorders [Carlson et al., 1994], and sometimes overdiagnosed [Carlson, 1990]. Bipolar children are not likely to exhibit classic symptoms of adult

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bipolar disorder; rather, they are more likely to exhibit atypical manic or mixed-mood symptoms [Bowring and Kovacs, 1992]. Adding to the complexity of making the diagnosis is the broad differential diagnosis and co-occurrence of other neuropsychiatric disorders [AACAP, 2002]. Mood stabilizers are used to treat the acute episodes of mood disturbances and are used prophylactically during the maintenance phase of the disorder [APA, 2002]. Mood stabilizers used in clinical practice can be grouped into four categories: 1. Lithium 2. Anticonvulsants approved for use in adults with bipolar disorder (e.g., valproic acid, lamotrigine) 3. Neuroleptics approved for use in adults with bipolar disorder (e.g., risperidone, olanzapine, quetiapine) 4. Anticonvulsants prescribed off-label (e.g., gabapentin, carbamazepine) Case series and open trials using the newer anticonvulsants show promise, but large, placebo-controlled trials are lacking. Each mood stabilizer is not equally effective for all phases of the disorder or as prophylaxis. Lithium, valproate, risperidone, olanzapine, ziprasidone, and quetiapine are approved for treating manic symptoms. Lamotrigine is the only mood stabilizer labeled for use during the depressive phase [Calabrese et al., 1999; Evins, 2003]. Lamotrigine, lithium, and olanzapine are approved for use during the maintenance phase of treatment to delay the occurrence of acute mood episodes [Lamictal, 2003; Zyprexa, 2004]. Polypharmacy in the treatment of bipolar affective disorder in adults is common. Typical treatment consists of long-term maintenance with a mood stabilizer as prophylaxis. A neuroleptic or an additional mood stabilizer may be added to stabilize the acute symptoms of a manic episode. During a depressive episode, an antidepressant or lamotrigine may be added while cautiously monitoring for the possible emergence of antidepressant-induced manic or rapid-cycling symptoms. The pediatric literature is less well developed than that for adults, and all pharmacologic treatments used in clinical practice for the treatment of childhood bipolar disorder are off-label. As with childhood depression, children with bipolar affective disorder are thought to be less responsive to medication compared with adults [AACAP, 2002]. Combination of mood stabilizers [Findling et al., 2003] or a mood stabilizer with a neuroleptic [Kafantaris, 1995] is sometimes required to stabilize acute manic symptoms. Given the complexity of making an accurate diagnosis, the treatment-resistant nature of pediatric bipolar illness, and the complicated regimens of off-label medication sometimes required, the average pediatric neurologist may wish to request a consultation from a child psychiatrist if faced with a patient with possible bipolar disorder.

Lithium Clinical Applications Lithium is approved for use in the treatment of bipolar affective disorder. It is effective in managing acute manic

and depressive episodes, preventing or diminishing the intensity of subsequent episodes in maintenance treatment and decreasing mood instability between episodes [Goodwin and Jamison, 1990]. Data in children and adolescents with bipolar disorder are sparse and mixed. Several studies have shown good response rates. However, one study [Carlson et al., 1992] did not demonstrate superiority over placebo [DeLong and Aldershof, 1987; Geller and Fetner, 1989; Strober et al., 1990; Varanka et al., 1988]. Lithium also has been used with positive results in the treatment of severe aggression in adults [Sheard, 1975] and children [Campbell et al., 1984; Malone et al., 2000].

Pharmacology Lithium is an alkali metal, similar to sodium and potassium, and it is available in salt form as lithium carbonate or lithium citrate. Lithium has effects at the cellular level (i.e., cell membrane ion channels and cyclic adenosine monophosphate second-messenger cellular processes) and in neurotransmitter systems [Alessi and Bos, 1991]. The specific mechanism of action in the CNS is unclear [Viesselman et al., 1993]. Lithium is available in immediate-release and sustainedrelease preparations. Ninety percent of immediate-release lithium is absorbed by the gastrointestinal tract; 60% to 90% of extended-release lithium is absorbed. Immediate-release lithium reaches peak serum levels in 1 to 1.5 hours (4 to 12 hours for the extended-release form), and it is almost completely excreted in urine, with the remainder excreted in the feces and breast milk. Lithium has a half-life of about 20 hours and reaches steady-state levels after 1 week of administration [Eskalith-CR, 2002].

Clinical Management Before starting lithium therapy, the patient should be screened for conditions that may contraindicate or complicate lithium therapy, such as pregnancy, renal disease, or diabetes mellitus. A medical evaluation should be completed, including an ECG, laboratory screen for electrolytes, kidney and thyroid function tests, complete blood cell count, urinalysis, and urine pregnancy screen. Lithium is started at dosages ranging from 300 to 600 mg/day. Formulas [Weller et al., 1986] and nomograms [Alessi and Bos, 1991; Geller and Fetner, 1989] have been developed to guide lithium dosing. Trough lithium levels are drawn when steady state is achieved, at least 5 days after initiating lithium or changing the dose. The recommended therapeutic serum levels range from 0.6 to 1.2 mEq/L [Viesselman et al., 1993]. Patients maintained at serum levels between 0.8 and 1.0 mEq/L were less likely to relapse compared with patients with lower serum levels. Lithium levels above the therapeutic range increase the risk of toxicity. Early therapeutic effects may be detected at 10 to 14 days after achieving a therapeutic level; however, there is often a significant lag of 4 to 6 weeks [Kowatch et al., 2000]. Between 4 and 6 weeks of lithium at therapeutic serum concentrations constitutes an adequate trial. Because several days are required to achieve therapeutic plasma concentrations, neuroleptic medications may be necessary

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to acutely stabilize severe mania, especially if psychotic symptoms are present. After target mood symptoms are stabilized, lithium levels should be routinely checked every 3 to 6 months. Other

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indications to obtain a lithium level include symptoms of toxicity, worsening side effects, and breakthrough mood symptoms. Urinalysis, renal evaluation, and thyroid function tests should be repeated every 3 to 6 months to

TABLE 39-7 Mood Stabilizers: Baseline Assessment, Monitoring, and Adverse Effects DRUG

PREPARATIONS

BASELINE ASSESSMENTS

MONITORING

ADVERSE EFFECTS

Lithium, immediate release

Lithium carbonate (150-, 300-, and 600-mg tablets) Lithium citrate syrup (8 mEq/mL)

Laboratory screening: thyroid function tests, electrolytes, renal function tests, complete blood cell count, urinalysis, pregnancy test Electrocardiogram

Sedation, tremor, acne, weight gain, polydipsia, polyuria, renal effects, electrocardiographic changes, leukocytosis, hypothyroidism

Lithium, sustained release Valproic acid

Litho bid (300-mg tablets) Eskalith CR (450-mg tablets) Depakote, divalproex (125-, 250-, and 500-mg delayed-release tablets) Depakene syrup (250 mg of valproic acid/5 mL) Depakote Sprinkle, divalproex (125-mg capsules with coated particles) Depakote ER, divalproex extended release (250and 500-mg tablets) Tegretol (200-mg scored tablets) Tegretol XR (100-, 200-, and 400-mg extendedrelease tablets) Carbatrol (200- and 300-mg extended-release capsules) Tegretol (100 mg/5 mL suspension) Tegretol (100-mg chewable tablets) Lamictal (25-, 100-, 150-, and 200-mg tablets) Lamictal (2-, 5-, and 25-mg chewable/dispersible tablets)

Same as for immediate-release form Laboratory screening: liver function tests, pancreatic enzymes, complete blood cell count, pregnancy test

Lithium level (target of 0.8-1.0 ng/mL) during dose titration, every 3-6 months or with signs of toxicity or breakthrough symptoms Urinalysis, thyroid-stimulating hormone test, and renal function tests every 3-6 months or with signs and symptoms of toxicity Same as for immediate-release form Valproic acid level (target of 80-100 ng/mL) during dose titration, every 3-6 months, or with signs of toxicity or breakthrough symptoms Liver function tests, complete blood cell count, and pancreatic enzymes every 3-6 months or with signs and symptoms of toxicity

Topiramate

Gabapentin

Carbamazepine

Lamotrigine

Same as for immediaterelease form Sedation, weight gain, elevated liver function test results, nausea, liver failure, pancreatitis, polycystic ovary syndrome

Laboratory screening: liver function tests, complete blood cell count, electrolytes, pregnancy test

Carbamazepine level (target of Nausea, vomiting, anorexia, 4-12 μg/mL) during dose ataxia, sedation, tremor, titration, every 3-6 months, aplastic anemia, or with signs of toxicity or agranulocytosis, elevated breakthrough symptoms liver function test results, Liver function tests, complete acute hepatitis, blood cell count, and cholestasis, lifeelectrolytes every 3-6 months threatening skin or with signs and symptoms conditions of toxicity

None

Laboratory screening: None Monitor for rash

Topamax (15- and 25-mg capsules) Topamax (25-, 50-, 100-, and 200-mg film-coated tablets)

Baseline electrolytes

Laboratory screening: none Electrolytes for metabolic acidosis Routine clinical monitoring

Neurontin (100-, 300-, and 400-mg capsules) Neurontin (250 mg/5 mL solution) Neurontin (600- and 800-mg film-coated tablets)

None

Laboratory screening: none Routine clinical monitoring

Dizziness, ataxia, somnolence, headache, diplopia, blurred vision, nausea, vomiting, rash Serious rashes requiring hospitalization and discontinuation of treatment, StevensJohnson syndrome (1% of pediatric population); rare cases of toxic epidermal necrolysis and rash-related death have been reported Fatigue, ataxia, confusion, impaired concentration and memory, sedation, agitation, anorexia with weight loss, kidney stones and diplopia, metabolic acidosis Dizziness, ataxia, sedation, fatigue, nystagmus, dyspepsia, peripheral edema, diplopia and amblyopia.

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monitor for the emergence of subclinical renal and thyroid dysfunction (Table 39-7). Stabilization of manic symptoms may be prolonged up to several years [Biederman et al., 1998]. Lithium should be continued for at least 18 months after manic symptoms have been stabilized [APA, 2002], because discontinuation of lithium therapy, especially abrupt discontinuation, is associated with increased relapse rates [Strober et al., 1990].

Adverse Effects Side effects of lithium are polydipsia, polyuria or enuresis, gastric distress (i.e., nausea, vomiting, and diarrhea), weight gain, tremor, fatigue, leukocytosis, acne, and mild cognitive impairment [Alessis et al., 1999; Silva et al., 1992; Viesselman et al., 1993]. Serious renal side effects are rare and include nephrotic syndrome, features of distal renal tubular acidosis, nonspecific interstitial fibrosis, and renal failure [Alessis et al., 1999; Gelenberg and Schoonover, 1991]. Lithium therapy can induce alterations in thyroid function tests and produce hypothyroidism [Alessis et al., 1999]. Lithium can have rare cardiac side effects, including first-degree atrioventricular block, irregular sinus rhythm, and increased premature ventricular contractions [Gelenberg and Schoonover, 1991]. Reversible conduction abnormalities in children have been demonstrated on their ECGs [Campbell et al., 1972]. Studies examining the longterm effects of lithium treatment of children are lacking. Intrauterine exposure to lithium during the first trimester has been associated with teratogenic effects, most commonly Ebstein’s anomaly of the tricuspid valve [Eskalith-CR, 2002].

Drug Interactions Lithium levels are affected by medications or conditions that can alter the body’s fluid and electrolyte status. Dehydration and extremely low salt intake can result in elevated lithium levels. Likewise, an extremely high salt intake can result in lowered lithium levels. Many medications, such as diuretics and nonsteroidal anti-inflammatory drugs, can cause an increase or decrease in lithium level by influencing renal clearance [Green, 1995]. Lithium is commonly used in combination with other psychotropic medications in the treatment of bipolar disorder. However, case reports have described interactions with neuroleptic medications (i.e., encephalopathic syndrome and neuroleptic malignant syndrome), and carbamazepine may increase lithium serum concentration by decreasing lithium renal clearance [Green, 1995].

studies of valproic acid in children and adolescents with bipolar mania have yielded mixed results. In one study, 61% of patients with mania, hypomania, or mixed symptoms were rated responders to valproic acid; however, there was a high dropout rate (23 of 40) [Wagner et al., 2002]. In a retrospective chart review of pediatric bipolar patients, 53% appeared to respond to divalproex; approximately one third of the patients discontinued the medication, mostly because of side effects [Henry et al., 2003]. In a small, double-blind, placebocontrolled, crossover-design study, children and adolescents with explosive temper and mood lability had superior response to divalproex sodium compared with placebo [Donovan et al., 2000]. In a retrospective examination of divalproex sodium treatment of autistic children, 71% were rated improved in the core symptoms of autism and associated symptoms of affective instability, aggression, and impulsivity [Hollander et al., 2001].

Pharmacology The mechanism of action of valproic acid is unidentified, although it is known to increase brain concentrations of the inhibitory neurotransmitter GABA [Viesselman et al., 1993]. Valproic acid is available in several preparations: valproic acid (Depakene capsules); valproate (Depakene syrup); divalproex (Depakote); divalproex capsules with coated particles (Depakote Sprinkle); divalproex, delayedrelease tablets (Depakote), which are released from particles in the small intestine; and divalproic acid in extendedrelease tablets (Depakote ER). Valproate rapidly converts to the acid form in the stomach. Divalproex dissociates into valproic acid in the gastrointestinal tract. Valproic acid is rapidly and almost entirely absorbed from the gastrointestinal tract. Peak plasma concentrations are achieved 1 to 4 hours, 3 to 5 hours, and 7 to 14 hours after oral administration of valproate, divalproex, and extended-release tablets, respectively. Valproic acid binds plasma proteins; therefore, protein binding can be altered by the presence of other protein-bound drugs and by renal or hepatic disease. Plasma protein binding of valproic acid is concentration dependent. Peak and trough concentrations with delayed-release tablets and capsules containing coated particles may differ from the equivalent dose valproic acid. Concentrations of therapeutically effective free valproic acid increase at serum concentrations (total) above 50 to 100 μg/mL. Valproic acid is metabolized in the liver and excreted predominantly in the urine [Depakote, 2003]. No therapeutic serum concentrations for the treatment of behavioral or psychiatric disorders have been determined.

Clinical Management

Valproic Acid Clinical Applications Valproic acid is approved for the treatment of seizures, migraine prophylaxis, and the manic phase of bipolar affective disorder in adults. In adults, valproic acid appears to be more helpful than lithium in treating rapid cycling and dysphoric or mixed mania [McElroy et al., 1992]. Support for use of valproic acid in child psychiatric practice is primarily based on the adult literature. The few

In addition to the routine psychiatric or neurologic history, patients should be asked about risk factors affecting treatment with valproate, including pregnancy, disorders of metabolism, hepatic or renal disease, concomitant medications, and coagulation disorders. Laboratory screening should include liver function tests, a complete blood cell count, coagulation studies, and determinations of pancreatic enzyme levels [Davanzo and McCracken, 2000]. Parents should be educated about potential signs of hepatic or pancreatic toxicity and polycystic ovary disease.

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Recommended initial dosing of valproic acid is 10 to 15 mg/kg/day, given in divided doses two or three times per day. Dosage may be increased by 5 to 10 mg/kg/day at weekly intervals [Depakote, 2003]. The manufacturer’s maximum recommended dosage is 60 mg/kg/day. However, starting at lower doses and using slower upward adjustments of dose may be required for tolerability. Although therapeutic levels for treating mania have not been established, achieving a plasma concentration of 85 to 110 μg/L [Kowatch et al., 2000] is needed to consider a trial adequate for determining outcome in an individual patient. In adult psychiatry, an oral loading dose of valproate is sometimes used to achieve a therapeutic plasma concentration and to gain rapid control over mania. The tolerability of an oral loading dose of divalproex sodium was examined in children and adolescents [Good et al., 2001]. A loading dose of 15 mg/kg/day resulted in therapeutic plasma levels by day 5 of treatment, and it was well tolerated. Dosage adjustment was required for overweight children to avoid supratherapeutic drug levels [Good et al., 2001]. Total valproic acid levels should be checked when steady state is reached, after any dosage change, after conversion to a different preparation of valproate, for signs of toxicity, or for a change in clinical status. Maintenance involves monitoring of the therapeutic response and side effects, and it requires laboratory screening. Liver and pancreatic enzymes, complete blood cell count, and serum valproic acid levels should be periodically monitored, although the exact frequency of testing has not been ascertained. Initially, monitoring may be done every 3 to 6 months for the first year and semiannually thereafter (see Table 39-7).

unclear. Other reports suggest that oral carnitine can be useful in reducing ammonia levels [Bohan et al., 2001]. Rare cases of pancreatitis have been reported [Depakote, 2003]. Cases of polycystic ovary disease have been reported in some women treated with valproate for seizure disorder [Isojarvi et al., 1993]. It is unclear whether this is related to the medication or an endocrine abnormality related to the seizure disorder [Davis et al., 2000]. Intrauterine exposure to valproic acid during the first trimester is associated with neural tube defects [Depakote, 2003].

Adverse Effects

Clinical Applications

Side effects include sedation, nausea, vomiting, gastrointestinal upset, increased appetite, weight gain, and hair loss. Rare side effects include thrombocytopenia, platelet dysfunction, prolonged bleeding time, elevation in liver transaminase levels, and lactate dehydrogenase without clinical symptoms. Children younger than 2 years appear to have an increased risk of hepatotoxicity and extreme caution should be used in this population. This heightened risk may result from an undiagnosed metabolic or mitochondrial disorder. In particular, children with urea cycle defects such as ornithine transcarbamylase deficiency should not receive this medication. Carnitine supplementation should be considered when prescribing this medication as this may facilitate the processing of valproate in the mitochondrial βoxidation pathway. Valproate has also been associated with rare cases of hyperammonemic encephalopathy [Barrueto, 2001; Elgudin et al., 2003; Verrotti et al., 1999, 2002], which occurs more commonly with polypharmacy and with associated liver dysfunction [Verrotti et al., 1999]. One case reported in the child psychiatry literature manifested as increased aggression and confusion, an electroencephalogram with symmetric 5- to 6-Hz waves, elevated serum ammonia levels, and normal levels of serum liver transaminases [Yehya et al., 2004]; the situation resolved with valproic acid discontinuation. Elevated ammonia levels have also been observed in the absence of encephalopathy, but the clinical relevance of such laboratory abnormalities is

Few data are available on the use of carbamazepine for the treatment of bipolar disorder in children and adolescents. Case reports describe its effectiveness in stabilizing symptoms of juvenile bipolar disorder [Hsu, 1986; Woolston, 1999]. Justification for its use in clinical practice has rested on the adult literature, which is difficult to interpret. Studies have shown carbamazepine to be superior to placebo and comparable to lithium [Lerer et al., 1987; Small et al., 1991] in improving manic symptoms. However, another study indicated that it was not as effective as valproate, and patients on carbamazepine required adjunctive medication to achieve stabilization [Vasudev et al., 2000]. Carbamazepine may be helpful in the depressive phase of bipolar disorder [Ballenger and Post, 1980; Dilsaver et al., 1996]. Carbamazepine can have multiple drug interactions resulting from hepatic enzyme induction that complicates the management of bipolar disorder, because polypharmacy is often required. Clinicians and patients may prefer carbamazepine to the other mood stabilizers because of its reduced tendency to cause weight gain.

Drug Interactions Valproic acid, alone or in combination with lamotrigine, may cause potentially fatal Stevens-Johnson syndrome. When valproic acid is combined with neuroleptics, CNS depressant effects and extrapyramidal side effects may increase. Valproic acid may increase lithium-associated tremor. Carbamazepine can induce metabolism of valproic acid and decrease plasma levels. Aspirin has been shown to decrease the metabolism of valproic acid and decrease valproic acid protein binding. Valproic acid may displace warfarin from protein binding sites and prolong coagulation time. Increases in valproic acid levels have been reported when combined with guanfacine, amitriptyline, and fluoxetine. Valproic acid can cause increases in plasma concentrations of carbamazepine, lamotrigine, diazepam, amitriptyline, nortriptyline, and phenobarbital. Valproic acid can decrease plasma concentrations of phenytoin and desipramine [Depakote, 2003].

Carbamazepine

Pharmacology Carbamazepine is structurally related to tricyclic antidepressants. It reduces activity at sodium and calcium channels resulting in reduced synaptic transmission. It is

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available in immediate-release forms (e.g., Tegretol tablets, chewable tablets, suspension) and extended-release capsules (i.e., Tegretol XR). It is slowly absorbed from the gastrointestinal tract. The plasma half-life gradually decreases over 3 to 5 weeks from 25 to 65 hours to approximately 12 to 17 hours due to autoinduction. Steady-state concentrations are achieved in 2 to 4 days. Between 75% and 90% of the drug is bound to plasma proteins. It is metabolized in the liver and excreted in the urine [Tegretol, 2002].

Clinical Management Patients should be evaluated for medical conditions that may contraindicate use of carbamazepine, including liver disease, hematologic disorders, immune disorders, cardiac disease, and pregnancy. Laboratory screening should include a urine pregnancy screen, liver function tests, and a complete blood cell count. Because laboratory screening can fail to predict impending hepatic and hematologic complications, parents should be aware of signs and symptoms indicating serious adverse effects, such as rash, symptoms of aplastic anemia or agranulocytosis, and hepatitis or cholestasis. Sexually active patients should be informed of its teratogenic effects and the possible decrease in effectiveness of oral contraceptives [Tegretol, 2002]. Dosage is initiated at 100 to 300 mg/day, increasing as tolerated while monitoring blood levels. Therapeutic blood levels in the treatment of mania have not been established. Recommended levels are the same as those for seizure disorder, 4 to12 μg/mL [Rosenberg et al., 1994]. Blood levels should be checked 5 days after initiating or changing doses and again in 4 weeks because of an anticipated reduction in plasma levels due to autoinduction. Although it is recommended that liver function tests, bilirubin levels, and complete blood cell counts be routinely checked every 3 months, the utility of such testing in predicting serious hepatic or hematologic complications is questionable (see Table 39-7). Hyponatremia resulting from carbamazepine use is rare in children, and if it is clinically suspected, sodium levels should be obtained.

Adverse Effects The most common side effects are nausea, vomiting, sedation, and ataxia [Tegretol, 2002]. Carbamazepine can cause benign elevations in liver transaminases; hepatitis, indicated by elevated liver transaminase levels greater than three times normal; and cholestasis, indicated by elevations in bilirubin and alkaline phosphatase. Carbamazepine therapy has been associated with leukopenia in 1% to 2% of patients and agranulocytosis or aplastic anemia in 1 of 250,000 patients. Although blood dyscrasias are not always predicted by leukopenia, complete blood cell counts are recommended at 3- to 6-month intervals. Other adverse effects observed with carbamazepine include cognitive or behavioral disturbance [Carpenter and Vining, 1993], CNS toxicity, altered cardiac conduction, and lifethreatening dermatologic conditions (i.e., exfoliative dermatitis, toxic epidermal necrolysis, and Stevens-Johnson syndrome). Intrauterine exposure has been associated with neural tube defects and other fetal malformations [Rosa, 1991].

Drug Interactions Carbamazepine is an inducer of CYP3A4, leading to decreased plasma concentrations of medications metabolized by that isoenzyme. Several medications that are commonly combined with carbamazepine in psychiatric practice may be affected, including anticonvulsants (e.g., lamotrigine, clonazepam, valproic acid), antidepressants (e.g., bupropion, clomipramine, desipramine, imipramine), and neuroleptics (e.g., clozapine, fluphenazine, haloperidol). Carbamazepine levels can be increased by fluoxetine, lamotrigine, and valproate. Carbamazepine levels can be reduced by valproate and carbamazepine itself (i.e., autoinduction). Combination with lithium or neuroleptics may increase the risk of adverse neurologic effects (e.g., drowsiness, dizziness, ataxia) [Tegretol, 2002].

Novel Anticonvulsants Although lithium and valproate are first-line pharmacologic treatments for bipolar disorder in adults [APA, 2002], many children and adolescents do not respond adequately to these medications and cannot tolerate the side effects or the requirement of laboratory monitoring. In clinical practice, newer anticonvulsants are beginning to be used for the treatment of bipolar disorder. Many of the novel anticonvulsants have a more favorable side-effect profile and do not require blood tests. Support for their use in clinical practice, however, has been primarily based on case reports and open trials. Use of these medications is more appropriate for patients with bipolar disorder who are unresponsive to traditional therapies or cannot tolerate traditional agents.

Lamotrigine CLINICAL APPLICATIONS Lamotrigine (Lamictal) is approved for use in the treatment of seizure disorders and for prophylaxis of mania during maintenance therapy for type 1 bipolar disorder [Lamictal, 2003]. In adults, lamotrigine appears to be helpful in the treatment of patients with bipolar depression [Calabrese et al., 1999; Evins, 2003], some patients with rapid-cycling bipolar disorder [Bowden et al., 1999; Frye et al., 2000], and as a prophylactic agent to prevent or attenuate recurrences of bipolar episodes [Bowden et al., 2003; Calabrese et al., 2000, 2003; McElroy et al., 2004]. It was reported to be an effective add-on agent to valproate in adolescents with bipolar depression [Kusumakar and Yatham, 1997].

PHARMACOLOGY Lamotrigine has weak inhibitor effects on the 5HT3 receptor. Its mechanism of action is unknown. Lamotrigine is available in tablets and chewable dispersible tablets, which should not be divided. Lamotrigine is rapidly absorbed through the gastrointestinal tract, metabolized in the liver, and excreted in urine [Lamictal, 2003].

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CLINICAL MANAGEMENT

DRUG INTERACTIONS

Because supporting data are lacking for the pediatric population, the use of lamotrigine in children for the treatment of bipolar disorder should be reserved for extreme cases, in which patients have failed alternative treatments [Scahill and Martin, 2002]. Before initiating treatment, a urine pregnancy test should be obtained. The patient and family should be educated about the risk of serious rash or hypersensitivity reaction and instructed about how to recognize the signs and symptoms requiring immediate medical attention. These dosage recommendations are based on those for patients who are being treated for seizure disorder and who are not taking valproate concomitantly; physicians should refer to the product package insert for dosage recommendations for lamotrigine added to valproate. Therapeutic doses for the treatment of bipolar disorder have not been determined. For children between the ages of 2 and 12 years, 0.6 mg/kg/day of lamotrigine is administered in one or two divided doses (rounded down to the nearest 5 mg) during the first 2 weeks. During the third and fourth week, 1.2 mg/kg/day is administered in two divided doses (rounded down to the nearest 5 mg). The dose may be titrated up in increments of 1.2 mg/kg/day (rounded down to the nearest 5 mg) every 2 weeks. The usual maintenance dose of seizures is 15 mg/kg/day. For pediatric patients older than 12 years, 50 mg of lamotrigine is administered daily during the first 2 weeks of treatment. During the third week, the dose is increased to 100 mg/day and given in two divided doses. The dose may be increased by increments of 100 mg/day every 1 to 2 weeks (see Table 39-7). Maintenance dosage ranges from 300 to 500 mg daily given in two divided doses [Lamictal, 2003].

Carbamazepine, phenytoin, phenobarbital, and primidone increase clearance of lamotrigine. Valproate decreases clearance of lamotrigine and may increase the risk of potentially life-threatening rashes [Lamictal, 2003].

ADVERSE EFFECTS Common side effects observed in clinical studies include dizziness, ataxia, somnolence, headache, diplopia, blurred vision, nausea, vomiting, and rash [Lamictal, 2003]. Lamotrigine has been associated with serious rashes requiring hospitalization and discontinuation of treatment. The manufacturer reports the incidence of Stevens-Johnson syndrome as 1% in the pediatric population. Rare cases of toxic epidermal necrolysis and rash-related death have been reported. Potential risk factors for serious rash are concomitant use of valproate, rapid dose escalation, and use of exceedingly high doses [Lamictal, 2003]. Rashes have been reported in 10% of patients in clinical trials. Because it is difficult to distinguish a benign rash from the early stages of a more serious rash, the manufacturer recommends discontinuation of treatment at the first sign of a rash, unless it is clearly not medication related. Rare but potentially life-threatening hypersensitivity reactions have occurred with lamotrigine. Symptoms such as fever and lymphadenopathy, with or without a rash, should prompt immediate evaluation and possible discontinuation of treatment. Lamotrigine accumulates in melanin-rich tissues, such as skin and the eye. Clinical trials did not detect ophthalmologic adverse effects; however, no long-term data are available. Lamotrigine inhibits dihydrofolate reductase; administration of lamotrigine to rats reduced serum folate levels. Low folate levels have been associated with teratogenic effects [Lamictal, 2003].

Gabapentin CLINICAL APPLICATIONS Gabapentin is indicated as a treatment for post-herpetic neuralgia, adjunctive therapy in the treatment of partial seizures in adults and children 12 years or older, and partial seizures in children 3 years or older [Gabapentin, 2002]. Case reports and open studies of gabapentin as adjuvant therapy in bipolar patients were promising; however, double-blind trials have not confirmed efficacy in mania as monotherapy [Frye et al., 2000] or adjunctive treatment [Pande, 2000] or treatment of resistant rapid-cycling bipolar disorder [Evins, 2003; Yatham et al., 2002].

PHARMACOLOGY Gabapentin (Neurontin) is available in capsules, tablets, and solution. Plasma half-life is 5 to 7 hours. It is not metabolized in the liver, and it is excreted in the urine unchanged. No clinically significant drug interactions have been described [Gabapentin, 2002].

CLINICAL MANAGEMENT The dose can be started at 300 mg, given two or three times daily, and titrated gradually up to 1800 mg/day, given in divided doses three times daily. Clinical trial data do not indicate any routine monitoring of laboratory screens. No therapeutic plasma concentrations have been established (see Table 39-7).

ADVERSE EFFECTS Gabapentin is generally well tolerated. Common side effects include dizziness, ataxia, sedation, fatigue, and nystagmus [Gabapentin, 2002]. Less common side effects include dyspepsia, peripheral edema, diplopia, and amblyopia. Behavioral adverse effects are possible, including agitation and emotional lability. Gabapentin has been associated with teratogenic effects in animal studies [Gabapentin, 2002].

Topiramate CLINICAL APPLICATIONS Topiramate (Topamax) has an indication as adjuvant therapy for partial seizures and primary generalized tonic-clonic seizures in adults and children ages 2 and older [Topamax, 2003]. In adults, topiramate appears to be effective as adjuvant therapy in treatment-resistant bipolar disorder [Ghaemi et al., 2001; Vieta et al., 2002]. It may be more effective in managing the manic phase or in rapid-cycling bipolar disorder [Chengappa et al., 1999; McElroy et al., 2000]. A retrospective chart review of children and adolescents with bipolar disorder

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treated with topiramate as an adjuvant mood stabilizer indicated response rates of 73% for mania [DelBello et al., 2002a]. Potential advantages of topiramate over other mood stabilizers are its weight-neutral and appetite-suppressive effects [Chengappa et al., 1999; McElroy et al., 2000].

PHARMACOLOGY Topiramate is available in tablets or sprinkle capsules, which are bioequivalent. Its absorption is rapid, reaching peak plasma concentrations at 2 hours. Antacids can decrease absorption of topiramate. Plasma elimination half-life is 21 hours, and steady state is reached in about 4 days. About 70% of topiramate is excreted unchanged in the urine. The remainder is metabolized in the liver [Topamax, 2003].

CLINICAL MANAGEMENT Topiramate should be initiated at 25 to 50 mg daily (1 to 3 mg/kg/day), with small weekly increases of 1 to 3 mg/kg/day to minimize adverse effects. The recommended total daily dose in the treatment of seizures is 5 to 9 mg/kg/day [Topamax, 2003]. Monitoring the plasma concentration is unnecessary unless it is concomitantly used with phenytoin or carbamazepine (see Table 39-7).

ADVERSE EFFECTS AND DRUG INTERACTIONS Adverse effects include fatigue, ataxia, confusion, impaired concentration and memory, sedation, agitation, anorexia with weight loss, kidney stones, and diplopia. Topiramate may decrease systemic levels of bicarbonate, leading to a metabolic acidosis. Consequently, slow titration, clinical observation, and laboratory monitoring are advised. Carbamazepine, valproic acid, and phenytoin can lower the plasma concentration of topiramate. Topiramate may increase the concentration of phenytoin and decrease that of valproic acid [Topamax, 2003].

DOPAMINE RECEPTOR ANTAGONISTS: TYPICAL NEUROLEPTICS Dopamine receptor antagonist is a term used to refer to a medication that is a high-affinity antagonist of dopamine receptors. Other terms used to refer to these drugs include typical neuroleptics, typical antipsychotics, and major tranquilizers. The first neuroleptic, chlorpromazine, was initially used in the early 1950s in France to manage preoperative anxiety and postoperative shock [Sadock and Sadock, 2003]. When it was found to have a calming effect on patients with schizophrenia and mania, it gained widespread use in psychiatry. Unfortunately, these patients developed neurologic side effects, including extrapyramidal symptoms, associated with short- and long-term use of chlorpromazine. Other antipsychotic agents were developed that were effective in treating a variety of psychiatric conditions, but they could not escape the risk of producing extrapyramidal symptoms. Uncovering their pharmacodynamic properties led to more sophisticated drug development. The antipsychotic effects of these medications are thought to be

mediated through the inhibition of dopamine binding at dopamine D2 receptors, resulting in the reduction of dopaminergic neurotransmission in the mesocortical region. The neurologic side effects appear to be mediated by dopamine antagonism in the nigrostriatal pathway. Other side effects associated with neuroleptics were found to be associated with its activity at adrenergic, cholinergic, and histaminic receptors. Dopamine receptor antagonists are distinguished from serotonin-dopamine antagonists, also called novel or atypical antipsychotics or neuroleptics. In contrast to typical neuroleptics, the serotonin-dopamine antagonists are antagonists at dopaminergic and serotonergic receptors. They also differ in their ability to reduce negative symptoms of schizophrenia and their reduced risk of short- and longterm neurologic side effects. Unfortunately, as patients and clinicians gained experience with serotonin-dopamine antagonists, other adverse effects, such as hyperglycemia and hyperlipidemia, were recognized. Serotonin-dopamine antagonists have become first-line medications in the treatment of psychotic disorders in adults [APA, 1997], and their apparently lower risk of extrapyramidal symptoms makes them more appealing in the clinical practice of child psychiatry. Nonetheless, haloperidol and pimozide continue to be used, especially in the treatment of Tourette’s syndrome.

Common Characteristics of Typical Neuroleptics The common characteristic among typical neuroleptics is their ability to antagonize dopamine receptors in the CNS. Activity in the mesocortical region is presumed to result in their therapeutic effects, and their neurologic side-effect profile is attributed to activity in the nigrostriatal region. Dopamine antagonism in the tuberoinfundibular tract results in endocrine effects, such has hyperprolactinemia [Sadock and Sadock, 2003]. Typical neuroleptics can be classified by their chemical structure. In clinical practice, classification according to dopamine receptor binding potency is more practical. Highpotency neuroleptics (e.g., haloperidol, fluphenazine, pimozide) are more likely to cause extrapyramidal symptoms, whereas low-potency neuroleptics (e.g., chlorpromazine, thioridazine) are more likely to cause side effects mediated by cholinergic (e.g., dry mouth, constipation), α1adrenergic (e.g., vasodilation and orthostatic hypotension), and histaminic receptor activity (e.g., sedation, weight gain) (Table 39-8) [Sadock and Sadock, 2003]. Non–dopamine-mediated side effects include orthostatic hypotension, peripheral anticholinergic effects (i.e., dry mouth, blurred vision, constipation, urinary retention, and mydriasis), central anticholinergic effects (i.e., agitation, delirium, hallucinations, seizures, and coma), hyperprolactinemia, leukopenia, agranulocytosis, jaundice, photosensitivity, decreased seizure threshold, and weight gain. Thioridazine has been associated with irreversible retinal pigmentation. Chlorpromazine has been associated with skin pigmentation and deposits in the lens and cornea, which usually do not affect vision. Cardiotoxicity and sudden death have been associated with some typical neuroleptics, especially low-potency neuroleptics. Dose-related prolongation of the QTc interval,

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TABLE 39-8 Representative Dopamine Antagonists: Comparison of Potency, Side-Effect Profile, and Dosing DRUG

PREPARATIONS

POTENCY

SEDATIVE EFFECT

ANTICHOLINERGIC EFFECT

EXTRAPYRAMIDAL EFFECT

DOSING

Chlorpromazine

Thorazine (10-, 25-, 50-, 100-, and 200-mg tablets) Syrup (10 mg/5 mL) Concentrate (30 mg/mL, 100 mg/mL) Haldol (0.5-, 1-, 2-, 5-, 10-, and 20-mg)

Low

High

High

Low

High

Low

Low

High

Orap (1- and 2-mg tablets)

High

Low

Low

High

Age ≤ 12 yr: 0.25 mg/kg every 4 to 6 hr as needed Age >12 yr: 10 mg tid to 25 mg qid; titrate with increases of 20 to 50 mg once or twice per week. Initial dose of 0.5 mg/day; increase gradually by 0.5 mg every 5-7 days until therapeutic effect is achieved or increase is prohibited by side effects Initial dose of 0.05 mg/kg; increase gradually by 0.5 mg once or twice per week until therapeutic effect is achieved or increase is prohibited by side effects; maximum dose of 10 mg/day or 0.2 mg/kg/day

Haloperidol

Pimozide

arrhythmias, torsade de pointes, and sudden death have been reported with thioridazine. Chlorpromazine may cause nonspecific, reversible Q- and T-wave abnormalities, and sudden death has been reported. Pimozide, especially when combined with CYP3A4 inhibitors, has been associated with cardiotoxicity. Neurologic adverse effects are seen more commonly with high-potency neuroleptics (Table 39-9). Parkinsonism has been observed in children and adolescents treated with typical neuroleptics [Campbell et al., 1985; Richardson

et al., 1991]. Symptoms include cogwheel rigidity, shuffling gait, bradykinesia, masklike facies, stooped posture, coarse tremor, perioral tremor (i.e., rabbit syndrome), and akinesia (i.e., lack of initiative). Symptoms may be managed by reducing the dose of the neuroleptic or addition of anticholinergic medications such as benztropine (Cogentin) or antihistamines such as diphenhydramine (Benadryl). Acute dystonic reactions, which are slow, sustained muscular contractions, may occur within hours to days of initiation of neuroleptics. They may be painful and

TABLE 39-9 Extrapyramidal Symptoms Associated with Neuroleptic Medications NEUROLOGIC SIDE EFFECTS

TIME COURSE

SYMPTOMS

INTERVENTION

Parkinsonism

Within 5 to 90 days of initiation

Anticholinergic medications: benztropine (Cogentin) and diphenhydramine (Benadryl)

Acute dystonia

Within hours to days of initiation

Akathisia

Any time during treatment

Cogwheel rigidity, shuffling gait, bradykinesia, masklike facies, stooped posture, coarse tremor, perioral tremor (rabbit syndrome), akinesia (lack of initiative), ataraxia (indifference toward the environment) Slow, sustained muscular contractions involving any part of the body, which may be painful: eyes (oculogyric crisis), neck (torticollis or retrocollis), tongue, jaw, whole body (opisthotonos) Motor restlessness and muscular discomfort.

Tardive dyskinesia

Any time during treatment; risk increases with duration of treatment

Neuroleptic malignant syndrome

Any time during treatment

Involuntary choreoathetoid movements in muscles of the head (perioral movements, lip smacking, grimacing, tongue protrusion, lateral jaw movements), trunk (trunk twisting and pelvic thrusting), and extremities Muscle rigidity, fever, autonomic instability, delirium, elevated levels of creatine phosphokinase, leukocytosis, rhabdomyolysis, myoglobinuria, renal failure

Intramuscular anticholinergic medication

Decreased dose of neuroleptic; anticholinergic medications; propranolol Monitor severity of movements with objective ratings; decreased dose of typical neuroleptic; discontinue typical neuroleptic; switch to atypical neuroleptic Emergency medical treatment and immediate discontinuation of neuroleptic

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frightening to patients and families who are not forewarned of this possible side effect. Dystonias may involve the eyes (i.e., oculogyric crisis), neck (i.e., torticollis or retrocollis), tongue, jaw, or entire body (i.e., opisthotonos). Use of 1 to 2 mg of intramuscular benztropine or 25 to 50 mg of oral or intramuscular diphenhydramine can relieve the dystonia within several minutes. Akathisia is a persistent, uncomfortable restlessness. Patients may constantly rock or pace around the room and secondarily feel depressed and dysphoric. Extreme cases have been described of patients developing suicidal ideation and behavior [Van Putten and Marder, 1987]. Dosage reduction or propranolol sometimes brings relief [Adler et al., 1986]. Tardive dyskinesia is a syndrome of involuntary movements, characterized by choreoathetoid movements of the muscle in the head, trunk, extremities, or the entire body. Tardive dyskinesia may occur any time during treatment with neuroleptics, or it may be associated with neuroleptic withdrawal (i.e., withdrawal dyskinesia). The prevalence of neuroleptic-induced and withdrawal dyskinesia in children and adolescents has ranged from 0% to 51%. The risk of developing withdrawal dyskinesias increases with the duration of neuroleptic treatment. The risk is higher in females, children, the elderly, and patients with brain damage or mood disorders. Withdrawal dyskinesias may resolve over the course of weeks to months [Baldessarini, 1990]; however, irreversible tardive dyskinesia has been reported. The presence of preexisting involuntary movements should be assessed with objective rating scales, such as the Abnormal Involuntary Movement Scale (AIMS). Serial assessments should be completed every 3 months during neuroleptic therapy. An increase in involuntary movements should prompt a discussion with the patient and family about treatment options. There are no consistently useful treatments for tardive dyskinesia, although symptom reduction has occurred with many medications from different classes. The most consistently effective medications are neuroleptics, but continued exposure may make tardive dyskinesia symptoms worse over time. Neuroleptic malignant syndrome is a rare and potentially fatal adverse effect, which may occur any time during treatment with neuroleptics, but it may be more likely to occur in the first 2 weeks [Addonizio et al., 1987]. The frequency of occurrence has been 0.02% to 2.44% with typical neuroleptics [Khan and Farver, 2000]. It is characterized by symptoms in four major areas: autonomic instability, extrapyramidal symptoms, hyperpyrexia, and altered mental status. Specific symptoms include muscle rigidity, hyperpyrexia (mean temperature of 103 ± 1.9° F [Rosebush and Stewart, 1989]), sweating, increased blood pressure and heart rate, confusion, agitation, and possible renal failure. Laboratory findings include leukocytosis; elevated levels of serum creatine phosphokinase, liver transaminases, and myoglobin; and myoglobinuria. In a review of 49 cases of neuroleptic malignant syndrome, the mortality rate among children was 27%, and the mortality rate among adolescents was 13% [Latz and McCracken, 1992]. Treatment involves immediate hospitalization for supportive treatment and discontinuation of the neuroleptic drug.

Haloperidol Clinical Applications Haloperidol is approved for the treatment of psychotic disorders and for Tourette’s syndrome. It is approved for use in treating children with severe behavioral disorders that have not responded to nonpharmacologic interventions or non-antipsychotic medications [Haloperidol, 2001]. In clinical practice, it is sometimes administered intramuscularly as a chemical restraint to acutely stabilize agitated and aggressive patients who pose an immediate threat to themselves or others when alternative measures have failed. Haloperidol appears to be effective in children with schizophrenia [Green et al., 1992; Spencer et al., 1992]. It appears to be effective in improving behavior in children with autism [Anderson et al., 1984; Joshi et al., 1988] and in reducing tics in Tourette’s syndrome [Sallee et al., 1997; Shapiro and Shapiro, 1989].

Pharmacology Haloperidol is a high-potency dopamine receptor antagonist. It is available in oral tablets, an oral concentrate, parenteral preparations (intramuscular or intravenous), and depot intramuscular injections (Haldol decanoate). Oral haloperidol is well absorbed from the gastrointestinal tract and undergoes first-pass metabolism in the liver. Peak plasma concentrations are reached within 2 to 6 hours. Peak plasma haloperidol concentration occurs 10 to 20 minutes after intramuscular injection. Peak pharmacologic action occurs within 30 to 45 minutes in agitated patients. In psychotic patients, improvement may be seen within 30 to 60 minutes, and the effects increase over the next 2 hours. Haldol decanoate is released slowly, with peak concentrations occurring 6 to 7 days after injection. Steady-state concentrations are achieved in approximately 3 months with monthly injections. Haloperidol is metabolized by the liver and excreted in urine and feces [Haldol, 2001].

Dosing For children between the ages of 3 and 12 years, haloperidol may be initiated at 0.5 mg/day. The dose may be increased by increments of 0.5 mg at 5- to 7-day intervals to a clinically therapeutic dose. Dosing recommendations for psychotic disorders is 0.05 to 0.15 mg/kg/day. For nonpsychotic behavior disorders and Tourette’s syndrome, the therapeutic range is 0.05 to 0.075 mg/kg/day [Haldol, 2001].

Adverse Effects Adverse effects of haloperidol are characteristic of highpotency typical neuroleptics (see “Common Characteristics of Typical Neuroleptics”). Rates of acute dystonic reaction with haloperidol have been observed to be 16.7% and 25% in children treated for schizophrenia [Green et al., 1992; Spencer et al., 1992]. The rate of withdrawal tardive dyskinesia observed in a long-term study in autistic children was 33.9%. Higher cumulative dose, female gender, and perinatal complications appeared to increase risk [Campbell et al., 1997].

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Drug Interactions

Clinical Management

Medications that inhibit the cytochrome P-450 isoenzyme system can increase serum concentrations of haloperidol. The combination of such medications with haloperidol has been associated with neurotoxicity and cases of irreversible brain damage.

Before beginning pimozide, the patient should undergo a thorough psychiatric and medical evaluation. Potential drug interactions and co-occurring psychiatric or medical conditions that may contraindicate pimozide (e.g., history of arrhythmias, congenital long QT, pregnancy, conditions that alter potassium levels) require adjustment in medication management or independent intervention (e.g., ADHD, obsessive-compulsive disorder). Baseline measurements that may be helpful include laboratory screening (i.e., complete blood cell count, electrolyte determinations, tests of renal function and thyroid function, prolactin level, glucose concentration, and urine drug screen), height, weight, and baseline assessment of the extrapyramidal system [Bryden et al., 2001]. Because pimozide can prolong the QT interval, serial ECGs should be obtained at baseline and during dose titration. When monitoring ECGs, the QTc interval should remain less than 0.47 seconds or less than 25% above baseline [Green, 1995]. A pediatric cardiologist should be consulted if the ECG is equivocal. In addition to the baseline ECG, electrolyte levels should be obtained, because serum potassium levels can affect cardiac conduction. Pimozide may be initiated at 0.05 mg/kg and gradually increased by 0.5 mg once or twice weekly. Doses greater than 0.2 mg/kg/day or 10 mg/day are not recommended [Orap, 2004]. Efficacy (i.e., severity and frequency of tics) and safety (i.e., serial ECGs and serum electrolytes) of pimozide should be actively monitored over time.

Pimozide Clinical Applications Pimozide (Orap) is labeled for use in the treatment of Tourette’s syndrome in patients who have failed to respond to standard treatment and experience severe impairment from tics. Pimozide has been shown to be effective in decreasing tics [Sallee et al., 1997; Shapiro and Shapiro, 1984; Shapiro et al., 1983]. However, the atypical neuroleptic risperidone appears to be more efficacious in decreasing tics when directly compared with pimozide [Bruggeman et al., 2001; Gilbert et al., 2004], and it has a more favorable side-effect profile.

Pharmacology Pimozide is a high-potency dopamine receptor antagonist. It is metabolized by the liver, primarily by CYP3A4 and to a lesser extent by CYP1A2, and it is excreted in urine. Mean serum half-life is about 55 hours [Orap, 2004].

TABLE 39-10 Serotonin-Dopamine Antagonists: Comparison of Receptor Activity and Dosing DRUG

PREPARATIONS

DOPAMINE RECEPTOR ACTIVITY

SEROTONIN RECEPTOR ACTIVITY

Risperidone

Risperdal (0.25-, 0.5-, 1-, 2-, 3-, and 4-mg tablets) Risperdal M-TAB (0.5-, 1-, and 2-mg tablets) Risperdal Elixir (1 mg/mL) Zyprexa (2.5-, 5-, 7.5-, 10-, 15-, and 20-mg tablets) Zyprexa Zydis (5-, 10-, 15-, and 20-mg tablets) Seroquel (25-, 100-, 200-, and 300-mg tablets) Geodon (20-, 40-, 60-, and 80-mg tablets)

D2

5HT2A

D1, D2, D4

5HT2A

D1, D2

Olanzapine

Quetiapine Ziprasidone

Aripiprazole

Abilify (5-, 10-, 15-, 20-, and 30-mg tablets)

ANTICHOLINERGIC RECEPTOR ACTIVITY

ADRENERGIC RECEPTOR ACTIVITY

HISTAMINE RECEPTOR ACTIVITY

DOSING

α1, α2

H1

Initial dose of 0.25 to 0.5 mg; increase by 0.25 to 0.5 mg/week

α1

H1

Initial dose of 2.5 to 5 mg; increase by 2.5 to 5 mg/week; maximum dose of 20 mg/day

5HT2, 5HT6

α1, α2

H1

D2, D3, D4

5HT1D, 5HT2A, 5HT2C

α1

H1

Partial D2 agonist

5HT1A, 5HT2A

α1

H1

Initial dose of 12.5 to 25 mg/day; increase by 25 to 50 mg/day Initial dose of 20 mg/day; increase gradually; maximum of 160 mg/day Initial dose 5 mg to 10 mg per day; gradually increase by 5 mg to 10 mg every 2 wk; maximum 30 mg/day

M1-M5

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Adverse Effects Adverse effects of pimozide are those typical of highpotency neuroleptics (see “Common Characteristics of Typical Neuroleptics”). Pimozide has been associated with QT prolongation, serious cardiac arrhythmias, and sudden death. Use of pimozide with clarithromycin (Biaxin), erythromycin, azithromycin (Zithromax), and dirithromycin (Dynabac) is contraindicated by the Food and Drug Administration because of the risk of cardiotoxicity with these combinations [Orap, 2004].

SEROTONIN-DOPAMINE ANTAGONISTS: ATYPICAL NEUROLEPTICS Common Characteristics Serotonin-dopamine antagonists, or atypical neuroleptics, differ from conventional or typical neuroleptics in that they block serotonin receptors in addition to dopamine receptors. Each atypical neuroleptic possesses different affinities at dopamine, serotonin, adrenergic, cholinergic, and histaminic receptors, which result in different side-effect profiles and clinical effects (Table 39-10). Atypical neuroleptics offer advantages over typical neuroleptics in their ability to improve the negative and positive symptoms of schizophrenia and their lower risk of producing extrapyramidal symptoms. However, they may pose other health risks with regard to weight gain, insulin resistance, and hyperlipidemia. Compared with adults, children appear to carry a greater risk of developing extrapyramidal symptoms [Lewis, 1998]. Development of tardive dyskinesia was more likely in children and adolescents treated with typical neuroleptics compared with atypical agents [Connor et al., 2001]. Among the atypical neuroleptics, extrapyramidal symptoms appear to occur more frequently with risperidone than with quetiapine or olanzapine [Findling et al., 2000; Grcevich et al., 1996]. As experience with atypical neuroleptics in the pediatric population has increased, greater attention has been paid to their weight gain effects. In children and adolescents, weight gain has been associated with risperidone [Hellings et al., 2001; Martin et al., 2000; Zuddas et al., 2000], olanzapine [Findling et al., 2000], and quetiapine therapy [Findling et al., 2000]. Olanzapine appears to have the greatest tendency to produce weight gain, followed by risperidone and then quetiapine [Findling et al., 2000]. Aripiprazole and ziprasidone do not appear to cause significant weight gain in adults [Keck and McElroy, 2003; Marder et al., 2003; Nasrallah, 2003]. Clinicians need to be sensitive to the weight gain effects of these medications, because significant weight gain is likely to affect a child or adolescent’s selfesteem and may lead to noncompliance with the medication and reduced efficacy. Recommendations to increase exercise and to make healthier food choices may be effective with motivated patients and families. Studies have indicated that atypical antipsychotic medications are associated with metabolic disturbances such as increased insulin resistance [Haupt and Newcomer, 2001], metabolic syndrome [L’Italien, 2003], and dys-

lipidemia [Lindenmayer et al., 2003]. Patients treated with olanzapine and clozapine appear to have higher insulin resistance compared with those treated with risperidone, typical antipsychotics, and control subjects [Newcomer et al., 2002]. Clozapine, olanzapine, and quetiapine treatment were more frequently associated with elevations of serum lipids (i.e., triglycerides, total cholesterol, and lowdensity lipoprotein cholesterol) compared with risperidone, ziprasidone, and aripiprazole [Casey, 2004]. New-onset cases of type 2 diabetes mellitus have been associated with atypical neuroleptics, 25% of which occur in the absence of substantial weight gain or obesity [Haupt and Newcomer, 2001]. These patients are at risk for diabetic ketoacidosis, which has a mortality rate of 6% to 10% if not recognized and treated promptly [Gomez Diaz et al., 1996; Lebovitz, 1995; Malone et al., 1992]. Typical antipsychotics, risperidone, and olanzapine increase serum prolactin levels [Tandon and Halbreich, 2003]. These elevations have not been observed with clozapine and quetiapine [Stigler et al., 2001]. Given the possible adverse effects of neuroleptics and the increasing use of neuroleptics for off-label use, careful monitoring of pediatric patients is necessary. A comprehensive psychiatric evaluation should include an assessment for the risk of adverse effects. Recommended baseline measurements include laboratory screening (e.g., complete blood cell count, electrolytes, liver and renal function tests, thyroid function test, prolactin and glucose levels, urine drug screen), height, weight [Bryden et al., 2001], and baseline assessment of extrapyramidal symptoms using clinician ratings (e.g., AIMS). A baseline ECG is recommended before initiating risperidone, olanzapine, quetiapine, or ziprasidone.

Risperidone Clinical Applications Risperidone (Risperdal) is labeled for use in the treatment of psychotic disorders and the manic phase of bipolar disorder in adults. In children and adolescents, it has been found to be effective for psychotic disorders [Armentaros et al., 1997; Grcevich et al., 1996; Quintana and Keshavan, 1995], bipolar disorder [Frazier et al., 1999; Schreier, 1998], conduct disorder [Findling et al., 2000], aggressive behavior in children with subaverage IQ [Aman et al., 2002; Buitelaar et al., 2001; Snyder et al., 2002], autism [Fisman and Steele, 1996; Hellings et al., 2001; Masi et al., 2001; McCracken et al., 2002; McDougle et al., 1997; Zuddas et al., 2000], tic disorders [Bruggeman et al., 2001; Dion et al., 2002; Gaffney et al., 2002; Lombroso et al., 1995; Scahill et al., 2003], and co-occurring tic disorders and obsessive-compulsive disorder [Bruggeman et al., 2001; Gaffney et al., 2002].

Pharmacology Risperidone is a serotonin-dopamine antagonist with activity at serotonin 5HT2A, dopamine D2, α1- and α2adrenergic, and histaminic H1 receptors. It is available in tablets, solution, orally disintegrating tablets, and injectable preparations. It is well absorbed in the gastrointestinal tract, and it undergoes extensive first-pass metabolism by

Lee and Walkup / Neuropsychopharmacology

CYP2D6 to its active metabolite, 9-hydroxyrisperidone. The mean half-life of both forms is about 20 hours [Risperdal, 2004].

Clinical Management Given the risks of serious adverse effects and the lack of knowledge regarding possible long-term adverse effects in the pediatric population, consideration of alternative nonpharmacologic and pharmacologic interventions is advised. A thorough risk-benefit analysis should be part of the informed consent discussion with the parent or guardian. Baseline assessment includes evaluation of potential risk factors (i.e., cardiovascular disease, hepatic or renal impairment, pregnancy, and diabetes), preexisting movement disorders, and fasting glucose levels. Risperidone can be initiated at 0.25 to 0.5 mg/day, increasing the dose by small increments weekly.

Adverse Effects Risperidone may be associated with sedation, orthostatic hypotension [Toren et al., 1998], gastrointestinal side effects, elevations in hepatic transaminase levels, fatty liver infiltrates [Kumra et al., 1997], and increased appetite with weight gain [Toren et al., 1998]. Neurologic side effects include extrapyramidal symptoms [Mandoki, 1995], which are dose dependent, and tardive dyskinesia, whose risk increases with duration of treatment [Leucht et al., 1999]. The most serious adverse effect is neuroleptic malignant syndrome [Feeney and Klykylo, 1996; Toren et al., 1998]. This potentially fatal condition is characterized by hyperpyrexia, muscle rigidity, altered mental status, autonomic instability, elevated creatine phosphokinase level, myoglobinuria, and acute renal failure. Risperidone or its metabolite can prolong the QT interval in some patients, which can lead to cardiac arrhythmia if combined with medications with similar effects. Risperidone has been associated with hyperprolactinemia. In 2003, the labeling of risperidone was revised to include warnings of cerebrovascular adverse events in elderly patients with dementia [Risperdal, 2004].

Drug Interactions Risperidone may potentiate sedative and hypotensive effects of other medications. Risperidone can increase plasma concentrations of clozapine. Combination with phenytoin or selective serotonin re-uptake inhibitors may cause increased extrapyramidal symptoms [Sadock and Sadock, 2003]. Inhibitors of CYP2D6 decrease the metabolism of risperidone to 9-hydroxyrisperidone, which does not appear to cause adverse effects. Risperidone is a weak inhibitor of CYP2D6 and has little effect on the metabolism of other medications.

Olanzapine

969

prophylaxis in bipolar disorder. In adults with schizophrenia, olanzapine was found to be comparable to haloperidol in treating positive symptoms and superior in treating negative symptoms [Tollefson and Kuntz, 1999]. It has been shown to be beneficial in the treatment of schizophrenia in children and adolescents [Findling et al., 2003; Kumra et al., 1998; Mozes et al., 2003]. It has also been used in the treatment of juvenile bipolar disorder [Chang and Ketter, 2000; Frazier et al., 2001], autism [Heimann, 1999; Malone et al., 2001; Potenza et al., 1999; Rubin, 1997], and Tourette’s syndrome [Stamenkovic et al., 2000].

Pharmacology Olanzapine is a serotonin-dopamine antagonist with activity at serotonin 5HT2A/2C; dopamine D1, D2, and D4; α1adrenergic; muscarinic M1-5; and histaminic H1 receptors (Zyprexa, 2004]. Olanzapine is available in a tablet, oral disintegrating tablet (Zyprexa-Zydis), and injectable form. It is well absorbed from the gastrointestinal tract. Approximately 40% of the dose is metabolized by first-pass metabolism. It reaches peak concentration in about 6 hours; its mean half-life is 30 hours [Zyprexa, 2004].

Clinical Management Before initiation of olanzapine, patients should be assessed for risk factors complicating or contraindicating treatment (e.g., diabetes, pregnancy, liver disease, cardiovascular disease). Baseline weight, assessment for preexisting involuntary movements, and laboratory screening, including a fasting blood glucose determination and liver panel, should be completed. Dosing is started at 2.5 to 5.0 mg/day and may be increased by small increments weekly, not to exceed 20 mg/day. Weight, serum glucose concentration, and levels of liver transaminases should be monitored during ongoing therapy.

Adverse Effects Side effects include sedation, orthostatic hypotension, and sialorrhea. The risk of weight gain may be higher than with most atypical neuroleptics [Allison and Casey, 2001; Allison et al., 1999; Wirshing et al., 1999]. Olanzapine has been associated with elevations in liver transaminases, γ-glutamyltransferase, and serum prolactin [Risperdal, 2004]. As with other neuroleptics, patients may experience extrapyramidal symptoms, tardive dyskinesia, and neuroleptic malignant syndrome. In 2004, the labeling of olanzapine was revised to include warnings of possible hyperglycemia, ketoacidosis, hyperosmolar coma, or death resulting from atypical neuroleptics [Zyprexa, 2004]. Patients with diabetes mellitus or those at risk for the disorder are advised to undergo fasting blood glucose testing at baseline. The fasting blood glucose level and clinical symptoms of hyperglycemia should be monitored routinely.

Clinical Applications

Drug Interactions

Olanzapine (Zyprexa) is labeled for use as a treatment for psychotic disorders, manic phase of bipolar disorder, and

Fluvoxamine can increase serum concentrations of olanzapine [Zyprexa, 2004].

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Neurobehavioral Disorders / 39

Quetiapine Clinical Applications Quetiapine (Seroquel) is labeled for use in the treatment of psychotic disorders, schizophrenia, and the manic phase of bipolar disorder. In adolescents, quetiapine has shown efficacy in the treatment of psychotic disorders [McConville et al., 2000, 2003; Shaw et al., 2001] and bipolar mania [DelBello et al., 2002b]. Two case reports and one small study describe usefulness of quetiapine in Tourette’s syndrome [Mukaddes and Abali, 2003; Parraga et al., 2001]. In one small study of patients with autism and mental retardation, quetiapine was ineffective [Martin et al., 1999].

Pharmacology Quetiapine is a serotonin-dopamine antagonist similar to clozapine in its neurochemical profile. It has activity at serotonin 5HT2A and 5HT6; dopamine D1, D2, and D4; α1and α2-adrenergic; and histaminic H1 receptors. It has been associated with minimal or transient elevations of prolactin. Quetiapine is rapidly absorbed through the gastrointestinal tract, reaching peak plasma levels in 1 to 2 hours. The steady-state half-life is about 6 hours [Seroquel, 2004].

Clinical Management Quetiapine may be initiated at 12.5 to 25 mg/day and increased by increments of 25 to 50 mg/day. The drug is usually given in divided doses two or three times daily. Mean dose in studies of adolescents with psychotic disorders was 467 mg/day [Shaw et al., 2001]. The mean dose in a study of adolescents with bipolar mania was 450 mg/day [DelBello et al., 2002b].

Adverse Effects Side effects of quetiapine include dizziness, postural hypotension, dry mouth, and dyspepsia. Quetiapine is thought to have less risk of weight gain [Findling et al., 2000] and serum prolactin elevation [Stigler et al., 2001]. Development of cataracts in dogs has been observed during animal testing. Lens changes have been observed in patients with long-term use of quetiapine. The manufacturer recommends a baseline ophthalmologic examination and serial examinations every 6 months during treatment [Seroquel, 2004].

Drug Interactions Phenytoin and thioridazine increase clearance of quetiapine. Inhibitors of CYP3A4 decrease clearance of quetiapine, significantly increasing serum concentrations [Seroquel, 2004].

Ziprasidone Pharmacology Ziprasidone (Geodon) is a serotonin-dopamine antagonist with activity at serotonin 5HT1D, 5HT2A, 5HT-2C; dopamine D2, D3, and D4; α1-adrenergic; and histaminic H1 receptors. It is an agonist at 5HT1A and inhibits uptake of serotonin and norepinephrine [Geodon, 2004].

Clinical Applications Ziprasidone is labeled for use in the treatment of psychotic disorders in adults. In clinical practice, its main advantage over other atypical antipsychotics is its weight-neutral effects [Keck and McElroy, 2003; Marder et al., 2003; Nasrallah, 2003]. Clinicians may be hesitant to use it because of its effects on the QT interval and the lack of data on safety and efficacy in the pediatric population. In a study of 12 patients with autism spectrum disorder, 6 were responders, and 2 patients with co-occurring bipolar disorder were rated much worse [McDougle et al., 2002]. In a study of children and adolescents with Tourette’s syndrome, reduction of tics was significant in patients treated with ziprasidone versus placebo (35% versus 7%) [Sallee et al., 2000b].

Pharmacology Ziprasidone is extensively metabolized in the liver. About one third of ziprasidone’s metabolic clearance is mediated by the CYP3A4 isoenzyme [Geodon, 2004].

Clinical Management Before initiating ziprasidone, a careful history must be obtained to identify possible contraindications, including concomitant use of drugs known to prolong the QTc interval, history of congenitally long QT syndromes, history of cardiovascular disease or cardiac arrhythmia, and conditions that place the patient at risk for electrolyte disturbances. Baseline ECG, serum electrolytes, renal and hepatic screens, and complete blood cell count should be obtained. Ziprasidone is available in oral (ziprasidone hydrochloride) and injectable (ziprasidone mesylate) forms. Initial adult dosage of ziprasidone hydrochloride is 20 mg taken twice daily, which may be incrementally increased after a minimum of 2 days. Maximum dosage recommended by the manufacturer is 80 mg taken twice daily [Geodon, 2004]. The mean dosage used by Sallee and colleagues [2000b] in a study of ziprasidone in 28 children and adolescents with tic disorders was 28 mg/day. Ziprasidone was initiated at 5 mg/day and flexibly titrated to a maximum dose of 40 mg/day. Within this dosage range, ziprasidone was well tolerated with no cardiac adverse effects. In adults, intramuscular ziprasidone can be used to control acute agitation in patients with schizophrenia; 10 to 20 mg is given as a single dose. Use in patients who are already receiving oral ziprasidone should be avoided because the safety of concomitant use has not been established [Geodon, 2004]. No data are available on the safety or efficacy of intramuscular ziprasidone in children or adolescents.

Adverse Effects The most common side effects of ziprasidone are somnolence, extrapyramidal symptoms, and respiratory disorder. Other side effects of ziprasidone include rash, orthostatic hypotension, decreased seizure threshold, and hyperprolactinemia. Ziprasidone has been associated with prolongation of the QT interval, which may increase the risk of

Lee and Walkup / Neuropsychopharmacology

fatal arrhythmias, such as torsades de pointes, or sudden death [Geodon, 2004].

Drug Interactions Use of ziprasidone is contraindicated in patients who are taking medications that are known to prolong the QTc interval. Psychiatric medications in this category include thioridazine, chlorpromazine, droperidol, pimozide, and tricyclic antidepressants. Ziprasidone may potentially interact with inducers or inhibitors of CYP3A4. It potentially has additive hypotensive effects when combined with hypotensive agents and potential additive sedative effects when combined with CNS agents [Geodon, 2004].

Aripiprazole Clinical Applications Aripiprazole (Abilify) is labeled for use in the treatment of schizophrenia in adults. It has been shown to be superior to placebo in managing positive and negative symptoms of schizophrenia [Kane et al., 2002; McGavin and Goa, 2002].

Pharmacology Aripiprazole differs from other atypical neuroleptics in its pharmacodynamic properties. It is a partial agonist at the dopamine D2 receptor. It has serotonin antagonist activity at 5HT2A receptors and partial agonist activity at 5HT1A receptors. It has moderate affinity for α1-adrenergic and histaminic H1 receptors, but it has no activity at cholinergic muscarinic receptors. Aripiprazole is well absorbed, with peak plasma concentrations attained in 3 to 5 hours. It is highly bound to plasma proteins, and it is metabolized by the liver. The isoenzymes CYP3A4 and CYP2D6 are involved in its metabolism [Abilify, 2004].

Clinical Management Initial evaluations should incorporate an assessment of risk factors, including a history of cardiovascular disease, seizure disorder, pregnancy, and use of medications that potentially interact with aripiprazole. In adults, the recommended initial and target dosages of aripiprazole are 10 or 15 mg/day. Dosage adjustments should not be made at intervals less than 2 weeks because of the slow rate at which steady-state concentrations are achieved [Abilify, 2004].

Adverse Effects Side effects include headache, fatigue, hypotension, gastrointestinal side effects, anorexia, insomnia, somnolence, and blurred vision. In short-term and long-term placebocontrolled trials there were no differences in the extrapyramidal symptoms, lipid profile, or electrocardiographic parameters between active drug and placebo [Abilify, 2004].

Drug Interactions Because aripiprazole is metabolized by CYP3A4 and CYP2D6, serum concentrations may be affected by medica-

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tions that induce or inhibit these isoenzymes. In vivo studies revealed that aripiprazole had no significant effect on metabolism through CYP2D6, CYP2C9, CYP2C19, or CYP3A4. In vitro studies demonstrated that it had no effect on CYP1A2 activity [Abilify, 2004].

CONCLUSIONS Many factors have led to an increased use of psychotropic medications in children and adolescents. Newer data suggest more opportunities for children to benefit but also raise more concerns about safety and monitoring. To support this increased use of psychotropic medications, more studies are needed to assess the acute efficacy of newer medications and the long-term safety and efficacy of most psychotropic agents. Developing standards for active monitoring of children on psychotropic medications may result in changes in physician practice, increasing problems with access to physicians and perhaps worsening outcomes. Despite these many challenges, children can and do benefit from medications when treatment is provided in the context of a thorough diagnostic assessment that integrates information from multiple sources; knowledge of the available data for adults and children in the literature; knowledge of standards of community care, especially when prescribing medications off-label; an analysis of the risks and benefits of treatment options; appropriate involvement of the parent or guardian in the informed consent process; and close monitoring for adverse effects during therapy. REFERENCES AACAP. American Academy of Child and Adolescent Psychiatry practice parameters for the assessment and treatment of children and adolescents with anxiety disorders. J Am Acad Child Adolesc Psychiatry 1997a;10 (Suppl):69S. AACAP. American Academy of Child and Adolescent Psychiatry practice parameter for assessment of children and adolescents. J Am Acad Child Adolesc Psychiatry 1997b;10 (Suppl):49S. AACAP. American Academy of Child and Adolescent Psychiatry practice parameters for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 1997c;10 (Suppl):177S. AACAP. American Academy of Child and Adolescent Psychiatry practice parameter for the assessment and treatment of children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 2002;10 (Suppl):157S. Abilify. Abilify product information. Princeton, NJ: Bristol-Myers Squibb, 2004. Adderall. Adderall product information. Newport, KY: Shire Pharmaceuticals, 2004. Addonizio G, Susman VL, Roth SD. Neuroleptic malignant syndrome: Review and analysis of 115 cases. Biol Psychiatry 1987;22:1004. Adler L, Angrist B, Peselow E, et al. A controlled assessment of propranolol in the treatment of neuroleptic-induced akathisia. Br J Psychiatry 1986;149:42. Alessi N, Bos T. A controlled assessment of propranolol in the t reatment of neuroleptic-induced akathisia. Am J Psychiatry 1991;11:1605. Alessis N, Naylor MW, Ghaziuddin M, et al. Update on lithium carbonate therapy in children and adolescents. J Am Acad Child Adolesc Psychiatry 1999;33:291. Allison DB, Casey DE. Antipsychotic-induced weight gain: A review of the literature. J Clin Psychiatry 2001;62 (Suppl 7):22. Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: A comprehensive research synthesis. Am J Psychiatry 1999;156:1686.

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CHAPTER 40

Pediatric Epilepsy: An Overview Peter R. Camfield and Carol S. Camfield

Epilepsy may be diagnosed after a child has had two or more unprovoked seizures [Camfield et al., 1985a; Shinnar et al., 2000]. The term unprovoked implies that there has been no closely associated concurrent illness, fever, or acute brain injury. Recurrent seizures immediately after a head injury or associated with drug intoxication do not qualify for the diagnosis of epilepsy. Some specific provoking factors leading to reflex seizures are permitted, such as seizures provoked by patterns and flashes from video terminals for children with photosensitive epilepsy. Seizures are still viewed as unprovoked if they occur with stresses related to personal activity, such as sleep deprivation or severe emotional distress, unless these stresses are extreme.

SEIZURE TYPE AND EPILEPSY SYNDROME The definition of epilepsy allows for a tremendous variety of disorders. The seizure types, age of onset, cause, severity, comorbid conditions, response to medication, and clinical course vary widely. There are two main ways of grouping patients to bring an ordered approach to classification, treatment, and prognosis: seizure type and epilepsy syndrome. Both concepts continue to evolve. The International League against Epilepsy defined the seizure types listed in Box 40-1 [Commission on Classification and Terminology of the International League against Epilepsy, 1981]. There is a basic distinction between seizures with a generalized onset that seem to arise everywhere in the cortex at once and seizures with a partial or focal onset that begin in a defined area of cortex. A proposed update in the classification of epileptic seizures suggested that the distinction between simple partial and complex partial seizures is often difficult to assess and not needed [Engel, 2001]. A given seizure type may occur with many different associations. For example, a 2-year-old child with severe mental handicap may have generalized tonic-clonic seizures that are completely resistant to medication, or a normal teenager may have the same seizure type that is completely suppressed by medication. Factors beyond seizure type allow a more comprehensive diagnosis—an epilepsy syndrome diagnosis. Epileptic syndromes may have one or more seizure types, often with a characteristic interictal electroencephalogram. Each syndrome has a defined group of causes, sometimes a clear response to specific treatments, and sometimes a defined clinical course and prognosis. As with seizure types, syndromes have been classified as localizationrelated (focal) or generalized and then subdivided into idiopathic (when a genetic cause is likely), symptomatic (when a diffuse or localized brain abnormality is known), and

cryptogenic (when a diffuse or localized brain abnormality is suspected but unproven) (Table 40-1). In adults, localization-related epilepsy syndromes are most common, are usually symptomatic, and caused by a localized, structural abnormality. Children have similar disorders, but there are many other important syndromes. The idiopathic partial and generalized syndromes all begin in childhood, and genetic influences are significant. The generalized symptomatic syndromes of childhood account for most intractable epilepsy in children [Arzimanogolou et al., 2004; Camfield and Camfield, 2003]. The International League against Epilepsy classified febrile seizures as a special syndrome. Febrile seizures are the most common convulsive event in the human species. Because these seizures are provoked by fever, febrile seizures do not fit well with the usual definition of epilepsy, and few children with febrile seizures later develop unprovoked seizures. The disorder merits special consideration, as reviewed in Chapter 46. The 1989 International League against Epilepsy syndrome classification scheme is still in wide use, and most patients can be “forced” into one of the broad categories, but many children, especially those with symptomatic generalized epilepsy, do not meet the criteria for a more specific syndrome [Commission on Classification and Terminology of the International League Against Epilepsy, 1989]. There are many recently described epilepsy syndromes, but a newer, comprehensive syndrome classification system has been elusive. Advances in genetics have revealed that the same mutation may cause a variety of epilepsy syndromes, including partial and generalized epilepsies, even within the same family (see Chapter 41). The term cryptogenic has been troublesome because it depends on the sophistication of imaging techniques. A new proposal for syndrome classification in 2001 is based on a five-axis system [Engel, 2001]. Axis 1 concerns ictal phenomenology (i.e., what the seizure looks like). Axis 2 is the specific seizure type. Axis 3 is the specific epilepsy syndrome, when it can be defined; axis 4 is the cause; and axis 5 describes the degree of impairment associated with epilepsy. This proposal comes with a more comprehensive list of epilepsy syndromes, although the system is less categorical than the 1989 classification [Commission on Classification and Terminology of the International League against Epilepsy, 1989]. The validity of this proposal remains to be established, but it does serve well to alert the clinician to the many aspects of epilepsy in an individual patient. Table 40-1 summarizes some of the differences in accepted syndromes in the two classification schemes. A physician interested in epilepsy should be conversant with the 1989 and 2001 classification schemes and must anticipate additional revisions.

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TABLE 40-1 International Classification of Epilepsies and Epileptic Syndromes and Related Seizure Disorders of 1989 and Epilepsy Syndromes Recognized in the Proposed 2001 International League against Epilepsy Classification Scheme 1989 ILAE CLASSIFICATION* Localization-Related (Local, Focal, Partial) Epilepsies and Syndromes Idiopathic (with age-related onset) Benign childhood epilepsy with centrotemporal spikes Childhood epilepsy with occipital paroxysms

2001 ILAE PROPOSAL†

Primary reading epilepsy

Benign childhood epilepsy with centrotemporal spikes Early-onset benign childhood occipital epilepsy (Panayiotopoulos type) (new) Late-onset childhood occipital epilepsy (Gastaut type) (new) Idiopathic photosensitive occipital lobe epilepsy (new) Primary reading epilepsy Now called reflex epilepsies, which also include: Other visual sensitive epilepsies Primary reading epilepsy Startle epilepsy

Symptomatic or cryptogenic Chronic progressive epilepsia partialis continua Syndromes characterized by seizures with specific modes of precipitation Temporal lobe epilepsies

No longer listed; see Rasmussen’s syndrome Now a reflex epilepsy

Frontal lobe epilepsies Parietal lobe epilepsies Occipital lobe epilepsies Generalized Epilepsies and Syndromes Idiopathic (with age-related onset) Benign familial neonatal seizures Benign neonatal convulsions Benign myoclonic epilepsy in infancy Childhood absence epilepsy Juvenile myoclonic epilepsy Epilepsy with grand mal seizures on awakening Childhood absence epilepsy Other generalized idiopathic epilepsies Juvenile myoclonic epilepsy

Epilepsies with seizures precipitated by specific modes of activation Cryptogenic or symptomatic West’s syndrome Lennox-Gastaut syndrome Epilepsy with myoclonic-astatic seizures Epilepsy with myoclonic seizures Epilepsy with myoclonic absences Early infantile epileptic encephalopathy with suppression burst Early myoclonic encephalopathy Other symptomatic generalized epilepsies

Limbic epilepsies (expanded) Mesial temporal lobe epilepsy with hippocampal sclerosis Mesial temporal lobe epilepsy defined by specific causes Other types defined by location and cause Neocortical epilepsies (new) Rasmussen’s syndrome (new) Hemiconvulsion-hemiplegia syndrome Migrating partial seizures of infancy (new) Other types defined by location and cause (new) Familial temporal lobe epilepsies (new) Familial focal epilepsy with variable foci (new) No longer listed, because location or onset of seizures is insufficient for classification of a syndrome No longer listed, because location or onset of seizures is insufficient for classification of a syndrome No longer listed, because location or onset of seizures is insufficient for classification of a syndrome

Benign familial neonatal seizures Benign neonatal convulsions (diagnosis of epilepsy not required) Benign myoclonic epilepsy in infancy Benign familial infantile seizures Benign infantile seizures (nonfamilial) Childhood absence epilepsy Juvenile absence epilepsy (new) Juvenile myoclonic epilepsy Epilepsy with generalized tonic-clonic seizures only (renamed) Childhood absence epilepsy Other undetermined epilepsies not defined above Juvenile absence epilepsy (new) Juvenile myoclonic epilepsy Landau-Kleffner syndrome (LKS) (new) Epilepsy with continuous spike and waves during slow-wave sleep (other than LKS) (new) Progressive myoclonus epilepsies (new) Now called reflex epilepsies

West’s syndrome Lennox-Gastaut syndrome Epilepsy with myoclonic-astatic seizures No longer listed Epilepsy with myoclonic absences Ohtahara’s syndrome (renamed) Early myoclonic encephalopathy Myoclonic status in progressive encephalopathies (new)

Camfield and Camfield / Pediatric Epilepsy: An Overview

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TABLE 40-1, cont’d International Classification of Epilepsies and Epileptic Syndromes and Related Seizure Disorders of 1989 and Epilepsy Syndromes Recognized in the Proposed 2001 International League against Epilepsy Classification Scheme 1989 ILAE CLASSIFICATION* Specific Syndromes Epileptic seizures complicating other disease states Epilepsies and syndromes undetermined whether focal or generalized with generalized and focal seizures Neonatal seizures Severe myoclonic epilepsy of infancy Epilepsy with continuous spike waves during slow-wave sleep Acquired epileptic epilepsies (Landau-Kleffner syndrome)

2001 ILAE PROPOSAL†

No longer listed Dravet’s syndrome (renamed) Epilepsy with continuous spike waves during slow-wave sleep (not LKS) Acquired epileptic epilepsies (renamed) (Landau-Kleffner syndrome) Generalized epilepsies with febrile seizures plus (new) Autosomal dominant nocturnal frontal lobe epilepsy

Other undetermined epilepsies without unequivocal generalized or focal features Special Syndromes Situation-related seizures Febrile convulsions Isolated seizures of isolated status epilepticus Seizures occurring only with acute metabolic or toxic events

Febrile seizures (renamed) No longer listed Drug or other chemically induced seizures (expanded) Alcohol-withdrawal seizures Single seizures or isolated clusters of seizures Rarely repeated seizures (oligoepilepsy) Immediate and early post-traumatic seizures

*Modified from the 1989 International League against Epilepsy (ILAE) Proposal. † Modified from the 2001 ILAE Proposal. In this proposal, there are no headings or subheadings, only a listing of epilepsy syndromes by specific syndrome name. This presentation indicates where syndromes are removed or renamed from the 1989 ILAE proposal or are newly recognized in the 2001 proposal. Each syndrome was “forced” into the 1989 proposed schema. Adapted from Engel J. A proposed diagnostic scheme for people with epileptic seizures and epilepsy: Report of the ILAE task force on classification and terminology. Epilepsia 2001;42:796, and from Commission on Classification and Terminology of the International League against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389.

INCIDENCE The overall incidence of childhood epilepsy from birth to 16 years is approximately 40 cases in 100,000 children per year [Camfield et al., 1996b; Hauser et al., 1993]. The incidence in the first year of life is about 120 in 100,000. Between 1 and 10 years of age, the incidence plateaus at 40 to 50 cases in 100,000 children and then drops further in the teenage years to about 20 in 100,000. The details of

FIGURE 40-1. Incidence of epilepsy by age of onset. (From Camfield CS, Camfield PR, Wirrell E, et al. Incidence of epilepsy in childhood and adolescents: A population based study in Nova Scotia from 1977-1985. Epilepsia 1996b;37:19.)

incidence by year of life from the Nova Scotia childhood epilepsy study are illustrated in Figure 40-1. Hauser estimates that about 1% of all children will have at least one afebrile seizure by age 14 years and that 0.4% to 0.8% will have epilepsy by age 11 years [Hauser and Hesdorffer, 1990]. Epilepsy types vary in incidence. Syndromes dominated by generalized tonic-clonic or partial seizures account for 75% of childhood epilepsy. Syndromes dominated by absence seizures account for approximately 15%, and the secondary generalized epilepsies account for 10%. The latter group includes most of the “catastrophic” epilepsy syndromes, such as West and Lennox-Gastaut syndromes [Camfield et al., 1996b]. Prevalence data for seizure type or epilepsy syndrome are not easily collated because of various definitions of active epilepsy. When active epilepsy was defined as receiving daily antiepileptic drugs or a seizure within the past 5 years, the prevalence of epilepsy in children was 4.3 to 9.3 in 1000 [Hauser and Hesdorffer, 1990]. Because some epileptic syndromes rarely remit, they contribute more to prevalence of epilepsy than its incidence. The relative prevalence of symptomatic generalized epilepsies is higher than their relative incidence. This finding means that physicians who focus on newly diagnosed children will encounter a predominance of benign epilepsy syndromes. Those primarily treating chronic cases will observe a higher proportion of more malignant seizure disorders. A population-based prevalence study from Finland

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found that the main seizure types for each patient were focal in 43%, with complex partial and partial with secondary generalization most common. For 44%, generalized seizures were dominant, with generalized tonic-clonic seizures most common. Overall, 45% had localization-related epilepsy syndromes, and 48% had generalized syndromes [Eriksson and Koivikko, 1997].

DIFFERENTIAL DIAGNOSIS The diagnosis of epilepsy is based almost exclusively on a clinical history of two or more unprovoked seizures [Van Donselaar et al., 1989]. Parents vary in their capacity to describe these frightening events, and physicians vary in their ability to ask good questions. Some children are misdiagnosed. A Dutch group of neurologists shared case descriptions of childhood seizure disorders and were able to agree about most diagnoses of epilepsy. However, even experts sometimes disagree. Studies of interobserver reliability have demonstrated important differences in

BOX 40-1 INTERNATIONAL CLASSIFICATION OF SEIZURE TYPE Partial Seizures Simple partial seizures With motor signs With somatosensory or special sensory hallucinations With autonomic symptoms With psychic symptoms Complex partial seizures Simple partial followed by impairment of consciousness With impaired consciousness at onset Partial seizures evolving to secondary generalized seizures Simple partial seizures evolving to generalized Complex partial seizures evolving to generalized Simple partial seizures evolving to complex partial seizures Generalized Seizures Absence seizures Atypical absence seizures Myoclonic seizures Clonic seizures Tonic seizures Tonic-clonic seizures Atonic seizures Unclassifiable Epileptic Seizures Adapted from the Commission on Classification and Terminology of the International League against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489.

BOX 40-2 DISORDERS THAT MAY MIMIC CHILDHOOD EPILEPSY Confused with Generalized Tonic-Clonic Seizures Pallid syncope (reflex anoxic seizure) Vasodepressor syncope (reflex anoxic seizure) Cyanotic breath-holding attacks Collapsing attacks with cardiac dysrhythmias Cataplexy Confused with Generalized Absence Seizures Behavioral staring attacks Complex partial seizures Tic disorder Confused with Complex Partial Seizures Self-stimulatory behavior, especially in children with autistic spectrum disorders Sleep walking Night terrors Temper tantrums with amnesia for the rage event Benign paroxysmal vertigo Migraine-related disorders [Dooley, 1990] Confused with Epileptic Myoclonus Physiologic hypnagogic myoclonus Benign infantile sleep myoclonus Startle disease

observations when families and neurologists have reviewed the same video seizures, and neurologists often disagree with each other. Neurology residents and faculty often classify seizures differently based on written histories [Camfield and Camfield, 2003]. When the history is not clear-cut, it is better to wait for additional attacks before diagnosing epilepsy. A list of disorders in children that are frequently confused with epilepsy is found in Box 40-2. Reflex anoxic seizures associated with pallid or vasodepressor syncope or with cyanotic breath-holding are particularly likely to be misinterpreted [Stephenson, 1991] (see Chapter 53). The electroencephalogram can be used to make the diagnosis of epilepsy only if a seizure is recorded—a rare event on routine electroencephalographic (EEG) acquisition because most children with epilepsy have infrequent seizures. A small percentage of normal children have epileptiform activity on electroencephalograms but never have a seizure [Petersen and Eeg-Olofsson, 1968], and up to 40% of children with chronic epilepsy never demonstrate epileptiform discharges on interictal electroencephalograms [Camfield et al., 1995]. EEG findings may change significantly over time and reveal conflicting findings [Camfield et al., 1995; Trojaborg, 1968]. An interictal electroencephalogram is often useful for syndrome clarification but must be interpreted in the clinical context. Likewise, the diagnosis of epilepsy cannot be based on brain-imaging studies. The presence of an anomaly on magnetic resonance imaging increases the possibility of epilepsy and, depending on the nature of the abnormality, increases the likelihood of a specific syndrome. For example, lesions typical of tuberous sclerosis in the first year of life increase the risk that a child will have West’s syndrome.

Camfield and Camfield / Pediatric Epilepsy: An Overview

NATURAL HISTORY OF CHILDHOOD EPILEPSY Recurrence after a First Seizure Many children are seen by a physician after a first unprovoked generalized tonic-clonic seizure, a few after a first complex partial seizure, but almost none after a single absence or myoclonic seizure. For children presenting after a single unprovoked seizure, there is an immediate question: Will it happen again? Berg and Shinnar’s meta-analysis of the recurrence risk after a first seizure concluded that, overall, about 40% will have a second seizure [Berg and Shinnar, 1991; Shinnar et al., 1996]. There is much less information about the further recurrence risk after a second seizure, especially if medication is withheld. Current data suggest that the risk of a third seizure after a second is at least 80% [Camfield et al., 1985b; Shinnar et al., 2000]. These observations validate the restriction of the diagnosis of epilepsy to those with two or more unprovoked seizures, because the concept of epilepsy implies a chronic, recurring disorder. If a child has a single seizure, a small number of clinical features are helpful to predict the risk of a second seizure. These include remote symptomatic cause, partial seizures, presence of intellectual or mental handicap, and possibly EEG spike discharge [Berg and Shinnar, 1991]. A normal child with a first generalized tonic-clonic seizure and a normal electroencephalogram has a recurrence risk of 20% to 30%, whereas a child with mental handicap, a partial seizure, and spike discharge on the electroencephalogram has a recurrence risk of 80% to 90% [Berg and Shinnar, 1991; Camfield et al., 1985b]. If a second seizure is to occur, it usually happens shortly after the first. At least 75% of recurrences happen within 6 months of the first, and most occur within a few weeks. Few recurrences are observed after 2 years. Very few children presenting with a first seizure develop severe epilepsy. Of 407 children with a first seizure identified by Shinnar and colleagues [2000], only 13% went on to have more than 10 seizures over the next 10 years. However, 28% of those with two seizures had more than 10 subsequent seizures.

Starting Medication Treatment There is little justification for beginning daily medication after a child’s first unprovoked seizure because 60% of these children will never have another attack [Van Donselaar et al., 1989.] Population-based studies have found that medication prescription after the first seizure does not alter the recurrence rate, probably because of poor compliance in taking the medication [Camfield et al., 1985b; Hauser et al., 1982; Hirtz et al., 1984]. An open-label, randomized trial of medication versus no medication after a first seizure in 397 children and adults demonstrated a significant reduction in recurrences for those on medication over a 2-year treatment period [First Seizure Trial Group, 1993]. The risk of recurrence without treatment was 51% by 24 months, but there were still relapses in 25% of those randomized to medication (i.e., 2.8 times higher; 95% confidence interval [CI ], 1.9 to 4.2). When this cohort was followed for several more years, the eventual remission rate was the same for those treated or untreated after the first seizure [Musicco et al., 1997].

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It has become common practice to prescribe medication after a second seizure. There is no evidence that the prescription of medication alters the long-term outlook of childhood epilepsy. There is convincing information that delaying antiepileptic drug treatment until the child has had up to 10 seizures does not alter the ease of seizure control or the long-term remission rate [Camfield et al., 1996a]. In other words, if a child has few seizures, there is no evidence that each seizure facilitates the next. The main reasons to treat children with antiepileptic drugs are the avoidance of bodily injury from seizures and improvement in psychosocial function. Results from several studies indicate that injury is uncommon with most seizure types in children. Peters and associates [2001] described 79 children with benign rolandic epilepsy who together had more than 900 seizures over an 8.5-year period. There were no significant injuries. In a group of 59 children with generalized absence seizures followed over 15 years, Wirrell and colleagues [1997] observed that 16 had a serious physical injury as the result of a seizure. Kirsch and colleagues [2001] compared 31 cognitively normal children with epilepsy with bestfriend controls and found no significant differences in injury number or severity. Hodgman and co-workers [1979] described 25 adolescents with generalized tonic-clonic epilepsy and observed that those with poorer seizure control were better able to communicate about seizures and had a better self-image. The “hidden handicap” for children with controlled seizures may have important effects on social adjustment. When medication is started, most children still have more seizures. Only about 20% have “smooth-sailing epilepsy,” meaning that they start medication, become immediately seizure free, and later are able to successfully discontinue medication without ever having another seizure [Camfield et al., 1993]. Only 50% of children continue to receive the same medication 1 year after initiating treatment [Camfield et al., 1985b; Canadian Childhood Epilepsy Study Group, 1996; Verity et al., 1995]. The decision to start medication is often not the end of the seizure problem.

Long-Term Remission For many children, epilepsy is transient, and with maturation, the problem seems to vanish. At the time of diagnosis, it is possible to predict that at least 50% of children will outgrow their disorder and be able to discontinue medication [Camfield et al., 1993]. The Dutch Study of Epilepsy in Childhood followed 453 newly diagnosed children and found that 64% were no longer receiving medication 5 years later [Arts et al., 2004]. The longer the follow-up, the higher the proportion with remission of symptoms. In Rochester, Minnesota, 115 children with epilepsy beginning before age 10 years were followed through the Mayo Clinic record linkage system. Ten years later, 75% had been seizure free for at least 5 years, and 51% no longer received medication [Hauser et al., 1993]. At the end of a remarkable 30-year follow-up study of children with epilepsy from a population-based sample in Turku, Finland, Sillanpaa [1993] found that 76% of survivors had been seizure free for at least 3 years. Across most studies, factors that predict which children will outgrow their epilepsy have included normal intel-

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TABLE 40-2 Scoring System for Remission of Childhood Epilepsy at the Time of Diagnosis VARIABLE Age of first seizure (months) <12 12 to 144 >144 Intelligence Normal Retardation Previous neonatal seizures No Yes Number of seizures before starting medication 1 or 2 3 to 20 >20

SCORE* 99 142 0 111 0 218 0 72 123 0

*Add the scores from this column. If the total score is greater than 495, the child is predicted to have remission of epilepsy. Adapted from Sillanpaa M, Camfield PR, Camfield CS. Predicting long term outcome of childhood epilepsy in Nova Scotia, Canada, and Turku: Validation of a simple scoring system. Arch Neurol 1995;52:589.

ligence, normal neurologic examination findings, relatively small numbers of seizures at diagnosis (possibly a proxy measure for complex partial seizures), age of the first seizure younger than about 12 years, and absence of a remote symptomatic cause (an identified brain problem that preceded the onset of epilepsy). In an 8-year follow-up study of a population-based study of 504 children with epilepsy from Nova Scotia, a predictive scoring system was developed; it is outlined in Table 40-2 [Sillanpaa et al., 1995]. Those with a good prognosis had an 80% chance of remission (i.e., seizure free and no longer receiving medication). For those with one or more of these adverse factors, the chance of remission was less but still about 40%. The Dutch Study of Epilepsy in Childhood found comparable predictive variables and supplemented these with the clinical course in the first 6 months of treatment. Rates of correct prediction were similar. Based on clinical features present at the time of diagnosis, it is possible to predict the long-term outcome with moderate accuracy. Surprisingly, most epilepsy syndromes do not have a definite outcome; however, a few specific syndromes allow an accurate prognosis [Camfield et al., 2003]. Epilepsy is always outgrown in cases of benign rolandic epilepsy, benign myoclonic epilepsy of infancy, and benign occipital epilepsy, early-onset type. Epilepsy is never outgrown by children with Rasmussen’s syndrome, Lennox Gastaut syndrome, or Dravet’s syndrome.

Stopping Medication About 70% of children with epilepsy who have become seizure free for 1 to 2 years can successfully stop medication treatment [Berg and Shinnar, 1991; Dooley et al., 1996]. The rate of success is no greater if medication is continued for up to 5 years seizure free [Hollowach-Thurston et al., 1982]. Factors that predict successful discontinuation of medication include generalized seizures, age of onset before 10 to 12 years, normal neurologic examination, and in some studies, resolution of interictal EEG spike discharges. Chil-

dren with no adverse factors may have an 80% to 90% success rate. Each factor has an additive effect and those with all of the adverse factors may have only a 10% to 20% success rate. If an initial discontinuation trial is unsuccessful, medication is usually restarted. About 50% of children again become seizure free for sufficient time to try to discontinue medication a second time, with a 70% success rate [Camfield et al., 1993]. The remission rate for juvenile myoclonic epilepsy is so low that further attempts to discontinue medication after an initial failure are probably not warranted [Delgado-Escueta and Enrile-Bacsal, 1984]. A Scandinavian study randomized 207 children at the time of diagnosis of epilepsy to receive 1 or 3 years of treatment [Braathen and Melander, 1997]. If the child was seizure free for the last 6 months of study, medication was discontinued. This practice meant that some of the children in the 1-year treatment group had been seizure free for only 6 months before medication was stopped. The success rate for those in the short-treatment group was significantly less than for the 3-year group (53% versus 71%). A Dutch study randomized 161 children with epilepsy that was controlled within 2 months of starting treatment to 6 months or 1 year of treatment. The 6-month group had a higher relapse rate when medication was stopped; however, by 2 years later, the rates of remission were identical [Peters et al., 1998]. Nonetheless, for a substantial number of children, epilepsy was a short-lived disorder requiring only short-term medication use. Medication treatment for benign rolandic epilepsy often is not needed [Peters et al., 2001], and further studies will likely identify other children who do not require drug treatment.

Intractability Defining intractable epilepsy is difficult, and many definitions have been suggested. For a study of 613 children with epilepsy from Connecticut, Berg and Shinnar [2001] defined intractability as a “failure, for lack of seizure control, of more than 2 first-line antiepileptic drugs with an average of more than one seizure per month for 18 months and no more than 3 consecutive months seizure free during that interval.” There were 60 intractable cases in the first 24 months after diagnosis. The proportions of intractable patients in each major syndrome grouping were as follows: cryptogenic/symptomatic generalized, 34.6%; idiopathic generalized, 2.7%; other localization-related, 10.7%; and unclassified, 8.2%. Sillanpaa’s [1993] follow-up study from Turku, Finland, defined intractability as one or more seizures per year in the past 10 years of follow-up. After 20 years of follow-up, 22% of the subjects met these criteria. Predictors of intractability included poor initial response to medication, remote symptomatic cause, and status epilepticus. The Dutch Study of Childhood Epilepsy (using Berg and Shinnar’s definition of intractability), with 453 children followed for 5 years, found that 6% were intractable [Arts et al., 2004]. Camfield and colleagues [1993] defined intractability as “at least one seizure each three months for the last year of follow-up, with failure of at least 3 antiepileptic drugs.” For those with partial and generalized tonic-clonic epilepsies, 8% of 511 children became intractable during an average of 8 years of follow-up. After 20 years of follow-up,

Camfield and Camfield / Pediatric Epilepsy: An Overview

51% of 75 patients with childhood-onset symptomatic generalized epilepsy had intractable seizures. In this study, the major predictor was severe neurologic deficit at the time of diagnosis. An important issue in the definition of intractability is the length of follow-up. In the clinical setting, many children with intractable epilepsy eventually become well controlled. In a series of 145 children with intractable seizures (i.e., less than one per month for at least 2 years) followed over 18 years, Huttenlocker and Hapke observed that 75% of normally intelligent children and 30% with mental handicap had complete or nearly complete seizure remission (i.e., less than one seizure per year). In the Nova Scotia cohort, 39 patients with partial and generalized tonic-clonic epilepsies had intractable epilepsy after 7 years’ follow-up. After 12.5 years of followup, 7 (18%) of 39 became seizure free [Camfield et al., 1996a]. There is controversy about how many drug failures are required before intractability can be declared. In a Scottish study of 470 newly treated adults, 47% became seizure free with their first antiepileptic drug [Kwan and Brodie, 2000]. Only 11% gained control with subsequent medications. In children, the failure of a first drug is important but far less ominous [Camfield et al., 1997]. Of 417 eligible patients with partial and generalized tonic-clonic epilepsies with at least 4 years of follow-up, 83% were successfully treated with a single antiepileptic drug during the first year of treatment. Of these, 61% eventually had remission of epilepsy, and 4% had intractable seizures. Among the 17% who failed treatment with their first antiepileptic drug, 42% eventually had complete remission of epilepsy, although 29% developed intractable seizures. Children with absence epilepsies had nearly identical findings [Wirrell et al., 2001]. In summary, intractability for an individual child is difficult to predict before several years of antiepileptic drug treatment. Intractability appears to decrease with prolonged follow-up, although the burden of this wait-and-see approach may be substantial. Failure of a first antiepileptic drug is a risk factor for intractability but nonetheless many remit. As a general rule, consideration for epilepsy surgery should await failure of three appropriate drug treatments. Other factors influence this decision, including seizure severity, frequency, and duration of epilepsy.

Psychosocial Outcome for Children with Epilepsy Children with epilepsy have high rates of behavior and cognitive problems that contribute to social dysfunction in childhood and in later adulthood even if the epilepsy resolves. These issues are reviewed in more detail in Chapter 51. Austin and colleagues [2002] reported that at the time of diagnosis, 40% of children were at significant risk of behavior problems, as judged by scores on the Child Behavior Checklist. Those with multiple recurrent seizures were at even higher risk. The Isle of Wight study found that children with epilepsy had high rates of behavioral disorders [Rutter et al., 1970], which might have had their origins in social stigmatization, comorbid cognitive disorders, or medication effects. Oostrom and colleagues [2003] demonstrated greater cognitive and behavioral problems and the need for special educational assistance among 51 outpatient children with idiopathic or cryptogenic epilepsy compared with their classmate controls. Trostle [1988] reported that

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parents indicate a reluctance to have their normal children play with a child with epilepsy. Less than one third of 20,000 U.S. high school students indicated that they would date a person with epilepsy [Austin et al., 2002]. These behavioral, cognitive, and social stigma problems in childhood all point to grave concerns for the social adjustment and success of children with epilepsy after they reach adulthood. Kokkonen and colleagues [1997] described the social outcome (by interview or questionnaire) of 81 young, “noninstitutionalized” adults from the catchment area of Oulu, Finland, compared with 211 randomly selected controls from the same birth cohort. At least 20% of this sample were unable to complete 9 years of education and presumably had severe learning disorders or mental retardation. They accounted for most of the poor social outcome, including a high rate of educational failure, failure to marry, and unemployment. In Nova Scotia and Finland, children with epilepsy only were followed into young adulthood [Camfield et al., 1993; Jalava et al., 1997]. Epilepsy only meant having normal intelligence and no other neurologic handicaps. About 30% of each cohort had significant social adjustment problems with decreased rates of stable relationships, marriage, social contacts, job satisfaction, and work achievement. Rates of unemployment or underemployment were high. Social outcome was not clearly related to epilepsy remission, and in the Nova Scotia study, variables related directly to epilepsy, such as age of onset, type of medication treatment, presence or absence of seizure remission, and frequency and severity of seizures, did not appear to predict social outcome in young adulthood [Camfield et al., 1993]. The strongest predictor of poor social outcome was the presence of a learning disorder, although predictive models were inaccurate; the main reasons for the unsatisfactory outcomes were unclear. Wakamoto and colleagues [2000] studied 148 normally intelligent young adults (>20 years old) living in a rural district of Japan who had childhood-onset epilepsy. This population-based study found that 72% attended regular classes (versus 99% of those without epilepsy), 66% (versus 97%) entered high school, 67% (versus 95%) had employment, and 23% (versus 33%) married. There were 49 patients with mental handicap having a less satisfactory outcome: 14% attended regular class, 6% entered high school, 20% were employed, and 2% married. Few studies have addressed the social outcome of children with specific epilepsy syndromes. Several studies have indicated a favorable outcome for adults with previous benign rolandic epilepsy (Loiseau et al., 1983; Peters et al., 2001]. In the Nova Scotia study, 56 children with typical Childhood absence epilepsy were followed to young adulthood [Wirrell et al., 1997] and compared with a similar cohort with mild juvenile rheumatoid arthritis. Those with absence had significantly greater problems with impulsive behavior, including a 34% risk of an unplanned pregnancy. Educational and work achievement, family and other social relationships, and alcohol abuse were more often unsatisfactory. Those with ongoing seizures despite medication had greater problems; however, most of the poor social outcome was unrelated to epilepsy-specific factors. Childhood epilepsy may have a life-long, serious effect on social function, an effect that is greater than some other

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chronic disorders of childhood. Intervention studies have not been undertaken; however, the role of learning disorders and inadequate education is clear. If the long-term social outcome is to be rectified, physicians must address these areas with equal enthusiasm to the drug treatment of childhood epilepsy. Early referral to an epilepsy support group may be of benefit. REFERENCES Arzimanogolou A, Guerrini R, Aicardi J. Epilepsy in children, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2004. Arts WF, Brouwer OF, Peters AC, et al. Course and prognosis of childhood epilepsy: 5-year follow-up of the Dutch study of epilepsy in childhood. Brain 2004;127:1774. Austin JK, Shafer PO, Deering JB. Epilepsy familiarity, knowledge, and perceptions of stigma: Report from a survey of adolescents in the general population. Epilepsy Behav 2002;3:368. Berg AT, Shinnar S. The risk of seizure recurrence following a first unprovoked seizure: A meta-analysis. Neurology 1991;41:965. Braathen G, Melander H. Early discontinuation of treatment in children with uncomplicated epilepsy: A prospective study with a model for prediction of outcome. Epilepsia 1997;38:561. Camfield PR, Camfield CS. Nova Scotia Pediatric Epilepsy Study. In: Jallon P, ed. Prognosis of childhood epilepsy. London: John Libby Publishers, 2003. Camfield CS, Camfield PR, Gordon K, et al. Does the number of seizures before treatment influence ease of control or remission of childhood epilepsy? Not if the number is 10 or less. Neurology 1996a;46:41. Camfield CS, Camfield PR, Gordon K, et al. Outcome of childhood epilepsy: A population-based study with a simple predictive scoring system for those treated with medication. J Pediatr 1993;122:861. Camfield CS, Camfield PR, Wirrell E, et al. Incidence of epilepsy in childhood and adolescents: A population based study in Nova Scotia from 1977-1985. Epilepsia 1996b;37:19. Camfield PR, Camfield CS, Dooley JM, et al. Epilepsy after a first unprovoked seizure in childhood. Neurology 1985a;35:1657. Camfield PR, Camfield CS, Smith E, et al. Newly treated childhood epilepsy: A prospective study of recurrences and side effects. Neurology 1985b;35:722. Camfield PR, Camfield CS, Gordon K, Dooley JM. If a first antiepileptic drug fails to control a child’s epilepsy, what are the chances of success with the next drug? J Pediatr 1997;131;821–824. Camfield PR, Gordon K, Camfield CS, et al. EEG results are rarely the same if repeated within six months in childhood epilepsy. Can J Neurol Sci 1995;22:297. Canadian Childhood Epilepsy Study Group. Monotherapy clobazam has equivalent efficacy to carbamazepine and phenytoin in childhood epilepsy. Epilepsia 1996;37:117. Commission on Classification and Terminology of the International League against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489. Commission on Classification and Terminology of the International League against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389. Delgado-Escueta AV, Enrile-Bacsal F. Juvenile myoclonic epilepsy of Janz. Neurology 1984;34:285. Dooley J, Gordon K, Camfield P. “The rushes.” A migraine variant with hallucinations of time. Clin Pediatr 1990;29:536. Dooley JM, Gordon K, Camfield PR, et al. Discontinuation of anticonvulsant therapy in children free of seizures for 1 year. Neurology 1996;46:969. Engle J. International League against Epilepsy (ILAE). A proposed diagnostic scheme for people with epileptic seizures and with epilepsy. Report of the ILAE Taskforce on Classification and Terminology. Epilepsia 2001;42:796–803. Eriksson KJ, Koivikko MJ. Prevalence, classification, and severity of epilepsy and epileptic syndromes in children. Epilepsia 1997;38:1275. First Seizure Trial Group. Randomized clinical trial on the efficacy of antiepileptic drugs in reducing the risk of relapse after a first unprovoked tonic-clonic seizure. Neurology 1993;43:478.

Hauser WA, Anderson VE, Loewneson RB, et al. Seizure recurrence after a first unprovoked seizure. N Engl J Med 1982;307:522. Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935-84. Epilepsia 1993;34:453. Hauser WA, Hesdorffer DC. Epilepsy, frequency, causes, and consequences. New York: Demos Publications, 1990. Hirtz DG, Ellenberg JH, Nelson KB. The risk of recurrence of non-febrile seizures in children. Neurology 1984;34:637. Hirtz D, Berg A, Bettis D, et al. Practice parameter: Treatment of the child with a first unprovoked seizure: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2003;60:166–175. Hodgman CH, McAnarney ER, Myers GJ, et al. Emotional complications of adolescent grand mal epilepsy. J Pediatr 1979;95:309. Hollowach-Thurston J, Thurston DL, Hixton BB, et al. Prognosis of childhood epilepsy: Additional follow-up study of 148 children 15–23 years after withdrawal of anticonvulsant therapy. N Engl J Med 1982;306:831. Huttenlocker PR, Hapke RJ. A follow-up study of intractable seizures in childhood. Ann Neurol 1990;28;699–705. Jalava M, Sillanpaa M, Camfield CS, et al. Social adjustment and competence 35 years after onset of childhood epilepsy: A prospective controlled study. Epilepsia 1997;38:708. Kirsch R, Wirrell E. Do cognitively normal children with epilepsy have a higher rate of injury than their nonepileptic peers? Child Neurol 2001;16:100–104. Kokkonen J, Kokkonen ER, Saukkonen AL, Pennanen P. Psychosocial outcome of young adults with epilepsy in childhood. J Neurol Neurosurg Psychiatry 1997;62:265–268. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342:314–319. Loiseau P, Pestre M, Dartigues JF, et al. Long term prognosis in two forms of childhood epilepsy. Typical absence seizures and epilepsy with rolandic (centrotemporal) EEG foci. Ann Neurol 1983;13:642–648. Musicco M, Beghi E, Solari A, Viani F. Treatment of first tonic-clonic seizure does not improve the prognosis of epilepsy. First Seizure Trial Group (FIRST Group). Neurology 1997;49:991. Oostrom KJ, Smeets-Schouten A, Kruitwagen CL, et al. Not only a matter of epilepsy: early problems of cognition and behavior in children with “epilepsy only”—a prospective, longitudinal, controlled study starting at diagnosis. Pediatrics 2003;112(Pt 1):1338. Peters AC, Brouer OF, Geerts AT, et al. Randomized prospective study of early discontinuation of AEDs in children with epilepsy Neurology 1998;50:724–730. Peters J, Camfield CS, Camfield PR. Benign rolandic epilepsy can be safely managed without medication: A population-based study. Neurology 2001;57:537. Petersen O, Eeg-Olofsson O. Paroxysmal activity in EEG of normal children. In: Kelleway P, Peterson I, eds. Clinical electroencephalography of children. New York: Grune & Stratton, 1968. Rutter M, Graham P, Yule W. A neuropsychiatric study in childhood. Clin Dev Med 1970;35/36:175. Shinnar S, Berg AT, Moshe SL, et al. The risk of seizure recurrence after a first unprovoked afebrile seizure in childhood: An extended follow-up. Pediatrics 1996;98:216. Shinnar S, Shinnar S, Berg AT, et al. Predictors of multiple seizures in a cohort of children prospectively followed from the time of their first unprovoked seizure. Ann Neurol 2000;48:140–147. Sillanpaa M. Remission of seizures and predictors of intractability in long-term follow-up. Epilepsia 1993;34:930. Sillanpaa M, Camfield PR, Camfield CS. Predicting long term outcome of childhood epilepsy in Nova Scotia, Canada, and Turku, Finland: Validation of a simple scoring system. Arch Neurol 1995;52:589. Stephenson JB. Fits and faints. Philadelphia: JB Lippincott, 1991. Trojaborg W. Changes in spike foci in children. In: Kelleway P, Peterson I, eds. Clinical electroencephalography of children. New York: Grune & Stratton, 1968. Trostle JA. Social aspects of epilepsy. In: Hauser WA, ed. Current trends in epilepsy, Unit 1. Landover, MD: Epilepsy Foundation of America, 1988. Van Donselaar CA, Geerts AT, Meulstee J, et al. Reliability of the diagnosis of a first seizure.Neurology 1989;39:267–271.

Camfield and Camfield / Pediatric Epilepsy: An Overview Verity CM, Hosking G, Easter DJ. A multicentre comparative trial of sodium valproate and carbamazepine in paediatric epilepsy. The Paediatric EPITEG Collaborative Group. Dev Med Child Neurol 1995;37:97–108. Wakamoto H, Nagao H, Hayashi M, et al. Long-term medical, educational, and social prognoses of childhood-onset epilepsy: A population-based study in a rural district of Japan. Brain Dev 2000;22:246. Wirrell E, Camfield CS, Camfield PR, et al. Long-term psychosocial outcome in typical absence epilepsy: Sometimes a wolf in sheep’s clothing. Arch Pediatr Adolesc Med 1997;151:152. Wirrell E, Camfield C, Camfield P, Dooley J. Prognostic significance of failure of the initial antiepileptic drug in children with absence epilepsy. Epilepsia 2001;42:760–763.

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SUGGESTED READING Arzimanogolou A, Guerrini R, Aicardi J. Epilepsy in children, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2004. Freeman JM, Vining EPG, Pillas DJ. Seizures and epilepsy in childhood: A guide, 3rd ed. Baltimore: Johns Hopkins University Press, 2003. Devinsky O. Epilepsy patient and family guide, 2nd ed. Philadelphia: FA Davis, 2002. Devinsky O, Westbrook LE. Epilepsy and developmental disabilities. Woburn, MA: Butterworth-Heinemann, 2002. Jallon P. Prognosis of epilepsies. London: John Libby, 2003. Roger J, Bureau M, Dravet C, et al. Epileptic syndromes in infancy, childhood and adolescence, 3rd ed. London: John Libby, 2003. Wyllie E. The treatment of epilepsy: Principles and practice, 3rd ed. Philadelphia: Lea & Febiger, 2001.

CHAPTER 41

Neurophysiology of Epilepsy Jong M. Rho and Carl E. Stafstrom

Epilepsy is defined by the occurrence of recurrent spontaneous seizures arising from aberrant electrical activity within the brain. Such electrical activity is the net product of biochemical processes at the cellular level occurring in the context of large neuronal networks, and it likely involves cortical and several key subcortical structures. The output of this activity is reflected on the surface electroencephalogram (EEG), which is the primary clinical tool with which normal and abnormal electrical activities in the brain are measured. At the cellular level, the two hallmark features of epileptiform activity are neuronal hyperexcitability and neuronal hypersynchrony. However, a single neuron discharging abnormally is insufficient to produce a temporary disruption of brain function; generally, a focal interictal discharge on an EEG cannot be seen unless a minimum of 1 to 2 cm2 of cortex exhibits increased excitability and synchrony [Niedermeyer and Lopes da Silva, 1999]. The cellular mechanisms of seizure genesis should always be viewed in this larger context. In many ways, clinical neurophysiologists and cellular electrophysiologists study the same phenomenon at macroscopic and microscopic levels. Although an extensive discussion of electricity and field theory is beyond the scope of the present discussion, it is helpful to understand the basic mechanisms that regulate neuronal activity. This chapter reviews the cellular basis for focal and generalized seizure activity (with specific attention to ion channels, the essential currency of neuronal excitability) and the factors that influence the enhanced susceptibility of the immature brain to seizures. The actions of antiepileptics that target the same ion channels that are required for normal brain function are summarized.

Generalized seizures begin with abnormal electrical discharges in both hemispheres and critically involve reciprocal thalamocortical connections (see Fig. 41-1). The electroencephalographic signature of a primary generalized seizure is bilaterally synchronous spike-wave discharges seen across all scalp electrodes. The manifestations of such widespread epileptiform activity can range from brief impairment of consciousness (e.g., an absence seizure) to rhythmic jerking movements of all extremities accompanied by loss of posture and consciousness. Although there are differences in the mechanisms that underlie partial and generalized seizure activity, it is still useful to view any seizure activity as a perturbation in the normal balance between inhibition and excitation in a localized region, in multiple areas (but linked in a multinodal network), or throughout the whole brain [McCormick and Contreras, 2001; Faingold, 2004]. This imbalance is likely a combination of increased excitation and decreased inhibition and, perhaps somewhat paradoxically, in some instances increased inhibition impinging on individual cells. However, it is important to recognize that epilepsy is not a singular disease. It is heterogeneous in terms of clinical expression, underlying causes, and pathophysiology (Table 41-1). As such, specific mechanisms and pathways underlying specific seizure phenotypes may vary when perturbations at a given hierarchical level lead to structural and functional changes at higher (e.g., network) or lower (e.g., molecular) levels of analysis.

CELLULAR ELECTROPHYSIOLOGY The Hippocampus

CLASSIFICATION OF SEIZURES Epileptic seizures are broadly divided into two groups, depending on their site of origin and pattern of spread (Fig. 41-1). Partial seizures arise from a localized region of the brain, and the associated clinical manifestations are related to the function ordinarily served by that area. Focal discharges can spread locally through synaptic and nonsynaptic mechanisms, distally to subcortical structures, and through commissural pathways to eventually involve the entire cortex. Such is the evolution believed to occur when focal seizures secondarily generalize. For example, a seizure arising from the left motor cortex may cause jerking movements of the right upper extremity. If the epileptiform discharges subsequently spread to adjacent areas and eventually encompass the entire brain, a secondarily generalized tonicclonic seizure may ensue.

The hippocampus has been a preferred brain region for many basic and epilepsy-related electrophysiologic studies, and hippocampal pyramidal cells have become one of the most intensively studied cell types in the central nervous system. Moreover, the orderly and relatively simple organization of hippocampal circuits have made them favorites among cellular electrophysiologists interested in studying synaptic and nonsynaptic mechanisms relevant to seizure genesis. Much of the following discussion focuses on studies conducted in the hippocampus. More details regarding the electrophysiology of the hippocampal formation have been provided by Schwartzkroin and Mueller [1987] and by Lopes da Silva and colleagues [1990]. The hippocampal formation consists of the dentate gyrus, the hippocampus proper (i.e., Ammon’s horn, with subregions CA1, CA2, and CA3), the subiculum, and the entorhinal cortex (Fig. 41-2). These four regions are linked

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Epilepsy / 41 FIGURE 41-1. Coronal brain sections depicting seizure types and potential routes of seizure spread. A, Focal area of hyperexcitability (star under electrode 3) and spread to adjacent neocortex (solid arrow under electrode 4) by the corpus callosum (dotted arrow) or other commissural pathways to the contralateral cerebral hemisphere or by subcortical pathways (e.g., thalamus, upward dashed arrows). Accompanying electroencephalographic (EEG) patterns show brain electrical activity under electrodes 1 to 4. Focal epileptiform activity is maximal at electrode 3 and is seen at electrode 4 (left traces). If a seizure secondarily generalizes, activity may be seen synchronously at all electrodes after a delay (right traces). B, A primarily generalized seizure begins simultaneously in both hemispheres. The characteristic bilateral synchronous spike-wave EEG pattern is generated by reciprocal interactions between the cortex and thalamus, with rapid spread by means of the corpus callosum (CC) contributing to the rapid bilateral synchrony. One type of thalamic neuron (dark neuron) is a GABAergic inhibitory cell that displays intrinsic pacemaker activity. Cortical neurons (triangles) send impulses to thalamic relay neurons (diamond) and to inhibitory neurons, setting up oscillations of excitatory and inhibitory activity, which gives rise to the rhythmic spike-wave EEG pattern. (From Stafstrom CE. An introduction to seizures and epilepsy: Cellular mechanisms underlying classification and treatment. In: Stafstrom CE, Rho JM, eds. Epilepsy and the ketogenic diet. Totowa, NJ: Humana Press, 2004;6.)

TABLE 41-1 Pathophysiologic Defects Leading to Epilepsy LEVEL OF BRAIN FUNCTION

CONDITION

PATHOPHYSIOLOGIC MECHANISM

Neuronal network

Cerebral dysgenesis, post-traumatic scar, mesial temporal sclerosis (in TLE) Down syndrome and possibly other syndromes with mental retardation and seizures Pyridoxine (vitamin B6) dependency

Altered neuronal circuits; formation of aberrant excitatory connections (i.e., sprouting) Abnormal structure of dendrites and dendritic spines; altered current flow in neuron Decreased GABA synthesis; B6, a cofactor for GAD Abnormal GABA receptor subunits

Neuron structure Neurotransmitter synthesis Neurotransmitter receptors, inhibitory Neurotransmitter receptors, excitatory Synapse development

Angelman’s syndrome, juvenile myoclonic epilepsy

Neonatal seizures

Ion channels (i.e., channelopathies)

Benign familial neonatal convulsions

Nonketotic hyperglycinemia

Excess glycine leads to activation of NMDA receptors Many possible mechanisms, including the depolarizing action of GABA early in development Potassium channel mutations; impaired repolarization

GABA, γ-aminobutyric acid; GAD, glutamic acid decarboxylase; NMDA, N-methyl-D-aspartate; TLE, temporal lobe epilepsy.

by prominent excitatory, largely unidirectional feed-forward connections. There are, however, some “backward” projections, most prominently from the entorhinal cortex to Ammon’s horn and from the CA3 field to the dentate gyrus. The predominant forward-projecting trisynaptic circuit begins with neurons in layer II of the entorhinal cortex that project axons to the dentate gyrus along the perforant pathway, where they synapse on granule cell and interneuron dendrites. Granule cells, the principal cell type of the dentate gyrus, send their axons, called mossy fibers, to synapse on cells in the hilus and in the CA3 field of Ammon’s horn. CA3 pyramidal cells project to other CA3 pyramidal cells through local collaterals, to the CA1 field of Ammon’s horn through Schaffer collaterals, and to the contralateral hippocampus. CA1 pyramidal cells send their axons into the subicular complex, and neurons of the subicular complex project to the entorhinal cortex and other cortical and subcortical targets.

Overview of Ion Channels To understand abnormal electrical activity in the brain, it is essential to review the elements of normal synaptic functioning and neuronal firing (Fig. 41-3). The key channels and receptors involved in normal and epileptic firing are summarized in Table 41-2. Two major types of ion channels are responsible for inhibitory and excitatory activity. The first are voltage-gated sodium and calcium channels, whose function is to depolarize the cell membrane toward the action potential threshold, and voltage-gated potassium channels, which largely function to dampen excitation in the nervous system. These voltage-gated channels are activated by membrane potential changes that subsequently alter the conformational state of the channel and allow selective passage of charged ions through a pore. Ligand-gated receptors, such as glutamate and γ-aminobutyric acid (GABA) receptors, constitute the second type. In this group, a neurotransmitter

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FIGURE 41-2. Schematic of major pathways of excitatory synaptic transmission in the hippocampal formation. The hippocampal trisynaptic pathway begins with neurons in layer II of the entorhinal cortex that project axons to the dentate gyrus along the perforant path (1), where they synapse on granule cell dendrites. Dentate granule cells send their axons (called mossy fibers) to synapse on cells in the hilus and in the CA3 field of Ammon’s horn (2). CA3 pyramidal cells project to the CA1 field of Ammon’s horn by means of Schaffer collaterals (3). CA1 neurons send projections outward through the fornix to other brain regions and back to the subiculum. For simplicity, only the classic feed-forward projections of the trisynaptic pathway are shown. Omitted are the known backward projections and local circuit interactions.

Ent

I

FIGURE 41-3. Normal neuronal firing is illustrated by the schematic of a neuron with one excitatory (E) and one inhibitory (I) input. Right trace shows membrane potential (in millivolts [mV]), beginning at a typical resting potential (–70 mV). Activation of E leads to graded excitatory postsynaptic potentials (EPSPs), the larger of which reaches threshold (approximately –40 mV) for an action potential. The action potential is followed by an after-hyperpolarization (AHP), the magnitude and duration of which determine when the next action potential can occur. Activation of I causes an inhibitory postsynaptic potential (IPSP). The inset shows a magnified portion of the neuronal membrane as a lipid bilayer with interposed voltage-gated Na+ and K+ channels; the direction of ion fluxes during excitatory activation is indicated. After firing, the membrane-bound Na+-K+ pump and star-shaped astroglial cells restore ionic balance. (From Stafstrom CE. An introduction to seizures and epilepsy: Cellular mechanisms underlying classification and treatment. In: Stafstrom CE, Rho JM, eds. Epilepsy and the ketogenic diet. Totowa, NJ: Humana Press, 2004;11.)

(prepackaged in vesicles) is released from a presynaptic terminal (after presynaptic calcium influx) into the synaptic cleft and then binds with selective affinity to a membranebound receptor on the postsynaptic membrane. Binding of neurotransmitter to its receptor recognition site activates a

cascade of events, including a conformational shift to reveal an ion-permeant pore. Passage of ions across these channels results in depolarization (i.e., inward flux of cations) or hyperpolarization (i.e., inward flux of anions or outward flux of cations).

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TABLE 41-2 Roles of Channels and Receptors in Normal and Epileptic Firing CHANNEL OR RECEPTOR

ROLE IN NORMAL NEURONAL FUNCTION

POSSIBLE ROLE IN EPILEPSY

Voltage-gated Na+ channel Voltage-gated K+ channel Ca2+-dependent K+ channel Voltage-gated Ca2+ channel Non-NMDA receptor (i.e., AMPA) NMDA receptor

Subthreshold EPSP; action potential up-stroke Action potential down-stroke AHP after action potential; sets refractory period Transmitter release; carries depolarizing charge from dendrites to soma Fast EPSP Prolonged, slow EPSP

GABAA receptor GABAB receptor Electrical synapses Na+-K+ pump

IPSP Prolonged IPSP Ultrafast excitatory transmission Restores ionic balance

Repetitive action potential firing Abnormal action potential repolarization Limits repetitive firing Excess transmitter release; activates pathophysiologic intracellular processes Initiates PDS Maintains PDS; Ca2+ activates pathophysiologic intracellular processes Limits excitation Limits excitation Synchronization of neuronal firing Prevents K+-induced depolarization

AHP, after-hyperpolarization; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid; EPSP, excitatory postsynaptic potential; GABA, γ-aminobutyric acid; IPSP, inhibitory postsynaptic potential; NMDA, N-methyl-D-aspartate; PDS, paroxysmal depolarization shift.

Voltage-Dependent Membrane Conductances Depolarizing Conductances A rapidly inactivating inward sodium conductance underlies the depolarizing (excitatory) phase of the action potential, and a non-inactivating, persistent sodium current can augment cell depolarization (e.g., produced by excitatory synaptic input) in the range immediately subthreshold for spike initiation. Most antiepileptics are thought to act in part through interactions with voltage-dependent sodium channels [Rogawski and Löscher, 2004]. Each sodium channel exists as a complex of three polypeptide subunits; there is a major α subunit and two smaller β subunits that influence the kinetic properties of the α subunit. The shape of action potentials is determined by the types of α and β subunits present in an individual neuron [Catterall et al., 2003a]. Neurons also display voltage-gated inward calcium conductances. In the hippocampus, the most significant calcium currents occur in CA3 pyramidal cells and underlie burst discharges in these cells [Wong and Prince, 1978]. Activation of voltage-dependent calcium channels contributes to the depolarizing phase of the action potential, and it can affect neurotransmitter release, gene expression, and neuronal firing patterns. Several distinct subtypes of calcium channels are distinguished on the basis of electrophysiologic properties, pharmacologic profile, molecular structure, and cellular localization [Catterall et al., 2003b]. The molecular structure of voltage-gated calcium channels is similar to that of sodium channels. Voltage-dependent calcium channels are hetero-oligomeric complexes containing a principal pore-forming α1 subunit and one or more smaller subunits (α2, β, γ, and δ) that are not obligatory for normal activity but can modulate the kinetic properties of the channel.

Hyperpolarizing Conductances Depolarizing sodium and calcium currents are counterbalanced by an array of voltage-dependent hyperpolarizing (inhibitory) currents, primarily by potassium channels. Potassium channels represent the largest and most diverse family

of voltage-gated ionic channels, and they function to inhibit or decrease excitation in the nervous system. The prototypic voltage-gated potassium channel is composed of four membrane-spanning α subunits and four regulatory β subunits that are assembled in an octameric complex to form an ion selective pore. In hippocampal neurons, potassium conductances include a leak conductance, which is a major determinant of the resting membrane potential; an inward rectifier (involving the flux of other ions), which is activated by hyperpolarization; a large set of delayed rectifiers, which are involved in the termination of action potentials and repolarization of the neuron’s membrane potential; an A-current, which helps determine interspike interval and affects the rate of cell firing; an M-current, which is sensitive to cholinergic muscarinic agonists and affects resting membrane potential and rate of cell firing; and a set of calcium-activated potassium conductances, which are sensitive to intracellular calcium concentration and affect cell firing rate and interburst interval. Rectification is a term that comes from circuit theory, and it refers to a situation when the conductance of ions through an ion channel changes according to voltage in such a way that they flow better in one direction than another; rectification can also result from blocking of the pore by other ions. Modulation or facilitation of these hyperpolarizing conductances can be viewed as potentially antiepileptic. However, none of the traditional antiepileptics in clinical use today is thought to act directly and principally on voltagegated potassium channels. Newer antiepileptics appear to act in part by affecting potassium channel function. For example, topiramate induces a steady membrane hyperpolarization mediated by a potassium conductance [Herrero et al., 2002], and levetiracetam blocks sustained repetitive firing by paradoxically decreasing voltage-gated potassium currents [Madeja et al., 2003]. Retigabine, an investigational compound with broad efficacy in animal seizure models, appears to enhance activation of KCNQ2 and KCNQ3 potassium channels [Rogawski, 2000; Wickenden et al., 2000]. This finding is particularly intriguing, given that mutations in genes encoding these proteins have been linked to a rare form of inherited epilepsy, benign familial neonatal seizures [Biervert et al., 1998; Singh et al., 1998].

Rho and Stafstrom / Neurophysiology of Epilepsy

Synaptic Physiology Inhibitory Synaptic Transmission Synaptic inhibition in the hippocampus is mediated by two basic circuit configurations. First, feedback or recurrent inhibition occurs when excitatory principal neurons synapse with and excite inhibitory interneurons, which project back to the principal neurons and inhibit them (i.e., a negativefeedback loop). Second, feed-forward inhibition occurs when axons projecting into the region synapse with and directly activate inhibitory interneurons, which then inhibit principal neurons. Both feed-forward and feedback inhibitory circuits abound in the hippocampal formation [Lacaille et al., 1987], and in both circuit configurations, the major inhibitory neurotransmitter is GABA. GABA, the principal inhibitory neurotransmitter in the mammalian central nervous system, is a neutral amino acid synthesized from glutamic acid by the rate-limiting enzyme glutamic acid decarboxylase. GABA, released from axon terminals, binds to at least two classes of receptors, GABAA and GABAB, which are found on almost all cortical neurons [Martin and Olsen, 2000]. GABAA receptors also are found on glial cells, although their functional significance on these cells is unclear. The GABAA receptor is a macromolecular receptor complex consisting of an ion pore and binding sites for agonists and a variety of allosteric modulators, such as benzodiazepines and barbiturates, each differentially affecting the kinetic properties of the receptor [MacDonald and Olsen, 1994]. The GABAA receptor is a heteropentameric complex composed of combinations of several polypeptide subunits arranged in topographic fashion to form an ion channel. This channel is selectively permeable to chloride and bicarbonate ions. Seven subunits (α, β, γ, δ, ε, π, ρ) have been described, each with one or more subtypes. Although several thousand receptor isoforms are possible from differential expression and assembly of these various subtypes, there is likely to be only a limited number of functional combinations, but the precise subunit composition of native GABAA receptors has yet to be identified. However, it is thought that most functional GABAA receptors follow the general motif of containing either α and β or α, β, and γ subunits with uncertain stoichiometry. Because individual subunits may be differentially sensitive to pharmacologic agents, GABA receptor subunits represent potentially useful molecular targets for new antiepileptics. Activation of GABAA receptors on the somata of mature cortical neurons generally results in the influx of chloride ions (Cl–) and consequent membrane hyperpolarization, inhibiting cell discharge. In hippocampal cell dendrites and in the immature brain, however, GABAA receptor activation causes depolarization of the postsynaptic membrane. This reversal of the conventional GABAA effect is thought to reflect a reversed Cl– electrochemical gradient, a consequence of the immature expression of the K+-Cl– cotransporter, KCC2, which ordinarily renders GABA hyperpolarizing [Rivera et al., 1999]. Outward flux of bicarbonate through GABAA channels may further contribute to depolarization [Staley et al., 1995]. In addition to GABAA receptors, there are metabotropic GABAB receptors located on postsynaptic membrane and on presynaptic terminals. GABAB

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receptors act through guanosine triphosphate (GTP)–binding proteins to control calcium or potassium conductances. Whereas GABAA receptors generate fast, high-conductance, inhibitory postsynaptic potentials close to the cell body, GABAB receptors on the postsynaptic membrane mediate slow, long-lasting, low-conductance inhibitory postsynaptic potentials, primarily in hippocampal pyramidal cell dendrites. Perhaps of more functional significance, activation of GABAB receptors on axon terminals blocks synaptic release of neurotransmitter. It is thought that GABAB receptors are associated with terminals that release GABA onto postsynaptic GABAA receptors. In such cases, activation of GABAB receptors reduces the amount of GABA released, resulting in disinhibition [Mott and Lewis, 1994; Simeone et al., 2003].

Excitatory Synaptic Transmission Glutamate, an excitatory amino acid, is the principal excitatory neurotransmitter of the mammalian central nervous system, including the hippocampal formation. Glutamatergic pathways are widespread throughout the brain, and excitatory amino acid activity is critical to normal brain development and activity-dependent synaptic plasticity [Simeone et al., 2004]. Ionotropic glutamate receptors are broadly divided into N-methyl-D-aspartate (NMDA) and non-NMDA receptors, based on biophysical properties and pharmacologic profiles [Dingledine et al., 1999]. Each subtype of glutamate receptor consists of a multimeric assembly of subunits that determine its distinct functional properties. Glutamate receptor channel subunits are classified into six subfamilies based on amino acid sequence homology [Hollmann and Heinemann, 1994]. The NMDA receptor contains a binding site for glutamate (or NMDA) and a recognition site for a variety of modulators (e.g., glycine, polyamines, MK-801, zinc). NMDA receptors also demonstrate voltage-dependent block by magnesium ions [Mori and Mishina, 1995]. When the membrane is depolarized and the magnesium block of the NMDA receptor is alleviated, activation of the NMDA receptor results in an influx of calcium (Ca2+) and sodium (Na+) ions. Calcium entry is central to the initiation of a number of second messenger pathways, such as stimulation of a variety of kinases that subsequently activate signal transduction cascades leading to changes in transcriptional regulation. Activation of the NMDA receptor leads to generation of relatively slow and long-lasting excitatory postsynaptic potentials. These synaptic events contribute to epileptiform burst discharges, and NMDA receptor blockade results in the attenuation of bursting activity in many models of epileptiform activity. Non-NMDA ionotropic receptors are divided into αamino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) and kainate receptors [Dingledine et al., 1999]. The AMPA receptor in particular is responsible for the major part of the excitatory postsynaptic potential—fast rising and brief in duration—generated by release of glutamate onto postsynaptic neurons. The depolarization generated by AMPA receptors is necessary for effective activation of NMDA receptors. Consequently, AMPA receptor antagonists block most excitatory synaptic activity in pyramidal neurons. Metabotropic glutamate receptors represent a large, heterogeneous family of G-protein–coupled receptors that

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subsequently activate various transduction pathways—phosphoinositide hydrolysis and activation of adenylate cyclase and phospholipases C and D [Conn, 2003]. These metabotropic receptors are important modulators of voltagedependent potassium and calcium channels, nonselective cation currents, ligand-gated receptors (i.e., GABA and glutamate receptors), and they can regulate glutamate release. It is not surprising that they have been invoked in the description of a wide variety of neurologic processes (e.g., long-term potentiation) and disease states (e.g., epilepsy). A detailed discussion of these receptors is beyond the scope of this chapter, but it is clear that different metabotropic glutamate receptor subtypes are specific for different intracellular processes. Although ubiquitous within the central nervous system, subtypes of metabotropic receptors appear to be differentially localized.

Abnormal Neuronal Firing What happens at the neuronal network level when neurons transition from their normal firing pattern to interictal epileptiform bursts and then to an ictal state in which there is an evolution of electrophysiologic changes that is sustained, evolving, and with a terminal event, followed by postictal changes? Much of our understanding of epilepsy mechanisms comes from electrophysiologic studies in which

microelectrodes are placed inside individual neurons to record intracellular potential changes. Figure 41-4 depicts electroencephalographic and intracellular changes that can be seen in normal, interictal, and ictal states. In the normal situation, action potentials (which represent all-or-none events) are generated in neuron 1 when the membrane potential reaches threshold for firing (approximately –40 mV). These discharges may influence the activity of an adjacent neuron (neuron 2) through electrical field (i.e., ephaptic) or synaptic mechanisms, resulting in an excitatory postsynaptic potential. An adjacent interneuron (neuron 3, which is inhibitory) may also be activated by a discharge from neuron 1 after a brief delay, giving rise to an inhibitory postsynaptic potential. The activity recorded in neuron 2 reflects the temporal and spatial summation of excitatory postsynaptic potential and inhibitory postsynaptic potential inputs. If this integrative concept is extrapolated to thousands of interconnections (i.e., synaptic contacts), it is easy to envision the “sculpting” or grading of individual cellular responses modulated by degrees of inhibition. If we consider that a single inhibitory interneuron, such as in the hippocampus, can connect with hundreds to several thousand pyramidal neurons, it is straightforward to see how hypersynchronous behavior can be influenced by even a single cell. For a localized collection of hyperexcitable neurons

FIGURE 41-4. Abnormal neuronal firing at the levels of the brain (A) and a simplified neuronal network (B), consisting of two excitatory neurons (1 and 2) and an inhibitory interneuron (solid circle, 3). Electroencephalographic (EEG) (top set of traces) and intracellular recordings (bottom set of traces) are shown for normal (left column), interictal (middle column), and ictal (right column)conditions. Numbered traces refer to like-numbered recording sites. Notice the time scale differences in different traces. A, Three EEG electrodes record activity from superficial neocortical neurons. In the normal case, activity is low voltage and desynchronized (i.e., neurons are not firing together in synchrony). In the interictal condition, large spikes are seen focally at electrode 2 (and to a lesser extent at electrode 1, where they may be called sharp waves), representing synchronized firing of a large population of hyperexcitable neurons (expanded in time below). The ictal state is characterized by a long run of spikes. B, At the neuronal network level, the intracellular correlate of the interictal EEG spike is called the paroxysmal depolarization shift (PDS). The PDS is initiated by a non–NMDA-mediated, fast excitatory postsynaptic potential (EPSP) (shaded area), but it is maintained by a longer, larger, NMDA-mediated EPSP. The post-PDS hyperpolarization (asterisk) temporarily stabilizes the neuron. If this post-PDS hyperpolarization fails (right column, arrow), ictal discharge can occur. The lowest traces, recordings from neuron 2, show activity similar to that recorded in neuron 1, with some delay (double-headed arrow). Activation of inhibitory neuron 3 by firing of neuron 1 prevents neuron 2 from generating an action potential (i.e., the inhibitory postsynaptic potential [IPSP] counters the depolarization caused by the EPSP). If neuron 2 does reach firing threshold, additional neurons will be recruited, leading to an entire network firing in synchrony (i.e., a seizure). NMDA, N-methyl-D-aspartate. (From Stafstrom CE. An introduction to seizures and epilepsy: Cellular mechanisms underlying classification and treatment. In: Stafstrom CE, Rho JM, eds. Epilepsy and the ketogenic diet. Totowa, NJ: Humana Press, 2004;18).

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receptors (i.e., AMPA receptors), whereas the sustained depolarization is a consequence of NMDA receptor activation. Afterward, the paroxysmal depolarization shift terminates with a repolarization phase, primarily as a consequence of inhibitory potassium and chloride conductances carried by voltage-gated potassium channels and GABA receptors. The prolonged period of hyperpolarization after the paroxysmal depolarization shift is mediated by inhibitory conductances and constitutes a refractory period.

Synchronizing Mechanisms

INTRACELLULAR RECORDING

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ION CHANNELS

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AMPA receptor activation NMDA receptor activation Sodium conductance Calcium conductance

Potassium conductance GABA inhibition Chloride conductance FIGURE 41-5. The paroxysmal depolarization shift (PDS) is the intracellular correlate of an interictal spike on the surface electroencephalogram. The temporal correlations are illustrated for an interictal epileptiform discharge (top, spike and slow-wave complex), intracellular recording (middle), and sequence of ionic conductance changes. The PDS is initiated by excitatory conductances (dark bars) and terminated by inhibitory conductances (light bars). The initial depolarization (phase 1), which is an excitatory postsynaptic potential (EPSP), is mediated by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors and sustained by N-methyl-D-aspartate (NMDA) receptors, whereas the overriding action potentials (phase 2) are generated by voltage-gated sodium channels and calcium channels. Repolarization and after-hyperpolarization (phase 3) are mediated by inhibitory conductances (i.e., multiple voltage-gated potassium channels and chloride flux such as through γ-aminobutyric acid [GABA] receptors).

to spread to adjacent areas, the epileptic firing must overcome the powerful inhibitory influences that normally keep aberrant excitability in check (i.e., concept of the inhibitory surround).

Paroxysmal Depolarization Shift The intracellular correlate of the focal interictal epileptiform discharge on the EEG is known as the paroxysmal depolarization shift. It is seen when recording changes in membrane potential of a single neuron with a microelectrode while simultaneously recording a focal spike on the EEG (Fig. 41-5). Initially, there is a rapid shift in the membrane potential in a depolarizing direction, followed by a burst of repetitive action potentials lasting several hundred milliseconds. The initial depolarization is mediated by non-NMDA glutamate

The hippocampal formation (see Fig. 41-2) normally displays robust neuronal synchronization. Sharp waves, dentate spikes, theta activity, 40-Hz oscillations, and 200-Hz oscillations are all forms of neuronal synchronization that can be recorded in various regions of the hippocampal formation [Buzsáki et al., 1994]. Synchronization of neuronal activity appears to be intrinsic to the mechanism by which the hippocampus performs its normal functions. However, neuronal synchronization also is a hallmark of epilepsy. Exaggerated synchrony among hippocampal neurons may directly generate “seizures,” because seizures are defined by hypersynchronous neuronal activity. Normal forms of synchronized activity that do not trigger seizures in a normal hippocampus may trigger epileptiform discharges in a hippocampus that has undergone selective neuronal loss, synaptic reorganization, or changes in receptor expression. For example, electroencephalographic spikes have been recorded from the dentate gyrus of normal rats. They reflect the synchronized discharges of entorhinal cortical neurons, which synapse on granule cells to initiate inward currents in dentate granule cell dendrites [Bragin et al., 1995]. In the hippocampal formation, synchronizing mechanisms include inputs from subcortical nuclei and intrinsic interneuron-mediated synchronization. For example, highamplitude theta activity is a salient feature of the hippocampus. The theta rhythm represents synchronized activity of hippocampal neurons and largely depends on input from the septum [Buzsáki et al., 1983]. Subcortical nuclei such as the septum have divergent inputs that target hippocampal interneurons. The divergent axon projections of interneurons and the powerful effect of the GABAA receptor–mediated conductances that they produce enable interneurons to entrain the activity of large populations of principal cells [Cobb et al., 1995]. These characteristics make interneurons a very effective target for subcortical modulation of hippocampal principal cell activity. Mutual inhibitory interactions among hippocampal interneurons also can produce synchronized discharges [Jefferys et al., 1996]. Recurrent excitatory circuits are another basis for neuronal synchronization in the hippocampus. Recurrent excitatory collaterals are a normal feature of the CA3 region; CA3 pyramidal cells form direct, monosynaptic connections with other CA3 pyramidal cells. These recurrent excitatory interactions contribute to the synchronized burst discharges that characterize this region of Ammon’s horn [Traub and Miles, 1991]. The epileptic temporal lobe, synaptic reorganization, and axonal sprouting may lead to aberrant recurrent excitation, providing a synchronizing mechanism in other parts of the hippocampal formation, including the CA1 region, subicular complex, entorhinal cortex, and dentate

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(+)

FIGURE 41-6. Granule cells (GC) receive their major input by the perforant path. The perforant path also stimulates hilar interneurons (e.g., mossy cells, basket cells) to provide feed-forward inhibition of the granule cells. Granule cell axons, the mossy fibers (MFs), make synaptic contact with CA3 pyramidal cells. Mossy fiber collaterals innervate the hilar interneurons such as the mossy cell shown in the diagram. Mossy cells are excitatory to GABAergic basket cells that provide feedback inhibition to the granule cell. Sprouting of mossy fibers (in response to seizure-induced loss of CA3 pyramidal cells and hilar mossy cells) can result in enhanced excitation by forming autapses (i.e., an axon sprout synapsing with the dendrites of the same cell) and can augment synchronization by stimulating neighboring granule cells (not shown), contributing to epileptogenicity. It has been suggested that the sprouted mossy fibers may restore inhibition lost after seizure-induced death of hilar mossy cells by direct stimulation of deafferented (dormant) basket cells. (From Menkes JH, Sankar R. Paroxysmal disorders. In: Menkes JH, Sarnat HB, eds. Child neurology, 6th ed. Philadelphia: Lippincott Williams & Wilkins, 2000;919.)

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(+)

CA3 pyramidal cell To fornix via alveus and CA1 via Schaffer collaterals

gyrus. In the dentate gyrus of the normal hippocampus, for example, granule cells form few or no monosynaptic contacts with neighboring granule cells. However, in the epileptic hippocampus, mossy fiber sprouting results in direct excitatory interactions among granule cells (Fig. 41-6). Mechanisms independent of chemical synaptic transmission may synchronize hippocampal neuronal firing under some circumstances. Such mechanisms include gap junctions, electrical field effects, and changes in extracellular ion concentrations. Gap junctions allow electrical signals to pass directly between cells. Studies suggest that gap junctions are upregulated in epileptic brain tissue [Li et al., 2001] and that blockade of gap junctions significantly affects the duration of seizure activity [Kohling et al., 2001]. Electrical field effects are generated by current flow through the extracellular space. Earlier studies demonstrated the potential synchronizing effect of “ephaptic” interactions, and later experiments suggest that manipulations that alter the extracellular space volume (i.e., affecting current flow through this compartment) can impact the epileptogenic synchronization neurons [Hochman et al., 1995]. Increases in extracellular potassium concentration have long been thought to affect epileptogenic excitability and synchronization, and experiments have demonstrated clear epileptogenic effects of blocking potassium regulation (e.g., through inwardly rectifying potassium channels) [Emmi et al., 2000].

Glial Mechanisms for Modulating Epileptogenicity The role of glial cells in epileptiform discharge received considerable attention in the past, but glial contributions have been significantly neglected in studies of epileptogenic mechanisms. Because the ionic balance between the intracellular and extracellular compartments is altered after

CA1

neuronal activity (especially after sustained, repetitive discharges seen with seizures), there must exist mechanisms to restore ion homeostasis. Otherwise, even normal neuronal activity would cease. Astrocytes are perhaps most closely associated with regulation of extracellular potassium levels (i.e., potassium buffering) because glial cell membranes are preferentially permeable to potassium. A variety of inwardly rectifying potassium ion (K+) channels provide an appropriate means for potassium uptake, and the association of glial end-feet with brain microvasculature provides a convenient “sink” for potassium release. Glial cell membrane potential changes are directly correlated with changes in extracellular potassium, and blockade of potassium channels that is selective for glial cells results in neuronal hyperexcitability. It seems certain that glial cells help to modulate neuronal discharge through their regulation of extracellular potassium. Despite the circumstantial evidence for glial potassium regulation, some investigators think that the glial cells play an even more important role in the maintenance of neuronal excitability—transporting glutamate (released from neuronal terminals to excite other neurons) out of the extracellular space. Glia cells are uniquely equipped for this role, having at least two powerful glutamate transport molecules in their membranes [Gegelashvili and Schousboe, 1998]. Rapid and efficient removal of extracellular glutamate characterizes normal, healthy brain tissue, and it is essential because residual glutamate would continue to excite surrounding neurons. Blockade of glutamate transporters (or knockout of the genes for these transport proteins) results in epileptic or excitotoxic activities, or both [Meldrum et al., 1999; Rothstein et al., 1996]. Glial cells contribute to modulation of excitability in a number of other ways. First, they play a critical role of regulating extracellular pH by a proton exchanger [Deitmer

Rho and Stafstrom / Neurophysiology of Epilepsy

999

jections to thalamic relay neurons and inhibitory GABAergic neurons comprising the nucleus reticularis thalami. Excitatory outputs of the thalamic relay neurons impinge on the apical dendrites of layer VI pyramidal neurons in the neocortex. This so-called thalamocortical relay is a critical substrate for the generation of cortical rhythms, and it is influenced by sensory inputs (e.g., from the retina) and by several brainstem nuclei that constitute the origin of cholinergic, noradrenergic, serotonergic, and other projections. This reciprocal circuitry, which is responsible in large part for normal electroencephalographic oscillations during wake and sleep states, can become hyperactive to generate generalized spike-wave discharges or can be dampened to reduce or eliminate spontaneous cortical rhythms. The anatomy implies that spike-wave discharges can be interrupted at cortical or thalamic levels. Although multiple ionic conductances are involved in rhythmic pacemaking activity, two specific channels are believed to play a key role in regulating such thalamocortical activity. The first is a subtype of voltage-gated calcium channel known as the low-threshold calcium channel (T-type channel). These channels can be activated by small depolarizations of the plasma membrane. In many neurons, calcium influx through these channels triggers lowthreshold spikes and activates a burst of action potentials [McCormick and Contreras, 2001; Perez-Reyes, 2003]. Such an excitatory burst is thought to underlie the spike portion of a generalized spike-wave oscillation. Antiepileptics known to be clinically effective against absence seizures (e.g., ethosuximide, valproic acid) can block T-type calcium currents. Whether augmentation of T-type calcium currents is essential in the genesis of absence seizures remains controversial [Leresche et al., 1998; Song et al., 2004]. The second important ion channel involved in the regulation of thalamocortical rhythmicity is the hyperpolarization-activated cation channel, responsible for the

and Rose, 1996] and by bicarbonate transporter mechanisms [Newman, 1999]. Even low levels of neuronal activity create significant pH transients. The pH modulates receptor function, particularly the NMDA receptor that appears to play such an important role in epileptic discharges [Traynelis and Cull-Candy, 1990]. Second, glial cells are thought to release powerful neuroactive agents into the extracellular space. Studies have indicated that glial glutamate release can excite neighboring neurons, and some investigations have suggested that other glia-related factors—such as the cytokine interleukin-1—can have profound antiepileptic efficacy [Vezzani et al., 2000].

Physiology of Absence Epilepsy Absence seizures represent a subtype of generalized-onset seizures with distinct pathophysiologic substrates. As the term implies, an absence seizure is characterized by a temporary loss of consciousness with total amnesia for the event—usually, a sudden cessation of motor activity without falling. These seizures usually are short lived (<20 seconds) in most patients, begin without an aura, and end abruptly without postictal changes. The lack of a postictal change is sometimes the only clinical feature that distinguishes between absence seizures and nonconvulsive complex partial seizures. Infrequently, but usually with longer absence attacks, there can be motor automatisms (i.e., head nodding, eye rolling or eyelid fluttering, and minor changes in tone such as head nodding), overlapping somewhat with the clinical presentation of complex partial seizures. The generalized spike-wave discharges accompanying absence seizures reflect a widespread, phase-locked oscillation between excitation (i.e., spike) and inhibition (i.e., slow wave) in mutually connected thalamocortical networks [McCormick and Contreras, 2001]. As depicted in Figure 41-7, pyramidal neurons from layer VI of the neocortex send excitatory pro-

Layer VI cortex +

+ –

– – – –

Nucleus reticularis thalami +

Noradrenergic Serotonergic Cholinergic Histaminergic

Inputs

Thalamic relay neurons

–

Sensory input

FIGURE 41-7. Thalamocortical circuitry is thought to form the basis of normal oscillatory rhythms, which when perturbed, can produce generalized spike-wave discharges seen with absence seizures. This circuitry involves excitatory projections from layer VI neocortical pyramidal neurons onto thalamic relay (TR) neurons and inhibitory neurons comprising the nucleus reticularis thalami (NRT). TR neurons send excitatory axons back to the neocortex. Activation of NRT neurons results in recurrent inhibition of adjacent neurons and TR neurons. The neurotransmitters at the excitatory (+) and inhibitory (−) synapses are thought to be glutamate and γ-aminobutyric acid (GABA), respectively. Low-threshold (T-type) calcium channels and hyperpolarization-activated cation (HCN) channels in TR and NRT neurons help regulate intrinsic rhythmicity. Extrinsic modulatory influences on this circuitry include inputs from the forebrain and brainstem nuclei and the sensory inputs from other thalamic nuclei.

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Epilepsy / 41

so-called Ih or h-current. Hyperpolarization-activated cation channels, densely expressed in the thalamus and hippocampus, are activated by hyperpolarization and produce a depolarizing current carried by an inward flux of Na+ and K+ ions [Robinson and Siegelbaum, 2003]. This depolarization helps to bring the resting membrane potential toward threshold for activation of T-type calcium channels, which produces a calcium spike and a burst of action potentials. Hyperpolarization-activated cation channels are highly expressed in dendrites and expressed to a lesser extent in the soma. They are also likely critically involved in developmental plasticity [Santoro and Baram, 2003]. Unlike other voltage-gated conductances that can be labeled inhibitory or excitatory, h-currents are both inhibitory and excitatory [Poolos, 2004]. Hyperpolarization-activated cation channels possess an inherent negative-feedback property; hyperpolarization produces an activation of hyperpolarization-activated cation channels, which then leads to depolarization that then deactivates these channels. The net effect of hyperpolarization-activated cation channel activation is a decrease in the input resistance of the membrane, which is the voltage change produced by a given synaptic current. H-currents tend to stabilize the neuronal membrane potential toward the resting potential against hyperpolarizing and depolarizing inputs. The relevance of hyperpolarizationactivated cation channels in the pathogenesis of absence seizures was underscored by the demonstration that lamo-

trigine, an anti-absence agent, enhanced activation of dendritic h-currents in hippocampal pyramidal neurons [Poolos et al., 2002] and by the experimental finding that deletion of a specific hyperpolarization-activated cation isoform results in absence epilepsy and sinus dysrhythmia in mice [Ludwig et al., 2003]. With respect to antiepileptic action, it is uncertain whether known T-type calcium channel blockers such as ethosuximide in fact block absence seizures through interactions with this type of calcium channel [Leresche et al., 1998]. Antagonists of GABAB receptors and dopaminergic agonists can also interrupt abnormal thalamocortical discharges in experimental absence epilepsy models [Snead, 1995]. GABAB receptors are involved in mediating longlasting thalamic inhibitory postsynaptic potentials involved in the generation of normal thalamocortical rhythms, whereas brainstem monoaminergic projections disrupt these rhythms. Although it is appealing to think of absence seizures as a by-product of dysfunction of the T-type calcium channel or h-channel, or both, the actual pathophysiologic mechanisms are much more complex.

Increased Seizure Susceptibility of the Immature Brain Seizure incidence is highest during the first decade and especially during the first year of life [Hauser and Hers-

TABLE 41-3 Factors Promoting Increased Seizure Susceptibility in the Developing Brain FACTOR

CONSEQUENCE

SELECTED REFERENCES

Input resistance and time constant: increased in immature neurons Voltage-gated ion channels: earlier maturation of sodium and calcium channels, delayed development of potassium channels Synapse development: excitatory synapses appear before inhibitory synapses Synapse development: overexpression of excitatory synapses during critical period Developmental changes in glutamate receptor subunits: NR2B/NR2A ratio favors prolonged depolarizing responses; NR2D relative overexpression reduces Mg2+ block Late appearance of functional inhibitory synapses

Small inputs result in relatively large voltage changes Longer action potentials, shorter refractory periods, increased neuron firing

McCormick and Prince, 1987

Relative predominance of excitation over inhibition early in development Corresponds to window of heightened seizure susceptibility Favor relative hyperexcitability

Swann et al., 1999

Developmental changes in GABAA receptor function and Cl− gradient Developmental changes in GABAA receptor subunits Developmental sensitivity to glutamate toxicity Immature GABAA binding pattern in substantia nigra Electrical synapses; more common early in development Immature homeostatic mechanisms: Na+,K+-ATPase, glial K+ regulation, K+-Cl− cotransporter

Ribera and Spitzer, 1998

Swann et al., 1999 Vallano, 1998

Along with other factors favoring excitation, contributes to neuronal excitatory drive and lack of functional inhibition GABA is depolarizing early in life, enhancing excitability Partially accounts for developmental differences in inhibitory effectiveness and benzodiazepine responsiveness Less glutamate-induced excitotoxicity early in development Proconvulsant effect

Brooks-Kayal et al., 1998; Luhmann and Prince, 1991

Mechanism for enhanced synchrony of neuronal networks Prolonged exposure to elevated extracellular K+ leads to further neuronal depolarization

Velazquez and Carlen, 2000

Ben-Ari, 2002; Rivera et al., 1999; Staley et al., 1995 Brooks-Kayal et al., 2001 Liu et al., 1996 Moshe et al., 1994; Velisek et al., 1995

Haglund and Schwartzkroin, 1990

GABA, γ-aminobutyric acid; NR, N-methyl-D-aspartate (NMDA) receptor. Adapted from Stafstrom CE, Lynch M, Sutula TP. Consequences of epilepsy in the developing brain: Implications for surgical management. Semin Pediatr Neurol 2000;7:147.

Rho and Stafstrom / Neurophysiology of Epilepsy

dorffer, 1990]. Multiple physiologic factors (Table 41-3) contribute to the increased susceptibility of the developing brain to seizures [Holmes, 1997; Sanchez and Jensen, 2001]. This information is principally derived from experimental epilepsy models in rodents, in which a window of heightened excitability in the second postnatal week gives rise to a lowered seizure threshold. This period of hyperexcitability in the rodent is approximately analogous to the first year of life in the human infant [Avishai-Eliner et al., 2002]. Each seizure susceptibility factor alters the net brain excitatory-inhibitory balance in favor of enhanced excitation, and each involves a multiplicity of substrates and mediators, including ion channels, neurotransmitters and their receptors, structural changes in the maturing brain, and ionic gradients. Seizure propensity in the very young involves a complex interplay between the timing of these cellular and molecular changes. Excitability varies by brain region and cell type. Although there are disadvantages to the physiologic adaptations that make the immature brain especially vulnerable to hyperexcitability and seizure generation, such idiosyncrasies of early brain development also provide the opportunity for producing novel, age-specific therapies, none of which currently exist.

Ionic Channels and Membrane Properties The excitability of the neuronal membrane is determined in part by voltage-dependent ionic conductances. The relative timing of ion channel development plays a major role in the enhanced excitability of the immature brain [Moody, 1998; Spitzer et al., 2002]. Sodium and calcium ion channels, which mediate neuronal excitation, develop relatively early. Action potentials persist longer in early development, and this prolonged excitation mediates a greater Ca2+ current, particularly at the presynaptic terminal; these factors increase excitability by enhancing neurotransmitter release. However, the brain must achieve a critical balance; activitydriven Ca2+ channel activation is necessary for normal developmental processes such as cellular differentiation, migration, and synaptogenesis, but excessive inward Ca2+ current can cause seizures and neuronal damage. Outward currents through a large variety of K+ channels counter depolarizing influences and tend to stabilize membrane excitability. The K+ channels develop slightly later than Na+ and Ca2+ channels. During a window of development, the net balance of ion fluxes favors excitation. Intrinsic membrane properties, such as membrane resistance and time constants, contribute to the neuron’s response to a synaptic input. During development, neurons have relatively higher membrane resistances and shorter time constants, and a depolarizing stimulus of a given amplitude and duration can have a greater effect in an immature neuron than in a mature one [McCormick and Prince, 1987]. Such electrical factors act in concert with ionic conductances to determine the magnitude of the membrane’s response to a synaptic input.

Neurotransmitters and Their Receptors Most intercellular communication occurs by means of chemical synaptic transmission. Excitatory synapses, which use glutamate as the main transmitter, tend to form before

1001

inhibitory ones. Multiple glutamate receptor types exist, each with a specific function in neural activity. Each glutamate receptor type, and each receptor subunit within the receptor type, possesses a distinct ontogenetic profile. For example, excitatory NMDA receptors are transiently overexpressed early in postnatal development, when they are needed for critical developmental processes [Represa et al., 1989; Simeone et al., 2004]. The early developmental stoichiometry of NMDA receptor subunits favors prolonged depolarizing responses [Ben-Ari et al., 1997; Vallano, 1998]. GABA receptors also exhibit a developmental profile, with different expression of GABAA receptor subunits at different stages of development [Brooks-Kayal et al., 2001]. GABA’s physiologic action also varies during development, perhaps in a paradoxical manner. Early in development, GABA exerts an excitatory action, rather than the inhibitory effect seen later [Ben-Ari, 2002]. At these early stages, the intracellular Cl– concentration is greater than the extracellular concentration, and the reversal potential for Cl– is close to action potential threshold. When GABA binds to its receptors and opens Cl– channels, the negatively charged chloride ions flow from inside to outside the neuron, down their electrochemical gradient. The loss of negative charge from inside the neuron depolarizes it to a membrane potential closer to the threshold for an action potential. Later in development, the opposite situation occurs—Cl– predominates in the extracellular space due to the expression of KCC2, a membrane protein. KCC2 extrudes Cl–, keeping the basal Cl– concentration inside the neuron at about one fourth of its concentration early in life, and the Cl– reversal potential is more negative than resting membrane potential [Miles, 1999; Staley and Smith, 2001]. In the mature brain, GABA receptor activation causes entry of Cl–, hyperpolarizing the neuron and keeping it further away from the action potential threshold. It is unknown whether this mechanism exerts a critical effect in human neonates. Phenobarbital, which blocks GABAA receptors, is used to suppress seizures in the neonatal period. Phenobarbital’s clinical efficacy against neonatal seizures is imperfect [Painter et al., 1999], but it clearly has an effect in newborns. GABAA receptor ontogeny is also associated with varying sensitivity to benzodiazepines, an observation relevant to seizure treatment [Coulter, 2001]. Electrical synapses appear to be more prevalent in the developing brain than in the mature brain. Electrical synapses have been reported in several brain regions, including neonatal neocortex and hippocampus. Fast-acting electrical transmission can facilitate rapid synchrony of the neuronal network and precipitate seizures [Velazquez and Carlen, 2000].

Structural Maturation of the Brain and Seizure Susceptibility In the developing brain, synaptic connections are formed and pruned as a function of neuronal activity. Neuronal activity also determines which connections remain stable and which are lost [Desai et al., 1999]. Such changes are referred to as plasticity, a general phenomenon that likely influences the brain’s capacity to learn and respond to the environment. The same properties that govern plasticity may also contribute to increased susceptibility to epileptic network synchronization in association with brain pathologies or injury. For example, during the second week of life in the rat, the

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Epilepsy / 41

hippocampal CA3 region is characterized by an exuberance of excitatory connections between pyramidal cells that endow the region with heightened excitability and epileptiform activity [Swann and Hablitz, 2000]. These connections are later pruned, with stabilization of the excessive excitation seen during this developmental window.

Regulation of the Ionic Environment The development of several ion transport mechanisms favors excitability early in life. Expression of the chloride gradient depends on the development of the KCC2 chloride transporter, which determines whether GABA mediates a depolarizing or hyperpolarizing effect. Expression of the sodium-potassium ion pump (Na+,K+-ATPase) also follows a developmental pattern [Haglund and Schwartzkroin, 1990]. Extracellular accumulation of K+ after neuronal activity (e.g., during a seizure) can further depolarize the neuronal membrane, exacerbating or prolonging ictal activity. The ability of glial cells to clear extracellular K+ improves with age.

ANTIEPILEPTIC DRUG MECHANISMS Procedures for Antiepileptic Testing Since the introduction of phenobarbital in 1912, dozens of antiepileptic drugs have been approved for medical use by the U.S. Food and Drug Administration after extensive testing in a variety of animal seizure models and in human clinical trials [Rogawski and Porter, 1990]. Until recently, the paradigms of drug discovery have been biased toward the development of drugs sharing properties exhibited by older agents, such as phenytoin and phenobarbital [Rogawski and Porter, 1992]. Antiepileptic drug screening programs have incorporated advances in molecular and cellular neurobiology, resulting in more rational screening programs based almost exclusively on neuronal membrane-bound ion channels and enzymes involved in neurotransmitter metabolism and re-uptake. The two most commonly used models for the routine screening and identification of new antiepileptics are the maximal electroshock and subcutaneous pentylenetetrazol (Metrazol) tests conducted with mice or rats [White, 2003]. The former tests the ability of an investigational compound to eliminate the tonic extensor component of an electrically evoked seizure, whereas the latter tests the ability of a drug to inhibit a generalized clonic seizure resulting from subcutaneous administration of pentylenetetrazol, a GABAA receptor antagonist. Maximal electroshock seizures can be blocked by agents such as phenytoin and carbamazepine, which are effective in treating partial seizures that may or may not secondarily generalize. In contrast, drugs effective in treating generalized absence seizures (e.g., ethosuximide) effectively inhibit pentylenetetrazol-induced seizures. Valproic acid, a broad-spectrum agent, is active in maximal electroshock and pentylenetetrazol tests, and it is clinically effective against most seizure types. Despite the prevailing view that acute animal seizure models can predict efficacy against partial or generalized seizures in humans, there is a significant limitation of this

time-honored strategy. These screening tests may fail to identify substances acting through potentially novel mechanisms. Such is the case with levetiracetam, a newer antiepileptic drug that is effective in the treatment of temporal lobe epilepsy but that is inactive in maximal electroshock and pentylenetetrazol models [Klitgaard, 2001]. Since 1993, many new antiepileptics have been approved for use in the United States—felbamate, gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide. Outside the United States, vigabatrin has been another useful agent for the treatment of partial seizures and particularly for infantile spasms in patients with tuberous sclerosis. Many of these agents were successful products of an extensive drug discovery campaign carried out in collaborative fashion by the National Institutes of Health, academic medical centers, and the pharmaceutical industry [Rogawski and Porter, 1992]. Although the newer drugs appeared promising in early studies, particularly with regard to their side-effect profile, they have not yielded significantly higher clinical efficacy rates than older medications. The real impact of these newer drugs has been in diminished adverse effects and fewer drug interactions. Many people with epilepsy continue to experience intractable seizures and long-term cognitive, systemic, and perhaps developmental impairment.

Antiepileptics and Their Mechanisms of Action Most antiepileptics exert their principal effects on any number of the following molecular targets: GABAA receptors, glutamate receptors (both NMDA and non-NMDA), voltagedependent sodium channels, and voltage-dependent calcium channels [Rogawski and Löscher, 2004]. Each antiepileptic drug is likely to have multiple mechanisms of action because there is no single action of an antiepileptic agent that can completely account for all of its clinical effects. Almost every clinically useful antiepileptic drug has been found to block voltage-gated sodium channels, but it is interactions with other molecular targets that help define a drug’s clinical spectrum. Although this discussion focuses primarily on studies of hippocampal neurons and circuits, insights into antiepileptic mechanisms have emerged from studies of many neural tissues (e.g., spinal cord, peripheral nerve, neocortex) and experimental preparations [Rho and Sankar, 1999; Rogawski and Löscher, 2004]. Putative molecular targets of clinically approved antiepileptic drugs are shown in Figures 41-8 and 41-9, which depict key elements of central nervous system excitatory and inhibitory synapses, respectively. For many years, the primary drugs of choice for the treatment of partial epilepsy have been phenytoin and carbamazepine. Both drugs cause voltage-, frequency-, and usedependent block of sodium channels in a wide variety of neuronal preparations. Sustained, high-frequency, repetitive firing of neurons, thought to play a significant role in neuronal excitability, is limited by both agents at free plasma concentrations found in patients treated for epilepsy [Rogawski and Löscher, 2004]. Oxcarbazepine, a structural analog of carbamazepine that is reduced to a monohydroxy derivative, also blocks sustained repetitive firing. As predicted on the basis of its mechanistic profile, which is remarkably similar to that of phenytoin and carbamazepine,

Rho and Stafstrom / Neurophysiology of Epilepsy

Excitatory presynaptic terminal

Propagated action potential

Levetiracetam Oxcarbazepine –

– N-type voltage-dependent calcium channel

Ca2+ Na+

Gabapentin

1003

Phenytoin Carbamazepine Oxcarbazepine Valproic acid Lamotrigine Felbamate Topiramate Zonisamide

Voltage-dependent sodium channel

Depolarization

–

Vesicular release

␣2␦ subunit of L-type calcium channel

Postsynaptic neuron

Glutamate Felbamate

Topiramate K+

K+

–

– Outside

Inside NMDA receptor

AMPA/kainate receptor Ca2+, Na+

Na+ (Ca2+)

FIGURE 41-8. Schematic diagram of an excitatory synapse in the central nervous system and the putative major sites of action of various antiepileptic drugs. Levetiracetam has been found to bind to a synaptic vesicle protein, SV2A, which is involved in exocytosis. AMPA, α-amino-3-hydroxy-5-methyl4-isoxazole propionic acid; NMDA, N-methyl-D-aspartate. (Adapted from Rho JM, Sankar R. The pharmacological basis of antiepileptic drug action. Epilepsia 1999;40:1471. Reprinted with the permission of Blackwell Publishing Ltd.)

oxcarbazepine has been found to be effective only against partial seizures. Although structurally unrelated to classic agents such as phenytoin and carbamazepine, lamotrigine has been demonstrated to block sodium channels in a voltage-, frequency-, and use-dependent manner. However, lamotrigine appears to have a much broader spectrum of activity than phenytoin or carbamazepine, demonstrating efficacy against several forms of generalized seizures in addition to partial seizures. The mechanistic basis for this difference remained unclear until the demonstration that lamotrigine enhances activation of dendritic hyperpolarization-activated cation channels [Poolos et al., 2002], which are highly expressed in thalamic neurons involved in pacemaking activity. It is well established that the principal molecular targets of benzodiazepine and barbiturate antiepileptics are postsynaptic GABAA receptors [MacDonald and Olsen, 1994]. Binding of benzodiazepines or barbiturates to their respective recognition sites results in enhancement of GABAA receptor current. Two newer agents affecting the GABA system include vigabatrin, an irreversible inhibitor of the major GABA degradative enzyme, GABA transaminase, and tiagabine, a highly potent, selective presynaptic re-uptake blocker. Both vigabatrin and tiagabine result in elevations of synaptic GABA levels.

For many patients with epilepsy, valproic acid has largely replaced phenobarbital as an effective, broad-spectrum antiepileptic drug. Valproic acid can evoke a wide variety of biochemical and neurophysiologic changes in multiple neurotransmitter systems [Löscher, 2002]. Despite numerous studies, valproic acid’s precise mechanisms of action remain a mystery. Much of the scientific attention has focused on its multiple effects on the GABAergic system, resulting in elevated brain GABA levels. At therapeutically attainable levels, valproic acid also diminishes sustained repetitive firing of cultured mouse spinal cord and neocortical neurons, implicating actions on voltage-gated sodium channels as well. Another antiepileptic whose mechanism of action is yet unclear is gabapentin. Contrary to the prediction that gabapentin, a GABA analog, may act on GABAergic systems, gabapentin does not interact with GABAA or GABAB receptors and does not affect GABA re-uptake, synthesis, or metabolism. However, the existence of a specific binding site for gabapentin has been reported. Unlike other pharmacologic agents (e.g., flunarizine, dihydropyridines) that interact with the α1 subunit of voltage-dependent calcium channels, gabapentin binds to the α2δ subunit of the L-type calcium channel [Thurlow et al., 1993]. Gabapentin (much like lamotrigine) was found to enhance h-currents in hippocampal neurons, but the clinical significance of this remains

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Epilepsy / 41

Inhibitory presynaptic terminal

Glutamate GAD

– Succinic semialdehyde

GABA-T

–

T

GABA

BA

Vigabatrin

A

GABA

G

Succinic semialdehyde –

– Tiagabine

Glial cell

Zn2+ GABA transporter

GABA transporter

Levetiracetam

– GABA

+

Benzodiazepines

Barbiturates +

+ Outside

Felbamate Topiramate

Inside Postsynaptic neuron

GABAA receptors

CI– FIGURE 41-9. Schematic diagram of an inhibitory synapse in the central nervous system, and the putative major sites of actions of various antiepileptic drugs. GABA, γ-aminobutyric acid; GABA-T, GABA transaminase; GAD, glutamic acid decarboxylase. (Adapted from Rho JM, Sankar R. The pharmacological basis of antiepileptic drug action. Epilepsia 1999;40:1471. Reprinted with the permission of Blackwell Publishing Ltd.)

unclear [Surges et al., 2003]. Despite an earlier controversy regarding potential effects on GABAB receptors, later data confirm an interaction with GABAB receptor coupling to G-proteins and modulation of an inwardly rectifying potassium channel and N-type, voltage-gated calcium channels [Bertrand et al., 2003]. Whatever the relevant mechanisms toward an antiepileptic action, elevated entire-brain GABA levels have been found in patients taking gabapentin [Petroff et al., 1996]. Felbamate is the first pharmacologic agent to potentiate GABAA receptor–mediated responses and inhibit NMDA receptor–mediated responses within the same drug concentration range [Rho et al., 1994]. These dual actions may result in synergism with respect to seizure protection. Similarly, topiramate inhibits the AMPA or kainate subtype of glutamate receptors—specifically the GluR5 kainate receptors [Gryder and Rogawski, 2003; Kaminski et al., 2004] —and augments GABAA receptor–mediated Cl– currents [White et al., 1997]. Zonisamide is a broad-spectrum agent that has a unique mechanistic profile. In cultured spinal cord neurons, zonisamide reduced sustained repetitive firing of action potentials, consistent with actions on voltage-gated sodium channels [Rock et al., 1989]; in cultured neurons from rat cerebral cortex, zonisamide blocked low-threshold T-type calcium currents, which predicts efficacy against generalized spikewave epilepsies [Suzuki et al., 1992].

One of the newest antiepileptics has challenged our conceptual understanding of relevant mechanisms of action. Levetiracetam failed the maximal electroshock and pentylenetetrazol seizure threshold tests in animals, but it had a profound effect in retarding amygdala kindling in rats [Löscher et al., 1998], and it has proven clinical efficacy against partial and perhaps some generalized seizures. The strongest clue in identifying levetiracetam’s principal molecular target is the demonstration of a specific high-affinity neuronal binding site [Noyer et al., 1995]. The identity of this binding site remains unclear, but the demonstration that levetiracetam binds to a specific synaptic vesicle protein, SV2A, which is involved in neurotransmitter release, is a novel and intriguing observation [Lynch et al., 2004]. This example illustrates that there is still much to learn about the mechanisms underlying epileptogenesis and seizure genesis. Despite their diverse molecular actions, current antiepileptic drugs fail to cure the disease; rather, they attempt to eliminate the major symptom—seizures—by dampening neuronal excitation, synchronization, and spread of seizure activity. There is little experimental evidence to support the idea that these drugs are truly antiepileptogenic or antiepileptic (i.e., prevent the development or maintenance of epilepsy, a clinical state of chronic recurrent seizures) [Pitkänen, 2002; Temkin et al., 2001]. As epileptogenic mechanisms are better understood, it will be possible to design more specific and rational interventions [Stables et al., 2002].

Rho and Stafstrom / Neurophysiology of Epilepsy

SUMMARY Epileptic seizures arise from a multiplicity of factors that regulate neuronal excitability and synchrony. Important mechanisms and substrates are believed to underlie seizure activity in the mature and the developing brain. There are unique differences in the ontogeny of ion channels and transporters that render the immature brain more susceptible to seizures than the adult brain. Although much has been learned about the molecular and cellular alterations that produce or accompany seizure activity, neurologists have yet to fully integrate these findings with the largely phenomenologic electroclinical observations and treatment responses in experimental animal models of epilepsy and in humans. In dissecting the basic neurophysiology of epilepsy, it is tempting to invoke causality on any identifiable alteration that could theoretically enhance neuronal excitation. However, investigators frequently discover that it is not easy to identify the critical mediators and pathways in the processes of seizure genesis and epileptogenesis and that, ultimately, seizures are a reflection of a complex array of perturbations occurring at multiple hierarchical levels of cell structure and function and as yet unpredictable consequences of large neuronal network activity. REFERENCES Avishai-Eliner S, Brunson KL, Sandman CA, et al. Stressed-out, or in (utero)? Trends Neurosci 2002;25:518. Ben-Ari Y. Excitatory actions of GABA during development: The nature of the nurture. Nat Rev Neurosci 2002;3:728. Ben-Ari Y, Khazipov R, Leinekugel X, et al. GABAA, NMDA and AMPA receptors: A developmentally regulated ‘menage a trois.’ Trends Neurosci 1997;20:523. Bertrand S, Nouel D, Morin F, et al. Gabapentin actions on Kir3 currents and N-type Ca2+ channels via GABAB receptors in hippocampal pyramidal cells. Synapse 2003;50:95. Biervert C, Schroeder BC, Kubisch C, et al. A potassium channel mutation in neonatal human epilepsy. Science 1998;279:403. Bragin A, Jandó G, Nádasdy Z, et al. Dentate EEG spikes and associated interneuronal population bursts in the hippocampal hilar region of the rat. J Neurophysiol 1995;73:1691. Brooks-Kayal AR, Jin H, Price M, et al. Developmental expression of GABA(A) receptor subunit mRNAs in individual hippocampal neurons in vitro and in vivo. J Neurochem 1998;70:1017. Brooks-Kayal AR, Shumate MD, Jin H, et al. Gamma-aminobutyric acid(A) receptor subunit expression predicts functional changes in hippocampal dentate granule cells during postnatal development. J Neurochem 2001;77:1266. Buzsáki G, Bragin A, Chrobak JJ, et al. Oscillatory and intermittent synchrony in the hippocampus: Relevance to memory trace formation. In: Buzsáki G, Llinas R, Sing W, et al., eds. Temporal coding in the brain. Berlin: Springer-Verlag 1994;145. Buzsáki G, Leung LWS, Vanderwolf CH. Cellular bases of hippocampal EEG in the behaving rat. Brain Res Rev 1983;6:139. Catterall WA, Goldin AL, Waxman SG, et al. International Union of Pharmacology. XXXIX. Compendium of voltage-gated ion channels: Sodium channels. Pharmacol Rev 2003a;55:575. Catterall WA, Striessnig J, Snutch TP, et al. International Union of Pharmacology. XL. Compendium of voltage-gated ion channels: Calcium channels. Pharmacol Rev 2003b;55:579. Cobb SR, Buhl EH, Halasy K, et al. Synchronization of neuronal activity in hippocampus by individual GABAergic interneurons. Nature 1995;378:75. Conn PJ. Physiological roles and therapeutic potential of metabotropic glutamate receptors. Ann N Y Acad Sci 2003;1003:12. Coulter DA. Epilepsy-associated plasticity in gamma-aminobutyric acid receptor expression, function, and inhibitory synaptic properties. Int Rev Neurobiol 2001;45:237.

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Martin DL, Olsen RW, eds. GABA in the nervous system: The view at fifty years. Philadelphia: Lippincott, Williams and Wilkins, 2000. McCormick D, Prince D. Post-natal development of electrophysiological properties of rat cerebral cortical pyramidal neurones. J Physiol 1987;393:743. McCormick DA, Contreras D. On the cellular and network bases of epileptic seizures. Annu Rev Physiol 2001;63:815. Meldrum BS, Akbar MT, Chapman AG. Glutamate receptors and transporters in genetic and acquired models of epilepsy. Epilepsy Res 1999;36:189. Menkes JH, Sankar R. Paroxysmal disorders. In: Menkes JH, Sarnat HB, eds. Child neurology, 6th ed. Philadelphia: Lippincott Williams & Wilkins, 2000;919. Miles R. A homeostatic switch. Nature 1999;397:215. Moody WJ. The development of voltage-gated ion channels and its relation to activity-dependent development events. Curr Top Dev Biol 1998;39:159. Mori H, Mishina M. Structure and function of the NMDA receptor channel. Neuropharmacology 1995;34:1219. Moshe SL, Brown LL, Kubova H, et al. Maturation and segregation of brain networks that modify seizures. Brain Res 1994;665:141. Mott DD, Lewis DV. The pharmacology and function of central GABAB receptors. Int Rev Neurobiol 1994;36:97. Newman EA. Sodium-bicarbonate cotransport in retinal astrocytes and Muller cells of the rat. Glia 1999;26:302. Niedermeyer E, Lopes Da Silva F. Electroencephalography: Basic principles, clinical applications, and related fields, 4th ed. Philadelphia: Lippincott Williams & Wilkins, 1999. Noyer M, Gillard M, Matagne A, et al. The novel antiepileptic drug levetiracetam (ucb L059) appears to act via a specific binding site in CNS membranes. Eur J Pharmacol 1995;286:137. Painter MJ, Scher MS, Stein AD, et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med 1999;341:485. Perez-Reyes E. Molecular physiology of low-voltage-activated T-type calcium channels. Physiol Rev 2003;83:117. Petroff OA, Rothman DL, Behar KL, et al. The effect of gabapentin on brain gamma-aminobutyric acid in patients with epilepsy. Ann Neurol 1996;39:95. Pitkänen A. Efficacy of current antiepileptics to prevent neurodegeneration in epilepsy models. Epilepsy Res 2002;50:141. Poolos NP. The Yin and Yang of the H-channel and its role in epilepsy. Epilepsy Curr 2004;4:3. Poolos NP, Migliore M, Johnston D. Pharmacological upregulation of h-channels reduces the excitability of pyramidal neuron dendrites. Nat Neurosci 2002;5:767. Represa A, Tremblay E, Ben-Ari Y. Transient increase of NMDA-binding sites in human hippocampus during development. Neurosci Lett 1989;99:61. Rho JM, Donevan SD, Rogawski MA. Mechanism of action of the anticonvulsant felbamate: Opposing effects on N-methyl-D-aspartate and γ-aminobutyric acid receptors. Ann Neurol 1994;35:229. Rho JM, Sankar R. The pharmacological basis of antiepileptic drug action. Epilepsia 1999;40:1471. Ribera A, Spitzer N. Development of electrical excitability in embryonic neurons: Mechanisms and roles. J Neurobiol 1998;37:190. Rivera C, Voipio J, Payne JA, et al. The K+/Cl– co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 1999;397:251. Robinson RB, Siegelbaum SA. Hyperpolarization-activated cation currents: From molecules to physiological function. Annu Rev Physiol 2003;65:453. Rock DM, Macdonald RL, Taylor CP: Blockade of sustained repetitive action potentials in cultured spinal cord neurons by zonisamide (AD 810, CI 912), a novel anticonvulsant. Epilepsy Res 1989;3:138. Rogawski MA. KCNQ2/KCNQ3 K+ channels and the molecular pathogenesis of epilepsy: Implications for therapy. Trends Neurosci 2000;23:393 Rogawski MA, Löscher W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci 2004;5:553. Rogawski MA, Porter RJ. Antiepileptic drugs: Pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacol Rev 1990;42:223.

Rogawski MA, Porter RJ. New antiepileptic drugs: From serendipity to rational discovery. Epilepsia 1992;33 (Suppl 1):S1. Rothstein JD, Dykes-Hoberg M, Pardo CA, et al. Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 1996;16:675. Sanchez RM, Jensen FE. Maturational aspects of epilepsy mechanisms and consequences for the immature brain. Epilepsia 2001;42:577. Santoro B, Baram TZ. The multiple personalities of H-channels. Trends Neurosci 2003;26:550. Schwartzkroin PA, Mueller AL. Electrophysiology of hippocampal neurons. In: Jones EG, Peters A, eds. Cerebral cortex, Vol. 6. Further aspects of cortical function, including hippocampus. New York: Plenum Press, 1987;295. Simeone TA, Donevan SD, Rho JM. Molecular biology and ontogeny of gamma-aminobutyric acid (GABA) receptors in the mammalian central nervous system. J Child Neurol 2003;18:39. Simeone TA, Sanchez RM, Rho JM. Molecular biology and ontogeny of glutamate receptors in the mammalian central nervous system. J Child Neurol 2004;19:343. Singh NA, Charlier C, Stauffer D, et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet 1998;18:25. Snead OC 3rd. Basic mechanisms of generalized absence seizures. Ann Neurol 1995;37:146. Song I, Kim D, Choi S, et al. Role of the alpha1G T-type calcium channel in spontaneous absence seizures in mutant mice. J Neurosci 2004;24:5249. Spitzer NC, Kingston PA, Manning TJ, et al. Outside and in: Development of neuronal excitability. Curr Opin Neurobiol 2002;12:315. Stables JP, Bertram EH, White HS, et al. Models for epilepsy and epileptogenesis: Report from the NIH workshop, Bethesda, Maryland. Epilepsia 2002;43:1410. Stafstrom CE. An introduction to seizures and epilepsy: Cellular mechanisms underlying classification and treatment. In: Stafstrom CE, Rho JM, eds. Epilepsy and the ketogenic diet. Totowa, NJ: Humana Press, 2004;3. Stafstrom CE, Lynch M, Sutula TP. Consequences of epilepsy in the developing brain: Implications for surgical management. Semin Pediatr Neurol 2000;7:147. Staley KJ, Smith R. A new form of feedback at the GABA-A receptor. Nat Neurosci 2001;4:674. Staley KJ, Soldo BL, Proctor WR. Ionic mechanisms of neuronal excitation by inhibitory GABAA receptors. Science 1995;269:977. Surges R, Freiman TM, Feuerstein TJ. Gabapentin increases the hyperpolarization-activated cation current Ih in rat CA1 pyramidal cells. Epilepsia 2003;44:150. Suzuki S, Kawakami K, Nishimura S, et al. Zonisamide blocks T-type calcium channel in cultured neurons of rat cerebral cortex. Epilepsy Res 1992;12:21. Swann J, Pierson M, Smith KL, et al. Developmental neuroplasticity: Roles in early life seizures and chronic epilepsy. In: Delgado-Escueta A, Wilson W, Olsen R, et al, eds. Jasper’s basic mechanisms of the epilepsies. Philadelphia: Lippincott Williams & Wilkins, 1999. Swann JW, Hablitz JJ. Cellular abnormalities and synaptic plasticity in seizure disorders of the immature nervous system. Ment Retard Dev Disabil Res Rev 2000;6:258. Temkin NR. Antiepileptogenesis and seizure prevention trials with antiepileptic drugs: Meta-analysis of controlled trials. Epilepsia 2001;42:515. Thurlow RJ, Brown JP, Gee NS, et al. [3H]gabapentin may label a system L-like neutral amino acid carrier in brain. Eur J Pharmacol (Mol Pharmacol) 1993;247:341. Traub RD, Miles R. Neuronal networks of the hippocampus. New York: Cambridge University Press, 1991. Traynelis SF, Cull-Candy SG. Proton inhibition on N-methyl-D-aspartate receptors in cerebellar neurons. Nature 1990;345:347. Vallano M. Developmental aspects of NMDA receptor function. Crit Rev Neurobiol 1998;12:177. Velazquez JP, Carlen P. Gap junctions, synchrony and seizures. Trends Neurosci 2000;23:68. Velisek L, Veliskova J, Moshe SL. Developmental seizure models. Ital J Neurol Sci 1995;16:127.

Rho and Stafstrom / Neurophysiology of Epilepsy Vezzani A, Moneta D, Conti M, et al. Powerful anticonvulsant action of IL-1 receptor antagonist on intracerebral injection and astrocytic overexpression in mice. Proc Natl Acad Sci U S A 2000;97:11534. White HS. Preclinical development of antiepileptic drugs: Past, present, and future directions. Epilepsia 2003;44 (Suppl 7):2. White HS, Brown SD, Woodhead JH, et al. Topiramate enhances GABA-mediated chloride flux and GABA-evoked chloride currents in

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murine brain neurons and increases seizure threshold. Epilepsy Res 1997;28:167. Wickenden AD, Yu W, Zou A, et al. Retigabine, a novel anti-convulsant, enhances activation of KCNQ2/Q3 potassium channels. Mol Pharmacol 2000;58:591. Wong RK, Prince DA. Participation of calcium spikes during intrinsic burst firing in hippocampal neurons. Brain Res 1978;159:385.

CHAPTER 42

Genetics of Epilepsy Ingrid E. Scheffer and Samuel F. Berkovic

The genetics of epilepsy are complex, akin to those of other common disorders such as asthma and hypertension. Progress in finding genes in these disorders has been slow, presumably because the disorders result from the interaction of a number of genes with or without environmental effects. A majority of epilepsies follow complex inheritance (Fig. 421, shaded oval), with the first insights into relevant genes only now emerging. A smaller group of epilepsy syndromes follow simple inheritance (see Fig. 42-1, white circle); elucidation of the molecular basis of the disorders in this group has been successful. Genes encoding ion channel receptor subunits account for a majority of genes identified to date. These discoveries raise the question of whether related genes may be involved in the complex inheritance pattern that underlies most epilepsy syndromes. The epilepsies are broadly classified into generalized and partial (focal) epilepsy syndromes and further subdivided into those due to idiopathic and symptomatic disorders [Engel, 2001; International League against Epilepsy, 1989]. The idiopathic epilepsies are regarded as having a genetic basis, whereas the symptomatic epilepsies frequently have an acquired etiology. With the advent of gene discovery, these distinctions are becoming increasingly blurred. For example, certain “symptomatic” epilepsies such as severe myoclonic epilepsy of infancy are known to have a genetic basis [Claes et al., 2001], whereas the genetic basis of the most common “idiopathic” partial epilepsy syndrome, benign rolandic epilepsy, recently has been drawn into question [Vadlamudi et al., 2004]. In this chapter progress in the clinical and molecular genetics of generalized and focal epilepsies is reviewed, and the chapter begins with an underrecognized group of epilepsies of infancy of autosomal-dominant inheritance. The genetics of febrile convulsions [Baulac et al., 2004], epilepsies due to chromosomal anomalies [Singh et al., 2002], or epilepsies associated with inherited metabolic diseases, storage disorders, or degenerative processes are not addressed [Mole, 2004; Zeviani and Di Donato, 2004].

AUTOSOMAL-DOMINANT EPILEPSIES OF INFANCY Three seizure disorders with autosomal-dominant inheritance beginning in the first year of life are now known. All three disorders have been localized to chromosomal regions, and genes have been identified in two. The clinical presentations of the three disorders are similar, the main distinguishing feature is the predominant age at onset in a family. Of importance, all three disorders overlap in their ranges of age at onset, so that the age at onset in a single family member will not necessarily indicate which is the most likely disorder. In

each condition, a previously well and developmentally normal neonate or infant experiences clusters of seizures over a few days or weeks. The seizures often have focal clinical and electroencephalographic features. Seizures usually are controlled with antiepileptic medication, and the prognosis is good, with later febrile seizures or epilepsy observed in only a minority of patients.

Benign Familial Neonatal Seizures Since Rett and Teubel’s original description of benign familial neonatal seizures, affected families have been recognized around the world [Rett and Teubel, 1964]. Well infants experience seizures beginning on day 2 or 3 of life, with a flurry of seizures over a few days. Detailed characterization of seizure types has demonstrated definite focal features [Bye, 1994]. These infants have an excellent developmental outcome, with only 5% having febrile seizures later and 11% having epilepsy later [Plouin and Anderson, 2002]. In rare infants, the outcome may be poor, and a single family with myokymia in later life has been described [Borgatti et al., 2004; Dedek et al., 2001, 2003]. Benign familial neonatal seizures is the only epilepsy syndrome for which the molecular basis has been found in a majority of affected families. Most families have mutations of potassium-channel subunit genes, KCNQ2 and KCNQ3 [Biervert et al., 1998; Charlier et al., 1998; Singh et al., 1998]. A majority of mutations are in KCNQ2, with only three reported to date in KCNQ3 [Hirose et al., 2000; Singh et al., 2003]. The potassium-channel subunits KCNQ2 and KCNQ3 together form a heteromultimeric potassium channel that has a key role in stabilization of resting membrane potential. In vitro functional studies of mutations report impairment of channel function [Biervert et al., 1998; Jentsch, 2000; Singh et al., 2003]. De novo mutations in KCNQ2 have been described in infants with benign neonatal seizures, in which there is no family history. This finding further highlights the importance of this gene in seizures in the first week of life [Claes et al., 2004].

Benign Familial Neonatal-Infantile Seizures In 1983, Kaplan and Lacey described a single large North American family with benign familial neonatal-infantile seizures [Kaplan and Lacey, 1983]. No additional families were recognized until 2002, when two families were reported with mutations in the alpha 2 subunit of the neuronal sodium channel (SCN2A) [Heron et al., 2002]. Benign familial neonatal-infantile seizures have been associated with mutations in SCN2A in eight families, including the original

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relevant to ma jor es n e

ity

es cas of

?g

Majority of cases: Complex inheritance Many genes, currently unknown Modified by environmental factors

Rare families: Simple inheritance Multiple single-gene disorders Genes encode ion channel subunits FIGURE 42-1. Genetics of common diseases: Epilepsies.

chromosome 16; however, the regions do not all overlap [Demir et al., 2004; Lee et al., 1998]. Presence of a number of duplicated genes in the centromeric region of chromosome 16 has made it hard to identify the specific genes involved. In addition to the chromosome 16 locus for benign familial infantile seizures and infantile convulsions and choreoathetosis, two other loci have been reported. A chromosome 1 locus has been described in a single family who had familial hemiplegic migraine with a few members with infantile convulsions. This family had a mutation of ATP1A2, a gene encoding a sodium-potassium ATPase transporter [Vanmolkot et al., 2003]. The relationship to benign familial infantile seizures requires confirmation. A single report maps benign familial infantile seizures to chromosome 19 [Guipponi et al., 1997].

GENETICS OF GENERALIZED EPILEPSIES North American family [Berkovic et al., 2004]. These families have a mean age at seizure onset of 11 weeks, but a wide range of onset ages, from 2 days to 6 months, has been reported. These infants do well, with no later epilepsy reported. Of the eight families with SCN2A mutations, three have the same mutation, although these are not the result of a founder effect [Berkovic et al., 2004]. A number of other early childhood epilepsies have been studied for mutations of SCN2A including GEFS+; however, no further mutations have been identified, apart from a severe myoclonic epilepsy of infancy-like phenotype in a single patient [Kamiya et al., 2004]. It is possible that other families previously regarded as having benign familial infantile seizures may actually have benign familial neonatal-infantile seizures, but this will be established only with further SCN2A testing.

Benign Familial Infantile Seizures Benign infantile seizures with a familial pattern were recognized in 1963 by Fukuyama [1963]; infantile convulsions of autosomal-dominant inheritance were described by Vigevano and colleagues [1992]. Onset of seizures typically is between the ages of 4 and 8 months, although extremes of 2 to 20 months have been reported. Seizures often are characterized by head and eye deviation that may alternate to different sides in different attacks. Unilateral clonic or bilateral hypertonic features also may occur. Interictal electroencephalogram (EEG) studies demonstrate parieto-occipital discharges. A special subgroup of families with infantile convulsions and choreoathetosis [Szepetowski et al., 1997] has been recognized. These families have a paroxysmal movement disorder of autosomal-dominant inheritance in addition to infantile seizures, although not all affected persons have both disorders [Hattori et al., 2000]. The choreoathetosis may begin any time from infancy to adolescence and can be associated with dystonic features. It may be triggered by exertion, anxiety, or rest. In some families, onset of seizures is at a later age [Lee et al., 1998; Spacey et al., 2002]. In many families from around the world with benign familial infantile convulsions with or without paroxysmal kinesigenic choreoathetosis, the disorder maps to the pericentromeric region of

The idiopathic generalized epilepsies fall into two major categories. The first category is classic idiopathic generalized epilepsy, incorporating the well-recognized subsyndromes of childhood absence epilepsy, juvenile myoclonic epilepsy, juvenile absence epilepsy, and generalized tonic-clonic seizures alone (GTCA). Although affected persons most commonly have no family history of epilepsy or febrile convulsions, small families in which a few members have seizure disorders are not unusual. Studies of small families with classic idiopathic generalized epilepsy demonstrate that phenotypic heterogeneity is usual, with different family members having different subsyndromes [Italian League against Epilepsy Genetic Collaborative Group, 1993; Marini et al., 2004]. Variable combinations and permutations of genes are likely to produce specific subsyndromes within families. The second major subgroup of idiopathic generalized epilepsies is generalized epilepsy with febrile seizures plus (GEFS+), a more recently described “familial epilepsy syndrome.” GEFS+ also is characterized by phenotypic heterogeneity ranging from very mild seizure disorders including febrile seizures to severe epileptic encephalopathies such as severe myoclonic epilepsy of infancy. Clinical genetic studies of families with idiopathic generalized epilepsy suggest only limited overlap in subsyndromes between the two major subgroups of idiopathic generalized epilepsy, but overlap can occur [Marini et al., 2003].

Idiopathic Generalized Epilepsies The classic idiopathic generalized epilepsies comprise epilepsy syndromes such as childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and generalized tonic-clonic seizures alone [International League, 1989]. Generalized tonic-clonic seizures alone previously have been known as generalized tonic-clonic seizures on awakening, but in some persons, generalized tonic-clonic seizures occur at any time of day, so this syndrome is now regarded more broadly as generalized tonic-clonic seizures at any time without other seizure types. The hallmark of the idiopathic generalized epilepsy is generalized spike-andwave activity with a regular 3-Hz pattern in childhood

Scheffer and Berkovic / Genetics of Epilepsy

absence epilepsy and fast polyspike-and-wave pattern in adolescent idiopathic generalized epilepsy. Although exceptionally rare families with idiopathic generalized epilepsy segregating in an autosomal-dominant manner [Cossette et al., 2002], and perhaps even as autosomal-recessive traits [Zara et al., 2000], have been described, the vast majority of idiopathic generalized epilepsy cases are consistent with complex inheritance. The risk to siblings of having idiopathic generalized epilepsy is about 6%. Clinical genetic studies have found that families with multiple members with idiopathic generalized epilepsy typically show phenotypic heterogeneity [Italian League against Epilepsy Genetic Collaborative Group, 1993; Marini et al., 2004]. Analysis of seizure types reveals that absence seizures are more likely to run in families, either with childhood absence epilepsy or juvenile absence epilepsy, whereas myoclonic seizures segregate in other families [Winawer et al., 2003]. This finding suggests that specific gene defects predispose affected persons to certain seizure types. Many genetic loci have been implicated in idiopathic generalized epilepsy studies, but few genes have been found and confirmed to have a pathogenic role [Durner et al., 1999, 2001; Sander et al., 2000]. A few genes have been confirmed to be associated with idiopathic generalized epilepsy. GABRG2, the gene encoding the gamma 2 subunit of the GABAA receptor, has been associated with childhood absence epilepsy in two large families (see earlier) [Kananura et al., 2002; Wallace et al., 2001]. Mutation of the alpha 1 subunit gene of the GABAA receptor, GABRA1, has been reported in a single family with a rare autosomal-dominant form of juvenile myoclonic epilepsy [Cossette et al., 2002]. There are two reports of mutations of CLCN2, a chloride channel subunit gene, in families with idiopathic generalized epilepsy with variable phenotypes [D’Agostino et al., 2004; Haug et al., 2003]. Mutations in the gene EFHC1 have been reported by one group of investigators in families with juvenile myoclonic epilepsy [Suzuki et al., 2004]. Single reports implicate other genes in idiopathic generalized epilepsy, but no mutations have been found. One such gene is BRD2, a putative transcriptional regulator, which was found to have single-nucleotide polymorphisms in linkage disequilibrium with 20 persons with juvenile myoclonic epilepsy; however, no specific mutations have been identified [Pal et al., 2003]. Similarly, the mitochondrial enzyme malic enzyme 2, encoded by ME2, has been implicated in idiopathic generalized epilepsy without a specific mutation [Greenberg et al., 2005]. Mutations in CACNA1H, the alpha 1H subunit of the calcium channel, also have been reported. Mutations have been found in persons with childhood absence epilepsy and also in families with generalized epilepsy with febrile seizures plus and idiopathic generalized epilepsy phenotypes [Chen et al., 2003; Heron et al., 2004]. The existence of CACNA1H mutations also requires confirmation. Recently a mutation in another calcium channel subunit gene, CACNA1A, has been reported in childhood absence epilepsy with episodic ataxia [Imbrici et al., 2004]. Idiopathic generalized epilepsy results from complex inheritance, but it is not clear how many genes are necessary to produce a specific phenotype. What is clear is that with these disorders, genetic heterogeneity results in one syndrome and variable expressivity results from one gene.

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Generalized Epilepsy with Febrile Seizures Plus Generalized epilepsy with febrile seizures plus subsyndromes or phenotypes occur in sporadic cases but are more easily recognized in families in which a spectrum of phenotypes is seen [Scheffer and Berkovic, 1997; Singh et al., 1999]. The most common phenotype in generalized epilepsy with febrile seizures plus families is febrile seizures, defined as convulsions with fever (temperature above 38° C) between 3 months and 6 years of age at its widest limits. The second most common phenotype is febrile seizures plus, which refers to febrile seizures continuing past the age of 6 years or to presence of afebrile convulsions at any time in addition to febrile seizures. Other generalized epilepsy with febrile seizures plus family members may have isolated afebrile convulsions in childhood, a less common phenotype in the generalized epilepsy with febrile seizures plus spectrum. Febrile seizures or febrile seizures plus may be associated with later generalized or focal seizures. Generalized seizure types include absence, atonic, and myoclonic seizures. Focal seizures in generalized epilepsy with febrile seizures plus families may arise from the temporal lobe and the frontal lobe [Abou-Khalil et al., 2001; Baulac et al., 1999; Scheffer et al., 2000]. More severe epileptic encephalopathies in the generalized epilepsy with febrile seizures plus spectrum include myoclonic-astatic epilepsy, described by Doose and colleagues, and severe myoclonic epilepsy of infancy, recognized by Dravet and associates [Doose et al.; 1970, Dravet et al., 2002; Singh et al., 1999]. Myoclonic-astatic epilepsy begins with febrile seizures in approximately 30% cases [Doose et al., 1970]. Onset usually is between the ages of 1 and 5 years; males are more frequently affected. Then follows the evolution of multiple seizure types, including the key manifestation of myoclonicastatic seizures, and a constellation of myoclonic, atonic, absence, and generalized tonic-clonic seizures. Tonic seizures and nonconvulsive status epilepticus are seen with a more unfavorable outcome. The EEG reveals generalized spike-and-wave activity without focal features. Cognitive outcome is highly variable, ranging from normal to severe intellectual disability [Guerrini and Aicardi, 2003; Guerrini et al., 2002]. So far, three genes have been confirmed as important in families with generalized epilepsy with febrile seizures plus, although overall, they account for only a minority of cases of generalized epilepsy with febrile seizures plus [Wallace et al., 2001]. The genes encode subunits of the sodium channel and the GABAA receptor. Moreover, genes of major dominant effect, identified in large families, do not explain the phenotypic heterogeneity that is the hallmark of generalized epilepsy with febrile seizures plus. Phenotypic variation in the large generalized epilepsy with febrile seizures plus families is likely to be due to modifier genes with a possible environmental contribution. The neuronal sodium channel comprises a pore-forming alpha subunit and two regulatory beta subunits that regulate channel-gating kinetics. The alpha 1 subunit is made up of four transmembrane domains: each has a S5-6 region and linker that form the pore of the channel, the S4 region is the voltage sensor, and the carboxyl terminus localizes the channel to the axonal membrane. The gene encoding the alpha 1 subunit, SCN1A, is most frequently mutated in gen-

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eralized epilepsy with febrile seizures plus, although accounting for only a small proportion of generalized epilepsy with febrile seizures plus families overall [Escayg et al., 2000; Wallace et al., 2001]. Missense mutations are scattered throughout the gene in generalized epilepsy with febrile seizures plus [Mulley et al., 2005]. In vitro functional studies of SCN1A mutations report variable effects ranging from gain of function to loss of function [Lossin et al., 2002, 2003; Spampanato et al., 2004]. The beta 1 subunit gene, SCN1B, was the first gene identified in generalized epilepsy with febrile seizures plus, and to date, four mutations have been described but account for only a minority of generalized epilepsy with febrile seizures plus families [Audenaert et al., 2003; Wallace et al., 1998, 2002]. All four mutations localize to the extracellular immunoglobulin-like fold critical for modulation of channel function. GABAA receptors are heteropentameric ligand-gated chloride channels most commonly comprising two alpha, two beta, and a gamma subunit in brain. The gamma 2 subunit gene, GABRG2, is associated with mutations in generalized epilepsy with febrile seizures plus and also childhood absence epilepsy [Baulac et al., 2001; Harkin et al., 2002; Kananura et al., 2002; Wallace et al., 2001]. A proband of a large generalized epilepsy with febrile seizures plus family with a GABRG2 mutation has severe myoclonic epilepsy of infancy, although GABRG2 appears to be a rare cause of severe myoclonic epilepsy of infancy overall, with only one other case identified to date [Fukuma et al., 2003; Harkin et al., 2002]. Recently another subunit of the GABAA receptor has been implicated in generalized epilepsy with febrile seizures plus and idiopathic generalized epilepsy more generally. The gene GABRD encodes the delta subunit that forms a GABAA receptor, typically with two alpha and two beta subunits. This GABAA receptor is relatively nondesensitizing and has extrasynaptic localization and an important role in tonic, as opposed to phasic, inhibition. A small family with a GABRD mutation and generalized epilepsy with febrile seizures plus has been described, with functional effects on in vitro studies suggesting that GABRD could be a susceptibility gene for idiopathic generalized epilepsy and generalized epilepsy with febrile seizures plus; however, this finding requires confirmation [Dibbens et al., 2004]. Generalized epilepsy with febrile seizures plus was recognized through study of large families with multiple affected members over many generations, allowing the identification of relevant genes. These families are rare and do not account for a majority of cases of generalized epilepsy with febrile seizures plus. Generalized epilepsy with febrile seizures plus most commonly arises on a sporadic basis or in small families, in which it follows complex inheritance, likely as the result of interaction of a number of genes, with an environmental contribution. The challenge is to find these susceptibility genes of lesser effect, and perhaps GABRD is the first entrée to this arena.

Severe Myoclonic Epilepsy of Infancy Severe myoclonic epilepsy of infancy, or Dravet’s syndrome, begins in the first year of life, typically at 6 months. A previously well and developmentally normal infant pre-

sents with febrile hemiclonic or generalized status epilepticus. Shortly thereafter, the child may present at a subsequent visit with recurrent seizures and often febrile status, and hemiclonic seizures may involve the other side. Convulsive seizures continue, and between the ages of 1 and 4 years, the child develops other seizures of other types including myoclonic, partial, atonic, and absence seizures. The child’s development slows from 1 year and then may regress with the evolution of pyramidal signs and ataxia. Cognitive outcome often is poor. EEG findings are normal for the first year or two, and then generalized spike-and-wave activity is seen, often with photosensitivity and focal features. From the initial description of severe myoclonic epilepsy of infancy, many authors have noted that up to 50% of patients with severe myoclonic epilepsy of infancy have a family history of seizure disorders including febrile seizures and epilepsy. Formal clinical genetic studies reveal that family members have epilepsy syndromes that fall within the generalized epilepsy with febrile seizures plus spectrum [Singh et al., 2001; Veggiotti et al., 2001]. Claes and colleagues investigated the role of SCN1A in severe myoclonic epilepsy of infancy in view of the predilection for children with severe myoclonic epilepsy of infancy to have seizures with fever. They found that 7 of 7 children with severe myoclonic epilepsy of infancy had de novo truncation mutations of SCN1A [Claes et al., 2001]. More than 100 SCN1A mutations have subsequently been described in severe myoclonic epilepsy of infancy patients, with mutational rates of 33% to 100% in severe myoclonic epilepsy of infancy cohorts [Claes et al., 2003; Fukuma et al., 2003; Mulley et al., 2005; Nabbout et al., 2003; Sugawara et al., 2002; Wallace et al., 2003]. Mutations are commonly truncation in nature, although missense mutations can occur and tend to be in the S5-6 region that forms the pore of the sodium channel [Claes et al., 2003; Kanai et al., 2004; Mulley et al., 2005]. Fewer than 10% of mutations are familial in origin and these usually are missense mutations found in the broader family with generalized epilepsy with febrile seizures plus phenotypes [Gennaro et al., 2003; Nabbout et al., 2003]. The familial SCN1A mutation in these patients with severe myoclonic epilepsy of infancy is one part of a polygenic etiology leading to severe myoclonic epilepsy of infancy. Considerable debate exists about the phenotypic spectrum of severe myoclonic epilepsy of infancy, and this led Japanese authors to describe a related group of patients with severe myoclonic epilepsy of infancy–borderline. These patients lack at least one of the key features of severe myoclonic epilepsy of infancy, such as myoclonic seizures. In certain subgroups within severe myoclonic epilepsy of infancy–borderline, such as intractable childhood epilepsy with tonic-clonic seizures, the clinical course is similar, but affected children have only tonic-clonic seizures [Doose et al., 1998]. Approximately 30% (depending on the subgroup) of affected persons in these subgroups also have SCN1A mutations [Fukuma et al., 2004]. Genotype-phenotype correlations are beginning to emerge; for example, missense mutations are found exclusively in intractable childhood epilepsy with tonic-clonic seizures [Fujiwara et al., 2003]. A single case of idiopathic infantile spasms has been associated with an SCN1A defect [Wallace et al., 2003]. A single

Scheffer and Berkovic / Genetics of Epilepsy

severe myoclonic epilepsy of infancy–borderline-like case with older age at onset has been associated with a mutation of SCN2A, the gene encoding the alpha 2 subunit of the sodium channel [Kamiya et al., 2004].

GENETICS OF FOCAL EPILEPSIES The focal epilepsies are subdivided into the idiopathic focal and symptomatic focal epilepsies. The more common idiopathic focal epilepsies follow complex inheritance. More recently, a number of mendelian focal epilepsies have been recognized; within this subgroup, elucidation of the molecular basis has met with some success.

Mendelian Focal Epilepsies Autosomal-Dominant Nocturnal Frontal Lobe Epilepsy Autosomal-dominant nocturnal frontal lobe epilepsy begins in mid-childhood at a mean age of 8 years and a median age of 12 years. Autosomal-dominant nocturnal frontal lobe epilepsy is characterized by clusters of nocturnal motor attacks, with multiple attacks occurring over several hours. Seizures comprise hyperkinetic thrashing attacks or tonic seizures, and awareness often is retained; seizures may begin with a nonspecific aura. Seizures have a variable course and are mild and easily controlled in many affected persons, although they may be highly refractory to treatment in some family members [Scheffer et al., 1994, 1995]. Interictal EEG recordings are often normal but may demonstrate frontal discharges. Ictal studies may show frontal onset but more commonly are marred by movement artifact [Hayman et al., 1997]. MRI findings are normal, and radioisotope imaging studies such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) may reveal focal frontal abnormalities [Hayman et al., 1997]. Persons with autosomal-dominant nocturnal frontal lobe epilepsy usually are of normal intellect; however, intellectual disability and psychiatric difficulties have been described in specific kindreds [Khatami et al., 1998; McLellan et al., 2003; Nakken et al., 1999]. A gene for autosomal-dominant nocturnal frontal lobe epilepsy was identified in 1995 when a mutation was found in the neuronal acetylcholine receptor alpha 4 subunit gene (CHRNA4). Three mutations have been found in families from around the world, indicating the existence of mutation hot spots, all localizing to the ion channel pore [Hirose et al., 1999; McLellan et al., 2003; Phillips et al., 2000; Saenz et al., 1999; Steinlein et al., 1995, 1997, 2000]. Mutations also were identified in the beta 2 subunit of the neuronal acetylcholine receptor, CHRNB2, with mutations reported in a few families [De Fusco et al., 2000; Phillips et al., 2001]. Functional studies report variable effects that relate to the expression systems and testing performed [Bertrand, 1999; Bertrand et al., 2002; Kuryatov et al., 1997].

Autosomal-Dominant Partial Epilepsy with Auditory Features Ottman and colleagues described autosomal-dominant partial epilepsy with auditory features, which typically begins

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in adolescence or early adult life [Ottman et al., 1995]. This condition, also known as autosomal-dominant lateral temporal lobe epilepsy, is characterized by lateral temporal lobe seizures with prominent auditory manifestations such as ringing or humming. Some affected persons experience visual phenomena or aphasia [Gu et al., 2002; Poza et al., 1999; Winawer et al., 2000]. Autosomal-dominant partial epilepsy with auditory features has been localized to the long arm of chromosome 10, where the gene involved is LGI1 [Berkovic et al., 2004; Bisulli et al., 2004; Gu et al., 2002; Kalachikov et al., 2002; Morante-Redolat et al., 2002; Ottman et al., 1995]. LGI1 (leucine-rich, glioma-inactivated 1) is thought to have a role in tumor suppression, and mutations have been found in a significant proportion of families with autosomal-dominant partial epilepsy with auditory features, although genetic heterogeneity exists [Berkovic et al., 2004]. LGI1 has an epilepsy-associated repeat region that also is found in the MASS1 gene, a gene associated with epilepsy in murine models and possibly human febrile seizures [Nakayama et al., 2002; Staub et al., 2002].

Familial Mesial Temporal Lobe Epilepsy Familial mesial temporal lobe epilepsy is a complex area of study, with a number of subgroups emerging that are defined by their semiology and association with structural abnormalities such as hippocampal sclerosis. The most clearly differentiated syndrome is familial mesial temporal lobe epilepsy, which begins in adolescence or adult life and usually is a benign syndrome characterized by typical temporal lobe seizures with déjà vu [Aguglia et al., 1998; Berkovic et al., 1994, 1996; Gambardella et al., 2000; Regesta and Tanganelli, 2002]. Familial mesial temporal lobe epilepsy originally was not associated with febrile seizures or hippocampal sclerosis. Familial mesial temporal lobe epilepsy follows autosomal-dominant inheritance with low penetrance, and attempts to map relevant genetic loci have not been successful. More recently, familial mesial temporal lobe epilepsy has been found to be heterogeneous, with some families having more severe disorders associated with hippocampal sclerosis, a variable association with febrile seizures, and onset in the first to third decades of life [Cendes et al., 1998; Kobayashi et al., 2001]. An underlying familial malformation may predispose the patient to febrile seizures and the development of hippocampal sclerosis [Fernandez et al., 1998]. Familial mesial temporal lobe epilepsy also has been described in a few families, with many members having both temporal lobe epilepsy and febrile seizures. Temporal lobe epilepsy begins by the age of 20 years; imaging findings are normal, and it has a benign course [Baulac et al., 2001; Depondt et al., 2002]. In a French family, digenic inheritance was postulated, with a chromosomal locus with significant linkage at 18qter and supportive linkage at 1q25-q31 [Baulac et al., 2001]. It is probably more common to find families in which many members have febrile seizures and isolated or few members have temporal lobe epilepsy with or without hippocampal sclerosis [Ward et al., 2002]. Prolonged febrile seizures are more likely to be associated with hippocampal

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sclerosis [Maher and McLachlan, 1995]. A single family with generalized epilepsy with febrile seizures plus and a few members with temporal lobe epilepsy, including hippocampal sclerosis, have had an SCN1A mutation [AbouKhalil et al., 2001].

Familial Partial Epilepsy with Variable Foci Familial partial epilepsy with variable foci was first identified in an Australian family in which different family members had different forms of focal epilepsy that emanated from a consistent cortical region in each person throughout life. Within each family, different members had frontal, temporal, centroparietal, or occipital lobe epilepsy. Daytime seizures were common, and the interictal EEG revealed frequent focal epileptiform activity with a focus consistent with clinical seizures. In that first Australian family, the relevant gene was tentatively mapped to chromosome 2 [Scheffer et al., 1998]. More recently, familial partial epilepsy with variable foci in Canadian, Spanish, and Dutch families has been reported and mapped definitively to chromosome 22 [Berkovic et al., 2004; Callenbach et al., 2003; Xiong et al., 1999]. The chromosome 22q form of familial partial epilepsy with variable foci differs from the original form of familial partial epilepsy with variable foci in two ways: A prominent phenotype of nocturnal frontal lobe epilepsy indistinguishable from autosomal-dominant nocturnal frontal lobe epilepsy occurs in some family members, and interictal EEG studies are less active. In 22q familial partial epilepsy with variable foci, frontal and temporal lobe epilepsies predominate [Berkovic et al., 2004]. Epilepsies in these families can begin in childhood, adolescence, or young adulthood. No gene has been identified as yet.

Focal Epilepsies with Complex Inheritance Benign Childhood Epilepsy with Centrotemporal Spikes Benign rolandic epilepsy, or benign childhood epilepsy with centrotemporal spikes, is the most common idiopathic partial epilepsy [International League, 1989]. It is characterized by nocturnal orofaciomotor attacks with prominent drooling and speech arrest. It may be preceded by an aura of perioral paresthesia. The EEG shows classic centrotemporal spikes, which have a horizontal dipole across the rolandic fissure. This classic EEG signature has a genetic basis, and early studies suggested (incorrectly) that this abnormality followed autosomal dominant inheritance with agedependent penetrance [Bray and Wiser, 1964]. Recognition of the genetic etiology of the centrotemporal discharges led to the conventional wisdom that benign childhood epilepsy with centrotemporal spikes is essentially a genetic disorder—that it is an “idiopathic” epilepsy. Clinical genetic data suggest otherwise: Siblings with benign childhood epilepsy with centrotemporal spikes are very rare; moreover, twin studies show low concordance rates for benign childhood epilepsy with centrotemporal spikes in monozygotic twin pairs [Vadlamudi et al., 2004]. A locus for centrotemporal spikes was reported on chromosome 15 in the q14 region [Neubauer et al., 1998], but this finding has not been confirmed, and no genes have been

identified to date. It appears that conventional genetic factors play a far smaller role in the etiology of benign childhood epilepsy with centrotemporal spikes, and it remains to be clarified if benign childhood epilepsy with centrotemporal spikes is determined by unconventional genetic factors or is largely due to environmental influences [Vadlamudi et al., 2004]. Some rare familial forms of rolandic epilepsy have been described. Rolandic epilepsy with speech dyspraxia, with evidence of anticipation, was reported in a single family; the mode of inheritance was autosomal-dominant [Scheffer et al., 1995]. An autosomal-recessive form of rolandic epilepsy, with paroxysmal exercise-induced dystonia and writer’s cramp, was described in a single Italian family; the relevant gene was mapped to the p12-11.2 region of chromosome 16 [Guerrini et al., 1999].

CONCLUSION The rapidly evolving field of epilepsy genetics is still in its infancy but already is providing an entrée into the neurobiology of seizure disorders. The discovery of the central role of ion channels in seizure disorders is crucial to the development of targeted therapies and, ultimately, gene therapy. Gene therapy in complex diseases such as epilepsy will be very challenging because a host of factors are likely to have an impact on epilepsy syndromes and response to antiepileptic therapies.

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Phillips HA, Favre I, Kirkpatrick M, et al. CHRNB2 is the second acetylcholine receptor subunit associated with autosomal dominant nocturnal frontal lobe epilepsy. Am J Hum Genet 2001;68:225. Phillips HA, Marini C, Scheffer IE, et al. A de novo mutation in sporadic nocturnal frontal lobe epilepsy. Ann Neurol 2000;48:264. Plouin P, Anderson VE. Benign familial and non-familial neonatal seizures. In: Roger J, Bureau M, Dravet C, et al, eds. Epileptic syndromes in infancy, childhood and adolescence, Vol. 17. Eastleigh, UK: John Libbey, 2002:3. Poza JJ, Saenz A, Martinez-Gil A, et al. Autosomal dominant lateral temporal epilepsy: Clinical and genetic study of a large Basque pedigree linked to chromosome 10q. Ann Neurol 1999;45:182. Regesta G, Tanganelli P. Temporal lobe epilepsy of adult age of possible idiopathic nature. Seizure 2002;11:131. Rett A, Teubel R. Neugeborenenkrämpfe im Rahmen einer epileptisch belasteten familie. Wien Klin Wochenschr 1964;76:609. Saenz A, Galan J, Caloustian C, et al. Autosomal dominant nocturnal frontal lobe epilepsy in a Spanish family with a Ser252Phe mutation in the CHRNA4 gene. Arch Neurol 1999;56:1004. Sander T, Schulz H, Saar K, et al. Genome search for susceptibility loci of common idiopathic generalised epilepsies. Hum Mol Genet 2000;9:1465. Scheffer IE, Berkovic SF. Generalized epilepsy with febrile seizures plus. A genetic disorder with heterogeneous clinical phenotypes. Brain 1997;120:479. Scheffer IE, Bhatia KP, Lopes-Cendes I, et al. Autosomal dominant frontal epilepsy misdiagnosed as sleep disorder. Lancet 1994;343:515. Scheffer IE, Bhatia KP, Lopes-Cendes I, et al. Autosomal dominant nocturnal frontal lobe epilepsy. A distinctive clinical disorder. Brain 1995;118:61. Scheffer IE, Jones L, Pozzebon M, et al. Autosomal dominant rolandic epilepsy and speech dyspraxia: A new syndrome with anticipation. Ann Neurol 1995;38:633. Scheffer IE, Phillips HA, O’Brien CE, et al. Familial partial epilepsy with variable foci: A new partial epilepsy syndrome with suggestion of linkage to chromosome 2. Ann Neurol 1998;44:890. Scheffer IE, Wallace R, Wellard MR, et al. Temporal lobe epilepsy and febrile seizures associated with a sodium channel beta 1 subunit (SCN1B) mutation. Epilepsia 2000;41:71. Singh NA, Charlier C, Stauffer D, et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet 1998;18:25. Singh NA, Westenskow P, Charlier C, et al. KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: Expansion of the functional and mutation spectrum. Brain 2003;126:2726. Singh R, Andermann E, Whitehouse WPA, et al. Severe myoclonic epilepsy of infancy: Extended spectrum of GEFS+? Epilepsia 2001;42:837. Singh R, Gardner RJ, Crossland KM, et al. Chromosomal abnormalities and epilepsy: A review for clinicians and gene hunters. Epilepsia 2002;43:127. Singh R, Scheffer IE, Crossland K, et al. Generalized epilepsy with febrile seizures plus: A common, childhood onset, genetic epilepsy syndrome. Ann Neurol 1999;45:75. Singh R, Scheffer IE, Whitehouse W, et al. Severe myoclonic epilepsy of infancy is part of the spectrum of generalized epilepsy with febrile seizures plus (GEFS+). Epilepsia 1999;40:175. Spacey SD, Valente EM, Wali GM, et al. Genetic and clinical heterogeneity in paroxysmal kinesigenic dyskinesia: Evidence for a third EKD gene. Mov Disord 2002;17:717. Spampanato J, Aradi I, Soltesz I, et al. Increased neuronal firing in computer simulations of sodium channel mutations that cause generalized epilepsy with febrile seizures plus. J Neurophysiol 2004;91:2040. Staub E, Perez-Tur J, Siebert R, et al. The novel EPTP repeat defines a superfamily of proteins implicated in epileptic disorders. Trends Biochem Sci 2002;27:441. Steinlein OK, Magnusson A, Stoodt J, et al. An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy. Hum Mol Genet 1997;6:943. Steinlein OK, Mulley JC, Propping P, et al. A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 1995;11:201.

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CHAPTER 43

Generalized Seizures Gregory L. Holmes

As reviewed in Chapter 40, seizures are classified into two basic groups: partial and generalized [Commission on Classification and Terminology of the International League Against Epilepsy, 1981]. Partial seizures involve only a portion of the brain at the onset but can spread, resulting in generalized tonic-clonic seizures. Primary generalized seizures are those in which the first clinical changes indicate initial synchronous involvement of both hemispheres without clinical, electroencephalographic, or other evidence of focal or partial onset. Impairment of consciousness is usual during generalized seizures, although some seizures, such as myoclonic, may be so brief that level of consciousness cannot be assessed. The generalized seizures span a wide range in clinical presentation, ranging from the rather benign-appearing absence seizure to the dramatic and frightening generalized tonic-clonic seizure. In most epidemiologic studies, primary generalized seizures are reported to be less common than partial seizures [Hauser and Kurland, 1975; Juul-Jensen and Foldspang, 1983]. For example, Hauser and Kurland [1975] and Juul-Jensen and Foldspang [1983] found that primary generalized seizures accounted for 40.5% and 45.8% of the seizure types, respectively. Studies confined to children have been more variable. Todt [1984], in a study of children with seizures ranging in age from 3 to 16 years, found that 61.5% had primary generalized seizures, compared with only 26.6% of children between 2 months and 14 years of age in a series reported by Sofijanov [1982]. Of the primary generalized seizures, generalized tonic-clonic are the most common, followed by absence and myoclonic seizures [Hauser and Kurland, 1975]. These epidemiologic studies may be somewhat misleading. With improvement of diagnostic techniques in recent decades, especially with long-term video monitoring using electroencephalography (EEG), it has become clear that the prevalence of primary generalized tonic-clonic epilepsy has been overestimated. In fact, most generalized tonic-clonic seizures begin as partial seizures and then generalize [Porter, 1984; Schmidt et al., 1983]. This chapter discusses generalized tonic-clonic seizures and absence, tonic, clonic, and atonic seizures, along with the syndromes in which these are the predominant seizure type. Myoclonic seizures, which are generalized seizures, are reviewed in Chapter 46 and partial seizures in Chapter 44.

GENERALIZED TONIC-CLONIC SEIZURES Clinical Features Some children with generalized tonic-clonic seizures, or their parents, are aware of the impending seizure, hours or

days before it occurs. The child may have a headache, insomnia, irritability, or a change in appetite. This prodrome is to be distinguished from an aura, which is a simple partial seizure that may occur before generalization of the seizure. Unlike the aura, the prodrome is not associated with any EEG epileptiform activity. As indicated by the name, generalized tonic-clonic seizures have two distinct phases: tonic and clonic [Gastaut and Broughton, 1972]. Loss of consciousness usually occurs simultaneously with the onset of a generalized stiffening of flexor or extensor muscle—the tonic phase. The loss of consciousness usually is complete, and it is rare for patients to have any partial awareness of what happened during the seizure. During the tonic phase, prolonged extension of the back, neck, and all limbs often occurs. The eyes remain open, and a cry or yell is common. The tonic phase typically lasts 10 to 30 seconds and is followed by the clonic phase. The clonic phase usually starts with a rapid tremor and then slows to massive jerks of the extremities and trunk. A decrescendo pattern to the frequency (although not necessarily the strength) of the jerks is seen as the seizure ceases. The clonic phase typically lasts 30 to 60 seconds. Cyanosis is common and results from the arrest of ventilation during the tonic phase and insufficient short breaths during the following clonic phase. Pupillary dilation, salivation, sweating, hyperthermia, and incontinence are common. A postictal state always follows the clonic phase. The duration is quite variable. Some patients, even after a severe and prolonged seizure, respond within a minute or so, whereas other patients may be difficult to arouse for 20 to 30 minutes. Although the postictal phase initially consists of stupor, it may be followed by confusion or agitation. In a number of syndromes, generalized seizures are a predominant feature. Epilepsy with so-called grand mal seizures on awakening is a rare syndrome in which the generalized tonic-clonic seizures occur only on awakening [Gastaut et al., 1963; Janz and Wolf, 1997; Wolf, 1992]. In generalized epilepsy with febrile seizures plus, patients initially have febrile seizures; later, as the condition evolves, they experience afebrile generalized tonic-clonic or other types of generalized seizures [Abou-Khalil et al., 2001; Baulac et al., 2004; Scheffer and Berkovic, 1997; Wallace et al., 2000, 2002]. Generalized tonic-clonic or clonic-tonicclonic seizures often can be a prominent component of juvenile myoclonic epilepsy, a condition discussed in Chapter 46. Children with Lennox-Gastaut syndrome may have generalized tonic-clonic seizures, although tonic seizures are the core seizure type in this syndrome. Although their disorder currently is not classified as a syndrome, a distinct group of patients with photosensitive epilepsy have seizures provoked by flickering lights and have

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Epilepsy / 43 FIGURE 43-1. Photoconvulsive response in patient with primary generalized epilepsy. Note the burst of irregular spike-and-wave activity during the photic stimulation. (Calibration: 50 μV, 1 second.)

Fp1–F3 F3–C3 C3–P3 P3–O1 Fp2–F4 F4–C4 C4–P4 P4–O2 Fp1–F7 F7–T3 T3–T5 T5–O1 Fp2–F8 F8–T4 T4–T6 T6–O2 FZ–CZ CZ–PZ [LLOC–A1] [ROUC–A1] [EKG [Photic

a photoconvulsive response to strobe light on EEG. The photoconvulsive response is characterized by spike-and-wave and multiple spike-and-wave complexes that are bilaterally synchronous, symmetric, and widespread (Fig. 43-1). These should be contrasted with spikes that are time-linked with the photic stimulation and confined to the occipital region, which in children are normal. The photoconvulsive response may be self-limited and cease during stimulation or continue beyond the stimulation [Reilly and Peters, 1973]. The most effective frequency of the flash is 10 to 20 Hz. The seizures evoked by photic stimulation usually are primary generalized in type: generalized tonic-clonic, absence, or myoclonic seizures. Although patients with partial seizures may have photoconvulsive responses during an TABLE 43-1 Comparison of Primary and Secondary Generalized Tonic-Clonic (GTC) Seizures Feature

Primary GTC

Secondary GTC

Prodrome Aura Usual duration Family history for seizures Acquired lesions EEG findings Interictal

Occasionally Never 1-3 min Frequently

Occasionally Frequently 1-3 min Occasionally

Rarely

Frequently

Normal or generalized spike-and-wave activity

Normal or focal or multifocal spikes Rarely

Photoconvulsive Frequently response Hyperventilation May activate spike-and-wave discharges

EEG, electroencephalogram.

Usually does not activate epileptiform discharges

EEG study, it is unusual for a partial seizure to be precipitated by photic stimulation [Jayakar and Chiappa, 1990]. Generalized epileptiform discharges during photic stimulation correlate with generalized seizures, whereas focal discharges are more commonly associated with partial seizures [Gilliam and Chiappa, 1995]. Photosensitive epilepsy can be classified into two major groups: (1) pure photosensitive epilepsy, in which clinical seizures occur only when the patient is exposed to the photic stimulus, and (2) photosensitive epilepsy, in which spontaneous seizures occur in addition to those induced by light stimulation [Binnie and Jeavons, 1992]. Precipitating stimuli that can produce a seizure include sunlight reflected from water, sunlight viewed through leaves of trees in a breeze or while driving along tree-lined streets, discotheque lighting, faulty fluorescent lamp (“nervous ballast”), television, and video games. Photosensitive epilepsy usually appears around puberty, with a mean age at onset of 14 years and a higher incidence in girls than in boys [Jeavons, 1982].

Differential Diagnosis Difficulty is rarely encountered in correctly diagnosing generalized tonic-clonic seizures (formerly termed grand mal seizures). Generalized tonic-clonic seizures can be divided into those that are primarily generalized from onset and those that begin as partial seizures and then secondarily generalize [Schmidt et al., 1983]. Differentiating features are listed in Table 43-1. On very rare occasions, generalized tonic-clonic seizures begin as another generalized seizure type such as absence [Niedermeyer, 1976] before evolving into tonic-clonic activity. Breath-holding attacks, pseudoseizures (nonepileptic events), and syncope occasionally may resemble generalized tonic-clonic seizures. These are discussed in Chapters 54 and 55.

Holmes / Generalized Seizures

Electroencephalographic Findings In patients with partial seizures with secondary generalization, the interictal EEG features are similar to those described for partial seizures. Patients with primary generalized tonic-clonic seizures typically have either normal interictal EEG activity or bursts of generalized spike-and-wave discharges. As with absence seizures, spike-and-wave or polyspike-and-wave activity can occur with photic stimulation and hyperventilation. Normal EEG activity, however, can be observed in patients with generalized tonic-clonic seizures. The ictal EEG features begin suddenly and are widespread. The tonic phase usually begins as loss of background frequencies, with sudden generalized suppression of the background activity (flattening or attenuation of the EEG signal), followed by a gradual buildup of low-voltage fast spikes, usually starting at 20 to 40 Hz and then decreasing to 10 Hz, lasting up to 10 seconds, with a progressive increase in amplitude and decrease in frequency—the so-called “epileptic recruiting rhythm.” This is followed by the clonic phase, with slow waves following the spikes. The spikeand-wave complexes gradually slow in frequency before stopping. During the postictal phase, the EEG shows either suppression of background activity or diffuse slowing. The duration of the postictal changes is variable, with background abnormalities lasting minutes to even days following the seizure. Focal slowing during the postictal phase suggests that the seizure had a partial onset. The absence of any slowing during the postictal phase should raise the question of nonepileptic seizures.

Etiology The etiology of seizures in children who have secondary generalized tonic-clonic seizures is the same as that described in Chapter 44. Patients with primary generalized tonic-clonic seizures usually do not have structural lesions and often have a familial disorder, such as juvenile myoclonic epilepsy. The genetics of generalized tonicclonic seizures are discussed in Chapter 42.

Initial Evaluation The initial steps in the evaluation depend to a major degree on the patient’s clinical status on first presentation to the physician. For example, the patient who arrives at the emergency department following a generalized seizure with fever and confusion is evaluated differently from the otherwise normal child who presents several hours after a generalized seizure. The former needs an urgent evaluation to look for an infectious etiology, such as meningitis or encephalitis, whereas the latter can be managed less hastily. This chapter deals with the evaluation and treatment indicated for patients with generalized seizures as their only presenting clinical sign. In all children with their first seizure, a careful history should be obtained, with particular attention to whether the seizure was preceded by an aura or if the seizure had any focal features. An aura, focal onset to the seizures, or Todd’s paralysis would suggest that the seizure had a partial onset. A review of potential precipitating factors, such as

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sleep deprivation or photic stimulation, may be useful in counseling the patient and the parents. A past medical history of birth asphyxia or trauma, head injury, prolonged febrile seizures, meningitis, or encephalitis may offer etiologic clues indicating that the seizures have a partial onset. A history of other neurologic symptoms should be sought. Headaches, especially those associated with vomiting or occurring at night, should raise the possibility of a structural lesion. Although neuroimaging appears to have reduced the importance of the neurologic examination, abnormal findings, even if subtle, may provide clues to the location of seizure onset and etiology of the seizures. For example, asymmetries in facial expression or strength may indicate focal deficits even in the presence of normal neuroimaging findings. Diagnostic studies ordered depend on findings during the history and neurologic examination. Children with an unremarkable history other than for the seizures and with normal findings on neurologic examination typically require only an EEG and neuroimaging. An EEG should always be obtained because it may help differentiate partial from generalized seizures. Focal epileptiform activity or slowing would raise the possibility of a structural lesion. Neuroimaging is recommended in all patients presenting with their first unexplained generalized tonic-clonic seizure, with the recognition that in patients with normal neurologic examinations, the chance of finding a treatable lesion is quite low [Hirtz et al., 2000]. Because generalized tonic-clonic may have a partial onset with subsequent rapid generalization, however, the seizure may be incorrectly diagnosed as primary generalized in type. In nonemergency settings, the imaging test of choice is the magnetic resonance imaging (MRI) scan. Computed tomography (CT) scans can be used in acute situations to rule out mass lesions and hemorrhage. The need for further diagnostic testing such as metabolic screening and cerebrospinal fluid examination depends on the clinical presentation. In the absence of mental retardation, developmental regression, or abnormalities on neurologic examination, these studies usually are not indicated following the initial seizure.

Treatment The treatment of generalized seizures that have a partial onset is the same as for generalized seizures. Although a number of the newer antiepileptic drugs are being used for the treatment of primary generalized tonicclonic seizures, definitive evidence for their effectiveness is lacking [Faught, 2003; French et al., 2004a]. One of the issues is that in many studies, partial seizures with secondary generalization are included along with primary generalized tonic-clonic seizures. In addition, data for adults and children often are combined when studies are reported. Antiepileptic drug studies done solely in children with primary generalized tonic-clonic seizures are limited. The evidence is insufficient to determine effectiveness in newly diagnosed primary generalized tonic-clonic seizures in children [French et al., 2004a]. Therefore, the older-generation antiepileptic drugs typically are used initially in the treatment of primary generalized tonic-clonic seizures in children. These drugs include valproate [Chadwick, 1987; Marson et al., 2002; Mattson, 1995; Murphy and Delanty, 2000; Ramsay and

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DeToledo, 1997; Wilder and Rangel, 1988], carbamazepine [Murphy and Delanty, 2000; Ramsay and DeToledo, 1997; Tudur et al., 2002, 2003], and phenytoin [Murphy and Delanty, 2000; Ramsay and DeToledo, 1997; Taylor et al., 2001; Tudur et al., 2002]. Although phenobarbital is effective in the treatment of primary generalized tonic-clonic seizures, the adverse side effects profile has reduced its use as initial therapy for primary generalized tonic-clonic seizures [Taylor et al., 2001; Tudur et al., 2003]. Topiramate has been demonstrated to be effective for the treatment of refractory generalized tonic-clonic seizures [Biton et al., 1999; French et al., 2004a]. The drug has not yet been demonstrated to be effective for initial therapy in children with primary generalized tonic-clonic seizures. The four drugs for generalized tonic-clonic seizures are reviewed briefly here. Additional information about the antiepileptic drugs is available in Chapter 49. Carbamazepine is indicated for initial or adjunctive therapy for generalized generalized tonic-clonic seizures. The drug is not helpful in other forms of primary generalized tonic-clonic seizures; indeed, it can exacerbate these conditions [Shields and Saslow, 1983; Snead and Hosey, 1985]. The drug is relatively nonsedating and is well tolerated by children [Seetharam and Pellock, 1991]. Carbamazepine should be started at a low dose, and the dosage slowly increased. Carbamazepine is metabolized by the liver into multiple metabolites, some of which (especially carbamazepine epoxide) possess antiepileptic activity. Multiple drug interactions can occur and result in either toxicity or loss of seizure control. Carbamazepine demonstrates self-induction, which means that the plasma concentration may fall during the first 2 months of administration. Unless anticipitated, this drop in blood level may result in seizure recurrence. Monthly determination of carbamazepine blood levels is therefore recommended during the first 3 months of therapy, with dose adjustments made accordingly. Carbamazepine is marketed as both immediate-release and extended-release preparations. The extended-release preparations are better tolerated than the immediate-release preparation and can be administered twice daily [Miller et al., 2004]. In children, carbamazepine typically is started at 5 to 10 mg/kg per day, with increases of 5 mg/kg per day. Most children require between 20 and 30 mg/kg per day. Serum blood levels can be very helpful in assessing compliance and ensuring that the child is taking an adequate dose. The target serum level for carbamazepine is 8 to 12 μg/mL. Most children with blood levels greater than 12 μg/mL will have signs of toxicity. In children younger than 12, the drug should be taken twice daily; in teenagers, once a day is sufficient. Evidence of local toxicity consists of gastric irritability that usually is minimized if the patient takes the drug after meals. Common manifestations of dose-related toxicity include diplopia or blurred vision, dizziness, drowsiness, ataxia, and headache. Idiosyncratic toxic reactions are rash (common) and, more rarely, anemia, agranulocytosis, leukopenia, thrombocytopenia, hypersensitivity syndrome (dermatitis, eosinophilia, lymphadenopathy, splenomegaly), and cholestatic and hepatocellular jaundice [Holmes, 1995]. Phenytoin is efficacious in primary generalized tonicclonic seizures but is not effective in other forms of primary

generalized epilepsy such as absence or myoclonic. It is relatively nonsedating (sedation is mild and similar in degree to that of carbamazepine). Although serious toxicity is rare [Dodson, 1993a; Ramsay, 1986], phenytoin may result in reversible gingival hyperplasia and other cosmetic side effects (hirsutism, acne, and coarsening of facial features). Phenytoin is metabolized by the liver to the major metabolite 5-(4-hydroxyphenyl)-5-phenylhydantoin, which is saturable, giving rise to a nonlinear dose-serum concentration relationship [Richens, 1979]. Therefore, the dose range compatible with a therapeutic serum concentration is narrow, and monitoring serum concentrations is of particular value in tailoring dosage. Drug interactions are common with phenytoin. The usual pediatric dose is 5 to 8 mg/kg per day. Prepubescent children should be given the drug in two divided doses; teenagers can take the drug once daily. Because of phenytoin’s concentration-dependent pharmacokinetics, it is recommended that the daily dose be changed by only 25 or 50 mg when the phenytoin plasma concentration is 10 μg/mL or higher, and a month should be allowed for attainment of steady-state plasma concentration after a change in dosing rate. Common dose-related side effects are nystagmus, ataxia, dysarthria, and sedation [Bruni, 2002]. High plasma concentration may be associated with changes in mental state ranging from dysphoria and mild confusion to coma, and with choreiform movements, external ophthalmoplegia, and increased seizure frequency. Idiosyncratic toxicity commonly includes rash (usually morbilliform and appearing within the first 12 weeks of therapy). Rare side effects include agranulocytosis, thrombocytopenia, aplastic anemia, Stevens-Johnson syndrome, hepatitis, nephritis, lymphomalike syndrome, thyroiditis, systemic lupus erythematosus, and hyperglycemia. Gingival hyperplasia occurs in approximately 20% of patients taking long-term phenytoin. The gingival hyperplasia can be managed with good oral hygiene or, rarely, gingivectomy. The gingival hyperplasia usually resolves within a few months if phenytoin is discontinued. Hirsutism, acne, and coarsening of facial features all have been attributed to phenytoin. Because of the nonlinear kinetics and side effect profile, phenytoin use in primary generalized tonic-clonic seizures is not recommended. Valproate (valproic acid and divalproex sodium) is widely used in children to treat primary generalized seizures, including generalized tonic-clonic seizures. In children with both absence and primary generalized tonic-clonic seizures, valproate is an excellent choice because it is efficacious in both conditions. Valproate is approximately 90% protein bound. Protein binding varies with drug plasma concentration, and the free fraction increases with increasing plasma concentration [Davis et al., 1994]. Therefore, with high blood levels of valproate, the free, or active, portion of valproate becomes greater, and toxicity may occur. In addition, drugs or endogenous substances such as free fatty acids can alter protein binding. The primary metabolism is by hepatic hydroxylation (mitochondrial beta oxidation) and conjugation with glucuronide. Eighty percent of an administered dose of valproic acid is metabolized through these two pathways and then excreted by the kidney [Levy et al., 2002]. The

Holmes / Generalized Seizures

remainder of a dose is excreted in other oxidized metabolites. Drug interactions are common with valproate [Scheyer, 2002]. In children, the recommended starting dose is 10 to 15 mg/kg per day, with gradual increases by 5 to 10 mg/kg per day every week until therapeutic success is achieved or toxicity occurs. Although most patients do well with blood levels of 60 to 100 μg/mL, some patients tolerate blood levels up to 150 μg/mL. Gastrointestinal toxicity includes anorexia, nausea, and indigestion. These symptoms may be reduced with the divalproex sodium preparations. Dose-related toxicities are action tremor (seen in 40% of adults, less frequent in children), elevated plasma transaminase (usually transient but a possible harbinger of serious hepatic disease), and hyperammonemia. Idiosyncratic toxicity includes hepatic necrosis (treatable with L-carnitine), thrombocytopenia, pancreatitis (in 0.5%, sometimes fatal), teratogenicity, and stupor and coma. The risk of hepatic fatality is greatest in children younger than 2 years and in patients taking valproic acid in combination with other antiepileptic drugs [Dreifuss et al., 1987, 1989]. Toxic effects with long-term use are weight gain, hair loss, and platelet dysfunction. Routine monitoring with liver function tests, complete blood count, and valproate blood level determination is recommended. Topiramate has a broad spectrum of efficacy in children [Ormrod and McClellan, 2001] and has been found to be beneficial in the treatment of medically refractory primary generalized tonic-clonic seizures [Biton et al., 1999; French et al., 2004b; Wheless, 2000]. Topiramate is rapidly absorbed and has very low protein binding [Bourgeois, 2000]. In the absence of enzymeinducing drugs, 80% of a dose is excreted unchanged in the urine, with an elimination half-life of 20 to 30 hours. In the presence of enzyme-inducing drugs, 50% to 80% of a dose is excreted unchanged in the urine, with an elimination halflife of 12 to 15 hours in teenagers. The metabolic products of topiramate are formed in the liver and do not appear to be biologically active. Prepubescent children have a higher clearance and shorter elimination half-life than in adults [Bourgeois, 2000]. The recommended total dose of topiramate for pediatric patients (ages 2 to 16 years) is 5 to 9 mg/kg per day in two divided doses. Titration should begin at 25 mg (or less, based on a range of 1 to 3 mg/kg per day) nightly for the first week.

The dose should then be increased at 1- or 2-week intervals by increments of 1 to 3 mg/kg per day (administered in two divided doses) to achieve optimal clinical response. The most common side effects with topiramate are central nervous system related: drowsiness, dizziness, decreased attention or impaired concentration, paresthesia, nervousness, confusion, and impaired memory. These side effects usually are mild to moderate, develop during the first weeks of therapy, and may decline over time. The central nervous system side effects appear to be fewer when topiramate is used for monotherapy than when it is used in polytherapy and are less common in children than in adults. Weight loss [Ormrod and McClellan, 2001] and acidosis [Izzedine et al., 2004; Takeoka et al., 2001] can occur with topiramate therapy. Renal stones [Kuo et al., 2002; Lamb et al., 2004] and acute myopia [Coats, 2003] associated with secondary angle closure glaucoma have been reported. These side effects appear to be very rare in children. Although most of the newer antiepileptic drugs have been used in the treatment of generalized tonic-clonic seizures, their usefulness in children has not yet been established [Holmes, 2003; Jarrar and Buchhalter, 2003]. Table 43-2 summarizes the antiepileptic drugs used in the treatment of generalized tonic-clonic seizures and other generalized seizures in childhood. This listing is based on both efficacy and tolerability and reflects the author’s personal preferences. Antiepileptic drug therapy should always be tailored to the needs of the particular patient.

ABSENCE SEIZURES Clinical Features Absence seizures, formerly termed petit mal seizures are characterized by an abrupt cessation of activity, change in facial expression, and impairment of consciousness [Browne et al., 1974; Holmes et al., 1987; Porter et al., 1973]. Absence seizures are not common, accounting for less than 10% of all seizure types [Hauser and Hersdorffer, 1990; Hauser and Kurland, 1975; Sofijanov, 1982]. Absence seizures may be the most common seizure type to go undetected. The prevalence of absence seizures is highest

TABLE 43-2 Antiepileptic Drugs of Choice for Treatment of Generalized Seizures in Children GTC First Choice Valproate

Second Choice Carbamazepine Phenytoin Topiramate GTC, generalized tonic-clonic.

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Absence

Myoclonic

Tonic

Atonic

Ethosuximide Lamotrigine Valproate

Valproate

Lamotrigine Valproate

Lamotrigine Valproate

Levetiracetam Topiramate Zonisamide

Clonazepam Levetiracetam Zonisamide

Phenytoin Topiramate Felbamate (with caution)

Lamotrigine Topiramate Felbamate (with caution)

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during the first 10 years of life and then drops dramatically to a very low level [Hauser and Kurland, 1975; Hertoft, 1963; Sato et al., 1976]. Absence seizures are more common in girls than in boys [Hertoft, 1963; Sato et al., 1976]. Typical absence seizures rarely start before the age of 2 years or after the teenage years [Sato, 1983; Sato et al., 1976]. In a study of 83 patients with absence seizures, Sato and co-workers [1983] found the average age at onset was 3.8 years. Absence seizures are classified as typical or atypical in type (Table 43-3). Typical absence seizures are short, rarely lasting over 30 seconds; as with other generalized seizures, they are never associated with an aura or postictal impairment. The sudden onset of impaired consciousness, usually associated with a blank facial appearance without other motor or behavioral phenomena, is characteristic. The degree of impairment of consciousness is variable. Some children remember virtually everything that is said during the seizure, whereas for others, the entire duration of the seizure is “time lost.” Although the absence seizure is commonly thought to consist only of staring, in fact the behavioral changes associated with the seizure type usually are more complex. Most absence seizures are accompanied by motor, behavioral, or autonomic phenomena, and seizures characterized by only staring and altered consciousness are unusual. Penry and associates [1975] reviewed 374 absence seizures recorded on videotape from 48 patients and found simple absences, characterized by staring and cessation of activities, to constitute only 9.4% of the seizures. A majority of the patients had other clinical manifestations. Automatisms, semipurposeful behaviors of which the patient is unaware and subsequently cannot recall, are very common in absence seizures [Holmes et al., 1987; Penry et al., 1975]. They either may be perseverative, reflecting continuation of preictal activities, or may arise de novo. Simple behaviors, such as rubbing the face or hands, licking the lips, chewing, grimacing, scratching, or fumbling with clothes, tend to be de novo automatisms. Complex activities such as dealing cards, moving a chess piece, or handling a toy are generally perseverative. Speech, if it occurs during the seizure, usually is perseverative and may be slow and slurred, but also may be totally normal [McKeever et al., 1983]. The longer the absence seizure lasts, the more likely automatisms are to occur [Penry et al., 1975].

Clonic or myoclonic components are common but may be quite subtle, most frequently consisting of blinking. Clonic activity also may be manifested by nystagmus, rapid jerking or trembling of the arms, or head nods. Alterations in muscle tone may lead to stiffening of the trunk or a fall. A study of 426 typical and 500 atypical absence seizures studied in 54 children using simultaneous EEG and video monitoring, Holmes and colleagues [1987] found myoclonic jerks in 13% of typical absences and 12% of atypical absences. Children with the syndrome of epilepsy with myoclonic absences have prominent myoclonus during the seizure. Autonomic phenomena occasionally may be seen with absence seizures and include dilation of the pupils, pallor, flushing, sweating, salivation, piloerection, and even urinary incontinence. The frequency of absence seizures varies considerably from day to day and even from hour to hour. The number of absence seizures varies significantly with different environmental situations [Borkowski et al., 1992; Pearl and Holmes, 2001]. Seizures are more likely to occur during periods of inactivity than when the child is busily engaged in a task. Fatigue also may dramatically increase seizure susceptibility. A majority of children with typical absence seizures have normal findings on neurologic examination [Dalby, 1969; Sato, 1983]. When neurologic abnormalities are found, they usually are mild and nonprogressive. Most children with typical absence seizures have normal or mildly low intelligence [Dalby, 1969; Sato, 1983]. Compared with agematched controls, children with absence seizures have lower general cognitive function with impaired visual-spatial skills and memory disturbances [Pavone et al., 2001]. Children with absence seizures have higher rates of behavioral problems and psychopathology than in the normal population [Ott et al., 2001]. Typical absence seizures may be associated with generalized tonic-clonic seizures in 40% to 60% of patients [Hertoft, 1963; Holmes et al., 1987; Loiseau et al., 1983; Sato, 1983]. In most children, the generalized tonic-clonic seizures occur after onset of the absence seizures [Loiseau et al., 1983]. Although atypical absence seizures form a separate category of absences, overlap between the two seizure types is considerable, and they appear to represent a clinical

TABLE 43-3 Classification of Absence Seizures EEG FINDINGS Clinical Seizure

Type

Interictal Ictal

Typical absence Impairment of consciousness only With mild clonic components With tonic components With automatisms With autonomic components Atypical absence

Normal background; short bursts of regular and symmetric 2.5- to 4-Hz spike-and-wave; rare frontal or multifocal spikes, sharp waves; photoconvulsive response

Regular and symmetric 2.5-4 Hz spike-and-wave; often induced by hyperventilation or photic stimulation

Abnormal background; short bursts of irregular, asymmetric <2.5-Hz spike-and-wave; multifocal spikes, sharp waves; photoconvulsive response is rare

Bursts of irregular, asymmetric <2.5-Hz spike-and-wave; rarely induced by hyperventilation or photic stimulation

EEG, electroencephalogram.

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continuum [Holmes et al., 1987, 1992]. Diminished postural tone, or tonic or myoclonic activity, is significantly more likely to be the initial clinical feature in atypical than in typical absences. Automatisms are less likely in atypical absences than in typical absences. Like typical absences, atypical absences have a distinct onset and ending, without auras or postictal symptoms. Although atypical absences usually are of longer duration than typical absences, a considerable amount of variability exists. Atypical absences usually begin before the age of 5 years and often are associated with other seizure types and mental retardation. In children who have profound mental retardation, it may be difficult to detect subtle behavioral changes associated with the absence seizures. Many children with atypical absence seizures have Lennox-Gastaut syndrome. Four syndromes are associated with typical absence seizures: childhood absence epilepsy (pyknolepsy), juvenile absence epilepsy, epilepsy with myoclonic absences, and juvenile myoclonic epilepsy. Childhood absence epilepsy (pyknolepsy) describes typical absence seizures (i.e., both simple and complex) in children between the age of 3 years and puberty, who are otherwise normal. A strong genetic predisposition has been noted, and girls are more frequently affected. The absences are very frequent, occurring at least several times daily, and tend to occur in clusters. The EEG reveals a bilateral, synchronous, and symmetric 2.5- to 3-Hz spike-and-wave discharge with normal interictal background activity. The absences may remit during adolescence, but generalized tonic-clonic seizures occasionally may develop. Juvenile absence epilepsy begins around puberty and differs from pyknolepsy primarily in that the seizures are more sporadic. This syndrome may be confused with juvenile myoclonic epilepsy, because generalized tonic-clonic seizures and myoclonic seizures often are seen on awakening. Generalized tonic-clonic seizures are more common in children with this syndrome than in those with childhood absence epilepsy. Gender distribution is equal, and on EEG the spike-and-wave frequency often is slightly greater than 3 Hz. Epilepsy with myoclonic absences is characterized clinically by absences accompanied by severe bilateral rhythmic myoclonus, often associated with a tonic contraction [Tassinari et al., 1992]. On the EEG, these seizures are accompanied by bilateral synchronous and symmetric

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discharges of spike-and-wave activity occurring at a frequency of 3 Hz. These seizures often are resistant to drug therapy. Juvenile myoclonic epilepsy is a familial disorder that typically begins in the second decade of life and is characterized by mild myoclonic seizures, generalized tonic-clonic or clonic-tonic-clonic seizures (a variation of generalized tonic-clonic seizures in which an initial clonic phase precedes the usual pattern), and occasionally absence seizures. This syndrome is discussed in Chapter 46.

Differential Diagnosis The primary diagnostic considerations in the child referred because of “staring attacks” include absence seizures, complex partial seizures, and daydreaming (Table 43-4). Complex partial seizures are more common than absence seizures and also are manifested by an alteration in consciousness with staring, automatisms, changes in tone, and autonomic symptoms. Complex partial seizures tend to be longer and less frequent, but clinically no absolute distinguishing factor may be present. The presence of an aura or postictal impairment is strongly suggestive of a complex partial seizure. In the child not on antiepileptic medications, 3 minutes of hyperventilation usually precipitates an absence seizure. It is unusual for complex partial seizures to be precipitated by hyperventilation. Abnormalities documented on the EEG constitute the best confirmation of either seizure type. Daydreaming is associated with boredom, can be “broken” with stimulation, and is not associated with motor activity. Absence seizures, however, also can be terminated with stimulation and tend to increase during periods of relaxation and tiredness. Tics and pseudoseizures may need to be considered as well. Normal findings on an EEG study that includes several trials of 3 to 5 minutes of hyperventilation, however, virtually rule out absence seizures. Repeated studies or prolonged monitoring occasionally may be necessary when diagnostic confusion persists.

Etiology Both acquired and inherited factors are implicated in the etiology of absence seizures, reflecting the heterogeneity of the patient population. Genetic factors predominate in

TABLE 43-4 Differential Diagnosis of Absence Seizures Clinical/Laboratory Characteristics

Absence Seizures

Complex Partial Seizures

Daydreaming

Frequency/day Duration Aura Clonic component Postictal impairment Seizures activated by: Hyperventilation Photic stimulation EEG findings Interictal Ictal

Multiple Frequently <10 second; rarely >30 sec Never Common, eye blinking common Never

Rarely >1-2 Average duration >1 min; rarely <10 second Frequent Rare Frequent

Situation dependent Seconds to minutes Never Never Never

Frequent Frequent

Rarely Rarely

Never Never

Generalized spike-and-wave Generalized spike-and-wave

Focal spikes, sharp waves Rhythmic spikes, sharp waves, or slow waves

Normal Normal

EEG, electroencephalogram.

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FIGURE 43-2. EEG from a patient with typical absences. Technician spoke the phrase “green pizza” during the spike-and-wave discharge. After the absence seizure, the patient did not recall the phrase. (Calibration: 50 μV, 1 second.)

children with typical absence seizures, whereas acquired disorders are more common in children with atypical absences. The genetics of absence seizures are discussed in Chapter 42.

Electroencephalographic Findings The EEG signature of a typical absence seizure is the sudden onset of 3-Hz generalized symmetric spike-and-wave or multiple spike-wave complexes (Fig. 43-2). The voltage of the discharges often is maximal in the frontal-central regions. The frequency tends to be faster, about 4 Hz, at the onset and may slow to 2 Hz toward the end of a discharge lasting longer than 10 seconds. Hyperventilation is a potent activator of typical absence seizures [Adams and Lueders, 1981; Dalby, 1969]. Failure to induce an absence seizure with several trials of hyperventilation of 3 to 5 minutes’ duration in a child not receiving antiepileptic medication would make the diagnosis of typical absence seizures unlikely. Photic stimulation also may precipitate seizures, although the frequency of activation does not appear as high as with hyperventilation [Newmark and Penry, 1979]. When closely observed, children typically demonstrate behavioral changes with spike-and-wave discharges lasting longer than a few seconds. In studies of auditory reaction times, it has been found that responses are abnormal in 80% of the situations in which a stimulus is presented after onset of the spike-and-wave activity [Porter et al., 1973]. In a test of visual motor coordination in children with spike-and-

wave activity on the EEG, discharges lasting longer than 3 seconds were associated with impaired function [Opp et al., 1992]. The interictal EEG in children with typical absence seizures typically shows a normal background. Brief bursts of generalized spike-and-wave activity, frontal spikes, or, less commonly, multifocal spikes can be seen. In absences, focal or multifocal spikes do not necessarily indicate a focal epileptiform process; rather, they may represent portions of generalized discharge that do not totally propagate uniformly to the cortex. In atypical absences, the ictal EEG is more heterogeneous, showing 1.5- to 2.5-Hz slow spike-and-wave or multiple spike-and-wave discharges that may be irregular or asymmetric (Fig. 43-3). Interictal EEG findings usually are abnormal, with background slowing and multifocal epileptiform features. The EEG features of typical and atypical absences are summarized in Table 43-3.

Pathophysiology The observation that 3-Hz spike-and-wave discharges in absence seizures appear simultaneously and synchronously in all electrode locations led early investigators to speculate that the pathophysiologic mechanisms of absence seizures must involve “deep” structures with widespread connections between the two hemispheres. A number of studies have demonstrated that the basic underlying mechanism in generalized absence epilepsies

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FIGURE 43-3. Slow, irregular generalized spike-and-wave discharges in a patient with Lennox-Gastaut syndrome and atypical absences. (Calibration: 50 μV, 1 second.)

involves thalamocortical circuitry and the generation of abnormal oscillatory rhythms in this neuronal network [Coulter and Zhang, 1994; Crunelli and Leresche, 2002; Hosford

et al., 1995; Huguenard and Prince, 1994; Steriade and Conteras, 1998; Steriade et al., 1993]. The neuronal circuits that generate the oscillatory thalamocortical burst firing ob-

FIGURE 43-4. Principal neuronal populations and connections of thalamocortical circuits generating absence seizures. GABA, γ-aminobutyric acid; Glu, glutamatergic transmission; T, T-current. (From Holmes GL. Basic mechanisms in epilepsy. Int Pediatr 1996;11:343.)

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served during absence seizures have now been identified. This circuit includes cortical pyramidal neurons, thalamic relay neurons, and the nucleus reticularis thalami (Fig. 43-4) [Steriade and Llinas, 1988; Steriade et al., 1993]. The principal synaptic connections of the thalamocortical circuit include glutamatergic fibers between neocortical pyramidal cells and the nucleus reticularis thalami, γ-aminobutyric acid (GABA)-ergic fibers from nucleus reticularis thalami neurons that activate GABAA and GABAB receptors on thalamic relay neurons, and recurrent collateral GABAergic fibers from nucleus reticularis thalami neurons that activate GABAA receptors on adjacent nucleus reticularis thalami neurons. The nucleus reticularis thalami, therefore, is in a position to influence the flow of information between the thalamus and cerebral cortex [Snead, 1995]. The nucleus reticularis thalami cells undergo rhythmic burst firing during periods of sleep and continuous single spike firing during wakefulness. The cellular events that underlie the ability of nucleus reticularis thalami neurons to shift between an oscillatory and a firing mode include activation of the low-threshold, transient Ca2+ channels (T-channels) [Coulter et al., 1989; 1990; Crunelli and Leresche, 1991, 2002; Snead, 1995]. These channels appear to be important in the generation of absence seizures [Snead, 1995; Tsakiridou et al., 1995]. Mild depolarization of these neurons is sufficient to activate these T-channels and to allow the influx of extracellular Ca2+. Further depolarization produced by Ca2+ inflow often exceeds the threshold for firing a burst of action potentials. After T-channels are activated, they become inactivated rather quickly—hence the name transient. T-channels require a lengthy, intense hyperpolarization to reverse their inactivation (a process termed deinactivation). The requisite hyperpolarization can be provided by GABAB receptors that are present on thalamic relay neurons. The interplay between GABAB-mediated inhibition and the low-threshold T-type calcium channel therefore plays a critical role in generating the oscillating hyperpolarization/depolarization activity seen in the thalamus. In animal models of absences, GABAB agonists produce an increase in seizure frequency (by facilitating deinactivation of T-channels), whereas GABAB antagonists reduce seizure frequency. Recurrent collateral GABAergic fibers from the nucleus reticularis thalami neurons activate GABAA receptors on adjacent nucleus reticularis thalami neurons. Activating GABAA receptors in the nucleus reticularis thalami, therefore, results in reduction of GABAergic output to the thalamic relay neurons and serves to reduce hyperpolarization and delay deinactivation of the T-channels. In animal studies, injection of the GABAA agonists bilaterally into the nucleus reticularis thalami reduces absence seizure frequency. GABAA activation of thalamic relay neurons, however, would be expected to have the opposite effect, increasing hyperpolarization and deinactivation of the T-channel. Abnormal oscillatory rhythms could be caused by abnormalities of the T-channel or enhanced GABAB function [Crunelli and Leresche, 1991; Snead, 1995]. In some animal models of absence seizures, T-channel activation in the nucleus reticularis thalami is significantly different than in control animals [Tsakiridou et al., 1995]. These aberrant Tchannels may be one basis for absence seizures. In other animal models, an increase in GABAB receptors in thalamic

and neocortical neuronal populations, compared with that in controls, has been described [Hosford et al., 1995]. Because an increase in GABA in the thalamic relay neurons would lead to enhanced hyperpolarization and consequently deinactivation of the T-channels, GABAB agonists produce an increase in seizure frequency, whereas GABAB antagonists reduce seizure frequency in rodent models of absence epilepsy [Hosford et al., 1992; Liu et al., 1992; Marescaux et al., 1992; Tsakiridou et al., 1995]. Supporting these animal findings are the clinical observations that three drugs efficacious in the treatment of absence seizures—valproic acid, ethosuximide, and trimethadione— suppress T-currents [Coulter et al., 1990]. In addition, some clinical evidence indicates that vigabatrin, which increases endogenous GABA levels and thereby increases the activation of GABAB receptors, worsens absence seizures in patients. Clonazepam, which activates GABAA levels in the nucleus reticularis thalami, can be an effective antiabsence drug [Huguenard and Prince, 1994].

Treatment The extent of the diagnostic evaluation required in patients with absence seizures is variable and depends somewhat on findings on the history and physical examination. All patients need a neurologic examination, with hyperventilation, and an EEG. Patients who have normal development, normal findings on neurologic examination, a history suggestive of typical absence seizures, and 2.5- to 4-Hz spike-wave discharges on an otherwise normal-appearing EEG require no further studies. Children with developmental delay, an abnormal neurologic examination, a history suggestive of atypical absences, or an EEG showing slow spike-and-wave (less than 2.5 Hz) discharges, background slowing or focal epileptiform discharges should have neuroimaging, preferably MRI, and possibly more specific tests such as metabolic studies and a lumbar puncture. Antiepileptic drug therapy is recommended for children with absence seizures. Although not life-threatening, absence seizures may lead to poor school performance, ridicule, and accidents. Because even brief generalized spike-and-wave discharges can affect cognitive function, it is therefore reasonable to begin drug therapy in most patients once the diagnosis is secure. The primary drugs for absence seizures are valproic acid, ethosuximide, and lamotrigine [Posner et al., 2003]. Unfortunately, data are insufficient to recommend a single drug as the most efficacious [Posner et al., 2003]. A single agent should be chosen and, after appropriate laboratory studies, initiated at a low dose and gradually increased. Antiepileptic drug levels may be helpful, but dose changes in either direction should follow clinical indications. On dosage modifications, drug levels should be obtained only after sufficient time has elapsed to reach steady-state serum concentrations. In the United States, many physicians will begin therapy with ethosuximide, primarily because of the rare, but severe, hepatotoxicity and pancreatitis associated with valproic acid [Dreifuss et al., 1987, 1989; Penry and Dean, 1993]. Ethosuximide has proved over the past 2 decades to be a safe and effective antiepileptic drug used almost exclusively for absence seizures [Holmes et al., 1987; Perucca, 1990; Schneider, 1993]. Valproic acid is equally effective and

Holmes / Generalized Seizures

generally is considered the drug of choice in the patient who has both absence and generalized tonic-clonic seizures, because ethosuximide is not effective in the treatment of generalized tonic-clonic seizures. Lamotrigine appears to be a promising drug in the treatment of absence seizures [Duchowny et al., 2002; Frank et al., 1999; Mikati and Holmes, 1997]. Although the U.S. Food and Drug Administration has not yet approved lamotrigine for treatment of absence seizures, the consensus is that the drug is effective in this condition [French et al., 2004b]. Benzodiazepines such as clonazepam may be effective, but they usually are reserved for refractory cases because of the relatively high incidence of drowsiness and behavioral side effects [Pearl and Holmes, 2001]. Topiramate [Cross, 2002; Wheless, 2000], levetiracetam [Cohen, 2003], and acetazolamide [Reiss and Oles, 1996] may be useful. Carbamazepine, vigabatrin, and tiagabine should be avoided because these drugs may exacerbate absence seizures [Knake et al., 1999; Yang et al., 2003]. In addition to obtaining an interim history, the clinician should always have the child perform a hyperventilation test at follow-up visits. Eliciting a seizure during hyperventilation strongly indicates that the epilepsy disorder is not totally controlled [Adams and Lueders, 1981]. The duration of therapy is variable, although a general rule is to gradually discontinue therapy after 2 seizure-free years have elapsed. Continued presence of spike-and-wave activity on the EEG indicates a high risk for relapse following discontinuation of the drug. Normal EEG findings while the child is on therapy, however, cannot be used as a firm indication that the child will remain seizure free, because the antiabsence drugs can suppress spike-and-wave activity on the EEG.

Prognosis Approximately two thirds of children with childhood absence epilepsy can be expected to enter long-term remission [Wirrell, 2003]. Sato and colleagues [1976] identified favorable prognostic signs in absence seizures as a negative family history of epilepsy, normal EEG background activity, and normal intelligence. Nearly 90% of children with these characteristics stopped having absence seizures. Juvenile absence epilepsy may occasionally persist into adulthood, however, and juvenile myoclonic epilepsy, as discussed later on, does not spontaneously remit [Wirrell et al., 1996]. As a rule, onset of generalized tonic-clonic seizures before absence seizures carries a poorer prognosis than that noted with the reverse order [Sato et al., 1976].

CLONIC SEIZURES Clinical Features Clonic seizures are similar to generalized tonic-clonic seizures but are characterized by only rhythmic or semirhythmic contractions of a group of muscles. These jerks can involve any muscle group, although the arms, neck, and facial muscles are most commonly involved. The jerking often is asymmetric and irregular. Differentiating a flurry of myoclonic seizures from a clonic seizure may be difficult. Clonic seizures, however,

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are associated with a more marked impairment of consciousness than is seen with a series of myoclonic seizures and typically include a postictal period, although it may be quite brief. Clonic seizures are more common in children than in adults and usually occur during the first few years of life.

Etiology and Prognosis Clonic seizures are more likely to be symptomatic than are generalized tonic-clonic seizures. The prognosis is related to the etiology of the seizures.

Electroencephalographic Findings The EEG may show fast activity, fast activity mixed with slow waves, or polyspike-and-wave discharges.

TONIC SEIZURES Clinical Features Tonic seizures are brief seizures (usually lasting less than 60 seconds) consisting of the sudden onset of increased tone in the extensor muscles [Egli et al., 1985; Holmes, 1988]. If standing, the patient typically falls to the ground. Electromyographic activity is dramatically increased in tonic seizures. Impairment of consciousness during the seizure is characteristic, although in short seizures this change may be difficult to detect. Tonic seizures frequently are seen in patients with Lennox-Gastaut syndrome, a disorder consisting of a mixed seizure disorder, mental retardation, and the EEG findings of a slow spike-and-wave pattern [Aicardi, 1973, 1988; Markand, 2003]. The seizures usually occur more frequently at night. Tonic seizures frequently begin with a tonic contraction of the neck muscles, leading to fixation of the head in an erect position, widely opened eyes, and jaw clenching or mouth opening [Holmes, 1988]. Contraction of the respiratory and abdominal muscles often follows, sometimes leading to a high-pitched cry and brief periods of apnea. The tonic contractions may extend to the proximal musculature of the upper limbs, elevating the shoulders and abducting the arms. Asymmetric tonic seizures vary in severity, ranging from a slight rotation of the head to a tonic contraction of all of the musculature on one side of the body. Eyelid retraction, staring, mydriasis, and apnea also may occur [Aicardi, 1988]. Occasionally tonic seizures terminate with a brief clonic phase. Unlike in generalized tonic-clonic seizures, however, the clonic phase is abbreviated. Postictal impairment with confusion, tiredness, and headache is common. The degree of postictal impairment usually is related to the duration of the seizure. Tonic seizures typically are activated by sleep and may occur repetitively throughout the night. They usually are more frequent during non–rapid eye movement sleep than during wakefulness and usually do not occur during rapid eye movement sleep. Arousal from light sleep may occur after a tonic seizure. Because the child often does not wake up during the seizure, these seizures often go undetected.

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Etiology and Prognosis Tonic seizures usually occur in children with Lennox-Gastaut syndrome, which is discussed later.

Electroencephalographic Findings The interictal EEG pattern in patients with tonic seizures usually is quite abnormal, consisting of slowing of the background, with multifocal spikes, sharp waves, and bursts of irregular spike-and-wave activity. The EEG ictal manifestations of tonic seizures usually consist of bilateral synchronous spikes of 10 to 25 Hz, of medium-to-high voltage, with a frontal accentuation. Simple flattening or desynchronization may also occur (Fig. 43-5). Occasional multiple spike-and-wave or diffuse slow-wave activity may occur during a tonic seizure.

ATONIC SEIZURES Clinical Features Atonic (astatic) seizures, or “drop attacks,” are characterized by a sudden loss of muscle tone [Oguni et al., 1992, 1997]. They begin suddenly and without warning and cause the patient, if standing, to fall quickly to the floor. Children with atonic seizures are more likely to fall backward than chil-

dren with tonic seizures [Oguni et al., 1997]. Because muscle tone may be completely absent, the children have little means by which to protect themselves, and injuries often occur. The attack may be fragmentary and manifest as dropping of the head with slackening of the jaw or dropping of a limb. At times it may be difficult to distinguish epileptic from nonepileptic head drops. Children with head drops secondary to seizures often have a change in facial expression and subtle myoclonic extremity movements associated with the head drops. Head drops with a rapid head descent, followed by a slow recovery to the upright position, usually represent seizures [Brunquell et al., 1990]. In atonic seizures, a loss of electromyographic activity is characteristic. Consciousness is impaired during the fall, although the patient may regain alertness immediately on hitting the floor. Atonic attacks are frequently associated with myoclonic jerks either before, during, or after the atonic seizure [Egli et al., 1985; Schneider et al., 1970]. This combination has been described as myoclonic-astatic seizures. Atonic seizures are rare [Egli et al., 1985; Ikeno et al., 1985]; a majority of children with drop attacks have myoclonic or tonic seizures [Ikeno et al., 1985].

Etiology and Prognosis Atonic seizures usually occur in children with LennoxGastaut syndrome or Doose’s syndrome. Doose’s syndrome is discussed in Chapter 46.

FIGURE 43-5. Tonic seizure characterized by rapid discharge of rapid spikes. (Calibration: 50 μV, 1 second.)

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Electroencephalographic Findings Atonic seizures usually are associated with rhythmic spikeand-wave complexes varying from slow, 1- to 2-Hz, to more rapid, irregular spikes or multiple spike-and-wave activity.

LENNOX-GASTAUT SYNDROME Lennox-Gastaut syndrome is characterized by a mixed seizure disorder of which tonic seizures are a major component and a slow spike-and-wave EEG pattern. The syndrome always begins in childhood and often is accompanied by mental retardation [Markand, 2003]. The child with Lennox-Gastaut syndrome typically has a mixture of seizure types. The most frequently occurring are tonic, tonic-clonic, myoclonic, atypical absences, and “head drops,” which represent a form of atonic, tonic, or myoclonic seizures. Lennox-Gastaut syndrome is characterized by very frequent seizures, usually occurring multiple times per day. Tonic seizures, in particular, are a major problem in this syndrome [Aicardi, 1988; Chevrie and Aicardi, 1972]. The tonic seizures usually are brief, lasting from a few seconds to a minute, with an average duration of about 10 seconds. Myoclonic seizures, occurring either in isolation or as a component of an absence seizure, can occur in this disorder. In some patients, the myoclonus may be so prominent that some investigators have described a myoclonic variant of the Lennox-Gastaut syndrome [Aicardi, 1988]. Atypical

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absence and generalized tonic-clonic seizures are seen in greater than half of the patients with Lennox-Gastaut syndrome [Schneider et al., 1970]. Generalized tonic-clonic seizures usually cause the most concern to parents and often are the seizure type to precipitate hospitalization. Mental retardation is present before onset of seizures in 20% to 60% of patients [Aicardi, 1988]. Some patients, with an idiopathic or cryptogenic etiology of their seizures, have normal intelligence quotient (IQ) scores or developmental histories before the onset of their seizures. The proportion of retarded patients increases with age because of the deterioration that frequently occurs in Lennox-Gastaut syndrome. Fluctuations in cognitive abilities may occur and are correlated to some degree with the intensity of EEG abnormalities. Behavioral problems also are common in Lennox-Gastaut syndrome, ranging from hyperactivity to frank psychotic and autistic behavior. Abnormalities on the neurologic examination have been reported in 30% to 88% of patients with Lennox-Gastaut syndrome [Kurokowa et al., 1980; Markand, 1977; Schneider et al., 1970]. Patients with Lennox-Gastaut syndrome typically have very frequent seizures [Markand, 1977; Papini et al., 1984]. It is not unusual for some children with this syndrome to have hundreds of seizures per day. Seizure frequency may vary during the course of a day, with the highest frequency during drowsiness and inactivity [Papini et al., 1984]. In addition, in many of the patients, a weekly or monthly periodicity in seizure frequency is observed unrelated to antiepileptic drug therapy [Aicardi, 1973]. Periods of prolonged repetitive seizures of a mixed type are interspersed with periods of relative freedom from attacks. During times when the child is seizure free, marked improvements in alertness, motivation, and academic progress can be seen. Unfortunately, these periods usually are short-lived, leading to a great deal of frustration for the child, parent, school personnel, and medical professionals.

Electroencephalographic Findings The hallmark of the EEG pattern in Lennox-Gastaut syndrome is the slow spike-and-wave discharge superimposed on an abnormal, slow background. The slow spike-and-wave or sharp-and-slow-wave complexes consist of generalized discharges occurring at a frequency of 1.5 to 2.5 Hz. The morphology, amplitude, and repetition rate may vary both between bursts and during paroxysmal bursts of spike-andwave activity, and asymmetries of the discharge are frequent. The area of maximum voltage, although variable, usually is frontal or temporal in location. Often, sleep increases the number of epileptiform discharges, but these discharges may slow in frequency and become even more irregular than during the awake state (Fig. 43-6). In rapid eye movement sleep, the paroxysmal activity decreases markedly. Hyperventilation and photic stimulation rarely activate these discharges.

Etiology

FIGURE 43-6. Irregular spike and slow-wave complexes during sleep in child with Lennox-Gastaut syndrome. (Calibration: 100 μV, 1 second.)

The syndrome may arise de novo in a previously well child or may supervene in an already neurologically or medically handicapped patient. Lennox-Gastaut syndrome has been divided into primary and secondary cases. Primary refers to cases in which the etiology is idiopathic, whereas secondary

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refers to cases in which the disorder is symptomatic of a definable etiology. Markand [1977] was able to identify an underlying disorder in 64% of 83 patients, and Chevrie and Acardi [1972] were able to do so in 66% of 80 patients. Other investigators, however, have reported a smaller incidence of identifiable causes in Lennox-Gastaut syndrome [Kurokowa et al., 1980; Schneider et al., 1970]. The causes of Lennox-Gastaut syndrome are listed in Table 43-5 and are similar to those seen in infantile spasms. In fact, in many patients (30% to 40%) with infantile spasms, the disorder will progress to Lennox-Gastaut syndrome [Kurokowa et al., 1980; Olmos-Garcia de Alba et al., 1984; Riikonen, 1996]. Often, the seizures occurring at the time of onset of the infantile spasms continue and become one of the seizure types in Lennox-Gastaut syndrome [Donat and Wright, 1991]. Although a majority of patients with Lennox-Gastaut syndrome have a static disorder, degenerative disorders may occasionally manifest as this syndrome [Markand, 1977; Pampiglione and Harden, 1977]. Genetic factors do not play a significant role in a majority of individuals with this disorder.

Treatment Management of the child with Lennox-Gastaut syndrome is difficult. Because the degree of heterogeneity with this syndrome is considerable, the response to antiepileptic drug therapy is variable. Individualized treatment approaches are necessary. Usually no single antiepileptic drug is effective in controlling all of the seizure types in Lennox-Gastaut syndrome. This frequently leads to polypharmacy. In addition, the sedating side effects of the antiepileptic drugs may lead to an increase in seizure frequency. The other notable problem is tolerance. In patients who have an initial improvement, loss of efficacy often occurs after a few months of treatment. This decreased efficacy usually leads to an increase in dosage, often with accompanying side effects, or to additional polytherapy. Although polytherapy sometimes cannot be avoided, the physician must be aware of the potential for harm. Withdrawal of antiepileptic drugs, particularly the barbiturates and benzodiazepines, may lead to improved alertness and an actual reduction in seizure frequency. In the United States, valproate likely is the most commonly used drug in the treatment of Lennox-Gastaut TABLE 43-5 Disorders Commonly Associated with Lennox-Gastaut Syndrome Prenatal

Perinatal

Postnatal

Cerebral dysgenesis Tuberous sclerosis Congenital infection Stroke

Hypoxia/ischemia Intracranial hemorrhage

Meningitis/ encephalitis Postinfectious Cerebral vascular disease Hypoxia/ischemia Status epilepticus Head injury Hypoglycemia Degenerative disorders

syndrome. It is a broad-spectrum drug with effectiveness against all of the common seizure types in the syndrome. The lack of sedative side effects and the broad spectrum of action make the drug appealing. The drug has been associated with hepatotoxicity, however, particularly in children younger than 2 years of age. Phenytoin is considered by some investigators to be the drug of choice for tonic seizures and intravenous phenytoin is used as a first-line drug for tonic status epilepticus [Richard et al., 1993]. Felbamate, released in the United States in 1993, was the first drug to be demonstrated to be effective in LennoxGastaut syndrome [Dodson, 1993b; The Felbamate Study Group, 1993]. After the drug was released, it was found to result in fatal aplastic anemia and hepatic failure. The overall risk of aplastic anemia for patients taking felbamate is estimated to be 1:5000, 100 times greater than the risk in the normal population, and the risk of fatal outcome is approximately 1:10,000 [Kaufman et al., 1997]. Felbamateassociated aplastic anemia has not been reported in children younger than 13 years [Pellock and Brodie, 1997]. Risk factors associated with aplastic anemia include a history of blood dyscrasia or of substantial toxicity to other antiepileptic drugs, serologic or clinical evidence of an autoimmune disorder, and a history of treatment with felbamate for less than 1 year. Both lamotrigine [Donaldson et al., 1997; Motte et al., 1997] and topiramate [Guerreiro et al., 1997; Ormrod and McClellan, 2001; Sachdeo et al., 1999] have demonstrated efficacy in Lennox-Gastaut syndrome but rarely with total control of the seizures. In a double-blind, placebo-controlled trial of lamotrigine in 169 patients with Lennox-Gastaut syndrome, either lamotrigine or placebo was added to the maintenance medications. After 16 weeks, 33% of children receiving lamotrigine and 16% of placebo recipients had more than a 50% reduction in seizure frequency [Motte et al., 1997]. In a doubleblind, placebo-controlled, multicenter trial of topiramate for adjunctive therapy for Lennox-Gastaut syndrome, the frequency of drop attacks was reduced compared with that in the placebo group [Sachdeo et al., 1999]. The ketogenic diet (see Chapter 50), one of the oldest methods of treating childhood epilepsy, remains a reasonable therapy for children with seizures refractory to standard drug therapy [Coppola et al., 2002; Kinsman et al., 1992; Nordli and De Vivo, 1997; Prasad et al., 1996; Schwartz et al., 1989]. Although the diet was considered a therapy of last resort for many years, recent resurgence in interest has occurred, primarily owing to its success in several highly publicized cases. The diet consists of a high proportion of fats and small amounts of carbohydrate and protein, with a fat-to-carbohydrate and protein ratio of 4:1. Although it is clear that the child must remain in a state of ketosis for the diet to be effective, the basis of the therapeutic effectiveness of the ketogenic diet remains uncertain. The resurgence in interest in the diet is appropriate because it does provide an attractive alternative in the treatment of childhood epilepsy. The literature supports the view that the ketogenic diet improves seizure control in a significant number of children with medically intractable epilepsy [Prasad et al., 1996; Rubenstein and Vining, 2004]. One third to one half of children appear to have an excellent response to the ketogenic

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diet in terms of a marked or complete cessation of seizures or reduction in seizure severity. In another one third of the children, a partial reduction in seizure frequency or severity occurs; the remaining children have no appreciable benefit from the diet. Improvement in alertness and behavior often is seen when the child is placed on the diet. It is not clear whether this benefit is secondary to withdrawal of drugs, reduction in seizure frequency, or a direct result of the diet. No controlled, double-blind studies on the efficacy or safety of the ketogenic diet have been performed, and it is not known whether the diet is more efficacious or safer than the commonly prescribed antiepileptic drugs. Also of concern are the potential long-term consequences of being on a high-fat diet for several years. Aspects of the surgical evaluation of children with generalized epilepsies, including use of vagal nerve stimulators, are reviewed in Chapter 51. REFERENCES Abou-Khalil B, Ge Q, Desai R, et al. Partial and generalized epilepsy with febrile seizures plus and a novel SCN1A mutation. Neurology 2001;57:2265. Adams DJ, Lueders H. Hyperventilation and six-hour EEG recording in evaluation of absence seizures. Neurology 1981;31:1175. Aicardi J. The problem of the Lennox syndrome. Dev Med Child Neurol 1973;15:77. Aicardi J. The Lennox-Gastaut syndrome. Int Pediatr 1988;3:152. Baulac S, Gourfinkel-An I, Nabbout R, et al. Fever, genes, and epilepsy. Lancet Neurol 2004;3:421. Binnie CD, Jeavons PM. Photosensitive epilepsies. In: Roger J, Bureau M, Dravet C, et al, eds. Epileptic Syndromes in Infancy, Childhood and Adolescence. London: John Libbey, 1992:299. Biton V, Montouris GD, Ritter F, et al. A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures. Neurology 1999;52:1330. Borkowski WJ Jr, Ellington RJ, Sverdrup EK. Effect of sleep deprivation on the EEG of learning-impaired children with absence seizures. Clin Electroencephalogr 1992;23:62. Bourgeois BF. Pharmacokinetics and pharmacodynamics of topiramate. J Child Neurol 2000;15 (Supp 1):S27. Browne TR, Penry JK, Porter RJ, et al. Responsiveness before, during, and after spike-wave paroxysms. Neurology 1974;24:659. Bruni J. Phenytoin and other hydantoins. Adverse effects. In: Levey RH, Mattson RH, Meldrum BS, et al, eds. Antiepileptic drugs, 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2002:605. Brunquell P, McKeever M, Russman BS. Differentiation of epileptic from nonepileptic head drops in children. Epilepsia 1990;31:401. Chadwick DW. Valproate monotherapy in the management of generalized and partial seizures. Epilepsia 1987;28 (Suppl 2):S12. Chevrie JJ, Aicardi J. Childhood epileptic encephalopathy with slow spike-wave. A statistical study of 80 cases. Epilepsia 1972;13:259. Coats DK. Bilateral angle closure glaucoma in a child receiving oral topiramate. J AAPOS 2003;7:303. Cohen J. Levetiracetam monotherapy for primary generalised epilepsy. Seizure 2003;12:150. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:249. Coppola G, Veggiotti P, Cusmai R, et al. The ketogenic diet in children, adolescents and young adults with refractory epilepsy: An Italian multicentric experience. Epilepsy Res 2002;48:221. Coulter DA, Huguenard JR, Prince DA. Characterization of ethosuximide reduction of low-threshold calcium current in thalamic neurons. Ann Neurol 1989;25:582. Coulter DA, Huguenard JR, Prince DA. Differential effects of petit mal anticonvulsants and convulsants on thalamic neurones: Calcium current reduction. Br J Pharmacol 1990;100:800. Coulter DA, Zhang Y. Thalamocortical rhythm generation in vitro: Physiological mechanisms, pharmacological control, and relevance to generalized absence epilepsy. In: Malafosse A, Genton P, Hirsch E,

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et al, eds. Idiopathic generalized epilepsies: Clinical, experimental, and genetic aspects. London: John Libbey, 1994:123. Cross JH. Topiramate monotherapy for childhood absence seizures: An open label pilot study. Science 2002;11:406. Crunelli V, Leresche N. Childhood absence epilepsy: Genes, channels, neurons and networks. Nat Rev Neurosci 2002;3:371. Crunelli V, Leresche N. A role for GABAB receptors in excitation and inhibition of thalamocortical cells. Trends Neurosci 1991;14:16. Dalby MA. Epilepsy and 3 per second spike and wave rhythm. A clinical electroencephalographic and prognostic analysis of 346 patients. Acta Neurol Scand 1969;45 (Suppl 40):1. Davis R, Peters DH, McTavish D. Valproic acid. A reappraisal of its pharmacological properties and clinical efficacy in epilepsy. Drugs 1994;47:332. Dodson WE. Phenytoin and related drugs. In: Dodson WE, Pellock JM, eds. Pediatric epilepsy: Diagnosis and therapy. New York: Demos Publications, 1993a:291. Dodson WE. Felbamate in the treatment of Lennox-Gastaut syndrome: 12 months follow-on experience after a randomized controlled trial of felbamate versus placebo. Epilepsia 1993b;34 (Suppl 7):S17. Donaldson JA, Glauser TA, Olberding LS. Lamotrigine adjunctive therapy in childhood epileptic encephalopathy (the Lennox-Gastaut syndrome). Epilepsia 1997;38:68. Donat JF, Wright FS. Seizures in series: Similarities between seizures of the West and Lennox-Gastaut syndromes. Epilepsia 1991;32:504. Dreifuss FE, Langer DH, Moline KA, et al. Valproic acid hepatic fatalities: US experience since 1984. Neurology 1989;39:201. Dreifuss FE, Santilli N, Langer DH, et al. Valproic acid hepatic fatalities: A retrospective review. Neurology 1987;37:379. Duchowny M, Gilman J, Messenheimer J, et al. Long-term tolerability and efficacy of lamotrigine in pediatric patients with epilepsy. J Child Neurol 2002;17:278. Egli M, Mothersill I, O’Kane M, et al. The axial spasm—the predominant type of drop seizure in patients with secondary generalized epilepsy. Epilepsia 1985;26:401. Faught E. Clinical trials for treatment of primary generalized epilepsies. Epilepsia 2003;44 (Suppl 7):44. Frank LM, Enlow T, Holmes GL, et al. Lamictal (lamotrigine) monotherapy for typical absence seizures in children. Epilepsia 1999;41:357. French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2004a;62:1252. French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2004b;62:1261. Gastaut H, Broughton R. Epileptic seizures: Clinical and electrographic features, diagnosis and treatment. Springfield, Ill: Charles C Thomas, 1972. Gastaut H, Roger J, Ouahchi S, et al. An electroclinical study of generalized epileptic seizures of tonic expression. Epilepsia 1963;4:15. Gilliam FG, Chiappa KH. Significance of spontaneous epileptiform abnormalities associated with a photoparoxysmal response. Neurology 1995;45:453. Guerreiro MM, Manreza ML, Guerreiro CA, et al. A pilot study of topiramate in children with Lennox-Gastaut syndrome. Neurology 1997;48:A39. Hauser WA, Hersdorffer DC. Epilepsy: Frequency, causes and consequences. New York: Demos Publications, 1990. Hauser WA, Kurland LT. The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967. Epilepsia 1975;16:1. Hertoft P. The clinical, electroencephalographic and social prognosis in petit mal epilepsy. Epilepsia 1963;4:298. Hirtz D, Ashwal S, Berg A, et al. Practice parameter: Evaluating a first nonfebrile seizure in children. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000;55:616–628. Holmes GL. New drugs in the treatment of epilepsy. Ann Nestlé [Fr] 2003;61:107. Holmes GL. Carbamazepine. Toxicity. In: Levy RH, Mattson RH, Meldrum BS, eds. Antiepileptic drugs, 4th ed. New York: Raven Press, 1995:567.

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Miller AD, Krauss GL, Hamzeh FM. Improved CNS tolerability following conversion from immediate- to extended-release carbamazepine. Acta Neurol Scand 2004;109:374. Motte J, Trevathan E, Arvidsson JFV, et al. Lamotrigine for generalized seizures associated with the Lennox-Gastaut Syndrome. N Engl J Med 1997;337:1807. Murphy K, Delanty N. Primary generalized epilepsies. Curr Treat Options Neurol 2000;2:527. Newmark ME, Penry JK. Photosensitivity and epilepsy: A review. New York: Raven Press, 1979. Niedermeyer E. Immediate transition from a petit mal absence into a grand mal seizure; case report. Eur Neurol 1976;14:11. Nordli DR Jr, De Vivo DC. The ketogenic diet revisited: Back to the future. Epilepsia 1997;38:743. Oguni H, Fukuyama Y, Imaizumi Y, et al. Video-EEG analysis of drop seizures in myoclonic astatic epilepsy of early childhood (Doose syndrome). Epilepsia 1992;33:805. Oguni H, Uehara T, Imai K, et al. Atonic epileptic drop attacks associated with generalized spike-and-slow complexes: Video-polygraphic study of two patients. Epilepsia 1997;38:813. Olmos-Garcia de Alba G, Valdez JM, Crespo FV. West syndrome evolving into the Lennox-Gastaut syndrome. Clin Electroencephalogr 1984;15:61. Opp J, Wenzel D, Brandl U. Visuomotor coordination during focal and generalized EEG discharges. Epilepsia 1992;33:836. Ormrod D, McClellan K. Topiramate: A review of its use in childhood epilepsy. Paediatr Drugs 2001;3:293. Ott D, Caplan R, Guthrie D, et al. Measures of psychopathology in children with complex partial seizures and primary generalized epilepsy with absence. J Am Acad Child Adolesc Psychiatry 2001;40:907. Pampiglione E, Harden A. So-called neuronal ceroid lipofuscinosis: Neurophysiological studies in 60 children. J Neurol Neurosurg Psychiatry 1977;40:323. Papini M, Pasquinelli A, Armellini M, et al. Alertness and incidence of seizures in patients with Lennox-Gastaut syndrome. Epilepsia 1984;25:161. Pavone P, Bianchini R, Trifiletti RR, et al. Neuropsychological assessment in children with absence epilepsy. Neurology 2001;56:1047. Pearl PL, Holmes GL. Absence seizures. In: Pellock JM, Dodson WE, Bourgeois BFD, eds. Pediatric epilepsy. Diagnosis and treatment. New York: Demos Publications, 2001:219. Pellock JM, Brodie MJ. Felbamate: 1997 update. Epilepsia 1997;38:1261. Penry JK, Dean JC. Valproate. In: Dodson WE, Pellock JM, eds. Pediatric epilepsy: Diagnosis and therapy. New York: Demos Publications, 1993:315. Penry JK, Porter RJ, Dreifuss FE. Simultaneous recording of absence sizures with videotape and electroencephalography. Brain 1975;98:427. Perucca E. Succinimides. In: Dam M, Gram L, eds. Comprehensive epileptology. New York: Raven Press, 1990:603. Porter RJ. Epilepsy. 100 elementary principles. Philadelphia: WB Saunders, 1984. Porter RJ, Penry JK, Dreifuss FE. Responsiveness at the onset of spikewave bursts. Electroencephalogr Clin Neurophysiol 1973;34:239. Posner EB, Mohamed K, Marson AG. Ethosuximide, sodium valproate or lamotrigine for absence seizures in children and adolescents. Cochrane Database Syst Rev 2003;CD003032. Prasad AN, Stafstrom CE, Holmes GL. Alternative epilepsy therapies: The ketogenic diet, immunoglobulins, and steroids. Epilepsia 1996;37 (Suppl 1):S81. Ramsay RE. Use of phenytoin and carbamazepin in treatment of epilepsy. Neurol Clin 1986;4:585. Ramsay RE, DeToledo J. Tonic-clonic seizures: A systematic review of antiepilepsy drug efficacy and safety. Clin Ther 1997;19:433. Reilly EL, Peters JF. Relationship of some varieties of electroencephalographic photosensitivity to clinical convulsive disorders. Neurology 1973;23:1050. Reiss WG, Oles KS. Acetazolamide in the treatment of seizures. Ann Pharmacother 1996;30:514. Richard MO, Chiron C, d’Athis P, et al. Phenytoin monitoring in status epilepticus in infants and children. Epilepsia 1993;34:144. Richens A. Clinical pharmacokinetics of phenytoin. Clin Pharmacokinet 1979;4:153. Riikonen R. Long-term outcome of West syndrome: A study of adults with a history of infantile spasms. Epilepsia 1996;37:367. Rubenstein JE, Vining EPG. Efficacy of the ketogenic diet. In: Stafstrom EE, Rho JM, eds. Epilepsy and the ketogenic diet. Totowa, NJ: Humana Press, 2004:95.

Holmes / Generalized Seizures Sachdeo RC, Glauser TA, Ritter F, et al. A double-blind, randomized trial of topiramate in Lennox-Gastaut syndrome. Topiramate YL Study Group. Neurology 1999;52:1882. Sato S. Generalized seizures: Absence. In: Dreifuss FE, ed. Pediatric epileptology. Littleton, Mass: John Wright, 1983:65. Sato S, Dreifuss FE, Penry JK. Prognostic factors in absence seizures. Neurology 1976;26:788. Sato S, Dreifuss FE, Penry JK, et al. Long-term follow-up of absence seizures. Neurology 1983;33:1590–1595. Scheffer IE, Berkovic SF. Generalized epilepsy with febrile seizures plus. A genetic disorder with heterogeneous clinical phenotypes. Brain 1997;120:479. Scheyer RD. Valproic acid. Drug interactions. In: Levey RH, Mattson RH, Meldrum BS, et al, eds. Antiepileptic drugs, 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2002:801. Schmidt D, Tsai JJ, Janz D. Generalized tonic-clonic seizures in patients with complex partial seizures. Natural history and prognosis relevance. Epilepsia 1983;24:43. Schneider H, Vassella F, Karbowski K. The Lennox syndrome. A clinical study of 40 children. Eur Neurol 1970;4:289. Schneider S. Clinical utilization of ethosuximide, methsuximide, and trimethadione in children. In: Dodson WE, Pellock JM, eds. Pediatric epilepsy: Diagnosis and therapy. New York: Demos Publications, 1993:325. Schwartz RM, Eaton J, Bower BD, et al. Ketogenic diets in the treatment of epilepsy: Short term clinical effects. Dev Med Child Neurol 1989;31:145. Seetharam MN, Pellock JM. Risk-benefit assessment of carbamazepine in children. Drug Saf 1991;6:148. Shields WD, Saslow E. Myoclonic, atonic and absence seizures following institution of carbamazepine therapy in children. Neurology 1983;33:1487. Snead OC III. Basic mechanisms of generalized absence seizures. Ann Neurol 1995;37:146. Snead OC, Hosey LC. Exacerbation of seizures in children by carbamazepine. N Engl J Med 1985;313:916. Sofijanov NG. Clinical evolution and prognosis of childhood epilepsies. Epilepsia 1982;23:61. Steriade M, Conteras D. Spike-wave complexes and fast components of cortically generated seizures. I. Role of neocortex and thalamus. J Neurophysiol 1998;80:1439. Steriade M, Llinas RR. The functional states of the thalamus and the associated neuronal interplay. Physiol Rev 1988;68:649.

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Steriade M, McCormick DA, Sejnowski TJ. Thalamocortical oscillations in the sleeping and aroused brain. Science 1993;262:679. Takeoka M, Holmes GL, Thiele E, et al. Topiramate and metabolic acidosis in pediatric epilepsy. Epilepsia 2001;42:387. Tassinari CA, Bureau M, Thomas P. Epilepsy with myoclonic absences. In: Roger J, Bureau M, Dravet C, et al, eds. Epileptic syndromes in infancy, childhood and adolescence. London: John Libbey, 1992:151. Taylor S, Tudur SC, Williamson PR, et al. Phenobarbitone versus phenytoin monotherapy for partial onset seizures and generalized onset tonic-clonic seizures. Cochrane Database Syst Rev 2001;CD002217. The Felbamate Study Group in Lennox-Gastaut Syndrome. Efficacy of felbamate in childhood epileptic encephalopathy (Lennox-Gastaut syndrome). N Engl J Med 1993;328:29. Todt H. The late prognosis of epilepsy in childhood: Results of a prospective follow-up study. Epilepsia 1984;25:137. Tsakiridou E, Bertollini L, de Curtis M, et al. Selective increase in T-type calcium conductance of reticular thalamic neurons in a rat model of absence epilepsy. J Neurosci 1995;15:3110. Tudur SC, Marson AG, Clough HE, et al. Carbamazepine versus phenytoin monotherapy for epilepsy. Cochrane Database Syst Rev 2002;CD001911. Tudur SC, Marson AG, Williamson PR. Carbamazepine versus phenobarbitone monotherapy for epilepsy. Cochrane Database Syst Rev 2003;CD001904. Wallace RH, Scheffer IE, Parasivam G, et al. Generalized epilepsy with febrile seizures plus: Mutation of the sodium channel subunit SCN1B. Neurology 2002;58:1426. Wallace RH, Wang DW, Singh R, et al. Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B. Nat Genet 2000;19:366. Wheless JW. Use of topiramate in childhood generalized seizure disorders. J Child Neurol 2000;15 (Suppl 1):S7. Wilder BJ, Rangel RJ. Review of valproate monotherapy in the treatment of generalized tonic-clonic seizures. Am J Med 1988;84:7. Wirrell EC. Natural history of absence epilepsy in children. Can J Neurol Sci 2003;30:184. Wirrell EC, Camfield CS, Camfield PR, et al. Long-term prognosis of typical childhood absence epilepsy: Remission or progression to juvenile myoclonic epilepsy. Ann Neurol 1996;47:912. Wolf P. Epilepsy with grand mal on awakening. In: Roger J, Bureau M, Dravet C, et al, eds. Epileptic Syndromes in Infancy, Childhood and Adolescence. London: John Libbey, 1992: 329. Yang MT, Lee WT, Chu LW, et al. Anti-epileptic drugs-induced de novo absence seizures. Brain Dev 2003;25:51.

CHAPTER 44

Focal and Multifocal Seizures Douglas R. Nordli, Jr.

Focal or partial seizures originate in one region of the brain, where they may stay confined or spread to other areas. Multifocal seizures arise from multiple locations and constitute an important type of seizure in infancy and childhood. Both focal and multifocal have been underrecognized in children, but modern epidemiologic studies show that focal epilepsies account for about 60% of all seizure disorders [Berg et al., 1999a and b; Sillanpaa et al., 1999]. The behavioral manifestations of focal seizures relate not only to the region of the brain involved during the ictal discharge but also to the maturation of the nervous system and the integrity of the pathways necessary for clinical expression. Focal seizures in the very young are subtler and less declarative than focal seizures seen later in life [Acharya et al., 1997; Hamer et al., 1999; Nordli et al., 1997]. This is particularly true in infants and children with diffuse encephalopathies, in whom brain immaturity, diffuse cerebral dysfunction, or both make manifestations of focal seizures difficult to recognize. Focal seizures also can be mistaken in older children when the presence of secondary convulsive movements prompts casual observers to label the event a “generalized tonic-clonic” seizure. With this misdiagnosis, critical elements of the seizures are overlooked. As described later, careful consideration of the unique features present in pediatric focal seizures can help to improve the diagnostic accuracy. In a majority of children with focal seizures, no focal structural lesion is present, and the seizures either are the expression of an idiopathic disorder (benign rolandic epilepsy) or are cryptogenic. This finding is in contrast with adults, in whom a focal seizure strongly implies the presence of a focal structural lesion (e.g., stroke, brain tumor). Instead, only 10% of children with focal seizures have brain tumors or strokes. In one large epidemiologic study, only 4 of 613 children with epilepsy had a brain tumor [Berg et al., 2000a]. Sometimes, despite meticulous attention to the clinical features, it is not possible to rigorously distinguish simple from complex partial seizures in children. A classification system that constrains one to this dialectic is therefore limited in its clinical applicability. In these circumstances, as is often the case in infants and children younger than 6 years of age, a descriptive categorization or a brief narrative of the seizure is more helpful [Nordli et al., 1997]. A slight modification of the classic 1981 International League against Epilepsy scheme (reviewed in Chapter 40) is presented in Box 44-1. In older children, it often is possible to elicit more elaborate descriptions of auras and to determine alteration of consciousness [Nordli et al., 2001]. Other elements of the classic International League against Epilepsy scheme are reviewed in detail, because they are applicable in many older children and adults. The prognostic value of seizure classification by itself is limited, and a fuller understanding of the patient is achieved by

making an epilepsy syndrome diagnosis. As pointed out in Chapter 40, two children with the same seizure type can have markedly different outcomes. Establishing an epilepsy syndrome diagnosis is the best way to decide on management options for different patients. An epilepsy syndrome diagnosis is preferred for assessing prognosis and treatment. Although it may not be possible to diagnose every child immediately on presentation, prospective population-based studies suggest that most children can ultimately be diagnosed with an epilepsy syndrome. Many factors contribute to the diagnosis of a syndrome, but in practice, three are most important: (1) age and development of the patient; (2) type or types of observed seizures; and (3) interictal electroencephalogram (EEG) features. Many well-known epilepsy syndromes are delineated by specific clinical triads comprising these factors. Accordingly, this chapter includes a discussion of epilepsy syndromes that frequently manifest with focal or multifocal seizures. Children with multifocal seizures (three or more foci, involving both hemispheres) may have unfavorable forms of epilepsy (e.g., migrating partial seizures, Dravet’s syndrome, symptomatic diffuse epileptogenic encephalopathies not otherwise specified). Although these epilepsies manifest with focal seizures, the children usually have evidence of concomitant diffuse cerebral dysfunction on clinical examination, developmental history, and interictal EEG studies. Correct diagnosis is particularly challenging in the group of children with focal seizures and evidence of widespread, diffuse, or multifocal cerebral dysfunction; too often, these patients end up in broad, poorly descriptive “wastebasket” categories such as Lennox-Gastaut syndrome or generalized symptomatic epilepsy not otherwise specified. Lennox-Gastaut syndrome has particular diagnostic features and is not synonymous with diffuse symptomatic epilepsy, as discussed in Chapter 43. The importance of correctly recognizing focal seizures cannot be overstated. A modification of the existing syndrome classification system is presented in order to accommodate this important group of seizures (Box 44-2). The International League against Epilepsy is currently working to improve and revise the classification of epilepsies. A proposal for a systematic approach has been advocated [Engel, 2001].

RECOGNITION OF FOCAL SEIZURES IN CHILDREN Clinical features alone cannot always allow one to correctly diagnose a focal seizure. Rather, “focal seizure” is actually an electroclinical diagnosis. It usually is made following consideration of multiple factors related to the patient and the clinical event but may require EEG confirmation, particularly in the very young. Still, a number of important clues can help point to the presence of focal seizures in children (Box 44-3).

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BOX 44-1 INTERNATIONAL CLASSIFICATION OF SEIZURE DISORDERS (MODIFIED) Classification of Focal Seizures A. Simple partial seizures Clinical seizure type: Simple partial seizures, conciousness not impaired EEG ictal discharge: Local contralateral discharge starting over the corresponding area of cortical representation (not always recorded on the scalp; broad, diffuse rhythms possible when the source is deep) EEG interictal expression: Local contralateral interictal epileptiform discharge, usually stereotypic (or “cloned”) in idiopathic epilepsies and pleomorphic (or varied) with associated slowing when associated with symptomatic etiologic disorder 1. With motor signs a. Focal motor without march b. Focal motor with march (jacksonian) c. Versive d. Postural e. Phonatory (vocalization or arrest of speech) 2. With autonomic symptoms (including epigastric sensation, pallor, sweating, flushing, piloerection, and pupillary dilation) 3. With somatosensory or special sensory symptoms (simple hallucinations, e.g., tingling, light flashes, buzzing) a. Somatosensory b. Visual c. Auditory d. Olfactory e. Gustatory f. Vertiginous 4. With psychic symptoms (disturbance of higher cerebral function): rarely occur without impairment of consciousness; more commonly seen as complex partial seizures a. Dysphasic b. Dysmnesic (e.g., déjà vu) c. Cognitive (e.g., dreamy states, distortions of time sense) d. Affective (i.e., fear, anger, and other emotional states) e. Illusions (e.g., macropsia) f. Structured hallucinations (e.g., music, scenes) B. Complex partial seizures Clinical seizure type: Complex partial seizures, with impairment of consciousness, sometimes beginning with simple symptoms EEG ictal discharge: Unilateral or frequently bilateral discharge, diffuse or focal in temporal or frontotemporal regions Experience using video EEG monitoring suggests that certain clinical features tend to have certain EEG correlates that are briefly reviewed [Nordli et al., 2001] (Fig. 44-1).

Auras Auras are special sensory or psychic phenomenon that can be described only by the patient. They occur in a variety of

EEG interictal expression: Unilateral or bilateral, generally asynchronous focus; usually in the temporal regions 1. Simple partial onset followed by impairment of consciousness a. With simple partial features (described in part A) followed by impaired consciousness b. With automatisms 2. With impairment of consciousness at onset a. With impairment of consciousness only b. With automatisms C. Partial seizures evolving to generalized tonic-clonic seizures Clinical seizure type: Generalized tonic-clonic seizures with partial or focal onset EEG ictal discharge: Discharges like those for complex partial seizures, becoming secondarily and rapidly generalized 1. Simple partial seizures evolving to generalized tonic-clonic seizures 2. Complex partial seizures evolving to generalized tonic-clonic seizures 3. Simple partial seizures evolving to complex partial seizures evolving to generalized tonic-clonic seizures D. Partial seizures with uncertain alteration of consciousness (useful for infants and other special populations) EEG ictal discharge: Behavioral arrest seizures often are accompanied by rhythmic discharges in the temporoparieto-occipital region. Clonic seizures have a contralateral ictal expression, usually consisting of repetitive spikes, spike-and-wave discharges, or highly rhythmic delta. Spasms themselves are associated with electrodecrements, but focal seizures may precede, accompany, or follow the cluster. Tonic postures often are accompanied by diffuse attenuation or lowvoltage fast patterns. Versive seizures in the younger population often have a posterior quadrant correlate. Interictal EEG expression: Pleomorphic interictal epileptiform discharges and focal slowing may be seen. In the immature infant, it is common to observe multifocal spikes, even in the setting of focal structural lesions. Here, focal slowing, attenuation, or both are useful features indicating a focal process. 1. Behavioral arrest 2. Clonus: focal or unilateral 3. With associated spasms (may come before, during, or after the cluster) 4. Tonic 5. Versive forms and have important localizing value. The concurrent ictal EEG often does not reveal clear electrographic expression in most patients. When a somatosensory aura is specific and an ictal EEG correlate is present, the ictal discharge is often low-voltage fast activity localized over the corresponding region of the sensory homunculus. Other auras arising from limbic structures often are “indescribable,” or may have a fearful quality or include a feeling of

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Box 44-2 PROPOSED CLASSIFICATION OF EPILEPSIES AND EPILEPTIC SYNDROMES A. Epilepsies with focal seizures 1. Idiopathic with age-related onset At present, several syndromes are established, but more may be identified in the future. a. Benign childhood epilepsy with centrotemporal spike b. Late-onset childhood epilepsy with occipital paroxysms, Gastaut type c. Early-onset benign childhood occipital epilepsy, Panayiotopoulos type d. Idiopathic photosensitive occipital lobe epilepsy e. Some forms of reflex epilepsies such as primary reading epilepsy 2. Symptomatic This category comprises syndromes of great individual variability, which are based mainly on anatomic localization, clinical features, seizure types, and etiologic factors (if known). a. Limbic epilepsies b. Neocortical epilepsies c. Other types defined by localization and etiology B. Epilepsies with generalized seizures 3. Idiopathic, with age-related onset, listed in order of age a. Benign neonatal familial convulsions b. Benign neonatal convulsions c. Benign myoclonic epilepsy in infancy d. Childhood absence epilepsy (pyknolepsy) e. Juvenile absence epilepsy f. Juvenile myoclonic epilepsy (impulsive petit mal) g. Epilepsy with grand mal seizures (generalized tonic-clonic seizures) on awakening Other generalized idiopathic epilepsies, if they do not belong to one of the foregoing syndromes, can still be classified as generalized idiopathic epilepsies. 2. Idiopathic and/or symptomatic, in order of age of appearance a. West syndrome (infantile spasms, Blitz-NickSalaam-Krämphe)

b. Lennox-Gastaut syndrome c. Epilepsy with myoclonic-astatic seizures d. Epilepsy with myoclonic absences 3. Symptomatic a. Nonspecific etiology (early myoclonic encephalopathy) b. Specific syndromes (epileptic seizures may complicate disease states) Included here are those diseases in which seizures are an initial or a predominant feature. C. Epilepsies and syndromes undetermined as to whether they are focal or generalized 1. With both generalized and focal seizures, or multifocal seizures a. Neonatal seizures b. Severe myoclonic epilepsy in infancy (Dravet’s syndrome) c. Epilepsy with continuous spike-waves during slow-wave sleep d. Acquired epileptic aphasia (Landau-Kleffner syndrome) e Migrating partial seizures of infancy f. Diffuse encephalopathy with multifocal seizures (not recognized by ILAE) 2. Without unequivocal generalized or focal features Covers all cases with generalized tonic-clonic seizures in which clinical and EEG findings do not permit classification as clearly generalized or localization-related, such as in many cases of sleep grand mal. D. Special syndromes 1. Situation-related seizures (Gelegenheitsanfälle) a. Febrile convulsions b. Seizures related to other identifiable situations, such as stress, hormonal changes, drugs, alcohol, or sleep deprivation 2. Isolated, apparently unprovoked epileptic events 3. Epilepsies characterized by specific modes of seizure precipitation 4. Chronic progressive epilepsia partialis continua of childhood

Modified from Dreifuss FE, Martinez-Lage M, Roger J, et al. Epilepsia 1985;26:268.

Box 44-3 SEIZURE SEMIOLOGY INDICATING A FOCAL SEIZURE • Aura • Behavioral arrest (in most cases, although patients with absence also have behavioral arrest) • Focal clonus • Focal dystonic posture • Focal limb automatisms • Spasms (approximately one fourth of patients with spasms have associated focal seizures) • Tonic postures (particularly asymmetric tonic posture, although symmetric tonic postures also are seen in infants with focal seizures) • Version (involving the head, eyes, or both)

epigastric discomfort. These discharges arise from subcortical structures, so the EEG may reveal no to little change other than ipsilateral diffuse delta activity or a rhythmic theta-alpha pattern in the anterior to midtemporal region, particularly when the onset of activity is mesial temporal in location.

Behavioral Arrest In some infants and young children, the most conspicuous feature of a focal seizure may be the sudden, abrupt cessation of ongoing activity or a marked change in demeanor, as indicated by subtle but distinct changes in facial expression. Parents easily identify these features because they represent a clear paroxysmal alteration in the child’s

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Epilepsy / 44 FIGURE 44-1. Typical interictal findings on electroencephalogram (EEG) in children with focal seizures. A, This EEG from a child with benign rolandic epilepsy of childhood (BREC) shows focal stereotypic spikes appearing on a normal background. Notice that each spike closely resembles the others in morphology and location, as is typical of idiopathic localizationrelated epilepsies. B, By contrast, this EEG from a child with an epileptogenic focal structural lesion in the left temporal region demonstrates pleomorphic spikes and background slowing in the same region. C, EEGs from children with multifocal seizures often show multifocal interictal epileptiform discharges.

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behavior. Parents are particularly well attuned to the nature of their child’s habitual behavior, but these behavioral changes may be challenging for a person unacquainted with the child to identify on videotape. In the preverbal child, or in many children with special needs, it is impossible to reliably ascertain alteration of consciousness. Alteration of consciousness cannot be unambiguously inferred from behavior (e.g., daydreaming in school). To accurately assess consciousness, test items must be given and recall tested after the seizure. In children, this often is not possible, so the simple description of a behavioral arrest is more reliably used rather than trying to infer if a seizure was truly “complex partial.” Behavioral arrest seizures also have been described as hypomotor seizures. This description refers to a sudden reduction in the motor activity of the child. The electro-

graphic ictal accompaniment often emanates from the temporal lobe or posterior quadrant and may be composed of monotonous rhythmic delta, rhythmic theta-alpha patterns with an electrographic “crescendo” appearance, or low-voltage fast discharges that subsequently evolve to other rhythms (Fig. 44-2).

Focal Clonus Hand or arm clonus (clonic seizure) is another reliable feature of focal epilepsy. This activity is easily recognized as ictal by the repetitive nature of the jerking, and the inability to suppress the motion by passive restraint. It usually is accompanied by runs of rhythmic spike discharges in the contralateral rolandic region.

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FIGURE 44-2. Common infantile ictal patterns on electroencephalogram (EEG) in focal seizures. A, EEG during a behavioral arrest seizure shows an ictal discharge in the left temporal region. Notice the rhythmic buildup of fast activity. Ictal discharges usually have an evolution in frequency, amplitude, and spatial distribution (like a crescendo in music). B, During a clonic seizure involving the left arm, the EEG demonstrates an ictal correlate consisting of repetitive spikes in the right central region. Notice that the ictal discharge remains very localized. C, EEG obtained during a versive seizure with eyes deviating to the right, or the same side as for the ictal discharge, shows a fast ictal pattern superimposed on some rhythmic slowing in the right posterior head region.

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Spasms Spasms can be recognized by their tendency to recur in clusters, many times in an almost periodic fashion, with a fairly constant interval between some of the individual spasms. Spasms have a quick or myoclonic component at the start, followed by a brief sustained posture (tonic phase), followed in turn by a relaxation. Spasms that are asymmetric, that occur in a child with hemiparesis or other focal pathology, or that are associated with marked interhemispheric asymmetries on EEG are most likely focal seizures. In about 25% of patients with spasms, clear electrographic focal seizures can be detected before, during, or after the cluster. The EEG accompaniment of spasms often contains diffuse electrodecrements, even if they are preceded by clear focal seizures [Kubota et al., 1999].

Tonic Postures Tonic postures, both symmetric and asymmetric, are seen with focal seizures It is surprising to observe how often symmetric tonic postures can occur as a manifestation of a focal seizure in infants, and also how unreliable asymmetries of tonic postures can be in localizing ictal onsets. It is possible that these tonic postures are generated in deeper brainstem or subcortical structures and are not direct manifestations of the ictal discharges. This finding would explain why some asymmetric tonic postures can be reversed by passive turning of the head during a seizure, in a fashion similar to the tonic neck reflex elicited in the newborn.

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Version Pronounced and sustained lateral version of the eyes (versive seizure) is rarely encountered as an ictal manifestation in infants or young children. When present, version is another indicator of a focal seizure. In contrast with older children and adults, in whom the electrographic discharge often is best developed in the contralateral frontotemporal region, the ictal discharge in infants is more often in the ipsilateral occipital lobe.

SEIZURE CLASSIFICATION: MODIFIED INTERNATIONAL LEAGUE AGAINST EPILEPSY SCHEME The current official classification of seizures was created by the International League against Epilepsy Commission on Classification in 1981. For older children and young adults, the presentation of focal seizures is nearly identical to that in older adults. Patients can be interviewed to discern whether there has been an aura, alteration of consciousness, or amnesia. The presence of focal features reported by the patient or noted by observers, including an aura, signifies the presence of a focal seizure. Those partial or focal seizures with alteration of consciousness are referred to as complex, as opposed to simple partial seizures, in which consciousness is not impaired. This distinction was an important branch point in the 1981 International League against Epilepsy classification scheme. These features cannot be reliably ascertained in the preverbal infant and in many children with special needs; therefore, a descriptive categorization is more useful. A slight modification of the classification is proposed, reserving a category for seizures in which alteration of consciousness cannot be reliably determined (see Box 44-1). A wide variety of features may be seen during focal seizures. These seizures sometimes may be broadly classified using the most prominent and early feature of the seizure, but the various combinations of features, patterns, and time course of the seizure cannot be adequately summarized in a single word or phrase. Nothing can replace a thorough and meticulous description of the seizure. Indeed, the historical narrative of the seizure as described or observed by parents is the single most helpful piece of information allowing proper diagnosis of the seizure disorder and should be recorded, as accurately as possible, with few or no editorial comments.

SIMPLE PARTIAL SEIZURES Simple Partial Seizures with Motor Signs Any body part may be activated during partial seizure activity; the anatomic location within the motor cortex in which the abnormal discharge occurs is the determining factor. There is disproportionate representation of the tongue, lips, and hands (particularly the thumbs and forefingers) in the motor cortex, thus enhancing the likelihood that focal seizures will affect these areas. Although partial motor seizures may remain localized, they may be disseminated to adjacent subcortical and cor-

tical areas, resulting in sequential motor movements of body parts. Often, body parts initially are involved distally, and then more proximal portions become involved in an “epileptic march”; this phenomenon is a jacksonian seizure. Adversive seizures are focal motor phenomena during which the eyes and head are turned to the contralateral side in relation to the discharging cortical focus. At times the patient may be forced to gaze at the hand contralateral to the discharging hemispheral focus; furthermore, the hand may be tonically raised with the adversive movements of the eyes and head. These seizures likely originate in the supplementary motor strip. In another variation, the patient experiences a hallucination in the contralateral visual field; then the head and eyes move in that direction. Such seizures originate in the temporal lobe. Although this phenomenon is not explained, several patients report the abortion or termination of an epileptic seizure by engaging in volitional forced thinking or by placing concerted pressure on the limb proximal to the area of clonic movement.

Simple Partial Seizures with Special Sensory or Somatosensory Symptoms The homunculus of sensory distribution within the parietal cortex is similar to the frontal cortex motor homunculus. Somatosensory seizures originate from these sensory cortical areas, primarily in the region of the postcentral gyrus. Partial sensory seizures can take many forms and often are unaccompanied by motor phenomena. The patient may describe numbness or dysesthesias, such as a pins-andneedles sensation in a body part. Less frequently, abnormalities of proprioception that interfere with the appreciation of spatial position of the arms or legs may occur. A sensory epileptic march, analogous to a motor seizure march, usually begins in the distal limb and spreads proximally. Such sensory seizures involving the arms may propagate to the face or to the leg on the ipsilateral side. Partial sensory seizures may become generalized to involve both cerebral hemispheres, resulting in unconsciousness. It is common for these sensory seizures to remain localized. If the partial sensory seizure spreads to affect the motor function of the same limb, Todd’s paralysis may result. Seizures that initially affect the visual system are uncommon but well known. The complexity of the alteration in the visual pattern depends on the locale of the involved cortex. Organized hallucinations are the most complex form of visual seizures and are initiated in the temporal lobe area, where more complex integration of visual functions occurs. The simplest visual seizures are initiated in primary areas of the occipital cortex. Visual seizures initiating in the occipital lobe may include flashing lights or scotomas in the homonymous field contralateral to the focus. The positive or flashing-light sensations may take the form of teichopsias (zigzag lines) or fiery, circumscribed circles. Discharges emanating from associated areas result in more highly complex visual sensations ranging from geometric shapes, such as squares and stars, to animal forms; the hallucinations may be so well formed and recognizable that vivid visual memories remain. Hallucinations that objects appear smaller than actual size (lilliputian hallucinations, or micropsia) may result from temporal lobe discharges. Many characteristics of auditory

Nordli / Focal and Multifocal Seizures

seizures parallel the characteristics of visual seizures. Auditory seizures range from primitive auditory perceptions, such as loud swishing noises, to easily recognized, complex auditory hallucinations. Loss of consciousness frequently follows the onset of auditory seizures, which also may precede a motor component. Other special sensory seizures, including vertigo, known as vertiginous seizures, have been termed tornado fits and may arise from suprasylvian parietal cortex. Olfactory and gustatory sensations usually are unpleasant and difficult to categorize. Olfactory sensations may become associated with a dreamy state, and this alteration of consciousness then characterizes the attack as a complex partial seizure. These attacks frequently arise from the uncal region of the temporal lobe and thus are known as uncinate fits. Seizures with autonomic phenomena may involve pupillary dilation, which accompanies many seizure types. Rarely, transient Horner’s syndrome may be observed on the side contralateral to a discharging parietal lobe focus. Seizure manifestations may include recurrent episodes of abdominal discomfort and vomiting, as well as unilateral piloerection, pallor, flushing, and salivation—which may be so profuse that saliva gushes from the mouth.

Simple Partial Seizures with Psychic Symptoms (Disturbances of Higher Cerebral Function) Although psychic symptoms occur frequently in complex partial seizures, they may be observed in focal disturbances of temporal lobe function that do not lead to alteration in consciousness and therefore manifest as simple partial seizures. These features may include dysmnesic symptoms in which there is distortion of memory or time, flashback experiences, or déjà vu. Occasionally, as a form of forced thinking, the patient may experience a rapid recollection of episodes from his or her life, known as panoramic vision. Cognitive disturbances may occur, as may sensations of extreme pleasure or displeasure. Such disturbances frequently involve feelings of fear and intense depression accompanied by attacks of unworthiness and rejection that last for several minutes. Anger or rage is rare. Unlike temper tantrums, these episodes are unprovoked and abate as rapidly as they begin. Illusions may be distorted perceptions in which objects appear deformed in size or shape. Distortions also may affect sound and body image (corporeal awareness); thus, altered perception of limb size or weight may be experienced.

Structured Hallucinations Structured hallucinations may occur as perceptions without a corresponding stimulus and may be sensory, visual, auditory, olfactory, or gustatory. Usually the hallucinations are quite primitive, but when visual association areas are affected, they may become elaborate, including scenes, sounds of voices, or music.

Complex Partial Seizures The primary feature that separates complex partial seizures from simple partial seizures is impairment, distortion, or loss of consciousness. These manifestations are the result of

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the epileptic discharge involving a region in which structures subserving consciousness, emotion, memory, and vision are affected; thus, a different order of sensation supervenes and can effect a dreamy state, visual symptoms, autonomic manifestations, affective disturbances, and frequently automatic behavior. All of the psychic symptoms referred to previously are based in the temporal lobe and limbic cortex; however, an alteration in consciousness in complex partial seizures occurs either near the beginning of or during the attack. As in simple partial seizures, hallucinatory phenomena may characterize seizure onset. These phenomena may affect various systems, and their complexity depends on the association areas involved. Unlike in simple partial seizures, most complex partial seizure hallucinatory phenomena are elaborate and realistic. As with simple partial seizures, the patient may experience affective symptoms, particularly fear, loneliness, depression, sadness, anger, joy, or ecstasy. At times, fear during a seizure is pervasive and leads to running away; if consciousness is impaired, the patient may end up located a long distance from where the seizure began. Psychomotor automatisms are the most prominent aspect of complex partial seizures. Automatisms are activities occurring during a period of altered consciousness for which the patient is amnesic. While engaged in these episodes, the patient may respond perfunctorily to the immediate milieu or may execute complex motor activities that are inappropriate. A distinction has been made between forced automatisms, such as mastication or swallowing, and reactive motor activities, such as scratching or fumbling with clothes or objects; the former are believed to result from epileptic discharges, and the latter from unrecalled psychosensory manifestations. Automatisms that have been identified include oroalimentary automatisms, such as chewing, lip smacking, and swallowing; automatisms of mimicry, such as fear, anger, anxiety, and joy; gestural automatisms, such as clapping, scratching, and stereotypic hand movements; ambulatory automatisms, such as walking or riding a bicycle, in which the activity may appear to be either goal-directed or completely disorganized; and verbal automatisms, which may be in response to stimulation or may be a stereotypic repetitive utterance. Some automatisms may represent the continuation of ongoing activities (perseverative automatisms), whereas others may be provoked during seizures and thus are regarded as reactive to external or internal environmental stimuli. Postictal disorientation is a prominent feature in psychomotor automatisms. Automatisms have little localization significance; they may emanate not only from temporal regions but also from the frontal lobes, and they can be produced experimentally by stimulating the fornix, circuminsular cortex, amygdala, hippocampal gyrus, and anterior part of the sylvian fissure. Delgado-Escueta and colleagues [1982] reported that complex partial seizures emanating from the frontal lobe begin with automatic behavior; conversely, those seizures emanating from temporal regions initially are associated with cessation of activities and a blank stare, which is followed by the development of automatisms. It is unknown whether such a distinction is valid on clinical grounds. Occasionally, complex partial seizures occur in the form of status epilepticus as a continuous aura, or as an episodic

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dreamy state with a prolonged confusional state; such seizures may be difficult to distinguish from absence status or spike-and-wave stupor. Sometimes psychomotor status is not continuous, with periods of relatively good orientation interspersed with periods of confused, restless, and disoriented behavior. Complex partial seizures may occasionally manifest as impaired consciousness only; this temporal lobe absence may closely simulate the absence exhibited in so-called petit mal seizures. Temporal lobe absence, however, usually is more prolonged, is unaccompanied by the expected 3-Hz spike-and-wave EEG activity, and terminates in postictal confusion. Intensive monitoring in association with patient evaluation for epilepsy surgery has revealed much information about complex partial seizures arising from the frontal lobes. The syndrome of frontal lobe epilepsy is of special interest because of the ease with which it is confused with pseudoepileptic seizures, by virtue of the varied behavioral repertoire and the frequently difficult-to-detect EEG concomitant. Complex gestural automatisms, prominent tonic or postural manifestations, and the frequent absence of postictal confusion contribute to diagnostic difficulty.

Partial Seizures, Secondarily Generalized Whether the discharge that initiates a partial seizure becomes propagated from its focal cortical site depends on the intensity of the epileptiform discharges; the individual, innate threshold; and inhibition. The evolution of a focal seizure into a generalized seizure probably requires dissemination to the thalamic, diencephalic, and mesencephalic areas, which subsequently results in discharges that invade the cortex of both hemispheres. It is known that brainstem structures are not always necessary for developing bilateral synchrony. In addition, the belief that involvement of so-called centrencephalic structures in humans is required for the development of bilateral synchrony is not firmly supported by clinical studies. Orbitofrontal and parasagittal lesions enhance the likelihood of resultant bilateral synchrony [Tukel and Jasper, 1952]. There is little question that some seizures believed to be generalized are the result of focal cortical discharges with secondary bilateral synchrony [Stewart and Dreifuss, 1967]. In fact, this method of propagation probably underlies many seizures that are considered to be generalized. It is likely that some generalized seizures are subsequent to a focal cortical discharge, even though the only symptoms evident— amnesia or alteration of consciousness—are not focal symptoms [Bancaud et al., 1965]. Before generalization of a focal seizure, the manifestation of the episode that precedes loss of consciousness is the aura. The patient is not amnesic but remains aware during this event. By convention, if no loss of consciousness occurs and the epileptic episodes continue to be focal, the result is similar, but the experience is not termed an aura.

Partial Seizures with Uncertain Alteration of Consciousness Infants, young children, children with autism, youngsters with moderate to severe mental retardation, and other chil-

dren with special needs may not be able to reliably describe how they are feeling during a seizure. Formal response testing during seizures (e.g., “remember purple cow”) may be impossible to perform. Because inattention is not synonymous with impaired consciousness, it is not reliable to attempt to infer whether a seizure is simple or complex in these patient populations. Instead, descriptive accounts of the external manifestations are more reliable. Some of the common manifestations in infants and young children are listed here and include behavioral arrest, clonus, spasms, tonic postures, and version. If a child is truly able to describe somatosensory or psychic phenomena, consciousness obviously is not impaired, and a simple partial seizure can be diagnosed. Some investigators have found this type of simple classification system particularly well suited for use in infants.

EPILEPSY SYNDROMES WITH FOCAL SEIZURES The International League against Epilepsy classification of epilepsy syndromes is reviewed in Chapter 40. A recent modification of the International League against Epilepsy classification eliminated the “focal” and “generalized” headings, but with some slight modification, the 1989 classification system can lend itself for pediatric use (see Box 44-2). Indeed, the 1989 classification system has been successfully applied to infants and children [Beilmann and Talvik, 1999; Berg et al., 2000b; Eriksson et al., 1997; Sarisjulis et al., 2000].

Benign Focal Epilepsies of Childhood Benign focal epilepsy with central-midtemporal spikes (also called central-temporal epilepsy or rolandic epilepsy) is most common in previously healthy children ages 4 to 13 years. It is an idiopathic localization-related epilepsy with characteristic EEG and clinical features. It represents 14.4% of all childhood seizure disorders in Israel and Sweden. When awake, children experience brief focal seizures, with twitching of one side of the face, anarthria, drooling, and paresthesias of the face, gums, tongue, or inner cheeks. These manifestations may be followed by hemi-clonic movements or hemi-tonic posturing. These diurnal seizures are simple; consciousness is preserved. Postictal weakness (Todd’s paralysis) of the involved face and limbs may occur. Most children have purely nocturnal seizures that usually become secondarily generalized. In such cases, the focal onset of the seizure usually is not observed, but parents are alerted by the sounds of the secondarily generalized convulsion. The prognosis is good, and seizures remit by adolescence. The EEG abnormality also resolves, although spikes may persist long after seizures have ceased. Prior genetic studies indicate that the EEG trait is controlled by an autosomal-dominant gene with agedependent penetrance [Bray and Wiser, 1965; Heijbel et al., 1975]. Genetic contributions to the partial epilepsies are well established, based on the work from familial aggregation studies, twin studies, positional cloning, and clinical descriptions of families. Susceptibility genes have been localized in five syndromes: autosomal-dominant nocturnal frontal lobe epilepsy (20q, 1q, and 15q),

Nordli / Focal and Multifocal Seizures

TABLE 44-1 Genetic Syndromes Associated with the Focal Epilepsies SYNDROME

GENE LOCUS

Autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE) Autosomal-dominant partial epilepsy with auditory features Familial partial epilepsy with variable foci Benign rolandic epilepsy of childhood (BREC) Benign familial infantile convulsions

20q, 1q, 15q 10q 22q 15q 19q

autosomal-dominant partial epilepsy with auditory features (10q), familial partial epilepsy with variable foci (22q), benign epilepsy of childhood with centrotemporal spikes (15q), and benign familial infantile convulsions (19q) (Table 44-1) [Ottman, 2001]. In the case of benign focal epilepsy with central-midtemporal spikes, more than half of siblings who have typical central midtemporal spikes on EEG never have clinical attacks. EEG findings are distinctive and diagnostic in benign focal epilepsy with central-midtemporal spikes. Focal di- or triphasic sharp waves of almost invariant morphology occur in the central and midtemporal regions (see Fig. 44-1). Epileptiform discharges usually are of high voltage (greater than 100 mV), tend to occur in clusters, and activate dramatically during sleep, when they may seem almost continuous. In a single EEG, discharges may be unilateral, but with prolonged or repeated recordings, they are almost always bilateral. Lateralization may switch in serial tracings [Lerman, 1985]. Generalized spikes and spike-and-wave activity occasionally occur, although more often the spikes are maximal in either central region and are simply bisynchronous. “Benign” occipital spikes or multifocal spikes may coexist, especially in younger patients. No correlation has been found between EEG findings and seizure occurrence or frequency. As a rule, EEG abnormalities are much more impressive than clinical seizure activity. Indeed, when central-midtemporal spikes are recorded in children without seizures in whom EEGs are performed for other reasons, typical seizures eventually develop in only approximately half of the children. Furthermore, in symptomatic children, EEG abnormalities persist long after seizures cease. Thus, EEG does not provide assistance in making decisions about when or how long to treat. When treatment is elected because of recurrent attacks that are interfering with the child’s function or because of parental concern, carbamazepine and gabapentin are options. In some European countries, sulthiame (a drug not readily available in the United States) is used because of its reported beneficial effects of reducing spike frequency and clinical tolerance [Bast et al., 2003; Rating et al., 2000]. In addition, some authors are concerned that certain drugs (carbamazepine and lamotrigine, in particular) may induce aggravation in this form of epilepsy [Cerminara et al., 2004; Parmeggiani et al., 2004], although such exacerbation appears to be rare [Corda et al., 2001]

Benign Focal Epilepsy with Occipital Spikes Gastaut [1982] described another form of idiopathic localization-related epilepsy in children, in which visual

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symptoms, either amblyopia or hallucinations, are a common early feature of ictal events. The EEG shows stereotypic, high-voltage (200 to 300 mV) sharp-wave discharges over one or both occipital regions. Epileptiform activity is attenuated by eye opening and activated by sleep. Discharge morphology resembles that of central-midtemporal spikes. Background activity is normal. This electroclinical entity is more heterogeneous than benign focal epilepsy with centralmidtemporal spikes. Nonetheless, in a typical case, outcome usually is excellent, with complete resolution of clinical and EEG abnormalities in most children by 18 years of age. Like central-midtemporal spikes, occipital spikes do not correlate with clinical seizure activity or prognosis, and they often persist after seizures cease. Generalized spike-and-wave discharges and central-midtemporal spikes can coexist.

Panayiotopoulos’ Syndrome More recently, the International League against Epilepsy recognized early-onset childhood epilepsy with occipital spikes (Panayiotopoulos type) and differentiated it from the later-onset occipital epilepsy as described by Gastaut [Panayiotopoulos, 1999; Lada et al., 2003]. This syndrome is about half as frequent as benign focal epilepsy with central-midtemporal spikes by some estimates and carries an excellent prognosis. It is characterized by autonomic and behavioral disturbances with vomiting, deviation of the eyes, and impairment of consciousness that can progress to convulsions. Seizures are long-lasting, often more than 3 minutes. Typical age at onset is 5 years. Occipital spikes may be present, but stereotypic spikes in other locations (cloned spikes) are reported, particularly as the child ages [Ohtsu et al., 2003]. Panayiotopoulos has indicated that diagnosis is important for several reasons, including the fact that prophylactic treatment may not be necessary.

Familial Partial Epilepsy with Auditory Features Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features, a form of familial temporal lobe epilepsy with auditory ictal manifestations. This disorder is characterized by simple partial seizures with auditory symptoms and secondary generalization. Sensory and psychic symptoms also may be present. Typical age at onset is in the first 2 decades [Ottman et al., 2004]. The most common auditory symptoms are simple, unformed sounds (e.g., buzzing, ringing).

Autosomal-Dominant Familial Nocturnal Frontal Lobe Epilepsy Autosomal-dominant familial nocturnal frontal lobe epilepsy is characterized by clusters of brief hypermotor and tonic seizures with a nocturnal predominance (see Chapter 42). Onset typically is in childhood, and seizures may persist through life, with a wide variation in severity of presentation. The ictal EEG shows bilateral anterior ictal discharges, but interictal findings usually are normal. Three different mutations in the gene encoding the alpha 4 subunit of a neuronal nicotinic acetylcholine receptor (CHRNA4) on chromosomal region 20q13.2 have been described, but other mutations in the gene encoding the beta 2 subunit of the

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neuronal nicotinic acetylcholine receptor (CHRNB2) on 1p21 were identified [Phillips et al., 1995, 2001]. One study has identified a region, q24, on chromosome 15, but the gene is yet to be characterized [Phillips et al., 1998].

Familial Partial Epilepsy with Variable Foci Another recently described condition is familial partial epilepsy with variable foci. Members of affected families have focal seizures with a variety of foci. The onset of seizures typically is in middle childhood, and attacks usually are easy to control. Seizure semiology varies among family members but is stereotypic for each affected person. In some reports, a pattern of nocturnal frontal lobe seizures suggested autosomal-dominant familial nocturnal frontal lobe epilepsy. Linkage to chromosome 22q has been found [Callenbach et al., 2003].

Symptomatic Localization-Related Epilepsy Localization-related epilepsy may manifest at any age with simple or complex partial seizures. The clinical presentation varies widely depending on the age of the patient, degree of cerebral maturation, location of the epileptogenic focus, and integrity of the underlying nervous system. When a cause is identified, the epilepsy is referred to as symptomatic. By contrast, the term cryptogenic is used when a focal lesion is thought to exist but its true nature is not evident. Recent advances in MRI and functional imaging have allowed identification of a larger number of previously cryptic foci, and the current trend is to substitute the term probably symptomatic for cryptogenic. One such lesion, mesial temporal sclerosis, is being identified in some children and young adolescents.

Limbic Epilepsies: Mesial Temporal Sclerosis Seizures involving the limbic structures produce characteristic clinical and electrographic features. Patients may complain of a rising epigastric aura or an indescribable sensation. Propagation of the ictal discharges can cause alteration of consciousness. Observers can document alteration of consciousness by asking the child to carry out simple commands such as “point to the door,” and to remember a peculiar test item such as “purple elephant.” Amnesia can be ascertained by asking about this test item after the seizure is finished and the child’s clinical condition has returned to baseline. Other characteristic clinical features that may evolve are ipsilateral picking automatisms and contralateral hand dystonic postures. Seizures may secondarily generalize; this sequence often begins with contralateral head and eye version followed by contralateral clonus. This sequence represents a mature pattern usually seen beyond the age of 6 years. In younger children, only fragments of this activity may be seen (Nordli et al., 2001). Mesial temporal sclerosis is a condition characterized by pathologic changes in the medial temporal region. It is a common cause of refractory temporal lobe seizures in adults that come to epilepsy surgery, but it is not commonly seen in population-based studies in children. Indeed, Berg and colleagues [2000a] found that only 3 children of 613 with epilepsy had evidence of hippocampal atrophy on their

scans. One of these patients was later found to have a tumor. One possible explanation for this discrepancy is that mesial temporal sclerosis may be an acquired lesion. As mentioned, mesial temporal sclerosis frequently has been found in patients who have undergone temporal lobectomy for uncontrolled complex partial seizures [Corellis and Meldrum, 1976]. Such sclerosis may also affect the amygdala and the parahippocampal gyrus. Patients who have undergone temporal lobectomy with subsequent pathologic documentation of mesial temporal sclerosis frequently experience prolonged febrile convulsions in infancy and early childhood. Ounsted and co-investigators [1966] stressed that early-onset seizures and severe generalized tonic-clonic seizures accompanied by a high frequency of temporal lobe attacks were associated with an adverse prognosis. Meldrum [1978] stressed the metabolic process by which neuronal hippocampal changes could be produced by recurrent seizures. Prospective epidemiologic studies have failed to prove a clear connection between prolonged febrile convulsions and mesial temporal sclerosis, but experience at surgical centers suggests that many patients with mesial temporal sclerosis have had prolonged febrile convulsions in early life. A primate model of hippocampal sclerosis induced by epilepsy has been produced by administering bicuculline or allylglycine to baboons [Meldrum, 1983]. The initiation of such seizures is associated with ischemic changes in cerebellar Purkinje cells, a finding that also is observed in patients with long-standing epilepsy. The effect of prolonged seizures in immature animals is far less pronounced. A large prospective study is in progress and attempts to address this association by carefully examining children with prolonged febrile convulsions. Brain MRI is very helpful in establishing the diagnosis of mesial temporal sclerosis. The afflicted hippocampus can be best visualized in coronal sequences obtained orthogonal to the long axis of the temporal lobe. Combinations of highresolution images, inversion recovery sequences, and thincut images are used to compare the morphology, signal characteristics, and size of the hippocampus and adjacent structures. Characteristically, the interictal EEG shows focal pleomorphic interictal epileptiform discharges in the anterior to midtemporal region. Additional electrode placements including anterior temporal and subtemporal leads may assist in the detection and characterization of the interictal epileptiform discharges. The ictal EEG may reveal broad, relatively nonlocalizing delta discharges at onset, but evolution to a rhythmic theta-alpha pattern within the first 10 to 20 seconds is a supportive feature. Patients with this lesion who have intractable epilepsy usually responds favorably to focal resection of the involved anterior temporal region. A randomized study of patients with temporal lobe epilepsy showed the superiority of surgical over medical management of mesial temporal sclerosis [Wiebe et al., 2001]. These results argue for early and aggressive surgical management of patients with intractable seizures resulting from mesial temporal sclerosis.

Cryptogenic or Probably Symptomatic LocalizationRelated Epilepsy Despite advances in imaging, in some children with focal seizures, such studies will not yield sufficient information to

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allow diagnosis of an etiology or to precisely identify the region of onset. In these cases, the terms cryptogenic and probably symptomatic are used. This is a heterogeneous group of youngsters: Some have small focal structural lesions that are below the current resolution of scanners; others have an inherent diffuse predisposition to seizures that manifest with partial seizures. The true idiopathic nature of these syndromes is not yet described. Although certain benign focal epilepsies of childhood have been delineated, other entities of benign focal seizures manifesting in the neonatal period, infancy, and childhood have been reported. The true incidence of benign partial seizures that do not fit into the current International League against Epilepsy classification is difficult to determine, because partial seizures in younger children may be associated with subtle clinical manifestations or even bilateral tonic posture. These seizures may easily be confused with generalized seizures and therefore classified by investigators as idiopathic generalized epilepsy. Watanabe and Okumura [2000] have described two types of benign partial epilepsies in infancy, one with “complex partial seizures” and the other with “secondarily generalized seizures.” Onset of these seizures was from the temporal region in the former and central, parietal, or occipital region in the latter. Concordant with earlier comments, Watanabe and others reported that in many of these children, the partial features of the seizures would have been easily overlooked, and the interictal EEG findings often were normal. These children fared well with easy control of their seizures and good neurologic outcome. Other children with variations of this clinical presentation have been described [Capovilla and Vigevano, 2001].

with myoclonus, which may appear early. Progressive motor deficits develop during the illness, as does loss of mental function. The seizures are extremely resistant to treatment, and the condition usually progresses to complete hemiplegia with progressive unilateral brain atrophy [Andermann, 1991]. EEG findings are variable, and their topography often is difficult to precisely characterize [Bancaud, 1985]. Most often, interictal EEGs show excessive dysrhythmic or rhythmic delta activity, which usually is bilateral but accentuated over a large area contralateral to the partial seizures. Epileptiform discharges are rarely well localized and often are sporadic, especially early in the illness. As the disease progresses, more abundant pleomorphic spike and sharpwave discharges appear over an extensive area or in both hemispheres. With scalp recordings, it is usually difficult to recognize distinct ictal discharges, and correlation of EEG changes with muscle jerking is always poor to nonexistent. This is one form of epilepsy in which hemispherectomy is widely believed to be of benefit.

Epilepsia Partialis Continua and Rasmussen’s Syndrome

Acquired Epileptic Aphasia (Landau-Kleffner Syndrome)

Epilepsia partialis continua manifests as several different subtypes, but one subtype, Rasmussen’s syndrome, occurs primarily in children as a reasonably distinct entity [Rasmussen and McCann, 1968]. In a majority of patients, onset is before age 10 years. About two thirds of children or their family members have an infectious or inflammatory illness before the onset of the epilepsia partialis continua. The first seizures are reported as generalized, and the intractable focal nature of the attack becomes apparent only over time. When fully established, the syndrome is characterized by unremitting seizure activity limited to part or one side of the body. Unlike those in more typical simple partial seizures of motor type, muscle movements usually are asynchronous in different muscle groups and seem to ebb and flow in waves, sometimes involving fewer muscles, sometimes more. The clinical course is marked by slow neurologic deterioration with development of hemiparesis, diminished mental capacity, and usually, hemianopia. Although progressive, the disease is only rarely fatal, and a permanent but stable neurologic deficit emerges. Although childhood epilepsia partialis continua is considered the result of chronic encephalitis, the cause is unknown [Andrews and McNamara, 1996]. Evidence of antiglutamate receptor (anti-Glu R3) antibodies suggests that an autoimmune process may be involved, but this has not been substantiated. Partial motor seizures often are associated

Acquired epileptic aphasia, also known as Landau-Kleffner syndrome, is not a primary epileptic disorder, although epileptiform activity is part of the diagnostic criteria (Chapter 45). Seizures occur in about 70% of cases but usually are infrequent. The syndrome is one of typically healthy children who acutely or sometimes with a fluctuating course lose previously acquired language skills. The aphasia begins with verbal auditory agnosia, and EEGs show abundant, highvoltage epileptiform activity that can be temporal, bitemporal, or generalized. Considerable slow-wave activity accompanies epileptiform discharges. In the early stages, EEG abnormalities may occur only during sleep, and throughout the illness, slow-wave sleep produces marked activation, sometimes with almost continuous generalized spike-and-wave activity. Review of original and subsequent cases of Landau-Kleffner syndrome does not support any single EEG feature or combination of features as being distinctive of this syndrome [Holmes et al., 1981; Landau and Kleffner, 1957]. Antiepileptic drug treatment does not clearly alter the natural evolution of EEG abnormalities, clinical findings, or outcome, but corticosteroids may be of benefit [Lerman, 1991; Marescaux et al., 1990]. Recent enthusiasm has arisen for subpial transection to treat acquired epileptic aphasia surgically, but no controlled data are available to suggest that this approach is effective in favorably modifying the natural history.

EPILEPSIES WITH MIXTURES OF GENERAL AND FOCAL SEIZURES OR WITH MULTIFOCAL SEIZURES In the category of epilepsies with mixed or multifocal seizures are neonatal seizures, severe myoclonic epilepsy of infancy (e.g., Dravet’s syndrome), acquired epileptic aphasia, and migrating partial seizures of infancy as described by Coppola and colleagues [1995]. Neonatal seizures (Chapter 13) and severe myoclonic epilepsy of infancy (Chapter 46) are reviewed elsewhere in this book and are not discussed here.

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Migrating Partial Seizures of Infancy

Congenital and Perinatal Factors

Migrating partial seizures of infancy was a term used by Coppola and colleagues [1995] to describe a disorder of infants with severe encephalopathies and very frequent partial seizures that arose independently from multiple regions. These infants often experienced epochs of nearly continuous electrographic and clinical ictal activity during portions of the EEG recordings. No etiology for these patients was determined despite careful metabolic analysis. Treatment was problematic, and outcome was poor in all cases, with a high degree of mortality. In some centers, it has been shown that other patients who have less frequent seizures fit this description. Whether these are distinct patient groups or just variants on a clinical spectrum is not currently known but may be determined by careful evaluation of larger series and, ultimately, pinpointing the cause of this disorder.

Chromosomal pathologic conditions may result in malformations. Intrauterine infections, specifically cytomegalic inclusion disease, toxoplasmosis, and rubella, are well known for their ability to cause abnormal brain development. Syphilis, rare in many parts of the world, also may cause intrauterine brain infection, with severe neurologic residua. Maternal exposure to radiation during pregnancy or ingestion by the mother of teratogenic drugs also may lead to cerebral malformations. In addition to other manifestations, these disorders also may result in focal and multifocal seizures. An unusual seizure type, myoclonic spasms, sometimes results from intrauterine infections. Tuberous sclerosis may manifest during the first few months of life and may be accompanied by focal seizures or infantile myoclonic spasms. Other causes of seizures in the perinatal period are discussed in Chapter 13.

ETIOLOGY

Brain Tumors

Although partial seizures are more likely to be associated with focal hemispheric lesions than are generalized seizures, structural causes are rarely identified. In children, approximately 30% to 50% of these seizures have no determinable etiology, whereas others have vague putative causes, such as a difficult delivery at birth or early childhood head trauma that cannot be substantiated. Moreover, genetic factors evidently determine susceptibility to focal seizures. In the past, prenatal and perinatal complications were thought to cause pediatric seizure disorders, but more recent epidemiologic evidence suggests that cerebral malformations are the most commonly identified underlying cause. Berg and colleagues [2000a] found that 16 of 613 children with epilepsy had cortical malformations, whereas 13 had presumed intrauterine insults, 8 had a neurocutaneous syndrome, and 5 had intraventricular hemorrhage. Only one had an anoxic encephalopathy, and three had defined genetic or chromosomal abnormalities. Four patients had tumors, three had vascular lesions, and three had clear evidence of an infectious disorder (based on neuroimaging). Only two patients had neuroimaging findings indicating previous brain trauma.

Tumors are an uncommon cause of seizures during childhood. Tumors occur less frequently in children than in adults and are more commonly found in regions of the brain that are not predisposed to developing epileptogenic activity (e.g., thalamus, cerebellum, brainstem). Nonetheless, focal seizures in children can be caused by tumors [Backus and Millichap, 1962]. In a study of 100 patients with seizures of focal origin, 4 had associated hemispheric gliomas and 2 had arteriovenous malformations. During the subsequent 10 years, temporal lobe tumors were discovered in three additional patients. A more recent study using a communitybased approach and using modern imaging techniques revealed brain tumors in only 4 of 613 children with epilepsy. One case each of ganglioglioma, astrocytoma grade II, dysembryoblastic neuroepithelial tumor, and oligodendroglioma was reported [Berg et al., 2000a]. Although MRI has facilitated the diagnosis of tumors, older studies clearly had a skewed perspective, owing to ascertainment bias. Tumors that are relatively less malignant and slow growing are more often associated with seizures than are malignant tumors. Nevertheless, focal seizures accompanied by a history of headaches may be caused by tumor.

Cortical Malformations

Postnatal Infectious Diseases

Cortical malformations are more commonly diagnosed today because of the widespread availability of MRI scanning and better appreciation of the subtle findings in some of these conditions. Of particular importance for focal seizures are focal and hemispheric malformations including cortical dysplasia (Taylor types I and II), schizencephaly, isolated heterotopias, and hemimegalencephaly. Patients with lissencephaly may have focal seizures, but the widespread nature of the malformation places patients with this disorder in the generalized symptomatic epilepsy syndrome category. EEG clues to the presence of a cortical malformation may be the presence of periodic spikes or precocious fast rhythms early in life. This latter feature can be responsible for an incorrect EEG lateralization of the abnormal hemisphere in hemimegalencephaly. The electroencephalographer must be alert to the invariant peculiar quality of the precocious alpha rhythm over the involved hemisphere in this disorder, particularly during the first year of life.

Seizures often are the first indication of bacterial meningitis in infants and children; moreover, seizures frequently are associated with established bacterial meningitis. The simultaneous presence of generalized seizures and fever generally suggests bacterial meningitis. Mechanisms of seizure production in bacterial meningitis include cortical vein and sagittal sinus thrombosis, primary involvement of the cortical tissue, cerebritis and subsequent abscess formation, and subdural effusions. Hydrocephalus and seizures may result from ependymitis, ventriculitis, or involvement of the meninges with subsequent impairment of spinal fluid absorption. Focal or multifocal seizures may be associated with viral encephalitis. Many patients with viral encephalitis have only minor neurologic impairment, and their seizures may be transient. Conversely, severe encephalitis, resulting from herpes simplex virus or Epstein-Barr virus, both of which preferentially affect the temporal lobes, may result in severe

Nordli / Focal and Multifocal Seizures

sequelae with intractable seizures and permanent intellectual and memory dysfunction. Subacute sclerosing panencephalitis is associated with rubeola infection. This condition often is heralded by multifocal myoclonic seizures and focal and multifocal seizures. Diphtheria-pertussistetanus immunization may be followed by focal or generalized seizures. It generally is believed that these seizures are fever induced and that pertussis encephalopathy is exceedingly rare. Conversely, it is recommended that persons with epilepsy or other neurologic diseases, particularly if progressive, should have pertussis inoculation deferred. Parasitic infestation (Chapter 70) may result in focal seizures. In particular, cysticercosis is accompanied by circumscribed cortical cysts and acute obstructive hydrocephalus. Echinococcosis is another parasitic infection that results in focal brain lesions. Tuberculosis with tuberculoma formation in the brain continues to be a problem in certain areas of the world.

Trauma One of the most important consequences of traumatic brain injury is the development of convulsions, although the incidence depends on many factors, including injury severity. Epilepsy occurs more frequently after penetrating wounds [Jennet, 1975]. In closed head injuries, which constitute most of the wounds suffered by the general population, the incidence of traumatic epilepsy is relatively low. Cerebral damage during or near the time of birth may be manifested by early or late seizures. The effect of closed head injuries depends on the mechanical factors involved. In children, the most frequent traumatic causes of epilepsy are linear or depressed skull fractures. Except for some instances of early traumatic epilepsy after relatively trivial injury, the incidence of epilepsy after head trauma is generally proportional to the duration of post-traumatic amnesia. Early-onset epilepsy usually is associated with simple partial seizures and motor signs. In more than 50% of patients, it arises within 24 hours of injury. Children younger than 5 years of age frequently manifest status epilepticus after severe injuries. Patients suffering early-onset posttraumatic epilepsy have favorable outcomes compared with those in whom late-onset epilepsy develops. Late-onset posttraumatic epilepsy represents most post-traumatic seizures. Generally, these seizures occur within 3 years of injury and are more frequently generalized tonic-clonic than partial seizures, in contrast with early-onset traumatic epilepsy. The pathogenesis of post-traumatic epilepsy remains unknown despite the standard explanation of meningocerebral scarring and focal ischemic factors. Experimental animal models suggest that neurons in affected regions are structurally abnormal, with changes in dendritic spine density and electrical hyperexcitability. Extravasation of blood and deposition of hemoglobin may stimulate peroxidation of microsomal lipids; this process may be epileptogenic. Although epilepsy develops in nearly 50% of patients with penetrating head wounds and dural tears, seizures develop in only about 5% of patients after closed head injury [Jennett, 1975]. In a community-based study of 613 children with epilepsy in Connecticut, Berg and co-investigators found that only 2 children had neuroimaging findings consistent with trauma [Berg et al., 2000a].

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Focal seizures may result from subdural hematomas in childhood; multifocal seizures can result from bilateral subdural hematomas. Bilateral subdural hematomas frequently are found in infants. Unless acute, an associated increase in the occipitofrontal circumference along with increased tension of the anterior fontanel is common. Nonaccidental trauma must be considered in the differential diagnosis in these cases, particularly with other associated features such as parenchymal brain lesions, retinal hemorrhages, or bone fractures.

Cerebrovascular Disease Focal seizures in children rarely result from cerebrovascular disease. Sturge-Weber syndrome (i.e., encephalofacial angiomatosis) usually manifests with a port-wine nevus in the distribution of one or more divisions of cranial nerve V. The associated angiomatosis is found over the ipsilateral cortex in the pia-arachnoid. The associated gyri are atrophied, and linear calcifications may be present, most often in the occipital lobes. Other features may include brain hypoplasia and focal seizures; hemiparesis may compromise the contralateral extremities [Thomas-Sohl et al., 2004]. Hemispherectomy often is indicated and likely should be undertaken early in life when seizures are intractable and particularly when learning is impaired and a hemiplegia exists [Vining et al., 1997]. As a cautionary note, Kosoff and colleagues did not find a clear improvement in development in those children who underwent surgical treatment for their disease [Kossoff et al., 2002]. Congenital heart disease or bacterial endocarditis may cause emboli that flow to the brain and precipitate seizures. Unfortunately, not only is hemiplegia beginning in infancy that results from hemispheral infarction likely to be associated with early-onset seizures, but the seizures may persist for years and be difficult to manage. The rate of hemiplegia associated with early-onset seizures in patients is about 50%. Considerations in the differential diagnosis of earlyonset hemiplegia include fibromuscular hyperplasia, intraoral trauma to the internal carotid artery, carotid artery dissection, and arteritis (both autoimmune and associated with the use of intravenous amphetamines and of cocaine, which may produce consequences if used by the mother). Moyamoya disease and mitochondrial disorders, sickle cell disease, circulating lupus anticoagulant, and homocystinuria may produce similar insults. These conditions are discussed in more detail in Chapter 72 and elsewhere in this book.

MANAGEMENT Idiopathic Epilepsies Evaluation Epilepsy syndromes can be identified by considering the age, functional developmental level of the child, clinical features of the seizures, and the interictal EEG findings. Idiopathic focal epilepsies can present at any age, but the most common and well-described syndromes manifest in the school-age child before adolescence. Infantile idiopathic localization-related epilepsies have been reported and are

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Epilepsy / 44

common in Japan; they are rarely reported in the United States. Similarly, idiopathic focal epilepsies are reported in adolescents but are rarely encountered in clinical practice. Thus, an infant with focal seizures needs to be carefully examined for the presence of an irritative lesion or an underlying metabolic derangement, and an adolescent, for a focal structural lesion. Findings on the developmental and neurologic examinations should be normal in children with idiopathic epilepsies. The seizure semiology and interictal EEG findings usually are distinctive, allowing definitive diagnosis. If an idiopathic epilepsy is diagnosed, extensive evaluations are not necessary, and in the case of benign rolandic epilepsy, neuroimaging is not compulsory. Berg and colleagues [2001] found that 48 of 613 children with epilepsy in a population-based study had idiopathic localization-related epilepsy. Neuroimaging was performed in a majority of these children (78.7%); no abnormalities were found. Interictal EEG findings that suggest an idiopathic form of localization-related epilepsy include the presence of a normal background, lack of focal slowing, and stereotypic spikes in which each interictal epileptiform discharge closely resembles the other (see Fig. 44-1). Guidelines for the evaluation of the first afebrile seizure have been published, and the recommendations concur that neuroimaging is not necessary in all cases [Hirtz et al., 2000].

Treatment If the child is determined to have an idiopathic form of localization-related epilepsy, then therapy should not be automatic, even if several seizures have occurred. It can be particularly useful to discuss precipitating factors with the parents and to give appropriate anticipatory guidance and counseling. A useful point to highlight is the importance of good sleep hygiene with keeping the same bedtime within an hour or so for weekdays and weekends. If therapy is warranted, carbamazepine, which is widely used in the United States, can be given, although many European practitioners avoid this drug because of concerns of aggravating the epilepsy. Another option is gabapentin. This agent is particularly useful because of its lack of drug-drug interactions and favorable safety profile. Sulthiame is used in some European countries for treatment of benign focal epilepsy with central-midtemporal spikes.

Symptomatic Localization-Related Epilepsy Evaluation If the clinical features and EEG findings are not consistent with a known idiopathic disorder, then MRI scanning is indicated. In the experience of Berg and colleagues, 177 of 613 children had symptomatic localization-related epilepsy, and findings on MRI were abnormal in 28.3% of these children [Berg et al., 2000a]. Any focal features on the neurologic examination or interictal EEG (focal slowing, focal attenuation, focal polymorphic spikes) can help to guide the MRI and target certain areas for detailed scrutiny (see Fig. 44-1). A symptomatic form of epilepsy can be diagnosed by virtue of defining the precise location of the lesion, or by identifying the lesion itself.

Treatment If a symptomatic form of localization-related epilepsy is confirmed by clinical testing, then consideration should be given to primary treatment of the lesion. In some circumstances, a policy of “waitful watching” may be the most prudent management, but excessive delays in resection of surgically remediable lesions should be avoided, particularly if seizures are not well controlled or if development is not progressing normally. Carbamazepine often is used for first-line treatment, but other medications could be considered. A task force from the American Academy of Neurology and American Epilepsy Society recently reviewed the literature on antiepileptic drugs for treatment of new-onset seizures and concluded that treatment could begin with any of the classic medications: carbamazepine, phenobarbital, phenytoin, or valproate. In addition, the task force findings supported use of gabapentin, lamotrigine, oxcarbazepine, or topiramate as an alternative [French et al., 2004a]. A careful consideration of the side effect profile of the various drugs in pediatrics is important before a specific antiepileptic drug is selected. Four drugs, all released before 1978, have been most frequently used in pediatrics for focal seizures: carbamazepine, phenobarbital, phenytoin, and valproate. None is clearly superior to the others [Mattson et al., 1985], although randomized studies have found a disproportionately high incidence of side effects with phenobarbital [de Silva et al., 1996]. For this reason, chronic use of phenobarbital should be avoided, even in infants, unless special circumstances prevail. Most clinicians use carbamazepine as a first-line drug for management of epilepsies with focal seizures. Phenytoin had been a favorite choice in the past, but cosmetic side effects and complicated kinetics make it less attractive than other agents. With valproate, a concern is the possibility of idiosyncratic, potentially fatal hepatotoxicity, particularly in children younger than 2 years of age who are receiving two or more antiepileptic agents [Dreifuss and Santilli, 1986].

Epilepsies with Multifocal Seizures, or Combinations of Focal and Generalized Features As mentioned earlier, these epilepsies are diagnosed when the clinical and electrographic features demonstrate a combination of focal and generalized features. One could also include in this category children who have multifocal seizures, particularly in the setting of diffuse cerebral dysfunction. No published guidelines or practice parameters that apply to these patients are available. The literature on the subject is limited, so only anecdotal advice can be provided. These epilepsies appear to respond better to an agent with a wider spectrum of action, such as valproate. Newer agents offer the hope of better side effect profiles with equivalent effectiveness (Table 44-2), but sufficient comparison data are lacking in children to permit a strong recommendation for their use for first-line treatment. The classic broad-spectrum agent is valproate, but newer agents with broad profiles include felbamate, lamotrigine, levetiracetam, topiramate, and zonisamide. To date, none of these newer medications have been systematically studied in this patient population.

Nordli / Focal and Multifocal Seizures

TABLE 44-2 Practical Guide to Antiepileptic Drugs DRUG*

USE

HOW SUPPLIED

Phenobarbital (1912)

Broad spectrum

Phenytoin (1938) [Dilantin]

Focal

Primidone (1949) [Mysoline] Ethosuximide (1958 [Zarontin] Carbamazepine (1968) [Tegretol, Tegretol-XR, Carbatrol]

Broad spectrum

Valproate (1978) [Depakene, Depakote]

Broad spectrum

Suspension: qd-bid 20 mg/5 mL Tablets: 15, 30, 60, 100 mg Suspension: qd-tid 125 mg/mL Chewable Infatabs: 50 mg Capsules: 30, 100 mg Suspension: tid 250 mg/5 mL Tablets: 50, 250 mg Suspension: bid 250 mg/5 mL Capsules: 250 mg Suspension: bid‡-tid 100 mg/5 mL Chewable tab: 100 mg Tablets: 200 mg; timed-release [Tegretol-XR]: 100, 200, 400 mg Sprinkles: 100, 200, 300 [Carbatrol] mg Suspension: bid-tid 250 mg/5 mL [Depakene] Capsules: 250 mg [Depakene] Sprinkles: 125 mg Tablets: 125, 250, 500 mg Suspension: tid-qid 600 mg/5 mL Tablets: 400, 600 mg Suspension: tid-qid 250 mg/5 mL Capsules: 100, 300, 400 mg Tablets: 600, 800 mg Tablets: 25, 100, bid 150, 200 mg; chewable: 2, 5, 25 mg Tablets: 25, 100, bid 200 mg Sprinkles: 15, 25 mg Tablets: 2, 4, 12, bid-tid 16, 20 mg Tablets: 250, 500, bid-tid 750 mg Suspension: 100 mg/mL Suspension: bid 300 mg/5 mL Tablets: 150, 300, 600 mg Capsules: 100 mg qd-bid

Absence Focal

Felbamate (1993) Broad [Felbatol] spectrum Gabapentin (1993) Focal [Neurontin]

Lamotrigine Broad (1994) spectrum [Lamictal] Topiramate (1996) Broad [Topamax] spectrum Tiagabine (1997) [Gabitril] Levetiracetam (1999) [Keppra] Oxcarbazepine (2000) [Trileptal]

Focal Broad spectrum Focal

Zonisamide (2000) Broad [Zonegran] spectrum Diazepam rectal Emergency gel [Diastat]

Pediatric: 2.5, 5 mg Universal: 10 mg Adult: 15, 20 mg

DOSING

prn

STARTING DOSE (mg/kg/day)

STARTING DOSE DURATION

MAINTENANCE DOSE (mg/kg/day)

BLOOD LEVEL† (ug/mL)

3-5

Immediate

3-8

15-45

4-7

Immediate

4-7

10-25

5

Average: 2-3 wk

15

PRM: 4-12 PB: 15-40

10

Average: 2-3 wk

15-40

40-120

5

Average: 2-4 wk

12-20

4-12

10

Average: 2-4 wk

30-60

50-120

15

Average: 2-4 wk

45

18-45

15

Quick: 1 wk

30-45

5-15†

0.2 (with VPA); 0.5 (with CBZ/PHT) 1-2

Slow: 2-4 mo Slow:6-8 wk

1-5 5-15

2-20†

Average: 2-4 wk

5-10

2-25†

0.05

Average: 2-4 wk

1-2

5-70†

10

Average: 2-4 wk

20-45

20-60†

8-10

Average: 2-4 wk

20-40

5-50†

2-4

Average: 2-4 wk

4-12

10-40†

0.2-0.5 mg/kg

*Year of availability is given in parentheses; trade names appear in brackets. †Not well established. ‡Twice-daily dosing with Tegretol-XR or Carbatrol. CBZ, carbamazepine; PHT, phenytoin; PRM, primidone; PB, phenobarbital; VPA, valproate.

0.2-1.5

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Epilepsy / 44

Refractory Focal Seizures

ACKNOWLEDGMENT

Evidence to rationally guide the order of selection of antiepileptic drugs for children with refractory focal seizures is scarce. According to recently published practice parameters, gabapentin, lamotrigine, oxcarbamzepine, and topiramate are useful adjunctive agents in the treatment of refractory pediatric focal seizures [French et al., 2004b]. Evidence is insufficient to make any recommendations concerning the use of levetiracetam, tiagabine, or zonisamide for the treatment of refractory focal seizures. Relevant comparative drug trials are lacking to assist the clinician in the selection of the best medications in most of the pediatric epilepsies. Considerations in management include the selection of the initial medication, the second or third choice for persistent seizures, and whether it is better to treat with combination therapy or monotherapy in refractory cases. Treatment strategies change over time, with the current trend being to use drugs in sequential monotherapy, although in practice, some overlap between agents is almost always present. A recurrent theme that reverberates in the epilepsy community is rational polypharmacy versus sequential monotherapy. A pediatric consortium is needed to address the following issues:

I would like to recognize the contribution of the late Dr. Fritz Dreifuss to this chapter.

• For selected epilepsy syndromes, what is the best initial treatment? • What is the proper order for trial of medications if the first medication fails? • Do patients benefit from combination therapy or is sequential monotherapy superior? • How long should a child be given a trial with medications if a focal lesion is present and seizures are intractable?

Long-Term Outcome and Multidisciplinary Issues Pediatric epilepsy is more than just two afebrile seizures. Environmental and genetic factors that cause susceptibility to recurrent seizures also may increase the risk for other manifestations of central nervous system dysfunction, including psychopathology, attention difficulties, behavioral disorders, and socialization problems (see Chapter 52). Like the seizures themselves, these clinical features may be expressed only during special developmental windows and, if not promptly recognized and treated, can have long-lasting insidious effects. Sillanpaa and colleagues [1998] have found that children with epilepsy are at increased risk of failing to match the social, educational, and vocational achievement of their peers. A multidisciplinary team approach to epilepsy can address these concerns by effectively screening at-risk patients and referring affected children to health-care professionals with special expertise. This process moves in parallel with the medical evaluation of the seizures, but careful case management by experienced personnel also is required. Resources vary in different regions and facilities, but intermittent multidisciplinary meetings can facilitate optimal care. Specialized epilepsy centers often are staffed with such teams, and children with refractory epilepsies may benefit from these services. The ultimate goal of treatment is not just seizure control but also maximization of the long-term potential of the child with epilepsy.

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Nordli / Focal and Multifocal Seizures French J, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs, I: Treatment of new-onset epilepsy: Report of the TTA and QSS subcommittees of the American Academy of Neurology and the American Epilepsy Society. Epilepsia 2004a;45:401. French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs, II: Treatment of refractory epilepsy: Report of the TTA and QSS subcommittees of the American Academy of Neurology and the American Epilepsy Society. Epilepsia 2004b;45:410. Gastaut H. A new type of epilepsy: Benign partial epilepsy of childhood with occipital spike-waves. Clin Electroencephalogr 1982;13:13. Hamer HM, Wyllie E, Luders HO, et al. Symptomatology of epileptic seizures in the first three years of life. Epilepsia 1999;40:837. Heijbel J, Blom S, Rasmuson M. Benign epilepsy of childhood with centrotemporal EEG foci: A genetic study. Epilepsia 1975;16:285. Hirtz D, Ashwal S, Berg A, et al. Practice parameter: Evaluating a first nonfebrile seizure in children. Neurology 2000;55:616. Holmes GL, McKeever M, Saunders Z. Epileptiform activity in aphasia of childhood: An epiphenomenon? Epilepsia 1981, 22:631. Jennet B. Epilepsy after non-missile head injuries, 2nd ed. London: William Heinemann Medical Books, 1975. Kossoff EH, Buck C, Freeman JM. Outcomes of 32 hemispherectomies for Sturge-Weber syndrome worldwide. Neurology 2002;59:1735. Krynauw RA. Infantile hemiplegia treated by removing one cerebral hemisphere. J Neurol Neurosurg Psychiatr 1950;13:243. Kubota T, Aso K, Negoro T, et al. Epileptic spasms preceded by partial seizures with a close temporal association. Epilepsia 1999;40:1572. Landau WM, Kleffner FR. Syndrome of acquired aphasia with convulsive disorder in children. Neurology 1957;7:523. Lada C, Skiadas K, Theodorou V, et al. A study of 43 patients with Panayiotopoulos syndrome, a common and benign childhood seizure susceptibility. Epilepsia 2003;44:81. Lerman P. Benign partial epilepsy with centro-temporal spikes. In: Roger J, Dravet C, Bureau M, et al, eds. Epileptic syndromes in infancy, childhood and adolescence. London: John Libbey, 1985. Lerman P. Effects of corticosteroid therapy for Landau-Kleffner syndrome. Develop Med Child Neurol 1991;33:257. Marescaux C, Hirsch E, Finck P, et al. Landau-Kleffner syndrome: A pharmacologic study of five cases. Epilepsia 1990;31:768. Mattson RH, Cramer JA, Collins JF, et al. Comparison of carbamazepine, phenobarbital, phenytoin and primidone in partial and secondary generalized tonic-clonic seizures. N Engl J Med 1985;313:145. Meldrum BS. Metabolic factors during prolonged seizures and their relation to cell death. In: Delgado-Esceuta AV, Wasterlain CJ, Treiman DM, et al., eds. Advances in neurology, vol 34. New York: Raven Press, 1983. Meldrum BS. Physiological changes during prolonged seizures and epileptic brain damage. Neuropaediatrie 1978;9:203. Nordli DR Jr, Bazil CW, Scheuer ML, et al. Recognition and classification of seizures in infants. Epilepsia 1997;38:553. Nordli DR, Kuroda MM, Hirsch LJ. The ontogeny of partial seizures in infants and young children. Epilepsia 2001;42:986.

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Ohtsu M, Oguni H, Hayashi K, et al. EEG in children with early-onset benign occipital seizure susceptibility syndrome: Panayiotopoulos syndrome. Epilepsia 2003;44:435. Ottman R. Progress in the genetics of the partial epilepsies. Epilepsia 2001;42 (Suppl 5):24. Ottman R, Winawer MR, Kalachikov S, et al. LGI1 mutations in autosomal dominant partial epilepsy with auditory features. Neurology 2004;62:1120. Ounsted C, Lindsey J, Norman R. Biological factors in temporal lobe epilepsy. London: William Heinemann Medical Books, 1966. Panayiotopoulos CP. Early-onset benign childhood occipital seizure susceptibility syndrome: A syndrome to recognize. Epilepsia 1999;40:621. Parmeggiani L, Seri S, Bonanni P, et al. Electrophysiological characterization of spontaneous and carbamazepine-induced epileptic negative myoclonus in benign childhood epilepsy with centro-temporal spikes. Clin Neurophysiol 2004;115:50. Phillips HA, Scheffer IE, Berkovic SF, et al. Localization of a gene for autosomal dominant nocturnal frontal lobe epilepsy to chromosome 20q13.2. Nat Genet 1995;10:117. Phillips HA, Scheffer IE, Crossland KM, et al. Autosomal dominant nocturnal frontal-lobe epilepsy: Genetic heterogeneity and evidence for a second locus at 15q24. Am J Human Genet 1998;63:1108. Phillips HA, Favre I, Kirkpatrick M, et al. CHRNB2 is the second acetylcholine receptor subunit associated with autosomal dominant nocturnal frontal lobe epilepsy. Am J Hum Genet 2001;68:225. Rasmussen T, McCann W. Clinical studies of patients with focal epilepsy due to “chronic encephalitis.” Trans Am Neurol Assoc 1968;93:89. Rating D, Wolf C, Bast T. Sulthiame as monotherapy in children with benign childhood epilepsy with centrotemporal spikes: A 6-month randomized, double-blind, placebo-controlled study. Sulthiame Study Group. Epilepsia 2000;41:1284. Sarisjulis N, Gamboni B, Plouin P, et al. Diagnosing idiopathic/cryptogenic epilepsy syndromes in infancy. Arch Dis Child 2000;82:226. Sillanpaa M, Jalava M, Kaleva O, et al. Long-term prognosis of seizures with onset in childhood. N Engl J Med 1998;338:1715. Sillanpaa M, Jalava M, Shinnar S. Epilepsy syndromes in patients with childhood-onset epilepsy Pediatr Neurol 1999;21:533. Stewart LF, Dreifuss FE. “Centrencephalic” seizures in focal hemispheral lesions. Arch Neurol 1967;17:60. Thomas-Sohl KA, Vaslow DF, Maria BL. Sturge-Weber syndrome: A review. Pediatr Neurol 2004;30:303. Tukel K, Jasper H. The electroencephalogram in parasagittal lesions. Electroencephalogr Clin Neurophysiol 1952;4:481. Vining EP, Freeman JM, Pillas DJ, et al. Why would you remove half a brain? The outcome of 58 children after hemispherectomy—the Johns Hopkins experience: 1968 to 1996. Pediatrics 1997;100:163. Watanabe K, Okumura A. Benign partial epilepsies in infancy. Brain Dev 2000;22:296. Wiebe S, Blume WT, Girvin JP, et al. Effectiveness and Efficiency of Surgery for Temporal Lobe Epilepsy Study Group. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med 2001;345:311.

CHAPTER 45

Epileptiform Disorders with Cognitive Symptoms Roberto Tuchman

It is well established that children with epilepsy are at increased risk for cognitive and behavioral problems [Camfield and Camfield, 2002]. A variety of different cognitivebehavioral manifestations have been linked to epilepsy, and some interictal behavioral disturbances may actually reflect unrecognized ictal events [Aldenkamp and Arends, 2004; Besag, 2004]. The determinants of this relation are complex and must take into account numerous factors including etiology, site and degree of brain dysfunction, associated disabilities, seizure type, seizure frequency, seizure duration, age at onset of seizures, psychosocial factors, and medication effects [Aldenkamp et al., 2004; Hermann and Seidenberg, 2002]. Features of the epileptic encephalopathies, such as infantile spasms and Lennox-Gastaut syndrome, include both convulsive seizures and severely abnormal electroencephalogram (EEG) findings, with frequent spikes that can be multifocal and associated with slowing of the background rhythms. In the epileptic encephalopathies, cognitive and behavioral deterioration is thought to be attributable to either the seizures or to the interictal epileptiform activity [Nabbout and Dulac, 2003]. Interictal epileptiform activity is characterized by spikes or sharp waves that appear abruptly from the electrographic background with or without an associated slow wave. These electrographically defined abnormalities are limited in duration and do not evolve in frequency and distribution over time but can at times be responsible for disruption of cognitive function [Fisch, 2003]. It is difficult to know to what extent the neurologic manifestations and deterioration in these epilepsies are secondary to the seizures per se, to the interictal epileptiform activity, or to both the seizures and the interictal epileptiform activity. In contrast with the epileptic encephalopathies, in which seizures usually are severe and frequent, epileptiform disorders in children have been identified in which seizures are infrequent, or are absent entirely, and in which interictal epileptiform activity coexists with language or behavioral dysfunction that may be developmental or acquired. Although no one definition or consensus of what constitutes an epileptiform disorder with cognitive symptoms has been presented, this group of children can be defined as the subgroup of patients in whom interictal epileptiform activity is associated with cognitive, language, social, or behavioral dysfunction. Of importance, in a majority of children with cognitive and behavioral disturbances and interictal epileptiform activity, a causal relation between epileptiform activity on the EEG and the specific cognitive deficit cannot be established. The concept that transitory changes in higher cortical functions can be secondary to EEG discharges not accompanied by seizures was proposed more than 60 years ago [Schwab, 1939]. The term transient cognitive impairment is

used to describe momentary disruption of adaptive cerebral function in association with epileptiform EEG discharges [Aarts et al., 1984; Binnie, 2003]. Several studies have demonstrated that epileptiform discharges on the EEG without clinical seizures can cause behavioral and cognitive impairments [Binnie, 2003]. The spectrum of language and cognitive impairment secondary to an active epileptic focus even in the absence of clinical seizures is wide [Deonna et al., 1997]. Several well-documented case studies have described patients with epilepsy who have fluctuating disturbances such as intermittent drooling, oromotor dyspraxia, dysphagia, and transient isolated deterioration of speech production occurring secondarily to interictal epileptiform activity [Deonna et al., 1993, 2000; Dubois et al., 2003, 2004]. Similar correlations have been made with respect to other clinical syndromes associated with electrical status epilepticus during slow-wave sleep [Roulet Perez et al., 1998; Shafrir and Prensky, 1995]. This evidence supports the concept that in selected patients, interictal epileptiform activity can cause specific cognitive, language, and behavioral impairments. The clinical model that serves as the classic paradigm for this concept is Landau-Kleffner syndrome, an epileptic encephalopathy in which seizures are not present in up to 25% of children, suggesting that the interictal epileptiform activity independent of the seizures may be responsible for the language impairment [Tuchman, 1994]. In this chapter, the association of epileptiform abnormalities with cognitive symptoms is considered within the larger framework of epilepsy and neurodevelopmental disorders.

CLINICAL CHARACTERISTICS AND SUBCLASSIFICATION Language Impairment Verbal auditory agnosia is a severe form of a receptive language impairment [Rapin et al., 1977] and is associated with the highest rate of epilepsy among children with primary language disorders and with autistic spectrum disorders (discussed later) [Klein et al., 2000; Tuchman et al., 1991]. Verbal auditory agnosia is the language disorder most likely to be present in children with Landau-Kleffner syndrome [Aicardi, 1994; Beaumanoir, 1985; Tuchman et al., 1991].

Language Impairment with an Epileptiform Electroencephalogram An increased frequency of seizures and paroxysmal EEG discharges has been reported in children with language

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impairment [Echenne et al., 1992; Robinson, 1991]. In one study, when risk factors for epilepsy were taken into account, 8% of children with language impairment had seizures, and in the group of children without seizures, 20% had abnormal EEG findings, including 9% with epileptiform and 11% with nonepileptiform EEG abnormalities [Tuchman et al., 1991]. Because of the high frequency of epileptiform abnormalities in this group of children with language impairment without seizures, it has been postulated that a subgroup of children, in whom language development was always abnormal, have electrographic abnormalities in the temporal regions, and that it is the abnormal electrographic activity that is responsible for the language impairment [Deonna, 1991]. The supposition is that this subgroup of children have a developmental form of Landau-Kleffner syndrome [Maccario et al., 1982; Sato and Dreifuss, 1973]. A more recent report of a 2-year-old boy with a developmental disorder of language secondary to interference with prelinguistic skills by interictal epileptiform activity suggests that at least in some situations, what appears to be a developmental language disorder may be secondary to epileptic dysfunction [Dubois et al., 2004].

Landau-Kleffner Syndrome: Acquired Epileptiform Aphasia Landau-Kleffner syndrome is defined as an acquired aphasia in association with an abnormal EEG demonstrating spikes, sharp waves, or spike-and-wave discharges that usually are bilateral and occur predominantly over the temporal and parietal regions [Landau and Kleffner, 1998]. Seizures and aphasia are equally likely to be the first presenting complaint in this disorder. Up to 25% of children with Landau-Kleffner syndrome may not have convulsive seizures. Although Landau-Kleffner syndrome serves as the best available clinical model to assess the importance of electrographic abnormalities in language impairment in the absence of convulsive seizures, significant controversy still exists regarding the etiologic relation between the epileptiform activity and the language disorder found in LandauKleffner syndrome [Bourgeois and Landau, 2004; Landau, 1992]. Landau-Kleffner syndrome frequently is associated with behavioral and cognitive dysfunction. Reports in the literature have described associated behavioral problems such as hyperkinesis, rage outbursts, aggressiveness, stereotypies, and poor social communication skills in children with LandauKleffner syndrome [Robinson et al., 2001]. One could argue that the associated behavioral problems that occur in LandauKleffner syndrome are secondary to the language disorder, and that “pure” Landau-Kleffner syndrome is associated with language regression and not with primary behavioral or cognitive regression. In the subclassification of children with epileptiform disorders and cognitive symptoms, a diagnosis of Landau-Kleffner syndrome is best suited for children in whom regression of language is the primary symptom [Rapin, 1995]. This primary regression of language differentiates children with Landau-Kleffner syndrome from other groups of children with acquired epileptiform language disorders in association with equally significant behavioral, social, or cognitive regression.

Autistic Spectrum Disorders The autistic spectrum disorders are behaviorally defined syndromes of varied biologic etiology. They are defined by deficits in verbal and nonverbal communication, impaired social interaction, and restricted and repetitive behaviors [Rapin, 1997]. Although children with autistic spectrum disorder have language impairments, it is the social deficit that differentiates these children from those with primary language disorders.

Autism Spectrum Disorders with an Epileptiform Electroencephalogram Epilepsy develops in approximately one third of the children on the autistic spectrum [Deykin and MacMahon, 1979; Olson et al., 1988; Volkmar and Nelson, 1990]. The major risk factors for seizures in this population are the degree of cognitive impairment and the associated motor deficits. In children with normal or near-normal intelligence, the cumulative probability of developing seizures is 0.02, 0.08, and 0.08 at 1, 5, and 10 years, respectively. This cumulative probability increases to 0.07, 0.16, and 0.27 in children with severe mental retardation but without motor deficits, and in severely retarded autistic children with motor deficit, the cumulative probability is 0.29, 0.35, and 0.67 at ages 1, 5, and 10 years. In children with autistic spectrum disorder and without severe cognitive or motor deficit, the only other risk factor for seizures is the type of language dysfunction, with the highest percentage of seizures occurring in children with verbal auditory agnosia. In children with verbal auditory agnosia with or without autism, the probability of developing seizures is greater than 40% [Tuchman et al., 1991]. In children with autistic spectrum disorder without seizures 8% have an epileptiform EEG, and 10% of children have a nonepileptiform but abnormal EEG pattern [Tuchman and Rapin, 1997; Tuchman et al., 1991]. Approximately 50% of the epileptiform discharges found in children with autistic spectrum disorder and no seizures occur over the perisylvian region [Tuchman and Rapin, 1997].

Autistic Regression with an Epileptiform Electroencephalogram Approximately 30% of children with autistic spectrum disorder demonstrate language regression [Burack and Volkmar, 1992; Kurita, 1985]. In comparison with Landau-Kleffner syndrome children, autistic regression is associated with regression of both language and behavior in association with significant social deficits. The regression in autistic spectrum disorder usually is associated with the loss of only a few words and with the additional loss of nonverbal communication skills [Goldberg et al., 2003; Lord et al., 2004]. Regression in autistic spectrum disorder usually occurs at an early age, so it is difficult to determine if development was completely normal before the regression [Shinnar et al., 2001]. Some evidence suggests that in a subgroup of children with autistic spectrum disorder and without convulsive seizures, an epileptiform EEG is significantly more likely to be associated with a history of regression in language [Tuchman and Rapin, 1997]. The entity autistic regression with an epileptiform EEG includes children with

Tuchman / Epileptiform Disorders with Cognitive Symptoms

regression in language, plus regression in sociability and nonverbal communication skills, in association with an epileptiform EEG. Children with autistic regression and an epileptiform EEG are differentiated from those with LandauKleffner syndrome by their deficits in social interaction and nonverbal communication skills, as well as by the earlier age at regression.

Syndromes with Specific or Global Cognitive Impairment Specific Cognitive Impairment Associated with an Epileptiform Electroencephalogram The available evidence suggests that learning disabilities are more prevalent in children with epilepsy, with specific deficits in reading, spelling, and mathematical skills reported in this group of children [Klein, 1991]. Furthermore, learning difficulties and specific abnormal patterns of cognitive functioning are more likely in children with epilepsy with frequent interictal epileptiform activity, and these interictal discharges themselves contribute significantly to specific cognitive dysfunction [Binnie, 2003]. A majority of children with learning disabilities without epilepsy do not demonstrate epileptiform activity on the EEG. Increasing evidence, however, indicates that in children with epilepsy, subclinical epileptiform discharges can cause transient cognitive impairment [Aldenkamp and Arends, 2004]. Transient cognitive impairment may not be clinically evident but can be documented when specific neuropsychologic testing is done simultaneously with ongoing EEG monitoring. Studies by numerous investigators suggest that transient cognitive impairment is not a consequence of general impairment of attention but that it reflects disruption of specific functions located in the region or regions of the brain where the epileptiform discharges arise [Aldenkamp and Arends, 2004; Kasteleijn-Nolst Trenite, 1995]. Specific functions such as perception, reaction time, and scholastic performance have been disrupted by brief epileptiform discharges in the absence of convulsive seizures [KasteleijnNolst Trenite, 1995; Sengoku et al., 1990; Shewmon and Erwin, 1988, 1988].

Global Cognitive Dysfunction in Association with an Epileptiform Electroencephalogram In children, frequent epileptiform activity can in rare circumstances be associated with cognitive dysfunction. This usually is associated with a distinctive EEG pattern termed electrical status epilepticus during slow wave sleep [Tassinari et al., 1995]. This EEG-defined syndrome is characterized by nearly continuous (greater than 85% of the time) spike-and-slowwave complexes during non–rapid eye movement sleep, but not during rapid eye movement sleep or the awake state [Jayakar and Seshia, 1991]. Electrical status epilepticus during slow wave sleep is the EEG pattern present in a number of childhood syndromes associated with sleep-related epileptic encephalopathies with cognitive and language dysfunction including “continuous spikes and waves during slow-wave sleep” syndrome, in some children with Landau-

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Kleffner syndrome, and rarely as an atypical evolution in children first manifesting as benign childhood epilepsy with centrotemporal spikes [Galanopoulou et al., 2000]. A majority of children with electrical status epilepticus during slowwave sleep have normal development before the onset of electrical status epilepticus during slow-wave sleep, but almost all deteriorate cognitively and behaviorally (with increased aggressiveness, poor social contact, decreased attention span, and hyperactivity) during electrical status epilepticus during slow wave sleep [Beaumanoir et al., 1995].

Disintegrative Epileptiform Disorder Disintegrative disorder is a recent term used to describe a regression in language, behavior, and cognition occurring after the age of 2 years in children with previously normal development [Volkmar and Rutter, 1995]. Disintegrative disorder is based on the description early in the 1900s of children with normal development until age 3 or 4 who regressed in multiple developmental areas. This entity was first described by Heller in 1908 [Mouridsen, 2003], and differentiation from autism, especially from autistic regression, is still in progress [Kurita et al., 2004]. In addition, our understanding of the epidemiology of this disorder is limited [Fombone, 2002]. A significant number of children with disintegrative disorder have an epileptiform EEG, and seizures will develop in greater than 70% of children with disintegrative disorder [Mouridsen et al., 1999].

Age at Onset of First Symptoms and Natural History An important consideration in the evaluation of children with epileptiform disorder with cognitive symptoms is to differentiate cases that are developmental from those that are acquired. The mean age at first symptoms in the acquired forms varies and may be helpful in classifying these disorders and in predicting prognosis. The mean age at onset of the language regression in autistic spectrum disorders is 21 months, and greater than 90% of children with autism who undergo a regression do so before age 3 years [Tuchman and Rapin, 1997]. By contrast, in Landau-Kleffner syndrome, only 12% to 14% of children experience regression before age 3 years [Bishop, 1985]. The peak age at onset of symptoms in Landau-Kleffner syndrome is between 5 and 7 years [Bureau, 1995]. In only 5% of cases does Landau-Kleffner syndrome begin after age 9 years, and it appears to rarely if ever occur after age 12 years [Bureau, 1995]. In children with the EEG-defined disorder of electrical status epilepticus during slow wave sleep, the first symptoms occur in up to 20% of those between 9 and 12 years of age [Bureau, 1995]. It will be of interest to determine if the mean age at presentation in children with LandauKleffner syndrome is the same as or older than in children with disintegrative epileptiform disorder, which by definition manifests after age 2 years, and whether disintegrative disorder is a distinct entity separate from autistic regression [Rapin, 1995]. The age at symptom onset seems to be an important indicator of outcome at least in Landau-Kleffner syndrome. Bishop found that prognosis for recovery is worse in children with Landau-Kleffner syndrome who lose their language at an early age [Bishop, 1985]. In a series of studies, age at

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language regression differentiates autistic regression from Landau-Kleffner syndrome. Children with autism are more likely to regress earlier, usually before age 2, in contrast with those with Landau-Kleffner syndrome, who experience language regression usually after age 3 years. In addition, seizures are more likely to occur in children in whom language regresses after age 3 years [Klein et al., 2000; Shinnar et al., 2001; Wilson et al., 2003]. In Landau-Kleffner syndrome, improvement occurs usually toward late childhood or early adolescence. Approximately one third of affected children make a good recovery [Mantovani and Landau, 1980]. The prognosis for seizure control and normalization of the EEG is excellent, but prognosis for recovery of language and cognitive function is variable and in general not as good as it is for the seizures [Smith and Hoeppner, 2003]. In the group of children with regression and global cognitive deficits in the context of electrical status epilepticus during slow-wave sleep, a significant majority are left with some degree of neurologic impairment [Robinson et al., 2001; Rossi et al., 1999]. In disintegrative disorder, prognosis generally is poor [Gillberg, 1991]. In general, children with autistic regression have significant long-term morbidity [Wilson et al., 2003]. What is still not known is whether the prognosis in children with autistic epileptiform regression is less favorable than in children with regression without an epileptiform EEG.

ETIOLOGY AND PATHOPHYSIOLOGY The defining feature of the epileptiform disorder with cognitive symptoms is an epileptiform EEG in the context of specific or global cognitive impairment. The conclusion that the epileptiform EEG has a direct causal relationship to the cognitive impairment is still controversial. Studies of transitory cognitive impairment, as discussed erlier, have provided evidence to suggest a causal link between epileptiform activity and cognitive impairment. These studies suggest that with appropriate testing, even brief epileptiform discharges can in certain instances be related to specific cognitive dysfunction. It also has been suggested that interictal discharges are likely to interfere with the consolidation of new information even beyond the initial processing leading to cognitive impairment [Binnie, 2003]. Landau-Kleffner syndrome is considered the “model” implicating electrographic discharges in a specific aspect of cognitive function—namely, language impairment. In addition, in epilepsies such as the benign focal epilepsies of childhood, it is frequently recognized that the spikes in a significant minority of this group of patients can evolve into a pattern similar to that in Landau-Kleffner syndrome [Fejerman et al., 2000]. It has been suggested that the difference between Landau-Kleffner syndrome and other conditions associated with acquired aphasia or electrical status epilepticus during slow-wave sleep is that in LandauKleffner syndrome, the spike focus has a dipolar distribution across the sylvian fissure, with negativity above the fissure and positivity at the temporal site [Gregory and Wong, 1992; Morrell et al., 1995]. The mechanism of developmental or acquired epileptiform aphasia is not understood, and both structural and functional abnormalities have been implicated in at least some

cases of acquired epileptiform aphasia. Landau-Kleffner syndrome has been associated with neurocysticercosis [Otero et al., 1989], sylvian arachnoid cyst [De Volder et al., 1994], and left temporal astrocytoma [Nass et al., 1993; Solomon et al., 1993], suggesting that this syndrome may result from unilateral brain lesions present at a critical age of development and affecting areas essential for language development. In addition, an association between congenital hydrocephalus and continuous spikes and waves during slowwave sleep syndrome and Landau-Kleffner syndrome has recently been reported [Ben-Zeev et al., 2004]. On the other hand, a reported case of Landau-Kleffner syndrome secondary to inflammatory demyelinating disease suggests that multiple and diffuse lesions are needed to cause the syndrome [Perniola et al., 1993]. Reports of Landau-Kleffner syndrome in siblings [Nakano et al., 1989] have raised the possibility of a familial basis for this disorder, but other reports of Landau-Kleffner syndrome occurring discordantly in monozygotic twins suggest an “environmental trigger” [Feekery et al., 1993]. A variety of different triggers, including an autoimmune process [Nevsimalova et al., 1992], an infectious or inflammatory process [Connolly et al., 1999], and possibly an arteritis [Pascual-Castroviejo et al., 1992], have been proposed as potential causes for Landau-Kleffner syndrome. No evidence of encephalitis was found in two patients with Landau-Kleffner syndrome who underwent temporal lobectomy [Cole et al., 1988]. It is likely that this syndrome has more than one possible cause, and that what may be important in determining the degree of epileptiform dysfunction is the timing of the insult and the region of the brain affected. Findings on functional neuroimaging studies in LandauKleffner syndrome have been consistent with abnormalities in the temporal lobes. A study using fluorodeoxyglucose positron emission tomography (PET) during sleep in three males with Landau-Kleffner syndrome demonstrated metabolic disturbances that varied among the children but predominated in the temporal lobes [Maquet et al., 1990]. Studies using single-photon emission computed tomography imaging (SPECT) have found abnormal perfusion in the left temporal lobe only in Landau-Kleffner syndrome [Guerreiro et al., 1996; O’Tuama et al., 1992]. Abnormalities using PET scanning in the temporal lobes in children with LandauKleffner syndrome also have been found in association with electrical status epilepticus during slow wave sleep [Rintahaka et al., 1995]. The functional neuroimaging studies suggest that functional disruption secondary to epileptiform discharges in the areas concerned with linguistic function is responsible for the language dysfunction in Landau-Kleffner syndrome. This suggestion is supported by a study of four children with Landau-Kleffner syndrome in whom a significant reduction in the cortical volume of the superior temporal areas, corresponding to the auditory association cortex, was documented using magnetic resonance imaging (MRI) volumetric analysis. This difference was significant in comparison with findings in controls, and the volume reduction was greatest in the two children who had the most frequent epileptiform activity in the temporal lobes [Takeoka et al., 2004]. Although these results do not allow determination of whether the atrophy is the cause of the Landau-Kleffner syndrome or the consequence of the excitoxicity from the epileptiform discharges, they do add

Tuchman / Epileptiform Disorders with Cognitive Symptoms

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TABLE 45-1 Classification of Epileptiform Disorders with Language Impairment CLINICAL SYNDROME

CLINICAL IMPLICATIONS

TREATMENT IMPLICATIONS

Language impairment with epileptiform EEG

In children with loss or plateau of language skills, an EEG with sleep should be considered.

Landau-Kleffner syndrome

The classic paradigm, in which the epileptiform activity on the EEG is is presumed to be responsible for the language loss.

If the EEG findings can be related causally to the language impairment, the use of AEDs should be considered. Treatment with AEDs, steroids, and surgery has met with limited success and rarely has resulted in dramatic improvement and recovery of language function.

AEDs, antiepileptic drugs; EEG, electroencephalogram.

support to the concept that epileptiform activity may account for language regression in Landau-Kleffner syndrome [Bourgeois and Landau, 2004]. The controversy that still exists is over whether the frequency of the epileptiform discharges as linked to appearance or disappearance of electrical status epilepticus during slow-wave sleep is responsible for the course of language deterioration [Tassinari et al., 2000], or whether the large phenotypic variability reflects differences in location, with the EEG providing only limited insight that reflects a focal hyperexcitability that varies with maturational state and genetic and environmental influences [Doose et al., 1996].

TREATMENT No controlled clinical trials have focused on treatment for children with epileptiform disorder with cognitive symptoms, and recommendations for treatment are based on studies with small groups of children and on clinical experience. The largest clinical experience is in the acquired disorders, and the few studies done have focused specifically on treatment to reverse language loss in Landau-Kleffner syndrome (Table 45-1). In general, traditional antiepileptic drugs such as phenobarbital, carbamazepine, and phenytoin are not efficacious, whereas valproic acid, ethosuximide, and benzodiazepines are in some cases somewhat effective [Marescaux et al., 1990]. These latter antiepileptic agents usually are effective in stopping the seizures, but language improvement that can be directly attributed to the antiepileptic drugs used is more difficult to determine [Prasad et al., 1996]. A recent study using levetiracetam in a child with Landau-Kleffner syndrome resulted in improvement in language [Kossoff et al., 2003]. One study reported that calcium channel agents are effective in the treatment of Landau-Kleffner syndrome, but this has not been replicated [Pascual-Castroviejo et al., 1992]. The clinical experience with antiepileptic drugs in Landau-Kleffner syndrome has been that they are successful at treating the seizures but dramatically less impressive with regard to their effect on improvement in language function. The greatest success in the treatment of Landau-Kleffner syndrome has not been with the traditional antiepileptic drugs but instead with the use of steroids and intravenous gamma globulin. This finding is not different from the experience that clinicians have in treating all epileptic encephalopathies [Cavazzuti, 2003; Dulac, 2001; Prasad et al., 1996]. Two frequently cited studies demonstrated that

steroid therapy in Landau-Kleffner syndrome may provide dramatic improvement in language function, especially if used during the acute phase of the regression of language [Lerman et al., 1991; Marescaux et al., 1990]. The combined number of children in these two studies was nine, of which seven demonstrated a positive response to steroid treatment, with documented sustained improvement in language function. Other anecdotal reports have described success with the use of corticosteroids, especially at high doses and given early in the clinical course, but all of these reports have in common a lack of uniformity in diagnostic categorization and in outcome measures. Successful treatment with intravenous gamma globulin infusion in Landau-Kleffner syndrome also has been reported [Mikati and Saab, 2000; Mikati et al., 2002; Villani and Avanzini, 2002]. The studies that have suggested a beneficial response to intravenous immunoglobulin in Landau-Kleffner syndrome, like those that used steroids, consist of clinical case reports using variable assessment measures of language, behavioral, and cognitive outcome. With no controlled clinical trials on the use of steroids or intravenous immunoglobulin in Landau-Kleffner syndrome, one needs to be cautious and use sound clinical judgment in determining which child may benefit from treatment with corticosteroids or intravenous immunoglubulin. More controversial are several studies suggesting a role for surgery in Landau-Kleffner syndrome, particularly subpial cortical transactions, which have been associated with dramatic improvements in language recovery [Irwin et al., 2001; Morrell et al., 1995; Rintahaka et al., 1995; Robinson et al., 2001; Sawhney et al., 1995]. In addition, in one openended study that included 6 children with Landau-Kleffner syndrome and 59 children with autism and intractable epilepsy, vagus nerve stimulation therapy resulted in a 50% reduction in seizure frequency and improvement in quality of life [Park, 2003]. As stated by the study investigators, prospective studies with appropriate outcome measures are needed before definite conclusions regarding the use of vagus nerve stimulation can be drawn or before it can be recommended for management of patients with Landau-Kleffner syndrome or autistic regression with an epileptiform EEG. Clinical improvement in children with autism and epileptiform discharges on EEG without clinical seizures treated with valproic acid has been reported, but no controlled clinical trials are available to support this observation [Nass and Petrucha, 1990; Plioplys, 1994]. Of note, in children with autistic spectrum disorders, antiepileptic drugs can have positive effects on mood but, in specific situations,

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TABLE 45-2 Classification of Epileptiform Disorders with Autism CLINICAL SYNDROME

CLINICAL IMPLICATIONS

TREATMENT IMPLICATIONS

Autistic spectrum disorder with epileptiform EEG

Significance of EEG findings in this group of children remains unknown. The EEG could be a biologic marker predictive of a specific outcome, but this is presently not known. These children demonstrate both language regression and social regression. It is not known whether the prognosis in children with AREE is worse than in children with autism without regression. In children who are receiving educational remediation without good progress, pharmacologic treatment should be considered.

No specific recommendations can be made; in general, the use of AEDs in this group of children is limited.

Autistic regression with epileptiform EEG (AREE)

The treatment model that has been used for this group is that for LKS. No formal treatment studies have been conducted, and anecdotal reports on use of AEDs in this group of children are mixed. Subpial transection, which has met with limited success in LKS, has no role in this group of children.

AEDs, antiepileptic drugs; EEG, electroencephalogram; LKS, Landau-Kleffner syndrome.

also can account for worsening of behavior and learning ability [Di Martino and Tuchman, 2001; Loring and Meador, 2004; Reijs et al., 2004] (Table 45-2). The treatment for epileptiform discharges in the absence of clinical seizures remains controversial. The classic teaching is not to treat the EEG but to treat the patient. A degree of skepticism is appropriate in attempts to correlate an epileptiform EEG with specific cognitive, language, or behavioral dysfunction. Evidence from clinical case studies and the occurrence of transient cognitive impairment in some patients suggest that if appropriate testing is done with concurrent EEG monitoring, a reliable correlation can be made between epileptiform discharges and performance on numerous tasks. Some studies have used valproic acid for treatment in children with learning disabilities and severely epileptiform EEG but without clinical seizures; both positive and negative results in terms of improvement in cognitive performance have been reported [Gordon et al., 1996; Ronen et al., 2000]. In children with more global cognitive impairment and an epileptiform EEG, it is extremely difficult to correlate the EEG findings with cognitive and behavioral dys-

function; accordingly, treatment recommendations are controversial at best (Table 45-3). In those children with acquired global impairment in association with electrical status epilepticus during slow-wave sleep, however, the treatment recommendations for Landau-Kleffner syndrome may be applicable.

CONCLUSION There are no definite answers in regard to either the extent of the cognitive problems that can be attributed to epileptiform abnormalities or the mechanisms for cognitive impairment in the context of an epileptiform EEG. The available evidence suggests that in some children with an acquired language disorder, epileptiform abnormalities may be responsible for the loss of language, but identifying these children remains a difficult task. At present, no definite recommendations can be made in regard to specific interventions for the child who presents with cognitive dysfunction and is found to have an epileptiform EEG. Comprehensive assessment and treatment of the

TABLE 45-3 Classification of Epileptiform Disorders with Global Cognitive Impairment CLINICAL SYNDROME

CLINICAL IMPLICATIONS

TREATMENT IMPLICATIONS

Learning disabilities with transient cognitive impairment

The relationship of the epileptiform activity to the specific impairments in this group of children is difficult to measure. Nevertheless, there are clear examples of children in which the abnormal electrical activity can be correlated casually to specific learning impairments. These children manifest mental retardation that was not acquired. Relationship of EEG abnormalities to severity of cognitive dysfunction is assumed to be secondary to common mechanisms for both.

Treatment with AEDs in this group of children is complicated by the potentially negative effects of these medications on learning. At present, treatment remains controversial, and no specific recommendations can be made.

Global cognitive impairment with epileptiform EEG

Disintegrative epileptiform disorder

This is an acquired disorder associated with mental retardation and autism. Outcome usually is very poor.

Treatment studies have not been conducted using AEDs. The role of AEDs here likely is very limited and if effective may be related to secondary effects of the AEDs and not to primary treatment of the EEG discharges. No treatment studies have been formally conducted. When associated with ESES or with very frequent epileptiform EEG discharges, treatment with AEDs has been attempted, but the results usually are not impressive, and current knowledge is based on anecdotal reports.

AEDs, antiepileptic drugs; EEG, electroencephalogram; ESES, electrical status epilepticus during slow-wave sleep.

Tuchman / Epileptiform Disorders with Cognitive Symptoms

language, behavioral, and cognitive symptoms of each child with epileptiform disorder with cognitive symptoms is essential. Until further studies are done, treatment of the child with epileptiform disorder with cognitive symptoms remains an individualized decision based on the severity of clinical symptoms, the degree of correlation between the epileptiform discharges and the cognitive symptoms, and the potential side effects of the intervention. REFERENCES Aarts J, Binnie C, Smith A, et al. Selective cognitive impairment during focal and generalized epileptiform EEG activity. Brain 1984;107:293. Aicardi J. Syndrome of acquired aphasia with seizure disorder: Epileptic aphasia, Landau-Kleffner syndrome, verbal auditory agnosia with convulsive disorder. In: Procopis P, Rapin, I, eds. Epilepsy in children, 2nd ed. New York: Raven Press, 1994. Aldenkamp A, Arends J. The relative influence of epileptic EEG discharges, short nonconvulsive seizures, and type of epilepsy on cognitive function. Epilepsia 2004;45:54. Aldenkamp AP, Arends J. Effects of epileptiform EEG discharges on cognitive function: is the concept of “transient cognitive impairment” still valid? Epilepsy Behav 2004;5 (Suppl 1):S25. Aldenkamp AP, Baker GA, Meador KJ. The neuropsychology of epilepsy: What are the factors involved? Epilepsy Behav 2004;5 (Suppl 1):S1. Beaumanoir A. The Landau-Kleffner syndrome. In: Roger J, Dravet C, Bureau M, et al, eds. Epileptic syndromes in infancy, childhood and adolescence. London: John Libbey, 1985. Beaumanoir A, Bureau M, Deonna T, et al, eds. Continuous spikes and waves during slow sleep, electrical status epilepticus during slow sleep, acquired epileptic aphasia and related conditions. London: John Libbey, 1995. Ben-Zeev B, Kivity S, Pshitizki Y, et al. Congenital hydrocephalus and continuous spike wave in slow-wave sleep—a common association? J Child Neurol 2004;19:129. Besag FM. Behavioral aspects of pediatric epilepsy syndromes. Epilepsy Behav 2004;5 (Suppl 1):3. Binnie CD. Cognitive impairment during epileptiform discharges: Is it ever justifiable to treat the EEG? Lancet Neurol 2003;2:725. Bishop DV. Age of onset and outcome in ‘acquired aphasia with convulsive disorder’ (Landau-Kleffner syndrome). Dev Med Child Neurol 1985;27:705. Bourgeois BF, Landau WM. Landau-Kleffner syndrome and temporal cortical volume reduction: Cause or effect? Neurology 2004;63:1152. Burack JA, Volkmar FR. Development of low- and high-functioning autistic children. J Child Psychol Psychiatry 1992;33:607. Bureau M. Outstanding cases of CSWS and LKS: Analysis of data sheets provided by the participants. In: Beaumanoir A, Bureau, M, Deonna T, et al, eds. Continuous spikes and waves during slow sleep, electrical status epilepticus during slow sleep, acquired epileptic aphasia and related conditions. London: John Libbey, 1995. Camfield P, Camfield C. Epileptic syndromes in childhood: Clinical features, outcomes, and treatment. Epilepsia 2002;43 (Suppl 3):27. Cavazzuti GB. Infantile encephalopathies. Neurol Sci 2003;24 (Suppl 4):S244. Cole AJ, Andermann F, Taylor L, et al. The Landau-Kleffner syndrome of acquired epileptic aphasia: Unusual clinical outcome, surgical experience, and absence of encephalitis. Neurology 1988;38:31. De Negri M. Electrical status epilepticus during sleep (ESES). Different clinical syndromes: Towards a unifying view? Brain Dev 1997;19:447. Connolly AM, Chez MG, Pestronk A, et al. Serum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders. J Pediatr 1999;134:607. De Volder AG, Michel C, Thauvoy C, et al. Brain glucose utilization in acquired childhood aphasia associated with a sylvian arachnoid cyst: Recovery after shunting as demonstrated by PET. J Neurol Neurosurg Psychiatry 1994;57:296. Deonna T, Davidoff V, Maeder-Ingvar M, et al. The spectrum of acquired cognitive disturbances in children with partial epilepsy and continuous spike-waves during sleep. A 4-year follow-up case study with prolonged reversible learning arrest and dysfluency. Eur J Paediatr Neurol 1997;1:19.

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CHAPTER 46

Myoclonus, Myoclonic Seizures, and Infantile Spasms Tallie Z. Baram

DEFINITIONS AND DIAGNOSIS OF MYOCLONUS Myoclonus (from the Greek myo, “muscle,” and klonus, “agitation/violent contraction”) has been defined as a “sudden, involuntary, brief, shock-like muscle contraction arising from the central nervous system” (CNS) [Fahn et al., 1986]. Myoclonus may be focal or generalized, single or repetitive, rhythmic or irregular. The origin of myoclonus may involve the spinal cord, cortex, brainstem, and cerebellum and provides the basis for several of the many classifications of myoclonic movements [Serratosa and DelgadoEscueta, 1993]. The range of myoclonic phenomena includes nonepileptic events such as sleep myoclonus, opsoclonusmyoclonus, and narcotic-induced myoclonus (Fig. 46-1). Epileptic myoclonus types include progressive disorders and nonprogressive syndromes such as juvenile myoclonic epilepsy. This chapter presents the spectrum of myoclonic events observed in the neonate, infant, and child, to distinguish myoclonic seizure syndromes from other entities, and provides current information on and practical guidelines for the diagnosis and management of discrete types of myoclonic seizures. In addition, the diagnosis and management of infantile spasms, traditionally grouped with the myoclonic epilepsies, are discussed. The electrophysiologic [Hallet, 1985] and locationrelated [Fahn et al., 1986; Halliday, 1967] classifications of myoclonus are complex and fall outside the scope of this chapter. In general, nonepileptic myoclonus is not associated with electroencephalographic correlates, whereas epileptic myoclonus is defined electrophysiologically as muscle jerks related temporally to an discharge on the electroencephalogram (EEG) recording and accompanied by a short-duration burst (50 to 100 milliseconds) on the electromyogram (EMG) recording [Hallet, 1985]. Epileptic myoclonus may be the major manifestation of an EEG-defined seizure or a minor component of other seizures such as classic absence. In a majority of circumstances, the distinction between nonepileptic and epileptic myoclonus in neonates, infants, and children can be based on the history and on observation. In this regard, the value of videotapes provided by the parents, permitting the clinician to evaluate infrequently occurring or nocturnal myoclonus, cannot be overemphasized. Box 46-1 presents the major categories of nonepileptic myoclonus, based on age at presentation. Additionally, myoclonus should be distinguished from similar movement disorders, particularly tics. Table 46-1 enumerates features that discriminate between these two clinically similar entities.

CLASSIFICATION OF MYOCLONIC SEIZURES AND SYNDROMES Myoclonic seizures are defined as events of CNS origin, consisting of rapid muscle movements that are caused by paroxysmal depolarization shift [Hallet, 1985]. As a group, the myoclonic seizures constitute one of the most prevalent and challenging seizure categories and can manifest in infancy, childhood, or adolescence (Table 46-2). They range from self-limiting “benign” disorders, through nonprogressive yet life-long entities (e.g., juvenile myoclonic epilepsy), to progressive myoclonic epilepsies associated with cognitive decline and death. The diagnosis, classification, and management of myoclonic seizures have been evolving. The current International League Against Epilepsy classification of pediatric myoclonic seizures in the context of other epilepsy syndromes can be found in Chapter 40. A practical classification of myoclonic seizures is presented in Table 46-2, and of epilepsy syndromes, in Table 46-3, based on age at presentation. A useful distinction can be made between myoclonic seizures, a descriptive term based on the phenomenology of the seizure as confirmed by EEG, and myoclonic epilepsy syndromes. In addition to its associated seizure characteristics and EEG findings, a syndrome is characterized by distinct age at occurrence, natural evolution, associated features, and response to specific medications [Dreifuss, 1989]. A defined syndrome often is a homogeneous entity, with common etiology, genetic predisposition, or pathophysiology. Therefore, recognizing a seizure as belonging to a specific syndrome provides valuable information regarding its treatment and prognosis [Delgado-Escueta et al., 2003] (see Table 46-3).

MYOCLONIC SEIZURES OF THE NEONATAL PERIOD Myoclonic seizures are a frequent type of neonatal seizures [Mizrahi and Kellaway, 1987; Tharp, 2002]. A majority of these seizures are symptomatic—that is, they occur in response to a wide variety of insults inflicted on the developing CNS either before or at the time of birth [Miller et al., 2002; Mizrahi and Clancy, 2000; Scher, 2002]. Thus, myoclonic seizures in the neonate merit the same evaluation process triggered by other neonatal seizures. Infection (congenital, prenatal, or perinatal), stroke and hemorrhage, hypoxia, and metabolic derangement all can be causative (see Table 46-2). A particularly malignant form of neonatal myoclonic seizures has been described in association with nonketotic hyperglycinemia in otherwise healthy newborns.

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Epilepsy / 46 FIGURE 46-1. Overview of myoclonus categories. CNS, central nervous system; JME, juvenile myoclonic epilepsy. (From Leppik IE: Classification of the myoclonic epilepsies. Epilepsia 2003;44 [Suppl 11]:2-6. Reprinted with permission of Blackwell Publishing Ltd.)

Myoclonus

Epileptic

Nonepileptic

Inherited

Benign primary epilepsy syndromes (e.g., JME) Severe myoclonic epilepsy syndromes Progressive myoclonic epilepsies

Acquired

Anoxia Head trauma Tumors Uremia and other metabolic encephalopathies Degenerative CNS disease Stroke Viral infections

BOX 46-1 DIFFERENTIAL DIAGNOSIS OF NONEPILEPTIC MYOCLONUS BY AGE AT PRESENTATION Neonates Common • Sleep myoclonus of preterm infant • Sleep myoclonus of full-term infant • Narcotic-induced myoclonus • Drug withdrawal myoclonus • Perinatal asphyxia • Congenital infection, including AIDS • Nonspecific, induced (startle) myoclonus Rare • Hyperekplexia (stiff baby syndrome) [Ryan et al., 1992] • Metabolic myoclonus (e.g., uremia) • Polyunsaturated fatty acid disease Infants • Sleep myoclonus • Opsoclonus-myoclonus with or without neoplasm [Mitchell et al., 2002] • CNS infections (e.g., coxackievirus infection) • Concomitant genetic syndrome (e.g., startle myoclonus in Tay-Sachs) • Benign familial (autosomal-dominant) myoclonus Children • Tics or chorea mimicking myoclonus • CNS infections, opsoclonus-myoclonus, other entities listed for infants • Drug-induced: penicillins, narcotics, some antihistamines, valproate, carbamazepine, phenytoin toxicity • L-Dopa, chlorambucil, benzodiazepine withdrawal AIDS, acquired immunodeficiency syndrome; CNS, central nervous system.

TABLE 46-1 Distinguishing Features of Tic and Myoclonus TIC

MYOCLONUS

Complex or simple motion Often variable location

Simple motion Stereotypic: involving the same muscle group Typically in extremities, often bilateral Vocalization absent No perceived urge Nonsuppressible

Bilateral extremities rare; midline or lateralized Vocalization frequent Desire to move Can be transiently suppressed Incorporated in purposeful motion

Nonpurposeful

Determination of serum and cerebrospinal fluid glycine levels is therefore required [Chien et al., 2004]. Specific clinical syndromes of neonatal or early infantile myoclonic epilepsy with distinctive features that permit prognostication have been defined. Ohtahara, working alone [1976] and with Yamatogi [2003], and Aicardi [1978] described a severe form of myoclonic seizures with a burstsuppression EEG pattern. Clinically, massive axial bilateral myoclonia is seen in this early myoclonic encephalopathy syndrome, which typically commences during the first postnatal month. Although the etiology of this syndrome may be heterogeneous, the outcome for affected children is uniformly poor, including a high mortality rate (up to 60%) during the first year of life. In many cases, the seizures evolve to classic infantile spasms, and the EEG develops a hypsarrhythmic pattern.

Evaluation and Treatment Because a majority of myoclonic seizures in the neonate are symptomatic, a search for a treatable cause is warranted. If levels of electrolytes, glucose, calcium, and magnesium are not revealing, evaluation should be directed by findings on

Baram / Myoclonus, Myoclonic Seizures, and Infantile Spasms

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TABLE 46–2 Myoclonic Seizures of Neonates, Infants, Children, and Adolescence Seizure or Syndrome

Additional Information [References]

Neonates Symptomatic myoclonic seizures Metabolic disorders with myoclonic seizures Early myoclonic encephalopathy Myoclonic epilepsy with CNS malformation

CNS insult: infection, hypoxia, stroke, drugs Nonketotic hyperglycinemia [Dalla Bernardina and Dulac, 1994] Burst-suppression EEG, poor prognosis [Aicardi and Goutieres, 1978] Aicardi’s syndrome; lissencephaly; agyria-pachygyria; other migration disorders [Dalla Bernardina and Dulac, 1994]

Infants Early infantile epileptic encephalopathy Benign myoclonic epilepsy of infancy Severe myoclonic epilepsy of infancy

Burst-suppression; may overlap neonatal syndrome [Ohtahara and Yamatogi, 2003] Rare; brief seizures, normal EEG background [Dravet et al., 1985a] Rare; start as seizures with fever; positive family history [Dravet et al., 1985b]; sodium channelopathy [Claes et al., 2001] Clusters of myoclonic jerks [Baram, 1993; Dulac and Plouin, 1994] GM1, GM2 gangliosidoses (Tay-Sachs disease, Sandhoff’s disease); Niemann-Pick disease; Krabbe’s disease; metachromatic leukodystrophy; neuronal ceroid lipofuscinosis (early and late infantile) MELAS; early Leigh’s disease; other mitochondrial MERRF variants Phenylketonuria and variants; Menkes’s disease; others Infantile Huntington’s disease

Infantile spasms Storage disorders Mitochondrial disorders Other metabolic disorders Other progressive entities Children and Adolescents Familial myoclonic epilepsy Myoclonic seizures in Lennox-Gastaut syndrome Absence with myoclonic features Juvenile myoclonic epilepsy Mitochondrial disorders Progressive myoclonic epilepsies Degenerative/storage disorders

Typically a minor component of the syndrome [Gastaut, 1985] EEG 3-sec spike-wave; prognosis guarded [Tassinari and Bureau, 1985] Generalized seizures may precede myoclonus MERRF; myoclonus with MELAS, others [DiMauro and Moraes, 1993] Lafora body disease [Genton and Roger, 1993]; Baltic and Mediterranean types (Unverricht-Lundborg) [Delgado-Escueta et al., 2003] Juvenile neuronal ceroid lipofuscinosis; Gaucher disease type 3 (juvenile neuropathic) [Nishimura et al., 1980]; sialidosis type I (cherry-red spot myoclonus) [Delgado-Escueta, 2003]

TABLE 46–3 Myoclonic Epilepsies in Infancy and Early Childhood DISORDER

Feature Age at onset Gender predominance Psychomotor development Family history; genetics

Early Myoclonic Severe Myoclonic Epilepsy Encephalopathy (Ohtahara’s, of Infancy (SMEI) Aicardi’s Syndromes) (Dravet’s Syndrome)

Benign Myoclonic Epilepsy of Infancy [Dravet et al., 1985a]

Early Childhood Myoclonic-Astatic Epilepsy (MAE)

Myoclonic-Astatic Epilepsy (MAE) of Early Childhood (Doose’s Syndrome)

~1 mo M:F

~6 mo to 1 yr M:F

4 mo to 3 yr M:F

1 to 4 yr M:F

Peaks at 4 yr M:F

Variable

Slow

Normal

Normal

Variable

Positive in 50-60% of cases

Positive in 30% of cases Myoclonic; in adolescence, also tonic-clonic

Positive in 60% of cases; maternal transmission? Myoclonic, astatic (drop attacks), absence, rare tonic-clonic No tonic seizures

Positive in 32% of cases, if EEG included Onset: tonic-clonic (60%); astatic, myoclonic-astatic, or myoclonic/absence, SE common Nocturnal tonic seizures Irregular general spike/polyspike waves; multifocal spikes; slow background common

Seizure types

Massive axial bilateral myoclonia

Febrile and tonic-clonic → myoclonic, partial, atypical absence

EEG

Burst suppression

Generalized spike and Generalized polyspike polyspike waves; and spike waves; variable multifocal/ normal background focal; slow background

Prognosis

Grim: 60-80% mortality rate in first year

Unfavorable: drug resistance, low IQ, ataxia, tremors, dysarthria

Favorable with early treatment; may remit

Generalized 3- to 6-Hz spike/ polyspike waves mixed with classic 3-Hz waves; normal background Favorable with early therapy; typically persists

Variable; nocturnal seizures worsen prognosis

EEG, electroencephalogram, IQ, intelligence quotient, SE, status epilepticus. Modified from Delgado-Escueta AV, Perez-Gosiengfial KB, Bai D, et al. Recent developments in the quest for myoclonic epilepsy genes. Epilepsia 2003;44 (Suppl 11):13, with permission.

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the history and the physical and neurologic examinations. Thus, required analyses include drug screens; determination of serum (and cerebrospinal fluid) amino acids, urea, lactate, and ammonia concentrations; and a congenital infection screen. In addition, neuroimaging studies should be performed. The EEG may be useful both for delineating specific syndromic categories (for example, a burst-suppression pattern in a nonmedicated neonate) and for prognosis [Scher, 1993; Tharp et al., 1989]. Treatment should focus on reversing the trigger for the seizures, if possible, and on seizure control [Wheless and Sankar, 2003]. Benzodiazepines should be used for myoclonic seizures in the neonate, and valproate avoided if possible, owing to the significant mortality associated with the latter medication in this age group [Bryant et al., 1996].

SYNDROMES OF INFANTS: INFANTILE SPASMS (WEST’S SYNDROME) Often classified among the myoclonic epilepsies, infantile spasms constitute the most prevalent and perplexing entity that appears specifically in the infancy period of brain development (Table 46-2). Therefore, this syndrome is discussed in detail, followed by a review of other seizures consisting primarily of myoclonic events. Infantile spasms occur primarily during the first year of life, especially between the third and eighth months, regardless of the timing of any instigating factors (e.g., intrauterine infection or stroke, tuberous sclerosis, perinatal asphyxia, postnatal insult). It is thus useful to consider infantile spasms a highly age-specific epileptic response of the infant brain to innumerable causes [Brunson et al., 2002]. This concept is consistent with the natural evolution of infantile spasms (with or without treatment), in which the

FP1-F3 F3-C3 C3-P3 P3-O1 FP2-F4 F4-C4 C4-P4 P4-O2 50␮V 1 sec

A

spasms disappear or evolve into other seizures [Hrachovy et al., 1991; but see de Menezes and Rho, 2002]. Infantile spasms are relatively common, occurring in 1 per 2000 infants [Cowan and Hudson, 1991; Riikonen, 2001]. Because the outcome with infantile spasms, in terms of cognitive function and intellect, is poor (with mental retardation in 80% to 90% of children and epilepsy in greater than 50%), the economic and emotional burdens to society associated with this disorder are enormous. Early recognition and diagnosis, as well as new therapies, hold the most promise for this severe form of epilepsy in infants. Infantile spasms were first brought to attention by Dr. W. J. West in 1841, who documented the disorder in his own son [West, 1841]. Other reports of this myoclonic epilepsy in infants with its poor neurodevelopmental outcome followed, and the term West’s syndrome was coined in the early 1960s [Eling et al., 2002]. Hypsarrhythmia, the highvoltage, chaotic EEG abnormality associated with infantile spasms interictally, was defined in the 1950s [Gibbs and Gibbs, 1952]. The ictal correlates of the spasms themselves were delineated by Hrachovy and colleagues [1984]. The poor response of infantile spasms to conventional antiepileptic drugs [Aicardi, 1986; Holmes, 1987] led to the discovery of the efficacy of adrenocorticotropic hormone for treatment of this type of seizure [Sorel and Dusaucy-Bauloye, 1956]. Adrenocorticotropic hormone and also glucocorticoids (prednisone or hydrocortisone) have since been used as major therapeutic agents for infantile spasms (see later on) [Baram et al., 1996; Hrachovy and Frost, 1989; Lerman and Kivity, 1982; Mackay et al., 2004].

Clinical Features and Diagnosis The syndrome of infantile spasms consists of a constellation of myoclonic-like seizures in infants whose EEG pattern is that of hypsarrhythmia or its variants [Jeavons, 1985]. The EEG FIGURE 46-2. Samples of electroencephalograms (EEGs) from a normal infant and from a patient with hypsarrhythmia. A, Awake EEG from a normally developing 8-month-old male with a suspected seizure. Coherence of EEG waves is evident.

Baram / Myoclonus, Myoclonic Seizures, and Infantile Spasms

pattern, lack of response to conventional antiepileptic agents, and poor outcome distinguish infantile spasms from the similar epilepsies of infancy [Aicardi, 1986; Dreifuss, 1989; Lombroso, 1990]. Clinically, clusters of jerks, subtle or massive, occur mainly on awakening. The movements may consist of head, truncal, and hip flexion or extension or, most commonly, head and body flexion with leg extension [Hrachovy and Frost, 1989]. The number of jerks per cluster and of clusters per day are highly variable, as are associated features such asymmetry (typically in the presence of a focal brain lesion) [Kramer et al., 1997], autonomic phenomena (flushing, pallor), or a cry [Jeavons and Bower, 1964]. The location of the origin of these movements, and whether or not they truly are myoclonus, have been topics of debate [e.g., Pinard et al., 1993]. Arrest of development and loss of developmental milestones often accompany the onset of infantile spasms. In a large majority of affected infants, infantile spasms are a symptom of an abnormally developing brain (symptomatic infantile spasms), as is evident from the history, examination, or diagnostic evaluation [Jeavons and Bower, 1964]. In a second, smaller group of infants, presence of an underlying CNS dysfunction is suggested by delayed development or abnormal findings on physical examination. Infantile spasms in this group have been defined as cryptogenic, and the prevalence of the disorder has been decreasing with the availability of better diagnostic modalities, which allow more infants to be classified in the symptomatic group. A minority of infants (approximately 10%) have an apparently normal CNS, as defined by normal development, imaging studies, and etiologic evaluation. Dulac and colleagues have coined the term idiopathic for the disorder in these infants to emphasize the important concept that with successful treatment, these are the infants with potentially excellent outcome [Caplan et al., 2002; Dulac et al., 1993; Ito et al., 2002; Kivity et al., 2004; Lombroso, 1983; Ohtsuka et al., 2000].

FP1-F3 F3-C3 C3-P3 P3-O1 FP2-F4 F4-C4 C4-P4 P4-O2 50 ␮V 1 sec

B

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Because symptomatic infantile spasms arise from an abnormal CNS, the nature of the underlying insult or lesion may affect the phenomenology of the spasms (and often of other seizure types diagnosed before the onset of infantile spasms). In some children with infantile spasms, a focal seizure triggers or coincides with a generalized spasm [Carrazana et al., 1993], or the spasm may be strongly asymmetrical. In infants with generalized or multifocal brain dysfunction, the spasms typically are symmetric. It should be noted, however, that during the stage of CNS maturation of infants, generalized spasms may be generated by a localized epileptic focus [Acharya et al., 1997; Chugani et al., 1990; Dulac, 2001; Wyllie, 1996].

Clinical Laboratory Tests The evaluation of an infant suspected of having infantile spasms should include a prolonged EEG, consisting of at least a full sleep-wake cycle. The EEG hallmark of infantile spasms is the presence of hypsarrhythmia (Fig. 46-2), a disorganized, high-voltage pattern with no normal background. The hypsarrhythmia may thus signify diffuse, abnormal neuronal activity interictally, perhaps contributing to the loss of milestones and poor outcome. The brief seizures typically are associated with “flattening” of the EEG pattern [Hrachovy et al., 1984]. The hypsarrhythmia may not be evident early in the course of infantile spasms or may be present only during deep sleep. Therefore, a prolonged EEG or, optimally, a video EEG may be required for diagnosis [Hrachovy and Frost, 1989]. An infant with suspected infantile spasms should have a search for treatable disorders or precipitating factors. Neuroimaging may reveal tuberous sclerosis or CNS malformations [Dulac et al., 1984]; the latter accounts for a significant percentage of cases of infantile spasms (20% to 30% in recent FIGURE 46-2, cont’d. B, A hysparrhythmic EEG from a 10-month-old infant with sequelae of extreme prematurity (adjusted chronologic age of 7 months) and clinical infantile spasms. A disorganized pattern of very high voltage slow and sharp waves, without synchrony, predominates. Note the different voltage scale of the two samples. Horizontal bars = 1 second; vertical bars = 50 μV.

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series) [Baram et al., 1996; Kramer et al., 1997; Riikonen, 2001]. Treatable causes such as tumors [Gabriel, 1983; Mimaki et al., 1983] or hydrocephalus [Baram et al., 1996] should be excluded. Stroke [Alvarez et al., 1987] and preor postnatal infection may be apparent on magnetic resonance imaging (MRI). A search for metabolic disorders is recommended [Kramer et al., 1997; Riikonen, 2001], and may be supported by abnormal basal ganglia signal on MRI [Desguerre et al., 2003].

Natural History In a majority of cases, the hypsarrhythmia disappears over weeks to months, regardless of treatment, followed by waning of the spasms themselves. Even without treatment, 89% of patients have been reported to be spasm free by age 5 years [Hrachovy et al., 1991; but see de Meneses and Rho, 2002]. In many infants with infantile spasms who demonstrate diffuse or multifocal neuronal dysfunction, the disorder progresses to Lennox-Gastaut syndrome (see Chapters 40 and 44), with multiple seizure types and a typical EEG pattern. Among survivors of infantile spasms in whom lesions such as those of tuberous sclerosis were the trigger, the spasms often revert or evolve to a focal epilepsy [Chugani et al., 1990; Shields et al., 1999]. As mentioned earlier, the intellectual outcome in a majority of the survivors of infantile spasms is poor [Caplan et al., 2002; Dulac, 2001; Jeavons and Bower, 1964]. Therefore, the goal of optimal treatment of infantile spasms should focus not only on seizure control but also on improvement of cognitive outcome. To date, no single treatment mode has been documented to provide these therapeutic benefits for a majority of infants with infantile spasms. Adrenocorticotropic hormone therapy, use of newer antiepileptic drugs such as vigabatrin, and occa-

BOX 46-2 ACTH TREATMENT REGIMEN FOR INFANTILE SPASMS Two-Week Treatment Schedule • ACTH (Acthar Gel) 75 U/m2 of body surface area per dose, intramuscularly, twice a day (150 U/m2/day) Monitoring • Plasma electrolytes and glucose at onset and end of treatment • Blood pressure twice weekly, measured when child is not crying; expect diastolic pressure of >80 mm Hg in 50% of patients • If kidneys are intact (need assessment in TS), continue medication Tapering Schedule • For 3 days: 30 U/m2 in the morning • For 3 days: 15 U/m2 in the morning • For 3 days: 10 U/m2 in the morning • For 6 days: 10 U/m2 every other morning ACTH, adrenocorticotropic hormone; TS, tuberous sclerosis. Modified from Baram TZ, Mitchell WG, Tournay A, et al. High-dose corticotropin (ACTH) versus prednisone for infantile spasms: A prospective, randomized, blinded study. Pediatrics 1996;97:375, with permission.

sionally surgical resection of a focal lesion that triggers the spasms may offer the best results in appropriate patients.

Treatment Whether early treatment of infantile spasms with rapid resolution of both spasms and the hypsarrhythmic EEG improves cognitive outcome is not fully resolved. Glaze and associates [1988], in a prospective study, did not find improved outcome in infants who received treatment within a month of onset of infantile spasms, compared with those in whom treatment was delayed. Overall success of treatment in that study was low, however. Other prospective [Kivity et al., 2004; Lombroso, 1983] and retrospective [Koo et al., 1992; Singer et al., 1980] studies concluded that prompt successful treatment, presumably through elimination of the hypsarrhythmia, promotes resumed acquisition of cognitive milestones and improved outcome. Currently recommended treatment for infantile spasms, based on information gathered over the past decade, involves adrenocorticotropic hormone, vigabatrin, or, in selected infants with focal lesions that trigger the spasms, surgical resection.

Adrenocorticotropic Hormone In accordance with the results of several studies including both prospective randomized, controlled [Baram et al., 1996; Hrachovy et al., 1983, 1994], and uncontrolled studies [Snead et al., 1989], the American Academy of Neurology and the Child Neurology Society have issued a practice parameter recommending the use of adrenocorticotropic hormone for the treatment of infantile spasms [Mackay et al., 2004]. Because of the apparent increased efficacy of high doses of adrenocorticotropic hormone, the recommended therapy for infantile spasms consists of adrenocorticotropic hormone in depot formulation (e.g., Acthar Gel), at a dose of 150 U/m2 body surface per day in two daily doses (Box 46-2), typically 80 to 90 U/day in a 5-month-old infant. Parents are taught the procedure for intramuscular injection; blood pressure and urinalysis for glucose are measured twice a week; and parents and care providers are educated about the high likelihood of adrenocorticotropic hormone-induced reversible hypertension, voracious appetite, irritability, and acne. Treatment success requires elimination of both the spasms and the hypsarrhythmia, as determined by a video EEG (or EEG) encompassing at least a complete sleep-wake cycle. The 2-week treatment is followed by a 12-day taper period (see Box 46-2), with morning adrenocorticotropic hormone dosing, to reinstate normal circadian peaks of endogenous adrenocorticotropic hormone. This adrenocorticotropic hormone regimen eliminates the spasms and the hypsarrhythmia in more than 85% of affected infants. Its advantages over other hormonal approaches are a high rate of short-term efficacy and short duration, which minimize the severe side effects of chronic adrenocorticotropic hormone/steroid treatment [Heiskala et al., 1996; Lerman and Kivity, 1982; Snead et al., 1989]. Thus, high dose and short duration of adrenocorticotropic hormone therapy may provide the optimal balance of efficacy and adverse effects [Baram, 2003]. If seizures recur, their identity should be confirmed, because infantile spasms commonly evolve to other seizure types that may require a different therapy. For recurrent infantile spasms, a second course of adrenocorticotropic hormone

Baram / Myoclonus, Myoclonic Seizures, and Infantile Spasms

has been successful [Baram, unpublished observations; Snead, 1993]. Although high adrenocorticotropic hormone doses are advocated in the United States and may be required for the neurobiologic mechanism of infantile spasm suppression [Brunson et al., 2002; Rho, 2004], much lower doses are suggested in Japan [e.g., Ito et al., 2002], where synthetic, highly brain-penetrating preparations, different population characteristics, or other factors may influence therapy success [Baram, 2001].

Vigabatrin

Vigabatrin, an inhibitor of γ-aminobutyric acid (GABA) degradation, has been extensively used in Europe, and its effectiveness, particularly for children with tuberous sclerosis–associated infantile spasms, has been demonstrated. In a multicenter retrospective study, 50% of all patients of infantile spasms and 27 of 28 infants with tuberous sclerosis– associated spasms responded to vigabatrin [Aicardi, 1996; Chiron et al., 1997]. A controlled randomized study of vigabatrin in the United States found an efficacy rate of only 35% using high-dose vigabatrin [Elterman et al., 2001; Lux et al., 2002]. Unlike adrenocorticotropic hormone, vigabatrin does not result in an all-or-none response, and increasing doses (to 150 to 200 mg/kg per day) gradually decrease spasm frequency. Remarkably, studies in France have suggested that vigabatrin may improve cognitive outcome of patients with tuberous sclerosis–associated infantile spasms [Chiron et al., 1997]. The duration of required treatment with vigabatrin is unclear, but a year or more has been recommended [Aicardi, 1996; Elterman et al., 2001]. Prolonged treatment may be associated with retinal changes and irreversible visual field constriction [Johnson et al., 2000; Krauss et al., 1998], effects that have resulted in lack of Food and Drug Administration (FDA) approval of the drug in the United States.

Surgical Treatment The role of surgical treatment for infantile spasms has not been fully defined [Caplan et al., 2002; Chugani et al., 1990; Shields et al., 1999]. As discussed earlier, infantile spasms may be triggered by focal CNS lesions, and in affected infants, focal seizures often precede the onset of infantile spasms or trigger individual spasms. The natural history of these spasms typically consists of a recrudescence of focal seizures with a focal EEG [Kramer et al., 1997]. As with any “lesional” pediatric epilepsy, surgical resection of the focus may often be curative [Wyllie, 1996]. In the special case of tuberous sclerosis–associated infantile spasms, exciting novel technology may permit identification of the “epileptogenic” tuber, allowing resection [Juhasz et al., 2003]. Useful criteria for infants with infantile spasms who may benefit from surgical resection have been suggested [Kramer et al., 1997].

Other Treatments Numerous additional treatments have been used for infantile spasms. These include therapy with nitrazepam, valproate, lamotrigine, topiramate [Conry 2004], zonisamide [Lotze and Willfong, 2004; Suzuki, 2001], neurosteroids [Kerrigan et al., 2000], pyridoxine [Ohtsuka et al., 2000], immunoglobulins, or thyrotropin-releasing hormone [Takeuchi et al., 2001] and the ketogenic diet [Kossoff et al., 2002; Nordli et al., 2001]. Variable efficacy has been reported for each. Because spasms disappear spontaneously at a rate of ap-

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proximately 1% per week, effects of prolonged treatment should be carefully considered. Occasionally, treatment of the precipitating factor of infantile spasms (such as tumor or hydrocephalus) will eliminate the seizures.

Pathophysiology Infantile spasms are associated with diverse genetic (e.g., Kato et al., 2004], teratogenic, perinatal, and postnatal etiologic factors. This diversity points to a “final common pathway” for the etiologic conditions, leading to infantile spasms only during the state of CNS maturation present in infancy. Mechanistic theories for the development of infantile spasms have included autoimmune or brainstem dysfunction [Hrachovy and Frost, 1989], developmental “arrest” [Riikonen, 1983], and cortical microdysplasia [Dalla Bernardina and Dulac, 1994; Vinters et al., 1992]. The recent improvement of the resolution of MRI has led to the identification of structural malformations in a relatively larger proportion of children with infantile spasms. Frequency of CNS malformations in infantile spasms has been reported to be 20% [Baram et al., 1996; Kramer et al., 1997] and 30% to 34% [Dalla Bernardina and Dulac, 1994]. These malformations may consist of a diffusely dysplastic brain, such as in pachygyria, or as relatively small regions of cortical dysplasia and even microscopic areas of microdysgenesis [Meencke and Gerhard, 1985]. A current hypothesis for the pathogenesis of infantile spasms suggests that abnormal excitability generated by the focal areas of dysplastic brain spreads throughout the cortex [Dulac et al., 1997] and is propagated to brainstem structures [Juhasz et al., 2002], leading to the generalized spasms. This spread of the epileptic activity happens only during infancy, a developmental period characterized by cortical excitability. Studies in excised dysplastic adult brain [Avoli et al., 2003] and in animal models of cortical dysplasia [Zhu and Roper, 2000] have provided evidence for epileptogenic neuronal activity within these regions. Foci of microdysgenesis, however, have been described in brains of normal persons examined postmortem [Lyon and Gastaut, 1985], casting doubt on the etiologic role of these regional heterotopias in infantile spasms. In addition, in a majority of infants with symptomatic infantile spasms, the underlying disorders do not include cortical dysplasias. Theories for the pathogenesis of infantile spasms have to be consistent with the unique features of this disorder. For example, how can a single entity have so many causes? Why do infantile spasms arise only in infancy, even when a known insult had occurred prenatally, and why do they disappear? Why are infantile spasms associated with lasting cognitive dysfunction, and why do these seizures— unlike most others—respond to adrenocorticotropic hormone? The unique response of infantile spasms to hormonal treatment with high doses of adrenocorticotropic hormone may provide a key for elucidating the pathophysiology of this disorder. In randomized, controlled blinded approaches, adrenocorticotropic hormone doses that are much higher than those required for maximal hormonal effects offer additional efficacy: elimination of the spasms and the hypsarrhythmia in 86% to 88% of infants within a week [Baram et al., 1996], compared with approximately 40% efficacy of

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high-dose prednisone or lower doses of adrenocorticotropic hormone. Does adrenocorticotropic hormone have additional nonhormonal effects that ameliorate infantile spasms? Although analogs of adrenocorticotropic hormone without hormonal effects did not eliminate infantile spasms [Pentella et al., 1982; Willing and Lagenstein, 1982], suggesting that the hormonal actions of adrenocorticotropic hormone are necessary for efficacy, it is known that these analogs do not bind adrenocorticotropic hormone receptors within the brain [Brunson et al., 2001b, 2002]. Therefore, the additional efficacy of supramaximal adrenocorticotropic hormone doses is consistent with the hypothesis that the hormone exerts additional effects in the brain that are independent from the release of endogenous steroids. It is unlikely that these effects of adrenocorticotropic hormone are simply anticonvulsant: adrenocorticotropic hormone is not anticonvulsant in animal models [Baram and Schultz, 1995; Holmes, 1987]. In addition, the rapid, “all-or-none” and often permanent effects of adrenocorticotropic hormone on infantile spasms are not consistent with conventional anticonvulsant properties [Baram, 1993; Hrachovy and Frost, 1989]. Recent work has demonstrated that high doses of adrenocorticotropic hormone that permit penetration of the peptide across the blood-brain barrier reduce the levels of the seizurepromoting endogenous peptide corticotropin-releasing hormone in seizure-prone brain regions including the amygdala [Brunson et al., 2001b]. Thus, the efficacy of adrenocorticotropic hormone suggests a “final common pathway” for the mechanisms by which the many causes of infantile spasms trigger these seizures. This hypothesis suggests that infantile spasms occur in the context of an insulted and stressed developing CNS [Baram, 1993; Brunson et al., 2002]. The many causative disorders underlying infantile spasms all lead to activation of the stress response, including the stress neurohormone corticotropin-releasing hormone. Corticotropinreleasing hormone has been found, in infant animal models, to cause severe seizures and long-term deficits of learning and memory [Baram et al., 1992; Brunson et al., 2001a]. These effects of corticotropin-releasing hormone are restricted to infancy because the receptors for corticotropinreleasing hormone, which mediate its action on CNS neurons, are most abundant during this developmental period. Adrenocorticotropic hormone administration inhibits production and release of corticotropin-releasing hormone both through steroid release and a negative feedback mechanism and directly, by activation of brain adrenocorticotropic hormone receptors. Therefore, the efficacy of adrenocorticotropic hormone for infantile spasms may depend on its ability to decrease the levels of the seizurepromoting stress neurohormone corticotropin-releasing hormone. This supposition is consistent with the profile of adrenocorticotropic hormone effect, the myriad different “causes” of infantile spasms, the abnormal adrenocorticotropic hormone levels in the cerebrospinal fluid of affected infants [Baram et al., 1992, 1995; Nagamitsu et al., 2001], and the spontaneous disappearance of the seizures. Furthermore, if corticotropin-releasing hormone is responsible for the seizures and the worsened cognitive outcome in persons with infantile spasms, then drugs that block the actions of corticotropin-releasing hormone on its receptors may provide a better therapy for this disorder [Baram, 2003; Baram and Hatalski, 1998].

SEVERE MYOCLONIC EPILEPSY OF INFANCY Myoclonic seizures are the major manifestation of several epileptic entities confined to the first 2 years of life. Dalla Bernardina and colleagues [1983], Dravet and associates [1985a, 1985b], Ohtahara working alone [1976] and with Yamatogi [2003], and others have defined clinical and EEG criteria to distinguish among these disorders—benign or severe myoclonic epilepsies of infancy—but significant clinical overlap among these syndromes remains. Thus, the prognosis for infants presenting with myoclonic epilepsy other than infantile spasms cannot be predicted with certainty. Specifically, in these rare syndromes, normal findings on the neurodevelopmental examination at presentation do not necessarily predict a good outcome, although in general, a normal-appearing interictal EEG is consistent with the benign syndrome described by Dravet and associates [1985a], with good response to valproate and a relatively low likelihood of development of other epilepsies. Since the mid-1990s, a syndrome of severe myoclonic epilepsy of infancy has been characterized [Dravet, 1985b; Scheffler et al., 2001], and the molecular basis of this entity has been discovered. The onset of this disorder is typically with clonic seizures, provoked by fever, that progress to massive or subtle myoclonic events associated with other seizure types (absence, partial tonic-clonic). The clinical course is one of intractable seizures with cognitive deterioration and poor response to treatment. Because severe myoclonic epilepsy of infancy commonly manifests with febrile seizures and occurs in children from families with generalized epilepsy and febrile seizures (GEFS+), severe myoclonic epilepsy of infancy has been considered a severe manifestation of the GEFS+ spectrum (Scheffer et al., 2001]. Indeed, mutations in a sodium channel gene (SCN1A), leading to defective channel function, have been found in severe myoclonic epilepsy of infancy, as discovered also for GEFS+ [Claes et al., 2003; Wallace et al., 2003]. Several related genes may be involved, and the severity of the clinical phenotype may depend on the location and type of the mutation (see Chapter 42 for a comprehensive discussion).

Symptomatic Myoclonic Epilepsies of Infancy Several genetic disorders of lysosomal and other enzyme dysfunction may have their clinical onset during the first 2 years of life (see Tables 46-2 and 46-3). In these entities, seizures are rarely the major presenting symptom, and a thorough history and examination often reveal other stigmata of specific entities (e.g., organomegaly, spasticity, retinal cherry-red spot). Laboratory evaluation should be guided by the genetic background, associated features, and other aspects of the clinical presentation. Storage disorders that merit consideration include the two early-presenting variants of the neuronal ceroid lipofuscinoses (see Chapter 59). The infantile (Santauuori-Haltia) and late infantile (JanskyBielschowsky) forms are characterized by myoclonic and other seizures, developmental regression, visual loss, and a rapidly progressive course. Gangliosidoses manifesting at this age include GM1 and GM2, particularly in infants of Jewish Ashkenazi background (see Table 46-2). Among mitochondrial disorders, myoclonic epilepsy with ragged red

Baram / Myoclonus, Myoclonic Seizures, and Infantile Spasms

fibers rarely begins in the infancy period, as may other disorders related to mutation of mitochondrial genes (e.g., Leigh’s syndrome).

MYOCLONIC EPILEPSIES OF CHILDREN AND ADOLESCENTS Juvenile Myoclonic Epilepsy The most common type of myoclonic epilepsy of childhood seen in adolescents is juvenile myoclonic epilepsy, a nonprogressive, genetically inherited disorder that accounts for 15% to 20% of all epilepsies at this age [Wheless and Kim, 2002]. Typically, onset is at or near the time of puberty, but many cases occur earlier or manifest in the early 20s. The heraldic event commonly is a generalized tonic-clonic seizure, and only careful history reveals that early-morning myoclonus, the cardinal feature of this disorder, has been present for some time. The myoclonia occurs as repetitive irregular or semirhythmic myoclonic jerks involving shoulders and arms, sometimes with dropping of objects, sometimes asymmetric or unilateral, and confined to the awakening minutes or hours. The myoclonia may be mistaken for “nervousness” and classically precedes the generalized tonic-

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clonic seizures, which can occur at any time of day or night and are found in 90% of patients. Alternatively, juvenile myoclonic epilepsy may evolve clinically from apparently typical childhood absence seizures [Delgado-Escueta et al., 2003; Wirrell et al., 1996]. The diagnosis is confirmed by the pathognomonic EEG pattern (Fig. 46-3). The myoclonia is precipitated by sleep deprivation and alcohol.

Evaluation and Diagnosis EEG is the most useful test for the diagnosis of juvenile myoclonic epilepsy. EEG abnormalities are accentuated by sleep deprivation, and an early-morning EEG (with video) also may clarify the nature of “nervousness” on awakening. EEG background usually is normal, without slowing or disorganization. The characteristic abnormality consists of bursts of bifrontal or generalized, bilaterally synchronous, spike/polyspike-and-wave activity, typically at 3.5 to 4 Hz [Janz, 1989]. Fast spike-and-wave activity of 4 to 6 Hz also is frequently observed [Dreifuss, 1989]. Absence seizures (which occur in 30% of patients) are accompanied by typical spike-and-wave activity, but the frequency usually is faster than 3 Hz [Asconape and Penry, 1984; Delgado-Escueta, 2003]. Focal polyspike-and-wave activity accompanied by

FIGURE 46-3. Sample of an electroencephalogram (EEG) from an adolescent with juvenile myoclonic epilepsy (JME). Generalized spike-wave discharge, maximal over the frontal leads, erupts suddenly from a normal background. The typical spike or polyspike discharges in JME are 3.5 to 4 Hz in frequency. (Courtesy of Dr. Howard Kim, University of California, Irvine.)

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focal jerks also has been reported [Panayiotopoulos et al., 1991]. Photoparoxysmal response composed primarily of generalized or frontally predominant polyspike-and-wave activity occurs in approximately 30% to 35% of patients [Janz, 1989]. The myoclonic jerks themselves are accompanied by an EEG burst of 10 to 16 Hz polyspikes, followed by highamplitude slowing at a frequency of 2 to 5 Hz. Juvenile myoclonic epilepsy clearly is a familial disorder, although the exact genes responsible have not been cloned [Minassian et al., 1995; Serratosa and Delgado-Escueta, 1993].

Treatment The treatment of juvenile myoclonic epilepsy should focus on both avoidance of the precipitating factors, as well as on the use of antiepileptic medications. These life-long seizures are triggered by fatigue and alcohol; therefore, lifestyle management, such as ample sleep and avoidance of alcohol, significantly influences the likelihood of successful drug management. In adolescent girls, hormonal changes occuring with menstruation are a significant precipitant of the seizures, requiring special care in obtaining adequate sleep

or increased medication dose. Valproate is reportedly effective in 86% to 90% of cases [Delgado-Escueta and Enrile-Bacsal, 1984]. When valproate is not effective or leads to unacceptable side effects, lamotrigine may provide an alternative option. Treatment of juvenile myoclonic epilepsy with felbamate, zonisamide, and clorazepate has been reported. Unlike most idiopathic seizures of the developing human, juvenile myoclonic epilepsy rarely remits, so that affected persons require medication for life. A relapse rate of 75% to 100% when medication is withdrawn has been documented [Delgado-Escueta and Enrile-Bacsal, 1984; Penry et al., 1989].

PROGRESSIVE MYOCLONIC EPILEPSIES Progressive myoclonic epilepsies are rare genetic entities, accounting for approximately 1% of epilepsies in childhood. These syndromes typically consist of massive myoclonic seizures, cognitive deterioration, and other neurologic signs, often including ataxia (Table 46-4). Several of the progressive myoclonic epilepsy syndromes have been characterized clinically, have specific EEG characteristics, and

TABLE 46–4 Progressive Myoclonic Epilepsy (PME) Syndromes in Children and Adolescents SIGNS OF NEUROLOGIC DETERIORATION ONSET AGE (yr)

SEIZURES AT ONSET

UnverrichtLundborg PME

6-15

Lafora body disease

10-18

Generalized, myoclonus including face; stimulus sensitive Generalized (absence; drops) then myoclonus; stimulus sensitive Face myoclonias seizures 1-4 yr later; generalized and absence; stimulus sensitive

SYNDROME

Neuronal ceroid 4-10 lipofuscinoses: Batten (late infant) or Batten-VogtSpielmeyer disease Adult ceroid 11-50 lipofuscinosis (Kufs’ disease)

Stimulus sensitive generalized and myoclonia late, or no seizures

Visual

Cerebellar

Pyramidal Tract

Extrapyramidal

Dementia

NEUROPATHOLOGY

No

Worse on phenytoin

Rare, infrequent

Rare

Slow to develop

Vesicular changes in eccrine sweat glands

North Europe, U.S., Canada, Mediterranean countries

Age 50-60 yr

Occipital seizures with visual hallucinations

Mid to late course

Common

Not common

Central visual loss Not prominent heralds disease Retinitis pigmentosa

Common

Common

Rapidly progressive (1-2 yr after onset) Rapidly progressive

Mediterranean, Middle East, Africa, India, Pakistan Scandinavia, U.S.

Age 20–25 yr ⬃10 yr after onset Late teens or early 20s

—

Common

Common

Athetosis, dyskinesia common

Slowly progressive

PAS+ cytoplasmic inclusions in skin, muscle, liver, and brain biopsies Vacuolated lymphocytes fingerprint profiles and acurvilinear inclusion on skin biopsy Fingerprint profile; osmiophilic granular profiles in brain biopsy and lipofuscin deposits in liver biopsy specimen Osteopenia, bone lesions; organomegaly; Gaucher’s cells; diminished lucocerebrosidase activity Lacticacidosis, myopathy, short stature, deafness; muscle biopsy; ragged red fibers; abnormal mitochondrial enzymes Painful neuropathy; increased urinary oligosaccharides; neuroaminidase deficit ß-N-acetylhexosaminidase A deficit

Worldwide

10 yr from onset

—

<10 yr from onset

Worldwide

3–30 yr from onset

Common in Italy

10–40 yr from onset

Ashkenazi Jews—U.S., Israel

5–15 yr

Juvenile Gaucher’s disease

~5-15; rarely later

Generalized, partial; Abnormal eye photomyoclonic movements, gaze response palsies herald onset

Ataxia early in course

Common

Can be present

Early in course

Mitochondrial encephalomyopathy with ragged red fibers (MERRF)

3-65

Generalized, partial; Rare optic atrophy photosensitive

Can occur

Dysarthria ataxia

No

Slowly progressive

Sialidosis 8–15 (cherry-red spot myoclonus)

Facial myoclonus; generalized; no photosensitivity

Visual deficit

Ataxia

Present

No

Present

2–6 Juvenile GM2 gangliosidosis

Generalized in mid-course

Optic atrophy and retinitis pigmentosa

Progressive ataxia

Early

No

Early with decerebrate rigidity

PAS+, periodic acid–Schiff positive.

GEOGRAPHIC DISTRIBUTION

DEATH

Baram / Myoclonus, Myoclonic Seizures, and Infantile Spasms

are known to be a result of specific genetic disturbance disorders (see Chapter 42). They are described briefly here. The distinguishing EEG features of the progressive myoclonic epilepsies are summarized in Box 46-3.

Unverricht-Lundborg Progressive Myoclonic Epilepsy The Unverricht-Lundborg type of progressive myoclonic epilepsy is a disorder of autosomal recessive inheritance found in Finnish and other northern European populations along the Baltic seashore. This “Baltic myoclonus” (EPM1), with an incidence of 1:20,000, manifests typically between ages 6 and 15 years with stimulus-sensitive myoclonus, followed by ataxia, dysarthria, and slowly progressive cognitive decline. Unlike in juvenile myoclonic epilepsy, the EEG background often is slow, with irregular, generalized spike- or polyspike-and-slow-wave complexes maximal over the anterior head regions. A large majority of affected persons have photosensitive epileptiform EEG discharges and myoclonus. A similar, Mediterranean form of this disorder is common in North Africa. Both variants have been traced to the q22.3 band on chromosome 21 and may involve different mutations of the cystatin B gene [Lalioti et al., 1997a, 1997b; Malafosse et al., 1992]. Mechanistically, abnormalities of cystatin B, a cysteine protease inhibitor, hamper its ability to inactivate proteases that leak out of the lysosome.

Lafora Body Disease Lafora body disease typically manifests between the ages of 6 and 18 years, with nonmyoclonic, generalized tonic-clonic seizures. Asymmetric myoclonic jerks follow, as well as progressive dementia, ataxia, and visual loss, with death in approximately 10 years. At presentation, the EEG may still show a normal background with isolated generalized spikeand-slow-wave discharges, but a slow background with predominance of irregular generalized spike- or polyspikeand-slow-wave discharges evolves rapidly. Pathologically, Lafora bodies are intracellular polyglucosan-containing inclusions in neurons, muscle, liver, and skin glands. The gene mutated in Lafora body disease, EPM2A, is located on chromosome 6 and encodes an intracellular tyrosine phosphatase, laforin [Minassian, 1998, 2000].

Other Progressive Myoclonic Epilepsies (see Table 46-4) The juvenile and young adult forms of neuronal ceroid lipofuscinosis (Vogt-Spielmeyer [or Batten’s] disease and Kufs’

BOX 46-3 EEG CHARACTERISTICS IN PATIENTS WITH PROGRESSIVE MYOCLONIC EPILEPSIES • Generalized multiple spike (polyspike) waves • Slow background, disorganized sleep • Photosensitivity (even to single flashes: neuronal ceroid lipofuscinosis) • Imperfect relation of spikes to myoclonus • Giant somatosensory evoked potentials • Focal, especially occipital, epileptiform discharges • Vertex-positive spikes in sialidosis EEG, electroencephalogram.

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disease, respectively) also may present during adolescence, with myoclonic seizures (see Chapter 59). Juvenile neuronal ceroid lipofuscinosis, the form common in the United States, commences in late childhood with visual loss, often facial myoclonus, and progressive cognitive decline and seizures. The EEG deteriorates slowly, with abnormal visual-evoked potentials (VEPs) and electroretinograms. The adult form of neuronal ceroid lipofuscinosis can commence in the early teens, heralded by progressive myoclonic epilepsy and dementia, as well as extrapyramidal signs. Visual loss is rare. The diagnosis of the neuronal ceroid lipofuscinosiss has progressed significantly. Each of the four age-dependent syndromes described here has typical neuropathologic features, with a distinctive pattern of intracellular inclusions. Genotypephenotype analyses, however, have suggested 8 to 10 discrete entities, and recent genetic analyses suggested that at least some are a result of defects in lysosomal enzymes, including tripeptidylpeptidase I (TTPI), and palmitoyl protein thioesterase. These are encoded by a series of genes, named CLNs, located on several chromosomes: 1 (CLN1), 11 (CLN2), and so on [Wisniewski et al., 2001]. Among the mitochondrial disorders, myoclonic epilepsy with ragged red fibers [DiMauro and Moraes, 1993] may manifest as myoclonic seizures in children and adolescents. Syndrome phenotype and severity vary greatly, as is typical for this class of disorders, depending on the amount and tissue distribution of mutant mitochondrial DNA (mtDNA) in each affected person. Intention myoclonus, epilepsy, muscle weakness, neurosensory hearing loss, and ataxia are seen in various combinations. A mutation of the lysine transfer DNA (tRNA) gene commonly is the cause [DiMauro and Moraes, 1993]. The EEG features consist of slow background and generalized (or focal) irregular spike-and-wave or polyspike-and-wave discharges. Other degenerative disorders in which myoclonus is present early or is a prominent feature include juvenile Gaucher’s disease and sialidosis type I (see Tables 46-2 and 46-4). The latter, “cherry-red spot myoclonus,” typically arises at 8 to 15 years. In addition to myoclonus (often facial), neuropathy, ataxia, and other seizures occur, with vertex spikes seen on the EEG (see Box 46-3, Table 46-4). Diagnosis is based on increased urine oligosaccharides. Although each of these entities is quite rare, the progressive myoclonic epilepsies in the aggregate comprise 1% of childhood/ adolescent epilepsies. Therefore, children and adolescents presenting with myoclonic epilepsy that defies rapid diagnosis merit an evaluation for mitochondrial, storage, and other progressive disorders.

MYOCLONUS OR MYOCLONIC SEIZURES ASSOCIATED WITH OTHER ENTITIES Classic absence seizures, with the typical 3-per-second spikeand-wave discharges on EEG, may be associated with eyelid or lip myoclonus (see also Chapter 43). The myoclonic features may be rather prominent and have led to debates regarding the boundaries between “true” absence and “myoclonic absence” [Delgado-Escueta et al., 2003; Tassinari and Bureau, 1985]. These controversies notwithstanding, it is generally agreed that the prognosis for absence may be worse

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Epilepsy / 46

TABLE 46–5 Anticonvulsants Exacerbating Myoclonus and Myoclonic Seizures DRUG

EPILEPSY SYNDROME

Carbamazepine

Acquired or cryptogenic myoclonic epilepsy Lennox-Gastaut syndrome (may evoke myoclonia) Angelman’s syndrome Autosomal dominant cortical myoclonus and epilepsy Juvenile myoclonic epilepsy Severe myoclonic epilepsy in infancy Myoclonic-astatic epilepsy (Doose’s syndrome) Myoclonic-astatic epilepsy, (Doose’s syndrome) Lennox-Gastaut syndrome (may evoke myoclonia) Progressive myoclonic epilepsies Juvenile myoclonic epilepsy Severe myoclonic epilepsy of infancy Lennox-Gastaut syndrome (may evoke myoclonia) Juvenile myoclonic epilepsy Lennox-Gastaut syndrome (may evoke myoclonia) Myoclonic-astatic epilepsy (Doose’s syndrome) Juvenile myoclonic epilepsy Severe myoclonic epilepsy in infancy Lennox-Gastaut syndrome Partial seizures

Phenytoin

Lamotrigine

Vigabatrin

Gabapentin

Data from Genton P. When antiepileptic drugs aggravate epilepsy. Brain Dev 2000;22:75, and Wheless JW, Sankar R. Treatment strategies for myoclonic seizures and epilepsy syndrome. Epilepsia 2003;44 (Suppl 11): 27.

if the myoclonic features predominate [Panayiotopoulos et al., 1989]. A syndrome of “drop attacks” with onset at ages 1 to 5 years accounts for about 2% of all childhood epilepsies. This entity occurs more commonly in males and likely is of genetic origin [Doose and Baier, 1987]. The seizures have been termed myoclonic-astatic epilepsy. The drop attack begins with a major myoclonic jerk and is followed by loss of body tone and a fall. These seizures typically arise in previously normal children, and response to medication and prognosis are variable. They are distinguished from LennoxGastaut syndrome by several features: (1) tonic seizures are not seen, except during sleep; (2) drop attacks predominate; (3) previous development is normal or only mildly delayed; and (4) the EEG background may be normal or often includes “absence-like” spike-and-wave discharges (see Table 46-2). By contrast, among the multiple seizure types of LennoxGastaut syndrome, “myoclonic” jerks are rarely prominent, and EMG studies suggest that a majority of such seizures likely are atonic. New onset of myoclonic seizures in a child with Lennox-Gastaut syndrome should prompt evaluation for an iatrogenic cause (see later on) (see Chapter 43 for a discussion of Lennox-Gastaut syndrome). The treatment of myoclonic-astatic epilepsy remains challenging, and no controlled studies have been undertaken. Felbamate, benzodiazepines, valproate, lamotrigine, and ethosuximide reportedly have been used (Wallace, 1995; Wheless and Sankar, 2003]. The combination of lamotrigine and topiramate has been successful in anecdotal reports.

Finally, subacute sclerosing panencephalitis is characterized by myoclonic seizures and progressive dementia, most commonly subsequent to measles infection or vaccination [Dyken et al., 1989]. The pathogenesis of this disorder involves persistence of a “defective” measles virus in the CNS [Asher, 1991]. The average latency period from measles infection or vaccination to the onset of symptoms is 8 years, although onset in infancy has been reported [Baram et al., 1994]. Clinical myoclonic seizures, often massive, are accompanied by semiperiodic sharp or slow waves on EEG, which occur every 3 to 4 seconds. The diagnosis depends on the demonstration of high cerebrospinal fluid measles titers [Asher, 1991]. Subacute sclerosing panencephalitis progresses over months or years to a vegetative state or death [Risk and Haddad, 1979]. Current available treatment is unsatisfactory, but antiviral treatment and interferons have been reported to yield stabilization or improvement of the clinical status [Gascon et al., 2003; Yalaz et al., 1992], so that early diagnosis and rapid initiation of treatment before severe neurologic deterioration are warranted.

APPROACH TO TREATMENT OF MYOCLONIC SEIZURES The rational approach to the treatment of myoclonic seizures involves exclusion of nonepileptic myoclonus and, when feasible, treatment of reversible causes of symptomatic epileptic myoclonus. An additional step in the management of apparent myoclonic jerks with an epileptic EEG is the exclusion of atonic (rapid loss of muscle tone) or tonic (rapid muscle tightening) seizures, because these may respond better to different antiepileptic drugs from those useful for myoclonic seizures. The EEG correlates of myoclonic seizures often are high-amplitude multiple spikes followed by a slow wave, whereas atonic and tonic seizures generally are accompanied by spike/polyspike and “flattening” of the EEG pattern and by fast low-voltage activity with increasing amplitude, respectively. The development of new myoclonic seizures in an infant or a child with known epilepsy should lead to the consideration of adverse effects of concomitant antiepileptic drugs [Bauer, 1996; Wheless and Sankar, 2003]. Carbamazepine and phenytoin have been reported to cause myoclonic seizures, as have newer anticonvulsants such as vigabatrin [Lortie et al., 1993], gabapentin [Vossler, 1996], lamotrigine, and pregabalin (Table 46-5). Dose reduction or elimination of the offending drug may stop these myoclonic seizures. The management of specific myoclonic seizures such as infantile spasms and juvenile myoclonic epilepsy is discussed in the relevant sections. For other myoclonic seizures, the current therapeutic mainstays include valproate, benzodiazepines, lamotrigine, zonisamide, and felbamate, and nonpharmacologic approaches may be suitable for specific cases. Further discussion of specific antiepileptic drugs is found also in Chapter 49. Valproate is very effective for myoclonic seizures, including those associated with other seizure types [Jeavons et al., 1977; Pellock, 1991]. It is the first-line drug for treatment of juvenile myoclonic epilepsy. High-dose valproate monotherapy, with plasma levels higher than 100 mg/dL,

Baram / Myoclonus, Myoclonic Seizures, and Infantile Spasms

may provide optimal results. Valproate therapy is associated with both dose-dependent and dose-independent side effects [Brodie and Dichter, 1996]. Moreover, 70 fatalities due to valproate-induced hepatotoxicity were reported in the United States between 1978 and 1996 [Bryant et al., 1996]. The highest risk for death (1:500 to 1:600) has been found in patients younger than 2 years of age who were on polytherapy regimens. Accordingly, although many myoclonic seizures that may respond to valproate manifest during the first 2 years of life, the use of valproate at this age should be undertaken with caution, and then only for monotherapy. Several benzodiazepines including clonazepam have efficacy in the treatment of refractory myoclonic seizures [Hanson and Menkes, 1972], including severe myoclonicastatic epilepsies. Benzodiazepines may be first-line drugs for treatment of myoclonic seizures (except for infantile spasms) in infants, in whom the use of valproate should be undertaken with caution. Sedation and the development of tolerance often limit the long-term usefulness of benzodiazepines, and high doses (e.g., greater than 3 mg/kg per day of clonazepam) often lead to congestion and accumulation of respiratory tract secretions, at least partially because of impaired swallowing [Wyllie et al., 1986]. Lamotrigine has been extensively used for myoclonic seizures in Europe and has been considered as effective as valproate [Wallace, 1995]. The drug has demonstrated excellent efficacy for myoclonic seizures in the context of Lennox-Gastaut syndrome, often including an improvement in interictal mental status [Besag et al., 1995; Wallace, 1995]. The major side effect of lamotrigine is a rash that can be severe. Therefore, the use of lamotrigine requires careful dose escalation and supervision. (The manufacturer currently does not advocate use of lamotrigine in children; see medication insert.) Dooley and colleagues [1996] have demonstrated that lamotrigine can be reinitiated in children whose rash had required temporary elimination of this medication. Use of zonisamide has been reported in the treatment of juvenile myoclonic epilepsy, as well as the progressive myoclonic epilepsies [Kyllerman et al., 1998]. In mitochondrial disorders with myoclonic seizures, coenzyme Q10 and/or carnitine might be helpful. The use of acetazolamide for myoclonic seizures has been debated [Resor et al., 1990], whereas adrenocorticotropic hormone [Snead et al., 1989] may result in temporary improvement in patients with myoclonic seizures. Nonpharmacologic treatment approaches may be considered in severe cases: The ketogenic diet (see Chapter 50) may offer a useful alternative for management of refractory myoclonic seizures, with reported efficacy of up to 70% to 80% [Prasad et al., 1996]. Vagus nerve stimulation has been reported to be effective in reducing frequency of generalized tonic-clonic seizures in some myoclonic seizure types. Its efficacy in myoclonic seizures remains unclear [Wheless and Sankar, 2003]. Finally, corpus callosotomy has been advocated for debilitating massive myoclonic seizures that result in severe injury [Pinard et al., 1993; Smith et al., 1999; but see Cendes et al., 1993]. ACKNOWLEDGMENTS This chapter is dedicated to the memory of Dr. Rita T. Lee, teacher and cherished friend.

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The research on which this chapter is based was supported by NIH grants NS01307, NS28912, NS39307, and NS35439 and by awards from the Epilepsy Foundation of America and the American Epilepsy Society. The excellent assistance of Michele Hinojosa is appreciated.

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CHAPTER 47

Febrile Seizures Shlomo Shinnar

Febrile seizures are a form of acute symptomatic seizures. They occur in 2% to 5% of children and are the most common form of childhood seizures. In the past, it was believed that most febrile seizures represented a form of epilepsy and that the prognosis was not favorable [Lennox, 1949, 1953; Livingston et al., 1947; Taylor and Ounsted, 1971]. Febrile seizures were believed to cause brain damage and subsequent epilepsy [Fowler, 1957; Taylor and Ounsted, 1971; Wallace, 1980]. One author summarized this view of prognosis in an article titled “They Don’t Do Very Well” [Wallace, 1980]. This pessimistic view was based on a selected population of children seen in tertiary care centers and on patients with refractory epilepsy seen at these centers who had a history of febrile seizures [Bruton, 1988; Falconer, 1971; Falconer and Serafetinides, 1964; Livingston et al., 1947]. These patients, however, were not representative of a majority of children with febrile seizures [Ellenberg and Nelson, 1980]. Over the past 25 years, much more information on febrile seizures has accumulated from both human and animal studies [Baram and Shinnar, 2002]. The prognosis for febrile seizures usually has been found to be good. Such seizures are not associated with any detectable brain damage [Ellenberg and Nelson, 1978; Knudsen et al., 1996; Maytal and Shinnar, 1990; National Institutes of Health (NIH), 1980; Nelson and Ellenberg, 1978; Verity and Golding, 1991; Verity et al., 1985b, 1993; Wolf and Forsythe, 1989], and epilepsy will eventually develop in only a small minority of children who have had febrile seizures [Annegers et al., 1979, 1987; Berg, 1992; Berg and Shinnar, 1996b; Knudsen et al., 1996; Nelson and Ellenberg, 1976, 1978; van den Berg and Yerushalmi, 1969; Verity and Golding, 1991; Verity et al., 1985b, 1993; Wolf and Forsythe, 1989]. This understanding is based on large epidemiologic studies [Annegers et al., 1979, 1987; Berg, 1992; Nelson and Ellenberg, 1976, 1978; van den Berg and Yerushalmi, 1969; Verity and Golding, 1991; Verity et al., 1985b, 1993], as well as on prospective studies from emergency departments not selected for tertiary referral bias [Berg et al., 1992; Knudsen, 1985a, 1985b; Wolf and Forsythe, 1989]. It also has been learned that although antiepileptic drugs can prevent recurrent febrile seizures, they do not alter the risk of subsequent epilepsy [American Academy of Pediatrics (ΑΑP), 1999; Berg and Shinnar, 1997; Knudsen et al., 1996; Rosman et al., 1993b; Shinnar and Berg, 1996; Wolf and Forsythe, 1989]. This finding has led to a changing view of the treatment of these common and largely benign seizures [AAP, 1999; Knudsen, 2002]. This chapter reviews the current understanding of the prognosis and management of febrile seizures.

DEFINITIONS A febrile seizure is defined by the International League Against Epilepsy as a seizure occurring in association with a febrile illness in the absence of a central nervous system (CNS) infection or acute electrolyte imbalance in children older than 1 month of age without prior afebrile seizures [Commission on Epidemiology and Prognosis, 1993]. This definition is similar to the one adopted earlier by the NIH Consensus Conference [1980]. The febrile illness must include a body temperature of greater than 38.4° C, although the increased temperature may not occur until after the seizure. The child may be neurologically normal or abnormal. In the International League against Epilepsy guidelines for epidemiologic research [Commission on Epidemiology and Prognosis, 1993], febrile seizures and, by extension, febrile status epilepticus are further divided into those occurring in children without prior neonatal seizures and those in children with prior neonatal seizures. In earlier epidemiologic studies, the lower age range used was either 1 month [Annegers et al., 1979, 1987, 1990; Berg et al., 1990, 1992, 1997; Verity et al., 1985a] or 3 months [Nelson and Ellenberg, 1976, 1978]. No specific upper age limit is used. Febrile seizures are most common, however, between the ages of 6 months and 3 years, with peak incidence at approximately 18 months of age. Onset after the age of 7 years is uncommon. Febrile seizures are further classified as simple or complex. A febrile seizure is complex if it is focal, prolonged (lasting for more than either 10 minutes [Annegers et al., 1979, 1987, 1990; Berg and Shinnar, 1996a; Berg et al., 1992, 1997] or 15 minutes [Berg and Shinnar, 1996a; Nelson and Ellenberg, 1976, 1978]), or multiple (occurrence of more than one seizure during the febrile illness). Conversely, it is simple if it is an isolated, brief, generalized seizure. Although neurologically abnormal children are more likely to experience complex febrile seizures and have a higher risk for subsequent afebrile seizures, the child’s prior neurologic condition is not used to classify the seizure as simple or complex [Commission on Epidemiology and Prognosis, 1993; NIH, 1980]. When a careful history is obtained, approximately 30% of patients with febrile seizures presenting to the emergency department are found to have complex features [Berg and Shinnar, 1996a].

EPIDEMIOLOGY Febrile seizures are the most common form of childhood seizures. The peak incidence is at the age of approximately 18 months. In the United States and Western Europe, they

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occur in 2% to 4% of all children [AAP, 1996; Annegers et al., 1990; Berg, 1995; Nelson and Ellenberg, 1978; van den Berg and Yerushalmi, 1969; Verity et al., 1985a]. In Japan, however, 9% to 10% of all children experience at least one febrile seizure [Tsuboi, 1984], and rates as high as 14% have been reported from the Mariana Islands in Guam [Stanhope et al., 1972]. Traditionally, it was thought that febrile seizures most commonly occur as the first sign of a febrile illness. More recent studies, however, found that only 21% of the children experienced their seizure either before or within 1 hour of the onset of the fever, 57% had a seizure after 1 to 24 hours of fever, and 22% experienced their febrile seizure more than 24 hours after the onset of the fever [Berg et al., 1992, 1997]. Some children are at increased risk to experience a febrile seizure. In a case-control population-based study, Bethune and associates [1993] examined risk factors for a first febrile seizure and found that the following four factors were associated with an increased risk of febrile seizures: (1) a history of febrile seizures in a first- or second-degree relative, (2) a neonatal nursery stay of more than 30 days, (3) developmental delay, or (4) attendance at day care. Children with two of these factors had a 28% chance of experiencing at least one febrile seizure. In another case-control study using febrile controls matched for age, site of routine pediatric care, and date of visit, Berg and colleagues [1995] examined the issue of which children with a febrile illness were most likely to experience a febrile seizure. On multivariate analysis, significant independent risk factors were the height of the peak temperature and a history of febrile seizures in an immediate relative. Gastroenteritis as the underlying illness had a significant inverse (i.e., protective) association with febrile seizures. Similar results on the importance of the peak temperature were reported from a hospital-based study [Rantala et al., 1995]. The majority of febrile seizures are simple seizures. In a recent study of 428 children with a first febrile seizure, Berg and Shinnar [1996a] found that 35% had at least one complex feature, including focality in 16%, multiple seizures in 14%, and prolonged duration (longer than 10 minutes) in 13%. Approximately 6% of children had at least two complex features, and 1% had all three complex features. Of most concern have been prolonged febrile seizures. In that study, 14% of the children had seizures lasting longer than 10 minutes; 9%, longer than 15 minutes; and 5%, longer than 30 minutes, or febrile status epilepticus. Although febrile status epilepticus accounts for only 5% of febrile seizures, it accounts for approximately 25% of all cases of childhood status epilepticus [Aicardi and Chevrie, 1970; DeLorenzo et al., 1996; Dodson et al., 1993; Dunn, 1988; Maytal et al., 1989; Shinnar et al., 1997] and for more than two thirds of cases of status epilepticus in the second year of life [Shinnar et al., 1997].

INITIAL EVALUATION As implied by the definition, to make the diagnosis of a febrile seizure, one must exclude meningitis, encephalitis, serious electrolyte imbalance, and other acute neurologic

illnesses. These exclusions usually are feasible and are based on a detailed history and physical and neurologic examination. The most common issue in the emergency department is whether a lumbar puncture is necessary to exclude CNS infection, particularly meningitis or encephalitis. As reported in several studies, the incidence of meningitis in children with an apparent febrile seizure is between 2% and 5% [AAP, 1996; Heijbel et al., 1980; Jaffe et al., 1981; Joffe et al., 1983; Lorber and Sunderland, 1980; McIntyre et al., 1990; Rutter and Metcalf, 1978; Rutter and Smales, 1977; Wears et al., 1986]. In all of the reported series, however, a majority of the children with meningitis had identifiable risk factors. In one series, Joffe and associates [1983] reported that the children with meningitis had one of the following four features: a visit for medical care within the previous 48 hours, seizures on arrival to the emergency room, focal seizures, or suspicious findings on physical or neurologic examination. Other authors also have found a low yield on routine lumbar puncture in the absence of risk factors [AAP, 1996; Lorber and Sunderland, 1980; McIntyre et al., 1990; Rossi et al., 1986; Wears et al., 1986]. The AAP [1996] issued guidelines for the neurodiagnostic evaluation of the child with a simple febrile seizure between the ages of 6 months and 5 years. It recommended that a lumbar puncture be strongly considered in the infant younger than 12 months of age. The child between 12 and 18 months of age needs careful assessment, because the signs of meningitis may be subtle. In the absence of suspicious findings on history or examination, a lumbar puncture is not necessary in a child older than 18 months. A lumbar puncture is still recommended in children with a first complex febrile seizure, as well as in any child with persistent lethargy. It also should be strongly considered in a child who has already received prior antibiotic therapy. A lumbar puncture also should be considered in the child older than 5 years of age who presents with an apparent first febrile seizure, to exclude the possibility of encephalitis, as well as meningitis. In the absence of suspicious findings in the history (e.g., vomiting, diarrhea) or on physical examination, routine blood cell counts and determination of serum electrolyte, calcium, phosphorus, magnesium, or blood glucose levels are of limited value in the evaluation of a child older than 6 months of age with a febrile seizure [AAP, 1996; Gerber and Berliner, 1981; Heijbel et al., 1980; Jaffe et al., 1981; Rutter and Smales, 1977]. Skull radiographs are of no value. Computed tomography (CT) scans also are of limited benefit in this clinical setting. Magnetic resonance imaging (MRI) scans are not indicated in children with a simple febrile seizure [AAP, 1996]. Whether an MRI study is indicated in the evaluation of a child with a prolonged or focal febrile seizure remains unclear [Lewis et al., 2002; Mitchell and Lewis, 2002; Rosman, 2002; VanLandingham et al., 1998]. MRIs often are clinically indicated in the diagnostic evaluation of the child who presents with status epilepticus, whether febrile or not [Dodson et al., 1993] Electroencephalograms (EEGs) are of limited value in the evaluation of the child with febrile seizures [AAP, 1996; Koyama et al., 1991; Maytal et al., 2000; Millichap, 1991; Sofianov et al., 1983, 1992; Stores, 1991]. They are more likely to be abnormal in the older child with febrile seizures

Shinnar / Febrile Seizures

and in children with a family history of febrile seizures, with a complex febrile seizure, or with preexisting neurodevelopmental abnormalities [Doose et al., 1983; Frantzen et al., 1968; Koyama et al., 1991; Millichap et al., 1960; Sofianov et al., 1983, 1992; Tsuboi, 1978]. Although EEG abnormalities may be present in these children, their clinical significance is unclear. There is no evidence that they help predict either recurrence of febrile seizures or the development of subsequent epilepsy [AAP, 1996; Doose et al., 1983; Frantzen et al., 1968; Koyama et al., 1991; Kuturec et al., 1997; Maytal et al., 2000; Millichap et al., 1960; Sofianov et al., 1983, 1992; Tsuboi, 1978]. In most cases, they are of limited clinical value in the evaluation of the child with a febrile seizure.

PATHOPHYSIOLOGY The pathophysiology of febrile seizures remains unclear. An age-specific increased susceptibility to seizures induced by fever is likely. Although it was thought that the rate of rise of the temperature was the key factor [Livingston et al., 1947], more recent data suggest that it is the actual peak temperature [Berg, 1993; Berg et al., 1995; Rantala et al., 1995]. Although, by definition, CNS infections are excluded, the nature of the illness does appear to play a role. Gastroenteritis is associated with a lower incidence of febrile seizures [Berg et al., 1995], and herpesvirus-6 and herpesvirus-7 infections have had a high reported rate of association with febrile seizures [Barone et al., 1995; Caserta et al., 1998; Hall et al., 1994; Kondo et al., 1993]. Animal models of febrile seizures also reveal an agedependent effect [Baram et al., 1997; Germano et al., 1996; Holtzman et al., 1981; Olson et al., 1984]. In addition, in vitro preparations demonstrate induction of epileptiform activity by temperature elevation in hippocampal slices in young rats [Tancredi et al., 1992]. Animal data suggest that young rats with neuronal migration disorders are more susceptible to hyperthermia-induced seizures and also are more susceptible to hippocampal damage [Germano et al., 1996]. Of interest, in this model, hippocampal damage occurs with hyperthermia even in the absence of seizures. An animal model developed by Baram and colleagues [1997] mimics the age-specific human condition and has been providing many insights into the pathophysiology and physiologic consequences of febrile seizures. In this model, febrile seizures appear to be of limbic origin [Baram et al., 1997; Chen et al., 1999; Dube et al., 2000; Toth et al., 1998]. As in humans, brief febrile seizures have no detectable anatomic or physiologic sequelae [Chen et al., 1999; Dube et al., 2000; Toth et al., 1998]. Febrile seizures lasting longer than 20 minutes, however, although not causing cell death [Toth et al., 1998], are associated with long-lasting changes in h-channels, The h-channel is the hyperpolarizationactivated cation channel, also known as the pacemaker channel, which can be either “excitatory” or “inhibitory” [Poolos, 2004]. These changes are associated with increased susceptibility to seizures, although not with spontaneous seizures [Chen et al., 1999; Dube et al., 2000]. A full review of the findings from this model is outside the scope of this chapter, and the interested reader is referred to a recent monograph on this rapidly evolving field [Baram and Shinnar, 2002].

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RELATED MORBIDITY AND MORTALITY The mortality associated with febrile seizures is extremely low. No deaths were reported from the National Collaborative Perinatal Project [Nelson and Ellenberg, 1978; 1976] or the British cohort study [Verity et al., 1985a, 1985b, 1993]. Even in cases of febrile status epilepticus, which represents the extreme end of complex febrile seizures, the mortality rates in recent series are extremely low [DeLorenzo et al., 1996; Dodson et al., 1993; Dunn, 1988; Maytal and Shinnar, 1990; Maytal et al., 1989; Shinnar et al., 2001; Towne et al., 1994; Verity et al., 1993]. In one recent report of 172 cases of febrile status epilepticus, only one death occurred, which in retrospect likely was related to Shigella encephalopathy, rather than to the febrile seizure [Shinnar et al., 2001]. Neither the National Perinatal Project nor the British studies found any evidence of permanent motor deficits after febrile seizures. This finding coincides with a recent series of febrile status epilepticus studies [DeLorenzo et al., 1996; Dunn, 1988; Maytal et al., 1989; Shinnar et al., 2001; Towne et al., 1994; Verity et al., 1993]. The cognitive abilities of children with febrile seizures have been extensively studied. No reports describe acute deterioration of cognitive abilities after febrile seizures, even when studies limited to status epilepticus are included [Dunn, 1988; Ellenberg and Nelson, 1978; Hirtz, 2002; Maytal and Shinnar, 1990; Maytal et al., 1989; Shinnar et al., 2001; Verity et al., 1993]. Cognitive abilities and school performance of children with febrile seizures were found to be similar to those of controls in three large studies [Ellenberg and Nelson, 1978; Ross et al., 1980; Verity et al., 1985b, 1993]. The Collaborative Perinatal Project found no difference in IQ scores or performance on the Wide Range Achievement Test at the age of 7 years between children with febrile seizures and their siblings [Ellenberg and Nelson, 1978]. The British National Child Development Study reported that children with febrile seizures performed as well in school at 7 and 11 years of age as their peers without a history of febrile seizures [Ross et al., 1980]. The more recent British Cohort Study also found no difference between 5 year olds with febrile seizures and 5 year olds without a history of febrile seizures on a variety of performance tasks [Verity et al., 1985b, 1993]. A recent study from Taiwan, in addition to comparing intelligence and behavior, also found no difference in memory between children with febrile seizures, including complex ones, and population-based controls [Chang et al., 2000, 2001]. This finding is of particular interest, because febrile seizures appear to be of limbic origin [Baram et al., 1997; Dube et al., 2000], and memory is subserved by the hippocampus. Even prolonged febrile seizures do not appear to be associated with adverse cognitive outcomes [Ellenberg and Nelson, 1978; Shinnar and Babb, 1997; Shinnar et al., 2001; Verity et al., 1993]. In the British Cohort Study, no differences were found between 5 year olds with and those without febrile seizures, even when the analysis was limited to complex febrile seizures [Verity et al., 1985b, 1993]. Ellenberg and Nelson [1978] examined 27 children with febrile convulsions lasting more than 30 minutes and found no differences in cognitive function at 7 years of age between them and their siblings. Insufficient data are available

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on memory function in children who experienced prolonged febrile seizures, although memory is known to be impaired in those with chronic temporal lobe epilepsy [Bell and Davies, 1998].

RECURRENT FEBRILE SEIZURES Approximately one third of children with a first febrile seizure will experience a recurrence, and 10% will have three or more febrile seizures [AAP, 1996; Annegers et al., 1990; Berg, 2002; Berg et al., 1990, 1992, 1997; Knudsen, 1985b; Nelson and Ellenberg, 1976, 1978; Offringa et al., 1992, 1994; van den Berg, 1974; Verity et al., 1985a]. Factors associated with a differential risk of recurrent febrile seizures are summarized in Table 47-1. The most consistent risk factors reported are a family history of febrile seizures and age at first febrile seizure (before age 18 months) [AAP, 1996; Annegers et al., 1990; Berg, 2002; Berg et al., 1990, 1992, 1997; Knudsen, 1985b; Nelson and Ellenberg, 1978; 1976; Offringa et al., 1992, 1994; van den Berg, 1974]. This relation appears to be due to the longer period during which a child with a younger age at onset will be in the age group at risk for febrile seizures, rather than to a greater tendency to have seizures with each specific illness [Offringa et al., 1992, 1994; Shirts et al., 1987]. In studies that examined features of the acute illness, the peak temperature [Berg et al., 1990, 1992, 1997; El-Rahdi and Banajeh, 1989; Offringa et al., 1992, 1994] and also the duration of the fever before the seizure [Berg et al., 1992, 1997] were associated with a differential risk of recurrent febrile seizures. The higher the peak temperature, the lower the chance of recurrence. In the studies by Berg and colleagues [1992, 1997], patients with a peak temperature of 101° F had a 42% recurrence risk at 1 year, compared with 29% for those with a peak temperature of 103° F and only 12% for those with a peak temperature of 105° F or greater. The shorter the duration of recognized fever, the higher the chance of recurrence. For those with a febrile seizure within an hour of recognized onset of fever, the recurrence risk at 1 year was 46%, compared with 25% for those with prior fever lasting 1 to 24 hours and 15% for those with more than 24 hours of recognized fever before the febrile seizure. The fact that those infants in whom the febrile seizure occurs at the onset of fever have the highest risk of recurrence has implications for prophylactic strategies that rely on giving medications at the onset of the febrile illness. The data regarding a family history of unprovoked seizures or epilepsy are conflicting. A large study in Rochester, Minnesota, found no difference in recurrence risk between children with a family history of epilepsy (25%) and those with no such family history (23%) [Annegers et al., 1990]. Other studies have found more equivocal results [Berg et al., 1992, 1997; Offringa, 1992, 1994]. However, even those studies that report an increased risk of recurrence in children with a family history of unprovoked seizures found only a modest increase in risk. A complex febrile seizure is not associated with an increased risk of recurrence in most studies [Annegers et al., 1990; Berg et al., 1990, 1992, 1997; Berg and Shinnar, 1996a; Nelson and Ellenberg, 1978; Offringa, 1992, 1994]. If the initial febrile seizure is prolonged, however, a recurrent febrile seizure also is

more likely to be prolonged [Berg and Shinnar, 1996a; Offringa et al., 1994]. The presence of a neurodevelopmental abnormality in the child also has not been demonstrated to be significantly associated with an increased risk of subsequent febrile seizures [Annegers et al., 1990; Berg et al., 1990, 1992, 1997; Offringa et al., 1992, 1994]. Ethnicity and gender also have not been associated with a clear differential risk of recurrent febrile seizures. Children with multiple risk factors are at highest risk for recurrence [Βerg, 2002; Berg et al., 1997; Offringa et al., 1994]. A child with two or more risk factors has a greater than 30% recurrence risk at 2 years, and the child with three or more risk factors has a greater than 60% recurrence risk [Berg et al., 1997]. By contrast, the child older than 18 months with no family history of febrile seizures who experiences a first febrile seizure associated with a peak temperature higher than 40° C after a recognized fever longer than 1 hour in duration (i.e., no risk factors) has a 2year recurrence risk of greater than 15% [Berg et al., 1997; Offringa et al., 1994].

FEBRILE SEIZURES AND SUBSEQUENT EPILEPSY Data from five large cohorts of children with febrile seizures indicate that epilepsy subsequently develops in 2% to 10% of children who experience febrile seizures [Annegers et al., 1979, 1987; Berg and Shinnar, 1996b; Nelson and Ellenberg, 1978; van den Berg and Yerushalmi, 1969; Verity and Golding, 1991]. The higher number comes from the study by Annegers and co-workers [1987], which had the longest follow-up period. In addition, in population- and community-based studies, 15% to 20% of children and adults with epilepsy have a history of prior febrile seizures [Berg et al., 1999; Camfield et al., 1994; Hammati-Haddad and Abou-Khalil, 1998; Rocca et al., 1987a, 1987b, 1987c; Sofianov et al., 1983]. In most studies, the risk of developing epilepsy after a single simple febrile seizure is not substantially different from the risk for this disorder in the general population [Annegers et al., 1979, 1987; Berg and Shinnar, 1996b; Nelson and Ellenberg, 1978; van den Berg and Yerushalmi, 1969; Verity and Golding, 1991]. The risk factors for the development of epilepsy after febrile seizures are summarized in Table 47-1. In all five studies that have examined the issue, presence of a neurodevelopmental abnormality, the occurrence of a family history of epilepsy, and the occurrence of complex febrile seizures are associated with an increased risk of subsequent epilepsy [Annegers et al., 1979, 1987; Berg and Shinnar, 1996b; Nelson and Ellenberg, 1978; van den Berg and Yerushalmi, 1969; Verity and Golding, 1991]. Two studies also have found that the occurrence of multiple febrile seizures was associated with a slightly but statistically significant increased risk of subsequent epilepsy [Annegers et al., 1987; Berg and Shinnar, 1996b]. In addition, in the one study that examined this issue, febrile seizures that occurred within 1 hour of a recognized fever (i.e., at onset) were associated with a higher risk of subsequent epilepsy [Berg and Shinnar, 1996b]. Some controversy exists regarding whether the number of complex features affects the risk of recurrence. Two studies have examined this issue in detail. Both found that

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TABLE 47-1 Risk Factors for Recurrent Febrile Seizures and for Epilepsy after a Febrile Seizure Recurrent Febrile Seizures

Epilepsy

Definite Risk Factor Family history of febrile seizures Age younger than 18 months Height of peak temperature Duration of fever

Neurodevelopmental abnormality Complex febrile seizure Family history of epilepsy Duration of fever

Possible Risk Factor Family history of epilepsy

More than one complex feature

Not a Risk Factor Neurodevelopmental abnormality Complex febrile seizure More than one complex feature Gender Ethnicity

Family history of febrile seizures Age at first febrile seizure Height of peak temperature Gender Ethnicity

Data from Annegers et al., 1979, 1987, 1990; Berg and Shinnar, 1996b; Berg et al., 1990, 1992, 1997; El-Rahdi and Banajeh, 1989; Knudsen, 1985b; Nelson and Ellenberg, 1976, 1978; Offringa et al., 1992, 1994; van den Berg, 1974; Verity and Golding, 1991.

prolonged febrile seizures (i.e., febrile status epilepticus) were associated with an increased risk of subsequent epilepsy above that for a complex febrile seizure that was less prolonged [Annegers et al., 1987; Berg and Shinnar, 1996b]. The study by Annegers and co-workers [1987], however, found that the presence of two complex features (e.g., prolonged and focal) further increased the risk of subsequent epilepsy, whereas this association was not found in the study by Berg and Shinnar [1996b]. Note that these two factors are not independent because prolonged febrile seizures are more likely to be focal [Annegers et al., 1987; Berg and Shinnar, 1996a; Chevrie and Aicardi, 1975; Shinnar et al., 2001]. Age at first febrile seizure, the height of peak temperature at first seizure, and a family history of febrile seizures, all of which are associated with a differential risk of recurrence for febrile seizures, are not associated with a differential risk of developing epilepsy (see Table 47-1) [Annegers et al., 1979, 1987; Berg and Shinnar, 1996b; Nelson and Ellenberg, 1978; Verity and Golding, 1991]. Duration of fever before the febrile seizure appears to be the only common risk factor for both recurrent febrile seizures and subsequent epilepsy [Berg et al., 1992, 1997; Berg and Shinnar, 1996b]. It may well be a marker for overall seizure susceptibility. The type of epilepsy that develops after febrile seizures is variable [Annegers et al., 1987; Berg et al., 1999; Camfield et al., 1994]. Annegers and co-workers [1987] report that in persons with generalized febrile seizures, generalized epilepsies usually develop, whereas focal epilepsies develop in those with focal seizures. This finding suggests that the febrile seizures may be an age-specific expression of seizure susceptibility in patients with an underlying seizure diathesis [Annegers et al., 1987; Shinnar and Moshe, 1991]. Febrile seizures also can be the initial manifestation of specific epilepsy syndromes, such as severe myoclonic epilepsy of infancy [Dravet et al., 2002]. In general, the types of epilepsy that occur in children with prior febrile seizures are varied and not very different from those that occur in children without such a history [Berg et al., 1999; Camfield

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et al., 1994; Sofianov et al., 1983]. Whether febrile seizures are simply an age-specific marker of future seizure susceptibility or have a causal relationship with the subsequent epilepsy remains a matter of controversy [Berg and Shinnar, 1997; Shinnar, 2003, 2002]. The weight of the epidemiologic data is against a causal association in a majority of cases. Populations with a cumulative incidence of febrile seizures of 10%, such as in Tokyo, Japan, do not have an increased incidence of epilepsy [Tsuboi, 1984]. Morevover, evidence that treatment of febrile seizures alters the risk of subsequent epilepsy is lacking [AAP, 1999; Berg and Shinnar, 1997; Knudsen et al., 1996; Rosman et al., 1993b; Shinnar and Berg, 1996; Wolf and Forsythe, 1989]. The data regarding the association between prolonged febrile seizures and subsequent epilepsy are discussed later on.

FEBRILE SEIZURES AND MESIAL TEMPORAL SCLEROSIS One of the most controversial issues in epilepsy is whether prolonged febrile seizures cause mesial temporal sclerosis [Shinnar, 2002, 2003]. Falconer [1964, 1971] described a series of 100 patients with intractable temporal lobe epilepsy, 47% of whom had mesial temporal sclerosis on pathologic review. Of the patients with mesial temporal sclerosis, 40% had a history of prolonged convulsions in infancy. Since then, a number of retrospective studies from tertiary epilepsy centers report that many adults with intractable mesial temporal lobe epilepsy had a history of prolonged or atypical febrile seizures in childhood [AbouKhalil et al., 1993; Bruton, 1988; Cendes et al., 1993a, 1993b; French et al., 1993; Sagar and Oxbury, 1987; Taylor and Ounsted, 1971]. Population-based studies, however, have failed to find this association, as have prospective studies of febrile seizures [Annegers et al., 1987; Berg and Shinnar, 1996b, 1997; Nelson and Ellenberg, 1978; van den Berg and Yerushalmi, 1969; Verity et al., 1985a, 1993]. This lack of association may be in part due to the low incidence of febrile seizures sufficiently prolonged to cause damage. Maher and McLachlan [1995] described a large family with a high rate of both febrile convulsions and temporal lobe epilepsy. The mean duration of the febrile seizures in family members in whom temporal lobe epilepsy subsequently developed was 100 minutes. VanLandingham and associates [1998] reported that, in rare cases, prolonged focal febrile seizures can be associated with mesial temporal sclerosis. A few children with prolonged (mean duration of 100 minutes) focal febrile seizures had acute changes on MRI, which in some cases were followed by later chronic changes. These MRI changes occurred in only a small minority of their patients, however. Furthermore, all cases of mesial temporal sclerosis in this study occurred in patients who had focal seizures, some of whom also had focal lesions, which raises the question of preexisting focal pathology. The frequent finding of associated heterotopias and subtle migration defects in patients with mesial temporal sclerosis and intractable complex partial seizures whose temporal lobes are resected supports this concept [Mathern et al., 1995a, 1995b; Shinnar, 1998, 2003]. Although prolonged febrile seizures may in some cases produce mesial temporal sclerosis, the epidemiologic data

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suggest that febrile seizures are not likely to account for a majority of cases of mesial temporal sclerosis. Febrile seizures lasting more than 90 minutes are rare and are uncommon even in series of patients with febrile status epilepticus [Annegers et al., 1987; Berg and Shinnar, 1996a, 1996b; Chevrie and Aicardi, 1975; Dunn, 1988; Ellenberg and Nelson, 1978; Maytal and Shinnar, 1990; Maytal et al., 1989; Nelson and Ellenberg, 1978; Shinnar et al., 2001; VanLandingham et al., 1998; Verity et al., 1993]. Prolonged febrile seizures also are usually focal [Βerg and Shinnar, 1996a; Chevrie and Aicardi, 1975; Shinnar et al., 2001; VanLandingham et al., 1998]. Note that even in cases of febrile status epilepticus, imaging abnormalities are relatively uncommon [VanLandingham et al., 1998]. Mesial temporal sclerosis also can be found in many patients who have no prior history of febrile seizures [Falconer, 1971; Falconer et al., 1964; Mathern et al., 1995a, 1995b, 1995c, 1996]. Clinicopathologic studies have provided evidence for multiple potential causes of mesial temporal sclerosis and for the frequent presence of dual pathology, such as coexistent subtle migration defects [Mathern et al., 1995a, 1995b, 1995c, 1996]. As previously discussed, in many cases febrile seizures may be an age-specific marker for future seizure susceptibility [Shinnar and Moshe, 1991]. With all of these caveats, it is increasingly clear, from both animal and human data, that prolonged febrile seizures are associated with physiologic and anatomic changes that may lead to subsequent epilepsy in some cases. More recent imaging findings suggest that as many as 30% to 40% of children with prolonged febrile seizures have acute changes on MRI [Lewis et al., 2002; Mitchell and Lewis, 2002; Shinnar, 2003]. Moreover, the presence and severity of these acute changes are predictive of subsequent anatomic mesial temporal sclerosis that may occur before the development of clinical seizures [Lewis et al., 2002; Mitchell and Lewis, 2002; Shinnar, 2003]. These findings offer an opportunity to resolve this controversy. A multicenter study is under way to prospectively address whether or not and under what circumstances prolonged febrile seizures cause mesial temporal sclerosis.

GENETICS Genetic influences clearly play a major role in febrile seizures. Children with a positive family history of febrile seizures are more likely both to experience a febrile seizure [Berg et al., 1995; Bethune et al., 1993] and to experience recurrent febrile seizures [Annegers et al., 1990; Berg et al., 1990, 1992, 1997; Nelson and Ellenberg, 1978; Offringa et al., 1992, 1994] than children without such a family history. In a study of 32 twin pairs and 673 sibling relationship cases, Tsuboi [1987] reported a concordance rate of 56% in monozygotic twins and 14% in dizygotic twins. Concordance for clinical symptoms, including age at onset and degree of fever, was higher in the twin pairs than in the sibling relationship patients. The results were consistent with a multifactorial mode of inheritance for febrile convulsions and in an analysis of the Rochester, Minnesota, data set [Rich et al., 1987]. In population-based studies, a majority of children with febrile seizures do not have a first- or second-degree relative with a history of febrile seizures [Bethune et al., 1993]. At this time, no definitive identification of a gene or locus for febrile seizures has been established. Although gene map-

ping studies have demonstrated significant linkages between risk for febrile seizures and five regions of the genome [Johnson et al., 1998; Nabbout et al., 2002; Nakayama et al., 2000; Peiffer et al., 1999; Wallace et al., 1996], the specific loci involved in determining the risk for febrile seizures have yet to be identified. It is also clear that these loci account for only a small fraction of cases of febrile seizures [Greenberg and Holmes, 2002; Racacho et al., 2000]. An autosomal-dominant mode of inheritance has been postulated for a subset of children with febrile seizures [Greenberg and Holmes, 2002; Johnson et al., 1998; Rich et al., 1987], but such cases are relatively rare. Candidate genes in these autosomal-dominant families include both sodium [Baulac et al., 1999] and γaminobutyric acid (GABA) [Wallace et al., 1996] channel mutations. A related syndrome of generalized epilepsy with febrile seizures plus also has been mapped to several different loci in different families and has been associated with mutations in both sodium and GABA channels [Baulac et al., 1999; Greenberg and Holmes, 2002; Lopez-Cendes et al., 2000; Moulard et al., 1999; Peiffer et al., 1999; Racacho et al., 2000]. Rapid advances in this area in the next 5 years are anticipated. Febrile seizures represent a good example of the interplay between genetic susceptibility and environmental factors. Most likely, all children have some increased susceptibility to seizures from fever at the specific age window. The degree of this susceptibility is influenced by a number of factors, including genetic ones. A febrile illness during the susceptibility period, however, is required for a febrile seizure to occur. Given the appropriate illness with a high enough fever, many 18-month-old infants will have a febrile seizure. Genetic influences are therefore likely to account for some but not all of the cases.

TREATMENT Treatment of febrile seizures is a controversial subject. Two major rationales for treatment have evolved, each of which leads to different approaches. The first approach is based on the old idea that febrile seizures are harmful and may lead to the development of epilepsy and is aimed at preventing febrile seizures, using either intermittent or chronic treatment with medications [Hirtz et al., 1986; Millichap, 1991; Millichap and Colliver, 1991]. The second approach is based on the epidemiologic data that febrile seizures are by and large benign. Therefore, the only concern is about prolonged febrile seizures. This singular concern leads to a therapeutic approach that does not treat brief febrile seizures [AAP, 1999; Knudsen, 2002]. Preventing or aborting prolonged febrile seizures to prevent status epilepticus with its attendant complications, however, remains a rational goal [Knudsen, 2002]. The following section reviews the current data regarding available treatments of febrile seizures and their efficacy.

Terminating a Febrile Seizure In-Hospital Management If seizure activity is ongoing when the child arrives at the emergency department, treatment to terminate the seizure is mandatory. Intravenous diazepam or lorazepam is effective in most cases [Dodson et al., 1993; Maytal and Shinnar, 1995].

Shinnar / Febrile Seizures

Rectal diazepam or diazepam gel also is appropriate for use in a prehospital setting, such as an ambulance, and in cases in which intravenous access is difficult [Camfield et al., 1989; Dodson et al., 1993; Knudsen, 1979, 2002; Morton et al., 1997]. Other benzodiazepines, such as lorazepam, also may be effective but have not been adequately studied, and their absorption properties are such that they are less suitable for rectal administration [Dodson et al., 1993; Graves et al., 1987; Knudsen 2002]. If the seizure activity continues after an adequate dose of a benzodiazepine, then a full status epilepticus treatment protocol should be used [Dodson et al., 1993; Maytal and Shinnar, 1995].

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[Autret et al., 1990; Knudsen, 1985a, 1985b; Knudsen and Vestermark, 1978; McKinlay and Newton, 1989; Rosman et al., 1993a]. Although the effect is statistically significant, it is clinically modest. In one large randomized trial comparing placebo with oral diazepam (in a dose of 0.33 mg/kg every 8 hours with fever), recurrence by 36 months was noted in 22% of the diazepam treatment group, compared with 31% of the placebo treatment group [Rosman et al., 1993a]. This modest reduction in seizure recurrence must be weighed against the side effects of sedating children every time they have a febrile illness [Knudsen, 2002].

Barbiturates

Home Management A majority of febrile seizures are brief, lasting less than 10 minutes, and no intervention is necessary. Rectal diazepam has been demonstrated to be effective in terminating febrile seizures [Camfield et al., 1989; Knudsen, 1979, 2002; Morton et al., 1997]. It is widely used in Europe, Canada, and Japan and now has been widely accepted in the United States. Now that rectal diazepam gel is available in the United States [Morton et al., 1997], use of this agent would seem a rational therapy in those situations in which acute treatment of a febrile seizure at home is appropriate [O’Dell, 2002; O’Dell et al., 2000, 2003]. This approach has the obvious advantage of minimizing drug exposure. It should be used with caution, however, and only with reliable caregivers who have been trained in its use. Candidates for this treatment include children at high risk for prolonged or multiple febrile seizures [Berg and Shinnar, 1996a; Knudsen, 2002; O’Dell, 2002] and those who live far from medical care.

Preventing a Febrile Seizure Intermittent Medications at Time of Fever Antipyretics Because febrile seizures, by definition, occur in the context of a febrile illness, aggressive treatment with antipyretic medication could be expected to reduce the risk of having a febrile seizure. In support of use of these agents, studies [Berg et al., 1995; Rantala et al., 1995] find that the risk of a febrile seizure is directly related to the height of the fever. Little evidence, however, is available to suggest that antipyretic agents reduce the risk of a recurrent febrile seizure [Knudsen, 2002]. In one study, a group of patients who received aggressive antipyretic therapy had a 25% risk of recurrence [Camfield et al., 1980]. Another study found that 50% of children who experienced a febrile seizure had received antipyretic medication before the seizure [Rutter and Metcalf, 1978]. The children in whom the febrile seizure occurs at the onset of the fever have the highest risk of recurrent febrile seizures [Berg et al., 1992, 1997]. Recommendations for antipyretic therapy should recognize its limitations and avoid creating undue anxiety and feelings of guilt in the parents [Knudsen, 2002; O’Dell, 2002].

Benzodiazepines Diazepam given orally or rectally at the time of onset of a febrile illness will reduce the probability of a febrile seizure

Intermittent therapy with phenobarbital at the onset of fever is ineffective in reducing the risk of recurrent febrile seizures [Knudsen, 2002; Pearce et al., 1977; Wolf et al., 1977]. Nevertheless, it is still fairly widely used for this purpose [Hirtz et al., 1986; Millichap, 1991; Millichap and Colliver, 1991].

Daily Medications Barbiturates Phenobarbital, given daily at doses that achieve a blood level of 15 μg/mL or higher, was effective in reducing the risk of recurrent febrile seizures in several well-controlled trials [Anthony and Hawke, 1983; Bacon et al., 1981; Camfield et al., 1980; Herranz et al., 1984; Knudsen and Vestermark, 1978; McKinlay and Newton, 1989; Newton, 1988]. In those studies, however, a substantial proportion of the children demonstrated adverse effects, primarily hyperactivity, that required discontinuation of therapy [AAP, 1995; Camfield et al., 1979; Wolf and Forsythe, 1978]. More recent studies have cast some doubt on the efficacy of the drug in this setting and, of greater importance, have raised concerns about potential long-term adverse effects on cognition and behavior [AAP, 1995; Farwell et al., 1990]. Prolonged phenobarbital therapy is rarely indicated because the risks seem to outweigh the benefits in most cases [AAP, 1999; Knudsen, 2002].

Valproate Daily treatment with valproic acid also has been found to be effective in reducing the risk of recurrent febrile seizures in both human and animal studies [Herranz et al., 1984; McKinlay and Newton, 1989; Newton, 1988; Olson et al., 1984]. It is rarely used, however, because the children who would be considered most often for prophylaxis (young and/or neurologically abnormal) also are the ones at highest risk for fatal idiosyncratic hepatotoxicity [AAP, 1999; Dreifuss et al., 1987, 1989; Knudsen, 2002].

Other Antiepileptic Drugs Although benzodiazepines have been used in intermittent therapy, experience with chronic use for treatment of febrile seizures is lacking. These agents may well be effective, but their toxicity and adverse effect profile preclude widespread use in this setting. Phenytoin and carbamazepine are ineffective in preventing recurrent febrile seizures in humans and in animal models of hyperthermia-induced seizures [Anthony and Hawke, 1983; Bacon et al., 1981; Camfield et al., 1982; Olson et al., 1984]. Published data are

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lacking on the efficacy of the newer antiepileptic drugs, such as gabapentin, lamotrigine, levetiracetam, topiramate, tiagabine, vigabatrin, or zonisamide, in the treatment of febrile seizures. Although on a theoretical basis some of these drugs would be expected to have efficacy in preventing recurrent febrile seizures, available data are insufficient to justify their use in this setting. Moreover, long-term antiepileptic drug therapy is rarely indicated in the treatment of febrile seizures [AAP, 1999; Knudsen, 2002].

Preventing Epilepsy One reason often given for treating febrile seizures is to prevent future epilepsy [Hirtz et al., 1986; Millichap, 1991; Millichap and Colliver, 1991]. Unfortunately, prevention of febrile seizures has not been found to reduce the risk of subsequent epilepsy. Three studies comparing placebo with treatment, either with daily phenobarbital or with diazepam administered at the onset of fever, demonstrated that treatment significantly and substantially reduced the risk of febrile seizure recurrence [Knudsen, 1985b; Rosman et al., 1993a; Wolf et al., 1977]. In all three studies, the risk of later development of epilepsy was no lower in the treatment groups than in the control groups [Knudsen et al., 1996; Rosman et al., 1993b; Shinnar and Berg, 1996; Wolf and Forsythe, 1989]. Two of these studies include more than 10 years of follow-up and found no difference between the treatment group and the control group in the occurrence of epilepsy or in school performance and other cognitive outcomes [Knudsen et al., 1996; Wolf and Forsythe, 1989]. In general, antiepileptic drugs are effective in lowering the risk of a recurrent seizure, whether febrile or afebrile, but are ineffective in preventing the development of subsequent epilepsy, whether in the setting of febrile seizures [AAP, 1999; Shinnar and Berg, 1996] or acute post-traumatic seizures [Temkin et al., 1990] or after a first unprovoked seizure in childhood [Hirtz et al., 2003; Musicco et al., 1997]. Their lack of efficacy in altering long-term prognosis has considerably diminished the enthusiasm for use of these agents for febrile seizures.

who have just experienced a frightening and traumatic event [O’Dell, 2002]. Many parents are afraid that their child could have died [Baumer et al., 1981]. Parents need to be reassured that the child will not die during a seizure and that keeping the child safe during the seizure generally is the only action that needs to be taken. The basic facts about febrile seizures should be presented to the family [O’Dell, 2002]. The recommended amount of information and level of content depend in large part on the medical sophistication of the parents and on their ability to attend to the information given them at that particular time. The parents’ perception of their child’s disorder will be an important factor in their later coping and will ultimately affect their perception of quality of life. Parents usually will be interested in information that will help them manage the illness or specific problems; lengthy explanations usually are not helpful. It also is important for the physician to provide information about how to manage further seizures should they occur. This includes what should be done during a seizure, when it may be necessary to call the physician, and when the child should be taken to the emergency department. In those cases in which rectal diazepam or rectal diazepam gel is being recommended for a subsequent seizure, explicit instructions regarding its use should be given. Because it is difficult to absorb all of this information in an emergency department setting, it usually is advisable for the physician to see the family again a few weeks later, to review the information and answer any additional questions. Febrile seizures are a common and mostly benign form of childhood seizures. An understanding of the natural history and prognosis will enable the physician to reassure the families of affected children and to provide appropriate counseling and management while avoiding unnecessary diagnostic and therapeutic interventions. More studies are needed on the outcome of prolonged febrile seizures and their optimal treatment. Advances in basic science, genetics, and imaging are providing new insights into this common pediatric disorder that continues to be the subject of active research.

Guidelines for Therapy Febrile seizures, although a frightening event, usually are benign. Treatment is only rarely indicated for a simple febrile seizure [AAP, 1999]. Even in most children with complex febrile seizures or recurrent febrile seizures, no treatment is needed [Knudsen, 2002]. In view of the available data, a rational goal of therapy would be to prevent prolonged febrile seizures. Therefore, when treatment is indicated, particularly in children at risk for prolonged or multiple febrile seizures [Berg and Shinnar, 1996a] or those who live far from medical care, use of rectal diazepam or diazepam gel at the time of seizure as an abortive agent would seem the most logical choice [Camfield et al., 1989; Dodson et al., 1993; Knudsen, 1979, 2002; Maytal and Shinnar, 1995; Morton et al., 1997; O’Dell, 2002; O’Dell et al., 2000, 2003].

COUNSELING AND EDUCATION In a majority of cases, counseling and education will be the sole treatment. Education is key to empowering the parents,

ACKNOWLEDGMENT Supported in part by grant IR01 NS43209 (S. Shinnar) from the National Institute of Neurological Disorders and Stroke, Bethesda, MD.

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Stores G. When does an EEG contribute to the management of febrile seizures? Arch Dis Child 1991;66:554. Tancredi V, D’Arcangelo G, Zona C, et al. Induction of epileptiform activity by temperature elevation in hippocampal slices from young rats: An in vitro model for febrile seizures? Epilepsia 1992;33:228. Taylor DC, Ounsted C. Biological mechanisms influencing the outcome of seizures in response to fever. Epilepsia 1971;12:33. Temkin NR, Dikmen SS, Wilensky AJ, et al. A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures. N Engl J Med 1990;323:497. Toth Z, Yan XX, Haftoglou S, et al: Seizure-induced neuronal injury: Vulnerability to febrile seizures in immature rat model. J Neurosci 1998;18:4285. Towne AR, Pellock JM, Ko D, et al. Determinants of mortality in status epilepticus. Epilepsia 1994;35:27. Tsuboi T. Correlation between EEG abnormality and age in childhood. Neuropediatrics 1978;9:229. Tsuboi T. Epidemiology of febrile and afebrile convulsions in children in Japan. Neurology 1984;34:175. Tsuboi T. Genetic analysis of febrile convulsions: Twin and family studies. Hum Genet 1987;75:7. van den Berg BJ. Studies on convulsive disorders in young children. III. Recurrence of febrile convulsions. Epilepsia 1974;15:177. van den Berg BJ, Yerushalmi J. Studies on convulsive disorders in young children, I. Incidence of febrile and nonfebrile convulsions by age and other factors. Pediatr Res 1969;3:298. VanLandingham KE, Heinz ER, Cavazos JE, Lewis DV. MRI evidence of hippocampal injury following prolonged, focal febrile convulsions. Ann Neurol 1998;43:413. Verity CM, Butler NR, Golding J. Febrile convulsions in a national cohort followed up from birth. I. Prevalence and recurrence in the first 5 years of life. BMJ 1985a;290:1307. Verity CM, Butler NR, Golding J. Febrile convulsions in a national cohort followed up from birth. II. Medical history and intellectual ability at 5 years of age. BMJ 1985b;290:1311. Verity CM, Golding J. Risk of epilepsy after febrile convulsions: A national cohort study. BMJ 1991;303:1373. Verity CM, Ross EM, Golding J. Outcome of childhood status epilepticus and lengthy febrile convulsions: Findings of national cohort study. BMJ 1993;307:225. Wallace RH, Berkovic SF, Howell RA, et al. Suggestion of a major gene for familial febrile convulsions mapping to 8q13-21. J Med Genet 1996;33:308. Wallace SJ. They don’t do very well. Pediatrics 1980;65:678. Wears RL, Luten RC, Lyons RG. Which laboratory tests should be performed on children with apparent febrile convulsions? An analysis and review of the literature. Pediatric Emerg Care 1986;2:191. Wolf SM, Carr A, Davis DC, et al. The value of phenobarbital in the child who has had a single febrile seizure: A controlled prospective study. Pediatrics 1977;59:378. Wolf SM, Forsythe A. Behavior disturbance, phenobarbital and febrile seizures. Pediatrics 1978;61:728. Wolf SM, Forsythe A. Epilepsy and mental retardation following febrile seizures in childhood. Acta Paediatr Scand 1989; 78:291.

CHAPTER 48

Status Epilepticus Lawrence D. Morton and John M. Pellock

Typically, seizures are brief and self-limited. Considerable research and conjecture have been directed at efforts to explain the mechanisms underlying seizure termination, as well as perpetuation, as in status epilepticus. Status epilepticus is a pediatric and neurologic emergency associated with significant morbidity and mortality [Dodson et al., 1993; Mitchell, 1996; Pellock, 1993a, 1994; Towne et al., 1994; Weise and Bleck, 1997; Wilson and Reynolds, 1990]. Its prompt recognition and management lead to the best chance for successful outcome. Status epilepticus occurs in children and adults and may represent the brain’s reaction to an acute insult, or it may be a manifestation of already existing epilepsy, either as the initial symptom or as a prolonged exacerbation of seizures [DeLorenzo et al., 1992, 1995, 1996]. Although the definition and classification of status epilepticus have been changed numerous times, the term refers to seizures that continue for a prolonged period. Studies suggest that status epilepticus frequently goes unrecognized, and that its occurrence has been underestimated in the general population [Treiman, 1993]. This chapter reviews the pathophysiology, definition, classification, epidemiology, etiology, treatment, and prognosis of status epilepticus as it occurs in children. The mortality associated with status epilepticus is greater in adults than in children, but morbidity and mortality in children are considerable without treatment. Accordingly, optimal management includes prompt recognition, appropriate medical therapy, and investigation for the cause of the episode, followed by correction of the underlying abnormality if possible [Pellock and DeLorenzo, 1997].

PATHOPHYSIOLOGY The biochemical basis and pathophysiology underlying the means by which chronic seizures evolve to status epilepticus remain unclear [Lowenstein and Alldredge, 1998; Pellock, 1994; Wasterlain et al., 1993]. Because of the loss of inhibitory mechanisms, neuronal metabolism is unable to keep up with the metabolic demands of continuing ictal activity. The pathophysiologic changes that accompany status epilepticus can be divided into neuronal (cerebral) and systemic effects. Continuing seizures lead to biochemical changes within the brain, as well as systemic pathology, both of which further complicate these cerebral changes. Glutamate is the primary excitatory amino acid neurotransmitter and binds to several neuronal receptors including the N-methyl-D-aspartate (NMDA) receptor, which is activated by depolarization. The resulting calcium influx causes further depolarization, thereby perpetuating seizures. Glutamate also activates receptors that open channels that conduct sodium and calcium into the cell. Through this

excessive excitatory neurotransmission, further neuronal damage results. In experimental animal models, glutamate also may act to perpetuate seizures. Using a paired pulse method in a continuous hippocampal stimulation–induced status epilepticus model, NMDA receptors become activated during continuous hippocampal stimulation, and NMDA antagonists block the deterioration of γ-aminobutyric acid (GABA)-mediated inhibition [Kapur and Lothman, 1990]. Endogenous potentiation of NMDA receptor function by means of mass reduction of redox sites hs been proposed as a possible mechanism to facilitate transition to status epilepticus. In addition, redox-active compounds may have therapeutic use by reversing NMDA receptor–mediated pathophysiologic changes without blocking normal NMDA receptor function [Sanchez et al., 2000]. In a model of selfsustaining status epilepticus, the seizures are enhanced by substance P and abolished by NMDA receptor antagonists [Wasterlain et al., 2000]. Other work demonstrates a role for the neuropeptide galanin, which can suppress seizure activity [Mazarati et al., 1998]. GABA is the most prevalent inhibitory neurotransmitter in the brain. GABAA receptors are postsynaptic ionotropic receptors that bind directly to chloride channels, producing a fast inhibitory postsynaptic potential (IPSP). GABAB receptors exist both postsynaptically and presynaptically. GABAB is a metabotropic receptor exercising a slower response. The postsynaptic receptors lead to a slow IPSP, whereas the presynaptic GABAB receptors may allow feedback inhibition of GABAA and paradoxically cause seizures. Excessive GABA may in fact increase activity on GABAA receptors and on both pre- and postsynaptic GABAB receptors. Additionally, in animal models, investigators studied GABAA receptor currents by whole-cell patch-clamp techniques in CA1 pyramidal neurons acutely dissociated from rats undergoing lithium/pilocarpine-induced limbic status epilepticus and from naive rats [Kapur and Coulter, 1995]. The GABAA receptor current was absent in 47% of status eptilepticus neurons and reduced in 55% of the remainder, compared with naive neurons, thus aiding in seizure perpetuation. Other neurotransmitters that may be important in the initiation and maintenance of status epilepticus include acetylcholine, adenosine, and nitric oxide [Fountain and Lothman, 1995]. Neuronal injury and cell death from status epilepticus are most prominent in areas rich in NMDA glutamate receptors, including the limbic region. The increase in intracellular calcium is critical to cell death, and calcium activates proteases and lipases that degrade intracellular elements, leading to mitochondrial dysfunction and fatal cellular necrosis. Laminar necrosis and neuronal damage after prolonged seizures are similar to those after cerebral hypoxia. Although

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young animals may be less likely to develop brain damage from status epilepticus [Holmes, 1997; Moshè, 1987], studies using alternative models demonstrate hippocampal cellular injury even in immature rodents [Sankar et al., 1997; Thompson and Wasterlain, 1994]. It is believed that the glutamate-initiated calcium-dependent cascade is mechanistically similar to the NMDA receptor-mediated cell death occurring during cerebral ischemia. In status epilepticus, degree of neuronal injury is related to seizure duration. The exact role of glutamate remains unclear, because elevated extracellular concentrations of glutamate have not been demonstrated in the brain during prolonged seizures, even when neuronal injury was profound in experimental animals [Tanaka et al., 1996], whereas a case report in an adult patient noted focal increases of glutamate seen on proton magnetic resonance spectroscopy [Fazekas et al., 1995]. Status epilepticus likely associated with excessive inhibitory influences, such as absence status, is modulated by GABAB-mediated hyperpolarization and activation of folinic T-type calcium channels [Fountain and Lothman, 1995]. Recent work indicates that the alpha 4 subunit of the GABAA receptor complex may be involved in the maintenance and termination of absence seizure activity in the γ-hydroxybutyrate animal model of absence seizures [Banerjee et al., 1995]. Absence status epilepticus does not appear to cause permanent neurologic damage [Drislane, 1999]. Furthermore, recent evidence suggests that acute and long-term changes in gene expression may occur after prolonged seizures. These changes in the expression of messenger RNA (mRNA) may lead directly to some of the observed hyperexcitability [Rice and DeLorenzo, 1998]. In animal studies using adolescent baboons, induced status epilepticus lasting 1.5 to 5 hours produced neuronal loss in the hippocampus, cerebellum, and neocortex. Significant cell loss continued to occur, although to a lesser extent if the animals were paralyzed and ventilated with maintenance of oxygen, carbon dioxide, serum glucose, body temperature, and blood pressure [Meldrum, 1974, 1983]. Similar changes have been produced in rat models as well [Cavalheiro et al., 1987; Sperber et al., 1989]. Generalized convulsive status epilepticus is associated with serious systemic effects resulting from the metabolic demands of prolonged seizures and the autonomic changes that accompany them: alterations in blood pressure and heart rate, incontinence, emesis, acidosis, hypoxia, changes in respiratory function and body temperature, leukocytosis, rhabdomyolysis, and extreme demands on cerebral oxygen and glucose use [Simon et al., 1997]. Circulating catecholamines increase during the initial 30 minutes of status epilepticus, resulting in a hypersympathetic state. Tachycardia, sometimes associated with more severe cardiac dysrhythmias, occurs and may be fatal, but this seems more common in adults [Boggs et al., 1993]. Cardiac output also diminishes, and total peripheral resistance increases, along with mean arterial blood pressure, perhaps because of the sympathetic overload. Hyperpyrexia may become significant during the course of status epilepticus even without prior febrile illness in both children and adults. Fever may influence the process of neuronal injury [Liu et al., 1993]. In addition, serum pH and glucose levels frequently are abnormal because lactic acidosis increases from increased anaerobic metabolism. Associated respiratory acidosis also

may occur as a result of hypoventilation, hypoxia, and pulmonary edema. An increase in the peripheral white blood cell count frequently occurs in the absence of infection. Rhabdomyolysis may compromise renal function. Thus, the cerebral physiologic changes linked to status epilepticus are accompanied by increased metabolic demand for oxygen and glucose and are further complicated by a variety of systemic changes along with the pathology responsible for status epilepticus. As the cascade of neurophysiologic changes occurs, increased lactate from anaerobic metabolism continues, and excitatory neurotransmitters bombard cells, which accelerates metabolic activity and leads to overall neuronal failure. Recovery from this complicated derangement of metabolism is time dependent; more prolonged seizures produce further neuronal injury and death. The question of whether episodes of status epilepticus worsen the risk and severity of subsequent epilepsy remains controversial [Berg and Shinnar, 1997]. Unlike in adults, in whom biology is more static, the effect of growth and development influences the impact of seizures both in clinical presentation and in the biologic consequences for the developing brain. Most of our knowledge derives from animal models, so its applicability to the human situation is unclear. Experimental models of seizures in immature animals suggest comparatively less vulnerability to seizure-induced brain injury than in mature animals [Wong and Yamada, 2001]. Repetitive or prolonged neonatal seizures may increase the susceptibility of the developing brain to experience subsequent seizure-induced brain injury later in life. This susceptibility appears to be more closely related to alterations in neuronal connectivity and network properties, rather than to increased cell death during the neonatal period [Holmes et al., 1998; Koh et al., 1999; Schmid et al., 1999]. Altered receptor function and changes in representation effect both seizure representation and consequences in the neonatal brain. GABAA receptors are heteromeric protein complexes that mediate most fast synaptic inhibition in the forebrain and have many distinct subtypes. Adult rats that develop epilepsy following pilocarpine-induced status epilepticus and adult patients with refractory temporal lobe epilepsy demonstrate significant alterations in GABAA receptor properties in hippocampal dentate granule neurons [Gibbs et al., 1997; Brooks-Kayal et al., 1998, 1999]. In rat pups exposed to pilocarpine-induced status epilepticus, different changes are seen in α1 subunit expression and augmentation compared with those in adult rats. This produced the opposite effect and may serve to enhance inhibition; the rat pups did become epileptic, unlike the adult rats who developed recurrent spontaneous seizures [Zhang et al., 2004]. Nevertheless, changes in the function of the immature GABAA receptor, from the dual role of excitatory-inhibitory to inhibitory as the rat matures in infancy, may contribute to increased excitability and hence more seizure susceptibility in the neonate [(Khazipov et al., 2004]. Additionally, alteration in glutamate receptor representation may alter seizure susceptibility. AMPA receptors are overrepresented in the premature brain in the oligodendrocytes initially; later they shift their main representation to neurons in the cortex and hippocampus. This condition may partly explain increased risk of periventricular leukomalacia in the preterm infant and increased seizure susceptibility in the term infant [Jensen, 2002]. Rats exposed to early-life seizures demonstrate persistent changes in CA1 hippocampal pyramidal cells, possibly

Morton and Pellock / Status Epilepticus

leading to long-term changes in behavior and learning and epileptogenicity [Villeneuve et al., 2000].

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BOX 48-1 PROPOSED CLASSIFICATION OF STATUS EPILEPTICUS Partial

DEFINITION Status epilepticus is best considered as a state produced by continuous or repetitive seizures that has the potential to produce significant systemic or neuronal injury if not aborted. This definition, however, does not provide a clinically useful treatment guideline. Descriptions of status epilepticus were recorded as early as the first millennium BC on Babylonian cuneiform tablets [Wilson and Reynolds, 1990]. The first modern description is attributed to the French physician Calmeil in his observations of an “état de mal” in the early 19th century [Calmeil, 1824]. Clark and Prout [1904] described status epilepticus as “the maximum development of epilepsy, in which one paroxysm so closely follows another that the coma and exhaustion are continuous between seizures.” Status epilepticus is internationally classified as a seizure lasting for more than 30 minutes or recurrent seizures lasting for more than 30 minutes from which the patient does not regain consciousness [ILAE, 1981]. The World Health Organization previously defined status epilepticus as “a condition characterized by epileptic seizures that is so frequently repeated or so prolonged as to create a fixed and lasting condition” [Gastaut, 1982]. Lack of recovery for a fixed period, possible frequent repetition, prolongation, and possible propagation of further seizures are inherent in this definition. In the past, the definition of status epilepticus required 1 hour of continuous seizures, but more recent studies have used a 30-minute duration of continuous or recurrent seizures without full recovery as the standard clinical and electrographic definition of status epilepticus. The more recent clinical trend has been to define status epilepticus with shorter times. Lowenstein and associates proposed an “operational” definition of 5 minutes or more of continuous seizures or “two discrete seizures between which there is incomplete recovery of consciousness” in adults and children older than 5 years of age [Lowenstein et al., 1999]. This definition applies primarily to generalized convulsive status epilepticus and may be used to direct treatment to avoid refractory status epilepticus, as well as any sequelae. Aggressive early treatment is justified by recent work demonstrating a 10-fold decrease in mortality for seizures of 10 to 29 minutes in duration versus those lasting longer than 30 minutes [DeLorenzo et al., 1999]. Because of the difficulty in diagnosing and quantifying seizures in the neonate, no broadly accepted definition of status epilepticus in the neonate exists. A proposed definition is either 30 minutes of continuous electroencephalographic seizures or presence of seizure activity for 50% of the electroencephalographic recording time, with or without the expression of coincident clinical signs (Scher et al., 1993b).

CLASSIFICATION Any type of seizure may become prolonged and thus develop into status epilepticus (Box 48-1). Classification of status epilepticus should be performed by observing the clinical events and combining electrographic information

Convulsive Tonic Hemiclonic status epilepticus, hemiconvulsionhemiplegia-epilepsy Clonic Hemi–grand mal, status epilepticus, grand mal Nonconvulsive Simple Focal motor status, focal sensory, epilepsia partialis continuans, adversive status epilepticus Complex partial Epileptic fugue state, prolonged epileptic stupor, prolonged epileptic confusional state, temporal lobe status epilepticus, psychomotor status epilepticus, continuous epileptic twilight state Generalized Convulsive Tonic-clonic Grand mal, epilepticus convulsivus Tonic Clonic Myoclonic Myoclonic status epilepticus Nonconvulsive Absence Spike-and-wave stupor, spike-and-slow-wave or 3/second spike-and-wave status epilepticus, petit mal, epileptic fugue, epilepsia minora continua, epileptic twilight state, minor status epilepticus Undetermined Subtle Epileptic coma Neonatal Erratic status epilepticus when possible. The fundamental distinction between seizures is that some are generalized from onset, whereas others are partial in onset. The latter type may or may not then secondarily generalize. Partial-onset seizures are thought to originate from a single cortical focus and spread from that area, whereas seizures that are generalized from the onset seem to involve the entire cortex simultaneously. Status epilepticus characterized by seizures generalized from onset occurs more frequently in children. Partial seizures that evolve to status epilepticus are clinically noted to be secondarily generalized convulsive seizures and may occur at any age but probably account for an overwhelming majority of adult cases. Classification of patients in whom status epilepticus is characterized by only partial or subtle clinical signs (i.e., nonconvulsive status epilepticus), even though the seizures are associated with marked impairment of consciousness and bilateral ictal discharges on the electroencephalogram (EEG), is controversial [Pellock and DeLorenzo, 1997]. Treiman uses the term subtle generalized convulsive status epilepticus to describe this condition [Treiman, 1990, 1993; Treiman et al., 1990]. These patients have severe encephalopathies stemming from a variety of intracranial processes or prolonged uncontrolled convulsive seizures. This type of status epilepticus is manifested clinically by the occurrence of mild motor movements, such as nystagmus, or by clonic twitches, which may be unilateral and are intermittent, brief, and without a true sequential pattern. These subtle movements are associated with marked impairment of conscious-

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ness, usually with continuous bilateral EEG ictal patterns. These continuing electrographic seizures that are not accompanied by clinical manifestations demonstrate a true “electroclinical dissociation” and may be seen not only in neonates but also in severely ill children and adults [Mizrahi and Kellaway, 1987; Scher et al., 1993a]. Treiman described a sequential progression of EEG and clinical manifestations that can lead to and be associated with subtle status epilepticus [Treiman, 1993; Treiman et al., 1990]. Initially, discrete electrographic and clinical seizures are noted. Discrete seizures give way to and merge with a waxing and waning ictal pattern evident both clinically and on EEG. The patient typically demonstrates less wellformed seizure activity, and the EEG progressively becomes uniform to produce a pattern of continuous ictal discharges, which then becomes interrupted by periods of relative flatness and then severe cortical depression. Some controversy exists as to whether those patients with EEG recordings exhibiting only periodic epileptiform discharges require aggressive treatment to prevent the possibility of progressive epileptic brain damage, beyond that caused by the underlying encephalopathy. In general, these patients respond poorly to traditional treatment with antiepileptics; more aggressive treatments in these very ill patients may lead to severe hypotension and cardiac dysrhythmias. Nonconvulsive status epilepticus also may include complex partial, simple partial, and absence seizures that continue for more than 30 minutes [Kaplan, 1996; Scholtes et al., 1996; Stores et al., 1995]. Complex partial status epilepticus may be manifested as an epileptic twilight state marked by a cyclic variation between periods of partial responsiveness and episodes of seemingly motionless staring and complete unresponsiveness accompanied, at times, by automatic behavior [Delgado-Escueta and Treiman, 1987; Privitera, 1997; Scher et al., 1993a; Treiman, 1993]. Simple partial status epilepticus is characterized by focal seizures that may persist or be repetitive for at least 30 minutes without impairment of consciousness. When this condition lasts for hours or days, it is termed epilepsia partialis continua [Cockerell et al., 1996; Takahashi et al., 1997]. Absence, or petit mal, status also has been referred to as spike-wave stupor. This type of nonconvulsive status epilepticus may be extremely difficult to differentiate from complex partial status epilepticus without the aid of an EEG. Classical features of absence status include a continuous alteration of consciousness without the cyclic variations seen with complex partial status epilepticus [Grin and DiMario, 1998]. The EEG recording exhibits prolonged, sometimes continuous, generalized synchronous 3-Hz spikeand-wave complexes, rather than focal ictal discharges, which characterize partial status epilepticus [Porter and Penry, 1983; Treiman, 1993]. The child presenting with a prolonged confused state, with a fluctuating level of consciousness or with prolonged unconsciousness, may require both clinical and EEG evaluations in addition to other studies. Myoclonic, generalized clonic, and generalized tonic status epilepticus occur primarily in children. These children usually have encephalopathic epilepsies [Lockman, 1990; Pellock, 1994; Treiman, 1993], and their consciousness is preserved throughout the attacks. The EEG pattern is bilaterally symmetric, with polyspike discharges coinciding with the myoclonic jerks. The term myoclonic status epilepticus should not be used when children with severe

encephalopathy exhibit repetitive myoclonic jerks not accompanied by ictal discharges on EEG. These patients have subtle, generalized, convulsive status epilepticus as defined by Treiman [1993]. About one half of the cases of generalized clonic status epilepticus occur in normal children, in whom it is associated with prolonged febrile seizures; the remaining half of the cases are distributed among those children with acute and chronic encephalopathies [DeLorenzo et al., 1992]. Generalized tonic status epilepticus appears most frequently in children, particularly those with the Lennox-Gastaut syndrome. Prolonged generalized tonic convulsions have been precipitated by benzodiazepine administration. Debate continues regarding what constitutes a neonatal seizure. Neonatal seizures can be broken down into three categories: electroclinical, electrographic, and clinical only. Controversy still exists about whether episodic abnormal movements seen in some infants, not accompanied by simultaneous ictal discharges on the EEG, are true seizures. Many neonatal paroxysmal events classified as “subtle seizures” have no EEG correlate (Mizrahi and Kellaway, 1998). Typical subtle seizures include movements of progression, such as bicycling, oral-buccal-lingual movements such as chewing and tongue thrusting, and other movements such as random eye movements. Other movements that typically have no EEG correlate include generalized tonic posturing. Movements typically demonstrating simultaneous ictal discharges on EEG include focal clonic, multifocal clonic, and focal tonic; myoclonic movements may or may not have an EEG correlate (Mizrahi and Kellaway, 1998). This topic is discussed in Chapter 13.

EPIDEMIOLOGY A prospective population-based study of status epilepticus revealed the incidence of status epilepticus to be 41 patients per year per 100,000 population, resulting in 50 episodes of status epilepticus per year per 100,000. It is projected that between 102,000 and 152,000 events occur in the United States annually, an incidence 2 to 2 –21 times greater than that previously proposed by Hauser [1990], who reported that status epilepticus occurs annually in 50,000 to 60,000 persons in the United States [DeLorenzo et al., 1996; Hauser et al., 1990]. Approximately one third of cases manifest as the initial seizure of developing epilepsy, one third occur in patients with previously established epilepsy, and one third occur as the result of an acute isolated brain insult. Among those previously diagnosed as having epilepsy, estimates of status epilepticus occurrence range from 0.5% to 6.6%. Hauser reported that up to 70% of children who have epilepsy that begins before the age of 1 year will experience an episode of status epilepticus [Hauser, 1990]. Also, within 5 years of the initial diagnosis of epilepsy, 20% of all patients will experience an episode of status epilepticus. Although the subsequent development of epilepsy is likely in adults with status epilepticus as their first unprovoked seizure [Hauser et al., 1990], a prospective study of children with status epilepticus found only a 0.3 probability that epilepsy will develop later in those who initially presented with status epilepticus [Maytal et al., 1989]. Among children, status epilepticus is most common in infants and young toddlers, with more than 50% of cases of

Morton and Pellock / Status Epilepticus

status epilepticus occurring in children younger than 3 years of age [Shinnar et al., 1995]. In the Richmond, Virginia, study, total status epilepticus events and incidence per 100,000 population per year demonstrated a bimodal distribution, with the highest values during the first year of life and during the decades beyond 60 years of age [DeLorenzo et al., 1992, 1995, 1996]. Infants younger than 1 year of age represent a subgroup of children with the highest incidence of status epilepticus whether events, total incidents, or recurrence is counted. The recurrence rate for status epilepticus in the Richmond study was 10.8% [DeLorenzo et al., 1996], but 38% of patients younger than 4 years of age had repeat episodes. Extrapolating these figures worldwide suggests that more than 1 million cases of status epilepticus occur annually. Because this condition is a neurologic emergency that requires immediate, effective treatment to prevent neurologic complications or death, status epilepticus poses a substantial health risk. Mortality rates as high as 50% have been reported, but children have a much lower mortality rate than that in adults. The highest mortality rate is seen in the elderly [Hauser, 1990; Hauser et al., 1990; Maytal et al., 1989; Towne et al., 1994]. Multiple studies confirm the lower mortality rate in children after adequate emergency treatment [Dunn, 1988; Maytal et al., 1989; Pellock, 1993b; Phillips and Shanahan, 1989; Shinnar et al., 1995]. Age, etiology, and duration directly correlate with mortality [DeLorenzo et al., 1996; Towne et al., 1994].

ETIOLOGY Status epilepticus usually is a manifestation of an acute precipitating event that affects the central nervous system (CNS) or an exacerbation of symptomatic epilepsy. Less than 10% of cases of status epilepticus in adults and children are truly idiopathic in that no precipitating or associated cause can be identified [DeLorenzo et al., 1995, 1996]. Acute symptomatic causes are those most commonly associated with prolonged status epilepticus lasting for longer than 1 hour [DeLorenzo et al., 1996]. Thus, a full evaluation for etiology must be undertaken in every case of

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status epilepticus [Dodson et al., 1993; Pellock, 1994]. In patients with preexisting epilepsy, a precipitating or associated factor may be clearly identified. Identification of this factor may help in treating this episode of status epilepticus, preventing further consequences of status epilepticus, and perhaps preventing future recurrences. Although typically a precipitant to status epilepticus can be identified, a genetic susceptibility may predispose certain persons to develop prolonged seizures in response to an acute insult. Recent work in twins demonstrated a higher incidence in monozygotic twins than in dizygotic twins, providing evidence for a genetic contribution to the risk for status epilepticus [Corey et al., 2004]. Seizure type and specific epilepsy syndrome may differ between monozygotic twins, however, and status epilepticus may not be a function of the seizure type or syndrome experienced by each person. A clear difference between causative disorders of status epilepticus in children and those in adults has been identified (Table 48-1) [Dodson et al., 1993; Pellock and DeLorenzo, 1997]. The major cause of status epilepticus in children is that associated with fever secondary to non-CNS infections. Inadequate antiepileptic drug levels and remote causes, including congenital malformations, also account for a significant number of episodes of status epilepticus in children, although some studies have found that patients may have reasonable drug levels when status epilepticus occurred [Maytal et al., 1996]. Of note, many patients with subtherapeutic levels of antiepileptic drugs closely followed the instructions of their physicians and recently had drug-dosage alterations. The distribution of causes associated with status epiepticus in children is highly age dependent [Shinnar et al., 1995]. More than 80% of children younger than 2 years of age have status epilepticus from a febrile or acute symptomatic cause, whereas cryptogenic or remote symptomatic causes were more common in older children. By contrast, in adults, subtherapeutic levels of antiepileptic drugs, remote causes, and cerebrovascular accidents represent the three most common causes of status epilepticus [Pellock and DeLorenzo, 1997]. In adults, status epilepticus resulting from remote causes occurred primarily in relation to stroke,

TABLE 48-1 Cause and Mortality Data for Status Epilepticus in Children and Adults PEDIATRIC CASES

ADULT CASES

ETIOLOGIC DISORDER/CONDITION

% of Cases

Mortality Rate (%)

% of Cases

Mortality Rate (%)

Anoxia Hypoxia Cerebrovascular accident Hemorrhage Tumor Infection CNS infection Metabolic Low antiepileptic drug level Drug overdose Alcohol withdrawal Trauma Remote Idiopathic

0 5 10 0 0 52 2 7 21 2 0 0 38 5

0 0 0 0 0 5 0 0 0 0 0 0 0 0

5 13 22 1 7 7 3 15 34 3 13 3 25 3

71 53 33 0 30 10 0 30 4 25 20 25 14 25

CNS, central nervous system. From Pellock JM, DeLorenzo RJ. Status epilepticus. In: Porter RJ, Chadwick D, eds. The epilepsies 2. Boston: Butterworth-Heinemann, 1997;267.

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FIGURE 48-1. Age-specific distribution of the frequency of status epilepticus events, the incidence of status epilepticus, and the frequency of status epilepticus recurrence per year per 100,000 population in Richmond, Virginia. The population in each group was determined from the National Census Bureau data on the demographics of Richmond, 1990. Status epilepticus events included all episodes of status epilepticus per 100,000 population per year. The incidence of status epilepticus represents the number of patients per 100,000 in whom status epilepticus developed in Richmond and did not include recurrent episodes of status epilepticus. (Reprinted from DeLorenzo RJ, Hauser WA, Towne RA, et al. A prospective, population-based study of status epilepticus in Richmond, Virginia. Neurology 1996;46:1029.)

so that both acute and previously occurring strokes account for a significant proportion of adult episodes of status epilepticus. Stroke is the etiologic disorder in approximately 10% of childhood status epilepticus episodes, either as the primary acute cause or as a remote event. Risk factors related to EEG or neuroimaging abnormalities have been reported in certain series [Novak et al., 1997], and in other situations, genetic factors also may contribute to the risk for developing status epilepticus [Corey et al., 1998]. Recurrence rates for status epilepticus are age specific, as illustrated in Figure 48-1. Repeat occurrences are much more common in children younger than 1 year of age. In the prospective Richmond study of status epilepticus, pediatric, adult, and elderly recurrence rates were 35%, 7%, and 10%, respectively [DeLorenzo et al., 1996]. Recurring status epilepticus is more frequent in children with remote symptomatic encephalopathy or progressive degenerative disease [DeLorenzo et al., 1995, 1996]. The extent of clinical and laboratory evaluation that should be performed in each child with recurrent status epilepticus will depend on the presentation, signs and symptoms, and underlying medical condition of the patient. For example, a child with recurring status epilepticus who has an indwelling shunt for hydrocephalus will almost always need to be evaluated for the possibility of shunt malfunction or infection.

MANAGEMENT AND THERAPY Overview Status epilepticus is a neurologic and medical emergency and requires maintenance of respiration, general medical support, and specific treatment aimed at stopping both electrographic and clinical seizures while the cause of the event is investigated [Epilepsy Foundation of America,

1993]. Prompt diagnosis and management provide the best outcome [DeLorenzo, 1990; Pellock, 1993a, 1993b, 1994; Pellock and DeLorenzo, 1997; Rider and Thapa, 1995; Treiman, 1993]. Continuous repetitive seizures occurring within a set period of time should provide the clinical diagnosis of status epilepticus. For purposes of studies, a 30-minute time span has been selected as the definition of status epilepticus. In clinical practice, a 10- to 15-minute duration of seizures may be a more reasonable criterion for initiation of emergency treatment [DeLorenzo et al., 1999; Pellock, 1994; Pellock and DeLorenzo, 1997; Treiman, 1993]. A single generalized convulsion in a child with a prolonged period of impaired consciousness is much more difficult to diagnose, and an EEG should be obtained urgently. If ongoing ictal discharges or electrographic seizures are noted, the patient should be considered to be in electrographic status epilepticus, and prompt treatment is indicated. The goals of status epilepticus emergency management are listed in Box 48-2. Clinical and electrographic seizure activity must be rapidly terminated while ensuring optimal oxygenation and metabolic balance. Both clinical and electrical seizure activity should be terminated as soon as possible [Treiman, 1990]. The longer an episode of status epilepticus continues, the more likely it is to result in permanent neurologic damage and to become refractory to treatment [DeLorenzo, 1990; DeLorenzo et al., 1996; Hauser, 1990; Pellock and DeLorenzo, 1997; Towne et al., 1994; Treiman, 1990; Treiman et al., 1992, 1994]. Rapid initiation of care is essential to ensure the best possible outcome. Increased seizure duration commonly is regarded as an important factor contributing to increased morbidity and mortality. Prolonged seizures of any type are associated with an increased risk of complications [Lowenstein et al., 1999]. In a study in adults and children, the mortality rate in status epilepticus was 34.8% when seizures lasted longer than 1 hour, compared with 3.7% when seizure duration was less than 1 hour [DeLorenzo et al., 1992]. Therefore, limiting the time from seizure onset to initial treatment and attainment of control is essential to minimize the complications of prolonged seizures. In a retrospective study, patients with status epilepticus may not arrive at the emergency department for 30 minutes or longer, and treatment initiation may not occur for 40 to 263 minutes, thereby increasing risk for prolonged seizures [Jordan, 1994]. The

BOX 48-2 GOALS OF EMERGENCY MANAGEMENT FOR STATUS EPILEPTICUS • Ensure adequate brain oxygenation and cardiorespiratory function. • Terminate clinical and electrical seizure activity as rapidly as possible. • Prevent seizure recurrence. • Identify precipitating factors, such as hypoglycemia, electrolyte imbalance, lowered drug levels, infection, and fever. • Correct metabolic imbalance. • Prevent systemic complications. • Further evaluate and treat cause of status epilepticus. From Pellock JM, DeLorenzo RJ. Status epilepticus. In: Porter RJ, Chadwick D, eds. The epilepsies 2. Boston: Butterworth-Heinemann, 1997:267.

Morton and Pellock / Status Epilepticus

Veterans Affairs Cooperative Study reported that the mean delay before treatment of status epilepticus was 2.8 hours in generalized convulsive status epilepticus and 5.8 hours in subtle status epilepticus; this study involved exclusively adult patients [Treiman et al., 1998]. In a prospective study of 889 patients (625 adults, 264 children), 41.5% received treatment within 30 minutes and 70.9% within 60 minutes of seizure onset; 18.1% did not have treatment initiated until after 90 minutes of seizures. This latter group of patients, however, included patients in coma diagnosed with subtle or nonconvulsive status epilepticus [Pellock et al., 2004].

Supportive Care In children in status epilepticus, cardiorespiratory function must be assessed immediately by vital sign determination, auscultation, airway inspection, and determination of arterial blood-gas concentrations, with suctioning when necessary. Although these children may appear to be breathing spontaneously on arrival at the emergency department, they may already be hypoxic, with respiratory and metabolic acidosis, apnea, aspiration, or central respiratory depression. The need for ventilatory support depends not only on the respiratory status at the time of presentation but also on the conditions before arrival and the ability to maintain adequate oxygenation throughout the ongoing seizures and during the intravenous administration of large doses of antiepileptic drugs, all of which may cause respiratory depression. In the neurologically depressed patient, elective intubation and respiratory support are recommended. Placement of an oral airway or nasal oxygen cannula will prove to be insufficient in most patients, because respiratory drive is depressed [Pellock, 1994]. Respiratory arrest and depression are principal factors contributing to morbidity and mortality [DeLorenzo et al., 1996]. Rapidly assessing vital signs and performing a general neurologic examination may provide clues to the etiology of status epilepticus.

Laboratory Testing Blood should be drawn for the determination of blood gases, glucose, calcium, electrolytes, complete blood count, and antiepileptic drug levels, as well as for cultures (bacterial and viral) and toxicologic studies to help with the overall determination of etiology. Urine drug and metabolic screening should be performed whenever the etiology cannot be determined. As previously noted, the most common etiologic or associated factor found in children with status epilepticus is intercurrent infection. In a small number of these children, the clinical presentation will include manifestations similar to the initial symptoms of CNS infection. Lumbar puncture should be done early in the course of management, although not necessarily during the initial phase of stabilization [Rider et al., 1995]. In most children, only rarely should the clinician wait to obtain neuroimaging studies before performing a lumbar puncture. Hyperpyrexia may become significant during the course of status epilepticus even in the absence of a febrile illness. Rectal temperatures should be monitored and fever aggressively treated; significant elevations of temperature may contribute to brain damage [Dodson et al., 1993]. Bradyarrhythmias are commonly noted in children when large doses of antiepileptic drugs are administered. In adults,

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changes range from evidence of myocardial ischemia to tachyarrhythmia [Boggs et al., 1993, 1994; Tigaran et al., 1997]. These are less frequently noted in children. In children with known congenital heart disease or dysrhythmias, electrocardiographic monitoring must be implemented and continued.

Use of Neuroimaging The decision to perform neuroimaging studies in the child presenting with status epilepticus needs to be individualized according to the available history, general physical and neurologic examination findings, and the possibility of significant structural intracranial pathology or increased intracranial pressure, or the presence of lateralizing findings. Although guidelines have been published on the role of neuroimaging in the patient presenting with a seizure in the emergency department [Practice parameter, 1996], consensus guidelines are lacking concerning when neuroimaging should be done in the patient with status epilepticus. In cases in which status epilepticus is the initial presentation of a seizure disorder, it is appropriate to perform imaging studies to look for cerebral dysgenesis or dysplasia, atrophy, tumor, vascular malformations, and so on. Often, magnetic resonance imaging (MRI) findings may be normal. A growing literature recognizes peri-ictal changes on neuroimaging and their significance. Local and immediate findings have been described in children. Local swelling of the hippocampus has been described in children with prolonged febrile convulsions [Scott et al., 2002; VanLandingham et al., 1998]. At follow-up evaluation in some patients, edema later appeared atrophic [Scott et al., 2002]. Focal edema with effacement of gyri [Silverstein and Alexander, 1998] can develop, with subsequent atrophy [Meierkord et al., 1997]. This finding appears to represent cytotoxic edema; in animal models, increased lactate has been found, and this increase correlates with the degree of histologic damage [Najm et al., 1998}. More confounding is the finding of lesions remote from the ictal focus. The lesions may be remote in time, such as in cases in which transient lesions develop days after status epilepticus [Hisano et al., 2000], or remote anatomically. These remote lesions typically are associated with transient focal findings on examination, such as weakness [Hisano et al., 2000] or personality changes. Lesions in the splenium have been associated with psychiatric disease [Cole, 2004].

Use of Electroencephalographic Monitoring EEG monitoring allows optimal management of status epilepticus and should be used whenever available. EEG monitoring is extremely useful, but underutilized, in initial and subsequent management of status epilepticus [Jaitly et al., 1994; Pellock, 1993a, 1993b; Pellock and DeLorenzo, 1997; Treiman, 1993]. Classification of seizure type and evidence regarding etiology and prognosis may be determined from the EEG. Especially useful are the findings in patients with hysterical attacks and those associated with medication overdoses or focal pathologic entities [Dodson et al., 1993; Sonnen, 1997]. In children with prolonged coma or confusional states, nonconvulsive status epilepticus can sometimes be diagnosed only with the use of EEG recordings. Researchers in one study used EEG to diagnose status epilepticus in 37% of patients with altered consciousness

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whose diagnosis was unclear clinically [Privitera et al., 1994]. In another study, 8% of coma patients met the criteria for nonconvulsive status epilepticus [Towne et al., 2000]. EEG can help to confirm that an episode of status epilepticus has ended. When use of neuromuscular blocking agents is contemplated or when recurrence of seizures cannot be documented by clinical observation (i.e., because of coma or large doses of medication), EEG monitoring is mandatory. Electroclinical dissociation may result from the administration of large doses of antiepileptic drugs in newborns and older children. In one study, 50% of patients continued to experience electrographic seizures with no clinical correlate in the 24 hours following cessation of status epilepticus [DeLorenzo et al., 1998]. Patients with status epilepticus who fail to recover rapidly and completely should be monitored with EEG for at least 24 hours after an episode to ensure that recurrent seizures are not missed. The presence of periodic discharges in these patients suggests the possibility of preceding status epilepticus, and careful monitoring may clarify the etiology of these discharges and allow detection of recurrent status epilepticus. Conversely, patients whose clinical status has not returned to baseline may have abnormal movements or postures that without EEG monitoring may lead to overtreatment [Ross et al., 1999]. The EEG may provide prognostic information as well. The presence of periodic epileptiform discharges during or after status epilepticus is associated with a higher risk of poor outcome [Nei et al., 1999]. Additionally, in refractory status epilepticus in children, outcome was poorer with multifocal or generalized abnormalities than with a focal abnormality on the initial EEG [Sahin et al., 2001].

Medical Therapy Treatment should begin with placement of an intravenous line. Fluid restriction is rarely necessary. In children, immediately after placement of the intravenous line, 25% glucose (2 to 4 mL/kg) should be given by bolus. In adolescents and adults, the intravenous line typically is kept open with normal saline, and the patient is given 100 mg of thiamine, followed by 50 mL of 50% glucose by slow intravenous push if hypoglycemia is suspected [Pellock and DeLorenzo, 1997; Treiman, 1993]. Whenever the intravenous route cannot be established, the intraosseous route can be used efficiently for fluid and medication administration [Orlowski et al., 1990]. The most frequent error committed in the treatment of status epilepticus is the initial administration of inadequate doses of an antiepileptic drug. This suboptimal regimen is then followed by a waiting period until more seizures occur before administration of the necessary total dose [Dodson et al., 1993; Pellock and DeLorenzo, 1997]. Management of status epilepticus is best accomplished by use of a predetermined protocol in most settings [Pellock, 1994; Pellock and DeLorenzo, 1997; Treiman, 1990]. In almost all situations in which it is medically possible, drugs should be administered intravenously to ensure the most rapid delivery of maximal doses to the brain. The ideal antiepileptic drug for the treatment of status epilepticus should optimally have the following properties: (1) rapid onset of action; (2) wide spectrum of activity; (3) intravenous preparation; (4) ease of administration; (5) minimal redistribution from the CNS; (6) short elimination half-life; and (7) wide therapeutic safety margin [Pellock, 1993a].

TABLE 48-2 Medical College of Virginia Status Epilepticus Treatment Protocol for Children* ELAPSED STEP TIME† 1

0 to 5 min

2 3 4

6 to 9 min 10 to 30 min 31 to 59 min

5

60 min

6

61 to 80 min

PROCEDURE Determination of status epilepticus. As soon as the diagnosis is made, institute monitoring of temperature, blood pressure, pulse, and respirations, plus ECG and EEG monitoring. Insert oral airway and administer oxygen if necessary. Insert an intravenous catheter and draw venous blood for checking levels of antiepileptics, glucose (using Dextrostix), electrolytes, calcium, BUN, CBC. Perform frequent suction. Place an intravenous line with normal saline. Administer a bolus of 50% glucose 2 mL/kg. Initial treatment consists of an infusion of intravenous lorazepam given at a rate of 1 to 2 mg/minute (0.1 mg/kg) to a maximum dose of 8 mg. This treatment is followed by intravenous phenytoin (fosphenytoin) 18 to 20 mg/kg, infused at a rate not to exceed 1 mg/kg/min or 50 mg/minute. Monitor ECG and blood pressure. May repeat phenytoin (fosphenytoin) 10 mg/kg before proceeding to next step. If seizures persist, administer a bolus infusion of phenobarbital at a rate not to exceed 50 mg/minute until seizures stop or to a loading dose of 20 mg/kg. If control is still not achieved, other options include the following: (1) Midazolam with an initial intravenous loading dose of 0.15 mg/kg followed by a continuous infusion of 1 to 2 μg/kg/minute, titrating every 15 minutes to produce seizure control on EEG. Treatment typically is for 12 to 48 hours. (2) Pentobarbital with an initial intravenous loading dose of 5 mg/kg with additional amounts given to produce a burst-suppression pattern on EEG. Maintenance of pentobarbital anesthesia is continued for approximately 4 hours by an infusion of 1 to 5 mg/kg/hour. The patient is then checked for the reappearance of seizure activity by decreasing the infusion rate. If clinical seizures and/or generalized discharges persist on EEG, the procedure is repeated; if not, the pentobarbital is gradually withdrawn over 12 to 24 hours. If seizures still are not controlled, call the anesthesia department to begin general anesthesia with halothane and neuromuscular blockade.

*Note: Continuous monitoring of EEG is recommended in an obtunded patient to ensure that status epilepticus has not recurred. For management of intractable cases, a neurologist who has expertise in status epilepticus should be consulted, and advice from a regional epilepsy center should be sought. Lumbar puncture should be performed as soon as possible, especially in a febrile child or infant younger than 1 year of age. For infants with a history of neonatal seizures, infantile spasms, or early-onset seizures, pyridoxine 100 mg should be administered intravenously while EEG monitoring is being performed, for both diagnosis and treatment of seizures due to a vitamin B6 deficiency (a rare cause). †Time from beginning of intervention. BUN, blood urea nitrogen; CBC, complete blood count; D5W, 5% dextrose in water; ECG, electrocardiogram; EEG, electroencephalogram. Adapted from Pellock JM, DeLorenzo RJ. Status epilepticus. In: Porter RJ, Chadwick D, eds. The epilepsies 2. Boston: Butterworth-Heinemann, 1997;267.

Morton and Pellock / Status Epilepticus

Rapid onset of action and bioavailability of parenteral forms have made benzodiazepines the preferred initial agents for treatment of status epilepticus. Lorazepam has become popular in many centers as the initial agent because of its overall advantages over diazepam of rapid onset of action and longer pharmacologic effect [Appleton et al., 1995; Pellock, 1994; Pellock and DeLorenzo, 1997; Treiman, 1990]. When status epilepticus continues after the initial dose of benzodiazepines is administered and persists after a primary antiepileptic drug, such as phenytoin, fosphenytoin, or phenobarbital, is given, a second benzodiazepine dose should be administered before changing to an alternative antiepileptic drug. A protocol currently used for the management of status epilepticus in children by investigators at the Medical College of Virginia of Virginia Commonwealth University is outlined in Table 48-2 [Pellock and DeLorenzo, 1997]. Similar protocols are becoming universally accepted. Recently, in the United Kingdom a committee investigating ideal therapy for status epilepticus in children recommended a protocol using a rapid-onset medication such as a benzodiazepine after initial stabilization, followed by phenytoin or phenobarbital, and then, if necessary, an anesthetic [Appleton et al., 2000]. The choice of the optimal pharmacologic agent may not be identical for every patient with status epilepticus. Benzodiazepines and phenytoin (or fosphenytoin) as initial therapy are preferred by some clinicians, but others may wish to use alternative agents if the patient is known to be on maintenance therapy or already has received smaller doses of phenytoin or phenobarbital [Holmes, 1990; Pellock and DeLorenzo, 1997]. Lorazepam, diazepam, phenytoin or fosphenytoin, and phenobarbital are accepted agents for initial and continued therapy of status epilepticus. The large status epilepticus treatment study done in adults and sponsored by the U.S. Veterans Administration compared four intravenous drug regimens: (1) diazepam 0.15 mg/kg plus phenytoin 18 mg/kg, (2) lorazepam 0.1 mg/kg, (3) phenobarbital 15 mg/kg, and (4) phenytoin 18 mg/kg. The first three regimens were found to be superior to phenytoin alone for initial management of generalized convulsive status epilepticus [Treiman et al., 1994]. The choice of an initial agent may depend on individual patient characteristics, prior antiepileptic drug therapy, and physician preference. Intravenous lorazepam and intravenous diazepam have been found to be of equal efficacy in children [Qureshi et al., 2002], but intravenous lorazepam has a longer half-life and less respiratory depression [Appleton et al., 1995; Treiman et al., 1998]. The availability of a rectal preparation provides an alternative when intravenous access cannot be obtained.

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Intubation is less often required with rectal diazepam than with intravenous diazepam, and seizure recurrence is reduced [Diekmann, 1994]. Diazepam rectal administration may be used in many out-of-hospital settings for patients with recurrent status epilepticus, prolonged seizures, or acute repetitive seizures [Camfield et al., 1989; Dooley, 1998; Pellock, 1998]. Although midazolam is rarely used in the United States for initial treatment of status epilepticus, it is efficacious and offers alternative administration routes. Unlike other benzodiazepines, midazolam is water soluble, allowing for intramuscular injection. The intramuscular administration of midazolam may be particularly useful when intravenous access is unavailable or for prehospital treatment. A prospective, randomized study compared intramuscular midazolam with intravenous diazepam in the emergency department. In evaluating time to seizure control after administration, a 4-minute difference favoring midazolam was found [Chamberlain et al., 1997]. Nasal administration is possible, but absorption may be affected by nasal secretions [Wallace, 1997]. Liquid midazolam is rapidly absorbed through the buccal mucosa and is as effective as rectal diazepam [Scott et al., 1999]. Availability of two new forms of these medications is altering the approach to the treatment of status epilepticus. Fosphenytoin is a water-soluble prodrug of phenytoin delivered in a neutral pH solution [Browne, 1997; Leppik et al., 1987; Ramsay and DeToledo, 1996]. This prodrug likely will replace the present injectable phenytoin preparation [Pellock, 1996]. Dosing is safe at 150 mg/minute (3 mg/kg/minute), a rate three times more rapid than that for phenytoin. Fosphenytoin is quickly converted to phenytoin by systemic phosphatases, and higher unbound phenytoin peak levels are more rapidly attained after the intravenous infusion of fosphenytoin than with the older phenytoin preparation. Studies of infants and children furthermore demonstrate no significant difference among conversion rates for infants, children, and adults [Morton et al., 1997a]. Fosphenytoin is administered in “phenytoin equivalents” to obtain similar phenytoin levels, so that 20 mg/kg of fosphenytoin administered is the derived amount of phenytoin equal to a dose of 20 mg/kg of phenytoin. This compound does not cause local irritation or tissue destruction and therefore may be given intramuscularly or intravenously. Intramuscular administration of fosphenytoin may be of particular advantage because it allows expeditious initiation of therapy when intravenous access is not available and prehospital treatment in other settings. Recommended doses for intravenous administration of medications for the treatment of status epilepticus are given

TABLE 48-3 Recommended Initial Intravenous Doses for Status Epilepticus PATIENT AGE

Lorazepam (0.1 mg/kg)

ANTILEPTIIC DRUGS (mg) Diazepam (0.3 mg/kg) Phenobarbital (20 mg/kg)

Phenytoin/fosphenytoin (20 mg/kg)

Younger than 6 months 6 to 12 months 1 to 5 years 5 to 12 years 13 years and older

0.3 to 1 0.5 to 1.2 0.8 to 2.5 1.5 to 6 3 to 6

1 to 2 2 to 4 3 to 10 5 to 15 10 to 20

60 to 200 100 to 250 160 to 250 300 to 1200 500 to 1500+

60 to 200 100 to 250 160 to 500 300 to 1200 500 to 1500+

Modified from Pellock JM. Status epilepticus. In: Dodson WE, Pellock JM, eds. Pediatric epilepsy, diagnosis and therapy. New York: Demos, 1993b.

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in Table 48-3 [Pellock, 1993a]. Recommended doses for fosphenytoin are identical to those for phenytoin in mg/kg phenytoin equivalent units. Rectal diazepam is administered according to age and weight. Based on the long history of use of rectal diazepam in Europe, as well as experience in the United States and Canada, the following dosages are recommended: age 2 to 5 years, 0.5 mg/kg/dose; age 6 to 11 years, 0.3 mg/kg/dose; and age 12 years and older, 0.2 mg/kg/dose. These dosages yield an effective minimum plasma concentration of approximately 150 to 500 ng/mL [Morton et al., 1997b]. Valproate (valproic acid) is useful in the management of both generalized and partial epilepsy and particularly useful in absence status epilepticus [Holle et al., 1995; Pellock, 1993a]. In the past, administration of valproate by the oral, nasogastric, or rectal route followed benzodiazepine administration. The U.S. Food and Drug Administration approved intravenous valproate for use in 1997. Although the drug is not approved for treatment of status epilepticus, reports of effective and rapid seizure control with good tolerability have been published. In one study of 20 patients with generalized and partial motor seizures, 15 mg/kg of valproate achieved control within 30 minutes [Czapinski and Terczynski, 1998]. Several studies have been carried out in children demonstrating efficacy in a wide variety of seizures using loading doses of 20 to 40 mg/kg [Campistol et al., 1999; Kian-Ti et al., 2003; Uberall et al., 2000]. In addition, recent work has confirmed that intravenous valproate may be infused rapidly at rates of up to 6 mg/kg/minute; the drug was well tolerated, with no significant infusion site reactions or systemic side effects— specifically, no dysrhythmias, hypotension, or respiratory suppression [Venkataraman and Wheless, 1999]. Its role in the treatment of status epilepticus is being defined [Devinsky et al., 1995]. Intravenous valproate conveys some advantages over intravenous phenobarbital: lack of sedation, lack of respiratory suppression, and low risk of hypotension. In addition, valproate may be the drug of choice in certain seizures or a second-line agent for use after administration of a benzodiazepine. In one study of patients with recurrent episodes of absence status epilepticus as a manifestation of their primary generalized epilepsy, chronic therapy with valproate markedly reduced seizure recurrence [Berkovic et al., 1989]. This benefit also has been seen with the intravenous formulation [Alehan et al., 1999; Chez et al., 1999; Uberall et al., 2000]. Also reported is a case series indicating its utility in myoclonic status epilepticus [Sheth and Gidal, 2000; Wheless, 2003]. Some recent reports have found topiramate to be efficacious in treating refractory status epilepticus in adults and children. Topiramate was safe and well tolerated, with sedation being the primary adverse effect [Kahriman et al., 2003; Towne et al., 2003]. Its role is unclear but clearly limited by the lack of a commercially available parenteral formulation. Status epilepticus resistant to therapy with these first-line agents requires urgent treatment with agents that depress cerebral activity. Refractory status epilepticus usually is treated with continuous intravenous anesthesia maintained by pentobarbital, midazolam, or propofol. The dose is regulated to control all clear-cut clinical or electrographic seizures and to maintain a suppression-burst pattern on the EEG. Therefore, continuous bedside EEG monitoring is indicated. Consensus is lacking regarding the duration of “burst” and

“flat” periods for optimal dosing [Krishnamurthy and Drislane, 1999]. Most investigators consider that establishing and maintaining any degree of suppression-burst pattern constitute an adequate therapeutic effect. Continuous infusion of high-dose pentobarbital most commonly is used [Eriksson and Koivikko, 1997; Kinoshita et al., 1995; Pellock and DeLorenzo, 1997] (see Table 48-2). Continuous benzodiazepine infusion with diazepam, midazolam [Chamberlain et al., 1997; Lal Koul et al., 1997; Nordt and Clark, 1997], or lorazepam also may be used. Continuous infusion with midazolam has been demonstrated to be as efficacious as pentobarbital infusion, but with overall fewer cardiovascular adverse effects [Gilbert et al., 1999; Holmes and Riviello, 1999; Igartua et al., 1999]. The choice depends on the practitioner’s level of comfort with the various agents, as well as their specific treatment-related complications. Propofol anesthesia [Harrison et al., 1997; Singhi et al., 1998; Stecker et al., 1998] also has been effective. Of concern, however, is that it may be proconvulsant in some patients [Makela et al., 1993], and a more recent retrospective study reported a high mortality rate with use of this regimen in refractory status epilepticus [Prasad et al., 2001].

MEDICAL COMPLICATIONS OF STATUS EPILEPTICUS The treatment of status epilepticus requires close monitoring of physiologic variables and excellent nursing to prevent secondary complications [Pellock, 1993b, 1994; Treiman, 1993]. Besides underlying or precipitating disease states associated with status epilepticus, other medical complications are quite common. Pulmonary care, proper positioning, and careful observation of seizures to note possible changes in seizure pattern are mandatory. Constant maintenance of intravenous fluids with adequate glucose and electrolyte administration with appropriate corrections, particularly in neonates and small infants, is essential. Optimal oxygenation, expectant observation, and treatment for hyperthermia and other medical complications lead directly to a lessening of morbidity and mortality. Cardiovascular, respiratory, and renal effects may be severe. Medical complications of status epilepticus that may occur in both infants and older children are listed in Box 48-3. When hyperthermia is resistant to rectally administered antipyretics and cooling blankets, use of neuromuscular blocking agents may be necessary. EEG monitoring is necessary when these agents are used. A physiologic rise in blood pressure may accompany seizures but rarely requires antihypertensive medications unless the child is at risk for malignant hypertension. Treatment, unfortunately, may result in hypotension and reduced cerebral perfusion pressure. Very infrequently does cerebral edema or increased intracranial pressure become problematic in most children with status epilepticus that is not associated with an intracranial mass. Use of osmotic diuretics and corticosteroids is rarely indicated in the treatment of status epilepticus.

PROGNOSIS Status epilepticus is recognized as a medical and neurologic emergency because of the associated significant morbidity

Morton and Pellock / Status Epilepticus

BOX 48-3 MEDICAL COMPLICATIONS OF STATUS EPILEPTICUS Tachycardia Bradycardia Cardiac dysrhythmia Cardiac arrest Conduction disturbance Congestive heart failure Hypertension Hypotension Altered respiratory pattern Pulmonary edema Renal tubular necrosis Lower nephron nephrosis Rhabdomyolysis Increased creatine kinase Myoglobinuria Carbon dioxide narcosis Intravascular coagulation Metabolic and respiratory acidosis Cerebral edema Excessive perspiration Dehydration Endocrine failure Altered pituitary function Elevated prolactin Elevated vasopressin Hyperglycemia Hypoglycemia Increased plasma cortisol Autonomic dysfunction Fever Modified from Pellock JM. Status epilepticus. In: Pellock JM, Meyer EC, eds. Neurologic emergencies in infancy and childhood, 2nd ed. Boston: Butterworth-Heinemann, 1993.

and mortality. Common sequelae of status epilepticus include intellectual dysfunction, permanent neurologic deficits, and continuing recurrent seizures. Neuropathologic studies in animals have demonstrated that prolonged electrical activity results in irreversible neuronal damage to the CNS [Meldrum, 1983]. Experimental studies suggest that seizures lasting for less than 30 to 60 minutes may produce neuronal injuries that are reversible. Seizures lasting longer than 1 hour produce neuronal death [Meldrum, 1983; Simon, 1985]. As noted previously, prolonged seizures are associated with inadequate blood flow, decreased glucose use and oxygen consumption, and increased excitatory amino acid release, all of which lead to impaired mitochondrial function and neuronal destruction [Dwyer et al., 1986; Lothman, 1990; Wasterlain, 1983]. The duration of the status epilepticus episode, the patient’s age, and the causative disorder all influence the resultant insult to involved neuronal populations. In the aforementioned prospective population-based epidemiologic study, the annual incidence of status epilepticus was 41 cases per 100,000 population, and the annual incidence of total status epilepticus episodes was 50 per 100,000. The mortality rate was 22%, suggesting that for the approximately 126,000 to 195,000 status epilepticus events, 22,000 to 42,000 deaths per year will occur in the United States. A

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majority of patients with status epilepticus have no previous history of epilepsy. The highest mortality rate is among the elderly, and the lowest is seen in healthy children or those with febrile status epilepticus [van Esch et al., 1996]. Although the overall mortality is extremely low in pediatric patients, younger children are at highest risk, with a mortality rate of 17.8% for those younger than 1 year in one study [Morton et al., 2001]. Mortality in these children typically is associated with specific underlying disorders, such as severe brain damage secondary to hypoxia. Recurrences of status epilepticus are common in young children. These patients usually have chronic neurologic disabilities. In those patients who die, death rarely occurs during the acute episode of status epilepticus. Rather, most deaths occur 13 to 30 days after onset of the status epilepticus episode. Children with epilepsy and low antiepileptic drug levels have the lowest mortality rate. One reason for the low mortality rate in children is that they are less likely than adults to have systemic diseases. In the elderly, cardiovascular decompensation occurring during the stress of status epilepticus may play an important role in the higher mortality in this age group [Boggs et al., 1993, 1994]. The morbidity associated with status epilepticus in children was examined in this same database from Virginia [Fortner et al., 1993]. Before their status epilepticus event, 81% of children with no prior seizures were neurologically normal, in contrast with only 31% of children with seizure histories. Of the neurologically normal children with no prior seizures, more than 25% deteriorated after their first status epilepticus event, in comparison with less than 15% of neurologically normal children with a seizure history. Children who were neurologically abnormal without prior seizures deteriorated less frequently (6.7%), compared with 11.3% of the children who were neurologically abnormal who had a seizure history. In some children, neurologic deficits, such as mild ataxia, incoordination, or mild motor deficits, are transient. Symptoms usually can be attributed to the acute therapies or clinical changes after prolonged seizures. Determining whether language deficits or school performance difficulties will be transient or more permanent is much more difficult. A previous retrospective study yielded a high rate of morbidity of nearly 30%, suggesting a sampling bias [Fortner et al., 1993]. In a prospective study, only 11% to 15% of affected patients had significant morbidity after an episode of status epilepticus [Morton et al., 1998]. These more recent findings suggest that the neurologic morbidity is substantially lower than the “greater than 50%” rate previously reported in children with status epilepticus [Aicardi and Chevrie, 1987]. The morbidity and mortality rates in sick infants, however, are higher than those in older children [Morton et al., 1998]. Patients with refractory status epilepticus represent a special population at particularly high risk for mortality and morbidity. Status epilepticus typically is diagnosed when seizures have persisted for longer than 60 minutes and have not responded to use of three or more medications. Several series have demonstrated mortality rates ranging from 16% to 32% [Gilbert, 1999; Kernitsky et al., 2002; Sahin et al., 2001; Singhi et al., 1998]—much higher than the rate typical for childhood status epilepticus of approximately 3% [DeLorenzo et al., 1996; Maytal et al., 1989; Towne et al., 1994]. In addition, the morbidity rate was quite high in this

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population, with 34% experiencing developmental deterioration after refractory status epilepticus [Sahin et al., 2001]. Status epilepticus constitutes a neurologic emergency that must be treated aggressively. Children may suffer significant morbidity and mortality associated with status epilepticus. In addition to treating the seizures, the clinician must investigate the cause of status epilepticus and design specific treatments depending on the etiology. An emergency status epilepticus treatment and evaluation plan should be established and followed to ensure expedited care. Antiepileptic agents, although successful in treating a majority of status epilepticus cases, are not completely successful, and new agents must be developed. In addition, since status epilepticus has detrimental effects systemically (e.g., ventilation, blood pressure, cardiac), future therapies may well include agents that provide systemic as well as nervous system protection to decrease the morbidity and mortality associated with status epilepticus. Rapid recognition and treatment of status epilepticus offer the best opportunity to improve the outcome in those afflicted with this worldwide neurologic emergency. REFERENCES Aicardi JF, Chevrie JJ. Convulsive status epilepticus in infants and children: A study of 239 cases. Epilepsia 1987;11:187. Alehan F, Morton LD, Pellock JM. Treatment of absence status with intravenous valproate. Neurology 1999;52: 889. Appleton R, Sweeney A, Choonara I, et al. Lorazepam versus diazepam in the acute treatment of epileptic seizures and status epilepticus. Dev Med Child Neurol 1995;37:682. Appleton R, Choonara I, Martland T, et al. The treatment of convulsive status epilepticus in children. The Status Epilepticus Working Group. Arch Dis Child 2000;83:415. Banerjee PK, Tillakaratne NJK, Brailowsky S, et al. g-Hydroxybutyrate (GHB)-induced absence-like seizures decrease the expression of GABAA receptor a4 mRNA in thalamus. Soc Neurosci Abs 1995;21:1592. Berg AT, Shinnar S. Do seizures beget seizures? An assessment of the clinical evidence in humans. J Clin Neurophysiol 1997;14:102. Berkovic SF, Andermann F, Griberman A, et al. Valproate prevents the recurrence of absence status. Neurology 1989;39:1294. Boggs JG, Painter JA, DeLorenzo RJ. Analysis of electrocardiographic changes in status epilepticus. Epilepsy Res 1993;14:87. Boggs JG, Painter JA, Wood MA, et al. Signal-averaged electrocardiograms in patients with status epilepticus [abstract]. Neurology 1994;44 (Suppl):A205. Brooks-Kayal AR, Shumate MD, Jin H, et al. Selective changes in single cell GABA(A) receptor subunit expression and function in temporal lobe epilepsy. Nat Med 1998;4:1166. Brooks-Kayal AR, Shumate MD, Jin H, et al. Human neuronal gammaaminobutyric acid(A) receptors: Coordinated subunit mRNA expression and functional correlates in individual dentate granule cells. J Neurosci 1999;19:8312. Browne TR. Fosphenytoin (Cerebyx). Clin Neuropharmacol 1997;20:1. Calmeil J. De l’epilepsie, etude sous la rapport de son siege et de son influence sur la production de alienation mentale. Université de Paris, 1824 (thesis). Camfield CS, Camfield, PR, Smith E, Dooley JM. Home use of rectal diazepam to prevent status epilepticus in children with convulsive disorders. J Child Neurol 1989;4:125 Campistol J, Fernandez A, Ortega J. Status epilepticus in children. Experience with intravenous valproate. Update of treatment guidelines. Rev Neurol 1999;29:359. Cavalheiro EA, Silva DF, Turski WA, et al. The susceptibility of rats to pilocarpine-induced seizures is age-dependent. Dev Brain Res 1987;37:43 Chamberlain JM, Altieri MA, Futterman C, et al. A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Pediatr Emerg Care 1997;13:92. Chez MG, Hammer MS, Loeffel M, et al. Clinical experience of three pediatric and one adult case of spike-and-wave status epilepticus treated with injectable valproic acid. J Child Neurol 1999;14:239.

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CHAPTER 49

Antiepileptic Drug Therapy in Children Jeannine M. Conway, Robert L. Kriel, and Angela K. Birnbaum

Rational management of drug therapy in children requires an understanding of pharmacokinetics, pharmacodynamics, and toxicology. Pharmacokinetics is the study of drug absorption, distribution, metabolism, and elimination, or what the body does to a drug. Pharmacodynamics is the study of a drug’s biochemical and physiologic effects, or what the drug does to the body. Children, much more than adults, have widely varying abilities to absorb, distribute, metabolize, and eliminate drugs [Rane and Wilson, 1976]. Evidence also exists that antiepileptic drug pharmacodynamics in children differ from those in adults [Henriksen, 1988]. Application of basic pharmacokinetic and pharmacodynamic principles to antiepileptic drug therapy facilitates the attainment and maintenance of targeted serum concentrations, clinical response, control of drug interactions, and optimization of clinical response. Adverse reactions often dictate the choice of an antiepileptic drug and subsequent adjustment of therapy. An understanding of these reactions, including their differences and similarities among various antiepileptic drugs, and the application of appropriate clinical and laboratory monitoring provide the tools needed for the clinician to rationally prescribe drug therapy.

PHARMACOKINETIC PRINCIPLES Antiepileptic drug pharmacokinetics differ qualitatively and quantitatively between children and adults. Compared with adults, children, particularly neonates, have greater variability in their ability to absorb and eliminate antiepileptic drugs. Potential sources of variability are numerous and include drug formulation, behavior (compliance, diet, substance abuse), environment, and physiology. Physiologic variability may be correlated with the health of the patient, but also with factors such as pregnancy, gender, age, and maturation. In the management of pediatric seizures, the concern is with the effects of age and maturation on the pharmacokinetic profile; however, behavior, especially in adolescence, also can be a major determinant influencing clinical decisions. Other than age-related differences, drugspecific pharmacokinetics such as saturable metabolism, protein binding, and enzyme induction are similar for children and for adults. An overview of pharmacokinetic principles and the most clinically relevant features of specific antiepileptic drug pharmacokinetics is presented here. A comprehensive list of absorption characteristics is provided in Table 49-1, and other pharmacokinetic data are presented in Tables 49-2 and 49-3.

Absorption Absorption is a complex phenomenon controlled by the physicochemical properties of the drug, the formulation, and the physiologic conditions at the site of absorption. A solid formulation must first disintegrate into small particles, which then are dissolved in gastrointestinal fluid. Once a drug is dissolved, it is available for absorption, usually by passive diffusion of the un-ionized form. Absorption is influenced by age-dependent changes in physiologic variables such as gastric emptying time, stomach and intestinal pH, absorptive area, and gastrointestinal transit time. Absorption is described in terms of rate and extent. An absorption half-life is commonly used to describe the rate at which drug reaches the blood. An indirect measure of absorption rate is the time to maximum plasma concentration (Tmax), which is useful in comparing the rates of absorption of different brands or formulations of the same drug. An earlier time to maximum plasma concentration usually is an indication of a faster rate of absorption. When all other pharmacokinetic parameters are constant, a faster rate of absorption will result in a higher maximum concentration. The extent of absorption defines the amount of drug that reaches the blood. Bioavailability (F) is the fraction of the dose that reaches the systemic circulation after crossing the gastrointestinal wall and liver. Absolute bioavailability of a drug is determined by comparing the area under the concentration-time curve after an oral (or rectal, intramuscular, and so on) dose with the area under the concentration-time curve after intravenous administration of the same drug. Relative bioavailability can be determined by comparing the area under the concentration-time curve for a test brand or formulation and that for a reference product. For example, the relative bioavailability of a generic brand of phenytoin sodium 100-mg capsule is measured by comparing its area under the concentration-time curve with that for phenytoin (Dilantin 100-mg capsule). Bioavailability, along with the rate of elimination, determines average plasma concentration, as follows: Average plasma concentration at steady state = (bioavailability × daily dose)/clearance Therefore, changes in bioavailability due to alteration in drug, dosage form, gastrointestinal physiology, or interactions can result in clinically significant increases or decreases in plasma drug concentration. Profiles of absorption, including the maximum concentration, the time of maximum concentration, and even the total bioavailability, may vary considerably among dosage

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Epilepsy / 49

TABLE 49-1 Formulations, Routes of Administration, and Bioavailability of Antiepileptic Drugs MEDICATION Acetazolamide Carbamazepine

Clonazepam Clorazepate Diazepam

AVAILABLE FORMULATION(S)

POSSIBLE ROUTE(S)*

Tmax (hr)

FRACTION ABSORBED (F)

Tablet ER capsule Injectable Tablet

PO PO IV, IM PO

1-4 3-6 0.25 3-8

NA NA NA 0.79

Chewable tablet Suspension

PO PO. PR

2 0.5-3

0.79 0.7-0.9 estimate

ER tablet

PO

3-12

0.89 relative to susp.

ER capsule

PO

4-8

0.79

Tablet Tablet Tablet

PO PO PO PO PR IM, IV

1-8 0.7-1.5 0.5-2 0.1-0.5 0.75 1-1.5

0.85 0.91 0.8-1 0.8-1 0.9 0.8-1

2 1.5-4 3-7 1-4 3.7 0.5 (IM)

NA NA NA NA NA 1

Gel Injectable Ethotoin Ethosuximide

Tablet Capsule

Felbamate

Tablet

Fosphenytoin

Injectable

PO PO PO PO PO IV, IM

Gabapentin

Capsule

PO

2-4

0.6-0.27

Tablet

2-4 2-4 0.5-4 0.5-4 0.3-2 0.3-2 1-2.5 0.75-2 1 NA NA 4.5 6 1.5-2 (PR)

0.6-0.27 0.6-0.27 0.98 0.98 0.95-1 0.95-1 0.85-1 0.85-1 0.90 NA NA 1 1 NA

Methsuximide Oxcarbazepine

Compressed tablet Dispersible tablet Tablet Solution Tablet Injectable Concentrated oral solution Buccal Tablet Tablet

Paraldehyde

Solution

PO PO PO PO, PR PO PO PO IM, IV, PR PO PO PO PO PO PR, PO

Phenobarbital

Syrup

PO (PR)

1

0.8-1

Phenytoin

Tablet Injectable Suspension (phenytoin acid)

PO IM, IV PO

0.5-8.6 0.25-1 6-12

0.8-1 1 0.9-1

Lamotrigine Levetiracetam Lorazepam

SPECIAL PROBLEMS

Prolonged absorptive phase with variable Tmax; induction results in earlier Tmax Earlier Tmax results in higher Cmax, which can produce transient side effects Tablet must be swallowed whole; do not crush or chew Capsules may be opened and the beads sprinkled over food, such as a teaspoon of applesauce or other similar food products. Capsules or their contents should not be crushed or chewed

IM absorption is slow and variable

Fosphenytoin concentrations after IM administration are lower but more sustained than those after IV administration owing to time required for absorption of fosphenytoin from injection site Gabapentin bioavailability decreases as dose increases

Do not use discolored solution; avoid plastic equipment Withdrawn from U.S. market Unpleasant taste, rejected by many Patients should use accurate measuring device; dosing errors possible if suspension not adequately resuspended; strength of suspension must be clearly emphasized when prescribing

Conway, Kriel, and Birnbaum / Antiepileptic Drug Therapy in Children

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TABLE 49-1, cont’d Formulations, Routes of Administration, and Bioavailability of Antiepileptic Drugs MEDICATION

Pregabalin Primidone Tiagabine Topiramate

Valproate

Vigabatrin Zonisamide

AVAILABLE FORMULATION(S)

POSSIBLE ROUTE(S)*

Tmax (hr)

FRACTION ABSORBED (F)

SPECIAL PROBLEMS

Chewable tablet (phenytoin acid) Prompt-release capsule (phenytoin sodium) ER capsule (phenytoin sodium) Injectable

PO

4-8

0.9-1

Tmax dependent on Cmax

PO

2-6

0.9-1

PO

2-10

0.9-1

Tmax dependent on Cmax

IV, IM

0.25-0.5

0.9-1

IM injection not recommended; absorption is slow and erratic; injection is painful and must be diluted with normal saline without glucose and slowly administered

Capsule Solution Suspension Tablet Tablet Tablet Sprinkle capsule

PO PO PO PO PO PO, PR PO

1.3 1.3 4-6 4-6 0.75-3 1.4-4.3 1.4-4.3

0.89-1 0.89-1 NA NA 0.9 0.8 0.8

Capsule

PO

1-3

0.9-1

Enteric-coated tablet Sprinkle capsules

PO PO

2-6 4-6

0.9-1 0.9-1

ER tablet Syrup

PO PO, PR

4-17 0.5-1

0.9 0.9-1

Injectable Capsule Capsule

IV PO PO

1 0.75-2 2-6

1 0.5 1

Capsules may be opened and the beads sprinkled over food, such as a teaspoon of applesauce or other similar food products Capsules or their contents should not be crushed or chewed Capsule filled with liquid valproic acid; avoid opening Food delays Tmax Capsules may be opened and the beads sprinkled over food, such as a teaspoon of applesauce or other similar food products Capsules or their contents should not be crushed or chewed Valproate has objectionable aftertaste May not give IM

*Primary and alternates. Cmax, maximum plasma concentration; ER, extended-release; NA, not available; Tmax, time to maximum plasma concentration.

TABLE 49-2 Pharmacokinetics of Phenytoin

AGE GROUP

Vd (L/kg)

PROTEIN BINDING (%)

Neonates

0.7-1.2

74-90

0.25-3 years 4-6 years 7-9 years >10 years

85-91 0.7-0.8

87-93

Vmax (mg/kg/day) Km (mg/L)

T1/2 (hr) 3-140

13.9 11 9.75 8.1

4-6.6 4-6.8 3.6-6.5 3-5.7

1.2-31.5 6-60

ROUTES OF ELIMINATION

ACTIVE METABOLITES

INITIAL MAINTENANCE DOSE (mg/kg/day)

Hepatic 95% Renal 5%

No

4-6

COMMENTS Half-life varies with concentrations

6-10 5-7 4-7 4-6

Km, concentration at which metabolism occurs at half the maximum rate; T1/2, half-life; Tmax, time to maximum plasma concentration; Vd, volume of distribution; Vmax, maximum velocity for metabolism of drug.

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Epilepsy / 49

TABLE 49-3 Pharmacokinetics of Other Antiepileptic Drugs

DRUG

AGE GROUP*

Carbamazepine

Clonazepam

INITIAL MAINTENANCE DOSE (mg/kg/day) COMMENTS

Vd (L/kg)

Protein Binding (%) T1/2 (hr)

ROUTE(S) OF ELIMINATION

ACTIVE METABOLITES

N

1.1-2.6

65-70

7.2-27

Hepatic

Carbamazepine-10,11- 5-20 epoxide

C C

0.8-2.0 1.5-4.4

75-85 80-90

5-26 22-33

Hepatic

None

15-20 0.05-0.2

0.69 0.7 0.73-0.82 (A)

None

15-40

<10 30

32-41 15-68 14-21 (A)

Hepatic

Felbamate

N C C

None

15-45

Gabapentin

C

0.6-0.8 (A)

0

5-7

Hepatic 50-55%, renal 45-50% Renal

None

10-15

Lamotrigine

1-4 years

0.9-1.4

55

+ ind: 8 + VPA: 45

Hepatic

None

With VPA 1-5 With enzyme inducer 5-15

5-10 years

None 10,11-Dihydro10-hydroxycarbamazepine (MHD)

10-60 8-10

None

3-4

Ethosuximide

Levetiracetam Oxcarbazepine (OXC)

C A

+ ind: 7 + VPA: 66 24-31 (A) 0.5-0.7 (A) <10 4-8 Renal 0.7-0.8 40 (MHD) 1-2.5 Hepatic 60 (OXC) (OXC) 8-10 (MHD) (A)

Phenobarbital

N

0.8-1

32

82-199

Pregabalin

I C A

0.6-0.9 0.7 NA

40-55 0

37-73 21-75 4.6-6.8

Primidone

C

0.43-1.1 (A)

20

4.4-11

Tiagabine

A

0.74-0.85

96

Topiramate

C

0.6-0.8

15

Valproate (valproic acid [VPA])

N

0.28-0.43

68-89

5-13 Hepatic None Healthy (A) 20-30 (A) Renal >80%; None hepatic <20% 17-40 Hepatic 95%; 2-en-VPA, 4-en-VPA, renal 5% 2, 4-dien-VPA

I

0.2-0.34

C

0.1-0.3

6-8 80-95

4-15

Hepatic 50-80%; renal 20-50% Renal >90%; hepatic <10% Hepatic 60-70%; renal 30-40%

None Phenobarbital PEMA

4-5 2-3 No pediatric data Adult dose 150-600/day 10-15

Therapy should be initiated at 30% to 50% of initial dose and increased as autoinduction occurs Tolerance to antiepileptic effect frequently occurs

Slow-dose titration is necessary to lessen incidence of rash; see product information packet for details about titrating In severe renal impairment dose should be cut 50% to avoid glucuronide accumulation

Therapy should be initiated at 30% to 50% of initial maintenance dose

0.375-1.3 1-3 5-10 10-20 (monotherapy), 20 to 30 (induced) 10-20 (monotherapy), 20-30 (induced)

Conway, Kriel, and Birnbaum / Antiepileptic Drug Therapy in Children

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TABLE 49-3, cont’d Pharmacokinetics of Other Antiepileptic Drugs

DRUG

AGE GROUP*

Vigabatrin

I

3.5-7.5 (S) 0.8 (A)

C

3.5-7.5 (S) 5-7 0.8-1.6 h

Zonisamide

A

Vd (L/kg)

Protein Binding (%) T1/2 (hr)

ROUTE(S) OF ELIMINATION

ACTIVE METABOLITES

INITIAL MAINTENANCE DOSE (mg/kg/day) COMMENTS

0

Renal

None identified

50-100

4-7 (S)

2.5-4.5 (S) 40-60 h

63-69

Vigabatrin is available as a racemic mixture; the S(+) enantiomer is the active enantiomer

40-80 Renal 40-50%; hepatic 50-60 %

None

2-12 (C)

*A, adults; C, children; I, infants; N, neonates. MHD, monohydroxy derivative of oxcarbazepine; PEMA, phenylethyl malonamide; S, S(+)-enantiomer of vigabatrin; T1/2, half-life; Vd, volume of distribution.

forms of the same drug. The relative rates of absorption generally adhere to the following order: solutions > suspensions > capsules > tablets > extended-release formulations [Garnett and Cloyd, 1993]. Formulation-related differences in absorption characteristics can also be determined by the composition of the inactive ingredients (e.g., filler, particle size of drug, nature of the capsule or tablet, coating).

Distribution Volume and Protein Binding Volume of distribution in its simplest form is the ratio of the amount of drug in the body to blood concentration and is expressed in terms of liters or liters per kilogram. Mathematically, the ratio is expressed as the following: Volume of distribution = intravenous dose (mg)/plasma concentration (mg/L) attained immediately after injection Because calculation of distribution volume is based on plasma concentration, volume usually does not directly relate to a physiologic space. For example, drugs that concentrate in certain tissues and have relatively low plasma concentrations may have distribution volumes measured in hundreds of liters. Changes in body composition such as increases or decreases in fat, muscle, or water can alter volume.

Distribution volume in drug therapy is useful in calculating loading doses. The purpose of a loading dose is to rapidly fill body compartments to reach a targeted plasma concentration and thus a targeted concentration at the site of action. The equation for calculating a loading dose is the following: Loading dose = volume of distribution (L/kg) × body weight (kg) × desired change in plasma concentration The change in plasma concentration denotes the desired increase after administration of the loading dose. For example, if a patient has a plasma concentration of 5 mg/L and the target concentration is 20 mg/L, the desired change in concentration is 15 mg/L. When loading doses are administered intramuscularly, orally, or rectally, resultant maximum plasma concentrations are usually less than after intravenous administration, owing to slower and incomplete absorption and the elimination of some drug during the absorption phase. Table 49-4 presents loading dose information for five major antiepileptic drugs. Several antiepileptic drugs are highly bound to one or more plasma proteins, most commonly albumin or α1-acid glycoprotein. Drug assays usually measure the total concentration of drug, which is a combination of the bound and

TABLE 49-4 Loading Doses of Antiepileptic Drugs DRUG

Vd (L/kg)

LOADING DOSE (mg/kg)

ROUTE, FORMULATION

Cmax (mg/L)

Tmax (hr)

Carbamazepine Fosphenytoin Phenobarbital Phenytoin (PHT)

0.8 0.04 0.8 0.75 0.75 0.75 0.15-0.25 0.15-0.25

10 10-20 20 20 20 20 20 15-25

PO, suspension IV, intramuscular IV IV PO, prompt-release capsule PO, ER capsule PO, syrup IV

6-9 PHT 15-25 15-25 20-30 15-25 10-20 60-100 90-100

2-6 <0.25 Immediate Immediate 8-12 10-36 0.5-2 Immediate

Valproate

Cmax, maximum plasma concentration; ER, extended-release; PE, phenytoin equivalents; Tmax, time to maximum plasma concentration; Vd, volume of distribution.

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Epilepsy / 49

Metabolism and Elimination Vascular space

Nonvascular space (site of action)

Blood-bound drug

Tissue-bound drug

Free drug

Free drug

Eliminated drug

FIGURE 49-1. Relationship of unbound drug in vascular and nonvascular compartments.

unbound concentrations. The free fraction is the ratio of unbound to total plasma drug concentration: Free fraction = unbound concentration/total concentration

Average serum concentration (mg/L)

Generally, only unbound drug is free to cross the bloodbrain barrier and correlates best with brain and spinal fluid concentrations (Fig. 49-1). Clinical response and toxicity also correlate better with unbound drug concentration than with total drug concentration. For drugs that have limited protein binding (less than 50%) or a constant ratio of unbound to total concentration, total plasma concentration is equally reliable. If the drug is highly protein bound (greater than 85% to 90%) (see Table 49-3) and the unbound-to-total concentration ratio varies, the unbound concentration is a better measure of the amount of drug at the site of action. For low-extraction drugs, disruptions in protein binding such as those due to hypoalbuminemia or drug interactions alter total concentrations but do not affect the steady-state concentration of unbound drug. When alterations in protein binding are suspected, measuring the unbound concentration and determining the free fraction may be useful. Dosing adjustments generally are not necessary when protein binding is altered, because the unbound concentrations remain unchanged.

Most antiepileptic drugs are eliminated from the body primarily through hepatic metabolism, although the kidney is an important route of elimination for several agents. Clearance and elimination half-life are the pharmacokinetic terms that quantitatively describe drug elimination. Clearance is the more useful of the two for describing the rate of elimination and dosage requirements, whereas half-life is useful in determining time to steady state and dosing intervals. Clearance is the volume of blood from which drug is removed (cleared) per unit of time. It is identical conceptually and mathematically to the more familiar physiologic parameter of creatinine clearance. For antiepileptic drugs that are eliminated by the liver, clearance is determined by the free fraction of drug and the intrinsic ability of hepatic enzymes to metabolize unbound drug. Some drugs exhibit nonlinear pharmacokinetics in which clearance changes with concentration (Fig. 49-2). The following points are important to remember: • Clearance and absorption determine the amount of drug a patient requires to maintain a targeted plasma concentration. • Changes in unbound clearance result in changes in unbound concentration and, potentially, in the resultant pharmacologic response. • Changes in protein binding affect total but not unbound drug concentration. Changes in total drug concentration without a corresponding change in unbound concentration therefore do not require a dosage adjustment. Elimination half-life (T1/2) is the time required for the amount of drug in the body or plasma concentration to decline by 50%. Half-life is determined by both distribution volume and clearance: T1/2 = (0.693 × distribution volume)/clearance Thus, half-life is not a direct measure of metabolizing capacity but is useful in calculating the time to reach steady state or the time required for drug elimination. After initiation or modification of therapy or after any change in clearance, 5 half-lives must elapse for a new steady-state plasma concentration to be reached (see Fig. 49-2). The time required to attain steady state can be explained by using the definition of half-life. As stated previously, the plasma concentration in the body declines 50% in one half-life;

B A

C

Daily dose (mg/kg/day)

FIGURE 49-2. Effect of dose on elimination kinetics. Curve A plots nonlinear pharmacokinetics (of the Michaelis-Menten type) in which clearance decreases with increasing dose, as with phenytoin. Curve B plots linear pharmacokinetics, in which clearance remains the same with increasing dose, as with phenobarbital, felbamate, vigabatrin, tiagabine, topiramate, and valproic acid (unbound drug). Curve C plots nonlinear pharmacokinetics in which clearance increases with dose, as with valproic acid (total), carbamazepine, and lamotrigine.

Conway, Kriel, and Birnbaum / Antiepileptic Drug Therapy in Children

therefore, the percentage of drug remaining in the body as indicated by the plasma concentration after 2, 3, 4, and 5 half-lives is 75%, 87.5%, 93.75%, and 96.875%, respectively. The actual amount of drug remaining in the body and the additional amount of drug removed in subsequent half-lives are so small (after 5 half-lives) that for practical purposes it is essentially zero. After therapy is discontinued, 5 half-lives must elapse before drug is completely eliminated from the body. Biotransformation of foreign compounds such as medications is accomplished through biochemical reactions. These reactions create more polar compounds that are eliminated from the body. Phase I reactions (e.g., using the cytochrome P-450 system) are oxidation and reduction of compounds. Phase II reactions (non–cytochrome P-450– mediated) couple the drug or its metabolite with endogenous substrates by conjugation or synthesis. The endogenous substrate may be glucuronic acid, glutathione, glucose, sulfate, or acetate, making the drug more polar and hence water soluble [Capparelli, 1994]. Drugs may undergo metabolism by phase I or II reactions, or by sequential phase I and phase II reactions. In the neonate, phase I reactions such as hydroxylation and, to a lesser extent, dealkylation are significantly depressed [Battino et al., 1993]. In older children, however, phase I activity generally exceeds that in adolescents or adults. As a general rule, the rate of drug metabolism reaches a peak at 0.5 to 2 years of age and then declines in an exponential manner, reaching adult values in early adolescence. As an example, the clearance of valproic acid, in which metabolism includes both phase I and phase II reactions, is fastest in young children and then declines to reach adult values at the age of approximately 12 to 15 years. For most drugs, the evaluation of maturation-related (as contrasted with chronologic age–related) enzymatic clearance has not been studied systematically. It is likely that some of the variance in drug clearance noted in children of the same age is due to differences in maturational development. Active metabolites formed after biotransformation of the parent compound can contribute significantly to desired and

1111

toxic effects of the parent drug. Metabolites exist in both bound and unbound states. Only the unbound metabolite is available for elimination or biotransformation to an inactive metabolite. As with unbound parent drug, the unbound metabolite concentration in the plasma most closely correlates with the concentration of metabolite at the site of action. The presence of active metabolites complicates interpretation of plasma drug concentrations and clinical response. As with the parent drug, the relationship between unbound and total metabolite concentrations can be disrupted by displacement from serum proteins or changes in metabolism. In fact, parent or metabolite concentrations may be altered independently by drug interaction or physiologic change in metabolism. Table 49-5 shows the cytochrome P-450 isoform families involved in antiepileptic drug metabolism along with known inducers and inhibitors. Renal elimination is accomplished by glomerular filtration and/or renal tubular secretion. Glomerular filtration rate and renal tubular function in newborns are less efficient than in adults [Linday, 1994]. After 1 year of age, glomerular filtration rate, corrected for body surface area, is the same as for older children and young adults. Renal tubular function reaches adult values, normalized to body surface areas, within several months [Linday, 1994]. Decreases in clearance can be better correlated with sexual maturity than with chronologic age [Linday, 1994]. Making correlations with physiologic or sexual maturation and developmental age rather than chronologic age may be helpful in accounting for the variability observed in clearance of drugs that are renally eliminated [Finkelstein, 1994].

PHARMACOKINETIC CHARACTERISTICS OF ANTIEPILEPTIC DRUGS Benzodiazepines As a group, the benzodiazepines are rapidly (time to maximum plasma concentration of 30 to 180 minutes) and completely absorbed when given orally. Intramuscular administration of diazepam or lorazepam is not recommended

TABLE 49-5 Antiepileptic Drug (AED) Involvement with Cytochrome P-450 System METABOLIC PATHWAY

CYP1A2

CYP2C

CYP3A

GLUCURONATE

NOT DETERMINED

RENAL

AED substrates

Carbamazepine

Phenytoin Diazepam Barbiturates

Lamotrigine Valproic acid

Topiramate

Gabapentin Levetiracetam Pregabalin Vigabatrin

Inducers

Carbamazepine Cigarette smoke Lansoprazole Omeprazole

Carbamazepine Phenobarbital Phenytoin Rifampicin

Inhibitors

Cimetidine Fluoroquinolones Fluvoxamine

Cimetidine Felbamate Fluoxetine Fluvoxamine Lansoprazole Omeprazole Oxcarbazepine Topiramate

Carbamazepine Diazepam Tiagabine Zonisamide Carbamazepine Glucocorticoids Oxcarbazepine Phenobarbital Phenylbutazone Phenytoin Rifampicin Antifungals Cimetidine Diltiazem Erythromycin Fluoxetine Nefazodone Verapamil

Barbiturates Cigarette smoke Phenytoin

Epilepsy / 49

because of slow or erratic absorption. Diazepam also is absorbed rectally. The benzodiazepines rapidly cross the blood-brain barrier. Brain concentrations reach equilibrium with plasma concentrations within seconds after intravenous administration. The highly lipid-soluble nature of diazepam and lorazepam causes them to redistribute to other body tissues, resulting in a decrease in brain concentrations. This redistribution, which takes place in minutes, is responsible for the short duration of action after a single dose [Greenblatt et al., 1989; Leppik et al., 1983]. The benzodiazepines follow a linear elimination pattern and are metabolized by the liver. Some of the metabolites that possess antiepileptic activity also contribute to toxicity. Pharmacologically active metabolites are formed from diazepam and chlorazepate.

Carbamazepine Carbamazepine is a water-insoluble, neutral compound with a slow dissolution rate in gastrointestinal fluid. The relative bioavailability is similar for all four formulations (i.e., suspension, chewable tablet, extended-release, and regular tablet), ranging from 75% to 90%, although marked intrapatient and interpatient variability have been observed [Faigle and Feldmann 1975; Mass et al., 1987]. In children on maintenance therapy, the rate of absorption is much faster for the suspension than for tablet formulations, resulting in a significantly earlier time to maximum plasma concentration and higher maximum plasma concentration (Cmax) (Fig. 49-3), which occasionally produces transient concentration-dependent central nervous system (CNS) side effects. Administering the same daily dose in smaller amounts, given more frequently, usually will correct this problem. Studies conducted by the U.S. Food and Drug Administration have demonstrated that carbamazepine tablets are significantly less well absorbed when exposed to high humidity [Meyer et al., 1992; Wang et al., 1990]. These reports emphasize the importance of storing all antiepileptic drugs at room temperature in a dry location. The volume of distribution in children for carbamazepine ranges from 0.8 to 2.0 L/kg. Carbamazepine and its active metabolite, carbamazepine-10,11-epoxide, both are bound to several plasma proteins [Eichelbaum et al., 1975; Rawlins et al., 1975]. Approximately 65% to 85% of carbamazepine and 30% to 60% of carbamazepine-10,11-epoxide are bound to albumin. Both compounds also bind to the reactant protein α1acid glycoprotein. In particular, binding to α1-acid glycoprotein increases after physiologic stress such as from burn injuries, inflammatory diseases (e.g., juvenile rheumatoid arthritis), and concurrent drug therapy with enzyme-inducing drugs. Increased binding to α1-acid glycoprotein can increase total carbamazepine and carbamazepine-10,11-epoxide concentrations without necessarily increasing unbound drug concentrations. In such situations, patients may have total concentrations above the desired range but have no side effects. Adjusting dosage is not necessary; plasma concentrations return to baseline as α1-acid glycoprotein declines. Carbamazepine is eliminated primarily by cytochrome P-450–mediated metabolism (see Table 49-5), forming an active metabolite (10,11-epoxide). Carbamazepine displays dose-dependent elimination pharmacokinetics, in which dosage increases produce a less than proportionate increase in steady-state total concentration (see Fig. 49-2). Carbamazepine undergoes autoinduction, in which clearance

12 Serum concentration (␮g/mL)

1112

CBZ tablet 10

CBZ suspension

8 6 4 2 0 0

2

4

6

8

10

Time FIGURE 49-3. Comparison of serum concentration–time curves after administration of carbamazepine (CBZ) tablets and suspension. Data are from a crossover study in a child with epilepsy on steady-state, maintenance therapy.

increases over time after exposure to the drug. Within 30 days after beginning therapy, carbamazepine clearance increases by 300%. Recent evidence suggests that further increases in maintenance doses may result in further induction [Koudriakova et al., 1992]. In some children, induction causes plasma carbamazepine concentrations to remain unchanged or even to decline despite increasing dosages up to 40 to 50 mg/kg per day [Curatolo et al., 1988]. Carbamazepine-10,11-epoxide metabolism also can be induced by phenytoin or phenobarbital, resulting in a 100% increase in clearance [Kerr and Levy 1989]. Initial carbamazepine half-life ranges from 10 to 20 hours, but the half-life decreases with autoinduction to 4 to 12 hours. Consequently, many children require three or four doses a day to maintain targeted plasma concentrations.

Felbamate Approximately 95% of a dose of felbamate is absorbed in adults after oral administration. Absorption of the drug is fairly rapid, with time to maximum plasma concentration values ranging from 1 to 4 hours [Wilensky et al., 1985]. Felbamate has a volume of distribution of approximately 0.8 L/kg [Devinsky et al., 1994; Ward and Shumaker, 1990; Wilensky et al., 1985]. Distribution of felbamate is fairly uniform throughout the entire body. The drug binds mainly to albumin (22% to 25%), and binding is dependent on albumin concentration [Perhach and Shumaker, 1995; Wagner et al., 1991]. About 90% of felbamate is eliminated in the urine. Approximately 40% to 50% of the absorbed dose is eliminated as the unconjugated parent compound, and up to 58% is found as metabolites and conjugates [Shumaker et al., 1990]. Felbamate is cleared at a faster rate in children. Population pharmacokinetic analysis of data from 139 pediatric patients gives clearance values approximately 40% higher in younger children (2 to 12 years of age) than those in older children and adults (13 to 65 years) [Banfield et al., 1996]. Therefore, higher doses may be needed to achieve therapeutic levels in children [Battino et al., 1995].

Fosphenytoin Fosphenytoin is a prodrug that is rapidly hydrolyzed by tissue and red blood cell alkaline phosphatases to phenytoin.

Conway, Kriel, and Birnbaum / Antiepileptic Drug Therapy in Children

It is water soluble, thus permitting formulation in nontoxic, parenteral solutions. The pharmacokinetics of phenytoin derived from fosphenytoin are identical to phenytoin given directly [Leppik et al., 1989]. Fosphenytoin is packaged as milligram phenytoin equivalents and is well tolerated when given intramuscularly [Leppik et al., 1989]. Fosphenytoin is rapidly converted to phenytoin in the body, and absorption, not its conversion to phenytoin, appears to be the rate-limiting step in achieving therapeutic phenytoin levels [Perucca and Bialer, 1996]. The mean halflife of fosphenytoin is 8 minutes after intravenous administration [Donn et al., 1987; Gerber et al., 1988; Leppik et al., 1990] and 33 minutes after intramuscular injection [Leppik et al., 1990]. Age does not affect the phosphatase enzyme responsible for the conversion of fosphenytoin to phenytoin. Therefore, any age effects in pharmacokinetics are the same as for phenytoin, because the pharmacokinetics of fosphenytoin and of phenytoin are the same. Fosphenytoin is more avidly bound to albumin, compared with phenytoin, resulting in increases of free phenytoin concentrations after infusion [Hussey et al., 1990; Jamerson et al., 1990]. The observed decrease in total phenytoin concentrations returns to those expected when the conversion from fosphenytoin to phenytoin is completed; therefore, monitoring of plasma concentrations should not begin until a couple of hours after administration of fosphenytoin.

Gabapentin The absolute bioavailability after oral administration of gabapentin is 60% [Vollmer et al., 1987]. Absorption is linear up to daily doses of 1800 mg, after which bioavailability begins to decrease, dropping to 35% at daily doses of 4800 mg [Richens, 1993]. Gabapentin uses the L-amino acid transporter system in the gut to enter the body. The dependence of gabapentin on and saturation of this active transport system may explain the decrease in bioavailability with increasing doses above 1800 mg [Stewart et al., 1993]. Gabapentin has a volume of distribution of approximately 0.6 to 0.8 L/kg [Richens, 1993] and does not bind to plasma proteins [Vollmer et al., 1986; Elwes and Binnie, 1996]. It has been demonstrated that gabapentin uses the L-amino acid transporter system, an active transport system, to enter the brain, which is also saturable [Luer et al., 1999]. Gabapentin is eliminated renally. Clearance in children 1 month to 12 years of age was well correlated with creatinine clearance. Clearance was higher in children younger than 5 years of age, necessitating a 30% higher dose to attain equivalent concentrations as observed in children older than age 5 and older and in adults [Haig et al., 2001; Ouellet et al., 2001].

Lamotrigine Lamotrigine has a bioavailability approaching 100%. Peak concentrations are reached 2 to 3 hours after administration of a single oral dose. With doses in the range of 15 to 240 mg, time to maximum plasma concentration and area under the concentration-time curve are directly proportional to dose [Yuen and Peck, 1987]. The volume of distribution of lamotrigine is approximately 1.5 L/kg in children [Chen et al., 1999]. It is distributed uniformly throughout the body, and approximately 55% of lamotrigine is bound to plasma proteins [Garnett, 1997].

1113

Lamotrigine is extensively metabolized to an inactive glucuronide by an inducible uridine diphosphate (UDP) glucuronyltransferase reaction [Lamictal, 2004]. Clearance is greater in younger children [Battino et al., 2001]. Infants (younger than 2 months of age) metabolize lamotrigine more slowly, and metabolic rates increase during the first year of life [Mikati et al., 2002].

Levetiracetam Levetiracetam has a bioavailability of 100%. Peak concentrations are reached within 2 hours of dose administration. When the drug is administered with food, the rate of absorption is decreased, but the extent of absorption is unchanged. Therefore, levetiracetam can be administered without regard to timing of meals. Levetiracetam also exhibits linear pharmacokinetics after single doses ranging from 250 up to 5000 mg [Patsalos, 2000]. The volume of distribution for levetiracetam is 0.5 to 0.7 L/kg, and protein binding is less than 10% [Patsalos, 2000]. Levetiracetam is eliminated renally. Two thirds of a dose is eliminated unchanged, whereas the remaining third is excreted as inactive metabolites [Keppra, 2004]. The clearance is 30% to 40% higher in children than in adults [Pellock et al., 2001].

Oxcarbazepine Oxcarbazepine is rapidly absorbed, with a time to maximum plasma concentration of less than 1 hour after a single oral dose. Absorption is nearly 100%. Less than 2% of the area under the concentration-time curve is attributed to the parent compound, and approximately 70% to the 10-hydroxycarbamazepine metabolite [Theisohn and Heinmann, 1982]. Coadministration of oxcarbazepine and food leads to an increase in the bioavailability and maximum plasma concentration; however, time to maximum plasma concentration remains unchanged. The slight changes in the absorption parameters with food administration do not appear to be clinically significant [Degen et al., 1994]. Oxcarbazepine is a prodrug that is converted extensively to 10,11-dihydro-10-hydroxy-carbamazepine (the monohydroxy derivative [MHD]). Both oxcarbazepine and its major metabolite, MHD, have anticonvulsant activity similar to that of carbamazepine; however, in humans, the parent compound is extensively and rapidly metabolized to MHD, which is responsible for the anticonvulsant effect. The major advantage of oxcarbazepine is that it is not metabolized to the active epoxide metabolite, which is believed to contribute to the side effect profile of carbamazepine. Both the parent drug and its metabolite are lipophilic, which facilitates their movement across the blood-brain barrier. MHD has a volume of distribution of 0.7 to 0.8 L/kg [Feldmann et al., 1977, 1981; Theisohn and Heinmann, 1982], and both oxcarbazepine and MHD bind to plasma proteins at approximately 60% and 40%, respectively [Klitgaard and Kristensen, 1986; Patsalos et al., 1990]. Approximately 96% of an oral dose is eliminated in the urine, with less than 1% of oxcarbazepine being excreted unchanged. The greater part of the dose is conjugated and excreted as the glucuronide (9% oxcarbazepine glucuronide and 49% monohydroxylated glucuronide) [Lloyd et al., 1994; Schutz et al., 1986]. Unlike carbamazepine, oxcarbazepine does not appear to induce its own metabolism [Larkin et al., 1991].

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Phenytoin Phenytoin is a poorly soluble acid that is slowly absorbed. Phenytoin is available as a suspension, chewable tablet, capsule, and a parenteral formulation. Important differences exist among the dosage forms with regard to the amount of phenytoin contained and the rate of absorption (see Table 49-1). The chewable tablet and the suspension contain phenytoin acid, whereas the capsules contain phenytoin sodium, which yields 92% phenytoic acid. Thus, two 50-mg chewable tablets deliver 9% more phenytoin than a 100-mg phenytoin sodium capsule. The nonlinear, saturation pharmacokinetics of phenytoin make even these small differences in dose clinically significant. Differences in phenytoin content may make dose adjustment necessary when formulations are changed. Monitoring plasma concentrations is advisable. The suspension is available in a 125-mg/5-mL strength. In the past, the reliability of the suspension has been questioned owing to its tendency to settle [Pellock, 1994]. It has been demonstrated that minimal agitation (i.e., one inversion of the bottle) is sufficient to permit delivery of the specified amount of drug [Sarkar et al., 1989]. Unexpected fluctuations in plasma phenytoin concentrations associated with the use of suspensions likely have been the result of pharmacokinetics rather than formulation problems. Intramuscular injection of the parenteral solution (with a pH of 11) is not recommended because it results in precipitation of drug that is then slowly and erratically absorbed [Kostenbauder et al., 1975]. Injection also is painful and may result in tissue necrosis [Serrano and Wilder, 1974]. Phenytoin capsules are available in both prompt-release and extendedrelease formulations. Extended-release formulations (e.g., Dilantin Kapseals) may be particularly useful in some children who rapidly eliminate phenytoin, because the slower rate of absorption may permit fewer daily doses. Patient and family education about the differences in phenytoin dosage forms is important to maintain optimal therapy. Bioavailability, time to maximum plasma concentration, and maximum plasma concentration are altered when large amounts of phenytoin are given as a single oral loading dose, presumably because of the formation of a multicapsule

concretion. In a study involving six healthy adults, absorption was reduced by 10% to 15% and time to maximum plasma concentration increased from 18 to 32 hours, when phenytoin sodium capsules were given in single dose of 10 mg/kg or more [Jung et al., 1980]. Dividing the total loading dose into 5-mg/kg doses given every 2 to 3 hours overcomes this problem. The most rapid way to attain therapeutic plasma concentrations after oral loading is to use prompt-release phenytoin sodium capsules or suspension [Goff et al., 1984]. Some reports have suggested that phenytoin is poorly absorbed in newborns because of irregular gastric emptying time, relatively high gastric pH (greater than 4), or decreased absorptive surface [Morrow and Richens, 1989; Morselli, 1983; Painter et al., 1978]. Other evidence indicates that formulation-related differences in absorption, nonlinear pharmacokinetics, and age-dependent changes in elimination account for much of the variability in plasma concentrations [Dodson, 1984]. Phenytoin distribution volume in children and adolescents is approximately 0.7 ± 0.1 L/kg [Koren et al., 1984]. The relatively small variability in phenytoin distribution volume permits precise calculation of loading doses. For example, a 15-mg/kg loading dose given intravenously will result in a postinfusion mean concentration of 20 mg/L, with a range of 15 to 25 mg/L. Phenytoin is also highly protein bound to albumin. Phenytoin undergoes extensive hepatic metabolism. A small fraction, 5% or less, is excreted unchanged [Battino et al., 1995]. It is metabolized by a saturable cytochrome P-450 (see Table 49-2) enzymatic pathway. Phenytoin follows Michaelis-Menten or saturable elimination kinetics (see Fig. 49-2). As the plasma concentration rises, phenytoin clearance decreases, owing to saturation of enzymatic metabolism. Therefore, increases in dose result in disproportionately greater increases in steady-state plasma concentration. Phenytoin half-life also varies with plasma concentration. As plasma concentration rises, the half-life is prolonged. Half-life ranges from 8 to 12 hours at low concentrations to more than 60 hours at concentrations above 20 mg/L. At

Phenytoin concentration (␮g/mL)

50

40

Age groups

30

0.5 to 3 years 4 to 6 years 20

7 to 9 years 10 to 16 years

10

0 0

2

4

6

8 Dose

10

12

14

FIGURE 49-4. Phenytoin dosing requirements in children. Curves were derived from data of maximum capacity of the enzyme system to metabolize phenytoin (Vmax) and the plasma concentration at which the rate of metabolism is 50% of maximum capacity for children (Km) (see Table 49-2).

Conway, Kriel, and Birnbaum / Antiepileptic Drug Therapy in Children

concentrations within or above the therapeutic range, 1 to 4 weeks may be required to reach steady state. Phenytoin metabolism in neonates is reduced compared with that in older children. Within days to weeks after birth, the rate of metabolism accelerates, reaching a maximum in the 0.5- to 3-year age range. Children in this age group require the highest mg/kg daily doses (Fig. 49-4). Thereafter, metabolism and dosage requirements decline gradually, reaching adult values during adolescence. Figure 49-5 illustrates that even minor alterations in dosage produce disproportionately large changes in plasma concentration. Therefore, small adjustments in daily dose are indicated as the plasma concentration approaches or exceeds Km, which usually falls in the range of 5 to 10 mg/L. Use of the scored 50-mg chewable tablet, the 30-mg phenytoin sodium capsule, or the suspension facilitates making such adjustments in dose.

Pregabalin In adults, pregabalin is rapidly absorbed within an hour. Its bioavailability is greater than 90%. Unlike gabapentin, pregabalin demonstrates no changes in absorption as dose increases. Pregabalin does not bind to plasma proteins and is not metabolized in humans, with 98% of the dose recovered unchanged in urine [Ben-Menachem, 2004; Brockbrader et al., 2000].

Tiagabine Oral bioavailability of tiagabine is greater than 90%, and the bioavailability of tablets and that of the oral solution appear to be similar [Mengel et al., 1991]. The absorption rate for tiagabine is reduced up to 65% when the drug is administered with food, although the extent of absorption is not affected [Mengel et al., 1991]. Tiagabine has a volume of distribution of 0.74 to 0.85 L/kg [Gustavson et al., 1997], and protein binding is approximately 96% [Gustavson et al., 1997; Østergaard et al., 1995; Wilson and Brodie, 1996]. Tiagabine has a half-life of 5 to 9 hours [Gustavson and Mengel, 1995]. Although no active metabolites have been identified, tiagabine undergoes extensive metabolism by means of cytochrome P-450 3A isoform. As seen with other drugs, clearances in children are faster than in adults; adjusting both volume and clearance values according to body size gives values similar to those seen in adults [Gustavson et al., 1997].

Topiramate Topiramate’s relative bioavailability is approximately 80% that of a solution. It is rapidly absorbed, with a time to maximum plasma concentration of approximately 2 hours [Easterling et al., 1988]. Overall absorption is not affected by coadministration with food [Doose et al., 1992]. Topiramate’s protein binding is less than 15% [Ben-Menachem, 1995a], and its distribution volume is 0.6 to 0.8 L/kg [Johannessen, 1997]. Elimination is mainly through the kidney, although a portion of the dose is removed by the liver [BenMenachem, 1995a]. Preliminary observations in pediatric patients indicate that the mean oral topiramate clearance is 44% to 55% higher in children [Glauser, 1997].

Valproic Acid Valproic acid appears to be completely absorbed from all the available products (except for the extended-release for-

1115

mulation), but the rate of absorption varies significantly with dosage form (see Table 49-1). Maximum plasma concentration occurs in 0.5 to 1 hour after ingestion for the syrup, 0.5 to 2 hours after the capsule, 1 to 6 hours for the entericcoated tablet, and 3 to 6 hours for the sprinkle capsule [Cloyd et al., 1983, 1985, 1992]. Absorption after ingestion of the enteric-coated tablet is delayed for several hours; during this lag phase, plasma concentrations may continue to decline. Food further delays, but does not decrease, valproic acid absorption from the enteric-coated tablet [Fischer et al., 1988]. The extended-release tablet has an absolute bioavailability of 90% [Dutta et al., 2004]. The extendedrelease tablets and the enteric coated tablets are not interchangeable. The extended-release tablets need to be prescribed at a dose that is 8% to 20% higher than the enteric-coated dose, to result in similar plasma concentrations (Dutta and Zhang, 2004]. An intravenous formulation is also commercially available. Valproic acid distribution volumes vary more than those of carbamazepine, phenobarbital, or phenytoin, ranging from 0.12 to 0.49 L/kg. When loading doses are calculated a volume of 0.2 L/kg is recommended. Valproic acid protein binding to albumin is saturable. At concentrations below 40 to 50 mg/L, the bound fraction averages 90% to 95%. As total concentration rises to the upper boundary of the therapeutic range, the percentage bound falls to 80% to 85%. Saturable protein binding results in a nonlinear relationship between total valproic acid concentration and dose. Unbound valproic acid concentrations, however, remain linear with dose [Cloyd et al., 1993; Riva et al., 1983]. The percent of unbound valproate can be unpredictable and unusually high after rapid infusion in children who are critically ill [Birnbaum et al., 2003]. Valproic acid is extensively metabolized to both active and inactive metabolites. Principal pathways include glucuronidation, β-oxidation in the mitochondria, and oxidation through cytochrome P-450. The monounsaturated metabolites 2-ene-valproic acid and 4-ene-valproic acid possess anticonvulsant activity; the 2-ene-valproic acid achieves pharmacologically relevant concentrations in the brain. 2-Ene-valproic acid accumulates in the brain more slowly than does valproic acid, which may account for the slow onset and cessation of valproic acid anticonvulsant activity. Although the diunsaturated metabolite 2,4-diene-valproic acid is a potent hepatotoxin, its role in valproic acid hepatotoxicity remains unclear. The elimination half-life of valproic acid is short. In the first few weeks after birth, half-life ranges from 17 to 40 hours but rapidly declines from 3 to 20 hours in infants and young children. Evidence suggests that the full antiepileptic effect of valproic acid is obtained days to weeks after steady state is reached, and that this effect continues for some time after the drug is discontinued. The lingering effect may be partly the result of its inhibitory effect on the enzymes responsible for the degradation of γ-aminobutyric acid (GABA) or may be due to the accumulation of 2-ene-valproic acid. This prolonged duration has prompted some investigators to propose single daily dosing [Stefan et al., 1984]; however, with other proposed mechanisms of action, seizure control is related to plasma valproic acid concentrations. Under these circumstances, dosing at least every half-life is indicated to minimize fluc-

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tuations in plasma concentrations. Monotherapy with long half-lives maintains therapeutic concentrations for up to 24 hours in some children. Such children may be able to take valproic acid once a day [Cloyd et al., 1985].

Vigabatrin Vigabatrin is a 50:50 racemic mixture of R(-) and S(+) enantiomers, with the S(+) enantiomer responsible for the drug’s pharmacologic activities and toxic effects [Challier et al., 1992; Haegele et al., 1983; Rey et al., 1990]. Bioavailability is approximately 75% in adults when the drug is given orally and is similar for both the tablet and the solution [Hoke et al., 1991]. Administration of vigabatrin with food does not significantly affect vigabatrin pharmacokinetics [Frisk-Holmberg et al., 1989]. Vigabatrin has been studied in children [Rey et al., 1989, 1990], and bioavailability appears to be somewhat lower in children than in adults [Rey et al., 1992]. Vigabatrin does not bind to plasma proteins, and it has an apparent volume of distribution of 0.8 L/kg [Ben-Menachem, 1995b]. Most of a vigabatrin dose appears unchanged in the urine. Studies in infants and children show that the half-life of the inactive R(-) enantiomer, but not the half-life of the active S(+) enantiomer, increases with linear age. Vigabatrin exerts its pharmacologic effect by irreversible inhibition of GABA transaminase, causing increases in synaptic GABA concentrations by inhibiting its breakdown. Because the half-life of GABA transaminase is much longer than that of vigabatrin itself, the pharmacologic effect is determined by the half-life of the enzyme [Ben-Menachem, 1995b; Jung et al., 1977].

Zonisamide Absolute bioavailability of zonisamide has not been assessed owing to the lack of an intravenous formulation. The drug evidently is nearly completely absorbed, as indicated by early studies in which radioactive drug was measured in the urine and bile of rats [Matsumoto et al., 1983]. Human data indicate that after multiple doses, 65% of zonisamide is recovered in urine (62%) or feces (3%). Food does not affect bioavailability [Zonegran, 2004]. Zonisamide is only 40% bound to plasma proteins, and its apparent volume of distribution is approximately 1.45 L/kg [Zonegran, 2004]. Zonisamide is highly bound to erythrocytes, resulting in whole blood concentrations that are higher than plasma concentrations. Binding to erythrocytes causes nonlinearity in plasma concentrations after a dose of greater than 400 mg [Matsumoto et al., 1989]. Zonisamide is eliminated by renal and hepatic routes. The metabolism of zonisamide is mediated in part by cytochrome P-450 3A4 [Zonegran, 2004].

Generic Formulations Absorption may differ among similar formulations (such as tablets) from various manufacturers (e.g., carbamazepine) [Kauko and Tammisto, 1974; Pynnonon et al., 1978; Silanpaa, 1981]. Significant increases in serum phenytoin concentration have been observed when the same maintenance doses of medication are taken from different manufacturers. For drugs with nonlinear pharmacokinetics such as phenytoin, such increases can lead to clinical toxicity [Mikati et al., 1992]. Substitution of drugs made by differing manufacturers may lead to problems, especially when drugs with narrow therapeutic ranges or nonlinear pharmacokinetics are used.

Therefore, counseling patients to keep taking medication prepared by the same pharmaceutical source whenever possible usually is advisable [Nuwer et al., 1990]. Additional antiepileptic drugs will be available generically as patents expire, and they may prove to be acceptable substitutes.

PHARMACODYNAMICS Pharmacologic and many toxicologic responses are determined by a drug’s intrinsic activity and the amount of drug at the site of action. Generally, seizure control and side effects are related to drug concentration; the exceptions include hypersensitivity and idiosyncratic adverse reactions.

Dose-Response or Concentration-Response Concept Substantial evidence exists that both the number of patients experiencing seizure control increases and the degree of seizure control for a given patient improves with higher antiepileptic drug concentrations [Porter, 1989; Schmidt and Haenel, 1984]. The minimum effective concentration defines the concentration at which the desired pharmacologic response is first observed. The intensity of response increases in direct proportion to drug concentration, until a response is maximized. This result is the maximum pharmacologic effect for that drug. With some drugs such as phenytoin, further increases in concentration may reduce response (e.g., phenytoin-induced exacerbation of seizures) [Troupin and Ojemann, 1975]. It is not known whether other antiepileptic drugs share this property. The incidence and severity of side effects also increase with drug concentration. The concentration at which side effects appear is usually, but not always, greater than the concentrations needed to achieve seizure control. The difference between concentrations that produce desired and toxic responses defines the therapeutic range. Optimal ranges, representing population averages, for commonly used antiepileptic drugs are listed in Table 49-6. TABLE 49-6 Optimal Target Ranges for Commonly Prescribed Antiepileptic Drugs TARGET DRUG LEVEL DRUG

Total (mg/L)

Carbamazepine Ethosuximide Felbamate Gabapentin Lamotrigine Levetiracetam MHD (oxcarbazepine active metabolite) Phenobarbital Phenytoin Primidone

4-12 0.5-3.6 40-100 — 40-100 — 4-16 — 2-20* — 5-45* 10-35 — 15-40 6-20 10-20 1-2 5-12 — (15-40 PB) 2-25* — 2-25* — 50-100 6-20 ND — 15-30*

Tiagabine Topiramate Valproic acid Vigabatrin Zonisamide

Free (mg/L)

*Range is not defined, and values are concentrations found in clinical trials. ND, not determined; PB, phenobarbital.

Conway, Kriel, and Birnbaum / Antiepileptic Drug Therapy in Children

Tolerance Tolerance is a phenomenon in which pharmacologic or toxicologic effect diminishes with repeated doses, even at the same or increasing plasma concentrations. Different mechanisms for the development of tolerance have been recognized [Froscher and Engels, 1986; Koella, 1986]. One mechanism is the result of biochemical adaptation (e.g., upregulation or downregulation of receptor sites). For example, the effectiveness of benzodiazepine therapy diminishes over time, necessitating even larger doses. Animal studies have demonstrated that chronic exposure to benzodiazepines causes a downregulation of benzodiazepine receptors, which reduces their anticonvulsant effect. Another mechanism of tolerance is behavioral: The patient becomes progressively insensitive to drug effect without any apparent biochemical change [Siegel, 1986]. For example, many patients initiated on phenobarbital or primidone exhibit mild neurotoxicity even at low plasma concentrations [Leppik et al., 1984]. Neurotoxicity clears within hours to a few days even as plasma concentrations increase. Tolerance can produce changes in clinical response that mimic certain drug interactions. For example, loss of seizure control may result from either tolerance, as in the case of clonazepam, or enzyme induction, which decreases carbamazepine or valproic acid concentrations. Differentiating between these phenomena is important in considering adjustments in drug therapy.

PHYSIOLOGIC FACTORS AFFECTING DRUG DISPOSITION IN CHILDREN General Considerations Antiepileptic drug pharmacokinetics and dosage requirements are influenced by the changing physiology of children as they age. Table 49-7 summarizes the effect of various developmental stages on absorption, protein binding, metabolism, and excretion. The physiologic changes associated with maturation produce marked alterations in antiepileptic drug pharmacokinetics. The variability with which children reach developmental milestones, along with genetic and environmental factors, causes antiepileptic drug pharmacokinetics to vary substantially, even in children of the same age. As a result of the differences between children and adults, children require more frequent and larger doses relative to body size to attain targeted plasma concentrations. Although important agerelated, quantitative differences in antiepileptic drug TABLE 49-7 Drug Disposition at Different Ages

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pharmacokinetics are recognized, the pattern of drugspecific pharmacokinetics, such as saturation of absorption, protein binding, metabolism, and enzyme induction, is similar for children and for adults. A number of physiologic and pathophysiologic processes can alter antiepileptic drug pharmacokinetics. Gastrointestinal disorders, particularly those that increase transit time, can alter the endothelial lining and decrease absorption. Antiepileptic drugs that are slowly absorbed, such as carbamazepine and phenytoin, are most likely to be affected. Physiologic stress, such as that associated with myocardial infarction, burns, traumatic injury, chronic inflammation, and surgery, increases α1-acid glycoprotein, resulting in greater binding with carbamazepine and carbamazepine 10–11 epoxide [MacKichan, 1992]. Febrile illnesses may produce increases in phenytoin clearance that persist for several weeks, resulting in lowering of plasma concentrations by as much as 50% [Leppik et al., 1986]. Renal failure can affect the excretion of antiepileptic drugs for which the kidney is the primary route of elimination. Both clinical response and plasma antiepileptic drug concentrations should be carefully assessed in patients with renal disease. Severe liver disease can alter the metabolism of antiepileptic drugs, resulting in accumulation of the parent drug [Kutt, 1983]. Antiepileptic drug metabolism appears to be well preserved in mild-to-moderate liver disease. Clinical response may vary, depending on the particular antiepileptic drug. Plasma antiepileptic drug concentrations can fluctuate over a 24-hour cycle. Reports have described a day-night cycle in which both valproic acid and carbamazepine concentrations decrease at night [Lockard and Levy, 1990; Pisani et al., 1990]. The mechanism for this alteration is presumably an increase in clearance. Absorption of entericcoated valproic acid tablets may be reduced at night [Cloyd, 1991]. In either case, evaluating night-time plasma antiepileptic drug concentrations in patients with poorly controlled seizures may be helpful.

Neonates Gastric emptying time is irregular, absorption area is reduced, and biliary function is underdeveloped for several months or more after birth. These factors can contribute to erratic drug absorption [Morselli, 1983]. In addition, gastric pH is elevated, which may reduce the absorption of certain drugs such as clonazepam [Meyer and Straughn, 1993]. In contrast with the oral route, rectal absorption is reliable and efficient. Protein binding is reduced because of lower plasma albumin concenrations, whereas greater extracellular water and less adipose tissue can either increase or decrease distribution volume. Neonatal drug metabolism and renal excretion are reduced. Reactions mediated by hepatic cytochrome P-450 enzymes reach and then exceed adult values within a few weeks after birth. By contrast, renal elimination of drugs and active metabolites may be lower than in adults until the age of 6 months.

Infants and Children From Morrow JI, Richens A. Disposition of anticonvulsants in childhood. Clin Pharmacokin 1989;17 (Suppl 1):89. ↑, Increased from adult levels; ↓, decreased from adult levels; A, equivalent to adult levels.

Gastric emptying time and intestinal motility are increased. Absorptive area, microbial flora, and biliary function approach those in the adult. Conversely, gastrointestinal blood

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Epilepsy / 49

flow is greater than in adults. These physiologic characteristics contribute to faster absorption of most drugs, resulting in earlier time to maximum plasma concentrations. Plasma albumin remains less than adult values, particularly in infancy, resulting in an increased free fraction. Infants and children are capable of synthesizing α1-acid glycoprotein, which will alter the free fraction of drugs bound to this protein. Metabolism remains elevated for the first 2 years of life; in some cases, drug clearances may be two to three times the values seen in adults. Thereafter, metabolism slowly declines, reaching adult values at puberty. After the first 6 months of life, renal excretion is comparable with that in adults.

ANTIEPILEPTIC DRUG INTERACTIONS Interactions involving antiepileptic drugs may alter pharmacokinetics (Fig. 49-5). The clinical significance of pharmacokinetic interactions is determined by several factors, including concentration of the interacting drugs, the patient’s seizure control, and presence of toxicity.

Absorption Concomitant therapy may influence absorption of antiepileptic drugs. For example, continuous tube feedings interfere with phenytoin absorption [Maynard et al., 1987]. Calcium- and magnesium-containing antacids appear to complex with phenytoin, thereby adversely affecting its rate and extent of absorption. They should not be administered concurrently [Cacek, 1986; Fischer et al., 1988]. Gastric pH affects the rate and extent of benzodiazepine absorption; thus, use of antacids and histamine H2 blockers may decrease the plasma concentration of these drugs [Meyer and Straughn, 1993].

Protein Binding Concurrent administration of either aspirin or valproic acid may decrease phenytoin binding. When this occurs, un-

Total plasma concentration

5 half-lives

Steady-state drug concentration

bound phenytoin briefly rises, potentially leading to clinical toxicity. Total phenytoin concentration decreases; however, unbound phenytoin rapidly re-equilibrates to the original concentration, which can be confusing to the clinician, who might be monitoring only total phenytoin concentrations. In general, phenytoin dosing does not have to be adjusted when valproic acid or aspirin is administered, even though total phenytoin levels decrease, unless clinical response so indicates [Scheyer and Cramer, 1990].

Metabolism Drugs interact in many ways, such as induction and inhibition of liver enzyme. Information on how drugs are metabolized may provide insight into the potential for a drug interaction. For example, if a drug is known to be an inducer or an inhibitor of a particular P-450 isoenzyme, it may be possible to predict if a medication will affect the plasma concentrations of a second drug that is metabolized by that P-450 particular isoenzyme when the drugs are given concomitantly. This approach may be particularly useful in predicting the interaction between the many new antiepileptic drugs being developed and other possible concomitant medications (see Table 49-5).

MECHANISM OF ACTION OF ANTIEPILEPTIC DRUGS Epilepsy can be thought of as an imbalance of excitatory and inhibitory activity in the nervous system that can involve alterations in synaptic function or intrinsic membrane properties. Antiepileptic drugs can be used to compensate or correct for this imbalance in opposing activities. Although the mechanism of action of most antiepileptic drugs was discovered after their potential for use as an anticonvulsant was determined, their type of action at the neuronal level can still be placed into these two types of actions: those that increase inhibitory actions and those that decrease excitatory actions.

+ Inhibitor – Inducer – Displacer – Absorption interference

New steady-state drug concentration

– Inhibitor + Inducer + Displacer + Absorption interference

Addition of interacting co-medication

Time

FIGURE 49-5. Schematic of steady-state plasma concentrations of antiepileptic drugs (AEDs) when a particular AED is given alone or in combination with other medications. (We wish to thank Nina Graves, Pharm.D., for her contribution to this figure.)

Conway, Kriel, and Birnbaum / Antiepileptic Drug Therapy in Children

Decreasing excitatory responses may be effected by mimicking antagonists to excitatory amino acid receptors, inhibiting excitatory neurotransmitter release into the synapse, or inhibiting an enzyme needed in the synthesis of the excitatory neurotransmitter. By contrast, drugs can be used to increase inhibitory activity at the synaptic level, such as increasing GABA release into the synapse, increasing synthesis of GABA, or using an antiepileptic drug that has a GABA agonist effect. Activity at sodium or calcium channels can result in bursts of action potentials (e.g., an excitatory response) or in a release of neurotransmitter. The latter activity can be inhibitory or excitatory, depending on the neurotransmitter involved (e.g., glutamate, an excitatory neurotransmitter, versus GABA, an inhibitory neurotransmitter). The newer antiepileptic drugs have multiple and more unique mechanisms for seizure control. Use of drugs with unique mechanisms of action may lead to control of additional types of seizures. Moreover, drugs that have multiple mechanisms of action also can be advantageous because they increase the possibility of controlling seizures in patients with multiple seizure types with one or at least fewer drugs. This practice can result in fewer side effects and lower drug costs. Table 49-8 presents the mechanisms of action proposed for both the older and the newer antiepileptic drugs.

DOSAGE FORMULATIONS AND ROUTES OF ADMINISTRATION Antiepileptic medications are most commonly and conveniently given orally. In many circumstances, however, use of an alternative route of administration is necessary. Oral administration is not possible, for example, before and during surgery and with acute severe trauma, inability to swallow when consciousness is impaired, and gastrointestinal illnesses. Interruption of oral administration occurs in children because of more frequent bouts of vomiting and diarrhea. In acute emergencies, especially within medical facilities, some antiepileptic drugs can be given by intravenous or intramuscular administration. Unfortunately, parenteral formulations are not available for most antiepileptic medications because of their poor solubility in water. This creates a significant dilemma for those persons on maintenance antiepileptic therapy when oral adminis-tration cannot be continued. The rectal route of administration has been extremely useful for those situations [Graves and Kriel, 1987].

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Intravenous and Intramuscular Administration Intravenous administration is a good alternative to oral therapy when patients are hospitalized. Fosphenytoin, a phenytoin prodrug, is not formulated in propylene glycol. It can be given intramuscularly, and the drug can be infused more rapidly than is possible with phenytoin, with fewer adverse effects [Leppik et al., 1989]. Other antiepileptic drugs that are suitable for intravenous administration include valproate, diazepam, lorazepam, and phenobarbital.

Rectal Administration When administered as a solution, diazepam is rapidly absorbed rectally, reaching the time to maximum plasma concentration within 5 to 20 minutes in children [Lombroso, 1989]. By contrast, rectal administration of lorazepam is relatively slow, with a time to maximum plasma concentration of 1 to 2 hours [Graves et al., 1987]. Table 49-9 provides a comprehensive list of antiepileptic drugs available for rectal administration and recommendations for use. Only one rectal formulation is available commercially (Diastat). The bioavailability of carbamazepine oral suspension diluted with an equal amount of water given rectally is similar to that of the oral tablet [Graves and Kriel, 1987]. The bioavailability of topiramate tablets crushed in water and given rectally is similar to that of oral tablets [Conway et al., 2003]. The availability of lamotrigine tablets crushed in water and given rectally is about half that of oral tablets [Birnbaum et al., 2000, 2001]. Some drugs cannot be administered rectally owing to factors such as poor absorption or poor solubility in aqueous solutions. The relative bioavailability of gabapentin and phenytoin has proved to be so low that the current formulations are not considered to be suitable for administration by this route [Fuerst et al., 1988; Kriel et al., 1997; Kvan and Johannessen, 1975; Moolenaar et al., 1981]. The dependence of gabapentin on an active transport system and the much reduced surface area of the rectum compared with the small intestine may be responsible for the lack of absorption from the rectum.

Intranasal Administration Intranasal administration is a potentially attractive alternative route when intravenous administration is impossible or impractical. Nasal access is readily available, even when a patient is having a seizure; requires little, if any, caregiver

TABLE 49-8 Antiepileptic Drug Mechanisms of Action

Sodium Calcium GABA EAA

BZD

CBZ

ESM

FBM

GBP

LTG

LEV

TGB

TPM

PB/PRM

PHT

VPA

VGB

ZNS

+ − ++ −

++ − − −

− ++ − −

++ ? + +

? ++ +/? −

++ + + ?

_ + ? –

− − ++ –

++ ? + +

+ − + −

++ – – −

++ + +/? −

? ? ++ ?

++ ++ ? –

BZD, benzodiazepines; CBZ, carbamazepine; EAA, excitatory amino acid system; ESM, ethosuximide; FBM, felbamate; GABA, γ-aminobutyric acid; GBP, gabapentin; LEV, levetiracetam; LTG, lamotrigine; PB/PRM, phenobarbital/primidone; PHT, phenytoin; TGB, tiagabine; TPM, topiramate; VGB, vigabatrin; VPA, valproic acid; ZNS, zonisamide, ++, main mechanism of action; +, minor mechanism of action; ? inconclusive evidence; –, not a mechanism of action.

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TABLE 49-9 Antiepileptic Drugs Available for Rectal Administration DRUG

TREATMENT USEFULNESS

DOSE (mg/kg/dose)

Carbamazepine (CBZ)

Maintenance

Same as oral

Clonazepam

?Acute

0.02-0.1 mg

Oral suspension (dilute Peak concentration 4-8 hr with equal volume of 80% absorbed water) *Suppository gel (CBZ powder dissolved in 20% alcohol and methylhydroxy cellulose) Suspension Peak concentration 0.1-2 hr

Diazepam

Acute

0.2-0.5 mg

Gel

Lamotrigine

?Maintenance

1.5-2× oral dose

Lorazepam Paraldehyde

Acute Acute

0.05-0.1 mg 0.3 mL

Phenobarbital

?Acute

10-20 mg

100-mg tablet crushed and suspended in 10 mL of water Parenteral solution Oral solution (dilute with equal volume of mineral oil) Parenteral solution

Secobarbital Topiramate

Maintenance Acute ?Maintenance

Same as oral 5 mg Same as oral

Valproic acid (VPA)

Acute

5-25 mg

Maintenance

Same as oral

PREPARATION

PHARMACOKINETICS

Same as acute Parenteral solution 200 mg tablet crushed and suspended with 20 mL of water Oral solution (dilute with equal volume of water) *VPA liquid from capsules mixed into Supocire C lipid base

COMMENTS Definite cathartic effect

Onset may be too slow for acute use Peak concentration in ~45 min; Well tolerated; concentration >200 ng/mL Nordiazepam reached in 15 min accumulates with repeated doses Well tolerated Peak concentration 0.5-2 hr Effect in 20 min; peak concentration 2.5 hr Peak concentration 4-5 hr 90% absorbed Same as for acute Peak concentration 0.5-1.5 hr Peak concentration 2-3 hr, 95% absorbed

Well tolerated Moderate cathartic effect; use glass syringe Onset may be too slow for acute use Well tolerated

Peak concentration 1-3 hr

Definite cathartic effect

Peak concentration 2-4 hr 80% absorbed

Well tolerated

*Extemporaneously prepared using commercial product; all other preparations are commercial products given rectally. Adapted from Graves NM, Kriel RL. Rectal administration of AEDs in children. Pediatric Neurol 1987;3:321 ; and Garnett, WR, Cloyd JC. Dosage from considerations in the treatment of epilepsy. In: Dodson WE, Pellock JM, eds. Pediatric epilepsy: Diagnosis and therapy. New York: Demos, 1993;373–385. Additional data from Birnbaum et al, 2000, 2001; and Conway et al., 2003.

training; and, under the right circumstances, allows rapid drug absorption. Although the absorptive area of the nasal cavity is approximately the same as that of the rectum, the volume of solution that can be instilled is 0.5 mL or less [Romeo et al., 1998]. Several studies comparing intranasal midazolam with intravenous diazepam have been done in children. In summary, both drugs had similar onset of effect and seizure control, although intranasal midazolam has been used for preoperative sedation. Several disadvantages are associated with intranasal midazolam administration: (1) many patients complain of significant nasal discomfort, presumably owing to the acidic pH of the solution, (2) the volume of a clinically relevant dose is too large for many patients, (3) bioavailability after intranasal administration is intermediate and variable, and (4) its elimination half-life in children is short [Burstein et al., 1997]. The rapid elimination half-life may explain the reports of seizure breakthrough within a few hours after intranasal delivery of midazolam [Scheepers et al., 2000]. Intranasal administration of midazolam has been used for preoperative sedation. Absorption of diazepam has been demonstrated after intranasal delivery [Lindhardt et al., 2001]. There are currently no commercial intranasal formulations available.

Other Routes of Administration Lorazepam is absorbed after sublingual administration and can be useful in treatment of serial and prolonged seizures [Yager and Seshia, 1988]. Delivery of antiepileptic agents directly into the cerebral subarachnoid or intraventricular space should be possible. Spinal intrathecal administration of baclofen for control of spasticity is currently used for persons with spinal cord disease and cerebral palsy and can be administered by a programmable continuous pump surgically placed in the abdomen [Albright et al., 1993; Penn et al., 1989]. Transdermal administration of antiepileptic medications is under experimental investigation.

MONITORING OF PATIENTS ON ANTIEPILEPTIC DRUG THERAPY Clinical Monitoring of Efficacy Clinical assessment of patients is of paramount importance in the assessment of the effectiveness of therapy. The ideal response would be the total elimination of seizures without

Conway, Kriel, and Birnbaum / Antiepileptic Drug Therapy in Children

any adverse effects of therapy. A satisfactory clinical response for many patients, however, might be substantial reduction of seizures with elimination of or decrease in adverse effects. One of the most common clinical errors is the premature interpretation of the clinical response. Assessment of seizure control requires an accurate record of seizure frequency and severity before and during therapy. Seizures may be eliminated, reduced or increased in frequency, and more or less severe during therapy. Patients with epilepsy have varying seizure frequency rates before therapy. The length of time required to assess clinical response varies with the frequency of seizures observed before beginning therapy. Patients with infrequent seizures need a longer period of observation on therapy to permit assessment of clinical response. Statistical interpretation of the change in seizure frequency based on modified sequential analysis has been proposed [Leppik et al., 1989]. In addition, achievement of steady state with the new drug regimen is necessary to determine if a medication has been given an adequate trial at any specific dose. The time to achieve a steady state varies considerably from drug to drug, depending on the drug’s half-life. In every case, 5 half-lives must elapse before a steady state is reached. Interpretation of clinical response in patients in whom polypharmacy is necessary is especially difficult. Clinical improvement or deterioration after the addition of a second antiepileptic drug could be due to numerous factors. Such factors include the additive or synergistic effect of the two medications, the effect of the second drug alone, and the effect of the second drug on the metabolism and/or displacement of the initial drug. It is important to make clinical conclusions only after a steady state is reached with the new drug regimen. If improvement is obtained after the addition of the second medication, the clinician should attempt to discontinue the first medication, to determine whether the clinical improvement is an effect of synergistic therapy or that of the second medication itself. Finally, it is necessary to remember that withdrawal of co-medication might have an effect on the disposition of the remaining drug(s), which could influence clinical response (see Fig. 49-5).

Clinical Monitoring of Adverse Effects The clinical state of the patient is more important than laboratory testing for the assessment of adverse effects. It is possible to continuously monitor clinical states, whereas laboratory tests generally are obtained at arbitrary times; therefore, impending organ dysfunction often may be detected earlier by clinical changes, rather than by laboratory tests. The most frequent adverse effects are dose related and often involve the nervous system. Common manifestations of adverse effects are cognitive changes and drowsiness, impaired attention, incoordination, ataxia, and diplopia. In addition to CNS adverse reactions, the liver also may produce signs of toxicity. Early signs of liver failure include anorexia, nausea, vomiting, lethargy, and abdominal pain.

Monitoring of Drug Concentrations The ability to measure blood levels of antiepileptic drugs has been a major advance in the understanding of drug metabolism and disposition and has led to more rational drug

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therapy. The influence of periodic monitoring of blood levels may reduce the number of therapeutic failures by 50% [Kutt and Penry, 1974]. As expected, drug concentrations generally are related to the dose administered; however, unexpected results may occur, especially in cases of patient noncompliance or with drugs that follow nonlinear kinetics.

Interpretation of “Optimal Drug Concentrations” Numerous factors should be considered in the interpretation of drug concentrations. Medications that have rapid absorption and clearance have wide fluctuation between dosing intervals. For example, the liquid formulation of valproic acid, especially when given to a child also receiving enzyme-inducing co-medications, is rapidly absorbed and eliminated; therefore, a twofold fluctuation during dosing intervals is possible. Recording the time of the blood sample in relation to the last dose is needed to properly interpret laboratory results. Unexpectedly low concentrations are most frequently the result of poor compliance; however, they might be seen after the addition of an enzyme-inducing co-medication. Very high drug concentrations are seen with administration of high doses, in persons with genetically low clearance or some disease states, or with use of enzyme-inhibiting comedications such as valproate [Perucca et al., 2001]. The terms optimal drug concentration and target range are preferred over therapeutic range, for several reasons. First, these newer terms express the concept that the optimal dose and drug concentration need to be determined for each individual patient. The ideal or optimal dose and drug concentration would be those associated with complete control of seizures with no adverse effects. Clinical effects and toxicity of antiepileptic drugs correlate better with drug concentrations than with total daily dosage [Glauser and Pippenger, 2000]. Published “optimal drug concentrations” are attempts to report ranges of concentrations at which most patients have improved seizure control without significant adverse effects. These ranges generally have not been determined by controlled studies in large populations. Obviously, more clinical experience correlating clinical response with drug concentrations is available for the older antiepileptic drugs. Although measurement of drug concentrations has contributed greatly to the development of rational drug management, such management is performed less frequently in current clinical practice. In a randomized controlled trial of the impact of drug monitoring, no benefit with regard to improved seizure control or reduced adverse effects was observed in the study group in which levels were routinely sampled [Jannuzzi et al., 2000]. A retrospective study of antiepileptic drug monitoring in a pediatric emergency room setting failed to find a correlation between drug concentrations and clinical decisions [Kozer et al., 2003].

When to Obtain Drug Concentrations Although enthusiasm for routine monitoring of drug concentrations has moderated, this assistance from the laboratory often is helpful in clinical management. Laboratory results are easiest to interpret when the specimen is obtained before a dose once the drug is at steady state. We agree with the published guidelines with regard to specific clinical situations in which determination of drug concentration is useful (Box 49-1) [Glauser and Pippenger, 2000].

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BOX 49-1 CLINICAL INDICATIONS FOR OBTAINING ANTIEPILEPTIC DRUG (AED) CONCENTRATIONS • • • •

Establishing baseline effective concentration Change in dosage Addition or elimination of another AED Evaluation of lack of efficacy (noncompliance or fast metabolizer) • Evaluation of toxicity (excessive dose, drug interaction, slow metabolizer, renal or liver failure) • Evaluation of loss of efficacy (compliance, drug interaction, change in formulation, pregnancy) • Estimation of the “room to move” Modified from Glauser TA, Pippenger CE. Controversies in blood-level monitoring: Reexamining its role in the treatment of epilepsy. Epilepsia 2000;41 (Suppl 8):S6.

It is useful to determine the optimal drug concentration at steady state for the individual patient when seizure control is obtained. Likewise, it can be helpful to demonstrate concentrations associated with adverse effects for a specific patient. Generally, levels should be measured after changes in dosage or changes in co-medication. Obviously, measurement of drug concentrations is essential in most cases to determine if poor seizure control is the result of lack of compliance.

What to Measure Total drug concentrations generally are measured; however, it also is possible to determine levels of free or unbound drug, as well as of metabolites of the administered drug. Free drug concentrations correlate best with clinical effect and toxicity; however, they are more expensive and difficult to obtain. In most cases, the ratio of free to bound drug is relatively constant for a particular patient; therefore, total drug concentrations usually are adequate. In certain instances, however, particularly with critically ill patients under intensive care, determination of free drug levels, especially for phenytoin and valproate, is essential. In such patients, typically many drugs are administered, increasing the likelihood that antiepileptic drugs will be displaced from protein-binding sites. The percentage of unbound valproate increases with higher drug concentrations and with comedication [Cloyd et al., 1992] or when valproic acid is rapidly administered [Birnbaum et al., 2003]. When the bound fraction is doubled, the valproic acid free fraction may be eight times higher [Fenichel, 1986]. Occasionally, measurement of antiepileptic drug metabolites is useful. With several antiepileptic drugs, metabolites are clinically active and contribute to both response and toxicity. Phenobarbital is an active metabolite present during primidone therapy. Carbamazepine-10,11-epoxide is a derivative of carbamazepine and contributes to toxicity [Schoeman et al., 1984]. Oxcarbazepine is therapeutically monitored by measuring its primary metabolite, MHD [Lloyd et al., 1994].

Laboratory Tests Other than Determination of Drug Concentrations In an effort to identify patients in whom serious or potentially life-threatening adverse effects may develop, obtain-

ing complete blood counts and chemistry profiles at routine intervals has become common practice. The cost for this routine monitoring can exceed the costs of medication [Hart and Easton, 1982]. Moreover, controversy is ongoing regarding whether routine laboratory monitoring can actually identify patients as risk for serious reactions or can identify significant adverse events better than clinical monitoring. Identification of life-threatening reactions is rarely made by routine laboratory screening of asymptomatic children [Camfield et al., 1986]. Fulminate or irreversible hepatic failure during valproate therapy is not reliably predicted by laboratory monitoring [Willmore et al., 1991]. Many clinicians, therefore, believe that routine laboratory screening of asymptomatic patients is of little value [Camfield et al., 1989; Pellock and Willmore, 1991]. Perhaps a reasonable compromise would be to obtain complete blood counts and chemistry profiles before, and once after, initiation of antiepileptic drug therapy [Harden, 2000]. Testing for inborn errors of metabolism is often performed before administering valproic acid in very young children.

ADVERSE DRUG REACTIONS TO ANTIEPILEPTICS Adverse drug reactions are defined by the World Health Organization as “any response to a drug that is noxious or unintended, and which occurs at doses used in man for prophylaxis, diagnosis, or therapy” [Venulet and ten Ham, 1996]. The most frequent adverse drug reactions are dose related, mild, and reversible. Less frequently observed but potentially more serious are the idiosyncratic adverse reactions, which generally are not related to dosage.

Central Nervous System Adverse Reactions The CNS adverse reaction profile for children is similar to that for adults. Most of the older antiepileptic drugs— phenytoin, phenobarbital, primidone, carbamazepine, and valproate—and their active metabolites have similar side effect profiles, comprising cognitive impairment, sedation, dizziness, diplopia, ataxia, headaches, and effects on somnolence. The effects of antiepileptic drugs on cognitive function generally are concentration (and dose) dependent. Drug therapy is known to contribute to cognitive deficits, especially treatment with multiple drugs [Thompson and Trimble, 1982]. Removal of antiepileptic drugs frequently results in improved cognitive function and motor skills [Duncan et al., 1990]. It is important to recognize that reaction times, disordered attention, and impulsivity differ even in untreated children with epilepsy from those in control subjects. The differences in attention and reaction time, however, are small between children with mild versus severe seizure disorders [Mitchell et al., 1992]. Side effects frequently occur in children who are given phenobarbital. Phenobarbital has been associated with a significant depression of cognitive function when it is used for treatment of febrile seizures in children. In a randomized, placebo-controlled prospective study, children had lower mean intelligence quotient (IQ) scores both during and 6 months after stopping therapy with phenobarbital [Farwell et al., 1990]. Clinical tolerance does develop to some degree; however, an unacceptably high frequency of adverse effects from phenobarbital commonly is observed in children

Conway, Kriel, and Birnbaum / Antiepileptic Drug Therapy in Children

[Farwell et al., 1990; Wolf and Forsythe, 1978]. The adverse effects are reminiscent of complaints present in attention deficit disorders and include overactivity, aggressiveness, inattention, and irritability. The behavioral disorders are observed in 20% to 50% of children receiving phenobarbital for febrile seizures and result in discontinuation of therapy in 20% to 30% of children [Herranz et al., 1984]. The existence of preexisting behavior problems, especially hyperactivity, is strongly predictive of adverse reactions during phenobarbital therapy. In a study of children receiving phenobarbital for febrile seizures, 80% of those with abnormal behavior before drug therapy reported aggravation of preexisting hyperactive behavior with phenobarbital versus only 20% for children with normal preseizure behavior [Wolf and Forsythe, 1978]. In some cases, these adverse effects may resolve with continuation or with a lower dose of phenobarbital; however, discontinuation of therapy or alternative medication should be considered. The newer antiepileptic drugs—gabapentin, felbamate, topiramate, lamotrigine, tiagabine, oxcarbazepine, levetiracetam, vigabatrin, and zonisamide—are thought to have fewer and less severe adverse effects; however, their adverse CNS effects are similar to those of the older antiepileptic drugs. Although gabapentin has a good safety profile and seems well tolerated in adults, significant behavioral side effects are observed in some children. In a nonblinded, uncontrolled series, adverse behavioral effects were reported in 47% of children given gabapentin for add-on therapy; however, only 12% of children were withdrawn from gabapentin because of these problems [Khurana et al., 1996]. In other reports, aggression, hyperactivity, temper tantrums, and increased oppositional behavior developed in 12 children taking the drug [Lee et al., 1996; Tallian et al., 1996; Wolf et al., 1996]. Most, but not all, of these children had preexisting cognitive dysfunction such as mental retardation, autistic features, or behavioral difficulties. The adverse cognitive changes resolved with discontinuation of gabapentin; if administration of the drug was resumed, the adverse cognitive changes tended to recur. In one 6-year-old female, the drug was clinically effective in controlling seizures as monotherapy and was well tolerated for 6 months before the aggressiveness developed [Tallian et al., 1996]. In limited pediatric trials, 36% of children taking tiagabine have experienced treatment-emergent adverse effects, most commonly somnolence [Gustavson et al., 1997]. In approximately 15% of children, decreased functioning in school, aggression, and other cognitive changes occurred within the first 4 months of initiation of topiramate therapy [Gerber et al., 2000]. A previous history of behavioral changes and concurrent lamotrigine therapy were associated factors. CNS-related adverse effects from topiramate tend to decrease over time [Ritter et al., 2000]. Of greater concern are reports of the development of major depression, schizophrenic-like reactions, and organic psychoses in adults taking vigabatrin (Ferrie et al., 1996; Ring et al., 1993]. A reversible acute psychosis has been reported in a child taking vigabatrin [Martinez et al., 1995]. Development of hyperkinesia, somnolence, and insomnia in children taking vigabatrin has been reported by a number of investigators [Aicardi et al., 1996; Bernardina et al., 1995; Dulac et al., 1991]. Generally, these effects have not led to

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discontinuation of the drug. Although placebo-controlled trials have been conducted in children, statistical analysis of adverse effects was not done.

Gastrointestinal Effects Weight Gain A survey in children and adolescents taking valproic acid found the most common side effects to be weight gain; however, for many patients, the weight gain was “beneficial.” The incidence of unwanted weight gain was 26% in adults and 15% in children and adolescents. An increase in weight was observed more than twice as frequently in females [Clark et al., 1980; Wirrell, 2003]. Weight increase was independent of dose [Covanis et al., 1982]. Weight gain also was reported in children during carbamazepine [Herranz et al., 1988; Hogan et al., 2000] and vigabatrin [Bernardina et al., 1995; Dulac et al., 1991] therapy. Weight gain has been reported in adults taking gabapentin [DeToledo et al., 1997].

Weight Loss Sustained weight loss was reported in children on maintenance topiramate therapy [Reiter et al., 2004]. Seventyfive percent of children and adults during clinical research trials reported a loss of appetite and decrease in body weight while taking felbamate [Bergen et al., 1995]. Zonisamide is being studied as a possible medication to decrease weight in obese adult patients in whom a mean weight loss of 10% has been reported [Gadde et al., 2003].

Gastric Irritation Signs of gastric irritation with heartburn and indigestion are seen with use of some antiepileptic drugs. Gastric irritation during valproic acid therapy can be reduced with administration of lower doses or by taking medication with food [Dean and Penry, 1992]. Use of enteric-coated preparations of valproic acid will enable most patients who did not tolerate valproic acid because of gastrointestinal symptoms (nausea/vomiting, eructation, heartburn) to resume valproic acid therapy [Clark et al., 1980; Wilder et al., 1983]. Aggressive medical intervention with antacids and H2 receptor antagonists (other than cimetidine) has been helpful for some children with clinical signs of gastritis, allowing valproic acid therapy to continue [Marks et al., 1988]. Approximately 20% of patients receiving ethosuximide will demonstrate dose-related adverse effects, primarily gastric distress, vomiting, hiccups, and anorexia [Sherwin, 1983]. Gastrointestinal disturbances also are encountered in 14% of patients taking carbamazepine, with symptoms of nausea, vomiting, anorexia, and constipation [Herranz et al., 1988]. Nausea and vomiting commonly are observed with felbamate [Dodson, 1984; Theodore et al., 1991].

Gingival Hyperplasia Gingival hyperplasia occurs in 10% to 20% of persons treated with phenytoin and is somewhat more frequent in

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Epilepsy / 49

young persons. It is observed more frequently in persons with higher dosages, often appears 2 to 3 months after beginning therapy, and reaches its maximum severity in 12 to 18 months [Babcock, 1965; Little et al., 1975]. Gingival hyperplasia generally resolves within 2 to 5 months after discontinuation or a reduction in medication [Little et al., 1975]. A vigorous program of good oral hygiene started before and continued during phenytoin therapy can be effective in minimizing gingival enlargement [Angelopoulos, 1975; Modeer and Dahloff, 1987; Pihlstrom et al., 1980]. Drugs other than antiepileptic drugs, including nifedipine and cyclosporine, have been associated with the development of gingival hyperplasia [Butler et al., 1987].

Increased Seizures Some patients, especially those with generalized or absence seizures, may experience an increase in seizure activity when carbamazepine is added [Horn et al., 1986; Perucca et al., 1998; Snead and Hosey, 1985]. Vigabatrin also has been reported to increase seizure activity and even lead to status epilepticus [DeKrom et al., 1995]. Aggravation of seizures occurred in 3% of children with generalized seizures, most often in those with nonprogressive myoclonic epilepsy, and was extremely unusual in children with partial epilepsies and infantile spasms [Lortie et al., 1997]. Oxcarbazepine has been reported to increase myoclonic jerks and absence seizures [Gelisse et al., 2004].

Osteomalacia Osteomalacia (rickets) occasionally is seen in patients taking antiepileptic drugs. In a survey of institutionalized patients, 52 of 144 mentally retarded patients ranging in age from 3 to 26 years who were on antiepileptic drug therapy for at least 2 years had elevations of serum alkaline phosphatase levels greater than 2 standard deviations above normal. Most patients were taking phenytoin or phenobarbital [Hunt et al., 1986]. The cause of osteomalacia during antiepileptic drug therapy appears to be multifactorial [Farhat et al., 2002]. Many antiepileptic drugs presumably enhance hepatic conversion of 25-hydroxyvitamin D to biologically inactive metabolites. Clinically significant rickets seldom develops in ambulatory children on antiepileptic drug therapy, or in institutionalized children who are not taking medication. On the other hand, clinically overt rickets was observed in 10% of institutionalized children on phenobarbital and/or phenytoin. In these patients, sunlight was more important for the maintenance of serum 25-hydroxyvitamin D than were supplements of vitamin D [Morijiri and Sato, 1981]. Current evidence indicates that antiepileptic drugs decrease bone mineral density in adults. In adults, correlation with 25-hydroxyvitamin D levels was poor [Farhat et al., 2002]. In children, no correlation was observed between duration of antiepileptic drug therapy and 25-hydroxyvitamin D levels. Bone mineral density measurements tended to be lower in patients on older antiepileptic drugs than in patients on newer antiepileptic drugs but were lower in all patients on any antiepileptic drug than in the control population. It was previously thought that older antiepileptic drugs resulted in induction of vitamin D metabolism, resulting in

decreased bone mineral density; however, the lack of correlation between vitamin D levels and bone mineral density suggests that other mechanisms are operative. Some authors recommend routine bone mineral density monitoring for patients on chronic antiepileptic drug therapy [Farhat et al., 2002]. Consensus is lacking on treatment of patients who have low bone mineral density secondary to antiepileptic drug therapy.

Tremor and Movement Disorders A benign essential type of tremor has been observed with use of valproic acid, beginning within 1 month of initiating therapy. It is dose dependent, occurring in some patients with blood valproic acid levels greater than 40 μg/mL. Reduction of tremor may occur with reduction of dose [Karas et al., 1982]. Tremor also has been seen with use of lamotrigine and gabapentin [Schmidt and Kramer, 1994]. Oculogyric crises and choreoathetotic movements have developed in several adults while taking gabapentin [Buetefisch et al., 1996; Reeves et al., 1996].

Other Effects Hair changes have been associated with antiepileptic drug treatment. Hair changes (thinning or wavy hair) are seen in 12% of children during valproic acid therapy [Clark et al., 1980]. Additional dose-related adverse effects of phenytoin include hirsutism, coarse facial features, and acne, especially in children and teenagers. Pancreatitis has been associated with valproate therapy [Coulter and Allen, 1980; Grauso-Eby et al., 2003; Wyllie et al., 1984]. Visual field changes, which may be irreversible, may occur with vigabatrin treatment [Krauss et al., 1998]. Topiramate has been reported to cause acute myopia and secondary angle closure glaucoma. Patients present with decreased visual acuity and ocular pain. In a majority of cases, immediate discontinuation of topiramate results in a resolution of symptoms [Sankar et al., 2001; Thambi et al., 2002]. Hyponatremia occasionally is encountered in patients taking carbamazepine and oxcarbazepine [Borusiak et al., 1998; Holtmann et al., 2002; Koivikko and Valikangas, 1983]. Hyperthermia and oligohydrosis has been reported in several children taking topiramate and zonisamide. Clinical signs included fever, decreased sweating, and exercise intolerance, which resolved in a majority of cases when topiramate or zonisamide was discontinued [Arcas et al., 2001; Knudsen et al., 2003]. Topiramate and zonisamide may cause nephrolithiasis. The risk is increased with topiramate or zonisamide treatment and the ketogenic diet [Kossoff et al., 2002].

Anticonvulsant Hypersensitivity Syndrome in Children Clinical Features The hypersensitivity syndrome is characterized by rash, fever, and malaise, generally occurring within the first several months of therapy. Certain types of rash may be particularly alarming, such as those of Stevens-Johnson syndrome or toxic epidermal necrolysis. Often hepatic involvement is part of the syndrome, and the liver is the most frequently involved inter-

Conway, Kriel, and Birnbaum / Antiepileptic Drug Therapy in Children

nal organ. Affected children may present with hepatomegaly and elevations in serum transaminase levels. The involvement may progress to hepatic necrosis. Other systems may be involved, including kidney, lungs, bone marrow, and the lymphatic system [Handfield-Jones et al., 1993].

Pathogenesis Although the mechanism of the hypersensitivity syndrome is not completely understood, current evidence implicates toxic metabolites [Glauser, 2000; Verrotti et al., 2002]. The aromatic antiepileptic drugs (phenobarbital, phenytoin, carbamazepine, oxcarbazepine), lamotrigine, and felbamate have been more frequently implicated in causing this syndrome. Presumably, accumulation of toxic metabolites, such as reactive aromatic epoxide intermediates, precipitate the syndrome [Glauser, 2000].

Prevention Routine laboratory monitoring (i.e., with complete blood counts or liver function tests) will not prospectively identify which patients are at high risk for the development of an acute hypersensitivity reaction. Nevertheless, research has allowed practitioners to identify factors that place some patients at high risk. Clinical profiles that identify patients at high risk for hypersensitivity reactions differ for specific antiepileptic drugs (valproic acid, felbamate, and lamotrigine) (Table 49-10). When one of these drugs is being considered for a patient at high risk, the clinician should proceed with caution. Alternative therapy, if possible, should be considered. Additional laboratory tests to screen for inborn errors of metabolism may be indicated when use of valproic acid is under consideration in children younger than 2 years of age. Families need to be advised that the child is in a high-risk category and counseled on the early recognition of the syndrome. Although the identification of a high-risk clinical profile is the most inexpensive practical way available to reduce the TABLE 49-10 Clinical Profiles for Patients at High Risk for Idiosyncratic Reactions to Valproic Acid, Lamotrigine, and Felbamate

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risk of hypersensitivity syndrome, various biomarkers also have been identified [Glauser, 2000]. These biomarkers may indicate that some patients have genetic susceptibility to the accumulation of toxic metabolites due to deficient detoxification pathways. The biomarkers that have been investigated include deficient epoxide hydrolase activity and deficiencies in free radical-scavenging enzyme activity. Unfortunately, assays for these markers are not routinely available at this time.

Managing Adverse Effects The clinician and the patient are faced with adverse effects approximately 30% of the time when antiepileptic medication is used, especially during initiation of therapy. In many instances, this rate is acceptable, especially when the patient and the physician mutually agree on which problems are most important to avoid. When no urgency exists, many adverse effects can be avoided during initiation of therapy by gradually increasing doses. In general, management of adverse effects depends on the problem. Most adverse effects are concentration dependent and are less prominent at lower doses and blood concentrations. Seizure control may or may not be maintained at the lower dose; if not, the clinician and the patient need to consider whether a compromise is acceptable with regard to either increased seizures or increased adverse effects, or if alternative medication should be considered. At times, toxicity is encountered only with high drug concentrations and is seen only at peak times; for these patients, it may be possible to avoid toxicity by more frequent and lower doses or by the use of extended release formulations. Gastric irritation generally is dose dependent and may be managed in several ways: The amount of drug can be reduced, the effective dose to the gastric mucosa can be lowered by use of enteric-coated formulations, or the patient can be protected by use of H2 receptor antagonists. Idiosyncratic reactions pose another problem. Asymptomatic elevations of liver enzymes in general do not mandate discontinuation of therapy if not in excess of two to three times normal values. On the other hand, StevensJohnson syndrome and toxic epidermal necrolysis, clinically symptomatic hepatotoxicity, pancreatitis, and most rashes are indications for immediate cessation of the responsible medication. If the rash was mild, however, and especially if the patient had an otherwise favorable clinical response to the drug, a cautious rechallenge might be considered. Successful resumption of therapy has been reported in a number of patients, especially with valproic acid after that drug was discontinued, when a more gradual dose escalation was used [Schlumberger et al., 1994; Tavernor et al., 1995].

SELECTION OF DRUGS FOR INITIATION OF ANTIEPILEPTIC DRUG THERAPY

From Glauser TA. Idiosyncratic reactions: New methods of identifying high-risk patients. Epilepsia 2000;41 (Suppl 8):S16.

The selection of a specific drug for the treatment of epilepsy is based primarily on the criteria of therapeutic efficacy expected for the patient and seizure type. Certain epileptic syndromes require specific therapy. For most patients and seizure types, however, efficacy differences are minimal, and the selection of the initial drug for antiepileptic therapy is guided equally by a consideration of potential adverse

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effects. Although highly effective, phenytoin is rarely a drug of first choice in children because of a higher incidence of dysmorphic effects. In children, especially those with preexisting tendencies for attention deficit disorders, an unacceptable incidence of behavioral problems, as well as of cognitive dysfunction, has been noted with barbiturate therapy. The principles to be used during initiation and selection of antiepileptic drug therapy in children have been summarized in the literature [Crumrine, 2002; Fenichel, 1986].

DISCONTINUATION OF ANTIEPILEPTIC DRUG THERAPY The decision to discontinue antiepileptic drug therapy often is as challenging as the decision to initiate and continue long-term drug therapy. Most commonly, the question arises after a patient has done well and has become seizure free for some substantial period. At other times, the question arises because of chronic noncompliance, or because no therapy has had a measurable effect on seizure control. Many factors are considered in making these decisions, including the length of the seizure-free interval, drug history, presence of adverse effects, and the neurologic and epilepsy syndrome diagnosis of the patient. Numerous retrospective and prospective investigations are available for review by the clinician who is facing this difficult decision. Ultimately, the decision to withdraw or to continue antiepileptic drug therapy is that of the patient and family, and their perception of acceptable risk of recurrence often differs from that of the treating physician [Gordon et al., 1996].

Benefits of Drug Discontinuation The potential benefits of drug discontinuation are numerous. Most obvious is the immediate reduction in cost to the family and third-party payer with elimination of drug therapy and usually in associated expenses of laboratory tests and physician and clinic charges. In addition, in many patients, the adverse, sometimes previously unrecognized effects of antiepileptic drug therapy are reversed. Patients who have been on phenobarbital, phenytoin, valproate, and topiramate have subtle improvement in various psychometric tasks such as memory, vigilance attention, and visual motor performance [Gallassi et al., 1992; Lee et al., 2003], and in psychomotor speed [Aldenkamp et al., 1993], when therapy was discontinued.

A guideline has been published to assist the physician and the family considering discontinuation of antiepileptic drug therapy. The conclusions were based on a MEDLINE search [Practice Parameter, 1996]. Children who were seizure free for 2 or more years while on antiepileptic drugs, who had a single type of partial or generalized seizure, who had a normal IQ and normal findings on neurologic examination, and a normalized EEG on therapy had a 69% chance of discontinuing antiepileptic drug therapy without seizure recurrence. A similar conclusion was reached by another meta-analysis, in which 75% of “relatively unselected” patients were seizure free 1 year after discontinuation and 71% 2 years after discontinuation of antiepileptic drug therapy [Berg and Shinnar, 1994]. Children with remote symptomatic seizures and those with seizure onset in adolescence (rather than earlier) were at greatest risk of recurrence. Although relapse was observed in every study, in one prospective series, relapse rates were slightly higher in children who had epileptiform activity on the last EEG before antiepileptic drug discontinuation [Andersson et al., 1997]. The authors concluded that the persistence of 3-Hz spikewave activity during therapy also was an unfavorable prognostic sign. Children more frequently had recurrences of seizures when antiepileptic drugs were stopped after 1 year versus 3 years of therapy. In another randomized, prospective study of 6 versus 12 months of antiepileptic drug therapy in children who became seizure free on antiepileptic drug therapy, no difference between relapse rates was observed [Peters et al., 1998]. That report again presented the predictive variables for relapse, which were partial epilepsy, a remote symptomatic etiology, an older age at onset (12 years and older), and an epileptiform EEG during therapy. Families should be encouraged to consider withdrawing antiepileptic drugs once children have become free of seizures for 1 year or longer while on antiepileptic drug therapy. Children whose EEGs have become normal have a somewhat better chance of successful withdrawal of therapy. We particularly encourage an attempt to stop therapy when appropriate in teenagers before they leave home or go to college. Finally, for some patients, withdrawal of antiepileptic drugs is rarely successful—for example, those with abnormalities on neurologic examination or with certain seizure syndromes as juvenile myoclonic epilepsy, LennoxGastaut syndrome, or infantile spasms [Peters et al., 1998; Shinnar et al., 1994]. REFERENCES

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CHAPTER 50

The Ketogenic Diet James W. Wheless

Seizure disorders in childhood represent a frequently occurring neurologic problem. The incidence of epilepsy in children and adolescents ranges from 50 to 100 cases per 100,000 [Hauser, 1994; Hauser and Hesdorffer, 1980]. Antiepileptic drugs are the primary treatment modality and provide good seizure control in most children. However, more than 25% of children with seizure disorders have intractable seizures or uncontrolled seizures, or they suffer significant adverse effects secondary to medication [Heller et al., 1993; Pellock, 1993, 1995, 1996]. Standard antiepileptic drugs produce side effects in 50% or more patients and are associated with a number of chronic toxicity syndromes [Patsalos and Duncan, 1993; Pellock and Pippenger, 1993]. Only a limited number of children benefit from surgical therapy. Uncontrolled seizures pose a variety of risks to children, including higher rates of mortality, accidents, and injuries; a greater incidence of cognitive and psychiatric impairment; poorer self-esteem; higher levels of anxiety and depression; and social stigmatization or isolation [Fisher et al., 1996]. Effective treatment to control seizures is fundamental to improving overall outcome in childhood epilepsy. The shortcomings of antiepileptic drug therapy and epilepsy surgery have allowed alternative treatments to emerge. The ketogenic diet has proved to be an effective alternative treatment for many children with epilepsy [Levy et al., 2003; Wheless, 1995a, 1995b]. An independent review of the role of the efficacy of the ketogenic diet by the Blue Cross and Blue Shield Technology Assessment Center [LeFever et al., 2000] concluded that “… the ketogenic diet appears efficacious in reducing the frequency of seizures in children with refractory epilepsy … this improvement is in the range of, or greater than that reported with the addition of newer antiepileptic drugs.” This evaluation verifies the efficacy and the utility of the ketogenic diet even in the modern era with many more medication treatment options available. In this

chapter, the history of the development of the diet, current understanding of the biochemistry of ketone body formation and its relation to the anticonvulsant effect of the diet, considerations related to patient selection, and diet efficacy, complications, advantages, and disadvantages are reviewed.

HISTORY For centuries, fasting has been used to treat many diseases, including seizures, and it might have been used since Biblical times [Bible, 1982; Livingston, 1972]. Contemporary accounts of fasting were also reported earlier in the 20th century (Table 50-1); the first was the patient of an osteopathic physician Hugh Conklin [Freeman et al., 1994; Hendricks, 1995]. This child did not respond to the conventional treatment of the day, which was a combination of bromides and phenobarbital [Lennox and Lennox, 1960]. Conklin managed the child’s seizures with prayer and fasting, producing dramatic improvement in seizure control during the period of starvation. However, when the period of starvation was terminated, the seizures returned [Bridge, 1949; Conklin, 1922; Freeman et al., 1994]. The child’s uncle, a pediatrician, enlisted the aid of John Howland at Johns Hopkins Hospital to understand how starvation and fasting controlled seizures and discover how to maintain the beneficial effects of fasting [Lennox and Lennox, 1960]. Concurrently, Wilder [1921] at the Mayo Clinic suggested that a diet high in fat and low in carbohydrates could maintain ketosis and its accompanying acidosis longer than fasting [Freeman et al., 1994; Schwartz et al., 1989a, 1989b]. Wilder also coined the term ketogenic diet. Wheless [2004] reviews the history of the ketogenic diet. The beneficial effects of this diet were initially recorded by investigators from Johns Hopkins University, the Mayo

TABLE 50-1 Efficacy of Fasting (1921-1928) PATIENTS STUDY

N

Age (yr)

SEIZURE TYPE

DIET

SUCCESS RATE

COMMENTS

Geyelin, 1921

30

3.5-35

PM, GTC

Fasting

87% seizure free

Weeks et al., 1923

64

7-61

PM, GTC

Fasting

Talbot et al., 1926 Lennox, 1928

23 27

Children 13-42

UN UN

Fasting Fasting

47% seizure free during fast Seizure free during fast 50% had marked reduction in seizures during fast

Results based on 20-day fast; no long-term follow-up Patients fasted for 3 weeks; all had seizures after return to regular diet Seizures returned in all after fast PB stopped on admission; fast lasted 4 to 21 days

GTC, generalized tonic-clonic; PB, phenobarbital; PM, petit mal; UN, unknown.

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Epilepsy / 50

Clinic, and Harvard University. Use of the ketogenic diet was included in almost every comprehensive textbook on epilepsy in childhood that appeared between 1941 and 1980 [Bower, 1980; Bridge, 1949; Keith, 1963; Lennox, 1941; Lennox and Lennox, 1960; Livingston, 1954, 1963, 1972; Livingston et al., 1977; Penfield and Erickson, 1941; Withrow, 1980]. Until 1938, the ketogenic diet was one of the few available therapies for epilepsy. The ketogenic diet fell into disfavor when researchers turned their attention to antiepileptic drug development [Livingston and Pauli, 1975]. After the introduction of sodium valproate, it was believed that this branched-chain fatty acid could treat those children previously placed on the ketogenic diet and that the diet could no longer be justified [Aicardi, 1994]. Use of the ketogenic diet decreased greatly until it received national media attention in October 1994, when NBC Dateline aired a program on the ketogenic diet [Charlie Foundation to Help Cure Pediatric Epilepsy, 1994a, 1994b; Freeman et al., 1990, 1994, 1996; Hendricks, 1995; NBC Dateline, 1994; Schneider and Wagner, 1995]. After an almost 2-decade hiatus, the renewed public and scientific interest led to a better understanding of the use of the ketogenic diet, its inclusion in the American Academy of Pediatrics textbook on pediatric nutrition [Kleinman, 2004], and the publication of a textbook devoted to the ketogenic diet [Stafstrom et al., 2004].

EFFICACY As presented in Table 50-2, reports began to appear in the 1920s and 1930s that documented the efficacy of the ketogenic diet [Barborka, 1928a, 1928b, 1929; Fischer, 1935; Geyelin, 1921; Helmholz, 1927; Helmholz and Keith, 1930; Helmholz and Goldstein, 1937; Lennox and Cobb, 1928; McQuarrie and Keith, 1927; Peterman, 1925; Pulford, 1932; Wilder, 1921; Wilder and Pollack, 1935; Wilkins, 1937]. These were all retrospective reports; some described a small number of patients, and many provided few clinical details or specification of epilepsy syndrome type. The studies clearly demonstrated that some patients had improved seizure control on the diet. Over the next 60 to 70 years, many more clinical reports appeared (Table 50-3) [Keith, 1942; Prasad et al., 1996]. Meta-analysis of the published data is not possible given the differences in study design, sparse clinical details, and the lack of any standardized definitions of what is meant by a good or partial response to the diet [Prasad et al., 1996]. Despite these limitations in some of the older studies, the literature supports the view that the diet improved seizure control in selected children. About one third to one half of children appeared to have had an excellent response to the diet, defined by cessation or marked reduction in seizure activity. When the diet was discontinued, it was usually because of a lack of efficacy. It appeared that younger children were

TABLE 50-2 Efficacy of the Ketogenic Diet (1921-1976) PATIENTS STUDY

N

Age (yr)

SEIZURE TYPE

Peterman, 1925

37

2.25-14.5

PM, GTC

Talbot et al., 1926

12

Children

Cooder, 1933

38

≤12

Helmholz and Goldstein, 1937

501

Children

Wilkins, 1937

30

3-14

Keith, 1963

729

UN

Hopkins and Lynch, 1970

34

1-13

Livingston, 1972

1001 UN

Dodson et al., 1976

50

0.5-38

DIET SUCCESS RATE

COMMENTS

KD 60% seizure free All idiopathic causes; follow-up 0.33 to 2.5 years; 34.5% improved only 2 on PB 5.5% not improved PM, GTC KD 50% seizure free Follow-up for 3-6 months; all idiopathic causes 33% improved 17% no change. GTC, SP, PM KD 50% seizure free >3-month follow-up 34% improved 16% not improved UN KD Idiopathic causes: 92 had symptomatic epilepsy; 142 could not 31% seizure free maintain diet. All children had > 1 year follow-up. 16% definite improvement Results from children treated between 1922 and 53% not improved 1936; 1 child developed pellagra Symptomatic causes: 11% seizure free GTC, PM, MM KD 27% seizure free Idiopathic causes; follow-up > 1.5 years; all 50% no benefit seizure-free patients resumed normal diet UN KD For 530 patients with Patients treated between 1922 and 1944; follow-up idiopathic causes: for 1-30+ years (some included in Helmholz, 1937); 31% seizure free excluded 84 with symptomatic epilepsy; 115 unable 24% improved to follow diet; no deaths due to diet 39% no benefit. GTC, MM KD 29% successful (seizure 1 renal calculus free or much reduced) 32% unsuccessful 26% inadequate trial. UN KD 52% seizures controlled 27% seizures marked improvement 21% no improvement UN KD 50% seizure free 20-30% seizures improved considerably

GTC, generalized tonic-clonic; KD, classic ketogenic diet; MM, minor motor; PB, phenobarbital; PM, petit mal; SP, simple partial; UN, unknown.

Wheless / The Ketogenic Diet

1133

TABLE 50-3 Efficacy of the Ketogenic Diet (1989-2002) PATIENTS STUDY

N

Age (yr)

SEIZURE TYPE

Schwartz et al., 1989b

59

<5-54

M, A, IS, GTC, AB, SP, CP

Kinsman et al., 1992

58

1-20

Vining et al., 1998

51

1-8

Swink et al., 1997a, 1997b

18

0.5-1.75

Freeman et al., 1998a

150

1-16

Hassan et al., 1999 Freeman and Vining, 1999 Kaytal et al., 2000

52 17

5.5 (mean) Children

48

1-15

Hemingway et al., 2001

150

1-16 (mean, 5.3)

Maydell et al., 2001

143

0.34-29 (mean, 7.5)

Nordli et al., 2001

32

Kossoff et al., 2002

23

All < 2 (mean, 1.15) 0.4-2 IS

DIET

KD-24* 81% had >50% reduction of MCT-22 seizures Mod. MCT-13 80% multiple KD 29% seizure controlled seizure type 38% had ≥50% seizure reduction 29% no improvement 230 seizures/mo KD At 1 year: average (IS, 53% off diet (one half with SP, GTC, AB, poor seizure control, one CP, A, M) half with poor tolerance) 40% of original group with ≥50% decrease in seizure frequency 10% seizure free 934 seizures/mo KD At 6 months: average 50% seizure free 42% have ≥50% seizure reductions only 1 discontinued diet 410 seizures/mo KD At 1 year: average (AB, M, 55% remained on diet A, IS, GTC) 43% of original group had ≥50% decrease in seizure frequency 7% seizure free 81% mixed KD-49 MCT-3 Only 13.5% continued diet seizure types >12 months. LGS – M, A KD 100% had >50% decrease in seizure frequency by fifth day. Multiple seizure KD 46% remained on >1 year. types Of those on at least 45 days, 38% had >90% seizure reduction, 33% had 50-90% reduction. Multiple seizure KD 83 on at 1 year types 58 on at >24 months 30 on at >3 years Of original 150: 13% seizure free 14% had 90-99% seizure decrease Many off or on fewer AEDs Multiple types: KD 68% on at 1 year: 34 focal 16% seizure free onset, 100 10% had 90-99% seizure decrease generalized 47% on fewer AEDs Average: 23.8 seizures/day Partial, IS, KD 19% seizure free generalized 35.5% had improvement KD

DiMario and 24 Holland, 2002

1-15 Not given (mean, 6.5)

KD

Coppola, 2002

1-23 CP, GTC, (mean, LGS, M, 10.4) GT, SMEI, AA

KD

56

SUCCESS RATE

At 6 months: 18 on diet 3 seizure free 4 >90% improved 6 >50%, <90% improved At 12 months: 18 on diet 22% seizure free 39% had >50% seizure reduction Mean duration, 5 months At 12 months: 5 patients (8.9%) on diet and all had a >50% to <90% seizure reduction None seizure free at 1 year

COMMENTS MCT diet more unpalatable, prospective series All had severe neurology handicaps: mental retardation (84%), cerebral palsy (45%), microcephaly (15%); 3 renal stones Prospective, multicenter trials; patients failed average of 7 drugs previously

Prospective, all children < 2 years old at enrollment

Prospective, 70% had IQ or DQ < 69, prior trials of 6.2 AEDs (average)

Retrospective; all had cognitive impairment, mean duration of 6.8 mo Inpatient—5-day duration Retrospective; duration > 45 days on diet (mean, 350 days)

Prosepective; 3- to 6- year follow-up of Freeman, 1998

Retrospective; 83 patients had mental retardation

Retrospective; IS responder better than other seizure types Retrospective; age younger than 1 year and exposure to ≤ 3 AEDs predicted improvement Retrospective

Prospective. multicenter; 96.4% had MR, 67% had cerebral palsy, and 16% had microcephaly

*Hyphenated numbers indicate the number of patients on the diet. A, atonic; AA, atypical absence; AB, absence; AEDs, antiepileptic drugs; CP, complex partial; DQ, development quotient; GT, generalized tonic; GTC, generalized tonic-clonic; IQ, intelligence quotient; IS, infantile spasms; KD, classic ketogenic diet; LGS, Lennox-Gastaut syndrome; M, myoclonic; MCT, medium-chain triglyceride diet; Mod MCT, modified medium-chain triglyceride diet; MR, mental retardation; SMEI, severe myoclonic epilepsy of infancy (Dravet’s syndrome); SP, simple partial.

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Epilepsy / 50

more likely to have a more favorable response than older children, because younger children were able to produce more elevated levels of serum ketones and to adhere to the diet’s regimen [Freeman et al., 1998a]. There is a striking lack of data regarding its efficacy in infants from these prior studies. Many studies attest to the efficacy and safety of the ketogenic diet in infants [Klepper et al., 2002; Kossoff et al., 2002; Nordli et al., 2001]. Nordli and colleagues [2001] retrospectively reviewed their experience with 32 infants who had been treated with the ketogenic diet, 17 of whom had infantile spasms. Most infants (71%) were able to maintain strong ketosis. The overall effectiveness of the diet in infants was similar to that reported for older children; 19.4% became seizure free, and an additional 35.5% had a more than 50% reduction in seizure frequency. The diet was particularly effective for children with infantile spasms. Kossoff and colleagues [2002] retrospectively reviewed their experience with the ketogenic diet as a treatment for infantile spasms during a 4-year period. Twenty-three children (5 months to 2 years old), 39% of whom had symptomatic infantile spasms and 70% of whom had hypsarrhythmia, were started on the ketogenic diet. The children had been previously exposed to an average of 3.3 (range, 0 to 7) antiepileptic drugs, and 74% had previously failed or relapsed after adrenocorticotropic hormone or steroids. The average time on the diet was 1.6 years, with 56% remaining on the diet at 12 months, 46% of whom were more than 90% improved (three were seizure free) and 100% of whom were more than 50% improved. Factors that predicted more than 90% improve-

ment at 12 months were age younger than 1 year (P = 0.02) and exposure to more than three antiepileptic drugs (P = 0.03). Improvement in development was related to seizure control. A few early studies evaluated use of the ketogenic diet in adults (Table 50-4). Some revealed improved seizure control [Barborka, 1928a, 1928b, 1930], but subsequent reports concluded that the diet was not particularly beneficial in adolescents and adults with epilepsy [Bridge, 1949; Lennox, 1941; Livingston, 1954, 1963, 1972; Notkin, 1934; Withrow, 1980]. Reasons cited for this finding were poor dietary compliance, types of seizures seen in these age groups, and the developmental differences in the ability of the brain to use ketone bodies. As a result, past studies suggested that the optimum age of response to the diet might be in young children before the onset of adolescence. Some studies have challenged the belief that older patients could not maintain therapeutic ketosis or could not comply with the rigors of the diet and that the ketogenic diet was less efficacious in this age group. Sirven and colleagues [1999] reviewed the tolerability, efficacy, and adverse events in 11 adult patients prospectively begun on the classic ketogenic diet for refractory symptomatic epilepsy. All were on stable medication and had not achieved seizure control with two or more medications, and four had prior surgery. At 8 months of follow-up, one patient was seizure free, five patients had a more than 50% decrease in seizure frequency, one patient had a less than 50% seizure decrease, and four patients discontinued the diet. Common adverse events included gastrointestinal complaints (100%), menstrual irregularities

TABLE 50-4 Efficacy of the Ketogenic Diet in Adolescents and Adults PATIENTS STUDY

N

Age (yr)

SEIZURE TYPE

DIET

SUCCESS RATE

COMMENTS

Barborka, 1928b

49

17-42

GTC, PM

KD

No patients with symptomatic epilepsy; only 5 on an AED (PB); 3-36 month follow-up

Baborka, 1930

100

16-51

GTC, PM

KD

Bastilble, 1931

45

19-57

GTC, PM

KD

Notkin, 1934

20

22-47

GTC

KD

Sirven et al., 1999

11

19-45

PE, GE

KD

Mady et al., 2003

45

12-19

MT, LGS, CP, GTC, M, AT, SP

KD

16% seizure free 22% improved 27% not benefited 35% did not cooperate and stay on diet 12% seizure free 44% improved 44% not benefited Of those staying on diet: 7% seizure free 72% improved 21% seizures increased 16 of 45 unable to maintain diet No improvement in any 90% had increased number of seizures 9% seizure free 46% had >50% decrease in seizure number 9% slight decrease in seizure number 36% discontinued diet Of 20 who remained on diet at 1 year: 6 had >90% efficacy 7 had 50-90% efficacy

No patients with symptomatic epilepsy; 3-60 month follow-up All institutionalized females diagnosed with “epileptic insanity” without known cause; 6-month follow-up; best response seen in those with least “mental disorder” All institutionalized patients and off AEDs; no known cause; average time on the diet 11 months All symptomatic epilepsy; 8-month follow-up

Average duration 1.2 years

AED, antiepileptic drug; AT, atonic; CP, complex partial; GE, generalized epilepsy; GTC, generalized tonic-clonic; KD, classic ketogenic diet; LGS, Lennox-Gastaut syndrome; M, myoclonic; MT, myoclonic-tonic; PB, phenobarbital; PE, partial epilepsy; PM, petit mal; SP, simple partial.

Wheless / The Ketogenic Diet

in all women, and increased serum cholesterol and highdensity lipoprotein (HDL) cholesterol ratios. Subjective improvements in thinking and mood, without a decrease in antiepileptic drugs, were reported in seven patients, one without improved seizure control. Mady and colleagues [2003] reviewed their experience with 45 adolescents who had been on the ketogenic diet for an average duration of 1.2 years. They found no evidence to support the beliefs that the diet was not efficacious and too restrictive in this age group. Adolescents with multiple seizure types did best, and simple and complex partial seizures had the poorest response. The retention rate for motivated adolescents on the diet was not significantly different than reports in younger children. Studies have critically reexamined the benefits of the diet in selected groups of patients (see Table 50-3). Schwartz and colleagues [1989a, 1989b] reported the results of metabolic profiles and seizure control in 59 epileptic children receiving a normal diet or one of three forms of the ketogenic diet: a classic diet (4:1 ratio of fat to protein and carbohydrate), a medium-chain triglyceride (MCT) diet, and a modified MCT diet. Patients fasted for 18 hours and then were placed on one of the diets and monitored for 6 weeks. All three diets produced a significant increase in total ketone body (e.g., acetoacetate, 3-hydroxybutyrate) levels that was most marked using the classic ketogenic diet as described in the Johns Hopkins protocol [Freeman et al., 2000]. Ketone body concentrations reached a maximum in the afternoon and were frequently lower in the morning. Urinary ketones were measured and reflected changes found in the serum. All three diets improved seizure control, and none were superior to the others during the 6 weeks of observation. Overall, these investigators found that 81% of patients had greater than a 45% reduction in seizures. Drowsiness, occurring in 25% of patients during initiation of the diet, usually resolved. The MCT diet was considered less palatable and associated with more side effects, including diarrhea and vomiting. Data for 59 patients have been reported from the group at Johns Hopkins [Kinsman et al., 1992]. All had severe intractable epilepsy, 80% had multiple seizure types, and 88% were on multiple antiepileptic drugs. Improved seizure control occurred in 67% of patients, 64% were able to reduce the amount of antiepileptic drugs they were taking, 36% became more alert, and 23% had better behavior. Comorbid neurologic conditions in this group of patients with refractory epilepsy included mental retardation (84%), microcephaly (15%), and cerebral palsy (45%). Seizure type did not predict success with the diet. Moreover, 75% of the improved patients continued the diet for at least 18 months, confirming the efficacy and palatability of the diet and the willingness to continue administration of the diet by patients and their families. This study confirmed the earlier work by Livingston [1972] on a large number of patients at the same institution demonstrating that 52% had complete control and an additional 27% had improved control. The first multicenter prospective study of the efficacy of the ketogenic diet was based on data collected on 51 children at seven comprehensive epilepsy centers [Vining et al., 1998]. All children had intractable epilepsy, averaging 230 seizures per month. It was found that 10% of treated patients were seizure free at 1 year. A greater than 50% decrease in seizure frequency was observed at 3 months in

1135

54% of patients. This improvement was maintained at 6 (53% controlled) and 12 months (49% controlled) after initiation of the diet. Patient age, seizure type, and electroencephalographic (EEG) abnormalities were not related to outcome. Approximately 47% remained on the diet for at least 1 year. Reasons for discontinuation included insufficient seizure control, inability to medically tolerate the diet, concurrent medical illnesses, or inability to tolerate the restrictive nature of the dietary regimen. Although the number of patients was small, the study demonstrated that the diet could be effectively used in different epilepsy centers with different support staff and that children and their families were able to comply with the diet when it was effective. The study also confirmed results similar to those reported over the past 5 decades. The first large, prospective evaluation of the ketogenic diet was conducted in 150 consecutive children who were 1 to 16 years old (mean age, 5.3 years) [Freeman, 1998a]. The children were followed for a minimum of 1 year, had previously been on an average of 6.24 medications, and were on a mean of 1.97 medications at the diet’s initiation. Seventy percent of children had an intelligence or a developmental quotient of less than 69. The children averaged 410 seizures per month before the ketogenic diet. At 6 months, 71% remained on the diet, and 32% had a more than 90% decrease in seizure frequency. At 1 year, 55% remained on the diet, 7% were seizure free, and 27% had a more than 90% decrease in seizure frequency. There was no statistically significant difference in seizure control based on age, gender, or seizure type, although none had purely partial seizures. Most of those discontinuing the diet did so because it was insufficiently effective or too restrictive. All of the prior reports of efficacy for the ketogenic diet were open-label trials (retrospective or prospective). The first blinded, crossover study of the diet evaluated its efficacy for atonic or myoclonic seizures in patients with Lennox-Gastaut syndrome [Freeman, 1999]. This attempt documented that it was feasible to perform a larger, blinded, placebo-controlled, crossover trial enrolling a population with frequent seizures. The Atkins diet is less restrictive than the ketogenic diet and induces a metabolic ketosis. A small pilot study revealed three of six patients had a more than 50% seizure reduction, with two becoming seizure free [Kossoff et al., 2003]. This report raises important questions about the level of restrictions on protein and calories imposed by the ketogenic diet, and there may be a subgroup of patients who benefit from a less restrictive diet. Dietary therapies may become even more valuable in the therapy of epilepsy when the mechanisms underlying their success are understood.

MECHANISM OF ACTION Clinical reports detailed the efficacy of the ketogenic diet, and several theories emerged to explain the diet’s mechanism of action [Schwartzkroin, 1999]. Four major areas have been investigated: cerebral acidosis, water balance, the direct effect of ketones or lipids, and alteration in brain energy substrates. The importance of ketone body formation was recognized early in the search for a mechanism of the ketogenic diet [McQuarrie and Keith,

1136

Epilepsy / 50

1927]. Initially, acidosis and partial dehydration were considered likely factors contributing to its success [Bridge and Lob, 1931; Lennox, 1928]. Even later, the diet’s effects on water and electrolyte metabolism were thought responsible for its efficacy [Millichap et al., 1964]. Animal studies have found no change in intracellular pH of the cerebral cortex on the ketogenic diet [Al-Mudallal et al., 1996; Harrik et al., 1997]. Preliminary studies using magnetic resonance spectroscopy (MRS) have demonstrated that children on the diet do not develop alteration of brain water and electrolyte distribution [Seymour et al., 1999] or cerebral acidosis [Marks et al., 1997; Seymour et al., 1999]. This finding suggests that although ketoacidosis occurs in these children, changes in brain pH may not be a critical factor. Animal models and human evidence suggest a prominent role for ketonemia [Al-Mudallal et al., 1995; Appleton and DeVivo, 1973, 1974; DeVivo et al., 1975; Stafstrom, 1999; Uhlemann and Neims, 1972]. One study considered elevated levels of plasma lipids a good index in predicting the extent of seizure control in children [Dekaban, 1966]. Subsequent analysis of blood metabolites in nine children on the ketogenic diet revealed a rise in the total serum arachidonate concentration correlated with improved seizure control, suggesting elevated polyunsaturated fatty acids may represent an anticonvulsant mechanism of the ketogenic diet [Fraser et al., 2003]. Despite its prolonged use and proven value, the exact mechanism of action of the diet remains unknown [Nordli and DeVivo, 1997].

Oxidation of Fatty Acids: Ketogenesis Ketonemia is essential for the ketogenic diet to work. Ketonemia occurs because of fatty acid oxidation during fasting or while on the ketogenic diet [Cahill, 1982; DeVivo, 1980; Hawkins and Biebuyck, 1980; Mayes, 1996a, 1996b]. Fatty acids are oxidized to and synthesized from acetylcoenzyme A (acetyl-CoA) [Roe and Coates, 1995]. However, these are not reverse processes. Fatty acid biosynthesis (i.e., lipogenesis) takes place in the cytosol, whereas fatty acid oxidation occurs in mitochondria and generates adenosine triphosphate (ATP). The oxidizable substrate may come from dietary sources (e.g., ketogenic diet) or from mobilization of peripheral adipose stores (e.g., starvation) (Fig. 50-1). The brain does not directly use fatty acids but readily oxidizes ketone bodies [Hawkins and Biebuyck, 1979, 1980]. Increased fatty acid oxidation leading to ketone body (i.e., acetoacetate and β-hydroxybutyrate

Triglycerol

Adipose tissue

Hormone-sensitive lipase

FFA

FFA

BLOOD

FFA

LIVER

FIGURE 50-1. Initial steps in ketogenesis: lipolysis. FFA, fatty acids.

[BHB]) formation by the liver is characteristic of starvation or the ketogenic diet (Fig. 50-2) [Mayes, 1996]. Glucose, present in small concentrations, is necessary to facilitate ketone body metabolism. This condition is referred to as the permissive effect of glucose and is explained metabolically by the conversion of glucose-derived pyruvate to oxaloacetate. Oxaloacetate is the key rate-limiting metabolite of the tricarboxylic acid (TCA) cycle and is necessary for the condensation reaction with acetyl-CoA to form citrate. Acetoacetate continually undergoes spontaneous decarboxylation to yield acetone, which is volatilized in the lungs and gives the breath its characteristic odor. The ratio of BHB to acetoacetate in blood varies between 1:1 and 10:1; the concentration of total ketone bodies in the blood does not normally exceed 0.2 mmol/L. The liver is the only organ capable of synthesizing significant quantities of ketone bodies that are released into the blood (see Fig. 50-2). The liver is equipped with an active enzymatic mechanism for the production of acetoacetate. Once formed, acetoacetate cannot be significantly metabolized back to fatty acids in the liver because it lacks the enzyme 3-oxoacid-CoA transferase. This accounts for the net production of ketone bodies by the liver. Ketone bodies are then transported to and oxidized in extrahepatic tissues in proportion to their concentration in the blood. Oxidation and brain influx rates of ketone bodies are proportional to their blood concentration up to approximately 12 mmol/L. At this level, the oxidative machinery and uptake mechanisms of the cell are saturated [Mayes, 1996]. Glucose is the principal source for brain metabolism. Until 1967, glucose was thought to be the obligate fuel source. Under certain conditions (e.g., fasting, ketogenic diet), the human brain uses ketone bodies for fuel [Owen et al., 1967], with the movement of ketone bodies into the brain depending on a monocarboxylic transport system [DeVivo, 1980]. Acetoacetate and BHB are metabolized primarily in the mitochondrial compartment. In the brain, the main pathway for the conversion of acetoacetate to acetoacetyl-CoA involves succinyl-CoA (Fig. 50-3). Acetoacetyl-CoA is split to acetyl-CoA and oxidized in the TCA cycle. The enzymes that break down BHB and acetoacetate into acetyl-CoA are regulated developmentally, with maximal expression early in life [Dahlquist et al., 1972; Hawkins et al., 1971; Nehlig, 1999]. This finding is consistent with the higher use of ketones by the brain in children compared with adults [Kraus et al., 1974]. The oxidation of ketone bodies serves as a source of energy and contributes to certain cerebral metabolic pathways that normally depend on glucose metabolism (i.e., glutamate, γ-aminobutyric acid (GABA)) [Cooper et al., 1996; Cremer, 1971; DeLorey and Olsen, 1994; Rodwell, 1996; Sokoloff, 1973]. TCA cycle activity is governed by the availability of oxaloacetate and the rate-limiting enzyme, α-ketoglutarate dehydrogenase, which is regulated by the concentration of succinyl-CoA. Increased α-ketoglutarate and decreased succinyl-CoA levels imply maximal TCA cycle activity. Fatty acid oxidation increases brain ATP concentration [Mayes, 1996a, 1996b]. Elevation of brain ATP concentration has been verified in an animal model of the ketogenic diet [DeVivo et al., 1978; Nakazawa et al., 1983] and suggests that the ketogenic diet improves cerebral energetics. Increased cerebral energy reserves are hypothesized to be important

Wheless / The Ketogenic Diet

1137

FFA

Blood

Cytosol

Blood

Mitochondrion Carnitine ␤-Oxidation

Thiolase Acetoacetyl-CoA

Acetyl-CoA Tricarboxylic acid cycle (TCA)

HMG-CoA synthetase ␤-OH-␤-methylglutaryl-CoA HMG-CoA lyase CO2 Acetone

ATP Acetyl-CoA + Acetoacetate ␤-OH-butyrate NADH+H+ dehydrogenase NAD+ ␤-Hydroxybutyrate

Acetoacetate

␤-Hydroxybutyrate

FIGURE 50-2. Ketogenesis in the liver. Fatty acids (FFA) from the circulation enter the hepatocyte and then cross the mitochondrial membrane by carnitine transport (long-chain FA) or diffusion (short- and medium-chain FA).

Blood

Brain

␤-Hydroxybutyrate

␤-Hydroxybutyrate (1)

Acetoacetate

NAD+ NADH + H+

Acetoacetate Succinyl CoA (2) succinate Acetoacetyl CoA (3) Acetyl-CoA + OAA

TCA CYCLE

Succinate

Citrate

Succinyl CoA ␣-Ketoglutarate Succinic semialdehyde (5) GABA shunt

GABA

(4)

Glutamate

FIGURE 50-3. Ketone body use and oxidation in the brain. 1, β-hydroxybutyrate dehydrogenase; 2, 3-oxoacid coenzyme A (CoA) transferase; 3, acetoacetyl-CoA thiolase; 4, glutamic acid decarboxylase (GAD); 5, γ-aminobutyric acid (GABA); OOA, oxaloacetate; TCA, tricarboxylic acid cycle.

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for the anticonvulsant effect. Another mechanism may be alteration of the synthesis or function of GABA. Increases in α-ketoglutarate levels when on the diet may increase input into the GABAA shunt [DeVivo, 1980; McGeer and McGeer, 1989; Peng et al., 1993]. Although entire-brain GABA levels are not changed in an animal model of chronic ketosis [Al-Mudallal et al., 1996; Harik et al., 1997], local differences may occur [Rho et al., 1999b; Yudkoff et al., 2001a]. Two children studied with two-dimensional., double-quantum MRS had low initial GABA levels that increased over time on the ketogenic diet [Wang et al., 2003]. The addition of acetoacetate or BHB to rat synaptosomes increased the rate of GABA formation by 35% and 43%, respectively [Erecinska et al., 1996]. At the same time, the conversion of glutamate to aspartate, which has excitatory properties in the brain, is reduced [Erecinska et al., 1996; Yudkoff et al., 1997, 2001b]. Human studies correlate GABA receptor stimulation with increased energy demand, likely at the synaptic or glial cell level [Peyron et al., 1994]. Activation of GABA pathways, although inhibitory, requires increased energetic demand. The ketogenic diet increases cerebral energetics, potentially helping to meet this demand, and increases the overall GABA inhibitory effects by activating certain GABA receptor subtypes. Many types of epilepsy may involve disruptions of brain energy homeostasis, facilitating potential management through dietary elevations of ketone bodies and reduction of glucose [Greene et al., 2003].

Evidence from Clinical Studies Although the exact mechanism of action of the ketogenic diet is unknown, it is generally accepted that for the diet to be successful, the child must remain in ketosis and generate ketone bodies. Ketonemia is necessary but not sufficient for ketogenic diet-induced seizure control [Stafstrom and Spencer, 2000; Vining, 1999b]. Urine ketones are the only readily available inexpensive approach to ketone assessment, and the desired range is typically 80 to 160 mmol/L. Seizure control correlates significantly (P = 0.03) with serum BHB levels greater than 4 mmol/L, although urinary ketone levels of 160 mmol/L can be found when blood BHB levels exceed 2 mmol/L [Gilbert et al., 2000]. Although serum ketones, particularly BHB, are believed to more accurately reflect the immediate state of ketosis, it is not certain whether it is the presence of these ketone bodies that produces the antiseizure effect. Brown and colleagues [1998] measured serum BHB levels in 12 children during routine clinic visits and during illness. Eight experienced an increase in seizures and decrease in BHB during illness, and four had no seizure increase and no lowering of BHB levels. This finding suggests BHB levels are important for the antiseizure effect. Subsequently, Freeman and associates [1998b] evaluated BHB levels of 35 children 3 months after diet initiation. There was a significant correlation between higher levels of BHB and seizure control. The mean BHB concentration in patients with more than 90% seizure control was greater than 6 mM. The classic ketogenic diet is thought to produce the greatest amount of ketone bodies [Schwartz et al., 1989a]. Despite the fact that ketone bodies partially replace glucose for cerebral metabolism [DeVivo, 1980; Haymond et al., 1983], cerebral glucose levels are unaltered [Al-Mudallel et al., 1995; DeVivo et al., 1978]. Ketones from the circulation

are transported across the blood-brain barrier by facilitated diffusion, using a monocarboxylate transport system [Moore et al., 1976; Pellerin et al., 1998]. The efficacy of the diet in childhood and the apparent slightly lower efficacy in older children and adults may reflect maturational changes in this transport system [Dahlquist et al., 1976; DeVivo, 1980; Dodson et al., 1976; Kraus et al., 1974; Persson et al., 1972; Williamson, 1985]. A child’s ability to extract ketones from the blood into the brain is four to five times greater than that seen in adults [DeVivo, 1983]. This developmentally based ability to extract ketones from the blood may in part explain why the diet is more successful in children. However, even adult animals placed on the ketogenic diet can upregulate brain monocarboxylate transporter levels [Leino et al., 2001]. MRS has documented that fasting and intravenous BHB infusion in humans increase brain BHB levels [Pan et al., 2000, 2001]. Proton magnetic resonance spectroscopy (1H-MRS) carried out on occipital gray matter in five children on the ketogenic diet demonstrated a single resonance identified as acetone [Seymour et al., 1999]. No resonance for BHB or acetoacetate was detected, despite their presence in the blood, indicating the principal intracellular ketone accumulated in response to the ketogenic diet is acetone. Subsequent experiments in rats and mice found that acetone is an antiepileptic agent and that chronic administration may enhance its action [Likhodii et al., 2002; Rho et al., 2002]. MRS has also been used to study changes in cerebral energetics induced by the ketogenic diet. Alteration of the TCA cycle activity by ketosis, resulting in an increased ATP/ADP ratio or greater cerebral energy is thought to have an anticonvulsant effect. This hypothesis is supported by experiments in patients with Lennox-Gastaut syndrome that used phosphorus magnetic resonance spectroscopy (31P-MRS) to document improvement in cerebral energy metabolism on the ketogenic diet [Pan et al., 1999]. During chronic ketosis, adaptive mechanisms occur that increase the cerebral extraction of ketone bodies [Gjedde and Crone, 1975]. These mechanisms may be why ketosis develops promptly within several days after initiation of the diet, although the anticonvulsant effect may be delayed for 1 to 2 weeks [Appleton and DeVivo, 1973, 1974]. This observation suggests that ketosis per se is insufficient to explain the anticonvulsant effect. After ketone bodies are extracted, it is postulated that there is a secondary biochemical change or a cascade of biochemical effects that have some form of anticonvulsant effect [Prasad et al., 1996]. The importance of ketosis was demonstrated by Huttenlocher in 1976. He studied two children with a prior history of myoclonic seizures who were seizure free on the ketogenic diet. After a 50-minute infusion of glucose, the first patient’s serum ketones decreased 67%, with no change in serum pH, and a seizure occurred. The second child’s EEG pattern changed from normal to diffuse polyspike and slow-wave complexes accompanied by myoclonic jerks after 90 minutes of intravenous glucose. Another study, involving nine children with intractable atypical absence seizures treated with the MCT diet, found a significant decrease in the mean number of epileptiform discharges in treated patients [Ross et al., 1985]. A rise in serum ketone levels was the only prominent early biochemical change. DeVivo and associates [1991] also reported two children

Wheless / The Ketogenic Diet

suffering from seizures resulting from a glucose transporter type I defect who were treated with the ketogenic diet, resulting in complete control of seizures and improvement in neurologic development. These observations and others suggest a pivotal role for ketone bodies in providing an alternative energy source and in achieving a still unknown role in seizure control [Aicardi, 1992; DeVivo, 1983; DeVivo et al., 1978; Huttenlocher, 1976; Lamers et al., 1995; Livingston, 1954; Millichap et al., 1964; Schwartz et al., 1989b; Withrow, 1980].

Evidence from Experimental Studies In the past decade, the results of basic research have shed light on the ketogenic diet and its effect on brain chemistry. Several animal models have been used to study the effects of the ketogenic diet [Bough et al., 2002, 2004; Stafstrom, 1999; Stafstrom, 2003]. In general these animal models demonstrate that the ketogenic diet provides protection for partial-onset seizures with secondary generalization and generalized myoclonic, tonic, and tonic-clonic seizures, providing laboratory evidence that the diet is effective against a variety of seizure types. However, some studies have failed to demonstrate a protective effect for the ketogenic diet in models when animals were acutely challenged with a convulsant stimulus (i.e., kainic acid, strychnine, or maximal electroconvulsive shock) [Bough et al., 2000a, 2002; Thavendiranathan et al., 2000]. The discrepancy is likely explained by the fact that the later studies did not test the diet in animals with spontaneous seizures. The relative efficacy of the ketogenic diet in different animal models suggests that different areas of the brain may be affected more than others, and this pattern may be related to localized differences in the function of GABA, other neurotransmitters (e.g., norepinephrine) [Szot et al., 2001], or protein phosphorylation [Ziegler et al., 2002]. A direct effect by acetoacetate or BHB on the primary voltage- and ligandgated ion channels mediating excitatory or inhibitory neurotransmission in the hippocampus could not be demonstrated [Thio et al., 2000]. Despite differences in ketogenic diet protocols and laboratory models, they collectively document improvement in control of multiple seizure types by increasing seizure threshold [Thavendiranathan et al., 2003]. The response of most seizure types to the ketogenic diet implies that the diet exerts a general suppressant effect on neuronal excitability. A limited number of animal studies have investigated the effect of age at diet onset versus efficacy. These studies used different diet types and durations and different seizure models. However, all conclude that the diet provides a greater level of seizure protection for younger animals than for older animals [Bough et al., 1999c; Rho et al., 1999a]. However, adult animal models also demonstrate an elevated seizure threshold [Appleton et al., 1974; Bough et al., 1999b; Hori et al., 1997]. The relation between the degree of seizure control and extent of ketonemia has only recently been explored. Although it would seem intuitive that increasing ketonemia would correlate with efficacy of the ketogenic diet, experimental studies have not revealed a positive correlation [Bough et al., 1999a, 2000b; Likhodii et al., 2000]. However, rats that developed higher levels of ketosis also

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had higher thresholds for seizure induction [Bough et al., 1999b]. A threshold level of ketosis may be required that must be maintained for the ketogenic diet to be effective; whether seizure control is improved by further degrees of ketosis is not clear. These same investigators and others have suggested that caloric restriction can significantly influence seizure threshold and augment the effects of the ketogenic diet on seizure control [Bough et al., 2000a, 2002, 2003; Cheng et al., 2004; Greene et al., 2001]. The classic ketogenic diet is composed primarily of long-chain saturated fatty acids. Experimental studies in rats have found no difference in the level of seizure protection or brain fatty acid profiles when they were fed a variety of qualitatively different types of diets [Dell et al., 2001; Likhodii et al., 2000]. In addition to an anticonvulsant effect, several animal models (i.e., kainic acid, knockout mice, EL mice) provide evidence that the ketogenic diet can prevent epileptogenesis, the process by which the brain develops an epileptic condition [Bough et al., 2003; Muller-Schwarze et al., 1999; Rho et al., 1999c, 2000; Stafstrom et al., 1999; Su et al., 2000; Todorova et al., 2000]. These studies support the clinical observation that children can be gradually weaned off the ketogenic diet, resume a normal diet, and not experience loss of seizure control. These animal models help explain the mechanism of action of the ketogenic diet, ultimately aiding in the development of novel antiepileptic drugs or treatments.

SELECTION OF CANDIDATES FOR THE DIET Indications Indications for the use of the ketogenic diet have unfortunately grown out of experience, not from understanding its physiologic action. Despite the fact that several thousand patients have been treated, there are no consensus criteria describing which patients are candidates for the diet [Maria et al., 1997] (see Tables 50-1 to 50-4). Many seizure types appear to respond to the ketogenic diet. In general, several groups of children are potential candidates for treatment. These include children with the following conditions: 1. Medically intractable seizures 2. Poor tolerance or significant side effects from antiepileptic drugs 3. Intractable seizures in persons who are being considered for epilepsy surgery (i.e., callosotomy, nonlesional resection, or extratemporal resection) 4. Specific neurometabolic disorders or neurologic syndromes (Box 50-1) The physician must also consider age for patients with medically intractable epilepsy or those who have serious side effects from medication. Children 1 to 12 years old have had successful outcomes. It is often more difficult for older children to maintain ketosis. Seizure type appears to be less important. Almost all seizure types respond to the ketogenic diet. The success of the diet for children is determined far more by circumstances within the home than by the epilepsy itself. The ketogenic diet is a strictly regulated medical diet. Its success depends on the detailed

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Box 50-1 SPECIFIC CONDITIONS TREATED WITH THE KETOGENIC DIET • Glucose transporter deficiency syndrome (GLUT1-DS, McKusick 138140) • Pyruvate dehydrogenase complex deficiency (McKusick 312170) • Associated with Leigh’s syndrome • Associated with lactic acidosis and cerebral dysgenesis • Phosphofructokinase deficiency • Ketotic hypoglycemia • Acquired epileptiform opercular syndrome • Rett’s syndrome

accuracy and consistency with which the regimen is carried out within the home. Continued support, monitoring, and education by a team of professionals, including physicians, dietitians, nurses, and social workers, are necessary. Little is known about whether the ketogenic diet should be considered for patients who are being evaluated for epilepsy surgery. The diet could be used preferentially in selected candidates who are being considered for corpus callosotomy, nonlesional resection, or extratemporal resection. For patients in whom a malignancy or vascular malformation is detected, surgery is preferable. Additional research is needed in this area.

Brain

Blood

Glucose

A

Glucose

1

Pyruvate Acetoacetyl-CoA

2

Acetyl-CoA

B

Citric acid cycle

Respiratory chain

ATP

BBB

Ketones (acetoacetate, ␤-hydroxybutyrate)

The ketogenic diet may be the preferred initial therapy for children with seizures and specific metabolic defects or seizures associated with specific neurologic syndromes (Fig. 50-4 and see Box 50-1) [DeVivo, 1991; DeVivo et al., 1973; Haas et al., 1986; Klepper et al., 2002, 2004; Liebhaber et al., 2003; Melvin et al., 1996; Shafrir and Prensky, 1995; Weber et al., 2001; Wexler et al., 1997; Wijburg et al., 1991]. These specific metabolic disorders are reviewed in other sections of this textbook, as is the use of the ketogenic diet for their treatment. For some patients, the ketogenic diet is contraindicated (Box 50-2). Children with acute intermittent porphyria and seizures should not be treated with the ketogenic diet because carbohydrate restriction can be harmful in this condition. The ketogenic diet may also worsen some mitochondrial diseases, pyruvate carboxylase deficiency, or organic acidurias [Demeritte et al., 1996b; Kleinman, 2004; Nordli, 2001]. When indicated, obtaining a metabolic screen, including urine amino and organic acids, serum amino acids, lactate, pyruvate, and carnitine profile should be done before starting the ketogenic diet [Wheless, 2001]. The combination of the use of the ketogenic diet with topiramate or zonisamide appears to be associated with an increased risk of acidosis.

Candidate Selection and Encephalography The predictive value of an electroencephalogram obtained before, during, or after initiation of the ketogenic diet is

FIGURE 50-4. Metabolic defects and the ketogenic diet. Glucose enters the brain by the glucose transporter, GLUT1 (A); ketones penetrate the blood-brain barrier (BBB) by the medium-chain triglyceride transporter (MCT1) (B). GLUT1 deficiency syndrome is caused by a defect in glucose transport into the brain (1). Pyruvate dehydrogenase deficiency impairs acetyl-CoA production (2). The ketogenic diet bypasses these two defects and provides acetyl-CoA for brain energy production.

Wheless / The Ketogenic Diet

Box 50-2 SPECIFIC CONTRAINDICATIONS TO THE KETOGENIC DIET • • • • • • • •

Pyruvate carboxylase deficiency Organic acidurias Mitochondrial disease Porphyria Defects in fatty acid oxidation Carnitine deficiency Glutaric aciduria, type II Pyruvate dehydrogenase phosphate deficiency

unknown. In 1933, Eley described 29 children with epilepsy studied before institution of the ketogenic diet. Approximately 90% of children with normal EEG results responded favorably to the diet, compared with only 12% with abnormal EEG patterns [Eley, 1933]. Penfield and Erickson [1941] mentioned that patients with abnormal hyperventilation study results were more likely to respond to the diet. Livingston [1954] reported on the EEG findings for 102 patients and found that those patients who did best on the diet had petit mal variants (i.e., spike-and-wave forms). Surprisingly, carefully done studies examining the relation of the EEG results and response to dietary treatment have not been reported. The multicenter study was unable to correlate any baseline EEG pattern with outcome, except for children with multifocal spikes, who did less well at 3 months but had no differences at 6 or 12 months [Vining et al., 1998]. Many studies, including the original works of Bridge [1949], Livingston [1954], and Keith [1963], have suggested improvement or normalization of the EEG pattern after the diet has been implemented. Nellhaus [1971] correlated normalization of the EEG pattern with the onset of ketosis, clinical improvement, and prognosis. Others have observed that EEG improvement might be seen with clinical improvement in patients with minor motor and petit mal seizures but not in those with focal or generalized tonic-clonic seizures [Janaki et al., 1976]. Children with atypical absence seizures demonstrated a significant decrease in the number of epileptiform discharges at initiation of MCT therapy. However, their EEG patterns were unchanged from baseline at the end of a 10-week treatment period, despite two thirds having a greater than 50% decrease in seizure frequency [Ross et al., 1985]. Demeritte [1996a] stated that there was no correlation between epileptiform activity and seizure improvement. However, background EEG improvements did correlate with a significant reduction in seizures. Ambulatory 24-hour electroencephalograms used to document the extent of ictal abnormalities in patients with frequent astatic events have shown sensitivity in documenting the rapid impact of the ketogenic diet in decreasing electroclinical seizures [Freeman et al., 1999].

INITIATION AND MAINTENANCE A comprehensive monograph on the evaluation and management of patients being considered for placement on the ketogenic diet was published and then revised by Freeman and colleagues at Johns Hopkins University [Freeman et al., 1994, 2000]. A videotape, “The Ketogenic

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Diet for Families, Dietitians, Nurses and Physicians,” and other resource materials are available from the Charlie Foundation (see “Resources” at the end of this chapter). The following sections offer an overview of how the diet can be implemented.

Prehospital Evaluation After a child is considered a candidate for the diet, a screening evaluation by selected members of the team responsible for implementing the diet is initiated. Screening usually includes a comprehensive evaluation by the dietitians and nursing staff. The purpose of this evaluation is to educate the family and to assess their ability on many levels to carry out the rigorous and exacting program necessary to maximize the diet’s success. At the same time, the different types of meal plans and foods that the child can eat and their preparation are discussed. Issues involved in this evaluation are carefully considered and reviewed by Casey and colleagues [1999] and by Freeman and associates [2000].

Hospitalization The child is scheduled for elective admission to the hospital for initiation of the ketogenic diet (Box 50-3). Parents are told to view this treatment as a 4-week trial. During this time, they must adhere strictly to the diet, with proof of persistent ketosis. The frequency of seizures usually decreases gradually, but reversal of the effect can occur rapidly. Weeks of hard work can be undone if a child eats a cookie or a piece of candy. If the seizures are improved, this usually is sufficient motivation for the parents to continue.

Box 50-3 INITIATION OF THE KETOGENIC DIET Hospitalization for 3 to 5 days Day 1 Initial fast Fluids, 75% of maintenance Check urine ketones each void Check fingerstick blood glucose every 6 hours Initial electroencephalogram, laboratory tests Simplify antiepileptic drug (AED) regimen; change to low or carbohydrate-free formulation Dietitian consultation Education Days 2 to 3 When urine ketone level is 160 mg/dL, start ketogenic diet, 4:1 ratio, with one third of total calories using eggnog for 2 or 3 meals, then two thirds of total calories for 2 or 3 meals Stop fingerstick blood glucose checks. Days 3 to 4 First regular meal on 4:1 ratio Discharge—AED regimen B vitamins, sugar-free multivitamin Calcium supplements

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If there are any questions that the child may have an underlying metabolic disease that could be exacerbated by the initial fast, an appropriate evaluation should be done before initiating the diet. Valproate has been proved experimentally to reduce fasting ketonemia [Thurston et al., 1983; Turnbull et al., 1986]. Clinically, valproate has not impaired the ability to initiate the ketogenic diet and achieve adequate ketosis. The day before hospital admission, the parents are asked to eliminate carbohydrates from the child’s diet. The child eats foods that contain only protein or fat. After dinner, the child begins fasting with only noncaloric, noncaffeinated beverages given. On the first hospital day, a wake-and-sleep electroencephalogram may be obtained. Laboratory studies (i.e., complete blood cell count, platelet count, chemistry panel, and antiepileptic drug levels) are carried out before or at the time of admission. During this time, the child receives 75% of maintenance fluids and may have one caffeine-free diet drink per day. Blood glucose levels are checked every 4 hours. The dietitian uses this time to further review meal plans and the child’s food preferences and eating habits with the parents [Lasser and Brush, 1973]. When the concentration of urinary ketones reaches 60 to 80 mg/dL, the child is started on the ketogenic diet, using a 3:1 or 4:1 ratio (fat to protein plus carbohydrate), depending on the child’s age. Ketogenic eggnog is used for the initial feedings. The child receives three meals at one third of the total calories, is advanced as tolerated to two thirds of the total calories for three meals, and then eats his or her first full meal. If the child does not achieve maximum urinary ketone levels by 48 hours of fasting, the diet is begun. More prolonged fasting has not been considered helpful. Before discharge, the parents prepare their first ketogenic meal for their child under the supervision of the dietitian. At discharge, the parents have several meal plans for their child and are instructed to monitor the urinary ketone levels on a daily basis and record all seizures. Individual decisions are made during the hospital stay about whether the antiepileptic drug regimen will be simplified. The child is given a prescription for sugar-free multivitamin, mineral, and calcium supplementation and instructed to begin these at home. Vitamin B supplement is given to prevent optic nerve dysfunction [Hoyt and Billson, 1979]. Vitamin D and calcium supplementation prevents osteomalacia and decreased bone mass while on the ketogenic diet [Hahn et al., 1979]. Inadvertent administration of carbohydrates may occur when intercurrent illnesses are treated. Parents and pediatricians must appreciate that decongestants, antipyretics, and antibiotics are often formulated in carbohydrate-containing vehicles [Feldstein, 1996; Freeman et al., 2000; Lebel et al., 2001; McGhee et al., 2001]. The child is seen regularly for follow-up evaluations (Box 50-4). Special attention should be given to the serum albumin and total protein concentrations to make sure that the diet is providing enough protein. Cholesterol and triglyceride levels typically rise when the diet is started, but the diet may be continued unless the cholesterol level rises above 1000 mg/dL and consistently stays there. It is not known whether cholesterol-reducing drugs can be safely given while the child is maintained on the diet. It is not unusual to see minor elevations in the direct bilirubin level. Decisions regarding withdrawal of antiepileptic drugs

Box 50-4 KETOGENIC DIET MAINTENANCE One Month Neurologist, dietitian, nurse Adjust diet as needed Laboratory tests: complete blood cell count (CBC), platelets; SMA20; antiepileptic drug (AED) levels Urine calcium, creatinine Three, 6, and 12 Months Neurologist, dietitian, nurse Labs, CBC, platelets, SMA20 AED levels, if needed, and urine calcium, creatinine New meals Maintain for 2 years, seizure free Wean over 1 year 3.5-3 months → 3:1-3 months → 3.5-3 months → 2:1-3 months → Off

depend on the child’s response to the diet. At follow-up, the dietitian reviews parental concerns about implementing the diet and makes adjustments in the meal plan as necessary to maintain the child in maximum ketosis. If the child is in apparent maximum ketosis (i.e., urinary ketone levels are more than 160 mg/dL) and seizures recur, the problem may be an excess amount of calories, which may manifest as an excessive gain in weight. Lowering the total caloric intake (and carbohydrates) may help reduce the number of seizure recurrences. If the child is not in maximum ketosis, seizures may be caused by a break in the diet (e.g., “cheating,” medicine with sugar) or perhaps a lower than 4:1 ratio of fat to protein and carbohydrate. For children who can be successfully withdrawn from antiepileptic drug therapy and are seizure free for 2 years on the ketogenic diet (about 10% of treated children), an electroencephalogram is repeated, and the ketogenic diet is slowly withdrawn over 1 year. Many of these families elect to continue a low-carbohydrate diet, concerned that seizures may recur.

COMPLICATIONS Physicians should stress to parents that the diet is a form of medical therapy, and as such, although it is relatively safe, it is not without side effects [Ballaban-Gil et al., 1996; Wheless, 2001]. However, only 6% to 12% of patients discontinued the diet for medical reasons [Thompson et al., 1998; Vining et al., 1998]. Like antiepileptic drugs, the ketogenic diet has an adverse event profile, consisting of possible complications seen during initiation or maintenance (Boxes 50-5 and 50-6) [Wheless, 2001]. If the child has an unrecognized metabolic defect, a catastrophic event could occur during the fasting phase (see Box 50-2). Other adverse events can occur during the initial hospital stay, and if recognized, they are usually easily treated (see Box 50-5). A number of adverse events can occur during the maintenance phase. Many can be prevented with close monitoring,

Wheless / The Ketogenic Diet

Box 50-5 POSSIBLE ADVERSE EVENTS DURING INITIATION OF THE KETOGENIC DIET Adverse Events Dehydration Hypoglycemia Vomiting Monitoring and Treatment Strategy Encourage fluids (do not limit fluids to less than 75% of maintenance); use intravenous fluids if necessary (without dextrose). Check blood glucose levels every 6 hours until the diet is initiated. If the patient is symptomatic or blood glucose < 30 mg/dL, give orange juice. Screen for metabolic errors in advance. Use intravenous fluids; give orange juice.

Box 50-6 POSSIBLE ADVERSE EVENTS DURING MAINTENANCE OF THE KETOGENIC DIET Adverse Events Constipation, exacerbation of gastroesophageal reflux disease Poor growth Kidney stones Dyslipidemia, hyperlipidemia Prolonged QT interval, cardiomyopathy; excessive bruising; optic neuropathy; elevated levels of very-long-chain fatty acids Vitamin D deficiency, osteomalacia Trace mineral deficiencies Monitoring and Treatment Strategy Medical management may include the use of mineral oil and suppositories. Check albumin and total protein levels. Ensure adequate protein in diet. Monitor height and weight. Assess with renal ultrasonography. Analyze stone (specific treatment). Increase fluids and alkalinize urine. Check liver function test results and lipid profile; for sustained elevations of cholesterol or triglycerides, adjust diet or treat, or both. Assess with electrocardiography or echocardiography. Check selenium levels. Obtain complete blood cell and platelet counts. Supplement B vitamins. Check patient before ketogenic diet starts if problems clinically suspected. Supplement vitamin D, calcium, copper, selenium, and zinc. vitamin supplementation, and anticipatory treatment. The most common side effect encountered is constipation, which can be reduced if a calcium supplement with magnesium is given. Many of the children who begin the diet are already prone to this problem because of limited mobility, hypotonia, or spasticity. Constipation can be treated with regular doses of mineral oil, intermittent pediatric Fleet

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enemas, or milk of magnesia. Renal stones have occurred in less than 5% to 10% of patients and can usually be easily managed [Casey et al., 1999; Chesney et al., 1999; Freeman et al., 1994, 1996; Furth et al., 2000; Herzberg et al., 1990; Kaytal et al., 2000; Kielb et al., 2000; Kossoff et al., 2002; Maydell et al., 2001; Nordli et al., 2001]. The risk of stone formation is increased in younger patients (<3 years old), particularly those with hypercalciuria [Furth et al., 2000]. Children can be screened for hypercalciuria (i.e., urinary creatinine-to-calcium ratio), and fluid intake can be maximized to minimize the risk of nephrolithiasis. Asymptomatic hematuria or an unexplained increase in seizure frequency may be signs of nephrolithiasis. Even children who develop renal calculi may be able to remain on the ketogenic diet. In most children, stones are the result of hypercalciuria. Evaluation to determine the type of renal stone and the patient’s urinary calcium-to-creatinine ratio is necessary. If renal stones appear to be caused by hypercalciuria, the patient can be treated with hydrochlorothiazide (2 mg/kg/day), given as Polycitra to alkalinize the urine, and monitored with repeated urinary studies and renal ultrasound examinations. If the calcium-to-creatinine ratios normalize or dramatically improve and no additional renal stones occur, the diet can be maintained. Acetazolamide, which is sometimes used to treat certain forms of seizures, should not be used during initiation of the diet for fear of producing symptomatic metabolic acidosis [Dodson et al., 1976]. Topiramate (Topamax) and zonisamide (Zonegran) are weak carbonic anhydrase inhibitors that when combined with the ketogenic diet, predispose to metabolic acidosis. The ketogenic diet can be cautiously initiated in children on these drugs. However, the physician should be aware that this may cause worsening of metabolic acidosis in some children, especially during ketogenic diet initiation, and it may require adjustments in the drug dose, alterations of the diet, or addition of Polycitra [Takeoka et al., 2002]. No increased risk of nephrolithiasis has been reported in patients on topiramate or zonisamide and the ketogenic diet [Kossoff et al., 2002; Takeoka et al., 2002]. All children treated with one of these medicines should be treated with increased hydration, monitoring of their urinary calcium-to-creatinine ratio and, if elevated, alkalinization of urine. Fatigue occurs in many children during initiation of the diet, but it is prolonged in only a small number. Children with gastroesophageal reflux, especially if they have cerebral palsy, may have increased gastroesophageal reflux while on the diet. The high fat content decreases gastric emptying, which promotes gastroesophageal reflux. This problem usually can be managed medically. Use of the ketogenic diet in infants to treat their seizure disorder or selected metabolic disorder has rarely been associated with fat malabsorption and secondary failure to thrive due to physiologic pancreatic insufficiency [Goyens et al., 2002]. This condition has been corrected by alteration of the diet by the use of MCTs and pancreatic extract. Close attention to growth measurements, laboratory data, and medical supervision is indicated for infants on the ketogenic diet. Only short-term information on growth in a limited number of patients had previously been available [Couch et al., 1999; Kossoff et al., 2002; Liu et al., 2003; Williams et al., 2002]. A prospective cohort study of 237 children, with an average follow-up of 308 days, analyzed age- and sex-appropriate

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height and weight measurements over time on the ketogenic diet [Vining et al., 2002]. A small decrease in height scores was observed in the first 6 months, with larger changes seen by 2 years. There was a drop in weight in the first 3 months, and after this, the weight remained constant in children who started the diet below the 50% level for their weight, but it continued to decrease in children starting above the 50% level. Very young children (0 to 2 years old) grew poorly on the diet, whereas older children (7 to 10 years old) grew almost normally. Several laboratory abnormalities have been reported in children on the ketogenic diet, although none was found to have clinical significance. Patients on the ketogenic diet are in a chronic acidotic state, putting them at risk for osteopenia, but no formal studies evaluating bone health have been done. As a result of this compensated metabolic acidosis, the young child may become markedly acidotic, ketotic, or dehydrated. This problem can be addressed by forewarning parents to increase fluid intake during illness. Serum cholesterol and triglyceride levels may increase, especially during the first 6 months, and tend to plateau after 6 months; they require routine monitoring [Bergqvist et al., 1998; Chesney et al., 1999; Dekaban et al., 1966; Vining, 1999a]. Adjustments to the diet (e.g., increased protein and polyunsaturated fat) can be made in children with significantly high cholesterol and triglyceride concentrations. Impaired neutrophil function was described in ketotic children, but only one child had severe, recurrent infections [Woody et al., 1989]. This finding has not been replicated. Slight to significant prolongation of the bleeding time and abnormal platelet aggregation despite normal platelet count and partial thromboplastin time were reported in six children [Berry-Kravis et al., 2001a]. Patients on the diet undergoing surgery should be evaluated for symptoms of bleeding tendency. Elevated very-long-chain fatty acids were found in one medical center in 59% of patients on the diet and subsequently raised concerns about confusing this side effect with peroxisomal disorders [Theda et al., 1993]. Changes in the serum carnitine ratios have also been described. Some authorities believe a carnitine supplement should be given routinely [Demeritte et al., 1996b]. Carnitine status should be monitored, although most children do not need supplementation [Berry-Kravis et al., 1998, 2001b; Lin et al., 1998]. Carnitine supplementation may have opposing effects; carnitine deficiency may restrict fatty acid beta-oxidation, and carnitine may also improve glucose transport into cells. Supplementation with magnesium, zinc, calcium, vitamin D, and B vitamins is recommended to avoid deficiency-related disease states [Hahn et al., 1979; Hort et al., 1979]. The ketogenic diet is deficient in several trace minerals, and if children are maintained on the diet for more than 2 years, these should be supplemented [Bergqvist et al., 1999, 2003; Chee et al., 1998; Goodwell et al., 1998]. Serious complications of the ketogenic diet are rare and typically consist of single reports: Fanconi’s renal tubular acidosis (co-treatment with valproate) [Ballaban-Gil et al., 1998], severe hypoproteinemia [Ballaban-Gil et al., 1998], marked increase in liver function tests (co-treatment with valproate) [Ballaban-Gil et al., 1998], cardiomyopathy [Ballaban-Gil et al., 1999; Best et al., 2000; Bergqvist et al., 2003], prolonged QTc [Best et al., 2000], acute hemorrhagic pancreatitis [Stewart et al., 2001], and basal ganglia injury

[Erickson et al., 2003]. There are no reports of long-term complications (>2 years of treatment) on the ketogenic diet.

ADVANTAGES AND DISADVANTAGES Advantages The ketogenic diet has several advantages compared with other medical therapies. Anecdotal reports have indicated that many of the children who are maintained on the diet are able to have their antiepileptic drugs decreased or withdrawn. This typically results in the child being more alert and exhibiting better behavior [Maydell et al., 2001; Nordli et al., 2001]. However, even children whose antiepileptic drugs cannot be substantially decreased or withdrawn may have marked behavioral or cognitive improvements [Katyal et al., 2000]. These improvements have occurred in children who have become seizure free on the diet and had antiepileptic drugs withdrawn and in those whose seizures are only minimally improved and have not had dramatic changes in their antiepileptic drug regimen. Parents are concerned about cognitive side effects, and although the newer antiepileptic drugs tend to have fewer such effects, there are no cognitive effects with the diet. A prospective, pilot study assessed the effects of the ketogenic diet on development and behavior in 65 children with intractable epilepsy [Pulsifer et al., 2001]. Formal evaluation of development, behavior, and parental stress using parental report measures was utilized before diet initiation and 1 year later. At follow-up, the mean developmental quotient indicated statistically significant improvement (P < 0.05), with significant behavioral improvements (P < 0.05) in attention and social functioning. The observed developmental and behavioral improvements were not statistically related to reductions in seizure frequency or antiepileptic medications. Parental stress was essentially unchanged. This preliminary report supports the prior anecdotal observations of the beneficial effects of the diet on cognition and behavior. Experiments in rats have discovered no adverse effect of the ketogenic diet on spatial learning and memory, the animal’s response to a novel environment, or a battery of behavioral tests [Bough et al., 2000b; Hori et al., 1997]. These reports of a positive cognitive effect of the diet in children and experimental models are in contrast to a single study of cognition in rats [Zhao et al., 2004] and one weight loss study in adults [Wing et al., 1995]. Twenty-three rats were fed a ketogenic diet for 1 month. These animals had a severe impairment in visual-spatial memory and decreased brain growth. Adults on the ketogenic diet for weight loss fared worse on some neurocognitive tasks than untreated control subjects [Wing et al., 1995]. These concerns have not been raised by any study of human beings but should be pursued in experimental and clinical research arenas [Snead, 2004]. With the ketogenic diet, there appear to be no concerns about organ failure or toxicity. For many families, the ketogenic diet provides a dramatic change in their role in the treatment of their children’s epilepsy. This form of therapy requires preparation by the parents and monitoring of urinary ketone levels. This requirement gives the parents an active role in the treatment of their children and a sense that what they are doing is influencing their children’s epilepsy and has a positive

Wheless / The Ketogenic Diet

psychosocial effect. Only occasionally can this become a disadvantage when children on the diet do not improve. Because the diet is totally provided by the parents, they may feel guilty, take the failure personally, and wonder if it is not something they have done wrong with the preparation of the diet that has kept it from working. In such instances, it is important to assure the parents that they have carried out the diet correctly, that the diet does not work in all children, and that they are not responsible for its failure. Rarely, even if the ketogenic diet is not working, parents may not want to stop it. The diet is the first therapy for their children’s seizures they are in charge of, and the parents may not want to lose this empowerment.

Disadvantages The most common reasons cited for discontinuation of the ketogenic diet are lack of efficacy, complications, noncompliance (more common in older children), and caregiver concerns [Lightstone et al., 2001]. The ketogenic diet is a strictly regulated medical diet that requires an epilepsy team for success. The team typically consists of a pediatric neurologist, dietitian, nurse, and social worker. The ketogenic diet requires active participation by the parents and children, if possible. The work required to initiate and maintain this rigorous diet by the parents may be considered a disadvantage. In the 1930s and 1940s the cost of the diet was considered a major disadvantage. However, at that time, the diet was compared with the cost of bromides or phenobarbital. Currently, the child with intractable epilepsy can incur costs of up to or more than $1000 per year for new antiepileptic drugs. A retrospective study of medical costs for 15 children with intractable epilepsy who were placed on the ketogenic diet found savings of more than $10,000 per child for the 1to 2-year period after initiation of the diet, compared with the same period before the diet [Mandel et al., 2002]. Successful maintenance on the ketogenic diet can provide a substantial financial benefit. Many physicians perceive the diet as unpalatable and difficult to initiate and maintain. However, modern nutritional labeling requirements and the use of computers allow the dietitian to construct a palatable diet with the patient’s food preferences in mind that permits a much more varied meal plan [Brake and Brake, 1997].

KETOGENIC DIET IN THE 21ST CENTURY More than 75 years have passed since the ketogenic diet was initially used, and many more therapies are now available for children with epilepsy. The ketogenic diet compares favorably with other new treatments that have been introduced to treat epilepsy in children [Felbamate Study Group, 1993; George, 1994; LeFever et al., 2000; Vagus Nerve Stimulation Study Group, 1995]. Studies on the newer antiepileptic drugs such as zonisamide, lamotrigine, tiagabine, gabapentin, topiramate, oxcarbazepine, and levetiracetam typically indicate that only 3% to 10% of all intractable patients achieve complete relief of seizures. One question remains unanswered: When in the course of therapy for a child with intractable epilepsy should

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the ketogenic diet be used? Currently, it is not used until children have failed multiple medications and are not considered surgical candidates. However, for some epilepsy syndromes, the diet should be offered as a treatment strategy after failure of one or two drugs. If the child has an epilepsy syndrome that is often resistant to current therapy, the ketogenic diet should be mentioned at the time of the initial therapeutic discussions as an alternative therapy if the seizures are not controlled on medication. This recommendation is especially appropriate for children who are not good candidates for epilepsy surgery or whose parents do not wish to have epilepsy surgery. Renewed interest in the ketogenic diet has again raised several research questions that, if answered, have the potential to improve our understanding of the neurochemistry of epilepsy and to allow better treatment of all patients with epilepsy [Nordli and DeVivo, 1997; Prasad et al., 1996]. In addition needing a better understanding of the underlying neurochemical changes induced with the ketogenic diet, other clinical questions remain. For example, for what seizure types or epilepsy syndromes does this diet have a greater chance of successful short- or long-term treatment? It would be helpful to have more long-term (i.e., 10 to 20 years) follow-up data on patients who appear not to have a return of seizures after the diet is stopped [Keith, 1963]. Issues that require investigation include the duration of treatment with the diet, the risk of late seizure recurrence after the diet is terminated, long-term effects of the diet on growth and development, and whether the response to treatment is because the patient has a specific subset of known seizure type or epilepsy syndrome. Feasibility of prolonged treatment also needs to be determined. Many children who are not seizure free or who are not able to discontinue all antiepileptic drugs are improved on the ketogenic diet. The improvement in seizure control or behavior and cognitive abilities is such that parents wish to continue the ketogenic diet. How long can we safely maintain these children on the ketogenic diet without encountering new side effects because of micronutrient deficiency? What is the feasibility of prolonged therapy? If no other therapy works better, how do we counsel parents about remaining on the diet when there is no apparent chance of withdrawing it? This same set of questions could be raised for a child who is seizure free on the diet for 2 years but then does not tolerate withdrawal without recurrence of seizures. The effects of the ketogenic diet on family dynamics are unknown. Are there different psychosocial effects on the siblings of the child with epilepsy who depends on this form of therapy? There are additional questions about the role of the ketogenic diet in treating less affected or normal children with epilepsy. How does the risk-benefit ratio of the ketogenic diet compare with other therapies? Many adults with intractable epilepsy wish to know if any of them could benefit from the ketogenic diet. The ketogenic diet also may be useful in other childhood neurologic disorders such as alternating hemiplegia of childhood or tumors of the nervous system [Nebeling et al., 1995]. The ketogenic diet is a therapy that started at the beginning of the 20th century and still appears to have a definitive role in the treatment of childhood epilepsy in the 21st century. The preferred sequence of treatments for

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children with epilepsy will continue to be reassessed and redefined. It will likely be several years before the exact roles for all current therapies are characterized. Until then, it is critical that those taking care of children with seizures be aware of all the treatment options and refer children whose seizures are not controlled to medical centers specializing in the care of such children [National Association of Epilepsy Centers, 1990]. For many of these children, the ketogenic diet continues to represent a therapeutic alternative. REFERENCES Aicardi J. Clinics in developmental medicine 115/118: Diseases of the nervous system in childhood. New York: MacKeith, 1992. Aicardi J. The international review of child neurology. In: Epilepsy in children, 2nd ed. New York: Raven Press, 1994. Al-Mudallal AS, LaManna JC, Lust WD, et al. Diet-induced ketosis does not cause cerebral acidosis. Epilepsia 1996;37:258. Al-Mudallal AS, Levin BE, Lust WD, et al. Effects of unbalanced diets on cerebral glucose metabolism in the adult rat. Neurology 1995;45:2261. Appleton DB, DeVivo DC. An experimental model for the effect of ketogenic diet on epilepsy. Proc Aust Assoc Neurologists 1973;10:75. Appleton DB, DeVivo DC. An animal model for the ketogenic diet. Epilepsia 1974;15:211. Ballaban-Gil K, Callahan C, O’Dell C, et al. Complications of the ketogenic diet. Ann Neurol 1996;40:307. Ballaban-Gil K, Callahan C, O’Dell C, et al. Complications of the ketogenic diet. Epilepsia 1998;39:744. Ballaban-Gil KR. Cardiomyopathy associated with the ketogenic diet. Epilepsia 1999;40 (Suppl 7):129. Barborka CJ. The ketogenic diet. Proc Meet Mayo Clin 1928a;3:273. Barborka CJ. Ketogenic diet treatment of epilepsy in adults. JAMA 1928b;91:73. Barborka CJ. The ketogenic diet and its use. Med Clin North Am 1929;12:1639. Barborka CJ. Epilepsy in adults: Results of treatment by ketogenic diet in one hundred cases. Arch Neurol Psychiatry 1930;23:904. Bastible C. The ketogenic treatment of epilepsy. Irish J Med Sci 1931;2:506. Bergqvist AGC, Chee C, Fink L, et al. Serial measurements of serum cholesterol and triglycerides in the ketogenic diet. Ann Neurol 1998;44:565. Bergqvist AGC, Chee CM, Bettler JE, et al. Zinc deficiency resulting from the ketogenic diet. Epilepsia 1999;40 (Suppl 7):133. Bergqvist AGC, Chee CM, Lutchka L, et al. Selenium deficiency associated with cardiomyopathy: A complication of the ketogenic diet. Epilepsia 2003;44:618. Berry-Kravis E, Booth G, Sanchez C, et al. The ketogenic diet: Need for carnitine supplementation. Ann Neurol 1998;44:566. Berry-Kravis E, Booth G, Taylor A, et al. Bruising and the ketogenic diet: Evidence for diet-induced changes in platelet function. Ann Neurol 2001a;49:98. Berry-Kravis E, Booth G, Sanchez, AC, et al. Carnitine levels and the ketogenic diet. Epilepsia 2001b;42:1445. Best TH, Franz DN, Gilbert DL, et al. Cardiac complications in pediatric patients on the ketogenic diet. Neurology 2000;54:2328. Bible, The New King James Version, Mark 9:14-29. Carmel, NY: Guideposts, 1982. Bough K, Chen R, Eagles D. Path analysis shows that increasing ketogenic diet ratio but not beta-hydroxybutyrate, elevates seizure threshold in the rat. Dev Neurosci 1999a;21:400. Bough KJ, Eagles DA. A ketogenic diet increases the resistance to pentylenetetrazole-induced seizures in the rat. Epilepsia 1999b;40:138. Bough KJ, Valiyil R, Han FT, et al. Seizure resistance is dependent upon age and caloric restriction in rats fed a ketogenic diet. Epilepsy Res 1999c;35:21. Bough KJ, Matthews PJ, Eagles DA. A ketogenic diet has different effects upon seizures induced by maximal electroshock and by pentylenetetrazole infusion. Epilepsy Res 2000a;38:105. Bough KJ, Yao SG, Eagles DA. Higher ketogenic diet ratios confer protection from seizures without neurotoxicity. Epilepsy Res 2000b;38:15. Bough KJ, Gudi K, Han FT, et al. An anticonvulsant profile of the ketogenic diet in the rat. Epilepsy Res 2002;50:313.

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Wheless / The Ketogenic Diet DeVivo DC, Pagliara AS, Prensky AL. Ketotic hypoglycemia and the ketogenic diet. Neurology 1973;23:640. DeVivo DC, Trifiletti RR, Jacobson RI, et al. Glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures and developmental delay. N Engl J Med 1991;325:703. DiMario FJ, Holland J. The ketogenic diet: A review of the experience at Connecticut Children’s Medical Center. Pediatr Neurol 2002;26:288. Dodson WE, Prensky AL, DeVivo DC, et al. Management of seizure disorders. Selected aspects, part II. J Pediatr 1976;89:695. Eley RC. Epilepsy. The value of encephalography in the selection of patients for treatment by the ketogenic diet. J Pediatr 1933;3:359. Erecinska M, Nelson D, Daikhin Y, et al. Regulation of GABA level in rat brain synaptosomes: Fluxes through enzymes of the GABA shunt and effects of glutamate, calcium, and ketone bodies. J Neurochem 1996;67:2325. Erickson JC, Jabbari B, Difazio MP. Basal ganglia injury as a complication of the ketogenic diet. Mov Disord 2003;18:448. Felbamate Study Group in Lennox-Gastaut Syndrome. Efficacy of felbamate in childhood epileptic encephalopathy (Lennox-Gastaut syndrome). N Engl J Med 1993;328:29. Feldstein TJ. Carbohydrate and alcohol content of 200 oral liquid medications for use in patients receiving ketogenic diets. Pediatrics 1996;97:506. Fischer L. Epilepsy: Its treatment by the use of the ketogenic diet versus drugs. Arch Pediatr 1935;52:131. Fisher RS, Parks-Trusz SL, Lehman C. Social issues in epilepsy. In: Shorvon S, Dreifuss F, Fish D, et al., eds. The treatment of epilepsy. Woburn, Mass: Blackwell Science, 1996. Fraser DD, Witing S, Andrew RD, et al. Elevated polyunsaturated fatty acids in blood obtained from children on the ketogenic diet. Neurology 2003;60:1026. Freeman JM, Freeman JB, Kelly MT. The ketogenic diet, 3rd ed. New York: Demos, 2000. Freeman JM, Kelly MT, Freeman JB. The epilepsy diet treatment: An introduction to the ketogenic diet. New York: Demos, 1994. Freeman JM, Vining EPG. Seizures decrease rapidly after fasting: Preliminary studies of the ketogenic diet. Arch Pediatr Adolesc Med 1999;153:946. Freeman JM, Vining EPG, Pillas DJ. Seizures and epilepsy in childhood: A guide for parents. Baltimore: Johns Hopkins University Press, 1990. Freeman JM, Vining EPG, Pillas DJ, et al. The efficacy of the ketogenic diet—1998: A prospective evaluation of intervention in 150 children. Pediatrics 1998a;102:1358. Freeman JM, Vining EPG, Pyzik PL, et al. Beta-hydroxybutyrate levels in blood correlate with seizure control in children on the ketogenic diet. Epilepsia 1998b;39 (Suppl 6):167. Freeman JM, Kelly MT, Freeman JB. The epilepsy diet treatment. New York: Demos, 1996. Furth SL, Casey JC, Pyzik PL, et al. Risk factors for urolithiasis in children on the ketogenic diet. Pediatr Nephrol 2000;15:125. George R, Salinsky M, Kuzniecky R, et al. Vagus nerve stimulation for treatment of partial seizures. 3. Long-term follow-up on the first 67 patients exiting a controlled study. Epilepsia 1994;35:637. Geyelin HR. Fasting as a method for treating epilepsy. Med Rec 1921;99:1037. Gilbert DL, Pyzik PL, Freeman JM. The ketogenic diet: Seizure control correlates better with serum beta-hydroxybutyrate than with urine ketones. J Child Neurol 2000;15:787. Gjedde A, Crone C. Induction processes in blood-brain transfer of ketone bodies during starvation. Am J Physiol 1975;229:1165. Goodwell W, Chez MG, Buchana CP, et al. Bone marrow suppression from copper deficiency in 2 patients on the ketogenic diet. Ann Neurol 1998;44:568. Goyens P, DeLaet C, Ranguelov N, et al. Pitfalls of the ketogenic diet in a neonate. Pediatrics 2002;109:1185. Greene AE, Todorova MT, McGowan R, et al. Caloric restriction inhibits seizure susceptibility in epileptic EL mice by reducing blood glucose. Epilepsia 2001;42:1371. Greene AE, Todorova MT, Seyfried TN. Perspectives on the metabolic management of epilepsy through dietary reduction of glucose and elevation of ketone bodies. J Neurochem 2003;86:529. Haas RE, Rice MA, Trauner DA, et al. Therapeutic effects of a ketogenic diet in Rett syndrome. Am J Med Genet 1986;1:225. Hahn TJ, Halstead LR, DeVivo DC. Disordered mineral metabolism produced by ketogenic diet therapy. Calcif Tissue Int 1979;28:17.

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Harik SI, Al-Mudallal AS, LaManna JC, et al. Ketogenic diet and the brain. Ann N Y Acad Sci 1997;835:218. Hassan AM, Keene DL, Whiting SE, et al. Ketogenic diet in the treatment of refractory epilepsy in childhood. Pediatr Neurol 1999;21:548. Hauser WA. The prevalence and incidence of convulsive disorders in children. Epilepsia 1994;35:S1. Hauser WA, Hesdorffer DH. Epilepsy: Frequency, causes and consequences. New York: Demos Press, 1980. Hawkins RA, Biebuyck JF. Ketone bodies are selectively used by individual brain regions. Science 1979;205:325. Hawkins RA, Biebuyck JF. Regional brain utilization of ketone bodies. In: Passoneau JV, Lust WD, Hawkins JR, et al., eds. Cerebral metabolism and neural function. Baltimore: Williams and Wilkins, 1980: 255. Hawkins RA, Williamson DH, Krebs HA. Ketone-body utilization by adult and suckling rat brain in vivo. Biochem J 1971;122:13. Haymond MW, Howard C, Ben-Galim E, et al. Effects of ketosis on glucose flux in children and adults. Am J Physiol 1983;245:E373. Heller AJ, Stewart J, Hughes E, et al. Comparative efficacy and toxicity of phenobarbital, phenytoin, carbamazepine, and valproate in adults and children with newly diagnosed previously untreated epilepsy: A randomized long-term trial. Epilepsia 1993;34:66. Helmholz HF. The treatment of epilepsy in childhood: Five years experience with the ketogenic diet. JAMA 1927;88:2028. Helmholz HF, Goldstein M. Results of 15 years’ experience with the ketogenic diet in the treatment of epilepsy in children. Proc Staff Meet Mayo Clinic 1937;12:433. Helmholz HF, Keith HM. Eight years’ experience with the ketogenic diet in the treatment of epilepsy. JAMA 1930;95:707. Helmholz HF, Keith HM. Ten years’ experience in the treatment of epilepsy with the ketogenic diet. Arch Neurol Psychiatry 1932;29:808. Hemingway C, Freeman JM, Pillas DJ, et al. The ketogenic diet: A 3- to 6-year follow-up of 150 children enrolled prospectively. Pediatrics 2001;108:898. Hendricks M. High fat and seizure free. Johns Hopkins Magazine 1995;April:14. Herzberg GZ, Fivush BA, Kinsman SL, et al. Urolithiasis associated with the ketogenic diet. J Pediatr 1990;117:743. Hopkins IJ, Lynch BC. Use of ketogenic diet in epilepsy in childhood. Aust Pediatr J 1970;6:25. Hori A, Tandon P, Holmes GL, et al. Ketogenic diet: Effects on expression of kindled seizures and behavior in adult rats. Epilepsia 1997;38:750. Hoyt CS, Billson FA. Optic neuropathy in ketogenic diet. Br J Ophthalmol 1979;63:191. Huttenlocher PR. Ketonemia and seizures: Metabolic and anticonvulsant effects of two ketogenic diets in childhood epilepsy. Pediatr Res 1976;10:536. Janaki S, Rashid MD, Gulati MS, et al. A clinical electroencephalographic correlation of seizures on a ketogenic diet. Indian J Med Res 1976;64:1057. Kaytal NG, Koehler AN, McGhee B, et al. The ketogenic diet in refractory epilepsy: The experience of Children’s Hospital of Pittsburgh. Clin Pediatr 2000;39:153. Keith HM. Results of treatment of recurring convulsive attacks of epilepsy. Am J Dis Child 1942;74:140. Keith HM. Convulsive disorders in children: With reference to treatment with ketogenic diet. Boston: Little, Brown, 1963. Kielb S, Koo HP, Bloom DA, et al. Nephrolithiasis associated with the ketogenic diet. J Urol 2000;164:464. Kinsman SL, Vining EPG, Quaskey SA, et al. Efficacy of the ketogenic diet for intractable seizure disorders: Review of 58 cases. Epilepsia 1992;33:1132. Kleinman RE, ed. The ketogenic diet. Pediatric nutrition handbook, 5th ed. Chicago: American Academy of Pediatrics, 2004:773. Klepper J, Diefenbach S, Kohlschutter A, et al. Effects of the ketogenic diet in the glucose transporter 1 deficiency syndrome. Prostaglandins Leukot Essent Fatty Acids 2004;70:321. Klepper J, Leiendecker B, Bredahl R, et al. Introduction of a ketogenic diet in young infants. J Inherit Metab Dis 2002;25:449. Kossoff EH, Krauss GL, McGrogan JR, et al. Efficacy of the Atkins diet as therapy for intractable epilepsy. Neurology 2003;61:1789. Kossoff EH, Pyzik PL, McGrogan JR, et al. Efficacy of the ketogenic diet for infantile spasms. Pediatrics 2002;109:780. Kraus H, Schlenker S, Schwedesky D. Developmental changes of cerebral ketone body utilization in human infants. Hoppe Seylers Z Physiol Chem 1974;355:164.

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Lamers KJB, Gabreels FJM, Renier WO, et al. Fasting studies in cerebrospinal fluid and blood in children with epilepsy of unknown origin. Epilepsy Res 1995;21:59. Lasser JL, Brush MK. An improved ketogenic diet for treatment of epilepsy. J Am Diet Assoc 1973;62:281. Lebel D, Morin C, Laberge M, et al. The carbohydrate and caloric content of concomitant medications for children with epilepsy on the ketogenic diet. Can J Neurol Sci 2001;28:232. Lefevre F, Aronson N. Ketogenic diet for the treatment of refractory epilepsy in children: A systematic review of efficacy. Pediatrics 2000;105. Available at http://www.pediatrics.org/cgi/content/full/ 105/4/e46. Leino RL, Gerhart DZ, Duelli R, et al. Diet-induced ketosis increases monocarboxylate transporter (MCT1) levels in rat brain. Neurochem Int 2001;38:519. Lennox WG. Ketogenic diet in the treatment of epilepsy. N Engl J Med 1928;199:74. Lennox WG. Science and seizures: New light on epilepsy and migraine. New York: Harper, 1941. Lennox WG, Cobb S. Studies in epilepsy. VIII. The clinical effect of fasting. Arch Neurol Psychiatry 1928;20:771. Lennox WG, Lennox MA. Epilepsy and related disorders, Vol. 2. Boston: Little, Brown, 1960. Levy R, Cooper P. Ketogenic diet for epilepsy. Cochrane Database Syst Rev 2003;3:CD001903. Liebhaber GM, Riemann E, Baumeister FA. Ketogenic diet in Rett syndrome. J Child Neurol 2003;18:74. Lightstone L, Shinnar S, Callahan CM, et al. Reasons for failure of the ketogenic diet. J Neurosci Nurs 2001;36:292. Likhodii SS, Musa K, Mendonca A, et al. Dietary fat, ketosis, and seizure resistance in rats on the ketogenic diet. Epilepsia 2000;41:1400. Likhodii SS, Burnham WM. Ketogenic diet: Does acetone stop seizures? Med Sci Monit 2002;8:HY19. Lin M, Mitchell WG, Chen LS, et al. Symptomatic carnitine depletion is uncommon in children on ketogenic diet. Epilepsia 1998; 39 (Suppl 6):168. Liu YM, William S, Basualdo-Hammond C, et al. A prospective study: Growth and nutritional status of children treated with the ketogenic diet. J Am Diet Assoc 2003;103:707. Livingston S. The diagnosis and treatment of convulsive disorders in children. Springfield, Ill: Charles C Thomas, 1954. Livingston S. Living with epileptic seizures. Springfield, Ill: Charles C Thomas, 1963. Livingston S. Comprehensive management of epilepsy in infancy, childhood and adolescence. Springfield, Ill: Charles C Thomas, 1972. Livingston S, Pauli LL. Ketogenic diet and epilepsy. Dev Med Child Neurol 1975;17:818. Livingston S, Pauli LL, Pruce I. Ketogenic diet in the treatment of childhood epilepsy. Dev Med Child Neurol 1977;19:833. Mady MA, Kossoff EH, McGregor AL, et al. The ketogenic diet: Adolescents can do it, too. Epilepsia 2003;44:847. Mandel A, Ballew M, Pina-Garza JE, et al. Medical costs are reduced when children with intractable epilepsy are successfully treated with the ketogenic diet. J Am Diet Assoc 2002;102:396. Maria BL, Borum PR, Friedman T, et al. The ketogenic diet. In: Maria BL, ed. Consensus in child neurology. Hamilton, Ontario: Decker Periodicals, 1997. Marks WJ, Vermathen P, Sum JM, et al. Brain pH in humans treated with the ketogenic diet. Neurology 1997;48:A111. Maydell BV, Wyllie E, Akhtar N, et al. Efficacy of the ketogenic diet in focal versus generalized seizures. Pediatr Neurol 2001;25:208. Mayes PA. Integration of metabolism and the provision of tissue fuels. In: Murray RK, Granner DK, Mayes PA, et al., eds. Harper’s biochemistry, 24th ed. Stamford, Conn: Appleton and Lange, 1996a. Mayes PA. Oxidation of fatty acids: Ketogenesis. In: Murray RK, Granner DK, Mayes PA, et al., eds. Harper’s biochemistry, 24th ed. Stamford, Conn: Appleton & Lange, 1996b. McGeer PL, McGeer EG. Amino acid neurotransmitters. In: Siegel GJ, Agranoff BW, Albers RW, et al., eds. Basic neurochemistry. New York: Raven Press, 1989. McGhee B, Katyal N. Avoid unnecessary drug-related carbohydrates for patients consuming the ketogenic diet. J Am Diet Assoc 2001;101:87. McQuarrie I, Keith HM. Epilepsy in children. Am J Dis Child 1927;34:1013.

Melvin JJ, Legido A, Faerber EN, et al. Pyruvate dehydrogenase complex deficiency associated with brain dysgenesis: Response of lactic acidemia to a ketogenic diet. Neurology 1996;46:A114. Millichap, JG, Jones JD, Rudis BP. Mechanism of anticonvulsant action of ketogenic diet. Am J Dis Child 1964;107:593. Moore T, Lione A, Sugden M, Regen D. Hydroxybutyrate transport in rat brain: Developmental and dietary modification. Am J Physiol 1976;230:619. Muller-Schwarze AB, Tandon P, Liu Z, et al. Ketogenic diet reduces spontaneous seizures and mossy fiber sprouting in the kainic acid model. Neuroreport 1999;10:1517. National Association of Epilepsy Centers. The National Association of Epilepsy Centers Guidelines for diagnosis and treatment in specialized epilepsy centers. Epilepsia 1990;31:1. Nakazawa M, Kodama S, Matsuo T. Effects of ketogenic diet on electroconvulsive threshold and brain contents of adenosine nucleotides. Brain Dev 1983;5:375. NBC Dateline. The ketogenic diet. October 26, 1994. Nebeling LC, Miraldi F, Shurin SB, et al. Effects of a ketogenic diet on tumor metabolism and nutritional status in pediatric oncology patients: Two case reports. J Am Coll Nutr 1995;14:202. Nehlig A. Age-dependent pathways of brain energy metabolism: The suckling rat, a natural model of the ketogenic diet. Epilepsy Res 1999;37:211. Nellhaus G. The ketogenic diet reconsidered: Correlation with EEG. Neurology 1971;21:424. Nordli DR. The ketogenic diet: Uses and abuses. Neurology 2000; 58 (Suppl 7):S21. Nordli DR Jr, DeVivo DC. The ketogenic diet revisited: Back to the future. Epilepsia 1997;38:743. Nordli DR, Kuroda MM, Carroll J, et al. Experience with the ketogenic diet in infants. Pediatrics, 2001;108:129. Notkin J. Epilepsy: Treatment of institutionalized adult patients with a ketogenic diet. Arch Neurol Psychiatry 1934;31:787. Owen OE, Morgan AP, Kemp HG, et al. Brain metabolism during fasting. J Clin Invest 1967;46:1589. Pan J, Bebin E, Chu W, et al. Ketosis and epilepsy: 31P spectroscopic imaging at 4.1 T. Epilepsia 1999;40:703. Pan JW, Rothman DL, Behar KL, et al. Human brain betahydroxybutyrate and lactate increase in fasting-induced ketosis. J Cereb Blood Flow Metab 2000;20:1502. Pan JW, Telang FW, Lee JH, et al. Measurement of beta-hydroxybutyrate in acute hyperketonemia in human brain. J Neurochem 2001;79:539. Patsalos PN, Duncan JS. Antiepileptic drugs: A review of clinically significant drug interactions. Drug Safety 1993;9:156. Pellerin L, Pellegri G, Martin J-L, et al. Expression of monocarboxylate transporter mRNAs in mouse brain: Support for a distinct role of lactate as an energy substrate for the neonatal vs. adult brain. Proc Natl Acad Sci U S A 1998;95:3990. Pellock JM. Seizures and epilepsy in infancy and childhood. Neurol Clin 1993;3:755. Pellock JM. Antiepileptic drug therapy in the United States: A review of clinical studies and unmet needs. Neurology 1995;45:S17. Pellock JM. Utilization of new antiepileptic drugs in children. Epilepsia 1996;37:S66. Pellock JM, Pippenger CE. Adverse effects of antiepileptic drugs. In: Dodson WE, Pellock JM, eds. Pediatric epilepsy: Diagnosis and therapy. New York: Demos, 1993. Penfield W, Erickson TC. Epilepsy and cerebral localization. A study of the mechanism, treatment and prevention of epileptic seizures. Baltimore: Charles C Thomas, 1941. Peng L, Hertz L, Huang R, et al. Utilization of glutamine and of TCA cycle constituents as precursors for transmitter glutamate and GABA. Dev Neurosci 1993;15:367. Persson B, Settergress G, Dahlquist G. Cerebral arterio-venous difference of acetoacetate and D-beta-hydroxybutyrate in children. Acta Paediatr Scand 1972;61:273. Peterman MG. The ketogenic diet in epilepsy. JAMA 1925;84:1979. Peyron R, LeBars D, Cinotti L, et al. Effects of GABAA receptor activation on brain glucose metabolism in normal subjects and temporal lobe epilepsy (TLE) patients. A positron emission tomography (PET) study. Part I. Brain glucose metabolism is increased after GABAA receptor activation. Epilepsy Res 1994;19:45. Prasad AN, Stafstrom CF, Holmes GL. Alternative epilepsy therapies: The ketogenic diet, immunoglobulins, and steroids. Epilepsia 1996;37:S81.

Wheless / The Ketogenic Diet Pulford DS. The present status of the ketogenic diet. Ann Intern Med 1932;6:795. Pulsifer MB, Gordon JM, Brandt J, et al. Effects of ketogenic diet on development and behavior: Preliminary report of a prospective study. Dev Med Child Neurol 2001;43:301. Rho J, Kim D, Robbins C, et al. Age-dependent differences in flurothyl seizure sensitivity in mice treated with a ketogenic diet. Epilepsy Res 1999a;37:233. Rho JM, Shin DH, Robbins CA, et al. GABA levels are increased in the hippocampus of mature mice fed a ketogenic diet. Epilepsia 1999b;40 (Suppl 7):161. Rho JM, Szot P, Tempel BL, et al. Developmental seizure susceptibility of Kv1.1 potassium channel knockout mice. Dev Neurosci 1999c;21:320. Rho JM, Robbins CA, Wenzel J, et al. An experimental ketogenic diet promotes long-term survival and reduces synaptic reorganization in the hippocampus of epileptic Kv1.1 null mutant mice. Epilepsia 2000;41 (Suppl 7):34. Rho JM, Anderson GD, Donevan SD, et al. Acetoacetate, acetone, and dibenzylamine (a contaminant in L-(+)-beta-hydroxybutyrate) exhibit direct anticonvulsant actions in vivo. Epilepsia 2002;43:358. Rodwell VW. Conversion of amino acids to specialized product. In: Murray RK, Granner DK, Mayes PA, et al., eds, Harper’s biochemistry, 24th ed. Stamford, Conn: Appleton & Lange, 1996. Roe CR, Coates PM. Mitochondrial fatty acid oxidation disorders. In: Scriver CR, Beaudet AL, Sly WS, et al., eds. The metabolic and molecular basis of inherited disease. New York: McGraw-Hill, 1995:1501. Ross DL, Swaiman KF, Torres F, et al. Early biochemical and EEG correlates of the ketogenic diet in children with atypical absence epilepsy. Pediatr Neurol 1985;1:104. Schneider KS, Wagner J. Recipe for hope. People Magazine 1995; April 17:54. Schwartz RM, Boyes S, Aynsley-Green A. Metabolic effects of three ketogenic diets in the treatment of severe epilepsy. Dev Med Child Neurol 1989a;31:152. Schwartz RH, Eaton J, Bower BD, et al. Ketogenic diets in the treatment of epilepsy: Short term clinical effects. Dev Med Child Neurol 1989b;31:145. Schwartzkroin PA. Mechanisms underlying the anti-epileptic efficacy of the ketogenic diet. Epilepsy Res 1999;37:171. Seymour KJ, Bluml S, Sutherling J, et al. Identification of cerebral acetone by 1H-MRS in patients with epilepsy controlled by ketogenic diet. MAGMA 1999;8:33. Shafrir Y, Prensky AL. Acquired epileptiform opercular syndrome: A second case report, review of the literature, and comparison to the Landau-Kleffner syndrome. Epilepsia 1995;36:1050. Sirven J, Whedon B, Caplan D, et al. The ketogenic diet for intractable epilepsy in adults: Preliminary results. Epilepsia 1999;40:1721. Snead OC III. The ketogenic diet: A cautionary note. Pediatr Res 2004;55:368. Sokoloff L. Metabolism of ketone bodies by the brain. Annu Rev Med 1973;24:271. Stafstrom CE. Animal models of the ketogenic diet: What have we learned, what can we learn? Epilepsy Res 1999;37:241. Stafstrom CE, Spencer S. The ketogenic diet: A therapy in search of an explanation. Neurol 2000;54:282. Stafstrom CE, Bough KJ. The ketogenic diet for the treatment of epilepsy: A challenge for nutritional neuroscientists. Nutr Neurosci 2003;6:67. Stafstrom CE, Rho JM, eds. Epilepsy and the ketogenic diet. Totowa, NJ: Humana Press, 2004. Stafstrom CE, Wang C, Jensen FE. Electrophysiological observations in hippocampal slices from rats treated with the ketogenic diet. Dev Neurosci 1999;21:393. Stewart WA, Gordon K, Camfield P. Acute pancreatitis causing death in a child on the ketogenic diet. J Child Neurol 2001;16:682. Su SW, Cilio MR, Sogawa Y, et al. Timing of the ketogenic diet initiation in an experimental epilepsy model. Dev Brain Res 2000;125:131. Swink T, Vining E, Casey, et al. Efficacy of the ketogenic diet in children under 2 years of age. Epilepsia 1997a;38:26. Swink TD, Vining EPG, Freeman JM. The ketogenic diet: 1997. Adv Pediatr 1997b;44:297. Szot P, Weinshenker D, Rho JM, et al. Norepinephrine is required for the anticonvulsant effect of the ketogenic diet. Dev Brain Res 2001;129:211. Takeoka M, Riviello JJ, Pfeifer H, et al. Concomitant treatment with topiramate and ketogenic diet in pediatric epilepsy. Epilepsia 2002;43:1072.

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Talbot FB, Metcalf K, Moriarty M. The ketogenic diet in the treatment of idiopathic epilepsy. Am J Dis Child 1926;32:316. Thavendiranathan P, Mendonca A, Dell C, et al. The MCT ketogenic diet: Effects on animal seizure models. Exp Neurol 2000;161:696. Thavendiranathan P, Chow C, Cunnane S, et al. The effect of the ‘classic’ ketogenic diet on animal seizure models. Brain Research 2003;959:206. Theda C, Woody RC, Naidu S, et al. Increased very long chain fatty acids in patients on a ketogenic diet: A cause of diagnostic confusion. J Pediatr 1993;122:724. Thio LL, Wang M, Yamada KA. Ketone bodies do not directly alter excitatory or inhibitory hippocampal synaptic transmission. Neurology 2000;54:325. Thompson JA, Van Orman CB, Peterson P. Ketogenic diet: Long-term efficacy and patient tolerance in the treatment of efficacy and patient tolerance in the treatment of intractable pediatric epilepsy. Epilepsia 1998;39 (Suppl 6):167. Thurston JH, Carroll JE, Dodson WE, et al. Chronic valproate administration reduces fasting ketonemia in children. Neurology 1983;33:1348. Todorova MT, Tandon P, Madore RA, et al. The ketogenic diet inhibits epileptogenesis in EL mice: A genetic model for idiopathic epilepsy. Epilepsia 2000;41:933. Turnbull DM, Dick DJ, Wilson L, et al. Valproate causes metabolic disturbance in normal man. J Neurol Neurosurg Psychiatry 1986;49:405. Uhlemann ER, Neims AH. Anticonvulsant properties of the ketogenic diet in mice. J Pharmacol Exp Ther 1972;180:231. Vagus Nerve Stimulation Study Group. A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. Neurology 1995;45:224. Vining EPG, Freeman JM, Ballaban-Gil K, et al. Multi-center study of the efficacy of the ketogenic diet. Arch Neurol 1998;55:1433. Vining EPG, Freeman JM, Kwiterovich P, et al. The ketogenic diet induces dyslipidemia. Epilepsia 1999a;40 (Suppl 7):122. Vining EPG. Clinical efficacy of the ketogenic diet. Epilepsy Res 1999b;37:181. Vininig EPG, Pyzik P, McGrogan J, et al. Growth of children on the ketogenic diet. Dev Med Child Neurol 2002;44:796. Wang ZJ, Bergqvist C, Hunter JV, et al. In vivo measurement of brain metabolites using two-dimensional double-quantum MR spectroscopyexploration of GABA levels in a ketogenic diet. Magn Reson Med 2003;49:615. Weber TA, Antognetti R, Stacpoole PW. Caveats when considering ketogenic diets for the treatment of pyruvate dehydrogenase complex deficiency. J Pediatr 2001 138:390. Weeks DF, Renner DS, Allen FM, et al. Observations on fasting and diets in the treatment of epilepsy. J Metab Res 1923;3:317. Wexler ID, Hemalatha SG, McConnell J, et al. Outcome of pyruvate dehydrogenase deficiency treated with ketogenic diet. Neurology 1997;49:1655. Wheless JW. The epilepsy diet treatment: An introduction to the ketogenic diet, book review. J Child Neurol 1995a;10:489. Wheless JW. The ketogenic diet: Fa(c)t or fiction. J Child Neurol 1995b;10:419. Wheless JW. The ketogenic diet: An effective medical therapy with side-effects. J Child Neurol 2001;16:633. Wheless JW. History and origin of the ketogenic diet. In: Stafstrom CE, Rho JM, eds. Epilepsy and the ketogenic diet. Totowa, NJ: Humana Press, 2004:31. Wijburg FA, Barth PG, Bindoff LA, et al. Leigh syndrome associated with a deficiency of the pyruvate dehydrogenase complex: Results of treatment with a ketogenic diet. Neuropediatrics 1992;23:147. Wilder RM. The effects of ketonuria on the course of epilepsy. Bull Mayo Clin 1921;2:307. Wilder RM, Pollack H. Ketosis and the ketogenic diet: Their application to treatment of epilepsy and infections of the urinary tract. Int Clin 1935;1:1. Wilkins L. Epilepsy in childhood. III. Results with the ketogenic diet. J Pediatr 1937;10:341. Williams S, Basualdo-Hammond C, Curtis R, et al. Growth retardation in children with epilepsy on the ketogenic diet: A retrospective chart review. J Am Diet Assoc 2002;102:405. Williamson DH. Ketone body metabolism during development. Fed Proc 1985;44:2342. Wing R, Vazquez J, Ryan C. Cognitive effects of ketogenic weight-reducing diets. Int J Obes Relat Metab Disord 1995;19:811.

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Withrow CD. Antiepileptic drugs, the ketogenic diet: Mechanism of anticonvulsant action. In: Glaser GH, Penry JK, Woodbury DM, eds. Antiepileptic drugs: Mechanism of action. New York: Raven, 1980. Woody, RC, Steele RW, Knapple W, et al. Impaired neutrophil function in children with seizures treated with the ketogenic diet. J Pediatr 1989;115:427. Yudkoff M, Daikhin Y, Nissim I, et al. Effects of ketone bodies on astrocyte amino acid metabolism. J Neurochem 1997;69:682. Yudkoff M, Daikhin Y, Nissim I, et al. Brain amino acid metabolism and ketosis. J Neurosci Res 2001a;66:272. Yudkoff M, Daikhin Y, Nissim I, et al. Ketogenic diet, amino acid metabolism, and seizure control. J Neurosci Res 2001b;66:931. Zhao Q, Stafstrom CE, Fu DD, et al. Detrimental effects of the ketogenic diet on cognitive function in rats. Pediatr Res 2004;55:498. Ziegler DR, Araujo E, Rotta L, et al. A ketogenic diet increases protein phosphorylation in brain slices of rats. J Nutr 2002;132: 483.

RESOURCES Brake D, Brake C. The ketogenic cookbook. Gilman, Conn: Greider Pennycorner Press, 1996. Both authors are culinary arts graduate chefs whose children were on the ketogenic diet treatment program. George M. Greider, Pennycorner Press, P.O. Box 8, Gilman, CT 06336; phone: (860) 873-3545; fax: (860) 873-1311. Freeman JM, Freeman JB, Kelly MT. The epilepsy diet treatment, 3rd ed. New York: 2000. Demos Vermande, 386 Park Avenue South, Suite 210, New York City, NY 10016; phone: (800) 532-8663. The Keto Klub, a quarterly newsletter devoted to the ketogenic diet. Elaine Huffman, Editor, 61557 Miami Meadows Court, South Bend, IN 46614; fax: (210) 299-8602. Video tapes on the ketogenic diet for families, dietitians, nurses, and physicians. The Charlie Foundation to Help Cure Pediatric Epilepsy, 501 10th Street, Santa Monica, CA 90402; fax: (310) 393-2347.

CHAPTER 51

Epilepsy Surgery in the Pediatric Population Mary L. Zupanc

Epilepsy is one of the most common chronic problems facing children and adolescents. The overall prevalence of epilepsy has been estimated to be 5 to 8 per 1000 [Bharucha et al., 1988; Hauser et al., 1975, 1994, 1996, 1998; Olafsson et al., 1996; Osuntokun et al., 1987; Zielinski, 1974]. Extrapolating the Hauser data from Rochester, Minnesota, of 6.66 per 1000 to the total population in 2004, approximately 2.3 million persons in the United States will have epilepsy [Hauser et al., 1991]. In developed countries, the incidence of epilepsy is 50 to 100 cases per 100,000 population per year, and the prevalence is approximately 5 to 8 per 1000 [Hauser et al., 1991, 1994, 1996, 1998]. The cumulative risk of developing epilepsy from birth through adolescence is 1% [Hauser et al., 1991, 1994]. What are the best ways to determine the prognosis of epilepsy, and who may be a candidate for epilepsy surgery? Several studies have addressed these questions. The identification of a specific epilepsy syndrome is one of the best determinants of prognosis. Some epilepsy syndromes are genetically determined “channelopathies” and are selflimited in their time course. Other epilepsy syndromes, particularly the lesional epilepsies, are life-long conditions. As an example, benign rolandic epilepsy is characterized by nocturnal focal motor seizures, age at onset between 3 and 8 years, normal findings on neurologic examination, and sleep-activated central-temporal epileptiform discharges on the electroencephalogram (EEG). In this case, the parents can be reassured that their child’s epilepsy will remit by puberty. On the other hand, predictors for the low probability of epilepsy remission include (1) the presence of a symptomatic localization-related epilepsy secondary to a remote central nervous system injury; (2) abnormalities on neurologic examination or cognitive/motor delays; (3) persistent epileptiform abnormalities on EEG; and (4) older age at onset [Arts et al., 1988; Berg et al., 2001; Camfield and Camfield, 2003; Emerson et al., 1981; Hauser et al., 1975, 1996, 1998; Juul-Jensen and Foldsprang, 1983; Schmidt et al., 1983; Shafer et al., 1988; Sillanpaa et al., 1998; Sofijanov, 1982; Todt, 1984]. In addition, the longer epilepsy persists without control, the smaller the chance of its going into remission. Specifically, if seizures remain under inadequate control for longer than 4 years, the chance of remission decreases to approximately 10% [Annegers et al., 1979]. The presence of multiple seizure types and frequent generalized tonic-clonic seizures also lessens the chance for complete remission. It is estimated that in 20% to 25% of all persons with epilepsy, accounting for approximately 20,000 cases annually, the seizures eventually will become intractable. Approximately 60% of these patients will have partial seizures. Estimates by several investigators suggest that approximately 3000 patients with newly diagnosed

epilepsy will ultimately be epilepsy surgery candidates [Hauser, 1993]. This figure may increase as new technologies enable more precise identification of an underlying epileptogenic focus. Additionally, as medical intractability for children with epilepsy is further defined, the number of pediatric epilepsy surgical procedures likely will increase. An increasing number of pediatric comprehensive epilepsy centers are equipped to handle the complexities of the preoperative evaluation in children and infants. Many issues must be addressed before a child becomes a candidate for epilepsy surgery. The number of children undergoing epilepsy surgery in the United States is rising, with greater than 200 pediatric epilepsy surgical procedures performed annually. Costs for a temporal lobectomy are estimated at $20,000 to $30,000 [King et al., 1997]. Costs for an extratemporal resection can be twice as high, especially if invasive subdural EEG monitoring and newer neuroimaging techniques are used. The developing brain is highly susceptible to recurrent seizures. Until recently, the brain was believed to be relatively resistant to brain injury. A growing body of evidence in animal models, however, suggests that early seizures, even if brief and recurrent, can result in demonstrable structural and physiologic changes in the developing brain’s circuitry, resulting in aberrant excitation and inhibition. Clinically, this defect produces spontaneous seizures (epilepsy) and cognitive impairments [Holmes and Ben-Ari, 1998; Holmes et al., 1998; Stafstrom et al., 2000], with the possibility of missed windows of developmental opportunity. Thus, plasticity of the brain in a young infant and child is a “double-edged sword”: It protects the brain from the neurologic consequences of destructive lesions and status epilepticus; however, recurrent seizures in this age group can produce permanent abnormal neuronal circuitry, resulting in long-term developmental delays and continued, intractable seizures. In addition, chronic uncontrolled epilepsy in infants and children poses a significant risk for emotional, behavioral, social, cognitive, and family dysfunction. Population studies have demonstrated that epilepsy reduces life expectancy, and poorly controlled seizures further increase the risk of death in adults and children [Nashef et al., 1995]. The estimated risk of sudden unexpected death in epilepsy may be as high as 1 in 500 in the adolescent population (the incidence in young children remains undetermined) [Harvey et al., 1993c; Hauser, et al., 1980]. What are the outcomes of epilepsy surgery in the pediatric population? A majority of the outcome studies have been performed in older adolescents and adults. In these outcome studies, the focus has been primarily on the improvement of seizure control, with 64% to 69% of patients having seizurefree outcomes [Engel, 1996; Wyllie, 1998; Wyllie et al., 1998]. These studies have placed less emphasis on

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improvement in quality of life—for example, enhancement of self-image, improvement in academic performance and psychosocial functioning, and increased independence in activities of daily living [Spencer, 1996; Taylor et al., 1997]. A growing number of long-term follow-up studies have infants and young children as their major focus. Malformations of cortical development are the most frequently cited pathologic abnormalities in pediatric surgical patients [Duchowny et al., 1996; Wyllie et al., 1998]. The overall outcome of pediatric epilepsy surgery in young infants and children is roughly comparable to that in the older adolescent and adult population. In infants, 61% to 65% have seizure-free outcomes following epilepsy surgery [Chugani et al., 1993; Duchowny et al., 1998; Sinclair et al., 2003; Wyllie et al., 1996, 1998a]. In young children, the rate of seizure-free outcomes varies, ranging from 59% to 67% [Paolicchi et al., 2000; Sinclair et al., 2003; Wyllie et al., 1998]. The etiology of the epilepsy appears to play the major role in the prognosis in young infants and children, regardless of location (temporal versus extratemporal). Specifically, in the series of patients from Miami Children’s Hospital, 62% of children (13 of 21) with malformations of cortical development had a seizure-free outcome, as opposed to patients with low-grade tumors; 100% of them were seizure free after epilepsy surgery [Duchowny et al., 1998]. Several studies have reported on cognitive function after surgery in children who have undergone temporal lobectomy (predominantly older children and adolescents) [Gillam et al., 1997; Gleissner et al., 2002; Mabbott and Smith, 2004; Meyer et al., 1986; Szabo et al., 1998; Westerveld et al., 2000]. These studies generally have found that memory and intelligence are unchanged, although some reports note a decline in verbal memory and improvements in language, attention, and memory. Reports on the cognitive effects of extratemporal resections have been relatively few, in part because of the young age of the patients. In patients who have undergone successful frontal lobe resection, outcomes include apparent improvements in attention and concentration but no change in executive functions, manual coordination, and language [Blanchette and Smith, 2002; Lendt et al., 2002]. Studies on postoperative psychosocial functioning in children have been relatively rare, almost exclusively retrospective, and based on subjective measures. In children who have undergone temporal lobectomies, studies indicate improvement in behavior, mood, and selfesteem, with the changes linked to improvement in seizure control [Danielsson et al., 2002; Davidson and Falconer, 1975; Duchowny et al., 1992; Meyer et al., 1986]. Of children who have undergone extratemporal resections, improved social behavior was found in about 50% [Adler et al., 1991]. Other retrospective studies that combine temporal and extratemporal cases suggest that reduction of seizure frequency, although not necessarily complete elimination of seizures, results in improved family life, socialization and behavior, and quality of life [Adler et al., 1991; Keene et al., 1998; Mihara et al., 1994; Whittle et al., 1981]. Other reports indicate that a reduction in seizures may result in a favorable and significant improvement in the quality of life with behavioral and developmental “catch-up” progress [Asarnow et al., 1997; Bourgeois et al., 1999; Chugani et al., 1990; Duchowny et al., 1990, 1992; Wyllie et al.,

1996; Zupanc, 1996]. A recent study looking at patients 1 year after surgery, however, challenges the assumptions that the elimination of seizures results in improved cognitive, psychosocial, and family functioning [Smith et al., 2004]. Fifty-seven percent of these patients were seizure free. Cognitive and psychosocial status did not change over time. The differences between this study and other studies may be due to the relatively short duration between epilepsy surgery and follow-up evaluation. Nonetheless, this study had a nonsurgical comparison group, was prospective in nature, and used well-known standardized outcome measures. Further data on epilepsy surgery outcome are needed.

HISTORICAL BACKGROUND Epilepsy has always been a part of human existence. A generalized tonic-clonic seizure was first described in Akkadian, the oldest written language, more than 3000 years ago [Goldensohn et al., 1997]. Since that time, many descriptions of epilepsy appear in the literature, including the Bible. In On the Sacred Disease, written in the fifth century, Hippocrates wrote that epilepsy was a brain disease caused by an excess of phlegm that resulted in an abnormal brain consistency. He proposed diet and drugs as therapy [Scott, 1993]. Until the late 19th century, the treatment of epilepsy was surrounded by superstition, exorcism, magic, and alchemy. Caton’s (1842 to 1926) discovery in 1875 of spontaneous electrical activity of the brain and evoked potentials suggested that seizures might be the result of aberrant electrical activity in the brain [Caton, 1875]. The first effective treatment for epilepsy was potassium bromide, introduced in 1857 [Locock, 1857]. A few years later, in 1886, Horsley performed the first epilepsy surgery on a patient with intractable post-traumatic epilepsy. Several decades later, the antiepileptic drug phenobarbital was introduced in 1912, followed by phenytoin in 1937. Similarly, epilepsy surgery did not advance until 1950, when Penfield published his article on 70 cases of temporal lobectomy [Flanigin et al., 1991; Penfield and Flanigin, 1950]. His neurosurgical career was devoted to the study of seizure semiology (i.e., clinical description) and its correlation with the brain cortex. He used cortical mapping and stimulation in much the same way in which it is used today. He also recognized the substrates of epilepsy, particularly trauma and infection. His seminal clinical research has been instrumental in guiding the hands of contemporary epileptologists and neurosurgeons interested in the surgical approach to epilepsy. Epilepsy surgery was not regarded as a conventional treatment for intractable epilepsy until recently. In the past 25 years, dramatic improvements in brain imaging that identify specific anatomic substrates of epilepsy have sparked renewed interest in this modality. Temporal lobectomy with amygdalohippocampectomy has become the standard of care in adult patients with intractable epilepsy emanating from the temporal lobe. The surgical success rate for a seizure-free outcome in these carefully selected patients approaches 80% to 90% [Duchowny et al., 1992; King et al., 1986; Penfield and Flanigin, 1950]. Unfortunately, surgical success does not necessarily translate to an improvement in quality of life. The accumulation of years of low selfesteem, loss of independence, poor peer relations, and

Zupanc / Epilepsy Surgery in the Pediatric Population

academic failure, coupled with high financial costs, often without benefit of full insurance coverage, translates to continued lack of employment and depression [Reeves et al., 1997]. The lifetime cost of epilepsy for an estimated 181,000 people with onset in 1995 is projected at $11.1 billion dollars, and the annual cost for the estimated 2.3 million people with epilepsy estimated at 12.5 billion dollars [Bazil, 2004; Begley et al., 1994, 2000; Hathaway et al., 1995]. Indirect costs account for 80% to 85% of the total costs and include delayed or missed educational opportunities, psychiatric and social service needs, and lost employment. The direct costs of epilepsy are concentrated in the patients with intractable epilepsy. The growing recognition of the real costs of epilepsy—medical, psychological, educational—have led to increased interest in the early identification of children who might benefit from epilepsy surgery [Jalava et al., 1997]. Attempts have been made to calculate the cost-benefit ratio for anterior temporal lobectomy. Even with the most conservative estimates, the benefit to society outweighs the costs when projected over an affected person’s life span. In the older child and adolescent, temporal lobectomies are common epilepsy surgical procedures. In younger children and infants, however, extratemporal resections, including multilobar resections and hemispherectomies, are the more typical procedures. Demonstration of seizure control and long-term developmental improvement should be the goals for any pediatric epilepsy surgery [Nordli, 2000].

INDICATIONS FOR EPILEPSY SURGERY In determining whether a child is a candidate for epilepsy surgery, several key issues must be considered. The decision-making task must take into account the following: • Seizure recurrence despite appropriate antiepileptic drug management • Natural history of the epilepsy syndrome (likelihood of continued intractability usually can be determined on the basis of the identification of symptomatic lesional epilepsy) • Identification of a known epileptogenic substrate • Impact of epilepsy on the quality of life as defined by cognitive and developmental parameters—now and in the future The proper classification of seizure type and epilepsy syndrome is crucial in the determination of whether or not a patient is an appropriate epilepsy surgery candidate [Aicardi, 1994; Holmes, 1993]. The benign seizure disorders, such as benign rolandic epilepsy or benign epilepsy with central centrotemporal spikes, must be recognized. With rare exceptions, these syndromes usually are easily treated, and affected patients do not present to tertiary epilepsy centers. The catastrophic epilepsies of infancy and childhood are recognizable early, and affected patients should be referred to a tertiary epilepsy center for consideration for epilepsy surgery. These epilepsy syndromes are characterized by the triad of (1) multiple daily seizures, (2) medical intractability to the standard antiepileptic drug therapies, (3) cognitive/ developmental stagnation or decline, and (4) presumed or known epileptogenic pathology. The patients should be

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surgically treated at an early age as soon as these catastrophic epilepsies are recognized and the preoperative evaluation can be completed with confidence. The catastrophic epilepsies of infancy and childhood include (1) SturgeWeber syndrome; (2) large unilateral or focal malformations of cortical development such as hemimegalencephaly or unilateral schizencephaly; (3) symptomatic infantile spasms with focal malformations of cortical development, typically temporal-parietal-occipital dysplasias; and (4) Rasmussen’s syndrome. Children with Sturge-Weber syndrome who have frequent, medically refractory seizures accompanied by progressive hemiparesis and cognitive impairment should be evaluated promptly for hemispherectomy [Thomas-Sohl et al., 2004; Vining et al., 1997]. Clinical outcome studies indicate that early surgical resection can result in the elimination of seizures, improvement in cognitive abilities, and overall improvement in quality of life despite hemiparesis and visual field defect as residual neurologic deficits [Erba and Cavazzuti, 1990; Hoffman et al., 1979; Ogunmekan et al., 1991]. Another category of patients with catastrophic epilepsy comprises those with unilateral or focal malformations of cortical development. Children with hemimegalencephaly can present in infancy with multiple daily seizures, developmental stagnation or decline, and hemiparesis. Again, hemispherectomy provides relief from seizures (especially in those patients with unilateral epileptiform abnormalities) and improved developmental outcome [Andermann et al., 1993; Vigevano and DiRocco, 1990; Vigevano et al., 1989]. Another subset of patients with symptomatic infantile spasms who have underlying focal cortical dysplasias, usually temporal-parietal-occipital, should be considered for focal cortical resection. University of California at Los Angeles investigators have provided the seminal clinical research in this area and have documented a significant improvement in seizure control and enhanced developmental gains, greater than would have been predicted using the natural history of infantile spasms as a comparison [Asarnow et al., 1997; Chugani et al., 1990, 1993; Duchowny et al., 1990]. Rasmussen’s encephalitis is characterized by intractable focal motor seizures, often evolving into epilepsia partialis continua, cognitive decline, and progressive hemiparesis. Recent findings of glutamate receptor antibodies in some patients with Rasmussen’s encephalitis implicate an autoimmune pathophysiology [Antel and Rasmussen, 1996; Pardo et al., 2004; Rogers et al., 1994]. Although initial trials of intravenous immunoglobulin and plasmapheresis have been encouraging, long-term studies have not confirmed efficacy [Andrews et al., 1996; Hart et al., 1994; Krauss et al., 1996]. Therefore, the only definitive treatment for Rasmussen’s encephalitis remains hemispherectomy. In addition to those with the catastrophic epilepsies of infancy and childhood, all children with tumors and concomitant localization-related epilepsy should be considered for early surgical intervention. Compelling reasons for such intervention exist. Most tumors need to be biopsied or excised. Additionally, although the tumors associated with epilepsy usually are slow growing, cortical, and well circumscribed, some tumors, especially astrocytomas, are not necessarily benign and can undergo malignant change over

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FIGURE 51-1. MRI scans from a patient with a ganglioglioma of the right temporal lobe. A, T1-weighted imaging without gadolinium (TR 500 msec/TE 16 msec). B, T1-weighted imaging with gadolinium (TR 500 msec/TE 16 msec). MRI, magnetic resonance imaging; TE, echo time; TR, recovery time.

time [Jack, 1995]. Without resection, the natural history of these tumor-associated epileptic syndromes is one of continued seizures with little hope of remission. Antiepileptic drugs produce side effects; subtle and overt side effects can affect cognitive function and behaviors, with concomitant impact on psychosocial development [Vining et al., 1987]. Examples of tumors that usually are easily resectable are the gangliogliomas and dysembryonic neuroectodermal tumors, which have a predilection for the temporal lobe (Fig. 51-1) [Duchowny et al., 1992; Tice et al., 1993; Vali et al., 1993]. Children with other types of lesional symptomatic localization-related epilepsy also should be considered epilepsy surgery candidates. Common substrates of epilepsy include encephalomalacias, vascular malformations, tubers, and malformations of cortical development. Sometimes these patients present with generalized epileptiform discharges on surface EEG monitoring. In the presence of a lesion on magnetic resonance imaging (MRI) scan of the brain, the epilepsy syndrome is most likely to be due to a symptomatic localization-related epilepsy with rapid secondary bisynchrony. With the improvement in neuroimaging, source localization on EEG, and magnetoencephalography (MEG), our ability to identify the epileptogenic zone is greatly enhanced, making a surgical resection a possibility. Patients with tuberous sclerosis and medically refractory symptomatic localization-related epilepsy also should be considered for epilepsy surgery. In patients with multiple tubers, emerging neuroimaging techniques, particularly interictal α-[11C]methyl-L-tryptophan (AMT) positron emission tomography (PET) scans, offer promise in identifying the most highly epileptogenic tuber [Asano et al., 2000; Chugani et al., 1998; Juhasz et al., 2003]. If the presurgical evaluation points to a specific tuber, studies have shown that it can be successfully removed, with a significant improvement in seizure control [Bebin et al., 1993; Koh et al., 2000; Romanelli et al., 2004].

Factors that favor early intervention with epilepsy surgery include the following: (1) seizure recurrence despite an adequate trial of two or three antiepileptic drugs; (2) seizures severe enough to interfere with progression in development or overall quality of life; (3) location of the lesion in the temporal lobe; and (4) epilepsy caused by identifiable malformations of cortical development. Even if the lesion is outside the temporal lobe, in carefully selected patients, lesionectomies generally can be performed with little risk of neurologic sequelae [Britton et al., 1994; Cascino et al., 1990, 1992, 1993, 1994; Montes et al., 1995; Paolicchi et al., 2000]. Data from our own retrospective study and from the work of Palmini and co-workers suggest that malformations of cortical development, no matter where the cortical location, carry a greater than 35% risk for status epilepticus [Laoprosert et al., 1997; Palmini et al., 1997]. Focal cortical dysplasias, as opposed to unilateral or bilateral polymicrogyria and schizencephaly, are almost universally refractory to antiepileptic drugs [Palmini et al., 1997]. Histopathologic examination, therefore, may play a large role in identifying the natural history of these epileptic syndromes. If the epilepsy is temporal in onset and pathologic features include associated hippocampal formation atrophy or mesial temporal sclerosis, the surgical success rate approaches 80% to 90% [Cascino et al., 1993; Sinclair et al., 2001] (Fig. 51-2). Epilepsy surgery should be considered early in these patients. Those children with intractable nonlesional extratemporal localization-related epilepsy represent the biggest challenge to the epileptologist but should still be considered for epilepsy surgery if their seizures remain intractable. The benefits of surgery must be weighed against the risks, especially the risk of neurologic deficits. As an example, localization-related epilepsy emanating from the sensorimotor cortex demands a more conservative approach. Several antiepileptic drugs and suitable investigational anti-

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FIGURE 51-2. MRI scan from a patient with left temporal hippocampal atrophy. The scan shows a coronal cut obtained with T1-weighted imaging (TR 24 msec/TE 9 msec). MRI, magnetic resonance imaging; TE, echo time; TR, recovery time.

epileptic drugs should be tried before embarking on a surgical approach with its attendant risks of hemiparesis. On the other hand, if a child has severe, frequent seizures with developmental stagnation and the preoperative evaluation demonstrates congruence of data from seizure semiology, electroencephalography, MRI, single-proton emission computed tomography (SPECT), PET, MEG, and MR spectroscopy (MRS), epilepsy surgery can be performed. Children with generalized or multifocal epilepsy also may be considered for epilepsy surgery if data suggest an underlying focal generator for the epileptic condition [Wyllie, 1995]. Approximately 10% to 15% of children with LennoxGastaut syndrome, one of the most common symptomatic “generalized” epilepsy syndromes, have underlying focal malformations of cortical development and should be evaluated carefully for epilepsy surgery. Children with intractable epilepsy who have tonic-atonic seizures associated with generalized spikes/polyspikes (usually Lennox-Gastaut syndrome) and no identifiable lesion on neuroimaging may respond to a corpus callosotomy, a palliative treatment that can have a significant impact on quality of life [Wyllie et al., 1993].

PREOPERATIVE EVALUATION Once a child has been selected as a possible epilepsy surgery candidate, further questions need to be addressed before epilepsy surgery can take place: (1) Can the epileptogenic zone be identified using video EEG, neuroimaging, and other modalities? Is there congruence of the data? (2) Can

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the epileptogenic focus be removed without causing unacceptable neurologic deficits? (3) Will a delay in epilepsy surgery cause loss of developmental plasticity? A multidisciplinary team is required to address the many issues surrounding the prospect of surgery in a child with chronic epilepsy. Epilepsy surgery itself may cure the seizures but will not necessarily address other needs of the family. A child with medically intractable epilepsy and the child’s family have complex and diverse problems—not just medical but also developmental, educational, psychosocial, economic, and relational. The coordinated services of a pediatric neurologist or epileptologist, child psychiatrist, pediatric neurosurgeon, pediatric neuropsychologist, speech and language pathologist, and pediatric neuroradiologist, along with diagnostic studies including electroencephalography, neuroimaging, and nuclear isotopic scanning, are required to evaluate the medical aspects before surgery is considered. Clinical nurse specialists are integral, often acting as the case managers and coordinators of the care designed to meet patient and family needs. The social worker is a critical part of the team, providing families with avenues for financial assistance, counseling families, and assisting with transitional services from hospital and clinic to the home environment. In addition, networking with other families who have undergone similar evaluations and treatment also is a critical aspect of the multidisciplinary evaluation, which cannot be effectively carried out without the integration of these services.

Concept of Congruence Under ideal conditions, identification of the epileptogenic focus is made by the congruence of data obtained during the preoperative evaluation, with the precise localization based on seizure semiology, physical examination, surface ictal and interictal EEG monitoring (and, if necessary, invasivedepth electrodes or subdural electrode strips or grid), MRI scan of the brain, ictal and interictal SPECT scans, interictal PET scan, MEG, functional MRI scan, and/or MR spectroscopy. Each case must be individualized, with some cases requiring the acquisition of data from all of these studies. Others may be resolved with a less complicated approach. At a minimum, seizure semiology, surface ictal EEG monitoring, and MRI scan of the brain should be congruent. With lesional localization-related epilepsy, the use of invasive EEG monitoring generally is not necessary. Electrocorticography at the time of surgery usually can assist with identifying the dimensions of the epileptogenic zone. The sensorimotor cortex can be identified intraoperatively using motor-evoked potentials, somatosensory-evoked potentials, or direct electrical cortical stimulation mapping. If the surgical excision is near functional speech and language cortex, older children and adolescents usually can be cooperative enough to tolerate an awake surgical procedure. In younger children (before the age of 5 to 6 years), plasticity of the brain is sufficient that removal of the primary speech and language centers will result in transition to the other hemisphere [Peacock, 1995; Shields, 2000]. The most complex cases are those of nonlesional extratemporal epilepsy. The patients usually require an interictal PET scan, subtraction SPECT scan, MR spectroscopy, or MEG, to look for evidence of a localized abnormality. In

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these patients, placement of invasive subdural strips or grids may be needed for precise localization of the epileptogenic focus.

Techniques and Technologies Seizure Semiology Seizure semiology can provide insightful clues to the lateralization and localization of the underlying epileptogenic focus. The presence of adversive head movements, unilateral motor clonic activity, and eye deviation may constitute critical lateralizing information. In similar fashion, seizures consisting of olfactory or gustatory hallucinations followed by complex motor automatisms and staring unresponsively are virtually diagnostic of involvement of the temporal lobe. These seizures generally are seen in older children or adolescents but also may occur in younger children. It should be noted, however, that seizures emanating from the temporal lobe in infants and young children commonly are associated with behavioral arrest, motor dystonic posturing, and fewer automatisms [Brockhaus and Elger, 1995; Jayakar and Duchowny, 1990; Wyllie et al., 1993]. Additionally, young children usually are incapable of describing the premonitory symptoms before the onset of the more overt clinical seizure. Video EEG monitoring has been helpful in fully elucidating the seizure semiology in these patients. Children with infantile spasms may have partial seizures before, during, or after the onset of the infantile spasms [Kobayashi et al., 2001; Watanabe et al., 2001]. Partial seizures can be a helpful clue that informs the epileptologist to screen carefully for an underlying focal abnormality, such as a tuber or focal cortical dysplasia.

Physical Examination The physical examination also can provide very valuable lateralizing information. As with seizure onset or its evolution, a focal abnormality on physical examination may point to an underlying focal structural lesion. For example, a child with schizencephaly and partial seizures may have a subtle hemiparesis, effectively demonstrating the affected hemisphere.

Electroencephalography The surface EEG is a critical element in the evaluation of children with epilepsy. The advent of computerized prolonged video EEG monitoring has ushered in a new era in the evaluation and management of epilepsy. This technique is used for many purposes, including (1) differentiation of epileptic versus nonepileptic events; (2) seizure classification; (3) recognition of specific epileptic syndromes; (4) preoperative evaluation with identification of the epileptogenic zone; (5) determination of seizure frequency; and (6) management of status epilepticus. In the adult preoperative evaluation, prolonged video EEG monitoring provides the baseline data with which all of the other data are compared. In children, however, it is becoming increasingly clear that the surface EEG data may be poorly localized and at times misleading in the preoperative evaluation [Wyllie, 1995]. Therefore, this modal-

ity may be less important in localizing the epileptogenic focus. In these children, other modalities, particularly neuroimaging studies (MRI, MRS, PET, and SPECT), may provide the pivotal information that determines the location of the epileptogenic zone and the need for invasive subdural EEG monitoring. Indeed, in the near future, the improvement of noninvasive functional brain imaging techniques may obviate the need for invasive EEG monitoring. Even now, invasive EEG monitoring may be deferred if surface EEG monitoring and MRI data are congruent [Wyllie et al., 1998].

Magnetic Resonance Imaging MRI scans have greatly enhanced the ability to visualize intraparenchymal brain structures. The linkage between intracranial abnormalities and epilepsy is well accepted [Zupanc, 1997a]. The mechanism(s) involved in the production of epilepsy is an area of intense research and involves structural changes, synaptic reorganization, stimulation of mossy fibers, astroglial proliferation with neuronal cell loss, and neurotransmitter or corresponding receptor changes. With the recent advances in MRI technology, the ability to identify these substrates of epilepsy has been greatly enhanced. This modality provides some of the most sensitive and specific neuroimaging data for localization of the epileptogenic zone [Brooks et al., 1990; Cascino, 1994; Cascino et al., 1989, 1991; Kuzniecky et al., 1993a, 1993c]. The following new technologies are exciting and innovative [Jack, 1995]: • Use of thin contiguous cuts of 1.5 to 1.6 mm in multiple sections of the cortex in combination with a three-dimensional volumetric pulse sequence provides the necessary resolution to detect small lesions that would be missed with conventional MRI scans. Specific areas can be targeted, and images can be reformatted to correct for head rotation and other perturbations in data collection. This technique has allowed detection of even small amounts of unilateral hippocampal atrophy (see Fig. 51-2), as well as identification of small areas of focal cortical dysplasia. • The ability to conduct quantitative volumetric analysis of the hippocampus has resulted in the determination of unilateral or bilateral hippocampal atrophy. In patients with epilepsy emanating from the temporal lobe, the identification of unilateral hippocampal atrophy combined with concordant surface ictal EEG data is sufficient to allow a temporal lobectomy with amygdalohippocampectomy to proceed without invasive EEG monitoring. • The fluid-attenuated inversion recovery imaging (FLAIR) technique highlights lesions such as mesial temporal sclerosis and malformations of cortical development and allows detection of previously unidentifiable small lesions. This sequence produces a T2-weighted image that subtracts out the cerebrospinal fluid signal (white and bright on T2) but keeps the T2 signal for intraparenchymal structures (Figs. 51-3 and 51-4). • Diffusion tensor imaging is an MRI imaging technique that can identify white matter tracts [Rugg-Gunn et al., 2001] that may be disrupted in areas of cortical

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FIGURE 51-3. MRI scans from a patient with focal cortical dysplasia of the posterior left parasagittal region. A, With T1-weighted imaging (TR 24 msec/TE 9 msec), thickening of the cortex and blurring of the white/gray matter are evident. B, The dysplasia is seen more clearly with fluid-attenuated inversion recovery imaging (FLAIR) sequencing (TR 1100 msec/TE 142 msec/TI 2600 msec) (see text). MRI, magnetic resonance imaging; TE, echo time; TI, inversion time; TR, recovery time.

dysplasia. With use of these techniques, MRI scans can identify many substrates of epilepsy, including malformations of cortical development, tumors, vascular malformations, and encephalomalacias secondary to trauma, infection, and infarction. Malformations of cortical development are increasingly recognized as being highly epileptogenic [Kuzniecky and Ruben, 1995; Kuzniecky and Barkovich, 2001; Palmini et al., 1995; Raymond et al., 1995]. Advances in MRI technology have greatly improved the ability to identify these abnormalities. They may account for greater than 60% of the intractable localization-related epilepsies of childhood [Kuzniecky et al., 1993c]. These malformations can be small and difficult to detect even with sophisticated MRI scans of the brain or can be widespread and diffuse, as with lissencephaly [Dobyns and Truwit, 1995; Dobyns et al., 1996] (Figs. 51-5 and 51-6). The unilateral and focal malformations of cortical development are most often targeted for surgical excision. Clinically, information on the natural history of the malformations of cortical development is emerging. Status epilepticus is a common initial presentation, usually in the latter half of the first decade of life [Laoprasert and Zupanc, 1997]. Many of the malformations of cortical development produce an epileptic syndrome that is intractable to medical management [Palmini et al., 1997]. Finally, although mesial temporal sclerosis and hippocampal atrophy are not commonly found in children with intractable epilepsy younger than 10 years of age, identification of these abnormalities is a powerful indicator of the zone of epileptogenesis [Cascino, 1994; Cascino et al.,

1991; Jack, 1995; Swartz et al., 1992]. The pathophysiology of mesial temporal sclerosis and hippocampal formation atrophy is poorly understood. Do the seizures themselves cause mesial temporal sclerosis and hippocampal formation atrophy? Does an underlying malformation of cortical development cause the initial seizures, ultimately resulting in mesial temporal sclerosis and hippocampal formation atrophy? [Cendes et al., 1993; Kuks et al., 1993; Trenerry et al., 1993]. These questions have not yet been clearly answered. We do know, however, that the degree of volume loss correlates with the amount of cellular loss as measured in pathologic specimens [Cascino et al., 1991]. The neuronal cell loss, coupled with the presence of aberrant mossy fibers and synaptic reorganization, probably accounts for the recurrent, recalcitrant seizures [Fuerst et al., 2003; Holmes and Ben-Ari, 1998; Jokeit et al., 1999; Kalviainen et al., 1998; Kotloski et al., 2002; Sutula et al., 1988, 1989; Tasch et al., 1999]

Single-Photon Emission Computed Tomography SPECT also has enhanced the ability to identify the epileptogenic zone. Penfield and colleagues observed relative hyperperfusion in the epileptogenic zone during a seizure [Penfield, 1958]. Interictally, blood flow and metabolism decrease. SPECT scan technology enables quantification of cerebral blood flow and identification of areas of relative blood flow change. SPECT images are reconstructed from data obtained by recording photon emissions from radiotracers injected intravenously. These radiotracers rapidly

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FIGURE 51-4. MRI scans showing coronal cuts through the temporal lobes, from a patient with left temporal hippocampal atrophy. The atrophy is seen best with T1-weighted imaging (top panel) (TR 24 msec/TE 9 msec). Concomitant left temporal mesial temporal sclerosis is seen best with FLAIR sequencing (bottom panel) (TR 1100 msec/TE 142 msec/TI 2600 msec). Middle panel represents the picture created on T2-weighted imaging (TR 2000 msec/TE 80 msec). FLAIR, fluid-attenuated inversion recovery imaging; MRI, magnetic resonance imaging; TE, echo time; TR, recovery time.

FIGURE 51-6. MRI scan from a patient with unilateral perisylvian dysplasia with polymicrogyria (left hemisphere). T1-weighted imaging (TR 24 msec/TE 9 msec) was used. MRI, magnetic resonance imaging; TE, echo time; TR, recovery time.

FIGURE 51-5. MRI scan from a patient with focal cortical dysplasia of the left frontal region. With T1-weighted imaging (TR 24 msec/TE 9 msec), thickening of the cortex and blurring of the white/gray matter are seen. MRI, magnetic resonance imaging; TE, echo time; TR, recovery time.

cross the blood-brain barrier because of their lipophilic nature and bind within minutes to the brain, producing an instantaneous picture of cerebral blood flow [English and Brown, 1990]. Clinical research has focused on both interictal and ictal SPECT scans, with a substantial portion of the clinical research using the radioisotope 99mtechnetiumhexamethylpropyleneamine oxime (99mTc-HMPAO). More recently, 99mTc ethyl cysteinate dimer (ECD) (i.e., 99mTcN,N′(1,2-ethylenediyl)bis-L-cysteine diethyl ester), prepared as technetium Tc-99m bicisate (Neurolite), has been introduced [Lanceman et al., 1997]. Logistically, Neurolite provides distinct advantages for ictal SPECT scans because it is a stable isotope tracer that can be mixed well ahead of the time of injection, as opposed to 99mTc-HMPAO, which decomposes quickly in vitro and must be used less than 30 minutes after it is reconstituted. For ictal SPECT scans, a technologist or nurse trained in the delivery of these radioisotopes can sit at the bedside and deliver the Neurolite within seconds after the onset of a seizure. Spatial resolution with SPECT scans also has improved because of the development of gamma cameras with multiple detectors that provide more data points, with subsequent enhanced sensitivity. Interictal SPECT scans have been used for longer than 10 years as a method for identifying the epileptogenic focus in patients with medically intractable localization-related epilepsy who are candidates for epilepsy surgery. With interictal SPECT scans, the epileptogenic zone can be identified by a regional area of reduced cerebral blood flow [Adams et al., 1992; Berkovic et al., 1992, 1993; Cordes et al., 1990; Coubes et al., 1993; Denays et al., 1988; Dietrich et al., 1991; Grunwald et al., 1991; Hajek et al., 1991; Kuzniecky

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et al., 1993b; Lamanna et al., 1989; Launes et al., 1992; Lee et al., 1988; Rowe et al., 1989, 1991; Ryding et al., 1988; Ryvlin et al., 1992; Shen et al., 1990; Verhoeff et al., 1992]. Clinical research clearly indicates that interictal studies alone have a relatively low sensitivity for identification of the epileptogenic focus in adults with temporal lobe epilepsy and even lower sensitivity with extratemporal epilepsy. Data pooled from several studies yield estimates of interictal SPECT sensitivity of 66% for temporal lobe epilepsy and 60% for extratemporal epilepsy localized by EEG [Spencer, 1994]. Interictal SPECT scans do demonstrate regional hypoperfusion, most prominent in those persons who have frequent seizures, but the hypoperfusion generally is over a larger region of cortical tissue than found with ictal recordings. Other studies suggest that the sensitivity of interictal SPECT studies in children may be higher than in adults, but the studies are still not as reliable as the ictal studies [Cross et al., 1995; Harvey et al., 1993a, 1993b]. Ictal SPECT scan data, however, have proved valuable with respect to localization of the epileptogenic focus. Ictal SPECT scans typically reveal an area of regional hyperperfusion that corresponds to the underlying epileptogenic focus as verified by surgical pathology and surface EEG localization [Bauer et al., 1989; Grunwald et al., 1991; Ho et al., 1994; Hwang et al., 1990; Katz et al., 1990; Lee et al., 1988; Marks et al., 1992; Newton et al., 1992b; Rowe et al., 1989, 1991; Shen et al., 1990; Stefan et al., 1990]. Using data pooled from several centers, the sensitivity of ictal SPECT (as judged by EEG correlation) has been estimated at 90% for temporal and 81% for extratemporal epilepsy, with specificity at 77% and 93%, respectively [Spencer, 1994]. Critical to the efficacy of the ictal SPECT scan is the timing of the injection. If the injection can be given within

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30 seconds of the seizure onset, the isotope remains localized and can “capture” the epileptogenic focus or generator before the epileptogenic discharge spreads [ Newton et al., 1995]. When the injection cannot be given immediately or if it is recognized that seizure propagation is rapid, observation at the time of injection for comparison with known patterns of propagation enables determination of the epileptogenic focus. Specifically, in temporal lobe epilepsy, ipsilateral basal ganglia hyperperfusion may be observed in some instances, usually correlated with contralateral arm dystonia in seizures emanating from the temporal lobe [Newton et al., 1992a]. In addition, if clonic motor activity is seen during an ictal event and before the isotope injection, contralateral hyperperfusion involving the motor cortex, basal ganglia, and thalamus may be present regardless of the location of the epileptogenic focus. Comparison of ictal and interictal scans also is important in determining whether any abnormality in blood flow is significant. With the assistance of computerized technology and surface matching techniques, co-registration of the ictal SPECT scan to the volumetric MRI scan has demonstrated a close relationship between the region of ictal hyperperfusion and MRI structural lesions [Hogan et al., 1995; Mountz et al., 1994]. A technique has been developed whereby the ictal and interictal SPECT scan data are co-registered with one another and the interictal image is subtracted from the ictal image, producing the area of true ictal hyperperfusion [Zubal et al., 1995]. This difference image, called a subtraction SPECT scan, then is co-registered with a three-dimensional representation of the MRI scan. In nonlesional extratemporal epilepsy, this information may prove to be especially helpful in either guiding placement for subdural invasive EEG monitoring or obviating the need for invasive monitoring altogether. Several studies have

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FIGURE 51-7. SPECT scans. A, Ictal (upper left) and interictal (upper middle) scans, along with subtraction SPECT scan (upper right). B, Using SISCOM software (see text), subtraction scans coregistered to the MRI study (left) and with volumetric MRI (right) were obtained. MRI, magnetic resonance imaging; SPECT, single-photon emission computed tomography.

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demonstrated that periictal subtraction SPECT provides useful information for seizure localization in patients with focal malformations of cortical development, even when the MRI study is nonlocalizing (i.e., “nonlesional”) [O’Brien et al., 1998, 2000, 2004]. In a large series involving pediatric and adult epilepsy patients, if the site of the surgical resection was concordant with the subtraction SPECT localization (using SISCOM technology, a Mayo Clinic– patented computer program that performs subtraction SPECT and then co-registers the results to a volumetric MRI scan of the brain), postoperative seizure frequency scores were significantly lower and postoperative improvement was greater [O’Brien et al., 1998] (See Fig. 51-7). In summary, SPECT scan technology holds great merit and promise for the future. It is widely available and is reasonable in cost. Additionally, the new stable tracers have simplified the procedure and improved the ability to obtain accurate ictal scans. These facts, coupled with increasing resolution of the image scanners, ensure that SPECT scan technology will gain increasing prominence.

Positron Emission Tomography PET is another technique used for localization of the epileptogenic focus [Mohan et al., 1999]. It uses radiotracers

A

labeled with specific positron-emitting isotopes (11C, 15O, and 18F) to measure a variety of biochemical functions in the brain. With the aid of computerized technology and mathematical modeling, the source and concentration of the emission are either qualitatively or quantitatively plotted on a three-dimensional representation of the brain. Cerebral glucose metabolism is the most commonly measured parameter, using 18F-fluorodeoxyglucose (FDG) (Fig. 51-8). Other tracers also can be used to measure cerebral blood flow, benzodiazepine and opiate receptors, pH, serotonin metabolism, and amino acid transport [Henry et al., 1993; Mohan et al., 1999; Shah et al., 1995]. FDG PET images are averaged over a 40-minute time interval, suggesting the limited value of this technique for ictal studies. The interictal images, on the other hand, are highly sensitive in complex partial seizures emanating from the temporal lobe. In several studies in adult patients with medically refractory epilepsy of temporal lobe origin, glucose hypometabolism in the temporal lobe correlated highly with localized ictal EEGs and MRI abnormalities in this region [Abou-Khalli et al., 1987; Chugani et al., 1990; Coubes et al., 1993; Debets et al., 1990; Engel et al., 1982; Hajek et al., 1993; Henry et al., 1993; Liederman et al., 1992; Radtke et al., 1993; Sackellares et al., 1990; Stefan et al., 1987, 1990; Swartz et al., 1992; Theodore et al., 1986,

B

FIGURE 51-8. FDG PET scan from a 12-year-old girl with complex partial seizures, showing a focal decrease in glucose metabolism in the left parietal and, to a lesser extent, the left occipital cortex. The images in A and B were obtained at two different horizontal levels of the brain. EEG obtained during the scan demonstrated occasional sharp-wave discharges over the left parietal and central regions. EEG, electroencephalogram; FDG PET, fluorodeoxyglucose positron emission tomography. (Courtesy of Dr. HG Chugani and Children’s Hospital of Michigan PET Center, Wayne State University, Detroit, Michigan.)

Zupanc / Epilepsy Surgery in the Pediatric Population

1990; Valk et al., 1993]. Glucose hypometabolism in the temporal lobe, as obtained on interictal FDG PET scan, has been found to have an overall sensitivity of 84% and a specificity of 86% [Spencer, 1994]. In a study by Theodore and co-workers [1997], the presence of glucose hypometabolism on PET scan in the temporal lobe in the presence of a nonlocalizing surface ictal EEG predicted successful outcome with temporal lobectomy. Localization to the temporal lobe was confirmed with invasive EEG monitoring in these patients, but the authors make the point that invasive EEG monitoring may be unnecessary and may even provide false localizing information in some patients being evaluated for epilepsy surgery. As technology improves, concordance of noninvasive neuroimaging techniques may be all that is necessary before proceeding with the surgery. Analysis of nonlesional extratemporal epilepsy in adult patients with PET scans has provided data that have been less conflicting or less definitive. [Chugani et al., 1990; Sackellares et al., 1990; Stefan et al., 1990]. In children with refractory epilepsy, however, despite poor localization on surface EEG and negative findings on MRI scans of the brain, FDG PET scans have been useful in identifying an underlying epileptogenic focus. Specifically, University of California at Los Angeles investigators were the first to recognize a small subset of children with intractable infantile spasms and underlying deficits of focal glucose metabolism on PET scan [Chugani et al., 1988, 1990; Olson et al., 1990]. These deficits usually were temporal-parietaloccipital in origin. Many of these patients had partial seizures before, during, or after the onset of their infantile spasms, often providing a clue to localization. Additionally, interictal surface EEG examined retrospectively often disclosed focal delta slowing or an asymmetry in beta activity. Large cortical resections of the underlying epileptogenic zone were performed, guided by PET scan data and electrocorticography. After surgery, the seizures (infantile spasms and/or partial seizures) disappeared. Results indicate that not only did seizure control improve but also that these patients’ development improved at a faster rate and to a greater degree than would have been predicted without surgery [Asarnow et al., 1997; Chugani et al., 1988]. Newer ligands also have been developed. In flumazenil PET scans, the flumazenil binds to benzodiazepine receptors [Juhasz et al., 1999; Mohan et al., 1999]. In the area of the epileptogenic zone, benzodiazepine binding appears to be decreased. In one clinical study, the flumazenil PET scan demonstrated a more restricted area of decreased binding than was apparent on the FDG PET scan; the resection of this cortical region was associated with good surgical outcome [Juhasz et al., 2000]. In addition, diffuse cortical abnormalities on flumazenil PET scans predict poor seizure control following epilepsy surgery [Juhasz et al., 2001]. AMT PET scans also have been studied. AMT is a precursor for serotonin synthesis [Chugani et al., 1998; Juhasz et al., 2003]. Data suggest that the AMT PET scans can identify the most epileptogenic tuber in patients with tuberous sclerosis, multiple tubers, and medically intractable epilepsy. Concordance of the epileptogenic tuber with increased AMT uptake has been observed on PET scans [Asano et al., 2000; Chugani et al., 1998, Chugani and Muzik, 2000]. In addition, AMT PET scans also appear to be very helpful in

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reevaluating patients in whom epilepsy surgery has failed to effect improvement. In the patients studied with AMT PET, the area of increased AMT binding correlated closely with the epileptogenic zone [Juhasz et al., 2004].

Magnetic Resonance Spectroscopy MRS has been used in the study of patients with intractable epilepsy. Specifically, phosphorus MRS measures phospholipid metabolism. In the region of the epileptogenic focus, investigators have found abnormal phosphocreatine– to–inorganic phosphate ratios. Phosphocreatine (Pcr), intracellular pH, and inorganic phosphorus (Pi) increase during a seizure. Adenosine triphosphate concentration, however, only decreases slightly [Duncan, 1997; Prichard, 1994]. Proton MRS also can measure regional abnormalities in lactate, N-acetyl-aspartate (NAA), creatine (Cr), and choline (Cho). Lactate levels increase during a seizure and remain elevated for several hours. Data also indicate reductions in the NAA/Cho and NAA/Cr ratios in the region of the epileptogenic zone, presumed to reflect neuronal loss and reactive astrocytosis [Petroff et al., 1984, 1986; Prichard, 1994]. Therefore, abnormal NAA/Cr and NAA/ Cho ratios may serve as indices of regional cellular pathology. MRS is being applied in clinical research as an additional tool in assisting with the localization of nonlesional epilepsy [Connelly et al., 1994; Kuzniecky et al., 1992; Laxer et al., 1992; Matthews et al., 1990; Ng et al., 1993, 1994; Novotny, 1995]. In a study of children with temporal lobe epilepsy and mesial temporal sclerosis on MRI of the brain, low NAA/Cho and NAA/Cr ratios were found ipsilateral to the abnormal MRI; none demonstrated false localization [Cross et al., 1997]. Interictal SPECT scans using 99mTc-HMPAO also were performed in these children. About 71% of the children (10 of 14) had regional hypometabolism in the MRI-identified abnormal temporal lobe, and 81% demonstrated abnormal NAA/Cho + Cr ratios. The excellent correlation among interictal SPECT, MRS, and mesial temporal sclerosis on brain MRI studies suggests that neuronal cell loss is the physiologic change reflected in these noninvasive technologies. MRS holds promise as an important adjunctive noninvasive technique for assisting with the identification of the underlying epileptogenic zone.

Magnetoencephalography MEG is another technology that has been developed to improve the ability to identify epileptogenic foci. It measures tiny magnetic fields in the brain that are created by the electrical activity of the brain. Most institutions are using 128-channel MEG technology to enhance resolution. MEG offers several advantages over EEG. First, the magnetic fields are not attenuated by the skull, scalp, and skin, as are electrical potentials; therefore, the MEG signal contains fewer distortions or changes [Barth, 1993]. Second, the MEG is a monopolar measure and does not require a dipolar montage, eliminating the possibility of artifact associated with an “active reference.” Finally, and of greatest importance, MEG measures postsynaptic intracellular currents in the dendrites of neurons situated tangentially to the skull, whereas the EEG measures the extracellular postsynaptic ionic currents [Barth, 1993; Barth et al., 1984].

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Clinical research suggests that although surface interictal EEG spike recordings may indicate multifocal activity, MEG can more precisely localize the underlying epileptogenic focus [Barth, 1993; Stefan et al., 2003; Sutherling et al., 1988; Wheless et al., 1999]. MEG has provided pivotal information and may become the most precise way of identifying the size, location, and dipole orientation of the epileptogenic zone [Minassian et al., 1999; Stefan et al., 2003; Wheless et al., 1999, 2004]. In addition, MEG may be a very useful tool in children with respect to functional imaging, particularly imaging language cortex [Papanicolaou et al., 2004; Simos et al., 1999].

Functional Mapping If an underlying epileptogenic focus is identified, the next question to consider is whether the epileptogenic zone can be removed without causing unacceptable neurologic deficits. In infants and young children, this proves to be less problematic because of brain plasticity. Classically, in the older child and adolescent, the sodium amytal test (Wada test) is used in the preoperative evaluation for the localization of speech and language and to determine whether memory can be supported in the contralateral hemisphere [Loring, 1997; Wyllie et al., 1990]. This test involves injecting sodium amytal into either the left or the right internal carotid artery, in an attempt to chemically ameliorate ipsilateral hemispheric function and determine which hemisphere is “dominant” (i.e., responsible for speech and language function and, to a lesser extent, memory). It is a time-consuming test that is invasive and provides a broad but nonspecific overview of hemispheric function. Additionally, controversy is ongoing over its interpretation and its ability to predict postoperative function, particularly with respect to memory [Loring et al., 1992; Perrine, 1994]. As an example, language is a complex function. Although speech arrest after sodium amytal injection usually is in the dominant hemisphere, this is not always the case [Loring et al., 1992]. Language involves spontaneous speech, repetition, comprehension, reading, and counting. These aspects of language are all interactive, but their correponding cortical areas may be located in different areas of the brain, making it difficult

to relegate language to one specific hemisphere or region. In younger children, the Wada test can be even more challenging and technically difficult. Obtaining full cooperation from a child requires preparation, time, and patience. If the child becomes frightened during the test, test validity becomes questionable. Two other techniques also used frequently to identify eloquent cortex (i.e., cortex controlling vital motor, language, or memory functions) are somatosensory-evoked potentials and stimulation mapping. The measurement of somatosensory evoked potentials has the advantage of being able to be applied successfully regardless of the state of the patient. This modality can be used in the operating room in the anesthetized patient or in an awake and cooperative patient. Somatosensory-evoked potentials are used primarily to identify the sensorimotor cortex. Stimulation mapping is another useful technique in the identification of eloquent cortex. This technique involves the application of subdural electrodes followed by sequential electrical stimuli at various intensities and durations. Penfield pioneered this technique during the 1930s through the 1950s to localize language and motor functions intraoperatively, to avoid postoperative neurologic deficits. Subsequent investigators have used cortical stimulation preoperatively (using implanted grid electrodes) and intraoperatively to map out functional cortex, such as the sensorimotor cortex or expressive language cortex [Ojemann, 1978, 1979, 1993; Ojemann and Dodrill, 1987]. Although cortical stimulation mapping has yielded a tremendous amount of information about the localization of functions, several other emerging techniques are providing valid, noninvasive methods for mapping out functional areas of the brain. These techniques include functional MRI scans, MEG and magnetic source imaging, and transcranial magnetic stimulation [Binder, 1997; Detre, 2004; Knowlton and Shih, 2004; Peresson et al., 1998; Perrine, 1994; Powell et al., 2004; Sabsevitz et al., 2003; Wheless et al., 2004]. In view of the limitations of the previously described techniques for functional mapping, other noninvasive techniques that might provide more specific and salient information are being developed. Functional MRI scans are being used experimentally in a number of epilepsy centers to define eloquent cortex [Kwong et al., 1992; Lee et al., 1996;

FIGURE 51-9. Functional MRI scan. Identification of left hemisphere motor cortex was achived by asking the patient to open and close his right hand repetitively. Functional activity (in white) is superimposed on gray scan multishot echo planar images. MRI, magnetic resonance imaging.

Zupanc / Epilepsy Surgery in the Pediatric Population

Ogawa et al., 1992]. Functional MRI is based on the fact that performance of a specific act will activate the anatomically appropriate cortex in the brain. With activation, a concomitant increase in blood flow occurs, resulting in a change in the paramagnetic properties of the affected cortex. This produces a signal that can then be detected by the MRI scanner. Functional MRI is a technique that will be increasingly used in the future to map out eloquent functions, such as sensorimotor cortex and speech and language centers [Logan et al., 1995, 1997, 1998]. It is still unsuitable for the young, uncooperative infant or child, but for older children and adolescents, clinical research is yielding increasing proof that functional MRI can provide important localization data. In the young infant and child, functional studies are less likely to alter surgical resection because the enhanced plasticity of the brain in these age groups makes localization less criticial [Shields, 2000; Stafstrom et al., 2000; Wyllie, 1998]. An example of a functional MRI scan is illustrated in Figure 51-9.

TYPES OF SURGERY Several types of epilepsy surgery are performed in children and adults, depending on the identification of the epileptogenic focus and its location and extent [Zupanc, 1997b]. The most common surgical procedures are (1) temporal lobectomy; (2) cortical resection; (3) stereotactic lesionectomy; (4) hemispherectomy—either functional, modified hemispherectomy or anatomic hemispherectomy; (5) multiple subpial transection; and (6) corpus callosotomy. Temporal lobectomy is the most common epilepsy surgery performed in adolescents and adults. This procedure is almost exclusively a temporal lobectomy with amygdalohippocampectomy, because the removal of the mesial temporal structures is correlated with good surgical outcome. Often an associated abnormality or lesion, such as a tumor (DNET or ganglioglioma), mesial temporal sclerosis, hippocampal formation atrophy, or malformation of cortical development, is found to be present. The new technologies currently available in MRI have been helpful in identification of these substrates of epilepsy. Those patients with mesial temporal sclerosis or hippocampal atrophy concordant with ictal surface EEG abnormalities have an excellent prognosis for successful epilepsy surgery, with a 90% chance of becoming seizure free [Duchowny et al., 1992; Falconer, 1970; Mizrahi et al., 1990]. Younger children do not commonly have mesial temporal sclerosis or hippocampal atrophy [Ng et al., 2004]. Many of the intractable epilepsies in childhood are extratemporal and nonlesional. Extratemporal cortical resection commonly is performed in children, often involving extensive lobar or multilobar resections. The extent of the resection is dictated primarily by the extent of the lesion. For example, a simple tuberectomy in a patient with tuberous sclerosis or a multilobar resection in a child with infantile spasms and an underlying focal cortical dysplasia involving the temporal-parietaloccipital lobes might be performed. As the ability to identify focal cortical dysplasias and the concomitant epileptogenic zone improves, epilepsy surgical outcomes also will improve. Focal cortical dysplasias are a common cause of intractable partial epilepsy in children, accounting for 60%

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of the cases [Kuzniecky and Barkovich, 2001; Kuzniecky et al., 1993c]. The best predictive factor in successful surgical outcome is completeness of the resection. Stereotactic lesionectomy is performed in highly selected cases in children and adults, with a reported 50% to 60% chance of rendering the patient seizure free [Britton et al., 1994; Cascino et al., 1990, 1992, 1993, 1994]. Outcome is improved if intraoperative electrocorticography is used to remove not only the lesion but also the surrounding “epileptogenic zone” [Jooma et al., 1995; Montes et al., 1995; Palmini et al., 1995; Pilcher et al., 1993]. To date, no prospective, controlled studies of statistically significant numbers of patients have critically compared the different operative strategies with respect to outcome [Shields, 2000; Tonini et al., 2004; Wyllie, 1998]. The surgical outcome in these patients may vary, depending on the age of the patient, location of lesion, and most important, the type of lesion. In a review of 47 published articles about epilepsy surgery outcome, the best predictors for seizure-free outcome were found to include history of febrile seizures as a child, mesial temporal sclerosis, tumors, EEG and MRI data concordance, and an extensive surgical resection [Tonini et al., 2004]. Hemispherectomy also is performed in young children [Vining et al., 1997]. The indications for this type of surgery are catastrophic epilepsies in which the substrate of epilepsy is limited to one hemisphere. Epileptic syndromes that frequently meet these criteria include the following: (1) Sturge-Weber syndrome, (2) hemimegalencephaly, and (3) Rasmussen’s encephalitis. In Sturge-Weber syndrome, the pathologic features consist of unilateral leptomeningeal angiomatosis, frequently resulting in changes in the involved hemisphere with concomitant focal seizures, progressive hemiparesis, and cognitive decline [Roach et al., 1994]. Hemimegalencephaly, by definition, is a malformation of cortical development involving one hemisphere and is characterized by general disorganization and overgrowth of the neuronal tissue. Early hemispherectomy, particularly if the EEG reveals unilateral discharges, can significantly alter the prognosis in affected children [Andermann et al., 1993; Vivegano et al., 1989; Vivegano and DiRocco, 1990]. With Rasmussen’s encephalitis, children have intractable focal seizures, often progressing to epilepsia partialis continua, accompanied by progressive hemiparesis and cognitive decline. Although debate is ongoing about the pathophysiology (autoimmune versus infectious), the only long-term successful treatment has been hemispherectomy [Antel and Rasmussen, 1996]. Multiple subpial transection is a newer surgical technique that is used when the epileptogenic zone overlies an area of functional cortex. Multiple subpial transection involves the disruption of connecting horizontal fibers, rather than resection of actual tissue [Blount et al., 2004; Devinsky et al., 2003; Schramm et al., 2002; Spencer et al., 2002]. This technique has been used in the treatment of LandauKleffner syndrome [Morrell et al., 1995]. Children with this syndrome have an acquired epileptic aphasia, often intractable to medication. The multiple subpial transection technique has been used over the area deemed to be the epileptogenic zone on electrocorticography. Although good surgical results have been reported, the technique remains controversial. Multiple subpial transection also is being used in areas involving functional cortex. Data indicate that although multiple sub-

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pial transection may be an appropriate adjunctive surgical technique, it will not eliminate seizures if the primary epileptogenic focus is not completely removed [Hufnagel et al., 1997; Spencer et al., 2002]. Corpus callosotomy is a palliative surgery that can reduce the seizure burden in carefully selected patients. It most commonly is used in children with Lennox-Gastaut syndrome, with the goal being reduction of tonic and atonic seizures. It can be highly effective [Carson, 2000; Maehara and Shimizu, 2001; McInerney et al., 1999; Sassower et al., 2001; Sorenson et al., 1997]. Most often, callosotomy of the anterior two thirds of the corpus callosum initially is performed, to minimize postoperative side effects. If seizures return or persist, the corpus callosotomy can be completed [Geoffroy et al., 1983; Wyler, 1993].

GOALS OF SURGERY With use of innovative, noninvasive technologies, the ability of the clinician to identify the underlying epileptogenic zone has improved. In patients with medically intractable epilepsy, this ability allows one of the principal goals of epilepsy surgery to be achieved—that is, the elimination of seizures. The goals of epilepsy surgery, however, may vary, depending on the epileptic syndrome, the underlying pathophysiology, the cognitive and developmental status of the child or adolescent, and the identification and location of an epileptogenic zone [Taylor et al., 1997]. Specifically, if a cognitively normal patient has temporal lobe epilepsy as documented by congruence of seizure semiology and EEG and MRI data, the goals of epilepsy surgery are clear: elimination of seizures and improvement in psychosocial, behavioral, emotional, and family functioning without significant loss of cognitive abilities. On the other hand, a cognitively impaired patient with an extensive bilateral malformation of cortical development might be considered for a corpus callosotomy. In this case, the primary goals of epilepsy surgery would be the reduction of seizures and possible improvement in cognitive and behavioral functions. Although improvement in cognition, development, and behavior usually is achieved by virtue of decreased seizure frequency and reduction of antiepileptic drug doses, such results are not always obtained, and outcomes will vary with each patient, depending on the epilepsy syndrome and the identified etiology for the epilepsy. The goals of epilepsy surgery and potential limitations of the results of surgery need to be discussed openly with the family before any decision is made. In patients with malformations of cortical development (in children, typically extratemporal), epilepsy surgery usually has involved lobar or multilobar resections, as well as hemispherectomies. Approximately 60% to 65% of these patients are seizure free after surgery, and a majority achieve a significant reduction in seizure burden [Shields, 2000; Wyllie, 1998]. At critical stages of development, this reduction in seizure burden is associated with an improvement in development that appears to be sustained. In patients with malformations of cortical development and medically refractory epilepsy who undergo surgical resection, withdrawal of antiepileptic medication is rarely successful. The cortical dysplasia often is very extensive,

involving multiple lobes. On the other hand, children with lesions such as mesial temporal sclerosis, low-grade tumors, or middle cerebral artery infarctions can achieve seizurefree status, with eventual discontinuation of antiepileptic medication.

RESEARCH ISSUES: TRENDS FOR THE FUTURE The following are some of many unanswered questions to be addressed in the pursuit of helping children with intractable epilepsy: • What are the age-specific developmental mechanisms in childhood epilepsy? Can they be targeted for the development of new and more effective antiepileptic drugs or surgical therapy? • In children with similar electrographic findings and seizure semiology, why do some respond to antiepileptic drugs whereas others do not? What clues might this information provide about the mechanisms of epilepsy and possible treatments? • What is the definition of seizure intractability in children? This concept is in evolution and likely depends on multiple factors, including the natural history of the epileptic syndrome, etiology of the seizures, seizure frequency, and the degree to which the seizures and antiepileptic drug therapy impact the quality of life. • Does a time frame exist during which specific epileptic syndromes mandate intervention, because of either (1) windows of developmental opportunity or (2) diminishing capabilities of neural plasticity? What can we learn about the dimensions of neural plasticity? • Do seizures contribute to the development of cognitive impairments and to what degree? Can prompt surgery in patients with catastrophic epilepsy ameliorate cognitive impairments? • Can early successful intervention, with either antiepileptic drugs or epilepsy surgery, result in an improvement in the quality of life for patients with epilepsy? Future trends for exploration will involve several avenues of research: source localization and predictive EEG patterns for identification of the epileptogenic zone [Smart et al., 2004; Worrell, 2004]; implantable devices that can detect predictive EEG patterns before a clinical seizure and deliver either an abortive dose of antiepileptic medication or an abortive electrical stimulus; deep brain cortical-thalamic stimulation to diminish seizure frequency in those patients with subcortical-cortical epileptogenic networks (intractable nonlesional, generalized epilepsy syndromes); and, finally, “designer” antiepileptic drugs targeting specific mechanisms of epilepsy—most likely sodium, potassium, calcium, and γ-aminobutyric acid channels—to be delivered locally or systemically. REFERENCES Abou-Khalil BW, Siegel GJ, Sackellares JC, et al. Positron emission tomography studies of cerebral glucose metabolism in chronic partial epilepsy. Ann Neurol 1987;22:480.

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Cascino GD, Hulihan JF, Sharbrough FW, et al. Parietal lobe lesional epilepsy: Electroclinical correlation and operative outcome. Epilepsia 1993;34:52. Cascino GD, Jack CR Jr, Parisi JE, et al. MRI-based volume studies in temporal lobe epilepsy: Pathologic correlations. Ann Neurol 1991;30:31. Cascino GD, Kelly PJ, Hirschorn KA, et al. Stereotactic resection of intra-axial cerebral lesions in partial epilepsy. Mayo Clinic Proc 1990;65:1053. Cascino GD, Kelly PJ, Sharbrough FW, et al. Long-term follow-up of stereotactic lesionectomy in partial epilepsy: Predictive factors and electroencephalographic results. Epilepsia 1992;33:639. Cascino GD, Sharbrough FW, Trenerry MR, et al. Extratemporal cortical resections and lesionectomies for partial epilepsy: Complications of surgical treatment. Epilepsia 1994;35:1085. Cascino GD. Commentary: How has neuroimaging improved patient care? Epilepsia 1994;35:S103. Caton R. The electrical currents of the brain. BMJ 1875;2:278. Cendes F, Andermann F, Gloor P, et al. Atrophy of mesial structures in patients with temporal lobe epilepsy: Causes or consequence of repeated seizures? Ann Neurol 1993;34:795. Chugani DC, Chugani HT, Muzik O, et al. Imaging epileptogenic tubers in children with tuberous sclerosis complex using alpha 11 C-methyl-L-tryptophan positron emission tomography. Ann Neurol 1998;44:858. Chugani DC, Muzik O. Alpha (C-11) methyl-L-tryptophan PET maps brain serotonin synthesis and kynurenine pathway metabolism. J Cereb Blood Flow Metab 2000;20:2. Chugani HT, Shewmon A, Shields WD, et al. Pediatric epilepsy surgery: Pre-and postoperative evaluation with PET. J Epilepsy 1990;3:75. Chugani HT, Shewmon DA, Peacock WJ, et al. Surgical treatment of intractable neonatal onset seizures: The role of positron emission tomography. Neurology 1988;38:1178. Chugani HT, Shewmon DA, Shields WD, et al. Surgery for intractable infantile spasms. Neuroimaging perspectives. Epilepsia 1993;34:764. Chugani HT, Shields WD, Shewmon DA, et al. Infantile spasms: I. PET identified focal cortical dysgenesis in cryptogenic cases for surgical treatment. Ann Neurol 1990;24:405. Connelly A, Jackson GD, Duncan JS, et al. Magnetic resonance spectroscopy in temporal lobe epilepsy. Neurology 1994;44:1411. Cordes M, Christie W, Henkes H, et al. Focal epilepsies: HMPAO SPECT compared with CT, MR, and EEG. J Comput Assist Tomogr 1990;14:402. Coubes P, Awad IA, Antar M, et al. Comparison and spatial correlation of interictal HMPAO-SPECT and FDG-PET in intractable temporal lobe epilepsy. Neurol Res 1993;15:160. Cross JH, Gordon I, Connelly A, et al. Interictal 99mTc HMPAO SPECT and 1H MRS in children with temporal lobe epilepsy. Epilepsia 1997;38:338. Cross JH, Gordon I, Jackson GD, et al. Children with intractable focal epilepsy: Ictal and interictal 99mTc HMPAO single photon emission computed tomography. Dev Med Child Neurol 1995;37:673. Danielsson S, Rydenhag B, Uvebrant P, et al. Temporal lobe resection in children with epilepsy: Neuropsychiatric status in relation to neuropathology and seizure outcome. Epilepsy Behav 2002;3:76. Davidson S, Falconer MA. Outcome of surgery in 40 children with temporal-lobe epilepsy. Lancet 1975;1:1260. Debets RMC, van Veelen CWM, Maquet P, et al. Quantitative analysis of 18 FDG-PET in the presurgical evaluation of patients suffering from refractory partial epilepsy: Comparison with CT, MRI, and combined subdural and depth EEG. Acta Neurochir Suppl (Wien) 1990;50:88. Denays R, Rubinstein M, Ham H, et al. Single photon emission computed tomography in seizure disorders. Arch Dis Child 1988;63:1184. Detre JA. Functional MRI: Applications in epilepsy. Epilepsia 2004;45 (Suppl 4):26. Devinsky O, Romanelli P, Orbach D, et al. Surgical treatment of multifocal epilepsy involving eloquent cortex. Epilepsia 2003;44:718. Dietrich ME, Bergen D, Smith MC, et al. Correlation of abnormalities of interictal N-isopropyl-p-iodoamphetamine single-photon emission tomography with focus of seizure onset in complex partial seizure disorders. Epilepsia 1991;32:187. Dobyns WB, Andermann E, Andermann F, et al. X-linked malformations of neuronal migration. Neurology 1996;47:331. Dobyns WB, Truwit CL. Lissencephaly and other malformations of cortical development: 1995 update. Neuropediatrics 1995;26:132.

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Vigevano F, Bertini E, Boldrini R, et al. Hemimegalencephaly and intractable epilepsy: Benefits of hemispherectomy. Epilepsia 1989;30:833. Vigevano F, DiRocco C. Effectiveness of hemispherectomy in hemimegalencephaly with intractable seizures. Neuropediatrics 1990;21:222. Vining EPG, Freeman JM, Pillas DJ, et al. Why would you remove half a brain? The outcome of 58 children after hemispherectomy—the Johns Hopkins experience: 1968 to 1996. Pediatrics 1997;100:163. Vining EPG, Mellits ED, Dorwen MM, et al. Psychologic and behavioral effects of antiepileptic drugs in children: A double-blind comparison between phenobarbital and valproic acid. Pediatrics 1987;80:165. Watanabe K, Negoro T, Okumura A. Symptomatology of infantile spasms. Brain Dev 2001;23:453. Westerveld M, Sass KJ, Chelune GL, et al. Temporal lobectomy in children: Cognitive outcome. J Neurosurg 2000;92:24. Wheless JW, Castillo E, Maggio V, et al. Magnetoencephalography (MEG) and magnetic source imaging (MSI). Neurologist 2004;10:138. Wheless JW, Willmore LJ, Breier JI, et al. A comparison of magnetoencephalography, MRI and V-EEG in patients evaluated for epilepsy surgery. Epilepsia 1999;40:931. Whittle IR, Ellis HJ, Simpson DA. The surgical treatment of intractable childhood and adolescent epilepsy. Aust N Z J Surg 1981;51:190. Worrell, GA, Parish L, Craunstoun SD, et al. High frequency oscillations and seizure generalization in neocortical epilepsy. Brain 2004;127:1496. Wyler AR. Corpus callosotomy: The treatment of epilepsy. In: Wyllie E, ed. Principles and practice. Philadelphia, Lea and Febiger, 1993. Wyllie E. Developmental aspects of seizure semiology: Problems in identifying localized onset seizures in infants and children. Epilepsia 1995;36:1170. Wyllie E. Surgical treatment of epilepsy in children. Pediatr Neurol 1998;19:179. Wyllie E, Chee M, Granström ML, et al. Temporal lobe epilepsy in early childhood. Epilepsia 1993;34:859. Wyllie E, Comair YG, Kotagal P, et al. Epilepsy surgery in infants. Epilepsia 1996;37:625. Wyllie E, Comair YG, Kotagal P, et al. Seizure outcome after epilepsy surgery in children and adolescents. Ann Neurol 1998;44:740. Wyllie E, Luders H, Murphy D, et al. Intracranial amobarbital (Wada) test for language dominance: Correlation with results of cortical stimulation. Epilepsia 1990;31:156. Zielinski JJ. Epidemiology and medical-social problems of epilepsy in Warsaw. Warsaw, Poland: Psychoneurological Institute, 1974. Zubal IG, Spencer SS, Imam K, et al. Difference images calculated from ictal and interictal technetium-99m-HMPAO SPECT scans of epilepsy. J Nucl Med 1995;36:684. Zupanc ML. Neuroimaging in the evaluation of children and adolescents with intractable epilepsy: I. Magnetic resonance imaging and the substrates of epilepsy. Pediatr Neurol 1997a;17:19. Zupanc ML. Neuroimaging in the evaluation of children and adolescents with intractable epilepsy: II. Neuroimaging and pediatric epilepsy surgery. Pediatr Neurol 1997b;17:111. Zupanc ML, Abrahamson KD, Cascino GD, et al. Efficacy of surgery on seizure control and resultant quality of life in pediatric patients—Mayo Clinic experience, 1988-1994. Epilepsia 1996;37:105.

CHAPTER 52

Behavioral, Cognitive, and Social Aspects of Childhood Epilepsy Wendy G. Mitchell and Michèle Van Hirtum-Das

Children and adolescents with epilepsy and adults with childhood-onset epilepsy often are reported to have social maladjustment, including poor educational attainment, lower-than-expected occupational status, poorer perceived health and fitness, more frequently reported behavior problems, lower rates of marriage as adults, and higher rates of social isolation at all ages [Camfield et al., 1993; Clement and Wallace, 1990; Hoare, 1984; Jalava and Sillanpaa, 1997; Mitchell, 1995; Rutter et al., 1970; Sillanpaa, 1990]. These poor outcomes have multiple causes. In any particular patient, one or more causes of poor functioning may be identified and, at times, remedied. In general, neither epilepsy nor the seizures themselves are the most important cause of cognitive or behavioral disability. The underlying causes of cognitive and behavioral dysfunction may be subtle or obvious but generally are complex and multifactorial. In some instances, underlying neurologic structural lesions cause both epilepsy and other disabilities, including cognitive dysfunction. In others, such as benign focal epilepsy of childhood, learning and behavioral disorders are more difficult to explain, and the relationship with epilepsy is almost certainly not causal.

in populations surveyed for both mental retardation and epilepsy. Again, definitions of both epilepsy and mental retardation are not uniform. Prevalence of epilepsy is highest in cohorts of mentally retarded children with associated cerebral palsy [Curatolo et al., 1995; Sussova et al., 1990]. More subtle cognitive dysfunction has been found by many researchers, even when study groups are restricted to children with epilepsy syndromes thought to be independent of structural brain disease, such as benign focal epilepsy of childhood, childhood-onset absence epilepsy, or idiopathic generalized epilepsy [Chen et al., 1996; D’Allessandro et al., 1990; Dieterich et al., 1985; Olsson and Campenhausen, 1993; Piccirilli et al., 1994; Singhi et al., 1992]. Conflicting evidence exists regarding the role of interictal epileptiform discharges on cognitive function. Research using sophisticated computerized cognitive test batteries time-locked to EEG discharges has noted transient cognitive impairment, primarily slowing of reaction times, during epileptiform discharges [Aldenkamp et al., 1996; Binnie, 1993; Shewmon and Erwin, 1989]. The clinical significance of such findings is uncertain.

Learning Disabilities and Academic Underachievement COGNITIVE AND BEHAVIORAL DISORDERS Cognitive Function in Children with Epilepsy Although not all children with epilepsy have cognitive deficits, epilepsy is more frequent in mentally retarded children than in the general population [Britten et al., 1986; Forsgren et al., 1990; Sillanpaa, 1992]. Various populationbased prospective studies and cohort studies of mentally retarded children have documented the prevalence of epilepsy to be 15% to 35%. Children with severe mental retardation and cerebral palsy have the highest rates of epilepsy. Table 52-1 contains information from selected population-based or cohort studies that estimate the prevalence of epilepsy in mentally retarded populations. Caution must be used in interpreting this information, since definitions of both epilepsy and mental retardation vary. Several studies divide mentally retarded groups into mild (intelligence quotient [IQ] of 50 to 70) and moderate to severe mental retardation (IQ is under 50). Epilepsy is substantially more prevalent in more severely retarded cohorts. Even excluding children with major structural brain disease causing epilepsy and associated disabilities, mental retardation is more common in children with epilepsy than in children without epilepsy, with or without other chronic illnesses. Table 52-2 lists selected studies of the prevalence of mental retardation in cohorts of children with epilepsy or

Learning disability is diagnosed when one or more areas of learning are significantly below expectations, not explained by overall cognitive level (mental retardation), sensory abnormalities, or lack of opportunity or teaching (see Chapter 34). Learning disabilities are reported to be more frequent in children with epilepsy. Educational underachievement, particularly in reading, has been reported in a variety of settings, with comparisons of children with epilepsy both with their normal peers and with other children with chronic illnesses, such as asthma [Bagley, 1970; Holdsworth and Whitmore, 1974; Mitchell et al., 1991; Seidenberg et al., 1986; Stores, 1981; Stores and Hart, 1976; Sturniolo and Galletti, 1994]. It is unclear, however, whether the relationship is a direct one (in which the epilepsy, seizures, or medications themselves cause learning disability) or an indirect one (in which an underlying neurologic condition causes both seizures and abnormalities in perception, memory, visual-motor skills, and so on, which contribute to learning disabilities). In addition, many studies of children with epilepsy draw subjects from teaching hospitals with excessive representation of inner-city, immigrant, poor, minority, or non–English-speaking families. Educational underachievement may be excessive in subjects drawn from such teaching hospitals because of social factors entirely unrelated to medical conditions [Mitchell et al., 1991]. Parental expectations for their child with epilepsy are often lowered, at times inappropriately [Chavez, 1985; Hartlage and Green,

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TABLE 52-1 Rates of Epilepsy in Mentally Retarded Children and Adolescents: Population and Cohort Studies STUDY LOCALE [author(s), year] Sweden [Blomquist et al., 1981] Sweden [Hagberg et al., 1981] United States (Atlanta) [Trevathan et al., 1986] Same as preceding study Sweden [Steffenberg et al., 1996] Same as above Australia [Wellesley et al., 1992] Same as preceding study Sweden [Gustavson et al., 1977] United States (New York) [Jacobson and Janicki, 1983] United States (Oakland) [van den Berg and Yerushalmy, 1969] Scotland [Goulden et al., 1991] United States (Atlanta) [Murphy et al., 1995]

AGE (years)

% WITH EPILEPSY

8 to 19 8 to 12 10

18 12 8 32 15 44 11 15 36 23 29 15 30

6 to 13 6 to 16 5 to 16 0 to 21 0 to 7 0 to 22 10

SEVERITY OF MENTAL RETARDATION Mild Mild-moderate Mild Moderate-severe Mild Severe Mild Moderate Severe Undefined Undefined Undefined Two or more unprovoked seizures on separate days

Adapted from Steffenburg S, Gillberg C, Steffenburg U. Psychiatric disorders in children and adolescents with mental retardation and active epilepsy. Arch Neurol 1996;53:904; and Hauser WA, Hesdorffer DC. Seizures and the developmental disabilities. In: Hauser WA, Hesdoffer DC, eds. Epilepsy: Frequency, causes and consequences. New York: Demos Publications, 1990.

TABLE 52-2 Frequency of Mental Retardation in Children with Epilepsy: Population and Cohort Studies STUDY LOCALE [Author(s), Year]

AGE (years)

% MENTALLY RETARDED

EPILEPSY DEFINITION

Sweden [Brorson, 1970] England [Ross et al., 1980] Finland [Sillanpaa, 1992] Sweden [Sidenvall et al., 1996] Sweden [Steffenburg et al., 1996]

6 to 13 11 4 to 15 0 to 16 6 to 13

35 33 31 40 38

Active epilepsy with one or more seizures in previous 3 years Two or more unprovoked seizures Two or more unprovoked seizures Active epilepsy with one or more seizures in previous 5 years Active epilepsy with one or more seizures in previous 5 years

Adapted from Steffenburg S, Gillberg C, Steffenburg U. Psychiatric disorders in children and adolescents with mental retardation and active epilepsy. Arch Neurol 1996;53:904.

1972; Hoare and Kerley, 1991; Long and Moore, 1979]. Even after the effects of sociocultural variability have been accounted for, at least some children with epilepsy manifest learning disabilities. In one study comparing children with newly diagnosed epilepsy to children with recently diagnosed moderate asthma, academic underachievement was significantly more common in children with epilepsy, particularly boys with severe epilepsy [Austin et al., 1998]. Testing of groups of children with epilepsy using detailed neurocognitive batteries has demonstrated higher-thanexpected rates of dyslexia, visuospatial difficulties, nonverbal learning difficulties, and slowed reaction times [Farwell et al., 1985; Mitchell et al., 1992]. Some of these findings may be related to subtle or overt underlying structural lesions causing both the epilepsy and the learning disability, but not all can be explained on the basis of abnormalities detectable on neuroimaging.

Attention Deficit, Impulsivity, and Overactivity Attention, impulsivity, and activity level can be measured in various ways, ranging from parent and teacher questionnaires to psychometric testing to computerized continuous performance tasks. Regardless of method, most studies of children and adults with epilepsy demonstrate an excess incidence of inattention, impulsivity, and slowed reaction time [Kinney et al., 1990; Mitchell et al., 1992; Stores, 1978]. This finding should not imply that clinical attention-

deficit–hyperactivity disorder is extremely common in children with epilepsy, although the prevalence is probably somewhat increased. As with overall cognitive function in children with epilepsy, simple cause-and-effect relationships are uncommon. Underlying neurologic conditions may cause both symptoms of attention-deficit–hyperactivity disorder and epilepsy [Kinney et al., 1990]. Antiepileptic medications may affect attention and impulsivity, both positively and negatively, at least in some persons [Mitchell et al., 1993; Riva and Devoti, 1996]. Generally measured effects on attention are small, however, and may not be clinically significant. In rare instances, frequent seizures may affect attention, and seizure control may eliminate an apparent attention deficit. There is some evidence that frequent epileptiform discharges may disrupt attention, which may improve with antiepileptic treatment [Gordon et al., 1996]. Children with epilepsy and low IQ have a higher rate of significant behavior problems and mood disorders than those with normal IQ [Buelow et al., 2003]. It is unlikely that the relationship is a simple one of cause and effect. More likely, underlying neurologic abnormalities explain the coexistence of low IQ, epilepsy, and psychiatric abnormalities.

Psychiatric Disorders in Childhood Epilepsy Major “psychiatric” disorders of young childhood, such as autistic spectrum disorders, are associated with an increased incidence of epilepsy, but evidence that one causes the other

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is lacking [Carlton Ford et al., 1995; Cavazzuti and Nalin, 1990; Olsson et al., 1988; Steffenburg et al., 1996; Wong, 1993]. Child neurologists and psychiatrists recognize that these disorders are neurobiologic in origin. A number of syndromes are associated with a high incidence of both autistic behavior and seizures (e.g., Angelman’s syndrome, tuberous sclerosis), but the coincidence of seizures and behavior disorder is due to the underlying neurobiologic condition. A possible rare exception is the child in whom autistic behavior develops along with language regression, accompanied by an epileptiform electroencephalogram (continuous spike-and-wave pattern during sleep) [Hirsch et al., 1990; Kyllerman et al., 1996; Perez et al., 1993; Roulet et al., 1991]. This condition has been considered to be a variant of Landau-Kleffner syndrome. Behavior and language may improve with treatment with antiepileptics (rarely), corticosteroids, or corticotropin, or after subpial transection of epileptogenic cortex [Hirsch et al., 1990]. Little evidence exists to support the notion that severe psychiatric disorders are more common in children with epilepsy. Although major psychiatric illnesses, such as schizophrenia, obsessive-compulsive disorder, or affective disorders, may coexist with childhood epilepsy, the prevalence is not higher than in the general population. Treatment of coexisting severe psychiatric disorder and epilepsy may be complex. Some antiepileptics (carbamazepine, valproic acid) are reported to be beneficial in treatment of certain psychiatric disorders, most notably bipolar affective disorder [Fenn et al., 1996]. In general, however, treatment of epilepsy does not relieve symptoms of major psychiatric illness. Occasionally, “paradoxical normalization,” or “forced normalization,” is reported in children who experience a decrease in psychiatric symptoms when seizures are uncontrolled, with worsening of symptoms when seizures are in good control [Amir and Gross-Tsur, 1994]. Depressive disorders and mood disturbances have been reported more frequently in adolescents and adults with epilepsy than in healthy peers. The etiology of depressive symptoms may be complex; social stigmas, lack of employment opportunities, and lack of social contacts may contribute to depression. Phenobarbital occasionally may contribute to depressed mood in some adolescents with epilepsy [Brent et al., 1987]. Self-reported lower quality of life is lower in adolescents with epilepsy than in adolescents with asthma. Although this difference was more striking for young persons with active epilepsy, quality of life measures were low even when seizures were fully controlled or inactive [Austin et al., 1996].

Behavioral Problems, Conduct Disorders, and Delinquency Behavioral disturbances in children and adolescents with epilepsy may be due to family factors and parental anxiety about epilepsy, rather than a primary result of epilepsy or of the underlying neurologic disorder [Austin et al., 1992; Carlton Ford et al., 1995; Gortmaker et al., 1990; Hoare and Kerley, 1991; Lothman and Pianta, 1993; Mitchell et al., 1994; Pianta and Lothman, 1994]. Self-esteem is reported to be lower and behavioral problems are more frequent in children and adolescents with epilepsy than in peers without chronic illness or with other chronic illnesses, such as asthma or diabetes [Apter et al., 1991; Austin, 1989; Hoare

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and Mann, 1994; Matthews et al., 1982; Westbrook et al., 1991]. Increasing evidence, however, suggests that epilepsy may be frequently associated with behavior problems, perhaps if both are the result of an underlying neurologic disturbance. When children with epilepsy are assessed at the time of first seizure diagnosis, behavior problems are frequently reported by parents and teachers, particularly in children who had previously unrecognized seizures [Austin et al., 2001, 2002]. Adolescents and young adults with childhood-onset epilepsy have slightly higher-than-expected rates of delinquency in some studies [Camfield et al., 1993]. It is uncertain whether this propensity is due to underlying brain disease with poor impulse control, stigma, and lack of opportunity or to other sociocultural factors. A populationbased study in Finland, however, failed to find a relationship between delinquency and epilepsy in males up to age 22 years, although delinquency was associated with a history of central nervous system trauma [Rantakallio et al., 1992].

Epilepsies Specifically Associated with Poor Cognitive and Behavioral Outcome Certain pediatric epilepsy syndromes have been associated with particular, sometimes devastating, cognitive or behavioral declines, or both. Perhaps the most well studied of the catastrophic childhood epilepsies is infantile spasms. Mental retardation has been reported in up to 80% of children with infantile spasms and is described as severe in more than half of the cases [Jambaqué, 1994]. Although many patients exhibit arrest of global learning, specific cognitive deficits such as speech difficulties and impaired visuospatial abilities have been noted in others [Besag, 2004]. Thirteen percent of those with cryptogenic infantile spasms were reported to exhibit persistent autistic features; this number is higher (58%) if the child was diagnosed with tuberous sclerosis, with some further association with temporal lobe tubers in particular [Bolton et al., 2002; Hunt and Dennis, 1987; Riikonen and Amnell, 1981]. What has become clear is that effective early treatment of both cryptogenic and symptomatic spasms improves cognition and behavior [Caplan et al., 2002; Jambaqué et al., 2000; Kivity et al., 2004]. Many of the epileptic encephalopathies with onset in the neonatal or early infancy period are associated with frequent seizures that are notoriously refractory to treatment with both conventional and newer antiepileptic medication. Included in this group are severe myoclonic epilepsy in infancy (Dravet’s syndrome), early infantile epileptic encephalopathy (Ohtahara’s syndrome), neonatal myoclonic encephalopathy (or early infantile myoclonic encephalopathy), and migrating partial seizures of infancy. Delayed development usually is seen by the second year, and interpersonal relationships rarely progress past a level expected for that of a 2 year old [Besag, 2004]. Behavior in the affected child typically is hyperactive with autistic features. It is difficult to fully attribute the abnormalities in cognition and behavior to the frequent seizures and paroxysmal findings on EEG when an undiagnosed metabolic or genetic etiology may play a causative or contributory role. On the other hand, control of seizures in the context of tuberous sclerosis or Sturge-Weber syndrome plays a role in the favorable outcome of neurodevelopment and behavior [Jambaqué et al., 2000; Kramer et al., 2000].

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Lennox-Gastaut syndrome frequently has been associated with autistic features and cognitive deficits, although published literature specific to this topic is sparse [Besag, 2004]. Long-term follow-up evaluation of these patients commonly reveals slowness of intellectual ability and motor speed, apathy (possibly better described as an inability to engage with the environment secondary to frequent epileptiform discharges) and perseverative behavior [Kieffer-Renaux et al., 2001]. Electrical status epilepticus in sleep is an EEG pattern detected in some cases of pediatric epilepsy that often is associated with specific cognitive and language dysfunction. It frequently is encountered in those syndromes described as continuous spikes and waves (continuous spike-and-wave sleep syndrome) during slow-wave sleep and Landau-Kleffner syndrome. With continuous spike-and-wave activity in sleep, a typical decrease in the IQ or developmental quotient is noted by most investigators [Boel and Casaer, 1989; Roulet-Perez et al., 1993]. Approximately 50% to 100% of affected children exhibit impaired temporospatial orientation, and two thirds are noted to have attention deficits and exhibit hyperactivity. Of interest, some 40% to 60% of children with continuous spike-wave sleep exhibit an expressive aphasia, which is in contrast with children with Landau-Kleffner syndrome, who tend to present with a verbal or auditory agnosia [Galanopoulou et al., 2000]. In patients with Landau-Kleffner syndrome, language may recover spontaneously, partially improve with therapy, or unfortunately remain permanently affected despite improvement of the EEG abnormality [Besag, 2004]. Of specific note is the syndrome termed benign childhood epilepsy with centrotemporal spikes. Although this disorder was once thought of as a universally benign syndrome, increasing evidence suggests that a subpopulation of children may present with recently impaired IQ, visual perception, concentration, and short-term memory [Weglage et al., 1997].

FAMILY, COMMUNITY, AND CULTURAL PERCEPTIONS OF EPILEPSY Social acceptance and inclusion of children and adolescents with epilepsy are far from complete, even when seizures are infrequent or fully controlled. In some cultural settings, it is not generally disclosed to friends or extended family that a child has epilepsy [Ju et al., 1990]. Some children are not sent to school if seizures are uncontrolled. Despite laws guaranteeing disabled and medically impaired children access to schools, some schools discourage attendance by children with active seizure disorders. All of these prejudices and stigmas may further impair social and academic function in children with epilepsy. Fear of stigma may contribute to the high frequency of nondisclosure of epilepsy among adolescents [MacLeod and Austin, 2003].

SOCIAL ADJUSTMENT OF ADULTS WITH CHILDHOOD-ONSET EPILEPSY Population-based studies from several countries document that social functioning is impaired in adults who had childhood-onset epilepsy, compared with their healthy peers

[Farmer et al., 1992; Sillanpaa, 1990]. Marriage is less frequent, employment is less frequent and at less skilled occupations, and social isolation is more frequent. Differences are more striking when adults have ongoing seizures but are present even when complete remission or control has been obtained. Even when studies were restricted to adults with childhood-onset absence epilepsy, a disorder thought to be benign and likely to remit, social functioning continued to be impaired in comparison with that in nonepileptic peers [Dieterich et al., 1985]. In a long-term follow-up (30 years) of a population-based cohort of children with epilepsy in Finland, about 60% of subjects were independent in activities of daily living, and 57% were employed, most in manual labor or semiskilled positions [Sillanpaa and Helenius, 1993]. Several studies are notable for including only adults with childhood-onset absence [Olsson and Campenhausen, 1993] or mixed generalized seizures (absence plus generalized tonic-clonic) [Dieterich et al., 1985]. Young adults with persisting absence seizures since childhood or adolescence, who were originally identified during a population-based study of absence epilepsy diagnosed from 1973 to 1982, were compared with a Swedish reference sample of young adults, using a questionnaire to assess the impact of epilepsy on schooling, occupation, leisure-time activities, friends, daily routines, and housing. Although the overall employment rate did not differ from that in the reference subjects, persons with epilepsy were more likely to be employed in an unskilled job or employed in an occupation below that expected for educational level. Social isolation, defined by the reply of “no close friend,” was reported in 34.5%, compared with 7.9% of the reference group. A high percentage of subjects (74%) reported that epilepsy had affected at least one area of their social functioning [Olsson and Campenhausen, 1993]. In a Finnish study of adults who had uncomplicated childhoodonset epilepsy, quality of life of adults with epilepsy in remission on medication was lower, and rates of unemployment were higher, than in comparison subjects or in adults whose epilepsy was in remission after withdrawal of medication [Sillanpaa et al., 2004]. Other studies of outcome in adults with childhood-onset epilepsy find substantial maladaptation as well, particularly in social and vocational function. Social functioning is generally much more impaired in the subgroup of adults with ongoing seizures than in those who attain complete remission.

EFFECTS OF ANTIEPILEPTIC DRUGS ON BEHAVIOR, ATTENTION, AND MOOD General Effects of Antiepileptic Drugs Cognitive, psychiatric, and behavioral abnormalities in children with epilepsy often are attributed to antiepileptic medications. Most of these effects are unsupported by wellcontrolled clinical research. It is clear, however, that idiosyncratic adverse behavioral and cognitive responses can occur with any antiepileptic drug (see Chapter 49). In addressing issues of abnormal cognition and behavior in the management of pediatric epilepsy, several factors need to be recognized. Epilepsy occurring in the developing brain is

Mitchell and Van Hirtum-Das / Behavioral, Cognitive, and Social Aspects of Childhood Epilepsy

likely to be substantially different from that in an adult in both its qualities and response to treatment. In addition, the most refractory epilepsies are likely to begin in childhood. The management of severe childhood epilepsy may prove challenging in that the choice of antiepileptic medication depends on the type of syndrome in which the seizures often occur, as well as the cognitive and behavioral abnormalities that may occur with these syndromes. Finally, treating a combination of several seizure types in one patient may be difficult, because many drugs that are effective in treating one type of seizure may exacerbate another type. In well-designed controlled studies, evidence of longterm adverse cognitive effects of antiepileptic medications is generally slight or difficult to document objectively. A few studies have randomized subjects at the onset of seizures to receive one of several antiepileptic drugs [Forsythe et al., 1991; Mitchell and Chavez, 1987]. Most studies, however, examine patients assigned nonrandomly to receive various antiepileptic drugs when medication is started, changed, or withdrawn [Aldenkamp et al., 1993; Aman et al., 1994; Chen et al., 1996; Mitchell et al., 1993; Sabers et al., 1995; Stores et al., 1992]. Only a few double-blind, placebocontrolled studies of the behavioral effects of antiepileptic drugs are available and are limited to studies of phenobarbital for febrile seizures in infants and toddlers [Farwell et al., 1990; Camfield et al., 1979]. In older children and adults, the major effect of antiepileptic medications on cognitive function appears to be a slowing of motor speed. Early reports that phenytoin caused generalized declines in cognitive function were later disputed when further data analysis and research found that the major effect of phenytoin was on motor speed [Aldenkamp et al., 1994; Dodrill and Tempkin, 1989; Duncan et al., 1990]. Other cognitive functions are relatively spared, if analyzed independent of response speed. Many standardized cognitive tests are at least partly dependent on timed performance. Thus, IQ may appear to be lowered by medications, whereas the sole effect is on motor speed. Nevertheless, some patients perceive that their responses are slower and are bothered by this, despite otherwise normal functioning by most other measures. Conversely, improvement in cognitive function, impulsivity, and behavior has been reported with several antiepileptic drugs. This improvement may occasionally be dramatic, resulting from control of frequent seizures, such as when a child with frequent petit mal seizures is started on ethosuximide or valproic acid. Improved behavior and cognitive function as a direct result of antiepileptic medication also has been documented for some antiepileptic drugs, most consistently carbamazepine [Aman et al., 1994; Mitchell et al., 1993]. Effects are slight, however, and probably not clinically significant in most instances and may even be disputed (Seidel and Mitchell, 1999). Most sedative drugs have the potential for causing excitement and agitation when they are first initiated, but this effect dissipates in most children over a few weeks. Phenobarbital causes sustained behavioral difficulties, primarily overactivity, in some children and can cause irritability and disturbed sleep in infants and toddlers [Camfield et al., 1979; Wolf et al., 1977]. Estimates of the number of children who do not tolerate phenobarbital because of resulting overactivity range from 5% to 25%. This effect is more frequent in toddlers and preschoolaged children but may occur at any age.

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Published case reports document a variety of idiosyncratic behavioral adverse reactions to virtually all antiepileptic drugs. Valproic acid occasionally causes a confused state or psychosis [Papazian et al., 1995]. Felbamate also has been reported to cause agitation and significant behavioral effects early in treatment, although overall this drug tends to improve behavior with prolonged treatment [Gay et al., 1995].

BEHAVIORAL AND COGNITIVE EFFECTS OF THE NEWER ANTIEPILEPTIC AGENTS Over the last decade, several new medications have been formulated for use as antiepileptic drugs—namely, levetiracetam, lamotrigine, tiagabine, topiramate, zonisamide, gabapentin, and oxcarbazepine. The newer antiepileptic drugs also have been reported to cause behavior change, both positive and negative. Virtually none have been studied in properly designed, blinded studies, either in comparison with placebo or in comparison to another antiepileptic drug. Nearly all published information regarding neurocognitive effects of the newer medications is anecdotal and from uncontrolled studies. Comparison across studies of antiepileptic drugs is further hampered by varying criteria for selection of participants for studies, and use of differing neuropsychologic tests and study designs [Brunbech and Sabers, 2002]. In addition, most published studies use either overall IQ or developmental quotient as the outcome measure, which may be insufficiently sensitive to medication effects, particularly subtle ones. A recent review of the literature regarding anticonvulsant effects in children summarizes published studies, nearly all of which examined phenobarbital, carbamazepine, or valproic acid (Loring and Meador, 2004).

Specific Medications Topiramate Topiramate is a sulfamate-substituted monosaccharide that blocks sodium and calcium channels and DL-α-amino3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)/ kainate-gated ion channels, positively modulates γ-aminobutyric acid type A (GABAA) receptors, and weakly inhibits carbonic anhydrase [Ketter et al., 1999]. It generally is well tolerated, although it has been reported in adult epileptic and nonepileptic persons to cause significant cognitive difficulties, primarily involving word-finding and verbal memory, particularly during initial treatment and titration [Fisher and Blum, 1995; Lee et al., 2003; Martin et al., 1999]. These adverse effects apparently dissipate over time, particularly if the dosage is increased slowly, although they may persist [Aldenkamp et al., 2003; Tatum et al., 2001]. Behavioral and cognitive abnormalities reported in pediatric epilepsy patients appear to be unrelated to either rate of dosage titration or maximal dose. However, prior behavioral or cognitive deficits may be predisposing factors [Gerber et al., 2000]. As yet, no controlled studies have evaluated the cognitive impairment induced by topiramate. In one double-blind, randomized, placebo-controlled trial of topiramate for add-on therapy in 86 children with partial epilepsy, children receiving topiramate had an increased frequency of

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emotional lability, difficulties with concentration, and fatigue, but the changes were not severe enough to cause any subject to discontinue treatment [Elterman et al., 1999].

Lamotrigine Lamotrigine is an agent that blocks voltage-dependent sodium channels, thereby preventing glutamate release, a phenomenon known to occur with the mood-stabilizing antiepileptics carbamazepine and oxcarbamazepine [Ketter et al., 1999]. Since its introduction in the United States in 1994, lamotrigine has received much attention with respect to its potential positive psychotropic effects. Significant improvements in behavior, cognition, and motor skills (unrelated to seizure control) are noted in pediatric patients, although these effects have not yet been formally studied [Culy and Goa, 2000; Meador and Baker, 1997]. Lamotrigine has been reported to have fewer cognitive effects in adults with newly diagnosed epilepsy than those described for carbamazepine and phenytoin [Brodie et al., 1995; Meador et al., 2001; Steiner et al., 1999]. A short-term treatment study performed on healthy volunteers using low-dose lamotrigine revealed improvement in cognitive activation and mood and reported subjective positive effects on quality of life relative to that achieved with use of valproate [Aldenkamp et al., 2002]. In addition, lamotrigine reportedly exhibits a positive effect on age-associated memory difficulties and social functioning in the mentally retarded [Earl et al., 2000; Mervaala et al., 1995]. In a trial of lamotrigine for add-on therapy in children with Lennox-Gastaut syndrome, responders with improved seizure control were noted to be more alert and attentive, whereas nonresponders were more likely to experience agitation. Further controlled trials are necessary to evaluate whether a positive effect on cognition and behavior occurs in children [Ericksson et al., 1998].

Gabapentin Gabapentin is similar in structure to GABA but does not seem to have effects at the GABA receptors. Rather, it potentiates GABA-mediated inhibition by increasing GABA release from glia and possibly inactivates sodium channels as well [Aldenkamp et al., 2003; Ketter et al., 1999]. Double-blind, placebo-controlled trials suggest efficacy of gabapentin in treatment of social phobia and in severe panic disorder in adults [Crockatt et al., 1998; Pande et al., 1997]. In both adult volunteer studies and studies with double-blind, randomized, crossover designs, gabapentin produced no significant alteration of psychomotor or memory abilities when used for either monotherapy or add-on treatment (Leach et al., 1997; Martin et al., 1999; Meador et al., 1999). Gabapentin occasionally has been reported to cause aggressive or agitated behavior, however [Lee et al., 1996; Tallian et al., 1996]. Children in whom significant adverse behavioral changes occur with use of gabapentin tend to have some degree of documented mental retardation [Khurana et al., 1996]. No published controlled studies have evaluated the cognitive and behavioral effects of gabapentin in children who have epilepsy.

Levetiracetam Levetiracetam, a structurally and mechanistically novel antiepileptic drug, has a favorable pharmacokinetic profile and is effective in treating partial seizures in adults, although pediatric studies are not yet published. [Dooley and Plosker, 2000]. Among adult patients with epilepsy who received

levatiracetam, behavioral abnormality was reported in a significant proportion relative to those patients with anxiety or cognitive disorders but without epilepsy. However, the behavioral events cited were less common than those reported with other antiepileptic agents [Cramer et al., 2003]. A prospective open-label, add-on trial using levetiracetam to treat refractory partial and generalized seizures in children younger than 16 years of age revealed adverse events in 51% of subjects. Most of these events were behavioral in nature, although most children did not require discontinuation of the medication. As with the gabapentin study, a majority of the children were developmentally delayed or mentally retarded. In this same study, however, improvement in behavior and/or cognition after the addition of levetiracetam was reported in 25.6% [Wheless and Ng, 2002]. A few anecdotal reports have described improved behavior in children with autism treated with levetiracetam, but in the same population, some children experienced an increase in aggressive behavior [Rugino and Samsock, 2002].

Oxcarbazepine Oxcarbazepine is a keto homolog of carbamazepine, although it has a very distinct metabolic profile. It is labeled for use for monotherapy or adjunctive therapy for partial seizures with or without secondarily generalized seizures in children 6 years of age and older. Although no deterioration in cognitive function test results were reported in one crossover and several comparative monotherapy studies in adult epilepsy patients, cognitive function has not been systematically studied in children and adolescents.

Tiagabine Tiagabine acts as a GABA uptake inhibitor in neurons and glial cells and is effective for add-on therapy in the treatment of refractory partial epilepsy. Very few data are currently published regarding the psychotropic effects of this medication, and no information is available for the pediatric population.

Zonisamide No published trials have included cognitive or behavioral observations in pediatric patients with either partial or generalized seizures treated with zonisamide. Reports from Japan, where the medication has been in use for longer than 15 years, suggest that psychotic episodes and behavior changes may occur in children given zonisamide, despite improved seizure control [Hirai et al., 2002; Kimura, 1994].

Fear of Side Effects and Effective Antiepileptic Drug Use Despite the relative paucity of documentation of sustained adverse cognitive effects of antiepileptics, sophisticated parents and teachers often are well versed in the possible adverse effects of medications, exaggerated, to some degree, by frightening stories in the lay media and, increasingly, on the Internet. Parents may be under the erroneous impression that a particular antiepileptic drug will “make the child retarded” and may blame developmental problems that subsequently emerge on previous administration of antiepileptic drugs or may avoid administration of these medications because of fear of disturbing the child’s behavior or development.

Mitchell and Van Hirtum-Das / Behavioral, Cognitive, and Social Aspects of Childhood Epilepsy

TREATMENT As with all medical treatment, care of the child with epilepsy must be individualized. Nevertheless, several general principles apply. The developmental, cognitive, academic, and behavioral status of the child and the social functioning of the family must be integral and ongoing concerns in the management of a child with epilepsy. Brief developmental, cognitive, or academic testing is appropriate on initial evaluation and at follow-up visits. Although treatment generally will not alter the underlying cognitive capacity of the child, early intervention and referral to appropriate community and school resources will maximize function. Appropriate counseling of the family may minimize later behavioral and adjustment difficulties. Group programs to help families with their children with epilepsy may be effective in altering parental attitudes, reducing fears, and improving the children’s participation in family and community activities [Lewis et al., 1990].

School Issues At times, parents report that a child with epilepsy is being excluded from school programs, sent home repeatedly, or placed in a more restrictive class setting than is appropriate for their abilities. It may be essential that the treating neurologist or pediatrician intervene with appropriate authorities if a child is being denied appropriate educational experiences because school personnel are concerned about the possibility of seizures occurring at the school. Local branches of voluntary organizations, such as the Epilepsy Foundation of America, may be helpful in providing informational programs to schools. At least in the United States, federal law mandates inclusion of children with disabilities and medical conditions in educational programs in the least restrictive environment appropriate for the child’s needs.

Behavior Problems and Discipline Behavioral problems and parent-child interaction should be addressed regularly in the management of children with epilepsy. Parents may avoid disciplining a child with epilepsy in an age-appropriate manner out of fear that the child’s becoming angry or upset may trigger seizures. Parents must be reassured that this is not the case. Significant abnormalities in behavior, activity, or attention warrant a more detailed evaluation, including comprehensive psychometric testing. Psychometric testing, along with clinical history gathered from parents, teachers, and patients, may be necessary to differentiate behavioral difficulties associated with coexisting attention-deficit–hyperactivity disorder from those due to family dysfunction, oppositional disorders, inappropriate parental expectations, and other factors.

Attention-Deficit Disorders: Treatment in Children with Epilepsy Alteration in antiepileptic treatment may improve behavior and attention if the original treatment has substantially affected behavior. Nevertheless, attention-deficit–hyperactivity dis-

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order may coexist with epilepsy, independent of antiepileptic treatment. Treatment of attention-deficit–hyperactivity disorder with stimulants (e.g., methylphenidate, pemoline, dextroamphetamine) or with tricyclic antidepressants (e.g., imipramine, desipramine) generally does not compromise seizure control [Gross-Tsur et al., 1997]. A newer medication for attention-deficit disorder, atomoxetine (a nonamphetamine selective norepinephrine reuptake inhibitor with stimulant properties), does not significantly affect seizure control, nor does it have significant pharmacokinetic interactions with antiepileptic medications. Bupropion, an anti-depressant drug occasionally useful for attention deficit disorder, particularly when associated with mood disorder, may increase tendency toward seizures, particularly at high doses. Most pediatric neurologists avoid its use at doses greater than 100 mg per day in children with epilepsy.

Peer Relationships, Teasing, and Social Isolation Social isolation and poor peer relationships are a particular problem in school-aged and adolescent children with epilepsy and are difficult to address therapeutically. Nonverbal learning disabilities may make the child socially maladroit and target them for teasing by peers. Children may be particularly at risk for teasing and exclusion by peers if they also have had seizures at school or are singled out by the need to leave the classroom to take medication during the school day. Therapeutic or educational programs that emphasize social skills and assertiveness training may be helpful in some children and adolescents [Henriksen, 1990; Lewis et al., 1990; Strang, 1990].

Occupational Planning and Adjustment Occupational adjustment may be poor in adults with childhood-onset epilepsy. Vocational plans and postsecondary education should be discussed with adolescents who have epilepsy, with appropriate goal-setting. Adolescents with well-controlled epilepsy may be assured that their epilepsy will not interfere with career goals, with a few notable exceptions; military service, airlines, and public safety professions (police and fire) generally will exclude applicants with epilepsy, regardless of control. Some states will restrict commercial driver’s licenses, even with good seizure control. Appropriate resources for assessment, training, and placement should be identified in the community. In addition to school-based programs, local epilepsy foundations may be a good resource, as may departments of vocational rehabilitation in many states. REFERENCES Aldenkamp AP, Alpherts WC, Blennow G, et al. Withdrawal of antiepileptic medication in children—effects on cognitive function: The Multicenter Holmfrid Study. Neurology 1993;43:41. Aldenkamp AP, Alpherts WC, Diepman L, et al. Cognitive side effects of phenytoin compared with carbamazepine in patients with localization related epilepsy. Epilepsy Res 1994;19:37. Aldenkamp AP, Arends J, Bootsma HPR, et al. Randomized double-blind parallel-group study comparing cognitive effects of a low-dose lamotrigine with valproate and placebo in healthy volunteers. Epilepsia 2002;43:19. Aldenkamp AP, De Krom M, Reijs R. Newer antiepileptic drugs and cognitive issues. Epilepsia 2003;44 (Suppl 4):21.

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Seidel WT, Mitchell WG. Cognitive and behavioral effects of carbamazepine in children: Data from benign rolandic epilepsy. J Child Neurol 1999;14:716. Seidenberg M, Beck N, Geisser M, et al. Academic achievement in children with epilepsy. Epilepsia 1986;27:753. Sidenvall R, Forsgren L, Heijbel J. Prevalence and characteristics of epilepsy in children in Northern Sweden. Seizure 1996;5:139. Shewmon DA, Erwin RJ. Transient impairment of visual perception induced by single interictal occipital spikes. J Clin Exp Neuropsychol 1989;11:675. Sillanpaa M. Epilepsy in children: Prevalence, disability, and handicap. Epilepsia 1992;33:444. Sillanpaa M. Children with epilepsy as adults: Outcome after 30 years of follow up. Acta Paediatr Scand 1990;368 (Suppl):1. Sillanpaa M, Haataja L, Shinnar S. Perceived impact of childhood-onset epilepsy on quality of life as an adult. Epilepsia 2004;45:971. Sillanpaa M, Helenius H. Social competence of people with epilepsy: A new methodologic approach. Acta Neurol Scand 1993;87:335. Singhi PD, Bansal U, Singhi S, et al. Determinants of IQ profile in children with idiopathic generalized epilepsy. Epilepsia 1992;33:1106. Steffenburg S, Gillberg C, Steffenburg U. Psychiatric disorders in children and adolescents with mental retardation and active epilepsy. Arch Neurol 1996;53:904. Steiner TJ, Dellaportas CI, Findley LJ, et al. Lamotrigine monotherapy in newly diagnosed untreated epilepsy: A double-blind comparison with phenytoin. Epilepsia 1999;40:601. Stores G. Problems of learning and behavior in children with epilepsy. In: Reynolds EH, Trimble MJ, eds. Epilepsy and psychiatry. Edinburgh: Churchill Livingstone, 1981. Stores G. School-children with epilepsy at risk for learning and behavior problems. Dev Med Child Neurol 1978;20:502. Stores G, Hart J. Reading skills of children with generalized or focal epilepsy attending ordinary schools. Dev Med Child Neurol 1976;18:705.

Stores G, Williams PL, Styles E, et al. Psychological effects of sodium valproate and carbamazepine in epilepsy. Arch Dis Child 1992;67:1330. Strang JD. Cognitive deficits in children: Adaptive behavior and treatment techniques. Epilepsia 1990;31 (Suppl 4):S54. Sturniolo MG, Galletti F. Idiopathic epilepsy and school achievement. Arch Dis Child 1994;70:424. Sussova J, Seidl Z, Farber J. Hemiparetic forms of cerebral palsy in relation to epilepsy and mental retardation. Dev Med Child Neurol 1990;32:972. Tallian KB, Nahata MC, Lo W, et al. Gabapentin associated with aggressive behavior in pediatric patients with seizures. Epilepsia 1996;37:501. Tatum WO, French JA, Faught E. Postmarketing experience with topiramate and cognition. Epilepsia 2001;42:1134. Trevathan E, Yeargin-Allsopp M, Murphy CC, et al. Epilepsy among children with mental retardation. Ann Neurol 1988;24:321. van den Berg BJ, Yerushalmy J. Studies on convulsive disorders in young children. I. Incidence of febrile and nonfebrile convulsions by age and other factors. Pediatr Res 1969;3:298. Weglage J, Demsky A, Pietsch M, et al. Neuropsychological, intellectual, and behavioral findings in patients with centrotemporal spikes with and without seizures. Dev Med Child Neurol 1997;39:646. Wellesley DG, Hockey KA, Montgomery PD, et al. Prevalence of intellectual handicap in Western Australia. A community study. Med J Aust 1992;156:94. Westbrook LE, Silver EJ, Coupey SM, et al. Social characteristics of adolescents with idiopathic epilepsy: A comparison to chronically ill and nonchronically ill peers. J Epilepsy 1991;4:87. Wheless JW, Ng YT. Levetiracetam in refractory pediatric epilepsy. J Child Neurol 2002;17:413. Wolf SM, Carr A, Davis DC, et al. The value of phenobarbital in the child who has had a single febrile seizure: A controlled prospective study. Pediatrics 1977;59:378. Wong V. Epilepsy in children with autistic spectrum disorder. J Child Neurol 1993;8:316.

CHAPTER 53

Headaches in Infants and Children Donald W. Lewis

Headache is a universal affliction of humankind from which children are not spared. Headache is the most common reason that children are referred to child neurology practices. It is therefore essential for clinicians to have a thorough, systematic approach to the evaluation and management of the child or adolescent with the complaint of headache. Headaches are classified into two categories, primary and secondary (Box 53-1). Migraine and tension-type are examples of primary headache in which there is no underlying pathology and the pain arises from intrinsic processes. Alternatively, the headache pain may result from secondary causes such as brain tumors, increased intracranial pressure, drug intoxications, paranasal sinus disease, or acute febrile illnesses such as influenza. The evaluation of a child presenting with headache follows the traditional medical model with extraction of necessary history and performance of a thorough physical and neurologic examination. In most instances, this initial process will yield a diagnosis or indicate the need for further ancillary testing. Once the diagnosis is established, a comprehensive treatment program can be put into place, blending pharmacologic and biobehavioral measures and being mindful of both physical and emotional factors. The purpose of this chapter is to explore the symptom of headache, reviewing the epidemiology, current classification system, appropriate evaluation, and differential diagnosis.

EPIDEMIOLOGY Headaches are common during childhood and become increasingly more frequent during adolescence. The prevalence of headache ranges from 37% to 51% in 7 year olds, gradually rising to 57% to 82% by age 15. Recurring or frequent headaches occurred in 2.5% of 7 year olds and 15% of 15 year olds [Bille, 1962]. Before puberty, boys are affected more frequently than girls, but after puberty, headaches occur more frequently in girls [Dalsgaard-Nielsen, 1970; Deubner, 1977; Laurell et al., 2004; Sillanpaa, 1983]. The prevalence of migraine headache steadily increases throughout childhood, and the male-to-female ratio shifts during adolescence. The prevalence rises from 3% at ages 3 to 7 years, to 4% to 11% by ages 7 through 11, and up to 8% to 23% during adolescence (Table 53-1). The mean age of onset of migraine is 7.2 years for boys and 10.9 years for girls [Dalsgaard-Nielsen, 1970; Lipton et al., 1994; Mortimer et al., 1992; Sillanpaa, 1976; Small and Waters, 1974; Stewart et al., 1991; Stewart et al., 1992; Valquist, 1955]. Data regarding tension-type headache are limited. Two recent studies including school children, ages 7 to 19 years, using the International Headache Society criteria found a 1year prevalence of tension-type headache to be 10% to 23%.

The prevalence of tension-type headache increased with age in both boys and girls, up to age 11 years, and thereafter increased only in girls [Laurell et al., 2004; Zwart et al., 2004].

CLASSIFICATION The International Headache Society has recently published an updated classification system for headache disorders (see Box 53-1) that is available online at www.ihs.org. Each headache category is further subclassified. The classification for the most common primary headache disorder, migraine, has been modified based on current views of the pathophysiology of migraine, in that the focal, comTABLE 53-1 The Prevalence of Migraine Headache through Childhood By age Prevalence Gender ratio

3–7 years 1.2%–3.2% boys > girls

7–11 years 4%–11% boys = girls

15 years 8%–23% girls > boys

Box 53-1 THE INTERNATIONAL CLASSIFICATION OF HEADACHE DISORDERS Primary Headache Disorders 1. Migraine 2. Tension-type 3. Cluster headache 4. Other primary headache disorders Secondary Headaches 5. Headache attributed to head or neck trauma 6. Headache attributed to cranial or cervical vascular disorder 7. Headache attributed to nonvascular intracranial disorder 8. Headache attributed to substance or withdrawal from substances 9. Headache attributed to infection 10. Headache attributed to disorders of homeostasis 11. Headache attributed to disorders of the cranium, neck, eyes, ears, nose, sinuses, teeth, or other facial or cranial structures 12. Headache attributed to psychiatric disorders 13. Cranial neuralgia and central causes of facial pain 14. Other headache, cranial neuralgia, central or primary facial pain

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BOX 53-2 2003 INTERNATIONAL CLASSIFICATION OF HEADACHE DISORDERS CRITERIA FOR MIGRAINE

Acute ? Symptoms

Migraine Migraine without aura Migraine with aura Typical aura with migraine headache Typical aura with nonmigraine headache Typical aura without headache Familial hemiplegic migraine Sporadic hemiplegic migraine Basilar-type migraine Childhood periodic syndromes that are commonly precursors of migraine Cyclical vomiting Abdominal migraine Benign paroxysmal vertigo of childhood Retinal migraine Complications of migraine Chronic migraine Status migraine Persistent aura without infarction Migrainous infarction Probable migraine

Acute recurrent Chronic progressive Chronic nonprogressive Mixed

0

30 Time (d)

60

FIGURE 53-1. Five temporal patterns of pediatric headache.

plicated, or variants of migraine are all included under migraine with aura (Box 53-2). For example, a migraine with hemiparesis (e.g., familial or sporadic hemiplegic migraine) falls in the category of migraine with aura. Another change in the new classification system is the inclusion of cyclic vomiting and abdominal migraine within the category of “Childhood periodic syndromes that are commonly precursors of migraine.” The new classification system also recognizes that many patients experience frequent or near daily migraine (more than 15 headaches per month) in a category of “chronic migraine” (see “Chronic Daily Headache”). Omitted from the 2004 classification are “Alternating hemiparesis of childhood” and the “Alice in Wonderland” syndrome. The rare and bizarre entity of alternating hemiparesis of childhood, once thought to be a migrainous phenomenon, is viewed as a metabolic disorder, probably

because of a mitochondrial disorder or a channelopathy. Recently, however, a novel ATP1A2 mutation in a kindred with features that bridge the phenotypic spectrum between alternating hemiparesis of childhood and familial hemiplegic migraine has been reported, which may draw alternating hemiparesis of childhood back into the migraine spectrum [Swoboda et al., 2004]. The Alice in Wonderland syndrome represents transient visual or perceptual disturbances with micropsia or macropsia and, when heralding an otherwise typical migraine headache, is appropriately viewed as migraine with aura. Anatomically, the aura is arising from the occipital, parietal, or posterior temporal lobes to produce these distorted visual symptoms. Another modification in the new classification is to remove “Ophthalmoplegic migraine” from the category of migraine to the group of cranial neuralgias. Although paradoxically still labeled as “migraine,” this clinical entity is characterized by transient disturbances of cranial nerves III, IV, or VI coupled with intense peri- or retro-orbital pain. A separate, clinically useful classification system was proposed by Rothner that divides headache into five temporal patterns (Fig. 53-1): acute, acute-recurrent, chronic-progressive, chronic-nonprogressive, and mixed. Each of these temporal patterns suggests differing pathophysiologic processes and has distinctive differential diagnoses (Table 53-2).

TABLE 53-2 Examples of Syndromes That Cause Headaches ACUTE GENERALIZED

ACUTE LOCALIZED

ACUTE RECURRENT

CHRONIC PROGRESSIVE

CHRONIC NONPROGRESSIVE

Fever Systemic infection Central nervous system infection Toxins: lead CO2 After seizure Electrolyte imbalance Hypertension Hypoglycemia After lumbar puncture Trauma Embolic Vascular thrombosis Hemorrhage Collagen disease Exertional

Sinusitis Otitis Ocular abnormality Dental disease Trauma Occipital neuralgia Temporomandibular joint dysfunction

Migraine Complex migraine Migraine variants Cluster Paroxysmal hemicrania After seizure Tic douloureux Exertional

Tumor Pseudotumor Brain abscess Subdural hematoma Hydrocephalus Hemorrhage Hypertension Vasculitis

Muscle contraction Conversion Malingering After concussion Depression Anxiety Adjustment reaction Hemicrania continua

Lewis / Headaches in Infants and Children

The acute, sudden onset of headache in an otherwise healthy child is usually due to intercurrent viral infection (e.g., upper respiratory infection or pharyngitis). The acute headache with focal neurologic signs must raise concerns for intracranial hemorrhage from aneurysm, vascular malformation, or coagulopathy. Sudden headache with fever warrants consideration of cerebrospinal fluid analysis for the possibility of meningitis. Acute-recurrent pattern implies attacks of headache, separated by symptom-free intervals. The primary headache disorders—migraine and tension-type—are the most common causes of this pattern, although, infrequently, complex partial seizures, substance abuse, cluster headache, and recurrent trauma can produce recurring headache syndromes. Chronic-progressive headaches implies a gradually increasing frequency and severity of headache and is the most ominous of the five temporal patterns. The pathologic correlate is increasing intracranial pressure. Causes of this pattern include brain tumor, hydrocephalus, pseudotumor cerebri, chronic meningitis, brain abscess, or subdural collections. Chronic-nonprogressive or chronic daily headache represents a pattern of frequent or near-constant headache. The definition of CDH requires a period longer than 4 months during which the patient experiences more than 15 headaches per month and the headaches last more than 4 hours per day. Many adolescents will have continual, unremitting, disabling daily headache. Affected patients generally have normal neurologic examinations, and there are usually interwoven psychologic factors and heightened anxiety about unrecognized, underlying organic causes. “Mixed” headache pattern represents the superimposition of acute-recurrent headache (usually migraine) upon a chronic daily background pattern; therefore, it represents a variant of chronic-nonprogressive headache (see later sections).

DIAGNOSTIC CRITERIA The 2004 International Classification of Headache Disorders also establishes the diagnostic criteria for the primary headache disorders (Box 53-3). Beginning in the 1950s, efforts were made to define migraine in children. Valquist, Bille, and later, Prensky and Sommer all proposed the criteria for pediatric migraine, which included the following features: 1. Paroxysmal headache separated by pain-free intervals 2. Accompanied by a variable number of associated features including: Visual aura Nausea Abdominal pain Throbbing quality Unilateral pain Family history of migraine [Bille, 1962; Prensky and Sommer, 1979; Valquist, 1955] In 1988, the International Headache Society established the gold standard for the definition of migraine [Olesen, 1988]. Although these criteria provided a solid framework for adult migraine, their sensitivity for the pediatric population was less than satisfactory. Therefore, in 2003, the International Headache Society revised the diagnostic criteria, incorporating many developmentally sensitive changes that

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BOX 53-3 2003 INTERNATIONAL HEADACHE SOCIETY DIAGNOSTIC CRITERIA FOR THE PRIMARY HEADACHE DISORDERS: MIGRAINE AND TENSION-TYPE Pediatric Migraine without Aura A. At least five attacks fulfilling criteria B through D B. Headache attacks lasting 1 to 72 hours C. Headache has at least two of the following characteristics: 1. Unilateral location, may be bilateral, frontotemporal (not occipital) 2. Pulsing quality 3. Moderate or severe pain intensity 4. Aggravation by or causing avoidance of routine physical activity (e.g., walking or climbing stairs) D. During the headache, at least one of the following: 1. Nausea and/or vomiting 2. Photophobia and phonophobia, which may be inferred from behavior E. Not attributed to another disorder Episodic Tension-Type Headache A. At least 10 episodes occurring on more than 1, but fewer than 15 days per month for at least 3 months and fulfilling criteria B through D. B. Headache lasting 30 minutes to 7 days. C. Headache has at least two of the following characteristics: 1. Bilateral location 2. Pressing or tightening (nonpulsing) quality 3. Mild or moderate intensity 4. Not aggravated by routine physical activity such as walking or climbing stairs. D. Both of the following: 5. No nausea or vomiting (anorexia may occur) 6. Photophobia or phonophobia (but not both) F. Not attributed to another structural or metabolic disorder permit a broader applicability for children and adolescents, maintaining specificity and improving sensitivity [Olesen, 2004]. These new criteria accept the clinical observations that pediatric migraine may be brief (≈1 hour) and bifrontal, and that the associated symptoms of photophobia and phonophobia may be inferred by the child’s behavior, such as withdrawing to a dark, quiet room to rest during the headache attack. The diagnostic criteria also include cyclic vomiting and abdominal migraine (Boxes 53-4 and 53-5).

EVALUATION OF THE CHILD WITH HEADACHE The evaluation of a child with headaches follows the traditional medical model and begins with a thorough medical history and complete physical and neurologic examination. A brief series of questions shown in Box 53-6 provides a logical framework for evaluating headaches and generally yields sufficient information to diagnose most primary headaches and reveal clues to the presence of secondary headache disorders.

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Box 53-4 INTERNATIONAL CLASSIFICATION OF HEADACHE DISORDERS CRITERIA FOR CYCLIC VOMITING Description Recurrent episodic attacks, usually stereotypical in the individual patient, of vomiting and intense nausea. Attacks are associated with pallor and lethargy. There is complete resolution of symptoms between attacks. Diagnostic Criteria A. At least five attacks fulfilling criteria B and C B. Episodic attacks, stereotypical in the individual patient, of intense nausea and vomiting lasting 1 to 5 days C. Vomiting during attacks occurs at least 5 times/hour for at least 1 hour D. Symptom-free between attacks E. Not attributed to another disorder. History and physical examination do not reveal signs of gastrointestinal disease.

Box 53-5 INTERNATIONAL CLASSIFICATION OF HEADACHE DISORDERS CRITERIA FOR ABDOMINAL MIGRAINE Description An idiopathic recurrent disorder seen mainly in children and characterized by episodic midline abdominal pain manifesting in attacks lasting 1 to 72 hours with normality between episodes. The pain is of moderate-to-severe intensity and associated with vasomotor symptoms, nausea, and vomiting. Diagnostic Criteria A. At least five attacks fulfilling criteria B through D B. Attacks of abdominal pain lasting 1 to 72 hours C. Abdominal pain has all of the following characteristics: 1. Midline location, periumbilical or poorly localized 2. Dull or “just sore” quality 3. Moderate or severe intensity D. During abdominal pain, at least two of the following: 1. Anorexia 2. Nausea 3. Vomiting 4. Pallor Not attributed to another disorder. History and physical examination do not indicate signs of gastrointestinal or renal disease, or such disease has been ruled out by appropriate investigations. The role of further ancillary diagnostic studies such as laboratory testing, electroencephalography (EEG), and neuroimaging has been extensively reviewed in a practice parameter of the American Academy of Neurology [Lewis et al., 2002]. The practice parameter determined that there is inadequate documentation in the literature to support any recommendation as to the appropriateness of routine laboratory studies (e.g., hematology or chemistry panels) or

Box 53-6 KEY QUESTIONS TO ASK IN THE EVALUATION OF CHILDREN WITH HEADACHES Headache Database 1. How and when did your headache(s) begin? 2. What is the time pattern of your headache: sudden first headache, episodes of headache, an everyday headache, gradually worsening, or a mixture? 3. Do you have one type of headache or more than one type? 4. How often does the headache occur and how long does it last? 5. Can you tell that a headache is coming? 6. Where is the pain located and what is the quality of the pain: pounding, squeezing, stabbing, or other? 7. Are there any other symptoms that accompany your headache: nausea, vomiting, dizziness, numbness, weakness, or other? 8. What makes the headache better or worse? Do any activities, medications, or foods tend to cause or aggravate your headaches? 9. Do you have to stop your activities when you get a headache? 10. Do the headaches occur under any special circumstances or at any particular time? 11. Do you have other symptoms between headaches? 12. Are you taking or are you being treated with any medications (for the headache or other purposes)? 13. Do you have any other medical problems? 14. Does anyone in your family suffer from headaches? 15. What do you think might be causing your headache? Adapted from Rothner, 1995.

performance of lumbar puncture. Routine EEG is not recommended as part of the headache evaluation. Data compiled from eight studies demonstrated that the EEG was not necessary for differentiation of primary headache (e.g., migraine, tension-type) from secondary headache due to structural disease involving the head and neck or from headaches due to a psychogenic etiology. EEG is unlikely to define or determine an etiology of the headache or distinguish migraine from other types of headaches. Furthermore, in those children undergoing evaluation for recurrent headache who were found to have paroxysmal EEGs, the risk of future seizures is negligible. The role of neuroimaging is better defined. Data compiled from six pediatric studies permitted the following recommendations: 1. Obtaining a neuroimaging study on a routine basis is not indicated in children with recurrent headaches and a normal neurologic examination. 2. Neuroimaging should be considered in children in whom there are historical features to suggest the following: a. Recent onset of severe headache b. Change in the type of headache c. Neurologic dysfunction

Lewis / Headaches in Infants and Children

3. Neuroimaging should be considered in children with an abnormal neurologic examination (e.g., focal findings, signs of increased intracranial pressure, significant alteration of consciousness) and the coexistence of seizures. Care must be taken not to over- or underinterpret these recommendations. Neuroimaging may be considered in children with recurrent headache based on clues extracted from the medical history or on the findings of neurologic examination. Since publication of this parameter, feedback from clinicians and personal experience has demonstrated that many in the “managed care industry” have focused only on recommendation number one and not recognized numbers two and three, which clearly places the responsibility in the hands of the clinician to make the decision to perform ancillary testing, including neuroimaging, based on good clinical judgment. The findings of the American Academy of Neurology support the medical decision to perform scans or to withhold scans, based on clinical determinants for the individual patient.

PRIMARY HEADACHE SYNDROMES Migraine Migraine is the most common acute-recurrent headache syndrome. The classifications of migraine are shown in Box 53-2 and the cardinal diagnostic features are shown in Box 53-3.

Pathophysiology Migraine is considered to be a primary neuronal process (Fig. 53-2) [Pietrobon and Striessnig, 2003; Silberstein,

Abnormal cortical hyperexcitability

?

CORTICAL SPREADING DEPRESSION Brainstem nuclei Activation of trigeminovascular system

Sterile neurogenic inflammation

Central and peripheral sensitization

MIGRAINE ATTACK

FIGURE 53-2. Migraine pathophysiology. (Adapted from Pietrobon D, Striessnig J. Neurobiology of migraine. Nat Rev 2003;4:386.)

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2004]. The principal underlying phenomenon of migraine is a hyperexcitable cerebral cortex. Polygenic influences produce disturbances of neuronal ion channels (e.g., calcium channels), leading to a lowered threshold for external and/or internal factors that trigger episodes of cortical spreading depression. Cortical spreading depression represents a slowly propagating wave (≈2 to 6 mm/minute) of neuronal depolarization and is now viewed as the key initial phase that is responsible for (1) migraine aura and (2) activation of the “trigeminovascular system.” The aura of migraine represents transient, focal somatosensory phenomena such as visual scotomata or distortions, dysesthesias, hemiparesis, or aphasia. The aura is viewed to be caused by the regional neuronal depolarization and/or the accompanying regional oligemia observed with cortical spreading depression. In addition to sustained cortical oligemia, cortical spreading depression is accompanied by extravasation of plasma proteins from dural vessels and activation of meningeal afferents. The sum of these effects is to increase FOS expression in the trigeminal nucleus within the brainstem [Prensky and Sommer, 1979]. Cortical spreading depression, then, is the key event for episodic activation of the trigeminal vascular system that culminates in the migraine attack. The role played by the brainstem nuclei is controversial. Some investigators believe the locus ceruleus and dorsal raphe nuclei act as the “migraine generator,” initiating noradrenergic and serotonergic signals to the cortex and dural vessels in a parallel fashion. Other investigators favor the view that cortical spreading depression is the initiating phenomenon and believe that the brainstem nuclei provide a “permissive” role, favoring “central trigeminal hyperexcitability.” Although cortical spreading depression nicely explains the somatosensory aura, only about 30% of children and adolescents experience aura. Clearly, the processes leading to pain may occur in the absence of a perceived aura. Two mechanisms are thought to be responsible for the generation of the pain of migraine: (1) neurogenic inflammation of the meningeal vessels and (2) “sensitization” of peripheral and central trigeminal afferents. Cortical spreading depression initiates vascular dilation with extravasation of plasma proteins from dural vessels and activates trigeminal meningeal afferents. These processes set the stage for “neurogenic” inflammation of the dural and pial vessels, mediated principally by neuropeptides and calcitonin gene-related protein. The inflammatory cascade stimulates nociceptive afferents, leading to pain. Many authors question whether neurogenic inflammation alone is sufficient to produce the pain of migraine. One of the striking features noted during an attack of migraine is that seemingly innocuous activities, such as coughing, walking up stairs, or bending over greatly intensify the pain. In fact, the International Classification of Headache Disorders criteria include “aggravation” by activities as one of the diagnostic features of migraine. This observation coupled with elegant research has led to the concepts of “sensitization” of trigeminal vascular afferents, whereby both peripheral and central afferent circuits become exceptionally sensitive to mechanical, thermal, and chemical stimuli. These circuits become so sensitive that

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virtually any stimulation is perceived as painful, the concept of allodynia [Burstein et al., 2000; Burstein et al., 2004; Burstein and Jakubowski, 2004]. Therefore, the current view of the pathophysiology of migraine begins with an inherited vulnerability with a hyperexcitable cerebral cortex. A variety of stimuli may trigger episodes of cortical spreading depression, which, in turn, initiates the processes of localized, neurogenic inflammation and of sensitization of both peripheral and central afferent circuitry.

Clinical Manifestations MIGRAINE WITHOUT AURA The diagnostic criteria for migraine without aura are shown in Box 53-3. Migraine without aura is the most frequent form, accounting for 60% to 85% of all migraine in children and adolescents. Patients often recognize prodromal features: mood changes (euphoria to depression), irritability, lethargy, yawning, food cravings, or increased thirst. Perhaps the most frequent heralding feature is a change in behavioral patterns or withdrawal from activities. A migraine headache begins gradually and is usually localized to the frontal or temporal region. The pain may be unilateral. The quality is generally described as pounding, pulsing, or throbbing, but the key feature is its intensity. Routine activities will be interrupted. Photophobia and phonophobia are common and may be inferred by the child’s desire to seek a quiet, dark place to rest or even to sleep because sleep often produces significant relief. Nausea, vomiting, and abdominal pain may be the most disabling feature because a student with headache may be able to stay in the classroom with pain, but the onset of nausea or vomiting necessitates a visit to the school nurse. A migraine headache typically last for hours, even days (1 to 72 hours) but does not generally occur more fre-

TABLE 53-3 Migraine Aura Visual:

Sensory: Motor: Aphasia Psychic:

Negative scotoma “Fortification” scotoma Field deficits: Hemianopsia Quadrantanopsia Photopsia Visual distortions: Teichopsia Metamorphopsia Prosopagnosia “Alice in Wonderland” Parasthesias Dysesthesias Perioral and/or hand numbness (chiro-oral) Hemiparesis Monoparesis Confusion Dysphasia Amnesia Disequilibrium

quently than 6 to 8 times per month. More than 8 to 10 attacks per month must warrant consideration of alternative diagnoses such as organic conditions (i.e., pseudotumor cerebri) or the chronic daily headache syndromes [American College of Emergency Physicians, 1996; Gladstein et al., 1997]. The time of day when the headache occurs tends to shift through childhood. Younger children often complain in the afternoon, after school. Younger teenagers frequently begin to report their headaches about lunchtime, often precipitated by the chaos of the school cafeteria with its combination of bright lights, loud noise, and peer pressure. Older teens acquire the more adult patterns of morning headache, often a concern because morning occurrence frequently raises suspicion of space-occupying lesions. Although most verbal children can readily relate to these symptoms, the developmentally challenged child may be unable to express these complaints. Caregivers report repeated cycling events of quiet, withdrawn behavior with pallor, regurgitation, vomiting, and desire to rest. These stereotyped episodes may prompt investigation for epilepsy, gastroesophageal reflux, or hydrocephalus, when in fact they may represent migraine.

MIGRAINE WITH AURA Approximately 14% to 30% of children report visual disturbances, distortions, or obscuration before or as the headache begins (Table 53-3) [Lewis, 1995]. The aura (“cool breeze”) is, however, an inconsistent feature in childhood and adolescents. The presence of an aura must be elicited with very specific questions: “Do you have spots, colors, lights, or dots in your eyes before or as you are getting a headache?” Typically, the aura is a visual phenomenon, but, as discussed in the pathophysiology section previously, the cortical spreading depression responsible for the aura may disturb virtually any cortical region including language, motor, or sensory areas. The classic visual symptomatology during migraine include three dominant visual phenomena: 1. Binocular visual impairment with scotoma (77%) 2. Distortion or hallucinations (16%) 3. Monocular visual impairment or scotoma (7%) [Hachinshi et al., 1973] The onset of the visual aura is gradual and lasts minutes. Sudden images and complicated visual perceptions should prompt consideration of complex partial seizures, even if followed by headache. Young adolescents may experience strange visual effects (distortions, illusions, micropsia, and macropsia) within the spectrum of the Alice in Wonderland syndrome. Transient visual obscurations, brief episodes of near-complete blindness, are also features of pseudotumor cerebri. The aura has long been thought to be an extremely useful feature therapeutically, with early warning of an impending headache permitting the institution of abortive measures such as ergotamine or the “triptan” agents. Unfortunately, the therapeutic utility of treating the headache at the onset of the aura in adolescent migraine is not reliable or effective.

Lewis / Headaches in Infants and Children

Alice in Wonderland Syndrome Bizarre visual illusions and spatial distortions occasionally precede migraine headaches. Similar to Alice’s visual distortions after eating mushrooms in Through the Looking Glass, affected children describe visual distortions before or as the headache is beginning. The children may describe bizarre or vivid visual illusions, such as the following: Macropsia: objects appear larger Micropsia: objects appear smaller Metamorphopsia: objects (such as faces) appear distorted Teleopsia: objects appear far away These patients are often not confused or frightened by these illusions and are able to relate the experience in enthusiastic detail. This unusual visual symptomatology is best considered as migraine with aura, though historically, Alice-in-Wonderland syndrome is included as a distinct variant. This type of visuoperceptual abnormality has been reported with infectious mononucleosis, complex partial seizures, and hallucinogenic drug ingestion.

Retinal Migraine Also referred to as ocular, ophthalmic, or anterior visual pathway migraine, retinal migraine is uncommon in young children but occurs during adolescence. Affected patients will report brief (seconds to <60 minutes), sudden, monocular blackouts or gray-outs, or bright, blinding episodes (e.g., photopsia) of visual disturbance, before, after, or during the headache. A 60-minute interval between visual symptom and headache may occur. As with ophthalmoplegic migraine, the pain is often described as retro-orbital and ipsilateral to the visual disturbance. Examination of the optic fundus during an attack may disclose constriction of retinal veins and arteries with marked retinal pallor. An occasional patient may suffer significant visual sequelae (e.g., scotoma, altitudinal defects, or monocular blindness) in retinal migraine presumably due to vasoconstriction with retinal infarction. Although the patient population with retinal migraine is generally much younger than those who experience amaurosis fugax from atheromatous carotid disease, evaluation for hypercoagulable states, embolic sources, and carotid dissection must be considered.

Basilar-Type Migraine Also known as basilar artery or vertebrobasilar migraine, basilar-type migraine is the most frequent of complicated migraine variants and is estimated to represent 3% to 19% of all migraine [Bickerstaff, 1961; Golden and French, 1975; Lapkin and Golden, 1978]. This wide range of frequency relates to the rigorousness of the definition. Some authors included any headache with dizziness to be within the spectrum of basilar migraine, whereas others require the presence of clear signs and symptoms of posterior fossa involvement before establishing this diagnosis. The International Classification of Headache Disorders criteria require two or more symptoms (Table 53-4) and emphasize bulbar and bilateral sensorimotor features. Onset of basilar migraine tends to occur in younger children, with a mean age of 7 years, although the clinical

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TABLE 53-4 Signs and Symptoms of Basilar-Type Migraine Vertigo Nausea or vomiting Ataxia Visual field deficits Diplopia Tinnitus Vertigo Hearing loss Confusion Dysarthria Weakness (hemiplegia, quadriplegia, diplegia) Syncope

73% 30%-50% 43%-50% 43% 30% 13% 73% * 20% * 20% *

*No figures available.

entity probably appears as early as 12 to 18 months in the form of “benign paroxysmal vertigo” with episodes of ataxia, vertigo, clumsiness, pallor, and vomiting. Affected children have attacks of intense dizziness, vertigo, visual disturbances, ataxia, and diplopia. These early, transient features last from minutes up to an hour and are followed by the headache phase. The headache may be occipital. The quality of the pain may be ill defined and the terms such as pulsing or throbbing may not be used. A small subset of patients with basilar migraine will have their posterior fossa symptoms after the headache phase is well established. The pathogenesis of basilar migraine is not well understood. Although focal cortical processes, oligemia or depolarization, can explain the deficits in hemiplegic migraine, the posterior fossa signs of basilar migraine are more problematic. A single case report of a 25-year-old woman with basilar migraine exists wherein transcranial Doppler and single photon emission tomography were performed through the course of a basilar migraine attack. These data suggest decreased posterior cerebral artery perfusion through the aura phase at a time when the described patient was experiencing transient bilateral blindness and ataxia [LaSpina et al., 1997]. The sudden appearance of diplopia, vertigo, and vomiting must prompt consideration of disorders within the posterior fossa such as arteriovenous malformations, cavernous angiomas, tumors (medulloblastoma, ependymoma, brainstem glioma), congenital malformations (e.g. Chiari, DandyWalker), or vertebrobasilar insufficiency (e.g., vertebral dissection or thrombosis). Acute labyrinthitis or positional vertigo can mimic basilar migraine. Complex partial seizures and drug ingestions must be considered at any age. Rarely, metabolic diseases such as Hartnup’s disease, hyperammonemias (urea cycle or organic acidemias), or disorders of pyruvate or lactate metabolism may present with episodic vertigo, but these inborn errors of metabolism usually have some degree of altered consciousness, even coma.

Hemiplegic Migraine Familial Hemiplegic Migraine Familial hemiplegic migraine is an uncommon autosomaldominant form of migraine headache in which the aura has a “strokelike” quality, producing some degree of hemiparesis. The nosology is somewhat misleading because there

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Nonepileptiform Paroxysmal Disorders and Disorders of Sleep / 53

is actually a wide diversity of focal symptoms and signs that can accompany this migraine variant beyond motor deficits. Barlow proposed the more appropriate term hemi-syndrome migraine to emphasize the diversity of associated symptoms, but this term has not received broad acceptance [Barlow, 1984]. The International Headache Society criteria clearly require that “some degree of hemiparesis” must be present, so the term will likely persist. A series of recent exciting discoveries into the molecular genetics of familial hemiplegic migraine have broadened the understanding of the fundamental mechanisms of migraine and demonstrated the overlap with other paroxysmal disorders such as acetazolamide-responsive episodic ataxia [Joutel et al., 1993]. Genetic linkage to chromosome 19p13 has been identified in half of the known familial hemiplegic migraine pedigrees and, more recently, a separate pedigree with linkage to chromosome 1q31 has been reported [Gardner et al., 1997; Ophoff et al., 1997]. The chromosomal 19 defect produces a missense mutation in a neuronal calcium channel gene providing compelling evidence that familial hemiplegic migraine represents a channelopathy. These discoveries have revolutionized the understanding of migraine and may open new territory for pharmacologic interventions. From the clinical perspective, hemiplegic migraine is characterized by transient (hours to days) episodes of focal neurologic deficits, hemiparesis, hemisensory changes, aphasia, and visual field defects that precede the headache phase by 30 to 60 minutes but occasionally extend well beyond the headache itself. The headache is often, but not invariably, contralateral to the focal deficit. The appearance of acute, focal neurologic deficits in the setting of headache in an adolescent necessitates vigorous investigation for disorders such as intracranial hemorrhage, stroke, tumor, vascular malformations, acute disseminated encephalomyelitis, or focal infection. Complex partial seizure or drug intoxication with a sympathomimetic must also be considered. Neuroimaging (magnetic resonance imaging [MRI] and magnetic resonance angiography) and EEG may be indicated. Investigations for embolic sources or hypercoagulable states and for mitochondrial disorders (MELAS—mitochondrial myopathy, encephalography, lactic acidosis and stroke-like attacks) are likewise appropriate. Sporadic hemiplegic migraine represents an identical clinical phenomenon but lacks the identifiable family history.

Alternating Hemiplegia of Childhood Traditionally, alternating hemiplegia of childhood has been considered a variant of hemiplegic migraine, but more recent perspectives suggest other mechanisms, and the 2003 International Classification of Headache Disorders has omitted it from the migraine spectrum. Affected patients have their initial symptoms before 18 months of life. These unfortunate children have attacks of paralysis (hemiparesis, monoparesis, diparesis, ophthalmoparesis, and bulbar paralysis) that may be accompanied by variable tone changes (flaccid, spastic, or rigid). A variety of paroxysmal involuntary movements, including chorea, athetosis, dystonia, nystagmus, and respiratory irregularities (hyperpnea), can be seen. The attacks of paralysis can be brief (minutes) or prolonged (days) and potentially life threatening during periods of bulbar

paralysis. Curiously, the attacks generally subside after sleep. Affected children are frequently developmentally challenged [Aicardi et al., 1995; Verret and Steele, 1971]. The link to migraine was tenuous but was based on the presence of a high prevalence of migraine in the families of affected children and on cerebral blood flow data that suggest a “migrainous” mechanism. In 1997, an international workshop was conducted to address the various hypotheses surrounding alternating hemiparesis of childhood and the proceedings have been reviewed by Rho and Chugani, [1998]. Proposed mechanisms include channelopathy, mitochondrial cytopathy, and cerebrovascular dysfunction, though the former seems to be the most likely hypothesis. Recently however, a novel ATP1A2 mutation in a kindred with features that bridge the phenotypic spectrum between alternating hemiparesis of childhood and familial hemiplegic migraine has been reported that may draw alternating hemiplegia of childhood back into the migraine spectrum [Swoboda et al., 2004]. Investigations into the etiology of this entity warrant aggressive evaluation for vascular disorders, inborn errors of metabolism, mitochondrial encephalomyopathies, or epileptic variants. Management is difficult. The calcium channel blocker flunarezine not available through U.S. pharmacies, can be remarkably effective in reducing attack frequency and severity.

Confusional Migraine Omitted from the International Classification of Headache Disorders classification system is the entity “Confusional migraine,” which most likely represents a hybrid or overlap between hemiplegic and basilar-type migraine. The term confusional migraine was omitted with the expectation that those patients who have attacks associated with language disturbances, hemiparesis, and confusion represent the spectrum of hemiplegic migraine and those with bilateral blindness, ataxia, vertigo, and confusion represent the spectrum of basilar-type migraine. The clinical entity was first described in 1970 by Garcon and Barlow, who reported a series of children, ages 8 to 16 years, with acute confusional states lasting 4 to 24 hours, associated with agitation and aphasia. The authors suggested the confusional state was a manifestation of juvenile migraine [Garcon and Barlow, 1970]. Ehyai and Fenichel [1978] later introduced the term acute confusional migraine. Subsequent reports have broadened the clinical phenomenology to include blindness, paresthesias, hemiparesis and amnesia. Amnesia can be such a prominent feature that Jensen [1980] proposed the term transient global amnesia of childhood, but amnesia is only part of the clinical spectrum. Affected children, more commonly males, become agitated, restless, disoriented, and, occasionally, combative for minutes to hours. Once consciousness has returned to baseline, the patients may describe an inability to communicate, frustration, confusion, loss of orientation to time, and may not recall a headache phase at all. A strong family history of migraine is elicited in 75% of patients. There is a clear link to head trauma in many cases [Ferrera and Reicho, 1996]. The term footballer’s migraine is applied in Europe when a soccer player, after “heading”

Lewis / Headaches in Infants and Children

the ball, develops an acute confusional state with headache. Similar symptoms may follow other causes of minor head injury. This variant should be viewed within the spectrum of trauma-triggered migraine. Acute confusional states in children and adolescents warrant aggressive investigation for encephalitis, brain abscess, drug intoxication, cerebrovascular disease, vasculitis, or metabolic encephalopathies [Amit, 1988]. Particular attention must be focused on the possibility of complex partial seizures or postictal states.

CHILDHOOD “PERIODIC SYNDROMES” The following curious and pediatric-specific clinical entities represent episodic conditions with stereotyped features that are considered precursors of migraine. Cyclic vomiting syndrome is a disorder characterized by recurrent self-episodes of intense vomiting (more than four emeses/hour), recognizable by their stereotypical time of onset, duration, and symptomatology in the individual (see Box 53-4). The vomiting is uniquely intense, the subjective nausea disabling, and the resultant dehydration often necessitates hospital-based treatment. The attacks are accompanied by pallor, listlessness, anorexia, abdominal pain, retching, headache, and photophobia. The interval between attacks is 2 to 4 weeks and a typical attack lasts 24 to 48 hours. The children are, by definition, healthy between attacks. Boys and girls are equally affected by cyclic vomiting syndrome. The usual age of onset is 5 years, but the diagnosis is often delayed until age 8 and many, if not most, children “outgrow” these attacks by age 10. A thorough diagnostic evaluation must be performed to rule out intermittent bowel obstruction, elevated intracranial pressure, epilepsy, and metabolic disorders such as urea cycle defects and organic acidurias. The pediatric gastroenterology community is currently developing practice guidelines. The link to migraine is based on natural history data that suggest the evolution toward more typical migraine, parallels based on autonomic data (i.e., “neurocardiac”), and presence of family history of migraine in children with cyclic vomiting syndrome. The management of cyclic vomiting syndrome involves both acute strategies and preventive measures. As soon as an attack begins, these patients must be volume replenished with glucose-containing solutions. Pharmacologic options have not been systematically investigated, but anecdotal information suggests a role for antiemetics (e.g., ondansetron, promethazine, or prochlorperazine) and sedation (e.g., diphenhydramine, benzodiazepine). Subcutaneous sumatriptan (2 to 3 mg) has been used widely but no controlled trials have been conducted. Preventive agents such as cyproheptadine, amitriptyline or nortriptyline, valproate, topiramate, propranolol, or verapamil have all been used, but again no clinical trials have been reported. Abdominal migraine is a new addition to the International Headache Society classification. The diagnostic criteria for abdominal migraine are shown in Box 53-5. This clinical entity is characterized by recurrent episodes of midline epigastric abdominal pain lasting 1 to 72 hours. The pain is of moderate-to-severe intensity and associated with vasomotor symptoms (e.g., flushing, pallor), as well as nausea and

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vomiting. The patients are well between attacks. Clearly, thorough gastrointestinal and renal investigation must be conducted before this diagnosis is entertained. Benign paroxysmal vertigo of childhood is common and occurs in young children as abrupt, brief episodes of unexplained unsteadiness, with the child appearing to be “off balance” or falling. Careful observation may disclose nystagmus. Older children may be able to report symptoms of dizziness, clumsiness, headache, and nausea. The attacks may occur in clusters and typically resolve with sleep. In a small series of patients with long-term follow-up, most of the children had resolution of the episodes of vertigo but later developed migraine. The diagnosis of benign paroxysmal vertigo is one of exclusion. Epilepsy, otologic pathology, and central nervous system pathology should be considered. Treatment for benign paroxysmal vertigo can include symptomatic treatment such as antiemetics, although sleep aborts the attack in most patients. For a child in whom frequent events occur, a trial of cyproheptadine prophylaxis may be helpful in aborting attacks. A dosage of 2 to 4 mg nightly may be all that is required, and medication should be discontinued after the attacks have stopped. The majority of patients do not require any treatment. Reassurance regarding the benign nature of the condition may be all that is required. Benign paroxysmal torticollis is a rare paroxysmal dyskinesia characterized by attacks of head tilt alone or tilt accompanied by vomiting and ataxia that may last hours to days [Chaves-Carballo, 1996]. Other tortional or dystonic features, including truncal or pelvic posturing, are described by Chutorian [1974]. Attacks first manifest during infancy between 2 and 8 months of age. The original descriptions of benign paroxysmal torticollis by Snyder [1969] suggested a form of labyrinthitis and demonstrated abnormal vestibular reflexes. The link to migraine is strengthening. Paroxysmal torticollis is likely an early onset variant of basilar migraine, which itself is a variant of benign paroxysmal vertigo. Additionally, there is often a family history of migraine. More intriguing information has recently been reported wherein four children with this clinical entity have been found to have the mutation in the CACNA1A gene [Giffin et al., 2002]. The differential diagnosis must include gastroesophageal reflux (e.g., Sandifer’s syndrome), idiopathic torsional dystonia, and complex partial seizure, but particular attention must be paid to the posterior fossa and craniocervical junction, where congenital or acquired lesions may produce torticollis. Rarely, trochlear nerve dysfunction produces compensatory head tilt. If the episodes continue to recur, the management is unclear. There are no clinical trials reported. There is clearly the question of whether these events, once determined to be benign, require any treatment beyond reassurance. The author suggests a trial of cyproheptadine as a safe measure that may provide some benefit if the episodes are judged to be painful in an individual patient.

MANAGEMENT OF PEDIATRIC MIGRAINE Once the diagnosis of migraine is established and appropriate reassurances provided, a balanced and individually

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Nonepileptiform Paroxysmal Disorders and Disorders of Sleep / 53

tailored treatment plan can be instituted. The first step is to appreciate the degree of disability imposed by the patient’s headache. Understanding of the impact of the headache on the quality of life should guide the decisions regarding the most appropriate therapeutic course [Powers et al., 2003; 2004]. An American Academy of Neurology Practice Parameter has established the general principles for the management of migraine headache. The fundamental goals of long-term migraine treatment include the following: 1. Reduction of headache frequency, severity, duration, and disability 2. Reduction of reliance on poorly tolerated, ineffective, or unwanted acute pharmacotherapy 3. Improvement in the quality of life 4. Avoidance of acute headache medication escalation 5. Education and enablement of patients to manage their disease 6. Reduction of headache-related distress and psychologic symptoms [Silberstein, 2000] To achieve these goals, it is becoming increasingly clear that a balanced treatment must include biobehavioral strategies and nonpharmacologic methods, as well as pharmacologic measures. Biobehavioral treatments include biofeedback, stress management, sleep hygiene, exercise, and dietary modifications (Box 53-7) [Holroyd and Mauskop, 2003].

Box 53-7 COMPLEMENTARY AND ALTERNATIVE TREATMENTS Identification of migraine triggers Biobehavioral Biofeedback Electromyographic biofeedback Electroencephalography Thermal hand warming Galvanic skin resistance feedback Relaxation therapy Progressive muscle relaxation Autogenic training Meditation Passive relaxation Self-hypnosis Cognitive therapy/stress management Cognitive control Guided imagery Dietary measures “Avoidance diets” Caffeine moderation Herbs Feverfew (Tanacetum parthenium) Ginkgo Valerian root Minerals Magnesium Vitamins Riboflavin (B2) Acupuncture Massage therapy Aroma therapy

Biofeedback has demonstrated effectiveness in the treatment of both adults and children with migraine in controlled trials. Although the physiologic basis for its effectiveness is unclear, data suggest that levels of plasma beta-endorphin can be altered by biofeedback therapies [Baumann, 2002]. Biofeedback therapies commonly use electrical devices that provide audio or visual displays to demonstrate a physiologic effect. Thermal biofeedback is the most commonly used technique in pediatrics wherein children are taught to raise the temperature of one of their fingers. These techniques can easily be taught to children, and their use is associated with fewer and briefer migraine headaches. Once taught these methods, children can manage headaches, allowing them to have greater control of their health. Stress management and relaxation therapies use techniques such as progressive relaxation, self-hypnosis, and guided imagery. Controlled trials have found relaxation therapies to be as effective in reducing the frequency of migraine attacks as the beta-blocker propranolol [Olness et al., 1987]. Sleep disturbances occur in 25% to 40% of children with migraine. One recent study found too little sleep (42%), bruxism (29%), co-sleeping (25%), and snoring (23%) in a population of 118 children. When children with migraine were compared with matched controls, statistically significant differences were found in sleep duration, daytime sleepiness, night awakenings, sleep anxiety, parasomnias, sleep-onset delay, bedtime resistance, and sleep-disordered breathing [Miller et al., 2003]. It remains unclear, however, whether sleep disturbances increase the occurrence of migraine, whether frequent and intense migraine leads to sleep disturbances, or whether the two are unrelated. Current practice is to recommend good sleep hygiene. Exercise is recommended for patients with frequent migraines, and a review of Internet web sites serving headache sufferers reveals the common endorsement of regular physical activity. A recent study to evaluate the effects of exercise on plasma beta-endorphin levels in 40 migraine patients found beneficial effects on all migraine parameters [Koseoglu et al., 2003]. The role of dietary measures has recently been reviewed, yet the subject remains controversial [Millichap and Yee, 2003]. Seven to 44% of children and adults with migraine report that a particular food or drink can precipitate a migraine attack [Stang et al., 1992; Van den Bergh et al., 1987]. In children, the principal dietary triggers were cheese, chocolates, and citrus fruits. Other purported dietary precipitants include processed meats, yogurt, fried foods, monosodium glutamate, aspartame, and alcoholic beverages. For chocolate, the median time interval to the onset of headache after ingestion was 22 hours (3.5 to 27 hours) [Gibb et al., 1991]. Nonetheless, wholesale dietary elimination of a laundry list of foods is not recommended. Once popular, elimination diets are now judged to be excessive and generally set the stage for a battleground at home when parents attempt to enforce a restrictive diet on an unwilling adolescent, ultimately producing heightened tensions. A more reasonable approach is to review the list of foods thought to be linked to migraine and invite the patient to keep a headache diary

Lewis / Headaches in Infants and Children

to see if a temporal relationship exists between ingestion of one or more of those foods and the development of headache. If a link is found, prudence dictates avoidance of the offending food substance. In addition to paying attention to what is eaten, it is important to encourage regular meals and drinking plenty of fluids. Many teenagers routinely skip breakfast. Missing meals is a common precipitant of migraine and identified by adolescents as one of the leading triggers [Lewis et al., 2004a]. A simple lifestyle modification for adolescents with frequent migraine includes eating three meals a day, including breakfast, and consuming plenty of water. Overuse of over-the-counter analgesics has been a particular focus recently. Recognized in adults some years ago, overuse (more than five times per week) of acetaminophen, ibuprofen, and, to a lesser extent, aspirin-containing compounds can be a contributing factor to frequent, even daily, headache patterns. When recognized, patients who are overusing analgesics must be educated to discontinue the practice. Retrospective studies have suggested that this recommendation alone can decrease headache frequency [Reimschisel, 2003; Rothner and Guo, 2004]. Caffeine in coffee and sodas warrants special mention. A link between caffeine and migraine has been established [James, 1998; Mannix et al., 1997]. Not only does caffeine seem to have an influence on headache, it also may disrupt sleep or aggravate mood, both of which can exacerbate headache. Furthermore, caffeine withdrawal headache, which begins 1 to 2 days after cessation of regular caffeine use, can last up to a week [Dusseldorp and Katan, 1990]. Every effort must be made to moderate caffeine use. The pharmacologic management of pediatric migraine has been subjected to thorough review, and controlled data are, unfortunately, limited (Table 53-5) [Lewis et al., 2004a; Victor and Ryan, 2003]. For the acute treatment of migraine, the most rigorously studied agents are ibuprofen, acetaminophen, and sumatriptan nasal spray, all of which have been found to be safe and efficacious in controlled trials. Although none of the triptan agents has yet been approved by the U.S. Food and Drug Administration for use in children and adolescents, multiple studies have demonstrated the safety of their use in children [Major et al., 2003]. Thus far, only sumatriptan in the nasal spray form (5 and 20 mg) has demonstrated efficacy in adolescents [Ahonen et al., 2004; Ueberall, 2001; Winner et al., 2000]. For young children, younger than 12 years of age, ibuprofen (7.5 to 10 mg/kg) and acetaminophen (15 mg/kg) have demonstrated efficacy and safety for the acute treatment of migraine [Hamalainen et al., 1997; Lewis et al., 2002b]. Butalbital preparations are no longer recommended. For preventive or prophylactic treatment in the population of children and adolescents with frequent, disabling migraine, flunarizine (not available in the United States) is the most efficacious agent, but encouraging data are emerging regarding several antiepileptic agents such as topiramate, sodium valproate, and levetiracetam, as well as the antihistamine cyproheptadine and the antidepressant amitriptyline [Ferrera and Reicho, 1996; Hershey et al., 2002; Lewis et al., 2004b; Miller, 2004; Serdaroglu et al., 2002].

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OTHER PRIMARY HEADACHE SYNDROMES Chronic Daily Headache Many adolescents report the experience of headache virtually every day, sometimes, during every waking hour. This chronic, nonprogressive, unremitting, daily, or near daily, pattern of headache represents one of the most difficult subsets of headache known as chronic daily headache. Chronic daily headache may be formally defined as longer than 4 months during which the patient has more than 15 headaches per month, with the headaches lasting more than 4 hours per day. The estimated prevalence of chronic daily headache in adolescents is about 1% and may be as high as 4% of the adult population [Abu-Arefeh and Russell, 1994; Castillo et al., 1999; Lipton and Stewart, 1997]. Chronic daily headache is very common in referral headache clinics, where up to 15% to 20% of patients present with daily or near-daily head pain [Viswanathan et al., 1998]. Understandably, the quality of life of patients with chronic daily headache is significantly influenced. The negative effect extends beyond the affected patient to family, friends, and society as a whole. The extensive disability that results from chronic daily headache can be measured in school absence, abstinence from after-school activities, and family discord that invariably results. Therefore early diagnosis and management of frequent or chronic daily headaches are essential. Four primary chronic headache categories have been identified: Chronic migraine (“transformed” migraine) Chronic tension-type New daily persistent headache Hemicranium continuum Chronic (“transformed”) migraine represents chronic daily migraines that have slowly evolved from episodic migraine headache, whereas the chronic tension-type headaches evolved from episodic tension-type headaches. The new daily persistent headaches appeared to represent a unique entity in that the chronic daily headaches started quite abruptly, de nouveau, without any history of previous headache syndrome. Uncommon in children, hemicrania continua represented a cluster variant with daily or continuous unilateral pain with conjunctival injection, lacrimation, rhinorrhea and, occasionally, ptosis. One of the key features of hemicrania continua is responsiveness to indomethacin. Each of these four types of chronic daily headache is further separated into those with or without superimposed analgesic overuse. The medications implicated in this analgesic overuse syndrome include most over-the-counter analgesics (e.g., acetaminophen, aspirin, ibuprofen), opioids, butalbital, isometheptene, benzodiazepines, ergotamine, and the triptans [Mathew et al., 1990]. Secondary causes of the chronic daily headache pattern in children and adolescents include neoplasm, idiopathic intracranial hypertension (pseudotumor cerebri), hydrocephalus, chronic subdural hematomas, chronic sinusitis, glaucoma, malocclusion, temporomandibular dysfunction, and psychologic conditions. The “medicolegal headache” falls into this category as pending litigation tends to exacerbate stress

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Nonepileptiform Paroxysmal Disorders and Disorders of Sleep / 53

TABLE 53-5 Acute and Preventive Agents for Childhood Migraine Acute Therapies CLASSIFICATION OF EVIDENCE*

“N”

EFFICACY

I I I

88 84 88

P <0.05* P <0.006 P <0.05*

I I IV I IV IV IV

14 510 58 83 23 17 50

Other oral triptans Rizatriptan

I

296

Zolmitriptan

IV

38

AGENTS NSAIDs and Nonopiate Analgesics Ibuprofen Acetaminophen Triptan agents Sumatriptan Nasal

Oral Subcutaneous

CLINICAL IMPRESSION OF EFFECT†

ADVERSE EFFECTS

+++

Infrequent

++

Infrequent

P <0.03 P <0.05 78% P <0.003 NS 64% 78%

+++

Occasional to frequent

++ ++

Occasional to frequent Occasional to frequent

NS 66% active, 56% placebo 85% 2.5 mg 70% 5.0 mg

++

Occasional to frequent Occasional to frequent

++

Occasional to frequent

CLINICAL IMPRESSION OF EFFECT†

ADVERSE EFFECTS

Commonly Used Agents for the Acute Treatment of Migraine AGENTS

DOSE

Ibuprofen Acetaminophen Naproxen sodium

7.5-10 mg/kg 15 mg/kg 2.5-5 mg/kg

Triptans Sumatriptan Subcutaneous Tablets Nasal spray Rizatriptan Zolmitriptan Frovatriptan Almotriptan Eletriptan Naratriptan

6 mg 25, 50, 100 mg 5, 20 mg 5, 10 mg tablets 5, 10 mg oral disintegrating tablets 2.5, 5 mg tablet 2.5, 5, mg oral disintegrating tablets 2.5 mg nasal spray 2.5 mg tablets 6, 12.5 mg tablets 20, 40 mg tablets 1.0, 2.5 mg tablets Preventive Therapies

AGENTS

CLASSIFICATION OF EVIDENCE*

“N”

EFFICACY

Antiepileptic Medications Divalproex sodium/ sodium valproate

IV IV

42 10

Topiramate Levetiracetam Gabapentin

IV IV IV

75 19 18

76% had >50% reduction in headache frequency P=0 P <0.001 P <0.0001 80% ≥ 50% reduction in headache frequency and severity

++ +++

Occasional to frequent

+++ +++ ++

Occasional to frequent Occasional to frequent Occasional

Lewis / Headaches in Infants and Children

1195

TABLE 53-5, cont’d Acute and Preventive Agents for Childhood Migraine AGENTS Antidepressant Medications Trazodone Pizotifen Amitriptyline Antihistamines Cyproheptadine Calcium Channel Blockers Flunarizine

CLASSIFICATION OF EVIDENCE*

EFFICACY

CLINICAL IMPRESSION OF EFFECT†

ADVERSE EFFECTS

“N”

II I IV IV

35 47 192 73

NS NS

0 0

Occasional to frequent Occasional to frequent

80% 89%

+++

Occasional to frequent

IV

30

83%

+++

Occasional to frequent

I I IV

42 63 12

+++

Occasional

Nimodipine Antihypertensive Agents Propranolol

I

37

P < 0.001 P < 0.001 75% had 75%-100% reduction in headache frequency NS

0

Occasional

II II II

39 28 28

++ 0 0

Occasional to frequent

Timolol Clonidine

II II II

19 43 57

81% had >66% reduction in headache frequency NS NS NS NS NS

0 0

Occasional Occasional to frequent

IV

10

60% had >60% reduction in headache frequency

++

Occasional

NSAID Naproxen sodium

Commonly Used Preventive Agents for Migraine Management AGENTS Calcium Channel Blocker Flunarizine Antidepressant Amitriptyline Antiepileptic Agents Topiramate Sodium valproate Antihistamine Cyproheptadine Beta-Blockers Propranolol Metoprolol Atenolol NSAID Naproxen sodium

DOSE 5-10 mg daily 5-25 mg orally at bedtime 1-10 mg/kg divided bid 10-40 mg/kg Usual (250-500 mg extended release at bedtime) 2-8 mg/day (at bedtime or divided bid) 2-4 mg/kg/day 2-6 mg/kg/day 2-6 mg/kg/day 250-500 mg bid

*American Academy of Neurology classification of evidence: Class I: Prospective, randomized, controlled clinical trial with masked outcome assessment, in a representative population. The following are required: A. Primary outcome(s) is/are clearly defined. B. Exclusion/inclusion criteria are clearly defined. C. Adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias. D. Relevant baseline characteristics are presented and are substantially equivalent among treatment groups, or there is appropriate statistical adjustment for differences. Class II: Prospective matched group cohort study in a representative population with masked outcome assessment that meets A-D above or a randomized controlled trial in a representative population that lacks one criterion in A-D. Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population in which outcome is independently assessed or independently derived by objective outcome measurement. Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion. † Classification of effect: 0, ineffective: most patients get no improvement; +, somewhat effective: few patients get clinically significant improvement; ++, effective: some patients get clinically significant improvement; +++, very effective: most patients get clinically significant improvement. NS, not significant; NSAID, nonsteroidal anti-inflammatory drug.

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Nonepileptiform Paroxysmal Disorders and Disorders of Sleep / 53

levels and contribute to prolongation of the headache syndrome. Because the patient and family who present with the complaint of chronic daily headache are understandably concerned about the possibility of organic causes, it is critical to consider and exclude possible secondary causes for the headache. No treatment regimen will be successful until clear and confident reassurances as to the absence of serious underlying disease are provided. Breaking the cycle of chronic daily headache is the principal goal of management. Pharmacologic efforts, however, used in isolation, will be uniformly unsuccessful. Therefore, initiation of a multidisciplined approach with emphasis on preventive strategies takes precedence over the use of intermittent analgesics. This population of patients has already likely been overusing over-the-counter analgesic agents, so a fundamental change in treatment philosophy must be taught to the patient and family. An integral part of the educational process will be the incorporation of wholesale lifestyle changes, such as regulation of sleep and eating habits, regular exercise, identification of triggering factors, stress management, biofeedback-assisted relaxation therapy, and biobehavioral programs (see Box 53-7) [Rothrock, 1999]. The genesis of the chronic daily headache pattern may have its roots in psychosocial factors. Therefore, thorough social and educational history must be explored. Issues relating to life at school (e.g., bullying, learning disabilities), family conflict (e.g., parental discord, impending divorce), grief and loss (e.g., grandparent’s illness, break-up of personal relationship), drug and alcohol use, and other factors shed light on a teenager’s world that help the practitioner and patient understand some of the issues that may complicate management. For the chronic daily headache population, a group of lifestyle changes must be incorporated into the treatment plan. This maintenance of a healthy lifestyle includes the following five major components: 1. Return to the routine of adolescent “life” 2. Adequate and regular sleep 3. Regular exercise (20 to 30 minutes per day of aerobic exercise)

TABLE 53-6 Preventive Agents for the Treatment of Chronic Daily Headache in Adolescents Antidepressant Agents Amitriptyline Antiepileptic Agents Topiramate Sodium valproate

5-25 mg orally at bedtime 50-100 mg orally bid 250-500 mg orally bid 500 mg extended-release preparation

Nonsteroidal Anti-inflammatory Agents Naproxen 250-500 mg orally bid Antihypertensive Agents Propranolol

60-120 mg orally once a day

Antihistamines Cyproheptadine

2–8 mg orally divided tid, bid, or at bedtime

4. Balanced nutrition, including avoidance of skipping meals 5. Adequate fluid intake with avoidance of caffeine The pharmacologic treatment of chronic daily headaches requires an individually tailored regimen with the judicious use of appropriate prophylactic and analgesic agents. Recognizing the degree of disability helps guide the aggressiveness of the management. Unfortunately, no controlled studies have explored the pharmacologic management of chronic daily headache in children.

Preventive Therapy for Chronic Daily Headache For the population of children and adolescents with chronic daily headache, preventive therapy takes center stage and represents the mainstay of drug treatment (Table 53-6). Because the majority of children with chronic daily headache have chronic migraine or have prominent migrainous features, a modification of standard migraine therapy is appropriate, but emphasis must be placed on prevention measures rather than analgesic or abortive strategies. The one exception may be patients with a recent onset of chronic daily headache attributed almost exclusively to analgesic rebound. In this infrequent group, a trial of an analgesicfree period as noted earlier may be the sole successful treatment. Preventive therapies used for chronic daily headache include tricyclic antidepressants, antiepileptic agents, betablockers, serotonergic agents, and calcium channel blockers; however, none of these medications have been subjected to control trials and none are currently approved for the prevention of headaches in children [Redillas and Solomons, 2000]. When making the clinical decision regarding choice of pharmacologic agents, it is important to consider comorbid conditions. For the patient with difficulty falling asleep, amitriptyline at bedtime may provide dual benefits. Similarly, if there are mild-to-moderate affective issues, amitriptyline, valproic acid, or one of the selective serotonin reuptake inhibitors may be beneficial. If there is comorbid obesity, topiramate may decrease the appetite. Alternatively, if the patient’s appetite is low, valproate often stimulates the appetite.

ANTIDEPRESSANTS The tricyclic antidepressant amitriptyline has been widely used for the prevention of migraine headaches. The mechanism of action is unclear but thought to be due to a multiple reuptake inhibitor action. The agent is well tolerated in children and adolescents; its side effects are attributable to their anticholinergic effects with additional concerns of cardiac dysrhythmias. The most frequently cited side effect is sedation. To minimize the side effects, a slow taper starting at 0.25 mg/kg (5 to 10 mg) and increasing by 0.25 mg every 2 to 3 weeks until dose of 1 mg/kg (10 to 25 mg) results in a well-tolerated, effective management [Hershey et al., 2000]. Selective serotonin reuptake inhibitors have not been studied for chronic daily headache, but may have a role in those patients with comorbid depression.

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ANTIEPILEPTICS Several antiepileptic drugs have been effective in preventing adult migraine; however, very limited evidence is available for children. Topiramate, one of the newer antiepileptic drugs, has demonstrated efficacy in preventing adult and adolescent migraine [Brandes et al., 2004]. A multicenter, double-blind, placebo-controlled multidose trial included patients between the ages of 12 and 65 years with a 6-month history of International Headache Society migraine and 3 to 12 migraines per month but excluded patients with more than 15 headache days per month. A significant reduction in headache frequency was demonstrated at doses of 50 to 100 mg twice a day. Adverse events resulting in discontinuation in the topiramate groups included paresthesias, fatigue, and nausea. One retrospective study assessing the efficacy of topiramate for pediatric headache included 41 evaluable patients. Topiramate at daily doses of 1.4 (± 0.74) mg/kg/day were reached and headache frequency was reduced from 16.5 (± 10) headaches per month to 11.6 (± 10) headaches per month (P < 0.001). Mean headache severity, duration, and accompanying disability were also reduced. Side effects included cognitive changes (12.5%), weight loss (5.6%), and sensory symptoms (2.8%) [Hershey et al., 2002]. This study population was predominantly children with very frequent migraine headaches approaching the spectrum of chronic daily headache as defined by more than 15 headaches per month. The most common side effects observed included paresthesias, weight loss, and cognitive problems. The cognitive problems appear to decline with use, and can be minimized by slow taper, starting at a very low dose. This starting dose may be as low as 12.5 mg. per day, and slowly increased by 12.5 to 25 mg every 2 weeks to a dose of 50 mg twice a day [Hershey et al., 2002]. The weight loss needs to be monitored, although for the majority it does not appear to be significant. Sodium valproate is effective and approved for the prevention of migraines in adults [Mathew et al., 1995]. It is also effective for chronic daily headache and in an extendedrelease formulation [Freitag et al., 2001; 2002]. A small study of 42 patients, demonstrated that it was effective and well tolerated in 7- to 16-year-olds [Caruso et al., 2000]. Two of the side effects that may limit its use in adolescents include weight gain and the development of ovarian cysts. Gabapentin has also been used for prevention of adult headaches. It appears to be well tolerated; however, its effectiveness in children and adolescents is unknown [Mathew et al., 2001].

ANTIHISTAMINES The antihistamine cyproheptadine has been widely used for the prevention of migraine headaches in young children, but it has not been studied in chronic daily headache [Bille et al., 1977]. It tends to be very well tolerated, with its most significant side effects being sedation and weight gain, specifically limiting its tolerability in adolescents.

BETA-BLOCKERS Both propranolol and atenolol have been approved for the prevention of migraines in adults. There are conflicting data

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regarding the efficacy of propranolol for migraine in children and there are no data regarding its use in chronic daily headache. The exact dosing parameters have also not been identified. Two of its more common side effects of concern for children include exacerbation of reactive airway disease and depression. This reactive airway disease may be of special concern for the athletic adolescent who is unaware of the conditon until the combination of exercise and a betablocker results in shortness of breath.

NONSTEROIDAL ANTI-INFLAMMATORY AGENTS Naproxen sodium was shown to be effective in adolescent migraine in one small (n = 10) trial using a double-blind, placebo-controlled crossover design [Lewis et al., 1994]. Sixty percent of the patients experienced a more than 60% reduction in headache frequency and severity with naproxen 250 mg twice a day, whereas only 40% responded favorably to placebo. No adverse effects were noted in this study. Naproxen should not be used for longer than 8 weeks because of potential gastrointestinal toxicity. Naproxen is often used in conjunction with amitriptyline or topiramate. Patients are begun on a schedule of 250 to 500 mg twice a day and at the same time an evening dose of 5 to 25 mg of amitriptyline is started. After about 4 to 6 weeks, the naproxen is discontinued and the amitriptyline continued. Alternatively, naproxen is begun and topiramate titrated upward by 25 mg per week to a target dose of 50 to 100 mg twice a day. Naproxen is then discontinued after 6 to 8 weeks and topiramate continued.

Analgesic Agents for Chronic Daily Headache The use of analgesic agents for children and adolescents with chronic daily headache is controversial, particularly in view of a growing body of literature regarding analgesic overuse in children. Because the children describe continuous or near-continuous pain, it is often difficult to decide when and how to use analgesics to avoid the “slippery slope” of analgesic overuse. One approach is to map or graph the pattern of headaches to identify the epochs of intense migraine pain when it arises from the background daily pain, at which time analgesics, including the triptan agents, may be most useful. Patients with chronic daily headache are often able to report that they may have headache every waking hour, but twice a week they have an intense headache that likely represents the migraine component. Once this is teased out of the history, analgesics can be more rationally used. Analgesic overuse may be one of the leading precipitants of the phenomenon of chronic daily headache, so care must be taken not to fan the flames further with overuse. The keys for effective use include catching the migraine component of the headache as soon as it starts, using an adequate dose, and avoiding overuse.

Nonpharmacologic Measures for Chronic Daily Headache A variety of vitamins (e.g., riboflavin), minerals (e.g., magnesium), and herbal remedies (e.g., feverfew) have been attempted for prevention of headaches. Unfortunately, none of

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these remedies has been thoroughly evaluated in children with chronic daily headache but may play a role, particularly in families in which traditional pharmacologic approaches are considered unacceptable (see Box 53-7). Biofeedback-assisted relaxation training has been shown to be an effective treatment for aborting and preventing recurrent headaches in a large number of studies in children. This technique is typically taught over a multisession analysis. It is also effective in a single session with tape recordings provided for home practie [Powers et al., 2001]. It does require a degree of motivation in the child and is difficult to assess effectiveness in isolation. However, it has low side effect potential, and may provide a benefit, including moderation of stress as well as sleep-onset difficulties. Psychologic or psychiatric intervention is quite valuable if emotional comorbidity has been demonstrated [Juant et al., 2000]. In addition, if stress has been implicated as a possible migraine trigger, psychologic or psychiatric intervention, stress management, or self-hypnosis may be beneficial for chronic daily headache treatment and management. The outcome of adolescents with chronic daily headache is poorly understood. No long-term follow-up data exist. One abstracted report provides short-term follow-up of 24 adolescents with a peak age 13 years and chronic daily headache of whom greater than half experienced a more than 75% reduction in headache frequency and one third experienced a greater than 90% improvement in a 6-month follow-up. A wide variety of preventive agents were used, but amitriptyline and topiramate provided the largest proportion of successful outcomes.

Tension-Type Headache Tension-type headache may be episodic or chronic, the differentiation being a lower frequency (fewer than 15 days per month) with episodic and greater frequency (more than 15 days per month) for chronic tension-type headache. Episodic tension-type headache may be the most prevalent type of all primary headaches, but infrequently prompts referral to subspecialty clinics. Pathophysiologically, tension-type and migraine headaches may be similar, and there is a growing appreciation that the two may lie within the same spectrum, with milder, less disabling headache being tension-type and the more severe patterns being migraine. The diagnostic criteria for tension-type headache (see Box 53-3) emphasize the distinction from migraine. Generally, nausea and vomiting are not present in tension-type headache, and either photophobia or phonophobia may be present, but not both. On occasion, associated symptoms such as tiredness, sleep disturbances, and light-headedness may occur with episodic tension-type headache. The management of tension-type headache has not been rigorously studied, but simple over-the-counter analgesics are commonly used. Various agents such as acetaminophen (1000 mg), ibuprofen (400 to 600 mg), or naproxen (220-500 mg) may be very helpful. A major concern is with overuse of these types of medications. Chronic tension-type headache is often associated with a significant degree of stress and anxiety for the child and family because of the frequent, unrelenting nature of this type of headache (see “Chronic Daily Headache”).

Cranial Neuralgias Ophthalmoplegic Migraine Once classified as migraine, ophthalmoplegic migraine is now viewed as a cranial neuralgia but oddly is still called migraine. Migraine is one of the most dramatic and clinically challenging headache syndromes and, fortunately, one of the least common. Available epidemiologic data suggest an annual incidence of 0.7 per million [Hansen et al., 1990]. The two key features are ophthalmoparesis and headache, although the headache may be mild or a nondescript retro-orbital discomfort. Ptosis, adduction defects, and skew deviations are the common objective findings. The clinical course of ophthalmoplegic migraine is quite different from that of the more commonly encountered migraine with a heralding “aura.” Symptoms and signs of oculomotor dysfunction may appear well into the headache phase rather than precede the headache. The signs may persist for days or even weeks after the headache has resolved. The oculomotor nerve, or its divisions, is most frequently involved, but pupillary involvement is inconsistent and controversial. Some authors report pupillary involvement in only one third of patients [Vijayan, 1980]. The third nerve involvement may be incomplete, with partial deficits in both inferior and superior division of the third nerve. Abduction defects, due to abducens involvement, are the second most frequent reported variants of ophthalmoplegic migraine, and trochlear nerve involvement is the least common. The mechanism of ophthalmoplegic migraine is controversial. The primary theories suggest ischemic, compressive, or inflammatory processes [Stommel et al., 1994]. Lack of pupillary involvement argues for an ischemic mechanism, whereas a higher incidence of pupillary involvement weighs toward a compressive mechanism. Alternatively, recent reports have questioned whether ophthalmoplegic migraine may be an inflammatory process within the spectrum of Tolosa-Hunt syndrome, particularly given the steroid responsiveness of many patients. Furthermore, high-resolution neuroimaging has demonstrated a reversible enhancement and even thickening of the oculomotor nerve during attacks, which lends further credence to an inflammatory mechanism [Mark et al., 1998]. The most recent International Headache Society classification comments that ophthalmoplegic migraine may be a recurrent demyelinating neuropathy. The differential diagnosis for ophthalmoplegic migraine includes aneurysm or mass lesion in or around the orbital apex and parasellar region. Imaging study with MRI or magnetic resonance angiography is usually indicated. Repeated attacks of ophthalmoplegic migraine can lead to permanent deficits; therefore, acute treatment with steroids and prophylactic treatment must be considered. Occipital neuralgia is characterized by a stabbing pain in the upper neck or occipital region, often precipitated by neck flexion or head rotation. It may occur posttraumatically. Examination of the craniocervical region may disclose point tenderness, C-2 distribution sensory changes, or limitation of motion. MRI of the craniocervical junction is warranted to exclude congenital or pathologic processes.

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Treatment includes soft collars, nonsteroidal antiinflammatory drugs (naproxen), muscle relaxants, local injections, and physical therapy. The prognosis is good. A similar entity is neck-tongue syndrome, wherein head movements trigger occipital pain accompanied by ipsilateral tongue numbness. Again, craniocervical anomalies must be sought, though the majority of children and adolescents have not demonstrated abnormalities, and it occasionally occurs in families.

Cluster Headache Cluster headache is uncommon in children and adolescents. The prevalence of childhood onset of cluster is approximately 0.1% [Lampl, 2002]. The diagnostic criteria require at least five attacks of severe unilateral orbital pain lasting 15 to 180 minutes with a sense of restless agitation accompanied by ipsilateral conjunctival injection, lacrimation, nasal congestion, rhinorrhea, eyelid edema, forehead sweating, miosis, or ptosis. Cluster headaches may be episodic or chronic, and attacks occur in series that last for weeks or even months. A cluster headache may be precipitated by alcohol, histamine, or nitroglycerin. Males are three times more likely to be affected than females. Management is difficult. Acute treatments include inhalation of 100% oxygen at 8 to 10 L/minute for 10 to 15 minutes through a nonrebreathing facemask; sumatriptan 6 mg subcutaneous injections or 20 mg intranasally; and intravenous, intramuscular, or subcutaneous injections of dihydroergotamine, 0.5 to 1 mg, at headache onset. Prophylactic medications useful in preventing attacks during cluster cycles include verapamil, sodium valproate, lithium carbonate, methysergide, and ergotamine tartrate [Newman et al., 2001].

Paroxysmal Hemicrania Paroxysmal hemicrania is a cluster-like syndrome characterized by intense attacks of periorbital pain lasting only 5 to 30 minutes but occurring up to dozens of times per day. In distinction to cluster headache, there are no accompanying autonomic symptoms of lacrimation or rhinorrhea. One of the most striking features is the exquisite responsiveness to indomethacin (25 to 50 mg/day), which has prompted the alternative nosology, “indomethacinsensitive” headache.

Temporomandibular Joint Dysfunction Temporomandibular joint dysfunction manifests with unilateral pain just anterior or inferior to the ear. The pain is aggravated by chewing, teeth clenching, or yawning. Patients may describe a clicking or locking of their jaw. Family members may describe bruxism, and there may be antecedent trauma. Examination reveals tenderness over the temporomandibular joint and limitation of mouth opening. Treatment includes nonsteroidal anti-inflammatory drugs, muscle relaxation, and avoidance of provocative processes like chewing gum or hard candy. Major oral surgery is rarely necessary.

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SPECIFIC SECONDARY HEADACHE SYNDROMES Post-traumatic Headache Headache following closed-head injury or neck trauma in children is one of the most common secondary headache syndromes but has not been systematically studied. No epidemiologic data are available. Post-traumatic headache is divided into acute and chronic patterns based on duration of symptoms, less than 3 months being acute, and greater than 3 months being chronic. Acute post-traumatic headache must immediately raise concerns for traumatic brain injury such as cerebral hematoma (subdural or epidural), subarachnoid hemorrhage, cerebral contusion, or skull fracture and warrant urgent neuroimaging, particularly if associated with alteration of consciousness, seizures or Glasgow Coma Scale less than 13. Cerebrospinal fluid leaks following meningeal tears can lead to positional, or “low pressure” headaches. Post-traumatic headache may arise within hours or up to a week after head injury, and the clinical manifestations are quite variable. “Footballer’s migraine” may occur immediately after relatively minor head trauma that occurs playing sports such as soccer or football, and may happen after accidental head injury. The clinical features of confusion, language disorders, and agitation are discussed in earlier sections of this chapter (see “Confusional Migraine”). Chronic post-traumatic headache may be part of a global postconcussive syndrome with behavioral changes (e.g., hyperactivity, hypoactivity), dizziness, tinnitus, vertigo, blurred vision, memory changes, sleep disorder, irritability, and attentional disorders. The duration of symptoms is variable, with some patients having brief, self-limited syndromes, others suffering from headaches for greater than 6 months. One retrospective study of 23 children with chronic post-traumatic headache found a mean duration of 13.3 months (range 2 to 60 months, median 7 months) [Callaghan, 2001]. The headache forms span the spectrum from tension-type, migraine, chronic daily headache, neuralgias (e.g., occipital neuralgia), temporomandibular joint, and on rare occasions, cluster headache. Many athletes competing in contact sports experience posttraumatic headache as part of a postconcussion syndrome. A common question is when it is safe to return to a full-contact sport. Two organizations, the American Academy of Neurology and the American College of Sports Medicine, have provided guidelines regarding return to activities, which range from 1 to 4 weeks [American College of Sports Medicine, 1991; Quality Standards Subcommittee, American Academy of Neurology, 1997]. Both guidelines are available online. The management of post-traumatic headache requires an appreciation of the degree of disability produced by the headache. Post-traumatic tension-type headaches can generally be managed with nonsteroidal anti-inflammatory agents such as ibuprofen or naproxen sodium. Posttraumatic migraine is treated as discussed earlier with a balance of analgesic or triptan agents and, if warranted, daily preventive therapies. For patients with frequent or daily headaches, the management strategies in the chronic daily headache discussion apply with daily preventive programs, both pharmacologic and nonpharmacologic, as well as analgesics, for episodes of intense pain.

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There are no outcome data on post-traumatic headache in children and adolescents, but typically, 3 to 6 months is the anticipated course of recovery. If the post-traumatic headache syndrome is associated with pending “personal injury” litigation, stress levels and compensation issues may contribute to prolongation of the headache syndrome.

Idiopathic Intracranial Hypertension Also known as pseudotumor cerebri, idiopathic intracranial hypertension produces a global, daily, pounding headache and is an important consideration in the differential diagnosis of chronic daily headache. The incidence of idiopathic intracranial hypertension is 3.5 to 19 per 100,000 population; the majority of sufferers are female. Neck stiffness (30% to 59%) and transient visual disturbances may be present. The key finding on physical examination is papilledema. Neuroimaging will likely be normal. The pathogenesis of idiopathic intracranial hypertension is unclear but somehow involves impairment of cerebrospinal reabsorption. Idiopathic intracranial hypertension can be caused by multiple disorders including endocrinopathies (e.g., hypothyroidism, Addison’s disease, oral steroids), pregnancy, drugs (e.g., tetracycline, oral contraceptive agents), vitamin A intoxication, anemia, systemic lupus erythematosus, chronic sinopulmonary infection, and obesity, or it may be idiopathic. Other secondary headaches that present with chronic daily headache include intoxications of lead or other heavy metals, chronic carbon monoxide poisoning, chronic meningitis with such pathogens as tuberculosis, fungi, or spirochetal syphilis and Lyme disease. A chronic daily pattern can also be seen with central nervous system leukemia or lymphoma or leptomeningeal metastasis. Rarely, diffuse “butterfly” gliomatosis of the brain can produce this picture, but cognitive decline and pyramidal tract signs would be expected. Uncontrolled hypertension can lead to optic disc changes with headache, but this would be uncommon during adolescence. Chronic sinusitis or venous sinus thrombosis can also produce a pattern of slowly increasing intracranial pressure with normal computed tomography scan. The diagnostic test of choice for idiopathic intracranial hypertension is lumbar puncture with measurement of opening pressure. Given a normal computed tomography scan, the test can be accomplished safely even though the examination shows a fifth nerve palsy because this can be a “false localizing” sign, indicative of diffuse increase in intracranial pressure. The mechanism is likely compressive, though some degree of ischemia to the fifth nerve can occur in this setting. The normal cerebrospinal fluid opening pressure is less than 180 mm of water; in idiopathic intracranial hypertension, the opening pressure will exceed 200 mm of water, often exceeding 400 mm of water. Cerebrospinal fluid must be collected for glucose, protein, cell counts, and bacterial cultures. Neuroborreliosis can mimic idiopathic intracranial hypertension, so polymerase chain reaction studies for Lyme disease may be indicated. If cerebrospinal fluid pleocytosis is found, cultures (fungal and tuberculosis) and special studies for detection of fungi (cryptococcal antigen), syphilis, and cytopathology may be considered. Not only does the lumbar puncture yield critical diagnostic information, but the relief of pressure also usually provides significant decrease in headache symptoms. The

volume of cerebrospinal fluid to be removed is controversial. Generally, removal of sufficient volume to lower the pressure down to about 200 mm of water is valid and safe. Care must be taken to limit the risk of post–lumbar puncture headache by keeping the patient recumbent for several hours after the lumbar puncture. Once the diagnosis is established, the carbonic anhydrase inhibitor acetazolamide can be used to lower cerebrospinal fluid pressures, probably by a diuretic mechanism. The side effects are few and include paresthesias, polyuria, and sedation. The dose is typically 250 mg twice a day up to 1000 mg per day. There is a once daily preparation available. The recovery is slow, taking weeks or months. If obesity is a contributing factor, a weight loss program is recommended. If the visual symptoms are severe, progressive, or if there is visual compromise, ophthalmologic intervention may be necessary with performance of an optic nerve sheath fenestration.

Brain Tumor Headache About two thirds of children with brain tumors have headache as a presenting symptom. There is, however, no invariable “brain tumor headache” profile. A steady, gradual rise in intracranial pressure typically produces the chronic progressive pattern, but on occasion an anaplastic tumor or hemorrhage into tumor may cause an acute pattern (see Fig. 53-1). Several historical clues suggest space-occupying lesions such as brain tumors, but these clues may also be present in other expanding masses such as brain abscess, hematoma, or vascular anomaly. Morning headache or headaches that awaken the child from sleep are classic symptoms of the dependent edema of intracranial lesions. Likewise, nocturnal or morning emesis, with or without headache, suggests increased intracranial pressure and is a particularly common symptom of tumors arising near the floor of the fourth ventricle. Head pain aggravated by exertion or Valsalva’s maneuver suggests a mass lesion. In addition to headache, parents may note behavioral or mood changes, cognitive changes, or declining school performance. Accompanying symptoms may suggest localized disturbances of neurologic function. Ocular symptoms are common: loss of vision (e.g., craniopharyngioma, optic pathway tumors) or diplopia (e.g., brainstem glioma, medulloblastoma). Disorders of coordination such as truncal ataxia (e.g., medulloblastoma, ependymoma) or dysmetria (e.g., cerebellar astrocytoma) suggest posterior fossa tumors. The presence of seizures indicates cortical disturbances often localized to the temporal lobes. The key physical examination signs that indicate brain tumor include the following: Papilledema Abnormal eye movements Hemiparesis Ataxia (truncal or appendicular) Abnormal tendon reflexes [The Childhood Brain Tumor Consortium, 1991] As stated in the American Academy of Neurology practice parameter, neuroimaging (MRI or CT) is appropriate for children with headache in whom there are historical features or recent onset of severe headache, a change in the type of

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Mannix LK, Frame JR, Soloman GD. Alcohol, smoking and caffeine use among headache patients. Headache 1997;37:572. Mark AS, Casselman J, Brown D, et al. Ophthalmoplegic migraine: Reversible enhancement and thickening of the cisternal segment of the oculomotor nerve on contrast-enhanced MR images. Am J Neuroradiol 1998;9:1887. Mathew NT, Kurman R, Perez F. Drug-induced refractory headache—Clinical features and management. Headache 1990;30:634. Mathew N, Rapoport A, Saper J, et al. Efficacy of gabapentin in migraine prophylaxis. Headache 2001; 41:119. Mathew N, Saper J, Siberstein S, et al. Migraine prophylaxis with divalproex. Arch Neurol 1995;52:281. Miller GS. Efficacy and safety of levetiracetam in pediatric migraine. Headache 2004;44:238. Miller V, Palermao T, Powers S, et al. Migraine headaches and sleep disturbances in children. Headache 2003;43:362. Millichap J, Yee M. The diet factor in pediatric and adolescent migraine. Pediatr Neurol 2003;28:9. Mortimer MJ, Kay J, Jaron A. Epidemiology of headache and childhood migraine in an urban general practice using ad hoc, Vahlquist and IHS criteria. Dev Med Child Neurol 1992;34:1095. Newman L, Goadsby P, Lipton R. Cluster and related headaches. Med Clin North Am 2001;85:997. Olesen J. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgia, and facial pain. Cephalgia 1988;8(Suppl 7): 1. Oleson J. The international classification of headache disorders. Cephalalgia 2004;24(Suppl 1): 1. Olness K, MacDonald JT, Uden DL. Comparison of self-hypnosis and propranolol in the treatment of juvenile classic migraine. Pediatrics 1987;79:593. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Involvement of a Ca2+ channel gene in familial hemiplegic migraine and migraine with and without aura. Headache 1997;37:479. Pietrobon D, Striessnig J. Neurobiology of migraine. Nature Revs 2003;4:386. Powers S, Mitchell M, Byars K, et al. Effectiveness of one-session biofeedback training in a pediatric headache center: A pilot study. Neurology 2001;56:133. Powers S, Patton S, Hommel K, Hershey A. Quality of life in childhood migraine: Clinical aspects and comparison to other chronic illness. Pediatrics 2003;112:e1. Powers S, Patton S, Hommell K, Hershey A. Quality of life in paediatric migraine: Characterization of age-related effects using PedsQL 4.0. Cephalalgia 2004;24:120. Prensky AL, Sommer D. Diagnosis and treatment of migraine in children. Neurology 1979;29:506. Quality Standards Subcommittee, American Academy of Neurology. Practice parameter. The management of concussions in sports. Neurology 1997;48:581. Redillas C, Solomons S. Prophylactic pharmacological treatment of chronic daily headache. Headache 2000;40:83. Reimschisel T. Breaking the cycle of medication overuse headache. Contemp Pediatr 2003;20:101. Rho JM, Chugani HT. Alternating hemiplegia of childhood: Insights into its pathogenesis. J Child Neurol 1998;13:39.

Rothner A, Guo Y. An analysis of headache types, over-the-counter (OTC) medication overuse and school absences in a pediatric/adolescent headache clinic. Headache 2004;44:490. Rothner AD. Miscellaneous headache syndromes in children and adolescents. Semin Pediatr Neurol 1995;2:159. Rothrock J. Management of chronic daily headache utilizing a uniform treatment pathway. Headache 1999;39:650. Serdaroglu G, Erhan E, Tekgul, et al. Sodium valproate prophylaxis in childhood migraine. Headache 2002;42:819. Silberstein S. Migraine. Lancet 2004;31:381. Silberstein SD. Practice parameter: Evidence-based guidelines for migraine headache (an evidence-based review). Neurology 2000;55:754. Sillanpaa M. Prevalence of migraine and other headache in Finnish children starting school. Headache 1976;15:288. Sillanpaa M. Changes in the prevalence of migraine and other headache during the first seven school years. Headache 1983;23:15. Small P, Waters WE. Headache and migraine in a comprehensive school. In: Waters, ed. The epidemiology of migraine. Bracknell-Berkshire, England: Boehringer Ingel-helm, Ltd., 1974;56. Snyder CH. Paroxysmal torticollis in infancy. A possible form of labyrinthitis. Am J Dis Child 1969;117:458. Stang P, Yanagihar P, Swanson J, et al. Incidnece of migraine headache: A population based study in Olmsted County, Minn. Neurology 1992;42: 1657. Stewart WF, Linet MS, Celentano DD, et al. Age and sex-specific incidence rates of migraine with and without visual aura. Am J Epidemiol 1991;34:1111. Stewart WF, Lipton RB, Celentano DD, Reed ML. Prevalence of migraine headache in the United States. JAMA 1992;267:64. Stommel EW, Ward D, Harris R, et al. Ophthalmoplegic migraine or Tolosa-Hunt syndrome? Headache 1994;34:177. Swoboda KJ, Kanavakis E, Xaidara A, et al. Alternating hemiplegia of childhood or familial hemiplegic migraine? A novel ATP1A2 mutation. Ann Neurol 2004;55:884. Ueberall M. Sumatriptan in paediatric and adolescent migraine. Cephalalgia 2001;21(Suppl 1):21. Valquist B. Migraine in children. Int Arch Allergy 1955; 7:348. Van den Bergh V, Amery W, Waelkens J. Trigger factors in migraine: A study conducted by the Belgian Migraine Society. Headache 1987;27:191. Verret S, Steele JC. Alternating hemiplegia in childhood: A report of eight patients with complicated migraine beginning in infancy. Pediatrics 1971;47:675. Victor S, Ryan S. Drugs for preventing migraine headaches in children. Cochrane Database System Reviews 2003;4:CD 002761. Vijayan N. Ophthalmoplegic migraine: Ischemic or compressive neuropathy? Headache 1980;20:300. Viswanathan V, Bridges SJ, Whitehouse W, et al. Childhood headaches: Discrete entities or continuum? Dev Med Child Neurol 1998;40:544. Winner P, Rothner AD, Saper J, et al. A randomized, double-blind, placebo-controlled study of sumatriptan nasal spray in the treatment of acute migraine in adolescents. Pediatrics 2000;106:989. Zwart JA, Dyb G, Holmen TL, et al. The prevalence of migraine and tension-type headaches among adolescents in Norway. The Nord-Trondelag Health Study (Head-HUNT-Youth), a large population-based epidemiological study. Cephalalgia. 2004;24:373.

CHAPTER 54

Breath-Holding Spells and Reflex Anoxic Seizures Sarah M. Roddy

Breath-holding spells and reflex anoxic seizures are nonepileptic paroxysmal events. The events are benign but can be frightening to parents and others observing an episode. It is important to differentiate these episodes from epileptic seizures so that the child is not inappropriately treated with antiepileptic medication. Possibly the earliest report of breath-holding spells was published in 1737 by Nicholas Culpepper, who gave the following description: There is a disease … in children from anger or grief, when the spirits are much stirred and run from the heart to the diaphragms forceably, and hinder or stop the breath … but when the passion ceaseth, this symptom ceaseth.

The clinical characteristics were well recognized and described in the pediatric literature in the 19th and early 20th centuries. More recent reports have provided a better understanding of the pathophysiology of these events.

BREATH-HOLDING SPELLS Clinical Features The term breath holding is a misnomer and implies that the child is voluntarily holding his or her breath in a prolonged inspiration. Breath-holding episodes actually occur during expiration and are involuntary. Breath-holding spells are not uncommon, with an incidence of 4.6% to 4.7% [Linder, 1968; Lombroso and Lerman, 1967]. The typical age of onset is between 6 and 18 months, although occasionally the onset may occur in the first few weeks of life [Breukels et al., 2002]. Less than 10% have onset after 2 years of age [DiMario, 1992]. The frequency of episodes ranges from several times daily to once yearly. The spells are often spaced weeks to months apart at onset and increase in frequency to as many as several per day during the second year of life [Laxdal et al., 1969; DiMario, 2001]. Breathholding spells are classified by the color change manifested in the child during an event. Cyanotic episodes are more common than pallid episodes. In some instances, there are features of both cyanosis and pallor, and these are termed mixed episodes. Cyanotic breath-holding spells are often precipitated by emotional stimuli, such as anger or frustration. The child typically cries vigorously but usually for less than 15 seconds, then becomes silent, and holds the breath in expiration. The apnea is associated with the rapid onset of cyanosis. Some episodes may resolve at this point, but there may be loss of consciousness and a brief period of limpness followed by opisthotonic posturing. Recovery is usually within 1 minute, with the child having a few gasping

respirations and then a return to regular breathing and consciousness. Pallid breath-holding spells are usually provoked by sudden fright or pain. A fall with a minor injury to the head is frequently the precipitating event. An unexpected event or a surprise seems to play a role in triggering the spell. Sometimes the provoking event is not witnessed, and the child is found already in an episode. The child may gasp and cry, although it is usually for only a brief period of time. The child then becomes quiet, loses consciousness, and becomes pale. Limpness and diaphoresis are common. Clonic movements of the extremities and incontinence may occur with more severe episodes. Cyanosis may occur during the episode but is much milder than with cyanotic breath-holding spells. The child typically regains consciousness in less than 1 minute but may sleep for several hours after the episode. An association between behavior problems, emotional factors, and breath-holding spells has been discussed by many investigators. Breath-holding spells were described by Abt [1918] as occurring in “neuropathic children of neuropathic parents.” Bridge and colleagues [1943] stated that children susceptible to breath holding are usually of the active energetic type who react vigorously to situations and that episodes were precipitated by “spoiled child reactions.” Breath-holding spells were felt to be a sign of a disturbed parent-child relationship by Kanner [1935]. Laxdal and associates [1969] reported that 30% of the children with breath-holding spells had abnormal behavior, including temper tantrums, hyperactivity, and stubbornness. To further investigate the role of behavior and breath holding, DiMario and Burleson [1993b] studied behavior in children with breath-holding spells compared with controls and found no differences in the behavioral profiles, suggesting that breathholding spells are nonvolitional and cannot be equated with a temperamentally difficult child. Breath-holding spells generally decrease in frequency during the second year of life. By 4 years of age, 50% of children will no longer have episodes. Almost all will have stopped having episodes by age 7 to 8 years [DiMario, 1992: Goraya and Virdi, 2001]. Syncopal episodes occur in late childhood or adolescence in as many as 17% of patients with breath-holding spells [Lombroso and Lerman, 1967]. Serious complications with breath-holding spells are rare. Taiwo and Hamilton [1993] reported a prolonged cardiac arrest in a patient with breath-holding spells. The few reported deaths may have been precipitated by aspiration or occurred in children who were at the severe end of the spectrum of breath holders, often with structural abnormalities of the respiratory tract or complicated medical histories [Paulson, 1963; Southall et al., 1987; 1990].

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Clinical Laboratory Tests A detailed history of the event, including the precipitating circumstances, is essential in making the diagnosis of breath-holding spells. If the event was not witnessed from onset, important details may not be available. A video recording by the parents may be helpful in confirming the diagnosis. Usually no laboratory tests are needed to make the diagnosis. An electroencephalogram (EEG) is usually not indicated unless the convulsive activity is prolonged or the clinical description is incomplete and epileptic seizures cannot be ruled out. If ocular compression is performed in patients with pallid breath-holding spells, there may be asystole on cardiac monitoring and slowing or suppression of voltage on EEG [Lombroso and Lerman, 1967; Stephenson, 1978]. Long-QT syndrome is rare but should be considered as part of the differential diagnosis in a child with breath-holding spells. Patients with long-QT syndrome have episodes of loss of consciousness that may be induced by injury, fright, or excitement. An electrocardiogram should be considered in any patient with breath-holding spells [Breningstall, 1996; Franklin and Hickey, 1995].

Pathophysiology Cyanotic Spells The pathophysiology of cyanotic breath-holding spells is complex and not completely understood. Cyanosis occurs early in the episode, which is unusual during voluntary breath holding. In breath-holding spells, the breath is held in full expiration, which also is not typical with voluntary breath holding [Livingston, 1970]. Gauk and colleagues [1963] studied a child during a cyanotic breath-holding episode with cinefluorography and noted the diaphragm to be high, as would be seen in full expiration, and motionless during the period of apnea. Peiper [1939] studied a child during intentionally precipitated breath-holding spells and noted small periodic movements of the diaphragm during the expiratory apnea without corresponding effects on pulmonary ventilation or the degree of cyanosis, indicating that spasm of the glottis occurred as part of the generalized rigidity. Spasm of the glottis and respiratory muscles with increased intrathoracic pressure occurs during expiration. Increased intrathoracic pressure reduces cardiac output, causing a decrease in cerebral perfusion. Lombroso and Lerman [1967] suggested that violent crying could lead to hypocapnia, which would also impair cerebral circulation. Southall and associates [1985] further evaluated the prolonged expiratory mechanism in nine infants with cyanotic episodes that were usually triggered by noxious stimuli. Arterial oxygen saturation fell below 20 mm Hg within 20 seconds. Loss of consciousness occurred after 30 seconds. Measurements of respiratory movements, airflow, and esophageal pressure and, in some patients, microlaryngoscopy and chest fluoroscopy were obtained. They documented no inspiratory flow during the period of apnea but continued expiratory muscle activity at low lung volumes with partial or complete glottic closure. No intracardiac shunt could be demonstrated. The rapid fall in arterial oxygen saturation was attributed to lack of ventilation at a maximum expiratory position in the presence of

a rapid circulation time. They hypothesized that central and peripheral neural respiratory control was functioning normally but was interfered with by a mechanical defect involving lung-volume maintenance. This defect could occur because of an excessively compliant rib cage, allowing alveolar collapse. This collapse in turn could lead to stretching of the airways and their stretch receptors, inappropriately simulating maximum lung volumes and thereby inhibiting inspiration. Southall and colleagues [1990] did further evaluations of prolonged expiratory apnea with krypton infusion scans and demonstrated krypton outside the lung fields, without evidence of an intracardiac shunt. They felt there was intrapulmonary shunting that contributed to the rapid onset and severity of the hypoxemia. The relation between breath holding and chemosensitivity has also been investigated. Anas and associates [1985] hypothesized that persons with cyanotic breath-holding episodes have blunted ventilatory chemosensitivity. Because of the difficulty of measuring chemosensitivity in toddlers, they measured ventilatory responses to progressive hypercapnia and to progressive hypoxia in subjects ages 11 to 50 who had a history of cyanotic breath-holding spells and compared the results with a control group. Contrary to their hypothesis, the majority of persons with a history of cyanotic breath-holding spells had normal ventilatory responses. However, no one with a history of breath-holding spells had high normal responses to hypercapnia or hypoxia, as did some individuals in the control group. They postulated that the difference between the groups might represent the vestige of a disorder of ventilatory chemosensitivity that resolved with maturation. Kahn and colleagues [1990] also investigated the relation between breath holding and cardiorespiratory control. The study included 71 infants with a history of breath-holding spells and age- and gender-matched controls. The median age of infants in the study was 14 weeks, which is younger than the typical age for onset of breath-holding episodes. The infants with breath-holding spells were significantly more often covered with sweat during sleep and wakefulness compared with control infants. One-night sleep studies were obtained in each infant. The infants with breathholding spells had significantly less non–rapid eye movement stage III sleep, more indeterminate sleep, more arousals, and more sleep-stage changes than the control infants. Airway obstructions during sleep occurred in 41 infants with a history of breath holding compared with 6 in the control group. The obstructions were generally short and not accompanied by significant bradycardia or oxygen desaturation. They concluded that there was a common underlying mechanism resulting in airway obstruction during breath-holding spells and sleep, which possibly involved the autonomic nervous system because the autonomic nervous system controls the patency of the upper airways. Kohyama and associates [2000] did polysomnography to evaluate rapid eye movement sleep in seven children with breath-holding spells and nine normal age-matched controls. The children with breath-holding spells had a significant decrease in ocular activity during rapid eye movement sleep, especially during the last third of the night, compared with the controls. Relative elevation of cholinergic tone compared with monoaminergic tone is considered to be involved in the physiologic increase of rapid eye

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movement sleep in the later cycles of the night. The vestibular nucleus and the medioventral caudal pons are believed to be involved in bursts of eye movements during rapid eye movement sleep. They hypothesized that there was a functional disturbance in the pons of children with breathholding spells. The study also suggests that the autonomic nervous system is involved because of the more pronounced decrease in eye movement in the later cycles of the night, which are regulated by the autonomic nervous system. DiMario and Burleson [1993a] used noninvasive methods to evaluate autonomic nervous system function in children with severe cyanotic breath-holding spells. Compared with controls, the breath holders had a significantly greater increase in pulse rate at 15 seconds of standing after rising from the supine position. Breath holders also had a greater decrease in diastolic blood pressure without an increase in systolic blood pressure after standing from the supine position. These results suggest that there is autonomic dysregulation in children with cyanotic breath-holding spells. Based on the results of this study and prior studies, DiMario and Burleson postulated that in addition to evidence of parasympathetic excess, children with cyanotic breath holding exhibit subtle sympathetic excess, which mediates vascular resistance, arterial distensibility, and blood flow through the lungs. This sympathetic overactivity could cause the intrapulmonary shunting and subsequent hypoxemia [Southall et al., 1990].

Pallid Spells Excessive vagal tone leading to cerebral hypoperfusion is the underlying cause of pallid breath-holding spells. Observation of children during a typical episode reveals marked bradycardia or asystole [Bridge et al., 1943]. Ocular compression that triggers the oculocardiac reflex has been used to evaluate vagal tone in children with breath holding [Lombroso and Lerman, 1967; Stephenson, 1978]. This maneuver results in transmission of afferent signals to the brainstem via the ophthalmic division of the trigeminal nerve and efferent parasympathetic signals via the vagus nerve. In 61% to 78% of children with pallid breath-holding spells, ocular compression resulted in asystole of 2 seconds or longer compared with 23% to 26% of children with cyanotic breath-holding spells [Lombroso and Lerman, 1967; Stephenson, 1978]. Episodes that occurred spontaneously during cardiac monitoring were also associated with asystole [Lombroso and Lerman, 1967; Maulsby and Kellaway, 1964]. The asystole during spontaneous episodes is believed to be vagally mediated. When asystole is prolonged, a reflex anoxic seizure may occur. The role of underlying autonomic dysfunction in children with pallid breath-holding spells has been investigated in a small number of patients. Measurements of mean arterial pressures, pulse rates, electrocardiograms, and plasma norepinephrine levels were obtained in patients and controls during changes in position. The breath holders had a statistically significant decrease in mean arterial pressure and an unsustained increase in pulse rate during the prone to standing maneuver. One child with pallid breath-holding spells had a plasma norepinephrine level that was 60% below the mean for both groups [DiMario et al., 1990]. Further evaluation of autonomic function was performed in

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children with either pallid or cyanotic breath-holding spells. Respiratory sinus arrhythmia, which is an established measure of vagal tone, was measured. There were no significant differences between controls and children with cyanotic breath-holding spells. The children with pallid spells, however, had a marked difference in respiratory sinus dysrhythmia with less variability compared with controls and those with cyanotic episodes [DiMario et al., 1998]. These studies suggest that there may be an underlying parasympathetic dysregulation in children with pallid breathholding spells. The role of anemia in the pathophysiology of breathholding spells was suggested by Holowach and Thurston [1963]. They found that 23.5% of 102 children with breath holding had a hemoglobin level less than 8 grams/100 mL compared with 7% and 2.6% in two control groups. Subsequent studies did not find any significant difference in hemoglobin levels in the breath-holding group compared with the control group [Laxdal et al., 1969; Maulsby and Kellaway, 1964]. There are reports of children with breathholding spells and concomitant anemia who had resolution of their spells with correction of the anemia [Bhatia et al., 1990; Colina and Abelson, 1995; DiMario, 1992; Mocan et al., 1999; Orii et al., 2002]. Tam and Rash [1997] described a child with pallid breath-holding spells associated with transient erythroblastopenia of childhood. The spells resolved after treatment with iron but before the anemia resolved. Daoud and colleagues [1997] studied 67 children with breath-holding spells to investigate the effect of iron therapy. Treatment and placebo groups were similar in respect to gender, age at onset, and frequency and type of spells and had similar blood indices, including packed cell volume, mean corpuscular volume, saturation index, total iron binding capacity, and serum iron. At the end of the treatment period, 51.5% of the children treated with ferrous sulfate had complete remission of spells and an additional 36.4% experienced a greater than 50% reduction. No children in the placebo group had total remission of spells, and only 5.9% had a greater than 50% reduction. As expected, the treatment group experienced significant improvement in the hemoglobin level and total iron-binding capacity. However, some children who were not iron deficient had a favorable response to iron therapy and some who were iron deficient did not respond. Iron deficiency may play a role in the pathophysiology of breath-holding spells because iron is important for catecholamine metabolism and neurotransmitter function [Daoud et al., 1997].

Genetics In children with breath-holding spells, there is a positive family history of similar episodes in 23% to 38%, suggesting a genetic influence [Laxdal et al., 1969; Lombroso and Lerman, 1967]. An evaluation of family pedigrees found that 27% of 114 proband parents and 21% of proband siblings had a history of breath holding. Several families had some members with pallid spells and other members with cyanotic spells. The male-to-female ratio was 1:1.2 and the risk of transmission from parent to child was 50:50. There were seven instances of father-to-son transmission, ruling out an X-linked inheritance. Using a regression model for pedigree analysis, the inheritance pattern was consistent

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with an autosomal-dominant pattern with reduced penetrance [DiMario and Sarfarazi, 1997].

Treatment The most important aspect of treatment of breath-holding spells is to reassure the family of the benign nature of the spells. It is important to emphasize that the episodes do not lead to mental retardation or epilepsy. Although parents are inclined to pick up a child who is having a breath-holding spell, they should be instructed to place the child in a lateral recumbent position so as not to prolong the period of cerebral anoxia. Initiation of cardiopulmonary resuscitation should be avoided. Although anger and frustration are often precipitants for breath-holding spells, parents should be encouraged not to alter customary discipline for fear of triggering an episode [DiMario, 1992]. Parenting a child with breath-holding spells has been associated with more maternal stress than parenting a child with a convulsive seizure disorder, and parents of children with breath-holding spells are at risk for developing dysfunctional parenting behaviors [Mattie-Luksic et al., 2000]. Referral of parents to professionals to help with stress and parenting skills should be considered. Treatment with iron therapy should be initiated in any child who has iron deficiency anemia and should be considered in any child with breath-holding spells because children without anemia may have improvement in their breath-holding spells. The convulsive movements seen during breath-holding spells are reflex anoxic seizures, which are not epileptic and do not require antiepileptic treatment. There have been a few patients who have been reported to have prolonged seizures and even status epilepticus from breath-holding spells [Emery, 1990; Kuhle et al., 2000; Moorjani et al., 1995; Nirale and Bharucha, 1991]. It is presumed that these patients have a lowered seizure threshold and that hypoxia-ischemia triggered the seizures [Emery, 1990]. Stephenson [1990] has termed these events anoxicepileptic seizures. Treatment with antiepileptic medication may stop the seizure activity but not the breath-holding spells. Atropine (0.01 mg/kg two or three times daily) is effective for pallid breath-holding spells, but its use is rarely warranted [McWilliam and Stephenson, 1984; Stephenson, 1980]. Piracetam, which has a chemical structure similar to γaminobutyric acid, has been used to treat children with breath-holding spells. In a study of 76 children with breathholding spells, treatment with piracetam for 2 months resulted in 92% having no recurrence of episodes for 6 months after treatment compared with 30% who received placebo [Donma, 1998]. Piracetam has not received approval from the U.S. Food and Drug Administration and is designated only as an orphan drug for use in myoclonus.

REFLEX ANOXIC SEIZURES Reflex anoxic seizures are nonepileptic events resulting from cardiac asystole of vagal origin [Stephenson, 1990, 2001]. Pain and surprise are common provoking factors for the events [Stephenson, 1980]. Reflex anoxic seizures may occur with pallid breath-holding spells but also have been

reported with minor blows to the occiput, expelling hard stools past an anal fissure, venipuncture, intramuscular injections, and seeing an intravenous scalp drip [Braham et al., 1981; Gordon, 1982; Lombroso and Lerman, 1967; Roddy et al., 1983; Stephenson, 1980]. Nonepileptic anoxic seizures may also occur after syncope, cyanotic breathholding spells, or any event that results in a sudden reduction in cerebral perfusion or hypoxia.

Clinical Features Reflex anoxic seizures occur a few seconds after the provocation and are characterized by loss of muscle tone initially and later by tonic posturing. There may be opisthotonic posturing in some patients. A few jerks at the onset and end of an anoxic seizure may occur and probably represent myoclonic phenomena. A snoring type of inspiration or snort occurring close to the restoration of the cardiac rhythm is often noted. Urinary incontinence happens in approximately 10% of children with anoxic seizures, with bowel incontinence occurring less commonly [Stephenson, 1990]. Other less common features include adversive head movements, limb quivering or twitching, agitation or fear, vomiting, and tongue biting. The color change seen with an anoxic seizure may be cyanosis or pallor, depending on the mechanism producing loss of consciousness. The duration of unconsciousness is almost always less than 1 minute. Most patients experience a rapid recovery of consciousness, but some will be dazed or disoriented for a short period. Some will be drowsy after an episode and may sleep [Stephenson, 1990]. Occasionally patients will have prolonged seizure activity after syncopal spells. These events, termed anoxicepileptic seizures, are epileptic seizures triggered by hypoxia in patients with a lowered seizure threshold [Stephenson, 1990].

Pathophysiology The mechanism of reflex anoxic seizures has been studied by using ocular compression with EEG and cardiac monitoring [Gastaut and Fischer-Williams, 1957; Gastaut and Gastaut, 1958; Lombroso and Lerman, 1967; Stephenson, 1978;]. Ocular compression induced asystole in susceptible patients. If asystole lasted 3 to 6 seconds, there were no clinical symptoms and the EEG demonstrated only desynchronization. When asystole lasted 7 to 13 seconds, slow waves appeared, usually associated with altered consciousness. If asystole was prolonged for 14 seconds or more, there were often myoclonic jerks or tonic posturing. The EEG during this time reveals no electrocerebral activity. With return of cardiac activity, there was again high-voltage slow-wave activity on the EEG with return of normal activity over 20 to 30 seconds [Gastaut and Fischer-Williams, 1957]. At no time during EEG monitoring were epileptiform discharges present. Some patients have had spontaneous episodes or episodes triggered by other stimuli, such as venipuncture during EEG and cardiac monitoring, and have demonstrated similar changes to those seen with ocular compression [Braham et al., 1981; Gordon, 1982; Lombroso and Lerman, 1967; Roddy et al., 1983]. Ocular compression increases vagal tone with the afferent pathway involving fibers from the trigeminal nerve originating from the cornea,

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iris, and eyelids. In contrast, episodes induced by exteroceptive stimulation, such as pain and emotion, have afferent fibers in various sensory pathways. In both situations the vagal reflex centers are located in the brainstem in the nucleus ambiguus [Chen and Chai, 1976]. The efferent pathway involves the cardioinhibitory fibers of the vagus nerve.

Laboratory Tests Diagnosis of reflex anoxic seizures is usually made by obtaining a history of the episode. Details about the precipitating circumstances and onset are essential. Parents may state that their child had a seizure, and a careful description of the movements and posture, length of the episode, and recovery period will be helpful. Usually no laboratory tests are needed, although consideration should be given to obtaining an electrocardiogram to evaluate for a cardiac cause if the episodes are not typical. Rarely is it necessary to obtain an EEG. If an EEG is obtained, ocular compression may be helpful in confirming the diagnosis.

Treatment Treatment of reflex anoxic seizures focuses on explaining the nature of the event to the parents and reassuring them that the episodes are not epileptic seizures and do not need treatment with antiepileptic medication. In more severe cases atropine, theophylline, and transdermal scopolamine have been helpful [Benditt et al., 1983; McWilliam and Stephenson, 1984; Palm and Blennow, 1985; Stephenson, 1979]. Pacemaker implantation has also been useful in the rare patient with severe episodes [Kelly et al., 2001; McLeod et al., 1999; Porter et al., 1994; Sapire et al., 1983]. Children with reflex anoxic seizures are at risk of bradycardia during surgical procedures, and modifications in the anesthesia protocol may be warranted [Onslow and Burden, 2003; Pollard, 1999].

REFERENCES Abt IA. Breath holding in infants. Am J Dis Child 1918;16:118. Anas NG, McBride JT, Boettrich C, et al. Ventilatory chemosensitivity in subjects with a history of childhood cyanotic breath-holding spells. Pediatrics 1985;75:76. Benditt DG, Benson DW, Kreitt J, et al. Electrophysiologic effects of theophylline in young patients with recurrent symptomatic bradyarrhythmias. Am J Cardiol 1983;52:1223. Bhatia MS, Singhal PK, Dhar NK, et al. Breath holding spell: An analysis of 50 cases. Indian Pediatr 1990;27:1073. Braham J, Hertzeanu H, Yahini JH, et al. Reflex cardiac arrest presenting as epilepsy. Ann Neurol 1981;10:277. Breningstall GN. Breath-holding spells. Pediatr Neurol 1996;14:91. Bridge EM, Livingston S, Tietze C. Breath-holding spells: Their relationship to syncope, convulsions, and other phenomena. J Pediatr 1943;23:539. Breukels MA, Plotz FB, van Nieuwenhulzen O, et al. Breath holding spells in a 3-day-old neonate: An unusual early presentation in a family with a history of breath holding spells. Neuropediatrics 2002;33:41. Chen HI, Chai CY. Integration of the cardiovagal mechanism in the medulla oblongata of the cat. Am J Physiol 1976;231:454. Colina KF, Abelson HT. Resolution of breath-holding spells with treatment of concomitant anemia. J Pediatr 1995;126:395. Culpepper N. A directory for midwives: Or a guide for women in their conception, rearing, and suckling their children. London: A. Bettesworth and C. Hitch, 1737.

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Daoud AS, Batieha A, Al-Sheyyab M, et al. Effectiveness of iron therapy on breath-holding spells. J Pediatr 1997;130:547. DiMario FJ Jr. Breath-holding spells in childhood. Am J Dis Child 1992;146:125. DiMario FJ Jr. Prospective study of children with cyanotic and pallid breath-holding spells. Pediatrics 2001;107:265. DiMario FJ Jr, Bauer L, Baxter D. Respiratory sinus arrhythmia in children with severe cyanotic and pallid breath-holding spells. J Child Neurol 1998;13:440. DiMario FJ Jr, Burleson JA. Autonomic nervous system function in severe breath-holding spells. Pediatr Neurol 1993a;9:268. DiMario FJ Jr, Burleson JA. Behavior profile of children with severe breath-holding spells. J Pediatr 1993b;122:488. DiMario FJ Jr, Chee CM, Berman P. Pallid breath-holding spells. Evaluation of the autonomic nervous system. Clin Pediatr 1990;29:17. DiMario FJ Jr, Sarfarazi M. Family pedigree analysis of children with severe breath-holding spells. J Pediatr 1997;130:647. Donma MM. Clinical efficacy of piracetam in the treatment of breathholding spells. Pediatr Neurol 1998;18:41. Emery ES. Status epilepticus secondary to breath-holding and pallid syncopal spells. Neurology 1990;40:859. Franklin WH, Hickey RW. Long-QT syndrome. N Engl J Med 1995;333:335. Gastaut H, Fischer-Williams M. Electroencephalographic study of syncope: Its differentiation from epilepsy. Lancet 1957;2:1018. Gastaut H, Gastaut Y. Electroencephalographic and clinical study of anoxic convulsions in children. Electroencephalogr Clin Neurophysiol 1958;10:607. Gauk EW, Kidd L, Prichard JS. Mechanism of seizures associated with breath-holding spells. N Engl J Med 1963;268:1436. Goraya JS, Virdi VS. Persistence of breath-holding spells into late childhood. J Child Neurol 2001;16:697. Gordon N. The differential diagnosis of epilepsy and the use of the ambulatory electroencephalogram. J Electrophysiol Tech 1982;8:15. Holowach J, Thurston DL. Breath-holding spells and anemia. N Engl J Med 1963;268:21. Kahn A, Rebuffat E, Sottiaux M, et al. Brief airway obstructions during sleep in infants with breath-holding spells. J Pediatr 1990;117:188. Kanner L. Child psychiatry. Springfield, IL: Charles C Thomas, 1935. Kelly AM, Porter CJ, McGoon MD, et al. Breath-holding spells associated with significant bradycardia: Successful treatment with permanent pacemaker implantation. Pediatrics 2001;108:698. Kohyama J, Hasegawa T, Shimohira M, et al. Rapid eye movement sleep in breath holders. J Child Neurol 2000;15:449. Kuhle S, Tiefenthaler M, Seidl, R, et al. Prolonged generalized epileptic seizures triggered by breath-holding spells. Pediatr Neurol 2000;23:271. Laxdal T, Gomez MR, Reiher J. Cyanotic and pallid syncopal attacks in children (breath-holding spells). Dev Med Child Neurol 1969;11:755. Linder CW. Breath-holding spells in children. Clin Pediatr 1968;7:88. Livingston S. Breathholding spells in children: Differentiation from epileptic attacks. JAMA 1970;212:2231. Lombroso CT, Lerman P. Breathholding spells (cyanotic and pallid infantile syncope). Pediatrics 1967;39:563. Mattie-Luksic M, Javornisky G, DiMario FJ Jr. Assessment of stress in mothers of children with severe breath-holding spells. Pediatrics 2000;106:1. Maulsby R, Kellaway P. Transient hypoxic crises in children. In: Kellaway P, Petersen I, eds. Neurological and electroencephalographic correlative studies in infancy. New York: Grune and Stratton, 1964. McLeod KA, Wilson N, Hewitt J, et al. Cardiac pacing for severe childhood neurally mediated syncope with reflex anoxic seizures. Heart 1999;82:721. McWilliam RC, Stephenson JBP. Atropine treatment of reflex anoxic seizures. Arch Dis Child 1984;59:473. Mocan H, Yildiran A, Orhan F, et al. Breath holding spells in 91 children and response to treatment with iron. Arch Dis Child 1999;81:261. Moorjani BI, Rothner D, Kotagal P. Breath-holding spells and prolonged seizures. Ann Neurol 1995;38:512. Nirale S, Bharucha NE. Breath-holding spells and status epilepticus. Neurology 1991;41:159. Onslow JM, Burden J. Anaesthetic considerations for a child with reflex anoxic seizures. Paediatr Anaesth 2003;13:550. Orii KE, Kato Z, Osamu F, et al. Changes of autonomic nervous system function in patients with breath-holding spells treated with iron. J Child Neurol 2002;17:337.

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Palm L, Blennow G. Transdermal anticholinergic treatment of reflex anoxic seizures. Acta Paediatr Scand 1985;74:803. Paulson G. Breath holding spells: A fatal case. Dev Med Child Neurol 1963;5:246. Peiper A. Das “Wegbleiben.” Monatschr Kinderh 1939;79:236. Pollard RC. Reflex anoxic seizures and anaesthesia. Paediatr Anaesth 1999;9:467. Porter CJ, McGoon MD, Espinosa RE, et al. Apparent breath-holding spells associated with life-threatening bradycardia treated by permanent pacing. Pediatr Cardiol 1994;15:260. Roddy SM, Ashwal S, Schneider S. Venipuncture fits: A form of reflex anoxic seizures. Pediatrics 1983;72:715. Sapire DW, Casta A, Safley W, et al. Vasovagal syncope in children requiring pacemaker implantation. Am Heart J 1983;106:1406. Southall DP, Samuels MP, Talbert DG. Recurrent cyanotic episodes with severe arterial hypoxaemia and intrapulmonary shunting: A mechanism for sudden death. Arch Dis Child 1990;65:953.

Southall DP, Stebbens V, Shinebourne EA. Sudden and unexpected death between 1 and 5 years. Arch Dis Child 1987;62:700. Southall DP, Talbert DG, Johnson P, et al. Prolonged expiratory apnoea: A disorder resulting in episodes of severe arterial hypoxaemia in infants and young children. Lancet 1985;2:8455. Stephenson JBP. Reflex anoxic seizures (“white breath-holding”): Nonepileptic vagal attacks. Arch Dis Child 1978;53:193. Stephenson JBP. Atropine methonitrate in management of near-fatal reflex anoxic seizures. Lancet 1979;2:955. Stephenson JBP. Reflex anoxic seizures and ocular compression. Dev Med Child Neurol 1980;22:380. Stephenson JBP. Fits and faints. Philadelphia: JB Lippincott, 1990. Stephenson JPB. Anoxic seizures: Self-terminating syncopes. Epileptic Disord 2001;3:3. Taiwo B, Hamilton AH. Cardiac arrest: A rare complication of pallid syncope? Postgrad Med J 1993;69:738. Tam DA, Rash FC. Breath-holding spells in a patient with transient erythroblastopenia of childhood. J Pediatr 1997;130:651.

CHAPTER 55

Syncope and Paroxysmal Disorders Other than Epilepsy Enrique Chaves-Carballo

Epilepsy is the most common paroxysmal disorder seen in the practice of pediatric neurology. However, other paroxysmal events are confused with epilepsy or have unusual clinical features [Bleasel and Kotagal, 1995; Bye et al., 2000; Donat and Wright, 1990; Kotagal et al., 2002; Sotero, 2002; Stephenson, 1990a]. Paroxysmal disorders other than epilepsy are described in this chapter (Box 55-1). Breath-holding spells, migraine, pseudoseizures, and sleeprelated paroxysmal disorders are reviewed elsewhere in this book.

SYNCOPE Syncope (derived from the Greek synkoptein, “to cut or break”) is defined as a sudden loss of consciousness and postural tone, because of transient cerebral hypoperfusion, followed by spontaneous recovery [Feit, 1996; Gastaut, 1974; Grubb and Kosinski, 1996; Kapoor, 2000]. Transient interruption of cerebral blood flow is followed by loss of consciousness within 8 to 10 seconds [Manolis et al., 1990]. More relevant to syncope is the rate of cerebral perfusion; less than 30 mL per 100 grams of brain tissue per minute results in syncope [Schraeder et al., 1994]. The critical threshold of cerebral hypoperfusion at which syncope ensues is 50% below baseline (horizontal) mean cerebral flow velocity [Njemanze, 1992]. Although syncope in children is usually benign and selflimiting, physical injury may result from unprotected falls. Older children and adolescents may suffer emotional trauma from embarrassment or fear of having epilepsy, cardiac disease, or sudden death.

Incidence Syncope is seldom brought to medical attention and, therefore, its incidence is unknown. An estimated 30% to 50% of children have at least one episode by adolescence, yet syncope accounts for only about 1% of pediatric emergency room visits [Kudenchuk and McAnulty, 1985; Pratt and Fleischer, 1989]. Among 5207 adults in the Framingham study cohort, 3% of the men and 3.5% of the women had a syncopal episode [Savage et al., 1985]. Of 7814 adult participants in the Framingham study followed for an average of 17 years, 822 (10.5%) reported syncope, and the incidence of a first report of syncope was 6.2 per 1000 person-years [Soteriades et al., 2002]. In the Rochester Epidemiological Project, the incidence of syncope brought to medical attention was 125.8 per 100,000 for the 5-year period between 1987 and 1991, with this incidence peaking among adolescents 15 to 19 years of age [Driscoll et al.,

1997]. The recurrence rate of syncope ranges from 33% to 51% when patients are followed up to 5 years [Kapoor, 1990]. Syncope may result from cardiovascular or neurologic causes (cardiovascular-mediated or neurally mediated syncope). Each of these categories accounts for about 50% of

Box 55-1 SYNCOPE AND OTHER NONEPILEPTIC PAROXYSMAL DISORDERS Syncope Cardiovascular-mediated syncope Neurocardiogenic syncope Convulsive syncope Reflex syncope Situational syncope Cough syncope Defecation syncope Deglutition syncope Diving syncope Hair-grooming syncope Micturition syncope Sneeze syncope Trumpet-playing syncope Weight-lifting syncope Hyperventilation syncope Suffocation syncope Drug-induced syncope Psychogenic syncope Other Nonepileptic Paroxysmal Disorders Benign paroxysmal vertigo Paroxysmal dystonic choreoathetosis Paroxysmal kinesigenic choreoathetosis Dopa-responsive dystonia with diurnal variation Acetazolamide-responsive paroxysmal ataxia Benign paroxysmal tonic upgaze Benign paroxysmal torticollis Sandifer’s syndrome Cyclic vomiting Benign myoclonus of early infancy Hyperekplexia Spasmus nutans Shuddering attacks Hyperventilation syndrome Rhythmic movements Stereotypes Gratification phenomena Masturbation

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adult syncope [Kapoor et al., 1983]. Cardiovascular-mediated syncope is less frequent in children than it is in adults.

Cardiovascular-Mediated Syncope Cardiovascular-mediated syncope has a higher mortality and a higher incidence of sudden death than neurally mediated syncope [Kapoor et al., 1983; Kapoor, 2000]. Pediatric neurologists should become familiar with risk factors that suggest structural or conduction heart defects [Aicardi, 1992]. A previous history of heart murmur or congenital heart disease, acute attacks associated with hyperpnea or cyanosis, abrupt loss of consciousness during exercise, and absence of the usual premonitory symptoms or precipitating factors associated with neurally mediated syncope are suggestive of cardiovascularmediated syncope. If any of these risk factors are present, an appropriate referral should be made for cardiac evaluation. Cardiovascular causes of syncope in children include aortic stenosis, hypertrophic obstructive cardiomyopathy, primary pulmonary hypertension, sick-sinus syndrome, long Q-T syndrome, supraventricular tachycardia, ventricular tachycardia, and heart block [Feit, 1996]. Further discussion of cardiovascular-mediated syncope is outside the scope of this chapter and the interested reader is referred elsewhere [e.g., Fogoros, 1993; Kapoor, 2000; Linzer et al., 1997a; 1997b; Manolis et al., 1990; Shen and Gersh, 1993]. An acceptable classification of syncope is hampered by a lack of uniform terminology. Some refer to syncope as generalized anoxic seizures, whereas others object to the implication of epilepsy in syncope [Aicardi, 1992; Gastaut, 1974; Stephenson, 1990b]. Thomas Lewis reintroduced the term vasovagal syncope more than 50 years after Gowers identified the term in 1882 [Lewis, 1932]. However, this designation is under scrutiny as inconsistent with current understanding of the pathophysiology of syncope [Kosinski et al., 1995]. Neurocardiogenic syncope has been proposed as a more meaningful and descriptive term [Abboud, 1993; Sra et al., 1991]. Despite objections, the recent literature evidences acceptance of the new terminology [Landau and Nelson, 1996].

Neurocardiogenic Syncope Neurocardiogenic syncope, previously known as vasodepressor, vasovagal, or neurally mediated syncope, is commonly confused with epilepsy [Stephenson, 1990c].

CLINICAL FEATURES A diagnosis of syncope rests mainly on clinical grounds [Kapoor, 2000; Lerman-Sagie et al., 1994]. A prodromal phase or presyncope consists of light-headedness, blurred vision, epigastric discomfort, nausea, pallor, or diaphoresis [Manolis et al., 1990; Feit, 1996]. When present, these clinical features help to differentiate syncope from epilepsy. A detailed history usually reveals contributory environmental factors before the loss of consciousness and postural tone. These environmental factors include upright posture, prolonged standing, change in posture (orthostasis), crowding, heat, fatigue, hunger, or a concurrent illness [Sutton, 1996]. Emotional or stress factors, such as venipuncture, public speaking, “fight-or-flight” situations, pain, and fear,

are also commonly identified [Driscoll et al., 1997]. The loss of consciousness is usually brief, lasting from a few seconds to 1 or 2 minutes, followed by rapid spontaneous recovery without persistent neurologic deficits. During the ictus the patient may have tonic posturing or a brief clonic seizure, rarely associated with incontinence. The postictal period may be accompanied by nausea, pallor, diaphoresis, and a generally “washed-out” appearance. Complete recovery usually evolves in less than an hour [Feit, 1996]. Differentiation of neurocardiogenic syncope from an epileptic seizure is mainly based on the clinical features. However, interobserver agreement is poor when a retrospective diagnosis is made on information obtained after a single syncopal episode [Hoefnagels et al., 1992]. The evaluation of syncope may result in unnecessary and costly tests [Landau and Nelson, 1996]. A complete investigation includes neuroimaging studies, Holter monitoring, electroencephalography, glucose tolerance test, and, in selected cases, intracardiac electrophysiologic studies [Grubb et al., 1992] or implantable continuous loop-recordings [Krahn et al., 1999]. More than 40% of patients with recurrent syncope do not have a specific diagnosis after extensive investigation [Kapoor, 1991]. Introduction of the tilt-table test may help to resolve some of these problems.

PATHOPHYSIOLOGY Explanation of the pathophysiology of neurocardiogenic syncope has been revised [Abboud, 1993; Benditt et al., 1996b; Grubb and Kosinski, 1996; Kosinski et al., 1995; Mosqueda-García et al., 2000]. Among predisposed individuals who experience recurrent syncope, excess peripheral venous pooling on prolonged standing results in diminished venous return. Decreased cardiac ventricular filling activates mechanoreceptors located mainly in the inferoposterior wall of the left ventricle that send afferent impulses via C-fibers to the dorsal nucleus of the vagus [Lieshout et al., 1991]. Arterial baroreceptors and carotid sinus afferent activation may also contribute to the complex pathophysiology of syncope [Kinsella and Tuckey, 2001]. These inhibitory cardiac and arterial receptors mediate increased parasympathetic activity and inhibit sympathetic activity that result in bradycardia, vasodilation, and hypotension (Bezold-Jarisch reflex) [ Kinsella and Tuckey, 2001; Shen and Gersh, 1993]. The normal response during upright posture is an increased heart rate and diastolic pressure and an unchanged or slightly decreased systolic pressure [Rea and Thames, 1993]. In individuals susceptible to recurrent syncope, a “paradoxical” reflex bradycardia and peripheral vascular dilation occur [Grubb and Kosinski, 1996]. The previous emphasis on parasympathetic (vagal) output is shifting to sympathetic withdrawal as the main mechanism responsible for the bradycardia or asystole (cardioinhibitory response) and hypotension (vasodepressor response) that accompany neurocardiogenic syncope [Hannon and Knilans, 1993]. Although parasympathetic-mediated bradycardia remains a contributory factor in syncope, the responsible phenomena are vasodilation and hypotension [Kosinski et al., 1995]. Current hypotheses propose that the primary efferent event is systemic vasodilation and that this vasodepressor element is mediated by a profound centrally mediated sympathetic

Chaves-Carballo / Syncope and Paroxysmal Disorders Other than Epilepsy

withdrawal [Kosinski et al., 1995]. The persistence of neurocardiogenic syncope in subjects who had cardiac transplants and, therefore, technically denervated hearts, as well as the finding of increased epinephrine levels during upright position and syncope, are strong evidence supporting a sympathetic withdrawal mechanism in syncope [Fitzpatrick et al., 1993; Njemanze, 1993; Sra et al., 1994]. Altered cerebral autoregulation may also be contributory in neurocardiogenic syncope [Rodríguez-Nuñez et al., 1997]. Transcranial Doppler studies have demonstrated cerebral vasoconstriction during tilt-table–induced syncope [Grubb et al., 1991]. These observations may stimulate future research and modify current insight about neurocardiogenic syncope.

Tilt-Table Testing The tilt-table test was developed during World War II to study the effect of centrifugal forces on pilots during aircraft operation [Graybiel and McFarland, 1941]. Almost half a century later, the head-upright tilt-table test was introduced for clinical use to induce hypotension and bradycardia and confirm the diagnosis of neurocardiogenic syncope among individuals susceptible to recurrent syncope [Kapoor, 1996; Kenny et al., 1986; Sra et al., 1991]. Despite criticism that this provocative test suffers from “naive rationale,” lacks patient selection standards, and needs controlled treatment and outcome studies [Landau and Nelson, 1996], the tilt-table test continues to enjoy popularity as a noninvasive and physiologically appropriate neurophysiologic test for the diagnosis of neurocardiogenic syncope [Dijane et al., 1996; Kapoor, 1999]. The test is done by positioning the patient head-upright at an angle of 60 to 80 degrees for 15 to 60 minutes on a tilt table with a supporting footboard. A tilt-table test result is positive when the symptoms of syncope or presyncope are reproduced [Sra et al., 1991]. If the result is negative, isoproterenol is administered intravenously and the dose increased until the heart rate increases by at least 20%. To standardize the test, the duration of head-up tilting has been increased to 45 minutes or two standard deviations of the mean time required to reproduce syncope [Sneddon and Camm, 1993]. A comprehensive analysis of available tilttable data suggests that administration of isoproterenol has no added benefit, and 60 degrees for 45 to 60 minutes is recommended [Kapoor et al., 1994]. Experience with tilt-table test among pediatric populations is limited. Of 35 adolescents who had recurrent presyncope or syncope, 26 had positive tilt-table test results at 60 degrees for 30 to 60 minutes and isoproterenol infusion from 1 to 5 μg/minute [Thilenius et al., 1991]. Among 54 pediatric patients who had recurrent syncope, tilt-table testing at 80 degrees for 30 minutes was superior to studies, such as chest radiograph, electrocardiogram, echocardiogram, EEG, or neuroimaging, in arriving at a diagnosis of neurocardiogenic syncope [Strieper et al., 1994]. Tilt-table studies in 20 children with unexplained syncope and 10 controls using 60 degrees for 25 minutes and isoproterenol infusion from 0.02 to 0.08 μg/kg/minute were positive in 75% of patients and in 10% of controls for a sensitivity of 75% and a specificity of 90% [Alehan et al., 1996]. The tilt-table test has been used in children as young as 3 years of age [Grubb et al., 1992]. In addition to heart rate and blood pressure monitoring during tilt-table testing, electroencephalographic recording

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may be used to differentiate anoxic from epileptic seizures [Grubb et al., 1992]. More controlled studies and standardization of degree and duration of tilting are necessary to validate the tilt-table test as a safe, practical, and useful diagnostic tool for neurocardiogenic syncope in children [Benditt and Lurie, 1996a; Mansourati and Blanc, 1996; Moya et al., 1996a; 1996b; Victor, 1996].

TREATMENT Once a diagnosis of neurocardiogenic syncope is confirmed, treatment requires counseling of the patient (when appropriate) and his or her parents. The benign nature of these events should be explained to allay concerns about epilepsy or sudden death. Avoidance of identified environmental factors may remediate or prevent most attacks. If a prodromal phase is consistently present, the patient may be taught to recline or sit to avoid injury from a fall. Supplemental fluids and electrolytes may be beneficial when excess environmental heat or diaphoresis is contributory. If these conservative measures fail to prevent recurrent syncope, several medications may be tried [Grubb and Kosinski, 1996]. Favorable response to treatment has been reported with beta-blockers, anticholinergics, serotonin reuptake inhibitors, methylxanthines, mineralocorticosteroids, and estrogens (Box 55-2) [Boehm et al., 1997; Milstein et al., 1990; O’Marcaigh et al., 1994; Raviale et al., 1996; Scott et al., 1995; Sra et al., 1991]. Subjects who require isoproterenol

Box 55-2 MEDICATIONS FOR TREATMENT OF NEUROCARDIOGENIC SYNCOPE* Beta-Adrenergic Blockers Atenolol Esmolol Metoprolol Nadolol Propranolol Anticholinergics Disopyramide Hyoscine Propantheline Scopolamine Alpha-Adrenergic Agonists Ephedrine Methylphenidate Midodrine Pseudoephedrine

1 to 2 mg/kg/day 1 to 2 mg/kg/day 0.5 to 4 mg/kg/day 10 to 15 mg/kg/day

5 to 10 mg tid 60 mg bid

Serotonin Receptor Uptake Inhibitors Fluoxetine Sertraline Mineralocorticoids Fludrocortisone

0.1 to 0.3 mg/day

*Pediatric doses are given for those medications used in children in which dosages have been recommended. Data from Grubb and Kosinski, 1996; Lazarus and Mauro, 1996; Raviele et al., 1996; Sra et al., 1997.

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to induce syncope during tilt-table testing or who experience tachycardia before syncope may respond better to betablocker therapy [Leor et al., 1994; Sra et al., 1992].

Convulsive Syncope A brief tonic or, rarely, a clonic seizure may accompany syncope. In a study of blood donors, 0.05% suffered a convulsion associated with syncope (convulsive syncope) [Lin et al., 1982]. Among 216 children who had a positive tilt-table test, 25 (11.6%) had seizures during the test [Fernández Sanmartín et al., 2003]. Most convulsions consisted of tonic spasms (65%) characterized by eye rolling, nuchal rigidity, arms flexed at the elbow, and fists clenched, followed usually by prompt recovery [Lin et al., 1982]. Other types of convulsions were myoclonic (23%), clonic (6%), and tonic-clonic (6%). No difference was found in severity of bradycardia or hypotension among those who had syncope associated with convulsion and those who did not [Lin et al., 1982]. In subjects who had cardiac asystole induced by ocular compression, only those who remained asystolic for more than 14 seconds experienced convulsive phenomena [Lin et al., 1982]. Convulsive syncope results from cerebral ischemia and is not indicative of an epileptic predisposition. The electroencephalogram (EEG) reveals diffuse slowing followed by loss of electrocerebral activity; epileptiform activity is absent [Fernández Sanmartín et al, 2003; Stephenson, 1990d]. Rarely, an epileptic seizure is triggered by syncope. In such cases the EEG, in contrast to what is seen in convulsive syncope, reveals epileptiform activity [Stephenson, 1990g].

onds of asystole, a typical paroxysm is reproduced, thus confirming the diagnosis of reflex syncope. Reproduction of reflex syncope by ocular compression suggests that these children have an exaggerated oculocardiac reflex [Stephenson, 1990f]. Despite assurances about the safety and diagnostic usefulness of the ocular compression test to reproduce this type of syncope [Gastaut, 1974; Stephenson, 1980a; 1990f], its acceptance as a provocative test has been limited.

Situational Syncope Other triggering factors associated with syncope include cough, deglutition (cold liquids), defecation, diving, micturition, sneezing, trumpet-playing, and weight lifting [Hannon and Knilans, 1993]. These events are more common in adults than in children and are referred to as situational syncope. A common denominator in situational syncope is that most of the triggering factors are accompanied by a Valsalva-like maneuver. Hair-grooming syncope is an uncommon type of situational syncope among adolescent females; it is often followed by brief seizure activity [Igarashi et al., 1988; Lewis and Frank, 1993].

Hyperventilation Syncope Loss of postural tone and consciousness during hyperventilation is thought to result from cerebral vasoconstriction induced by hypocapnia. This type of syncope is discussed in more detail in a later section (see the section on hyperventilation syndrome).

Reflex Syncope

Suffocation or Strangulation Syncope

Syncope that is triggered by specific factors or events is known as reflex or situational syncope. The most common of these among infants and children is breath-holding spells. These are discussed in greater detail in Chapter 54. A related but distinctive type of syncope (known by various names in the past, including pallid breath-holding spells or pallid infantile syncope) is frequently confused with breathholding spells. A simple and more appropriate designation for this type of paroxysm is reflex syncope. In reflex syncope the antecedent event is minor trauma (usually to the head) before loss of postural tone and consciousness, without any audible inspiratory stridor or expiratory cry. Reflex syncopal episodes are easily confused with typical breath-holding spells, but evidence is lacking that these result from transient cerebral hypoxia because of breath holding. The rapid or immediate onset of syncope after minor trauma or other unexpected painful stimuli differentiates reflex syncope from breath-holding spells. In breath-holding spells, several seconds may elapse before loss of consciousness. There is general agreement that reflex syncopal attacks do not represent epileptic seizures, but the mechanism responsible is less clear. Some refer to these events as reflex anoxic seizures [Stephenson, 1978]. According to Stephenson, cardiac arrest is inducible in individuals susceptible to reflex syncope by the ocular compression test. This test is performed by applying pressure over the closed eyelids for 10 seconds during cardiac and electroencephalographic monitoring [Stephenson, 1980a]. After 7 to 15 sec-

Meadow’s syndrome (Munchausen by proxy) is a rarely suspected cause of syncope. A caretaker induces loss of consciousness by obstructing the infant’s airway using a pillow or by pressing the infant’s face against the caretaker’s trunk [Stephenson, 1990e]. In other cases, compression of the neck by strangulation results in cerebral hypoxia and, after repeated attempts, brain damage. A solicitous and omnipresent caretaker should raise suspicion of foul play [Folks, 1995]. The morbid events have been documented in some cases during video/EEG monitoring, but the incriminating evidence may not be admissible in court.

Drug-Induced Syncope Among the medications that can cause syncope are those that induce ventricular tachycardia or cause hypotension. Cardiovascular medications (vasodilators and antiarrhythmics), psychotropics, diuretics, and glucose-controlling medications are the most common drugs associated with syncope [Lazarus and Mauro, 1996]. Illicit drugs may also cause syncope (particularly alcohol but also cocaine and marijuana). Drug-induced syncope is common among the elderly but rare among children.

Psychogenic Syncope Failure to rapidly regain consciousness after a syncopal episode should raise suspicion of psychogenic syncope.

Chaves-Carballo / Syncope and Paroxysmal Disorders Other than Epilepsy

Psychogenic syncope is seen mainly among adolescents who demonstrate no cardiovascular or neurologic abnormalities and, in addition, lack any of the usual precipitating or triggering factors. A detailed psychosocial history may provide clues about the possible mechanisms involved. The general (including pulses, heart rate, and blood pressure) and neurologic examinations are unremarkable. A useful clinical maneuver in the unresponsive patient whose eyes are closed is to gently touch the eyelashes. This touch elicits a blink reflex in the conscious patient and alerts the examiner about the underlying psychopathology. Appropriate referral to a behavioral specialist should be made for further evaluation and management.

Other Nonepileptic Paroxysmal Disorders

TABLE 55-1 Medications for Treatment of Nonepileptic Paroxysmal Disorders DISORDER

MEDICATION

Acetazolamide-responsive paroxysmal ataxia Benign paroxysmal tonic upgaze Benign paroxysmal vertigo Cyclic vomiting

Acetazolamide*

Dopa-responsive dystonia with diurnal variation Hyperekplexia Paroxysmal dystonic choreoathetosis

Benign Paroxysmal Vertigo Since Basser [1964] described benign paroxysmal vertigo, few studies have contributed additional information to clarify its etiology, pathophysiology, and presumed relationship to migraine. The paroxysms are stereotyped and easily recognized in the typical case. The child suddenly appears frightened and falls unless supported or, alternatively, holds on to the nearest person or object to maintain balance and upright posture [Finkelhor and Harker, 1987]. The duration of the episode is usually less than 1 minute. There is no associated impairment of consciousness and rarely is there vomiting. Recovery is rapid and complete. Nystagmus during the ictus is seldom described and its presence is usually unknown in most cases unless witnessed by a physician or other reliable observer. The majority of cases are observed in early childhood. The frequency of the attacks ranges from several daily to only one or two per month until these disappear spontaneously several months or years later. Older children may report vertigo as a spinning sensation and may experience nausea. The disorder is benign and resolves spontaneously without any specific treatment [Finkelhor and Harker, 1987]. Results of oculovestibular testing with ice-water calorics vary, probably because of different techniques used, as well as the difficulties in performing this test in younger children. Because ocular fixation suppresses nystagmus, the test must be carried out in a dark room [Finkelhor and Harker, 1987]. When properly done, no abnormalities in vestibular function have been detected [Eeg-Olofsson et al., 1982; Finkelhor and Harker, 1987]. The pathophysiology of benign paroxysmal vertigo is not understood. Evidence to support vestibular or labyrinthine dysfunction in children is incomplete. The rapidity of the onset of the vertiginous attacks and their abrupt cessation favor a vascular etiology. Some consider these as transient ischemic attacks of the posterior circulation, but supportive evidence is lacking. The relationship between benign paroxysmal vertigo and childhood migraine remains conjectural [Fenichel, 1967]. It is not unusual to find a positive family history of migraine among immediate relatives. The possibility that benign paroxysmal vertigo represents a “migraine equivalent” is strengthened when a child with the typical syndrome reports associated headache and subsequently develops classic or vertebrobasilar migraine. In the typical case of benign paroxysmal vertigo, neurophysiologic studies are unnecessary [Drigo et al., 2001].

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Paroxysmal kinesigenic choreoathetosis

Sandifer’s syndrome Shuddering attacks

Levodopa Diphenhydramine, meclizine Lorazepam, propranolol, amitriptyline, erythromycin succinate Levodopa* Clonazepam,* valproic acid Clonazepam,* haloperidol, acetazolamide, valproic acid Carbamazepine,* phenytoin,* barbiturates, scopolamine, levodopa, belladona, chlordiazepoxide, diphenhydramine, oxcarbazepine Antigastroesophageal reflux medications (ranitidine, cimetidine, omeprazole) Propranolol

*Treatment medication of choice.

Brainstem auditory-evoked potentials are seldom abnormal. Treatment is also of limited value unless the episodes are unusually frequent or severe. Diphenhydramine or meclizine may be helpful in such children (Table 55-1). The most important aspect of management is reassurance that the attacks are not epileptic seizures or life threatening [Dunn and Snyder, 1976].

Paroxysmal Dystonic Choreoathetosis Paroxysmal choreoathetosis is the essential symptomatology in the following four syndromes: paroxysmal dystonic (nonkinesigenic) choreoathetosis of Mount and Reback, paroxysmal kinesigenic choreoathetosis, supplementary sensorimotor seizures, and paroxysmal nocturnal dystonia [Luders, 1996]. The last disorder has been reported in children [Oguni et al., 1992; de Saint-Martin et al., 1997; Veggiotti et al., 1993] and is characterized by paroxysmal dystonic posturing in which the EEG shows interictal epileptiform discharges; such discharges are not usually observed during the periods of posturing. Tonic limb and body movements, automatisms, behavioral changes, and vocalizations may also be seen [Hirsch et al., 1996]. The description of paroxysmal choreoathetosis by Mount and Reback in 1940 established as a nosologic entity a familial paroxysmal movement disorder manifested by involuntary writhing and posturing of the trunk and extremities, more correctly labeled as paroxysmal dystonic choreoathetosis [Mount and Reback, 1940]. Kertesz introduced the term paroxysmal kinesigenic choreoathetosis to differentiate cases in which the episodes were brief and precipitated by movement instead of by prolonged immobility or intake of specific beverages (coffee, tea, cola

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Nonepileptiform Paroxysmal Disorders and Disorders of Sleep / 55

drinks, alcohol), as in the cases of Mount and Reback [Kertesz, 1967]. Both paroxysmal dystonic (nonkinesigenic) choreoathetosis and paroxysmal kinesigenic choreoathetosis are included under the paroxysmal dyskinesias [Demirkiran and Jankovic, 1995; Shulman and Weiner, 1995]. A revised classification of the paroxysmal dyskinesias based on phenomenology, duration of the attacks (5 minutes or less and longer than 5 minutes), and etiology (idiopathic or secondary) was introduced by Demirkiran and Jankovic and has gained acceptance [Demirkiran and Jankovic, 1995; Jankovic and Demirkiran, 2002; Temudo, 2004]. Furthermore, these authors prefer the designations paroxysmal kinesigenic dyskinesia and paroxysmal nonkinesigenic dyskinesia because the paroxysmal attacks may include any combination of dystonia, chorea, athetosis, and ballism [Jankovic and Demirkiran, 2002]. Paroxysmal dystonic (nonkinesigenic) choreoathetosis is characterized by episodes of dystonia and choreoathetosis involving the face, trunk, and extremities, often associated with dysarthria and dysphagia lasting from minutes to several hours and occurring up to several times a week [Bressman et al., 1988; Demirkiran and Jankovic, 1995; Kinast et al., 1980; Lance, 1977; Pryles et al., 1952; Tibbles and Barnes, 1980]. The attacks begin spontaneously at rest or after intake of caffeine or alcohol. Other precipitating factors are fatigue, stress, hunger, and excitement. An aura consisting of twitching, feeling funny, or light-headedness has been noted [Williams and Stevens, 1963]. The disorder begins in early childhood and is inherited in most cases by autosomal dominant transmission. Linkage analysis has established a locus for paroxysmal dystonic choreoathetosis on distal chromosome 2q in an affected kindred [Fink et al., 1996]. Response to treatment with antiepileptic drugs is poor. Clonazepam is the treatment of choice for the majority of patients. Others respond to haloperidol, acetazolamide, or valproic acid [Przuntec and Monninger, 1983].

Paroxysmal Kinesigenic Choreoathetosis The attacks are brief (usually lasting less than 2 minutes) and characterized by dystonic posturing, choreoathetosis, or ballistic movements, either singly or in combination, and affecting one or both sides concomitantly [Lance, 1977]. The patient remains conscious throughout the episodes, which may be as many as 100 daily, and without any postictal impairment. In a review of 100 cases of paroxysmal kinesigenic choreoathetosis, 79 were male and

21 female [Lance, 1977]. Seventy-two were familial, and the majority of these were consistent with autosomal-dominant inheritance. The age at onset in the familial cases was between 5 and 15 years. An aura consisting of tightness, numbness, tingling, or paresthesias in the extremities was not uncommon. The ictus consisted of dystonic posturing, choreoathetosis, or ballistic movements alone or in combination. In these cases the most common precipitating factor was sudden movement after rest. In some, however, startle, excitement, stress, and hyperventilation could induce the paroxysmal movements [Lance, 1977]. In a series of 23 men and 3 women with paroxysmal kinesigenic choreoathetosis, two thirds had attacks lasting between 30 and 60 seconds, more than one half experienced 1 to 10 attacks daily, and most consisted of pure dystonia [Houser et al., 1999]. Neurophysiologic and neuroimaging studies are normal, except for occasional slowing noted in the EEG [Buruma and Roos, 1986]. No epileptiform activity is usually seen, even when recordings are made during an episode. Nevertheless, reports of epilepsy among members of the same family raise the question about the possible association between these disorders [Demirkiran and Jankovic, 1995]. Lombroso has demonstrated ictal discharges emanating from the supplementary sensorimotor cortex and ipsilateral caudate nucleus in a female with paroxysmal kinesigenic choreoathetosis by invasive long-term monitoring [Lombroso, 1995]. Treatment of paroxysmal kinesigenic choreoathetosis is facilitated by an exquisite sensitivity to antiepileptic medications [Wein et al., 1996]. Paroxysmal control may be achieved even with subtherapeutic levels of phenytoin or carbamazepine. Other medications found to be effective, but to a lesser degree, are barbiturates, scopolamine, levodopa, belladonna, chlordiazepoxide, and diphenhydramine [Kinast et al., 1980]. This marked sensitivity to antiepileptic medications has been used to differentiate paroxysmal dystonic choreoathetosis of Mount and Reback from paroxysmal kinesigenic choreoathetosis. The etiology of these disorders is unknown. The obvious localization to the basal ganglia lacks supporting evidence from available neuropathologic and neuroimaging studies [Demirkiran and Jankovic, 1995]. The proximity of the paroxysmal dystonic choreoathetosis gene locus to a cluster of ion-channel genes on distal chromosome 2q raises the possibility that, as in several other paroxysmal neurologic disorders (periodic ataxia with myokymia and potassiumrelated periodic paralyses), the underlying cause may be

TABLE 55-2 Genetics of Nonepileptic Paroxysmal Disorders DISORDER

INHERITANCE

CHROMOSOME

GENE

CHANNELOPATHY

Acetazolamide-responsive paroxysmal ataxia Dopa-responsive dystonia Hyperekplexia

AD

19p

CACNA1A

Calcium

AD AD AR AD

14q 5q 4q 21

GCH-I GLRA1

AD

16p

Paroxysmal dystonic choreoathetosis Paroxysmal kinesigenic choreoathetosis

AD, autosomal dominant; AR, autosomal recessive. Data from Ducros et al., 2001; Hejazi et al., 2001; Jankovic and Demirkiran, 2002.

Glycine (α1 subunit) Glycine (β subunit)

Chaves-Carballo / Syncope and Paroxysmal Disorders Other than Epilepsy

related to ion-channel gene mutations (Table 55-2) [Fink et al., 1996].

Dopa-Responsive Dystonia with Diurnal Variation Few disorders in the practice of pediatric neurology provide the opportunity to reverse a disabling condition in the dramatic manner afforded by dopa-responsive dystonia with diurnal variation. The condition was not recognized until 1971, when Segawa reported two children with the typical clinical features [Segawa et al., 1986]. The mode of inheritance is thought to be autosomal dominant, and more than 200 cases have been reported [Nygaard, 1993]. The estimated prevalence in England and Japan is 0.5 per million [Nygaard, 1993]. The onset presents between 1 and 9 years of age (average is 5 years) with fatigability and foot dystonia. These symptoms are aggravated by standing, by assuming a certain posture, or by voluntary movements. The most characteristic feature is the diurnal variation of the dystonia, which worsens in the evening and improves in the morning. According to Segawa, the dystonia progresses to involve all extremities within 5 or 6 years from onset and usually follows a letter N pattern, affecting the ipsilateral upper extremity, followed by the contralateral lower extremity and, finally, the contralateral upper extremity [Segawa et al., 1986]. The foot dystonia is mainly flexion inversion (pes equinovarus), whereas the arm is that of flexion pronation at the elbow and palmar flexion at the wrist with thumb adduction. When assuming the standing posture, the knee joint ipsilateral to the affected foot is hyperextended and the lumbar lordosis is exaggerated [Segawa et al., 1986]. Dystonic posturing of the big toe (striatal toe) may mimic a positive plantar (Babinski) response [Iivanainen and Kaakola, 1993]. Features of parkinsonism, such as rigidity, bradykinesia, postural instability, action, postural tremor of the arms, and, rarely, a resting tremor, may also be present and eventually develop in most cases [Nygaard et al., 1994]. The unusual presentation may be confused with cerebral palsy, spastic paraparesis, or hysteria [Nygaard et al., 1994]. Response to treatment is dramatic. Fatigability is usually alleviated within a week and dystonia within 6 weeks. A 20 mg/kg/day dose of levodopa without inhibitor is effective in most cases. A few patients benefit from increased doses of levodopa to 30 mg/kg/day. The therapeutic response is sustained and cumulative side effects are few [Segawa et al., 1986]. The neurophysiologic mechanisms involved in this disorder implicate the nigrostriatal dopaminergic system. Cerebrospinal fluid homovanillic acid levels are reduced, and biopterin concentrations are markedly reduced in all patients studied [Nygaard, 1995]. Positron emission tomography studies have been normal in most cases [Snow et al., 1993]. Neuropathologic data in one case demonstrated marked reduction of dopamine levels in the substantia nigra and in the striatum [Rajput et al., 1994]. The gene responsible for autosomal dominant hereditary progressive dystonia with marked diurnal fluctuation has been identified as guanosine triphosphate cyclohydrolase I located on 14q22.1-q22.2 [Furukawa et al., 1995; Segawa, 2000; Segawa et al., 2003; Tanaka et al., 1995].

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Acetazolamide-Responsive Paroxysmal Ataxia Recurrent episodes of vertigo, dysarthria, nystagmus, and gait ataxia starting in childhood and lasting for minutes or hours have been reported in several kindreds. The mode of inheritance of paroxysmal ataxia is autosomal dominant. Although asymptomatic between attacks, neurologic examination may reveal ocular abnormalities, including gaze-evoked nystagmus, abnormal optokinetic nystagmus, and hypermetric saccades [Van Bogaert et al., 1993]. Acetazolamide-responsive paroxysmal ataxia is also known as episodic ataxia associated with nystagmus (EA-2) [Jankovic and Demirkiran, 2002]. MRI and positron emission tomography studies may demonstrate atrophy of the anterosuperior aspect of the cerebellar vermis [Vighetto et al., 1988]. Intermittent rhythmic delta activity, sometimes associated with low-amplitude spikes and resulting in irregular spike-and-wave patterns, has been reported in EEG studies [Van Bogaert and Szliwowski, 1996]. Paroxysmal ataxia is almost always responsive to treatment with acetazolamide and the favorable response has been sustained for up to 5 years [Griggs et al., 1978]. The responsible gene has been mapped to the short arm of chromosome 19p [von Brederlow et al., 1995]. Localization of the gene responsible for familial hemiplegic migraine also to chromosome 19 suggested that these paroxysmal disorders were allelic [Joutel et al., 1993]. Acetazolamide-responsive paroxysmal ataxia and familial hemiplegic migraine are both associated with mutations in the gene CACNA1A, which encodes the α1A subunit of voltage-gated neuronal calcium channels [Ducros et al., 2001; Ophoff et al., 1996]. Other closely related autosomaldominant paroxysmal ataxias associated with myokymia (also known as episodic ataxia type 1, or EA-1) have been mapped to the short arm of chromosome 12p [Lubbers et al., 1995].

Benign Paroxysmal Tonic Upgaze Sudden onset of constant or variably sustained upward deviation of the eyes with or without ataxia was described only recently [Deonna et al., 1990; Ouvrier and Billson, 1988]. More than 30 cases have been reported to date [Merino-Andreu et al., 2004]. The episodes are usually brief (lasting about 2 minutes each) recurring over a period of several hours or days, and may be exacerbated by infections, fatigue, or stress [Merino-Andeu et al., 2004; Temudo, 2004]. The paroxysmal upward gaze is accompanied by compensatory flexion of the neck and downward deviation of the chin [Merino-Andreu et al., 2004]. On attempted downward gaze below horizontal, nystagmus or down-beating saccades are elicited. The onset is usually in early life (within the first 12 months) and the abnormal eye movements improve or resolve spontaneously within a few years [Verrotti et al., 2001]. Associated findings, in addition to ataxia, may include developmental delay, intellectual disability, and language delay [Hayman et al., 1998]. Familial cases suggest an autosomal-dominant mode of inheritance [Guerrini et al., 1998]. Response to treatment with levodopa has been, with few exceptions, poor. Neuroradiologic and neurophysiologic studies usually have normal results. However, focal or generalized epileptiform discharges recorded by polysomnography in four cases require further studies for confirmation [Merino-Andreu et al., 2004].

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Nonepileptiform Paroxysmal Disorders and Disorders of Sleep / 55

Benign Paroxysmal Torticollis Intermittent twisting of the neck (wryneck or torticollis), without persistent or obligatory abnormal head positioning, followed by subsequent spontaneous resolution is characteristic of benign paroxysmal torticollis. The onset is seen more often between 2 and 8 months of age. Truncal posturing (retrocollis and tortipelvis) is an added feature in some cases [Chutorian, 1974]. The episodes may last from 10 minutes to 14 days, recur two or three times a month, and involve either side [Snyder, 1969]. An attack may be anticipated by the onset of irritability, distress, or vomiting [Chaves-Carballo, 1996]. Most affected individuals recover by 2 to 3 years of age without treatment. A few cases have been familial [Gilbert, 1977; Lipson and Robertson, 1978]. Most cases described since the initial report by Snyder conform to this clinical description [Bratt and Menelaus, 1992; Cataltepe and Barron, 1993; Cohen et al., 1993; Hanukoglu et al., 1984; Sanner and Bergstrom, 1979; Snyder, 1969]. The pathophysiology of benign paroxysmal torticollis is subject to speculation. The observation of eye rolling or deviation in some cases suggests labyrinthine involvement. Abnormal oculovestibular function was found in 9 of 12 cases [Snyder, 1969]. Others believe that benign paroxysmal torticollis is related to benign paroxysmal vertigo or migraine [Deonna and Martin, 1981; Dunn and Snyder, 1976; Eviatar, 1994; Giffin et al., 2002]. The differential diagnosis includes seizures, vertigo, gastroesophageal reflux, diaphragmatic hernia (Sandifer’s syndrome), dystonia, posterior fossa, and craniocervical junction abnormalities (basilar impression, platybasia, atlantoaxial instability, Chiari malformation, and Klippel-Feil syndrome). Vestibular testing may be difficult to perform and interpret in young children. Brainstem auditory-evoked potentials are of interest because hearing impairment may be an associated finding. Neuroimaging studies are necessary to exclude congenital and acquired lesions involving the craniocervical region. Treatment with diphenhydramine, meclizine, and chlorpromazine has not been successful [Snyder, 1969]. The prognosis, however, is favorable and follow-up studies suggest spontaneous resolution in most cases [Dunn and Snyder, 1976].

Sandifer’s Syndrome Sandifer’s syndrome or complex consists of torsion spasms and abnormal posturing with or without gastroesophageal reflux or hiatal hernia [Gellis and Feingold, 1971; Kinsbourne and Oxon, 1964; Werlin et al., 1980]. The paucity of reports suggests that the disorder may not be well recognized [Kotagal et al., 2002]. It is not uncommon for a diagnosis of neurologic disease, such as dystonia or epilepsy, to be entertained before the true nature of the problem is identified [Mandel et al., 1989]. Among 126 infants and children with gastroesophageal reflux studied at a children’s hospital, 7.6% had Sandifer’s syndrome [Shepherd et al., 1987]. Abnormal posturing of the neck, trunk, and limbs results in bizarre positions. The torticollis is not associated with spasm of the neck muscles. At times, head nodding and gurgling sounds are noted. However, it is not necessary to demonstrate gastroesophageal reflux or hiatal hernia to

make a diagnosis of Sandifer’s syndrome [Werlin et al., 1980]. The initial explanations given for the contortions focused on the relief these positions afforded from the discomfort of acid regurgitation. However, there has been no correlation between the frequency or severity of gastroesophageal reflux and contortions. More sophisticated techniques and criteria for diagnosis of gastroesophageal reflux cast doubts on the validity of the association between Sandifer’s syndrome and gastroesophageal reflux. In a study of eight patients with Sandifer’s syndrome who had a barium swallow, pH monitoring, esophageal manometry, endoscopy, and biopsy for esophagitis, the most frequent finding was esophageal dysmotility [Gorrotxategi et al., 1995]. Because medical or surgical treatment of gastroesophageal reflux is effective, recognition of Sandifer’s syndrome may carry a good prognosis for amelioration of the contortions. Children who have a diagnosis of paroxysmal torticollis, paroxysmal dystonia of the neck without palpable increased tone of the corresponding muscle groups, or adversive seizures without alteration of the level of consciousness should have Sandifer’s syndrome included in their differential diagnosis.

Cyclic Vomiting The syndrome of cyclic vomiting is characterized by repeated, unpredictable, explosive episodes of nausea and vomiting lasting for hours or days and separated by asymptomatic intervals [Li, 1995]. Although there are no diagnostic laboratory or neurophysiologic markers, the clinical features are sufficiently distinctive to allow a clinical diagnosis to be made confidently in most cases. The etiology and pathogenesis of cyclic vomiting remain elusive more than a century since the initial description as “fitful or recurrent vomiting” [Walker-Smith, 1995]. Among school-aged children, the prevalence of cyclic vomiting is 1.9% [Abu-Arafeh and Russell, 1995]. This figure agrees with a prevalence rate of 2.3% in a populationbased study among 4- to 15-year-old children in western Australia [Cullen and MacDonald, 1963]. It is suspected, based on these reports, that cyclic vomiting remains underreported. The age at onset is variable. Of the 44 patients reported from the Mayo Clinic, 82% had the onset of recurrent vomiting before the age of 6 years [Hoyt and Stickler, 1960]. Among 141 patients from three combined series, the peak age at onset was 3 years [Fleisher, 1995]. Although cyclic vomiting usually begins in early childhood, cases among preadolescents are not uncommon [Fleisher and Matar, 1993]. A typical episode is characterized by persistent nausea accompanied by intense vomiting, gagging, or retching [Fleisher, 1995]. The onset may be abrupt or be preceded by malaise, anxiety, or mild nausea lasting for minutes to hours [Fleisher, 1995]. Abdominal pain, diarrhea, headache, lowgrade fever, tachycardia, and hypertension may be additional features. The attack is more common at night or in the early morning. The duration of the episodes is more often between 6 and 48 hours. The episodes are regular or cyclic in only about half of the patients. Precipitating or triggering factors are identified in about 80% of patients [Fleisher and Matar, 1993]. These are most often emotional stress, excite-

Chaves-Carballo / Syncope and Paroxysmal Disorders Other than Epilepsy

ment, or concomitant infections. The peak intensity (number of emeses per hour) and frequency (number of attacks per month) may help to differentiate cyclic vomiting from chronic vomiting caused by other gastrointestinal disorders. Children who have cyclic vomiting experience more intense emesis (12.6 times per hour versus 1.9 times per hour) and fewer episodes (1.9 attacks per month versus 36.6 attacks per month) than children who have chronic vomiting from identifiable causes [Pfau et al., 1996]. About one third of affected children continue to have episodes of cyclic vomiting well into their teens [Dignan et al., 2001]. A diagnosis of cyclic vomiting requires exclusion of other causes. The differential diagnosis is extensive and should consider gastrointestinal, neurologic, renal, endocrine, and metabolic etiologies. Recommended studies include blood, urine, and stool examinations; gastrointestinal ultrasonography, endoscopy, and motility studies; and electroencephalographic and neuroimaging tests [Fleisher and Matar, 1993]. However, each case needs to be investigated individually, taking into consideration the circumstances associated with the recurrent bouts of vomiting. Olson and Li found upper gastrointestinal studies with small bowel followthrough (combined with empiric antimigraine therapy) to be more cost effective than extensive diagnostic evaluation in children with cyclic vomiting [Olson and Li, 2002]. There is no uniform recommended management for children with cyclic vomiting. Supportive measures may require administration of parenteral fluids and electrolytes. The use of antiemetics is elective. These are more effective when given during the first hour of emesis. Some prefer to induce sleep and use lorazepam, which has antiemetic, anxiolytic, and sedative properties, at a dose of 0.05 to 0.2 mg/kg intravenously. Long-term therapy using propranolol or amitriptyline has been successful in many cases [Fleisher and Matar, 1993]. Treatment with erythromycin ethylsuccinate, an agonist of the neuroenteric peptide, at a dose of approximately 20 mg/kg/day in two to four divided doses daily for 7 days ameliorated the symptoms in 18 of 24 children with cyclic vomiting [Vanderhoof et al., 1995]. Cyclic vomiting has been known in the past by different names, including periodic syndrome, acetonemic vomiting, autonomic epilepsy, abdominal epilepsy, migraine or convulsive equivalent, and abdominal migraine [Pfau et al., 1996]. Although the etiology of cyclic vomiting is unknown, suspicions abound that it is related to migraine. Headaches are present in about half of the children with cyclic vomiting [Fleisher and Matar, 1993]. Migraine headaches were found in 38% of children with cyclic vomiting in the AberdeenHartlepool Childhood Migraine database [Symon and Russell, 1995]. Family history is positive for migraine in 40% of first- and second-degree relatives [Fleisher and Matar, 1993]. The prevalence rate of migraine in children with cyclic vomiting is twice that of the general childhood population (21% versus 10.6%) [Abu-Arafen and Russell, 1995]. Many of the following clinical features are common to both disorders: mode of presentation, triggering and relieving factors, associated gastrointestinal and sensory symptoms, vasomotor changes, electroencephalographic findings, and associated personality and psychosocial dysfunction [Fleisher and Matar, 1993]. For these reasons, cyclic vomiting has been grouped among the “migraine equivalents.” The importance of stress stemming from

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psychologic conflicts in children with cyclic vomiting has been emphasized [Hammond, 1974; Reinhart et al., 1977]. However, cyclic vomiting as a major symptom of epilepsy is rare [Mitchell et al., 1983].

Benign Myoclonus of Early Infancy Benign myoclonus of early infancy describes a group of infants between 3 and 8 months of age who develop myoclonic activity, usually in flurries and predominantly involving flexion or extension of the neck and rarely demonstrating adversive clonic activity of the head (cephalic myoclonus) [Lombroso and Fejerman, 1977]. Additional abnormal movements may include spasms of the head, trunk, or extremities; eye blinking; and brief jerking of the upper extremities or trunk [Maydell et al., 2001]. The paroxysmal activity resembles infantile spasms but lacks the electroencephalographic correlate of hypsarrhythmia and the associated neurologic abnormalities seen in West’s syndrome. The myoclonic activity increases for a few weeks or months after onset but within an average of 3 months decreases considerably in most infants and disappears spontaneously by 2 years of age [Lombroso and Fejerman, 1977]. The condition is differentiated from stimulussensitive or action myoclonus as seen in posthypoxic encephalopathies; periodic myoclonus noted in subacute sclerosing panencephalitis and herpes simplex encephalitis; burst myoclonus encountered in Lennox-Gastaut syndrome; and from degenerative disorders of gray or white matter including gangliosidoses, leukodystrophies, and UnverrichtLundborg and Lafora body diseases [Lombroso and Fejerman, 1977]. Other protracted but eventually selflimiting disorders, such as myoclonic infantile encephalopathy, hereditary essential myoclonus, benign essential myoclonus, and shuddering attacks, are also excluded. The condition is also differentiated from benign neonatal sleep myoclonus, which represents an exaggeration of normal physiologic phenomena during sleep [Noone et al., 1995]. Although initially some thought this could represent “stomach fits” instead of “brain fits” as manifestations of gastroesophageal reflux mimicking neurologic syndromes [Bray, 1977], benign myoclonus of early infancy is recognized as a distinct syndrome [Dravet et al., 1986]. Electroencephalographic studies fail to reveal any epileptiform activity during the paroxysmal episodes of myoclonus; however, more prolonged video/EEG monitoring may be required to establish the nonepileptic nature of the myoclonus [Bleasel and Kotagal, 1995; Pachatz et al., 1999].

Hyperekplexia An exaggerated startle response may be a component of epilepsy (startle epilepsy) or of nonepileptiform paroxysmal disorders (jumping and hyperekplexia) [Andermann and Andermann, 1988]. The term hyperekplexia is derived from Greek and means excessive jerking or jumping. It refers to a strikingly excessive response to startle elicited by visual, auditory, or proprioceptive stimuli that fail to produce a startle response in most normal individuals [Aicardi, 1992]. In the normal individual the startle response is a basic alerting reaction with stereotyped features consisting of eye blinking, facial grimacing, flexion of the head, elevation of

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Nonepileptiform Paroxysmal Disorders and Disorders of Sleep / 55

the shoulders, and flexion of the elbows, trunk, and knees [Andermann et al., 1980]. This involuntary reflex is enhanced by tension, fatigue, and heightened expectation and decreased with repeated stimulation. The reflex is said to appear during infancy at the same time as the Moro reflex [Andermann and Andermann, 1988]. The abnormal or pathologic response consists of an exaggerated startle response associated with generalized muscle stiffness and loss of postural control, causing the subject to fall en statue without loss of consciousness [Aicardi, 1992]. This propensity to fall may result in injuries, including head trauma. Hyperekplexia presents in its major form during the neonatal period as stiff-baby syndrome (stiff-man syndrome in the newborn) [Klein et al., 1972; Lingam et al., 1981; Stephenson, 1980b]. The onset of stiffness becomes evident a few hours after birth and the shoulder-girdle muscles are hypertonic. There may be difficulty in swallowing and frequent choking. Apnea may result from hyperekplexia and cause death [Kurczynski, 1983; Nigro and Lim, 1992]. The hypertonia usually disappears during sleep, although repetitive and violent movements of the extremities may be seen during the hypnagogic stage, which lifts the child off the bed [Aicardi, 1992; Andermann and Andermann, 1988]. The neonatal form improves spontaneously during the first year of life, although later on there may be absence of crawling and delay in walking. Hip dislocation, as well as umbilical, inguinal, and diaphragmatic hernias, result from increased intra-abdominal pressure and muscle stiffness [Aicardi, 1992; Gordon, 1993]. A clinically useful maneuver is to tap the tip of the nose or the glabella (glabellar tap). This maneuver will elicit an exaggerated nonhabituating startle response in affected individuals [Shahar et al., 1991]. Similar results may be obtained by blowing air directly on the face of neonates and infants with hyperekplexia [Shahar and Raviv, 2004]. Neurophysiologic studies demonstrate that hyperekplexia is not an exaggerated normal startle response [Hallet et al., 1986]. Electromyogram latencies are shorter than normal. EEG studies may reveal an initial spike maximally in the frontocentral region followed by slow waves and desynchronization of background activity [Andermann and Andermann, 1988]. Auditory- and somatosensory-evoked potentials are reported as increased or normal [Andermann and Andermann, 1988; Hallet et al., 1986]. Caudorostral recruitment of cranial nerve innervated muscles supports a brainstem origin for the abnormal startle response in hyperekplexia [Brown, 2002]. The condition is familial and transmitted as an autosomaldominant trait. Linkage analyses demonstrate genetic homogeneity in typical cases linked to DNA markers in the long arm of chromosome 5q [Ryan et al., 1992; Shiang et al., 1993]. Familial cases demonstrate point mutations in the α1 subunit of the inhibitory glycine receptor (GLRA1) [Shiang et al., 1995]. Sporadic and autosomal-recessive hyperekplexia cases may show abnormalities in the β subunit of the glycine receptor (GLRB) [Hejazi et al., 2001; Rees et al., 2002]. Glycine receptors are found primarily in the brainstem and spinal cord [Rajendra et al., 1997]. The main inhibitory neurotransmitter receptor is the γ-aminobutyric acid type A receptor. Affected individuals usually reveal a favorable response to treatment with clonazepam, an agonist of γ-aminobutyric acid type A receptors [Shiang et al., 1995].

The relationship of hyperekplexia to other nonepileptic startle disorders, such as jumping (jumping Frenchmen of Maine), latah (ticklishness associated with echopraxia and coprolalia in Malaysia), and myriachit (to act foolishly as reported from Siberia, Asia, and Africa), although discussed a century ago by Gilles de la Tourette [1884; 1899] in the context of tic convulsif, remains conjectural [Andermann and Andermann, 1988]. Treatment is most effective with clonazepam (0.1 to 0.2 mg/kg/day), but in some cases symptoms may not be totally suppressed [Aicardi, 1992]. Valproic acid is recommended in cases of late onset [Dooley and Andermann, 1989]. Vigabatrin did not reduce startle activity among four patients with hyperekplexia [Tijssen et al., 1997]. The prognosis is variable. Neonatal hyperekplexia may result in apnea, neonatal encephalopathy, cerebral palsy, and unexpected death [Chaves-Carballo et al., 1999]. Early identification and treatment improve the outcome in most children. Although hyperekplexia may persist into adult life, in some families the exaggerated startle response ameliorates or disappears spontaneously by 2 years of age [Shahar et al., 1991]. In the minor form of hyperekplexia, there is only an abnormal startle response without generalized stiffness or tonic spasms. The minor form is not associated with neurologic or catastrophic sequelae and no mutations have been detected in the genes encoding the glycine receptor [Tijssen et al., 1997].

Spasmus Nutans Spasmus nutans is a benign, self-limiting condition manifested by the clinical triad of asymmetric ocular oscillations, head nodding, and anomalous head positions in infants. Differentiation of spasmus nutans from other similar but more serious disorders has been hampered by the fact that patients often do not demonstrate all of the typical diagnostic features [Gottlob et al., 1990]. Furthermore, clinical detection of asymmetric nystagmus and head nodding may be difficult. Monocular or dissociated nystagmus occurs also in spasmus nutans [Farmer and Hoyt, 1984]. The head nodding corresponds to a normal compensatory oculovestibular reflex [Gottlob et al., 1992]. The pathophysiologic mechanisms involved in spasmus nutans are undetermined. The initial speculation that spasmus nutans results from environmental deprivation of sunlight has not been substantiated. Certain demographic and low socioeceonomic conditions may, however, represent risk factors for the development of spasmus nutans [Wizov et al., 2002]. Numerous cases of spasmus nutans have been associated with chiasmatic lesions [Albright et al., 1984; Anthony et al., 1980; Farmer and Hoyt, 1984; Kelly, 1970], diencephalic syndrome, porencephalic cysts [Gottlob et al., 1990], opsoclonus-myoclonus [Allarakhia and Trobe, 1995], empty sella [Gottlob et al., 1990], ependymoma [Gottlob et al., 1990], and retinal disorders [Gottlob et al., 1995a; Lambert and Newman, 1993]. Spasmus nutans is no longer regarded as a benign entity [Hoefnagel and Biery, 1968; Norton and Cogan, 1954]. To differentiate congenital nystagmus from spasmus nutans, eye and head movements were recorded in 23 patients with spasmus nutans, 10 patients with spasmus nutans-

Chaves-Carballo / Syncope and Paroxysmal Disorders Other than Epilepsy

like disease (associated with central nervous sytem [CNS] lesions), and 25 patients with congenital nystagmus [Gottlob et al., 1990]. The mean onset of nystagmus and head nodding was 8 months, and the mean onset of head tilt was 15 months in the spasmus nutans group. These findings permitted differentiation of spasmus nutans from infantile nystagmus: ocular oscillations were of later onset; head nodding was more frequent, of larger amplitude, and clinically easier to detect; and nystagmus was asymmetric and intermittent in spasmus nutans compared with infantile nystagmus. Optokinetic nystagmus was usually present in spasmus nutans and absent in most patients with infantile nystagmus. Head tilt was not found to be a useful differentiating criterion. The recordings were unable to differentiate spasmus nutans from spasmus nutans associated with neurologic abnormalities. The authors concluded that patients with signs suggestive of spasmus nutans should have neuroimaging studies [Gottlob et al., 1990]. A normal electroretinogram may help to substantiate a diagnosis of spasmus nutans [Smith et al., 2000]. Long-term follow-up studies are important to substantiate a diagnosis of spasmus nutans. Most patients eventually attain good visual acuity. However, subclinical nystagmus persists until at least 5 to 12 years of age [Gottlob et al., 1995b].

Shuddering Attacks Shuddering or shivering attacks are uncommon paroxysmal events rarely reported and poorly understood. These may start as early as 4 to 6 months of age or after 3 years of age and are precipitated or aggravated by fear, anger, frustration, or embarrassment [Vanesse et al., 1976]. The episodes last usually for a few seconds and are characterized by stiffening; adduction of the knees and arms; flexion of the head, elbows, trunk and knees; and flexion or extension of the neck. There is no change in the level of consciousness associated with the abnormal movements. In five of six cases reported, one of the parents had an essential tremor [Vanesse et al., 1976]. These characteristics suggested that shuddering attacks represent “the expression of an essential tremor in the immature brain.” Head tremor may evolve from shuddering attacks [DiMario, 2000]. Electroencephalographic recording of shuddering attacks in seven children failed to reveal any epileptiform activity [Holmes and Russman, 1986; Kanazawa, 2000]. Treatment with antiepileptic medications has not been effective. Propranolol, however, has eliminated shuddering attacks [Barron and Younkin, 1992]. Monosodium glutamate has been implicated in other cases, and avoidance or elimination from the diet has been effective [Reif-Lehrer and Stemmermann, 1975]. The prognosis is favorable; most children improve spontaneously before 10 years of age [Kanazawa, 2000; Vanesse et al., 1976].

Hyperventilation Syndrome Although hyperventilation syndrome has been known in the medical literature for more than 50 years, it frequently remains unrecognized by both patients and physicians [Evans, 1995]. The syndrome is defined by its symptoms, which are commonly related to anxiety, and by their reproducibility during voluntary hyperventilation [Evans, 1995]. Common

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chronic symptoms manifested in children with hyperventilation syndrome include anxiety, headaches, depression, and irritable bowel [Herman et al., 1981]. During attacks of hyperventilation, tachypnea, anxiety, breathlessness, light-headedness, and paresthesias are predominant. Among pediatric patients, the syndrome is more frequent among adolescents, although it has been recorded as early as 6 years of age. Many of the affected children have psychiatric problems before the onset of hyperventilation attacks. Unfortunately, 40% of surveyed patients are still having hyperventilation episodes when they reach adulthood [Herman et al., 1981]. Diagnosis requires a high index of suspicion and reproduction of the symptoms during voluntary hyperventilation. Inability to reproduce these symptoms does not necessarily negate the diagnosis. In such cases, empiric treatment consisting of breath holding, slow breathing, or breathing into a paper bag may be worthwhile. Treatment in the majority, however, requires more than reassurance and physiologic remediation of hypocapnia and alkalosis. The underlying psychopathology may be recalcitrant to such simple measures and will require careful follow-up and psychiatric intervention. Recent studies question the pathophysiology and validity of the hyperventilation syndrome [Bass, 1997].

Rhythmic Movements, Stereotypes, Gratification Phenomena, and Masturbation Repetitive stereotyped movements are not uncommon among both normal and neurologically impaired children. Examples of such self-stimulating or gratification phenomena are body rocking, head banging (jactatio capitis), and head rolling [Sallustro and Atwell, 1978]. Rocking motions of the trunk observed among mentally and visually impaired children may represent a form of vestibular stimulation akin to the maternal rocking that effectively comforts a crying, tired, or sleepy infant. The peculiar purposeless hand-wringing, repetitive hand movements seen among autistic children and in Rett’s syndrome may also be grouped into the category of self-stimulating behavior. Children who have a photoconvulsive response may learn to induce a seizure by repetitive hand movements in front of their eyes as a form of photic stimulation. More difficult to recognize is masturbatory behavior, particularly when this occurs in young children and infants [Fleisher and Morrison, 1990; Nechay et al., 2004]. The repetitive movements usually involve the lower trunk and may be accompanied by pelvic thrusting or contractions of the gluteal muscles. The physical effort may be prolonged and lead to diaphoresis, hyperpnea, flushing, and grunting [Fleisher and Morrison, 1990]. The paroxysms may terminate in fatigue, exhaustion, or sleep. The pediatric neurologist is usually asked to evaluate the child because of concern that these events may represent a form of epilepsy. Detailed observation of an episode or review of a videotaped event may be necessary to clarify the diagnosis, particularly in infants younger than 1 year of age [Casteels et al., 2004]. Any explanation of the benign nature of the paroxysms should take into account unusually sensitive or incredulous parents [Leung and Robson, 1993]. Reassurance that the episodes are benign and self-limiting should help to avoid

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unjustified concerns and unnecessary investigations [Mink and Neil, 1995].

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Lerman-Sagie T, Lerman P, Mukamel M, et al. A prospective evaluation of pediatric patients with syncope. Clin Pediatr 1994;33:67. Leung AKC, Robson WLM. Childhood masturbation. Clin Pediatr 1993;32:238. Lewis T. A lecture on vasovagal syncope and the carotid sinus mechanism with comments on Gowers’ and Nothnagel’s syndrome. BMJ 1932;1:873. Lewis DW, Frank LM. Hair-grooming syncope seizures. Pediatrics 1993;91:836. Li BUK. Cyclic vomiting: The pattern and syndrome paradigm. J Pediatr Gastroenterol Nutr 1995;21(Suppl 1):S6. Lieshout JJV, Wieling W, Karemaker JM, et al. The vasovagal response. Clin Sci 1991;81:575. Lin JT-W, Ziegler DK, Lai C-W, et al. Convulsive syncope in blood donors. Ann Neurol 1982;11:525. Lingam S, Wilson J, Hart EW. Hereditary stiff-baby syndrome. Am J Dis Child 1981;135:909. Linzer M, Yang EH, Mark Estes NA, et al. Diagnosing syncope. Part 1: Value of history, physical examination, and electrocardiography. Ann Int Med 1997a;126:989. Linzer M, Yang EH, Mark Estes NA, et al. Diagnosing syncope. Part 2: Unexplained syncope. Ann Int Med 1997b;127:76. Lipson EH, Robertson WC. Paroxysmal torticollis of infancy: Familial occurrence. Am J Dis Child 1978;132:422. Lombroso CT. Paroxysmal choreoathetosis. An epileptic or non-epileptic disorder? Italian J Neurol Sci 1995;16:271. Lombroso CT, Fejerman N. Benign myoclonus of early infancy. Ann Neurol 1977;1:138. Lubbers WJ, Brunt ER, Scheffer H, et al. Hereditary myokymia and paroxysmal ataxia linked to chromosome 12 is responsive to acetazolamide. J Neurol Neurosurg Psych 1995;59:400. Luders HO. Paroxysmal choreoathetosis. Europ Neurol 1996;36(Suppl 1):20. Mandel H, Tirosh E, Berant M. Sandifer syndrome reconsidered. Acta Paediatr Scand 1989;78:797. Manolis AS, Linzer M, Salem D, et al. Syncope: Current diagnostic evaluation and management. Ann Int Med 1990;112:850. Mansourati J, Blanc JJ. Tilt test procedure: Angle, duration, positive criteria. In: Blanc JJ, Benditt D, Sutton R, eds. Neurally mediated syncope: Pathophysiology, investigations, and treatment. Armonk, NY: Futura, 1996. Maydell BV, Berenson F, Rothner AD, et al. Benign myoclonus of early infancy: An imitator of West’s syndrome. J Child Neurol 2001;16:109. Merino-Andreu M, Arcas J, Izal-Linares E, et al. Desviación ocular paroxística benigna infantil: Un trastorno no epiléptico? Rev Neurol 2004;39:129. Milstein S, Buetikofer J, Dunnigan A, et al: Usefulness of disopyramide for prevention of upright tilt-induced hypotension-bradycardia. Am J Cardiol 1990;54:1339. Mink JW, Neil JJ. Masturbation mimicking paroxysmal dystonia or dyskinesia in a young girl. Movement Disorders 1995;10:518. Mitchell WG, Greenwood RS, Messenheimer JA. Abdominal epilepsy. Cyclic vomiting as the major symptom of simple partial seizures. Arch Neurol 1983;40:251. Mosqueda-García R, Furlan R, Tank J, et al. The elusive pathophysiology of neurally mediated syncope. Circulation 2000;102:2898. Mount LA, Reback S. Familial paroxysmal choreoathetosis: Preliminary report on a hitherto undescribed clinical syndrome. Arch Neurol 1940;44:841. Moya A, Permanyer-Miralda G, Sagrista J, et al. Is there a role for tilt testing in the evaluation of treatment of vasovagal syncope? In: Blanc JJ, Benditt D, Sutton R, eds. Neurally mediated syncope: Pathophysiology, investigations, and treatment. Armonk, NY: Futura, 1996a. Moya A, Sgrista J, Permanyer-Miralda G, et al. Isoproterenol and tilt test: Protocol, importance, contraindications. In: Blanc JJ, Benditt D, Sutton R, eds. Neurally mediated syncope: Pathophysiology, investigations, and treatment. Armonk, NY: Futura, 1996b. Nechay A, Ross LM, Stephenson JB, et al. Gratification disorder (“infantile masturbation”): A review. Arch Dis child 2004;89:225. Nigro M, Lim HC. Hyperekplexia and sudden neonatal death. Pediatr Neurol 1992;8:221. Njemanze PC. Critical limits of pressure-flow relation in the human brain. Stroke 1992;23:1743. Njemanze PC. Isoproterenol induced cerebral hypoperfusion in a heart transplant recipient. PACE Pacing Clin Electrophysiol 1993;16:491.

Noone PG, King M, Loftus BG. Benign neonatal sleep myoclonus. Irish Med J 1995;88:172. Norton EWD, Cogan DG. Spasmus nutans: A clinical study of twenty cases followed two years or more since onset. Arch Ophthalmol 1954;52:442. Nygaard TG. Dopa-responsive dystonia. Delineation of the clinical syndrome and clues to the pathogenesis. Adv Neurol 1993;60:577. Nygaard TG. Dopa-responsive dystonia. Curr Opinion Neurol 1995;8:310. Nygaard TG, Waran SP, Levine RA, et al. Dopa-responsive dystonia simulating cerebral palsy. Pediatr Neurol 1994;11:236. Oguni M, Oguni H, Kozasa M, et al. A case of nocturnal paroxysmal unilateral dystonia and interictal right frontal epileptic EEG focus: A lateralized variant of nocturnal paroxysmal dystonia. Brain Dev 1992;14:412. Olson AD, Li BU. The diagnostic evaluation of children with cyclic vomiting: A cost-effectiveness assessment. J Pediatr 2002;141:724. O’Marcaigh AS, MacLellan-Tobert S, Coburn JP. Tilt-table testing and oral metoprolol in young patients with unexplained syncope. Pediatrics 1994;93:278. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type 2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 1996;87:543. Ouvrier RA, Billson F. Benign paroxysmal tonic upgaze of childhood. J Child Neurol 1988;3:177. Pachatz C, Fusco L, Vigevano F. Benign myoclonus of early infancy. Epileptic Disord 1999;1:57. Pfau BT, Li BUK, Murray RD, et al. Differentiating cyclic from chronic vomiting patterns in children: Quantitative criteria and diagnostic implications. Pediatrics 1996;97:364. Pratt JL, Fleisher GR. Syncope in children and adolescents. Pediatr Emerg Care 1989;5:80. Pryles CV, Livingston S, Ford FR. Familial paroxysmal choreoathetosis of Mount and Reback. Pediatrics 1952;9:44. Przuntek H, Monninger P. Therapeutic aspects of kinesiogenic paroxysmal choreoathetosis and familial paroxysmal choreoathetosis of the mount and reback type. J Neurol 1983;230:163. Rajendra S, Lynch JW, Schofield PR. The glycine receptor. Pharmacol Therap 1997;73:121. Rajput AH, Gibb WRG, Zhong XH, et al. Dopa-responsive dystonia: Pathological and biochemical observations in a case. Ann Neurol 1994;35:396. Raviele A, Themistoclakis S, Gasparini G. Drug treatment of vasovagal syncope. In: Blanc JJ, Benditt D, Sutton R, eds. Neurally mediated syncope: Pathophysiology, investigations, and treatment. Armonk, NY: Futura, 1996. Rea R, Thames MD. Neural control mechanisms and vasovagal syncope. J Cardiovasc Electrophysiol 1993;4:587. Rees MI, Lewis TM, Kwok JBJ, et al. Hyperekplexia associated with compound heterozygote mutations in the β-subunit of the human inhibitory glycine receptor (GLRB). Hum Mol Genet 2002;11:853. Reif-Lehrer L, Stemmermann MG. Monosodium glutamate intolerance in children. New Engl J Med 1975;293:1204. Reinhart JB, Evans Sl, McFadden DL. Cyclic vomiting in children: Seen through the psychiatrist’s eye. Pediatrics 1977;59:371. Rodríguez-Nuñez A, Couceiro J, Alonso C, et al. Cerebral oxygenation in children with syncope during head-upright tilt test. Pediatr Cardiol 1997;18:406. Ryan SG, Sherman SL, Terry JC, et al. Startle disease, or hyperekplexia: Response to clonazepam and assignment of the gene (STHE) to chromosome 5q by linkage analysis. Ann Neurol 1992;31:663. Sallustro F, Atwell CW. Body rocking, head banging, and head rolling in normal children. J Pediatr 1978;93:704. Sanner G, Bergstrom B. Benign paroxysmal torticollis in infancy. Acta Paediatr Scand 1979;68:219. Savage DD, Corwin L, McGee DL, et al. Epidemiological features of isolated syncope: The Framingham study. Stroke 1985;16:626. Schraeder PL, Lathers CM, Charles JB. The spectrum of syncope. J Clin Pharmacol 1994;34:454. Scott WA, Pongiglione G, Bromberg BI, et al. Randomized comparison of atenolol and fludrocortisone acetate in the treatment of pediatric neurally mediated syncope. Am J Cardiol 1995;76:400. Segawa M, Nomura Y, Kase M. Diurnally fluctuating hereditary progressive dystonia. In: Vinken PJ, Bruyn GW, Klawans HL, eds. Handbook of clinical neurology, Vol. 5 (Revised Series) (49). Amsterdam: Elsevier, 1986.

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Stephenson JBP. Specific syncopes and anoxic seizure types. In: Stephenson JBP. Fits and faints. Oxford: Blackwell, 1990e. Stephenson JBP. Vagocardiac syncope and reflex anoxic seizures. In: Stephenson JBP. Fits and faints. Oxford: Blackwell, 1990f. Stephenson JBP. Anoxic-epileptic seizures. In: Stephenson JBP. Fits and faints. Oxford: Blackwell, 1990g. Strieper MJ, Auld DO, Hulse JE, et al. Evaluation of recurrent pediatric syncope: Role of tilt table testing. Pediatrics 1994;93:660. Sutton R. Vasovagal syncope: Clinical features, epidemiology, and natural history. In: Blanc JJ, Benditt D, Sutton R, eds. Neurally mediated syncope: Pathophysiology, investigations, and treatment. Armonk, NY: Futura, 1996. Symon DNK, Russell G. The relationship between cyclic vomiting syndrome and abdominal migraine. J Pediatr Gastroenterol Nutr 1995;21(Suppl 1):S42. Tanaka H, Endo K, Tsuji S, et al. The gene for hereditary progressive dystonia with marked diurnal fluctuation maps to chromosome 14q. Ann Neurol 1995;37:405. Temudo T. Discinesia paroxística en la infancia. Rev Neurol 2004;38:53. Thilenius OG, Quinones JA, Husayni TS, et al. Tilt test for diagnosis of unexplained syncope in pediatric patients. Pediatrics 1991;87:334. Tibbles JAR, Barnes SE. Paroxysmal dystonic choreoathetosis of Mount and Reback. Pediatrics 1980;65:149. Tijssen MA, Schoemaker HC, Edelbroek PJ, et al. The effects of clonazepam and vigabatrin in hyperekplexia. J Neurol Sci 1997;149:63. Tijssen MA, Vergouwe MN, van Dijk JG, et al. Major and minor form of hereditary hyperekplexia. Mov Disord 2002;17:826. Van Bogaert P, Van Nechel C, Goldman S, et al. Acetazolamideresponsive hereditary paroxysmal ataxia: Report of a new family. Acta Neurol Belg 1993;93:268. Van Bogaert P, Szliwowski HB. EEG findings in acetazolamideresponsive hereditary paroxysmal ataxia. Neurophysiol Clin 1996;26:335. Vanderhoof JA, Young R, Kaufman SS, et al. Treatment of cyclic vomiting in childhood with erythromycin. J Pediatr Gastroenterol Nutr 1995;21(Suppl 1):S60. Vanesse M, Bedard P, Andermann F. Shuddering attacks in children: An early clinical manifestation of early tremor. Neurology 1976;26:1027. Veggiotti P, Zambrino CA, Balottin U, et al. Concurrent nocturnal and diurnal paroxysmal dystonia. Childs Nerv Syst 1993;9:458. Verrotti A, Trotta D, Blasetti A, et al. Paroxysmal tonic upgaze of childhood: Effect of age-of-onset on prognosis. Acta Paediatr 2001;90:1343. Victor J. Tilt test. Environment, material, patient preparation. In: Blanc JJ, Benditt D, Sutton R, eds. Neurally mediated syncope: Pathophysiology, investigations, and treatment. Armonk, NY: Futura, 1996. Vighetto A, Forment JC, Trillet M, et al. Magnetic resonance imaging in familial paroxysmal ataxia. Arch Neurol 1988;45:547. Von Brederlow B, Hahn AF, Koopman WJ, et al. Mapping the gene for acetazolamide responsive hereditary paroxysmal cerebellar ataxia to chromosome 19p. Hum Mol Genet 1995;4:279. Walker-Smith J. Historical perspectives of cyclic vomiting. J Pediatr Gastroenterol Nutr 1995;21(Suppl 1):ix. Wein T, Andermann F, Silver K, et al. Exquisite sensitivity of paroxysmal kinesigenic choreoathetosis to carbamazepine. Neurology 1996;47:1104. Werlin SL, D’Souza BJ, Hogan WJ, et al. Sandifer syndrome: An unappreciated clinical entity. Dev Med Child Neurol 1980;22:374. Williams J, Stevens H. Familial paroxysmal chorea-athetosis. Pediatrics 1963;31:656. Wizov S, Reinecke RD, Bocarnea M, et al. A comparative demographic and socioeceonomic study of spasmus nutans and infantile nystagmus. Am J Ophthalmol 2002;133:256.

CHAPTER 56

Sleep-Wake Disorders Suresh Kotagal

Complaints about insufficient or nonrestorative sleep are quite common during childhood and adolescence. In a questionnaire survey of 332 children of 11 through 15 years of age, Ipsiroglu and associates [2001] observed that 28% of the subjects complained of snoring, insomnia, or a parasomnia. In another study of 472, 4- to 12-year-old urban and rural children receiving routine pediatric care, Stein and co-workers [2001] noted a 10% prevalence of sleep disorders on a questionnaire survey, but that less than one half of the parents had discussed the sleep problems with the child’s pediatrician. Childhood sleep disorders can have a significant effect on the quality of life. Many are also easily treatable, thus underscoring the importance of their prompt recognition and management. This chapter covers salient aspects of childhood sleep-wake function and common pediatric sleep disorders.

SLEEP PHYSIOLOGY AND ONTOGENY Sleep onset is facilitated by melatonin, which is a hormone released by the pineal gland. Bright light suppresses melatonin release, whereas dim light facilitates its release. The ultimate command center for the once-a-day (circadian) rhythm of sleep and wakefulness is the suprachiasmatic nucleus of the hypothalamus [Miller et al., 1996; Steriade et al., 1993], which has cells with receptors for melatonin. The suprachiasmatic nucleus is also strongly infiuenced by light-mediated impulses received through the retinohypothalamic tract. Clock and period genes, remarkably preserved across various phyla, were studied initially in Drosophila melanogaster; they also influence the timing of activity of the suprachiasmatic nucleus cells [Challet et al., 2003; Hamada et al., 2001]. The body temperature rhythm is also regulated by the hypothalamus [van Someren, 2000]— a rise in body temperature leads to postponement of sleep. Conversely, individuals are most sleepy around the nadir of body temperature, that is, around 0400 hours. An artificial increase in body temperature in the 1 to 2 hours before bedtime, such as through vigorous exercise, may provoke sleep-onset insomnia. Wakefulness can be differentiated from sleep by 27 to 28 weeks’ postconceptional age in the preterm infant. At this age, sleep is primarily of the active or rapid eye movement type, which is associated with irregular breathing, phasic or intermittent electromyographic activity, and low-voltage electroencephalographic activity. Cerebral blood fiow and cerebral metabolism are higher in rapid eye movement relative to non–rapid eye movement sleep (also termed quiet *Portions of this chapter have appeared in Kotagal S. Sleep disorders in childhood. Neurol Clin 21:961;81, 2003.

sleep in newborns). By 40 weeks’ postconceptional age, active (rapid eye movement) sleep decreases to about 50% of the total sleep time, with a corresponding rise in the proportion of quiet (non–rapid eye movement) sleep. By 46 to 48 weeks postconceptional age, sleep spindles appear during stages II and III of non–rapid eye movement sleep. By 4 to 6 months of age, non–rapid eye movement has fully differentiated into four stages. Stages III and IV non–rapid eye movement sleep together are also termed slow wave sleep, and are characterized by the presence of slow electroencephalogram (EEG) activity of predominantly the delta frequency, that is, less than 4 hertz (Fig. 56-1). The bulk of slow wave sleep occurs during the first third of the night. Growth hormone release is closely linked to slow wave sleep [Van Cauter and Plat, 1996], with suppression of the last leading to impaired growth hormone release. Rapid eye movement sleep decreases to about 20 to 25 percent of total sleep time by the age of 3 years. Until the age of 3 months, the initial transition from wakefulness is into rapid eye movement sleep. Subsequently, however, the physiologic transition from wakefulness is first into non–rapid eye movement sleep, with rapid eye movement sleep occurring 90 to 140 minutes later. Physiologic sleep-onset time in elementary school-age children is usually around 8:00 PM to 8:30 PM. Around adolescence, there is a physiologic delay in sleep-onset time, which shifts to around 10:30 PM TO 11:00 PM [Carskadon et al., 1998]. Teenage girls generally have their final morning awakening about one half hour earlier than boys. When juxtaposed with early high school start times of around 7:30 AM, it is easy to understand why most teenagers are chronically sleep deprived.

THE INTERNATIONAL CLASSIFICATION OF SLEEP DISORDERS The International Classification of Sleep Disorders [American Sleep Disorders Association, 1997] was introduced in 1990. It was developed through collaborative efforts of the American Sleep Disorders Association, the European Sleep Research Society, the Japanese Society of Sleep Research, and the Latin American Sleep Society. Primary sleep disorders are separated from those due to medical or psychiatric conditions (Table 56-1). Primary sleep disorders are further subdivided into (1) dyssomnias, or disorders that are accompanied by excessive sleepiness or insomnia, and (2) parasomnias, or disorders that intrude onto sleep, but are not associated with complaints of insomnia or sleepiness. Dyssomnias are further subdivided into intrinsic, extrinsic, and circadian rhythm sleep disorders. The classification

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Nonepileptiform Paroxysmal Disorders and Disorders of Sleep / 56 FIGURE 56-1. Normal nocturnal polysomnogram during stage III of non–rapid eye movement sleep, showing continuous delta (<4 hertz) activity on the EEG (arrow), regular respiration, and tonic chin electromyographic activity. Stage III and stage IV non–rapid eye movement sleep are together also termed “slow wave” sleep, which is most abundant in the first third of the night’s sleep. Nocturnal growth hormone release is closely linked to slow wave sleep. Parasomnias such as sleepwalking and confusional arousals generally occur during the transition from slow wave sleep to the lighter stages of non–rapid eye movement sleep. (Paper speed 10 mm/second.)

LOC-Fpz ROC-Fpz Fz-Cz Cz-Oz C4-A1 CHN1-CHN2 LLEG-RLEG ECG-ECG2 ONFLOW-RF SONO-RF 100.0

SAO2-RF xSaO2 70.0

SUM-RF RC-RF ABD-RF 97

97

97

97

97

97

97

97

97

provides a unique code number for each sleep disorder so that disorders can be efficiently tabulated for diagnostic, statistical, and research purposes. Diagnostic severity, duration, and duration criteria are presented in an axial system so that clinicians can standardize the relevant information about their patients. Axis A contains the primary sleep diagnosis. Axis B lists the procedures that are performed in the practice of sleep medicine, and axis C comprises the medical and psychiatric disorders that are not primarily sleep disorders in and of themselves. Numbers in parentheses after each diagnosis or procedure indicate its specific International Classification of Disease code number. As an example, narcolepsy is recorded as: Axis A: Narcolepsy, moderate, chronic, with excessive daytime sleepiness and cataplexy (347)

97

97

97

QA

QA

QA

Axis B: Nocturnal polysomnogram (89.17) Multiple sleep latency test (89.18) The International Classification of Sleep Disorders is undergoing revision, and a new version (International Classification of Sleep Disorders-2) that reflects recent advances in the field of sleep medicine will be released shortly. An abbreviated classification is presented in Table 56-1.

ASSESSMENT OF SLEEP-WAKE COMPLAINTS Sleep History The sleep history is provided by the patient, parent, or guardian. It is crucial to the planning of appropriate

TABLE 56-1 The International Classification of Sleep Disorders Dyssomnias

Parasomnias

Disorders associated with psychiatric, neurologic, or medical disorders Proposed sleep disorders

Intrinsic sleep disorders (examples): idiopathic insomnia, narcolepsy, idiopathic hypersomnia, post-traumatic hypersomnia, obstructive sleep apnea, central alveolar hypoventilation syndrome, restless legs syndrome, periodic limb movement disorder Extrinsic sleep disorders (examples): inadequate sleep hygiene, environmental sleep disorder, limit-setting sleep disorder, sleep-onset association disorder, hypnotic-dependent sleep disorder, stimulant-dependent sleep disorder, nocturnal eating-drinking syndrome Circadian rhythm sleep disorders (examples): irregular sleep-wake patterns, jet lag, non–24-hour sleep disorder, advanced sleep phase syndrome, delayed sleep phase syndrome Arousal disorders: confusional arousals, sleepwalking, sleep terrors Sleep-wake transition disorders: rhythmic movement disorder, sleep starts, sleeptalking, nocturnal leg cramps Parasomnias usually associated with REM sleep (examples): nightmares, sleep paralysis, REM-sleep-related sinus arrest, REM-sleep behavior disorder Other parasomnias (examples): bruxism (teeth grinding), sleep enuresis, benign neonatal sleep myoclonus With mental disorders (examples): psychoses, mood disorders, anxiety disorders, panic disorders With neurologic disorders (examples): cerebral degenerative disorders, parkinsonism, fatal familial insomnia, sleep-related epilepsy, electrical status epilepticus of sleep, sleep-related headaches With other medical disorders (examples): sleep-related asthma, sleep-related gastroesophageal reflux, fibromyalgia, nocturnal cardiac ischemia Examples: Terrifying hypnagogic hallucinations, sleep hyperhidrosis

Source: American Sleep Disorders Association, 1997.

Kotagal / Sleep-Wake Disorders

diagnostic procedures and arriving at a specific diagnosis. Questions relevant to infants and preschool-age children include the following: • The sleeping environment (e.g., crib, bassinet, parent’s room) • The sleeping position (e.g., prone or supine, semiupright) • Habitual need for sleep aids (e.g., pacifier, rocking, patting) • The time of going to bed, sleep onset, and the final morning awakening • Sensation of restlessness in the legs before sleep onset, intrusive thoughts or worries that interfere with sleep onset • Presence of habitual snoring, mouth breathing, observed apnea, restless sleep, sweating, gastroesophageal refiux, and abnormal behavior at night suggestive of seizures or parasomnias • Behavior during the daytime (irritability, inattentiveness, hyperactivity, sleepiness) • Number of daytime naps and their duration • Medications that may affect sleep-wake function (e.g., sedatives, stimulants) • Interventions that the parents have used to improve sleep In adolescents, one should also inquire about events in the 3 to 4 hours before bedtime like after-school employment, vigorous exercise, heavy meals, caffeine use, nicotine or substance abuse that may interfere with sleep onset, as well as about hypnagogic hallucinations, or sleep paralysis. Daytime sleepiness assessment should include questions about taking involuntary naps in the classroom, automatic behavior, and the impact of sleepiness on driving, cataplexy, hypnagogic hallucinations, medications used to promote alertness, academic function and behavioral and mood problems, and the number of school days missed because of sleepiness.

Sleep-Related Examination Height, weight, and body mass index should be recorded because obstructive sleep apnea may be associated with poor weight gain during infancy, and with obesity in adolescents. The blood pressure should be recorded because patients with long-standing and severe obstructive sleep apnea may develop hypertension. The patient should also be evaluated for craniofacial abnormalities like micrognathia, dental malocclusion, macroglossia, myopathic face and midface hypoplasia [Brooks, 2002; Colmenero et al., 1991]. Deviated nasal septum, swollen inferior turbinates, tonsillar hypertrophy and mouth breathing may accompany obstructive sleep apnea. Consultation with an otolaryngologist may be required to exclude adenoidal hypertrophy. Inattentiveness, irritability, and mood swings may suggest daytime sleepiness. Obstructive sleep apnea related to brainstem abnormalities like the Chiari type I or II malformations [Doherty et al., 1995] can lead to hoarseness of voice, decreased gag reflex, and changes in the amplitude of the jaw jerk relative to that of other tendon reflexes. Neuromuscular disorders like myotonic dystrophy may be associated with chronic obstructive hypoventilation from a combination of upper airway collapse and diminished chest wall–abdominal

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excursion [Givan, 2002; Labanowski et al., 1996; Misuri et al., 2001]. The parent-child interaction should be observed not only for clues toward parental anxiety and reluctance to set limits on inappropriate behaviors that sometimes perpetuate insomnia in toddlers, but also for subtle clues to a child maltreatment syndrome. Home videos, if available, may also provide valuable clues to etiology for disorders such as restless legs syndrome, confusional arousals, and nocturnal seizures.

Nocturnal Polysomnography The technique of nocturnal polysomnography is useful for monitoring multiple physiologic parameters during sleep in the evaluation of intrinsic sleep disorders like narcolepsy, obstructive sleep apnea, the upper airway resistance syndrome, and the periodic limb movement disorder. It is not indicated for diagnosing obstructive sleep apnea secondary to severe adenotonsillar enlargement, which can be easily recognized on the basis of clinical findings combined with severe oxygen desaturation on overnight oximetry. The nocturnal polysomnogram usually consists of simultaneous monitoring of two to four channels of the EEG, eye movements, chin and leg electromyogram, nasal pressure, thoracic and abdominal respiratory effort, electrocardiogram, and oxygen saturation [Kotagal and Goulding, 1996; Kotagal and Herold, 2002]. Patients with Down syndrome, neuromuscular disorders, and obesity have hypoventilation, characterized by shallow chest and abdominal wall movement with resultant CO2 retention. It is therefore important to also measure end-tidal CO2 levels in these patients. Esophageal pH can be monitored simultaneously when there is a suspicion of gastroesophageal reflux. In patients with obvious upper airway obstruction secondary to obesity or neuromuscular disorders like myotonic dystrophy, a therapeutic trial of continuous positive pressure airway breathing can be attempted midway during the course of the sleep recording. Synchronized video monitoring and a full 16- to 20-channel EEG montage are recommended when nonepileptic parasomnias need to be distinguished from nocturnal seizures. Normative data for commonly used polysomnographic variables are listed in Table 56-2 [Marcus and Loughlin, 1996]. There is insufficient evidence to determine the utility of ambulatory, in-home polygraphic monitoring, especially in the preschool age group; thus, traditional sleep laboratory monitoring is the gold standard.

Multiple Sleep Latency Test The multiple sleep latency test measures the speed with which one falls asleep, as well as the nature of the transition from wakefulness into sleep, that is, into non–rapid eye movement or rapid eye movement sleep. It can reliably detect sleepiness under clinical and experimental conditions [Carskadon et al., 1986]. The lower age limit at which one can use the multiple sleep latency test is about 6 to 7 years. Application in children younger than 6 years is unhelpful because younger children experience physiologic napping during the daytime. In order to derive valid conclusions, the multiple sleep latency test must be preceded the night before by a polysomnogram in which the total sleep time should approximate that observed at home.

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Nonepileptiform Paroxysmal Disorders and Disorders of Sleep / 56

TABLE 56-2 Normal Polysomnographic Values in Children PARAMETER

VALUE

COMMENTS

Total sleep time (hours)

6-7 hours

“Acceptable” value during laboratory conditions

Sleep efficiency (%)

>90

“Acceptable” value during laboratory conditions

REM sleep (% of TST)

15-30

Higher values of REM sleep are seen during infancy

Slow wave sleep (stage III–stage IV of NREM sleep; % of TST)

10-40

Apnea index (events per hour of sleep)

<1

Peak end-tidal CO2

<53 mm Hg

Duration of hypoventilation (PETCO2 > 50 mm Hg as % of TST) Oxygen saturation nadir Oxygen desaturations > 4% (number/hour of TST)

<8 % 92% 1.4

Normal peak CO2 may be lower during infancy

NREM, non–rapid eye movement; REM, rapid eye movement; TST, total sleep time. From: Marcus and Loughlin, 1996.

The multiple sleep latency test consists of the provision of four or five daytime nap opportunities at 2-hour intervals, for example, 1000, 1200, 1400, and 1600 hours while the EEG, chin electromyogram, and eye movements are being monitored. The patient should be dressed in street clothes. The attending parent or guardian should prevent the child from dozing off involuntarily in between the scheduled naptimes. At each planned nap opportunity, the lights are turned off and the patient is invited to try to sleep. The time from “lights out” to sleep onset is measured, and constitutes the sleep latency. The nap opportunity is terminated either 15 minutes after sleep onset, or if the patient does not fall asleep, at 20 minutes after “lights out.” A mean sleep latency is also derived for the four naps. Normative values have been established for the mean sleep latency. Mean sleep latency decreases inversely with an increase in the Tanner stage of sexual development, and ranges between 12 to 18 minutes [Carskadon, 1982]. A mean sleep latency of less than 5 minutes indicates severe daytime sleepiness; a value between 5-10 minutes indicates moderate daytime sleepiness. A urine drug screen is obtained in between the naps if stimulant or hypnotic abuse is suspected. The occurrence of rapid eye movement sleep within 15 minutes of sleep onset constitutes a sleep-onset rapid eye movement period (SOREMP). The presence of SOREMPs on two to four or more multiple sleep latency test nap opportunities in association with shortened mean sleep latency of less than 5 minutes is highly suggestive of narcolepsy. In adults, a mean sleep latency of less than 5 minutes in association with two or more SOREMPs is 70% sensitive and 97% specific for the diagnosis of narcolepsy [Aldrich et al., 1997]. Comparable data on the sensitivity and specificity are not available for children and adolescents. The recent work of Gozal and associates [2001] suggests that in prepubertal children, the normal mean sleep latency is 23.7 minutes, plus or minus 3.1 minutes. Palm and co-workers [1989] also found a mean sleep latency of 26.4 minutes plus or minus 2.8 minutes in 18 prepubertal children. These data suggest that the normal mean sleep latency in children may be actually higher than previously reported and that normative data for the multiple sleep latency test in childhood

might perhaps need revision. One of the merits of the multiple sleep latency test is that it provides reliable and quantitative information about the propensity for sleepiness. It has been validated as a measure of daytime sleepiness following episodes of sleep loss [Rosenthal et al., 1993], sleep disruption [Stepanski et al., 1987], and hypnotic drug and alcohol abuse [Billiard et al., 1987; Papineau et al., 1998]. The effects of treatment of daytime sleepiness with stimulants cannot be reliably measured, however. In addition, although one can control ambient noise and light that might affect sleep during the testing process, one cannot control for internal factors like anxiety and apprehension that also affect sleep propensity.

Maintenance of Wakefulness Test The maintenance of wakefulness test is the mirror image of the multiple sleep latency test in that it measures the ability to stay awake in a darkened, quiet environment during the daytime while the patient is seated in a semireclining position [Mitler et al., 1982, 2000]. EEG, eye movements, and chin electromyography are monitored in a manner identical to that in the multiple sleep latency test. The patient is provided four or five nap opportunities. The duration of each session is set at 20 or 40 minutes. The average mean sleep latency for normal adults is 35.2 minutes. Normative values have not been established for children. The test is useful in documenting the effect of therapeutic interventions on daytime sleepiness, for example, stimulant medications [Mitler, 1994].

Actigraphy The technique involves the recording and storing of skeletal muscle activity continuously for 1 to 2 weeks, generally from the nondominant forearm, using a wristwatch-shaped microcomputer device that records linear acceleration and translates it into a numeric and graphic representation. This numeric representation is sampled frequently, that is, every 0.1 second, and aggregated at a constant interval or epoch length [Sadeh et al., 1995]. The device captures signals during periods of muscle activity (generally correlating with

Kotagal / Sleep-Wake Disorders Time of day

18:00

00:00

06:00

12:00

12-Dec 13-Dec 14-Dec

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FIGURE 56-2. Wrist actigraph showing 2 weeks of sleep-wake recording in a teenager with delayed sleep phase syndrome, who presented with difficulty 18:00 falling asleep. The dark bars indicate presence of muscle activity, which correlates closely with wakefulness, and the clear areas indicate lack of muscle activity, which generally correlates with sleep. Notice sleep onset late in the early morning hours (down arrow) and awakening in the afternoon (up arrow).

15-Dec 16-Dec 17-Dec 18-Dec 19-Dec

wakefulness) and periods of no muscle activity (generally correlating with sleep; Fig. 56-2). There is a close correlation with polysomnographically defined total sleep time, sleep latency, and sleep efficiency (total sleep time or total time in bed × 100; [Sadeh et al., 1995]). Wrist actigraphy should be combined with 1 to 2 weeks of “sleep logs” that detail specific wake-up and sleep-onset times, daytime naps, and so on. Wrist actigraphy is useful in the study of insomnia and circadian rhythm disorders like the delayed sleep phase syndrome. In the latter instance, it will show sleep onset late at night or in the early morning hours, uninterrupted sleep thereafter, with a final awakening late in the morning or early afternoon (see 179

180

L eye R eye Fz-Cz Cz-Oz C4-A1 Chin EMG Leg EMG ECG O/N Flow Snoring

Obstructive Apnea

SpO2

100%

Sum

70%

RC ABD

Fig. 56-1). In patients being evaluated for suspected narcolepsy, two weeks of actigraphy before nocturnal polysomnography and the multiple sleep latency test helps exclude the possibility of sleepiness resulting from a circadian rhythm disorder or insufficient night sleep.

COMMON CHILDHOOD SLEEP DISORDERS Sleep-Related Breathing Disturbances Between 10% and 12% of children snore on a habitual basis [Corbo et al., 2001; O’brien et al., 2003]. The snoring sound FIGURE 56-3. Nocturnal polysomnogram showing obstructive sleep apnea. Notice lack of signal in the nasal pressure channel (bold down arrow) despite persistence of abdominal respiratory effort (upward arrow). The oxygen desaturation resulting from the obstructive apnea event triggers an EEG arousal (small downward arrow). (Paper speed 10 mm/second.)

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Nonepileptiform Paroxysmal Disorders and Disorders of Sleep / 56

is largely caused by vibration of the soft palate as a result of narrowing of the oropharynx. Children who snore but do not fulfill the polysomnographic criteria for obstructive sleep apnea are defined as having primary snoring. Although some guidelines [American Academy of Pediatrics, 2002] suggest that primary snoring may be a “benign condition that does not warrant any specific therapy,” a recent study of 87 5- to 7-year-olds [O’brien et al., 2004] found that compared with age-matched nonsnoring children, those with primary snoring performed worse on neuropsychologic measures of attention and had more social problems and anxious or depressive symptoms. Obstructive sleep apnea is characterized by partial or complete upper airway occlusion with impaired oronasal air exchange despite persistence of thoracic and abdominal respiratory effort, in association with transient oxygen desaturation of 4% (Fig. 56-3). Community-based studies have determined the prevalence of childhood obstructive sleep apnea at 1.1% to 2.9% [Ali et al., 1993; Brunetti et al., 2001]. The most common etiologic factors are adenotonsillar hypertrophy, craniofacial anomalies like micrognathia or maxillary hypoplasia, neuromuscular disorders such as myotonic dystrophy or congenital nonprogressive myopathies, and obesity [Marcus and Loughlin, 1996]. Repetitive occlusion of the upper airway during sleep with resultant oxygen desaturation provokes cortical arousals, and suppression in the proportion of rapid eye movement sleep and slow wave sleep. Nocturnal symptoms of childhood obstructive sleep apnea include habitual snoring, restless sleep with snort arousals, increased frequency of parasomnias such as confusional arousals, excessive sweating, mouth breathing, choking sounds, and parental reports of having observed apnea. Daytime symptoms consist of inattentiveness, impaired academic performance [Chervin et al., 2002], hyperactivity (in preschool children), and sleepiness. Nocturnal polysomnography is not needed

to confirm the diagnosis in patients with severe symptoms of obstructive sleep apnea who have severe tonsillar hypertrophy—one night of oximetry in the home environment that documents recurrent oxygen desaturation is sufficient for establishing the diagnosis [Brouilette et al., 2000]. Nocturnal polysomnography in the sleep laboratory is, however, indicated for patients with less obvious symptoms and etiology; in those with multiple neurologic handicaps, for example, Down syndrome patients; and when the patient needs to be considered for nonsurgical therapeutic options like continuous positive airway pressure breathing. Obstructive sleep apnea secondary to adenotonsillar hypertrophy responds favorably to adenotonsillectomy, but patients younger than 3 years old and those with severe obstructive sleep apnea should be monitored postoperatively in the intensive care unit for respiratory compromise from upper airway edema. Weight-reduction measures are indicated in obese patients. Orthodontic consultation and the use of oral appliances during sleep is indicated in those with retrognathia and tongue prolapse [Rondeau, 1998]. The upper airway resistance syndrome is a form of upper airway obstruction in which no frank apneas or oxygen desaturation are observed during sleep, but the airway narrowing leads to recurrent arousals, fragmented sleep, and daytime sleepiness [Guilleminault et al., 1996]. Some patients exhibit subtle posterior displacement of the tongue, narrow nostrils, or a high-arched palate, but others might not show any craniofacial anomalies. The nocturnal polysomnogram may appear superficially normal, with the exception of snoring and increased EEG arousals of 3 or more seconds (normally less than 10 to 12 per hour of sleep). Simultaneously obtained intraluminal pressures from an esophageal balloon demonstrate a marked increase in the intrathoracic negative pressure during the upper airway resistance syndrome episodes. The management is the same as for obstructive sleep apnea.

FIGURE 56-4. Central sleep apnea in a child with a primary brainstem tumor involving the medulla. Notice the simultaneous cessation of signal in the airflow channel (wide arrow) as well as in the thoracic and abdominal effort channels (thin arrows).

L eye R eye Fz-Cz Cz-Oz

C4-A1 Chin EMG Leg EMG ECG Airflow Snoring SaO2

100%

Sum

70%

Chest Abdomen SCA

ECA

ARL

Kotagal / Sleep-Wake Disorders ⬍5 years 5%

Central Hypoventilation Syndrome Defective automatic regulation of breathing during sleep due to brainstem dysfunction is characteristic of this syndrome. The disorder may present in infancy or childhood. Developmental malformations of the brainstem are common, but may be visible only on microscopic examination. Head injury, bulbar poliomyelitis, syringobulbia, hyperendorphinism, Chiari type II malformation [Zolty et al., 2000], and inborn errors of metabolism (e.g., Leigh’s syndrome) are other predisposing factors. Polysomnography may reveal central sleep apnea (Fig. 56-4). Except for surgical decompression in Chiari malformation and syringobulbia-associated hypoventilation, the management in these secondary central hypoventilation syndromes is similar to that for idiopathic congenital central alveolar hypoventilation, discussed below. Congenital central alveolar hypoventilation is a disorder in which no obvious structural or metabolic etiology is found for the defective control of breathing during sleep [Gozal, 2004; Gozal and Harper, 1999]. Onset of symptoms may be in infancy or early childhood. From a clinical standpoint, the respiratory rate and depth are initially normal during wakefulness, but shallow breathing (hypoventilation), hypercarbia, and oxygen desaturation appear during sleep. Ventilatory challenge with inhalation of a mixture of 5% CO2 and 95% O2 fails to evoke the physiologic, three- to fivefold increase in minute volume. Common sites of neuronal loss and gliosis include the arcuate nucleus in the medulla, the ventrolateral nucleus of the tractus solitarius, nucleus ambiguus, nucleus retroambigualis, the chemosensitive ventral medullary surface, and the nucleus parabrachialis in the dorsolateral pons. Between 15% and 20% of congenital central alveolar hypoventilation patients have coexisting Hirschprung’s disease or neural crest tumors such as neuroblastoma or ganglioneuroma [Roshkow et al., 1988; Swaminathan et al., 1989]. It has been hypothesized that congenital central alveolar hypoventilation is a neural crest disorder, because brainstem neurons that regulate chemosensitivity are derived from the neural crest during fetal development. The proto-oncogene, receptor tyrosine kinase, is involved in this process [Bolk et al., 1996]. Recently mutations in the PHOX2B gene have been identified in more than 90 percent of patients with central hypoventilation syndrome [Traochet et al., 2005]. There is no definitive and satisfactory treatment for congenital central alveolar hypoventilation, though acetazolamide and theophylline enhance chemoreceptivity of the brainstem respiratory neurons to a modest degree. Home ventilation via tracheostomy and diaphragmatic pacing are other therapeutic modalities. Patients may die in infancy or early childhood.

Narcolepsy Chronic daytime sleepiness, hypnagogic hallucinations (vivid dreams at sleep onset), sleep paralysis, cataplexy (sudden loss of skeletal muscle tone in response to emotional triggers like laughter, fright, or surprise), and fragmented night sleep are the characteristic clinical features of narcolepsy. The incidence of narcolepsy in the United States is 1.37 per 100,000 persons per year (1.72 for men and 1.05 for women; 35). It is highest in the second decade, followed by a gradual decline. The prevalence is approximately 56 per 100,000 persons [Silber et al., 2002]. A meta-analysis of

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10–15 years 16%

10–15 years 14% ⬎15 years 65%

FIGURE 56-5. Graph depicting the age of onset of narcolepsy. Data derived from: Challamel, et al., 1994.

235 pediatric cases derived from three studies [Challamel et al., 1994] found that 34% of all narcolepsy subjects had onset of symptoms before the age of 15 years, 16% before the age 10 years, and 4.5 % before age 5 years (Fig. 56-5). Although the age of onset is generally in the latter half of the first decade or the second decade, rare cases with onset of extreme sleepiness and cataplexy during infancy have also been reported [Nevsimalova et al., 1986; Sharp and D’Cruz, 2001]. Childhood daytime sleepiness may be overlooked by parents, schoolteachers, and physicians alike. Sleepy children are frequently mistaken for being “lazy.” They may exhibit mood swings and inattentiveness. Cataplexy, present in about two thirds of patients, is due to abrupt hyperpolarization of the spinal alpha motor neurons. The cataplectic muscle weakness generally lasts for a few minutes, and is associated with muscle atonia, absence of muscle stretch reflexes, and full preservation of consciousness. Because it can be very subtle, the examiner might need to ask leading questions about sudden muscle weakness in the lower extremities, neck, or trunk in response to laughter, fright, excitement, or anger. Children younger than 7 or 8 years do not provide a reliable history of hypnagogic hallucinations or sleep paralysis. Fragmentation of night sleep is also common in narcolepsy. This fragmentation may or may not be accompanied by periodic limb movement activity [Wittig et al., 1983]. Patients exhibit less circadian clock–dependent alertness during the daytime and also less circadian clock– dependent sleepiness at night [Broughton et al., 1998]. In rare instances secondary narcolepsy may develop in patients after closed head injuries, primary brain tumors, lymphomas, and encephalitis [Autret et al., 1994]. The presence of the histocompatibility antigen DQB1*0602 in close to 100% of persons with narcolepsy, as compared with a 12% to 32% prevalence in the general population indicates a genetic susceptibility, which is insufficient to precipitate the clinical syndrome. Monozygotic twins have been reported to be discordant for narcolepsy [Langdon et al., 1986; Mignot et al., 1999, 2001]. In genetically susceptible individuals, acquired life stresses like minor head injury, systemic illnesses such as infectious mononucleosis, and bereavement may play a role in triggering the

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Nonepileptiform Paroxysmal Disorders and Disorders of Sleep / 56

disorder, and have been reported in close to two thirds of subjects—“the two-hit hypothesis” [Billiard et al., 1986]. The defining pathophysiologic event in narcolepsycataplexy is hypocretin deficiency [Nishino et al., 2000, 2001]. Hypocretin (orexin) is a peptide that is produced by neurons of the dorsolateral hypothalamus. Hypocretins 1 and 2 (synonymous with orexins A and B) are peptides that are synthesized from preprohypocretin. They have corresponding receptors. Whereas the hypocretin type 1 receptor binds only to hypocretin-1, the hypocretin type 2 receptor binds to both type 1 and 2 ligands [Hungs et al., 2001]. Hypocretin neurons have widespread projections to the forebrain and brainstem. Hypocretin promotes alertness and increases motor activity and basal metabolic rate [John et al., 2000]. Of significance is the postmortem examination finding in humans with narcolepsy of Thannickal and colleagues [2000], documenting an 85% to 95% reduction in the number of hypocretin neurons in the hypothalamus, whereas melanin-concentrating hormone neurons that are intermingled with hypocretin neurons remained unaffected, thus suggesting a targeted neurodegenerative process. It is hypothesized that degeneration of the hypocretin-producing cells of the hypothalamus (perhaps linked to HLA DQB1*0602 by mechanisms yet unknown) provokes a decrease in forebrain noradrenergic activation, which in turn decreases alertness. A corresponding decrease of noradrenergic activity in the brainstem leads to disinhibition of brainstem cholinergic systems, thus triggering cataplexy and other phenomena of rapid eye movement sleep such as hypnagogic hallucinations and sleep paralysis. The decrease in secretion of hypocretin-1 that is characteristic of human narcolepsy-cataplexy is also reflected in the cerebrospinal fluid. Using a radioimmunoassay, Nishino and associates [2000, 2001] found that the mean level of hypocretin-1 in healthy controls was 280.3 plus or minus 33.0 pg/mL; in neurologic controls it was 260.5 plus or minus 37.1 pg/mL; and in those with narcolepsy, hypocretin-1 was either undetectable or less than 100 pg/mL. Low-to-absent levels were found in 32 of 38 narcolepsy patients, who were all also HLA DQB1*0602 positive. Narcolepsy patients who were HLA DQB1*0602 antigen negative tended to have normal to high cerebrospinal fluid hypocretin-1 levels. In another study of narcolepsy with cataplexy, narcolepsy without cataplexy, and idiopathic hypersomnia, Kanbayashi and associates [2002] found that their nine cerebrospinal fluid hypocretin–deficient patients were all HLA DQB1*0602 positive, including three preadolescents. In contrast, narcolepsy without cataplexy and idiopathic hypersomnia patients exhibited normal cerebrospinal fluid hypocretin levels (Fig. 56-6). The assay may be most useful when an HLA DQB1*0602–positive patient with suspected narcolepsy-cataplexy is already receiving central nervous system stimulants on initial presentation, and when discontinuation of these medications for the purpose of obtaining polysomnography and a multiple sleep latency test is inconvenient or impractical. A combined battery of nocturnal polysomnogram and multiple sleep latency test remains the most widely used method to diagnose narcolepsy. The nocturnal polysomnogram demonstrates increased arousals, decreased initial rapid eye movement latency of less than 70 minutes (time from sleep onset to onset of the first rapid eye movement

300

277 pg/mL, SD 54

259 pg/mL SD 57

250 200 150 88 pg/mL, SD 87 100 50 0

NarcolepsyCataplexy

Narcolepsywithout Cataplexy

Idiopathic Hypersomnia

FIGURE 56-6. Cerebrospinal fluid levels of hypocretin-1 in patients with narcolepsy-cataplexy, narcolepsy without cataplexy, and idiopathic hypersomnia. Data derived from Kanbayashi, et al., 2002.

sleep epoch; normal value in teenagers is around 140 minutes), and absence of any other significant sleep pathology such as obstructive sleep apnea. The multiple sleep latency test, which is obtained on the day after the nocturnal polysomnogram, records sleep onset on each of the four nap opportunities within 5 minutes of “lights out,” whereas the reference value is approximately 16 to 18 minutes. Sleeponset rapid eye movement periods are also seen during at least two out of four nap opportunities. Because narcolepsy is a lifelong condition, the diagnostic test results need to be clear and unambiguous. Management of narcolepsy requires a combination of lifestyle changes and pharmacotherapy. A planned daytime nap of 20 to 30 minutes at school and another one in the afternoon upon return home may enhance alertness. The patient should observe regular sleep onset and morning wake-up times, avoid alcohol, and exercise regularly. To minimize the risk of accidents, the patient should avoid sharp, moving objects. Daytime sleepiness is treated pharmacologically with modafinil (100 to 400 mg/day in two divided doses) or regular or extended-release preparations of methylphenidate (20 to 60 mg/day in two divided doses) and dextroamphetamine (10 to 30 mg/day in two divided doses) [Littner et al., 2001]. Cataplexy is treated using clomipramine (25 mg at bedtime) or protryptiline (2.5 to 5 mg/day in two divided doses) or sodium oxybate (gamma hydroxybutyrate). Sodium oxybate is administered in two divided doses or at night, and seems to work by improving noc-turnal sleep architecture. There are insufficient data on its use in childhood. Emotional and behavioral problems that commonly accompany childhood narcolepsy may require the addition of fluoxetine (10 to 30 mg every morning) or sertraline (25 to 50 mg twice daily) and supportive psychotherapy. Teenagers should be counseled against driving if they have uncontrolled sleepiness. They should also avoid work and social situations in which they could endanger themselves or others.

Idiopathic Hypersomnia Idiopathic hypersomnia is defined by the International Classification of Sleep Disorders as “a disorder of presumed central nervous system cause that is associated with a normal or prolonged major sleep episode and excessive sleepiness

Kotagal / Sleep-Wake Disorders

consisting of prolonged (1 to 2 hour) sleep episodes of nonrapid eye movement sleep” [Roth, 1976]. In contrast with the mean sleep latency on the multiple sleep latency test of less than 5 minutes that is typically observed in narcolepsy, the mean sleep latency in idiopathic hypersomnia is generally in the 5- to 10-minute range. Patients do not exhibit cataplexy, hypnagogic hallucinations, or sleep paralysis. Two or more SOREMPs that are typically seen on the multiple sleep latency test in patients with narcolepsy are also not present. In a review of 42 patients evaluated at the University of Michigan over a 10-year period, Basetti and Aldrich [1997] observed that hypersomnia began at a mean age of 19 plus or minus 8 years (range 6 to 43). Almost half of the subjects described restless sleep with frequent arousals. Habitual dreaming was present in about 40% of the subjects. They described three subtypes of idiopathic hypersomnia: 1. The classic form, in which sleepiness was not overwhelming, and there was a tendency to take long, unrefreshing naps, prolonged nighttime sleep, and difficulty awakening 2. The narcolepsy-like idiopathic hypersomnia, with overwhelming daytime sleepiness, a tendency to take short, refreshing naps, and awakening without difficulty; sleep attacks tended to occur even while standing 3. The “mixed” form, in which the naps were brief, but unrefreshing They mention that there is substantial clinical overlap between narcolepsy and idiopathic hypersomnia. In a subset of children, idiopathic hypersomnia may represent a transitional phase en route to the development of classic narcolepsy [Kotagal and Swink, 1996].

Restless Legs Syndrome Restless legs syndrome is an autosomal-dominant, sensorimotor disorder in which the subject complains of a peculiar “creepy or crawling” feeling in the extremities. There is an urge to move the limbs. The discomfort appears in the evening and nighttime hours, is exacerbated by immobility, and is momentarily relieved by movement of the limb [Allen et al., 2003]. This discomfort interferes with sleep initiation and maintenance, and may be accompanied by daytime fatigue, inattentiveness, or sleepiness. Childhood restless legs syndrome may be synonymous with “growing pains” in some children [Walters, 2002]. On nocturnal polysomnography, the patient may or may not demonstrate periodic limb movements, which are defined as a series of three or more rhythmic, electromyographically recorded movements of the legs lasting 0.5 to 5 seconds and occurring 5 to 90 seconds apart, generally during stages I or II of non–rapid eye movement sleep. The favorable response to dopamine receptor agonists like pramipexole and carbidopa-levodopa suggests that central nervous system dopamine deficiency is a pathophysiologic feature. There may be an associated systemic iron deficiency in the form of low levels of serum ferritin [Kotagal and Silber, 2004] because iron is a cofactor in the synthesis of dopamine. There also appears to be an association between restless legs syndrome and attentiondeficit disorder [Chervin et al., 2002; Picchietti et al.,

1233

1999]—in a community-based questionnaire survey of 866 children ages 2 to 13.9 years, Chervin and co-workers [2002] found an odds ratio for significant hyperactivity and restless legs of 1: 9. Besides dopamine agonists, oral iron, clonazepam, and gabapentin have also been used to treat restless legs syndrome, but there have been no randomized controlled trials to determine which drug is the most effective.

Periodic Hypersomnia (Kleine-Levin Syndrome) Periodic hypersomnia is generally seen in adolescents with a male predominance. Patients develop 1- to 2-week periods of hypersomnolence, characterized by sleeping 18 to 20 hours per day, cognitive and mood disturbances in association with compulsive hyperphagia, and hypersexual behavior, with intervening 2 to 4 months of normal alertness and behavior [Brown and Billiard, 1995]. Incomplete forms of the syndrome have also been recognized. The hyperphagia may be in the form of binge eating, and can actually be associated with a 2- to 5-kg increase in body weight. Nocturnal polysomnography during the sleepy periods exhibits decreased sleep efficiency, shortened rapid eye movement latency, and decreased percentage of time spent in stages III and IV of non–rapid eye movement sleep and rapid eye movement sleep. The multiple sleep latency test reveals moderately shortened mean sleep latency in the 5- to 10-minute range, but lacks the two or more SOREMPs typically seen in narcolepsy. The episodic hypersomnia gradually diminishes, ultimately resolving completely over 2 to 3 years or evolving into classic depression, thus bringing up the issue of whether the disorder is a variant of depression. A disturbance of hypothalamic-thalamic function has been hypothesized but not established. The association of Kleine-Levin syndrome with histocompatibility antigen DQB1*0201, the occasional precipitation after systemic infections, as well as the relapsing and remitting nature, are suspicious for an autoimmune etiology [Dauvilliers et al., 2002]. There is no satisfactory treatment, although lithium has been reported to be effective in case reports [Poppe et al., 2003].

Delayed Sleep Phase Syndrome Delayed sleep phase syndrome is a circadian rhythm disorder initially described in a medical student who was unable to wake up in time to attend his morning classes [Weitzman et al., 1981]. Despite hypnotic use, the patient was unable to fall asleep before the early morning hours and was mistaken initially to have insomnia. Sleep in the laboratory was, however, quantitatively and qualitatively normal. The delay in the timing of occurrence of the sleeping phase of the 24-hour sleep-wake cycle was due to a constitutional inability to prepone sleep, which in turn is secondary to altered function of the circadian timekeeper, that is, the suprachiasmatic nucleus. The disorder typically has onset in adolescence, with a male predominance. The increased frequency of HLA DR1 and the occasional familial clustering of delayed sleep phase syndrome suggest a genetic predisposition [Garcia et al., 2001]. The condition must, however, be differentiated from school avoidance seen in adolescents with delinquent and antisocial behavior,

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Nonepileptiform Paroxysmal Disorders and Disorders of Sleep / 56

because these individuals can fall asleep at an earlier hour at night in the controlled sleep laboratory setting. Maintenance of sleep logs and wrist actigraphy for 1 to 2 weeks is helpful in establishing the diagnosis of delayed sleep phase syndrome (see Fig. 56-2). “Bright light” therapy is helpful in advancing the sleep-onset time [Cole et al., 2002]. It consists of the provision of 2700 to 10,000 lux of bright light via a “light box” for 20 to 30 minutes immediately upon awakening in the morning. The light box is kept at a distance of 18 to 24 inches from the face. The phototherapy leads to a gradual advancement (shifting back) of the sleep-onset time at night. Bright light therapy may be combined with administration of melatonin about 5 to 5.5 hours before the required bedtime in a dose of 0.5 to 1 mg. The other therapeutic option is one of gradually delaying bedtimes by 3 to 4 hours per day until it becomes synchronized with socially acceptable sleep-wake times, and then adhering to this schedule (chronotherapy). Over time, however, all delayed sleep phase syndrome patients are at risk for drifting back to progressively later and later bedtimes. Daytime stimulants like modafinil (100 to 400 mg/day in two divided doses) may also improve the level of daytime alertness. The physician may also need to write a letter to the school, requesting a late midmorning school starting time on medical grounds.

The Relationship between Sleep and Epilepsy The onset of sleep may be associated with increased interictal spiking, as well as with an increased propensity for clinical seizures. Frontal and temporal lobe seizures are especially prone to occur during sleep, and to secondarily generalize during sleep [Bourgeois, 1996; Kotagal P, 2001]. Interictal epileptiform discharges may at times be observed only during sleep [Shinnar et al., 1994]. Nocturnal seizures are most likely to occur during stage II, followed by stage I, stage III, stage IV of non–rapid eye movement, and rapid eye movement sleep, in that order. The syndrome of electrical status epilepticus during slow wave sleep is characterized by continuous spike and wave discharges during 85% or more of nocturnal non–rapid eye movement sleep, along with cognitive and behavioral regression. Landau-Kleffner syndrome is characterized by regression in language function, typically in the form of auditory verbal agnosia, in association with continuous epileptiform activity during both rapid eye movement and non–rapid eye movement sleep [Landau and Kleffner, 1957]. Prolonged daytime and nighttime EEG may be needed to establish the diagnosis of either entity. Intravenous lorazepam or diazepam may transiently suppress the epileptiform discharges. Long-term maintenance with valproic acid is modestly effective. Sleep deprivation leads to activation of seizures. Ellingson and colleagues [1984] observed that clinical seizures occurred after sleep deprivation in 19 of 788 (2.4%) otherwise healthy subjects. Patterns of epileptiform abnormality are also considerably infiuenced by sleep. [Kotagal P, 2001]. For example, the three-per-second spike and wave complexes of absence seizures are replaced by single spike and waves or by polyspike and wave complexes. The hypsarrythmia of infantile spasms is replaced during sleep by brief periods of generalized voltage attenuation. Patients

with Lennox-Gastaut syndrome may manifest long runs of generalized spike and wave discharges. Conversely, seizures also influence sleep by suppressing rapid eye movement sleep, with a corresponding increase in slow wave sleep. This effect of slowing of the background EEG frequency may persist for days after a seizure. Frequent nocturnal seizures also tend to disrupt sleep continuity, with an increased number of arousals. Patients with Lennox-Gastaut syndrome frequently exhibit tonic seizures during sleep. Sleep disorders can also adversely affect seizure control. Patients with obstructive sleep apnea may manifest poor seizure control, which improves after correction of obstructive sleep apnea with CPAP, positional therapy, or tracheostomy [Britton et al., 1997]. In some instances, the daytime somnolence sleep apnea may be mistaken as a side effect of antiepileptic therapy when in fact it is a consequence of an associated sleep disorder. Antiepileptic drugs in general lead to stabilization of sleep, with a decrease in the amount of sleep fragmentation. Phenobarbital therapy is associated with suppression in the proportion of time spent in rapid eye movement sleep and increased stage III and IV non–rapid eye movement sleep (slow wave sleep). Both phenytoin and carbamazepine also increase stage III and IV non–rapid eye movement sleep at the expense of stages I and II non–rapid eye movement sleep. Benzodiazepines increase stages III and IV non–rapid eye movement sleep at the expense of stages I and II rapid eye movement sleep. Lamotrigine therapy is associated with an increase in the proportion of time spent in rapid eye movement sleep, with fewer sleep stage shifts [Kotagal P, 2001]. Felbamate is associated with insomnia in about 11 % of subjects [Cilio et al., 2001].

Sleep in Neurologically Compromised Children Children with spastic quadriparetic cerebral palsy may exhibit daytime irritability, fragmented sleep with frequent nighttime awakenings, and oxygen desaturation from obstructive sleep apnea due to upper airway collapse or adenotonsillar hypertrophy [Kotagal et al., 1994]. They are unable to compensate for the disordered breathing by changes in body position, which makes obstructive sleep apnea especially severe for them. Jouvet and Petre-Quadens [1966] described prolonged initial rapid eye movement latency and suppression in the proportion of time spent in rapid eye movement sleep in patients with severe mental retardation. Decreased rapid eye movements and spindle density, as well as the presence of “undifferentiated” sleep correlate with low levels of intelligence [Zucconi, 2000]. Patients with Leigh’s syndrome manifest recurrent central apneas or hypoventilation as a consequence of brainstem involvement [Cummiskey et al., 1987]. Joubert’s syndrome is associated with periods of hyperpnea and panting respiration. Rett’s syndrome is characterized by deep, sighing respiration during wakefulness and normal breathing patterns during sleep, consistent with impairment of the voluntary, cortical control of breathing, and a normal automatic or brainstem control of respiration [Zucconi, 2000]. Patients with Down syndrome have a complicated set of sleep problems. First, they develop obstructive sleep apnea from the combination of macroglossia, midface

Kotagal / Sleep-Wake Disorders

hypoplasia, and hypotonic upper airway musculature [Levanon et al., 1999]. Superimposed on this is an element of hypoventilation and CO2 retention due to the hypotonic intercostal and diaphragmatic musculature. Sleep architecture is frequently disrupted, with decreased sleep efficiency, increased arousals, suppression of slow wave sleep, and rapid eye movement sleep. Patients with achondroplasia may develop obstructive and central apnea in infancy as a result of macroglossia. Zucconi and colleagues [1996] found sleep-related breathing disorders in close to 75% of achondroplasia patients. There is no correlation between the diameter of the foramen magnum and severity of the sleep apnea, but patients need close follow-up of their neurologic and respiratory function. Certain lysosomal storage disorders like the mucopolysaccharidoses, especially Hurler syndrome, have been associated with severe obstructive sleep apnea that resolves with reduction in macroglossia and augmentation of upper airway diameter after bone marrow transplantation. Patients with Niemann-Pick type C disease frequently manifest cataplexy from brainstem involvement, but lack other features characteristic of narcolepsy [Kandt et al., 1982]. Circadian rhythm disorders like irregular sleep-wake rhythms are also common in patients with severe mental retardation and cerebral palsy, especially if there is associated blindness with impaired light perception, which interferes with light-dark entrainment, melatonin secretion, and the development of circadian rhythms. Many blind patients with complete lack of light perception fall asleep relatively early in the evening and are wide awake in early morning hours (3 or 4 AM) or exhibit multiple periods of daytime sleepiness. Melatonin administration and bright light (if light perception is intact) may be used to manipulate the sleep schedule in these patients.

Parasomnias Parasomnias are unpleasant or undesirable events that intrude onto sleep, without altering sleep quality or quantity. These events may occur during the transition to sleep, during rapid eye movement sleep, or in the transition from the deeper stages to the lighter stages of non–rapid eye movement sleep. The incidence of parasomnias is variable, though 30% of children have at least one episode of sleepwalking, and sleeptalking is noted in about half the population [D’Cruz and Vaughn, 2001]. Frequently, the patient remains unaware of the events but medical attention is sought owing to disruption of the sleep of other family members or serious injury to the patient. Non–rapid eye movement parasomnias such as confusional arousals, sleepwalking, and sleep terrors are most commonly seen during stages III and IV of non–rapid eye movement sleep, and thus in the first third of night sleep. They are linked to attempted transition from stages III and IV non–rapid eye movement sleep into stage I or II of non–rapid eye movement sleep. Confusional arousals are seen in toddlers, whereas sleepwalking and sleep terrors may occur throughout the first decade. Because non–rapid eye movement sleep is most abundant during the first third of night sleep, a useful historical clue for non–rapid eye movement parasomnias is the occurrence of the events during the 2 to 3 hours after initial sleep onset. Children with confusional arousals may sit up in bed, moan or whimper inconsolably,

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and utter words like “no” or “go away.” Autonomic activity is minimal. The events may last 5 to 30 minutes, after which the patient goes right back to sleep and has no recollection of the events whatsoever on the following morning. A simultaneously obtained EEG recording reveals rhythmic delta activity consistent with slow wave sleep in all of these three non–rapid eye movement parasomnias. Patients with night terrors and sleepwalking may exhibit flushing of the face, increased sweating, inconsolability, and agitation, with complete amnesia for the events the following morning. The events may last 2 to 20 minutes during which the EEG might show continuous slow activity in the delta range. A low dose of clonazepam (0.25 to 0.5 mg at bedtime) is helpful in preventing most non-rapid eye movement parasomnias. Attention to environmental safety, like installing a deadbolt lock on the door may also be necessary in patients with habitual sleep walking. Most non–rapid eye movement parasomnias subside after 10-12 years of age. Common rapid eye movement parasomnias include nightmares (scary dreams), terrifying hypnagogic hallucinations, and the rapid eye movement sleep behavior disorder. Because rapid eye movement sleep is most abundant during the final third of night sleep, nightmares and rapid eye movement sleep behavior disorder tend to occur during the early morning hours. The rapid eye movement sleep behavior disorder is characterized by actual motoric dream enactment during which the patient might kick, jump, or struggle against an imaginary assailant as a result of failure of the customary inhibition of skeletal muscle activity in rapid eye movement sleep by the medullary nucleus gigantocellularis. The nocturnal polysomnogram reveals increased phasic electromyographic activity during rapid eye movement sleep. Although rapid eye movement sleep behavior disorder is infrequent during childhood, sporadic cases do occur. Treatment with clonazepam (0.25 to 0.5 mg at bedtime) is effective in preventing most rapid eye movement parasomnias. Nocturnal paroxysmal dystonia was initially described as a sleep-related movement disorder and a parasomnia of non–rapid eye movement sleep that responded favorably to treatment with carbamazepine. Detailed video-EEG studies have now confirmed, however, that the disorder is a form of nocturnal frontal lobe epilepsy [Zucconi et al., 1998]. It often becomes difficult to distinguish nocturnal seizures from parasomnias. Non–rapid eye movement parasomnias can be distinguished by history from nocturnal seizures because the former are generally time-locked to occur within 2 to 3 hours of initial sleep onset, whereas nocturnal seizures tend to occur randomly through night sleep, sometimes on more than one occasion on a given night. Video-EEG polysomnography plays a crucial role in accurately characterizing the nature of nocturnal spells.

FUTURE TRENDS Future revisions in the International Classification of Sleep Disorders might need to consider the inclusion of some of the newer sleep disorders such as the upper airway resistance syndrome. Normative values for polysomnographic variables in infants and children will become better defined. Improvements in technology and pressures from third party payers are leading to a re-assessment of the role of ambulatory

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Nonepileptiform Paroxysmal Disorders and Disorders of Sleep / 56

(in-home) polysomnography as an alternative to the relatively more expensive sleep laboratory testing. The recent discovery of hypocretin deficiency as the pathophysiologic basis for narcolepsy-cataplexy is likely to spur the development of hypocretin analogs for definitive treatment [John et al., 2000; Mignot et al., 2002]. The link between disrupted sleep, inattentiveness, and impaired learning remains a challenging area of behavioral child neurology, wherein progress is likely once methodologic issues pertaining to the correlation of sleepiness with neuropsychologic disturbance has been firmly established. There may be a greater application of functional neuroimaging to the study of sleep-wake disorders. The discovery of the clock and period genes in Drosophila has also stimulated the study of human chronobiology. In many ways, therefore, sleep medicine is benefiting from recent advances in the neurosciences, genetics, bioinformatics, and biotechnology. REFERENCES Aldrich MS, Chervin RD, Malow BA. Value of the multiple sleep latency test (MSLT) for the diagnosis of narcolepsy. Sleep 1997;20(8):620. Ali NJ, Pitson DJ, Stradling JR. Snoring, sleep disturbance and behavior in 4-5 year olds. Arch Dis Child 1993;68:360. Allen RP, Picchietti D, Hening WA, et al. Restless legs syndrome: Diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med 2003;4:101. American Academy of Pediatrics Policy Statement. Clinical practice guideline: Diagnosis and management of childhood obstructive sleep apnea syndrome. Pediatrics 2002;109:704. American Sleep Disorders Association: The International Classification of Sleep Disorders: Diagnostic and coding manual. Rochester, MN: American Sleep Disorders Association, 1997. Autret A, Lucas F, Henry-Lebras F, de Toffol B. Symptomatic narcolepsies. Sleep 1994;17(Suppl 1):21. Basetti C, Aldrich MS. Idiopathic hypersomnia: A series of 42 patients. Brain 1997;120:1423. Billiard M, Besset A, de Lustrac C, Brissaud L. Dose response effects of zopiclone on night sleep and on night time and day time functioning. Sleep 1987;10(Suppl 1):27. Billiard M, Seignalet J, Besset A, Cadilhac J. HLA DR2 and narcolepsy. Sleep 1986;9:149. Bolk S, Augrist M, Schwartz S, et al. Congenital central hypoventilation syndrome: Mutation analysis of the receptor tyrosine kinase (RET). Am J Med Genet 1996;63:603. Bourgeois B. The relationship between sleep and epilepsy in children. Semin Pediatr Neurol 1996;3(1):29. Britton TC, O’Donoghue M, Duncan JS. Exacerbation of epilepsy by sleep apnea. J Neurol Neurosurg Psychiatry 1997;63:808. Brooks LJ. Genetic syndromes affecting breathing during sleep. In: Lee-Chiong TL, Sateia M, Carskadon MA, eds. Sleep medicine. Philadelphia: Hanley and Belfus, 2002;305. Broughton R, Krupa S, Boucher B, et al. Impaired circadian waking arousal in narcolepsy-cataplexy. Sleep Res Online 1998;1(4):159. Brouillette RT, Morielli A, Leimanis A, et al. Nocturnal pulse oximetry as an abbreviated testing modality for pediatric obstructive sleep apnea. Pediatrics 2000;105:405. Brown LW, Billiard M. Narcolepsy, Kleine-Levin syndrome, and other causes of sleepiness in children. In: Ferber R, Kryger M, eds. Principles and practice of sleep medicine in the child. Philadelphia: WB Saunders, 1995;125. Brunetti L, Rana S, Losppalluti ML, et al. Prevalence of obstructive sleep apnea syndrome in a cohort of 1207 children of Southern Italy. Chest 2001;120:1930. Carskadon MA. The second decade. In: Guillleminault C, ed. Sleeping and waking disorders. Indications and techniques. Menlo Park, CA: Addison Wesley, 1982;99. Carskadon MA, Dement WC, Mitler MM, et al. Guidelines for the multiple sleep latency test (MSLT): A standard measure of sleepiness. Sleep 1986;9:519.

Carskadon MA, Wolfson AR, Acebo C, et al. Adolescent sleep patterns, circadian timing, and sleepiness at a transition to early school days. Sleep 1998;21:871. Challamel MJ, Mazzola ME, Nevsimalova S, et al. Narcolepsy in children. Sleep 1994;17S:17. Challet E, Caldelas I, Graff C, Pevet P. Synchronization of the molecular clockwork by light- and food-related cues in mammals. Biol Chem 2003;384:711. Chervin RD, Archbold KH, Dillon JE, et al. Associations between symptoms of inattention, hyperactivity, restless legs, and periodic leg movements. Sleep 2002;25:213. Cilio MR, Kartashov AI, Vigevano F. The long-term use of felbamate in children with severe refractory epilepsy. Epilepsy Res 2001;47:1. Cole RJ, Smith JS, Alcala YC, et al. Bright-light mask treatment of delayed sleep phase syndrome. J Biol Rhythms 2002;17:89. Colmenero C, Esteban R, Albarino AR, et al. Sleep apnea syndrome associated with maxillofacial abnormalities. J Laryngol Otol 1991;105:94. Corbo GM, Forastiere F, Abigail N, et al. Snoring in 9 to 15 year old children: Risk factors and clinical relevance. Pediatrics 2001;180:1149. Cummiskey J, Guilleminault C, Davis R, et al. Automatic respiratory failure: Sleep studies and Leigh’s disease. Neurology 1987;37:1876. Dauvilliers Y, Mayer G, Lecendreux M, et al. Kleine Levin syndrome. An autoimmune hypothesis based on clinical and genetic analyses. Neurology 2002;59:1739. D’Cruz FO, Vaughn BV. Parasomnias—An update. Semin Pediatr Neurol 2001;8:251. Doherty MJ, Spence DPS, Young C, et al. Obstructive sleep apnea with Chiari malformation. Thorax 1995;50:690. Ellingson RJ, Wilken K, Bennet DR. Efficacy of sleep deprivation as an activating procedure in epilepsy patients. J Clin Neurophysiol 1984;1:83. Garcia J, Rosen G, Mahowald M. Circadian rhythms and circadian rhythm disorders in children and adolescents. Semin Pediatr Neurol 2001;8:229. Givan DC. Sleep in children with neuromuscular disorders. In Lee-Chiong TL, Sateia M, Carskadon MA, eds. Sleep medicine. Philadelphia: Hanley and Belfus, 2002;297. Gozal D. New concepts in abnormalities of respiratory control in children. Curr Opin Pediatr 2004;16:305. Gozal D, Harper RM. Novel insights into congenital hypoventilation syndrome. Curr Opin Pulm Med 1999;5:335. Gozal D, Wang M, Pope DW. Objective sleepiness measures in pediatric obstructive sleep apnea. Pediatrics 2001;108:693. Guilleminault C, Pelayo R, Leger D, et al. Recognition of sleepdisordered breathing in children. Pediatrics 1996;98:871. Hamada T, LeSauter J, Venuti JM, Silver R. Expression of Period genes: Rhythmic and nonrhythmic compartments of the suprachiasmatic nucleus pacemaker. J Neurosci 2001;21:7742. Hungs Fan J, Lin X, Maki RA, Mignot E. Identification and functional analysis of mutations in the hypocretin (orexin) genes of narcoleptic canines. Genome Res 2001;11:531. Ipsiroglu OS, Fatemi A, Werner I, et al. Prevalence of sleep disorders in school children between 11 and 15 years of age (German). Wiener Klinische Wochenschrift 2001;113:235. John J, Wu M-F, Siegel JM. Systemic administration of hypocretin-1 reduces cataplexy and normalizes sleep and waking durations in narcoleptic dogs. Sleep Res Online 2000;3:23. Jouvet M, Petre-Quadens O. Paradoxical sleep and dreaming in the mentally deficient. Acta Neurol Psychiatr Belg 1966;66:116. Kanbayashi T, Inoue Y, Chiba S, et al. CSF hypocretin-1 (orexin-A) concentrations in narcolepsy with and without cataplexy and idiopathic hypersomnia. J Sleep Res 2002;11:91. Kandt RS, Emerson RG, Singer HS, et al. Cataplexy in variant forms of Niemann-Pick disease. Ann Neurol 1982;12:284. Kotagal P. The relationship between sleep and epilepsy. Semin Pediatr Neurol 2001;8:241. Kotagal S. A developmental perspective on narcolepsy. In: Loughlin GM, Carroll JL, Marcus CL, eds. Sleep and breathing. A developmental approach. New York: Marcel Dekker, 2000;347. Kotagal S, Gibbons VP, Stith J. Sleep abnormalities in patients with severe cerebral palsy. Dev Med Child Neurol 1994;36:304. Kotagal S, Goulding PM. The laboratory assessment of daytime sleepiness in childhood. J Clin Neurophysiol 1996;13:208. Kotagal S, Herold DL. The laboratory assessment of childhood sleepwake disorders. Am J End Technol 2002;42:73.

Kotagal / Sleep-Wake Disorders Kotagal S, Silber MH. Childhood-onset restless legs syndrome. Ann Neurol 2004;56:803. Kotagal S, Swink TD. Excessive daytime sleepiness in a 13-year old. Semin Pediatr Neurol 1996;3:170. Labanowski M, Schmidt-Nowara W, Guilleminault C. Sleep and neuromuscular disease: Frequency of sleep-disordered breathing in a neuromuscular disease clinic population. Neurology 1996;47:1173. Landau WM, Kleffner FR. Syndrome of acquired aphasia with convulsive disorder in children. Neurology 1957;7:523. Langdon N, Lock C, Welsh K, et al. Immune factors in narcolepsy. Sleep 1986;9:143. Levanon A, Tarasiuk A, Tal A. Sleep characteristics in children with Down syndrome. J Pediatr 1999;134:755. Littner M, Johnson SF, McCall WV, et al. Practice parameters for treatment of narcolepsy: An update for 2000. Sleep 2001;24:451. Marcus CL, Loughlin GM. Obstructive sleep apnea in children. Semin Pediatr Neurol 1996;3:23. Mignot E, Lin L, Rogers W, et al. Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am J Hum Genet 2001;68:686. Mignot E, Taheri S, Nishino S. Sleeping with the hypothalamus: Emerging therapeutic targets for sleep disorders. Nat Neurosci Suppl 2002;5:1071. Mignot E, Young T, Lin L, Fin L. Nocturnal sleep and daytime sleepiness in normal subjects with HLA-DQB1*0602. Sleep 1999;22:347. Miller JD, MorinLP, Schwartz WJ, Moore RY. New insights into the mammalian circadian clock. Sleep 1996;19:641. Misuri G, Lanini B, Gigliotti F, et al. Mechanisms of CO2 retention in patients with neuromuscular disease. Chest 2000;117:447. Mitler MM. Evaluation of treatment with stimulants in narcolepsy. Sleep 1994;17(Suppl 8):103. Mitler MM, Doghramji K, Shapiro C. The maintenance of wakefulness test. Normative data by age. J Psychosom Res 2000;9:63. Mitler MM, Gujavarty KS, Brownman CP. Maintenance of wakefulness test: A polysomnographic technique for evaluation of treatment efficacy in patients with excessive somnolence. Electroencephalogr Clin Neurophysiol 1982;53:658. Nevsimalova S, Roth B, Zouhar A, Zemanova H. Narkolepsie-kataplexie a periodicka hypersomnie se zacatkem v kojeneckem veku. Cs Pediatr 1986;41:324. Nishino S, Ripley B, Overeem S, et al. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 2000;355:39. Nishino S, Ripley B, Overeem S, et al. Low cerebrospinal fiuid hypocretin (orexin) and altered energy homeostasis in human narcolepsy. Ann Neurol 2001;50:381. O’brien LM, Holbrook CR, Mervis CB, et al. Sleep and neurobehavioral characteristics in 5–7 year old hyperactive children. Pediatrics 2003;111:554. O’brien LM, Mervis CB, Holbrook CR, et al. Neurobehavioral implications of habitual snoring in children. Pediatrics 2004;114:44. Palm L, Persson E, Elmquist D, Blennow G. Sleep and wakefulness in normal pre-adolescents. Sleep 1989;12: 299. Papineau KL, Roehts TA, Petrucelli N, et al. Elecrophysiological Assessment (the multiple sleep latency test) of the biphasic effects of ethanol in humans. Alcohol Clin Exp Res 1998; 2:231. Picchietti DL, Underwood DJ, Farris WA, et al. Further studies on periodic limb movement disorder and restless legs syndrome in children with attention deficit-hyperactivity disorder. Movement Disorders. 1999;14:1000. Poppe M, Friebel D, Reuner U, et al. The Kleine-Levin syndrome—Effects of treatment with lithium. Neuropediatrics 2003;34:113.

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Rondeau BH. Dentist’s role in the treatment of snoring and sleep apnea. Funct Orthodont 1998;15:4. Rosenthal L, Roehrs TA, Rosen A, Roth T. Level of sleepiness and total sleep time following various time in bed conditions. Sleep 1993;16:226. Roshkow JE, Haller JO, Berdon WE, Sane SM. Hirschprung’s disease, Ondine’s curse, and neuroblastoma—Manifestations of neurocristopathy. Pediatr Radiol 1988;19:45. Roth B. Narcolepsy and hypersomnia: Review and classification of 642 personally observed cases. Schweiz Arch Neurol Neurochir Psychiatr 1976;119:31. Sadeh A, Hauri PJ, Kripke DF, Lavie P. The role of actigraphy in the evaluation of sleep disorders. Sleep 1995;18:288. Sharp SJ, D’Cruz OF. Narcolepsy in a 12 month old boy. J Child Neurol 2001;16:145. Shinnar S, Kang H, Berg AT, et al. EEG abnormalities in children with a first unprovoked seizure. Epilepsia 1994;35:471. Silber MH, Krahn LE, Olson EJ, Pankrantz S. Epidemiology of narcolepsy in Olmstead County, Minnesota. Sleep 2002;25:197. Stein MA, Mendelsohn J, Obermeyer WH, et al. Sleep and behavior problems in school-aged children. Pediatrics 2001;107:E60. Stepanski E, Lamphere J, Roehrs T, et al. Experimental sleep fragmentation in normal subjects. Int J Neurosci 1987;33:207. Steriade M, Contreras D, Curro Dossi R, Nunez A. The slow (< 1 Hz) oscillation in reticular thalamic and thalamocortical neurons: Scenario of sleep rhythm generation in interacting thalamic and neocortical networks. J Neurosci 1993;13:3284. Swaminathan S, Gilsanz V, Atkinson J, Keens TG. Congenital central hypoventilation syndrome associated with multiple ganglioneuromas. Chest 1989;96:423. Thannickal TC, Moore RY, Nienhuis R, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 2000;27:469. Trochet D, O’brien LM, Gozal D, et al. PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome. Am J Hum Genet 2005;76:421. Van Cauter E, Plat L. Physiology of growth hormone secretion during sleep. J Pediatr 1996;128(Part 2):S32. Van Someren EJ. More than a marker: Interaction between the circadian regulation of temperature and sleep, age-related changes, and treatment possibilities. Chronobiol Int 2000;17:313. Walters AS. Is there a subpopulation of children with growing pains who really have restless legs syndrome? A review of the literature. Sleep Med 2002;3:93. Weitzman ED, Czeisler CA, Coleman RM, et al. Delayed sleep phase syndrome. A chronobiological disorder with sleep-onset insomnia. Arch Gen Psychiatry 1981;38:737. Wittig R, Zorick F, Roehrs T, et al. Narcolepsy in a 7 year old. J Pediatr 1983;102:725. Zolty P, Sanders MH, Pollack IF. Chiari malformation and sleepdisordered breathing: A review of diagnostic and management issues. Sleep 2000;23:637. Zucconi M. Sleep disorders in children with neurological disease. In: Loughlin GM, Carroll JL, Marcus CL, eds. Sleep and breathing in children. A developmental approach. New York: Marcel Dekker, 2000;363. Zucconi M, Ferini-Strambi L, Oldani A, et al. Nocturnal motor behaviors in children: A video- polysomnographic study. Sleep 1998;21(Suppl):148. Zucconi M, Weber G, Castronovo V, et al. Sleep and upper airway obstruction in children with achondroplasia. J Pediatr 1996;129:743.

CHAPTER 57

The Cerebellum and the Hereditary Ataxias Stephen M. Maricich and Huda Y. Zoghbi

The cerebellum functions mainly to monitor and coordinate complex motor movements. Disruptions of its input or basic structure secondary to developmental anomalies, degenerative diseases, vascular insults, or trauma result in a characteristic spectrum of motor symptoms and signs. Advances in understanding the cellular, molecular, and physiologic composition of the cerebellum have provided new insights into both its normal functions and disruptions in specific disease processes. This chapter begins by describing the basic structure, connectivity, and functions of the cerebellum because this provides a starting point for understanding how the organ functions within the rest of the central nervous system (CNS). Next, derangements of cerebellar function are considered, with a primary emphasis on the hereditary ataxias. Other conditions associated with cerebellar dysfunction also are discussed in this text.

BASIC CEREBELLAR STRUCTURE, FUNCTION AND DYSFUNCTION Cerebellar Structure Anatomically, the cerebellum can be divided in the anteroposterior and mediolateral dimensions (Fig. 57-1A and B). Fissures divide the rostrocaudal length of the cerebellum into 10 lobules, which are analogous to the gyri of the cerebral cortex. These lobules can be grouped into three lobes: the anterior lobe (lobules I through V), the posterior lobe (lobules VI through IX), and the flocculonodular lobe (lobule X) (see Fig. 57-1C). The mediolateral divisions are the vermis, which lies medially, and the hemispheres, which lie laterally and are separated from the vermis by shallow grooves. Functional regions of the cerebral cortex, which roughly correspond to Brodmann’s areas, differ in their cellular histology. The same is not true of the cerebellar cortex. Rather, the same five cell types, arranged in the same relative orientation, are present regardless of anatomic or functional location (Fig. 57-2A). Purkinje cells are among the largest neurons in the CNS, and represent the sole output of the cerebellar cortex. Cerebellar granule cells, which reside in the internal granular layer, form the most numerous neuronal population in the central nervous system (their numbers are nearly equal to all other CNS neurons combined). Granule cells extend long, bifurcated axons (parallel fibers) into the molecular layer, where they travel for several millimeters and synapse with 1000 to 2000 Purkinje cells on their dendritic arbors; in turn, each Purkinje cell forms synapses with as many as 1 million parallel fibers. Granule cells are the only excitatory cell type

in the cerebellar cortex. Three local inhibitory interneurons also reside in the cortex. Golgi type II cells are large neurons found in the internal granular layer that receive mossy fiber inputs and inhibit granule cells. Basket and stellate cells are found in the molecular layer, where they receive excitatory inputs from parallel fibers and are inhibitory to Purkinje cells. The neurons of the deep cerebellar nuclei form four separate clusters in the cerebellar white matter (see Fig. 57-1A). These cells receive inhibitory cortical input from the Purkinje cells and excitatory extracerebellar afferents from climbing and mossy fibers. The fastigial nuclei lie most medially, and receive input from vermal Purkinje cells. The interposed nuclei (nucleus globose and nucleus emboliform) receive input from paravermal Purkinje cells. The dentate nuclei, which are the largest deep cerebellar nuclei in primates, receive input from the cerebellar hemispheres. Along with some Purkinje cells found in the flocculonodular lobe, the deep cerebellar nuclei represent the sole efferent output of the cerebellum, projecting to multiple brainstem nuclei in the medulla and pons, as well as the red nucleus and thalamus. Cerebellar input consists of three classes of afferents. Climbing fibers originate in the inferior olives, which project to the contralateral cerebellar hemisphere. They provide strong excitatory input to Purkinje cells and neurons of the deep cerebellar nuclei. Each climbing fiber synapses on no more than 10 Purkinje cells, whereas each Purkinje cell receives input from only one climbing fiber. Mossy fibers originate in multiple locations in the thalamus, brainstem, and spinal cord and form excitatory synapses on granule cells and Golgi type II neurons in the internal granular layer, as well as on neurons of the deep cerebellar nuclei. Climbing fibers, and to a lesser extent mossy fibers, are arranged in a series of parasagittal bands that “stack” next to one another in the mediolateral dimension (see Fig. 57-2B); the functional significance of this arrangement is discussed later in the chapter. Finally, multilayer fibers originate in the hypothalamus, locus ceruleus, and raphe nuclei and form a diffuse fiber network in the cortex and deep cerebellar nuclei. Like the cerebral cortex, cerebellar cortical afferents and efferents are arranged in a somatotopic manner [Manni and Petrosini, 2004]. This organization is more complex than that of the cerebral cortex in two ways. First, at least three separate homunculi (one in the anterior lobe and one in each of the paravermian lobules) can be identified (Fig. 57-3A). These are believed to converge on separate, continuous somatotopic maps in the four cerebellar nuclei. This arrangement, which was initially described in other species, has recently been directly demonstrated in humans using functional neuroimaging [Bushara et al., 2001; Manni and

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Disorders of Balance and Movement / 57 Caudate nucleus Putamen Internal capsule Thalamus

Primary fissure

Vermis

Hemisphere

FIGURE 57-1. A, Dorsal view of the human cerebellum. The deep cerebellar nuclei are shown in their approximate positions. B, Ventral view of the human cerebellum. The brainstem is cut away, and the cerebellar peduncles are labeled. C, Sagittal midline section of human cerebellum. The lobules are labeled, and the anterior, posterior and flocculonodular lobes are shaded with different tones for easier distinction. Dorsal is at the top of the photograph, and anterior is to the right. (A and B, From Kandel ER and Schwartz, JH, eds. Principles of neural science, 2nd ed. New York: Elsevier, 1985;504; C, Photograph courtesy of Dr. Dawna Armstrong.)

Cerebellar peduncles: Superior Middle Inferior Dentate nucleus Emboliform nucleus Globose nucleus Fastigial nucleus Tonsil

A IV III

V

II Anterior lobe

I

VI Fourth ventricle

Posterior lobe Cerebellar peduncles: Superior Middle Inferior

Flocculonodular lobe: Nodulus Flocculus

VII

IX VIII

Nodulus (X)

Tonsil

Tonsil Posterolateral fissure

B

C

Petrosini, 2004; Rijntjes et al., 1999]. Second, the sensory map within a cerebellar folium is not continuous. Instead, a fractured somatotopy exists, in which each region of the face or limb has multiple representations within the folium that may not be directly adjacent to one another (see Fig. 57-3B). The reason for this arrangement is unknown but may be necessary to bring climbing fiber and mossy fiber inputs into register with one another.

Three major fiber tracts connect the cerebellum with the rest of the neuraxis. The inferior cerebellar peduncle, or restiform body, contains mossy fiber projections from the spinal cord (dorsal spinocerebellar tract) and medulla (cuneocerebellar, vestibulocerebellar, reticulocerebellar, arcuatocerebellar, and trigeminocerebellar tracts) and climbing fibers from the inferior olives. Cerebellovestibular and cerebelloreticular efferents also course through this

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SC

GII

BC

ML

PCL

IGL

A

WM

IGL

PCL

ML

B

FIGURE 57-2. A, Major cell types of the cerebellar cortex. This is a representation of a sagittal section through a cerebellar folium. Granule cell parallel fibers are omitted for clarity. B, Climbing fiber input delineates parasagittal Purkinje cell bands that run perpendicular to parallel fiber input. Purkinje cells in the same band tend to project to the same cells in the deep cerebellar nuclei. (B, From Kandel ER, Schwartz JH, and Jessel TM, eds. Principles of neural science, 4th ed. New York: McGraw-Hill, 2003;838.)

tract. The middle cerebellar peduncle, or brachium pontis, is the largest peduncle and contains primarily cerebellar afferents from the pons. The superior cerebellar peduncle, or brachium conjunctivum, connects the cerebellum to the midbrain. It is mainly an efferent pathway, connecting the cerebellum to the red nucleus and thalamus via the dentatorubral and dentatothalamic tracts, and contains outputs to the vestibular nuclei and reticular formation as well. Afferents from the ventral spinocerebellar, tectocerebellar, trigeminocerebellar, and cerulocerebellar tracts also travel within it.

Cerebellar Function As a whole, the cerebellum functions to integrate multiple sources of sensory information, then uses this information to

coordinate motor movements and direct motor learning. Three main anatomic regions divide up these tasks. The archicerebellum, also called the vestibulocerebellum, roughly corresponds to the flocculonodular lobe. This division makes connections with the vestibular nuclei and is integrally involved in the maintenance of balance and the control of reflexive head and eye movements. The paleocerebellum, or spinocerebellum, consists of the vermis and paravermal (intermediate) regions of the cerebellar hemispheres, and the fastigial and interposed nuclei. The spinocerebellum functions in the regulation of limb movement and posture. The neocerebellum, or cerebrocerebellum, is made up of the lateral hemispheres and dentate nuclei. In primates, the cerebrocerebellum is the largest division and is involved not only in the planning of movements but also in motor learning.

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Anterior lobe Posterior lobe Flocculonodular lobe

the underlying function of the cerebellum. Comparison of climbing fiber to mossy fiber excitatory inputs within these bands may be important for refining movements and motor learning [Ito, 2002]. It has also been proposed that mossy fiber input, which is translated through granule cells and their parallel fibers, could transform spatial relationships into temporal ones as the signal beam passes from Purkinje cells closest to the granule cells to those farther down the parallel fiber path. The receptive Purkinje cells could then detect timing differences between the incoming granule cell and climbing fiber signals. Thus, the cerebellum could act as an alarm clock, stopwatch, or coincidence/time shift detector [Braitenberg, 1961, 1967]. Recent studies using advanced imaging techniques such as functional magnetic resonance imaging and positronemission tomography scanning suggest that the cerebellum is also involved in several nonmotor functions. These include sensory discrimination, attention, working memory, semantic association, verbal learning, memory, and complex problem solving [Allen et al., 1997]. In addition, a number of studies have linked the cerebellum to various higher-order cognitive processes [Daum and Ackermann, 1995; Leiner and Leiner, 1991; Middleton and Strick, 1994]. Most of these functions are subserved by the cerebellar hemispheres and the dentate nuclei.

I II III IV V VI VII A VII B VIII

IX

X

A

Cerebellar Dysfunction

1 mm

1 cm

B FIGURE 57-3. A, Sensorimotor representation in the human cerebellar cortex based on functional MRI data. The face representation is not shown. B, Fractured somatotopy of the cerebellum. Patches of tactile projections to left paramedian lobe. Black patches on body figurines depict receptive fields, which optimally activate multiple units in granular cell layer at sites marked by black dots in inset. MRI, magnetic resonance imaging. (A, From Manni E and Petrosini L. A century of cerebellar somatotopy: A debated representation. Nat Rev Neurosci 2004:5;241; B, From King JS, ed. Neurology and neurobiology, vol. 22. New York: AR Liss, 1987. Reprinted with permission of Wiley-Liss Inc., a subsidiary of John Wiley & Sons, Inc.)

As previously described, cerebellar afferent input is predominantly segregated into a series of parasagittal bands. This parasagittal arrangement is thought to be essential to

Cerebellar lesions or dysfunction disturb regulation of muscle tone, motor control, and coordination of movement. The constellation of symptoms is sometimes useful for localizing the cerebellar lesion, but often there is considerable overlap. Hypotonia is a decrease in muscle tone in response to stretch. It is typically seen with acute cerebellar hemispheral lesions and is often accompanied by hyporeflexia. Hypotonia likely results from decreased fusimotor activity resulting in decreased muscle spindle afferent response. It is usually a transient phenomenon after an acute lesion but can be seen in chronic lesions as well. Ataxia is a broad term that refers to a disturbance in the smooth performance of voluntary motor acts. It includes abasia (unsteadiness of stance), asynergia (decomposition of complex movements into isolated, successive parts), dysmetria (abnormal excursions in movement), dysdiadochokinesis (impaired performance of rapid alternating movements), and impaired check/excessive rebound responses. Vermal lesions result in truncal ataxia and titubation (a bobbing of the head predominantly in the anteroposterior dimension), whereas hemispheric lesions cause limb ataxia. Cerebellar dysarthria is characterized by abnormalities in articulation and prosody of speech. Slow, staccato, or scanning speech with uneven articulation or phonation can result from hemispheric damage and may be a manifestation of dysdiadochokinesis or hypotonia, or both. There is also evidence that left cerebellar lesions interfere with speech prosody because of disruptions of interconnections with the right cerebral hemisphere, which mediates this process [Brazis et al., 2001]. Cerebellar mutism is sometimes seen after removal of vermian tumors and may result from bilateral involvement of the dentatorubrothalamic tracts. Intention tremor can occur after lesions of the dentate nuclei and is manifest only when the individual attempts to

Maricich and Zoghbi / The Cerebellum and the Hereditary Ataxias

make a directed movement. Postural tremor is a rare manifestation of cerebellar damage. Eye movement abnormalities, predominantly in the form of nystagmus, are also a manifestation of cerebellar disease. They usually occur when the vermis or flocculonodular lobe is affected. Ocular dysmetria (conjugate overshoot or undershoot of a visual target accompanied by voluntary saccades) can result from midline or hemispheric lesions. Nonmotor manifestations of cerebellar disease can also occur. A cerebellar cognitive affective syndrome has been described in patients with isolated cerebellar lesions resulting from a number of different etiologies [Schmahmann and Sherman, 1998]. In this syndrome, executive functions, spatial cognition, personality changes, and language deficits are present. The postulated neural substrate involves circuits that link prefrontal, posterior parietal, superior temporal, and limbic cortices to the cerebellum. Disorders that specifically affect different cerebellar subdivisions lead to a characteristic spectrum of motor abnormalities. Midline cerebellar disease causes disorders of stance and gait, truncal titubation, rotated postures of the head, and disturbances in eye movements. These can be subdivided into rostral vermal lesions that result in abasia and gait ataxia, and caudal vermal lesions that add nystagmus as well. Likewise, lesions of the fastigial nuclei, which receive their input from the vermis, also result in abasia. Intermediate hemisphere disease or lesions of the interposed nuclei cause delayed check (rebound) responses, truncal titubation, abnormal rapid alternating movements, action tremor, oscillation of outstretched extremities, and ataxia on finger-nose-finger and heel-knee-shin maneuvers. Disruption of the cerebellar hemispheres and dentate nuclei result in dysarthria, limb ataxia, hypotonia, terminal and intention tremor, and abnormal eye movements.

DIFFERENTIAL DIAGNOSIS OF ATAXIA The underlying cause of ataxia is virtually always primary or secondary dysfunction of the cerebellum. Cerebellar disease is a result of a number of underlying conditions, many of which are listed in Box 57-1. The most prevalent causes of acute cerebellar ataxia are viral infections (e.g., coxsackievirus, rubeola, varicella), toxins (e.g., alcohol, barbiturates, antiepileptic drugs), and trauma. Tumors of the cerebellum (vermal and hemispheric) and tumors of the brainstem, particularly pontine gliomas, are also relatively common. Numerous metabolic conditions affecting the central and peripheral nervous systems lead to ataxia. Congenital abnormalities of the nervous system, particularly those related to Chiari malformation, Dandy-Walker malformation, and basilar impression, are associated with ataxia. Endocrinologic abnormalities, particularly hypothyroidism, may also present with ataxia as the predominant manifestation. Vascular abnormalities are unusual, but cerebellar hemorrhage, infarction, and embolism do occur. Angioblastomas of the cerebellum are rare; von Hippel-Lindau disease, a neurocutaneous condition, is associated with vascular lesions of the cerebellum, as is the PHACE (Posterior fossa malformations, Hemangiomas, Arterial anomalies, Coarctation of aorta and Cardiac defects, and Eye abnormalities) syndrome [Frieden et al., 1996]. Although

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psychogenic presentation in the form of conversion reaction can suggest the presence of ataxia, careful examination often discloses incongruencies in the findings, distinguishing the motor difficulties from true ataxia.

MANAGEMENT OF CEREBELLAR DYSFUNCTION AND ATAXIA When ataxia is the result of specific metabolic disorders, specific therapies are sometimes possible (Table 57-1). The presence of toxins, trauma, and neoplasms requires specific therapy for the underlying condition. Patients may require various aids for ambulation. Most often, physical therapy and occupational therapy are not significantly helpful in moderate-to-severe ataxia.

THE HEREDITARY ATAXIAS Classification of the hereditary ataxias has long posed a significant challenge. Before the advent of gene cloning technology, these conditions were classified based on their mode of inheritance, clinical features, and pathologic findings. These approaches ultimately proved to be unsatisfactory and often led to more confusion than clarity. Patients with known hereditary ataxia have a range of cerebellar dysfunction that may be exclusively cerebellar in origin or combined with other features including brainstem dysfunction, spinal cord abnormalities, extrapyramidal findings, neuropathy, retinopathy, deafness, cataracts, seizures, and dementia [Berciano, 1982; Greenfield, 1954; Harding et al., 1985; Koeppen and Barron, 1984; Zoghbi, 1993]. The age of onset and clinical manifestations of any given disorder may differ significantly from family to family and even in the same kindred, making specific assignment beyond mode of inheritance difficult [Currier et al., 1972; Zoghbi and Caskey, 1998]. Likewise, attempts to classify ataxia according to the anatomic site of the most dominant pathology (e.g., spinal cord, cerebellum) are also flawed. Descriptors such as “olivopontocerebellar atrophy,” a pathologic finding seen most predominantly in the dominantly inherited ataxias, do not adequately serve to distinguish between them. The application of genetic and molecular biologic techniques to the hereditary ataxias has resulted in the most precise classification scheme to date and will ultimately provide insight into pathologic mechanisms and possible therapeutic interventions. There has been an explosion of knowledge in this area over the past 20 years, with a concomitant expansion in the number of new hereditary ataxias identified as old classifications are found to be groupings of genetically unrelated disorders. The following sections subdivide the hereditary ataxias by their predominant mode of inheritance. Chromosomal loci, genes and gene products, and molecular mechanisms are presented where they are known.

Autosomal-Recessive Inherited Syndromes The autosomal-recessive inherited ataxias (summarized in Table 57-2) are a varied group of disorders that tend to have

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Box 57-1 SELECTED CAUSES OF ATAXIA IN CHILDHOOD Congenital Agenesis of vermis of the cerebellum Aplasia or dysplasia of the cerebellum Basilar impression Chiari malformation Cerebellar dysplasia with microgyria, macrogyria, or agyria Cervical spinal bifida with herniation of the cerebellum (Chiari malformation, type 3) Dandy-Walker syndrome Encephalocele Hydrocephalus (progressive) Hypoplasia of the cerebellum Degenerative and/or Genetic Acute intermittent cerebellar ataxia [Hill and Sherman*] Ataxia, retinitis pigmentosa, deafness, vestibular abnormality, and intellectual deterioration [Francois and Descampas*] Ataxia-telangiectasia Biemond’s posterior column ataxia Cerebellar ataxia with deafness, anosmia, absent caloric responses, nonreactive pupils, and hyporeflexia [Brown, 1959] Cockayne’s syndrome Dentate cerebellar ataxia (dyssynergia cerebellaris progressiva) Familial ataxia with macular degeneration [Foster and Ingram*] Friedreich’s ataxia Hereditary cerebellar ataxia, intellectual retardation, choreoathetosis, and eunuchoidism [Altchule and Kotowski*] Hereditary cerebellar ataxia with myotonia and cataracts [Brown, 1959] Hypertrophic interstitial neuritis Marie’s ataxia Marinesco-Sjögren syndrome Pelizaeus-Merzbacher disease Periodic attacks of vertigo, diplopia, and ataxia—autosomal-dominant inheritance [Farmer and Mustian*] Posterior and lateral column difficulties, nystagmus, and muscle atrophy [Burge and Wuthrich*] Progressive cerebellar ataxia and epilepsy [von Bogaert and Colle*] Ramsay Hunt disease (myoclonic seizures and ataxia) Roussy-Lévy disease Spinocerebellar ataxia (SCA); olivopontocerebellar ataxias Endocrinologic Acquired hypothyroidism Cretinism Infectious or Postinfectious Acute cerebellar ataxia Acute disseminated encephalomyelitis Cerebellar abscess Coxsackievirus Diphtheria Echovirus Fisher’s syndrome Infectious mononucleosis (Epstein-Barr virus infection) Infectious polyneuropathy Japanese B encephalitis Mumps encephalitis Mycoplasma pneumoniae Pertussis Polio Postbacterial meningitis Rubeola Tuberculosis Typhoid Varicella *Cited in Brown, 1962.

Metabolic Abetalipoproteinemia Argininosuccinic aciduria Ataxia with vitamin E deficiency (AVED) GM2 gangliosidosis (late) Hartnup’s disease Hyperalaninemia Hyperammonemia I and II Hypoglycemia Kearns-Sayre syndrome Leigh’s disease Maple syrup urine disease (intermittent) Myoclonic epilepsy with ragged red fibers Metachromatic leukodystrophy Mitochondrial complex defects (I, III, IV) Multiple carboxylase deficiency (biotinidase deficiency) Neuronal ceroid-lipofuscinosis Neuropathy, ataxia, retinitis pigmentosa (NARP) Niemann-Pick disease (late infantile) 5-Oxoprolinuria Pyruvate decarboxylase deficiency Refsum’s disease Sialidosis Triose-phosphate isomerase deficiency Tryptophanuria Wernicke’s encephalopathy Neoplastic Frontal lobe tumors Hemispheric cerebellar tumors Midline cerebellar tumors Neuroblastoma Pontine tumors (primarily gliomas) Spinal cord tumors Primary Psychogenic Conversion reaction Toxic Alcohol Benzodiazepines Carbamazepine Clonazepam Lead encephalopathy Neuroblastoma Phenobarbital Phenytoin Primidone Tic paralysis poisoning Traumatic Acute cerebellar edema Acute frontal lobe edema Vascular Angioblastoma of cerebellum Basilar migraine Cerebellar embolism Cerebellar hemorrhage Cerebellar thrombosis Posterior cerebellar artery disease Vasculitis von Hippel-Lindau disease

Maricich and Zoghbi / The Cerebellum and the Hereditary Ataxias

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TABLE 57-1 Treatable Causes of Inherited Ataxia DISORDER

METABOLIC ABNORMALITY

DISTINGUISHING CLINICAL FEATURES

TREATMENT

Ataxia with vitamin E deficiency

Mutation in α-tocopherol transfer protein Abetalipoproteinemia

Ataxia, areflexia, retinopathy

Vitamin E

Bassen-Kornzweig syndrome

Mitochondrial complex defects

Acanthocytosis, retinitis pigmentosa, fat malabsorption Tryptophan malabsorption Pellagra rash, intermittent ataxia Mutations in potassium channel Episodic attacks, worse with pregnancy or birth control pills (KCNA1) and α1A voltage-gated calcium channel, respectively Complexes I, III, IV Encephalomyelopathy

Multiple carboxylase deficiency

Biotinidase deficiency

Pyruvate dehydrogenase deficiency Refsum’s disease

Block in E-M and Krebs cycle interface Phytanic acid, α-hydroxylase

Urea cycle defects

Urea cycle enzymes

Hartnup’s disease Familial episodic ataxia type 1 and type 2

Alopecia, recurrent infections, variable organic aciduria Lactic acidosis, ataxia Retinitis pigmentosa, cardiomyopathy, hypertrophic neuropathy, ichthyosis Hyperammonemia

Vitamin E Niacin Acetazolamide Possibly riboflavin, CoQ10, dichloroacetate Biotin Ketogenic diet, possibly dichloroacetate Dietary restriction of phytanic acid Protein restriction, arginine, benzoate, α-ketoacids

Modified from Stumpf DA. The inherited ataxias. Pediatr Neurol 1985;1:129.

an early age of onset in infancy or childhood. They can involve multiple regions of the central and peripheral nervous systems. In general, earlier age of onset usually heralds a more aggressive disease course. Several causative mutations have been identified, leading to a clear genetic classification scheme.

Friedreich’s Ataxia (Spinocerebellar Ataxia; MIM 229300) Friedreich’s ataxia is one of the most common hereditary ataxias, with a prevalence of approximately 1 to 2 per 100,000 in the general population [Harding, 1984]. Whites are affected more often than other racial groups, with a

prevalence closer to 1 per 50,000 [Cossée et al., 1997]. Clinically, the disease is signaled by the presence of ataxia and corticospinal tract impairment. Other associated features include nystagmus, kyphoscoliosis, and an unusual cardiomyopathy. Originally reported by Friedreich [1863], who believed the disease was associated only with spinal cord abnormalities, subsequent findings demonstrated involvement of the medulla, peripheral nerves, and cerebral cortex in some cases.

CLINICAL MANIFESTATIONS Symptoms typically begin in the last half of the first decade, although onset may be detected at age 2 years or may be delayed until the second decade [Harding, 1981]. The initial

TABLE 57-2 Autosomal Recessive Cerebellar Ataxias ATAXIA

CHROMOSOME

GENE

GENE PRODUCT

MECHANISM

AGE OF ONSET (YEARS)

Friedreich’s ataxia Friedreich’s ataxia 2 AVED

9q13 9p23-p11 8q13

X25 Unknown TTP1

Frataxin Unknown TTPA

2-51 5-20 2-52

Ataxia-telangiectasia

11q22.3

ATM

ATM

Ataxia-telangiectasia–like disorder Ataxia-ocular apraxia 1

11q21

hMRE11

MRE11A

9p13.3

APTX

Aprataxin

Ataxia-ocular apraxia 2

9q34

SETX

Senataxin

Ataxia, Cayman type IOSCA Progressive Myoclonic Epilepsy ARSACS

19q13.3 10q24 21q22.3

ATCAY Unknown CST6

Caytaxin Unknown Cystatin B

GAA repeat Unknown Missense mutation, deletion, insertion Missense and deletion mutations Missense and deletion mutations Frameshift, missense, nonsense mutations Frameshift, missense, nonsense mutations Missense mutation Unknown 5′ Dodecamer repeat

13q12

SACS

Sacsin

Frameshift and nonsense mutations

1-20

Infancy 9-48 months 2-18 9-22 Birth 9-24 months 6-13

APTX, aprataxin gene; ARSACS, autosomal recessive spastic ataxia of Charlevoix-Saguenay; ATCAY, Cayman-type cerebellar ataxia gene; ATM, ataxia-telangiectasia mutated gene; AVED, ataxia with vitamin E deficiency; CST6, cystatin 6 gene, hMRE11, meiotic recombination 11 gene; IOSCA, infantile-onset spinocerebellar ataxia; SACS, sacsin gene; SETX, senataxin gene; TTP1, tocopherol transfer protein 1 gene.

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presentation is usually progressive gait ataxia and slowing. The pattern of gait may be extremely wide, and may have a reeling or lurching quality. Asymmetries are sometimes present but more commonly both legs are equally involved. Bladder dysfunction may manifest at any time during the disease course; symptoms of spastic bladder are common. Difficulties with the upper extremities and distal muscle wasting become apparent as the disease progresses. Incoordination of the arms becomes evident, limb and head tremor begins, and choreiform movements of the arms and face are often seen. Lateral or horizontal nystagmus may be prominent, and visual pursuit is punctuated with small jerks. Muscles of speech become involved, and cerebellar dysarthria is seen. The dysarthria rapidly worsens, and the patient’s speech is rendered ineffective early in the disease course. Difficulties in swallowing, if present, are delayed until the terminal phases. Cranial nerve involvement is not limited to nerves VII, XI, and XII. Impairment of pupillary responsivity and limited extraocular movements are also common. Additional ophthalmologic abnormalities include cataracts, retinitis pigmentosa, and optic atrophy. Auditory dysfunction is common [Cassandro et al., 1986] and is documented by abnormal brainstem auditory-evoked potentials that are likely the result of impairment of both central and peripheral acoustic pathways [De Pablos et al., 1991; Knezevic and Stewart-Wynne, 1985]. The degree of hearing compromise is variable. Vertigo has been reported to accompany this condition. Although higher cortical function appears intact when evaluated clinically, some studies suggest a decrease in speed of information processing [Hart et al., 1985; 1986]. Examination reveals that deep tendon reflexes are absent after the illness has been present for a short time; the patellar reflexes are often lost first. The deep tendon reflexes may be preserved for a longer period in young children [Salih et al., 1990]. Bilateral extensor toe signs are easily elicitable. Cremasteric and abdominal reflexes may be lost. The masseter reflex remains intact [Auger, 1992]. Occasionally weakness, muscle atrophy, and profound hypotonia may be evident, usually associated with spinal nerve disintegration. As mentioned, virtually all facets of cerebellar function are involved, and both gross and fine coordination are affected. Position sense, vibration sense, and other skills requiring normal posterior column function are grossly impaired. Autonomic innervation of superficial layers of skin may be involved. Pain and temperature sensation are usually intact, although some impairment may be present late in the course of the illness. Evidence of axonal sensory neuropathy indicated by electrodiagnostic studies is invariably present. Somatosensory-evoked potentials are abnormal, as is central motor function as determined by magnetic stimulation [Claus et al., 1988]. Patients with Friedreich’s ataxia virtually always have talipes equinovarus and pes cavus. Grotesque deformities of the hand, including the claw deformity, can occur. Flexor spasms with attendant pain may be a great source of discomfort. Many patients suffer from kyphoscoliosis [Daher et al., 1985; Labelle et al., 1986] and may be unable to walk secondary to poor balance and an abnormally shifted center of gravity (Fig. 57-4). Surgical intervention may correct the abnormal spinal curve, but an absence of compensation by the impaired motor system may still render the patient unable to ambulate.

FIGURE 57-4. Friedreich’s ataxia and moderate scoliosis in a 13-year-old boy who is unable to walk independently.

Cardiomyopathies are the most common accompanying cardiac abnormalities, although congenital heart disease has been described. The cardiomyopathy is often progressive and is documented even before clinical manifestations by the presence of electrocardiogram abnormalities (e.g., deep Q waves, low wave QRS complexes, S-T segment changes, T-wave inversion) [Child et al., 1986; Harding and Hewer, 1983; Heck, 1963]. Dysrhythmias may be particularly worrisome and life threatening [Baldwin and Lane, 1987]. Electrocardiogram and vectorcardiographic changes are demonstrable in more than 90% of patients [Child et al., 1986]. Left ventricular hypertrophy or symmetric ventricular hypertrophy is frequently evident on echocardiography [Pentland and Fox, 1983]. Hypertrophic cardiomyopathy is the leading cause of death in Friedreich’s ataxia patients. Diabetes mellitus is associated with Friedreich’s ataxia; even in its absence, the glucose tolerance curve may be abnormal. Insulin resistance appears to be the explanation

Maricich and Zoghbi / The Cerebellum and the Hereditary Ataxias

[Fantus et al., 1991; Khan et al., 1986]. Unaffected relatives may also manifest insulin resistance. Episodic hypothermia, intermittent vomiting, and ventilatory dysfunction have also been reported [Heck, 1963; Thoren, 1959, 1962]. Imaging studies reveal both structural and functional changes that correlate with pathologic changes. MRI studies document atrophy of the upper cervical spinal cord and cerebellum [Wessel et al., 1989]. Positron emission tomography demonstrates a widespread increase in cerebral metabolic rate for glucose in the brain of ambulatory patients with Friedreich’s ataxia. As the disease progresses, glucose metabolism decreases in a regionally specific manner; only the caudate and lenticular nuclei have increased metabolic rate in nonambulatory patients [Gilman et al., 1990]. Diagnosis is suggested by the presence of the expected clinical manifestations and sometimes by family history. Distinct diagnostic criteria for diagnosing Friedreich’s ataxia were advanced by Geoffroy and colleagues [1976]. These criteria included autosomal-recessive inheritance, onset before 10 years of age, gait ataxia, dysarthria, absent deep tendon reflexes, dorsal column signs, and weakness. The presence of an abnormal 5-hour glucose tolerance curve may be corroborative. Spinal fluid findings may include elevated protein content and mild pleocytosis.

PATHOLOGY The primary site of involvement on pathologic examination is the spinal cord. Gross examination reveals a shrunken cord with the posterior columns, spinocerebellar tracts, corticospinal tracts, and posterior rootlets strikingly involved by varying degrees of fiber loss, demyelination, and gliosis. Axons and myelin alike are involved, although the medullary nuclei (Burdach’s nuclei) are usually spared [Greenfield, 1954]. Structures in the medial root zone, including ganglion cells and the posterior roots that terminate within them, manifest varying degrees of involvement but are typically decreased in number. The lumbar and sacral roots are most severely affected, and the large, myelinated lumbar spinal nerves lose many axons. In contrast, anterior horn cells and their rootlets are usually uninvolved; however, minor pathologic alterations may be evident. Although reported, myopathic changes are rare. At the gross level the cerebellum, brainstem, and cerebral hemispheres are relatively normal. However, microscopic study of the cerebellum often reveals varying degrees of cerebellar cortical degeneration with minimal involvement of the deep nuclei. The inferior olives, vestibular nuclei, and pontine nuclei may be involved to varying degrees. In the cerebrum, subtle neuronal changes affecting Betz cells in the motor strip have been reported. Reduction in the density of large myelinated fibers in sural nerve biopsies can be present even in young children, and often worsens with age [Said et al., 1986]. Pathologic changes in the heart include evidence of cardiomyopathy and involvement of blood vessels, nerves, and ganglia [James et al., 1987].

GENETICS Friedreich’s ataxia is transmitted as an autosomal-recessive disorder; the finding of consanguinity among several fam-

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ilies clearly supported the autosomal-recessive inheritance pattern. The disease affects males and females equally. The establishment of the criteria proposed by Geoffroy and coworkers [1976] provides a basis for research studies and allows clinical identification of families for linkage studies. Genetic linkage studies mapped the Friedreich’s ataxia gene to chromosome 9 and confirmed that the “Acadian” form of ataxia characterized by a slower course of degeneration [Barbeau et al., 1984; Keats et al., 1989] also maps to chromosome 9 [Chamberlain et al., 1988; Fujita et al., 1989; Keats et al., 1989]. Friedreich’s ataxia is caused by the decreased expression of a mitochondrial protein, frataxin, encoded by the X25 gene located at 9q13 [Bidichandani et al., 1998; Koeppen, 1998; Montermini et al., 1995]. Campuzano and co-workers [1996] were the first to identify an unstable GAA trinucleotide repeat in the first intron of X25 [Campuzano et al., 1996]. They also identified three different point mutations. In the group of 74 patients without a point mutation, 71 were homozygous for expanded alleles, and 3 were heterozygous for the expanded repeat. Five patients with point mutations were heterozygous for the expansion. The size of the repeat ranged from 7 to 22 on normal alleles and from 200 to 900 on Friedreich’s ataxia chromosomes. Further studies revealed that the triplet repeat could get as large as 1700 units, and that the lengths of both the larger and smaller expanded alleles correlated inversely with the age of onset and severity of disease [Durr et al., 1996; Filla et al., 1996]. The mean allele length is significantly higher in Friedreich’s ataxia patients with diabetes, cardiomyopathy, and loss of reflexes in the upper extremities. Of 187 patients with autosomalrecessive ataxia, 140 were homozygous for a GAA expansion [Durr et al., 1996]. Approximately one fourth of the patients had atypical Friedreich’s ataxia with retained deep tendon reflexes and/or later onset of disease, suggesting that the clinical spectrum of Friedreich’s ataxia is wider than expected, and that deoxyribonucleic acid (DNA)–based testing is the most accurate means for diagnosis and subsequent genetic counseling. Frataxin is localized to the inner mitochondrial membrane and is thought to play a role in mitochondrial respiration and iron accumulation. Deletion of the frataxin homolog in yeast leads to mitochondrial iron accumulation and increased susceptibility to oxidative stress, with an increased production of free radicals [reviewed in Voncken et al., 2004]. These observations, coupled with the fact that expanded trinucleotide repeats interfere with transcription elongation of the X25 gene and cause a frataxin deficiency state, might explain the human phenotype [Bidichandani et al., 1998]. The production of a viable animal model has been complicated by early embryonic lethality in X25-null mice and absence of a phenotype in mice that have had a human FRDA allele “knocked-in” to the murine locus. Data from yeast, a mouse model, and human fibroblast experiments have led to the hypothesis that frataxin plays a role in the biosynthesis of iron/sulfur complex–containing proteins, which are critical elements in the mitochondrial respiratory chain [Voncken et al., 2004]. Frataxin has also been found to function as an iron chaperone protein that aids in the regeneration of aconitase, an enzyme essential in the citric acid cycle [Bulteau et al., 2004]. Why only selective neuronal systems are vulnerable to the loss of frataxin function remains unknown.

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TREATMENT Given the proposed function of frataxin protein in iron or sulfur cluster biosynthesis and the increased oxidative stress found with decreased protein levels, several groups have initiated treatment with idebenone, a short-chain analog of coenzyme Q10 [Buyse et al., 2003; Hausse et al., 2002; Mariotti et al., 2003; Rustin et al., 1999; Schols et al., 2001]. All but one of these trials (the shortest trial) have demonstrated improved cardiac function and decreased ventricular mass, which are important findings because cardiac dysfunction is the leading cause of death in Friedreich’s ataxia patients. Unfortunately, idebenone treatment has no effect on the progression of ataxia. Therapy with other antioxidants, iron chelators, or glutathione peroxidase mimetics has been suggested (and in some cases tried), but no clear beneficial effect has been established. Symptomatic treatment in the form of antispasticity agents can be helpful to relieve painful muscle spasms, and surgical correction of scoliosis can sometimes be palliative, at least for a time.

Friedreich’s Ataxia 2 (MIM 601992) Other families with a Friedreich’s ataxia disease phenotype but without point mutations or GAA expansions in the X25 gene have been described [Christodoulou et al., 2001; Kostrzewa et al., 1997]. In one family, linkage to a locus on chromosome 9p23-p11 has been found [Christodoulou et al., 2001]. The biologic basis for the genocopy is not known, but it has been proposed that mutations in genes in the iron metabolism pathway may be responsible.

Vitamin E Deficiency and Related Syndromes Ataxia with isolated vitamin E deficiency (MIM 277460) is a rare but important cause of early onset ataxia. The clinical presentation closely resembles that of Friedreich’s ataxia with the exceptions that cardiac involvement is rarely seen, diabetes is not part of the clinical constellation, and occasionally head titubation and/or dystonia is present. Symptoms typically begin in childhood or adolescence. Similar features can be seen in individuals with malabsorption syndromes, chronic steatorrhea, abetalipoproteinemia (Bassen-Kornzweig disease), or primary vitamin E deficiency; these individuals should be identified by their risk factors. Numerous mutations have been identified in the tocopherol transfer protein gene (TTP1), which encodes the α-tocopherol transfer protein (TTPA) [Cavalier et al., 1998; Ouahchi et al., 1995]. TTPA is expressed in the liver and is responsible for the incorporation of tocopherol (vitamin E) into very-low-density lipoprotein [Traber et al., 1990]. Mutations in the gene disrupt vitamin E recycling, leading to its rapid elimination from the body and a profound deficiency state. Because this disease is treatable, all patients with a Friedreich’s ataxia phenotype should be evaluated for vitamin E deficiency. Supplementation rapidly normalizes plasma vitamin E levels and halts disease progression. Unfortunately, once symptoms occur, recovery of neurologic deficits may be incomplete.

Ataxia-Telangiectasia (Louis-Bar Syndrome; MIM 208900) Ataxia-telangiectasia is one of the most common inherited causes of early childhood–onset ataxia in most countries, with a prevalence of one in 40,000 to 100,000 live births in the United States. The disease is characterized by progressive cerebellar ataxia, ocular apraxia, oculocutaneous telangiectasias, choreoathetosis, proclivity to sinopulmonary infections, and lymphoreticular neoplasia. Death often occurs by the fourth or fifth decade of life, typically resulting from sinopulmonary disease, neoplasms, or neurologic deterioration. The initial clinical description of this disease was reported by Syllaba and Henner [1926], who called it congenital double athetosis-aconjunctival vascular plexus syndrome [Syllaba and Henner, 1926]. Louis-Bar [1941] reported a 9-year-old male with associated ataxia and cutaneous telangiectasias, classifying the case as a previously unrecognized phakomatosis [Louis-Bar, 1941]. Three additional independent reports subsequently appeared in the literature [Biemond, 1957; Boder and Sedgwick, 1957, 1958], and Boder and Sedgwick named the condition ataxia-telangiectasia.

CLINICAL MANIFESTATIONS Early motor development appears to be normal until the onset of ataxia, which often begins during infancy but is not noted until around the time that the child starts walking. The ataxia is progressive and ultimately leads to an inability to ambulate by the beginning of the second decade. Choreoathetosis and dystonia occur in up to 90% of patients, and these motor findings become more prominent with increasing age. A characteristic impassive facies, as well as drooling and dysarthria, are common features as well. Although strength is initially normal, many patients in their 20s and 30s develop progressive spinal muscular atrophy, predominantly affecting the hands and feet [Gatti et al., 1991]. Peripheral neuropathy in the form of diminished deep tendon reflexes and loss of large fiber sensation is also seen. Mental function is well preserved, although deficits in shortterm memory can occur in the third and fourth decades [Gatti et al., 1991]. Oculomotor apraxia is a distinguishing feature of the disease. The apraxia commonly presents before the appearance of conjunctival telangiectasias and is characterized by defects of initiating voluntary saccades, hypometric voluntary saccades accompanied by compensatory eye blinking and/or head thrusting movements, and disrupted smooth pursuit movements [Baloh et al., 1978; Sedgwick and Boder, 1972; Smith and Cogan, 1959]. Involuntary saccade initiation and optokinetic nystagmus can be impaired as well, and vestibulo-ocular reflexes can be increased. Telangiectasias are usually first observed in patients between the ages of 2 and 4 years, although they can occur as early as birth and as late as 14 years of age [Centerwall and Miller, 1958; McFarlin et al., 1972] (Fig. 57-5). In addition to the conjunctivae, they appear on exposed areas of the skin, particularly areas of friction and trauma such as the auricle, nasal bridge, and antecubital and popliteal spaces. Exposure to sun enhances their appearance. Pre-

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LABORATORY FINDINGS Serum α-fetoprotein and carcinoembryonic antigen levels are often elevated in affected individuals. Most patients have decreased concentrations or absence of immunoglobulins A and E secondary to reduced synthesis, even though a high catabolic rate has been reported. Immunoglobulin M, G1, and G3 concentrations are normal or elevated, and immunoglobulin G2 and G4 concentrations are generally decreased. These humoral defects result in impaired antibody response to various bacterial and viral antigens. Fibroblast and lymphoid cell lines from ataxia-telangiectasia patients exhibit increased radiosensitivity, leading to spontaneous and radiation-induced chromosomal breakage and rearrangement that can be assessed in culture [Shiloh et al., 1985]. In lymphoid cell lines, the chromosomal breaks occur at the loci of T-cell antigen receptors and immunoglobulin genes, where DNA rearrangements and deletions naturally occur [Arlett and Priestley, 1985; Davis et al., 1985; Hecht and Hecht, 1985]. Whereas these tests can be useful for screening, genetic analysis has become the gold standard for diagnosis (see later discussion).

PATHOLOGY FIGURE 57-5. Characteristic conjunctival telangiectasias observed in a 12 year old with ataxia-telangiectasia.

mature aging of hair and skin is frequent, as are skin infections, including chronic blepharitis. Other skin changes consisting of vitiligo and café au lait spots can be seen. Rarely, scleroderma-like lesions occur. Recurrent sinopulmonary infections are common, affecting 90% of patients, and usually result in chronic bronchitis, bronchiectasis, or both. The impairment of cellular immunity is also manifest by abnormally developed or absent adenoids, tonsils, lymphoid tissue, and thymus gland. Patients have an impaired delayed hypersensitivity response to skin-sensitizing antigens and a delayed homograft-rejection response [McFarlin and Oppenheim, 1969]. Patients with ataxia-telangiectasia are prone to develop tumors and are more likely than the general population to have Hodgkin’s disease, leukemia, lymphoma, and lymphosarcoma. Other associated neoplasms include brain tumors, gastric adenocarcinomas, ovarian dysgerminomas, gonadoblastomas, cystic adenofibromas, uterine leiomyomas, and thyroid adenomas [Gatti and Good, 1971; Miller and Chatten, 1967; Spector et al., 1982]. Hypogonadism is frequent in both genders, and growth retardation is notable despite normal levels of growth hormone. Insulin-resistant diabetes is also occasionally seen as part of the clinical constellation. Patients with less severe variant forms of ataxiatelangiectasia have been described [Gilad et al., 1998; Saviozzi et al., 2002]. Immunodeficiency, telangiectasias, cancer, and sinopulmonary infections may be absent or reduced, but the neurologic manifestations still occur. These individuals have a later onset and slower progression of neurologic signs, longer life spans, and decreased chromosomal instability and cellular radiosensitivity.

Cerebellar atrophy primarily affects the Purkinje and granular cells, although basket cells can also be involved. Neuronal degeneration of the dentate and olivary nuclei and the substantia nigra has been demonstrated, and nuclear changes occur in the cells of the oculomotor complex, pretectal nuclei, and hypothalamus. Pituitary cells often have enlarged or dysplastic nuclei. Older patients have denervation of the posterior columns of the spinal cord. Degeneration of the anterior horn cells, decreased numbers of satellite cells in the dorsal root ganglia, and nucleomegaly of Schwann cells have been described [Boder, 1987; De Leon et al., 1976; Sourander et al., 1966].

GENETICS The worldwide incidence of ataxia-telangiectasia is approximately 1 in 40,000 to 100,000 live births; the carrier frequency ranges from 0.5% to 1%. The gene locus maps to chromosome 11q22-23 [Gatti et al., 1988]. The ATM (ataxia-telangiectasia mutated) gene is very large, with 66 exons spanning 150kb of genomic DNA [Uziel et al., 1996]; this fact makes mutation detection a challenge. In addition, because of the large number of different mutations the majority of patients are compound heterozygotes. Still, using a combination of techniques the estimated mutation detection rate is greater than 95% in affected individuals. It is estimated that truncating mutations account for about 85% of mutations, whereas point mutations are responsible for the rest [Buzin et al., 2002]. The ATM protein is a nuclear phosphoprotein homologous to a family of phosphatidylinositol kinase-related proteins that functions in the DNA damage response and in cell cycle regulation [Savitsky et al., 1995a; 1995b]. Individuals with classic ataxia-telangiectasia have little or no active ATM protein, whereas most individuals with variant ataxia-telangiectasia have one severe mutation

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coupled with a mild mutation. In this latter condition some ATM activity is preserved, which probably explains the milder phenotype [Saviozzi et al., 2002]. Loss of ATM activity could lead to neuronal degeneration in at least two ways. As a monitor of DNA strand breaks important for initiating repair, it has been suggested that the ATM protein is necessary for the elimination of neural cells with genomic damage and that the preservation of those cells may contribute to neuronal dysfunction [Herzog et al., 1998]. Several other diseases that affect DNA repair (ataxiatelangiectasia–like disorder, ataxia-ocular apraxia 1, xeroderma pigmentosum, Cockayne’s syndrome, Nijmegen’s breakage syndrome and de Sanctis-Cacchione syndrome) have a cerebellar phenotype, suggesting that cerebellar neurons may be sensitive to DNA damage. This hypothesis highlights a nuclear role for the ATM protein. In neurons, however, a large percentage of the protein is found in the cytoplasm and axons. Increased numbers of lysosomes are found in Purkinje cell bodies and axons in ATM-deficient mice [Barlow et al., 2000]. This increase, coupled with an observed interaction with β-adaptin, a protein important for clathrin-mediated endocytosis, suggests that vesicle/protein transport may also be disrupted in ATM-defective cells [Lim et al., 1998].

TREATMENT Patients should receive vigorous supportive therapy, with particular attention directed to recurrent sinopulmonary infection. Attempts to improve immunologic status by plasma transfusion of thymosin and provision of fetal thymus transplants have not altered the course of the neurologic signs and symptoms [Wara and Ammann, 1978]. Treatment of neoplasms must proceed with caution because patients are extremely sensitive to radiation and chemotherapy, and demonstrate resultant ulcerative dermatitis, severe esophagitis, dysphagia, and deep-tissue necrosis [Gotoff et al., 1967; Morgan et al., 1968].

Ataxia-Telangiectasia–like Disorder (MIM 604391) Four patients have been described with clinical presentations that are essentially identical to that of ataxia-telangiectasia except that ocular telangiectasias are absent [Hernandez et al., 1993; Klein et al., 1996]. Two of the patients, who are brothers, presented first with chorea that later progressed to ataxia. Increased susceptibility to DNA damage was noted in all four patients. Stewart and colleagues [1999] found that the disorder maps to chromosome 11q21 in all four patients. Loss-of-function mutations in the hMRE11A gene are causative. Like ATM, MRE11A is important for DNA repair and may act as a sensor of DNA damage. Stewart and associates [1999] estimate that approximately 6% of ataxia-telangiectasia patients may in fact have ataxia-telangiectasia–like disorder.

Ataxia-Oculomotor Apraxia 1 (Early Onset Ataxia with Oculomotor Apraxia and Hypoalbuminemia; MIM 208920) Ataxia-oculomotor apraxia is an autosomal-recessive ataxia that was initially described in Japanese families but has

subsequently been described in other areas of the world as well [Tranchant et al., 2003]. It is the most frequent cause of autosomal-recessive cerebellar ataxia in Japan and the second most common cause in Portugal. The presentation is nearly identical to that of ataxia-telangiectasia without the non-neurologic features [Aicardi et al., 1988], and accounts for up to 10% of autosomal-recessive cerebellar ataxias [Le Ber et al., 2003]. Gait imbalance and dysarthria are the typical presenting features, although chorea can sometimes be the presenting symptom. Ocular apraxia typically occurs a few years after symptom onset; with time, progressive ophthalmoplegia occurs as well. Areflexia, dystonia, choreoathetosis, sensory and motor neuropathy, mental retardation, and retinal/macular lesions seen on funduscopy can also be part of the presentation. Life span is not affected. Laboratory studies reveal hypoalbuminemia and hypercholesterolemia in the majority of cases as a later manifestation of the disease. Neuroimaging demonstrates cerebellar and sometimes brainstem atrophy. Pathology studies report loss of Purkinje cells in the cerebellum, degeneration of the posterior columns, spinocerebellar tracts, and anterior horn cells of the spinal cord [Sekijima et al., 1998]. The gene APTX maps to chromosome 9p13.3 and is expressed in all body tissues [Date et al., 2001; Moreira et al., 2001]. Several mutations have been described, as have compound heterozygotes; frameshift and nonsense mutations result in more severe phenotypes than missense mutations. The APTX gene product, aprataxin, has domains that suggest a potential role in single-strand DNA repair and has been found to interact with another protein implicated in this process [Sano et al., 2004].

Ataxia-Oculomotor Apraxia 2 (Spinocerebellar Ataxia, Recessive, Non-Friedreich’s Type 1; MIM 606002) A second ataxia-telangiectasia–like spinocerebellar ataxia with slightly different features than ataxia-oculomotor apraxia type 1 has been described in families of several different ethnic backgrounds. The clinical features of ataxiaoculomotor apraxia type 2 include gait ataxia, sensorimotor neuropathy, and ocular apraxia, with the latter occurring about 50% of the time. Although overall cognitive function is normal, subtle changes in executive function can be seen on neuropsychologic testing [Le Ber et al., 2004]. Neuroimaging demonstrates cerebellar atrophy. Ataxiaoculomotor apraxia type 2 is distinguished from ataxiaoculomotor apraxia type 1 by the later age of onset, less common ocular apraxia, high levels of serum α-fetoprotein, and normal serum albumin. The functional prognosis is also better in ataxia-oculomotor apraxia type 2. The gene SETX maps to chromosome 9q34 [Nemeth et al., 2000]. Mutations cause premature termination of the senataxin protein, which is a member of the helicase family and is involved in ribonucleic acid maturation and termination [Moreira et al., 2004]. Interestingly, other mutations in senataxin are transmitted in an autosomal-dominant manner and cause juvenile amyotrophic lateral sclerosis [Chen et al., 2004a]; the basis for the dramatic phenotypic difference between the two diseases is unknown.

Maricich and Zoghbi / The Cerebellum and the Hereditary Ataxias

Cerebellar Ataxia, Cayman Type (MIM 601238) Cerebellar ataxia, Cayman type, is a recessive disorder described in an isolated population from Grand Cayman Island, mapping to chromosome 19q13.3 [Brown et al., 1984; Johnson et al., 1978; Nystuen et al., 1996]. The disorder consists of hypotonia from birth, followed by psychomotor retardation, nystagmus, intention tremor, dysarthria, and ataxic gait. The cerebellar findings are typically nonprogressive. Brain imaging demonstrates isolated cerebellar atrophy. The ATCAY gene is expressed only in neurons in the brain and in components of the spinal cord and peripheral nervous system. Two nucleotide substitutions, one in exon 9 resulting in a serine to arginine substitution, and one in intron 9 that interferes with splicing, have been identified as causative [Bomar et al., 2003]. ATCAY codes for the caytaxin protein, a protein that shares a conserved domain with TTPA (see earlier section on vitamin E deficiency syndromes). However, it does not appear that caytaxin binds vitamin E, and its function is currently unknown.

Infantile-Onset Spinocerebellar Ataxia (MIM 271245) Infantile-onset spinocerebellar ataxia has been described in 19 patients from 13 Finnish families, and maps to chromosome 10q24 [Koskinen et al., 1994; Nikali et al., 1995; 1997]. It is thought that a single founder mutation occurred 30 to 40 generations ago in an ancestral Finnish kindred, with subsequent spread of the mutation throughout Finland. Affected children are healthy and develop normally until the onset of symptoms, usually between the ages of 1 and 2 years. Clumsiness, head tilt, athetosis of the arms and face, and loss of the ability to walk are the typical presenting symptoms, and they can begin in the setting of an acute infection. Ataxia, hypotonia, muscle atrophy, loss of deep tendon reflexes, and loss of proprioceptive sense are found on initial examination. Abnormal eye movements culminate in ophthalmoplegia by age 5. Mild-to-moderate sensorineural hearing loss starts at 2 to 5 years of age and progresses to a severe hearing deficit. Sensory axonal neuropathy, optic atrophy, decreased cognitive performance, and epilepsy occur by adolescence. Patients can present in status epilepticus that is refractory to medical management and can result in death. Female patients have primary hypogonadism, with amenorrhea and poor development of secondary sexual characteristics; sexual maturation appears to be normal in males [Koskinen et al., 1994; Koskinen et al., 1995a]. Although the early onset, progressive nature of the disease, and exacerbation with illness suggest a mitochondrial disorder, metabolic analyses, mtDNA testing, and muscle biopsy are normal in these patients. On neuroimaging, cerebellar atrophy is absent until about 5 years of age, and then progresses to olivopontocerebellar and spinocerebellar atrophy with time [Koskinen et al., 1995b]. Pathology studies reveal atrophy that is most pronounced in the posterior columns of the spinal cord and dorsal roots, with loss of myelinated fibers in the sural nerve; the cerebellar cortex and dentate nuclei, inferior olives, oculomotor nuclei, trochlear nuclei, abducens nuclei, and cochlear nerve and nuclei are all affected [Lonnqvist et al., 1998]. Based on these findings it is postulated that, as in Friedreich’s ataxia,

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the sensory degeneration may be the primary process with secondary degeneration of the cerebellar system. The genetic defect is not known.

Ramsay Hunt Syndrome: Progressive Myoclonic Ataxia and Progressive Myoclonic Epilepsy (Baltic Myoclonus, Mediterranean Myoclonus, Unverricht-Lundborg Syndrome) The Ramsay Hunt syndrome is a heterogeneous group of disorders whose clinical hallmarks are cerebellar ataxia and myoclonus [Hunt, 1922]. The presentation and severity can be quite variable, and the differential diagnosis includes myoclonic epilepsy with ragged red fibers, sialidosis, and progressive myoclonic epilepsy. These disorders are described in other chapters in this text. Progressive myoclonic epilepsy (MIM 254800) was first described in families from Estonia and eastern Sweden, but is most common in Finland. The disease typically presents with generalized tonic-clonic seizures and myoclonus, with ataxia seen later in the course. Dodecamer repeats in the promoter region of the cystatin B gene are the most frequent cause [Lafreniere et al., 1997; Virtaneva et al., 1997].

Other Childhood-Onset Ataxias Other early onset ataxias with associated deafness and varying degrees of mental retardation have been reported. In Behr’s syndrome, mental retardation, ataxia, sensory neuropathy, spasticity, and optic atrophy are the predominant findings [Thomas et al., 1984]. Mental retardation, ataxia, cataracts, short stature, and limited sexual maturation characterize Marinesco-Sjögren syndrome. Yet other conditions have been reported associated with atypical findings of dementia, muscular atrophy, ichthyosis, and familial spastic paralysis. Both autosomal-dominant and X-linked transmission have been described in these patients [Bell and Carmichael, 1939; Farlow et al., 1987; Spira et al., 1979].

Autosomal-Dominant Inherited Ataxias (Spinocerebellar Ataxias) The dominantly inherited spinocerebellar ataxias (Table 57-3) are a group of conditions characterized by premature cerebellar neuronal loss, with some types involving other structures such as the optic nerve, basal ganglia, brainstem, and spinal cord. These heterogeneous disorders were often referred to in the past as the olivopontocerebellar atrophies, a descriptive pathology term used because of the frequent presence of atrophy involving the cerebellum, and pontine and olivary nuclei [Koeppen and Barron, 1984]. Parallel with the pathologic abnormalities, patients with spinocerebellar ataxia display various clinical features of progressive ataxia, motor impairment, extrapyramidal symptoms, retinal degeneration, deafness, ophthalmoplegia, dorsal column dysfunction, and peripheral neuropathy. The overall incidence of spinocerebellar ataxia is 1 to 5 per 100,000, with an average age of onset in the third decade of life. Harding proposed a classification system for the autosomaldominant cerebellar ataxias that uses the constellation of

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TABLE 57-3 Autosomal Dominant Cerebellar Ataxias ATAXIA

CHROMOSOME

GENE

GENE PRODUCT

MECHANISM

AGE OF ONSET (YEARS)

NORMAL REPEAT

EXPANDED REPEAT

Polyglutamine Expansion SCA1 SCA2 SCA3/MJD SCA6 SCA7 SCA17 DRPLA

6p23 12q24 14q24.3-q31 19q13 3p21.1-p12 6q27 12p13.31

SCA1 SCA2 MJD1 CACNA1A SCA7 SCA17 DRPLA

Ataxin-1 Ataxin-2 Ataxin-3 CACNA1A Ataxin-7 TBP Atrophin-1

CAG repeat CAG repeat CAG repeat CAG repeat CAG repeat CAG repeat CAG repeat

6-60 2-65 11-70 16-73 Birth-53 3-48 4 months-55

6-44* 15-24 13-36 4-20 4-35 25-42 7-34

39-82* 35-59 61-84 21-33 37-460 45-66 53-93

Noncoding Expansion SCA8

13q21

SCA8

SCA8 RNA

18-72

2-91*

110-155*

SCA10

22q13

SCA10

Ataxin-10

14-45

10-22

750-4500

SCA12

5q31-q33

SCA12

PPP2R2B

CTG repeat in 3′ UTR ATTCT repeat in intron 9 CAG repeat in 5′ UTR

8-55

7-32

55-78

Missense Mutation SCA14

19q13.4

PKC-γ

PKC-γ

10-69

FGF14-SCA

13q34

FGF14

FGF14

Missense mutation Fibroblast growth factor deficiency

Channelopathy EA1

12p13

EA1

KCNA1

Channelopathy

EA2/FHM

19p13

CACNA1A

CACNA1A

Channelopathy: missense and nonsense mutations

Early Childhood 4-30

Mutation Unknown SCA4 SCA5 SCA11 SCA13 SCA15 SCA16 SCA18/SMNA SCA19 SCA20 SCA21 SCA22 SCA23 SCA25 EA3 EA4 SAX1

16q22 11p11-q11 15q14-q21.3 19q13.3-q13.4 3p24.2-3pter 8q22.1-q24.1 7q31-q32 1p21-q21 11 7p21.3-p15.1 1p21-q23 20p13-p12.2 2p Unknown Unknown 12p13

Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown

Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown

Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown

SPAR

Unknown

Unknown

Unknown

Unknown

15-20

19-59 10-68 15-43 <1-45 Child–Adult 20-66 12-25 10-45 19-64 6-30 10-46 43-56 1.5-39 23-42 1-42 Early childhoodearly 20s 15-35

*There is some ovelap of pathogenic and nonpathogenic repeat length. See text for details. DRPLA, dentatorubral-pallidoluysian atrophy; EA, episodic ataxia; FHM, familial hemiplegic migraine; SAX, spastic ataxia; SCA, spinocerebellar ataxia; SMNA, sensorimotor neuropathy with ataxia; SPAR, spastic paraplegia, ataxia, and mental retardation; TBP, TATA-binding protein; UTR, untranslated region.

clinical symptoms for categorization [Harding, 1993]. Type I autosomal-dominant cerebellar ataxias have a cerebellar syndrome plus pyramidal signs, supranuclear ophthalmoplegia, extrapyramidal signs, and dementia. Type II autosomal-dominant cerebellar ataxias demonstrate a cerebellar syndrome plus pigmentary maculopathy. Type III autosomal-dominant cerebellar ataxias are “pure” cerebellar syndromes that have mild, if any, pyramidal symptoms. Some authors have attempted to keep these clinical categories and assign genetically defined spinocerebellar

ataxias to them. Practically speaking, however, the age of onset and the clinical findings vary not only from family to family but within the same kindred as well [Berciano, 1982; Currier et al., 1972; Nino et al., 1980; Schut, 1954; Zoghbi et al., 1988]. Genetic studies over the past 20 years have been directed at mapping the gene loci for many of these disorders. These studies confirmed genetic heterogeneity in addition to the clinical heterogeneity, identifying 28 separate genetic loci. The next section describes the clinical features and

Maricich and Zoghbi / The Cerebellum and the Hereditary Ataxias

molecular genetic profiles of the various spinocerebellar ataxias, including the periodic ataxias and dentatorubralpallidoluysian atrophy.

Spinocerebellar Ataxia Type 1 (MIM 164400) Spinocerebellar ataxia type 1 is characterized by progressive loss of balance and coordination, mild cognitive impairments, oculomotor deficits including gaze palsy and slowing of saccades, speaking and swallowing difficulties, and eventually respiratory failure. The primary sites of neurodegeneration in spinocerebellar ataxia type 1 include cerebellar Purkinje cells, brainstem cranial nerve nuclei, and the inferior olive and spinocerebellar tracts [Zoghbi and Orr, 2000]. The onset is typically in the third or fourth decade of life, but patients with onset as early as 4 years of age and as late as 60 years of age have been reported [Zoghbi and Orr, 2000]. The disorder has been described in many ethnic groups including whites, blacks, Asians, and Iakuts [Ranum et al., 1994a]. The spinocerebellar ataxia type 1 gene was mapped to chromosome 6p22-23 and the mutation identified using a positional cloning approach [Banfi et al., 1994; Orr et al., 1993]. A highly polymorphic CAG repeat was found to be unstable and expanded in all individuals with spinocerebellar ataxia type 1 [Orr et al., 1993]. The number of CAG repeats ranges from 6 to 44 on normal chromosomes and from 39 to 82 on spinocerebellar ataxia type 1 chromosomes [Servadio et al., 1995]. The repeat configuration on normal chromosomes is interrupted by 1 to 4 CAT trinucleotides in alleles with 20 or more repeats, whereas a perfect CAG repeat configuration is found on spinocerebellar ataxia type 1 chromosomes [Chung et al., 1993]. This finding led to the hypothesis that loss of the CAT interruption rendered the spinocerebellar ataxia type 1 CAG repeat unstable [Chong et al., 1995; Chung et al., 1993]. The presence of CAT interruptions in normal alleles containing 39 to 44 repeats is useful for distinguishing them from disease-associated alleles. There is a strong inverse correlation between repeat size and age of onset; individuals with 70 or more CAG repeats have childhood onset, a rapidly deteriorating course, and death within 4 to 5 years, whereas adult-onset cases have fewer than 70 repeats and typically live 10 to 20 years after symptoms appear [Zoghbi and Orr, 2000]. Genetic anticipation, or the tendency of affected individuals in successive generations of a kindred to have decreasing ages of disease onset, is a prominent feature of this and other polyglutamine repeat diseases. The mechanism involves progressive expansion of the polyglutamine repeats in disease alleles, particularly those that are paternally transmitted [Orr et al., 1993] The spinocerebellar ataxia type 1 CAG repeat falls within the open reading frame of a transcript that is widely expressed and whose size is approximately 11.5 kb [Orr et al., 1993]. The CAG repeat codes for polyglutamine within ataxin-1, a protein predicted to contain 792 to 830 amino acids according to the size of the repeat [Banfi et al., 1994]. Ataxin-1 is predominantly nuclear in neurons and cytoplasmic in peripheral cells; shuttling between the two compartments may occur in neurons [Servadio et al., 1995]. A 120-residue region of the protein (573-694 in alleles containing 30 glutamines) shares significant sequence similarity with the HMG-box transcription factor HBP1 and has been

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implicated in protein-protein interactions and possibly in protein–ribonucleic acid interactions [Chen et al., 2004b]. The exact cellular functions of ataxin-1 are currently unknown, but data from animal models are providing some useful clues. Mice lacking ataxin-1 have spatial and motor learning deficiencies, as well as impairment of short-term plasticity [Matilla et al., 1998], but do not display ataxia or neuronal degeneration. These findings argue that spinocerebellar ataxia type 1 is not caused by loss of function of ataxin-1. Support for a gain-of-function pathogenic mechanism first came from mice overexpressing a mutant SCA1 cDNA with 82 glutamines (82Q) specifically in Purkinje cells. These mice developed progressive ataxia and Purkinje cell degeneration [Burright et al., 1995]. The mutant ataxin1 accumulates in nuclear inclusions [Skinner et al., 1997] along with components of the proteasome, suggesting that mutant ataxin-1 might misfold and resist degradation [Cummings et al., 1998]. Similarly, fruitflies that overexpress human ataxin-1 (82Q) also developed progressive neuronal degeneration and ataxin-1-containing nuclear inclusions that co-localized with chaperones and ubiquitin. To characterize the effects of the spinocerebellar ataxia type 1 mutation on all ataxin-1-expressing neurons, an expanded CAG tract of 154 repeats was targeted in place of the typical 2 CAGs present in the endogenous mouse locus. Sca1154Q/+ mice reproduced all features of human spinocerebellar ataxia type 1 including ataxia, brainstem dysfunction, Purkinje cell degeneration, and premature death [Watase et al., 2002]. Consistent with the in vivo data, cellular and in vitro studies demonstrated that ataxin-1 is ubiquitinated, the expanded polyglutamine tract retards its degradation, and inhibition of the proteasome enhances its accumulation [Cummings et al., 1998; 1999]. Chaperone overexpression, which presumably aids in the folding or elimination of the expanded protein, resulted in improved motor coordination and suppressed Purkinje cell degeneration in SCA1 (82Q) transgenic mice [Cummings et al., 2001]. The important roles of protein misfolding and degradation have also been demonstrated in several other polyglutamine diseases [Opal and Zoghbi, 2002; Paulson, 1999]. Ataxin-1 is phosphorylated at serine 776 (S776); when this serine is mutated to alanine (S776A), mutant ataxin-1 does not accumulate when overexpressed in cultured cells. Moreover, mice that express ataxin-1 (82Q) with an alanine at position 776 do not develop ataxia or pathology in spite of the long glutamine tract. These data show that (1) toxicity is mediated by the protein and not ribonucleic acid; (2) that the protein context is important given that a single amino acid change abrogated accumulation and toxicity; and (3) that a long polyglutamine tract can be efficiently handled by the cell’s degradation machinery [Emamian et al., 2003]. Akt is the kinase that phosphorylates ataxin-1 at S776, allowing interactions between ataxin-1 and the 14-3-3 proteins. The binding of 14-3-3 to ataxin-1 enhances its levels both in cells and in vivo (Drosophila model) and hence provides an explanation for the importance of S776 in ataxin-1’s pathogenicity. Genetic interaction studies in Drosophila indicated that overexpression of 14-3-3, phosphatidylinositol 3-kinase (PI3K, which activates Akt), and Akt enhanced neurodegeneration, whereas decreasing Akt levels by half suppressed ataxin-1–induced degeneration and decreased ataxin-1 levels [Chen et al., 2003b]. These studies

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identified a pathway that can be targeted pharmacologically (the PI3kinase/Akt pathway) to decrease mutant ataxin-1’s toxicity. Preclinical studies using PI3K/Akt inhibitors are being conducted in spinocerebellar ataxia type 1 mouse models to evaluate their potential benefit for this disease.

Spinocerebellar Ataxia Type 2 (MIM 183090) In 1989, Orozco and associates [1989] described a form of dominantly inherited spinocerebellar ataxia that occurs at an estimated frequency of 41 per 100,000 in the province of Holguine, Cuba. Age of onset varies from 2 to 65 years, with 40% of the patients presenting with symptoms before 25 years of age. Onset before the age of 20 years correlates with a more aggressive disease course. The clinical features include ataxia, dysarthria, tremor, and extremely slow saccades. Hyporeflexia of the upper limbs and ophthalmoparesis are seen in over half the patients. Dementia occurs in a significant minority of patients. The locus was termed spinocerebellar ataxia type 2 and mapped to chromosome 12q24 [Gispert et al., 1993]. Families with this disorder have been described from other regions of the world outside of Cuba as well [Lopes-Cendes et al., 1994]. Pathology specimens demonstrate severe loss of Purkinje cells and of neurons in the substantia nigra and basis pontis. Mild-to-moderate neuronal loss is seen in the inferior and accessory olives; dentate, arcuate, gracile, and accessory cuneate nuclei; internal granule cell layer of the cerebellum; and in the anterior horns of the spinal cord. Axonal loss from the dorsal roots and posterior columns, the dorsal spinocerebellar tract, and often from the anterior spinal roots is also found. Reactive gliosis can be seen in the globus pallidus, thalamus, subthalamus, and periaqueductal regions [Durr et al., 1995; Hunyh et al., 1999; Koeppen, 1998]. By using three different approaches the spinocerebellar ataxia type 2 gene was identified, and the mutation was determined to involve an expansion of a CAG trinucleotide repeat that lies within the coding region of a novel protein termed ataxin-2 [Imbert et al., 1996; Pulst et al., 1996; Sanpei et al., 1996]. Normal ataxin-2 alleles contain 15-24 CAG repeats (with 22 repeats found 94% of the time), whereas disease alleles have 35 to 59 repeats. The range of pathogenic alleles in spinocerebellar ataxia type 1 is shifted toward shorter repeats compared with other spinocerebellar ataxias, suggesting that the expanded repeat within ataxin-2 is more deleterious to neurons. The CAG repeat in the spinocerebellar ataxia type 2 gene is interrupted by one to three CAA units only on normal alleles, suggesting that, as in spinocerebellar ataxia type 1, interruption of CAG repeats may confer stability. Finally, there is a strong inverse correlation between the size of the repeat and the age of onset of symptoms. The spinocerebellar ataxia type 2 gene, ataxin-2, contains 25 exons and spans approximately 130 kb of genomic DNA. Two alternately spliced forms of messenger ribonucleic acids are generated, one of which results in a protein that is truncated by 70 amino acids [Sahba et al., 1998]. Ataxin-2 messenger ribonucleic acid is found in multiple tissues and in all regions of the CNS [Imbert et al., 1996; Pulst et al., 1996; Sanpei et al., 1996], where it is present predominantly in neurons and is highly expressed in Purkinje cells [Hunyh

et al., 1999]. Ataxin-2 is a cytoplasmic protein and is subcellularly localized to the Golgi apparatus [Shibata et al., 2000]. Although a definitive function of ataxin-2 has not been established, several lines of evidence suggest that the protein may function in messenger ribonucleic acid processing, stability, and transport. First, ataxin-2 contains two domains that have been implicated in ribonucleic acid splicing. Second, a ribonucleic acid–binding protein (ataxin2 binding protein 1) with a similar expression pattern has been found to interact with ataxin-2 [Shibata et al., 2000]. Third, related proteins from other species are involved in ribonucleic aicd processing. The morphologic changes seen in diseased Purkinje cells may result from abnormal cytoskeletal architecture, as suggested by two further studies. Purkinje cells in transgenic mice that express mutant ataxin2 lose their dendritic arbors before cell body degeneration [Huynh et al., 2000], and a Drosophila homolog of ataxin-2 (Datx2) is involved in microtubule assembly through an indirect mechanism [Satterfield et al., 2002]. Whether these effects are mediated through ribonucleic acid interactions is unknown.

Machado-Joseph Disease and Spinocerebellar Ataxia Type 3 (MIM 109150) More than 100 families with Machado-Joseph disease have been evaluated [Coutinho and Andrade, 1978; Fowler, 1984; Rosenberg et al., 1976]. First described in families of Azorean-Portuguese origin, Machado-Joseph disease or spinocerebellar ataxia type 3 has subsequently been described in families from around the world [Bharucha et al., 1986; Sasaki et al., 1992a; 1992b]. The vast majority of cases are linked to a single haplotype that probably originated in mainland Portugal, with subsequent spread to the Azores and beyond [Gaspar et al., 2001]. The clinical features of Machado-Joseph disease include progressive ataxia, areflexia, peripheral amyotrophy, external ophthalmoplegia, bulging eyes, facial and lingual fasciculations, muscle atrophy, parkinsonian features, dystonia, and spasticity. Based on the constellation of clinical findings and the age of onset of symptoms, attempts have been made to categorize this disorder into different clinical subtypes [Barbeau et al., 1984; Coutinho and Andrade, 1978; Rosenberg et al., 1976]. However, this approach has not proven diagnostically useful because different subtypes occur in the same kindred, and affected individuals often evolve from one subtype to another. The Machado-Joseph disease gene was mapped to the long arm of chromosome 14 (14q24.3-q32) [Takiyama et al., 1993]. Subsequently, Stevanin and colleagues [1994] mapped the gene in a family with a dominantly inherited spinocerebellar ataxia to chromosome 14q24.3-qter. They designated the new locus as spinocerebellar ataxia type 3 because the familial phenotype was clinically distinct from Machado-Joseph disease and more closely resembled that of spinocerebellar ataxia type 1. Further studies have demonstrated that both spinocerebellar ataxia type 3 and MachadoJoseph disease result from a CAG repeat expansion in the MJD1 gene and emphasize the marked clinical heterogeneity associated with this mutation [Cancel et al., 1995; Kawaguchi et al., 1994; Maciel et al., 1995; Maruyama et al., 1995; Matilla et al., 1995; Ranum et al., 1995]. Nor-

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mal MJD1 alleles contain 13-36 CAG repeats, and expanded alleles contain 61 to 84 repeats. Ataxin-3 is the smallest of the polyglutamine proteins. Its normal function is unknown, and the pathogenesis of Machado-Joseph disease or spinocerebellar ataxia type 3 is poorly understood. The introduction of ataxin-3 with an expanded polyglutamine tract into cultured cells induces apoptosis, suggesting that the mutant protein is either directly or indirectly involved with a cellular suicide pathway [Ikeda et al., 1996]. Other studies suggest that protein misfolding, presumably initiated by the expanded polyglutamine tract, leads to ubiquitination and subsequent formation of intranuclear inclusions [Chai et al., 1999]. This is a common pathway in polyglutamine expansion diseases. How this leads to cell dysfunction and death and why the clinical time course takes so long to evolve remain unknown.

Spinocerebellar Ataxia Type 4 (MIM 600223) Seven kindreds (one from Utah and six from Japan) have been described thus far [Gardner et al., 1994; Nagaoka et al., 2000]. Clinically, affected individuals in the Japanese families have a pure cerebellar ataxia, whereas those in the Utah kindred also have dysarthria and sensory axonal neuropathy [Flanigan et al., 1996]. Detailed genetic mapping studies show that the gene involved in spinocerebellar ataxia type 4 maps to the long arm of human chromosome 16. Anticipation does not occur.

Spinocerebellar Ataxia Type 5 (MIM 600224) The locus for spinocerebellar ataxia type 5 was localized to the centromeric region of human chromosome 11 based on detailed mapping studies on two major branches of a family descended from the paternal grandparents of President Abraham Lincoln [Ranum et al., 1994b]. The phenotype is that of pure cerebellar ataxia and dysarthria. The disease is milder than that observed in other spinocerebellar ataxias, without substantial effects on life span.

Spinocerebellar Ataxia Type 6 (MIM 183086) Spinocerebellar ataxia type 6 accounts for 1% to 13% of families with autosomal-dominant cerebellar ataxia from European centers, 6% to 31% from Japanese centers, and zero to 11% in Chinese series [Mantuano et al., 2003; Schöls et al., 1998; ]. The mutation is occasionally found in sporadic cases as well. The clinical features consist predominantly of mild but slowly progressive cerebellar ataxia of the limbs, gait ataxia, dysarthria, nystagmus, and mild vibratory and proprioceptive sensory loss. Cognitive function is not affected. Patients often have acute episodes of ataxia or vertigo that are responsive to acetazolamide. Onset is later than the other dominantly inherited spinocerebellar ataxias, typically occurring in the third decade at the earliest. Brain imaging reveals atrophy of the cerebellum. Pathology specimens demonstrate loss of Purkinje and granule cells, with proliferation of Bergmann glia, which is more prominent in the vermis than in the hemispheres [Gomez et al., 1997; Takahashi et al., 2004; Tsuchiya et al., 1998]. Loss of inferior olive neurons also occurs, but may be secondary to the cerebellar changes.

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The genetic locus was mapped to chromosome 19q13, where a CAG repeat expansion in exon 47 at the 3′ region of the CACNA1A gene was identified as the causative mutation [Zhuchenko et al., 1997]. CACNA1A codes for the brainspecific, voltage-sensitive α1A (Cav2.1) subunit of the P/Qtype calcium channel, which is highly expressed in Purkinje cells [Ishikawa et al., 1999]. Alternative splicing leads to six isoforms, three of which contain the polyglutamine sequence. Repeat expansions are the smallest of the triplet repeat diseases, with 21 or more repeats being pathogenic. Individuals who are homozygous for expanded repeats have no phenotypic or age of onset differences [Takiyama et al., 1998]. Phenotypic severity is inversely correlated with the number of CAG repeats, as is the age of onset [Takahashi et al., 2004]. Clinical anticipation has been observed, but does not always appear to stem from CAG repeat instability. No CAA interruptions are present in the repeats. Proteins with the expanded repeat aggregate specifically in the cytoplasm of Purkinje cells [Ishikawa et al., 1999]. These inclusions are not ubiquitinated and lack several other components found in the inclusions of other CAG repeat disorders. It is not clear whether spinocerebellar ataxia type 6 is caused by a “gain-of-function” mechanism similar to that in other polyglutamine diseases or a channelopathy that alters calcium homeostasis. As will be discussed later (see “Episodic Ataxias”), point mutations and deletions in the CACNA1A coding sequence cause episodic ataxia type 2 and familial hemiplegic migraine type 1. Families with significant phenotypic overlap have been identified, leading some to postulate that the three disorders represent a spectrum of disease rather than truly separate entities. The identification of small triplet expansions (20 and 23 repeats) in two kindreds whose members presented with EA2, and the identification of a point mutation leading to early hemiplegic migraine and later progressive ataxia, is supportive of this interpretation [Alonso et al., 2003; Jodice et al., 1997].

Spinocerebellar Ataxia Type 7 (MIM 164500) Spinocerebellar ataxia type 7 is distinguished clinically from the other spinocerebellar ataxias by the presence of macular dystrophy leading to pigmentary retinal degeneration [Bjork et al., 1956; Colan et al., 1981; Enevoldson et al., 1994; Gouw et al., 1994; Havener, 1951; Jampel et al., 1961]. The retinal changes in spinocerebellar ataxia type 7 start in a central location and move peripherally as the disease progresses, thus distinguishing the eye findings from those in retinitis pigmentosa. Progressive ataxia or dysmetria, pyramidal tract signs, supranuclear ophthalmoplegia, and dysarthria or dysphagia are also present, and occasionally dementia and deafness are seen as well [Benton et al., 1998]. Either ataxia or visual changes can be the presenting symptom, depending on the number of CAG repeats in the expanded allele (see later). Brain imaging in all cases typically demonstrates cerebellar atrophy; ventricular dilation and delayed myelination can be found in infantile cases. Brain pathologic specimens reveal atrophy of the cerebellum with loss of dentate neurons and Purkinje cells and loss of inferior olivary neurons in the brainstem; posterior column, dorsal and ventral spinocerebellar tract loss in the spinal cord; and macular degeneration with loss of photoreceptive cells in the retina.

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An extremely aggressive infantile-onset form of spinocerebellar ataxia type 7 that occurs only on paternal transmission has been described [Benton et al., 1998; Enevoldson et al., 1994]. It presents with hypotonia, dysphagia, myoclonic seizures, and visual disturbances that typically lead to rapid mental deterioration and severe physical disability culminating in death by age 3 or earlier. The infantile-onset form is also associated with cardiac abnormalities, particularly patent ductus arteriosus [Benton et al., 1998; Johansson et al., 1998; van de Warrenburg et al., 2001]. Childhood-onset spinocerebellar ataxia type 7 is less aggressive than the infantile-onset form but more progressive than the adult-onset form. Spinocerebellar ataxia type 7 maps to the short arm of chromosome 3 [Benomar et al., 1995; Gouw et al., 1995; Holmberg et al., 1998]. By using an antibody that selectively detects proteins containing an expanded polyglutamine tract, it was demonstrated that the mutational mechanism in spinocerebellar ataxia type 7 is expansion of a CAG repeat [Trottier et al., 1995]. SCA7 encodes a novel protein, ataxin7, with a polyglutamine tract at the amino terminus [David et al., 1997]. The SCA7 CAG repeat ranges in size from 4 to 35 repeats in normal alleles, and from 37 to 306 repeats in expanded alleles. Typically, larger expansions are paternally inherited and result from significant intergenerational repeat instability. An inverse correlation exists between repeat length and age of onset, and repeat expansions larger than 59 repeats tend to develop visual impairment prior to ataxia [Johansson et al., 1998]. Alleles ranging in size from 34 to 36 repeats have been observed in individuals who are at risk but asymptomatic at the time of evaluation [Benton et al., 1998; David et al., 1997, 1998; Del-Favero et al., 1998; Gouw et al., 1998; Holmberg et al., 1998; Johansson et al., 1998; Moseley et al., 1998]. Mouse models of spinocerebellar ataxia type 7 have provided some insight into the pathogenesis of the disease. Expression of the expanded ataxin-7 protein in transgenic mice leads to the development of intranuclear inclusions and the degeneration of rod photoreceptors and Purkinje cells, findings consistent with the human phenotype [Yvert et al., 2000]. In retinal photoreceptor cells, the expression of expanded ataxin-7 is associated with alterations in gene expression that predate photoreceptor degeneration [La Spada et al., 2001; Yoo et al., 2003]. Another interesting finding is that the speed of ataxin-7 accumulation varies in different neuronal populations, suggesting that intrinsic differences in the ability to clear mutant protein may explain the variable susceptibility of different cell types in this and other polyglutamine diseases. Finally, cellular dysfunction predates the appearance of neuronal inclusions, suggesting that although they are part of the pathogenesis, inclusions in and of themselves are not the primary cause of dysfunction [Yoo et al., 2003].

Spinocerebellar Ataxia Type 8 (MIM 608768) Described predominantly in white families from the United States and Canada, the clinical presentation of spinocerebellar ataxia type 8 is similar to that of the other slowly progressive spinocerebellar ataxias. Ataxic dysarthria, nystagmus, limb and gait ataxia, limb spasticity, and diminished vibratory sense are present [Koob et al., 1999]. MRI

of the brain demonstrates cerebellar atrophy. Spinocerebellar ataxia type 8 was mapped to chromosome 13q21, and the vast majority of disease alleles in individuals of European descent share a common haplotype [Ikeda et al., 2004]. Unlike other repeat disorders (with the exception of myotonic dystrophy) that are caused by polyglutamine expansions, spinocerebellar ataxia type 8 is caused by a CTG repeat in a noncoding gene; that is, no open reading frame is present in the gene, suggesting that it is transcribed into messenger ribonucleic acid but not translated into protein [Koob et al., 1999]. This is only one of several unusual characteristics of spinocerebellar ataxia type 8. There is high variability in the repeat length of the wild-type allele, with some unaffected individuals having repeat lengths as high as 174, by far the largest number of wild-type repeats of any spinocerebellar ataxia. The substantial overlap of repeat size in pathogenic and nonpathogenic alleles is also unique among the spinocerebellar ataxias. Furthermore, homozygosity for an expanded allele does not appear to exacerbate the disease phenotype as it does in spinocerebellar ataxia type 1 and dentatorubral-pallidoluysian atrophy. Repeat lengths contract with paternal transmission and expand with maternal transmission, another unusual finding of this disease. Although a relationship between repeat size and clinical effects was demonstrated in the initial report, other families with this disorder have greater variability in penetrance [Ikeda et al., 2004]. Further confusing the picture is the coexistence of spinocerebellar ataxia type 8 expansions with those of spinocerebellar ataxia type 1 or spinocerebellar ataxia type 6 in some kindreds [Izumi et al., 2003; Sulek et al., 2003]. Spinocerebellar ataxia type 8 expansions have also been found in patients with Alzheimer’s disease, Parkinson’s disease, and an individual with vitamin E deficiency heterozygous for the TTPA mutation [Cellini et al., 2002; Izumi et al., 2003; Sobrido et al., 2001]. How these factors influence the pathogenesis of the disease is unknown and has led some authors to question the pathogenesis of the expansion itself [Schols et al., 2003; Stevanin et al., 2000; Worth et al., 2000]. The genomic arrangement of the spinocerebellar ataxia type 8 locus suggests a potential function of the gene. The SCA8 gene lies in a reverse orientation to and partially overlaps the locus of another gene (KLHL1). It has been suggested that the SCA8 messenger ribonucleic acid functions as an endogenous inhibitory RNA for KLHL1, or as a regulator of ribonucleic acid–binding proteins [Mutsuddi et al., 2004], although further evidence of these functions is needed.

Spinocerebellar Ataxia Type 10 (MIM 603516) Grewal and associates [1998] described a dominantly inherited spinocerebellar ataxia in a single four-generation Mexican kindred. The locus was independently mapped to chromosome 22q13 by two different groups [Matsuura et al., 1999; Zu et al., 1999]. Spinocerebellar ataxia type 10 is the second most common form of dominantly inherited ataxia (spinocerebellar ataxia type 2 is the most common) in people of Mexican descent; this fact, coupled with the rarity of expanded alleles in other populations, has led to the hypothesis that the mutation arose in the New World [Matsuura

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et al., 2002]. The phenotype consists of ataxia, dysarthria, nystagmus, and epilepsy. Mood disorders and polyneuropathy diagnosed by nerve conduction studies can also be seen. A pentanucleotide (ATTCT) repeat in intron 9 of the ataxin-10 gene is responsible for the phenotype; instability of the repeat region can lead to as many as 4500 repeats [Matsuura et al., 2000]. There is an inverse correlation between expansion size and the age of onset, and genetic anticipation is present. The repeats are highly unstable when transmitted paternally, whereas maternal transmission results in more stable repeats. Brain imaging reveals cerebellar atrophy. Ataxin-10 is a protein that is widely expressed throughout the brain and in several other tissues [Marz et al., 2004]. It is localized to the cytosol and perinuclear region in neurons. Whether the disease phenotype stems from genomic disruption, ribonucleic acid gain-of-function, or ataxin-10 loss of function is unknown, although decreased ataxin-10 ribonucleic acid levels in primary cerebellar and cortical neuronal culture result in increased apoptosis, suggesting that loss of function may be the pathogenetic mechanism [Marz et al., 2004].

Spinocerebellar Ataxia Type 11 (MIM 604432) Worth and colleagues [1999] described a single family with a benign, slowly progressive, pure cerebellar syndrome linked to chromosome 15. Mean age of onset was about 25 years; genetic anticipation did not appear to be present. The gene has yet to be identified.

Spinocerebellar Ataxia Type 12 (MIM 604326) Identified in a family of German descent [Holmes et al., 1999], spinocerebellar ataxia type 12 is unique in that action tremor is the most distinguishing clinical feature and is typically the initial symptom. Slow progression over several decades leads to head tremor, gait ataxia, dysmetria, dysarthria, hyperreflexia, parkinsonian signs, abnormal eye movements, and occasionally dementia. Two patients in the initial kindred were reported with childhood-onset symptoms: one had nystagmus from birth; the other had lower extremity dystonia that developed in childhood [O’Hearn et al., 2001]. Brain imaging reveals both cortical and cerebellar atrophy. Pathology is available only on a single brain, and revealed diffuse atrophy of cerebral and cerebellar cortices and specifically loss of Purkinje cells. Spinocerebellar ataxia type 12 is rare except in India, where it is the third most common spinocerebellar ataxia [Holmes et al., 2003; Srivastava et al., 2001]. Genetic analysis revealed a triplet CAG expansion on chromosome 5q31-q33. No apparent relationship exists between repeat size and age of onset. Unlike other spinocerebellar ataxias with CAG expansions, the expanded allele does not lead to a polyglutamine tract. Rather, the CAG expansion is found 133 nucleotides upstream of the transcription start site for PPP2R2B, a brain-specific regulatory subunit of protein phosphatase 2A. The B subunits are thought to modulate PP2A function by regulating substrate specificity and intracellular targeting [Holmes et al., 2003]. How this expansion affects PPP2R2B function is unknown.

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Spinocerebellar Ataxia Type 13 (MIM 605259) A dominantly inherited disorder of slowly progressive childhood-onset cerebellar gait ataxia associated with cerebellar dysarthria, moderate mental retardation (IQ = 62 to 76), and mild developmental delays in motor skills acquisition has been described in a single French kindred [Herman-Bert et al., 2000]. Nystagmus and pyramidal signs were also observed in some affected individuals. Cerebral magnetic resonance imaging in two patients revealed moderate cerebellar and pontine atrophy. No evidence of genetic anticipation was found.

Spinocerebellar Ataxia Type 14 (MIM 605361) Three families (one Japanese, one Dutch, and one English/ Dutch) have been described, all with a locus mapping to 19q13.4 telomeric to the locus for spinocerebellar ataxia type 13 [Brkanac et al., 2002a; van de Warrenburg et al., 2003; Yamashita et al., 2000]. The phenotype varies from family to family and within families as well. In the Japanese kindred, subjects with onset of symptoms before 27 years of age presented with axial myoclonus before development of ataxia, whereas those with onset after age 39 presented with a pure cerebellar ataxia. Gait ataxia, dysarthria, horizontal gaze nystagmus, abnormal smooth pursuit movements, hyper- and hyporeflexia, and peripheral neuropathy were described in all of the families [Brkanac et al., 2002a; van de Warrenburg et al., 2003; Yamashita et al., 2000]. Imaging reveals atrophy of the cerebellar vermis and hemispheres. Life span does not appear to be affected in any of the kindreds, and ataxia displays a slowly progressive course. Genetic anticipation occurs. Limited pathologic specimens suggest a primary Purkinje cell defect [Brkanac et al., 2002a]. Molecular studies reveal that missense point mutations in exon 4 of the protein kinase C gamma gene are responsible, although the mechanism of pathogenesis remains unknown [Chen et al., 2003a; van de Warrenburg et al., 2003; Yabe et al., 2003].

Spinocerebellar Ataxia Type 15 (MIM 606658) Spinocerebellar ataxia type 15 was described in a single Australian family with Anglo-Celtic ancestry, whose affected members had a slowly progressive ataxia with associated nystagmus and dysarthria [Storey et al., 2001]. Age of onset was not reported, although it was commented that childhood and adolescence fell in the spectrum. Neuroimaging demonstrated cerebellar vermal atrophy. A candidate gene approach has thus far failed to identify the target gene.

Spinocerebellar Ataxia Type 16 (MIM 606364) Miyoshi and co-workers [2001] reported a single Japanese family with adult-onset gait ataxia, dysarthria, nystagmus, impaired smooth pursuit movements, and head tremor. Linkage to chromosome 8q22.1-q24.1 was established. Imaging demonstrated cerebellar vermal atrophy. Anticipation was not present.

Spinocerebellar Ataxia Type 17 (MIM 607136) This spinocerebellar ataxia may variably present with predominant symptoms of cerebellar ataxia associated with

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dysarthria and extrapyramidal symptoms (e.g., parkinsonism and dystonia), with mental deterioration or dementia and psychiatric symptoms such as depression and hallucinations, or as a Huntington’s disease phenocopy with chorea as a major manifestation [Bauer et al., 2004; Koide et al., 1999; Maltecca et al., 2003; Nakamura et al., 2001; Rolfs et al., 2003; Stevanin et al., 2003; Toyoshima et al., 2004]. Different individuals in the same family may have dramatically different presenting phenotypes and, as the disease progresses, symptoms from each of the subtypes can occur in the same individual. Neuroimaging demonstrates diffuse cortical and cerebellar atrophy that is most pronounced in the vermis. Pathologic specimens reveal neuronal loss in many brain areas, including loss of Purkinje cells [Nakamura et al., 2001; Rolfs et al., 2003]. Spinocerebellar ataxia type 17 is caused by CAG repeat expansions in the TATA-binding protein (TBP) gene on chromosome 6q27 [Nakamura et al., 2001]. Like other spinocerebellar ataxias, short CAA tracts interrupt the CAG repeats; however, both the CAG and CAA tracts are replicated in the expansions, distinguishing this spinocerebellar ataxia from the others. Marked anticipation was observed in an Italian kindred, with the youngest family member in the fourth generation presenting with dysarthria and ataxia at age 3 [Maltecca et al., 2003]. Repeat sizes of 42 to 48 repeats have variable penetrance. Like other expansion diseases, an inverse correlation exists between repeat size and age of onset. TBP is the DNA-binding subunit of ribonucleic acid polymerase II transcription factor D complex, which is important in general gene transcription [Tsuji, 2004]. Immunostaining for ubiquitin, TBP, and polyglutamine tracts demonstrates their presence in intranuclear inclusions in several neuronal cell types, including Purkinje cells [Nakamura et al., 2001; Rolfs et al., 2003].

Spinocerebellar Ataxia Type 18 (Sensorimotor Neuropathy with Ataxia; MIM 607458) Spinocerebellar ataxia type 18, or sensorimotor neuropathy with ataxia, was described in a five-generation American family of Irish descent [Brkanac et al., 2002b]. Clinically, affected individuals present first with gait instability in the dark, followed by limb ataxia, nystagmus, decreased vibratory and position sense, decreased deep tendon reflexes, and proximal or distal muscle weakness and atrophy. Upgoing plantar responses and pes cavus are occasionally seen. Neuroimaging is either normal or demonstrates mild cerebellar atrophy. Electromyography/nerve conduction velocities show evidence of denervation and axonal sensory neuropathy. Thus, the overall picture is one of a mixed cerebellar degeneration and peripheral neuropathy. The disorder was mapped to chromosome 7q31-32; the causative gene has yet to be identified.

Spinocerebellar Ataxia Type 19 (MIM 607346) A single Dutch family with ataxia, cognitive impairment, irregular postural tremor, myoclonus, and poor performance on the Wisconsin Card Sorting Test has been described [Schelhaas et al., 2001; Verbeek et al., 2002]. Imaging

reveals atrophy of the cerebellar hemispheres or vermis. The genetic locus maps to chromosome 1p21-q21, where it overlaps with the locus for spinocerebellar ataxia type 22 (see later).

Spinocerebellar Ataxia Type 20 (MIM 608687) A dominantly inherited cerebellar ataxia associated with palatal tremor and a characteristic dysphonia has been described in a single Anglo-Celtic kindred [Knight et al., 2004]. Imaging demonstrates mild-to-moderate cerebellar atrophy and the unique finding of dentate calcification in the absence of basal ganglia calcification. The genetic locus overlaps that of spinocerebellar ataxia type 5, so the separate identity of this spinocerebellar ataxia remains to be established.

Spinocerebellar Ataxia Type 21 (MIM 607454) Spinocerebellar ataxia type 21 was described in a single French kindred with gait ataxia; extrapyramidal signs such as tremor, akinesia, and cogwheeling; and mental impairment mapping to chromosome 7p21.3-p15.1 [Devos et al., 2001; Vuillaume et al., 2002]. Eye movements are normal, and disease progression is slow. Anticipation is suggested. Brain imaging reveals marked atrophy of the cerebellum. The responsible gene has not yet been identified.

Spinocerebellar Ataxia Type 22 Chung and associates [2003] reported a pure cerebellar ataxia syndrome consisting of gait and limb ataxia, dysarthria, and nystagmus in a single Chinese kindred mapping to chromosome 1p21-q23 [Chung et al., 2003]. Neuroimaging found diffuse involvement of the cerebellum. Anticipation is suggested. Based on their chromosomal loci, it has been suggested that spinocerebellar ataxia type 19 and spinocerebellar ataxia type 22 might be the same disorder [Schelhaas et al., 2004]; identification of the responsible gene(s) should answer this question.

Spinocerebellar Ataxia Type 23 A single, three-generation Dutch family with a late onset (>40 years), slowly progressive spinocerebellar ataxia was identified with locus linkage at 20p13-p12.2 [Verbeek et al., 2004]. The clinical presentation includes gait and limb ataxia, disturbance of oculomotor control, dysarthria, and hyperreflexia. Neuroimaging demonstrates severe cerebellar atrophy. Pathology in a single individual who died at 80 years of age exhibited loss of Purkinje cells and of neurons in the dentate nuclei and inferior olives; thinning of the cerebellopontine tracts; demyelination of the posterior and lateral columns in the spinal cord; and ubiquitin-positive, polyglutamine-negative intranuclear inclusions in nigral neurons that resembled Marinesco bodies. The pathogenic significance of this last finding is uncertain. A candidate gene approach has thus far failed to identify the responsible gene.

Spinocerebellar Ataxia Type 25 (MIM 608703) Stevanin and colleagues [2004] reported a single French kindred with cerebellar ataxia and peripheral sensory

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neuropathy manifest as loss of vibratory, light, touch, and pain sensation. Initial symptoms often include vomiting and gastrointestinal features. No evidence of anticipation was found. Brain imaging demonstrates global cerebellar atrophy. A candidate gene search failed to identify the affected gene.

Fibroblast Growth Factor 14—Spinocerebellar Ataxia (MIM 601515) A single Dutch kindred was described with a spinocerebellar ataxia that begins with trembling of the hands during childhood [van Swieten et al., 2003]. Limb ataxia develops between the ages of 15 and 20 years. Ataxia, dysmetric saccades and smooth pursuit movements, nystagmus, smallamplitude hand tremor, psychiatric symptoms, and decreased cognitive performance are part of this slowly progressive disease. Brain imaging is normal or reveals cerebellar atrophy. The same investigators demonstrated that a single nucleotide change in exon 4 of the FGF14 gene, resulting in a phenylalanine to serine substitution and a predicted destabilization of the protein structure, is the responsible mutation. Although the effects of this mutation have not been examined in an animal model, mice lacking FGF14 are ataxic and have a paroxysmal dystonia [Wang et al., 2002]. The authors also demonstrated that FGF14 is transported into neuronal processes, suggesting that disruption of this process may lead to the clinical phenotype.

Episodic Ataxia There are four episodic ataxias, all of which are rare dominant disorders characterized by intermittent ataxia. Episodic ataxias type 1 and type 2 are caused by channelopathies; the pathogenesis of episodic ataxia type 3 and episodic ataxia type 4 is unknown, but channelopathies are also suspected in the latter two diseases. Acetazolamide is useful for treating three of the four disorders [Griggs et al., 1978]. Episodic ataxia type 1 (MIM 160120), also known as episodic ataxia with myokymia, is characterized by intermittent episodes of ataxia that may occur spontaneously but are often precipitated by exercise, fever, stress, or even sudden movement. The attacks may last seconds to minutes and may occur several times per day. Myokymia, a rippling movement of muscle, is usually observed in the periorbital and small hand muscles and persists between ataxic attacks. Episodic ataxia type 1 maps to human chromosome 12p13, and the disease is caused by point mutations in the potassium channel gene KCNA1 (Kv1.1) [Browne et al., 1994; 1995; Comu et al., 1996]. All affected individuals are heterozygous. Episodic ataxia type 2 (MIM 108500), also known as hereditary paroxysmal cerebellar ataxia, is characterized by intermittent attacks of ataxia and dysarthria lasting from a few minutes to a few days. Nausea, migraine, weakness, vertigo, diplopia, oscillopsia, or dystonia may accompany an attack. Attacks are often followed by a period of fatigue. Interictal neurologic findings include nystagmus (either gaze evoked or downbeat), mild cerebellar ataxia, and occasionally epilepsy. A progressive cerebellar ataxia is seen in some kindreds. The ataxia and number of attacks typically decrease with acetazolamide treatment; 4-aminopyridine

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may be a useful alternative if acetazolamide fails or loses effectiveness [Strupp et al., 2004]. The gene locus for this disease was mapped to the short arm of chromosome 19 in a position that overlaps the locus for familial hemiplegic migraine [Joutel et al, 1993; Vahedi et al., 1995; von Brederlow et al., 1995]. Ophoff and associates [1996] subsequently demonstrated that both episodic ataxia type 2 and FHM are caused by mutations in the CACNA1A gene. Thus, episodic ataxia type 2, familial hemiplegic migraine, and spinocerebellar ataxia type 6 are allelic disorders. CACNA1A codes for the brain-specific, voltage-sensitive α1A (Cav2.1) subunit of the P/Q-type calcium channel, which is highly expressed in Purkinje cells [Ishikawa et al., 1999]. Several different missense and nonsense mutations in the gene are associated with episodic ataxia type 2 [Jen et al., 2004]. Although there initially appeared to be a clear genotypephenotype relationship, further studies have demonstrated that the nature of the mutation in the gene is not predictive of whether an individual will clinically present with episodic ataxia type 2 or familial hemiplegic migraine. Episodic ataxia type 3, or periodic vestibulocerebellar ataxia (MIM 606552), has been described in two white families from North Carolina [Farmer and Mustian, 1963; Vance et al., 1984]. Clinically, the disorder consists of episodic attacks of vertigo, nausea, tinnitus, horizontal nystagmus, oscillopsia, and ataxia that begin in the third decade and may evolve into a constant condition. The visual sensation of objects moving past the patient, such as occurs while riding in a car, can exacerbate attacks, but lying quietly for 15 to 30 minutes can alleviate an attack. Acetazolamide is not therapeutic, although antihistamines have been anecdotally reported to decrease the frequency and severity of attacks in at least some individuals [Farmer and Mustian, 1963]. Neuroimaging and pathology studies have not been done. Several spinocerebellar ataxias, as well as episodic ataxias type 1 and type 2, have been eliminated as causative [Damji et al., 1996]. The gene locus is not known. Episodic ataxia type 4 (MIM 606554) was described in a large Canadian kindred [Steckley et al., 2001]. Clinical attacks consist of vertigo, incoordination, imbalance, tinnitus, diplopia, or visual blurring lasting for 1 minute to 6 hours. Interictal myokymia or ataxia is also present. Attacks often occur once or twice per day, followed by a refractory period. Generalized seizures occur in some members of the kindred, suggesting that a channelopathy might be reponsible. Acetazolamide was useful for reducing the frequency of attacks in one patient. Episodic ataxias type 1 and type 2 loci were excluded by mapping studies.

Dentatorubral-Pallidoluysian Atrophy (MIM 125370) Dentatorubral-pallidoluysian atrophy is a rare autosomaldominant, neurodegenerative disorder characterized by progressive ataxia, myoclonus, epilepsy, chorea, athetosis, and dementia [Smith, 1975; Smith et al., 1958]. The hereditary nature of the disease was confirmed through detailed clinical, genetic, and neuropathologic studies of five Japanese families with familial myoclonic epilepsy and choreoathetosis [Naito and Oyanagi, 1982]. Clinically, age of onset is linked to disease phenotype. Early onset cases (<20 years of age) tend to present with a progressive myoclonic epilepsy syndrome consisting of epilepsy,

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myoclonus, cerebellar ataxia, and mental retardation, whereas adult onset cases (>20 years of age) tend to present with cerebellar ataxia, choreoathetosis, or dementia. The phenotypic diversity within and among families is striking, as is the overlap with the clinical presentation of Huntington’s chorea. Imaging studies demonstrate cerebellar, tegmental, and cerebral atrophy, as well as signal changes in the white matter. In late onset cases, signal change can also be found in the pons, midbrain, thalamus, and globus pallidus [Kanazawa, 1998]. Pathologic findings in dentatorubralpallidoluysian atrophy include neuronal loss in the dentate nucleus, red nucleus, globus pallidus, and subthalamic nucleus. There is also diffuse loss of myelin staining in the cerebral white matter [Kanazawa, 1998; Munoz et al., 2004]. The disorder is very rare except in Japan, where it accounts for a significant proportion of autosomal-dominant spinocerebellar ataxias [Watanabe et al., 1998]. By using a candidate gene approach, the mutation causing dentatorubral-pallidoluysian atrophy was identified by two research groups [Koide et al., 1994; Nagafuchi et al., 1994]. They both found linkage to chromosome 12 and identified a CAG repeat as responsible for the disorder. An inverse correlation exists between the number of repeat units and the age of onset. Anticipation has been demonstrated in both paternal and maternal transmission of the disease allele, and extreme expansions (>90 repeats) can lead to infantile disease [Shimojo et al., 2001]. Gene dosage also plays a role in severity of phenotype, with homozygosity for a pathogenic allele causing more severe clinical manifestations than would otherwise be predicted based on repeat length [Sato et al., 1995]. The clinical heterogeneity of dentatorubral-pallidoluysian atrophy belies its genetic cause. Haw River syndrome shares many clinical and neuropathologic features with dentatorubralpallidoluysian atrophy, Huntington’s disease, and the spinocerebellar ataxias. However, this clinical entity differs from dentatorubral-pallidoluysian atrophy in the absence of myoclonic epilepsy, as well as the presence of basal ganglia calcifications and neuroaxonal dystrophy. Despite these phenotypic differences, the dentatorubral-pallidoluysian atrophy expansion was detected in a black family with Haw River syndrome [Burke et al., 1994]. Similarly, Warner and co-workers [1994] reported the CAG repeat expansion in a family of Maltese origin with variable clinical features that included dementia and seizures in younger patients, and dementia, psychosis, ataxia, and chorea in older patients. The neuropathologic findings in this family were not consistent with dentatorubral-pallidoluysian atrophy. These examples illustrate the wide phenotypic diversity encountered in dentatorubral-pallidoluysian atrophy. Genetic testing for the disorder is therefore indicated in patients with an autosomal dominant disorder causing dementia, ataxia, seizures, psychiatric symptoms, dystonia, chorea, or myoclonus. Also, patients with features of Huntington’s disease but no evidence of expansion of the Huntington’s disease CAG repeat should be evaluated for the CAG repeat at the dentatorubral-pallidoluysian atrophy locus. The pathogenesis of dentatorubral-pallidoluysian atrophy remains a mystery. The number of CAG repeats varies in different tissues and tends to be larger in brain, suggesting somatic instability of the repeat [Ueno et al., 1995]. However, the degree of expansion does not seem to parallel neuro-

pathologic involvement. Intranuclear inclusions are found in both neurons and glia; their presence in oligodendrocytes may cause the white matter lesions that are sometimes seen [Hayashi et al., 1998]. Atrophin-1, the DRPLA gene product, is expressed ubiquitously in human tissue. Several proteins proposed to interact with atrophin-1 have been identified using a yeast two-hybrid screen [Wood et al., 1998]. Recent evidence suggests that the wild-type atrophin-1 protein is involved in regulation of transcription, both positively and negatively [Shimohata, 2000; Zhang, 2002]. The target genes and the effect of polyglutamine expansion on this function remain unknown.

Hereditary Spastic Ataxia The hereditary spastic ataxias are a heterogeneous group of disorders that combine the features of hereditary spastic paralysis and spinocerebellar ataxia. They typically present first with lower limb spasticity followed by ataxia, dysarthria, and gait disturbance. Autosomal-dominant, recessive, and X-linked forms have been described. Autosomal-dominant hereditary spastic ataxia (SAX1-MIM 108600): Described in three kindreds from Newfoundland, these patients typically present first with progressive leg spasticity, followed by dysarthria and ocular movement abnormalities [Meijer et al., 2002]. The dentatorubral-pallidoluysian atrophy locus has not been excluded, although genetic anticipation is not observed. Autosomal-recessive spastic ataxia of CharlevoixSaguenay (ARSACS-MIM 270550): Originally described in French-Canadians from the Charlevoix-Saguenay region of Quebec, this autosomal-recessive disorder has also been found in a large Tunisian family [Bouchard, 1978; Mrissa et al., 2000]. Early onset is a rule, with the condition first being noticed when a child begins to walk; however, age of onset can be as late as 20 years. In addition to spasticity and ataxia, affected individuals also have sensory disturbances in the lower limbs (electromyography shows absent sensorynerve conduction and reduced motor-nerve velocity), as well as hypermyelination of retinal-nerve fibers. Physical examination often reveals absent or reduced tendon reflexes in the lower limbs with a present Babinski sign; claw hand deformity and pes cavus can also be seen. Eye movements are not affected. Nonverbal intelligence quotient scores are often at the low end of normal. The SACS gene was mapped to chromosome 13q12. Frameshift and nonsense mutations lead to truncations in the gene product, sacsin, which is expressed throughout the CNS and may be involved in chaperonemediated protein folding [Engert et al., 2000].

Spastic Paraplegia, Ataxia, and Mental Retardation (MIM 607565) Hedera and colleagues [2002] identified a single kindred whose older members presented with uncomplicated spastic paraplegia, whereas later generations had either spastic paraplegia and ataxia or spastic paraplegia, ataxia, and mental retardation. Multiple spinocerebellar ataxias and hereditary spastic paraplegias were excluded by gene tests and linkage analysis, demonstrating that spastic paraplegia, ataxia, and mental retardation is a distinct disorder. Neuroimaging demonstrates dorsal column atrophy in all three types,

Maricich and Zoghbi / The Cerebellum and the Hereditary Ataxias

although only the latter two had cerebellar atrophy. Pathologic studies are not available. Genetic anticipation, both in age of onset and disease severity, was suggested. The causative gene is unknown.

X-Linked Spinocerebellar Ataxia A group of hereditary ataxias can be classified as X-linked based on the pattern of inheritance in specific kindreds. Shokeir [1970] described three families with an X-linked recessive pattern of inheritance and onset of ataxia in the late teens or early 20s. No extrapyramidal or posterior column deficits were noted. Another syndrome of X-linked cerebellar ataxia with hypotonia, optic atrophy, and sensorineural deafness has been described [Schmidley et al., 1987]. The disease occurs in infancy, is progressive, and causes death in childhood. Remarkable degeneration occurs in the red nucleus, dorsal motor nucleus of the vagus nerve, and auditory pathway, with some neuronal loss and gliosis in the dentate nucleus and inferior olive. Apak and associates [1989] described a progressive ataxia combined with paraplegia in a family in which seven males were affected; death typically occurred in the third or fourth decade. A pure X-linked cerebellar ataxia with slow progression has also been seen [Lutz et al., 1989]. An X-linked recessive disease characterized by ataxia, early onset floppiness, liability to infections (especially of the upper respiratory tract), deafness, and eventually flaccid quadriplegia and areflexia was reported [Arts et al., 1993]. This disease is rapidly progressive and results in death in early childhood. No precise genetic localization of the X-linked ataxias has been established.

PROPOSED DIAGNOSTIC APPROACH TO THE HEREDITARY ATAXIAS Although the constellation of symptoms and signs may be suggestive of a hereditary ataxia, the clinical overlap of these disorders often precludes precise classification on clinical grounds alone. Still, important clues can be gleaned from the history and physical examination. Involvement of non-neural systems (e.g., frequent infections; ataxiatelangiectasia; absence of female sexual maturation; ataxiatelangiectasia, ataxia-oculomotor apraxia type 1; diabetes mellitus; Friedreich’s ataxia) or intermittent symptoms (episodic ataxias) can suggest a diagnosis. A careful family history (including possible consanguinity) is needed to separate dominant from recessive conditions, although the sporadic appearance of a dominant disorder can sometimes create confusion. Physical examination findings such as the presence of pes cavus (Friedreich’s ataxia, ataxiatelangiectasia), telangiectasias (ataxia-telangiectasia), or bulging eyes (Machado-Joseph disease or spinocerebellar ataxia) may also suggest a particular disorder. Laboratory testing, such as measuring serum vitamin E (low in AVED) or albumin levels (low in ataxia-oculomotor apraxia type 1) can be useful. Ancillary tests such as EEG to further evaluate seizures and nerve conduction studies/ electromyography to characterize peripheral nerve involvement can be helpful as well. MRI of the brain and spinal

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cord can help to distinguish “pure” cerebellar ataxias (such as spinocerebellar ataxia type 5) from those that involve multiple CNS regions (such as dentatorubral-pallidoluysian atrophy and Friedreich’s ataxia). However, all of these tests have their limitations and may not provide the correct diagnosis. In the current age of molecular diagnostics, the gold standard is genetic testing. Genetic testing has the added benefit of providing information that can be used for genetic counseling. Mutation testing is available for all of the disorders presented in this chapter whose causative gene has been identified. Although the majority of mutations will be detected by this analysis, these tests occasionally miss certain abnormalities such as single nucleotide substitutions (e.g., FRDA) or massive repeat expansions. When the constellation of clinical features suggests a particular disorder, directed testing for that disorder is appropriate. However, in new-onset cases lacking a specific presentation, a more comprehensive approach may be needed to identify the correct diagnosis. ACKNOWLEDGMENT The section on ataxia-telangiectasia was modified from Chapter 29 by Bruce O. Berg from the 3rd edition (1999) of this book.

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CHAPTER 58

Movement Disorders Terence D. Sanger and Jonathan W. Mink

APPROACH TO CHILDHOOD MOVEMENT DISORDERS Movement disorders are syndromes characterized by impaired voluntary movement, presence of involuntary movements, or both. There may be impaired targeting and velocity of intended movements, abnormal involuntary movements, abnormal postures, or excessive normal-appearing movements at inappropriate or unintended times. Movement disorders in children include athetosis, chorea, dystonia, myoclonus, parkinsonism, stereotypies, tics, and tremor [Sanger, 2003b]. Movement disorders may be accompanied by weakness, spasticity, hypotonia, ataxia, apraxia [Koski et al., 2002], and other motor deficits, although many authors do not include these accompanying deficits among the movement disorders. Movement disorders have been divided into hyperkinetic disorders in which there is excessive movement, and hypokinetic disorders in which there is a paucity of movement. Hyperkinetic disorders consist of abnormal, repetitive involuntary movements and include most of the childhood movement disorders such as chorea, dystonia, athetosis, myoclonus, stereotypies, tics, and tremor. Hypokinetic movement disorders are primarily akinetic or rigid. The primary syndrome in this category is parkinsonism, occurring most commonly in adulthood as Parkinson’s disease or one of the many forms of secondary parkinsonism. In children, hypokinetic disorders are much less common than hyperkinetic disorders. Abnormalities of movement that are presumed to be due to central nervous system disorders are typically divided into two primary categories: pyramidal and extrapyramidal. Many authors consider only the extrapyramidal symptoms to be movement disorders. Pyramidal symptoms typically involve weakness, specific patterns of weakness, or spasticity. Pyramidal symptoms are thought to be due to injury to the pyramidal tract, including the corticospinal tract, and therefore to represent, to some extent, the effect of a denervated spinal cord. Extrapyramidal disorders are often described as everything that is not a pyramidal disorder. In particular, the term usually includes disorders of movement that are not due to weakness. Movement disorder terminology has been well defined for adults but less so for children. Therefore, it is likely that movement disorders are underreported in children and that there is inconsistent terminology. Recently, there have been attempts to provide specific definitions of childhood hypertonic disorders, including dystonia and rigidity [Sanger et al., 2003]. The prevalence in children of different types of hypertonic disorders, as well as other movement disorders, is not well known, although there have been studies invest-

igating this in certain populations. Consistent definitions of nonhypertonic disorders in childhood are not yet available. In this chapter, use of terminology for nonhypertonic disorders is based on current adult definitions. In adult movement disorders, it is frequently helpful to divide disorders into primary and secondary disorders, although there is no consistent definition of these terms. Many authors refer to disorders as primary if there is only a single dominant symptom and the underlying cause is presumably genetic or is due to an identified gene. However, the existence of a single symptom in childhood movement disorders is probably the exception rather than the rule.

Characteristic Features of Pediatric Movement Disorders Movement disorders in children differ from those in adults in several important aspects. Perhaps the most important is that movement disorders in childhood are primarily symptoms of other diseases, rather than diseases in and of themselves [Sanger, 2003b; Sanger et al., 2003). In adults, dystonia and parkinsonism are usually due to primary dystonia or idiopathic Parkinson’s disease, respectively. However, dystonia or parkinsonism in children are more likely to be features of an underlying static or progressive neurologic disorder. Diagnosis in children is complicated by the fact that many symptoms have more than one cause, and any particular underlying pathophysiology may lead to a complex combination of symptoms. The diagnostic evaluation in children is guided by symptoms, but the existence of a large class of diseases that can lead to the same set of symptoms often necessitates a broad etiologic evaluation. There may be specific etiologic treatments and symptomatic treatments, both of which may be beneficial in an individual child. In particular, many of the causes of childhood movement disorders do not yet have any specific treatment, yet symptomatic treatment for the resulting movement disorder can be extremely helpful and lead to improvement in quality of life. Another distinction between movement disorders in adults and children is that many adult neurologic disorders can be attributed to anatomically localized injury, but childhood disorders frequently result from a global or multifocal injury that may affect particular cell types, receptor types, or metabolic pathways. Therefore in children, the injury is often sparse but global, with manifestations across multiple areas of function, including sensorimotor and cognitive functions. The clinical manifestations of a movement disorder will depend on the child’s developmental stage. The same illness

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may present differently depending on the age at onset of symptoms. Detection of a progressive disorder may be complicated by superposition of a progressive disorder on the natural improvement of function that is expected throughout childhood. Therefore, a child with a progressive movement disorder may continue to develop new skills despite falling further and further behind in age-appropriate behavior. The presence of a movement disorder may affect the current and continuing development of the child’s normal motor and cognitive abilities. Therefore, an acute illness may have developmental consequences that outlast the duration of the injury itself.

Diagnosis of Movement Disorders Classification of the movement disorder based on the spatial and temporal pattern is essential for diagnosis. It is also important to define the context in which the movements occur. Although it is often helpful to list the characteristics of the movements (Table 58-1), the diagnosis relies on pattern recognition, and the clinician must see the movements. If the movements are not apparent during the neurologic examination, repeating the examination at another time or obtaining video recordings of the movements is essential. The widespread availability of video cameras has substantially improved diagnosis of movement disorders. When approaching a patient with a movement disorder, it is helpful to determine the answers to some key questions: (1) Is the number of movements excessive (hyperkinetic) or diminished (hypokinetic)? (2) If hyperkinetic, do the individual movements appear normal or abnormal? (3) Is the movement paroxysmal (sudden onset and offset), continual (repeated again and again), or continuous (without stop)? (4) What is the developmental stage of the child, and has the development been normal? (5) How does voluntary movement affect the movement disorder? Are the symptoms and TABLE 58-1 Phenomenologic Classification of Movement Disorders MOVEMENT DISORDER

BRIEF DESCRIPTION

Athetosis

Slow, continuous writhing movements of distal body parts, especially the fingers and hands Chaotic, random, repetitive, brief, purposeless movements. Rapid, but not as rapid as myoclonus. When very large amplitude affecting proximal joints, choreic limb movements are often called ballism. Repetitive, sustained, abnormal postures or movements. Abnormal postures typically have a twisting quality. Sudden, brief, shocklike movements that may be repetitive or rhythmic Hypokinetic syndrome characterized by a combination of rest tremor, slow movement (bradykinesia), rigidity, and postural instability Patterned, episodic, repetitive, purposeless, rhythmic movements Stereotyped intermittent, sudden, discrete, repetitive, nonrhythmic movements, most frequently involving head and upper body Rhythmic oscillation around a central point or position involving any one body part or more than one

Chorea, ballism

Dystonia Myoclonus Parkinsonism Stereotypy Tics Tremor

signs present at rest (body part supported against gravity), with maintained posture, with action, with approach to a target (intention), or a combination? (6) Has the movement disorder changed over time? (7) Do environmental stimuli or emotional states precipitate, exacerbate, or alleviate the movement disorder? (8) Is the patient aware of the movements? (9) Can the movements be suppressed voluntarily? (10) Are the movements heralded by a premonitory sensation or urge? (It may be helpful to ask the patient, “Why do you do that?”) (11) Does the movement disorder abate with sleep? (12) Are there other findings on the examination suggestive of focal neurologic deficit or systemic disease? (13) Is there a family history of a similar or related condition? Laboratory tests, imaging, and other diagnostic testing should be based on the specific movement disorder. There is no universal “movement disorder workup” because the causes are varied and some movement disorders (e.g., tics) are rarely symptomatic of an underlying disease. Movement disorders may be difficult to characterize unless other symptoms and behavioral context are taken into account. Chorea can resemble myoclonus. Dystonia can resemble spasticity. Paroxysmal movement disorders such as dystonia and tics may resemble seizures. Movements in some contexts may be normal and in others may indicate underlying pathology. For example, frequent eye blinking can be perfectly normal and appropriate in one setting (a windy day on the beach) but excessive in another (tics). Movements that raise concern about a degenerative disorder in older children (progressive myoclonus) may be completely normal in an infant (benign neonatal myoclonus). Thus, it is important to view the movement disorder in the context of a complete history and neurologic examination.

Role of the Basal Ganglia in Movement Disorders Most movement disorders can be attributed to dysfunction of the basal ganglia. However, basal ganglia disorder and movement disorder are not synonymous. Some movement disorders (e.g., tremor and myoclonus) may have little to do with the basal ganglia. Conversely, basal ganglia lesions may cause cognitive or affective symptoms and minimal or no motor impairment. Nonetheless, because most movement disorders involve the basal ganglia, it is useful to have some understanding how this system is organized. The basal ganglia are subcortical structures comprising several interconnected nuclei in the forebrain, midbrain, and diencephalon (Fig. 58-1). They include the striatum (caudate, putamen, nucleus accumbens); the subthalamic nucleus; the globus pallidus (internal segment [GPi], external segment [GPe], and ventral pallidum); and the substantia nigra (pars compacta [SNpc] and pars reticulata [SNpr]). The striatum and subthalamic nucleus are the primary input structures of the basal ganglia, receiving excitatory input from cerebral cortex. The GPi and SNpr are the primary output nuclei, sending inhibitory output to thalamus and brainstem targets. Acting through the thalamus, the basal ganglia output influences frontal lobe cortical neurons. By virtue of the inhibitory output from the basal ganglia, conditions associated with destruction of the output nuclei are associated with unwanted and nonspecific overactivity of thalamocortical and brainstem targets.

Sanger and Mink / Movement Disorders

FIGURE 58-1. Simplified schematic diagram of basal ganglia circuitry. Excitatory connections are indicated by open arrows, inhibitory connections by filled arrows, and the modulatory dopamine projection is indicated by a three-headed arrow. DYN, dynorphin; ENK, enkephalin; glu, glutamate; GPe, globus pallidus external segment; GPi, globus pallidus internal segment; IL, intralaminar thalamic nuclei; MD, mediodorsal nucleus; PPA, pedunculopontine area; SC, superior colliculus; SMA, supplementary motor area; SNpc, substantia nigra pars compacta; SNpr, substantia nigra pars reticulata; SP, substance P; STN, subthalamic nucleus; VA ventral anterior nucleus; VL, ventral lateral nucleus.

Motor cortex Premotor cortex SMA Frontal eye fields Prefrontal cortex

Cerebral cortex

Glu

Glu Glu Glu Caudate/Putamen Glu

Glu GABA

ALAMUS TH

way ath tp ec

Direct pathway

GABA/ Ind ENK ir GPe

GABA/ DYN/ SP GPi

Hyperdirect pathway

D2

D1 GABA

IL VA/ VL/ MD

1273

GABA

GABA

GABA Glu

SNpr

Glu

STN

GABA SNpc

GABA GABA

Excitatory

SC

PPA

Inhibitory Exc / Inhib Brainstem and spinal cord

The striatum receives excitatory input from virtually all of cerebral cortex. In addition to the cortical input, the striatum receives a dense input from dopamine-containing neurons in the SNpc. The action of dopamine on striatal neurons depends on the type of dopamine receptor involved. Five types of G protein–coupled dopamine receptors have been described (D1 to D5) and have been grouped into two families. The D1 family includes D1 and D5 receptors and the D2 family includes D2, D3, and D4 receptors. D1 receptors potentiate the effect of cortical input to striatal neurons, whereas D2 receptors decrease the effect of cortical input to striatal neurons. The main neuron type is the medium spiny neuron, accounting for 95% of striatal neurons. In addition to cortical and nigral inputs, medium spiny striatal neurons receive a number of other inputs, including (1) excitatory glutamatergic inputs from thalamus; (2) cholinergic input from striatal interneurons; (3) γ-aminobutyric acid (GABA), substance P, and enkephalin input from adjacent medium spiny striatal neurons; and (4) GABA input from local inhibitory interneurons. The neurochemistry of the striatum is complicated but provides many options for pharmacologic therapeutics. Both dopamine and acetylcholine modulate the activity of striatal output neurons and are the targets for the most commonly used medications for treating movement disorders. GABA is ubiquitous in the basal ganglia and is another target for

pharmacologic therapeutics, but because it is ubiquitous, the effects of medications such as benzodiazepines and baclofen may be rather nonspecific. Medium spiny striatal neurons contain the inhibitory neurotransmitter GABA and are inhibitory to their targets. In addition, they have peptide neurotransmitters that are colocalized with GABA. Based on the type of neurotransmitters and the predominant type of dopamine receptor they contain, the medium spiny neurons can be divided into two populations. One population contains GABA, dynorphin, and substance P and primarily expresses D1 dopamine receptors. These neurons project to the basal ganglia output nuclei, GPi and SNpr, and form the “direct pathway” [Albin et al., 1989; Alexander and Crutcher, 1990; DeLong, 1990]. The second population contains GABA and enkephalin and primarily expresses D2 dopamine receptors. These neurons project to GPe and form the first limb of the “indirect pathway” [Albin et al., 1989; Alexander and Crutcher, 1990; DeLong, 1990]. The subthalamic nucleus receives an excitatory, glutamatergic input from many areas of frontal lobes with especially large inputs from motor areas of cortex. The subthalamic nucleus also receives an inhibitory GABA input from GPe. The output from the subthalamic nucleus is glutamatergic and excitatory to the basal ganglia output nuclei, GPi and SNpr. This projection forms the second limb

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of the indirect pathway [Albin et al., 1989; Alexander and Crutcher, 1990; DeLong, 1990]. There are several routes through which information flows from the cerebral cortex to the basal ganglia output nuclei. The two most direct are the disynaptic, inhibitory, direct pathway from cortex to striatum to GPi and SNpr and the disynaptic, excitatory, “hyperdirect pathway” [Nambu et al., 2000] from cortex to subthalamic nucleus to GPi and SNpr. The direct pathway is inhibitory to GPi and SNpr; the hyperdirect pathway is excitatory to GPi and SNpr. The hyperdirect pathway is the fastest route through the basal ganglia. There are several indirect routes, but the most important is the indirect pathway from cortex to striatum to GPe to subthalamic nucleus to GPi and SNpr. Organization of these pathways confers a pattern of fast, powerful, and relatively broad excitation through the hyperdirect pathway and more focused inhibition through the direct pathway (Fig. 58-2) [Mink, 1996; Nambu et al., 2000; Parent and Hazrati, 1993]. The indirect pathway confers additional focus. The primary basal ganglia output arises from GPi and SNpr, uses GABA, and is entirely inhibitory. The outputs from GPi and SNpr project to parts of the ventral anterior, ventral lateral, and mediodorsal thalamic nuclei. GPi and SNpr also project to the brainstem in the area of the pedunculopontine nucleus and to the intralaminar centromedian-

Cerebral cortex

Basal Ganglia Pathophysiology in Movement Disorders

Striatum

GPi

STN Thalamocortical and brainstem targets

Competing motor patterns

Excitatory Desired motor pattern

parafascicular complex of the thalamus. A portion of the SNpr projects to the superior colliculus, where it contributes to eye movement control. The output from basal ganglia to thalamocortical circuits appears to be segregated anatomically and possibly functionally. The thalamic targets of GPi and SNpr project, in turn, to frontal lobe, with the strongest output going to motor areas. The basal ganglia motor circuit has a somatotopic organization, with separate representation of different body parts maintained throughout the basal ganglia. There also appears to be relative segregation of motor from nonmotor basal ganglia circuits [Hoover and Strick, 1993]. A popular model of basal ganglia dysfunction in movement disorders was developed in the late 1980s (Fig. 58-3) [Albin et al., 1989, 1995; DeLong, 1990]. In simple terms, the model proposes that hypokinetic movement disorders (e.g., parkinsonism) can be distinguished from hyperkinetic movement disorders (e.g., chorea, dystonia, tics) based on the magnitude and pattern of the basal ganglia output neurons in GPi and SNpr [Wichmann and DeLong, 1996]. Because basal ganglia output neurons are inhibitory to thalamus and the pedunculopontine nucleus, their function is analogous to a braking mechanism such that increased activity inhibits and decreased activity facilitates motor pattern generators in cerebral cortex and brainstem [Mink, 1996]. As described earlier, the anatomic organization of the basal ganglia confers a pattern of focused facilitation and surround inhibition of motor mechanisms in thalamocortical and brainstem circuits (see Fig. 58-2). The normal function of this organization is to selectively facilitate desired movements and to inhibit potentially competing movements [Mink, 1996; Mink, 2003].

Inhibitory

FIGURE 58-2. Model of the functional organization of basal ganglia output for selective facilitation and surround inhibition of competing motor patterns. Excitatory projections are indicated with open arrows; inhibitory projections are indicated with filled arrows. Relative magnitude of activity is represented by line thickness. GPi, globus pallidus internal segment; STN, subthalamic nucleus.

Basal ganglia dysfunction can occur on many levels. There can be destructive lesions of specific nuclei (e.g., infarction, hemorrhage, metabolic disorders) that may result in specific movement disorders. There can also be injury to multiple nuclei than may result in single or multiple movement disorders (e.g., hypoxia, carbon monoxide poisoning, metabolic disorders). Movement disorders can also be caused by loss of specific neuron types (e.g., Huntington’s disease, Parkinson’s disease) or by cellular dysfunction without neuronal death (e.g., DYT1 dystonia). As in other areas of neurology, lesion localization is important in movement disorders and may often provide important clues to guide an efficient evaluation and treatment plan. Lesions in the striatum produce variable results that depend in part on the location of the lesion, in part on the lesion method, and in part on what is measured. Lesions in the caudate nucleus most commonly cause behavioral disturbance such as abulia but may also cause chorea or dystonia. Lesions in the putamen are likely to produce movement deficits and typically cause dystonia (most common) or parkinsonism [Bhatia and Marsden, 1994]. A unilateral subthalamic nucleus lesion is the classic cause of hemiballism; smaller amplitude chorea can also result from subthalamic nucleus lesions [Carpenter and Carpenter, 1951]. When bilateral, subthalamic nucleus lesions cause bilateral chorea or ballism. Most commonly, the

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FIGURE 58-3. Summary of the main connections of the “motor circuit” of the basal ganglia and a model for the role of dopamine in hyperkinetic and hypokinetic disorders. In the normal state, the putamen receives afferents from the motor and somatosensory cortical areas and communicates with the globus pallidus internal segment (GPi)/substantia nigra reticulata (SNpr) through a direct inhibitory pathway and though a multisynaptic (globus pallidus external segment [GPe], subthalamic nucleus [STN]) indirect pathway. Dopamine is believed to modulate striatal activity, mainly by inhibiting the indirect and facilitating the direct pathways. In hypokinetic movement disorders, dopamine deficiency may lead to increased inhibitory activity from the putamen onto the GPe and disinhibition of the STN. STN hyperactivity produces excessive excitation of the GPi/SNr neurons, which overinhibit the thalamocortical and brainstem motor centers. In some hyperkinetic movement disorders, decreased activity of the STN may lead to disinhibition of the GPi output to the thalamocortical projection. PPA, pedunculopontine area; SNpc, substantia nigra compacta; VL, ventral lateral nucleus.(From Obeso JA, Rodriguez-Oroz MC, Rodriguez M, et al. The basal ganglia and disorders of movement: Pathophysiological mechanisms. News Physiol Sci 2002;17:51.)

chorea or hemiballism resulting from subthalamic nucleus lesions involves the lower extremities more than the upper extremities and can persist for days to months. The intensity of hemiballism usually diminishes over time. Lesions of globus pallidus usually involve GPe and GPi, GPe and putamen, or GPi and SNpr. Lesions involving globus pallidus can cause dystonia, parkinsonism, or both [Bhatia and Marsden, 1994; Heidenreich et al., 1988; Mink, 1996]. Chorea rarely accompanies globus pallidus lesions. Focal lesions of SNpr can cause involuntary eye movements [Hikosaka and Wurtz, 1985]. Lesion of SNpc dopamine neurons cause depletion of dopamine in the striatum, resulting in parkinsonism, dystonia, or both [Calne et al., 1997]. Focal basal ganglia lesions are uncommon in children. Movement disorders in children most likely result from global dysfunction of basal ganglia circuits. The model shown in Figure 58-3 has been used to explain the basis for hypokinetic and hyperkinetic movement disorders but does not distinguish among the different hyperkinetic movement disorders. However, based on what is known about these disorders and the underlying neural circuitry, specific models have been proposed [Mink, 2003]. Diseases affecting the basal ganglia cause movement disorders that can be understood as failure to facilitate desired movements (e.g., Parkinson’s disease), failure to inhibit unwanted movements (e.g., chorea, dystonia, tics), or both [Albin

et al., 1989; DeLong, 1990; Mink, 1996; Mink, 2003]. The involuntary movements of chorea, dystonia, and tics differ in important spatial and temporal characteristics that reflect important pathophysiologic differences. More extensive discussion of the neural basis of these disorders has been undertaken [Mink, 2003].

Etiology of Movement Disorders in Children The etiology of movement disorders in children is extensive and is discussed further below. The most common cause of secondary disorders is likely to be cerebral palsy, with a prevalence of 2 per 1000. However, cerebral palsy itself represents a constellation of both injuries and symptoms, and there is a wide range of types of injury, localization, and combinations of symptoms [Surveillance of Cerebral Palsy in Europe, 2002]. Cerebral palsy can be associated with almost all forms of childhood movement disorders, and despite the lack of an ongoing destructive process, the clinical picture may change during development. The diagnosis and management of cerebral palsy are complex and are discussed in Chapter 20. Specific types of movement disorders may represent injury to particular localized regions of the central nervous system [Sanger, 2003a]. Ataxia most likely results from injury to the cerebellum or its inflow and outflow [Taroni and DiDonato, 2004]. Bradykinesia most likely occurs with injury to the substantia nigra or striatum of the basal ganglia

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leading to either presynaptic or postsynaptic failure of dopaminergic transmission [Albin et al., 1989]. Chorea occurs in severe cortical injury or basal ganglia injury, particularly if the subthalamic nucleus is involved. Dystonia most likely involves injury to basal ganglia, but the possibility of cortical or cerebellar abnormalities cannot be excluded as contributors [Hallett, 1998; Sanger, 2003a]. Myoclonus most likely involves cortical, brainstem, or spinal injury to gray matter [Caviness and Brown, 2004]. The localization of tremor depends on the type, but some forms of tremor involve cerebellum or brainstem circuits [Jankovic et al., 2004; Uddin and Rodnitzky, 2003]. Tic disorders probably involve an abnormality of the basal ganglia, but cortical mechanisms may also contribute [Mink, 2001a].

Approach to Treatment Treatment of childhood movement disorders is based primarily on symptomatology independent of the underlying cause. When a specific treatment for the underlying cause is available, certainly this should be applied, but in many cases such treatment is only partly effective. The goal of symptomatic treatment is to break the connection between the pathophysiology and the expression of clinical impairment. It is essential to ask both the child and the parents for the most significant cause of disability. In some children, the impairment that is most evident to the clinician is not the primary cause of disability. Sometimes treatment of the functional limitation or direct treatment of a disability is more effective, less time-consuming, and less risky than attempts to treat the underlying pathophysiology, and therefore it is essential to be certain that any treatment addresses the needs and goals of the child and family. In particular, it is usually neither necessary nor possible to treat all symptoms. It is most helpful to pick specific goals and to monitor progress toward those goals. In many cases, a team approach has been found to be helpful, particularly when there are multiple impairments leading to disability, and the team approach allows appropriate focusing and selection of interventions. In some individuals, a supportive environment and adaptive equipment are more effective than any medical intervention.

CLASSIFICATION OF CHILDHOOD MOVEMENT DISORDERS The first step to diagnosing and treating a movement disorder is to define the disorder (see Table 58-1). Individual names of movement disorders can refer to neurologic signs or to neurologic syndromes or diseases, which can cause some confusion. In this section, the definitions are limited to the neurologic signs to which they refer. Subsequent sections present a more complete discussion of the syndromes and diseases in which the different signs are seen either alone or in combination with other signs. The most common movement disorder in the pediatric population is the group of tic disorders. The prevalence of tic disorders in schoolchildren may be as high as 25% [Snider et al., 2002]. Most tic disorders are not severe, and the level of morbidity is low. Nevertheless, because of the lack of association with other neurologic symptoms, it is not

unreasonable to consider a tic disorder as a primary disorder in idiopathic cases. There are rare exceptions in which tics are due to secondary disorders, such as brain injury or neuroacanthocytosis. Dystonia is a relatively prevalent disorder in children, most likely because of its incidence in cerebral palsy. Dystonia as the primary symptom in cerebral palsy is less common, but dystonia as a complicating factor, particularly in the upper extremities of children with cerebral palsy otherwise characterized by weakness or spasticity, is probably more common. The incidence and classification of cerebral palsy are discussed in Chapter 20. In contrast to adults, task-specific dystonia, or occupational cramps, is not seen in younger children. Certainly focal dystonias do occur, but the task specificity seems to be a consequence of practiced skill, which would not be expected to present in the early childhood years. The incidence of parkinsonism, including bradykinesia and rigidity, is unknown in children and probably underreported. However, it is likely that parkinsonism is less common in children, given that its primary cause in adults is dopaminergic failure, whereas disorders known to cause failure of dopamine transmission in children more commonly present as dystonia. Choreoathetosis is a term that has been applied to a specific subset of children with a dyskinetic form of cerebral palsy. This term is not generally used in adults. It is not known whether choreoathetosis represents a form of dystonia, chorea, or an entirely different disorder [Turny et al., 2004]. Choreoathetotic cerebral palsy is an easily recognized syndrome, and because many of these children also possess some degree of dystonia, as well as chorea, choreoathetosis may simply be the expression of a combination of other movement disorders [Morris et al., 2002b]. Spasticity and weakness are very common in childhood motor disorders, again owing to the higher prevalence of cerebral palsy. However, these are not discussed further in this chapter. Hypotonia, or decreased muscle tone, is a disorder that appears to be unique to children and is not traditionally classified as a movement disorder, although it may be associated with movement disorders. Certainly flaccid paralysis is described in adults, but the particular picture of a generalized hypotonia without significant weakness, or disproportionate to the degree of weakness, seems to occur only in young children, generally younger than 2 years. In many cases, hypotonia is associated with abnormalities of cerebellar development or cerebellar injury, and many of these children subsequently develop ataxia. Therefore, it is possible to hypothesize that hypotonia may be the early childhood or infantile expression of cerebellar disease, whereas ataxia is the later childhood, juvenile, or adult expression of cerebellar disease.

Chorea Chorea describes an apparently random, nonrhythmic, purposeless set of movements of either distal or proximal muscles that appears to flow from one muscle or muscle group to another without any evident pattern. Chorea occurs at rest and with action and gives the child a “fidgety” appearance and the inability to hold still. It is associated with motor

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impersistence (e.g., the inability to maintain the tongue extended). Chorea may worsen or improve with voluntary movement, but even very severe chorea may not prevent accurate voluntary movement for some children, suggesting that compensatory mechanisms exist. Many individuals with chorea incorporate the involuntary movements into a voluntary movement to mask the impairment. However, the involuntary movements can lead to significant disability, and some children will injure themselves or others as a result of rapid ballistic flinging movements of the arms or legs. Tone is normal or reduced in pure chorea, but in children chorea may occur in the presence of hypertonic disorders including dystonia. As with most movement disorders, chorea disappears in sleep, but it may be at its worst when the child is drowsy. The term choreiform is often used to describe the minimal twitching or “piano playing” movements seen in many normal young children when arms are extended during the neurologic examination. The movements of chorea are briefer than the sustained muscle contractions seen in dystonia and are longer in duration than the shocklike movements of myoclonus [Marsden et al., 1983].

Primary Chorea HUNTINGTON’S DISEASE Huntington’s disease is autosomal dominant, caused by a trinucleotide repeat expansion within the IT-15 gene on chromosome 4 [Li et al., 1993]. This disorder is characterized by a combination of dystonia, chorea, myoclonus, behavioral abnormalities, ataxia, and ultimately dementia. When Huntington’s disease begins in childhood, the typical presentation is dystonia and rigidity, and not chorea. This has been referred to as the Westphal variant of Huntington’s disease [Quinn and Schrag, 1998; Topper et al., 1998]. The age of onset is earlier for children with a higher number of repeats [Langbehn et al., 2004]. There tends to be amplification of the number of repeats, particularly when it is transmitted from father to child, and therefore most cases of juvenile Huntington’s disease are inherited from the father and involve repeat lengths that are significantly higher than those seen in adults. Diagnosis is based on identification of the trinucleotide repeat sequence. Although at least 38 repeats are usually required for the occurrence of symptoms in adults, a larger number of repeats would be expected when symptoms present in childhood [Langbehn et al., 2004; Quinn and Schrag, 1998]. Magnetic resonance imaging (MRI) reveals atrophy of the caudate heads and, in later stages, generalized cerebral and cerebellar atrophy. In teenagers, the initial presentation of Huntington’s disease may be with psychiatric illness, and in particular, major depression may be the presenting symptom [Tost et al., 2004]. Dystonia or chorea supervenes later. The pathology includes basal ganglia, cerebellar, and cortical degeneration [de la Monte et al., 1988; Myers et al., 1988; Vonsattel et al., 1985]. The origin of the chorea has been hypothesized to be a primary loss of medium spiny cells in the striatum that bear D2-like receptors [Deng et al., 2004]. In children, there may be a relatively symmetric loss of D1-bearing and D2-bearing medium spiny neurons, which could account for

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the primarily dystonic rather than choreatic presentation [Albin et al., 1990; Augood et al., 1997]. Treatment of Huntington’s chorea in adults is typically based on modification of the chorea or myoclonus. Because the chorea has been presumed to be due to loss of medium spiny neurons in the indirect pathway, neuroleptic medications have been most frequently used in the adult population [Bonelli and Hofmann, 2004; Bonelli et al., 2004]. Neuroleptic agents would be expected to partially compensate for early loss of indirect pathway neurons by blocking the inhibitory effects of dopamine and thereby disinhibiting the remaining neurons. There is much less experience in children, in whom dystonia and rigidity may be greater contributors to disability. Other medications that have been used successfully in Huntington’s disease include tetrabenazine [Asher and Aminoff, 1981; Ondo et al., 2002], clonazepam [Thompson et al., 1994], and valproic acid [Grove et al., 2000]. There is currently no treatment that modifies the progression of the disease. Prognosis is poor for childhood-onset Huntington’s disease, and the movement disorder is expected to worsen progressively over the years after diagnosis. Life expectancy depends on the severity of symptoms and the number of repeats, but typically children will survive 10 to 15 years from the time of diagnosis.

ATAXIA-TELANGIECTASIA Despite the name of this disorder, ataxia is not always the presenting finding, and ataxia may be a much less prominent early symptom than upper extremity chorea (see Chapter 57). However, the chorea is usually less disabling than the ataxia. Other symptoms associated with ataxia-telangiectasia include dystonia, which is often proximal [Bodensteiner et al., 1980]. Ataxia-telangiectasia (Louis-Bar syndrome) is most commonly due to mutations in the ATM (ataxiatelangiectasia mutated) gene on chromosome 11q22-23 [Chun and Gatti, 2004; Coutinho et al., 2004; Gatti et al., 1998]. Mutation in this gene leads to decreased inhibition of cell cycling in the context of injury to nuclear DNA, and this leads to an accumulation of mutations at known “hot spots,” including translocations between regions on chromosome 7 and 14 known to be involved with immune function [Farina et al., 1994]. Therefore, one of the cardinal features of this disorder is a history of frequent sinopulmonary infections [Centerwall and Miller, 1958], which requires very close attention to pulmonary function and aggressive treatment of pulmonary infections at all ages. In later stages of the disorder, hematologic malignancy may occur [Stankovic et al., 1998]. Children with ataxia-telangiectasia may be particularly vulnerable to injury from ionizing radiation and certain chemotherapy agents, and this must be taken into consideration in planning any treatment for malignancy. The cause of the cerebellar degeneration is discussed further in Chapter 57. The pathology suggests a characteristic loss of Purkinje cells, such that by late stages in the disease, Purkinje cells are often completely absent. The cause of the chorea is not known, and basal ganglia pathology is minimal. Eye movement disorders are well described and include an inability to suppress and an inability to initiate saccades [Bundey, 1994; Lewis et al., 1999]. The inability to initiate saccades leads to a characteristic finding of

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oculomotor apraxia, in which a child will use thrusts of the head to position the eyes on the target. Diagnosis is based on laboratory testing, including decreased immunoglobulin G2 and immunoglobulin A, abnormalities in T-cell subsets, elevated α-fetoprotein, increased lymphocyte radiosensitivity, and decreased radiation-induced mitotic suppression [StrayPedersen et al., 2004]. Treatment of this disorder is primarily supportive, although there are isolated reports of dystonic symptoms responding to either trihexyphenidyl or levodopa. The chorea generally is mild and does not require specific treatment. There is no known treatment for the ataxia. Ataxia–oculomotor apraxia is an autosomal-recessive disorder with similar motor symptoms caused in some cases by mutations in the aprataxin gene AOA-1 [Moreira et al., 2001; Shimazaki et al., 2002; Tranchant et al., 2003]. This disorder commonly presents with chorea, ataxia, and oculomotor apraxia [Sano et al., 2004]. It is most prevalent in Japan and Europe. AOA-1 does not seem to be involved with cell cycle regulation, and therefore the DNA breakage, immune abnormalities, and malignancies seen in ataxiatelangiectasia do not occur. These patients have hypoalbuminemia [Shimazaki et al., 2002]. The long-term prognosis is considerably better than for ataxia-telangiectasia.

OTHER PRIMARY CHOREAS Other primary causes of chorea include familial benign hereditary chorea [Breedveld et al., 2002a; Kleiner-Fisman et al., 2003], which is an autosomal-dominant disorder that in some cases is due to mutations in the TITF-1 gene on chromosome 14 [Breedveld et al., 2002b]. Affected family members have normal or near-normal intelligence, and chorea is often the only complaint, although mild truncal dystonia and gait ataxia have been reported [Fernandez et al., 2001]. The severity of chorea can vary among different affected family members. Symptomatic treatment may yield some mild benefit. Neuroacanthocytosis is also a potential cause of chorea [Marson et al., 2003], although classification as a primary or secondary chorea is not universally agreed on.

Secondary Chorea There is a very long list of secondary causes of chorea in children, and these can be divided into several categories. The categories and disorders are summarized in Table 58-2.

SYDENHAM’S CHOREA Of the secondary causes of chorea in children, Sydenham’s chorea is the most common [Garvey and Swedo, 1997; Jordan and Singer, 2003; Jummani and Okun, 2001]. It has onset weeks or months after an acute infection with group A β-hemolytic streptococcus and is one of the cardinal symptoms of rheumatic fever (see Chapter 73). Symptoms may persist for weeks or months, but chorea almost always resolves spontaneously within 6 months [Jordan and Singer, 2003], although there have been a few reported cases of continued or recurring symptoms [Faustino et al., 2003]. The chorea is typically described involving distal musculature of the hands with a “piano playing” pattern, but other forms of chorea, including ballism, have been ob-

served. Large generalized body movements in some patients previously inspired the term St. Vitus’s dance. Anti–basal ganglia antibodies are found in some children [Church et al., 2002], and it has been hypothesized that production of these antibodies is triggered because of molecular mimicry by streptococcal antigens [Goldenberg et al., 1992; Kirvan et al., 2003; Loiselle and Singer, 2001; Singer et al., 2003]. Anti–basal ganglia antibodies can be detected TABLE 58-2 Causes of Chorea Static Injury, Structural Cerebral palsy, stroke, trauma, moyamoya disease, vasculitis, tumors, congenital malformations, Joubert’s syndrome Hereditary, Degenerative Ataxia-telangiectasia, ataxia ocular motor apraxia (includes AOA-1 and early-onset cerebellar ataxia and hypoalbuminemia, EOCAHA), Fahr’s disease, pantothenate kinase–associated neurodegeneration (PKAN associated with mutations in PANK-2, the pantothenate kinase-2 gene), Huntington-disease–like disorder type 2 (associated with mutation in junctophilin), Rett’s syndrome, HARP syndrome (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration) Metabolic Disease Acyl–coenzyme-A dehydrogenase deficiency, mitochondrial disorders, including Leigh’s syndrome, Wilson’s disease, GM1 gangliosidosis, metachromatic leukodystrophy, Lesch-Nyhan disease, Niemann-Pick type C, methylmalonic aciduria, nonketotic hyperglycinemia, Pelizaeus-Merzbacher disease (now classified as a form of hereditary spastic paraparesis), kernicterus, hypoparathyroidism, hyperthyroidism, propionic acidemia, hypernatremia, hypomagnesemia, hypocalcemia, hypoglycemia or hyperglycemia, vitamin E deficiency or malabsorption, BassenKornzweig disease, and complications of cardiac bypass Infectious, Parainfectious Encephalitis and postencephalitis Immune Mediated Sydenham’s chorea, lupus erythematosus, Henoch-Schönlein purpura, anticardiolipin or antiphospholipid antibody syndrome, chorea gravidarum Drugs, Toxins Neuroleptic medications, including antiemetics (haloperidol, chlorpromazine [Thorazine], pimozide, prochlorperazine [Compazine], metoclopramide), calcium channel blockers (flunarizine, cinnarizine), antiseizure medications (phenytoin, carbamazepine, valproate, phenobarbital), anticholinergic medications (trihexyphenidyl, benztropine), antihistamines, tricyclic antidepressants, clomipramine, benzodiazepines, stimulants (including methylphenidate, dextroamphetamine, pemoline, and bronchodilators), clonidine, levodopa, cocaine, bismuth, lithium, manganese, ethanol, carbon monoxide, oral contraceptives, general anesthesia (including propofol) Paroxysmal Disorders Complex migraine, alternating hemiplegia, paroxysmal kinesigenic choreoathetosis (PKC), paroxysmal nonkinesigenic choreoathetosis (PNKC, or paroxysmal dystonic choreoathetosis [PDC], or Mount and Reback disease), paroxysmal choreoathetosis and spasticity, paroxysmal exercise-induced choreoathetosis (PEC) Physiologic Chorea This is seen in normal development before 1 year of age. Disorders That Mimic Chorea Spasmus nutans, tics, shaking and shuddering spells, proprioceptive loss, masturbation, psychogenic disorders

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in cerebrospinal fluid [Singer et al., 2003], and antistreptolysin antibodies can be detected in serum. However, the high prevalence of positive antistreptolysin antibody titers in the general population means that both acute and convalescent titers must be measured to confirm an acute infection. The clinical situation often provides a strong indication for the diagnosis, but if other neurologic symptoms are present or there is doubt about etiology, a more complete evaluation may be needed, including tests for thyroid function, toxins, metabolic disorders, or encephalitis. Sydenham’s chorea usually does not require treatment, although the acute streptococcal infection should be treated to reduce the incidence of rheumatic fever. Valproic acid, carbamazepine, or neuroleptics may have some benefit [Genel et al., 2002; Kulkarni and Anees, 1996; Pena et al., 2002]. Treatment with immune suppressant medication, including corticosteroids or intravenous immunoglobulin preparations, has been studied, but the natural history with spontaneous resolution of symptoms makes interpretation of efficacy in open-label clinical trials difficult [Cardoso et al., 2003; Garvey and Swedo, 1997; Green, 1978]. Long-term treatment with antibiotics may reduce the low risk for recurrence [Gebremariam, 1999]. There are sometimes associated obsessive-compulsive or behavioral symptoms [Moore, 1996; Wilcox and Nasrallah, 1988], and these symptoms are often managed with selective serotonin reuptake inhibitors. Acute streptococcal illness needs to be treated, and prolonged antibiotic prophylaxis is usually needed in cases of rheumatic fever. The prognosis for the movement disorder is excellent, and complete resolution occurs in most cases. Recurrence is rare and is sometimes associated with recurrence of other symptoms of rheumatic fever [Korn-Lubetzki et al., 2004]. There appears to be a higher risk for chorea gravidarum in women with a previous history of Sydenham’s chorea [Korn-Lubetzki et al., 2004]. The rapid onset of Sydenham’s chorea has raised the question of whether an autoimmune mechanism could be responsible for other acute-onset movement disorders. This has led to the hypothesis of pediatric autoimmune neuropsychiatric disorders associated with streptococcus (PANDAS) [March, 2004; Trifiletti and Packard, 1999]. PANDAS are characterized by an abrupt or explosive onset of tics, obsessive-compulsive behavior, and a movement disorder (usually chorea) that is temporally associated with streptococcal infection [Chmelik et al., 2004; Pavone et al., 2004; Snider and Swedo, 2004; Swedo, 2002]. Symptoms may persist with a relapsing and remitting course. The existence of this disorder has been debated [Kurlan, 2004; Kurlan and Kaplan, 2004; Singer and Loiselle, 2003; Swedo et al., 2004], and anti–basal ganglia antibodies have not been found to be elevated [Singer et al., 2004]. It has not been possible to transmit the disorder passively to animals by inoculation with antibodies from affected humans [Loiselle et al., 2004]. Nevertheless, there have been an increasing number of case reports of explosive onset of neurobehavioral disorders, including tic disorders, chorea, and obsessive-compulsive disorder, after streptococcal infections, and therefore the hypothesis merits further investigation. It is not clear that there is any specific treatment, although some authors advocate immune modulation, long-term antibiotics, or tonsillectomy [Araujo et al., 2002;

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Gebremariam, 1999; Green, 1978; Heubi and Shott, 2003; Leonard and Swedo, 2001; van Toorn et al., 2004].

MEDICATION-INDUCED CHOREA Chorea is frequently associated with administration of medications, and any child with chorea needs to be carefully examined for the possibility of iatrogenic causes. In particular, treatment of other movement disorders with anticholinergic medication such as trihexyphenidyl can precipitate chorea, even at relatively low doses [Nomoto et al., 1987]. Antiepileptic medications, including carbamazepine and phenytoin, have been associated with precipitation of chorea, and in children with diffuse brain injury, sedating medications can sometimes precipitate chorea. Chorea can appear as a tardive symptom many months after being on a medication, or after discontinuing a medication. Tardive chorea is probably less common than tardive dystonia or dyskinesia, but it nevertheless does occur, and the onset of chorea, even many months or years after being treated with neuroleptic or anticholinergic medications, should raise suspicion of a tardive medication effect. There is a more complete description of tardive syndromes later in this chapter.

CHOREA ASSOCIATED WITH BRAIN INJURY Chorea is frequently seen in children with cerebral palsy on awakening or when drowsy. A common form of more persistent chorea that can last several months often follows encephalitis. In particular, children with encephalitis, in many cases, develop a severe and persistent chorea within several weeks of recovery from the acute phase of the illness. This chorea often lasts 6 to 12 months. It may respond to treatment with benzodiazepines, including clonazepam, or valproic acid. It does not appear to respond to other antichorea treatments, such as neuroleptic medication or tetrabenazine. Whether treatment of the chorea hastens its improvement or in any way alters the natural course is not known, but treatment may help with feeding and rehabilitation. A severe form of chorea or ballism can occur in children with cerebral palsy or other static brain injury after the onset of an otherwise unremarkable febrile illness. Often there is a combination of chorea and dystonia, and this syndrome is described below in the section on dystonic storm.

CHOREA ASSOCIATED WITH SYSTEMIC ILLNESS Hyperthyroidism can be a cause of chorea, and any child with unexplained acute or persistent chorea should have serum testing for thyroid function. The mechanism is unknown. It should be noted that the TITF-1 gene responsible for benign hereditary chorea is a transcription factor involved with both thyroid and basal ganglia development, although in this disorder thyroid function is reduced. Autoimmune diseases including lupus erythematosus and antiphospholipid antibody syndromes can be a cause of chorea, possibly through an autoimmune mechanism. In such cases, treatment should be directed at the underlying autoimmune disorder. This class of disorders may be a relatively common cause of chorea in children, and it is par-

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ticularly important because of the potential for response to treatment.

Ballism Ballism is a high-amplitude, flinging movement, usually due to involuntary movements of proximal joints. Ballism is part of the spectrum of chorea and involves similar pathophysiologic mechanisms [Albin et al., 1989; DeLong, 1990]. When ballism involves one side of the body, it is called hemiballism. Hemiballism is the classic manifestation of vascular events affecting the subthalamic nucleus but can be associated with lesions in other parts of the basal ganglia.

Treatment of Chorea Chorea is often difficult to treat. Secondary chorea may respond to a combination of clonazepam and valproic acid. Sedation may be helpful for short-term management. In some cases, tetrabenazine [Asher and Aminoff, 1981; Chatterjee and Frucht, 2003; Jankovic and Orman, 1988], reserpine, or neuroleptics may be helpful, but the use of neuroleptics requires caution because chorea may mask the onset of tardive dyskinesia or tardive dystonia. If dystonia is present with chorea, then neuroleptics should be used only with great caution because of their ability to precipitate acute or tardive dystonia and the potential for worsening dystonia owing to dopaminergic failure. Trihexyphenidyl, levodopa, carbamazepine, and phenytoin can worsen chorea and should be avoided in most cases. Chorea that is due to global cerebral injury, such as that following encephalitis, may worsen when the child is sleepy, and therefore sedating medications should be avoided if possible, although clonazepam is sometimes helpful. Some forms of chorea are time limited and may only require brief treatment. It is possible that there may be a role for deep brain stimulation in some forms [Thompson et al., 2000]. Before any treatment for chorea, it is important to evaluate the child’s current medications to rule out an iatrogenic cause.

Dystonia Dystonia is probably the next most common movement disorder in children after tics. This prevalence is because dystonia can occur as an associated feature in many static and degenerative childhood disorders. In children, dystonia is defined as “a movement disorder in which involuntary sustained or intermittent muscle contractions cause twisting and repetitive movements, abnormal postures, or both” [Fahn and Williams, 1988; Sanger et al., 2003]. Although the term seems to imply an abnormality of tone, dystonia is not primarily a disorder of tone, but rather a disorder of movement. When individuals with dystonia are at rest, tone is often diminished, although in severe dystonia, involuntary contractions persist during attempted rest, and tone may be increased. Dystonia can manifest as hypertonic dystonia with increased stiffness, hyperkinetic dystonia with increased movements, or a combination of the two. Dystonia can also be reflected in very slow twisting or writhing movements or very quick ballistic movements, and it can have rhythmicity, appearing like tremor, in which case it would be referred to as dystonic tremor.

Dystonia is commonly triggered or exacerbated by voluntary movement, and it may fluctuate in presence and severity over minutes, weeks, or months. Dystonia can be task or movement specific, so that a muscle may exhibit involuntary contraction only during certain voluntary movements and not others. For example, walking forward may elicit severe lower extremity and truncal twisting, yet walking backward, running, or swimming may be completely unaffected. Stress or excitement exacerbates most forms of dystonia. Dystonic contractions resolve during sleep. Individuals with dystonia sometimes discover that touching one part of the body may relieve the dystonic spasms; this phenomenon is called a sensory trick or geste antagoniste. Dystonia may be generalized or focal, involving just a single body part. Childhood-onset dystonia is more likely to be generalized than adult dystonia [Bressman et al., 1994]. Task-specific dystonia in which symptoms occur only during performance of a specific skilled action does not occur commonly in children, although focal dystonia that affects one part of the body during many actions certainly is seen.

Classification Dystonia is classified by etiology as either primary or secondary, and by location as focal, segmental, hemidystonia, multifocal, or generalized dystonia [Fahn et al., 1998]. Focal dystonia involves a single part of the body such as a limb, the neck, or the face. Examples include blepharospasm (forceful eye closure), oromandibular dystonia (involving the jaw or mouth musculature, or both), spasmodic dysphonia (vocal cord involvement), torticollis (twisting or tilting of the neck), or focal hand or foot dystonia. Segmental dystonia involves the muscles of two contiguous body parts, for example, cranial segmental dystonia involving multiple muscles of the face and neck, axial dystonia involving the neck and trunk, brachial dystonia involving the arm and trunk, and crural dystonia involving one or both legs and the trunk. Hemidystonia involves all or most muscles on one side of the body. Multifocal dystonia involves two or more noncontiguous body regions. Generalized dystonia involves multiple limbs on both sides of the body including at least one leg. In children, dystonia often starts distally, and it may initially involve only a hand or foot. Typical patterns include spooning deformity of the fingers, with forceful extension at the metacarpal-phalangeal and interphalangeal joints of the hand, or a combination of inversion (supination) and extension of the ankle. An upgoing “striatal toe” is a common finding that is often confused with the Babinski sign but that seems to be due to extrapyramidal dysfunction. Proximal forms of dystonia include opisthotonus (arching), truncal sway, side bending, twisting of the neck, and proximal fixed postures or random movements of the large muscles of the legs or arms. Orofacial movements include dysarthria, involuntary tongue protrusion, involuntary jaw opening or closing, blinking, and facial contortions. Dystonia is considered primary when it is the predominant or only clinical feature (Table 58-3). At least 17 different inherited phenotypes designated with the “DYT” genetic locus specification have been defined so far [Bressman, 2004; Misbahuddin and Warner, 2001; Nishiyama et al., 2000]. Most of these are quite rare. Only seven

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TABLE 58-3 Causes of Dystonia Static Injury, Structural Cerebral palsy, hypoxic-ischemic injury, kernicterus, head trauma, encephalitis, tumors, stroke in the basal ganglia (which may be due to vascular abnormalities or varicella), congenital malformations Hereditary, Degenerative DYT1 (9q34, encodes torsin-A), DYT2 (autosomal recessive), DYT3 (X-linked dystonia-parkinsonism syndrome of Lubag-Xq13), DYT4, DYT5 (14q22.1-2, encodes GTP cyclohydrolase I, leading to doparesponsive dystonia or Segawa’s disease), DYT6 (8p21-q22), DYT7 (18p), DYT8 (2q33-q35, causing paroxysmal nonkinesigenic choreoathetosis [PNKC]), DYT9 (1p, causing PNKD and spasticity), DYT10 (16p11.2-q12.1, causing paroxysmal kinesigenic choreoathetosis [PKC]), DYT11 (heterogeneous, causing familial myoclonus-dystonia). Rapid-onset dystonia-parkinsonism (linked to chromosome 19), Fahr’s disease (often due to hypoparathyroid disease), pantothenate kinase–associated neurodegeneration (PKAN, neuronal brain iron accumulation type 1, formerly HallervordenSpatz disease, sometimes due to mutations in pantothenate-kinase-2 [PANK-2]), Huntington’s disease (particularly the Westphal variant, IT15-4p16.3), spinocerebellar ataxias (SCAs), including SCA3/Machado-Joseph disease, neuronal ceroid lipofuscinoses (NCL), Rett’s syndrome, striatal necrosis, Leigh’s disease, neuroacanthocytosis, HARP syndrome (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration), ataxia-telangiectasia, Tay-Sachs disease, Sandhoff’s disease, Niemann-Pick type C, GM1 gangliosidosis, metachromatic leukodystrophy (MLD), Lesch-Nyhan disease Metabolic Disease Glutaric aciduria types 1 and 2, acyl coenzyme A dehydrogenase deficiency, dopa-responsive dystonia (tyrosine hydroxylase deficiency, GTP cyclohydrolase 1 deficiency, DYT5), dopamine agonist–responsive dystonia (aromatic L-amino acid decarboxylase deficiency [ALAD]), mitochondrial disorders, Wilson’s disease, vitamin E deficiency, homocystinuria, methylmalonic aciduria, tyrosinemia Drugs, Toxins Neuroleptic and antiemetic medications (haloperidol, chlorpromazine [Thorazine], olanzapine, risperidone, prochlorperazine [Compazine]), calcium channel blockers, stimulants (amphetamine, cocaine, ergot alkaloids), anticonvulsants (carbamazepine, phenytoin), thallium, manganese, carbon monoxide, ethylene glycol, cyanide, methanol, wasp sting Paroxysmal PKC, PNKC, exercise-induced dystonia, complex migraine, alternating hemiplegia of childhood (AHC), paroxysmal torticollis of infancy Disorders That Mimic Dystonia Tonic seizures (including paroxysmal nocturnal dystonia caused by nocturnal frontal lobe seizures), Arnold-Chiari malformation type II, atlantoaxial subluxation, syringomyelia, posterior fossa mass, cervical spine malformation (including Klippel-Feil syndrome), skew deviation with vertical diplopia causing neck twisting, juvenile rheumatoid arthritis, Sandifer’s syndrome (associated with hiatus hernia in infants), spasmus nutans, tics, masturbation, spasticity, myotonia, rigidity, stiff-person syndrome, Isaac’s syndrome (neuromyotonia), startle disease (hyperekplexia), neuroleptic malignant syndrome, central herniation with posturing, psychogenic dystonia

of the genes have been identified. Many of these disorders do not present in childhood. Many of these disorders represent “dystonia-plus” syndromes that include dystonia as a primary feature but also have other associated movement disorders. Examples of dystonia-plus syndromes include

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dopa-responsive dystonia, myoclonus dystonia, and rapidonset dystonia-parkinsonism.

Diagnosis Dystonia must be distinguished from other disorders, including spasticity, rigidity, tics, tremor, and ataxia, although in some cases this is difficult. Spasticity is associated with increased reflexes and frequently has a spastic catch whose position depends on the velocity of movement [Sanger et al., 2003]. Rigidity does not tend to have a particular fixed posture; it has a “lead pipe” quality and resists attempts at passive movement of the arm or leg, although the limb can be placed into an arbitrary posture by the examiner [Sanger et al., 2003]. Tics can be differentiated by their episodic and repeatable nature and normal posture and function between tics. In addition, tics rarely have the same degree of motor disability as is seen in dystonia. Dystonic tremor tends to be less rhythmic than regular tremor, and often exhibits a “null point,” in which there exists a particular joint angle at which the tremor decreases or is absent [Deuschl, 2003]. To one side of that joint angle, movement in one direction will cause the tremor to worsen, but often beating in a particular direction that is different from the direction in which the tremor will beat if the joint is moved in the opposite direction. Ataxia does not have characteristic postures, it does not have overflow of muscle activity, and quality of movement may improve at slow speeds [Paulson and Ammache, 2001].

Dystonic Storm A particularly dramatic presentation of dystonia that is seen primarily in children with preexisting motor abnormalities is dystonic storm [Dalvi et al., 1998; Opal et al., 2002]. Usually this is seen in the context of an acute illness in a child with a previous history of dystonia, cerebral palsy, or other movement disorder. The child will become ill with an otherwise unremarkable disease such as a respiratory illness but then will rapidly develop severe and intractable hyperkinetic dystonia with ballistic or flinging movements of the arms, legs, or head. This dystonia can also be associated with severe limb extension or opisthotonic posturing with dorsiflexion at the neck or trunk. In many cases, these symptoms will not have been seen previously. In some cases, this clinical picture is associated with encephalitis or other causes of acute striatal injury. Treatment is extremely difficult and may require general anesthesia to abate the movement. Multiple medications have been tried, including benzodiazepines, levodopa, anticholinergic medications, tetrabenazine, reserpine, dantrolene, and baclofen. It is possible that intrathecal baclofen [Dalvi et al., 1998] or deep brain stimulation [Angelini et al., 2000] could be helpful in severe cases when medications are ineffective [Kyriagis et al., 2004]. Dystonic storm can continue for months and can be life-threatening, usually requiring intensive care monitoring. It can recur in the context of a subsequent illness.

Associated Movement Disorders Athetosis literally means “not fixed,” which refers to the continuous writhing movements that characterize this dis-

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order [Morris et al., 2002b]. Athetotic movements are often caused or worsened by attempts at voluntary movement. In this respect, athetosis is very similar to dystonia, and particular dystonic postures of the arms or hands can occur simultaneously. The use of the term athetosis has diminished substantially in recent years. It has been argued that in most cases, athetosis is actually a form of dystonia [Turny et al., 2004]. Currently, the term is used most commonly to describe a form of cerebral palsy (athetoid) but is also used in conjunction with the term chorea (choreoathetosis) to describe the apparent random and hyperkinetic quality of the movements [Morris et al., 2002a]. Dystonia in children is frequently associated with bradykinesia [Nygaard and Duvoisin, 1986], possibly because both dystonia and bradykinesia can be caused by failure of dopamine transmission [Riederer and Foley, 2002; Segawa et al., 1999]. Bradykinesia may be a relatively common finding in children with hypertonic disorders, but it is likely to be underreported because the slow movement may be attributed to the hypertonia rather than to the underlying bradykinesia.

Primary Dystonias DYT1 DYSTONIA DYT1 dystonia is known as Oppenheim’s dystonia after Hermann Oppenheim, who first described it in 1911. It has also been referred to as dystonia musculorum deformans, which was Oppenheim’s original term. This is probably the most common genetically determined cause of dystonia in children. In some populations, this is the most common explanation for dystonia with onset in the foot before the age of 20 years [Klein et al., 1999; O’Riordan et al., 2004]. The median age at onset is 10 years, with a range of 4 years to adulthood. Usually onset is in a lower extremity, but upper extremity onset has been described. The general features include a gradually progressive dystonia that eventually involves multiple limbs and progresses to generalized dystonia, often involving both distal and proximal musculature [Bressman et al., 2002]. However, there is great variation in the progression and severity. When DYT1 dystonia presents in adulthood, it is usually mild. DYT1 dystonia is autosomal dominant, but it has about 30% penetrance [Saunders-Pullman et al., 2004b]. Recent evidence suggests that nonmanifesting carriers do have abnormalities of brain networks on fluorodeoxyglucose positron-emission tomography, but the reason that they do not express symptoms of the disease is currently not known [Eidelberg et al., 1998]. The gene is on chromosome 9Q34, and its product is torsin-A [Bressman et al., 1994; Ozelius et al., 1999]. Torsin-A is an adenosine triphosphate–binding protein with homology to heat shock and chaperone proteins [Ozelius et al., 1997]. The homology to heat shock proteins has been proposed as a possible explanation for the onset of symptoms after injury, surgery, or other situations in which such proteins would be expected to be expressed. The common deletion is a three-base-pair GAG deletion, resulting in loss of a single glutamate from a highly conserved region of the protein [Ozelius et al., 1999]. This mutation seems to have arisen independently from founders in different populations. The prevalence of manifesting DYT1

dystonia is higher in Ashkenazi Jews, for whom it is about 1 in 5000. The general population has a rate of 1 in 15,000 worldwide, but there may be other groups for whom higher prevalence occurs. There are very little data on pathology, and many of the early pathologic reports did not detect abnormalities. More recent reports suggest that there may be some abnormalities in brainstem nuclei, but no specific abnormalities of the dopaminergic or basal ganglia systems have been found. Gene testing is currently available for the common GAG deletion. DYT1 dystonia does not respond to dopaminergic medication. The mainstay of treatment is anticholinergic medication, but often very high doses are required [Bressman, 2000; Bressman and Greene, 2000]. Other medications such as benzodiazepines, baclofen, carbamazepine, neuroleptics, and tetrabenazine have been tried with varied success, and these are summarized below. In multiple case reports, pallidotomy or deep brain stimulation seems to be particularly helpful in DYT1-positive patients with dystonia [Cif et al., 2003; Coubes et al., 2004; Coubes et al., 2000; Eltahawy et al., 2004]. Untreated, DYT1 dystonia will progress gradually over many years, although it may reach a plateau in adulthood. The prognosis and life span depend on the severity of the disorder. There do not appear to be associated abnormalities in other organ systems, and mortality is usually due to pulmonary complications of the motor dysfunction.

DOPA-RESPONSIVE DYSTONIA Dopa-responsive dystonia is labeled DYT5 dystonia [Bandmann et al., 1998b] and is also known as Segawa’s disease after Segawa first described it in 1976 [Bandmann and Wood, 2002; Segawa et al., 1999; Segawa et al., 2003]. The presentation is very similar to DYT1 dystonia in many cases, although it can have onset at an earlier age. The average age of onset is 6 years, with a range of onset from 1 to 12 years. It frequently starts in a limb in children. In adults, it has been reported as a cause of parkinsonism, with a bradykinetic rigid onset rather than limb dystonia onset [Uncini et al., 2004]. In children, the dystonia is often combined with parkinsonism, although without tremor [Nygaard et al., 1990; Uncini et al., 2004]. The combination of dystonia and parkinsonism is due to decreased but not absent dopamine production. Diurnal variation is present in 77% of children [Nygaard et al., 1988]. Such children appear to be significantly improved upon awakening in the morning or after a nap, with a gradual worsening of symptoms the longer they remain awake and active. Doparesponsive dystonia can mimic many of the features of cerebral palsy [Jan, 2004], and there have been reported cases of associated hyperreflexia [Bandmann et al., 1998a]. Untreated, dopa-responsive dystonia is a progressive disorder, and this helps to distinguish it from static disorders such as cerebral palsy. Dopa-responsive dystonia is due to mutations in either the guanosine triphosphate cyclohydrolase 1 gene [Bandmann et al., 1996; Bandmann et al., 1998b; Furukawa et al., 2000] or the tyrosine hydroxylase gene [Grattan-Smith et al., 2002; Ichinose et al., 1999]. Guanosine triphosphate cyclohydrolase 1 is on chromosome 14Q22.1-2, and expression is auto-

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somal dominant with variable penetrance [Uncini et al., 2004], which may be greater in girls than in boys [Furukawa et al., 1998]. Guanosine triphosphate cyclohydrolase is an enzyme that is important for the synthesis of biopterins and neopterins, which are cofactors for the enzyme tyrosine hydroxylase (see Chapter 30). The pterins are also cofactors for tryptophan hydroxylase and phenylalanine hydroxylase, although reduced function of these enzymes does not seem to be a cause of symptoms. Rare cases of homozygosity for guanosine triphosphate cyclohydrolase mutations have been reported, with a more severe phenotype [Thony and Blau, 1997]. Significant improvement during a trial with levodopa strongly suggests the diagnosis, although a similar response can be seen in juvenile Parkinson’s disease and even in some cases of secondary dystonia. The diagnosis can be confirmed by quantitative evaluation of cerebrospinal fluid neurotransmitters and pterins. In particular, biopterin, neopterin, and homovanillic acid (a dopamine metabolite) are low in cerebrospinal fluid. Another test that has been used is the phenylalanine loading test [Bandmann et al., 2003; Hyland et al., 1997; Ponzone et al., 1994; Saunders-Pullman et al., 2004a]. This test reflects a defect in phenylalanine hydroxylase that is present in liver and depends on biopterin as a cofactor. To perform the test, 100 mg/kg of phenylalanine is given orally, and the serum phenylalanine to tyrosine ratio is measured at intervals over 6 hours. However, this test may not be as sensitive and specific as cerebrospinal fluid neurotransmitter metabolite measurement. There is no common mutation in guanosine triphosphate cyclohydrolase 1 [Ichinose et al., 1999; Nishiyama et al., 2000], so full sequencing of the gene is usually required for genetic diagnosis; sequencing detects about 60% of cases. Tyrosine hydroxylase deficiency is due to mutations in the tyrosine hydroxylase gene on chromosome 11P15.5 [Nagatsu and Ichinose, 1996; Royo et al., 2005]. Expression is autosomal recessive with full penetrance. The onset of the dystonia tends to be earlier, usually in infancy, with more severe symptoms [Brautigam et al., 1999; Furukawa et al., 2001], but mild forms have been reported [Furukawa et al., 2004b]. Examination of the cerebrospinal fluid reveals normal biopterins and neopterins but low homovanillic acid [Wevers et al., 1999]. Confirmation of the diagnosis requires demonstration of low tyrosine hydroxylase function in fibroblasts or lymphocytes, or sequencing of the tyrosine hydroxylase gene. In both autosomal-recessive and autosomal-dominant dopa-responsive dystonia, treatment involves replacement of dopamine using oral levodopa [Nutt and Nygaard, 2001]. In particular, the combination of levodopa and a peripheral dopa decarboxylase inhibitor such as carbidopa usually results in a dramatic improvement in symptoms with minimal side effects [Hwang et al., 2001; Nutt and Nygaard, 2001]. Often very low doses are required, and treatment can be continued throughout life with no adverse events. In particular, the escalation of dose frequently seen in Parkinson’s disease and the development of motor dyskinesias over time does not seem to occur or occurs only rarely. There are reports that a gradual escalation of dose may be needed after several years. Although many children and adults will achieve complete resolution with doses of 100 mg/day or less of levodopa, some children have required up to

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10 mg/kg/day. Medication is usually given three times per day. Other medications for Parkinson’s disease will also work, including anticholinergic medication, dopamine agonists, and amantadine, although these are usually not needed. Peripherally induced side effects of levodopa include nausea and hypotension, and these can often be ameliorated by giving an extra dose of carbidopa 30 minutes before administration of the levodopa-carbidopa combination. Intestinal absorption of levodopa is increased by simultaneous carbohydrate intake and decreased by simultaneous protein intake. The prognosis is excellent with treatment [Nygaard et al., 1991], but untreated children are at risk for severe dystonia with progressive orthopedic deformities.

MYOCLONUS DYSTONIA Myoclonus dystonia is a disorder with a combination of both symptoms [Asmus and Gasser, 2004; Lang, 1997]. In some but not all families with these symptoms, the disorder is due to a mutation in the epsilon-sarcoglycan gene on chromosome 7Q21 [Nygaard et al., 1999], and this has been designated DYT11 [Furukawa and Rajput, 2002; Schule et al., 2004; Valente et al., 2003]. The details of the myoclonus are discussed further in the section on myoclonus. Myoclonus involves the neck, trunk, and arms and is often alcohol responsive. Dystonia occurs in about half of patients and can be the only manifestation. Dystonia usually expresses as either torticollis or arm dystonia. In addition, behavioral symptoms and obsessive-compulsive disorder have been associated with gene mutations. Onset is in late childhood or adolescence. This disorder is autosomal dominant, although de novo mutations are frequent [Hedrich et al., 2004]. When the epsilon-sarcoglycan gene is inherited from the father, there is about 100% symptomatic expression, but when inherited from the mother, there is only 10% symptomatic expression, suggesting an important role of maternal imprinting [Grabowski et al., 2003; Muller et al., 2002]. It can be diagnosed by sequencing of the epsilon-sarcoglycan gene, and this detects 95% of patients in affected families. Treatment is with benzodiazepines, valproate, and alcohol, although chronic use of alcohol frequently leads to dependence, and this has not been proposed as an appropriate long-term therapy. Some reports have suggested the use of γ-hydroxybutyrate, which has alcohol-like effects and seems to be helpful in small case series [Priori et al., 2000]. There have also been reports of the use of deep brain stimulation in both the globus pallidus and the ventral intermediate nucleus of the thalamus with symptomatic relief [Cif et al., 2004]. The prognosis is excellent, and children would be expected to have a normal life span, although symptoms do not spontaneously resolve.

OTHER IDENTIFIED PRIMARY DYSTONIAS DYT8 is the designation for paroxysmal nonkinesigenic dyskinesia, and DYT10 is the designation for paroxysmal kinesigenic choreoathetosis, and both of these are discussed in the section on paroxysmal disorders. DYT12 is the designation for rapid-onset dystonia parkinsonism, which has been associated with the ATP-1A3 gene [de Carvalho Aguiar et al., 2004]. In this disorder, a

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combination of dystonia and bradykinesia can develop over hours to days. It is autosomal dominant with variable penetrance [Brashear et al., 1998]. Once the dystonia has developed, it does not resolve [Dobyns et al., 1993]. Treatment is entirely symptomatic. The disorder does not appear to be progressive, and once the initial symptoms have developed, they remain at about the same level of severity or progress only gradually [Dobyns et al., 1993].

and sometimes head trauma. Symptoms most often affect the arms, with the legs often being affected either by spasticity or a combination of spasticity and dystonia. There may be associated bradykinesia or choreoathetosis. Although the dystonia in cerebral palsy presumably is due to a static injury, the symptom can worsen over time. In fact, the onset of dystonia may be many years after the initial injury leading to cerebral palsy [Saint Hilaire et al., 1991].

PSYCHOGENIC DYSTONIA

KERNICTERUS

Dystonia as a manifestation of psychiatric disorders is not uncommon. It is most often a form of conversion reaction. Common features of psychogenic disorders include maximal severity at onset, entraining to rhythmic stimuli, distractibility, suggestibility, and a posture or presentation that is otherwise atypical for the disease [Fahn and Williams, 1988; Kirsch and Mink, 2004; Ozekmekci et al., 2003; Pringsheim and Lang, 2003; Thomas and Jankovic, 2004]. Children may not be aware of the psychogenic origin, and there may be no history of other psychopathology. There may be no secondary gain. In some cases, psychogenic dystonia occurs in the presence of true dystonia, worsening its apparent severity [Bentivoglio et al., 2002]. It can also appear in families in which other family members have dystonia or other movement disorders. It is essential to exclude organic causes in testing. Surface or needle electromyography can be helpful because certain patterns of rhythmic contraction sometimes seen in dystonia cannot be mimicked voluntarily [Hallett, 1983], and if these patterns occur, that would be a clue to an organic cause. The primary treatment is psychiatric, but this is considered a very primitive psychiatric defense mechanism, and the prognosis for spontaneous resolution is poor [Feinstein et al., 2001; Miyasaki et al., 2003].

Kernicterus occurs because of high bilirubin levels in the perinatal period, but the effects are variable and unpredictable (see Chapter 90) [Shapiro, 2005]. There is probably an increased susceptibility to hyperbilirubinemia with prematurity, hypoxia, or infection [Volpe, 2000]. It has been hypothesized that in such cases there is a reduction of the efficacy of the blood-brain barrier, which allows unconjugated bilirubin to penetrate and affect multiple brain regions including the globus pallidus. Injury to the globus pallidus is thought to be the etiology of the movement disorder [Govaert et al., 2003; Johnston and Hoon, 2000]. The overall severity later in life is quite variable, and symptoms include choreoathetosis, dystonia (which can be progressive), sensorineural hearing loss, and supranuclear gaze palsy [Shapiro, 2005]. In the absence of other associated injury, the intellect is usually normal, and the motor disorder is often the single greatest cause of disability. The acute toxicity of bilirubin is described by three distinct clinical phases. In phase one, there is hypotonia and lethargy for the first few days, which is often misinterpreted as perinatal depression from hypoxic injury. In phase two, starting after the first few days, there is a sudden rise in tone, with hypertonia manifesting primarily as extension of the neck and back with opisthotonus. This may be associated with an otherwise unexplained fever. The presence of early extensor posturing is probably a poor prognostic sign for later development, but this early symptom will resolve after 1 to 2 weeks. Subsequently, in phase three, the child is normal or hypotonic. The child will remain hypotonic during much of the first year, although with delayed motor milestones. The hypertonia will subsequently return after months, or in some cases years, with development of dystonia and choreoathetosis. Children may have seizures and oculogyric crises. Diagnosis is based on the characteristic history, although it is often difficult to verify. The most effective treatment is prevention of neonatal hyperbilirubinemia [Bhutani et al., 2004; Blackmon et al., 2004; Rubaltelli, 1998; Stevenson et al., 2004]. Treatment of symptomatic cases is often quite difficult. Many children receive cochlear implants for the hearing loss. There is only a slight benefit of anticholinergic medications, valproic acid [Kulkarni, 1992], benzodiazepines, or botulinum toxin. Some children have benefited from intrathecal baclofen. In general, treatment of this disorder is frustrating. Life span is shortened in severely affected children because of pulmonary complications.

Secondary Dystonia There is a long list of possible secondary causes for dystonia, as shown in the Table 58-3. This section reviews several of the most important causes. Many of these disorders are discussed elsewhere or in other chapters.

CEREBRAL PALSY Cerebral palsy is probably the most common cause of dystonia in childhood. This is because of its relatively high prevalence. Further details about this disorder, including the etiology and details of the symptomatology, can be found in Chapter 20. Only the elements contributing to dystonia are summarized here. Dyskinetic cerebral palsy represents between 6% and 15% of all cases of cerebral palsy [Surveillance of Cerebral Palsy in Europe (SCPE), 2002], and in dyskinetic cerebral palsy, dystonia is usually the primary feature. Dystonia occurs frequently as an associated feature in other forms of cerebral palsy, including tetraplegic and hemiplegic cerebral palsy. Dystonia is usually associated with lesions of the basal ganglia or thalamus [KragelohMann et al., 2002], and these lesions are commonly caused by hypoxic-ischemic injury in the full-term neonate [Volpe, 2000]. A similar syndrome can occur in victims of near drowning or other forms of asphyxia, as well as in stroke

PANTOTHENATE KINASE–ASSOCIATED NEURODEGENERATION Pantothenate kinase–associated neurodegeneration is a member of the group of diseases now referred to as neuronal

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brain iron accumulation [Bertrand, 2002a, 2002b]. Pantothenate kinase–associated neurodegeneration was previously referred to as Hallervorden-Spatz disease, although this eponym is no longer favored because of unethical behavior of the physicians who initially described the disorder. Symptoms of pantothenate kinase–associated neurodegeneration include progressive dystonia, dysarthria, rigidity, ballism, choreoathetosis, spasticity, dementia, and pigmentary retinal degeneration [Swaiman, 1991]. In its later stages, this disorder has characteristic ballistic flinging movements of arms and legs, as well as involuntary and repetitive tongue protrusion. The limb and tongue movements may lead to injury, requiring restraint of the arms and legs and dental extraction [Sheehy et al., 1999]. There is a gradual progression over years, with loss of ambulation within 5 to 15 years of onset. The initial symptoms usually occur either in the childhood or juvenile years. Pantothenate kinase–associated neurodegeneration has been divided into the characteristic type with presentation in the first decade (average onset at 3 years), and an atypical form with onset in the second decade, which seems to have slower progression and lesser severity [Thomas et al., 2004]. Dystonia in pantothenate kinase–associated neurodegeneration usually starts in the leg, but sometimes the earliest presenting sign is visual loss. There is often associated bradykinesia. The rate of progression is more rapid with younger onset. The overall incidence is estimated to be about 3 cases per 1 million population. The amount of dementia is variable and unknown because the severity of the movement disorder makes assessment of cognitive function in later stages difficult. The atypical form generally starts later, between 10 and 30 years of age at onset, with a mean of 13 years. It has slower progression, and retinopathy is quite rare. The atypical form presents with dysarthria and psychiatric disturbances, which include emotional lability, depression, and sometimes aggressive or violent behavior. There are also freezing episodes similar to those seen in Parkinson’s disease. The gene responsible for pantothenate kinase–associated neurodegeneration is pantothenate-kinase-2 (PANK-2) on chromosome 20p13-p12.3 [Hayflick, 2003b; Zhou et al., 2001]. Inheritance is autosomal recessive. Pantothenate kinase is responsible for synthesis of coenzyme A, and the neurologic abnormalities may be due to a combination of factors, including accumulation of upstream metabolites causing iron chelation and decreased availability of coenzyme A for fatty acid metabolism [Gordon, 2002; Hayflick, 2003a]. The pathophysiology is characterized by rust-colored iron pigmentation of the globus pallidus and SNpr. Injury to the globus pallidus with consequent abnormalities of outflow patterns may be responsible for the movement disorder [Mink, 2001b]. In addition, there are axonal spheroids similar to those seen in neuroaxonal dystrophy [Gordon, 2002]. MRI reveals a characteristic “eye of the tiger” sign. This sign consists of a dark globus pallidus internus on T2weighted imaging, with a bright region in the center of the globus pallidus that is thought to be due to central necrosis (Fig. 58-4). The dark signal is due to iron accumulation [Hayflick et al., 2001], although deposition of iron may be secondary to other metabolic deficits rather than the primary

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FIGURE 58-4. T2-weighted magnetic resonance imaging (MRI) view of an 11-year old patient with pantothenate kinase–associated neurodegeneration, showing the characteristic “eye of the tiger” sign within the internal globus pallidus.

cause of symptoms [Koeppen and Dickson, 2001]. When the full eye of the tiger sign is present in childhood, 100% of such cases have the PANK-2 mutation [Hayflick et al., 2003]. Similarly, 100% of children with PANK-2 mutations exhibit the eye of the tiger sign at some point during the illness [Trimble, 2003]. Children with clinical features of pantothenate kinase–associated neurodegeneration but without the eye of the tiger sign only have a 50% chance of being positive for the PANK-2 mutation. Ophthalmologic examination and electroretinogram may detect presymptomatic retinopathic changes and early visual loss [Swaiman, 1991]. Acanthocytes are sometimes, but not always, present, and there may be a low level of prebetalipoprotein. These findings are similar to those seen in the HARP syndrome (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration). Some families with HARP syndrome have the PANK-2 mutation, and therefore it is not known whether this is a separate disorder or a variant of pantothenate kinase– associated neurodegeneration [Houlden et al., 2003]. It is important to test for other disorders that can present with similar generalized dystonia in childhood, including Huntington’s disease, neuronal ceroid lipofuscinosis, and hexosaminidase A deficiency (Tay-Sachs disease). Treatment is symptomatic. Some children benefit from benzodiazepines, anticholinergic medications, botulinum toxin, baclofen, or intrathecal baclofen. It is unlikely that any of these treatments slow the progression of the underlying disease, but several case reports of treatment with pallidotomy or deep brain stimulation of the globus pallidus internus suggest the possibility of symptomatic improvement [Justesen et al., 1999; Umemura et al., 2004]. The prognosis is universally poor, with death from medical complications usually within 10 to 20 years of onset in the typical form; in the atypical form, survival may be longer.

LESCH-NYHAN DISEASE Lesch-Nyhan disease is a progressive neurodegenerative disorder that initially presents with hypotonia and develop-

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mental delay in the first year of life. It progresses over several years and can mimic athetotic cerebral palsy, with ballism, choreoathetosis, axial dystonia, and spasticity [Nyhan, 1968a, 1968b, 1972]. There is a striking prevalence of self-mutilation behavior, including tongue biting, head banging, biting the fingers and lips, and thrusting arms or legs against objects [Lee et al., 2002; Robey et al., 2003]. There are also compulsive behaviors, and slowly progressive dementia is characteristic [Matthews et al., 1999]. There is increase in uric acid in both the blood and the urine, and this leads to symptoms of gout in advanced cases, as well as in some late onset cases, although this is less common in children. Both arthritis and renal stones have been reported but usually at older ages. The responsible gene is HPRT-1 (hypoxanthine-guanine phosphoribosyltransferase) [Mak et al., 2000]. Deficiency of HPRT-1 can be detected in fibroblasts and leukocytes. The disorder is X-linked recessive, and the incidence of symptomatic cases is about 1 in 400,000 boys. MRI shows only nonspecific atrophy. Treatment is symptomatic. Allopurinol may alleviate signs of gout and prevent renal calculi [Brock et al., 1983; Hiraishi et al., 1987]. Behavioral programs can be used to reduce self-mutilation [Olson and Houlihan, 2000]. Benzodiazepines, carbamazepine, and possibly selective serotonin reuptake inhibitors can be helpful for the behavior disorder [Cusumano et al., 2001; Roach et al., 1996; Saito and Takashima, 2000]. Tetrabenazine or levodopa may be helpful to treat the dystonia [Jankovic et al., 1988]. Naltrexone has been attempted to reduce self-mutilation with only limited success. In some cases, restraint and removal of dentition are required to prevent self-mutilation, and patients who can communicate often request to be placed in restraint to reduce self-injury. The injury behavior seems to become worse in times of stress, and avoidance of stressful situations may be helpful. A single case report suggests the possibility of treatment with deep brain stimulation [Taira et al., 2003]. The prognosis is poor. Most children never walk, and there is progression of symptoms and dementia over several years. Survival is possible into the second or third decade.

SPINOCEREBELLAR ATAXIA The spinocerebellar ataxias are reviewed in Chapter 57. However, it is worth mentioning that spinocerebellar ataxia type 3 (Machado-Joseph disease) has a characteristic presentation with a dystonic-rigid or parkinsonian syndrome. This is referred to as type 1 Machado-Joseph disease, with type 2 presenting more typically with ataxia and spasticity. The type 1 dystonic-rigid form tends to present more commonly in children and can resemble juvenile Huntington’s disease [Jardim et al., 2001a, 2001b]. There is often progressive external ophthalmoplegia and bulging eyes, superimposed on a nuclear or supranuclear gaze palsy. Presentation can be as early as 5 years of age, although it is more common to present in the second decade or later. MachadoJoseph disease is due to a CAG triplet repeat on chromosome 14Q24.3-Q31, and children with 53 to 86 repeats are symptomatic. Higher numbers of repeats are associated with earlier onset and greater severity. Inheritance is autosomal dominant. Treatment is primarily symptomatic, although some cases have responded to treatment with levodopa early in the course.

ORGANIC ACIDEMIAS Organic acidemias, including methylmalonic aciduria, glutaric aciduria types 1 and 2, biotinidase deficiency, disorders of fatty acid oxidation, and mitochondrial respiratory chain disorders can lead to dystonia. Many of these disorders do not present until a time of metabolic stress, at which time a rapid decompensation with onset of severe generalized dystonia over a period of hours to days is possible. Once dystonia has occurred, symptoms are often irreversible. Specific treatment is usually urgently needed, and, in some cases, this requires limitation of intake of specific amino acids, whereas in other cases, specific medications or enzyme replacement is needed. Many of these disorders can be detected with newborn screening. For children with new onset of symptoms or rapid progression of symptoms, there needs to be high index of suspicion to detect these disorders because any delay in treatment usually leads to significantly worse prognosis. Most of these diseases are autosomal recessive. A particularly striking presentation that often occurs in infancy, but that can occur later in childhood, has been referred to as infantile bilateral striatal necrosis [BaselVanagaite et al., 2004; Straussberg et al., 2002]. This presentation can occur with any of these metabolic disorders, but it also seems to be able to occur in the context of acute infections, particularly with mycoplasma, and it has been reported in children with PANK-2 mutations. Most often the cause is unknown. There have been some rare familial cases. This disorder is characterized by a rapid onset of dystonia and dyskinesia, sometimes associated with chorea [Mito et al., 1986; Roytta et al., 1981], and MRI often exhibits evidence of irreversible striatal and sometimes pallidal injury on diffusion T2-weighted or enhanced images [Mito et al., 1986; Roytta et al., 1981]. Early diagnosis of a possible metabolic defect is essential, and treatment of any precipitating infectious process should be initiated rapidly. Once the injury has occurred, usually only symptomatic treatment is available. There have been a few reported cases of a biotin-responsive type of striatal necrosis that has been thought to be due to an abnormality of biotin transport, and such cases may have rapid and effective resolution when treated with biotin [Straussberg et al., 2002]. There have been reported cases of trauma being the inciting event, but whether trauma by itself is able to cause this, or whether another associated metabolic abnormality is required, is not known.

FAHR’S DISEASE Fahr’s disease is characterized by basal ganglia calcification, as well as calcification of other gray matter structures, including cerebellar nuclei and punctate calcifications in thalamus and sometimes cortex [Oliveira et al., 2004]. This is usually an adult-onset disease, but in rare cases can occur in the second decade of life. When it does, it is characterized by microcephaly, hypertonia, and choreoathetosis. The etiology is often unknown, but in some cases it is due to hypoparathyroidism, and therefore parathyroid function should be checked. It is autosomal dominant, with reduced penetrance in most families, and appears to be slowly progressive. Diagnosis is based on evidence of calcification detected

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A

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B

FIGURE 58-5. Magnetic resonance imaging view of an adolescent with Fahr’s disease. A, T2-weighted axial image shows low signal in the basal ganglia secondary to calcification. Calcification was noted in the corresponding area in a previous computed tomography scan. B, Same patient with susceptibility weighted axial (SWI) image showing low signal in the basal ganglia secondary to calcification. Accentuated susceptibility effect in this imaging technique has resulted in more intense signal change due to the calcification. (Courtesy of Dr. Daniel Wycliffe, Department of Radiology, Loma Linda University Medical Center, Loma Linda, CA.)

by head computed tomography scanning [Koller et al., 1979; Koller and Klawans, 1980; Oliveira et al., 2004] or MRI (Fig. 58-5). Treatment is supportive, unless a specific disorder of parathyroid hormone can be found, in which case specific treatment will be available.

NEUROACANTHOCYTOSIS Neuroacanthocytosis has also been referred to as chorea acanthocytosis or Levine-Critchley syndrome. It is characterized by spiky projections on erythrocytes (Fig. 58-6), although such projections are often seen in non-neurologic disease, including hepatic disease. Acanthocytes are also seen in abetalipoproteinemia (Bassen-Kornzweig disease) [Bohlega et al., 1998], vitamin E deficiency, hypoprebetalipoproteinemia, HARP syndrome, and with abnormal Kell blood group antigens (McLeod syndrome) [Danek et al., 2001; Dotti et al., 2000; Mehndiratta et al., 2000; Rampoldi et al., 2002]. Onset is usually in the adult years, but onset as early as 8 years of age has been reported. Symptoms in childhood resemble juvenile Huntington’s disease, with dystonia and an akinetic-rigid syndrome, as well as a severe and progressive tic disorder [Kutcher et al., 1999; Yamamoto et al., 1982]. Presentation in adults is more typically with chorea or psychiatric illness [Bruneau et al., 2003; Dixit et al., 1993; Robinson et al., 2004]. There is frequent tongue protrusion and difficulty eating, and severe dysarthria is often a presenting feature. Some children and adults show areflexia or impulsive behavior, and there is occasionally mild dementia. Testing for this disease requires examination of a fixed smear of blood under the microscope, stressed by mixing

1:1 with normal saline, and this requires an experienced and knowledgeable technician. Greater than 3% acanthocytes is diagnostic. MRI shows caudate atrophy [Kutcher et al., 1999; Okamoto et al., 1997]. Positron-emission tomography scanning shows decreased fluoro-dopa uptake and decreased raclopride binding, suggesting both presynaptic and postsynaptic disorders of striatal function [Brooks et al., 1991; Peppard et al., 1990]. Treatment is symptomatic. Benzo-

FIGURE 58-6. Stressed blood smear showing acanthocytes. (Courtesy of Tracy George, MD.)

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diazepines are often helpful. When chorea is present, neuroleptics are helpful, but this is probably less useful in childhood. There has been an isolated report of improvement with calcium channel blockers. Although the use of the term neuroacanthocytosis is intended for the lack of other known causes of acanthocytes, many of these other known causes do present with dystonia, and some with peripheral neuropathy and retinal degeneration. In particular, vitamin E deficiency, Bassen-Kornzweig disease, and HARP syndrome can have a similar neurologic presentation.

MEDICATION-INDUCED DYSTONIA Medications are able to cause dystonia, and this is most commonly seen with neuroleptic medications. In particular, there is a higher rate of acute dystonic reactions in children than in adults, and this has been reported to be as high as 10% to 20% in some series [Ayers and Dawson, 1980; Olsen et al., 2000; Spina et al., 1993]. Acute dystonic reactions are easily treated with diphenhydramine (1 mg/kg usually given intravenously) or other anticholinergics [Dahiya and Noronha, 1984]. Other types of acute reactions to neuroleptics such as akathisia can be more difficult to treat, but in some cases respond to benzodiazepines. Acute dystonic reactions often present with uncontrollable tongue movements, opisthotonus, and neck hyperextension or torticollis. Medications not normally classed with the neuroleptics, including antiemetic medications such as metoclopramide [Cowan, 1982; Lu and Chu, 1988; Renwick, 1990], domperidone [Madej, 1985], and prochlorperazine [Leeman, 1965], are able to produce the full range of neuroleptic side effects. It is likely that any medication that either blocks or depletes central catecholamines has the potential to cause an acute dystonic reaction [Burke et al., 1985; McCann et al., 1990]. Tardive dystonia and tardive dyskinesia are particularly worrisome consequences of neuroleptic use because symptoms may not resolve following discontinuation of the causative medication [Burke et al., 1982]. Tardive syndromes and their treatment are described in a separate section.

OTHER DISORDERS CAUSING SECONDARY DYSTONIA Aromatic L-amino acid decarboxylase deficiency leads to dopamine agonist–responsive dystonia. In this disorder, conversion of levodopa to dopamine is impaired, and therefore administration of levodopa is not helpful [Swoboda et al., 1999; Swoboda et al., 2003]. This disorder does respond to dopamine agonists, but because of the combination of severe autonomic and sleep disturbances, treatment with serotonergic medication is often required as well [Swoboda et al., 1999]. Very few cases have been reported. This disorder is detectable by a characteristic pattern of cerebrospinal fluid neurotransmitter metabolites. Symptoms include dysautonomia, sleep disturbances, eye movement disturbances, and severe generalized dystonia, usually with onset in the first year of life. It appears to be autosomal recessive. Juvenile Parkinson’s disease can present with a picture very similar to dopa-responsive dystonia, with a combination of progressive dystonia and bradykinesia, and this is

described further in the next section. Huntington’s disease in children often presents with a rigid-akinetic syndrome and severe dystonia, as described earlier in this chapter. Pontocerebellar hypoplasia type 2 is characterized by infantile onset of a combination of extrapyramidal symptoms, dyskinesia, and dystonia [Coppola et al., 2000; Grellner et al., 2000; Grosso et al., 2002]. Alternating hemiplegia is characterized by episodes of hemiplegia or dystonia that can last for hours to days and then resolve [Bassi et al., 2004; Saltik et al., 2004]. Transmission appears to be recessive, although in some cases, there is autosomal dominant transmission [Kanavakis et al., 2003]. Cases with dominant transmission must be distinguished from familial hemiplegic migraine. There is usually a slowly progressive generalized dystonia between episodes [Swoboda et al., 2004]. Treatment for alternating hemiplegia with calcium channel blockers, in particular flunarizine (5 to 15 mg/day), may reduce the frequency and severity of attacks. Symptomatic treatment, including anticholinergic medication, amantadine, and levodopa, may help in some cases [Sasaki et al., 2001; Sone et al., 2000].

Treatments for Dystonia Because dopa-responsive dystonia can mimic cerebral palsy, it has been recommended that all children with unexplained dystonia or cerebral palsy be given a trial of levodopa [Jan, 2004; Nygaard et al., 1988]. Levodopa may be helpful in some children even with secondary dystonia [Brunstrom et al., 2000]. The required dose of levodopa is very low in dopa-responsive dystonia (typically 50 to 100 mg/day) but may be much higher in juvenile Parkinson’s disease and secondary causes of dystonia, including cerebral palsy. Dosages as high as 10 mg/kg/day divided three times per day are sometimes needed. Common side effects of levodopa include nausea, vomiting, and diarrhea. Orthostatic hypotension occurs rarely in children. Levodopa must be combined with a peripheral decarboxylase inhibitor, such as carbidopa, to increase central uptake and decrease peripheral side effects. Commercial preparations with a ratio of levodopa to carbidopa of 4:1 are typically used. Peripheral side effects can often be reduced by an additional dose of the peripheral decarboxylase inhibitor given one half hour before the levodopa dose. Levodopa competes for absorption with neutral amino acids, and therefore absorption is slowed and the peak effect is less when it is taken with a protein meal. Conversely, absorption rate is increased, the peak effect is greatest, and the side effects may be greatest when it is taken with carbohydrates. Levodopa and anticholinergic medications are frequently used together. The appropriate dose of levodopa is difficult to determine, and it needs to be titrated gradually over a period of 2 weeks to 2 months. Rapid titration is possible, but the purpose of gradual titration is to find the optimal dose. Excessive doses of levodopa usually cause dyskinesias or worsen dystonia, and often an intermediate dose is most effective. Rapid withdrawal can lead to worsening of dystonia, and there are rare reports of symptoms similar to neuroleptic malignant syndrome after rapid withdrawal in adults. Anticholinergic medication is very effective in acute dystonic reactions, as described earlier. It is partly effective in a subset of children with chronic dystonia [Hoon et al., 2001],

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and trihexyphenidyl remains the best studied centrally active antidystonia medication [Burke and Fahn, 1983; Burke et al., 1986; Greene et al., 1988]. Its mechanism of action for dystonia is not known, although it is presumed to have an effect on the large cholinergic interneurons of the striatum. Its anticholinergic effects would be expected to be widespread throughout the basal ganglia and cortex [Fahn, 1987]. It is often necessary to proceed to very high doses: 1 mg/kg, and in some cases higher [Fahn, 1983a, 1983b]. In younger children, lower doses may be sufficient, but children will tolerate the high doses better than adults. In particular, adults and older children are more likely to develop confusion or behavior changes on high doses. The effectiveness may be greater in young children, and speech and hand function seem to improve the most [Hoon et al., 2001]. The dose must be increased gradually, and it may often take 3 to 4 months to achieve an appropriate dosage. Appropriate initial dosage is 0.1 mg/kg/ day or less. The medication is usually divided three times per day and given during the day. Side effects are similar to those of other anticholinergic medications. Behavior changes are not uncommon, and deficits in attention have been reported in adult trials. Anticholinergic medications can worsen chorea and possibly choreoathetosis. The benefit on dystonia is often delayed, and there may be no apparent benefit for several months after starting the medication. At high doses, abrupt withdrawal could be dangerous, and there are rare reports of neuroleptic malignant syndrome following abrupt withdrawal of high doses of trihexyphenidyl in adults. Other anticholinergic medications may work as well, but others have not been extensively tested. Diazepam and other benzodiazepines or sedative medications can occasionally be helpful. Orthopedic procedures may not have expected outcomes in children with dystonia because there is a tendency for dystonia to transfer to other muscles following an orthopedic procedure. Restraint of a dystonic limb, casting, or braces may make the dystonia worse, and there is a tendency for the dystonia to “fight against” any restraining force. This problem needs to be considered very carefully when planning prolonged casting of the lower extremities, such as after hip surgery, because the dystonia may worsen significantly after removal of the cast. Selective dorsal rhizotomy has been reported to have a very poor outcome in dystonia, and it is therefore essential to exclude dystonia when selecting cases for this intervention. When dystonia is associated with increased tone, botulinum toxin has been found to be very effective [Boyd et al., 2001; Graham et al., 2003]. It may be effective in directly reducing the tone in the hypertonic muscles, but may also be effective in changing the overall pattern of dystonia. In particular, it is sometimes observed that botulinum toxin injection into one muscle will relax other muscles of the same limb. Injection is often performed with electromyographic guidance, and although some practitioners perform this procedure using general anesthesia, many have now chosen to use only local anesthesia. The procedure should not be performed more frequently than every 3 months because of the risk for buildup of neutralizing antibodies. In some individuals, repeated doses of botulinum toxin every 3 months are needed, but in others, short-term treatment can be effective. Neurolysis and dantrolene have not been commonly used in dystonia.

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Baclofen has been used and may be effective in some cases, although its mechanism of effectiveness in dystonia remains unknown. Intrathecal baclofen can reduce tone in generalized dystonia if the catheter is placed at cervical levels [Albright et al., 1996; Albright et al., 1998; Albright et al., 2001; Butler and Campbell, 2000; Ford et al., 1998]. There is a high rate of complications, up to 35% in some series [Campbell et al., 2002]. Complications can be serious and can include meningitis. Overdoses are rare, but pump failure or catheter disconnection with acute and possibly life-threatening baclofen withdrawal can occur. Withdrawal needs to be treated with a combination of oral baclofen and intravenous diazepam, as well as surgical reimplantation of the catheter as soon as possible. For this reason, many clinicians recommend that children with intrathecal baclofen pumps remain within 30 minutes of an appropriately trained emergency room at all times. Neurosurgical intervention is reserved for the most severe cases, but the possibility that earlier surgical intervention may slow progression of the disease or lead to a longer disease-free interval has been raised. Pallidotomy and thalamotomy have been in use for many years with some success [Gros et al., 1976a; Gros et al., 1976b; Vercueil, 2003]. More recently, deep brain stimulation has become available, and multiple targets have been attempted, including the ventrolateral thalamus [Ghika et al., 2002; Thompson et al., 2000], internal globus pallidus [Coubes et al., 2000; Tronnier and Fogel, 2000; Vercueil et al., 2001], and most recently subthalamic nucleus [Benabid et al., 2001]. The advantage of deep brain stimulation is the ability to control the current delivery and the ability to select one or a combination of up to four electrodes through an external programmer. The stimulation wire is implanted using a combination of stereotactic neurosurgical techniques and usually microelectrode recording for precise localization. There is emerging evidence that the precision of implantation affects the outcome. The lead is connected to a pacemaker implanted in the chest. For generalized dystonia, usually both sides need to be implanted. The full effect of ablative surgery or stimulation implantation is often not seen for many months, and there are reports of continued improvement up to 1 year after pallidotomy [Lin et al., 2001]. Surgical procedures in the globus pallidus internus seem to be particularly effective in DYT1 and other primary dystonias [Coubes et al., 2004; Eltahawy et al., 2004; Ford, 2004; Lozano et al., 1997; Vercueil et al., 2002; Vitek et al., 1998], and these are cases in which earlier intervention may be most effective [Coubes et al., 2000]. The secondary causes of dystonia may also respond [Ghika et al., 2002; Rakocevic et al., 2004], but surgery seems to be less effective for secondary dystonia [Cif et al., 2003; Coubes et al., 2002; Krack and Vercueil, 2001; Teive et al., 2001]. The largest case series suggests up to 50% effectiveness in children with secondary dystonia but up to 80% effectiveness in children with primary dystonia. Complications are essentially those of the implantation procedure. Infections do occur, but these are rare outside of the immediate perioperative period. Batteries need to be replaced every 3 to 5 years, and this requires a brief surgical procedure. The long-term efficacy of deep brain stimulation is not known. Whether there is a difference in programming parameters between children and adults is likewise not known.

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Treatment of Dyskinesia and Hyperkinetic Dystonia

TABLE 58-4

Hyperkinetic disorders are more difficult to treat, and although they represent a positive symptom, it is often difficult to remove the effects of dyskinetic movements through botulinum toxin owing to the likely need to completely paralyze the affected muscle. Trihexyphenidyl can often make dyskinesia worse, as can levodopa. There is some effectiveness of clonazepam and valproate. Tetrabenazine [Jankovic and Beach, 1997; Jankovic and Orman, 1988], reserpine, and amantadine have been tried, but there are no consistent reports of benefit. Whether hyperkinetic dystonia and dyskinesia respond to pallidotomy or deep brain stimulation is not currently known. In Parkinson’s disease, pallidotomy does seem to improve dyskinesias, but the mechanism of dyskinesia in this case may be very different from the hyperkinetic symptoms seen in children, and there is not yet adequate data to guide therapy.

Causes of Tremor

Tremor Classification of Tremor Tremor has been described as “a rhythmical, involuntary, oscillatory movement of a body part” [Deuschl et al., 1998]. It can be classified based on the time of greatest severity at rest, postural, action, or intention tremor. Rest tremor is defined as tremor involving a body part that is inactive and supported against gravity. It may improve during movement. Rest tremor is most commonly associated with other signs of parkinsonism but may occur in isolation. Postural tremor is worse when a child attempts to sustain a posture against gravity, such as with the arms outstretched in front or with the hands near the nose. It may improve with movement or with rest supported against gravity. Action tremor is worse during active movement, but postural or rest components may be present as well. Intention tremor is a specific form of tremor associated with cerebellar disorders, in which the tremor becomes worse as the arm approaches an end point or target, and there is great difficulty achieving target accuracy. Tremor can affect the head [DiMario, 2000], extremities, trunk, or voice. Tremor can be described in terms of its frequency. Tremor associated with Parkinson’s disease or parkinsonism is between 4 and 6 Hz [Findley et al., 1981], whereas essential tremor is more likely at 5 to 8 Hz [Elble, 2000], and physiologic tremor has two components at 8 to 12 Hz and at 20 to 25 Hz [Makabe and Sakamoto, 2002; Takanokura et al., 2002]. In diagnosing tremor, it is important to distinguish it from dystonic tremor and myoclonus. Dystonic tremor, as described earlier, tends to be less regular and often exhibits a null point. Myoclonus can be rhythmic and can be a form of tremor, but the rapid shocklike quality distinguishes it. Electromyography may be helpful in distinguishing myoclonic-type tremor from other forms of tremor, because of the short bursts of less than 50 milliseconds and correlation with scalp potentials that are often seen with myoclonus [Shibasaki, 2000; Shibasaki et al., 1986].

Primary Tremor The various etiologies of tremor are listed in Table 58-4. Familial essential tremor is an autosomal-dominant disorder

Benign Enhanced physiologic tremor, shaking and shuddering episodes, spasmus nutans Static Injury, Structural Stroke (particularly in the midbrain or cerebellum), multiple sclerosis Hereditary, Degenerative Familial essential tremor, juvenile parkinsonism (tremor is rare), pallidonigral degeneration, Wilson’s disease, Huntington’s disease Metabolic Hyperthyroidism, hyperadrenergic state (including pheochromocytoma and neuroblastoma), hypomagnesemia, hypocalcemia, hypoglycemia, hepatic encephalopathy, vitamin B12 deficiency Drugs, Toxins Valproate, lithium, tricyclic antidepressants, stimulants (cocaine, amphetamine, caffeine, thyroxine, bronchodilators), neuroleptics, cyclosporine, toluene, mercury, thallium, amiodarone, nicotine, lead, manganese, arsenic, cyanide, naphthalene, ethanol, lindane, serotonin reuptake inhibitors Other Causes of Tremor Peripheral neuropathy, cerebellar disease or malformation, anxiety, psychogenic tremor

with variable penetrance and severity. It can present in childhood and often is slowly progressive over many years [Jankovic et al., 2004; Louis et al., 2001; Paulson, 1976]. It is rarely disabling in childhood, except in extreme cases. Tremor is primarily postural but can also be worsened with action. Tremors when holding a cup or with handwriting are often some of the earliest complaints, but head, trunk, and voice can be affected [Jankovic, 2000]. There is no specific treatment. In adults, there may be a statistical association between essential tremor and Parkinson’s disease [Yahr et al., 2003]. Task-specific tremor is rare in children, and when it occurs, it most often seems to involve handwriting. Whether task-specific tremors are a variant of dystonic tremor with task specificity or whether this is a form of essential tremor is not known [Rosenbaum and Jankovic, 1988]. It is important to examine the child for other evidence of dystonia either in the affected limb or elsewhere. Medical treatment is usually ineffective, but occupational therapy may be helpful to develop compensatory strategies. Physiologic tremor is a normal response that becomes particularly noticeable when a muscle is exerting high levels of force [Makabe and Sakamoto, 2002; Takanokura et al., 2002]. The characteristic of physiologic tremor is that it occurs only with or worsens only when the child is carrying a heavy object or otherwise needs to contract the muscle against high resistance. Some children have an enhanced physiologic tremor that can become noticeable but is only rarely bothersome. There is no effective treatment for enhanced physiologic tremor, but progression is probably rare. Tremor is a frequent manifestation seen in psychogenic movement disorders. As noted in the section on Psychogenic Dystonia, psychogenic tremor likely represents a conversion reaction and may reflect relatively serious psychopathology

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with consequent poor prognosis [Kim et al., 1999; Miyasaki et al., 2003]. Psychogenic tremor can often be distinguished from organic bases of tremor by entrainment to the examiner. In particular, when a child is asked to make a rhythmic movement with a hand or foot at a rhythm different from the tremor, often the tremor will entrain to the rhythmic movement, or the rhythmic movement will entrain to the tremor, such that either the tremor becomes irregular during accurate performance of the rhythmic movement or performance of the rhythmic movement is impossible [Zeuner et al., 2003]. Similarly, distraction using mathematical tasks or other difficult cognitive tasks can often change the nature or frequency of a physiologic tremor, but this would not be expected to occur for an organic tremor. However, the severity (but usually not the frequency) of an organic tremor could worsen in the context of a cognitive performance task if it were worsened by stress. Other causes of tremor include Parkinson’s disease, although the tremor-dominant form is much more common in adults than children. Huntington’s disease can cause tremor, although other symptoms usually dominate. Spasmus nutans is an unusual tremor-like disorder seen in young children, usually starting as early as 4 months of age and lasting several years. It is described in a separate section. Shaking and shuddering spells are rarely observed in the clinic, and diagnosis rests on parental description of the typical episodes. These are a benign phenomenon described in a separate section.

Secondary Tremor There are a large number of secondary causes of tremor, and most of these are listed in the table. It is important to exclude Wilson’s disease. This disorder is characterized by a wingbeating tremor that often involves the adductors of the arm, and is seen when the child is asked to abduct the arms with elbows bent [Saito, 1987; Stremmel et al., 1991]. The tremor is primarily postural but may occur at rest. Other forms of tremor are possible in Wilson’s disease. Other symptoms include dystonia, rigidity, dysarthria, and psychiatric disorders. The defect is due a mutation in the ATP7B coppertransport atp-ase gene on 13q14.3, which leads to reduced biliary excretion of copper and consequent accumulation of copper in multiple tissues. Symptom onset is between 6 and 45 years of age. Diagnosis of Wilson’s disease is made by noting a low serum ceruloplasmin and elevated excretion of copper in the urine, as measured by a 24-hour urine collection with measurement of the copper-to-creatinine ratio. In patients with neurologic symptoms, slit-lamp examination almost always reveals Kayser-Fleischer rings. Overt or occult liver disease is usually present. Because Wilson’s disease is treatable, it is extremely important to exclude this disorder. Common treatments include zinc acetate, trientine, or penicillamine, although if not detected early, liver transplantation may be needed [Roberts and Schilsky, 2003]. Rubral tremor describes a large-amplitude rhythmic but partly ballistic movement that often affects the arms and can be unilateral. It is associated with attempts at movement and is therefore an action tremor. In some cases it can be difficult to distinguish chorea from rubral tremor, although rubral tremor is much less common. It is associated with lesions in the thalamus [Tan et al., 2001], midbrain [Leung et al.,

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1999], pons, or cerebellar peduncles, although not necessarily the red nucleus. Rubral tremor is usually nonprogressive, but it can be severely disabling. It is important in the evaluation of a tremor to exclude hyperthyroid states, and this can either be a primary cause of tremor or can worsen a preexisting tremor. Hyperadrenergic states can cause tremor, and this may occur in the presence of tumors that secrete epinephrine, such as pheochromocytoma or neuroblastoma, but it can also occur in the context of severe anxiety disorders. Tremor can occur with electrolyte or glucose abnormalities, vitamin B12 deficiency, and in response to medication, including valproate, lithium, tricyclic antidepressants, and stimulant medication such as methylphenidate.

Treatment of Tremor The first goal in treatment of tremor is to exclude other possible causes of rhythmic movement, including myoclonus, dystonia, seizures, or cerebellar dysfunction. Any underlying metabolic or hormonal cause must be corrected. Essential tremor is treated with propranolol, primidone, benzodiazepines (clonazepam may be particularly effective), or gabapentin [Gironell et al., 1999; Jankovic et al., 2004; Paulson, 1976; Rajput et al., 2004]. If tremor is caused or worsened by anxiety, benzodiazepines may be particularly helpful. Tremor due to stage fright, social phobia, or panic disorder often responds to propranolol. These same medications can be tried in other forms of tremor, but usually there is minimal responsiveness. Rubral tremor is notoriously refractory to all attempts at intervention, although some cases respond to levodopa [Findley and Gresty, 1980; Yuill, 1980], clonazepam [Jacob and Pratap Chand, 1998], or thalamic deep brain stimulation [Nikkhah et al., 2004].

Parkinsonism Parkinsonism is defined by presence of two or more of the cardinal signs of Parkinson’s disease. These signs are tremor at rest, bradykinesia, rigidity, and postural instability. Tremor is rare in childhood parkinsonism. Bradykinesia is slowness of movement in the absence of weakness or ataxia. There may also be hypokinesia with paucity of movement, few spontaneous movements, and decreased amplitude of movement. Hypokinesia is often seen as diminished spontaneous facial expression, soft speech (hypophonia), small handwriting (micrographia), and general slowness. Rigidity is increased muscle tone that is equal in all directions of movement, does not increase with increased velocity of passive movement, and does not have a particular preferred posture. Rigidity may have a “lead pipe” quality, in which the limb can be moved with difficulty into arbitrary postures, but once placed in a posture, will remain there against gravity. If there is superimposed tremor, the rigidity can feel ratchety, like a cogwheel. Postural instability manifests as increased likelihood of falling and is due to dysregulation of postural reflexes. Clinically, it is evaluated with the “pull test,” in which the patient stands, facing away from the examiner with feet apart at shoulder width. The examiner gives a gentle pull backward at the shoulders bilaterally. A normal individual may take a step backward, but an

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individual with parkinsonian postural instability will take many steps backward (retropulsion) or may fall backward with no attempt to compensate. Bradykinesia can be difficult to detect when hypertonia is present because hypertonia may be interpreted as the reason for slow movement. In parkinsonian syndromes in children, bradykinesia is likely to be a more disabling symptom than rigidity. Rigidity can be difficult to distinguish from other causes of hypertonia, including dystonia or spasticity. The absence of a spastic catch or fixed posture distinguishes rigidity from spasticity. The absence of overflow movements or a fixed abnormal posture helps to distinguish rigidity from dystonia, although both may exhibit co-contraction [Sanger et al., 2003]. Arm rigidity is often suspected by observing decreased arm swing when examining the patient’s gait and is most easily seen when it is asymmetric. Rigidity can be brought out by facilitation maneuvers, such as having the child open and close one fist while the resistance to movement at the opposite elbow is tested. In adults, the most common cause of parkinsonism is Parkinson’s disease. In children, parkinsonism is uncommon but can be a manifestation of several different disorders, as discussed later [Riederer and Foley, 2002]. It is often associated with a dopaminergic deficit, and because dopaminergic deficits can produce dystonia in children, dystonia may be present as well [Yokochi, 2000].

Parkinson’s Disease Primary causes of parkinsonism in children are rare [Pranzatelli et al., 1994]. Dopa-responsive dystonia may be a relatively common cause compared with others, and has been described previously. Juvenile Parkinson’s disease presents with leg dystonia in younger children and bradykinesia and rigidity in older children. It rarely demonstrates tremor. It most commonly presents in young adults, and childhood or juvenile onset is rare. Many cases are due to mutations in the parkin gene, labeled PARK-2, on chromosome 6q25.2-27 [Huynh et al., 2003; Ruiz-Linares, 2004]. This is autosomal-recessive and can be contrasted with the autosomal-dominant inheritance of some forms of adult parkinsonism associated with mutations in the α-synuclein gene. The autosomal-dominant form does not appear to occur in childhood. Other genes have been identified in specific families [Bentivoglio et al., 2001; DeStefano et al., 2002; Valente et al., 2002; West et al., 2002a; West et al., 2002b; West et al., 2003]. The pathology of parkin-associated Parkinson’s disease does not show Lewy bodies, although there is neuronal loss and neurofibrillary tangles. Fluoro-dopa positron-emission tomography scanning can reveal decreased uptake, suggesting a presynaptic abnormality consistent with degeneration of the nigro-striatal pathways, rather than a metabolic defect in the synthesis of dopamine, as seen in dopa-responsive dystonia [Khan et al., 2002; Pal et al., 2002]. Juvenile Parkinson’s disease is levodopa responsive in the early years. It will also respond to anticholinergic medication, dopamine agonists, and inhibitors of dopamine breakdown. However, escalating doses are required, and children eventually develop dyskinesias similar to those seen in adults on chronic dopaminergic therapy. It is important to differentiate this disorder from dopamine-responsive dys-

tonia, as well as from other disorders that may respond to dopaminergic medication, because the prognosis is different and it may be helpful to consider treatment with dopaminesparing medications, including dopamine agonists or inhibitors of dopamine breakdown, to prolong the efficacy and delay the onset of dyskinesias.

Secondary Parkinsonism Causes of secondary parkinsonism are listed in Table 58-5. These include infarcts, particularly in the striatum or pallidum, as well as the ceroid lipofuscinoses, in which a combination of bradykinesia and visual loss leads to a very striking hesitancy of gait [Nijssen et al., 2002]. Pantothenate kinase–associated neurodegeneration can be a cause of bradykinesia. Similarly, spinocerebellar ataxia, Rett’s syndrome, Huntington’s disease, and Wilson’s disease can be a cause of bradykinesia. Parkinsonism can be associated with acute encephalitis or postencephalitic parkinsonism. The widespread epidemic of encephalitic parkinsonism (von Economo’s disease) that occurred between 1916 and 1930 has not recurred, and the term encephalitis lethargica should probably be reserved for patients who were victims of that epidemic. There are reported cases of a similar syndrome after streptococcal illness [Dale et al., 2004; Kiley and Esiri, 2001; Vincent, 2004]. Whether the original epidemic of encephalitis lethargica was due to influenza virus has been called into doubt recently [Jellinger, 2001; Lo et al., 2003]. Several medications and toxins are known to be able to cause parkinsonism [Pranzatelli et al., 1994]. Parkinsonism is a common side effect of tetrabenazine and reserpine and can be seen with neuroleptic treatment as well. The chemical MPTP, which is a synthetic methamphetamine derivative used for illicit recreational purposes, led to several cases of very rapid onset of irreversible parkinsonism; its use also has TABLE 58-5 Causes of Parkinsonism Static Injury, Structural Basal ganglia infarcts, brain tumor, hydrocephalus Hereditary, Degenerative Juvenile Parkinson’s disease, spinocerebellar ataxia, Huntington’s disease (Westphal variant), PKAN, Rett’s syndrome, PelizaeusMerzbacher disease, Machado-Joseph disease (SCA3) Metabolic Dopa-responsive dystonia, tyrosine hydroxylase deficiency and other abnormalities of bioamine metabolism, abnormalities of folate metabolism, Wilson’s disease, basal ganglia calcification (Fahr’s disease, hypoparathyroidism) Infectious, Parainfectious Encephalitis lethargica (Von Economo’s disease), viral encephalitis, acute demyelinating encephalomyelitis Drugs, Toxins MPTP poisoning, rotenone, tetrabenazine, reserpine, methyldopa, sedatives, neuroleptics, antiemetics, calcium channel blockers, isoniazid, serotonin reuptake inhibitors (sertraline, fluoxetine), meperidine Disorders That Mimic Parkinsonism Catatonia, spasticity, hypothyroidism, depression PKAN, pantothenate kinase–associated neurodegeneration; SCA, spinocerebellar ataxia.

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become very important in research into the pathogenesis and treatment of parkinsonian syndromes [Burns et al., 1985; Eldridge and Rocca, 1985].

Treatment of Parkinsonism Bradykinesia is the primary symptom that is responsive to treatment in childhood parkinsonism. It is usually assumed to be due to dopamine deficiency and therefore is treated with levodopa or dopamine agonists. Levodopa is combined with a peripheral decarboxylase inhibitor such as carbidopa to reduce side effects and increase delivery to the brain. Treatment is often initiated with a single dose of levodopa, 1 mg/kg (or 50 to 100 mg total) given in the morning, to evaluate for potential side effects including nausea or postural hypotension. If this dose is tolerated for 3 or 4 days, then therapeutic treatment can be initiated three times per day. Unless symptoms are present at night, the doses are usually given during the daytime to maximize effect. Dosage can be increased to a maximum of 10 to 15 mg/kg/day depending on effectiveness. In addition to nausea and hypotension, common side effects can include dystonia, agitation, sleeplessness, and behavior changes. The dosage must be adjusted gradually to find the optimal dose, and the optimal dose may change as the child grows. Additional carbidopa may be given to decrease nausea. In adults and children with Parkinson’s disease, long-term treatment with dopamine or dopamine agonists will eventually lead to dyskinesias and freezing episodes that can limit its use. Some authors have advocated “dopaminesparing” strategies that involve the early use of dopamine agonists such as pergolide, pramipexole, or ropinirole, or dopamine breakdown inhibitors such as entacapone or selegiline [Jenner, 2003]. This approach remains controversial and has not been studied in children. Amantadine may be used to treat dyskinesias associated with acute or chronic use of levodopa [Furukawa et al., 2004a], and it has some antiparkinsonian effects as well [Crosby et al., 2003; Paci et al., 2001]. Anticholinergic medication will improve parkinsonism, but it is more commonly used to treat associated dystonia. Deep brain stimulation in the internal globus pallidus or subthalamic nucleus has met with tremendous success in ameliorating symptoms of adult Parkinson’s disease [Germano et al., 2004; Peppe et al., 2004]. Whether similar neurosurgical procedures would be effective in children is not known. Failure of dopaminergic transmission can be divided into presynaptic and postsynaptic forms. In presynaptic failure, there is reduced production or release of dopamine at nigro-striatal nerve terminals. These reductions are typical in juvenile Parkinson’s disease and dopa-responsive dystonia. In postsynaptic failure, there is injury to the striatal targets. This is typical following encephalitis or hypoxic injury. Treatment with dopaminergic medication is most successful when there is presynaptic failure. If injury is primarily postsynaptic, there may be some mild benefit from dopaminergic medication, but the effect is limited.

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involving a single muscle or muscle group. The rapidity of these movements warrants the descriptor “shocklike,” as if an electric shock had just been applied to the peripheral nerve innervating the muscle [Marsden et al., 1983]. Myoclonus can be rhythmic, in which case it often appears tremor-like. However, in true tremor, the movement oscillates with near equal amplitude around a midpoint, whereas in myoclonus, the movement has a more sawtooth character. In some cases, myoclonus can be elicited by a sensory stimulus (reflex myoclonus; the most famous example is the acoustic startle response in infancy) or volitional movement (action myoclonus). Myoclonus is perhaps the most protean of abnormal movements. It is present in normal (associated with sleep, exercise, anxiety) and pathologic situations, both epileptic and nonepileptic. Epileptic myoclonus is discussed in Chapter 46. This chapter limits its focus to nonepileptic myoclonus.

Classification of Myoclonus Several different schemes have been used to classify myoclonus, using clinical, anatomic, or etiologic criteria. Perhaps the simplest classification is based on when the myoclonus occurs. Thus, myoclonus may occur at rest, with action, or in response to a sensory stimulus (reflex myoclonus). In adults it is helpful to classify myoclonus based on presumed neuroanatomic location (e.g., cerebral cortex, thalamus, brainstem, or spinal cord). The neurophysiology of myoclonus has been reviewed elsewhere [Caviness and Brown, 2004; Shibasaki and Hallett, 2004]. In children, etiologic classification is the most useful. This classification is summarized in Table 58-6.

Physiologic and Developmental Myoclonus Physiologic myoclonus is that which occurs in normal individuals in specific settings. It includes such entities as hiccups, sleep starts, and sleep myoclonus. Sleep starts, also known as hypnic myoclonus, occur with sleep initiation [Montagna, 2004]. They are often accompanied by a sense of falling. Sleep starts are normal physiologic phenomena, and no treatment is required. Sleep myoclonus (nocturnal myoclonus) is also a part of normal sleep physiology. It is thought to result from paradoxical excitation during rapid-eye-movement sleep due to transient failure of brainstem inhibition [Montagna, 2004]. Sleep myoclonus in older children is more fragmentary than neonatal sleep myoclonus and tends to persist throughout life. No treatment is required. Benign myoclonus may occur in association with specific developmental stages. Benign neonatal sleep myoclonus and benign myoclonus of early infancy are discussed in other sections of this chapter. Myoclonus can also occur with fever in otherwise normal children [Dooley and Hayden, 2004]. The myoclonic jerks may be quite frequent, but they are self-limited, ceasing when the fever resolves. Febrile myoclonus may be more common in younger children. No treatment is required.

Myoclonus

Essential Myoclonus

Myoclonus is very brief, abrupt, involuntary, nonsuppressible, jerky contractions (or interruption of contraction)

Essential myoclonus is a relatively mild condition starting in the first or second decade. It is inherited as an autosomal-

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TABLE 58-6

Symptomatic Myoclonus

Causes of Myoclonus

Myoclonus can be symptomatic of many disorders, as listed in Table 58-6. Many of these conditions are discussed elsewhere in this text. This section covers specific conditions in which myoclonus can be the primary feature.

Physiologic Hiccups, hypnic jerks (sleep starts), nocturnal (sleep) myoclonus Developmental Benign neonatal sleep myoclonus, benign myoclonus of early infancy, myoclonus with fever Essential (familial myoclonus dystonia syndrome) Psychogenic Storage diseases Juvenile Gaucher’s disease (type III), sialidosis type 1 (cherry red spot myoclonus), GM-1 gangliosidosis, neuronal ceroid lipofuscinosis (late infantile to juvenile) Degenerative Conditions Dentatorubro-pallidoluysian atrophy (DRPLA), Huntington’s disease, progressive myoclonus, ataxia, Ramsay Hunt syndrome, dementias, bovine spongiform encephalopathy, Creutzfeldt-Jacob disease Infectious and Postinfectious Meningitis (viral or bacterial), encephalitis, Epstein-Barr virus, coxsackievirus, influenza, human immunodeficiency syndrome, acute disseminated encephalomyelitis Metabolic Uremia, hepatic failure, electrolyte disturbances, hypoglycemia or hyperglycemia, aminoacidurias, organic acidurias, urea cycle disorders, myoclonus epilepsy with ragged red fibers (MERRF), mitochondrial encephalomyopathy–lactic acidosis–and strokelike symptoms (MELAS), biotinidase deficiency (usually epileptic), cobalamin deficiency (infantile), opsoclonus-myoclonus syndrome (myoclonic encephalopathy of infancy) Toxic Psychotropic medications (tricyclic antidepressants, lithium, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, neuroleptics) Antibiotics (penicillin, cephalosporins, quinolones) Antiepileptics (phenytoin, carbamazepine, lamotrigine, gabapentin, benzodiazepines [in infants], vigabatrin) Opioids General anesthetics Antineoplastic drugs Strychnine, toluene, lead, CO, mercury Hypoxia (Lance-Adams syndrome) Focal lesions

dominant trait with incomplete penetrance [Fahn and Sjaastad, 1991; Quinn, 1996]. It is usually slowly progressive for a few years after onset and then stabilizes. The myoclonus may fluctuate slightly over the years, or may demonstrate mild spontaneous improvement. The myoclonus usually responds to ethanol, but the magnitude of benefit varies across individuals. The most common mutation identified is in the epsilon-sarcoglycan gene (7q21-q31). Mutations in this gene have also been associated with myoclonus-dystonia syndrome (see section on Myoclonus Dystonia). Many patients with essential myoclonus also have dystonia, and it appears that the two clinical syndromes may have the same underlying genetic basis [Nygaard et al., 1999; Quinn, 1996]. Some family members may have only myoclonus, others may have only dystonia, and others may have both myoclonus and dystonia. Essential myoclonus may respond to benzodiazepines, primidone, or propranolol.

MYOCLONIC ENCEPHALOPATHY OF INFANCY (OPSOCLONUSMYOCLONUS SYNDROME) Myoclonic encephalopathy is an uncommon acquired disorder of late infancy. It was first described by Kinsbourne and often is referred to as Kinsbourne’s syndrome [Kinsbourne, 1962]. It has also been called infantile polymyoclonia [Dyken and Kolar, 1968] and opsoclonus-myoclonus syndrome. The clinical features of the syndrome include acute or subacute onset of rapid, dancing eye movements and myoclonic jerking of the limbs and trunk. The eye movements (opsoclonus) are usually conjugate but can be dysconjugate. As the disorder progresses, there is increased severity of the truncal myoclonus, which often prevents children from standing or walking. The myoclonus usually ceases during sleep but may persist. The opsoclonus may also persist during sleep. In some children, the myoclonus is stimulus sensitive, and it usually increases with action. The marked increase of myoclonus with action may make it difficult to distinguish this from ataxia. Many children with this condition have prominent irritability. Myoclonic encephalopathy has several potential causes. An important association has been made between myoclonic encephalopathy and neuroblastoma [Warrier et al., 1985]. The opsoclonus and myoclonus typically occur before the tumor is diagnosed [Dyken and Kolar, 1968]. The pathophysiology of myoclonic encephalopathy associated with neuroblastoma is unknown but is presumed to be immune mediated [Pranzatelli et al., 2004]. Removal of the tumor does not prevent relapse or permanent sequelae. Immunomodulatory therapy can be effective in some patients, but even with treatment, most patients have at least mild neurologic sequelae [Hayward et al., 2001]. About half the patients with myoclonic encephalopathy do not have an identifiable neuroblastoma [Tate et al., 2005]. In some instances the cause is most likely infectious or postinfectious. It has been associated with aseptic meningitis but more commonly follows a viral infection [Kinsbourne, 1962; Sheth et al., 1995]. There can be elevation of cerebrospinal fluid protein and mild lymphocytic pleocytosis, but the presence of cerebrospinal fluid pleocytosis does not distinguish paraneoplastic from infectious opsoclonusmyoclonus syndrome [Mitchell and Snodgrass, 1990; Tate et al., 2005]. Similar serum antineuronal antibodies have been detected in patients with postinfectious or neuroblastoma-associated opsoclonus-myoclonus syndrome [Connolly et al., 1997]. It is necessary to undertake a careful investigation for occult neuroblastoma in all infants and children with myoclonic encephalopathy unless the cause is obvious. The symptoms of children with and without neuroblastoma respond to adrenocorticotropic hormone therapy [Tate et al., 2005] (40 units/m2/day), which has proved highly effective in many instances. Removal of the tumor may lead to symptom resolution, but it may be followed by recurrence.

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DYSSYNERGIA CEREBELLARIS MYOCLONICA (RAMSAY HUNT SYNDROME) Hunt reported six patients with seizures, action myoclonus, and intention tremor and termed their condition dyssynergia cerebellaris myoclonica [Hunt, 1921]. One twin whose progressive neurologic symptoms began in the third decade of life came to postmortem examination; the other twin experienced myoclonus 2 years before seizures began. Atrophy of the dentate nucleus and hypodense myelin in the superior cerebellar peduncle were evident, as was disruption of the spinocerebellar tracts. Hunt ascribed the clinical findings to the dentate nucleus pathology. A familial pattern was suggested. A number of patients have been reported since the first description. There is not a single underlying cause for this syndrome, and it has been debated whether this is even a unique syndrome.

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Ataxia Ataxia is discussed in detail in Chapter 57 and in several other chapters of this textbook. For a detailed list of the causes of ataxia in children, see Table 58-7. Ataxia can be defined by a combination of features that lead to poor coordination. Children with ataxia exhibit intention tremor with worsening amplitude and frequency of tremor on approach to a target, particularly with finger-to-nose testing. They also display dysmetria with inaccuracy pointing to a target with either the hand or the foot, and poor coordination. Gait often is wide based and unsteady, and when ataxia affects the mouth, it leads to dysarthria, without the abnormal muscle contractions seen in spasmodic dysphonia TABLE 58-7 Causes of Ataxia

DENTATORUBRO-PALLIDOLUYSIAN ATROPHY Dentato-rubropallidoluysian atrophy (DRPLA) is an autosomal-dominant, degenerative disorder of the dentate nucleus, red nucleus, globus pallidus, and subthalamic nucleus [Becher et al., 1997]. Clinical features include myoclonus (see Chapter 57), cerebellar ataxia, epilepsy, choreoathetosis, and dementia. The disease is caused by a CAG repeat expansion in the DRPLA gene, on chromosome 12p13. It is most common in people of Japanese or Portuguese origin, but it has been reported in other groups.

POSTANOXIC MYOCLONUS Lance and Adams described myoclonus as a consequence of severe hypoxia during surgery in adults [Lance and Adams, 1963]. Postanoxic myoclonus is primarily an action or intention myoclonus. It can be disabling and can include negative myoclonus that may lead to falls. Some infants who undergo hypoxic-ischemic brain injury at birth develop continuous myoclonic activity of the face and limbs. This condition has been called polymyoclonus but may be a variant of LanceAdams syndrome.

Treatment of Myoclonus Myoclonus is often refractory to medical treatment. Cortical myoclonus may respond to benzodiazepines and is commonly treated with clonazepam (although sleep myoclonus may worsen [Reggin and Johnson, 1989]). Valproic acid is sometimes helpful, but it must be used with caution because of the ability to cause tremor as a side effect with consequent confusion of symptoms. Piracetam has been used for many years to treat myoclonus with good efficacy. Levetiracetam is a piracetam analogue but does not seem to have equivalent efficacy to piracetam. There are recent reports of efficacy with zonisamide, but this is still under evaluation. Posthypoxic myoclonus seems to be particularly responsive to serotonergic medications, including selective serotonin reuptake inhibitors and oral administration of 5-hydroxytryptophan or 5-hydroxytryptamine. Baclofen has been occasionally used, but the mechanism of action is not clear. Carbamazepine can make myoclonus worse.

Static Injury, Structural Cerebral palsy, stroke, trauma, hypoxic injury, Joubert’s syndrome, Dandy-Walker malformation, basilar impression, vermian agenesis, cerebellar dysgenesis, rhombencephalosynapsis, Chiari malformation types 2 and 3, pontocerebellar hypoplasia Hereditary, Degenerative Ataxia-telangiectasia, ataxia oculomotor apraxia, Friedreich’s ataxia, spinocerebellar ataxia (including Machado-Joseph disease), dentatorubro-pallidoluysian atrophy (DRPLA), olivopontocerebellar atrophy (OPCA), Marinesco-Sjögren syndrome, Pelizaeus-Merzbacher disease, childhood ataxia with central hypomyelination (CACH) syndrome Metabolic Hartnup’s disease, lipidoses, mitochondrial disorders (including Leigh’s disease, myoclonus epilepsy with ragged red fibers [MERRF], NARP, and pyruvate dehydrogenase complex deficiency), glutaric aciduria, Refsum’s disease, vitamin deficiency (B12, E, thiamine), abetalipoproteinemia (Bassen-Kornzweig disease), lysosomal storage disorders (including Krabbe’s disease, metachromatic leukodystrophy, carnitine acetyltransferase deficiencies, juvenile Gaucher’s disease, Tay-Sachs disease), ceroid lipofuscinosis, congenital disorders of glycosylation (CDG), biotinidase deficiency, holocarboxylase deficiency, Niemann-Pick type C, hypothyroidism, propionic acidemia, maple syrup urine disease and its thiamine-responsive variant, urea cycle disorders, porphyria, and electrolyte or glucose abnormalities Neoplastic, Paraneoplastic Tumors of the cerebellum or brainstem, neuroblastoma in the chest or abdomen (associated with the opsoclonus-myoclonus-ataxia syndrome) Immune Mediated, Demyelinating Acute postinfectious cerebellar ataxia, antigliadin antibody (gluten enteropathy), Miller-Fisher variant of Guillain-Barré syndrome, multiple sclerosis Drugs, Toxins Antiepileptic medication (particularly phenytoin and carbamazepine), antihistamines, barbiturates, lithium, alcohol, chemotherapy, heavy metal poisoning (lead, mercury, thallium), bromide intoxication Paroxysmal Dominant familial episodic ataxias (EA1, EA2), calcium channel disorders, basilar migraine Disorders that Mimic Ataxia Weakness, low blood pressure, any peripheral neuropathy or central cause of proprioceptive loss (with lack of sensation in the feet), astasia-abasia (usually psychogenic), seizures (pseudo ataxia), paroxysmal vertigo (may be a migraine variant)

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or dystonic dysarthria. Movements in ataxia appear to be disjointed, with a lack of coordination between the movements of different joints, and in some cases movement of one joint will lead to a loss of balance owing to inappropriate compensation for the resulting forces. Children appear very unsteady in all their movements, with reduced accuracy. Slow movements tend to be performed much more accurately than fast movements, and this has led to the hypothesis that in ataxia there is difficulty compensating for the dynamics of movement and difficulty with accurate estimation of the forces required to both accelerate and decelerate objects of known mass. Rapid repetitive or small cyclic movements may be particularly difficult, a symptom referred to as dysdiadochokinesia. It is important to distinguish ataxia from weakness, dystonia, chorea, athetosis, and tremor, all of which can lead to inaccurate or apparently uncoordinated movements. Weakness exacerbates or mimics ataxia, and therefore adequate strength needs to be tested. Ataxia is worsened if there is poor support of proximal joints. For example, a child with ataxia affecting reaching appears much worse if he or she must reach with the trunk unsupported. The primary causes of ataxia include the spinocerebellar ataxias, ataxia-telangiectasia, ataxia-oculomotor apraxia, Friedreich’s ataxia, DRPLA, and other genetic causes known to lead to ataxia. In addition, certain congenital malformations, including Joubert’s syndrome, pontocerebellar hypoplasia, Dandy-Walker syndrome and its variants, and vermian agenesis, can cause of ataxia. Secondary causes of ataxia include cerebral palsy, of which the ataxic form is rare, but this term is often used to encompass some of the malformations described earlier. Metabolic disease can lead to intermittent ataxia [Parker and Evans, 2003] or secondary cerebellar degenerative diseases. Such metabolic diseases include congenital disorders of glycosylation, mitochondrial disorders, vitamin E deficiency, and Refsum’s disease, with abnormalities of processing of phytanic acid. It is important to exclude opsoclonus-myoclonus ataxia, even when neither opsoclonus nor myoclonus is present [Mitchell et al., 2002]. This disorder presents in early childhood but can present later in the juvenile years, and is thought to be due to cross-reactivity of antibodies against neuroblastoma. Even after removal of the tumor the antibodies may persist, and long-term immunosuppressive treatment with corticosteroids, adrenocorticotropic hormone, intravenous immunoglobulins, or chemotherapeutic agents may be required. If left untreated, the ataxia will worsen, and there may be progressive cognitive decline.

Acute Cerebellar Ataxia Acute cerebellar ataxia is a clinical syndrome defined by the rapid onset of cerebellar dysfunction, which manifests primarily as gait disturbance and incoordination [Davis et al., 2003; Connolly et al., 1994; Gieron-Korthals et al., 1994]. Acute cerebellar ataxia is relatively rare and the annual incidence has been estimated to be approximately 1 case in 100,000 to 500,000 children [Davis and Marino, 2003]. A recent study of 39 children with acute cerebellar ataxia found the mean age of children presenting with this disorder to be 4.8 years [Nussinovitch et al., 2003]. A prodromal febrile illness was noted in about 75%, and the latency from

the prodromal illness to the onset of ataxia was approximately 9 days. The most common infections included varicella (31%), mumps (20%), nonspecific viral infection (15.4%), mycoplasma (5%), and Epstein-Barr virus (3%). Other studies have found that enterovirus [Huang et al., 1999] and parvovirus [Shimizu et al., 1999] infections also can cause acute cerebellar ataxia. Acute cerebellar ataxia may also occur after immunizations for varicella, hepatitis B, and rabies. Symptoms typically include ataxia and difficulties with fine motor coordination; some patients develop headache. The occur-rence of fever, altered mental status, or nuchal rigidity should prompt evaluation for a central nervous system (CNS) infection (Chapter 68). In a study of 39 children, recovery occurred within a mean of 2 weeks but took up to 24 days in some patients, a time frame shorter than that previously reported [Nussinovitch et al., 2003]. About 90% of patients with acute cerebellar ataxia will make a complete recovery [Connolly et al., 1994]. The risk of chronic cerebellar symptoms is associated with an older age or if Epstein-Barr virus infection is present [Davis and Marino, 2003]. About 20% of children have transient behavioral or intellectual difficulties and only rarely will long-term learning problems persist [Connolly et al., 1994]. The etiology of acute cerebellar ataxia is uncertain, but it is considered, in part, to be a postviral inflammatory disease. Viral nucleic acids and antiviral antibodies have been isolated from the cerebrospinal fluid of affected patients [Abdul Hafiz et al., 1996; Adams et al., 2000; Davis and Marino, 2003]. The evaluation of the child with acute cerebellar ataxia initially should focus on whether there may be a mass lesion or infection in the CNS, to determine whether neuroimaging and lumbar puncture are indicated. Neuroimaging, including computed tomography (CT) and magnetic resonance imaging (MRI), is normal in the majority of patients with acute cerebellar ataxia, but in some patients evidence of cerebellar inflammation is present [Connolly et al., 1994; Soussan et al., 2003]. It has been suggested that the presence of lesions on MRI is associated with a poorer prognosis but this observation is inconsistent. Likewise children with normal neuroimaging may have sequelae of chronic ataxia. An increase in the number of white cells may be seen on cerebrospinal fluid examination, and on occasion the cerebrospinal fluid protein is elevated [Gieron-Korthals et al., 1994]. Early in the course, it may be difficult to distinguish a para-infectious acute cerebellar ataxia syndrome from an acute viral or bacterial CNS infection, and in such cases, antiviral agents or antibiotics should be administered until cultures and serologic test results become available. Currently, routine assays for cerebrospinal fluid autoantibodies or for myelin basic protein do not appear to be clinically indicated, because the yield from such testing is unknown. There is no specific therapy for acute cerebellar ataxia. Steroids and intravenous immune globulin have been anecdotally used for treatment but no class I studies have been conducted to ascertain whether either is of clinical benefit. Because of the association with varicella, antiviral therapy with acyclovir has been used in patients with immune deficiency syndromes, but this treatment also has not been prospectively evaluated. Pleconaril, which is believed to be of benefit in treating enteroviral meningitis, is another potential treatment option, but recent small studies

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have shown that it is not effective in enteroviral meningitis in children [Tunkel, 2004]. In addition to infectious causes, the differential diagnosis of acute onset of ataxia includes several metabolic diseases. In particular the urea cycle disorders need to be excluded because these can present with episodic ataxia. Other disorders, including mitochondrial disease and congenital disorders of glycosylation, can present with acute onset or episodic ataxia. Developmental disorders that lead to ataxia and that present in the first year of life often exhibit hypotonia, which only later evolves to ataxia. Because it is known that the cerebellum is involved with the control of tone, it is not surprising that early cerebellar abnormalities might lead to hypotonia, but whether this is an obligate feature of later ataxia is not known. Ataxia is very difficult to treat and constitutes a negative symptom, meaning that it is lack of a particular skill rather than an excess of muscle activity. The mainstay of treatment is physical and occupational therapy, and in some cases adaptation of the environment may be successful. Nevertheless, treatment is often not successful, and children with even static forms of ataxia generally fail to improve despite intervention.

Paroxysmal Dyskinesia Paroxysmal dyskinesias are a relatively rare subset of hyperkinetic movement disorders that are defined by their episodic nature. Mount and Reback reported an apparent familial form in which the proband had infantile onset of episodes that began with a tight sensation in the neck and abdomen and a sense of fatigue followed by involuntary flexion of the arms and extension of the legs (dystonia) [Mount and Reback, 1940]. The spells progressed to involuntary choreoathetosis and dysarthria despite normal consciousness; Mount and Reback called the condition familial paroxysmal choreoathetosis. Kertesz described a group of patients who primarily had a childhood onset of movementinduced paroxysmal choreoathetosis. He highlighted the kinesigenic component and coined the term paroxysmal kinesigenic choreoathetosis [Kertesz, 1967]. The kinesigenic form was defined by a brief (seconds to minutes) duration of the episode, whereas the nonkinesigenic form was defined to be longer lasting (minutes to hours). Subsequently, the term paroxysmal dystonic choreoathetosis of Mount and Reback was used to delineate this form from the more common paroxysmal kinesigenic choreoathetosis [Richards and Barnett, 1968]. Another form with intermediateduration attacks precipitated by prolonged exercise has been described [Lance, 1977]. The traditional terminology has been a cause for confusion about the types of movements and the relationship between precipitating factors and the duration of episodes. The paroxysmal dyskinesias can manifest as chorea, dystonia, or both. Specifically, paroxysmal dystonic choreoathetosis is not always dystonic, and paroxysmal kinesigenic choreoathetosis may be purely dystonic. The kinesigenic form is not always brief, and the Mount and Reback form is not always of long duration. Therefore, Demirkiran and Jankovic [1995] developed a classification scheme that was based primarily on the precipitating events, arguing that the

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precipitant is the best predictor of clinical course and response to specific medications. They proposed the following classification of paroxysmal dyskinesias: kinesigenic, nonkinesigenic, exertion induced, and hypnogenic (also called paroxysmal nocturnal dystonia of sleep). Secondary categorization is based on duration; short is less than or equal to 5 minutes, and long is greater than 5 minutes. The tertiary classification is based on etiology: idiopathic (familial versus sporadic) and secondary.

Paroxysmal Kinesigenic Dyskinesia Paroxysmal kinesigenic dyskinesia is often inherited in an autosomal dominant fashion, but one fourth of the cases are sporadic. Males are affected more often than females by a ratio of 4:1 [Goodenough et al., 1978; Lotze and Jankovic, 2003]. The age of onset is 5 to 15 years in familial cases but may be variable in sporadic cases. The attacks are typically precipitated by startle or making a sudden movement after a period of rest. There is often a refractory period after an episode during which a sudden movement will not provoke an attack. The attacks may occur up to 100 times per day. The duration is typically a few seconds to a few minutes, but longer-lasting attacks may occur [Demirkiran and Jankovic, 1995]. The movements may be preceded by an abnormal sensation in the affected limbs, and some patients may only have an abnormal sensation without developing involuntary movements. Most patients have dystonia, but some have a combination of chorea and dystonia and rarely ballism. The attacks may be limited to one side of the body or even one limb. The attacks decrease in frequency during adulthood [Kertesz, 1967; Lotze and Jankovic, 2003]. Three types of paroxysmal kinesigenic dyskinesia have been linked to chromosome 16. The first is the syndrome of familial infantile convulsions and paroxysmal choreoathetosis, which has been linked to the pericentromeric region of chromosome 16 [Swoboda et al., 2000; Szepetowski et al., 1997]. Individuals homozygous for the disease haplotype in the pericentromeric region of chromosome 16 have earlier age of onset and higher frequency of attacks than heterozygous family members [Demir et al., 2004]. A syndrome of paroxysmal kinesigenic dyskinesia without infantile convulsions has also been linked to the pericentromeric region of chromosome 16 that overlaps with the region for infantile convulsions and paroxysmal choreoathetosis [Bennett et al., 2000]. A family with paroxysmal kinesigenic dyskinesia has been described with linkage to 16q and with no overlap with the pericentromeric region reported for the other families [Spacey et al., 2002]. In addition to idiopathic or genetic causes, there are many other causes of paroxysmal kinesigenic dyskinesia. These include multiple sclerosis, cerebral palsy, head trauma, strokes, hypoparathyroidism, maple syrup urine disease, infection, and methylphenidate therapy [Blakeley and Jankovic, 2002; Gay and Ryan, 1994; Kato et al., 1987; Temudo et al., 2004]. Paroxysmal kinesigenic dyskinesia responds well to antiepileptic drugs, including phenytoin, carbamazepine, phenobarbital, and levetiracetam [Chatterjee et al., 2002; Goodenough et al., 1978]. The dose required is usually less than the standard antiepileptic dosage, and familial paroxysmal kinesigenic dyskinesia is exquisitely responsive to

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carbamazepine [Wein et al., 1996]. With or without treatment, the attacks tend to diminish during adulthood, and individuals do not have progressive neurologic deficits.

Paroxysmal Nonkinesigenic Dyskinesia Paroxysmal nonkinesigenic dyskinesia is usually inherited as an autosomal-dominant trait. Males are affected more often than females (2:1 ratio). The age of onset is usually in early childhood, but attacks may not start until the early 20s. The frequency varies from three per day to two or fewer per year. Typical precipitating factors are fatigue, alcohol, caffeine, and emotional excitement. An episode may start with involuntary movements of a single limb, but may spread to involve all extremities and the face. The usual duration is minutes to 3 to 4 hours, but shorter and longer episodes have been reported [Demirkiran and Jankovic, 1995]. During the attack, the patient may be unable to communicate, but remains conscious and continues to breathe normally. Some individuals have mostly dystonia [Forssman, 1961], whereas others have predominant chorea [Mount and Reback, 1940]. Attacks may be relieved by sleep. Paroxysmal nonkinesigenic dyskinesia has been linked to chromosome 2q in the region of a putative ion channel gene [Fink et al., 1997; Hofele et al., 1997]. Nongenetic causes include multiple sclerosis, infection, hypoglycemia, thyrotoxicosis, hypoparathyroidism, moyamoya disease, pseudohypoparathyroidism, and biopterin synthesis defects [Blakeley and Jankovic, 2002; Dure and Mussell, 1998; Factor et al., 1991; Gonzalez-Alegre et al., 2003]. Management of paroxysmal nonkinesigenic dyskinesia relies on avoidance of precipitating factors such as alcohol, caffeine, and stress. Several medications have been used, including clonazepam, haloperidol, oxazepam, acetazolamide, and anticholinergics [Micheli et al., 1987]. Antiepileptic drugs are ineffective in most cases. Prognosis is variable and depends on the underlying cause. In familial cases, neurologic function between the attacks is normal, even after repeated attacks.

Paroxysmal Exertion-Induced Dyskinesia Paroxysmal exertion-induced dyskinesia is usually inherited in an autosomal-dominant fashion, although sporadic cases have been described [Bhatia et al., 1997]. The attacks are triggered by prolonged exercise [Lance, 1977]. The frequency varies from one per day to two per month. The usual duration is 5 to 30 minutes. Autosomal-dominant paroxysmal choreoathetosisspasticity, an exercise-induced dyskinesia frequently with spastic paraplegia during the episode, has been mapped to a 12 cM region on chromosome 1p in the vicinity of a potassium channel gene cluster [Auburger et al., 1996]. Another family has been described with paroxysmal exercise-induced dystonia and migraine that was not linked to the paroxysmal nonkinesigenic dyskinesia locus on chromosome 2, the infantile convulsions and paroxysmal kinesigenic dyskinesia locus on chromosome 16, or the familial hemiplegic migraine locus on chromosome 19, suggesting that other loci exist for paroxysmal exertioninduced dyskinesia [Munchau et al., 2000]. In addition to genetic causes, paroxysmal exertion-induced dyskinesia has

been reported after head trauma [Demirkiran and Jankovic, 1995]. Avoidance of prolonged exercise may help diminish the frequency of attacks. Drug therapy is often ineffective, but there are isolated reports of improvement with levodopa and acetazolamide [Bhatia et al., 1997; Demirkiran and Jankovic, 1995]. Prognosis is variable; neurologic function remains normal between attacks in familial and idiopathic forms.

Paroxysmal Hypnogenic Dyskinesia Paroxysmal hypnogenic dyskinesia is sometimes known as paroxysmal nocturnal dystonia. It is characterized by attacks of dystonia, chorea, or ballism during non–rapideye-movement sleep [Lugaresi and Cirignotta, 1981; Lugaresi et al., 1986]. The frequency may be from five times per year to five times per night. These attacks may be associated with electroencephalographic signs of arousal, and the patient usually falls asleep after the attack. The usual duration of the attacks is 30 to 45 seconds but may be longer. Sometimes the patients may have daytime attacks of dyskinesia. Paroxysmal hypnogenic dyskinesia is probably a heterogeneous condition comprising attacks of different durations and clinical features, but it appears that many cases result from frontal lobe seizures, and it has been reported in association with orbitofrontal cortical dysplasia [Lombroso, 2000; Provini et al., 2000]. Short-duration paroxysmal hypnogenic dyskinesia may respond to antiepileptic drugs, including carbamazepine and phenytoin. The longer-lasting attacks respond less well but may improve with haloperidol or acetazolamide. It is essential to rule out frontal lobe epilepsy as the underlying cause. Prognosis depends on the etiology.

Tic Disorders Tics are the most common movement disorder in children. Tics are repeated sudden, stereotyped, discrete, intermittent movements. When movements involve skeletal muscle, they are called motor tics. When the movements involve the diaphragm or laryngeal-pharyngeal muscles, and a sound is produced, they are called phonic or vocal tics. There is a great range of severity, and mild tics are not uncommon in healthy children [Kurlan et al., 1988]. Tics occur many times a day, nearly every day. They typically change anatomic location, frequency, type, complexity, and severity over time. Tics can be classified by mode of manifestation (motor or vocal) and complexity (simple or complex). Motor tics can be further classified by speed and quality as clonic (abrupt and fast) or dystonic-tonic (slow and sustained). Simple motor tics include blinking, nose twitching, grimacing, neck jerking, shoulder elevation, sustained eye closure, gaze shifts, bruxism, and abdominal tensing. Simple vocal tics include sniffing, throat clearing, grunting, squeaking, humming, coughing, blowing, and sucking sounds. Complex tics appear more “purposeful” than simple tics and may include combinations of movements of multiple body parts. Complex motor tics include head shaking, trunk flexion, scratching, touching, finger tapping, hitting, jumping, kicking, and gestures (obscene gestures are termed copropraxia). Complex vocal tics include spoken syllables

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words or phrases, shouting of obscenities or profanities (coprolalia), repetition of the words of others (echolalia), and repetition of final syllable, word, or phrase of one’s own words (palilalia) [Robertson, 2003]. Tics and Tourette’s syndrome are described in greater detail in Chapter 37.

Treatment of Tic Disorders Mild or moderate tic disorders often do not require treatment, and appropriate modification of the environment and reassurance of parents may be all that is needed [Bower, 1981]. For example, a child who is having social difficulty because of a tic may be able to do a class presentation or otherwise explain to their friends the nature of the disease, and the demystification of the disease may resolve the social complications. Anxiety, depression, or stress can often be triggers, and treatment of the triggers may be more helpful than treatment of the resulting tics. Treatment should be directed at improvement of specific abilities of the child, usually involving school participation or the ability to work. Discomfort or embarrassment of the parents should not be the sole indication for treatment. Medications that are effective include clonidine, guanfacine, benzodiazepines, and neuroleptics. Neuroleptics must be used with caution but these are often the most effective medicines. The goal of medication is not to completely eliminate the tics, but rather to reduce them to an adequate level that allows the child to achieve his or her functional goals. Complete elimination of tics is generally not possible. Because tic disorders wax and wane over time, it is essential to make frequent attempts to discontinue medications because apparent success of the medication may instead be the result of waning of the underlying disorder rather than any direct effect of the intervention. Similarly, apparent lack of effect could be due to a worsening of the disorder, and therefore it is essential to continually reevaluate the use of all medications, particularly when children are taking multiple medications. The use of multiple neuroleptics simultaneously is strongly discouraged because this seems to increase the risk for tardive symptoms. Tic disorders are frequently associated with obsessivecompulsive disorder or attention-deficit disorder, and these disorders may be much more disabling and lead to much more significant effects on school performance than the tic disorder itself. Therefore, it is important to screen for these disorders and treat them appropriately.

Stereotypy Motor stereotypies are rhythmic, patterned, repetitive, involuntary movements that can occur in association with specific diseases or in otherwise normal children [Bodfish et al., 2000; Mahone et al., 2004]. In the minds of many physicians, stereotypies are associated with autism, sensory deficits, or mental retardation. However, they are not uncommon in normal children. The term physiologic stereotypies has been suggested for when these movements occur in normal children [Mahone et al., 2004]. Typical movements include repeated recurrent raising and lowering of the arms, flapping, waving, wrist rotation, and finger wiggling. They are often accompanied by facial movements or grimacing. Other terms have been used to describe stereotypies, including rhythmic habit patterns, gratification phenomena, self-stimulation, and motor

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rhythmias. Physiologic stereotypies may be present in any setting but are most common when the child is excited, mentally engaged, stressed, or bored. They may increase with fatigue. A hallmark of stereotypies is that they usually cease when the child is distracted or engaged in a new activity. Most children appear to be unaware of the stereotypies. When a child is asked during the movement, “Why are you doing that?” the most common response is “Doing what?” The clinical characteristics of physiologic stereotypes have been described in a small number of studies [Mahone et al., 2004; Tan et al., 1997]. The typical age of onset for childhood stereotypies is less than 2 years. They are more common in boys (almost a 2:1 ratio). Unlike tics, stereotypies tend not to change in anatomic location or complexity over time. Stereotypies are not preceded by an urge or thought as is common with tics or compulsions. Physiologic stereotypies last for multiple years in most children. In some children, they disappear over time, but in other cases, they persist into adulthood. Although commonly seen in otherwise normal children, there appears to be an increased incidence of attention-deficit–hyperactivity disorder or learning disabilities in children with stereotypies. There is no consistently effective pharmacologic treatment for physiologic stereotypies. Stereotypies typically do not bother the patient but can be distressing to the parents. They rarely interfere with task performance by the individual with stereotypies but may cause embarrassment or have other social impact. Behavioral therapy may be effective [Miller, 2004]. Repeated instruction to the child to “stop that” is usually not effective.

Transient Developmental Movement Disorders The presence of a movement disorder in a child usually raises concerns about an underlying serious, progressive, degenerative, or metabolic disease. However, many movement disorders are benign and related to normal stages of development. In fact, it may be difficult to justify the term disorder in describing many of these movements. The developing nervous system may produce a variety of motor patterns that would be pathologic in older children and adults but are simply a manifestation of central nervous system immaturity. Like many of the neonatal reflexes (e.g., grasping, rooting, placing, tonic neck reflexes), these motor patterns disappear as neuron connectivity and myelination matures. Examples include the minimal chorea of infants, the mild action dystonia commonly seen in toddlers, and the overflow movements that are commonly seen in young children. Other transient or developmental movement disorders may be manifestations of abnormal neural function but do not correlate with serious underlying pathology. These are typically associated with complete resolution of the abnormal movements and ultimately normal development and neurologic function. Most of these conditions occur during infancy or early childhood. It is important to recognize these transient developmental movement disorders, distinguish them from more serious disorders, and be able to provide reassurance when possible.

Benign Neonatal Sleep Myoclonus Benign neonatal sleep myoclonus is characterized by repetitive myoclonic jerks occurring during sleep [Coulter and

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Allen, 1982]. The myoclonic jerks are typically in the distal more than proximal limbs and are more prominent in the upper than lower extremities. In some cases, jerks of axial or facial muscles can be seen. The myoclonus can be focal, multifocal, unilateral, or bilateral. The movements can be rhythmic or nonrhythmic. Typically, the movements occur in clusters of jerks at 1 to 5 Hz over a period of several seconds. Benign neonatal sleep myoclonus begins during the first week of life, diminishes in the second month, and is usually gone before 6 months of age but has been reported to persist as long as 3 years in one patient [Egger et al., 2003]. Ictal and interictal electroencephalograms are typically normal [DiCapua et al., 1993]. The movements are most likely to occur during quiet (non–rapid-eye-movement) sleep [Resnick et al., 1986]. Waking the infant causes the movements to cease. Episodes of myoclonus can be exacerbated by treatment with benzodiazepines [Reggin and Johnson, 1989]. Treatment is not required, and neurologic outcome is normal.

Benign Myoclonus of Early Infancy Benign myoclonus of early infancy is characterized by episodes of myoclonic spasms involving flexion of the trunk, neck, and extremities in a manner resembling the infantile spasms of West’s syndrome [Lombroso, 1990; Lombroso and Fejerman, 1977]. The myoclonic spasms typically occur in clusters. In some cases they involve a shuddering movement of the head and shoulders, and in others the movements of the trunk and limbs are extensor. There is no change in consciousness during the spells. Unlike benign neonatal sleep myoclonus, the movements in benign myoclonus of early infancy occur only in the waking state. The onset of these spells is usually between ages 3 and 9 months, but they may begin in the first month of life. The spells usually cease within 2 weeks to 8 months of onset [Maydell et al., 2001] but may persist for 1 to 2 years [Lombroso, 1990]. Both ictal and interictal electroencephalograms are normal, distinguishing this entity from infantile spasms. Treatment is not required, but an electroencephalogram is usually needed to exclude infantile spasms or infantile myoclonic epilepsy syndromes. Development and neurologic outcome are normal.

Jitteriness Jitteriness is a movement disorder that is commonly observed in the neonatal period. Jitteriness manifests as generalized, symmetric, rhythmic oscillatory movements that resemble tremor or clonus. Up to 50% of term infants exhibit jitteriness during the first few days of life, especially when stimulated or crying. Jitteriness usually disappears shortly after birth but can persist for months or recur after being gone for several weeks [Kramer et al., 1994; Shuper et al., 1991]. Persistent jitteriness has been associated with hypoxic-ischemic injury, hypocalcemia, hypoglycemia, drug withdrawal, and other causes of metabolic encephalopathies. Jitteriness is highly stimulus sensitive. It can be precipitated by startle and suppressed by gentle passive flexion of the limb. Unlike seizures, there are no associated abnormal eye movements or autonomic changes [Volpe, 2000]. Idiopathic jitteriness is usually associated with nor-

mal development and neurologic outcome. The outcome of infants with symptomatic jitteriness depends on the underlying cause.

Shuddering Shuddering episodes are characterized by periods of rapid tremor of the head, shoulders, and arms that resemble shivering [Holmes and Russman, 1986; Kanazawa, 2000]. Onset is in infancy or early childhood but can occur as late as 10 years of age. The episodes last several seconds and can occur up to 100 times per day, often triggered by excitement or surprise. During a spell, there is no change in consciousness. Ictal and interictal electroencephalograms are normal. Preservation of consciousness, predictable triggers, ability to abort an episode when distracted by a parent, and normal electroencephalogram distinguish this entity from seizures. Similarity to benign myoclonus of early infancy has been suggested [Kanazawa, 2000], but shuddering is better classified as tremor than myoclonus. Shuddering episodes typically abate as the child grows older. The prognosis for development and neurologic function is uniformly good.

Paroxysmal Tonic Upgaze of Infancy Paroxysmal tonic upgaze of infancy is a disorder characterized by repeated episodes of upward gaze deviation [Ouvrier and Billson, 1988]. The gaze deviation can be sustained or intermittent during an episode. The typical episode lasts for a few hours but can persist for days. Attempts to look downward are accompanied by down-beating nystagmus. Horizontal eye movements are normal during an episode. Spells may resolve with sleep and be aggravated by fatigue or infection. This condition remits spontaneously and completely within 1 to 4 years [Verrotti et al., 2001]. Some infants may have ataxia during episodes. There can be a positive family history in some cases. Laboratory investigations and imaging are usually unrevealing, although there is one report of a child with this condition with psychomotor retardation and MRI findings of periventricular leukomalacia [Campistol et al., 1993; Ouvrier and Billson, 1988]. There is no specific treatment, but there have been a few reports of improvement with levodopa treatment [Campistol et al., 1993; Ouvrier and Billson, 1988].

Spasmus Nutans Spasmus nutans is a condition beginning in late infancy (3 to 8 months) that is characterized by a slow head tremor (about 2 Hz) that can be horizontal (“no-no”) or vertical (“yes-yes”). The head movements are accompanied by a small-amplitude nystagmus that can be dysconjugate, conjugate, or uniocular [Anthony et al., 1980]. When the child is looking at an object, the nodding or nystagmus may increase, and if the head is held, the nystagmus typically increases. These observations have led to the suggestion that the head nodding is compensatory for the nystagmus [Gottlob et al., 1992]. Spasmus nutans generally resolves within several months, but most patients continue to have a fine subclinical nystagmus until at least 5 to 12 years of age [Gottlob et al., 1995]. Long-term outcome for visual acuity is good.

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Spasmus nutans must be distinguished from congenital nystagmus [Gottlob et al., 1990]. Congenital nystagmus usually begins in the newborn period before 6 months of age. Congenital nystagmus is usually bilaterally symmetric, whereas spasmus nutans is often asymmetric. Congenital nystagmus persists beyond a few months. Visual acuity is abnormal in about 90% of children with congenital nystagmus. Although these features are useful in distinguishing congenital nystagmus from spasmus nutans, some children who clinically appear to have spasmus nutans at the time of presentation have been found to have retinal abnormalities by electroretinography [Smith et al., 2000]. Neuroimaging abnormalities, including tumor and aplasia of the cerebellar vermis, have been described in patients with spasmus nutans, but this is a rare association [Kim et al., 2003; Unsold and Ostertag, 2002]. Routine neuroimaging in the absence of other evidence for intracranial pathology has limited yield [Arnoldi and Tychsen, 1995], but the possibility of a mass lesion or destructive process in the posterior fossa must be considered.

Head Nodding Head nodding without accompanying nystagmus can occur as paroxysmal events in older infants and toddlers [Nellhaus, 1983]. These head movements can be lateral (“no-no”), vertical (“yes-yes”), or oblique. The episodes may occur several times per day. The frequency (1 to 2 Hz) is slower than that of shuddering. The movements do not occur when the child is lying down but can occur in the sitting or standing position. The movements typically resolve within months but can persist longer. Some children with head nodding have a prior history of shuddering spells; others may have a family history of essential tremor [DiMario, 2000]. Development and neurologic outcome are unaffected by this condition.

Benign Paroxysmal Torticollis Benign paroxysmal torticollis is an episodic disorder starting in the first year of life. It typically manifests as a head tilt to one side for a few hours or days. Spells can last as little as 10 minutes or as long as 2 months, but this is uncommon [Giffin et al., 2002]. The torticollis may occur without any associated symptoms or may be accompanied by pallor, vomiting, irritability, or ataxia. Episodes typically recur with some regularity, up to twice a month initially and becoming less frequent as the child grows older. The spells abate spontaneously, usually by 2 to 3 years of age but always by age 5. The child is normal between spells. Interictal and ictal electroencephalograms are normal. It has been suggested that benign paroxysmal torticollis is a migraine variant [Al-Twaijri and Shevell, 2002]. There is often a family history of migraine. Some older children complain of headache during a spell, and many children go on to develop typical migraine after they have “outgrown” the paroxysmal torticollis [Deonna and Martin, 1981; Roulet and Deonna, 1988]. Two patients with benign paroxysmal torticollis have been reported from a kindred with familial hemiplegic migraine linked to a CACNA1A mutation [Giffin et al., 2002]. The differential diagnosis is broad, and diagnosis of benign paroxysmal torticollis is one of exclusion. Torticollis

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can be seen as an acute dystonic reaction to medication, as a symptom of a posterior fossa or cervical cord lesion, or as a cervical vertebral abnormality, such as Klippel-Feil syndrome. It is important to exclude posterior fossa abnormalities, such as Chiari syndrome or a mass. In the case of structural lesions, the torticollis tends to be persistent and not paroxysmal. Torticollis can also be a sign of cranial nerve palsy. Congenital muscular torticollis is another possibility; it is present from birth, is nonparoxysmal, and is associated with palpable tightness or fibrosis of the sternocleidomastoid muscle unilaterally.

Benign Idiopathic Dystonia of Infancy Benign idiopathic dystonia of infancy is a rare disorder characterized by a segmental dystonia, usually of one upper extremity, that can be intermittent or persistent [Deonna et al., 1991; Willemse, 1986]. The syndrome usually appears before 5 months of age and disappears by 1 year of age. The characteristic posture is of shoulder abduction, pronation of the forearm, and flexion of the wrist. The posture occurs when the infant is at rest and disappears completely with volitional movement. Occasionally, both arms, an arm and leg on one side of the body, or the trunk can be involved. In some infants the posture is only apparent with relaxation or in certain positions. In others it may be present during all waking hours. The rest of the neurologic examination is normal, and the developmental and neurologic outcome is normal. Exclusion of progressive dystonia, brachial plexus injury, infantile hemiplegia, and orthopedic abnormalities is important.

Posturing during Masturbation Masturbation is a normal behavior that occurs in both boys and girls. Although masturbation occurs at all ages and has even been observed in utero, it is most common at about 4 years of age and during adolescence [Leung and Robson, 1993]. Masturbation in young children may involve unusual postures or movements [Bower, 1981], which may be mistaken for abdominal pain or seizures [Fleisher and Morrison, 1990]. Masturbatory movements in boys are usually obvious to the observer because of direct genital manipulation. In girls, they are more subtle and often involve adduction of the thighs, or sitting on a hand or foot and rocking. When the movements are accompanied by posturing of the limbs they are often mistaken for paroxysmal dystonia. Several characteristic features of masturbating girls who present for diagnosis have been identified [Fleisher and Morrison, 1990; Mink and Neil, 1995]: (1) onset after 2 months of age and before 3 years of age; (2) stereotyped posturing with pressure applied to the pubic area; (3) quiet grunting, diaphoresis, or facial flushing; (4) episode duration of less than a minute to several hours; (5) no alteration of consciousness; (6) normal findings on examination; and (7) cessation with distraction or engagement of the child in another activity. Multiple diagnostic tests are often performed before the true nature of the behavior is recognized. No imaging or laboratory evaluation is required if the movements abate when the child is distracted, the movements involve irregular rocking, the child remains interactive, there is some degree of volitional control, direct

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genital stimulation is involved, and the neurologic and physical examinations are normal. There appears to be no association with sexual thoughts in the child. Instead, it is probably better to view these movements on the spectrum of other self-comforting behaviors such as thumb sucking or rocking, which have no concerning connotations for the parents [Mink and Neil, 1995]. Masturbation is a normal human behavior, so there is no expectation that this behavior will cease as the child grows older. However, the frequency of the behavior usually decreases as the child gets older, and the behavior is less likely to occur under the observation of the parents. Neurologic and developmental outcome is normal.

Transient Tic Disorder Transient tic disorder is a disorder of childhood with one or several tics that are indistinguishable from the tics of chronic tic disorder but that last only several months. The diagnosis is made in retrospect because only with complete resolution can this be distinguished from a chronic tic disorder or Tourette syndrome. Transient tics can occur at any time during childhood but are most commonly seen in children of preschool and primary school age. About 10% of children may have a transient tic or tics [Robertson, 2003]. In most cases, transient tics do not require treatment. The cause is unknown, but transient tic disorder has been reported in members of a large kindred with Tourette syndrome, suggesting that transient tic disorder is a possible expression of the Tourette syndrome gene or genes [Kurlan et al., 1988]. Once the tics have resolved, they usually do not recur, and long-term prognosis is excellent.

Tardive Movement Disorders Many medicines and environmental toxins are able to cause movement disorders, and examples were listed earlier under the specific relevant disorders. A particularly frustrating class of chemical-induced movement disorders is the tardive syndromes, including tardive dyskinesia, tardive dystonia, and tardive chorea. Tardive syndromes are most often caused by high-potency neuroleptic medications, including haloperidol, pimozide, or fluphenazine but can also be caused by atypical neuroleptics such as risperidone, olanzapine, and quetiapine and by medium- or low-potency neuroleptics used as antiemetics such as metoclopramide, chlorpromazine, and droperidol. All neuroleptics, with the exception of clozapine, are able to cause tardive reactions. Whether some neuroleptics have a lower rate of tardive movement disorders than others is not yet known. Children with preexisting mild brain injury may be at particularly high risk [Pourcher et al., 1995].

Symptoms of Tardive Movement Disorders Onset of symptoms can occur shortly after starting the medication, or months or years later. In some cases, symptom onset can occur after termination of the medication, although this is rare. When symptoms start at the time of withdrawal of medication they are called withdrawal emergent. Tardive symptoms, when recognized rapidly, often resolve after discontinuation of the causative agent.

However, in some cases tardive symptoms persist and may present a greater cause of disability than the original disorder for which the causative medication was prescribed. Tardive dyskinesia involves rabbit-like mouth movements with pursing of the lips, rotational jaw and tongue movements, and other uncontrolled continuous but usually nonrhythmic facial movements. Limbs and trunk may be involved as well, but this is more common with tardive dystonia. Tardive dystonia can present as any of the forms of dystonia, involving a single limb or multiple body segments. Tardive chorea appears similar to other forms of chorea but can be severe with large proximal movements or ballism.

Treatment of Tardive Movement Disorders Treatment of tardive symptoms relies on rapid withdrawal of the offending medication; therefore, patients must be warned of the possibility of these symptoms, so that they can alert their physicians and be taken off the medications as soon as possible after symptoms occur. Often the symptoms resolve spontaneously, in which case a rechallenge with neuroleptics should be avoided [Simpson, 2000]. If symptoms do not resolve, treatment with tetrabenazine may be helpful [Swash et al., 1972]. Tetrabenazine is a presynaptic dopamine depleter. It may be effective in dystonia but seems to be particularly effective in tardive dystonia and tardive dyskinesia [Asher and Aminoff, 1981]. Reserpine has a similar mechanism of action and may also be effective [Kang et al., 1986]. Treatment with a combination of large neutral amino acids (Tarvil), including phenylalanine and tyrosine, decreases the uptake of dopamine precursors and therefore is expected to have a similar effect to tetrabenazine. Pilot trials in tardive dyskinesia have shown promise [Richardson et al., 2003; Richardson et al., 1999; Richardson et al., 2004]. Neuroleptic medications themselves reduce tardive symptoms that persist after withdrawal from neuroleptics [Lucetti et al., 2002; Sasaki et al., 2004]; however, such treatment may perpetuate the disorder.

Other Movement Disorders Restless Leg Syndrome and Periodic Leg Movements of Sleep Restless leg syndrome manifests as an uncomfortable sensation in the legs that is typically relieved by movement. The sensation is poorly described by most children, but adults often use the descriptors “crawling,” “pulling,” or a “creeping” sensation under the skin. The sensation and movements occur most often at night and usually peak within the first 20 minutes of lying down. Relief is obtained by moving the legs while lying down or by walking. Restless leg syndrome responds to treatment with dopaminergic medication, and dopamine agonists are most often used for adults with this condition [Allen et al., 2004; Earley and Allen, 1996]. Treatment may not be needed in most children. It is frequently associated with periodic leg movements of sleep, which most often consist of brief flexion movements at the hip, knee, and ankle, occurring every few seconds while the child is asleep [Mahowald, 2003]. Periodic leg movements of sleep do not require treatment but can be helpful in the diagnosis of restless leg syndrome symptoms appearing while awake. There

Sanger and Mink / Movement Disorders

appears to be increased risk for both syndromes in children with symptoms of attention-deficit–hyperactivity disorder [Chervin et al., 2002; Picchietti et al., 1998].

Hyperekplexia Hyperekplexia, otherwise known as familial startle disease, is an autosomal-dominant disorder characterized by an exaggerated startle reaction in response to sudden, unexpected auditory or tactile stimuli [Ryan et al., 1992]. Symptoms may begin in the neonatal period with profound and potentially fatal paroxysmal hypertonia and opisthotonic extensor posturing. Such episodes often resolve if the examiner flexes the neck, back, and knees of the child. Older children and adults may display nonadapting head retraction in response to nose tapping. The disorder is associated with mutations in the α1 subunit of the glycine receptor [Shiang et al., 1993]. Symptoms respond well to treatment with clonazepam.

Bobble-Head Doll Syndrome The bobble-head doll syndrome is a condition in which an infant or child has jerky head movements similar to certain types of toy dolls [Benton et al., 1966]. The movement is a continuous or episodic involuntary forward and backward or side to side movement of the head at the frequency of 2 to 3 Hz. The condition is usually associated with structural abnormalities leading to third ventricular dilation, including third ventricular cyst, aqueductal stenosis, or tumor [Mussell et al., 1997; Wiese et al., 1985]. It has been suggested that the tremor results from pressure on the red nucleus and that the bobbing behavior lessens the symptoms of hydrocephalus [Wiese et al., 1985]. However, most authors view the movement as involuntary and not compensatory [Mussell et al., 1997]. Volitional restraint momentarily controls the movements, but the movements recur when the patient ceases to concentrate on restraining them. Brain imaging virtually always confirms the presence of a structural abnormality. Surgical treatment is usually beneficial [Goikhman et al., 1998].

Spasticity Spasticity is described in Chapter 20 on cerebral palsy. However, it is frequently associated with other movement disorders and is thus briefly addressed here. Along with dystonia and rigidity, spasticity is an important cause of hypertonia in childhood. Children with hypoxic-ischemic injury or other causes of cerebral palsy often have a combination of spasticity and dystonia [Sanger et al., 2003]. In some cases, treatment can be directed at both symptoms simultaneously. Although spasticity is a reflection of increased sensitivity of the spinal motor neuron pools, prolonged spasticity leads to changes in the muscle and tendon and potential changes in the joint that may require mechanical treatment [Gracies, 2001]. In particular, long-standing spasticity and weakness are known to lead to shortening of the muscle-tendon unit, and therefore stretching, serial casting, and orthopedic procedures including tenotomy or tendon-lengthening procedures may be needed. Mechanical shortening of the muscle will

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CHAPTER 59

Degenerative Diseases Primarily of Gray Matter Rose-Mary N. Boustany and Adam Zucker

This chapter groups together the seemingly disparate entities of Rett’s syndrome, Menkes’ disease, Alpers’ disease, and various forms of Batten’s disease. The first assumption is that they are neurodegenerative diseases that progress after a relatively normal period of early development. That is true for most, with the exception of Menkes’ disease, for which affected children are abnormal from birth. The second assumption is that cerebral and cerebellar cortex and deep gray structures are affected, with neuronal loss occurring in most and defective cellular function occurring in all. The third and most tenuous assumption is that the white matter or myelin is spared or only secondarily affected because of wallerian degeneration. As more is learned about the cellular pathobiology of these disorders, it has become apparent that myelin and white matter are affected in a primary way and as a result of neuronal loss or malfunction. Great strides have been made in defining the underlying genetics and molecular defects of these diseases. The next frontier is to understand function of the identified proteins and to devise intelligent, effective, and targeted therapies for these devastating disorders.

RETT’S SYNDROME Rett’s syndrome is an X-linked disease that primarily affects females. It is the second leading cause of mental retardation in females, with an incidence of 1 case per 10,000 to 22,000 females [Hagberg et al., 1985; Kozinetz et al., 1993]. All ethnicities are equally affected. The hallmarks of this syndrome are a period of normal development followed by regression of speech and development of stereotypical hand gestures. The gene that causes this syndrome is MECP2, which maps to the Xq28 locus. The MECP2 protein is thought to be necessary for the maintenance of neurons during the later stages of development and after neuronal maturation is complete. The structure and function of the MECP2 protein continue to be the focus of intense scrutiny. Although this syndrome has many severe manifestations, approximately 50% of affected individuals live into the third decade of life. Despite the advances in knowledge about the cause and defects of Rett’s syndrome during the past decade, treatment remains primarily supportive.

History Rett’s syndrome was first reported in 1966 by Dr. Andreas Rett [Rett, 1966]. This initial case report was followed in 1978 with a report of Japanese female patients with a particular pattern of symptoms, including mental retardation and stereotypical hand-wringing [Ishikawa et al., 1978]. It

was not until 1983, when Hagberg and colleagues [1983] published a case report of 35 female patients, that Rett’s syndrome gained international attention. Intense investigation of Rett’s syndrome over the past 20 years led to identification of the genetic defect in 1999 [Amir et al., 1999].

Clinical Description The diagnosis of Rett’s syndrome is based on a set of clinical observations accompanied by changes in various laboratory test results. The clinical criteria for classic Rett’s syndrome were established in the 1980s [Hagberg et al., 1985; Trevathan and Moser, 1988] and include loss of speech, seizures, mental retardation, and classic motor (specifically hand) movements. Criteria for atypical Rett’s syndrome were reported in 1993 [Hagberg and Gillberg, 1993]. More than 75% of patients have classic Rett’s syndrome, whereas 25% have atypical Rett’s syndrome variants [Hagberg, 2002]. In classic Rett’s syndrome (Table 59-1), the newborn initially appears developmentally normal. This period is followed by deceleration of head growth, loss of purposeful hand movements, development of stereotypic hand movements, and gait dyspraxia. These five criteria must be met for the diagnosis of classic Rett’s syndrome [Hagberg, 1995]. The chronology of these symptoms is critical for the diagnosis. Normal development is typical for the first 3 to 6 months of life. Deceleration in the rate of head growth occurs between 3 months and 4 years. Patients lose the ability to use their hands in a purposeful manner between 9 months and 2.5 years. Stereotypic hand movements appear between 1 and 3 years of age, and a dyspraxic gait manifests between 2 and 4 years of age if the patient is ambulatory. Clinical manifestations of classic Rett’s syndrome are grouped into four stages: early onset (3 to 6 months of age), regression (1 to 4 years of age), stabilization, and late motor impairment (after the age of 3 years) [Jellinger, 2003]. The early-onset stage is characterized by developmental delay, deceleration of head growth [Neul and Zoghbi, 2004; Schultz et al., 1993], onset of autistic-like behavior, and classic handwringing [Jellinger, 2003]. Weight and height percentiles for age also decrease; the median values fall below the fifth percentile by age 7 years [Percy, 2002]. Although Rett’s syndrome can manifest earlier, clear signs of a central nervous system abnormality are usually not evident until 6 months of age [Akbarian, 2003]. The second stage of the syndrome is characterized by cognitive decline and regression [Hagberg, 2002]. Loss of speech and purposeful hand movements, emergence of stereotypic movements, seizures, breathing irregularities, other signs of autonomic instability, inattentive behavior, and hypotonia appear [Hagberg, 2002;

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TABLE 59-1 Obligatory Criteria for the Diagnosis of Rett’s Syndrome MANIFESTATION

AGE

COMMENTS

Period of normal neonatal development Stagnation of rate of head circumference growth Loss of purposeful hand skills

0–6 mo

Prenatal or perinatal period into the first 6 months of life, sometimes longer Normal at birth, then decelerates

3 mo–4 yr

9 mo–2.5 yr

Classic stereotypic hand movements

1–3 yr

Gait or posture dyspraxia Absence of organomegaly, optic atrophy, retinal changes, or delayed intrauterine growth

2–4 yr

Communicative dysfunction, social withdrawal, mental deficiency, loss of speech or babbling Hand-washing or hand-wringing and variants, including clapping and tapping, are common. Truncal “ataxia”

Data from Hagberg B. Clinical manifestations and stages of Rett syndrome. Ment Retard Dev Disabil 2002;8:61–65, and from Percy AK. Clinical trials and treatment prospects. Ment Retard Dev Disabil 2002;8:106–111.

Jellinger, 2003; Kerr et al., 2001]. The third stage consists of stabilization of symptoms; this stage differentiates Rett’s syndrome clinically from other pediatric neurodegenerative disorders. Sometimes there is a return of communication skills, with preservation of remaining ambulatory skills. This stage is also known as the pseudostationary stage because slow neuromotor regression continues [Hagberg, 1995]. In patients older than 3 years, bradykinesia and rigidity set in [Fitzgerald et al., 1990]. Stabilization can last years to decades. Late motor impairment begins when ambulation ceases; this signals the end of the stabilization or pseudostationary stage. This final stage of Rett’s syndrome is characterized by nonambulation and severe disability. The length of late motor impairment is variable and can last decades. Common clinical manifestations of classic Rett’s syndrome include stereotypical hand movements, intense staring, breathing irregularities, bruxism, sleep disturbances and night laughter, scoliosis, lower limb spasticity and dystonia, seizures, swallowing dysfunction, constipation, gastroesophageal reflux, and small, bluish or red feet. The stereotypic hand movements occur while the individual is awake. These gestures are individualized, but they typically include continuous and repetitive twisting, wringing, knitting, and clapping motions. The intense eye communication may be compensatory for the loss of speech. This eye pointing has been observed in many individuals with Rett’s syndrome. The breathing irregularities are of two types: hyperventilation and breath-holding. Typically, they occur only while the individual is awake. Periods of apnea can last 30 to 40 seconds, and they disrupt stretches of hyperventilation. Most individuals with Rett’s syndrome experience sleep disturbances. It has also

been reported that up to 90% of young children interrupt sleep with night laughter. Although not pathognomonic, many individuals with Rett’s syndrome have early growth retardation of their feet. The nails and skin demonstrate trophic changes, and the skin is cool to touch and discolored with a blue-red color. Autonomic dysregulation may produce some of these changes. The scoliosis in Rett’s syndrome is a double-curve deformation that develops during the first decade of life. Most commonly, the double curve has a longer upper curve and a shorter lower curve. The incidence of scoliosis increases with age, occurring in 8% of preschool patients and 80% of patients older than 16 years. Abnormalities of the lower extremities in Rett’s syndrome include asymmetric distal dystonia, mild spasticity, and feet that tend to orient in a flexed and supinated position. Seizures are reported in 30% to 80% of individuals with Rett’s syndrome. The electroencephalogram (EEG) is always abnormal after the age of 2 years. Infrequent clinical manifestations of classic Rett’s syndrome include bloating, violent screaming, and abnormal nociception. Bloating or air swallowing is generally mild, but 5% to 10% of individuals with Rett’s syndrome demonstrate severe bloating. The gastrointestinal disturbances are attributed to changes within the autonomic nervous system. Screaming typically is encountered in teenage patients. The screaming may be associated with ill-defined pain, but no known pathology can be found. Occasionally, patients have abnormally prolonged responses to pain. Although a decreased life span is characteristic for this syndrome, many patients to survive into adulthood [Sekul and Percy, 1992], with 50% still alive in their 30s [Akbarian, 2003]. The three most common atypical Rett’s syndrome variants include a forme fruste variant, a preserved speech variant, and congenital Rett’s syndrome. Diagnosis of atypical Rett’s syndrome is complex. The criteria for variants of classic Rett’s syndrome as outlined by Hagberg and Skjeldal [1994] are especially helpful (Box 59-1). Forme fruste is the most common atypical variant, accounting for about 80% of nonclassic Rett’s syndrome. There is a wide variability of function in forme fruste; it is a milder variant. It is seldom diagnosed before 8 to 10 years of age, and it is usually suspected in older individuals who are just beginning to develop symptoms of Rett’s syndrome. The preserved speech variant was first described in 1992 [Zappella, 1992]. It is characterized by the preservation of speech, but preserved head size and obesity are also common features [Zappella, 1992; Zappella et al., 2001]. There is some debate about whether the preserved speech variant is part of the autistic spectrum disorders, as well as the Rett’s syndrome spectrum [Percy et al., 1990]. Congenital Rett’s syndrome is rare. It differs from classic Rett’s syndrome because of the absence of the 3- to 6-month period of normal development [Hagberg and Skjeldal, 1994].

Clinical Diagnostic Tests Routine Laboratory Tests Levels of lactate, pyruvate, and glutamate are increased in cerebrospinal fluid [Budden et al., 1990; Lappalainen et al., 1997]. Cerebrospinal fluid testing yields decreased levels of β-phenylalanine, substance P, and gangliosides [Lekman

Boustany and Zucker / Degenerative Diseases Primarily of Gray Matter

Box 59-1 DEFINING VARIANTS OF RETT’S SYNDROME Inclusion Criteria 1. A girl of at least 10 years of age with mental retardation of unexplained origin 2. And three of the six primary criteria defined below 3. And six of the eleven supportive manifestations defined below Primary Criteria 1. Partial or subtotal loss of acquired fine finger skill in late infancy or early childhood 2. Loss of acquired single words, phrases, or nuanced babble 3. Stereotypic Rett’s syndrome hand movements, with hands together or apart 4. Early deviant communicative ability 5. Deceleration in head growth of two standard deviations below the mean (even if head growth or circumference is still within normal limits) 6. Rett’s syndrome profile Stage I—early-onset stagnation Stage II—period of regression Stage III—recovery of some contact and communicative abilities after stage II. Slow neuromotor regression that lasts through school age and adolescence Stage IV—late motor deterioration. Slow neuromotor regression that lasts through school age and adolescence Supportive Manifestations 1. Breathing irregularities (e.g., hyperventilation, breath-holding) 2. Bloating or air swallowing 3. Teeth grinding 4. Gait dyspraxia 5. Neurogenic scoliosis or high kyphosis (in ambulant girls) 6. Development of abnormal lower limb neurology 7. Small, blue or cold, impaired feet; autonomic or trophic dysfunction 8. Abnormal electroencephalogram, consistent with Rett’s syndrome 9. Unprompted laughing or screaming spells 10. Impaired or delayed nociception 11. Intensive eye communication (i.e., eye pointing) et al., 1991; Matsuishi et al., 1997; Satoi et al., 2000]. There are increased levels of biogenic amines and creatine in the urine [Lekman et al., 1990]. Plasma levels of levels of β-endorphin and prolactin are decreased [Fanchetti et al., 1986]. The increased levels of lactate and pyruvate in the cerebrospinal fluid may result from hyperventilation [Budden et al., 1990], whereas the decreased levels of cerebrospinal fluid βphenylalanine are caused by dysregulation of the dopaminergic pathways in patients with Rett’s syndrome [Satoi et al., 2000].

Neurophysiologic Tests The EEG is abnormal in Rett’s syndrome. Initial abnormalities are noticed in the rapid eye movement stage of

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sleep [Kudo et al., 2003]. During the stabilization stage of Rett’s syndrome, a slow spike-wave pattern resembling that in Lennox-Gastaut syndrome is observed [Glaze, 1987]. After 3 years of age, there is a decrease in alpha activity with a subsequent increase in theta activity [Bashina et al., 1994]. There is a prolongation of somatosensory-evoked responses in older patients, suggesting involvement of the upper spinal cord and spinothalamic tracts [Bader et al., 1989]. Results of nerve conduction studies are consistent with an axonopathy and denervation indicative of lower motor dysfunction [Jellinger et al., 1990].

Neuroimaging Studies Initial cranial computed tomographic (CT) scans and magnetic resonance imaging (MRI) are normal. As the patient ages and neurologic symptoms develop, generalized atrophy of the cerebral hemispheres and decreased volume of the caudate nucleus become apparent [Reiss et al., 1993]. Imaging of the basal ganglia reveals decreased volume of the caudate head [Dunn et al., 2002]. Commonly, there is a decrease in gray and white matter volumes, specifically within the frontal and temporal regions of the midbrain and cerebellum [Subramaniam et al., 1997]. Hypoperfusion of the prefrontal and temporoparietal regions is also reported [Lappalainen et al., 1997]. Although imaging studies can help in making the diagnosis, there is no correlation between spectroscopic changes and clinical status [Gokcay et al., 2002]. One study reported an association between the level of hypoperfusion and early-onset Rett’s syndrome [Lappalainen et al., 1997].

Pathology Brain Gross findings include generalized atrophy of the frontal and temporal regions, the cerebellum, and especially the vermis. The corpus callosum decreases in size by as much as 30% [Oldfors et al., 1990; Reiss et al., 1993]. The brain is the only organ that is decreased in size compared with height [Armstrong et al., 1999]. Cerebellar volume is reported to remain relatively normal. The average weight of a brain from a patient with Rett’s syndrome is about 950 grams, equivalent to the weight of a brain from a developmentally normal 1-year-old child [Armstrong, 2000]. More importantly, the brain weight does not continue to decrease with age, because Rett’s syndrome is not a progressive neurodevelopmental disorder in the classic sense. There are many microscopic findings in the brain tissue from Rett’s syndrome patients. Neuronal size is decreased, but cell density in the cerebral cortex, thalamus, basal ganglia, amygdala, and hippocampus is increased [Bauman et al., 1995]. The previous findings contrast with a report of an overall decrease in the number of neurons in the frontal cortex, the temporal cortex, and the cholinergic nucleus basalis of Meynert [Belichenko et al., 1994; Kitt and Wilcox, 1995]. Decreases in dendritic branching and dendritic number are found in the frontal, motor, and subicular areas [Armstrong, 1997; Armstrong et al., 1995; Cornford, 1994]. In addition to decreases in dendritic number and branches, shortening of the apical and basilar dendritic branches within these same regions of the brain has been

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reported [Armstrong et al., 1998]. Afferent neurons have decreased synaptic contacts. The striatum and internal pallidum exhibit hypochromia, whereas hypomyelination is observed in the substantia nigra pars compacta [Jellinger et al., 1988]. The neocortex has decreased expression of microtubule-associated protein 2, and disruption of the cytoskeleton within the neocortex is apparent [Kaufmann et al., 1995]. The caudate nucleus and putamen exhibit reduced levels of dopamine transporter protein [Wong et al., 1998]. There are conflicting results regarding the expression of nerve growth factor in Rett’s syndrome patients. One study documented no reduction in the cortical levels of nerve growth factor [Wenk and Hauss-Wgrzyniak, 1999], and others demonstrated large decreases in the expression of nerve growth factor and the neurotrophic tyrosine kinase type receptor, which binds to nerve growth factor with high affinity [Lipani et al., 2000]. Adults with Rett’s syndrome also have axonal degeneration, loss of motor neurons, loss of spinal ganglion cells, and decreased glutamate and γaminobutyric acid type B (GABAB) receptor density [Oldfors et al., 1988; Blue et al., 1999]. Blue and colleagues [1999] reported age-specific alterations in amino acid neurotransmitter receptors within the basal ganglia of adults. Electron microscopy of neurons depicts distinct abnormalities [Papadimitriou et al., 1988]. These changes include abnormal neurites that are filled with lysosomes and laminate bodies. Axonal swellings, large mitochondria, and membranous multilamellar bodies are seen. Although electron microscopy reveals intraneuronal inclusion bodies that contain lipofuscin-like material, there are no other characteristics of a lipid storage disorder.

Muscle Type I and type II fiber atrophy are sometimes seen on muscle biopsy [Wakia et al., 1990]. Decreased cytochrome c oxidase and succinate cytochrome c reductase activities in muscle biopsies have also been reported [Coker and Melnyk, 1991]. The myocardium has no gross abnormalities. The atrioventricular node has an abnormal or immature rearrangement of muscle fibers within the conduction system [Armstrong, 1997]. Electron microscopy of muscle biopsy specimens reveals dumbbell-shaped mitochondria with foamy vacuoles [Ruch et al., 1989].

Genetics Rett’s syndrome is an X-linked dominant disorder that has been mapped to the Xq28 locus [Ellison et al., 1992; Sirianni et al., 1998]. Although most cases of Rett’s syndrome are sporadic, genetic mapping was possible because familial inheritance does occur, and there is concordance in monozygotic twins [Jellinger, 2003]. Mutations within the methyl-CpG-binding protein 2 gene (MECP2) cause 70% to 80% of reported cases of Rett’s syndrome in females [Auranen et al., 2001; Van den Veyver and Zoghbi, 2002]. This gene was identified in 1999 [Amir et al., 1999]. Most mutations in males lead to fetal demise. Although DNA mitochondrial mutations are found in some cases of Rett’s syndrome, there is no indication that mitochondrial DNA

plays a part in the development of this syndrome [Nielson et al., 1993; Colantuoni et al., 2001]. Mutations within MECP2 have also been linked to childhood-onset schizophrenia, Angelman’s syndrome, and mild mental retardation [Watson et al., 2001]. The MECP2 protein has three known functional domains: an amino-terminal methyl-CpG-binding domain [Lewis et al., 1992], a transcriptional repressor domain, and a carboxyl-terminal domain [Chandler et al., 1999]. The MECP2 protein binds to methylated CpG dinucleotides by the methyl-CpG-binding domain [Nan et al., 1993]. The transcriptional repressor domain interacts with various corepressor complexes and disrupts transcription [Nan et al., 1996, 1997]. The nuclear localization signal (NLS), consisting of amino acid residues 265-271, is contained within the transcriptional repressor domain. The biochemical function of the carboxyl-terminal region is unknown [Kriaucionis and Bird, 2003]. Seventy percent of the mutations within MECP2 are in eight hotspots affecting translation of the following amino acids: R106, R133, T158, R168, R255, R270, R294, and R306. Seven of these eight mutation hotspots affect arginine, which contains a CpG in its codon. These mutations may result from unrepaired deamination of 5-methylcytosine. This mechanism is thought to cause one third of all point mutations that lead to human genetic disease [Cooper and Youssoufian, 1988]. Eighty percent of females with classic Rett’s syndrome have nonsense or frameshift mutations within the MECP2 gene [Van den Veyver and Zoghbi, 2002].

Genotype-Phenotype Correlation Genotype-phenotype correlation has been attempted, but it is complicated by MECP2 gene X-chromosome inactivation. This inactivity allows a mother with a mutation of MECP2 to have a normal phenotype because of skewing of X-chromosome inactivation. If this mother has a daughter with the mutation of MECP2 but balanced X-chromosome inactivation, the daughter will have Rett’s syndrome [Amir et al., 2000]. Despite the problems with X-chromosome inactivation, many studies of genotype-phenotype correlations exist. It is reported that truncated mutations of MECP2 are more severe than missense mutations [Chae et al., 2002; Cheadle et al., 2000; Monros et al., 2001]. The location of the truncation generally does not affect the phenotype [Bienvenu et al., 2000; Giunti et al., 2001; Huppke et al., 2000; Satoi et al., 2000]. Amir and coworkers [2002] reported that truncation mutations led to increased levels of homovanillic acid in cerebrospinal fluid and to increased respiratory problems. The same study reported an increased incidence of scoliosis in cases of missense mutations. Huppke and colleagues [2002] examined mutations from 123 patients with Rett’s syndrome. They determined that mutations affecting the NLS caused the most severe phenotype. They also reported that deletions within the carboxyl terminus caused the least severe clinical presentation. Truncations result in more severe disease than missense mutations, except when the truncation affects the carboxyl terminus. Single–amino acid mutations cause less severe phenotypes, presumably because they lead to mild impairment of protein function [Laccone et al., 2002].

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Rett’s Syndrome Variants Most of the mutations within MECP2 cause classic Rett’s syndrome. Twenty-nine cases of the preserved speech variant of Rett’s syndrome have mutations within the MECP2 gene [Conforti et al., 2003; Hoffbuhr et al., 2001; Huppke et al., 2000; Neul and Zoghbi, 2004; Nielsen et al., 2001; Obata et al., 2000; Weaving et al., 2003; Yamashita et al., 2001; Zappella et al., 2001]. These mutations were evenly distributed among the three known functional domains of the MECP2 gene—the methyl-CpG-binding domain, the transcriptional repressor domain, and the carboxyl-terminal domain. Mutations resulting in less severe phenotypes (i.e., mutations within the carboxyl terminus or a truncation after the NLS motif) were common in patients with the preserved speech variant of Rett’s syndrome. Patients with the preserved speech variant who had mutations normally associated with severe disease had skewed X-chromosome inactivation (92:8 in one case), explaining the less severe phenotypes [Hoffbuhr et al., 2001; Zappella et al., 2001].

MECP2 Mutations in Males Three outcomes occur in males: Rett’s syndrome, severe encephalopathy with neonatal fatality, and mild neuropsychiatric phenotypes [Geerdink et al., 2002; Villard et al., 2000; Wan et al., 1999; Zeev et al., 2002]. The classic form of Rett’s syndrome can occur in males [Jan et al., 1999]. Although similar mutations are seen in males and females with this disease, there is a report of a unique mutation within MECP2 that causes Rett’s syndrome in males [Ravn et al., 2003]. Male siblings of female Rett’s syndrome patients with identical MECP2 mutations develop a severe encephalopathy and die by 1 to 2 years of age. These mutations typically affect the methyl-CpG-binding domain or the NLS portion of the MECP2 protein. Rett’s syndrome is produced as a result of somatic mosaicism, meaning there is a mixed population of cells with the wild type of MECP2 and mutated MECP2 [Armstrong et al., 2001; Clayton-Smith et al., 2000; Topcu et al., 2002a]. Males with Rett’s syndrome have a unique genetic composition. Klinefelter’s syndrome (46,XXY) allows phenotypic males to replicate the somatic mosaicism achieved by females and avoid neonatal fatality [Leonard et al., 2003; Schwartzman et al., 2001]. There are case reports of Rett’s syndrome occurring in a phenotypic male, in whom the SRY region of the Y chromosome that produces “maleness” is translocated onto an X chromosome, so that a phenotypic male is genotypically a female (46,XX) [Maiwald et al., 2002]. Mutations in the MECP2 gene also occur in males with mental retardation and no other symptoms of Rett’s syndrome. These mutations generally affect the carboxyl terminus of the methyl-CpG-binding domain region of the MECP2 protein [Couvert et al., 2001; Kleefstra et al., 2002; Yntema et al., 2002a]. Whether these mutations contribute to the phenotypes observed, or are normal polymorphisms is being explored [Laccone et al., 2002; Yntema et al., 2002b].

Cell Biology Because Rett’s syndrome is caused primarily by mutations within the MECP2 gene, it is necessary to understand

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the function and interactions of the MECP2 protein. The MECP2 gene encodes a protein with three known functional domains: the methyl-CpG-binding domain, the transcriptional repressor domain, and the carboxyl terminus. Human MECP2 has 48 amino acids (about 80 kDa) [Akbarian, 2003]. The methyl-CpG-binding domain contains 85 amino acids [Nan et al., 1993] and binds to single- and double-methylated CpG dinucleotides [Bird and Wolfe, 1999; Lewis et al., 1992]. There is a correlation between the capability of the methylCpG-binding domain to bind to pericentromeric heterochromatic regions of DNA and the ability of the protein to repress methylated promoters [Kudo et al., 2003]. Residues R111, R133C, and R134C within the methyl-CpG-binding domain are thought to come into contact with methylated cystines. Mutations affecting R111 cause the MECP2 protein to lose its binding ability to heterochromatic DNA and its capability to repress transcription. Mutations resulting in R133C or R134C affect neither of the aforementioned protein properties. The MECP2 protein associates with chromatin remodeling complexes and aids in the regulation of the structure and function of chromatin. The transcriptional repressor domain is 100 base pairs (bp) long, and it interacts with various corepressor complexes [Nan et al., 1997]. One of these complexes is the Sin3A corepressor complex. This complex contains histone deacetylases 1 and 2, which remove acetyl groups from histones and create a compressed form of chromatin that then inhibits or represses gene expression [Nan et al., 1998]. The action of the transcriptional repressor domain is partially reversed by trichostatin A, a histone deacetylase inhibitor. This finding suggests that repression by means of the transcriptional repressor domain is caused by histone deacetylation. MECP2 recruits these histone deacetylases and other chromatin remodeling complexes to methylated CpG dinucleotides. This leads to chromatin condensation that interferes with the binding of transcription complexes [Akbarian, 2003]. The transcriptional repressor domain has also been seen to bind to TFIIB (also designated GTF2B), SKI (a proto-oncogene), DNMT1 (which codes for a DNA methyltransferase), and SUV39H1 (which codes for a histone methyltransferase), although the importance of these interactions is unknown [Fuks et al., 2003; Kaludov and Wolffe, 2000; Kimura and Shiota, 2003]. Repression can be mediated in other ways, because the MECP2 protein binds to general transcription factors and interferes with the binding of transcription complexes. The transcriptional repressor domain is able to repress transcription when bound as far as 2000 bp from the transcription initiation site. The carboxyl terminus is thought to be involved in the binding of MECP2 to naked and nucleosomal DNA. Specifically, the carboxylterminal region of the MECP2 protein binds to DNA that is coiled around histone octamers [Chandler et al., 1999]. The MECP2 protein is mostly located within the nucleus of cells, and a small portion is seen within the perikarya [Kaufmann et al., 1995]. Although MECP2 binds throughout chromosomes, binding is most dense around pericentromeric heterochromatic regions of DNA. Forty percent of methyl-CpGs (i.e., binding sites for the methyl-CpGbinding domain) are found within pericentromeric heterochromatic DNA. The immunoreactivity of MECP2 is increased around centromeric and perinucleolar heterochromatin. MECP2 does not associate with ribosomal DNA,

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despite its many methylations. MECP2 distribution is regulated by unknown factors and does not simply distribute to where methylated CpGs are found. The MECP2 protein is thought to play a role in the maintenance of neuronal nuclei in the later stages of development and within the mature brain [Akbarian, 2003]. It is hypothesized that MECP2 makes chromatin more stable and less accessible to transcription factors by anchoring chromatin fibers into the nuclear matrix. There are reduced levels of dopamine, serotonin, and their metabolites homovanillic acid and 5-hydroxy-indole acetic acid in Rett’s syndrome [Lekman et al., 1990]. Some researchers have noticed a decreased density of postsynaptic D2 receptors in older patients with Rett’s syndrome [Dunn, 2001], whereas others describe increased specific binding at D2 receptors. The latter finding implies that the decreased levels of dopamine are causing increased levels or density of postsynaptic receptors [Chiron et al., 1993; Dunn et al., 2002]. The D1 receptor density is unchanged [Wenk, 1995]. Jellinger and associates [1990] proposed that the different densities of postsynaptic receptors within the dopaminergic pathways might be age specific. Increased choline concentrations and decreased choline acetyltransferase levels are thought to result from problems within the cholinergic system in the forebrain [Gokcay et al., 2002]. The frontal cortex and striatum have decreased levels of ferritin [Sofic et al., 1987]. Decreased levels of binding protein for the benzodiazepine receptor in the frontotemporal, parietal, and occipital regions of the brain also have been reported [Yamashita et al., 1998].

Animal Models In a model of MECP2-null mice, males and females were affected. Homozygous female mice and heterozygous male mice were developmentally normal for the first several weeks of life, but they died soon after neurologic symptoms appeared [Chen et al., 2001; Guy et al., 2001]. This model replicates the genetic component of Rett’s syndrome, but it was difficult to study because of the rapid deterioration and early death of the animals after symptoms appeared. Shahbazian and co-workers [2002b] developed a mouse model that has a truncation mutation within the MECP2 gene with a less severe phenotype than the MECP2-null mice. The truncated protein mimics a commonly observed human mutation, and it is partially functional, containing the methyl-CpG-binding domain and transcriptional repressor domain. This group observed that the mice appeared developmentally normal up to 6 weeks after birth. After this period of normal development, the mice developed neurologic symptoms, including tremors, motor impairment, hypoactivity, seizures, kyphosis, and the classic forearm movements associated with human Rett’s syndrome [Shahbazian et al., 2002b]. Random X inactivation causes a variety of phenotypes due to a single genotype in females, which makes analysis of the mouse model difficult [Young and Zoghbi, 2004]. One solution is to use male mice, because they are not subject to random X inactivation. Luikenhuis and colleagues [2004] overexpressed MECP2 in postmitotic neurons of homozygous MECP2-null mice. These mice did not display any neurologic symptoms, and they were developmentally equivalent to the control popu-

lation. In normal mice, MECP2-encoded RNA is not expressed until about 10 days after conception, and it reaches adult levels by 16 days after conception. It has been postulated that the defect in Rett’s syndrome involves neuronal maintenance and maturation and therefore affects developmental stability.

Pathogenesis The timeline of MECP2 expression suggests that it is needed in the later phase of cortical development in neonates and after maturation in adults. MECP2 is expressed in normal fetal brains until 20 weeks’ gestation, after which it disappears from the cerebellum. It disappears from the brainstem after the perinatal period. MECP2 does not reappear in the brain until after adolescence. Lack of MECP2 during any of these developmental periods may lead to synaptic and neuronal dysfunction of the catecholaminergic neurons in patients with Rett’s syndrome [Itoh and Takashima, 2002]. Mice with MECP2 overexpressed in postmitotic neurons are rescued from the Rett’s syndrome phenotype. A decrease in MECP2 in postmitotic neurons during the later stages of development is sufficient to cause Rett’s syndrome [Chen et al., 2001], but MECP2 deficiency in neuronal precursors is probably not a major contributor to the pathogenesis in Rett’s syndrome. MECP2 causes transcriptional repression, and loss of function of this protein may cause an imbalance between transcription and gene silencing, leading to dysregulated gene expression and pathologic changes. Some groups have found no evidence for MECP2 transcriptional repression in neurons or glia. Gene expression studies found an increase in glial transcription, in contrast to the predicted decrease. Levels of presynaptic proteins, however, were decreased. MECP2 may be causing perturbations within the presynaptic signal transduction pathway [Colantuoni et al., 2001]. The critics of this theory point out that these studies were performed on postmortem brains, suggesting that relevant time points in gene expression may have been missed. Additional evidence argues against MECP2 deficiency unsilencing transcription and causing Rett’s syndrome. Affymetrix GeneChip analysis of MECP2-deficient human fibroblasts did not demonstrate any large-scale dysregulation of gene expression. There were only small differences in gene expression in presymptomatic, early symptomatic, and late symptomatic MECP2-deficient mouse brains [Tudor et al., 2002]. If MECP2 does not act as a transcriptional repressor, it may play a maintenance role during development. MECP2encoded mRNA is undetectable in the mouse forebrain during mid-gestation [Coy et al., 1999]. Immunohistochemical studies in nonhuman primates and mice demonstrate MECP2 expression in neuronal nuclei correlates with neuronal maturity, and levels of expression are highest in the adult cerebral cortex [Akbarian et al., 2001]. In human cerebral cortex, MECP2 is seen only in Cajal-Retzius cells, the earliest maturing neurons [Marin-Padilla, 1998], at 14 weeks’ gestation. At 26 weeks’ gestation, MECP2-immunoreactive neurons are seen in the deeper, more differentiated cortical layers. MECP2 neuronal immunoreactivity increases with age. Only about 10% of cells are immunoreactive during the third trimester of pregnancy, but approximately

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80% of neurons demonstrate immunoreactivity for MECP2 at 10 years of age [Shahbazian et al., 2002a]. These findings are also seen in rodents and nonhuman primates. The observation that MECP2 expression is decreased in immature neurons and elevated in mature neurons suggests a role for MECP2 in neuronal maintenance. MECP2 expression studies show high levels of the protein in mature neurons but not in glia or astrocytes. MECP2 may also play a role in cell division. Removing pericentromeric heterochromatin or disrupting heterochromatin silencing by inhibition of histone deacetylases in Drosophila and yeast reduced chromosome transmission during cell division [Henikoff, 2001]. Because MECP2 associates with pericentromeric heterochromatin, it may influence cell division.

Treatment Rett’s syndrome has no cure. The treatments available have been empirically derived and are designed to combat specific symptoms. Antiepileptic agents include carbamazepine, valproic acid, and lamotrigine. The use of L-dopa and dopamine agonists to increase motor ability in Rett’s syndrome patients is controversial. [Zappella, 1990]. The breathing irregularities associated with Rett’s syndrome can be treated with naltrexone, an opiate antagonist. Naltrexone (1 to 3 mg/kg/day) can reduce disorganized breathing and increases oxygen saturation levels [Percy, 2002]. Use of high-fat, high-calorie diets is recommended in the late stages of the disease, and it has been suggested that individuals with Rett’s syndrome require a higher protein intake [Motil et al., 1999]. Feeding by means of a gastrostomy tube is sometimes indicated [Jellinger, 2003]. Constipation in Rett’s syndrome has been managed with high-fiber foods, enemas, mineral oils, milk of magnesia, and polyethylene glycol or MiraLax, with various degrees of success. Orthopedists and physical therapists routinely see individuals with Rett’s syndrome. The goals are to improve balance, enhance flexibility, and strengthen atrophying muscles. Bracing for scoliosis is necessary when a 25-degree curvature exists, and surgery is advised when the curvature exceeds 40 degrees. Speech and occupational therapy are occasionally used to improve communication. Small-scale clinical trials using L-carnitine and the ketogenic diet have been completed. L-Carnitine has been reported to improve the respiratory features of Rett’s syndrome [Ellaway et al., 2001], and the ketogenic diet may reduce seizure frequency during the first 3 months, but no long-term clinical trials have been reported.

MENKES’ DISEASE Menkes’ disease is an X-linked disorder caused by mutations in the ATP7A gene. The protein it encodes is necessary for absorption of copper from the intestinal epithelium and for transport of copper across the blood-brain barrier. The reported incidence is 1 case per 100,000 to 300,000 persons. Menkes’ disease has three variants: classic disease, mild disease, and occipital horn syndrome. In classic disease, a 2to 3-month period of normal development is followed by severe neurologic regression characterized by seizures,

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hypotonia, visual impairment, and failure to thrive. Death ensues by 4 years of age. Kinky, coarse, and lightly pigmented hair is pathognomonic for this disease, although many other phenotypic features may be observed. Connective tissue disorders are common in all three variants because of dysfunction of the cupric enzyme lysyl oxidase. Two biochemical markers, decreased serum copper and ceruplasmin, in conjunction with clinical manifestations aid in the diagnosis. The only available treatment is replacement therapy using copper histidine. Early intervention is essential for the therapy to be neuroprotective.

History The story of the discovery of Menkes’ disease begins in 1930s, when veterinary physicians in Australia noticed the importance of copper for the normal development of sheep [Bennetts and Chapman, 1937]. They observed that mothers that grazed in copper-deficient pastures had offspring with cerebral demyelination, ataxia, and porencephaly. They concluded that copper deficiency in sheep was associated with ataxia and a demyelinating disease. The disease was described in 1962 by John Menkes [Menkes et al., 1962]. He described five males of English-Irish heritage who had peculiar hair, failure to thrive, and a neurodegenerative disorder. The syndrome was initially called Menkes’ kinky hair syndrome in reference to the peculiar hair that was unique to these patients. The basis for Menkes’ disease was not known until the association was made with the illness in sheep [Danks et al., 1972, 1973]. The distinctive hair found in the copper-deficient sheep and in patients provided the necessary link. Serum testing revealed that patients who had this distinctive hair also had decreased serum copper and ceruplasmin levels. Danks and colleagues [1972, 1973] then concluded that Menkes’ disease was a human example of a neurodevelopmental disorder caused by copper deficiency. In 1993, three groups used positional cloning to discover the ATP7A gene [Chelly et al., 1993; Mercer et al., 1993].

Clinical Description Menkes’ disease typically occurs in males and has an incidence of 1 case per 100,000 to 300,000 people [Kaler, 1994]. Menkes’ disease has three clinical variants: classic Menkes’ disease, mild Menkes’ disease, and occipital horn syndrome, also known as X-linked cutis laxa [Danks, 1995]. In classic Menkes’ disease, there is a period of normal development that typically lasts for 2 to 3 months [Kaler, 1994]. Developmental regression follows with seizures, hypotonia, and failure to thrive [Kaler, 1998]. Patients exhibit severe mental retardation with symptoms of neurodegeneration [Mercer, 1998]. Most individuals with classic Menkes’ disease die between the ages of 7 months and 4 years [Bankier, 1995]. Occipital horn syndrome is characterized by a less severe genetic mutation that results in a connective tissue disorder. The characteristic findings in classic Menkes’ disease are related to the patient’s hair. Commonly described as steelwoolish, the hair on the scalp and eyebrows is short, sparse, coarse, and twisted. The amount of hair is decreased, and it is generally shorter on the sides of the head. Color is often light, with white, silver, and gray being common. Light

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microscopy of hair reveals three characteristic findings [Kaler, 1998; Moore and Howell, 1985]: 1. Pili torti is a 180-degree twisting of the hair shaft that is pathognomonic for Menkes’ disease. 2. Trichoclasis is a transverse fracture of the hair shaft. 3. Trichoptilosis is longitudinal splitting of the hair shaft. Hypopigmentation is common but not the rule, and it is caused by a deficiency of catechol oxidase. Patients typically have large jowls, sagging cheeks, large ears, and a high-arched palate. The skin appears loose at the nape of the neck, in the axillae, and on the trunk. Delayed tooth eruption and pectus excavatum are common, and the incidence of umbilical hernias is increased. Classic Menkes’ disease has several distinctive neurologic findings. These patients exhibit truncal hypotonia with poor head control, hyperactive deep tendon reflexes, impaired visual fixation or tracking, and cortical adducted thumbs. There is increased appendicular tone, and asymmetric growth failure that appears shortly after neurodegeneration begins. EEGs are moderately or severely abnormal, and hypsarrhythmia occurs frequently [Venta-Sobero et al., 2004]. Ophthalmologic findings common in Menkes’ disease include myopia, strabismus, and problems with visual fixation and tracking. Connective tissue disorders are common in the three variants. Pelvic ultrasound and cystograms reveal diverticula of the urinary bladder [Daly and Rabinovitch, 1981; Harke et al., 1977]. Skull and skeletal radiographs are notable for wormian bones in the skull, metaphyseal spurring of the long bones, and anterior flaring or multiple fractures of the ribs [Adams et al., 1974; Capesius et al., 1977; Koslowski and McCrossin, 1979; Stanley et al., 1976]. MRI demonstrates white matter changes and impaired myelination, cerebral blood vessel tortuosity, ventriculomegaly, and diffuse cerebral atrophy [Faerber et al., 1989; Johnsen et al., 1991]. Patients with occipital horn syndrome have hyperelastic skin and may develop other connective tissue disorders, including aortic aneurysms, hernias, bladder diverticula, and skeletal abnormalities, which most likely result from lysyl oxidase deficiency. These individuals also have mild mental retardation and autonomic dysfunction that manifests as syncope, hypothermia, and diarrhea [Byers et al., 1980]. The severity of mild Menkes’ disease falls between that in the classic form and the much milder occipital horn syndrome [Procopis et al., 1981]. It is important for patients with milder variations of Menkes’ disease to have frequent vision examinations because ophthalmologic problems can greatly impair functioning of affected individuals.

Clinical and Biochemical Diagnoses The clinical diagnosis of Menkes’ disease is supported by specific laboratory findings [Poulsen et al., 2002]. Early diagnosis of affected newborns is necessary for the institution of appropriate therapy and survival. A high index of suspicion based on clinical grounds is essential because supportive laboratory findings may be problematic in the first few months of life. Initially, few or no neurologic manifestations occur [Gunn et al., 1984]. Kinky hair with light hair pigmentation

is most suggestive of Menkes’ disease. The pili torti pathognomonic for Menkes’ disease are usually seen only in older patients. The diagnosis should be considered for a neonate born after premature labor and delivery with large cephalohematomas, unexplained hypothermia or hypoglycemia, jaundice requiring phototherapy, pectus excavatum, and inguinal or umbilical hernias [Kaler, 1998]. The classic biochemical markers of Menkes’ disease are low serum levels of copper and ceruplasmin. Decreased intestinal copper absorption leads to low levels of copper in the plasma, liver, and brain. In contrast, copper stores are increased in the duodenum, kidney, spleen, pancreas, and skeletal muscle [Heydorn et al., 1975; Horn, 1984; Williams and Atkins, 1981]. Early laboratory diagnosis of neonates is complicated by the fact that copper and ceruloplasmin concentrations are normally low in healthy newborns, and these values can overlap with those typically found for older patients with Menkes’ disease [Lockitch et al., 1986, 1988]. Copper egress assay in cultured fibroblasts is the definitive diagnostic study at this age, but the test is lengthy and requires several weeks of cell culture. Rapid diagnosis of Menkes’ disease can be achieved by measurement of plasma catecholamines or polymerase chain reaction (PCR) detection of known deletions or point mutations in the ATP7A gene. The copper deficiency in Menkes’ disease affects the function of many enzymes requiring copper. Dopamine monooxygenase is one of the cuproenzymes that is dysfunctional in Menkes’ disease, resulting in abnormal plasma catechol concentrations in newborns and fetuses [Kaler et al., 1993a, 1993b, 1993c]. The plasma catecholamine profile is considered to be the most rapid and reliable way to diagnose Menkes’ disease during the neonatal period. PCR methods are helpful in the diagnosis of partial deletions and point mutations when they are already identified for a specific family. The DNA-based technologies used for screening ATP7A for point mutations are chemical cleavage mismatch detection [Das et al., 1994], single-strand conformational polymorphism analysis [Tumer et al., 1997], and dideoxy fingerprinting [Moller et al., 2000]. PCR-based methods for screening ATP7A for large partial deletions include multiplex PCR, genomic PCR, and reverse transcriptase PCR [Poulsen et al., 2002]. These PCR methods are useful in neonatal and prenatal diagnosis, and they are helpful for carrier screening. Prenatal diagnosis and identification of carrier status are important for families that are at risk for Menkes’ disease. Assays looking for increased levels of copper in cultured fibroblasts also can be used for prenatal diagnosis and for testing of potential carriers [Goka et al., 1976; Poulsen et al., 2002; Tumer et al., 2003], but random X inactivation renders carrier testing using this technique uninformative when negative. The only definitive tests that can exclude this disease are DNA-based assays. An important component of all variants of Menkes’ disease is connective tissue involvement. Deoxypyridinoline is a cross-linking residue of type I collagen and is a good marker for lysyl oxidase activity, the cuproenzyme deficiency that is responsible for the connective tissue disorders observed in these patients. Deoxypyridinoline has been proposed as a marker for the presence of connective tissue disorders associated with Menkes’ disease [Kodama et al., 2003].

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Genetics Menkes’ disease is an X-linked disease, and one third of cases are thought to represent new mutations [Haldane, 1935]. The gene responsible for Menkes’ disease, ATP7A, was discovered in 1993 [Chelly et al., 1993; Mercer et al., 1993; Vulpe et al., 1993]. The gene encodes the copper transporting ATPase known as ATP7A [Mercer, 1998]. ATP7A is part of a highly conserved family of cation transporting ATPase proteins [Odermatt et al., 1993; Pederson and Carafoli, 1987]. This protein family includes the protein WD that is defective in Wilson’s disease. The ATP7A gene (formerly known as MNK) is located at Xq13.2-q13.3 [Tumer et al., 2003]. It has 23 exons and is about 140 kb long [Dierick et al., 1995]. ATP7A is 8.5 kDa. Occipital horn syndrome results from point mutations (75%), chromosomal rearrangements (about 1%), and large or partial deletions (about 15%) in the ATP7A gene [Liu et al., 1999; Tumer et al., 1999]. Severe classic Menkes’ disease RNA contains low levels of active ATP7A mRNA, whereas mild variants of Menkes’ disease have higher levels of active ATP7A mRNA. Occipital horn syndrome has 20% to 35% residual ATP7A mRNA in cultured cells, whereas classic Menkes’ disease has lower levels of mRNA in the cells [Kaler, 1994, 1998]. Decreased mRNA levels result from premature stop codons, missense mutations, frame shifts, and other deletions or mutations that affect RNA splicing [Das et al., 1995]. Patients with the identical deletion or mutation may have different clinical outcomes [Tumer et al., 2003]. This finding suggests that other modifying genes or proteins must play a role in the pathogenesis of this disease. Alternatively, other pathways for copper transport may exist at the cellular level. Alternate splice products of ATP7A exist. One of the splice variants lacks exon 10, but the product is in-frame. This exon encodes transmembrane domains 3 and 4. This protein may act as a copper transporter, but it may not be able to function as a copper-transporting ATPase. It is also possible that alternate exons exist within intronic sequences.

Biochemistry The genetic mutation of the ATP7A gene leads to problems with copper transport within the body. Normally, ATP7A allows efflux of copper from gut epithelium into the portal circulation, transport of copper across the blood-brain barrier, and transfer of copper that is reabsorbed by the kidney back into circulation. ATP7A protein deficiency results in an inability of the body to absorb copper from the gastrointestinal tract in amounts required to satisfy nutritional needs, as well as in impaired use and handling of the copper that is absorbed from the intestine. Copper is mobilized from the cytoplasm of cells so that it can be incorporated into secretory pathways [Tumer et al., 2003]. The mutation of a copper-transporting ATPase causes impaired cellular copper efflux, leading to increased intracellular copper concentrations. Patients with Menkes’ disease have high concentrations of copper in gut epithelial cells, and they absorb little copper from their diet. Copper accumulates in kidney tubules. At high levels, copper causes lipid peroxidation, protein cleavage, enzyme inhibition, and DNA damage. Normally, basal intracellular stores are maintained at low

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levels [Rae et al., 1999; Voskoboinik and Camakaris 2002]. The disease is caused by a decreased amount of the ATP7A protein, or it can result from alterations to the protein that impair its ability to transport copper. ATP7A has six to eight transmembrane domains, and it transports Cu2+ ions using energy from ATP hydrolysis [Vulpe et al., 1993]. The protein has several known motifs or domains within it, such as the ATP binding domain. The phosphorylation motif (DKTG) contains an aspartic acid that becomes phosphorylated during the protein’s cycle (present in all P-type ATPases). The cation transduction motif (CPC) features a conserved proline, which plays a role in the conformation changes that occur with cation transport [Silver et al., 1989]. There are six metal binding sites (MBSs) in the amino-terminal region of ATP7A. The consensus sequence of the MBS is GMxCxxC. Although human ATP7A has six different forms of MBSs, microbial cells show that only one or two are necessary for a functional protein [Odermatt et al., 1993; Solioz et al., 1994]. Human ATP7A does not need a MBSs, demonstrated by the fact that mutations in all six MBSs do not stop ATP7A from functioning [Forbes et al., 1999; Payne and Gitlin, 1998; Tsivkovskii et al., 2002]. The MBS may act as a sensor for intracellular copper levels, and it may play a regulatory role when concentrations are low [Goodyer et al., 1999; Strausak et al., 1999; Voskoboinik and Camakaris 2002]. ATP7A also features a magnesium binding motif (TGE), the “hinge” domain of the protein, and a phosphatase motif (DKTG). ATP7A-encoded mRNA is found is most cell types, but it is missing in liver. ATP7B, the protein mutated in Wilson’s disease (Table 59-2), transports copper in the liver [Vulpe et al., 1993; Paynter et al., 1994]. ATP7A and ATP7B are members of the P-type ATPases group IB family, as are bacterial heavy metal transporters [Tsivkovskii et al., 2002; Voskoboinik et al., 2001]. ATP7A has been localized to the trans-Golgi compartment under basal conditions [Petris et al., 1996]. This is consistent with the ability of ATP7A to supply cuproenzymes (i.e., lysyl oxidase) that are in secretory pathways. There is continuous recycling of ATP7A between the plasma membrane and the trans-Golgi compartment [Petris and Mercer, 1999]. ATP7A traffics to the plasma membrane with increased extracellular copper concentrations and is endocytosed back to the trans-Golgi compartment after extracellular levels decrease to normal. Copper-dependent vesicular trafficking moves ATP7A from the plasma membrane to the trans-Golgi network and back. Lower organisms have two copper ATPases, but this is unnecessary in humans because ATP7A traffics between the two areas where such ATPases are needed [Yuan et al., 1997]. Cu(I) may be the type of copper used by ATP7A as its substrate. It is unknown whether Cu(I) becomes Cu(II) before or after it is released in the Golgi lumen. Menkes’ disease is caused by mutations that result in a substitution of highly conserved amino acids or those in highly conserved motifs. Any mutation that affects the structure and function of the ATP7A gene will lead to disease [Guy et al., 2001]. Mutations that induce Menkes’ disease include those that abolish the Mg2+ binding domain [Seidel et al., 2001] and those that change the cation transduction motif. Classic Menkes’ disease is usually caused by a premature truncation, typically occurring before the first

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TABLE 59-2 Comparison of Menkes’ Disease and Wilson’s Disease CHARACTERISTIC

MENKES’ DISEASE

WILSON’S DISEASE

Inheritance pattern

X-linked recessive

Location Incidence Clinical manifestations

Autosomal recessive 13q14.3 1:100,000 Dysarthria Kayser-Fleisher rings

Xq13.3 1:300,000 Onset at birth Cerebral degeneration Global delay Kinky hair Pili torti Abnormal facies Hypopigmentation Arterial rupture or thrombosis Bone changes or cutis laxa ↓ Serum Cu ↓ Serum Cu ↓ Serum ceruloplasmin ↓ Serum ceruloplasmin ↑ Intestinal or ↑ Urinary Cu kidney Cu ↓ Liver Cu ↑ Liver Cu Lethal in classic cases Can be treated Death < 3 yr effectively with chelating agents 1500–amino acid 1411–amino acid copper-binding copper-binding ATPase ATPase All tissues except liver Liver, kidney, and placenta Partial deletions in Point mutations 15%; most others and small are point mutations rearrangements

Laboratory test findings

Prognosis

Gene product Location, expression Mutation

transmembrane domain and resulting in loss of all catalytic activity. Occipital horn syndrome and mild Menkes’ disease usually result from missense or splice mutations. It is unknown how much catalytic activity is needed to result in a milder phenotype (i.e., ATP7A still able to absorb sufficient amounts of intestinal copper and enable its delivery to the requisite enzymes) [Tumer et al., 1997]. A case study of a patient with occipital horn syndrome showed that the splice mutation allowed 2% to 5% of ATP7A transcripts to be produced. This amount of protein was sufficient to allow partial absorption of copper from the gut epithelium and partial transport across the blood-brain barrier [Moller et al., 2000]. There was, however, too little protein for lysyl oxidase to function correctly. Between 2% and 5% of ATP7A activity is the proposed amount of protein necessary to decrease the severity of the Menkes’ disease phenotype. Most of the clinical manifestations of Menkes’ disease can be explained by understanding which cuproenzymes are affected. Intracellular copper is necessary for oxidative reactions. Most clinical symptoms are caused by dysfuntion of dopamine monooxygenase, peptidylglycine monooxygenase, cytochrome c oxidase, lysyl oxidase, and Cu/Zn superoxide dismutase (SOD). Dopamine monooxygenase, also known as dopamine β-hydroxylase, is part of the catecholamine biosynthetic pathway. In Menkes’ disease, there is complete or partial deficiency of dopamine β-hydroxylase. This deficiency causes abnormal plasma and cerebrospinal fluid patterns. The degree of deficiency can be evaluated by looking at

norepinephrine concentrations or looking at the ratio of dihydroxyphenylalanine to dihydroxyphenylglycol. Cases of Menkes’ disease with deficient dopamine β-hydroxylase exist that have normal plasma and cerebrospinal fluid concentrations of norepinephrine. It is unknown why compensatory mechanisms are active in some patients but not in others. In the mouse model of Menkes’ disease, normal concentrations of norepinephrine are observed in certain areas of the brain [Prohaska and Bailey, 1994]. The dopamine βhydroxylase deficiency causes temperature instability, hypoglycemia, eyelid ptosis, and loss of sympathetic adrenergic function [Biaggioni et al., 1990; Robertson et al., 1986]. Peptidylglycine monooxygenase is a cuproenzyme necessary for the removal of the carboxyl-terminal glycine residue from neuroendocrine precursors, including gastrin, cholecystokinin, vasoactive intestinal peptide, corticotropin releasing factor, calcitonin, vasopressin, and thyrotropinreleasing hormone [Eipper et al., 1983, 1992]. When this enzyme is deficient, these neuroendocrine factors have 100to 1000-fold decreased bioactivity. Affected animal models of Menkes’ disease have decreased peptidylglycine monooxygenase activity within their brains [Prohaska and Bailey, 1995]. The decreased activity of these neuroendocrine factors contributes to the phenotype of Menkes’ disease. Cytochrome c oxidase is a copper-dependent enzyme that is deficient in Menkes’ disease. The decreased cytochrome c oxidase activity causes a subacute necrotizing encephalomyelitis without the severe lactic acidemia that is generally associated with complex IV defects [DiMauro et al., 1990; Robinson, 1989; Robinson et al., 1987]. Peripheral hypotonia and muscle weakness in patients with Menkes’ disease is partially caused by decreased activity of this enzyme. The normal function of lysyl oxidase (protein lysine 6-oxidase) is to deaminate lysine and hydroxylysine during the first step of collagen cross-link formation [Siegel, 1979]. ATP7A may be needed to transport copper into the transGolgi for use by lysyl oxidase. Deficiency of lysyl oxidase decreases the strength of connective tissue in certain tissues or organs and leads to a host of connective tissue disorders that usually are associated with Menkes’ disease, including vascular tortuosity [Royce and Steinmann, 1990], bladder diverticula [Daly and Rabinovitch, 1981; Harke et al., 1977], and gastric polyps. ATP7A deficiency affects lysyl oxidase more profoundly than any of the other cuproenzymes [Gacheru et al., 1993]. It is possible that other cuproenzymes can acquire copper from cytoplasmic carriers without using ATP7A (an intermediate carrier), and this may explain why some mutations of ATP7A lead to the less severe occipital horn syndrome. Cu/Zn SOD is also deficient in this disease [Rohmer et al., 1977]. Lowered levels of Cu/Zn SOD can increase susceptibility to damage by oxygen free radicals. It is not known whether decreased Cu/Zn SOD causes any developmental regression, because animal models without Cu/Zn SOD have normal development [Reaume et al., 1996]. Postmortem studies of patient with Menkes’ disease have found increased levels of manganese SOD, which may be a compensatory change for the decreased levels of Cu/Zn SOD [Shibata et al., 1995]. It is unknown whether the decrease in this enzyme contributes to the phenotype observed in Menkes’ disease.

Boustany and Zucker / Degenerative Diseases Primarily of Gray Matter

Pathology Kidney Copper accumulation within the kidneys leads to problems with renal reabsorption. Animal models of Menkes’ disease demonstrate an accumulation of copper within the proximal tubules of the kidney [Kodama and Murata, 1999]. β2Microglobulin is absorbed by the renal proximal tubules. Urinary β2-microglobulin levels increase with increasing age of Menkes’ disease patients, regardless of whether they undergo treatment [Ozawa et al., 2003].

Brain Microscopy of tissues from animal models of Menkes’ disease reveal an increased number of apoptotic cells within the neocortex and the hippocampus [Rossi et al., 2001]. Brain CT scans demonstrate atrophy that is generalized or diffuse. Brain MRI reveals infarcts that result from tortuous arteries [Venta-Sobero et al., 2004]. MRI also demonstrates white matter disturbances, ventriculomegaly, and diffuse atrophy [Faerber et al., 1989].

Connective Tissue Urinary diverticula can be seen on pelvic ultrasound and cystography. Bone abnormalities are common and include wormian bones in the skull, metaphyseal spurring of the long bones, and anterior flaring and multiple fractures of the ribs [Adams et al., 1974; Stanley et al., 1976].

Pathogenesis Defective copper trafficking explains most changes seen in Menkes’ disease. Nutritional needs of the body for copper are crucial the first 12 months of life. Brain growth and motor development are most rapid during this phase. Neurodevelopment and motor development are processes that require copper [Berg, 1994]. Expression of BCL2, an antiapoptotic protein, is decreased in children with Menkes’ disease. Decreased levels of copper lead to mitochondrial damage that causes decreased levels of BCL2 [Rossi et al., 2001]. These decreased levels of BCL2 may explain the increased number of apoptotic cells seen in the brain of the animal model, as well as the mechanism behind neurodegeneration in Menkes’ disease. Phenotypic differences in animal models and in humans appear to depend on the amount of functional ATP7A-encoded mRNA. During different stages of development, the various organs and tissues have different copper requirements. If the requirement is not met, the organ or tissue undergoes developmental failure.

Animal Models Complete deficiency of the Menkes’ protein in mice causes lethality before birth, whereas humans can survive for a limited time without ATP7A [Mercer, 1998]. The murine homolog of ATP7A is Atp7a [Levinson et al., 1994; Mercer et al., 1994]. Just as in humans, there are a variety of observed phenotypes, with most of them reflecting their human

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counterparts. The severity of the murine phenotypes depends on the amount of ATP7A-encoded mRNA. Four murine genotypes are used to study Menkes’ disease: 1. Jax brindled, akin to classic Menkes’ disease, does not respond to copper treatment. 2. Macular brindled corresponds to classic Menkes’ disease. Mice are hypopigmented because of catechol oxidase deficiency. They have severe neurologic deficits and die about 15 days after birth if untreated. However, if copper is given before the seventh day of life, the mice are able to survive [Fujii et al., 1990; Mercer, 1998]. 3. Viable brindled corresponds to mild Menkes’ disease. These mice are similar to the other brindled mutants, but they have increased viability. 4 Blotchy corresponds to occipital horn syndrome. These mice display less severe phenotypes than the other mutants. Their defects are mostly limited to connective tissue abnormalities. Assays reveal that full-length Atp7a-encoded mRNA is present [Levinson et al., 1994; Mercer et al., 1994].

Treatment Treatment of Menkes’ disease is limited to supportive therapy and supplementation with copper histidine. Unlike nutritional copper deficiency, Menkes’ disease cannot be cured by copper replacement. Copper histidine is more effective in patients with milder phenotypes. A small subset of patients can achieve normal neurodevelopment. Early detection and intervention are critical for the copper histidine treatment to have an effect. Many individuals with Menkes’ disease fare poorly, with little or no developmental improvement despite early intervention. Older patients with neurologic signs of Menkes’ disease demonstrate little improvement with copper histidine replacement. Therapy may, however, reduce irritability and allow for calmer sleeping patterns and minor improvements in personal and social development [Kaler, 1998]. These minor responses to therapy may help lessen the burden placed on caretakers. Copper histidine therapy helps the neurologic signs and symptoms of Menkes’ disease, but it has no effect on connective tissue disorders associated with this disease. Early copper histidine replacement therapy is most effective in patients with milder phenotypes who have some residual copper transport activity. These milder variants result from mutations that do not affect the regions of ATP7A necessary for catalytic activity and allow for residual levels of copper transport. The beneficial response to copper histidine therapy can be predicted by PCR-based analysis of mutations.

Future Directions Improved therapeutic strategies are critical for better outcomes. Biochemical approaches to bypass the block in copper absorption from the intestine and allow requisite copper absorption are needed. Affected individuals must be identified early to initiate treatment before manifestations of neurologic signs and symptoms occur. This is the period when treatment has the most potential. ATP7A is necessary

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for the transport of copper through the blood-brain barrier. To prevent neurologic developmental regression, other ways of delivering copper stores to the brain must be identified. The symptoms of Menkes’ disease result from the dysfunction of multiple cuproenzymes, and copper must be made available to these enzymes to reduce the nonneurologic symptoms experienced by these patients [Kaler, 1998]. Although advances have been made in early detection of affected individuals, there has been little progress in finding ways to deliver copper to the necessary cuproenzymes or through the blood-brain barrier. Because classic Menkes’ disease is the result of the partial or complete absence of the traditional copper transport pathway, identification of alternate routes may allow the delivery essential for normal development.

ALPERS’ DISEASE Alpers’ disease is a fatal, progressive disease that affects the gray matter of the brain [Simonati et al., 2003]. This disease was initially described formally in 1931 [Alpers, 1931]. Alpers’ disease is known by other names: diffuse progressive degeneration of the gray matter, poliodystrophia cerebri progressiva, degeneration of the cerebral gray matter of Alpers [Ford et al., 1951], diffuse cerebral degeneration of infancy [Blackwood et al., 1963], progressive poliodystrophy [Dreifuss and Netsky, 1964], spongy glioneuronal dystrophy [Klein and Dichgans, 1969], spongy degeneration of the gray matter [Janota, 1974], and progressive neuronal degeneration of childhood with liver disease [Harding et al., 1986]. Characteristic manifestations include neurologic deterioration, intractable seizures, and liver failure [Harding, 1990]. There is no known treatment. The clinical manifestations of Alpers’ disease are caused by myriad genetic defects with various forms of inheritance. Most of the genetic mutations that lead to Alpers’ disease are still unknown.

History While visiting a colleague’s laboratory in Hamburg, American neuropathologist Bernard Alpers conducted a detailed study of a 4-month-old girl who died after a month of intractable seizures. The patient had a normal birth and normal development until age 4 months. There was necrosis of the deep gray matter nuclei and diffuse loss of ganglion cells in the third layer of the cortex. Alpers believed that the degeneration had a toxic cause. Many similar case reports have been made since then. Huttenlocher and co-workers [1976] were first to report that the neuronal degeneration was associated with liver failure. Alpers’ disease is also referred to as AlpersHuttenlocher syndrome. The pattern of inheritance has been postulated to be autosomal recessive [Sandbank and Lerman, 1972]. A mitochondrial defect leading to Alpers’ disease has also been hypothesized [Naviaux et al., 1999]. The disease most likely has several causes, accounting for subtypes such as hepatocerebral or myopathic Alpers’ disease.

Clinical Features Alpers’ disease is a clinical diagnosis that is documented on MRI but confirmed on postmortem examination. The

disease is a diagnosis of exclusion, but specific clinical findings suggest its presence. Characteristic manifestations are liver failure, refractory seizures, and psychomotor retardation [Wefring and Lamvik, 1967]. Patients with Alpers’ disease are initially developmentally normal. Onset can occur between 1 month and 25 years of age [Harding et al., 1995]. Onset is more common during a patient’s infancy and adolescence, with most cases showing initial symptoms in infancy, usually before the age of 5. Death occurs between 3 months and 12 years of age, with most patients dying before the age of 3 years. The course of Alpers’ disease is variable, alternating among periods of development, degeneration, and mild recovery or stasis. Rare cases of Alpers’ disease have been reported in individuals as old as 25 years. Because of the variable age of onset, Alpers’ disease has been categorized as juvenile, infantile, and prenatal forms [Frydman et al., 1993; Harding et al., 1995; Montine et al., 1995; Simonati et al., 2003; Worle et al., 1998]. Prenatal Alpers’ disease has been described in one family, and it is characterized by microcephaly, intrauterine growth retardation, retrognathia, joint limitations, and chest deformity. The infantile form manifests with early onset, a slowly progressive course, and lateoccurring severe signs and symptoms. The juvenile form of Alpers’ disease is identical to the infantile form, but it is notable for a peripheral ataxia resulting from central and peripheral sensory axonopathy. In addition to the classic triad of symptoms (i.e., psychomotor retardation, intractable seizures, and liver failure), patients with Alpers’ disease may have other manifestations. Hypotonia may occur initially [Egger et al., 1987]. Ataxia, febrile illness, and cortical blindness are less common [Naviaux and Nguyen, 2004]. A progressive ataxia that involves the sensory pathways has been described. This occurrence is similar to other sensory neuropathies caused by mitochondrial disorders [Fadic et al., 1997]. Liver failure is a complication that manifests late in the course of the disease [Smith et al., 1996], and it is usually the cause of death. Most cases of liver failure in these patients were attributed to hepatotoxicity caused by antiepileptic drugs, specifically valproic acid. However, some cases of liver failure and identical hepatic histology have occurred in patients who did not receive antiepileptic drugs. Valproic acid may cause hepatotoxicity in some cases of Alpers’ disease, but it cannot explain all cases. Orthotopic liver transplantation has not been helpful in cases with liver failure. Liver transplantation in patients with Alpers’ disease has been associated with neurologic deterioration [Delarue et al., 2000; Kayihan et al., 2000]. Complications of neuronal degeneration can lead to death from respiratory failure or primary hypoventilation.

Clinical Laboratory Tests Initial laboratory test results can be normal. Liver function test results can be elevated initially, although this finding is rare [Egger et al., 1987]. Values are elevated in the later stages of the disease because of liver cirrhosis. There are no specific in vivo serum or cerebrospinal fluid markers for Alpers’ disease, and the diagnosis must rely on neuropathologic evaluation. Cranial CT scans demonstrate progressive atrophy and low densities in the occipital and temporal lobes. There is

Boustany and Zucker / Degenerative Diseases Primarily of Gray Matter

involvement of the cortex and the white matter [Kendall et al., 1987; Flemming et al., 2002]. Generalized atrophy is common throughout the brain in the later stages of the disease. Multiple findings are apparent on conventional MRI scans. These include diminished white matter and cortical thinning of the frontal, posterotemporal, and occipital lobes [Barkovich et al., 1993]. Lesions of the thalamus also have been reported. Occipital lobe atrophy is widespread. Proton MR spectroscopy reveals increased cerebrospinal fluid levels of lactate [Charles et al., 1994] and a reduced N-acetylaspartate-to-creatine ratio. The increase in lactate marks the switch from oxidative to anaerobic metabolism. N-acetylaspartate is an indicator of neuronal viability [Neumann-Haefelin et al., 2000]. Electroencephalographic findings correlate with the lesions seen on MRI most apparent in the occipital lobes. The EEG of Alpers’ disease is described as slow (<1 Hz) with high-amplitude activity (0.2 to 1.0 mV). Loweramplitude polyspikes are also recognized on the EEG. This pattern is seen in 75% of patients, but it may be present only transiently in periodic bursts [Martinez-Mena et al., 1998]. These bursts increase in number and duration as the disease progresses. The triad of requisite clinical symptoms and MRI and electroencephalographic findings suggest the diagnosis of Alpers’ disease.

Pathology Alpers originally described the neuronal pathology as cortical lesions with reactive gliosis, demyelination, nerve cell loss, spongy degeneration, and accumulation of neutral lipids. The occipital cortices are usually involved, and involvement can be symmetric or asymmetric. Patchy cerebral cortical destruction usually is worst within the striate cortex. Striate cortex involvement is a hallmark of Alpers’ disease [Harding, 1990; Harding et al., 1986]. Because of the destruction of the visual cortices, patient often have cortical blindness [Charles et al., 1994; Dietrich et al., 2001; Parsons et al., 2000]. Multiple case studies have described the cortical destruction as neuronal loss, spongiosis, astrocytosis, and gliosis. Milder changes are seen in the parietal cortices [Montine et al., 1995]. Necroses in the hippocampi, lateral geniculate nuclei, amygdala, substantia nigra, and dorsal columns may be evident. In patients with severe liver failure in the late stages of Alpers’ disease, Alzheimer’s disease type II astrocytes are seen. The white matter is only minimally affected. Premortem liver biopsies reveal lobular disarray, microvesicular steatosis, and inflammation with acute and chronic hepatocyte necrosis [Narkewicz et al., 1991]. Common hepatic findings at autopsy are fibrosis, regenerative nodules, hepatocyte dropout, bile duct proliferation, fatty changes, and bile stasis. Pancreatitis is infrequently observed in these patients. Muscle biopsies may contain ragged red fibers and cytochrome c oxidase–negative fibers when Alpers’ disease is caused by a mitochondrial defect. A subset of patients with Alpers’ disease lack any detectable energy metabolism defect and have normal hepatic histology [Frydman et al., 1993].

Biochemistry The clinical manifestations of Alpers’ disease have several causes. Abnormalities within the citric acid cycle of leukocytes, cultured fibroblasts, and hepatocytes due to a defect in

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pyruvate metabolism or mitochondria have been suggested [Gabreels et al., 1984; Prick et al., 1981]. These defects result in deficiencies of cytochrome c oxidase, pyruvate cocarboxylase, and mitochondrial electron transport chain complex I. Mitochondrial DNA (mtDNA) polymerase gamma activity is less than 5% of normal in muscle and liver cells [Naviaux and Nguyen, 2004]. Immunoreactive subunits of the mtDNA polymerase are still present in patients. The deletion that causes the reduced amount of mtDNA polymerase is small because detectable levels of protein are still present. Southern blot analysis of two infants with Alpers’ disease revealed decreased mtDNA in muscle, liver, brain, and fibroblasts. The loss of mtDNA may be tissue specific [Tesarova et al., 2004].

Genetics The mode of transmission of Alpers’ disease is understood, and it is consistent between families. Case studies and biochemical evidence support autosomal recessive inheritance and maternal or mitochondrial inheritance patterns. Cases with autosomal-recessive inheritance patterns have no mitochondrial deficiencies [Harding, 1990]. Simonati and associates [2003] observed that although the disease affects both genders, there appears to be a mild male predominance. The same group also observed that children with juvenile Alpers’ disease do not have depletion or significant mutations in mtDNA. Two mutations within the polymerase gamma gene (POLG) are associated with Alpers’ disease: G2899T and G1681A. G2899T causes a premature stop codon (Glu873Stop). Some Alpers’ disease patients are heterozygous for the POLG mutation Glu873Stop. It has been theorized that this stop codon is incomplete and allows a small number of ribosomes to be read. The number of ribosomes that are able to bypass the premature stop codon may be regulated in an age- and tissue-dependent manner, allowing Alpers’ disease to manifest at different ages and in different tissue types. In Drosophila melanogaster, proteins are regulated in a tissuespecific manner by changing the ratio of short to long forms of the protein [Robinson and Cooley, 1997]. The premature stop codon in POLG may change the ratio and cause tissuedependent regulation. The G1681A causes an Ala167Thr substitution. This corresponds to the linker region of the POLG protein. POLG is located on chromosome 15q24-26 [Zullo et al., 1977]. No other polymerase can substituted for decreased POLG activity. POLG is the only polymerase of the 15 known DNA polymerases that has a mitochondrial import signal. Mutations within POLG are found in other mitochondrial diseases: progressive external ophthalmoplegia (autosomal recessive and dominant forms) [Van Goethem et al., 2002, 2003], ophthalmoparesis, sensory ataxia, neuropathy, dysarthria, and male infertility. Children homozygous for the G2899T mutation are affected with Alpers’ disease, whereas control groups consisting of patients with neuromuscular diseases or patients with other mitochondrial diseases do not have this mutation. Many patients with Alpers’ disease are heterozygous for G1681A, but the mutation is not specific. Heterozygous G1681A mutations are also seen in ophthalmoparesis, both types of progressive external ophthalmoplegia, and in the asymptomatic parents of children with Alpers’ disease.

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Pathogenesis Alpers’ disease was originally believed to be a complication of concomitant hypoxia and epilepsy. Comparisons with status epilepticus cases are not valid because the cortical lesions in the two diseases differ significantly. Others have proposed that the underlying defect is metabolic. Alpers’ disease most likely can be caused by multiple metabolic defects. The cerebral destruction of the striate cortex in Alpers’ disease may result from a novel form of hepatocerebral toxicity, which is different from that seen in wilsonian hepatocerebral degeneration.

Management There is no known treatment for Alpers’ disease. It is important to recognize this disease early and avoid the use of valproic acid, because it increases the incidence of hepatotoxicity in these patients. Although some patients may respond to antiepileptic medications early in their disease course, the seizures become refractory to treatment.

NEURONAL CEROID-LIPOFUSCINOSIS: BATTEN’S DISEASE The neuronal ceroid-lipofuscinoses, or Batten’s disease, comprise a group of inherited neurodegenerative diseases of childhood caused by defects in different genes and proteins. Their unifying clinical hallmarks are seizures, blindness, cognitive and motor decline, and early death. Six genes and their protein products have been identified to account for 8 of the 10 or more described clinical entities: CLN1/protein palmitoyl thioesterase (PPT1), CLN2/tripeptidyl peptidase (TTP1), CLN3/battenin, CLN5, CLN6, and CLN8/EPMR. The clinical types are classic infantile (INCL/CLN1); classic late infantile (LINCL/CLN2); variant late infantile Finnish (CLN5); variant late infantile, also known as Costa Rican or Portuguese but not limited to these populations (CLN6); classic juvenile (JNCL/CLN3); Scottish juvenile (CLN1); epilepsy with mental retardation (EPMR/CLN8); Turkish variant infantile, previously classified as CLN7 (with defects in the CLN8 gene); CLN9 variant (CLN9; gene location yet to be identified); and a number of adult-onset variants that are dominantly or recessively inherited (CLN4, gene location yet to be identified) [Boustany, 1996; Goebel et al., 1999; Mole 2004] (Table 59-3). Most of the variants manifest neuronal and photoreceptor programmed cell death. Massive neuronal loss is documented as cerebral and cerebellar cortical atrophy on CT scans and by MRI, and photoreceptor loss as attenuated a and b waves is demonstrated on electroretinograms (ERGs). Autofluorescent material accumulates in these cells. Ultrastructural features characteristic for the clinical types consist of granular osmiophilic deposits (GRODs) in INCL, curvilinear bodies in LINCL, curvilinear and fingerprint-like inclusions in JNCL, and combinations of these features in the others. These inclusions have been observed in neurons, liver, muscle, conjunctival, and other cell types from affected patients. A plethora of novel information has emerged over the past decade regarding the genetics, molecular and cell biology, and biochemistry of this group of disorders. [Gao et al., 2002;

Persaud-Sawin, 2004; Puranam et al., 1997; Ranta et al., 1999; Schulz et al., 2004; Sleat et al., 1997]. Two of the proteins identified, protein palmitoyl thioesterase and tripeptidyl peptidase, are soluble lysosomal proteins, although INCL and LINCL are not typical lysosomal storage diseases. Two other proteins, CLN6 and CLN8, are resident proteins in the endoplasmic reticulum, and CLN3 is a protein that traffics among the Golgi, early recycling endosomes, and lipid rafts in the plasma membrane. CLN3, CLN6, and CLN8 are hydrophobic membrane proteins. CLN5 is characterized as a lysosomal membrane glycoprotein. There are many naturally occurring animal models. Two of these, the nclf mouse and the New Zealand Southhampshire sheep, are models for CLN6. Transgenic models for INCL, LINCL, and CLN6-deficient variant LINCL also are available. Diagnosis is primarily made on clinical grounds, documented by appropriate neuroradiologic and electrophysiologic studies, and confirmed by the appropriate enzymatic (PPT1 or TTP1 activity in CLN1 and CLN2 deficiencies, respectively) or DNA-based laboratory tests. Ultrastructural examination of skin fibroblasts continues to be a valuable diagnostic tool, particularly for identification of novel clinical variants not accounted for by the known genetic defects. Abnormal ultrastructural findings in the setting of a convincing clinical picture is what led to pursuit of the cause, genetics, and biochemistry of the CLN8-, CLN6- and CLN9-deficient variants. Treatment options are beginning to expand beyond anticonvulsants and supportive nutritional and physical measures. Targeted therapies have been used in patients with known biochemical and cell biologic processes, such as cysteamine in INCL and flupirtine in INCL, LINCL, variant forms of LINCL, JNCL, and CLN6- and CLN9-deficient variants [Batten and Mayou, 1915; Dhar et al., 2002; Mayou, 1904]. Gene- and protein-based delivery systems are being developed for the classic late infantile and infantile types with defects in soluble proteins, and they are being tested in transgenic mouse models. Stem cell replacement is being explored in animal models as potential therapy for these terminal diseases.

History and Terminology The first clinical description of neuronal ceroid-lipofuscinosis was that of the juvenile form Stengel [1826]. This description was soon followed by clinical and pathologic descriptions by Batten, Mayou, Spielmeyer, Vogt, and Sjögren [Batten and Mayou, 1915; Mayou, 1904; Spielmeyer, 1923; Vogt, 1909]. The CLN3 gene responsible for the juvenile form (JNCL) was discovered in 1995 [Lerner et al., 1995]. The late infantile form (LINCL) was described by Jansky and Bielchowski in 1908 and 1913 [Jansky, 1908]. These two variants were previously referred to as Batten’s disease, a term that now refers to all variants. The adult form or Kufs disease, an earlyonset dementia with seizures and absence of visual findings was described in 1925 [Dom et al., 1979]. The adult form (ANCL) has been described in sporadic cases and familial cases, with some families suggesting a dominant pattern of inheritance. Chromosomal location of the CLN4 gene or genes responsible for the adult disease remains unknown. The term neuronal ceroid-lipofuscinosis was introduced by Zeman and Dyken in 1969 as a descriptive term referring to the autofluorescent, waxy, dusky lipid accumulating in

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TABLE 59-3 Batten’s Disease Variants

GENE

EPONYM FOR MAJOR CLINICAL PRESENTATION

AGE OF ONSET

AFFECTED ETHNICITIES

9–18 mo

Primarily Finnish, Seizures, described in cognitive and others motor decline, blindness, microcephaly

CLN1*

INCL, HaltiaSantavuori

CLN2†

LINCL, Jansky- 2.5–3.5 yr Pan-ethnic Bielchowski

CLN3

JNCL, SpielmeierVogt

4–8 yr

CLN4‡

ANCL, Kufs’ disease, dominant forms known as Parry’s disease

30 yr

CLN5

vLINCL, Finnish 5–7 yr late infantile

Finnish

CLN6

vLINCL, Costa Rican, Portuguese, Indian

4–6 yr

Costa Rican, Portuguese, Indian, Pakistani

CLN7‡

vLINCL, Turkish

5–7 yr

Turkish

CLN8

EPMR or northern epilepsy with mental retardation

5–8 yr

Finnish

MAIN CLINICAL FEATURES

Seizures, ataxia, cognitive and motor decline, retinitis pigmentosa

Northern European, Retinitis described in pigmentosa, many others seizures, echolalia, psychosis, dystonia, tremor, bradycardia

DIAGNOSTIC TESTS

GRODs, saposins A and D

PPT1 enzymatic Signal loss in Soluble assay, the thalami, lysosomal gene-based test, T2-weighted protein, skin biopsy, high signal lysosome isoelectric intensity for EEG by age periventricular 3 yr rims, cerebral atrophy TTP1 enzymatic Increased T2 Soluble assay, geneperiventricular lysosomal based test, signal; signal protein, giant occipital loss in thalami; lysosome EEG spike, caudate, and PM ERG cerebral, and cerebellar atrophy Gene-based test, Cerebellar and Membrane ERG cerebral protein, atrophy, PM, Golgi, caudate and early putamen endosomes, atrophy, lipid rafts decreased thalamic density

Curvilinear inclusions, subunit C or 9 of ATP synthase

Fingerprint or curvilinear inclusions, subunit C or 9 of ATP synthase

Early dementia, Fingerprint Clinical, psychosis; inclusions, pathologic type A pigmentation, examinations; myoclonic subunit C of exclude other seizures; type B ATP synthase dementias extrapyramidal signs and facial dyskinesias Clumsiness, Curvilinear or Gene-based test visual failure, fingerprint cognitive and inclusions, motor decline, subunit C of seizures ATP synthase, saposins A and D Loss of speech, Fingerprint, Gene-based test seizures, curvilinear, retinitis, or rectilinear cognitive and inclusions; motor decline lipid drops; subunit C of ATP synthase

Fingerprint or curvilinear inclusions Seizures Curvilinear Gene-based test, increased with inclusions, EEG puberty and fine GRODs, decreased with lipid drops, age; clumsiness, subunit C of dysarthria, ATP synthase, decreased saposin D cognition, agitation, decreased visual acuity

MRI And CT FINDINGS

PROTEIN TYPE, LOCATION

EM-DETECTED PROTEIN

Normal or mild cerebral cortical atrophy

Unknown

Severe early cerebellar atrophy, cerebral atrophy

Soluble lysosomal glycoprotein, lysosome, ER

Increased T2 Membrane periventricular protein, signal, ER, PM cerebellar and cerebral atrophy, decreased T2 signal for the thalamus and putamen Similar to Unknown findings for CLN2, CLN6 Cerebral cortical Membrane atrophy protein, ER, ER-Golgi intermediate compartment

Continued

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TABLE 59-3, cont’d Batten’s Disease Variants

GENE

EPONYM FOR MAJOR CLINICAL PRESENTATION

AGE OF ONSET

AFFECTED ETHNICITIES

MAIN CLINICAL FEATURES

DIAGNOSTIC PROTEIN

EM-DETECTED TESTS

CLN8

vLINCL Turkish 5–7 yr (previously classified as CLN7)

Turkish

Loss of speech, seizures, retinitis, cognitive and motor decline

Curvilinear or Clinical, exclude fingerprint CLN2, CLN5, inclusions, CLN6 forms subunit C of ATP synthase

CLN9‡

vJNCL

Serbian, German

Myoclonus, seizures, cognitive and motor decline

Fingerprint or curvilinear inclusions, GRODs, subunit C of ATP synthase

4–8 yr

EM, increased cell growth, decreased cell adhesion, GeneChip analysis

MRI And CT FINDINGS

PROTEIN TYPE, LOCATION

Cerebral cortical Membrane atrophy protein, ER, ER-Golgi intermediate compartment Cerebellar and Unknown cerebral cortical atrophy

*Rare cases of adolescent and adult forms of CLN1 deficiency have been described. The CLN1 gene is also designated PPT1. † Patients with CLN2 deficiency of later onset survive into the fourth and fifth decades. ‡ CLN4, CLN7, and CLN9 genes are unidentified. ANCL, adult neuronal ceroid-lipofuscinosis; CLN, ceroid-lipofuscinosis, neuronal; CT, computed tomography; EEG, electroencephalogram; EM, electron microscopy; EPMR, epilepsy with mental retardation; ER, endoplasmic reticulum; ERG, electroretinography; GRODs, granular osmiophilic deposits; INCL, infantile neuronal ceroid-lipofuscinosis; JNCL, juvenile neuronal ceroid-lipofuscinosis; LINCL, late infantile neuronal ceroid-lipofuscinosis; MRI, magnetic resonance imaging; PM, plasma membrane; PPT1, palmitoyl protein thioesterase-1; TTP1, tripeptidyl peptidase-1; v, variant.

neuronal endosomes, reminiscent of lipofuscin, the aging pigment [Zeman et al., 1970]. The infantile form (INCL) was described by Hagberg and then by Haltia and Santavuori in 1973 [Hagberg et al., 1968; Haltia et al., 1973a, 1973b; Santavuori et al., 1973]. The CLN1 gene was identified in 1995, followed by the CLN2 gene responsible for LINCL [Sleat et al., 1997]. Other types have been described since then, including variant late infantile forms and early juvenile forms due to defects in the CLN5, CLN6, and CLN8 genes [Gao et al., 2002; Klockars et al., 1998; Ranta et al., 2001; Savukoski et al., 1998; Wheeler et al., 2002]. A CLN9 form is also described that is clinically similar to the juvenile form [Lin et al., 2001; Schulz, Dhar et al., 2004]. The CLN9 gene remains to be characterized. The terminology is confusing because it was established before many variants or clinical forms were defined and before any of the genes were identified. The terms INCL, LINCL, JNCL, and ANCL were initially chosen to separate the forms according to age of onset. This holds true for the main classic variants described. Since discovery of the various genes, many atypical cases have been described with variable ages of onset. Different defects in one gene can manifest with dissimilar ages of onset and a variety of clinical phenotypes. The best approach may be to refer to CLN1-, CLN2-, CLN3-, CLN5-, CLN6- and CLN8deficient types (see Table 59-3). The decision to name the genes CLN as opposed to neuronal ceroid-lipofuscinosis genes is most unfortunate, because it causes confusion with yeast cyclin genes, especially in scientific and medical literature searches. The decision to refer to all forms as Batten’s disease, although historically incorrect, is a simple and practical one, because of the length and wordiness of neuronal ceroid-lipofuscinoses. The term Batten’s disease has been universally adopted and accepted by family groups, private foundations, and U.S. government agencies.

Major Neuronal Ceroid-Lipofuscinosis Clinical Types or Syndromes The clinical features, laboratory tests, pathology, biochemistry, and genetics are summarized for each of the major types (see Table 59-3).

Infantile Neuronal Ceroid-Lipofuscinosis INCL (i.e., Haltia-Santavuori variant, CLN1-defective, PPT1deficient form) is caused by a deficiency in palmitoyl protein thioesterase. The function of this lysosomal thioesterase is to remove fatty acids attached in thioester linkages to cysteine residues in proteins [Schriner et al., 1996]. The first description of this disease was in 1968 by Hagberg and colleagues [1968]. A comprehensive clinical and pathologic characterization of this autosomal-recessive disorder was provided later from Finland [Haltia et al., 1973b; Santavuori et al., 1973].

CLINICAL DESCRIPTION The Finnish cases represent the most severe form of the disease. Development is normal until 10 to 18 months of age. Deceleration of head growth can start as early as 5 months of age. Developmental arrest, hypotonia, and ataxia ensue. All children become microcephalic. Visual impairment is apparent at 1 year of age, and children are blind by the age of 2 years. Optic atrophy, thinned retinal vessels, and a discolored, brownish macula are seen funduscopically. Frequent myoclonic jerks begin after year 1, and many affected children develop generalized seizures. Hand-knitting movements reminiscent of Rett’s syndrome are observed early but disappear by age 2 years. By the third year of life, patients are bedridden, hypotonic, irritable, and spastic. At age

Boustany and Zucker / Degenerative Diseases Primarily of Gray Matter

5 years, severe flexion contractures, acne, hirsutism, and rarely, precocious puberty are observed. Most children die between the ages of 7 and 13 years. There are rare cases in which the age of onset may be as late as 4 years. A distinct adolescent phenotype reminiscent of the classic juvenile variant has been described in some patients of Scottish descent [Mitchison et al., 1998].

CLINICAL DIAGNOSTIC TESTS The single best diagnostic test is measurement of PPT1 enzyme activity in leukocytes [Das et al., 1998]. Enzyme activity can be measured from a dried blood spot on filter paper or from cultured fibroblasts. In the proper clinical setting, an enzyme activity less than 5% of normal is diagnostic for INCL. DNA diagnostics are also widely available. Before the availability of the enzyme assay or DNA diagnostics for this disease, the diagnosis was based on the clinical presentation and electron microscopic examination of skin or other available tissue. The characteristic finding is membrane-bound GRODs, which typically are seen in endothelial, periepithelial, and autonomic nerve cells of the submucosal myenteric nerve plexus, but they also have been reported in other cell types. The EEG may initially be normal but then reveals lack of sleep spindles and absence of the attenuation in amplitude seen with eye opening by the ages of 16 to 24 months. There is gradual loss of amplitude, and the EEG becomes isoelectric by age 3 years. The ERGs, visual-evoked responses, and somatosensory-evoked responses are also abnormal but tedious to demonstrate in young children, and they are they not needed for the diagnosis. The ERG is abnormal, with cone function affected before rod function. CT and MRI findings are present early and include signal loss in the thalami and cerebral atrophy with high-signal-intensity, thinned periventricular rims. Postmortem T2-weighted MRI scans reveal a remarkable hypointensity of the gray matter with respect to the white matter. Prenatal diagnosis has been performed on chorionic villus samples as early as 11 weeks, and it can be achieved by examining amniocytes at a later stage (16 to 18 weeks). Initially, electron microscopic or ultrastructural studies were performed to look for GRODs, but the PPT1 enzyme assay and a DNA analysis can be performed instead. There remains a role for electron microscopy when enzymatic diagnosis is not available, when enzyme activities and DNA analysis are not clear-cut or when identification of the existing mutation is absent. Ideally, all three diagnostic methods should be used because of the importance of the decision based on these results to be taken by the family, treating obstetrician, and geneticist. The diagnosis of a normal or carrier fetus should be confirmed at birth by analysis of cord blood.

PATHOLOGY At the time of death, brain weight is drastically reduced to 250 to 400 grams. Serial pathologic studies in Finland revealed progressive cortical neuronal beginning at 1 year of age, with a subtotal loss of neurons by 4 years. Giant Betz cells and neurons of the hippocampal CA1 and CA4 sectors are relatively preserved. Reactive astrocytes become more prominent with time. GRODs are apparent in neurons and macrophages as early as 8 weeks’ gestation. Ultimately, cere-

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bellar Purkinje cells and granule cells are destroyed and are replaced by a rim of Bergman glia. The white matter appears gliotic. The brainstem and basal ganglia are also involved. The spinal cord is relatively preserved with anterior horn cells that demonstrate storage only. Storage granules can be seen in many different tissues of the body, but tissue destruction is reserved for the brain and retina [Goebel and Wisniewski 2004; Wisniewski et al., 2004b].

BIOCHEMISTRY, CELL BIOLOGY, AND PATHOPHYSIOLOGY There is loss of function of PPT1, which removes longchain fatty acids attached in thioester linkage to the cysteine residues of proteins. Proteins containing the fatty acylated cysteine residues are usually found at the inner plasma membrane leaflet. Normally, reversible acylation and deacylation of these may have impact on protein-protein and protein-lipid membrane interactions. S-acylated proteins are degraded in lysosomes, and this function also may be impaired in INCL. INCL, like other neuronal ceroidlipofuscinosis disorders, differs from other storage diseases in that the material that accumulates in the cell has no demonstrable link to the actual defect and may be a secondary occurrence. PPT1 is located in the lysosome and taken up in a mannose-6 phosphate– dependent manner, but it is also activated at neutral and basic pH and likely functions in the lysosome and elsewhere in the cell. PPT1 colocalizes with synaptophysin to presynaptic vesicles in neurons. Sphingolipid activator proteins A and D accumulate in storage cytosomes, probably as a secondary phenomenon [Tyynela et al., 1993]. There are reported abnormalities in brain sphingomyelin and other phospholipids, levels of which are decreased in the INCL brain. There are reports of increased rates of apoptosis in lymphocytes, cultured lymphoblasts, and fibroblasts from patients, as well as neurons rendered deficient in PPT1 [Cho et al., 2001]. Increased apoptosis is a common finding in a number of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and other forms of Batten’s disease. Recognizing the defect in deacylation of S-acylated proteins and the increased apoptosis rate of PPT1-deficient cells and neurons has led to some targeted therapies (see “Management and Treatment”).

GENETICS All cases of INCL in Finland are caused by an identical common missense mutation (R122W, arginine to tryptophan) that leads to an unstable protein that is degraded in the endoplasmic reticulum [Mole et al., 1999]. At 1 in 70, the carrier frequency is high in Finland, and the incidence of the disease is 1 case per 20,000 individuals. The incidence in the United States has never been accurately computed, but it probably accounts for about 20% of all diagnosed cases of Batten’s disease. A juvenile-onset variant of this disorder was first described in a person from Scotland; it has a threonine to proline substitution at position 75 [Mitchison et al., 1998]. This mutation and another with a premature stop codon at arginine 151 account for most alleles from patients in the United States, all of whom have Irish or Scottish ancestry. The former is found in juvenile cases and

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the latter in infantile cases. At least 40 mutations in the CLN1 gene have been described.

MANAGEMENT AND TREATMENT Supportive therapies are still the mainstay. Muscle relaxants, including baclofen and benzodiazepine derivatives, are given to combat irritability, sleep problems, athetosis, spasticity, and rigidity. Lamotrigine, valproic acid, and many of the benzodiazepine derivatives are used to manage the seizures and the previously described symptoms. Pain is a common feature that is helped by these medications. Physical therapy plays a role early in the course and delays the onset of painful contractures. In a mouse model for PPT1 deficiency, virally mediated CLN1 gene delivery has cleared storage and improved the clinical condition of these neurologically impaired mice. This therapy is being developed for use in humans. Enzyme replacement is a theoretical possibility, although protein delivery to the central nervous system is not trivial. Under development are methods to chemically open the bloodbrain barrier or chemically camouflage proteins to enable them to selectively cross it. Bone marrow replacement has failed, but stem cell therapies are being explored. An ongoing clinical trial is using phosphocysteamine, an oral and safe drug that deacylates proteins and is anti-apoptotic. Clinical efficacy is unknown, but the drug clears storage material and decreases apoptosis in vitro [Zhang et al., 2001]. Flupirtine is an oral anti-apoptotic drug with analgesic, antispasmodic, and weak antiepileptic properties that protects PPT1-deficient cells from apoptosis. It is approved for use as an analgesic and antispasmodic in Europe, but it has not been approved by the U.S. Food and Drug Administration. Its clinical efficacy in INCL remains unknown.

Classic Late Infantile Neuronal Ceroid-Lipofuscinosis or Late Infantile Batten’s Disease LINCL (i.e., Jansky-Bielchowski, CLN2-defective, TPP1deficient form) results from a deficiency of lysosomal tripeptidyl peptidase. The defect was discovered by comparing mannose-6-phosphate–modified lysosomal proteins from a normal and an LINCL-affected brain [Sleat et al., 1997]. It was first described by Jansky in 1908 and then by Bielchowski in 1913. It is the most pan-ethnic of neuronal ceroid-lipofuscinosis disorders, having been described in European, Middle-Eastern, Chinese, Pakistani, and Indian patients. It is the second most common form of Batten’s disease in the United States, although the total number of cases at any time is less than 500, making it an orphan disease according to the Food and Drug Administration. It is thought that a large number of cases originate from Europe.

CLINICAL DESCRIPTION LINCL manifests with a generalized seizure disorder and ataxia due to unrecognized, frequent absence seizures occurring between the ages of 2.5 and 3.5 years. Within 6 months, vision, motor, and cognitive skills deteriorate rapidly. Affected children are blind by age 4 years because of tapetoretinal degeneration. Most children are nonambulatory and mute by age 5 years, and they require gavage feeding. In addition to

prolonged, generalized tonic-clonic seizures, all have frequent myoclonic jerks, which are most prominent in the face but are also observed in the trunk and extremities. An early hypotonia gives way to severe spasticity with flexion contractures. Autoregulation of vascular tone is lost, resulting in mottled, cold hands and feet. Hypothalamic involvement leads to temperature instability vacillating between hyperthermia and hypothermia. Hyperthermia often leads to unnecessary fever evaluations. Copious secretions and shallow breathing resulting from poor chest wall excursions often cause pneumonias. Sepsis and uncontrollable seizures are frequently the cause of death at the end of the first decade or in the early teens [Boustany, 1996; Zhong et al., 2000]. Some atypical cases have a later onset and protracted course [Wisniewski et al., 2004c].

CLINICAL DIAGNOSTIC TESTS The most definitive test for is measurement of TPP1 enzyme activity when the clinical history and course fit the description. Typically, enzyme activity less than 5% of normal is diagnostic for LINCL. This test can be performed on leukocytes, cultured fibroblasts, or amniocytes and on dried blood from a filter paper. DNA-based diagnosis is also available, but it is more tedious, particularly if the specific family mutation or mutations are not known. In this instance, the diagnostic laboratory excludes the most commonly reported mutations first. Before availability of enzyme or DNA diagnosis, ultrastructural study of a skin biopsy provided objective proof for the disease. The appearance of curvilinear bodies enclosed within unilamellar endosomes in multiple cell types (i.e., endothelial cell, pericyte, Schwann cell, and others) is the most characteristic feature. Rarely, few fingerprint profiles may be seen. Electron microscopy continues to be a valuable diagnostic tool when other forms of diagnosis are not available and in evaluating atypical cases. It has sometimes led to identification of novel neuronal ceroid-lipofuscinosis variant. The ERG reveals reduced amplitudes early in the course of this illness, even before changes of thinned vessels and pale discs become apparent. The process is extinguished within a few months of presentation. Characteristic giant occipital polyspike-spike discharges are seen on the EEG in response to a single flash of light or to low-frequency, repetitive stimulation. These discharges represent the early phase of an exaggerated visual-evoked response. Wave amplitudes of visual-evoked and somatosensory-evoked responses are also high. These tests are seldom used diagnostically. Neuroimaging studies often help to confirm the diagnosis. An initial CT or MRI scan may be normal, but usually within 6 months of onset and before the age of 4 years, cerebral and cerebellar atrophy is prominent. Within 2 years of onset, there is a 40% loss of volume of the cerebellum and a fivefold increase in lateral ventricle-to-hemisphere volume ratio. Caudate and thalamic volumes are markedly reduced compared with agematched controls, and there is relative preservation of brainstem volume early in the course [Boustany and Filipek, 1993].

PATHOLOGY Brain weight at the time of death is markedly diminished to between 250 and 700 grams. The calvarium is thickened, and the sulci are prominent, particularly in the occipital regions. Cerebellar folia are prominent, the ventricles are

Boustany and Zucker / Degenerative Diseases Primarily of Gray Matter

widened, and laminar necrosis is observed. There is massive neuronal loss, with some neurons preserved in layer III. Those cells demonstrate meganeurites. Purkinje and granule cells are almost completely absent from the cerebellum. The putamen and subthalamic nuclei, as well as nuclei in the brainstem, manifest neuronal loss. There is pallor of the white matter. A reactive astrocytosis is seen with activation of microglia, but monocyte-derived macrophages seen in chronic and acute inflammation are conspicuously absent. This absence suggests that the initial event in LINCL is neuronal destruction and loss with a secondary, reactive gliosis. The small number of remaining neurons has distended cell bodies and granular cytoplasm. This material is periodic acid–Schiff (PAS), Luxol fast blue, and Sudan black B positive in light microscopy sections. White matter appears relatively intact, strongly speaking against a primary inflammatory component in LINCL. Condensed chromatin identified by electron microscopy, upregulation of BCL2 protein, and positive TUNEL stains all provide evidence for the occurrence of apoptosis, a feature common to multiple neurodegenerative diseases [Puranam et al., 1995, 1997]. There is strong reactivity with an antibody to subunit C of mitochondrial ATP synthase [Johnson et al., 1995]. The reason for this is still unknown, but it may represent a form of apoptosis observed in neurodegenerative illnesses called mitopsis. Ultrastructurally, neurons and many other cells contain curvilinear inclusions enclosed within a single membrane. Frequently, these inclusions are admixed with fingerprint profiles. This is more commonly observed in cells outside the central nervous system, such as smooth muscle cells, eccrine sweat glands, endothelial cells, and pericytes. Before the availability of enzymatic diagnosis, prenatal diagnosis was determined by analyzing the ultrastructure of amniocytes obtained at 16 to 17 weeks’ gestation [Wisniewski et al., 2004a].

BIOCHEMISTRY LINCL is caused by defects in a pepstatin-insensitive lysosomal tripeptidyl peptidase that normally removes tripeptides from the amino terminus of proteins. The defect was discovered by comparing mannose-6-phosphorylated glycoproteins from a normal and an LINCL-affected brain. TPP1 is a 46-kDa protein with strong similarity to bacterial proteases. Subunit C or 9 of mitochondrial ATP synthase accumulates. It is unknown how or whether this relates to the TPP1 deficiency. Other neuronal ceroid-lipofuscinosis disorders with normal TPP1 activity (i.e., CLN3, CLN4, CLN6, and CLN8 forms) also accumulate subunit C. It is most likely a secondary process and may be related to the increase in apoptotic activity observed in CLN2, CLN3-, CLN6- and CLN8-deficient cells. TPP1 deficiency and measurement of its activity constitute the cornerstone of diagnostic tools available to the clinician for objective diagnosis of LINCL. This test can also be performed on dried blood filter paper spots.

GENETICS LINCL is an autosomal-recessive disorder that appears to be pan-ethnic, with cases diagnosed from many countries from all continents except Africa. There is a notable lack of African and Jewish cases. It is the second most common

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form of Batten’s disease in the United States, accounting for one third of diagnosed cases. More than 53 mutations have been described. In the United States, two common mutations account for 65% of diagnosed cases. One is a nonsense mutation, Arg208X, and the other affects a splice junction site, IVS5-1G>C. The few cases with a milder course and later onset carry one of these two mutations on one allele and an Arg447His on the other. A mouse model for this disease has been developed [Sleat et al., 2004].

MANAGEMENT AND TREATMENT Treatment is primarily supportive. Areas requiring attention include seizures that become uncontrollable with antiepileptic drug monotherapy. Single or combined use of valproic acid, clonazepam, and clorazepate is helpful, particularly in the early stages. There is also a role for phenobarbital, zonisamide, and levetiracetam. Gavage feeding becomes a necessity by age 5 to7 years, when frequent pneumonias imply difficulty swallowing and aspiration. Attention should be given to development of contractures. Bone marrow transplantation has been tried and has failed [Lake et al., 1997]. Gene and enzyme replacement strategies are being developed and soon may be tried in a developed mouse model. Gene replacement achieved by a number of strategically placed burr holes in three patients with advanced disease is being evaluated. Stem cell therapy also is being developed as a treatment option. It has been proposed that oral use of an anti-apoptotic drug such as flupirtine may slow the progression of this disease. The safety of this drug and its analgesic, antispasmodic, and weak antiepileptic effects make it particularly attractive [Dhar et al., 2002]. The efficacy of this drug in LINCL remains unproven.

Variant Late Infantile Forms Several variant late infantile types (i.e., vLINCL; Finnish type: CLN5-deficient form; Costa Rican/Portuguese/Lake Cavanaugh variant: CLN6-deficient form; northern epilepsy or epilepsy with mental retardation [EPMR] and Turkish vLINCL or tLINCL: CLN8-deficient form) have been described with an age of onset between 5 and 8 years and a clinical profile reminiscent of the late infantile type but with a more protracted course. Three genes have been described. The gene for the variant Finnish type, CLN5, was the first to be identified. This rare variant is mostly restricted to a region in Finland and has been found in 16 families, with one Swedish and one Dutch case also reported. Northern epilepsy and its gene, CLN8, were identified in cases from the northeast part of Finland. A subset of Turkish cases with variant LINCL are also caused by mutations in the CLN8 gene. The variant LINCL type referred to as Costa Rican/Portuguese or CLN6 deficient has been identified in patients of Venezuelan, Pakistani, and Indian descent, as well as in a case from the United States. It had been previously described as an early juvenile form, and it is also referred to as the Lake Cavanaugh variant [Gao et al., 2002; Savukoski et al., 1998; Wheeler et al., 2002].

CLINICAL DESCRIPTION For the Finnish variant LINCL (i.e., CLN5-deficient form), the initial symptoms are motor clumsiness at age 4.5 years,

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followed by cognitive decline at age 6 years and by generalized and myoclonic epilepsy at age 8 years. Blindness due to macular degeneration is evident by age 8 years. Children lose the ability to ambulate by age 10 years, and most die between the ages of 14 and 34 years. For northern epilepsy or EPMR (i.e., CLN8-deficient form) [Ranta et al., 1999], the first stage of disease occurs from age 5 to puberty and is characterized by frequent but short generalized tonic-clonic convulsions and complex partial seizures, as well as by cognitive decline to a low average level. After puberty, the second stage is notable for slowness of movement and a slowing of the rate of cognitive decline. In the final stage of the illness, seizures diminish in frequency, but mental dullness and cognitive decline lead to moderate mental retardation by the end of the third decade. This stage is also notable for clumsiness, ataxia, and impaired vision. Age at death varies from 17 years to late middle age. For Turkish vLINCL (i.e., tLINCL or CLN8-deficient form), the clinical phenotype is substantially more severe than that of EPMR. Patients present between the ages of 2 and 5 with severe seizures. Intellectual decline, blindness, and behavioral problems follow and are prominent by age 8 or 9 years. By 10 years of age, most of the children are wheelchair bound. For the Costa Rican/Portuguese vLINCL/Lake Cavanaugh variant (i.e., CLN6-deficient form) [Teixeira et al., 2003], the initial presenting symptoms at the age of 4 years are ataxia and speech difficulties after a period of normal development. Visual failure due to retinitis pigmentosa, myoclonic jerks, and seizures are accompanied by ataxia and intellectual decline. Death occurs in the early to middle teens.

CLINICAL DIAGNOSTIC TESTS Presenting symptoms suggesting classic LINCL or JNCL with atypical features, normal TPP1 enzyme activities, absence of vacuolated lymphocytes, and a normal CLN3 gene screen strongly suggest one of the variant LINCL types. Electron microscopic results of a skin biopsy, the patient’s ethnic background, and subtle characteristic clinical features for one of these subtypes may tip the scale in favor of one of the LINCL variants over the others. Fingerprint and rectilinear structures favor the Finnish variant. A combination of curvilinear and fingerprint bodies favors the Costa Rican/Portuguese variant. Electron microscopic findings for the Finnish CLN8 variant include loose curvilinear-like structures, and electron microscopic assessment of the Turkish variant demonstrates dense fingerprint profiles in addition to dark amorphous material. The definitive confirmatory test is DNA-based proof of defects in one of the relevant genes: CLN5, CLN6, or CLN8. MRI scans of Costa Rican/Portuguese/Venezuelan CLN6-deficient patients and those with Finnish vLINCL demonstrate severe cerebral and cerebellar cortical atrophy, low densities in the thalami and basal ganglia, and hyperintensities of the white matter. MRI scans of patients with tLINCL demonstrate cerebellar and cerebral atrophy and tissue loss in the brainstem. The EEGs for all of these variants record large-amplitude occipital spikes in response to low-frequency photic stimulation.

PATHOLOGY In cases of Finnish variant LINCL (i.e., CLN5-deficient form), the brain weighs about 500 grams at postmortem

examination. Most notable is the severe cerebellar atrophy. Findings are otherwise quite similar to those for classic LINCL. There is strong immunoreactivity to subunit C or 9 of mitochondrial ATP synthase and weak immunoreactivity to the saposins. Electron microscopic findings are notable for the presence of rectilinear profiles and curvilinear and fingerprint bodies [Goebel and Wisniewski, 2004; Goebel et al., 1999; Topcu et al., 2004b; Wisniewski et al., 2004b]. For the Costa Rican/Portuguese vLINCL/Lake Cavanaugh variant (i.e., CLN6-deficient form), the brain weighs between 600 and 900 grams at postmortem examination. Neuronal loss is pervasive and particularly prominent in neocortex layer V. Although granule cells in the cerebellum are completely eliminated, some Purkinje cells remain. There is strong immunoreactivity with subunit C of mitochondrial ATP synthase in neuronal tissues. It is, however, absent from peripheral organs. At the electron microscopic level, there are primarily fingerprint bodies and, to a lesser extent, rectilinear profiles in the brain. Rectilinear, fingerprint, and curvilinear components are found in organs. For northern epilepsy or EPMR (i.e., CLN8-deficient form), the brain weight at postmortem examination has been in excess of 100 grams but less than 1600 grams. The brain may appear entirely normal, or mild atrophy can be observed. Most storage material is seen in layer III of the cortex. Neuronal loss is most prominent in cortex layer V. Deep gray structures and cerebellar Purkinje cells demonstrate little storage. There is strong reactivity with antibodies to β-amyloid, subunit C, and saposin D. Ultrastructure of the storage bodies demonstrates curvilinear bodies and granular material. For Turkish vLINCL or tLINCL (i.e., CLN8-deficient form), no pathology reports of are available in the literature. The ultrastructure of skin fibroblasts reveals the presence of curvilinear, rectilinear, and fingerprint profiles [Topcu et al., 2004b].

GENETICS For the Finnish vLINCL (i.e., CLN5-deficient form), the major mutation accounting for 94% of Finnish cases is a 2-bp deletion in exon 4 (c.1175delAT). There is a minor Finnish mutation, D279N, and two other mutations, W75X and c669insC, reported in rare Dutch and Swedish cases. For the Costa Rican/Portuguese vLINCL/Lake Cavanaugh variant (i.e., CLN6-deficient form), more than 19 mutations are recognized. The most prevalent are the nonsense mutation (c.214G>T) reported in 20 Costa Rican families and the 3-bp deletion (I154del) in 6 Portuguese families [Teixeira et al., 2003]. Other mutations have been described in those of Venezuelan, Indian, Pakistani, Greek, U.S., Trinidadian, or East Indian ancestry. The nclf mouse is a naturally occurring model for CLN6-deficient vLINCL [Mole, 2004]. For northern epilepsy or EPMR (i.e., CLN8-deficient form) and variant Turkish tLINCL, one mutation, R24G, accounts for all patients with northern epilepsy. The four other mutations result in the more severe phenotype of tLINCL. Two missense mutations (R204C and W263C) occur in exon 3, and two others, L16M and T170M, occur in exon 2 and are also missense mutations. R204C occurs in the conserved TLC lipid-sensing domain and predicts a potential role for CLN8 in the sphingolipid synthetic pathways. The mnd mouse is a naturally occurring mouse model for

Boustany and Zucker / Degenerative Diseases Primarily of Gray Matter

CLN8-deficient forms of neuronal ceroid-lipofuscinosis [Ranta et al., 2004].

BIOCHEMISTRY AND CELL BIOLOGY CLN6 and CLN8 are transmembrane proteins that reside in the endoplasmic reticulum. The CLN5 protein has been reported as being a transmembrane protein in some papers and a secreted lysosomal glycoprotein in others [Holmberg et al., 2004; Savukoski et al., 1998]. CLN5 has been reported to coimmunoprecipitate with CLN2 protein and with CLN3 protein [Vesa et al., 2002]. This interaction implies that these are dynamic proteins that most likely exist in many subcellular locations and that they may functionally interact forming a complex whereby one protein may substitute for the other. This finding can have great implications for therapy, because some of these proteins, such as CLN2, are soluble and amenable to protein or gene replacement therapy, whereas transmembrane proteins such as CLN3 are not.

MANAGEMENT AND THERAPY Treatment for these variants is almost identical to that outlined for the classic LINCL and JNCL types. The relatively mild northern epilepsy variant responds very well to monotherapy with clonazepam. Patients have been reported to remain seizure free for a number of years on this drug. Seizure frequency in this variant tends to wane with age.

Juvenile Neuronal Ceroid-Lipofuscinosis or Juvenile Batten’s Disease Although cases of JNCL (i.e., JNCL, Spielmeier-VogtBatten-Mayou, CLN3-defective or -deficient form) from all over the world have been described, there is a preponderance of cases with Northern European ancestry (i.e., Finland, Iceland, Norway, Sweden, Denmark, Germany, and Holland). There is a notable absence of African or Jewish cases. Japanese, Portuguese, Polish British, Turkish, Moroccan, and Lebanese cases and cases from other countries have been described. It is the most prevalent type of neuronal ceroid-lipofuscinosis in the United States [Boustany, 1996]. JNCL was the first Batten variant to be recognized, and the gene responsible for it, CLN3, was the first to be cloned [Lerner et al., 1995]. Description of the first juvenile cases is credited to a Danish physician, Otto Christian Stengel [Stengel, 1826]. The genetic nature of the illness was established in the Norwegian family he described who had four affected siblings. Because they were raised in different geographic areas by different family members, an environmental cause for the illness was eliminated.

CLINICAL DESCRIPTION Early development is normal. The first sign of trouble is decreased central vision caused by retinitis pigmentosa. This sets in between 4 and 6 years of age. These children are followed by ophthalmologists as normal children with retinitis pigmentosa. They ultimately are enrolled in schools for the visually impaired. Patients become completely blind between the ages of 10 and 14 years, but sometimes even later. Complete blindness is accompanied by a disturbed

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sleep-wake cycle and insomnia. Retrospectively, a subset of affected children may manifest difficult behavior between the ages of 7 and 9 years. By age 10 years, cognitive decline sets in. The diagnosis is first suspected by teachers, who may be familiar with this condition in the pediatric visually impaired population. Seizures make their appearance as early as age 12 years, but they often do not occur until 14 years of age. Early-onset seizures that are difficult to control often foretell a more rapidly declining course. Speech becomes echolalic. Perseveration of speech and actions becomes routine. A cogwheel rigidity of the limbs sets in. Patients walk with a stooped, shuffling gait reminiscent of patients with Parkinson’s disease. An intention tremor of variable severity is often observed. Patients generally plateau in their middle teens. A large number of patients become depressed and agitated, and a small number become aggressive and psychotic. These adolescents often have a positive family history for unipolar or bipolar illness. Treatment is often necessary. It can aggravate extrapyramidal signs and symptoms. Hallucinations are common. They can, however, be of a pleasant and repetitive nature. A number of patients have imaginary friends with names and include them in their daily routine. Growth and physical maturity are not affected, which can make sexual development a problem, particularly for teenage girls. Contraception is often sought by parents for affected teenage daughters. Late-stage symptoms include drooling, difficulty swallowing, and weight loss. These problems are obviated by the use of feeding tubes. Temperature instability with episodes of extreme hypothermia down to 92° F alternating with hyperthermia points to hypothalamic involvement. Seizures increase in number and are difficult to control. Some patients develop a cardiomyopathy or sick sinus syndrome with bradycardia. Most patients succumb in their early to mid-20s to seizures and cardiopulmonary arrest. A small number can survive into the fourth decade of life.

CLINICAL DIAGNOSTIC TESTS When clinical suspicion is strong, DNA-based CLN3 gene tests can confirm the diagnosis (see “Genetics”). The EEG is abnormal from age 9 years onward. Large-amplitude spike and slow-wave complexes are observed. CT and MRI scans may initially be normal and can remain so until age 12 years. Ultimately, cerebral atrophy with gaping sulci and large ventricles is the norm. Cerebellar atrophy is often present. Morphometric MRI measurements indicate loss of hemispheric, caudate, thalamic, and lenticular volumes [Boustany and Filipek, 1993]. There is a low signal in the white matter seen in T2-weighted images. Positron emission tomography has demonstrated decreased glucose use that starts in the calcarine area and progresses to involve all gray matter structures. The latter two techniques are not done routinely on patients, but when carried out, they can help to better understand disease progression. The ERG is often abnormal, even before the patients complain of decreased vision. Visual-evoked potentials reveal reduced-amplitude potentials, and somatosensory-evoked potentials are enhanced, but these are not particularly useful tests. The ultrastructure of the skin biopsy sample is often helpful, particularly if the common 1-kb deletion is absent from one or both alleles. Schwann cells, endothelial cells, pericytes,

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neurons, macrophages, and eccrine sweat glands all show inclusions. Fingerprint-like inclusions enclosed by a unit membrane are typical. Curvilinear inclusions are frequently seen, sometimes within the same cell. Vacuolated lymphocytes are a hallmark of JNCL, but these have to be processed swiftly and correctly, otherwise the number of false-positive results becomes high. Unfortunately, very few diagnostic laboratories can accurately evaluate vacuolated lymphocytes. Skin fibroblast electron microscopy is a more robust test that has proved extremely helpful over the years.

PATHOLOGY Brain weight at the time of death is 450 to 1100 grams. There is thinning of the cortical mantle. There is moderate neuronal loss with gliosis and accumulation of autofluorescent material. This material is Sudan black B and PAS positive. Meganeurites are seen in the basolateral amygdaloid complex and in cortical layer V. Purkinje cell and granule cell dropout is observed in the cerebellum. Electron microscopy reveals apoptotic neurons with dark, shrunken, and fragmented chromatin in the cerebral cortex. A number of neurons are TUNEL stain–positive, confirming the existence of apoptotic neurons. Surviving neurons demonstrate immunoreactivity with antibodies to BCL2, a neuroprotective protein, and to subunit C or 9 of mitochondrial ATP synthase. Lipopigment accumulates in anterior horn cells of the spinal cord and the receptor cells of the organ of Corti. In neuronal cells, fingerprint profiles predominate, whereas in non-neuronal cells, curvilinear inclusions are common.

BIOCHEMISTRY, CELL BIOLOGY, AND PATHOPHYSIOLOGY An initial observation was that ceramide, the pro-apoptotic lipid second messenger was elevated in JNCL brains [Puranam et al., 1999]. This elevation correlated with the identification of apoptosis in JNCL brains and antiapoptotic amino acid stretches within the CLN3 protein [Persaud-Sawin et al., 2002]. In addition to ceramide, galactosyl-ceramide, glucosylceramide, ceramide trihexoside, and sphingomyelin levels are elevated, pointing to sphingolipid overproduction [Persaud-Sawin et al., 2004]. The CLN3 protein is upregulated in a number of human and mouse cancer cell lines and in solid colon cancer specimens [Rylova et al., 2002]. The CLN3 protein localizes to the Golgi, early recycling endosomes, and lipid rafts in plasma membranes. The VYFAE motif within the CLN3 protein is embedded in a larger galactosylceramide lipid raft binding domain. In CLN3-deficient cells, mutant CLN3 incorrectly localizes to late endosomes and lysosomes, and mutant CLN3 protein and galactosylceramide, an important component of lipid rafts, remain stuck in the Golgi, never reaching the plasma membrane and lipid rafts. Reversal of this after restoring CLN3 to the deficient cells suggests that CLN3 normally functions as a galactosylceramide transporter from the Golgi to lipid rafts by recycling endosomes. This may explain the increase in apoptosis that is often initiated from lipid rafts and the increased production of sphingolipids in an attempt to rectify the galactosylceramide deficiency in lipid rafts.

GENETICS JNCL is the most common form of Batten’s diseases in the United States. This autosomal-recessive disease has a prevalence of 7 per 100,000 live births in Iceland and 0.71 per 100,000 live births in Germany. The prevalence decreases as the distance increases from Scandinavian countries, and the prevalence in the United States therefore is much less. JNCL is classified as an orphan disease according to Food and Drug Administration guidelines. The gene has 15 exons, which translates into a protein that is 438 amino acids long. The hydrophobic protein has five to seven potential transmembrane domains. This protein is highly conserved among species, indicating a significant role for cell maintenance. Thirty-six mutations have been described. The same 1.02-kb deletion accounts for 85% of cases in the United States. DNA-based carrier testing is available, provided the family mutation is known. Prenatal diagnosis has been performed using ultrastructure and DNA-based tests as early as 11 weeks’ gestation. It is best to confirm diagnosis again at birth using cord blood.

MANAGEMENT AND TREATMENT JNCL is the most challenging of the clinical types to manage. Although initially seizure control is easily achieved with one drug, as the disease advances, some patients progress to having over 100 seizures per day despite use of a multitude of antiepileptic medications. The seizures are of mixed type, including generalized, myoclonic, and partial complex seizures. The emotional and psychiatric aspects of this disorder present a therapeutic dilemma. Many patients require antipsychotic drugs and mood stabilizers, which lower seizure threshold and aggravate parkinsonian symptoms. Insomnia is a problem that should be addressed with the use of benzodiazepines and other drugs. Weight loss becomes an issue in the final few years. It requires gastrostomy tubes for adequate provision of calories, liquids, and anticonvulsants. Anecdotal reports of the use of the antiapoptotic medication flupirtine suggests improved seizure control and sleep patterns. Of those patients that develop bradycardia, only a handful have needed pacemakers placed. Death invariably ensues in the early to middle 20s, with some patients dying as young as age 13 and others surviving to age 40 years. The average survival has increased with the advent of vigorous treatment of infections, use of feeding tubes, and better antiepileptic drugs. Unfortunately, because CLN3 is a membrane protein, there is little enthusiasm for protein or gene replacement strategies. Stem cell approaches have not been explored but may some day have a role in therapy. There are multiple mouse models for this disease. The hope for lessening the burden of JNCL continues to rely on achievement of a better understanding of the pathobiology and biochemistry of this disorder.

CLN9-Deficient Juvenile-like Variant Two German brothers and two American sisters of Serbian descent had been clinically diagnosed with the JNCL variant before identification of the CLN3 gene [Lin et al., 2001; Schulz, Dhar et al., 2004]. When DNA from these cases was examined, it was determined that they had no defects in the

CNL9 (1) CNL9 (2) CNL9 (1) CNL9 (2) CNL1 CNL2 CNL3 CNL6 Normal Normal

Boustany and Zucker / Degenerative Diseases Primarily of Gray Matter

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other died at age 19 years after suffering from swallowing difficulties and many seizures. The two sisters remain alive. One is in her early 20s and has been bedridden since she was 14 years old. She has well-controlled seizures and requires a feeding tube. The younger sister is now 12 years old and is following a similar course.

CLINICAL DIAGNOSTIC TEST The ERG showed diminished wave amplitudes in one of the brothers with JNCL variant. The EEGs in all four patients demonstrated slowing and frequent polyspike discharges. Electron micrographs of lymphocytes show numerous membrane-bound inclusions containing a mixture of electrondense storage material and fingerprint patterns. CT and MRI scans showed progressive cerebral and cerebellar cortical atrophy. Abnormal signal intensity was observed in the periventricular white matter. A diagnostic brain biopsy from one of the sisters showed neurons that contained granular osmiophilic inclusions and curvilinear bodies.

PATHOLOGY

FIGURE 59-1. Partial dendrogram depicting gene expression pattern for CLN1-, CLN2-, CLN3-, CLN6-, CLN9-deficient and normal fibroblast RNA. Upregulated genes are red, downregulated genes are green, and no change from control is black. Notice the similarity of gene expression in the CLN9(1) and CLN9(2) patients. CLN, ceroid-lipofuscinosis, neuronal. See also Color Plate.

CLN3 gene, and they had normal levels of CLN3 mRNA. Analysis of cDNA from CLN3-, CLN1-, CLN2-, and CLN6-deficient variants, together with cDNA from these unknown cases, using Affymetrix GeneChips revealed a distinctive gene profile that grouped them together as a separate variant (Fig. 59-1). Results of enzyme assays and molecular tests for all other known neuronal ceroidlipofuscinosis variants were normal.

CLINICAL DESCRIPTION The clinical course for CLN9-deficient juvenile-like variant is almost identical to that of JNCL, with decreased vision occurring at age 4 years, cognitive decline at age 6 years, and ataxia and rigidity by age 9 years. These patients develop dysarthria and scanning speech, and they are mute by age 12 years. One of the German brothers developed hallucinations and behavior problems. All four patients developed intractable seizures in their early to middle teens that eventually diminished. Retinitis with pigmentary changes was documented in one of the two brothers. One of the brothers died of pneumonia at age 15 years, and the

The brain weight of the older brother at the time of death was 1140 grams. Neurons were ballooned with fine, granular material. Large neurons remaining in the cerebral cortex and the deep gray structures were ballooned. The substantia nigra and nuclear thalami showed moderate-to-severe astrogliosis, as did the spinal cord. The storage material was stained gray with Sudan black, and it had a yellow autofluorescence. The ultrastructure of neurons reveals GRODs and curvilinear bodies (Fig. 59-2). Neurons also demonstrated immunoreactivity to subunit C or 9 of mitochondrial ATP synthase.

GENETICS Chromosomal location of the underlying CLN9 gene remains unknown, but candidate genes include those encoding for proteins that impact the ceramide synthetic and catabolic pathways. The small number of affected cases has precluded traditional linkage analysis studies.

BIOCHEMISTRY AND CELL BIOLOGY Although the gene remains unidentified, the biochemistry and cell biology of this variant is well understood. CLN9deficient cells have a distinctive morphology and phenotype. Cells are small and rounded rather than elongated, and they have prominent nucleoli as seen by filipin staining. They have rapid growth rates because of increased DNA synthesis, but they have an increased sensitivity to apoptosis. They have an adhesion defect, and a number of the genes involved in cell adhesion and apoptosis are dysregulated, as determined by gene profiling and as listed in a table posted at www.dbsr.duke.edu/pub/cln9/. Gene expression of cyclins A2, B1, C, E2, G1, and T2 were increased. Cyclin D1, encoded by a proto-oncogene involved in malignant transformation of breast tissue, was significantly downregulated, as was member 1A of the tumor necrosis factor superfamily. Expression of subunits of cytochrome c oxidases and glutathione S-transferase was also increased. Ceramide,

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Gray and White Matter Degenerative Disorders / 59 FIGURE 59-2. Electron micrographs of CLN9-deficient frontal cortex. A, Notice the secondary lysosomes with curvilinear bodies (magnification ×20,000). B, Granular osmiophilic deposits (GRODs) are denoted by arrows, and curvilinear bodies are denoted by a framed arrow (magnification ×54,000). C, Enlarged inset from B (magnification ×100,000).

A

B

C sphingomyelin, lactosylceramide, ceramide trihexoside, and globoside levels were decreased by 60% to 100%. The key regulating enzyme in the ceramide de novo synthetic pathway, serine palmitoyl transferase, was threefold to fourfold upregulated, suggesting a block further downstream. The low levels of glycosphingolipids can explain the defect in cell adhesion observed in CLN9-deficient fibroblasts.

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CHAPTER 60

Disorders Primarily of White Matter Edward M. Kaye and Marjo S. van der Knaap

The concept of a leukodystrophy has changed considerably from its original pathologic definition, which was first introduced by Bielschowski and Henneberg in 1928 [Bielschowsky and Henneberg, 1928]. The sensitivity of magnetic resonance imaging (MRI) to demonstrate abnormalities in myelin development and maintenance has also expanded our concept of the disorders affecting myelin. The understanding of the pathophysiology of leukodystrophies is evolving, and the classification of the leukodystrophies must continue to be arbitrary. The term leukodystrophy should be restricted to inherited diseases that affect myelin development and maintenance and should exclude acquired disorders affecting myelin, such as multiple sclerosis and other disorders that are associated with inflammatory lesions affecting myelin, and toxic disorders, such as organic solvent exposure. The term leukodystrophy is controversial because many genetic diseases that affect the white matter, even those disorders that are considered primary leukodystrophies, may involve non–white matter regions of the nervous system but not primarily or not only the myelin, and even the primary leukodystrophies may involve non–white matter regions of the nervous system. The term leukoencephalopathy is more neutral and may also be more accurate. Leukoencephalopathies comprise all inherited and acquired disorders that selectively or predominantly involve the white matter of the central nervous system (CNS), irrespective of the underlying pathophysiologic mechanism and histopathologic basis. In the pathologic classification, leukoencephalopathies can be grossly divided into (1) dysmyelinating (abnormal formation of myelin with disturbed myelination); (2) hypomyelinating (decreased myelin production); (3) demyelinating (loss of previously normal myelin both morphologically and functionally normal myelin), (4) spongiform (splitting of myelin and intramyelinic vacuole formation), and (5) cystic (white matter rarefaction and cystic degeneration) (Table 60-1). An etiologic classification

can also be used to classify leukoencephalopathies into the following categories: (1) immune mediated, (2) lipid disorders, (3) protein disorders, (4) amino or organic acid disorders, (5) defects of energy metabolism, and (6) other causes (Table 60-2). As might be expected, some diseases, such as X-linked adrenoleukodystrophy, resist being placed into a distinct category because, although it is usually considered a lipid disorder, there is an inflammatory response similar to the immune-mediated disorders. These classifications will certainly change as the molecular mechanisms for more of the leukoencephalopathies become elucidated. It is important to realize that the classification of diseases into disorders primarily affecting gray matter and disorders primarily affecting white matter is quite artificial. Although conceptually easier to consider, neurologic diseases often cannot be easily separated into highly compartmentalized disorders. For example, hypomyelinating and dysmyelinating disorders are frequently noted as a consequence of generalized metabolic diseases that secondarily affect the nervous system, such as galactosemia, phenylketonuria, glutaricaciduria type I, pyridoxine-dependent seizures, and Pompe’s disease, among others [Kolodny, 1993].

IMMUNE-MEDIATED DEMYELINATING DISORDERS The lack in understanding the basic pathophysiology of many of the diseases that affect white matter has led to a somewhat arbitrary categorization, which will evolve as the molecular and genetic causes of myelin diseases become elucidated. Childhood demyelinating disorders, which appear to be immunologically mediated, are characteristically the most difficult to separate because of the overlap and clinical similarities. These diseases consist of multiple sclerosis, acute disseminated encephalomyelitis, acute hemorrhagic leukoencephalitis, and myelinoclastic diffuse cerebral scler-

TABLE 60-1 Pathologic Classification of the Leukoencephalopathies DEMYELINATING OR DYSMYELINATING

HYPOMYELINATING

SPONGIFORM

CYSTIC

X-linked adrenoleukodystrophy

Pelizaeus-Merzbacher disease

Canavan’s disease

Globoid cell leukodystrophy

Alexander’s disease

Metachromatic leukodystrophy Glutaric aciduria type I Phenylketonuria

Myelin basic protein deficiency Aicardi-Goutières syndrome

Megaloencephalic leukoencephalopathy Maple syrup urine disease

Vanishing white matter disease/childhood ataxia with cerebral hypomyelination Alexander’s disease Mitochondrial disorders

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TABLE 60-2 Etiologic Classification of the Leukoencephalopathies IMMUNE MEDIATED

LIPID ABNORMALITIES

PROTEIN ABNORMALITIES

AMINO/ORGANIC ACID DISORDERS

Multiple sclerosis

Adrenoleukodystrophy

Pelizaeus-Merzbacher disease

Schilder’s disease

Globoid cell leukodystrophy Metachromatic leukodystrophy Sjögren-Larsson syndrome Cerebrotendinous xanthomatoses

Acute disseminated encephalomyelitis Acute hemorrhagic leukoencephalitis Aicardi-Goutières syndrome

ENERGY DEFECTS

OTHER CAUSES

Canavan’s disease

MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and stroke)

Vanishing white matter disease/childhood ataxia with cerebral hypomyelination

Myelin basic protein deficiency Alexander’s disease

Methylmalonic aciduria Propionic aciduria

Leber’s disease

Merosin deficiency

Maple syrup urine disease Phenylketonuria

Complex II deficiency

Megaloencephalic leukoencephalopathy

osis of Schilder. An interesting hypothesis that tries to explain some of the similarities of these disorders is based on the age of exposure to certain viral antigens that share homologous regions with potentially encephalitogenic peptides, such as myelin basic protein and proteolipid protein [Alvord et al., 1987]. According to this theory, very young children develop complete immunity to certain pathogens, but intermediate-aged children may develop a fulminant hypersensitivity to these epitopes, resulting in acute immunemediated demyelination or an intermediate response with perhaps relapsing-remitting symptoms. Until the basic mechanisms of immune-mediated demyelination are better understood, the classification of these diseases will remain difficult.

Multiple Sclerosis Multiple sclerosis is a demyelinating disorder that affects discrete areas of the CNS, including the optic nerves, in a quite variable relapsing-remitting fashion over a prolonged period of time. The disorder occurs worldwide and has a twofold more common incidence in females than males. Although usually considered to be a disease that affects people in early to middle adulthood, children develop multiple sclerosis and may account for up to 4% to 5% of all reported cases [Ghezzi et al., 1997; Ruggieri et al., 1999; Sindern et al., 1992]. The disease may be divided into a true childhood onset when it begins before age 10 and juvenile onset when it begins between the ages of 10 and 15 years [Hanefeld et al., 1991]. Multiple sclerosis in children younger than 10 years is considered unusual, but children younger than 6 years have been diagnosed using the standard diagnostic criteria used in adults [Ruggieri et al., 1999]. The juvenile onset, which appears to follow a course very similar to the adult-onset disorder, is the most common age for presentation, accounting for 80% of the childhood cases. The etiology for multiple sclerosis continues to be elusive. Many theories have been proposed and have included environmental, infectious, toxic, immunologic, and genetic causes for multiple sclerosis. The environmental or ecologic causes for multiple sclerosis have been difficult to study because of variability of disease and exposure rates. Cli-

Complex I deficiency

Cytochrome oxidase deficiency

mactic features such as low temperature, high humidity, and precipitation in the winter, for which respiratory tract infections were considered an intermediary, have been associated with a higher risk for the development of multiple sclerosis, especially if these environmental factors are present in the first 15 years of life. Infections, especially viral, have been proposed as etiologic factors for the development of multiple sclerosis [Delasnerie-Laupretre and Alperovitch, 1990]. Antibodies to measles, in addition to other viruses such as herpes simplex, varicella, rubella, Epstein-Barr, influenza C, and some parainfluenza viruses, have been detected in the serum and cerebrospinal fluid of multiple sclerosis cases [Kurtzke, 1995]. To date, no specific virus has been consistently isolated from people with multiple sclerosis. Nonviral organisms have been implicated in demyelination, including Acanthamoeba, Borrelia, Brucella, Campylobacter, and Hartmannella species; Chlamydia pneumonia; and mycobacterium, trypanosomes, diphtheria toxin, human herpes virus type 6, and tetanus toxoid. Dietary features, such as higher consumption of animal fat, protein, and meat, appear to correlate with an increased risk for development of multiple sclerosis. Toxic exposure to such items as organic solvents has been suggested but not proved as an etiologic factor in the development of multiple sclerosis. An immunopathogenic hypothesis has been proposed for the etiology of multiple sclerosis, which suggests that potentially autoaggressive T lymphocytes specific for myelin basic protein preexist in the normal immune system. One proposal suggests that the activation of autoreactive T cells occurs through molecular mimicry during bacterial or viral infection, which is likely to occur outside the CNS. The activated T cells then are likely to enter the CNS irrespective of their antigen specificity. Once inside the CNS, the recognition of an autoantigen within the CNS initiates a cascade of immunopathologic reactions, which include a pronounced inflammatory response and a breakdown of the blood-brain barrier. It is also probable that B cells are equally important in multiple sclerosis, especially for the development of demyelination. It appears that autoantibodies against surface antigens of myelin or oligodendrocytes are necessary to produce severe demyelination. Once these demyelinating antibodies have adhered to the myelin surface, complement is

Kaye and van der Knaap / Disorders Primarily of White Matter

activated and macrophages and microglia enter the region. The macrophages not only physically strip the myelin but also release complement, inflammatory mediators, and tumor necrosis factor-α, and they produce inducible nitric oxide synthase, which all participate in the injury to myelin. Studies in experimental autoimmune encephalomyelitis have documented the role of tumor necrosis factor-α in demyelination because administration of tumor necrosis factor-α augments experimental autoimmune encephalomyelitis, whereas inhibitors of tumor necrosis factor-α or its receptor will ameliorate the disorder [Kuroda and Shimamoto, 1991; Ruddle et al., 1990]. Adhesion molecules, such as the integrins leukocyte function-associated antigen 1 and very late appearing antigen 4, are cell surface proteins that participate in leukocyte circulation and in transendothelial migration [Hohlfeld, 1997]. These adhesion molecules can be found on activated leukocytes and likely participate in the migration of leukocytes across the vascular endothelium into the brain.

Clinical Characteristics and Subclassification Because of the slow, intermittent course and variety of symptoms in multiple sclerosis, the diagnosis may be difficult, especially in children. Various algorithms and classification schemes have been proposed over the years to address this issue [Poser and Brinar, 2001]. The Poser Criteria [Poser et al., 1983], widely adopted during the past two decades, advanced the diagnostic schema by integrating the results of laboratory, neuroimaging, and neurophysiologic tests with the clinical criteria. More recently, the International Panel on Multiple Sclerosis Diagnosis presented revised diagnostic criteria for multiple sclerosis, commonly known as the McDonald criteria [McDonald et al., 2001]. The McDonald criteria integrate MRI into the overall diagnostic scheme that establishes the dissemination of lesions in time and space. Unfortunately, the MRI criterion used in the McDonald criteria may not always be applicable to the pediatric population because the MRI lesions in childhood multiple sclerosis may be fewer and less dramatic than those seen in adult multiple sclerosis patients [Hahn et al., 2004]. Additionally, the new criteria simplified the diagnostic classification. In particular, previously used terms such as “clinically definite” and “probable multiple sclerosis” are no longer recommended. The outcome of a diagnostic evaluation is either “multiple sclerosis,” “possible multiple sclerosis,” or “not multiple sclerosis.” A summary of the McDonald criteria is available from the web site of the National Multiple Sclerosis Society at http://www.nationalmssociety.org/pdf/forpros/dx_tipsheet. pdf. The category of possible multiple sclerosis describes patients who have a clinical condition consistent with multiple sclerosis but who do not at present fully meet the diagnostic criteria. One of the diagnostic requisites is that there must be no better explanation for the clinical and paraclinical abnormalities. This category is particularly useful in children because other diseases, which include other leukodystrophies such as X-linked adrenoleukodystophy, Leber’s hereditary optic neuropathy, and acute disseminated encephalomyelitis, can appear clinically as multiple sclerosis.

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Subtypes of multiple sclerosis can be defined by the clinical course. An international consensus definition proposed these four categories for subgroups of multiple sclerosis [Lublin and Reingold, 1996]: 1. Relapsing-remitting multiple sclerosis. Clearly defined disease relapses with full recovery or with sequelae and residual deficit upon recovery. 2. Secondary progressive multiple sclerosis. Initial relapsing-remitting course is followed by progression. 3. Primary progressive multiple sclerosis. Disease is progressive from onset with only temporary plateaus and minor improvements allowed. 4. Progressive-relapsing multiple sclerosis. Progressive disease from onset with clear acute relapses. The same categories may apply in pediatric multiple sclerosis. In children, multiple sclerosis presents most often as a relapsing-remitting disease, but it may appear as a primary progressive form. In one study, 56% of children with multiple sclerosis had a relapsing-remitting course, 22% had an initially progressive course, and 22% had a mixed course [Duquette et al., 1987]. The clinical symptoms in children are much like those in adults. Common symptoms are visual changes, paresthesias, focal weakness, ataxia or unstable gait, vertigo, sphincteric problems, and cognitive changes. In a large study of 149 children with multiple sclerosis diagnosed before age 16, brainstem dysfunction was noted in 25%, motor and sensory disturbance in 17.5%, optic neuritis in 16.5%, and cerebellar disturbance in 9.1% [Ghezzi et al., 1997]. Visual disturbances are particularly common in pediatric multiple sclerosis, with optic neuritis occurring in as many as 25% to 70% of children [Ghezzi et al., 1997]. Other visual findings include nystagmus, dysmetria, diplopia, internuclear ophthalmoplegia, abducens nerve palsy, and saccadic pursuits. The long-term prognosis for childhood multiple sclerosis does not appear to be more severe than for adults, and in some cases, a more favorable outcome was noted in children when compared with adults, although the difference did not reach statistical significance because of the small number of children studied [Cole et al., 1995]. Very young children presenting with multiple sclerosis symptoms before 24 months of age may have a more unfavorable outcome [Ruggieri et al., 1999].

Clinical Studies Laboratory studies have proved extremely useful to augment the clinical diagnosis of multiple sclerosis. MRI and cerebrospinal fluid examination appear to be the most reliable tests in children with multiple sclerosis. MRI may be positive in as many as 80% of cases and demonstrates lesions on T2-weighted images in the cerebellum, brainstem, and central white matter, especially in the periventricular and juxtacortical regions [Golden and Woody, 1987; Selcen et al., 1996] (Fig. 60-1). Conventional mildly T2-weighted spin-echo MRI studies have shown the greatest efficacy to date for identifying multiple sclerosis lesions in brain [Gawne-Cain et al., 1997]. Cerebrospinal fluid immunoglobulin G index and oligoclonal bands are positive in as many as 75% of children with multiple sclerosis [Selcen et al., 1996]. The immunoglobulin G index

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FIGURE 60-1 Sagittal fluid-attenuated inversion recovery and T2-weighted magnetic resonance images in a 12-year-old female with multiple sclerosis. The images show multiple small white matter lesions in the periventricular and juxtacortical regions. The sagittal image shows the typical ovoid shape of the periventricular lesions, so-called Dawson fingers. There is also a brainstem lesion.

is derived from the ratio of cerebrospinal fluid immunoglobulin G–albumin to serum immunoglobulin G–albumin, which should be greater than 0.65 [Hershey and Trotter, 1980]. The use of evoked potentials, such as visual-evoked

potential and brainstem auditory-evoked potential, for the diagnosis of multiple sclerosis has increased over the years. An increased latency in the P100 potential of the visual evoked potential or an increase in the interpeak latency (I-III

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or I-V) on brainstem auditory-evoked potential often gives evidence of clinically silent lesions in the nervous system.

Pathology The characteristic lesion noted in multiple sclerosis is the white matter plaque, which is a sharply delineated, irregularly shaped, gray or pink region characterized by complete loss of myelin, reduced numbers of oligodendrocytes, but relative sparing of axons. These plaques may occur anywhere in the brain or spinal cord but have a predilection for the periventricular regions, corpus callosum, periaqueductal region, floor of the fourth ventricle, optic nerves and tracts, corticomedullary areas, and cervical spinal cord. The plaques are frequently macroscopic, ranging from 1 mm to 4 cm [McFarlin and McFarland, 1982a, 1982b]. In acute multiple sclerosis lesions, there is perivascular and parenchymal infiltration primarily with T cells and macrophages, although some B cells are also present. As the plaques mature, axonal degeneration, astrocytic proliferation, and lipid-laden macrophages become prominent. The final evolution of the plaque is the development of pronounced gliosis, which is much more dramatic in multiple sclerosis than in other diseases affecting white matter.

Genetics The prevalence of multiple sclerosis can vary according to region with as many as 250 cases per 100,000 population in the Orkney Islands north of the mainland of Scotland to 2 per 100,000 population in Japan [Kurtzke, 1995]. The best information available about possible genetic influences on the development of multiple sclerosis comes from monozygotic twin studies. It appears that a monozygotic twin may have up to a 25% risk for developing multiple sclerosis after the identical sibling is diagnosed with this disorder. The most information about genetic linkage concerns the major histocompatibility locus. The human leukocyte antigen type best studied in multiple sclerosis is the DR2 haplotype. Results have demonstrated that the DR2 allele itself or a closely related gene linked to this region may be associated with the development of multiple sclerosis [Hauser et al., 1989]. Although the major histocompatibility complex is the only region that clearly and consistently demonstrates linkage and association in multiple sclerosis studies, there is substantial evidence for polygenic inheritance of the disease [Kenealy et al., 2004; Sawcer et al., 2002]. In addition to genomic screens, a number of candidate genes have been evaluated for possible linkage to the development of multiple sclerosis. The diverse list of candidates has included genes encoding myelin proteins, cytokines and chemokines, T-cell receptors and costimulatory molecules, and matrix metalloproteinases, and some involved in viral pathogenesis. Further strategies such as high-density genome scanning may eventually unravel the complex inheritance of multiple sclerosis.

Treatment The drugs currently available to treat adult multiple sclerosis have not been extensively studied in children and adole-

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scents. Information on treatment of childhood multiple sclerosis has been gleaned mostly from studies of adults with the disease and from pediatric case reports or small case series. However, interferon-β and glatiramer acetate have been in used in children with no unexpected negative effects, and they appear to provide the same benefits as seen in adults with multiple sclerosis. Evidence-based clinical practice guidelines have been developed for the treatment of adult multiple sclerosis [Goodin et al., 2002]. In North America, the National Multiple Sclerosis Society has issued consensus recommendations regarding use of the current multiple sclerosis disease-modifying agents (http://www.nationalmssociety. org/pdf/forpros/Exp_Consensus.pdf) and when to consider changing therapy (http://www.nationalmssociety.org/pdf/ forpros/Exp_ChangTherapy.pdf).

TREATMENT OF ACUTE EXACERBATIONS Acute exacerbations of multiple sclerosis are generally treated with corticosteroids, administered as a short course of oral or parenteral therapy, which appear to shorten the course of the relapse. It is less certain whether steroid treatment favorably influences the extent of recovery. In the Optic Neuritis Treatment Trial [Beck et al., 1992], the group receiving intravenous methylprednisolone, 1 gram daily for 3 days, had a faster recovery of visual function than the placebo group in the first month, but by 6 months, the two groups were not statistically different with respect to visual recovery. However, the group that received methylprednisolone followed by oral steroids had a lower rate of developing multiple sclerosis in the first 2 years [Beck et al., 1993]. In the United States, intravenous methylprednisolone is the preferred treatment, although there is controversy about whether its superiority over high-dose oral steroids has been definitively established. Some practitioners provide a tapering dose of oral corticosteroids to follow the intravenous treatment, but there are limited clinical data to guide decision making on this point. Patients with severe, acute episodes of demyelination that have not responded to corticosteroid therapy with a recent (within about 2 months) severe exacerbation may benefit from a series of plasma exchanges involving 1.1 plasma volumes (54 mL/kg) every other day for 14 days [Weinshenker et al., 1999]. Intriguing data from a small series suggest that only patients with type II pathology (i.e., with immunoglobulin-mediated demyelination and activated complement deposition) will respond favorably to plasma exchange, but that all or most such patients will respond [Keegan et al., 2004].

APPROVED DISEASE-MODIFYING THERAPIES In 1993, interferon-β-1b (Betaseron or Betaferon) became the first medication approved by the U.S. Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis and offered a 31% reduction in exacerbation rate compared with placebo [IFNB Multiple Sclerosis Study Group, 1993]. Subsequently, other interferon-β products (Avonex, Rebif) were approved that offer lower immunogenicity and greater convenience. The relative safety and efficacy of these drugs is a highly contentious issue beyond

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the scope of this review. Administration of all interferon-β products requires frequent parenteral injection, either subcutaneous or intramuscular, depending on the product. All interferon-β formulations commonly cause a flulike syndrome upon initial administration, but this problem can be minimized by gradual dose escalation and pretreatment with ibuprofen or other nonsteroidal anti-inflammatory drugs. In most cases, the flulike syndrome lessens with continued use, and these drugs are generally well tolerated for long-term administration. Hepatotoxicity may occur particularly during the initial 6 months of therapy, and liver function tests are recommended for all patients taking interferon-β. Glatiramer acetate (Copaxone, copolymer-1) is chemically unrelated to the interferons but is roughly comparable in efficacy. A synthetic random copolymer of L-alanine, L-glutamic acid, L-lysine, and L-tyrosine, it also requires frequent subcutaneous administration but does not cause a flulike syndrome. Clinical trials with glatiramer acetate have shown a 29% reduction in relapse rate in relapsing-remitting multiple sclerosis, with a low-side effect profile [Johnson et al., 1995]. The product label for mitoxantrone (Novantrone [Serona, Inc., Rockland, MA]) says that it is “indicated for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis.” The drug is an immunosuppressive anthracenedione, chemically related to anthracyclines such as doxorubicin (Adriamycin). Mitoxantrone has been found in vitro to inhibit B-cell, T-cell, and macrophage proliferation and impair antigen presentation, as well as the secretion of interferon-γ, tumor necrosis factor-α, and interleukin-2. In clinical trials, mitoxantrone has demonstrated strong efficacy for reducing relapses, new MRI lesions, and accrual of disability. It appears more effective than the interferons and glatiramer but also carries a greater risk for adverse effects. A dose-dependent cardiotoxicity has led regulators to limit the lifetime cumulative dose to 140 mg/m2, effectively limiting patients to a 2- or 3-year course of therapy. The cardiotoxicity is manifested by reduced left ventricular ejection fraction and can lead to irreversible congestive heart failure. There is also a risk for inducing malignancy; acute myelogenous leukemia is a recognized complication of anthracycline therapy and has also been reported in patients receiving mitoxantrone.

INVESTIGATIONAL THERAPIES In view of the limited efficacy, inconvenience, toxicities, and high cost of the five approved disease-modifying drugs discussed previously, there is a clear need for new multiple sclerosis therapies. As of this writing, more than a dozen treatments are in clinical trials to evaluate their safety and effectiveness in multiple sclerosis patients. A review of these studies is beyond the scope of this chapter. However, a few of these therapies merit mention here because they are already commercially available (for other indications) or nearing regulatory approval. Natalizumab (Tysabri) is a monoclonal antibody that disrupts the interaction between lymphocytes and CNS vascular endothelial cells and thereby reduces the entry of inflammatory cells into the CNS. The target antigen is a4 integrin, a component of the very late, appearing antigen 4

membrane protein on the surface of T lymphocytes. Antegren is administered by monthly intravenous injection. In a phase II clinical trial lasting 6 months, this compound reduced exacerbation rate by 50% compared with a placebo in subjects with relapsing-remitting multiple sclerosis, and effected an even more marked reduction in new MRI lesions [Miller et al., 2003]. Two large phase III trials demonstrated efficacy in multiple sclerosis, and approval by the U.S. Food and Drug Administration occurred in 2004. In February 2005, the drug was suspended from marketing in the United States after the discovery of two patients with progressive multifocal leukoencephalopathy. Further clinical trials are expected to advance an understanding of the toxicity of the drug. Alemtuzumab (Campath-1H, MabCampath) is a lymphocyte-depleting humanized monoclonal antibody that is approved in many jurisdictions for the treatment of certain leukemias. In a pilot study of patients with relapsingremitting or secondary progressive multiple sclerosis, a single 5-day course of intravenous therapy led to a profound reduction in both relapses and new MRI lesions that was sustained for at least a year [Coles et al., 1999a]. Curiously, 30% of treated subjects in this study developed autoimmune thyroid disorders (Graves’ disease, thyroiditis), a toxicity not reported among patients receiving alemtuzumab for treatment of cancers or for other indications [Coles et al., 1999b]. A phase II study is underway that should help to establish the efficacy and safety of alemtuzumab. This 3-year study involves 300 subjects with early multiple sclerosis who were randomized to receive either 60 or 120 mg of Campath or treatment with an interferon-β product, Rebif, 44 μg, for subcutaneous injection. Results are expected by 2007. Daclizumab (Zenapax) is an immunosuppressive humanized monoclonal antibody that is approved for prophylaxis of acute renal transplant rejection. Daclizumab binds to a component of the receptor for interleukin-2 on activated T lymphocytes and thereby blocks binding of interleukin-2. In preliminary results from small phase II studies, both relapsing-remitting and secondary-progressive volunteers stabilized or improved following treatment. The phase II studies are continuing. Mycophenolate mofetil (Cellcept) is an immunosuppressive agent approved for prophylaxis of organ transplant rejection. Its mechanism of action is inhibition of inosine 5′-monophosphate dehydrogenase type II, the enzyme responsible for the de novo synthesis of the purine nucleotide guanine within activated T and B lymphocytes and macrophages. Open-label pilot studies of Cellcept in the treatment of multiple sclerosis have reported that the clinical course of multiple sclerosis was either unchanged or subjectively improved in many of the treated patients. Small randomized trials are underway.

Schilder’s Disease The term Schilder’s disease has been a source of confusion in the neurologic literature because the three cases, reported by Schilder between 1912 and 1924, were actually three different diseases [Poser et al., 1986]. One case, described in 1924, likely was a postinfectious encephalitis (subacute sclerosis panencephalitis); another case published in 1913 appears to have been X-linked adrenoleukodystrophy; and the third case, documented by Schilder in 1912, was a 14-year-

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FIGURE 60-2 Axial T2-weighted (A) and coronal contrast-enhanced T1-weighted images (B) in a young adult male with Schilder’s disease. Note the bilateral large, swollen lesions in the cerebral white matter, connected through a lesion in the corpus callosum. The peripheral rim of the lesion enhances.

old female with multifocal demyelination in the cerebrum associated with increased intracranial pressure and rapidly progressive neurologic signs. The last case is now considered an example of true Schilder’s disease.

Clinical Characteristics and Subclassification Schilder’s disease (myelinoclastic diffuse sclerosis) is a sporadic disease of unknown etiology, but it appears to be immune mediated with pathologic features identical to those of multiple sclerosis. It is likely that Schilder’s disease represents a more acute form of multiple sclerosis in children and adults [Poser et al., 1986]. The disease affects children usually between the ages of 5 and 14 years. The most common manifestation of this disease is an acute hemiplegia with headache, vomiting, behavioral deterioration, and ataxia. The clinical examination often reveals hemiplegia, aphasia, abnormal swallowing, ataxia, and increased reflexes. Some children may develop papilledema that may mimic a spaceoccupying mass or tumor [Kotil et al., 2002].

Clinical Studies The CT and MRI scans are remarkable for revealing usually one to three well-demarcated large areas of abnormal density or signal, with rim enhancement frequently noted in the frontal regions (Fig. 60-2). Unlike multiple sclerosis, the remainder of the CNS is normal on imaging studies. Cerebrospinal fluid studies may indicate a pleocytosis and at times

oligoclonal bands, increased synthesis of immunoglobulin G, and increased protein. The clinical diagnosis usually depends on the imaging studies once other entities have been excluded. An important differential diagnostic possibility to be considered in all cases of Schilder’s disease is X-linked adrenoleukodystrophy. In the case of doubt, very long chain fatty acids should be studied. X-linked adrenoleukodystrophy will have an elevation in the C26 fatty acids and an increase in the C26/C22 ratio. On MRI, there is usually symmetric posterior white matter involvement. Whereas the enhancement in Schilder’s disease affects the border of the lesion, the enhancement in X-linked adrenoleukodystrophy involves a rim inside the lesion.

Treatment The natural history of Schilder’s disease is variable, but sequelae are frequent. Five patients reported by Aicardi did not have any recurrences over 9 years, but other studies have shown relapses [Aicardi, 1992; Lyon et al., 1996]. Steroids bring a dramatic improvement in the neuroradiologic appearance of the cerebral lesion [Aicardi, 1992].

Acute Disseminated Encephalomyelitis Acute disseminated encephalomyelitis is usually a monophasic illness that may follow many infections or immunizations. The common infections include rubeola, rubella,

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varicella, herpes zoster, mumps, upper respiratory tract infections, and Mycoplasma pneumoniae infection [Johnson et al., 1985]. Acute disseminated encephalomyelitis commonly presents after a latent period after the infection, which may only be a few days. The clinical features in children include multifocal neurologic signs, lethargy, coma, and seizures that often implicate widespread areas of the brain, spinal cord, and optic nerves [Kesselring et al., 1990]. The optic neuritis in acute disseminated encephalomyelitis is usually bilateral, and the myelopathy is often complete, associated with areflexia. The laboratory studies, such as cerebrospinal fluid examination, often do not help differentiate acute disseminated encephalomyelitis from multiple sclerosis because pleocytosis, oligoclonal bands, and increased immunoglobulin G synthesis may be seen in both disorders [Kesselring et al., 1990]. The MRI abnormalities in acute disseminated encephalomyelitis are often more extensive, and lesions tend to be larger than multiple sclerosis lesions. The MRI findings in acute disseminated encephalomyelitis frequently include gray matter structures (cortex, basal ganglia, thalamus), as well as the brainstem, cerebellar peduncles or cerebellar hemispheres (Fig. 60-3). These features help differentiate acute disseminated encephalomyelitis from multiple sclerosis [Kesselring et al., 1990]. CT scan may be normal in many patients, and MRI is usually required to confirm the diagnosis [Leake et al., 2004]. The MRI lesions may persist even after a clinical recovery has occurred [Anlar et al., 2003].

Pathology

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The pathologic appearance of acute disseminated encephalomyelitis is very similar to what is seen in animal models of experimental allergic encephalomyelitis, which suggests a hypersensitivity reaction to a viral product or immune dysregulation. The appearance histologically is a periventricular demyelination and inflammation with lymphocytes and macrophages.

Treatment Medical management in these cases usually consists of highdose steroids or intravenous immunoglobulins, which may result in clinical improvement and resolution of the neuroimaging findings. About 71% of patients with childhoodonset acute disseminated encephalomyelitis recovered completely after 12 months of follow-up in one study involving 39 patients; however, there was a 33% incidence of relapse [Anlar et al., 2003].

Acute Hemorrhagic Leukoencephalitis In 1941, E. Weston Hurst described three young adults who developed an acute fatal encephalopathy after respiratory illnesses [Hurst, 1941]. These three individuals developed focal neurologic signs, confusion, and aphasia and died within a few days of the onset of the illness. The

FIGURE 60-3 Axial T2-weighted (A) and coronal contrast-enhanced T1-weighted (B) images in a 6-year-old female with acute disseminated encephalomyelitis. Note the multifocal white matter lesions, which have an asymmetric distribution over the cerebral white matter. The cortex and basal ganglia are not entirely spared. Contrast enhancement is usually subtle in acute disseminated encephalomyelitis.

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FIGURE 60-4 The two images of the top row originate from a 5-year-old female with Aicardi-Goutières syndrome; the two images of the bottom row originate from her clinically more severely affected brother of 4 months. Note the dotlike calcium deposits in the basal ganglia in both patients. The cerebral white matter disease is mild in the female, severe in her brother. The cerebral atrophy is also much more severe in the male.

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pathologic findings in two cases included edema and hemorrhage in the centrum semiovale with microscopic evidence of perivascular demyelination, necrosis, and infiltration with polymorphonuclear cells. The clinical picture of acute hemorrhagic leukoencephalitis includes an abrupt onset, usually after an infection with fever, with headache, meningismus, focal neurologic signs, altered sensorium, and occasionally seizures [Rosman et al., 1997]. The cerebrospinal fluid examination in acute hemorrhagic leukoencephalitis demonstrates a polymorphonuclear pleocytosis with an elevated protein and normal glucose. This entity is considered by most investigators to be a more severe and rapidly fulminant form of acute disseminated encephalomyelitis and probably should not be separated from acute hemorrhagic leukoencephalitis on an etiologic basis until a clear understanding of the pathophysiology of the disorder becomes available. Treatment consists of aggressive use of corticosteroids, which has been associated with a favorable outcome in some cases, although severe neurologic injury and death frequently occur [Rosman et al., 1997].

Aicardi-Goutières Syndrome In 1984, Aicardi and Goutières reported eight infants from five families who suffered from an early-onset familial encephalopathy with chronic cerebrospinal fluid lymphocytosis and basal ganglia calcifications mimicking an intrauterine infectious process but with negative TORCH (toxoplasmosis, other infections, rubella, cytomegalovirus infection, and herpes simplex) associations [Aicardi and Goutières, 1984]. Clinically, the patients revealed bilateral spasticity, dystonia, ocular jerks, and acquired progressive microcephaly with a rapid course toward profound deterioration and death. In addition, CT scan showed diffuse and progressive brain atrophy and deep white matter hypodensities. The authors suggested a probable genetic condition with autosomal recessive inheritance. Leukoencephalopathy is often noted on MRI, which may lead to diagnostic confusion if no CT scan is available to indicate the calcium deposits. CT scan also shows white matter hypodensities located mainly around the ventricles (Fig. 60-4). These hypodense lesions appear as hyperintense on MRI T2-weighted sequences, but they are not constant (see Fig. 60-4), and a diffuse leukodystrophic appearance is uncommon [Goutières et al., 1998]. Signs of severe and progressive brain atrophy with enlarged ventricles and sulci increasing on successive examinations are an almost constant finding on CT and MRI. The diagnosis is confirmed by the clinical picture, identification of cerebrospinal fluid lymphocytosis, and MRI and CT findings, especially basal ganglia calcifications. A systemic sign that can occasionally be noted in patients is vascular necrotic cutaneous lesions on the toes, which appear similar to chilblains with acrocyanosis [Goutières et al., 1998]. Many of the patients studied have had elevated serum and cerebrospinal fluid levels of interferon-α, which has been used as a diagnostic marker for the disease and may be implicated in the pathophysiology for the disorder [Goutières et al., 1998; Lebon et al., 2002]. Interferons constitute a family of signal proteins. Upon binding to specific receptors, they induce activation of a

signal transduction pathway that activates a broad range of genes, which are involved in antiviral, immunomodulatory, and antiproliferative activities. Transgenic mice with astrocyte-targeted chronic overproduction of interferon-α develop a progressive inflammatory encephalopathy with angiopathy and calcifications in the basal ganglia [Campbell et al., 1999]. These neuropathologic features are very similar to those found in Aicardi-Goutières syndrome, suggesting a causal relationship between the elevated levels of interferonα and the disease. The inheritance of Aicardi-Goutières syndrome is presumed to be autosomal recessive, but no gene has been identified.

HYPOMYELINATING AND DYSMYELINATING DISORDERS Pelizaeus-Merzbacher Disease Classic Pelizaeus-Merzbacher disease is an X-linked disorder of proteolipid protein expression. The disease was first described clinically by Pelizaeus in 1885, and later in 1910 the clinical and pathologic features of the same family were documented by Merzbacher [Merzbacher, 1910; Pelizaeus, 1885]. The classification of PelizaeusMerzbacher disease as a hypomyelinating disorder was proposed by Zeman and co-workers in 1964, and they perspicaciously predicted proteolipid protein as being involved in this disease [Zeman et al., 1964]. Previous reports had divided Pelizaeus-Merzbacher disease into types I to VI based on neuropathologic and hypomyelinating features, but recent molecular genetic information more accurately defines Pelizaeus-Merzbacher disease as an X-linked disease consisting of hypomyelination that is linked to the PLP gene [Gencic et al., 1989; Hudson et al., 1989; Seitelberger, 1970]. The nosology of Pelizaeus-Merzbacher disease has been further complicated by the discovery that a form of Xlinked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic conditions [Saugier-Veber et al., 1994].

Clinical Characteristics and Subclassification The clinical features of Pelizaeus-Merzbacher disease are slowly progressive and consist of peculiar pendular eye movements, head shaking, hypotonia, mental retardation, choreoathetosis, dystonia, cerebellar ataxia, and pyramidal signs [Adams et al., 1996; Boulloche and Aicardi, 1986]. There is a spectrum, however, in the ages of presentation and progression of symptoms that is somewhat arbitrarily divided into three types [Seitelberger et al., 1996]. A fourth type of Pelizaeus-Merzbacher disease, X-linked spastic paraplegia type 2, can also be considered as a later manifestation of proteolipid protein expression difficulties because X-linked spastic paraplegia has been described in one family in which a classic form of Pelizaeus-Merzbacher disease was also noted [Seitelberger et al., 1996].

TYPE I—CLASSIC The classic form of Pelizaeus-Merzbacher disease begins in the first months of infancy with abnormal eye movements consisting of rapid, irregular, small- or large-amplitude oscil-

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lations that can occur in either a horizontal or vertical direction [Adams et al., 1996; Boulloche and Aicardi, 1986]. A head tremor is also noted at this time. Motor development progresses very slowly, with the eventual onset of spasticity, ataxia, and involuntary movements. Pelizaeus-Merzbacher disease is frequently misdiagnosed as cerebral palsy at this stage because of the slow onset of symptoms. Later, optic atrophy and seizures may occur. Although the physical handicaps are severe, mental abilities are usually better preserved. Typically, the progression of the disease slows towards the middle or end of the first decade, with death occurring in the adolescent or early adult ages.

TYPE II—CONNATAL The connatal type, which presents shortly after birth, has a more aggressive clinical course consisting of severe hypotonia, extrapyramidal signs, stridor, and feeding difficulties [Boulloche and Aicardi, 1986; Seitelberger et al., 1996]. The laryngeal stridor may be a frequently overlooked presenting feature in these early-onset cases [Boulloche and Aicardi, 1986]. The marked hypotonia in the connatal form of this disease can mimic spinal muscular atrophy, although pathologic studies do not confirm an abnormality in anterior horn cells or peripheral nerve [Kaye et al., 1994]. Optic atrophy can usually be identified early, and death may occur within months to years.

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TYPE III—TRANSITIONAL Transitional forms of Pelizaeus-Merzbacher disease have a clinical presentation that often combines features from both the classic and connatal types but with quite a variable progression [Seitelberger et al., 1996]. Included in this subtype are patients with null mutations in the PLP1 gene. These mutations prevent expression of both PLP1 and DM20 and are typically associated with a complicated phenotype that includes a slowly spastic paraplegia with a loss of ambulation and impaired cognitive function [Garbern et al., 2002]. These patients also have electrophysiologic evidence of mild, nonuniform demyelinating peripheral neuropathy [Shy et al., 2003].

SPASTIC PARAPLEGIA Spastic paraplegia type 2 had been known to be an X-linked form of spastic paraplegia that could occur in a pure form consisting of a slowly progressive spastic paraplegia involving only lower limbs or a complicated form with other features of Pelizaeus-Merzbacher disease such as nystagmus, dysarthria, and ataxia. Spastic paraplegia type 2 is considered an allelic variant of Pelizaeus-Merzbacher disease with defects in the PLP gene identified [SaugierVeber et al., 1994].

FIGURE 60-5 T2- and T1-weighted images in a 6-year-old male with Pelizaeus-Merzbacher disease. The degree of myelination would be normal for a neonate. Repeated follow-up magnetic resonance images indicated an unchanged pattern of myelin deposition in this male, indicative of an arrest of myelination early in life.

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Clinical Studies CT scan of the brain is frequently unrevealing, but MRI is helpful in demonstrating the hypomyelination that is characteristic of the disorder. The MRI shows a decrease on T1-weighted signal and an increase on T2-weighted signal in white matter regions demonstrating deficient myelin development [Kendall, 1993] (Fig. 60-5). Repeated MRI head studies from early infancy demonstrate the lack of the expected maturational decrease in the T2-weighted signal, suggesting the diagnosis of Pelizaeus-Merzbacher disease [Ono et al., 1993]. Brainstem auditory-evoked responses and somatosensory-evoked potentials are consistently abnormal. Electrophysiologic evidence of motor neuron dysfunction has been reported in infants, and a mild, nonuniform demyelinating peripheral neuropathy has been noted in adolescents with a more slowly progressive disease [Kaye et al., 1994; Shy et al., 2003].

Pathology The gross morphologic examination of brain demonstrates cerebral and cerebellar atrophy, which is especially prominent in the early-onset forms of the disease [Seitelberger, 1970]. The characteristic neuropathologic appearance of Pelizaeus-Merzbacher disease consists of a marked deficiency of CNS myelin except for preserved islands of myelin surrounding blood vessels (tigroid appearance) [Boulloche and Aicardi, 1986; Zeman et al., 1964]. Myelin staining reveals a marked deficiency of myelin, especially in the deeper cerebral structures. Oligodendrocytes are reduced in number, whereas astrocytes are markedly increased [Seitelberger, 1995]. The nerve cells are typically normal, but heterotopic neurons can be found. There is increasing evidence of axonal pathology in Pelizaeus-Merzbacher disease, in particular in the milder variants [Garbern et al., 2002]. Myelin appearance, both macroscopically and microscopically, in peripheral nerves is normal [Boulloche and Aicardi, 1986; Zeman et al., 1964].

Biochemistry The biochemical studies in CNS myelin led to the discovery of a defect in the metabolism of proteolipid protein. Myelin basic protein and proteolipids were reduced in PelizaeusMerzbacher disease [Bourre et al., 1978]. The absence of proteolipid protein, demonstrated by immunocytochemistry and enzyme-linked immunosorbent assay, was compared with the proteolipid protein defect in the jimpy mouse [Koeppen et al., 1987]. The fact that proteolipid protein is not normally found in peripheral myelin was thought to explain the sparing of peripheral nerve myelin in this disorder.

Genetics The PLP gene has been linked to the Xq21-22 region [Mattei et al., 1986; Willard and Riordan, 1985] and found to be about 17 kilobases in length and to contain 7 exons [Diehl et al., 1986]. The gene encodes two protein isoforms, PLP and DM20 proteins, by means of alternative splicing [Nave et al., 1987]. The PLP/DM20 gene is similar to some other genes, such as those encoding the neuron-specific

membrane glycoprotein M6 and shark proteolipid myelin proteins, which are expressed early in development and have a broad functional range [Kittagawa et al., 1993; Yan et al., 1993]. Studies of animal models have tried to define the functions of these two myelin proteins. Based on numerous clinical and histopathologic analyses, it is clear that proteolipid protein gene products have an important structural role in the CNS myelin sheath, but these gene products also play a role in the development of oligodendrocytes. For example, the dysmyelinating proteolipid protein animal mutants such as the jimpy mouse (a splice acceptor site mutation resulting in deletion of exons and a frameshift) and the shaking pup (a His75Pro substitution) are also associated with a block in oligodendrocyte development [Hudson et al., 1987; Nadon et al., 1990]. The nonlethal mouse model for PelizaeusMerzbacher disease, rumpshaker (a Ile86Thr substitution), is associated with myelin deficiency but normal numbers and appearance of oligodendrocytes, suggesting potentially independent roles for proteolipid protein gene products in oligodendrocyte maturation and CNS myelin assembly [Schneider et al., 1992]. DM20 is expressed earlier than PLP in the developing CNS, but at later time points, proteolipid protein is the predominant protein, suggesting that DM20 and PLP may play different roles during CNS development [Macklin et al., 1990]. DM20 mRNA but not PLP mRNA can be detected in the peripheral nervous system, but no function for the DM20 protein in the peripheral nervous system has yet been demonstrated. In people affected with Pelizaeus-Merzbacher disease, point mutations that result in amino acid substitutions, frameshift deletion and insertion mutations, or complete deletions of the PLP protein have been identified, but mutations in the coding region have been identified in only 25% of these cases [Nave and Boespflug-Tanguy, 1996]. Mutations that disrupt the PLP1 gene-specific domain (residues 116 to 150), as well as null mutations, cause mild, demyelinating peripheral neuropathy [Shy et al., 2003]. It appears that up to 50% of children with Pelizaeus-Merzbacher disease may have a duplication in the PLP gene, similar to the 1.5kilobase duplication in the PMP22 gene identified in CharcotMarie-Tooth disease, which results in a defect in PLP gene expression [Cailloux et al., 2000]. Also, even families without identified mutations in the PLP gene may demonstrate linkage to the PLP gene region on Xq22, suggesting that the molecular defect resides in the PLP genomic region, perhaps affecting gene expression [Boespflug-Tanguy et al., 1994]. In two brothers with Pelizaeus-Merzbacher disease, increased PLP gene expression was also identified without duplication of the gene [Carango et al., 1995]. There appears to be at least one other X locus for a Pelizaeus-Merzbacher–like disease because a family with a clinical appearance very similar to classic PelizaeusMerzbacher disease was noted to have linkage not to the PLP gene but to a new locus on Xq [Lazzarini et al., 1997]. In addition, there appear to be several autosomal loci, one of which contains the gene encoding alpha 12 (connexin 46.6) [Uhlenberg et al., 2004].

Alexander’s Disease Alexander’s disease was first described in 1949 in a child with macrocephaly [Alexander, 1949]. This disorder is an

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uncommon degenerative disorder of the CNS occurring most often in children. It leads to relentless cognitive and motor decline. The pathologic hallmark of the disorder is the presence of Rosenthal fibers located within astrocytes. The genetic inheritance has been identified as a spontaneous de novo, dominant mutation in one of the alleles of the gene for the astrocytic intermediate filament protein: glial fibrillary acidic protein (GFAP) [Brenner et al., 2001; Rodriguez et al., 2001]. In several families with later-onset disease, autosomal-dominant inheritance has been documented [Namekawa et al., 2002; Stumpf et al., 2003; Thyagarajan et al., 2004].

Clinical Features and Subclassification Alexander’s disease has been classified into three distinct types; although without a biochemical or molecular genetic assay to verify the diagnosis, this distinction may be somewhat arbitrary, with progression of disease not always dependent on the age of onset [Pridmore et al., 1993]. These variants have an infantile, juvenile, and adult onset [Russo et al., 1976].

INFANTILE ONSET The first case, which was described by Alexander, occurred in a 15-month-old child with megalencephaly, hydrocephalus, and psychomotor retardation [Alexander, 1949]. This child died 8 months after the onset of the illness and was noted on postmortem examination of the brain to have refractile bodies in the subependymal, subpial, and perivascular regions throughout the neuraxis. These refractile bodies were subsequently found to be identical to Rosenthal fibers [Schlote, 1966]. Subsequent reports confirmed the clinical features as consisting of psychomotor retardation, megalencephaly or hydrocephalus, spastic quadriparesis, and seizures. The head circumference in these children frequently exceeds the 98th percentile within 6 to 18 months [Johnson, 1996]. In children who present at a later age, the megalencephaly may not be apparent. The disease may start in the neonatal period, and some infants appear unresponsive, never even learning to smile. The ventricular system is often enlarged, with some children developing an obstructive hydrocephalus, which appears to be due to subependymal Rosenthal fibers that accumulate and obstruct the aqueduct of Sylvius [Garcia et al., 1992]. The progression of the disease is unremitting, with death occurring anywhere from age 1 to 10 years, although rarely children may survive until their teens. There appears to be an equal sex distribution for the disease, although earlier studies based on small sample sizes and ascertainment biases demonstrated a male preponderance [Reichard et al., 1996].

JUVENILE ONSET Children who present after early childhood typically have an average onset of symptoms at age 3 to 4 years with a reported range of 3 months to 12 years [Reichard et al., 1996]. The clinical symptoms are distinct from the infantileonset form, with progressive paresis, bulbar involvement, increased deep tendon reflexes, ataxia, and preservation of sensory and mental functions [Russo et al., 1976]. The dur-

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ation of the illness is much longer, with the possibility of survival as long as 8 to 15 years after onset of symptoms.

ADULT ONSET The adult-onset disease is an allelic variant of the infantileand juvenile-onset disorder with mutations in the GFAP gene. The cases described in adults have been divided into those with a relapsing-remitting course similar to that of multiple sclerosis or asymptomatic individuals who have developed the disease in the setting of a prolonged medical illness [Russo et al., 1976]. Upon postmortem examination of the brain, Rosenthal fibers are present, but demyelination is variable, which may make the distinction from other diseases difficult because Rosenthal fibers may also be present in disorders such as multiple sclerosis. However, reports on these patients were published before the gene for Alexander’s disease was found. A more recent report described three sisters and their father who had a progressive neurologic disease that consisted of palatal myoclonus, spastic paraparesis, and cerebellar ataxia starting in the adult years associated with Rosenthal fibers on postmortem examination [Schwankhaus et al., 1995]. The adult patients with Alexander’s disease and documented GFAP mutations have a chronic progressive disease dominated by bulbar symptoms [Namekawa et al., 2002; Stumpf et al., 2003; Thyagarajan et al., 2004].

Clinical Studies The MRI and CT scans are usually highly suggestive of the disorder. The CT scan early in the course of the disease reveals prominent low density in the frontal deep white matter that may become cystic over time [Johnson, 1996]. The areas immediately adjacent to the ventricles may demonstrate increased density, with enhancement noted in the periventricular, thalamic, and basal ganglia regions [Farrell et al., 1984] (Fig. 60-6). The MRI is more sensitive than CT scan and demonstrates similar findings with extensive cerebral white matter changes with frontal predominance, a periventricular rim with high signal on T1-weighted images and low signal on T2-weighted images, and abnormalities of basal ganglia, thalami, and brainstem, which may be used to make a presumptive diagnosis of Alexander’s disease [van der Knaap et al., 2001] (see Fig. 60-6). Neurophysiologic studies performed on these patients have included electroencephalograms, which demonstrated slow activity and sharp waves at times localized over one or another frontal or frontocentral brain region [Pridmore et al., 1993]. The brainstem auditory-evoked responses have shown slowing after wave I [Pridmore et al., 1993].

Pathology The two major pathologic features of Alexander’s disease are a progressive failure of central myelination and the widespread presence of Rosenthal fibers within structural and reactive astrocytes [Reichard et al., 1996]. The cortical neurons appear unaffected. Over time, white matter throughout the brain is affected, with demyelination occurring in the centrum semiovale, although there is frequent sparing of the subcortical white matter. Rosenthal fibers are present in

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A FIGURE 60-6 A, Computed tomography scan (top row) in a 1-month-old male with Alexander’s disease demonstrates increased density of the periventricular rim (left), which enhances after contrast (right). Magnetic resonance images (bottom row) demonstrate a periventricular rim of low signal intensity on the T2-weighted image (left), which shows prominent enhancement after contrast on the T1-weighted image (right). There are signal abnormalities in the basal ganglia. Because both unmyelinated white matter and abnormal white matter have a high signal on T2-weighted images and a low signal on T1-weighted images, it is difficult or impossible to appreciate white matter abnormalities in a young infant.

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B FIGURE 60-6 B, T2-weighted images (top row) in a male with Alexander’s disease at the ages of 6 (left) and 10 years (right). Note the mild signal abnormalities and slight swelling of the basal ganglia at the age of 6. At the age of 10, the basal ganglia have become atrophic. The T1-weighted images at the age of 10 years (bottom row) show a discontinuous thin rim of high signal on the unenhanced image (left) and some enhancement of this rim after contrast (right). (A, Courtesy of Dr. S. Blaser, Department of Diagnostic Imaging, Hospital for Sick Children, Toronto.)

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astrocytes throughout the neuraxis in both gray and white matter regions. There is a preponderance of Rosenthal fibers in subpial regions, subependymal zones, and perivascular cuffs [Alexander, 1949]. On the ultrastructural examination, the Rosenthal fibers appear as a dense mass of finely granular osmophilic material, enmeshed in glial filaments, located in the footplates and in the perikaryon of cells [Reichard et al., 1996]. The degree of demyelination does not always correlate with the density of Rosenthal fibers [Johnson, 1996].

Biochemistry There has been no biochemical defect consistently described in Alexander’s disease. A stress protein, alpha B crystallin, has been elevated in Alexander’s disease, but this may be a nonspecific finding because no defect has been found in the gene for alpha B crystallin [Iwaki et al., 1992]. One report described elevation of tiglylglycine in urine of patients with Alexander’s disease [Johnson, 1996].

Genetics Almost all cases of childhood Alexander’s disease (infantile and juvenile) are sporadic and are believed to be caused by a spontaneous de novo, heterozygous, dominant mutation in one of the alleles of the gene for the astrocytic intermediate filament protein, GFAP [Brenner et al., 2001; Gorospe et al., 2002; Li et al., 2002; Rodriguez et al., 2001; Shiroma et al., 2003]. Adult cases are more often familial and are caused by an inherited, dominant mutation in one of the GFAP alleles [Namekawa et al., 2002; Stumpf et al., 2003; Thyagarajan et al., 2004]. At least 21 different mutations at 15 sites (often in exons 1, 4, or 8) have been identified in more than 50 patients, many of which are predicted to cause the substitution of an arginine by another amino acid [Johnson and Brenner, 2003]. The clinical phenotype cannot be completely predicted by the genotype, although mutations in the adult-onset patients tend to occur at different locations on the gene. The severity of disease also does not strictly parallel the particular mutation present, but in some instances, a general correlation exists [Rodriguez et al., 2001]. The mutations in the GFAP gene have been found in the United States, Europe, and Japan [Shiroma et al., 2003]. The genetic testing for Alexander’s disease has replaced the cerebral biopsy as the major tool for diagnosis. However, in two infantile cases, no GFAP mutation was found by sequencing despite a pathologically proven diagnosis of Alexander’s disease [Brenner et al., 2001; Rodriguez et al., 2001], suggesting that there may be additional genes that are responsible for Alexander’s disease. A transgenic mouse was created that overexpressed the GFAP gene. This mouse model died within 10 days of birth and was noted to have widespread Rosenthal fibers throughout the CNS [Messing et al., 1998]. Although this does not necessarily provide an exact model for Alexander’s disease, it provides a means to study the formation of Rosenthal fibers.

Treatment At this time, no treatment other than supportive care and treatment of possible seizures is available to these children.

Myelin Basic Protein Deficiency A deficiency of myelin basic protein has been described, caused by a deletion of the 18q 22.3-qter region, which contains the locus for myelin basic protein, in a 25-year-old woman who had symptoms of involuntary movements, ataxia, and mild mental retardation [Lyon et al., 1996]. The MRI demonstrated deficient and abnormal myelination. The woman’s 18-month-old son was also affected. It is probably not surprising that a deficiency of myelin basic protein has been identified in humans because a mouse model, the shiverer mouse, has been recognized for some time. A relatively frequent chromosomal deletion syndrome, the 18q- syndrome, is caused by the loss of the distal part of the long arm of chromosome 18. Children with this syndrome have short stature because of growth hormone deficiency, narrow or atretic external ear canals with hearing loss, midfacial hypoplasia, microcephaly, and frequently mental retardation. MRI scans demonstrate a diffuse decrease in central white matter that is thought to be related to a reduction in the MBP gene [Gay et al., 1997; Lyon et al., 1996]. White matter T1 and T2 relaxation times were significantly prolonged in patients compared with controls at all ages studied, suggesting incomplete myelination. Chromosome analysis using fluorescence in situ hybridization techniques showed that all patients with abnormal MRI scans and prolonged white matter T1 and T2 relaxation times were missing one copy of the MBP gene [Gay et al., 1997]. The one patient with normal-appearing white matter and normal white matter T1 and T2 relaxation times possessed two copies of the MBP gene. MRI and molecular genetic data suggest that incomplete cerebral myelination in 18q– is associated with haplo-insufficiency of the MBP gene [Gay et al., 1997].

SPONGIFORM LEUKOENCEPHALOPATHIES Canavan’s Disease The first neuropathologic observation of a form of leukodystrophy known as spongy degeneration of brain was published by Myrtelle Canavan in 1931, although at the time, this pathology was attributed to Schilder’s disease [Canavan, 1931]. Because of this classic description, however, the most commonly recognized name for spongy degeneration of brain is the eponym Canavan’s disease. The clinical and inherited delineation of Canavan’s disease was first recognized by van Bogaert and Bertrand in 1949 [van Bogaert and Bertrand, 1949]. In this report, five Jewish patients developed macrocephaly and severe mental retardation associated with spongy degeneration of brain. In 1988, Canavan’s disease was identified as caused by a deficiency of aspartoacylase, which leads to an increase in N-acetylaspartic acid in brain and urine. The gene encoding aspartoacylase was cloned in 1993 [Matalon et al., 1988, 1993].

Clinical Characteristics and Subclassification Canavan’s disease is a relentlessly progressive autosomalrecessive leukodystrophy, which is frequently fatal within the first decade. There are three recognized clinical variants:

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the most common infantile variant and two unusual presentations consisting of congenital and juvenile-onset forms. Although separating Canavan’s disease into these categories is useful in terms of diagnosis, it is likely that they represent merely a spectrum of clinical manifestations.

INFANTILE ONSET The classic presentation in infancy consists of a period of normal development followed by lethargy and significant hypotonia, especially manifested as a head lag. Frequently by 4 months of life, the head growth exceeds the 90th percentile, and by 6 months, the development is clearly delayed. The macrocephaly may not always exceed the 95%, but there is invariably a relative increase in the head size compared with the percentiles for height and weight [Gascon et al., 1990]. The diagnosis of Canavan’s disease should be considered in any infant who presents with signs of hypotonia, head lag, and macrocephaly. In the later half of the first year, the children develop hyperextension of the extremities and eventually develop spasticity. Irritability and difficulty sleeping usually manifest by the end of the first year. Optic atrophy and seizures are typically apparent by the second year. Feeding inevitably becomes a major problem requiring the placement of a nasal or gastric feeding tube. The life span is limited, with most patients dying within the first decade

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congenital variant is uncommon, with only 2 of 165 biochemically confirmed cases occurring in children with symptoms during the first weeks of life [Matalon et al., 1993]. Early in the disease, the children appear to have severe visual problems despite a frequently normalappearing funduscopic examination. Coarse pendular nystagmus or strabismus is usually noted, and optic atrophy develops later. This disease progresses to cause severe difficulty with sucking and swallowing, loss of motor control, and spasticity [Adachi et al., 1973]. Seizures, associated with hypotonia and developmental delay, may begin very early in the congenital variant, which often makes the diagnosis difficult until white matter abnormalities or macrocephaly can be appreciated.

JUVENILE VARIANT Only a few cases of the juvenile variant of Canavan’s disease have been described. These children may appear normal until as late as 4 or 5 years of age. Many of the juvenile patients had been described before the biochemical characterization of Canavan’s disease [Adachi et al., 1973], but some confirmed juvenile cases have been recognized [Toft et al., 1993]. These children have a much slower progression of the disease, with dysarthria, seizures, and developmental delay as prominent features.

CONGENITAL TYPE

Clinical Studies

Children with congenital Canavan’s disease begin in the first weeks of life with hypotonia and poor feeding. This

The CT scan early in the course of the disease is associated with a diffusely decreased attenuation of the white matter

FIGURE 60-7 Axial T2-weighted images in a 12-month-old male with infantile Canavan’s disease. Note the diffusely abnormal cerebral and cerebellar white matter and brainstem. There are signal abnormalities in the thalamus and globus pallidus, whereas the putamen and caudate nucleus are spared.

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that affects subcortical white matter [Rushton et al., 1981]. The MRI scan is remarkable for an increased signal on T2weighted images and decreased signal on the T1-weighted images in white matter, primarily affecting the cerebral white matter, thalamus, and globus pallidus, with sparing of the putamen and caudate nucleus [Engelbrecht et al., 1995] (Fig. 60-7). Initially, especially in the congenital variant, the MRI or CT scans may appear normal [Matalon et al., 1990]. Magnetic resonance spectroscopy may be diagnostic revealing an elevated N-acetylaspartate–to-creatine ratio. The electroencephalogram may also be normal despite the presence of seizures, with slowing of the background and abnormal sleep spindles at times being the only abnormality [Gascon et al., 1990]. Brainstem auditory-evoked potentials are frequently associated with slowing after wave I or slowing of the waves III to V or I to V latency [Gascon et al., 1990]. Visual-evoked potentials are usually absent or have a delayed latency of the P100 wave [Gascon et al., 1990]. Because Canavan’s disease does not affect the peripheral nerve myelin, the nerve conduction velocities are normal. Since 1988, the standard for diagnosis of Canavan’s disease has been the measurement of urinary N-acetylaspartic acid in urine, with Canavan’s disease patients typically having values at least 5- to 10-fold higher than control urine samples [Matalon et al., 1995]. Other leukodystrophies tested do not demonstrate an increase in N-acetylaspartic acid levels [Matalon et al., 1989]. The serum, cerebrospinal fluid, and brain also typically have elevated N-acetylaspartic acid levels [Matalon et al., 1990]. The deficiency of the enzyme aspartoacylase results in the accumulation of N-acetylaspartic acid. This enzyme is measured in fibroblasts because plasma or blood cells do not have measurable levels [Matalon et al., 1989]. Obligate heterozygotes have been found to have about a 50% level of aspartoacylase enzyme activity compared with controls, which makes carrier detection possible [Matalon et al., 1995].

Pathology The prominent pathology noted on light microscopy is the presence of multiple vacuoles (spongy degeneration) seen in

FIGURE 60-8 Light microscopy from infant with Canavan’s disease demonstrating the dysmyelination with vacuoles but sparing of axons on the Bodian stain.

the deeper cortical regions but to a greater extent in the subcortical white matter [Adachi et al., 1973] (Fig.60-8). There is evidence of demyelination without evidence of breakdown products and sparing of axonal fibers and oligodendroglial cells early in the disease course. At a cellular level, type II Alzheimer cells are present, and there is a relative absence of microglial and inflammatory cells [Luo and Huang, 1984]. The electron microscopic appearance is noteworthy for splitting of myelin lamellae and swelling of the astrocytic cytoplasm and processes, but the neurons and their processes and synaptic complexes appear unchanged [Adachi et al., 1973].

Biochemistry The synthesis of N-acetylaspartic acid is performed exclusively in brain by the enzyme L-aspartate-N-acetyltransferase [Goldstein, 1959]. Despite the relative abundance of this amino acid, which is second only to glutamic acid, little is known about the functional significance of N-acetylaspartic acid in brain. Postulates to explain the purpose of N-acetylaspartic acid have suggested that it may function as a neurotransmitter [Miyake et al., 1981] or perhaps as a necessary factor for the conversion of fatty acids, which are components of myelin [Shigematsu et al., 1983]. The enzyme required to hydrolyze N-acetylaspartic acid into aspartate and acetate is aspartoacylase. This enzyme can be found in several tissues, including brain, but aspartoacylase activity is localized within white matter and not cortical brain tissue [Kaul et al., 1991]. The biologic function of N-acetylaspartic acid is not understood, but its accumulation in Canavan’s disease suggests that the breakdown of N-acetylaspartic acid by aspartoacylase is essentially for the normal maintenance of myelin or other white matter components.

Genetics Canavan’s disease is inherited as an autosomal-recessive disorder. The molecular basis of Canavan’s disease was elucidated in 1993 with the cloning of the gene and the identification of a common missense mutation [Kaul et al., 1993]. This gene for human aspartoacylase is localized to the 17p13-ter region and spans 29 kb of the genome [Kaul et al., 1994]. The transcript is 1.8 kb in length and contains an open reading frame on the complementary DNA that is 939 bases long and predicts a 313–amino acid residue [Matalon et al., 1993]. The identified mutations can be divided according into Ashkenazi Jewish and non-Jewish mutations. Two mutations account for 97% of the mutant alleles in Jewish families. These two mutations include the most frequent mutation, which causes a substitution of glutamic acid for alanine at codon 285 (Glu285Ala), and another common mutation, which results in a nonsense mutation changing a tyrosine at codon 231 to a stop codon (Tyr231ter) [Matalon et al., 1995]. Based on carrier detection frequency in the Ashkenazi Jewish population, the overall incidence of the disease in this specific population is estimated to be 1 in 5000 [Matalon, 1997]. In the nonJewish families, an alanine to glutamic acid substitution at codon 305 (Ala305glu) occurs in about 36% of identified mutations. In the non-Jewish families, only 70% of mutations have been identified so far, with a total of 24 additional mutations being characterized [Matalon et al., 1995]. If a

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mutation has been identified for a pregnancy at risk for the disease, mutational analysis can be performed on chorionic villus sampling to aid in diagnosis. Prenatal diagnosis of Canavan’s disease is complicated because cultured amniocytes or chorionic villus samples have low levels of aspartoacylase activity, making enzyme analysis unsatisfactory for disease detection in the fetus [Matalon et al., 1992].

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Treatment At present, there is no treatment available for children with Canavan’s disease. Management is symptomatic and palliative. Physical therapy may help prevent contractures. Seizures need to be controlled, and one small study suggested the use of topiramate for treatment of megal-

FIGURE 60-9 Sagittal T1-weighted images (top row) and axial T2-weighted images (bottom row) of a 14-year-old male with megaloencephalic leukoencephalopathy. The sagittal images show subcortical cysts in the anterior temporal and frontal areas. The T2-weighted images show diffusely abnormal and slightly swollen cerebral white matter. The corpus callosum is spared.

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encephaly [Topcu et al., 2004]. Special care is needed to avoid aspiration with feedings. Nasogastric feeding or gastrostomy feeding will be needed in many of these children. There is a current clinical protocol to study the gene therapy of Canavan’s disease using adeno-associated virus type 2 as a vector for aspartoacylase [Janson et al., 2002], but there are no data available yet from that trial. One previous study reported transfer of the aspartoacylase gene to two children with Canavan’s disease [Fink, 2000; Leone et al., 2000]. More evaluation of these experiments will be required over time to assess the efficacy and safety of these trials. A knockout mouse for Canavan’s disease has been created [Matalon et al., 2000] that should be helpful in exploring the possibilities of gene therapy in humans. A report of a naturally occurring tremor rat may also be a model for Canavan’s disease [Kitada et al., 2000]. Baslow and colleagues [Baslow et al., 2002] used lithium chloride for 5 days and showed a 13% reduction of N-acetylaspartic acid in the brains of these tremor rats.

Leukoencephalopathy with Subcortical Cysts without Megalencephaly There appears to be a similar but distinct clinical syndrome associated with a leukoencephalopathy and subcortical cysts, but instead of the megalencephaly seen in megaloencephalic leukoencephalopathy with subcortical cysts, the head size is normal or small [Olivier et al., 1998]. This is apparently inherited in an autosomal recessive manner and does not have a mutation in the MLC gene. The MRI in these patients demonstrates bilateral cysts in the anterior temporal regions, with the signal intensity of the cysts being isointense with cerebrospinal fluid. Signal changes were present on MRI in the periventricular regions, but there was a characteristic sparing of the central white matter and cerebellar white matter. Although the disease is associated with delayed development in most children, the course appears to be rather static or slowly progressive.

CYSTIC LEUKOENCEPHALOPATHIES Megaloencephalic Leukoencephalopathy with Subcortical Cysts Megaloencephalic leukoencephalopathy with subcortical cysts is a recently described disease that includes the triad of leukoencephalopathy, megalencephaly, and mild clinical course. The disorder has initially described as “leukoencephalopathy with swelling and discrepantly mild clinical course” [van der Knaap et al., 1995] but has also been referred to as vacuolating leukoencephalopathy and leukoencephalopathic megalencephaly with mild clinical course [Goutières et al., 1996]. Because of the number of names for this disease, the term megaloencephalic leukoencephalopathy with subcortical cysts has been suggested because it correlates with neuropathologic changes seen in this disorder [van der Knaap et al., 1996]. The first description was likely by Harbord and associates when two siblings with megalencephaly and dysmyelination were reported, but van der Knaap and colleagues, Singhal and associates, and Goutières and co-workers have characterized the clinical and radiographic aspects of this disease [Goutières et al., 1996; Harbord et al., 1990; Singhal et al., 1996; van der Knaap et al., 1995]. The clinical features consist of macrocephaly occurring in the first year of life with a delayed onset of relatively mild neurologic symptoms consisting of cerebellar ataxia, pyramidal signs, and seizures [Goutières et al., 1996; van der Knaap et al., 1995]. The MRI demonstrates diffuse supratentorial white matter increased signal on T2-weighted images and decreased signal on T1-weighted images and mild swelling of the abnormal white matter (Fig. 60-9). Cysts are invariably present in the subcortical temporal region and often also in the parietal region. The brainstem and cerebellum appear largely unaffected. The disease is inherited in an autosomal recessive pattern. Mutations in the gene MLC1 have been identified as the cause [Leegwater et al., 2001b], but there is likely at least one other gene also responsible for the clinical features in some patients with megaloencephalic leukoencephalopathy with subcortical cysts [Blattner et al., 2002; Patrono et al., 2003].

Vanishing White Matter Disease and Childhood Ataxia with Cerebral Hypomyelination Vanishing white matter disease and childhood ataxia with cerebral hypomyelination has been characterized in the past few years by a number of groups of investigators. In 1993, Hanefeld and colleagues reported three patients with a diffuse leukoencephalopathy and an unusual proton magnetic resonance spectrum of the affected white matter with absence of normal metabolites and presence of small glucose and lactate resonances [Hanefeld et al., 1993]. This disorder was further clarified by Schiffmann and co-workers in 1994, who described four girls with ataxia and spasticity but without peripheral nerve or cognitive involvement [Schiffmann et al., 1994]. The MRI demonstrated a diffuse confluent abnormality of the cerebral white matter, which was noted early in the course of the disease. On proton magnetic resonance spectroscopy, these girls were also noted to have a reduction of N-acetylaspartic acid, choline, and creatine in white matter only. The brain biopsy from two of the girls revealed a generalized reduction in myelin specific proteins and lipids but no evidence of any storage material. In 1997, nine other children were identified by van der Knaap and associates, and the term vanishing white matter was used to describe the entity [van der Knaap et al., 1997]. The MRI findings were similar to previous reports, but on proton density and fluid-attenuated inversion recovery studies, the white matter was noted to have signal intensity similar to that of cerebrospinal fluid (Fig. 60-10). Magnetic resonance spectroscopy also found severe reduction in N-acetylaspartic acid, choline, and creatine; and again, lactate and glucose peaks were observed in white matter that were suggested to originate from the cerebrospinal fluid replacing the white matter. On one postmortem examination from this series of children, the histopathology demonstrated a cavitating leukoencephalopathy with replacement of white matter between ependyma and U fibers by cerebrospinal fluid. In areas with some preservation of white matter, astrogliosis and macrophage proliferation were present.

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FIGURE 60-10 Axial fluid-attenuated inversion recovery images of 31/2-year-old female with classic vanishing white matter disease and childhood ataxia with cerebral hypomyelination (VWM/CACH) (top row), and a severely affected 31/2-year-old female with a severe form of VWM/CACH (bottom row). The top row images show the typical white matter rarefaction and vanishing of the cerebral white matter, with many small stripes and dots within the cystic white matter indicative of remaining tissue strands. The bottom row images show that the cerebral white matter is much more cystic. Still, the dots and radiating stripes of remaining tissue strands are visible.

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A set of criteria were suggested by van der Knaap and associates [van der Knaap et al., 1997] to identify children with this disease: • Normal or mildly delayed initial psychomotor development • Onset in early childhood with an episodic and chronic progressive course • Deterioration that may follow infection or minor head trauma • Cerebellar ataxia and spasticity with relative preservation of mental function • Diffuse symmetric white matter involvement with all or part of cerebral white matter manifesting signal intensity on MRI similar to that of cerebrospinal fluid on proton density, fluid-attenuated inversion recovery, T2-weighted, and T1-weighted images The molecular defect of vanishing white matter disease and childhood ataxia with cerebral hypomyelination was first elucidated when the gene for this disorder was mapped to 3q27 [Leegwater et al., 1999]. The gene responsible for this disease was found to be located in the epsilon subunit of the eukaryotic initiation factor 2B (eIF2B) [Leegwater et al., 2001a], which is essential in the regulation of translation initiation. The eIF2B gene converts the eukaryotic protein synthesis initiation factor 2 (eIF2) from an inactive guanosine diphosphate–bound form into an active eukaryotic protein synthesis initiation factor 2–guanosine diphosphate complex. It is interesting to speculate why a gene that appears to be so basic to protein synthesis should only affect cerebral white matter. Subsequently, it was determined that all five subunits (alpha, beta, gamma, delta, and epsilon) of eIF2B contained mutations in patients with vanishing white matter disease and childhood ataxia with cerebral hypomyelination [van der Knaap et al., 2002]. The clinical spectrum of vanishing white matter disease and childhood ataxia with cerebral hypomyelination was expanded further through molecular studies to include other leukoencephalopathies, such as Cree leukoencephalopathy reported in the Cree Indians and ovario-leukodystrophy (a later-onset white matter disease with ovarian failure) as variants of vanishing white matter disease and childhood ataxia with cerebral hypomyelination [Fogli et al., 2002, 2003]. The phenotypic expression also expanded when reports were made of fatal infantile forms due to mutations in the eIF2B subunits [van der Knaap et al., 2003]. Initial reports suggested that there was no genotype–phenotype correlation, but recent information suggests that for some mutations in the eIF2B genes, phenotypic correlation can be considered. In a study involving 93 leukoencephalopathy patients identified by MRI criteria, Fogli and co-workers [2004] identified 83 individuals from 68 families with 46 distinct eIF2B gene mutations. Although a clear genotype–phenotype correlation could not be made in all the mutations identified, some genetic defects, such as the R113H in the eIF2B epsilon subunit and the E213G substitution in the eIF2B beta subunit, were associated with a mild clinical course. Also, van der Knaap and co-workers [2004] confirmed that the R113H mutation is associated with a milder clinical course in adults that may not always be accompanied by clinical signs such as spasticity. Although the MRI in these patients demonstrates a diffuse leukoencephalopathy, the charac-

teristic cavitary lesions may be missing. Finally, Ohtake and colleagues from Japan identified a patient with adult-onset vanishing white matter and a point mutation in the epsilon subunit of eIF2B, T182M that was associated with slowly progressive neuropsychiatric symptoms and mild spasticity [Ohtake et al., 2004].

OTHER DISEASES THAT HAVE MAJOR WHITE MATTER ABNORMALITIES Because of the sensitivity of MRI, many diseases not thought of primarily as white matter diseases need to be included in the differential diagnosis of abnormally appearing white matter on MRI.

Sjögren-Larsson Syndrome Sjögren-Larsson syndrome is an autosomal recessive disorder consisting of the clinical triad of spasticity, congenital ichthyosis, and mental retardation and a leukoencephalopathy on MRI [Sjögren and Larsson, 1957].

Biochemistry The primary biochemical defect in Sjögren-Larsson syndrome is deficient activity of the fatty aldehyde dehydrogenase component of fatty alcohol:NAD+ oxidoreductase [Rizzo and Craft, 1991]. Enzymatic studies may determine genetic carriers for Sjögren-Larsson syndrome [Kelson et al., 1992] and allow prenatal diagnosis [Rizzo et al., 1994]. Leukotriene B4 is broken down by fatty aldehyde dehydrogenase and is excessively secreted in the urine of SjögrenLarsson patients. Because it is a proinflammatory agent, leukotriene B4 appears to be involved in some of the pathologic aspects of Sjögren-Larsson syndrome, especially the pruritus [Willemsen et al., 2001a, 2001b].

Genetics The gene is localized to chromosome 17p11.2 [Pigg et al., 1994; Rogers et al., 1995]. The complementary DNA for fatty aldehyde dehydrogenase is cloned, and several mutations have been identified in this gene [De Laurenzi et al., 1996]. At present, more than 70 different mutations, including missense and nonsense mutations, deletions, insertions, and splice-site alterations, have been reported [Carney et al., 2004; De Laurenzi et al., 1996, 1997; Rizzo et al., 1999; Sillen et al., 1997; Tsukamoto et al., 1997]. Many patients of Swedish and northern European descent carry an identical missense mutation (943C(T; Pro315[Ser]), and haplotype studies indicate that they share a common ancestor [De Laurenzi et al., 1997; Sillen et al., 1997]. Most Swedish patients are homozygous for this mutation, which is consistent with their consanguineous history. A second deletion mutation, 1297-1298delGA, is frequently seen in European patients [Rizzo et al., 1999]. About one half of European Sjögren-Larsson syndrome patients carry 943C(T or 12971298delGA. Overall, there appears to be a diversity of mutations associated with different haplotypes in patients with Sjögren-Larsson syndrome [Carney et al., 2004].

Kaye and van der Knaap / Disorders Primarily of White Matter

Clinical Features The clinical features of Sjögren-Larsson syndrome consist of three major signs: congenital ichthyosis, mental retardation, and spastic diplegia or tetraplegia [Sjögren and Larsson, 1957]. The neurologic features usually begin before 1 year of age and consist of motor and language delay. Spastic diplegia is more common than tetraplegia, and many patients either never walk or require leg braces [Jagell and Heijbel, 1982]. The degree of mental retardation tends to correlate with the severity of spasticity, and most patients are moderately or profoundly retarded with intelligence quotient scores of less than 50. Many patients have speech defects of various types, and one third of the patients have an associated seizure disorder [Jagell and Heijbel, 1982; Theile, 1974]. Unlike with most other lipid disorders, patients with Sjögren-Larsson syndrome generally do not demonstrate neuroregression. A loss of ambulation can occur with age, but it is usually due to progressive contractures. Most patients with Sjögren-Larsson syndrome have short stature, usually due to leg contractures and decreased leg growth. Kyphoscoliosis is not uncommon, particularly in severely spastic patients. Nerve conduction studies are normal [Jagell and Heijbel, 1982]. The ichthyosis in Sjögren-Larsson syndrome is usually apparent at the time of birth, but a small proportion of patients first develop ichthyosis after several months of age or later [Jagell and Liden, 1982]. The ichthyosis tends to be mild to moderate in severity. Scales can be fine and dandruff-like, larger and more lamellar-like, or even thick and dark brown in appearance. The ichthyosis is generalized and typically affects the flexures, trunk, abdomen, back, extremities, nape of the neck, and dorsal areas of the hands and feet. Less severely affected are the palms and soles, whereas the face is usually spared. A collodion membrane is rarely seen in this disease [Rizzo, 1996]. Ophthalmologic abnormalities of the retina have been reported in Sjögren-Larsson syndrome [Jagell et al., 1980]. The most consistent finding is the presence of glistening white dots on the fundus, usually present in the foveal and perifoveal areas. These glistening white dots were observed in all 35 Swedish patients who could be examined, including young children [Jagell et al., 1980], but they have been reported in a lower percentage of non-Swedish patients. Retinal pigmentary changes and macular degeneration have also been seen in some patients, but corneal opacities or cataracts are not associated with Sjögren-Larsson syndrome [Rizzo, 1996]. A leukoencephalopathy is evident on MRI, revealing retardation of myelination and a mild persistent myelin deficit [Willemsen et al., 2004]. The MRI shows white matter disease involving primarily the parietal and frontal lobes [Hussain et al., 1995;Miyanomae et al., 1995]. A zone of increased signal intensity is seen in the periventricular white matter on T2-weighted images [Willemsen et al., 2004]. Proton magnetic resonance spectroscopy of white matter revealed a prominent peak at 1.3 ppm, normal levels of N-acetyl aspartate, and elevated levels of creatine (+14%), choline (+18%), and myoinositol (+54%) [Willemsen et al., 2004].

Treatment Patients with Sjögren-Larsson may benefit from treatment with zileuton, a drug that inhibits the synthesis of leuko-

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triene B4 and other leukotrienes. It is especially effective for disabling pruritus [Willemsen et al., 2001a].

Cerebrotendinous Xanthomatosis The clinical triad of cerebrotendinous xanthomatosis includes tendon xanthomas (especially of Achilles tendons), juvenile ocular cataracts, and nervous system dysfunction. The CNS abnormalities may consist of behavioral problems, mental retardation, dementia, pyramidal weakness, cerebellar ataxia, seizures, psychiatric disorders, and, rarely, parkinsonism [Berginer et al., 1989]. Juvenile cataracts are observed in more than 90% of cerebrotendinous xanthomatosis patients and may be the presenting symptom of the disease [Cruysberg et al., 1991]. Tendon xanthomas are found in 85% to 90% of patients with cerebrotendinous xanthomatosis. There is a strong preference for the Achilles tendon, but xanthomas and tuberous xanthomas are observed also in the tendons of other extensor muscles [Berginer et al., 1989]. Typically, banana-like swellings of the Achilles tendon develop and are documented by x-ray, CT, and MRI. Neuroimaging (CT and MRI) in patients with cerebrotendinous xanthomatosis demonstrates diffuse brain and spine atrophy, white brain matter abnormalities above and especially below the tentorium, and, in some patients, focal lesions [Barkhof et al., 2000; Bencze et al., 1990]. The white matter of the cerebellum appears to be particularly affected in cerebrotendinous xanthomatosis. Because some patients may have only the CNS changes without the cataracts or tendon xanthomas, cerebrotendinous xanthomatosis may be frequently overlooked as a diagnosis. Patients with CNS degeneration and white matter changes on MRI primarily affecting cerebellum should be screened for cerebrotendinous xanthomatosis. Cerebrotendinous xanthomatosis may be diagnosed after finding increased plasma and tissue cholestanol concentrations and low or normal plasma cholesterol levels. The brain of patients with cerebrotendinous xanthomatosis was discovered by Menkes and colleagues [1968] to have increased amounts of cholestanol. Cholestanol is the 5-α-dihydro derivative of cholesterol and is present in small quantities associated with cholesterol in virtually every tissue and plasma. In normal subjects, cholestanol represents about 0.1% to 0.2% of the cholesterol. In contrast, cholestanol is increased 10-fold to 100-fold in cerebrotendinous xanthomatosis. The biologic basis for cerebrotendinous xanthomatosis is a deficiency of the sterol 27-hydroxylase enzyme. This enzyme is responsible for the production of bile acids. Recently mutations in the sterol 27-hydroxylase gene on the human chromosome 2 were determined to be the cause of cerebrotendinous xanthomatosis. Many mutations in the sterol 27-hydroxylase gene have been identified [Chen et al., 1998]. Because cerebrotendinous xanthomatosis results from an inherited defect in bile acid synthesis, treatment with the bile acid chenodeoxycholic acid has been used in cerebrotendinous xanthomatosis. Chenodeoxycholic acid appears to reverse the metabolic encephalopathy before destructive xanthomas appear in the brain [Salen et al., 1994]. Longterm treatment with chenodeoxycholic acid (750 mg/day) suppresses abnormal bile acid synthesis, as evidenced by the

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FIGURE 60-11 T2-weighted images (top row) and fluid-attenuated inversion recovery images (bottom row) in a 16-month-old female with isolated complex I deficiency. Note the extensive cerebral white matter abnormalities. The fluid-attenuated inversion recovery images show that there are multiple welldelineated cysts within the abnormal white matter.

Kaye and van der Knaap / Disorders Primarily of White Matter

almost total replacement of chenodeoxycholic acid in the enterohepatic pool and the disappearance of bile alcohol glucuronides from bile, plasma, and urine [Batta et al., 1987]. Plasma and cerebrospinal fluid cholestanol concentrations decline to normal levels. The neurologic improvement is better when treatment is started in young patients [van Heijst et al., 1998].

Mitochondrial Disorders Mitochondrial disorders, diseases caused by abnormalities in mitochondrial respiratory chain function, frequently have white matter abnormalities. These include Leber’s hereditary optic neuropathy, which affects optic nerve myelin, and MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and stroke), which has white and gray matter changes often in the parietal-occipital regions, not in a vascular distribution but probably related to a metabolic stroke. Diffuse white matter abnormalities have been noted in other mitochondrial diseases such as ubiquinone deficiency [Artuch et al., 1999] and succinate dehydrogenase deficiency [Brockmann et al., 2002]. In essence, many respiratory chain complex defects caused from mutations in either the mitochondrial or nuclear genomes may result in white matter lesions in addition to abnormalities in the gray matter [De Lonlay-Debeney et al., 2000]. The deep white matter lesions in mitochondrial diseases often appear necrotic with cystic degeneration and may occur more often in infants [Kang et al., 2002]. The white matter cysts in mitochondrial disorders tend to be multiple, small, and well delineated (Fig. 60-11). This pattern is in contrast to the white matter rarefaction and cystic degeneration in vanishing white matter disease and childhood ataxia with cerebral hypomyelination, which occurs in a melting-away pattern, usually without well-delineated cysts (see Fig. 60-10).

Cerebral Autosomal-Dominant Arteriopathy Subcortical Infarcts and Leukoencephalopathy Cerebral autosomal-dominant arteriopathy subcortical infarcts and leukoencephalopathy (CADASIL) is a cause of leukoencephalopathy primarily affecting adults. The entity was described in 1977 as a familial multi-infarct dementia, although the disease is recognized more often because of the leukodystrophy noted on MRI [Sourander and Walinder, 1977]. The phenotypic spectrum usually begins after age 40, but asymptomatic at-risk individuals may have MRI abnormalities noted at times in childhood. The clinical manifestations consist of ischemic deficits, cognitive loss including dementia, migraine, psychiatric disturbances, and rarely seizures [Dichgans et al., 1998]. The clinical course is unrelenting and occurs very slowly over decades. Men appear to be at higher risk for the earlier loss of ambulation and life compared with women with CADASIL [Opherk et al., 2004]. The MRI pattern consists of hyperintensities on T2-weighted images in periventricular regions, deep white matter, anterior temporal lobes, basal ganglia, and infratentorial areas, which increase with age [Chabriat et al., 1998]. The cerebral pathology consists of white matter gliosis and a small vessel angiopathy with periodic acid-Schiff– positive material in the media of the vessel [Desmond et al., 1998]. Although confined to the CNS, CADASIL is a sys-

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temic vascular disease. The pathologic hallmark of the disease is a nonamyloid, nonatheroslerotic microangiopathy. Because of the ubiquitous nature of the vasculopathy, electron microscopy of skin can be used as a diagnostic tool. Electron microscopy of small arterioles in the skin demonstrates characteristic granular osmophilic material in the basement membranes, which indent the surface and appear to rise as flames of electron-dense material [Desmond et al., 1998]. The genetic basis for this autosomal-dominant disease was elucidated in 1993 when the gene was mapped to chromosome 19p13.1 and clarified further in 1996 when mutations in the NOTCH3 were discovered [Joutel et al., 1997a]. The NOTCH3 gene encodes a 300-kd transmembrane protein with a receptor and cell signal transduction function, which is important to embryonic development for many species. The gene contains 33 exons and contains 33 epidermal growth factor domains. As yet, the exact mechanism by which NOTCH3 mutations cause the CADASIL phenotype is not understood. The mutations in NOTCH3 appear to be very stereotyped, involving missense mutations with either a gain or loss of a cysteine residue [Joutel et al., 1997b]. A proposed mechanism of the disease pathology may be related to the abnormal accumulation of NOTCH3 in the vascular smooth muscle of vessels and the abnormal NOTCH signaling through the RPB/JK pathway [Joutel et al., 2004]. Mutational analysis will greatly aid in diagnosis and improve the sensitivity of diagnostic testing.

Merosin Deficiency An important cause for a leukoencephalopathy indicated on MRI is a merosin-deficient form of congenital muscular dystrophy or laminin-α2 deficiency [Lamer et al., 1998]. These children often have dramatic and unexpected white matter findings but no evidence of upper motor neuron signs and minimal cognitive findings. The clinical picture consists of hypotonia and gross motor delays caused by the muscle disease or at times peripheral neuropathy. The disease may be severe, with the child never able to walk, or mild, with walking occurring between the ages of 2 or 3 years. The disorder does not appear to be progressive. The MRI usually reveals a diffuse white matter signal increase on the T2weighted image, but the cortex is not involved. The disease is associated with mutations in the laminin-2 gene, which is located on chromosome 6q2 [Hillaire et al., 1994]. Lamininα-2 is associated with α-dystroglycan in muscle, but the protein is also found in CNS and Schwann cells within the basal lamina.

Glycogen Storage Disease Type IV (Branching Enzyme Deficiency) Glycogen storage disease type IV (branching enzyme deficiency) usually appears in infancy with severe liver disease causing cirrhosis, portal hypertension, and early death [DiMauro et al., 1997]. Myopathy may be the presenting feature in many children, and cardiomyopathy has been reported in some individuals [Tang et al., 1994]. A lateonset variant of glycogen storage disease type IV, referred to as adult polyglucosan storage disease, consists of progressive weakness and spasticity of the legs, which may

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progress to quadriparesis, urinary incontinence, and a peripheral neuropathy. Cognitive impairments may be present, and a leukodystrophy has been noted in many patients. The branching enzyme is 1,4-glucan-6-glucosyltransferase. The gene expressing this enzyme has been identified and mapped to chromosome 3. The complementary DNA is 3 kb in length and encodes a protein of 702 amino acids [Thon et al., 1993]. One mutation (Tyr329Ser) in the gene encoding the branching enzyme has been reported in a series of Ashkenazi families with adult polyglucosan storage disease [Lossos et al., 1998]. ACKNOWLEDGMENT The authors would like to thank David Margolin, M.D., Ph.D., for his thoughtful review and assistance on the multiple sclerosis section in this chapter.

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CHAPTER 61

Impairment of Consciousness and Coma Donald A. Taylor and Stephen Ashwal

The study of consciousness represents one of the oldest areas of neuroscience. Multiple philosophical, metaphysical, and psychologic theories of consciousness have been elucidated [Zeman, 2001]. William James, in 1890, wrote that the cortex is the sole organ of consciousness in man [James, 1890]. Nonetheless, reconciliation of the concept of mind (consciousness and awareness) and the structure and function of the brain has long been elusive [Sperry, 1952]. Evidence that there is a neural correlate of consciousness, however, is clearly established [Crick and Koch, 1998]. An early step in the neurobiologic understanding of consciousness and its alterations was the identification of brainstem structures essential for cortical activation [Damasio, 2003; Moruzzi and Magoun, 1949; Neylan, 1995]. Recent theories that the brain’s electromagnetic field is the equivalent of the conscious mind allow reconciliation of the mindbrain problem and suggest methodology to scientifically study consciousness and alteration of consciousness at the neurophysiologic level [John, 2001, 2002; John et al., 2001; McFadden, 2002a, 2002b]. Because neurobiologic processes that are realized in brain structures are responsible for consciousness [Baars et al., 2003; Neylan, 1995; Searle, 2000], neurologic disorders of the cortex and its brainstem activators result in impairment of consciousness and coma. Understanding neurologic disease depends on the clinical assessment and interpretation of consciousness, the content of consciousness, and alterations of consciousness. The evaluation of all disorders of higher cortical function fundamentally begins with consciousness assessment, and all signs and symptoms of neurologic impairment must be interpreted based on the state of consciousness and awareness [Giacino, 1997]. Consciousness refers to the state of awareness of self and environment [James, 1890; Plum and Posner, 1982]. Evaluation of consciousness in the pediatric patient must take into account age and the appropriate developmental level. Conscious individuals may have abnormal content of consciousness, such as hallucinations, delirium, or dementia. Therefore, normal consciousness must be distinguished from abnormal consciousness as objectively as possible. Unconsciousness is unawareness of self and environment and may be physiologic (sleep) or pathologic (coma or the vegetative state). The fundamental difference between sleep and coma is that with appropriate stimulus intensity and duration, a sleeping person can be aroused to a normal state of consciousness, whereas a comatose patient cannot. Thus, the diagnosis of coma and other impairments of consciousness involves both state and reactivity. The physiologic differences between sleep and coma are actually more profound. Sleep is a biologically active state with identifiable behavioral and electroencephalographic stages,

whereas coma is a state of reduced neuronal activity [Moruzzi, 1972]. Along the continuum from normal consciousness to coma or unarousable unconsciousness, many terms are used to describe mental state and reactivity. When there is doubt about the appropriate use of one of these terms, it is far better to describe the state and reactivity of the individual rather than label it. Definitions of consciousness, impairment of consciousness, coma, and related states have been proposed throughout the history of medicine and have been reviewed, refined, and stated systematically during the past several decades [Ashwal, 1996; Ashwal and Cranford, 2002; Bates, 1993; Bozza Marrubini, 1984; Medical Research Council Brain Injuries Committee, 1941; Michelson and Ashwal, 2004; Plum and Posner, 1982].

DEFINITIONS Consciousness is the spontaneously occurring state of awareness of self and environment. Consciousness has two dimensions—wakefulness and awareness [Multi-Society Task Force on Persistent Vegetative State, 1994]. Normal consciousness requires arousal, an independent, autonomicvegetative brain function subserved by ascending stimuli— emanating from pontine tegmentum, posterior hypothalamus, and thalamus—that activate mechanisms inducing wakefulness. Awareness is subserved by cerebral cortical neurons and their reciprocal projections to and from the major subcortical nuclei. Awareness requires wakefulness, but wakefulness can be present without awareness. In preterm and term newborns and in infants, consciousness may require a more operational definition. Crying when uncomfortable or hungry at least suggests awareness of self, and visual alertness or soothing to an auditory stimulus (such as parent’s voice) suggests environmental awareness. The presence of an appropriate socially responsive smile in the younger infant is a clear marker of consciousness. The bilateral absence of the cerebral cortex, as in anencephaly or severe hydranencephaly, may make realistic assessment of consciousness impractical. Clouding of consciousness is the minimal reduction of wakefulness or awareness wherein the main difficulty is attention or vigilance. Clouding of consciousness is distinguished from daydreaming in that the child cannot be easily stimulated to normal consciousness. It is also distinguished from the inattention of attention-deficit–hyperactivity disorder by failure to improve with one-to-one confrontation or removal of distractions. Confusion is the state of impaired ability to think and reason clearly at a developmentally and intellectually appro-

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priate level. Confused children have persistent difficulty with orientation, simple cognitive processing, and acquisition of new memory. Normal suggestibility and anxiety in younger children may be misleading when assessing confusion. In newborns, infants, and younger children, clouding of consciousness and confusion are difficult to assess and are not of practical value. In the older child or adolescent, confusion may be an important indicator of drug ingestion, toxin exposure, or severity of concussion. Other definitions of impairment of consciousness states may be divided into the following categories: • Impairment of consciousness with activated mental state • Impairment of consciousness with reduced mental state • Impairment of consciousness along the continuum of coma–vegetative state–minimally conscious state and related conditions

Impairment of Consciousness with Activated Mental State Several altered states of consciousness with activated mental state can be seen in older children and may be difficult to differentiate from each other. Hallucinations are perceptions of sensory input that are not present; illusions are misinterpretations of actual sensory stimuli. Delusions are incorrect thoughts or beliefs that do not change when challenged by contradictory evidence or logical reason. Delirium is an activated mental state that may include disorientation, irritability, fearful responses, and sensory misperception. Patients may be hyperactive and have signs of increased sympathetic tone. Visual hallucinations, when present, are more common than auditory hallucinations, and the patient may experience delusional thought or illusions. Delirium is more likely to involve both cerebral hemispheres than one side of the cerebrum or the brainstem alone. Search for causes of delirium, there-

fore, should begin with consideration of pathology of both hemispheres. In children, common causes include intoxication, infection, fever, metabolic disorders, and epilepsy. Night terrors are non–rapid-eye-movement sleep disorders that occur commonly in children and closely resemble the delirious state. Children experiencing night terrors, however, will return to normal sleep, from which they can be aroused to normal wakefulness.

Impairment of Consciousness with Reduced Mental State Obtundation is mild to moderate alertness reduction with decreased interest in the environment and slower than normal reactivity to stimulation. Obtunded patients appear abnormally drowsy and often sleep when left alone. Stupor is a state of unresponsiveness with little or no spontaneous movement resembling deep sleep from which the patient can only be aroused by vigorous and repeated stimulation. Communication is absent or minimal. The best responsive level of consciousness is still quite abnormal, and without continuous stimulation, the patient returns to the prestimulation state. Coma is a state of deep, unarousable, sustained pathologic unconsciousness with the eyes closed that results from dysfunction of the ascending reticular-activating system in the brainstem or in both cerebral hemispheres [MultiSociety Task Force on Persistent Vegetative State, 1994]. Coma usually requires the period of unconsciousness to persist for at least 1 hour to distinguish coma from syncope, concussion, or other states of transient unconsciousness. The term unconsciousness implies global or total unawareness and applies equally to patients in coma or vegetative states. Patients in coma are unconscious because they lack both wakefulness and awareness. In contrast, patients in vegetative states are unconscious because, although they have retained wakefulness, they lack awareness. The depth of coma may be further specified by assessment of brainstem reflexes, breathing pattern, change of pulse or res-

TABLE 61-1 Severe Disorders of Consciousness and Related Conditions CONDITION

SELF-AWARENESS

PAIN AND SUFFERING

SLEEP-WAKE CYCLES

MOTOR FUNCTION

RESPIRATORY FUNCTION

Coma

Absent

No

Absent

No purposeful movement

Variably depressed

Vegetative state

Absent

No

Intact

Normal

Minimally conscious state Akinetic mutism

Very limited

Yes

Intact

Variably depressed

Recovery unknown

Limited

Yes

Intact

Present

Yes

Intact

Normal to variably depressed Normal to variably depressed

Recovery unlikely or limited

Locked-in syndrome Brain death

Absent

No

Absent

No purposeful movement Severe limitation of movement Moderate limitation of movement Quadriplegia; pseudobulbar palsy; eye movements preserved None or only reflex spinal movements

Evolves to persistent vegetative state, dies, or recovers in 2-4 weeks Depends on etiology

Absent

None

OUTCOME

Recovery unlikely; remains quadriplegic

Taylor and Ashwal / Impairment of Consciousness and Coma

piratory rate to stimulation, or stimulus-induced nonspecific movement.

Vegetative State, Minimally Conscious State, and Related Conditions Table 61-1 lists several of the major neurologic conditions that the clinician must be capable of differentiating from coma. This table was modified from the report issued by the Multi-Society Task Force on the Persistent Vegetative State [1994] and more recent work that is defining the concept of the minimally conscious state [American Congress of Rehabilitation Medicine, 1995; Giacino et al., 1997]. The principal neurologic conditions in which there may be overlap of clinical findings on examination that should be differentiated from coma are discussed in the next sections.

Vegetative State The vegetative state can be described as a condition of complete unawareness of the self and the environment accompanied by sleep-wake cycles with either complete or partial preservation of hypothalamic and brainstem autonomic (vegetative) functions [Zeman, 1997]. Criteria to diagnose the vegetative state have been recommended for adults and children by the Multi-Society Task Force on Persistent Vegetative State and are listed in Box 61-1. Children in a vegetative state lack evidence of self-awareness or recognition of external stimuli [Feinberg and Ferry, 1984]. Rather than being in a state of “eyes-closed” coma, they remain unconscious but have irregular periods of wakefulness alternating with periods of sleeping. Vegetative patients demonstrate a variety of sounds, emotional expressions, and body movements, and they may smile or shed tears. They have inconsistent head- and eye-turning movements to sounds and inconsistent, nonpurposeful trunk and limb movements. The most objective sign is lack of sustained visual fixation or visual tracking. It is estimated that there are about 4,000 to 10,000 children in a vegetative state in the United States [Ashwal, 1996]

BOX 61-1 CRITERIA FOR THE DIAGNOSIS OF THE VEGETATIVE STATE • No evidence of awareness of themselves or their environment; they are incapable of interacting with others • No evidence of sustained, reproducible, purposeful, or voluntary behavioral responses to visual, auditory, tactile, or noxious stimuli • No evidence of language comprehension or expression • Intermittent wakefulness manifested by the presence of sleep-wake cycles • Sufficiently preserved hypothalamic and brainstem autonomic functions to survive if given medical and nursing care • Bowel and bladder incontinence • Variably preserved cranial nerve (pupillary, oculocephalic, corneal, vestibulo-ocular, gag) and spinal reflexes

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and about 100,000 worldwide [Ashwal, 2005]. The etiology of the vegetative state in children can be classified into the following three broad groups of disorders: (1) acute traumatic and nontraumatic brain injuries; (2) metabolic and degenerative disorders affecting the nervous system; and (3) developmental malformations. The percentage of children having these etiologies of the vegetative state is as follows: acute traumatic and nontraumatic injuries (30%), perinatal insults (17.7%), chromosomal disorders or congenital malformations (13.0%), infections (10.3%), and unknown causes (28%) [Ashwal et al., 1994]. The most common causes of acute brain injury leading to the vegetative state in children are head trauma and hypoxicischemic encephalopathies [Adams et al., 2000]. Severe traumatic brain injury in children is often due to nonaccidental trauma but also occurs after a motor vehicle crash, particularly when infant restraints have not been used or when a pedestrian versus motor vehicle crash occurs. Hypoxic-ischemic injuries after cardiorespiratory arrest occur at birth, after episodes of near-miss sudden infant death syndrome or near drowning, and after other acute life-threatening episodes, including shock due to systemic trauma or infection. The clinical course of evolution to a vegetative state after an acute injury usually begins with eyes-closed coma for several days to weeks followed by the appearance of sleepwake cycles. Gillies and Seshia retrospectively determined that the transition from eyes-closed coma to the vegetative state averaged 8.6 ± 1.7 days in 17 children aged 1 month to 6 years [Gillies and Seshia, 1980]. Other responses, such as decorticate and decerebrate posturing (1.7 days), roving eye movements (1.8 days), and eye blinking (3.3 days), appeared earlier than sleep-wake cycles [Gillies and Seshia, 1980]. The progression of many metabolic and degenerative nervous system disorders in children may result in an irreversible vegetative state. In contrast to patients who become vegetative within several weeks after an acute injury, patients with metabolic or degenerative diseases slowly evolve to a vegetative state over several months or years. Severe congenital central nervous system (CNS) malformations can also result in a vegetative state. At birth, anencephaly is the only malformation in which an infant can be diagnosed as being in a vegetative state because of the absence of the cerebral cortex. Other malformations, such as hydranencephaly, may result in a vegetative state but, because of the limitations of the neurologic examination in assessing higher cortical functions and in differentiating voluntary from involuntary responses until about 3 to 6 months of age, it is recommended that such infants not be diagnosed as being vegetative until there is certainty about the diagnosis. Diagnosis of the vegetative state is made clinically [AAN Quality Standards Subcommittee, 1995]. There are no confirmatory laboratory tests, in contrast to establishing the diagnosis of brain death. However, the absence of cortical (scalp-recorded) potentials of the somatosensory-evoked response to median nerve stimulation has been associated with the vegetative state in some studies [Beca et al., 1995; Frank et al., 1985]. Neuroimaging studies usually demonstrate diffuse or multifocal cerebral disease involving the gray and white matter or major CNS malformations (Ashwal, 1996). In patients with traumatic and nontraumatic

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brain injury, serial imaging studies may demonstrate progressive atrophy. Positron emission tomography studies may demonstrate significant global reductions of cerebral glucose metabolism in infants [Larsen et al., 1993]. Proton magnetic resonance spectroscopy measurement of increased cerebral lactate in newborns, infants, and children with nervous system disease is associated with severe disability, survival in the vegetative state, or death [Ashwal et al., 1997]. Recovery from the vegetative state in children depends on the etiology and is reviewed in more detail in the MultiSociety Task Force on the Persistent Vegetative State report [1994]. In children with severe closed-head injuries who were vegetative 1 month after injury, follow-up at 1 year found that 29% remained in a vegetative state, 9% had died, and 62% recovered consciousness. Recoveries after 12 months were not reported, although one study found that 2 of 40 children with traumatic brain injury began to recover after 1 year in a vegetative state [Kriel et al., 1993]. In contrast, children in a nontraumatic vegetative state have a much poorer potential for recovery than those in a traumatic vegetative state. At 1 year, most children remained in a vegetative state (65%) or died (22%); only 13% demonstrated recovery, usually to a severe disability. It was based on this data, and consensus opinion that the Task Force came to the conclusions that in children (as well as in adults) the vegetative state could be judged permanent 12 months after traumatic brain injury and 3 months after nontraumatic injury. The chance for recovery after these time periods was exceedingly slim, and the patient almost always progressed to a severe disability. This perspective has received general acceptance, although concerns have been raised about the certainty of diagnosis and whether there is a greater potential for patients to recover than previously realized [Giacino et al., 1997; Jennett, 1997]. It is important to correctly identify children who are in a vegetative state because of the implications for continued care, family expectations, and the need for rehabilitation. Specialty programs for coma recovery are usually directed at patients who are severely disabled or are in a minimally conscious or vegetative state. Management issues are confounded by a lack of understanding of expected recovery patterns, terminology inconsistency, lack of or inappropriate use of outcome measures, and inadequate knowledge concerning medical management based on scientifically sound practices for this special patient population [Zasler et al., 1991]. Children in a vegetative state have been reported to have a considerably shorter than normal life expectancy [Ashwal et al., 1994]. Children in a vegetative state who are younger than 1 year of age had a median survival of 2.6 years, whereas the median survival of children aged 2 to 6 years was 5.2 years. In children 7 to 18 years of age, the reported median survival was 7 years.

Minimally Conscious State Recovery from coma depends on the cause of coma, extent of brain injury, and ability of injured areas to recover or of uninjured areas to assume the functions of injured areas. Not all comatose patients recover rapidly or completely. A variety of terms have been used to define these states, and there is often confusion between recovery states and prognostic categories. The term minimally conscious state has

been proposed to describe those patients who were in coma or a vegetative state and who are beginning to demonstrate minimal signs of awareness. Minimally conscious state may also be used to describe patients with degenerative disorders who are no longer functionally interactive but are not in the vegetative state. The minimally conscious state has been defined as a condition of severely altered consciousness in which the person demonstrates minimal but definite behavioral evidence of self- or environmental awareness [Giacino et al., 1997]. Patients in a minimally conscious state are able to do the following: (1) follow simple commands, (2) gesture or verbally give “yes” or “no” responses (regardless of accuracy), (3) verbalize intelligibly, and (4) perform movements or affective behaviors, which are not attributable to reflexive activity, in contingent relation to relevant environmental stimuli. Criteria to diagnose the minimally conscious state are in Box 61-2 [Giacino et al., 2002]. Children in the minimally conscious state are usually victims of acquired brain injury (traumatic and nontraumatic), neurodegenerative and neurometabolic disorders, or congenital or developmental disorders [Ashwal, 2003]. Based on limited literature on this disorder in adults [Giacino and Kalmar, 1999], it is possible that such children, depending on the etiology of the insult, may have a better potential for neurologic recovery and a longer life expectancy than children in the vegetative state. In a study of 5,075 children aged 3 to 15 years in a vegetative state or minimally conscious state, 564 were in the vegetative state, 705 in the minimally conscious state and immobile, and 3,806 in the minimally conscious state and mobile. The 8-year survival rates were 63% for vegetative state, 65% for

BOX 61-2 DIAGNOSTIC CRITERIA FOR THE MINIMALLY CONSCIOUS STATE • Simple command following • Gestural or verbal yes-no responses (regardless of accuracy) • Intelligible verbalization • Purposeful behavior, including movements or effective behaviors that occur in contingent relation to relevant environmental stimuli and are not due to reflexive activity. Some behavioral examples of qualifying purposeful behaviors include the following: • Appropriate smiling or crying in response to the linguistic or visual content of emotional but not to neutral topics or stimuli • Vocalizations or gestures that occur in direct response to the linguistic content of questions • Reaching for objects that demonstrates a clear relationship between object location and direction of reach • Touching or holding objects in a manner that accommodates the size and shape of the object • Pursuit eye movement or sustained fixation that occurs in direct response to moving or salient stimuli Adapted from Giacino JT, Ashwal S, Childs N, et al. The minimally conscious state. Definition and diagnostic criteria. Neurology 2002;58:349.

Taylor and Ashwal / Impairment of Consciousness and Coma

immobile minimally conscious state, and 81% for mobile minimally conscious state. Thus, presence of consciousness was not a critical variable in determining life expectancy in this study, and mobility was more important than consciousness in predicting survival [Strauss et al., 2000].

panied by a similar loss of speech [Plum and Posner, 1982]. The original description of this condition in 1941 was in an adolescent with symptoms of intermittent depressed states of consciousness secondary to a craniopharyngioma [Cairns et al., 1941]. Since then, akinetic mutism has been seen with bacterial and viral CNS infections, other tumors of the nervous system, and hydrocephalus, and occasionally as a postoperative phenomenon [Lin et al., 1997; Melton et al., 1991]. Wakefulness and self-awareness are usually preserved in most patients, but the level of mental function is reduced. The condition characteristically accompanies gradually developing or subacute, bilateral damage to the paramedian mesencephalon, basal diencephalon, or inferior frontal lobes. The long-term outlook for children with akinetic mutism is unknown because few patients with this disorder have been reported. It is most likely related to the etiology and severity of the associated disease.

Locked-In Syndrome The locked-in syndrome refers to a condition in which patients retain consciousness and cognition but are unable to move or communicate because of severe paralysis. This condition is a result of diseases involving the descending corticospinal and corticobulbar pathways at or below the pons or of severe involvement of the peripheral nervous system. By definition, patients in coma or a vegetative state are unconscious and differ from patients in a locked-in syndrome, who retain awareness, although this difference may be difficult to determine. The locked-in syndrome is quite rare in children [Habre et al., 1996; Scott et al., 1997]. Some patients with this condition can establish limited communication using eye movements.

Brain Death Brain death describes the permanent absence of all brain functions, including those of the brainstem [Task Force for the Determination of Brain Death in Children, 1987]. Braindead patients are irreversibly comatose and apneic, and they have absent brainstem reflexes, including the loss of all cranial nerve functions. The appearance of brain death can

Akinetic Mutism Akinetic mutism is a rare condition consisting of pathologically slowed or nearly absent bodily movement accom-

IS PATIENT CONSCIOUS? Patient has sustained or reproducible purposeful response to external stimuli ? NO

YES

Patient has absent brainstem function and apnea YES Patient is braindead

NO

Patient has sleep-wake cycles and opens eyes spontaneously or to stimulation

NO

Patient is in coma

Patient has functional interactive communication and/or functional use of one or more objects

NO

YES

Patient is in a vegetative state

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Patient has: 1. Simple command following and/or 2. Gestural or verbal ‘yes/no’ responses and/or 3. Intelligible verbalization and/or 4. Purposeful behaviors in response to environmental stimuli, not due to reflexive activity 5. Patient is not able to express preferences

Patient is in a minimally conscious state

YES Communication is limited to vertical eye movements and/or eyelid blinking

YES

Patient has locked-in syndrome

NO

Patient has emerged from MCS and may have mild to severe disability or may become normal

FIGURE 61-1 An algorithm useful for distinguishing among brain death, vegetative state, locked-in syndrome, and higher-order consciousness. MCS, minimally conscious state. (From Ashwal S, Cranford R. The minimally conscious state in children. Semin Pediatr Neurol 2002;9:19.)

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be imitated by deep anesthesia, sedative overdose, or severe hypothermia. Patients who are brain dead differ from patients who are in a coma in that comatose patients usually have preserved brainstem functions and some degree of respiratory drive. Guidelines for the diagnosis of brain death in infants and children are well established and are reviewed in greater detail in Chapter 67. A useful algorithm for distinguishing among brain death, vegetative state, locked-in syndrome, and higher-order consciousness is presented in Figure 61-1 [Ashwal and Cranford, 2002].

CONSCIOUSNESS RATING SCALES

4. Define intracategory scoring based on reasonable developmental assumptions. The Pediatric Coma Scale [Reilly et al., 1988; Simpson et al., 1991; Simpson and Reilly, 1982] makes minor changes in the verbal scale of the Glasgow Coma Scale and redefines the “best” score based on developmental and age-appropriate norms (Table 61-3). It has the advantage of prospective evaluation and inter-rater reliability and the disadvantage of different maximum scores based on age,

TABLE 61-3

Because of the difficulty with imprecise use of terminology and because of the need for a truly reproducible assessment of consciousness with good inter-rater reliability, several behavior rating scales have been developed. Although typically referred to as coma scales, these scales have value in assessing consciousness alterations other than coma. The best known and most widely used is the Glasgow Coma Scale, which yields a score of 3 to 15 based on best response to stimuli in the following three categories: eye opening, verbal response, and motor response (Table 61-2) [Teasdale and Jennett, 1974]. In its original form, the Glasgow Coma Scale was not developmentally suitable for assessment of newborns, infants, and younger children, and a variety of alternate scales have been proposed [Duncan et al., 1981; Hahn et al., 1988; Raimondi and Hirschauer, 1984; Reilly et al., 1988; Rubenstein, 1994; Simpson et al., 1991; Simpson and Reilly, 1982]. An ideal pediatric modification of the Glasgow Coma Scale would meet the following criteria: 1. Maintain the same maximum and minimum score as the Glasgow Coma Scale. 2. Maintain the same three categories. 3. Maintain the same numeric score range within each of the three categories.

Pediatric Coma Scale RESPONSE

SCORE

Eye Opening Spontaneous To speech To pain None

4 3 2 1

Best Verbal Response Oriented Words Vocal sounds Cries None

5 4 3 2 1

Best Motor Response Obeys commands Localizes pain Flexion to pain Extension to pain None

5 4 3 2 1

Normal Aggregate Score Birth to 6 months Less than 6-12 months Less than 1-2 years Less than 2-5 years More than 5 years

9 11 12 13 14

TABLE 61-2 Glasgow Coma Scale and Modification for Children SIGN

GLASGOW COMA SCALE

GLASGOW COMA SCALE—MODIFIED FOR CHILDREN

Eye opening

Spontaneous To command To pain None Oriented Confused Disoriented Inappropriate words Incomprehensible sounds None

Spontaneous To sound To pain None Age-appropriate verbalization, orients to sound, fixes and follows, social smile Cries, but inconsolable Irritable, uncooperative, aware of environment Irritable persistent cries, inconsistently consolable Inconsolable crying, unaware of environment or parents, restless, agitated None Obeys commands, spontaneous movement Localizes pain Withdraws Abnormal flexion to pain Abnormal extension to pain None

Verbal response

Motor response

Best total score

Obeys commands Localizes pain Withdraws Abnormal flexion to pain Abnormal extension None

SCORE 4 3 2 1 5 4 3 2 1 6 5 4 3 2 1 15

Taylor and Ashwal / Impairment of Consciousness and Coma

TABLE 61-4 Children’s Coma Scale SIGN

SCORE

Ocular Response Pursuit Extraocular movement intact, pupils react appropriately Fixed pupils or extraocular movement impaired Fixed pupils and extraocular movement paralyzed

4 3 2 1

Verbal Response Cries Spontaneous respiration Apneic

3 2 1

Motor Response Flexes and extends Withdraws from painful stimuli Hypertonic Flaccid Best Total Score

4 3 2 1 11

thus making outcome prediction and comparison difficult to study using the Glasgow Coma Scale. The Children’s Coma Scale redefines intracategory criteria and “maximum” score and changes the eye-opening category to “ocular response” [Raimondi and Hirschauer, 1984]. The Children’s Coma Scale meritoriously included pupillary reflexes, extraocular movements, and apnea in its categories and is therefore substantially different from the Glasgow Coma Scale and requires different training and forms to be used (Table 61-4). The Glasgow Coma Scale—Modified for Children maintains the same categories as the Glasgow Coma Scale and the same maximum and minimum scores, while allowing developmental and age-appropriate scoring [Hahn et al., 1988; Rubenstein, 1994]. It does, however, equate spontaneous movement with following commands to achieve 6 points in the best motor response category to allow inclusion of infants and young children (see Table 61-2). Nonetheless, the Glasgow Coma Scale—Modified for Children allows the best direct comparison with the Glasgow Coma Scale for scoring of consciousness impairment and assessment of outcome. The Glasgow Coma Scale and its modifications for children are useful to more objectively evaluate and quantify the continuum from consciousness to coma and to allow serial reassessment that meaningfully reflects the state of the patient at a particular moment in time with good inter-rater reliability. The scores also allow a relatively large amount of information to be conveyed quickly and concisely with minimal need to remember cumbersome definitions or to write long descriptions. Their ease of use makes them even more valuable in the critical care and emergency department settings. The Glasgow Coma Scale and its pediatric modifications do not take into account the important brainstem reflexes, such as pupillary reactivity or oculocephalic, oculovestibular, or corneal reflexes. These should be a routine part of the assessment of the patient with impaired consciousness [Narayan et al., 1981]. The sum of the Glasgow Coma Scale may convey less useful information than the ocular, motor, and verbal responses individually [Teasdale et al., 1983]. In a study of

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270 children aged 2 months to 12 years with acute nontraumatic coma, multivariate analysis suggests that the ocular and motor response score and not the total score were predictors of short-term survival. Additionally, the absence of one or more brainstem reflexes (oculocephalic, oculovestibular, or pupillary reactivity) predicted short-term adverse outcomes [Nayana Prabha et al., 2003].

PATHOPHYSIOLOGY Consciousness is the result of the complex interplay between the cerebral cortex and the ascending reticular-activating system. The ascending reticular-activating system is a somewhat diffuse and poorly circumscribed group of neurons that lie in the reticular formation of the brain that extends from the lower medulla to the midbrain and diencephalon [Moruzzi and Magoun, 1949; Plum and Posner, 1982]. Coma is produced by diseases or conditions that cause bilateral cerebral cortical dysfunction, ascending reticular-activating system dysfunction, or both. Pathologically, these can be subdivided as follows [Adams et al., 1982; Gennarelli et al., 1982; Plum and Posner, 1982]: • Metabolic, toxic, or infectious encephalopathies that diffusely affect the cerebral hemispheres, the ascending reticular-activating system, or both • Supratentorial mass lesions that compress or displace the diencephalon or brainstem • Subtentorial mass or destructive lesions that compress or damage the ascending reticular-activating system • Traumatic axonal injury that affects both cerebral hemispheres, the ascending reticular-activating system, or their interconnections Impairment of consciousness results from partial disruptions of neuronal function in these same areas. Prolonged coma after severe traumatic brain injury may be due to traumatic axonal injury or diffuse axonal injury without severe injury to the cortex or ascending reticular-activating system. This finding explains why patients with traumatic brain injury have a better potential for recovery than patients with hypoxic-ischemic injury.

CAUSES A more relevant and practical classification for the etiology of impairment of consciousness and coma in children produces three distinct but overlapping categories: infectious or inflammatory; structural; and metabolic, nutritional, or toxic (Box 61-3). Bacterial, viral, rickettsial, or protozoan infections of the CNS may cause conscious alteration by direct involvement of brain parenchyma, interference with blood flow, production of cerebral edema with resulting increased intracranial pressure, and increasing metabolic activity beyond metabolic substrate availability. Viral infections are more likely to involve brain parenchyma (encephalitis). The meningitis produced by bacterial infections may produce injury as a result of large blood vessel occlusion, microvascular inflammation, or disturbance of cerebral autoregulation.

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BOX 61-3 ETIOLOGIES OF IMPAIRED CONSCIOUSNESS AND COMA Infectious or Inflammatory

Structural

Metabolic, Nutritional, or Toxic

A. Infectious Bacterial meningitis Viral encephalitis Rickettsial infection Protozoan infection Helminth infestation B. Inflammatory Sepsis-associated encephalopathy Vasculitis, collagen vascular disorders Demyelination Acute disseminated encephalomyelitis Multiple sclerosis

A. Traumatic Concussion Cerebral contusion Epidural hematoma or effusion Intracerebral hematoma Diffuse axonal injury Shaken-baby syndrome B. Neoplasms C. Vascular disease Cerebral infarction Thrombosis Embolism Venous sinus thrombosis Cerebral hemorrhage Subarachnoid hemorrhage Arteriovenous malformation Aneurysm Congenital abnormality or dysplasia of vascular supply Trauma to carotid or vertebral arteries in the neck D. Focal infection Abscess Cerebritis E. Hydrocephalus

A. Hypoxic-ischemic encephalopathy Shock Cardiac or pulmonary failure Near drowning Carbon monoxide poisoning Cyanide poisoning Strangulation B. Metabolic disorders Sarcoidosis Hypoglycemia Fluid and electrolyte imbalance Endocrine disorders With acidosis Diabetic ketoacidosis Aminoacidemias Organic acidemias With hyperammonemia Hepatic encephalopathy Urea cycle disorders Disorders of fatty acid metabolism Reye’s syndrome Valproic acid encephalopathy Uremia Porphyria Mitochondrial disorders Leigh’s syndrome C. Nutritional Thiamine deficiency Niacin or nicotinic acid deficiency Pyridoxine dependency Folate and B12 deficiency D. Exogenous toxins and poisons Alcohol intoxication Over-the-counter medications Prescription medications (oral and ophthalmic) Herbal treatments Heavy-metal poisoning Mushroom and plant intoxication Illegal drugs Industrial agents E. Hypertensive encephalopathy F. Burn encephalopathy

Cerebral edema, focal mass or abscess, and hydrocephalus as a result of intracranial infection may produce injury by reducing cerebral blood flow or leading to herniation. Structural causes of consciousness impairment or coma include intracranial neoplasm, infectious space-occupying lesion (abscess, tuberculoma), nonaccidental and acci-

dental trauma, cerebral infarction or hemorrhage, and hydrocephalus. Nutritional causes of alteration of consciousness or coma are relatively uncommon in the United States but represent a significant problem in other areas of the world. Wernicke’s encephalopathy is related to a deficiency of thiamine. In

Taylor and Ashwal / Impairment of Consciousness and Coma

addition to consciousness alteration, patients may have eyemovement abnormalities, ataxia, and deep tendon reflex changes. Wernicke’s encephalopathy has been reported in children and adolescents as a result of systemic malignancy and because of thiamine deficiency in total parenteral nutrition, and it may occur related to anorexia nervosa, acquired immunodeficiency syndrome (AIDS), and prolonged fasting [Bruck et al., 1991; Hahn et al., 1998; Nautiyal et al., 2004; Pihko et al., 1989; Salas-Salvado et al., 2000; Vasconcelos et al., 1999]. Niacin or nicotinic acid deficiency (pellagra) with the typical features of mental changes, dermatitis, and diarrhea is rarely seen in the United States. However, disorders of the synthetic pathway from tryptophan to niacin or nicotinic acid or impaired intestinal absorption of tryptophan in Hartnup’s disease may produce symptoms in children or adolescents [Clayton et al., 1991; Freundlich et al., 1981]. Metabolic and toxic causes of impaired consciousness or coma include hypoxic-ischemic injury (focal or generalized), electrolyte abnormality, endocrinopathy, hepatic or renal failure and inherited disorders, including organic and aminoacidurias, urea cycle disorders, mitochondrial disorders, and porphyria. Paroxysmal disorders such as uncontrolled seizures, nonconvulsive status epilepticus, or migraine may produce changes in consciousness that may be episodic. The diagnosis, pathophysiology, and treatment of specific disorders are reviewed elsewhere in this book. There may be considerable overlap between these categories, and it is always necessary to consider combined causes of impaired consciousness and coma. Disorders that produce abnormalities of osmolality, such as hyponatremia, hypernatremia, and diabetic ketoacidosis, may also lead to structural complications, such as intracranial hemorrhage or stroke as a consequence of sinovenous thrombosis. Both have been reported as rare complications of diabetic ketoacidosis [Atlluru, 1986]. Cerebral edema may complicate treatment of ketoacidosis, causing alterations of consciousness or herniation [Green et al., 1990]. Children with psychiatric disorders, such as conversion, panic, or anxiety disorders, may present with neurologic symptoms including genuine or apparent impairment of consciousness. Symptoms may include dizziness, hyperventilation, paresthesias, agitation, or restlessness. The episodic and paroxysmal nature of these episodes and the complete recovery between episodes should suggest the diagnosis [Herskowitz, 1986].

EVALUATION The clinical approach to impairment of consciousness must be comprehensive and systematic. It is especially important to evaluate the evolution of symptoms and to interview any potential witnesses to the onset of symptoms. Not all patients with impairment of consciousness progress to coma, but early recognition of the progression and intervention often yields better outcome. Coma is a medical and neurologic emergency requiring immediate consideration of key issues, including immediate life support, identification of the cause of coma, and institution of specific therapy. These critical issues will be reviewed in sequence, but all have immediate importance and significance in the coma-

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tose child. The approach to the child with impaired consciousness but not coma is similar but may be modified based on the evaluation of symptoms and clinical need.

Clinical Evaluation The ABCs of basic life support (immediate life support— airway, breathing, and circulation) must be evaluated and managed emergently. Additionally, it is essential to assess adequacy of perfusion because children in shock may appear stable initially but then rapidly deteriorate. Glucose, the essential substrate for brain energy metabolism, must be provided through an intravenous line. Because unobserved or unreported trauma may have occurred, it is important to consider the possibility of a cervical fracture or other injury while implementing immediate life-support measures.

Identification of Cause Accurate and rapid identification of the cause of coma is important to direct specific treatment. The history and physical examination are the basis for identification of the cause of coma. Time constraints during evaluation of symptoms and signs often require rapid transition from history and examination to diagnostic tests, such as arterial blood gas determination or computed tomography. Nonetheless, these simple steps are exceedingly important and must not be overlooked or minimized. If the eyewitness to the onset of symptoms is not with the child in the emergency department (e.g., when symptoms begin at school or day care), a member of the emergency response team (usually a physician or nurse) is assigned to interview the eyewitness by telephone, and others attend to the patient’s immediate needs. If the child requires immediate resuscitation, accompanying parents, relatives, or other eyewitnesses in the emergency department are best interviewed in a quiet area to allow the most accurate elucidation of events surrounding the onset of symptoms.

History Coma may manifest as the progression of a known underlying illness, unpredictable consequence, or complication of a known disease, or it may be the result of a totally unexpected event or illness [Bates, 1993; Michelson and Ashwal, 2004]. An accurate history of the events and circumstances before the onset of symptoms and basic information concerning past medical history and medications may be invaluable in determining the cause of coma and quickly lead to the most appropriate diagnostic testing and treatment [Bates, 1993; Plum and Posner, 1982; Vannucci and Wasiewski, 1993]. Sudden onset of coma in an otherwise normal and awake child suggests convulsions or intracranial hemorrhage. Coma preceded by sleepiness or unsteadiness suggests ingestion of a drug or toxin in an otherwise well child. Fever is typical when coma is due to an infectious process but may not be present when shock is present or if the ambient temperature is low. A history of headache may suggest elevated intracranial pressure resulting from hydrocephalus or neoplasm but may also be seen in migraine syndromes with alteration of consciousness.

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When traumatic brain injury has occurred, coma may exist from the moment of impact or may be preceded by a lucid interval. The presence of a period of consciousness followed by coma warrants immediate computed tomography (CT) scanning of the head to assess for an expanding intracranial mass lesion, such as an epidural hematoma. Evaluation of accidental versus nonaccidental trauma in children can be especially difficult. In a study of 152 children aged 2 years or younger with traumatic brain injury who died or were admitted to a pediatric intensive care unit, 80 (52.6%) had inflicted (i.e., nonaccidental) injury, and 72 (47.3%) had noninflicted traumatic brain injury [Keenan et al., 2004]. Clinical history may make the cause relatively obvious, such as a history of an automobile accident or plausible history of a fall. Retinal hemorrhage, metaphyseal fracture, rib fracture, and subdural hemorrhage are more commonly seen in children with inflicted traumatic brain injury. Skeletal survey and ophthalmologic examination alone missed 10% of inflicted traumatic brain injury cases in one recent study [Keenan et al., 2004]. When there is a high degree of suspicion of inflicted injury, CT or magnetic resonance imaging (MRI) of the head, or both, should be performed. A history of fever or recent illness suggests an acute infectious etiology but should also lead to consideration of complications from infectious disease, such as acute disseminated encephalomyelitis, Reye’s syndrome, metabolic or mitochondrial disorders. Children with diabetes may have coma because of hypoglycemia or ketoacidosis. Children with congenital heart disease may be susceptible to brain abscess or infarction. Intermittent episodes of coma should suggest ingestion, drug overdose, inborn errors of metabolism, or Munchausen’s syndrome by proxy. Review of current medications should include use of ophthalmic drops, often overlooked as unlikely to have systemic effects. Brimonidine, an α2-adrenergic antagonist used in the treatment of glaucoma, caused recurrent episodes of coma at home and in hospital in a 1-month-old infant [Berlin et al., 2001]. A history of the use of a kerosene stove or heater should suggest carbon monoxide poisoning.

General Physical Examination The general physical examination begins with assessment of the vital signs, including temperature, heart rate, respiration, blood pressure, and the response to pain. Fever usually suggests infection but infrequently can be caused by an abnormality of the central control mechanisms that regulate body temperature. Fever with coma suggests sepsis, pneumonia, meningitis, encephalitis, intracranial abscess, or empyema. Very high fever and dry skin may be due to heat stroke. In children, hypothermia is most often seen with drug intoxication, especially if the ambient temperature is cold. Rapid heart rate suggests hypovolemic shock, secondary effects of fever, heart failure, or a tachyarrhythmia, such as paroxysmal atrial tachycardia. An abnormally low heart rate may reflect myocardial injury, the late effect of hypoxemia, or increased intracranial pressure. Rapid respiration suggests a primary abnormality of oxygenation, as seen in pneumonia, asthma, or pulmonary embolus, or acidosis, as in diabetic ketoacidosis and uremia. Brainstem lesions may cause central neurogenic hyperventilation.

Slow, irregular, or periodic breathing patterns may indicate toxic ingestion or increased intracranial pressure. Hypotension is seen in shock, sepsis, certain drug ingestions, myocardial injury or failure, and adrenal insufficiency. Hypertension may be a primary cause of unresponsiveness, as in hypertensive encephalopathy, but may also be a compensatory mechanism to ensure brain perfusion in children with increased intracranial pressure or stroke. Inspection of the head, scalp, and skin can be most helpful. Cyanosis suggests poor oxygenation, and jaundice is seen in liver failure. Extreme pallor may be seen in anemia and shock, and a cherry-red color suggests carbon monoxide poisoning. The presence of a cephalohematoma, boggy or swollen areas of the scalp, or head bruises suggests cranial trauma. Bleeding or clear fluid leaking from the nose or ears suggests a basilar skull fracture. Certain types of burns and multiple bruises of characteristic shape and location or varied age may suggest child abuse. Various rashes may be seen with infectious causes of coma, such as meningococcemia or rickettsial disease. The presence of neurocutaneous lesions, such as the depigmented areas of tuberous sclerosis, suggests seizures or intracranial mass as the cause of coma. Generalized increased pigmentation may be seen in Addison’s disease or in adrenoleukodystrophy [Ravid et al., 2000]. The odor of exhaled breath can be characteristic in alcohol intoxication, diabetic ketoacidosis (sweet-fruity), uremia (urine-like), and hepatic coma (musty). The cardiovascular examination may suggest congenital heart disease or endocarditis, both of which are sources of intracranial abscess dissemination. Abdominal discoloration or rigidity may suggest intra-abdominal bleeding as a source of shock. A palpable linear abdominal mass may lead to the diagnosis of intussusception encephalopathy and underscores the need to include a thorough general examination in the evaluation of the child with an altered state of consciousness or coma [Goetting et al., 1990].

Neurologic Examination The neurologic examination is of paramount importance in the assessment of the comatose patient. In particular, examination of the optic fundi, pupillary size and reactivity, eye movement control, corneal reflexes, motor responses, body posture, and the presence or absence of meningeal signs gives important information about the potential causes and localization of brain dysfunction in the comatose patient [Bates, 1993; Plum and Posner, 1982; Vannucci and Wasiewski, 1993]. Localization may be especially aided by detailed understanding of brainstem pathways involved in the eye examination. Funduscopic examination offers important clues about the etiology of coma, including papilledema as an indicator of raised intracranial pressure and retinal hemorrhages in occult trauma. In acute increased intracranial pressure, there may not have been time for papilledema to develop at the time of presentation in the emergency department. Passive resistance to neck flexion suggests meningeal irritation, tonsillar herniation, or craniocervical trauma. Resistance to thigh flexion with the leg extended (Kernig’s sign) and thigh flexion when the neck is flexed (Brudzinski’s sign) are more reliable indicators of generalized meningeal

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irritation. Patients with acute subarachnoid hemorrhage may not develop signs of meningeal irritation for several hours. Pupil size and reactivity are controlled by reciprocal sympathetic and parasympathetic innervation. Sympathetic pupil innervation originates in the hypothalamus and descends to the lower cervical and upper thoracic spinal cord. After synapsing in the intermediolateral columns, preganglionic sympathetic fibers exit the spinal cord and ascend in the cervical sympathetic chain, course near the apex of the lung, and end in the superior cervical ganglion where postganglionic fibers pass along the internal carotid artery. Intracranially, the fibers travel with branches of the ophthalmic division of the trigeminal nerve to the pupil. Sympathetic innervation to sweat glands of the upper face also follows the internal carotid arteries, and other fibers innervate the smooth muscles of the eyelid. The sympathetic pathways are vulnerable at several locations, and an appropriately placed injury may produce unilateral pupillary constriction, ptosis, and facial anhidrosis (Horner’s syndrome). Parasympathetic pupil innervation originates in the midbrain at or near the Edinger-Westphal nucleus and travels as a component of the oculomotor nerve to the pupils [Montgomery et al., 1986]. Pupillary reactivity can be elicited by shining a light on the eye or by opening and closing the eyelid. The afferent limb of the pupillary light reflex is through the optic nerve, and the efferent limb is through the parasympathetic fibers that travel with the oculomotor nerve. In the presence of normal visual acuity and the absence of corneal clouding, an abnormality of the pupillary light reflex suggests midbrain dysfunction. With unilateral loss of visual acuity, the opposite pupil may dilate when the light is moved from the unaffected to the affected side. This reaction results from a defect in the afferent limb of the reflex arc on the affected side. Most metabolic disorders and drug ingestions produce symmetrically small pupils that retain some reactivity to light. Severe hypoxic-ischemic injury produces symmetric dilated pupils that may not respond to light. Structural or mass lesions of the cerebral hemispheres typically do not produce pupillary abnormalities unless herniation occurs. For example, herniation of the temporal lobe over the tentorium with compression of the parasympathetic fibers traveling with the oculomotor nerve may produce unilateral pupillary dilation because of unopposed sympathetic innervation. Hypothalamic lesions produce small pupils by interrupting sympathetic fibers at the point of origin. Structural lesions in the pons may disrupt sympathetic fibers descending from the hypothalamus. In either case, unopposed parasympathetic tone produces small or “pinpoint” pupils that may mimic those seen in metabolic disorders or in patients with toxin or drug ingestions. Midbrain injuries may interrupt both sympathetic and parasympathetic pupillary innervations, producing midposition unresponsive pupils. Extraocular movements are controlled by the oculomotor (cranial nerve III), trochlear (cranial nerve IV), and abducens (cranial nerve VI) nuclei in the midbrain and pons. Conjugate gaze is coordinated by these cranial nerve nuclei through the medial longitudinal fasciculus. Supranuclear control of conjugate gaze resides in the two primary cerebral gaze centers found in the frontal lobes and parieto-occipital areas, respectively. The frontal gaze center produces rapid or saccadic eye movement contralateral to the side stimulated, whereas the more posterior center produces smooth pursuit

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or tracking movements ipsilateral to the side stimulated. The relatively large amount of cortex represented in these pathways is the basis for believing that the presence of the opticokinetic nystagmus response distinguishes coma from pseudocoma. Unilateral stimulation of the frontal gaze center produces conjugate eye deviation to the opposite side and can be produced by seizure activity or other unilateral irritating stimuli. Unilateral injury, destruction, or metabolic exhaustion of the frontal gaze center produces conjugate deviation toward the affected side (the patient is said to look toward the lesion). This yoked system also has important input from the vestibular system, the cerebellum, and proprioceptive pathways from neck muscles. These pathways are the basis for the “doll’s eyes” (oculocephalic) and caloric (oculovestibular) responses. The oculocephalic maneuver is performed by moving the head side to side or vertically and should only be performed when there is certainty that there is no cervical spine injury or abnormality. A positive oculocephalic response consists of conjugate deviation of the eyes in the direction opposite head movement. Absence of a positive oculocephalic response may be seen in structural abnormalities of the brainstem, where it may be asymmetric, and in metabolic-toxic encephalopathies, where it is almost always symmetric. A common cause of an abnormal oculocephalic response is medication routinely given to sedate patients for procedures, tests, or critical care support. Absence of an oculocephalic response may also be seen in patients who are awake with psychogenic unresponsiveness. Caloric or oculovestibular responses are obtained by irrigating one or both external ear canals with warm and cold water and should only be performed when the external canal is clean and the tympanic membrane intact. The usual protocol for unconscious patients involves cold-water irrigation with the head elevated 30 degrees from the horizontal, which induces convection currents in the endolymphatic fluid of the labyrinth. The resulting vestibular nuclei stimulation affects the ipsilateral paramedian pontine reticular formation–abducens nuclear complex and also the contralateral oculomotor and trochlear nuclei through the medial longitudinal fasciculus. In awake patients, cold-water irrigation produces a lateral nystagmus, with the quick phase away from the stimulated ear. Warm-water stimulation has the opposite effect. This finding gives rise to the mnemonic COWS (cold opposite, warm same). In the unconscious patient, however, the quick phase is lost, and slow tonic deviation is noted toward the irrigated ear. An intact oculovestibular response suggests functional connections from the vestibular system in the medulla to the ocular cranial nerve nuclei in the mesencephalon and pons connected by the medial longitudinal fasciculus. Unilateral or asymmetric caloric responses suggest a brainstem structural abnormality, whereas bilateral absence can be seen in metabolic, as well as structural, abnormalities. The oculocephalic response is an objective measure of lower brainstem integrity and an important addition to the neurologic examination when other medullary-controlled activities, such as respiration, are abnormal or controlled by mechanical ventilation. Caloric stimulation of the noncomatose patient may provoke nausea and vomiting, and care should be exercised to avoid the possibility of aspiration.

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The corneal reflex consists of closure of the eyelid elicited by gently touching the cornea with a suitable stimulus, such as sterile gauze or cotton. The afferent or sensory limb of this reflex involves the first division of the trigeminal nerve (cranial nerve V), and the efferent or motor limb is through the facial nerve (cranial nerve VII). A normal response to unilateral corneal stimulation is bilateral blinking resulting from pontine interconnections. An absent response suggests abnormal afferent or trigeminal input or bilateral pontine involvement. A contralateral blink response suggests intact sensory input through the fifth cranial nerve, whereas an abnormal motor limb response on the ipsilateral side is more consistent with an ipsilateral structural abnormality. Metabolic lesions typically produce bilateral loss of response. Absence of the corneal reflex must be interpreted with caution in the presence of conjunctival edema or injury, or with the use of sedative or paralytic agents that are commonly used in the intensive care unit setting. Observation of spontaneous movement and motor responses to stimulation are important clues in the assessment of coma and localization of the level of injury or lesion. Asymmetric involvement is a hallmark of structural abnormality. Unilateral cortical or subcortical structural lesions may cause contralateral weakness. Bilateral absence of movement or tone (flaccidity) occurs in metabolic-toxic encephalopathies, such as drug intoxications, and in disruption of brainstem-cortical interconnections above the pontomedullary junction. Flaccidity resulting from spinal cord injuries or neuromuscular paralysis is not associated with coma unless other injuries exist. Posturing may occur spontaneously or in response to stimulation. Decorticate posturing involves flexion of the upper extremities and extension of the lower extremities and usually involves cortical or subcortical abnormalities with preservation of brainstem function. Decerebrate posturing involves extension of all extremities with internal rotation and may be seen with metabolic-toxic disorders or midbrain compression. Decorticate and decerebrate posturing do not have the same exquisite localizing value in clinical medicine as they do in experimentally lesioned animals. It is generally believed, however, that decerebrate posturing is “worse” than decorticate posturing and that asymmetry of posturing is more likely seen in patients with structural than with metabolic-toxic disorders. Herniation syndromes should always be considered when posturing is present.

HERNIATION SYNDROMES The historical value of the concept of herniation syndromes was the correlation of clinical course with pathology findings to allow early identification of problems that may be progressive and life threatening and hasten appropriate early intervention. In the age of neuroimaging, the fundamental understanding of the cause of herniation symptoms is changing, but the importance of correlation of clinical signs and symptoms with intracranial pathology in vivo and in vitro remains. In this regard, an especially important concept has been the rostral-caudal deterioration—that is, that herniation proceeds from more generalized or diffuse symptoms through an orderly progression of brainstem dysfunction from diencephalon to mesencephalon to pons to

medulla. That this may not always be the case does not alter the importance of critical findings, such as a unilaterally enlarged pupil in a patient with deterioration of consciousness. Whenever there is clinical evidence consistent with risk for a herniation syndrome, immediate neuroimaging and treatment to lower intracranial pressure may be life saving. Three herniation syndromes are presented: uncal herniation, central or transtentorial downward herniation, and infratentorial herniation. Although signs and symptoms may overlap, and uncal herniation may just be a pathologically more distinct variant of transtentorial downward herniation, better understanding of the patient with consciousness alteration or coma is available to the student who studies these syndromes. Within the skull are unique dural reflections that divide the intracranial contents into compartments. The falx cerebri lies between the cerebral hemispheres, and the tentorium cerebelli separates anterior fossa structures (cerebral hemispheres and diencephalon) from posterior structures (brainstem and cerebellum). The opening in the tentorium through which the midbrain passes is called the tentorial notch. Excised dura is leathery and malleable, but the dural reflections, in vivo, are relatively rigid and firm. Focal or generalized lesions, which produce mass effect or increased intracranial pressure, may produce one of the three brain herniation syndromes based on squeezing of brain structures over or through the tentorium or through the foramen magnum. It is extremely important to recognize early signs and symptoms of these herniation syndromes so that urgent and appropriate intervention can be provided.

Uncal Herniation Uncal herniation refers to the medial displacement of the uncal gyrus of the temporal lobe over the free lateral edge of the tentorium associated with an asymmetric supratentorial mass or edema. Neuropathology-based studies presume that the uncal gyrus (uncus) comes in direct contact with the oculomotor nerve, producing ipsilateral pupillary dilation and external ophthalmoplegia. Radiologic studies, however, emphasize horizontal shift of the mesencephalon away from the lesion as the cause of early consciousness alteration because the ambient cistern and prepontine cistern are widened ipsilaterally. In this scenario, the ipsilateral pupillary dilation is due to stretch of the oculomotor nerve over the clivus rather than direct pressure from the uncus. Another early radiologic finding may be enlargement of the contralateral temporal horn of the lateral ventricle caused by compression of the ipsilateral lateral ventricle. In either explanation, there is typically early ipsilateral pupillary dilation with sluggish reactivity to light because of interruption of parasympathetic innervation to the pupil producing unopposed sympathetic response (dilation). Parasympathetic fibers to the pupil are located peripherally along the oculomotor nerve and are therefore affected first. Further, horizontal displacement of the upper brainstem may cause the contralateral cerebral peduncle to be pressed against the opposite tentorial edge and produce hemiparesis ipsilateral to the lesion (and ipsilateral to the enlarged pupil). This finding is consistent with the often-seen pathologic finding of a hemorrhagic lesion in the contralateral cerebral peduncle, the Kernohan notch phenomenon.

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False localization may occur if the uncus compresses the ipsilateral cerebral peduncle, producing contralateral hemiparesis, or if the contralateral oculomotor nerve is caught between the mesencephalon and the edge of the tentorium, producing contralateral pupillary dilation and external ophthalmoplegia. Consciousness alteration or coma associated with unilateral pupillary dilation and ultimately external ophthalmoplegia and unilateral hemiparesis are early signs of uncal herniation and should lead to urgent evaluation for causes of increased intracranial pressure and intracranial mass lesion. Unilateral pupillary dilation is most likely to indicate ipsilateral mass lesion or asymmetric cerebral edema. However, because of the variability of normal anatomy and the possibility of progression such that the primary clinical signs may be on either side, cerebral imaging is required to make the diagnosis. Uncal herniation is often ultimately associated with the central or transtentorial downward herniation syndrome.

alteration [Reich et al., 1993]. Other studies have found downward herniation of the diencephalon in consciousness alteration and coma by MRI, seeming to confirm the traditional clinical-pathologic correlation [Feldmann et al., 1988; Wijdicks and Miller, 1997]. In addition, downward transtentorial herniation may be associated with unilateral findings similar to those seen in uncal herniation. Recognition of the typical progressive deterioration may further be confounded by partial or total ischemia of the brainstem due to downward displacement of perforating branches of the basilar artery leading to allat-once brainstem dysfunction at multiple levels. In central or transtentorial downward herniation, early recognition of higher or more rostral brainstem dysfunction (e.g., abnormal pupil size or response) before lower or more caudal brainstem dysfunction (irregular or absent breathing), with or without, but generally without, focal findings suggests central herniation. Early recognition of the clinical signs may allow more effective intervention.

Central or Transtentorial Downward Herniation

Infratentorial (Cerebellar) Herniation Syndromes

With generalized increases in intracranial pressure, there is gradual downward displacement of the diencephalon (thalamus and hypothalamus) through the tentorium cerebelli, producing progressive compression and ischemia of the brainstem from mesencephalon (rostral brainstem) to medulla (caudal brainstem). The traditional clinical-pathologic correlation is progressive deterioration of consciousness and brainstem function in a rostral to caudal direction [Plum and Posner, 1982; Young et al., 1998]. In the diencephalic stage, patients do not follow instructions but will localize to noxious stimuli and have small reactive pupils and preserved oculocephalic and oculovestibular reflexes. Respiration may be regular with yawns or sighs, or CheyneStokes respirations may appear. Cheyne-Stokes respirations consist of a cyclical gradual buildup and decrease in the volume of air inhaled with each breath. Increased rigidity or decorticate posturing may appear. In the midbrain–upper pons stage, patients have decerebrate rigidity or no movement, midposition pupils that may be irregular in shape and demonstrate no reactivity, and abnormal or absent oculocephalic and oculovestibular reflexes. Patients usually hyperventilate, although Cheyne-Stokes respirations may still be noted. In the lower pontine–medullary stage, there is no spontaneous motor activity or activity in response to stimuli, midposition fixed pupils, absent oculocephalic and oculovestibular reflexes, and shallow and rapid or slow and irregular (ataxic) respirations. The lower extremities may withdraw to plantar stimulation. Finally, in the medullary stage, there is generalized flaccid tone, absence of pupillary reflexes and ocular movements, further slowing and irregularity of respiration, and ultimately death. Clinical-radiologic correlation studies have indicated that horizontal brainstem displacement may be likely to produce progressive impairment of consciousness and coma [Fisher, 1995; Ropper, 1986; Ross et al., 1989]. Horizontal shift of midline structures may be greater than their downward vertical displacement in patients who are in coma [Ropper, 1993]. Additionally, significant downward displacement of brainstem structures may be seen in individuals with low spinal fluid pressure syndromes without consciousness

Space-occupying lesions in the posterior fossa can produce upward herniation of brainstem structures through the tentorial notch and may result in obstructive hydrocephalus, brainstem ischemia, and death. Progressive alteration of consciousness or coma associated with miotic pupils, gaze paresis, decerebrate posturing, and asymmetric or absent caloric response with relative preservation of respiration suggest upward transtentorial herniation in the setting of posterior fossa tumor, hemorrhage, stroke, or cerebellar edema [Cuneo et al., 1979]. Downward herniation of the cerebellum and medulla at the foramen magnum may cause apnea and death because of pressure on medullary respiratory centers. The impressive shape of the lower cerebellum at postmortem examination is often referred to as the cerebellar pressure cone. Rapid onset of respiratory deterioration and apnea in the setting of increased posterior fossa pressure (with or without supratentorial pressure) is often called coning. The lesions that cause upward or downward cerebellar herniation in children are often subacute or chronic and are discovered before herniation as a result of widespread use of neuroimaging. However, some acute illnesses such as meningitis or encephalitis may be associated with either cerebellar herniation syndrome [Gohlich-Ratmann et al., 1998; Roulet Perez et al., 1993]. Early identification of impending herniation by CT or MRI criteria may allow effective treatment and improved outcome [Karantanas et al., 2002]. However, in children with meningitis, the cerebellar pressure cone effect has been implicated as a cause of death after lumbar puncture even with a normal CT scan of the head. In cases of suspected bacterial meningitis, lumbar puncture should be avoided if there is evidence of increased intracranial pressure or early coning. When lumbar puncture is performed, measurement of opening pressure is essential to allow early treatment if increased intracranial pressure persists. In all such cases, concern about risks for lumbar puncture should not delay appropriate antibiotic treatment [Oliver et al., 2003; Rennick et al., 1993; Shetty et al., 1999].

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The practice of placing preoperative ventriculostomy or ventriculoperitoneal shunt before surgery for posterior fossa tumor with hydrocephalus has fallen out of favor in most situations because of the risk for precipitation of upward transtentorial herniation [Cuneo et al., 1979; Epstein and Murali, 1978; Raimondi and Tomita, 1981]. Infratentorial herniation, either upward transtentorial herniation or downward cerebellar pressure coning, should be considered in the clinical setting of deterioration of consciousness or coma associated with posterior fossa mass lesion, cerebellar edema, or cerebrospinal fluid drainage whether by ventriculostomy, ventriculoperitoneal shunt, or lumbar puncture. Cerebellar herniation associated with lumbar puncture in the clinical setting of a child with meningitis and with evidence of increased intracranial pressure is an especially important consideration.

Herniation Syndromes, Summary That brain tissue deforms intracranially and moves from higher to lower pressure when there is asymmetric, unilateral, or generalized increased intracranial pressure is not disputed. The importance of the phenomenon is that associated symptoms, which begin with alteration of consciousness or coma and progress to involve brainstem areas from more rostral to caudal distribution, give important clues to the etiology of the deterioration and, thus, lead to more rapid and appropriate treatment.

DIAGNOSTIC TESTING All patients with significant impairment of consciousness or coma should have immediate blood glucose finger stick determination by Chemstrip or Dextrostix and should have blood drawn for a chemistry profile and complete blood count. The blood chemistry profile should minimally include glucose, sodium, potassium, blood urea nitrogen, calcium, magnesium, and ammonia. Hypoglycemia, derangements of osmolality (hyponatremia, hypernatremia), and ketoacidosis are important causes of mental status change in children. Uremia with encephalopathy may be seen in patients with acute renal failure with evolution over hours to days. It may also be the presenting feature in the hemolytic-uremic syndrome. Disorders of calcium metabolism may impair consciousness and cause peripheral symptoms. Abnormalities of calcium or magnesium may precipitate unexpected seizures, especially in infants and young children. Hyperammonemia may alter consciousness, particularly in conjunction with hepatotoxicity resulting from valproic acid or other agents, Reye’s syndrome, inborn errors of metabolism, or other disorders. A complete blood count assists in determining the presence of infection, anemia, or toxin exposure, such as lead poisoning. A urine specimen should be sent for toxicology screening (see Chapter 87). Arterial blood gas determination is often necessary, as is pulse oximetry. When infection is suspected, blood and urine cultures should be obtained. Additional blood and urine studies that may be worth obtaining when the patient is first seen but are not usually immediately available, include urine and blood specimens for amino and organic acid disorders, thyroid function studies, plasma cortisol, free fatty acid, very-long-chain fatty acids

and total and free carnitine levels, comprehensive drug testing, and screening for disorders of porphyrin metabolism. Lumbar puncture should be performed when there is a suggestion of infection of the CNS with or without fever. Depending on the clinical findings and evaluation, CT needs to be performed before the lumbar puncture. When medically stable, all patients in coma and most, if not all, patients with impairment of consciousness of undetermined etiology should have a CT performed as rapidly as possible. In children with closed-head injury, CT or preferably MRI may be critical in identifying the specific cause of impaired loss of consciousness [Ashwal and Holshouser, 1997]. MRI is also invaluable in identifying evidence of herpes simplex encephalitis or an acute demyelinating process, such as acute disseminated encephalomyelitis. The electroencephalogram is essential to diagnose clinically inapparent status epilepticus (i.e., nonconvulsive status epilepticus). Certain electroencephalogram patterns, such as periodic lateralized epileptiform discharges, may suggest herpes simplex encephalitis, especially in the setting of a febrile illness [Misra and Kalita, 1998]. In addition, the electroencephalogram is useful in the serial reassessment and evaluation of patients in status epilepticus or persistent coma, as well as in patients requiring pharmacologic paralysis or sedation.

TREATMENT Treatment of the child with impaired consciousness or coma requires scrupulous attention to certain basic principles while definitive diagnostic tests are obtained and therapy initiated. Specific etiologies of many individual causes of disordered consciousness are listed in Box 61-3 and are reviewed by specific diagnostic category in other sections of this book. The following principles of management are similar in most patients and are outlined in Box 61-4. 1. Ensure oxygenation. Maintenance of an adequate airway remains one of the most important principles in the management of children with altered states of consciousness and coma. When necessary, an artificial airway should be established and artificial ventilation provided, even if this necessitates the use of sedative or paralytic agents. It is important, however, to ensure that cervical spine injuries are not worsened in the process of managing a patient’s respiratory problems. 2. Maintain circulation. The second important principle in the management of these patients is to maintain cardiovascular function. Intravascular access is critical and should be provided by an appropriate intravenous line or through intraosseous access. 3. Administer glucose. Glucose is the essential source of adenosine triphosphate for cerebral energy metabolism. Once the initial glucose level is ascertained, glucose administration is recommended if the results reveal an abnormally low level. All other therapies are superfluous when oxygen and essential metabolic substrates (e.g., glucose) are not delivered to neurons and toxic metabolites are not removed.

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BOX 61-4 TREATMENT GOALS FOR PATIENTS WITH IMPAIRED CONSCIOUSNESS AND COMA • • • • • • • • • •

Ensure oxygenation Maintain circulation Give glucose Correct acid-base and electrolyte imbalance Consider specific antidotes Reduce increased intracranial pressure Stop seizures Treat infection Adjust body temperature Manage agitation

4. Correct acid-base and electrolyte imbalance. Electrolyte imbalance seen after CNS insults is often mediated by inappropriate antidiuretic hormone secretion. Inappropriate administration of fluids may worsen this situation. More commonly, hyponatremia, hypernatremia, hypocalcemia, or hypomagnesemia may occur in conjunction with systemic illness and be the cause of coma. Metabolic or respiratory acidosis or alkalosis should also be corrected. 5. Consider specific antidotes. Naloxone is available for treatment when an opiate overdose is suspected. Although opiate overdosage is rare in children, the risks of naloxone are minimal, and administration should always be considered. Physostigmine may reverse CNS and cardiac effects of anticholinergic agents. However, physostigmine may cause nonspecific CNS stimulation or seizures. Flumazenil, a benzodiazepine receptor antagonist, may be valuable in such patients. 6. Reduce increased intracranial pressure. Increased intracranial pressure may exist for a variety of structural, metabolic, or toxic reasons. It is essential to identify surgically treatable causes of elevated intracranial pressure quickly to allow appropriate intervention. Head CT should be performed in all children with coma resulting from closed-head injuries and in all children in whom the cause of coma is not immediately apparent or in whom the onset was not observed or is unknown. When intracranial pressure elevation is not caused by a surgically treatable lesion, a variety of therapeutic interventions can be considered. Fluid administration can be limited to half or two thirds of maintenance, provided that cardiovascular function and systemic blood pressure are maintained. Fluid restriction as a treatment for increased intracranial pressure should only be used when cerebral perfusion is deemed adequate. Positioning of the head at 30 degrees above the horizontal to maximize venous outflow from the head has merit so long as cerebral perfusion pressure is not harmed. Hyperventilation through mechanical ventilation reduces intracranial pressure by lowering cerebral blood flow and may have short-term merit if cerebral perfusion pressure and delivery of metabolic

7.

8.

9.

10.

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substrate is maintained. Reduction of intracranial volume by reduction of brain water content using mannitol, furosemide, or hypertonic saline may be beneficial. Sedation is valuable to reduce Valsalva response and resulting reduction in brain venous outflow during noxious, but necessary, critical care such as suctioning. Barbiturate therapy to reduce cellular metabolic demand may help control intracranial pressure but does not seem to influence outcome. Reduction of fever, however, may be valuable in lowering brain metabolic demands. High-dose corticosteroid therapy may have a role in treating increased intracranial pressure due to brain tumors and in some infections but is not useful in managing traumatic brain injury, infarction, and hemorrhage [Smith and Madsen, 2004a]. Optimal treatment of increased intracranial pressure must take into consideration that metabolic substrate supply must equal critical metabolic requirement to prevent secondary brain injury. Simply controlling intracranial pressure and cerebral perfusion pressure by using diuretics to reduce brain water content and hyperventilation to reduce cerebral blood flow and volume does not adequately take into account strategies to prevent secondary injury [Meyeret al., 2001]. Therefore, monitoring of intracranial pressure is essential, and monitoring cerebral blood flow and brain tissue PO2 adds monitoring power. Decompressive craniectomy, with or without opening the dura, lowers intracranial pressure and is increasingly used for refractory increased intracranial pressure in certain situations [Figaji et al., 2003; Smith and Madsen, 2004b; Taylor et al., 2001]. Stop seizures. Treatment of status epilepticus and other seizure emergencies is discussed elsewhere. It is always important to consider seizures even when there are no obvious outward seizure manifestations. Electroencephalography is essential in identifying subclinical nonconvulsive status epilepticus or other forms of seizure activity. Treat infection. Underlying infectious processes should be treated if specific treatment is available. Usually, the diagnosis of infectious diseases that involve the CNS requires lumbar puncture. When there is concern about elevated intracranial pressure, it may be appropriate to start antibiotic therapy for meningitis or antiviral therapy for encephalitis before lumbar puncture. In certain clinical situations, treatment can be initiated and the lumbar puncture deferred. Adjust body temperature. Usually, normal body temperature is best for recovery and prevention of acidosis. Patients with fever should have appropriate antipyretic agents administered. The use of hypothermia is being re-evaluated as a potential treatment for coma [Bernard et al., 1997; Biagas and Gaeta, 1988; Clifton, 1995; Safar and Kochanek, 2002]. This is discussed in more detail in Chapters 62 and 63. Manage agitation. It is particularly important to prevent agitation because of the problems it may

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present in the critical care management of patients with altered consciousness or coma. Agitation may increase intracranial pressure and make it difficult to control respiration with mechanical ventilation. The decision to sedate, however, may make serial neurologic examination as a measure of change in a patient’s status difficult. In these circumstances, additional serial neurodiagnostic tests, such as electroencephalography, may be valuable.

MONITORING OF THE COMATOSE PATIENT After initiation of treatment, it is necessary to serially reevaluate the patient’s condition and effectiveness of intervention. The neurologic examination is the gold standard for evaluation and re-evaluation but often is significantly modified by iatrogenic intervention such as mechanical ventilation, sedation, and paralysis. Many clinical neurophysiology monitors are available to improve critical care monitoring; some are in more widespread use than others. All clinical neurophysiology monitors are used in one or more of the following situations: • As extension of the neurologic examination to identify nonconvulsive status epilepticus or electroencephalographic patterns that suggest a diagnosis and to evaluate the integrity of certain neural pathways • To improve assessment of the neurologic condition of patients who are sedated or sedated and paralyzed and on mechanical ventilation • To assist in assessment of availability of metabolic substrate critical to maintain brain integrity and function • To evaluate treatment effect in status epilepticus • To improve outcome assessment Traditionally, the electroencephalogram has been used to identify presence of or risk for seizures and has additive value in that certain patterns may suggest specific pathology such as triphasic waves in metabolic causes of coma and periodic lateralized epileptiform discharges in focal injury and infection. Electroencephalographic reactivity to sensory stimulation is considered a favorable sign in coma recovery [Young, 2000]. Electroencephalography has the advantage of ready availability in most centers and is usually definitive in the evaluation for ongoing seizures. However, there is not universal agreement about criteria to diagnose nonconvulsive status epilepticus in obtunded or comatose patients [Brenner, 2002]. Other drawbacks to the use of long-term electroencephalographic monitoring include technical training necessary to apply and maintain the electrode-scalp interface, specialized training necessary for interpretation, and electroencephalographic susceptibility to artifact in the critical care setting. Processed derivations of electroencephalographic activity, therefore, have been successfully used to monitor brain activity. The Bispectral Index monitor is a recorder that uses processed electroencephalogram data to measure sedation depth on a scale from 0 to 100 (0, coma; 40-60, general anesthesia; 60–90, sedated; 100, awake). The Bispectral Index monitor is useful in monitoring depth of sedation

during conscious sedation [Agrawal et al., 2004] and neurologic status in critically ill unsedated patients. It is also easily applied to children in critical care settings and has been used to monitor children in barbiturate coma, sedation to assist mechanical ventilation, and procedural sedation and to evaluate sedation effects of multiple medications [Grindstaff and Tobias, 2004]. Although the Bispectral Index Scale does not have the monitoring power of a full-montage electroencephalogram, it has the advantage of easier electrode application and more ready interpretation. In a study of 16 patients between 10 and 192 months of age with consciousness alteration admitted to a pediatric intensive care unit, the Bispectral Index Scale correlated well with the Glasgow Coma Scale [Hsia et al., 2004]. Amplitude-integrated electroencephalography is an alternative methodology that has been used for the evaluation of the neonate but is now being used in older children and adults to assess the severity of neurologic injury [Scheuer and Wilson, 2004; ter Horst et al., 2004]. Sensory-evoked potentials allow assessment of the integrity of visual, auditory, and somatosensory pathways in the unconscious patient. Somatosensory-evoked potentials have been especially valuable because their neural pathways extend from brainstem through thalamus and subcortical white matter to cortex. Somatosensory-evoked potentials are relatively resistant to sedation effect and are useful in predicting outcome in comatose patients. Visual-evoked potentials have not been as valuable as somatosensory-evoked potentials for outcome prediction in comatose children [Shewman, 2000a, 2000b; Taylor and Farrell, 1989]. Brainstem auditory-evoked potentials are valuable for monitoring brainstem function but do not predict cortical function [Shewman, 2000a, 2000b]. The presence of normal brainstem auditory-evoked potentials with abnormal somatosensory-evoked potentials is seen on patients who are in a vegetative state [Frank et al., 1985]. Middle latency auditory-evoked potentials have cortical representation and have been shown to improve coma outcome prediction in adults, although they may be less resistant to environmental artifact and sedation than somatosensory-evoked potentials. Event-related potentials (auditory P300 response) may assist in evaluating severity of injury and may correlate with closed-head injury outcome in adults [Fischer et al., 2004; Keren et al., 1998; Litscher, 1985; Logi et al., 2003]. Motor-evoked potentials have limited value in evaluation of the comatose patient and have not been studied in children for this purpose. Adult studies have found that electrically elicited but not magnetoelectrically elicited motor-evoked potentials may predict postcoma pyramidal motor deficit but do not allow prediction of severity of motor deficit. Motor-evoked potentials do not have the predictive value of somatosensory-evoked potentials for coma outcome. Motor-evoked potentials may be valuable in evaluating clinical deterioration in the acute phase of coma [Rohde et al., 1999; Zentner and Rohde, 1992, 1994]. Measurement of cerebral blood flow is a direct way to determine delivery of essential metabolic substrate to the brain but is not useful for continuous monitoring. Brain tissue PO2 measurement, however, is suitable for continuous monitoring. In 25 patients older than 16 years with severe traumatic brain injury (Glascow Coma Scale value less than 8), it was found that intraparenchymal brain PO2 favorably

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compared with stable xenon CT for measurement of cerebral blood flow and allowed continuous monitoring of this critical substrate [Doppenberg et al., 1998]. Another study of 22 severe head injury patients aged 11 to 52 years found that continuous monitoring of partial pressure of brain tissue oxygen was practical and safe, allowed monitoring of ischemia on a continuous basis, allowed demonstration of abnormalities of oxygen autoregulatory mechanisms, and was superior to jugular oximetry [Van Santbrink et al., 1996]. Low brain tissue PO2, as a measure of cerebral hypoxia, is predictive of poor neurologic outcome and is an important independent measurement parameter in adults with severe traumatic brain injury [Bardt et al., 1998]. Monitoring of brain tissue PO2 may also allow early detection of critical and potentially irreversible worsening and allow measurement of intervention effect on a continuous basis. This is exemplified in a case report of a 15-year-old patient with severe traumatic brain injury and uncontrollable intracranial hypertension who developed bilateral fixed and dilated pupils and critically low brain tissue PO2 on the third day after injury, and who underwent bilateral decompressive craniotomy with immediate normalization of intracranial pressure and complete recovery of brain tissue PO2 to normal level [Kiening et al., 1997]. Local sampling of energy substrates by microdialysis during ischemia is feasible and allows measurement of glucose, lactate, pyruvate, and glutamate in brain tissue serially over time. Glucose concentration closely follows brain tissue PO2, lactate concentration significantly increases when brain tissue O2 falls below critical level, and glutamate is significantly elevated with very low brain tissue PO2 levels in adult head trauma patients [Hlatky et al., 2004]. Microdialysis measurements have thus far only been applied in children for monitoring of severe traumatic brain injury. In one study of nine children aged 2 to 14 years, a low glutamine-to-glutamate ratio was associated with increased morbidity [Tolias et al., 2002]. Near-infrared spectroscopy noninvasively monitors brain tissue oxygenation by measuring the distinct absorption spectra of oxygenated and deoxygenated hemoglobin in the frontal cortex. Near-infrared spectroscopy compares favorably to brain tissue PO2 monitoring in adults with severe traumatic brain injury or aneurysmal subarachnoid hemorrhage [Brawanski et al., 2002]. Additionally, in a study of 43 children monitored after corrective surgery for noncyanotic congenital heart defects, noninvasive measurement of the cerebral tissue oxygenation index by near-infrared spectroscopy correlated with central venous oxygen saturation measured with a catheter placed in the right atrium [Nagdyman et al., 2004]. At least one commercially available device for near-infrared spectroscopy monitoring is approved by the U.S. Food and Drug Administration for children [Andropoulos et al., 2004] and has been used extensively to monitor brain tissue oxygenation during surgery for congenital heart disease. In a study of 26 infants and children having heart surgery with bypass and deep hypothermic circulatory arrest, low cerebrovascular hemoglobin oxygen saturation was associated with postoperative neurologic complications in 3 children (1 with seizure and 2 with prolonged coma) [Kurth et al., 1995]. Cerebral oxygenation measured by near-infrared spectroscopy has been found to be valuable in two pediatric

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patients (ages 4 months and 16 years) being monitored for seizures in the pediatric intensive care unit and the epilepsy monitoring unit and demonstrated preictal increase in cerebral oxygenation and suggested perfusion-metabolism mismatch during seizure activity. Thus, the monitoring of cerebral oxygenation by near-infrared spectroscopy has value in the critical care setting for continuous monitoring of dynamic changes in cerebral oxygenation in relation to changes in metabolic need [Adelson et al., 1999]. Nonetheless, use of near-infrared spectroscopy to monitor brain tissue oxygenation has not been studied extensively in children, except in surgery for congenital heart defects, and a recent study in children indicated a poor agreement between two commercially available cerebral oximeters using near-infrared spectroscopy [Dullenkopf et al., 2003]. Transcranial Doppler ultrasonography measures real-time cerebral blood flow velocity and is useful for monitoring middle cerebral artery flow velocity transcranially in all ages and through the anterior fontanel in infants. Transcranial Doppler has been used in pediatric cardiac surgery to evaluate cerebrovascular response to cardiopulmonary bypass, hypothermia, and deep hypothermia circulatory arrest [Andropoulos et al., 2004]. It has also been used to evaluate detectable cerebral perfusion threshold in low-flow cardiopulmonary bypass in neonates [Zimmerman et al., 1997]. It is important to note, however, that cerebral blood flow velocity depend on vessel diameter and is not the same measurement as cerebral blood flow, which depends on cerebral vascular resistance and varies with temperature, CO2 pressure, cerebral perfusion pressure, and bypass flow. Therefore, cerebral blood flow velocity may correlate best with cerebral blood flow in deep hypothermia when autoregulation is lost and blood vessel diameter does not change. Brain tissue PO2 monitoring and microdialysis to evaluate energy substrates are complementary, and both monitoring probes require neurosurgical installation into brain parenchyma. Therefore, they are primarily used clinically to evaluate and monitor victims of severe traumatic brain injury. Near-infrared spectroscopy and transcranial Doppler are currently used to monitor brain oxygenation in children during and after cardiac surgery. The devices are small and relatively portable and can be used in the pediatric critical care environment safely, effectively, and continuously. Their ultimate value in monitoring of children in coma and guiding therapeutic interventions has yet to be delineated. However, in a prospective study of 250 patients undergoing pediatric cardiac surgery, it was found that interventions based on neurophysiologic monitoring (electroencephalography, transcranial Doppler, near-infrared spectroscopy) appeared to decrease the incidence of postoperative neurologic sequelae and reduce length of stay [Austin et al., 1997].

OUTCOME MEASUREMENT When consciousness is impaired, outcome is related to the etiology of the insult and rapid identification and treatment of the underlying cause. Early appropriate treatment may prevent further deterioration of the mental state and injury to the nervous system and improve outcome. Outcome studies in childhood coma are available for traumatic and non-

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traumatic causes and typically emphasize predictive value of signs and symptoms at the time of initial medical intervention. A commonly used and widely accepted measurement of outcome after severe closed-head injury is the Glasgow Outcome Scale [Jennett and Bond, 1975]. The Glasgow Outcome Scale has the following five broad outcome categories: (1) death; (2) persistent vegetative state; (3) severe disability (conscious but disabled); (4) moderate disability (disabled but independent); and (5) good recovery. The Glasgow Outcome Scale heavily emphasizes functional independence in mobility, transportation, and self-care. Significant functional improvement can be seen within the first three categories. The Glasgow Outcome Scale is limited in its ability to quantify impairments related to social skills and emotional and cognitive dysfunction; it does not take into account special issues of injury and recovery during the developmental period. A modified form of the Glasgow Outcome Scale for children, the Pediatric Cerebral Performance Category Scale, was published by Fiser in 1992. This six-point outcome scoring system was validated in 1469 pediatric patients suffering acute CNS injuries. It has also been correlated with neuropsychological test scores [Fiser et al., 2000]. The score includes the following outcomes: (1) normal—able to perform all age-appropriate activities; (2) mild disability—conscious, alert, and able to interact at an age-appropriate level but may have a mild neurologic deficit; (3) moderate disability—conscious, sufficient cerebral function for most age-appropriate independent activities; (4) severe disability—conscious, dependent on others for daily support because of impaired brain function; (5) persistent vegetative state; and (6) death. This scale has been used in outcome prediction studies after acute brain injury in children who were acutely evaluated with proton magnetic resonance spectroscopy [Ashwal et al., 2000; Brenner et al., 2003; Holshouser et al., 1997]. In a prospective study of 53 children less than 3 years old with severe brain injury or hypoxic-ischemic encephalopathy, the Glasgow Outcome Scale indicated good recovery in 46% of 50 children with known outcome [Robertson et al., 2002]. However, only 16% had average or above-average scores on both the mental and motor developmental sections of the Bayley Scales of Infant Development II at 18 to 36 months of age. Thus, a commonly used developmental assessment tool, the Bayley Scales of Infant Development II, provides a greater distinction between normal and delayed development than does the good recovery level of the Glasgow Outcome Scale [Robertson et al., 2002]. Early studies using the Glasgow Outcome Scale as an outcome measure after closed-head injury reported that patients advance to the highest functional level by 6 months after injury [Jennett et al., 1976, 1979; Jennett and Bond, 1975; Lange-Cossack et al., 1981]. Meaningful recovery, however, may occur for months to years after injury [Mahoney et al., 1981, 1983]. Because there may be significant functional improvement within the three highest Glasgow Outcome Scale categories (i.e., good recovery, moderate disability, and severe disability) and because long-term improvement is possible, especially when injury occurs during early childhood, alternative outcome scales have been developed. The Disability Rating Scale consists of eight items

divided into four categories: (1) arousability and awareness (best eye opening, verbal, and motor response); (2) cognitive ability for self-care activities (feeding, toileting, and grooming); (3) physical dependence on others; and (4) psychosocial adaptability for work or school [Rappaport et al., 1982]. The Disability Rating Scale is a more sensitive measure of improvement during inpatient rehabilitation than the Glasgow Outcome Scale [Hall et al., 1985] and is suitable for use in adolescents and some older children. The Functional Independence Measure and its pediatric counterpart, the Wee Functional Independence Measure, further refine outcome assessment using six items and 18 categories [Data Management Service of the Uniform Data System of Medical Rehabilitation and the Center for Functional Assessment Research, 1989]. The Wee Functional Independence Measure items and categories are as follows: (1) self-care (eating, grooming, bathing, dressing—upper body, dressing—lower body, toileting); (2) sphincter control (bladder and bowel); (3) mobility: transfer (chair or wheelchair, toilet, tub, shower); (4) locomotion (walking, wheelchair, crawling, stairs); (5) communication (auditory and visual comprehension, verbal and nonverbal expression); and (6) social cognition (social interaction, problem solving, memory). The Wee Functional Independence Measure has good inter-rater reliability and allows serial assessment throughout the pediatric age range. The Pediatric Evaluation of Disabilities Inventory measures both capability and performance of multiple functional activities in three areas: (1) self-care, (2) mobility, and (3) social function [Haley et al., 1992]. The Pediatric Evaluation of Disabilities Inventory is designed for use from 6 months to 7 years of age but is appropriate for older children whose functional level is within the intended age range. Specialized derivations of the Pediatric Evaluation of Disabilities Inventory specific to acquired brain injury do not improve the assessment value of the generic inventory, although further refinement may allow better functional recovery scoring in acquired brain injury [Kothari et al., 2003]. Pediatric Evaluation of Disabilities Inventory score change of about 11% has been found clinically meaningful during inpatient rehabilitation in a cohort of 53 children ages 1 to 19 years [Iyer et al., 2003]. The Wee Functional Independence Measure and the Pediatric Evaluation of Disabilities Inventory are sensitive measures of functional outcome and are suitable for inpatient rehabilitation monitoring and long-term outpatient follow-up. They are two of the most commonly used functional outcome measures in children [Ziviani et al., 2001] and are superior to the Glasgow Outcome Scale and its pediatric variants for assessment of long-term functional improvement in children across more relevant domains of recovery. The School Functional Assessment was developed to measure performance of functional tasks that are important for participation in an elementary school level program (kindergarten through grade 6). The School Functional Assessment evaluates (1) ability to participate in major school activity settings, (2) support necessary to participate effectively in an education program, and (3) performance of specific school-related functional activities [Coster et al., 1998]. The School Functional Assessment provides for further functional assessment of short-term and long-term outcome

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more specific to the educational setting and may allow prediction of specialized school needs before discharge from inpatient rehabilitation. Other standardized measures used to assess intellectual, cognitive, language, and behavioral development in children without injury are useful in evaluating and assessing outcomes in children after severe acquired brain injury. In children old enough and cooperative enough, neuropsychologic testing is the most sensitive and specific way to measure and monitor change in these domains. Valuable reviews of these issues are available [Fletcher et al., 1987; Hannay and Sherer, 1996; Levin, 1994; Ylvisaker et al., 1990]. In a retrospective analysis of 83 children aged 1 to 18 years admitted to hospital after head injury, 70% had severe head injury, and 13 died. Forty-five patients had at least one cognitive assessment, and 17 were evaluated with intelligence testing less than 4 months after injury, 5 to 15 months after injury, and 16 to 38 months after injury. Continued improvement in cognitive functioning was seen at 16 to 38 months’ follow-up assessment [Campbell et al., 2004]. This improvement underscores the fact that continued cognitive recovery may progress for years and that more long-term studies are necessary.

PROGNOSIS—TRAUMATIC INJURY Prolonged coma after global hypoxic ischemic injury as in cardiac arrest has a poor prognosis [Kirkham, 1994]. Children who survive traumatic or infectious injury may have a better prognosis depending on the specific pathophysiology and the presence of hypoxia-ischemia as a complicating variable. How prognosis is defined, however, is significant. For example, in a study of 127 children said to be in the persistent vegetative state for at least 30 days, 84% of the traumatic brain injury group, but only 55% of the hypoxic-ischemic injury group, improved beyond the vegetative state [Heindl and Laub, 1996]. This study highlights that hypoxic-ischemic injury is worse than traumatic brain injury but uses the term persistent vegetative state (a statement of prognosis) rather than vegetative state (a moment in time description). It is important, therefore, to understand the operational challenges in the evaluation of coma prognosis in children. Shewman has identified and reviewed the following problems and caveats with studies of coma prognosis in children: (1) definition of coma; (2) definition of study population and outcome variables; (3) basic study design; (4) self-fulfilling nature of poor prognosis; (5) early death rate from nonneurologic causes; (6) lumping of etiologies, age groups, and outcome categories; (7) short and inhomogeneous follow-up; and (8) failure to provide confidence intervals [Shewman, 2000a, 2000b]. Lumping of etiology, age groups, and outcome categories often is an effort to compensate for low statistical power related to small total number of patients and early death rate from other causes, which further reduces sample size. Clearly, there are better outcome descriptors than the Glasgow Outcome Score and its variants. In an effort to provide a sense of the current state of outcome data in this area, several outcome studies are reviewed. In studies of coma in children resulting from traumatic

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brain injury, substantially better outcome is seen in children when compared with adults [Broman and Michel, 1995]. Up to 80% to 90% of children with severe traumatic brain injury have good outcomes or recover to a moderate disability based on studies using the Glasgow Outcome Scale. In a small retrospective review of eight survivors of severe traumatic brain injury at a mean age of 14 years, neuropsychologic evaluation was performed 1, 7, and 14 years after the injury. Three of the eight subjects went from a school situation with no adjustments to adult life without ability to be employed [Jonsson et al., 2004]. In a review of 65 children and adolescents with acquired brain injury aged 6 months to 18 years (mean age, 9.5 years), 82% were discharged home, but only 3% to 27% were deemed ready for age-expected participation in home, school, and community life [Bedell et al., 2002a]. Social behavioral activity performance at discharge explained 74% of the variance associated with participation at discharge. In the same cohort of patients, functional assessment scales of daily and social behavioral activity allowed assessment of response to treatment [Bedell et al., 2002b]. In survivors of severe traumatic brain injury, potential problems involving community re-entry including home, school, and community life can be evaluated and treatment interventions monitored serially. After school, capacity for employment may be greatly impaired by behavior and social problems, even in the individual cognitively able to be employed. Early recognition of these problems and effective intervention while in school may allow better functional outcome. Brink and associates reported a large series of 344 pediatric patients (younger than 18 years) with severe closed-head injury and coma for a minimum of 24 hours who were admitted to a rehabilitation center between 1959 and 1977 [Brink et al., 1970, 1980]. Median coma duration was 5 to 6 weeks. One year after injury, 73% were independent in ambulation and self-care, but only 10% were physically normal. Coma duration of less than 6 weeks was associated with better outcome than coma duration of longer than 12 weeks. However, less than one third of these children had normal intelligence; about half had significant behavior problems, and most required special education services at school. A study of 33 survivors of severe closed-head injury enrolled at 17 years of age or younger demonstrated the following Glasgow Outcome Scale distribution 5 to 7 years after injury: 27% good recovery, 55% moderate disability, and 18% severe disability. At the time of follow-up, 70% were independent in self-care, 64% in mobility, and only 24% in cognitive items on the Functional Independence Measure [Massagli et al., 1996]. More importantly, 70% received special education services, and employment histories were poor. This clearly illustrates the better specificity of the Functional Independence Measure over the Glasgow Outcome Scale when evaluating long-term quality of life and community re-entry. Moreover, most of these individuals were not involved in neurologic or rehabilitation follow-up, suggesting the need for better long-term programs of monitoring and care. Both the Wee Functional Independence Measure and the Pediatric Evaluation of Disabilities Inventory measure functional ability taking into account amount of caregiver

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assistance necessary and use of special equipment. The Wee Functional Independence Measure assesses 18 variables in self-care, mobility, and cognition, whereas the Pediatric Evaluation of Disabilities Inventory evaluates 197 functional items in self-care, mobility, and social function. In a study of 205 children with disability aged 11 to 87 months, the Wee Functional Independence Measure measured similar skill areas to those assessed by the Battelle Developmental Inventory Screening Test or the Vineland Adaptive Behavior Scale. The Wee Functional Independence Measure requires less administration time than the Pediatric Evaluation of Disabilities Inventory, the Battelle Developmental Inventory Screening Test, or the Vineland Adaptive Behavior Scale and provides directly relevant functional outcome information for children and their families [Ottenbacher et al., 1999]. Further, the Wee Functional Independence Measure was an improvement over the Battelle and the Vineland scales in predicting the amount of assistance that parents or teachers must provide for basic activities of daily living [Ottenbacher et al., 2000].

PROGNOSIS—NONTRAUMATIC INJURY Outcome after coma resulting from nontraumatic causes has been extensively reviewed and available information suggests that, as with closed-head injury, outcome in children is better than in adults. In a cohort of 104 children ranging in age from 1 month to 17 years with nontraumatic coma (average duration of coma was 3 hours to 35 days), 32% died, 50% were normal, and the remaining 18% had handicaps ranging from mild to severe. Stepwise multivariate discriminant analysis within 12 hours of onset of coma classified 75% of 102 cases correctly into one of five outcome groups and misclassified 8% of patients. When the discriminant analysis was used on data collected 24 hours after the onset of coma, 67% of the cases were correctly classified, and only 3% were misclassified. Variables that correlated best with outcome were coma severity, motor patterns, blood pressure, and seizure type. Age correlated well with outcome based on data obtained at 24 but not at 12 hours. Extraocular movements, pupillary responses, and temperature correlated with outcome at less than 12 hours but not at 24 hours. Mortality rate was highest in patients less than 1 year of age (44%), and only 24% were considered normal at follow-up. For patients aged 6 to 17 years, 24% died, and 73% were normal. Patients who died all had hypothermia, inability to maintain body temperature, and absent pupillary responses or extraocular movements [Johnston and Seshia, 1984; Seshia et al., 1983]. In a retrospective population study of nontraumatic coma in children aged 1 month to 16 years, 278 individuals were identified, representing 283 episodes of coma. The most common cause of coma was infection, and the most common cause of recurrent episodes of coma was epilepsy. Causes of nontraumatic coma were infection, 37.9%; unknown, 14.5%; intoxication, 10.3%; epilepsy, 9.6%; congenital malformation, 8.2%; other, 7.8%; accident, 6.7%; and metabolic, 5.0%. Within the unknown group, half of the cases were suspected to be due to infection because of the clinical course, but pathogens were not identified. At 12 months’ follow-up, the overall mortality rate was 46%, and the etiology-specific

mortality rate varied from 3% (intoxication) to 84% (accident). Most individuals were either intact (normal) at 12 months’ follow-up or were deceased. Highest intact survival rates were seen in patients with epilepsy (71.4%), metabolic etiologies (60%), or unknown causes of coma (47.5%). Mortality was highest in patients in coma from accidents (84.2%), congenital malformations (72.7%), and infections (60%) [Wong et al., 2001]. In this study of 278 individuals, cognitive and adaptive outcomes were evaluated 6 weeks and 12 months after admission. Age-appropriate psychometric instruments were employed as follows: Bayley Scales of Infant Development (younger than 3.5 years); Wechsler Preschool and Primary Scale of Intelligence—Revised (3.5-6 years), and the Wechsler Intelligence Scale for Children III (older than 6 years). When appropriate, adaptive behavior was evaluated using the Vineland Adaptive Behavior Scales. Of 278 patients, 151 survived to late follow-up, and 141 (93% of survivors) completed follow-up assessment. Significant differences in outcome based on etiology could not be established, but children younger than 2 years of age at admission had no improvement, and children older than 2 years of age had improvement when evaluated 6 weeks and 12 months after initial admission. The overall incidence of moderate-to-severe disability (cognitive quotient less than 70 and moderate-to-severe behavioral disturbances) was 70%. The relation between early age at first coma episode and poor outcome was particularly evident in children with nontraumatic coma caused by epilepsy [Forsyth et al., 2001].

PROGNOSIS—CLINICAL NEUROPHYSIOLOGY In the comatose patient, clinical neurophysiology evaluation (electroencephalogram, somatosensory-evoked potential) is the most valuable for prediction of survival, brain death, and functional recovery beyond the vegetative state [Beca et al., 1995; DeMeirleir and Taylor, 1986, 1987; Fischer et al., 2004; Goodwin et al., 1991; Mandel et al., 2002; Mewasingh et al., 2003; Shewman, 2000b; Wohlrab et al., 2001]. There are, however, a few reports of contrary findings such as normal somatosensory-evoked potentials in a child in a vegetative state following near drowning [Tsao and Ellingson, 1989]. Therefore, the clinical neurophysiology assessment is used as an adjunct to the clinical examination and other outcome predictors such as neuroimaging and cerebral blood flow. To date, there are no studies linking neurophysiologic tests to very long-term functional outcome measures such as the Wee Functional Independence Measure or the Pediatric Evaluation of Disabilities Inventory. Several studies have indicated the prognostic value of proton magnetic resonance spectroscopy in newborns, infants, and children with CNS insult or injury of different types [Holshouser et al., 1997, 2000]. Patients with elevated cerebral lactate are more likely to die or have serious long-term disability [Ashwal et al., 1997]. Metabolic ratios of N-acetylaspartate/choline–containing compounds and N-acetylaspartate/creatine and phosphocreatine were significantly lower in patients with bad outcomes. Outcome measurement was performed at 6 to 12 months using the Pediatric Cerebral Performance Scale, and outcomes were

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expressed as good/moderate outcome (good, mild, moderate disability) or poor outcome (severe disability, persistent vegetative state, death). When magnetic resonance spectroscopy data were combined with clinical data and MRI scores, outcome was correctly predicted in 91% of neonates and 100% of infants and children [Ashwal et al., 1997; Auld et al., 1995; Holshouser et al., 1997; Shu et al., 1997]. In a magnetic resonance spectroscopy study of 26 infants (1 to 18 months old) and 27 children (18 months or older) with nonaccidental or other forms of traumatic brain injury, lactate was evident in 91% of infants and 80% of children with poor outcome, whereas none of the patients with good outcome had elevated lactate. Metabolic ratios were abnormal (low N-acetylaspartate/creatine and phosphocreatine, low N-acetylaspartate/choline-containing compounds, and high choline-containing compounds/creatine and phosphocreatine) in patients with poor outcome. Clinical variables alone predicted outcome in 77% of infants and 86% of children. Lactate alone predicted outcome in 96% of infants and 96% of children. Addition of metabolic ratios and clinical variables did not improve outcome prediction over lactate alone [Ashwal et al., 2000]. Myoinositol, a marker of astrocyte activity, is measurable by magnetic resonance spectroscopy, and in a study of 38 children with traumatic brain injury, aged 1.6 to 17 years, myoinositol was higher in patients with poor outcomes than in patients with good outcomes (Ashwal et al., 2004]. Susceptibility-weighted imaging, a new high-resolution gradient-echo MRI technique, is superior to conventional T2-weighted two-dimensional gradient-recalled echo imaging in identifying hemorrhagic lesions associated with diffuse axonal injury [Tong et al., 2003]. In 40 children and adolescents with traumatic brain injury and suspected diffuse axonal injury, those with Glasgow Coma Scale scores of 8 or lower, prolonged coma of more than 4 days’ duration, or poor neurologic outcomes 6 to 12 months after injury had significantly increased numbers and volume of hemorrhagic lesions. More accurate evaluation of diffuse axonal damage soon after injury may provide improved prognostic information about coma duration and long-term outcome in children with traumatic brain injury [Tong et al., 2004].

CONCLUSIONS Altered states of consciousness in pediatric patients are urgent situations, and coma is a medical emergency requiring rapid and organized intervention. Basic life support needs, evaluation of the history and physical examination, and specific laboratory and neurodiagnostic tests are of paramount importance and should proceed simultaneously in the emergency department. Specific diagnoses must be treated appropriately, but there are key general principles to impaired consciousness and coma management that apply in all situations. The outcome for children with coma is substantially better than for adults and may be affected by the speed and appropriateness of intervention. Even with the best and most appropriate care, some children die, some survive on mechanical ventilation and become brain dead, and some survive beyond mechanical ventilation and have minimal

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Task Force for the Determination of Brain Death in Children. Guidelines for the determination of brain death in children. Pediatrics 1987;80:298. Taylor A, Butt W, Rosenfeld J, et al. A randomized trial of very early decompressive craniectomy in children with traumatic brain injury and sustained intracranial hypertension. Childs Nerv Syst 2001;17:154. Taylor MR, Farrell EJ. Comparison of the prognostic utility of VEPs and SEPs in comatose children. Pediatr Neurol 1989;5:145. Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974;2:81. Teasdale G, Jennett B, Murray L, et al. Glasgow coma scale: To sum or not to sum. Lancet 1983;2:678. ter Horst HJ, Sommer C, Bergman KA, et al. Prognostic significance of amplitude-integrated EEG during the first 72 hours after birth in severely asphyxiated neonates. Pediatr Res 2004;55:1026. Tolias CM, Richards DA, Bowery NG. Extracellular glutamate in the brains of children with severe head injuries: A pilot microdialysis study. Childs Nerv Syst 2002;18:368. Tong KA, Ashwal S, Holshouser BA, et al. Hemorrhagic shearing lesions in children and adolescents with post-traumatic diffuse axonal injury: Improved detection and initial results. Radiology 2003;22:332. Tong KA, Ashwal S, Holshouser BA, et al. Diffuse axonal injury in children: Clinical correlation with hemorrhagic lesions. Ann Neurol 2004;56:36. Tsao CY, Ellingson RJ. Normal somatosensory evoked potentials in a child in persistent coma. Pediatr Neurol 1989;5:257. Vannucci RC, Wasiewski WW. Diagnosis and management of coma in children. In: Pellock JM, Meyer ED, eds. Neurologic emergencies in infancy and childhood, 2nd ed. London: Butterworth-Heinemann, 1993;103-122. Van Santbrink H, Maas AIR, Avezaat CJJ. Continuous monitoring of partial pressure of brain tissue oxygen in patients with severe head injury. Neurosurgery 1996;38:21. Vasconcelos MM, Silva KP, Vidal G, et al. Early diagnosis of pediatric Wernicke’s encephalopathy. Pediatr Neurol 1999;4:289. Wijdicks EF, Miller GM. MR imaging of progressive downward herniation of the diencephalons. Neurology 1997;48:1456. Wohlrab G, Boltshauser E, Schmitt B. Neurological outcome in comatose children with bilateral loss of cortical somatosensory evoked potentials. Neuropediatrics 2001;32:271. Wong CP, Forsyth RJ, Kelly TP, et al. Incidence, aetiology and outcome of non-traumatic coma: A population based study. Arch Dis Child 2001;84:193. Ylvisaker M, Chorazy AJL, Cohen SB, et al. Rehabilitation assessment following head injury in children. In: Rosenthal M, Griffith ER, Bond MR, eds. Rehabilitation of the adult and child with traumatic brain injury, 2nd ed. Philadelphia: FA Davis, 1990. Young GB. The EEG in coma. J Clin Neurophysiol 2000;17:473. Young GB, Ropper AH, Bolton CF. Coma and impaired consciousness: A clinical perspective. New York: McGraw-Hill, 1998. Zasler ND, Kreutzer JS, Taylor DA. Coma stimulation and coma recovery: A critical review. NeuroRehabilitation 1991;1:33. Zeman A. Persistent vegetative state. Lancet 1997;350:795. Zeman A. Consciousness. Brain 2001;124:1263. Zentner J, Rohde V. The prognostic value of somatosensory and motor evoked potentials in comatose patients. Neurosurgery 1992;31:429 Zentner J, Rohde V. SEP and MEP in comatose patients. Neurol Res 1994;16:89. Zimmerman AA, Burrows FA, Jones RA, et al. The limits of detectable cerebral perfusion by transcranial Doppler sonography in neonates undergoing deep hypothermic low-flow cardiopulmonary bypass. J Thorac Cardiovasc Surg 1997;114:594. Ziviani J, Ottenbacher KJ, Shephard K, et al. Concurrent validity of the Functional Independence Measure for Children (WeeFIM) and the Pediatric Evaluation of Disabilities Inventory in children with developmental disabilities and acquired brain injuries. Phys Occup Ther Pediatr 2001;22:91.

CHAPTER 62

Traumatic Brain Injury in Children Christopher C. Giza

Epidemiology of Pediatric Traumatic Brain Injury Traumatic brain injury is a leading cause of death and disability in children and has been identified as a significant public health problem in the United States and worldwide [Engberg and Teasdale, 1998; Murgio et al., 1999; Thurman, 2000; Tsai et al., 2004; Weiner and Weinberg, 2000]. Agerelated incidence rates for traumatic brain injury in children have been estimated to be as high as 670 per 100,000 when head injuries of all severities are included [McCarthy et al., 2002]. When limited to traumatic brain injury resulting in hospitalization, the incidence has declined over the past 15 years, most likely because of injury prevention measures and improved motor vehicle safety. Nonetheless, traumatic brain injury is responsible for most trauma-related deaths and hospitalizations. The incidence rate of traumatic brain injury–related hospitalization remains significant, consistently around 75 to 80 per 100,000 [McCarthy et al., 2002; Reid et al., 2001]. Childhood traumatic brain injury results in an estimated 3,000 deaths, 29,000 hospitalizations, and 400,000 emergency department visits annually in the United States (children 0-14 years old) [Thurman, 2000]. Traumatic brain injury is six times more likely to cause death in childhood than acquired immunodeficiency virus and is 20 times more likely than asthma to cause death [Centers for Disease Control and Prevention, 2000]. Moderate and severe pediatric traumatic brain injury has been associated with long-standing cognitive, neurologic, and behavioral impairments [Fay et al., 1994; Massagli et al., 1996a], and the cost of these disabilities is often sustained over the person’s lifetime. Fortunately, most traumatic brain injuries are mild, although recent studies suggest that even mild pediatric traumatic brain injury may have adverse long-term functional consequences [Hawley et al., 2004]. There is also increasing evidence that repeated mild traumatic brain injury, as commonly occurs in a sports-related setting, results in chronic cognitive impairment [Collins et al., 1999; Matser et al., 1999]. Despite these facts, no specific treatment standards exist for pediatric traumatic brain injury, either acutely or during recovery. A recent review of guidelines for pediatric traumatic brain injury management concluded that acute supportive therapies are often administered inconsistently or simply extrapolated from adult traumatic brain injury protocols and do not take into account the unique physiology of the immature brain [Adelson et al., 2003b]. The peak incidence of pediatric traumatic brain injury occurs during adolescence and in the young adult years, with a secondary peak in infancy [Kraus and McArthur, 2000]. The etiology of traumatic brain injury varies with age

(Fig. 62-1). Adolescents sustain most head injuries in motor vehicle crashes, sports-related injuries, and assaults. Preadolescent children are also frequent victims of motor vehicle crashes, but more often as a pedestrian or while riding a bicycle. Those younger than 5 years are more prone to falls [Thurman, 2000], whereas infants are particularly vulnerable to repeated severe traumatic brain injury in the form of nonaccidental trauma (inflicted head injuries/child abuse). Traumatic brain injury is about twice as common in boys as in girls overall, with this gender distinction becoming increasingly evident in the childhood and adolescent years [Kraus and McArthur, 2000; Rivara, 1994]. In the United States annually, about 30,000 pediatric patients incur permanent disability as a result of traumatic brain injury. These sequelae include headaches, post-traumatic epilepsy, motor disturbances, learning disabilities, cognitive impairment, and behavioral problems. Furthermore, most children suffering traumatic brain injury, even those surviving moderate or severe injury, fail to receive adequate medical, rehabilitative, or psychosocial follow-up after hospital discharge [Armstrong and Kerns, 2002; Hawley et al., 2004]. Finally, given the magnitude of recurrent head trauma as a problem of youth, it is increasingly noted that health-care providers should take every opportunity to provide important information and education to patients and their families, particularly with regard to potential sequelae of repeated injuries and effective injury prevention. 80 70 60 Rates per 100,000

INTRODUCTION AND BACKGROUND

Falls Transport Assault Firearms

50 40 30 20 10 0

0–4

5–9

10–14

15–19

Age group FIGURE 62-1. Etiology of pediatric traumatic brain injury by age group. (From Thurman D, for the Centers for Disease Control and Prevention. Traumatic brain injury in the U.S.: Assessing outcomes in children, Appendix B. Available at: http://www.cdc.gov.)

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In this chapter, injury mechanisms and the biomechanics of injury, as well as the cellular and molecular pathophysiology of traumatic brain injury and recovery, are reviewed. In addition, a framework for the clinical evaluation and initial treatment of head trauma in children is described. Critical distinctions between traumatic injury in the developing brain and in the adult brain are also considered. Specific acute syndromes of pediatric head injury are individually described in detail, followed by discussion of appropriate management, review of published treatment guidelines, and an overview of determining prognosis after severe pediatric traumatic brain injury. Finally, this chapter describes the chronic clinical syndromes and sequelae associated with pediatric head injury.

Anatomy To best understand the mechanisms and types of traumatic brain injury, knowledge of the basic anatomy of the brain and its coverings is essential (Fig. 62-2). The scalp is the outermost covering and is highly vascular, tending to bleed profusely when lacerated. Under the scalp is a tendinous sheath extending from the frontal to occipital regions called the galea. The potential space beneath this is the subgaleal compartment, an occasional site of significant bleeding after head injury. The skull is next, with the periosteum covering its outer surface. The skull is composed of three layers, the bony outer and inner tables, separated by the diploic space, which is more vascular. Between the inner table of the skull and the dura mater is the epidural space, another potential space that is a significant site for arterial bleeding, particularly after skull fracture. The dura itself is the tough outer protective layer covering the brain. Below the dura is the subdural space, which is crossed by small veins that drain into the venous sinuses and another site for post-traumatic hematomas. The next layer of brain coverings is the arachnoid, and under this, the subarachnoid space, that contains cerebrospinal fluid and into which posttraumatic bleeding is fairly common. The subarachnoid space is contiguous with the basal cisterns and the ventricular system, and cerebrospinal fluid normally flows from Galea

1 3

2

Pericranium 4

5 6

Skull Sutura or fracture site Dura

1. Caput succedaneum 2. Subgaleal hematoma 3. Cephalohematoma 4. Porencephalic cyst or leptomeningeal cyst 5. Epidural hematoma 6. Subdural hematoma 7. Cerebral contusion 8. Cerebral laceration

Arachnoid Subarachnoid space (CSF) Pia Brain

FIGURE 62-2. Schematic representation of the brain, skull, scalp, and pathologic entities related to head trauma. (From Rosman NP, Herskowitz J, Carter AP, et al. Pediatr Clin North Am 1979;26:707.)

its site of production at the choroid plexus within the ventricles, out into the basal cisterns, over the convexities of the cerebrum, and into the venous drainage of the brain through the arachnoid villi. Subarachnoid blood can impair the flow of cerebrospinal fluid after trauma and occasionally result in hydrocephalus. The last layer is the pia mater, which lies directly over the brain surface itself. The vascular supply of the brain originates in the great arteries of the neck (carotid and vertebral arteries; see Chapter 72). These enter the skull through foramina at its base and then arborize over the surface of the brain in fairly consistent vascular distributions. Venous drainage from the brain is routed either through deep draining veins or through small penetrating veins that traverse the subdural space, in either circumstance entering venous sinuses and eventually leaving the intracranial space through the jugular veins. One important developmental aspect of brain and skull anatomy is the rigidity of the skull itself. Intracranial pressure is determined by the three main contents of the skull, namely, the brain itself, blood, and cerebrospinal fluid. In infancy, the skull is more pliable, with flexible sutures and open fontanels. These features provide a mechanical outlet for elevated intracranial pressure that is not present once the sutures fuse. In older infants and children, as in adults, posttraumatic brain swelling can be accommodated only by displacement of blood and cerebrospinal fluid from the intracranial space, followed in severe cases by herniation of the brain through the foramen magnum.

Biomechanics Trauma is a unique form of brain injury, whereby a biomechanical force is imparted to the brain. In general, the forces applied to the brain may be described as linear or rotational. The clinical significance to identifying these forces is that they are often associated with particular mechanisms and types of injury. Linear forces refer to acceleration or deceleration forces in a straight line. As the brain “floats” in the cerebrospinal fluid, these forces often result in compression of the brain at the site of contact (i.e., “coup” injury). This injury can take the form of local hemorrhage or contusion, accompanied by overlying soft tissue swelling and occasionally skull fracture. As the intracranial contents are shifted toward the point of contact, however, a relatively low-pressure area evolves in a location opposite the coup injury. Injury in this area is termed contrecoup and can often be larger and more serious than the coup injury. Because of the relative irregularity of the skull floor in the anterior and middle cranial fossae, there is a propensity for focal traumatic injuries to occur in the frontal and temporal lobes. This propensity is an important consideration when evaluating a child for neurologic and cognitive impairment after injury because memory, attention, impulse control, judgment, and personality are all behavioral functions that may be localized in these brain regions and that also are undergoing rapid change during brain maturation. Because the brain parenchyma is itself soft and deformable and brain regions are connected by fiber tracts, the brain is also prone to injury from rotational forces. This describes the forces imparted when one part of the brain is twisted in relationship to another part. In these circumstances, the underlying white matter tracts are subjected to

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significant shearing forces that can result in stretch injury and microhemorrhages seen clinically [Tong et al., 2004] and in experimental models [Raghupathi and Margulies, 2002]. This type of damage after trauma is referred to as diffuse axonal injury and can result in significant clinical disability. By its nature, diffuse axonal injury can occur throughout the brain, with a propensity for regions with major fiber tracts (e.g., corona radiata, corpus callosum, brainstem). Although the developing brain has been shown to have remarkable resilience to focal injuries such as strokes or surgical resection, its ability to recover from diffuse injuries may be much more limited. Linear forces can play a role in collisions or falls, although it is generally difficult to separate these completely from rotational forces. Severe rotational forces are common with motor vehicle crashes. Because impact forces are offset or at an angle, the child can be injured inside a car, when thrown from a vehicle, or as a pedestrian struck by a vehicle. Rotational forces also can be seen with sports concussion, a milder but more common form of injury in older children and adolescents [Pellman et al., 2003]. Penetrating trauma, although less common, often results in enormous biomechanical forces and physical disruption of tissue along the path of the foreign object. Although the tissue destruction and surrounding necrosis, hemorrhage, and edema are major factors in determining long-term disability, the transmitted forces from the passage of the projectile to more distant parts of the brain can result in immediate death, presumably by affecting respiratory and autonomic centers [Carey, 1995]. One large series reported that younger age was associated with worse outcome from gunshot wounds [Levy et al., 1993].

Injury Types Although specific injury types are discussed in greater detail later in the chapter, an overview of the types of injuries commonly seen in children ranges from superficial injuries to the scalp to severe diffuse cerebral edema with herniation. Scalp injuries are very common and include contusions, lacerations, and hematomas. Although scalp injuries may occur with little if any evidence of underlying brain damage, careful history and examination should be undertaken in each case to rule out the possibility of concussion or, more rarely, intracranial injury. Concussion has been redefined as any trauma-induced transient disturbance of neurologic function, even in the absence of unconsciousness [American Academy of Neurology, 1997]. A large scalp hematoma may conceal a skull fracture and, in infants, can result in significant blood loss. Skull fractures are reported after 20% of childhood traumatic brain injuries [Harwood-Nash et al., 1971], and although simple linear fractures are generally benign, the presence of any fracture greatly increases the risk for intracranial hemorrhage [Lloyd et al., 1997]. Posttraumatic intracranial bleeding may occur in the form of cerebral contusion, cerebral laceration, and epidural, subdural, or subarachnoid hemorrhage, individually or often in combination. Diffuse axonal injury represents stretch and shearing of white matter tracts and can have profound clinical consequences with prolonged unconsciousness and poor outcome. Traumatic injury at its most severe can lead to

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5 1

2

3 4

FIGURE 62-3. Different forms of brain herniation: 1, cingulated; 2, uncal; 3, cerebellar tonsillar; 4, upward cerebellar; 5, transcalvarial. (From Fishman RA. Cerebrospinal fluid in diseases of the nervous system. Philadelphia: WB Saunders, 1980.)

cerebral swelling and elevated intracranial pressure. Although this problem may be accommodated to some degree by flexible sutures and open fontanels in infants, all ages are vulnerable to cerebral herniation. Based on location of edema or focal lesions, distinct types of herniation can occur (Fig. 62-3). Each of these injury types is discussed later in this chapter and is also reviewed in Chapter 65. Although all the previously described injuries are associated with clinical syndromes of primary traumatic brain injury, it is important to be aware that in conjunction with the primary injury are the effects of so-called secondary injuries. Secondary injuries may be additional pathologic insults independent of the original traumatic brain injury, such as hypotension due to systemic hemorrhage, hyperthermia caused by concomitant infection, or airway occlusion by a foreign body resulting in hypoxia. In many patients, secondary injury may be directly or indirectly related to the original brain injury but occurs after it. Thus, the spectrum of secondary injury encompasses entities such as cerebral edema with reduced brain perfusion, intracranial hemorrhage, early post-traumatic seizures, respiratory compromise of neurologic origin resulting in hypoxia, and post-traumatic hydrocephalus. More general etiologies of secondary injury include ongoing excitotoxicity, free radical generation, oxidative stress, and inflammation. Clinical secondary injuries such as hypotension, hypoxia, hydrocephalus, edema, and seizures are of great clinical significance because they are generally treatable in the intensive care unit and are often independent predictors of poor outcome [Chesnut et al., 1993a; Chiaretti et al., 2002].

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PATHOPHYSIOLOGY OF TRAUMATIC BRAIN INJURY Distinctions of Injury to the Developing Brain Biomechanical Factors Clearly, the physics of traumatic brain injury is different in a child than in an adult. The relatively large head size, reduced muscular strength in the neck, and increased flexibility of the neck may promote a greater range of biomechanical force to be imparted to the head. On the other hand, there is less cerebrospinal fluid space around the brain, and the prominent bony ridges of the anterior and middle cranial fossae are less developed. These factors may contribute to a lower occurrence of focal lesions in pediatric traumatic brain injury [Berney et al., 1994; Bruce et al., 1979; Levi et al., 1991; Luerssen et al., 1988]. The physical properties of the developing skull also confer advantages and disadvantages. It is thinner and more prone to diffuse deformation [Margulies and Thibault, 2000]. Some investigators have reported a higher risk for skull fracture in children [Berney et al., 1994], although this finding is not universal [Levin et al., 1992]. The open fontanels and flexible sutures may serve to dampen traumatic forces and accommodate a greater degree of intracranial swelling. The brain itself, particularly in infants and young children, has a higher water content and is incompletely myelinated [Holland et al., 1986; Paus et al., 2001]. The higher water content tends to make the brain less compressible and less compliant than in the adult. The physical properties of the immature brain may thus provide unique benefits as well as potential vulnerabilities to traumatic brain injury.

Changes in Cerebral Metabolism It is well known that cerebral metabolism changes throughout maturation. The primary source of energy for the brain changes from lactate in the perinatal period, to ketones while nursing, to glucose after weaning and on through to adulthood [Nehlig, 2004; Vannucci and Vannucci, 2000]. The ability to use alternative fuels may have important consequences on acute energy metabolism in the injured brain at different ages [Prins et al., 2004]. Even after the brain has switched to predominantly glucose metabolism, the levels of this metabolism continue to change throughout the developing years. Basal glucose metabolism rates peak at about 6 years of age, correlating with the time of maximal synaptogenesis. As synaptic pruning and dendritic rearrangement occur throughout childhood and adolescence, cerebral glucose metabolism declines, although it still remains elevated compared with the adult [Chugani et al., 1987]. Also, the brain does not mature uniformly, and brain metabolism changes have different time courses regionally.

Distinct Neurovascular Regulation Neurovascular control may also differ in the young brain. Early studies suggested a propensity for diffuse cerebral swelling in children after closed head injury, occurring two to five times more often than in adults [Aldrich et al.,

1992; Lang et al., 1994]. Recent studies report that normal children have higher baseline cerebral blood flow than adults, with significant variation across narrow age groups [Suzuki, 1990; Zwienenberg and Muizelaar, 1999]. At birth, cerebral blood flow is lower than adults but increases rapidly to peak at about age 5 years. Cerebral blood flow then appears to decline through adolescence to adult levels [Suzuki, 1990]. The effect of these developmental differences on injury-induced changes in cerebral blood flow and the mechanisms of these differences are not yet well understood. Certainly, molecular mediators of neurovascular tone, such as nitric oxide synthase, have differential expression patterns in the immature brain [Keilhoff et al., 1996; Ohyu and Takashima, 1998], and these may play a role in agedependent changes in blood flow and response to injury.

Increased Excitatory Neurotransmission As mentioned earlier, the number of synapses in the human brain appears to peak in early childhood and is associated with a peak in cerebral glucose metabolism. Levels of excitatory transmitter receptors are higher in the immature brain [Fosse et al., 1989; Insel et al., 1990; Miller et al., 1990]. The occurrence of early post-traumatic seizures is also noticeably higher in children, particularly infants and younger children [Annegers et al., 1980; Berney et al., 1994]. Because excessive release of excitatory neurotransmitters can result in neuronal injury (excitotoxicity) and death, the fact that the developing brain is more active might suggest that blocking excitatory transmission would be neuroprotective. However, early in development, neuronal activation also plays a critical role in both survival of immature nerve cells and proper wiring of cerebral circuitry. In fact, in animal models, use of glutamate antagonists early in postnatal development (while protective against some degrees of excitotoxic insult) resulted in a large degree of programmed cell death (apoptosis) [Bittigau et al., 1999; Ikonomidou et al., 1999; Pohl et al., 1999]. Evidence like this suggests that optimal recovery from brain injury may require a proper balance of excitation and inhibition and may also account for the relative ineffectiveness of glutamate antagonists following human brain injury [Ashwal et al., 2004b; Biegon et al., 2004; Ikonomidou and Turski, 2002].

Ongoing Cerebral Maturation In general, the developing brain is thought to recover better after many types of brain injury, including stroke, traumatic brain injury, and even surgical resection. In fact, developmental plasticity clearly confers an advantage when the brain must recover from a focal lesion [Kennard, 1942; Kolb et al., 2000; Villablanca and Hovda, 1999] if the lesion occurs at a specific age. However, the complex task of responding to environmental stimuli and rearranging neuronal networks, a fundamental developmental principle termed experience-dependent plasticity, may be transiently impaired after a diffuse injury. In the mature brain, consequences of such impairment might be overcome with time; in the young brain, it is possible that reduced responsiveness at a critical window of development can result in long-term dysfunction. Furthermore, studies looking at brain development occurring after traumatic brain injury,

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both in experimental animals and in children, must necessarily take into account the effects of brain maturation in normal controls.

traumatic pathophysiology at the cellular level is summarized in Figure 62-4. Specific components of the brain’s response to traumatic injury are discussed next.

Post-traumatic Neurometabolic Cascade

Glutamate Release and Ionic Flux

Traumatic brain injury results in an immediate release of glutamate, widespread changes in ionic flux, fluctuating cerebral glucose metabolism (initially elevated, then reduced), and dynamic changes in blood flow. Later, axonal damage and disconnection, reduced responsiveness to physiologic stimuli, impaired neurotransmission, and delayed cell death occur [Giza and Hovda, 2001]. An overview of post-

After traumatic injury to the brain, there is an immediate and indiscriminate release of the excitatory neurotransmitter glutamate [Bullock et al., 1998; Katayama et al., 1990]. This release can result from widespread triggering of action potentials, synaptic neurotransmitter release, and membrane disruption. This flood of glutamate results in a massive efflux of potassium into the extracellular space [Katayama

FIGURE 62-4. Neurometabolic cascade after traumatic injury. Cellular events: (1) nonspecific depolarization and initiation of action potentials; (2) release of excitatory neurotransmitters; (3) massive efflux of potassium; (4) increased activity of membrane ionic pumps to restore homeostasis; (5) hyperglycolysis to generate more adenosine triphosphate (ATP); (6) lactate accumulation; (7) calcium influx and sequestration in mitochondria leading to impaired oxidative metabolism; (8) decreased energy (ATP) production; (9) calpain activation and initiation of apoptosis. Axonal events: (A) axolemmal disruption and calcium influx; (B) neurofilament compaction via phosphorylation or sidearm cleavage; (C) microtubule disassembly and accumulation of axonally transported organelles; (D) axonal swelling and eventual axotomy. ADP, adenosine diphosphate; AMPA, alpha-amino-3hydroxy-5-methyl-4-isoxazole propionic acid; Glut, glutamate; NMDA, N-methyl-D-aspartate. (From Giza CC, Hovda DA. The neurometabolic cascade of concussion. J Athl Train 2001;36:230).

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et al., 1990; Nilsson et al., 1993] and an influx of sodium and calcium [Nilsson et al., 1996; Osteen et al., 2001]. Although hyperacute measures of extracellular glutamate are obviously unobtainable in human patients, microdialysis of extracellular fluid or cerebrospinal fluid samples from severely injured patients (including children) in the days after injury has demonstrated glutamate elevations and has been associated with secondary injury and possibly with poorer outcomes [Ashwal et al, 2004b; Bullock et al., 1998; Ruppel et al., 2001; Vespa et al., 1998].

Dynamic Changes in Cerebral Metabolism As the injured cells attempt to restore ionic equilibrium after injury, membrane pumps such as the sodium-potassium adenosine triphosphatase pump are activated. An increase in cerebral glucose uptake, termed hyperglycolysis, is seen early after experimental traumatic brain injury and has been postulated as a mechanism of providing additional substrate to generate the energy necessary to drive these membrane ionic pumps [Kawamata et al., 1992; Yoshino et al., 1991]. Acute studies of cerebral glucose metabolism using positron emission tomography in adult patients have found increased cerebral glucose uptake [Bergsneider et al., 1997]. Interestingly, there is increasing laboratory evidence that injured neurons are capable of utilizing alternative fuels to glucose [Magistretti et al., 1999; Pellerin and Magistretti, 2004; Prins et al., 2004], and it is well known that the capacity to use alternative fuels in uninjured neurons is age specific [Vannucci and Vannucci, 2000]. After the acute period of hyperglycolysis, there is a prolonged period of diminished cerebral glucose uptake. This hypometabolism is seen in adult and immature rats, although it lasts longer in adults (7-10 days [Yoshino et al., 1991]) than in rat pups (3 days [Thomas et al., 2000]). In traumatically injured adult patients, the period of reduced glucose metabolism has been found to last weeks to months [Bergsneider et al., 2001].

Cerebral Blood Flow Hyperemia? Hypoperfusion? Cerebral blood flow undergoes dynamic changes after injury, and the pattern of these changes may depend on the type of injury and its severity. A pattern of diffuse cerebral swelling has been reported more frequently in children than in adults [Aldrich et al., 1992; Lang et al., 1994]. This phenomenon was originally attributed to hyperemia [Bruce et al., 1981], but more recent studies suggest that the incidence of post-traumatic hyperemia has been overestimated [Muizelaar et al., 1989]. In the earlier studies of posttraumatic brain injury cerebral blood flow in children, flow values were compared with normal values from a young adult control group. Cerebral blood flow measured in normal children appears to change dramatically across development, and it is generally much higher in young children than in adults [Chiron et al., 1992; Suzuki, 1990; Zwienenberg and Muizelaar, 1999]. Subsequent studies of cerebral blood flow in children suffering traumatic brain injury, when compared with that in age-appropriate control values, have failed to demonstrate clear hyperemia [Adelson et al., 1997a; Sharples et al., 1995]. Interestingly, in an experimental model of traumatic brain injury, there is evidence for

dramatically increased cerebral blood flow adjacent to a traumatic contusion; this focal hyperemia was most pronounced in immature animals [Biagas et al., 1996]. Although clinically it is important to recognize that diffuse cerebral swelling is more common in children, the mechanism of this swelling does not appear to be solely attributable to hyperemia. The relation between cerebral blood flow and outcome appears to depend on the state of cerebral autoregulation. In the presence of intact autoregulation, increased cerebral blood flow has been associated with better perfusion and improved outcome in both children and young adults [Kelly et al., 1996; Vavilala et al., 2004]. However, after severe injuries in which autoregulation is dysfunctional and cerebral vasculature is pressure passive, increased cerebral blood flow can result in intractable elevations of intracranial pressure and poorer outcomes. Beyond the acute phase of head injury, cerebral blood flow generally declines. Post–traumatic brain injury cerebral blood flow can decline below normal, and it is important to monitor for ischemia because this is associated with worse outcome [Bouma et al., 1991; Vespa et al., 2003]. Investigations are in progress to determine whether neurovascular coupling is intact during this period of reduced flow.

Altered Neurotransmission Reductions in excitatory neurotransmitter systems have been reported after traumatic brain injury in experimental animals, including impairments in glutamatergic [Miller et al., 1990; Osteen et al., 2004; Sihver et al., 2001] and cholinergic [Gorman et al., 1996] transmission. These changes may correlate with the injury-induced reduction in cerebral metabolism. Furthermore, these changes may be an underlying mechanism for post–traumatic brain injury deficits in neuronal activation [Dietrich et al., 1994; Sanders et al., 2000], diminished activity-dependent molecular responsiveness [Giza et al., 2002; Griesbach et al., 2004], and impaired experience-dependent plasticity in developing animals [Fineman et al., 2000; Ip et al., 2002; Giza et al., 2005]. Activation studies using functional magnetic resonance imaging (fMRI), even after relatively mild traumatic brain injury, have shown reduced or aberrant activation patterns in traumatically injured teenagers and young adults [Jantzen et al., 2004; McAllister et al., 1999].

Axonal Disconnection Mechanical stretch can disrupt axonal membranes, resulting in calcium influx and microtubule and neurofilament disruption. Damage to these important cytoskeletal components impairs normal axonal transport, endangering distal axonal segments and synapses. Over time, disrupted axonal transport leads to an accumulation of transported proteins and organelles at the injury site, causing axonal blebs and, eventually, disconnection [Pettus and Povlishock, 1996; Povlishock and Christman, 1995; Povlishock and Pettus, 1996]. This type of damage is seen after experimental traumatic brain injury in immature [Raghupathi and Margulies, 2002] and adult [Povlishock and Pettus, 1996] animals. In postmortem human specimens, evidence of axonal blebbing and damage has been reported long after injury

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[Maxwell et al., 1997], and MRI can show abnormalities of diffuse axonal injury in pediatric and adult traumatic brain injury patients [Tong et al., 2004].

Cell Death: Necrosis and Apoptosis Mechanisms of post–traumatic brain injury cell death occur across a spectrum from necrosis to apoptosis. Necrosis represents acute energy failure, inability to maintain ionic homeostasis, cell swelling, and eventual disruption of the plasma membrane. This type of cell death occurs when energy is depleted and does not require protein synthesis. Necrosis is seen as a direct result of traumatic injury, generally occurs acutely, and evolves in regions experiencing profound energy failure. When the cell ruptures, there is release of intracellular contents and a significant inflammatory response. Apoptosis is characterized by nuclear condensation, DNA fragmentation, and preservation of the cell membrane. Apoptosis, also referred to as programmed cell death, requires energy and protein synthesis and initiates a less acute inflammatory response. Usually, apoptotic cell death takes longer to evolve after injury and continues to occur long after experimental trauma [Conti et al., 1998; Wilson et al., 2004]. Although apoptosis is seen after traumatic brain injury, it is also part of the brain’s normal maturational program. Thus, apoptotic pathways are more active in the immature brain, and apoptotic cell death appears more prominently after experimental injury to the developing brain [Bittigau et al., 1999; Pohl et al., 1999].

Impaired Plasticity An important aspect of injury in the young brain is the effect of this injury on normal neuronal responsiveness and on developmental plasticity. As mentioned earlier, increased plasticity in the immature brain results in significantly better recovery than in the adult after a focal lesion, and this has been well described in rats [Kolb and Tomie, 1988], cats [Burgess and Villablanca, 1986; Villablanca and Hovda, 1999], primates [Kennard, 1942], and humans [Hogan et al., 2000; Trauner et al., 1993]. However, the benefits of youth are less apparent when the injury is more diffuse or occurs at a critical window of brain development. Environmental enrichment is an experimental model of enhancing brain development, and animals reared in an enriched environment grow up to have larger brains [Bennett et al., 1964; Diamond et al., 1964; Rosenzweig and Bennett, 1996], increased dendritic arborization [Faherty et al.,, 2003; Greenough et al., 1973; Juraska, 1984; Volkmar and Greenough, 1972], and superior performance on neurobehavioral tasks [Tees et al., 1990; Venable et al., 1988; Williams et al., 2001]. Although injured rat pups exhibit less overt cell death and less behavioral impairment than adults [Gurkoff et al., 2005; Prins et al., 1996; Prins and Hovda, 1998], they lose the ability to benefit from being reared in an enriched environment. Specifically, they show a loss of enriched environment–induced experience-dependent plasticity: cortical thickening is blocked [Fineman et al., 2000], expansion of dendritic arbors is inhibited [Ip et al., 2002], and enriched environment–induced cognitive enhancements are absent [Giza et al., 2005]. These studies

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of altered developmental plasticity are also supported by findings of Prins and colleagues using a different model [Prins et al., 2003]. Following a lesion, regrowth of entorhinal cortical axons in a nontraumatically injured brain occurs in a well-characterized fashion. In juvenile rats subjected to experimental traumatic brain injury, this normal pattern of axonal regrowth was markedly disturbed, with evidence of disruption down to the synaptic level. Studies of developmental plasticity in traumatically injured children are difficult because the effects of both age at injury and age at assessment must be considered in the control groups. However, there is growing evidence that pediatric traumatic brain injury results in altered brain development. First, although children generally have better outcome after traumatic brain injury than adults, those injured at the earliest ages (i.e., in infancy) actually have poorer outcomes [Levin et al., 1992; Luerssen et al, 1988]. Some of this may be due to different mechanisms of injury, including nonaccidental trauma (inflicted head injury), which has a very poor developmental prognosis and is predominantly an etiology seen in infancy. It is also possible that the very young brain is decidedly more vulnerable to injury, as suggested by experimental studies using hypoxiaischemia [Ikonomidou et al., 1989] and traumatic brain injury [Bittigau et al., 1999; Pohl et al., 1999]. Second, there are anecdotal reports of cases of rare, neonatal head trauma that appear to have resulted in abnormal cortical development that was subsequently confirmed pathologically after epilepsy surgery for intractable seizures [Lombroso, 2000; Marin-Padilla et al., 2002]. Third, studies of severe pediatric traumatic brain injury show more persistent cognitive deficits when the injury was diffuse rather than focal [Levin et al, 2000]. Finally, in studies of repeated, mild sportsrelated traumatic brain injury sustained during adolescence or early adulthood, subtle but significant cognitive impairments are detected [Collins et al., 1999; Matser et al., 1999].

HISTORY The clinical approach to pediatric traumatic brain injury differs based on whether the presentation is acute (e.g., emergency department, urgent care clinic) or delayed (e.g., persistent post–traumatic brain injury symptoms in regular clinic). For an acutely injured child, history taking and initial assessment begin rapidly and simultaneously. Elements of the history should be obtained from parents, witnesses, and emergency personnel. Essential information includes mechanism of injury (e.g., pedestrian struck by motor vehicle, fell 10 feet out of a tree, bicycle crash), protective factors (e.g., helmet, seatbelt), any loss of consciousness (and duration), any post-traumatic amnesia (and duration), seizure activity (with duration and description), current medications (including allergies), and any persistent neurologic signs (e.g., confusion, focal deficit). Examination, monitoring for ABCs (airway, breathing, circulation, spine), and initial management are begun simultaneously. Additional components of the history that may be relevant are sought once the patient is stabilized and include premorbid cognitive and behavioral development, prior head injuries, prior neurosurgical procedures, history of epilepsy or other neurologic disorder, and other pertinent medical

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conditions (e.g., coagulopathy, asthma). In older children and teenagers, the possibility of drug or alcohol use should be considered. In infants and toddlers, inconsistencies in the injury story and presence of associated injuries should raise suspicion of child abuse. For patients presenting in clinic with persistent neurologic problems after (presumably) milder head injury, the same historical information should be sought. In addition, the child and parent should be asked about the nature of post-traumatic symptoms, including headache, neck pain, nausea, vomiting, dizziness, ataxia, visual disturbances, cognitive impairment, behavioral changes, and any focal neurologic deficits. Pain should be localized, if possible. The duration of constant symptoms should be ascertained, along with alleviating or exacerbating factors. Episodic symptoms should also be carefully investigated, including triggers, duration, pattern of episodes, and actions that result in symptom resolution.

EXAMINATION For the acutely and severely brain injured child, physical and neurologic examination must be done expediently, with the aim of identifying immediately life-threatening signs that would direct initial management. The presence of secondary insults is a strong independent predictor of poor traumatic brain injury outcome; thus, careful assessment of airway and breathing is paramount. Pattern of breathing should be noted (e.g., irregular, tachypneic). Adequate circulation and perfusion are also critical; look for skin color, pulses, blood pressure, capillary refill, and excessive bleeding. In a hypotensive patient, bodily injuries that result in internal bleeding, such as hemothorax, liver or splenic lacerations, pelvic fracture, and long bone fractures, should be identified as soon as possible, although they may not be evident from physical examination. In infants, massive scalp hematomas may result in hypotension and shock. Spinal cord injury or cardiac injury can also result in low blood pressure. In patients who are or were unconscious, careful stabilization of the spine is necessary.

The patient’s Glasgow Coma Scale score should be determined. The Glasgow Coma Scale is a quick, reproducible means of rating the severity of the patient’s neurologic injury (Table 62-1) [Teasdale and Jennett, 1974] that has three components: eye opening (ranging from 1 to 4), best verbal response (ranging from 1 to 5), and best motor response (ranging from 1 to 6), for a total score from 3 (worst) to 15 (normal). There are obvious limitations to this scale in the setting of pediatric trauma, such as how to determine verbal score in infants and young children. Several Glasgow Coma Scale modifications have been proposed to make it more usable in this age group (see Chapter 61), and one modified scale is shown in Table 62-1. By convention, mild traumatic brain injury is defined by a Glasgow Coma Scale score of 13 to 15, moderate is 9 to 12, and severe is 8 or less. A patient with a Glasgow Coma Scale score of 13 to 15 who has an intracranial lesion is generally classified as having a moderate traumatic brain injury. After the ABCs, assessment of the patient’s mental state should be made, including alertness, orientation, confusion, combativeness, or unresponsiveness. Use specific descriptions of mental status (e.g., “able to follow simple commands but becomes quiet and sleepy if unstimulated”) rather than vague words such as “lethargic” or “obtunded.” Inspection of the head can reveal lacerations, contusions, and hematomas. Careful examination is warranted in either circumstance to identify stepoffs (i.e., palpation of a bone edge indicative of a fracture or bony separation), foreign bodies, fractures, or penetrating injuries that may underlie more superficial damage. In infants, the fontanel can be assessed quickly to look for elevated intracranial pressure. Periorbital ecchymosis (“raccoon eyes”) or rhinorrhea raises concern for fracture of the anterior skull base. Retroauricular ecchymosis (“Battle’s sign”), hemotympanum, and otorrhea are signs indicative of a basilar skull fracture involving the temporal bone. Ophthalmoscopic examination to detect retinal hemorrhage is very important, particularly in cases of suspected nonaccidental trauma. Patients rendered unconscious by the injury and those who retain consciousness but report post-traumatic neck

TABLE 62-1 Glasgow Coma Scale

GLASGOW COMA SCALE Eye opening (E) • Spontaneous • To speech (to shout) • To pain • None Motor response (M) • Obeys commands • Localizes pain • Withdraws • Abnormal flexion • Extensor response • None Verbal response (V) • Oriented • Confused conversation • Inappropriate words • Incomprehensible sounds • None

INFANT MODIFICATION 4 3 2 1 6 5 4 3 2 1 5 4 3 2 1

Eye opening (E) • Spontaneous • To speech (to shout) • To pain • None Motor response (M) • Purposeful movements • Localizes pain • Withdraws • Abnormal flexion • Extensor response • None Verbal response, modified for infants • Babbles, coos appropriately • Cries, but consolable • Cries inconsolably • Grunts or moans to pain • None

4 3 2 1 6 5 4 3 2 1 5 4 3 2 1

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pain should have the cervical spine immobilized until it can be assessed for any significant fracture or dislocation. With the head in neutral position, the cervical spine should be carefully palpated, noting any angulation, stepoff, crepitus, or point tenderness. The post-trauma neurologic examination is by necessity short and directed and should be able to be performed in just a few minutes. Cranial nerve testing offers rapid, objective evaluation of brainstem functions. The pupillary response tests integrity of cranial nerves II and III. Fixed midposition pupils suggest symmetric midbrain dysfunction. A unilateral fixed dilated pupil in conjunction with declining mental status is a sign of impending transtentorial herniation, usually due to a mass lesion ipsilateral to the abnormal pupil, and warrants immediate intervention. Bilateral pinpoint pupils raise the possibility of opiate ingestion, or severe pontine injury. Bilateral fixed dilated pupils are evidence of widespread injury but can also be due to systemic effects of resuscitation drugs. A pupil that fails to constrict under direct light (but does when light is presented to the opposite eye) is indicative of an afferent pupillary defect, a sign of ipsilateral optic nerve injury due to fracture of the orbit. Integrity of nerves to the extraocular muscles (cranial nerves III, IV, and VI) and their brainstem connections can be tested in three ways. First, simply observe the eyes for spontaneous conjugate roving movements. Second is the oculocephalic response (“doll’s eye” maneuver), performed by turning the child’s head rapidly to one side. A normal response is for the eyes to move conjugately in the direction opposite the head turning. This test is rarely used acutely following trauma because it is not generally safe to move the head and neck until the cervical spine has been cleared. If it is absolutely necessary to assess these specific nerves, the third method is to test the vestibulo-ocular reflex (calorics). Before caloric testing, one must check for a nonoccluded ear canal, an intact tympanic membrane, and the absence of either hemotympanum or otorrhea. Then, with head positioned 30 degrees above horizontal, 30 to 60 mL of icecold water is irrigated rapidly into the ear. An intact response is tonic eye deviation toward the irrigated ear. After a few minutes, the response may be tested in the opposite ear. An intact corneal response demonstrates function of cranial nerves V and VII. If, on corneal stimulation, the globe rotates upward but the eyelid does not close, this suggests an intact afferent limb but impaired motor output. Examination for other evidence of a cranial nerve VII palsy, as might be seen with a basilar skull fracture, should be performed. Tickling the inside of the nose with a wisp of cotton or administering a noxious stimulus may elicit a grimace, which should be observed for facial symmetry. Sensorimotor examination can also be done quickly, starting with the best motor response elicited on Glasgow Coma Scale testing. Limb posture and muscle tone should be examined, and particular note should be made of any asymmetry. If the patient is unable to follow commands, then sensorimotor response may be assessed by application of a peripheral noxious stimulus (e.g., nailbed pressure) in each limb. If no response occurs, then the site of noxious stimuli can be moved centrally (e.g., sternal rub, supraorbital pressure) to distinguish between afferent and efferent

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TABLE 62-2 Rapid Pediatric Trauma Exam 1. ABCs, brief history—mechanism of injury, loss of consciousness, amnesia, persistent neurologic symptoms 2. Glasgow Coma Scale score 3. Physical examination, particularly head and neck a. Scalp—depressions, stepoffs, fluid collections, lacerations b. Other signs of skull facture—otorrhea, hemotympanum, rhinorrhea, raccoon eyes, Battle’s sign c. Cervical spine—deformity, point tenderness d. Associated severe bodily injuries—thoracic, abdominal, long bone 4. Mental status—describe succinctly, avoid ambiguous terms 5. Cranial nerves a. Pupillary response (CN II, III) b. Oculocephalic “doll’s eye” response (CN III, IV, VI) c. Vestibulo-ocular “caloric” response (CN III, IV, VI, VIII) d. Corneal response, facial grimacing (CN V, VII) e. Gag response (CN IX, X) 6. Sensorimotor—asymmetry, abnormal muscle tone, coordination (if possible), movement (spontaneous, to command), movement to pain (withdrawal, decorticate, decerebrate, no movement) 7. Reflexes—asymmetry, areflexia, hyperreflexia/clonus. upgoing toes

impairment. Application of painful stimulus centrally allows the examiner to determine more readily whether a child can localize pain (distinction between a 4 and 5 for best motor score). If the child is awake, coordination should be assessed by observation of posture, spontaneous movements, and directed movements when the child reaches for an object or mimics the examiner. Deep tendon reflexes should be checked for asymmetry, hyperreflexia, clonus, or areflexia. Flaccid paresis with no reflexes should immediately raise suspicion of a spinal injury. An outline of the rapid trauma examination is provided in Table 62-2. In the mildly injured child who is conscious at the time of initial evaluation, the neurologic examination can be conducted less urgently and more completely. In such patients, mental status testing can be more extensive, starting with observation and possibly requesting the patient to repeat a series of numbers (i.e., digit span) to assess the child’s attention. This assessment can be followed by evaluation of orientation, language, behavior, and memory (both anterograde, for new items, and retrograde, for past events, including events surrounding the injury). Cranial nerve, motor, coordination, and sensory examinations can include voluntary responses to the examiner’s commands and subjective reports of sensory input (visual fields, tactile stimulation). Gait should be observed for signs of unsteadiness or ataxia. As with the more severely injured child, deep tendon reflexes and plantar responses should be assessed. Neurologic reassessment is mandated based on the severity of injury. Mental status should be recorded in distinct descriptive wording such as “awake but mumbling incoherently and unable to follow commands” or “crying when approached but consolable by parent.” Deterioration of the neurologic examination may be a sign of progression of the underlying injury (cerebral edema, expansion of a subdural hematoma) or may represent a new complication (hemorrhagic transformation of a contusion, seizure) and should be evaluated immediately so that appropriate treatment is instituted.

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IMMEDIATE MANAGEMENT Initial management of the child suffering from moderate or severe traumatic brain injury centers on the ABCs and avoidance of secondary insults. The airway must be secured and supplemental oxygen provided. In circumstances in which the child is unable to adequately maintain the airway, endotracheal intubation should be performed. Appropriate noninvasive monitors should be placed, including cardiac, respiratory, temperature, blood pressure, and pulse oximetry. Intubated patients should also have an end-tidal CO2 monitor. Intravenous access must be established immediately and fluid resuscitation begun. Blood should be drawn for electrolytes, glucose, renal and hepatic function, complete blood count, prothrombin and partial thromboplastin times, type and cross-match, and, if indicated, arterial blood gas determinations and alcohol or drug screens.

ACUTE CLINICAL SYNDROMES Because traumatic brain injury is a heterogeneous disorder with multiple manifestations, syndromes may occur in isolation but are often overlapping. For example, nonaccidental trauma is a particular etiology of infantile head trauma that can include subdural hematomas, other intracranial hematomas, cerebral edema, diffuse axonal injury, cerebral contusion, skull fracture, and early post-traumatic seizures. Epidural hematomas are often associated with skull fractures. Concussion can occur alone or as a repeated injury; it can be associated with acute seizures and, rarely, with malignant cerebral edema, second impact syndrome, herniation, and death. Fortunately, concussion can also, and almost always does, last briefly and be symptomatically self-limited.

Herniation Syndromes Herniation is the displacement of brain tissue from one intracranial compartment to another. This injury can occur as a result of a space-occupying lesion in one region or diffuse swelling of both cerebral hemispheres (see Fig. 62-3) [Fishman, 1980; Plum and Posner, 1980]. The Cushing response is a paradoxical bradycardia with hypertension and slow irregular respiration that can be seen in the setting of elevated intracranial pressure and impending herniation. Definitive treatment for herniation requires surgical removal of the offending mass. In cases in which herniation is triggered by edema, position the head so that it is slightly elevated and in the midline (to facilitate venous drainage) and immediately initiate first tier measures to control elevated intracranial pressure: sedation, hyperventilation, and hyperosmolar therapy. Ventriculostomy with cerebrospinal fluid drainage, if feasible, should be instituted as soon as possible. Infants can tolerate elevation of intracranial pressure better because of unfused sutures and an open fontanel. These properties also allow for additional physical examination clues to the presence of increased intracranial pressure, like a tense or bulging fontanel or a steadily increasing head circumference (if chronic). In lateral transtentorial herniation, a hemispheric mass such as an epidural or subdural hematoma can displace the

medial temporal lobe structures across the tentorial notch. This displacement compresses the midbrain, resulting in impaired consciousness and ipsilateral cranial nerve III palsy with pupillary dilation and contralateral hemiparesis. Unilateral pupil dilation in an awake patient cannot be the result of herniation. Occasionally, this type of herniation compresses the posterior cerebral artery, resulting in an ipsilateral occipital lobe cerebral infarction and contralateral homonymous hemianopia. A unilateral mass can also result in translocation of brain tissue across the midline. At first, the falx cerebri will simply be displaced away from the side of the mass. This is termed midline shift and can be readily seen on a computed tomography (CT) scan. When more severe, the cingulate gyrus will actually be pushed under the falx cerebri, resulting in subfalcine herniation. This herniation syndrome is associated with compression of the anterior cerebral arteries and infarction of the medial frontal lobes. Diffuse bilateral cerebral edema or bilateral mass lesions can cause symmetric herniation of the supratentorial contents down into the posterior fossa. This result is termed central transtentorial herniation and is more common than the lateral syndrome. Physical examination findings consistent with the early stage of this syndrome include impaired mental status, fixed midposition pupils, impaired upward gaze, hyperventilation (central neurogenic hyperventilation), and posturing. Posturing will first take the decorticate form (arms flexed, legs extended), but as herniation progresses, decerebrate posturing (arms and legs extended) is seen. In these later stages of central herniation, pupils may become symmetrically constricted, and respirations may become irregular. Cerebellar tonsillar herniation occurs when the posterior fossa contents are pushed down through the foramen magnum. This type of herniation usually is seen in the setting of a posterior fossa mass. Because the infratentorial compartment is smaller than the supratentorial, critical pressure effects can occur rapidly and with much smaller spaceoccupying lesions. Tonsillar herniation can cause head tilt, neck stiffness, and lower cranial neuropathies and can appear relatively abruptly with cardiorespiratory compromise. Posterior fossa masses can also cause herniation of cerebellar contents upward through the tentorium. Herniation can then lead to ischemic and hemorrhagic complications (Duret’s hemorrhages) in the brainstem. The final stages of herniation occur as medullary centers are compressed, resulting in apnea, cardiac collapse, and death. Brain herniation also can occur through a traumatic or surgical defect in the skull. Transcalvarial herniation occurs when brain swelling is relieved by extrusion of brain tissue out of the cranial cavity through a fracture, burr hole, or craniotomy. In some circumstances, this type of herniation may alleviate disastrous brainstem consequences of downward herniation syndromes.

Diffuse Cerebral Swelling Because trauma, particularly closed head trauma, is by nature a diffuse process, bilateral swelling can occur even in the absence of discrete focal lesions. In fact, diffuse cerebral swelling is more common in children [Aldrich et al., 1992; Lang et al., 1994], whereas focal cerebral damage, such as

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contusion, is more common in older adolescents and adults. The etiology of this swelling was originally postulated to be hyperemia [Bruce et al., 1981]. However, as discussed earlier in this chapter, original reports of post-traumatic hyperemia in children may have overestimated the frequency of this phenomenon by comparing cerebral blood flow values with those of uninjured young adult controls rather than uninjured children [Muizelaar et al., 1989; Zwienenberg and Muizelaar, 1999]. An alternative etiology could be diffuse cerebral edema. Cerebral edema is generally of two types: (1) cytotoxic, which occurs as a result of dying neurons undergoing energy failure, with loss of membrane ionic gradients and a rapid increase in intracellular water; and (2) vasogenic, which results from fluid seeping into the extracellular space across a damaged or dysfunctional blood-brain barrier. Cytotoxic edema is thought to predominate after traumatic injury. Diffuse edema can occur as a direct response to trauma but also can be due to a post-traumatic secondary insult, such as hypotension or hypoxia. At its extreme, diffuse edema can result in central transtentorial herniation and death.

Diffuse Axonal Injury A clinical correlate to the pathophysiologic process of axonal injury and disconnection, diffuse axonal injury is thought to result from the effect of shearing and rotational forces on white matter fiber tracts [Adams et al., 1982]. These forces are usually considerable, and diffuse axonal injury is most commonly seen after a high-impact injury such as a motor vehicle crash or a high fall. Clinically, the patient with diffuse axonal injury has a prolonged period of unresponsiveness or coma that is not explained by a mass lesion or diffuse hypoxia. Gradually, the patient recovers some movement and can initially appear to be posturing or restless. Because of brainstem involvement, autonomic symptoms may be prominent, particularly in severe cases of diffuse axonal injury.

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Diffuse axonal injury can occur in the presence or absence of hypoxia-ischemia or elevated intracranial pressure but is a discrete process. The pathology of these lesions includes tearing and necrosis of nerve fibers, often with microhemorrhages. Blebs and swellings occur at points of axonal injury, locations that may subsequently become sites of axonal disconnection [Maxwell and Graham, 1997; Pettus and Povlishock, 1996; Povlishock and Christman, 1995]. These lesions are often seen at the gray-white junction of the frontal and temporal lobes, in the corpus callosum, and in the rostral brainstem. Diffuse axonal injury is rarely seen on CT, and then only if hemorrhage is present. MRI, however, is more sensitive in detecting diffuse axonal injury, which appears as areas of hypointensity on T2-weighted, two-dimensional gradient recall echo imaging (Fig. 62-5). Recently, MRI using susceptibility-weighted imaging has more clearly demonstrated and allowed quantification of hemorrhagic diffuse axonal injury lesions [Tong et al., 2004]. In general, patients with diffuse axonal injury have lasting neurologic impairments, with good outcome at 3 months ranging from 65% of mild diffuse axonal injury patients to only 15% of severely injured patients [LeRoux et al., 2000]. The aforementioned autonomic impairments may be the etiology of significant mortality in patients with diffuse axonal injury.

Nonaccidental Trauma Child abuse has previously been termed shaken-baby syndrome because the etiology of the cerebral injuries was thought to be due to rapid shaking of the infant (see Chapter 63). Biomechanical studies attempting to model these injuries found that shaking alone may not be capable of generating the forces necessary to cause the severe and diffuse intracranial injuries that are typically seen [Prange et al., 2003]. It has been proposed that most injuries involve shaking and also a final impact [Duhaime

FIGURE 62-5. Areas of microhemorrhage (arrows) indicative of diffuse axonal injury are evident on an MRI T2-weighted, two-dimensional gradient recall echo sequence in a 15-year-old male after a motor vehicle crash.

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et al., 1987]. Many experts now prefer the terms nonaccidental trauma, inflicted head injury, or shaken impact syndrome to describe this clinical entity. The clinical presentation is rarely straightforward because clinical signs in infants are often nonspecific, and parents may be less forthcoming about the circumstances of the infant’s injury. Infants can present with lethargy, irritability, seizures, and vomiting. Physical signs include a tense or bulging fontanel, split sutures, enlarged head circumference, retinal hemorrhages, and often evidence of other inflicted bodily injuries, such as fractures, bruising in unusual locations (back, upper legs), and burns. Eventually, these infants undergo CT scanning, which may be normal on initial presentation but can reveal subdural hematomas, contusions, and other intracerebral hemorrhage. Subdural hematomas of differing ages are particularly suspicious for nonaccidental trauma and are frequently seen over the cerebral convexities or along the falx (Fig. 62-6B). Inconsistencies between the reported history and the severity of injuries should alert the physician to suspect child abuse. Infants with nonaccidental trauma often require vigorous resuscitation, controlled ventilation, antiepileptic drug treatment, and intensive care unit management. In addition to CT neuroimaging, diagnostic evaluation should include wholebody x-rays to determine whether there are other acute or partially healing fractures. Ophthalmoscopic examination is essential to identify retinal hemorrhages (see Fig. 62-6A), as is a careful inspection for burns or excessive bruises that are often in unusual locations and in various stages of resolution. Laboratory tests should be ordered to rule out coagulopathy. Evaluation for rare inborn errors of metabolism such as glutaricaciduria and Menkes’ disease needs to be considered because these disorders can manifest with bilateral subdural fluid collections, hematomas, and retinal hemorrhages. The outcome for infants suffering nonaccidental trauma is exceedingly poor. Mortality rates range from 7% to 30%, and severe neurocognitive sequelae are reported in one third to one half [Weiner and Weinberg, 2000]. Up to 80% of

deaths due to trauma before the age of 2 years are attributed to nonaccidental injury [Bruce and Zimmerman, 1989]. It is believed that these children account for the poorer prognosis reported in the very young age group, which goes against the general trend of improved outcome with younger age. Several explanations may account for this observation. The very young brain may be selectively vulnerable—it is well known to be particularly sensitive to excitotoxicity but also depends on excitatory glutamatergic stimulation for neuronal survival and development of connectivity. Second, the nature of nonaccidental trauma is such that repeated, fairly severe injuries are sustained, and the cumulative effect of this injury pattern may result in the dismal outcomes. Third, biomechanical properties of the infantile brain, including incomplete myelination and increased water content, may predispose it to shearing and disconnection types of injuries, and disconnection at this maturational stage may result in developmental failure. Finally, medical care for these children is often delayed, perhaps setting the stage for significant secondary injuries due to hypoperfusion, hypoxia-ischemia, and recurrent seizures.

Subarachnoid Hemorrhage Subarachnoid hemorrhage occurs commonly after traumatic brain injury. Clinical symptoms of subarachnoid hemorrhage are fairly nonspecific in infants (irritability, lethargy, poor feeding), but older children present with persistent headache, nausea, vomiting, neck stiffness, and altered mental status. Blood products are irritating to the brain and the cerebral vasculature. Cortical irritation can result in seizures, and subarachnoid blood can provoke cerebral vasospasm, usually after several days. Vasospasm can be severe enough to cause cerebral ischemia or infarction. Subarachnoid hemorrhage is easily seen on CT, with hyperdense signal of acute blood visible in sulci and fissures and often in the basal cisterns (Fig. 62-7). Occasionally, when subarachnoid blood is seen in the ventricular system the risk for post-traumatic hydrocephalus is increased. FIGURE 62-6. Signs suggestive of nonaccidental trauma. A, Retinal hemorrhage (arrows) on funduscopic examination. See also Color Plate. B, Bilateral subdural hematomas on T1-weighted MRI showing different signal intensities, indicating that the hemorrhages occurred at different times.

A

B

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FIGURE 62-7. Post-traumatic subarachnoid hemorrhage outlining the basal cisterns (arrow) is clearly seen on this noncontrast head CT.

Subdural Hematoma Subdural hematomas, as the name implies, occur underneath the dura mater and often result from tearing of bridging cortical veins. Subdural hematomas can be seen after significant head trauma, including accidental and nonaccidental trauma. These hemorrhages can manifest with a sudden or, more often, gradually progressive focal deficit. Mass effect can lead to neurologic symptoms of depressed mental status and, in severe cases, signs of impending herniation. Appearance of subdural hematomas on CT scans is characteristic. An acute subdural hematoma appears as a crescentshaped hyperdensity along the inner surface of the skull. Large subdurals may track across suture lines (Fig. 62-8). Sudural hematomas can also occur over the cerebral convexities, along the falx or tentorium, or, more rarely, in the posterior fossa. Often there is associated focal edema in the vicinity of the subdural hematoma, and midline shift can lead to subfalcine or transtentorial herniation. Definitive treatment of an acute symptomatic subdural hematoma involves neurosurgical consultation and probable surgical evacuation. If edema is extensive, then external ventriculostomy is helpful to monitor intracranial pressure and for potentially therapeutic cerebrospinal fluid drainage. Other immediate and first-tier interventions to control elevated intracranial pressure should be instituted if necessary, including elevation of the head of the bed, maintaining the head in a neutral position, sedation, neuromuscular blockade, gentle hyperventilation, and hyperosmolar therapy. Outcome after subdural hematoma is fairly good, with up to

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FIGURE 62-8. Bilateral subdural hematomas of mixed density are seen in this noncontrast head CT (arrows). Note the characteristics of subdural location, including concave morphology and extension of the hematomas across suture lines.

75% of infants having normal development. Infants with subdural hematomas due to nonaccidental trauma have a much more guarded prognosis, as mentioned earlier. Subacute and chronic subdural hematomas appear as crescent-shaped subdural fluid collections that can be isodense and then become hypodense. In infants, a bulging fontanel and an enlarging head size may be clues in an otherwise nonspecific picture of irritability, poor feeding, lethargy, and vomiting. Seizures are frequently seen. Chronic subdural hematomas needs to be distinguished from benign extracerebral collections of childhood, which are associated with a mildly enlarged head circumference, have a predilection for a frontal or bifrontal location, appear hypodense on CT, and occur with no history of head trauma. These collections are associated with a normal developmental prognosis and spontaneously resolve by around 18 months.

Epidural Hematoma Epidural hematomas are acute collections of blood that occur in the potential space over the dura but beneath the calvarium. They are more commonly caused by arterial bleeding in adults, particularly underlying the pterion, where they are often due to skull fracture with tearing of the middle meningeal artery. On CT, an epidural hematoma classically appears as a convex lens–shaped hyperdensity adjacent to the skull (Fig. 62-9). Epidural hematomas generally are constrained by dural attachment to the skull and do not cross suture lines. Although these characteristics are typical for epidural hematoma, in children there are significant distinctions.

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Cerebral Contusion and Laceration Cerebral contusion and laceration represent types of direct, focal damage to the brain. These types of injury are less common in children than in adults. Contusions, when they occur, tend to be frontal or temporal in location, usually along the surface of gyri (Fig. 62-10). The appearance may be as a subtle hypodensity on CT. Over time, some contusions evolve into hemorrhagic lesions (and thus become hyperdense on CT; see Fig. 62-10), and in adults, checking serial CT scans has been recommended. In severe cases with edema and mass effect, surgical excision of necrotic material has been performed. Lacerations are also fairly rare and involve physical tearing of brain tissue. These can be associated with a depressed fracture or penetrating injury. Dura and vascular structures can be similarly torn. In infants, tearing of white matter can occur even in the setting of blunt head trauma [Calder et al., 1984]. This is due to the lack of myelin and increased water content of the very young brain.

Concussion

FIGURE 62-9. Typical appearance of an epidural hematoma (arrow), including convex shape and limitation of hematoma at suture lines. Also noted is mass effect, with shift of midline structures (septum pellucidum—triangle) away from the side of the hematoma.

First, epidural hematomas occur less frequently in children than in adults. Second, epidural hematomas are more likely to be due to bleeding from bridging veins or dural sinuses and thus are less commonly associated with skull fracture. Those associated with fracture in infants can occasionally push through the fracture line of the thin skull to decompress, masking symptoms and allowing the epidural hematoma to accumulate to the point at which anemia may be noted. Because they are more often venous in origin, the clinical presentation of epidural hematomas in children can be more gradual. Some reports indicate that more than 50% of children and more than 80% of infants demonstrate no alteration in mental state at the time of injury [Choux et al., 1975]. Third, although most epidural hematomas in adults or children are supratentorial, the percentage of posterior fossa epidural hematomas is higher in the pedia-tric population [Wright, 1966]. These are more often associated with occipital trauma, are venous in origin, and have delayed symptoms (ataxia, vomiting, and headache), occurring a few days after the injury. Because of the risk for compression of critical brainstem structures and potential cardiorespiratory collapse, surgical removal is preferred. The mortality rate associated with epidural hematomas ranges from 7% to 15%. Most mortality and morbidity are due to effects of rapid enlargement of these hemorrhages with concomitant damage to underlying brain tissue. Prognosis is less certain with infants, whose nonspecific presenting symptoms increase the likelihood of diagnostic delays. If recognized and evacuated promptly, however, recovery is generally good in up to 90% of children.

Concussion has been defined as any traumatically induced disturbance of neurologic function and mental state, occurring with or without actual loss of consciousness [American Academy of Neurology, 1997]. Concussion in isolation is

FIGURE 62-10. Typical frontopolar location of a small cerebral contusion (arrow), with increased density indicative of hemorrhage. If no hemorrhage is present, a contusion may simply appear as a slight hypodensity.

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often referred to as mild traumatic brain injury, and it is important to be aware that concussive-type injuries can occur in almost every setting of head trauma, although they may be overshadowed by greater symptomatology from a skull fracture or mass lesion. Mild traumatic brain injury remains the most common form of traumatic brain injury in any age group, accounting for more than 75% to 85% of all head injuries [Kraus and McArthur, 2000]. Acute clinical symptoms are fairly consistent, including headache, transient confusion, amnesia, dizziness, unsteadiness, nausea, and vomiting. In most cases, there is no actual loss of consciousness. Signs of concussion include vacant staring, observable confusion, disorientation, memory disturbance, ataxia, incoordination, slurred speech, behavioral disturbances, and any witnessed unconsciousness. The hallmark of concussion is that the acute symptoms are selflimited and occur in the absence of demonstrable structural brain injury. Because there is little evidence of structural damage, the etiology of concussion symptoms is often ascribed to neural dysfunction that recovers over time. Several issues regarding concussion are particularly relevant in children. There is much concern about proper evaluation of concussion or mild traumatic brain injury so as not to miss any associated intracranial injury, although exceedingly rare. This problem is addressed in the later section discussing general management of the mildly injured child. Second, duration of postacute physiologic derangement is uncertain but has significant implications for returning to normal activity. For example, a child returning to normal activity before complete physiologic recovery may have subtle cognitive or fine motor deficits that need to be considered to best integrate the child back into preinjury educational settings. Also, there is some concern that premature return to physical activity, such as contact sports, may place the individual at greater risk for a second injury. Third, although mild traumatic brain injury in adults is well described to result in persistent neurobehavioral problems, studies of a single mild traumatic brain injury in children differ with regard to the significance of long-term sequelae [Asarnow et al., 1995; Hawley et al., 2004]. Finally, there is increasing evidence that repeated mild traumatic brain injury, clinically encountered most commonly in a setting of sports-related concussion, results in a chronic accumulation of subtle deficits [Collins et al., 1999; Matser et al., 1999]. Many of these recurrent sports concussions occur in the late childhood and adolescent age groups, developmental periods where demonstrable brain maturation continues to occur, particularly in the frontal lobes [Sowell et al., 1999, 2001]. Because of the unique nature of sports concussion, with its mild, repetitive character, often occurring in brains still undergoing maturation, these issues are discussed separately.

Acute Postconcussive Syndromes Acute behavioral change commonly occurs after mild pediatric traumatic brain injury, including lethargy, irritability, disorientation, and listlessness. These symptoms can be worrisome for worsening intracranial injury, but in the presence of a normal CT scan, they must be attributed to an undetermined physiologic dysfunction. Spreading depression, seizure activity, changes in blood flow, and even mi-

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graine have all been proposed [Ryan and Edmonds, 1988; Sanford, 1988]. Vomiting is common following childhood head injury, occurring in up to 50% of individuals [Hugenholtz et al., 1987]. Some report that frequent vomiting is actually rare in more severe head injury but is characteristic of mild traumatic brain injury [Luerssen, 1991]. However, the presence of vomiting is nonspecific, and if it is persistent or worsening, a CT scan should be performed. Acute post-traumatic migraine is predominantly a behavioral syndrome and is diagnosed only after more serious lesions have been ruled out [Haas and Lourie, 1988]. After a mild injury, with normal postinjury behavior, the child becomes progressively more agitated, aggressive, and combative. This behavior is followed by postictal tiredness and sleep, sometimes with no recollection of the earlier events upon awakening. Headache may occur but is not invariable. A prior history or family history of migraine is not uncommon. Cortical blindness has also been reported after mild pediatric traumatic brain injury, in the absence of intracranial pathology [Kaye and Herskowitz, 1986; Yamamoto and Bart, 1988]. Pupillary responses are preserved, and malingering may be suspected. Complete recovery usually occurs. Migraine, spreading depression, or other neurovascular changes may be responsible. Seizure activity also may occur immediately upon impact, with no subsequent clinical or neuroimaging abnormality. Sometimes termed impact seizure or immediate posttraumatic seizure, these are generally self-limited, with complete recovery within minutes. However, seizures can also occur in response to intracranial pathology and should always be evaluated carefully.

Sports Concussion and Repeated Concussion Sports concussion is an increasingly common problem in childhood, occurring during team play in contact sports such as football and soccer, but also in basketball, wrestling, hockey, and other sports. Children also frequently experience mild traumatic brain injury with accidents involving bicycles, rollerblades, skateboards, and scooters. Because of its association with particular recreational activities, the occurrence of sports-related concussion is more predictable than other forms of head trauma. This situation provides the opportunity to better understand this injury type by premorbid testing of at-risk individuals and by instituting postinjury clinical assessments beginning immediately after the concussion and reassessing symptoms over the range of minutes to days. Another important opportunity is the possibility of more effective prevention strategies, by using approved protective gear when engaging in these activities and by avoiding return to at-risk sports activity until recovery from injury is complete.

Epidemiology It is estimated that more than 300,000 sports-related head injuries occur annually in the United States, most of which are mild [Thurman et al., 1998]. In high school athletes, 5% to 6% of all injuries are head injuries, most occurring during football play, but almost every sport encounters some

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concussions [Guskiewicz et al., 2000; Powell and BarberFoss, 1999]. Interestingly, after sustaining a concussion, there is a threefold risk for a subsequent concussion during the same sports season [Guskiewicz et al., 2000], possibly because of a concussion-induced physiologic vulnerability, a manifestation of a particularly risky style of play in certain individuals, or perhaps subtle coordination and reaction time impairments in concussed individuals, setting them up for repeated injuries when they return to practice or play before full recovery. Most sports concussions (91%) do not involve loss of consciousness, and headache is the most common complaint (86%). Perhaps because of the mild nature of these injuries, almost one third of these players returned to play the same day [Guskiewicz et al., 2000]. There is a common mentality among both players and coaches that one can “shake it off” and “take one for the team” that sets the stage for recurrent injuries.

Pathophysiology Physiologic studies of sports concussion have demonstrated abnormalities in brain metabolism and activation in the absence of anatomic lesions (Fig. 62-11) [Bergsneider et al., 2000; McAllister et al., 1999]. Positron emission tomography of mildly injured young adults has demonstrated dramatic reductions in cerebral glucose metabolism in walking, talking players that resemble abnormalities seen in comatose patients [Bergsneider et al., 2000]. Experimental studies of diffuse concussive injury in immature rats suggest periods of reduced glucose metabolism lasting for 2 to 3 days [Thomas et al., 2000]. More recently, functional MRI has been used to study brain activation in mildly injured patients. Even while overall performance on particular cognitive tasks was acceptable, task-associated activation patterns seen in these patients were decidedly abnormal [McAllister et al., 1999].

A general theme of functional MRI testing in concussed patients is that task-specific activation patterns become less focused and more diffuse in the injured brain [Jantzen et al., 2004]. This has been interpreted as a compensatory strategy to bypass dysfunctional circuits by using less efficient alternative routes.

Symptomatology Symptomatology in sports concussions is similar to that described regarding concussions in general. One consideration with subjective reporting of symptoms in a sports setting is that the player, being motivated to return to play, may attempt to minimize symptoms. Many athletic teams and physicians are using a concussion checklist to assess symptoms semiquantitatively [McCrea et al., 2003]. This can be administered before injury and repeated at intervals during the recovery period. There is also increasing use of computerized neuropsychologic tests that can be administered by an athletic trainer using a laptop, shortly after injury and again repeatedly during recovery. Interestingly, there is some evidence that recovery from sports concussion is prolonged in high school compared with college athletes [Field et al., 2003]. This raises legitimate concerns about blanket return-to-play guidelines and suggests that agespecific guidelines may be more appropriate.

Sequelae Although the long-term significance of a single mild pediatric traumatic brain injury is uncertain, several large studies have demonstrated multiple neurocognitive deficits in athletes who experienced an accumulation of lifetime concussions. One study [Collins et al., 1999] reported impairments in executive functions and information processing speed in college football players who experienced two or

FIGURE 62-11. Reduced cerebral metabolism of glucose (CMRglc) is seen after mild or severe diffuse traumatic brain injury in human patients, suggesting a commonality in the underlying pathophysiology of different severities of traumatic injury. See also Color Plate. GCS, Glasgow Coma Scale. (From Bergsneider M, Hovda DA, Lee SM, et al. Dissociation of cerebral glucose metabolism and level of consciousness during the period of metabolic depression following human traumatic brain injury. J Neurotrauma 2000;17:389.)

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more lifetime concussions. Another study found similar neuropsychological deficits in amateur soccer players when compared with control athletes participating in noncontact sports [Matser et al., 1999]. Studies in adult rats have modeled this effect, demonstrating no significant deficit after a single mild injury, but definite impairment in spatial learning tasks after multiple repeated mild injuries [DeFord et al., 2002]. More recently, it was reported that the duration of symptoms and length of recovery from concussion was longer in patients with previous concussions [Bruce and Echemendia, 2004; Guskiewicz et al., 2003]. Further studies are needed to delineate the risk for chronic cognitive impairment and its relation to timing of injuries, number of injuries, and age at injury.

Second Impact Syndrome Some controversy surrounds the existence of the so-called second impact syndrome [Cantu, 1998; McCrory and Berkovic, 1998]. In general, this term was invoked in circumstances in which a mild traumatic brain injury, often in a child or adolescent, resulted in catastrophic brain swelling (Fig. 62-12) and often death. On some occasions, an earlier head injury was reported, and it has been suggested that the initial injury somehow primed the brain for the dramatic and seemingly disproportionate response seen after the second injury [Kelly and Rosenberg, 1997]. A careful review of the

FIGURE 62-12. Diffuse cerebral edema on noncontrast head CT demonstrating sulcal effacement, constriction of lateral ventricles, and loss of gray-white distinction. When occurring after mild trauma, this clinical picture has been referred to as second impact syndrome or malignant brain edema.

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literature raised concerns regarding poor documentation of a “first impact” in many cases [McCrory and Berkovic, 1998], and the terminology malignant brain swelling was proposed. Nonetheless, much of the effort to devise returnto-play guidelines is aimed at reducing the likelihood of this syndrome, as well as the chronic, apparently cumulative effects of repeated injuries.

Skull Fractures Skull fractures are relatively common (20%) in the pediatric traumatic brain injury population, particularly in the youngest age groups. A main concern is their association with underlying intracranial damage such as hematomas, but fortunately, this relationship is not as strong in infants. That is, despite infants having more skull fractures than older children or adults, they are less likely to be associated with intracranial hemorrhage. Linear fractures account for 66% to 75% of all pediatric skull fractures (Fig. 62-13). These are most commonly temporoparietal in location and can be associated with an overlying scalp injury. Although the fractures rarely require intervention, CT scanning should be performed to rule out underlying pathology. Depressed skull fractures involve displacement of the bony skull and increase the risk for underlying cerebral contusion or laceration. In neonates, the “ping-pong” fracture is a type of depressed fracture wherein the softer infant skull is simply indented rather than broken. Scalp injuries can be a sign of an underlying depressed fracture, with pain, swelling, or contusion at the site of injury. Indications for surgical repair of depressed fractures vary, but repair is certainly indicated in patients with displaced bony fragments into brain parenchyma, dural tears, underlying large hematomas, associated focal neurologic deficits, seizures,

FIGURE 62-13. Lateral skull film of a 3-year-old child disclosing a linear fracture of the frontal bone (arrow) extending posteriorly and crossing the coronal suture. (From Rosman NP, Herskowitz J, Carter AP, et al. Pediatr Clin North Am 1979;26:707.)

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and overt wound contamination. Depressions greater than 5 mm or in cosmetically unappealing locations have been considered relative indications. Surgical repair has not been shown to alter neurologic outcome or later risk for epilepsy [Braakman, 1972; Jennett et al., 1974; van den Heever and van der Merwe, 1989], presumably because any cerebral injury was likely sustained at the moment of impact. Basal skull fractures tend to occur frontally or in the area of the petrous bone. Although these fractures can be seen on radiographs, a number of clinical signs are highly indicative of their presence. Periorbital or retroauricular ecchymosis (raccoon eyes or Battle’s sign, respectively), rhinorrhea, otorrhea, and hemotympanum suggest fracture of the skull base. Traumatic cranial neuropathies are associated with these fractures, typically involving cranial nerves I, II, VII, or VIII. The presence of cerebrospinal fluid leakage (rhinorrhea or otorrhea) theoretically increases the risk for central nervous system (CNS) infection, although studies have reported conflicting results [Brown, 1990; Langley et al., 1993], and the prophylactic use of antibiotics in these patients is not universal [Einhorn and Mizrahi, 1978; Francel and Honeycutt, 2004]. Most cerebrospinal fluid leaks resolve spontaneously; however, a longer duration of the leak increases the risk for meningitis. Persistent leaks require cerebrospinal fluid diversion with a lumbar drain; if unsuccessful, surgical repair is indicated. Compound or open skull fractures involve direct communication between the fracture and the outside environment through a scalp defect. There may be underlying brain injury, with swelling, hemorrhage, or edema that requires specific management. An open fracture represents a significant risk for infection, and surgical débridement, removal of foreign bodies, repair of any existing dural defects, and prophylactic antibiotics are indicated. A diastatic suture represents a bony separation along suture lines. Although not necessitating acute intervention, these fractures do need to be followed to detect the development of a chronic “growing skull fracture” or leptomeningeal cyst.

Scalp Lacerations and Hematomas Scalp injuries are one of the most common types of accidental injury in childhood. Swelling and bruising are common (sometimes referred to as a “goose egg”), even in minor head injuries in which risk for significant brain injury is minimal. Scalp lacerations, because of their propensity to bleed profusely, also tend to generate significant parental concern. Superficial injuries should be examined closely to determine whether there is any possibility of an underlying fracture. In particular, a detailed history of the accident and the child’s behavior and neurologic examination after the accident should be assessed for signs and symptoms of concussion, even after a seemingly mild injury. Treatment of scalp injuries includes proper cleansing, débridement, suturing of significant lacerations, and possibly prophylactic antibiotics. In infants, large scalp or subgaleal hematomas can sometimes result in anemia and volume loss, requiring fluid resuscitation or transfusion. It is not recommended to attempt to aspirate or drain scalp hematomas because this increases the risk for infection. Most scalp injuries resolve without significant complication.

DIAGNOSTIC EVALUATION Neuroimaging Neuroimaging is required for the diagnostic evaluation of children with traumatic brain injury. Although some studies have suggested that clinical variables are inconsistent in predicting the presence of intracranial pathology, certain variables warrant evaluation with neuroimaging.

Skull X-rays Skull x-rays are still the most sensitive method to detect fractures. The presence of a skull fracture increases the likelihood of an underlying intracranial abnormality 21- to 80-fold [Quayle et al., 1997; Teasdale et al., 1990]. However, the absence of fracture on skull x-ray does not preclude intracranial pathology. The frequency of intracranial lesions discovered on CT in the absence of skull fracture on x-ray ranges from 16% to 39% [Levi et al., 1991; Lloyd et al., 1997], but these results are skewed toward more severe injuries because CT scans were obtained only in patients with “clinical indications” and in those admitted to the hospital. Of all pediatric traumatic brain injuries with CT scans positive for an intracranial lesion, 35% to 50% occurred in the absence of a skull fracture [Lloyd et al., 1997; Quayle et al., 1997; Teasdale et al., 1990]. Thus, in patients in whom underlying brain injury is already suspected, the value of screening skull radiography has been questioned [Bell and Loop, 1971; Lloyd et al., 1997]. Skull fracture does occur much more frequently in children younger than 1 or 2 years [Lloyd et al., 1997; Quayle et al., 1997; Schutzman et al., 2001] and is associated with intracranial hematomas, although less so than in older children. Nonetheless, identification of isolated skull fractures in infants is still important, with the implications of diagnosing nonaccidental trauma. Also, significant scalp injuries or hematomas may overlie a skull fracture. Skull x-rays may be warranted in evaluation of traumatic brain injury under the following circumstances: when there is a suspicion of nonaccidental trauma; in head-injured children younger than 1 or 2 years, particularly if there is scalp swelling or hematoma; or as a screening tool in older children only in areas where CT scanning is not readily available.

Computed Tomography Noncontrast CT scanning is the neuroimaging examination of choice in the evaluation of acute head trauma. Many studies have been performed to determine clinical indications for CT after pediatric traumatic brain injury [Dunning et al., 2004; Halley et al., 2004; Homer and Kleinman, 1999; Murgio et al., 2001; Quayle et al., 1997]. Proper use of CT scanning depends on the severity of the injury sustained and the age of the child. The rationale behind use of CT is to identify intracranial complications, particularly those that would warrant urgent or emergent surgical or medical intervention to achieve optimal outcome. In a large, prospective series of 653 children with traumatic brain injury of all severities admitted to a neurosurgical department, 34.6% demonstrated significant intracranial abnormalities [Levi et al., 1991]. Fractures were excluded,

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but nonsurgical pathologies such as diffuse axonal injury and contusions were included along with acute hematomas. When only acute hematomas were tabulated, 23.7% of severely injured children (Glasgow Coma Scale scores of 3 to 8) had a lesion, as compared with 12.4% of moderate (Glasgow Coma Scale scores of 9 to 12) and 5% of mild (Glasgow Coma Scale scores of 13 to 15) patients. A consecutive, prospective study of 322 children seen in an urban emergency department for “nontrivial” head injury reported an 8.3% rate of intracranial pathology. In this case, nontrivial was defined as head injury with symptoms or physical findings, except for superficial scalp injuries, that were deemed nontrivial only in infants younger than 12 months [Quayle et al., 1997]. Differences in these studies may be attributed to geographic area, inclusion criteria (neurosurgical admissions vs. emergency department visits), distribution of injury severity, and age range. In 10 studies published since 1990, each with more than 100 patients, the frequency of significant intracranial pathology in all pediatric traumatic brain injuries ranged from 1.3% [Chan et al., 1990; Teasdale et al., 1990] to 34.6% [Levi et al., 1991]. A recent meta-analysis of 16 published papers examining variables predictive of intracranial hemorrhage in pediatric traumatic brain injury reported that skull fracture was associated with a relative risk of 6.1 (i.e., the presence of a skull fracture carried a 6.1-fold increased risk for intracranial bleed) [Dunning et al., 2004]. Other variables that increased the risk for intracranial hemorrhage included focal neurologic deficits (relative risk, 9.4), Glasgow Coma Scale score less than 15 (relative risk, 5.5), and loss of consciousness (relative risk, 2.2). Seizure activity had a relative risk of 2.8 but, because of its variability between studies, did not reach statistical significance. Headache and vomiting were not predictive of Glasgow Coma Scale score. Given the high frequency of intracranial lesions in children with moderate or severe traumatic brain injury, cranial CT is warranted in patients with a Glasgow Coma Scale score of less than 13. Although the presence of risk factors listed previously should increase suspicion for an intracranial process, the absence of a factor does not mean that the risk for a lesion is reduced. Imaging recommendations are summarized in Tables 62-3 and 62-4. Indications for CT are more controversial when only mild traumatic brain injury pediatric patients are considered. In TABLE 62-3 Pediatric Traumatic Brain Injury (>2 years): Indications for Computed Tomography Definite Indications • Glasgow Coma Scale score <15 in emergency department • Altered mental status • Skull fracture (on x-ray or clinically) • Focal neurologic signs • Deteriorating neurologic condition • Suspected nonaccidental trauma Relative Indications • Loss of consciousness or post-traumatic amnesia • Seizure • Known coagulopathy • Need for anesthesia or prolonged sedation • Persistent or worsening headache, nausea, or vomiting

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TABLE 62-4 Pediatric Traumatic Brain Injury (<2 years): Indications for Computed Tomography Definite Indications (High-Risk Patient) • Altered mental status, irritability • Focal neurologic signs • Skull facture (on x-ray or clinically) • Seizure • Bulging fontanel • Vomiting ≥5 times or >6 hours • Loss of consciousness ≥1 minute • Deteriorating neurologic condition • Suspected nonaccidental trauma Relative Indications (Intermediate-Risk Patient) • Vomiting 3-4 times • Loss of consciousness <1 minute • Previous irritability or lethargy, now resolved • Caregivers concerned about patient’s current behavior • High-energy mechanism of injury • Scalp hematoma, especially if large or nonfrontal • Known coagulopathy • Need for anesthesia or prolonged sedation

this population, the true prevalence of intracranial injury is difficult to determine. Review of 12 studies published since 1986, each with more than 100 patients, showed that 0% [Immordino, 1986] to 19.1% [Wang et al., 2000] of mildly injured children have a significant CT abnormality. Davis and colleagues reported intracranial bleeding in 7% of 168 pediatric patients who suffered a loss of consciousness after mild traumatic brain injury; however, in a subset of 49 patients with normal neurologic examination, 0% had CT abnormalities [Davis et al., 1994]. Other studies have found less utility to clinical variables and normal neurologic examination in predicting the absence of intracranial problems in mildly injured children [Halley et al., 2004; Quayle et al., 1997]. A recent review of this question [Homer and Kleinman, 1999] concluded that only a small number of mildly injured children have significant intracranial damage but that clinical history and examination are relatively insensitive predictors of those who do. Intracranial lesions requiring surgical intervention do occur, although very rarely, even when neurologic examination is normal. The American Academy of Pediatrics consensus guideline for mild head injury states that CT imaging (in conjunction with observation) is a reasonable management option, but not required, in children older than 2 years who experience brief (less than 1 minute) loss of consciousness and have no abnormal physical or neurologic findings at the time of medical evaluation [American Academy of Pediatrics, 1999]. Currently, there are no definitive guidelines for children with mildly abnormal Glasgow Coma Scale (13 or 14) or normal Glasgow Coma Scale (15) scores with loss of consciousness for longer than 1 minute; careful observation in all children and liberal use of CT is recommended (see Table 62-3) [Dietrich et al., 1993; Halley et al., 2004; Savitsky and Votey, 2000]. Recommendations for CT scanning are even broader when children younger than 2 years are concerned. Skull fractures are more common, and abnormalities on neurologic examination may not be as easily detected as in older children [Berney et al., 1994; Dietrich et al., 1993]. A recent expert review of the literature has resulted in a proposed guideline for stratification of risk in head-injured infants

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younger than 2 years [Schutzman et al., 2001]. Indicators of high- and intermediate-risk stratification are presented in Table 62-4. In general, this algorithm recognizes that lowrisk patients (low-energy mechanism of injury, no signs or symptoms, more than 2 hours since injury, and older than 12 months) may be discharged from the emergency department with-out CT scanning but with continued observation by reliable caretakers.

Lumbar Puncture Lumbar puncture in the setting of acute trauma holds the risk for precipitating herniation if cerebral edema is present and is absolutely contraindicated in the presence of a mass lesion. In a subacute or chronic setting after traumatic brain injury, lumbar puncture may be useful in diagnosing CNS infection due to a basilar skull fracture or neurosurgical complication.

Magnetic Resonance Imaging Although MRI is less able to visualize bony structures and fractures, it is better able to delineate structures in the posterior fossa and subacute hematomas that may appear isodense on CT. The ability of MRI to distinguish the approximate age of an intracranial hemorrhage makes it useful in patients with nonaccidental trauma (Table 62-5). Particular MRI sequences (i.e., T2-weighted gradient recall echoing and, more recently, susceptibility-weighted imaging) are especially good at detecting microhemorrhages that indicate foci of diffuse axonal injury [Tong et al., 2004] and that might not be seen on conventional CT. Magnetic resonance spectroscopy performed subacutely (within the first week) in patients with persistent coma has been highly accurate at predicting outcome [Ashwal et al., 2000, 2004a, 2004b; Holshouser et al., 2000].

Angiography Angiography is useful to diagnose traumatic vascular lesions, particularly cavernous carotid fistulas and dissections of the great cervical arteries. In some cases, magnetic resonance angiography can substitute for conventional angiography.

Ultrasound An open fontanel in younger infants provides a window for ultrasound examination. Although able to visualize more centrally located intracranial lesions, ultrasound is less sensitive in detecting epidural or subdural hematomas and is not generally used in an acute trauma setting. TABLE 62-5 Distinguishing Age of Intracranial Hemorrhage on Magnetic Resonance Imaging BLOOD COMPONENT

AGE

T1WEIGHTED

Oxyhemoglobin

4-6 hours Iso- or low (hyperacute) intensity Deoxyhemoglobin and 7-72 hours Iso- or low high protein (acute) intensity Intracellular 4-7 days High methemoglobin and (subacute) intensity high protein Free methemoglobin 1-4 weeks High and high protein (late intensity subacute) Hemosiderin

Months to years (chronic)

Low intensity

T2WEIGHTED High intensity Low intensity Low intensity High intensity with low intensity rim Low intensity

Electrodiagnostic Testing Electroencephalography (EEG) may help in the evaluation of the persistently comatose patient whose mental status is disproportionate to the documented injury. In some cases, subclinical seizures (i.e., nonconvulsive status epilepticus) may underlie prolonged unresponsiveness after traumatic brain injury [Vespa et al., 1999]. EEG and evoked potentials are more commonly used for prognostic pur-poses and are discussed with regard to this role later in this chapter.

GENERAL MANAGEMENT PRINCIPLES FOR SEVERE PEDIATRIC TRAUMATIC BRAIN INJURY A recent expert review summarized the existing published literature regarding medical management of severe pediatric traumatic brain injury [Adelson et al., 2003b]. An evidencebased approach was used; however, the literature did not support any treatment standards. Only five recommendations achieved the level of treatment guidelines (i.e., clinical strategy or range of strategies that reflects moderate clinical certainty): (1) take children with traumatic brain injury preferentially to a pediatric trauma center; (2) avoid hypoxia— provide supplemental oxygen; (3) avoid hypotension— search for bodily injuries that may cause hypotension; (4) maintain cerebral perfusion pressure higher than 40 mm Hg; and (5) do not use antiepileptic drugs to prevent later development of post-traumatic epilepsy. However, multiple treatment options were provided, along with the rationale for their use. The following section summarizes the recommendations of this expert review and synthesizes them with traditional management strategies.

Stabilization and Prevention of Secondary Injury Although it is clear that hypoxemia results in poorer outcome after traumatic brain injury [Ong et al., 1996; Pigula et al., 1993], studies aimed at prehospital endotracheal intubation for children have failed to prove any significant benefit in outcome [Cooper et al., 2001; Gausche et al., 2000]. After initial assessment and resuscitation, acute management is aimed primarily at avoiding or preventing secondary injuries until more definitive therapy can be instituted. Airway maintenance and provision of supplemental oxygen is crucial, and on arriving at the hospital or intensive care unit, intubation and ventilation are often necessary for the more severely injured child. Fluid resuscitation to avoid hypotension is also essential [Luerssen et al., 1988; Pigula et al., 1993]. It is rare for pediatric head injury alone to cause systemic hypoperfusion;

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FIGURE 62-14. Algorithm for first-tier management of elevated intracranial pressure (ICP) in children after severe traumatic brain injury. CPP, cerebral perfusion pressure; CSF, cerebrospinal fluid; GCS, Glasgow Coma Scale; HOB, head of bed; ICP, intracranial pressure; OSM, osmolality; PRN, as necessary. (From Guidelines for the acute medical management of severe traumatic brain injury in infants, children, and adolescents. Pediatr Crit Care Med 2003;4[3]Supplement:S65-S67.)

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an alternative cause should be sought and may include internal or external bleeding or spinal cord injury. Signs of hypoperfusion and shock include diminished pulses, prolonged capillary refill, tachycardia, and reduced urine output. Hypotension is a late sign in pediatric shock. Fluid restriction out of concern for exacerbation of cerebral edema is to be avoided in the shocky head-injured child; perfusion must be maintained.

First-Tier Intracranial Pressure Management Intracranial pressure is determined by the brain, the cerebrospinal fluid, and blood. Management strategies targeting elevated intracranial pressure are based on the principle that to reduce intracranial pressure, the volume of one of these components must be reduced (Fig. 62-14).

Sedation and Neuromuscular Blockade Sedatives and analgesics may be useful to reduce struggling and exacerbation of elevated intracranial pressure, promote optimal ventilation, alleviate pain, and allow for adequate nursing care (e.g., suctioning, catheter placement). A theoretical benefit of sedatives is to minimize increases in cerebral metabolic activity provoked by pain or stress. In addition, some sedatives possess antiepileptic or antiemetic properties. A potential adverse effect of sedation is hypotension, which can exacerbate poor cerebral perfusion if not addressed promptly. A recent expert literature review found insufficient evidence to recommend a specific choice of sedative medications in the setting of pediatric traumatic brain injury [Adelson et al., 2003d]. Sedatives with published reports of use in pediatric traumatic brain injury include fentanyl, morphine, sufentanil, remifentanil, diazepam, ketamine, propofol, etomidate, and barbiturates. However, most of these reports were small series, often with mixed adult and adolescent patients. There is anecdotal evidence of intracranial pressure reduction with remifentanil [Tipps et al., 2000], ketamine [Albanese et al., 1997], propofol [Farling et al., 1989; Spitzfaden et al., 1999], and barbiturates. The use of a continuous propofol infusion in children has been associated with a lethal syndrome of metabolic acidosis [Bray, 1998; Canivet et al., 1994; Cray et al., 1998; Hanna and Ramundo, 1998; Parke et al., 1992] and has not been approved for pediatric sedation by the U.S. Food and Drug Administration. Neuromuscular blockade may aid in the management of traumatic brain injury patients by promoting ease of ventilation, reducing intracranial pressure, and stopping metabolic demands from skeletal muscle. Complications of neuromuscular blockade include an increased risk for pneumonia, cardiovascular depression, immobilization stress (if used with inadequate sedation), unnoticed seizure activity, and prolonged paralysis or myopathy. Myopathy appears to be associated with the combination of nondepolarizing agents and corticosteroids [Martin et al., 2001; Rudis et al., 1996]. When using iatrogenic paralysis, it is important to periodically monitor the depth of blockade using a “train of four” stimulation. Vecuronium, pancuronium, and doxacurium have all been used for pediatric neuromuscular blockade in the setting of traumatic brain injury.

Hyperventilation Hyperventilation reduces blood and tissue PCO2 , resulting in vasoconstriction, decreased cerebral blood volume, and reduced intracranial pressure. These effects can be seen within minutes, making hyperventilation an important tool in managing acute neurologic deterioration or impending herniation due to edema. Excessive hyperventilation in adults [Kiening et al., 1997; von Helden et al., 1993] and children [Skippen et al., 1997] can result in reductions in cerebral blood flow that may reach ischemic levels. The routine use of prophylactic hyperventilation (PCO2 less than 35 mg Hg) in severe pediatric traumatic brain injury is no longer recommended. Controlled hyperventilation (PCO2, 30 to 35 mg Hg) may be useful to control elevated intracranial pressure that is refractory to sedation, neuromuscular blockade, cerebrospinal fluid drainage, and hyperosmolar therapy. More aggressive hyperventilation (PCO2 less than 30 mg Hg) should be considered a second-tier therapy for intractable increased intracranial pressure. The risk for potential ischemic complications must be considered and the patient monitored appropriately for these problems. Jugular venous oxygen saturation measurements should be made through a jugular bulb catheter. This methodology provides a more global measure of cerebral tissue perfusion and can be monitored frequently as the patient’s condition and treatment change. Alternative methods of determining whether ischemia is present include cerebral blood flow studies and brain tissue oxygen monitoring. Cerebral blood flow studies have the advantage of providing some regional data but are usually limited to the actual time of the testing. Brain tissue oxygen levels can be monitored continuously but are limited to measurements in the vicinity of the probe. Despite the potential for hyperventilation to induce ischemia, hyperventilation remains a potent modulator of intracranial pressure. In the setting of acute deterioration or imminent herniation, aggressive hyperventilation may still be used for short periods of time. With the advantage of fast onset of action, hyperventilation may provide a window during which diagnostic testing can be completed and additional first-tier intracranial pressure measures optimized.

Hyperosmolar Therapy Two agents have been recommended for hyperosmolar therapy in pediatric traumatic brain injury: mannitol and 3% saline. Hyperosmolar therapy raises the solute concentration of the serum, creating an osmotic gradient whereby free water is drawn out from the brain’s extracellular space.

MANNITOL Mannitol, an agent whose clinical use for intracranial pressure management has become almost ubiquitous, appears clearly effective in many older studies of adults [James, 1980b; Marshall et al., 1978; McGraw et al., 1978; Mendelow et al., 1985; Muizelaar et al., 1984; Schwartz et al., 1984], as well as studies including both children and adults [Nara et al., 1998; Rosner et al., 1995; Smith et al.,

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1986]. Unfortunately, the pediatric component of the mixed studies was not separately defined. Mannitol exerts its beneficial effects through several mechanisms. First, it reduces blood viscosity, improving blood flow and allowing for a reduction in cerebral blood volume [Levin et al., 1979; Muizelaar et al., 1983, 1986]. Second is the osmotic effect, drawing free water out of the brain (across an intact blood-brain barrier) and back into the bloodstream [James, 1980a]. A less well understood effect of mannitol is its ability to act as an antioxidant [Kontos and Hess, 1983]. Mannitol is administered with bolus dosing at 0.25 to 1.5 g/kg up to every 4 hours. Overall, mannitol begins to exert its intracranial pressure–reducing effects within 10 to 20 minutes, and these effects can last for several hours. In the presence of a leaky or damaged blood-brain barrier, mannitol can potentially enter the injured area and cause a rebound osmotic effect [Kaieda et al., 1989; McManus and Soriano, 1998]. Partially for this reason, bolus rather than continuous administration of mannitol is recommended.

HYPERTONIC SALINE Hypertonic saline (3%) has been more recently investigated [Peterson et al., 2000], and several studies used prospective data collection specifically in pediatric patients to document the effectiveness of this agent in controlling refractory intracranial pressure [Khanna et al., 2000; Simma et al., 1998], yet this therapy lacks widespread clinical experience. Hypertonic saline operates through several mechanisms. It reduces blood viscosity, osmotically draws free water from brain parenchyma, restores cell membrane potential and volume [McManus and Soriano, 1998; Nakayama et al., 1985], reduces inflammation [Qureshi and Suarez, 2000], and improves cardiovascular function. The effectiveness of hypertonic saline in pediatric patients has been demonstrated in several studies [Khanna et al., 2000; Peterson et al., 2000; Simma et al., 1998]. Despite reducing intracranial pressure, none of these studies investigated whether hypertonic saline therapy resulted in better outcomes. Dosing of hypertonic (3%) saline was on a sliding scale titrated to intracranial pressure, and serum sodium and infusion rates ranged from 0.1 to 1.0 mL/kg/hour. Potential adverse effects of 3% saline include osmotic rebound, central pontine myelinolysis, and subarachnoid hemorrhage. For the four published pediatric 3% saline studies described, higher serum osmolalities were well tolerated (mean, 365 mOsm/L; highest, 431 mOsm/L), and none of the potential complications occurred. With either hyperosmolar therapy, euvolemia is the goal, although serum osmolality is generally kept below 320 mOsm when using mannitol. Other osmotic agents used to treat brain edema have been less thoroughly evaluated, including urea and glycerol. Although older management schemes attempted to reduce brain edema by systemic dehydration using diuretics, this strategy is no longer supported. Hyperosmolar therapy is effective in controlling elevations in intracranial pressure, although the effects on improving cerebral perfusion pressure are not as well demonstrated. The particular agent used (mannitol or hypertonic saline) is a decision left to the treating physician.

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Intracranial Pressure Monitoring: Indications and Treatment Threshold Outcome from pediatric and adult traumatic brain injury depends on avoiding secondary insults such as ischemia and hypoperfusion [Chesnut et al., 1993a; Narayan et al., 1981]. Elevated intracranial pressure can lead to global hypoperfusion and precipitate herniation, which can cause tissue ischemia through compression and, in some situations, by impinging on cerebral arteries. Many of the specific therapies for severe traumatic brain injury are directed at preventing excessive intracranial pressure; thus, it logically follows that monitoring of intracranial pressure is an important component of traumatic brain injury management [Becker et al., 1977; Marshall et al., 1979; Narayan et al., 1982]. Although there has been no randomized clinical trial specifically validating the benefits of intracranial pressure monitoring in children, many studies have demonstrated benefits of aggressive management of elevated intracranial pressure in head-injured children [Bruce et al., 1981; Cho et al., 1995; Peterson et al., 2000; Taylor et al., 2001]. There are several commonly used intracranial pressure monitors. The mechanisms of these monitors may be divided into three distinct types. First are monitors that measure intracranial pressure through an external pressure transducer. These include ventricular catheters as well as subdural and subarachnoid catheters or bolts that measure pressure by maintaining a continuous fluid connection with the intracranial space. They are accurate and can be recalibrated, but erroneous readings can result from obstruction of the connecting line or from inconsistent placement of the external transducer in relation to the patient’s head. The second type of monitor is a pressure transducer that is located at the tip of an inserted catheter. These monitors are not dependent on maintaining a long, continuous fluid connection between an external gauge and the intracranial space; however, once placed, they cannot be readily recalibrated. The third type of monitor is a fiberoptic sensor placed at the catheter tip. It has restrictions similar to the catheter-tip–mounted transducers. A pediatric study comparing Camino fiberoptic catheters with ventricular catheters found sufficient correlation, although there were slight differences between the measured intracranial pressure from the two devices, depending on the patient’s Glasgow Coma Scale score [Gambardella et al., 1993]. Several studies addressing these questions are available from the adult literature and summarized in published guidelines for traumatic brain injury management in adults [Brain Trauma Foundation et al., 2000]. A ventricular catheter with an external sensor is considered the simplest and most reliable means of measuring intracranial pressure and has the added benefit of allowing therapeutic removal of cerebrospinal fluid. Catheter-tip–mounted devices (pressure transducers or fiberoptic) are more expensive but similarly accurate when placed within the ventricular catheter. Catheter-tip devices used for intraparenchymal placement may experience measurement drift. External transducers coupled to subarachnoid, epidural, or subdural devices were thought to be less reliable; these modalities may be useful when ventricular access is problematic. Intracranial pressure monitoring is an invasive procedure that requires a burr hole at a minimum, although suture lines

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or an open fontanel may be used in infants and neonates. It is important to have standard indications for children who are at greatest risk for elevated intracranial pressure following traumatic brain injury and who would be most likely to benefit from monitoring. In one series, 19 of 22 (86%) children with a Glasgow Coma Scale score of 8 or less (i.e., severely injured) who received intracranial pressure monitoring had intracranial pressure values greater than 20 mm Hg [Shapiro and Marmarou, 1982]. In a large series of 654 severely injured patients from the National Traumatic Coma Data Bank, 72% had intracranial pressure greater than 20 mm Hg during the course of their monitoring [Marmarou et al., 1991]. These studies suggest that clinical determination of severe injury (Glasgow Coma Scale score of 8 or less) delineates a group of patients at high risk for elevated intracranial pressure. Certainly, examination of less severely injured patients can provide greater sensitivity in determining clinical deterioration. This may be the situation in young children and infants, in whom the clinical examination and Glasgow Coma Scale score are less reliable than in older children or adults [Humphreys et al., 1990; Shapiro and Marmarou, 1982]. Using CT findings to predict elevated intracranial pressure is also questionable in children because they are less likely than adults to present with mass lesions. Despite the presence of open fontanels and flexible sutures, infants can still develop elevated intracranial pressure [Cho et al., 1995]. Given this information, intracranial pressure monitoring is recommended in children with a Glasgow Coma Scale score of 8 or less. In addition, intracranial pressure monitoring may be reasonable in selected patients with moderate traumatic brain injury, particularly those whose clinical examination may be clouded by concomitant sedation, paralysis, or anesthesia. Intracranial pressure monitoring also can be beneficial in infants, particularly those with severe injuries due to nonaccidental trauma. Normative values for intracranial pressure are generally thought to be lower in children, but the consequences of exceeding particular intracranial pressure levels have only been incompletely examined (see Chapter 65). Several retrospective studies in children have shown poorer outcomes with intracranial pressure elevations above 20 mm Hg [Esparza et al., 1985; Pfenninger et al., 1983] or 30 mm Hg [Cho et al., 1995]. Other studies have indicated cerebral compliance and cerebral blood flow to be inversely proportional to intracranial pressure [Shapiro and Marmarou, 1982; Sharples et al., 1995]. It is recommended to institute intracranial pressure–lowering therapy in pediatric patients whose intracranial pressure exceeds 20 mm Hg [Adelson et al., 2003c]. Complication rates for fiberoptic monitoring in 98 children have been reported, with 7% of catheters becoming colonized (all with Staphylococcus aureus; average duration of catheter placement more than 7 days) and 13% having mechanical failure (on average by 9.5 days) [Jensen et al., 1997]. Complication rates were significantly different for catheters placed in the emergency department or intensive care unit. No pediatric reports of significant brain injury, hemorrhage, or seizures due to an intracranial pressure monitor placement or use were found, suggesting a very low rate of these complications.

Cerebral Perfusion Pressure Cerebral perfusion pressure is defined as the difference between the mean arterial pressure and intracranial pressure. Reduced cerebral perfusion pressure can occur during hypotension, intracranial hypertension, or both. Retrospective pediatric studies have found a strong correlation between cerebral perfusion pressure of less than 40 mm Hg and death [Downard et al., 2000; Elias-Jones et al., 1992]. One study of 118 children with intracranial pressure monitors placed within 24 hours of traumatic brain injury found that none of the children with a mean cerebral perfusion pressure of less than 40 mm Hg survived (0 of 22) [Downard et al., 2000]. When outcome was assessed in comparison with cerebral perfusion pressure decile (e.g., 40 to 50 mm Hg, 50 to 60 mm Hg), no further relation was found. Mean cerebral perfusion pressure of less than 40 mm Hg was interpreted as a limit of survivability in severe pediatric traumatic brain injury. Although low cerebral perfusion pressure is associated with poor outcome in children and adults, the benefits of cerebral perfusion pressure–directed therapy are uncertain. In adults, cerebral perfusion pressure of greater than 80 mm Hg was associated with better outcome in two large, retrospective studies [Changaris et al., 1987; McGraw, 1989]. Another study reported improved neurologic outcome at 6 months in patients managed for cerebral perfusion pressure and cerebral oxygen extraction (using jugular venous oxygen saturation monitoring) [Cruz, 1998]. However, a large randomized trial of 189 adults comparing cerebral perfusion pressure–directed therapy with intracranial pressure–directed therapy failed to demonstrate an outcome benefit of the former and also reported an increased risk for adult respiratory distress syndrome in the cerebral perfusion pressure group [Robertson et al., 1999]. Because systemic blood pressure varies by age, it is reasonable to assume that optimal cerebral perfusion pressure is age dependent. Based on the available evidence, maintaining cerebral perfusion pressure above 40 mm Hg at all times in pediatric traumatic brain injury patients is recommended, and the range of cerebral perfusion pressure from 40 to 65 mm Hg most likely represents a spectrum of optimal pressures across the pediatric age range. Use of vasopressors may be associated with an increased risk for pulmonary complications. Further studies are necessary to delineate optimal age-specific cerebral perfusion pressure ranges.

Cerebrospinal Fluid Drainage Physical drainage of cerebrospinal fluid is the most direct means of reducing intracranial pressure and has been done through intraventricular or lumbar catheters. In most studies, it is difficult to separate cerebrospinal fluid drainage from other first- and second-tier means of intracranial pressure reduction. One report prospectively divided adult patients into medical management only or medical management with ventriculostomy groups after removal of surgical lesions [Ghajar et al., 1993]. The group without intracranial pressure monitoring had a fourfold higher mortality rate (53% vs. 12%), and a lower rate of independent living (20% vs. 59%).

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In children, the risk for sudden increases in intracranial pressure was assessed using the pressure-volume index technique [Shapiro and Marmarou, 1982]. This method relied on the fact that brain compliance does not change linearly as fluid volume is added to the intracranial space. As the threshold for brain compliance was neared, addition of even small volumes of fluid resulted in dramatic increases in intracranial pressure. Reduced pressure-volume index (less than 80% of predicted normal) accurately predicts intracranial hypertension. All these patients were managed with cerebrospinal fluid drainage, which was found to reduce intracranial pressure and increase pressure-volume index. Cerebrospinal fluid drainage is a reasonable treatment option to reduce elevated intracranial pressure in children.

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Second-Tier Intracranial Pressure Management When elevated intracranial pressure is refractory to first-tier interventions, more intensive therapies are often instituted. These “second-tier” strategies involve methods to reduce brain metabolism and activity (e.g., barbiturates, hypothermia) or physical opening of the intracranial space to relieve pressure (craniectomy) (Fig. 62-15). In addition, more aggressive hyperventilation, in the setting of perfusion monitoring to avoid ischemia, remains an option, as does lumbar cerebrospinal fluid drainage, provided a ventriculostomy is in place and basal cisterns are open. Second-tier therapies are generally less proven or have an increased risk for potential side effects. Despite their apparent efficacy in spinal cord injury, corticosteroids have been associated with

FIGURE 62-15. Algorithm for second-tier management of elevated intracranial pressure (ICP) in children following severe traumatic brain injury. CBF, cerebral blood flow; EEG, electroencephalogram.(From Guidelines for the acute medical management of severe traumatic brain injury in infants, children, and adolescents. Pediatr Crit Care Med 2003;4[3]Supplement:S65-S67.)

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increased mortality in a very large, international multicenter, randomized, placebo-controlled trial of severe traumatic brain injury and are not recommended [Roberts et al., 2004].

Barbiturates Barbiturate coma has benefit in cases of intractable intracranial pressure elevation by several potential mechanisms. Barbiturates suppress cerebral metabolism [Piatt and Schiff, 1984] and can reduce cerebral blood flow and volume, perhaps by reducing cerebral metabolic activity [Kassell et al., 1980]. Barbiturates also reduce markers of free radical– induced damage in neonates with perinatal asphyxia [Singh et al., 2004]. Evidence for the efficacy of barbiturates in refractory intracranial hypertension comes primarily from a study that included patients 15 to 50 years of age [Eisenberg et al., 1988]. In this study, intracranial pressure control was achieved in 32% of the barbiturate group, which was about twice the response rate in the conventional treatment group. The 1-month survival rate was 92% in barbiturate responders compared with 17% in nonresponders. The use of barbiturates in children with traumatic brain injury has been described in several case series. Kasoff and associates reported cardiovascular complications and a high rate of requiring pressor support (91%) but did not mention whether there was any effect on cerebral hemodynamics or intracranial pressure [Kasoff et al., 1988]. In a different series of children with refractory intracranial pressure, addition of pentobarbital therapy achieved intracranial pressure control (less than 20 mm Hg) in 52% [Pittman et al., 1989]. Dosing of pentobarbital is best titrated to burst suppression on EEG rather than serum levels; thus, continuous EEG monitoring should be used. Intravenous loading doses of pentobarbital range from 5 to 15 mg/kg, followed by either slow continuous infusion at 1 mg/kg/hour or 5-mg/kg intermittent doses every 4 to 6 hours. The major complications of barbiturate therapy are myocardial depression and hypotension. Infants are perhaps particularly prone to these adverse effects. There is also some experimental evidence in neonatal rat pup models that even brief blockade of synaptic activity with barbiturates can result in a significant increases in neuronal apoptosis [Bittigau et al., 2002; Ikonomidou et al., 1999; Olney et al., 2002; Pohl et al., 1999]. Use of barbiturates is an option in patients with intractable elevation of intracranial pressure. Proper EEG and cardiovascular monitoring should be used at all times. The use of barbiturate coma in traumatically injured neonates and infants should be approached with caution.

Temperature Control and Hypothermia Temperature control can be thought of as avoidance of hyperthermia or institution of hypothermia. There is substantial experimental and adult clinical literature suggesting that hyperthermia can exacerbate brain injury by increasing metabolism, triggering seizures, elevating levels of excitotoxins, promoting inflammation, and so forth [Busto et al., 1989; Dietrich et al., 1996; Ginsberg and Busto, 1998; Wass et al., 1995]. It is recommended that fever or hyperthermia be avoided in brain-injured children.

Since the original report of hypothermia used to treat traumatic brain injury in children [Hendrick, 1959], interest in reducing temperature therapeutically has waxed and waned. Hypothermia can substantially reduce cerebral activity and has been anecdotally associated with neurologic preservation after prolonged drowning [Young et al., 1980]. In adults, several single-center studies suggested either physiologic benefits (improved cerebral perfusion pressure, reduced intracranial pressure) or trends toward better neurologic outcomes [Clifton et al., 1993; Marion et al., 1993, 1997; Shiozaki et al., 1993]. However, a more recent multicenter hypothermia trial that excluded children younger than 16 years failed to find efficacy in improving outcome [Clifton et al., 2001]. There was a trend toward better outcomes in patients who were hypothermic at presentation and in younger patients. A multicenter hypothermia trial in children is currently in progress [Adelson et al., 2005].

Surgical Management of Intracranial Pressure Decompressive craniectomy has been used to “open the box” and relieve pressure in cases of intractable intracranial hypertension and cerebral edema. This procedure has been reported to lower intracranial pressure on average 9 to 47 mm Hg in children and adolescents [Cho et al., 1995; Polin et al., 1997; Ruf et al., 2003; Taylor et al., 2001]. One study divided 23 pediatric victims of nonaccidental trauma into a surgical group (with intracranial pressure greater than 30 mm Hg) and two medical groups (intracranial pressure greater than 30 mm Hg and less than 30 mm Hg). Children in the surgical group and the medical group with less severe intracranial pressure elevation had significantly better outcome than the medically managed patients with intracranial pressure greater than 30 mm Hg [Cho et al., 1995]. A prospective study compared 14 children with best medical management with ventricular drainage with 13 children treated with decompressive craniectomy with best medical management [Taylor et al., 2001]. Mean intracranial pressure was reduced 9 mm Hg postoperatively in the latter group, and over a 48-hour period, there were fewer episodes of intracranial pressure higher than 30 mm Hg (9 vs. 59), fewer episodes of intracranial pressure higher than 20 mm Hg (107 vs. 223), and a narrower range of intracranial pressure (11 to 25 mm Hg vs. 11 to 44 mm Hg). The surgically managed patients also tended toward a better Glasgow Outcome Scale score, although follow-up times were not standardized, and mild pre-existing cognitive impairments were identified in 2 of the medically managed patients. Other studies reporting outcome after decompressive craniectomy were case series without a control or medical-only group. The most commonly used surgical approach for decompressive craniectomy is a combination of bilateral craniectomy and expansion duraplasty [Cho et al., 1995; Dam et al., 1996; Guerra et al., 1999; Polin et al., 1997]. The studies reported previously had another feature in common: surgery was undertaken less than 48 hours after injury. Expert review of the literature suggested that severely injured children with intractably elevated intracranial pressure who were more likely to benefit from decompressive craniectomy could be selected on the basis of meeting at least some of the criteria listed in Table 62-6. In clinical practice, unilateral craniec-

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TABLE 62-6 Criteria Suggestive of Potential Benefit of Decompressive Craniectomy 1. Diffuse cerebral swelling on cranial CT 2. Within 48 hours of injury 3. No episodes of sustained intracranial pressure > 40 mm Hg before surgery 4. Glasgow Coma Scale score >3 at some point after injury 5. Secondary clinical deterioration 6. Evolving cerebral herniation syndrome

tomy has been performed ipsilateral to the hemisphere with greater edema or a surgical lesion, although there are fewer published studies using this procedure.

Early Post-traumatic Seizures and Seizure Prophylaxis Seizures are not infrequent after traumatic brain injury. Acutely, seizures may result from stretch-induced depolarization of neurons, post-traumatic glutamate release, toxic effects of blood products, focal necrotic damage due to contusion or skull fracture, compression of neurons secondary to mass effect or cerebral edema, infection secondary to penetrating injury or skull fracture, or hypoxia-ischemia. Chronic changes after traumatic brain injury can also result in recurrent seizures. Mechanisms of post-traumatic epilepsy or seizures include neuronal death, gliosis or scarring, toxic effects of blood breakdown products, compression of neurons secondary to chronic mass lesions or post-traumatic hydrocephalus, aberrant axonal sprouting, and loss of inhibitory neurotransmission. Typically, post-traumatic seizures are divided into early and late types. Early post-traumatic seizures occur within the first week after injury and are generally reactive seizures in response to some acute or subacute insult. Late post-traumatic seizures occur after the first 7 days. They may be reactive to some subacute process, such as post-traumatic hydrocephalus; delayed infection secondary to skull fracture, cerebrospinal fluid leak, or neurosurgical complication; delayed hemorrhage or mass effect; fever; or electrolyte or metabolic disturbance. However, the main concern with late post-traumatic seizures is the development of post-traumatic epilepsy (recurrent unprovoked seizures). This development may be due to neuron death, gliosis, or scarring (e.g., mesial temporal sclerosis), development of recurrent excitatory neuronal pathways (sprouting, kindling), and loss of inhibitory γ-aminobutyric acid interneurons. In rare circumstances, neonatal head trauma has been found to result in abnormal neuronal migration, with generation of dysplastic cortical regions [Lombroso, 2000; Marin-Padilla et al., 2002].

Acute Antiepileptic Therapy Children, particularly infants, are more prone to seizures than adults [Annegers et al., 1980; Kollevold, 1976]. Early after traumatic brain injury, an acute seizure may act as a secondary injury, increasing cerebral metabolic demand, depleting neuronal energy reserves, causing release of excitotoxins, inducing hypoxia by impairing respiration or

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because of aspiration, or, particularly in generalized tonicclonic seizures, increasing body temperature and raising intracranial pressure. The incidence of early post-traumatic seizures is higher in children than in adults, and, after severe pediatric traumatic brain injury, early seizure rates of 20% to 39% have been reported [Annegers et al., 1980; Lewis et al., 1993; Ratan et al., 1999]. This risk is increased with lower Glasgow Coma Scale scores and younger age [Hahn et al., 1988a, 1988b; Hendrick and Harris, 1968; Lewis et al., 1993; Ratan et al., 1999]. Most early post-traumatic seizures in children occur within the first 24 hours. In adults, prophylactic phenytoin and carbamazepine reduce the risk for early post-traumatic seizures [Chang et al., 2003; Glotzner et al., 1983; Temkin et al., 1990]. In children, one study determined early seizure prophylaxis based on caregiver preference [Lewis et al., 1993]. Fiftythree percent of untreated children and only 15% of treated children experienced early seizures. A larger pediatric study retrospectively described 128 severely injured children (of a total of 477) and compared treatment differences between centers. Use of prophylactic antiepileptic drugs for early seizures ranged from 10% to 35%, and the overall risk for an early post-traumatic seizure in the entire cohort was 9%. However, the risk for early seizure by treatment group or severity group was not reported. It was reported that the group treated for early seizures had an improved survival rate [Tilford et al., 2001]. Given the apparent effectiveness of prophylaxis against early post-traumatic seizure in adults, the potential risk for complications from an early seizure, the increased risk for early seizure in children, and the frequent difficulty in identifying clinical seizure activity in infants and very young children, early prophylaxis for post-traumatic seizure activity in children should be considered. Fosphenytoin can be administered intravenously more rapidly and has fewer infusion-related side effects than phenytoin. Loading doses of either drug range from 10 to 20 mg/kg, and maintenance doses are typically 5 to 7 mg/kg/day divided at least twice a day (in the case of fosphenytoin, 1 mg = 1 PE, or phenytoin equivalent). For acute seizures occurring before early prophylaxis can be initiated, or breaking through prophylaxis, intravenous bolus doses of lorazepam, 0.05 to 1.0 mg/kg/dose, may be administered until the level of fosphenytoin becomes therapeutic.

Prevention of Post-traumatic Epilepsy Despite the effectiveness of early prevention, several prospective, randomized adult studies have revealed the inability of antiepileptic prophylaxis to prevent subsequent development of late post-traumatic epilepsy [Temkin et al., 1990; Young et al., 1983]. Given the potentially different mechanisms underlying the genesis of early and late posttraumatic epilepsy, this finding is not entirely surprising. In a trial of antiepileptic prophylaxis for late posttraumatic epilepsy, 41 children were randomized in a double-blind placebo-controlled study [Young et al., 1983]. Phenytoin or placebo was administered; those with phenytoin sensitivity were treated with phenobarbital. Patients were then followed for 18 months, and 12% of the treated group had a late post-traumatic seizure, compared with 6% of the untreated group (not significant). Importantly, com-

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pliance with treatment was poor. Therapeutic levels were present in only 50% of treated patients at 3 months’ follow-up, and by 1 year, only 10% were therapeutic. Given the available data for adult and pediatric late posttraumatic epilepsy, antiepileptic prophylaxis cannot be recommended [Chang et al., 2003]. After the acute period, antiepileptic drugs can be gradually weaned. If a late posttraumatic seizure occurs, it should be evaluated and treated as a new-onset seizure [Adelson et al., 2003f].

Supportive Care Management of severe traumatic brain injury includes general supportive measures to prevent complications of intensive care unit hospitalization and potentially prolonged immobilization. Aspiration precautions should be maintained, including nasogastric tube placement acutely (orogastric placement in the case of frontobasal skull fractures). Particular care should be taken shortly after a recovering patient is extubated. Meticulous skin care is necessary to prevent breakdown, decubiti, and potential infection in sedated or paralyzed critically ill children and in recovering but debilitated children after severe traumatic brain injury. Consideration should be given to prophylaxis against deep venous thromboembolism, although anticoagulants should be used cautiously if at all in a setting of acute or chronic intracranial hemorrhage. Children with hypothalamic, brainstem, or spinal cord injury are at risk for autonomic instability and should be carefully monitored and treated as needed. Pain is a common problem after traumatic injury, including head pain and bodily pain due to musculoskeletal injury. Although analgesia should not be withheld, care must be taken not to overly sedate patients when neurologic examination is necessary to observe for signs of deterioration (e.g., a more moderately injured patient without an intracranial pressure monitor). At the least, sedation and analgesia may be lightened once daily to allow for clinical assessment of mental status (see Chapter 93). Nutritional status must not be neglected. Although enteral feedings are preferred, total parenteral nutrition should be provided in individuals in whom the gastrointestinal tract is nonfunctioning. Because of the catabolic state after severe injury, nutritional calculations should attempt to provide 130% to 160% of resting metabolic needs [Adelson et al., 2003a]. Psychosocial support is also necessary for the patient and family as the patient begins to recover from injury. Children in whom nonaccidental trauma is suspected should be reported to social services for full investigation.

GENERAL MANAGEMENT OF MILD TRAUMATIC BRAIN INJURY AND CONCUSSION Two management guidelines for children with mild traumatic brain injury and concussion have been published. The first guideline represents expert consensus guidelines developed by the American Academy of Pediatrics for the evaluation and management of the mildly head-injured child [American Academy of Pediatrics, 1999]. The second parameter was developed specifically for sports-related concussion by the American Academy of Neurology [American

Academy of Neurology, 1997]. It is important to realize that the sports concussion guidelines did not specifically take into account potential age-dependent differences in symptoms or recovery. All children with head injuries who present for medical evaluation, even those with mild traumatic brain injury or concussion, should undergo a careful history and a physical and neurologic examination. As part of this assessment, the physician should determine whether the description of the injury is consistent with the objective findings (if any) and whether the child’s caregivers are capable of home observation (e.g., sufficiently educated, seemingly reliable, not intoxicated). None of these guidelines are intended for children with multiple traumatic injuries, unobserved loss of consciousness, or spinal cord injury. Other considerations that exceed the breadth of these guidelines include children with bleeding diatheses (including chronic anticoagulation) or neurologic disorders that may be worsened by traumatic brain injury (e.g., arteriovenous malformations, shunts, possibly even arachnoid cysts) and those suspected of being victims of nonaccidental trauma. In the setting of a language barrier without a reliable translator (not including the child!), these guidelines should not apply.

Mild Traumatic Brain Injury without Loss of Consciousness in Children Older than 2 Years For children older than 2 years without loss of consciousness and in whom the physical and neurologic examination reveals no worrisome findings, careful observation is the appropriate management [American Academy of Pediatrics, 1999; Homer and Kleinman, 1999]. Neuroimaging is not generally recommended because the likelihood of a significant intracranial abnormality is exceedingly small. Observation of the child may take place in the clinic, emergency department, or home under the supervision of a competent caregiver. Observation should continue for at least 24 hours. Signs and symptoms to be monitored include deteriorating mental status, seizure, focal neurologic signs, worsening headache, and nausea and vomiting. Postinjury instructions should be verbally explained to caregivers, who should also be provided with written instructions and a means of returning for medical care should deterioration occur.

Mild Traumatic Brain Injury with Brief Loss of Consciousness in Children Older than 2 Years Brief loss of consciousness is defined as less than 1 minute. For children older than 2 years, the previous guidelines are applicable. The only exception is that observation alone and observation in conjunction with CT scanning are both considered acceptable strategies. The risk for an intracranial abnormality on CT remains very low in this group (reported rates range from 0% to 7% depending on the study). Clinical signs are of uncertain significance in predicting the presence of intracranial pathology. In these children (with brief loss of consciousness), the likelihood of an abnormality requiring neurosurgical intervention may be in the range of 2% to 5%. However, these percentages are likely to be over-

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estimates owing to selection bias—most of these studies examined patients seen in emergency departments or trauma centers. Population-based studies have estimated the prevalence of a lesion requiring neurosurgical intervention after mild traumatic brain injury to be as low as 0.02%. This management algorithm does not require immediate neuroimaging of affected children. A period of observation may be implemented first. Although clinical signs such as headache, nausea, and vomiting are probably more common in children with intracranial injury, they are not sensitive, and most children with these symptoms do not have an intracranial lesion. There are children with documented normal neurologic examination who eventually require neurosurgical intervention. Rather than obtaining a CT scan in every patient immediately, a reasonable strategy is to evaluate and observe the patient. Neuroimaging can be reserved for those with worsening symptoms and those who do not improve. If neuroimaging is warranted, CT scanning is the examination of choice (see Table 62-3). If CT scanning is not available, skull radiographs may provide useful information for triaging and assessing the risk for intracranial hemorrhage and the need for CT. If the CT scan and examination are normal, the likelihood of clinically significant late deterioration is very low, so that children in this category could be discharged home under parental observation.

Mild Traumatic Brain Injury in Children Younger than 2 Years Because clinical assessment of the very young head-injured child can be difficult and the risk for skull fracture is particularly high in infants, special consideration needs to be given for evaluation of mild traumatic brain injury in a child younger than 2 years [Schutzman et al., 2001]. In this age group, more emphasis may be placed on the need to obtain neuroimaging depending on assessment of risk (see Table 62-4). The lowest risk group before 2 years of age includes children with low-energy mechanisms of injury (e.g., short falls) and no signs or symptoms, who have been observed for more than 2 hours. Intermediate risk is ascribed to those infants with a more forceful mechanism of injury, repeated nausea and vomiting (three or four instances), loss of consciousness for less than 1 minute, prior history of irritability or lethargy resolved at time of evaluation, unwitnessed trauma, significant scalp hematoma, nonacute skull fracture, and parental concern about patient’s behavior. Intermediate-risk infants may undergo observation or CT imaging. Following either plan, and presuming that no problems are identified, infants who meet the following criteria may be discharged home (with continued observation): (1) the patient has no significant extracranial injuries or other clinical indications (e.g., repeated vomiting), (2) the patient is easily awake and alert and with normal neurologic examination, (3) there is no suspicion of abuse or neglect, and (4) the patient lives nearby with reliable parents who can observe the child and who are ready to return if necessary. Patients identified as high risk have one or more of the following clinical characteristics: altered mental status, focal neurologic findings, depressed or basilar skull fracture (on x-ray or just clinical signs), seizure, excessive irrita-

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bility, acute skull fracture, bulging fontanel, vomiting five times or more or for more than 6 hours, and loss of consciousness for 1 minute or longer. These patients should undergo noncontrast CT scanning.

Guidelines for Return to Play after Sports Concussion Concussion severity is determined by a simple scale [American Academy of Neurology, 1997] from grades 1 to 3 (Table 62-7). Grade 1 concussion refers to injuries for which the duration of neurologic signs or symptoms is less than 15 minutes and no loss of consciousness occurs. Grade 2 is when signs or symptoms last longer than 15 minutes. Grade 3 is used for traumatic closed head injuries with any loss of consciousness. Return to play guidelines, based primarily on expert consensus, are listed in Table 62-8. Briefly, the athlete must be symptom free at rest and with exertion; then, the designated amount of time must elapse before the individual is cleared for return to play. The duration of time off is dependent on the “severity” of the concussion (grades 1 to 3) and whether the player has sustained more than one concussion. Remember that longer symptom duration has been linked to younger patients [Field et al., 2003] and patients with multiple concussions [Guskiewicz et al., 2003]. Be aware that these studies were published after the original guidelines were made and suggest that modifications may be necessary to adequately reflect these particular clinical scenarios. More recent sports concussion guidelines have moved toward some standardized type of premorbid cognitive testing, with return to play being determined by TABLE 62-7 Concussion Grading Scale Grade 1` Transient confusion No loss of consciousness Symptoms or signs last <15 minutes Grade 2 Transient confusion No loss of consciousness Symptoms or signs last > 15 minutes Grade 3 Any loss of consciousness

TABLE 62-8 Return to Play Guidelines TIME UNTIL RETURN TO PLAY* CONCUSSION GRADE

Single

Multiple

1 2 3—Brief loss of consciousness (seconds) 3—Long loss of consciousness (minutes)

Same day 1 week 1 week 2 weeks

1 week 2 weeks ≥1 month ≥1 month

*Only if asymptomatic and normal neurologic examination at rest and with exercise.

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resolution of symptoms and return to baseline for each individual [McCrory et al., 2005]. However, maturational differences in cognitive function in children still limit extrapolation of these strategies for those younger than 15 years [McCrory et al., 2004].

PROGNOSIS AND OUTCOME Determining outcome after pediatric traumatic brain injury remains difficult. Despite the overall better prognosis seen in children compared with adults, there are certain characteristics worth considering during the first few days when discussing outcome with the child’s parents.

Clinical Predictors of Outcome It is important to define what is meant by outcome in assessment of the recovering traumatic brain injury patient (see Chapter 61). The most common measure of outcome from traumatic brain injury is the Glasgow Outcome Scale, which divides patients into five categories: (1) dead, (2) persistent vegetative state, (3) severe disability (conscious but disabled and dependent on others), (4) moderate disability (disabled but independent for daily activities), and (5) good recovery (back to normal). This scale was later expanded to the modified Glasgow Outcome Scale, which divided levels 3 to 5 into higher and lower levels of disability [Jennett et al., 1981]. Others report outcomes based on elaborate batteries of neuropsychologic tests. A recent review of pediatric outcome scales gives some idea of the range of potential measures currently available [Okada et al., 2003].

Demographics: Age and Gender One of the strongest predictors of outcome after traumatic brain injury is age. Younger age has been associated with improved outcome in large series of traumatic brain injury patients. However, within the pediatric age group, younger is not always better. With regard to mortality, infants younger than 4 years had a 1-year mortality rate of 62%, as compared with only 22% in children ages 5 to 10 years, and 48% in adults [Levin et al., 1992]. Similar results were reported by other investigators [Luerssen et al., 1988]. More recently, the percentage of fatal traumatic brain injury outcome was calculated to be only 7.5% in the 0 to 4 and 5 to 9 year age groups, increasing significantly to a peak of 17.1% in 15- to 19-year-olds [Centers for Disease Control and Prevention, 2000]. Population-based death rates for traumatic brain injury suggest a nadir in the 5- to 9-year age group (about 4 per 100,000), with slight increases in younger children (8 per 100,000) and dramatic increases in adolescence (15 to 19 years, about 40 to 50 per 100,000) [Thurman, 2001]. This general reduction in mortality among pediatric headinjured patients has also been reported from an Israeli pediatric neurosurgical center and has been attributed to improved prehospital care and dedicated pediatric intensive care [Levi et al., 1998]. Overall, children 14 years old or younger admitted with traumatic brain injury had a 33% mortality rate from 1984 to 1988. This mortality was reduced to 10% during the years 1994 to 1996.

Gender plays a role in mortality rate, with males having higher mortality at all ages, although this gap is substantially greater in the 15- to 19-year age bracket (males, 40 to 50 per 100,000 vs. females, 10 per 100,000). Much of this difference can be attributed to the higher use of firearms in males [Thurman, 2001]. The issue of whether gender plays a role in outcome from traumatic brain injury is less clear, and no firm conclusions can yet be drawn.

Injury Characteristics Injury severity as assessed by the Glasgow Coma Scale is one of the strongest predictors of mortality and outcome. In 1998, among severely injured children, a fairly strong correlation was reported between mortality and Glasgow Coma Scale score. For Glasgow Coma Scale score values of 3, 4, 5, 6, 7, and 8, mortality rates were, respectively, 100%, 47%, 22%, 14%, 7%, and 0% [Levi et al., 1998]. A similar relation was recently reported in adults [Jiang et al., 2002]. Earlier, a prospective study of 653 children with traumatic brain injury found poor outcome in 56% of those with a Glasgow Coma Scale score of 3 to 8; 3.3% of those with a score of 9 to 12, and 0% of those with a score of 13 to 15 [Levi et al., 1991]. Initial Glasgow Coma Scale score has also been correlated with cerebral blood flow and gross outcome [Sharples et al., 1995], as well as with more comprehensive neurobehavioral measurements [McDonald et al., 1994]. However, some limitations of Glasgow Coma Scale on predicting outcome have also been reported [Ong et al., 1996], with good outcomes remaining a possibility even in some pediatric patients with Glasgow Coma Scale scores of 3 to 5 [Lieh-Lai et al., 1992]. Another powerful predictor of poor outcome, generally independent of age, is the presence of secondary injuries. Secondary injuries associated with poorer outcome include hypotension [Chesnut et al., 1993a, 1993b; Jiang et al., 2002], hypoxemia [Chesnut et al., 1993a; Jiang et al., 2002; Ong et al., 1996], and possibly even hyperthermia [Jiang et al., 2002].

Physiologic Measurements INTRACRANIAL PRESSURE Elevations of intracranial pressure higher than 20 to 30 mm Hg have been associated with poorer outcomes in children [Cho et al., 1995; Esparza et al., 1985; Shapiro and Marmarou, 1982; Sharples et al., 1995] and adults [Miller et al., 1977]. This result is primarily because high intracranial pressure is associated with poor cerebral perfusion and inadequate substrate delivery to injured brain. It is generally accepted that intracranial pressure higher than 20 mm Hg deserves therapeutic intervention.

CEREBRAL BLOOD FLOW AND CEREBRAL PERFUSION PRESSURE Because of the close relationship between intracranial pressure and cerebral blood flow with actual tissue perfusion and subsequent neurologic outcome, cerebral perfusion pressure has been studied with regard to predicting outcome from traumatic brain injury. In 54 adults, patients with higher cerebral blood flow on postinjury days 1 to 5 had improved outcome at 6 months by Glasgow Outcome Scale assess-

Giza / Traumatic Brain Injury in Children

ment and that the group with the higher average cerebral blood flow could be further divided into patients with good and poor outcomes [Kelly et al., 1997]. Patients with high cerebral blood flow and poor outcome were discovered to have severe intracranial hypertension, and this elevated intracranial pressure failed to respond to metabolic suppressive measures. It was also shown that in the presence of preserved neurovascular coupling, increased cerebral blood flow was associated with better outcome; however, when vasoreactivity was impaired, higher cerebral blood flow resulted in intractable elevations of intracranial pressure and worse outcome. Several other investigators have studied autoregulation in head-injured adults and arrived at similar conclusions [Czosnyka et al., 1996, 2000; Lam et al., 1997]. A recent study of moderately to severe pediatric traumatic brain injury found a similar relation between impaired autoregulation, hyperemia, and poor outcome [Vavilala et al., 2004]. In 36 children younger than 15 years of age, transcranial Doppler was used to measure middle cerebral artery blood velocity. Cerebral autoregulation was calculated by using the autoregulatory index, defined as the percentage change in estimated cerebrovascular resistance per percentage change in mean arterial pressure or cerebral perfusion pressure (depending on whether the patient had an intracranial pressure monitor in place). The rate of impaired autoregulation was 42% in the moderately and severely injured groups but only 17% in those more mildly injured. Hyperemia as measured by transcranial Doppler was more common in the group with impaired autoregulation and was associated with poor outcome (Glasgow Outcome Scale score of less than 4). These studies indicate the dynamic nature of blood flow changes after traumatic brain injury and how repeated assessment of cerebral perfusion can provide useful information for optimal management.

Neuroimaging and Prognosis Computed Tomography Several CT features have been associated with poorer shortterm outcomes and mortality among head-injured children. In the Traumatic Coma Data Bank series, diffuse cerebral swelling on CT (with or without shift) and mass lesion were associated with the highest mortality rates (25% to 52.2%). The poor outcomes with these CT findings were attributed to a longer duration of time with elevated intracranial pressure. Diffuse swelling also occurred in patients with the highest rates of severe functional outcome (17.4% to 22.2%), although a high percentage (20%) of the children with diffuse axonal injury also had a severe disability [Levin et al., 1992]. These results concur with other pediatric studies that also report poorer outcome with diffuse swelling or mass lesions with shift [Bruce et al., 1978; Ong et al., 1996; Tomberg et al., 1996]. The presence of post-traumatic subarachnoid blood has also been associated with poorer outcomes in two pediatric studies [Ong et al., 1996; Pillai et al., 2001].

Structural Magnetic Resonance Imaging Traditionally, T2-weighted gradient echo sequences have been used to visualize small hemorrhagic lesions associated with diffuse axonal injury. Using a new susceptibilityweighted imaging protocol, a recent study demonstrated a

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strong correlation between the number and volume of susceptibility-weighted imaging–detected hemorrhagic lesions with low initial Glasgow Coma Scale scores or coma lasting more than 4 days [Tong et al., 2004]. At 6 to 12 months’ follow-up, normal or mildly disabled children had significantly fewer lesions and lower lesion volume than those in the moderate to severely disabled group. This new sequence is apparently more accurate and sensitive for detecting small hemorrhagic lesions that had a strong association with eventual outcome [Tong et al., 2003]. A study of MRI confirmed the previously reported association of diffuse cerebral edema (seen on CT) with poor outcome, at least in infants. None of 15 infants (0%) with a good outcome but 5 of 11 infants (45%) with poor outcome demonstrated diffuse edema in this series [Ashwal et al., 2000].

Magnetic Resonance Spectroscopy Magnetic resonance spectroscopy is a method of identifying particular brain metabolites based on regional spectral patterns. When analyzing a voxel located over uninjuredappearing occipital gray matter, reduced N-acetylaspartateto-creatine and N-acetylaspartate-to-choline ratios were associated with poorer clinical outcomes. N-acetylaspartateto-creatine ratio was predictive in children and infants, whereas N-acetylaspartate-to-choline ratio was predictive in infants and neonates. In addition, a lactate peak was seen in a larger proportion of children with poor outcomes [Holshouser et al., 1997, 2000]. In another study from the same group, high choline-to-creatine ratios were also associated with poor outcome, as were reduced N-acetylaspartate-tocreatine ratios, reduced N-acetylaspartate-to-choline ratios, and again, the presence of lactate [Ashwal et al., 2000]. In fact, none of the patients with good outcome had a lactate peak (Fig. 62-16). In a recent follow-up study [Brenner et al., 2003], early clinical predictors (EEG, Glasgow Coma Scale) and magnetic resonance spectroscopy predictors (N-acetylaspartateto-choline ratios in infants; choline-to-creatine ratios in children; lactate in both) were compared with neuropsychologic test scores, including full-scale intelligence quotient, attention and executive function, language, sensorimotor skills, visuospatial function, and memory. Increased choline-to-creatine ratio and the presence of lactate were significantly associated with children scoring in the belowaverage range for each of the neuropsychologic variables tested. A decreased N-acetylaspartate-to-choline ratio was also associated with below-average performance on language, sensorimotor, and memory testing. Another spectroscopy metabolite, myoinositol, has also been found to be elevated in the occipital gray matter of children with traumatic brain injury compared with controls, and was higher in those with poor outcomes than those with good neurologic outcomes [Ashwal et al., 2004a]. It was hypothesized that myoinositol, found primarily in astrocytes, was perhaps a marker for gliosis in the injured brains. Elevated levels of glutamate/glutamine have also been detected by magnetic resonance spectroscopy after pediatric traumatic brain injury and appear to be correlated with worse outcomes [Ashwal et al., 2004b]. Recent studies have also shown that a normal-appearing brain may have abnormalities detected by

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Brain Injury and Disorders of Consciousness / 62 7.0 6.5 Cho

6.0

NAA

5.5 Cre

5.0 4.5

Signal

4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 4.2

3.8

3.4

A

3.0 2.6 2.2 1.8 Chemical shift

1.4

1.0

0.6 ppm

C

0.6 ppm

D

4.0 3.5 Cre

3.0

Signal

2.5

Cho NAA

2.0

Lac

1.5 1.0 0.5 0.0 -0.5 4.2

B

3.8

3.4

3.0 2.6 2.2 1.8 Chemical shift

1.4

1.0

FIGURE 62-16. Examples of children after traumatic brain injury with good or bad outcomes. Anatomic MRI images (A, patient with good outcome; B, patient with poor outcome) and magnetic resonance spectroscopy (C, patient with good outcome; D, patient with poor outcome) are shown. Note the relative reduction of the N-acetylaspartate (NAA) peak and the presence of a lactate peak in the patient with the poor outcome. Cho, choline; Cre, creatine; Lac, lactate. (From Ashwal S, Holshouser BA, Shu SK, et al. Predictive value of proton magnetic resonance spectroscopy in pediatric closed head injury. Pediatr Neurol 2000;23:119–120.)

susceptiblity weight imaging or spectroscopy that correlate with outcomes [Holshouser et al., 2005].

Electrodiagnostic Testing and Prognosis Electroencephalography EEG has been loosely correlated with neurologic outcome after pediatric traumatic brain injury. Using a rating system

that stratified EEG results into four categories (normal and mildly, moderately, or severely abnormal), one study reported a 73% positive predictive value for the dichotomous variable of good/moderate versus poor outcome [Ashwal et al., 2000]. It was also reported in additional studies that there was a correlation between the average EEG category score and neuropsychologic test results for full-scale intelligence quotient, attention and executive function, and memory [Brenner et al., 2003]. One caveat

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against using EEG to prognosticate in traumatic brain injury patients is that EEG should only be used if the patient is not sedated or anesthetized.

Somatosensory-Evoked Potentials Median nerve somatosensory-evoked potentials have been used to help prognosticate in coma of many etiologies. A recent review and combined analysis of 41 published studies divided study patients into four groups [Robinson et al., 2003]. One group was adults and adolescents with traumatic brain injury; another group was adolescents and children with coma of any etiology (but most were traumatic brain injury). Outcomes were divided into not awakened (dead or vegetative) and awakened (severe, moderate, or no disability). In the adult and teenager traumatic brain injury group, 5% of patients with bilaterally absent somatosensoryevoked potentials eventually regained consciousness (confidence interval, 2% to 7%), as compared with 82% (confidence interval, 79% to 85%) of those with any somatosensory-evoked potential. Of the 5% who regained consciousness after having no somatosensory-evoked potentials, only 3 of 11 had better than severe disability (about 1% of total tested patients). In the child and teenager coma group, 7% of those with bilaterally absent somatosensory-evoked potentials eventually regained consciousness (confidence interval, 4% to 10%), in contrast to 80% (confidence interval, 76% to 84%) of those with any somatosensory-evoked potential. Of those 7% who awoke after absent somatosensory-evoked potentials, 10 of 16 had moderate or good recovery (4.5% of the total tested patients in this group). The authors concluded that somatosensory-evoked potentials were very good at predicting outcome from various types of coma, but that after traumatic brain injury, a small percentage of patients with absent somatosensory-evoked potentials did eventually awaken, and that after pediatric traumatic brain injury, a fairly significant number (7%) of patients with absent bilateral somatosensory-evoked potentials would eventually awaken, and more than half (4.5%) could go on to a decent recovery. It was considered important that somatosensory-evoked potentials done within the first 24 hours after injury be interpreted with caution or repeated after the first day. There was a tendency for a few patients who had absent somatosensory-evoked potentials to eventually awaken. Somatosensory-evoked potentials, although highly sensitive, were not recommended to be used alone to determine ultimate prognosis [Beca et al., 1995; Carter et al., 1999; Robinson et al., 2003].

LATE CLINICAL SYNDROMES Vegetative and Minimally Conscious States After severe traumatic brain injury, children may emerge from coma into a vegetative state (see Chapter 61). This condition is characterized by the eyes being open with intact sleep-wake cycles but with no self-awareness and no purposeful movement. In the Glasgow Outcome Scale, it is given its own level (score of 2) and is generally combined

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with severe disability (score of 3) to describe a poor outcome. In the Traumatic Coma Data Bank series, the percentage of patients in a vegetative state at the time of discharge was relatively constant in all age groups (12% to 15% in the 0- to 4-, 5- to 10-, and 11- to 15-year and adult age ranges) [Levin et al., 1992]. However, the proportion of patients in a vegetative state declined over time in all age ranges, so that by 6 months after injury, less than 5% of any age range was classified in this category. By 1 year, the number of patients in a vegetative state declined still further, such that only about 2% of the adult group was described as having a Glasgow Outcome Scale score of 2. This percentage could have been due to death of these patients, but it is apparent that some patients in a vegetative state slowly recover and may regain self-awareness. Although patients in a vegetative state as a result of a hypoxic event are designated in a permanent vegetative state if there is no improvement by 3 months, a vegetative state secondary to traumatic brain injury is not considered “permanent” until 12 months because prolonged recoveries occur more often after traumatic brain injury. These findings are reviewed in the document prepared by the Multi-Society Task Force on Persistent Vegetative State [1994]. More recently, specific diagnostic criteria have been proposed for a distinct state of consciousness, termed the minimally conscious state [Giacino et al., 2002]. This is distinguished from the vegetative state by the presence of self-awareness and some limited purposeful movements, as well as the potential to experience pain and suffering, and is reviewed in Chapter 61 [Ashwal, 2003]. However, this designation has been questioned by some [Burke, 2002; Shewmon, 2002]. In a long-term follow-up of children 3 to 15 years old in a vegetative state or minimally conscious state, Strauss and colleagues [2000] found that survival in the minimally conscious state group was determined more by the degree of mobility than the level of consciousness. Mobility was defined as the ability for spontaneous or induced movements of the extremities or trunk, specifically the ability to raise one’s head when prone, roll either front to back or vice versa, or sit for 5 minutes. Over 8 years of follow-up, vegetative state and immobile minimally conscious state patients had similar survival rates (63% and 65%, respectively), whereas significantly more of the mobile minimally conscious state children survived (81%) [Strauss et al., 2000]. Understanding the natural course of these states of chronically impaired consciousness is crucial to provide families with realistic expectations of outcome after severe brain injury, as well as to allow for the possibility of recovery over time.

Cognitive Impairment and Behavioral Disorders Cognitive and behavioral impairments are some of the more debilitating sequelae of childhood traumatic brain injury and also some of the more difficult to quantify, particularly when subtle impairments follow milder injuries or when such disabilities are diagnosed years after a more severe traumatic brain injury. Nonetheless, deficits in many cognitive domains have been demonstrated after moderate-to-severe traumatic brain injury in children, including impaired executive function [Ewing-Cobbs et al., 2004], language

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[Levin, 2003], memory [Levin et al., 1982, 1988, 2002], and visual-motor integration [Yeates et al., 2002]. Tests of intelligence quotient [Fay et al., 1994; Jaffe et al., 1995; Levin et al., 1982], adaptive function [Taylor et al., 2002], and academic achievement [Ewing-Cobbs et al., 1998; Taylor et al., 2002] reveal post-traumatic brain injury deficiencies. When evaluated over time, several studies demonstrate that most post-traumatic brain injury cognitive and academic recovery occurs within the first year, and the rate of improvement diminishes significantly after that [Ewing-Cobbs et al., 1998; Jaffe et al., 1995; Yeates et al., 2002]. Lower socioeconomic status has also been associated with poorer outcomes from pediatric traumatic brain injury in multiple studies [Hawley et al., 2004; Taylor et al., 2002]. Several studies suggest that the age at which the injury occurs can affect cognitive outcome and later academic performance [Ewing-Cobbs et al., 1998; Levin et al., 1982, 1988]. It has been proposed that cognitive skills under development at a particular stage of maturation are more vulnerable to injury at that age. There is some evidence that younger children may be more likely to develop later cognitive and behavioral impairments that become evident when they fail to normally acquire higher level functions [Taylor and Alden, 1997]. The presence of lasting cognitive and academic impairments after mild pediatric brain injury is controversial. Several large studies have failed to detect significant neurocognitive impairment in mildly head-injured children [Asarnow et al., 1995; Fay et al., 1993]. However, when multiple neuropsychologic outcome measures were pooled, subtle overall impairments were reported that may indicate weak injury effects across a large spectrum of measures, rather than a major effect in a single cognitive domain [Polissar et al., 1994]. More recently, several studies have reported data that suggest, at least in younger children (less than 6 years old at injury), cognitive impairment after mild traumatic brain injury may be more noticeable in particular domains at longer follow-up periods [Bijur et al., 1990; Gronwall et al., 1997]. Earlier studies with shorter follow-up periods may have underestimated impairment associated with mild traumatic brain injury. When outcomes were assessed broadly using a parental questionnaire and an expanded outcome scale, increased symptoms and diminished outcomes were detected even in mildly injured children [Hawley et al., 2004]. Of great concern is the finding that, across all injury severities, only 30% of all head-injured children received follow-up after hospital discharge. Even in patients with identified special education needs, more than one third did not receive appropriate educational placement [Hawley et al., 2004]. Minimal medical follow-up after pediatric head injury is common despite the presence of persistent problems [Massagli et al., 1996b]. A number of animal studies have also investigated the cognitive effects of developmental traumatic brain injury. Younger animals have better behavioral outcomes than adults after traumatic brain injury [Prins and Hovda, 1998]. However, after severe traumatic brain injury with a secondary hypoxic injury, lasting motor and cognitive impairments have been reported [Adelson et al., 1997b]. Furthermore, there is evidence that experience-dependent plasticity is impaired after early traumatic brain injury. Last-

ing deficits in cognitive ability have been detected in animals injured early in life and subsequently reared in an enriched environment when compared with enriched but uninjured controls [Fineman et al., 2000; Giza et al., 2005]. There is also considerable evidence that pediatric traumatic brain injury results in later behavioral disturbances, including problems with impulse control, attention, and socialization [Max et al., 2004; Yeates et al., 2004]. Some investigators have suggested that many of these problems can be demonstrated premorbidly [Haas et al., 1987]. Nonetheless, a growing literature also indicates that new-onset psychiatric and behavioral disorders are more frequent following traumatic brain injury sustained during development [Bloom et al., 2001; Luis and Mittenberg, 2002; Max et al., 1997].

Spasticity and Motor Impairment Focal or diffuse injury may affect upper motor neuron pathways, resulting in spasticity, weakness, and loss of dexterity. The resulting motor deficit will depend on the location and nature of the primary injury. Hemiparesis and quadriparesis occur depending on whether the brain injury was predominantly unilateral (focal contusion, severe hematoma with edema) or bilateral (diffuse axonal injury, bilateral hematomas, diffuse hypoxia as a secondary injury). As a general rule, focal deficits recover better than diffuse ones, and younger age appears to predict better recovery in these circumstances (except perhaps in the earliest age groups, younger than 1 to 4 years). Passive range of motion should be instituted early enough to prevent development of contractures. Active physical and occupational therapy should be instituted when cognitive recovery sufficient to participate and follow commands has been achieved (see Chapter 92). Splints and orthotic devices (ankle-foot-orthoses, wrist splints) assist in improving function and avoiding contractures. Assistive devices to aid in ambulation should be provided when appropriate. In some cases, medical management of spasticity may also prove beneficial. Baclofen, tizanidine, dantrolene, and, rarely, benzodiazepines may be administered systemically to alleviate severe spasticity. The limiting factor for most of these medications is sedation and CNS depression. Dantrolene acts at the level of the muscle, and so avoids these central effects, but must be monitored carefully for hepatotoxicity. Botulinum toxin injections are increasingly used to locally treat spasticity in cases of cerebral palsy and brain injury. Botulinum toxin also avoids central depressive effects but can be costly. An intrathecal baclofen pump may also be considered in traumatic brain injury patients with severe spasticity who are responsive to baclofen but get limited benefits because of sedation.

Post-traumatic Hydrocephalus Post-traumatic hydrocephalus is not a common complication but can occur after intraventricular hemorrhage and post-traumatic subarachnoid hemorrhage. Chronic headache, sometimes with nausea, vomiting, impaired vertical eye movements, and diminished level of consciousness, may be manifestations of developing hydrocephalus. Shunting may be necessary to alleviate pressure. Ventriculomegaly is

Giza / Traumatic Brain Injury in Children

perhaps more common, with enlargement of ventricular and cerebrospinal fluid spaces as brain atrophy develops over time after more severe traumatic brain injury. In the latter instance the ventricular system is not under pressure, and shunting is not warranted.

Post-traumatic Epilepsy Epilepsy is defined as a disorder of recurrent seizures that are not reactive to an underlying metabolic derangement (e.g., electrolyte disturbance, hypoglycemia). Traumatic brain injury is responsible for about 5% of all new epilepsy cases annually in the United States [Hauser et al., 1993; Jennett, 1975]. Predictors of post-traumatic seizures include severity of traumatic brain injury, age, and type of traumatic brain injury [Annegers et al., 1980, 1998; Hahn et al., 1988b; Salazar et al., 1985; Weiss et al., 1986]. Although children are more likely than adults to experience an early post-traumatic seizure [Annegers et al., 1980, 1998], the relation between early and late post-traumatic seizures in children is unclear. Some report an increased risk for late seizures in children who experience an early one [Jennett, 1975], but this correlation has not been described in other studies [Annegers et al., 1980; Hendrick and Harris, 1968]. To some extent, the lower relative risk for posttraumatic brain injury epilepsy in children may be related to the higher spontaneous rate of developing epilepsy in the pediatric age range. The rationale for early antiepileptic prophylaxis following pediatric traumatic brain injury was covered earlier under the guidelines for acute management. The inability of early prophylaxis to alter the subsequent development of late post-traumatic epilepsy argues against routine chronic antiepileptic prophylaxis in head-injured children, particularly given the adverse effects of antiepileptic drugs, which include sedation, cognitive impairment, behavioral disturbances, and toxicity. Recent animal studies using anticonvulsants in neonatal rodents have revealed a worrisome tendency for these drugs to trigger widespread neuronal apoptosis in the developing rat brain [Bittigau et al., 2002; Olney et al., 2002]. Such concerns necessitate clear indications and demonstration of clear benefits when considering use of these medications in the maturing brain. Post-traumatic epilepsy includes late, recurrent, unprovoked seizures with a significant antecedent history of traumatic brain injury. Because routine prophylaxis is not generally recommended, when these patients present with their first seizure, they will likely not be taking antiepileptic drugs and should undergo a complete evaluation and workup. Evaluation includes a thorough history with a description of the prior head injury, as well as investigation for other risk factors (e.g., family history, history of other brain injury). Examination should be aimed at detecting focal neurologic impairments and determining whether these deficits are consistent with the history of the prior head injury. For example, a spastic hemiparesis on examination with a history of only a minor concussion 6 months earlier should raise suspicions for alternative etiologies. EEG is an essential part of the evaluation, with focal or multifocal abnormalities being more consistent with a diagnosis of post-traumatic epilepsy than generalized spike wave

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discharges. Focal findings on examination or EEG should prompt neuroimaging, with MRI being the modality of choice. MRI can identify areas suggestive of earlier traumatic brain injury, including encephalomalacia, gliosis, hemosiderin deposition, ventriculomegaly, and sulcal enlargement. Specific findings of mesial temporal sclerosis, hydrocephalus, chronic subdural fluid accumulations, prior ischemic cerebral infarction, or cerebral dysgenesis may also be revealed. Because the specific type of post-traumatic seizure is usually one of partial onset, medication choice is generally directed toward agents with effectiveness for localizationrelated epilepsy (see Chapter 44). The specific choice may also take into account potential side effects of the individual drugs. Phenytoin is associated with coarsening of facial features, hirsutism, and gingival hyperplasia and thus is perhaps less desirable for chronic use in children. Phenobarbital is sedating or paradoxically activating in children, and these behavioral effects are often limiting factors. Carbamazepine, lamotrigine, valproate, topiramate, oxcarbazepine, and even gabapentin and levetiracetam may be useful. Tailoring the choice of agent to take advantage of potentially beneficial side effects is often worthwhile. For example, in a patient with coexisting migraine headaches, topiramate and valproate are logical considerations; for the obese patient, valproate and carbamazepine may be avoided in favor of topiramate or at least the weight-neutral lamotrigine. Patients with mania and seizures may benefit from the moodstabilizing qualities of carbamazepine or valproate. Ideally, monotherapy would be attempted, with gradual increase of the medication to the therapeutic range, watching carefully for idiosyncratic or dose-related side effects. Careful attention should be given not only to parental concerns but also to school and teacher reports because chronic administration of antiepileptic drugs may result in subtle cognitive or behavioral impairments [Loring and Meador, 2004].

Subacute and Chronic Subdural Hematomas Subacute and chronic subdural hematomas can be seen because the predominantly venous bleeding that feeds the hematoma occurs slowly over a period of time, or because of multiple repeated traumas. Clinical manifestations are those of gradually increasing intracranial pressure—recurrent vomiting, macrocrania, papilledema, seizures, slowly progressive motor deficits, and spasticity—and occasionally systemic signs such as anemia, poor appetite, or fever. Because traumas can result in subdural hematomas of differing ages, the possibility of nonaccidental trauma should be considered whenever the radiographic appearance is consistent with subdural hematomas of varying age. Because blood products undergo a predictable pattern of breakdown visible on MRI, this remains the neuroimaging test of choice when attempting to age a subacute or chronic hematoma (see Table 62-5). In the hyperacute phase (4 to 6 hours), T1-weighted images are hypointense or isointense, and T2-weighted images are hyperintense, indicating oxyhemoglobin. Following this is a period (7 to 72 hours) during which deoxyhemoglobin becomes the predominant component. T1-weighted images are hypointense or isointense, whereas T2-weighted images become hypointense. In the early subacute period (4 to 7 days), T1-weighted

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images become hyperintense and T2-weighted images hypointense, representing intracellular methemoglobin. After 1 week, for the next few weeks, free or extracellular methemoglobin is present, sometimes with a thin rim of hemosiderin. T1-weighted images are hyperintense, as are T2-weighted images, with a rim of low intensity. In the chronic phase, hemosiderin is deposited and is hypointense on both T1- and T2-weighted images. Often, an inner and outer membrane may be visible. Treatment of these hematomas often includes drainage of the offending fluid collection. In cases suspected of nonaccidental trauma, a careful search for other bodily injuries is warranted, including a whole-body x-ray series (to look for multiple fractures in varying states of healing) and skin examination (to look for bruising in unusual locations, with bruises of different ages, as well as other signs and shapes of injuries or burns) (see Chapter 63).

Post-traumatic Headache Acute post-traumatic headache is usually self-limited. Trauma may also appear to precipitate migraines acutely or chronically. A direct causal relationship has not been proved, and it is uncertain whether this represents activation of migraines in those already predisposed to the condition. Worsening or progressive headache, particularly associated with nausea and vomiting, should warrant careful history and examination to rule out a delayed progressive intracranial complication (chronic subdural, hydrocephalus). If necessary, cranial CT can rule out the more worrisome diagnoses. Management of chronic post-traumatic headaches is directed at the presumed underlying etiology of the headache. Chronic nonmigrainous headaches may be treated with analgesics, nonsteroidal anti-inflammatory agents, antidepressants (e.g., amitriptyline), or antiepileptic drugs (gabapentin). Narcotics should be avoided. Migraine headaches should be treated based on their frequency, with prophylaxis considered for migraines occurring more often than once or twice every couple weeks (particularly if they result in missed school). Effective migraine prophylactic medications include topiramate, valproic acid, β blockers, amitriptyline, and possibly other medications, such as selective serotonin reuptake inhibitors, gabapentin, and calcium channel blockers. Infrequent migraines should be treated abortively using standard medications such as triptans. Neuralgic pain may respond better to antiepileptic drugs than to analgesics. Nonpharmacologic interventions should also be considered if chronic pain becomes a significant problem. These may best be addressed in a multidisciplinary pediatric pain clinic and include acupuncture, yoga, biofeedback, and counseling.

Postconcussive Syndrome Although most postconcussive symptoms resolve spontaneously within days to weeks after injury, persistent problems can arise. These symptoms can be difficult to quantify and even more difficult to treat and can become very disruptive to the child’s daily life if they result in exclusion from school or from social or extracurricular activities.

The constellation of symptoms seen in postconcussive syndrome in children is similar to that in adults, with chronic headache, dizziness, irritability, behavior change, inattention, and listlessness being prominent. The mechanisms of postconcussive symptoms are unknown, but in general, anatomic lesions are not seen. Demonstration of brain dysfunction after mild traumatic brain injury has been performed using quantification of persistent symptoms [Collins et al., 2002; Field et al., 2003; Ponsford et al., 1999], neuropsychologic testing [Collins et al., 1999, 2003; Matser et al., 1999], functional MRI [Jantzen et al., 2004; McAllister et al., 1999], positron emission tomography [Bergsneider et al., 2000; Chen et al., 2003; Roberts et al., 1995], and single-photon emission computed tomography [Kant et al., 1997; Umile et al., 2002]. The exact relation between these physiologic abnormalities and the patient’s symptoms has not been elucidated. Furthermore, other nonphysiologic factors have been implicated in the development of postconcussive symptoms, including premorbid personality traits, socioeconomic status, educational level, medicolegal compensation, and family dynamics. Most of the research into postconcussive syndrome has been performed in late adolescents and adults; thus, these findings may not be readily generalized to younger age groups. Management of postconcussive syndrome in children should focus on a return to normalcy as much as is possible given the symptoms. Partial return to school is usually preferable to complete absence in cases in which complete return is not possible. Prolonged absence from school may soon take on a life of its own and become clouded with issues of secondary gain and avoidance. Medical management should be aimed at identifying treatable problems and initiating appropriate interventions. Headaches may be approached as described earlier. Postconcussive behavior disturbances should be evaluated by a child psychiatrist or psychologist. Although it is uncertain whether mild traumatic brain injury results in an increased risk for new-onset behavioral diagnoses, it is clear that children with particular behavioral tendencies (attentiondeficit–hyperactivity disorder, oppositional behavior) are more prone to mild traumatic brain injury, and treatment of these underlying problems is often beneficial. Cognitive problems identified after mild traumatic brain injury may be best addressed by school assessment or neuropsychological testing. Often children with developmental delay or learning disabilities have disproportionate cognitive problems after mild traumatic brain injury. In a study of high school football players, in addition to a history of more than two prior concussions, a history of learning disability was associated with poorer results on neuropsychologic tests [Collins et al., 1999].

Late Complications of Skull Fracture Most nondisplaced skull fractures will heal without aggressive management. However, a number of chronic complications can result from skull fracture and need to be mentioned. “Growing skull fracture,” also known as craniocerebral erosion or leptomeningeal cyst, complicates less than 1% of all skull fractures. It occurs most commonly with linear fractures of the cranial vault, usually in the parietal region in

Giza / Traumatic Brain Injury in Children

infants younger than 1 year. After a linear fracture with separation of the bony edges by 2 to 3 mm, the pulsatile nature of the intracranial contents gradually results in outward herniation of dura and underlying brain. These fractures require carefully planned surgical correction because they do not resolve spontaneously and are often associated with local brain injury in the form of degeneration, necrosis, and gliosis. Clinically, hydrocephalus, motor deficits, and seizures have been reported as sequelae. Traumatic cranial neuropathies can also occur after fractures of the skull base, most commonly affecting olfactory, optic, facial, and vestibulocochlear nerves. Loss or impairment of olfaction can be associated with frontobasal fracture but is rarely tested and perhaps underdiagnosed. Traumatic optic neuropathies are associated with facial fractures, including fractures directly involving the optic canal. In cases in which no surgical lesion is detected, use of corticosteroids has been reported to speed recovery [Cook et al., 1996; Mahapatra and Tandon, 1993]. Complete paralysis of facial musculature suggests transection of the facial nerve in the petrous portion of the temporal bone. More often, transient facial weakness occurs, presumably because of edema and inflammation of perineural structures. Post-traumatic hearing loss may be due to cranial nerve VIII injury or direct injury to the ossicles. Again, fracture of the petrous bone should be considered. Steroids have not proved beneficial for post-traumatic facial or vestibulocochlear palsies. In cases of basilar skull fracture, particularly with persistent cerebrospinal fluid leakage, there is an increased risk for CNS infection because of parameningeal seeding. Patients with known basilar skull fractures who present with fever, meningismus, seizures, or focal neurologic findings should be evaluated promptly for brain abscess, empyema, or meningitis.

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CHAPTER 63

Inflicted Childhood Neurotrauma Elizabeth E. Gilles and Ann-Christine Duhaime

Inflicted head injury is a form of traumatic brain injury resulting from assault. Despite increasing prevention efforts, it remains a major cause of morbidity and mortality among children [Aldrich et al., 1992; Bonnier et al., 1995; Duhaime et al., 1996b; Gilles and Nelson, 1998; Irazuzta et al., 1997]. Infants with inflicted head injuries have the most severe illness, the highest mortality risk, and the worst outcome in comparison with other forms of childhood trauma [Goldstein et al., 1993b; Gilles and Nelson, 1998; Irazuzta et al., 1997; Pfenninger and Santi, 2002; Rivara et al., 1996]. Children younger than 3 years, particularly those younger than 1 year, are at highest risk for inflicted neurotrauma [Duhaime et al., 1998]. In one study, the incidence of inflicted head injury among children younger than 2 years was 17 per 100,000 children [Keenan et al., 2003]. Other studies suggest that as many as 60% of deaths resulting from abuse or neglect are not recorded [Crume et al., 2002].

TERMINOLOGY Inflicted and nonaccidental childhood neurotrauma are used in this chapter as inclusive terms to describe the range of craniospinal injuries sustained by infants and young children as a consequence of violent assault by parents or other caretakers. Unintentional or accidental head injury refers to injury sustained by chance and unrelated to specific deliberate actions of caretakers. The terms shaken baby syndrome and shaken-impact infant syndrome imply a uniform injury event sequence, mechanism of injury, and age at time of injury that belie the actual complexity of injury and postinjury event sequences [Budenz et al., 1994; Duhaime et al., 1987; Gilles and Nelson, 1998]. Popularization of this simplistic terminology has led to at least two types of errors. First, overly simplistic analyses of clinical and imaging data can result in either overdiagnosis or underdiagnosis of abuse. Second, there is a tendency to rely on symptoms common to accidental injuries, such as the presence of impact evidence, as well as the absence of retinal hemorrhages, to prove a child was not shaken when, in fact, there is clear and convincing evidence.

HISTORICAL PERSPECTIVE The acceptance of inflicted head injury as an age-related subtype of traumatic brain injury and of physical abuse is a relatively recent phenomenon, although descriptions of this disorder were made at least as early as the 19th century [Tardiéu, 1860]. Tardiéu was the first to document the range

of injury patterns found in abused and neglected children as distinct from those in adults and to link them to caregiver actions. Although a number of researchers independently associated fractures, subdural hematomas, and retinal hemorrhages in infants with trauma starting in the 1920s, association of these findings with caregiver actions was not made clearly until the 1950s [Caffey, 1972, 1974; Frauenberger and Lis, 1950; Guthkelch, 1971; Kempe et al., 1962; Lindenberg and Freytag, 1969; Silverman, 1952; Woolley and Evans, 1955]. Recognizing that the history offered by the caregiver was biomechanically inconsistent with the severity of injury was an important step in accepting inflicted neurotrauma as a distinct form of trauma [Billmire and Myers, 1985; Duhaime et al., 1987, 1992; Goldstein et al., 1993b; Weston, 1973]. Few authors have specifically addressed the discrepancies between initial historical data and subsequent caregiver admissions [Gilles and Nelson, 1998; Tardiéu, 1860; Weston, 1973]. John Kempe coined the term battered child syndrome to describe severe physical abuse with fractures, bruises, failure to thrive, brain injury, and subdural hematomas [Kempe et al., 1962]. Subsequently, Guthkelch [1971] and Caffey [1972, 1974] independently hypothesized that head injury in the absence of obvious blunt force trauma was caused by whiplash shaking of the infant’s head by the caregiver. In 1974, Caffey coined the term shaken baby syndrome for infants who had severe head injuries but lacked signs of blunt force trauma on imaging studies. Inflicted childhood neurotrauma has increasingly become the focus of investigation in both clinical and laboratory studies. It is important to realize that the majority of the relevant literature is observational and retrospective in nature. Most studies have failed to specify explicit inclusion or exclusion criteria and have accepted with minimal or no question histories obtained from perpetrators [Weston, 1973; Chadwick et al., 1991].

DEVELOPMENTAL DIFFERENCES PREDISPOSING THE IMMATURE NEURAXIS TO INJURY Structural and functional changes of central and peripheral nervous system organization and function are greatest during the first 2 years of life, when nonaccidental head injury occurs most frequently [Brody et al., 1987; Duhaime et al., 1987; Kinney et al., 1988; Lenn, 1987]. A number of biologic and mechanical factors predispose the infant and young child to injury of the craniospinal axis (Box 63-1).

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Box 63-1 BIOLOGIC AND MECHANICAL FEATURES PREDISPOSING THE INFANT TO HEAD INJURY Biomechanical Factors Large head-to-body ratio Proportionally heavy head in relation to body mass and neck strength Greater skull compliance Anatomy of inner skull table (smoother in younger infants) More firmly attached dura Neuroanatomic Factors Immature brain (incomplete myelination) Increased brain water content Increased excitotoxicity Increased synaptic density Increased excitatory amino acid receptors Decreased inhibitory networks

Mechanical Factors Although a larger head-to-body ratio than in adults and less developed neck and shoulder girdle musculature render the infant more vulnerable to significant applied forces, the immature brain is, in some ways, more resistant to injury than is the adult brain. The smaller head requires larger rotational input for the same force as a larger brain, and the higher water content makes the brain more resistant to deformation. These features reinforce the observation that trivial trauma does not appear sufficient to cause the kinds of injuries seen in the context of abuse [Brody et al., 1987; Prange et al., 2003]. Incomplete myelination and increased percentage of brain fluid also contribute to distensibility and compliance of brain tissue during injury events [Brody et al., 1987]. The infant has a relatively smooth inner cranial table and greater skull compliance [Carter and McCormick, 1983; Courville, 1965; Duhaime et al., 1992; Lindenberg and Freytag, 1969].

Biologic Factors Many biologic factors are important to the immediate and subsequent responses of the immature central nervous system to injury. Mechanisms initiated by mechanical brain injury may enhance vulnerability to secondary ischemic brain damage [DeWitt et al., 1995; Novack et al., 1996; Teasdale and Graham, 1998]. Some factors are age-specific differences in cerebral autoregulation, as well as differences in the structure, number, and function of neuronal synapses and receptors [Armstead and Kurth, 1994; Azzarelli et al., 1996; Herlenius and Lagercrantz, 2004; Johnston, 1996; Lea and Faden, 2001; Ruppel et al., 2001]. Synaptic density in human infants is 50% to 60% above the adult mean, and N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy5-methyl-4-isoxazole propionic acid (AMPA) excitatory amino acid receptors are increased [Huttenlocher, 1984; Johnston, 1995; Kubova and Moshe, 1994]. These receptors are functionally and structurally different from those of adults [Johnston, 1995; McDonald et al., 1992].

The immature central nervous system has structural and organizational differences in neuronal differentiation that decrease ischemic and seizure thresholds, in comparison with the mature central nervous system, particularly after trauma and hypoxic-ischemic injury [Adelson et al., 1997; D’Souza et al., 1992; Goldstein et al., 1993b; Johnston, 1996; Kubova and Moshe, 1994; Mares et al., 2004]. Neuronal and glial injury leads to excessive release of excitatory amino acids, which in turn trigger activation of immature NMDA and AMPA receptors in the hippocampus [Hagberg et al., 1993; Mares et al., 2004]. Excessive activation triggers excitotoxic injury via intracellular calcium-mediated events [Hablitz and Lee, 1992; Johnston, 1996; Kubova and Moshe, 1994; Teasdale and Graham, 1998]. The inhibitory amino acids γ-aminobutyric acid and glycine are excitatory in the developing brain [Herlenius and Lagercrantz, 2004]. Other mediators of secondary injury include inflammatory and excitotoxic mechanisms, oxidative stress, and apoptosis [Bittigau et al., 2003; Ruppel et al., 2002]. Developmental differences alone, however, fail to explain why children with inflicted head injury have more severe illness and a higher mortality risk than do children of the same age with unintentional head injury [Bell et al., 1997; Goldstein et al., 1993b; Haviland and Russell, 1997; Irazuzta et al., 1997]. When age is removed as a confounding variable, inflicted head injury still differs substantially from unintentional head injury [Haviland and Russell, 1997]. It is still unclear which features increase or decrease vulnerability of the immature brain to the various types and combinations of traumatic insults seen in the setting of inflicted injury, but they are the focus of much ongoing research [Duhaime et al., 2000, 2003; Durham et al., 2000b; Fan et al., 2003; Tong et al., 2002].

MECHANISMS OF INJURY Child abuse is rarely premeditated. It occurs when caregivers lose control, often when trying to stop certain behavior (such as crying) or when punishing perceived transgressions (such as toileting accidents). Although many inflicted injuries are one-time events, children may have been subjected to repeated and complex injury scenarios occurring during a single day or as a series of events over days, weeks, or months [Alexander et al., 1990; Gilles and Nelson, 1998; Weston, 1973]. The sequence of injury events is highly variable. Injury events can include shaking, throwing, hitting, slapping, gagging, strangulation, and smothering [Bonnier et al., 1995; Duhaime et al., 1987; Gilles and Nelson, 1998]. Only children with injuries severe enough to frighten the caregiver are likely to be brought to medical attention. Resuscitation delay is also a potential factor, although not a uniform finding or unique to abuse [Adelson et al., 1997]. Presumably, resuscitation delay accentuates neuronal and biochemical ischemic cascades, which contribute to the severity of secondary neuronal injury [Gilles and Nelson, 1998; Goldstein et al., 1993b; Johnson et al., 1995]. Significant forces are required to cause severe inflicted injury [Duhaime et al., 1987; Prange et al., 2003]. In general, greater applied forces result in more severe injuries, regardless of whether the injury was inflicted. As with other tissues, brain injuries occur when applied forces strain the

Gilles and Duhaime / Inflicted Childhood Neurotrauma

tissue beyond its structural or functional tolerance, or both. Primary mechanisms of injury include both impact and inertial forces. Impact forces occur at the surface of the scalp, skull, and brain as a result of contact. Inertial forces arise from head movement, when the head accelerates or decelerates. Inertial forces may be translational, when the head moves in a straight line, or rotational, also known as angular, when the head rotates around its center of gravity. The exact type and the magnitude of applied forces determine the severity of injury. Most severe primary brain injuries in the clinical world result from head contact, because the forces generated are much higher than those produced by noncontact mechanisms. In the brain, the term primary injury refers to immediate, irreversible damage that occurs at the time of the insult. Secondary injuries potentiate primary injuries and occur as a consequence of the initial trauma, causing further damage to tissue that may have otherwise been viable. Examples include hypoperfusion/ischemia of brain tissue (from hypotension/shock), hypoxia, seizures, and parenchymal injury sustained when brain is compressed by an expanding mass lesion (e.g., clot). Numerous metabolic and inflammatory cascades are triggered by trauma. Infants with inflicted head injury frequently have both diffuse and focal injury as a consequence of force dynamics generated during the primary injury events and secondary hypoxic-ischemic injury [Barlow and Minns, 1999; Gilles and Nelson, 1998; Johnson et al., 1995]. In severe inflicted head injury, it is thought that secondary hypoxic-ischemic injury is a significant contributing factor in the evolution of brain swelling and deleterious outcome [Aldrich et al., 1992; Ashwal et al., 1996; Biousse et al., 2002; Chesnut et al., 1993; Geddes et al., 2003; Goldstein et al., 1993b; Johnson et al., 1995; Pigula et al., 1993; Takahashi et al., 1993]. Differences in regional cerebral blood flow, autoregulatory mechanisms, and regional sensitivity to hypoxia

A

B

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all contribute to the extent of hypoxic-ischemic injury [Han et al., 1990; Takahashi et al., 1993]. Imaging features include cortical laminar necrosis, border zone infarctions, and cerebral atrophy (Fig. 63-1) [Liwnicz et al., 1987; Takahashi et al., 1993].

CLINICAL FEATURES Symptoms Acute Presentation Regardless of age, there is a predictable pattern of brain response to mechanical trauma, whether blunt force, primarily angular acceleration-deceleration, or both. Studies have demonstrated that severe primary brain injuries result in immediate decrease in the level of consciousness and an apneustic response, associated with apnea and initial hypertension from catecholamine surge, followed by hypotension [Atkinson, 2000; Denny-Brown and Russell, 1941; Ommaya and Gennarelli, 1974]. The apneustic response results from primary disruption of cerebral circuits between the cerebralbrainstem reticular activating system and respiratory centers or between diencephalon-brainstem connections [Atkinson et al., 1998; Ommaya and Gennarelli, 1974; Willman et al., 1997]. Preliminary data suggest a lowered threshold to disruption of respiratory and cardiovascular drive mechanisms in moderate-to-severe head injury in the younger child [Adelson et al., 1997; Biswas et al., 2000; Goldstein et al., 1996]. Trauma-induced hypoxia and hypotension are strongly associated with adverse outcome in adults and children [Chesnut et al., 1993; Gilles and Nelson, 1998; Johnson et al., 1995; Takahashi et al., 1993]. Most infants with severe head injury, inflicted or not, experience apnea or altered

C

FIGURE 63-1. A, Nonenhanced computed tomographic (CT) scan of a 3-month-old child found limp and unconscious. The scan reveals diffuse cerebral hypoattenuation and thin bilateral convexity acute subdural hematoma. B, Nonenhanced CT scan of the same patient 10 days after admission, revealing laminar hyperdensity along the cerebral cortex, which is consistent with cortical laminar necrosis. C, Nonenhanced CT scan of same patient 6 months after injury. The patient is microcephalic with profound mental retardation, spastic quadriparesis, and post-traumatic epilepsy. The scan reveals diffuse cerebral atrophy.

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respiration during or just after injury [Gilles and Nelson, 1998; Johnson et al., 1995; Kemp et al., 2003]. Hypotension develops frequently and is an index of neurologic insult and shock [Aldrich et al., 1992; Vavilala et al., 2003]. Apnea and hypotension can also be a response to smothering or to direct vessel compromise caused by strangulation [Bird et al., 1987, Gilles and Nelson, 1998; Glasier et al., 1987]. However, apnea or hypotension do not completely explain why one third of infants have hypodensity affecting one hemisphere, insofar as these processes would be expected to be symmetric [Duhaime et al., 1993; Gilles and Nelson, 1998] (see also “Swelling or Edema” section). Hemispheric hypodensity is generally observed subjacent to an ipsilateral subdural hematoma. Symptoms of brain injury are nonspecific, varying by the severity of injury. The classic presentation is that of a previously healthy infant who suddenly decompensates neurologically and develops severe respiratory distress and flaccidity, with or without seizures or posturing (usually extensor) [Bonnier et al., 1995; Gilles and Nelson, 1998; Hadley et al., 1989; Johnson et al., 1995; Kemp et al., 2003]. This presentation varies considerably, however, but may be more common in younger infants. Persistence of coma, apnea or respiratory distress, irritability, seizures, hypotonia, and vomiting reflects the severity of mechanical and physiologic disruptions and evolving secondary pathophysiologic cascades [Gilles and Nelson, 1998; Goldstein et al., 1993a; Johnson et al., 1995; Zuccarello et al., 1985]. Infants with increased intracranial pressure may have a bulging fontanel and diastatic sutures. Young children with inflicted brain injury develop the same patterns of brainstem abnormalities (pupils, eye movements, and breathing) as children and adults with severe unintentional brain injury [Atkinson et al., 1998; Gilles and Nelson, 1998; Hahn et al., 1988a; Johnson et al., 1995]. Infants who are severely injured cannot regulate behavior that requires higher cortical functions, such as coordinated action, eating, sitting, and walking. As Graham and colleagues [1989] noted, if an individual who sustains a head injury is able to talk, brain damage at the moment of injury cannot have been overwhelming. Less severely injured infants with concussive symptoms may exhibit a depressed level of consciousness, irritability, altered behavior, seizures, decreased feeding, vomiting, fever, and altered respiration. They may not appear sick enough for the perpetrator to seek medical attention. The accompanying caregiver may be unaware of the injury or may be the nondisclosing perpetrator.

EARLY POST-TRAUMATIC SEIZURES Early post-traumatic seizures (those occurring in the first 72 to 96 hours after trauma) are more common in infants and young children with inflicted head injury than in older children or adults with unintentional head injury or cerebral infarction from other etiologies. Frequency ranges from 30% to 100% [Annegers et al., 1980; Bonnier et al., 1995; Gilles and Nelson, 1998; Goldstein et al., 1993b; Hadley et al., 1989; Hahn et al., 1988b; Johnson et al., 1995; Lewis et al., 1993; Ludwig and Warman, 1984]. Seizures correlate with age younger than 18 months, loss of consciousness, low Glasgow Coma Scale score, and abnormal computed tomographic (CT) scan [Gilles and Nelson, 1998; Hadley et al.,

1989; Johnson et al., 1995; Lewis et al., 1993; Ludwig and Warman, 1984]. The majority of early post-traumatic seizures start in the first 24 hours after trauma, and although seizures can accompany injury events, extensor posturing is more common [Lewis et al., 1993]. Seizures are typically partial, partial complex, or partial with or without secondary generalization. Clinical signs may be subtle or even absent. Although the onset of symptoms generally correlates with the timing of injury, early post-traumatic seizures cannot and should not be used to time the injury events. Early post-traumatic seizures may have potentially deleterious effects on the acute and subacute clinical course in the immature brain [Wasterlain et al., 2002]. They potentiate ischemic cascades by compromising oxygen and substrate delivery to neurons and, if unrecognized, can be the source of severe secondary injury. The high incidence of early post-traumatic seizures and the difficulties encountered in their control supports the early use of prophylactic antiepileptic medication in the child with severe inflicted closed-head injury, particularly if an infarction syndrome is suspected.

Subacute or Chronic Presentation A child with chronic subdural hematomas may present with macrocephaly alone and look well. The true diagnosis in such children may be missed by conventional evaluation, and a level of suspicion is needed to suggest the appropriate evaluation, usually including magnetic resonance imaging (MRI) [Duhaime et al., 1998]. Other children present with a tense anterior fontanel; failure to thrive; developmental delay; and seizures, spasticity, or both [Ingraham and Heyl, 1939; Sherwood, 1930]. Anemia, recurrent vomiting, and a shrill cry are also frequent.

Sequelae of Inflicted Head Injury Outcome data regarding inflicted childhood head injury have been accumulating since the 1950s. In contrast to the majority of children with severe unintentional head injury, who tend to be older and generally have better outcomes, infants tend to have a higher mortality rate and significant sequelae [Bonnier et al., 2003; Duhaime et al., 1987; Gilles and Nelson, 1998; Goldstein et al., 1993b; Hahn et al., 1988a; Johnson et al., 1995; Kemp et al., 2003]. Predictors of poor outcome are similar to those for other types of head injury, and include low scores on the Glasgow Coma Scale or other infant coma indexes, hyperglycemia, extensor posturing, lack of brainstem reflexes on presentation, and coma duration of more than 7 days (Box 63-2) [Durham et al., 2000a; Gjerris, 1986; Johnson et al., 1995; Prasad et al., 2002]. In inflicted head injury, the age at injury, severity of secondary insults, decreased cerebral perfusion pressure, and presence of focal lesions are other important factors [Barlow and Minns, 1999; Bonnier et al., 2003]. Visual impairment and behavioral, cognitive, and motor disabilities are common after inflicted head injury, and infants have an increased likelihood of developing post-traumatic epilepsy [Bonnier et al., 1995, 2003; Duhaime et al., 1996b; Ewing-Cobbs et al., 1999; Gilles and Nelson, 1998; Gilles et al., 2003; Haviland and Russell, 1997; Kemp et al.,

Gilles and Duhaime / Inflicted Childhood Neurotrauma

Box 63-2 FACTORS AFFECTING SEVERITY OF INJURY Types of injury events Biomechanical Acceleration-deceleration Translational Strangulation Smothering Sequence of events Single or multiple events Other factors Duration of apnea, hypotension Delay in seeking medical care Level of consciousness at the time of the event or events Neuromuscular maturity of the child Antecedent dehydration and/or malnutrition Premorbid brain injury

2003]. The majority of such infants initially become macrocephalic, frequently with diastatic sutures and bulging fontanel. With time, in more severely injured children, cerebral atrophy and associated microcephaly develop with ex vacuo enlargement of the cerebrospinal fluid spaces [Bonnier et al., 2003; Gilles and Nelson, 1998; Lo et al., 2003]. On occasion, such children develop hydrocephalus. Long-term imaging anomalies include diffuse cortical atrophy, generalized white matter attenuation, multicystic encephalomalacia, porencephaly, and ulegyria [Bonnier et al., 2003; Geddes et al., 2001a; Marin-Padilla et al., 2002]. Sequelae of ocular pathology are numerous, with visual impairment found in 32% to 90% of patients [Gilles and Nelson, 1998; McCabe and Donahue, 2000; Riddoch and Goulden, 1925]. Cortical visual impairment contributes more to long-term visual deficits than do anterior visual defects [Poggi et al., 2000]. Small peripheral retinal hemorrhages resolve without compromising vision. Larger hemorrhages, however, especially those near or obscuring the macula, may affect central vision permanently [Ehrenfest, 1922].

PATHOLOGY About two thirds of abused children who die have lesions involving the craniospinal axis. The pathologic features parallel those found on the clinical and imaging examinations (see also “Clinical Assessment and Management” and “Radiographic Evaluation” sections). A full postmortem examination, including examination of the eyes, is mandatory for any child with an unexplained death [Case et al., 2001; Gilliland and Folberg, 1992]. This requirement is especially true in infants younger than 1 year, in whom the possibility of sudden infant death syndrome is actually stronger than that of inflicted head injury. Postmortem examination findings frequently assist in establishing an unintentional or inflicted etiology [Bass et al., 1986]. A broad range of physical findings is associated with inflicted head injury. Not all injuries have to be present to make the diagnosis, and no individual markers are pa-

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Box 63-3 NONACCIDENTAL HEAD INJURY: MARKERS OF INJURY Intracranial Extra-axial fluid collections Subdural hematoma Subarachnoid hemorrhage Subdural effusions Brain injury Brain swelling Infarction syndromes White matter contusional tears Evidence of shearing injury Diffuse axonal injury Skull fractures Extracranial Scalp and soft tissues Subgaleal hematoma Cephalohematoma Soft tissue swelling Hair loss Bruising Ear Pinna bruising Hemotympanum Ruptured ear drum Ocular Retinal hemorrhages Retinal folds Retinal detachment Hyphema Lens dislocation Mouth Lip injury Frenulum tear Soft palate petechiae Dental injury Other Pattern bruising (e.g., from strangulation) Long bone and rib fractures Liver, kidney, or genital injury Dehydration Malnutrition Burns Excessive scarring

thognomonic of abusive injury. The major markers of injury are outlined in Box 63-3. In establishing the likelihood that the injuries resulted from inflicted versus unintentional mechanisms, the differential alternatives for each marker must be considered with the pattern of injuries as a whole, along with the history of injury. Severe mechanical trauma to the developing neuraxis results in specific injuries. Particular findings that support more significant force generation are injuries to the neck and rostral spine (such as radicular avulsion), contusions or lacerations of the olfactory system (bulbs, tracts, and gyrus recti), partial or complete transection of the corpus callosum, tearing of the septum pellucidum, and acute neuronal necrosis on microscopy.

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FIGURE 63-2. Gross photograph of an unstained section of retina, revealing a prominent sublaminar hemorrhage and multiple intraretinal hemorrhages.

FIGURE 63-4. Hematoxylin and eosin stain photomicrograph of retina, revealing prominent hemosiderin-laden macrophages (center).

FIGURE 63-3. Retinal section stained for iron. This section came from an infant who died approximately 2 weeks after injury. Extensive resolving retinal hemorrhages are seen in multiple interretinal layers.

Aside from greatly assisting in documenting the full extent of injuries, the postmortem examination provides additional information about the pathologic timing of injury events. The presence of intra-alveolar siderophages, for instance, is suggestive of previously imposed suffocation [Becroft and Lockett, 1997]. Confirmation of specific findings, such as subdural neomembranes and positive retinal staining for hemosiderin and iron, can further assist in the timing of injuries (Figs. 63-2, 63-3, and 63-4). In instances in which the infant has been kept alive while brain death and resultant necrosis evolve, however, clinical timing of injury is typically more precise than is timing based on pathologic findings.

Ocular Pathology Retinal Hemorrhages A variety of injuries to the globe and optic nerve have been reported after inflicted injury, including retinoschisis, retinal folds, retinal detachment, periorbital edema and ecchymosis, subconjunctival hemorrhage, hyphema, and cataract [Buys et al., 1992; Gaynon et al., 1988; Greenwald et al., 1986; Massicotte et al., 1991; Mushin, 1971; Schloff et al.,

2002]. Periorbital bleeding can result from either direct impact to the eye or a basilar fracture. Retinal and optic nerve sheath hemorrhages are the most common injuries. The frequency varies from 47% to 100% of all children with inflicted head trauma, depending on study inclusion criteria [Budenz et al., 1994; Buys et al., 1992; Duhaime et al., 1987; Elner et al., 1990; Gilliland et al., 1994; Laskey et al., 2004; Ophthalmology Child Abuse Working Party, 1999; Riffenburgh and Sathyavagiswaran, 1991; Schloff et al., 2002; Wilkinson et al., 1989]. Retinal hemorrhages, if present, may be unilateral or bilateral, with variable appearance and distribution within the retina, and are often asymmetric (Figs. 63-5 and 63-6) [Betz et al., 1996; Elner et al., 1990; Gilles et al., 2003]. The terminology used to describe retinal hemorrhages is based on the location within the retinal layers (Table 63-1). They are most frequently found in the bipolar and nerve fiber layers [Riffenburgh and Sathyavagiswaran, 1991]. Controversy exists as to their terminology, pathogenesis, associations, and resolution. Younger age and greater hypoxic-ischemic injury are correlated with more severe retinal hemorrhages [Gilliland et al., 1994; Matthews and Das, 1996; Riffenburgh and Sathyavagiswaran, 1991; Wilkinson et al., 1989]. Retinal hemorrhages are occasionally found in children after certain forms of nonsevere accidental head injury but are usually small and scattered hemorrhages, often occurring unilaterally, in an otherwise well-appearing child [Buys et al., 1992; Christian et al., 1999]. In four prospective studies,

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TABLE 63-1 Terminology for Retinal Hemorrhages

FIGURE 63-5. Nerve fiber layer and intraretinal layer retinal hemorrhages.

NAME

LOCATION

Vitreal Subhyaloid (sublaminar or boat) Intraretinal Flame or splinter Dot (dot and blot)

Vitreous Preretinal Nerve fiber layer Inner retinal layers (including bipolar)

nomonic for inflicted injury (see Fig. 63-6) [Bechtel et al., 2004; Mills, 1998; Rao et al., 1988]. This pattern is particularly suspect in the setting of a trivial mechanism of injury in an otherwise healthy child [Betz et al., 1996; Buys et al., 1992]. In contrast, these patterns have not been reported in the setting of a low-height fall in an otherwise healthy child; therefore, in this context, some workers consider these findings clearly indicative of abuse. The resolution rates of retinal hemorrhages after inflicted injury have not been studied systematically. The only large study is that of Pierre-Kahn and coworkers [2003], who prospectively monitored 231 children younger than 3 years who were admitted with subdural hematoma; they found that 88% of retinal hemorrhages resolved within 4 weeks. Most birth-related retinal hemorrhages are small and disappear within the first few days to 2 weeks after birth [Baum and Bulpitt, 1970; Ehrenfest, 1922; Emerson et al., 2001; Suzuki and Awaya, 1998]. Macular hemorrhages may take longer to resolve [Suzuki and Awaya, 1998].

THEORIES OF RETINAL HEMORRHAGE PATHOGENESIS

FIGURE 63-6. Extensive sublaminar and intraretinal layer retinal hemorrhages.

investigators examining a total of 290 children after accidental head injury found three children with retinal hemorrhages [Buys et al., 1992; Duhaime et al., 1992; Elder et al., 1991; Johnson et al., 1993]. Two of the three children with retinal hemorrhages were involved in side-impact car accidents [Johnson et al., 1993]. A pattern of severe, bilateral, diffuse retinal hemorrhages; retinal folds or retinoschisis; or detachment in a child with severe brain injury is highly suggestive but not pathog-

The pathogenesis of retinal and vitreal hemorrhages in infants with inflicted trauma is multifactorial and not yet understood. Several hypotheses have been proposed, with varying amounts of supportive data. These hypotheses include increased intracranial pressure, hydraulic forces, traumatic retinoschisis from deceleration forces, increased optic nerve sheath pressure, and anoxic injury [Gilles et al., 2003; Lyle et al., 1957; Massicotte et al., 1991]. Perhaps the strongest association is that with sudden intracranial hypertension, with or without intracranial hemorrhage, support for which dates back to the 1800s [de Schweinitz and Holoway, 1912; Ehrenfest, 1922; Hedges et al., 1964; Medele et al., 1998; Muller and Deck, 1974; Tureen, 1939]. Further support for the relationship between intracranial pressure and retinal hemorrhage pathogenesis comes from the observation that symmetry of retinal hemorrhages has been correlated to hemispheric intracranial pathologic processes (e.g., ipsilateral to acute subdural hematoma and regional brain swelling) in a variety of settings. The literature includes cases of unintentional and inflicted head injury in childhood and studies of adults after head injury or ruptured vascular malformations [Budenz et al., 1994; Christian et al., 1999; Drack et al., 1999; Giangiacomo et al., 1988; Gilles et al., 2003; Keane, 1979; Paviglianiti and Donahue, 1999; Shaikh et al., 2001; Shaw et al., 1977]. Cardiac compressions during cardiopulmonary resuscitation do not generate enough transmutive force to raise intracranial pressure and secondarily intraretinal pressure

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[Fackler et al., 1992; Paradis et al., 1989]. Three studies documenting retinal examinations before or after death in more than 200 children who underwent either chest compressions or prolonged resuscitative efforts have failed to find an association between cardiopulmonary resuscitation and retinal hemorrhages [Budenz et al., 1994; Gilliland and Luckenbach, 1993; Kanter, 1986; Odom et al., 1997]. They do not appear to develop after seizures or Valsalva maneuvers [Herr et al., 2004; Sandramouli et al., 1997].

Optic Nerve Sheath Hemorrhage The optic nerve sheath has dural and arachnoid components, with only the subarachnoid space in continuity with the subarachnoid spaces of the brain. Hemorrhages are found in both the subdural and potential subarachnoid space. The frequency of optic nerve sheath hemorrhages is unknown. They are found in 70% to 100% of children at postmortem examination but have not been identified accurately in the living child [Budenz et al., 1994; Elner et al., 1990; Duhaime et al., 1992; Gilliland et al., 1994; Lambert et al., 1986]. Optic nerve sheath hemorrhages are not specific to inflicted injury, having been reported secondary to sudden or prolonged increases in intracranial pressure (e.g., extensive subarachnoid hemorrhage) and, in rare cases, with unintentional head injury [de Schweinitz and Holoway, 1912; Elner et al., 1990; Muller and Deck, 1974; Munger et al., 1993; Weissgold et al., 1995]. Potential pathogenic mechanisms include local rupture of intradural vessels and bridging veins within the optic nerve sheath, injury to the optic nerve sheath with fracture of the base of the skull near the optic foramina, and spread of subarachnoid blood from the pericerebral subarachnoid space [Brinker et al., 1997; Elner et al., 1990; Muller and Deck, 1974; Munger et al., 1993].

Retinal and Optic Nerve Sheath Differential Retinal and optic nerve sheath hemorrhages are found in numerous disorders. They have been reported most commonly in newborns but also with vascular malformations, coagulopathies, anemia, leukemia, meningitis, bacterial endocarditis, hypertension, infections, and papilledema [Carraro et al., 2001; Eisenbrey, 1979; Emerson et al., 2001; Kessler and Siegel-Stein, 1984; Marshman et al., 1999; Schloff et al., 2002; Sung et al., 2000; Weissgold et al., 1995]. Retinal hemorrhages have been reported in rare cases in children after unintentional head injury, such as high-speed motor vehicle accidents, in association with epidural hematoma, and after some falls [Buys et al., 1992; Christian et al., 1999; Elder et al., 1991; Vinchon et al., 2002]. When present in this setting, retinal hemorrhages are typically small and few in number [Betz et al., 1996]. They are not found after seizures [Mei-Zahav et al., 2002; Sandramouli et al., 1997]. Retinal hemorrhages in the presence of papilledema cannot be causally related to nonaccidental head injury. Finally, retinal hemorrhages are not usually found in the context of acute life-threatening events [Pitetti et al., 2002].

Extracranial Injuries The most common extracranial impact injuries in inflicted injury are scalp bruising, soft tissue swelling, cephalo-

FIGURE 63-7. Occipital skull fracture extending into the foramen magnum in a 6-month-old infant. There is extensive subgaleal hematoma, seen here as soft tissue swelling around the occiput.

hematoma, and subgaleal hematoma (Fig. 63-7) [Duhaime et al., 1987; Zimmerman et al., 1979]. Scalp bruising may be difficult to discern clinically [Atwal et al., 1998]. Atwal and associates found that facial and forehead bruising predominated in a series of fatal inflicted head injury, whereas limb and chest bruising were uncommon, which suggests that slapping or punching of the head, not gripping of the chest or arms and shaking, was more common. Subgaleal hematomas result from shearing injury to the scalp from impact or from a violent hair pulling [Hamlin, 1968]. At postmortem examination, evaluation of the reflected scalp allows for the identification of galeal hemorrhage and impact sites (periosteal hemorrhages). The temporalis muscle and posterior cervical muscles are additional sites where internal soft tissue injury is found.

Skull Fractures A variety of skull fractures have been reported after blunt trauma, regardless of etiology (see Fig. 63-7). As such, they are not specific to either unintentional or inflicted trauma [Greenes and Schutzman, 1997]. Depending on the study, between 25% and 74% of infants and children with inflicted neurotrauma sustain skull fractures [Case et al., 2001; Duhaime et al., 1992; Ewing-Cobbs et al., 2000; Geddes et al., 2001a; Rubin et al., 2003]. Simple linear fractures are the most common and tend to be parietal or occipital in location [Hobbs, 1984; Meservy et al., 1987; Rubin et al., 2003; Shane and Fuchs, 1997]. In general, fractures that are bilateral, comminuted, or multiple or that cross suture lines are more suggestive of infliction [Arnholz et al., 1998; Banaszkiewicz et al., 2002; Geddes et al., 2001a; Hobbs, 1984; Meservy et al., 1987; Shane and Fuchs, 1997]. Fractures in infants with open sutures do not usually cross suture lines. Bilateral or other

Gilles and Duhaime / Inflicted Childhood Neurotrauma

multiple fractures usually indicate that more than one impact occurred but have also been reported after simultaneous, severe head compression between two unyielding surfaces or from direct occipital impacts [Arnholz et al., 1998; Hiss and Kahana, 1995]. In rare cases, complicated fractures occur after falls. Spinal trauma, although rare, has also been reported as the result of inflicted injury [Diamond et al., 1994; Ghatan and Ellenbogen, 2002; Ranjith et al., 1998; Rooks et al., 2002; Swischuk, 1969].

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Intracranial Injuries Extra-axial Collections In most severely injured children, initial CT scan reveals intracranial abnormalities, most often acute subdural hematoma, cerebral hypodensity, and intraparenchymal hemorrhage (Figs. 63-8, 63-9, and 63-10; see also Figs. 63-1A and 63-15) [Cohen et al., 1985].

SUBDURAL HEMATOMA Regardless of etiology, subdural hematomas are the most common intracranial pathologic processes in inflicted head injury observed in 38% to 100% of infants and young children with inflicted neurotrauma [Biousse et al., 2002; Dias et al., 1998; Dykes, 1986; Duhaime et al., 1992; Gjerris, 1986; Hadley et al., 1989; Hahn et al., 1983; Ludwig and Warman, 1984; Shugerman et al., 1996]. In fatal cases, some blood is almost always present in the subdural potential space. Subdural hematomas develop from several mechanisms, alone or in combination, including the tearing of bridging veins extending from the cortex to the dural sinuses (particularly the superior sagittal sinus), injured surface vessels (about 10%), and dural lacerations [Gennarelli et al., 1982; Shenkin, 1982; Stålhammer, 1986]. Acute subdural hematomas liquefy and are resorbed, become chronic and eventually calcify, or persist as chronic subdural effusions (see the following section). These either are space occupying, in

FIGURE 63-8. Nonenhanced computed tomographic scan of an 11-monthold infant admitted with acute loss of consciousness and apnea with no history of trauma. The scan, obtained shortly after arrival, demonstrates an acute right convexity subdural hematoma with ipsilateral hemispheric swelling and mild midline shift.

FIGURE 63-9. Nonenhanced computed tomographic scan of an acute interhemispheric subdural hematoma.

FIGURE 63-10. Nonenhanced computed tomographic scan with an acute mixed-density right subdural hematoma. Blood is layering inferiorly. There is associated subjacent hemispheric swelling and midline shift. Incidental acute post-traumatic hydrocephalus is present in the left ventricular system.

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FIGURE 63-11. Nonenhanced computed tomographic scan of a 9-monthold infant admitted with macrocrania, seizures, and irritability. The scan reveals bilateral acute and chronic subdural hematoma. Ventricles are mildly enlarged.

the case of evolving cerebral atrophy, or in some cases are thought to persist as a result of abnormalities in clotting within the subdural collection. On occasion, acute subdural hematomas resolve rapidly, in 1 to 2 days [Duhaime et al., 1996a]. Extra-axial collections that mimic subdural hematoma include venous epidural collections from contact, as well as subarachnoid collections [Duhaime et al., 1996a]. Subdural hematomas associated with inflicted injuries in children are typically interhemispheric, unilateral, or bilateral over the frontoparietal convexities (see Figs. 63-1, 63-8, 63-9, 63-10, and 63-15) [Biousse et al., 2002]. Interhemispheric or falcine subdural hematomas are particularly suspect for inflicted injury and have not been reported after

mild or moderate head injury, although they are observed clinically after moderate-to-severe accidental traumatic head injury (see Figs. 63-8 and 63-9) [Tzioumi and Oates, 1998]. Significant convexity or interhemispheric subdural hematomas with associated neurologic signs are extremely rare as a result of any etiology other than trauma. Mixed-density subdural hematomas are more likely to result from a rapidly accumulating blood collection or from settling, washout, or compartmentalization of hemorrhage products than from repetitive injury events (Fig. 63-11; see also Figs. 63-10 and 63-15) [Greenberg et al., 1985; Sargent et al., 1996]. Cerebrospinal fluid mixed with blood in a subdural hematoma may also appear to be of mixed density (see Fig. 63-10) [Vinchon et al., 2002; Zouros et al., 2004]. In subdural hematomas that fail to organize, both acute and subacute components are found within the chronic hematoma. The presence of acute blood in a chronic hematoma does not necessarily mean that acute significant trauma has occurred. Chronic subdural hematomas can bleed again with minimal or no trauma [Crooks, 1991; Sargent et al., 1996]. Careful attention to the history and clinical findings is necessary in this situation.

Chronic Subdural Effusions Proteinaceous subdural collections frequently evolve from resolving acute subdural hematomas in young infants (Figs. 63-13 and 63-14; see also Fig. 63-11). They may develop within days of the injury [Vinchon et al., 2002]. Sometimes referred to as hygromas, they either resolve with time or persist when there is diffuse brain injury with secondary atrophy [Hasegawa et al., 1992; Kaufman, 1993; Wetterling et al., 1988]. The use of the term hygroma is controversial [Wetterling et al., 1988]. Hygromas are defined as accumulations of fluid in the subdural space. They are variably attributed to resolving subdural hematomas or to abnormal collections of cerebrospinal fluid, alone or mixed with blood, in the subdural space [Zouros et al., 2004]. Analysis of attenuation coefficients on CT scan is often adequate for making the

FIGURE 63-12. Computed tomographic appearance of healed white matter tears in the bifrontal regions.

Gilles and Duhaime / Inflicted Childhood Neurotrauma

diagnosis. If there is any question, MRI is the preferred technique, as it is accurate in determining whether extraaxial fluid is of cerebrospinal fluid intensity and whether fluid is in the subarachnoid or subdural space [Hasegawa et al., 1992; Wilms et al., 1993]. The majority of subdural collections resolve without intervention (see Fig. 63-14). Enlarged subarachnoid spaces in infants (also known as benign external hydrocephalus) can be differentiated from subdural hygromas or subdural hematomas on MRI by sulcal prominences, prominent basilar cisterns, and normal or minimally enlarged ventricles [Aoki, 1994]. These infants, typically younger than 1 year, present with macrocrania, usually have normal growth and development, and have no history of trauma [Mori et al., 1980; Nishimura et al., 1996].

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SUBARACHNOID HEMORRHAGE Small patchy areas of subarachnoid hemorrhages are almost universally found at postmortem examination in infants who die from inflicted injury [Case et al., 2001]. Subarachnoid hemorrhage develops after direct surface trauma to the brain or from leakage of blood from injured cerebral vessels within the subarachnoid space. They are difficult to identify with CT scans and to differentiate from subdural hematoma, especially when interhemispheric.

Differential of Extensive Subarachnoid Hemorrhage Among the conditions that can cause subarachnoid hemorrhages are vascular malformations, birth trauma, coagulopathy, meningitis, and unintentional trauma [Cohen et al., 1985; Govaert et al., 1990]. These are uncommon causes of subarachnoid hemorrhages, and, in the presence of extensive subarachnoid bleeding, vascular malformation is the most likely etiology. Vascular malformations, however, are an exceedingly rare cause of subarachnoid hemorrhage in young children [Crisostomo et al., 1986; Hayashi et al., 1994; Matson, 1965; Matsuzaka et al., 1989; Perret and Nishioka, 1966; Sedzimir, 1955]. Three large series, involving more than 10,000 patients with subarachnoid hemorrhages, identified no children aged 1 year or younger [Matson, 1965; Perret and Nishioka, 1966; Sedzimir, 1955].

EPIDURAL HEMATOMA

FIGURE 63-13. Nonenhanced computed tomographic scan obtained 2 weeks after admission with seizures, apnea, and left hemiparesis. There are bilateral extra-axial collections consistent with subdural hematoma and ischemia caused by right posterior cerebral artery infarction.

A

B

Epidural hematoma is uncommon after trauma, especially after inflicted head injury [Shugerman et al., 1996; Schutzman et al., 1993]. It is discussed here to clarify its pathogenesis and clinical course. Epidural hematoma can occur after relatively minor trauma [Schutzman et al., 1993]. The majority of such hematomas develop adjacent to the middle meningeal artery or over the cerebral convexity, but they can also occur in the posterior fossa and are usually venous, rather than arterial, in this location. Skull fracture does not have to be present, particularly in an infant, whose increased skull compliance allows increased

C

FIGURE 63-14. Images of a 3-month-old presenting with a growing head and with rib fractures. The father admitted that he had thrown the infant across the room; the mother had “no idea.” Collections gradually resolved without intervention. A, Magnetic resonance image (MRI) with chronic subdural collections (arrow). B, T2-weighted MRI with corpus callosal tear. C, Gradient echo-sequence coronal MRI depicting tear of a convexity bridging vein (arrow).

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skull deformation at the impact site [Shugerman et al., 1996]. Symptom progression varies from dramatic to more protracted, paralleling the rate of epidural accumulation. Children with epidural hematomas are much more likely to have a lucid interval and do well clinically than are severely abused infants (see also “Timing of Injuries” section) [Schutzman et al., 1993]. This finding is congruent with the biomechanics of injury because epidural hematomas result primarily from brief linear deceleration impacts, such as falls [Shugerman et al., 1996; Schutzman et al., 1993]. Locally deforming forces do not usually injure brain parenchyma away from the impact site. Children with epi-

A

C

dural hematomas typically do well with prompt surgical intervention when needed and aggressive supportive care.

Cerebral Injuries SWELLING OR EDEMA Diffuse or focal brain hypodensity is the most common parenchymal pattern found on initial CT imaging [Kazan et al., 1997; Rao et al., 1999]. Traumatic brainstem lesions are quite rare [Eder et al., 2000]. Younger infants are more likely to present with diffuse hypodensity, with or without bilateral acute subdural hematomas (see Figs. 63-1 and

B

D

E

FIGURE 63-15. Images of a 4-year-old who was picked up, strangled, and thrown, hitting the occiput on a marble coffee table edge. A, Right eye: predominantly nerve fiber layer and three subhyaloid retinal hemorrhages. B, Left eye: three retinal hemorrhages less than 2 optic disc diameters from the optic nerve. C, Computed tomographic scan within 3 hours of the event: acute right convexity subdural hematoma with hemispheric hypoattenuation, midline shift, and early hydrocephalus of the left temporal horn. D and E, Axial T1-weighted (1.5 T; repetition time = 500 msec; echo time = 10 msec) and T2-weighted (1.5 T; recovery time = 3300 msec; echo time = 90 msec) magnetic resonance images from the same patient 3 months after injury. Scans demonstrate evolving right hemispheric and left frontal infarct and atrophy with encephalomalacia of the right hemisphere and compensatory ventriculomegaly.

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63-14), whereas older infants and children more often present with focal or hemispheric brain swelling and ipsilateral acute subdural hematomas (Fig. 63-15; see also Fig. 63-10) [Aldrich et al., 1992; Bruce et al., 1981; Gilles and Nelson, 1998; Kemp et al., 2003; Rao et al., 1999]. The particular pattern of bilateral hypodensity involving the entire hemisphere is rare in adults and likely reflects a specific pathophysiologic process that is still incompletely understood [Duhaime et al., 1993; Duhaime et al., 1998; Han et al., 1990; Kazan et al., 1997; Rao et al., 1999]. Focal swelling has several patterns: hemispheric subjacent to an ipsilateral acute subdural hematoma or, less often, in a vascular distribution from an evolving infarction, or patchy scan hypodensity that is not in a vascular distribution. None of these patterns is specific for abuse [Lobato et al., 1988; Sarabia et al., 1988; Tomita et al., 1997]. Although there is a tendency to infer that focal brain swelling equates to localized brain injury, the finding of persistent coma in severely injured children in the absence of significant midline shift is supportive evidence that diffuse injury has also occurred. The etiology of hemispheric swelling and secondary necrosis subjacent to an acute subdural hematoma is not understood, although local pressure effects in addition to compromised cerebral blood flow in the involved hemisphere are thought to contribute to evolving edema and increased intracranial pressure [Miller et al., 1990; Orlin et al., 1992; Salvant and Muizelaar, 1993; Schröder et al., 1994; Tomita et al., 1997; Tornheim et al., 1983; Xu et al., 1993]. Strangulation has been proposed as a causal mechanism of brain swelling, particularly hemispheric swelling, but corroborative clinical data are scanty (Figs. 63-16 and 63-17) [Bird et al., 1987; Bonnier et al., 1995; Drack et al., 1999; Duhaime et al., 1996b; Gilles and Nelson, 1998]. Circumferential strangulation in a young child can simultaneously compress carotid and vertebral arteries (the carotid arteries by anterior neck compression and the vertebral arteries as they pass through the scaleni muscles) [Rossen et al., 1943]. Traumatic vascular injury secondary to strangulation should be diagnosed only if there is unequivocal clinical, imaging, or postmortem examination evidence.

FIGURE 63-16. Strangulation injuries in a 4-year-old child. Note the thumbprints on the anterior neck and finger bruising along the mandible. Difficult to discern are the petechiae that are prominent around the neck and over the face.

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FIGURE 63-17. Three-year-old child injured because of a toileting accident. He was beaten and thrown against the wall. A unique pattern injury is present on the anterior neck consisting of the markings on the watchband.

DIFFUSE AXONAL INJURY Diffuse axonal shear injury is an important determinant of clinical status and outcome from nonmissile head injury [Adams et al., 1982; Hammoud and Wasserman, 2002; Strich, 1961]. It is a common feature of severe traumatic brain injury in older children and adults; its frequency is not established in infants, and there is conflicting evidence about its importance in inflicted head injury [Tokutomi et al., 1997; Tong et al., 2004]. Vowles and associates [1987] described diffuse axonal shear injury in infants younger than 5 months of age. More recently, however, Geddes and coworkers [2001b] found diffuse axonal shear injury in only 2 of 37 infants younger than 9 months who died from inflicted head injury. Major angular deceleration forces are required. The most common accidental cause is a highspeed motor vehicle crash or a pedestrian struck by a highvelocity vehicle. It occurs at the moment of injury and, when severe, is associated with loss of consciousness at the moment of impact [Adams et al., 1977; Gennarelli, 1993]. Imaging findings of shear injuries include punctate hemorrhages particularly in the white matter, and tearing of the corpus callosum (see Fig. 63-14) [Mendelsohn et al., 1992].

CEREBRAL CONTUSIONS An infant younger than 8 months is much less likely to develop cortical contusions in coup or contrecoup locations

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Brain Injury and Disorders of Consciousness / 63 FIGURE 63-18. Gross specimens from a 2-month-old infant with multiple acute white matter contusions of the left hemisphere. One contusion is marked.

than are older children and adults [Lindenberg and Freytag, 1969]. The incidence of contrecoup injuries rises rapidly from later infancy to 3 years of age, when it begins to approximate that of the adult [Digraham et al., 1989; McLaurin and Tutor, 1961]. On occasion, young infants present with white matter tears, also referred to as white matter contusional tears or gliding contusions, which presumably are the result of rotational shearing forces [Calder et al., 1984; Jaspan et al., 1992; Lindenberg and Freytag, 1969; Vowles et al., 1987]. Contusional tears occur where shear strain is greatest: namely, deep to the gray matter–white matter junction (Fig. 63-18; see also Fig. 63-12) [Calder et al., 1984; Gentry et al., 1988; Jaspan et al., 1992; Lindenberg and Freytag, 1969]. From 1 to 3 cm in length, they are most often located in the frontal and temporal lobes, although they may be seen throughout the brain [Lindenberg and Freytag, 1969]. These tears are considerably larger than the tissue tear hemorrhages in the adult brain after closed-head injury that are punctate and are found most often in the periventricular white matter, corpus callosum, and brainstem [Wilberger et al., 1990]. When white matter tears are filled with fresh blood, they may be mistaken for parenchymal hemorrhages (rare in childhood inflicted or unintentional head injury). In an acutely swollen brain, white matter contusional tears may be difficult to visualize on CT or magnetic resonance imaging [Gentry et al., 1988]. They are more easily visualized on follow-up imaging studies, in which they appear as slitlike or oval lesions within the cerebral parenchyma (see Fig. 63-12).

CEREBRAL INFARCTION Post-traumatic cerebral infarction develops after traumatic brain injury in both children and adults, predominantly as a result of vascular compression and herniation [Gilles and Nelson, 1998; Mirvis et al., 1990; Server et al., 2001]. The extent of infarction is correlated with poor outcome [Gilles and Nelson, 1998; Server et al., 2001]. Post-traumatic cerebral infarction after inflicted head injury has received relatively little attention [Bird et al., 1987; Gilles and Nelson, 1998; Zimmerman et al., 1979]. Posterior cerebral artery and branch anterior cerebral artery distribution infarctions predominate (see Figs. 63-13 and 63-15). Infarction in the lenticulostriate-thalamoperforating distribution leads to basal ganglia and thalamic injury. Hemispheric necrosis and border zone infarction are other prominent patterns (see Fig. 63-15). Strangulation is not a common cause of cerebral infarction in this setting [Gilles and Nelson, 1998].

DIFFERENTIAL DIAGNOSIS The range of clinical and physical findings is unique to inflicted neurotrauma. Falls and birth trauma are the most frequently offered explanations for injury, but these are uncommon causes of severe brain injury [Duhaime et al., 1992; Feldman et al., 2001; Hobbs, 1984; Meservy et al., 1987]. It is uncommon for infants to suffer severe brain injuries from nonaccidental mechanisms. Significant applied forces are required, such as those sustained in a vertical fall

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greater than 10 feet or a high-speed motor vehicle accident [Meservy et al., 1987; Williams, 1991]. Birth trauma is usually excluded as a reasonable explanation by the clinical course and imaging findings.

Falls Fall data can be grouped into short falls (less than 4 feet), falls down stairs, falls from heights, and walker falls. These data overwhelmingly support the conclusion that severe traumatic brain injury and severe retinal hemorrhages are unlikely to result from household falls, although venous or arterial extra-axial hemorrhages may occur in both younger and older children through this mechanism [Betz et al., 1996; Duhaime et al., 1992; Elder et al., 1991; Hobbs, 1984; Johnson et al., 1993; Kravitz et al., 1969; Nimityongskul and Anderson, 1987; Paret et al., 1999; Williams, 1991]. Fall data should be interpreted cautiously. The majority of data in the studies just cited were collected retrospectively without consistent evaluation protocols. Routine neuroimaging was not performed in children who were not clinically symptomatic; thus, intracranial injuries, such as small, insignificant subdural hematoma, would have been missed [Doezema et al., 1991].

Short Falls Short falls are generally low-impact, low-velocity injuries. The most common findings are concussions, scalp contusions, some fractures, an occasional epidural hematoma, and an occasional focal subarachnoid hemorrhage. In falls of less than 2 feet that involve fracture, clavicle fractures predominate; skull fractures are more common in falls of 2 to 4 feet. In four studies, with a total of 917 short falls (ranging from 1 to 5 feet), there were seven skull fractures, four clavicle fractures, and one humerus fracture [Musemeche et al., 1991; Roshkow et al., 1990]. Except for epidural hematoma, which can be a lifethreatening injury if not treated promptly, household free falls from furniture or other surfaces, with a head-to-ground distance of less than 3 feet, do not appear to result in serious injury or in significant primary brain injuries [Duhaime et al., 1992]. Falls 2 to 4 feet onto a hard surface, such as pavement, cement, linoleum, and wood, have on rare occasion resulted in complicated fractures in infants younger than 6 months [Lyons and Oates, 1993; Nimityongskul and Anderson, 1987; Reiber, 1993; Rivara et al., 1996]. Studies suggesting that serious, life-threatening injury can occur in children allegedly falling from short distances have typically relied on uncorroborated histories given by caretakers. Uncorroborated falls have a six times greater rate of serious injury, which suggests that the history was, in fact, suspect [Chadwick et al., 1991]. Small extra-axial hemorrhages can develop after simple falls. These are typically located directly under the impact site and likely result from direct injury of the surface blood vessels. Affected children have no physical injuries except those consistent with the single focal impact (e.g., soft tissue swelling, cephalohematoma, or linear nondisplaced skull fractures). In very rare cases, a complicated short fall, usually with impact to the occiput, results in more severe injury.

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Falls down Stairs Children falling down stairs (or infants dropped while being carried down stairs) most often have either no injury or fractures of the skull or extremities [Chiavello et al., 1994; Joffe and Ludwig, 1988]. Stairway falls usually are less serious than free falls of the same vertical distance [Joffe and Ludwig, 1988]. No correlation exists between the number of steps and the severity of injury. Most children who fall down stairs tumble and never develop significant acceleration, but exceptions to this general rule do exist, and the specific injuries depend on the exact mechanism and forces involved.

Falls from Heights Children falling from heights differ from children who have been maltreated or who have had minor falls [Roshkow et al., 1990; Musemeche et al., 1991; Reiber, 1993; Williams, 1991]. Extremity injuries again outnumber head injuries, and, overall, children recover better than adults. Rare injuries from falls include superior sagittal sinus rupture after impact to the vertex of the cranium (Fig. 63-19). The brain and skull accelerate at the same rate in a high free fall. The brain may escape major injury, and the skull may shatter with impact because the skull absorbs much of the translational energy and there is little rotational component [Lindenberg, 1973]. In infants and young children, inward deformity of the skull may cause significant surface

FIGURE 63-19. Seventeen-month-old child who fell from an unprotected 8foot high porch onto a 2 × 4 piece of wood and suffered immediate sustained loss of consciousness and posturing. Nonenhanced computed tomographic scan is notable for a subgaleal hematoma and extensive right frontal cerebral contusion with an overlying subdural hematoma. Not well seen is an extensive right superior frontal fracture that runs into and splits the metopic suture. There is significant hemispheric swelling on the right with marked midline shift and an associated superior sagittal sinus laceration. This injury proved to be fatal.

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trauma when falls are from major heights (such as out windows). Comminuted skull fracture with surface brain contusion, subarachnoid hemorrhage, or both in older children is consistent with a history of a high free fall. Venous or arterial epidural hemorrhages may occur in both older and younger children through this mechanism.

Walker Falls Walkers continue to be widely used in this country despite the substantial amount of data detailing their risks [American Academy of Pediatrics, 2001; Chiavello et al., 1994; Emanuelson, 2003; Partington et al., 1991; Smith et al., 1997]. Mechanisms of injury include tipping over and walker falls down stairs [Ridenour, 1999]. The most common injuries are extremity trauma, bruises, skull and other fractures, and minor concussions. Some children with significant velocities can develop more significant intracranial injuries, including subdural hemorrhages and growing fractures.

Birth Trauma Stresses applied to the cranial vault and its coverings during the birth process are an uncommon cause of a number of injuries [Shapiro and Smith, 1993]. Extracranial injuries predominate, including caput succedaneum, cephalohematomas, and subgaleal hematomas. Skull fractures, found after vaginal delivery, forceps use, or cesarean section, are generally either linear or depressed. Complicated skull fractures usually herald serious intracranial pathologic processes. Epidural and subdural hematomas, subarachnoid hemorrhage, and intracerebral hemorrhage have all been reported [Hayashi et al., 1987; Shapiro and Smith, 1993]. Subdural hematomas are usually associated with a difficult delivery or an infant large for gestational age. Approximately 70% of neonates with subdural hematoma have good outcome, which is consistent with the absence of associated primary cerebral injury [Hayashi et al., 1987]. Eleven percent to 50% of full-term newborns have retinal hemorrhages after vaginal delivery [Baum and Bulpitt, 1970; Egge et al., 1980; Emerson et al., 2001; Govind et al., 1989; O’Leary et al., 1986]. These have been hypothesized to be a consequence of molding and compression of the cavernous sinus, but exactly how they develop is unknown [Ehrenfest, 1922]. Retinal hemorrhages are more frequent after complicated or traumatic births (such as those involving vacuum extraction), protracted labor, and prematurity [Demissie et al., 2004; Egge et al., 1980; Ehrenfest, 1922; Emerson et al., 2001; O’Leary et al., 1986; Sezen, 1971; Williams et al., 1993]. Types of hemorrhage are equivalent to those in infants with inflicted injuries (flame, dotand-blot, subhyaloid) but are rarely severe and are not usually associated with visual loss [Baum and Bulpitt, 1970; Ehrenfest, 1922; Sezen, 1971; Zwaan et al., 1997]. Infants injured during the birth process exhibit symptoms in the perinatal period, which makes the differentiation from the abused infant fairly straightforward unless the infant is just a couple of weeks old. Review of the maternal and infant birth records, as well as any pediatric records, is exceedingly helpful. This review can firmly establish any birth-related complications or other conditions that were or were not factors contributing to the acute clinical presentation.

Neurometabolic Disease There are rare case reports of infants with metabolic disease who present with signs and symptoms that are misdiagnosed as abusive injury. Careful history taking, physical examination, and imaging characteristics usually suggest metabolic disease as a differential possibility. Infants with glutaricaciduria type 1 may present with macrocephaly, subdural effusions, and spasticity [Drigo et al., 1996; Kimura et al., 1994; Land et al., 1992; Osaka et al., 1993]. The infants in these studies had other neuroimaging features of organic acidurias: namely, widened operculae and alterations of signal intensity in the basal ganglia [Brismar and Ozand, 1994]. Menkes’ disease may also manifest in infancy with subdural fluid collections and severe neurologic findings such as seizures and developmental delay [Nassogne et al., 2002]. Ganesh and coworkers [2004] reported three infants with type I osteogenesis imperfecta who presented with small subdural hematoma and retinal hemorrhages after minor trauma. These conditions are extremely rare causes of extra-axial fluid collections. Metabolic screening tests should be considered in infants presenting with somnolence, vomiting, seizures, dystonia, or dyskinesia and extra-axial fluid collections (either subdural effusion or subdural hematoma), particularly if ketoacidosis is present.

CLINICAL ASSESSMENT AND MANAGEMENT A detailed history of the circumstances of the injury and a timeline of the infant’s behavior for a minimum of the 72 hours preceding the injury is invaluable. This history should be documented in a legible summary, with quotations from caregivers as much as possible. Histories of minor injury should be closely examined, and any available caretakers should be questioned independently if at all possible. The biomechanical history of the fall should include details such as the specific surface onto which the child fell, the location and type or types of injury, and the presence of corroborative witnesses [Duhaime et al., 1992]. It is also useful to ask about exactly what happened after the event— “What did the child look like?” “What position was he or she in?” “What did he or she do next?” “What happened then?”— and so on, until the child arrived at a medical center. Also relevant are the age of the child and the baseline gross motor and language development level (e.g., “Can the child crawl, stand, walk, or run?” “Can the child talk in words?”).

General Examination After initial coma scale scoring and resuscitative efforts, an extensive physical examination should be completed. Although the Glasgow Coma Scale is the measure most commonly used, it actually has poor interobserver variability in infants. The Infant Face Scale is a coma scale designed specifically in an attempt to correctly identify seriously injured infants who have sustained inflicted or other types of traumatic brain injuries, and it has improved interobserver variability in comparison with other impairment scales [Durham et al., 2000a]. All vital signs, including rectal temperature, should be measured. Growth parameters, including head circumfer-

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ence, state of hydration, and any obvious signs of neglect, need to be documented. The examiner should palpate and inspect all skin surfaces, particularly the cranium, behind the ears, and the occiput. The presence of otorrhea and rhinorrhea can be easily confirmed as cerebrospinal fluid with a Clinitest that reveals increased glucose concentration. Battle’s sign (bruising over the mastoid) or “raccoon eyes” (periorbital ecchymoses) are suggestive of a basilar skull fracture. Hemotympanum can result either from direct impact over the ear or from basilar fracture. The examiner should inspect the frenula and the palate for tears and petechiae; forced feeding, smothering, and gagging can cause these injuries. Any unusual pattern of injuries should be documented (see Figs. 63-16 and 63-17). Classic features of asphyxia are facial cyanosis, petechial hemorrhages of the eyes and face, foam in the nose and mouth, and prominent bulging eyes [Matsumura and Ito, 1996; Taff et al., 1996]. All or some of these features may be present, depending on the amount of force applied to the neck, its rate and duration, and the surface area involved. Decreased carotid pulsations ipsilateral to neck bruising are suggestive of carotid injury. The neck should also be inspected closely, particularly along the mandible, to assess for subtle signs of strangulation. The examiner should note the location and extent of any skin lesions, including bruises and bite marks. Bruises involving skin surfaces that are fairly protected, such as inner arms and other flexor surfaces, buttocks, and lower back, are of particular concern [Pascoe et al., 1979; Roberton et al., 1982]. A history of a simple fall is incongruous with multiple bruises of the same or different age if the bruises are on multiple and different body planes. Documentation includes both a complete written record of the examiner’s involvement with the child, as well as appropriate photographic documentation [Dubowitz and Bross, 1992].

Neurologic Examination Neurologic examinations, including level of coma, should be documented sequentially (see Chapter 61). Serial funduscopic examinations are useful for documenting the final extent of retinal hemorrhage development. Particular attention needs to be given to identifying and documenting asymmetries on the examination. Children younger than 3 years are particularly at risk for spinal cord injury without radiographic findings and should also be carefully examined for possible spinal cord or vertebral injuries, with MRI if indicated [Cirak et al., 2004].

Autonomic and Neuroendocrine Responses Traumatic brain injury and other critical illnesses are potent activators of the hypothalamic-pituitary-adrenal axis and the sympathetic efferent pathways [Chiolero and Berger, 1994; Reincke et al., 1993]. As injury severity increases, loss of adaptive negative feedback control mechanisms results in sustained activity of either or both of these pathways [Arita et al., 1993; Clifton et al., 1983; Koiv et al., 1997]. Autonomic cardiac control in children with traumatic brain injury is disrupted in proportion to the severity of injury, with autonomic uncoupling potentiated in young children [Biswas et al., 2000; Goldstein et al., 1996]. When

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efferent sympathetic pathways are completely interrupted, heart rate variability is lost and low-frequency heart rate power decreases; these findings are highly correlated with brain death in both children and adults [Baillard et al., 2002; Goldstein et al., 1996]. Young infants may develop evidence of hypopituitarism or adrenal insufficiency during their post-injury course.

Clinical Laboratory Evaluation Infants who have sustained inflicted head injuries are frequently anemic and acidotic on admission. Leukocytosis is not uncommon. As in adults, hyperglycemia at presentation has been associated with a poor prognosis and more severe head injury, and it is also suggestive of more recent injury [Atkinson, 2000; Michaud et al., 1991; Paret et al., 1999]. Some data suggest that the serum glucose level is optimally maintained between 100 and 200 mg/dL, which may require an insulin infusion. As in other head-injured populations, secondary consumptive coagulopathy (disseminated intravascular coagulation) is associated with a higher mortality rate and more severe brain injury [Hulka et al., 1996]. More commonly, mild elevations of the prothrombin time or evidence of activated coagulation may be found [Hymel et al., 1997]. These abnormalities do not appear to reflect preexisting coagulation abnormalities. In situations in which a clinical index of suspicion arises or an alternative diagnosis has been proposed, such as an inherited metabolic disease, additional studies or consultation with a metabolic geneticist may be useful.

Biochemical Markers A number of biomarkers (e.g., lactate, S-100B protein, neuron-specific enolase) have been proposed as indexes of severity of injury in several disorders, including brain injury, stroke, and neonatal encephalopathy [Ashwal et al., 2000]. Of these, S-100B protein, a glial marker, and neuronspecific enolase, a neuronal glycolytic enzyme, are most specific to traumatic brain injury. Neuron-specific enolase is a nonspecific indicator of neuronal injury and ischemia, correlated with both reversible and irreversible damage after traumatic brain injury, stroke, cardiorespiratory arrest, and perinatal hypoxicischemic injury [Blennow et al., 2001; Butterworth et al., 1996; Correale et al., 1998; Fridriksson et al., 2000; Herrmann et al., 2000; Martens et al., 1998; McKeating et al., 1998; O’Regan and Brown, 1998; Raabe et al., 1998]. Transient elevations have been documented just before elevations in intracranial pressure, after cardiac surgery, after seizures, and after both convulsive and nonconvulsive status epilepticus [Correale et al., 1998; O’Regan and Brown, 1998; Schmitt et al., 1998; Woertgen et al., 1997]. Fridriksson and associates [2000] were the first to evaluate neuron-specific enolase as a biomarker in childhood traumatic brain injury. Mean neuron-specific enolase levels were significantly higher in children with an intracranial lesion (26.7 ± 21.4 versus 17.7 ± 7.8). Sensitivity of neuron-specific enolase at a level of 15.3 was 77% and specificity was 52%, with a negative predictive value of 74%. Acute inflammatory responses to traumatic brain injury are characterized by upregulation of adhesion molecules on

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cerebrovascular endothelium and production of cytokines [Morganti-Kossmann et al., 2002; Woiciechowsky et al., 2002; Yakovlev and Faden, 1995]. Investigations have documented significantly greater increases in adhesion molecules (P-selectin), interleukin-8, and interleukin-10 in children younger than 4 years of age and those with inflicted head injury [Bell et al., 1997, 1999; Whalen et al., 1998, 2000]. The clinical significance of these findings is not clear. Elevations of biomarkers do not differentiate whether an injury was inflicted or unintentional. Infants with inflicted traumatic brain injury have a greater ischemic load; greater increases in markers of neuronal and glial injury or of enhanced inflammatory and biochemical cascades likely reflect the severity of injury. Whether this is also related to patient age remains unknown [Ruppel et al., 2001].

Radiographic Evaluation A noncontrast CT scan to include bone windows is the initial imaging study of choice [Bernardi et al., 1993]. A CT scan may miss skull fractures within the plane of the section, so skull films should be considered as part of the skeletal survey. Repeat or serial imaging is often helpful in establishing the extent of injury [Demaerel et al., 2002; Dias et al., 1998; Feldman et al., 1995]. MRI is more sensitive in defining the extent of hemorrhagic and nonhemorrhagic injury, demonstrating infarctions and delineating small extra-axial collections [Ball, 1989; Bernardi et al., 1993; Bigler, 2001; Biousse et al., 2002; Gean, 1994; Sato et al., 1989; Suh et al., 2001]. MRI is also helpful in delineating intracranial sequelae of abuse. Specific MRI sequences include diffusion-weighted imaging, T2-weighted gradient echo, T2-weighted spin echo, and susceptibility-weighted imaging [Biousse et al., 2002; Gerber et al., 2004; Huisman et al., 2003; Suh et al., 2001; Tong et al., 2004]. If carotid or vertebral injury is suspected, MRI and angiography are useful. Tong and associates [2004] described a high-resolution MRI susceptibility-weighted technique sensitive for detecting hemorrhagic diffuse axonal injury in children. A full skeletal survey should be obtained in any child younger than 2 years or in any older child with multiple traumatic injuries suspected to be nonaccidental in origin [Demaerel et al., 2002]. A bone scan may be indicated in equivocal or negative cases with a high level of suspicion; follow-up skeletal survey may also be useful [Howard et al., 1990; Kleinman, 1990; Mandelstam et al., 2003]. There is considerable variability in the radiologic interpretation of neuroimaging data [Hymel et al., 1997]. Limited clinicopathologic studies have been published to date, and caution should be exercised in relying only on imaging to establish timing of injury. It is strongly recommended that clinicians review the neuroimaging themselves, in addition to obtaining a radiologist’s interpretation.

MAKING THE DIAGNOSIS OF INFLICTED HEAD INJURY General Considerations Establishing the diagnosis of inflicted trauma is frequently problematic and requires a high index of suspicion. Children

Box 63-4 KEY QUESTIONS IN THE EVALUATION OF THE CHILD WITH SUSPECTED ABUSE What is the distribution of injuries? Are the injuries confined to the head? Are the brain injuries focal, diffuse, or both? What is the clinical timing of the injury? Are there injuries that suggest a specific injury mechanism (slap mark, strangulation bruising, etc.)? Are there other suspicious patterns of injury (e.g., rib fractures)? What forces were necessary to cause such injuries? Is the history congruent with the physical injuries? Is there an accidental mechanism that would explain these injuries? Is there a nonaccidental mechanism that would explain these injuries? Is there evidence of injuries of varying ages (e.g., old bite marks)? Was there a delay in seeking medical attention? Was the injury witnessed? Are there more than one history for the injury or injuries? Changing histories? If there is suspicion of a nonaccidental etiology, has the child been reported to the hospital child abuse team and to the local child protective services? interface with the medical system at all points along their response curve after brain injury. It is unrealistic to expect findings in all children to be similar. Certain key questions should be asked and answered (Box 63-4). The physical findings in conjunction with historical features usually point to trauma as the most likely etiology. Obvious cases are those with clear and convincing findings. The combination of acute serious brain injury, retinal hemorrhages, and posterior interhemispheric subdural hematomas appear to have greater specificity for an inflicted etiology but are not unique to inflicted injury. Evidence of impact is helpful in establishing inflicted injury when caregivers have specifically denied trauma. In the infant who survives, however, the absence of external scalp bruising, soft tissue swelling, or skull fracture does not conclusively exclude blunt-force trauma, inasmuch as evidence of impact may be found only at postmortem examination. Severe, diffuse retinal hemorrhages, especially with retinal folds or detachments, in the setting of a trivial mechanism of injury in an otherwise healthy child is strongly suggestive of an abusive mechanism (for details, see the earlier “Retinal Hemorrhages” section) [Betz et al., 1996; Buys et al., 1992]. For example, a child with multiple skull fractures, acute subdural hematoma, brain swelling, and retinal hemorrhages with no history of trauma was abused and does not have a rare arteriovenous malformation [also see Chadwick and Krous, 1997, for additional case studies]. The presence of certain fracture patterns, such as rib fractures or metaphyseal injuries of the long bones, helps exclude accident or disease as alternative causes of the intracranial pathologic processes [Hahn et al., 1988a]. Conversely, the fewer markers of injury and the more nonspecific the history, the more difficult it is to distinguish inflicted from unintentional injury [Morris et al., 2000].

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Box 63-5 FACTORS ASSOCIATED WITH AN INflICTED ETIOLOGY Age younger than 1 year Greater severity of illness Unexplained injuries A biomechanically inconsistent history A changing history or one inconsistent with the child’s developmental level A delay in seeking medical attention Parental risk factors History of past abuse and neglect Alcohol and drug use Previous social service intervention

Evaluating the History of the Injury or Injuries Histories provided to clinicians typically minimize actual injury events. Most often, there is either a history of minor trauma (such as a short fall with no neurologic symptoms) or no history at all [Chadwick et al., 1991; Dykes, 1986; Shugerman et al., 1996; Weston, 1973]. Changing histories, either by the same caregiver or by multiple caregivers, should also raise concerns. Typically, the actual injury and timeline of those events are understated, whereas descriptions of the clinical behaviors of the infant are accurate [Gilles and Nelson, 1998; Hettler and Greenes, 2003]. There are a number of clues that suggest an inflicted etiology (Box 63-5) [Bechtel et al., 2004; Duhaime et al., 1998; Feldman et al., 2001; Goldstein et al., 1993b; Hettler and Greenes, 2003; Tzioumi and Oates, 1998].

Timing of Injuries The timing of injury events in the still-living child can usually be estimated by using a combination of clinical course, physical findings, and imaging data, although best estimates are often insufficiently precise to eliminate all possible perpetrators. Children who sustain moderate to severe traumatic brain injury are almost always immediately symptomatic, often demonstrating an immediate apneustic response to mechanical events whether abused or not [Gilles and Nelson, 1998; Nashelsky and Dix, 1995; Willman et al., 1997; Zuccarello et al., 1985]. Persistence of coma, apnea or respiratory distress, irritability, seizures, hypotonia, and vomiting reflect the severity of injury and evolving secondary pathophysiologic cascades [Aldrich et al., 1992; Gilles and Nelson, 1998; Goldstein et al., 1993b; Johnson et al., 1995; Zuccarello et al., 1985]. Xanthochromic cerebrospinal fluid supernatant with elevated protein levels suggests that subarachnoid bleeding occurred at least 4 hours previously. Timing an injury by neuroimaging findings alone is difficult. Dias and associates [1998] found that the timing of injury could be determined by imaging findings to a reasonable certainty in only 50% of infants in a series of 33 with inflicted head injury.

Lucid Interval Issues The lucid interval consists of a period of clinical improvement after an initial loss of consciousness, followed by

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deterioration within minutes to hours. Lucid intervals occur in fewer than 3% of children after traumatic brain injury of all etiologies and generally imply a nonlethal injury if prompt care can be delivered [Bruce et al., 1981; Hahn et al., 1988a; Willman et al., 1997]. In Hahn and colleagues’ [1988] study, only 2.2% of 738 children aged 0 to 16 years (318 younger than 36 months) with head injuries had a lucid interval. Bruce and colleagues [1981] detailed the temporal course of the lucid interval in 23 patients. Eight children with Glasgow Coma Scale scores higher than 8 had a variable period of consciousness and speech, followed by the progressive loss of speech and decreased motor activity, but none progressed to coma. All 15 children with initial Glasgow Coma Scale scores lower than 8 were unconscious after trauma, had a period of improved consciousness, and then experienced rapid secondary deterioration within minutes to hours. In a study by Willman and associates [1997] of 95 accidental childhood head injury fatalities, it was obvious in all but one child that the injury was serious from time of injury until death. Only one child (who had an epidural hematoma) had a lucid interval.

Dating of Injuries by Neuroimaging Brain swelling may develop quite rapidly, even within 20 to 30 minutes, or more slowly [Dias et al., 1998; Gean, 1994; Kobrine et al., 1977; Waga et al., 1979]. Well-developed parenchymal abnormalities were already present on admission CT scans in nine infants whose injury had occurred within the previous 3 hours, which supports findings in the literature that evolution of cerebral parenchymal abnormalities occurs rapidly after injury [Dias et al., 1998; Duhaime et al., 1993; Lobato et al., 1988; Zimmerman et al., 1978]. In children dying from accidental head injury, Willman and associates [1997] found that head CT scans revealed cerebral hypodensity as early as 1 hour, 17 minutes after injury. Imaging criteria for the dating of subdural hematoma are discussed in detail elsewhere [Gean, 1994]. In general, hyperdense subdural collections on noncontrast CT imaging are less than 7 days old; isointense collections, 7 to 14 days old; and hypodense collections, more than 14 days old. Subdural neomembranes, visualized with contrast CT scans, begin to develop between 7 and 10 days after injury. Subdural hematomas may appear hypodense in the very anemic infant or if there is a mixture of cerebrospinal fluid with subdural blood. The degree to which the subdural membrane has consolidated at postmortem examination and the evolution of the subdural membrane is helpful in pinpointing the age of the collection. MRI, like CT scanning, cannot precisely date injuries, and the finding of blood of different intensities does not always mean that there has been repeated trauma, inasmuch as blood in various compartments may have different signal characteristics.

Medicolegal Issues Unlike the majority of medical diagnoses, differentiating inflicted from unintentional injury has significant medicolegal consequences, in addition to important prognostic and therapeutic implications. The diagnosis is most specific and sensitive when the event is witnessed or when there is major craniospinal trauma in the absence of any history. The

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diagnosis is less specific when there are particular patterns of injury that indicate a certain pathophysiologic process. Examples are strangulation evidence in the case of neck bruising and hyoid injury and white matter contusional tears in a young infant. Other pattern injuries that indicate blunt-force trauma are cord marks, bruising in unusual regions (such as abdomen or buttocks), human bites, acute genitoanal trauma, pulmonary or liver contusions, and certain rib and long bone fractures. Evidence of previous maltreatment or neglect is supportive of an inflicted etiology but does not necessarily assist in the determination of the perpetrator, unless he or she is the only caregiver. Mandated reporting laws require physicians and other health-care professionals to report patterns of injuries and behavior when reasonable suspicion of abuse or neglect arises. Reasonable suspicion does not mean that the clinician must be certain of the diagnosis; it means only that the clinical picture warrants full investigation and protection of the injured child and any siblings. Health-care providers actually fail to diagnose or misdiagnose about a third of inflicted head injuries in infants and children during initial examinations, especially when injuries are not severe [Jenny et al., 1999; Rubin et al., 2003]. The law protects the physician if suspicion should prove erroneous but was made in good faith. Conversely, failure to report both is actionable and places children at significant risk for further harm if they are returned to the setting in which they were injured [Rubin et al., 2003]. Although there is a cross-reporting mandate between social service and law enforcement officials, it may not happen immediately. When serious physical injury is suspected to have resulted from assault, notification of both law enforcement and social services is recommended. Translating complex information from the medical to the legal arena is a critical component of the evaluation of suspected inflicted head injury for the protection of the child, other siblings, and the alleged perpetrator [Chadwick and Krous, 1997]. This process begins with adequate written, photographic, and schematic documentation, and extends through communication with Child Protective Services, law enforcement agencies, legal counsel, and the judicial system. Investigating agencies want treating clinicians to know whether the injuries were inflicted or not, but the clinician is sometimes unable to say more than that the injuries are clearly traumatic in origin. If there is uncertainty about the significance or timing of particular findings, an expert opinion, usually from a child abuse team physician, neurosurgeon, child neurologist, or forensic neuropathologist with expertise in this area is often helpful. Ultimately, the diagnosis of inflicted injury relies on the constellation of physical findings, a history of injury that is biomechanically feasible, and the timing of injury.

CONCLUSION Inflicted childhood neurotrauma is a complicated form of neurotrauma with a well-defined continuum of injury findings. The pathophysiology of early life traumatic brain injury needs to be systematically investigated. Neurologic, clinical, and temporal indexes need to be defined in combination with laboratory and imaging data for all children

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CHAPTER 64

Hypoxic-Ischemic Encephalopathy in Infants and Older Children Ronald M. Perkin and Stephen Ashwal

Cardiopulmonary arrest in infants and children remains a significant cause of morbidity and mortality [Fink et al., 2004; Young et al., 2004]. The principal factor that influences outcome in survivors of cardiopulmonary arrest is the neurologic sequelae resulting from hypoxic-ischemic injury [Robertson et al., 2002]. This chapter reviews the pathophysiologic and clinical aspects of this disorder. Unfortunately, there are currently no interventions to reverse the cellular consequences of hypoxic-ischemic injury [Fink et al., 2004; Kochanek et al., 2001]. Therefore, most children surviving out-of-hospital cardiopulmonary arrest have serious neurologic sequelae [Michelson and Ashwal, 2003; Morris and Nadkarni, 2003; Schindler et al., 1996; Thompson et al., 1990; Young et al., 2004]. In addition, deaths of approximately 40% of infants and children with diagnoses of brain death are caused by severe asphyxial central nervous system (CNS) injury [Ashwal and Schneider, 1991; Parker et al., 1995]. In the United States, it is estimated that 16,000 children die annually of unexpected cardiopulmonary arrest [Fink et al., 2004]. In a review summarizing the results from 44 studies totaling 3094 pediatric patients after cardiopulmonary arrest, the overall rate of survival after cardiopulmonary arrest was 13% (24% of those with in-hospital arrest, 9% with out-of-hospital arrest), with unfavorable neurologic outcome in survivors for whom outcome was reported [Young and Seidel, 1999]. Fewer than 10% of patients were found to have ventricular tachycardia or fibrillation; most had asystole, bradycardia, or pulseless electrical activity as a consequence of asphyxia [Young et al., 2004; Young and Seidel, 1999]. In addition to physical debilitation in pediatric survivors of cardiopulmonary arrest and the emotional burden to family, there are also significant monetary and psychosocial burdens [Fink et al., 2004]. The lifelong cost for continued care of a moderately to severely disabled child can easily exceed $1 million [Ronco et al., 1995]. Asphyxial cardiac arrest in infants and children most commonly results from submersion accidents, airway obstruction, aspiration, severe acute asthma, and inhalation injury (Table 64-1 and Box 64-1). In asphyxia-induced cardiac arrest, cardiac standstill or pulseless electrical activity is preceded and precipitated by a period of anoxic or hypoxic perfusion. Ventricular fibrillation is a common cause of cardiopulmonary arrest in adults. In ventricular fibrillation–induced cardiac arrest, respiration ceases as a result of the loss of perfusion (ischemic hypoxia). Although ventricular fibrillation can occur in children, asphyxia is the most common cause of cardiopulmonary arrest and the primary cause of hypoxic-ischemic encephalopathy in children [O’Rourke, 1986; Torphy et al., 1984]. Ventricular

fibrillation–induced and asphyxia-induced cardiac arrest differ in pathophysiology despite having been traditionally grouped as cardiopulmonary arrests. Results of clinical trials in adult patients suggest that some degree of hypoxic-ischemic injury can be prevented if treatment is initiated early after cardiac arrest [Bernard et al., 2002]. However, whereas a cardiac etiology is the principal cause of cardiopulmonary arrest in adults, asphyxia is the principal cause of cardiopulmonary arrest in infants and children; it results in systemic hypoxemia, hypercapnia, acidosis, and, ultimately, hypotension and bradycardia, culminating in complete cardiovascular collapse [Young and Seidel, 1999]. Until recently, there was no contemporary age-appropriate pediatric model of hypoxic-ischemic injury for the evaluation of prolonged neurodegeneration and long-term neurologic outcome [Fink et al., 2004]. Such a model may be useful for the preclinical testing of novel and currently available interventions aimed at improving neurologic outcome in infants and children after cardiopulmonary arrest.

RESPONSE TO INADEQUATE OXYGEN DELIVERY: MECHANISMS OF INJURY In an attempt to explain the mechanisms involved in hypoxic-ischemic injury after cardiopulmonary arrest, several modes of injury that occur during ischemia and reperfusion must be considered: (1) brain energy failure, (2) calcium-mediated injury, (3) excitotoxic injury, (4) activation of intracellular proteases, (5) release of free fatty acids, (6) activation of nitric oxide synthesis, (7) formation of oxygen radicals, (8) reperfusion injury, and (9) genetic damage and regulation. In addition, there is accruing evidence that local inflammatory responses of microglia, macrophages, neutrophils, and prostaglandins are responsible for some of the neuronal injury after hypoxia-ischemia.

Brain Energy Failure The brain depends on large amounts of exogenous substrate (oxygen and glucose) because of its high metabolic demands, limited energy stores, and reliance on oxidative metabolism. Cellular energy depletion is postulated to be the triggering event that initiates the many cascades of injury that occur during ischemia [Krause et al., 1988]. Adenosine 5-triphosphate (ATP) is the energy source that drives all cellular physiologic processes [Bellamy et al., 1996; Sweeney et al., 1995]. One of the most vital processes performed is the preservation of ATP to maintain membrane ionic gradients [Ackerman and Clapham, 1997]. Under nor-

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TABLE 64-1 Etiology of Cardiac Arrest in Children ETIOLOGY

PATIENTS (%)

Submersion Sudden infant death syndrome Trauma Respiratory Sepsis Heart disease/arrhythmia Other/unknown

27 20 15 9 9 6 14

Data from Hickey et al., 1995, and Schindler et al., 1996.

Box 64-1 MAJOR CAUSES OF PEDIATRIC CARDIOPULMONARY ARREST Upper airway obstruction Croup Foreign body obstruction Supraglottitis Angioedema Trauma (blunt and penetrating) Abscess, bacterial infection Lower airway disease Drowning Inhalation injury Asthma Pneumonia Bronchiolitis Bronchopulmonary dysplasia Chest trauma Foreign body obstruction Neurologic Head trauma Central nervous system infection Botulism Cervical spine trauma Increased intracervical pressure Ventriculoperitoneal shunt obstruction Status epilepticus Cardiovascular Hypovolemic shock Septic shock Congenital heart defect Cardiogenic shock Dysrhythmias Myocarditis Pericardial effusion Other Sudden infant death syndrome Coronary artery disease Burns Intoxications Metabolic disorders mal conditions, maintenance of ionic gradients across the cell membrane accounts for nearly 50% of total cellular expenditure [Erecinska and Silver, 1989]. Interruption of cerebral blood flow results in loss of consciousness and reductions in electroencephalographic activity within

seconds. Within 5 to 7 minutes, complete energy failure occurs, accompanied by disturbances of neuronal and glial ion homeostasis, including sodium and water influx and efflux of potassium (Fig. 64-1). When the extracellular potassium concentration reaches a critical threshold, voltage-gated channels undergo depolarization, precipitating extracellular calcium influx [Sweeney et al., 1995]. If flow remains inadequate and energy failure persists, calcium-mediated events such as phospholipase and protease activation can lead to irreversible cellular injury and necrosis, as well as cerebral acidosis with elevated lactate levels and decreased hydrogen ion concentration (pH). If blood flow is restored, recovery of basal cellular metabolism (ATP levels, protein synthesis, oxygen consumption) and normal pH occurs if the ischemic injury is of limited duration [Ljunggren et al., 1974]. Certain neurons have long been known to be especially vulnerable to global hypoxic-ischemic insults, particularly the hippocampal CA1 and CA4 zones and cortical layers III and V [Krause et al., 1988; White et al., 1996]. Five minutes of complete global brain ischemia produces cell death in these regions within 48 to 72 hours. This time interval between ischemia and cell death consists of an early postischemic period when ATP and lactate levels recover, followed after 24 hours by a decrease in ATP levels and lactate reaccumulation [Kochanek, 1993; Siesjo et al., 1995]. After anoxia or ischemia, restoration of aerobic metabolism is essential but not sufficient for recovery. Despite global metabolic recovery, certain neurons progress to cell death. Restoration of blood flow and oxidative metabolism after energy failure in the brain leads to specific cellular and molecular dysfunction because of two related processes, cell necrosis and programmed cell death (i.e., apoptosis), both of which evolve during and after resuscitation [Hockenbery, 1995; Schnaper, 1994]. These processes, coupled with the need to restore highly integrated functions, explain the unfortunate clinical scenario of the vegetative state despite restoration of normal function in other organ systems. The relation of these two forms of cell death to selective vulnerability of neurons in the brain is beginning to emerge. A clinically relevant model of pediatric cardiopulmonary arrest that has been developed may prove useful for investigating mechanisms resulting in hypoxic-ischemic encephalopathy in the developing brain [Fink et al., 2004]. Cell necrosis, which is characterized by denaturation and coagulation of cellular proteins, is the basic pattern of pathologic cell death that results from progressive reduction in cellular ATP content [Buja et al., 1993; Sweeney et al., 1995]. Necrosis involves progressive derangements in energy and substrate metabolism that are followed by a series of morphologic alterations, including swelling of cells and organelles, development of subsurface cellular blebs, amorphous deposits in mitochondria, condensation of nuclear chromatin, and breaks in plasma and cell organelle membranes [Brierley et al., 1973]. It was traditionally assumed that all ischemic cell death occurred through this process and that selective vulnerability represented a specific predilection for the development of necrosis in certain neurons after transient ischemic insults. It has been demonstrated, however, that cell death after hypoxic-ischemic insults can occur by a second pathway: programmed cell death. Apoptosis has emerged as a mech-

Perkin and Ashwal / Hypoxic-Ischemic Encephalopathy in Infants and Older Children

Reduction in blood flow

Cellular ATP

Rise in ATP degradation products: adenosine hypoxanthine

Fall in membrane potentials

(

Release of K+ Extracellular K+)

Glutamate release

FIGURE 64-1. Global ischemia results in a cascade of events, including reduction in adenosine triphosphate (ATP), loss of cellular ionic gradients, increases in extracellular K+ concentration, glutamate release with activation of N-methyl-D-aspartate (NMDA) and non-NMDA receptors, calcium influx and release of intracellular calcium, and activation of secondary messenger systems and a variety of destructive enzymatic processes.

Activation of NMDA and non-NMDA receptors

Depolarization of adjacent cells

ATP consumption by Na+- K+-ATPase

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Activation of voltagedependent Ca2+ channels

Ca2+ influx

Activation of Ca2+ pumps

anism of cell death that plays an important role during development, in normal physiology, and in the pathogenesis of disease [Schnaper, 1994]. Apoptosis has been described as directed cell suicide [Hockenbery, 1995]. Its unique feature is that, although external events may trigger apoptosis, all of the machinery for the process is contained within the cell. Activation of this machinery may result from toxicity of the extracellular milieu, binding to a specific cell receptor, or removal of a factor that prevents apoptosis from occurring. Apoptosis is thus clearly distinct from necrosis (Box 64-2). Necrosis occurs despite the cell’s effort to survive. The development of programmed cell death involves new protein synthesis and the activation of endonucleases with a resultant characteristic cleavage of DNA at linkage regions between nucleosomes to form fragments of double-stranded DNA [Mackey et al., 1997]. Programmed cell death was classically described as associated with cell death during embryogenesis. The stimuli triggering programmed cell death are not clearly defined, although protease activation or oxidant injury to DNA has been proposed. Similarly, apoptosis may be involved in the pathophysiology of shock, trauma, and end-stage heart

Box 64-2 CELL DEATH MECHANISMS Necrosis Alterations of the extracellular environment Compromised membrane integrity due to adenosine triphosphate (ATP) depletion Nonspecific DNA degradation Apoptosis Gene-directed cellular self-destruction Protein synthesis is required Apoptotic cells require energy Specific DNA cleavage Multiple triggers

disease, in addition to ischemia [Narula et al., 1996; Rink et al., 1995]. Reports indicate that cell death in selectively vulnerable brain regions, such as the CA1 region of the hippocampus, after transient global brain ischemia, occurs by an apoptotic mechanism. After a global ischemic insult, DNA fragmentation is most pronounced in neurons of the CA1 region of the hippocampus, which suggests that apoptosis may play a role in both selective neuronal necrosis and delayed neuronal death [Nitatori et al., 1995]. The concept of delayed neuronal death is important because it implies that there is a window of opportunity for treatment after global ischemia. Programmed cell death in the post-ischemic brain is not limited to scattered neuronal death in what has traditionally been deemed selectively vulnerable regions; it is also seen in penumbral regions around evolving cerebral infarctions [Li et al., 1995]. The severity of the ischemic insult and other local factors likely determine whether an injured neuron recovers, undergoes programmed cell death, or dies a necrotic death. It is quite possible, although only a speculative notion, that after cardiopulmonary arrest and resuscitation, a continuum exists in neurons from recovery to necrosis that depends on the duration of the insult, the local milieu, and the given brain region. Nonetheless, in any given brain region, whether neuronal death is produced by necrosis, apoptosis, or both, a highly complex series of events is involved during the arrest and after restoration of spontaneous circulation. Because programmed cell death occurs in stages, there exist several potential strategies for reducing cell death [Kochanek et al., 2001].

Calcium-Mediated Injury Calcium plays a strategic role in the regulation of many cellular metabolic processes; therefore, the concentration of cytosolic free calcium is tightly controlled. Hypoxic-ischemic injury interrupts intracellular calcium homeostasis, which

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Intracellular Ca2+

Rate of ATP depletion

Activation of Ca2+dependent enzymes

Endonucleases

Phospholipases

Protein kinases

DNA fragmentation

Nitric oxide release

Lipid breakdown

Membrane damage

Arachidonic acid release

Prostaglandin and leukotriene formation

Free radical formations

Xanthine oxidase

Apoptosis

Induction of genes

Proteases

Cytoskeletal breakdown by attacking both structural and functional proteins of the cell

FIGURE 64-2. Increases in intracellular Ca2+ mediate several enzymatic pathways that cause cell injury, including those of protein kinases, proteases, phospholipases, nitric oxide synthase, other free radical synthesis, and endonucleases, as well as other second-messenger systems. The net effect is related to the severity and duration of ischemia and a series of complex events that results in cell necrosis and apoptosis, as well as other forms of partial injury that remain poorly understood. ATP, adenosine triphosphate.

results in massive increases in the intracellular concentration of calcium. This calcium accumulation is believed to promote irreversible cellular injury [Bellamy et al., 1996; Lipton et al., 1994] (Fig. 64-2). Transient calcium accumulation occurs in all cells during ischemia, but secondary irreversible accumulation occurs in the selectively vulnerable zones many hours later. Electrophysiologic studies demonstrate that delayed neuronal death is preceded by neuronal hyperactivity. It is hypothesized that ischemic and early post-ischemic calcium accumulation leads to complex series of derangements in cellular metabolism [Morgenstern and Pettigrew, 1997; Sweeney et al., 1995]. The intracellular accumulation of calcium (1) activates proteases, lipases, and endonucleases, which results in the breakdown of membrane phospholipids; (2) activates neuronal nitric oxide synthase, which results in nitric oxide production and, in the presence of superoxide, peroxynitrate formation; (3) damages mitochondria and uncouples oxidative phosphorylation; and (4) disrupts nucleic acid sequences. The disturbance of intracellular calcium homeostasis is recognized as a final common pathway of neuronal death, either necrotic or apoptotic. These conditions, in concert with excessive release of calcium-dependent excitatory neurotransmitters (glutamate, aspartate), lead to uncontrolled excitotoxicity and cell death.

Excitotoxic Injury During hypoxic-ischemic damage, pathologically prolonged membrane depolarization occurs and, in certain neuronal populations, leads to excessive release of neurotransmitters into the synaptic cleft [Lipton and Rosenberg, 1994; Rogers

and Kirsch, 1989]. The effect of these neurotransmitters is prolonged by failure of the ATP-dependent presynaptic re-uptake mechanisms. Glutamate and aspartate are the major excitatory amino acid neurotransmitters in the mammalian CNS; both also have neurotoxic properties [Rogers and Kirsch, 1989]. Hypoxia-induced neuronal death is mediated by synaptic activity. Inhibition of synaptic glutamate release or blockade of glutamate receptors may prevent hypoxic neuronal injury. Glutamate is the major neurotransmitter in the selectively vulnerable zones and accumulates extracellularly in these regions after hypoxic or ischemic insults. The mechanisms by which glutamate may harm neurons during ischemia and reperfusion are becoming more clearly defined. Glutamate is released at the presynaptic terminal in response to neuronal stimulation and acts by binding to postsynaptic dendritic receptors. Two main classes of excitatory neurotransmitter receptors have been identified. One class consists of the ligand-gated ion channels (ionotropic receptors) and includes N-methyl-D-aspartate (NMDA); alphaamino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), or quisqualate; and kainate receptor types [Rogers and Kirsch, 1989; Sweeney et al., 1995]. Toxicity caused by NMDA receptor activation is usually rapid, whereas AMPA or kainate receptor–mediated cell death is slower to develop [Dugan and Choi, 1994]. The current understanding of the glutamate receptor subtypes is that the NMDA receptor is more complex and contains more modulatory sites than does the kainate receptor [Lipton and Rosenberg, 1994]. The other class of excitatory neurotransmitter receptors includes the metabotropic receptors that are coupled with G proteins and modulate intracellular second messengers such as calcium, cyclic nucleosides, and inositol triphosphate. Seven

Perkin and Ashwal / Hypoxic-Ischemic Encephalopathy in Infants and Older Children

internal stores is still unclear, there is accumulating evidence that release from internal stores does indeed play a role.

Activation of Intracellular Enzymes The marked increase in intracellular calcium concentration activates at least four classes of enzymes [Morgenstern and Pettigrew, 1997; Sweeney et al., 1995]. Phospholipases break down the lipid cellular membrane, releasing arachidonic acid that generates prostaglandins and free radicals. Protein kinases activate enzymes in an unordered manner, including nitric oxide synthase and xanthine oxidase, which are also generators of free radicals. Proteases begin the uninhibited breakdown of the cytoskeleton, and endonucleases initiate DNA fragmentation. Protease activation may play a central role in mediating both necrosis and programmed cell death. With regard to necrosis, numerous calcium-dependent enzymes become activated during ischemia and produce important neuronal structural injury. One class of calcium-dependent proteases, calpains, has received the greatest amount of attention. Calpains are cytosolic thiol proteases that degrade numerous cytoskeletal proteins such as neurotubules and neurofilaments, as well as activate protein kinase C and phospholipases. Inhibition of calpain activation has produced marked reduction in ischemic brain injury, particularly after focal ischemia [Bartus et al., 1994]. Proteases may also play a pivotal role in the initiation of programmed cell death.

Phospholipase Release of Free Fatty Acids Metabolism of membrane phospholipids through activation of phospholipases is postulated to play a key role in the pathophysiology of ischemic brain injury (Fig. 64-3). Free fatty acids are released from neuronal membranes during ischemia; the amount of release is proportional to the duration of ischemia. Free fatty acid release is the only known cerebral metabolic indicator that continues to increase PC

PS

PI

IP3 PLC

A2

PL

A

1

PE

PL

DAG Arachidonic acid

en yg

yg en

ox

ox

-Increase membrane fluidity -Inhibit ATPases -Increase neurotransmitter release -Promote brain edema -Uncouple oxidative phosphorylation

as

Lip

DAG lipase

clo

as

e

"Other" FFA

Cy

e

subtypes of the metabotropic glutamate receptor have been identified [Nakanishi, 1992]. When activated, the inotropic glutamate receptors open sodium channels and may also have an important role in initiation and propagation of membrane depolarization and spreading depression. With inotropic receptor activation, rapid excitatory amino acid–mediated calcium accumulation occurs [Sweeney et al., 1995]. In the presence of ischemia, this calcium accumulation is exacerbated by cellular energy failure, which disables the Na+/K+-ATPase membrane pump and results in further calcium accumulation. Altered calcium homeostasis leads to activation of many deleterious processes, including activation of phospholipases, proteases, endonucleases, protein kinases, and calmodulin-regulated enzymes such as nitric oxide synthase. There is evidence that nitric oxide is an important mediator of glutamate neurotoxicity [Dawson, 1994]. Re-establishment of the energy supply can reverse these changes. Delayed glutamate-related neuronal injury is most likely caused by activation of inotropic receptors and subsequent calcium influx. Intracellular free calcium may increase during ischemia either by influx of extracellular calcium or by release of bound or sequestered intracellular calcium [Morgenstern and Pettigrew, 1997]. Cerebral ischemia is accompanied by a significant decrease in extracellular calcium concentration, which is consistent with an intracellular shift of calcium. Energy failure during ischemia results in membrane depolarization, which allows calcium influx via voltage-sensitive calcium channels and causes glutamate release. Glutamate can promote calcium influx by three different mechanisms [Haun et al., 1996]. The first and most obvious mechanism is by opening the NMDA receptor-gated calcium channel. Second, stimulation of nonNMDA receptors opens sodium channels and results in massive influx of sodium and subsequent membrane depolarization, which then allows calcium entry via voltage-sensitive calcium channels. Third, the ion channel gated by non-NMDA receptors allows direct influx of calcium. Three additional possibilities exist for calcium entry during ischemia: (1) reversal of sodium/calcium exchanger mechanisms, (2) nonspecific membrane leakage of calcium, and (3) release of bound or sequestered intracellular calcium. Massive influx of sodium during ischemia creates conditions that inhibit or even reverse sodium/ calcium exchange, leading to further calcium influx. It is also possible that calcium enters through areas of the cell membrane that have been damaged by the ischemic insult. Release of bound or sequestered calcium likely occurs through two different mechanisms. First, hydrogen ion, which accumulates during ischemia, can directly displace bound calcium. Second, sequestered intracellular calcium may be mobilized by inositol-1,4,5-triphosphate, which is produced by glutamate-stimulated hydrolysis of polyphosphoinositides, mediated by the metabotropic receptor [Berridge and Irvine, 1984; Sugiyama et al., 1987]. Although most work has centered on the role of calcium influx, some investigations have focused on the importance of the release of sequestered calcium. Mitani and colleagues [1993] demonstrated that two thirds of the increase in intracellular concentration of calcium seen in cultures of hippocampal neurons subjected to glucose and oxygen deprivation is caused by release of sequestered calcium, whereas only one third is caused by influx of extracellular calcium. Although the relative contribution of influx and release from

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Leukotrienes

O2− Prostaglandins

Further toxic effects FIGURE 64-3. Membrane phospholipids are hydrolyzed by two pathways: the PLA1/PLA2 pathway and the PLC/DAG lipase pathway. Arachidonic acid produced by phospholipid hydrolysis is the substrate for eicosanoid synthesis and oxygen radical production. DAG, diacylglycerol; FFA, free fatty acids; IP3, inositol 1,4,5-trisphosphate; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PI, phosphatidylinositol; PLA1, phospholipase A1; PLA2, phospholipase A2; PLC, phospholipase C; PS, phosphatidylserine.

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in proportion to the duration of ischemia after completion of energy failure [Shin et al., 1983]. Free fatty acids are released by two distinct but related processes. First, phosphatidylinositol is hydrolyzed by phospholipase C with the production of diacylglycerol and inositol phosphates [Abe et al., 1987]. Phospholipase C–mediated hydrolysis begins during the initial moments of ischemia and is related to the magnitude of neurotransmitter receptor stimulation. Diacylglycerol is then hydrolyzed by lipases to free fatty acids, predominantly arachidonic acid and stearic acid. Second, other brain glycerophospholipids are hydrolyzed by phospholipase A2, which is activated by increases in intracellular calcium concentration. The process of free fatty acid release and metabolism is not a generalized process in the neuronal membrane but is concentrated in synaptic regions and is thus related to excitotoxicity. The free fatty acids released have potential detrimental effects through at least three mechanisms. First, free fatty acid metabolism via the cyclooxygenase pathway contributes to oxygen radical production during reperfusion [Kontos, 1987]. Second, free fatty acid and diacylglycerol directly increase membrane fluidity, inhibit ATPases, increase neurotransmitter release, promote brain edema, and uncouple oxidative phosphorylation. Third, enzymatic oxidation of arachidonic acid during reperfusion by cyclooxygenase, lipoxygenase, or cytochrome P-450 produces a large number of bioactive lipids (prostaglandins, thromboxanes, leukotrienes, and hydroxyl acids), many of which have detrimental effects. Ischemia induces a proinflammatory state that increases tissue vulnerability to further injury on reperfusion [Collard and Gelman, 2001].

Activation of Nitric Oxide Synthesis Nitric oxide plays a multifaceted role in the brain as a neurotransmitter and a regulator of cerebral blood flow [Bhardwaj et al., 1997; Dawson and Dawson, 1995; Dawson et al., 1992]. Sites of nitric oxide production include neurons, vascular endothelium, perivascular neurons, and astrocytes [Bhardwaj et al., 1997]. If present in abnormally high concentrations, nitric oxide may exert neurotoxic effects [Dawson, 1994; Moncada and Higgs, 1993]. Nitric oxide is produced in a reaction catalyzed by nitric oxide synthase in which oxygen and L-arginine are converted into L-citrulline and nitric oxide. Three isoforms of nitric oxide synthase have been described [Samdani et al., 1997] (Table 64-2). There are two constitutive isoforms:

neuronal and endothelial. An inducible isoform has also been described and has been demonstrated in macrophages, microglia, and astrocytes. The constitutive enzymes are calcium-calmodulin–dependent enzymes. Inducible nitric oxide synthase is calcium independent, is induced by endotoxin and cytokines, and, when stimulated, produces large amounts of nitric oxide in a sustained manner [Clark et al., 1996]. Neuronal nitric oxide synthase is present in highest concentration in the cerebellum, and its lowest concentration is in the medulla. There are neurons that express nitric oxide synthase in all brain regions. In some neurons, nitric oxide synthase activity is regulated by the NMDA receptor. NMDA receptor stimulation results in calcium influx and activation of nitric oxide synthase. Nitric oxide is produced and then diffuses to target cells and stimulates guanylate cyclase, which leads to the production of cyclic guanosine monophosphate. Cyclic guanosine monophosphate then produces the physiologic effect (e.g., vasorelaxation, cell signaling). Inducible nitric oxide synthase is expressed by several cell types (including macrophages, microglia, and astrocytes) in response to stimulation by cytokines. Nitric oxide produced by this nitric oxide synthase isoform is involved in cell-mediated cytotoxicity [Samdani et al., 1997]. The mechanism of this cytotoxicity is not yet fully understood but may involve inhibition of key enzymes necessary for DNA replication and mitochondrial energy production. As part of the excitotoxic cascade of injury, glutamate release activates both endothelial and neuronal nitric oxide synthase, which increase nitric oxide production during focal and global ischemia [Bari et al., 1997; Samdani et al., 1997]. During ischemia, endothelial nitric oxide synthase production may be protective by increasing cerebral blood flow, whereas during ischemia, and more so during reperfusion, neuronal nitric oxide release synthase production may cause additional neurotoxicity. Nitric oxide produced under conditions of ischemia contributes to the cytotoxicity of glutamate, presumably through hydroxyl radical production (Fig. 64-4). Nitric oxide contributes to hydroxyl radical production through its reaction with the superoxide radical. Nitric oxide and superoxide radical react to form peroxynitrite. Peroxynitrite then decomposes to yield nitrogen dioxide and the toxic hydroxyl radicals. Several days after focal ischemia, activation of inducible nitric oxide synthase from phagocytic cells may contribute to delayed injury. The majority of evidence suggesting a role for nitric oxide has been demonstrated in models of focal ischemia.

TABLE 64-2 Nitric Oxide Synthase (NOS) Isoforms TYPE I: NEURONAL NOS

TYPE II: INDUCIBLE NOS

TYPE III: ENDOTHELIAL NOS

Activity depends on elevated Ca2+ First identified in neurons Constitutively expressed, but inducible under pathologic conditions Plays a prominent role in the early stage of neuronal injury after cerebral ischemia Protein and catalytic activity are upregulated within 10 minutes and peak 3 hours after cerebral ischemia

Activity is independent of Ca2+ First identified in macrophages Inducible under pathologic conditions

Activity depends on elevated Ca2+ First identified in endothelial cells Constitutively expressed, but inducible under pathologic conditions Plays a protective role in cerebral ischemia by maintaining cerebral blood flow

Plays a role in the later stages of neuronal injury after cerebral ischemia Protein and catalytic activity are upregulated within 12 hours and peak 48 hours after cerebral ischemia

Protein and catalytic activity are upregulated within 1 hour and peak 24 hours after cerebral ischemia

Perkin and Ashwal / Hypoxic-Ischemic Encephalopathy in Infants and Older Children

nitric oxide synthase leads to neurotoxicity; however, nitric oxide production from endothelial nitric oxide synthase protects brain tissue by maintaining regional cerebral blood flow. Studies emphasize the necessity of developing truly selective inhibitors for neuronal and inducible nitric oxide synthase to protect the brain adequately from ischemic injury caused by overproduction of nitric oxide and simultaneously to maintain or enhance regional cerebral blood flow [Samdani et al., 1997].

Ca2+ NMDA-R Ca2+

Ca2+-CAM

NOS L-Arg

Donor neuron L-Cit

Formation of Oxygen Radicals

NO Target neuron

NOS neuron NO NO + O2−

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Mitochondrial respiration

ONOO− DNA damage PARS activation Energy depletion

ONOOH

OH + NO2 Cell death

FIGURE 64-4. Excessive nitric oxide is formed on sustained glutamate stimulation of N-methyl-D-aspartate receptors (NMDA-R). Nitric oxide (NO) freely diffuses to adjacent target neurons, in which it combines with the superoxide anion (O2–) produced by mitochondria and xanthine oxidase to yield the peroxynitrite anion (ONOO-), which is an extremely potent oxidant. ONOO– also is protonated and decomposes to the hydroxyl (OH) free radical and the nitrogen dioxide (NO2) free radical, which are potent activators of lipid peroxidation. Damaged DNA activates the nuclear enzyme poly–adenosine diphosphate (ADP)–ribose synthetase (PARS). PARS transfers ADP-ribose units to nuclear proteins by using nicotinamide adenine dinucleotide (NAD) as the source of ADP-ribose. For every mole of NAD consumed in this reaction, it takes four energy equivalents of adenosine triphosphate to regenerate NAD from nicotinamide. PARS can transfer more than 100 ADP-ribose units/protein in a matter of seconds. This rapid consumption of energy can deplete a cell of its energy stores. It is hypothesized that if there is sufficient DNA damage and free radical production, the activation of PARS initiates a futile cycle, resulting in the complete depletion of cellular energy stores, impairment of the ability to regenerate those energy stores, and, subsequently, cell death. CaM, calmodulin; L-arg, L-arginine; L-cit, L-citrulline; NOS, nitric oxide synthase; ONOOH, peroxynitrous acid.

Less convincing but definite evidence exists for a potential neurotoxic role during global ischemia. Although one of the major effects of nitric oxide is to increase cyclic guanosine monophosphate, multiple mechanisms have been proposed to define its neurotoxic effects An established pathway of nitric oxide–mediated neuronal cell death is nitric oxide activation of the nuclear enzyme poly-adenosine diphosphate (ADP)-ribose-synthetase (PARS) [Dawson and Dawson, 1995; Samdani et al., 1997]. Nitric oxide activates PARS by damaging DNA. PARS participates in DNA repair by catalyzing the transfer of ADP-ribose units from nicotinamide adenine dinucleotide (NAD) to nuclear proteins. For every mole of ADP-ribose transferred, 1 mol of NAD is consumed, and four free energy equivalents of ATP are necessary to regenerate NAD. Therefore, overactivation of PARS can rapidly deplete cellular energy stores. Depending on its source, nitric oxide may be toxic to or protective of the brain under ischemic conditions. Overproduction of nitric oxide from either neuronal or inducible

Toxic oxygen radical species, produced during postischemic reperfusion, have been implicated as important contributors to reperfusion injury and delayed cell death [Siesjo et al., 1989]. Oxygen free radicals are not one specific compound. They are a group of substances that are formed during ischemia, when oxygen becomes unavailable as the terminal electron acceptor in the electron transport chain. A free radical is any molecule that has an unpaired electron in its outermost orbit; such molecules are shortlived and highly reactive. They include nitric oxide, superoxide anion, hydrogen peroxide (not itself a free radical), hydroxyl radical, and peroxynitrite. The lone electron results in molecular instability and the tendency to initiate and propagate chain reactions. Oxygen free radicals are generated during arachidonic acid metabolism to prostaglandins, as a byproduct of xanthine oxidase–catalyzed production of uric acid through catecholamine oxidation, through a mitochondrial leak during the oxidation of hemoglobin, and through the action of nitric oxide synthase [Kontos, 1987; Siesjo et al., 1995; Traystman et al., 1991] (Fig. 64-5). Free radicals are quite destructive to cellular components such as membrane lipids, especially in the presence of iron. Iron is normally transported in the blood, tightly bound to transferrin and stored inside the cell bound to ferritin. In ischemic conditions with accompanying acidosis, iron may be displaced from its normal binding sites and can catalyze reactions that promote oxygen radical formation [Komara et al., 1986]. Most com-

Xanthine oxidase

Promote release of excitatory amino acids and inhibit their uptake

Mitochondrial "leak"

Peroxidation of membranes

Activated neutrophils

Oxygen free radicals O2−, H2O2, NO, ONOO−

Arachidonic acid metabolism Auto-oxidation of catecholamine

NO synthase

Breakdown of bloodbrain barrier Inhibition of key enzymes

DNA fragmentation

FIGURE 64-5. Sources and physiologic effects of oxygen free radicals. Reperfusion of ischemic neurons and glia produces several highly destructive free radicals, including nitric oxide (NO), peroxynitrite (ONOO–), hydrogen peroxide (H2O2), and superoxide (O2–). These free radical species peroxidize cell membranes, alter the blood-brain barrier, and disrupt DNA.

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monly implicated is the Haber-Weiss/Fenton reaction, whereby potent hydroxyl radicals are produced from superoxide anions and hydrogen peroxide in the presence of free iron. The impact of the liver and the intestines in producing dysfunction in other organ systems needs further clarification. The liver and intestines have a great deal of xanthine dehydrogenase, which during ischemia can be converted to xanthine oxidase [Bellamy et al., 1996; Nielson et al., 1997]. The latter could enter the systemic circulation, generate free radicals, and cause additional dysfunction and injury at distant sites. The brain may be particularly vulnerable to free radical injury for several reasons. One is the high concentration of polyunsaturated fatty acids, especially arachidonic acid. As noted previously, free fatty acids are released throughout ischemia. On exposure to oxygen radical species, these free fatty acids are vulnerable to lipid peroxidation [Krause et al., 1988]. Cerebrospinal fluid has low concentrations of iron-binding proteins; therefore, iron released from injured neurons or glia is likely to contribute to these peroxidation reactions. Byproducts of these reactions—for example, malondialdehyde and conjugated dienes—have been used as markers of the extent of lipid peroxidation after brain injury [Schmidley, 1990]. Lipid peroxides accumulate in the selectively vulnerable zones during reperfusion after transient forebrain ischemia [Bromont et al., 1989; Komara et al., 1986]. The peroxides do not accumulate during the ischemic period itself or in areas that are not reperfused and thus are implicated in reperfusion injury [Oliver et al., 1990]. Lipid membranes are a natural target of free radicals, especially in the brain, because they are abundant, and their polyunsaturated nature makes them easy to oxidize [Schmidley, 1990]. The effects of free radicals on membranes include changes in membrane fluidity and alteration of ion channels and transport proteins. In addition to disruption of the cell membrane, fragmentation of the mitochondrial membrane results in a decrease in cellular energy production. The ability of the cell to defend itself against free radicals is limited, and free radical scavenging enzymes such as superoxide dismutase and catalase may be overwhelmed after an ischemic area is reperfused [Vannucci and Perlman, 1997]. Surprisingly, restoration of blood flow to hypoxicischemic areas is potentially detrimental because the influx of oxygen can be used as a source of oxygen free radicals through the processes noted previously. Stimulated by high tissue carbon dioxide tension, low oxygen tension, and low pH, restored blood flow to an ischemic area is often increased above normal (luxury perfusion). In experimental preparations, oxygen free radicals are detected primarily during reperfusion. After luxury perfusion, there is prolonged hypoperfusion and an associated decrease in cerebral metabolism. In animal experiments, these decreases are not seen with pretreatment with oxygen free radical scavengers.

Reperfusion Injury Cerebral reperfusion injury is a complex series of interactions between the brain parenchyma and microcirculation that results in detrimental effects that negate some of the benefits of reperfusion [Becker, 1997]. Many of the

mechanisms previously discussed contribute to additional injury during reperfusion, particularly those associated with release of free radicals. Some may be accelerated or accentuated. With circulatory return, substrate availability increases, as does the function of potentially toxic oxygen-dependent enzymes, and, separately or in combination, this may worsen injury. After focal insults, progressive microcirculatory failure is also thought to be an important aspect of reperfusion injury. Loss of blood flow to the brain results in neuronal injury as a result of both the cessation of blood flow, leading to oxygen and nutrient deprivation, and the initiation of a cascade of secondary mechanisms [Vaagenes et al., 1996]. This neurotoxic cascade involves derangements in normal metabolic and physiologic functions, as well as initiation of cell death processes. Thus, both restoration of blood supply and control of secondary neurotoxic cascades are necessary to limit ischemic neuronal damage [Sweeney et al., 1995].

Genetic Damage and Regulation Two aspects related to global asphyxial injury and genetic regulation are emerging as critical components of the injury cascade. The first concerns mechanisms associated with injury and repair of the genetic material itself, and the second concerns regulation of multiple genes and the proteins that they in turn regulate in response to hypoxiaischemia. Studies have demonstrated that ischemia and reperfusion can induce gene damage in the CNS. Reactive oxygen species generated by cerebral oxidative stress interact with nucleic acids and cause the formation of oxidative DNA and RNA lesions that result from DNA base modifications or single-stranded breaks in neurons or astrocytes [Liu and Arora, 2002; Liu et al., 2001]. Oxidative DNA lesions cause a change in coding properties during DNA and RNA synthesis (replication and transcription) or may terminate chain elongation during transcription and translation. Either process can affect protein synthesis. The development of microarray systems for gene expression profiling since the mid-1990s has provided insights into the mechanisms of the brain’s response to global hypoxic injury [Jin et al., 2001; Papadopoulos et al., 2000; Tang et al., 2002]. Future studies should not only increase the understanding of the molecular basis of ischemic injury but also suggest potential therapies. Because investigators in such studies frequently use several thousand gene transcripts, using different animal models with varying degrees of severity and duration of global hypoxia-ischemia, as well as varying time periods of reperfusion, it will be some time before a unified or general understanding of the underlying mechanisms of injury are more clearly appreciated. Early during hypoxia-ischemia, overall gene expression in the brain is reduced or ceases to maintain energy metabolism to support essential cell activities. Immediate early genes undergo rapid induction after global ischemia [Kogure and Kato, 1993]. Some of the immediate early gene products that have been identified include c-fos, c-jun, and the zinc finger family of proteins; heat-shock proteins; and amyloid precursor protein. Immediate early genes are transcription factors that bind to target genes and alter their expression. These stress response proteins may directly

Perkin and Ashwal / Hypoxic-Ischemic Encephalopathy in Infants and Older Children

affect neuronal death and survival after ischemia. However, despite much research into their expression, it remains unclear which ones contribute to the outcome of hypoxicischemic injury [Papadopoulos et al., 2000]. This confusion occurs partly because some are upregulated, whereas others are downregulated, and their respective neurotoxic or neuroprotective roles remain to be defined. Another early expressed group of proteins are the heat shock proteins that are molecular chaperones, which bind intracellular proteins and prevent their inappropriate folding [Papadopoulos et al., 2000]. Hsp-70 is markedly induced by hypoxia and is neuroprotective. Hsp-32 is another heat shock protein that may be neuroprotective after hypoxia. It encodes heme-oxygenase-1, which after induction has been found to protect neurons in models of transient forebrain ischemia, possibly by producing bile pigments that are strong antioxidants, as well as carbon monoxide, which can cause vasodilation and inhibits platelet aggregation. Growth factors are also released within hours after ischemia and may also serve a neuroprotective role. They are polypeptides and the major types of growth factors include nerve growth factor; brain-derived neurotrophic factor; neurotrophins-3, -4, -5; and basic fibroblast growth factor [Papadopoulos et al., 2000]. Nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 bind receptors on the cell surface that have tyrosine kinase activity, and activation of tyrosine kinase is associated with neuronal survival. Hours later, cytokines, adhesion molecules, isoforms of nitric oxide synthase, and gene products involved in apoptosis are upregulated. Some of these genes protect the cells from dying; some promote the death of injured cells; and others have no known effects on cell survival. Cytokines are produced by activated lymphocytes, macrophages, and astrocytes and include tumor necrosis factor α, transforming growth factor β, and interleukin-1β. Cytokines participate in the inflammatory response and accelerate entry of inflammatory cells from the circulation into the brain. Certain cytokines (e.g., tumor necrosis factor α and interleukin-1β) may also induce the expression of glycoproteins known as adhesion molecules on endothelial cells, which also facilitate recruitment of inflammatory cells into the ischemic brain [Papadopoulos et al., 2000]. Neuronal degeneration can also be promoted by induction of apoptosis genes or genes that cause a stress to the cells, such as those related to free radical production or to the production of various nitric oxide synthase isoforms [Koistinaho and Hokfelt, 1997]. Cells that undergo apoptosis shrink down and ultimately are phagocytosed by neighboring cells. Genes that accelerate apoptosis include members of the bax and bad families, p53, and Fas; those that inhibit apoptosis are associated with bcl-2, bcl-x (L), and DAD1 families [Papadopoulos et al., 2000]. When apoptosis is initiated, cytochrome c is released from damaged mitochondria and, in concert with apoptotic protease–activating factor, induce members of the caspase family, including interleukin-1–converting enzyme. As apoptosis proceeds, nuclear components and the cell skeleton are destroyed, detach other cell constituents and from neighboring cells, and are phagocytosed. Two studies demonstrated both the elegance of the application of microarray technology and the dilemmas in

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synthesizing the results. In one study, 15 minutes of global cerebral ischemia in rats was associated with 1.7-fold or greater increased expression of 57 genes and 1.7-fold or greater decreased expression of 34 genes studied up to 72 hours after hypoxia [Jin et al., 2001]. Induced genes included those involved in protein synthesis, proapoptotic genes, antiapoptotic genes, injury-response genes, receptors, ion channels, and enzymes. Transcriptional induction of several genes was also reported, as was co-induction of several groups of related genes (e.g., vascular endothelial growth factor and its receptor, neuropilin-1). A second study examined 8000 transcripts in rat brains 24 hours after exposure to 6 hours of hypoxia (8% oxygen) and found very little gene induction (15 upregulated genes and 11 downregulated genes) [Tang et al., 2002]. In contrast, the same investigators found that in a model of permanent focal ischemia, 415 genes were upregulated and 158 were downregulated. Presumably the differences between global hypoxia and ischemia were attributable to greater tissue injury in the ischemic model, but there is no apparent explanation of the differences in the response to global hypoxia in these two groups of studies.

CLINICAL PATHOPHYSIOLOGY The complex metabolic changes that occur after cardiopulmonary arrest have a direct relationship with the physiologic variables that are monitored both in animal studies and in patients.

Cerebral Blood Flow and Metabolism after Resuscitation The pioneering studies in which global cerebral blood flow and cerebral metabolic rate for oxygen were measured in animal models of global ischemia or cardiac arrest focused on the early postresuscitation period. In their classic study, Snyder and associates [1975] demonstrated that after 15 minutes of global brain ischemia in dogs, cerebral blood flow transiently increased to levels well above baseline. After 15 to 30 minutes, cerebral blood flow progressively decreased to a level below normal for the rest of the monitoring period (90 minutes). This pattern of early transient post-ischemic hyperemia and subsequent delayed post-ischemic hypoperfusion has been observed almost universally in global cerebral ischemia models, including asphyxia-induced cardiac arrest. The level of hyperemia and subsequent hypoperfusion varies in relation to the duration of the insult. Although these phases of increased and decreased cerebral blood flow characterize the net global effect, regional cerebral blood flow is often heterogeneous, particularly during post-ischemic hypoperfusion, when areas of decreased and increased perfusion may coexist. Metabolism, as assessed by cerebral metabolic rate for oxygen, is reduced during the early post-ischemic period and then progressively recovers to a level that varies, depending on the model used and the duration of ischemia. In some models, including ventricular fibrillation in dogs, significant recovery of cerebral metabolic rate for oxygen may occur during the first few hours, despite persistent post-ischemic hypoperfusion, creating the potential for a secondary ischemic insult during

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reperfusion. Whether this increase in cerebral metabolic rate for oxygen represents appropriate synaptic activity, seizures, or changes in the basal metabolic rate is uncertain. In other models, global cerebral blood flow and cerebral metabolic rate for oxygen are matched during the first few hours after ischemia. In such cases, post-ischemic cerebral blood flow appears to be determined by the metabolic needs of the brain, and delayed hypoperfusion may not be a significant cause of neuronal injury. Thus, delayed hypoperfusion is likely the result of brain injury rather than the cause [Michenfelder and Milde, 1990]. Of historic interest is the concept of “no reflow,” which was suggested in the 1960s by Ames and co-workers [1968]. These investigators noted that after a period of global cerebral ischemia, reflow could not be re-established. Early attempts at brain resuscitation were based on the concept that preventing “no reflow” would improve neurologic outcome. However, the relationship between delayed hypoperfusion and brain injury remains unclear, and therapies to improve blood flow such as hypertension and hemodilution remain controversial. Drugs such as nimodipine can increase cerebral blood flow during the early post-ischemic hypoperfusion phase after global cerebral ischemia. Cerebral metabolic rate for oxygen recovery generally is not increased by treatment, even though nimodipine improves neurologic outcome after global ischemia in some models. Safar and associates [1996] reported that a multifaceted flow-promotion treatment strategy to increase cerebral blood flow and reduce cerebral metabolic rate for oxygen early after ventricular fibrillation in dogs improved outcome. This improvement was accomplished with brief cardiopulmonary bypass, mild hypothermia, hemodilution, and transient hypertension. Studies in which investigators measured cerebral blood flow and cerebral metabolic rate for oxygen in humans after cardiac arrest shed interesting light on these data from animals. Whereas cerebral blood flow and cerebral metabolic rate for oxygen typically are measured early (0 to 2 hours after arrest) in experimental animal studies, such measurements in humans are obtained beginning 6 to 12 hours after arrest. Beckstead and associates [1978] measured global cerebral blood flow and cerebral metabolic rate for oxygen in 25 adults after cardiac arrest. In all, 21 of these patients had a vegetative outcome. In agreement with the experimental animal studies, Beckstead and associates observed hypoperfusion and hypometabolism with coupling of cerebral blood flow and cerebral metabolic rate for oxygen. During the subsequent 2 days, however, global cerebral blood flow increased to levels equal to or greater than normal, whereas metabolism failed to recover. Thus, in humans with poor neurologic outcome after cardiac arrest, absolute or relative delayed hyperemia followed the hypoperfusion phase. Results of two more studies in adults have confirmed these findings. Using xenon-133 washout, Cohan and colleagues [1989] observed that patients regaining consciousness had normal cerebral blood flow between 6 and 46 hours after arrest, whereas patients who died without regaining consciousness had increased cerebral blood flow (hyperemia) within 24 hours. Similarly, Love and associates [1989] used stable xenon-enhanced computed tomography (CT) and discovered that the combination of diffuse hyperemia and loss of reactivity of cerebral blood flow to changes in

PaCO2 was seen 100 hours after arrest in adults who never regained consciousness. Thus, immediately after cardiac arrest accompanied by restoration of systemic hemodynamic stability, transient global brain hyperemia occurs and is followed by a period of patchy hypoperfusion. The magnitude and duration of these alterations in flow appear to be related to the duration of the insult. In patients with good outcomes, global cerebral blood flow recovers over the subsequent 24 to 72 hours, and CO2 reactivity remains intact. In patients who do not regain consciousness or progress to brain death, absolute or relative cerebral blood flow hyperemia develops with impaired CO2 reactivity [Prough and Zornow, 1997]. It must be recognized that the measurement of metabolism in these studies has traditionally been cerebral metabolic rate for oxygen. Bergsneider and co-workers [1995] used positron emission tomography in humans after traumatic brain injury and reported the occurrence of delayed hyperglycolysis in some comatose patients. Studies of cerebral glucose utilization with positron emission tomography after cardiac arrest are needed. Results from clinical studies of asphyxia-induced cardiac arrest in children are scarce and somewhat conflicting with regard to the prognostic implications. Normal values of post–cardiac arrest cerebral blood flow with loss of responsivity to PaCO2 were observed in children with poor outcome at 24 hours after asphyxia-induced cardiac arrest by strangulation, as studied with stable-xenon CT [Ashwal et al., 1991]. Similarly, in studies of subjects between 24 and 48 hours after near-drowning, Ashwal and colleagues [1990] observed low cerebral blood flow and no relationship between cerebral blood flow and PaCO2 in the seven nonsurvivors, which again suggests loss of cerebral blood flow reactivity to changes in PaCO2. In this study, hyperemia was not routinely observed in either vegetative survivors or children who died, but only a single cerebral blood flow measurement was made. Beyda [1987] obtained serial measurements of post–cardiac arrest cerebral blood flow with xenon-enhanced CT in a series of children who had suffered asphyxia-induced cardiac arrest from submersion accidents. Children with good neurologic outcomes had slightly decreased cerebral blood flow values at 12 hours that increased to normal during the subsequent 24 to 60 hours. In these children, cerebral blood flow reactivity to CO2 was intact. Children with an eventual vegetative outcome or brain death exhibited hyperemia with loss or attenuation of CO2 reactivity. This hyperemia progressed to low or normal flow over the next 12 to 72 hours in children with vegetative outcome and progressed to low and then no flow, with the development of brain death.

CLINICAL OUTCOME AFTER CARDIAC ARREST The incidence of death and neurologic impairment from cardiac arrest in children is alarmingly high. Also dismaying is the suggestion that current approaches to resuscitation of these children may increase the number of successful cardiovascular resuscitations without equal neurologic recovery. Current medical literature has examined the mortality and neurologic morbidity resulting from prehospital cardiac arrest in pediatric patients (Table 64-3).

Perkin and Ashwal / Hypoxic-Ischemic Encephalopathy in Infants and Older Children

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TABLE 64-3 Results of Resuscitation in Prehospital Pediatric Cardiac Arrest* STUDY O’Rourke [1986] Zaritsky et al. [1987] Torphy et al. [1984] Nichols et al. [1986]

TOTAL NO. OF PATIENTS

LONG-TERM SURVIVORS

34 11 77 10

7 1 3 0

24 119 44 70 22 80 33 60

3 8 1 3 0 6 1 6

Dieckmann and Vardis [1995]

62

0

Hazinski et al. [1994]

22

0

Sheikh and Brogan [1994]

27

0

695

39

Rosenberg [1984] Eisenberg et al. [1983] Friesen et al. [1982] Thompson et al. [1990] Applebaum [1985] Schindler et al. [1996] Hickey [1995] Ronco et al. [1995]

Total

COMMENTS All survivors sent to chronic care facility Outcome of surviving patient not reported All survivors neurologically impaired No survivors among 10 of 13 patients asystolic on arrival to emergency department Neurologic outcome not reported for survivors Neurologic outcome not reported for survivors Outcome poor after asystole All survivors had serious sequelae 18 of 22 were asystolic All survivors had neurologic sequelae Severe neurologic injury in the survivor All survivors had severe deficits; 60 of 63 children were asystolic Study reports 62 of 65 children were asystolic at emergency department Trauma patients pulseless on emergency department evaluation CPR after blunt trauma; comparison of open- versus closed-chest CPR 5.6% survival, none described as neurologically normal

*All patients were asystolic or pulseless on arrival to the emergency department. CPR, cardiopulmonary resuscitation.

Interpretation of these studies’ results and comparisons among them are made difficult by several factors [Perkin and van Stralen, 1992]. In some reports, cardiac arrest is not clearly differentiated from respiratory arrest. Because the outcome of resuscitation is better after respiratory than cardiac arrest, failure to clearly distinguish the two groups results in falsely optimistic outcomes. Second, the time and location of arrest vary in these studies; some investigators evaluated prehospital arrests, some assessed in-hospital arrests, and others combined the two groups. Mortality and neurologic morbidity may occur at a higher rate among patients with prehospital cardiac arrest than among emergency department and in-hospital patients as a result of the lack of emphasis on pediatric basic and advanced life support, as well as the delay in discovery of the patient. Therefore, each group should be analyzed separately. Finally, successful resuscitation is often defined as the patient’s being discharged from the emergency department or hospital, without the consideration of residual neurologic damage. Review of evaluations of outcomes of pediatric prehospital cardiac arrest reveals the following: • Children who survived neurologically intact had cardiac activity on arrival in the emergency department. The combined rates of mortality and severe morbidity in children arriving pulseless in the emergency department approached 100%. • Children who had a delayed response to resuscitation had little chance for neurologically intact survival. Those with resuscitation times of less than 15 minutes had a far better outcome than did those whose

resuscitation times were longer [Gillis et al., 1986; Nichols et al., 1986]. Resuscitation efforts lasting more than 25 minutes were uniformly unsuccessful [Quan et al., 1990; Rosenberg, 1984]. • The extent of the resuscitation attempt, which is obviously related to the rapidity of the response to initial therapy, was another predictor of outcome in pediatric resuscitation. Many studies suggest that no pediatric patient with cardiac arrest who receives more than two doses of epinephrine survives to discharge [Nichols et al., 1986; Zaritsky et al., 1987]. Many explanations have been proposed for the poor outcome of pediatric cardiac arrest patients. Primary respiratory disorders and those that result in respiratory arrest account for the majority of cardiopulmonary arrests in children. Hypoxemia and acidosis, which occur because of the respiratory difficulty, result in bradycardia or asystole. Restoration of a cardiac rhythm is difficult, and even if it is restored, the victim is likely to suffer neurologic impairment [Goetting, 1994; O’Rourke, 1986]. Because most pediatric cardiac arrests are secondary to hypoxemia, it is logical to assume that if the hypoxemia lasts long enough and is severe enough to stop the heart, it will also have devastating neurologic effects. Additional reasons for poor survival from prehospital pediatric cardiac arrest include unwitnessed cardiac arrest, such as that seen with sudden infant death syndrome or neardrowning, which delays resuscitation; ineffective basic cardiopulmonary resuscitation; and delays in providing

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Brain Injury and Disorders of Consciousness / 64

advanced life support [Gausche, 1997; Kumar et al., 1997]. Unwitnessed cardiac arrest is associated with a high mortality rate, especially when the initial rhythm is bradycardia or asystole, and prehospital resuscitation is inadequate because of unavailable skills or no return to rhythm. In peditric patients, sudden infant death syndrome is a leading cause of death in infants 1 month to 1 year of age and is an example of the futility of resuscitating patients who have suffered unwitnessed cardiac arrest [Goyco and Beckerman, 1990]. It is important to note that sudden infant death syndrome is diagnosed only after a postmortem examination reveals no physiologic cause for the sudden death of the infant. Numerous studies have demonstrated no successful resuscitations in children with confirmed diagnoses of sudden infant death syndrome [Dolan et al., 1988; O’Rourke, 1986]. In fact, in infants younger than 1 year who are found pulseless and apneic at home and are documented to be pulseless and apneic in the emergency department, the likelihood of successful resuscitation is low enough to suggest that vigorous resuscitation efforts are unwarranted. Similarly, warm-water near-drowning victims who arrive in the emergency department with no spontaneous respirations and no perfusing heartbeat do poorly. Data from many studies confirm that all near-drowning victims who were not hypothermic (core body temperature of less than 30° C) and who were asystolic when they arrived at the first medical facility either died or survived with severe neurologic damage [Biggart and Bohn, 1990; Habib et al., 1996]. In view of these data, some experts recommend that nonhypothermic near-drowning pediatric victims who arrive in the emergency department without perfusing cardiac rhythms should not undergo prolonged and aggressive resuscitation or intensive care management [Biggart and Bohn, 1990; Habib et al., 1996; Spack et al., 1997]. Cardiopulmonary resuscitation and advanced life support that are ineffective or delayed are other variables that explain the poor outcome of prehospital pediatric resuscitation. Although paramedics may provide sophisticated advanced life support care to adults, they may not be adequately trained to establish an open and protected airway, initiate positive pressure ventilation, defibrillate, or start intravenous infusions in or give drugs to pediatric patients in cardiac arrest. In summary, a review of literature supports the following points: • Children who are asystolic or who experience a delay in resuscitation have little chance for neurologically intact survival. • Unsuccessful resuscitations of children are currently the rule rather than the exception. • Serious neurologic damage is common in survivors of cardiac arrest. • Recovery is much better in children who experienced witnessed cardiac arrests, cold water submersion, or isolated respiratory arrest; intact survival rates as high as 44% to 75% after these events have been reported [Lewis et al., 1983; O’Rourke, 1986; Torphy et al., 1984; Zaritsky et al., 1987]. Nevertheless, these clinical data seem to bear out the severe neuropathology observed in asphyxia-induced arrest in animal models because asphyxia-induced cardiac

arrest is the most common mode of cardiac arrest in all of the clinical pediatric series.

MAJOR DISORDERS CAUSING CARDIAC ARREST Table 64-1 and Box 64-1 list the common causes, by category, of pediatric cardiorespiratory arrest taken from major published pediatric cardiac arrest series. Common specific disease entities resulting in cardiac arrest are sudden infant death syndrome, drowning, strangulation, nonaccidental trauma, and lightning/electrical injury.

Sudden Infant Death Syndrome Sudden infant death syndrome is defined as the sudden death of an infant younger than 1 year that remains unexplained after a thorough case investigation, including performance of a complete postmortem examination, examination of the death scene, and review of the medical history [Willinger et al., 1991]. The addition of requirements for examining the death scene and reviewing the history give greater precision to the diagnosis, but it remains one of exclusion, based on the absence of any specific findings on routine postmortem examination. In many unresolved cases, the history, investigation, or postmortem examination reveals information that excludes the diagnosis of sudden infant death syndrome but does not explain the cause of death: Suspected abuse, neglect, or accidental suffocation; vomiting or diarrhea without evidence of infection; unreliable information; or findings such as mild bronchopneumonia, supraglottitis, or maternal drug abuse are not sufficient to explain death [GilbertBarness and Barness, 1995]. Even though almost all cases of sudden unexpected death in infants continue to be ascribed to sudden infant death syndrome, the uncritical certification of the syndrome as a diagnosis, without a postmortem examination, death scene investigation, and careful history, prevents accurate diagnosis of the cause of death [Bass et al., 1986; Valdes-Dapena, 1995].

Epidemiology INCIDENCE AND AGE AT DEATH After the neonatal period, sudden infant death syndrome is the leading cause of death during the first year of life. Although sudden infant death syndrome may occur during the first month of life, most neonatal deaths can be accounted for by specific perinatal factors, including prematurity, infection, and congenital diseases. The incidence of sudden infant death syndrome peaks between 2 and 4 months of age; 95% of all deaths from the syndrome occur by 6 months of age [Hunt, 1992]. Sudden infant death syndrome, therefore, is primarily a disorder that strikes children between the ages of 1 and 6 months. It is so rare outside those age limits that the diagnosis in such cases should be made with caution and only after all possible causes, including metabolic diseases, are excluded [GilbertBarness and Barness, 1995]. The age-at-death distribution of sudden infant death syndrome is the most consistent, unique, and provocative characteristic identified [Peterson, 1988].

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Box 64-3 EPIDEMIOLOGIC FACTORS ASSOCIATED WITH INCREASED RISK FOR SUDDEN INFANT DEATH SYNDROME Maternal and prenatal risk factors Intrauterine hypoxia Fetal growth retardation Smoking Anemia Drug exposure (cocaine and heroin) Low socioeconomic status Decreased maternal age and education Increased parity and shorter interpregnancy interval Postnatal risk factors Growth failure Perinatal asphyxia Prematurity and low birth weight Male gender Postnatal age of 2 to 4 months Formula feeding Thermal stress (overheating) Co-sleeping Recent (febrile) illness Passive smoking Soft bedding Prone sleeping position Ethnicity (black or Native American)

IDENTIFICATION OF RISK FACTORS An ambitious study designed to investigate risk factors for sudden infant death syndrome was the National Institute of Child Health and Human Development Cooperative Epidemiological Study of Sudden Infant Death Syndrome Risk Factors [Hoffman et al., 1988]. This study revealed an incidence of the syndrome of 1.7 per 1000 live births. In the study, sudden infant death syndrome was ruled as the cause of death after a detailed review of microscopic slides, gross postmortem examination review, and death investigation reports by a panel of expert pathologists. No epidemiologic differences have been of sufficient sensitivity and specificity to permit prospective identification [Hoffman and Hillman, 1992]. Maternal and prenatal factors (Box 64-3) suggest that the in utero environment of future victims of sudden infant death syndrome is suboptimal [Carroll and Loughlin, 1993]. Some of the postnatal risk factors suggest that the postnatal care is also suboptimal. A number of epidemiologic studies have documented that smoking during pregnancy and after birth are two major and independent risk factors for sudden infant death syndrome [Perkin, 2004]. With the reduction in the incidence of infants being put to sleep prone, maternal smoking has become the major modifiable risk factor for sudden infant death syndrome [Horne et al., 2002]. It has been argued that 30% of deaths from sudden infant death syndrome are preventable by not exposing infants to cigarette smoke [Chang et al., 2003]. Since the inception of infant monitoring, investigators have tried to define populations at increased risk for sudden infant death syndrome, even though it has not been demon-

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Box 64-4 GROUPS AT HIGH RISK FOR SUDDEN INFANT DEATH SYNDROME (SIDS) Survivors of apparent life-threatening event (ALTE) Subsequent siblings of SIDS victims Preterm infants, including those with bronchopulmonary dysplasia Infants of drug-dependent mothers

strated that monitoring prevents infant deaths or morbidity associated with apnea, such as neurodevelopmental delays. Four major groups could be considered to be at a high risk for sudden infant death syndrome (Box 64-4). Sleeping in the prone position (on the stomach) by infants has been one of the most consistent risk factors for sudden infant death syndrome, and avoidance of prone sleeping has been the focus of several national campaigns to prevent the syndrome. The evidence that prone sleeping is a risk factor for sudden infant death syndrome has been so compelling that the American Academy of Pediatrics Task Force on Infant Positioning and sudden infant death syndrome [1992] recommended the supine sleeping position for infants. The fear that aspiration would occur if an infant vomited or regurgitated while sleeping in the supine position appears to be unwarranted; in fact, the incidence of death from aspiration has actually decreased among infants sleeping in the supine position [Gilbert-Barness and Barness, 1995]. Although the lateral position for sleeping has also been recommended, positioning infants on their sides may not be as safe, because the infant may roll over into the prone position. The recommendation for sleep in a nonprone or supine position is for healthy infants only. Gastroesophageal reflux and certain upper airway anomalies that predispose to airway obstruction and perhaps some other illnesses may be indications for a prone sleeping position [“Positioning and sudden infant death syndrome (SIDS),” 1996]. There is evidence that the danger of the prone position is compounded by soft, yielding bedding [Gilbert-Barness and Barness, 1995]. Infants sleeping face down on thick, soft, cushiony surfaces such as lamb’s wool, pillows, cushions filled with synthetic material, or beanbags stuffed with polystyrene pellets may hollow out a “pocket” in the soft surface. In that position, infants may rebreathe their own expired air, which is high in carbon dioxide. An infant who cannot, for any reason, lift the head out of the pocket may suffocate. Scientific studies have demonstrated that bed sharing by mother and infant can alter and synchronize sleep patterns of the two. These studies have led to speculation in the lay press that bed sharing, sometimes referred to as co-sleeping, may also reduce the risk of sudden infant death syndrome. Although bed sharing may have certain benefits (such as encouraging breast-feeding), no scientific studies demonstrate that bed sharing reduces the incidence of sudden infant death syndrome. Conversely, there are studies suggesting that bed sharing, under certain conditions, may actually increase the risk of the syndrome [“Does bed sharing affect the risk of sudden infant death syndrome?” 1997].

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Pathophysiology The most compelling hypothesis to explain sudden infant death syndrome is that of a brainstem abnormality in cardiorespiratory control [Hunt, 1992]. Both the pathologic data derived from postmortem examination studies and the clinical data obtained in infants at increased epidemiologic risk for sudden infant death syndrome support this hypothesis. The postmortem findings, although subtle, are consistent with a maturational or developmental abnormality associated with the brainstem areas relevant to autonomic control of cardiorespiratory regulation. The clinical data to support the cardiorespiratory control hypothesis were initially obtained from assessments of patients with apnea of infancy and of asymptomatic infants at increased epidemiologic risk for sudden infant death syndrome. Respiratory pattern abnormalities have been observed in infants at increased risk for sudden infant death syndrome [Goyco and Beckerman, 1990]. Because of the extent of overlap between control infants and infants who later died of sudden infant death syndrome, however, overnight recordings of respiratory pattern and heart rate have been unable to identify accurately either future victims of the syndrome or infants who will develop apnea of infancy. Consequently, the practice of performing a pneumogram or polysomnogram in early infancy to assess later risk for sudden infant death syndrome, or for apparently life-threatening events, has no identifiable predictive validity. Respiratory pattern abnormalities are just one category of cardiorespiratory control and are perhaps not one of the more important categories. Infants at increased risk for sudden infant death syndrome have diminished ventilatory responsiveness to hypercarbia and hypoxia [Hunt, 1992]. The extent of overlap between control infants and at-risk infants, however, precludes the use of hypercarbic or hypoxic ventilatory responsiveness, or both, as a test to predict risk for the syndrome. Because of overlapping values, an individual infant cannot be classified as normal or abnormal. In addition, these tests are too time consuming and costly to be useful for large-scale application. Such tests, therefore, have no role in the routine clinical management of apnea of infancy or in the evaluation of any asymptomatic infants at increased epidemiologic risk for sudden infant death syndrome. Respiratory pattern abnormalities and diminished ventilatory responsiveness are not inherently life threatening. A deficiency in arousal responsiveness, however, would be life threatening because the infant is thereby rendered incapable of responding effectively to progressive sleep-related asphyxia, regardless of its cause. Infants with apnea of infancy and diminished ventilatory responsiveness to hypercarbia, hypoxia, or both also have a concomitant abnormality in hypercarbic hypoxic arousal responsiveness, or both [Carroll and Loughlin, 1993]. A deficit in arousal responsiveness is likely necessary for sudden infant death syndrome to occur, but it may well be insufficient to cause the syndrome unless or until another factor that can permit or cause sleep-related asphyxia occurs. One of the most tenable hypotheses of sudden infant death syndrome is that the sequence of events is initiated by a period of airway obstruction resulting from one of several causes, among them upper airway obstructions, edema secondary to a respiratory tract infection, or pharyngeal hypo-

tonia during sleep. Hypoxia, acidosis, and hypercarbia follow the obstructive event. These metabolic changes usually produce arousal during active sleep; however, inappropriately weak efforts, poor coordination, or diaphragmatic fatigue associated with the event may result in atelectasis at the lung bases, increased firing of airway stretch receptors, and secondary apnea from the Hering-Breuer reflex. Because the infant fails to become aroused adequately to stimulate the respiratory control centers in the brainstem, an episode of central apnea may occur, producing more severe hypoxia and acidosis. If the sequence of events is uninterrupted, respiratory arrest, cardiac dysrhythmia, shock, and death can occur. A strong history of sudden infant death syndrome, apparent life-threatening events, and obstructive sleep apnea in family members predisposes an infant to obstructive sleep apnea during the first year of life [McNamara and Sullivan, 2000]. The potential link among sudden infant death syndrome, apparent life-threatening events, and obstructive sleep apnea in infants is unclear; however, an increased incidence of obstructive sleep apnea in subsequent siblings of infants who died of sudden infant death syndrome and infants with apparent life-threatening events has been described. In addition, studies have documented obstructive events during sleep in infants who subsequently became victims of sudden infant death syndrome [Kato et al., 2001]. These findings suggest that sudden infant death syndrome and apparent life-threatening events are related to obstructive sleep apnea. Sleep studies should be obtained in young infants with multiple family histories of sudden infant death syndrome, apparent life-threatening events, and obstructive sleep apnea. Studies in normal infants, subsequent siblings of victims of sudden infant death syndrome, and patients with apnea of infancy indicate that arousal responsiveness to hypoxia normally decreases with maturation, reaching a low at 2 to 3 months, the age for peak vulnerability to sudden infant death syndrome [van der Hal et al., 1985]. As is the case with respiratory pattern abnormalities and ventilatory responses, unfortunately, there is again too much overlap between normal and abnormal infants to permit use of arousal responsiveness as a means of classifying an individual infant as normal or abnormal. In addition, arousal response assessments are too time consuming and costly for routine clinical use. Decreased heart rate variability has been reported in infants with apnea. Infants with sudden infant death syndrome have been reported to differ from control infants with regard both to higher overall heart rate in all sleep-waking states and to diminished heart rate during wakefulness [Schectman and Harper, 1993]. Through spectral analysis, it has become apparent that future victims of sudden infant death syndrome also differ from control infants in that cardiac and respiratory activity are coupled. Overall, these studies of diminished heart rate variability in infants who later died of sudden infant death syndrome indicate an abnormality of autonomic control that is consistent with the overall hypothesis of a brainstem abnormality involving, but not restricted to, cardiac control. Maturational studies indicate that the period immediately after the neonatal age is a time of increased vulnerability. Event recordings of the terminal episode have documented early and rapid development of severe bradycardia;

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it develops too soon to be explained by the progressive desaturation of prolonged apnea [Meny et al., 1994]. Although this finding lends support to the idea of an abnormality in cardiac control, it is also possible that the hypoxemia or obstructive apnea, or both, may, in at least some instances, be the underlying pathophysiologic mechanism for the terminal bradycardia.

Prediction Potential victims of sudden infant death syndrome cannot be identified by any method before death. No test, including pneumography and polysomnography, or any risk profile can identify a specific infant destined to die of the syndrome. In addition, no test that can be performed in parents or in siblings is predictive of sudden infant death syndrome in a family. Pneumography and polysomnography can be useful in the management of selected patients, but they are not predictive for the syndrome. More work is needed, for example, in the area of metabolic defects to identify means of predicting and preventing at least some deaths resulting from sudden infant death syndrome.

Management After a sudden infant death syndrome event, management involves the surviving parents (and the extended family), surviving siblings, and subsequent siblings.

Drowning and Near-Drowning (Submersion Injury) Drowning is defined as death by suffocation after submersion in a liquid medium. Near-drowning is a term used when a patient recovers, at least temporarily, from the drowning episode. Most investigators include loss of consciousness while submerged to complete the criteria of near-drowning. Patients who are initially resuscitated after submersion but who die within 24 hours are ultimately classified as drowning victims. Secondary drowning refers to patients who have recovered uneventfully from a submersion injury and are asymptomatic for a period of time but who later die from respiratory failure secondary to the episode. The existence of secondary drowning has been questioned in the literature, and the term should not be used [DeNicola et al., 1997]. Patients with so-called secondary drowning have subtle but clearly manifested respiratory compromise immediately after submersion [Pratt and Haynes, 1986]. As many as 15% to 20% of near-drowning victims who ultimately die do so with severe respiratory failure. Nonetheless, the term secondary drowning is misleading because most of these patients have secondary pulmonary infections and concomitant severe neurologic dysfunction. From 1990 to 2000, drowning was the second leading cause of unintentional injury death among U.S. children between 1 and 19 years of age [American Academy of Pediatrics Committee on Injury, Violence, and Poison Prevention, 2003]. In 2000, more than 1400 U.S. children younger than 20 years drowned. Rates of drowning vary with age, gender, and race. Drowning rates are the highest among children aged 1 to 2 years. In Arizona, California, Florida, and Texas, drowning is the leading cause of death in this age group (Swimming programs for infants and toddlers, 2000].

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Near-drowning events, in which the victim survives at least 24 hours, also result in significant numbers of injuries in children. It is estimated that for each drowning death, there are 1 to 4 nonfatal submersions serious enough to result in hospitalization [American Academy of Pediatrics Committee on Injury, Violence, and Poison Prevention, 2003]. Children who still require cardiopulmonary resuscitation at the time they arrive at the emergency department have a poor prognosis; at least half of survivors suffer significant neurologic impairment [Kyriacou et al., 1994].

Epidemiology Most immersions occur in privately owned swimming pools. Toddler drownings tend to occur because of a lapse in parental or adult supervision. A responsible supervising adult can be identified in 84% of toddler drownings, but only 18% of the incidents are actually witnessed [Quan et al., 1989; Wintemute, 1990]. Individuals with seizure disorders are at four times higher risk for submersion accidents regardless of age [Orlowski, 1979]. This threat extends to the bathtub as well, and some investigators have suggested that children with seizure disorders not bathe without supervision or shower instead. In all, 60% to 90% of drownings in children younger than 5 years occur in residential swimming pools; nearly two thirds occur in the child’s home pool. An additional third occur in the pools of relatives or neighbors. In most cases, the child has been unsupervised for less than 5 minutes. Bathtubs are the second most common site of drowning in young children. Bathtubs are a particular threat to children 6 to 12 months of age, who can sit but may not be able to right themselves if submerged. Bathtubs are a source of potential submersion injuries in the home as a result of inadequate adult supervision [Lavelle et al., 1995]. In a Seattle study, all of the bathtub drowning victims were left unattended or under the supervision of another sibling who was younger than 5 years. Four of the five victims older than 5 years had known seizure disorders. This same study reported that for 19% of the bathtub drowning victims, there was evidence of child abuse or neglect, lack of parental supervision, and delays in obtaining help [Quan et al., 1989]. More recent studies have demonstrated that many submersion accidents are inflicted (8% in one study) and that bathtubs were the most common site for inflicted submersions [Gillenwater et al., 1996]. Hot tubs and spas have been recognized as drowning sites because of the opportunity for entrapment under the heavy spa cover or in the suction drain apparatus. The high temperature of the spas and the risk for enhanced exposure to bacterial agents, such as Pseudomonas species, have been implicated as additional risk factors for poor outcomes. Jumbelic and Chambliss [1990] reported a new drowning hazard: the large 5-gallon industrial bucket. These buckets are constructed of rigid plastic and are difficult for a toddler to invert even when empty. Young toddlers, who have relatively large heads and a high center of gravity, fall into these buckets without tipping them and drown even in small amounts of liquid. The average number of young children who drowned in bucket-related injuries, 27 per year, is considerably lower than the number of drownings attributed to bathtubs for this age group. Nevertheless, it is higher than

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estimates of drowning in other in-home water sources (e.g., toilets or basins) [Mann et al., 1992].

Pathophysiology Drowning may be subdivided into wet and dry drowning. As the victim becomes submerged, breath holding occurs and panic ensues. In approximately 15% of drowning victims, severe larynogospasm prevents the aspiration of the liquid medium (dry drowning) [DeNicola et al., 1997]. In the majority of cases, however, wet drowning occurs, in which the patient aspirates the water in which he or she is submerged. In the 1970s, a large amount of literature made the distinction between fresh and salt water wet drowning. It was believed that the hypertonicity of seawater would result in an osmotic gradient, drawing plasma volume into the pulmonary interstitial space. Drowning in fresh water, on the other hand, was believed to create the opposite effect [Cohen et al., 1992; Conn and Barker, 1984]. Fresh water drowning would lead to hypervolemia and dilutional hyponatremia, with dilution of other serum electrolytes as well. Later experimental studies suggested that volumes far greater than is normally aspirated in a drowning victim are required to create the necessary proposed blood volume changes [Modell, 1985]. In a series of 91 victims of severe neardrowning, no serious fluid or electrolyte abnormalities were detected. It also became clear that both fresh water and salt water have the effect of washing out surfactant and creating the potential for the development of pulmonary edema. Today, the differences between salt water and fresh water drowning are downplayed. Rather, the temperature of the water and the possible contaminants contained therein appear more important. Home swimming pools that are well kept tend to have a paucity of bacteria, but the effect of chlorine on pulmonary tissues may be deleterious. Fresh water lakes may contain bacteria and various protozoan pathogens. Seawater tends to be contaminated with bacteria, algae, sand, and other particulate matter. Cerebral hypoxia is the final common pathway in all victims of drowning, both wet and dry, fresh water or salt water [Orlowski and Szpilman, 2001]. Sophisticated critical care management of the respiratory insult in the late 1970s and 1980s made death from isolated respiratory failure after near-drowning less frequent. Some patients develop secondary bacterial pneumonia, but the majority of patients who die of respiratory failure also have severe CNS injury. On the other hand, neurologic insult secondary to hypoxia and ischemia remains the limiting factor in physicians’ ability to successfully resuscitate near-drowning victims. Neurologic care of victims of severe near-drowning remains a controversial subject. The majority of physicians, however, believe there is no advantage of cerebral resuscitation techniques over routine supportive care in near-drowning victims [DeNicola et al., 1997; Spack et al., 1997]. This belief is based on the notion that anoxic injury with cytopathic cerebral edema is determined by the extent of the injury and is not substantially affected by postinjury interventions. Indeed, poor outcome and neurologic death occur commonly in patients in whom intracranial pressure and cerebral perfusion pressures are maintained within the normal range [Spack et al., 1997]. This result is consistent with

the general experience in the cerebral resuscitation literature, which also appears to indicate a lack of efficacy of interventions, such as intracranial pressure monitoring, barbiturate coma therapy, or hypothermia, for global cerebral anoxic injury. Submersion in ice water has long been thought to be associated with better chances of survival, especially in the pediatric population. Pediatric patients tend to have large ratios of surface area to body weight and therefore cool quickly in cold water. The so-called diving reflex, which in mammals tends to shunt blood flow to the brain and heart preferentially after submersion in cold water, and the reduction in metabolic needs because of hypothermia may play a role in protecting the submerged brain from injury in such cases [Gooden, 1972]. There are more than 17 reported cases in the world literature in which prolonged submersion in ice water (water temperature less than 45° to 50° F) was associated with survival and good neurologic recovery, despite the presence of coma and other poor prognostic signs in the emergency department [Orlowski, 1987]. Paradoxically, in victims of warm water near-drowning, the presence of hypothermia is a negative prognostic sign, because hypothermia in these patients is correlated with a longer time of submersion and absence of perfusion [DeNicola et al., 1997; Kyriacou et al., 1994]. As cerebral injury progresses, the victim becomes poikilothermic. Other organ systems besides the CNS and pulmonary system are affected by severe neardrowning episodes; complications include renal failure and disseminated intravascular coagulation [Fields, 1992]. The advisability of continuing cardiopulmonary resuscitation efforts and the duration that these efforts are continued represent ongoing and perplexing dilemmas for the emergency and critical care physician. Although most people would never want to cease resuscitative efforts in a patient who has an opportunity for neurologic recovery, the potential for resuscitating drowning victims to the level of only a persistent vegetative state is very real. Despite efforts to develop prognostic criteria, there is no consensus in the literature with regard to prognostic indexes that preclude meaningful survival [Christensen et al., 1997].

Prognosis Prognostic variables are best discussed in terms of prehospital (on-site) factors and postresuscitation (in-hospital) factors. The on-site factors affecting outcome are water temperature, duration of submersion, and duration of resuscitation. There is no doubt that near-drowning in icy water (less than 50° F) carries a higher chance of survival than that in warmer water. The duration of submersion may also influence outcome; however, this factor is sometimes difficult to ascertain. In addition, it is difficult to separate the effect of submersion times from all other confounding variables, such as water temperature and efficacy of initial resuscitation efforts. Although Frates [1981], using multivariate analysis on warmwater drownings, could not find any correlation between duration of submersion and survival, Quan and Kinder [1992] found that duration of submersion longer than 10 minutes resulted in death or severe neurologic impairment in six of six children. These investigators also found that field resuscitation duration longer than 25 minutes ended in poor out-

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come or death in 17 of 17 patients. In summary, short-term submersion in icy water offers the best chance of intact neurologic survival, whereas longer submersion and field resuscitation times are associated with poor outcomes. Predictors of outcome in the emergency department have been reported by several investigators [Habib et al., 1996]. One retrospective review revealed that age, sex, duration of submersion, core temperature, pH, absence of spontaneous respirations, lack of response to pain, and pupillary nonreactivity were unreliable predictors of outcome [Nichter and Everett, 1989]. However, use of cardiotonic medications to establish a cardiac rhythm in the initial resuscitation attempt was associated with an eventual outcome of death or severe neurologic damage in all instances. Another retrospective review of 44 admissions to the intensive care unit revealed that nonreactive pupils in the emergency department and a Glasgow Coma Scale score of less than 5 on arrival were the best independent predictors of poor neurologic outcome [Lavelle and Shaw, 1993]. No predictor was absolute, and two nonhypothermic patients who arrived at the emergency department in full cardiac arrest, requiring cardiopulmonary resuscitation and cardiotonic medications, had full neurologic recovery. Most investigators agree that the absence of a heartbeat on admission to the emergency department is a poor prognostic sign and is associated with a mortality rate greater than 90% unless there is significant hypothermia [Biggart and Bohn, 1990; Frewen et al., 1985]. Graf and colleagues [1995] reported that among comatose children, unfavorable outcomes could be predicted by a combination of absence of pupillary light reflex, increased initial blood glucose concentration, and male sex (specificity of 100% and sensitivity of 65%). These data indicate that all near-drowning victims who present to the emergency department should receive full attempts at cardiopulmonary resuscitation. If cardiovascular stability cannot be achieved in the emergency department after rewarming of hypothermic victims, the patient cannot be resuscitated and is considered a drowning victim. If cardiovascular stability can be accomplished in the emergency department, the patient should be transferred to the intensive care unit for further management. In summary, there is no medically practical index or score, applied at the scene or during emergency resuscitation, that predicts with 100% accuracy which patients will or will not survive normally. All near-drowning victims should therefore be treated initially unless rigor mortis is present. Whether treatment should be discontinued, however, is a judgment decision that has to be made by the physician in attendance. In the pediatric critical care unit, the prognosis for neurologic outcome has proved difficult to evaluate. Accurate predictors of the prognosis are necessary for limiting or withdrawing therapy. Several scoring systems have been devised to predict outcome. Conn and Barker [1984] and Modell and associates [1980] devised a scoring system based on whether the child (1) is awake, (2) has a blunted sensorium, or (3) is comatose. All patients in the first group survived intact, whereas among those in the second and third groups, the mortality rates were 10% and 34%, respectively. Dean and Kaufman [1981], using a retrospectively assigned Glasgow Coma Scale score, found a score of less than 5 to be associated with an 80% rate of mortality or severe brain damage. Orlowski [1979] devised a scoring

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system for pediatric near-drowning victims, using patient’s age, initial pH, submersion time, pupillary response, and the effectiveness of resuscitation. Other investigators have found that induced hypothermia, barbiturate therapy, and intracranial pressure monitoring, as well as control of intracranial pressure and maintenance of cerebral perfusion pressure, were not associated with improved outcomes. The use of brainstem auditory-evoked potentials, cerebral blood flow, and metabolic rate in combination with initial blood glucose values have all demonstrated some promise but are not available for widespread use [Ashwal et al., 1990; Fisher et al., 1992]. Studies involving xenon cerebral blood flow measurements revealed that total frontal gray and white matter and temporal and parietal gray matter flows were significantly decreased in patients who ultimately died, in comparison with those who were normal or survived in a vegetative state [Ashwal et al., 1990]. Cerebral blood flow measurements were not useful in discriminating the quality of life in those who survived. Proton magnetic resonance spectroscopy and magnetic resonance imaging are useful in predicting outcome in neardrowning victims [Auld et al., 1995; Dubowitz et al., 1998; Holshouser et al., 1997; Kreis et al., 1996]. When performed sequentially in occipital gray matter, proton magnetic resonance spectroscopy provides useful objective information that can significantly enhance the ability to establish prognosis after near-drowning. Patients with poor outcomes appear to have increasing lactate and lower metabolic ratios, specifically the N-acetylaspartate (NAA)/creatine and NAA/ choline ratios. It seems that the clinical examination, particularly after a stabilization period of 12 to 24 hours, provides the best estimate of long-term outcome. In children who manifest no neurologic improvement within the first 3 to 6 hours after admission to the intensive care unit (i.e., remain comatose, flaccid, without pupillary response), survival is extremely unlikely. Continuation of aggressive care beyond this point should be considered on a caseby-case basis. Evaluation at 12 to 24 hours has revealed that failure of return of spontaneous respiration after resuscitation is associated with a 100% rate of mortality [Jacobsen et al., 1983]. In addition, abnormal posturing or seizures persisting beyond 12 hours may also indicate a poor prognosis. In a retrospective investigation of 44 children, Bratton and colleagues [1994] found that the neurologic examination 24 hours after warm water near-drowning distinguished satisfactory outcome from unsatisfactory outcome (death or dependence on total custodial care). All survivors who were normal or had only mild deficits were awake and initiated spontaneous, purposeful movements within 24 hours after submersion. All children who survived with severe deficits or who died remained comatose 24 hours after submersion. Christensen and associates [1997], in a retrospective review of 274 near-drowning patients, demonstrated that an observation period of 48 hours was necessary to avoid loss of intact survivors. They suggested the following strategies to maximize the number of intact survivors while minimizing the personal, hospital, and social costs of poor outcome:

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• Prehospital resuscitation, including early intubation, ventilation, vascular access, and administration of advanced life support medications. • Continued resuscitation and stabilization in the emergency department. • Consideration of withdrawal of support if no neurologic improvement is detected after 48 hours. Ancillary testing such as evoked responses, electroencephalography, and magnetic resonance spectroscopy may prove helpful to corroborate the neurologic examination.

Prevention Quan and colleagues [1989], in a 10-year study of drowning and near-drowning in Kings County, Washington, found that 89% of all victims had no supervision, regardless of whether in a bathtub, pool, or ocean. Adults should be assigned specifically as observers without additional duties or distractions. Home pools should have accessible portable telephones so adults do not have to leave the poolside. If duties call the supervising adult into the house, children should leave the pool and preferably be barred from the area until the adult returns. Most toddlers who drown gain access to the pool from inside the house through doors to the pool area rather than being engaged in water activities. Fences are the only intervention that has proved effective, reducing pool immersion incidents by 50% to 70% [Present, 1987]. Risk of drowning or near-drowning involving unintended access to an unfenced pool is 3.76 times higher than the risk associated with a fenced pool [Pitt and Balanda, 1991]. There should be four-sided fencing immediately surrounding pools, not at the property line. This kind of fencing allows children access to their yards but isolates the pool. Cardiopulmonary resuscitation may produce acceptable outcomes if immersion times are less than 5 minutes and resuscitation time is less than 10 minutes; however, 42% of children who drowned in their own home pools were retrieved by a layperson, usually a family member, and cardiopulmonary resuscitation was not instituted until emergency personnel arrived [Wintemute et al., 1987]. Immediate resuscitation before the arrival of paramedical personnel is associated with a better neurologic outcome [Kyriacou et al., 1994]. Swimming lessons and water safety courses may be useful when instituted at 4 to 5 years of age. Adults should not, however, rely on a young child’s swimming ability to prevent drowning. Roughhousing, risk taking, diving, and other challenging activities increase the risk even for older children. It is highly recommended that swimming competence and basic life support certification be taught in elementary school and reinforced in middle school and high school. The American Academy of Pediatrics Committee on Injury, Violence, and Poison Prevention [2003] has produced a list of 23 recommendations to reduce the incidence of drowning in infants, children, and adolescents. Undoubtedly, the most effective and best proven intervention to prevent swimming pool drowning is four-sided fencing with self-closing, self-latching gates. Every coalition and municipality should work with pool contractors, public health officials, and local media to encourage isolation fencing on all new pools, particularly for families with young children. Institution of pool safety upgrades should be encouraged

when older homes with pools are sold. Industries should continue to explore aesthetically acceptable fencing and effective self-closures for gates, doors, and sliding doors that lead into pool areas. Child health practitioners should incorporate drowning prevention in their anticipatory guidance during well-child visits. This should include admonitions about unsupervised infant bathing, access to water-filled buckets, and open toilets, as well as the need for surveillance, isolation fencing, and door closures and locks. It is hoped that a concerted effort by parents, health workers, industry, and government can reduce the overwhelming losses caused by childhood drownings.

Strangulation Injury Strangulation injuries result from external compression of the neck. Several forms have been described according to the method of application of compression, including hanging, postural strangulation, manual strangulation, and ligature strangulation [Scott and Wiebe, 1997]. Hanging is “complete” when the suspension point is above the height of the victim and the body is totally suspended in air and is “incomplete” when the suspension point is below the height of the victim and a part of the body is supported by the floor or other object. Complete hangings are most commonly seen in judicial executions and, although rarely performed today, were a common method of execution in the United States before 1965. Incomplete hangings are more common. The cause of hanging varies with age. For children younger than 5 years, hanging is almost exclusively accidental [Sabo et al., 1996]. These occur secondary to getting heads caught in crib slats, curtain cords, electric windows, Venetian blinds, or hammock cords and when clothing or a pacifier ribbon becomes caught on an object. However, homicides in infants have been reported. From ages 5 to 12, hangings are both accidental and suicidal. After the age of 12, most hangings are suicidal or accidental during autoerotic actions [Krol and Wolfe, 1994; Sabo et al., 1996]. Suicide is the third leading cause of death in adolescents in North America, and hanging is the second most common method of suicide in this age group. Postural strangulation results when the neck of the victim is over an object and the weight of the body causes external compression of the neck. Manual and ligature strangulation is caused by an external mechanism, with the weight of the victim not contributing to the mechanism of injury. The most common ligature injuries are associated with ropes and extension cords. Nonintentional strangulation is seen in both adults and children. Infants are strangled when the neck is wedged between the slats of a crib or the infant becomes lodged between the mattress and crib. Toddlers and preschoolaged children are sometimes caught beneath garage doors. The mechanism of injury in strangulation and hangings is influenced by the amount of physical force used, how the force was applied, and the duration of the force. Death is a consequence of direct injury to the CNS, immediate cardiac arrest, or compression and injury to the structures of the neck. Direct injury to the CNS results from the drop force when the victim is completely suspended, as in complete hangings. The cervical spinal cord or brainstem is disrupted, and death is instantaneous. In complete or judicial hangings,

Perkin and Ashwal / Hypoxic-Ischemic Encephalopathy in Infants and Older Children

the ligature knot is located centrally over the occiput with the ligature curved symmetrically around the anterior portion of the neck. This placement may result in partial or complete avulsion of the carotid arteries, laryngeal fractures, and fractures of the vertebral bodies and base of the skull. Death from immediate cardiac arrest is thought to be secondary to a massive vagal reflex from bilateral carotid body or vagal sheath stimulation [Scott and Wiebe, 1997]. Compression of neck structures and its sequelae are the most common mechanisms of injury in strangulation and incomplete hangings. The venous drainage of the head and neck is through the jugular system and a series of intercommunicating veins related to the spinal column. Because of their superficial location, minimal external pressure results in occlusion of internal and external jugular veins, with obstruction of venous outflow from the head and neck. Venous obstruction results in ischemia, hypoxia, and loss of consciousness. The victim becomes flaccid, and with loss of muscle tone, compression of the carotid arteries occurs, resulting in increasing ischemia and hypoxia. Depending on the severity and duration of the insult, neuronal damage occurs with cerebral edema and elevated intracranial pressure [Sabo et al., 1996]. In contrast to other injuries, such as neardrowning, increased intracranial pressure occurs more frequently in childhood strangulation [Ashwal et al., 1991]. As the glottis and tongue are lifted into the pharynx, loss of muscle tone results in airway occlusion. The carotid arteries above the level of the cricoid cartilage are separated from the surface of the skin by the platysma and sternocleidomastoid muscles and deep cervical fascia. These vessels are not easily occluded by external pressure, but traction injuries can occur, ranging from small intimal tears to total disruption. The laryngeal skeleton includes the hyoid bone and thyroid and cricoid cartilages. These structures in children are semirigid, and calcification is not complete until the third decade. Laryngeal fractures are rare in childhood, but the prevalence of fractures increases with age, coincidentally with calcification of the laryngeal skeleton. The most common laryngeal injuries in childhood are mild and include endolaryngeal edema, hematomas, and mucosal tears. More severe injuries result in extensive edema, hematomas and lacerations, cartilage fractures, and vocal cord paralysis. These injuries may cause airway discontinuity and obstruction. Cervical fractures are also rare in children [Krol and Wolfe, 1994]. A 3.5- to 4.0-mm pseudosubluxation of C2 on C3 has been demonstrated in as many as 15% of healthy children, and it is believed that laxity of the ligaments and musculature is protective. Feldman and Simms [1980] reviewed 233 childhood strangulations and did not find cervical or laryngeal fractures or evidence of airway compromise. Cerebrovascular hemodynamic profiles have been obtained in children with hypoxic-ischemic injuries after strangulation [Ashwal et al., 1991; Hanigan et al., 1996]. In general, the profiles reveal cerebral hyperemia, loss of autoregulation, and intact but blunted vascular response to PaCO2. Not unexpectedly, the accumulated data demonstrate that absolute values of CO2 reactivity vary considerably, and single-point determinations encompassing wide epochs may not reflect the continuous changes in hemodynamics of the cerebrovascular bed to hypoxic-ischemic injury and sub-

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sequent treatment. Many patients manifest negative CO2 reactivities in various deep and cortical regions, which may represent redistribution of flow from responsive to nonresponsive vascular beds. The findings of cerebral hyperemia, loss of autoregulation, and the presence of vascular steal phenomenon during hypocarbia suggest that therapies such as flow promotion or hyperventilation are not indicated and are potentially dangerous in strangulation injuries.

Nonaccidental Trauma Patients with severe traumatic head injury experience immediate alterations in cerebral and systemic physiology that substantially influence neurologic outcome [Atkinson, 2000]. Two immediate pathophysiologic events occur with the onset of severe head injury that substantially affect subsequent outcome: head injury–induced apnea and a stressrelated massive sympathetic discharge. The combined effects of hypoxia, hypercarbia, and acidosis and a surge in blood pressure, as well as the direct effects of catecholamines on tissue, lead to a synergistic injury effect in the patient. The extent of apnea and catecholamine surge after severe head injury is directly related to the amount of energy transmitted to the brainstem [Atkinson, 2000]. As a result, many patients with severe head injury live or die at the scene, depending on whether they resume breathing. In patients who resume spontaneous respiration, apnea-induced hypoxic brain and cardiac injury augmented by elevated stress hormones may result in serious morbidity. Johnson and co-workers [1995] examined intentional closed-head injury (i.e., child abuse) in 28 children and found that 57% had a verifiable history of apnea before hospitalization. They concluded that trauma-induced apnea causes cerebral hypoxia and ischemia, and these were more important in modulating outcome than was the mechanism of primary brain injury (i.e., subdural hematoma, subarachnoid hemorrhage, diffuse axonal injury, or contusions). Geddes and colleagues [2001] identified a high incidence of widespread microscopic neuronal hypoxic brain damage in a cohort of children with nonaccidental head injury. In a proportion of infants, they found significant microscopic changes of focal axonal damage to the craniocervical junction on the cervical cord. For infants who presented with a history of apnea and hypoxic brain damage, they proposed a mechanism of cervical hyperextension and flexion during shaking, which led to damage of the brainstem respiratory centers with a consequent bad outcome from severe hypoxic brain damage. More recent evidence further confirms that in nonaccidental head injury, hypoxic-ischemic injury is of greater importance with regard both to signs and symptoms at presentation and to long-term outcome [Kemp et al., 2003].

Lightning and Electrical Injuries Lightning is a fascinating, albeit uncommon, form of electrical injury. Only 150 to 300 people die each year in the United States of injury secondary to lightning strike; the death rate is highest in adolescents [Fontanarosa, 1993; Volinsky et al., 1994]. Nearly two thirds of people struck by lightning survive, although many have significant sequelae.

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The lightning strike is a direct-current electrical discharge with a high magnitude of energy and short duration of exposure. When the electrical discharge in a cloud is greater than the air resistance (30,000 to 50,000 V), energy is discharged to the ground. Lightning energy is estimated to be about 25,000 to 200,000 A, or 100 million to 2 billion V. The duration of the electrical discharge is from 0.00001 to 0.001 second. The estimated heat generated from the electrical discharge is between 8000° and 30,000° C at the contact area [Patten, 1992]. Survival from lightning strikes is possibly related to the short duration of electrical contact. With the presence of metal objects on the body, however, the electrical contact time is increased, resulting in a deeper burn and increased rates of morbidity and mortality. Thermal forces generated by lightning are capable of producing tremendous pressure waves from the rapid expansion and cooling of the air around the lightning strike. These pressure waves are significant enough to cause serious blunt-force trauma. Lightning strikes produces a variety of injury patterns. A lightning strike that directly contacts the victim results in the most serious injuries. A side flash or splash injury occurs when lightning strikes a primary object and the electrical charge leaps from the object to the victim. This type of strike may seem less dangerous but can also be fatal. Lightning striking one person may be splashed to another person and has resulted in death in the second person. Lightning strike may cause injury as a result of one of three types of energy transfer: electrical, thermal, or mechanical. The electrical injury depends on the voltage, amperage, degree of resistance, and anatomic pathway. Electrical energy follows the path of least resistance. The decreasing order of resistance for human tissues is bone, fat, tendon, skin, muscle, blood vessels, and nerves [Fontanarosa, 1993; Patten, 1992]. When the skin is dry, the electrical path is deflected over the body because of the higher resistance of the skin. The thermal energy produced may cause a break in the skin, forming a pathway for the electrical charge to pass through to less resistant tissues such as muscle, nerves, and blood vessels. The primary effect of lightning results from a massive direct-current insult to the entire myocardium and CNS. This insult results in asystole and loss of function of the medullary respiratory centers. Lightning effects on the respiratory center last longer than the cardiac effects. Cardiac rhythm returns if apnea is corrected; if apnea is not corrected, secondary hypoxic cardiac arrest ensues. The mortality from lightning is related to the effects of apnea, not asystole. Resuscitation attempts in lightning victims have resulted in higher success rates than in victims of other cardiac dysrhythmias. The direct current of lightning causes a single countershock to the entire myocardium, as opposed to alternating current, which distributes a repetitive fibrillating stimulus to the heart. The resumption of spontaneous electrical activity may be secondary to the automaticity of the myocardium. Patients with initial rhythms associated with a poor prognosis may completely recover with prompt institution of respiratory and cardiac support. Aggressive and persistent resuscitation efforts should be continued until cerebral function can be assessed. Anoxic cardiac and cerebral injury may be reduced in lightning injuries by causing a delay in anoxic cellular

destruction. Several authors have suggested that the reason for possible recovery after prolonged cardiac arrest is that lightning causes cellular metabolism to cease instantly, thereby delaying the onset of anoxic tissue destruction and reducing the potential for anoxic cardiac and cerebral injury [Fontanarosa, 1993]. However, the metabolic basis for this concept has not been verified, and available clinical evidence does not support the concept that lightning strike confers any cellular protective mechanism. The CNS is highly sensitive to electrical injury. Injury to the CNS may result from direct electrical injury or anoxia or may be secondary to vascular injury [Patten, 1992]. The pathophysiologic mechanism of CNS injury includes coagulation in the cortex, formation of epidural or subdural hematomas, paralysis of the respiratory center, and intraventricular hemorrhage. Symptoms of CNS injury include loss of consciousness, confusion, transient disorientation, seizures, restlessness, retrograde amnesia, and varying degrees of transient paralysis. Coma and symptoms of cerebral edema are not unusual. Transient paralysis may involve the lower extremities in two thirds of victims and the upper extremities in one third. Late sequelae include amnesia, paraplegia, neuropathy, decreased reflexes, and chronic subdural hematomas. The presence of sequelae may be related to hypoxic or blunt-force CNS injury. Lightning strikes may also cause transient autonomic dysfunction, which may result in fixed and dilated pupils, mydriasis, anisocoria, loss of the red reflex, and Horner’s syndrome. Pupillary responses cannot be used reliably as an indicator of brainstem function.

Electrical Shock Victims of electrical shock sustain a wide spectrum of injuries ranging from a transient unpleasant sensation from brief exposure to low-intensity current to instantaneous sudden death from accidental electrocution. Electrical shock is associated with a fatality rate of 0.5 per 100,000 per year in the United States and accounts for approximately 1000 deaths annually. Electrical injuries cause an additional 5000 patients to require emergency treatment and constitute 4% to 7% of burn center admissions. More than 20% of all electrical injuries occur in children [Fontanarosa, 1993; Thompson and Ashwal, 1983]. Risktaking behavior among adolescent boys, such as climbing utility poles, playing near electrical railway lines, and trespassing through transformer substations, can expose them to high-tension electrical sources. The inquisitive nature of toddlers and their habit of exploring their environment with their mouths contribute directly to the most common electrical injury in childhood, the perioral burn, which affects 4000 children per year. Electrical injuries result from the direct effects of current and from the conversion of electrical energy into thermal energy as current passes through body tissues. Factors that determine the severity of electrical shock include the magnitude of energy delivered, resistance to current flow, type of current, duration of contact, and current pathway. Systemic effects and tissue damage resulting from electrical shock are proportional to the magnitude and intensity of current delivered to the victim. Current flow is directly related to voltage and inversely related to resistance in the

Perkin and Ashwal / Hypoxic-Ischemic Encephalopathy in Infants and Older Children

current path. Body tissues differ in their resistance to the passage of electricity. Tissues with high fluid and electrolyte content conduct current better than others. Bone is most resistant to the passage of electrical energy, followed in decreasing order of resistance by fat, tendon, skin, muscle, blood vessels, and nerves. Skin resistance is the most important factor impeding current flow. High skin resistance and a small area of contact usually concentrate electrical energy in a relatively small area and produce a severe local skin wound, limiting internal current flow. Once the skin becomes charred, the external barrier to flow is removed, allowing the current easy internal access. Skin resistance also can be reduced substantially by moisture, sweat, or skin contaminants, which decrease the impediment to current flow and convert what ordinarily may be a minor lowvoltage injury into a life-threatening shock. Alternating current at 60 cycles per second, the frequency used in most household and commercial sources of electricity, is substantially more dangerous than direct current of the same magnitude. Contact with alternating current may cause tetanic skeletal muscle contractions, preventing the victim from releasing hold of the electrical source and leading to increased current delivery. In contrast, direct current usually causes a single strong flexion of skeletal muscle and often thrusts the victim away from the current source. Low-voltage alternating current (60 Hz) has a narrow margin of safety [Fontanarosa, 1993]. Low-intensity current at 1 to 4 mA is perceived as an unpleasant tingling sensation. Contact with alternating current at 10 to 20 mA causes repetitive stimulation of muscle fibers, produces tetanic skeletal muscle contractions, which may prevent the victim’s hand from releasing its grasp from the current source, and lengthens the duration of contact with the energized source. Thoracic muscle tetany involving the diaphragm and intercostal muscles occurs at 30 to 50 mA and can result in respiratory arrest. Prolonged contact leads to sustained apnea with hypoxemia and secondary cardiac arrest. Ventricular fibrillation may occur with exposure to as little as 50 to 100 mA. The repetitive frequency of alternating current increases the likelihood of current delivery to the myocardium during the vulnerable recovery period of the cardiac cycle and can precipitate ventricular fibrillation. Cardiopulmonary arrest is the primary cause of immediate death from electrical injury. The initial dysrhythmia producing sudden death is a function of the magnitude of current. Alternating current (100 mA to 1 A) generally causes ventricular fibrillation, whereas higher intensity current (>10 A) may cause asystole. Respiratory arrest may occur immediately after electrical shock and results from one or a combination of the following mechanisms: (1) electrical current passing through the brain may cause inhibition of medullary respiratory center function, (2) tetanic contraction of the diaphragm and chest wall musculature may occur during current exposure, (3) prolonged paralysis of respiratory muscles may continue after contact with the electrical current has terminated, or (4) respiratory arrest may accompany cardiac arrest in patients with ventricular fibrillation or asystole. Respiratory arrest may last minutes to hours after the electrical shock terminates and may persist after restoration of spontaneous circulation. In some patients, cardiac activity

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may be maintained in the absence of spontaneous ventilation. If respiratory arrest is not corrected promptly by artificial ventilation and oxygenation, secondary hypoxic cardiac arrest may occur. Neurologic complications are reported frequently and include coma, seizures, agitation, myelopathy, and peripheral nerve damage. Vascular complications include arterial spasm, thrombosis and rupture, and venous thrombosis. Depending on the extent of injury, electrically injured extremities may appear edematous or, in cases of underlying coagulation necrosis, can be mummified. Arterial damage may cause peripheral pulses to be absent or difficult to palpate, and thrombosis of peripheral veins precludes their use for intravenous access.

Sudden Cardia Arrest in Children and Adolescents Sudden cardiac arrest is the sudden cessation of cardiac activity so that the victim becomes unresponsive with no normal breathing and no signs of circulation. Unless the victim receives immediate cardiopulmonary resuscitation and other treatment to restore normal cardiac activity, he or she will die. Although the precise incidence of sudden cardiac arrest in children is unknown, it is not a leading cause of death [Hazinski et al., 2004]. When sudden cardiac arrest does occur in children and adolescents, it may be precipitated by ventricular fibrillation or rapid ventricular tachycardia (pulseless ventricular tachycardia). These abnormal heart rhythms in children are typically caused by inherited or congenital cardiac conditions or by acute medical problems that cause inflammation of the heart. Examples of such conditions include long QT syndrome, hypertrophic cardiomyopathy, abnormal development of the coronary arteries, aortic dissection, myocarditis, coronary artery aneurysm associated with Kawasaki’s disease, and congenital aortic stenosis [Liberthson, 1996]. Many of these conditions are not detected during routine screening for school physical examinations or sports activities; thus, sudden cardiac arrest may be the first sign of these conditions [Maron, 2003]. Sudden cardiac arrest may also result from commotio cordis, a condition resulting from a blow to the chest that causes ventricular tachycardia or fibrillation. Each year approximately 10 cases of commotio cordis are reported in the United States for victims of all ages [Maron et al., 2002]. If a child develops sudden cardiac arrest caused by ventricular fibrillation or pulseless ventricular tachycardia, immediate cardiopulmonary resuscitation by a bystander and early defibrillation are needed. Automatic external defibrillators are computerized defibrillators designed for use by lay rescuers to treat sudden cardiac arrest. The automatic external defibrillator provides voice and visual prompts to guide the rescuer. When attached to an unresponsive victim in cardiac arrest, the automatic external defibrillator analyzes the victim’s heart rhythm and determines whether a shock is needed, charges to an appropriate shock dose, and prompts the rescuer to deliver a shock. The automatic external defibrillator delivers a shock only if ventricular fibrillation or ventricular tachycardia is present [Hazinski et al., 2004]. The U.S. Food and Drug Administration has cleared automatic external defibrillators for use in children younger than

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8 years. Two of these devices have accurately identified ventricular fibrillation and rapid ventricular tachycardia in young children [Atkinson et al., 2003]. The American Heart Association states that automatic external defibrillators may be used with cardiopulmonary resuscitation for treatment of prehospital cardiac arrest in children 1 to 8 years of age [Hazinski et al., 2004]. The American Heart Association continues to recommend the use of cardiopulmonary resuscitation with automatic external defibrillators for treatment of cardiac arrest in children 8 years of age and older and in adults.

NEUROLOGIC EXAMINATION AFTER CARDIAC ARREST Features of the neurologic examination of infants and children who have experienced prolonged cardiac arrest and global hypoxic-ischemic encephalopathy are reviewed in Chapter 61 on impairment of consciousness and coma. Several points need re-emphasis including the following: • Careful monitoring of brainstem reflexes, particularly pupillary and oculocephalic • Determination of whether the patient is apneic and assessment of the patterns of respiration present • Evidence of increasing intracranial pressure • Evidence of the development of worsening alterations of tone, either (1) severe hypotonia or flaccidity, suggestive of deteriorating cortical and brainstem function, or (2) severe increases in tone including posturing, suggestive of worsening white matter function as a result of edema, osmotic demyelination, or secondary degeneration

NEUROLOGIC COMPLICATIONS AFTER CARDIAC ARREST Delayed Posthypoxic Injury Delayed posthypoxic injury may occur 24 to 48 hours after the initial recovery of consciousness after coma. In children, this injury occurs most frequently after near-drowning accidents or cardiac surgery in which profound hypothermia and either low-flow bypass or circulatory arrest was used. Magnetic resonance imaging studies may reveal evidence suggestive of edema or demyelination, which may be postanoxic or osmotic in etiology. In addition, diffusionweighted imaging may reveal restricted diffusion, typically in the basal ganglia, cerebellum, and cortex. These changes are seen initially in gray matter and later in white matter [Arbelaez et al., 1999; Bydder and Rutherford, 2001]. Experience has revealed that early extubation of patients with post-ischemic injury is potentially dangerous. Even though the condition of these children may appear to have improved, development of a posthypoxic encephalopathy may result in inadequate airway control and ventilatory drive, which could add secondary injury.

Post-ischemic Seizures Excessive excitatory transmitter release during brain ischemia can lead to paroxysmal discharges in the cerebrum,

especially in the hippocampus, beginning within minutes and lasting several hours despite cerebral reperfusion. Repetitive discharges may progress to clinically overt seizures, and suppression is then necessary to prevent further injury. Seizures, including episodes of convulsive and nonconvulsive status epilepticus, frequently follow cerebral anoxia. Status epilepticus after anoxic injury is associated with poor outcome and persistent unconsciousness [Jumas and Brenner, 1990; Krumholz et al., 1988]. In addition, electrographically documented status epilepticus without somatic motor manifestations has also been suggestive of poor outcome [Simon and Aminoff, 1986]. Status epilepticus can itself result in permanent anoxic brain damage and necessitates immediate attention. Clinical seizures should be treated aggressively with benzodiazepines and phenytoin. If these agents are unsuccessful, barbiturates may be added. The disadvantage of barbiturates in this setting is that they will further depress the sensorium and make prognostication difficult. Post-ischemic seizures account for 5% to 10% of cases of childhood status epilepticus [Pellock, 1994]. Children who have these seizures should be treated aggressively; electroencephalography is indicated to guarantee that seizure activity is ablated. Nonconvulsive status epilepticus may exist after apparent successful treatment of convulsive status epilepticus [Perkin et al., 1996]. A potential risk of intensive care unit therapy is failure to recognize status epilepticus in the critically ill, paralyzed patient with injury [Michelson and Ashwal, 2004; Weise and Bleck, 1997]. This clinical setting may pose significant risk for increased morbidity in the already compromised patient; continuous encephalographic monitoring may be warranted if paralysis is truly required for cardiorespiratory management.

Delayed Postanoxic Myoclonic Seizures Delayed postanoxic myoclonic seizures may occur after severe anoxic brain injury. Myoclonus usually appears within the first 24 to 48 hours after cardiac arrest and is generalized, involving all voluntary muscles. The electroencephalogram (EEG) is usually abnormal, with generalized synchronous spike discharges or burst-suppression activity. Control of the myoclonic seizure activity is difficult with phenytoin or phenobarbital, and treatment with intravenous benzodiazepines is frequently necessary. The presence of postanoxic myoclonus is usually indicative of a high risk for long-term neurologic sequelae [Krumholz et al., 1988]. In one study of comatose adult patients after cardiac resuscitation, myoclonic seizures developed in 37%, and all of those patients died [Wijdicks et al., 1994]. The authors concluded that myoclonic status epilepticus in comatose survivors after cardiac resuscitation indicates devastating anoxic brain injury. Myoclonic status epilepticus should be considered an agonal phenomenon, and its presence should strongly influence the decision to withdraw life support.

LABORATORY TESTS USED TO PREDICT OUTCOME The clinical course and prognosis of coma after resuscitation from pediatric cardiac arrest must be clearly defined, and full documentation of the resulting morbidity must be

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made. Early, accurate predictors of outcome are important for guiding the difficult ethical, medical, and economic decisions involved in treating these children. Furthermore, such information is useful for counseling families, collaborating with organ transplant teams, evaluating experimental resuscitative therapies, and planning further therapies. Physicians are obligated to keep abreast of clinical, laboratory, and neurophysiologic markers that could help to determine how much neurologic damage a child might have sustained in a hypoxic-ischemic event. Currently, the most powerful individual predictor of neurologic outcome after cardiorespiratory arrest is the neurologic examination. Sequential observations of a patient’s breathing pattern, eye movements, body posture, and reflexes provide essential information to help establish expectation of outcome [Trubel et al., 2003]. Levy and co-workers [1985] applied multivariate analysis to variables from the neurologic examination in a series of 210 comatose adults studied after hypoxic-ischemic insults. Of the 15 patients who were vegetative at 1 month, none regained independent function. The oculocephalic response and the 3-day motor response enabled the investigators to identify all patients who gained independent function. This identification was true even for the 2 of 57 patients who remained in eyes-closed coma for 3 days and then ultimately regained independent function. Edgren and associates [1987] applied the Glasgow Coma Scale score to assess outcome in 262 adult comatose survivors of cardiac arrest. Glasgow Coma Scale scores of less than 6 at 3 days after cardiac arrest were predictive of poor outcome at 6 months, with no false-negative results. In a similar study of 216 adults after out-of-hospital cardiac arrest, Mullie and co-workers [1988] found that a best Glasgow Coma Scale score of less than 4 as early as 2 days after cardiac arrest was predictive of death or vegetative outcome in all but one patient. The one exception progressed from vegetative state to severe disability. A study involving 109 comatose children with hypoxic-ischemic encephalopathy documented that the absence of a motor response on the third day after admission was associated with an unfavorable outcome [Beca et al., 1995]. Nevertheless, in 23% of the children, clinical evaluation was difficult because of neuromuscular paralysis or heavy sedation. This reinforces the relevance of other early prognostic factors, such as electrophysiologic data. Although a few patients are thought to “defy the textbooks,” they likely represent cases of asphyxia without cardiac arrest, coma of an origin other than asphyxiainduced cardiac arrest, unrecognized hypothermia, or an associated overdose of a cerebrally protective drug. Although the Glasgow Coma Scale score was not predictive of outcome when applied after asphyxia-induced cardiac arrest in pediatric patients, its predictive power was tested with only a single score on initial presentation [Dean and Kaufman, 1981]. Careful studies to determine which components of the neurologic examination in children after hypoxic injury correlate best with outcome have not been done [Jacinto et al., 2001; Kriel et al., 1994; Trubel et al., 2003].

Electroencephalography The EEG also can provide prognostic information after cardiopulmonary arrest. Chen and associates [1996] retrospect-

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ively examined the relation between first post–cardiac arrest EEG and clinical outcome in 408 adult cases. A five-grade classification was used to categorize EEGs. Although permanent severe neurologic damage was observed in some patients with grade I EEG, none of the 208 patients with grade IV or V (i.e., severely abnormal) EEGs had a good neurologic recovery. Adjunctive prognostic information also can be derived from cerebrospinal fluid enzyme elevations of the brain isoenzyme of creatine phosphokinase or neuronspecific enolase. The neurologic examination, EEG, and cerebrospinal fluid neuron-specific enzyme levels used together could provide powerful prognostic information as early as 48 to 72 hours after resuscitation. Before a study by Mandel and co-workers [2002], there were no prospective studies on the pediatric population in which the relationship between early electroencephalographic criteria and long-term outcome was analyzed. In their study, the first EEG was obtained within the first 24 hours after admission. Among their population of children who were still comatose at 24 hours, the presence of a discontinuous tracing and the absence of reactivity were indicative of an unfavorable outcome, as was also observed by Chen and associates [1996]. The presence of spikes or epileptiform discharges was always associated with an unfavorable outcome. Electroencephalographic findings must be interpreted cautiously because they may be altered by sedative medication.

Somatosensory- and Auditory-Evoked Potentials Evoked potential monitoring has been used in an attempt to provide early prognostic information about outcome after cardiopulmonary resuscitation. Evoked potentials are inexpensive and can be obtained within the intensive care unit; their advantages over electroencephalography are that the responses are not affected by sedative administration and they are insensitive to electrical noise in the environment. Madl and colleagues [1996] tested somatosensory-evoked potentials in 441 adults after successful resuscitation from cardiac arrest. They reported that 20% of the patients had no N20 response and observed that the presence or absence and the latency of the cortical N20 peak reliably differentiated between bad and favorable outcome with 100% predictive ability. They also found that a preserved N20 peak was not useful for discriminating whether an individual patient would survive. Testing was performed within 48 hours of resuscitation, which is a clinically relevant time frame. Beca and associates [1995] used somatosensory-evoked potentials in children within 48 hours after different neurologic injuries (e.g., trauma, ischemia, meningitis). They demonstrated predictive power of 100% for good outcome in patients with normal somatosensory-evoked potentials and 100% prediction for poor outcome with absence of somatosensory-evoked potentials in 99 children tested, when they excluded certain cases in which there was a physical barrier that impeded cutaneous reception of the electrical impulse (e.g., subdural effusions). A systematic review of studies of somatosensory-evoked potential results in comatose patients enables estimation of outcomes with a higher degree of certainty than is available from individual studies [Robinson et al., 2003]. Adults in coma from hypoxic-ischemic injury with absence of somato-

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sensory evoked potential responses have less than a 1% chance of awakening. However, in children, exceptions to this rule occur; of the 7% who awaken despite absence of evoked responses, the majority have an outcome better than a severe disability [Robinson et al., 2003]. Brainstem auditory-evoked potential testing has been used in children who experienced cardiac arrest after submersion accidents [Fisher et al., 1992]. Normal evoked responses were observed in all children who recovered neurologically intact. Children who recovered with significant handicaps demonstrated reduction in wave V amplitude over time and prolonged wave I-V interpeak latencies. Other reports, how-

COMA

ever, have not found brainstem auditory-evoked potentials to be that reliable for outcome prediction after anoxic coma, although they were useful in comatose patients with traumatic brain injury [Guerit et al., 1993]. The predictive powers of the clinical examination, EEG, and somatosensory-evoked potentials in determining the prognosis of patients in anoxic coma have been evaluated and compared in adult patients to identify combinations that may improve the accuracy of prediction. In one study, clinical examination correctly predicted outcome in 58% of patients, somatosensory-evoked potentials in 59%, and EEG in 41% [Basetti et al., 1996]. The combination of clinical

RECOVERY OF CONSCIOUSNESS

N20 Fpz - C4

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C3 - C4 N13 Fpz - C5(s) EP

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Fpz - C3

C4' - C3' N13 Fpz - C5(s) EP FpL - EpR 1.22 μV DIV

B

8ms DIV

Rt. median

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FIGURE 64-6. Usefulness of somatosensory evoked response (SER) studies for outcome prediction after acute brain injury. Median nerve SERs in two children. A, SER in a 21/2-year-old child who was in a coma secondary to a near-drowning accident. His SER demonstrated an intact thalamocortical response (N20-P23), which is usually predictive of recovery from coma to a conscious state. He slowly recovered consciousness over several weeks. B, SER in a 6-month-old boy with medium-chain acetyl coenzyme A dehydrogenase deficiency who presented in coma and status epilepticus. The SER could be elicited at the level of the cervical spinal cord and brachial plexus. The thalamocortical response was absent; his condition evolved over 2 weeks to a persistent vegetative state (PVS), and as of 1 year later, he remained in this condition.

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examination, somatosensory-evoked potentials, and EEG raised the percentage of correct predictions to 82%. Another report of 34 adult patients with anoxic coma revealed that patients with extensor posturing to painful stimulation and a “malignant” EEG or those with flexed posturing and bilateral absence of somatosensory-evoked potentials on day 3 or later had poor outcomes [Chen et al., 1996]. These findings are important and suggest that evoked response measurement can provide important adjunctive information to aid in decision making after asphyxia-induced cardiac arrest (Fig. 64-6). However, decisions regarding continuation or forgoing of life-sustaining therapies should be based on all of the available clinically relevant information. The objective of establishing the most accurate information possible is essential in the discussion with the family. It is currently recommended that maximal support be given to the child for the first 24 hours. After this time, the association of the clinical factors (Glasgow Coma Scale score <5, absence of spontaneous respirations and pupillary reflexes) and the presence of electrophysiologic factors (discontinuous activity in the EEG, absence of electroencephalographic reactivity, and abolition of the N20 wave) are highly predictive of death or severe long-term disability [Mandel et al., 2002].

Biochemical Markers Biochemical variables in the cerebrospinal fluid, such as lactate, creatine phosphokinase BB-isoenzyme, lactate dehydrogenase, and neuron-specific enolase, have been investigated as early prognostic markers of neurologic outcome after cardiac arrest [Fogel et al., 1997; Garcia et al., 1994; Karkela et al., 1992]. Examination of the cerebrospinal fluid in the early phase after cardiac arrest may be hazardous, particularly if there is the possibility of an intracranial mass lesion. Moreover, serial examinations of cerebrospinal fluid might be difficult to justify. Therefore, valid biochemical markers of outcome in serum must be established. Several proteins synthesized in astroglial cells or neurons have been proposed as serum biochemical markers of cell damage in the CNS [Qureshi, 2002]. The ideal serum markers should have high specificity and sensitivity for brain injury, be released only after irreversible destruction of brain tissue, have a rapid appearance in serum, and have temporal correlation with the onset of injury. The variability in measurement should be low, to ensure a predictable relationship between the serum concentration and the amount of brain injury. The marker should be able to provide prognostic information regarding brain injury. Furthermore, reliable assays for immediate analyses should be available [Qureshi, 2002]. With regard to reliable biochemical markers of brain injury, increased serum levels of the low-molecular-weight protein S-100B have been reported in cases of cardiac arrest and traumatic brain injury [Mussack et al., 2002; Spinella et al., 2003]. Urinary S-100B protein concentrations are used as a marker for brain damage in asphyxiated infants [Gazzolo et al., 2004]. The biologic role of S-100B protein, a calcium-binding protein found in the nervous system, is still unclear [Dennery, 2003]. Its half-life is about 1 hour, and it is excreted mainly

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in the urine [Gazzolo et al., 2004]. Increased S-100B concentrations in biologic fluids are a reliable marker of brain damage in adults, infants, and fetuses [Gazzolo et al., 2004]. The short half-life of S-100B protein makes it an interesting marker for longitudinal monitoring. Elevated S-100B levels 12 hours after cardiac arrest are suggestive of severe global cellular brain damage, which is correlated with an unfavorable outcome after 12 months [Mussack et al., 2002]. In one analysis, neuron-specific enolase concentrations in serum samples were correlated with patient outcome after cardiac arrest [Fogel et al., 1997]. A serum neuron-specific enolase concentration of 33 ng/mL determined up to day 3 after cardiac arrest can predict poor neurologic outcome.

Neuroimaging Studies have indicated that normal results of head CT performed immediately after anoxic injury are not correlated with outcome [Han et al., 1990; Romano et al., 1993]. However, abnormal results obtained in the initial hours after injury are associated with a poor prognosis. Patients with anoxic-ischemic insults may exhibit a variety of findings on CT of the brain. In a study of 53 patients (all ages) scanned 3 days after an out-of-hospital cardiac arrest, clinical differences were found between patients who had cerebral edema and those who did not [Morimoto et al., 1993]. In all, 23 of 25 patients with cerebral edema had cardiac arrest as a result of respiratory distress, whereas this finding was true in only 5 of 28 patients without cerebral edema. Initial arterial pH was significantly lower in patients with cerebral edema, and significantly more of these patients remained comatose or were diagnosed as brain dead. Cerebral edema was apparent in 9 of these 25 patients when scanned the first day of hospitalization. Over the next 2 days, low-density areas involving the basal ganglia, midbrain, and thalamus developed in 22 of the 25 patients. Eventually, loss of the normal gray-white matter differentiation was seen in all patients. It was suggested that brain swelling in the early postresuscitation period might be one of the predictors of a poor neurologic outcome in patients who experience an out-of-hospital cardiac arrest [Morimoto et al., 1993]. Although basal ganglia injury is a well-known cerebral effect of hypoxic-ischemic injury, documentation comes from postmortem studies, with only sporadic reports in live patients [Jacobs et al., 1990]. Magnetic resonance imaging makes it possible to detect lesions in the basal ganglia after cardiopulmonary arrest, which are correlated with the development of movement disorder. The course of the clinical signs is correlated with the presence of abnormalities on magnetic resonance imaging [Jacobs et al., 1990; Wallays et al., 1995], as well as with the results of diffusion-weighted imaging [Arbelaez et al., 1999].

Magnetic Resonance Spectroscopy Proton magnetic resonance spectroscopy is clinically useful for identifying noninvasively the biochemical state of the CNS, as reviewed in Chapter 11. Proton magnetic resonance spectroscopy has been used to study patients after acute nontraumatic and traumatic injuries [Ashwal et al., 1995, 1997; Ross and Michaelis, 1994]. Pediatric patients with

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severe closed-head injuries or strokes with severe long-term neurologic sequelae exhibit reduced NAA peaks and reduced NAA/creatine ratios [Ashwal et al., 2000]. Adults with cardiac arrest, elevated brain lactate levels on proton magnetic resonance spectroscopy, and absence of N20 somatosensory-evoked responses had a poor prognosis if they were still alive 4 weeks after injury [Berek et al., 1995].

Several studies have addressed the metabolic changes in response to acute cerebral injury in children through the use of proton spectroscopy [Holshouser et al., 1997]. Proton magnetic resonance spectroscopy has been used to evaluate the prognosis of pediatric near-drowning victims [Dubowitz et al., 1998; Kreis et al., 1996]. Of 16 children reported, those with excessive lactate levels universally had a poor

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FIGURE 64-7. Proton magnetic resonance spectrum studies in a child without brain injury and in two children with acute global ischemic central nervous system insults. A, Spectra from occipital cortex in a normal 21-month-old female, displaying the increases in N-acetyl aspartate (NAA) and in creatinephosphocreatine (Cre), with decreases in choline (Cho) and myoinositol (mI) that is seen in comparison with younger patients (see Chapter 11 for spectra in younger children). Glx, glutamine. B, Spectra from the occipital cortex in an 18-month-old female with severe post–hypoxic-ischemic injury on day 4 after a near-drowning injury with a normal T2-weighted magnetic resonance image (MRI) at the same time. The decreases in NAA and Cre with increase in Glx are apparent (echo time [TE] = 20 milliseconds, repetition time [TR] = 3 seconds). This child made some recovery to a moderate-to-severe disability. (Courtesy of Dr. Barbara Holshouser, Department of Radiology, Loma Linda University Medical Center.)

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outcome, usually surviving in a vegetative state. Lactate level was also more likely to peak by day 4 rather than immediately after injury. Holshouser and colleagues [1997] demonstrated the potential value of proton magnetic resonance spectroscopy in predicting outcome after acute CNS injuries in 82 infants and children. In this study, changes in metabolite ratios and the presence or absence of lactate in combination with clinical and magnetic resonance imaging score data predicted outcome correctly in 91% of CNSinjured neonates and in 100% of CNS-injured infants and children. Poor-outcome groups had lower Glasgow Coma Scale scores, longer periods of unconsciousness, and lower NAA/creatine and NAA/choline ratios and were more likely to have lactate. Several clinical examples of children with acute brain injuries and abnormal proton spectra that demonstrate the clinical utility of magnetic resonance spectroscopy are depicted in Figure 64-7.

TREATMENT Treatment of children with global hypoxic-ischemic brain injuries involves multiple specialties and a systematic approach to initially providing emergency care in the field, emergency department, and intensive care unit. Urgent neuroimaging studies and early neurologic evaluation are helpful in the initial evaluation to determine the presence of a neurosurgical condition that necessitates immediate treatment, the etiology of injury, and the appropriate course of treatment.

Prehospital Care Currently, aggressive hospital treatment does not lead to intact survival for children who have out-of-hospital cardio-

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pulmonary arrests and present to the pediatric emergency department with a preterminal rhythm (asystole, idioventricular rhythm, electromechanical dissociation) and absence of spontaneous circulation. Resuscitation efforts in the emergency department, although commonly successful, lead to severe neurologic sequelae or death at discharge with extremely high costs of care. Prehospital emergency medical services are capable of providing the earliest medical interventions and hold the greatest promise for improving outcome from prehospital pediatric cardiopulmonary arrest. Emergency medical services have developed sophisticated methods for dispatch and transport, and personnel have been trained to perform advanced cardiac life support. However, for children in cardiopulmonary arrest, prehospital providers successfully perform endotracheal intubation, establish intravascular access, and administer epinephrine significantly less frequently than in their adult counterparts [Kumar et al., 1997]. Basic approaches likely have the greatest opportunity to affect outcome by simply opening the airway and providing adequate ventilation to prevent cardiac arrest. It is also likely that once asphyxia has led to cardiac arrest, novel therapies, to be effective, almost certainly need to be initiated in the field. In many animal models, high-dose epinephrine has improved resuscitation rates [Becker, 1997; Berg et al., 1996; Brown and Werman, 1990]. What have not been established are the effects of high-dose epinephrine on longterm survival and neurologic outcome in humans. A small study in children with previous victims used as control subjects demonstrated a beneficial effect on resuscitation and outcome in patients receiving high-dose epinephrine [Goetting and Paradis, 1991]. Subsequent studies in adult populations, however, have failed to reveal a significant benefit in terms of neurologic

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FIGURE 64-7. (continued) C, Spectra from occipital cortex in a 17-month-old female in a permanent vegetative state resulting from a near-drowning accident. Her spectrum discloses a low NAA peak, which was difficult to measure because of the greatly increased Glx with reversal of the Cho/Cre peaks and the presence of lactate, all of which suggest a poor prognosis (TE = 20 milliseconds, TR = 3 seconds). T2-weighted MRI demonstrates diffuse edema.

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outcome and survival to discharge, and some authors have questioned the advisability of routine use of high-dose epinephrine in resuscitation protocols [Brown et al., 1992; Callahan et al., 1992; Frank, 1994; Stiell et al., 1992]. Studies in pediatric patients with out-of-hospital and in-hospital cardiopulmonary arrest have failed to demonstrate benefits from the use of high-dose epinephrine in terms of either the rate of resuscitation or eventual outcome [Carpenter and Stenmark, 1997; Dieckmann and Vardis, 1995; Ronco et al., 1995]. Contrary to the conventional wisdom that if a little is good, more is better, evidence has been accumulating that high-dose epinephrine is not beneficial and may even impair organ function and survival after the arrest [Lister and Fontan, 2004; Perondi et al., 2004]. The key to understanding this adverse influence of high-dose epinephrine on survival may reside in the calorigenic effects of epinephrine on various tissues, including the myocardium. Epinephrine may increase myocardial and cerebral perfusion during resuscitation, but in the process, it also increases oxygen use for a given measure of mechanical work by the heart and for the delivery of a given amount of oxygen to many other organs [Lister and Fontan, 2004]. Therefore, although epinephrine has been used during cardiopulmonary resuscitation for more than 100 years, its use has become controversial because it is associated with myocardial dysfunction during the period after resuscitation [Paradis et al., 2002]. Because it was found that endogenous vasopressin levels in successfully resuscitated patients were significantly higher than levels in patients who died, it was postulated that it might be beneficial to administer vasopressin during cardiopulmonary resuscitation [Lindner et al., 1992]. Laboratory studies of cardiopulmonary resuscitation revealed that vasopressin administration was associated with better blood flow to vital organs, better delivery of cerebral oxygen, better chances of resuscitation, and better neurologic outcome than was epinephrine [Wenzel et al., 2004]. Wenzel and co-workers [2004] demonstrated the success of vasopressin alone and vasopressin followed by epinephrine in refractory asystolic cardiac arrest—an important breakthrough in the science of resuscitation. Epinephrine consumes oxygen, whereas vasopressin increases coronary blood flow and the availability of oxygen to the myocardium [McIntyre, 2004]. These dynamics may contribute to the success of vasopressin therapy in asystolic cardiac arrest and the lack of success of epinephrine therapy. The American Heart Association and International Liaison Committee on Resuscitation engaged in an evidence-based review of the literature on resuscitation, which culminated in an international consensus conference in January 2005, followed by treatment recommendations [Nolan et al., 2004]. Perhaps vasopressin will be incorporated into the new recommendations. The efficacy of pharmacologic therapy during cardiopulmonary resuscitation is likely limited by the minimal perfusion provided by this procedure [Goetting, 1994; Safar, 1996]. New methods are needed to increase perfusion pressure during cardiac arrest to allow delivery of these agents to the target organs [Halperin et al., 1996]. Debate continues regarding the use of open-chest cardiac massage during cardiac arrest, but social and technical limitations currently prevent its application in the prehospital setting [Dizon and

Santanello, 2003; Sheikh and Brogan, 1994]. Established mechanical methods such as cardiopulmonary bypass and mechanical ventricular assistance can restore cardiac and cerebral perfusion to near-normal values during cardiac arrest, but these present great technical problems for application, particularly in children. Development and implementation of improved perfusion techniques would provide an increased therapeutic window and a better chance of reducing long-term neurologic morbidity. Preventing brain damage after cardiac arrest requires minimizing normothermic no-flow times through early (automatic) defibrillation and early initiation of cooling [Safar et al., 2002]. Rapid induction of mild cerebral hypothermia requires novel cooling methods for use by paramedics and emergency physicians. The objective of the ongoing Smart aortic arch catheter research and development program is to engineer “smart” catheter systems for enabling rapid vascular access and catheter placement, primarily within the aorta, for emergency induction of hypothermia and suspended animation [Yaffe et al., 2004]. According to initial design developments and prototype demonstrations, moving suspended animation from the laboratory to the field is fully feasible and achievable in the near future.

Hospital Care The underlying foundation of neurointensive care is excellent supportive care. Until a neuroprotective agent is developed, state-of-the-art care for a patient who has suffered a hypoxic-ischemic injury consists of maintenance of adequate blood pressure; oxygenation; ventilation; electrolyte homeostasis; nutritional supplementation; and prevention of hyperglycemia, hyperthermia, and seizures [Gisvold et al., 1996]. Several features of supportive post-ischemic intensive care warrant further discussion. These include intracranial pressure monitoring and control, glucose homeostasis, cardiovascular support, temperature regulation, and reduction of metabolic rate.

Intracranial Pressure Monitoring and Control Improvements in outcome with appropriate monitoring and control of increased intracranial pressure in Reye’s syndrome and cerebral trauma fostered the routine application of intracranial pressure monitoring and intracranial pressuredirected therapy in the post–cardiac arrest setting. However, published studies in both clinical and laboratory settings have raised questions about both the rationale and the benefits of these maneuvers. Results of clinical studies suggest that intracranial pressure elevation is more common after asphyxia-induced cardiac arrest than after isolated global brain ischemia or ventricular pressure arrest [Scollo-Lavizzari and Bassetti, 1987]. This finding is not surprising in view of the severe histopathology of the asphyxia-induced cardiac arrest and the long insult times from which the myocardium can recover in children. Sustained elevation of intracranial pressure (>20 mm Hg) was a predictor of poor outcome in a series of pediatric submersion accidents [Dean and McComb, 1981; Frewen et al., 1985; Nussbaum and Galant, 1983; Sarnaik et al., 1985]. Unfortunately, as in ventricular

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fibrillation– induced cardiac arrest, the threshold for poor outcome from asphyxia-induced cardiac arrest appears to be below the threshold for the occurrence of intracranial hypertension because many patients experience poor outcome despite normal intracranial pressure. Although there are anecdotal cases of asphyxia-induced cardiac arrest in patients with intact neurologic outcome despite elevated intracranial pressure, the ability to control intracranial pressure elevation does not result in meaningful survival. Routine monitoring and treatment of intracranial pressure are not currently recommended after asphyxia-induced cardiac arrest. Hyperventilation has been advocated after cerebral injury as a means of decreasing intracranial pressure. However, the use of hyperventilation, even after traumatic brain injury, is being re-evaluated [Muizelaar et al., 1991; Skippen et al., 1997; Yundt and Diringer, 1997]. There is no evidence of any sustained beneficial effect of hyperventilation after hypoxic-ischemic brain injury, and its use should be avoided [Hickey and Zuckerbraun, 2003]. The failure of intracranial pressure–directed therapy to improve outcome after cardiopulmonary arrest and the commonly observed period of hypoperfusion in the first hours to days after the arrest raises serious questions about the blind application of an intervention with the potential to further reduce cerebral blood flow. Thus, hyperventilation should be reserved for patients with signs of cerebral herniation or suspected pulmonary hypertension [Hickey and Zuckerbraun, 2003]. The traditional approach to cerebral resuscitation has also recommended the use of mannitol in the post–cardiac arrest period. Again, studies in the setting of cardiopulmonary arrest are lacking. In dogs subjected to 6 minutes of global ischemia, mannitol (2 g/kg) further reduced cerebral blood flow during the post-ischemic hypoperfusion phase [Arai et al., 1986]. This unwanted effect of mannitol likely represents a result of dehydration. A theoretically beneficial oxygen radical–scavenging effect of mannitol has also been proposed, but if significant oxygen radical–induced brain injury occurs, significantly more potent oxygen radical scavengers are available.

Glucose Homeostasis Observations in animals and humans have suggested that an elevated serum glucose level at or about the time of an ischemic insult is associated with enhanced post-ischemic damage of cerebral tissue [Kushner et al., 1990]. Preexisting hyperglycemia worsens the outcome from global hypoxicischemic injury in adult and juvenile animals [Chopp et al., 1988; Combs et al., 1990; Kalimo et al., 1981; Lanier et al., 1987; Pulsinelli et al., 1982]. Outcome from out-of-hospital cardiac arrest is worse in adults with elevated glucose concentrations at admission [Longstreth, 1987] and in hyperglycemic children after submersion injury [Ashwal et al., 1990]. Hyperglycemia has also been described as increasing brain damage when traumatic brain injury is complicated by secondary ischemia [Cherian et al., 1997]. As a mechanism for the adverse effect of hyperglycemia, most attention has focused on the neuronal effects of increased tissue lactate production and lowered tissue pH [Cherian et al., 1997; Kawai et al., 1997]. Several studies have demonstrated that (1) lactate production during ischemia is directly related to pre-ischemic

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stores of glucose and glycogen and (2) pre-ischemic hyperglycemia results in a more pronounced fall in both intracellular and extracellular brain pH during ischemia [Ljunggren et al., 1974; Smith et al., 1986]. In addition, researchers have demonstrated that when subjected to the same ischemic insult, hyperglycemic animals have a more pronounced histopathologic injury than do normoglycemic animals [Kalimo et al., 1981]. In children, increased brain lactate level, as detected by magnetic resonance spectroscopy, has been associated with poorer long-term neurologic outcomes [Ashwal et al., 1997]. The mechanisms by which lactate and acidosis may augment cellular injury during ischemia remain unclear [Kim et al., 1996; Steingrub and Mundt, 1996]. Direct cytotoxicity, cellular swelling, oxygen radical–mediated damage, and alterations in intracellular calcium homeostasis have been proposed as mechanisms of acidosis-induced injury [Kim et al., 1996; Siesjo et al., 1993]. Lactate induces alterations in calcium homeostasis and may contribute to synaptic dysfunction. Other mechanisms by which hyperglycemia may enhance cerebral ischemic injury include effects on cerebral vasculature and cerebral blood flow [Cipolla et al., 1997; Kawai et al., 1997], alteration in the modulation of protein synthesis in the post-ischemic period [Lin et al., 1997], decreased adenosine production [Hsu et al., 1991], blood-brain barrier breakdown [Dietrich et al., 1993], and hyperosmolality [Gisselsson et al., 1992]. On the basis of these findings, it has also been suggested that in the presence of impaired oxygen delivery, ongoing delivery of glucose may be detrimental. The administration of glucose, once performed in every comatose patient, is questioned, and protocols involving glucose-free solutions are suggested [Sieber and Traystman, 1991]. The prospect of withholding glucose-containing solutions from patients should be considered in view of the following: (1) There is evidence that acidosis is not as harmful as previously thought and that mild acidosis may be neuroprotective via its modulating effect on the excitotoxic component of ischemic injury [Tombaugh and Sapolski, 1990]; (2) current investigations have raised questions about the association between the concentration of glucose after resuscitation and neurologic outcome [Steingrub and Mundt, 1996]; and (3) the influence of serum glucose levels on hypoxic-ischemic neuronal injury appears to depend on the age of the patient [Loepke and Spaeth, 2004]. In summary, the optimal level of blood glucose after resuscitation from either a global or focal hypoxic-ischemic event has not been determined. From a practical point, it seems wise to avoid hypoglycemia in a neonate with hypoxic-ischemic injury and to avoid hyperglycemia in older patients. There is evidence that hyperglycemia is common in acutely ill children and that time of onset, duration, and intensity of hyperglycemia are associated with mortality [Srinivasan et al., 2004].

Cardiovascular Support Although the optimal cerebral perfusion pattern for neuronal recovery remains to be defined, blood pressure fluctuations, both high and low, adversely affect outcome. In several important reviews, investigators have suggested a benefit of tran-

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sient hypertension during the immediate postresuscitation period, hypothesizing that this improves flow in areas with microvascular sludging. Safar and associates [1996] suggested that transient hypertension was beneficial after cardiac arrest in dogs. However, it was used as part of a multifaceted treatment protocol, and its specific benefit is controversial. Shock after a generalized hypoxic-ischemic episode is frequently encountered in infants and children without preexisting cardiovascular or pulmonary disease. The shock state after hypoxic-ischemic events is cardiogenic and is characterized by low flow and high resistance [Lucking et al., 1986]. The cardiac index is depressed in the early stages, with elevated systemic and pulmonary vascular resistance indexes and with elevated filling pressures of both the right and left sides of the heart. Investigators have documented systolic and diastolic myocardial dysfunction immediately after successful cardiac resuscitation with restoration of spontaneous circulation [Gazmuri et al., 1996; Tang et al., 1993]. In young children, these cardiopulmonary derangements resolve over time as the cardiac index increases and systemic and pulmonary vascular resistances decrease. The systemic vascular resistance after hypoxic-ischemic events in children is often inappropriately elevated. Although it is possible that this effect is secondary to the therapies given to these patients, it is also possible that other pathophysiologic mechanisms account for the elevated blood pressures. Renin-mediated hypertension may follow ischemic injury, or CNS injury can cause increases in vascular tone by increasing adrenergic tone. Because of the multiple influences on cardiac output, cardiac support can be difficult to manage. Careful use of fluids, inotropic agents, and vasoactive drugs is indicated. Vasodilators may result in profound reductions in blood pressure. In a retrospective human study, postresuscitative hypertension was associated with a better neurologic outcome [Morris and Nadkarni, 2003].

Temperature Control The effectiveness of hypothermia as a cerebral protective intervention (i.e., before cardiopulmonary arrest) is unquestioned. Hypothermia has been successfully applied during cerebrovascular and cardiovascular surgery for decades [Marion et al., 1996]. The beneficial effects of hypothermia applied immediately before and during cardiopulmonary arrest are clearly demonstrated by the clinical experience with victims of cold-water submersion accidents [Biggart and Bohn, 1990] and with victims of accidental deep hypothermia [Walpoth et al., 1997]. When considering hypothermia (defined as a core temperature <35° C), the clinician should distinguish between uncontrolled (i.e., spontaneous, accidental) and controlled hypothermia induced by artificial cooling, which is used to prevent or attenuate various forms of neurologic injury [Polderman, 2004]. There is growing evidence that induced hypothermia can have neuroprotective effects in some patients with neurologic injury. Class I evidence (from animal experiments, two randomized controlled trials, and various nonrandomized trials) supports the use of hypothermia in selected categories of patients after cardiopulmonary resuscitation [Bernard and

Buist, 2003; Bernard et al., 2002; The Hypothermia after Cardiac Arrest Group, 2002; Sessler, 1997]. Cooling should be initiated as soon as possible but should not be withheld even if delays of up to 8 hours occur [Polderman, 2004]. Treatment should be continued for 12 to 24 hours, with target temperatures of 32° to 33° C. Patients should be rewarmed slowly, because there is evidence that quick rewarming may have deleterious effects [Hickey et al., 2003; Safar and Kochanek, 2002]. The effect of hypothermia on the injured brain is complex. For each 1° C decrease in temperature, the cerebral metabolic rate for oxygen decreases by 6% to 7% [Bernard and Buist, 2003]. However, hypothermia’s main beneficial effect is to provide protection against numerous deleterious biochemical mechanisms [Safar and Kochanek, 2002]. Over a period of days after the restoration of spontaneous circulation, these mechanisms—which include calcium shifts, excitotoxicity, lipid peroxidation and other free radical reactions, DNA damage, mitochondrial injury, and inflammation—lead to death of neurons in vulnerable regions of the brain [Safar and Kochanek, 2002]. Potential mechanisms for the protective effect of hypothermia include inhibition of glutamate release, inhibition of adenine nucleotide depletion, prevention of brain acidosis, and preservation of protein kinase activity [Cardell et al., 1991; Chen et al., 1992; Duhaime and Ross, 1990; Sutton et al., 1991]. Hypothermia also may inhibit free radical mechanisms by decreasing free fatty acid release, preserving endogenous antioxidants, and antagonizing free radical insults [du Plessis and Johnston, 1997]. The marked amelioration of delayed energy failure and specific inhibition of apoptosis (demonstrated in a piglet model) suggest that hypothermia may delay apoptotic commitment, allowing endogenous protective mechanisms to restore cellular integrity [Thoresen and Wyatt, 1997]. The use of induced mild hypothermia should be considered in patients after cardiopulmonary resuscitation, provided that there are no significant contraindications (such as ongoing hemorrhage) and that the prognosis does not appear hopeless for other reasons (e.g., presence of malignancies, severe chronic diseases). Temperature levels are important; mild hypothermia (33° to 36° C) may be most effective, and it is simple and safe. Moderate hypothermia (28° to 32° C) can cause dysrhythmias, coagulopathy, and infection [Safar and Kochanek, 2002].

Reduction of Metabolic Rate The observation in certain animal models that hypermetabolism accompanies post-ischemic hypoperfusion formed the basis for early clinical cerebroprotective strategies in the post–cardiac arrest setting. Therapies directed at attenuating active cerebral metabolism (rate of cerebral O2 metabolism attributable to synaptic transmission) were applied in the hope of reducing this secondary insult of hypoperfusion plus hypermetabolism. The cerebral protective effects of interventions that decrease cerebral metabolic rate before the onset of ischemia, such as barbiturates and hypothermia, are well established and clinically important [Kuroiwa et al., 1990; Steen and Michenfelder, 1980]. The selective inhibitory effect of barbiturates on active cerebral metabolic rate of O2 was particularly

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attractive. However, therapeutic reductions in brain metabolism when applied after the insult, as in the “HYPER” therapy of the 1970s, did not improve outcome [Abramson et al., 1986]. This result may have arisen from the relative lack of post–cardiac arrest hypermetabolism in humans. In addition, adverse hemodynamic consequences of barbiturates and the ill effects of sustained deep hypothermia on immune function and blood rheology may have masked any beneficial effects [Biggart and Bohn, 1990]. The ability of barbiturates to protect against multifocal incomplete ischemia in selected cases of cardiac or neurologic surgery, to control seizures, and to aid in the reduction of intracranial hypertension is better confirmed than are their potential effects after cardiac arrest [Safar, 1993].

studies have demonstrated increased transcription of HSP70 messenger RNA and increased synthesis of HSP70 and HSP72 after global cerebral ischemia [Gonzalez et al., 1991; Nowak et al., 1993; Vass et al., 1988]. This gene appears to be expressed in proportion to the duration of ischemia. Increasing durations of ischemia lead to HSP70 expression, first in neurons from selectively vulnerable regions, next in relatively resistant neurons, then in glia, and, finally, in endothelial cells [Sharp et al., 1993; Simon et al., 1991]. Although a direct cause-and-effect relationship between heat shock proteins and neuroprotection in vivo has not been established, novel techniques to specifically increase heat shock proteins in neurons after injury should help in answering this question.

Potential Therapies

ADENOSINE

Modulation of Endogenous Defenses

An endogenous biochemical mediator that may serve a protective role after cerebral ischemia, particularly early after injury, is adenosine. Adenosine levels are increased in brain tissue after experimental ischemia and in response to hypoxia, hypotension, and hypoglycemia [Laudignon et al., 1991; Morii et al., 1987; Ruth et al., 1993]. The bulk of the extracellular adenosine derives from the intracellular catabolism of ATP. The release of adenosine after ischemia could afford neuroprotection by a combination of several mechanisms. When bound to A2 receptors, adenosine is a cerebrovasodilator [Sweeney et al., 1995]. When bound to A1 receptors, adenosine reduces neuronal metabolism and excitatory amino acid release, stabilizes postsynaptic membranes, and inhibits platelet activation and neutrophil function [Miller and Hsu, 1992]. Thus, the beneficial effects of adenosine after cerebral ischemia include improved regional blood flow, reduced local oxygen demand, attenuation of excitotoxicity, increases in intracellular calcium, and anti-inflammatory and rheologic effects. The effects of adenosine and synthetic adenosine derivatives on ischemic, hypoxic, or traumatic CNS damage, when given before or after the insult, protect against neuronal damage [Rudolphi and Schubert, 1996]. The therapeutic value of the agonist approach is questionable because most adenosine derivatives have prohibitive CNS and cardiovascular side effects, such as strong sedation, hypotension, cardiodepression, and renal vasoconstriction.

The potential mechanisms involved in cell death after cardiac arrest and restoration of circulation are complex. An evolving understanding of these mechanisms may allow clinicians to take advantage of these endogenous neuroprotectants as future therapies to improve neuronal survival after cardiac arrest. Several events are essential if neurons are to recover. First and foremost, ATP levels must be restored and maintained. Reperfusion is essential, although not the sole requirement for neuronal rescue, inasmuch as the cells require energy sources and the means to eliminate their waste. Therefore, a second factor that is critical is that the cells must not be subject to overwhelming cytosolic calcium burdens; therefore, not only must ATP levels be maintained but also excitotoxicity should be minimized [Sweeney et al., 1995]. Other factors thought to be important include avoiding excessive formation of free radicals and metabolism of free fatty acids. In response to the complex sequence of pathophysiologic events that evolve after brain injury, several biochemical and molecular mediators that may have neuroprotective roles are present. These endogenous neuroprotectants are produced, induced, or activated after ischemia, and their postulated or proven functions improve cell (specifically neuronal) survival in in vivo, in vitro, or both models.

HEAT SHOCK PROTEINS Heat shock proteins are one family of candidate neuroprotectants that are highly conserved among biologic species and are induced in cells after a variety of stimuli. Heat stress is the classic example; however, any insult that damages protein structure, including ischemic and traumatic brain injury, can produce a heat shock protein response [Raghupathi et al., 1995; Simon et al., 1991]. Heat shock proteins have generated major interest as potential neuroprotectants because their prior induction by a sublethal stress can afford protection from subsequent injury. Transient entire-body hyperthermia reduces subsequent ischemic brain injury in rats [Chopp, 1989]. Heat shock proteins likely play an important role in cellular defense against environmental stresses [Kogure and Kato, 1993]. The HSP70 gene is the heat shock gene that has been best characterized after cerebral ischemia. Numerous

Targeting Delayed Neuronal Death Although a portion of neuronal death occurs immediately after acute brain injury, it is clear that some portion of neurons die in a delayed manner by programmed cell death. The completion of programmed cell death leads to a distinct cell morphologic process termed apoptosis [Kochanek et al., 2001]. Because programmed cell death occurs in stages, there exist several potential strategies for reducing cell death. Targeting upstream regulators of the programmed cell death cascade, such as bcl-2 family proteins and cell death receptors is one such strategy [Kochanek et al., 2001]. Regulation of cell death may depend on the proportion of pro-apoptotic versus anti-apoptotic bcl-2 proteins in the cell after injury. Another potential anti-apoptotic strategy is to target the final common pathway of the programmed cell death cas-

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cade. Activation of caspase-8, caspase-9, and other caspases is the key committed step in the programmed cell death cascade [Clark et al., 2000]. Caspase-3 activates endonucleases and other proteases, inactivates enzymes important in DNA repair, and cleaves cytoskeletal proteins, culminating in morphologic features of apoptosis [Kochanek et al., 2001]. Pan-caspase and relatively selective peptide inhibitors of many caspases are available and undergoing experimental trials. Several contemporary strategies used for ischemic injury may reduce programmed cell death. Hypothermia, antioxidants, and anti-excitotoxic strategies may prevent programmed cell death and are discussed elsewhere in this chapter.

Reduction of Excitotoxicity Death of selectively vulnerable neurons is mediated by local release of excitatory neurotransmitters with hypermetabolism and calcium accumulation. This process has led to attempts to attenuate post-ischemic excitotoxicity more selectively by administering specific receptor antagonists. NMDA and non-NMDA receptor antagonists have been studied extensively in numerous animal models. Competitive antagonists at NMDA binding sites have been disappointing in animal studies because of the large doses (and hence systemic adverse effects) necessary to penetrate the blood-brain barrier and reduce the high ischemic levels of glutamate at the NMDA receptor. These factors limit the therapeutic index and clinical utility of competitive antagonists [du Plessis and Johnston, 1997]. Noncompetitive antagonism can be mediated at several sites within the NMDA ion channel. This discussion is confined to magnesium blockade and agents acting at the phencyclidine channel site, such as the experimental agent MK-801 (dizocilpine), and several agents already in clinical use, such as dextromethorphan and ketamine. These agents are not likely to be subjected to clinical trials because of concerns regarding their psychomimetic effects and potential toxicity. MK-801 is a noncompetitive NMDA antagonist; that is, it does not compete with glutamate for binding to the NMDA receptor but instead blocks influx of extracellular calcium by binding to a site within the NMDA receptor–gated calcium channel. Results of numerous studies suggest that this agent is neuroprotective in the setting of focal ischemia [McCulloch, 1992; Pulsinelli et al., 1993]; however, results of MK-801 treatment in the setting of global brain ischemia are discouraging. Sterz and co-workers [1989] gave MK-801 either before or after a 17-minute ventricular fibrillation–induced cardiac arrest in dogs and found that it did not improve neurologic or histologic outcome at 96 hours. In a similar study, MK801 administered after cardiac arrest in cats had no beneficial effect on neurologic outcome at 7 days [Fleischer et al., 1989]. Lanier and associates [1990] found comparable results of no benefit in a primate model of global brain ischemia. Blockade of non-NMDA receptors (i.e., AMPA and kainate receptors) with quinoxalinedione compounds has most consistently prevented delayed neuronal cell loss in the hippocampal CA1 region in animal models of global cerebral ischemia. NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-

benzoquinoxaline) is a non-NMDA receptor antagonist that appears to provide histologic protection in the cortex, hippocampus, or both in rat models of global ischemia [Buchan et al., 1991; Diemer et al., 1993; Nellgard and Wicloch, 1992]. Of interest, delayed treatment with NBQX appears to be effective. Treatment 12 hours after global ischemia in the rat [Li and Buchan, 1993] and 24 hours after global ischemia in the gerbil [Sherdown et al., 1993] resulted in significantly decreased delayed neuronal death in the CA1 region of the hippocampus. The protective efficacy of AMPA-receptor antagonists against delayed neuronal death may be explained in the following ways. First, in the post-ischemic phase, AMPA receptors may become upregulated and more responsive [du Plessis and Johnston, 1997]. Furthermore, NMDA antagonists increase and AMPA antagonists decrease glucose metabolism. Consequently, during the period of disturbed metabolism after ischemia, a decrease in glucose metabolism, as occurs with AMPA antagonists, promotes neuronal survival [du Plessis and Johnston, 1997]. The divalent cation Mg2+ acts as a glutamate receptor antagonist to the extent that it blocks the neuronal influx of Ca2+ within the ion channel. In this regard, magnesium sulfate has reduced the severity of hypoxic-ischemic brain damage in immature rats [Vannucci and Perlman, 1997]. Clinical trials have revealed variable effects [Christensen et al., 1996; Gisvold et al., 1996].

Inhibition of Calcium Accumulation Calcium accumulation in neurons and release of stored intracellular calcium are pivotal events leading to irreversible cellular damage during the reperfusion phase after an ischemic insult. Calcium accumulation occurs through receptor-operated channels such as the NMDA receptor– activated channels, voltage-operated calcium channels, nonspecific membrane channels, and release of intracellular calcium via the inositol second-messenger pathway. Conflicting results regarding the ability of the voltage-operated calcium channel antagonists (lidoflazine, nimodipine, nicardipine, flunarizine) to attenuate calcium accumulation in brain cells after ischemia have been obtained [Grotta et al., 1990]. The contribution of the voltage-gated channels to post-ischemic calcium accumulation is apparently less than that of the NMDA-operated channels in selectively vulnerable zones. Nevertheless, clinical experience with the voltageoperated calcium channel antagonists and their cerebral vasodilatory effects prompted laboratory and clinical evaluations. Calcium channel blockers have been studied in a variety of animal models of global ischemia and have been subjected to clinical trials. Despite some encouraging findings in animal models, the clinical trials have failed to yield positive results [Morgenstern and Pettigrew, 1997]. Nimodipine, a dihydropyridine compound that selectively blocks the L-type calcium channel, has been studied in animal models of global cerebral ischemia and in human survivors of cardiac arrest. Using a canine model, Steen and colleagues [1983] demonstrated that pre-ischemic treatment with nimodipine resulted in increased cerebral blood flow and improved neurologic outcome after 10 minutes of global ischemia. However, when the drug was administered after

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ischemia, the results were intermediate; cerebral blood flow was improved, but outcome was unchanged [Steen et al., 1984]. Subsequently, Milde and co-workers [1986] studied the effect of post-ischemic treatment with nimodipine on cerebral blood flow in the early reperfusion period. Nimodipine-treated dogs had significantly higher cerebral blood flow, but nimodipine treatment had no effect on cerebral metabolism. Again, this raises the question of whether improving blood flow in the early reperfusion period has any effect on neurologic outcome. These results culminated in a clinical trial of nimodipine treatment in survivors of cardiac arrest (ventricular fibrillation) [Roine et al., 1990]. There was no difference in neurologic outcome or survival at 3 or 12 months after cardiac arrest. Lidoflazine is a nonselective voltage-sensitive calcium channel antagonist that in early animal studies appeared to ameliorate hypoxic-ischemic brain injury. However, later studies, including a large clinical trial, failed to substantiate the results of the early experiments [Brain Resuscitation Clinical Trial II Study Group, 1991].

Antioxidants Free radicals can damage membrane lipids, cellular proteins, enzymes, and DNA. The importance of damage to each brain component and subsequent contribution to triggering or mediating the final pathway of neuronal death remain to be defined. As a result, a variety of approaches to preventing oxidative free radical–mediated brain injury have been devised. Most cerebral ischemia literature refers to antioxidants and agents that block the chain reaction of lipid peroxidation; however, other agents prevent oxidation of substances other than lipids and by multiple mechanisms. Because all biologic systems generate oxygen free radicals even under physiologic conditions, enzymes are present within the cell to protect its constituents from the oxidizing effect of hydrogen peroxide and its metabolic products; these enzymes include superoxide dismutase, endoperoxidase, and catalase, which convert hydrogen peroxide to either water or stable oxygen. Additional defenses are provided by endogenous scavengers, which include cholesterol, alpha-tocopherol (vitamin E), ascorbic acid (vitamin C), and thiol-containing compounds, notably glutathione. Thus, cells that include neurons are capable of rapidly destroying free radicals, once formed, through both enzymatic and nonenzymatic quenching. Free radicals and reactive oxygen species (superoxide and hydrogen peroxide) cause tissue injury only when the radicals overpower the brain’s endogenous antioxidant defenses. There are two distinct types of superoxide dismutases in mammalian cells: copper-zinc and manganese [Tainer et al., 1983]. Copper-zinc superoxide dismutase is located in the cytosol, whereas manganese superoxide dismutase is located in the mitochondria. Superoxide dismutases are widely distributed throughout the body, but plasma levels are very low as a result of efficient renal clearance [Marklund, 1984]. Copper-zinc superoxide dismutase has been proposed as a therapeutic agent for reperfusion injury because of its ability to scavenge oxygen radicals. Superoxide dismutase has two drawbacks as a therapeutic agent. First, it is cleared rapidly by the kidney and has a circulatory half-life of

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approximately 8 minutes [Turrens et al., 1984]. Second, and more important, copper-zinc superoxide dismutase is a large, water-soluble molecule and therefore cannot readily penetrate cell membranes or cross the blood-brain barrier in significant quantities after intravenous administration [Beckman et al., 1988; Freeman et al., 1983]. Thus, if access to intracellular compartments is required for therapeutic efficacy, it appears unlikely that copper-zinc superoxide dismutase would provide a protective effect. Investigators have tried two different modifications in the delivery of superoxide dismutase in an effort to increase the circulatory half-life and intracellular access of the intravenously administered enzyme: liposome-entrapped superoxide dismutase and polyethylene glycol–conjugated superoxide dismutase. Superoxide dismutase delivered in positively charged liposomes has a circulatory half-life of approximately 4 hours and has dramatically increased access into cultured endothelial cells [Freeman et al., 1983; Turrens et al., 1984]. Administration of liposome-entrapped superoxide dismutase produces both increased brain superoxide dismutase activity and reduced extent of infarctions in a rat model of global ischemia [Imaizumi et al., 1990]. Conjugation of polyethylene glycol monomers to superoxide dismutase increases its circulatory half-life to approximately 37 hours and increases its uptake into cultured endothelial cells [Beckman et al., 1988]. However, polyethylene glycol– conjugated superoxide dismutase does not appear to increase brain superoxide dismutase activity [Haun et al., 1991]. Multiple endogenous substances in the brain are capable of scavenging free radicals. The predominant lipid-soluble endogenous free radical scavenger in the brain is alphatocopherol. Alpha-tocopherol is incorporated directly into cell membranes and blocks the propagation of lipid peroxidation by interacting with intermediate peroxyl radicals, thus preventing further destruction of other lipids in the cell membrane. There is controversy over whether alpha-tocopherol levels are depleted during brain ischemia and reperfusion. The amount of oxygen administered during resuscitation also appears to influence the severity of the free radical damage, and the practice of using 100% oxygen during cardiac arrest needs to be re-examined [Feet et al., 1997; Lipinski et al., 1999; Liu et al., 1998; Zwemer et al., 1994]. Interventions directed at pathways indirectly related to free radical generation may be beneficial for reducing oxidative stress in the brain. Hypothermia reduces lipid peroxidation and maintains endogenous antioxidant activity during reperfusion from global brain ischemia [Baiping et al., 1994]. Acidosis during ischemia increases free radical production and may inactivate endogenous antioxidants [Links, 1988]; however, the role of buffer therapy is controversial.

Reduction of Lipid Peroxidation Lipid-soluble agents rapidly cross the blood-brain barrier, a beneficial property for cerebral resuscitation. Administration of alpha-tocopherol after cerebral ischemia reduces ischemic neuronal damage in gerbils. Lipid-soluble compounds termed lazaroids have been developed to reduce iron-dependent lipid peroxidation after cerebral ischemia. The 21-aminosteroid lazaroids are potent inhibitors of lipid peroxidation but lack classic steroidal activities [Braughler et al., 1987]. The 21-aminosteroids are

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potent inhibitors of free radical–induced lipid peroxidation, and they have multiple antioxidant actions: (1) scavenging of lipid peroxyl, (2) decreasing formation or scavenging of hydroxyl radicals, (3) reducing lipid peroxidation–induced arachidonic acid release, (4) maintaining the levels of endogenous vitamin E, and (5) membrane stabilization by decreasing membrane fluidity [Hall et al., 1994; SchmidElsaesser et al., 1997]. The most extensively studied 21aminosteroid, U74006F (tirilazad mesylate), appears to possess multiple antioxidant properties; however, preliminary studies of the use of this agent in global cerebral ischemia have yielded mixed results [Sweeney et al., 1995]. An explanation for the limited effect in global ischemia is that tirilazad is lipophilic and therefore accumulates in cell membranes with a high affinity for vascular endothelium. Tirilazad may protect the vascular endothelium from peroxidative damage but is not expected to cross the bloodbrain barrier [Schmid-Elsaesser et al., 1997]. Recent experimental study has demonstrated that the lazaroid compound U74389G, administered during cardiac arrest, mitigated postresuscitation myocardial dysfunction and improved survival rates [Wang et al., 2004]. It has been proposed that free radical injury of the brain mainly involves the microvasculature, although both brain parenchyma and vascular endothelium have the potential to generate free radicals [Grammas et al., 1993; Siesjo et al., 1995]. One newly discovered group of antioxidants, the pyrrolopyrimidines, have a significantly greater potential to enter the brain parenchyma. Results of early investigations suggest that these compounds, which are able to cross the blood-brain barrier, may have a greater potential to treat cerebral ischemia [Schmid-Elsaesser et al., 1997].

Iron Chelation An alternative approach to reducing the production of free radicals is to interfere with intermediates in the formation of free radicals. Transitional metals such as ferrous iron and possibly copper are involved with the formation of free radicals in the brain. A chelating agent such as hydroxyl starch–conjugated deferoxamine, which penetrates the bloodbrain barrier and interacts with these metals, can reduce free radical production and may decrease brain injury.

Nitric Oxide Inhibition As described earlier, nitric oxide could be both beneficial and detrimental to the brain during ischemia and reperfusion. Possible beneficial effects include vasodilation, inhibition of platelet aggregation, and downregulation of NMDA receptors, whereas possible detrimental effects include production of hydroxyl radicals, increased inflammatory effects mediated through inducible nitric oxide synthase, and inhibition of key enzymes necessary for DNA replication and mitochondrial energy production [Choi, 1993]. It is therefore not surprising that animal studies in which nitric oxide synthase inhibitors were used for treatment of cerebral ischemia have yielded both positive and negative results. Nitric oxide synthase inhibitors are analogs of L-arginine, the substrate for nitric oxide synthase. These analogs competitively inhibit the conversion of L-arginine to L-citrulline and nitric oxide.

In animal models, inhibitors of nitric oxide synthesis, including desmethyl tirilazad [Fernandez et al., 1997], 7-nitroindazole [O’Neill et al., 1996], and N-omega-nitroL-arginine [Kohno et al., 1997], have all reduced the effects of global hypoxic-ischemic injury. However, because the competing neurotoxic versus neuroprotective vasodilator effects of nitric oxide remain poorly understood in focal and global ischemic injury, extensive animal and subsequent human clinical research is needed.

Blood Flow Promotion Cerebral hypoperfusion follows cardiac arrest, including asphyxia-induced cardiac arrest. A brief period of systemic hypertension may improve cerebral blood flow after cardiac arrest. Hypertension early after cardiac arrest is associated with favorable outcome and was reviewed earlier [Sasser et al., 1999].

Modulation/Protein Synthesis Protein synthesis is essential for cell survival. Proteins are involved in nearly every process in the cell (e.g., enzymatic reactions, transport, storage, intracellular signaling, intercellular signaling, and cytoskeletal support). Obviously, intact protein synthesis is important for cellular recovery after hypoxic-ischemic injury. However, total protein synthesis is impaired after cerebral ischemia [Kleihues and Hossmann, 1971; Nowak et al., 1985]. Inhibition of protein synthesis is slow to recover, requiring hours to days to return to normal levels. The inhibition of protein synthesis is not regionally homogeneous; inhibition is more severe and prolonged in the cortex, hippocampus, and caudate [Bodsch et al., 1986; Widmann et al., 1991]. Failure of protein synthesis to recover after ischemia is the biochemical correlate of cell death. Protein synthesis in neurons of the vulnerable CA1 region of the hippocampus fails to recover after even short periods of ischemia. The inhibition of protein synthesis, which appears to be reperfusion-specific, prevents cells from responding to free radical damage by synthesizing the enzymes necessary to detoxify radicals and repair membrane damage [White et al., 1996]. Although total protein synthesis is decreased after cerebral ischemia, the synthesis of some proteins is actually increased. It is enticing to postulate that these proteins may play an important role in reparative processes after cerebral ischemia; however, it is equally plausible that the selective expression of some genes may contribute to delayed neuronal death, possibly through apoptotic mechanisms [Akins et al., 1996]. Ischemia appears to cause dramatic changes in gene expression [Kogure and Kato, 1993; Sharp et al., 1993]. Genes that have received the most attention in models of cerebral ischemia include the immediate early genes (c-fos and c-jun), heat shock protein genes, and trophic factor genes. Immediate early genes code for proteins (fos, jun, and others) that function as transcription factors and control the expression of many genes in the CNS [Nowak et al., 1993]. Increased expression of c-fos and c-jun has been demonstrated after global cerebral ischemia [Akins et al., 1996]. Trophic factors appear to be produced in the CNS after ischemic brain injury and may contribute to the repair of

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damaged cells [Kogure and Kato, 1993]. Fibroblast growth factor and nerve growth factor are two growth factors elaborated in the CNS that appear to be important for the survival and development of neurons. Takami and colleagues [1992] demonstrated increased production of fibroblast growth factor messenger RNA and fibroblast growth factor after global ischemia in the rat. Nerve growth factor levels have also been demonstrated to increase after cerebral ischemia. Both fibroblast growth factor and nerve growth factor, administered by injection into the lateral ventricle, decrease neuronal injury after cerebral ischemia in gerbils [Shigeno et al., 1991; Wen et al., 1995]. Thus, increased expression of growth factors after ischemia appears to be an attempt by the injured brain to prevent further injury and promote repair. Use of neurotrophic factors or novel brainpenetrating neurotrophic factor receptor agonists to prevent neuronal death or to promote regeneration and rewiring of injured brain represents an exciting area of study. Vascular endothelial growth factor is an angiogenic and neurotrophic peptide whose expression is transcriptionally induced in hypoxic tissues through the action of hypoxiainducible factor-1a [Jin et al., 2001]. Experimental studies have demonstrated initial upregulation of this factor, followed by increased vascular endothelial growth factor [Pichiule et al., 2003]. These findings suggest that cardiac arrest and resuscitation triggers hypoxia-inducible factor-1a induction, which might be partly responsible for the stimulation of vascular endothelial growth factor expression and the subsequent downstream adaptive mechanisms that might promote recovery. Insulin is a member of an important group of growth factors that includes insulin-like growth factor-1 and nerve growth factor. There is evidence that members of the insulin growth factor family, when delivered to the brain in the 2 hours after reperfusion, can salvage a percentage of the neurons that would otherwise die [White et al., 1996]. Gene expression after cerebral ischemia is incompletely understood but exciting in that it may provide a mechanism to improve outcome. In animal studies in which gene regulation was examined in a model of hypoxic conditioning in the newborn, preliminary data revealed the potential of manipulating gene regulation after hypoxic insults [Bernaudin et al., 2002].

Anti-inflammatory Therapy There is evidence of an important role of the inflammatory response after focal and global ischemic injury; this evidence provides alternative approaches directed at the “delayed” onset of treatment of such patients in a hospital setting [Becker, 1998; Lipton et al., 1998; Saikumar et al., 1998].

Inhibition of Arachidonic Acid Metabolism Although many avenues exist for manipulation of phospholipid-derived mediator formation after global cerebral ischemia or cardiorespiratory arrest, most studies have focused on the arachidonic acid cascade. Pretreatment with cyclooxygenase inhibitors (indomethacin, piroxicam, diclofenac, or ibuprofen) before 5 minutes of global brain ischemia in gerbils attenuated selectively vulnerable cell

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death [Nakagomi et al., 1989; Sasaki et al., 1988]. In contrast, inhibition of the lipoxygenase pathway did not prevent selectively vulnerable cell death. Prostaglandins potentiate the effects of excitatory amino acids, and inhibition of this effect may explain the protection afforded by these agents. Similarly, inhibition of superoxide anion synthesis during the metabolism of arachidonic acid also may be an important mechanism for this effect. Alternatively, cyclooxygenase metabolites of arachidonic acid are important regulators of normal cerebral blood flow, especially in the immature brain, and cyclooxygenase inhibitors increase cerebral blood flow after global ischemia. However, indomethacin administration after ischemia does not increase cerebral blood flow, and the effect of resuscitation with cyclooxygenase inhibitors on cerebral blood flow after cardiorespiratory arrest has not been studied. A limit to the clinical effectiveness of cyclooxygenase inhibitors may be that a burst of cyclooxygenase product formation occurs within seconds of reperfusion. Some studies have suggested that an inducible form of cyclooxygenase, cyclooxygenase II, is found after tissue injury [Szczepanski et al., 1994]. This enzyme may be a more appropriate therapeutic target, if prostanoids or arachidonic acid metabolites play an important role in ischemic brain injury.

Glucocorticoids Glucocorticoids inhibit phospholipase A2 activity and have a history of use in cerebral resuscitation. The use of corticosteroids as a therapy after cardiorespiratory arrest, however, is unsupported. Pretreatment with dexamethasone in global ischemia models worsened neuronal survival, perhaps because of steroid-induced hyperglycemia. Corticosteroid treatment after global cerebral ischemia in animal models has produced effects ranging from very detrimental to minimally protective. Jastremski and associates [1989] retrospectively assessed the impact of steroid use in the 262 patients who did not receive thiopental in the Brain Resuscitation Clinical Trial I. Four groups (receiving no, low-dose, medium-dose, or high-dose steroid) were compared. No effect on mortality or neurologic outcome was seen.

Hyperbaric Oxygen Treatment Hyperbaric oxygen treatment has been demonstrated to prolong survival [Krakovsky et al., 1998] and have some neuroprotective properties when used in acute settings in models of global ischemia [Kapp et al., 1982; Takahashi et al., 1992; Zhou et al., 2003]. However, clinical reviews of patients with traumatic brain injury [Longhi and Stochen, 2004] or stroke [Rusyniak et al., 2003] have suggested that it is unlikely to be of benefit, but clinical trials examining the potential benefits versus risk of hyperbaric oxygen treatment have not yet been performed.

Albumin Albumin treatment has been revealed to have some neuroprotective properties when used acutely in models of global ischemia [Belayev et al., 1999]. Further research is needed to determine whether this would be clinically applicable in

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studies of adults, as well as of children. Currently, high-dose albumin is being investigated in adult patients with strokes to determine whether it is neuroprotective.

DILEMMA OF NEUROLOGIC MORBIDITY The CNS is particularly vulnerable to injury from cardiac arrest. Although young children are considered more likely than adults to survive anoxic-ischemic events, much of this pediatric survival appears to result from brainstem recovery. Thus, after prolonged ventilatory support, a child may be more likely to recover the ability to breathe and survive, but there will be little or no return of cortical functions. Major efforts have been made to discover therapies that improve neurologic recovery after severe brain injuries; much research has been accomplished in the field of brain resuscitation since the mid-1990s. Nevertheless, there currently exists no specific therapy to lessen the incidence of post–cardiac arrest brain damage. It appears that the duration of hypoxia (from respiratory arrest leading to cardiac arrest), the duration of complete global ischemia (from the beginning of cardiac arrest until resuscitation begins), the duration of incomplete global ischemia (from resuscitation until perfusion is re-established), and the effect of reperfusion injury are the major determinants of brain damage after cardiac arrest. Currently, the outcome of these insults cannot be changed, but as more is learned about the pathophysiology of brain ischemia, ways of preventing secondary brain damage may be found. Because of the tremendous emotional and financial burdens associated with acute and chronic care of children who are severely disabled, minimally conscious, or in a vegetative state after cardiac arrest, the efficiency of resuscitative efforts must be continually evaluated. Physicians are often faced with decisions about the degree of continued medical support to be given to patients who do not awaken after cardiac arrest and, to a lesser degree, with decisions about specific treatment modalities. The degree of medical support that a patient needs after cardiac arrest is straightforward and is based on medical indications. Certain treatment modalities, such as mechanical ventilation, pharmacologic support of the heart, and intravenous nutrition, however, may be considered heroic or futile by the physician or the family. Brain damage in these severely injured survivors is typically profound, and long-term improvement is limited. Children in such situations require long-term intensive care, which is financially expensive whether supported at home or in longterm care facilities. In addition to issues of the child’s wellbeing and the financial burden, the effect on the family’s quality of life is profound, although difficult to quantify. Finally, there is evidence that almost one third of cardiac arrest survivors suffer from post-traumatic stress disorder and that the occurrence of this disorder seriously compromises an otherwise satisfying outcome of cost- and resource-intensive medical procedures [Gamper et al., 2004]. Post-traumatic stress disorder leads to an incapacitation that is well beyond the limitations imposed by the organic disease, and it may persist for a long time. This condition may be especially important because it affects predominantly younger patients, seriously compromising their social life [Gamper et al., 2004].

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Valdes-Dapena M. The postmortem examination. Pediatr Ann 1995;24:365. van der Hal AL, Rodriguez AM, Sargent CW, et al. Hypoxic and hypercapneic arousal responses and prediction of subsequent apnea in apnea of infancy. Pediatrics 1985;75:848. Vannucci RL, Perlman JM. Interventions for perinatal hypoxic-ischemic encephalopathy. Pediatrics 1997;100:1004. Vass K, Welch WJ, Nowak TX. Localization of 70-KDa stress protein induction in gerbil brain after ischemia. Acta Neuropathol (Berl) 1988;77:128. Volinsky JB, Hanson JB, Lustig JV, et al. Clinical picture. Lightning burns. Arch Fam Med 1994;3:657. Wallays C, Feve A, Bondghene F, et al. Hypoxic cerebral lesions: X-ray computed tomography and MRI aspects. J Neuroradiol 1995;22:77. Walpoth BH, Walpoth-Aslan BN, Mattle HP, et al. Outcome of survivors of accidental deep hypothermia and circulatory arrest treated with extra-corporeal blood warming. N Engl J Med 1997;337:1500. Wang J, Weil MH, Kamohara T, et al. A lazaroid mitigates postresuscitation myocardial dysfunction. Crit Care Med 2004;32:553. Weise KL, Bleck TP. Status epilepticus in children and adults. Crit Care Clin 1997;13:629. Wen TC, Matsuda S, Yoshimura H, et al. Protective effect of basic fibroblast growth factor–heparin and neurotoxic effect of platelet factor 4 on ischemic neuronal loss and learning disabilities in gerbils. Neuroscience 1995;65:513. Wenzel J, Krismer AC, Arntz HR, et al. A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation. N Engl J Med 2004;350:105. White BC, Grossman LI, O’Neil BJ, et al. Global brain ischemia and reperfusion. Ann Emerg Med 1996;27:588. Widmann R, Kuroiwa T, Bonnckoh P, et al. [14C] Leucine incorporation into brain proteins in gerbils after transient ischemia: Relationship to selective vulnerability of hippocampus. J Neurochem 1991;55:789. Wijdicks EFM, Parisi JE, Sharbrough FW. Prognostic value of myoclonus status in comatose survivors of cardiac arrest. Ann Neurol 1994;35:239. Willinger M, James LS, Catz C. Defining the sudden infant death syndrome (SIDS): Deliberations of an expert panel convened by the National Institute of Child Health and Human Development. Pediatr Pathol 1991;11:677. Wintemute GJ. Childhood drowning and near-drowning in the United States. Am J Dis Child 1990;144:663. Wintemute GJ, Kraus JF, Teret SP, et al. Drowning in childhood and adolescence: A population-based study. Am J Public Health 1987;77:830. Yaffe L, Abbott D, Schulte B. Smart aortic arch catheter: Moving suspended animation from the laboratory to the field. Crit Care Med 2004;32 (Suppl):S51. Young KD, Gausche-Hill M, McClung CD, et al. A prospective, population-based study of the epidemiology and outcome of out-othospital pediatric cardiopulmonary arrest. Pediatrics 2004;114:157. Young KD, Seidel JS: Pediatric cardiopulmonary resuscitation: A collective review. Ann Emerg Med 1999;33:195. Yundt KD, Diringer MN. The use of hyperventilation and its impact on cerebral ischemia in the treatment of traumatic brain injury. Crit Care Clin 1997;13:163. Zaritsky A, Nadkarni V, Getson P, et al. CPR in children. Ann Emerg Med 1987;16:1107. Zhou C, Li Y, Nanda A, Zhang JH. HBO suppresses Nogo-A, Ng-R, or RhoA expression in the cerebral cortex after global ischemia. Biochem Biophys Res Commun 2003;309:368. Zwemer C, Whitesall S, D’Alecy L. Cardiopulmonary-cerebral resuscitation with 100% oxygen exacerbates neurological dysfunction following nine minutes of normothermic cardiac arrest in dogs. Resuscitation 1994;27:267.

CHAPTER 65

Increased Intracranial Pressure Suresh Kotagal

Increased intracranial pressure (ICP) is seen in a diverse group of neurologic disorders. It may develop acutely over hours or have a subacute course that evolves over days to weeks. The clinical manifestations vary according to the age of the child, the nature of the disorder, and the rapidity of its progression. Common etiologies for raised ICP are listed in Box 65-1. Intracranial hypertension is eminently treatable in its early stages, but delay in recognition and treatment can have disastrous consequences for the patient. This chapter reviews some relevant basic concepts and clinical issues.

NORMAL INTRACRANIAL PRESSURE The normal value for ICP in newborns is about 82 mm H2O, or 6 mm Hg [Welch, 1980]. It rises gradually from 82 to 176 mm H2O in 1- to 7-year-olds to 136 to 204 mm H2O in adolescents. Minor fluctuations in the physiologic ICP occur with heartbeats, breathing, the Valsalva maneuver, and rapid eye movement sleep. Brief, sharp increases of up to 1000 mm H2O may occur transiently during sneezing and coughing. The normal brain is capable of adapting to these transient changes. In the first 3 years of life, subacute or chronically elevated ICP leads to the separation of cranial sutures, followed by excessive cranial enlargement. Serial measurements of head circumference that are plotted on an appropriate growth chart are a useful index against which to measure subacute or chronically elevated ICP in infancy and early childhood. The normal rate of growth of head circumference in infants born at full term is 2 cm per month for the first 3 months, 1 cm per month for the next 3 months, and 0.5 cm per month for the subsequent 3 months [Bray et al., 1969].

PATHOPHYSIOLOGY OF RAISED INTRACRANIAL PRESSURE According to the Monroe-Kellie doctrine, the skull is a rigid cavity and its contents are relatively noncompressible, consisting of the brain parenchyma, intravascular blood, and cerebrospinal fluid [Kellie, 1824; Monro, 1783]. Expansion in the volume of any one compartment is at the expense of the other two; for example, an increase in the volume of the brain parenchyma because of a neoplasm is compensated for by the expression of cerebrospinal fluid out of the brain compartment into the spinal subarachnoid space and a decrease in blood volume because of compression of the dural venous sinuses. Because each compartment is relatively noncompressible, its volume is directly proportional to its intrinsic pressure. The global ICP represents the sum

of the partial pressures of the individual compartments. Although the Monroe-Kellie doctrine is a useful concept, it is not as consistently applicable to infants as it is to adults [Luerssen, 1997] because of the inherent compressibility of the brain parenchyma, inasmuch as a neoplasm can expand locally in the relatively pliable, unmyelinated brain of an infant, exerting localized pressures that are not uniformly transmitted to the entire brain. Also, the cranial cavity is not a rigid container in infants, as it can continue to enlarge by separation of the cranial sutures. The pressure-volume relationships in the brain may be described by the following equation: C ~ dV/dp where C represents compliance and dV represents the change in volume that accompanies a change in pressure (dp) [Friden and Ekstedt, 1983; Trauner, 1989]. Compliance is the ability of the brain to accommodate increases in intracranial volume without changes in ICP. It follows a hyperbolic curve (Fig. 65-1). As ICP rises, compliance decreases. Along the horizontal segment of the curve, increases in intracranial volume raise the pressure only slightly because compensatory mechanisms maintain a physiologic state. Beyond a certain point, however, even minor increases in volume lead to a disproportionately greater rise in ICP. In the healthy brain, compliance is along the horizontal segment of the curve, whereas in a damaged, swollen brain, compliance is located along the vertical segment of the curve. The overall slope of the pressure-volume curve is steeper in infancy than in older children (Fig. 65-2). An increase in intracranial volume by 10 mL is not likely to cause as much of an increase in ICP in an adolescent as in an infant [Shapiro et al., 1994]. This steeper volume-pressure curve persists in infancy until the point of separation of the cranial sutures. Thereafter, the infant’s cranial cavity is able to accommodate relatively more volume than is the adult skull. An alternative measure of compensatory reserve in patients with brain edema is the correlation (R) between amplitude (A) and mean pressure (P) (RAP). This index is derived by calculating the linear correlation between consecutive, timeaveraged data points of ICP waveform amplitude and mean ICP over a short time, such as 4 minutes. A RAP coefficient close to 0 is physiologic and indicates a good pressurevolume compensatory reserve. In other words, when intracranial volume increases, there is no corresponding rise in ICP. When RAP rises to 1+, the working point of the pressure-volume curve shifts to the right, and increases in intracranial volume start becoming linked to ICP [Czosnyka and Pickard, 2004]. Brain edema occurs consistently in patients with increased ICP. It can be vasogenic, cytotoxic, or hydrostatic

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signal intensities in the T2 sequences in patients with vasogenic edema, which helps differentiate it from cytotoxic brain edema [Schaefer et al., 1997]. Endothelial damage triggered by the local release of cytokines such as tumor necrosis factor α, interleukin-1β, interleukin-6, histamine, and arachidonic acid may play a role in the development of vasogenic edema [Gourin and Schackford, 1997; Schilling and Wahl, 1997]. Cytotoxic edema results from processes, usually toxic or metabolic, that affect the integrity of cell membranes of neurons and glial cells so that they are unable to maintain a stable pump mechanism and internal milieu, leading to hydropic swelling. It commonly occurs during hypoxic-ischemic encephalopathy and is not steroid responsive. Interstitial edema is characterized by transependymal transudation of cerebrospinal fluid into the adjacent white matter and is generally seen in patients with hydrocephalus. The various forms of edema are not mutually exclusive and may coexist to varying degrees.

Box 65-1 COMMON CAUSES OF RAISED INTRACRANIAL PRESSURE Extracerebral disorders Primary craniosynostosis Crouzon’s disease Apert’s syndrome Kleeblattschädel deformity Extradural hemorrhage Chronic subdural hematoma Subarachnoid space lesions Communicating hydrocephalus Parenchymal/ventricular disorders Neoplasms Pseudotumor cerebri Obstructive hydrocephalus Communicating hydrocephalus Bacterial meningitis Viral meningoencephalitis Head injury Hypoxic-ischemic encephalopathy Reye’s syndrome Inborn errors of metabolism Diabetic ketoacidosis Hepatic coma

Impact on Cerebral Perfusion The normal cerebral blood flow rate in newborns is about 40 mL/100 grams/minute and 53 mL/100 grams/minute in older children and adults [Shapiro et al., 1994]. Increased ICP reduces cerebral blood flow. The primary objective in controlling brain swelling is therefore the prevention of brain ischemia [Luerssen, 1997]. This relationship between ICP and blood flow is best expressed by the following equations:

in nature. Vasogenic cerebral edema is related to opening of the tight junctions in the blood-brain capillaries and transudation of fluid into the extracellular space. It is commonly observed in head trauma, neoplasms, inflammatory disorders, and lead encephalopathy and is responsive to glucocorticoids. More recently, the brain swelling associated with head injury has been thought to be related to a combination of vasogenic and cytotoxic edema [Marmarou, 2003]. Neurogenic inflammation linked to the release of peptides such as substance P and calcitonin gene–related peptide may also play a major in the pathogenesis of posttraumatic brain edema [Nimmo et al., 2004]. Diffusionweighted magnetic resonance imaging reveals increased

INFANT

CPP ≅ MAP – ICP or CPP ≅

SAP + 2DAP – ICP 3

where: CPP = cerebral perfusion pressure, MAP = mean arterial pressure, SAP = systolic arterial pressure, and DAP = diastolic arterial pressure.

14 YEAR OLD

50

ICP (mm Hg)

40

30

20 Po

Po

10

−2

0

2

4 6 V (mL)

8

10

−2

0

2

4

6 8 V (mL)

10 12 14 16

FIGURE 65-1. Pressure-volume curves of an infant and a 14 year old, generated by injecting and withdrawing cerebrospinal fluid into the ventricular system. Note that the curve is steeper in the infant than in the 14 year old; this reflects the infant’s lesser ability to buffer increases in intracranial volume. ICP, intracranial pressure. (Adapted with permission from Shapiro K, Morris WJ, Teo C. Intracranial hypertension: Mechanisms and management. In: Cheek WR, Marlin AE, McLone DJ, et al., eds. Pediatric neurosurgery. Surgery of the developing nervous system. Philadelphia: WB Saunders, 1994;310.)

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PRESSURE-VOLUME INDEX (PVI) IN NORMAL ADULT (log ICP vs V) 80 60

log ICP (mm Hg)

40

20

10

and carbon dioxide tension. Small fluctuations in arterial oxygen tension do not alter cerebral blood flow, but there is an inverse relationship between cerebral blood flow and oxygen tension when the arterial oxygen tension drops below 50 mm Hg. The vascular response to changes in arterial carbon dioxide tension is even more sensitive. For each 1–mm Hg change in arterial carbon dioxide tension, cerebral blood flow changes in the same direction by 3% to 4% [Siesjo, 1984]. The lower limit for this response is about 20 mm Hg in adults and about 15 mm Hg in children [Trauner, 1989]. When compliance is impaired and shifted to the steep segment of the pressure-volume curve, autoregulation is also impaired, and even minor increases in cerebral blood flow—for example, because of hypercarbia— can lead to significant rises in ICP.

INTRACRANIAL PRESSURE MONITORING

8

Rationale

6 PVI = 25 mL (Calculated volume to raise ICP 10x)

4

0

1515

−8

0

8 V (mL)

16

24

FIGURE 65-2. Pressure-volume index (PVI) in a normal adult. The PVI is the calculated volume (in milliliters) needed to raise the cerebrospinal fluid pressure by a factor of 10. The concept is identical in children. The normal PVI of an infant is around 10, whereas that of a normal adult is around 25. When compliance is reduced, the PVI diminishes. (Adapted with permission from Shapiro K, Morris WJ, Teo C. Intracranial hypertension: Mechanisms and management. In: Cheek WR, Marlin AE, McLone DJ, et al, eds. Pediatric neurosurgery. Surgery of the developing nervous system. Philadelphia: WB Saunders, 1994.)

The normal cerebral perfusion pressure varies between 20 mm Hg in preterm infants at birth to 80 mm Hg at 12 months [Sato et al., 1988]; the value in young adults is 50 to 55 mm Hg. A drop in the cerebral perfusion pressure below the physiologic level may be associated with ischemic brain injury. When cerebral perfusion pressure decreases to 40% of normal, electrophysiologic function in the brain fails, and neuronal ischemia ensues [Trauner, 1989]. This underscores the importance of avoiding hypotension in any patient with increased ICP from overzealous fluid restriction or excessive use of volume-depleting, hyperosmolar agents. Autoregulation is the ability of the brain to maintain stable blood flow in the presence of fluctuations in the cerebral perfusion pressure. It is accomplished through regional vasoconstriction or vasodilation. Autoregulation is frequently compromised in patients with raised ICP, and this creates a “pressure-passive” system wherein systemic hypotension can provoke additional ischemic injury. The mediators of metabolic autoregulation are changes in tissue pH, potassium, and calcium ions [Siesjo, 1984]. The cerebral vasculature is also responsive to changes in arterial oxygen

Increased ICP is difficult to verify on clinical grounds alone. In comatose patients, the yield of the clinical examination may also be compromised by sedative agents or skeletal muscle paralytic agents that have been administered for ventilator management. The objective of management is to recognize and reduce ICP well before it leads to irreparable brain damage. The decision to monitor ICP in any given patient is based on the premise that the ICP elevation is going to persist for some time (more than a few hours). It should be combined with accurate measurements of systemic blood pressure and fluid balance through intraarterial and central venous pressure lines.

Methodology ICP monitoring requires the placement of a pressure-sensing device into the cranial cavity. Initial work on the direct monitoring of ICP after ventricular puncture was carried out by Guillaume and Janny [1951] and Lundberg [1960]. The following three basic patterns of ICP were described by Lundberg: • Plateau or A waves: increases of ICP in the range of 540 to 650 mm H2O (40 to 50 mm Hg) that are sustained for 2 to 10 minutes, followed by a return to a higher baseline than before. They are indicative of a significant decrease in brain compliance. • B waves: brief elevations of a moderate degree (range of 272 to 408 mm H2O [20 to 30 mm Hg]); related to fluctuations in respiration and also indicative of decreased compliance. • C waves: small-amplitude fluctuations related to intracranial transmission of arterial pulses. ICP is most reliably monitored by the placement of an intraventricular catheter that is connected to a pressure transducer and a recording device or continuous strip chart. Placement of an intraventricular catheter can be technically difficult when severe brain swelling leads to compression of the ventricles or, in some instances, to ventricular displacement. On the other hand, it has the advantage of facilitating a decrease in intracranial volume and pressure by

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withdrawing small amounts of cerebrospinal fluid (1 to 2 mL). Compliance can also be studied in patients with the intraventricular cannula by determining the pressure-volume index, which consists of plotting the ICP logarithmically against volume [Marmarou and Shulman, 1976]. A small amount of saline (0.5 to 1 mL) is instilled into the intraventricular catheter. The pressure-volume index is the volume (in milliliters) needed to raise the ICP by a factor of 10 (see Fig. 65-2). The normal pressure-volume index is approximately 25 mL in adults and approximately 10 mL in infants. Adult values are reached at approximately age 14 years. A decrease in compliance leads to a decrease in the pressurevolume index. The risks associated with the use of ventricular catheters include hemorrhage and infection. The overall risk of ventriculitis is 1% to 5% [Rosner and Becker, 1976] and rises when the catheter has been left in place for more than 3 to 4 days. Other ICP monitoring devices include the subarachnoid bolt, the epidural transducer, and the fiberoptic intraparenchymal catheter-transducer. One advantage of the intraparenchymal monitor is the ease of insertion. The disadvantage is that measurements may drift over time, because there is no way to recalibrate the system [Adelson et al., 2003]. The normal ICP in children between 1 and 7 years of age ranges from 82 to 176 mm of cerebrospinal fluid (5 to 15 mm Hg), and the generally acceptable threshold for treatment of raised ICP is over 200 to 240 mm (15 to 18 mm Hg). The cerebral perfusion pressure should also be monitored and kept well over 50 to 55 mm Hg; the normal cerebral perfusion pressure is 70 to 73 mm Hg in infants and 73 to 77 mm Hg in children [Shapiro et al., 1994]. Raised ICP is seen in 40% to 60% of patients with severe head injury and in 50% of those who die from it [Narayan et al., 1982].

Utility ICP monitoring is definitely indicated in all comatose headinjured patients with a Glasgow Coma Scale score of 8 or less, because studies have demonstrated that monitoring may contribute to enhancing the outcome in this group [Narayan et al., 1982]. It may also be beneficial in the management of patients with brain tumors, slit-ventricle syndrome, craniosynostosis, hepatic encephalopathy, and Reye’s syndrome. Its use does not, however, lead to improvement in the outcome in coma related to severe hypoxic-ischemic encephalopathy, as occurs in near-drowning, acute encephalitis, or hepatic failure [Luerssen, 1997].

Monitoring of Intracranial Pressure from the Anterior Fontanel The tension over the anterior fontanel can be used as a gauge of ICP in newborns and infants. A helpful review is provided by Volpe [2000]. The basis for all the available devices is the applanation principle [Menke et al., 1982; Salmon et al., 1977], which is that when the anterior fontanel is maintained in the flat position, pressure on either side is equal. A handheld pressure-sensing device is pressed over the anterior fontanel, and the pressure necessary to eliminate bulging of the skin is determined; this corresponds to the ICP. The manner of placement of each device over the fontanel is a

key issue. When it is used by trained individuals, there is excellent correlation between pressure readings obtained after lumbar puncture and those from the fontanellometers. Using this device, Volpe et al. [2000] found the ICP in newborns free of intracranial pathology was 40 to 50 mm H2O (2.9 to 3.6 mm Hg). Serial measurements by this noninvasive technique may help in the management of neonatal intraventricular hemorrhage, posthemorrhagic hydrocephalus, bacterial meningitis, and hypoxic-ischemic encephalopathy.

Blood-Flow Velocity Measurement by Doppler Devices and Intracranial Pressure Doppler assessments of cerebral blood flow velocity can be obtained serially at the bedside in critically ill neonates. A transducer placed over the anterior fontanel emits highfrequency sound waves that are directed at the pericallosal branch of the anterior cerebral artery. After closure of the anterior fontanel, vessels in the circle of Willis can be insonated through the temporal bone. The frequency shifts of the back-scattered echoes are converted into visual images. Blood-flow velocity measurements thus obtained provide indirect information about blood flow because velocity is inversely proportional to the diameter of blood vessels, and severe cerebral edema leads to compression of blood vessels. The resistive index is the most commonly assessed parameter. It is derived as follows: (Peak systolic amplitude of flow – peak diastolic amplitude of flow) Peak systolic amplitude of flow The resistive index is a useful index of blood flow velocity. Although isolated resistive index values are of not much significance, serial increases over time are correlated with rising ICP. Improvements in technology have made it easy to determine the resistive index in dural venous sinuses through transcranial color-coded duplex sonography [Mursch et al., 1999]. Blood flow velocity measurements from over the large venous sinuses are helpful in evaluating raised ICP secondary to venous sinus thrombosis.

CLINICAL MANIFESTATIONS OF RAISED INTRACRANIAL PRESSURE Headache Supratentorial mass lesions frequently lead to traction on the dura, which is innervated by the trigeminal nerve, thus causing pain that is referred to the frontal and temporal regions, whereas lesions of the infratentorial structures might lead to pain localized over the occipital regions. The headache is frequently exacerbated by measures that increase ICP, such as coughing, bending, and sneezing. It might also be worsened by the recumbent position, and patients frequently have a history of headache on awakening in the morning. The duration of the headache is generally brief, lasting days to weeks. Sutures can split in children younger than 10 years of age, thus providing temporary relief from symptoms, except that the headache returns within a few days because of further increases in

Kotagal / Increased Intracranial Pressure

ICP. Analgesics provide little to no relief. Patients with third ventricular tumors may sometimes find relief by assuming a kneeling position and flexing their necks forward. Headache from brain tumors is more likely to be recognized in children older than 2 years [Dobrovoljac et al., 2002] and is generally of only short duration (4 to 6 weeks).

Diplopia Of all the cranial nerves, the sixth cranial nerve is the longest, thus making it susceptible to displacement and traction from an enlarging mass lesion. Traction on cranial nerve VI can lead to its unilateral or bilateral paresis, thus causing a “false localizing sign” because there is no intrinsic pontine lesion. The patient presents with binocular diplopia, made worse in the direction of gaze of the paretic muscle. There is no relation of the paresis with the level of ICP.

Decreased Sensorium Stupor begins to appear in adults when the ICP reaches the 204 to 540 mm H2O (15 to 40 mm Hg) range [Ropper, 1984]. Comparable data are not available for children. The mechanisms postulated include one swollen hemisphere compressing the contralateral hemisphere and creating “bihemispheral coma” and compression of the ascending reticular formation in the mesencephalic-diencephalic regions.

Impaired Upward Gaze Pressure over the pretectal region of the midbrain from supratentorial mass lesions impairs upward gaze. Patients exhibit mild retraction of the upper eyelids because of sympathetic overactivity. These two elements combine to produce the sunset sign, which is especially obvious in infants in the form of prominent eyes with downward deviation of gaze.

Change in Personality Nonspecific manifestations such as irritability, mood swings, apathy, and lethargy are common in infants and children with subacute, progressive increases in ICP.

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Excessive Cranial Enlargement Increasing intracranial volume in infants and toddlers from subacute or chronic mass lesions frequently leads to tenseness and bulging of the anterior fontanel, prominence of the scalp veins, splitting of the cranial sutures, and macrocephaly. Serial measurements of the head circumference plotted on a head growth chart might demonstrate an upward shift to higher percentiles. In addition, it may be possible to palpate splitting of the sutures. Closure of the anterior fontanel, which generally occurs between 8 to 18 months, might also be delayed.

Papilledema Papilledema is the most reliable sign of increased ICP; it is caused by edema in the nerve fiber layer of the retina that arises because of impaired retinal venous return as a result of the increased ICP. It may be unilateral or bilateral with supratentorial mass lesions but is bilateral with infratentorial lesions. Most patients do not complain of visual symptoms, but in the late stages of papilledema, there might be “transient visual obscurations,” which are fleeting episodes of vision loss lasting seconds. Early papilledema is characterized by a loss of retinal venous pulsations (however, about 20% of normal children also do not demonstrate venous pulsations). This loss is followed by elevation and blurring of the optic disc margins, tortuosity of the retinal veins, hemorrhages, and exudates (Fig. 65-3). In contrast to papillitis, visual acuity remains normal in papilledema until the late stages. Although papilledema reliably indicates increased ICP, its absence does not exclude its possibility. In a population of 120 children with craniosynostosis (premature closure of the sutures), the presence of papilledema was 98% specific as an indicator for raised ICP, but its sensitivity was age dependent [Tuite et al., 1996]. It was a reliable indicator of raised ICP in children older than 5 years but not in preschool-aged children. Papilledema is generally also not seen in infants because of compensation for raised ICP by splitting of the sutures and cranial enlargement. A false impression of papilledema can be created by “drusen,” alternatively termed colloid or hyaline bodies. They are located over the optic nerve head, dominantly inherited [Fenichel, 2001] more common in white persons, and generally seen after the age of 11 years [Glaser, 1978].

FIGURE 65-3. Fundoscopy illustrating moderate papilledema, with slightly increased tortuosity of vessels, blurring, and elevation of the optic disc margins. (Reproduced with the kind permission of Dr. John B. Selhorst, St. Louis University, St. Louis, MO.)

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Cushing Response Compression of the brainstem may lead to slowing of the respiratory rate, bradycardia, and elevation of the blood pressure. It may be a beneficial, adaptive response that is designed to maintain adequate cerebral perfusion pressure in the presence of moderate intracranial hypertension [Barbiro-Michaely et al., 2003]. It is observed inconsistently, however, and only in one fifth to one third of patients with documented ICP elevations [Marshall et al., 1979]. In fact, tachycardia is seen with raised ICP as often as is bradycardia.

Acute Pulmonary Edema Acute pulmonary edema is a rare but significant complication of cerebral edema [Ducker et al., 1969]. It is triggered by an excessive autonomic discharge, which leads to increased pulmonary vascular permeability; it is reversible on reduction of ICP.

Brain Herniation Syndromes Severe cerebral edema (Fig. 65-4) ultimately leads to brain herniation, during which portions of the swollen brain become impacted in abnormal locations (e.g., the tentorial notch or the foramen magnum) [Plum and Posner, 2000]. The displaced brain tissue impinges on vessels, leading to impairment of venous return, additional swelling, and tissue injury. The following vicious cycle develops, which, if untreated, can be fatal: Cerebral edema → Vascular occlusion ↑ ↓ Cellular injury ← Brain ischemia

Transtentorial Herniation Transtentorial herniation is characterized by the swollen, uncal portion of the temporal lobe’s becoming displaced in a medial and caudal direction and becoming impacted in the tentorial notch, thus compressing the ipsilateral third cranial

nerve, midbrain, ipsilateral cerebral peduncle, and posterior cerebral artery. The initial clinical manifestations include an ipsilateral dilated pupil (resulting from extrinsic compression of the pupilloconstrictor fibers in the outer core of the third nerve), progressive decline in consciousness, loss of oculocephalic (doll’s-eye) reflexes, and the appearance of decorticate posturing. At times, there can also be pressure on the contralateral cerebral peduncle, leading to hemiparesis that is ipsilateral to the mass lesion.

Central Herniation Central herniation is seen when both diffusely swollen cerebral hemispheres compress the diencephalic structures and midbrain from above. In its early stages, central herniation is characterized by a progressive decline in the level of consciousness, constricted pupils (resulting from diencephalic sympathetic dysfunction), and Cheyne-Stokes respiration. With further progression, there is loss of oculocephalic reflexes, central neurogenic hyperventilation, and decerebrate posturing that ultimately progresses to complete loss of brainstem function.

Tonsillar Herniation The cerebellar tonsils become impacted in the foramen magnum, thus compressing the medulla oblongata and the upper cervical spinal cord. This type of herniation can occur with either supratentorial or infratentorial mass lesions, although it is encountered more often with posterior fossa mass lesions. It is characterized by an abrupt loss of consciousness, opisthotonic posturing, stiff neck, irregular respiration, and apnea. The late stages of uncal, central, and tonsillar herniation are indistinguishable, with the presence of flaccid limbs, unresponsive midsize pupils, loss of caloric and oculocephalic reflexes, and irreversible apnea that leads to death.

Cingulate Herniation Cingulate herniation is characterized by shifting of the swollen cingulate gyrus underneath the free edge of the falx

FIGURE 65-4. Noncontrast head computed tomographic scan in a child with severe closed-head injury, demonstrating severe, diffuse cerebral edema. Note that the brain swelling is leading to loss of gray-white matter junction differentiation, compression of the frontal horns of lateral ventricles (arrowhead), and obliteration of the cisterna ambiens (arrows).

Kotagal / Increased Intracranial Pressure

cerebri, causing compression of the ipsilateral or bilateral anterior cerebral arteries and the internal cerebral vein. This leads to infarction of the paracentral lobules.

LUMBAR PUNCTURE IN PATIENTS WITH RAISED INTRACRANIAL PRESSURE Lumbar puncture is contraindicated in patients with raised ICP because of the risk of precipitating brain herniation. The ocular fundi should be carefully assessed for papilledema in every patient before a lumbar puncture is initiated. If the fundi cannot be visualized and symptoms are suspect for increased ICP, pertinent diagnostic information may be obtained by computed tomographic or magnetic resonance image scanning. For suspected acute encephalitis and bacterial meningitis, cerebrospinal fluid sampling is still crucial to diagnosis and management, but the least amount of cerebrospinal fluid necessary should be withdrawn. A postlumbar puncture prophylactic dose of mannitol, 0.25 to 1 gram/kg, may also be administered. If the cerebrospinal fluid opening pressure exceeds 200 mm H2O, it is important to complete the measurement of the ICP and then carefully monitor the patient. In most clinical situations, the patient remains clinically stable, and so an individualized decision can be made in regard to the need for treatment with furosemide (Lasix), mannitol, or hypertonic saline for ICP monitoring or placement of a lumbar cerebrospinal fluid drain, additional treatment of the underlying disease, neurosurgical consultation or transfer to a critical care unit, and other measures. It is not uncommon for patients with elevated ICP (e.g., patients with idiopathic intracranial hypertension [IIH]) to feel better after a lumbar puncture. However, patients must be monitored for signs of neurologic deterioration if the ICP is increased.

MANAGEMENT OF ACUTELY ELEVATED INTRACRANIAL PRESSURE Whenever possible, treatment should be directed toward the underlying cause of the raised ICP, such as acute encephalitis or abscess. Supportive measures outlined in the following sections are also indicated. An algorithm for the evaluation of the child with suspected increased ICP is presented in Figure 65-5. This algorithm is intended to assist in the evaluation and management of raised ICP in childhood. It does not address each and every possible clinical scenario; rather, it serves as a broad road map. As is true for any medical emergency, there must be a high index of suspicion of the various possible disorders, as well as efficient team work between the emergency room physician/ intensivist, nursing staff, neurologist, and neurosurgeon, as well as the family.

Respiratory Management Children with increased ICP require sedation, analgesia, and skeletal muscle paralytic agents. These measures help suppress pain, coughing, and gagging, which might provoke reflex increases in ICP [Palmer, 2000]. These therapeutic

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measures also necessitate endotracheal intubation and placement on a ventilator. Hyperventilation with maintenance of arterial carbon dioxide tension between 25 and 30 mm Hg effectively reduces ICP by causing cerebral vasoconstriction, thus decreasing intracranial volume. For the purpose of endotracheal intubation, a topical anesthetic should be sprayed over the vocal cords to minimize procedural trauma, which may provoke a rise in ICP. In such instances, it is also advisable to lower the ICP by infusing hyperosmolar agents such as mannitol before the intubation. A drop in ICP occurs within 1 to 5 minutes of initiation of hyperventilation [Ropper, 1984]. ICP can be satisfactorily controlled in two thirds of patients by a combination of a hyperosmolar agent and hyperventilation. Failure to reduce ICP despite hyperventilation is a grave prognostic sign. Hyperventilation should be discontinued gradually over 24 to 48 hours, because abrupt cessation can lead to a rebound increase in ICP. A rise in ICP from indirect transmission of elevated intrathoracic pressure to intracranial vessels can be avoided by sedation and decreasing the inspiratory phase of the respirator [Ersson et al., 1990]. Positive end-expiratory pressure could also theoretically raise the ICP, but this does not appear to be an issue in clinical practice [Frost, 1977; Shapiro et al., 1994].

Positioning of the Head Elevation of the head by 15 to 30 degrees facilitates venous return from the head, thus helping to reduce ICP. This degree of head elevation does not lower the cerebral perfusion pressure [Rosner and Coley, 1986]. Hyperextension, twisting of the neck, and traction on the endotracheal tube should be avoided. The head should not be elevated in hypotensive patients.

Fluid Management A central venous pressure catheter should be placed in patients with significantly raised ICP to help manage fluid balance. Hypotonic intravenous fluids should be avoided because they can precipitate a fluid shift into the brain compartment and exacerbate cerebral edema. A 5% dextrose solution with half normal saline, normal saline, or Ringer’s lactate is preferred. The patient should be monitored closely for the syndrome of inappropriate secretion of antidiuretic hormone, with measurements of serum and urine osmolality. Fluid intake should be kept at maintenance levels but lowered if this syndrome develops. Hypovolemia should be avoided.

Hyperosmolar Agents Mannitol, urea, glycerol, and hypertonic saline are the most commonly recommended hyperosmolar agents. They produce an abrupt rise in intravascular osmolality in relation to the brain compartment. The rise in intravascular osmolality facilitates fluid shift from the brain into the vascular space [Bell et al., 1987]. Mannitol is most commonly used. Its intravascular and brain concentrations do not equilibrate as rapidly as those of glycerol or urea [Shapiro et al., 1994]. It is available as a 20% solution. The dose is 0.25 to 1 gram/ kg, given intravenously over 10 to 15 minutes as a bolus. The lower end of the dose range is recommended for infants and young children. The onset of mannitol action occurs

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Brain Injury and Disorders of Consciousness / 65

within 1 to 5 minutes, and the duration of action is 2 to 3 hours. Serum osmolality should be maintained below 320 mOsm/ liter. Despite the popularity of mannitol, evidence of its efficacy consists of only two class III studies [The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies, 2003]. Furosemide has synergistic effect with mannitol in terms of reducing the ICP by virtue of decreasing free water. It might also lower the rate of formation of cerebrospinal fluid, but this effect is not significant in the clinical setting [Shapiro, 1994]. Glycerol is available as a 10% solution, given intravenously in a dose of 1 gram/kg, three to four

times a day. Its onset of action occurs within 30 minutes. Hypertonic saline is a promising alternative for the reduction of ICP. The recommended dose of 3% saline is 0.1 to 1.0 mL/kg of body weight per hour, administered as a continuous infusion on a sliding scale, and serum osmolality should be maintained below 360 mOsm/liter. Evidence supporting the use of hypertonic saline consists of three class II studies and one class III study [The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies, 2003]. There have been no “head-to-head” studies comparing the efficacy of mannitol with that of hypertonic saline in reducing ICP in

Is child suspected of having increased ICP? Yes Suspected by History 1. Moderate/severe traumatic brain history 2. Febrile illness with symptoms of meningitis or encephalitis 3. Global cerebral hypoxic-ischemic injury (near drowning, cardiopulmonary arrest) 4. Exacerbation of metabolic disease (diabetic ketoacidosis, inborn error of metabolism) 5. Exacerbation of shunted or unshunted hydrocephalus 6. Unexplained headache, vomiting, of diplopia

Head CT without contrast shows surgical lesion? Yes

No

1. Lesion with significant mass effects 2. Hydrocephalus due to CSF obstruction 3. Unilateral cerebral edema with mass effect

1. Consider placement of an ICP monitor 2. Consider lumbar puncture for CSF collection or ICP measurement 3. Continue supportive medical care 4. Antibiotics/antiviral agents if indicated 5. Follow for clinical signs of increased ICP

Consider: 1. Lesionectomy 2. CSF diversion 3. Craniotomy

No

Does patient need ICP monitoring? Yes 1. Have ICP monitor placed. 2. Is ICP increased or CPP below physiologic range? No

Consider: 1. Continue to observe neurologic status 2. Maintain fluid and electrolyte balance 3. Maintain physiologic CPP 4. Maintain normothermia 5. Minimal stimulation and suctioning 6. Head of bed at 30 degrees 7. Prophylactic antiepileptic drugs

Yes Consider: 1. Head of bed at 30 degrees 2. Minimal stimulation and suctioning 3. Hyperventilation to Pco2 of 25-30 mm Hg 4. Hyperosmolar agents 5. Pharmacologic coma 6. Hypothermia 7. Repeat head CT scan 8. Prophylactic antiepileptic drugs

FIGURE 65-5. Algorithm for the evaluation of the child with suspected increased intracranial pressure (ICP). CPP, cerebral perfusion pressure; CSF, cerebrospinal fluid; CT, computed tomography; PCO2, carbon dioxide tension. Algorithm developed by Drs. Suresh Kotagal, David Michelson, and Stephen Ashwal.

Kotagal / Increased Intracranial Pressure

children or, for that matter, regarding the long-term outcome of children receiving these agents. Complications from the use of osmotic agents include dehydration, central pontine myelinolysis, and electrolyte imbalance, especially hypernatremia. Moreover, the administration of repeated doses of any osmotic agent over a short period of time, such as four to five doses over 24 hours, may lead to a rebound increase in ICP [Node and Nakazawa, 1990]. Placement of a central venous catheter to assess fluid balance and of an ICP monitor is vital in any subject receiving repeated infusions of intravenous osmotic agents.

Corticosteroids Lipid hydrolysis and free radical–induced lipid peroxidation are inhibited by corticosteroids [Hall and Braughler, 1982]. This inhibition might indirectly limit the development of vasogenic edema, but the exact mechanism of action of steroids has not been fully established. Although the efficacy of steroids in the treatment of brain edema associated with neoplasms is unquestionable, there is no clear proof that they alleviate edema seen with post-traumatic, metabolic, and inflammatory disorders. The recommended dose of dexamethasone in infants and young children is 0.4 to 1 mg/ kg/day in four divided doses; the dose in adolescents is 4 mg every 6 hours. Onset of action may take 12 to 24 hours.

Hypothermia Medically induced hypothermia to 34° C may be used in comatose head-injured children for decreasing the cerebral metabolic rate and blood flow and thus the ICP. There are no data that hypothermia necessarily improves outcome in children, however. It may be induced through use of tepid water sponging or a cooling blanket. Shivering should be avoided, because it inhibits cooling. Complications of cooling include cardiac dysrhythmias, neutropenia, diminished myocardial contractility, and clotting abnormalities. Rewarming should be gradual, with monitoring for hyperkalemia resulting from a sudden shift in potassium from the intracellular space into the extracellular compartment [Palmer, 2000].

Intracranial Pressure Monitoring Device Bedside neurologic examination is of limited value in a patient who is comatose or pharmacologically paralyzed for ventilatory management, especially when two or more doses of an osmotic agent have already been administered for control of suspected increased ICP. Placement of an ICP monitor should be considered for such patients.

Barbiturates Pentobarbital is more effective than phenobarbital in sharply reducing cerebral metabolism, which in turn leads to reduced cerebral blood flow and lowering of intracranial volume and, thus indirectly, of the ICP. Barbiturates are generally used only when standard therapy consisting of osmotic agents, hyperventilation, and head positioning has failed to control the ICP. An initial bolus of 5 to 10 mg/kg of pentobarbital given over 30 minutes is followed by its infusion at a rate of

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1 to 5 mg/kg/hour to maintain the serum pentobarbital level between 35 to 45 mg/mL. The electroencephalogram should also be monitored continuously to ensure that the lowering of cerebral metabolism is sufficient enough to create a suppression-burst pattern, as well as to monitor for electrographic seizures. Barbiturates should be used only in the intensive care setting, with close monitoring of the mean arterial pressure, ICP, cardiac index, and pulmonary artery wedge pressures. Hypotension, mostly from depressed cardiac contractility, develops in 50% of subjects despite adequate volume replacement. It may necessitate correction with dopamine or dobutamine. Other complications of barbiturate-induced coma include pneumonia and hyponatremia. Although barbiturates are effective in lowering the ICP in patients whose condition is refractory to standard therapy [Eisenberg et al., 1988], they do not improve the outcome in severe head injury [Ward et al., 1985], metabolic disorders [Ward et al., 1987], or stroke [Ropper, 1984].

Relief of Acute Hydrocephalus An emergency ventriculostomy can temporarily relieve raised ICP in patients with acute hydrocephalus. This procedure is especially useful in patients with brain tumors because hydrocephalus in some of these patients might be transient, and placement of a permanent ventriculoperitoneal shunt may be avoided. The pressure is monitored continuously and, if it exceeds a certain threshold, cerebrospinal fluid is drained. In other instances, however, on the basis of etiology, the neurosurgeon might well consider placement of a permanent ventriculoperitoneal shunt.

Control of Seizures The abrupt onset of seizures in a patient with raised ICP may indicate deterioration in neurologic function. Seizures provoke further rises in ICP by increasing cerebral blood flow. The seizures may develop as a consequence of the underlying cerebral insult, fluid and electrolyte imbalance, or infection. Unfortunately, they may be particularly difficult to recognize in a pharmacologically paralyzed and heavily sedated patient. A high index of suspicion and continuous electroencephalographic monitoring are needed. The ICP monitor may limit electrode application. There should be a low threshold for adding prophylactic antiseizure medications such as phenytoin, phenobarbital, lorazepam, or valproic acid.

Decompressive Surgery There is emerging literature on the value of decompressive craniotomy with durotomy or decompressive craniectomy in children who have refractory intracranial hypertension, specifically those with ICP greater than 20 mm Hg for more than 30 minutes. In traumatic brain injury, decompressive surgery seems to more effective when carried out early (within 48 hours of trauma) rather than later [Ruf et al., 2003]. The procedure may decrease the midline shift. Longterm outcome has not been adequately studied, but case reports with small numbers of patients suggest that half the subjects are free of major neurologic deficits [Figaji et al., 2003; Ruf et al., 2003].

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IDIOPATHIC INTRACRANIAL HYPERTENSION IIH, or primary idiopathic intracranial hypertension (previously termed pseudotumor cerebri), may develop at any age. To some extent, it is a diagnosis of exclusion, dependent on excluding identifiable causes of raised ICP [Friedman and Jacobson, 2002]. If untreated, the patient may experience progressive visual loss from ischemic optic neuropathy. The nomenclature remains a bit unclear. Benign intracranial hypertension has been discarded as patients may develop significant long-term visual deficits. The term pseudotumor cerebri is also not used as often because it leaves an impression that the disorder is not a real disease (Friedman and Jacobson, 2004). For those in whom an appropriate cause is found, the diagnosis should be “intracranial hypertension secondary to—.” IIH presents subacutely with daily headache that is made worse by maneuvers that raise ICP, such as coughing and bending. Infants may manifest irritability, the sunset sign, and a bulging anterior fontanel. Cranial nerve VI paresis from traction on the nerve caused by raised ICP may lead to diplopia that worsens with lateral gaze [Bergman, 1994]. Other manifestations of IIH include tinnitus, blurring of vision, vertigo, decreased visual acuity, and transient visual obscurations. Patients remain alert and fully oriented. Adolescents with IIH may be obese; among adolescents, IIH is slightly more common in girls than in boys, but there is no specific gender predilection during infancy and early childhood. The retinal examination discloses papilledema. Bedside and formal visual field testing may demonstrate enlargement of the blind spot but, in general, only in the advanced stages. Magnetic resonance imaging, magnetic resonance venographic, and computed tomographic studies usually yield normal results. Infrequently, the ventricles may appear slitlike. Lumbar puncture is needed to establish a definitive diagnosis. It reveals significantly raised opening and closing pressures, normal white blood cell count, protein, and glucose. Disorders associated with secondary intracranial hypertension are listed in Box 65-2 [Geenen et al., 1996; Gironell et al., 1997; Kone-Paut et al., 1997; Lombaert and Carton, 1976; Raghavan et al., 1997; Selhorst et al., 1984]. Dural venous sinus thrombosis is a significant cause of secondary intracranial hypertension. It is now being detected more often because magnetic resonance venography is increasingly used in the investigation of patients with headache and papilledema (Fig. 65-6). Lumbar puncture might show increases in opening pressure, red blood cells, and protein content. Before the advent of magnetic resonance venography, many affected patients received mistaken diagnoses of IIH. Sickle cell anemia with normal venous flow has also been linked to secondary intracranial hypertension or pseudotumor cerebri [Henry et al., 2004]. The treatment of IIH depends on whether visual function is compromised. In patients with unimpaired visual function, the treatment consists of agents that decrease the formation of cerebrospinal fluid (acetazolamide, 20 mg/kg/day in two divided doses) or diuretics such as furosemide (1 mg/kg/day in two divided doses). Patients receiving acetazolamide should be monitored for side effects such as drowsiness; anorexia; nausea; numbness of the hands, feet,

Box 65-2 DISORDERS ASSOCIATED WITH “IDIOPATHIC” INTRACRANIAL HYPERTENSION Drugs Use of corticosteroids and corticosteroid withdrawal Tetracyclines Oral contraceptives Hypervitaminosis A Nalidixic acid Phenothiazines Systemic disorders Iron deficiency anemia Guillain-Barré syndrome Leukemia Non-Hodgkin’s lymphoma Polycythemia Chronic otitis media or sinusitis Behçet’s disease Antiphospholipid antibody syndrome Familial deficiency of antithrombin III Systemic lupus erythematosus Other systemic infections Metabolic/endocrine disorders During initiation of treatment of hypothyroidism Hyperthyroidism Hypoparathyroidism Adrenal insufficiency Hyperadrenalism Obesity, menarche, pregnancy Hypophosphatasia

Thrombosed sinuses

FIGURE 65-6. Magnetic resonance venogram in a 10-year-old girl with acute lymphocytic leukemia who developed headache and papilledema during the course of chemotherapy with L-asparaginase. Note lack of flow signal in the superior and inferior sagittal sinuses and the sigmoid sinuses (arrows), which is consistent with sinus thrombosis.

Kotagal / Increased Intracranial Pressure

or face; and renal calculi. Patients taking furosemide should be monitored for hypokalemia. There are no data on the comparative efficacy of acetazolamide and furosemide. Weight reduction measures are also recommended for obese subjects. A 2- to 3-week course of dexamethasone may also be beneficial [Fenichel, 2001], but there is a risk of weight gain from steroid use. The discontinuation of steroids might also exacerbate the pseudotumor. Serial lumbar punctures, carried out every 5 to 7 days, with drainage of 20 to 25 mL of cerebrospinal fluid on each tap, are also helpful in lowering the closing pressure below 200 mm Hg. Pain at the lumbar puncture site and post–lumbar puncture headache are potential complications. Simple analgesics such as acetaminophen and ibuprofen, combined with bed rest, are used to treat these complications. A careful examination of the visual acuity and formal visual fields should be performed every 1 to 3 months. Patients who demonstrate compromise of visual function despite medical therapy may need optic nerve sheath fenestration, a surgical procedure that reduces pressure around the nerve. Medical therapy should continue. In a study of 29 eyes of patients with IIH who were subjected to optic nerve sheath fenestration and monitored for a mean of 15.7 months [Goh et al., 1997], the visual acuity improved in 4 eyes (13.8%), stabilized in 22 eyes (76%), and deteriorated in 3 eyes (10.3%). A lumboperitoneal shunt [Johnston et al., 1988] may also be used when IIH is refractory to standard medical therapy. The treatment of secondary intracranial hypertension is similar to that of IIH but additionally includes removal of the underlying precipitant, such as discontinuation of tetracycline or vitamin A, and the use of low-molecularweight heparin for dural venous sinus thrombosis [DeVeber et al., 1998; Johnson et al., 2003; Stam et al., 2002].

CEREBRAL EDEMA IN DIABETIC KETOACIDOSIS A mild degree of cerebral edema, characterized by effacement of the cortical sulci and mild compression of the lateral ventricles on computed tomographic scans, is a common finding in juvenile diabetic ketoacidosis [Krane et al., 1985]. Most patients, however, remain clinically asymptomatic from the standpoint of raised ICP. Severe cerebral edema, in contrast, is a rare but potentially lethal complication, with a mortality rate of 90% [Dunger et al., 2004; Krane et al., 1985]. Paradoxically, it becomes apparent 6 to 10 hours after initiation of therapy for diabetic ketoacidosis with intravenous fluids and insulin—at a time when the blood glucose levels are falling and adequate peripheral circulation has been restored [Krane et al., 1985]. The pathogenesis is not fully understood, but it may include osmotic dysequilibrium between the intravascular and intracerebral contents. Diabetic ketoacidosis is associated with accumulation in the brain of polyols (sorbitol, xylitol, and dulcitol) and other unidentified, osmotically active substrates termed idiogenic osmoles. An osmotic dysequilibrium may develop when the intravascular hyperosmolality is corrected sooner than the brain hyperosmolality, which results in a large fluid shift into the brain and cerebral edema [Arieff and Kleeman, 1973; Prockop, 1971]. However, Hale and colleagues [1997] believed that the syn-

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drome is more likely to develop in patients with low initial serum sodium levels and low serum osmolality. Other series of investigators have believed that the syndrome is related primarily to rapid correction of serum glucose and that a rapid movement of sodium into the brain is not the cause. It appears that acidosis does not play any significant role in the pathogenesis. There is active debate about whether this potentially fatal complication can be predicted or prevented [Dunger et al., 2004]. Once the massive brain swelling has begun, it leads to an abrupt deterioration in the level of consciousness in a patient who was otherwise becoming gradually more alert. Central or uncal herniation may develop, heralded by changes in pupillary size, tonic posturing, loss of oculocephalic reflexes, and respiratory arrest. The management calls for immediate intravenous administration of mannitol (0.25 to 1 gram/kg), followed by endotracheal intubation and hyperventilation if necessary.

CRANIOSYNOSTOSIS Secondary craniosynostosis is linked to micrencephaly, premature suture closure resulting from lack of brain growth. It does not lead to increased ICP. Primary premature closure of the cranial sutures (incidence about 0.4 per 1000) can, however, lead to raised ICP. Most cases of primary craniosynostosis are sporadic, although both autosomal-recessive and autosomal-dominant forms can also occur. At least 50 syndromic conditions have been linked to primary craniosynostosis (see Chapter 19) [Shapiro et al., 1994]. Sagittal synostosis is the most common type, leading to scaphocephaly, followed by coronal synostosis that leads to brachycephaly/plagiocephaly. Premature closure of one suture usually causes only a cosmetic deformity. Increased ICP is more likely to occur with premature closure of multiple sutures. Raised ICP has been documented in 33% [Reiner et al., 1982] to 73% [Thompson et al., 1995] of patients with primary craniosynostosis. Both reduced intracranial volume and deformation of the intracranial venous sinuses play a role in the development of raised ICP [Mursch et al., 1999]. This is manifested as irritability, opisthotonic posturing, headache, vomiting, or papilledema. There are probably multiple mechanisms underlying the premature closure of the sutures, including genetic factors, teratogens, metabolic bone disease, intrauterine positioning, and molding [Cohen, 2005]. Intracranial abnormalities such as septo-optic dysplasia and ventriculomegaly can also coexist. Crouzon’s disease is an autosomal-dominant disorder caused by mutations in the fibroblast growth factor receptor 2 gene. It is characterized by early closure of any or all sutures in association with midface hypoplasia [Theone, 1995]. Patients manifest hypertelorism, exophthalmos, a parrot-beaked nose, hypoplastic maxilla, and prognathism. Progressive visual and hearing loss occur in half the patients, and mental retardation in a third. Apert’s syndrome is characterized by coronal synostosis and syndactyly, hypertelorism, exophthalmos, cataracts, a high pointed palate, and normal intelligence [Theone, 1995]. Above-average parental age has been reported in sporadic cases. Mutations involving the fibroblast growth factor receptor 2 gene have also been observed. The kleeblattschädel (cloverleaf) deformity is seen

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with primary craniosynostosis involving all sutures. It may be inherited as a recessive or dominant trait. Skull radiographs in patients with craniosynostosis reveal obliteration of the sutures and sclerosis along their margins and a “beaten silver” appearance. Computed tomography is helpful in excluding associated intraparenchymal lesions. Elevated ICP can be established by lumbar puncture or by epidural or intraparenchymal ICP monitors. Serial measurements of the resistive index with transcranial color-coded duplex sonography of the superior sagittal sinus are also useful in the preoperative and postoperative assessment of ICP [Mursch et al., 1999]. Surgical treatment, whether for cosmetic reasons alone or for alleviation of increased ICP, requires a team approach, entailing the expertise of a primary care physician, a neurosurgeon, a craniofacial plastic surgeon, a neuro-ophthalmologist, an anesthesiologist, and a social worker. The operative procedure may vary from strip craniectomy along the suture margins to more extensive plastic procedures. There is a high incidence of recurrence of increased ICP in patients with syndromic craniosynostosis. In a study of 22 consecutive infants with syndromic craniosynostosis who underwent initial surgery between 6 to 18 months, Pollack and associates [1996] found that 8 (36%) of the infants developed asymptomatic increases in ICP at a median of 16.5 months after the initial surgery.

CONCLUSION In infants and children, a high index of suspicion should be maintained for raised ICP. The symptom is of diverse etiology. The presentation may be acute or subacute. Acutely elevated ICP may be life threatening and necessitates a team approach for management, with involvement of the family, nursing staff, pediatric intensivist, neurosurgeon, and child neurologist. The algorithm shown in Figure 65-5 may help in management. REFERENCES Adelson PD. Bratton SL, Carney NA, et al. Guidelines for the acute medical management of severe traumatic brain injury in infants, children, and adolescents. Pediatr Crit Care Med 2003;4:S28. Arieff AI, Kleeman CR. Studies on mechanisms of cerebral edema in diabetic coma: Effects of hyperglycemia and rapid lowering of plasma glucose in normal rabbits. J Clin Invest 1973;52:571. Barbiro-Michaely E, Mayevsky A. Effects of elevated ICP on brain function: Can the multiparametric monitoring system detect the “Cushing response?” Neurol Res 2003;25:42. Bell BA, Smith MA, Kean DM. Brain water measured by magnetic resonance imaging: Correlation with direct estimation and changes after mannitol and dexamethasone. Lancet 1987;1:66. Bergman I. Increased intracranial pressure. Pediatr Rev 1994;15:241. Bray PF, Shields WD, Wolcott GJ, et al. Occipito-frontal head circumference—An accurate measurement of intracranial volume. J Pediatr 1969;75:303. Cohen MM. Editorial: Perspectives on craniosynostosis. Am J Med Genet 2005;136A:313. Czosnyka M, Pickard JD. Monitoring and interpretation of intracranial pressure. J Neurol Neurosurg Psychiatry 2004;75:813. DeVeber G, Chan A, Monagle P, et al. Anticoagulation therapy in pediatric patients with sinovenous thrombosis: A cohort study. Arch Neurol 1998;55:1533. Dobrovoljac M, Hengartner H, Bolthauser E, et al. Delay in the diagnosis of pediatric brain tumors. Eur J Pediatr 2002;161:663. Ducker TB, Simmons RL, Martin AM. Pulmonary edema as a

complication of intracranial disease. Am J Dis Child 1969;118:638. Dunger DB, Sperling MA, Acerini CL, et al. ESPE/LWPES consensus statement on diabetic ketoacidosis in children and adolescents. Arch Dis Child 2004;89:188. Eisenberg HM, Frankowski RF, Contant CF, et al. High-dose barbiturate control of elevated intracranial pressure in patients with severe head injury. J Neurosurg 1988;69:15. Ersson U, Carlson H, Mellstrom A, et al. Observations on intracranial dynamics during respiratory physiotherapy in unconscious neurosurgical patients. Acta Anesthesiol Scand 1990;34:99. Fenichel GM. Increased intracranial pressure. In: Fenichel GB, ed. Clinical pediatric neurology. A signs and symptoms approach, 4th ed. Philadelphia: WB Saunders, 2001;91. Feske SK. Coma and confusional states: Emergency diagnosis and management. Neurol Clin 1998;16:237. Figaji AA, Fieggen AG, Peter JC. Early decompressive craniotomy in children with severe traumatic brain injury. Child’s Nerv System 2003;19:666. Friden HG, Ekstedt J. Volume/pressure relationship of the cerebrospinal space in humans. Neurosurgery 1983;13:351. Friedman D, Jacobson D. Diagnostic criteria for idiopathic intracranial hypertension. Neurology 2002;59:1492. Friedman D, Jacobson DM. Idiopathic intracranial hypertension. J Neuro-ophthalmol 2004;24:138. Frost EAM. Effects of positive end-expiratory pressure on intracranial pressure and compliance in brain-injured patients. J Neurosurg 1977;47:195. Geenen C, Tein I, Ehrlich RM. Addison’s disease presenting with cerebral edema. Can J Neurol Sci 1996;23:141. Gironell A, Marti-Fabregas J, Bello J, et al. Non-Hodgkin’s lymphoma as a new cause of non-thrombotic superior sagittal sinus occlusion. J Neurol Neurosurg Psychiatry 1997;63:121. Glaser, JS. Topical diagnosis: Prechiasmal visual pathways. In: Glaser JS, ed. Neuro-ophthalmology. Hagerstown, MD: Harper & Row, 1978;61. Goh KY, Schatz NJ, Glaser JS. Optic nerve sheath fenestration for pseudotumor cerebri. J Neuroophthalmol 1997;17:86. Gourin CG, Shackford SR. Production of tumor necrosis factor-alpha and interleukin-1-beta by human cerebral microvascular endothelium after percussive trauma. J Trauma 1997;42:1101. Guillaume J, Janny P. Manometrie intracranienne continue; interet physio-pathologique et clinique de la methode [Continuous intracranial manometry; physiopathologic and clinical significance of the method]. Presse Med 1951;59:953. Hale PM, Rezvani I, Braunstein AW, et al. Factors predicting cerebral edema in young children with diabetic ketoacidosis and new onset type I diabetes. Acta Pediatr 1997;86:626. Hall ED, Braughler JM. Effects of intravenous methylprednisolone on spinal cord lipid peroxidation and Na-K ATPase activity. Dose-response analysis during 1st hour after contusion injury in the cat. J Neurosurg 1982;57:247. Henry M, Driscoll MC, Miller M, et al. Pseudotumor cerebri in children with sickle cell disease: A case series. Pediatrics 2004;113:e265. Johnson MC, Parkerson N, Ward S, et al. Pediatric sinovenous thrombosis. J Pediatr Hematol Oncol 2003;25:312. Johnston I, Besser M, Morgan MK. Cerebrospinal fluid diversion in the treatment of benign intracranial hypertension. J Neurosurg 1988;69:195. Kellie G. The account of the appearances observed in the dissection of two of the three individuals presumed to have perished in the storm of the 3rd, and whose bodies were discovered in the vicinity of Leith on the morning of 4th November, 1821, with some reflections on the pathology of the brain. Trans Med Chir Sci Edinburgh 1824;1:84. Kone-Paut I, Chabrol B, Riss JM, et al. Neurologic onset of Behçet’s disease: A diagnostic enigma in childhood. J Child Neurol 1997;12:237. Krane EJ, Rockoff MA, Wallman JK. Subclinical brain swelling in children during the treatment of diabetic ketoacidosis. N Engl J Med 1985;312:1147. Lombaert A, Carton H. Benign intracranial hypertension due to A-hypervitaminosis in adults and adolescents. Eur Neurol 1976;14:340. Luerssen TG. Intracranial pressure: Current status in monitoring and management. Semin Pediatr Neurol 1997;4:146. Lundberg N. Continuous recording and control of ventricular fluid pressure in neurosurgical practice. Acta Psychiatr Neurol Scand

Kotagal / Increased Intracranial Pressure 1960;36 (Suppl 149):S1. Marmarou A. Pathophysiology of traumatic brain edema: Current concepts. Acta Neurochir Suppl 2003;86:7. Marmarou A, Shulman K. Pressure-volume relationships—Basic aspects. In: McLaurin RL, ed. Head injuries. New York: Grune & Stratton, 1976;5. Marshall LF, Smith RW, Shapiro HM. The outcome with aggressive treatment in severe head injuries. Part I. The significance of intracranial pressure monitoring. J Neurosurg 1979;50:20. Menke JA, Miles R, McIlhany M, et al. The fontanelle tonometer: A non-invasive method for measurement of intracranial pressure. J Pediatr 1982;100:960. Monro A. Observations on the structure and function of the nervous system. Edinburgh: Creech and Johnston, 1783. Mursch K, Enk T, Christen HJ, et al. Venous intracranial hemodynamics in children undergoing operative treatment for the repair of craniosynostosis. Childs Nerv Syst 1999;15:110. Narayan RK, Kishore PR, Becker DP, et al. Intracranial pressure: To monitor or not to monitor? A review of our experience with severe head injury. J Neurosurg 1982;56:650. Nimmo AJ, Cernak I, Heath DL, et al. Neurogenic inflammation is associated with development of edema and functional deficits following traumatic brain injury in rats. Neuropeptides 2004;38:40. Node Y, Nakazawa S. Clinical study of mannitol and glycerol on raised intracranial pressure and on their rebound phenomenon. Adv Neurol 1990;52:359. Palmer J. Management of raised intracranial pressure in children. Intensive Crit Care Nurs 2000;16:319. Plum F, Posner JB. Supratentorial lesions. In: Plum F, Posner JB, eds. The diagnosis of stupor and coma. New York: Oxford University Press, 1980;109. Pollack IF, Losken HW, Biglan AW. Incidence of increased intracranial pressure after early surgical treatment of syndromic craniosynostosis. Pediatr Neurosurg 1996;24:202. Prockop LD. Hyperglycemia, polyol accumulation, and increased intracranial pressure. Arch Neurol 1971;25:126. Raghavan S, DiMartino-Nardi J, Saenger P, et al. Pseudotumor cerebri in an infant after L-thyroxine therapy for transient neonatal hypothyroidism. J Pediatr 1997;130:478. Reiner D, Sainte-Rose C, Marchac D, et al. Intracranial pressure in craniosynostosis. J Neurosurg 1982;57:370. Ropper AH. Raised intracranial pressure in neurologic disease. Semin Neurol 1984;4:5. Rosner MJ, Becker DP. ICP monitoring: Complications and associated factors. Clin Neurosurg 1976;23:494. Rosner MJ, Coley IB. Cerebral perfusion pressure, intracranial pressure, and head elevation. J Neurosurg 1986;60:636. Ruf B, Heckmann M, Schorth I, et al. Early decompressive craniectomy

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and duroplasty for refractory intracranial hypertension in children: Results of a pilot study. Crit Care 2003;7:409. Salmon JH, Hajjar W, Bada HS. The fontogram: A non-invasive intracranial pressure monitor. Pediatrics 1977;60:721. Sato H, Sato N, Tamaki N, et al. Threshold of cerebral perfusion pressure as a prognostic factor in hydrocephalus during infancy. Childs Nerv Syst 1988;4:274. Saul TG, Ducker TB. The effect of intracranial pressure monitoring and aggressive treatment on mortality in severe head injury. J Neurosurg 1982;56:498. Schaefer PW, Buonanno FS, Gonzalez RG, et al. Diffusion-weighted imaging discriminates between cytotoxic and vasogenic edema in a patient with eclampsia. Stroke 1997;28:1082. Schilling L, Wahl M. Brain edema: Pathogenesis and therapy. Kidney Int Suppl 1997;59:S69. Selhorst JB, Waybright EA, Jennings S, et al. Liver lover’s headache: Pseudotumor cerebri and vitamin A intoxication. JAMA 1984;252:3365. Shapiro K, Morris WJ, Teo C. Intracranial hypertension: Mechanisms and management. In: Cheek WR, Marlin AE, McLone DJ, et al., eds. Pediatric neurosurgery. Surgery of the developing nervous system. Philadelphia: WB Saunders, 1994;307. Shapiro S, Bowman R, Callahan J, et al. The fiberoptic cerebral pressure monitor in 244 patients. Surg Neurol 1996;45:278. Siesjo BK. Cerebral circulation and metabolism. J Neurosurg 1984;60:883. Society of Critical Care Medicine and The World Federation of Pediatric Intensive and Critical Care Societies. 2003;4(3, suppl):SD40. Stam J, De Bruijn SF, DeVeber G. Anticoagulation for cerebral sinus thrombosis. Cochrane Database Syst Rev 2002;(4):CD002005. Theone JG, ed. Physician’s guide to rare diseases, 2nd ed. Montvale, NJ: Dowden, 1995. Thompson DN, Harkness WJ, Jones B, et al. Subdural intracranial pressure monitoring in craniosynostosis: Role in surgical management. Childs Nerv Syst 1995;11:269. Trauner DA. Increased intracranial pressure. In: Swaiman KF, ed. Pediatric neurology. Principles and practice, 2nd ed. St. Louis: CV Mosby, 1989. Tuite GF, Chong WK, Evanson J, et al. The effectiveness of papilledema as an indicator of raised intracranial pressure in children with craniosynostosis. Neurosurgery 1996;38272. Volpe JJ. Specialized studies in the neurological evaluation. In: Volpe JJ, ed. Neurology of the newborn, 4th ed. Philadelphia: WB Saunders, 2000;134. Ward JD, Becker DP, Miller JD, et al. Failure of prophylactic barbiturate coma in the treatment of severe head injury. J Neurosurg 1985;62:383. Welch K. The intracranial pressure in infants. J Neurosurg 1980;52:693.

CHAPTER 66

Spinal Cord Injury N. Paul Rosman and Chellamani Harini

In the United States and Canada, the annual incidence of traumatic spinal cord injury is 30 to 46 cases per 1 million population [Decker and Hergenroeder, 2004]. In the United States, 8000 to 12,000 new spinal cord injuries occur each year. Less than 10% of these patients die from their acute injuries [Walker, 1991], with 200,000 to 250,000 persons now living in the United States with sequelae of spinal cord trauma [Green and Eismont, 1984; Meyer et al., 1991; Oliver, 1992; Walker, 1991]. Pediatric patients constitute 0.3% to 10% of that number [Dias, 2004; Hadley et al., 1988; Hill et al., 1984; Proctor, 2002], with 3% to 5% of the spinal cord injuries that occur each year in the United States occurring in persons younger than 15 years of age and 20% occurring in persons younger than 20 years of age [Vogel and Anderson, 2003]. The risk of spinal cord injury is equal for males and females from birth to age 3 years; the male-to-female ratio is 6:4 from age 4 to 8 years, 7:3 from age 9 to 15 years, and 8.5:1.5 from age 16 to 20 years [Massagli, 2000]. Half of the spine injuries in children 0 to 3 years old occur at the C1 to C2 level, whereas only 8% affect this level in children age 4 to 12 years. These differences are probably explained by the higher fulcrum of motion in younger children and perhaps by weakness of C2 as a result of incomplete ossification of its synchondrosis [Proctor, 2002]. Motor vehicle accidents, including lap belt injuries to the lumbar spine, are the principal cause of spinal cord injuries, followed in decreasing order of frequency by falls, recreational or sports activities (especially diving accidents and football injuries), and penetrating injuries of the spinal column (e.g., gunshot, knife) [Gibson, 1992; Maroon et al., 1980; Massagli, 2000; Meyer et al., 1991; Mueller and Blyth, 1987; Schneider, 1964; Vogel and Anderson, 2003]. Since the 1980s, violence has increased from 10% to 30% as a cause of spinal cord injury in patients ages 16 to 20 years [Vogel et al., 1997]. Traumatic birth injury accounts for only 10% to 15% of all cases [Hadley, 1992]. Determinants of the severity of injury occurring after spinal cord trauma include the following: (1) nature, direction, and degree of the traumatic insult; (2) site of injury; (3) presence of any preexisting spine anomaly; (4) extent of tissue damage; (5) degree of vascular compromise complicating the spinal trauma; and (6) rapidity and efficacy of treatment [Rosman and Herskowitz, 1982]. The mortality from spinal cord injury in children is more than twice that seen in adults [Hamilton and Myles, 1992].

ANATOMY Bony Spine and Ligaments The structure of the bony spine provides protection for and prevents excessive movement of the underlying spinal cord.

Major ligaments that functionally divide the spine into anterior and posterior compartments maintain stability of the bony spinal column during movement [Chilton and Dagi, 1985]. Anteriorly, these ligaments are the anterior and posterior longitudinal ligaments; posteriorly, the ligaments include the ligamentum flavum and the interspinous, intertransverse, supraspinous, and facet capsular ligaments. Additionally the transverse or cruciate ligament provides important stability between the atlas and axis. Stability of the spine as a whole is ensured if all of the anterior ligaments or if all of the posterior ligaments plus one anterior ligament are intact [Chilton and Dagi, 1985]. The most mobile portion of the spinal column is the cervical region, making that area the most common site of spinal cord injury [Green and Eismont, 1984; Hill et al., 1984]. Younger children are particularly susceptible to injuries of the high cervical cord [Davis et al., 1993; Piper and Menezes, 1996; Vogel et al., 1997]. Factors predisposing the upper cervical spine to injury in the young child include a proportionally larger and heavier head, relative underdevelopment of the neck muscles and ligaments, incomplete ossification of the vertebral bodies with relative anterior wedging [Massagli, 2000], incomplete development of the uncinate processes, smaller vertebral bodies of C1 to C2 compared with C3 to C5, and the more horizontal orientation of the articular surfaces of the cervical facet joints [Glasser and Fessler, 1996; Hadley et al., 1988; White and Panjabi, 1990]. Approximately 55% of spinal cord injuries involve the cervical spine, 30% involve the thoracic spine, and 15% involve the lumbar spine [Marion, 1998]. With birth trauma, spinal cord injuries are most common in the high cervical region (usually during an instrumental cephalic delivery) and in the lower cervical and upper thoracic regions (usually during a breech delivery). With increased use of cesarean sections to avoid potentially problematic vaginal deliveries, the frequency of spinal cord injury incurred during delivery has lessened appreciably [Morgan and Newell, 2001]. Between infancy and 8 years of age, 75% of spinal injuries occur in the cervical spine, particularly in its upper portion. Between age 8 and 14 years, 60% of injuries occur in the cervical spine, and 20% occur in the thoracic region, with the remainder at lower spinal levels [Menezes et al., 1989]. Conditions predisposing to cervical spinal cord injury in children include Down syndrome (15% have atlantoaxial instability), Klippel-Feil syndrome, Morquio’s syndrome, Larsen’s syndrome, achondroplasia, and previous cervical spine surgery [Caviness, 2004; Massagli, 2000]. The most common causes of cervical spine trauma in persons 18 years old and younger were motor vehicle accidents (45%), diving (23%), falls (11%), gymnastics

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Brain Injury and Disorders of Consciousness / 66 C1 I I C1 2 II II 3 III III 4 IV IV 5 V V 6 7 VI VI 8 VII VII T1 T1 T1 2 3 II

3 4 5 6 7 8

II

4

III

2

III IV

IV

6

V VI

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9

Spinal Cord

2

A disparity exists between vertebral and segmental cord levels that changes with age. Early in fetal life, the spinal cord extends throughout the bony vertebral column, but during later development, the vertebral column becomes longer than the spinal cord. The caudal end of the cord comes to lie at successively higher vertebral levels; at birth, it is at the level of the second lumbar vertebra, and in adulthood, it is at the first lumbar level. Disparity also exists between the levels of exit of nerve roots from the spinal canal and corresponding spinal segmental levels from which they originate, with the nerve roots emerging below their sites of origin (see Chapter 2). Below the first lumbar segment, there is no spinal cord, only the lumbosacral roots composing the cauda equina (Fig. 66-1).

4

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IX

IX 11

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SI 2 3 4 5

LI

(7%), football (5%), and other miscellaneous causes (8%) [Hill et al., 1984]. The second most mobile portion of the spine is the thoracolumbar region. It also is the second most commonly injured area, with T10 the site most frequently fractured [Ruge et al., 1988]. Regardless of the mechanism of injury, the thoracic spine (T2 through T10) is the most common site of fracture in pediatric trauma patients [Reddy et al., 2003]. The thoracic and lumbosacral regions are the portions of the cord least often injured after trauma [Green and Eismont, 1984].

11 XII 12 LI L1 II 2

II III

3

III IV IV

4

Blood Supply The anterior spinal artery is an unpaired vessel formed by junction of a branch from the two vertebral arteries. It descends the entire length of the spinal cord ventrally in the anterior median sulcus. Between C3 and L3, the anterior spinal artery receives additional blood supply from anterior radicular arteries derived from lateral spinal arteries. Branches from the anterior spinal artery supply the entire anterior columns and most of the lateral columns of the spinal cord. The two posterior spinal arteries communicate with posterior radicular branches of the lateral spinal arteries to form a rich plexus of collaterals that supply the entire posterior columns and the remainder of the lateral columns of the spinal cord [Herren and Alexander, 1939; Suh and Alexander, 1939].

V V 5

S1 2 3 4 5 Coc

FIGURE 66-1. Spinal cord root levels in relation to the vertebral bodies. (From Haymaker W, Woodhall B. Peripheral nerve injuries, 2nd ed. Philadelphia: WB Saunders, 1953.)

PATHOGENESIS: MECHANISMS OF SPINAL CORD INJURY When the spinal cord sustains traumatic injury, the forces applied to the spine usually have been sufficient to cause displacement of vertebral ligaments and bones [Kakulas, 1984]. There are five major ways in which trauma to the spine can result in injury to the spinal cord: forward flexion, lateral flexion, rotation, axial compression, and hyperextension [Chilton and Dagi, 1985]. The forces generated by these movements can result in vertebral distraction, dislocation, fracture, and disk herniation. Often, as is the case in motor vehicle accidents and birth trauma, several forces act at the same time to injure the spine [Glasser and Fessler, 1996]. Osseous disruption (fracture or displacement) is the most common cause of spinal cord injury. Ligamentous injury, without osseous disruption, causing spinal cord injury

Rosman and Harini / Spinal Cord Injury

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FIGURE 66-3. Plain lateral view of the cervical spine disclosing anterior dislocation of C6, resulting in one of its inferior facets (arrow) locking into a superior facet of C7 immediately below. Both superior facets of C7 are visible because of rotation of that vertebra. FIGURE 66-2. Plain lateral view of the thoracic spine in an 8-year-old female who sustained a hyperflexion injury after a fall from a height of 10 feet. There is anterior wedging of the bodies of T4 and T6 (arrows).

is common in children, resulting in spinal cord injury without radiographic abnormality (SCIWORA). Disk herniation occurs in approximately 50% of spinal cord–injured patients [Flanders et al., 1990].

A

Forward flexion can lead to wedge or teardrop fractures, which usually begin at or near the intervertebral disk (Fig. 66-2). These fractures are often encountered in motor vehicle accidents in passengers not wearing seat belts, but

B

FIGURE 66-4. A, Plain anteroposterior view of upper cervical spine indicates a Jefferson fracture of the atlas (C1) with a lateral mass of C1 displaced laterally on the body of C2 (arrow). B, Plain lateral view of the skull and upper cervical spine in the same patient. Accompanying the Jefferson fracture are fractures (arrows) through the posterior arch of C1.

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also can be seen in children wearing ill-fitting adult types of lap-sash belts (cervical seat-belt syndrome) [Hoy and Cole, 1993]. Excessive lateral flexion of the cervical spine is always accompanied by rotation and can cause a unilateral locked facet (Fig. 66-3). This locked facet occurs when the inferior facet contralateral to the side of flexion rotates too far anteriorly and locks into the superior facet of the vertebral body below [Panjabi and White, 1980]. Simple flexion alone usually causes little damage, but with the addition of rotation, ligaments can rupture, rendering the spine unstable and prone to distraction and dislocation. Rotation and flexion, accompanied by posterior ligamentous tear, also can cause vertebral body shear fractures. Axial compression typically occurs in diving accidents, falls, and sports injuries. Axial compression can result in a burst fracture in which the vertebral end plate is injured, allowing the intervertebral disk to rupture into the vertebral body, which then bursts. In the Jefferson fracture, a direct blow to the top of the head results in axial compression that is transmitted through the occipital condyles to the atlas, the arch of which bursts, allowing fragments to be displaced outward (Fig. 66-4) [Shapiro et al., 1973]. Severe hyperextension is often encountered in rear-end motor vehicle accidents (whiplash injury) and in the head-shaking injury of child abuse. This hyperextension can result in transverse fractures of the neural arches of the cervical spine, usually accompanied by tearing of the anterior longitudinal ligament [Caffey, 1974; Janes and Hooshmand, 1965; Ommaya, 1969]. The so-called hangman’s fracture occurs from a hyperextension injury through the synchondrosis between the odontoid and the arch of C2 [Reynolds, 2000]. Because the vertebral arteries lie in the transverse processes of these vertebrae, they can be torn or thrombosed after such injuries with resultant ischemia to the anterior twothirds of the spinal cord. Such injuries have been reported after neck hyperextension in football games and in infants with C1 to C2 instability [Gilles et al., 1979; Schneider et al., 1970]. Displacement of the vertebrae during spinal trauma can compress the arteries of the spinal cord, resulting in ischemic injury, often without radiographic abnormalities.

NEUROPATHOLOGY The nature and severity of traumatic injury to the spinal cord are related to the type and location of vertebral damage, the presence of any preexisting disorder affecting the size of the spinal canal or mobility of the spinal cord (e.g., spinal stenosis, spondylitis, prolapsed disk), and the occurrence of concomitant vascular injury [Braakman and Penning, 1976; Chilton and Dagi, 1985]. Pathologic examination after spinal cord trauma has disclosed injuries that are either intraspinal intramedullary (affecting the spinal cord primarily) or, less often, intraspinal extramedullary (affecting the spinal cord secondarily). Intraspinal intramedullary pathologies include concussion, ischemia, contusion, compression, laceration, and intramedullary hemorrhage [Jellinger, 1976]. Intraspinal extramedullary injuries include epidural, subdural, and subarachnoid hemorrhages; epidural abscess; arachnoid cyst; epidermoid tumor; herniation of the nucleus pulposus; and cauda equina injuries.

Intraspinal Intramedullary Lesions Pathogenesis and Pathologies In spinal concussion, there is a functional rather than pathologic disturbance, usually with return of function within hours [Tator, 1996]. Extravasation of potassium from neurons into the extracellular space, after direct injury of nerve cell membranes or secondary nerve cell damage from vascular disruption, is the most likely mechanism of spinal cord concussion. Ischemia of the spinal cord can occur from anterior spinal artery or other vascular compression during spinal cord trauma, but also can occur when the trauma does not involve the spinal cord directly. Hypotension, systemic shock, and vascular injury to the aorta or a vertebral artery are the most common causes of this type of injury. With compression of the anterior spinal artery, the anterior two thirds of the spinal cord is affected, causing weakness and loss of pain and temperature perception, with preservation of proprioception and light touch. Contusion results from a blunt injury of the spinal cord without continued compression or disruption of nerve tissue, resulting in transient paresthesias and dysesthesias in the upper limbs, especially the hands (burning hands syndrome), accompanied by transient long tract signs. Recovery is incomplete, however, distinguishing contusion from concussion. Central cord necrosis (hemorrhagic or ischemic) is a common sequela that often can be seen on magnetic resonance imaging (MRI) [Bailes et al., 1991; Jellinger, 1976]. Compression of the spinal cord can be caused by vertebral dislocation or by pressure from bony fragments, a herniated disk, or extramedullary bleeding [Jellinger, 1976]. Laceration occurs when there is interruption of spinal cord tissue by bony fragments, knife or bullet wounds, fracture-dislocation, or severe stretching. In older children, the most frequent cause of laceration is a penetrating agent, whereas in newborns, hyperextension of the neck during breech delivery is the most likely cause [Allen et al., 1969; Bresnan and Abroms, 1974; Byers, 1975; Crothers, 1923]. Intramedullary hemorrhage, which can extend over several spinal cord segments (hematomyelia), is believed to result from direct injury to blood vessels or from altered vascular permeability, as from acidosis. The pathology of intraspinal intramedullary injuries has been studied in detail in experimental animals and in human postmortem examination material [DeLaTorre, 1981; Dumont et al., 2001a; Jellinger, 1976; Kakulas, 1984; Norenberg et al., 2004; Park et al., 2004; Profyris et al., 2004]. To mimic most events that lead to various forms of human spinal cord injury, several experimental models have been developed, the most common being transection, compression, or contusion [Rosenzweig and McDonald, 2004]. Because there are striking pathophysiologic similarities between human spinal cord injury and experimental models of spinal cord injury, particularly in the rat, findings in experimental spinal cord injury are commonly extrapolated to human injury. Such extrapolation requires caution, however, because regulation of secondary events after spinal cord injury varies greatly among different animal species and strains [Profyris et al., 2004]. The pathologic changes observed in the spinal cord after trauma can be subdivided into early, late, and very late.

Rosman and Harini / Spinal Cord Injury

EARLY CHANGES Fifteen to 30 minutes after cord injury, erythrocytes leak predominantly into the central gray matter owing to the region’s soft consistency, rich vascularity, and high metabolic demand [Dumont et al., 2001a; Profyris et al., 2004]. These small hemorrhages aggregate and within 1 to 2 hours spread outward; petechial hemorrhages appear, and edema develops, with spread to involve adjacent white matter. Coagulation necrosis, which can involve the entire crosssection of the cord, may develop within the next few hours (Fig. 66-5). Hemorrhage still evident by 3 days is totally gone by day 8. Liquefaction occurs, with formation of cavitations by 21 days; these coalesce, and by 14 weeks they form a large cystic region surrounded by gliotic scar tissue [Profyris et al., 2004; Silver and Miller, 2004].

Necrosis and Apoptosis A barrage of pathophysiologic events that cause necrosis and apoptosis governs the biology of secondary injury after acute spinal cord injury.

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NECROSIS. After acute spinal cord injury, a centripetal and rostrocaudal necrotic wave develops that originates at the site of primary injury and that may spread two vertebral levels above and two below the initial lesion; by 8 hours, these changes are irreversible. Contributors to this necrosis include (1) infarction, (2) excitotoxicity, and (3) reperfusion injury. Infarction is caused by vascular damage to small vessels (arterioles, capillaries, and venules), vasospasm, thrombosis, and neurogenic shock. At a cellular level, infarction results in a loss of oxidative phosphorylation and glycolysis, resulting in ATP depletion, which triggers several necrotic mechanisms. Also, after spinal cord injury, there is an increase in extracellular glutamate. Excess of this excitatory neurotransmitter overstimulates N-methyl-D-aspartate, α-amino-3-hydroxy5-methyl-4-isoxazole-propionate (AMPA), and kainate to trigger waves of excitotoxic cell death. This cell death is caused by an influx of intracellular sodium and water, resulting in cell lysis, and by an accompanying increase in intracellular calcium, which stimulates an array of calciumdepleted proteases and lipases, including calpains (which can degrade structural proteins of the myelin-axon unit) and cyclooxygenase-1 (injurious to cell membranes) [Dumont et al., 2001a]. Glutamate excitotoxicity plays a key role not only in neuronal cell death, but also in oligodendrocyte apoptosis, with the latter attributable to activation of specific caspases and an increase in intracellular calcium [Kim et al., 2003; Park et al., 2004]. Reperfusion of tissue within the first few days after spinal cord injury also exacerbates the ensuing tissue damage by generating deleterious free radicals and other toxic by-products, including oxygenderived free radicals (superoxide, hydroxyl radicals, nitric oxide) [Dumont et al., 2001a]. Reexposure of endothelial cells to oxygen after an earlier ischemic insult also triggers an enzymatic reaction that gives rise to reactive oxygen species (ROS), a potent stimulus for cell death by modifying cellular lipids, proteins, and nucleic acids [Profyris et al., 2004]. APOPTOSIS. Apoptosis is the other important mediator of secondary damage after acute spinal cord injury. Apoptosis occurs in two phases. It initially begins 6 hours after injury at the lesion center, and for several days thereafter, the number of apoptotic cells in this region increases steadily, with death of multiple cell types. By 1 week, the central apoptotic count decreases, but there is now an increase in apoptotic death away—sometimes far away—from the site of the primary injury center; this second phase of cell death is localized predominantly in spinal cord white matter [Profyris et al., 2004]. Oligodendrocyte apoptosis is a widely dispersed phenomenon in spinal cord injury that leads to long-term and persisting demyelination. This denudement of axons, with resultant deterioration of their conductive abilities, adds significantly to functional decline. The high concentration of tumor necrosis factor-α in the central nervous system after spinal cord injury, together with its ability to induce apoptosis, makes it a likely instigator of oligodendrocyte apoptosis, although other factors also play a role [Profyris et al., 2004].

Immunopathology FIGURE 66-5. Severe traumatic injury to the spinal cord with secondary hemorrhage and coagulation necrosis.

Inflammatory responses are of central importance in the pathogenesis of acute and chronic spinal cord injury. During

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both phases, the injured spinal cord recruits innate immunity and adaptive immunity. INNATE IMMUNITY. The injured environment during the acute phase of spinal cord injury is dominated by the presence of proinflammatory cytokines (tumor necrosis factor-α, interleukin-1, and interleukin-6). Binding of tumor necrosis factor-α and interleukin-1 to their receptors causes them to induce an inflammatory response by signaling through the nuclear factor-κB pathway. This response stimulates the production of inflammatory mediators (reactive oxygen species, cytokines, inducible nitric oxide synthase, and prostaglandin). The anti-inflammatory agent methylprednisolone, the most effective therapy in spinal cord injury (see later section on drug therapy) has been shown to inhibit the nuclear factor-κB pathway. Spinal cord injury also induces the expression of the anti-inflammatory cytokine transforming growth factor-β, which counteracts the effects of proinflammatory cytokines. After acute spinal cord injury, neutrophils are recruited to the site of primary injury, and by 24 hours they migrate into the lesion to phagocytose debris. As the numbers of neutrophils decline, increased numbers of monocytes appear in the injured parenchyma, which by 72 hours go on to differentiate into microglia and macrophages. When activated, microglia and macrophages phagocytose necrotic and apoptotic debris, but in contrast to neutrophils, their activity is sustained longer. In rat models of spinal cord injury, microglia and macrophages do not decrease until 1 week after injury, whereas the microglial/ macrophage presence in degenerating tracts does not plateau until 2 to 4 weeks. Given the wide array of noxious mediators that are secreted by neutrophils, microglia, and macrophages, treatments to reduce their presence have been widely used in models of spinal cord injury. Decreasing the numbers of these cells at the locus of primary injury may be potentially harmful, however, because microglia and macrophages also facilitate the release of mediators that promote central nervous system repair (ciliary neurotrophic factor, insulin-like growth factor-1, nerve growth factor, and brain-derived growth factor). After contributing to the acute phase of injury, these phagocytes potentially may aid regeneration at more chronic stages by secreting neuronal survival and regeneration factors [Profyris et al., 2004]. ADAPTIVE IMMUNITY. It is likely that most T helper cells activated in spinal cord injury are activated by macrophages. Silencing this adaptive immune response may impede functional recovery after spinal cord injury, however, because activated T helper cells secrete significant amounts of several neurotrophins (nerve growth factor, brain-derived growth factor, neurotrophins NT-3 and NT4/5) potentially important in enhancing spinal cord repair [Profyris et al., 2004].

Molecular Mechanisms After spinal cord injury, the proximal ends of cut axons reseal and form a growth cone, a structure that on elongation gives rise to an axon. From the midpoint of the growth cone, processes termed filopodia project to probe the surrounding environment and deduce whether axonal extension is feasible or, conversely, deterrent to axonal elongation. The principal axonal regrowth inhibitor in the acute phase of spinal cord injury is central nervous system myelin, which

contains numerous inhibitory components (myelin-associated glycoprotein, Nogo-A, and oligodendrocyte myelin glycoprotein). Growth cone “lipid rafts,” enriched in cholesterol and sphingolipids, provide an ordered platform for signal transduction. Concentrated in these rafts is the Nogo-66 receptor (NgR), which plays a central role because of its ability to bind all three myelin inhibitory molecules. With the recent finding of two novel proteins that are homologous both structurally and biochemically to NgR [NgR homologues 1 and 2 (NgR H1 and NgR H2)], it is likely that there is added complexity to membrane signaling by myelinassociated inhibitory molecules [Profyris et al., 2004].

LATE CHANGES In patients who have survived spinal cord injury for 3 to 6 months, the central portion of the spinal cord is replaced by a cystic cavity extending for several segments above and below the point of impact, resulting in post-traumatic syringomyelia; this extension can continue over many years, significantly increasing the patient’s neurologic deficit [Barnett and Jousse, 1976; Profyris et al., 2004]. Wallerian degeneration of ascending and descending tracts occurs within 6 to 12 months [Kakulas, 1999], and nerve roots at the level of the lesion become atrophic. The cord becomes thin in the area of injury, with fibrosis and thickening of the overlying meninges [Kakulas, 1984]. In 3% of such spinal cord injuries, a progressive syndrome develops, months to years later, characterized by causalgic pain followed by proprioceptive sensory loss and weakness [Tator, 1996].

VERY LATE CHANGES Enlarging traumatic neuromas and spinal stenosis (from accelerated osteoarthritis) are effects of spinal cord injury that can occur 5 or more years after the initial impact [Kakulas, 1984]. They are probably responsible for the late clinical deterioration encountered in some long-term survivors.

Intraspinal Extramedullary Lesions Pathogenesis and Pathologies The mode of spinal cord injury from intraspinal extramedullary conditions is primarily by spinal cord compression, although secondary vasospasm and ischemia also play a role. The causative pathologies include hemorrhage, infection, cystic fluid, and solid tissues. The degree of resultant injury to cord depends on the location and size of the mass and the duration of cord compression. Post-traumatic intraspinal extramedullary mass lesions occur relatively infrequently and, when present, are often small, causing little, if any, cord compression. Included among these disorders are spinal epidural, subdural, and subarachnoid hemorrhages; spinal epidural abscess; arachnoid cyst; epidermoid tumor; and herniation of the nucleus pulposus and cauda equina injuries.

CLINICAL ASSESSMENT History A detailed history of the circumstances of the spinal cord injury should be sought from the child and observers of the

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episode. The history often discloses the additional occurrence of head trauma, which complicates the evaluation of the child, particularly when there has been alteration of consciousness. Details concerning the mechanism of injury, the activity of the child at that time, and the use of restraining devices, such as seat belts, car seats, head rests, and air bags, should be ascertained. One should inquire about the possible presence of any genetic disorders (e.g., Down syndrome), congenital abnormalities of the bony spine (e.g., hemivertebrae), or blood dyscrasias (e.g., hemophilia) that may render a child more vulnerable to spinal cord injury, which in such circumstances can occur after relatively minor trauma. The condition of the child at the scene of the injury and any subsequent changes should be carefully documented.

General Physical Examination It is crucial to assess the entire child, even in the presence of an obvious spinal injury. Particular attention should be directed to the vital signs. Respiratory difficulty may be caused by a traumatic pneumothorax or by diaphragmatic paralysis consequent to injury of the mid cervical spinal cord. Hypotension with tachycardia may result from intraabdominal bleeding from a ruptured spleen. Temperature instability may accompany spinal shock. The entire spine, particularly the cervical portion, should be examined with great care. One should look for overlying bruising and any spinal deformity. While in-line immobilization of the spine, with particular attention to the neck, is maintained, the entire spine should be palpated for any point tenderness, deformities, crepitus, or muscle spasm [Kadish, 2001].

Neurologic Examination The diagnosis of spinal cord injury is often overlooked in children with multiple injuries, unless constant vigilance to detect such injury is maintained. Spinal cord trauma should be suspected in cases of breech or otherwise difficult delivery; multiple trauma; child abuse; and certain sports injuries, such as football, gymnastics, and ice hockey [Braakman and Penning, 1976; Torg et al., 1979]. Patients with spinal cord injury can present with any combination of the following symptoms and signs: neck or back pain, weakness, sensory loss, decrease in deep tendon reflexes, loss of bladder or bowel control, autonomic dysfunction, and meningismus. Such symptoms may be classified further as acute, subacute, chronic, intermittent, delayed or late, or progressive. After the initial neurologic deficit in acute spinal cord injury, secondary deterioration is sometimes seen. Such worsening can be (1) early (<24 hours) (e.g., from spinal immobilization and traction), (2) delayed (1 to 7 days) (e.g., from hypotension complicating fracture-dislocation, or (3) late (>7 days) (e.g., from vertebral artery injury) [Harrop et al., 2001]. Signs of spinal cord injury usually include impairment of motor and sensory function. The degree of motor involvement can vary from subtle weakness to complete paraplegia or quadriplegia. Loss of sensation is often ascertainable at an obvious dermatomal level. In 1992, the American Spinal Injury Association (ASIA) and the International Medical Society of Paraplegia (IMSOP) published a Standard Neurological Classification of Spinal Cord Injury (Fig. 66-6). Such a classification offers a systematic docu-

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Box 66-1 ASIA/IMSOP SPINAL CORD IMPAIRMENT SCALE* A. Complete: No motor or sensory function is preserved in sacral segments S4 to S5. B. Incomplete: Sensory but not motor function is preserved below the neurologic level and includes sacral segments S4 to S5. C. Incomplete: Motor function is preserved below the neurologic level, and more than half of key muscles below the neurologic level have a muscle grade less than 3. D. Incomplete: Motor function is preserved below the neurologic level, and at least half of key muscles below the neurologic level have a muscle grade of 3 or more. E. Normal: Motor and sensory function is normal. *This scale distinguishes complete spinal cord injury and three degrees of incomplete injury from an absence of injury with normal motor and sensory function. ASIA, American Spinal Injury Association; IMSOP, International Medical Society of Paraplegia.

mentation of motor, sensory, and sphincter function for the accurate classification and scoring of acute spinal cord injuries. Ten key muscle groups are tested for motor function, using the Medical Research Council 0-to-5 muscle grading system, and sensation is tested over 28 dermatomes on both sides of the body. The neurologic levels and completeness or incompleteness (partial preservation) of spinal cord involvement are documented [American Spinal Injury Association, 1992]. In 1992, the ASIA with the IMSOP developed the ASIA/ IMSOP Spinal Cord Impairment Scale (Box 66-1) [Tator, 1996]. The ASIA/IMSOP scale incorporates the Medical Research Council muscle grading and pinprick/light touch sensory testing into a system differentiating complete and incomplete spinal cord deficit. Complete injury is defined as loss of all motor and sensory function in all segments below the neurologic level, including the sacral dermatomes (S4 to S5). To make this determination, perineal and deep anal sensation and digital sphincter tone and contraction must be totally lacking. If there is preservation of any sensory or motor function below the neurologic level, the injury is classified as incomplete (see Fig. 66-6). Using this classification system, the examiner identifies the sensory and motor levels, defined as the most caudal spinal cord segment with normal sensory and motor function, on both sides. The zone of partial preservation is defined as the dermatomes caudal to the neurologic level with partial preservation of function in an otherwise complete injury. A zone of partial preservation implies injury of multiple spinal cord segments, whereas its absence implies injury at only one level. Occasionally, brachial or lumbosacral plexus injuries causing weakness and sensory loss in a radicular distribution may coexist with a spinal injury, complicating the clinical picture. After injury to the spinal cord, the deep tendon reflexes are depressed or absent, with this lack of response persisting until the phase of spinal shock has resolved (1 to 12 weeks) [Green and Eismont, 1984; Guttmann, 1976; Meinecke, 1976]. Thereafter, hyperreflexia and extensor posturing are evident below the level of the lesion. Accompanying autonomic dysfunction can be manifested by

FIGURE 66-6. American Spinal Injury Association (ASIA) and International Medical Society of Paraplegia (IMSOP) Standard Neurological Classification of Spinal Cord Injury. This classification provides quantitative assessment of motor, sensory, and sphincter function; neurologic level of dysfunction; and whether any loss is complete or incomplete. (Available at: http://www.asiaspinalinjury.org/publications/2001_Classif_worksheet.pdf.)

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Horner’s syndrome, hypertension, bowel and bladder atonia, and disturbances in temperature regulation.

Laboratory Studies Radiographic Evaluation Radiographic evaluation of the child suspected to have spinal cord injury should begin in the emergency department with plain films of the entire spine. The purpose of the evaluation is to look for evidence of unstable fractures or vertebral dislocations that may require emergency surgical intervention. Radiography of the entire spine is important because approximately 15% of patients have injury at multiple sites [Hadley, 1992; Hadley et al., 1988]. Radiologic evaluation of the spine is often neither possible nor desirable in an emergency situation, however, and may need to be deferred until the spine is stabilized. In such circumstance, only the spinal area clinically involved needs immediate imaging. In cases in which the patient cannot be assessed adequately by plain radiography, MRI may be required early in the evaluation. Stringer and Andersen suggested a diagnostic algorithm for spinal injury combining the findings on neurologic examination and results of radiographic studies [Andersen and Stringer, 1996; Stringer and Andersen, 1996]. Children with spinal cord injury routinely have sandbag and tape fixation of the head and neck, making optimal radiographic examination more difficult. Nonetheless, it is crucial to obtain anteroposterior, lateral, and oblique views of the spine. All seven cervical vertebrae and the C7 to T1 interspace must be visualized. Swimmer’s views are often necessary to visualize all of the lower cervical vertebrae, and an open-mouth view may be needed to visualize the odontoid process [Goldberg et al., 1990], although the openmouth view can be safely omitted if the other views are normal [Dias, 2004]. Flexion/extension cervical x-rays and fluoroscopy are sometimes indicated to exclude ligamentous instability when there is still suspicion of cervical spine instability after static x-rays have been obtained [Hadley, 2002b]. Care must be taken not to misinterpret normal variations in cervical spine films of a child. These variations include pseudosubluxation of C2 on C3 (seen in 20% of normal children age 1 to 7 years) and the cartilaginous plate at the base of the odontoid (normally seen in children <3 years old and often mistaken for a recent fracture) [Cattell and Filtzer, 1965]. In spine-injured children, the upper cervical spine is especially susceptible to injury. Specific injuries to this region include (1) occipitoaxial dislocations, (2) atlantoaxial instability, (3) fractures of the atlas (Jefferson fracture), (4) odontoid fractures, and (5) “hangman’s fractures” [Piper and Menezes, 1996]. Occipitoaxial dislocations can be identified on plain radiographs in some patients using the Powers ratio (distance of the basion [midpoint of the anterior border of the foramen magnum] to the posterior arch of C1, divided by the distance of the opisthion [midpoint of the lower border of the foramen magnum] to the anterior arch of C1). This ratio is usually 0.77. Ratios greater than 1 are abnormal. Most often, MRI is needed to identify occipitoaxial dislocations. Instability of the atlantoaxial region is suspected when the preodontoid space exceeds 5 mm in a child

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or 3 mm in an adult. Fractures of the atlas often can be stabilized by using a rigid (Philadelphia) collar [Alker et al., 1975]. Odontoid fractures and hangman’s fractures are rare in childhood and, if present, usually can be treated nonoperatively (halo brace) [Anderson and D’Alonzo, 1974]. Measurements made to assess alignment of the spinal column follow the “rule of 2,” that is, the allowable displacement between vertebrae in any direction should not exceed 2 mm in adults, with a greater allowance in children. The evaluation of bony integrity can be difficult at times, especially of the odontoid process and C1. If adequate quality cannot be obtained by plain radiographs, computed tomography (CT) is indicated [Andersen and Stringer, 1996; Stringer and Andersen, 1996]. Further limitations of plain radiographs of the spine include 40% false-positive and 20% false-negative interpretations. Also, significant spinal cord injury frequently occurs in children without radiographic abnormality (e.g., vertebral fracture or dislocation) (SCIWORA) [Burke, 1974; Pang and Wilberger, 1982], with this discrepancy observed in 15% to 70% of all pediatric spinal cord injuries [Hadley et al., 1988; Menezes et al., 1989; Pang and Wilberger, 1982]. Based on radiographic findings, spinal column injuries can be classified as follows: (1) isolated fractures (40% of cases), (2) fractures and subluxations (most common in adolescents), (3) subluxation without fractures (more common in younger patients), and (4) SCIWORA (more common in children <8 years old). SCIWORA, as first described, referred to cases of spinal cord injury with objective signs of myelopathy in the absence of abnormalities on standard radiographs, flexion/extension views, and cervical CT. With modern MRI, many such cases show radiologic evidence of injury to the spinal cord or spinal cord ligaments [Caviness, 2004; Davis et al., 1993; Matsumura et al., 1990; Proctor, 2002], with MRI abnormalities seen in about two thirds of cases [Massagli, 2000]. In a series of 20 pediatric cases of SCIWORA, in 19 of whom a spinal MRI was done, the MRI was normal in 17 of 19. The spinal injuries in all 17 cases were partial, whereas in the two cases with abnormal MRI scans, the spinal injuries were complete. In 14 of the 18 cases with partial injuries, the neurologic deficits resolved, suggesting that in this series of SCIWORA cases, the spinal trauma was milder than in many other reported cases [Dare et al., 2002]. Because the vertebral column in early life is quite elastic, allowing for significant flexion, hyperextension, and vertebral distraction without accompanying fracture or dislocations, SCIWORA is seen most often in infants and young children, in whom the frequency is three times greater than in children older than 10 years of age [Massagli, 2000]. Also predisposing to SCIWORA in young children is the greater elasticity of the spinal column than of the spinal cord; the bony spine can tolerate 5 cm of distraction, whereas the spinal cord can tolerate only 5 mm before disruption [Caviness, 2004]. SCIWORA most often affects the cervical spine, typically producing signs of a central cord syndrome [Babcock, 1975]. In some cases, transient neurologic symptoms may be the only indication that the cervical spinal cord has been injured; in other cases, permanent deficits may result, reflecting more severe spinal cord injuries that can be partial or complete [Caviness, 2004; Massagli, 2000]. In one study, 52% of children with SCIWORA had delayed onset of paralysis

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4 days after their injury [Pang and Wilberger, 1982]. Children with spinal trauma must be examined frequently for signs of clinical deterioration in the days after their injury, even when plain radiographs of the spine are normal. Children with SCIWORA should be treated with immobilization of the spine until (1) spine tenderness clears; (2) the neurologic examination has normalized; and (3) radiographic evaluation is negative for instability or for 12 weeks, whichever is longer. Avoidance of high-risk activities for 6 months is recommended [Gunnarsson and Fehlings, 2003]. CT is the best means of detecting subtle spinal fractures and clarifying equivocal areas seen on plain films. CT also should be used when plain films are normal, but clinical suspicion of instability or fracture still exists [Andersen and Stringer, 1996; Stringer and Andersen, 1996] or when fracture/ displacement is seen on plain radiography [Caviness, 2004]. More recently, MRI of the spine has replaced CT and myelography as the preferred means of imaging the injured spinal cord (Fig. 66-7) [Goldberg et al., 1988; Hyman and Gorey, 1988; Greenberg, 1991]. Many MRI sequences can be used, depending on the type of injury and the spinal cord area of concern, including spin-echo, fast-spin-echo, gradient-recall-echo, and inversion-recovery sequences. Excellent review articles on the use of these different sequences in specific situations are available [Andersen and Stringer, 1996; Stringer and Andersen, 1996]. MRI can distinguish intramedullary lesions from extramedullary ones and early pathologic changes from later ones [Davis et al., 1993; Kalfas et al., 1988; Levitt and Flanders, 1991; Sett and Crockard, 1991]. In general, findings on MRI correlate well with the degree of deficit found on neurologic examination [Bondurant et al., 1990; Davis et al., 1993; Flanders et al., 1990]. Additionally, the type and severity of spinal cord injury seen on MRI correlate well with the degree of recovery. In one study, MRI findings were classified into the following three categories: type I, inhomogeneous on T1weighted image, large central hypointensity with thin hyperintense rim on T2-weighted image; type II, normal T1-

weighted image, hyperintense cord on T2-weighted image; type III, normal T1-weighted image, isointense center with thick hyperintense rim on T2-weighted image. These findings correlated with a poor, intermediate, and good outcome [Kulkarni et al., 1987]. In general, spinal cord injuries in which there is no identifiable MRI abnormality carry a better prognosis for recovery than injuries in which MRI abnormalities are found [Davis et al., 1993]. The usefulness of MRI in visualizing spinal cord injury in neonates, in whom neurologic abnormalities can be difficult to find and in whom significance can be difficult to interpret, has been documented [Lanska et al., 1990]. MRI also is useful in showing abnormalities that may not be seen with other imaging modalities, including ligamentous instability and disruptions, other soft tissue injuries, disk herniations, intraspinal hemorrhage, and nerve root injuries [Kadish, 2001; Proctor, 2002]. In some cases, it may be necessary to use a combination of MRI and CT to identify coexisting injuries of the spinal cord and bony spine [Levitt and Flanders, 1991; Wittenberg et al., 1990]. MRI can be useful in predicting outcome in intramedullary lesions because it can differentiate hematoma (which often has a

A

B

FIGURE 66-7. A, CT of thoracic spine in a 19-year-old male after a car accident in which he was an unrestrained passenger. There is a fracture of the right lamina of T3, with a burst fracture of the body of T4, causing deformity and anteroposterior narrowing of the spinal canal. B, MRI of thoracic spinal cord in the same patient, obtained the same day (T1-weighted image). There is a wedge fracture of T4 (arrow), producing compression of the underlying spinal cord.

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poor prognosis) from spinal cord edema, which usually has a better outcome [Schaefer et al., 1992]. In 49 patients who underwent MRI within 72 hours of sustaining a cervical spinal cord injury, the imaging features that correlated with a poor functional recovery included hemorrhage, long segments of edema, and high cervical lesions [Flanders et al., 1999]. Functional MRI has been used to assess the degree of spinal cord damage in 27 patients with complete and incomplete cervical and thoracic spinal cord injuries. With thermal stimuli applied to the inner calf (L4 sensory dermatome), activity in ipsilateral dorsal gray matter was diminished with complete and incomplete injuries; in the ventral regions, however, activity was increased with complete injuries, but with incomplete lesions, it was similar to or diminished compared with healthy subjects (i.e., it was notably less than in subjects with complete spinal cord injuries) [Stroman et al., 2004]. Serial MRI studies also can be helpful in following the evolution of traumatic spinal cord lesions [Sett and Crockard, 1991; Sato et al., 1994]. The need for metrizamide CT, used previously in evaluating post-traumatic spinal cord cysts and syringomyelia [Quencer et al., 1983; Rossier et al., 1983; Mace, 1985], has diminished substantially with the accuracy of MRI in showing these lesions. Also, because of the availability of MRI, the need for myelography to identify surgically remediable spinal cord injuries (e.g., extramedullary hematomas and major fracture-dislocations) has diminished greatly. When the patient’s clinical condition permits, most centers currently advocate early MRI for acute spinal trauma.

Electrophysiologic Evaluation The usefulness of somatosensory-evoked potentials and electromyography in evaluating the level of spinal cord injury and predicting clinical outcome is controversial. Somatosensory-evoked potentials are often useful in identifying the level of spinal cord injury [Louis et al., 1985] and in identifying areas of spinal cord damage that have been clinically unapparent [Toleikis and Sloan, 1987]. This test can be especially helpful in infants and young children in whom the degree of deficit often cannot be determined confidently by clinical examination [Kamimura et al., 1988]. It is unknown, however, whether somatosensory-evoked potentials are superior to MRI in identifying the extent of a spinal cord injury and predicting clinical outcome. Some investigators have noted a high degree of correlation between abnormal somatosensory-evoked potentials and potential for neurologic recovery [Li et al., 1990; Perot, 1973; Rowed et al., 1976; Ziganow, 1986], but others have not [Katz et al., 1991; York et al., 1983]. One study of experimental spinal cord injury revealed no correlation between the absence of somatosensory-evoked potential waveforms and the degree of spinal cord injury [Singer et al., 1977]. In that study, animals demonstrated good return of function at 8 to 9 days, even though somatosensory-evoked potential waveforms were not recordable 3 to 19 days after injury. Other studies have suggested, however, that patients with absent somatosensory-evoked potentials after spinal cord injury are unlikely to have any meaningful recovery of neurologic function [Shurman et al., 1996].

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The presence of F-waves and H-reflexes depends on the integrity of the motor neuron pool. H-reflexes disappear in the first 24 hours of spinal shock, but return thereafter; F-waves disappear below the level of injury during spinal shock and reappear with its resolution [Horowitz and Patel, 2003]. F-wave and H-reflex latencies and electromyogram can show lower motor neuron unit abnormalities three to four myotome levels beyond the site of a spinal cord lesion [Shefner and Tun, 1991]. Based on such electrophysiologic findings, the extent of deficit, whether functional or anatomic, is often found to be more extensive than indicated by clinical examination. As with somatosensory-evoked potentials, it is uncertain whether abnormalities on electromyogram can increase significantly the predictability of clinical outcome in spinal cord injury.

Lumbar Puncture Lumbar puncture can provide useful diagnostic information in certain types of spinal injury. The presence of extramedullary hematomas should be suspected with bloody or xanthochromic cerebrospinal fluid. Conversely, spinal epidural abscess usually causes a mild cerebrospinal fluid pleocytosis with an elevated cerebrospinal fluid protein concentration and a normal glucose concentration. Very low cerebrospinal fluid pressure at the time of lumbar puncture suggests the presence of a spinal block.

CLINICAL SYNDROMES Intraspinal Intramedullary Injuries Intraspinal intramedullary injuries can cause complete or incomplete loss of spinal cord function [Chilton and Dagi, 1985; Tator, 1983; Tator et al., 1993]. With complete loss, there is absence of all motor, sensory, and reflex function below the level of injury. With incomplete loss, some motor, sensory, and reflex function persists (see Box 66-1).

Complete Spinal Cord Injuries Complete loss of spinal cord function, as defined by the ASIA/IMSOP Spinal Cord Impairment scale, can be either physiologic or pathologic. In physiologic loss, there is no morphologic alteration of the spinal cord, which becomes dysfunctional after impact. This dysfunction may occur with transient compression of the cord by a dislocated vertebra. With more sustained compression of the spinal cord, anatomic disruption of spinal cord elements may result, with accompanying pathologic loss of function. The frequency of complete spinal cord injury in pediatric patients varies widely, depending on the series reviewed, ranging from 20% to 95% of all pediatric spinal cord injuries [Anderson and Shutt, 1980; Burke, 1974]. The initial phase of complete loss of spinal cord function is characterized by spinal shock [Green and Eismont, 1984; Kiss and Tator, 1993]. The truncal and extremity muscles below the level of the lesion are flaccid, deep tendon and superficial reflexes are depressed or lost, plantar responses are absent, anesthesia is present to all modalities, and autonomic dysfunction (hypotension and bradycardia) is

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present. The mechanism of spinal shock is unknown, but its physiologic effects must be differentiated from the more permanent pathologic effects of spinal cord injury. Motor and sensory deficits resulting from spinal shock alone resolve within 1 hour. Persistence of motor and sensory deficits beyond 1 hour implies that pathologic, more permanent injury has occurred. After 6 to 13 weeks in adults and within 1 week in children, tendon reflexes return, and muscle tone improves. The reflexes later become pathologically active, and spasticity ensues if the injury is more permanent, and there usually is no significant return of motor or sensory function. A four-phase model of the sequential clinical changes seen in spinal shock and the neuronal mechanisms that may underlie those changes has been described: phase 1 (0 to 1 day), areflexia/hyporeflexia (from loss of descending facilitation); phase 2 (1 to 3 days), initial reflex return (from denervation supersensitivity); phase 3 (1 to 4 weeks), initial hyperreflexia (from axon-supported synapse growth); and phase 4 (1 to 2 months), final hyerreflexia (from soma-supported synapse growth) [Ditunno et al., 2004]. Autonomic dysfunction can persist for weeks to months. Also, ventilation may be compromised if the intercostal muscles are involved. Flaccid paralysis of the bladder can develop, with urinary retention and overflow incontinence. The gastrointestinal tract can be atonic. Vasomotor dysfunction can develop, with orthostatic hypotension, impaired shivering, sweating, and disturbances in temperature regulation persisting for weeks to months. After complete injury of the cervical or upper thoracic spinal cord, an acute syndrome of bradycardia, hypotension, and hypothermia can occur, probably because of disturbed sympathetic outflow at the cervical and upper thoracic levels; most patients with quadriplegia after spinal cord injury have chronic hypothermia with poor temperature control related to loss of sympathetic peripheral vascular control [Green and Eismont, 1984]. Recovery from complete spinal cord injury is rare. The prognosis is poor. Tator estimated that less than 2% of patients with complete injury recover some distal cord function [Tator, 1996]. More encouraging was a comprehensive review of several large series of patients with complete spinal cord injury that found that about 2% of the patients became ambulatory [Hansebout, 1982].

Incomplete Spinal Cord Injuries Incomplete spinal cord injuries warrant special attention because children with these injuries often demonstrate significant recovery of function with a relatively good prognosis. Included among incomplete spinal cord injuries are the cervicomedullary syndrome, central spinal cord syndrome, syndromes of the anterior spinal cord and posterior spinal cord, Brown-Séquard syndrome, and conus medullaris syndrome.

CERVICOMEDULLARY SYNDROME With upper cervical injury, there is often injury to the medulla as well, causing respiratory arrest, hypotension, quadriparesis, and facial and upper cervical (C1 to C4) anesthesia. The facial anesthesia is of onionskin or Dejerine type. It is important that facial sensation be tested carefully in all patients with spinal cord injury. As in the central spinal

cord syndrome (see later), there often can be more weakness in the arms than in the legs. This pattern of weakness is due to the crossing of fibers subserving the arms in the pyramidal decussation so that they come to be located more centrally than the leg fibers, which cross at a lower (C1 to C2) level [Tator, 1996]. There often is selective arm weakness with little, if any, weakness of the legs [Bell, 1970]. Several authors have challenged this concept, pointing to evidence that the fibers of the corticospinal tract may not be layered but are intermingled and that pathologically there is little evidence of central necrosis or hydromyelia in such patients [Quencer et al., 1992]. The mechanisms of injury causing cervicomedullary syndrome include atlantoaxial dislocation, atlanto-occipital dislocation, odontoid fracture, burst fracture of C1, and a ruptured C1 to C2 disk [Baskin, 1996; Donahue et al., 1994; Tator, 1996].

CENTRAL SPINAL SYNDROME Central spinal syndrome can complicate hyperextension injury, particularly when there is a preexisting spinal abnormality, such as spinal canal stenosis, disk herniation, bony spurs, or compression by an abnormal ligamentum flavum [Rand and Crowdall, 1962; Quencer et al., 1992]. Conversely, this syndrome often can occur, particularly in young children, without an accompanying radiographic abnormality [Osenbach and Menezes, 1989, 1992; Ruge et al., 1988]. Here the central portion of the cord (usually cervical) is damaged, probably from ischemia because the central cord is perfused by end arteries from the anterior spinal artery, making it vulnerable to states of low perfusion [Schneider et al., 1973]. Neurologically, motor and sensory deficits are partial and are greater in the arms than in the legs, with the greatest impairment in the distal upper limbs [Green and Eismont, 1984]. Bowel and bladder function can be lost early, but usually return. Patients are generally ambulatory with a spastic gait; painful dysesthesias in the arms may persist for years. There is still debate whether early surgery is warranted in this condition because many patients recover spontaneously [Schneider et al., 1973; Sonntag and Francis, 1995].

ANTERIOR SPINAL CORD SYNDROME Anterior spinal cord syndrome, which can follow hyperflexion injury of the spine, is characterized by analgesia and paresis below the level of the lesion, with preservation of proprioception, light touch, and vibration [Schneider, 1955]. This condition is usually caused by direct compression of the anterior and lateral white matter tracts by a herniated disk or by a fractured vertebra with posterior dislocation [Schneider, 1951]. The posterior columns are spared. There is no evidence for compression of the anterior spinal artery in this disorder [Tator, 1996]. Early surgery is probably warranted in all cases.

POSTERIOR SPINAL CORD SYNDROME Posterior spinal cord syndrome is an extremely rare disorder (some doubt its existence), characterized by major damage to the posterior spinal cord (resulting in loss of movement and proprioception), with some residual function of the

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anterior cord (with retained perception of pain and temperature) [Tator, 1996].

BROWN-SÉQUARD SYNDROME Brown-Séquard syndrome is caused by injury of the lateral half of the spinal cord (usually cervical) and is characterized by ipsilateral motor paralysis, ipsilateral loss of touch and proprioception, and contralateral loss of pain and temperature sensation below the level of the lesion [DeMyer, 1985]. Although this syndrome is often caused by penetrating trauma to the spine, cases also have been caused by hyperextension injury, compression fractures, and disk herniation. Blunt trauma with central cord injury sometimes can result in asymmetric pareses and sensory impairment that can mimic the true syndrome [Chilton and Dagi, 1985]. Recovery is variable.

CONUS MEDULLARIS SYNDROME Conus medullaris syndrome produces paralysis of the lower extremities and the anal sphincter. Such a lesion, by definition, would be a form of complete spinal cord injury [Tator, 1983]. There is sacral sparing in many cases, however, making the injuries frequently of the incomplete type. The lumbar cord is positioned opposite the T12 vertebra, and the sacral cord is opposite L1. Dislocation, displaced fractures, and disk herniation of T12 and L1 can produce this injury. Prognosis for recovery is poor [Tator, 1983].

Intraspinal Extramedullary Injuries Intraspinal extramedullary injuries include hemorrhage into the epidural, subdural, and subarachnoid spaces; spinal epidural abscess; spinal arachnoid cyst; spinal epidural tumors; herniation of the nucleus pulposus; and cauda equina injuries.

Spinal Epidural Hematoma Spinal epidural hematoma can occur with substantial trauma to a normal spine, particularly in a newborn after breech delivery, or with mild trauma to the spine in a patient with a bleeding diathesis, with a spinal epidural hemangioma, or after multiple lumbar punctures [Bruyn and Bosma, 1976; Hehman and Norrell, 1968; Robertson et al., 1979]. In contrast to most intracranial epidural hematomas, spinal epidural hemorrhage is of venous (not arterial) origin [Bruyn and Bosma, 1976]. The main venous structure within the spinal epidural space lies ventrolateral to the cord and comprises a “rope ladder” plexus of thin-walled veins lacking true valves. This internal plexus connects with an external plexus of veins around the spinal column, with segmental spinal veins draining into the inferior vena cava, and with intracranial dural sinuses [Bruyn and Bosma, 1976]. Signs of spinal epidural hematoma can be acute, chronic, or intermittent. A newborn with acute spinal epidural hematoma typically manifests respiratory depression, hypotonia, areflexia, and other signs of spinal shock [Francisco, 1970; Towbin, 1964]. The occurrence of clinically significant traumatic spinal epidural bleeding is uncommon after infancy. When it occurs in older children (as with minor trauma

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complicating a blood dyscrasia), there is usually severe back pain that is worsened by pressure over the spine, neck flexion, or the Valsalva maneuver. Over the ensuing hours to weeks, signs of spinal cord compression usually develop [Bruyn and Bosma, 1976].

Spinal Subdural Hematoma Spinal subdural hematoma occurs much less commonly; the source of bleeding in this hematoma is unclear. Similar to spinal epidural hematoma, it occurs mainly in the neonatal period, although it too is occasionally observed in children and adolescents with bleeding diatheses who sustain an otherwise insignificant injury to the spine, such as that occurring at the time of lumbar puncture [Edelson, 1976; Edelson et al., 1974; Towbin, 1964; Walter and Tedeschi, 1970]. Clinical features include back and radicular pain [Edelson, 1976].

Spinal Subarachnoid Hemorrhage Traumatic subarachnoid hemorrhage caused by injury to the spine also is uncommon. This hemorrhage can occur after penetrating injury, but most often occurs after birth trauma (often with accompanying epidural, subdural, or intraspinal hemorrhage) [Plotkin et al., 1966; Towbin, 1964]. The amount of blood that accumulates is usually not great, and significant compression of the cord is rare. Signs of spinal subarachnoid hemorrhage are difficult to distinguish from signs of other spinal hemorrhages (e.g., epidural) that often coexist. Spinal subarachnoid hemorrhage should be suspected when back pain, meningismus, or fever occurs. The diagnosis is indicated by the presence of blood in the spinal fluid or by cerebrospinal fluid xanthochromia. Occasionally the blood obstructs the subarachnoid space, resulting in a “dry tap.” Spinal subarachnoid hemorrhage must be differentiated from subarachnoid bleeding of intracranial origin and from blood caused by a traumatic lumbar puncture.

Spinal Epidural Abscess Infections of the skin overlying the spine or of the bony spine itself (osteomyelitis) can occur after spinal trauma and may result in a spinal epidural abscess [Baker et al., 1975; Browder and Meyers, 1941; Hancock, 1976; Heusner, 1948]. Staphylococcus aureus is the organism most often responsible for such infections [Joshi et al., 2003; Pereira and Lynch, 2005]. The signs and symptoms of spinal epidural abscess are difficult to differentiate from the signs and symptoms of spinal epidural hematoma. Usually, other signs of inflammation and local infection of the overlying skin or bone can be identified.

Spinal Arachnoid Cyst Spinal arachnoid cyst can develop after spinal trauma or may appear idiopathically and can cause significant spinal cord compression [Elsberg et al., 1934; Herskowitz et al., 1978; Nugent et al., 1959; Swanson and Fincher, 1947]. These cysts produce progressive signs with lower limb weakness in neonates and recurrent gait and sensory difficulties in older children. Scoliosis may accompany these

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cysts. The diagnosis is suggested on plain films by widening of the interpeduncular distances [Elsberg et al., 1934; Herskowitz et al., 1978; Nugent et al., 1959; Swanson and Fincher, 1947].

Spinal Epidermoid Tumor Epidermoid tumors are infrequent complications of lumbar puncture [Batnitzky et al., 1977; Gibson and Norris, 1958; Manno et al., 1962; Shaywitz, 1972]. These tumors may develop 1 to 20 or more years after a lumbar puncture and have been attributed to skin and subcutaneous tissues implanted intraspinally at the time of a spinal tap. The symptoms are slowly progressive and usually manifest by back and leg pain followed by gait difficulties [Batnitzky et al., 1977; Gibson and Norris, 1958; Manno et al., 1962; Shaywitz, 1972].

Herniation of the Nucleus Pulposus Herniation of the nucleus pulposus (protrusion of central intervertebral disk tissue) can result from severe flexion/ compression of the spine and can cause compression of the underlying spinal cord [Burke, 1976; Herkowitz and Samberg, 1978; Swischuk, 1969]. The symptoms and signs are similar to those of any intraspinal extradural mass: pain and dysesthesias in radicular distribution, loss of tendon reflexes, muscle weakness, and atrophy [Burke, 1976; Herkowitz and Samberg, 1978; Swischuk, 1969].

Cauda Equina Injuries A special category of extramedullary injury comprises injury involving the cauda equina, which is technically not a spinal cord injury. The level of spinal column and ligament displacement in these injuries varies with age, depending at which vertebral level the spinal cord terminates (L2 in infancy and L1 in adulthood). When any of the extramedullary pathologies just discussed are localized below the spinal cord, they can cause injury to the cauda equina. In incomplete injuries of the cauda equina, there is always preservation of sensation, often with only a partial motor deficit [Tator, 1996]. Bowel and bladder involvement is common. The prognosis in cauda equina injury is better than the prognosis in spinal cord injury because the lower motor neuron apparently has a greater capacity to recover than the upper motor neuron [Tator, 1996].

MANAGEMENT Medical management of spinal cord injury includes measures aimed at treating the acute cord injury and more longterm management.

Short-Term Management Spine Immobilization and Supportive Care The treatment of acute spinal cord injury must include stabilization of the spine to prevent further injury, in addition to maintenance of vital signs. First aid at the scene of the

accident should include placement of the child on a rigid stretcher or firm backboard and fixation of the head by sandbags or towel rolls with tape over the forehead to prevent movement of the head on the spine. A cervical collar alone does not accomplish this goal adequately [Green and Eismont, 1984]. Restriction of movement manually with the arm on the chest and hand on the mandible, exerting slight extension and traction on the head, can help stabilize the cervical spine until the head is taped. Care must be taken not to exert too much spinal distraction with this maneuver [Benzel and Doezema, 1996]. The disproportionately large head of a young child places the child into flexion when he or she is put on a neutral board. Because the high cervical region is the most likely level of injury, neck flexion is particularly dangerous. Flexion can be avoided with a special board with a recess for the occiput, allowing the head to rest in line with the body, or by placing something under the child’s shoulders to elevate the neck in line with the head [Proctor, 2002]. It has been estimated that careful attention to stabilization of the spine before mobilization at the scene has reduced occurrence of complete spinal cord injury by approximately 10% [Gunby, 1981]. More recently, it has been suggested that this type of immobilization is painful and potentially harmful (restricted breathing, tissue ischemia, decubiti, intracranial hypertension), offering little, if any, benefit. Although a spine board eases transfer of a patient with a potentially unstable spinal injury to and from an ambulance stretcher, when the patient arrives at the hospital, a hard cervical collar and a firm mattress adequately immobilize the patient before application of traction or definitive stabilization [Hauswald and Braude, 2002]. A patent airway must be established, which may necessitate endotracheal intubation, which is frequently required in complete cervical cord injury (with impairment of diaphragmatic and intercostal muscle function). Intubation should be accomplished by chin lift without or with minimal neck extension. Tracheostomy and cricothyroidotomy should be avoided. Cardiac rate and rhythm should be monitored, and intravenous, central venous, and arterial lines should be placed. Cervical spinal cord trauma is often associated with significant hemodynamic deficits, including hypotension. In addition, injury to other organs (e.g., a ruptured liver or spleen) can cause significant blood loss and hypotension, which must be treated promptly by intravenous crystalloid or blood. Intravenous atropine, glycopyrrolate, phenylephrine, or dopamine may be needed to maintain normal blood pressure after volume depletion is corrected. Aggressive treatment of hypotension after spinal cord injury may improve outcome significantly [Levi et al., 1993; Vale et al., 1997]. The stomach should be emptied by a nasogastric tube. With urinary retention, the bladder should be catheterized. Radiologic studies usually should be performed (see section on radiologic evaluation earlier). In the case of cervical spine trauma, if the child is alert and interactive and has no neurologic deficit, no midline cervical tenderness, no painful distracting injury, and no evidence of intoxication, cervical spine films are probably not needed [Hadley, 2002b]. Spinal alignment is an important next step that usually can be accomplished with skeletal traction [Ducker et al., 1983] (see section on long-term management later).

Rosman and Harini / Spinal Cord Injury

Drug Therapy Based on results of experimental models of spinal cord injury and its treatment (see section on leading investigational treatments later), a variety of therapies have been shown to be of proven or potential benefit in improving outcome after spinal cord injury.

BENEFICIAL TREATMENTS Methylprednisolone, Naloxone, and Tirilazad Steroids have often been used in treatment of acute spinal cord injury in an attempt to reduce cord swelling and limit central cord necrosis [Babcock, 1975; Ducker and Hamit, 1969]. In experimental models of spinal cord injury, methylprednisolone, given within hours of the injury, has been found to affect the cascade of inflammatory responses after spinal cord injury, mainly by scavenging damaging free radicals but also by influencing excessive calcium influx into cells and inhibiting the release of eicosanoids and cytokines. When methylprednisolone has been given later in such models, it has been found to block regenerative mechanisms. Other potential mechanisms of action of steroids include stabilizing membranes, maintaining the bloodspinal cord barrier, reducing vasogenic edema, enhancing spinal cord blood flow, altering electrolyte concentrations at the site of injury, blocking endorphin release, inhibiting lipid peroxidation, and limiting inflammation after injury [Ball and Nockels, 2001; Hadley, 2002a]. Until 1990, steroid treatment had shown no apparent benefit in humans, possibly related to the size and the timing of the steroid dose. In a randomized controlled study, a methylprednisolone bolus of 30 mg/kg given intravenously after an acute spinal cord injury and followed by methylprednisolone infusion at 5.4 mg/kg/hr for the next 23 hours was compared with naloxone and placebo, both also given by bolus followed by a 23-hour infusion (National Acute Spinal Cord Injury Study [NASCIS] 2 protocol). Naloxone, an opiate-receptor antagonist, has been used with apparent success after spinal cord trauma in animals demonstrating short-term motor function improvement [Baskin et al., 1993], suggesting that endorphins might influence outcome in spinal cord injury [Faden, 1996]. Administration of methylprednisolone within 8 hours of injury was associated with a significant improvement in motor function and sensation at a 6-month follow-up examination compared with patients receiving methylprednisolone more than 8 hours after injury and with patients receiving naloxone or placebo. This difference was found with complete and incomplete spinal cord lesions. Reanalysis of the data indicated, however, some benefit from the use of naloxone with injuries that were incomplete [Bracken and Holford, 1993]. At 1-year follow-up, patients who had received methylprednisolone within 8 hours of injury still exhibited significantly improved motor scores, but there were no significant differences in sensory scores among the three groups [Bracken et al., 1990, 1992]. The improvements noted were small, however, and the functional significance of these gains has been questioned [Wilberger, 1996]. Also, wound infections and gastrointestinal bleeding occurred more often in the patients given methylprednisolone than in the other two groups. A similar beneficial effect of methyl-

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prednisolone was not found when it was given in an identical fashion to patients after penetrating spinal cord injury [Levy et al., 1996]. In an earlier study by Bracken and colleagues (NASCIS 1), high-dose methylprednisolone (1000-mg bolus [14.3 mg/kg for a 70-kg patent] followed by 1000 mg/day for 10 days) was com-pared with standard-dose methylprednisolone (100-mg bolus [1.4 mg/kg for a 70-kg patient] followed by 100 mg/day for 10 days). No significant difference was found between the two groups in recovery of motor or sensory function 1 year after injury. There were no placebo control subjects in the study [Bracken et al., 1984]. A 1997 study by Bracken and colleagues compared the efficacy of methylprednisolone given for 24 hours with that of methylprednisolone given for 48 hours and with tirilazad, a 21-amino steroid lipid peroxidation inhibitor, given for 48 hours; there was no placebo control group (NASCIS 3). When treatment was begun 3 to 8 hours after injury, the patients who received methylprednisolone for 48 hours demonstrated significantly better motor function at 6 weeks and 6 months after injury than the other two groups. Also, at 6 months, the 48-hour methylprednisolone patients had significantly better functional recovery (self-care, sphincter control) than the other two groups. The 48-hour methylprednisolone patients also had more severe sepsis and severe pneumonia. When treatment was begun within 3 hours of injury, the rates of motor recovery were identical in the two groups given methylprednisolone and the one given tirilazad, confirming reports of tirilazad’s benefit in experimental spinal cord injury [Bracken et al., 1997; Francel et al., 1993]. One year after injury, when treatment had been started within 3 hours of the injury, neurologic and functional recovery was again equal among the three treatment groups. When treatment had not been started until 3 to 8 hours after injury, patients who had received methylprednisolone for 48 hours had greater motor recovery at 1 year, whereas motor recovery was diminished in patients who had received only 24 hours of methylprednisolone [Bracken et al., 1998]. Based on this study, it was concluded that patients who receive methylprednisolone within 3 hours of injury should be maintained on the drug for 24 hours, but when methylprednisolone is begun 3 to 8 hours after injury, it should be continued for 48 hours unless there are complicating medical factors. Many investigators have disagreed with this recommendation, citing largely insignificant differences in motor recovery scores and in functional outcome measures among study patients, while also detailing methodologic, scientific, and statistical flaws in the NASCIS 2 and 3 studies. The role of steroids as neuroprotective agents with acute spinal cord injury remains controversial [Ball and Nockels, 2001; Hadley, 2002a; Nesathurai, 1998]. Although neurologic outcome is improved by high-dose methylprednisolone, the benefit seems to be modest at best, and against this one needs to weigh the risk of potentially serious complications of highdose steroid therapy [Galandiuk et al., 1993; Hadley, 2002a].

GM1 Ganglioside Based on experimental studies that have shown GM1 ganglioside to induce the regeneration of damaged neurons, a randomized, placebo-controlled trial of GM1 was performed on 34 patients after spinal cord injury [Geisler et al., 1991]. Subjects were given 100 mg of either GM1 or placebo

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intravenously within 72 hours of injury and continued daily for a mean duration of 26 days. No untoward neurologic events related to GM1 administration were seen, and better recovery occurred in the GM1-treated patients than in the controls after 1 year of follow-up. The number of patients treated was small (16 GM1, 18 placebo), and there was a maldistribution between the two groups, with a smaller number of patients with the most severe injuries (complete spinal cord injury) randomized to the GM1 group (38% of GM1-treated patients versus 56% of the placebo group) [Landi and Ciccone, 1992]. Functional outcomes of patients were considered to be equivalent in the two groups. A multicenter GM1 ganglioside study in patients with acute nonpenetrating spinal cord injury of at least moderate severity was initiated in 1992. The study was prospective, double-blind, randomized, and stratified. By the study’s end in 1997, 797 patients had been enrolled (a primary efficacy analysis was done in 760 of the patients). All patients first received intravenous methylprednisolone within 8 hours of injury and following the NASCIS 2 protocol. The patients were randomized into three study groups: placebo, low-dose GM1 (300-mg loading dose followed by 100 mg/day for 56 days), and high-dose GM1 (600-mg loading dose followed by 200 mg/day for 56 days). A planned interim analysis resulted in discontinuation of the high-dose GM1 treatment strategy because of an early trend for higher mortality. There was no significant difference in mortality between treatment groups. Although the data suggested improved neurologic recovery in patients with acute spinal cord injury given GM1 ganglioside for 56 days after the administration of methylprednisolone within 8 hours of an acute spinal cord injury, the primary analysis failed to prove this difference to be statistically significant. Nonetheless, because numerous secondary analysis indicated that GM1 was beneficial in the treatment of acute spinal cord injury, the use of low-dose GM1 after initial intravenous methylprednisolone remains a therapeutic option. The authors could not confirm the NASCIS 2 and NASCIS 3 findings indicating that the timing of methylprednisolone therapy had an impact on spinal cord recovery [Geisler et al., 2001; Hadley, 2002a].

ADDITIONAL POTENTIALLY BENEFICIAL TREATMENTS Patients with hyperextension spinal cord injury without accompanying bone injury given hyperbaric oxygen seemed to do better than patients not given hyperbaric oxygen, but no data were provided to indicate whether or not that improvement was sustained [Asamoto et al., 2000]. Oral 4-aminopyridine, a voltage-gated fast potassium channel blocker, has been found to improve axonal conduction by facilitating the propagation of action potentials in demyelinated nerve fibers [Segal et al., 1999]. Although some studies have indicated that 4-aminopyridine given to patients with spinal cord injury enhances their motor and sensory function [Grijalva et al., 2003; Segal et al., 1999], improves their pulmonary function [Segal et al., 1999], lessens their spasticity [Segal et al., 1999], and results in functional gains [Grijalva et al., 2003], other studies have failed to show any significant benefit from the drug [Dumont et al., 2001b]. Other agents believed to be promising in experimental spinal cord injury, including thyrotropin-releasing hormone [Pitts et al., 1995], calcium channel blockers (e.g., nimodi-

pine), sodium channel blockers (e.g., riluzole), and cyclosporine [Dumont et al., 2001b], have demonstrated lack of efficacy, inconclusive efficacy, or inadequate study in humans [Dumont et al., 2001b]. In experimental spinal cord injury, neurotrophic factors have been used to augment the poor intrinsic regenerative capacity of central nervous system neurons, and the need for sophisticated delivery of such trophic agents has stimulated the application of gene therapy [Kwon and Tetzlaff, 2001]. This work is summarized in the next section. Before such treatments can be studied clinically, it is first necessary to resolve safety issues, including side effects of neurotrophic factor infusion and potential hazards accompanying the use of viral vectors [Kwon and Tetzlaff, 2001]. There is one report from Taiwan of fibroblast growth factor given to a patient with chronic paraplegia 4 years after a stabbing injury that resulted in a spinal cord gap at T11. The gap was bridged with four sural nerve grafts, stabilized with fibrin glue containing acidic fibroblast growth factor. After the procedure, there was a remarkable change in the patient’s functional status, which improved from his being wheelchair bound to being able to ambulate independently with a walker 2.5 years after the surgery [Cheng et al., 2004]. In an effort to overcome the inhibitory environment into which regenerating axons must grow in spinal cord injury, strategies have been developed to bridge the injury site and facilitate axonal growth across the site with a variety of cellular substrates. These include fetal tissue transplants and implants of stem cells, Schwann cells, and olfactory ensheathing glial cells [Dobkin and Havton, 2004; Kwon and Tetzlaff, 2001; Rabinovich et al., 2003]. In safety trials, patients with multiple sclerosis received autologous Schwann cells and olfactory ensheathing glial cells placed into plaques, and in another safety trial in patients with spinal cord injury, oligodendrocyte precursors from pigs were implanted into the lesion bed. The results of these trials are pending [Dobkin and Havton, 2004]. In a study in China, fetal olfactory ensheathing glial cells were injected above and below the lesion site in patients 6 or more months after a traumatic spinal cord injury; this reportedly resulted in improved sensation over a few levels and in increased motor function for two levels below the lesion [Dobkin and Havton, 2004]. In a study from Russia, cells from fetal neurons and hematopoietic tissues were implanted subarachnoidally into five patients with traumatic spinal cord injury. All of the injuries were cervical or thoracic in location, and all were severe, with complete motor and sensory loss (Frankel score A: a standardized grading scale of neurologic function [Frankel et al., 1969]). The times after spinal cord injury ranged from 1 month to 6 years, and each patient underwent one to four cell transplantations. Eleven of the 15 patients improved; 6 improved to a Frankel score of C (incomplete restoration of motor and sensory function), and 5 improved to a Frankel score of B (incomplete restoration of sensory function and contraction of some muscles). No improvement occurred in the remaining four patients. There were no serious complications to the cellular transplants [Rabinovich et al., 2003].

Leading Investigational Treatments Research into the repair of spinal cord injury has grown rapidly in the years since the groundbreaking work in which

Rosman and Harini / Spinal Cord Injury

a peripheral nerve graft was used as a bridge across a spinal cord injury site [Rosenzweig and McDonald, 2004]. Adances in treatment of spinal cord injury have accelerated as factors inhibiting or limiting spinal cord regeneration have been identified, and interventions have been developed to counteract those factors. Particularly encouraging progress has been made in limiting the occurrence and progression of secondary damage often seen after spinal cord injury [Rosenzweig and McDonald, 2004]. Most experimental work on spinal cord injury repair has been carried out in rodents. At least seven overlapping approaches to spinal cord injury repair have been studied [Rosenzweig and McDonald, 2004; Dobkin and Havton, 2004]. 1. Bridging the gap. An exogenous, growth-permissive matrix is placed across the injury site to allow regrowing axons to cross. Substances used have included biodegradable polymers, peripheral nerve, fetal spinal cord tissue, Schwann cells, olfactory ensheathing cells, fibroblasts, bone marrow stromal/stem cells, stem/progenitor cells, and skin [Dobkin and Havton, 2004; Kwon and Tetzlaff, 2001; Rosenzweig and McDonald, 2004]. 2. Constructing new spinal cord circuitry. This has been attempted with stem cells [Rosenzweig and McDonald, 2004]. 3. Remyelinating demyelinated axons. Such axons are frequently found in spinal cord injury, and neural stem cells, oligodendrocyte precursors, Schwann cells and olfactory ensheathing cells have been used in attempts to remyelinate these axons [Dobkin and Havton, 2004; Rosenzweig and McDonald, 2004]. 4. Providing neurotrophic support. A variety of neurotrophic factors have been given in an attempt to stimulate the sprouting of spared axons or the regeneration of axotomized axons. These include brainderived neurotrophic factor, neurotrophin-3, nerve growth factor, glia-derived neurotrophic factor, ciliary neurotrophic factor, fibroblastic growth factor, vascular endothelial growth factor, and insulin growth factor-1 [Dobkin and Havton, 2004; Rosenzweig and McDonald, 2004]. Trophic factors are diffusible. They can be provided orally, injected or pumped into the cerebrospinal fluid, or infused near the lesion site [Dobkin and Havton, 2004; Rosenzweig and McDonald, 2004]. Many of the cells that have been used for transplantation either secrete neurotrophins or can be engineered to do so. An advance in this area is gene therapy, employing the use of adenoviruses, adeno-associated viruses, or lentiviruses to transfer neurotrophin-encoded genes (e.g., nerve growth factor, fibroblastic growth factor, brain-derived neurotrophic factor, glia-derived neurotrophic factor, neurotrophin-3) directly to central nervous system cells [Hidaka et al., 2002; Rosenzweig and McDonald, 2004]. Neurotrophic factors have emerged as leading candidates for enhancing central nervous system regeneration because of their stimulation of numerous genes shown to be upregulated or constitutionally expressed in association with axonal growth; these collectively have been termed regeneration-associated genes. The

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products of these genes include cytoskeletal proteins (involved in axonal extension), cytoplasmic growth cone proteins (involved in mediating signal transduction), and cell adhesion molecules (involved in growth cone guidance) [Kwon and Tetzlaff, 2001]. 5. Overcoming myelin-associated growth inhibitors. Antibodies, peptides, genetic mutations, and elevations of cyclic adenosine monophosphate (cAMP) have been used to overcome myelinassociated growth inhibitors. Such inhibitors are produced by oligodendrocytes, including Nogo-A, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein [Dobkin and Havton, 2004; Rosenzweig and McDonald, 2004]. A GTPase called Rho, which interferes with growth cone support, is inactivated by cAMP, rendering the growth cone less sensitive to Nogo-A, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein [Dobkin and Havton, 2004]. 6. Overcoming glial scar–associated growth inhibition. Chondroitin sulfate proteoglycans and other extracellular matrix molecules associated with the glial scar seem to inhibit neurite outgrowth. The enzymatic digestion of chondroitin sulfate proteoglycan glycosaminoglycan chains is a promising means of overcoming this barrier to spinal cord regeneration [Dobkin and Havton, 2004; Rosenzweig and McDonald, 2004]. 7. Protecting neurons and glia from secondary cell death. Much research has focused on neural and glial protection—preventing the cascade of secondary cell death that follows spinal cord injury, a cascade caused by combinations of inflammation, excitotoxicity, apoptosis, ischemia, and delayed oligodendrocyte death [Dobkin and Havton, 2004].

Other Investigational Treatments A variety of additional therapies have provided encouraging results in experimental spinal cord injury, particularly in rats, by lessening the degree of spinal cord damage, improving functional outcome, or both. These therapies include hyperbaric oxygen [Huang et al., 2003]; erythropoietin [Kaptanoglu et al., 2004]; quercetin, an iron-chelating flavonoid [Schultke et al., 2003]; riluzole, a sodium-channel blocker [Schwartz and Fehlings, 2001, 2002]; and induction of manganese superoxide dismutase [Earnhardt et al., 2002].

Long-Term Management Cervical Spine Immobilization In spine and spinal cord injuries in children the main imperatives are to decompress the neural elements and to stabilize the spine to prevent further injury [Proctor, 2002]. Cervical traction serves to immobilize the spine and reduce fractures. Reduction of fractures or subluxation must be undertaken with care in young patients because overdistraction can worsen the patient’s neurologic dysfunction. Manual positioning under fluoroscopy often is required in cases of cervical ligamentous injury. Crown halo rings can be applied in younger patients at a pressure of 2 inches/

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pound of torque per pin [Pang and Hanley, 1990]. In older patients, cervical traction can be used with relative safety. Many spine-injured children can be managed with external stabilization without a need for later surgery [Hadley, 1992; Proctor, 2002]. Various devices can be used, depending on the level and severity of injury, including the Philadelphia cervical collar, Yale braces, SOMI braces, four-poster braces, halo rests, crown halo rings, and thoracolumbar orthoses. When such devices are used, frequent radiographic reevaluations are needed to ensure continuing proper alignment of spinal elements because adequate external (and internal) fixation can be difficult to achieve in a young child [Proctor, 2002]. Specific recommendations for the management of SCIWORA were discussed earlier [Gunnarsson and Fehlings, 2003].

Supportive Medical Care For patients with mid cervical or upper cervical spinal cord injuries, there is a high risk of respiratory failure. Because the lower motor neurons for the phrenic nerve are at cervical levels 3 through 5, patients with severe spinal cord injuries above this level require permanent mechanical ventilation. Although patients with mid cervical spinal cord injuries initially may have adequate spontaneous ventilation, their ventilatory ability may deteriorate within a few days consequent to ascending spinal cord edema [Marion, 1998]. Children with high cervical lesions who are ventilator dependent may be candidates for phrenic nerve pacing [Massagli, 2000]. In addition to causing respiratory difficulties, spinal cord trauma can result in a variety of other medical problems requiring ongoing care [Luce, 1985]. Cardiovascular function can be altered by the trauma and its acute management. In one study, four of nine patients developed pulmonary edema after spinal cord injury, probably from overhydration during acute resuscitation [Meyer et al., 1971]. Patients with spinal cord lesions above T7 requiring long-term management have decreased cardiac output, hypotension, and problems with temperature regulation, limiting adaption to exercise. Nasogastric tube feeding after restoration of normal intestinal activity, antacids, hyperalimentation when bowel atonia persists, and digital stimulation, especially in young children, may be needed [Goetz et al., 1998]. In some children, gentle disimpaction is indicated. The use of enema continence catheters for bowel dysfunction after spinal cord trauma may significantly facilitate bowel care in such patients [Liptak and Revell, 1992]. Intermittent catheterization of the bladder is preferred to placement of an indwelling catheter to reduce the risk of urinary tract infection and renal failure [Luce, 1985; Nygaard and Kreder, 1996; Pannek et al., 1997]. Renal failure is a major cause of mortality in patients with chronic spinal cord injury [Hackler, 1984]. Anticholinergic and botulinum toxin therapy can reduce the effects of detrusor hyperreflexia (neurogenic bladder), present in approximately 60% of patients rendered quadriparetic from spinal cord injuries [Curt et al., 1997; Schurch et al., 1997]. Hyperhidrosis, fever, and disrupted temperature regulation are additional autonomic dysfunctions frequently encountered in patients with spinal cord injury. Anticholinergic treatment may help [Canaday and Stanford, 1995].

Other general measures include chest physiotherapy to prevent pneumonia, frequent repositioning of the patient and the use of spinal beds (Stryker frame RotaBed) to avoid decubiti, and the use of Jobst stockings to minimize the risk of deep vein thromboses and the attendant potential for pulmonary emboli. Occasionally, ventilation-perfusion scanning and pulmonary angiography are needed to establish the diagnosis of pulmonary emboli. It is estimated that one third of the deaths within the first weeks of spinal cord injury are due to pulmonary embolism. The use of mini-heparin treatment (1 μg/kg/hr, continuous infusion) or intermittent lowdose heparin therapy may reduce the risk of pulmonary embolism [Borow and Goldson, 1983]. In patients for whom anticoagulant therapy is contraindicated, placement of an inferior vena cava filter may be necessary. The healing of decubitus ulcers is aided by treatment with vitamin C (15 to 20 mg/kg/day) [Taylor et al., 1974]. Muscle relaxants, such as diazepam, baclofen, cyclobenzaprine, and intravenous orphenadrine citrate [Casale et al., 1995], may be helpful in the long-term management of spasticity after spinal cord injury. Additional antispasmodic treatments include intrathecal baclofen and tizanidine [Abel and Smith, 1994; Lewis and Mueller, 1993; Nance et al., 1994]. Progressive spinal deformity is common in children after spinal cord injury, particularly after laminectomy [Lonstein, 1995]. Chronic pain is also common, and its management can be difficult, necessitating intervention by pain management specialists [Chiou-Tan et al., 1996; Drewes et al., 1994; Siddall et al., 1995; Yezierski, 1996]. In patients in whom there is delayed deterioration of neurologic functioning, the presence of a syrinx should be sought; if one is found, the syrinx may need to be shunted [Proctor, 2002].

Physical Therapy Physical therapy is an important component in the long-term care of all patients with spinal cord injury [Jacobs and Nash, 2004]. Physical therapy should begin early and continue indefinitely. Measures such as proper limb positioning and passive muscle stretching can be instituted when the patient is medically and surgically stable. Later, after spinal shock has resolved, and early spasticity is evident, inhibitive casting can be used to minimize the development of limb contractures. Despite such measures, many patients later require phenol blocks, botulinum toxin injections, tendon lengthenings, and tendon transfers. As an alternative to long leg bracing for upright mobility, lower limb functional electric stimulation has proved effective in children and adolescents rendered paraplegic after a spinal cord injury. Electrodes were placed in nine such patients to provide constant stimulation to their hip and knee extensors and hip abductors and adductors; the seven who were able to complete their training all gained increased functional abilities over traditional long leg braces and a decreased need for physical assistance by a caregiver [Johnston et al., 2003]. Functional electric stimulation has been used to augment function of the lower limbs, upper limbs, bladder, bowel, respiration, and erection/ejaculation [Creasey et al., 2004; Kirshblum, 2004]. Short-term stimulation can be provided by electrodes on the skin or by percutaneous fine wires, but implanted systems are preferable for long-term use [Creasey et al., 2004].

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Psychologic Therapy

Surgical Management

Counseling should be provided, beginning early in the postinjury period and continuing throughout all stages of rehabilitation to provide maximal, ongoing support for the child and family [Talbot, 1971; Geller and Greydanus, 1979]. Health professionals from many disciplines can assist in providing such support.

The surgical treatment of acute spinal cord injury may include traction, later immobilization by casting, reduction of dislocated vertebrae, removal of compressive substances (e.g., vertebral fragments, extramedullary hemorrhage), and bony spinal fusion. If surgery is necessary, a variety of surgical approaches and techniques are used, depending on

A

B

FIGURE 66-8. A, Plain lateral film of the cervical spine in a 12-year-old female. There is a wedge-shaped fracture of C5 (arrow) with posterior dislocation of C5 on C6 and loss of the disk space between those two vertebrae. B, CT sagittal reconstruction from 2-mm axial scans through the C4 to C6 level (unenhanced study) in the same patient as in Figure 66-7. Posterior dislocation of a fracture fragment (arrow) from the inferoposterior margin of C5 has resulted in narrowing of the anteroposterior diameter of the spinal canal. C, Plain lateral film of the cervical spine in the same patient as in Figure 66-7. The spine has been stabilized by anterior bony fusion (arrow) and posterior wiring to prevent further narrowing of the spinal canal.

C

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Brain Injury and Disorders of Consciousness / 66

the nature and level of the injury and individual surgeon preference [Chilton and Dagi, 1985]. An anterior approach is often used for removal of displaced fragments of a fractured vertebra or a herniated intervertebral disk. Posterior laminectomy usually is preferred for the removal of intraspinal extramedullary masses, such as epidural and subdural hematomas, and for the relief of spinal cord swelling. Surgical interventions include decompression, stabilization, and fusion. Surgical procedures usually are preceded by MRI; metrizamide CT (Fig. 66-8B) and myelography are less often used. The indications for and timing of surgical treatment for spinal cord injury continue to be debated [Chesnut, 2004; Tator et al., 1999]. Some authors maintain that early treatment of compressive lesions before central myelomalacia has occurred (at about 24 hours) favorably affects outcome [Baskin, 1996; Bruyn and Bosma, 1976]. Support for this view is found in experimental studies in animals indicating that there is a window of 4 to 8 hours after injury when decompression of the injured spinal cord can improve recovery [Fehlings et al., 2001]. In a retrospective review of 50 patients with traumatic central cord syndrome who underwent early (≤24 hours after injury) or late (>24 hours after injury) surgery, patients who underwent early surgery and had an underlying acute disk herniation or a fracturedislocation had significantly greater overall motor improvement than patients who underwent late surgery [Guest et al., 2002]. Other authors claim, however, that there is no difference in outcome when comparing early surgical, late surgical, and nonsurgical management in complete and incomplete spinal cord injury, arguing that maximal injury to the cord already has occurred at impact [Asazuma et al., 1996; Guttmann, 1963; Hadley et al., 1988; Kakulas, 1984; Katoh et al., 1996; Kewalramani and Tori, 1980; Levi et al., 1991]. Using data from NASCIS 2, the effectiveness of surgery on the treatment of acute spinal cord injury and its relation to pharmacologic treatment was studied. Three, nonrandomized study groups comprising 487 patients from 10 medical centers were recruited: (1) patients who underwent anterior surgery, (2) patients who underwent posterior surgery, and (3) patients who did not have surgery. Patients who did not undergo surgery had more severe spinal cord injuries initially than the surgical groups, yet there were no differences in neurologic improvement at 1-year follow-up between patients who underwent surgery and patients who did not. The data suggested that either early surgery (≤25 hours) or late surgery (>200 hours) might be followed by a better motor outcome. Surgery was not shown to influence the efficacy of drug treatment. As the authors themselves stated, a randomized study is needed to obtain valid comparisons of the effectiveness of different surgical treatments and of the timing of those interventions (Duh et al., 1994). More recently, 91 consecutive patients with acute traumatic spinal cord injury were studied prospectively; 66 patients (protocol group) underwent emergency MRI to determine the presence of persistent spinal cord compression, followed, if indicated, by immediate operative decompression and stabilization; the other 25 patients, for several different reasons, were managed outside the treatment protocol (reference group). Clinically the two groups were comparable. On follow-up, twice as many of the protocol patients (50%)

as the reference patients (24%) demonstrated improvement in their admitting Frankel grade. These findings further underscored the need for a prospective randomized, multicenter study to determine the true efficacy of immediate surgical intervention in the management of patients with acute spinal cord injury [Papadopoulos et al., 2002]. One reasonable approach to spinal surgery in acute spinal cord injury might be to limit surgery to patients with partial cord injuries and a progressing neurologic deficit and patients with an unstable fracture or dislocation; surgery in the latter group would minimize the risk of curvature of the spine developing later. Additional appropriate indications for surgery might include the following: (1) inadequate reduction of a spinal fracture by traction alone, (2) epidural hematoma, (3) traumatic disk herniation, and (4) spinal cord compression by bony fragments [Duh et al., 1994; Pang and Hanley, 1990; Parisini et al., 2002; Weinshel et al., 1990]. Other authors believe, however, that decompressive surgery should be done only when there is proven residual compression of neural elements after spinal alignment [Ducker et al., 1983]. Evidence indicating a clear relationship between the timing of spinal surgery and neurologic outcome is still lacking [Duh et al., 1994].

PROGNOSIS The most widely used rating scale to assess the severity of spinal cord injury and to quantify spinal cord function during recovery is the ASIA/IMSOP scale, a modification of the older Frankel scale. Other rating scales that have been used include the University of Miami Neurospinal Index and the Barthel Index [Klose et al., 1980; Mahoney and Barthel, 1965]. The disadvantage of such scoring systems is the difficulty in translating numerical scores into descriptions of clinical capability or activities of daily living [Walker, 1991]. A variety of functional scales have been used to measure changes that correlate highly with activity level and lifestyle [Geisler et al., 1991; Piepmeier and Collins, 1992]. Despite modern intensive care management and advances in therapy, mortality from spinal cord injury remains high, averaging 10% to 15%, with higher mortalities in patients rendered quadriplegic [Bracken et al., 1981; Ducker et al., 1983; Krause et al., 1997; Michaelis, 1976]. Two-year survival rates are better in younger patients (16 to 30 years old) than in older ones (61 to 86 years old), 95% versus 59% [DeVivo et al., 1990]. Overall morbidity (gastrointestinal hemorrhage, pulmonary emboli, and renal stones) also is lower in younger age groups. Limited recovery of neurologic function is possible after complete spinal cord injury, especially when there has been some improvement within the first 24 hours [Chilton and Dagi, 1985]. Nonetheless, approximately 70% to 95% of patients with complete lesions exhibit no improvement on long-term follow-up. Patients with complete injury persisting for longer than 1 week usually do not recover neurologic function, although some improvement may occur if there is a zone of partial preservation [Ditunno, 1996]. In general, recovery from thoracolumbar lesions is better than with higher lesions. Patients with partial spinal cord lesions can recover 25% of their power, and in patients with central cord lesions, recovery of power can be 80% [Ducker et al., 1983].

Rosman and Harini / Spinal Cord Injury

Additionally, patients with complete paralysis but with preserved sensation (ASIA/IMSOP grade B) have substantially greater improvement than patients with complete loss of motor and sensory function (ASIA/IMSOP grade A) [Landi and Ciccone, 1992]. Age at time of injury also influences recovery from spinal cord trauma. In one study, 90% of younger patients (<50 years old) with incomplete injury and preserved motor function (but with a muscle grade <3; ASIA/IMSOP grade C) became ambulatory compared with 42% of older patients. All patients with incomplete ASIA/IMSOP grade D lesions (muscle grade ≥3) developed independent ambulation [Burns et al., 1997]. Similar poor outcome in older patients with complete and incomplete spinal cord injury was noted in another study in which only 14% of complete injury and 50% of incomplete injury patients survived beyond 1 year [Alander et al., 1997]. Recovery from spinal injury is not only better in children than in adults, but also in children improvement can continue for many months after the injury [Wang et al., 2004]. As mentioned earlier, MRI, somatosensory-evoked potentials, and electromyography have been the main laboratory tests used to assist prediction of outcome after spinal cord injury. Of the three, MRI is the most helpful. MRI can distinguish intramedullary hematomas (poorer prognosis) from spinal cord edema (better prognosis). Patients in whom the edema is restricted to a single spinal segment or less have the best prognosis [Schaefer et al., 1992]. The clinical and prognostic value of emergency MRI was studied in 55 patients with acute cervical spinal cord injuries. Although the best single predictor of long-term improvement in neurologic function was the initial neurologic examination, four MRI characteristics provided additional prognostic information— the presence of intra-axial hematoma; the sagittal length of spinal cord hematoma; the extent of spinal cord edema; and spinal cord compression by extra-axial hematoma [Selden et al., 1999]. Conclusions about the usefulness of different laboratory investigations in aiding the prediction of neurologic outcome must be viewed with some circumspection, however, because in most series relatively few patients of different ages have been studied. Data comparing surgical and nonsurgical management in acute spinal trauma come mainly from adult studies. In patients with complete spinal cord lesions treated conservatively, 27% to 34% showed some improvement [Frankel et al., 1969; Guttmann, 1963]. Of 27 patients with complete lesions who were managed surgically, 25 improved, but this improvement was seen only in nerve root function at the site of the injury [Stauffer, 1984]. In patients with incomplete spinal cord lesions, 64% to 90% have improved with conservative treatment [Guttmann, 1963; Meinecke, 1964]. Surgical treatment of such patients had resulted in improvement in 82% [Forsyth et al., 1959]. In incomplete and complete spinal cord lesions, there are no clear differences in neurologic outcome between surgical and nonsurgical management. The mechanism of recovery after spinal cord injury is suggested by studies indicating reorganization of motor pathways rostral to the injury site (cortical or spinal or both), with these motor pathways facilitating later recovery [Topka et al., 1991]. There is considerable experimental evidence to indicate that neurons of the mammalian nervous system

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maintain an ability to regenerate and regain function. In spinal cord injury, however, environmental factors, such as nerve growth inhibitors (released at the time of spinal cord injury) and apoptosis or programmed cell death (occurring in areas of spinal cord injury), interfere with such regeneration. Much work is ongoing to try to develop methods to combat these and other adverse environmental factors found in acute spinal cord injury (see earlier section on leading investigational treatments).

PREVENTION Spinal cord injuries are devastating at any age, but are especially tragic and expensive in children. Preventing these injuries is probably the greatest challenge in dealing with spinal cord injuries. Continued investment in educational programs, with ongoing efforts to heighten public awareness of the risks and consequences of spinal cord injuries, is crucial. People who drink alcohol should not drive. Risktaking behavior must be minimized, particularly in people taking sedating medications or illicit drugs. The need for protective helmets, in sports such as skiing, snowboarding, and bicycling, cannot be overstressed. Diving into unfamiliar waters must be avoided. Certain sports, particularly tackle football, carry with them a substantial risk of spinal injury, and this needs to be recognized. Appropriate seat-belt designs, proper use of child restraints, and positioning small children in the rear seats of automobiles fitted with airbags save lives and neurologic function. Finally, any efforts that can result in reduction of societal violence, particularly involving guns and knives, can be expected to result in a corresponding reduction in spinal cord injuries [Ackery et al., 2004; Rekate et al., 1999]. A valuable resource for parents is the web site of the ASIA at http://www.asia-spinalinjury.org/ home/index.html. REFERENCES Abel NA, Smith RA. Intrathecal baclofen for treatment of intractable spinal spasticity. Arch Phys Med Rehab 1994;75:54. Ackery A, Tator C, Krassioukov A. A global perspective on spinal cord injury epidemiology. J Neurotrauma 2004;21:1355. Alander DH, Parker J, Stauffer ES. Intermediate-term outcome of cervical spinal cord-injured patients older than 50 years of age. Spine 1997;22:1189. Alker GJ, Oh YS, Leslie EV, et al. Postmortem radiology of head and neck injuries in fatal traffic accidents. Radiology 1975;14:611. Allen JP, Myers GG, Condon VR. Laceration of the spinal cord related to breech delivery. JAMA 1969;208:1019. American Spinal Injury Association, International Medical Society of Paraplegia (ASIA/IMSOP). International standards for neurological and functional classification of spinal cord injury. Revised, 1992. Andersen BJ, Stringer WA. Imaging after spinal injury. In: Narayan RK, Wilberger JE, Povlishock JT, eds. Neurotrauma. New York: McGraw-Hill, 1996. Anderson JM, Shutt AH. Spinal injury in children: A review of 156 cases seen from 1950 through 1978. Mayo Clin Proc 1980;55:499. Anderson LD, D’Alonzo RT. Fractures of the odontoid process of the axis. J Bone Joint Surg Am 1974;56:1663. Asamoto S, Sugiyama H, Doi H, et al. Hyperbaric oxygen (HBO) therapy for acute traumatic cervical spinal cord injury. Spinal Cord 2000;38:538. Asazuma T, Satomi K, Suzuki N, et al. Management of patients with an incomplete cervical spinal cord injury. Spinal Cord 1996;34:620. Babcock JL. Spinal injuries in children. Pediatr Clin North Am 1975;22:487.

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Bailes JE, Hadley MN, Quigley MR, et al. Management of athletic injuries of the cervical spine and spinal cord. Neurosurgery 1991;29:491. Baker AS, Ojemann RG, Swartz MN, et al. Spinal epidural abscess. N Engl J Med 1975;293:463. Ball PA, Nockels RP. Summary statement: Nonoperative management and critical care of acute spinal cord injury. Spine 2001;26:S38. Barnett HJM, Jousse AT. Posttraumatic syringomyelia (cystic myelopathy). In: Vinken PJ, Bruyn CH, Braakman R, eds. Injuries of the spine and spinal cord, II, Vol. 26. Handbook of clinical neurology. Amsterdam: North Holland Publishing Company, 1976. Baskin DS. Spinal cord injury. In: Evans RW, ed. Neurology and trauma. Philadelphia: WB Saunders, 1996. Baskin DS, Simpson RK Jr, Browning JL, et al. The effect of long-term high-dose naloxone infusion in experimental blunt spinal cord injury. J Spin Dis 1993;6:38. Batnitzky S, Keucher TR, Mealey J Jr, et al. Iatrogenic intraspinal epidermoid tumors. JAMA 1977;237:148. Bell HS. Paralysis of both arms from injury of the upper portion of the pyramidal decussation: “cruciate paralysis.” J Neurosurg 1970;33:376. Benzel EC, Doezema D. Prehospital management of the spinally injured patient. In: Narayan RK, Wilberger JE, Povlishock JT, eds. Neurotrauma. New York: McGraw-Hill, 1996. Bondurant FJ, Cotler HB, Kulkarni MV, et al. Acute spinal cord injury: A study using physical examination and magnetic resonance imaging. Spine 1990;15:161. Borow M, Goldson HJ. Prevention of postoperative deep venous thrombosis and pulmonary emboli with combined modalities. Am Surg 1983;49:599. Braakman R, Penning L. Injuries of the cervical spine. In: Vinken PJ, Bruyn GW, eds. Handbook of clinical neurology, Vol. 25. Amsterdam: North Holland, 1976. Bracken MB, Collins WF, Freeman DF, et al. Efficacy of methylprednisolone in acute spinal cord injury. JAMA 1984;251:45. Bracken MB, Freeman DH, Hellenbrand K. Incidence of acute traumatic hospitalized spinal cord injury in the United States, 1970-1977. Am J Epidemiol 1981;113:615. Bracken MB, Holford TR. Effects of timing of methylprednisolone or naloxone administration on recovery of segmental and long-tract neurological function in NASCIS 2. J Neurosurg 1993;79:500. Bracken MB, Shepard MJ, Collins WF, et al. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury: Results of the second national acute spinal cord injury study. N Engl J Med 1990;322:1405. Bracken MB, Shepard MJ, Collins WF, et al. Methylprednisolone or naloxone treatment after acute spinal cord injury: 1-Year follow-up data—results of the Second National Acute Spinal Cord Injury Study. J Neurosurg 1992;76:23. Bracken MB, Shepard MJ, Holford TR, et al. Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury: Results of the Third National Spinal Cord Injury Randomized Control Trial. National Acute Spinal Cord Injury Study. JAMA 1997;277:1597. Bracken MB, Shepard MJ, Holford TR, et al. Methylprednisolone or tirilazad mesylate administration after acute spinal cord injury: 1-Year follow up. J Neurosurg 1998;89:699. Bresnan MJ, Abroms IF. Neonatal spinal cord transection secondary to hyperextension of the neck in breech presentation. J Pediatr 1974;84:734. Browder J, Meyers R. Pyogenic infections of the spinal epidural space. Surgery 1941;10:296. Bruyn GW, Bosma MJ. Spinal extradural haematoma. In: Vinken PJ, Bruyn GW, eds. Handbook of clinical neurology, Vol. 25. Amsterdam: North Holland, 1976. Burke DC. Traumatic spinal paralysis in children. Paraplegia 1974;11:268. Burke DC. Injuries of the spinal cord in children. In: Vinken PJ, Bruyn GW, eds. Handbook of clinical neurology, Vol. 25. Amsterdam: North Holland, 1976. Burns SP, Golding DG, Rolle WA Jr, et al. Recovery of ambulation in motor-incomplete tetraplegia. Arch Phys Med Rehab 1997;78:1169. Byers RK. Spinal-cord injuries during birth. Dev Med Child Neurol 1975;17:103. Caffey J. The whiplash shaken infant syndrome. Pediatrics 1974;54:396. Canaday BR, Stanford RH. Propantheline bromide in the management of hyperhidrosis associated with spinal cord injury. Ann Pharmacother 1995;29:489.

Casale R, Glynn CJ, Buonocore M. Reduction of spastic hypertonia in patients with spinal cord injury: A double-blind comparison of intravenous orphenadrine citrate and placebo. Arch Phys Med Rehab 1995;76:660. Cattell HS, Filtzer DL. Pseudosubluxation and other normal variations in the cervical spine in children. J Bone Joint Surg Am 1965;47:1295. Caviness AC. Evaluation of cervical spine injuries in children and adolescents. UpToDate, Version 12.3, 2004. Cheng H, Liao KK, Liao SF, et al. Spinal cord repair with acidic fibroblast growth factor as a treatment for a patient with chronic paraplegia. Spine 2004;29:E284. Chesnut RM. Management of brain and spine injuries. Crit Care Clin 2004;20:25. Chilton J, Dagi TF. Acute cervical spinal cord injury. Am J Emerg Med 1985;3:340. Chiou-Tan FY, Tuel SM, Johnson JC, et al. Effect of mexiletin on spinal cord injury dysesthetic pain. Am J Phys Med Rehab 1996;75:84. Creasey GH, Ho CH, Triolo RJ, et al. Clinical applications of electrical stimulation after spinal cord injury. J Spinal Cord Med 2004;27:365. Crothers B. Injury of the spinal cord in breech extraction as an important cause of fetal death and of paraplegia in childhood. Am J Med Sci 1923;165:94. Curt A, Nitsche B, Rodic B, et al. Assessment of autonomic dysreflexia in patients with spinal cord injury. J Neurol Neurosurg Psychiatry 1997;62:473. Dare AO, Dias MS, Li V. Magnetic resonance imaging correlation in pediatric spinal cord injury without radiographic abnormality. J Neurosurg (Spine 1) 2002;97:33. Davis PC, Reisner A, Hudgins PA, et al. Spinal injuries in children: Role of MR. AJNR Am J Neuroradiol 1993;14:607. Decker JE, Hergenroeder AC. Overview of cervical spinal cord and cerivcal peripheral nerve injuries in the young athlete. UpToDate, Version 12.3, 2004. DeLaTorre JC. Spinal cord injury: Review of basic and applied research. Spine 1981;6:315. DeMyer W. Anatomy and clinical neurology of the spinal cord. In: Baker AB, Joynt RJ, eds. Clinical neurology, Vol. 3. Philadelphia: Harper & Row, 1985. DeVivo MJ, Kurtus PL, Rutt RD, et al. The influence of age at time of spinal cord injury on rehabilitation outcome. Arch Neurol 1990;47:687. Dias MS. Traumatic brain and spinal cord injury. Pediatr Clin North Am 2004;51:271. Ditunno JF. Rehabilitation assessment and management in the acute spinal cord injury (SCI) phase. In: Narayan RK, Wilberger JE, Povlishock JT, eds. Neurotrauma. New York: McGraw-Hill, 1996. Ditunno JF, Little JW, Tessler A, et al. Spinal shock revisited: A fourphase model. Spinal Cord 2004;42:383. Dobkin BH, Havton LA. Basic advances and new avenues in therapy of spinal cord injury. Annu Rev Med 2004;55:255. Donahue DJ, Muhlbauer MS, Kaufman RA, et al. Childhood survival of atlantooccipital dislocation: Underdiagnosis, recognition, treatment, and review of the literature. Pediatr Neurosurg 1994;21:105. Drewes AM, Andreasen A, Poulsen LH. Valproate for treatment of chronic central pain after spinal cord injury: A double-blind cross-over study. Paraplegia 1994;32:565. Ducker TB, Hamit HF. Experimental treatments of acute spinal cord injury. J Neurosurg 1969;30:693. Ducker TB, Lucas JT, Wallace CA. Recovery from spinal cord injury. Clin Neurosurg 1983;30:495. Duh M, Shepard MJ, Wilberger JE, et al. The effectiveness of surgery on the treatment of acute spinal cord injury and its relation to pharmacological treatment. Neurosurgery 1994;35:240. Dumont RJ, Okonkwo DO, Verma S, et al. Acute spinal cord injury, part I: Pathophysiologic mechanisms. Clin Neuropharmacol 2001a;24:254. Dumont RJ, Verma S, Okonkwo DO, et al. Acute spinal cord injury, part II: Contemporary pharmacotherapy. Clin Neuropharmacol 2001b;24:265. Earnhardt JN, Streit WJ, Anderson DK, et al. Induction of manganese superoxide dismutase in acute spinal cord injury. J Neurotrauma 2002;19:1065. Edelson RN. Spinal subdural hematoma. In: Vinken PJ, Bruyn GW, eds. Handbook of clinical neurology, Vol. 26. Amsterdam: North Holland, 1976. Edelson RN, Chernik NL, Posner JD. Spinal subdural hematomas complicating lumbar puncture. Arch Neurol 1974;31:134.

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CHAPTER 67

Determination of Brain Death in Infants and Children Stephen Ashwal

The diagnosis of brain death in infants and children can be established after careful review of the medical history and performance of a detailed neurologic examination. Although criteria in children follow those established in adults, there are no universally accepted worldwide criteria for brain death determination in adults [Haupt and Rudolf, 1999; Wijdicks, 2001, 2002]. In the United States and in most countries the 1987 pediatric guidelines have been employed with general agreement regarding their usefulness [Banasiak and Lister 2003; Farrell and Levine, 1993; Kaufman, 1989], although criticisms about their validity and specificity, particularly in young infants, have been raised [Freeman and Ferry, 1988; Shewmon, 1988; Volpe, 1987]. In some countries, such as Japan, criteria for brain death in children have been established only more recently [Miyasaka et al., 2001].

HISTORICAL PERSPECTIVE A state beyond coma, or coma depassé, was proposed in 1959 by Mollaret and Goulon to describe a premorbid clinical condition with loss of sensation, motor activity, consciousness, and vegetative functions [Mollaret and Goulon, 1959]. In 1968, an ad hoc committee of the Harvard Medical School faculty recommended clinical guidelines that subsequently shaped development of brain death concepts [Beecher, 1968]. The committee proposed that brain death could be defined by coma, apnea, lack of spontaneous or purposeful movements, and loss of selective cranial nerve functions, including the corneal reflex, pupillary response to light, pharyngeal gag and swallowing, yawning, vocalization, and failure of eye deviation to caloric stimulation of the tympanic membranes. Failure of improvement, sustained over 24 hours of observation, established a diagnosis of brain death. Two caveats were that the patient was normothermic and drugs capable of maintaining coma were excluded. Two isoelectric electroencephalograms (EEGs) performed 24 hours apart were considered confirmatory, but not essential in the declaration of brain death. The neurologic examination of brainstem function, an observation period, and ancillary neurodiagnostic tests when diagnostic doubt exists remain fundamental to a present-day diagnosis of brain death. In 1971, Mohandas and Chou emphasized the importance of determining the etiology of coma and documenting the persistence of apnea [Mohandas and Chou, 1971]. The Conference of Medical Royal College and Faculties in the United Kingdom in 1976 proposed the following definition: “Permanent functional death of the brainstem constitutes brain death” [Conference, 1976]. Irreversible structural brainstem damage was defined carefully and believed to be

clinically diagnosable without confirmatory EEG recordings. A follow-up report in 1979 recommended that brainstem death be considered death [Conference, 1979]. Subsequently a working group convened by the Royal College of Physicians further defined the criteria of brainstem death [Criteria, 1995]. In 1980, the National Institute of Neurologic and Communicative Disorders and Stroke (NINCDS) Collaborative Study of Brain Death reported on the outcome of 503 adult comatose and apneic patients, including neuropathologic brain studies and EEGs [NINCDS, 1980]. The combination of loss of pupillary light reflex, corneal reflex, oculocephalic reflex (doll’s eye phenomenon), and oculovestibular reflex (caloric eye deviation) was highly predictive of death. Apnea, coma, and absence of brainstem reflexes, combined with an electrocerebral silent EEG, were highly associated with pathology in a brain that had experienced long-term respirator exposure (“respirator brain”). Exceptions were rarely noted. A few respirator brains occurred in patients with persistent biologic EEG activity, and several brain specimens did not show the neuropathologic features of a respirator brain despite electrocerebral silence. EEG use was recommended in confirming brain death when the clinical neurologic examination was equivocal. An isoelectric EEG, despite its rare failure always to diagnose brain destruction, was predictive of a fatal outcome except in two patients with drug intoxication. The report emphasized that a patient was not considered brain dead if the EEG was not isoelectric. About 30% of the population had drug toxicity despite the absence of a history of ingestion; 28% had measurable amounts of drugs that would suppress EEG activity. The report concluded that drug screening and EEG monitoring were mandatory before declaring brain death. Subsequent reports in adults [Grigg et al., 1987] and children [Ashwal and Schneider, 1979] documented that EEG activity could persist in unequivocally brain dead patients. In 1981, a U.S. presidential commission was convened to establish guidelines for the determination of brain death [President’s Commission, 1981]. These guidelines, outlined in Box 67-1, emphasized diagnosis based on the irreversible cessation of function of the entire brain. This report recognized that adult criteria might not be applicable to children because of developmental factors, a possible greater tolerance to asphyxia, and the recognition that infants and children occasionally exhibited significant recovery despite prolonged coma. The age of 5 years was selected as the earliest age suitable for the application of adult criteria, although this age selection reflected no known biologic phenomena. Seeking to remedy this exclusion of infants and children, multiple professional neurologic and pediatric societies in 1987 convened a task force to propose a pediatric standard

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BOX 67-1 PRESIDENT’S COMMISSION GUIDELINES FOR THE DETERMINATION OF BRAIN DEATH An individual presenting with the findings in section A (cardiopulmonary) or section B (neurologic) is dead. A diagnosis of death requires that cessation of functions (subsection 1) and irreversibility (subsection 2) be shown. (A) An individual with irreversible cessation of circulatory and respiratory functions is dead. (1) Cessation is recognized by an appropriate examination. (2) Irreversibility is recognized by persistent cessation of functions during an appropriate period of observation or trial of therapy or both. (B) An individual with irreversible cessation of all functions of the entire brain, including the brainstem, is dead. (1) Cessation is recognized when evaluation discloses findings of (a) and (b). (a) Cerebral functions are absent. (b) Brainstem functions are absent. (2) Irreversibility is recognized when evaluation discloses findings of (a), (b), and (c). (a) The cause of coma is established and sufficient to account for loss of brain functions. (b) The possibility of recovery of any brain function is excluded. (c) Cessation of all brain functions persists for an appropriate period of observation or trial of therapy or both. Other Factors: 1. Complicating conditions, such as drug and metabolic intoxication and hypothermia (core temperature <32.2° C), should be excluded. 2. The presence of shock should alert the physician to be particularly cautious in applying neurologic criteria to determine death. 3. Children: The brains of infants and young children have increased resistance to damage and may recover substantial functions even after exhibiting unresponsiveness on neurologic examination for longer periods compared with adults. Physicians should be particularly cautious in applying neurologic criteria to determine brain death in children <5 years old. Adapted from the President’s Commission report for the study of ethical problems in medicine and biomedical and behavioral research. JAMA 1981;246:2184.

for brain death determination [Guidelines, 1987]. History of the etiology and reversibility of coma was emphasized, as was the loss of brainstem function and apnea (Box 67-2). Age-dependent observation periods of 12 to 48 hours were recommended. Ancillary EEG or radionuclide scanning was recommended in children younger than 1 year of age. Infants less than 7 days of age were excluded because of a lack of supportive literature. Later studies confirmed the validity of applying these specific guidelines in newborns greater than 34 weeks of conceptual life [Ashwal and Schneider, 1989].

Box 67-2 GUIDELINES FOR THE DETERMINATION OF BRAIN DEATH IN CHILDREN

From Report of special task force. Guidelines for the determination of brain death in children. Ad Hoc Task Force consisting of representatives from the American Academy of Pediatrics, American Academy of Neurology, Child Neurology Society, American Neurological Association, American Bar Association, and the NINCDS. Pediatrics 1987;80:298.

LEGAL DEFINITION OF BRAIN DEATH The American Medical Association and the American Bar Association supported universal enactment of the Uniform Determination of Death Act published in 1980 [Uniform, 1980]. The Act defined death stating that “an individual who has sustained either (1) irreversible cessation of circulatory and respiratory functions; or (2) irreversible cessation of all functions of the brain including the brainstem is dead.” Subsequently, all states of the United States have enacted legislation accepting death by this definition. Brain death can be declared despite heart-lung respirator maintenance.

EPIDEMIOLOGY Incidence of Brain Death The overall incidence of brain death in children is unknown. In the United States, data are available concerning the number of brain dead children who become organ donors (see United Network Organ Sharing [UNOS] web site at

Ashwal / Determination of Brain Death in Infants and Children

Etiologies of Brain Death Table 67-1 provides information on the age distribution of infants and children in whom brain death has been diagnosed and characterization by disease categories that were responsible for the cerebral insult. Brain death most commonly occurs in adolescents and is less common in infants

2000 No. of brain dead children

http://www.unos.org/), and more recent studies have suggested that approximately 55% of children declared brain dead become organ donors [Sheehy et al., 2003]. Combining such data suggests there are approximately 1800 children per year in the United States declared brain dead, with most being between 11 and 17 years of age (Fig. 67-1). Accurate data for neonates and infants younger than 1 year of age are not available. There also was a decrease between 1993 and 2003 in the number of brain dead children who were organ donors (from 1137 to 886 [22%]), suggesting that the total number of children who are annually being declared brain dead has decreased (see UNOS web site). This decrease likely is due to the 26% decline in the total number of pediatric deaths since the 1990s (data from the National Center for Health Statistics web site at http://www.cdc.gov/nchs/). Studies from pediatric intensive care units in the 1990s reported that the incidence of brain death in older infants and children ranges from 0.65% to 1.2% of admissions [Ashwal and Schneider, 1999]. In one study, the mortality rate in the pediatric intensive care unit was 8.7%, with 22% of these children declared brain dead [Ryan et al., 1993]. The mortality rate in the neonatal intensive care unit was 5.6%, with none of the infants declared brain dead. Another study reported the percentage of brain deaths to overall deaths to be 31.4% in children older than 1 month of age and 6.3% in neonates [Parker et al., 1995]. Similar findings from other countries have been reported [Goh et al., 1999; Gotay-Cruz and Fernandez-Sein, 2002; Lopez-Herce et al., 2000; Martinot et al., 1998]. Data from Loma Linda University Children’s Hospital indicate that the percentage of brain deaths to overall deaths is 28% and 2.1% in the pediatric and neonatal intensive care units. In some pediatric intensive care units, the percentage of patients diagnosed as brain dead compared with all deaths is even higher (37% to 38%) [Martinot et al., 1995; Mejia and Pollack, 1995].

1500 1000 500 0

<1

1-5

6-10

11-17

FIGURE 67-1. Number of children declared brain dead by age in the United States. Data based on the number of children who are brain dead who become organ donors and the assumption that approximately 55% of children who are brain dead become donors. (Data from the United Network Organ Sharing web site: http://www.unos.org/.)

younger than 1 year of age. Closed head injury was the most common clinical presentation leading to brain death (50%), followed by intracranial hemorrhage and stroke (12%). Asphyxial injury usually occurred as a complication of septic or hemorrhagic shock, with unexplained out-of-hospital cardiac arrest or from strangulation or suffocation. Sudden infant death syndrome was a rare cause of brain death. Brain death secondary to meningitis was seen in patients who developed massive cerebral edema with herniation within 2 to 24 hours of admission. Miscellaneous causes of brain death involve rare metabolic diseases, perioperative insults to the central nervous system, acute hydrocephalus, and a variety of other rare disorders that ultimately affect the brain.

Outcome after Diagnosis of Brain Death Most children are removed from life support or are used for organ donation within a 2-day time period when the diagnosis of brain death is confirmed [Ashwal and Schneider, 1988]. Some children are continued on ventilator support until cardiac arrest occurs, and their “survival” has averaged about 17 days. In rare cases, children have been maintained on ventilator support for periods ranging from 6 months to 5 years [Shewmon, 1998]. There have been no reports of children recovering neurologic function who met adult brain

Age Distribution and Etiologies of Brain Death in Children

Term 0–4 mo 4–12 mo 1–2 yr 2–5 yr 5–10 yr 10–18 yr

PERCENT PATIENTS (n = 219)* 6 12 15 17 32 8 10

Total >18

Years

TABLE 67-1

AGE

1555

ETIOLOGY Traumatic brain injury Intracranial hemorrhage/stroke Gunshot wound Unknown/other Asphyxia Cardiovascular disease Drowning Seizure/status epilepticus Drug associated Sudden infant death syndrome

*Data from Ashwal S, Schneider S. Brain death in children: Part I and part II. Pediatr Neurol 1988;3:69. †Data from UNOS web site: http://www.unos.org/.

PERCENT PATIENTS (n = 4794)† 50 12 10 8 7 6 4 1 1 1

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death criteria on neurologic examination [Moshe and Alvarez, 1986; Rowland et al., 1983]. These criteria include an absence of spontaneous activity; specific cranial nerve dysfunction; and cardiac response to ocular compression, decerebrate or decorticate posturing, and apnea.

NEUROLOGIC EVALUATION Reports indicate that a marked variability exists in the knowledge and use of the 1987 pediatric brain death guidelines [Ashwal, 1991; Mejia and Pollack, 1995]. A national survey of 16 pediatric intensive care units found that apnea testing either was not performed (25%) or was deemed “controversial” (22%) in children diagnosed as brain dead, and in many of these infants and children, appropriate confirmatory testing was not done [Mejia and Pollack, 1995]. Similar findings were noted in a survey of neurosurgeons and the criteria they employed in evaluating children with head injury for brain death [Chang et al., 2003]. Likewise, a survey of pediatric attending physicians and residents in the United States found a high percentage (39% to 58%) who could not define brain death correctly or recognize that brain death could be diagnosed without confirmatory testing in children older than 1 year of age [Harrison and Botkin, 1999].

Clinical Examination Cerebral Unresponsivity The neurologic evaluation for brain death is difficult in a comatose patient, particularly in infants and children. It is necessary to standardize the basal conditions under which the patient is examined. The patient should be normothermic, and pharmacologic agents capable of producing coma or neuromuscular blocking agents must be excluded [Kennedy and Kiloh, 1996; Tobin, 1996]. Assessment for cerebral unresponsivity, loss of cranial nerve function, and determination of apnea (tested with a hypercapneic stimulus) must be performed and documented. Confounding circumstances always increase the complexity of the evaluation. Cerebral unresponsivity or coma can be quantitated using the Glasgow Coma Scale score, which ranges from 3 (no response) to 15 (normal) using assigned scores for eye opening, motor activity, and vocalization (see Chapter 61) [Jennett and Bond, 1975]. The scale should be modified substituting socialization for verbalization for infants and children who are too young to have developed speech. The predictive value of the duration of unresponsivity in infants and young children may be less trustworthy than in adults. In young children, recovery may occur when unresponsiveness has occurred for prolonged periods and even when serious structural nervous system dysfunction is present. If the neurologic evaluation is uncertain or inconsistent in children younger than 1 year of age, supportive laboratory documentation, including EEG and cerebral blood flow determinations, should be considered.

Brainstem Examination Cessation of brainstem reflexes is generally accepted as the hallmark of brain failure. The NINCDS reported, however, that 141 of 459 comatose patients who died retained one or

more brainstem reflexes [NINCDS, 1980]. No single preserved brainstem reflex could discriminate the preservation of any other brainstem reflex. The combination of pupillary light response and oculocephalic and vestibular reflexes had the greatest specificity, but this combination included 4% of patients who retained other brainstem reflexes. Box 67-3 outlines the procedures used to assess the caloric response. Premature infants less than 32 weeks’ conceptual age do not have completely developed cranial nerve function. Neurologists examining these infants should be aware of the development of the different cranial nerve reflexes during gestation (Table 67-2). Newborns often present obstacles to examination. Ear canals are frequently small and may be plugged, pupils are small, adhesive tape obscures the face and extremities, and neuromuscular blocking agents alter the examination.

Apnea Documentation of apnea, under controlled conditions, is the most important determination in clinically evaluating brain

Box 67-3 COLD WATER CALORIC TYMPANIC MEMBRANE STIMULATION Equipment 400 mL of tap water/ice cubes 25- or 50-mL disposable syringe Large-bore intravenous catheter (shortened 2 to 3 inches from hub) Preparation Check ear canals for patency and integrity of drum Patient’s head flat Test Irrigate each drum with 80 mL of cold water over minimum of 3 minutes Repeat with head at 45-degree angle Positive Result in Coma Head level: Eyes deviate to side of irrigation Head at 45-degree angle: Eyes vertically depressed

TABLE 67-2 Reflex Development in Preterm Infants DEVELOPMENTAL REFLEX

GESTATIONAL AGE (WEEKS) WHEN REFLEX IS ELICITABLE

Suck, root, gag Auditory response Pupillary response to light Oculocephalic response Corneal response Moro response Grasp response (palmar) Alertness Apnea response to PaCO2 stimulus

32–34 30–32 30–32 28–32 28–32 28–32 30–32 30–32 33

Data from Fanaroff et al., 1987; Swaiman, 1994.

Ashwal / Determination of Brain Death in Infants and Children

death. Virtually all protocols recommend a period of unassisted ventilation, allowing hypercapnia maximally to stimulate the respiratory effort. The first formal observation period (3 minutes) was recommended by the Ad Hoc Harvard Medical School Faculty [Beecher, 1968]. The Conference of Royal Colleges and Faculties suggested administering a mixture of 5% carbon dioxide and 95% oxygen for 5 minutes while withholding respirator support and then supplying 100% tracheal oxygen [Conference, 1976]. The President’s Commission recommended 100% oxygen ventilation for 10 minutes followed by passive 100% tracheal oxygen for a period long enough to achieve a PCO2 of at least 60 mm Hg [President’s Commission, 1981]. The normal physiologic apneic threshold (minimum PCO2 at which respiration begins) depends on many factors and can be altered by anesthetic agents, narcotics, sedatives, and certain disease states. Schafer and Caronna described three patients, suspected to be brain dead, who developed spontaneous respiration at PCO2 levels between 45 mm Hg and 50 mm Hg, which suggested a maximal end point of 60 mm Hg [Schafer and Caronna, 1978]. Ropper and coworkers studied seven brain dead patients and reported a PCO2 of 44 mm Hg as a maximal excitatory end point [Ropper et al., 1981], but this has not been studied in children. The maximal PCO2 apneic threshold in children is probably similar to adults. Outwater and Rockoff studied 10 patients, age 10 months to 15 years, in whom they increased mean PCO2 from 34.4 mm Hg to 59.5 mm Hg over 5 minutes while supplying 100% tracheal oxygen [Outwater and Rockoff, 1984]. The PO2 exceeded 200 mm Hg during the test period. Rowland and colleagues performed 16 apnea tests on nine patients, age 4 months to 13 years, four of whom had detectable phenobarbital levels between 10 and 25 mg/dL [Rowland et al., 1984]. These patients received 100% oxygen for 10 minutes. Oxygen then was delivered at 6 liters/min through a catheter into the length of the endotracheal tube with the ventilator turned off during the 15-minute study period. These patients were moderately hyperventilated before the apnea test with a mean PCO2 of 28 mm Hg. The PCO2 increased 4.4 mm Hg, 3.4 mm Hg, and 2.6 mm Hg per minute at 5, 10, and 15 minutes. Arterial PCO2 at the end of 15 minutes ranged from 40 to 116 mm Hg, and by 15 minutes, 14 of 16 patients had PCO2 levels greater than 60 mm Hg. Two patients had PCO2 levels of 100 mm Hg and 116 mm Hg with pH determinations of 6.92 and 6.98. Arterial PO2 remained greater than 100 mm Hg, and in 12 of 16 patients it was greater than 200 mm Hg. Mild alterations of pulse or blood pressure or both also were observed in six patients but were reversible. Both studies concluded that apnea test periods of 5 to 10 minutes would result in PCO2 levels exceeding 60 mm Hg without danger of hypoxemia. Apnea challenges (Box 67-4), when initiated at Pco2 levels of 40 to 50 mm Hg, have a predictive Pco2 linear increase [Paret and Barzilay, 1995]. When the initial Pco2 was 40 to 51 mm Hg in 11 patients, the minute Pco2 increase was 5.1 to 6.7 mm Hg. During the pretest period, the Pco2 was stabilized for 10 minutes. Most studies recommend that Pco2 levels be determined at 5-minute intervals and continued out to 15 minutes if the Pco2 has not reached 60 mm Hg and the Po2 has not decreased to less than 50 mm Hg. Apnea testing of patients who are hypothermic or receiving medications that suppress respiration is not valid for docu-

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Box 67-4 APNEA CHALLENGE TEST Patient normothermic and normotensive No central nervous system pharmacodepressants or neuromuscular blocking agents Patient maintained at arterial PCO2 30 to 40 mm Hg Ventilate at constant rate with 100% oxygen for 20 minutes Endotracheal catheter delivering 8 L of oxygen (adult) after disconnecting respirator Pulse oximeter in place (or measure arterial PO2) Measure arterial PCO2 every 3 minutes until PCO2 >60 mm Hg or patient attempts periodic breathing

menting brainstem failure. It still can be performed under such circumstances, however, because the presence of respiratory effort would eliminate brain death as a diagnosis. Several case reports involving only a few patients have raised related issues concerning apnea testing in young infants and children that also apply to newborns. Ammar and coworkers reported five children, age 9 months to 7 years, with severe brainstem dysfunction, including loss of pupillary reflexes and apnea, that was due to surgically resectable brainstem lesions with return of spontaneous respirations and substantial neurologic function [Ammar et al., 1993]. None of these children were considered brain dead before surgery, although they were severely compromised. These investigators correctly pointed out that treatment of compressive brainstem lesions might reverse severe neurologic deficits that mimic brain death. A second report concerns a 3-month-old infant who met the task force criteria for brain death, but who, on day 43 after admission, developed two to three breaths per minute [Okamoto and Sugimoto, 1995]. The infant died 71 days after presentation. At issue is whether this case should be considered a return of respiratory function. An editorial commentary on this case by Fishman stated, “The return of no clinical neurologic function other than two to three ineffectual respirations/minute due to the survival of only a small group of neurons in the medulla should not be considered an example of reversible deficits and failure of current brain death criteria” [Fishman, 1995]. A third case report described a 4-year-old male with a posterior fossa mass who became brain dead 4 days after admission [Vardis and Pollack, 1998]. His first apnea test had a Pco2 of 91 mm Hg, at which time he developed spontaneous respirations. A repeat apnea test the following day found an initial Pco2 of 67 mm Hg, but no respiratory effort was detected; he began to breathe spontaneously when challenged again, and the Pco2 was 71 mm Hg. This last patient raises the question as to whether the carbon dioxide threshold may be age dependent or disease dependent. Because of the limited number of patients in these few case reports, additional research into these issues is required. Apnea testing should be performed in children only after a full explanation to the parents is provided, and permission for the procedure is obtained. Rarely, parents refuse to allow an apnea challenge. On these rare occasions, carbon dioxide augmentation at 1 liter/min, preceded by 100% preoxygenation, increases the Pco2 to 60 mm Hg within 2 minutes. At this time, a respirator can be interrupted for 3 to 5 minutes as a substitute test of apnea [Lang, 1995].

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ANCILLARY NEURODIAGNOSTIC STUDIES Virtually all guidelines have stressed that the historical events leading to coma, when combined with the clinical triad of coma, absence of brainstem reflexes, and a failed apnea challenge, are fundamental to brain death diagnosis. Many physicians are uncomfortable with a clinical diagnosis and have sought an absolute laboratory test to confirm brain death. A universally applicable, valid, and reliable study is a laudable, but probably unattainable goal [Shewmon, 1987]. All brain cells do not die simultaneously; highly selective tests lack the sensitivity to report absolutely that the brain has failed and such failure is permanent. The combination of clinical evaluation and pertinent diagnostic studies (EEG, cerebral blood flow studies) can yield a sound clinical decision, however.

Electroencephalogram Despite limitations of the EEG, especially in regard to measurement of brainstem activity, many physicians tend to equate an isoelectric EEG (electrocerebral silence) with brain death. Despite the obvious dangers in depending only on the EEG, the isoelectric EEG, combined with the clinical triad of coma, absent brainstem reflexes, and apnea, remains the best documented tool for determining brain death. It is widely available, has bedside portability, is noninvasive, is relatively inexpensive, and can be interpreted by most neurologists. The American Electroencephalographic Society Guidelines has developed criteria for brain death recordings [American Electroencephalographic Society, 1986, 1994]. The recording should be isoelectric for a minimum of 30 minutes and show no electrical activity beyond 2 μV at a sensitivity of 2 μV/mm, with filter settings at 0.1 or 0.3 second at 70 Hz. Telephone transmission of EEGs is unacceptable for brain death determinations. Technical problems in performing EEGs have been reviewed previously [Bennett et al., 1976; Chatrian, 1986; Moshe, 1989; Schneider, 1989] and summarized here.

Electroencephalogram in Pediatric Brain Death Pediatric patients present unique difficulties in interpretation of the EEG because of shorter interelectrode distances, greater electrocardiogram contamination, reduced cortical potentials in premature infants, and delayed metabolism of barbiturates. Reversible electrocerebral silence may occur with the use of central nervous system–depressant drugs, hypothermia, cardiovascular shock, or metabolic encephalopathies. In children, the most common medications causing the reversible loss of brain electrocortical activity include barbiturates, benzodiazepines, narcotics, and certain intravenous (thiopental, ketamine, midazolam) and inhalation (halothane and isoflurane) anesthetics. Phenobarbital is the most common drug responsible for reversible electrocerebral silence because it is widely used for seizure control. Previous studies have suggested that phenobarbital levels greater than 25 μg/mL might suppress EEG activity to the point of electrocerebral silence and that levels less than 20 to 25 μg/mL are unlikely to cause electrocerebral silence or affect apnea testing or the examination of brainstem reflexes [Ashwal and Schneider, 1989]. A study in 92 children reported data suggesting that

therapeutic levels of phenobarbital (i.e., 15 to 40 μg/mL) do not affect the EEG [LaMancusa et al., 1991]. The authors also recommended that physicians and families do not have to wait the 3.7 days for subtherapeutic (<15 mg/mL) or the 6 days for therapeutic (15 to 40 μg/mL) barbiturate levels to be completely metabolized to consider withdrawal of life support. Others have reported that absent brainstem reflexes could not be correlated to thiopentone levels [Grattan Smith and Butt, 1993]. A study performed in adults found residual postmortem toxic brain levels of barbiturates despite absent premorbid serum levels [Saito et al., 1995]. A core temperature greater than 32.2° C (>90° F) has been regarded as a prerequisite for reliably determining brain death by EEG [Hicks and Poole, 1981]. In adults, electrocerebral silence does not occur until the temperature decreases to less than 20° C (68° F). In children, suppression of EEG activity does not appear until 24° C (75.2° F), and complete loss of EEG activity does not occur until the temperature is less than 18° C (<64.4° F) [Jorgensen and Malchow-Moller, 1978]. The average temperature when EEGs are obtained for confirmation of brain death is 97.3° F ± 1.4° F. This finding suggests that hypothermia is not likely to be a significant problem for pediatric EEG interpretation. Reversible electrocerebral silence may occur soon after a child has had a cardiac arrest [Schmitt et al., 1993]. Several infants in whom the initial EEG was observed 8 to 10 hours after a cardiac arrest had electrocerebral silence, but a repeat study 12 to 24 hours later demonstrated diffuse low-voltage activity. Several of these infants survived in a vegetative or minimally conscious state; most died as a result of other complications of the acute catastrophic insult. Similar observations have been reported in adults [DeOliveira et al., 1984]. Although not well documented, electrolyte, acid-base, and blood-gas abnormalities; severe hepatic and renal dysfunction; and certain inborn errors of metabolism all have been considered capable of decreasing brain electrocortical activity to the point of causing complete cortical inactivity. In selected children in whom the etiology of brain death is uncertain, evaluation for metabolic diseases, including urea cycle enzyme defects; disorders of lactate, amino acid, and organic acid metabolism; and mitochondrial diseases, should be considered. Extensive literature exists documenting persistent EEG activity in brain dead infants, children, and adults [Ashwal and Schneider, 1979; Grigg et al., 1987]. Of patients meeting brain death criteria in the NINCDS report, 8% to 40% maintained EEG activity for brief periods. Conversely, 20 premature infants recovered from electrocerebral silence; however, 15 of these patients had clinical evidence of brain function during electrocerebral silence [Sher et al., 1996]. Since Green and Lauber’s report in 1972 of two infants who had return of some EEG activity after an initial electrocerebral silence recording [Green and Lauber, 1972], there have only been a few additional infants reported in whom EEG activity returned [Ashwal, 1997; Ashwal et al., 1977; DeOliveria et al., 1984; Juguilon and Reilly, 1982; Kohrman and Spivack, 1990; Pezzani et al., 1986; Toffol et al., 1987]. A previous report, based on most of these cases, estimated that the return of EEG activity when the initial study was isoelectric was approximately 0.02% [Ashwal, 1997]. There are presumably additional unreported cases in which EEG activity returned, but these additional cases are unlikely to

Ashwal / Determination of Brain Death in Infants and Children

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TABLE 67-3 Principal Methods to Assess Cerebral Blood Flow in Brain Dead Patients METHOD

MEASUREMENT

ABSENT CIRCULATION INDICATED BY

Cerebral angiography

High pressure and rapid, intra-arterial injection of contrast agent Intravenous rapid bolus injection of radionuclide isotope

Absence of intracranial filling of large cerebral arteries and their major branches Absence of radionuclide detection in distribution of large vessels and in brain parenchyma Absence of activity on dynamic scintigraphy or by delayed isotope uptake Serial changes with loss of diastolic flow, flow reversal, and loss of systolic flow Absence of contrast material within large cerebral vessels Cerebral blood flow values <5-10 mL/min/100 g indicate absence of cerebral circulation

Radionuclide imaging HMPAO SPECT Transcranial Doppler Digital subtraction angiography Xenon CT

Similar to radionuclide imaging but with different detection system and isotope Measures blood velocity from large intracranial vessels during diastole and systole Imaging that provides visualization of cerebral vessels Provides quantitative measure of cerebral blood flow by inhalation of xenon gas detected with cranial CT

CT, computed tomography; HMPAO, hexamethylpropyleneamine oxime; SPECT, single-photon emission computed tomography.

affect substantially this extremely low ratio. Concerns about the return of EEG activity have been overemphasized. In addition, if one considers issues related to subsequent clinical recovery of the patients in whom EEG activity returned, none of the patients made significant clinical recoveries. The lack of absolute correlation between EEG findings and other supportive ancillary brain death tests limits reliance on the EEG as a single confirmatory test [Paolin et al., 1995]. Despite these well-documented drawbacks, the EEG remains extremely valuable when combined with the neurologic examination and other confirmatory studies [Schneider, 1989]. The EEG continues as the most widely used ancillary study in brain death determinations.

Measurements of Cerebral Perfusion Several technologies are available for estimating or measuring cerebral blood flow (Table 67-3), cerebral perfusion, or cerebral blood velocity. Their use in children has followed after application and testing in adults. New and older technologies have been applied in the search for an ideal test. Each advance in technology needs to be carefully scrutinized in terms of availability, cost, 24-hour accessibility, portability, patient risk, invasiveness, and simultaneous outcomes comparison with established techniques. The neurologist who is requested to perform brain death determinations should be aware of individual institutional resources. Concerns exist about the validity and reliability of several of these methods in preterm and newborn infants, in whom cerebral blood flow values are quite low, and whether these methods possess the sensitivity to detect very low flow values [Altman et al., 1988; Greissen, 1986].

Cerebral Angiography Direct visualization of the cerebral circulation with angiography that shows the complete cessation of cerebral blood flow has long been accepted as the standard for comparing all other neuroimaging modalities for brain death confirmation. Near-simultaneous comparisons of multiple techniques confirm the sensitivity of this long-held but seldom challenged concept [Bradac and Simon, 1974; Conrad and Sinha, 2003; Paolin et al., 1995]. The technique should be considered only for unresolvable clinical situations, however,

because of its limitations, which include patient transfer, invasiveness, limited radiologic personnel, and prolonged study time. Few cases have been reported in which this invasive method has been performed in brain dead children to validate the absence of cerebral circulation [Ashwal and Schneider, 1979].

Radionuclide Imaging Several radionuclide techniques have been used in brain dead patients since the 1970s to determine noninvasively whether there has been cessation of cerebral circulation [Conrad and Sinha, 2003]. With most methods, circulation was assessed during an early “dynamic” phase and later by examining static images for cerebral uptake of the specific radionuclide (usually technetium-99m pertechnetate, technetium-99m glucoheptonate, or technetium-99m DTPA) (Fig. 67-2). During the dynamic phase, a bolus of the radionuclide was injected rapidly, and isotopic cranial images were obtained similar to that of a carotid arteriogram. Usually in the arterial phase, cerebral activity was detectable within several seconds, and from the time of peak cerebral activity, sagittal sinus activity was observed within 6 to 8 seconds [Thompson et al., 1987]. Various terms have been used to describe the early phase of this study, including radioisotopic bolus angiography and dynamic brain scintigraphy. If activity was not detectable in this early phase, cerebral blood flow was considered absent resulting from either low cardiac output or very high intracranial pressure (as is seen with brain death). Because most tracers have a half-life of several hours, the static phase of a radionuclide imaging study usually was done later, looking for the absence or presence of diffuse parenchymal isotopic uptake. Currently, most centers are using single-photon emission computed tomography scanning and technetium-99m hexamethylpropylene amine oxime (HMPAO) as the isotopic agent [Abdel Dayem et al., 1989; Bonetti et al., 1995; Galaske et al., 1988; Mrhac et al., 1995; Spieth et al., 1995; Valle et al., 1993; Wieler et al., 1993; Wilson et al., 1993]. This agent is more lipophilic, is not dependent on the quality of the bolus injection, and enables more precise static imaging of parenchymatous brain perfusion in contrast to conventional dynamic imaging because of retention in the intact brain parenchyma. With this technology, the isotope can be injected in the intensive care

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Brain Injury and Disorders of Consciousness / 67 FIGURE 67-2. Technetium cerebral blood flow study. This 13-year-old female was suspected of being brain dead after a cardiac arrest associated with exacerbation of an asthma attack. Her first study (A), using 1-second images selected from the dynamic cerebral blood flow studies done with 20 mCi of technetium99m pertechnetate, showed normal intracranial circulation. A repeat study (B) the following day showed a “light bulb sign”—no intracranial circulation. Also noted is the “hot nose sign” resulting from vasodilation around the cribriform plate in an attempt to develop collateral circulation. (Courtesy of Dr. Eloy Schulz, Department of Radiology, Loma Linda University Medical Center.)

A B unit, and better planar images can be obtained at a later time using a mobile camera or whenever the patient can be moved to the nuclear medicine department. Multiple studies in adults and children have documented radionuclide imaging to be accurate and reproducible, and it has been compared favorably with other methods of detecting the presence or absence of cerebral blood flow [Conrad and Sinha, 2003; Drake et al., 1986; Goodman et al., 1985; Holtzman et al., 1983; Kaukinen et al., 1995; Parker et al., 1995; Ruiz-Garcia et al., 2000; Schneider, 1989; Schwartz et al., 1984; Wieler et al., 1993]. This technique is particularly useful when hypothermia or elevated barbiturate levels prevent valid EEG interpretation [Holtzman et al., 1983]. Premature and full-term newborns, despite having extremely reduced cerebral blood flow compared with older children, can be readily evaluated using radionuclide measurements [Ashwal et al., 1989; Greissen, 1986]. Hospital nuclear medicine departments should be aware of improved advances in radiopharmaceuticals [Spieth et al., 1995; Wilson et al., 1993] and the ability to detect flow in the posterior fossa circulation [Spieth et al., 1995] and that ventricular drainage procedures may give a falsenegative indication that cerebral blood flow is absent [Hansen et al., 1993].

Transcranial Doppler Transcranial Doppler ultrasonography has advocates because of its obvious portability and noninvasiveness and isolette accessibility [Ahmann et al., 1987; Feri et al., 1994; Manno, 1997; McMenamin and Volpe, 1983]. More recent studies document a high rate of false-negative test results and lower levels of specificity and sensitivity, which suggest significant limitations for use of this technique for brain death confirmation [Chiu et al., 2003; de Freitas et al., 2003; Dosemeci et al., 2004; Rodriguez et al., 2002]. With the pulsed transcranial Doppler technique, characteristic blood velocity waveforms are detected during systole

and diastole, usually from the anterior cerebral and common carotid arteries [Petty et al., 1990]. McMenamin and Volpe reported six brain dead infants, 28 to 40 weeks’ gestation, who had the characteristic progression of velocity changes as cerebral edema and intracranial pressure increased [McMenamin and Volpe, 1983]. Changes included the loss of diastolic flow, the appearance of retrograde diastolic flow, the diminution of systolic flow in the anterior cerebral artery with unchanged flow in the common carotid artery, and the loss of any detectable flow in these vessels. Intracranial pressure in four of six infants was elevated, and EEGs in three infants revealed electrocerebral silence. Although cerebral and isotopic angiography was not performed to verify the Doppler results, postmortem examination revealed severe brain injury consistent with but not necessarily typical of injuries reported with brain death. In other studies with pulsed Doppler ultrasound, 19 of 23 brain dead children older than 4 months had a characteristic velocity pattern with a single sharp systolic peak followed by a rapid negative deflection below baseline, sharply rebounding to forward flow in early to mid diastole with gradual tapering at the end of diastole to the zero baseline or below [Ahmann et al., 1987]. Eight of the 19 patients with this waveform also exhibited absent cerebral blood flow by radionuclide angiography. Infants younger than 4 months who were studied had atypical waveforms, suggesting that use of the pulsed Doppler technique in the newborn period may not be as reliable. Another study in 17 comatose children found Doppler velocity changes similar to those reported by McMenamin and Volpe in 11 children who progressed to brain death [Messer et al., 1990]. Other investigations have indicated the limitations of this technique. In one study, only five of seven (71%) patients with the diagnosis of brain death had bilateral reversal of flow (characteristic of increased cerebrovascular resistance and absent cerebral circulation), yielding a specificity of 100% and sensitivity of only 71.4% [Jalili et al., 1994]. An earlier report by Bode and colleagues examined nine brain

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dead children, and in eight, typical findings were reported [Bode et al., 1989]. One newborn exhibited normal systolic and end-diastolic flow velocities in the basal cerebral arteries for 2 days despite clinical and EEG signs of brain death. Other authors also have encountered individual cases that did not follow a similar progression as that originally described [Glasier et al., 1989]. In one case study of an infant with sudden infant death syndrome declared brain dead, transcranial Doppler sonography indicated nearly normal cerebral perfusion, which increased day by day notwithstanding the persistence of other signs of brain death [Sanker et al., 1992]. In most of the more recently reported series, several patients who had Doppler findings typically seen with brain death recovered, and patients who were brain dead frequently did not have the previously described progression of Doppler abnormalities [Chiu et al., 2003; de Freitas et al., 2003; Dosemeci et al., 2004; Rodriguez et al., 2002]. Doppler studies have been used on at least one occasion to confirm the diagnosis of fetal brain death in a 23-week gestational age infant [Otsubo et al., 1999].

Digital Subtraction Angiography Digital subtraction angiography is another technique that has been used to assess the intracranial circulation. This technique can be performed intravenously [Van Bunnen et al., 1989] or by intra-arterial injection [Albertini et al., 1993]. A small amount of nonionic contrast material is injected while digital subtraction imaging of the cerebral vasculature is done similar to conventional cerebral angiography. This procedure allows visualization of contrast within the major intracranial vessels; lack of such visualization indicates absence of cerebral blood flow. There are few reports of this technique in children and only one case report in a neonate diagnosed with brain death [Albertini et al., 1993]. A report using intravenous digital subtraction angiography in 110 patients with clinical signs of brain death observed that the first study documented absent contrast enhancement in 105 patients [Van Bunnen et al., 1989]. Repeat studies in the remaining five patients within several hours also confirmed the cessation of cerebral blood flow.

Xenon Computed Tomography Stable xenon computed tomography (CT) and 133-xenon CT are examples of useful, reliable, and well-documented tests that are seldom available because of cost and limited personnel [Pistoia et al., 1991]. Xenon CT allows quantitative and regional measurement of cerebral blood flow. In brain dead adults, cerebral blood flow values of 1.6 ± 2 mL/min/100 grams have been reported [Darby et al., 1987]. Previous studies found an average cerebral blood flow of 1.3 ± 1.6 mL/min/100 grams in 10 brain dead children compared with 33.5 ± 16.3 mL/min/100 grams in 11 profoundly comatose children [Ashwal et al., 1989]. This finding compares favorably with average cerebral blood flow values of 12 mL/min/100 grams using 133-xenon CT [Greissen, 1986] and 7 to 11 mL/min/100 grams using positron emission tomography in preterm infants who were not brain dead [Altman et al., 1988].

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Positron Emission Tomography The results of positron emission tomography (see Chapter 11) have been reported in only a few brain dead patients [Medlock et al., 1993; Meyer, 1996; Vander Borght et al., 2001]. Because of limited availability, cost, and lack of comparison studies, positron emission tomography offers no advantages over the more standardized methods previously discussed. Meyer reported an 18-year-old brain dead adolescent whose dynamic positron emission tomography study, performed 7 days after a severe post-traumatic closed-head injury, found no intracerebral uptake or retention of tracer and was considered consistent with the diffuse absence of brain metabolism [Meyer, 1996]. Medlock and associates reported a 2-month-old brain dead infant with preserved cerebral blood flow whose positron emission tomography scan on the 11th day after injury revealed a normal glucose metabolic gradient between gray and white matter [Medlock et al., 1993]. Postmortem examination revealed widespread necrosis with mononuclear cell infiltrates throughout all cerebral cortical layers. The persistence of glucose metabolism was thought to be associated with the presence of inflammatory microglial cells and suggested that the persistence of cerebral blood flow and glucose metabolism in brain dead children might not indicate neuronal survival.

Magnetic Resonance Imaging Magnetic resonance imaging (MRI) also has been reported in small series of brain dead patients [Karantanas et al., 2002]. Characteristic features seen in most brain dead (but not comatose) patients include the following: (1) transtentorial and foramen magnum herniation, (2) absent intracranial vascular flow void, (3) poor gray-white matter differentiation, (4) no intracranial contrast enhancement, (5) carotid artery enhancement (intravascular enhancement sign), and (6) prominent nasal and scalp enhancement (MRI hot-nose sign) [Orrison et al., 1994]. Similar findings have been described by other investigators, although the loss of gray-white matter differentiation is not a consistent finding [Lee et al., 1995; Matsumura et al., 1996]. In another study, magnetic resonance angiography also was performed, and nonvisualization above the level of the supraclinoid portion of the internal carotid arteries was found [Ishii et al., 1996]. Abnormalities of diffusion-weighted imaging also have been observed in adult patients who are brain dead [Lovblad et al, 2000]. Presumably, similar neuroimaging findings would be present in children, but this has not yet been reported.

Magnetic Resonance Spectroscopy In the 1980s and 1990s, phosphorus (31P) and proton (1H) magnetic resonance spectroscopy (MRS) have been used to measure noninvasively aspects of brain metabolic activity (see Chapter 11). Studies in neonates, older infants, and children have reported significant abnormalities using these techniques with loss of metabolic activity associated with severe acute central nervous system insults and with poor long-term outcomes [Holshouser et al., 1997; Martin et al., 1996]. 31P-MRS has been reported in 3 infants, 4 children, and 17 adults who met adult criteria for brain death. Spectra in these patients indicated the absence of adenosine

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triphosphate (ATP) and phosphocreatine. The inorganic phosphate and phosphodiester peaks were still detectable [Kato et al., 1991]. Another 31P-MRS study involving three brain dead adults found similar spectral abnormalities [Aichner, 1992]. These findings suggest that MRS could provide another technique to assess objectively the complete loss of cerebral function. The advantage of MRS is that it can be done in conjunction with MRI, which allows acquisition of anatomic and metabolic data that could clarify the etiology of the central nervous system insult and determine whether there is irreversible neuronal loss. Terk and colleagues reported a term brain dead infant whose 31P spectra on days 11 and 18 demonstrated three distinct ATP peaks and several other peaks, however, which suggested the persistence of metabolic activity [Terk et al., 1992]. Although no definite reasons could be ascertained for this finding compared with the study of Kato and associates, they suggested that any proposed spectral signature for brain death would need to be modified. There are no published case reports concerning proton MRS and brain death in children. At Loma Linda University Children’s Hospital, 10 brain dead children were studied with proton MRS. All spectra were markedly abnormal with severe reductions or loss of the metabolite peaks (N-acetylaspartate, choline, creatinine) and a clearly identifiable and elevated lactate peak. These findings were similar to other patients, however, who ultimately were vegetative or severely disabled, suggesting that the specificity for brain death of MRS is insufficient.

Evoked Potentials Brainstem auditory potentials have been studied extensively as a brain death determinant [Guerit, 1992; Litscher et al., 1995; Lutschg et al., 1983; Machado et al., 1991; RuizGarcia et al., 2000; Ruiz-Lopez et al., 1999; Steinhart and Weiss, 1985]. The portability, rapidity, and noninvasiveness seem ideal, but multiple studies have raised significant doubts as to the reliability of brainstem auditory responses in brain death determinations [Dear and Godfrey, 1985; De Merlier and Taylor, 1986; Flannery, 1999; Schmitt et al., 1993; Steinhart and Weiss, 1985; Taylor et al., 1983]. Somatosensory-evoked potentials also have been used for the confirmation of brain death [Beca et al., 1995; RuizGarcia et al., 2000; Ruiz-Lopez et al., 1999; Wagner, 1996; Ying et al., 1992], but there are insufficient data to assess whether it is superior to brainstem-evoked responses for brain death determination.

BRAIN DEATH IN NEWBORNS Because there are no consensus-approved criteria, the ability to diagnose brain death in newborns is unresolved [Ashwal, 1997]. Not only have individual physicians expressed misgivings about being able to diagnose brain death in this age group, but also many institutions have had difficulty developing policies for the diagnosis of brain death. This problem is primarily due to the small number of brain dead neonates (i.e., <100) reported in the literature. As previously noted, preterm infants and term infants less than 7 days of age were excluded from the 1987 pediatric

brain death guidelines. Several years after the publication of these guidelines, data on 18 brain dead neonates were published, and it was suggested that brain death could be diagnosed in full-term newborn infants and preterm infants greater than 34 weeks gestational age within the first week of life [Ashwal and Schneider, 1989]. Because a newborn has patent sutures and an open fontanel, increases in intracranial pressure after acute injury are not as significant as in older patients. The usual cascade of events in older patients after acute brain injury that results in increasing intracranial pressure and reduced cerebral perfusion is less likely to occur in a newborn. Consequently, absent cerebral blood flow is less likely, as is the development of electrocerebral silence. The use of whole-brain death criteria might not be appropriate in a newborn. It might be more medically justifiable to use brainstem death as the major criterion for brain death in newborns. In many situations, the issue of whether a neonate is brain dead or just catastrophically and irreversibly brain injured is resolved by the decision of physicians caring for the neonate with the understanding and agreement of the family to withdraw ventilatory support.

Epidemiology It has been estimated that there are about 550 newborns diagnosed each year as brain dead out of a total of 3,900,089 live births [Ashwal, 1997]. Etiologies of brain death based on data from 88 newborns less than 1 month of age included hypoxic-ischemic encephalopathy (61%), birth trauma (8%), central nervous system malformations (6%), central nervous system hemorrhage (6%), infection (7%), sudden infant death syndrome (7%), nonaccidental trauma (4%), and metabolic disorders (1%).

Duration of Observation This section reviews the time period in newborns required to confirm the diagnosis of brain death. Additional aspects of the neurologic examination are discussed later. Discussions of specific issues regarding certainty of diagnosis, immaturity of the nervous system, and the effects of development on the pathophysiology and diagnosis of brain death in preterm and term infants have been published previously [Coulter, 1987; Freeman and Ferry, 1988; Kohrman, 1993; Volpe, 1987] and updated [Ashwal, 1997]. For the most part, the task force recommendations concerning the duration of observation of brain death in children of different ages were based on expert opinion and consensus rather than being evidence based. Data from 87 newborns allowed an estimation of the duration of coma after the insult until brain death was initially diagnosed (37 hours), duration of time before brain death confirmation (75 hours), and duration of time to transplantation (20 hours) [Ashwal, 1997]. The average duration of brain death in these patients was about 95 hours (i.e., 4 days). Recovery of brainstem function was not observed in any of the patients despite a variety of EEG and cerebral blood flow results. Further analysis examining the duration of brain death was done on the 53 neonates whose organs were donated for transplantation. The total duration of brain death (including time to transplantation) averaged 2.8 days in neonates less than 7 days of age. In neonates 1

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to 3 weeks old, the duration was approximately 5.2 days. The data suggest that a 24- to 48-hour observation period in neonates less than 7 days of age should be sufficient to confirm the diagnosis of brain death.

Neurodiagnostic Testing EEG and radionuclide imaging techniques, as in older infants, children, and adults, remain the most commonly used ancillary studies to confirm the diagnosis of brain death. The 1987 task force guidelines on pediatric brain death did recommend two examinations and EEGs 48 hours apart in neonates 7 days to 2 months old, but made no statement concerning the use of cerebral perfusion techniques because of limited data. Likewise, no recommendations were made for infants less than 7 days old or preterm infants. These recommendations frequently have been misinterpreted to mean that such testing should not be done or is unreliable or that brain death cannot be declared in infants less than 7 days of age. None of these conclusions were intended by the criteria set forth by the task force [Report of special task force, 1987]. Because of the significant physiologic and cerebrovascular differences in the neonatal response to injuries resulting in brain death, previous studies have observed a much higher incidence of newborns with EEG activity or cerebral perfusion [Ashwal, 1989]. In addition, some newborns with electrocerebral silence demonstrated preserved cerebral blood flow, and conversely, others without cerebral blood flow showed EEG activity. In neonates, even though cerebral blood flow and mean arterial blood pressures are much lower, increases in intracranial pressure after acute injury are less dramatic. In a neonate in whom the cerebral metabolic rate is lower, cerebral perfusion is likely to persist to the extent that even when the neonate is brain dead, cerebral blood flow can be detected, and some neuronal viability persists because of this low flow state. Data on 30 newborns who had EEGs and radionuclide perfusion studies found that one third (4 of 12) with electrocerebral silence showed evidence of cerebral blood flow, and 58% (11 of 19) of newborns with absent cerebral blood flow had evidence of EEG activity [Ashwal, 1997]. These data suggest that in this age group, clinical rather than laboratory data may be more appropriate, provided that a sufficient period of observation is allowed. Data on 37 of 53 brain dead newborns in whom EEGs were performed revealed the following: electrocerebral silence (n = 21), very low voltage (n = 13), burst suppression (n = 1), seizure activity (n = 1), and normal (n = 1) [Ashwal, 1997]. Almost all patients whose first EEG demonstrated electrocerebral silence had electrocerebral silence on the second study, and most of the patients who initially did not have electrocerebral silence on their first EEG did so on a repeat study. The data suggested that for confirmation of brain death only, one EEG demonstrating electrocerebral silence is necessary, provided that the examination remains unchanged. Also, if the first EEG indicates activity, a second EEG is likely to be isoelectric and confirm brain death. In the remaining newborns in whom a second EEG reveals activity, continued observation for a total period of at least 2 days is warranted. If the clinical examination is unchanged, brain death can be confirmed.

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Data from radionuclide imaging studies also suggest that not all newborns who are clinically brain dead have an absence of cerebral blood flow for the reasons discussed previously [Ashwal, 1997]. Only 13 of 18 patients showed absence of cerebral blood flow. No significant differences were observed, however, in the median duration of brain death for the neonates without cerebral blood flow compared with the neonates with cerebral blood flow. These findings emphasize the limitations of cerebral blood flow determinations for brain death confirmation in neonates. Brain death in a newborn can be diagnosed as long as the physician is aware of the limitations of the clinical examination and laboratory testing. It is important to examine these infants carefully and repeatedly with particular attention to the examination of brainstem reflexes and apnea testing. Brain death can be diagnosed in a term infant, even when less than 7 days of age. An observation period of 48 hours is recommended to confirm the diagnosis. If an EEG is isoelectric, or if a cerebral blood flow study reveals no flow, the observation period can be shortened to 24 hours. Although there are few cases of preterm infants who are brain dead, it is likely that the same time frame would be applicable. Based on available data, the risk of misdiagnosis seems exceedingly low. There have been a few instances of neonates or older infants who exhibited minimal transient clinical or EEG recovery, but none seem to have regained meaningful neurologic function; all died within a brief time [Goh and Mok, 2004].

Determination of Brain Death in the Comatose Pediatric Patient An algorithmic approach to the evaluation of a comatose child to determine whether the child is brain dead is presented in Figure 67-3. The question of whether a comatose child is brain dead arises within the first days of hospitalization. Occasionally, this issue occurs later because the long-term use of sedative and paralytic agents do not permit the necessary screening to assess for the presence of coma and loss of brainstem function, especially the loss of pupillary reflexes that triggers the question as to whether a child is brain dead. Neurologic or neurosurgical consultation usually is requested at this time by the intensive care unit staff for brain death determination. This assessment must include determination of the proximate cause of coma with review of all neuroimaging, neurophysiologic, metabolic, and toxicology screening studies that were performed to determine the etiology of the global cerebral insult and to determine whether the insult is or is not irreversible. Serum and urine studies should include toxicology screens and serum electrolytes, glucose, calcium, urea nitrogen, creatinine, liver enzymes, lactate, pyruvate, and ammonia determinations (see also Chapter 87) [Kennedy and Kiloh, 1996; Tobin, 1996]. If the history suggests a metabolic disorder, serum amino acid and urine organic acid studies should be considered. Neuromuscular blocking agents and all sedative agents also should be discontinued. As part of the examination, it is necessary to ensure that the core body temperature (i.e., 36.1° C [97° F] to 37.2° C [99° F]) and blood pressure are within the normal range. The presence of purposeful movements in response to external stimuli or spontaneous (not spinal related) movements, postur-

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Brain Injury and Disorders of Consciousness / 67 FIGURE 67-3. Algorithm for the evaluation for brain death in a comatose child. It is assumed that patients have had an extensive clinical and laboratory evaluation to determine the etiology of coma, including toxicology testing and, if indicated, evaluation for structural, infectious, and metabolic diseases. This algorithm suggests the process for confirmation of brain death in patients in whom this condition is suspected. CBF, cerebral blood flow; EEG, electroencephalogram. (Algorithm prepared by Dr. David Michelson and Dr. Stephen Ashwal, Loma Linda University School of Medicine.)

Evaluation for brain death

Is there is a known cause of irreversible brain injury? No Patient cannot be declared brain dead

Yes

Is patient free of potential confounding factors? A. Normothermic: with core temperature of 36.1º C (97º F) to 37.2º C (99º F) B. Normotensive: without volume depletion (pressors okay) C. Nontoxic: with no sedative or paralytic agents at or above therapeutic levels No Correct confounders and reexamine

Yes

Does patient meet clinical criteria for brain death? A. Coma: no purposeful responses to external stimuli, spontaneous movements. posturing, or seizures B. Absent brainstem reflexes: no pupillary, oculocephalic (doll's eye), corneal, vestibulo-ocular (caloric), or gag responses C. Apnea: no spontaneous respirations in presence of a Pco2 of at least 60 mm Hg No Continue care and reexamine

Yes

Patient can be declared brain dead after: A. Term infants >7 days to 2 months: Two exams and EEGs 48 hours apart B. Infants 2 months to 1 year: Two exams and EEGs 24 hours apart OR one exam and both confirmatory EEG and CBF studies C. Children >1 year: Two examinations 12 to 24 hours apart (EEG and CBF optional)

ing, or occurrence of seizures would obviate the diagnosis of brain death. A careful examination and documentation of the absence of brainstem reflexes is crucial and may be difficult to perform, particularly in an intubated neonate or young infant. Generally, parents should be allowed to observe the process, and nursing and respiratory therapy staff should be informed of the findings. As previously discussed (see Box 67-2), the duration of observation to confirm the diagnosis of brain death depends on the child’s age, as do recommendations for confirmatory testing (see Fig. 67-3). Children younger than age 2 months require 48 hours of observation, infants 2 months to 1 year require 24 hours, and children older than 1 year require 12 to 24 hours to confirm the diagnosis of brain death. There are no consensus criteria for term or preterm neonates, but recommendations based on available data suggest that 48 hours of observation (with EEGs) in term infants less than 7 days old and 72 hours of observation (with EEGs) in preterm infants are reasonable guidelines [Ashwal and Schneider, 1989]. Confirmatory studies, depending on the child’s age, are recommended as outlined in Box 67-2 and Figure 67-3. These tests are readily available in all hospitals and are helpful in establishing the diagnosis of brain death. Results of

these tests provide physicians with an opportunity to discuss with the child’s family the concept of brain death and the loss of electrocortical activity and cerebral blood flow. The tests also allow the physician to explain how the cause of injury ultimately caused brain death to develop.

Discussions with Family Members and Staff Most pediatric brain death determinations are done on patients who were normal children just hours or days before the injury, and even after extensive discussions with family members the concept of brain death remains unclear for many [Siminoff et al., 2003]. Grieving parents may not understand the futility of continued respirator support and may not accept that continuing care cannot benefit the child. Without being confrontational, physicians caring for the child should discuss the prognosis with parents. Frequently a conference with family members and members from the health-care team (e.g., physicians, nurses, therapists, social workers, clergy) is helpful in educating the family and assuring them that the health-care professionals are in agreement with the diagnosis and recommendations. Caregivers, particularly nursing and respiratory technicians, can be over-

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looked regarding their own need for emotional support and the grief they share with parents [House and Benitez, 1992; Stoyles, 1995].

Organ Donation The National Organ Transplant Act of 1987 requires that every hospital in the United States develop a protocol for requesting organ donation. After declaration of brain death, parents of a potential donor should be approached regarding donation [Williams et al., 2003]. Refusal from parents with whom donation has been explored should be respected. If the child is not a potential donor (sepsis, severe ischemia), it is important to discuss the reason why donation is not suitable so that parents do not believe donation was neglected. Strategies for retrieval of organs should be in place in the pediatric intensive care unit [Dutie et al., 1993; Tsai et al., 2000]. In many centers, the intensivist caring for the patient is the individual who may first declare the patient brain dead and initiate the discussion regarding organ donation, so it is important and prudent to have independent confirmation of brain death by a second physician. Brain dead child abuse victims represent a significant percentage of brain death diagnoses and as such require medicolegal evaluation before organ donation can proceed [Zenel and Goldstein, 2002]. Maintenance of brain dead patients requires careful management in anticipation of organ donation [Lutz-Dettinger et al., 2001]. Maintenance of temperature [Goldstein et al., 1993] and providing adequate fluids and supplemental oxygen to achieve satisfactory perfusion are necessary, as is consideration for hormone replacement [Rosendale et al., 2003] with corticosteroids [Arita et al., 1993], vasopressin [Pennefather et al., 1995], and thyroxine [Roels et al., 2000]. Diabetes insipidus, hypernatremia, hyperglycemia, and coagulopathies commonly occur in brain dead children and require special management if transplantation is being considered [Lutz-Dettinger et al., 2001]. By developing a careful balance between the care of a child who is brain dead and the desire to retrieve organs for donation, physicians can help grieving families and improve the opportunity to increase the number of organs that are being donated to save the lives of children with many different forms of severe, disabling, and life-threatening diseases. ACKNOWLEDGMENT This chapter is based on Chapter 62 in the third edition of this book, which was coauthored with Dr. Sanford Schneider.

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CHAPTER 68

Bacterial Infections of the Nervous System Martin G. Täuber and Urs B. Schaad

The brain is normally a sterile site that is protected from infection by specialized barriers, including the bony skull and the blood-brain barrier. Consequently, infections of the central nervous system (CNS) are comparatively rare. In the United States, the incidence of bacterial meningitis, the most frequent bacterial infection of the CNS, was 3 to 5 cases per 100,000 population in 1995 [Schuchat et al., 1997], in stark contrast to the incidence of sepsis, which was more than 200 cases per 100,000 in in 1995 [Martin et al., 2003]. Bacterial infections of the CNS are often devastating, leading to death or significant neurologic sequelae that can have a major negative impact on the development and wellbeing of affected children. The exquisite vulnerability of the brain to infection is related to deficient local host defenses that do not suppress the multiplication of pathogens, detrimental effects of cerebral blood flow alterations when the infection involves the cerebral vasculature, harmful effects of increased intracranial pressure caused by brain swelling and mass lesions, the destruction of brain tissue by the inflammatory process, and limited repair mechanisms of neuronal tissue. In many infections, such as bacterial meningitis, damage to the brain is a consequence not primarily of the invasion by the pathogen, but rather of the ensuing overwhelming inflammatory response. This chapter reviews pertinent information on the pathogenesis, clinical features, treatment, and prevention of bacterial infections of the nervous system.

ACUTE BACTERIAL MENINGITIS Bacterial meningitis is an inflammation of the leptomeninges triggered by bacteria present in the subarachnoid space. Children still die or suffer permanent neurologic sequelae as a result of meningitis [Klein et al., 1986]. Prevention or prompt diagnosis and aggressive management are the goals [Schaad, 1997]. Before the discovery of antibiotics, therapy consisted of withdrawal of cerebrospinal fluid through repeated lumbar puncture and intrathecal or intravenous administration of antimeningococcal antiserum raised in horses. More recent milestones include the introduction of new, potent bactericidal antibiotics, active vaccination, and anti-inflammatory therapy [Rockowitz and Tunkel, 1995].

Epidemiology Bacterial meningitis has a unique epidemiologic profile. The disease has a worldwide distribution, the typical host is a previously healthy patient, the typical symptoms usually develop rapidly, there are numerous and severe sequelae, and the disease is increasingly preventable [Schuchat et al.,

1997]. Bacterial meningitis occurs in people of all ages, but there are striking age-related differences in the predominant etiologic agents. Differences relate to immunologic maturation, social or behavioral influences, and the coexistence of other chronic or acute clinical conditions. Neonatal meningitis typically follows obstetric complications, and the predominant bacteria are group B streptococcus, Listeria monocytogenes, and gram-negative enteric bacteria. Older infants have substantial risk of meningitis caused by Haemophilus influenzae type b and Streptococcus pneumoniae, although where H. influenzae conjugate vaccines are in use, H. influenzae type b meningitis has been virtually eliminated. School-age children are at greatest risk of meningococcal disease, which occurs in outbreaks throughout the world and causes major epidemics in subSaharan Africa and parts of Asia. S. pneumoniae is the leading cause of bacterial meningitis in adults, and the emergence of antimicrobial-resistant pneumococci has complicated pediatric meningitis worldwide [Schuchert et al., 1997]. Bacterial meningitis occurs with increased frequency in certain population groups. Native Americans and aboriginal populations are at particular risk for H. influenzae type b disease [Coulehan et al., 1984; Ward et al., 1986]. Risk of group B streptococcal disease is substantially higher among African-Americans than other racial or ethnic groups in the United States [Zangwill et al., 1992]. Immunologic defenses against bacterial infection are reduced in certain chronic illnesses. Persons with sickle cell disease or other states of functional asplenia have increased susceptibility to encapsulated bacteria, especially the pneumococcus. Terminal complement deficiency predisposes these persons to meningococcal disease. Patients with human immunodeficiency virus infection are at substantially increased risk of invasive infection with S. pneumoniae and L. monocytogenes. Cell-mediated immunity is crucial for defense against listeriosis. Variation in the incidence of bacterial meningitis reported from different regions may relate to differences in diagnosis and reporting (surveillance artifact) but also may be caused by true environmental or population differences in risk of disease. The best example of geographic variation in meningitis is recurrent epidemic meningococcal disease in the meningitis belt of sub-Saharan Africa. Institutional settings, such as daycare centers, provide opportunities for enhanced transmission of respiratory pathogens, including H. influenzae type b, meningococcus, and pneumococcus. Transmission of antimicrobial-resistant infections among daycare center attendees is an emerging problem [Reichler et al., 1992]. Meningococcal meningitis clusters have been described in schools, on college campuses, and in refugee settings.

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Seasonal fluctuations in bacterial meningitis occur in some areas. Pneumococcal disease is most common in winter, when other respiratory infections predominate. The role of viral and bacterial respiratory cofactors in the risk of bacterial meningitis may explain some of the increased disease prevalence in winter months [Krasinski et al., 1987]. Most bacterial meningitis occurs as sporadic or isolated cases. After single cases of meningitis caused by H. influenzae type b and meningococcus, secondary cases can occur. Despite a high prevalence of pneumococcal colonization among young children, secondary cases of invasive pneumococcal disease are extremely rare.

Pathogenesis To establish bacterial meningitis, pathogens have to gain access to the subarachnoid space. Most cases of bacterial meningitis likely arise from bacteremia, which is caused by invasion of the bloodstream by the pathogen after colonization of the nasopharyngeal mucosa. Most meningeal pathogens are transmitted person to person by the respiratory route. In neonates, transmission usually occurs vertically during birth. Predisposing factors include maternal infection, premature rupture of maternal membranes, prolonged labor, obstetric trauma, and fetal distress. In the postnatal phase, premature or hospitalized infants are at increased risk for bacteremia and subsequent meningitis as a result of arterial and intravenous lines and mechanical ventilation. Adherence to the nasopharyngeal epithelium is mediated by specialized surface components (e.g., the polysaccharide capsule with specific epitopes and fimbriae or pili) of meningeal pathogens. These factors also are crucial for evasion of local host defense mechanisms and subsequent invasion of the bloodstream. The lack of specific mucosal antibodies correlates with an increased risk of invasive disease. Viral infection of the respiratory tract also may promote invasive disease. From the nasopharyngeal surface, encapsulated organisms cross the epithelial cell layer and invade the small subepithelial blood vessels. In the bloodstream, pathogens are protected from complement-mediated bactericidal mechanisms and neutrophil phagocytosis by their capsule. Impairment of the alternative complement pathway occurs in patients with sickle cell disease and in patients who have undergone splenectomy, and these patients are predisposed to the development of pneumococcal meningitis. Similarly, functional deficiencies of components involved in activation and function of complement-mediated defenses (i.e., mannose binding lectin, properdin, lack of terminal complement components) increase the susceptibility for invasive meningococcal infections [Van Deuren et al., 2000]. Neonates are at an increased risk of bacterial meningitis because of impaired nonspecific immunity. This impaired immunity includes defects in leukocyte chemotaxis, phagocytosis, bactericidal activity, and low levels of immunoglobulin M (IgM) antibodies and complement, which are not transferred across the placenta but are important in defense against gram-negative organisms [Mariscalco et al., 2002]. Studies in models of bacterial meningitis indicate that cells of the choroid plexus and cerebral capillaries possess receptors for meningeal pathogens and that the choroid plexus is the preferential site of primary invasion of the

cerebrospinal fluid space. For Escherichia coli, a complex interplay between endothelial factors and microbial genes orchestrates the crossing of the blood-brain barrier by bacteria [Hoffman et al., 2000]. Pneumococci are thought to enter the CNS by crossing the blood-brain barrier or the blood–cerebrospinal fluid barrier either by local tissue damage or by transcytosis through microvascular endothelial cells [Ring et al., 1998]. Not all bacterial infections of the CNS are the result of bacteremia. Nonhematogenous invasion of the cerebrospinal fluid by bacteria occurs in situations of compromised integrity of the barriers surrounding the brain (e.g., in otitis media, mastoiditis, sinusitis). Direct communication between the subarachnoid space and the skin or mucosal surfaces as a result of malformation or trauma gives rise to meningeal infection. Bacteria also can reach the cerebrospinal fluid as a complication of neurosurgery, spinal anesthesia, or ventriculostomy placement [Alleyne et al., 2000]. Infections of cerebrospinal fluid shunts are another cause of meningitis. Most cases occur shortly after implantation of the shunt and are attributed to intraoperative inoculation, but late shunt infections can occur several years after implantation [Vinchon et al., 2002]. Staphylococci, in particular coagulase-negative staphylococci, are the major pathogens in shunt infections [Filka et al., 1999]. These organisms have unique capabilities to colonize the surface of foreign bodies because of specialized surface proteins (e.g., clumping factor, fibronectin binding protein) that allow the organism to adhere to the catheters, in particular after they are coated with host-derived proteins, such as fibrin and fibronectin [Ziebuhr et al., 2000]. Adhering organisms rapidly develop into a biofilm, characterized by bacteria embedded in an extracellular matrix. Elimination of bacterial biofilms from the surface of foreign bodies by antibiotics or host defenses is notoriously difficult [Ziebuhr et al., 2000]. Colonization of cerebrospinal fluid shunts with coagulase-negative staphylococci leads to clinically apparent meningitis or ventriculitis in only approximately 30% [Odio et al., 1984; Vinchon et al., 2002]. Pathogens reaching the cerebrospinal fluid are likely to survive because of a paucity of resident macrophages and deficient opsonization caused by low concentrations of capsule-specific immunoglobulins and complement in the cerebrospinal fluid. Lack of opsonization greatly reduces the effectiveness of incoming granulocytes and allows largely unrestricted multiplication of the meningeal pathogens. Bacterial multiplication is associated with the release of bacterial products (fragments of cell wall, lipopolysaccharide) that trigger the inflammatory response in the subarachnoid space by inducing the production and release of inflammatory cytokines and chemokines. Cytokines, including tumor necrosis factor-α, interleukin-1, and interleukin-6; chemokines, such as interleukin-8, growth-related protein-α, and monocyte chemotactic protein-1; and lipid inflammatory mediators, such as platelet activation factor, upregulate adhesion molecules on brain vascular endothelial cells and promote the recruitment of granulocytes into the cerebrospinal fluid. Matrix metalloproteases contribute to the inflammatory process by mediating breakdown of blood-brain barrier and activating cytokines [Kieseier et al., 1999]. This granulocytic inflammation is primarily responsible for the complex pathophysiologic CNS alterations and clinical manifestations of bacterial meningitis [Meli et al., 2002].

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Diagnosis

TWO MODES OF PRESENTATION

Prompt diagnosis is crucial for a life-threatening illness such as bacterial meningitis. Routine early diagnosis requires educated suspicion of meningitis and immediate performance of lumbar puncture and adequate tests when the cerebrospinal fluid has been obtained [Schaad, 1995].

The first pattern develops over several days with fever and nonspecific manifestations suggesting viral infection without or with localization (e.g., upper respiratory or gastrointestinal tract). In these patients, it is difficult to pinpoint the exact onset of meningitis. The second pattern is acute, sometimes fulminant, and the symptoms and signs of sepsis (e.g., cardiovascular instability, cutaneous manifestations such as an erythematous, maculopapular, or petechial rash) and meningitis evolve rapidly over a few hours.

Clinical Features The sudden onset of a stiff neck with fever in a child who appears ill usually indicates the presence of meningitis (Table 68-1). In these cases, a lumbar puncture is a crucial part of the initial evaluation.

MENINGISMUS Meningismus reflects tense neck and back muscles as a reflex to avoid painful extension of inflamed meninges. Clinical findings of meningeal irritation include Kernig’s sign (passive extension of the knee from the flexed thigh position elicits pain in the back), Brudzinski’s sign (passive flexion of the neck elicits spontaneous flexion of the lower extremities), tripod sign (while sitting the patient holds the back erect by placing both extended arms behind the buttock), and knee-kissing sign (the patient is unable to kiss his or her own knees). Nuchal rigidity is absent throughout the course of meningitis in only 1% to 2% of infants and children; generally the younger the patient, the less prominent nuchal rigidity [Geiseler and Nelson, 1982]. Nuchal rigidity is not always the result of meningeal irritation secondary to infection. The patient’s history and physical examination usually lead to the consideration of other possibilities, such as other sites of infection (e.g., cervical adenitis, tonsillopharyngitis, retropharyngeal abscess, and cervical spine osteomyelitis), vascular abnormalities (e.g., subarachnoid hemorrhage), neoplasms (e.g., brain tumor and meningeal leukemia), or bony and muscular disorders (e.g., fracture, torticollis, and myositis).

NEUROLOGIC FINDINGS Seizures occur before hospital admission or within the first 2 days of hospitalization in 20% to 30% of pediatric patients with bacterial meningitis [Feigin et al., 1992]. Generalized seizures usually are not a predictor of poor outcome. In contrast, focal neurologic signs, such as paresis, cranial nerve palsy, and focal seizure activity, often precede more adverse outcomes of irreversible brain damage. Severely depressed consciousness at the time of hospital admission usually signals a poor prognosis because of the likelihood of extensive encephalitic involvement or massively increased intracranial pressure in both of these patients [Tunkel and Scheld, 1995].

ARTHRITIS AND OTHER SYSTEMIC MANIFESTATIONS Arthritis can precede or follow H. influenzae and Neisseria meningitidis meningitis and confuses the neurologic examination by producing the superficial appearance of a monoparesis. Knees and elbows are common sites for arthritis. Of patients with H. influenzae type b septic arthritis, approximately 30% have concurrent meningitis [Rotbart and Glode, 1985]. Periorbital cellulitis occurs in H. influenzae meningitis.

DIFFERENTIAL DIAGNOSIS INITIAL PRESENTATION Fever (94%), vomiting (82%), and nuchal rigidity (77%) are the most common presenting symptoms of meningitis in children 1 to 4 years old. Many children also experience lethargy, irritability, anorexia, and photophobia [Ashwal et al., 1993]. Seizures, bulging fontanel, and coma occur less commonly and usually occur later in the course of the illness. Older patients report headache and neck pain.

The differential diagnosis of bacterial meningitis includes aseptic meningitis, encephalitis, brain abscess, febrile seizure, head trauma, intracranial hemorrhage, and neoplastic meningitis. In addition, unusual infectious agents, such as fungus, rickettsia, or tuberculosis, must be considered. A fever with a simple seizure is unlikely to be bacterial meningitis [Green et al., 1993].

TABLE 68-1

NEONATAL MENINGITIS

Signs and Symptoms of Bacterial Meningitis

The traditional clinical signs of meningitis are usually lacking in neonates. Nuchal rigidity rarely occurs. Fever and a full fontanel may be absent. An associated sepsis is common. Bacterial meningitis should be considered at any age (so-called early and late onset) in any newborn who fails to thrive and has irritability, apnea, seizures, a tendency to opisthotonos, poor feeding, emesis, hypothermia or hyperthermia, hypotonia or hypertonia, a gray appearance, jaundice, or other evidence of sepsis. Apnea may be the only sign of meningitis in a neonate [Heath et al., 2003; Schaad, 1992].

Fever, acute course Vomiting, anorexia Nuchal rigidity Meningismus Kernig’s sign Brudzinski’s sign Tripod and knee-kissing sign Depression of consciousness, coma Irritability, photophobia, headache Seizures, focal neurologic deficits

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SHUNT INFECTIONS Infections of CNS shunt occur in approximately 5% to 10% of patients, usually within 1 to 2 months of surgical insertion [McGirt et al., 2003; Ronan et al., 1995]. Most of these infections are due to coagulase-negative Staphylococcus or Staphylococcus aureus; however, a variety of other organisms, including gram-negative bacteria and other skin flora, can be causative. Diagnosis of CNS shunt infection versus CNS shunt malfunction often represents a dilemma in children who present with constitutional signs and symptoms [McClinton et al., 2001]. Clinical manifestations of CNS shunt infection usually include low-grade fever, vomiting, irritability or lethargy, and other signs of increased intracranial pressure. The onset is often insidious but can be more acute, particularly if shunt malfunction also is present. Neck stiffness is uncommon. Shunt infection should be suspected in any child with an indwelling CNS drainage system and fever. The symptoms and signs of shunt infection are referable to the age of the patient, the infecting microorganisms, the degree of surgical trauma, and other underlying conditions of the host. Ventriculoperitoneal shunt infections may present with signs of acute peritonitis. Symptoms associated with bacteremia can range from general malaise to shock. A percutaneous aspiration of cerebrospinal fluid from the shunt reservoir should be performed. Treatment of shunt infections needs to be tailored to meet the specific susceptibilities of the infecting microorganism and to obtain high concentrations of antibiotics within the cerebrospinal fluid and shunt system. This goal most commonly is achieved by a combination of systemic and intraventricular antibiotics.

MENINGITIS AFTER COCHLEAR IMPLANTS Cochlear implant is the standard treatment for patients with severe-to-profound hearing loss in which well-fit hearing aids fail to permit effective oral communication. The implant is a neural stimulator whose electrode array is placed surgically in the lumen of the cochlea, near the auditory nerve. An external microphone picks up speech signals, and the signal processor transforms these signals into digital impulses that a radiofrequency carrier transmits percutaneously into the internal receiver-stimulator and electrode array. The auditory cortex is stimulated by the implant, permitting the perception of the digitally processed information as speech [Gates and Miyamoto, 2003]. Complications from cochlear implantation are unusual. Reports of postoperative meningitis have called attention to a previously unrecognized risk [Arnold et al, 2002; Reefhuis et al., 2003]. Most cases of meningitis occur in children with a typical presentation. Available information indicates that the mode for infection is a time-limited or, rarely, persistent cerebrospinal fluid leak into the middle ear. Bacteria from the middle ear—usually causing otitis media—may enter the meninges. The most common offending pathogens are S. pneumoniae and H. influenzae. Most meningitis cases were associated with a two-component electrode that has been withdrawn from the market. Prevention by active immunization against S. pneumoniae and H. influenzae type b, meticulous sealing of the cochleostomy site, and urgent treatment of otitis media are recom-

mended. The role of perioperative antimicrobial prophylaxis needs to be determined. On the first symptoms of meningitis, prompt antibiotic treatment in accordance with the guidelines described subsequently must be started, and high-resolution computed tomography (CT) and magnetic resonance imaging (MRI) must be performed. In most cases of otogenic meningitis in a cochlear implant patient, a surgical revision of the middle ear and mastoid is mandatory.

Lumbar Puncture The diagnosis of bacterial meningitis is based on examination of cerebrospinal fluid [Feigin et al., 1992]. A lumbar puncture should be performed whenever the diagnosis of meningitis is suspected on the basis of clinical signs. Rarely, other sites may be used to obtain cerebrospinal fluid, including ventricles or shunts installed to divert cerebrospinal fluid. Minimizing sequelae of bacterial meningitis depends on the prompt initiation of effective antibiotic therapy. Lumbar puncture is indicated whenever there is even minimal clinical evidence for meningitis. Such an approach in the ambulatory clinical setting results in the diagnosis of approximately 1 case of aseptic or bacterial meningitis for every 10 lumbar punctures [Feigin et al., 1992]. Lumbar puncture is a safe procedure for most patients. Minor discomfort may occur, but serious consequences are rare. Headache 1 to 6 hours after lumbar puncture is a troublesome but benign complication. When present, the headache is frontal and is exaggerated by movement from a lying to a sitting or standing position. Headache after lumbar puncture seems to be caused by continued leak of cerebrospinal fluid from the site of the lumbar puncture with resulting low cerebrospinal fluid pressure and traction on pain-sensitive structures. The problem can be mitigated by removal of a minimal amount of fluid and use of a smallbore needle [Lynch et al., 1992]. Pain in the low back or legs occurs occasionally after lumbar puncture; this pain is of uncertain etiology and resolves spontaneously in several days. Herniation of the brainstem and cerebellar tonsils into the foramen magnum is extremely rare in children [Marton and Gean, 1986]. A risk of hernation is clearly related to substantially increased intracranial pressure [Richards and Towu-Aghantse, 1986]. The risk of producing meningitis by performing a lumbar puncture in a child with septicemia is insignificant and is not a contraindication to the test [Shapiro et al., 1986]. Repeated lumbar puncture is indicated only when delayed cerebrospinal fluid sterilization or relapse or recurrence of meningitis is clinically suspected. Lumbar puncture should not be repeated, unless the expected findings would make a difference in management. Most patients with bacterial meningitis require just one initial diagnostic lumbar puncture.

LABORATORY TESTS As mentioned before, the initial diagnosis of meningitis is based on examination of cerebrospinal fluid. Bacterial infection is suggested by increased opening and closing pressure; a cloudy (i.e., not clear) cerebrospinal fluid; or a cerebro-

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TABLE 68-2 Cerebrospinal Fluid in Neurologic Infections DISEASE

PRESSURE

ASPECT

TOTAL WBC

PNC (%)

MNC (%)

Bacterial meningitis Aseptic meningitis Encephalitis Encephalopathy Brain abscess

↑↑ Normal/(↑) ↑ ↑

Cloudy Clear Clear Clear

>1000 10–1000 10–500 <10

+++ + (+) +++ (+) ++ − − Not indicated

PROTEIN

GLUCOSE

GRAM STAIN/ RAPID TEST

↑↑ Normal/(↑) Normal/(↑) Normal

↓↓ Normal Normal Normal

Positive Negative Negative Negative

MNC, mononuclear cells; PNC, polymorphonuclear cells; WBC, white blood cells; ↑, mildly elevated to normal; (+), few to none.

spinal fluid pleocytosis with polymorphonuclear predominance, increased protein concentration, or decreased glucose concentration. Details and normal values have been described previously (Table 68-2) [Ahmed et al, 1996; Bonadio, 1992]. Confirmation of the diagnosis requires the detection in the cerebrospinal fluid of a specific bacterial pathogen by microscopy or a positive culture, polymerase chain reaction, or rapid antigen-detection test of cerebrospinal fluid. Smears of cerebrospinal fluid should be examinated by Gram stain (acid-fast stain if tuberculosis is suspected). In experienced hands, Gram-stained smears of the cerebrospinal fluid sediment reveals bacteria in more than 90% of cases of pediatric bacterial meningitis [Stahelin-Massik et al., 1994]. The cerebrospinal fluid should be cultured on a blood agar plate, on a chocolate agar plate (or on Fildes or Leventhal medium), and in broth. Special cultures for mycobacteria, fungi, or other microorganisms should be undertaken if clinically indicated. In an area of increasing antimicrobial resistance, adequate in vitro susceptibility testing must be routine for any cultured neonatal pathogen. Various antigendetection tests have become available (e.g., countercurrent immunoelectrophoresis, latex particle agglutination, enzymelinked immunosorbent assay) and may be helpful in establishing an etiologic diagnosis rapidly. Polymerase chain reaction and other sequence-based microbial detection methods are being used increasingly in the clinical microbiology laboratory [Fredricks and Relman, 1999]. Polymerase chain reaction–based assays detect microbial nucleic acid in clinical samples including cerebrospinal fluid and do not require growth of the organism. Polymerase chain reaction–based assays can be fast, sensitive, and specific but also may be associated with technical problems, such as false-positive reactions secondary to sample contamination, and false-negative reactions secondary to the presence of polymerase chain reaction inhibitors in the sample. Many other nonspecific parameters have been studied in the cerebrospinal fluid to establish or exclude a bacterial etiology rapidly, including various indices of inflammation (e.g., cytokines, C-reactive protein, and lactate) and measurement of various enzyme activities [Gray et al., 1986; Lutsar et al., 1994]. Further refinements are needed to confirm the usefulness of these tests in unselected populations and different centers.

CONTRAINDICATIONS Four contraindications to lumbar punctures are as follows: (1) obvious signs of increased intracranial pressure iden-

tified by either clinical or neuroimaging examination; (2) clinically relevant cardiorespiratory compromise, especially in neonatal or older extremely sick patients; (3) history or signs of a bleeding disorder; and (4) signs of infection at puncture sites (e.g., pyoderma, cellulitis, erysipelas). In such cases, lumbar punctures should be withheld only until the condition has been corrected or excluded as a possibility. If lumbar puncture is withheld in a patient with suspected meningitis, appropriate age-specific antimicrobial and antiinflammatory treatment for meningitis should be started without delay (see later). A short period of antibiotic and corticosteroid therapy before lumbar puncture would not cause significant alteration in cerebrospinal fluid findings.

Other Tests Most pediatric patients with bacterial meningitis are initially bacteremic as might be expected based on the hematogeneous pathogenesis of the disease. Blood cultures taken at hospital admission are valuable and are positive in 80% to 90% of cases of bacterial meningitis [Feigin et al., 1992]. Cultured bacteria from skin or mucosal surfaces, including throat and nose, are neither sensitive (organisms causing the meningitis may not be present) nor specific (other organisms are often present) and are not helpful. The culture of appropriate sites of primary or concomitant infected foci, such as cellulitis (e.g., periorbital and buccal), middle ear effusions, sinusitis, and mastoiditis, and urine in young infants may yield the meningitis-causing pathogen. Petechiae often represent microemboli, with bacteria (e.g., meningococci) present in the lesion. Gram-stained smears made from petechiae may provide immediate clues as to the identity of the invading microorganisms. Tests of inflammatory responses, such as a total and differential peripheral white blood cell count, erythrocyte sedimentation rates, and measurement of C-reactive protein concentration, may be helpful diagnostically and during the treatment of invasive bacterial disease. Such tests are not useful, however, in making or excluding a diagnosis of bacterial meningitis.

Brain Imaging Neuroimaging studies, such as CT, MRI, and cranial sonography (in young infants with access through open fontanel), should be used in patients with signs of increased intracranial pressure (e.g., depressed consciousness, sluggishly reactive or dilated pupils, ophthalmoplegia, retinal changes, abnormal respiratory patterns, and cardiovascular

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BRAIN EDEMA

FIGURE 68-1. Postcontrast coronal magnetic resonance image of a 6-month-old infant with Streptococcus pneumoniae meningitis. Meningeal enhancement is visible (arrowheads). (Courtesy of Blaine Hart, MD.)

instability). Increased intracranial pressure usually is caused by fulminant cerebral edema or other intracranial complications, such as subdural collection, thrombosis, infarction, brain abscess, and hydrocephalus [Ashwal, 1995; Tunkel and Sheld, 1995]. MRI has improved resolution compared with CT, provides additional insights into the pathogenesis of neurologic complications, and eventually may replace CT in most situations [Smith and Caldemeyer, 1999]. Cortical enhancement may be identified and is presumed to indicate cerebritis. Repeat imaging is useful in following the evolution of abnormalities [Bodino et al., 1982] and in determining the need for subsequent intervention. Abnormalities on imaging are associated with an unfavorable outcome [Packer et al., 1982]. Contrast MRI, although not usually considered a diagnostic test for meningitis, can show meningeal enhancement (Fig. 68-1) [Kioumehr et al., 1995; Runge et al., 1995].

Brain edema during meningitis has vasogenic, cytotoxic, and interstitial components. Vasogenic cerebral edema is primarily a consequence of increased blood-brain barrier permeability (see earlier). Cytotoxic edema results from an increase in intracellular water after alterations of the cell membrane and loss of cellular homeostasis with influx of sodium and calcium into the cell. Cytotoxic mechanisms include ischemia and the effect of excitatory amino acids [Derugin et al., 2000]. Interstitial edema occurs as a result of an increase in cerebrospinal fluid volume, through either increased cerebrospinal fluid production (increased blood flow in the choroid plexus) or decreased resorption secondary to increased cerebrospinal fluid outflow resistance across the arachnoid villi system of the sagittal sinus [Scheld et al., 1980]. The major dangers of extensive brain edema during meningitis are herniation of brain tissue and compression of the brainstem secondary to increased intracranial pressure, which can cause complete cessation of cerebral circulation (Table 68-3). Brain edema contributes substantially to the acute fatal outcome of bacterial meningitis [Winkler et al., 2002].

HYPONATREMIA, DEHYDRATION, AND INAPPROPRIATE SECRETION OF ANTIDIURETIC HORMONE Patients with acute meningitis often present with hypovolemia secondary to dehydration, and some develop hyponatremia. Based on clinical signs, it is impossible to distinguish between hyponatremia secondary to dehydration and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) in patients with meningitis. It also is unclear how frequently the hyponatremia is related to SIADH with secondary fluid retention [Moller et al., 2001]. SIADH results in hypotonicity of extracellular fluid, which in meningitis may contribute to cytotoxic edema [Kaplan and Feigin, 1978]. The overall risk of worsened clinical outcome owing to SIADH seems small, however, and does not justify routine fluid restrictions in patients with meningitis and hyponatremia because fluid restriction may have harmful effects on systemic blood pressure and cerebral perfusion. In cases of severe or persistent hyponatremia, SIADH should be excluded with appropriate laboratory tests.

Complications

INTRACRANIAL HYPERTENSION

Pathophysiologic Changes

Increased intracranial pressure is present early in most patients with bacterial meningitis. In infants with open fon-

BLOOD-BRAIN BARRIER DISRUPTION The permeability of the blood-brain barrier increases in meningitis as a result of disrupted intercellular tight junctions and increased transendothelial pinocytosis [Quagliarello et al., 1986]. Inflammatory components, including granulocytes and matrix metalloproteinases, contribute to the increased permeability of the blood-brain barrier [Leppert et al., 2001]. This increased permeability results in increased extravasation of serum components and contributes to vasogenic brain edema but also allows for approximately fivefold higher concentrations of antibiotics in the cerebrospinal fluid during therapy compared with the uninfected state.

TABLE 68-3 Common Neurologic Sequelae after Bacterial Meningitis DEFICIT Hearing loss Parenchymal damage Cerebral palsy Learning disabilities Seizure disorders Cortical blindness Cerebral herniation Hydrocephalus

APPROXIMATE FREQUENCY (%) 15–30 5–30 5–10 5–20 <5 <5 3–20 2–3

Täuber and Schaad / Bacterial Infections of the Nervous System

tanels and symptoms compatible with meningitis, the full fontanel may lead to the correct diagnosis. Early in the course of meningitis, cerebral hyperemia may be the most important mechanism of intracranial pressure elevation. In more advanced stages, brain edema is probably the most important factor contributing to increased intracranial pressure, but obstructive hydrocephalus, cerebritis, cerebral infarction, cerebral venous thrombosis, status epilepticus, and SIADH also contribute to increases in intracranial pressure [Brown and Feigin, 1994]. Markedly elevated intracranial pressure during meningitis contributes to brain injury by compromising cerebral blood flow and leading to cerebral herniation in the most severe cases. The symptoms of massively increased intracranial pressure in meningitis are seizures and coma. In very advanced disease, signs of critical impairment of cerebral blood flow or impending herniation are observed, such as unresponsive pupils, decorticate or decerebrate posturing, abnormal respiratory patterns, bradycardia, elevated blood pressure, and irregular vital signs.

CEREBRAL BLOOD FLOW CHANGES In the early phase of bacterial meningitis, an increase in cerebral blood flow is observed, which seems to be mediated by nitric oxide and oxidative radicals resulting from the inflammation in the cerebrospinal fluid space. As the disease progresses, cerebral blood flow reductions are observed globally and focally [Pfister et al., 1992]. Global cerebral blood flow reduction is the result of reduced cerebral perfusion pressure because of increased intracranial pressure, systemic hypotension, or both, in the setting of impaired cerebral blood flow autoregulation. Focal ischemia is the result of vascular involvement of cerebral arteries and veins by the subarachnoid space inflammation [Pfister et al., 1992]. Reactive oxygen radicals and endothelins, a family of vasoactive peptides released into the cerebrospinal fluid during bacterial meningitis, contribute to reductions of cerebral blood flow [Koedel et al., 1997; Pfister et al., 2000]. Several clinical studies have found an association between severe cerebral blood flow reduction and adverse outcome in children and adults with meningitis, making ischemia an important mediator of brain damage in meningitis [Ashwal et al., 1992; Förderreuther et al., 1992; Odio et al., 1991].

Seizures Seizures complicate 20% to 30% of cases of childhood bacterial meningitis. Patients with severe illness are more likely to have seizures. They occur most frequently 2 to 3 days into the illness and cease 1 to 3 days later. Seizures may be focal or generalized, and the electroencephalogram may be normal or may show generalized or focal epileptiform abnormalities, focal slowing, or only background slowing. The functional and structural alterations of the brain resulting from the meningitic process that may induce seizures include vasculitis and infarction, fever, electrolyte imbalances, and metabolic changes. Chronic seizures after recovery from meningitis are approximately threefold more common in patients than in age-matched control children [Bedford et al., 2001].

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Deafness and Cranial Nerve Damage Deafness is the most frequent neurologic sequela of bacterial meningitis. Of patients with bacterial meningitis, 5% to 30% develop clinical deafness (see Table 68-3), and the risk is highest when meningitis is caused by S. pneumoniae. Low cerebrospinal fluid glucose concentrations are another risk factor for hearing loss [Eisenhut et al., 2003]. Hearing impairment after meningitis can improve for several months, but many children have severe, permanent, and bilateral hearing loss [Wellman et al., 2003]. Typically, sensorineural hearing loss in both ears is found; rarely a conductive hearing loss associated with a middle ear infection may be present. Hearing should be assessed in children with bacterial meningitis before discharge. Audiometry is an appropriate test in older children. In young infants, brainstem auditoryevoked responses or transient otoacoustic emissions can be used to detect hearing loss early [Cohen et al., 1988; Francois et al., 1997]. When hearing loss occurs, early intervention by a team that is knowledgeable in the management of this problem in infants and children should be encouraged. Cochlear implants are a consideration in the most severe cases. Experimental studies suggest that bacteria reach the cochlea primarily via the cochlear aqueduct [Bhatt et al., 1993]. The deafness is caused by infection and inflammation in the cochlea [Klein et al., 2003]. Nitric oxide, other inflammatory mediators, and bacterial products, specifically the pneumococcal toxin pneumolysin, contribute to the loss of hairy cells in the cochlea [Amaee et al., 1995]. Other cranial nerve abnormalities develop in bacterial meningitis because of the involvement of the cranial nerves by the inflammatory process in the subarachnoid space. Increased intracranial pressure also can cause cranial nerve dysfunction by pressure or stretching. Cranial nerves VI and III are involved relatively frequently. Ocular palsies are usually reversible.

Neuronal Damage The neurologic sequelae after meningitis, in addition to hearing loss (see previously), include focal sensorimotor deficits, mental retardation, seizure disorders, and cortical blindness (see Table 68-3). Detailed studies of the neurologic outcome after bacterial meningitis have led to an appreciation of the significant long-term functional impairment resulting from the disease [Grimwood et al., 1995; Bedford et al., 2001; Oostenbrink et al., 2002]. In a cohort of 5-year-old children who had survived bacterial meningitis during their first year of life, there was a 10-fold increase in the risk of moderate-to-severe disabilities, with 7.5% demonstrating learning difficulties; 8.1%, neuromotor disabilities; 7.3%, seizure disorders; 25.8%, hearing problems; and 11.9%, behavioral problems [Bedford et al., 2001]. Neurologic sequelae of childhood meningitis can persist at least into young adulthood, impairing learning during the entire time that children go to school [Grimwood et al., 2000]. S. pneumoniae consistently was associated with higher rates of disabilities than infection with H. influenzae or N. meningitidis [Grimwood et al., 1996]. Meningitis causes brain damage of cortical and subcortical structures (Fig. 68-2). For much of the brain damage,

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FIGURE 68-2. Axial T2-weighted MRI of 13-year-old child with Neisseria meningitidis meningitis complicated by multiple areas of cerebritis (arrowheads and other locations). (Courtesy of Blaine Hart, MD.)

tant for learning and memory acquisition and represents one of the few areas of the brain where neurogenesis is ongoing throughout life. Within this structure, pathology studies in humans dying from meningitis and animal models of meningitis consistently have documented damage to neurons [Gianinazzi et al., 2003; Nau et al., 1999]. Two forms of injury seem to affect the dentate gyrus neurons [Bifrare et al., 2003]. One is mediated by activation of caspase-3 and corresponds to classic apoptosis. This form of injury preferentially affects immature, postmitotic neurons, is associated with learning deficits in experimental animals surviving meningitis, and may represent an anatomic substrate for cognitive impairment and learning disabilities after meningitis [Bifrare et al., 2003; Leib et al., 2003]. The other form of dentate gyrus injury exhibits no obvious selectivity for a subset of neuronal cells and is associated with translocation of apoptosis-inducing factor. At least in the infant rat model, S. pneumoniae primarily induces apoptotic damage in immature neurons, whereas group B streptococcal meningitis leads to apoptosis-inducing factor–associated meningitis [Bifrare et al., 2003]. For both forms of dentate gyrus injury, the exact molecular triggers are unknown, but ischemia does not seem to be important. Potential mediators include pneumococcal products (pneumolysin and hydrogen peroxide), inflammatory mediators (e.g., tumor necrosis factor-α), matrix metalloproteinases, excitatory amino acids, reactive oxygen species, and others [Meli et al., 2002].

Hydrocephalus Meningitis leads to disturbances of cerebrospinal fluid homeostasis with increased cerebrospinal fluid production and reduced cerebrospinal fluid absorption across the sagittal sinus–arachnoid villi system [Scheld et al., 1980]. In the acute phase, these disturbances can lead to ventriculomegaly associated with intracranial hypertension. This form of ventriculomegaly is frequently transient. Chronic hydrocephalus occurs as a long-term sequela of bacterial meningitis in infants and children (see Table 68-3). Its pathogenesis is either obstructive secondary to inflammatory changes of cerebrospinal fluid drainage pathways or ex vacuo secondary to loss of brain parenchyma. Chronic internal shunting with internal drainage is necessary in patients with persistent obstructive hydrocephalus.

FIGURE 68-3. Computed tomography scan of 16-day-old neonate with group B streptococcal meningitis. There is massive infarction of anterior circulation. (Courtesy of Blaine Hart, MD.)

particularly in the cortex, ischemia represents an important mechanism of injury (Fig. 68-3) [Pfister et al., 2000]. In keeping with this notion, inhibition of excitatory amino acids and preservation of cerebral blood flow through inhibition of reactive oxygen radicals or endothelins are protective in experimental meningitis [Meli et al., 2002]. Matrix metalloproteinases, in addition to their effect on the bloodbrain barrier and on cytokine release, also may contribute directly to ischemic changes in the brain. A structure frequently damaged during meningitis is the dentate gyrus of the hippocampus. This structure is impor-

Septic Shock and Disseminated Intravascular Coagulation Bacterial meningitis can be complicated by sepsis and septic shock independent of the infecting organism. All patients with bacterial meningitis need to undergo close cardiovascular monitoring until they are clinically stabilized with antimicrobial and supportive therapy. The association of sepsis and extensive disseminated intravascular coagulation suggests infection caused by N. meningitidis [Yung and McDonald, 2003]. A similarly fulminant and devastating course can be seen with S. pneumoniae in patients without a functional spleen. These patients present with rapidly progressive signs of severe illness, rigors, severe muscular pain, and skin lesions that progress from an early maculopapular rash to petechiae to enlarging purpuric lesions [Yung and McDonald, 2003]. The organism sometimes can be visual-

Täuber and Schaad / Bacterial Infections of the Nervous System

ized on Gram stain of scrapings from purpuric lesions. Signs and symptoms of meningitis often are not prominent in patients with disseminated meningococcal sepsis. Laboratory abnormalities include thrombocytopenia, hypofibrinogenemia, and massively elevated D-dimers. Overt adrenal insufficiency seems to be relatively rare in children with meningococcal disease [Riordan et al., 1999]. The most fulminant form of sepsis and disseminated intravascular coagulation is the Waterhouse-Friderichsen syndrome, which leads to sudden cardiovascular collapse associated with adrenal hemorrhage.

Extra-axial Fluid Collections The subdural space is a potential intracranial space situated between the arachnoid and dura. Fluid can collect in the subdural space and in the subarachnoid space. The collection in the subarachnoid space may represent loculated cerebrospinal fluid, widening of the subarachnoid space in response to inflammation, or loss of brain parenchyma. Because imaging often cannot distinguish between a fluid collection and a widened subarachnoid space, the fluid collection as seen on imaging is referred to as an extra-axial fluid collection. Extra-axial fluid collections are found in 50% of children with bacterial meningitis who have cranial CT performed [Syrogiannopoulos et al., 1986]. Extra-axial fluid collections occur more commonly in bacterial meningitis during the first year of life and often are recognized during the first week of illness. The extra-axial fluid is preferentially situated over the convexities, may accumulate bilaterally, is serosanguineous with granulocytes and high protein concentrations, and is usually sterile (Fig. 68-4) [Snedeker et al., 1990]. Extra-axial fluid collections are detected often on imaging studies performed because of persistent fever, clinical signs of meningitis, seizures, or focal neurologic deficits. They may be the cause of persistent increase in intracranial pressure or focal neurologic deficits. More commonly, fluid collections represent a

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coincidental finding, and their causative role for the symptoms prompting the imaging studies is doubtful.

Pathology Subarachnoid space inflammation appears as a grayish yellow to green exudate covering the base and convexities of the brain. Histologic examination indicates that the exudate in acute bacterial meningitis consists predominantly of granulocytes; there is a mixture of lymphocytes, macrophages, and granulocytes in subacute to chronic forms of meningitis. Cerebral arteries and veins have focal infiltration of the vessel walls by the inflammatory cells. The inflammation of the vessel wall may be associated with thrombosis and vascular occlusion [Cairns and Russell, 1946]. In fatal cases of neonatal meningitis, inflammatory vasculitis is uniformly present, possibly indicating that the cerebral vasculature of the neonate is particularly susceptible to inflammatory damage [Berman and Banker, 1966]. Some of the severe structural damage in the neonatal brain after meningitis may be related to this susceptibility of the vasculature to inflammatory damage. Damage to the brain parenchyma is manifested by signs of brain edema and frequently cerebral herniation (see later) and by areas of cerebral infarction resulting from ischemia [Arseni and Nereantiu, 1972; Berman and Banker, 1966]. Throughout the brain, there is loss of neurons, usually in a focal pattern, most extensively in patients who survived the acute meningitis for several days before succumbing to the disease. Neuronal loss is associated with a marked reaction of astrocytes and microglia. In the dentate gyrus of the hippocampus, evidence of cell death of neurons seems common in meningitis based on limited pathologic studies in humans and extensive work in animal models [Nau et al., 1999]. Apoptotic neuronal cell death can be detected primarily in the subgranular zone of the dentate gyrus and is characterized morphologically by condensed, fragmented nuclei. The apoptotic nature of this form of cell death has been confirmed by the detection of fragmented DNA (i.e., TUNEL-stain) and activation of caspase-3 [Gianinazzi et al., 2003]. The second form of hippocampal neuronal damage is characterized by the appearance of uniformly shrunken, pyknotic nuclei forming clusters of damaged cells predominantly in the lower blade of the dentate gyrus [Leib et al., 1996]. This form of injury has been characterized primarily in animal models, and it is not clear to what extent it is found in humans.

Treatment Antibiotics

FIGURE 68-4. Coronal T2-weighted MRI of 6-month-old infant with Streptococcus pneumoniae meningitis. Massive extra-axial fluid collections are visible (arrowheads). (Courtesy of Blaine Hart, MD.)

Effective eradication of the infecting pathogen requires that antibiotics display bactericidal activity in the cerebrospinal fluid. Experimental studies have documented that cerebrospinal fluid concentrations that exceed the in vitro minimal inhibitory concentration severalfold (>10-fold for most antibiotics) are required to achieve maximal bacterial killing rates. Cerebrospinal fluid concentrations of antibiotics even with inflamed meninges are only a fraction of simultaneous serum concentration (usually between 5% and 25%), and antibiotics must be dosed higher for the treatment of meningitis than for most other infections [Täuber and Sande, 1990].

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Empiric therapy should be instituted rapidly in all children with suspected bacterial meningitis. The progressive pathophysiologic alterations during meningitis, which rapidly lead to brain damage and death in most untreated patients, strongly suggest that any delay in antibiotic treatment may be harmful and should be avoided [Aronin et al., 1998]. In practice, the appropriate sequence of obtaining cerebrospinal fluid and blood for cultures and other tests, instituting antibiotics, and obtaining imaging studies to exclude mass lesions and other pathologies needs to be adapted to the individual patient. The sicker the patient and the more rapidly progressive the disease, the more urgent is the start of antibiotic therapy. Antibiotic therapy should not be delayed by more than approximately 15 minutes in critically ill patients for an attempt to obtain cerebrospinal fluid or blood, despite the reduced yield of bacterial cultures if the samples are obtained after initiation of antibiotics. A CT scan is required before the lumbar puncture in all patients in whom there is suspicion of important CNS alterations, particularly if a mass lesion is suspected, and the patient has signs of increased intracranial pressure. In adults, criteria have been established to identify patients with suspected meningitis in

TABLE 68-5 Rare Causes of Bacterial Meningitis in Infants and Children PATHOGEN

PREDISPOSING FACTORS

Staphylococcus aureus Staphylococcus epidermidis Enterococcus faecalis Group A streptococcus Viridans streptococci Moraxella Escherichia coli*

Trauma, neurosurgery, shunt Trauma, neurosurgery, shunt Neonatal period Pharyngitis, sepsis Endocarditis, anatomic defect Otitis media Urinary tract infection, immunosuppression Immunosuppression Sickle cell disease, immunosuppression Neonatal period, immunosuppression Neonatal period, immunosuppression Immunosuppression Immunosuppression Animal bites Wild animal contacts Shunt Chronic pulmonary disease

Klebsiella pneumoniae Salmonella Proteus Citrobacter Other Enterobacteriaceae Pseudomonas aeruginosa Pasteurella multocida Francisella tularensis Propionibacterium acnes Nocardia *Rare past the neonatal period.

TABLE 68-4 Common Causes of Acute Bacterial Meningitis According to Age AGE

PATHOGEN

0–4 wk

Streptococcus agalactiae Escherichia coli Listeria monocytogenes Streptococcus pneumoniae E. coli L. monocytogenes Neisseria meningitidis S. agalactiae S. pneumoniae Haemophilus influenzae N. meningitidis S. pneumoniae H. influenzae

1–3 mo

3 mo–18 y

whom a lumbar puncture can be performed safely [Hasbun et al., 2001]. Whether these criteria are valid in children has not been established. The contraindications for lumbar puncture were discussed earlier. The choice of empiric antibiotics depends on the suspected pathogens and their antibiotic susceptibilities, which may display regional differences. All pathogens commonly encountered in a particular patient population should be covered empirically, and rare pathogens should be empirically targeted in patients with corresponding risk factors (Tables 68-4 and 68-5). Recommended empiric treatment regimens adequate for patients without additional risk factors are shown in Table 68-6. When the causative pathogen has been isolated, and antibiotic sensitivities are known, therapy should be adjusted to cover the respective pathogen optimally (see later).

TABLE 68-6 Recommendations for Empiric Antibiotic Therapy of Bacterial Meningitis PATIENTS AND SPECIAL MODIFYING CIRCUMSTANCES

ANTIBIOTIC

DOSAGE (IV)

Neonate/infant <3 mo

Ampicillin plus Cefotaxime or Gentamicin Vancomycin plus Ceftazidime Ceftriaxone or Cefotaxime Ceftriaxone plus Rifampin or Vancomycin Ceftazidime plus Nafcillin or Flucloxacillin (or Vancomycin plus Aminoglycoside)

50-100 mg/kg q6-8h 100 mg/kg q8h 2.5 mg/kg q8h 15 mg/kg q8-24h 100 mg/kg q8-12h 100 mg/kg q24h (max. 4 g q24h) 100 mg/kg q8h (max. 12 g per day) 100 mg/kg q24h (max. 4 g q24h) 10–20 mg/kg q24h (max. 600 mg q24h) 15 mg/kg q6h (max. 500 mg q6h) 100 mg/kg q8h (max. 12 g per day) 50 mg/kg q6h (max. 12 g per day) 15 mg/kg q6h (max. 500 mg q6h) 2.0-2.5 mg/kg q8h

Neonate preterm, low birth weight >3 mo to <50 yr Drug-resistant Streptococcus pneumoniae Neurosurgery, CSF shunt, or head trauma

CSF, cerebrospinal fluid.

Täuber and Schaad / Bacterial Infections of the Nervous System

The proper duration of therapy is not well defined. Meningitis caused by N. meningitidis can be treated for 5 to 7 days, and even shorter durations have been found to be effective [Viladrich et al., 1986]. For S. pneumoniae or H. influenzae, 10 to 14 days is deemed appropriate. Meningitis caused by Enterobacteriaceae, L. monocytogenes, or other unusual pathogens may require treatment courses of 3 weeks. Antibiotic therapy should not be prolonged past the recommended durations because of a persistent fever in a child who has otherwise displayed a favorable clinical response. Other causes for fever, such as drug fever, intravenous line infections, other undiagnosed infections, and extra-axial fluid collections, should be considered.

STREPTOCOCCUS PNEUMONIAE For sensitive S. pneumoniae, penicillin G remains the drug of choice, and third-generation cephalosporins (ceftriaxone or cefotaxime) are effective alternatives. Increasing resistance against β-lactam antibiotics is observed worldwide, regarding the prevalence of resistant strains and increasing levels of resistance [Jones et al., 2004]. Penicillin and chloramphenicol are ineffective against strains displaying any degree of resistance, whereas third-generation cephalosporins may fail in highly penicillin-resistant strains. A combination of a third-generation cephalosporin with vancomycin is most commonly recommended for these strains [Bradley and Scheld, 1997]. Dexamethasone reduces cerebrospinal fluid concentrations of vancomycin in adults but apparently not in children. Rifampicin can be used instead of vancomycin, if the strain is sensitive. There is currently limited clinical experience with newer quinolones [Saez-Llorens et al., 2002], which look promising in experimental meningitis [Cottagnoud and Täuber, 2004]. In these models, the newer quinolones display strong synergism with β-lactams or vancomycin, and these combinations may provide a treatment option in cases caused by high-level resistant pneumococci.

HAEMOPHILUS INFLUENZAE Ampicillin is the drug of choice for sensitive H. influenzae, but 5% to 30% of strains worldwide are resistant to ampicillin owing to a β-lactamase. These strains are best treated with a third-generation cephalosporin. Rapid spread of non– β-lactamase–producing, ampicillin-resistant H. influenzae type b strains has been reported from Japan [Hasegawa et al., 2004]. These strains exhibit mutations in their penicillinbinding proteins and increased minimal inhibitory concentration to cephalosporins. Optimal treatment of these strains may require the combination of high-dose third-generation cephalosporins with meropenem or possibly a fluoroquinolone [Hasegawa et al., 2004].

NEISSERIA MENINGITIDIS Most strains of N. meningitidis are sensitive to penicillin G, which continues to be the drug of choice. An increase in penicillin minimal inhibitory concentration has been documented in occasional strains, but the third-generation cephalosporins remain universally active and are a reliable alternative to penicillin [Canica et al., 2004].

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GROUP B STREPTOCOCCI Group B streptococcal meningitis in neonates is treated with penicillin G, to which the streptococci have retained universal sensitivity. Third-generation cephalosporins also are active. Whether addition of an aminoglycoside results in a clinical benefit has not been resolved in controlled studies.

LISTERIA MONOCYTOGENES The best treatment of L. monocytogenes meningitis is an aminopenicillin. Based on data in rabbits, which indicated increased bactericidal activity of the combination of penicillin with gentamicin [Scheld et al., 1979], an aminoglycoside usually is added to penicillin. Trimethoprim-sulfamethoxazole is used in patients who cannot tolerate penicillin.

GRAM-NEGATIVE BACILLI E. coli, Klebsiella, and Pseudomonas aeruginosa are among the more frequent causes of gram-negative bacillary meningitis. Treatment options include third-generation cephalosporins, fluoroquinolones, aminoglycosides, and meropenem. Given the unpredictability of resistance in these organisms, treatment has to be based on sensitivity testing. In severe and difficult-to-treat cases, the combination of a β-lactam with an aminoglycoside can be used. The aminoglycoside can be administered intrathecally in desperate cases.

STAPHYLOCOCCI Most S. aureus strains express a penicillinase, and a penicillinase-resistant penicillin (nafcillin or flucloxacillin, depending on availability) is used to treat meningitis. If the infecting strain is methicillin resistant, vancomycin must be used. Experiences with newer drugs active against grampositive pathogens (linezolide, streptogramins, lipopeptides) in the treatment of meningitis do not support their routine use for meningitis [Cottagnoud and Täuber, 2004]. Staphylococcus epidermidis is encountered mostly in shunt infections. The organism is often resistant to β-lactams, in which case it has to be treated with vancomycin. The combination of systemic and intraventricular administration of vancomcycin may achieve the highest concentrations at the site of infection. Whenever possible, the infected shunt should be removed and, if necessary, replaced by a temporary external drainage until the infection is cleared, and a new permanent shunt can be placed. Addition of rifampicin, if active against the infecting pathogen, can help clear the infection when the infected shunt cannot be removed.

Corticosteroids In studies of experimental meningitis, corticosteroids reduce brain edema, reduce intracranial pressure, and stabilize the blood-brain barrier [Täuber et al., 1985]. The last effect is associated with a reduction of antibiotic concentrations in the cerebrospinal fluid to a degree that does not, with the possible exception of vancomycin, jeopardize antibacterial effectiveness. Corticosteroids, when given at the time of the first antibiotic dose, reduce the increase in inflammation in the cerebrospinal fluid that follows the release of pro-

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inflammatory bacterial products induced by the antibiotics [Saez-Llorens et al., 1991]. As a potential risk, dexamethasone increased the number of apoptotic cells in the dentate gyrus of animals with experimental meningitis and was associated with impaired learning in infant rats 3 weeks after pneumococcal meningitis [Leib et al., 2003]. The relevance of this observation for humans is currently unknown. Dexamethasone has been tested in several controlled trials in patients with bacterial meningitis. Although some studies failed to prove a significant benefit, most studies found some beneficial effect on outcome with little toxicity and no adverse effect on clearing of bacteria from the cerebrospinal fluid [Van de Beek et al., 2003]. Based on a meta-analysis, dexamethasone reduces hearing loss in children with H. influenzae and possibly S. pneumoniae meningitis. Overall neurologic outcome also is improved in children with H. influenzae meningitis [Van de Beek et al., 2003]. A controlled study in adults found improved survival and overall outcome in patients with pneumococcal meningitis [De Gans et al., 2002]. Based on the available data, it seems reasonable to administer dexamethasone to all patients with strong clinical evidence of bacterial meningitis. Because the drug mitigates the inflammatory response after institution of antibiotics, it is best given shortly before or simultaneously with the first antibiotic dose [Odio et al., 1991]. The recommended dose is 0.15 mg/kg every 6 hours for a maximum of 4 days; 2 days is equally effective [Schaad et al., 1993]. It is not clear that the risk for major gastrointestinal bleeding is increased with dexamethasone, but patients should be examined for evidence of gastrointestinal blood loss. The course of nonbacterial meningitis is not adversely affected by dexamethasone [Waagner et al., 1990], but the drug temporarily reduces symptoms even if the empiric antimicrobial therapy is ineffective. Little experience exists with dexamethasone in the neonatal period, and the drug should not be used routinely in this patient population.

Approach to Seriously Ill Patients The approach to the treatment of a seriously ill patient with meningitis is based on a careful clinical assessment, with special attention to the presence of complications such as seizures, sepsis, or dehydration; on an estimate of intracranial pressure at the time of lumbar puncture; and on neuroimaging studies, which can be categorized as follows: (1) normal scan, (2) cerebral edema, (3) hydrocephalus, (4) subdural effusions, and (5) cerebral infarction [Ashwal, 1995].

SEIZURES Adequate ventilation and cardiovascular support must be ensured. There is no seizure treatment specific for meningitisassociated seizures. Drugs such as phenobarbital, fosphenytoin, diazepam, and lorazepam, individually or in combination, are used to control seizures.

SHOCK AND DISSEMINATED INTRAVASCULAR COAGULATION Standard support for all vital systems in an intensive care setting must be provided to critically ill patients who have signs of sepsis, organ failure, and disseminated intravascular

coagulopathy. A detailed discussion of these complex therapies is beyond the scope of this chapter. Attempts have been made to develop specific therapies for sepsis that are based on interfering with microbial mediators, host defense pathways, or coagulation pathways involved in the pathogenesis of sepsis. Although most of these attempts have failed in clinical trials, activated protein C (drotrecogin alfa) was found to improve organ failure, including disseminated intravascular coagulation, and survival in a large controlled trial [Bernard et al., 2001]. The limited data in children treated with drotrecogin alfa suggest that the drug can improve outcome in children with meningitis complicated by severe sepsis and disseminated intravascular coagulation. Contraindications include severe coagulopathy, trauma, and recent or impending invasive procedures, in particular procedures involving major vessels of the brain [Bernard et al., 2001].

FLUID BALANCE AND ELECTROLYTES In bacterial meningitis, a balanced fluid status should be established and maintained. Fluid restriction does not improve outcome and should be limited to a subset of patients with specific indications [Singhi et al., 1995]. Dehydration is potentially harmful because of hypotension and intravascular sludging and thrombosis, all of which can adversely affect cerebral perfusion and increase ischemia [Moller et al., 2001; Tureen et al., 1992]. Many meningitis patients are dehydrated at diagnosis. Their fluid deficit should be corrected promptly, and appropriate maintenance fluid should be administered subsequently [Powell et al., 1990]. Usually the fluid is given as one quarter to one third normal saline in 5% dextrose. Substantial overhydration should be avoided, but its potential to exacerbate brain edema probably has been overestimated in the past [Täuber et al., 1993]. Treatment of SIADH secretion is fluid restriction. It is recommended that fluid restriction be instituted only when SIADH has been documented by appropriate laboratory tests, and the serum sodium concentration has declined to less than 125 mEq/liter. Rapid correction of severe hyponatremia may be harmful.

INTRACRANIAL HYPERTENSION Invasive monitoring of intracranial pressure may be helpful in patients who have signs of severe meningitis, in particular patients with markedly reduced Glasgow Coma Scale and very high opening pressure on initial lumbar puncture. These patients usually must be mechanically ventilated. The PCO2 should be maintained at the lower range of normal, but pronounced hyperventilation must be avoided because it can worsen cerebral ischemia [Ashwal et al., 1990]. Sedation or administration of a neuromuscular blocking agent may be necessary to enhance controlled ventilation. A paradigm for the management of seriously ill patients with bacterial meningitis using the results of intracranial pressure measurements and neuroimaging has been published [Ashwal, 1995]. In patients with cerebral edema on CT or MRI, administration of dexamethasone is indicated given its beneficial effects on brain edema and intracranial hypertension [Odio

Täuber and Schaad / Bacterial Infections of the Nervous System

et al., 1991; Täuber et al., 1985]. Mannitol, 0.25 to 1 g/kg, can be administered intravenously over 20 to 30 minutes. This dose can be repeated every 2 to 4 hours, but the effect of subsequent doses progressively diminishes. Use of diuretics, such as furosemide (Lasix), 0.5 to 1 mg/kg, should be restricted to patients with evidence of fluid overload to avoid the adverse effects of fluid depletion and hypotension. An alternative approach to lower severely increased intracranial pressure during meningitis has been pioneered by Scandinavian groups. Their protocol consists of a combination of (1) normalizing plasma colloidal osmotic pressure and blood volume with blood transfusions and albumin infusions; (2) antihypertensive therapy with β1-antagonists and α2-agonists; and (3) “antistress” therapy with a combination of thiopental, clonidine, and fentanyl. Although randomized controlled trials have not been performed, the published case series, which included children, documented pronounced effects on intracranial pressure and outcome, including the reversal of impending cerebral herniation, in most patients [Grande et al., 2002; Lindvall et al., 2004]. If the intracranial pressure is elevated in the presence of a normal CT scan or MRI, this may be due to increased intracranial blood or cerebrospinal fluid volume. Controlled ventilation and dexamethasone therapy should be applied in these patients. Whether other means to lower intracranial pressure are necessary in this situation must be decided based on the severity of intracranial hypertension and the response to therapy with dexamethasone.

CEREBRAL INFARCTION In patients in whom neuroimaging studies reveal infarction, the treatment guidelines outlined earlier for increased intracranial pressure and fluid balance should be applied with particular care. Alternative therapies, such as use of barbiturates or hypothermia, have not been systematically studied in patients with stroke secondary to meningitis. The risk of severe intracranial bleeding seems to preclude the use of thrombolytic agents.

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therapy or if the fluid accumulates and acts as a mass, puncture of the fluid is indicated to exclude an empyema and to reduce possible mass effect.

Prognosis Knowledge about factors associated with a poor prognosis is important in selecting patients for more intensive surveillance and treatment and in identifying candidates for new preventive or therapeutic strategies. Various studies have reported different and partially conflicting risk factors [Algren et al., 1993; Baraff et al., 1993; Kaaresen and Flaegstad, 1995; Kornelisse et al., 1995]. Table 68-7 summarizes the major prognostic factors. Bacterial etiology has a substantial impact on outcome. A meta-analysis found a fourfold higher mortality from S. pneumoniae (15.3%) compared with H. influenzae (3.8%) and a corresponding twofold to threefold higher rate of neurologic sequelae (S. pneumoniae 15% to 30% versus H. influenzae 5% to 20%) [Kaaresen and Flaegstad, 1995; Kornelisse et al., 1995]. Although the mortality from N. meningitidis meningitis (7.5%) is midway between the other two principal etiologies of bacterial meningitis, sequelae from this infection are much less frequent (2% to 5%). This discrepancy is explained by the relatively frequent presence of sepsis with diffuse coagulopathy in patients with meningococcal meningitis [Algren et al., 1993]. The quantity of antigen in the initial cerebrospinal fluid specimen and the number of bacteria present (bacteriorrhachia) also are correlated significantly with sequelae of meningitis [Feldman et al., 1982]. Bacterial meningitis in newborns is associated with high mortality (15% to 30%), and 20% to 40% of survivors have permanent neurologic sequelae. Factors contributing to this poor prognosis are specific etiologies (e.g., gram-negative enteric bacilli), immaturity, delayed diagnosis, and concomitant disease [Schaad, 1992; Stevens et al., 2003]. Other indicators of poor outcome are focal neurologic findings (e.g., seizures), coma, cardiovascular compromise (e.g., peripheral vasoconstriction, shock), absence of fever, and less than 1000 × 106/liter leukocytes in cerebrospinal

HYDROCEPHALUS Patients with increased cerebrospinal fluid volume and normal intracranial pressure do not require treatment because spontaneous resolution of this abnormality occurs as the infection resolves. In patients with markedly elevated intracranial pressure as manifested by full fontanel, depressed consciousness, or signs of acutely jeopardized cerebral perfusion (i.e., new-onset focal neurologic deficits), ventricular drainage should be considered to reduce intracranial hypertension and improve cerebral perfusion pressure rapidly. The drainage should be to an external collection device because it is needed only transiently in most cases. In less acute situations, decreasing cerebrospinal fluid volume and pressure by one or more conventional therapies (furosemide, mannitol, dexamethasone) may be attempted.

SUBDURAL EFFUSION Most extra-axial fluid collections resolve without intervention. If fever and clinical signs persist despite antibiotic

TABLE 68-7 Risk Factors Associated with Poor Prognosis of Bacterial Meningitis Etiology Patient Severity of disease on admission

Type of management Course of meningitis CSF, cerebrospinal fluid.

Streptococcus pneumoniae Gram-negative enteric bacteria High bacterial titers Newborn infant Decreased immune defense Advanced disease Focal neurologic finding Coma Cardiovascular compromise Absence of fever <1000 × 106/L leukocytes in CSF Need for intensive care Inadequate antibacterial therapy Lack of anti-inflammatory therapy Delayed CSF sterilization High number/severity of complications

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fluid at the time of admission. There is no clear association between duration of symptoms before diagnosis and outcome [Kaaresen and Flaegstad, 1995; Kilpi et al., 1993]. Relevant for the prognosis after diagnosis are management (e.g., intensive care, antibacterial and anti-inflammatory therapies); time to cerebrospinal fluid sterilization; and number and severity of complications such as seizures, cranial nerve palsies, coma, subdural effusion, and cerebral herniation (see Table 68-3) [Schaad, 1997].

Prevention The goals of immunoprophylaxis and chemoprophylaxis are prevention of specific types of bacterial meningitis and limitation of the spread of disease when infection occurs.

Immunoprophylaxis The available conjugate vaccines against H. influenzae type b are dramatically effective and extremely safe [Feigin et al., 1992; Rockowitz and Tunkel, 1995]. The vaccine prevents all invasive diseases resulting from bacteremia, including meningitis and epiglottitis. Concerted efforts to vaccinate all infants in all countries must continue. Meningococcal disease remains a substantial problem worldwide, with approximately 1.2 million cases per year [Balmer and Miller, 2002]. Vaccines comprising the polysaccharide capsule of serogroups A, C, W-135, and Y have been available for approximately 25 years. These polysaccharide vaccines are not immunogenic in young children, however, and induce only short-lived protection. To improve the immunogenicity of the meningococcal serogroup C polysaccharide vaccine, a carrier protein was covalently attached, converting the vaccine to a T cell–dependent antigen, which can stimulate long-term immunity. This vaccine has proved to be successful in reducing the incidence of serogroup C meningococcal disease in various countries, including the United Kingdom [Miller et al., 2001], Spain [Salleras et al., 2001], and Canada [De Wals et al., 2001]. A comprehensive vaccine conferring protection against all disease-associated serogroups remains elusive. The major challenge in the prevention of meningococcal disease by vaccination is the development of an effective serogroup B meningococcal vaccine. Serogroup B disease is endemic in most industrialized countries, with the burden of disease occurring mainly in young children. The serogroup B capsular polysaccharide is poorly immunogenic, possibly because it shares homology with glycopeptides of neural cell adhesion molecules [Pon et al., 1997]. Advances in bacterial genomics and proteomics have provided new and promising approaches in the identification of novel vaccine candidates [Rappuoli, 2001; Pollard and Levin, 2000]. As is true for all meningeal pathogens, the polysaccharide capsule of S. pneumoniae is a critical virulence factor, helping the organism to avoid phagocytosis. Ninety different capsular serotypes have been identified. Vaccine development throughout most of the 20th century focused on using combinations of polysaccharides as the key vaccine components [Whitney, 2002]. As mentioned before, vaccines composed of polysaccharide antigens alone produce weak and short-lived

immune responses in infants and toddlers. Conjugating pneumococcal polysaccharide to a carrier protein induces a T cell–dependent response that can occur even in early infancy. The first protein-polysaccharide conjugate pneumococcal vaccine that is safe and effective in infants and toddlers was approved in February 2000 in the United States and is now licensed for use in many other countries. The vaccine includes polysaccharide antigens for the seven most common serotypes occurring in children in the United States and in many other countries [Pelton and Klein, 2002]. Other conjugate vaccine formulations are being tested in young children. Clinical trials indicate that conjugate vaccines are highly efficacious against invasive pneumococcal disease, including meningitis, and modestly efficacious against otitis media and pneumonia [Giebink, 2001]. In carriage studies, conjugate vaccines reduced vaccine-type carriage but usually led to an increase in carriage of other serotypes. Remaining questions include whether less frequent transmission of vaccine serotypes would mean less disease in unvaccinated children and adults or conversely nonvaccine serotypes would begin to cause more disease. The seven-valent pneumococcal conjugate vaccine is now part of routine infant immunization in the United States and some other countries.

Chemoprophylaxis Many studies have documented increased risk of disease in close contacts of index patients with invasive disease caused by N. meningitidis and H. influenzae type b [Feigin et al., 1992]. The risk is age dependent, and disease among unvaccinated household contacts younger than 4 years old is increased. The spread of such strains is a particular concern in daycare centers. Chemoprophylactic regimens are aimed at eradicating nasopharyngeal carriage of potentially invasive bacteria, preventing further transmission and development of disease in people already colonized. The preferred drug is rifampicin (20 mg/kg/day, maximum daily dose 600 mg) for either 2 days (N. meningitidis) or 4 days (H. influenzae). Alternatives for the elimination of nasopharyngeal carriage of N. meningitidis include single doses of either ciprofloxacin or ceftriaxone. Because treatment for bacterial meningitis with β-lactam antibiotics does not eradicate the organism from the nasopharynx, chemoprophylaxis also is recommended for the index patient before discharge. Careful observation of exposed persons is essential for identifying early signs of disease and initiating therapy, independent of whether they received chemoprophylaxis or not because chemoprophylaxis is far from being 100% effective. Cultures of the upper respiratory tract in contacts are not useful in the care of exposed persons and are valuable only in epidemiologic investigations. Numerous studies have found that maternal intrapartum chemoprophylaxis can prevent maternal febrile morbidity and early-onset neonatal group B streptococcal disease, including meningitis [Krohn et al, 1999]. Guidelines recommend the use of a risk-based or a screening-based approach to identify candidates for intrapartum prophylaxis with amoxicillin [Schrag et al, 2000]. Alternative algorithms combining the two strategies are also in use [Boyer and Gotoff, 1998].

Täuber and Schaad / Bacterial Infections of the Nervous System

Recurrent Acute Bacterial Meningitis Recurrent bacterial meningitis is rare and must prompt a careful evaluation for either an anatomic defect facilitating access of bacteria to the cerebrospinal fluid space or an immunologic deficit. Anatomic defects can be acquired or developmental [Schick et al., 1997] and typically lead to meningitis caused by S. pneumoniae or rarely H. influenzae. Defects may involve the temporal bone or the anterior skull base and are not always associated with cerebrospinal fluid rhinorrhea or otorrhea. Developmental defects include meningomyelocele, dermal sinus, or neurenteric cyst and malformations of the inner ear. Contrast-enhanced high-resolution CT, MRI cisternography, and search for cerebrospinal fluid leakage into the nose or middle ear can help identify an anatomic defect [Drummond et al., 1999; Meco and Oberascher, 2004]. If such a defect is found, surgical correction is indicated. Among the immunologic conditions predisposing to recurrent meningitis, deficiencies of the latter components of the complement pathway (C5 through C9) or properdin (alternative pathway) have been associated with recurrent infections caused by Neisseria [Overturf, 2003]. Functional or anatomic asplenia, agammaglobulinemia, and deficiencies of the early components of complement (C1 through C3) have been associated with recurrent episodes of meningitis caused by S. pneumoniae, H. influenzae, and N. meningitidis [Overturf, 2003]. Commonly, children with congenital immunodeficiencies have a history of frequent infections other than meningitis. After a second episode of bacterial meningitis, immunoglobulin levels, total complement activity (CH50), and possibly individual complement components should be determined. Splenic function should be assessed, if there is a risk for splenic dysfunction (e.g., sickle cell anemia) or congenital asplenia (e.g., congenital heart disease). Identified deficiencies should be corrected where possible, and chronic antibiotic prophylaxis must be considered in children at high risk for recurrent, severe infections (e.g., in children with asplenia). Conditions other than bacterial meningitis are frequently the cause of recurrent meningitis, but these are rare in children. They include Behçet’s syndrome, sarcoidosis, and Mollaret’s meningitis associated with recurrent herpes simplex infection [Ginsberg, 2004]. Acute meningitis indistinguishable clinically from bacterial meningitis can result from an allergic reaction to drugs (e.g., trimethoprim-sulfamethoxazole, nonsteroidal anti-inflammatory drugs, and intravenous immunoglobulins).

CHRONIC BACTERIAL MENINGITIS Chronic bacterial meningitis evolves over days to weeks. Patients complain of headaches, often associated with constitutional signs of infection (fever, anorexia). Nuchal rigidity may be subtle or absent in cases of chronic meningitis. Many forms of chronic meningitis involve the base of the brain and lead to cranial nerve palsies. As the syndrome progresses, signs of brain involvement with seizures, mental status changes such as confusion or hallucinations, and focal neurologic deficits may develop. Hydrocephalus and increased intracranial pressure also may

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accompany the syndrome. The bacterial causes of chronic meningitis include tuberculosis, Lyme borreliosis, syphilis, and leptospirosis. Other etiologies of chronic meningitis include fungal infections, such as Cryptococcus neoformans or Coccidioides immitis, viral infections (e.g., cytomegalovirus, human immunodeficiency virus), and noninfectious causes (e.g., neoplasms, sarcoidosis).

Tuberculous Meningitis Epidemiology and Pathogenesis Tuberculosis remains one of the most prevalent infections worldwide. Mycobacterium tuberculosis is transmitted by respiratory aerosols and frequently infects infants and children, particularly in developing countries. CNS involvement is a life-threatening extrapulmonary manifestation of tuberculosis, and 1% to 2% of children with untreated tuberculosis develop meningitis [Starke, 1999]. Tuberculous meningitis is rare before 3 months of age but increases during the first 5 years of life. A history of close contact with a known case of tuberculosis is often found in children with CNS tuberculosis. Tuberculosis of the CNS follows the dissemination of tuberculosis after primary infection, usually in the lung. During the primary disease, or on reactivation later in life, tubercle bacilli can be discharged into the subarachnoid space from a caseous subependymal lesion. Multiplying organisms induce basilar meningitis but also can cause focal parenchymal infections (tuberculomas). The inflammatory exudate in the subarachnoid space affects cerebral vessels and cranial nerves, resulting in ischemic changes and cranial nerve palsies. Hydrocephalus is often present already at the time of diagnosis and can be communicating or noncommunicating.

Clinical Characteristics Tuberculous meningitis usually evolves over several days to a few weeks, although an acute onset is found in about half of the affected children. Initial symptoms are vague and consist of generally poor health, irritability, and apathy (stage I). In young infants, fever, cough, altered consciousness, bulging anterior fontanel, and generalized tonic-clonic seizures are presenting symptoms [Tung et al., 2002]. In older children, low-grade fever, nausea, vomiting, headache, and abdominal pain occur [Farinha et al., 2000]. Nuchal rigidity is not prominent. In stage II, unilateral or bilateral cranial nerve deficits result from the basilar meningitis. Neuro-ophthalmologic changes, including retrobulbar neuritis, gaze palsies, and lesions of the chorioretina, are common [Amitava et al., 2001]. As the disease progresses to stage III, the patient develops depression of consciousness, convulsions, possibly papilledema, and major neurologic deficits. Tuberculosis can involve the spinal cord directly, by pressure from vertebral abscess, and by the production of arachnoiditis [HernandezAlbujar et al., 2000]. Many patients present with hyponatremia, either on the basis of SIADH or, less commonly, as a cerebral salt-wasting syndrome [Farinha et al., 2000].

Diagnosis Head CT and MRI document findings similar to those of bacterial meningitis, especially around the base of the brain,

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FIGURE 68-5. Postcontrast coronal low-field MRI of 16-month-old child with Mycobacterium tuberculosis meningitis. A tuberculoma is present (arrowhead). (Courtesy of Blaine Hart, MD.)

and may reveal parenchymal lesions, infarction, and tuberculomas (Fig. 68-5). Hydrocephalus is found in most patients [Farinha et al., 2000]. Intracranial tuberculomas, which continue to be found frequently in countries with a high prevalence of tuberculosis, present with symptoms of a spaceoccupying lesion with headache, seizures, and other focal neurologic symptoms. Imaging is essential in the diagnosis of spinal involvement [Bernaerts et al., 2003]. CT or MRI of the spine is indicated in a child with suspected tuberculosis and neurologic signs of cord involvement. Chest radiographs are commonly abnormal with lymphadenopathy or pulmonary infiltrates but can be normal [Yaramis et al., 1998]. Fifty percent of patients with tuberculous meningitis have a negative tuberculin skin test [Starke, 1999]. The cerebrospinal fluid opening pressure is often elevated. The cerebrospinal fluid seldom contains more than 500 cells/mm3, most of which are lymphocytes. Protein content is elevated but rarely greater than 500 mg/dL. Glucose concentration usually is decreased to varying degrees [Farinha et al., 2000]. Detection of the infecting organism in cerebrospinal fluid is notoriously difficult. Large quantities of cerebrospinal fluid (10 mL, if possible) should be collected and examined for acid-fast bacilli. Culture and detection of the M. tuberculosis genome may yield the diagnosis, but in a substantial proportion of cases, all tests remain negative [Farinha et al., 2000]. Repeated cerebrospinal fluid studies may allow the diagnosis to be established.

Treatment The appearance of organisms resistant to antituberculous drugs is an increasing problem in several areas of the world. Isoniazid, rifampin, ethambutol, pyrazinamide, and streptomycin remain the first-line drugs for the treatment for tuberculous meningitis caused by sensitive organisms. Newer fluoroquinolones also are highly active against tuberculosis, and although their role for the treatment of tuberculous meningitis

has not been clearly delineated, they may represent a backup option in difficult-to-treat cases. Initial therapy is started with four drugs for 2 months (isoniazid, rifampicin, pyrazinamide, and ethambutol or streptomycin), particularly when strains resistant to first-line drugs are a possibility. After 2 months, treatment is reduced to two active drugs based on sensitivity testing, with rifampin and isoniazid as first choices [Shingadia and Novelli, 2003]. Pyridoxine is recommended in malnourished children to prevent isoniazid-induced peripheral neuropathy [Shingadia and Novelli, 2003]. Response to antituberculous treatment usually is evident within 2 weeks. Therapy should be continued for at least 9 to 12 months, and in patients with slow responses, extensive disease or resistant organisms necessitating treatment with second-line drugs, for 18 to 24 months. Treatment of pulmonary tuberculosis in children reduces the incidence of CNS infection. Surgical shunting procedures may be necessary for hydrocephalus, particularly in cases of noncommunicating hydrocephalus [Schoeman et al., 2002]. Corticosteroids seem to reduce the mortality and the morbidity from inflammation and subsequent fibrosis in patients with tuberculous meningitis [Schoeman et al., 1997]. Their use is advocated, particularly in patients with a decreased level of consciousness, papilledema, focal deficits, or elevated intracranial pressure. A course of prednisone or dexamethasone for 6 weeks with subsequent tapering over several weeks is the most common regimen recommended. The mortality of tuberculous meningitis is 10% to 20%. Major sequelae occur and are most common in children in stage III. Visual and auditory impairments are common, as are hemiparesis, mental retardation, and seizures [Schoeman et al., 2002]. Involvement of the hypothalamus and basal cisterns leads to endocrinopathies, such as diabetes insipidus, growth retardation, sexual precocity, and obesity.

Syphilis Epidemiology and Pathogenesis Syphilis, which is caused by the spirochete Treponema pallidum, remains an important and prevalent sexually transmitted disease worldwide. The introduction of penicillin led to a decline of the disease, but its prevalence has increased in more recent years. In developed countries, syphilis in children is rare, but it is disproportionately frequent in underprivileged segments of the population and in the setting of drug abuse [Sison et al., 1997]. In countries with few resources, congenital syphilis remains an important health issue. Transmission occurs across the placenta after the fifth month of gestation or rarely at birth by contact with infectious maternal lesions. Congenital syphilis can be prevented by screening and treating pregnant women [Walker and Walker, 2002]. When older children acquire syphilis, this is the result of either sexual abuse or precocious sexual activity. T. pallidum disseminates widely in the body in congenital and acquired syphilis and can cause disease in various organs, including the CNS. Pathologic lesions involve endothelial cell proliferation and perivascular inflammation with lymphocytes and plasma cells.

Clinical Characteristics Congenital syphilis is associated with stillbirth or perinatal death in half of the cases [Darville, 1999]. Early congenital

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syphilis, which includes all manifestations in the first 2 years of life, manifests at birth or within the first weeks of life. Early signs include prematurity and low birth weight, skin and mucous membrane lesions, hepatosplenomegaly, and skeletal abnormalities (osteochondritis), which can be painful and prevent the child from moving affected limbs. Snuffles consist of a thick nasal discharge rich with spirochetes. The eyes (chorioretinitis, uveitis) and CNS (meningitis, meningovascular syphilis, hydrocephalus) are commonly involved, but clinical signs of neurosyphilis are rare in neonates [Parish, 2000]. In late congenital syphilis, clinical findings do not appear until several years of age. Interstitial keratitis occurs typically in the second decade. Usually, both eyes are involved. Bone lesions result in destruction of the palate and nasal septum, with depression of the nose (saddle nose). Scars appear about the mouth from earlier fissures (rhagades). The tibia may become bowed (saber shins), and the knee joint can be affected with hydrarthrosis (Clutton’s joints). Permanent dentition is abnormal, especially the upper central incisors, which are dwarfed and notched (Hutchinson’s teeth), and the first lower molars, which have poorly developed cusps (mulberry molars). CNS involvement can manifest with multiple defects. Meningovascular syphilis leads to findings of chronic meningoencephalitis, such as intellectual decline (juvenile paresis), which may begin by 4 to 5 years of age, headache, seizures, blindness, cranial nerve VIII deafness, other cranial nerve involvement, hemiparesis, and hydrocephalus. Hutchinson’s triad consists of Hutchinson’s teeth, interstitial keratitis, and nerve deafness [Parish, 2000]. Acquired syphilis, which resembles the disease in adults, can occur in children and adolescents. The primary stage with chancre appears 2 to 4 weeks after exposure, but the chancre may go unnoticed. The cutaneous eruptions of the second stage follow usually within 2 months and can be associated with mucous membrane patches, condylomata lata, and patchy alopecia. Mild constitutional symptoms, such as fever, malaise, arthralgias, rhinorrhea, and lymphadenopathy, occur as a result of the disseminating infection. Rarely, secondary syphilis is associated with meningitis, leading to headache, meningism, nausea, and vomiting. If the condition is not treated, the tertiary stage of neurosyphilis (tabes dorsalis) may develop after an asymptomatic period of many years; this is extremely rare in pediatric patients.

Diagnosis The diagnosis of syphilis relies on clinical suspicion, serologic testing, and visualization of the organism from infected superficial lesions. Tissue biopsy specimens and attempts to culture the organism do not play a role in clinical practice. Serology relies on nontreponemal tests (Venereal Disease Research Laboratory [VDRL]), which are useful for screening and monitoring of treatment, and treponemal tests, such as the microhemagglutination–T. pallidum (MHA-TP) and fluorescent treponemal antibody absorption (FTA-ABS) tests, which are used to confirm the diagnosis. Suspected infections should be investigated by serologic testing of the mother and child. The tests can be negative in a newborn if the mother acquired the disease late in pregnancy, whereas passive transfer of maternal antibodies can result in a falsepositive test in an unaffected newborn. Microscopic exami-

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nation by darkfield microscopy or direct fluorescence antibodies can identify organisms in mucocutaneous lesions. If acquired syphilis is diagnosed in a child, the possibility of sexual abuse must be investigated [Connors et al., 1998]. Laboratory diagnosis of CNS involvement depends on cerebrospinal fluid examination. CNS involvement is assumed if the cerebrospinal fluid has increased cell counts (mostly mononuclear cells), elevated protein, and a positive VDRL result. Cerebrospinal fluid VDRL results can be falsenegative, however, and reliable exclusion of CNS involvement in neonates may be difficult. If clinically indicated, radiographs of the chest and bones and ophthalmologic and audiometric examinations should be performed.

Treatment Penicillin remains the treatment of choice for all clinical forms of syphilis. For early stages of acquired syphilis, one injection of benzathine penicillin is sufficient. For neurosyphilis and congenital syphilis, high-dose treatment with intravenous penicillin G is recommended [Workowski and Berman, 2002]. In allergic patients, desensitization should be attempted because penicillin is more effective than alternative treatments that can be given in children.

Lyme Borreliosis Clinical Characteristics Lyme disease is caused by the spirochetes Borrelia burgdorferi. They are transmitted in endemic areas by the bite of Ixodes ticks during the warm season, and children frequently are affected. The species of Lyme Borrelia differ between the United States and Europe. The disease occurs in three stages: early localized disease (erythema chronicum migrans), early disseminated disease, and persistent late disease. Extracutaneous manifestations involve the heart, the joints, and the CNS. Neurologic manifestations of Lyme disease are observed in 10% of patients and include lymphocytic meningitis, radiculitis and neuritis, encephalomyelitis, peripheral neuropathy, and subtle encephalopathic syndromes with memory and cognitive dysfunctions [Gerber et al., 1996]. Neurologic symptoms develop within weeks after onset of erythema chronicum migrans and tend to be more frequent and severe in Europe than in the United States, likely as a result of the increased neurotropism of Borrelia garinii, which is found only in Europe. In children, meningitis and peripheral palsy of cranial nerve VII are the most common neurologic manifestations of Lyme disease [Christen, 1996]. Rare manifestations of neuroborreliosis in children include cerebrovascular disease with sensorimotor deficits, optic nerve impairment caused by inflammation, and increased intracranial pressure. Chronic neuroborreliosis is manifested as a failure to thrive, headaches, and pseudotumor cerebri [Rothermel et al., 2001; Wilke et al., 2000].

Diagnosis The diagnosis of erythema chronicum migrans is clinical and does not require laboratory confirmation. Serologic tests are used to diagnose later or disseminated manifestations

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of Lyme disease. Enzyme-linked immunosorbent assay or immunofluorescence tests with high sensitivity serve as screening tests in patients with symptoms compatible with Lyme disease. Positive or equivocal tests must be confirmed by a more specific Western blot test. With these tests, IgM and IgG can be measured. Chronic forms of Lyme disease elicit an IgG response, whereas the IgM response can persist at the same time for months or years. Isolated IgM responses in chronic conditions are usually false-positive. Neurologic involvement is diagnosed based on suggestive symptoms combined with cerebrospinal fluid signs of inflammation (lymphocytic pleocytosis, increased protein concentrations). Antibodies (IgM, IgG, and IgA) can be detected in the cerebrospinal fluid as a result of intrathecal antibody production. Direct demonstration of spirochetes in the cerebrospinal fluid is not feasible in most cases, whereas polymerase chain reaction may be positive in early stages of CNS involvement.

Treatment In early stages of the disease, doxycycline or amoxicillin is recommended. The latter is preferred in children younger than 8 years old; in the late stage with CNS or peripheral nervous system involvement, intravenous therapy with a cephalosporin (ceftriaxone or cefotaxime) or penicillin is the recommended therapy [Wormser et al., 2000]. The prognosis is excellent for children with early Lyme disease who are treated with appropriate antimicrobial therapy [Gerber et al., 1996].

Leptospirosis Leptospirosis, caused by spirochetes of the species Leptospira, is acquired through the skin in water infested by rats but also can be transmitted to children by dogs. After an incubation period of 1 to 2 weeks, the acute, septicemic illness manifests itself by high fevers and constitutional symptoms, headaches, gastrointestinal symptoms, muscle pain, and conjunctivitis. After a period of apparent recovery, a second, immunologically mediated phase occurs. During this second phase, the liver, kidney, and nervous system may be affected. Nervous system involvement takes the form of meningitis, encephalitis, or neuritis. Meningitis is documented in approximately 10% to 20% of cases [Rajajee et al., 2002]. Meningitis and encephalitis rarely may become chronic. Neuritis tends to involve the brachial plexus or cranial nerves. Pleocytosis is found in the cerebrospinal fluid, which in the initial phase is polymorphonuclear, whereas lymphocytes are found in the second phase. The protein is elevated with normal glucose concentrations. The diagnosis usually is established by documenting rising antibody titers in serum, but the organism also can be visualized by darkfield microscopy in blood, urine, and occasionally cerebrospinal fluid (in the early phase) and can be cultured using Fletcher medium. Polymerase chain reaction facilitates early diagnosis [Gerke and Rump, 2003]. Penicillin is the treatment of choice [Marotto et al., 1997], although proof of its benefit is lacking. Patients with encephalitis may be left with sequelae even when treated with antibiotics.

TABLE 68-8 Signs and Symptoms of Brain Abscess Fever, subacute course, headache Depressed consciousness, confusion Nuchal rigidity, papilledema Seizures, hemiparesis, dysphagia

BRAIN ABSCESS With refinement in diagnostic techniques, brain abscesses are being recognized more promptly and at earlier stages in their evolution [Mathisen and Johnson, 1997].

Clinical Characteristics The initial clinical appearance of bacterial brain abscess is seldom dramatic, and the history and clinical findings are typically vague (Table 68-8). The diagnosis of brain abscess is suggested by the subacute development of fever, headache, vomiting, confusion, depressed consciousness, seizures, papilledema, and focal neurologic signs. Nuchal rigidity may occur in a few patients. Multiple brain abscesses do not have a unique presentation [Basit et al., 1999]. A brain abscess behaves as an expanding intracranial mass that can obstruct cerebrospinal fluid flow and produce hydrocephalus. Papilledema, a distinctly uncommon finding with bacterial meningitis, occurs with brain abscess if cranial sutures have closed. Multiple abscesses are found especially in patients with cyanotic congenital heart disease [Basit et al, 1989]. The differential diagnosis includes neoplasm, subdural hematoma, and focal encephalitis, such as herpes simplex. Brain abscess is rare before 2 years of age except in neonates [Daniels et al., 1985; Wessalowksi et al., 1993].

Brain Imaging MRI and CT are appropriate tests during the stage of cerebritis. Enhanced MRI and CT are the definitive tests in a mature abscess, revealing a characteristic capsular ring. Magnetic resonance spectroscopy may be useful in differentiating an abscess from a neoplasm [Martinez-Perez et al., 1997]. The electroencephalogram may be normal, may display focal abnormalities in the region of the abscess as either slowing or spikes, may contain periodic lateralized epileptiform discharges, or may be diffusely slow.

Lumbar Puncture Lumbar puncture should be approached extremely cautiously in any patient with suspected brain abscess because of the risk of herniation secondary to elevated intracranial pressure. Brain abscess documented by imaging contraindicates lumbar puncture. The yield for recovery of causative bacteria is higher with stereotactic biopsy than with blood culture.

Pathogenesis and Pathology Either hematogenous or direct spread of the organism can lead to a brain abscess. Brain abscess occurs in children in association with cyanotic congenital heart disease, in asso-

Täuber and Schaad / Bacterial Infections of the Nervous System

ciation with lung infection, after neurosurgical procedures, after penetrating head trauma, secondary to infections about the sinuses and orbits, and spontaneously [Anderson, 1993; Mathisen and Johnson, 1997]. Abscesses also occur in immunosuppression; in chronic pulmonary disease, especially in patients with cystic fibrosis; and in association with a continuing focus of infection, such as chronic otitis [Tekkok and Erbengi, 1992]. Brain abscess is rare as a complication of bacterial meningitis except in neonates (typically caused by Citrobacter and other gram-negative organisms) [Renier et al., 1998; Schaad, 1992]. An abscess of hematogenous origin localizes at the border of the gray and white matter. The lesion is initially a cerebritis, which may persist for several weeks. Edema surrounds the cerebritis, leading to increasing mass effect. Progressing from the cerebritis phase, a capsule of inflammatory granulation tissue develops over a variable period around a necrotic infected area. Abscesses are usually in the hemispheres, but may occur in the brainstem or cerebellum. A wide spectrum of unusual aerobic and anaerobic organisms has been isolated from brain abscesses [Brook, 1992].

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abscess formation is still in the cerebritis stage, when there are multiple abscesses or when the abscess is located in a critical area [Aebi et al., 1991; Brook, 1995]. Serial CT or MRI can be used to determine when medical therapy is failing. Increased intracranial pressure rarely may indicate controlled hyperventilation, osmotic agents such as mannitol, corticosteroids, or surgical drainage.

Prognosis Because of difficulty in diagnosis and management of brain abscess, mortality is still high, and sequelae are frequent [Aebi et al., 1991; Saez-Llorens et al., 1989]. Imaging improves the ability to follow brain abscess and may reduce morbidity and mortality. The outlook is poor when multiple abscesses are present [Basit et al., 1989] and when age is less than 1 year [Wong et al., 1989]. Mortality in infants approaches 50% [Tekkok and Erbengi, 1992]. Chronic seizure disorders are common after brain abscess [Hegde et al., 1986].

CRANIAL AND SPINAL EPIDURAL ABSCESS Treatment Anaerobic bacteria are found in 90% of brain abscesses. Multiple organisms may be present. Streptococcus, Staphylococcus, and Bacteroides fragilis are common in abscesses. In neonates, the offending pathogen is often Proteus. Surgical drainage or excision and appropriate antibiotics constitute appropriate treatment [Stephanov, 1988]. Surgery provides an opportunity to culture the organisms and hastens the resolution of abscesses. Empiric therapy usually consists of vancomycin, ceftriaxone, and metronidazole for 3 to 6 weeks. Brain abscesses have been cured by antibiotics without surgical drainage [Aebi et al., 1991; Wong et al., 1989]. Medical management with or without needle aspiration should be considered when

Cranial Epidural Abscess The terms epidural and extradural are interchangeable terms and are used to describe a suppurative infection between the dura and cranium. Such infections are usually a complication of trauma, neurosurgery, or spread of infection from contiguous structures. The condition is rare in childhood [Auletta and John, 2001]. S. aureus, S. epidermidis, Streptococcus, and B. fragilis are some of the organisms found. Symptoms may be subtle and include fever, headache, stiff neck, focal seizures, and focal neurologic deficits, such as hemiparesis. The abscess acts as an enlarging mass. Lumbar puncture usually is contraindicated. Imaging of cranial epidural abscess typically reveals a lenticular collection of fluid between the bone and CNS of variable appearance and enhancement characteristics (Fig. 68-6). MRI is preferred to CT [Weingarten et al., 1989]. Treatment consists of antibiotics (see discussion on treatment of meningitis for appropriate choices) and surgical drainage [Auletta and John, 2001]. Delay in diagnosis and treatment is associated with an unfavorable outcome.

Spinal Epidural Abscess

FIGURE 68-6. Postcontrast coronal MRI of 15-year-old child with subdural empyema (arrowheads) and midline shift. (Courtesy of Blaine Hart, MD.)

Spinal epidural abscess is usually secondary to bacteremia. The condition is rare as a complication of lumbar puncture. S. aureus is the most common organism recovered, although M. tuberculosis is always a consideration. Presentation is a “painful, febrile, spinal syndrome” [Hancock, 1973]. Progression can be rapid with motor and sphincter involvement and a clinical picture resembling acute transverse myelitis. Children often have no clear-cut presentation. With a suspicion of spinal epidural abscess, immediate MRI with gadolinium is indicated, and lumbar puncture usually is contraindicated. Surgical treatment with appropriate antibiotic coverage is the mainstay of therapy [Hlavin et al., 1990; Rosenfeld and Rowley, 1994]. Antibiotics alone may be appropriate in selected cases [Slade and Lonano, 1990].

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OTHER BACTERIAL INFECTIONS OF THE NERVOUS SYSTEM Bartonella Bartonella species include, among others, B. henselae, an organism that is endemic in cats and transmitted to humans by cat scratches and fleas, and B. quintana, which is spread among humans under poor sanitary conditions by the human body louse. B. henselae is the agent of cat-scratch disease, a common disease in children characterized by a cutaneous papule at the inoculation site, regional lymphadenopathy, low-grade fever, malaise, and anorexia; a subset of patients present with Parinaud’s syndrome (oculoglandular disease). B. quintana causes the trench fever observed during World War I, a febrile illness associated with headaches, conjunctivitis, rash, myalgias, and bone pain. Both species can cause severe systemic diseases in immunocompromised patients, notably bacillary angiomatosis and peliosis hepatis. B. henselae causes CNS involvement in the form of encephalitis, cerebral vasculitis, or radiculitis. It is estimated that 2% to 10% of cases of cat-scratch disease are complicated by encephalitis. Typical symptoms include generalized tonic-clonic seizures and other deficits attributable to encephalitis [Carithers and Margileth, 1991]. Onset of the disease is usually subacute over days to weeks but may be acute if seizures are the primary manifestation. Imaging studies usually are normal, and cerebrospinal fluid indicates no signs of inflammation [Lewis and Tucker, 1986]. More recently, cases of encephalitis or focal cerebral lesions caused by B. quintana have been described [Parrott et al., 1997]. The diagnosis is based on serology, which does not discriminate reliably between the two species (cross-reactivity), and polymerase chain reaction, which can differentiate between them [Parrott et al., 1997]. The fastidious pleomorphic rods are difficult to culture, but can be detected in tissue by Warthin-Starry silver stain. Uncomplicated cat-scratch disease is self-limiting and does not require antimicrobial therapy. In patients with encephalitis or focal brain lesions associated with Bartonella infection, antibiotics may be prescribed, although their benefit is uncertain. Anecdotal reports indicate that trimethoprimsulfamethoxazole, macrolides, doxycycline, or quinolones, sometimes combined with rifampin, may be effective.

Mycoplasma pneumoniae Although Mycoplasma pneumoniae, a small bacterium without a cell wall, is primarily a respiratory tract pathogen causing pneumonia, it is prone to induce immune-mediated secondary clinical manifestations, such as hemolytic anemia, and has been implicated in diseases affecting the CNS. Of cases of encephalitis in children, 10% have been attributed to M. pneumoniae [Bitnun et al., 2001]. After a prodromal respiratory illness in about two thirds of patients, a variety of neurologic syndromes, such as meningitis, acute disseminated encephalomyelitis, hemorrhagic encephalitis, transverse myelitis, radiculitis, and an ascending paralysis similar to Guillain-Barré syndrome, have been described [Lin et al., 2002]. In 11 children with probable CNS involvement secondary to M. pneumoniae, the most common neurologic manifestations were seizures in 7 children and focal motor

deficits and ataxia in 4 each. Half of the children had cerebrospinal fluid abnormalities, primarily a mononuclear pleocytosis, and pathologic imaging studies, whereas 80% had abnormal findings on electroencephalogram [Bitnun et al., 2001]. The diagnosis of CNS involvement secondary to M. pneumoniae is difficult. Serology may indicate false-negative and false-positive results and should not be used as sole evidence to support the diagnosis. The organism can be cultured in cerebrospinal fluid or nervous tissue, but polymerase chain reaction seems to be more sensitive and provides the most compelling evidence for CNS invasion by the organism [Bitnun et al., 2001]. The mechanisms by which M. pneumoniae causes damage to nervous tissue have not been clearly delineated. Direct invasion of nervous tissue and immunemediated mechanisms may play a role, possibly depending on the type of neurologic manifestions. In suspected cases, antimicrobial therapy with drugs that penetrate into the CNS and have activity against M. pneumoniae (e.g., doxycycline, quinolones) should be instituted despite the lack of firm evidence of a beneficial effect [Bitnun et al., 2003]. The role of immune modulation (corticosteroids, immunoglobulins, plasmapheresis) is also of uncertain benefit [Sakoulas, 2001]. Recovery is prolonged, and permanent deficits are common, although children display a more favorable outcome than adults [Carstensen and Nilsson, 1987].

Leprosy Despite increasing efforts to control leprosy (Hansen’s disease), it is still prevalent in some countries of Asia, Africa, and South America. The disease should be considered in patients with persistent skin lesions and peripheral neuropathy who have lived in countries with warm climates and limited resources. Children comprise only a small proportion of patients presenting with leprosy (2% in India, the country with currently the highest prevalence) [Britton and Lockwood, 2004]. The disease is caused by Mycobacterium leprae, an obligatory intracellular bacillus with tropism for macrophages and Schwann cells. It is a chronic disease with incubation periods varying from months to many years. The clinical manifestations are determined by the host’s immune reaction based on genetic traits. On one extreme, tuberculous leprosy is characterized by limited disease, few bacilli, and a vigorous host defense driven by Th1 CD4 T cells. The other extreme is lepromatous leprosy, with extensive multibacillary disease of the skin and mucous membranes; many patients, including children, have intermediary forms. Leprosy affects only peripheral nerves and spares the CNS, probably because M. leprae binds to a form of laminin that is found only in the basal lamina of Schwann cells of peripheral nerves [Rambukkana et al., 1998]. The disease affects peripheral nerve trunks in fibro-osseus tunnels (e.g., ulnar, median, lateral popliteal, and posterior tibial nerves) and small dermal nerves. The symptoms are sensory and motor loss, hypesthesia, and anhydrosis. The diagnosis is made clinically based on the presence of one or more of the following signs: hypopigmented or reddish patches with reduced sensation, thickening of peripheral nerves, or acidfast bacilli on skin smears or biopsy material. Polymerase chain reaction methods are in development, but their clinical role has not been defined [Santos et al., 1997].

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Treatment depends on the form of disease and uses multidrug approaches consisting of dapsone, clofazimine, rifampin, ofloxacin, and minocycline [Britton and Lockwood, 2004]. Guidelines issued by the World Health Organization should be consulted. Neuritis (painful peripheral nerves, new anesthesia, or motor loss) and inflamed skin lesions should be treated with corticosteroids in addition to antimicrobial therapy [Britton, 1998]. REFERENCES Aebi C, Kaufmann F, Schaad UB. Brain abscess in childhood—long-term experiences. Eur J Pediatr 1991;150:282. Ahmed A, Hickey SM, Ehret S, et al. Cerebrospinal fluid values in the term neonate. Pediatr Infect Dis J 1996;15:298. Algren JT, Lal S, Cutliff SA, Richman BJ. Predictors of outcome in acute meningococcal infection in children. Crit Care Med 1993;21:447. Alleyne CH, Hassan M, Zabramski JM. The efficacy and cost of prophylactic and perioprocedural antibiotics in patients with external ventricular drains. Neurosurgery 2000;47:1124. Amaee FR, Comis SD, Osborne MP. N G-methyl-L-arginine protects the guinea pig cochlea from the cytotoxic effects of pneumolysin. Acta Otolaryngol 1995;115:386. Amitava AK, Alarm S, Hussain R. Neuro-ophthalmic features in pediatric tubercular meningoencephalitis. J Pediatr Ophthalmol Strabismus 2001;38:229. Anderson M. Management of cerebral infection. J Neurol Neurosurg Psychiatry 1993;56:1243. Arnold W, Bredberg G, Gstöttner W, et al. Meningitis following cochlear implantation: Pathomechanisms, clinical symptoms, conservative and surgical treatments. Otorhinolaryngology 2002;64:382. Aronin SI, Peduzzi P, Quagliarello VJ. Community-acquired bacterial meningitis: Risk stratification for adverse clinical outcome and effect of antibiotic timing. Ann Intern Med 1998;129:862. Arseni C, Nereantiu F. Multiple vascular thrombosis with vasculogenic lesions in the course of meningoencephalitis. Confin Neurol 1972;34:339. Ashwal S. Neurologic evaluation of the patient with acute bacterial meningitis. Neurol Clin 1995;13:549. Ashwal S, Perkin RM, Thompson JR, et al. Bacterial meningitis in children: Current concepts of neurologic management. Adv Pediatr 1993;40:185. Ashwal S, Stringer W, Tomasi L, et al. Cerebral blood flow and carbon dioxide reactivity in children with bacterial meningitis. J Pediatr 1990;117:523. Ashwal S, Tomasi L, Schneider S, et al. Bacterial meningitis in children: Pathophysiology and treatment. Neurology 1992;42:739. Auletta JJ, John CC. Spinal epidural abcesses in children: A 15-year experience and review of the literature. Clin Infect Dis 2001;32:9. Balmer P, Miller E. Meningococcal disease: How to prevent and how to manage. Curr Opin Infect Dis 2002;15:275. Baraff LJ, Lee SI, Schriger DL. Outcomes of bacterial meningitis in children: A meta-analysis. Pediatr Infect Dis J 1993;12:389. Basit AS, Ravi B, Banerji AK, et al. Multiple pyogenic brain abscesses: An analysis of 21 patients. J Neurol Neurosurg Psychiatry 1989;52:591. Bedford H, De Louvois J, Halket S, et al. Meningitis in infancy in England and Wales: Follow up at age 5 years. BMJ 2001;323:533. Berman PH, Banker BQ. Neonatal meningitis: A clinical and pathological study of 29 cases. Pediatrics 1966;38:6. Bernaerts A, Vanhoenacker FM, Parizel PM, et al. Tuberculosis of the central nervous system: Overview of neuroradiological findings. Eur Radiol 2003;13:1876. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699. Bhatt SM, Lauretano A, Cabellos C, et al. Progression of hearing loss in experimental pneumococcal meningitis: Correlation with cerebrospinal fluid cytochemistry. J Infect Dis 1993;167:675. Bifrare YD, Gianinazzi C, Imboden H, et al. Bacterial meningitis causes two distinct forms of cellular damage in the hippocampal dentate gyrus in infant rats. Hippocampus 2003;13:481. Bitnun A, Ford-Jones E, Blaser S, Richardson S. Mycoplasma pneumoniae encephalitis. Semin Pediatr Infect Dis 2003;14:96.

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Bitnun A, Ford-Jones EL, Petric M, et al. Acute childhood encephalitis and Mycoplasma pneumoniae. Clin Infect Dis 2001;32:1674. Bodino J, Lylyk P, de Valle M, et al. Computed tomography in purulent meningitis. Am J Dis Child 1982;136:495. Bonadio WA. The cerebrospinal fluid: Physiologic aspects and alterations associated with bacterial meningitis. Pediatr Infect Dis J 1992;11:423. Boyer KM, Gotoff SP. Alternative algorithms for prevention of perinatal group B streptococcal infections. Pediatr Infect Dis J 1998;17:973. Bradley JS, Scheld WM. The challenge of penicillin-resistant Streptococcus pneumoniae meningitis: Current antibiotic therapy in the 1990s. Clin Infect Dis 1997;24 (Suppl 2):S213. Britton WJ. The management of leprosy reversal reactions. Lepr Rev 1998;69:225. Britton WJ, Lockwood DN. Leprosy. Lancet 2004;363:1209. Brook I. Aerobic and anaerobic bacteriology of intracranial abscesses. Pediatr Neurol 1992;8:210. Brook I. Brain abscess in children: Microbiology and management. J Child Neurol 1995;10:283. Brown LW, Feigin RD. Bacterial meningitis: Fluid balance and therapy. Pediatr Ann 1994;23:93. Cairns H, Russell DS. Cerebral arteritis and phlebitis in pneumococcal meningitis. J Pathol Bacteriol 1946;58:649. Canica M, Dias R, Ferreira E. Neisseria meningitidis C:2b:P1.2,5 with intermediate resistance to penicillin, Portugal. Emerg Infect Dis 2004;10:526. Carithers HA, Margileth AM. Cat-scratch disease: Acute encephalopathy and other neurologic manifestations. Am J Dis Child 1991;145:98. Carstensen H, Nilsson KO. Neurological complications associated with Mycoplasma pneumoniae infection in children. Neuropediatrics 1987;18:57. Christen HJ. Lyme neuroborreliosis in children. Ann Med 1996;28:235. Cohen BA, Schenk VA, Sweeney DB. Meningitis-related hearing loss evaluated with evoked potentials. Pediatr Neurol 1988;4:18. Connors JM, Schubert C, Shapiro R. Syphilis or abuse: Making the diagnosis and understanding the implications. Pediatr Emerg Care 1998;14:139. Cottagnoud PH, Täuber MG. New therapies for pneumococcal meningitis. Expert Opin Investig Drugs 2004;13:393. Coulehan JL, Michaels RH, Hallowell C, et al. Epidemiology of Haemophilus influenzae type b disease among Navajo Indians. Public Health Rep 1984;99:404. Daniels SR, Price JK, Towbin RB, et al. Nonsurgical cure of brain abscess in a neonate. Childs Nerv Syst 1985;1:346. Darville T. Syphilis. Pediatr Rev 1999;20:160. De Gans J, Van de Beek D, for the European Dexamethasone in Adulthood Bacterial Meningitis Study Investigators. Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002; 347:1549. Derugin N, Wendland M, Muramatsu K, et al. Evolution of brain injury after transient middle cerebral artery occlusion in neonatal rats. Stroke 2000;31:1752. De Wals P, de Serres G, Niyonsenga T. Effectiveness of a mass immunization campaign against serogroup C meningococcal disease in Quebec. JAMA 2001;285:177. Drummond DS, de Jong AL, Giannoni C, et al. Recurrent meningitis in the pediatric patient—the otolaryngologist’s role. Int J Pediatr Otorhinolaryngol 1999;48:199. Eisenhut M, Meehan T, Batchelor L. Cerebrospinal fluid glucose levels and sensorineural hearing loss in bacterial meningitis. Infection 2003;31:247. Farinha NJ, Razali KA, Holzel H, et al. Tuberculosis of the central nervous system in children: A 20-year survey. J Infect 2000;41:61. Feigin RD, McCracken GH Jr, Klein JO. Diagnosis and management of meningitis. Pediatr Infect Dis J 1992;11:785. Feldman WE, Ginsburg CM, McCracken GH Jr, et al. Relation of concentrations of Haemophilus type b in cerebrospinal fluid to late sequelae of patients with meningitis. J Pediatr 1982;100:209. Filka J, Huttova M, Tuharsky J, et al. Nosocomial meningitis in children after ventriculoperitoneal shunt insertion. Acta Paediatr 1999;88:576. Förderreuther S, Tatsch K, Einhäupl KM, Pfister HW. Abnormalities of cerebral blood flow in the acute phase of bacterial meningitis in adults. J Neurol 1992;239:431. Francois M, Laccourreye L, Huy ET, Narcy P. Hearing impairment in infants after meningitis: Detection by transient evoked otoacoustic emissions. J Pediatr 1997;130:712.

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Fredricks DN, Relman DA. Application of polymerase chain reaction to the diagnosis of infectious diseases. Clin Infect Dis 1999;29:475. Gates GA, Miyamoto T. Cochlear implants. N Engl Med 2003;349:421. Geiseler PJ, Nelson KE. Bacterial meningitis without clinical signs of meningeal irritation. South Med J 1982;75:448. Gerber MA, Shapiro ED, Burke GS, et al. Lyme disease in children in southeastern Connecticut. Pediatric Lyme Disease Study Group. N Engl J Med 1996;335:1270. Gerke P, Rump LC. Leptospirosis—3 cases and a review. Clin Nephrol 2003;60:42. Gianinazzi C, Grandgirard D, Imboden H, et al. Caspase-3 mediates hippocampal apoptosis in pneumococcal meningitis. Acta Neuropathol (Berl) 2003;105:499. Giebink GS. The prevention of pneumococcal disease in children. N Engl J Med 2001;345:1177. Ginsberg L. Difficult and recurrent meningitis. J Neurol Neurosurg Psychiatry 2004;75 (Suppl 1):i16. Grande PO, Myhre EB, Nordstrom CH, Schliamser S. Treatment of intracranial hypertension and aspects on lumbar dural puncture in severe bacterial meningitis. Acta Anaesthesiol Scand 2002;46:264. Gray BM, Simmons DR, Mason H, et al. Quantitative levels of C-reactive protein in cerebrospinal fluid in patients with bacterial meningitis and other conditions. J Pediatr 1986;108:665. Green SM, Rothrock SG, Clem KJ, et al. Can seizures be the sole manifestation of meningitis in febrile children? Pediatrics 1993;92:527. Grimwood K, Anderson P, Anderson V, et al. Twelve year outcomes following bacterial meningitis: Further evidence for persisting effects. Arch Dis Child 2000;83:111. Grimwood K, Anderson VA, Bond L, et al. Adverse outcomes of bacterial meningitis in school-age survivors. Pediatrics 1995;95:646. Grimwood K, Nolan TM, Bond L, et al. Risk factors for adverse outcomes of bacterial meningitis. J Paediatr Child Health 1996;32:457. Hancock DO. A study of 49 patients with acute spinal extradural abscess. Paraplegia 1973;10:285. Hasbun R, Abrahams J, Jekel J Quagliarello VJ. Computed tomography of the head before lumbar puncture in adults with suspected meningitis. N Engl J Med 2001;345:1727. Hasegawa K, Chiba N, Kobayashi R, et al. Rapidly increasing prevalence of beta-lactamase-nonproducing, ampicillin-resistant Haemophilus influenzae type b in patients with meningitis. Antimicrob Agents Chemother 2004;48:1509. Heath PT, Nik NK, Baker CJ. Neonatal meningitis. Arch Dis Child Fetal Neonatal Educ 2003;88:F173. Hegde AS, Venkataramana NK, Das BS. Brain abscess in children. Child Nerv Syst 1986;2:90. Hernandez-Albujar S, Arribas JR, Royo A, et al. Tuberculous radiculomyelitis complicating tuberculous meningitis: Case report and review. Clin Infect Dis 2000;30:915. Hlavin ML, Kaminski HJ, Ross JS, et al. Spinal epidural abscess: A ten-year perspective. Neurosurgery 1990;27:177. Hoffman JA, Badger JL, Zhang Y, et al. Escherichia coli K1 aslA contributes to invasion of brain microvascular endothelial cells in vitro and in vivo. Infect Immun 2000;68:5062. Jones ME, Draghi DC, Karlowsky JA, et al. Prevalence of antimicrobial resistance in bacteria isolated from central nervous system specimens as reported by U.S. hospital laboratories from 2000 to 2002. Ann Clin Microbiol Antimicrob 2004;3:3. Kaaresen PI, Flaegstad T. Prognostic factors in childhood bacterial meningitis. Acta Pediatr 1995;84:873. Kaplan SL, Feigin RD. The syndrome of inappropriate secretion of antidiuretic hormone in children with bacterial meningitis. J Pediatr 1978;92:758. Kieseier BC, Paul R, Koedel U, et al. Differential expression of matrix metalloproteinases in bacterial meningitis. Brain 1999;122:1579. Kilpi T, Anttila M, Kallio MJT, Peltola H. Length of prediagnostic history related to the course and sequelae of childhood bacterial meningitis. Pediatr Infect Dis 1993;12:184. Kioumehr F, Dadsetan MR, Feldman N, et al. Postcontrast MRI of cranial meninges: Leptomeningitis versus pachymeningitis. J Comput Assist Tomogr 1995;19:713. Klein JO, Feigin RD, McCracken GH Jr. Report of the Task Force on Diagnosis and Management of Meningitis. Pediatrics 1986;78:959. Klein M, Koedel U, Pfister HW, Kastenbauer S. Morphological correlates of acute and permanent hearing loss during experimental pneumococcal meningitis. Brain Pathol 2003;13:123.

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CHAPTER 69

Viral Infections of the Nervous System James F. Bale, Jr.

Throughout recorded history, viral infections have caused considerable human suffering [Hughes, 1977]. Approximately 100 viral species from 13 different families have been associated directly or indirectly with disorders of the central or peripheral nervous systems (Box 69-1) [Johnson, 1998; McKendall and Stroop, 1994]. Although several viral infections have become infrequent because of immunization programs (Fig. 69-1), others remain potential threats to the well-being of children throughout the world. This chapter describes virus-induced neurologic disorders, emphasizing pathogenesis, clinical manifestations, epidemiology, and prevention.

GENERAL CONSIDERATIONS The pathogenesis of viral neurologic infections reflects the complex interactions of viral pathogens and host cells. Virusinduced neurologic disorders begin with virus entry and replication at extraneural locations, such as the skin, conjunctiva, or mucosal surfaces of the gastrointestinal, respiratory, and genital tracts [Fields and Knipe, 1990; Johnson, 1998; McKendall and Stroop, 1994]. Consequently, several factors, such as the gastric pH, local immune responses, integrity of the skin or mucosal barriers, or enzymes that inactivate viruses, influence whether viral pathogens successfully invade human tissues. Viruses, among the smallest microorganisms causing human disease, consist of an outer capsid, composed of glycoproteins and lipids, and an inner core, composed of RNA or DNA [Fields and Knipe, 1990]. Virus attachment and penetration of host cells depend on the virus encountering and attaching to receptors located on the surface of these cells. The molecular components of this interaction consist of the viral surface glycoproteins and the host cell surface proteins, such as preexisting cellular receptors that mediate certain essential cell functions [Fields and Knipe, 1990; Johnson, 1998; McKendall and Stroop, 1994]. An example of the virus-host interaction that leads to successful viral replication is the attachment of glycoprotein 120 of the human immunodeficiency virus (HIV) to the CD4 molecule and chemokine receptors of host cells [Deng et al., 1996]. Viruses enter host cells by endocytosis, release of genomic material, or fusion of the virus envelope with the cell membrane. Viruses use host cell synthetic pathways to uncoat their nucleic acid and to produce virus-encoded nucleic acids and proteins. Replicative strategies vary among viruses [Fields and Knipe, 1990]. The double-stranded DNA herpesviruses use RNA polymerases in the host cell nucleus to transcribe viral DNA into viral mRNA. The RNA of positive-strand RNA viruses serves as the viral mRNA,

whereas negative-strand RNA viruses first must be transcribed into an mRNA strand. By contrast, RNA-containing retroviruses, such as HIV, replicate via a DNA intermediary synthesized in the host cell cytoplasm by a viral-encoded reverse transcriptase [Fields and Knipe, 1990; McKendall and Stroop, 1994]. Next, virus-encoded immediate-early and early proteins facilitate the production of additional viral proteins and assembly of mature virus particles, called virions. Viral replication occurs within the nucleus or cytoplasm of the host

Box 69-1 SELECTED VIRUSES ASSOCIATED WITH HUMAN NEUROLOGIC DISEASE Family DNA viruses Herpesviridae

Adenoviridae RNA viruses Picornaviridae Togaviridae

Flaviviridae Bunyaviridae Reoviridae Paramyxoviridae Orthomyxoviridae Rhabdoviridae Arenaviridae Retroviridae

Examples Herpes simplex viruses; cytomegalovirus; varicellazoster virus; Epstein-Barr virus; human herpesviruses 6, 7, and 8 Adenovirus Poliovirus types 1 to 3; nonpolio enteroviruses, including enteroviruses 70 and 71 Eastern and western equine encephalitis viruses, Venezuelan equine encephalitis virus, rubella virus (non–arthropod borne) Japanese and St. Louis encephalitis viruses, West Nile virus La Crosse encephalitis virus (California encephalitis virus group) Colorado tick fever virus, rotavirus Mumps and measles viruses, parainfluenza virus, respiratory syncytial virus Influenza viruses Rabies virus Lymphocytic choriomeningitis virus Human T-cell lymphotropic virus type I, human immunodeficiency viruses type 1 and 2

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3000 2500

Vaccine-associated Total

1000

FIGURE 69-1. Data for paralytic poliomyelitis in the United States from 1960 to 1994 illustrate the dramatic decline in cases in the 1960s and the emergence of vaccine-related cases when oral polio vaccines were widely used [CDC, 1997b].

Cases

300 100 80 60 40 20 0

1960

1965

1970

1975

1980

1985

1990

Year

cell, depending on the viral species, and final assembly of viral particles uses existing host cell structures, such as the nuclear membrane or the Golgi apparatus [Fields and Knipe, 1990; McKendall and Stroop, 1994]. Mature virus particles are released from host cells by budding or lysis. Effective replication ultimately releases large quantities of infectious virions into the lymphatics and peripheral circulation of the infected host. Most viruses, including HIV and the enteroviruses, reach the central nervous system (CNS) hematogenously and penetrate the blood-brain barrier via the choroid plexus or through the vascular endothelium [Johnson, 1998; McKendall and Stroop, 1994]. CNS infection depends on the magnitude and duration of viremia, which reflect the efficiency of systemic viral replication and the ability of the virus to evade host defense mechanisms. Viral infections associated with transient viremia or low viral loads are less likely to lead to CNS invasion. A few viruses, notably the rabies virus and certain herpesviruses, reach the CNS predominantly through neural routes [Johnson, 1998; McKendall and Stroop, 1994]. Rabies virus, a negative-strand RNA virus, infects neuromuscular junctions, enters nerve endings, and travels by retrograde axonal transport to the neurons of the spinal cord. The virus then ascends to the brain. Transmission via nerve pathways also mediates the pathogenesis of herpes simplex virus type 1 encephalitis and the mucocutaneous reactivations of herpes simplex virus type 1, herpes simplex virus type 2, and varicella-zoster virus. Viruses induce neurologic signs and symptoms by damaging neural cells directly or by stimulating host-dependent immune responses that perturb neural cell function [Johnson, 1998; McKendall and Stroop, 1994]. The spectrum and severity of neurologic signs or symptoms depend on several factors, including neurovirulence (the capacity of the virus to cause disease within the nervous system), neurotropism (the propensity of the virus to infect specific cell groups of the CNS), and the nature of the host immune responses. Certain viruses, such as herpes simplex virus type 1, produce lytic infection of neuronal cells and cause hemorrhagic

necrosis within the brain, whereas other viruses, such as the La Crosse encephalitis virus, produce minimal cellular damage despite infection of neural cells. The JC virus, the cause of progressive multifocal leukoencephalopathy, selectively infects oligodendrocytes, causing demyelination [Johnson, 1998; McKendall and Stroop, 1994]. Some viruses may not infect neural cells directly, but induce immune-mediated processes, such as acute disseminated encephalomyelitis, a condition that accounts for approximately 10% to 15% of acute encephalitis cases in the United States [Gendelman et al., 1984; Johnson, 1996]. Cellular and humoral host immune responses and responses mediated by inflammatory cytokines (e.g., tumor necrosis factor and the interleukins) have major roles in inhibiting viral infections of the CNS [McKendall and Stroop, 1994]. The immune responses to viral infection also can provoke neurologic disorders, such as Guillain-Barré syndrome, Bell’s palsy, transverse myelopathy, or acute disseminated encephalomyelitis. These illnesses potentially complicate several childhood infections, including relatively benign viral syndromes [Johnson, 1996, 1998].

CLINICAL MANIFESTATIONS OF VIRAL NEUROLOGIC DISORDERS Neurologic disorders induced by viruses frequently begin with nonspecific, systemic features, such as malaise, anorexia, chills, fever, myalgias, vomiting, or headache. Certain viral infections produce rash, diarrhea, arthralgia, pharyngitis, cough, nausea, or abdominal pain during the prodrome. These prodromal symptoms and signs reflect viral invasion, replication in systemic tissues, and viremia.

Aseptic Meningitis Aseptic meningitis, the most frequent CNS disorder associated with viral infections (Box 69-2), produces headache, vomiting, irritability, and neck or back pain. Children appear moderately ill with photophobia and signs of meningeal

Bale / Viral Infections of the Nervous System

Box 69-2 VIRUSES ASSOCIATED WITH ASPETIC MENINGITIS AND ENCEPHALITIS IN CHILDREN Meningitis Nonpolio enteroviruses Herpes simplex virus types 1 and 2 Adenoviruses Colorado tick fever virus Polioviruses Lymphocytic choriomeningitis virus Epstein-Barr virus Human immunodeficiency virus St. Louis encephalitis virus Tick-borne encephalitis viruses Mumps virus Encephalitis Herpes simplex virus types 1 and 2 Eastern and western equine encephalitis viruses St. Louis encephalitis virus Japanese encephalitis virus West Nile virus La Crosse encephalitis virus Epstein-Barr virus Rabies virus Human immunodeficiency virus Tick-borne encephalitis viruses Varicella-zoster virus Cytomegalovirus Powassan virus Enterovirus 71 Mumps virus irritation, including Kernig’s sign (involuntary spasm of the hamstring muscle provoked by knee extension in a supine patient) or Brudzinski’s sign (flexion of the knees provoked by forced flexion of the neck). In a young infant, signs of meningeal irritation are often absent, and the features of CNS infection in general can be quite subtle. Systemic features in children with aseptic meningitis, such as skin rash, lymphadenopathy, hepatosplenomegaly, or parotid gland enlargement, can provide useful etiologic clues. The nonpolio enteroviruses, agents associated with the greatest proportion of aseptic meningitis cases in most regions, produce erythematous skin rashes or oral lesions. Hepatosplenomegaly or lymphadenopathy suggests infection with Epstein-Barr virus, cytomegalovirus, or possibly HIV. Children with aseptic meningitis have brief, self-limited illnesses and recover without sequelae.

Encephalitis Numerous viruses, including members of the arthropodborne and herpesvirus groups (see Box 69-2), have been associated with encephalitis in childhood. In addition to the headache, vomiting, and systemic features common in aseptic meningitis, children with viral encephalitis have seizures and altered sensorium, ranging from somnolence, or irritability, to coma [Whitley, 1990; Johnson, 1996]. Fever, a common but not invariable feature, ranges from low grade to 40° C or higher.

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Seizures affect 15% to 60% of infants or children with encephalitis and can be partial or generalized. Although partial seizures increase the probability of herpes simplex virus encephalitis, partial seizures can accompany several forms of viral encephalitis, including relatively mild cases resulting from the nonpolio enteroviruses or from the La Crosse encephalitis virus, the agent causing most cases of California encephalitis. Neurologic examination of children or adolescents with encephalitis reveals hyperreflexia, ataxia, cognitive disturbances, or focal deficits, such as aphasia or hemiparesis. Severely affected patients may exhibit signs of increased intracranial pressure, including pupillary, respiratory, and postural abnormalities. Outcome of viral encephalitis varies considerably, depending on the virulence of the pathogen, the immune competence of the infected host, and the availability of specific antiviral therapy.

Other Neurologic Disorders Myelitis, Guillain-Barré syndrome, Bell’s palsy, acute cerebellar ataxia, myositis, and poliomyelitis-like disorders are additional neurologic conditions that can be associated with antecedent childhood viral infections (Box 69-3). Myelitis and Guillain-Barré syndrome frequently begin with vague sensory phenomena, but flaccid weakness and areflexia become the predominant neurologic signs. Marked sensory dysfunction, such as a sensory loss corresponding to a spinal level, indicates spinal cord involvement, whereas facial paralysis favors Guillain-Barré syndrome. Autonomic nervous system dysfunction also can be a major complication of the latter condition, producing life-threatening cardiac dysrhythmias or blood pressure fluctuations. Children with myelitis or Guillain-Barré syndrome can have permanent neurologic deficits despite appropriate medical management. Cerebellar ataxia (see Chapter 58), as summarized by Connolly and associates, can complicate systemic infections with several different viruses [Connolly et al., 1994]. Varicella-associated ataxia typically begins 5 to 14 days after the onset of the characteristic rash, although occasional cases can appear during the preeruptive phase of infection. Virus-induced ataxia and the associated behavioral disturbance peak in severity at onset or within 1 to 2 weeks, then improve during the ensuing 4 to 8 weeks. Most children with ataxia after varicella recover completely [Connolly et al., 1994], but some children with virus-induced ataxia have residual cerebellar or behavioral deficits. Before widespread immunization, the polioviruses (usually type 1) could infect the anterior horn cells of the spinal cord and cause asymmetric paralysis of the extremities (infantile paralysis) and often respiratory failure [Johnson, 1998]. Currently, several viruses, including West Nile virus, enterovirus 71, and other nonpolio enteroviruses, produce disorders that can mimic classic poliomyelitis [Cheng-Yu et al., 2001; Huang et al., 1999; Li et al., 2003]. The features of these disorders consist of symmetric or asymmetric paralysis and magnetic resonance imaging (MRI) evidence of anterior horn cell damage [Maschke et al., 2004].

Intrauterine and Perinatal Viral Infections Intrauterine infections with certain viruses (and several nonviral pathogens) (see Box 69-3) can seriously damage the

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Box 69-3 VIRUSES ASSOCIATED WITH MYELOPATHY, GUILLAIN-BARRÉ SYNDROME, ACUTE CEREBELLAR ATAXIA, AND INTRAUTERINE INFECTION Myelopathy Varicella-zoster virus Herpes simplex viruses Nonpolio enteroviruses Human T-cell lymphotropic virus type I Human immunodeficiency virus Cytomegalovirus West Nile virus Guillain-Barré Syndrome Epstein-Barr virus Cytomegalovirus Nonpolio enteroviruses Mumps virus Human immunodeficiency virus Acute Cerebellar Ataxia Varicella-zoster virus Enteroviruses Epstein-Barr virus Mumps virus Measles virus Intrauterine Infection Cytomegalovirus Herpes simplex viruses (especially type 2) Rubella virus Lymphocytic choriomeningitis virus Varicella-zoster virus Human immunodeficiency virus Venezuelan equine encephalitis virus West Nile virus

developing CNS, causing hydrocephalus, cerebral atrophy, intracranial calcifications, schizencephaly, porencephaly, or hydranencephaly [Bale, 1994]. Linked conceptually by the TORCH (toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus) acronym, these viruses produce similar neonatal symptoms and signs consisting of intrauterine growth retardation, hepatosplenomegaly, jaundice, and petechial or purpuric rash [Bale and Murph, 1992]. Neurologic features include microcephaly, chorioretinitis, macrocrania, sensorineural hearing loss, seizures, hypotonia, and focal deficits. Infants with intrauterine infections have varied prognoses, depending on the virus, the timing of intrauterine infection, and the extent of CNS damage. Infants with perinatal viral infections involving the CNS challenge the clinician because the historical and clinical features can be vague during the initial phase of the illness. Early symptoms of serious viral CNS disease, including neonatal herpes simplex virus encephalitis, may consist only of poor feeding or fussiness, and the physical examination often reveals few signs localizing to the CNS [Bale and Murph, 1997]. Consequently the physician examining an illappearing young infant must consider the possibility of a CNS infection. Infants with perinatal viral infections have

varied prognoses, depending on the agent, extent of disease, and availability of specific antiviral therapy.

Slow Viral Infections Conventional viral pathogens have been associated with several unusual chronic disorders of the CNS, historically termed slow viral infections. These include subacute sclerosing panencephalitis [Dyken and Cunningham, 1989], postrubella panencephalitis, chronic nonpolio enterovirus infection, and progressive multifocal leukoencephalopathy caused by the JC virus (a polyomavirus unrelated to Creutzfeldt-Jakob disease, but named for the initials of the patient from whom the virus initially was isolated). Children with these disorders generally lack systemic signs of infection and have clinical signs restricted to the CNS, including dementia, spasticity, paralysis, vision loss, and seizures. These slow viral disorders typically cause progressive debility and death. Prions (transmissible proteinaceous particles), novel agents with biologic characteristics distinct from conventional viral pathogens, produce several progressive, degenerative neurologic disorders, including kuru, CreutzfeldtJakob disease, Gerstmann-Sträussler-Scheinker syndrome, fatal familial insomnia, and a Creutzfeldt-Jakob disease variant linked to bovine spongiform encephalopathy [Prusiner, 1997]. These disorders typically affect adults and manifest with progressive dementia, myoclonus, cerebellar ataxia, or sleep disturbances [Prusiner, 1997; Prusiner and Hsiao, 1994]. Adolescents have been described with variant Creutzfeldt-Jakob disease and with classic CreutzfeldtJakob disease acquired by contact with prion-contaminated cortical electrodes or human growth hormone extracts [Brown, 1988; Brown et al., 1985, 1994; Koch et al., 1985; Monreal et al., 1981]. Creutzfeldt-Jakob disease and other prion-induced disorders cannot be treated with specific antimicrobial agents and invariably lead to death.

EPIDEMIOLOGY OF VIRAL INFECTIONS Worldwide statistics suggest that viral encephalitis develops in several thousand persons annually, and that many thousands more experience aseptic meningitis. The rates of encephalitis range from 3 to 8 cases per 100,000 persons [Johnson, 1996; Nicolosi et al., 1986] to 33 per 100,000 person-years, with rates highest among children [Koskiniemi et al., 1991, 2001]. Japanese encephalitis, a disease of young children, accounts for several thousand cases of encephalitis annually in the endemic regions of India and eastern Asia [CDC, 1993a]. Until the emergence of West Nile virus in the United States in 1999, the Centers for Disease Control and Prevention received reports of 200 to 500 cases of arboviral encephalitis and several thousand cases of aseptic meningitis every year (Fig. 69-2) [CDC, 1993a]. In 2003, the Centers for Disease Control and Prevention recorded more than 2800 human cases of neuroinvasive disease caused by West Nile virus [CDC, 2004a]. Because of mandatory vaccination of domestic dogs, the United States has fewer than five indigenous cases of human rabies per year [Krebs et al., 2002; Plotkin, 2000]. By contrast, rabies cases average

Bale / Viral Infections of the Nervous System

FIGURE 69-2. Data regarding the incidence of aseptic meningitis in the United States as reported to the Centers for Disease Control and Prevention from 1986 to 1992 [CDC, 1993a].

1.2 1.1 Reported cases per 100,000 population

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1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 1986

1987

1988

1989 1990 Year (month)

between 1 per 1 million and 1 per 100,000 persons annually in Africa and Asia, causing several thousand deaths per year [Dutta, 1999; Fishbein and Robinson, 1993; Haupt, 1999]. Some viruses, such as arthropod-borne and rabies viruses, are maintained in environmental reservoirs and transmitted by animals or insect vectors, whereas others, such as members of the herpesvirus family, are harbored by humans and transmitted by contact with human blood, tissues, or body fluids [Bale, 2003]. This distinction, environmental versus human etiology, provides a useful paradigm for understanding the epidemiology of most viral infections of the CNS. Several additional factors, including the age and immunocompetence of the host and the availability of vaccines or other preventive measures, influence the probability or severity of viral neurologic diseases.

1991

1992

1993

Environmentally derived viral pathogens display relatively uniform epidemiologic characteristics. Mosquitoes, ticks, and biting flies serve as the vectors for most human viral diseases, aside from rabies. Human disease occurs most commonly when vectors are active, typically in spring, summer, and fall in temperate climates. Human disease also exhibits geographic distributions that correspond to the habitat of the vector. Hiking, camping, and outdoor professions facilitate vector contact and enhance the probability of infections with vector-borne diseases. By contrast, human-derived viral pathogens require direct contact with the infected host, either by exposure to aerosols that contain infectious viruses or by contact with tissues or body fluids from infected individuals. Herpes simplex virus type 1 can be acquired by oral-oral or oral-genital contact, whereas

FIGURE 69-3. Map showing the geographic distribution of California (La Crosse) encephalitis cases reported to the Centers for Disease Control and Prevention from 1964 to 1997. An average of 73 cases was reported annually. (Adapted from the Centers for Disease Control and Prevention. Available at: www.cdc.gov/ncidod/dvbid/arbor/lac _map_sm.htm.)

Human cases reported in 27 states

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varicella-zoster virus (the virus causing chickenpox) usually is transmitted by exposure to aerosolized particles that contain varicella-zoster virus. Cytomegalovirus can be acquired by direct contact with infected secretions or by transfusion of blood products or transplantation of organs or tissues from cytomegalovirus-seropositive persons [Bale, 1999]. La Crosse virus encephalitis, a frequently recognized arthropod-borne neurologic infection in the United States, illustrates the epidemiologic characteristics of environmentally derived agents [Balfour, 1974]. The disorder affects children who reside in the East and Midwest (Fig. 69-3), prime habitat for the Aedes triseriatus mosquito, a species that breeds preferentially in water that collects in tree trunks (“tree-holes”) and discarded automobile tires. Cases occur from June to early October, reflecting the seasonal activity of the mosquito vector, and frequently involve males 5 to 15 years old who enter wooded areas to hunt or play. Members of the herpesvirus family (herpes simplex virus types 1 and 2; cytomegalovirus; Epstein-Barr virus; varicellazoster virus; and human herpesviruses types 6, 7, and 8) display few seasonal or geographic predilections [Whitley et al., 1982]. When Whitley and colleagues reviewed the epidemiology of herpes simplex virus encephalitis, they observed no unique characteristics with regard to race, sex, age, season, or geographic location [Whitley et al., 1982]. Epidemiologic data indicate, however, that herpes simplex virus type 1 is the most common cause of nonepidemic encephalitis in persons older than age 50 years. These data reflect the current opinion that most cases of herpes simplex virus encephalitis in older individuals result from reactivated herpes simplex virus infections rather than primary exposures to the virus. Infection with HIV illustrates the potential effects that host behaviors and immune competence have on the epidemiology and spectrum of disease resulting from neurotropic viral agents. Early in the epidemic of acquired immunodeficiency syndrome (AIDS) in the United States, intravenous drug use, homosexuality, and sexual contact with persons in these groups increased substantially the probability of HIV infection. When CD4+ cell counts decrease to less than 200/mL in persons infected with HIV, opportunistic infections, including infections resulting from other neurotropic viruses, become more likely. The latter conditions include

progressive multifocal encephalopathy and cytomegalovirus retinitis and encephalitis [Jacobson, 1997], which are uncommon disorders in immunocompetent persons.

DIAGNOSTIC EVALUATION An infant, child, or adolescent with fever and neurologic signs or symptoms requires a thorough neurodiagnostic evaluation that may include a cerebrospinal fluid examination, electrophysiologic studies (e.g., electroencephalogram [EEG] or electromyography/nerve conduction velocities), and an imaging study of the brain or spinal cord. The precise sequence of these studies depends on the nature and severity of the child’s condition and the clinician’s concerns regarding the presence of increased intracranial pressure or systemic conditions requiring specific interventions. The clinician must remain alert for signs that suggest a treatable viral disorder, such as herpes simplex virus encephalitis, but also must consider nonviral causes of CNS dysfunction, such as bacterial meningitis, brain abscess, stroke, tumor, or noninfectious, inflammatory conditions.

Cerebrospinal Fluid The cerebrospinal fluid in viral meningitis or encephalitis typically has a lymphocytic pleocytosis (5 to 500 cells/mL), mildly elevated protein content (usually <200 mg/dL), and normal or slightly depressed glucose content (Table 69-1). The cerebrospinal fluid profile can vary, however, depending on the specific viral pathogen and the timing of the lumbar puncture. Many patients (5% to 15%) with herpes simplex virus encephalitis have an entirely normal initial cerebrospinal fluid examination [Koskiniemi, 1984; Whitley et al., 1982], and 10% or more of children with California encephalitis have normal cerebrospinal fluid parameters [Balfour, 1974]. Early in the course of viral CNS infections, the cerebrospinal fluid frequently has a preponderance of neutrophils, mimicking bacterial disease, but typically shifts to a lymphocytic pleocytosis over time [Feigin and Shackelford, 1973]. Protein elevations in viral meningitis and encephalitis tend to be modest (often <100 mg/dL), and glucose

TABLE 69-1 Cerebrospinal Fluid Profiles in Central Nervous System Infections ORGANISM PARAMETER

Virus

Bacterium

Mycobacterium

Fungus

Cell number* Cell type† Protein content‡ Glucose content§

N to ↑↑ Lymph N to ↑ N to ↓

↑ to ↑↑↑ PMN ↑ to ↑↑↑ ↓ to ↓↓↓

↑ to ↑↑ Lymph N to ↑↑ N to ↓

N to ↑↑ Mixed N to ↑↑ N to ↓

*Cell number: N, <5; ↑, 10-100/mm3; ↑↑, 100-1000/mm3; ↑↑↑, >1000/mm3. † Dominant cell type. Lymph, lymphocyte; PMN, polymorphonuclear leukocyte; Mixed, variable mix of PMNs and lymphocytes depending on the organism. PMNs can be the dominant cerebrospinal fluid leukocyte during the early phase of viral central nervous system infections, and meningitis with certain bacteria, notably Listeria monocytogenes, can be associated with a predominance of lymphocytes. Eosinophils occasionally can be observed in viral, fungal, or parasitic central nervous system infections. ‡ Protein content: N, <50 mg/dL; ↑, 50-100 mg/dL; ↑↑, 100-500 mg/dL; ↑↑↑, >500 mg/dL. § Glucose content: N, cerebrospinal fluid–to-serum ratio of >0.6; ↓, cerebrospinal fluid–to-serum ratio of <0.4; ↓↓↓, 0. Virus-associated reductions in the cerebrospinal fluid glucose content are usually modest, with levels ranging from 25 to 50 mg/dL in herpes simplex, lymphocytic choriomeningitis, and mumps viruses.

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content in viral diseases, although modestly depressed in some cases (30 to 50 mg/dL), rarely reaches the low levels (e.g., <20 mg/dL) common in acute bacterial meningitis. Nonetheless, some viral infections, such as eastern equine encephalitis, may have cerebrospinal fluid parameters that seem more “bacterial” than “viral” [Przelomski et al., 1988]. The cerebrospinal fluid in viral myelitis can be normal or have features similar to those of aseptic meningitis (lymphocytic or mixed pleocytosis, normal glucose content, and normal or mildly elevated protein content). Children with Guillain-Barré syndrome frequently display an albuminocytologic dissociation (elevated protein content and no or few white blood cells), but the cerebrospinal fluid may be entirely normal early in the course of Guillain-Barré syndrome. Children with acute disseminated encephalitis frequently have cerebrospinal fluid profiles that mimic cerebrospinal fluid profiles of viral encephalitis or meningitis.

Electrodiagnostic Studies The EEG has an important role in evaluating pediatric patients with suspected viral encephalitis. Although the EEG occasionally can be normal in such patients, infants or children with encephalitis usually have abnormal studies consisting of slowing or epileptiform discharges that can be diffuse or focal. Because herpes simplex virus encephalitis of children or adults frequently produces focal EEG features [Whitley et al., 1982], consisting of slowing, sharp-wave discharges, or periodic lateralizing epileptiform discharges, the EEG has considerable value in suspected herpes simplex virus encephalitis. Although these abnormalities usually localize to the temporal lobes in children, atypical cases of herpes simplex virus encephalitis with other cortical localizations have been confirmed by MRI and polymerase chain reaction detection of herpes simplex virus DNA in the cerebrospinal fluid [Schlesinger et al., 1995]. Neonates also may have early EEG abnormalities that alert clinicians to the possibility of herpes simplex virus encephalitis [Mikati et al., 1990; Mizrahi and Tharp, 1982]. The EEG has modest sensitivity and specificity in several other forms of encephalitis. Of patients with La Crosse encephalitis or eastern equine encephalitis, 40% to 50% have lateralizing EEG abnormalities that suggest focal brain disease [Hilty et al., 1972; Przelomski et al., 1988]. In many cases the EEG shows only diffuse slowing of variable severity. Electrophysiologic studies, such as electromyography and nerve conduction velocities, have utility in children with suspected postinfectious polyneuropathies. Although nerve conduction velocities can be normal early in Guillain-Barré syndrome, children have conduction block or absent F waves, a neurodiagnostic measure of the integrity of spinal reflex arcs. Within 3 weeks of disease onset, most patients with Guillain-Barré syndrome have reduced nerve conduction velocities, indicating segmental demyelination and differentiating Guillain-Barré syndrome from other causes of acute weakness, such as myelitis. Electrophysiologic studies of peripheral nerves also have diagnostic value in selected patients with Bell’s palsy or postinfectious lumbar or brachial plexopathies.

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Neuroimaging Computed tomography (CT) and MRI have major roles in evaluating infants and children with CNS viral infections [Bale, 1999; Barkovich, 1995; Kimberlin, 2004]. Depending on their clinical status, patients with suspected viral encephalitis should undergo a neuroimaging study early in the course of their illnesses. Although large mass lesions, such as tumors or brain abscess, can be detected reliably by CT, especially when obtained with contrast enhancement, MRI has sensitivity that exceeds CT, especially in patients with herpes simplex encephalitis [Domingues et al., 1998; Schroth et al., 1987]. Because of the sensitivity of MRI for the early changes of herpes simplex encephalitis, MRI is the preferred imaging modality in children with suspected viral encephalitis. MRI in non-neonatal herpes simplex encephalitis reveals T2 prolongation in the medial temporal lobe, orbitofrontal region, or cingulate gyrus and cortical enhancement in these regions when the paramagnetic agent, gadolinium, is administered intravenously [Barkovich, 1995]. Atypical features can be observed, however, including parieto-occipital localization of T2 prolongation and abnormalities of diffusionweighted images [Leonard et al., 2000; Maschke et al., 2004]. Neuroimaging frequently reveals diffuse or focal brain edema in infants with neonatal herpes simplex encephalitis, a disease that differs pathogenetically from herpes simplex encephalitis of older children [Bale, 2004; Kimberlin, 2004]. Neonatal herpes simplex encephalitis results from hematogenous transmission of the virus to brain, whereas herpes simplex encephalitis in older individuals usually reflects reactivation and neural transmission of herpes simplex virus. MRI can detect focal abnormalities of the basal ganglia in children with Japanese or Epstein-Barr virus encephalitis [Maschke et al., 2004], and patients with neuroinvasive West Nile virus infections can have imaging abnormalities of the substantia nigra, brainstem, or spinal cord [Maschke et al., 2004]. The sensitivity of MRI exceeds that of CT in detecting the lesions of acute disseminated encephalomyelitis, a condition that mimics the clinical features of viral encephalitis [Dunn et al., 1986; Rust, 2000] and often responds to corticosteroids. In this condition, MRI reveals multifocal areas of T2 prolongation involving the white matter of the cerebrum, cerebellum, and brainstem. MRI in other forms of viral encephalitis can be normal; reveal diffuse, nonspecific changes of edema or inflammation; or have focal abnormalities that mimic herpes simplex virus encephalitis [Barkovich, 1995]. Children with aseptic meningitis typically have normal brain parenchyma when studied by CT or MRI. Infants with suspected intrauterine viral infections should be evaluated by CT initially because small intracranial calcifications, a common feature of intrauterine infection, are detected better by this imaging modality than by MRI or ultrasonography [Bale and Murph, 1992; Barkovich, 1995]. These infants may benefit from a subsequent MRI study, however, to identify coexisting brain abnormalities, such as lissencephaly-pachygyria, periventricular leukomalacia, or cortical dysplasia. CT or MRI may reveal hydrocephalus, hydranencephaly, or cystic encephalomalacia in infants with intrauterine or perinatal viral infections.

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TABLE 69-2 Preferred Diagnostic Methods for Selected Viral Infections of the Nervous System AGENT

NEONATAL INFECTION

NON-NEONATAL INFECTION

HSV

CSF PCR

CMV

Cultures of CSF; swabs of nasopharynx, conjunctivae, and skin lesions; CSF PCR Cultures of urine and saliva

VZV

Difficult by any method

EBV HHV 6, HHV 7, HHV 8 Enteroviruses Arthropod-borne encephalitis viruses Rabies virus

— — Cultures of swabs of rectum and nasopharynx; serum and CSF PCRs Virus-specific IgM

Lymphocytic choriomeningitis virus HIV

Serologic studies of infant and mother

—

Plasma PCR

Cultures of urine, saliva, or circulating leukocytes; serum and CSF PCR Culture of skin vesicle fluid, immunohistology, CSF PCR Acute and convalescent sera, CSF PCR CSF PCR Serum and CSF PCR Virus-specific CSF or serum IgM; CSF PCR; acute and convalescent sera Virus culture, serum IgG after day 15; immunohistology of skin biopsy Acute and convalescent sera; CSF PCR Serologic studies; Western blot; plasma and CSF PCR

CMV, cytomegalovirus; CSF, cerebrospinal fluid; EBV, Epstein-Barr virus; HHV, human herpesvirus; HIV, human immunodeficiency virus; HSV, herpes simplex virus; PCR, polymerase chain reaction; VZV, varicella-zoster virus.

Microbiologic Evaluation The diagnostic techniques available to the clinician include serology, cell culture, immunohistology, and molecular methods, such as polymerase chain reaction (Table 69-2) [Gleaves et al., 1994]. Serology provides indirect evidence of infection because it depends on the host to mount an antibody response specific to the etiologic agent. Certain infections, such as infections resulting from Epstein-Barr, lymphocytic choriomeningitis, and West Nile viruses, usually are identified by serologic studies, and others, such as La Crosse, eastern and western equine, St. Louis, and Japanese encephalitis viruses, can be diagnosed rapidly by immunoglobulin M (IgM) antibody capture methods. Cell culture provides direct evidence of infection by detecting viral pathogens in cerebrospinal fluid, blood, or other body fluids. Viruses that lend themselves to this diagnostic approach include the herpesviruses (especially cytomegalovirus and certain herpes simplex virus infections), enteroviruses, adenoviruses (a rare cause of CNS infection), HIV, and rabies virus. Cultures of cerebrospinal fluid or mucosal surfaces often yield virus in neonatal herpes simplex virus infections [Kimberlin, 2004], but infectious virus can be detected in the cerebrospinal fluid in less than 5% of cases of non-neonatal herpes simplex virus encephalitis. Consequently, polymerase chain reaction has become the standard for evaluation of infants and children with suspected herpes simplex virus encephalitis or meningitis, especially as laboratories establish polymerase chain reaction protocols with high sensitivity and specificity [Mitchell et al., 1997; Whitley and Gnann, 2002]. Specific immunohistologic detection of herpes simplex virus and varicella-zoster virus has supplanted the nonspecific and insensitive Tzanck preparation. Polymerase chain reaction detects herpes simplex virus DNA in the cerebrospinal fluid in most neonatal or nonneonatal cases of herpes simplex virus encephalitis or meningitis [Domingues et al., 1998; Kimberlin et al., 1996; Lakeman and Whitley, 1995; Mitchell et al., 1997; Read

et al., 1997]. The specificity of polymerase chain reaction in herpes simplex virus encephalitis approaches 100%, whereas the sensitivity ranges from 75% in neonates to greater than 95% in children or adolescents [Johnson, 1996; Kimberlin, 2004]. Because polymerase chain reaction-negative cases of herpes simplex virus encephalitis occur, however, clinicians must use sound clinical judgment when making treatment decisions. Polymerase chain reaction also affords rapid diagnosis of infections with cytomegalovirus, enteroviruses, JC virus, human herpesvirus 6, varicella-zoster virus, and HIV and can be used to detect nonviral agents that cause intrauterine infection, encephalitis, or aseptic meningitis [Read et al., 1997; Souza and Bale, 1995].

OVERVIEW OF TREATMENT Therapy for CNS viral infections must be tailored to illness severity, the suspected agent, and the availability of specific antiviral medications. Numerous nonviral and noninfectious conditions can produce clinical signs that mimic signs of CNS infection. Children with life-threatening viral diseases, such as herpes simplex virus encephalitis, require hospitalization in a skilled nursing unit, such as a pediatric intensive care unit, which can provide frequent assessment of the child’s responsiveness and anticipatory monitoring for seizures and increased intracranial pressure. Outcome of CNS viral infection varies according to the viral pathogen, the child’s age, and availability of specific antiviral therapy (Table 69-3).

Antiviral Chemotherapy An increasing number of viral CNS infections, including herpes simplex virus encephalitis, varicella-zoster virus encephalitis, systemic or neurologic HIV infections, and invasive cytomegalovirus infections, can be treated with specific antiviral drugs. In general, the available agents inhibit viral infection by binding with viral nucleic acid and

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TABLE 69-3 Outcome of Selected Viral Central Nervous System Disorders DISORDER Herpes simplex virus* Congenital infection Neonatal encephalitis Non-neonatal encephalitis Cytomegalovirus Symptomatic congenital Encephalitis-AIDS Enterovirus Aseptic meningitis Encephalitis Togaviruses Eastern equine encephalitis Western equine encephalitis Rubella virus Symptomatic congenital Flaviviruses Japanese encephalitis St. Louis encephalitis West Nile virus Bunyaviruses La Crosse encephalitis Paramyxoviruses Measles encephalomyelitis Subacute measles encephalitis SSPE Rabies virus† Lymphocytic choriomeningitis virus Symptomatic congenital Aseptic meningitis Retroviruses‡ HTLV-I HIV

MORTALITY (%)

MORBIDITY (%)

10 <10 <10

100 40 40

5 >50

95 High

Negligible Negligible

Negligible Low

40 10

50 15

5

90

40 10 5

50 20 33

Negligible

15

20 80 100 100

50 100 — —

40 Negligible

80 Negligible

Negligible Variable

100 Variable

*Assumes appropriate management with acyclovir. Rates for untreated cases are higher. † Survival reported in <10 persons (total) with symptomatic rabies [American Academy of Pediatrics, 2003]. ‡ Outcomes related to current management. AIDS, acquired immunodeficiency syndrome; HIV, human immunodeficiency virus; HTLV-I, human T-cell lymphotropic virus type I; SSPE, subacute sclerosing

preventing successful DNA or RNA replication. Acyclovir, a drug effective against herpes simplex virus and varicellazoster virus, has few side effects and should be initiated as soon as the possibility of herpes simplex virus infection is considered. Additional useful antiviral agents include ganciclovir and foscarnet, effective in cytomegalovirus infections; ribavirin, potentially useful in RNA virus infections; inosine pranobex, potentially beneficial in subacute sclerosing panencephalitis; and several potent antiretroviral drugs, including zidovudine, didanosine, ritonavir, and others.

Supportive Care Many viral CNS infections, including West Nile encephalitis and other infections with arthropod-borne viruses, cannot be treated with specific therapy. Several other disorders, such as enteroviral meningitis or postvaricella ataxia, resolve spontaneously with conservative management. Children may require adjunctive therapies, consisting of antipyretics, intravenous fluids, antiepileptic drugs, and occasionally corticosteroids. Seizures, a frequent complication of viral encephalitis, can be treated acutely with lorazepam and may require maintenance therapy with phenobarbital or phenytoin in standard

doses. Occasionally, high-dose, intravenous barbiturate or benzodiazepine therapy is required to inhibit seizure activity refractory to standard therapies. Several of the newer antiepileptic drugs may also be used, although these have not been studied specifically for postencephalitic epilepsy. Increased intracranial pressure, another potentially lifethreatening complication of encephalitis, may require osmotic diuretic therapy, cautious fluid restriction, and hyperventilation. Critically ill patients require referral to tertiary medical centers for intensive monitoring and evaluation by specialists in neurology, critical care, neurosurgery, and infectious disease. Children or adolescents with optic neuritis, myelitis, inflammatory vasculitis, and acute disseminated encephalomyelitis may benefit from corticosteroid therapy. Regimens can be modeled after the successful treatment of optic neuritis in adults. Children can receive 2 weeks of daily corticosteroids, beginning with a short course of high-dose methylprednisolone intravenously (e.g., 15 mg/kg/day divided equally every 6 hours for 3 to 5 days) and followed by prednisone orally (e.g., 1 to 2 mg/kg/day for 7 to 10 days). Children with postviral Guillain-Barré syndrome do not benefit from corticosteroids but may improve after intravenous immunoglobulin [Abd-Allah et al., 1997; Jansen et al., 1992; Ropper, 1992].

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SPECIFIC VIRAL INFECTIONS Herpesviridae The human herpesviruses, a family of DNA viruses, commonly produce neurologic disease after infections in utero, perinatally, or postnatally. Important members of this family are herpes simplex virus types 1 and 2, both of which cause neonatal infection and focal encephalitis; cytomegalovirus, a major cause of intrauterine viral infection and opportunistic infections in immunocompromised hosts; Epstein-Barr virus, a cause of Guillain-Barré syndrome and encephalitis; human herpesvirus 6 and human herpesvirus 7, the agents of roseola and a frequent cause of febrile convulsions; and varicella-zoster virus, often associated with postinfectious ataxia. Other neurologic conditions linked to the herpesviruses include aseptic meningitis, myelitis, optic neuritis, Bell’s palsy, and postinfectious neuritis.

Herpes Simplex Virus CLINICAL FEATURES Most humans acquire herpes simplex virus type 1 by oral transmission during childhood [Corey and Spear, 1986]. Primary herpes simplex virus infections are frequently asymptomatic, although some children experience vesicular pharyngitis or gingivostomatitis, a condition associated with fever, diminished oral intake, drooling, and herpetic lesions of the face and mouth. By contrast, herpes simplex virus type 2, usually acquired by sexual contact, causes genital lesions in young adults. In children, herpes simplex virus-induced neurologic infections can be due to primary or reactivated infections, whereas most herpes simplex virus–induced disease after age 30 years, whether due to herpes simplex virus type 1 or type 2, reflects reactivated infection. Neonatal herpes simplex virus infection, most often due to herpes simplex virus type 2, can be categorized as (1) skin, eyes, and mouth disease; (2) disseminated disease; or (3) encephalitis and can affect approximately 43%, 23%, and 34% of herpes simplex virus–infected infants [Kimberlin, 2004; Whitley et al., 1988]. In addition, a small proportion (5%) of herpes simplex virus–infected infants have intrauterine infections [Hutto et al., 1987]. Neonatal herpes simplex encephalitis can be accompanied by pneumonitis, hepatitis, or disseminated intravascular coagulopathy, but one third of infants with neonatal herpes simplex virus encephalitis have disease restricted to the CNS [Koskiniemi et al., 1989]. Neonatal herpes simplex virus disease usually begins with nonspecific clinical features (poor oral intake, behavioral change, or fever) during the second or third weeks of life [Kimberlin, 2004]. Neonatal herpes simplex virus disease can begin as early as the first day of life, however [Koskiniemi et al., 1989]. Neonatal herpes simplex encephalitis produces focal or generalized seizures, paralysis, apnea, and lethargy or coma [Kimberlin, 2004; Koskiniemi et al., 1989; Whitley et al., 1988]. Vesicular rash is present in approximately two thirds of infants. The infection can be rapidly fatal with multiorgan system failure or be associated with apnea, impaired bulbar function, and intractable seizures. Approximately 5% of infants infected with herpes simplex virus acquire the virus

FIGURE 69-4. Unenhanced CT scan of an infant with congenital herpes simplex virus infection reveals dense thalamic and periventricular calcifications (dark arrows), an additional periventricular density that may be calcium or hemorrhage (white arrow), and abnormal cerebral parenchyma. (From Souza IE, Bale JF. The diagnosis of congenital infections: Contemporary strategies. J Child Neurol 1995;10:271.)

in utero and have a relatively characteristic disorder manifested by microcephaly, cataracts, intracranial calcifications (Fig. 69-4), intrauterine growth retardation, and vesicular rash [Grose, 1994; Hutto et al., 1987]. In older children or adolescents, herpes simplex encephalitis, typically herpes simplex virus type 1, begins nonspecifically with headache, fever, malaise, vomiting, and behavioral changes. Focal neurologic signs, such as hemiparesis, dysphasia, or visual field defects, appear subsequently in most patients. Seizures can occur in approximately 40% of patients with biopsy-confirmed herpes simplex encephalitis and may be generalized or partial [Whitley et al., 1982]. Focal abnormalities reflect the predilection of herpes simplex virus to infect frontotemporal brain regions, but other areas of the brain can be affected [Leonard et al., 2000]. The clinical course of herpes simplex encephalitis can be rapidly progressive, with refractory seizures, coma, increased intracranial pressure, and death within 2 weeks, or more indolent with memory loss and behavioral disturbances. In addition to causing necrotizing encephalitis, herpes simplex virus has been linked to Bell’s palsy by detecting herpes simplex virus type 1 DNA in facial nerve tissues or in the geniculate ganglia [Burgess et al., 1994]. Herpes simplex virus also has been associated with primary or recurrent aseptic meningitis (Mollaret’s meningitis) [Bergström et al., 1990]. Common clinical manifestations of herpes simplex virus-associated aseptic meningitis include fever, photophobia, vomiting, and headache, but children with herpes simplex virus–induced meningitis usually lack herpetic lesions

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of the skin or mucosal surfaces [Rathore et al., 1996]. The diagnosis can be established by assaying cerebrospinal fluid by culture or polymerase chain reaction. Although children with herpes simplex virus type 1 meningitis can recover uneventfully without therapy [Rathore et al., 1996], acyclovir therapy should be considered. Herpes simplex virus infection also has been associated with a necrotizing myelopathy in childhood, although it more commonly occurs in adults with reactivated herpes simplex virus infections [Ellstein-Shturman et al., 1976].

DIAGNOSIS Neonates with herpes simplex virus infections may have elevated serum transaminases, direct hyperbilirubinemia, and laboratory features of disseminated intravascular coagulopathy [Kimberlin, 2004; Koskiniemi et al., 1989]. The cerebrospinal fluid in neonatal herpes simplex encephalitis reveals a lymphocytic pleocytosis and elevations of the protein content. MRI and CT usually reveal diffuse edema during the acute stage and later exhibit atrophy, parenchymal calcification, or cystic encephalomalacia [Tien et al., 1993]. EEGs are frequently abnormal in infants with encephalitis, revealing slow background activity and paroxysmal discharges that occasionally are periodic [Mikati et al., 1990]. Herpes simplex virus infection can be confirmed by isolating virus from cerebrospinal fluid, skin lesions, or mucosal surfaces of the eye, oropharynx, or rectum or by detecting herpes simplex virus DNA in cerebrospinal fluid by using polymerase chain reaction. In a retrospective analysis of cerebrospinal fluid samples accumulated by the National Institutes of Health–Collaborative Antiviral Study Group, herpes simplex virus DNA was detected by polymerase chain reaction in the cerebrospinal fluid of 93% of the infants with disseminated infection, 76% of infants with encephalitis, and only 24% of infants with skin-eyes-mouth disease [Kimberlin et al., 1996]. In other National Institutes of Health–Collaborative Antiviral Study Group studies, herpes simplex virus DNA was detected in the cerebrospinal fluid of 98% of patients with biopsy-proven herpes simplex virus encephalitis, whereas only 6% of biopsy-negative patients had herpes simplex virus DNA in cerebrospinal fluid [Lakeman and Whitley, 1995]. These results and results from other laboratories indicate that the sensitivity and specificity of polymerase chain reaction for herpes simplex encephalitis are 90% to 95% [Mitchell et al., 1997; Read et al., 1997]. Cerebrospinal fluid analysis by polymerase chain reaction is the current standard for the diagnosis of encephalitis, as well as meningitis, resulting from herpes simplex virus. Because older infants, children, and adolescents with herpes simplex virus encephalitis rarely have systemic signs of infection, neurodiagnostic and cerebrospinal fluid polymerase chain reaction studies have major roles in establishing the diagnosis [Mitchell et al., 1997; Whitley and Lakeman, 1995; Whitley et al., 1982]. MRI may indicate unilateral or bilateral abnormalities consisting of T2 prolongation in the temporal lobe or insula and enhancement of the insula, temporal cortex, and cingulate gyrus on T1-weighted, gadolinium-enhanced images [Schroth et al., 1987; Tien et al., 1993]. Focal abnormalities involving other cortical regions, including parietal or occipital lobes, can be observed, however, in atypical cases of herpes simplex encephalitis

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[Schlesinger et al., 1995]. EEGs, abnormal in approximately 80% or more of patients, reveal focal or diffuse slowing and epileptiform discharges that can be periodic and lateralizing.

TREATMENT AND OUTCOME Infants with herpes simplex virus infections should receive acyclovir, 20 mg/kg every 8 hours for 21 days, and older children should be treated with 20 mg/kg every 8 hours for at least 21 days [Bale, 2004; Kimberlin et al., 2001b; Whitley et al., 1986, 1991a, 1991b]. Adolescents can receive 1500 mg/m2 for 21 days. Potential side effects include tremulousness, hematuria, and reversible nephropathy. Although the drug is well tolerated, complete blood counts and serum creatinine levels should be monitored during prolonged courses of acyclovir. Although favorable outcome after neonatal or childhood herpes simplex virus infections correlates with the early initiation of acyclovir, sequelae are common even after appropriate medical management. Fewer than 40% of the survivors of neonatal or childhood herpes simplex virus encephalitis recover to their baseline levels of function [Kimberlin et al., 2001a, 2001b; Whitley et al., 1991b]. Potential sequelae consist of partial and generalized seizure disorders, developmental delay, cerebral palsy, language dysfunction, behavioral abnormalities, and motor deficits. All acyclovir-treated infants with skin, eye, and mouth infections survive, and nearly all such infants have no long-term sequelae of their infections, other than the propensity to have occasional recurrences of skin lesions

FIGURE 69-5. Unenhanced CT scan of a young child who survived herpes simplex virus encephalitis reveals cerebral atrophy and destructive changes of the insular cortex bilaterally. Despite treatment with acyclovir, the infant sustained extensive damage to both opercular areas and manifested severe pseudobulbar palsy.

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[Kimberlin et al., 2001a]. Approximately 30% of the infants with disseminated neonatal herpes simplex virus infections die despite appropriate therapy, and 20% to 30% of the survivors have sequelae ranging from mild (speech delay or mild motor delay) to severe (spastic quadriparesis or severe developmental delay). Neonates with encephalitis have less than 10% mortality, but 40% of the surviving infants have severe sequelae despite acyclovir therapy [Kimberlin et al., 2001b]. Infants who survive herpes simplex virus encephalitis can have permanent pseudobulbar palsy with mutism and feeding difficulties (Fig. 69-5) [Grattan-Smith et al., 1989]. Infants with congenital herpes simplex virus infections have a uniformly poor prognosis [Hutto et al., 1987]. Relapse or persistence of symptoms in herpes simplex virus encephalitis, associated with fever, lethargy, headache, and movement disorder, can develop despite appropriate initial management and acyclovir therapy [Carpentier-Barthez et al., 1995; Gutman et al., 1986]. Such children require repeat cerebrospinal fluid polymerase chain reaction for herpes simplex virus, MRI, repeat treatment with acyclovir, and corticosteroid therapy if imaging suggests acute disseminated encephalitis. Because of the substantial morbidity associated with neonatal and childhood herpes simplex virus encephalitis, ongoing studies are evaluating the role for prolonged suppressive therapy with acyclovir in neonates with herpes simplex virus infections [Kimberlin, 2004].

Cytomegalovirus has been linked to infantile spasms, usually in infants with intrauterine infection [Riikonen, 1978]. Immunocompetent children or adolescents with cytomegalovirus infections can have a mild, self-limited encephalitis [Studahl et al., 1992] or Guillain-Barré syndrome [Dowling and Cook, 1981]. The latter disorder begins with paresthesias and causes weakness that usually begins in the lower extremities. Affected children can have bilateral facial paresis, respiratory failure, or cardiac dysrhythmias [Ropper, 1992]. Symptoms of a cytomegalovirus-induced mononucleosis syndrome [Horwitz et al., 1986]—malaise, lowgrade fever, or headache—may precede or accompany the onset of Guillain-Barré syndrome. Patients immunocompromised by AIDS, malignancy, transplantation, or immunosuppressive therapy are at risk for cytomegalovirus-induced retinitis, encephalitis, myelopathy, and Guillain-Barré syndrome–like disorders. Given the demographics of AIDS, most reported patients with cytomegalovirus retinitis, encephalitis, or myelitis are adults between the ages of 20 and 50 years [Holland et al., 1994; Jacobson, 1997; Morgello et al., 1987; Palestine et al., 1984]. Immunocompromised infants or children, especially those with HIV infection, are at risk for retinitis, colitis, pneumonitis, and CNS complications of cytomegalovirus infections [Chandwani et al., 1996; Darin et al., 1994].

DIAGNOSIS

Cytomegalovirus CLINICAL FEATURES Infection with cytomegalovirus, a ubiquitous member of the herpesvirus family, has been associated with several childhood neurologic conditions, including intrauterine infection; infantile spasms; Guillain-Barré syndrome; and encephalitis, myelitis, or retinitis in immunosuppressed hosts, especially persons with acquired immunodeficiency syndrome (AIDS) [Bale, 1984; McCuthan, 1995]. Approximately 1% of infants excrete cytomegalovirus at birth, and the virus is acquired steadily thereafter throughout life. Young children who attend daycare centers, adults who have contact with young children, and persons with multiple sexual partners acquire cytomegalovirus at annual rates of 8% to 25% or more, considerably higher than the background infection rates of 2% to 5% per year [Demmler, 1991; Murph and Bale, 1988]. Children acquire cytomegalovirus by contact with persons who shed cytomegalovirus in urine or saliva and by transfusion of blood products or transplantation of organs from cytomegalovirus-seropositive donors [Demmler, 1991]. At birth, 0.4% to 2.5% of newborns shed cytomegalovirus in urine or saliva, indicating congenital infection [Bale, 1984; Demmler, 1991]. Approximately 90% of cytomegalovirusinfected infants are asymptomatic at birth. Although sensorineural hearing loss develops subsequently in 7% to 10% of these infants [Fowler et al., 1997], they rarely have other CNS complications. The remaining 10% of infants with congenital cytomegalovirus infection have hepatomegaly, splenomegaly, jaundice, petechial or purpuric skin rash, intrauterine growth retardation, microcephaly, or chorioretinitis [Bale, 1984; Boppana et al., 1997; Demmler, 1991; Istas et al., 1995].

The diagnosis of intrauterine cytomegalovirus infection is established by assaying urine or saliva using shell vial methods. Polymerase chain reaction can be used to detect cytomegalovirus DNA in urine, saliva, or serum, but the shell vial assay is sensitive and cost-effective [Demmler et al., 1988]. Common, nonspecific laboratory features of congenital cytomegalovirus infections include thrombocytopenia, direct hyperbilirubinemia, and elevated serum transaminases [Istas et al., 1995]. CT scans reveal intracranial calcifications (Figs. 69-6 to 69-8) in 25% to 50% of symptomatic infants [Boppana et al., 1997; Pass et al., 1980]. Hydranencephaly, atrophy, lissencephaly, schizencephaly, and cerebellar hypoplasia also can accompany congenital cytomegalovirus infections [Hayward et al., 1991; Iannetti et al., 1998]. Approximately 50% of symptomatic infants have abnormal auditory-evoked responses indicating sensorineural hearing loss [Boppana et al., 1997; Pass et al., 1980; Rivera et al., 2002]. Infection in older infants or children can be established by isolating cytomegalovirus from urine, saliva, or circulating leukocytes; by detecting cytomegalovirus-specific antigens in circulating leukocytes; or by detecting cytomegalovirusspecific DNA in cerebrospinal fluid, serum, or urine [Clifford et al., 1993]. Some patients with cytomegalovirus infection have elevated serum transaminases or hematologic abnormalities, such as leukopenia, anemia, or thrombocytopenia. CT or MRI may reveal abnormalities of the brain or spinal cord consisting of demyelination or inflammation involving cortical or periventricular regions [Miller et al., 1997; Post et al., 1986].

TREATMENT AND OUTCOME Most infants who survive symptomatic, intrauterine cytomegalovirus infections have permanent neurodevelopmental sequelae consisting of mental retardation, seizure disorders,

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FIGURE 69-8. A higher CT section from the same infant in Figure 69-7 reveals diffuse parenchymal calcifications bilaterally and an abnormalappearing cortex.

FIGURE 69-6. Unenhanced CT scan of an infant with symptomatic congenital cytomegalovirus infection reveals dense periventricular calcifications and bilateral periventricular leukomalacia. (From Souza IE, Bale JF. The diagnosis of congenital infections: Contemporary strategies. J Child Neurol 1995;10:271.)

after silent, intrauterine cytomegalovirus infection, infants with known congenital cytomegalovirus infection require serial audiometry at frequent intervals during infancy and childhood [Williamson et al., 1992]. Infants with abnormal CT scans are more likely to have adverse neurodevelopmental outcomes [Boppana et al., 1997; Noyola et al., 2001]. At present, intrauterine cytomegalovirus infection cannot be prevented by vaccination. Ganciclovir, an antiviral drug closely related to acyclovir, may provide modest benefit to infants with congenital cytomegalovirus disease [Nigro et al., 1994]. A controlled trial of ganciclovir indicates that prolonged courses of ganciclovir, 10 to 12 mg/kg/day for 42 days, can improve hearing outcomes [Kimberlin et al., 2003]. Bone marrow suppression is a potentially serious side effect. Immunocompromised children with invasive cytomegalovirus disease, especially retinitis, should receive ganciclovir, beginning with 5 mg/kg intravenously twice daily for approximately 14 days. Long-term maintenance therapy, using 5 to 10 mg/kg/day, is required in persons with cytomegalovirus retinitis and HIV infection [Jacobson, 1997]. Complete blood counts and renal function should be monitored frequently. Outcome of acquired cytomegalovirus infection depends greatly on the immunocompetence of the infected host. Patients who are immunosuppressed by AIDS or transplantation have increased risks of death. By contrast, most children with normal immune systems generally recover from acquired cytomegalovirus infections. The prognosis of cytomegalovirus-induced Guillain-Barré syndrome in immunocompetent children is comparable with that of GuillainBarré syndrome resulting from other causes.

FIGURE 69-7. Unenhanced CT scan of an infant with symptomatic congenital cytomegalovirus infection reveals dense periventricular calcifications surrounding the occipital horn of the left lateral ventricle and bilateral cortical abnormalities suggesting lissencephaly/pachygyria.

Varicella-Zoster Virus

behavioral disturbances, visual impairment, and sensorineural hearing loss [Bale, 1984; Boppana et al., 1997; Pass et al., 1980]. Because hearing loss can be progressive, even

Varicella-zoster virus, the cause of chickenpox (varicella) and shingles (zoster), has been associated with several neurologic conditions in children, including acute ataxia, myelitis,

CLINICAL FEATURES

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stroke, postherpetic neuralgia, Bell’s palsy, Ramsay-Hunt syndrome, aseptic meningitis, encephalitis, congenital varicella syndrome, and Reye’s syndrome [Fleisher et al., 1981; Gilden, 2004; Huder, 1997; McKendall and Stroop, 1994; Weller, 1983]. These conditions affect immunocompetent or immunocompromised hosts, although immunosuppressed hosts, such as patients with AIDS or hematologic malignancies, have greater risks of severe, invasive infections. Certain conditions, such as varicella-induced ataxia or Reye’s syndrome (rarely seen, currently), occur almost exclusively in immunocompetent children. Chickenpox, the illness associated with primary varicellazoster virus infection, peaks among children between the ages of 5 and 9 years and occurs more often in winter months. The virus spreads by aerosolization and respiratory transmission; children are contagious 2 days before and 5 days after the onset of the chickenpox rash. The incubation period averages 14 days. After primary infection, the virus enters a latent stage in sensory ganglia and can reactivate, causing zoster or shingles [Gilden, 2004]. Consequently, zoster more commonly affects the elderly or persons with immunocompromising conditions. Zoster can occur in otherwise healthy children or adolescents, however [Fleisher et al., 1981; Guess et al., 1985]. Zoster in persons without obvious risk factors should be considered a potential harbinger of HIV infection [Gnann and Whitley, 1991]. Less than 0.1% of otherwise healthy children with chickenpox experience neurologic complications. Acute cerebellar ataxia, the most common complication, begins approximately 10 days after the onset of the rash. Ataxia preceding the rash or after varicella vaccination has been reported [Johnson and Milbourn, 1970; Sunaga, et al., 1995]. Truncal ataxia, dysmetria, vomiting, and irritability are common clinical features. The ataxia, often maximum at onset, frequently inhibits independent ambulation, and nystagmus can be present [Connolly et al., 1994]. The pathogenesis of ataxia after varicella remains undetermined. Other varicella-zoster virus–related neurologic complications are uncommon. Reye’s syndrome, a now rare disorder characterized by pernicious vomiting, coma, and increased intracranial pressure, can be prevented by avoiding aspirin therapy in children or adolescents with varicella or influenza. Varicella encephalitis, another rare complication of either varicella or zoster, usually appears 3 to 7 days after the onset of the rash and produces headache, fever, seizures, coma, or paralysis [Appelbaum et al., 1953; Gilden, 2004; Hausler et al., 2002]. Myelitis causes urinary retention or incontinence, paraparesis, and sensory abnormalities [Rosenfield et al., 1993]. Ramsay-Hunt syndrome, an uncommon complication of zoster in childhood, consists of acute facial palsy, pain, unilateral hearing loss, and occasionally other cranial palsies in association with zoster of the ear or neck [Grose et al., 2002; Huder, 1997]. Children infrequently have postherpetic neuralgia [Kost and Strauss, 1996]. Stroke [Bodensteiner et al., 1992; Askalan et al., 2001; Sebire et al., 1999] or, rarely, herpes zoster ophthalmicus [Gilden, 2004; Leis and Butler, 1987] has been reported in children after varicella. Usually occurring within 4 to 8 weeks of varicella or zoster infection, these disorders are characterized by headache, focal deficits, lethargy or somnolence, and occasionally seizures. The pathogenesis of stroke in these pediatric cases seems to reflect vasculopathy

mediated by varicella-zoster virus and is analogous to that of herpes zoster ophthalmicus and delayed infarction, a potential complication of varicella-zoster virus reactivation in adults [Hilt et al., 1983]. The intrauterine varicella syndrome affects approximately 2% to 3% of the offspring of women who have chickenpox during their first or second trimesters of pregnancy [Alkaly et al., 1987; Brunnell, 1992; Grose, 1994]. The characteristics of this disorder include intrauterine growth retardation, cicatricial skin lesions in a dermatomal distribution, eye abnormalities (chorioretinitis, cataracts, optic atrophy), limb hypoplasia, and neurologic abnormalities (hydrocephalus, microcephaly, seizures, or Horner’s syndrome) [Alkaly et al., 1987; Grose, 1994].

DIAGNOSIS Children or adolescents with neurologic conditions associated with varicella-zoster virus have cerebrospinal fluid abnormalities consisting of a lymphocytic pleocytosis and elevated protein content. Approximately 50% of children with ataxia after varicella have a lymphocytic pleocytosis, although the total leukocyte count and protein content rarely exceed 100 cells/mm3 and 40 mg/dL [Connolly et al., 1994]. Varicella-zoster virus infection is suspected when characteristic skin lesions are present and confirmed by detecting infectious virus in skin lesions or varicella-zoster virusspecific antibodies or varicella-zoster virus DNA in cerebrospinal fluid using polymerase chain reaction [Dangond et al., 1993; Gilden, 2004; Kido et al., 1991]. Some adults and, presumably, children or adolescents with varicellazoster virus–related neurologic complications lack cutaneous manifestations of varicella-zoster virus [Gilden, 2004]. This is especially true when remote complications of varicella-zoster virus, such as childhood stroke, occur [Askalan et al., 2001]. The results of neuroimaging studies vary, depending on the disorder and immune status of the child. Children with ataxia or encephalitis after varicella often have normal imaging studies, although MRI occasionally can detect edema or white matter lesions compatible with demyelination. Occasionally, features suggesting acute disseminated encephalitis are observed. MRI indicates focal cerebral or cerebellar lesions in children with stroke [Bodensteiner et al., 1992; Leis and Butler, 1987; Sunaga et al., 1995] and hydrocephalus, cortical atrophy, hydranencephaly, or intracranial calcifications in infants with congenital varicellazoster virus embryopathy [Alkaly et al., 1987; Cuthbertson et al., 1987; Grose, 1994].

TREATMENT AND OUTCOME Children with varicella-zoster virus–related ataxia recover without antiviral or corticosteroid therapy [Connolly et al., 1994], indicating that conservative management of these children is warranted. Virtually all children with varicellainduced ataxia recover completely within 8 weeks of onset, although behavioral disturbances may persist longer. In contrast, children or adolescents with encephalitis or myelitis should receive acyclovir, 1500 mg/m2/day in three equally divided doses for at least 10 days, especially if immunocompromised by AIDS, transplantation, or chemo-

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therapy [Gilden, 2004]. Children with Ramsay-Hunt syndrome also may benefit from acyclovir [Huder, 1997]. Corticosteroid therapy (e.g., intravenous methylprednisolone) should be considered in children or adolescents with myelitis, acute disseminated encephalitis, or stroke secondary to varicella-zoster virus vasculitis. Outcome of varicella-related stroke in children seems to be more favorable than the outcome in adults [Bodensteiner et al., 1992]. Infants with intrauterine infections have variable outcomes with high rates of permanent neurodevelopmental sequelae [Grose, 1994]. Varicella can be prevented by vaccination [CDC, 1996], suggesting that certain neurologic complications also may be preventable.

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ities, including thrombocytopenia, leukopenia, and an atypical lymphocytosis [Sumaya and Ench, 1985a]. A positive heterophil response supports recent Epstein-Barr virus infection, although children younger than age 4 years frequently have false-negative results [Sumaya and Ench, 1985b]. The diagnosis of Epstein-Barr virus infection can be established specifically by a serologic panel that assays Epstein-Barr virus–specific antibody responses to viral capsid, early, and

Epstein-Barr Virus CLINICAL FEATURES Epstein-Barr virus, the cause of infectious mononucleosis, has been associated with several neurologic disorders of children and adults, including encephalitis, Guillain-Barré syndrome, optic neuritis, Bell’s palsy, acute ataxia, chronic daily headaches, acute chorea, and “Alice in Wonderland” syndrome [Connelly and DeWitt, 1994; Dowling and Cook, 1981; Volpi, 2004]. Epstein-Barr virus, transmitted by contact with oral secretions, commonly infects children before the age of 5 years, children and adolescents after age 10 years, and young adults. Most primary infections are asymptomatic, although infected individuals can experience infectious mononucleosis, an illness associated with fever, malaise, headache, sore throat, lymphadenopathy, splenomegaly, and rash [Sumaya and Ench, 1985a]. Epstein-Barr virus encephalitis accounts for 5% of cases of acute encephalitis and produces fever, headache, altered consciousness, and seizures, including acute status epilepticus [Connelly and DeWitt, 1994; Domachowske et al., 1996; Hung et al., 2000]. In the National Institutes of HealthCollaborative Antiviral Study Group studies, Epstein-Barr virus was the most common infectious agent mimicking herpes simplex virus encephalitis [Whitley et al., 1989]. “Alice in Wonderland” syndrome, another cerebral manifestation of Epstein-Barr virus infection, causes personality changes and illusions of distorted size, shape, or distance (metamorphopsia) [Liaw and Shen, 1991]. Other neurologic conditions attributed to Epstein-Barr virus, such as optic neuritis [Frey, 1973], Guillain-Barré syndrome [Grose and Feorino, 1972], acute hemiplegia [Baker et al., 1983], and acute ataxia [Connolly et al., 1994], lack distinguishing features that allow the clinical diagnosis of Epstein-Barr virus. The association of Epstein-Barr virus with these disorders often has been established retrospectively by serologic studies and exclusion of other potential causative factors. The lymphoproliferative syndrome associated with Epstein-Barr virus in transplant patients may cause seizures or altered sensorium as a consequence of intracranial mass lesions or lymphomatous meningitis [Boyle et al., 1997].

FIGURE 69-9. T2-weighted MRI from a child with Epstein-Barr virus encephalitis reveals bilateral areas of T2 prolongation (arrows) reminiscent of acute disseminated encephalomyelitis. (From Bale JF, Andersen RA, Grose C. Magnetic resonance imaging of the brain in childhood herpesvirus infections. Pediatr Infect Dis J 1987;6:644.)

DIAGNOSIS, TREATMENT, AND OUTCOME Children with Epstein-Barr virus infection frequently have elevated serum transaminases and hematologic abnormal-

FIGURE 69-10. T1-weighted MRI from a child with neurologic sequelae from Epstein-Barr virus encephalitis shows cystic encephalomalacia and gliosis.

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nuclear antigens [Sumaya, 1985]. Acute infection is suggested by the presence of viral capsid antigen IgM or IgG and the absence of Epstein-Barr nuclear antigen IgG [Sumaya and Ench, 1985b]. Epstein-Barr virus infection of the CNS also can be diagnosed by detecting Epstein-Barr virus DNA in cerebrospinal fluid [Halsted and Chang, 1979; Landgren et al., 1994; Volpi, 2004]. EEG may indicate slowing or epileptiform discharges during acute Epstein-Barr virus encephalitis or “Alice in Wonderland” syndrome. Neuroimaging studies occasionally can be abnormal (Fig. 69-9) [Bale et al., 1987; Domachowske et al., 1996; Ono et al., 1998]. Current antiviral medications have minimal effect on Epstein-Barr virus, but most children recover completely with supportive care. Neurologic sequelae of Epstein-Barr virus encephalitis can occur, however (Fig. 69-10) [Domachowske et al., 1996].

Human Herpesviruses Types 6, 7, and 8 Human herpesviruses type 6 and type 7, discovered in 1986 and 1990, cause roseola (exanthem subitum) in young children and occasionally neurologic complications in children or adults [Leach et al., 1992; Torigoe et al., 1996]. These viruses commonly infect infants and toddlers such that virtually all children have serologic evidence of infection by 5 years of age. Although primary infections are frequently asymptomatic, human herpesvirus type 6 and human herpesvirus type 7 produce roseola, an acute childhood illness with high fever (often >40°C), lymphadenopathy, and an erythematous rash that characteristically appears after the fever. By causing high fever at a vulnerable age, these viruses account for a substantial proportion of febrile seizures of childhood [Barone et al., 1995; Hall et al., 1994]. In addition to inducing febrile seizures, human herpesvirus type 6 and human herpesvirus type 7 have been linked with acute encephalopathy or encephalitis in young children and myelitis or encephalitis in adults [Barone et al., 1995; Drobyski et al., 1994; Hall et al., 1994; Leach et al., 1992; Suga et al., 1993; Torigoe et al., 1996; Yoshikawa et al., 1992]. Young children with symptomatic infections have high fevers and seizures that are usually generalized. Transient or permanent hemiparesis and coma are additional clinical features. The diagnosis can be established serologically or by polymerase chain reaction [Yoshikawa et al., 2000]. Human herpesvirus type 8, a herpesvirus that was linked initially to Kaposi’s sarcoma in 1994, is acquired after adolescence in the United States and Europe, an epidemiologic feature that suggests sexual transmission [Chang et al., 1994; Martin et al., 1998]. Nonsexual modes contribute to the transmission of human herpesvirus type 8 in endemic regions of the developing world, however [Andreoni et al., 1999]. Although neurologic complications of human herpesvirus type 8 are rare, human herpesvirus type 6, human herpesvirus type 7, and human herpesvirus type 8 can be opportunistic CNS pathogens in persons with impaired cell-mediated immunity [Volpi, 2004]. Treatment of these infections consists of supportive care. Acyclovir, a potent inhibitor of herpes simplex virus and varicella-zoster virus, seems to be ineffective. Although most

children recover uneventfully, permanent neurologic sequelae and death have been reported after human human herpesvirus type 6 or human herpesvirus type 7 CNS infections.

Adenoviridae Adenoviruses, important causes of mild upper respiratory illnesses, pneumonia, and keratoconjunctivitis, have been associated occasionally with encephalitis or aseptic meningitis [Chany et al., 1958; Chuang et al., 2003; Kim and Gold, 1983]. Acquired by contact with infected respiratory or conjunctival secretions, childhood adenoviral infections produce low-grade fever, cough, coryza, and conjunctivitis. Adenovirus infections usually remit spontaneously. Infrequently, they can cause coma, seizures, and meningeal signs. The diagnosis can be established by isolating adenoviruses from cerebrospinal fluid, respiratory secretions, or urine. Treatment consists of supportive care. Although fatal cases have been described, most children recover uneventfully.

Picornaviridae CLINICAL FEATURES Members of the picornavirus family, especially the enteroviruses, are important potential causes of neurologic infections worldwide. Although paralytic poliomyelitis has been eliminated from nearly all regions of the world, nonpolio enteroviruses continue to be associated with a spectrum of neurologic disease that includes aseptic meningitis, acute ataxia, acute hemiplegia, opsoclonus-myoclonus, encephalitis, Guillain-Barré syndrome, and polio-like paralysis [Alexander et al., 1994; Berg and Jelke, 1965; Cheng-Yu et al., 2001; Cramblett et al., 1964; Huang et al., 1999; Kuban et al., 1983; Modlin et al., 1991; Rorabaugh et al., 1993; Rotbart, 1995; Sawyer, 2002]. The last case of wild poliomyelitis in the United States occurred in 1979 (see Fig. 69-1), and the World Health Organization has certified that the Americas, Europe, and the Western Pacific regions are free of polio [CDC, 1994a, 2004b]. Eradicating poliomyelitis from the remaining six endemic locations (Afghanistan, Egypt, India, Niger, Nigeria, and Pakistan) remains the objective of the World Health Organization. Before the use of the inactivated poliovirus vaccine for the complete childhood immunization series, vaccine-related poliomyelitis occurred occasionally in the United States [CDC, 1997b]. Spread by the fecal-oral route, the nonpolio enteroviruses, coxsackieviruses, and echoviruses produce several distinct systemic syndromes, including pharyngitis, herpangina, gastroenteritis, hand-foot-and-mouth syndrome, neonatal sepsis, and neurologic disorders. Data from the Centers for Disease Control and Prevention indicate that approximately 30 million cases of nonpolio enteroviral infections occur annually in the United States [CDC, 1997c]. More than 10,000 cases of nonpolio enterovirus aseptic meningitis are reported to the Centers for Disease Control and Prevention annually [Sawyer, 2002]. Aseptic meningitis, the most common neurologic manifestation of nonpolio enteroviral infection, appears epidemically during the late summer and early fall, although

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cases can be observed throughout the year. Affected children have fever, irritability, headache, photophobia, nausea, vomiting, meningeal signs, and other signs of enteroviral disease, including diarrhea, abdominal discomfort, and a maculopapular or petechial rash [Rorabaugh et al., 1993; Rotbart, 1995; Sawyer, 2002]. Signs of aseptic meningitis in a young infant may be remarkably subtle, consisting only of fussiness or poor oral intake. Fever is an inconsistent feature. Occasionally, children with nonpolio enteroviral infections have an acute encephalitic presentation with fever, seizures, somnolence, coma, or focal deficits [Modlin et al., 1991]. Such children may have focal clinical, EEG, or neuroimaging abnormalities that resemble herpes simplex encephalitis. Children with acute opsoclonus-myoclonus, a syndrome associated more commonly with occult neural crest tumors, have involuntary, chaotic eye movements and random myoclonus of the extremities [Kuban et al., 1983]. Enterovirus 71, in addition to being associated with encephalitis and aseptic meningitis, causes an acute neurologic disorder with unilateral or bilateral flaccid paralysis that can resemble poliomyelitis or GuillainBarré syndrome [Alexander et al., 1994; Cheng-Yu et al., 2001; Huang et al., 1999]. Children with poliomyelitis have a biphasic illness; the initial, nonspecific phase consists of fever, malaise, vomiting, or diarrhea, and the second, neurologic phase consists of aseptic meningitis or paralytic disease, usually more severe in the lower extremities [CDC, 1997b]. Mild or inapparent poliovirus infections greatly exceed the number of paralytic cases. Although the pathogenesis of their condition remains uncertain, persons with paralytic poliomyelitis may experience muscle pain, weakness, and fatigue after many years, a condition that has been labeled postpolio syndrome [Windebank et al., 1991]. Infants with nonpolio enteroviral infections can have a disseminated illness that resembles bacterial sepsis or herpes simplex virus infection. Clinical features of this condition include fever, respiratory distress, seizures, lethargy, shock, or disseminated intravascular coagulopathy [Morens, 1978]. During community enteroviral outbreaks, 10% to 15% of young infants acquire enteroviruses, usually asymptomatically [Jenista et al., 1984]. Children with agammaglobulinemia can have a persistent, often fatal neurologic condition caused by chronic nonpolio enterovirus infection of the CNS [Mease et al., 1981; Wilfert et al., 1977]. Patients with this rare disorder exhibit a dermatomyositis-like disorder and neurologic signs, which may include seizures, mental status changes, hemiparesis, and headache.

DIAGNOSIS Infants with disseminated enteroviral infections can have leukocytosis, elevated serum transaminases, and thrombocytopenia, whereas infants or children with aseptic meningitis have mild cerebrospinal fluid changes, consisting of a lymphocytic pleocytosis and protein elevation [Negrini et al., 2000] and occasionally laboratory abnormalities consistent with the syndrome of inappropriate antidiuretic hormone secretion [Chemtob et al., 1985]. The diagnosis of enteroviral infection can be established by isolating enteroviruses from cerebrospinal fluid or stool or throat swabs or by detecting enteroviral RNA in stool, serum, or cerebrospinal fluid by using reverse transcriptase polymerase chain

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FIGURE 69-11. Axial T2-weighted MRI from a child with agammaglobulinemia and presumed progressive nonpolio enterovirus encephalopathy shows ventriculomegaly and diffuse cortical atrophy.

reaction [Hamilton et al., 1999; Rotbart, 1995; Sawyer, 2002; Schlesinger et al., 1994]. Imaging studies are normal in nonpolio enterovirus aseptic meningitis. Children with progressive nonpolio enterovirus infections have progressive cortical atrophy (Fig. 69-11).

TREATMENT AND OUTCOME In most instances, children with enteroviral CNS infections require supportive care only. Children with severe nonpolio enteroviral infections may benefit from pleconaril, a novel antiviral drug with efficacy against several RNA viruses [Abzug et al., 2003; Sawyer, 2002]. Children with agammaglobulinemia and persistent echovirus infections may improve during immunoglobulin replacement therapy [Mease et al., 1981]. Infants with enteroviral aseptic meningitis recover uneventfully [Bergman et al., 1987], whereas the outcome in infants with myocarditis or children with encephalitis or enterovirus 71 infections can be less favorable [Modlin et al., 1991; Morens, 1978; Sawyer, 2002]. Persistent enterovirus infections in children with agammaglobulinemia are often fatal.

Togaviridae Togaviridae includes the alphaviruses—eastern equine encephalitis virus, western equine encephalitis virus, and Venezuelan equine encephalitis virus—potential causes of encephalitis among humans living in the Western hemisphere, and the rubiviruses—rubella virus—a cause of the congenital rubella syndrome worldwide. The alphaviruses, maintained in bird–mosquito–wild vertebrate cycles, infect

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equines and humans as dead-end hosts and typically cause human disease between June and October, when the mosquito vectors are active. Most exposures are asymptomatic, although attack rates have been highest historically among infants and young children. As their names imply, eastern equine encephalitis, western equine encephalitis, and Venezuelan equine encephalitis occur in the eastern United States, western United States and Canada, and Latin America. Rubella virus, a nonarthropod member of this family, causes an exanthematous illness that has become rare in many regions because of immunization.

Eastern Equine Encephalitis Virus Although having the lowest incidence of the major North American arthropod-borne encephalitides, with only 163 human cases reported to the Centers for Disease Control and Prevention during the 30-year interval from 1956 to 1985, eastern equine encephalitis has the highest mortality rate, ranging from 30% to 50% during the past several decades [Deresiewicz et al., 1997; Przelomski et al., 1988]. Cases among equines and humans, usually adults, appear during the summer months in states bordering the Atlantic Ocean and the Gulf of Mexico. Indigenous cases have been observed as far west as Michigan and Wisconsin. The disorder usually begins abruptly with high fever, lethargy, vomiting, and convulsions, although some patients have a prodromal phase lasting several days characterized by fever, headache, malaise, and myalgias. Signs are usually diffuse, but patients may have focal findings, raising consideration of herpes simplex virus encephalitis [Morse et al., 1992]. EEGs usually exhibit diffuse slowing, and neuroimaging studies can be normal or indicate diffuse edema or focal lesions involving the thalami or basal ganglia [Deresiewicz et al., 1997; Morse et al., 1992; Przelomski et al., 1988]. The diagnosis can be confirmed by detecting eastern equine encephalitis virus–specific IgM in serum or cerebrospinal fluid and by detecting eastern equine encephalitis virus RNA using reverse transcriptase polymerase chain reaction. Treatment consists of supportive care.

Western Equine Encephalitis Virus Although the western equine encephalitis virus can be detected in bird and mosquito reservoirs throughout the Americas, most human cases occur in the western United States or Canada, peaking in July and August [Calisher, 1994]. The incidence of western equine encephalitis varies considerably from year to year; however, epidemics appear at approximately 10-year intervals, with the largest affecting more than 3000 persons in 1941 [CDC, 1987]. The Centers for Disease Control and Prevention received reports of nearly 300 cases in 1975 and 37 cases in 1987, the largest more recent outbreaks. Residing in rural areas or engaging in outdoor occupations are risk factors associated with acquiring western equine encephalitis. Adults constitute most cases. The clinical features of western equine encephalitis consist of fever, headache, somnolence, stiff neck, nausea, vomiting, and myalgias [Leech et al., 1981]. Coma, paralysis, seizures, and other more severe neurologic complications, although infrequent in adults, were common in infants affected during the 1941 epidemic [Medovy, 1943]. Infants

can acquire the virus transplacentally and become symptomatic during the neonatal period [Shinefield and Townsend, 1953]. The diagnosis can be established by detecting western equine encephalitis virus–specific IgM in serum or cerebrospinal fluid or by using polymerase chain reaction [Calisher et al., 1986; Lambert et al., 2003]. Despite few reports of neurodiagnostic studies, EEG slowing and normal or nonspecific neuroimaging findings can be anticipated. Most children with western equine encephalitis recover completely, although developmental delay, an increased risk for seizures, and behavioral disturbance are potential sequelae [Earnest et al., 1971].

Venezuelan Equine Encephalitis Virus Venezuelan equine encephalitis virus causes influenza-like disease, encephalitis, and intrauterine infection among inhabitants of Latin America [CDC, 1993a, 1995a]. During major epidemics, equine and human cases have been observed as far north as the southern United States. A major outbreak of Venezuelan equine encephalitis occurred in 1995, affecting 75,000 persons in Colombia, but this epidemic did not spread to North America [Rivas et al., 1997]. Encephalitis affects approximately 10% of infected persons and tends to be mild with headache, somnolence, and occasionally convulsions. Intrauterine infection, a rare complication of maternal Venezuelan equine encephalitis virus infection, can cause fetal death or severe, encephaloclastic CNS lesions, including hydranencephaly [Wenger, 1977]. The diagnosis can be established serologically or by virus isolation.

Rubella Virus CLINICAL FEATURES Rubella virus causes neurologic dysfunction during acute childhood infection and in the offspring of women who are infected with rubella virus during the first trimester. These complications are rare in the United States and other regions with compulsory vaccination against rubella virus (Fig. 69-12). Before vaccine licensure in 1969, rubella epidemics occurred at 6- to 9-year intervals, and during the last major pandemic in the mid-1960s, 20,000 cases of congenital rubella syndrome were reported. Ten percent to 20% of adults living in regions with compulsory immunization remain susceptible to rubella [CDC, 1997f], however, and outbreaks of rubella and congenital rubella syndrome [CDC, 1997d; Panagiotopoulos and Georgakopoulou, 2004] indicate that the rubella virus continues to pose a real threat in many regions of the world [Spika et al., 2003]. Rarely, maternal reinfection with rubella virus causes fetal infection [Robinson et al., 1994]. Rubella virus produces fever, coryza, lymphadenopathy of the posterior auricular and occipital nodes, and a maculopapular rash involving the face and trunk. Rare neurologic complications after acquired rubella virus infection consist of headache, seizures, or Guillain-Barré syndrome. The clinical features of intrauterine rubella virus infection, recognized first by Gregg in 1941, include cataracts, congenital heart disease, sensorineural hearing loss, microcephaly, intrauterine growth retardation, hepatosplenomegaly, petechial rash, osteopathy, jaundice, and pneumonitis [Dudgeon,

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Vaccine licensed

14 13

1.00

26 Rate

24 22 20 Rubella rate

15

1.25

18 16

12

0.75

11 10

0.50

9

0.25

14 12

8 1982 1984 1986 1988 1990 1992 Year

6 5

10 Rubella, total Rubella, persons aged ≥15 years CRS

8 6 4

4 3

FIGURE 69-12. Data regarding the incidence of rubella and congenital rubella syndrome (CRS) in the United States from 1966 to 1992, as reported to the Centers for Disease Control and Prevention, show the dramatic decline in rubella and CRS. The inset depicts the resurgence of CRS that was observed in the early 1990s. Cases of rubella reported to the National Notifiable Diseases Surveillance System per 100,000 population; cases of congenital rubella reported to the National CRS Registry per 100,000 live births. (From Rubella and congenital rubella syndrome—United States. MMWR Morb Mortal Wkly Rep 1994;43:391, 397.)

2 1

2 0

7

CRS rate

30 28

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1966 1968 1970 1972 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 Year

1975]. Sequelae relate directly to the gestational timing of maternal infections, with severe defects common before 12 weeks, when the risk of congenital rubella syndrome approaches 90% [Ueda et al., 1979]. By contrast, maternal infections after 24 weeks of gestation tend to be benign.

DIAGNOSIS The diagnosis of rubella virus infection can be established serologically by isolating the rubella virus from urine or nasopharyngeal secretions or by detecting rubella virus RNA in cerebrospinal fluid or other fluids by using reverse transcriptase polymerase chain reaction [Bosma et al., 1995]. Direct hyperbilirubinemia, elevated serum transaminases, and thrombocytopenia are potential laboratory abnormalities after intrauterine infection. Imaging of infants with congenital rubella syndrome reveals cerebral atrophy, intracranial calcifications, periventricular cysts, or leukomalacia [Yamashita et al., 1991].

0

tick-borne encephalitis in Europe, Asia, and North America [Kunz, 1992; Tsai, 1991]. Japanese encephalitis, the most common arthropod-borne encephalitis worldwide, causes several thousand encephalitis cases annually in endemic areas of eastern Asia, although vaccine programs have reduced the incidence of Japanese encephalitis in some regions [CDC, 1993b]. Tick-borne encephalitides are infrequent in the United States and Canada but are relatively common in Europe and Asia [Kunz, 1992]. The Centers for Disease Control and Prevention received reports of nearly 5000 cases of St. Louis encephalitis between 1956 and 1985 [CDC, 1986], and nearly half of these were observed during the massive epidemic of 1975 involving 29 states and the District of Columbia [Creech, 1977]. Beginning in 1999, West Nile virus spread throughout the United States, causing systemic and neurologic illness among adults and children [Hayes and O’Leary, 2004].

Japanese Encephalitis Virus

TREATMENT AND OUTCOME

CLINICAL FEATURES

At present, therapy for rubella virus infections, including intrauterine infection, consists of supportive care. Survivors of intrauterine rubella virus infection have high rates of sequelae affecting vision, hearing, cardiac function, and intellect [Forrst et al., 2002; Givens et al., 1993]. Potential delayed sequelae of congenital rubella syndrome include endocrinopathies (diabetes mellitus, thyroid dysfunction, and growth hormone deficiency), progressive hearing loss, glaucoma, vascular abnormalities, and postrubella panencephalitis [Sever et al., 1985; Townsend et al., 1975].

Japanese encephalitis, a mosquito-borne virus endemic throughout much of eastern Asia, causes 50,000 or more cases of encephalitis each year, usually in children younger than 15 years of age [CDC, 1993b]. Disease activity peaks from May to October, although some countries, such as Indonesia, Malaysia, and India, experience cases yearround. The virus is maintained in a bird-vertebrate cycle involving Culex mosquitoes, domestic pigs, and wading birds [Fields, 1990; CDC, 1993b]. Children with Japanese encephalitis have an abrupt, fulminant illness with fever, convulsions, and coma [Burke et al., 1985; Kumar et al., 1990]. Headache, vomiting, increased muscle tone, breathing irregularities, and occasionally focal neurologic deficits are additional clinical manifestations [Kumar et al., 1990]. Although the prodromal phase is less than 24 hours long in most child-

Flaviviridae Flaviviridae, another large family of arthropod-borne viruses, include Japanese encephalitis virus; St. Louis encephalitis virus; West Nile virus; and several agents associated with

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Infections of the Nervous System / 69

ren with Japanese encephalitis, it can last 7 or more days.

DIAGNOSIS The diagnosis of Japanese encephalitis can be confirmed by isolating the virus from cerebrospinal fluid or brain tissue, detecting serologic responses to the virus [Burke et al., 1982], or detecting Japanese encephalitis virus RNA in cerebrospinal fluid using reverse transcriptase polymerase chain reaction [Meiyu et al., 1997]. MRI can reveal bilateral lesions of the thalami or basal ganglia [Kalita and Misra, 2000; Kumar et al., 1997].

TREATMENT AND OUTCOME Mortality rates for Japanese encephalitis range from 25% to 40%; most survivors have neurologic sequelae consisting of mental retardation, seizure disorders, motor deficits, or subtle behavioral and intellectual abnormalities [Kumar et al., 1993]. An inactivated Japanese encephalitis virus vaccine prevents infection. The vaccine has an 80% efficacy after two doses [CDC, 1993b]; adverse reactions occur at a rate of approximately 15 per 100,000 doses [Berg et al., 1997; Takahashi et al., 2000].

areas. The 1975 epidemic, the largest to date, affected more than 2000 persons [Creech, 1977]. The attack rates and disease severity of St. Louis encephalitis virus infections, similar to those of West Nile virus, increase with advancing age [Luby et al., 1969; Meehan et al., 2000]. The virus is maintained in a cycle involving Culex mosquitoes and pigeons, sparrows, doves, and other birds [Johnson, 1998; Luby et al., 1969]. Clinical syndromes associated with St. Louis encephalitis virus infection include nonspecific febrile illnesses, aseptic meningitis, and encephalitis, although most infections are asymptomatic [Creech, 1977; Riggs et al., 1965]. After an incubation period of 21 days, children with St. Louis encephalitis may have a biphasic illness, with low-grade fever, diarrhea, vomiting, and malaise preceding the neurologic signs and symptoms [Kaplan et al., 1978]. In patients with encephalitis, representing approximately two thirds of symptomatic infections, headache, vomiting, fever, neck stiffness, and lethargy or agitation begin abruptly. Tremor can be present; focal neurologic findings are infrequent, at least among reported adult cases [Riggs et al., 1965]. Fever may be 41°C and can persist 7 or more days. Clinical improvement usually begins within 7 to 10 days of disease onset [Riggs et al., 1965].

DIAGNOSIS, TREATMENT, AND OUTCOME

St. Louis Encephalitis Virus CLINICAL FEATURES St. Louis encephalitis virus, a mosquito-borne virus endemic to the midwestern United States, occasionally causes epidemics of aseptic meningitis, encephalitis, and influenzalike illness, often involving older adults in urban or suburban

The cerebrospinal fluid reveals a pleocytosis in most patients with St. Louis encephalitis. Neuroimaging studies are normal or nonspecifically abnormal, and EEGs may indicate diffuse slowing. The diagnosis can be established by detecting serologic responses in serum or cerebrospinal fluid [Monath et al., 1984]. Treatment consists of supportive care. Mortality, ranging from 8% to 20% [Creech, 1977; Meehan

Human disease case(s) Avian, animal, or mosquito infection WA MT (222) OR

CA (3)

ID (1) NV (2)

AZ (13)

ME

SD (1039)

WY (375) UT (1)

VT

ND (617)

MN (148)

NE (1942) CO (2947)

KS (91) OK (79)

NM (209)

TX (720)

AK

IA (147) MO (64) AR (25)

WI (17)

NY (71)

MI (19)

3

MA 17

PA(237) IN OH IL (108) (147) (47) WV VA (26) KY(14) NC(24) TN(26) SC(6) GA MS AL (87) (37) (50)

LA (124)

NH

RI

7

CT 17 NJ

34

DE 17 MD 73

FL (94)

DC

3

WV 2

HI

FIGURE 69-13. A map of the United States showing Centers for Disease Control and Prevention data regarding human West Nile virus cases in 2003. (From the Centers for Disease Control and Prevention. Available at: www.cdc.gov/ncidod/dvbid/westnile/ surv&control03Maps.htm.)

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et al., 2000; Riggs et al., 1965], is highest among persons older than age 50 years. Potential sequelae include seizures, parkinsonism, and intellectual deficits.

West Nile Virus CLINICAL FEATURES First identified in Uganda in 1937, West Nile virus later appeared in Egypt and Israel in the 1950s [Marberg et al., 1956]. Beginning in the mid-1990s, human outbreaks became more frequent and severe, causing meningitis, encephalitis, and fatalities among persons living in Israel, Algeria, and Romania [Hubalek and Halouzka, 1999]. In 1999, cases of West Nile virus infection occurred in the United States, marking the first appearance of the virus in the Western hemisphere. An encephalitis outbreak in the New York City metropolitan area, linked to a West Nile virus strain closely related to a strain identified in Israel in 1998, caused seven deaths among adults [Lanciotti et al., 1999; Nash et al., 2001]. In 2000, West Nile virus activity was detected in 12 states surrounding New York State, and by the end of 2001, 27 states and the District of Columbia reported the presence of West Nile virus [Petersen, et al., 2002]. The rapid spread of West Nile virus among North American birds and mosquitoes heralded an enormous human outbreak in 2003 that affected more than 4000 inhabitants of 45 states from New York to California (Fig. 69-13). Only two western states (Oregon and Washington) did not report West Nile virus activity [CDC, 2004a, 2004c]. West Nile virus is maintained in a bird-mosquito cycle, involving rural and urban wild birds and Culex and Aedes mosquitoes. Asymptomatic infections with West Nile virus outnumber symptomatic cases by approximately 5 to 1 [CDC, 2004c]. Neurologic manifestations, including meningitis, encephalitis, myelitis, polio-like illness, and others, occur in approximately 1 of every 150 infected persons. Adults constitute most cases. After an incubation period of 2 to 14 days, systemic symptoms of fever, malaise, headache, nausea, and vomiting occur in symptomatic infections. Of symptomatic patients, 50% have a maculopapular rash and lymphadenopathy. To date, most patients with the neurologic complications of West Nile virus infections have been older than age 25 years. Approximately 60% of persons with West Nile virus-induced neurologic disease have encephalitis [Sejvar et al., 2003]. Encephalitis can begin with the usual systemic prodrome or more abruptly with high fever and coma [Campbell et al., 2002]. Typical abnormalities in West Nile virus encephalitis include altered mental status, coma, diffuse muscle weakness (proximal greater than distal), respiratory paralysis, and hyporeflexia. Tremor, myoclonus, and parkinsonian features are additional components of the acute illness [Sejvar et al., 2003]. Less frequent neurologic manifestations of West Nile virus infection include aseptic meningitis, myelitis, optic neuritis, and Guillain-Barré syndrome [Campbell et al., 2002; Sejvar et al., 2003]. Involvement of the anterior horn cells can produce a poliomyelitis-like disorder with asymmetric paralysis of the upper or lower extremities [Li et al., 2003; Heresi et al., 2004; Sejvar, 2004]. This disorder pro-

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duces clinical, histopathologic, and electrophysiologic abnormalities comparable to those of classic poliomyelitis [Sevjar, 2004]. Although patients with West Nile virus– induced meningitis and encephalitis gradually recover, patients with limb paralysis usually have permanent deficits [Li et al., 2003; Sejvar et al., 2003]. A single case report indicates that West Nile virus can be transmitted to the fetus, causing intrauterine infection of the CNS [CDC, 2002]. In late 2002, an infant was born to a woman who had experienced meningoencephalitis during her pregnancy. At birth, the infant was found to have bilateral chorioretinitis and cystic encephalomalacia. Studies for the conventional causes of intrauterine infection, including cytomegalovirus, herpes simplex virus, lymphocytic choriomeningitis virus, and Toxoplasma gondii, were negative, but serologic studies of the mother and infant confirmed West Nile virus infection.

DIAGNOSIS, TREATMENT, AND OUTCOME Laboratory abnormalities include mild anemia and peripheral leukocytosis or leukopenia. The cerebrospinal fluid of West Nile virus encephalitis resembles that of most arboviral infections, consisting of a mild, lymphocytic pleocytosis (30 to 100 cells/mm3); elevated protein content (80 to 100 mg/dL); and normal glucose content. Cranial CT is normal, whereas MRI can reveal leptomeningeal enhancement, periventricular inflammation, or abnormalities of the spinal cord [Campbell et al., 2002]. The diagnosis of West Nile virus infection can be confirmed by serologic studies that detect neutralizing antibodies to the virus in acute or convalescent serum samples or West Nile virus–specific IgM in serum or cerebrospinal fluid. West Nile virus– specific IgM persists in serum for at least 16 months in more than half of infected persons [Campbell et al., 2002]. Infected patients experience brief periods of viremia, but infectious virus is rarely isolated from serum or cerebrospinal fluid. Reverse transcriptase polymerase chain reaction can be used to detect West Nile virus in clinical samples [Lanciotti and Kersat, 2001]. A Centers for Disease Control and Prevention protocol guides the evaluation of infants with suspected intrauterine West Nile virus infection [CDC, 2004f]. Therapy for the neurologic complications of West Nile virus infection currently consists of supportive care with close observation for respiratory decompensation. Ribavirin possesses activity against the West Nile virus in vitro, but there are no controlled trials on which to base management decisions. There were 284 deaths among the 4156 cases reported to the Centers for Disease Control and Prevention in 2003, corresponding to a mortality rate of slightly less than 7% [CDC, 2004a]. Deaths have been more common among the elderly. Approximately one third of survivors have permanent sequelae affecting cognition, behavior, or motor function.

Tick-Borne Flaviviruses Several closely related, tick-borne flaviviruses of Europe, Asia, and North America produce encephalitis or aseptic meningitis in children and adults [Kunz, 1992; Lesnicar et al., 2003]. Tick-borne encephalitis represents a major public

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health concern among unvaccinated persons in eastern Europe and Asia. Patients with European tick-borne encephalitis often have a biphasic illness, experiencing headache, malaise, myalgia, and low-grade fever during the initial, nonspecific phase. Approximately 20% of symptomatic patients have a second, neurologic phase with severe headache, high fever, somnolence, coma, convulsions, cranial nerve palsies, or paralysis that mimics Guillain-Barré syndrome [Kunz, 1992]. Cases of tick-borne encephalitis have been described after consumption of unpasteurized, virus-contaminated milk or in travelers to endemic regions [Cruse et al., 1979]. Immunization can prevent infection among children inhabiting or visiting endemic regions [Kunze et al., 2004]. In North America, the tick-borne Powassan virus, maintained in a vertebrate-mosquito cycle in eastern Canada and the northeastern United States, has been associated with cases of encephalitis, sometimes in children [Embil et al., 1983; McLean and Donohue, 1959; Smith et al., 1974]. Clinical features consist of seizures, somnolence, or coma; occasionally children can have focal features suggesting herpes simplex virus [Embil et al., 1983]. Cerebrospinal fluid examination usually reveals a mixed pleocytosis; EEGs may be slow or epileptiform. The diagnosis is established serologically. Children generally recover completely with supportive care, although sequelae and death have been described.

2001]. The diagnosis also has been established by brain biopsy and immunofluorescence staining [McJunkin et al., 1997], but invasive diagnostic procedures, such as brain biopsy, are rarely necessary. Reverse transcriptase polymerase chain reaction can detect the RNA of California group viruses [Kuno et al., 1996].

TREATMENT AND OUTCOME Because most cases of La Crosse encephalitis are mild, and current antiviral agents, with the possible exception of ribavirin [McJunkin et al., 1997], lack anti–California encephalitis virus activity, therapy consists of supportive care. Focal EEG or clinical manifestations of La Crosse encephalitis mimic herpes simplex virus and necessitate acyclovir therapy while awaiting the results of microbiologic studies. Most children with California encephalitis recover completely, although residual behavioral changes, seizure tendencies, or EEG abnormalities have been reported in 10% to 15% of children with proven California encephalitis [Balfour, 1974; Balkhy and Schreiber, 2000; Grabow et al., 1969; McJunkin et al., 2001; Rust et al., 1999].

Reoviridae Colorado Tick Fever Virus

Bunyaviridae La Crosse Virus CLINICAL FEATURES La Crosse virus, a California serogroup virus maintained in the wild through a mosquito-vertebrate animal, causes encephalitis—known as California or La Crosse encephalitis—among children living in the midwestern United States [Balfour, 1974]. Before the emergence of West Nile virus in the United States, La Crosse encephalitis represented the most common arthropod-borne encephalitis in America (see Fig. 69-3), accounting for approximately 100 reported cases among children per year [Bale, 2003; McJunkin et al., 2001; Rust et al., 1999]. Nonspecific clinical features, consisting of fever, vomiting, headache, abdominal pain, and malaise, begin 3 to 7 days after exposure to the virus. Neurologic features appear 2 to 4 days later and consist of seizures (60%), lethargy or coma (50%), and focal deficits (20%) [Balfour, 1974; Balfour et al., 1973; Hilty et al., 1972; McJunkin et al., 2001; Rust et al., 1999]. Neurologic symptoms usually resolve during the subsequent week.

DIAGNOSIS Laboratory findings include a peripheral leukocytosis (often with a neutrophil predominance) and mixed cerebrospinal fluid pleocytosis ranging from 10 to 500 leukocytes/mL in approximately 90% of children. Some children have normal cerebrospinal fluid profiles [Hilty et al., 1972]. EEGs can be diffusely or focally slow, whereas CT and MRI are usually normal. The diagnosis of California encephalitis can be established serologically using IgM capture assays of serum or cerebrospinal fluid [Dykers et al., 1985; McJunkin et al.,

Colorado tick fever, a disorder endemic in the western United States, causes an influenza-like illness that begins approximately 5 days after exposure to Colorado tick fever–infected Rocky Mountain wood ticks, Dermacentor andersoni [Goodpasture et al., 1978]. The disorder usually appears in May through July in young adults who engage in outdoor recreational activities and often report tick exposure. Typical signs and symptoms include fever, headache, malaise, myalgia, abdominal pain, and vomiting. CNS manifestations, consisting of meningitis or mild encephalitis, affect less than 5% of children with Colorado tick fever [Goodpasture et al., 1978; Spruance and Bailey, 1973]. Such patients may have peripheral leukocytosis, a mixed cerebrospinal fluid pleocytosis, and diffusely slow EEGs [Spruance and Bailey, 1973]. The diagnosis can be established by virus isolation during the prolonged viremic phase [Goodpasture et al., 1978] or serologic studies. Reverse transcriptase– polymerase chain reaction holds promise as a rapid, specific diagnostic method [Johnson et al., 1997]. Patients require supportive care and usually recover without sequelae.

Rotavirus Rotavirus commonly infects infants or young children during the winter months and causes fever, diarrhea, vomiting, and dehydration [Blacklow and Cukor, 1981; McCormack, 1982]. Rarely, children with rotavirus gastroenteritis experience seizures or altered sensorium [Salmi et al., 1978; Schumacher and Forster, 1999; Yoshida et al., 1995]. Cerebrospinal fluid findings in children with rotavirus-associated CNS complications include a normal glucose content, normal protein content, and normal or elevated cerebrospinal fluid white blood cell count [Yoshida et al., 1995]. The EEG may reveal diffuse, nonspecific slowing, whereas neuroimaging studies are usually normal. Rotavirus gastroenter-

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itis can be diagnosed by detecting rotavirus antigen in stool samples, and CNS involvement can be established by detecting rotavirus RNA in cerebrospinal fluid by using reverse transcriptase polymerase chain reaction [Yoshida et al., 1995]. Children with rotavirus infections have benign, self-limited illnesses, although fluid status must be monitored carefully.

Paramyxoviridae The paramyxovirus family, containing the mumps and measles viruses, has contributed historically to considerable mortality and neurologic morbidity [CDC, 1997f; Fields and Knipe, 1990; Hughes, 1977; Johnson, 1998]. Consequently, vaccines were developed for these viruses and introduced in the late 1960s. Although measles cases have declined in the United States and other countries with compulsory immunization programs, measles still caused 777,000 deaths worldwide in 2000 [CDC, 1997f; Henao-Restrepo et al., 2003]. Measles caused 5% of all deaths in children younger than age 5 years in 2000. Other members of the paramyxovirus family, parainfluenza viruses and respiratory syncytial virus, cause neurologic disease infrequently. Members of the closely related orthomyxovirus family, the influenza viruses, have been associated with Reye’s syndrome, a postinfectious disorder, and meningoencephalitis, albeit rarely.

Measles Virus CLINICAL FEATURES Despite the availability of the measles vaccine, a safe and effective live-virus preparation, measles remains a major worldwide public health concern [CDC, 1997f; HenaoRestrepo et al., 2003]. Measles virus spreads via the respiratory route, with contagion highest during the prodromal, catarrhal stage that precedes the rash. Before vaccine availability, measles typically caused disease in infants and young children during the winter and spring [Morgan and Rapp, 1977]. In the United States, only 216 cases of measles were reported to the Centers for Disease Control and Prevention between 2001 and 2003, a nearly 100% reduction compared with the number in the prevaccine era. Approximately 50% of the cases were imported, and a substantial proportion of the remainder was “import-linked” [CDC, 2004d]. The World Health Organization and other organizations have targeted measles for eradication worldwide by 2010. Symptoms of measles infection include fever, cough, coryza, and conjunctivitis, beginning approximately 12 days after exposure in susceptible persons. The characteristic maculopapular exanthem appears on the face and spreads centrifugally to involve the trunk and extremities. Neurologic complications consist of three distinct disorders: (1) measles encephalomyelitis, a postinfectious demyelinating disorder of immunocompetent hosts; (2) subacute measles virus encephalopathy (also known as subacute measles encephalitis or measles inclusion-body encephalitis), a disorder of immunocompromised hosts; and (3) subacute sclerosing panencephalitis, a neurodegenerative disorder of complex pathogenesis occurring several years after measles virus infection in otherwise healthy hosts. Subacute sclerosing panencephalitis, with an incidence of approximately 1 case per 1 million cases of measles [Modlin et al., 1979;

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Payne et al., 1969], has virtually disappeared in many regions as a consequence of measles vaccination [Dyken et al., 1989]. Because of the rarity of subacute sclerosing panencephalitis in the United States, however, the disorder is often unsuspected during the early stages [Honarmand et al., 2004]. Measles encephalomyelitis, an immune-mediated disorder with an incidence of approximately 1 case per 1000 cases of measles, begins within 7 days after the onset of the measles rash [Johnson et al., 1984; LaBoccetta and Tornay, 1964], and children younger than age 10 years constitute most cases. Clinical manifestations include headache, irritability, somnolence, coma, and seizures, although some children have ataxia, choreoathetosis, or focal deficits [ Johnson et al., 1984; LaBoccetta and Tornay, 1964]. Subacute measles encephalopathy, first reported in the 1970s [Murphy and Yunis, 1976], begins 1 to 7 months after measles infection or immunization in an immunocompromised host, often a child with acute leukemia [Mustafa et al., 1993]. Altered consciousness and generalized or focal seizures, including epilepsia partialis continua, are typical clinical signs; 15% to 40% of patients have hemiparesis, hemiplegia, ataxia, aphasia, or visual symptoms [Mustafa et al., 1993]. Subacute sclerosing panencephalitis, a rare disease currently, affects young children; the age at onset averages approximately 7 years, and the disorder begins 5 to 10 years after measles infection [Anlar et al., 2001; Honarmand et al., 2004; Modlin et al., 1979]. The disorder displays relatively stereotyped clinical stages, beginning with insidious declines in behavior and cognition that may mimic a psychiatric disorder. Myoclonus, a prominent component of the next phase of subacute sclerosing panencephalitis, involves the extremities, trunk, or head, and generalized or focal seizures may begin concurrently [Risk and Haddad, 1979]. As the disorder progresses, speech and intellectual function deteriorate; myoclonus intensifies; and other neurologic abnormalities, such as choreoathetosis, bradykinesia, or rigidity, appear. The typical course ends in debility, coma, and death. Approximately half of patients have chorioretinitis and visual impairment. A small proportion of patients with subacute sclerosing panencephalitis have atypical infections with rapid deterioration and death [Silva et al., 1981].

DIAGNOSIS The diagnosis of measles encephalomyelitis can be established by detecting measles virus IgG titer elevations in acute and convalescent serum or measles-specific IgM in serum or cerebrospinal fluid. Measles virus also can be detected in clinical samples by using reverse transcriptase polymerase chain reaction [Shimizu et al., 1993]. MRI may reveal white matter lesions compatible with acute demyelination. In subacute measles encephalopathy, the cerebrospinal fluid, although usually normal, may reveal a lymphocytic pleocytosis. EEGs typically reveal focal or generalized slowing or epileptiform discharges. CT is usually normal, but MRI can detect nonspecific changes involving the cortex, white matter, or deep nuclei (Fig. 69-14) [Chen et al., 1994]. Paramyxovirus particles or measles virus RNA can be detected in brain tissue. The pathogenesis of subacute sclerosing panencephalitis, although still obscure, reflects defective replication of the

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specific IgG. High cerebrospinal fluid titers of measlesspecific IgG establish the diagnosis of subacute sclerosing panencephalitis, and measles virus RNA can be detected in cerebrospinal fluid or plasma by reverse transcriptase– polymerase chain reaction [Nakayama et al., 1995]. EEGs show bilaterally synchronous spike-wave or slow-wave bursts that assume a suppression-burst pattern over time. MRI commonly exhibits T2 prolongation of subcortical and periventricular white matter and eventually cortical atrophy (Fig. 69-15) [Lum et al., 1986; Anlar et al., 1996].

TREATMENT AND OUTCOME

FIGURE 69-14. T1-weighted MRI from an immunocompromised child with measles encephalitis reveals diffuse cortical atrophy; patchy, hypointense areas at the gray-white matter interface; and subtle basal ganglia calcifications.

Treatment of measles encephalomyelitis consists of supportive care. Outcome varies, ranging from complete recovery to survival with impaired intellectual function, motor deficits, or death. Although one report suggests transient improvement after ribavirin therapy [Mustafa et al., 1993], most persons with subacute measles encephalopathy die or have severe neurologic sequelae. Subacute sclerosing panencephalitis progresses to death in 1 to 3 years in most cases, although some patients have extended plateau phases, either spontaneously or coincident with inosine pranobex or interferon alfa therapy or both [Risk and Haddad, 1979; Yalaz et al., 1992]. A multinational trial indicated that approximately 35% of patients with subacute sclerosing panencephalitis stabilize during inosine pranobex therapy, but found no added benefit from interferon alfa [Gascon, 2003].

Mumps Virus CLINICAL FEATURES

FIGURE 69-15. T2-weighted MRI from an adolescent with subacute sclerosing panencephalitis shows demyelination and early cortical atrophy.

measles virus in neural tissues. Patients with subacute sclerosing panencephalitis have elevated cerebrospinal fluid immunoglobulin levels, oligoclonal bands, and increased IgG synthesis rates, indicating massive production of measles-

Before vaccine licensure, mumps virus infection accounted for most cases of aseptic meningitis and mild encephalitis in the United States and many other regions. More than 150,000 cases of mumps were reported in the United States in 1968, with aseptic meningitis in 10% and encephalitis in 0.2%, whereas less than 2000 cases of mumps were reported in 1993, a 99% decrease [CDC, 1995b]. The Finnish epidemiologic survey [Koskiniemi et al., 1991] documented the dramatic decline in mumps meningoencephalitis and measles encephalomyelitis after vaccine licensure. By the early 1980s, mumps meningoencephalitis had disappeared in many regions of the world. Clinical features appear 2 weeks after acquisition and consist of anorexia, malaise, and low-grade fever; parotitis is a cardinal clinical feature. One third or more of mumps virus infections are asymptomatic. Aseptic meningitis or encephalitis, heralded by headache, vomiting, and high fever, is associated with stiff neck, somnolence, and occasionally seizures, coma, or focal deficits [Koskiniemi et al., 1983]. Additional neurologic complications of mumps include acute cerebellar ataxia and hydrocephalus secondary to mumps virus–induced ependymitis [Bray, 1972; Herndon et al., 1974; Ichiba et al., 1988].

DIAGNOSIS, TREATMENT, AND OUTCOME Cerebrospinal fluid pleocytosis is the rule in mumps virus meningitis or encephalitis. Cerebrospinal fluid protein content is usually normal, and the glucose content can be slightly

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reduced [Koskiniemi et al., 1983]. The diagnosis can be confirmed by detecting mumps virus–specific IgM or IgG. EEGs in children with encephalitis may reveal generalized or focal slowing. Children require supportive care; most recover completely.

Nipah Virus In fall 1998, an outbreak of severe encephalitis appeared in Malaysia [Chua, 2003; Chua et al., 2000; Johnson, 2003]. Electron microscopic studies of infected tissues identified a paramyxovirus, named Nipah virus after Kampung Sungei Nipah, the Malaysian village in which the virus was first detected. Fruit bats (genus Pteropus) serve as the natural reservoir of the virus. During the first outbreak, 265 cases of encephalitis occurred in humans ranging in age from 10 years to nearly 70 years. The clinical features included fever, headache, vomiting, cough, cerebellar signs, pupillary abnormalities, seizures, autonomic dysfunction, and coma [Goh et al., 2000]. Among the 265 human cases, there were 105 deaths, corresponding to a mortality rate of nearly 40%; ribavirin therapy was associated with reduced mortality [Chong et al., 2001]. Case-control studies indicated that Nipah encephalitis in humans resulted from contact with pigs or with pig excrement [Parashar, et al., 2000], and after slaughter and disposal of pigs, the initial outbreak ended [Chua et al., 2000].

Rhabdoviridae Rabies Virus CLINICAL FEATURES Dreaded since antiquity, rabies poses a threat to individuals in many regions of the world, especially in the developing countries of Africa and Asia, where the incidence of 1 in 100,000 to 1 in 1 million inhabitants corresponds to approximately 50,000 deaths annually [Fishbein and Robinson, 1993; Plotkin, 2000]. In these regions, domestic dogs or wild canines transmit rabies, and children constitute most human rabies cases. By contrast, human and animal rabies has been eradicated in a few regions as a result of quarantine and vaccination of domestic animals [CDC, 1997a; Haupt, 1999; Johnson, 1998]. In the United States, rabies remains endemic in certain wild animals, including raccoons, skunks, foxes, and bats. In the northeastern states, the number of infected raccoons has increased steadily since the 1970s [CDC, 1997e; Fishbein and Robinson, 1993; Krebs, et al., 2002; Rupprecht et al., 1995]. This epizootic constitutes a potential health hazard and an economic burden for postexposure prophylaxis [CDC, 1993b]. The cost of human rabies prophylaxis in the United States exceeds $40 million annually. The Centers for Disease Control and Prevention receives reports of one to three indigenous cases of human rabies annually in the United States. Many cases have no apparent history of animal bites and have been linked by molecular analysis to the rabies virus strain carried by the insectivorous silver-haired bat [CDC, 1993b]. Rabies, similar to many viral CNS infections, begins nonspecifically, mimicking upper respiratory or gastro-

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intestinal disorders. After a variable incubation period averaging 20 to 60 days, human rabies begins with chills, fever, headache, sore throat, malaise, nausea, or abdominal pain [Anderson et al., 1984; Johnson, 1998; Plotkin, 2000]. Pain or itching corresponding to the site of inoculation is common. Neurologic symptoms and signs begin thereafter; symptoms and signs are cerebral in 80% and Guillain-Barré syndrome–like in the remainder. Patients with cerebral symptoms have marked behavioral changes with agitation, hypersalivation, delirium, and occasionally opisthotonic posturing [Dupont and Earle, 1966; Warrell, 1976]. Hydrophobia, present in 20% to 50% of patients, produces spasms of the laryngeal muscles, diaphragm, and accessory respiratory muscles, which can lead to respiratory arrest and death [Warrell, 1976]. Seizures ensue in many cases. Eventually, patients with rabies encephalitis lapse into a fatal coma. Rabies-induced Guillain-Barré syndrome–like disease produces bulbar dysfunction, facial diplegia, and often respiratory arrest [Chopra et al., 1980]. Cardiac dysrhythmias and irreversible coma are additional causes of death in paralytic cases.

DIAGNOSIS Because of its rarity in the United States and Canada, human rabies is often unsuspected [Noah et al., 1998], especially during the early, nonspecific phase. Consequently, rabies usually is identified at postmortem examination. Premortem diagnosis can be established by immunofluorescence examination of skin from the nape of the neck, detection of rabies virus antibody in cerebrospinal fluid or serum (assuming the patient was not vaccinated previously), or isolation of rabies virus from saliva or cerebrospinal fluid [Plotkin, 2000; Smith, 1996]. Reverse transcriptase polymerase chain reaction can be used to detect rabies virus and determine the molecular profile and animal origin of the rabies virus strain. Cerebrospinal fluid may be normal or reveal nonspecific changes with a mixed or lymphocytic pleocytosis and mild protein elevation [Chopra et al., 1980; Plotkin, 2000]. CT is normal; MRI can demonstrate signal abnormalities of the basal ganglia or thalami [Awasthi et al., 2001].

TREATMENT AND OUTCOME Current antiviral drugs do not benefit patients with rabies, and virtually all patients die despite supportive care. The few reported survivors of rabies had received postexposure prophylaxis or had been immunized previously. A recent survivor of symptomatic rabies was treated with ribavirin, amantadine, and drug-induced coma [Willoughby et al., 2005]. Children with suspected rabies exposures should receive postexposure prophylaxis in accordance with Centers for Disease Control and Prevention and local public health guidelines, taking into account the animal species and the nature of the exposure. All postexposure treatment should begin with immediate and thorough cleansing of the wound with soap and water [Plotkin, 2000]. Bites are more likely to transmit the virus than scratches or other encounters [Fishbein and Robinson, 1993]. Because of the strong epidemiologic relationship between bat rabies strains and human rabies, prophylaxis should be administered after contact with bats, unless testing of the bat

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proves negative for rabies [CDC, 1997f]. Human-to-human transmission of rabies virus has been reported after corneal and organ transplantation [CDC, 2004e; Houff et al., 1979], but transmission by body fluids has not been described. Nonetheless, persons with suspected rabies should be maintained in strict isolation to minimize contact with rabies virus-contaminated fluids and to reduce the number of health-care workers who require postexposure prophylaxis. An average of 54 persons (family members and heath-care workers) per patient have required postexposure prophylaxis after contact with U.S. human rabies cases [Noah et al., 1998].

Arenaviridae Lymphocytic choriomeningitis virus, a rodent-borne arenavirus, infects humans in temperate regions throughout Europe and North America, and outbreaks of human lymphocytic choriomeningitis virus disease have been linked to hamsters and wild or laboratory mice [Deibel et al., 1975; Dykewicz et al., 1992; Peters et al., 1996]. Although many infections occur without symptoms, lymphocytic choriomeningitis virus can induce a nonspecific, influenza-like disorder with fever, headache, myalgia, nausea, vomiting, backache, and cough [Dykewicz et al., 1992]. Occasional patients, including children, have prominent CNS symptoms with aseptic meningitis or mild meningoencephalitis [Deibel et al., 1975]. Cerebrospinal fluid findings include a mixed pleocytosis, sometimes including eosinophils, normal or elevated protein content, and a normal or depressed glucose content [Hirsch et al.,

FIGURE 69-17. Unenhanced CT scan of another infant with congenital lymphocytic choriomeningitis virus infection reveals periventricular calcifications (arrow) and an abnormal cortex compatible with a disorder of neuronal migration. (From Wright R, Johnson D, Neumann M, et al. Congenital lymphocytic choriomeningitis virus syndrome: A disease that mimics congenital toxoplasmosis or cytomegalovirus infection. Pediatrics 1997;100:1.)

1974]. CT reveals hydrocephalus secondary to the meningeal and ependymal inflammation. Lymphocytic choriomeningitis virus causes an intrauterine infection with clinical and radiographic features that resemble intrauterine cytomegalovirus disease or intrauterine toxoplasmosis [Barton and Mets, 2001; Barton et al., 1993; Wright et al., 1997]. Infants with this disorder frequently display chorioretinitis, microcephaly, or macrocephaly [Barton and Mets, 2001; Wright et al., 1997], and imaging studies reveal hydrocephalus, cerebral atrophy, or intracranial calcifications (Figs. 69-16 and 69-17). The diagnosis of congenital lymphocytic choriomeningitis virus infection can be established by detecting lymphocytic choriomeningitis virus–specific antibodies in cerebrospinal fluid or serum and potentially by detecting lymphocytic choriomeningitis virus RNA in cerebrospinal fluid with reverse transcriptase polymerase chain reaction [Read et al., 1997]. Patients with acquired infections recover completely, whereas congenitally infected infants have high rates of neurodevelopmental sequelae [Barton and Mets, 2001; Wright et al., 1997]. Current antiviral drugs do not possess clinically useful antilymphocytic choriomeningitis virus activity.

Retroviridae FIGURE 69-16. Unenhanced CT scan of an infant with congenital lymphocytic choriomeningitis virus infection reveals massive ventriculomegaly compatible with aqueductal obstruction. (From Wright R, Johnson D, Neumann M, et al. Congenital lymphocytic choriomeningitis virus syndrome: A disease that mimics congenital toxoplasmosis or cytomegalovirus infection. Pediatrics 1997;100:1.)

HIV and human T-cell lymphotropic virus type I, linked in the 1980s to AIDS and progressive myelopathy, contribute to considerable neurologic morbidity among humans worldwide [Varmus, 1988]. Maintained in human reservoirs and transmitted via virus-contaminated human fluids or blood products, these retroviruses chronically infect the host, producing neurologic disease coincident with primary

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infection or subsequently during virus reactivation. Although antiretroviral therapy has advanced considerably since the 1990s, vaccines to prevent these infections are not yet available.

Human Immunodeficiency Virus CLINICAL FEATURES Cases of AIDS in children first appeared in the early 1980s before the causative agent, HIV, was identified [Falloon et al., 1989]. Early cases of childhood AIDS were traced epidemiologically to blood transfusions, hemophilia requiring factor replacement, or having a parent with AIDS or an AIDS-related condition. Subsequently, most HIV infections in infants and children were linked to mothers harboring HIV. The offspring of untreated, HIV-infected women have a 15% to 30% risk of acquiring the virus, whereas current combined antiretroviral treatment and management strategies in HIV-infected mothers and their infants can reduce the risk of perinatal transmission to 2% or less [American Academy of Pediatrics, 2003; CDC, 1994b, 1997g; Connor et al., 1994; Havens and Waters, 2004]. By the late 1980s, AIDS cases had been identified in more than 100 countries or territories, and the total number of AIDS cases worldwide rose exponentially from approximately 12,000 in 1984 to greater than 100,000 by 1989. Although the rates of HIV infection plateaued or declined in the United States and other regions of the developed world during the 1990s, HIV infection remains a major threat to the world’s population [De Cock et al., 2000; UNAIDS, 2002]. Currently, more than 90% of new HIV infections occur among persons living in Asia and Africa. More than 800,000 Chinese were living with HIV/AIDS in 2001 [UNAIDS, 2002]. Globally the number of people living with HIV continues to grow—from 35 million in 2001 to 38 million in 2003. The World Health Organization estimates that 16,000 new cases of HIV infection occur daily and that 100 million persons worldwide will be infected with HIV by 2010 [UNAIDS, 2002]. More than 20 million infants, children, and adults have died since the first cases of AIDS were identified in 1981. Infants infected with HIV vertically become symptomatic after the third month of life, manifesting hepatomegaly, lymphadenopathy, failure to thrive, interstitial pneumonitis, opportunistic infections (especially with Pneumocystis carinii or cytomegalovirus), or neurologic disease [Falloon et al., 1989]. The severity and spectrum of the clinical manifestations are modified, however, by antiparasitic, antiviral, and antiretroviral therapies. In some children, HIV can remain dormant, and 10 or more years may elapse before symptoms of HIV infection appear. Before current therapies, a child infected vertically with HIV had a 50% probability of severe HIV-related disease by age 5 years [Barnhart et al., 1996]. Neurologic complications were noted among adults early during the AIDS epidemic, and by the mid-1980s, similar disorders were reported in children [Belman et al., 1985; Epstein et al., 1985]. These early reports emphasized the dramatic, progressive decline in motor and intellectual skills in HIV-infected children, sometimes coinciding with the appearance of opportunistic infections with cytomegalovirus, P. carinii, Toxoplasma gondii, or other microorganisms.

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Early studies suggested that HIV-associated progressive encephalopathy develops in approximately 50% of children with advanced HIV disease, whereas improved antiretroviral therapies have modified the natural history of encephalopathy in HIV-infected children [Belman, 1992, 2002]. In utero exposure to HIV without evidence of perinatal infection does not adversely affect early neurologic development [Belman et al., 1996]. Before the availability of antiretroviral therapies, infants and children with HIV encephalopathy exhibited progressive motor dysfunction, cognitive abnormalities, developmental delay, and acquired microcephaly [Belman et al., 1985, 1986, 1988; Epstein et al., 1985]. Typical neurologic findings, attributable to the direct CNS effects of HIV, consist of apathy, dementia, ataxia, hyperreflexia, weakness, seizures, or myoclonus. Current antiretroviral therapies prevent or delay the onset of certain HIV-related neurologic complications [Gavin and Yogev, 1999; Belman, 2002]. The pathogenesis of brain abnormalities in infected infants and children has yet to be elucidated fully. HIV invades the CNS early after intrauterine or postnatal infection and displays tropism for microglia, macrophages, and astrocytes [Epstein and Gendelman, 1993; Epstein and Sharer, 1994; Ho et al., 1985]. Certain CNS cell populations, including neurons and oligodendrocytes, contain little or no HIV, suggesting that HIV causes dysfunction of these cell populations indirectly through cytokines or excitotoxins [Belman, 1997; Epstein and Sharer, 1994]. CNS disease parallels immunodeficiency [Belman, 1997, 2002] and reflects the viral load of infected persons. Additional disorders linked directly to HIV infection of the CNS or peripheral nervous system are aseptic meningitis, meningoencephalitis, myopathy, and Guillain-Barré syndrome–like conditions [Raphael et al., 1991; Srugo et al., 1992]. HIV infection and AIDS also produce numerous secondary CNS complications, including stroke [Park et al., 1990], primary CNS lymphoma [Epstein et al., 1988], and CNS infections with T. gondii, cytomegalovirus, varicellazoster virus, Mycobacterium tuberculosis, fungi, and JC virus, the cause of progressive multifocal leukoencephalopathy [Wrzolek et al., 1995]. The last-mentioned condition occurs in approximately 4% of adults with AIDS and some children and causes weakness, visual loss, cognitive decline, gait abnormalities, and sensory disturbances [Berger et al., 1987, 1992]. Polymerase chain reaction can be used to detect JC virus in clinical samples [McGuire et al., 1995].

DIAGNOSIS Passive transfer of maternal antibody complicates detection of HIV infection during the first 18 months of life, and 30% or more of exposed infants serorevert [American Academy of Pediatrics, 2003]. Consequently, detection of HIV nucleic acid by polymerase chain reaction is necessary to diagnose HIV infection in young infants [American Academy of Pediatrics, 2003; Belman, 1997, 2002; Bremer et al., 1996]. HIV infection in infants can be confirmed by serial serum polymerase chain reaction assays, with the first test in the immediate newborn period, a second test during the first or second month of life, and a third test after 4 months of age. If two samples are positive for HIV, the infant is considered infected; two successive negative tests indicate infection is

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FIGURE 69-18. Unenhanced CT scan of a male with hemophilia and progressive encephalopathy resulting from human immunodeficiency virus infection reveals diffuse cortical atrophy. (From Bale JF. Encephalitis and other virus induced disorders of the nervous system. In: Joynt RJ, Griggs RC, eds. Clinical neurology. New York: Lippincott-Raven, 1996.)

unlikley [American Academy of Pediatrics, 2003]. In children and adolescents, serologic studies using enzyme-linked immunosorbent assay and Western blotting can identify HIV infection. Reverse transcriptase–polymerase chain reaction monitoring of virus loads guides the treatment of HIVinfected infants, children, and adolescents [American Academy of Pediatrics, 2003; Nielsen and Bryson, 2000]. The cerebrospinal fluid is usually normal in HIV-associated progressive encephalopathy, whereas the EEG may exhibit diffuse slowing. Neuroimaging studies reveal cortical atrophy in vertically or horizontally acquired infections (Fig. 69-18). Calcifications of the basal ganglia or frontal white matter— best detected by CT—and nonspecific abnormalities of white or gray matter—most evident by MRI—also have been reported in vertically acquired HIV infections [DeCarli et al., 1993; Belman et al., 1986]. CT, MRI, and studies of cerebrospinal fluid or blood can identify secondary infectious and neoplastic complications in HIV-infected children. Highly active antiretroviral therapy (HAART) has improved the prognosis for many of the opportunistic infections in persons with AIDS [Belman, 2002; Clifford et al., 1999].

TREATMENT AND OUTCOME HAART and refined treatments for the infectious or neoplastic complications of AIDS have enhanced greatly the survival of HIV-infected persons [American Academy of Pediatrics, 2003; Belman, 1997, 2002; Melvin, 1997; van

Rossum et al., 2002]. The mean survival time for children with AIDS exceeds 9 years, which is substantially greater than that of children treated for HIV infection in the early 1990s [Palumbo, 2000; Pizzo et al., 1988]. Several infectious disorders, including cytomegalovirus retinitis, cerebral toxoplasmosis, P. carinii, herpes zoster, and CNS or systemic fungal infections, respond favorably to current antiviral, antiparasitic, and antifungal therapies. Intravenous immunoglobulin also benefits selected children with hypogammaglobulinemia or recurrent, serious bacterial infections [Spector et al., 1994]. Certain complications, such as progressive multifocal leukoencephalopathy or primary CNS lymphoma, remain poorly responsive to the available therapies, however; the prolonged survival of HIV-infected patients seems to increase their lifetime risk of developing progressive multifocal leukoencephalopathy or CNS lymphoma. HAART uses combinations of nucleoside/nucleotide reverse transcriptase inhibitors, such as zidovudine and didanosine; protease inhibitors, such as ritonavir and indinavir; and non-nucleoside reverse transcriptase inhibitors, such as nevirapine and efavirenz. The goal of therapeutic strategies is to reduce the HIV viral load to undetectable levels and to restore immunologic function. HAART produces immunologic and neurocognitive improvement, even in advanced HIV infection [Essajee et al., 1999; Tozzi et al., 1999]. Measurement of virus loads by quantitative reverse transcriptase–polymerase chain reaction has an essential role in monitoring the efficacy of therapy in HIV-infected children. The development of drug resistance remains a serious, potential threat for HIV-infected patients [Boden et al., 1999]. In addition, HAART-associated immune reconstitution in patients with AIDS can lead to immune restoration disease, a condition characterized by paradoxical exacerbation of secondary infections during the initial 6 months of HAART [French et al., 2004; Stoll and Schmidt, 2003]. Immune restoration disease may occur in 30% of AIDS patients with low CD4+ cell counts who begin HAART. Children who undergo HAART can experience lipodystrophy, insulin resistance, osteopenia, and growth failure [Leonard and McComsey, 2003]. Secondary infectious complications of AIDS, such as cytomegalovirus retinitis, Toxoplasma encephalitis, and cryptococcal or tuberculous meningitis, require therapy with appropriate antimicrobial agents. Treatment of primary CNS lymphoma in persons with AIDS remains problematic [Belman, 1997; Epstein et al., 1988]. Because treatment of HIV infection continues to evolve, centers experienced in HIV treatment should be consulted regarding current therapeutic approaches (for information regarding the available antiretroviral therapies and current treatment guidelines, see www.aidsinfo.nih.gov). Despite the remarkable success of HAART, current therapies do not eradicate HIV from infected persons [Lambotte et al., 2003]. Persons who reach end-stage AIDS despite HAART frequently experience AIDS-defining conditions, such as HIV dementia/encephalopathy, progressive multifocal leukoencephalopathy, lymphoma, or invasive cytomegalovirus infections, during the 12 months before death [Welch and Morse, 2002]. Vaccines to prevent HIV infection and AIDS are not yet available.

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Human T-Cell Lymphotropic Virus Type I Human T-cell lymphotropic virus type I, originally detected in adults with T-cell leukemia, causes a progressive myelopathy known as human T-cell lymphotropic virus type I–associated myelopathy/tropical spastic paraparesis, an endemic disorder in Japan, certain Caribbean Islands, the Seychelles, Africa, India, and certain regions of Latin America [Levin and Jacobson, 1997; Osame et al., 1987; Román et al., 1987]. Transmission of human T-cell lymphotropic virus type I parallels that of HIV, involving vertical (mother-to-child) and horizontal (person-to-person or transfusion of blood products) routes. Infection during childhood occurs commonly in endemic regions. Although most reported patients have been adults, a few have had onset of symptoms during late childhood or early adolescence [de Oliveira et al., 2004; Janssen et al., 1991; LaGrenade et al., 1995]. Clinical manifestations of human T-cell lymphotropic virus type I–associated myelopathy/tropical spastic paraparesis are those of a chronic, progressive myelopathy with spastic paraparesis, lower extremity hyperreflexia, sensory dysfunction, and bladder dysfunction. Although some patients respond temporarily to corticosteroid therapy, no curative antiviral therapy is currently available. REFERENCES Abd-Allah SA, Jansen PW, Ashwal S, et al. Intravenous immunoglobulin as therapy for pediatric Guillain-Barré syndrome. J Child Neurol 1997;12:376. Abzug MJ, Cloud G, Bradley J, et al. Double blind placebo-controlled trial of pleconaril in infants with enterovirus meningitis. Pediatr Infect Dis J 2003;22:335. Alexander JP, Baden L, Pallansch MA, et al. Enterovirus 71 infections and neurologic disease—United States, 1977-1991. J Infect Dis 1994;169:905. Alkaly AL, Pomerance JJ, Rimoin DL. Fetal varicella syndrome. J Pediatr 1987;111:320. American Academy of Pediatrics. 2003 Red Book: Report of the Committee on Infectious Diseases, 26th ed. Elk Grove Village, IL: American Academy of Pediatrics, 2003. Anderson LJ, Nicholson KG, Tauxe RV, et al. Human rabies in the United States, 1960 to 1979: Epidemiology, diagnosis, and prevention. Ann Intern Med 1984;100:728. Andreoni M, El-Sawaf G, Rezza G, et al. High seroprevalence of antibodies to human herpesvirus-8 in Egyptian children: Evidence of nonsexual transmission. J Natl Cancer Inst 1999;91:465. Anlar B, Köse G, Gürer Y, et al. Changing epidemiologic features of subacute sclerosing panencephalitis. Infection 2001;29:192. Anlar B, Saatçi I, Köse G, et al. MRI findings in subacute sclerosing panencephalitis. Neurology 1996;47:1278. Appelbaum E, Rachelson JH, Dolgopol VB. Varicella encephalitis. Am J Med 1953;15:223. Askalan R, Laughlin S, Mayank S, et al. Chickenpox and stroke in childhood: A study of frequency and causation. Stroke 2001;32:1257. Awasthi M, Parmar H, Patankar T, et al. Imaging findings in rabies encephalitis. AJNR Am J Neuroradiol 2001;22:677. Baker FJ, Kotchman GS, Foshee MS, et al. Acute hemiplegia of childhood associated with Epstein-Barr virus infection. Pediatr Infect Dis J 1983;2:136. Bale JF. Human cytomegalovirus infection and disorders of the nervous system. Arch Neurol 1984;41:310. Bale JF, ed. Congenital infections of the central nervous system. Semin Pediatr Neurol 1994;1. Bale JF. Human herpesviruses and neurological disorders of childhood. Semin Pediatr Neurol 1999;4:278. Bale JF. Virus induced disorders of the nervous system. In: Joynt RJ, Griggs RC, eds. Clinical neurology. New York: Lippincott-Raven, 2003. Bale JF, Miner LJ. Herpes simplex virus infections of the newborn. Curr Treat Options Neurol 2005;7:151.

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Fungal, Rickettsial, and Parasitic Diseases of the Nervous System Carol A. Glaser, Paul F. Lewis, and Frederick L. Schuster

FUNGAL DISEASES The importance of fungal infections has risen because progress in medicine has enabled more immunocompromised patients, including preterm infants, to survive. Patients, including children, with congenital immunodeficiency or poorly controlled human immunodeficiency virus infection are also at risk for invasive fungal infection as are diabetic, aplastic anemia, and oncology patients. The normal host is also susceptible to fungal infections, albeit to a smaller spectrum of organisms [Chimelli and MahlerAraujo, 1997]. Fungal diseases involving the brain are usually secondary to systemic or pulmonary infection, and, in most patients, spread hematogenously. Occasionally, they arise from local direct extension from adjacent sinuses or the cranial vault. With the exception of Candida meningitis in premature neonates and Aspergillus brain abscess in hematologic malignancy/hematopoietic stem cell transplant recipients, the individual fungal infections of the central nervous system (CNS) in children are rare. A review from a large university children’s hospital found that in a 6-year period, 2% of 1498 positive cerebrospinal fluid cultures recovered fungal isolates [Arisoy et al., 1994]. Candida species accounted for 94.5% of all positive fungal cerebrospinal fluid cultures. About 39% of all patients were neonates, almost all of whom were low-birth-weight infants. For children beyond the newborn period, risk factors were prior antimicrobial therapy, chronic systemic or CNS disease, and central venous catheterization. Disseminated fungal infection was documented in 40% of all patients with positive cerebrospinal fluid cultures but, surprisingly, in 35% of patients the fungi recovered in the cerebrospinal fluid were considered contaminants. Such findings demonstrate that the clinician must always consider fungal CNS infections, particularly in certain high-risk groups, but results of positive cerebrospinal fluid cultures need careful interpretation. Table 70-1 provides a more extensive list of risk factors associated with fungal infections of the nervous system. Clinical manifestations of fungal infections can be subtle, and errors or delays in diagnosis are common. Fungi may cause meningitis, brain abscesses, granulomas, and spinal cord disease, and may invade and occlude the cerebral vasculature [Salake et al., 1984].

FUNGAL INFECTIONS IN NORMAL HOSTS For purposes of discussion, separating fungi that infect normal hosts from those that infect immunologically compromised hosts is useful. Fungal infections in normal

hosts include the following: Cryptococcus neoformans, Coccidioides immitis, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Histoplasma capsulatum, and Nocardia asteroides. Compromised hosts may encounter the same pathogens as normal hosts but are especially susceptible to a wide range of opportunistic fungal pathogens including molds, such as Aspergillus and Rhizopus.

Cryptococcosis Cryptococcosis is globally distributed and is most commonly seen in patients with acquired immunodeficiency syndrome (AIDS) and in those receiving systemic corticosteroids; infection also occurs in those without apparent predisposition, but at a lower frequency [Wendisch et al., 1996]. Although children are less frequently infected than adults, infants have contracted the disease [Hung et al., 1995; Littman and Walter, 1968; Wang et al., 1996] and vertical transmission has been reported from a mother with advanced AIDS [Sirinavin et al., 2004]. C. neoformans is an encapsulated yeast that reproduces by budding and has a sexual stage (Fig. 70-1). Bird feces, particularly from pigeons, harbor numerous cryptococcal organisms. The mode of entry in humans is probably through inhalation or ingestion. Hematogenous dissemination to the nervous system is usually preceded by pulmonary infection.

Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis Cryptococcus causes a meningoencephalitis often characterized by typical features, including nausea, vomiting, headache, and fever, all of which may fluctuate. Caution is urged in ruling out the diagnosis based on history and physical examination alone because many patients are afebrile (40%), have no meningeal signs [Sabetta and Andriole, 1985], and presenting symptoms such as somnolence, clumsiness, poor memory, and confusion can be nonspecific. Ocular palsies and personality changes may also occur. In AIDS patients, CNS cryptococcosis tends to be acute with fever and headache in 70%, meningismus, photophobia, or mental status changes in 20% to 25%, and focal deficits in a small percentage [Daar and Meyer, 1992]. Most patients with cryptococcal meningitis have an abnormal chest radiograph (e.g., bilateral alveolar or interstitial pneumonitis). Some of these patients may have a second opportunistic infection as well, particularly Pneumocystis jiroveci (formerly known as Pneumocystis carinii) [Clark et al., 1990]. C. neoformans most often causes meningoencephalitis but can also cause brain abscesses and granulomas. Granulomas may result in findings associated with mass lesions,

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TABLE 70–1 Fungal Infections ORGANISM

DISEASE

GEOGRAPHIC DISTRIBUTION

Cryptococcus neoformans

Cryptococcosis

Worldwide

MOST COMMON CNS SYNDROME(S)

RISK FACTORS

HIV/AIDS, contact Meningoencephalitis, with pigeon abscesses, droppings granulomas Coccidiodes Coccidioidomycosis Southwest US, Dark-skinned Meningitis, immitis Latin America individuals meningoencephalitis (Hispanic, black, Filipino), HIV/AIDS, dry periods with airborne soil Blastomyces North American Worldwide, Black ethnicity; Meningitis, intracranial dermatitidis blastomycosis endemic in more common in mass, spinal mass parts of US males, diabetes (Great Lakes region) Paracoccidioides South American Mexico, South Age >30 years, poor Granulomatous lesions brasiliensis blastomycosis America nutrition, more in CSF (cerebellum), (particularly common in males meningeal Brazil) involvement Histoplasma Histoplasmosis Worldwide: Living in an endemic Meningitis, brain/spine capsulatum Mississippi region; contact abscess, encephalitis, River basin, with chicken coops, CVA Latin America soil; inhalation of coal dust Nocardia spp.

Nocardiosis

Worldwide

ImmunocomproBrain abscess, mised hosts, more meningitis common in males

Actinomyces spp. Actinomycosis

Worldwide

Aspergillus fumigatus

Aspergillosis

Age between 10 and Meningitis, brain 60 years; males abscess more affected; congenital heart disease Leukemia, Brain abscess, CVA, lymphoma intracranial invasion via sinuses

Candida spp.

Candidiasis

Rhizopus spp. Mucor spp.

Phycomycosis (mucormycosis, zygomycosis)

Worldwide (organism in soil/decaying vegetation) Worldwide Diabetes, (organism part neutropenia, of normal HIV/AIDS, microflora) nosocomial medical procedures Worldwide Diabetes, chronic illness, IV drug use, immunocompromised Worldwide Severe immunocompromised Survival of near drowning

Pseudoallescheria Allescheriosis boydii

DIAGNOSTIC TECHNIQUES

ANTIMICROBIAL THERAPY*

Cultivation of CSF, AMB, fiuconazole latex agglutination Cultivation and/or microscopic examination of CSF, CF, neuroimaging

Fluconazole, itraconazole, AMB

Cultivation of ventricular fluid, neuroimaging, biopsy

AMB, fiuconazole

Microscopic AMB, examination of itraconazole, mucosal lesions, ketoconazole, sputum, cultivation TMP-SMX Cultivation of sputum, AMB stomach aspirate, CSF, blood; radiography, CF, skin test, antigen in serum or urine Cultivation from Ceftriaxone, CSF amikacin plus imipenem, TMP-SMX Identification of the Penicillin, organism from cefotaxime, drained abscess, ceftriaxone neuroimaging Cultivation from biopsy material

AMB, voriconazole, caspofungin

Meningitis, brain abscesses (often multiple microabscesses)

Cultivation of organisms from CSF

Speciation essential, AMB, fiucytosine, fiuconazole

Intracranial invasion via sinuses

NP biopsy

AMB, surgery

Brain abscess

Brain biopsy, cultivation of organism

Voriconazole

*Note that optimal treatment for CNS fungal infections should be done with input from infectious disease consultant. AIDS, acquired immunodeficiency virus; AMB, amphotericin B; CF, complement fixation; CNS, central nervous system; CSF, cerebrospinal fiuid; CVA, cerebrovascular accident; HIV, human immunodeficiency virus; IV, intravenous; NP, nasopharyngeal; TMP-SMX, trimethoprim-sulfamethoxazole.

including papilledema, cranial neuropathies, and hemiparesis [Hung et al., 1995]. The disease course may be indolent but if untreated, the mortality is high. Hydrocephalus occurs regularly and often necessitates shunting [Richardson et al., 1976]. Definitive identification of cryptococcal disease is made by culturing cerebrospinal fluid on Sabouraud’s agar; large volume culture on more than one

occasion may be needed. Latex agglutination detection of cryptococcal antigen is a rapid and useful test for both serum and cerebrospinal fluid specimens. In the cerebrospinal fluid, the antigen detection has an estimated sensitivity of 90% [Sabetta and Andriole, 1985]. C. neoformans can also frequently be cultured from urine or sputum in patients with disseminated disease. Cranial computed to-

Glaser, Lewis, and Schuster / Fungal, Rickettsial, and Parasitic Diseases of the Nervous System

FIGURE 70-1. Capsulated budding yeast cells of Cryptococcus neoformans mounted in India ink.

mography (CT) and magnetic resonance imaging (MRI) scans reveal mass lesions and hydrocephalus caused by C. neoformans. Children with indolent CNS cryptococcal infection may have a modest increase in the cerebrospinal fluid ferritin levels despite traditional cerebrospinal fluid markers being normal [Katnik, 1995].

Management The initial combination of amphotericin B and flucytosine is the best therapeutic regimen for cryptococcal meningitis in both AIDS and non-AIDS patients [Bennett et al., 1979; Gilbert et al, 2004; van der Horst et al., 1997]. Fluconazole orally is an alternative to amphotericin B as the primary treatment of cryptococcal meningitis and is used for the prolonged, sometimes indefinite, suppressive therapy needed for this disease. Oral fluconazole is superior to weekly intravenous therapy with amphotericin B in preventing relapse after primary treatment with amphotericin B [Powderly et al., 1992; Saag et al., 1992]. In AIDS patients treated successfully for both cryptococcus and human immunodeficiency virus (HIV), clinicians may consider stopping fluconazole if the CD4 count remains greater than 100 cells/ mm3. All cases of CNS cryptococcal disease should be managed in consultation with an infectious disease specialist.

Coccidioidomycosis Epidemiology, Microbiology, Pathology Coccidioidomycosis is caused by the fungus C. immitis, a dimorphic fungus that grows as either a mycelium or a unique structure called a spherule. Disease caused by C. immitis most commonly occurs in endemic areas of the southwestern United States, northern Mexico, and portions of Central and South America. The San Joaquin Valley in California is the most notorious endemic zone, giving rise to the terms valley fever and desert fever, but infection is also common in parts of Arizona, New Mexico, and Texas. Most

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infections occur during the dry season when spores are borne by dust. Most often, C. immitis infection is unnoticed or causes a self-limited respiratory tract infection; dissemination (discussed later) is uncommon, but the risk is higher in patients of black, Filipino, and Hispanic backgrounds [Einstein, 1993] and especially in the setting of immunocompromise, such as HIV infection, organ transplantation, or prolonged use of corticosteroids. Coccidioidomycosis is acquired by inhalation of spore-laden dust or transcutaneously after skin abrasion. Because most (60%) infections are asymptomatic or mildly symptomatic, reported cases represent only a small fraction of the total burden of disease. Central nervous system infection in children is rarely reported, so the true frequency is unknown. The disease is not spread person to person, and there is no need for special infection control measures. Paranasal skin lesions may predispose a person to CNS infections [Salake et al., 1984]. The spectrum of neuropathologic change ranges from meningitis to meningoencephalitis and meningomyelitis with extensive parenchymal destruction, sometimes as a result of an associated endarteritis obliterans [Mischel et al., 1995]. Microscopic examination of the thickened leptomeninges demonstrates widespread infiltration with inflammatory cells (e.g., plasma cells, lymphocytes, macrophages). Polymorphonuclear leukocytes are present during the acute phases. In more chronic infections, early fibrosis indicated by collagen fiber formation may be present. Parenchymal brain lesions have been reported in fewer than 40 cases during the 20th century and may occur in the absence of meningitis [Banuelos et al., 1996]. The infection produces both obstructive and communicating hydrocephalus, which may require shunting, by blocking cerebrospinal fluid flow and absorption.

Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis Studies done on military recruits in the 1940s using skin testing demonstrated that many patients with acute coccidioidomycosis are asymptomatic; only 40% experience acute respiratory symptoms [Smith et al., 1946]. Pulmonary infection is evident within 3 weeks after exposure and is marked by fever, chills, night sweats, cough, anorexia, and weight loss. Chest pain occurs in approximately 40% of symptomatic patients and can be severe. Erythema nodosum or erythema marginatum is manifest in 5% of males and 10% or more of females. The painful subcutaneous nodules of erythema nodosum occur most often along the anterior shins and are considered pathognomonic of coccidioidomycosis in endemic areas [Hedges and Miller, 1990]. A fine macular skin rash and conjunctivitis sometimes occur. Chest radiographs often indicate unilateral infiltrates, pleural effusions, and hilar adenopathy; nodules (4%) or cavities (8%) in adult patients are less common findings. Diffuse infiltrates and a septic shocklike presentation can occur, usually in immunocompromised hosts. Dissemination of the infection from the pulmonary focus to distant sites occurs in approximately 0.5% of cases, half of which involve the CNS, usually as meningitis [Banuelos et al., 1996]. Other sites include skin, lymph nodes, bones, and joints. Dissemination usually occurs 1 to 6 months after primary infection but can be delayed for a number of years.

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The clinical characteristics of coccidioidal meningitis are nonspecific. Prompt diagnosis often proves difficult [Caudill et al., 1970]. The most prevalent manifestations are headache, fever, malaise, and weight loss; meningismus may be absent [Saitoh, 2000]. Mental aberrations, such as confusion, personality changes, and decreased level of consciousness, may ensue. Neurologic findings include focal defects, ataxia, obtundation, and coma. Brain and spinal cord abscesses can occur with or without concurrent meningitis [Banuelos et al., 1996]. Spinal cord involvement may occur in conjunction with coccidioidal osteomyelitis of the cervical vertebra [Jackson et al., 1964]. Cerebrospinal fluid abnormalities include mononuclear pleocytosis, increased protein content, increased chloride concentration, and normal or decreased glucose concentration. Diagnostic confirmation can be made by either direct microscopic study or culture of the cerebrospinal fluid (Fig. 70-2). Unfortunately cerebrospinal fluid cultures are often negative in C. immitis meningitis and serologic testing of serum and cerebrospinal fluid may be required for diagnosis. Complement fixation and precipitin tests are dependable and provide accurate diagnosis in more than 99% of patients with disseminated infection [Pappagianis, 1976]. Any discernible titer of complement fixation antibody in spinal fluid is considered diagnostic [Lyons and Andriole, 1986]. The coccidioidin skin test is not used for diagnosis of acute disease. Imaging by CT or MRI scan may reveal widespread cisternal and cervical subarachnoid meningeal involvement in patients with coccidioidal meningitis [Wrobel et al., 1992] and may demonstrate the need for serial imaging to detect developing hydrocephalus.

Management Until recently, amphotericin B administered intravenously and intrathecally was considered the recommended treatment [Galgani, 1997; Wright, 1978]. The drug must be given intrathecally because it is absorbed so poorly from the circulation into the cerebrospinal fluid and a subcutaneous reservoir for direct intraventricular instillation can be used [Diamond and Bennett, 1973]. Relapses can occur in all forms of disseminated coccidioidomycosis and especially in meningitis, even after prolonged treatment with amphotericin B. Fluconazole and itraconazole also are effective in the treatment of coccidioidal meningitis [Taylor et al., 1990;

Tucker et al., 1992; Wheat, 1994], and high-dose fluconazole is now recommended for primary therapy. Fluconazole is well tolerated in both children and adults and the oral form is highly bioavailable. In adults, the dose of 400 mg per day resulted in a 70% response rate [Galgani, 1997]; in children most authorities recommend using the high end of the 3- to 12-mg/kg/day dose range, but data on response rate are lacking. Patients with C. immitis meningitis must be treated indefinitely with fluconazole to prevent relapse.

North American Blastomycosis Blastomycosis is caused by inhalation of airborne spores from B. dermatitidis, a dimorphic fungus found in soil [Bradsher, 1996]. The spectrum of clinical manifestations in adults includes acute pulmonary disease, subacute and chronic pulmonary disease, and disseminated extrapulmonary disease. Lung and skin involvement is most common, followed by bone, the genitourinary tract, and the CNS. Children, who are infrequently affected, suffer a similar spectrum of illness as adults [Schutze et al., 1996] and may be at increased risk if they play near beaver dams [Dismukes, 1986; Klein et al., 1986]. The three major CNS clinical manifestations are meningitis, intracranial mass, and spinal mass [Gonyea, 1978]. In the past decade, the incidence of blastomycosis has increased because of its prevalence in patients with AIDS, in whom it is associated with a high and early mortality [Witzig et al., 1994]. Skin tests and serologic tests are not helpful in the diagnosis of North American blastomycosis. The organisms may be identified by culture of ventricular and cisternal fluid; lumbar cerebrospinal fluid cultures are rarely positive. Neuroimaging and myelography demonstrate brain, spinal cord, or extradural lesions [Ward et al., 1995]. Microscopic study of biopsy material provides positive identification of the fungus.

Management Amphotericin B is the most efficacious drug and may be used intraventricularly and intravenously [Morgan et al., 1979]. Early and aggressive therapy with amphotericin B is indicated for most immunocompromised patients with blastomycosis [Pappas et al., 1993]. Infectious Disease Society of America guidelines for CNS infection recommend conventional or liposomal amphotericin B as first-line therapy, with fluconazole at a high dose as an alternative in special circumstances [Chapman, 2000]. Surgery may be indicated in patients with mass lesions, those with a need for a diagnostic biopsy, or those with osteomyelitis refractory to pharmacotherapy [Ward et al., 1995].

South American Blastomycosis

FIGURE 70-2. Infectious fragmentation spores of Coccidioides immitis.

South American blastomycosis is caused by the fungus P. brasiliensis [Lutz, 1908]. The organism is a dimorphic fungal saprophyte found in soil and plants that grows as a yeast at body temperature. Acquisition of disease is restricted to people living in latitudes between Mexico and Argentina, with most patients reported from Brazil. Most disease occurs in people older than the age of 30 years with a striking male preponderance; among the rare childhood cases the gender distribution is equal [Restrepo, 2000].

Glaser, Lewis, and Schuster / Fungal, Rickettsial, and Parasitic Diseases of the Nervous System

The organism first invades the lymph nodes, and then bilateral pulmonary infection or a buccopharyngeal granulomatous lesion develops. The latter must be distinguished from mucocutaneous leishmaniasis. Nervous system involvement is generally thought to be rare but may follow disseminated infection. One review from Brazil found CNS involvement in 14% of symptomatic patients [de Almeida et al., 2004]. Osteomyelitis of the cranium without other lesions has been reported [Krivoy et al., 1978].

Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis The most common presenting complaints and findings in a series of 24 cases included seizures, hemiparesis, cerebellar signs, headache, and hydrocephalus [de Almeida et al., 2004]. CNS granulomas can be solitary or multiple and are located supratentorially or in the cerebellum. Brain CT scan with contrast shows solitary or multiple hypodensities with contrast enhancement. The abscesses contain a necrotic core in which inflamed blood vessels are found. The abscesses may cause focal neurologic signs, increased intracranial pressure, and symptoms of meningeal involvement. The diagnosis of South American blastomycosis is suggested by simultaneous involvement of several organs or by characteristic oral and skin lesions in patients who reside in endemic areas. Microscopic study of scrapings from mucous lesions, sputum, gastric contents, lymph nodes, or surgical specimens is most helpful. Typical morphology consists of round cells bearing many small buds at the periphery and affixed by slim openings to the surface of the parent cell. The etiology of brain lesions must be deduced from culture results outside the CNS or via brain biopsy. Cerebrospinal fluid findings are normal except for slightly elevated protein, and cerebrospinal fluid microscopy and culture are typically negative (de Almeida et al., 2004).

Management Sulfamethoxypyridazine therapy is one low-cost therapeutic option, although the treatment must be continued for 3 to 5 years. Amphotericin B is faster acting but more expensive, more difficult to administer, and more toxic [Araujo et al., 1978]. Itraconazole and ketoconazole, although effective for disease not involving the CNS, cannot be recommended because of poor penetration into the brain and spinal fluid. Authorities currently recommend trimethoprimsulfamethoxazole at high dose (480 mg/day of trimethoprim in three divided doses for adults); voriconazole is considered a promising but unproven alternative (de Almeida et al., 2004).

Histoplasmosis Epidemiology, Microbiology, and Pathology Histoplasmosis was first described by Darling in the Panama Canal Zone in a 27-year-old Martinique man [Darling, 1906] originally thought to have tuberculosis. Darling believed the disease was similar to the condition kala-azar reported by Leishman and Donovan. He named the disease histoplasmosis: “histo” signifying “histocyte” and “plasma” signifying “plasmodium-like organisms.” Not until 1934 did

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DeMonbreum definitively demonstrate the fungal association with histoplasmosis [DeMonbreum, 1934]. Histoplasmosis is globally distributed. Among the endemic zones are the Mississippi River basin, Mexico, and Central and South America [Loosli, 1957]. In these regions, as many as 80% of children manifest positive histoplasmosis skin test results by age 5 years [Rogers, 1967]. Humans and many wild and domestic animals are targets of infection. No racial predilection exists for skin test reactivity. With rare exception the condition is benign and self-limiting. About 10% of those infected with H. capsulatum have pulmonary disease to a degree prompting medical evaluation; those younger than the age of 2 years, the elderly, and those with immunocompromising conditions are more likely to be symptomatic. Overall, males are more likely to have symptomatic pulmonary disease, whereas the disseminated form of the disease affects males and females equally. Only a small subset of individuals with primary histoplasmosis develop disseminated disease, and an even smaller group develop a CNS infection. A review of 235 cases of histoplasmosis reported between 1952 and 1960 revealed that of the one third of the patients who had disseminated disease, one fourth exhibited CNS impairment [Cooper and Goldstein, 1963]. In contrast, a review of histoplasmosis among pediatric oncology patients from an endemic area found disseminated disease twice as common as pulmonary disease, but CNS infection was not described. Histoplasma capsulatum is found in the Americas, H. duboisii in Africa. This dimorphic fungus grows as a yeast at body temperature, whereas mycelia form at room temperature. The mycelia phase contains macroconidia (8 to 15 mm) and microconidia (2 to 5 mm); the later may be essential for human infectivity because they are small enough to reach the alveoli. The organism grows as a saprophyte in the soil. Dampness and nutrients from bird and bat droppings encourage growth in aviaries, chicken coops, mines, caves, and open fields [Ajello and Zeidberg, 1951]. During dry spells, the organism may become airborne and the spores inhaled. No evidence of person-to-person or animal-to-human transmission exists. The gross features at postmortem examination are primarily those of a granulomatous disease similar to miliary tuberculosis that affects the lungs and reticuloendothelial system. Biopsy of infected tissue, such as lymph nodes or liver, demonstrates granulomas that superficially resemble lymphoma, tuberculosis, sarcoidosis, Hodgkin’s disease, and leishmaniasis. The predominant pathologic alterations that occur within the CNS include perivenous miliary granulomatosis, parenchymatous granulomatosis, meningitis, histoplasmoma, and histiocytic histoplasmosis.

Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis Respiratory infection follows inhalation of spore-laden soil or dust. Most children remain asymptomatic or experience little clinical difficulty [Ibach et al., 1954]. A nonspecific mild lung infection may follow exposure after 5 to 15 days. Fever, chills, and a productive cough are common features, but more severe symptoms may occur, including chest pain, dyspnea, and, rarely, prostration. The initial chest radiograph may document a nodular or more dispersed infiltrate. Cultures of the sputum or

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stomach aspirate may grow the organism. After several years, chest radiographs demonstrate characteristic calcification in the central lymph nodes and peripheral lung fields. If untreated, the infection lasts 2 to 12 weeks. The histoplasmin skin test converts to positive during the course of the acute infection but this test is not used diagnostically. Complement fixation titers can be used to detect infection by detecting a fourfold rise between acute and convalescent specimens or finding a single elevated titer in the correct clinical setting. A rise in complement fixation titers after treatment suggests relapse. Progressive disseminated histoplasmosis is rare in normal children. In one report of 10 children with disseminated disease, most had fever, anemia, and hepatosplenomegaly. Only two children had neurologic involvement: one had nuchal rigidity, and the other had positive Babinski’s sign and tetany [Cooper and Goldstein, 1963]. Signs and symptoms associated with CNS involvement in children include intracranial hypertension, memory impairment, confusion, seizures, and urinary incontinence [Machado et al., 1993]. Reported CNS complications in children include hydrocephalus [Enarson et al., 1978], meningitis [Couch et al., 1978], ataxia, seizures, and cranial nerve palsy [Rivera et al., 1992]. Approximately 5% of adult patients with disseminated histoplasmosis will have CNS involvement [Borges et al., 1997] with the median time to diagnosis of 36 months [Machado et al., 1993]. Directed laboratory studies include culture of cerebrospinal fluid, blood, and bone marrow; biopsy of liver, bone marrow, and lymph nodes; and detection of Histoplasma antigen in serum or urine. [Wheat et al., 1986]. Histoplasma antigen is present in the cerebrospinal fluid of some patients with chronic Histoplasma meningitis, but its measurement and diagnostic precision are unreliable [Wheat et al., 1989]. All patients with disseminated histoplasmosis should be evaluated for adrenal insufficiency. In one series, half of the patients, regardless of treatment, had adrenal insufficiency, which was the most common cause of death [Sarosi et al., 1971]. Because Histoplasma can remain quiescent in the lungs or the adrenal glands for more than 40 years before dissemination, it needs to be considered in unexplained neurologic disease, particularly in people who lived in endemic areas as children [Tan et al., 1992].

Management Non-CNS Histoplasma infections are usually treated with itraconazole unless the disease is severe or occurs in immunocompromised hosts, in which case an amphotericin preparation is preferred [Bradsher, 1996; Carpentier et al., 1996; Wheat et al., 1995]. There are no prospective data comparing different treatments for Histoplasma meningitis or brain or spine disease. Current Infectious Disease Society of America guidelines recommend that Histoplasma disease involving the CNS initially be treated with conventional or lipid formulation of amphotericin B followed by fluconazole for a prolonged period [Wheat et al., 2000]. Neither itraconazole nor fluconazole is ideal for CNS histoplasmosis; itracona zole has excellent antifungal activity but poor CNS penetration, whereas fluconazole has inferior antifungal activity but excellent CNS penetration. The prognosis of Histoplasma CNS infections is guarded: 20% to 40% of patients die despite treatment, and relapse among survivors is common [Wheat et al., 2000]. The role of the

most recently released azole antifungal agent, voriconazole, in the treatment of histoplasmosis has not been defined.

Nocardiosis Nocardia spp. are ubiquitous in the environment. Nocardia asteroides, N. farcinica, and N. brasiliensis are the species most often responsible for nocardiosis. Nocardiosis is considered a bacterial infection but is included in this section for the sake of completeness [Threlkeld and Hooper, 1997]. Nocardial disease during childhood is relatively uncommon, and nocardial involvement of the CNS is rare [Stites and Glezen, 1967]. Risk factors for pediatric CNS infections include malignancy, chronic granulomatous disease, lupus, human immunodeficiency virus infection, organ transplantation, and surgery [Marlowe et al., 2000]. Pulmonary manifestations are most common in nocardiosis and include pneumonia, lung abscess, and empyema that may be present concurrently with brain disease. The CNS is involved in a substantial minority of Nocardia infections, many of which occur in those without immune suppression. In those with disseminated infection, CNS involvement should be viewed with concern because it is associated with mortality rates of 80% [Beaman and Beaman, 1994; Threlkeld and Hooper, 1997]. CNS disease may be the only manifestation of nocardiosis suggesting that inapparent pulmonary disease has resolved. Abscesses are the most frequently reported CNS complication, but meningitis accounts for one third. CNS disease caused by Nocardia often has a subacute or chronic course. A variety of neurologic and behavioral or psychiatric presentations occur. Although uncommon, nocardiosis should be considered in the differential diagnosis of subacute meningitis, especially when the cerebrospinal fluid contains a high concentration of neutrophils, elevated protein levels, and a low glucose level. Nocardial pulmonary disease or cerebral abscesses confirm the diagnosis, as do positive cultures from cerebrospinal fluid [Bross and Gordon, 1991]. Neuroimaging can detect abscess formation, hydrocephalus, and, in some patients, the presence of small subependymal nodules [LeBlang et al., 1995]. Parenteral therapy with amikacin plus imipenem or ceftriaxone is the currently recommended treatment [Gilbert et al., 2004]. A review of antibiotic treatment for nocardial infections has been published [Threlkeld and Hooper, 1997]. Serial neuroimaging studies during treatment are also helpful in monitoring resolution of the abscesses [Kirmani et al., 1978]. In selected patients, surgical extirpation of multiple abscesses can be successfully accomplished [Rosenblum and Rosegay, 1979].

FUNGAL AND OTHER INFECTIONS IN THE IMMUNOCOMPROMISED HOST Actinomycosis Epidemiology, Microbiology, and Pathology Actinomyces spp. are anaerobic or microaerophilic gram positive, non–spore forming branching bacilli that normally colonize the mouth, intestine, and female genital tract. Invasive disease, usually caused by Actinomyces israleii, is

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most common in those ages 10 to 60 years; males are more frequently affected than females. Risk factors include untreated focal infections, immunosuppression, and congenital heart disease with right-to-left shunts [Olah et al., 2004]. CNS disease is rare but can result from direct extension from a contiguous focus or by hematogenous spread from another site.

Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis Actinomycosis is a chronic, slow-growing, inflammatory mass most frequently affecting the lungs, cervicofacial region, abdomen, and pelvis (in association with intrauterine devices) [Vinard et al., 1992; Winking et al., 1996]. The mass has a tough, fibrous capsule, does not respect tissue planes, and develops sinus tracts. Concurrent chronic infections and other debilitating conditions predispose patients to dissemination. A review of 181 cases of actinomycosis revealed that less than 2% of patients had cerebral involvement as manifested by meningitis or abscess (solitary or multiple) [Brown, 1973; Fetter et al., 1967]. Neurologic involvement includes meningeal, granulomatous, and pseudotumoral forms [Winking et al., 1996]. Abscesses have been reported in the cerebrum, cerebellum, optic chiasm, parasellar region, and subdural space [Bebrova et al., 1994; Brown, 1973]. Osteomyelitis of the spine may be the origin of spinal cord abscess and compression [Fetter et al., 1967]. Neuroimaging demonstrates abscess easily, but microbiologic diagnosis of CNS disease can be challenging because the organism may be difficult to recover if antibiotics have been given. In addition, infections involving Actinomyces spp. are often polymicrobial, clouding the role of individual species. The etiology of CNS disease may be inferred if Actinomyces spp. are isolated at another site, particularly the lung.

Management Recommendations for treatment of actinomycosis at any site are based on experience and in vitro susceptibility testing rather than clinical trials. Standard recommended treatment for CNS disease is penicillin for at least 6 months. Recently, successful shorter courses of treatment with drugs other than penicillin such as ceftriaxone and cefotaxime for CNS and non-CNS disease have been reported [Olah, 2004; Sudhakar, 2004]. Surgical drainage of the abscess frequently is indicated [Jamjoom et al., 1994; Winking et al., 1996] and may be needed for definitive diagnosis of CNS disease.

Aspergillosis Epidemiology, Microbiology, and Pathology Aspergillus spp. (most commonly fumigatus) affecting humans (Fig. 70-3), like many fungal pathogens, initially gain entrance to the lung after inhalation. The name of this fungus was established because of the similarity of its fruiting head to the aspergillum, a perforated globe used to sprinkle holy water during religious ceremonies. Dissemination and CNS infection are nearly always accompanied by an underlying debilitating condition.

FIGURE 70-3. Spore heads of Aspergillus fumigatus in culture.

Aspergillosis of the CNS was rare until the large increase in immunocompromised hosts, including children, in the past two decades [Carpentier et al., 1996; Sparano et al., 1992; Torre Cisneros et al., 1993; Wright et al., 1993]. Among compromised hosts, the highest frequency of invasive aspergillosis is in heart and lung transplant recipients (19% to 26%) followed by those with chronic granulomatous disease (24% to 40%), acute leukemia (5% to 24%), bone marrow or hematopoietic stem cell recipients (0.5% to 9%), AIDS (0% to 12%), and solid organ transplant recipients (0.5% to 10%) [Denning, 1998]. Central nervous system disease complicates 10% to 20% of invasive disease and is nearly universally accompanied by concurrent infection at other sites. More than 150 species of Aspergillus have been identified. Pathogenic isolates grow quickly on both mycological media and standard bacteriologic plates at 37° C and the genus is identified quickly using microscopy. Disease occurs after spores evade local defenses in the respiratory tract, skin, or wounds weakened by underlying disease or treatment. After an incubation period that may range from days to months, pulmonary infection begins and may be followed by the dissemination to brain, eye, heart, kidney, liver, and bone. A frequent feature of invasive disease is vascular invasion leading to tissue necrosis. Hyphae are abundant and are best seen with silver stains; hyphae in tissue are characterized by frequent septae and branching at 45 degrees.

Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis The following three distinctive types of clinical presentation have been reported with CNS aspergillosis: (1) an intracranial form, the most common, presenting like a space-

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occupying lesion; (2) a rhinocerebral form with primary involvement of the sinuses and secondary involvement of the skull base, cranial nerves, and brain; and (3) a vascular form with strokelike symptoms [Haran and Chandy, 1993]. In addition to brain abscess, aspergillosis can also cause meningitis, meningoencephalitis, hemorrhagic or ischemic necrosis, solitary granulomas, and invasive fungal arteriitis [Torre Cisneros et al., 1993]. The clinical presentation is variable and depends on the host. Highly immunocompromised patients may have altered mental status and seizures, whereas more competent hosts may have headache and focal complaints. In one series, the most frequent neurologic symptoms included altered mental status (86%), seizures (41%), and focal neurologic deficits (32%) [Torre Cisneros et al., 1993]. Neuroimaging may reveal sinus invasion, enhancing or nonenhancing hypodense lesions indicative of abscess [Sparano et al., 1992], or prominent ischemic lesions in the basal ganglia [Miaux et al., 1995]; concurrent chest radiography or CT scan usually indicates multiple nodular lesions. Definitive diagnosis is made by smear and culture of biopsy material. A presumptive diagnosis can be made if cranial imaging is typical and aspergillus is demonstrated at another site. Serum galactomannan testing for invasive aspergillosis is available [Herbrecht et al., 2002] and provides a noninvasive alternative to support the diagnosis; however, published cutoffs of sensitivity and specificity are variable [Marr et al., 2004].

Management Cerebral aspergillosis has a poor prognosis, particularly in the immunocompromised host. Surgical drainage and removal of abscesses and granulomas are often performed but are usually of little value [Casey et al., 1994; Haran and Chandy, 1993]. Similarly, treatment with high-dose conventional amphotericin B contributes toxicity yet little efficacy. The availability of lipid formulations of amphotericin, voriconazole, and caspofungin may improve the prognosis. Case reports and one retrospective review suggest that a subset of patients will respond and some may be cured [Damaj et al., 2004; de Lastours et al., 2003; Schwartz and Thiel, 2004].

Candidiasis Candida spp. are responsible for the most common invasive fungal infections in infants and children [Arisoy et al., 1994]. Cerebral candidiasis is a rare sequela of disseminated disease in a debilitated patient. Predisposing factors include prematurity and its complications, use of broad-spectrum antibiotics, total parenteral nutrition, central venous catheterization, immunosuppression, immunodeficiency (congenital or acquired), chronic renal disease, diabetes, neutropenia, and ventriculoperitoneal shunts [Arisoy et al., 1994; Chiou et al., 1994; McAbee et al., 1995]. Historically, Candida albicans has been the most common species identified in CNS disease. Other species, including Candida tropicalis, Candida lusitaniae, and Candida parapsilosis, have also been reported. One series comprising pediatric oncology patients found that 11 of 12 cases of meningitis were caused by C. tropicalis [McCullers et al., 2000].

Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis Meningitis (most common), abscesses, and granulomas occur independently and in combination (Fig. 70-4). Typically, multiple microabscesses are found rather than a solitary abscess, and reflect the hematogenous dissemination of Candida [Incesu et al., 1994]. Intracerebral abscess after candida septicemia is illustrated in Figure 70-4B. The clinical presentation of meningitis may be subtle because many patients are seriously ill from other medical problems or primary infections. Hemiparesis, cranial nerve palsies, or signs of hydrocephalus may be found [Coker and Beltran, 1988]. Fungal arterial and venous involvement can cause serious complications as can the development of intracranial mycotic aneurysms [Goldman et al., 1979]. Diagnosis can be confirmed by identification of the organism in spinal fluid or infected neural tissue [McGinnis, 1983]. Pleocytosis or reduced cerebrospinal fluid glucose occurs in only about half of the patients who are culture positive [Hughes, 1992].

Management There are no comparative trials to permit definitive antifungal recommendations. Prompt speciation and susceptibility testing may help optimize empiric antifungal therapy. Standard of care suggests that initial combined treatment with amphotericin B (conventional or liposomal) and 5fluorocytosine or fluconazole may be successful [Lisch and Steudel, 1994; Smego et al., 1984], although amphotericin is often used alone [Incesu et al., 1994]. The role of voriconazole and caspofungin for this uncommon disease is not yet defined, and consultation with an infectious disease specialist is recommended. If feasible, use of antibacterials and immunosuppressive agents should be avoided during treatment of candidal infection.

Phycomycosis Extension of a phycomycotic infection from the nose and nasopharynx through the sinuses or cribriform plate into the meninges and CNS is termed rhinocerebral phycomycosis. The term mucormycosis is frequently used interchangeably with phycomycosis, although Mucoraceae represent only one of the subfamilies of the class Phycomycetes. Spread of infection into the orbit by way of the nasolacrimal duct is accompanied by proptosis and panophthalmitis.

Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis Diabetes mellitus is frequently associated with this fungal infection, but intravenous drug use, renal transplantation, and other immunocompromised conditions are additional risk factors; this infection rarely occurs in the immunocompetent individuals or in children [Hussain et al., 1995]. Fever, facial and ocular pain, or CNS symptoms may herald the onset, and a black eschar-like plaque may be seen in the oro- or nasopharynx. Etiology of CNS disease seen in MRI or CT imaging can be inferred from biopsy of nasopharyn-

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geal or sinus specimens. Hyphae can be seen with conventional and special stains and are distinguished by their lack of septae, 90-degree branching, and breadth (10 to 20 μM). Prognosis is usually poor; however, several case reports describe survival of well-controlled diabetic patients treated with surgical debridement plus local and systemic admin-

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istration of amphotericin B [Hamilton et al., 2003; Moll et al., 1994; Sandler et al., 1971].

Management The fungus tends to infect and obstruct cranial blood vessels, and thus, thwart drug treatment. General principles of

A

B

C

D

FIGURE 70-4. A, Pseudohyphae and budding yeast cells of Candida albicans. B, Candidal abscess. C, Cerebral vein clogged with Candida organism. D, Giant cell granuloma.

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management include correcting diabetic ketoacidosis, discontinuing immunosuppressive therapy, if possible, and removing infected tissue surgically. Standard treatment includes extensive debridement inside and outside of the CNS, in addition to amphotericin treatment [Cuadrado et al., 1988; Galetta et al., 1990; Hussain et al., 1995]. The rapid escalation of amphotericin dose is advocated because of the poor prognosis; renal toxicity should prompt use of lipid formulations of amphotericin and many experts would initiate therapy with a lipid formulation of amphotericin B. The recently available agents voriconazole and caspofungin are not typically active against phycomycosis. Some authors have advocated less radical surgery combined with systemic and local (via Omaya reservoir) amphotericin augmented by hyperbaric oxygen therapy (Hamilton et al., 2003).

Pseudallescheria boydii (Scedosporium angiospermum) Infection Allescheriosis is a rare cause of human disease, but when disseminated in compromised hosts, CNS involvement occurs. Risk groups include compromised hosts as well as survivors of near drowning in unclean water. A comprehensive review of CNS disease of 38 cases, the youngest reported case being 24 months, was recently published [Nesky et al., 2000].

Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis P. boydii can cause a chronic subcutaneous infection (mycetoma) or invasive lung, bone, joint, and CNS disease. Brain abscess is the typical CNS manifestation and can be solitary [Bell and Myers, 1978] or multiple [Rosen et al., 1965]. Definitive diagnosis is through brain biopsy, although culture of the organism from a nonsterile site can support the diagnosis. There are no available noninvasive or antigen detection tests. On biopsy, this organism can be confused with Aspergillus or Fusarium spp., but it is easily distinguished once cultured.

Management Surgical resection of brain abscesses along with antifungal therapy have been used, but this organism is notoriously resistant to antifungal therapy, and most cases succumb. The availability of voriconazole, which has in vitro activity, and case reports of success may change this grim prognosis when combined with surgical drainage [Nesky et al., 2000; Poza et al., 2000].

RICKETTSIAL DISEASES Rickettsiae are pleomorphic coccobacilli that are obligate intracellular bacteria whose arthropod vectors include ticks, mites, fleas, or lice [Kim and Durack, 1997]. Rickettsial diseases include the spotted fevers, typhus fevers, scrub typhus, Q fever, and ehrlichioses [Marrie and Raoult, 1992; Pai et al., 1997]. Rickettsial infections often have an accompanying skin eruption. Coxiella burnetii, the rickettsia causing Q fever, differs from the other organisms because it does not require a vector and rarely causes a skin rash.

CNS involvement can occur in all forms of rickettsial infections [Marrie and Raoult, 1992]. Pathologic changes may be extensive and, in some infections, systemic and cerebral vasculitis may be prominent. The clinical and pathologic response of the CNS to different infections caused by Rickettsia spp. is generally similar and differs only in severity [Harrell, 1953b; Woodward and Osterman, 1984]. Headache is often the earliest and most frequent symptom in all rickettsial infections [Harrell, 1953b]. Diagnostic testing is similar for most rickettsial infections. Isolation in cell culture, localization in patient tissues by immunohistochemical stains, or detection of the rickettsial agent in blood or tissues by molecular assays (e.g., polymerase chain reaction) may be useful for diagnosis of acute infection; however, these tests are often available only at specialized research laboratories. Serology is the most generally available and widely used method to establish a diagnosis of rickettsial infection. The indirect fluorescent antibody assay is considered the gold standard. However, because most patients with rickettsial diseases do not develop antibodies reactive with these agents in the first week of illness, serologic tests are often negative during the acute phase of the illness. Confirmation of disease is best accomplished by evaluation of paired serum specimens collected during the acute and convalescent phases of the illness for a fourfold or greater change in antibody titer. Extensive cross-reactivity exists among antigens of the spotted fever group rickettsiae (e.g., Rickettsia rickettsii, Rickettsia akari, and Rickettsia conorii), and among antigens in the typhus group (Rickettsia prowazekii and Rickettisa typhi). In this context, most indirect fluorescent antibody assays are group-specific rather than species-specific tests for rickettsial infection. Recommended treatment of rickettsial diseases in almost all clinical situations includes tetracyclines. Most broadspectrum antibiotics such as penicillins, cephalosporins, and penems are ineffective. Doxycycline is considered the drug of choice in almost all clinical situations for both pediatric and adult patients [Dalton et al., 1995; Kirkland et al., 1995]. The dosage is 100 mg twice per day for adults and 4 mg/kg/day, divided twice daily, intravenously or orally, for 10 to 14 days [Schutz and Jacobs, 1997]. Because tetracyclines are contraindicated during pregnancy, chloramphenicol is used as an alternate drug in this patient population; however, this drug has questionable efficacy for patients with ehrlichiosis and Q fever [Markley et al., 1998]. Empiric treatment with doxycycline should be initiated early in the course if clinical and epidemiologic findings are suggestive of a rickettsial infection because delays in treatment can lead to adverse outcomes. Tetracycline use in pediatric patients is often discouraged because of the potential association with tooth discoloration. For suspected cases of rickettsial illnesses, however, it is important to use a tetracycline. Tetracycline tooth staining is dose related and studies have found that perceptible tooth staining does not occur until multiple courses have been used [Grossman et al., 1971; Lochary et al., 1998]. Table 70-2 lists rickettsial diseases, organisms, vectors, reservoirs, and geographic distribution. Rocky Mountain spotted fever is the prototypic condition for these infections.

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TABLE 70–2 Rickettsia Infections

AGENT

DISEASE

Rickettsia rickettsii

Rocky Mountain spotted fever

Rickettsia Epidemic prowazekii typhus (louseborne typhus fever)

CASES/ YEAR (US)

GEOGRAPHY

MODE OF INFECTION/ VECTOR RESERVOIR

250–1000

North, Central, Tick and South America

Rodents

Imported cases only

North America, Human Europe, louse, some Asian rat and Southeast louse Asian countries, mountainous regions of Africa, Central and South America, and Mexico

Humans, eastern fiying squirrels (US)

Brill-Zinsser

Murine or endemic typhus

<50

Orientia tsutsugamushi

Scrub typhus

Imported cases only

Coxiella burnetti

Q fever

61

Ehrlichia Human 200 chaffeensis monocytic ehrlichia

Ehrlichia ewingii

LABORATORY STUDIES

TREATMENT

COMMENT

2–14 days HA, F, lethargy, periorbital edema, ARF, rash initially maculopapular then petechial (often begins on ankles or wrists) CNS; vasculitis, cerebral edema 7–14 days HA, F, cough, arthralgia MP rash (often begins on trunk) CNS: confusion, prostration, photophobia

Hyponatremia, thrombocytopenia DIC Serology: IFA DFA on skin biopsy PCR—limited availability

Doxycyline

Important to treat early; most common fatal tickborne disease in the US

Anemia, thrombocytopenia, hyponatremia, low albumin, increased LFTs Serology; IFA, EIA, CF, latex agglutination PCR

Doxycycline

Epidemics can occur, especially under poor hygienic conditions

Generally years

Rickettsia typhi

Anaplasma phagocytophilum

INCUBATION PERIOD CLINICAL

Human 500 granulocytic ehrlichia

25

Relapsing form of louse-borne; symptoms milder

Worldwide; in Rat fiea Rodents, 7–14 days Same as epidemic Same as epidemic US, endemic cats, typhus although typhus foci southern opossums, may not be as California, raccoons, severe Texas skunks Southwest Mite Mites, 7–21 days F, HA, conjunctival Leukopenia, Pacific, (chigger) rodents injection, thrombocytopenia, Southeast (secondary adenopathy, anemia Asia, Asia, reservoir) respiratory distress, Serology; ELISA Australia, eschar, rash (often India, Sri begins on trunk) Lanka CNS: meningitis, encephalitis Worldwide, Inhalation Cattle, 2–3 weeks F, HA, malaise, sore Elevated LFTs, most of sheep, throat, chills, sweats, thrombcytopenia, common infectious goats, non-productive Serology; IFA in rural aerosols cats,dogs, cough, nausea, IHC staining, PCR from wildlife vomiting, diarrhea, milk, abdominal pain, urine, chest pain, weight feces, loss, pneumonia, amniotic hepatitis fiuids of infected animals Western Lone Star Deer, 5–10 days F, HA, malaise, Leukopenia, Hemisphere, tick canines, nausea, occasionally thrombocytopenia, Europe, Asia, (American rodents rash, cough, neutropenia, anemia, Southeast dog tick) arthralgia elevated LFTs Asia, Africa, ARDS, renal failure, Serology; IFA blood Israel DIC in severe cases smears for morulae CNS: in mononuclear meningoencephalitis cells, culture (20%) PCR on blood/CSF US, Europe, China

Blacklegged Deer, ticks rodents (Ixodes scapularis and Ixodes pacificus)

US

Lone Star Humans, tick deer, (American canines dog tick)

Same as epidemic typhus

Can occur years to decades after primary infection Usually less severe than epidemic typhus

Doxycycline

Doxycycline

Complication of chronic disease include myocarditis and endocarditis

Doxycycline, Treatment failure chloramphenicol seen with only in chloramphepregnant nicol; women (see IFA test most text) sensitive for diagnosis, but may be negative acute sera Same as HME, except Doxycycline morulae in granulocytes

5–10 days F, HA, arthralgias, nausea, vomiting, rash (<10%), cough, pharyngitis, lymphadenopathy, respiratory and renal insufficiency, myocardial involvement in severe cases CNS: confusion, seizures, coma, stiff neck (20%), demyelinating polyneuropathy 5–10 days Same as HME Thrombocytopenia, Doxycycline leukopenia, elevated LFTs, morulae in granulocytes Serology: IFA

Occurs especially in patients with underlying immunosuppression

ARDS, acute respiratory distress syndrome; ARF, acute renal failure; CF, complement fixation; CNS, central nervous system; DIC, disseminated intravascular coagulation; DFA, direct fiuorescent antibody; EIA, enzyme immunoassay; ELISA, enzyme-linked immunosorbent assay; F, fever; HA, headache; HME, human monocytic ehrlichiosis; IFA, indirect fluorescent antibody; IHC, immunohistochemical; LFT, liver function test; MP, maculopapular; PCR, polymerase chain reaction.

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Rocky Mountain Spotted Fever Rocky Mountain spotted fever is caused by R. rickettsii and is the most common fatal tick-borne illness in the United States [CDC, 2004]. Early missionaries and settlers discerned the association of tick bites with the disease and called the disease tick fever [Aikawa, 1966]. Howard Ricketts identified the etiologic organism in 1906 and established the tick as the vector in transmitting the organism to humans. The disease is prevalent in wide geographic areas. Rocky Mountain spotted fever has been reported throughout the United States with the exception of Hawaii and Vermont [Walker, 1995]. Between 1981 and 1991, the states with the highest incidence of Rocky Mountain spotted fever were Oklahoma, North Carolina, Virginia, Maryland, Georgia, Missouri, Arkansas, Montana, and South Dakota [CDC, 1990]. Approximately 200 to 1000 cases are reported annually in the United States. Outside the United States, it has been described in Canada and several countries of Central and South America [Heldrich, 1987]. In the Northern Hemisphere, the incidence of the disease is greatest from April to September, when tick bites are most likely to occur. The American dog tick (Dermacentor variabilis) is the primary vector responsible for the transmission of R. rickettsii along the southern Atlantic coast and southeastern and south-central United States. In the western region of the United States, the vector is usually the wood tick (Dermacentor andersoni) (Fig. 70-5). Given the habitat preferences of the vector, rural and suburban populations are more likely to be infected than urban residents. Children have a higher risk of infection (half of the cases are younger than 19 years of age [Kamper, 1991]) because they are exposed to tick bites during outdoor play. Rocky Mountain spotted fever should be considered in the differential diagnosis of anyone with compatible clinical features and exposure to a grassy or wooded area where ticks may be present [Walker, 1995]. Dogs may carry ticks into households and yards and are a risk factor for infection [Paddock et al., 2002; Walker, 1995]. The absence of a reported tick bite history should not dissuade a clinician from suspecting Rocky Mountain spotted fever. The incubation period ranges from 2 to 14 days (mean 7 days) after a tick bite [Thorner et al., 1998]. Transmission

FIGURE 70-5. Dermacentor andersoni, the tick responsible for transmission of Rocky Mountain spotted fever in western regions of the United States.

of rickettsiae occurs as a tick feeds on the blood of its host. After entering the body, rickettsiae multiply and disrupt the endothelial cells of capillaries and arterioles. In Rocky Mountain spotted fever, the rickettsiae may also infect the smooth muscle cells of the tunica media. Loss of integrity of the small vessels in the brain results in hemorrhage into the subarachnoid space. Subsequent meningeal irritation and an accompanying perivascular mononuclear infiltrate develop. The brain parenchyma is studded with areas of microscopic infarctions. In the healing phase, a proliferative fibroblastic and gliotic response is evident; the ensuing focal nodules develop more often in white matter in spotted fever and more often in gray matter in typhus.

Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis Symptoms of Rocky Mountain spotted fever vary in severity from mild to severe; the course may rapidly lead to death. Initial symptoms are nonspecific and include fever, malaise, lethargy, and headache. The headache is usually intense and refractory to most analgesics. Progressive restlessness, irritability, confusion, and delirium may also occur. By day 5 of the illness, 85% of patients develop a rash. The rash often begins with a maculopapular appearance and becomes more defined as petechiae as the rash evolves. The rash often begins around the ankles or wrists and then spreads to other parts of the body (Fig. 70-6). Acute renal failure, coagulopathy and cerebral edema are well-recognized complications. Edema, usually periorbital at first and then generalized, is characteristic of and may suggest the diagnosis. Hepatosplenomegaly accompanied by liver dysfunction, including coagulation defects, may confound the diagnostic process. In fulminating disease, shock, coma, and general or focal neurologic impairment, including vertigo, seizures, hemiparesis and ataxia may dominate the clinical manifestations [Marrie, 1992]. Skin necrosis and gangrene can be a late complication (Fig. 70-7). Rocky Mountain spotted fever may manifest as a skeletal muscle disease. Muscle weakness may be overwhelming; therefore, GuillainBarré syndrome, viral myositis, and collagen disease may be erroneously diagnosed. Conversely, a case of Guillain-Barré syndrome associated with Rocky Mountain spotted fever has been documented [Toerner et al., 1996]. Muscle biopsy

FIGURE 70-6. Petechial rash of Rocky Mountain spotted fever involving the ankle. (Courtesy Dr. Daniel J. Sexton.)

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The use of polymerase chain reaction testing for R. rickettsii DNA can be applied to serum, whole blood, or tissue specimens but is generally available only at specialized research labs, and the sensitivity of the assay is directly related to the severity of the illness [Sexton et al., 1994].

Management

FIGURE 70-7. Necrosis and gangrene of digits is a late complication of Rocky Mountain spotted fever. (Courtesy Dr. Daniel J. Sexton.)

reveals perivascular infiltrates of chronic inflammatory cells and focal chronic interstitial myositis [Krober, 1978]. Other organs, including kidneys, heart, lungs, spleen, and epididymis may also be affected [Green et al., 1978]. Acute temporary hearing impairment has been described, but permanent auditory disruption is uncommon [Kelsey, 1979]. Ophthalmic features in all rickettsial disorders are virtually identical [Raab et al., 1969; Smith and Burton, 1977] and may include photophobia, conjunctivitis, petechiae on the bulbar conjunctiva, exudates and retinal venous engorgement, papilledema, and ocular palsies. Laboratory abnormalities are common in severe disease and often include hyponatremia and thrombocytopenia. Spinal fluid may indicate a lymphocytic pleocytosis and the protein is elevated in about 30% to 50% of patients [Kim and Durack, 1997]. The cellular response in cerebrospinal fluid may suggest bacterial meningitis, and the dermal petechiae may mimic those in meningococcemia. Magnetic resonance imaging of the brain reveals increased signal intensity in the distribution of perivascular spaces, which resolves in relation to clinical improvement [Baganz et al., 1995]. Postmortem examination of Rocky Mountain spotted fever cases has demonstrated that rickettsial vasculitis can result in focal neurologic damage in the brain and spinal cord as well as myocarditis and vasculitis in the lungs, kidney, and spleen [Walker and Mattern, 1980]. The most widely used and best serologic test for Rocky Mountain spotted fever is the indirect fluorescent antibody assay and is available through commercial labs and most state health departments [Lochary et al., 1998; Sexton et al., 2002]. Immunofluorescent antibody for immunoglobulin M or immunoglobulin G antibodies can be used to make a presumptive diagnosis of acute infection, although these antibodies are often undetectable in the early phase of the illness. Confirmatory indirect fluorescent antibody testing requires demonstration of a fourfold or greater rise in immunoglobulin G or immunoglobulin M antibody titer between paired serum specimens, and is generally considered as a retrospective diagnosis [Thorner et al., 1998]. Direct immunofluorescence antibody or immunohistochemical staining of skin biopsies is 70% to 90% sensitive for patients with a rash. For patients without a rash, diagnosis by direct immunofluorescence antibody can be problematic.

Early therapy with doxycycline for at least 7 days is recommended. The case fatality is 2% to 10% in treated patients and may be as high as 30% in untreated patients [Dalton et al., 1995]. Serologic confirmation may be delayed for 2 to 3 weeks; therefore, therapy should be administered when the diagnosis is suspected based on clinical and epidemiologic findings. A history of tick bite is a useful epidemiologic clue in making a presumptive diagnosis. With early treatment, the prognosis for full recovery from Rocky Mountain spotted fever is excellent. Neurologic sequelae may occur when therapy is postponed [Miller and Price, 1972]; mild intellectual impairment has been described [Wright, 1972].

TYPHUS FEVER GROUP The typhus fever group consists of epidemic (louse-borne typhus), Brill-Zinsser disease, and murine (flea-borne) typhus. Louse-borne typhus fever, caused by Rickettsia prowazekii, is distributed worldwide. Epidemics of typhus fever occur by human-to-louse-to-human transmission, typically after rubbing skin that is contaminated with infective louse feces. Epidemics of typhus fever are often associated with war, movements of large numbers of people, and squalid living conditions [Zinsser, 1935]. Systemic and neurologic symptoms are similar to Rocky Mountain spotted fever. A severe headache is almost always present. More severe CNS features such as neck stiffness, seizures, delirium, and coma can also be present. Treatment (e.g., with doxycycline) is the same as that used for the spotted fever group of infections. Brill-Zinsser disease is a relapsing form of louse-borne typhus that may occur years to decades after the primary attack [Feigin et al., 1992]. Presumably the rickettsiae remain dormant in the reticuloendothelial system until a subsequent reactivation occurs. Symptoms are similar to the primary attack although generally milder, and doxycycline is the recommended therapy. Murine, or flea-borne typhus, caused by R. typhi, is one of the most prevalent rickettsial diseases in humans throughout the world [Azad, 1990]. Before World War II, murine typhus was widespread in the United States and approximately 42,000 cases were reported between 1931 and 1946 [Azad, 1990; Pratt, 1958]. During the Vietnam War, murine typhus was one of the most common causes of acute febrile illness in American military personnel [Berman and Kundin, 1973; Miller, 1946]. Currently, endemic foci often exist around port cities and adjacent coastal areas [Azad, 1990]. R. typhi is transmitted from rat to rat by the rat flea. In addition to rats, many animals such as other rodents, skunks, opossums, shrews, and cats can serve as hosts for R. typhi and arthropod vectors. Human infection occurs after exposure of abraded or flea-bitten skin to infective flea feces [Feigin et al., 1992]. Unlike many other arthropod-borne infections, murine typhus can be acquired in households because the

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transmission cycle includes commensal rats and fleas [Azad, 1990]. Symptoms of murine typhus are similar to but generally milder than those occurring in Rocky Mountain spotted fever. R. typhi infections are likely underdiagnosed because the clinical and laboratory features are similar to viral infections. The illness is often characterized by fever (often prolonged), headache, myalgia, and sometimes a maculopapular or petechial rash [Gelston and Jones, 1977]. Lymphadenopathy was reported as a common manifestation in a study in children [Bitsori et al., 2002]. When present, the rash often occurs on the trunk. The infection may resemble Kawasaki’s disease [Bitsori et al., 2002]. There is considerable variability in the frequency of reports of neurologic manifestations of murine typhus ranging from 2% to 20% of cases [Allen and Saltz, 1945; Bitsori, 2002]. Meningitis and encephalitis are occasionally reported [Bitsori, 2002; Galanakis et al., 2002; Gelston, 1977]. Less commonly, focal symptoms such as papilledema, focal seizure, and hemiparesis have also been described [Masalha et al., 1998]. Diagnostic evaluation and treatment are similar to other diseases of the typhus group.

Scrub Typhus Scrub typhus, caused by Orientia tsutsugamushi, is a systemic illness that causes a generalized vasculitis [Pai, 1997]. O. tsutsugamushi was formerly a member of the spotted fever group of Rickettsia spp. but was placed in its own genus based on molecular phylogenetic studies [Tamura et al., 1995]. Trombiculid (chigger) mites serve as reservoirs and vectors of this disease, and human infection occurs after a chigger bite in endemic areas primarily in the southwest Pacific and Southeast Asia [Feigin et al., 1992]. An eschar, a characteristic feature of the disease, is seen in 60% to 80% of cases [Jelinek and Loscher, 2001] [Fig. 70-8]. Fever, headache, and rash are also common clinical manifestations. Complications include renal failure, pneumonitis, acute respiratory distress syndrome, and myocarditis. CNS complications include meningitis or meningoencephalitis [Fang et al., 1997; Pai, 1997]. Brachial plexus neuropathy has been described in one case report [Ting et al., 1992]. Approximately 50% of patients will have a mild cerebrospinal fluid monocytic pleocytosis or an increase in protein

concentration [Pai, 1997]. Doxycycline is considered the most effective treatment.

Q Fever Q fever, caused by Coxiella burnetii, is a worldwide zoonosis. Infection in humans occurs from inhalation of the organism in areas where infected livestock are kept and, on occasion, from ingestion of contaminated dairy products. Occasional outbreaks in research laboratories that use sheep or cattle have also been reported [Feigin et al., 1992]. Prominent symptoms include fever, headache, and pneumonia. A rash rarely, if ever, occurs. Cases of encephalitis have been reported to occur with Q fever and may occur late in the course [Maurin and Raoult, 1999].

Other Rickettsiae Several new rickettsiae have been described since the early 1990s: Rickettsia japonica in Japan, Rickettsia honei on Flinders Island, Rickettsia africae in Africa and the West Indies, Rickettsia slovaca in Europe, Rickettsia aeschlimannii in Africa and Europe, Rickettsia heilongjanghensis in Asia, and Rickettsia parkeri in the United States [Raoult, 2004]. The extent of neurologic involvement with these emerging infections is unknown.

Ehrlichiosis Ehrlichia are obligate intracellular bacteria and belong to the family Rickettsiaceae. Emerging infections, akin to those caused by other rickettsial agents, have been increasingly reported in recent years [Walker et al., 1996]. The term ehrlichiosis was initially used to described veterinary infections with rickettsia-like bacteria that infected leukocytes. Human infection with Ehrlichia in the United States was first identified in a 51-year-old male with a history of a tick bite, fever, leukopenia, thrombocytopenia, and elevated liver enzymes [Maeda et al., 1987]. The patient was initially diagnosed with Rocky Mountain spotted fever. Cytoplasmic inclusions were observed in peripheral lymphocytes, and the patient was subsequently diagnosed with an Ehrlichia species. Since then, two additional Ehrlichia infections have been described in humans caused by Ehrlichia ewingii and Anaplasma (formerly Ehrlichia) phagocytophilum. All Ehrlichia are transmitted by ticks, and the interval from tick exposure to onset of illness is between 2 and 21 days [Harkess, 1991]. Ehrlichia chaffeensis infects mononuclear cells and causes human monocytic ehrlichiosis. The incidence of human monocytic ehrlichiosis is equal to or higher than Rocky Mountain spotted fever [Fishbein et al., 1990]. Anaplasma phagocytophilum causes human anaplasmosis (formerly human granulocytic ehrlichiosis) and infects neutrophils. E. ewingii also infects neutrophils and has serologic cross-reactivity with E. chaffeensis. Rashes are generally less common with the ehrlichioses compared with rickettsial infections [CDC, 1988].

Human Monocytic Ehrlichiosis FIGURE 70-8. Eschar seen in scrub typhus. (Courtesy Dr. Daniel J. Sexton.)

Human monocyctic ehrlichiosis generally causes an acute febrile illness occurring after E. chaffeensis is inoculated by the Lone Star tick (Amblyomma americanum). Fever, head-

Glaser, Lewis, and Schuster / Fungal, Rickettsial, and Parasitic Diseases of the Nervous System

ache, and malaise are commonly described. A skin rash, appearing macular or maculopapular, occurs more commonly in children than adults and is often on the trunk or extremities [Everett et al., 1994; Fishbein et al.,1994; Ratnasamy, 1996]. Nausea, vomiting, abdominal pain, and cough are other frequent manifestations. Approximately 20% of infections result in meningoencephalitis. Long-term neurologic sequelae have been reported in a limited number of children, including a 7 year old with reading problems and impairment of fine motor skills and an 11-year-old with bilateral footdrop and speech impairment [Schutze, 1997]. Laboratory testing often reveals leukopenia, thrombocytopenia, anemia, and increases in hepatic transaminases. Peripheral blood examination can reveal intracytoplasmic inclusions (termed morulae) in white blood cells in a small percentage of cases (Fig. 70-9). Cerebrospinal fluid abnormalities often include lymphocytic pleocytosis (73%) and high protein (76%) [Ratnassamy, 1996]. Serologic testing can sometimes be helpful but is often negative during the early stages of the illness. Evaluation of paired serum samples is generally the optimal method of establishing the diagnosis but provides only retrospective confirmation. Molecular testing (e.g., polymerase chain reaction) is available in some settings and can be helpful during the acute phases of infection (particularly before antibiotic use) [Dumler, 2003]; however, the clinical sensitivity of polymerase chain reaction for human monocytic ehrlichiosis is unknown.

Human Anaplasmosis Human anaplasmosis was identified in humans in the 1990s. The organism in humans was initially believed to be the same organism that causes disease in horses (Ehrlichia equi) and ruminants (Ehrlichia phagocytophila) [Chen et al., 1994; Madigan et al., 1995]. Molecular analysis of these organisms resulted in a taxonomic reassignment of human anaplasmosis so that the organism is now considered to belong in the family Anaplasmataceae rather than family Rickettsiaeceae. Current terminology often refers to this disease as human anaplasmosis. Anaplasma phagocytophilum, the organism causing human anaplasmosis, is transmitted by blacklegged ticks (Ixodes scapularis and Ixodes pacificus).

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FIGURE 70-9. Intracytoplasmic inclusion (morulae) of Ehrlichia morula seen in the white blood cells from a bone marrow aspirate. Bar measures 10 μm. (Courtesy Dr. Christopher Paddock.)

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The clinical features of human anaplasmosis are similar to human monocytic ehrlichiosis, including fever, headache, and myalgias. Gastrointestinal symptoms are seen in about 25% and a rash in 10%. Unlike human monocytic ehrlichiosis, there are few data to support invasion of the CNS by A. phagocytophilum; however, neck stiffness [Dumler, 2003] and brachial plexopathy and demyelinating polyneuropathy have been described [Horowitz et al., 1996]. Severe clinical manifestations include septic shock manifestations, toxic shock syndrome, acute respiratory distress syndrome, myocarditis, and rhabdomyolysis. Laboratory testing often reveals leukopenia, thrombocytopenia, and mild increases in serum transaminases. Diagnostic testing during the active phase includes checking for morulae in a blood smear, polymerase chain reaction on blood, culture, and possibly serology. Serologic testing with paired sera is helpful for confirmation but not always helpful during the acute stage of infection. When found, morulae are helpful in making a rapid diagnosis, but this is considered to be an insensitive method.

Ehrlichia ewingii Ehrlichiosis In the late 1990s, another Ehrlichia species emerged in the United States: E. ewingii [Buller et al., 1999]. Similar to E. chaffeensis, E. ewingii is transmitted by the Lone Star tick. Of the few cases reported to date, clinical symptoms are similar to human monocytic ehrlichiosis and human anaplasmosis but are generally milder. Laboratory abnormalities such as leukopenia, thrombocytopenia, and elevated transaminases are seen in cases as in other Ehrlichia infections. Morulae can be identified in neutrophils, yet there can be serologic cross-reactivity to E. chaffeensis.

PARASITIC DISEASES Human parasitic infestation occurs worldwide [Bia and Barry, 1986; Markell et al., 1992; Warren and Mahmoud, 1984]. Parasites infect humans in tropical, temperate, and cold climates. Parasitic infections impair the CNS [Brown and Voge, 1982] by a variety of mechanisms, including the following: (1) direct invasion from the circulation or lymphatic system may cause local changes, such as inflammation and edema, (2) granuloma development may result in disturbances associated with mass lesions, (3) remote effects associated with nutrient deprivation of the CNS may cause diffuse or focal CNS symptomatology, and (4) immunologic or hypersensitivity effects may develop. Changes in society have spread what were once exotic diseases largely restricted to developing countries into the developed world. Ease and frequency of travel require that all clinicians have general familiarity of these infections when considering differential diagnoses. Population shifts, whether due to immigration or social unrest, have brought unfamiliar parasitic infections into urban and other areas. The following are some examples of the need for increased awareness of parasitic diseases: Peace Corps volunteers returning to the United States may bring with them parasitic worm infestations; malaria has developed in airport workers and people living in the vicinity of airports perhaps because of inadvertent importation of mosquitoes in airplane cabins;

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sleeping sickness should be considered in the differential of patients presenting with a neuropathology or encephalopathy and a recent travel history to west and central Africa. Many different classifications of parasitic disease have been proposed [Garcia, 1992; Markell et al., 1992], but none is completely satisfactory because of the complexity, widespread distribution, and incredible variety of infectious agents that are known. Modified or even new classification systems for parasites are being proposed based on data from DNA sequencing studies, which has become an important tool in the understanding of phylogeny and taxonomy of these organisms. Table 70-3 lists the most common parasitic diseases that are known to cause serious neurologic disease and are reviewed in this section. Another large group of parasites includes the helminths. The helminths (worms) are subdivided into three categories: nematodes, cestodes, and trematodes. Nematodes are cylindrical and nonsegmented worms. Trichinella, Angiostrongylus, and Toxocara are genera in this class that infect the CNS. Cestodes that infect humans belong to the subclass Eucestoda, the true tapeworms. These endoparasites have no epidermis or digestive tract and have elongated segmented bodies. Adults have a multihook organ of attachment at the anterior end called the scolex. Genera of cestodes associated with CNS infection in the larval stage include Dibothriocephalus (Diphyllobothrium), Taenia, Multiceps, and Echinococcus. Trematodes (flukes) are nonsegmented worms that possess a digestive tract. Trematodes infecting the nervous system include the genera Schistosoma and Paragonimus. Isolation and growth are important for accurate identification of etiologic agents, preparation of antibodies for serology, testing for efficacy of antimicrobial agents, and as a source of DNA for diagnostic and molecular biologic procedures [Visvesvara and Garcia, 2002]. Cultivation of parasitic protozoa is often demanding and may require complex media that are not readily available to most diagnostic laboratories or in the field. For this reason, in vitro cultivation of protozoal parasites is relegated to research or reference laboratories. In the United States, in vitro growth of these parasites is done primarily by the Centers for Disease Control and Prevention (CDC), specific (usually academic) research laboratories, or at state public health laboratories [Lowichik and Siegel, 1995]. In such cases, consulting with and sending specimens to these laboratories is usually helpful for early diagnosis and treatment. For the parasitic worms, in vitro cultivation has yet to be realized. Microsporidial infections in humans were once a rarity but are now one of the major infections, and often a cause of death, of AIDS patients. Similarly, systemic infections with Acanthamoeba occur almost exclusively in AIDS and organ transplant patients. Reactivated toxoplasmosis has also become an important disease of immunocompromised hosts. Baylisascariasis, caused by a nematode worm infecting raccoons, has been recognized to cause human illness, especially in children. The sequencing of genomes of parasites is another new contribution to developing new and effective controls. The sequencing of the Plasmodium falciparum genome opens the door to development of antimicrobials targeted to specific gene products. Progress has been made in the sequencing of the genome of the African trypanosome, the etiologic agent of sleeping sickness, leading to a better

understanding of the mechanisms of immune evasion of the parasite. The polymerase chain reaction was not considered a practical diagnostic tool at the time the previous edition appeared, but is now used in identification of many protozoal and other parasitic organisms. Its use, however, is restricted to reference and research laboratories. A drawback of polymerase chain reaction is that it cannot differentiate between DNA from viable and nonviable disease agents, perhaps leading to inappropriate or unnecessary additional therapy in a setting where antimicrobial therapy has been used successfully to combat infection.

PROTOZOAL INFECTIONS OF THE CENTRAL NERVOUS SYSTEM The major protozoal diseases that affect the nervous system include the amebic infections, toxoplasmosis, malaria, babesiosis, and trypanosomiasis. These diseases differ from one another in many respects, including the nature of the etiologic agents, mode of transmission of the parasites, mechanisms of pathogenesis, and responses to antimicrobials.

AMEBIC INFECTIONS OF THE CENTRAL NERVOUS SYSTEM Disease-causing amebas are a mixed group of organisms. Entamoeba histolytica is an obligate parasite, generally associated with enteric disease. The free-living amebas (Naegleria fowleri, Acanthamoeba spp., Balamuthia mandrillaris) are facultative parasites, with some acting as opportunistic pathogens. E. histolytica is an anaerobic protozoon found in nature only in the dormant cystic stage. The typical mode of infection is the fecal-oral route by ingestion of cysts, either from water or uncooked foods contaminated with fecal matter. Person-toperson spread of cysts, as by infected food handlers, is the main mode of transmission. The disease is more likely to occur in developing areas of the world where drinking water is not carefully monitored for sewage contamination. The pathogenic free-living amebas (Naegleria, Acanthamoeba, Balamuthia) are globally dispersed in soil and water, with many opportunities for contact between them and humans. Human-to-human spread does not occur. Acanthamoeba spp. cause infections chiefly in immunocompromised hosts, N. fowleri infects immunocompetent hosts, and B. mandrillaris infections have occurred in both groups of individuals. Because of the ubiquitous dispersal of free-living amebas, many are exposed to them as indicated by studies of antibody titers in healthy individuals, but clinical disease is a rarity. When infection results in disease, the difficulty in diagnosis of the infections and the lack of optimal antimicrobial therapy are responsible for a high mortality.

Cerebral Amebiasis: Entamoeba histolytica Epidemiology, Microbiology, and Pathology Amebiasis results from gastrointestinal infection by the protozoon E. histolytica. Amebic dysentery was described in

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TABLE 70–3 Parasite Infections CLASSIFICATION ORGANISM

DISEASES

GEOGRAPHIC DISTRIBUTION

Amebas

Amebiasis

Worldwide

Entamoeba histolytica

Naegleria fowleri

Primary amoebic meningoencephalitis Acanthamoeba Granulomatous spp. amebic encephalitis

Balamuthia Granulomatous mandrillaris amebic encephalitis Flagellates

MODE OF INFECTION

DIAGNOSTIC TECHNIQUE

ANTIMICROBIAL THERAPY

MRI/CT

Metronidazole, paromomycin

Diarrhea

Hemorrhagic necrosis of frontal lobes

Worldwide

ImmunoInhalation of compromised windblown status, soil, immunocontamination competent of wound with children soil

Hemorrhagic necrosis of cerebrum, cerebellum, granuloma formation

F, HA, stiff neck, fulminant disease F, mass effect

Worldwide

Same as Same as AcanthAcanthamoeba spp. amoeba spp. Exposure to Tsetse fly bites vector

Same as Acanthamoeba spp.

Worldwide

Trypanosoma cruzi

Chagas’ disease

Latin America, Exposure to southwestern vector US

Reduviid bug bites

Malaria

Southern Asia, Exposure to Southeast vector Asia, Africa, South America

Mosquito bites

Babesia spp.

Babesiosis

Toxoplasma gondii

Toxoplasmosis

Europe, north Exposure to Tick bites and south vector, Africa, splenectomy Middle East, US, Asia Worldwide Exposure to Ingestion of source of oocysts in oocysts, undercooked particularly meat; oocysts during present in cat pregnancy feces Worldwide Immunocompromised status

Trichinella Trichinosis spiralis (and other Trichinella sp.)

PREDOMINANT SYMPTOMS

Cyst formation in cerebrum

Sleeping sickness Africa

Microsporidia EncephalitoMicrosporidiosis zoon cuniculi

NEUROPATHOLOGY

Living in Ingestion of cysts regions with water or with poor food sewage treatment Swimming in Amebas entering fresh water nostrils

Trypanosoma brucei

Apicomplexa Plasmodium falciparum

Nematode

RISK FACTORS

Detection of Amphotericin B amebas in CSF, IIF of tissue Biopsy, MRI/CT, Combination IIF staining of drug therapy: serum or tissue fluconazole, 5-fluocytosine, pentamidine, azithromycin Same as Acanth- Same as Acanth- Same as Acanthamoeba spp. amoeba spp. amoeba spp.

Cerebral edema Somnolence (early), cerebral and cerebellar atrophy (late) Cerebral edema, Often acute in destruction of children: autonomic muscle/bone ganglia, nodules pain, neural in brain and disorders spinal cord Cerebral malaria, Fulminant in hemorrhagic children; necrosis mental deterioration, delirium, coma F, sweating, myalgia, depression

Blood smear

Suramin, meltefosin, melarsoprol, eflornithine

Blood/CSF smears serology; ELISA cultivation

Benznidazole, nifurtimox

Blood smear, Chloroquine, serology; IFA quinidine gluconate artemesinin

Blood smear

Necrotic cerebral Focal neurologic Serology; lesions, cerebral deficits, ELISA/IFA calcification seizures PCR

Quinine, clindamycin, atovaquone and azithromycin Sulfadiazine, pyrimethamine, folinic acid

CSF smears, Albendazole sputum and urinary samples Serology; Mebendazole, ELISA, IFA thiabendazole, muscle biopsy, corticosteroids, eosinophilia albendazole

Worldwide, Dietary habits Ingestion of CNS inflammatory Gastroenteritis especially uncooked meat infiltration myositis, in Balkans, (especially pork, facial/ Baltic bear, horse) periorbital Republics, edema, Russia, myocarditis, encephalitis China and Argentina Angiostrongylus Angiostrongyliasis SE Asia, Dietary habits Ingestion of larvae Leptomeningitis Eosinophilic CSF eosinophilia Supportive measures; cantonensis South Pacific, of ingestion in raw prawns, Small worm tracks meningitis, serology steroids, Taiwan of undersnails, or shrimp paresthesias (ELISA) analgesics, lumbar Caribbean, cooked punctures Africa, mollusks, or Australia unwashed US: Hawaii, vegetables Louisiana Gnathostoma Gnathostomiasis Southeast Asia, Dietary habits Ingestion of Myeloencephalitis Cutaneous Identification of Albendazole, spp. particularly undercooked larvans and worm in ivermectin Thailand and fish (e.g. visceral pain tissues, Japan, Latin cerviche), frogs, CNS, HA; eosinophilia America snakes, chickens, radicular pain ducks with later paralysis and bladder incontinence Baylisascaris Baylisascariasis North America, Young children Ingestion of Worm tracts with Eosinophilic Serology (IFA), No known effective procyonis Europe, or developraccoon inflammatory meningoeosinophilia treatment but parts of Asia mentally roundworm eggs cells encephalitis and blood albendazole and disabled steroids have been people, pica used in some cases

Continued

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TABLE 70–3, cont’d Parasite Infections GEOGRAPHIC DISTRIBUTION

CLASSIFICATION ORGANISM

DISEASES

Cestodes

Diphyllobothriasis Worldwide, Dietary habits especially in temperate and subarctic zones in Northern Hemisphere Cysticercosis Worldwide, Areas with especially in poor Latin sanitation America, Southeast Asia, Africa, eastern Europe

Diphyllobothrium latum

Taenia solium

Taenia multiceps

Coenurosis

Americas, Europe, Africa

Echinococcus spp.

Echinococcosis

Worldwide

RISK FACTORS

MODE OF INFECTION

NEUROPATHOLOGY

Eating undercooked Optic atrophy, freshwater fish spinal cord contaminated degeneration with the tapeworm

Adult tapeworms: Ingestion of pork tapeworm NC: ingestion of ova shed by tapeworm carrier

Rarely reported: unknown

Ingestion of food/water contaminated with dog feces Sheep or cattle Ingestion of herding food/water contaminated with feces from infected dogs

PREDOMINANT SYMPTOMS

ANTIMICROBIAL THERAPY

Usually minimal Blood smear: Adult worms: unless megaloblastic niclosamide, prolonged anemia praziquantel infection

Cysts in varying Signs of ICP stages of inflammation, cerebral edema, encephalitis

Similar to cysticercosis

DIAGNOSTIC TECHNIQUE

Serology; CF, HI, ELISA, eosinophilia CT/MRI

Similar to CT/MRI cysticercosis; seizures, meningitis Cyst formation RUQ pain/ CT/MRI common in jaundice (if serology liver, but also liver affected) may be found in chest pain, lungs and CNS, cough, fever, typically in hemoptysis (if white matter lungs affected) extending to neurologic: meninges and signs of ICP ventricles

Adult tapeworms: praziquantel or niclosamide NC: individualized for each case depending on presentation, number and location of cysts: steroids, antiseizure medications, and anthelmintic drugs Because rarely seen, limited information, may be similar to above Albendazole, mebendazole

CF, complement fixation; CNS, central nervous system; CSF, cerebrospinal fiuid; CT, computed tomography; ELISA, enzyme-linked immunosorbent assay; F, fever; HA, headache; HI, hemagglutination; ICP, intracranial pressure; IFA, indirect fluorescent antibody; MRI, magnetic resonance imaging; NC, neurocysticercosis; PCR, polymerase chain reaction; RUQ, right upper quadrant.

ancient times by Galen and Hippocrates, and even earlier descriptions of dysentery-like illness were found in Assyrian and Babylonian writings [Cox, 2002]. The role of E. histolytica in causing pathogenic intestinal and hepatic lesions was described definitively by Kartulis [1886] and Councilman and Lafleur [1891]. Its distribution is global, although it is more common in regions that have hot, humid climates. Despite its partiality for tropical climates, the organism was first isolated from a stool sample by Lösch in St. Petersburg, Russia, in 1873, and an outbreak of amebiasis occurred at a Chicago hotel at the time of the 1933 World’s Fair, resulting in about 100 deaths. Gross postmortem examination of the brain reveals abscesses, petechiae, and suppurative meningitis. Necrotic areas are distributed throughout the brain but are concentrated in the basal ganglia and frontal lobes. Cerebral edema and transtentorial herniation are often seen. Microscopic study demonstrates a zone of disruption; necrotic areas are more common than areas of inflammation. The inflammatory response is attended by mononuclear cells [Lombardo et al., 1964].

Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis From the intestine, the liver, lungs, and brain are secondarily affected. Cerebral amebiasis is the most unusual condition and principally occurs in patients with hepatic or pulmonary infections. Most patients with cerebral amebiasis have

symptoms that accompany the effects of systemic disease, such as fever, weight loss, and anorexia. Cerebral amebiasis is rare, and many of the patients who have this disorder do not manifest neurologic symptoms. In one series, only 5 of 17 patients had neurologic manifestations consisting of increased intracranial pressure, hemiplegia, meningeal irritation, nuchal rigidity, confusion, and headache [Lombardo et al., 1964]. The presence of a focal CNS lesion in a febrile patient with hepatic or intestinal disease should suggest amebiasis, particularly if there is a history of travel to an endemic area and if more common causes, such as bacterial brain abscesses or tumors, have been ruled out [Durack, 1997]. The diagnosis of cerebral amebiasis can usually be confirmed by serologic evaluation using an indirect hemagglutination assay or indirect immunofluorescent staining. Commercial kits are available for detection of ameba antigen, and the polymerase chain reaction has been used for detecting Entamoeba DNA [Leber and Novak, 1999; Tanyuksel and Petri, 2003]. Cerebrospinal fluid evaluation is usually not helpful; cultures are usually sterile, and cytology or changes in the protein or glucose concentrations are nonspecific. The polymerase chain reaction applied to fluid drained from a brain abscess in an adult detected E. histolytica DNA, though intact amebas were not seen [Ohnishi et al., 1994]. In a pediatric case, intact amebas were recovered in fluid aspirated from the thorax but were not detected in the child’s stool [Hughes et al., 1975]. Stool cultures are usually negative when nervous system involve-

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ment appears. Neuroimaging may reveal abscess formation with perilesional edema [Tikly et al., 1988]. General testing for amebic colitis and liver abscess is reviewed in Tanyuksel and Petri [2003].

Management Cerebral amebiasis is rarely treated successfully. Metronidazole is currently the preferred drug (15 mg/kg initially followed by 30 mg/kg/day divided into four doses) [Strickland, 1992], although trinidazole may be more effective than metronidazole [Medical Letter, 2004]. Emetine and chloroquine are alternative medications. A combination of metronidazole and chloroquine was used successfully in treating a pediatric case of cerebral amebiasis with three abscesses [Hughes et al., 1975]. Amebiasis in an adult was treated with metronidazole and dehydroemetine after drainage of a brain abscess [Ohnishi et al., 1994]; the patient recovered with minor neurologic impairment. An adult male in a stuporous state with signs of encephalitis and hepatic abscesses had a low titer for E. histolytica by indirect hemagglutination, but countercurrent immunoelectrophoresis was positive [Schmutzhard et al., 1986]. CT scans of the brain exhibited approximately 40 small ringlike lesions, mostly in the white matter of both hemispheres. Treatment with metronidazole, chloroquine, and tetracycline effected a partial recovery; further regression of the lesions and recovery occurred after a course of dehydroemetine treatment. Paromomycin has been used for asymptomatic cases [Medical Letter, 2004].

Primary Amebic Meningoencephalitis: Naegleria fowleri Epidemiology, Microbiology, and Pathology Primary amebic meningoencephalitis is a fulminant disease occurring in children and young adults. The disease was first reported from Australia and was initially attributed to Acanthamoeba [Fowler and Carter, 1965], which had been previously found to cause death of mice inoculated intranasally with amebas [Culbertson et al., 1958]. The disease was soon reported from Florida and was then characterized as primary amebic meningoencephalitis [Butt, 1966]. N. fowleri is a free-living, facultative parasite, with a life cycle that includes an ameboid trophic (feeding) stage, a transitory flagellate stage, and a double-walled cyst able to withstand desiccation. The amebas measure about 15 to 30 μm, and cysts from 7 to 15 μm in diameter. The ameba is found in water, soil, sewage, or other decaying organic material where there is a bacterial food source [Marshall et al., 1997], and grows optimally at elevated temperatures (37º C to 45º C). Of an estimated 200 cases since the first descriptions of primary amebic meningoencephalitis, more than 90% of the patients have died. The disease has been reported from Australia, Belgium, Czech Republic, Great Britain, Mexico, India, New Zealand, Nigeria, and the United States. Extended descriptions of the organism and the disease can be found in several review articles [Barnett et al., 1996; Duma, 1984; John, 1993]. In the United States, most of the cases have developed in the southern tier of the country, where warm water con-

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ditions are more likely to be encountered. In Florida, where a number of cases have been reported after swimming in lakes, the probability of infection was estimated to be 1 case per 2.6 million exposures [Wellings, 1977]. No cases have resulted from drinking water containing amebas. Typically, infection with N. fowleri occurs while swimming or washing in warm, fresh water containing the amebas, and early manifestations of the disease ensue. Bodies of water associated with amebic infections have included ponds, man-made lakes, hot springs, wading pools, irrigation canals, thermally polluted streams, and inadequately chlorinated swimming pools. Those affected are children or young adults without underlying disease. Infection has been associated with prolonged immersion in water, diving, underwater swimming, or other activities that allow water to enter the nostrils. Acute meningoencephalitis ensues usually within 2 to 3 days. Amebas enter the nasal passages and gain access to the nervous system by penetrating the olfactory mucosa, entering the submucosal nervous plexus, migrating along the olfactory nerves, and traversing the cribriform plate. Hemorrhagic destruction of gray matter and devastation of the olfactory bulbs follow sanguinopurulent meningitis and pronounced brain edema [Martinez et al., 1973]. Spinal cord involvement is signaled by similar gray matter disruption. Perivascular infiltrates include leukocytes and amebas (Fig. 70-10). Numerous eosinophils may be present. Simultaneous bronchopneumonia and pulmonary edema, myocarditis, and splenitis may occur.

Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis Among the most common symptoms of primary amebic meningoencephalitis are severe headache, stiff neck, nausea, vomiting, fever (39° C to 40° C), behavioral changes, seizures, diplopia, and coma [Duma, 1984; Martinez, 1985]. One patient complained of a violent headache and foul odors before becoming unconscious [Duma, 1984]. Distortion of taste has also been reported [Martinez, 1993]. Cerebrospinal fluid is typically cloudy with a slightly decreased glucose concentration, increased protein content (75 to 970 mg/dL), and innumerable white blood cells

FIGURE 70-10. Section through cerebral cortex of an individual with primary amebic meningoencephalitis, with large numbers of Naegleria fowleri amebas in the perivascular space. (Hematoxylin-eosin)

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(300 to 24,600/mm3) and erythrocytes [Martinez, 1985]. Polymorphonuclear cells make up 52% to 99%, lymphocytes 1% to 48%, and monocytes 1% to 2% of the white blood cells in the cerebrospinal fluid. High opening pressures may be observed. Differential diagnosis for primary amebic meningoencephalitis is bacterial meningitis, but the cerebrospinal fluid is sterile in primary amebic meningoencephalitis [Martinez, 1993]. A Gram stain of the cerebrospinal fluid is not particularly helpful in diagnosis because the amebas may lyse during preparation of the slide. In freshly obtained spinal fluid, motile Naegleria amebas can usually be seen in wet-mount preparations [Lowichik and Ruff, 1995a], which are best viewed with a phase-contrast microscope. The cerebrospinal fluid should not be refrigerated or frozen before examination. Low-speed centrifugation of the sample may help concentrate the amebas and make them easier to find. In cerebrospinal fluid from three primary amebic meningoencephalitis patients, amebas numbered from 26 to 118/mm3, as compared with 330 to more than 9000 leukocytes/mm3 [Duma et al., 1971]. The amebas can be recognized by their relatively swift movement with an anterior, eruptive pseudopod (Fig. 70-11), contrasting with the sluggish motility of the leukocytes with indistinct pseudopodal activity. As an aid in diagnosis, amebas can be readily cultured on non-nutrient agar plates spread with a suspension of Escherichia coli as a food source [Visvesvara, 1999]. Immunofluorescent staining for Naegleria antibodies in acute phase serum is of little diagnostic value because of the fulminant nature of the disease and a delayed humoral response. Neuroimaging is not particularly helpful in diagnosis, with results being nonspecific. CT and MRI scans of a 9-year-old child hospitalized with what was diagnosed upon postmortem examination as primary amebic meningoencephalitis showed no abnormalities at time of admission [Kidney and Kim, 1998]. Three days later, one day before

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FIGURE 70-11. Naegleria ameba from culture in wet mount. An ectoplasmic pseudopod is present at the anterior end of the ameba. When seen in cerebrospinal fluid samples, the clear pseudopod and rapid movement (~1μm/second) distinguishes Naegleria amebas from sluggishly motile leukocytes that may also be present in the cerebrospinal fluid. The nucleus is indicated by an arrow; some rod-shaped bacteria (Escherichia coli) can also be seen. Bar measures 10 μm. (Interferencecontrast)

the child died, a CT scan indicated developing hydrocephalus and brain edema but no focal lesions.

Management The high mortality from primary amebic meningoencephalitis is largely a consequence of delays in diagnosis and initiation of antimicrobial therapy. Early diagnosis and intensive care may improve the small chance of recovery [Seidel, 1985b]. Differences in virulence of primary amebic meningoencephalitis ameba isolates, when tested by mouse inoculations, indicate that this may be a factor affecting survival. Naegleria amebas are sensitive to amphotericin B, the drug of choice in treating primary amebic meningoencephalitis. In a well-documented primary amebic meningoencephalitis case, the patient, a 9-year-old female, had been swimming in a California hot spring before developing symptoms of meningoencephalitis. She was given intravenous and intrathecal amphotericin B and miconazole, oral rifampin, and sulfisoxazole, and recovered with minimal neurologic sequelae [Seidel et al., 1982]. Other successful treatments have been reported [Apley et al, 1970; Brown, 1991; Jain et al, 2002; Wang et al, 1993]. The macrolide azithromycin has demonstrated amebacidal activity in vitro and in the mouse model and may have potential for treating primary amebic meningoencephalitis [Goswick and Brenner, 2003]. Although azithromycin penetrates the brain, its low concentration in cerebrospinal fluid may render it less effective in primary amebic meningoencephalitis [Jaruratanasirikul et al., 1996]. Despite a small number of successful treatments, most cases are fatal [Seidel, 1985a].

Granulomatous Amebic Encephalitis: Acanthamoeba spp. Epidemiology, Microbiology, and Pathology It was largely through the observations of Culbertson that free-living amebas were recognized as potentially pathogenic organisms. He detected acanthamoebas in monkey kidney cell cultures used for growing poliovirus, and demonstrated their pathogenicity in mice [Culbertson et al., 1958]. It was N. fowleri, however, that was the first free-living ameba recognized in human infections. Two different, although closely related amebas, cause granulomatous encephalitis: Acanthamoeba spp. and Balamuthia mandrillaris. Acanthamoeba granulomatous encephalitis is an opportunistic, chronic disease that may have a prodromal period of weeks to months, with most patients being immunocompromised [Martinez, 1980]. A sharp increase in the number of cases followed the appearance of HIV/AIDS, but there have been non-AIDS cases reported in individuals on immunosuppressive medication after organ transplants. Among predisposing factors to acanthamebiasis, ordered in relative frequency, are antibiotic or steroid treatments, chemotherapy, radiation therapy, alcoholism, and pregnancy [Martinez, 1980]. A small number of Acanthamoeba granulomatous encephalitis cases have been described in immunocompetent children. Acanthamoeba is perhaps the most common ameba found in soil, which is often the source of infection. It is remarkably tolerant of a range of environmental conditions and can

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be isolated from seawater and fresh water, and from Arctic soils and beach sands. Acanthamoeba is also found in the home in aquaria, flowerpot soil, humidifiers, and sink taps and drains. It has been isolated from hot tubs, hydrotherapy baths, dental irrigation equipment, and laboratory eye wash stations. The life cycle consists of alternating ameboid and cyst stages. Cysts are particularly resistant to both physical (heat, desiccation, drying) and chemical (chlorine, antimicrobials) agents, and have remained viable in the laboratory in excess of 20 years. Infection may be through breaks in the skin that are contaminated with soil, or by inhalation of airborne ameba cysts originating from soil. In surveys of healthy groups of individuals (students, military recruits), Acanthamoeba has been cultured from the nasal passages, indicating exposure and infection but not disease [Badenoch et al., 1988; Cerva et al., 1973].

Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis In addition to encephalitis, Acanthamoeba can cause nasopharyngeal, cutaneous, and disseminated infections. Nasopharyngeal and cutaneous infections can be precursors to disseminated amebiasis or encephalitis, as amebas spread from their initial portal of entry. The CNS becomes infected by hematogenous transport of amebas, either from the lungs or from cutaneous lesions. A granulomatous reaction occurs, which can be seen in histopathologic slide preparations, but this reaction may be absent in immunocompromised hosts [Martinez, 1980]. Areas of the brain affected are usually the cerebrum, cerebellum, and brainstem, where the amebas produce hemorrhagic necrotic lesions. Large numbers of amebas can be found in the perivascular areas of brain tissue. Cysts of Acanthamoeba may be seen in histopathologic sections; Naegleria amebas do not form cysts in tissue. Reports of detecting amebas in cerebrospinal fluid are rare. Because of the absence of clear pathognomonic symptoms, Acanthamoeba granulomatous encephalitis is often unrecognized and diagnoses are often made postmortem. Unrelated to its role as etiologic agent of Acanthamoeba granulomatous encephalitis, Acanthamoeba can also cause amebic keratitis as a result of corneal trauma or wearing contact lenses. Ophthalmic solutions prepared from nonsterile tap water, and lens cases that harbor bacterial biofilms can support growth of the amebas. Keratitis has not been reported to develop into encephalitis; however, a child diagnosed with uveitis and pharyngitis caused by Acanthamoeba went on to develop fatal encephalitis [Jones et al., 1975]. Because the disease is chronic, an antibody response develops over time and the infection can be diagnosed by indirect immunofluorescence staining of the patient’s serum. Surveys of human populations for Acanthamoeba antibodies have found that many healthy people have elevated antibody titers, probably resulting from exposure to the amebas through contact with soil or water [Cerva, 1989; Cursons et al., 1980]. Diagnosis of Acanthamoeba granulomatous encephalitis is difficult and the disease mimics other types of encephalitis. Children infected with Acanthamoeba have exhibited headache, stiff neck, vomiting, abnormal behavior, seizures, fever, ataxia, and tonic-clonic seizures [Karande et al., 1991; Sharma et al., 1993; Singhal et al., 2001]. Hydrocephalus

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may also develop [Karande et al., 1991]. Differential diagnoses are neurotuberculosis, tuberculoma, and neurocysticercosis. Although the amebas are generally not recovered from cerebrospinal fluid, several cases were reported in which the amebas were seen in wet-mount preparations of spinal fluid, and/or were cultured from cerebrospinal fluid [Callicot et al., 1968; Karande et al., 1991; Kidney and Kim, 1998; Sharma et al., 1993]. In wet-mount slide preparations, trophic Acanthamoeba have radiating finger-like pseudopodia over the surface and are relatively slow-moving amebas. More often, amebas are cultured from biopsied brain tissue or skin ulcers onto plates of non-nutrient agar coated with E. coli and incubated at 37º C [Visvesvara, 1999]. Cerebrospinal fluid protein is elevated (range of 31 to 500 mg/dL), as is the white blood cell count (14 to 750 cells/μL) and glucose level (17 to 240 mg/dL); among the white blood cells are lymphocytes (19% to 100%) and polymorphonuclear leukocytes (2% to 70%) [Martinez, 1980; 1985]. The cerebrospinal fluid protein in an 8-year-old female with Acanthamoeba meningitis increased from 200 mg/dL at onset to a high of 500 mg/dL and then decreased to 41 mg/dL after completion of drug therapy 5 months after the patient was first seen [Singhal et al., 2001]. Neuroimaging by MRI of an adult male diagnosed with acanthamebiasis revealed punctate focal lesions mainly in the cerebellar hemispheres and fewer lesions in the cerebral hemispheres and the corpus callosum [Kidney and Kim, 1998].

Management There are several reported cases of acanthamebiasis in pediatric HIV/AIDS patients. An 8-year-old patient developed cutaneous and sinus lesions, in which Acanthamoeba cysts and trophozoites were seen, along with a weak granulomatous response [Friedland et al., 1992]. The infection progressed after about 3 months to disseminated disease with CNS involvement (multiple lesions within the right basal ganglia by MRI) and ultimately proved fatal, despite treatment with ketoconazole, fluconazole, sulfadiazine, and trimethoprim-sulfamethoxazole. Acanthamebiasis in another pediatric case with congenital HIV/AIDS developed as osteomyelitis and subcutaneous abscesses without neural involvement [Selby et al., 1998]. Initial treatment was with oral fluconazole but was subsequently changed to intravenous pentamidine, oral flucytosine (5-fluorocytosine), and oral itraconazole, and disease progression was successfully halted. In both adult and pediatric acanthamebiasis, death is usually a consequence of multiple AIDS-related infections rather than from the amebic infection per se. Acanthamoeba infections of the CNS are almost always fatal, although some reports of successful antimicrobial treatment are known. Often, however, the same antimicrobial agents used successfully in one case are unsuccessful in other acanthamebiasis cases. Response to therapy depends, to a large extent, on infective dose of amebas, virulence of the infecting strain, the time at which diagnosis is made, the extent of dissemination of the infection, and the immune status of the patient. As yet, there is no optimal antimicrobial therapy for treatment of Acanthamoeba encephalitis. Most recoveries have been treated successfully with combinations of antimicrobials: sulfadiazine, pyrimeth-

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amine, and fluconazole in an adult HIV/AIDS patient [Martinez et al., 2000], and with ketoconazole, rifampin, and trimethoprim-sulfamethoxazole in two pediatric patients [Singhal et al., 2001]. Isolates from patients vary in their virulence, as can be demonstrated by intranasal inoculation in a mouse model of encephalitis, or assessing cytopathology caused by amebas in tissue cultures. Variation is also seen among Acanthamoeba isolates in antimicrobial sensitivity, reflecting different strains isolated from clinical specimens.

Granulomatous Amebic Encephalitis: Balamuthia mandrillaris Epidemiology, Microbiology, and Pathology Balamuthia granulomatous encephalitis was initially described in immunocompromised humans [Anzil et al., 1991; Visvesvara et al., 1990], but more recent cases have occurred in immunocompetent children [Bakardjiev et al., 2003; Duke et al., 1997; Reed et al., 1997; Rowen et al., 1995]. The life cycle comprises trophic and cystic stages; the cyst is a triple-layered structure without pores. Little is known about the ecology of the ameba, other than that it is found in soil. Like Acanthamoeba, it is likely to enter the body by inhalation of cysts in windblown soil, or through breaks in the skin contaminated by soil, followed by hematogenous spread. Balamuthiasis can develop as cutaneous, nasopharyngeal, or CNS lesions. In a review of 30 cases reported from Peru, all developed initially as cutaneous lesions, mostly on the nose or the central region of the face, and progressed to infections of the CNS [Bravo and Sanchez, 2003]. The disease may be chronic with a prodrome that can extend as long as 2 years, but it often presents in an acute form [Bakardjiev et al., 2003]. The long incubation period makes it difficult to pinpoint the source and time of infection. A 3year-old female may have become infected through playing with soil in a flowerpot, from which Balamuthia was subsequently isolated (Fig. 70-12) [Schuster et al., 2003]. Evidence of exposure to Balamuthia among healthy individuals

FIGURE 70-12. Indirect immunofluorescent antibody–stained section of the brain of a 3-year-old child with Balamuthia granulomatous encephalitis. The amebas are clustered in a pavement-like arrangement around a blood vessel. Other amebas have moved away from the perivascular region into the brain tissue. (Fluoresence microscope) (Courtesy Dr. G.S. Visvesvara.)

is seen in elevated serum antibody titers in studies performed in Australia and the United States [Huang et al., 1999; Schuster et al., 2001]. The relative prevalence of Balamuthia granulomatous encephalitis in Hispanics is high [Schuster et al., 2004]: In the United States, about 50% of cases occurred in Hispanic Americans (who comprise ~12% of the U.S. population), and almost half of the number of cases worldwide have been described from Latin America and Mexico [Bravo and Sanchez, 2003; Galarza et al., 2002; Martinez et al., 1994; Recavarren-Arce et al., 1999; Taratuto et al., 1991; Uribe-Uribe et al., 2001]. The reasons for the high proportion of Hispanics with balamuthiasis could be because of genetic susceptibility or environmental or sociologic factors or a combination of these factors.

Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis Symptoms of Balamuthia granulomatous encephalitis include fever, headache, vomiting, ataxia, hemiparesis, tonic-clonic seizures, cranial nerve palsies (third and sixth cranial nerves), and diplopia [Bakardjiev et al., 2003; Martinez and Visvesvara, 2001]. Areas of the brain that are typically infected are the basal ganglia, midbrain, brainstem, and cerebral hemispheres [Martinez and Visvesvara, 1997]. Otitis media has preceded the onset of Balamuthia granulomatous encephalitis in several pediatric cases [Bakardjiev et al., 2003; Kodet et al., 1998; Rowen et al., 1995]. Cerebrospinal fluid may have mild to markedly elevated protein (>1000 mg/dL), and leukocyte levels but normal or slightly decreased glucose. Hydrocephalus develops in many cases [Duke et al., 1997; Kodet et al., 1998]. Because of its vague symptomatology, diagnosis of balamuthiasis requires a high index of suspicion by the physician, and differential diagnoses are bacterial or viral encephalitis, neurotuberculosis, tuberculoma, or neurocysticercosis [Bakardjiev et al., 2003]. What was initially identified as brainstem glioma in an infant was, at postmortem examination, recognized as a Balamuthia infection [Lowichik et al., 1995]. Balamuthia granulomatous encephalitis should also be considered in patients with suspected herpes simplex virus encephalitis when testing for the virus yields negative results [Deetz et al., 2003; Reed et al., 1997]. Most diagnoses of the disease are made at postmortem examination. In histopathologic sections of brain tissue, the amebas are found in large numbers within perivascular areas. Because of the chronic nature of the disease, an antibody response to Balamuthia develops over the course of the infection and is the basis for indirect immunofluorescent staining as a diagnostic aid. Likewise, immunohistopathology is useful for visualizing amebas in brain and other tissues. Neuroimaging is helpful in making a diagnosis [Deetz et al., 2003; Healy, 2002]; the presence of single or multiple space-occupying or ring-enhancing lesions in the brain on MRI may be indicative of balamuthiasis (Fig. 70-13). In brain and other tissue sections, the ameba is difficult to distinguish from Acanthamoeba because the organisms have similar morphologies. Trophic Acanthamoeba are somewhat smaller (~20 μm) than Balamuthia (~50 μm), though multiple nucleoli are sometimes seen in Balamuthia nuclei in situ. Both amebas form cysts in tissue, but Balamuthia cysts are larger (up to 30 μm) and have a wrinkled wall

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[Gelman et al., 2003]. A mass detected by MRI in the left temporal lobe was excised and, upon histopathologic examination, was found to contain an ameba with two closely apposed nuclei characteristic of Sappinia. The patient recovered after treatment with a combination of antimicrobials similar to those used for balamuthiasis. The infection had been preceded by a sinus infection, suggesting that the portal of entry into the body was the respiratory tract, with subsequent transport to the CNS. The recognition of Sappinia as an etiologic agent of human encephalitis suggests that it and other amebas previously regarded as innocuous might also be potential pathogens. Other amebas have been implicated as etiologic agents of neural disease. The soil ameba, Hartmannella, was isolated from the cerebrospinal fluid of a patient with meningoencephalitis, but the ameba was most likely a secondary invader of an existing lesion or possibly a contaminant of clinical specimens [Centeno et al., 1996]. Because of the ubiquity of these free-living amebas, caution is advised when assigning them an etiologic role based on results from cultivation of clinical specimens.

FIGURE 70-13. Magnetic resonance image of the brain of a 2 year old with Balamuthia amebic encephalitis. Arrow points to space-occupying lesion in the right occipitoparietal region of the brain.

without pores. Immunofluorescent staining, however, can distinguish between the two amebas. Balamuthia cannot be readily cultured from biopsied tissues because the organism grows slowly and requires tissue culture cells as a feeder layer. Attempts to culture from macerated brain tissue have taken from 10 to about 30 days at 37° C. Polymerase chain reaction technology is available for identification of Balamuthia DNA in tissues and in cerebrospinal fluid but is largely limited to research laboratories (e.g., the California Department of Health Services, Viral and Rickettsial Disease Laboratory, Richmond; The Ohio State University, Department of Molecular Genetics, Columbus).

Management Of the approximately 100 recognized Balamuthia cases, successful outcomes have been reported in 3 individuals [Deetz et al., 2003; Jung et al, 2004], one of them a 5-yearold female. Successful therapy was based on antimicrobial combinations: flucytosine, pentamidine isethionate, fluconazole, sulfadiazine, and a macrolide antibiotic (azithromycin or clarithromycin). In vitro testing of antimicrobials on clinical isolates indicates varied sensitivity to some of the drugs. Pentamidine, however, is particularly effective against all isolates in vitro [Schuster and Visvesvara, 2004], but the drug is slow to cross the blood-brain barrier [Donnelly et al., 1988].

Other Central Nervous System Amebic Infections A single case of encephalitis due to Sappinia diploidea, previously described in the feces of large herbivores but never associated with disease in humans or otherwise, has been reported from an immunocompetent adult male

MICROSPORIDIAL INFECTIONS OF THE NERVOUS SYSTEM Interest in the microsporidia developed in the 19th century largely because of their role in diseases of insects. Pébrine, a disease of silkworms that threatened the industry in France, was studied by Pasteur [Cox, 2002], but the role of microsporidia as etiologic agents of human disease was only recognized in the 20th century, during the HIV/AIDS epidemic. There are about 150 genera and 1400 species, of which 8 genera and 14 species are human parasites. Host specificity for the group is low and a number of the species that infect humans also parasitize other mammals. Evidence from genome sequencing, beta-tubulin gene analysis, and similarity in the types of mitotic figures, point to fungal affinities for this group [Katinka et al., 2001; Weiss, 2003]. In humans, microsporidia are responsible for a range of infections, including diarrhea, bronchitis, sinusitis, keratitis, keratoconjunctivitis, myositis, interstitial nephritis, CNS vasculitis, and disseminated infections. They are opportunistic pathogens and the majority of these infections have been reported from HIV/AIDS patients. Cases in immunocompetent individuals are rare.

Microsporidiosis Epidemiology, Microbiology, and Pathology The microsporidia are obligate intracellular parasites that cause infections in invertebrates and vertebrates, including humans [Weber et al., 1994]. The life cycle consists of an infective spore stage, in which the spore may be as small as a bacterium (typically 1 to 2 μm by 2 to 5 μm), and an intracellular proliferative stage that ultimately develops into spores. On release from infected cells, spores may be found in urine, sputum, conjunctival fluid, feces, and cerebrospinal fluid, depending on the site of infection. Spores discharged in urine can contaminate ground water, which is a possible source of infection. Ingestion of spores is the most common

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route of infection for all species, although transplacental infection is known for nonhuman mammals, particularly carnivores [Didier and Bessinger, 1999; Weber et al., 1994]. Other routes of infection include zoonotic transmission and aerosol dispersal. Depending on species, spore germination and discharge occur in the presence of enterocytes, respiratory and nasal epithelial cells, corneal epithelial cells or stroma, and macrophages as primary sites of infection. Infection may be secondarily spread to the kidneys and the CNS by macrophages.

Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis Human microsporidial infections of the neural system occur principally in HIV/AIDS adults. Pediatric cases are rare. The first recognized case of human microsporidiosis was in a 9-year-old Japanese male with severe headache, vomiting, and convulsions, and was suspected of having Japanese encephalitis or epilepsy (Matsubayashi et al., 1959). Toxoplasma-like bodies were seen in cerebrospinal fluid following staining and were also observed in the urine. The infection was transferable to mice by intraperitoneal injection of the patient’s cerebrospinal fluid, urine, or blood. Based on morphologic distinctions from Toxoplasma, the infective agent was tentatively identified as Encephalitozoon sp. The child, who had been treated for toxoplasmosis with penicillin and sulfisoxazole, recovered. The child lived on a farm and had contact with a variety of farm animals, and an animal reservoir is likely to have been the source of the infection. In another case of apparent zoonotic transmission, an adult male HIV/AIDS patient infected with Encephalitozoon cuniculi, a species found in rabbits, had handled rabbits while living on a farm [Weber et al., 1997]. Diagnosis of infections is by microscopic examination of tissues or body fluids [Weber et al., 1999]. The Gram and Giemsa stains are good for detection of spores, as is hematoxylin-eosin staining. Spores are gram-positive (purple) or stain blue with Giemsa. The polarization microscope is helpful in visualizing spores because of their birefringence due to the presence of chitin in the spore wall. Body fluids (urine, cerebrospinal fluid) containing spores can be inoculated into tissue culture monolayers for cultivation of the parasite [Visvesvara et al., 1999; Weber and Canning, 1999]. Definitive identification of microsporidial species is done by electron microscopy or polymerase chain reaction, or both. Magnetic resonance imaging reveals multiple ring-enhancing lesions in the brain. A comprehensive review of techniques for identification of microsporidia in clinical specimens is available [Garcia, 2002]. A child from Colombia who was adopted by a Swedish family developed convulsions. Serologic studies detected the presence of immunoglobulin G and immunoglobulin M antibodies against E. cuniculi [Bergquist et al., 1984]. Examination and staining of sediment from his urine revealed small bodies, either dispersed or in aggregates. The infection was transferable to mice by intraperitoneal injection of the bodies or to cultures of canine kidney cells. The child was successfully treated with carbamazepine and an anticonvulsive drug, and, aside from later minor arthritic symptoms that may have been sequelae of the microsporidial infection, remained in good health.

A 9-year-old black female with congenital HIV/AIDS and a CNS tumor developed tonic-clonic seizures and died after 8 days in the hospital [Yachnis et al., 1996]. Her symptoms, before hospitalization, included aphasia, hallucinations, inability to walk, and reduced consciousness. A CT scan exhibited multiple lesions in the cortical gray matter and at the gray-white junction. At postmortem examination, necrotic lesions were found in the cerebral cortex, cerebellum, pons, and medulla. Macrophages and astrocytes in histopathologic sections were filled with spores located in vesicles. Free spores released from destroyed cells were seen in the perivascular spaces. Spores were recognized in hematoxylin-eosin sections, in Gram- and Giemsa-stained preparations, and by polarization microscopy, and were later identified as Trachipleistophora anthropophthera.

Management Albendazole and other benzamidazoles, such as ebendazole and thiabendazole, are currently the recommended antimicrobials for treatment of microsporidiosis, although they may not be effective against mature spores [Weber et al., 2000]. The drugs act by binding to tubulin and inhibiting microsporidial divisions. Disseminated infections caused by E. cuniculi are treated in adults with a dose of 400 mg twice a day [Medical Letter, 2004].

APICOMPLEXAN INFECTIONS OF THE CENTRAL NERVOUS SYSTEM Apicomplexans are parasitic protozoa that contain an organelle at the anterior end of the organism called the apical complex. Components of the complex aid in locomotion of the parasite and penetration into host cells by the release of enzymes. Typical organelles of locomotion such as cilia, flagella, or pseudopods are absent. The Apicomplexa contains some of the most important and destructive parasites of humans, including the agents of toxoplasmosis, malaria, and babesiosis.

Toxoplasmosis Epidemiology, Microbiology, and Pathology The causal agent of toxoplasmosis was described from a desert rodent, the gondi, in 1908, but it was 1923 before the association with human disease was reported, and 1937 when its role in congenital infections was recognized [Cox, 2002; Remington et al., 2001]. It then became apparent that the main threat of toxoplasmosis was during gestation. Toxoplama gondii is a protozoon that reproduces only after gaining access to a host cell. The organism is found worldwide in a variety of mammals and birds. Toxoplasmosis is a major public health problem in both developed and developing countries. Approximately 20% to 40% of the adult population in the United States is seropositive. Factors that increased risk of infection in the United States were foreign birth, soil-related occupation, and little or no formal education [Jones et al., 2001]. The domesticated cat, the major reservoir and definitive host of the parasite, excretes oocysts in the feces. Ingestion of the oocyst by animals and humans

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continues the cycle [Frenkel, 1985]. After being ingested by the host, the oocyst releases sporozoites that invade cells, either by active penetration or by phagocytosis, giving rise to rapidly reproducing trophozoites, or tachyzoites. These tachyzoites proliferate within a parasitophorous vacuole, causing lysis of the host cell and release of more tachyzoites. Tachyzoites eventually transform into slower-growing bradyzoites that form intracellular tissue cysts and may remain quiescent for years in the host, particularly in muscle and brain tissues. Cyst formation is triggered by the host’s developing immune response, and the continued release of bradyzoites from tissue cysts stimulates the immune system, resulting in lasting immune protection. Humans are infected by ingestion of raw or inadequately cooked meat (particularly pork and lamb, and, to a lesser extent, beef) containing tissue or by ingestion of oocysts shed in cat feces. Of the two possible sources of infection, undercooked meat is the more likely vehicle of transmission. Through dissemination of the parasite by tissue cysts in undercooked meats, Toxoplasma has effectively bypassed the need for the cat as an intermediate host, relying entirely upon food as a vehicle for direct transmission [Su et al., 2003]. Bradyzoites, either free or within tissue cysts, are resistant to pepsin and trypsin digestion, whereas tachyzoites can withstand trypsin, but less so pepsin, and are destroyed in the stomach. Transfusion of whole blood from asymptomatic carriers can also serve as a mode of transmission. Reactivation of a latent infection can be triggered by the host becoming immunodeficient or immunocompromised. Studies of the Toxoplasma genome have revealed a clonal structure of the populations with recognition of three different genotypic patterns: types I, II, and III [Dardé, 2004; Howe and Sibley, 1995]. These have different virulence phenotypes, host specificity, and geographic distribution. Type I parasites are highly virulent for mice but rare in humans; type II is the type most commonly detected in humans and some domestic animals (pigs, sheep) with low virulence for mice; and type III is usually encountered in wild animals and some human populations with intermediate virulence [Dardé, 2004]. Type I parasites, however, have been detected in cases of congenital toxoplasmosis, suggesting that the virulence phenotype may also be expressed in humans [Fuentes et al., 2001]. Intrauterine or congenital toxoplasmosis may develop in the fetus if the mother is infected during pregnancy. The placenta is invaded by parasites from the maternal circulatory system that eventually pass into fetal circulation. Infection may be asymptomatic in the mother; however, the fetus develops a generalized infection involving spleen, liver, eyes, and CNS [Desmonts and Couvreur, 1974; Lowichik and Siegel, 1995]. The incidences of maternal and fetal infection in the United States are 6 and 2 per 1000, respectively [Wilson and Remington, 1992]. The risk of fetal infection increases as the pregnancy progresses: 25% in the first trimester, 54% in the second trimester, and 65% in the third trimester. However, severity of infection is inversely related to when infection occurs during pregnancy. When disseminated, acquired toxoplasmosis produces systemic manifestations consisting of multiple organ infection, including the brain. Calcium is deposited in necrotic cerebral lesions; cerebral calcification is often seen in CT or MRI scans and plain radiographs of neonates (Fig. 70-14).

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FIGURE 70-14. Toxoplasmosis. Radiograph of infant skull demonstrates fine intracranial calcifications.

Postmortem examination of brain tissue in the congenital form of the disease reveals pseudocysts or the organism itself. Severe fibrosis of the meninges develops with resultant thickening. The cortex contains many regions of encephalomalacia. Hydrocephalus occurs often. Microscopic study demonstrates that the numerous lesions comprise large or small granulomas accompanied by glial proliferation and inflammatory infiltrate; areas of nonspecific necrosis are usually present. Giemsa staining delineates the parasite. The acquired form of toxoplasmosis causes meningoencephalitis and pathologic changes similar to those associated with the congenital form (i.e., necrosis, cyst formation) [Townsend et al., 1975]. Long-term sequelae are common. The approximate incidence of abnormalities in 180 cases of intrauterine toxoplasmosis was as follows: microcephaly (20%), hydrocephalus (25%), microphthalmia (35%), seizures (40%), psychomotor retardation (45%), cerebral calcification (60%), and chorioretinitis (95%) [Feldman, 1969]. More recent studies have reported similar percentages [Lowichik and Siegel, 1995; Wilson and Remington, 1992]. Approximately 80% to 90% of survivors of overt congenital toxoplasmosis have mental retardation, cerebral palsy, epilepsy, or visual impairment [Stern et al., 1969]. Asymptomatic congenital toxoplasmosis may be associated with minimal intellectual impairment. Although the manifestations of some cases have been similar to those of congenital cytomegalic inclusion disease, CNS involvement is usually more common and extensive in toxoplasmosis. Hydrocephalus with a tense or bulging fontanel, vomiting, a high-pitched cry, and opisthotonic posturing may dominate the neonatal period (Fig. 70-15). Skull radiographs and ultrasound document punctate, scattered calcifications and separated cranial sutures. Hydranencephaly rather than hydrocephalus has been reported [Altshuler, 1973], as has infantile diabetes insipidus [Silver and Dixon, 1954] and growth hormone deficiency [Massa et al., 1989]. Delayed onset with hydrocephalus, seizures, chorioretinitis, and mental retardation can also occur [Miller et al., 1971]. Up to 85% of children

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FIGURE 70-15. Hydrocephalus in congenital toxoplasmosis.

with congenital toxoplasmosis will develop retinal and choroidal involvement [Wilson et al., 1980]. Lesions initially are edematous with hemorrhage, and a yellowish exudate gives rise to areas of peripheral irregular hyperpigmentation with a pale atrophic center. Even in those infants with toxoplasmosis who are asymptomatic at birth, up to 85% may develop chorioretinitis or serious neurologic disability by 8.3 years [Wilson et al., 1980]. Toxoplasmosis in the fetus and newborn is reviewed by Remington and colleagues [2001], and methods for diagnosis of the disease are discussed by Wilson and McAuley [1999] and Wilson and associates [2002].

Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis There have been reports of disseminated generalized toxoplasmosis after immunosuppressive therapy in patients receiving transplantation [Ghatak et al., 1970; Khan and Correa, 1997; Seong et al., 1993] and, to a lesser extent, in those with malignancy [Israelski and Remington, 1993]. Immunodeficiency can lead to reactivation of dormant tissue cysts and the release of bradyzoites. Meningoencephalitis, often fatal, is a major complication. Optic neuritis has also been reported in children [Roach et al., 1985]. Although cerebral toxoplasmosis is an important complication of AIDS in adults [Bertoli et al., 1995], it is not common in neonates or older children [Lowichik and Ruff, 1995a; Miller and Remington, 1990]. When present, children appear to have similar clinical and neuroimaging findings (although less severe) than adults. Maternal HIV infection appears to reactivate a latent toxoplasmosis, which can be transmitted to the fetus. These infants with both HIV and toxoplasmosis usually present at 3 to 4 months of age with similar symptoms as those seen in infants with severe intrauterine toxoplasmosis infection [Lowichik and Ruff, 1995a]. Neuroimaging studies in infants with both infections are similar to those in infants with just toxoplasmosis. Overall, MRI appears more sensitive in detecting lesions than CT. However, in older patients, it is frequently difficult to correlate neuroimaging abnormalities in gray-white matter regions or basal ganglia with either infection or the presence of lymphoma [Ciricillo and Rosenblum, 1990]. This subject has recently been reviewed, and there are recommended treatment protocols for children infected with HIV and CNS toxoplasmosis [Khan and Correa, 1997].

Immunologic diagnosis of toxoplasmosis relies on the Sabin-Feldman dye test (which detects live parasites), the direct hemagglutination test, the double-sandwich enzymelinked immunosorbent assay, the immunosorbent agglutination assay, the complement fixation test, the evaluation of immunoglobulin M levels, and the indirect fluorescent antibody test. Comparative information on commercially available kits for detecting immunoglobulin M in serum samples is available [Wilson et al., 1997]. The antibody test may be the most dependable, but the hemagglutination test is used most often (see Table 70-2). Examination of body fluids for parasites is problematic. Body fluids or macerated or digested tissue samples (with trypsin or pepsin), if inoculated into mice, can produce symptoms within 5 to 10 days [Wilson and McAuley, 1999]. Tissue cultures (human embryonic fibroblasts) inoculated with similar materials will exhibit cell destruction by parasites in about a week [Remington et al., 2001]. Prenatal diagnosis of congenital toxoplasmosis with a polymerase chain reaction test on amniotic fluid is possible and cost effective [Hohlfeld et al., 1994; Sahai and Onyett, 1996]. Neospora caninum is a parasite related to Toxoplasma that causes encephalitis and abortion in cattle and has been transmitted to monkeys. It has a similar pathology and clinical course as Toxoplasma. The dog, which passes oocysts in its feces, is the definitive host of the parasite rather than the cat. In a California population sample of more than 1000 humans tested for Neospora antibodies, approximately 7% tested positive by indirect fluorescent antibody staining, raising the possibility that some cases diagnosed as toxoplasmosis may, in reality, be neosporosis [Tranas et al., 1999]. A polymerase chain reaction technique has been developed to distinguish between the two parasites [Kaufmann et al, 1996].

Management The value of therapy for congenital toxoplasmosis has recently been demonstrated. Early treatment with spiramycin for the mother and sulfadiazine, pyrimethamine, and folinic acid for the infant is beneficial and 70% effective [Lowichik and Siegel, 1995; Roizen et al., 1995; Wilson and Remington, 1992]. In the acquired form of the disease, treatment is required. Again, sulfadiazine, pyrimethamine, and folinic acid (to counteract the folate-inhibiting effects of pyrimethamine) are most effective [Jones, 1979; Remington, 2001]. Duration of treatment, usually for 2 to 6 weeks after signs and symptoms have resolved, will depend on the severity of infection and the immunologic status of the patient. In the immunocompromised patient or in those patients whose symptoms do not resolve or recur, treatment for up to 1 year may be necessary [Mitchell et al., 1990].

Malaria Epidemiology, Microbiology, and Pathology Malaria is caused by protozoal parasites of the genus Plasmodium with life cycle stages alternating between the mosquito and a variety of mammals and birds. Several species of Plasmodium cause malaria in humans—Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae—

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but P. falciparum is the only member of the genus that affects the host’s nervous system. Awareness of the disease dates back some 5000 years, with the description of malarialike symptoms in writings from China, and later in texts from India, Sumer, Egypt, and ancient Greece [Carter and Mendis, 2002]. Hippocrates (ca. 400 BC) recognized the regular occurrence of febrile episodes of the disease, and used the terms “quotidian” (daily), “tertian” (every 3 days), and “quartan” (every 4 days) to characterize them. The disease derives it name from the misplaced belief that it was caused by miasmas, or “bad air.” The recent sequencing of the P. falciparum genome presents opportunities for development of drugs and vaccines targeted to specific gene products of the parasite [Gardner et al., 2002]. As early as 1640, long before the etiologic agent was demonstrated, the therapeutic attributes of cinchona (quinine, quinidine) for treatment of malaria were generally recognized. The mainstay of current therapy is chloroquine, whose efficacy has been compromised in many parts of the world by the appearance of drug-resistant strains of the parasite. Other factors, including insecticide-resistant species of mosquitoes, ecologic and practical constraints on drainage of swamps, and limits on widespread use of insecticides, make it likely that malaria will persist as a major public health problem throughout the world. From 200 to 500 million people are affected annually, particularly in many developing tropical and subtropical regions. Children younger than 5 years of age account for about 90% of the more than 2 million deaths that occur each year. Much of the knowledge gained about pediatric malaria has come from studies of children in the nations of sub-Saharan Africa: Kenya, Zambia, Nigeria, The Gambia, Malawi, and so on, comprising some 30 different countries. Malaria acquired by recipients of blood transfusions from infected but asymptomatic carriers is also a major problem in endemic regions of the world. Because of increased international travel, increasing numbers of cases in adults and children are being recognized in the United States [Emanuel et al., 1993]. Close to 100 cases have appeared in individuals living in the vicinity of or working at airports, probably as the result of inadvertent import of mosquitoes from malarial areas of the world in airplane cabins or luggage [Lusina et al., 2000; Thang et al., 2002]. The malaria literature is voluminous and is frequently reviewed, reflecting the importance of the disease [Birbeck, 2004; Maitland and Marsh, 2004; Newton and Krishna, 1998; Newton et al., 2000; Satpathy et al., 2004]. The definitive host and vector, the female Anopheles mosquito, is the site of sexual reproduction of plasmodia. The mosquito injects the organism as sporozoites when it bites humans, who are the intermediate hosts; in humans the organism undergoes asexual reproduction. The hepatic cells are the first location of asexual reproduction during the preerythrocytic phase. Reproduction in hepatic cells is followed by release of parasites that invade erythrocytes during the prepatent period, which lasts 5 or 6 days. The erythrocytic phase, which produces merozoites by schizogony, commences subsequent to the entry of the parasite into the erythrocyte and continues synchronously for 1 to 3 weeks, which is the incubation period. In its early stages of schizogony, the parasite appears as a ringlike structure within the parasitized erythrocyte. Hemozoin, the product of hemoglobin degradation by the parasite, accumulates in the erythrocyte.

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Hemolysis of the parasitized blood cells is signaled by chills and fever, with synchrony and periodicity typical for the different Plasmodium spp. For falciparum (subtertian) malaria, the period is about 48 hours. In the bloodstream of the host, some merozoites differentiate into gamete precursors. When the human host is bitten, infected erythrocytes enter the mosquito carrying micro- and macrogametocytes (male and female gamete precursors), and the cycle begins anew. The most serious consequence of falciparum malaria and the CNS develops when the parasitized erythrocytes lodge in the brain vasculature. Cerebral involvement follows binding of infected red blood cells to the microvascular endothelium. Sequestration and hemolysis follow and cause obstruction of blood vessels [Sein et al., 1993]. Parasite-induced knobby projections on the surface of infected erythrocytes bind to the endothelial cells in brain, heart, liver, and lungs, causing capillary congestion. By attaching to the endothelial lining of blood vessels, the parasitized erythrocytes effectively avoid destruction that might otherwise occur upon passage through the spleen. This is accompanied by a change in the erythrocyte from a readily pliant state to one of rigidity, which further contributes to blood vessel occlusion. Additionally, rosette formation resulting from clustering of parasitized and nonparasitized blood cells may facilitate transfer of parasites from hemolyzed cells to uninfected red blood cells. Rosette formation can be reversed by heparin. Local hypoxia, microinfarction, necrosis, hemorrhage, and inflammation subsequently occur. The sequestration and resulting occlusion may deplete the oxygen level in cerebral vasculature, providing a more optimal environment for metabolism and replication of the parasites [Chen et al., 2000]. Thrombi may form and be associated with clotting aberrations, including disseminated intravascular coagulation [Butler et al., 1973]. The blood-brain barrier is disrupted by changes in endothelial cell junctional permeability leading to cerebral edema, more commonly encountered in children than adults [Adams et al., 2002]. A number of theories have been proposed to explain the pathology of cerebral malaria. Hypoxia is one such theory based on the impedance of blood flow to the brain and the consequent oxygen deficiency. On recovery, however, there is no evidence of neuronal damage that might be expected to occur as a result of oxygen deprivation. Another explanation is that the surge of mediators that occurs in the CNS may be responsible for the pathology of cerebral malaria [Medana et al., 2001]. Release of proinflammatory cytokines and interleukins (tumor necrosis factor-α, IL-1, IL-6, nitric oxide lymphotoxin) results in endothelial damage and mimics the clinical condition of sepsis [Clark et al., 2004; Maitland and Marsh, 2004]. Presence of malarial antigens stimulates release of tumor necrosis factor-α that, in turn, upregulates endothelial adhesion molecules and promotes attachment of parasitized erythrocytes to the vascular lining [Gimenez et al., 2003]. Once parasites are cleared from the blood, the effects of cerebral malaria are reversible and long-term sequelae generally do not develop [Adams et al., 2002]. The role of proinflammatory cytokines in malarial pathology has been reviewed by Clark and associates [2004] in the context of other infectious diseases and noninfectious conditions, and the molecular aspects of cerebral malaria have been reviewed by Chen and co-workers [2000].

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Postmortem studies of gross specimens demonstrate fulminating cerebral edema and accompanying transtentorial herniation (Fig. 70-16). Congestion of arachnoid vessels causes the brain to appear pink or bright cherry red. Petechiae are evident on the cut surface. Microscopic examination reveals that small arterioles and capillaries are obstructed with parasitized erythrocytes. Mononuclear cells are readily discernible in meningeal and perivascular infiltrates. Microinfarction and ensuing multifocal necrosis and demyelination are widespread.

Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis Cerebral malaria is most often heralded by manifestations of mental deterioration, particularly confusion or delirium; further deterioration is signaled by progression to stupor and coma that transpires during the next 1 to 3 days. In children, cerebral involvement is more fulminant, with most becoming comatose within 2 days [Molyneux et al., 1989]. Early features include fever, anorexia, vomiting, diarrhea, and seizures, which may be confused with febrile seizures in young children [Osuntokun, 1977]. Severe hypoglycemia is also common. Elevated intracranial pressure occurs in fatal cases [Maitland and Marsh, 2004]. Lactic acidosis due to metabolic impairment is responsible for respiratory distress [Birbeck, 2004]. Extensor plantar responses, cerebellar impairment, abnormal movements, and psychosis may also occur [Daroff et al., 1967]. Children are more likely to have decreased tone compared with adults and impaired brainstem cranial nerve responses and abnormal respiratory function [Molyneux et al., 1989; Newton et al., 1991]. Children with severe illness exhibit evidence of transtentorial herniation [Newton et al., 1991]. Papilledema and extramacular retinal edema are markers of a poor prognosis [Lewallen et al., 1993]. The presence of impaired consciousness, prolonged seizure activity, hypoglycemia, or respiratory distress identifies those at high risk for death or long-term sequelae [Marsh et al., 1995; Steele et al., 1995]. In one study of 308 children with cerebral malaria, the mortality rate was 14%; of the survivors, 12% had significant long-

FIGURE 70-16. Cerebral malaria. Petechial hemorrhages are scattered throughout the brain.

term neurologic deficits, including language and motor deficits, ataxia, and cortical blindness [Bruster et al., 1990]. In endemic areas such as sub-Saharan Africa, neonates are protected from infection by maternal (transplacental) immunoglobulin G and, in part, from the vestigial presence of fetal hemoglobin. Studies using transgenic mice indicate that the parasite cannot readily break down fetal hemoglobin, thus impairing intraerythrocytic development and replication [Shear et al., 1998]. This protection lasts for about 1 year, after which the infant becomes susceptible to disease. The child of 1 to 4 years of age is the most vulnerable to infection and the development of severe malaria, with a mortality of about 5%. Once this period has passed, the host and parasite exist in a state of détente, with the host exhibiting chronic asymptomatic parasitemia [Kyes et al., 2001]. Additional infections due to continued exposure to parasites from mosquito bites result either in death or the development of clinical immunity. In endemic areas, a large percentage of adults and children will be infected, but only a small number of these will go on to develop clinical disease [Kyes et al., 2001]. The immunity that develops encompasses both cellular and humoral elements. Purified immunoglobulin preparations from individuals with naturally acquired immunity have been used for protection of children from recurrent malaria infections [Sabchareon et al., 1991]. Neurologic sequelae are not uncommon in children recovering from cerebral malaria. In studies combining data on African children, sequelae develop in about 10% to 30% of patients [Birbeck, 2004; Newton and Krishna, 1998]. The occurrence of sequelae has been attributed to a number of factors, including seizures, prolonged coma, hypoglycemia, elevated intracranial pressure, and neurologic pathology. The sequelae are manifested as ataxia, epilepsy, hemiparesis, cortical blindness, impaired hearing, behavioral abnormalities, and cognitive deficits (impaired learning, reasoning, dexterity, memory, perception, etc.). In most cases, recovery occurs within weeks to 6 months, but some sequelae, such as epilepsy, may persist. Diagnosis necessitates study of thick and thin peripheral blood films to ascertain the presence of small, ring-form trophozoites and crescent-shaped gametocytes; close scrutiny is required to ensure accuracy [Coatney et al., 1971; Lowichik and Ruff, 1995a]. In the hands of a skilled technician, thick films can detect 1 infected cell in 1000 red blood cells (0.001%), or 50 parasites/μL of blood [Moody, 2002]. Erythrocytes containing Plasmodium ring stages are more likely to be found in peripheral blood because the mature stages undergoing intraerythrocytic replication become sequestered in brain and other deep areas of the body. Blood smears should be prepared at 8- to 12-hour intervals, until diagnosis can be made [Birbeck, 2004]. If antimalarial therapy was started before preparation of blood smears, the smears may be negative. Polymerase chain reaction has also been used for diagnosis, with the capability of detecting 5 parasites or fewer per μL of blood a great advantage when parasites in peripheral blood samples are in low numbers. Immunochromatography in the form of a dipstick kit has also been employed for Plasmodium detection [Moody, 2002]. Sensitive indirect fluorescent antibody and hemagglutination tests provide further diagnostic capability [Wilson et al., 1975]. The electroencephalogram (EEG) in

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children with cerebral malaria reveals nonspecific generalized slowing [Molyneux et al., 1989] and may be helpful in detection of subclinical seizures that might otherwise pass unnoticed [Maitland and Marsh, 2004]. Neuroimaging may also be abnormal. Acutely, MRI may demonstrate multifocal T2-enhancing lesions indicative of capillary occlusion and cerebral edema [Chia et al., 1992]. Computed tomography scan has been reported to demonstrate generalized and sulcal atrophy as a sequela of disease [Newton et al., 1994]. Moody [2002] has reviewed testing for malarial parasites with emphasis on methods capable of giving results in 1 hour or less.

Management Cerebral malaria is defined as a coma without apparent etiology, inability to localize painful stimuli, and falciparum parasitemia as demonstrated by blood smears [Birbeck, 2004; Newton and Krishna, 1998; Warrell et al., 1982]. A coma is assessed on the basis of the Balantyre or Glasgow coma scales, taking into account eye movements and motor and verbal abilities. The scales may be of greater value in predicting mortality rather than as a diagnostic tool [Newton and Krishna, 1998]. In the management of malaria there are two considerations. One is treating an uncomplicated case of falciparum parasitemia, preventing it from developing into life-threatening, fulminant malaria. If the patient has already progressed to cerebral malaria, the second consideration goes beyond the use of antimalarial drugs and requires measures to treat deep coma, elevated intracranial pressure, hypovolemia, metabolic imbalance, anemia, convulsions, and other manifestations that accompany this often fatal phase of the disease. The chemoprophylaxis and therapy of malaria are major areas of complexity. Excellent review articles are available and should be consulted when appropriate [Birbeck, 2004]. Chloroquine, primaquine, and quinine remain the mainstays of both prophylaxis and therapy. However, because of the increasing prevalence of chloroquine-resistant strains of malaria in Southeast Asia, Africa, and South America, quinidine gluconate as a continuous infusion is currently recommended (in combination with doxycycline, tetracycline, and sulfadoxine-pyrimethamine) as the agent of choice for severe P. falciparum infection [Jotte and Scott, 1993; Medical Letter, 2004; Phillips et al., 1985]. The clinician should be aware of side effects and obvious toxic reactions, particularly hypoglycemia and cardiac dysrhythmias, before administration. Trial administration to determine individual reactions to the drugs is recommended before long-term, large-dose therapy is instituted [Randall and Seidel, 1985]. Most patients will respond within 72 hours to intravenous quinidine and should then be switched to oral administration for an additional 3 to 7 days [CDC, 1991; Molyneux et al., 1989]. Iron chelation therapy with deferoxamine has been found to hasten the clearance of parasitemia and enhance the recovery from deep coma in Zambian children with cerebral malaria [Goerduk et al., 1992]. However, survival rates of parasitemic-comatose Zambian children treated with deferoxamine plus quinine, or placebo plus quinine were compared and no difference was reported between the two

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groups [Thuma et al., 1998]; children in the deferoxaminetreated group showed a somewhat higher mortality. Deferoxamine may act by binding iron and withholding it from the parasite, or by formation of toxic complexes leading to free radical production and intracellular destruction of the parasite [Mabeza et al., 1999]. Other studies point to a third mechanism of action; the chelating agent may act on interferon-γ (IFN-γ) nitric oxide, and reactive oxygen intermediates [Fritsche et al., 2001]. Nitric oxide in particular may, through interaction with IFN-γ, activate macrophages to reduce parasitemia. Alternately, nitric oxide may contribute to the pathology of cerebral malaria by causing vasodilation and increased intracranial pressure. The use of iron chelation therapy for malaria has been reviewed [Mabeza et al., 1999]. The Chinese medicinal herb qinghao (Artemisia annua), also known as annual or sweet wormwood, has been used since antiquity to treat malaria. Recent efforts to understand its chemistry and pharmacology have been very fruitful. The plant yields a sesquiterpene compound called qinghaosu or artemisinin, which is active against plasmodium. Artemisinin and its derivatives have been found to cure malaria with much less toxicity than quinoline antimalarials [Hien and White, 1993], and resistance to artemisinin has not yet been encountered. Artemisinin is also effective against the gametocyte stage in the bloodstream (the stage taken up by the mosquito), thereby reducing disease transmission in malaria-endemic areas. To further lessen the chance of emergence of drug resistance, artemisinin has been coupled with other differently acting drugs in artemisinin-combination therapy [Adjuik et al., 2004]. Artemether (arthemeter), artesunate, and arteether are artemisinin derivatives that have been effective when used in combination with a second drug (e.g., artesunate-mefloquine) [Ashley, 2004; Olliaro and Taylor, 2004]. Arthemeter and artesunate, however, are not available in the United States [Birbeck, 2004]. Among other antimalarials, atovaquone-proguanil (Malarone or Malarone Pediatric) is used in areas where chloroquine resistance has been encountered [Medical Letter, 2004]. Sulfadoxine-pyrimethamine (Fansidar) has been widely used, but drug resistance is encountered, particularly in Southeast Asia and east Africa [Olliario and Taylor, 2004]. Mefloquine and quinine (available in the United States as quinidine) are other mainstays of the malaria pharmacopeia. Fosmidomycin is a phosphonic acid derivative that specifically targets a metabolic pathway in the apicoplast of malarial parasites, but not in human cells. It has been effective and is well tolerated in the treatment of uncomplicated falciparum malaria [Missinou et al., 2002]. The combination of chlorproguanil-dapsone (Lapdap) has been tested against sulfadoxine-pyrimethamine in treatment of uncomplicated malaria and was found to be more effective [Alloueche et al., 2004]. Halofantrine has also been used against resistant falciparum malaria. When given at high dosages (8 mg/kg q8h for 3 days for a total of 72 mg/kg), halofantrine compared favorably with mefloquine (25 mg/kg for one day) in treating multidrug-resistant falciparum malaria [Ter Kuile et al., 1993]. The drug, however, has demonstrated cardiotoxicity. Recent reviews of antimalarials emphasize increasing drug resistance and decreasing options for treatment [Kain, 1996; Ter Kuile et al., 1993; White, 1996]. The topic of antimicrobial treatment of falciparum

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malaria has been reviewed by Winstanley and colleagues [2004]. In cerebral malaria, the focus shifts from treating an infectious disease to dealing with a medical emergency. Fluid and electrolyte balance have to be restored or managed. This includes hypovolemia (remedied by hydration with saline), hypoglycemia (50% dextrose intravenously), hyponatremia and hypokalemia (hydration with saline), renal failure (peritoneal dialysis), and elevated intracranial pressure. Dexamethasone, used to relieve intracranial pressure, was found to be no better than a placebo in Thai patients (6 to 70 years); it prolongs coma, leads to complications, and is usually contraindicated [Warrell et al., 1982]. Neither heparin nor dextran has been shown to be beneficial in reducing intracranial pressure by lowering blood viscosity [Newton and Krishna, 1998]. Mannitol or glycerol can reduce intracranial pressure by creating an osmotic gradient across the blood-brain barrier and drawing fluid into the vascular system. Pentoxifylline, which acts as a vasodilator, reduces blood viscosity and reduces tumor necrosis factor-α and may be helpful in treating intracranial pressure, but additional controlled studies are needed to establish its efficacy [Birbeck, 2004; Newton and Krishna, 1998]. Fever can be controlled with antipyretics (acetaminophen, ibuprofen, aspirin). Blood problems include severe anemia (remedied by exchange transfusion), lactic acidosis (hydration, restoration of normal glucose level, improved oxygenation), and parasite load (transfusion to reduce parasitemia). Convulsions are treated with lorazepam, diazepam, and paraldehyde; recurrent seizures can be treated with phenytoin, fosphenytoin, and phenobarbital [Birbeck, 2004]. Because cerebral malaria can mimic bacterial meningitis, a lumbar puncture to obtain cerebrospinal fluid for cultivation may be advised. Caution, however, should be exercised due to the elevated intracranial pressure. Cerebrospinal fluid in cerebral malaria is clear, with protein ranging to a high of 0.4 g/L (400 mg/dL); septic cerebrospinal fluid is cloudy, with neutrophils comprising about 99% of leukocytes and protein ranging from approximately 1 to 3 g/L (1000 to 3000 mg/dL). Emergency measures for treatment of severe malaria have been described in several reviews [Birbeck, 2004; Maitland and Marsh, 2004; Newton and Krishna, 1998]. A vaccine for the prevention of malaria has yet to be realized, although several promising clinical trials are being conducted [Moorthy et al., 2004; Webster and Hill, 2003]. Development of an effective vaccine has been hampered by the presence of different stage-specific antigens displayed during the complex life cycle of the parasite. Of the 5300 genes present in the P. falciparum genome, approximately 4% are involved in immune evasion, including antigenic variation [Gardner et al., 2002]. Thus, it is likely that an effective vaccine will have to contain a combination of antigens able to protect against the infective sporozoite stage, the erythrocytic stage, and the transmissive gametocyte (sexual) stage. The role of antigenic variation in pathology of falciparum malaria has been reviewed by Kyes and associates [2001].

Babesiosis Babesia is the etiologic agent of babesiosis, a malaria-like tick-borne disease occurring in many species of wild and

domestic animals, and occasionally humans. The organism was named for Viktor Babès, who first recognized it in blood cells of cattle in the 19th century, but it was not until 1957 that the first human infection was recognized. Babesiosis is a zoonotic disease transmitted to humans from rodents and other mammals. The parasites are contained within erythrocytes and are transmitted by ixodid (hard-bodied) ticks. Human-to-human transmission can occur through blood transfusion [Gerber et al., 1994]. Unlike Plasmodium spp., Babesia does not have an exoerythrocytic stage, divides in the erythrocyte by binary fission rather than schizogony, develops within the cytoplasm of the host cell and not in a parasitophorous vacuole, and does not form hemozoin pigment from hemoglobin as do the malaria parasites. Two species of Babesia are important in human disease: Babesia microti from rodents and Babesia divergens from bovines. B. microti is the species present in the United States, whereas B. divergens is found in Europe. Of the two species, B. divergens is the more virulent with 42% mortality, compared with 5% mortality for B. microti [Gorenflot et al., 1998]. In the northeastern and upper midwestern United States, the transmission cycle of B. microti overlaps that of another well-known zoonotic agent, Borrelia burgdorferi, the causative agent of borreliosis, or Lyme disease [Persing and Conrad, 1995], which is reviewed in Chapter 68. Most cases of human infections have involved elderly adults [Meldrum et al, 1992]. Asplenic individuals are also at higher risk for infection; splenectomy predisposed four adult males to infection (two died) in a mini-epidemic in northern California [Persing et al., 1995]. Human infections on the West Coast of the United States have been due to Babesia-like parasites (the WA-1 strain, after a strain first detected in Washington state) that defy classification as either B. microti or B. divergens, and may be related to Babesia spp. from canines and rodents [Quick et al., 1993]. Other unusual strains have been isolated in northern California, Missouri, and Wisconsin.

Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis Clinical manifestations consist of a persistent fever, sweating, chills, myalgia, and mildly to moderately severe hemolytic anemia. Emotional depression has been reported, but severe neurologic symptoms are rare. Babesia in bovines can cause encephalitis, as does P. falciparum in humans. Parasitized red blood cells adhere to the endothelial lining of brain capillaries, thus evading destruction in the spleen [O’Connor et al., 1999; Wright et al., 1989]. Babesiosis should be suspected in patients who have spent time in tick-infested areas, had recent blood transfusions, or have undergone splenectomy [Homer et al., 2000]. The diagnosis is made by identification of the organism on thick and thin blood smears, but only if the parasitemia is high. In blood smears, the organism can be mistaken for the malaria parasite, but infected erythrocytes lack the malaria-characteristic hemozoin pigment (Fig. 70-17). Inoculation of hamsters with suspect blood samples is useful in cases with low parasitemia but may require weeks for the disease to develop. However, the development of indirect fluorescent antibody assays and the polymerase chain reaction provide more sensitive detection of the parasitemia asso-

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of the kinetoplast with respect to the nucleus. They infect a variety of vertebrates but the clinically important species for humans are Trypanosoma cruzi (Chagas’ disease or American trypanosomiasis) and Trypanosoma brucei (African sleeping sickness). Both species are transmitted to humans by insect vectors.

Chagas’ Disease

FIGURE 70-17. Blood film showing human erythrocytes, some of which are infected with Babesia. Although different in morphology, Babesia can be mistaken for Plasmodium in infected cells. The varied forms of the parasites can be seen: A, ring forms; B, ameboid shape; C, tetrad configuration. Bar in micrograph represents 10 μm. (Giemsa stain) (Courtesy Dr. Anne Kjemptrup. From Schuster, FL. Clin Microbiol Rev 2002;15:365. Copyright © 2002, the American Society of Microbiology. 2002.)

ciated with babesiosis [Homer et al., 2000; Pruthi et al., 1995]. Serologic confirmation of infection has been determined in asymptomatic children [Ruebush et al., 1977]. Cross-reactivity with Plasmodium surface antigens has been reported [Gorenflot et al., 1998].

Management Babesiosis was described in a neonate whose mother had been bitten by a tick 1 week before giving birth [EsernioJenssen et al., 1987]. Treatment with clindamycin and quinine was successful in effecting recovery. Two other cases of babesiosis in pregnancy were reported; in both, the pregnancies went to term and the infants were unaffected [Feder et al., 2003; Raucher et al., 1984]. Atovaquone (for pediatric patients 20 mg/kg twice a day for 7 to 10 days) plus azithromycin (12 mg/kg daily for 7 to 10 days) are the drugs of choice in treating babesiosis [Medical Letter, 2004], with clindamycin (20 to 40 mg/kg/ day orally in three doses for 7 days) plus quinine (25 mg/ kg/day orally in three doses for 7 days) as alternatives [Medical Letter, 2004]. Chloroquine therapy has been ineffective [Miller et al., 1978]. In seriously ill patients, exchange transfusion in combination with the above medications was reported to be efficacious, presumably by reducing the acute parasitic load [Doan-Wiggins, 1991]. Homer and colleagues [2000] have prepared a comprehensive review of the organism and of the disease.

TRYPANOSOMAL INFECTIONS OF THE NERVOUS SYSTEM The trypanosomes are a group of flagellated protozoa defined by the presence of the kinetoplast, a DNA-containing organelle. The parasites have morphologically distinct life cycle stages based on the length of the flagellum and the location

Chagas’ disease (American trypanosomiasis) is a public health problem in Latin America, from Argentina to the Mexican border with the United States. It is a disease of poverty, with the poor bearing the brunt of the disease. The disease has also crossed into the United States, mostly in the southern tier, because of immigration from Latin America, where 8% of the population is seropositive. As a result, more than 50,000 to 100,000 people living in the United States have been infected [Kirchoff, 1993]. Acute Chagas’ disease occurs primarily in childhood and usually is mild [Cegielski and Durack, 1997]. The source of infection is the triatomine bug (Triatoma spp.), which lives in walls and roofs of houses. The disease occurs mainly in rural areas, although population movements to the cities have shifted the disease to an urban setting. Humans, cats, dogs, and other mammals serve as reservoirs from which the vector acquires the parasite. The parasite is found in the midgut and rectum of the insect. At the time the triatomine bug bites a human, it defecates on the skin surface, leaving a drop containing parasites. The parasite penetrates the broken skin when the presumptive host scratches or rubs the deposited fecal matter into the site of the insect bite, or when fecal matter is transferred by fingers onto the corneal surface of the eye or mucous membranes. Inflammation develops at the portal of entry of the trypanosomes, producing a nodule (chagoma), and causing swelling of proximal lymph nodes. Initially in the bloodstream of the host, the parasite enters macrophages and other cell types, in which replication occurs. Pseudocysts filled with trypanosomes can be found in muscle tissue. Upon lysis of the infected host cell, new cells are attacked, with some parasites entering the bloodstream, where they are acquired by the bug when it takes a blood meal. The disease can also be passed by transplacental infection or through breast-feeding, though data to distinguish this route from intrauterine transmission are not available. Blood transfusions are another source of infection in endemic areas where the blood supply is not monitored for trypanosomes.

Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis Chagas’ disease in childhood can arise either as a result of congenital infection or after being bitten by the insect vector. Intrauterine Chagas’ disease occurs in 2% to 4% of infants born to mothers who have acute or chronic infection with T. cruzi [Lowichik and Ruff, 1995a]. Such infants are usually born prematurely and are small for gestational age. Systemic symptoms are similar to other intrauterine infections and include jaundice, hepatosplenomegaly, edema, petechiae, and dysrhythmias. When meningoencephalitis is present, seizures, hypotonia, and a weak suck are characteristically present [Bittencourt, 1976]. Almost half the infants who

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acquire infection in utero die by age 4 months. Unilateral orbital edema is frequently present and characteristic of the disease. Lymphadenopathy, vomiting, diarrhea, and cardiac symptoms suggestive of myocarditis and dysrythmias may be present. Signs of a generalized encephalopathy with meningeal irritation and, occasionally, seizures may occur. After a latent period, more chronic forms of Chagas’ disease develop, manifested by cardiovascular (cardiomyopathy) and gastrointestinal (megaesophagus and megacolon) involvement. Without treatment, infection with T. cruzi is lifelong. The disease is fulminant in children younger than 5 years but chronic in adults. Neuropathologic characteristics include leptomeningeal mononuclear infiltration, cerebral edema, and other abnormalities similar to those present in African trypanosomiasis [Pentreath, 1995; Pitella, 1993]. Parasitic nodules may be evident throughout the brain and spinal cord. T. cruzi can be isolated from cerebrospinal fluid in up to 75% of adult Chagas’ patients, but there is no evidence of overt CNS clinical symptoms [Cegielski and Durack, 1997]. Rarely, a fulminant meningoencephalitis will occur and be fatal. In a series of 11 children with CNS infection from Chagas’ disease, T. cruzi was isolated from the spinal fluid in 8 [Hoff et al., 1978]. Spasticity, mental deficiency, and cerebellar symptoms are sequelae of meningoencephalitis. Peripheral neuropathy is observed in chronic American trypanosomiasis. Stroke may complicate chronic cardiomyopathy [Spina-Franca, 1996]. The scarcity of parasites in the host and the severe nature of the disease have led to the suggestion that the pathology of the disease may be due to an autoimmune response caused by cross-reactivity between human antigens and T. cruzi [Brener, 1994]. The diagnosis of Chagas’ disease is made by culture, direct microscopy, or histologic detection of T. cruzi in the blood, cerebrospinal fluid, or tissue obtained from brain biopsy. Serology is useful for diagnosis of neonatal Chagas’ disease, but can also be misleading due to the presence of maternal antibodies in circulation. Positive serology in the absence of parasitemia and symptoms is probably due to antibody cross-reactivity. Cerebrospinal fluid reveals a monocytic pleocytosis with protein elevation. Neuroimaging studies may reveal nonspecific ring-enhancing lesions seen with many CNS infections [Leiguarda et al., 1990]. No EEG abnormalities were seen in children with Chagas’ disease, although temporary irregularities appeared [Moya, 1994]. Sequence data on the T. cruzi genome are now available, which may lead to future attempts at intervention at specific genic targets [El-Sayed et al., 2005b].

Resistance to the basic drug therapy is a concern, and there is interest in finding or developing new drugs that are effective in treatment of Chagas’ disease. Itraconazole [McCabe et al., 1986] and ketoconazole [McCabe et al., 1987] were effective against T. cruzi in a mouse model of disease, but no trials have been conducted in humans. Ketoconazole combined with benznidazole demonstrated synergism when tested in the mouse model, but different strains of parasites exhibited variability in response to the drugs [Araújo et al., 2000]. Miltefosine (hexadecylphosphocholine), a phospholipid analog and anticancer drug that has been used with success in treatment of visceral leishmaniasis [Sundar et al., 2002], has been tested in vitro against intracellular stages of T. cruzi and has promise as an antimicrobial [Croft et al., 2003; de Castro et al., 2004]. Alkylphosphocholines, including miltefosine, in combination with ketoconazole, had in vitro activity against T. cruzi [Lira et al., 2001].

African Sleeping Sickness Epidemiology, Microbiology, and Pathology Bruce and Nabarro [1903] reported the trypanosomal etiology of African sleeping sickness and its tsetse fly vector. Trypanosoma brucei gambiense is often the organism isolated in patients from western and central Africa (Fig. 70-18). Trypanosoma brucei rhodesiense infections occur in eastern and southern Africa. In the 1960s, the disease was kept in

Management The intracellular location of the parasite protects it from most drug therapy. Nifurtimox (for 1 to 10 yrs: 15 to 20 mg/kg/day in four doses for 90 days), available through the CDC, is used for the treatment of Chagas’ disease [Medical Letter, 2004]. Benznidazole (for ages up to 12 years, 10 mg/kg/day in two doses for 30 to 90 days) is an alternative drug [Medical Letter, 2004]. Nifurtimox has been associated with a higher risk of chromosomal abnormalities, suggesting that alternative medications might be better. Allopurinol has been found to be as effective as nifurtimox or benznidazole in treating T. cruzi infection at a dose of 300 mg two or three times a day for 60 days [Gallerano et al., 1990].

FIGURE 70-18. Trypanosoma gambiense in peripheral blood. (Leishman stain)

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check through surveillance and insect control. The past several decades in Africa have witnessed civil strife, population shifts, development of disease-resistant trypanosomes, and inadequate funding of programs to control trypanosomiasis, with a resultant resurgence of the disease. Large areas of Africa have been rendered unsuitable for raising and grazing cattle because of the risk of sleeping sickness in domestic stock. The reservoir consists of wild game; tsetse flies (Glossina spp.) are the vectors. Once infected, the tsetse fly remains a vector of parasites for its entire life. After the host is bitten by an infected fly, the trypanosomes traverse the lymphatic pathways to regional lymph nodes, where they reproduce, multiply, and subsequently enter the bloodstream. Splenomegaly follows accumulation of the trypanosomes within the splenic parenchyma. Pancarditis frequently occurs. Impairment of the nervous system is the result of leptomeningitis, usually centered over the vertex. The World Health Organization estimates that about 20 to 30 cases of Gambian sleeping sickness are diagnosed annually outside of Africa [Lejon et al., 2003a]. With increasing tourism to trypanosome-endemic regions of Africa, there is a greater likelihood that physicians outside of these areas will be seeing cases of sleeping sickness. Of the two types of sleeping sickness, the Gambian form, because it can develop as a chronic disease, is more likely to be encountered than the fulminant Rhodesian form [Lejon et al., 2003a]. The disease in humans has been reviewed by Kennedy [2004] and Pentreath [1995]. Dural thickening and adhesion to surrounding structures are often present at postmortem examination. Cerebral edema and petechiae are readily seen in most fatal cases. The perivascular infiltrate in the gray and white matter is delineated so clearly that it has been called a gray sleeve. Obstruction of cerebrospinal fluid flow may lead to ventricular dilation. Cerebral and cerebellar atrophy may occur in the late stages of the disease. The spinal cord remains unaffected. A mononuclear infiltrate is seen in the meninges and Virchow-Robin spaces during microscopic examination. Lymphocytes are more numerous than plasma cells. Endothelial proliferation of the capillaries may be present. The characteristic morular cell, a plasma cell with immunoglobulin M–containing inclusions (Russell bodies), was first reported by Mott [1906]. Differentiating the neuropathologic changes in African sleeping sickness from Chagas’ disease is relatively impossible. Endemic geographic areas of the diseases do not overlap, which is helpful in distinguishing between the two types of trypanosomiasis. Tryptophol, the 3-indole ethanol formed by the parasite in trypanosomal sleeping sickness, produces the characteristic sleep [Cornford et al., 1979; Feldstein, 1973; Stibbs and Seed, 1973a; 1973b]. Because tryptophol also gains access to lymphoid tissues, such as spleen, thymus, and mesenteric lymph nodes, it may foster immunosuppression in sleeping sickness [Ackerman and Seed, 1976]. The trypanosome induces formation of antibodies to antigens on its surface called variable surface glycoproteins. The variable surface glycoproteins are under genic control and generate antigenic variation by activation and expression of a succession of variable surface glycoprotein genes—of which there are about 1000 in a genome containing 10,000 genes [Donelson, 2003]. Thus, host antibodies aimed at one set of surface antigens are soon rendered ineffectual by selection of blood-

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stream forms exhibiting newly synthesized surface glycoproteins. The recurring appearance in the bloodstream of trypanosomes with new surface antigens gives rise to periodic fluctuations in parasitemia. Development of a mechanism to modify or terminate this process appears necessary before control or eradication of this disease is feasible [Donelson and Turner, 1985]. Given the immunologic evasion conferred by antigenic switching, the availability of a vaccine in the near future appears unlikely. The trypanosome genome and, in particular, the phenomenon of antigenic variation has been reviewed by Donelson [2003]. Comparative information on trypanosomatid genomes is now available [El-Sayed et al., 2005a], as are sequence data on the T. brucei genome [Berriman et al., 2005].

Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis Mid-African sleeping sickness results from infection by T. brucei gambiense and is a less severe but more chronic illness than Rhodesian sleeping sickness. A furuncle or chancre may appear at the site of the fly bite, followed by fever of about 1 week’s duration and a rash [Lejon et al., 2003a]. Regional lymphadenitis follows the bite and is the dominant feature for approximately 14 days. Fever, malaise, headache, arthralgia, erythematous and edematous cutaneous eruption, and generalized lymphadenopathy, particularly in the posterior cervical nodes (Winterbottom’s sign), compose the next stage, which persists for a week to a month. In the CNS, the disease progresses insidiously from meningitis to encephalopathy through sequential stages including inflammation and cellular infiltration, alteration of EEG patterns, edema, breakdown of the blood-brain barrier, and stimulation of cytokine production [Pentreath, 1995]. Disseminated intravascular coagulation may be a consequence of complement activation by immune complexes. Production of interferon-γ and tumor necrosis factor-α contributes to the overall inflammatory response in the CNS. Autoimmunity may develop, more likely as a consequence of late-stage neuropathology. Although acute rheumatoid arthritis and rheumatic fever are included in the differential diagnosis, they are readily excluded after appearance of manifestations of nervous system impairment, including confusion, somnolence, memory loss, ataxia, and loss of sphincter control. T. brucei rhodesiense infection causes East African sleeping sickness. The clinical course may be similar to Gambian trypanosomiasis or may appear as a fulminating infection that, if untreated, causes death within 6 to 9 months. Pancarditis with massive pericardial effusion often occurs, with death occurring before neurologic symptomatology appears. Criteria for diagnosis of trypanosomiasis are the presence of flagellates in the cerebrospinal fluid, elevated cerebrospinal fluid leukocyte levels (5 to 20/μL), and the presence of intrathecal immunoglobulin M as shown by the card agglutination trypanosomiasis test [Lejon et al., 2003b; Truc et al., 2002]. The elevated leukocyte count and the increase of intrathecal immunoglobulin M (as much as a 40-fold rise in late-stage trypanosomiasis) are taken as evidence of an intrathecal inflammatory process [Lejon et al., 2003a; 2003b]. Increase in cerebrospinal fluid protein (≥750 mg/L [≥75 μg/dL]) is a reflection of the elevated immunoglobulin

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levels [Lejon et al., 2003b]. The diagnostic profile for trypanosomiasis can mimic syphilis, tuberculosis, toxoplasmosis, borreliosis with neural involvement, and mumps meningoencephalitis [Lejon et al., 2003b]. Supporting evidence of infection includes irregular EEG patterns, and nonspecific CNS abnormalities seen by MRI and CT scans [Kennedy, 2004]. Demonstration of trypanosomes in thick and thin smears of peripheral blood remains the diagnostic gold standard, but parasites are less likely to be found in Gambian disease or in early stages of infection. The polymerase chain reaction has been used to detect trypanosomal DNA in cerebrospinal fluid. Diagnostic evidence of the parasite in the peripheral blood or cerebrospinal fluid is definitive. Spinal fluid pleocytosis and increased protein concentration are usually present but nonspecific. A sensitive and specific study results from inoculation of the patient’s blood into a mouse with subsequent demonstration of the organisms in the mouse’s blood. Blood stages of the trypanosomes can be cultured in a biphasic medium (blood-nutrient agar slant with an overlay of glucosecontaining Locke’s solution) [Tobie et al., 1950] but is best carried out in a reference laboratory. Serum immunoglobulin M content is increased greatly and, as noted above, is the basis for diagnostic testing [Lejon et al., 2003b]. The use of precipitin testing provides diagnostic proof (see Table 70-2), although complement fixation studies are reasonably reliable.

Management Staging of the disease, either early or late, is critical because the type of therapy employed depends on whether the trypanosomes have invaded the CNS. Staging is determined by a lumbar puncture. Use of inappropriate therapy in latestage disease can lead to relapse. Cerebrospinal fluid leukocyte counts of greater than 20/μL and high levels of immunoglobulin M (up to 100 times normal) are indicative of CNS disease [Lejon et al., 2003]. Suramin (or alternatively, pentamidine) is recommended for patients presenting before the development of CNS disease, although drug resistance is reported to both these agents. Both drugs penetrate poorly across the blood-brain barrier into the CNS, making them ineffective in late-stage disease, and both have serious side effects. The following drugs and dosages are recommended for pediatric patients: for suramin, 20 mg/kg on days 1, 3, 7, 14, and 21; for pentamidine, 4 mg/kg/day intramuscularly for 10 days [Medical Letter, 2004]. Pentamidine is reportedly less effective in treating Rhodesian than Gambian disease [Fairlamb, 2003]. A more recent alternative that is apparently less toxic and perhaps more effective is difluoromethylornithine (eflornithine) for both early- and late-stage disease [Doua and Boa Yapo, 1994; Fairlamb, 2003]. Difluoromethylornithine is not available in the United States but can be obtained through the World Health Organization [Medical Letter, 2004]. Recommended dosage is 400 mg/ kg/day intravenously in four divided doses for 14 days [Fairlamb, 2003; Medical Letter, 2004]. Difluoromethylornithine is effective against the Gambian but not the Rhodesian forms of the disease. Synergy has been found in combining suramin with eflornithine [Fairlamb, 2003]. In late stages of the disease, melarsoprol is recommended and is administered intravenously (for pediatric patients, initial dose of 0.36 mg/kg, increasing to maximum of 3.6 mg/kg at

intervals of 1 to 5 days for a total of 9 or 10 doses; for a total of 18 to 25 mg/kg over 1 month) [Medical Letter, 2004]. The drug can cross the blood-brain barrier. However, this agent is recognized to have serious toxicity, including seizures, psychosis, coma, and a fatal encephalopathy associated with increased intracranial pressure [Haller et al., 1986]. The drug is effective against both forms of trypanosomiasis. Mortality after melarsoprol use, however, is about 50%. Administration of corticosteroids (prednisolone) can lessen the likelihood of post-treatment sequelae and prevent arsenical encephalopathy [Pepin et al., 1995]. The clinician must be aware of the side effects of these drugs before therapy is initiated, and gradual increase in dosage is advised [Medical Letter, 2004; Seidel, 1985]. Nifurtimox, used in treating Chagas’ disease, has also been used in latestage disease, when other late-stage antimicrobials are ineffective. Antimicrobial therapy for trypanosomiasis has been reviewed by Burchmore and co-workers [2002] and Fairlamb [2003].

HELMINTHS The helminths include a broad range of organisms and are typically grouped into three categories: nematodes, cestodes, and trematodes. The helminths are generally larger than other parasites, and many are large enough to be visible to the human eye. They are extracellular parasites, and the host response is dominated by mechanisms aimed at extracellular parasites and often results in eosinophilia. Most helminths have complex life cycles with multiple hosts. The definitive host is the host in which the sexual reproduction of the parasites takes place. The intermediate host is typically one in which there is no reproduction of the parasite. In many cases, humans are an accidental or “dead end” host and not part of the parasite life cycle. Nematodes are cylindrical and nonsegmented worms. Trichinella, Angiostrongylus, and Toxocara are genera in this class that infect the CNS. Cestodes that infect humans belong to the subclass Eucestoda, the true tapeworms. These endoparasites have no epidermis or digestive tract and elongated segmented bodies. Adults have a multihook organ of attachment at the anterior end, which is called the scolex. Genera of cestodes associated with CNS infection include Dibothriocephalus (Diphyllobothrium), Taenia, Multiceps, and Echinococcus. Trematodes (flukes) are nonsegmented worms that possess a digestive tract. Trematodes infecting the nervous system include the genera Schistosoma and Paragonimus. Many helminth parasites of animals are potential causes of larva migrans. Larva migrans refers to the prolonged migration and persistence of helminth larvae in the tissues of humans [Beaver 1969, Kazacos 2001]. Larva migrans can be separated pathologically and clinically into visceral, ocular, neural, and cutaneous larva migrans based on the organ systems involved [Kazacos 2001]. Visceral larva migrans and neural larva migrans are usually diseases of childhood, affecting children 1 to 8 years old. These include various ascarids, hookworms, gnathostomiasis, Angiostrongylus cantonensis, Spirometra, Alaria, and others. Of these, the ascarids are the most important group with Toxocara and Baylisascaris accounting for the majority of cases in humans.

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Toxocariasis Epidemiology, Microbiology, and Pathology Toxocariasis results from infection with the ascarid worm, Toxocara, and is widely distributed throughout the world. Toxocariasis was first described in 1921 in a patient with eosinophilia, dyspnea, and cyanosis [Aubertin and Giroux, 1921]. Central nervous system involvement with Toxocara was demonstrated in later case reports [Beautyman et al., 1965; Dent et al., 1956]. Toxocara canis and Toxocara cati are common ascarid infections of dogs and cats, respectively, and are found worldwide. The prevalence of T. canis shedding is highest in puppies, and more than 90% of dogs less than 6 months in North America shed Toxocara eggs in their stool [Kazacos, 1991]. As dogs mature, the shedding of eggs decreases. Cats shed Toxocara cati, and the prevalence may be as high as 75% in kittens [Schantz and Glickman, 1981]. Infected animals can shed millions of eggs per day. Toxocara eggs are able to survive for long periods, especially in warm and humid environments, and extensive contamination of the environment can occur. Up to 30% of soil samples are contaminated with Toxocara eggs [Arpino et al., 1990]. Toxocara infects humans, primarily children, through the ingestion of soil contaminated with eggs. Young children may come into contact with eggs while playing on playgrounds and sandboxes contaminated by dogs and cats. Infected children often have a history of pica and many children with toxocariasis have had a dog in their household within 1 year of illness [Huang and Schantz, 2004]. Once eggs are ingested, larvae hatch in the small intestine, penetrate the mucosa, then migrate through many organs and tissues. The liver is a common site of involvement. Because humans are an aberrant host, Toxocara spp. do not complete their life cycle beyond the second-stage larvae. Seroprevalence studies have found varying rates of seropositivity: 83% in Saint Lucia, 51% in Taiwan, 6.4% in the United States, and 3.6% in Japan [Schantz, 1989].

Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis Most infections with Toxocara are asymptomatic. Symptomatic individuals often have features of visceral larva migrans, such as fever, hepatomegaly, cough, and wheezing. Splenomegaly and lymphadenopathy may also occur. Neurologic involvement is relatively uncommon. Meningoencephalitis, encephalopathy, transverse myelitis, focal mass lesions, psychiatric disturbances, seizures, and arachnoiditis have all been described [Mikhael et al., 1974; Bachli et al., 2004]. Fatalities from the infection have been described but are rare [Schochet, 1967]. Infection of the eye generally occurs in children 8 years and older and is usually unilateral. Patients often present with visual loss, strabismus, or eye pain. The larvae can cause endophthalmitis with retinal detachment, posterior and peripheral retinochoroiditis, optic papillitis and uveitis [Hotez, 1993; Molk, 1983; Shields, 1984]. Multiple studies have documented an association between seizure disorders and Toxocara antibodies, but a causal relationship has not been well established [Arpino et al., 1990; Glickman et al., 1979; Woodruff et al., 1966]. Similarly, behavioral disorders and declines of cognitive

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ability have been correlated with Toxocara seropositivity but the significance is unclear [Marmor et al., 1987; Worley et al., 1984]. Laboratory features of infection often include eosinophilia, leukocytosis, anemia, elevated sedimentation rate, and hypergammaglobulinemia. The diagnosis is usually suggested by the patient’s age, as well as clinical and laboratory features. Definitive diagnosis can be made when larvae are identified in affected tissue, but this has a low diagnostic yield. An enzyme-linked immunosorbent assay, available at the CDC, has a reported specificity of over 90% and can be used as supportive evidence of infection [Wilson, 2002]. Neuroimaging findings are variable. Hyperintense lesions in white matter with basilar enhancement, and ring-enhancing lesions have been described. [Bachli, 2004; Duprez, 1996; Ruttinger et al., 1991; Sommer and Hadidi, 1994]. One case report describes more than 25 lesions located in the cortical and subcortical regions with a hyperintense appearance on T2-weighted images [Ruttinger and Hadidi, 1991]. Neuropathology may reveal perivascular cuffing in the white matter, leptomeningeal inflammation, eosinophilic granulomas, or vasculitic lesions [Beautyman et al., 1965; Dent et al., 1956; Hill et al., 1985; Moore, 1962].

Management Most patients recover without specific treatment. There is no proven therapy, especially for CNS disease, but anthelmintic and anti-inflammatory medications should be considered in cases with serious complications. Albendazole (400 mg twice a day for 5 days) or mebendazole (100 to 200 mg twice day for 5 days) is the recommended therapy [Medical Letter, 2004], but optimal duration is unknown.

Baylisascaris Procyonis Infection Epidemiology, Microbiology, and Pathology Baylisascaris procyonis is a roundworm of raccoons and causes a rapidly fatal eosinophilic encephalitis in humans. Raccoons are the definitive host, and humans are considered an accidental intermediate host. B. procyonis infection in raccoons, like Ascaris lumbricoides infection in humans or any ascarid infection in its respective natural definitive host, is usually asymptomatic. B. procyonis occurs in raccoons in North America, Europe, and parts of Asia [Kazacos, 2001]. The prevalence of B. procyonis in raccoons is highest in the midwestern and northeastern United States, where more than 90% of juvenile raccoons are infected [Kazacos and Boyce, 1989]. The eggs become infectious for humans and other animals about 3 to 4 weeks after they are shed by the raccoon. Humans become infected by ingesting raccoon roundworm eggs in raccoon feces, by soil or water contaminated with raccoon feces, or via contaminated hands. Small children are particularly vulnerable to infection because of their propensity to put dirt and other objects in their mouth. Once swallowed, eggs hatch into larvae, then migrate through the liver, brain, spinal cord, and other organs. Larvae are found in tissues throughout the intermediate host but cause the most damage in the CNS and eye. The combination of marked larval growth and aggressive somatic migration make Baylisascaris more pathogenic than Toxocara infection in humans.

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Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis B. procyonis infection in humans was first recognized in a 10-month-old boy with eosinophilic meningoencephalitis in 1984 [Huff et al., 1984]. Many case reports have followed [Cunningham et al., 1994; Moertel et al., 2001; Park et al., 2000]. Infected humans may have classical visceral larva migrans with fever, leukocytosis, eosinophilia, hepatomegaly, and pneumonitis. If larvae reach the CNS, they produce damage and inflammation, resulting in progressive CNS disease, and the severity is often dose related [Kazacos et al., 2001]. Presenting CNS symptoms include lethargy, irritability, loss of muscle coordination, ataxia, nystagmus, loss of spontaneous movement, extensor rigidity, and ultimately result in coma and death [Fox et al., 1985; Moertel et al., 2001; Park et al., 2000]. Ocular larva migrans usually involves children seven years of age and older, with no history of pica and without marked eosinophilia. Ocular larva migrans is usually a result of an infection with a few larvae followed by chance migration [Kazacos, 1985]. The diagnosis of neural larva migrans is often suggested by a history of exposure to raccoons (or their feces) and clinical presentation. Laboratory findings of persistent eosinophilia in the blood and spinal fluid are important. Early in the course of illness neuroradiologic studies may document periventricular white matter disease. Atrophy occurs in later stages of illness [Rowley, 2000] (Fig. 70-19).

Larvae can sometimes be recovered from tissues or visualized in histopathology or biopsy. On pathology, larvae are generally surrounded by epithelial granulomas with a variable number of eosinophils, plasma cells, and lymphocytes. In ocular larva migrans, migrational tracks or live larvae are sometimes observed by funduscopic examination. Serologic testing is available in a limited number of laboratories throughout the world [Boyce et al., 1989].

Management There is no known effective treatment for neurologic involvement of Baylisascaris. Treatment with antiparasitic agents and steroids has been attempted but with only marginal success [Cunningham et al., 1994; Park et al., 2000].

Trichinosis Epidemiology, Microbiology, and Pathology Trichinosis develops when raw or undercooked meat contaminated with Trichinella spp. larvae is ingested. Trichinella spp. are widely distributed throughout the world and occur in a large number of carnivorous animals. Humans are incidental hosts. Most human infections involve Trichinella spiralis, which is often associated with pork, but there are many other species of Trichinella that can infect humans. These other species have been found in many other mammals, including horses, bears, foxes, hyenas, felines, and even whales. The incidence of trichinosis is highest in the Balkans, Russia, China, Argentina, and the Baltic Republics [Dupouy-Camet, 2000]. In the United States, the national trichinellosis surveillance system has documented a steady decline in the reported incidence of this disease. From 1947 to 1951, a median of 393 cases (range 327 to 487) was reported annually, including 57 trichinellosisrelated deaths [CDC, 2003]. From 1997 to 2001, the incidence decreased to a median of 12 cases annually (range 11 to 23), with no reported deaths. Although the United States has had a steady decline in cases, some European countries have had a re-emergence of the disease in the past 25 years. Infected horsemeat, rather than pork, was responsible for at least 3000 human cases in Italy and France [Dupouy-Camet, 2000].

Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis

FIGURE 70-19. Magnetic resonance image (axial T2 image) showing abnormal hyperintensity in the periventricular white matter 12 days after presentation of a child with Baylisascaris meningoencephalitis. (Courtesy Dr. Howard Rowley.)

Clinical symptoms are usually biphasic. After ingestion of the encysted larvae, gastroenteritis of varying severity ensues within 5 to 15 days. Larvae develop into adult worms within the small intestine and ultimately release motile larvae that gain access to the bloodstream. From the bloodstream, larvae seed the skeletal musculature. The second phase of symptoms begins about 1 to 2 weeks after infection and is characterized by muscle invasion and prominent facial and periorbital or facial edema, fever, conjunctivitis, subconjunctival hemorrhages, eosinophilia, and myalgias. High fevers are often seen during larval tissue migration. Myalgias and myositis are usually most severe 2 to 3 weeks after infection. The most common muscles affected are the extraocular, masseters, and diaphragmatic muscles. Severe

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complications of trichinosis include myocarditis, pneumonitis, and encephalitis. Neurotrichinosis occurs in only a small proportion of cases and during the late phase of illness. Meningoencephalitis is the most common manifestation. A variety of neurologic presentations have been reported, including confusion, memory loss, psychosis, flaccid monoparesis, urinary retention, cranial nerve deficits, and cerebellar ataxia [Ellrodt et al., 1987; Kreel et al., 1988; Mawhorter and Kazura, 1993]. A syndrome including both encephalopathy and acute myocardial injury has also been described [Fourestie et al., 1993] The diagnosis of acute infection is based on a combination of the history, clinical features, and laboratory findings. Eosinophilia, the most common laboratory abnormality, usually peaks at 3 to 4 weeks after infection and may range from 10% to 90% [Markell et al., 1992]. Leukocytosis and elevated immunoglobulin E are also common signs of infection. Enzyme-linked immunosorbent assay or indirect fluorescent antibody can be used for antibody detection; however, antibody levels are often not detectable for 3 to 5 weeks after infection [Wilson et al., 2002]. Molecular tests and antigen testing have been developed but are not widely available [Huang et al., 2004; Taratuto and Venturiello, 1997b]. Skin testing is unreliable. Muscle biopsy demonstrates an inflammatory myositis. The T. spiralis larvae are surrounded by inflammatory mononuclear, polymorphonuclear, and eosinophilic cells. Granuloma and capsule formation with encystment of the larvae develop over several months [Taratuto and Venturiello, 1997b]. In patients with CNS involvement, cerebrospinal fluid studies may indicate pleocytosis and eosinophilia or even the presence of larvae. Cerebrospinal fluid eosinophilia or larvae are found in 8% to 28% of cases [Huang et al., 2004]. Electroencephalographic studies reflect changes expected with a diffuse encephalopathy [Ryczak et al., 1987]. If vascular involvement occurs, subacute cortical infarcts may be found on CT and MRI [Feydy et al., 1996; Fourestie et al., 1993]. CT or MRI studies may show small contrastenhancing nodular lesions and focal calcifications [Ellrodt et al., 1987; Fourestie et al., 1993]. Neuropathology has found cortical vein thrombosis, granulomas, brain edema, and hyperemia of the meninges in these cases [Ellrodt et al., 1987; Gay et al., 1982]. Limited effective treatment is available for trichinosis. Mebendazole (200 to 400 mg three times a day for 3 days then 400 to 500 mg three times a day for 10 days) or albendazole (400 mg twice a day for 8 to 14 days) has been recommended. Corticosteroids may be helpful in reducing the risk of hypersensitivity reactions resulting from the dying parasites or the development of cerebral edema, myocarditis, or cerebritis [Ellrodt et al., 1987; Ryczak et al., 1987].

Angiostrongylus Infection Epidemiology, Microbiology, and Pathology Angiostrongylus cantonensis, the rat lungworm, is the principal cause of human eosinophilic meningitis worldwide. Human A. cantonensis was first reported in 1945 in a fatal case of eosinophilic meningitis [Beaver and Rosen, 1964]. Rodents are the definitive host of the parasite and mollusks

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are the intermediate host. Humans are the incidental host and become infected by ingestion of the third-stage larvae in the molluscan intermediate host (e.g., snails, crabs, freshwater prawns) or contaminated vegetables. After humans ingest infective larvae in undercooked or raw snails, the larvae penetrate the intestinal wall and reach the CNS via the bloodstream. The infection in humans often occurs in warm climates and is well known to occur in Southeast Asia, the South Pacific, and Taiwan [Kliks and Palumbo, 1992; Punyagupta et al., 1975; Yii et al., 1975]. In some regions of the world, children are most commonly affected; in Taiwan, for example, 80% of Angiostrongylus cases are in the pediatric age group [Chen, 1991]. Other areas include Africa, Polynesia, and eastern Australia [Prociv et al., 2000]. In the United States, Angiostrongylus has occurred in Hawaii and Louisiana. Other countries of the Western Hemisphere cases include Puerto Rico, Cuba, Jamaica, and the Dominican Republic. Rats on cargo ships are the principal mode of expansion of the parasite beyond the Indo-Pacific area [Kliks and Palumbo, 1992].

Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis The onset of CNS symptoms occurs 1 to 35 days after ingestion of the infective larvae [Huang et al., 2004]. Clinical illness often consists of severe headache, photophobia, meningeal signs, hyperesthesia, and paresthesia. The presence, height, and duration of fever vary. Whereas most cases are self-limiting, severe forms of the disease occur, including coma, paralysis of extremities, and seizures [Fuller, 1993; Kuberski and Wallace, 1979; Yii et al., 1975]. Conjunctivitis, periorbital swelling, retinal hemorrhage, retinal detachment, or blindness may occur if the eye is infected [Punyagupta et al., 1975; Toma et al., 2002]. In most cases recovery occurs approximately 4 weeks after onset but may take several months. In some cases involving very young children, progressive deterioration of CNS function has been described [Cooke-Yarbourough et al., 1999; Lindo et al., 2004]. The severity of the disease is often related to the number of larvae ingested. Deaths are uncommon but have been reported [Lindo et al., 2004]. The diagnosis is often suggested by the exposure history and clinical and laboratory features. Eosinophilic pleocytosis is very common. Peripheral eosinophilia and elevated immunoglobulin E levels may also be seen. The eosinophilia may persist for months [Jindrak, 1975]. The larvae can occasionally be visualized in the cerebrospinal fluid [Hwang and Chen, 1991]. An enzyme-linked immunosorbent assay test has been developed but is not widely available [Cross and Chi, 1982; Intapan et al., 2002]. Molecular tests are under development [Chye et al., 2004]. CT scans of the brain may show areas of attenuation with surrounding hypodense areas [Ko et al., 1987]. Meningeal enhancement and high signal intensity at the subcortical white matter on T2-weighted images may also be seen [Tsai et al., 2004]. In humans, postmortem examination has found infiltration of the meninges and around intracerebral vessels of lymphocytes, eosinophils, and plasma cells [Sonakul, 1978]. Small worm tracks (0.1 to 2.0 mm in size), with

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and without hemorrhage, are also seen [Kanpittaya et al., 2000; Sonakul, 1978]. Live larvae are sometimes seen, and tissues around them typically have little or no reaction. In contrast, dead worms are surrounded by a zone of suppurative necrosis or granuloma [Jindrak, 1975; Sonakul, 1978].

Management Treatment with anthelmintics has been attempted, but efficacy is questionable and may even worsen symptoms. Sequential lumbar punctures, steroids, and analgesics have been reported to improve symptoms [Chotmongkol et al., 2000; Tsai et al., 2004].

Gnathostomiasis Epidemiology, Microbiology, and Pathology Gnathostomiasis, most commonly caused by the nematode Gnathostoma spinigerum, is the cause of eosinophilic myeloencephalitis. Most cases are associated with the ingestion of raw or undercooked fish, frogs, snakes, chickens, or ducks. The disease is commonly reported from Southeast Asia, particularly Thailand and Japan, because of dietary habits in those countries. Gnathostomosis is an emerging public health problem in Peru, Ecuador, and most recently in Mexico [Pelaez and Perez-Reyes, 1970]. The consumption of cerviche is responsible for many of the cases seen in South America. The median time from ingestion of infected food to onset of symptoms may be several weeks to several months [Ogata et al., 1998].

Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis If the larva migrates to vital organs of the host, severe illness or death can occur [Rusnak and Lucey, 1993]. Common symptoms include intermittent episodes of cutaneous larva migrans (“creeping eruption”) with localized pain and pruritus. These lesions may recur for several years [Ogata, 1998]. Visceral symptoms occur if larvae migrate to deep tissues. CNS involvement is rare and occurs more frequently in adults but occasional cases occur in older children. CNS findings include the sudden onset of radicular pain or headache. Paralysis of the extremities and loss of bladder control typically follows [Boongird et al., 1977]. Cranial nerve abnormalities may also occur. Acute eosinophilic meningitis and encephalitis are also described [Chitanondh and Rosen, 1967]. Intermittent symptoms can occur for 10 to 15 years because the larvae are long-lived [Huang et al., 2004]. Deaths are usually due to direct involvement of the brainstem or secondary complications of pneumonia or sepsis [Boongrid et al., 1977]. Ocular involvement can result in iris holes, anterior uveitis, and subretinal hemorrhages [Biswas et al., 1994]. Definitive diagnosis is made when the worm is identified in biopsies of tissue, especially the skin. Patients with gnathostomiasis will often have pronounced eosinophilia, with values exceeding 50% of the total white blood count [Rusnak and Lucey, 1993]. In cases with CNS involvement, spinal fluid analysis shows eosinophilic pleocytosis and

normal to increased protein. Grossly bloody spinal fluid is common secondary to hemorrhage [Punyagupta, 1975]. CT scans may demonstrate subarachnoid or intracerebral hemorrhage. If there is ocular involvement, worms can sometimes be visualized by a routine eye examination [BaqueraHeredia et al., 2002]. An enzyme-linked immunosorbent assay test has been developed but is not widely available [Tapchaisri et al., 1991].

Management Treatment recommendations include albendazole (400 mg twice a day for 21 days) or ivermectin (0.2 mg/kg for 2 days) for dermal and subcutaneous gnathostomiasis [Nontasut et al., 2000]. Similar treatment is generally recommended for CNS disease, although data on efficacy are limited. Surgical removal is often needed if larvae are identified in the eye [Biswas et al., 1994; Funata et al., 1993].

CESTODES Diphyllobothriasis Epidemiology, Microbiology, and Pathology Diphyllobothrium latum, the fish tapeworm, is found throughout the world and causes a public health problem in many regions of the temperate and subarctic zones in the Northern Hemisphere. Megaloblastic anemia and neurologic illness in humans are the result of vitamin B12 deficiency caused by the tapeworm; optic atrophy and subacute combined degeneration of the spinal cord result [Bjorkenheim, 1966; Nyberg, 1963]. Fish tapeworm infestation can be prevented by thorough cooking of all freshwater fish. Freezing at 10° C for 48 hours is also recommended to kill the organism before ingestion. Diphyllobothriasis can be treated with niclosamide (single dose of 50 mg/kg) or praziquantel (single dose of 5-10 mg/kg).

Echinococcosis Epidemiology, Microbiology, and Pathology Echinococcosis, commonly referred to as hydatid disease, has a worldwide distribution and is a major public health problem. The term hydatid refers to the fluid-filled larval stage found in the intermediate host. These bladder-like cysts, particularly in the liver, were well known in ancient times, as noted by Hippocrates as early as the 4th century BC [Cox, 2002]. The two major species of Echinococcus that are of public health and medical importance are Echinococcus granulosus and Echinococcus multilocularis. E. granulosus disease is characterized by cystic lesions found primarily in the liver and lungs and is known as cystic hydatid disease. E. multilocularis disease is less common but is a more malignant form than that caused by E granulosus. E. multilocularis is characterized by tumor-like collections of vesicular parasites found primarily in the liver and is known as alveolar hydatid disease. Canines are the definitive host, and sheep are the most common intermediate host for E. granulosus. Dogs and other canids are the hosts to the adult tapeworm. When dogs pass

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eggs in their stool, sheep and other animals become infected when they ingest the eggs. After ingestion, eggs hatch in the intestine, penetrate the intestinal wall, and migrate to tissues. Humans become an inadvertent intermediate host by ingestion of food or water contaminated with feces from infected dogs. Direct contact with an infected dog may also lead to infection since Echinoccocus eggs can adhere to the dog’s fur [Eckert and Deplaze, 2004]. A similar life cycle occurs with E. multilocularis; foxes and wolves are the common definitive hosts, and rodents generally serve as the intermediate host. E. granulosus is found on all continents, and its distribution is related to sheep and cattle herding. It is particularly prevalent in the Mediterranean, Middle East, and northern and eastern regions of Africa, parts of Russia, China, Australia, and countries in South America [Eckert and Deplaze, 2004]. E. multilocularis is found mostly in alpine or artic regions in the Northern Hemisphere, including Central Europe, Russia, China, and North America.

Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis The clinical manifestations of hydatid disease are dependent on the number, size, and developmental stage of the parasite. During the initial stage of the infection humans are asymptomatic. The disease is often acquired in childhood, with latency periods lasting as long as 20 years. In cases of E. granulosa, cysts grow slowly and may ultimately contain several liters of fluid. Symptoms are frequently caused by pressure induced by the expanding cysts. The majority of hydatid cysts occur in the liver (75%) or lungs (15%) [Beggs, 1985]. Less common sites include the bone, pelvis, spleen, and CNS. With hepatic cysts, right upper quadrant pain, jaundice, or symptoms mimicking biliary disease occur [Dhar et al., 1996]. When the lungs are involved, chest pain, cough, fever, and hemoptysis are common. Anaphylaxis or dissemination of cysts may occur if the cysts rupture. E. granulosus infection of the CNS occurs in 2% to 5% of cases and may be primary or secondary when lesions occur in the CNS [Ciurea et al., 1995; Huang et al., 2004; Lunardi et al., 1991]). CNS disease is more common in children than adults [Carrea et al., 1975; Ersahin et al., 1993]. Most cysts are singular, intraparenchymal, and in the region of the middle cerebral artery [Gossios et al., 1997]. Patients with E. granulosus lesions in the CNS typically present with signs of increased cranial pressure: headache, vomiting, nausea, and papilledema [Altinros et al., 2000; Eckert and Deplaze, 2004; Taratuto et al., 1997a]. Hydatid disease involves the spine in 1% of cases and often resembles tuberculous spondylitis [Hughes and Biggs, 2002]. Extradural, intraventricular, cerebellar, thalamic, and orbital hydatid cysts have been reported in children but are rare [Copley et al., 1992; Ergun et al.,1997; Sener, 1996]. The clinical manifestation of E. multilocularis is characterized by invasive growth of larvae in the liver with occasional metastasis. Patients often complain of right upper quadrant pain or a palpable mass in the right upper quadrant. When metastasis to the brain occurs, the patient often presents with a mass lesion. E. multilocularis is almost always seen in adults.

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Diagnosis of hydatid disease is usually suggested by a history of residence in an endemic area, the clinical features, and characteristic radiologic findings. Neuroimaging is extremely helpful in the diagnosis of CNS hydatid disease. In cases of E. granulosus, CT and MRI brain scans often demonstrate oval or spherical, homogeneous, sharply demarcated cystic lesions with smooth borders [Gossios et al., 1997; Tuzun et al., 2002]. If the protoscolex, referred to as “hydatid sand,” is seen in the image, it is considered diagnostic. The cyst is often located in the white matter; as the cyst enlarges it extends toward the meninges or ventricles [Esharin et al., 1993]. Because there is little inflammation around the cysts, there is no edema or enhancement. Calcification of the wall is rarely observed [Tuzun et al., 2002]. In E. multilocularis of the CNS, cysts are less distinct on neuroimaging and may appear as an illdefined mass. A cauliflower-like contrast enhancement pattern on MRI is sometimes described [Tunaci et al., 1999]. Liver involvement is almost always present in these cases and ultrasound or other imaging of the abdomen may be helpful. Eosinophilia and elevated liver enzymes are variably present. Serology can be helpful in cases that have unclear neuroimaging studies. Enzyme-linked immunosorbent assay or indirect hemagglutination is available for screening, and immunoblot assay can help confirm the diagnosis. Falsepositive tests may occur in individuals with other helminth parasite infections, chronic immune disorders, and cancer [Wilson et al., 2002]. In extrahepatic disease, false negatives may occur [Huang et al., 2004].

Management Surgical removal and an antiparasitic drug are usually the recommended treatments for CNS disease. In cases of E. granulosus, meticulous care must be used during surgery to prevent spillage of the cysts’ contents. Intraoperative rupture rates for intracranial cysts were reported to be 17% in one recent study [Altinors et al., 2000]. Rupture of the cyst into the subarachnoid space may lead to widespread dissemination, followed by a severe inflammatory or anaphylactic reaction. Some authors have reported good outcomes with medical therapy alone [Kalaitzoglou et al., 1998; Singounas et al., 1992]. One of the newer benzoimidazoles, albendazole (15 mg/kg/ day [maximum 800 mg] for 1 to 6 months), is generally recommended [Medical Letter, 2004]. Praziquantel, in combination with albendazole, has shown utility [Anadol et al., 2001]. For E. multilocularis, CNS involvement is usually a consequence of advanced disease. Surgery and prolonged, often lifelong, antiparasitic medications are generally recommended [Reuter et al., 2004]. Case reports of successful outcomes using radiotherapy and interferon have also been described [Schmid et al., 1995; 1998].

Cysticercosis Epidemiology, Microbiology, and Pathology Cysticercosis, an infection caused by the larval form of the pork tapeworm Taenia solium, is the most common parasitic infection of the CNS worldwide. The encysted larvae in the

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Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis

FIGURE 70-20. Pork infected with the larval form of Taenia solium, also know as “measly pork.” (Courtesy Dr. Lawrence Ash.)

flesh of pigs, known as cysticerci, were known as “measly pork” to the ancient Greeks, although the correlation with human illness was not understood at that time (Fig. 70-20) [Cox, 2002]. There are descriptions of cysticerci in humans in the 16th century [Nieto, 1956], but the recognition that cysticerci were the larval stages of tapeworm was not made until almost 100 years later by Goeze Johann [Cox, 2004]. Cysticercosis is a disease found in areas with poor sanitation, especially in areas where pigs have access to human feces. The incidence of cysticercosis decreased in most European countries a century ago because of improvements in general sanitation. The disease is endemic in many lessdeveloped countries and is especially prevalent in Central and South America, sub-Saharan Africa, and Southeast Asia. Epidemiology surveys for human cysticercosis report seroprevalences of 8% to 12% in parts of Latin America [Carpio et al., 1998]. It is increasingly recognized in the United States and other industrialized nations because of immigration and increased travel to endemic areas [Maguire, 2004; Schantz et al., 1992; Sorvillo et al., 1992]. The life cycle of T. solium requires two hosts and two different forms of the parasite. Humans serve as the definitive host for the adult intestinal tapeworm form. Humans become infected with the intestinal tapeworm by consumption of undercooked pork containing cysticerci, the socalled measly pork (see Fig. 70-20). In the small intestine, the cysticerci then develop into adult tapeworms, sometimes reaching a length of 30 feet. The adult tapeworm typically causes minimal problems for the human host and can reside in the small intestine for 10 to 20 years. Eggs are periodically shed in the stool of an infected person. Taenia eggs can survive for long periods in the environment. Human feces used as fertilizer contaminates the environment. Pigs eating in this area become infected with eggs and serve as the most common intermediate host. Once the eggs are ingested, oncospheres hatch in the intestine, invade the small intestine, and invade muscle and other tissues of the body. The life cycle is complete when humans then eat pork containing cysticerci. Human cysticercosis is not acquired directly from pork but from ingestion of ova shed in human feces by a tapeworm carrier or by autoinfection.

The adult stage of T. solium (the tapeworm) is often asymptomatic but occasionally causes mild gastrointestinal complaints, such as nausea, diarrhea, and abdominal pain. The clinical manifestations of the larval stage are extremely variable and depend on the site of infection, the number of cysts, and the host response. At the time of larval migration there may be myalgia, fever, and eosinophilia, but this stage is usually not recognized. Larval migration occurs most commonly to the muscle, liver, brain, and other tissues, where the larvae then develop into cysticerci. Cysticerci located in sites other than the CNS or eye rarely cause damage. Neurocysticercosis occurs when larvae enter the CNS. Many individuals with neurocysticercosis have no symptoms. When CNS symptoms do occur, they often appear 5 to 7 years after the initial infection, but latencies of 6 months to 30 years have been described [Dixon and Lipscomb, 1961]. Neurocysticercosis can be either active or inactive. Inactive lesions are generally characterized by calcified foci. Active neurocysticercosis is usually associated with viable or degenerating cysticerci on CT or MRI. Seizures are the most frequent manifestations of neurocysticercosis and occur in 70% to 90% of reported cases [Shandera et al., 1994; White, 1997]. Other common clinical manifestations include headache, behavioral disturbances, and signs of increased intracranial pressure. In children, the most common presentation are focal or generalized seizures that are due to the acute reaction occurring at the time of cyst degeneration. Occasionally, children can present with acute encephalitis or cerebral edema when multiple inflammatory cysts exist. When cysts are located in the ventricular system, obstructive hydrocephalus can occur. A single cyst may also present as a space-occupying lesion and may appear as a brain tumor. A less common but severe form of neurocysticercosis occurs when cysticerci are clustered at the base of the brain and grow in subarachnoid space in grapelike clusters called the racemose cyst—this form is almost never seen in children. Spinal involvement may lead to cord compression. Evidence from a number of recent studies has found that chronic calcified cysts may be a major cause of epilepsy [Nash et al., 2004] and a primary reason for the higher incidence of epilepsy in underdeveloped countries compared with industrialized countries [Nicoletti, 2002]. Accurate diagnosis of neurocysticercosis requires a thorough review of the exposure history and clinical information, as well as neuroimaging and serologic data. Routine laboratory testing is usually nonspecific. Spinal fluid analysis is often normal or may show pleocytosis or increased protein [Mitchell and Crawford, 1988; Thomson et al., 1984], and eosinophilia is variably present [Dawood and Moosa, 1984; Mitchell and Crawford, 1988]. Immunoassays, such as an enzyme-linked immunosorbent assay and enzyme immunoelectrotransfer blot assay, are available to detect antibody against T. solium or cysticerci. Studies have found that the immunoelectrotransfer blot assay is both more sensitive and specific than enzyme-linked immunosorbent assay for the diagnosis of neurocysticercosis [Kojic and White, 2003; Schantz et al., 1994]. Serology is more sensitive in cases with multiple cysts than in cases with a

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single cyst or calcified lesions [Wilson et al., 1991]. In the United States, the immunoelectrotransfer blot assay is available at the CDC. Unfortunately, serology does not differentiate asymptomatic infections from infections with overt clinical symptoms. Diagnostic criteria based on the epidemiology, clinical history, neuroimaging, and serology results have been proposed for classification of neurocysticercosis [Del Brutto, 2001]. Neuroimaging may indicate a cystic lesion with an associated scolex and is considered pathognomonic for cysticercosis [Nash, 2003]. Most neuroimaging, however, will not reveal a scolex. More typically, cystic lesions, single or multiple ringlike or nodular enhancing lesions, and parenchymal brain calcifications will be seen (Fig. 70-21). Parenchymal cysts are often round, 5 to 20 mm in diameter and often found in the cerebral cortex and basal ganglia. [Carpio and Hauser, 2002; Huang et al., 2004]. Cysts in the subarachnoid space are typically larger and may be as large as 60 mm. Ring-enhancing or nodular enhancing lesions are also highly suggestive of neurocysticercosis. Parenchymal brain calcifications are usually 2 to 100 mm in diameter and are often solid, dense, and supratentorial. As cysts die, often when the patient is symptomatic, they lose their characteristic appearance and appear as dense granuloma with surrounding edema and may mimic a cerebral tumor. MRI provides better imaging detection and definition than CT [Garcia and Del Brutto, 2003]. Cysts in the brain undergo a number of different pathologic stages. After entering the brain, cysticerci are often dormant for years. Animal data suggest that the parasite uses mechanisms to suppress the immune response. Postmortem examinations in humans have demonstrated that patients with seizures have inflammatory infiltrates present, whereas viable cysticerci are found incidentally in individuals without CNS symptoms [Huang et al., 2004]. This finding suggests that seizures are likely a result of the host response rather than the parasite itself. In animal models, the granuloma, rather than the parasite, was the cause of seizure [Stringer et al., 2001]. After months to years, the cysticerci

FIGURE 70-21. Cerebral cysticercosis revealed on computed tomography scan.

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become infiltrated and are surrounded by host inflammatory cells composed of mononuclear cells, eosinophils, and neutrophils [Escobar, 1983]. Later the walls of the cysticerci degrade, and the cyst cavity is invaded by inflammatory cells (colloid stage). The granular nodular stage occurs next, with fibrosis and collapse of the cyst cavity. The calcific stage includes further fibrosis and calcifications.

Management Treatment of the adult tapeworm is routinely recommended. Praziquantel and niclosamide are highly effective for the eradication of the adult tapeworm. Treatment of neurocysticercosis should be individualized and based on clinical presentation and the number, location, and viability of cysticerci within the nervous system. Because seizures may recur for months, antiepileptic drug therapy is often recommended until there is evidence of resolution on CT or MRI, and no seizures have occurred for 1 to 2 years [Carpio and Hauser, 2002]. Considerable controversy exists about the role of antiparasitic treatment of neurocysticercosis [Proano et al., 2001]. Albendazole and praziquantel are the most common anthelmintics recommended. For individuals with multiple cysticerci or nonenhancing lesions (live parenchymal cysts) on brain scan, many experts recommend antiparasitic treatment together with steroids and an antiseizure medication [Garcia et al., 2004; St. Geme et al., 1993]. The argument in support of treatment is that the elimination of cysts reduces the risk of recurrent seizures, and the complications of cyst death can be managed better in a controlled situation (with both anti-inflammatory and anticonvulsant therapy), more than when cysts die naturally and unpredictably. The argument against treatment is that the cysts often die without causing symptoms, and there is the suggestion that antiparasitic drugs may enhance the development of scars and calcifications that lead to chronic seizures. Clinical studies have yielded conflicting results. Some studies have found evidence that the use of antiparasitic treatment gives a more favorable outcome [Del Brutto, 1992; Vasquez, 1992]. Other studies have not found an advantage with treatment [Carpio, 1995; Singhi, 2004; White, 2000]. Most recently, a large double-blind placebo controlled trial of patients with viable parenchymal cysts treated with both albendazole and steroids demonstrated a significant decrease in generalized seizures compared with individuals in the placebo group [Garcia et al., 2004]. Albendazole at 15 mg/kg/day (maximum 800 mg) in two doses for 8 to 30 days is recommended [Medical Letter, 2004]. Individuals with subarachnoid cysts or giant cysts in the fissures should be treated for at least 1 month [Proano, 2001]. No anthelmintic therapy is recommended by most experts for individuals with nonviable cysts on neuroimaging [Riley, 2003; Sotelo et al., 1985]. Furthermore, antiparasitic drugs may be contraindicated in patients with cerebral edema [Riley, 2003]. Because antiparasitic drugs may cause irreparable damage when used to treat ocular or spinal cysts, an ophthalmic examination should always precede antiparasitic treatment to rule out ocular cysts. Steroids are used in neurocysticercosis therapy to control inflammation and are particularly helpful in cases of encephalitis and subarachnoid, and spinal intramedullary diseases. Steroids are

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also recommended during the first few days of anthelmintic therapy to minimize the inflammation associated with the death of the parasite. In instances in which calcification of the cysts has occurred, prolonged use of antiepileptic drugs may be warranted [Nash, 2003]. Surgical intervention may be required to alleviate mass effect, remove cysts causing obstruction of the ventricles, or for shunt placement for hydrocephalus [Bale, 2000; Nash, 2003]. Ocular cysticercosis may also require surgical excision of the cyst.

Coenurosis Coenurois is caused by the larval stage of Taenia (Multiceps) spp. (T. multiceps, Taenia crassiceps, and Taenia serialis). Cerebral coenurosis is exceedingly rare in humans. Most cases are reported from Africa, but cases have reported from Europe and South and North America [Ing, 1998]. In North America, dogs, coyotes, and foxes are the definitive hosts for Taenia (Multiceps) spp. (where the adult tapeworm of T. serialis is found). Squirrels, hares, and rabbits serve as the intermediate hosts (where the cystic larval form is generally found). When humans are accidentally infected they serve as an intermediate host, and the cystic larvae may develop in the CNS, eye, or subcutaneous or intramuscular tissues. Basal arachnoiditis and hydrocephalus are common. The clinical manifestations typically present with signs of increased intracranial pressure. The parents may describe an insidious increase in head circumference [Lowichik et al., 1995]. Death has been reported in early childhood [Hermos, 1970; Schellhas and Norris, 1985].

TREMATODES Schistosomiasis Epidemiology, Microbiology, and Pathology Schistosoma haematobium infection was reported by Bilharz [1852], Schistosoma mansoni by Gonzalez-Martinez [1904], and Schistosoma japonicum was described as early as 1847 [Katsurada, 1904]. The history of schistosomiasis (bilharziasis) has been reviewed in detail [Mahmoud, 1984]. Schistosomiasis is a significant global public health problem; more than 200 million people are infected. S. mansoni is endemic in Africa, South America, and the Caribbean Islands. Highly concentrated areas of infestation are present in the Nile delta region and northeastern Brazil. S. haematobium, the organism that causes classic urinary tract bilharziasis, is found in Asia from Bombay to the Suez Canal and in Africa. S. japonicum causes illness in the Far East, including China, Japan, Indochina, the Philippines, and Indonesia. Several other species are recognized; Schistosoma mekongi and Schistosoma malayensis in Southeast Asia and Schistosoma intercalatum in Africa but are of lesser importance. Flukes (flatworms) have complicated life cycles. The eggs gain access to water from feces or urine, where the ciliated miracidia are released and then invade the intermediate host, which is a mollusk (snail). Cercariae then emerge from the snail, penetrate the skin of humans, and are transported by the blood to the distal afferent veins of the liver, where further growth ensues followed by migration of the fluke. The snail hosts are specific for the different schistosome species, a restriction that determines the spread of disease.

S. haematobium is brought by the circulation to the bladder venous plexus and lower abdominal vessels. Urinary tract symptoms and complications follow. The liver and lower gastrointestinal tract are sometimes affected. This pattern of involvement differs from that of S. mansoni and S. japonicum, in which the organism preferentially enters the mesenteric portal and caval circulation before infecting the liver, intestines, and other organs (e.g., spleen, lungs, heart, CNS). About 2% of patients have neurologic involvement during the third phase, with about 60% of cases caused by S. japonicum and 20% to 30% by S. mansoni. Of the three most common schistosome species, S. japonicum infections are more likely to involve the brain and meninges. S. japonicum is also the most prolific egg producer, with as many as 3500 eggs per day, about 10-fold more than the other two species produce. Eggs of the other species are more likely to produce lesions in the spinal cord, resulting in jacksonian epilepsy, transverse myelopathy, cord compression, and, in some cases, a massive and fatal necrosis [Liu, 1993]. Spaceoccupying lesions, or bilharziomas, are apparent on MRI and CT scans [Sun, 1982]. Adult worms, which can remain viable for 10 to 25 years, have also been reported in ectopic locations, such as brain tissue [Houston et al., 2004]. The pathogenesis of neurologic impairment is undetermined despite experimental efforts to reproduce the condition in primates [Jane et al., 1970]. Two types of lesions exist. One consists of isolated granulomatous masses that contain ova and can be surgically excised. The other type consists of diffuse small lesions that are located in both white and gray matter and are often asymptomatic. In one series of 97 patients with neurologic impairment from schistosomiasis, 60 patients were infected with S. japonicum, 11 with S. haematobium, and 26 with S. mansoni [Marcial-Rojas and Fiol, 1963]. Neurologic features include focal deficits, convulsions, vertigo, encephalitis, meningitis, tumor-like mass lesions, and transverse myelitis [Boyce, 1990; Brito et al., 1992; Liu, 1993; Pittella et al., 1996; Scrimgeour and Gajdusek, 1985]. Growth retardation in children, associated with depressed function of the pars anterior of the pituitary gland, has occurred [Jordan and Webbe, 1969; McGarvey et al., 1992]. A recent review has updated information on pathogenesis and diagnostic techniques relating to neuroschistosomiasis [Nascimento-Carvalho and Moreno-Carvalho, 2005].

Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis Clinical symptoms occur in three phases, the first being associated with cutaneous penetration and migration of the Schistosoma that results in an active dermatitis (“swimmer’s itch”). The second phase (Katayama fever or syndrome) occurs 6 to 8 weeks later and consists of a wide variety of symptoms including chills, headache, fever, fatigue, hepatosplenomegaly, lymphadenopathy, eosinophilia, urticaria, and gastrointestinal distress. This phase of the disease coincides with production of eggs by the parasites, and the humoral response of the host’s immune system [Sun, 1982]. Fibrous granulomas containing eosinophils, macrophages, lymphocytes, and fibroblasts develop around the eggs, producing pseudotubercles, which resemble the tubercles of tuberculosis. The third, or chronic, phase usually involves the

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liver, bladder wall, spleen, lung, and heart [Markell et al., 1992]. Bloody urine or bloody diarrhea may occur in S. japonica and intestinal schistosomiasis, but the chronic stage is often asymptomatic. The diagnosis of schistosomiasis can be made by finding ova in stool or urine samples. Concentration of the specimen may be necessary (Kato technique) because of the small number of eggs that might be present in clinical samples. In chronic schistosomiasis, however, eggs may not be passed, and rectal, bladder, or liver biopsies may be required for definitive diagnosis. Immunodiagnostic techniques for antibody detection are of limited worth because of crossreactivity with other helminth infections. Slow and diffuse alpha wave patterns have been reported in EEGs of some patients [Hayashi, 2003]. Diagnosis of schistosomiasis may be established with several tests, including an intradermal skin test, a complement fixation test, a cholesterol-lecithin cercarial slide flocculation test, and a bentonite flocculation test. The cholesterol-lecithin test has a sensitivity of 77% to 90% in parasitologically confirmed cases. Identification of the parasite in urine, feces, and tissue is diagnostic (see Table 70-3). An enzyme-linked immunosorbent assay test for circulating schistosome antigen can give both qualitative and quantitative (the parasite burden) results [Deelder et al., 1989]. Brain neuroimaging studies may reveal edema, multifocal lucencies, and atrophy in later stages of the disease [Kirchoff and Nash, 1984; Khalil et al., 1984; Pittella et al., 1996], whereas investigation of spinal cord schistosomiasis may reveal myelitis, swelling at the base of the cord (conus medullaris), or cord compression [Brito et al., 1992; van Leusen and Perquin, 2000]. In a study of patients ages 3 to 19 years living in an area endemic for S. mansoni and with stool or biopsy verification of infection, cerebrospinal fluid examination revealed pleocytosis (7 to 560 white blood cells/mm3), eosinophilia (1 to 66 cells/mm3), and elevated protein (45 to 3540 mg/dL) [Nascimento-Carvalho and Moreno-Carvalho, 2004]. Ova have not been found in cerebrospinal fluid [Hughes and Biggs, 2002]. Paraparesis, urinary retention, and paraplegia were the most common symptoms presenting by pediatric patients [Nascimento-Carvalho and Moreno-Carvalho, 2004].

Management Schistosomiasis should be considered in individuals with neurologic impairment and a travel history to endemic areas, particularly if patients had been bathing, swimming, or wading in sewage-contaminated rivers or streams. Praziquantel (40 to 60 mg/day divided into two or three doses for pediatric and adult patients) is the drug of choice for the treatment of S. haematobium, S. mansoni, and S. intercalatum infections [Markell et al., 1992; Medical Letter, 2004]. An antiepileptic drug is recommended in cases with more than two seizures per week [Hayashi, 2003]. In vivo testing of praziquantel on mice, at a dose 5 to 10 times that used in humans, found that the drug killed mature S. mansoni ova, and may be useful in treating CNS infections [Richards et al., 1989]. Corticosteroid use, with and without praziquantel, was effective in lessening symptoms in some cases, though controlled studies have not been done due to the relative rarity of the disease [Fowler et al., 1999;

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Haribhai et al., 1991; Houston et al., 2004]. Oxamniquine (pediatric dose of 20 mg/kg in two divided doses times 1 day) is an alternative agent for S. mansoni. Niridazole, stibophen, and antimony potassium tartrate are also of value. Intravenous injection of tartar emetic is the recommended therapy for S. japonicum. Surgical intervention may prove necessary for mass lesions in the brain or spinal cord.

Paragonimiasis Epidemiology, Microbiology, and Pathology Paragonimiasis, a neurologic and neurosurgical condition, has a high incidence in the Far East and occurs less frequently in some regions of Africa and South America [Kusner and King, 1993]. Otani first reported cerebral paragonimiasis in 1887 [Otani, 1887]. The condition is a serious complication of the benign infection caused by the lung fluke, Paragonimus westermani. The ingestion of the metacercarial parasite, while residing in its crab or crayfish intermediate host, is the usual mode of human infection. The crustaceans are infected after ingestion of cercaria-laden snails that have previously been infected by miracidia. A number of carnivorous mammals may serve as reservoir hosts for humans, passing ova in feces. Gross observation of the brain demonstrates meningeal adhesions and areas of exudate. Cortical atrophy is sometimes present. Nodules and cysts may be found in the subcortical region. Abscesses with suppurative material in their centers appear throughout the brain. Cavitation and liquefaction around the egg may be due to toxin release [Sun, 1982]. Ova are sometimes present in the abscesses and meningeal infiltrate. All types of leukocytes are seen in the areas of inflammation when examined microscopically. Granulomas with giant Langhans’ cells and epithelioid cells are frequently found in chronic granulomas. Gliosis and fibrosis, appropriate to anatomic location, are widespread. Calcification of the lesion eventually occurs. If cerebrospinal fluid circulation is impeded, hydrocephalus may result [Sun, 1982]. Spinal paragonimiasis, either epidural or intradural, is usually represented by ovum-filled cysts. Spinal cord atrophy may be prominent. The microscopic pathologic abnormalities are indistinguishable from those present in the brain.

Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis After human ingestion of infected raw or poorly cooked crab or crayfish, the metacercariae excyst in the small intestine and pierce the intestinal wall as larvae, embedding in the abdominal wall. After several days the larvae re-enter the abdominal cavity and migrate to the diaphragm, pleural cavity, and lungs before maturing into adult flukes. Although the worms are hermaphroditic, they usually occur in pairs and cross-fertilize. Adult worms are reported to live for 10 to 20 years [Hughes and Biggs, 2002]. The mechanism of entrance of the immature fluke into the brain or spinal cord is not precisely known. The most widely held theory of the mechanism of brain involvement is that larvae traverse the soft tissues of the neck surrounding the jugular vein and nerve trunks and then enter the brain through the jugular

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foramen, causing arachnoiditis, abscesses, or granulomas [Yokogawa, 1921]. Direct invasion of larvae from the lung is assumed to cause extradural spinal involvement, and extension of infection from the brain through the subarachnoid space is believed to be the mechanism of intradural spinal infection [Oh, 1978]. Lung disease, including pleurisy, pneumothorax, and hemoptysis, constitutes the cardinal clinical feature of paragonimiasis. Cerebral infection occurs in approximately 0.8% of patients; spinal cord involvement is even less common. Less than 50% of the patients with neurologic disease are younger than 20 years of age. Prominent cerebral characteristics include meningitis, subacute progressive encephalopathy, cerebral infarction, seizures, mass lesions, and dementia. Approximately two thirds of 62 patients were reported to have seizures [Oh, 1978]. The emergence of clinical manifestations is gradual. Meningitis is the initial condition in two thirds of patients. Headache, nausea and vomiting, visual impairment, hemiplegia, and mental deterioration often occur early in the course of the illness. Neurologic evaluation frequently documents dementia, homonymous hemianopia, optic atrophy, diminished visual acuity, hemiparesis, hemihypesthesia, and meningismus [Oh, 1978]. When the condition is diagnosed and treated in a timely manner, the prognosis is excellent. The most common location of spinal involvement is in the lower thoracic area. An extradural mass may cause spastic paraplegia. More rarely an intradural lesion occurs. Definitive diagnosis of paragonimiasis requires finding the operculated eggs in sputum or feces. Ova, however, may not be found in sputum for some species of Paragonimus or if adult worms are in an ectopic location. In one report, chest radiographs were abnormal in 80% of patients; they revealed pneumonia, pleural abnormalities, and cystonodular lesions. Approximately 70% of patients had abnormal cranial radiographs that indicated increased intracranial pressure (25%) and calcifications (50%). Porencephaly and cortical and subcortical atrophy were demonstrated by pneumoencephalography in several patients. Myelography proved necessary for the diagnosis of spinal cord lesions [Oh, 1978]. Newer imaging techniques may prove superior for screening purposes [Lowichik and Ruff, 1995b]. Other studies include intradermal skin injection, examination of sputum and stool for ova, and immunologic determinations. An enzyme-linked immunosorbent assay test is available. The complement fixation test is valuable and sensitive. Peripheral blood eosinophilia is often present. Pleocytosis (approximately equal numbers of polymorphonuclear cells and mononuclear cells), decreased glucose concentration, and increased protein and chloride content are frequent spinal fluid findings. Differential diagnoses are neurotuberculosis, neoplasm, encephalitis, neurocysticercosis, and cerebral hemorrhage [Sun, 1982]. A case of cerebral paragonimiasis, apparently acquired in childhood, lay dormant for about 30 years before becoming symptomatic [Kang et al., 2000].

Management Praziquantel (75 mg/kg day divided into three doses for 2 days, for both pediatric and adult patients) is used as initial treatment [Medical Letter, 2004]. Bithionol therapy (30 to

50 mg/kg on alternate days for 10 to 15 doses) can alternatively be used for meningitic involvement. Chronic cerebral lesions or spinal cord lesions require surgical intervention accompanied by adjunctive chemotherapy [Higashi et al., 1971; Oh, 1978]. ACKNOWLEDGMENTS The assistance of Sabrina Gilliam and Penny Savage is greatly appreciated. The comments of Dr. Chris Paddock, Peter Schantz, Kevin Kazacos, and Daniel Sexton are also appreciated.

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CHAPTER 71

Tumors of the Brain and Spinal Cord, Including Leukemic Involvement Michael E. Cohen and Patricia K. Duffner

Intracranial tumors of the brain and spinal cord are the second most common group of neoplasms in children, exceeded only by leukemia. The Third National Cancer Survey of the United States, in 1975, placed the incidence of central nervous system (CNS) neoplasia for children younger than 15 years of age at approximately 2.4 per 100,000 [Young and Miller, 1975]. Since this report in the mid-1970s, there is increasing evidence that the incidence of CNS neoplasia in young children may be rising (Fig. 71-1). Of interest is the observation that incidence rates of childhood brain tumors increased sharply in the mid-1980s with the concurrent introduction of magnetic resonance imaging (MRI) and have remained stable since then [Jukich et al., 2001]. To some extent the increasing incidence of childhood brain tumors has been offset by improving survivals [Davis et al., 2001; Smith 1998] (Fig. 71-2). The most accurate sources of information regarding the incidence of brain tumors in the United States are the Surveillance, Epidemiology, End Results (SEER) Registry and the Central Brain Tumor Registry of the United States (CBTRUS). The SEER program is a population-based data reporting system that is a continuing project of the National Cancer Institute. The population covered by these registries represents slightly more than 26% of the U.S. population. Completeness of reporting in the SEER Registry is estimated at greater than 95%, and follow-up is more than 80%. The SEER Registry’s areas include Connecticut, Detroit, Seattle, Hawaii, Utah, San Francisco, Iowa, Atlanta, and New Mexico. Until recently SEER data have been considered the most reliable source of incidence and survival information. CBTRUS is a database that compiles information from state cancer registries. Unlike SEER, the CBTRUS registry includes information about both benign and malignant tumors. SEER data are limited by the lack of information regarding craniopharyngiomas and nonmedulloblastoma primitive neuroectodermal tumors. In other series, craniopharyngiomas may account for 6% to 10% of all pediatric brain tumors [Rubinstein, 1972]. A report published by the CBTRUS has placed the annual incidence of childhood brain tumors at 4 per 100,000 person-years in children 0 to 19 years of age. Thus, based on the current U.S. population, approximately 3200 newly diagnosed cases of brain tumors can be expected to be identified each year in the United States. Of these two thirds or more will be in children younger than 15. Of interest, an analysis of trends of ageadjusted cancer incidence rates (1974 to 1991) revealed a rise in astroglial tumors in children younger than 5 years of more than 4% per year. Rates of ependymomas have also increased substantially in children less than 2 years old (4.8%) [Gurney et al., 1996]. The incidence of primary brain

tumors is highest in the 0 to 4 age group and lowest in the 10 to 14 age group. The rate is slightly higher in males (4.2/100,000) than females (3.8/100,000 person-years). The most common histologies are pilocytic astrocytomas (21%) and medulloblastomas (embryonal tumors) (18%) [CBTRUS, 2004] (Fig. 71-3). The majority are located within the cerebrum and cerebellum. A spinal cord tumor is much less common. The two most common intracranial sites are the cerebellum and the brainstem (Fig. 71-4). The 5-year relative survival rate in the 0 to 19 age group is approximately 64.3%. This compares with a 5-year survival rate of 6.5% to 4.7% in the 65 and older age group [CBTRUS, 2004] (Table 71-1). Most brain tumors derive from intrinsic elements of the CNS. Bailey and Cushing [1926] are generally credited with applying the term glioma to that group of tumors arising from parenchymatous elements of the nervous system. Since then, clusters of histologic features have been used to assess the benign or malignant potential of a given tumor. These observations gave rise to the postulate that morphologic properties could predict the clinical course. Thus astrocytomas with cysts and Rosenthal fibers were associated with a slowly evolving course, whereas those associated with necrosis, pseudopalisading, and anaplasia were associated with a more malignant course. Unfortunately, pathol-

FIGURE 71-1. SEER data 1995 CBTRUS. (From 2004-2005 Statistical Report. Primary Brain Tumors in the United States Statistical Report, 1997-2001 [years data collected]. CBTRUS [2004]. Statistical Report: Primary Brain Tumors in the United States, 1997-2001. Published by the Central Brain Tumor Registry of the United States.)

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Tumors and Vascular Disorders of the Nervous System / 71 Other brain 17.4% Brain stem 13.1%

Spinal cord and cauda equina 5.7% Cranial nerves 5.7% Other CNS 0.9% Meninges 2.7%

Cerebrum 18.4%

Pituitary 5.3% Pineal 2.5% Nasal cavity 0.1%

Ventricle 5.8%

Frontal lobe 6.3% Temporal lobe 6.8% Cerebrum lobe Occipital Parietal lobe 5.7% lobe 6.8% 5.7%

FIGURE 71-4. Distribution of all childhood primary brain and CNS tumors (0-19 years) by site. CBTRUS 1997-2001 (n = 5028). (From 2004-2005 Statistical Report. Primary Brain Tumors in the United States Statistical Report, 1997-2001 [years data collected]. CBTRUS [2004]. Statistical Report: Primary Brain Tumors in the United States, 1997-2001. Published by the Central Brain Tumor Registry of the United States.)

FIGURE 71-2. SEER survival data showing suggestive increase in survivals in the period 1985-1994 compared with the previous decade. (From 20042005 Statistical Report. Primary Brain Tumors in the United States Statistical Report, 1997-2001 [years data collected]. CBTRUS [2004]. Statistical Report: Primary Brain Tumors in the United States, 1997-2001. Published by the Central Brain Tumor Registry of the United States.)

FIGURE 71-3. Distribution of childhood primary brain and CNS tumors by histology. CBTRUS 1997-2001. (From 2004-2005 Statistical Report. Primary Brain Tumors in the United States Statistical Report, 1997-2001 [years data collected]. CBTRUS [2004]. Statistical Report: Primary Brain Tumors in the United States, 1997-2001. Published by the Central Brain Tumor Registry of the United States.)

ogy cannot fully predict outcome, and much confusion in the definition of terms and the ability to prognosticate remains. This imprecision led to a search for new classifications of tumors and a general reluctance to rely solely on pathologic features for prognosis. At the turn of the 21st century, traditional approaches to histopathology have been increasingly challenged as new techniques have been added to the pathologic armamentarium. Immunohistochemistry allows the pathologist to assay for the presence of antibodies

to epitopes of glial and neuronal proteins. Monoclonal technology has resulted in the identification of antibodies with specificity for various CNS tumors. Astrocytic tumors are now routinely stained for glial fibrillary acidic protein, an intermediate filament with a diameter of 10 to 12 nm observed in patients with well-differentiated astrocytomas. Glial fibrillary acidic protein reactivity is not specific because it is weakly observed in ependymomas, choroid plexus tumors, and oligodendrogliomas. Vimentin, a 57-kd fila-

Cohen and Duffner / Tumors of the Brain and Spinal Cord

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TABLE 71-1 One-, Two-, Three-, Four-, Five-, and Ten-Year Relative Survival Rates* for Selected Malignant Brain and Central Nervous System Tumors† by Age Groups, Seer 1973-2001 HISTOLOGY

AGE GROUP

NO. OF CASES 1-YR

2-YR

3-YR

4-YR

5-YR

10-YR

Pilocytic astrocytoma

0-14 0-19 20-44 45-54 55-64 65-74 75+

633 762 245 43 16 13 7

97.4 97.2 93.7 90.4 93.7 — —

96.5 96.4 91.0 87.9 83.8 — —

96.1 96.0 89.0 82.1 — — —

94.5 94.5 87.5 79.3 — — —

93.8 93.7 87.0 76.0 — — —

92.0 92.3 82.7 66.8 — — —

Total

1086

0-14 0-19 20-44 45-54 55-64 65-74 75+

106 134 288 92 85 82 27

92.4 92.5 89.9 71.6 46.5 30.5 27.8

85.4 86.9 82.0 49.8 21.8 16.4 8.9

82.2 83.6 73.3 40.1 16.0 9.9 4.7

82.2 83.6 63.7 37.7 13.7 8.7 —

81.2 82.8 57.5 35.1 10.2 7.2 —

80.0 82.0 39.3 19.1 7.6 — —

Total

708

0-14 0-19 20-44 45-54 55-64 65-74 75+

129 172 840 348 309 338 176

72.3 76.3 85.2 63.2 44.3 23.7 12.5

58.0 60.1 71.7 43.6 20.1 6.5 4.5

52.8 55.6 62.3 32.3 13.9 3.8 2.5

49.1 51.6 54.7 26.8 10.5 3.2 1.8

49.1 51.6 48.3 25.4 5.9 3.2 —

46.8 46.9 32.1 18.2 3.7 1.3 —

Total

2183

0-14 0-19 20-44 45-54 55-64 65-74 75+

881 1150 2121 951 1178 1186 600

87.5 87.7 86.6 62.6 40.0 22.3 12.4

82.3 81.8 75.6 41.0 20.1 9.1 5.5

80.2 79.2 68.3 33.0 15.1 6.2 4.2

78.5 77.7 61.5 29.0 12.9 5.6 3.8

78.0 76.7 54.8 26.7 11.1 5.0 3.5

74.4 73.2 38.1 17.6 6.5 2.3 —

Total

7186 47.2 50.5 59.4 41.9 31.1 16.6 7.9

23.9 27.7 30.0 11.7 5.9 2.6 1.4

19.6 21.3 21.1 6.0 2.6 1.0 0.6

18.3 19.6 16.5 3.9 1.7 0.6 0.4

17.0 18.8 13.6 3.5 1.4 0.4 0.4

15.5 16.2 8.9 1.7 0.5 0.2 0.2

93.4 92.9 95.7 91.2 81.8 61.7 45.5

90.4 87.9 91.9 82.5 67.3 50.9 32.2

89.4 85.9 88.3 76.1 58.1 50.3 19.0

88.3 85.2 84.4 69.4 47.0 41.6 —

87.1 84.4 80.6 64.4 44.1 35.0 —

79.7 79.7 62.6 38.1 29.2 11.8 —

— — 91.1 82.0 67.1 49.9 32.7

— — 75.9 62.6 52.6 35.3 —

— — 71.1 58.1 43.7 32.4 —

— — 64.2 43.5 35.7 32.4 —

— — 55.8 43.5 27.2 19.3 —

— — 37.2 35.5 — — —

Diffuse astrocytoma

Anaplastic astrocytoma

Astrocytoma, NOS

Glioblastoma

Oligodendroglioma

Anaplastic oligodendroglioma

0-14 0-19 20-44 45-54 55-64 65-74 75+

176 265 1787 2517 3918 4125 2486

Total

15,098

0-14 0-19 20-44 45-54 55-64 65-74 75+

109 175 886 313 212 118 44

Total

1748

0-14 0-19 20-44 45-54 55-64 65-74 75+

7 10 140 73 56 38 23

Total

340 Continued

1690

Tumors and Vascular Disorders of the Nervous System / 71

TABLE 71-1, cont’d One-, Two-, Three-, Four-, Five-, and Ten-Year Relative Survival Rates* for Selected Malignant Brain and Central Nervous System Tumors† by Age Groups, Seer 1973–2001 HISTOLOGY

AGE GROUP

NO. OF CASES 1-YR

2-YR

3-YR

4-YR

5-YR

10-YR

Ependymoma/ anaplastic ependymoma

0-14 0-19 20-44 45-54 55-64 65-74 75+

369 414 403 149 117 69

84.6 85.8 91.3 91.3 80.9 78.3 18

70.4 73.0 89.3 86.2 76.2 75.6 63.5

61.3 63.8 85.4 79.6 72.9 72.5 —

54.6 57.9 84.3 79.2 71.7 71.2 —

50.7 54.5 84.1 75.7 66.4 71.2 —

45.5 47.1 77.2 67.8 50.4 43.7 —

Total

1170

0-14 0-19 20-44 45-54 55-64 65-74 75+

76 108 374 118 89 53 12

88.1 86.9 92.3 78.9 78.1 50.9 —

80.1 80.1 84.9 64.7 52.4 37.1 —

76.0 77.1 79.2 53.1 38.6 27.1 —

70.5 72.0 72.7 45.9 33.3 17.8 —

69.1 71.0 68.3 39.3 30.6 15.4 —

62.9 65.5 49.3 30.6 15.2 6.7 —

Total

754

0-14 0-19 20-44 45-54 55-64 65-74 75+

578 653 455 250 329 430 456

68.3 69.9 80.3 55.2 42.0 23.7 10.4

49.7 52.7 67.7 37.5 26.2 13.1 6.6

46.3 49.1 61.9 31.0 21.6 11.9 5.6

45.5 48.2 56.2 29.7 19.1 8.4 4.2

44.1 46.8 51.1 28.3 16.8 7.5 3.3

41.0 42.7 36.6 20.0 11.6 5.0 2.9

Total

2573

Neuroepithelial

0-14 0-19 20-44 45-54 55-64 65-74 75+

47 63 65 34 31 30 15

85.1 87.3 77.1 53.3 36.1 20.7 —

74.2 77.6 64.7 32.8 20.0 14.2 —

67.7 72.6 58.5 24.1 16.9 11.1 —

63.3 69.3 53.9 21.0 — — —

59.0 66.0 52.4 21.0 — — —

56.8 64.3 32.7 11.1 — — —

Total

238

Malignant neuronal/glial, neuronal, and mixed

0-14 0-19 20-44 45-54 55-64 65-74 75+

108 122 63 48 44 15 15

75.0 75.5 93.8 89.3 89.6 — —

63.5 65.3 79.4 87.3 68.2 — —

57.5 58.3 77.8 85.1 66.3 — —

54.4 54.7 74.1 76.2 64.2 — —

54.4 52.7 72.2 73.1 64.2 — —

52.0 50.5 63.1 50.2 53.8 — —

Total

307

0-14 0-19 20-44 45-54 55-64 65-74 75+

919 1013 305 38 16 5 6

78.9 80.0 86.4 81.5 — — —

68.4 69.8 76.8 76.1 — — —

62.6 64.0 68.8 76.1 — — —

56.7 58.0 63.0 73.6 — — —

54.0 54.8 57.1 63.0 — — —

47.2 47.6 46.7 45.2 — — —

Total

1383

0-14 0-19 20-44 45-54 55-64 65-74 75+

18 35 910 365 363 461 280

56.3 66.7 22.5 41.9 53.8 44.6 33.7

48.2 60.1 16.3 34.2 40.9 29.9 20.7

40.2 56.8 14.1 31.1 31.4 22.7 15.5

— 49.7 12.7 28.4 26.6 18.3 12.7

— — 11.2 25.7 21.8 15.3 11.1

— — 9.3 16.1 12.4 8.2 2.6

Total

2414

Mixed glioma

Glioma malignant, NOS

Embryonal/primitive/ medulloblastoma

Lymphoma

Cohen and Duffner / Tumors of the Brain and Spinal Cord

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TABLE 71-1, cont’d One-, Two-, Three-, Four-, Five-, and Ten-Year Relative Survival Rates* for Selected Malignant Brain and Central Nervous System Tumors† by Age Groups, Seer 1973–2001 HISTOLOGY

AGE GROUP

NO. OF CASES 1-YR

TOTAL: ALL BRAIN †‡ AND CNS

0-14 0-19 20-44 45-54 55-64 65-74 75+

4541 5628 9403 5636 7146 7443 4785

Total

40,041

81.0 82.2 76.2 55.8 40.2 24.3 14.5

2-YR

3-YR

4-YR

5-YR

10-YR

71.4 72.9 63.4 33.7 18.7 11.1 7.6

67.3 68.8 57.0 27.3 14.1 8.6 6.0

64.3 65.9 51.9 24.2 12.1 7.3 5.2

62.9 64.3 47.6 22.5 10.6 6.5 4.7

58.8 59.9 35.7 15.4 6.9 4.0 3.3

*Rates are an estimate of the percentage of patients alive at 1, 2, 3, 4, 5, and 10 years, respectively. † In contrast with survival estimates reported in previous editions of the CBTRUS statistical report, brain lymphomas, olfactory tumors of the nasal cavity, and malignant tumors of the pituitary and pineal glands are included. ‡ Includes histologies not listed in this table. Abbreviations: SEER, Serveillance, Epidemiology, End Results; NOS, not otherwise specified; —, too few cases to estimate.

ment, is a neurofilament found in immature rather than differentiated glial cells. As myelination and differentiation proceed, vimentin decreases, whereas glial fibrillary acidic protein becomes more apparent. Vimentin has been found in meningiomas, schwannomas, carcinomas, sarcomas, melanomas, and lymphomas. Neurofilament markers are being used to identify neuronal tumors, such as gangliogliomas. Although these markers recognize neurons, axons, and mature neural elements, they are less helpful in identification of more primitive tumors such as medulloblastomas, primitive neuroectodermal tumors, and neuroblastomas. Conversely, synaptophysin, a glycosylated polypeptide component of the presynaptic vesicle membrane, has been used to determine neuroectodermal differentiation. New techniques complement standard histopathology in assessing cell proliferation. Flow cytometry, a technique that measures physical or chemical characteristics of single cells, is widely used to determine deoxyribonucleic acid (DNA) content. A DNA histogram is characterized by two peaks. The majority of cells in the resting phase (G-0) or in the G1 phase of the cell cycle contain a similar amount of DNA. Next to this dominant peak, histograms demonstrate smaller peaks composed of cells in G-2 or those undergoing mitosis. DNA of tumor cells is then compared with the DNA content of diploid standards and a DNA index is determined. A diploid sample with normal DNA content has a diploid index of 1, whereas a DNA index less than or greater than 1 is abnormal. Most malignant cells are commonly aneuploid with varying amounts of DNA, suggesting that the DNA content varies from the diploid standard [Coon et al., 1987]. Using these techniques, flow cytometry permits assessment of biologic behavior. Proliferation antigens have been identified to assess proliferative activity. These are nuclear antigens that estimate the growth fraction of normal and neoplastic cells, thereby providing an estimate of doubling time. Ki-67, a murine monoclonal antibody is a proliferation marker, which binds to human nuclear protein in various stages of the cell cycle. The monoclonal antibody MIB-1 is a variant of Ki67. Both markers are used to define tumors that have a high growth fraction. Another marker of DNA synthesis is the halogenated pyrimidine bromodeoxyuridine. Because it is incorporated into DNA during the S phase of the cell cycle,

this marker is used as a marker of cell proliferation. After exposure to bromodeoxyuridine, a labeling index is determined and the percentage of positive staining cells is used to determine a mitotic index. Identification of growth factors and oncogenes with tumor specificity will further add to the ability to classify tumors [Burger and Fuller, 1991; Cohen and Duffner, 1994a]. Loss of heterozygosity, fluorescein in situ hybridization, and quantitative polymerase chain reaction represent some of the newer molecular tools used to identify genetic aberrations that correlate with tumor type and degree of malignancy [Louis et al., 2001].

HISTOPATHOLOGIC GROUPINGS Until newer techniques become routinely accepted, tumors will be graded according to the World Health Organization’s system, which is based on site, histologic type, and degree of malignancy (Box 71-1) [Kleihues and Cavenee, 2000]. This classification, as well as many others that have preceded it, is somewhat arbitrary and presumptive in that classifications rely on the presence of a stem cell from which more differentiated cell types derive. For instance, medulloblastoma is believed to be a tumor of undifferentiated cells arising from putative stem cells of the developing nervous system. Similarly, a central tenet in the approach to the diagnosis of primitive neuroectodermal tumors is the assumption that these tumors, regardless of site of origin, were derived from a common precursor with the potential for glial, ependymal, neuronal, or bipolar differentiation. Objections to this approach have been raised because of the lack of a single stem cell and the tendency to fit all undifferentiated tumors into this category. Burger and associates [1991] suggested that an uncritical use of this grouping would place malignant ependymomas, pineoblastomas, glioblastomas, neurocytomas, and oligodendrogliomas into a similar grouping because of a focus on cellularity alone. It is well recognized that primitive neuroectodermal tumors, depending on site and age, have different responses to treatment and thus may suggest a different biology. The optimal classification of brain tumors should include pathologic characteristics, tumor biology, anatomic loca-

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Tumors and Vascular Disorders of the Nervous System / 71

Box 71-1 BRAIN TUMOR CLASSIFICATION (ADAPTED FROM THE WORLD HEALTH ORGANIZATION) Tumor of Neuroepithelial Tissue Astrocytic tumors Astrocytoma Variants: Fibrillary Protoplasmic Gemistocytic Anaplastic (malignant) astrocytoma Glioblastoma Variants: Giant cell glioblastoma Gliosarcoma Pilocytic astrocytoma Plemorphic xanthoastrocytoma Subependymal giant cell astrocytoma (tuberous sclerosis) Oligodendroglial tumors Oligodendroglioma Anaplastic (malignant) oligodendroglioma Ependymal tumors Ependymoma Variants: Cellular Papilary Clear cell Anaplastic (malignant) oligoastrocytoma Myxopapillary ependymoma Subependymoma Mixed gliomas Oligoastrocytoma Anaplastic (malignant) oligoastrocytoma Others Choroid plexus tumors Choroid plexus papilloma Choroid plexus carcinoma Neuroepithelial tumors of uncertain origin Astroblastoma Polar spongioblastoma Gliomatosis cerebri Neuronal and mixed neuronal-glial tumors Gangliocytoma Dysplastic gangliocytoma of cerebellum (Lhermitte-Duclos) Desmoplastic infantile ganglioglioma Dysembryoplastic neuroepithelial tumor Ganglioglioma Anaplastic (malignant) ganglioglioma Central neurocytoma Paraganglioma of the filum terminate

Olfactory neuroblastoma (esthesioneuroblastoma) Variant: Olfactory neuroepithelioma Pineal parenchymaltumors Pineocytoma Pineoblastoma Pinealoma Mixed transitional pineal tumors Enbryonal tumors Medulloepithelioma Pinealoblastoma Neuroblastoma Variant: Ganglioneuroblastoma Ependymoblastoma Primitive neuroectodermal tumors (PNETs) Medulloblastoma Variants: Desoplastic medulloblastoma Medullomyoblastoma Melanocytic medulloblastoma Tumors of the Meninges Tumors of meningothelial cells Meningioma Variants: Meningothelial Fibrous (fibroblastic) Transitional (mixed) Psammomatous Angiomatous Microcystic Secretory Clear cell Chordoid Lymphoplasmacyte-rich Metaplastic Atypical meningioma Papillary meningioma Anaplastic (malignant) meningioma Germ cell tumors Germinoma Embryonal carcinoma Yolk sac tumor (endodermal sinus tumor) Choriocarcinoma Teratoma Immature Mature Teratoma with malignant transformation Mixed germ cell tumors

From Kleihues and Cavenee, 2000.

tion, patient age, and response to therapy. With this information, physicians may provide a more realistic assessment of the prognosis associated with a given diagnosis. The largest histopathologic grouping in both the SEER and CBTRUS registries is for astrocytomas. This category includes such

diverse tumors as cerebellar astrocytomas, brainstem gliomas, high-grade supratentorial astrocytomas, and low-grade supratentorial astrocytomas. In the SEER database for children 0 to 15 years, astrocytomas represented 57%, medulloblastomas 23%, and ependymomas 8% of the total

Cohen and Duffner / Tumors of the Brain and Spinal Cord

population. The incidence for childhood brain tumors in the CBTRUS data for the age cohort 0 to 19 is somewhat different. Astrocytomas represent 40.5 % of the series; medulloblastomas 20.5%, and ependymomas 7.6% (see Table 71-1). Although individual series report some variation, astrocytomas remain the most common grouping. The type of tumor varies with age at diagnosis. In the age interval 0 to 4 years, glioblastomas, medulloblastomas/ primitive neuroectodermal tumors, pilocytic astrocytomas, and ependymomas predominate. Brainstem gliomas are less common in infancy but are increasingly recognized throughout childhood. Excluding infancy, the most common tumors identified in children are low-grade astrocytomas, medulloblastomas, high-grade astrocytomas, and cerebellar astrocytomas. Dysembryoblastic neuroepithelial tumors, central neurocytomas, hamartomas, craniopharyngiomas, and, to some extent, choroid plexus tumors represent a less common but more benign group of neoplasms with an excellent prognosis. Germ cell and non–germ cell tumors have an intermediate prognosis. Nonmedulloblastoma primitive neuroectodermal tumors were not coded in the SEER Registry data and are combined with medulloblastomas in the CBRTUS data. Increasingly more children, particularly in the first 2 years of life, are being identified with this diagnosis.

EPIDEMIOLOGY The causation of brain tumors is not a chance phenomenon. Proponents of causal inference generally agree on the following five criteria: 1. Biologic plausibility: Any agent implicated in the occurrence of a brain tumor should have direct access to the CNS, can interfere with intracranial cellular growth, and in some way can damage normal repair mechanisms. 2. The association between exposure and occurrence of tumor: Exposure is considered etiologically significant when the risk is increased fivefold rather than twofold. This epidemiologic axiom reflects the concept that the higher the risk, the less likely are confounding biases. 3. Consistency: The more reproducible, the more likely the association is meaningful. 4. Temporal order: Exposure occurs at a time in keeping with the known interval between tumor initiation and promotion. 5. Biologic gradient or dose-response relation: If the known factor (e.g., radiation) contributes to the risk of a brain tumor, those with the greatest exposure will have the highest risk of brain tumor development [Leviton, 1994]. There are well-known risk factors associated with the subsequent development of brain tumors. Genetic syndromes, such as neurofibromatosis, tuberous sclerosis, Lindau-von Hippel disease, Li-Fraumeni syndrome, Turcot’s syndrome, and the basal cell nevus syndrome, are all associated with increased risk of brain tumor in children. Patients with Wilms’ tumor and those with nevoid basal-cell carcinoma are more prone to develop medulloblastomas. It

1693

is also known that epilepsy and stroke tend to be more common in families of children with brain tumors [Schoenberg et al., 1975]. Another accepted risk factor is immunosuppression. Individuals immunosuppressed before or during renal transplantation have a 350 times greater risk of developing reticulum cell sarcoma [Schneck and Penn, 1971]. Similarly, children with ataxia-telangiectasia, who have a number of immunologic abnormalities, are also at greater risk for developing neoplasia [Swift et al., 1976]. Environmental factors are also believed to increase the risk for development of CNS tumors. These factors include exposure to aromatic hydrocarbons, N-nitroso compounds, triazines, and systemic hydrazines [Zeller et al., 1982]. Less well-documented associations implicated in the production of tumors are maternal consumption of barbiturates, background radiation, prenatal exposure to diagnostic x-ray studies [National Radiological Protection Board, 1981], trauma, infection, familial aggregation, and exposure to anesthetics at the time of pregnancy [Davis et al., 2001]. Ionizing radiation is a well-recognized cause of secondary oncogenesis in patients irradiated for CNS tumors. This is not exclusively a dose-related phenomenon as there are reports of low dose radiation associated with the subsequent development of meningiomas [Modan et al., 1974]. There is no accepted causal relationship however between CNS tumors and either electromagnetic field or microwave exposure. Of the inherited syndromes, neurofibromatosis may potentially provide the most information regarding oncogenesis. The association of neurofibromatosis with a diversity and multiplicity of tumors and the ability of these tumors to produce local hypertrophy of bone, skin, and muscle implies the presence of a substance capable of initiating or promoting tissue growth. Type 1 neurofibromatosis occurs with a loss of tumor suppressor gene and maps to the 17q11.2 chromosome region. The genes in this area encode for proteins instrumental in the signaling network of the P21 ras proteins [Buchberg et al., 1990]. The area of deletion on the long arm of chromosome 17 is quite large and therefore must have multiple functions. It is postulated that the NF1 gene product downregulates the function of the ras oncogene product, which provides a growth stimulus for signal transduction. These findings support the premise that advances in molecular biology will eventually lead to a basic understanding of oncogenesis. Tumors manifesting in the last half of the first decade of life, limited malignant features on histologic preparation, and long duration of symptoms before diagnosis are considered good prognostic signs. Neoplasms occurring in infancy, brainstem and thalamic location, and evidence of histologic aggressiveness are considered poor prognostic signs. Conditional probabilities address the question of the likelihood of survival for the next period of time if an individual has survived for a specified period. The probability of 5-year conditional survival if an individual has survived 2 years is greatest in the pediatric age group younger than 21 years, and for most tumors in this age group, other than glioblastoma, it is more than 70%. This suggests that 2 years may be a reasonable period in which to judge subsequent survival [Davis et al., 1999] (Fig. 71-5).

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Tumors and Vascular Disorders of the Nervous System / 71

FIGURE 71-5. Relative survival rates in patients with any primary malignant brain tumors (including those that were not confirmed microscopically) ages less than 21, 21 to 44, 45 to 64, and 65 years and older compared with relative survival conditional on having survived 1 to 2 years post diagnosis. (From Davis et al., 1999.)

DIAGNOSIS The diagnosis of a brain tumor depends on clinical suspicion, the diagnostic acumen of the physician, and the availability of MRI. Signs and symptoms of brain tumors vary, depending on age and development of the child, tumor location, and amount of neurologic integrity that is compromised. No pathognomonic features exist. The temporal course of a child with a brain tumor is usually progressive and insidious. At times, a remitting course followed by exacerbation is recognized. It is instructive to refer to Cushing’s monograph, which describes the course of a young child with a cerebellar astrocytoma [Cushing, 1931]. Cushing reported that a child, apparently normal in all respects, may have a history of early morning headache and vomiting. The symptoms may resolve during the course of the day. As an expansible head enlarges to accommodate increasing pressure, symptoms may abate and the episode may be forgotten. Subsequently, the child may develop an ataxic syndrome and present with papilledema, signaling uncompensated growth of a posterior fossa mass. Thus, although the temporal history of most brain tumors is insidious and progressive, remitting and exacerbating courses are well known. Signs and symptoms of a general nature without focal signature may reflect increased intracranial pressure. Elevation of intracranial pressure can result from obstruction of ventricular pathways or from a mass growing within a fixed cranial volume. Nonspecific symptoms of intracranial pressure include irritability, lethargy, vomiting, anorexia, headache, weight gain or weight loss, and changes in behavior, personality, or school performance. Focal pathology may not signify focal disease. For instance, the abducens nerve, because of its long free intracranial course and proximity to bony structures, may be

compromised as the result of increased pressure. Thus diplopia secondary to abducens paresis may not signal a focal pathologic condition but rather increased intracranial pressure. It is axiomatic that papilledema always suggests increased intracranial pressure and, by extension, the possible presence of a mass lesion. When present, optic atrophy or visual loss implies either long-standing, unrecognized pressure or a focal pathologic process. The earliest sign of papilledema is an increase in either the blind spot (cecal scotoma) or loss of color vision (dyschromatopsia). These signs must be assiduously sought because most children with insidious compromise of the visual axis do not spontaneously offer visual complaints. Obstruction of cerebrospinal fluid pathways occurs with tumors invading the midline of the cerebellum, mesencephalon, diencephalic regions, or within the ventricles. Because pontine tumors are primarily found on the ventral surface of the brainstem, they may not occlude the ventricular outflow tracts until late in their course. Hemispheric tumors tend to produce pressure by mass effect rather than by obstruction of the ventricular pathways. Increased intracranial pressure may not produce symptoms other than headache and vomiting until pressure rises high enough to impede cerebral circulation. Acute changes in pressure have the potential for producing dynamic effects within the head. Different herniation syndromes (uncal, transtentorial, and central herniation) may occur and are reviewed in Chapter 65 [Plum and Posner, 1982]. Unlike downward herniation syndromes, posterior fossa lesions may lead to alterations of consciousness because of upward rather than downward shift. Herniation of the superior vermis of the cerebellum through the tentorium may compromise midbrain and diencephalic structures. Both downward and upward herniation can interfere with the reticular formation, resulting in alterations in the level of consciousness. Early signs of tonsillar herniation may be head tilt and stiff neck. The latter occurs as a result of irritation of cervical roots by the herniating mass. Although herniation syndromes are not common, they do represent an acute neurologic emergency and require immediate intervention. Bailey and co-workers [1939] commented that headache was an uncommon symptom in children and, when present, suggested organic disease. Head pain is one of the most common complaints that a pediatric neurologist is asked to evaluate. This complaint involves all age groups and may not signify structural disease. Suspicion of a brain tumor should be greatest in the child with onset of headache within the past 4 to 6 months [Honig and Charney, 1982]. Location of headache is not pathognomonic. Headache associated with cerebellar tumors may be frontal or occipital in location. Focal headache, however, is more likely to imply organic disease than generalized headache and, in the absence of intracranial pressure, may suggest pathology underlying the point of pain or a referral pattern from a distant source (Fig. 71-6). Headaches that increase with coughing, sneezing, straining at stool, or other forms of Valsalva maneuvers are a reliable but often unsolicited symptom of increased intracranial pressure. Early morning headache relieved by vomiting, and headaches that awaken the child from sleep are particularly worrisome for increased intracranial pressure and mass lesions.

Cohen and Duffner / Tumors of the Brain and Spinal Cord

FIGURE 71-6. Focal headache in 2-year-old with dermoid. Note inner table defect in occiput.

Perhaps more than headache, changes in personality, energy level, or motivation are the harbingers of intracranial pathology. Anorexia, bulimia, abulia (i.e., lack of motivation), weight gain or loss, lethargy, sexual precocity, or autonomic abnormalities should raise the suspicion of hypothalamic or pituitary disease. Focal seizures, when accompanied by slow-wave changes in the electroencephalogram (EEG) or clinical observations of impaired neurologic function, may suggest an underlying mass. Signs pointing to location in the cerebellar hemisphere or vermis should suggest the presence of a cerebellar tumor. The findings of ataxia, cranial neuropathies, and long tract signs without evidence of increased intracranial pressure suggest a lesion of the brainstem. Alterations in mentation, endocrinopathy, and changes in visual acuity raise the pos-

FIGURE 71-7. Axial CT of a 16-year-old with an astrocytoma demonstrating ring enhancement.

1695

sibility of disease of the midline of the CNS. Hemisensory, hemimotor, and hemianopic abnormalities all suggest localization to specific parts of the cerebral hemispheres. Because most brain tumors are compressive rather than destructive, neurologic signs may be subtle. Visual inattention, decreased arm swing on one side, a hint of foot drag, or suggestive flattening of the nasolabial fold may be the first indication of a cerebral hemispheric mass. Similarly, increasing clumsiness, inability to run or hop, or changes in energy level may suggest disease of the posterior fossa or midline brain structures. On suspicion of a mass lesion, diagnosis is confirmed by neuroimaging studies. For the most part, MRIs with and without gadolinium or high-resolution computed tomography (CT) scans with contrast have replaced other forms of imaging. Although high-resolution CT scanners can provide exquisite definition of most mass lesions in the nervous system (Fig. 71-7), this technique has generally been replaced by MRI (Fig. 71-8). Because the MRI does not image bone, parts of the nervous system inaccessible by CT scan can now be readily imaged. Lesions of the parasellar area, posterior fossa, and spinal cord are easily visualized by MRI. Failure to define soft tissue density because of the presence of bone and partial volume effects is obviated by MRI. The ability to image tissue in multiple planes, as well as the many paradigms of imaging coupled with ferromagnetic contrast agents, provide unsurpassed definition in both pathology and anatomy. T1-weighted images obtained in any plane provide in vivo–like definition of anatomy, whereas T2-weighted images readily identify tumor spread and resultant edema. The time to obtain an image and the consequent need for anesthesia in the young child are limiting factors.

FIGURE 71-8. MRI revealing large temporal lobe mass in an 18-year-old who presented with a single seizure. Surprisingly, neurologic examination was normal.

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Tumors and Vascular Disorders of the Nervous System / 71

5.24

7.26 65 db (Hz)

1.93 2.85

Gain Sweeps Filters Sen. Rate Duration Window

FIGURE 71-9. Angiogram of a 9-year-old male with recent onset of seizures. CT was equivocal. Simultaneous MRI revealed increased T2 signal, and angiogram demonstrated venous angioma. Patient is believed to have a venous angioma occurring in association with a hamartoma.

131K=C 2048 150-3000 25 uvolts 11.1 sec. 100 msec. 12 msec.

I - III = 3.31 III - V = 2.02 I - V = 5.33 I = 1.8 V/1 ratio = 3.6 V = 6.9 FIGURE 71-11. Brainstem auditory-evoked response in a 16-year-old female with a brainstem glioma. V Jewett wave is prolonged on the left side of the brainstem.

sciousness and the presence of epileptogenic activity. Evoked potentials, both visual and auditory, provide information regarding functional assessment. These techniques are valuable in following the course of a patient with a mass lesion but add little to the diagnostic evaluation. Visual evoked responses are most useful in assessing patients with intraorbital or chiasmatic tumors. Auditory short-latency evoked responses are useful for the evaluation of a child with a brainstem mass or acoustic neuroma (Fig. 71-11).

GENERAL PRINCIPLES OF MANAGEMENT FIGURE 71-10. MRI angiogram of a patient with arteriovenous malformation. (Courtesy Siemens Medical Corporation.)

Other adjuncts to diagnosis continue to be used, although in a limited way. Arteriography provides information regarding the vascularity of the tumor and helps exclude the possibility of a vascular malformation (Fig. 71-9). As resolution improves, MRI and CT angiographies have the potential to replace standard more invasive angiography (Fig. 71-10). Magnetic resonance spectroscopy, perfusion MRI, positron emission tomography scans, and single-photon emission computed tomography (SPECT) are helpful adjunctive diagnostic tools. Positron emission tomography has been used to differentiate tumor recurrence or progression from radiation necrosis. Unfortunately, both of these commonly occur simultaneously rather than in an isolated fashion. EEG, although a functional diagnostic tool, provides limited confirmation of the presence or absence of a mass lesion. Its primary use is in assessment of the level of con-

Treatment modalities of CNS cancer are primarily those developed in the middle part of this century. Debulking surgery, in combination with radiation or chemotherapy, are the mainstays of treatment. At diagnosis, most children with brain tumors have a mass of 0.5 cm or greater, a tumor burden of greater than than 109 cells and will have gone through approximately 27 doublings (Fig. 71-12). All treatment modalities destroy tumor by a log-kill hypothesis. For any treatment, a specific percentage of the cells will be destroyed rather than an absolute number. In a tumor burden of 109 cells, 90% surgical removal may reduce the tumor bulk from 109 to 108. Radiation is believed to add two more log kills, reducing the tumor burden from 108 to 106, and chemotherapy, in the best of circumstances, will add another one to two log kills or reduce the tumor burden from 106 to 104. If a treatment is to be effective, the remainder of the cancerous cells must be removed by the body’s own immune mechanisms [Silver et al., 1977]. Biologic response modifiers are increasingly used by themselves or in combination with chemotherapy to augment the tumoricidal response.

Cohen and Duffner / Tumors of the Brain and Spinal Cord

1016 1000 kilogram mass

1014

Number of cells

1012

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FIGURE 71-12. Tumor size related to number of doublings. (From Silver RT, Young RC, Holland JF. Some new aspects of modern cancer therapy. Am J Med 1977;639:722.)

1 kilogram mass

1010 1 cm mass 0.5 cm mass

108

Tumor 1 foot in diameter (35 doublings) Tumor first palpable (30 doublings)

1 mm mass

106 104

32 cm mass 8 cm mass 4 cm mass 2 cm mass

Tumor first visualized on X-Ray (27 doublings)

102 1

5

10

15 20 Number of doublings

25

30 35 40 45 50

Surgery Therapy begins with surgical attempts at bulk removal. Cushing’s romantic words describing the surgical approach remain a clarion call for the surgeon today much as they did in 1931: “When to take great risks; when to withdraw in the face of unexpected difficulty; whether to force an attempted enucleation of a pathologically favorable tumor to its completion with the prospect of an operative fatality, or to abandon the procedure short of completeness with a certainty that after months or years even greater risks may have to be faced at subsequent session; all this takes surgical judgment which is a matter of long experience and which can scarcely be transmitted by the written word” [Cushing, 1931].

In 1930, Cushing cited a surgical mortality for medulloblastomas of 32% [Cushing, 1930]. With advances in surgery, pediatric anesthesia, the use of the dissecting microscope, laser surgery, and the introduction of the cavitron and stereotactic surgery, operative mortality has declined to less than 2% to 5%. Surgery is not without its risks and needs to be approached with a full knowledge of the possible consequences of treatment. The neurosurgeon should perform a gross total resection when possible, alleviate increased intracranial pressure, relieve local compression of tumor on functional areas, reestablish circulation if obstructed, and provide a tissue diagnosis. Surgical cure can be expected in the treatment of cystic cerebellar astrocytomas, a percentage of craniopharyngiomas, holocord astrocytomas, and extra-axial tumors, such as meningiomas. Although not associated with a definitive cure, it is recognized that gross total resection measurably increases survival in infants younger than 3 years of age with a variety of brain tumors, including medulloblastomas and ependymomas [Duffner et al., 1993].

Surgical techniques continue to evolve. Ultrasonography during surgery permits localization of deep tumors not readily apparent at surgery and provides a means of assessing the extent of tumor resection. For tumors located in eloquent areas such as speech areas, the motor strip, or the brainstem, neuroimaging-guided stereotactic methods are increasingly helpful. Targets can be mapped that encompass tumor volumes and avoid these sensitive areas. Deep-seated tumors can be approached using stereotactic technology coupled with sophisticated imaging. After surgery, most tumors require some form of radiation or chemotherapy, either independently or in combination. These treatments are not without risk and need to be approached with a full awareness of their possible consequences. With refinement of therapeutic techniques, surgeons are now asked to consider repeat operations in an effort to resect recurrent or residual tumor. This philosophy is recommended in an effort to establish the changing pathology of the tumor, to differentiate radiation necrosis from recurrent tumor and, based on the log-kill hypothesis, to reduce the tumor burden available for adjuvant therapies. Although they can provide irrefutable evidence of a mass, MRI/CT does not reliably differentiate radiation necrosis from recurrent tumor. Increasingly, positron emission tomography, by defining active metabolism of a tumor, is used to differentiate tumor necrosis from recurrent tumor [Valk et al., 1988]. In select cases, specifically in tumors of the posterior fossa, shunting procedures may be necessary to decompress a ventricular system that has expanded secondary to obstruction of cerebrospinal fluid pathways. Shunting provides gradual reduction of ventricular size and reduces the risk associated with sudden decompression as a consequence of tumor removal. As many as 30% of patients require cerebrospinal fluid diversion in the presence of a posterior fossa

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mass [Raimondi and Tomita, 1979b]. The temporary use of extraventricular drainage may obviate the need for a permanent shunt. Shunts should not be considered routine because they may provide a route for metastasis outside the nervous system. In addition to increasing the potential for metastasis, the presence of a foreign body increases the possibility of postoperative shunt infection, particularly if coupled with subsequent use of immunosuppressive agents. If an aggressive approach to treatment is to be undertaken, the pediatric neurosurgeon must be a strong advocate of the art of the possible and committed to debulk as much tumor as feasible without damaging normal tissue.

Radiation Radiation may contribute substantially to the patient’s progression-free and overall survival. The total dose of radiation necessary to destroy tumor and the amount tolerated by the developing brain are continually reexamined. The goal of therapeutic radiation must be the selective death of tumor cells. Ionizing radiation produces damage either by indirect or direct effects on the cell nucleus. The transfer of energy induced by radiation results in damage to the nucleic acid of the cell. The end result of this process is cell death or sublethal damage to the cell. Sublethal damage may result in either death or subsequent cell repair. Most brain tumors do not undergo active mitosis; therefore large doses of radiation are necessary. Other concerns are the volume of radiation and the dose per fraction. Volume of radiation refers to the total amount of brain and spinal cord to be irradiated and depends on the tendency of the tumor to seed the neuraxis. Because patients with medulloblastomas and primitive neuroectodermal tumors are prone to develop leptomeningeal disease, craniospinal radiation therapy coupled with a boost to the tumor bed is recommended. Low-grade supratentorial astrocytomas and brainstem gliomas usually do not seed the cerebrospinal fluid. As such, radiation can be limited to the tumor bed alone. Patients with ependymomas (unless they have leptomeningeal disease at diagnosis) are treated with local radiation, as the first site of failure is usually the primary site [Merchant, 2002]. Radiation doses for most CNS tumors, regardless of histology, range from 5500 to 6000 cGy to the tumor bed and 3000 to 3500 cGy to the craniospinal axis, usually given over 6 to 8 weeks. Most radiation protocols have been determined empirically. Although a great deal is known about radiation biology, the precise dose and schedule needed to destroy tumor and preserve normal tissue are not known. Young children are more susceptible to radiation toxicity than adults. Consequently, the total dose of radiation given to children younger than 2 years of age is generally reduced to a level 10% to 20% of the adult dose. Because the limits of tolerable radiation may have been reached, alternative ways of delivering high-dose radiation are being sought. Hyperfractionated radiation is an attempt to increase the total dose of radiation given over a defined period without increasing side effects. It is well recognized that radiation side effects can be reduced by decreasing the radiation dose per fraction. In most centers, 150 to 180 cGy of radiation are given as a single dose in a 24-hour period. With hyperfractionation, radiation dose is reduced to 110 to 120 cGy

per fraction but given every 12 hours. In this manner the total dose of radiation can theoretically be increased by 10% to 20% without increasing adverse effects on normal tissue. Hypoxic cells require two to three times the amount of radiation necessary to achieve the same degree of destruction as normally oxygenated tissue. As such, a reduction in oxygen tension below that normally present in tissue may lead to a substantial reduction in cell kill. The use of radiation sensitizers, treatment under increased oxygen tension, and different radiation modalities, such as neutrons or pimesons, are attempts to increase the radiation effect on hypoxic cells [Kun, 1994]. Brachytherapy (interstitial brain implants) is a technique used to deliver high-dose radiation to the tumor bed in an effort to improve local tumor control. Radioactive iridium or iodine is loaded into catheters that are stereotactically directed into the tumor bed. These implants are designed to achieve doses of 5000 to 6000 cGy within the radiated tissue over 5 to 6 days. Techniques have been developed to deliver doses as high as 10,000 cGy for intervals up to 7 or 8 weeks. Similarly, instillation of radionuclide colloids within a tumor cavity is used to deliver high-dose radiation. Radiosurgery (i.e., gamma knife, linear accelerator, proton beam) is the use of collimated radiation from multiple sources focused on a single volume in space. Radiosurgery typically delivers large doses (in excess of 2000 cGy) to tissue within the targeted volume. Although intralesional necrosis can be anticipated, marked injury to surrounding tissue is minimized because of the sharp falloff of the radiation dose from the center [Loeffler and Alexander, 1990]. Both radiosurgery and brachytherapy are limited to tumors less than 5 cm. In three-dimensional conformal radiation, stereotactic techniques are used to more precisely define a targeted volume, thereby decreasing radiation exposure to surrounding tissue. This technique is currently used in national studies for ependymomas and infants with medulloblastoma.

Chemotherapy The third arm of the treatment triad consists of chemotherapy. In the late 1950s, drugs became available that theoretically could reach and destroy tumor cells wherever they spread. This development provided a potential treatment not available by either surgery or radiation. In 1955, the Cancer Chemotherapy National Service Center was organized under the auspices of the National Cancer Institute. This plan set in motion a drug development program that included screening, toxicology, pharmacology formulation, clinical trials, and supportive care of patients with cancer. Only since the mid-1970s has interest in the chemotherapy of brain tumors heightened. Reasons for this delay have included the inaccessibility of the CNS to drugs administered systemically, the lack of accrual of large numbers of patients at individual centers, the previous difficulty in quantifying objective responses (before MRI), the fear of drug toxicity, and concerns about quality of life. Since the 1970s, however, there have been increasing numbers of organized efforts to develop chemotherapy protocols applicable for brain tumor trials. Two pediatric cancer cooperative groups (i.e., the Pediatric Oncology Group and the Children’s Cancer Study Group) undertook large multicenter trials investigating the

Cohen and Duffner / Tumors of the Brain and Spinal Cord

use of chemotherapy with and without radiation in children with CNS tumors. These two groups have since combined into the Children’s Oncology Group. Enrollment of large numbers of patients into cooperative ventures has permitted questions to be answered regarding the efficacy of new chemotherapeutic agents, delivery systems, immunotherapy, and other modalities of treatment not generally available at a single facility. All chemotherapeutic agents are first tested in vivo in animal models. Antitumor activity is identified on the basis of increased life span in these animal models. Toxicity is studied in large animals because qualitative and quantitative effects on various organ systems are more parallel to those in humans [Fewer, 1976]. After initial evaluation, chemotherapeutic agents are put through phase I studies in humans. These are essentially studies in which drugs are evaluated for toxic effects. Drugs then enter phase II trials to identify the spectrum of activity against human neoplasms and response of specific cancers to the drug. Phase II studies delineate the optimal dose schedule and establish validity of antitumor activity. Phase III trials are designed to determine whether the agent in question, when used in an adjuvant fashion, offers an advantage over “standard” therapy. Chemotherapeutic agents, in general, are considered cell cycle specific or cellcycle nonspecific. Knowledge of cell cycle kinetics is basic to the understanding of the mechanisms of action. The cell cycle is divided into four phases: G-1, the phase during which cells synthesize ribonucleic acid, enzymes, and proteins; S phase, the period during which DNA replicates and chromosomal proteins are laid down; G-2, the interval between the completion of DNA synthesis and mitosis; and M phase, mitosis. G-0 consists of those cells, although not actively proliferating, that have the potential to reenter the proliferating pool. Certain chemotherapeutic agents are considered cell cycle specific (i.e., they affect either the proliferating phase of the cell or a specific phase of the cell cycle). Cell cycle–nonspecific agents are effective during any stage of the cell cycle. Because of their broader spectrum of action, these agents have an advantage over cell cycle–specific agents [Valeriote and Vietti, 1977]; however, because the therapeutic index is narrow, significant morbidity often exists. To enter the CNS, a chemotherapeutic drug must be able to penetrate the blood-brain barrier. Consequently, those properties that allow access into the CNS include low molecular weight, high lipid solubility, nonionizable at physiologic pH, and lack of plasma-protein binding. Compounding the problem of effective drug delivery is the concept of the brain-adjacent tumor (Fig. 71-13). Malignant cells migrating from the center of a necrotic tumor into the periphery of normal brain adjacent to the tumor may be the most viable and have the greatest capacity for proliferation. Because of the intact blood-brain barrier, this region is the least accessible to treatment. Some have suggested that the importance of the blood-brain barrier has been overemphasized and that cellular mechanisms of drug resistance are more likely responsible for failures of chemotherapy than considerations of ability to breach the blood-brain barrier. The inability of a tumor to accumulate and retain drugs, the ability to metabolically degrade drugs, and the ability of a tumor to repair drug-induced damage to cellular constituents may be more important or just as important as

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Actively growing tumor (destroyed BBB, hence tumor likely susceptible to both hydrophilic and lipophilic agents) BAT TUMOR Necrotic center

BAT

BAT

Intact BBB (susceptible only to lipophilic agents) BAT = Brain-adjacent tumor

Dying cells in G-0 (no drug penetration) BBB = Blood-brain barrier

FIGURE 71-13. Diagrammatic representation of the brain-adjacent tumor.

drug delivery and the microenvironment of the brain [Phillips, 1991]. Thus location of the tumor, rate of growth, mitotic index, rate of entrance of drugs into the nervous system, and drug resistance all influence the choice of agents [Shapiro, 1975]. The optimum route of administration for chemotherapeutic agents is unknown. Although a great deal is known about mechanism of action, most chemotherapy protocols are developed on an empirical basis. Indications for intrathecal, intravenous, oral, or direct intra-arterial infusions have yet to be established. On theoretical grounds, those tumors that lie near the subarachnoid space should be the most susceptible to intrathecal administration, whereas those tumors occurring in the distribution of a specific arterial channel should be more susceptible to intra-arterial perfusion. To be effective, the therapeutic approach to patients with brain tumors must address problems inherent in the treatment of any cancer, as well as the added dimensions unique to the brain. These problems include (1) the ability to achieve a gross total resection of the tumor without serious neurologic residual, (2) the problem of pharmacologic sanctuary, and (3) the long-term and irreversible toxicity associated with treatment. The challenge for the future is the development of novel forms of therapy, targeted approaches for delivering current agents, and the development of agents that preserve normal tissue while destroying malignant cells.

MIDLINE TUMORS Midline tumors are those above the tentorium and that involve the hypothalamus, thalamus, optic pathways, pineal region, or arise in the ventricles. Tumors found in the region of the optic pathways, hypothalamus, and thalamic areas are most likely astrocytomas. Craniopharyngiomas occur in the parasellar area, whereas germ cell tumors are predominantly found in the pineal or suprasellar region. Tumors presenting in the ventricles are generally either choroid plexus papillomas or ependymomas. Less frequently, they may be

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FIGURE 71-15. CT demonstrating large thalamic glioma and obstructive hydrocephalus.

FIGURE 71-14. Colloid cyst of the third ventricle.

meningiomas. Infrequently, a colloid cyst of the third ventricle is identified (Fig. 71-14).

THALAMIC TUMORS Thalamic tumors are rare, more aggressive, and have a more truncated course than tumors found in the area of the hypothalamus or optic pathways. They are usually of the astrocytic series and vary in malignancy from relatively benign to highly aggressive. Long-term survival without treatment is well documented for low-grade astrocytomas, whereas the more malignant astrocytomas have a poor prognosis despite therapy [Arseni, 1958; Cheek and Taveras, 1966; McKissock and Paine, 1958; Tovi et al., 1961]. Less common tumors occurring in the lateral midline are ganglioneuromas, oligodendrogliomas, and ependymomas. Patients with thalamic tumors may present with headache, papilledema, confusion, memory loss, and emotional lability. Mental symptoms have been attributed to involvement of the medial thalamic nucleus or anterior thalamic projections. Abnormalities of speech occur with involvement of the ventrolateral nucleus [Ojemann and Ward, 1971]. Involvement of the cerebellar and rubrothalamic tracts may cause unilateral dysmetria, tremor, incoordination, or unsteady gait [Bendhein and Berg, 1981]. Dystonic movements and unilateral chorea implicate abnormalities of the subthalamus or basal ganglia. Visual loss may be secondary

to involvement of visual pathways or associated with increased intracranial pressure. Despite location in the thalamus, sensory findings in this region are not common. The thalamic syndrome is virtually never encountered. Behavioral changes may be associated with thalamic masses, suggesting that functional derangement not specifically related to the anatomic site of involvement may occur with tumors of the thalamus. Clinical suspicion of a mass in the thalamus or basal ganglia is confirmed by neuroimaging. Some degree of contrast enhancement on CT (Fig. 71-15) is common. MRI confirms the diagnosis and the anatomic definition of the tumor. EEG findings may consist of bursts of symmetric high-voltage slow waves, delta or theta, occurring in the waking state. EEG may lateralize findings to one hemisphere and consist of ipsilateral depression, normal background, or lateralized polymorphic delta slowing. Sleep spindles may be observed in the waking state.

Hypothalamic Tumors Astrocytomas occurring in the hypothalamus generally have a different pathology and biology than those occurring in the thalamus. Anterior hypothalamic tumors may blend imperceptibly into the area of the optic chiasm or tracts, thus making the distinction between optic gliomas and hypothalamic tumors arbitrary. Grossly, they are described as avascular, gelatinous masses. Histologically, the tumors are usually pilocytic, characterized by compact and spongy regions consisting of elongated cells surrounding spongy loose areas in which stellate astrocytes are observed. Necrosis, hemorrhage, and Rosenthal fibers may be manifest. An exophytic component is common. Signs and symptoms are commensurate with the location of the tumor. Hypothalamic tumors may invade the optic chiasm or extend inferior and posterior to invade the intrapeduncular fossa and basal cisterns. Depending on location,

Cohen and Duffner / Tumors of the Brain and Spinal Cord

FIGURE 71-16. A 5-year-old male with neurofibromatosis and precocious puberty. MRI demonstrates hypothalamic mass.

presenting signs may be autonomic, endocrinologic, or visual. Endocrinopathies may be associated with hypothalamic tumors and include failure to thrive, emaciation, loss of subcutaneous fat, sodium loss, hypoglycemia, and accelerated long bone growth [White and Ross, 1963]. Children with tumors in this region, such as hamartomas of the tuber cinereum, may also present with precocious puberty. Astro-

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cytomas, ependymomas, ectopic pinealomas, suprasellar germinomas, suprasellar cysts, and craniopharyngiomas have all been associated with precocious puberty. Non-neoplastic causes of precocious puberty are postinfectious states, neurofibromatosis, and hydrocephalus (Figs. 71-16 and 71-17). Tumors of this region are initially suspected because of the clusters of clinical signs pointing to the hypothalamus. The presence of a tumor is confirmed by the appropriate neuroimaging technique. Searching nystagmus, sometimes erroneously considered to be congenital nystagmus, should suggest a tumor in the region of the optic chiasm with posterior extension into the anterior hypothalamus. Although uncommon, the diencephalic syndrome, described by Russell in 1951, has been associated with astrocytomas (typically juvenile pilocytic astrocytomas) of the hypothalamus and optic chiasm [Perilongo et al., 1997; Russell, 1951]. This syndrome manifests in young children between 18 months and 3 years of age and is uncommon in the older child. The child develops normally followed by a period of profound inanition. Hypoglycemia may be present. Excessive appetite, without weight gain, and accelerated long bone growth may be the prominent features. Profound loss of subcutaneous tissue in a happy, normally developing child should raise the possibility of this syndrome. More common symptoms of hypothalamic tumors are obesity, diabetes insipidus, and hypogonadism. Lethargy rather than euphoria is regularly described. With extension into the region of the foramen of Monro, obstructive hydrocephalus may develop with subsequent signs of acute increased intracranial pressure. Leptomeningeal seeding has been increasingly reported in children with the diencephalic syndrome secondary to juvenile pilocytic astrocytomas [Gajjar et al., 1995; Perilongo et al., 1997a] (Fig. 71-18). As such, neuroimaging at diagnosis should include the brain and neuraxis.

Management “Watchful waiting” is often the approach to tumors of the hypothalamus, particularly for those identified on

FIGURE 71-17. Patient exhibits precocious puberty.

FIGURE 71-18. A 10-month-old child presented with large head, emaciation, and alert appearance. MRI revealed hypothalamic mass with enhancing metastatic lesions in the cerebellum, brainstem, and spinal cord.

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FIGURE 71-19. A 3-year-old child with widely disseminated juvenile pilocytic astrocytomas who developed progressive disease on chemotherapy and therefore received craniospinal radiation. The child developed moyamoya disease as a consequence of her radiation therapy.

“screening” MRIs in children with neurofibromatosis. However, in symptomatic cases, biopsy and, when feasible, debulking surgery is performed followed by consideration of radiation to the tumor bed. Radiation doses between 5000 and 6000 cGy have been associated with reversal of symptoms and even long-term cures. Five-year survival rates of 71% and 10-year survival rates of 56% for children with hypothalamic tumors are well known. In very young children with hypothalamic tumors, in whom there are concerns about radiation-induced vasculopathy, chemotherapy has been used with variable success [McCowage et al., 1996] (Fig. 71-19). Survival for patients with thalamic tumors is much worse. Treatment generally is limited to high-dose radiation to the tumor bed except in those tumors that seed the cerebrospinal fluid pathways. In such situations, craniospinal radiation therapy is indicated [Bernstein et al., 1984; Bloom et al., 1990; DeSousa et al., 1979]. On recurrence, chemotherapy should be considered.

In the absence of neurofibromatosis, diminished visual acuity is the most common presenting sign. Because children as well as adults are generally unaware of gradual decrements in visual acuity, visual loss may not be detected until late in the course of the disease. A nonpulsatile proptosis suggests the presence of an intraorbital mass, whereas nystagmus suggests chiasmatic involvement. The nystagmus usually consists of a series of short arcs and rapid oscillations with scanning or searching slow, wide arc movements [Chutorian et al., 1964]. Spasmus nutans and congenital nystagmus have been confused with the nystagmus occurring in patients with tumors involving the optic chiasm or visual pathways [Anthony et al., 1980]. An afferent pupillary light defect suggests pathology of the optic nerve, whereas a field defect is more apt to be associated with pathology involving the posterior portions of the optic nerve, chiasm, or tract. Field defects in these situations may be congruous or incongruous. Signs of papilledema suggest involvement of the anterior hypothalamus with extension posteriorly to involve the foramen of Monro. Conversely, blurring of the disk and loss of central vision should suggest an intraorbital mass. The presence of optic atrophy may preclude the development of papilledema despite evidence of increased intracranial pressure. CT and MRI have all but eliminated the need for other neurodiagnostic imaging. Both methods allow direct visualization of the optic nerve in both the axial and coronal projections. Sections cut oblique to the horizontal and longtudinal axis provide greater appreciation of the anatomy. MRI with gadolinium, because of the multiple paradigms of imaging and the ability to image in the coronal, sagittal, and axial planes, has essentially replaced CT. The midsagittal view is valuable in establishing the extent of a chiasmatic lesion but is limited in evaluating intraorbital tumors (Fig. 71-20). Unlike CT, MRI may also identify those T2-weighted lesions associated with neurofibromatosis believed to be non-neoplastic (Fig. 71-21). In patients with neurofibromatosis, streaking along the optic pathway and involving the optic radiations is not unusual and may not represent tumor. Similarly, T2-weighted signals on MRI involving the optic tract and geniculate bodies (Fig. 71-22)

Optic Pathway Tumors Optic gliomas comprise approximately 3% to 5% of all childhood tumors. Their association with neurofibromatosis is well recognized [Dutton 1994; Listernick et al., 1997; North, 1998]. The incidence of optic gliomas in children 2 to 9 years of age with neurofibromatosis may approach 3% to 10%. Conversely, of all children with optic gliomas, approximately 50% have neurofibromatosis [Rubinstein et al., 1981; Stern et al., 1979]. As with hypothalamic astrocytomas, most tumors of the anterior visual pathways are generally classified as juvenile pilocytic astrocytomas. Anaplastic astrocytomas and glioblastomas in this area are less common. Gliomas of the optic nerve can be quite variable and may be limited to a single optic nerve, occur bilaterally, involve the optic chiasm, or extend throughout the entire visual pathway [Cohen and Duffner, 1991].

FIGURE 71-20. Chiasmatic glioma in child with neurofibromatosis. T1weighted MRI demonstrates thickened chiasm.

Cohen and Duffner / Tumors of the Brain and Spinal Cord

FIGURE 71-21. Increased T2-weighted signals demonstrate unidentified bright objects in the basal ganglia in patient with neurofibromatosis.

have been associated with compression of white matter by an extrinsic lesion; therefore, these findings need to be viewed circumspectly. Despite knowledge of the existence of optic pathway tumors for more than 150 years, no universally accepted approach to treatment exists [Glaser et al., 1971], although

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this issue has recently been reevaluated [Listernick et al., 1997]. Many of these tumors are benign and have a long natural history. A consensus is now developing that on recognition of optic pathway tumors, patients should be monitored and not treated until there is evidence of progression either by neuroimaging or by ophthalmologic assessment. Continual evaluation of the patient should include serial MRIs, visual acuity, and visual field testing. MRI is the most sensitive procedure to evaluate progressive disease and, in the presence of known pathology, should be obtained every 3 to 6 months (Fig. 71-23). Treatment is initiated on evidence of progression as manifested by either continued visual loss or progression on neuroimaging. For patients whose tumors are intraorbital and in whom there is no useful vision, surgical removal of the nerve to the level of the chiasm is warranted. For children younger than 5 years in whom the tumor extends intracranially, the treatment of choice is chemotherapy. As surgical debulking or even biopsy may be associated with visual compromise, this approach remains somewhat controversial. Several reports have advocated the effectiveness of actinomycin D and vincristine [Packer et al., 1988b]. A Pediatric Oncology Group study evaluating 50 patients with progressive optic pathway tumors has shown that carboplatin used as a single agent may be effective [Mahoney and Cohen et al., 2000]. Others have advocated carboplatin in combination with vincristine [Packer et al., 1993]. These two drugs have become the standard chemotherapy for tumors of this region and are the combination that all other agents are measured against. For children older than 5 years of age, radiation with or without chemotherapy continues to be the treatment of choice.

Pineal Region Tumors Tumors arising in the pineal region are rare. Incidence rates are variable because of imprecise histology, tumor location, and different rates of occurrence in Asian as opposed to Western countries. For example, the incidence of germ cell tumors and pineal region tumors varies from 2.6% to 6.5% in several Japanese articles versus 0.4% to 0.7% in the

A

B

FIGURE 71-22. A, T1 axial MRI of a 3-year-old with a chiasmatic mass. B, T1 axial MRI of an optic pathway tumor involving the left optic tract.

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Tumors and Vascular Disorders of the Nervous System / 71

Clinical suspicion of optic glioma (visual symptoms) or Neurofibromatosis

CT scan orbit and head or MRI orbit and head

Abnormal Normal

Visual assessment a) Visual field b) Visual acuity c) Visual evoked response

Longitudinal evaluation

Abnormal Normal

Surgery if no useful vision and intraorbital Chemotherapy or Radiation if visual change, chiasmatic, location, and tumor progression*

FIGURE 71-23. Suggested approach to the evaluation of an optic pathway tumor. * For children less than 5 years of age, chemotherapy is preferred over radiation therapy. (From Cohen and Duffner, 1994a.)

Longitudinal evaluation Repeat studies at 6 months

Western literature [Cohen and Duffner, 1994e; Packer et al., 2000]. Further complicating understanding of the incidence rates is the confusion in the literature in distinguishing parenchymatous tumors of the pineal region from teratomas and germinomas. Germ cell tumors have been classified into three distinct groups: germ cell tumors that respond to radiation; nongerminomatous germ cell tumors that do not respond to radiation (i.e., embryonal carcinomas, yolk sac or endodermal sinus tumors, choriocarcinomas, and immature teratomas); and mature teratomas. The most common variant is the mixed germ cell tumor. Tumors that derive from the neuroepithelium of the pineal gland itself (i.e., pineal parenchymal tumors) are divided into pineoblastomas, pineocytomas with and without ganglion cells, and astrocytomas. Germ cell tumors most commonly occur either in the pineal or suprasellar regions but are also recognized in other areas of the brain including the basal ganglia, thalamus, and fourth ventricle. Germinomas tend to extend into neighboring structures and seed along cerebrospinal fluid pathways. The germinoma consists of large primitive spheroid cells indistinguishable from those of testicular or ovarian germinomas. Lymphoid cells are prominent in their stroma. The embryonal component of these neoplasms is more likely to be associated with elevation of either α-fetoprotein or β-human chorionic gonadotropin (β-HCG) and if so, are not true germinomas. Carcinoembryonic antigen has also

been associated with immature and mature teratomas [Allen, 1991; Edwards et al., 1985] (Table 71-2). Nongerminomatous germ cell tumors are more heterogeneous, tend to calcify, and for the most part are limited to the pineal region. Pineal area tumors peak in the latter half of the second decade of life and are more common in boys than in girls. Suprasellar germinomas, unlike those occurring in the region of the pineal, are more apt to affect the sexes equally or have a female preponderance. Clinical presentation is variable and may be associated with increased intracranial pressure and Parinaud’s phenomena (i.e., lack of convergence, upward gaze, and accommodation). Visual loss, diabetes insipidus, precocious puberty, and emaciation imply an anterior hypothalamic location or are the result of metastasis from the pineal region anteriorly into the third ventricle. The triad of visual loss, hypopituitarism, and diabetes insipidus should suggest a suprasellar location. CT and MRI demonstrate a vast radiologic heterogeneity in pineal region tumors. They are associated with isodense to variable enhancement with contrast, with or without calcification. Enhancement along the walls of the ventricles suggests cerebrospinal fluid seeding. On MRI, teratomas are characterized by hyperdense, lobulated masses with areas of decreased signal suggesting calcification or multiple cysts (Fig. 71-24). CT more readily identifies calcification.

TABLE 71-2 Tumor Markers and Survival TUMOR MARKERS HISTOLOGY

INCIDENCE* (% OF GCT)

AFP

HCG

CEA

5-YEAR SURVIVAL* (%)

Pure (56%) Germinoma Embryonal carcinoma Endodermal sinus tumor Choriocarcinoma Immature teratoma Mature teratoma Mixed (44%)

24 2 2 3 10 15 –

– +++ +++ – – – –

+ +++ — +++ – – –

– – – – + + –

80 <10 <10 <10 40 75 –

AFP, alpha-fetoprotein; HCG, human choroids gonadotropin; CEA, carcinoembryonic antigen; GCT, germ cell tumor; –, absent; +, weakly positive; +++, strongly positive. *Data from Allen, 1991.

Cohen and Duffner / Tumors of the Brain and Spinal Cord

FIGURE 71-24. MRI of 15-year-old male with teratoma who presented with hydrocephalus and visual compromise.

Management The treatment of children with pineal region tumors is determined by pathology. As such, biopsy (or resection if possible) should be performed on all patients. Although operative mortality of 30% to 60% was previously reported for direct approaches [Davidoff, 1967; DeGirolami and Schmidek, 1973], this rate has dropped dramatically in recent years. Ventricular cisternostomy is the most common diverting procedure for tumors that occupy the cavity of the third ventricle. Direct approaches to the tumor bed are complicated because of the presence of large venous channels in the pineal region. Increasingly, direct approaches to the tumor are being undertaken stereotactically. Nongerminomatous germ cell tumors are not radiosensitive but may respond to chemotherapy, especially platinum-based multiagent chemotherapy [Herrmann et al., 1994]. Conversely, germinomas are radiosensitive and, like their extracranial counterparts, are also chemosensitive. Administration of postoperative chemotherapy has successfully allowed reduction in the dose and volume of radiation in children with germinomas [Allen, 1991]. The 5-year survival rate, after standard radiation, may be as high as 50% to 80% [Brady, 1977; Jenkin et al., 1978; Rao et al., 1981]. Most chemotherapy regimens are platinum based in combination with a variety of other agents (i.e., cyclophosphamide, vinblastine, etoposide, bleomycin, ifosfamide [Allen, 1994; Buckner et al., 1999; Chang et al., 1995]. Overall, the survival for patients with true germinomas treated with 4000 cGy or greater is 90% or higher. The need for craniospinal radiation in the absence of cerebrospinal fluid dissemination remains controversial. There is growing evidence that reduced dose and volume radiation coupled with chemotherapy may provide equivalent survivals with fewer cognitive and endocrine side effects [Packer et al., 2000]. Although the need for prophylactic spinal irradiation in germinomas remains controversial, full neuraxis radiation should be given when the cerebrospinal fluid is positive for cells or MRI of the spine demonstrates seeding. If the tumor is resistant to radiotherapy or in situations in which tumor has regrown, chemotherapy should be considered. Platinum, carboplatin, vincristine, doxorubicin (Adria-

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mycin), cyclophosphamide, and procarbazine all have been associated with responses. Because pineoblastomas are likely to seed the neuraxis, all patients require craniospinal radiation. Radiation doses of 50 Gy or higher were associated in one study with better control than lower doses [Schild et al., 1996]. Unfortunately, responses and overall survival rate are extremely poor. In a review of 75 children with pineoblastomas, 76% either had died or had progressive disease [Duffner and Cohen, 1997]. Survival rate appears to vary with age because the prognosis is particularly grim in very young children in whom widespread metastases and early death can be anticipated [Duffner et al., 1995a]. In contrast, Jackacki and colleagues [1995] reported that older children treated with craniospinal radiation and either “8 in 1” or vincristine, CCNU, and prednisone had a 3-year progression-free survival of 70%. For patients with benign teratomas, dermoids, gliomas, or arachnoid or pineal cysts, surgery can be curative.

Craniopharyngiomas Craniopharyngiomas account for approximately 6% to 10% of all tumors in childhood [Rubinstein, 1972]. Diagnosis peaks in the latter half of the first decade and in the early part of the second decade (5 to 14 years). A second peak occurs in late adulthood (50 to 75 years). Survival rates are highest for those diagnosed at a young age. There is no obvious sex predominance. Tumors may be quite variable in location, although most are suprasellar. Occasionally the tumor presents as an intrasellar mass. These tumors usually fill the cavity of the third ventricle or extend inferiorly and posteriorly along the dorsum sella and clivus, displacing structures at the base of the brain (Fig. 71-25). Craniopharyngiomas putatively arise from embryonic squamous cell rests occurring in the pathway of the involuted tract of the hypophyseal pharyngeal duct. In 1838, Rathke reported the presence of an irregular globular depression at the base of the skull in the roof of the primitive stomatodeum of animals. This depression forms the analog of the anterior portion of the pituitary. Cells along the craniopharyngeal duct are considered to be the site of origin of the craniopharyngioma.

FIGURE 71-25. Gross picture of a craniopharyngioma.

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Craniopharyngiomas are largely cystic or partially solid with a firm capsule, usually at the superior end, blending in a finger-like fashion into the surrounding hypothalamus. Cyst contents tend to be thick, brownish yellow, or green, with machine oil-like fluid rich in cholesterol crystals. The cyst content may be gelatinous rather than fluid. Chemical arachnoiditis may result from spillage of cyst contents at surgery. Solid areas contain foci of calcification and early bone formation. Microscopically the tumor represents an epithelial, microcystic tumor. Keratin pearls may be observed among areas of squamous epithelium. Palisading or columnar cells similar to those seen in embryonic dental and oral mucosa have been described and account for the association of this tumor with the adamantinoma found in the jaw. Tumors found in childhood are more likely to resemble the adamantinoma or ameloblastoma of the jaw. Adult tumors are thought to arise from squamous epithelial rest cells rather than the involuted hypophyseal pharyngeal duct and are therefore less likely to resemble dental tissue [Bunin et al., 1998]. As is the case with most intracranial masses, children with craniopharyngiomas complain of headache and vomiting and have nonspecific signs of increased intracranial pressure. Various visual defects may be present, depending on whether the tumor occurs above, below, or behind the visual axis. Endocrine abnormalities include short stature and hypothyroidism. Diabetes insipidus, if not present on presentation, often occurs postoperatively. Less commonly, vegetative states, abnormalities of autonomic function, or disturbances of fluid or electrolyte balance may be recognized [Sotos and Romshe, 1975]. Lateralized neurologic abnormalities are distinctly uncommon. Diagnosis is made primarily by CT or MRI (Fig. 71-26). Calcification that is patchy, diffuse, or linear may be observed in up to 80% of children with craniopharyngiomas. CT features consist of calcification, areas of low density,

FIGURE 71-26. T1-weighted MRI in a child with craniopharyngioma.

cyst formation, and contrast enhancement. Because of the tumor’s location in the third ventricle, obstruction of cerebrospinal fluid outflow with resultant hydrocephalus is a common finding. Differentiation of a craniopharyngioma from a chiasmatic or hypothalamic tumor by CT may be quite difficult. MRI is superior to CT in delineating parasellar anatomic structures, such as blood vessels, the optic chiasm, the foramen of Monro, and the pituitary. However, the presence of calcium, a common feature in children with craniopharyngiomas, is best identified by CT.

Management Skilled endocrine management has eliminated fears of intraoperative and postoperative hypopituitarism and has led to more aggressive surgical management. The introduction of steroids has essentially eliminated intraoperative adrenal insufficiency. Currently there are two widely differing surgical approaches. Because the tumor may be densely adherent to the hypothalamus with finger-like projections into its floor, some have suggested that aggressive surgery results in trauma to the hypothalamus with postoperative endocrine and psychologic abnormalities. In these situations, surgical extirpation is not warranted and palliative surgery followed by radiation is the procedure of choice. In tumors in which there is no attachment to the hypothalamus, total surgical removal is contemplated, thereby eliminating the tendency for recurrence and the subsequent need for radiotherapy [Hoffman, 1982; Matson and Crigler, 1969; Yasargil et al., 1990]. Radiation for craniopharyngiomas was initially introduced in 1937. However, only since the 1960s has there been increasing acceptance of the use of radiation in combination with subtotal excision for the treatment of this tumor. The literature suggests that patients with subtotal surgical removal followed by radiotherapy are less apt to experience recurrence and have a better survival rate than patients treated by biopsy and cyst aspiration followed by radiotherapy. Results of total excision alone, compared with subtotal excision and postoperative radiotherapy, are more difficult to analyze. In general, most neurosurgeons and radiotherapists accept the recommendation of radiation once there is evidence of recurrence [Cavazzuti et al., 1983; Danoff et al., 1983; Fischer et al., 1990; Shillito, 1980]. The major morbidity, regardless of treatment, is significant endocrinopathy [Andler et al., 1979]. If not present before treatment, these conditions occur after treatment and consist of delayed or decreased growth hormone production, decreased adrenocorticotropic hormone, thyroid-stimulating hormone, luteinizing hormone/follicle-stimulating hormone, antidiuretic hormone production, and decreased prolactin after thyrotropin-releasing factor stimulation. Normal growth may occur after surgery and radiation despite growth hormone deficiency. The mechanism by which patients with documented low growth hormone levels exhibit catch-up growth after successful treatment of craniopharyngiomas has never been determined. Suggested answers are the levels of somatomedin, insulin, and thyroid and the effects these hormones have in promoting normal growth despite the absence of growth hormone. Perhaps the major untoward complication of treatment, other than diabetes insipidus, is hyperphagia with morbid

Cohen and Duffner / Tumors of the Brain and Spinal Cord

obesity. This complication responds only in a limited way to dietary restriction and can be an overwhelming problem for patients and their families. The decision to irradiate must be tempered by the possibility of radiation necrosis of the brain, damage to the visual axis, and long-term effects on intelligence. Only if total excision is not possible should subtotal excision followed by radiation to the tumor bed be considered. Unfortunately, approximately 50% of patients with a gross surgical resection will have a recurrence and require radiotherapy [Merchant et al., 2002c].

Pituitary Adenomas Pituitary adenomas causing Cushing’s disease are rare in children [Devoe et al., 1997]. Cushing’s disease manifests with excessive weight gain and delayed growth due to increased adrenocoticotropic hormone production that results in increased adrenal cortisol production. Diagnosis is established by a positive dexamethasone suppression test, provocative metapyrone and corticotropin-releasing hormone tests, as well as demonstration of the tumor with MRI. The mean age of presentation in one study was 15.7 years [Bickler et al., 1994]. Transsphenoidal surgery is the treatment of choice in children and adolescents. Long-term follow-up studies in 42 children have shown an initial remission rate of 83%. Seven children experienced a relapse of Cushing’s disease an average of 4.2 years postoperatively and required repeat transsphenoidal surgery [Devoe et al., 1997].

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VENTRICULAR TUMORS Choroid Plexus Tumors Although rare, choroid plexus papillomas are an important tumor of childhood. Davis and Cushing [1925] reported six patients with choroid plexus papillomas and distinguished them from papillary ependymomas. Some continue to consider these tumors an unusual manifestation of ependymoma [Russell and Rubinstein, 1989]. Fourth ventricular choroid plexus papillomas are most commonly found in adults, whereas the lateral ventricles are the usual site in children. The third ventricle is rarely involved. Papillomas arising in the lateral ventricles tend to occur in the atrium of the ventricle. Unlike benign choroid plexus papillomas, the malignant variety is characterized by cellular pleomorphism, mitosis, multinucleated cells, necrosis, and hemorrhage. Spinal fluid seeding may occur with both the benign and malignant varieties. In at least one patient, a choroid plexus papilloma metastasized extraneurally [Valladares et al., 1980]. Malignant transformation has also been reported [Chow et al., 1999]. Presentation usually consists of signs of increased intracranial pressure, vomiting, clumsiness, headache, and seizures. Unilateral calcification in the trigone should suggest a choroid plexus papilloma. Although CT and MRI are the diagnostic methods of choice, angiography is required to define the vascular supply of the tumor (Fig. 71-27).

Management Treatment of choroid plexus papillomas is primarily surgical but, because of the vascular supply of the tumor, operative mortality remains high. As such, preoperative embolization has become increasingly popular [Pencalet et al., 1998]. Despite the risks, total removal is associated with cure. [Chow et al., 1999; McEvoy et al., 2000]. The use of radiotherapy and chemotherapy is restricted to tumors having malignant features or those that recur after surgery. The treatment of choroid plexus carcinomas also begins with attempts at gross total resection. In those cases in which a gross total resection is not possible because of the highly vascular nature of the tumor, administration of several courses of chemotherapy has been associated with reduction in tumor vascularity, allowing removal of the tumor in toto at “second look surgery” [St. Clair et al., 1991]. Because most choroid plexus carcinomas occur in infants, surgery is typically followed by chemotherapy for 1 to 2 years. If residual tumor remains or if the tumor grows during chemotherapy, radiation to the tumor bed and neuraxis is required [Chow et al., 1999; Duffner et al., 1995b].

PROGNOSTIC FACTORS

FIGURE 71-27. CT of a 7-month-old female showing a large choroid plexus carcinoma.

A review of the literature from 1966 to 1998 identified 566 choroid plexus tumors. Prognostic factors included histology, degree of surgical resection, and radiotherapy. Choroid plexus papillomas had 1-, 5-, and 10-year overall survivals of 90%, 81%, and 77% in comparison with 71%, 41%, and 35% for these with choroid plexus carcinomas. Degree of surgical resection was a significant prognostic factor in both choroid plexus papillomas and choroid plexus carcinomas.

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Radiotherapy, in this metanalysis, was found to be associated with significantly better survivals for children with choroid plexus carcinomas [Wolff et al., 2002]. In general, the primary treatment of choroid plexus tumors is surgery, ideally a gross total resection. Chemotherapy, followed by “second look” surgery, is helpful in reducing vascularity and allowing complete surgical removal of tumors that were initially incompletely resected. Children with nonmetastatic choroid plexus carcinomas, treated with gross total resection, chemotherapy plus or minus radiation may enjoy long-term survivals. Those that progress on chemotherapy may be “salvaged” with radiation.

Giant Cell Astrocytomas Another tumor occurring in the region of the ventricles is the subependymal giant cell astrocytoma, found in 6% to 18% of patients with tuberous sclerosis [Franz, 1998]. Giant cells are characteristic. Although considered an astrocytoma, they are of mixed glioneuronal lineage [Goh et al., 2004]. These calcified tumors are commonly found in the region of the foramen of Monro (Fig. 71-28). Presenting signs are usually those of obstructive hydrocephalus.

Management If the patient is asymptomatic, “watchful waiting” is appropriate. Otherwise, shunting to relieve hydrocephalus may be all that is necessary. Others recommend attempts at surgical

FIGURE 71-29. A 16-year-old male received a scan because he injured his head during a football game. He had a completely normal neurologic examination and no history of neurologic symptoms. The MRI revealed a large enhancing mass extending across the midline. The tumor was a meningioma.

resection [Goh et al., 2004]. Long-term prognosis for persons with these tumors is excellent.

Meningiomas Meningiomas are uncommon tumors of childhood and, when observed, are more apt to be found in the ventricle or in the posterior fossa [Cohen and Duffner, 1994d]. As with other ventricular tumors, intraventricular meningiomas present with signs of obstructive hydrocephalus, headache, vomiting, visual impairment, and papilledema. CT features are relatively typical, consisting of well-circumscribed or somewhat lobulated, irregular, high-density lesions that enhance with contrast.

Management Treatment of meningiomas is primarily surgical and when total removal is accomplished, complete cure can be expected; however, because of their bulky size and tendency to be sarcomatous, total surgical removal is difficult. Recurrence rate is high. As with other tumors, lack of total removal or evidence of recurrence are indications for radiation. Factors influencing response to radiation are the tumor’s vascularity, location, and growth rate. Specific histology of the tumor may be the least important factor in determining prognosis (Fig. 71-29).

Colloid Cyst

FIGURE 71-28. Subependymal giant cell astrocytoma in a 6-month-old infant with tuberous sclerosis. T1-weighted MRI demonstrates mass in the right lateral ventricle at the level of the foramen of Monro.

Although benign, the colloid cyst may manifest in a precipitous manner. This tumor originates from ependymal cysts attached to the choroid plexus in the roof of the third ventricle (see Fig. 71-14). The intermittent symptoms and signs of increased intracranial pressure are produced by the ball-valve effect of the tumor related to head position. Intermittent obstruction of the foramen of Monro has been associated with precipitous herniation and sudden death.

Cohen and Duffner / Tumors of the Brain and Spinal Cord

Management Total surgical removal is the treatment of choice.

POSTERIOR FOSSA TUMORS Tumors of the posterior fossa account for approximately 50% to 55% of all tumors in childhood. Although they are less common in children younger than 1 year of age, the posterior fossa is the most common site for brain tumors in the first decade. Tumors occurring in this area are usually neuronal or glial in origin. Less frequently, hemangioblastomas, dermoids, or arachnoid cysts are encountered. Even rarer in the United States is the tuberculoma. This entity must still be considered in the differential diagnosis of any child living in an endemic area for tuberculosis. The posterior fossa is the area of the nervous system located beneath the tentorium of the cerebellum. Because the anterior reflection of the tentorium extends to the posterior clinoid process, some authors include tumors of the diencephalon under the rubric of posterior fossa tumors. In this section, we consider neoplasms of the brainstem (i.e., midbrain, pons, and medulla) and cerebellum as posterior fossa tumors. Diencephalic tumors (tumors of the hypothalamus and thalamus) are considered under the classification of midline tumors. The most commonly occurring posterior fossa tumors are medulloblastomas, cerebellar astrocytomas, ependymomas, and brainstem tumors.

Medulloblastomas Of all childhood brain tumors, the most dramatic change in survival has occurred with medulloblastomas. In Cushing’s series of medulloblastomas published in 1930, only 1 of 61 children (1.6%) was alive at the end of 3 years. In the 1980s, the survival rate for medulloblastoma in the SEER Registry data approached 40% [Duffner et al., 1986]. In select series, survival rates of greater than 70% have been reported [Brown et al., 1977; Packer et al., 1988a]. This increase in survival has occurred as a result of more aggressive neurosurgery and the administration of high-dose radiation to the tumor bed coupled with craniospinal irradiation. The best results have been reported in patients older than 3 years of age who have no evidence of tumor after surgery and no evidence of metastasis throughout the subarachnoid space. The suggested congenital nature of medulloblastoma has led several investigators to apply Collins’ rule in predicting the course of the tumor: The period of recurrence risk for an embryonic tumor is 9 months plus the patient’s age at diagnosis. Thus, a 1-year-old child with a gross total resection would be considered cured if there was no recurrence in 21 months [Collins, 1955]. Although this concept has some validity in determining the prognosis of patients with medulloblastoma, there have been several reports of late recurrence. Medulloblastoma is believed to derive from remnants of the fetal external granular layer of the cerebellum or from cell rests found in the posterior medullary velum and possibly the anterior medullary velum of the cerebellum. Although pathologists have more than 50 years of experience

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with this tumor, there is no consensus as to the nature or origin of the medulloblastoma. The tumor was termed medulloblastoma by Bailey because he believed that the neoplasm consisted of embryonal stem cells with a pluripotential nature [Bailey and Cushing, 1925]. However, the medulloblast, as a normally occurring cell capable of differentiating along multiple cell lines, has never been satisfactorily identified. As such, present day pathologists believe that the medulloblastoma is a primitive neuroectodermal tumor with nonspecific differentiation. Detailed histologic analysis reveals that these tumors may differentiate along ependymal, astroglial, or neuroblastic cell lines. These observations support the concept that the medulloblastoma may represent a tumor of stem cell origin. As a result of the histologic similarity of medulloblastomas to primitive neuroectodermal tumors these two entities previously were grouped together as primitive neuroectodermal tumors/medulloblastoma. What primarily differentiates the two are location, either above (primitive neuroectodermal tumor) or below the tentorium, response to therapy and presence or absence of molecular markers. Since location and prognosis of these entities are so different despite the histologic similarities, primitive neuroectodermal tumors are currently classified as embryonal/primitive neuroectodermal tumors rather than primitive neuroectodermal tumors/medulloblastoma. Despite a growing body of literature detailing the existence of biologic markers, their prognostic value has been confusing. TRkC expression and low N-myc expression have been associated with increased survival. Conversely, c-myc, deletion of chromosome 1p, increased mitotic index, and alteration of ploidy have been associated with poor prognoses. The most frequent cytogenetic abnormality, found in about 50% of those with medulloblastoma has been the presence of isochromosome 17q [Eberhart et al., 2004]. More recently the atypical teratoid/rhabdoid tumor has been identified. Atypical teratoid/rhabdoid tumors have their highest incidence in children older than 36 months Although superficially similar to primitive neuroectodermal tumors histologically, these tumors have a much more aggressive clinical course and differentiating histologic and cytogenetic features. The term derives from the observation that the tumor has putative epithelial elements (teratoid) or resembles the malignant rhabdoid tumor seen in the kidney, soft tissues, and other organs. An abundance of spindle cells is suggestive of a sarcoma. This entity is associated with either monosomy or deletion of chromosome 22. The specific gene involved has been identified as hSNF5/IN11. This gene maps to chromosome 22q11.2 Atypical teratoid/rhabdoid tumors, like primitive neuroectodermal tumors, are found in the posterior fossa as well as above the tentorium. Rather than the cavity of the fourth ventricle, the tumor has a predilection for the cerebellar hemisphere and cerebellar/pontine angle [MacDonald et al., 2003]. Medulloblastomas occurring in the midline tend to be soft, fleshy, and well demarcated. Hemorrhage, cyst formation, and calcification are uncommon (Fig. 71-30). There is a great deal of heterogeneity in their cytologic features, mitotic activity, and differentiation. Many medulloblastomas have a high mitotic index with potential for local aggressiveness and spread throughout the neural axis. Histo-

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FIGURE 71-30. Gross pathology of a medulloblastoma occurring in the cerebellar vermis.

logically, the tumor is characterized by small round to oval undifferentiated cells with hyperchromatic nuclei in a matrix surrounded by little or poorly defined cytoplasm. Mitosis is variable and has led some pathologists to suggest that a paucity of mitosis, nuclear uniformity and desmoplastic features may be associated with less malignant behavior. Tumors characterized by large cells and anaplasia are considered to have a poor prognosis [Eberhart and Burger, 2003]. However, because there is a limited consensus over the prognostic effect of these pathologic variables, current staging regimens are based solely on clinical and imaging criteria. As with other primitive tumors, medulloblastomas tend to seed the subarachnoid space, both locally and distally. Approximately 70% to 80% recur initially in the posterior fossa. Recurrence in the area of the cribriform plate has been related to the failure to adequately irradiate this region. Extraneural metastases are well documented and, in some series, approach 5% to 30% [Banna et al., 1970; Cohen and Duffner, 1994a; Kleinman et al., 1981].

FIGURE 71-32. Cerebrospinal fluid cytology in a patient with medulloblastoma. Note clumped cells containing prominent nuclei and limited cytoplasm.

The primary sites of extraneural metastases are bone and bone marrow.

Clinical Characteristics Children with medulloblastomas have either nonspecific signs of increased intracranial pressure or a midline cerebellar syndrome. These signs are similar to those present with other posterior fossa tumors. Vomiting, titubation, and headache may reflect increased pressure or invasion of the floor of the fourth ventricle. Head tilt may occur secondary to either ophthalmoparesis or incipient cerebellar herniation. This finding may accompany or precede other signs and may be associated with neck stiffness. Nystagmus is conspicuously absent or mild. As with other cerebellar tumors, hypotonicity, decreased or absent reflexes, and ataxia characterize the motor symptoms. MRI reveals a gadolinium-enhancing heterogeneous mass presenting in the midline of the cerebellum. The tumor often occupies the cavity of the fourth ventricle, resulting in obstructive hydrocephalus (Fig. 71-31). Presentation in a cerebellar hemisphere is uncommon and is more likely to be associated with an atypical histology. Before treatment, extent of disease should be staged by MRI of the spine, cerebrospinal fluid cytology (Fig. 71-32), bone scan, and bone marrow aspiration.

Management

FIGURE 71-31. MRI (T2-weighted image) of 5-year-old child with medulloblastoma.

Treatment of medulloblastomas begins with the attempt to achieve a gross total resection. Aggressive surgery, without compromising neurologic function, provides definitive pathologic diagnosis and reestablishes cerebrospinal fluid integrity. When possible, intraoperative shunting should be avoided in an effort to close a possible portal for extraneural metastasis. In 1930, Cushing recognized the value of bulk removal. In that year he stated: “Radical surgery has greatly augmented the operative mortality rate, which in survivors has notably prolonged the subsequent symptom-free period.” Others have concurred that the smaller the amount of tumor left after surgery, the more likely adjuvant therapy will be helpful, and the better the prognosis [Raimondi and Tomita, 1979a; Tait et al.,

Cohen and Duffner / Tumors of the Brain and Spinal Cord

1990]. In very young children (<3 years of age), the ability to achieve a gross total resection strongly correlates with improved survival [Duffner et al., 1993]. Many factors have influenced the changing prognosis of medulloblastoma. At the time of diagnosis patients are classified into either a high- or standard-risk group. The standard-risk group are children older than 3 years with less than 1.5 cm3 postoperative tumor residual who have no evidence of subarachnoid seeding. Parenchymal spread outside the primary tumor site is less of a risk factor. High-risk patients are those with greater than 1.5 cm3 postoperative residual, subarachnoid seeding, and/or evidence of brainstem involvement. Whereas 5-year survival rates for those with standard-risk disease is more than 80%, those with high-risk disease have a worse prognosis. There is overwhelming consensus that radiotherapy has been the major reason for improved survival. The use of neuraxis radiation with a boost to the tumor bed has accounted for a major change in survival rates since the early 1950s [Paterson and Farr, 1953]. The reason that medulloblastomas are radiosensitive is not known. Radiosensitivity may relate to in vivo factors, such as tissue oxygenation and growth kinetics, rather than inherent radiosensitivity. Radiation doses and schedules have changed over the past several decades. In the late 1960s, administration of 40 Gy was considered adequate to the posterior fossa, and 30 Gy was considered adequate for the spinal axis. Current recommended doses are 50 to 60 Gy to the posterior fossa and 24 to 36 Gy to the craniospinal axis. Changes in technology and radiation doses mirror increasing 5-year survival rates. The 5-year survival rates of 20% reported in the 1960s are in marked contrast with the 5-year survival rates of 50% to 70% reported in the 1970s, 1980s, and 1990s [Evans et al., 1990; Hope-Stone, 1970; Hughes et al., 1988; Tarbell et al., 1991]. Recurrence of medulloblastoma, as might be expected, carries a very poor prognosis. However, repeat surgery at the time of recurrence appears to significantly improve prognosis [Balter-Seri et al., 1997]. Chemotherapy, initially single agent but more recently multiagent, has been the most common approach to children with high-risk and recurrent disease [Packer et al., 1999a]. Medulloblastomas are theoretically well suited for treatment with chemotherapy because of their rapid growth rate, high mitotic index, and location in proximity to the ventricular cavity and subarachnoid space. Although the role of chemotherapy has yet to be fully established, evidence is mounting that supports the benefits of chemotherapy and warrants the continued search for appropriate combinations and routes of administration. The medulloblastoma treatment trials of the International Society of Pediatric Oncology [Bloom et al., 1990], the Children’s Cancer Study Group, and the Radiation Therapy Oncology Group have all reached similar conclusions [Evans et al., 1996]. These were two-arm studies. In one arm the children received surgery and radiation, whereas in the other arm the children received surgery, radiation, and chemotherapy. In the Children’s Cancer Study Group/Radiation Therapy Oncology Group study, vincristine, prednisone, and CCNU were used, whereas in the International Society of Pediatric Oncology only CCNU and vincristine were used.

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Initially, the International Society of Pediatric Oncology trial suggested an advantage to the chemotherapy arm; however, long-term differences did not persist (P = 0.07). Although an advantage to chemotherapy was not universal, it did persist in certain subgroups, that is, those children who had subtotal or partial excision (P = 0.007), those with brainstem involvement (P = 0.001), and those with stage T3 and T4 diseases (P = 0.002) [Tait et al., 1990]. In the Children’s Cancer Study Group trial, the 5-year event-free survival was 59% for children treated with radiation and chemotherapy compared with 50% for patients treated with radiation alone. Both the International Society of Pediatric Oncology and Children’s Cancer Study Group studies demonstrated that children with adverse risk factors appeared to benefit from the addition of chemotherapy. Even more impressive have been the results from the Children’s Hospital of Philadelphia, where 25 of 26 patients entered in a radiation and chemotherapy pilot were alive and free of disease a median of 24 months from diagnosis [Packer et al., 1988a]. As the number of long-term survivors has increased, concern over the adverse effects of standard dose radiation on intellect and endocrine function has led to trials in which the dose of radiation to the head and neuraxis has been reduced. Studies have been restricted to children considered to be standard risk (i.e., >3 years of age with gross totally resected tumors and no metastases). In the first multi-institutional trial in which reduced neuraxis radiation (2340 cGy) was compared with standard dose (3600 cGy), children treated on the reduced radiation arm had a significantly higher failure rate overall, as well as in the number of isolated neuraxis relapses [Deutsch et al., 1996]. In the hope that survivals would be improved if chemotherapy were added to reduced neuraxis radiation, the International Society of Pediatric Oncology and the German Society of Pediatric Oncology mounted a study of children with medulloblastoma, which in part asked whether “sandwich therapy” (i.e., up-front postoperative chemotherapy) would allow a reduction in the dose of neuraxis radiation. As in the Pediatric Oncology Group/Children’s Cancer Study Group study, the results revealed a worse outcome for children treated with reduced neuraxis radiation, despite the addition of postoperative chemotherapy [Bailey et al., 1995; Kortman et al., 2000]. These studies concluded that the disappointing results were attributed to the delay in giving radiotherapy. In contrast, other reports have suggested that the addition of chemotherapy to 24 Gy neuraxis radiation (with 50 Gy to the posterior fossa) enhanced rather than decreased survival [Packer et al., 1999b]. There are now multiple reports supporting the view that chemotherapy in conjunction either with reduced neuraxis radiation therapy (2400 cGy) or standard dose radiation therapy (3600 cGy) have consistently shown 5-year survival rates greater than 80% [Evans et al., 1990; Fukunaga-Johnson et al., 1998; Goldwein et al., 1996; Packer et al., 1994; 1999b]. Most of these studies have been in children with standard-risk disease. As a result of the above considerations, adjuvant chemotherapy with reduced dose neuraxis radiation has now become the recommended treatment of choice for both high- and low-risk disease. The choice and degree of intensity of the chemotherapy depend on whether the patient is low risk, high risk, or has recurrent disease.

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In summary, treatment of medulloblastomas has been the most successful and serves as the premier example of the value of cooperative trials taking place in the United States as well as internationally. Despite the success of these trials, concern continues about the potential for secondary oncogenesis and endocrine, growth, and intellectual compromise. The search continues for a treatment that provides a cure without the considerable complications associated with current therapies.

Cerebellar Astrocytomas Cerebellar astrocytomas represent 12% of brain tumors in children younger than 15 years [Duffner et al., 1986]. They are the second most common cerebellar tumor, comprising approximately one third of tumors found in the posterior fossa. Their peak incidence is in the latter half of the first decade, with a second peak in the first half of the second decade [Matson, 1956]. There is no clear-cut gender preference [Pollack and Campbell, 1996]. Astrocytomas may occur anywhere in the cerebellum and may involve the hemispheres, the vermis, or both regions simultaneously. Occasionally, a vermal mass may present largely within the cavity of the fourth ventricle [Ringertz and Nordenstam, 1951]. Invasion of the cerebellar peduncles or brainstem occurs more commonly with tumors of the vermis. Approximately 80% of cerebellar astrocytomas are cystic [Gol and McKissock, 1959]. Some have suggested that tumors located in the hemisphere are typically cystic, whereas solid tumors are more commonly located in the vermis [Ringertz and Nordenstam, 1951]. The tumors are generally well circumscribed, demarcated from surrounding tissue, and noninvasive. They either consist of a large cyst with a solid mural nodule or they may be largely solid with smaller cysts throughout the substance of the tumor. The wall of the cyst may contain reactive non-neoplastic tissue or occasionally may be fringed by tumor growth. Approximately 20% of cerebellar astrocytomas are solid and similar to those in the cerebral hemispheres (Fig. 71-33).

The histopathology of most (70% to 85%) cerebellar astrocytomas is that of the typical pilocytic astrocytoma and consists of compact, strongly fibrillated cells that alternate with loose, spongy areas composed of microcysts. Compact areas are generally devoid of microcysts but contain an abundance of Rosenthal fibers. Calcification may be found in 25% of patients. Oligodendroglial cells may be identified. Leptomeningeal dissemination is uncommon but has been reported with spread throughout the neuraxis [Figueiredo et al., 2003]. Dissemination occurs both at diagnosis and years later [Tamura et al., 1998]. Multinucleated giant cells, nuclear hyperchromasia, and endothelial proliferation in the cystic varieties of cerebellar astrocytoma are not necessarily associated with malignant potential. When mitoses are present, however, aggressive tumor behavior should be suspected [Rubinstein, 1972]. Diffuse or fibrillary astrocytomas occur in 15% to 30% of cases. Attempts to correlate the microscopic appearance of cerebellar astrocytomas with prognosis have been made. Gjerris and Klinken [1978] divided children with astrocytomas into two types: those with the classic juvenile cerebellar astrocytoma and those with diffuse astrocytoma. A total of 70% of the patients had juvenile astrocytomas, whereas 30% had diffuse tumors. The diffuse form was found primarily in the older age group (i.e., 10 to 14 years of age), whereas the juvenile form was found in 88% of children who were younger than 10 years. The 25-year survival rates were 94% for the juvenile and only 38% for the diffuse types. Unlike the cystic cerebellar astrocytoma, the diffuse form of astrocytoma behaved more like the fibrillary astrocytomas of the brainstem or cerebral hemispheres and was associated with recurrence according to the authors. Other more recent studies, however, have not found the marked differences in survival as reported by Gjerris and Klinken [Pollack and Campbell, 1996] (see “Prognostic Factors”). Gilles and associates [1977] also reviewed the histopathology of cerebellar astrocytomas in an attempt to redefine the prognostic meaning of microscopic features. They defined two groups of tumor: glioma A and B. Glioma A, the group defined as having microcysts, Rosenthal fibers, leptomeningeal deposits, and foci of oligodendroglia, is associated with a good prognosis and a 10-year survival rate of 94%. In contrast, the glioma B group has a far worse prognosis with a 10-year survival rate of 29%. Another later study confirmed the prognostic value of the Gilles classification, as patients with glioma B had a higher degree of disease progression and accounted for all deaths in that study [Conway et al., 1991]. Glioblastoma multiforme of the cerebellum is unusual in any age group, particularly in children. Prognosis is invariably poor and, as such, this tumor should be considered a different pathologic entity from the benign cerebellar astrocytoma [Bristot et al., 1999]. Leptomeningeal dissemination, even in the absence of local recurrence, may occur and is associated with a very poor outcome.

Clinical Characteristics FIGURE 71-33. Gross pathology of cystic hemispheric cerebellar astrocytoma. The arrow points to the mural nodule. (From Cohen and Duffner, 1994a.)

Cerebellar astrocytomas in children typically manifest with signs of increased intracranial pressure. Cerebellar symptoms vary depending on tumor location. Thus, children who

Cohen and Duffner / Tumors of the Brain and Spinal Cord

have tumors located primarily in the midline will have truncal ataxia, whereas those with primarily hemispheric tumors will have appendicular dysmetria of the ipsilateral limbs. In general, children with cerebellar astrocytomas appear to tolerate increased intracranial pressure far better than children with similar-sized medulloblastomas. Duration of symptoms may vary from days to years. There is generally a longer duration of symptoms before diagnosis in young adults and adolescents compared with younger children. The median duration of symptoms in one study was 3 months [Pollack and Campbell, 1996].

Diagnosis In the case of cystic cerebellar astrocytomas, a large cystic mass is identified on CT with an enhancing mural nodule. At times, the walls of the cyst may also enhance after intravenous contrast material, which may represent neoplastic lining of the cyst wall. A recent study, however, reported that at least some cases of cysts with enhancement represent reactive tissue rather than neoplasia [Beni-Adani et al., 2000]. Calcification is present in 10% to 20% of cases. Diffuse astrocytomas have slightly decreased density and uniform enhancement. On MRI, cerebellar pilocytic astrocytomas are hypointense or isointense on T1 and hyperintense on T2. Enhancement may be ringlike, nodular or uniform [Pollack and Campbell, 1996]. The mural nodule adjacent to a cyst typically enhances, but most cyst walls do not (64% versus 21%) [Pencalet et al., 1999]. Early postoperative MRI is not accurate in differentiating residual juvenile pilocytic astrocytomas from postoperative changes [Rollins et al., 1998]. CT may help to identify recurrent tumors from postoperative defects because cyst fluid has relatively higher density than cerebrospinal fluid. In addition, compression or alteration in anatomy of the fourth ventricle, cerebellopontine angle, and perimesencephalic cisterns point to recurrent disease [Kingsley and Kendall, 1979; Zimmerman et al., 1978]. In diffuse tumors, MRIs are more valuable in helping to identify recurrence and invasion of the brainstem.

Management Cushing’s surgical experience with cerebellar astrocytomas before 1931 was invariably associated with failure despite removal of the entire cystic mass. Once he recognized that the mural nodule was neoplastic and had to be removed to prevent regrowth of the cyst, survivals improved dramatically [Cushing, 1931]. Today the goal of surgery is complete resection of the tumor. When successful, this approach is associated with more than 90% survival at 10 years [Pollack and Campbell, 1996]. Complete resection may not be possible, however, in the 10% of those with brainstem invasion. Local recurrence is much more common after partial removal of the tumor. Recurrent tumor usually has pathology identical to that of the original tumor; therefore, repeat surgical resection after recurrence may provide a cure [Pollack and Campbell, 1996; Ringertz and Nordenstam, 1951]. Even partial resection has been associated with prolonged survival, although progression-free survivals are significantly less than with gross total resection. As such, there has been controversy about the appropriate postoperative management of those patients with incompletely

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excised tumor. At least one study reported that children who received radiation therapy after partial resection had better survival rates. Relapse-free survival in those children with partial resection alone was 36%, compared with a relapsefree survival of 83% in those who had irradiation after partial resection [Griffin et al., 1979]. Confirmatory studies have not been reported to date. With the advent of CT and MRI, close, noninvasive follow-up is now possible. When the residual tumor grows, repeat surgery or radiation should be considered. Surveillance neuroimaging has been recommended at 12, 18, 30, 42, and 66 months with one additional image if definite residual tumor on imaging is identified postoperatively. However, if a gross total resection has been achieved, some authors have not recommended surveillance imaging [Sutton et al., 1996]. The treatment of children with incompletely resected diffuse cerebellar astrocytomas remains controversial. Some investigators would irradiate partially resected diffuse cerebellar astrocytomas because of the putative 38% 25-year survival rate [Leibel et al., 1975]. The validity of this approach has yet to be confirmed. Natural history studies detailing the time interval before recurrence in children with diffuse cerebellar astrocytomas should provide this information. Children with anaplastic astrocytomas or glioblastomas of the cerebellum are at far greater risk than children with low-grade astrocytomas. Consequently, the recommended treatment is radiation therapy after surgical removal. The volume of radiation is debatable; some authors recommend full craniospinal radiation, whereas others believe radiation to the posterior fossa with wide ports is sufficient [Kopelson, 1982; Salazar and Rubin, 1976]. In view of the risk of leptomeningeal dissemination, even in the absence of local recurrence, craniospinal radiation may be more appropriate than local radiation [Bristot et al., 1999]. There has been little experience in the treatment of cerebellar astrocytomas with chemotherapy, although etoposide [Chamberlain, 1997] and cyclophosphamide have both been used in those with leptomeningeal disease [McCowage et al., 1996]. The tumors generally have such a good prognosis, even at recurrence, that repeat surgery or radiation has been considered to be preferable to chemotherapy. Quality of life studies of children treated for cerebellar astrocytomas have shown that by adulthood most have done fairly well, that is, they worked and had families but did not fare as well as control groups, especially in terms of depression, socialization, and self-reported life experiences [Pompili et al., 2002]. In another study in which children operated for cerebellar astrocytomas received neuropsychologic evaluations more than 1 year after surgery, poor attention span, poor memory, behavioral issues, and visuospatial deficits were identified in 40% to 70% of children [Aarsen et al., 2004].

PROGNOSTIC FACTORS Although some authors have attempted to correlate cell proliferation, apoptosis rate and p53 with survival in children with cerebellar pilocytic astrocytomas, they are not prognostic [Haapasalo et al., 1999]. Of interest, although MIB-1 may be high (0.6% to 12%; mean, 4.4%), there is no

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Tumors and Vascular Disorders of the Nervous System / 71

correlation with clinical behavior, histologic appearance, or neovascularization. Although those cerebellar astrocytomas that appear solid on imaging have significantly higher MIB-1 activity than radiologically cystic tumors with mural nodules, there has been no correlation with progression-free survival [Roessler et al., 2002]. Gross total resection is generally considered a strong prognostic factor [Desai et al., 2001; Bernhardtsen et al., 2003; Morreale et al., 1997], although in at least one study incomplete resection correlated with a worse progressionfree survival but not overall survival [Pencalet et al., 1999]. Another important prognostic factor for survival is brainstem involvement [Pencalet et al., 1999; Due-Tønnessen et al., 2002], although, in at least one study, brainstem infiltration was not found to be predictive [Smoots et al., 1998]. Analyses of duration of symptoms before diagnosis have also produced contradictory results, with a short duration of symptoms carrying a good prognosis in one study [Pencalet et al., 1999], whereas others have reported the opposite [Desai et al., 2001]. The previously reported prognostic advantage of cystic over solid tumors has not been supported in recent studies [Pencalet et al., 1999; Smoots et al., 1998] nor has location in the cerebellar hemispheres versus vermis or fourth ventricle been found to be consistently prognostic for survival [Bernhardtsen et al, 2003; Desai et al., 2001]. Even the role of histopathology has not been uniformly accepted. Despite the earlier study by Gjerris and Klinken, pilocytic versus nonpilocytic low-grade histopathology has not had a significant influence on prognosis [Pencalet et al., 1999]. In contrast, it is clear that children with high-grade fibrillary astrocytomas fare worse [Desai et al., 2001]. The literature is decidedly mixed on clearly defined prognostic factors for recurrence and survival. Most studies agree that a gross total resection carries a good prognosis, whereas brainstem infiltration is associated with a worse outcome. Although the earlier studies by Gjerris and Klinken strongly suggested that histopathology was highly prognostic, recent studies have found conflicting results (except for juvenile pilocytic astrocytomas and low-grade fibrillary astrocytomas versus high-grade fibrillary astrocytomas).

ependymomas are younger than 5 years of age, with only 4% older than 15 years of age at diagnosis [Dohrmann et al., 1976]. In fact, ependymomas represent the second most common malignant brain tumor in children younger than 3 years [Duffner et al., 1993]. Posterior fossa location is more common in younger children (less than 3 years), whereas a supratentorial location is more common in older patients (older than 3 years) [Smyth et al., 2000]. Ependymomas arise in relation to any part of the ventricular system. In general, two thirds of tumors are infratentorial, and one third are supratentorial. Infratentorial tumors arise from the roof, floor, or lateral recesses of the fourth ventricle. The tumor can occlude the ventricle and extend cephalad to the aqueduct. At times, tumor spreads laterally into the cerebellar pontine angle or lateral recesses or extends caudad through the foramina of Lushka and Magendie into the upper cervical canal. Supratentorial ependymomas may be entirely within the lateral or third ventricles or partly intraventricular and partly extraventricular. It is interesting, however, that they may be found anywhere within the cerebral hemispheres and may be entirely extraventricular [Cohen and Duffner, 1994c]. Ependymomas are well-defined, homogeneous, partially encapsulated mass lesions. They may be extensively cystic. Low-grade ependymomas are cellular with a regular histologic pattern. Ependymal rosettes are diagnostic and consist of tumor cells lining a small, central lumen. Pseudorosettes are observed even more commonly. Areas resembling oligodendrogliomas and astrocytomas are also frequently present [Russell and Rubinstein, 1989]. It has been extremely difficult to determine the degree of malignancy of ependymomas based on histologic features. Much of this confusion results from the lack of large numbers and the need to consider histologic characteristics of supratentorial and infratentorial ependymomas separately. The presence of mitotic figures and vascular proliferation has been associated with aggressive lesions, as have the findings of hypercellularity and necrosis. Foci of pleomorphism and hypercellularity may be identified in otherwise benign-appearing ependymomas.

Summary

Cytogenetics and Molecular Markers

Overall, cerebellar astrocytomas have the best prognosis of any intracranial tumor in childhood. The SEER Registry data reported a 5-year survival rate for cerebellar astrocytomas (excluding glioblastomas of the cerebellum) of 91% that has been confirmed in recent reviews [Duffner et al., 1986b; Pollack and Campbell, 1996]. Preferred treatment is complete surgical removal. In patients with recurrence, repeat surgery is recommended while radiation is reserved for those with progressive disease following a second complete resection or for those with unresectable residual disease who progress [Pollack and Campbell, 1996].

The most frequent alteration is loss of heterozygosity of chromosome 22q (30% of ependymomas). Other abnormalities of chromosome 22 have also been reported [DebiecRychter et al., 2003]. Another common chromosomal abnormality is monosomy 17 (50% of pediatric ependymomas). Loss of heterozygosity was found in one study in the long arms of chromosomes 6 and 9 (30% and 27%, respectively), suggesting that tumor suppressor genes may be found on these chromosomes [Huang et al., 2003]. Although a variety of chromosomal alterations have been identified, no finding is consistent at this time [Teo et al., 2003].

Ependymomas

Clinical Characteristics

Ependymomas constitute approximately 8% of brain tumors in children younger than 15 years of age [Duffner et al., 1986]. Most occur in young children, with a mean age at diagnosis of 5 to 6 years. Sixty percent of children with

The symptoms and signs of children with ependymomas vary with tumor location. Children with tumors located in the posterior fossa have signs and symptoms of increased intracranial pressure and cerebellar signs. Supratentorial tumors are

Cohen and Duffner / Tumors of the Brain and Spinal Cord

more likely associated with focal headaches, seizures, and focal motor signs. Signs vary with tumor location so that nystagmus, meningismus, papilledema, and dysmetria are frequently observed with posterior fossa lesions, whereas hemiparesis, hyperreflexia, and visual field abnormalities are more common with supratentorial tumors [Cohen and Duffner, 1994c; Dohrmann et al., 1976].

Diagnosis The appearance of ependymomas on precontrast CT scans is that of a usually isodense to gray matter mass, often cystic and typically calcified (50%). At times tumors may be hyperdense. The tumors typically enhance with intravenous contrast. On MRI T1 scans, the tumors may be hypointense or isointense, whereas on T2 scans, tumors are usually isointense to hyperintense [Comi et al., 1998]. Heterogeneous gadolinium enhancement can be quite intense at times. The heterogeneous signals are due to necrosis, hemosiderin, or vascularity [Chen et al., 2004]. Obstructive hydrocephalus is common, especially with infratentorial tumors. The infratentorial tumors tend to “flow” out of the foramen of Lushka and Magendie into the upper cervical canal and pontine cisterns in a manner sometimes called “plasticity.” This finding is observed best on MRI scans. The evaluation of the child with an ependymoma must include examination of the neuraxis (MRI) and cerebrospinal fluid cytology. Although ependymomas do not seed the neuraxis frequently (7%), failure to diagnose leptomeningeal spread will lead to inadequate therapy. As such, surveillance imaging is strongly recommended [Good et al., 2001]. Some authors have suggested that head scans should be obtained every 3 to 6 months for those who have had a gross total resection, whereas those with a subtotal resection should be scanned every 3 months for the first postoperative year. In the second to fifth year, scans of the head are obtained every 6 months. Spine imaging is limited to those with perioperative leptomeningeal disease or those with local recurrence. These recommendations are based on the fact that most children with ependymomas will fail first in the primary site [Goldwein et al., 1990]. However, with the newer approach of three-dimensional conformal radiation to the tumor bed, it might be prudent to perform spinal imaging on all children on a regular basis until long-term follow-up of patterns of failure has been established.

Management The ability to achieve a gross total resection significantly improves survival rates [Figarella-Branger et al., 2000; Good et al., 2001; Merchant et al., 2002a; Perilongo et al., 1997b; Pollack et al., 1995; VanVeelen-Vincent et al., 2002]. Some have even suggested that in these cases (particularly supratentorial lesions) no further therapy is warranted, but this view is not uniformly accepted [Paulino, 2000]. The importance of radical surgery has led to the increasingly accepted approach of delivering postoperative chemotherapy to children with subtotally resected tumors to improve the likelihood of a complete resection at “second look” surgery [Foreman et al., 1997]. Postoperative radiation is considered standard therapy for older children with ependymomas. As noted above, the only

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exception is the totally resected supratentorial low-grade ependymoma. A Children’s Oncology Group study has a postoperative observation arm for this group. Supratentorial ependymomas, however, are known to recur even after a gross total resection. The approach of withholding radiation to children with gross totally resected supratentorial ependymomas is not universally accepted and should be viewed as experimental only. For children older than 3 years, standard radiation treatment is 5400 cGy in 30 fractions (local) over 6 weeks. Some radiation therapists increase the dose to 5940 cGy in 33 fractions (local) over 6.5 weeks for highgrade tumors. It is of interest that in at least one study, duration of radiation therapy for more than 50 days was a poor prognostic factor [Paulino, 2000]. Previously, there was controversy regarding the volume of radiation (i.e., local versus neuraxis). In response, the Pediatric Oncology Group among others demonstrated that the first site of failure in most patients was the primary location of the tumor [Kovnar et al., 1991]. As such, routine neuraxis radiation is not recommended unless leptomeningeal disease is demonstrated at diagnosis [Chiu et al., 1992; Merchant et al., 1997; Rousseau et al., 1994]. In the presence of widespread disease, there is unanimity that children should receive craniospinal radiation. New trends in the radiation treatment of children with ependymomas include hyperfractionation (with and without chemotherapy), three-dimensional conformal radiation, and stereotactic radiation. Hyperfractionation given with and without vincristine, cyclophosphamide, and etoposide was not shown to improve survivals compared to historical controls in a large prospective Italian study [Massimino et al., 2004]. In contrast, preliminary data from a Pediatric Oncology Group study of hyperfractionation were promising in children with subtotally resected ependymomas compared with historical controls (3-year event-free survival, 52% versus 27%) [Kovnar, 1996]. Three-dimensional conformal radiation to the tumor bed has had very promising early results in children with ependymomas and has led to an ongoing group-wide Children’s Oncology Group study [Merchant et al., 2002c; Paulino, 2001]. If effective, this approach will measurably reduce neurotoxicity. Reports of postoperative stereotactic radiosurgery in children and adults with ependymoma either at diagnosis or recurrence are limited. Preliminary data suggest that this technique may be useful in patients with local recurrence following surgery and external beam radiation, and potentially helpful at diagnosis. Further trials are needed [Mansur et al., 2004; Stafford et al., 2000]. All patients require long-term followup because late failures are not uncommon. The role of chemotherapy at diagnosis and recurrence has been debated. Transient responses to chemotherapy, particularly cisplatinum, have been shown in recurrent tumors [Sexauer et al., 1985]. Various other chemotherapeutic agents have also been used with variable success [Chamberlain, 2001]. A postoperative chemotherapy regimen consisting of cyclophosphamide and vincristine for newly diagnosed children less than 3 years of age with ependymomas was associated with a 48% response rate [Duffner et al., 1993]. Even higher response rates have been observed on other “baby” studies, using dose intensification of the same agents. The role of adjuvant chemotherapy, however, is still unclear. The Children’s Cancer Study Group trial of surgery

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Tumors and Vascular Disorders of the Nervous System / 71

and craniospinal radiation with or without CCNU, vincristine, or prednisone found no difference in outcome between the two arms (10-year progression-free survival of 36% and overall survival of 39%). Bloom and co-workers [1990] reported similarly negative results using CCNU and vincristine. Although the 5-year survival was 70% compared with historical control subjects (40%), the curves converged after 6 to 7 years, and no statistical difference was identified. In contrast, a chemotherapy regimen of carboplatin, vincristine, ifosfamide, and etoposide after surgery and radiation was associated with a 5-year progression-free survival of 74% in one study [Needle et al., 1997]. The French trial of postoperative chemotherapy in children younger than 5 years of age using agents that included procarbazine, carboplatin, etoposide, cisplatin, vincristine, and cyclophosphamide without irradiation was associated with a 4-year survival of 74% in those children who had a gross total resection but only 35% for those with incomplete resection. It is of interest that in contrast to the U.S. baby studies, radiologic responses were limited [Grill et al., 2001]. The German HIT trials combined postoperative radiation with chemotherapy, which included ifosfamide, etoposide, methotrexate, cisplatinum, and cyclophosphamide. The overall survival was 75% at 3 years and the progression-free survival was 59.7%. As with the French study, children with incomplete resection had 3-year progression-free survivals of only 38.5% [Timmermann et al., 2000]. Because several of these studies used both postoperative radiation and chemotherapy, the role and efficacy of the chemotherapy cannot be determined. It appears in general that ependymomas may be chemosensitive but are not chemocurative. As such, it is unlikely that more intense chemotherapy such as bone marrow transplantation will provide improved cure rates. In all of these studies it must be recognized that ependymomas tend to recur late. As such, promising early results must be viewed with caution.

PROGNOSTIC FACTORS Survival varies with prognostic factors. There is no dispute that a gross total resection is the most significant prognostic factor. In recent years, several authors have reported 5-year progression-free survival of 70% to 80% in children with ependymomas who have had a gross total resection [Korshunov et al., 2004] but 5-year survival has been significantly worse in those who have had a subtotal resection, that is, 20% to 40% [Duffner et al., 1998b; Merchant, 2002a]. This has led to the concept of “second look” surgery, often following two courses of chemotherapy, in children whose tumors have been incompletely resected. Surprisingly, the presence of leptomeningeal seeding has not been consistently identified as a risk factor [Duffner et al., 1998b]. The role of tumor location is also debated as a prognostic factor. Whereas some series have found supratentorial location to be better than infratentorial, others have found conflicting results. Patients with infratentorial tumors located in the lateral recesses appear to have a worse prognosis than those that are more medial, possibly because of the difficulty in achieving a gross total resection in these children [FigarellaBranger et al., 2000; VanVeelen-Vincent et al., 2002]. Very young age (less than 2 years versus 2 to 3 years) was found to be a significant prognostic factor in the first “Baby

POG” (Pediatric Oncology Group) study. This may be misleading however, because children younger than 2 years in that study received chemotherapy for 2 years before they were irradiated while those between 2 and 3 years received radiation after only 1 year of chemotherapy. Thus, it may be the delay in radiation beyond 1 year rather than the younger age that led to the worse prognosis [Duffner et al., 1998b]. Young age per se has been considered to be a prognostic factor when children younger than 3 years are compared with older children, however. For example, children younger than 3 years had survivals of 22% versus 75% in those older than 3 [Pollack et al., 1995]. Dose of radiation also has been considered prognostic, that is, a radiation dose of less than 4500 cGy is a negative prognostic factor [Goldwein et al., 1990]. Perhaps the most controversial factor is histologic grade. Results from the first Baby POG study revealed no difference in progression-free or overall survival according to degree of malignancy, that is anaplastic versus low grade [Duffner et al., 1998b]. Recent studies, however, found that high-grade pathology had a significant effect on prognosis [Korshunov et al., 2004; Merchant et al., 2002a]. This area needs clarification because it may affect the type of treatment recommended.

Summary In summary, gross total resection plus local (possibly conformal) radiation appears to be the most effective treatment regimen at this time. Further studies of adjuvant chemotherapy, particularly to improve the likelihood of achieving a gross total resection at second look surgery, are in progress.

Brainstem Tumors Approximately 13% to 20% of brain tumors in the pediatric age group are found in the brainstem [CBTRUS, 2004; Duffner et al., 1986; Halperin, 1985]. These tumors occupy the region of the brain traversed by the fourth ventricle and aqueduct of Sylvius. Neoplasms found proximal to the mesencephalon or caudal to the medulla in the cervical spinal cord are not considered under the rubric of brainstem tumors. Pathologic diagnosis is hampered by the limited amount of tissue that can be obtained at surgery. Stereotactic biopsy is the procedure of choice because of fear of damaging vital brainstem structures and the possibility of brainstem swelling. Small biopsies cannot be viewed as definitive because sampling error and potential for malignant dedifferentiation may complicate interpretation. These considerations led many authors to reject the need for pathologic confirmation. Conversely, others have thought that because most patients have pilocytic tumors that are uniform with little regional variation, sampling error may not be a problem and biopsy is worthwhile [Cohen and Duffner, 1994b]. As with most other tumors, there is a growing tendency to stage these tumors according to location, histology, and clinical behavior. Tumors characteristically associated with the poorest prognosis are those in which symptoms are less than 6 months before diagnosis, have a pontine location, present with an abducens palsy, and engulf the basilar artery.

Cohen and Duffner / Tumors of the Brain and Spinal Cord

This group of children has been found to have fibrillary astrocytomas. Those with a better prognosis are those children with tumors either outside the ventral pons, with an exophytic component, a cervical medullary location or a pilocytic histology without the clinical features mentioned above (Fisher et al., 2000). Unlike intrinsic parenchymatous masses, fungating portions of exophytic tumors are surgically accessible. Evacuation of the tumor cysts found in low-grade astrocytomas may be associated with longterm cures and relief of symptoms [Epstein and Wisoff, 1988].

Clinical Characteristics The triad of long tract signs, cranial neuropathies, and ataxia localizes a suspected lesion to the brainstem. Cranial nerves arising in bulbar and pontine areas are most commonly involved. Vertical nystagmus on upward gaze, bilateral nystagmus on lateral gaze, positional nystagmus on horizontal gaze, and nonfatigable positional nystagmus suggest intrinsic abnormalities of the brainstem. Downbeating, small amplitude, positional nystagmus, with or without ocular myoclonus, suggests a medullary location, whereas localization to the midbrain is suggested by conversion retraction nystagmus. In addition, various oculomotor gaze disturbances have been described. Lower motor neuron facial nerve involvement may suggest a pontine lesion. Bulbar signs, swallowing and feeding difficulties, asymmetry of the palate, absent gag reflex, atrophy of the tongue, and nasal regurgitation imply involvement of the medulla. Appendicular ataxia suggests either involvement of the cerebellum or, more likely, compromise of the pathways passing through any of the three cerebellar peduncles to and from the cerebellum. Motor difficulties may also relate to abnormalities of the descending motor systems [Cohen and Duffner, 1994b]. Neuroimaging confirms the clinical suspicion of a pontine mass. Tumors found in the region of the brainstem on CT may be isodense, cystic, necrotic, or calcified. Low-density lesions with and without contrast enhancement are more likely to behave in a malignant fashion [Segall et al., 1985]. MRI more readily delineates the location and extent of tumor, and may more accurately provide information regarding an exophytic component (Fig. 71-34).

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Management Brainstem tumors are usually considered to be relentlessly progressive, with an inexorable course to death. Duration of symptoms until diagnosis may vary from weeks to several years. In most series, 5-year survival rates range from 5% to 30%. Examination of actuarial survival curves suggests there may be two populations of patients: (1) the majority are shortterm survivors who die within the first 1 to 2 years of diagnosis, and (2) a small group of long-term survivors who have a relatively plateaued course [Cohen et al., 1986]. Prognosis depends on location and duration of symptoms before diagnosis, neuroimaging characteristics, and to some extent, histologic diagnosis. Children with signs and symptoms of less than 6 months’ duration, tumors that infiltrate the pons, and those that have evidence of two or three brainstem signs have the poorest prognosis. Conversely, lesions that are focal or exophytic or that originate in adjacent anatomic structures, such as the cerebellar peduncle or cervical medullary junction, tend to have a better prognosis and may be amenable to surgery [Robertson et al., 1994]. There is also some suggestion, but not conclusive evidence, that patients with brainstem gliomas who have neurofibromatosis also have a better prognosis. Brainstem tumors occurring in these patients may have a different biology and there are reports of long, progressionfree survivals, even in the absence of treatment [Milstein et al., 1989; Pollack et al., 1996; Raffel et al., 1989]. As such, it has been suggested that in patients with neurofibromatosis, intervention should be limited to those with lesions that are relentlessly progressive or cause clinical dysfunction. Tumors located in the midbrain (tectal, pretectal, or tegmental) regions are another group of brainstem tumors that, other than producing obstructive hydrocephalus, may have a benign course [Robertson et al., 1995]. Periaqueductal location, uniform appearance on MRI with rare enhancement, and long periods of stability without change on clinical examination or neuroimaging are the usual features. Management consists of watchful waiting, periodic imaging studies, and shunting if appropriate [Bowers et al., 2000; Grant et al., 1999]. It has been standard teaching that after clinical evaluation and radiologic confirmation, surgery for typical diffuse pontine gliomas is not indicated and may lead to significant

FIGURE 71-34. T1 sagittal (A) and postcontrast coronal (B) views in a 19-year-old male with a large exophytic pilocytic astrocytoma. Following biopsy the patient has been followed for more than 10 years with little evidence of progression.

A

B

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Tumors and Vascular Disorders of the Nervous System / 71

cGy, and even 7800 cGy initially demonstrated trends of increasing time to progression and survival when compared with lower dose levels [Freeman et al., 1991]. Unfortunately, these results have not been sustained. For the most part, a dose-effect relationship regarding toxicity has been observed. Acute toxicity has been minimal, although in a few cases intralesional necrosis has been identified. Because almost all those children have died of progressive disease, long-term toxicity has not been assessed. Overall, although toxicity has been tolerable, survival of children with brainstem gliomas using escalating doses of hyperfractionation have failed to show improvement over that associated with conventional radiation [Mandell et al., 1999]. The margin for error in the treatment of brainstem tumors is extremely limited. Compactness of vital structures and limited room for expansion continue to dampen the enthusiasm for surgery other than biopsy. Poor treatment results using either standard radiation or hyperfractionated radiation have influenced the decision to treat aggressively with chemotherapy. Chemotherapy, that is, multiagent, myeloablative or dose escalating, however, has shown no advantage over radiation alone [Freeman and Perilongo, 1999]. FIGURE 71-35. Axial enhancing CT suggesting a brainstem tumor. After surgery a histopathologic diagnosis of an ependymoma was confirmed. Rather than treat as a brainstem glioma, this child was placed on a Pediatric Oncology Group treatment protocol for ependymoma.

neurologic compromise. This approach prevents pathologic confirmation of the tumor and hampers, to some degree, the ability to develop protocols based on predicted pathologic behavior. Further, imaging cannot effectively exclude the infrequent hemangioma, arachnoid cysts, telangiectasia of the pons, cavernous hemangioma, or hamartoma [Frank et al., 1988]. Using stereotactic biopsy, surgical morbidity can be minimized. With the advent of better anesthesia, agents to control edema, and microsurgery, there is a growing tendency toward surgical exploration and biopsy [Fisher et al., 2000]. Surgical confirmation avoids the pitfalls of wrong diagnosis, allows the removal of an extra-axial mass, and permits evacuation of cyst contents (Fig. 71-35). Epstein and others [Epstein and Wisoff, 1988; Robertson et al., 1994] have also suggested that prognosis and treatment decisions can be made based on anatomic localization. They defined four categories of brainstem tumors (i.e., diffuse, focal, cystic, cervical medullary). Those that present in a dorsal exophytic manner or at the cervical medullary junction are the most amenable to surgery and are the most likely to benefit from this approach. In this small subset of patients, radical surgery offers the possibility of long-term remission and even cure. For the majority of patients, the primary treatment of patients with brainstem tumors is radiotherapy. Although survival rates as high as 40% to 50% have been reported, most researchers report 5-year survival rates of less than 30% [Littman et al., 1980]. For children with diffuse pontine gliomas, survival rates are less than 10%. Radiation in doses of 5500 cGy over 5 to 6 weeks is recommended [Kim et al., 1980]. Hyperfractionated radiation has been used as an alternative to standard radiation. Hyperfractionated protocols using treatment schedules from 6400 cGy to as high as 7200

Summary Despite many innovative attempts at treatment, overall results in this group of tumors have been poor. Even with the poor overall prognosis, there remains a subgroup of patients who have favorable outcomes: those with focal, cystic, or cervical medullary lesions and those associated with neurofibromatosis. These children should be stratified to less aggressive treatment arms. Conversely, the child with diffuse pontine abnormalities on MRI or CT and a short duration of symptoms and signs carries a poor prognosis and merits aggressive therapy (Freeman and Perilongo, 1999).

SUPRATENTORIAL TUMORS Astrocytomas Approximately 50% to 60% of primary brain tumors in children are supratentorial in location, most of which are of an astrocytic lineage [CBTRUS, 2004]. CBTRUS coding includes cranial nerves and spinal cord in this assessment. A variety of differing histologies, such as primitive neuroectodermal tumors, oligodendrogliomas, ependymomas, central neurocytomas, and dysembryoplastic neuroepithelial tumors are supratentorial in location. Gliomas account for 46% of the total. The pathologic nosology of cerebral astrocytomas is complex. Some pathologists have subdivided the tumors according to cytologic architecture, whereas others have graded them according to malignant potential [Bailey and Cushing, 1926; Kernohan et al., 1949]. Unfortunately, because of the multiple classifications, it is often difficult to accurately interpret survival rate and treatment responses from the literature. The classification currently in use is that recognized by the World Health Organization [Kleihues and Cavenee, 2000]. In the World Health Organization classification grade I is benign, grade II is low grade, grade III is anaplastic or intermediately malignant, and grade IV is highly malignant.

Cohen and Duffner / Tumors of the Brain and Spinal Cord

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TABLE 71-3 Selected Childhood Primary (Malignant and Nonmalignant) Brain and Central Nervous System Tumor Age-Specific Incidence Rates* (Ages 0-19), by Age at Diagnosis, CBTRUS 1995-1999† AGE AT DIAGNOSIS 0-4 HISTOLOGY

N

Tumors of Neuroepithelial 719 Tissue Pilocytic astrocytoma 142 Anaplastic astrocytoma 8 Astrocytoma, NOS 59 Ependymoma/anaplastic 90 ependymoma Glioma, malignant, NOS 90 Benign and malignant 55 neuronal/glial, neuronal, and mixed Embryonal/primitive 178 medulloblastoma

5-9 Rate

10-14

15-19

0-19

0-14

N

Rate

N

Rate

N

Rate

N

Rate

N

Rate

3.73

665

3.37

529

2.77

447

2.38

2360

3.07

1913

3.29

0.74 — 0.31 0.47

171 27 60 35

0.87 0.14 0.30 0.18

139 19 55 25

0.73 0.10 0.29 0.13

89 21 50 30

0.47 0.11 0.27 0.16

541 75 224 180

0.70 0.10 0.29 0.23

452 54 174 150

0.76 0.09 0.30 0.26

0.47 0.29

87 23

0.44 0.12

52 40

0.27 0.21

40 48

0.21 0.26

269 166

0.35 0.22

229 118

0.39 0.20

0.92

167

0.85

86

0.45

53

0.28

484

0.63

431

0.74

Tumors of Cranial and Spinal Nerves

—

—

8

—

23

0.12

30

0.16

65

0.08

35

0.06

Tumors of the Meninges

18

0.09

17

0.09

35

0.18

63

0.34

133

0.17

70

0.12

Lymphomas and Hematopoietic Neoplasms

—

—

—

—

—

—

6

—

16

0.02

10

0.02

Germ Cell Tumors Germ cell

15 15

0.08 0.08

24 24

0.12 0.12

42 42

0.22 0.22

50 50

0.27 0.27

131 131

0.17 0.17

81 81

0.14 0.14

Tumors of the Sellar Region Craniopharyngioma

13 12

0.07 0.068

39 39

0.20 0.20

43 28

0.23 0.15

100 24

0.53 0.13

195 103

0.25 0.13

95 79

0.16 0.14

Local Extensions from Regional Tumors

—

—

—

—

—

—

6

—

15

0.02

9

—

Unclassified Tumors

41

0.21

17

0.09

31

0.16

29

0.15

118

0.15

89

0.15

816

4.23

774

3.92

712

3.73

731

3.89

3033

3.94

2302

3.96

TOTAL

‡

*Rates are per 100,000 person-years. † Includes data from 12 of the 16 registries listed in Table 71-1; New Mexico, North Dakota, Rhode Island, and Texas are excluded. ‡ Refers to all childhood brain tumors, including histologies not presented in this table. CBTRUS, Central Brain Tumor Registry of the United Statess; NOS, not otherwise specified; —, counts are not presented when fewer than 6 cases were reported for the specific histology category, and rates are not presented when fewer than 10 cases were reported for the specifichistology category. The suppressed cases are included in the counts and rates for totals.

The most common astrocytomas seen in children are pilocytic astrocytomas (World Health Organization grade I and grade II astrocytomas). Glioblastoma multiforme is less common but there is the concern that a grade II astrocytoma may dedifferentiate into more malignant pathology. Composite CBTRUS SEER data reflecting the years 1973 through 1999 indicated that 5- and 10-year survivals for children 0 through 19 years of age with “astrocytomas, not otherwise specified” was 78% and 74.4%: the data for anaplastic astrocytomas were 51.6% and 46.9%; for glioblastomas, 17% and 15%; and for pilocytic astrocytomas, 93.8% and 92%. The survival figures for adults with the same histologies are worse [CBTRUS, 2004] (Table 71-3). The fibrillary pattern (diffuse astrocytoma) is the most common microscopic pathology. Meningeal fibrils impart a firm consistency to the tumor. Mitoses are absent, and there is no endothelial proliferation. Pilocytic astrocytomas of the cerebrum are often microcystic or may have a single large cyst with a tumor nodule, resembling the cystic cerebellar astrocytoma. Gemistocytic astrocytomas are unusual and

have a tendency to evolve into glioblastoma multiforme. Microscopically, the cytoplasm is homogeneous and lightly eosinophilic. Anaplastic astrocytomas have increased cellularity, cellular pleomorphism, and mitoses, as well as features typical of astrocytomas. Glioblastoma multiforme is characterized by pleomorphism, endothelial proliferation, necrosis, and multinucleated giant cells. Mitoses are present in 70% and hemorrhage in 60% [Frankel and German, 1958; Rubinstein, 1972; Russell and Rubinstein, 1989]. Abnormalities of ploidy, loss of heterozygosity, and genetic mutations are increasingly recognized in these tumors. The most common chromosomal abnormalities are deletions of 17p and 22, p53 mutations, and overexpression of platelet-derived growth factor. Chromosomal abnormalities shared by anaplastic gliomas and glioblastomas probably represent the earliest changes in the transformation process from low-grade to high-grade tumor. Glioblastomas in adults, unlike those arising in children, may not undergo molecular transformation. These so-called de novo tumors are associated with overexpression of epi-

1720

Tumors and Vascular Disorders of the Nervous System / 71 Gligoastrocyte progenitor cell −19p −1p Oligodendroglioma mixed oligoastrocytoma

(Older patients) Astrocyte EGFR amplification

Glioblastoma −10* −22q Ependymoma

(Younger patients) Anaplastic astrocytoma astrocyte −13q −22 p53 mutation −9q −17q −19q

thelial growth factor and chromosome losses on chromosome 10 [Furnari et al., 1996, see illustration; Louis et al., 2001] (Fig. 71-36).

Clinical Characteristics The signs and symptoms of hemispheric astrocytomas, regardless of grade, relate to the area of cortex involved [Low et al., 1965]. Headaches, visual field abnormalities, seizures, focal motor weakness, and papilledema are common presenting symptoms. Headaches may be focal or nonfocal, but persistently focal headaches correlate with true localization in more than 90% of patients [Jelsma and Bucy, 1967]. Seizures are more common with slower growing tumors. The seizures are usually generalized, partial simple seizures

FIGURE 71-36. Graphic showing chromosome deletions associated with astrocytoma progression from benign to more malignant. The progression involves a broad region of chromosome 10. EGFR, epithelial growth factor receptor. (From Furnari FB, Huang HJ, Cavenee WK. Genetics and malignant progression of human brain tumours. Cancer Surv 1996;25:233-275.)

or partial complex seizures with complex symptomatology either with or without secondary generalization. Although brain tumors are an unusual cause of seizures in young children, certain clues to their presence should be recognized. Tumor should be suspected in the child who has had a long-standing seizure disorder and develops (1) change in school performance, (2) increasing frequency of seizures, (3) change in quality of seizures, (4) focal slowing on EEG, (5) change in personality, or (6) change in neurologic examination [Page et al., 1969] (Fig. 71-37). The duration of symptoms before diagnosis is longer with supratentorial gliomas than with tumors of the posterior fossa, which relates, in part, to the early onset of obstructive hydrocephalus associated with infratentorial tumors. There is an inverse relationship between grade of tumor and duration of symptoms. A longer duration of symptoms before diagnosis tends to carry a better prognosis [Walker et al., 1980].

Diagnosis CT and more recently MRI have increasingly identified children previously diagnosed as having idiopathic seizure disorders who actually harbor low-grade malignancies. Areas of decreased density on CT or increased signal on T2 MRI images may represent tumor, although mesial temporal sclerosis, trauma, and previous infarct complicate the differential diagnosis. High-grade tumors tend to be associated with alterations in the blood-brain barrier, and consequently enhancement with intravenous contrast occurs in more than 90%. However, not all high-grade tumors enhance on MRI or CT [Barker et al., 1997]. In addition, some low-grade astrocytomas may be associated with contrast enhancement. Thus the presence or absence of contrast enhancement is only suggestive of the degree of malignancy [Barker et al., 1997; Silverman and Marks, 1981; Steinhoff et al., 1978; Tchang et al., 1977].

Management

FIGURE 71-37. CT scan of 16-year-old female with long history of seizures. Pathology revealed a low-grade astrocytoma. After surgery and radiation, patient is doing well, with only an occasional seizure.

Although traditional treatment of low-grade astrocytomas has been surgery followed by local irradiation, there are differing approaches to the treatment of low-grade astrocytomas in children older than 5 years. Some neurooncologists believe that children with low-grade astrocytomas can be followed longitudinally by CT or MRI before com-

Cohen and Duffner / Tumors of the Brain and Spinal Cord

mitting the child to either surgery or radiation. Others recommend surgical intervention at diagnosis, followed by “watchful waiting” before committing the child to radiation. In the literature, event-free survival following gross total resection ranges from 50% to 90% [Gajjar et al., 1997]. A third group believes that identification of tumor should be followed by surgery and immediate postoperative local radiation. Although there may be a question as to whether radiation is indicated at diagnosis, there is universal agreement that when the patient undergoes operation, total removal should be attempted unless the location involves eloquent areas of the nervous system that might be damaged at surgery. As in the cerebellum, surgery is curative for children with cystic pilocytic astrocytomas of the cerebrum if the mural nodule is removed completely. Failures occur in those patients in whom the mural nodule is only partially excised [Palma and Guidetti, 1985]. Total resection is usually possible with tumors occupying the poles of the frontal or temporal lobes. In more deep-seated tumors, such as those involving the thalamus or in high-risk areas, total surgical extirpation may not be possible. The degree of resection can be maximized using stereotactic technology. On evidence of recurrence, attempts at gross total resection are again recommended [Gajjar et al., 1997]. The radiation oncologist’s approach to low-grade tumors is usually local volume radiation (the area of the primary tumor with a margin of approximately 2 cm). The dose of radiation is generally 54 Gy. The addition of postoperative radiation for partially resected grade I astrocytomas in adults reportedly increased the 5-year survival rate in one study from 25% to 58% [Sheline, 1977]. Increasingly radiation protocols involve conformal radiation. The margins included in the radiation port usually extend 1 cm beyond the margin of gross tumor [Merchant et al., 2002d]. Unfortunately, the data on children with grade I and II astrocytomas treated with surgery and radiation are difficult to interpret because many of these studies have included cerebellar astrocytomas. Although radiation appears to influence 5-year survival rates, it does not influence 10-year survival rates. Some investigators reported an increase in 5year survival rates from 13% to 41% with radiation, but by 10 years after diagnosis, irradiated patients had a 26% survival rate compared with a 32% survival rate for patients treated with surgery alone [Fazekas, 1977]. This view has not changed in the past 20 years. At present there are no large, well-documented, prospective studies assessing quality of life or long-term effects in children with lowgrade gliomas. For progressive low-grade tumors, radiation with and without chemotherapy is routinely recommended. There are ongoing phase II chemotherapy trials for efficacy of chemotherapy without radiation in children younger than 10 years of age [Freeman et al.,1998; Gajjar et al., 1997]. An interesting approach to low-grade astrocytomas is a study opened in 1991 by the Pediatric Oncology Group and the Children’s Cancer Study Group, which addressed the question of whether radiation improves progression-free survival rate after subtotal surgical resection. Children with totally resected low-grade supratentorial astrocytomas are being followed longitudinally and not committed to radiation; however, children older than 5 years with incomplete resection

1721

are randomized to either supportive care, local radiation, or investigators’ choice. It is hoped that at publication this study will provide answers regarding the need for radiation as well as the long-term effects of local radiation. In addition, information regarding dedifferentiation of low-grade astrocytomas in children will be clarified. There is little controversy regarding the need for postoperative radiation treatment of patients with anaplastic astrocytomas and glioblastoma multiforme. Unfortunately, despite postoperative radiation, survival rates are poor. Studies of adults with anaplastic astrocytomas have yielded significantly better survival rates when treatment included radiation: 0% to 3% 5-year survival rates in patients treated with surgery alone compared with 15% to 20% 5-year survival rates in patients treated with surgery and radiation. In contrast, response to treatment of glioblastomas is universally poor. Although radiation does offer a significant advantage over surgery alone, survival is measured in months rather than years [Bloom et al., 1990; Heideman et al., 1997]. Although the literature on glioblastomas and anaplastic astrocytomas in childhood has been limited, children with these tumors appear to have better prognoses than do adults. Survival relates, in part, to the dose of cranial radiation. Children with hemispheric malignant astrocytomas receiving 54 to 60 Gy had a 60% 5-year survival rate in one study compared with 14% for doses of 35 to 50 Gy. In the same study, children with glioblastoma multiforme had a 9% 5-year survival when treated with 54 to 60 Gy versus 0% with 35 to 50 Gy [Marchese and Chang, 1990]. The generally poor outcome of childhood malignant astrocytomas was reconfirmed in 27 patients treated with surgery or radiation, in which the 5-year survival was 25% and 13%, respectively, at 10 years [Hoppe-Hirsch et al., 1993]. Chemotherapy may offer an advantage over radiation alone in pediatric patients with high-grade astrocytomas. The Children’s Cancer Study Group reported a trial in which children with high-grade astrocytomas were treated with postoperative radiation alone or radiation plus chemotherapy, including vincristine, CCNU, and prednisone [Sposto et al., 1989]. The 5-year event-free survival was 46% for patients who received radiation and chemotherapy compared with 18% for those who received radiation therapy alone. The presence of mitosis or necrosis was associated with a worse outcome, as was the group who received a biopsy. The study found no difference between gross total resection and partial resection. These results suggest a possible role for chemotherapy in children with high-grade astrocytomas and are of particular interest because similar treatment regimens in adults have not been successful. Another approach to malignant gliomas of childhood is high-dose chemotherapy followed by autologous bone marrow transplantation [Finlay, 1992]. Although objective responses have been reported, the complications of these regimens, including pulmonary fibrosis (carmustine [BCNU]), leukoencephalopathy (methotrexate), and death from infection or thromboembolic events, currently limit this approach. Debate continues over the influence of risk factors on prognosis. In one study, deep white matter location carried a worse prognosis than location in the cerebral hemispheres, whereas other authors have not found location to be of prog-

1722

Tumors and Vascular Disorders of the Nervous System / 71

nostic value [Dropcho et al., 1987; Marchese and Chang, 1990]. Controversy also exists over the influence of age on survival. Although children with malignant gliomas and glioblastoma multiforme have better survival rates than adults, the influence of very young age is unclear. In at least one study of children ages 2 to 20 years, children younger than 5 years, and those older than 10 years had significantly better survival rates than any other age group [Al-Mefty et al., 1987]. In contrast, children older than 5 years of age had a better prognosis than children younger than 5 years in another study. In a third study of children 15 months to 18 years of age, a trend toward longer survival was found in children 12 years of age or younger [Dropcho et al., 1987]. The most intriguing group was the 18 infants on Baby POG with high-grade astrocytomas, in whom responses to a chemotherapy regimen of cyclophosphamide and vincristine revealed a 60% response rate and 5-year survival rates of 50% plus or minus 14% [Duffner et al., 1996b]. Reasons for the better survival rates in children compared with adults with similar tumor pathology are not clear but may suggest different tumor biology in different age groups.

Dysembryoplastic Neuroepithelial Tumor Dysembryoplastic tumors are benign cortical neoplasms usually identified in older children or young adults. They tend to be long standing and may be associated with intractable seizures. Grossly the tumor is nodular and intracortical. Histologically the tumor resembles the oligodendroglioma. Dysembryoplastic tumors are characterized by pleomorphism, glial-neuronal elements, and limited nuclear atypia, cellularity, mitosis, and endothelial proliferation. They initially were thought to be a form of cortical dysplasia without the potential of recurrence following complete surgical excision. However, recent literature has suggested that there are a small group of individuals who despite adequate surgery have recurrence of tumor. Hence, these children require continued surveillance following initial diagnosis and surgery [Nolan, 2004; Pomeroy, 2004].

Central Neurocytoma This tumor occurs in teenagers and young adults. It manifests as a midline intraventricular calcified mass that rarely obstructs the ventricular system (Fig. 71-38). The tumor is very cellular but has none of the other features of malignancy. Long survivals are the rule with or without surgery or adjuvant therapy [Nishio et al., 1988].

Primitive Neuroectodermal Tumors Cerebral primitive neuroectodermal tumors were first described in 1973 by Hart and Earle, who reported a group of tumors found in the cerebrum of children and young adults [1973]. The tumors had similar pathologic and clinical features with a rapid course from diagnosis until death. The reported incidence of cerebral primitive neuroectodermal tumors ranges from 2.5% to 7%. They most commonly occur in very young children [Ashwal et al., 1984]. Primitive neuroectodermal tumors are usually supratentorial in location, although occasionally they may be found elsewhere in the CNS, including the spinal cord. As a pathologic entity, the concept of primitive neuroectodermal tumors has not had universal acceptance, in part because Rubinstein [1972] classified neoplasms with similar features as cerebral neuroblastomas. In addition, other primitive neuroepithelial tumors, such as medulloepitheliomas, ependymoblastomas, and pineoblastomas, have been considered separate entities. The most confusing aspect of the primitive neuroectodermal tumor classification is whether to “lump” medulloblastomas with cerebral primitive neuroectodermal tumors. Their similar histopathologic appearance prompted this approach, but their differences in location and especially prognosis have made this approach less useful [Duffner and Cohen, 1997].

Pathology Grossly, the tumor is sharply delineated from surrounding brain tissue. Necrotic areas, cyst formation, calcification, and hemorrhage are frequently present. On microscopic examination, the tumors are characterized by small, undifferentiated cells with little observable cytoplasm and dark oval to irregular nuclei. The tumors are highly malignant, with numerous mitotic figures, areas of vascular endothelial hyperplasia, and necrosis. The tumor is 90% to 95% undifferentiated, although focal areas of differentiation may be present. On ultrastructural examination, this differentiation along ependymal, neuronal, and astrocytic cell lines can be confirmed [Markesbery and Challa, 1979]. Immunohistochemistry further permits neuropathologists to identify differentiation along various cell lines. Cerebral primitive neuroectodermal tumors in infancy have been found to have a particularly wide range of differentiation [Grieshammer et al., 1991].

Clinical Characteristics

FIGURE 71-38. Neurocytoma manifested in a teenager. The tumor extended to, but did not obstruct, the foramen of Monro.

The duration of symptoms prior to diagnosis is brief, usually less than 3 months. The most common presenting symptoms in the literature have been headache, followed by nausea, vomiting, and seizures. Infants and young children typically

Cohen and Duffner / Tumors of the Brain and Spinal Cord

present with large head circumferences, seizures, and focal motor deficits [Dai et al., 2003]. One of the striking clinical findings has been the patient’s ability to accommodate the large tumor mass [Duffner et al., 1981]. This likely reflects the fact that cerebral primitive neuroectodermal tumors are not typically associated with peritumoral edema.

Diagnosis The diagnosis of primitive neuroectodermal tumors is based on clinical signs and symptoms, abnormal radiologic studies, and pathology. CT demonstrates large, partially calcified hyperdense masses with well-defined margins but without peritumoral edema. There may be cyst formation. Enhancement has ranged from minimal to dense in a heterogeneous or ringlike pattern [Dai et al., 2003; Pigott et al., 1990]. As with CT, MRI reveals well-defined tumor margins and a relative lack of peritumoral edema [Figuerora et al., 1989]. Solid areas range from low- to high-signal intensity [Dai et al., 2003]. Primitive neuroectodermal tumors may seed the cerebrospinal fluid, producing spinal cord metastases in 20% to 40% of patients [Parker et al., 1975; Tomita et al., 1988]. As such, routine MRI of the spine and assessment of cerebrospinal fluid cytology should be performed at diagnosis and follow-up. Extraneural metastases to lung, lymph nodes, pericardium, diaphragm, and liver have been reported [Ashwal et al., 1984; Duffner et al., 1981].

Management Treatment of primitive neuroectodermal tumors begins with attempts at bulk resection of the tumor. Unlike medulloblastomas, the survival advantage of a gross total resection

A

1723

is not universally accepted [Duffner and Cohen, 1997; Tomita et al., 1988; Zeltzer et al., 1993]. A report from the Children’s Cancer Study Group found that less or greater than 1.5 cm3 postoperative residual tumor did not correlate with significant differences in survival, although a trend toward better survival was identified in children who had minimal residual disease [Albright et al., 1995]. In view of the tumor’s tendency to seed the subarachnoid space, craniospinal radiation is recommended [Paulino et al., 2004]. Despite radiotherapy, survivals have been poor [Tomita et al., 1988]. The dose of radiation to the primary site is 5000 to 6000 cGy with 3600 cGy to the neuraxis. Chemotherapy has been considered, in part, because of the chemosensitivity of medulloblastomas. Several authors have reported responses to a variety of chemotherapeutic agents, including carmustine (BCNU), vincristine, methotrexate, procarbazine, and platinum (Fig. 71-39). Despite this, Tomita and associates [1988] were unable to identify a clear survival advantage to chemotherapy versus nonchemotherapy-treated patients. The most successful regimen so far (in a limited number of patients) included surgery, hyperfractionated craniospinal radiation, and an adjuvant chemotherapy regimen of vincristine, cisplatin, and cyclophosphamide [Halperin et al., 1993]. For children with recurrent disease, high-dose chemotherapy with autologous stem cell rescue, usually with radiation, may salvage some patients [Broniscer et al., 2004]. Unfortunately, despite the pathologic resemblance of primitive neuroectodermal tumors to classic medulloblastomas, patients with primitive neuroectodermal tumors have very poor survival rates. A comparison of 5-year survival rates in children with cerebral primitive neuroectodermal tumors and medulloblastoma were 46.9% and 86.3%, respectively [Paulino and Melian, 1999]. Although they may

B

FIGURE 71-39. A, CT demonstrating biopsy-confirmed primitive neuroectodermal tumor. B, Same patient demonstrating marked reduction in tumor size after chemotherapy. Unfortunately, the response was transient and tumor subsequently recurred.

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Tumors and Vascular Disorders of the Nervous System / 71

respond transiently to drugs and radiation, few patients are long-term survivors. The vast majority of children die within 1 to 3 years after diagnosis. Prognostic factors that affect survival adversely include young age (<3 years) and metastatic disease at diagnosis [Albright et al., 1995]. As noted, the benefits of obtaining a gross total resection have been debated [Mikaeloff et al., 1998; Zeltzer et al., 1993]. In summary, primitive neuroectodermal tumors are highly malignant tumors found in childhood that appear to predominate in the very young. Because they tend to seed the cerebrospinal fluid, treatment must be directed to the entire cerebrospinal axis. General treatment recommendations include maximum debulking surgery, craniospinal irradiation, and chemotherapy. In cases of recurrence, there have been reports of transient responses to treatment with chemotherapy, high-dose chemotherapy with bone marrow transplantation, or repeat irradiation.

Oligodendrogliomas Oligodendrogliomas are rare tumors, accounting for less than 1% of childhood neoplasms [Farwell et al., 1977]. Most oligodendrogliomas are found in the cerebral hemispheres. Occasionally, an intramedullary tumor is encountered. The tumor is rarely found as a pure oligodendroglioma but usually represents the predominant cell type of a mixed glioma. Calcification, as well as cystic and mucoid degeneration, may be present. The tumor may be friable, calcific, or necrotic. Histologically, the tumor is characterized by a honeycomb appearance consisting of a monotonous collection of uniform cells with a rounded appearance and clear cytoplasm. The perinuclear halo gives the honeycomb appearance to the tumor. Compact areas of the tumor may lack such an appearance, suggesting that the finding of oligodendrogliocytes in a mixed glioma, regardless of predominance of cell types, imparts a favorable prognosis to the tumor. Although considered benign, dissemination of oligodendrogliomas in the cerebrospinal fluid pathways is well recognized. Leptomeningeal metastasis with resultant hydrocephalus, as well as remote extracranial metastasis, is occasionally identified. Seizures are by far the most common presenting symptom. Most oligodendrogliomas are in the cerebral hemispheres; therefore, clinical signs and symptoms relate, in large measure, to the area of involved brain. Many patients with this tumor may have a long, protracted clinical course characterized by seizures, with or without long tract signs. CT usually confirms the presence of a mass. Calcification is commonly present and may appear nodular, shell-like, or winglike. Factors associated with improved survival are age less than 20 years, calcification, low-grade tumor, frontal or parietal location, and lack of contrast enhancement [Shaw et al., 1992]. Of interest, the prognostic value of gross total resection is debated [Razack et al., 1998].

children with oligodendrogliomas and mixed gliomas, tumor progression was diagnosed in 68% of patients. Of most interest, the median time to progression and overall survival were not affected by postoperative treatment, suggesting that radiation or chemotherapy can be deferred until clinically necessary [Walter et al., 2000]. The 5-year survival in one group of 19 children with oligodendrogliomas and mixed oligodendrogliomas was 65% [Razack et al., 1998]. In the adult population, radiation doses of 60 Gy are required to improve prognosis [Allison et al., 1997]. There has been a great deal of interest in adults with anaplastic oligodendrogliomas because of reports of sensitivity to procarbazine, CCNU, and vincristine with good results as preirradiation therapy and adjuvant therapy or for postradiation progressive disease [Bouffet et al., 1998; Streffer et al., 2000]. Temozolimide has also had promising results with anaplastic oligodendrogliomas. At least one study found that treatment with postoperative radiation and procarbazine, CCNU, and vincristine in nonanaplastic oligodendrogliomas also produced excellent results, with no local failure in 28 to 240 months. The authors found that radiation alone (60 Gy) was effective but that procarbazine, CCNU, and vincristine without radiation therapy delayed time to progression, and as such may “buy time” for young children until definitive therapy with radiation can be administered [Allison et al., 1997]. Allelic loss of the 1p19q loci may predict the response to chemotherapy and duration of survival in adults with anaplastic oligodendrogliomas [Bauman, 2000]. With the advent of CT and MRI, the incidence of oligodendrogliomas as a cause of long-standing seizures may increase. Any child who has refractory seizures or who has a changing seizure pattern should be evaluated for the possibility of an underlying, slow-growing neoplasm, such as an oligodendroglioma (Fig. 71-40).

Treatment Treatment should initially consist of surgery alone because the tumor is slow growing [Hirsch et al., 1989]. With evidence of dissemination of tumor or on recurrence, radiation or combined modality chemotherapy should be considered. In one of the few large-scale retrospective analyses of

FIGURE 71-40. A 5-year-old female with long-standing seizures. MRI demonstrates an increased T2-weighted signal. An oligodendroglioma was removed at surgery. Patient is doing well with infrequent seizures.

Cohen and Duffner / Tumors of the Brain and Spinal Cord

BRAIN TUMORS IN INFANTS AND VERY YOUNG CHILDREN Approximately 13% of brain tumors in children ranging in age from newborn to 15 years of age are found in those younger than 2 years [Duffner et al., 1986]. The male-tofemale ratio is approximately equal, although medulloblastomas in infants, as in older children, tend to be more common in males. Brain tumors in infancy differ in location from those in older children. In the first 6 months of life, most series report a supratentorial predominance. By 7 to 12 months of age, there is a relatively equal distribution between the supratentorial and infratentorial compartments, but after 1 year of age the more typical location is in the posterior fossa. There are approximately equal numbers of supratentorial hemispheric and midline tumors, although there has been some suggestion that midline tumors predominate in the very young infant [Fessard, 1968; Tomita and McLone, 1985]. The types of tumors also tend to vary with age at diagnosis. Whereas most series report astrocytomas as the most common brain tumor in young children, teratomas are prominent in neonates younger than 3 months of age, particularly in Japan. In some Japanese series, teratomas account for 33% to 37% of neonatal brain tumors [Oi et al., 1990]. The most common malignant tumors in children from birth to 3 years of age are medulloblastomas, ependymomas, and primitive neuroectodermal tumors. The last group encompasses ependymoblastomas, pineoblastomas, cerebral neuroblastomas, medulloepitheliomas, and cerebral primitive neuroectodermal tumors (Fig. 71-41). In addition, this grouping encompasses a number of tumors of high-grade malignancy previously designated as “malignant neoplasms

A

1725

not otherwise specified.” In contrast with older children, brainstem gliomas and cerebellar astrocytomas are relatively unusual [Duffner et al., 1986]. In several series, high-grade gliomas, such as glioblastomas and anaplastic astrocytomas, have been considered rare [Matson, 1964]; however, wide variability occurs in the various series, depending on the number of patients and referral patterns. Certain tumors characteristically occur in infants. The majority of choroid plexus tumors, discussed earlier in this chapter, are diagnosed before 2 years of age. They tend to occur primarily in the lateral ventricles and less frequently in the third or fourth ventricles in this age group [Matson, 1964]. Approximately 17% are carcinomatous and are associated with a poor prognosis. Meningeal sarcomas also tend to predominate [Raimondi and Tomita, 1983]. Optic gliomas are prominent in all series, representing approximately 2% of patients. These rates will likely change as more children with neurofibromatosis undergo screening neuroimaging.

Clinical Characteristics Infants with brain tumors are often diagnosed quite late in the disease course. This delay in diagnosis may be one of the reasons that infants have a significantly poorer prognosis than older children. Diagnostic delays occur because the presenting signs and symptoms of brain tumors in infants and very young children are relatively nonspecific and are more often believed to represent common pediatric illnesses than structural CNS disease. Moreover, in young children the early symptoms of increased intracranial pressure may be masked by skull expansion with sutural diastasis. The classical signs and symptoms of increased intracranial pressure may not be present until the tumor bulk is considerable.

B

FIGURE 71-41. CT scans of infant with biopsy-confirmed poorly differentiated embryonal tumor. A, Initial appearance. B, Note rapid increase in size after 3 months despite aggressive therapy.

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Tumors and Vascular Disorders of the Nervous System / 71

A

B

FIGURE 71-42. A 14-month-old male with medulloblastoma. A, Note prominent forehead secondary to enlarging head circumference. B, Axial CT reveals large posterior fossa mass with hydrocephalus.

When the child does present for evaluation, the head may be markedly misshapen because of differential intracranial pressure effects [Jooma et al., 1984] (Fig. 71-42). One of the most common presenting symptoms is vomiting [Farwell et al., 1978]. Often vomiting is misdiagnosed as

FIGURE 71-43. Axial CT demonstrating a large chiasmatic glioma in a patient erroneously believed to have congenital nystagmus.

gastrointestinal disease, such as gastroesophageal reflux, pyloric stenosis, or intolerance to formula before vomiting secondary to either increased intracranial pressure or direct involvement of the floor of the fourth ventricle is considered [Papadakis et al., 1971]. Another common symptom in infants with brain tumors is irritability or behavioral changes, sensitive indicators of CNS disease at any age. Because the causes of irritability and behavioral change in infants are diverse, CNS disease is often low in the differential diagnosis. Seizures are a prominent symptom in most series. As expected, seizures are more common with hemispheric supratentorial tumors and are often partial with or without secondary generalization. Although seizures described as tonic extensor attacks are reported in association with posterior fossa masses, these usually are episodes of opisthotonos related to irritation of the brainstem rather than frank convulsive episodes. There have also been reports of infantile spasms in infants with brain tumors. In two such cases, the infants responded clinically and electroencephalographically to adrenocorticotropic hormone before the tumor was diagnosed [Ruggieri et al., 1989]. Visual loss is difficult to diagnose in the young child and is rarely a presenting symptom in the literature. Moreover, the physical signs of nystagmus or bizarre eye movements are frequently misdiagnosed as spasmus nutans or congenital nystagmus rather than nystagmus resulting from lesions of the chiasm [Baram and Tang, 1986] (Fig. 71-43). Children in the first decade of life with neurofibromatosis are at high risk for the development of visual pathway tumors. Because these children are generally not symptomatic until later in the disease course, routine neuroimaging of the optic nerves and chiasm should be considered.

Cohen and Duffner / Tumors of the Brain and Spinal Cord

1727

syndrome may be accompanied by nystagmus, suggesting chiasmatic involvement [Russell, 1951; Simpson et al., 1968].

Diagnosis

FIGURE 71-44. Contrast-enhanced CT of a 15-month-old child with progressive hemiparesis. Diagnosis was low-grade astrocytoma.

When focal motor signs are present, they are often attributed to static encephalopathy (i.e., hemiparetic cerebral palsy) rather than to progressive intracranial disease. A potentially important differentiating historical point is the presence of early hand preference. In general, children with hemiparetic cerebral palsy have a strong hand preference even from infancy. In contrast, with an expanding mass lesion, the child will be ambidextrous early in life and then develop a hand preference before 12 to 18 months of age. In cases of congenital brain tumors, handedness may be present from birth and strongly mimics static encephalopathy. The association of a focal motor deficit and an expanding head circumference, however, should suggest progressive intracranial pathology rather than the static, nonprogressive encephalopathy characteristic of cerebral palsy (Fig. 71-44). The presence of meningismus in a child with a large head may reflect incipient herniation rather than meningitis. In many series the constellation of irritability, vomiting, and bulging fontanel has suggested meningitis to the pediatrician, leading to a potentially dangerous lumbar puncture. Although this misdiagnosis inevitably occurs in some patients, careful review of previous head circumferences and the presence of split sutures will suggest a more chronic process and should prompt obtaining a CT scan before considering lumbar puncture [Gordon et al., 1995]. A relatively uncommon but classic presentation of brain tumors in infancy is the diencephalic syndrome, a condition that occurs with tumors involving the hypothalamus. Infants present with a progressive wasting syndrome, especially with loss of subcutaneous tissue in the presence of normal linear growth. The children vomit but not in sufficient amounts to explain the cachexia. They typically appear alert despite their notable emaciation. At times, the diencephalic

The diagnosis of brain tumors in infancy begins with clinical suspicion and then is confirmed by either CT or MRI. Although skull films may demonstrate split sutures and occasionally intracranial calcifications, their usefulness has been replaced by more modern imaging techniques [Jooma et al., 1984]. Cerebrospinal fluid examinations can be misleading because elevation in protein content or pleocytosis may represent a normal finding in infancy. Alternatively, these cerebrospinal fluid findings may suggest infection rather than tumor. Furthermore, the presence of blood in the cerebrospinal fluid may mislead the examiner into believing the child had a subarachnoid or intraventricular hemorrhage rather than bleeding into a necrotic tumor [Fessard, 1968]. The literature on the CT findings of infantile brain tumors is limited. The most striking abnormality on CT and MRI is the extremely large size of the tumor at diagnosis and the severity of hydrocephalus. In their series of children with brain tumors in the first year of life, Asai and colleagues [1989] reported diameters of tumors ranging from 4.6 to 16 cm (Fig. 71-45). MRI is very useful and is replacing CT as the procedure of choice, despite the need for anesthesia. Once the diagnosis of a brain tumor in an infant is made, a search for neuraxis dissemination is axiomatic. Infants are much more likely to have cerebrospinal fluid metastases than older children with similar tumors [Allen and Epstein, 1982]. Therefore, MRI of the spine and cerebrospinal fluid cytology should be performed in children with medulloblastomas, ependymomas, primitive neuroectodermal tumors (including pineoblastomas), high-grade gliomas, and choroid plexus carcinomas. There have even been reports of infants with juvenile pilocytic astrocytomas with widespread cerebrospinal fluid dissemination [Perilongo et al., 1997a]. Extraneural metastases have also been reported with malignant brain tumors. Therefore, bone marrow biopsy and

FIGURE 71-45. Contrast-enhanced CT of a 2-month-old child with a glioblastoma multiforme.

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bone scan are indicated as part of the metastatic evaluation of children with medulloblastomas and primitive neuroectodermal tumors.

Management Results of treatment of infants with brain tumors have been disappointing. Successful surgery in the infant with a brain tumor requires an experienced pediatric neurosurgeon, pediatric anesthesiologist, and pediatric intensive care support staff. Surgery of the very young infant is fraught with difficulties. Infants are sensitive to blood loss and hypothermia, and in the older series operative mortality ranged from 19% to 33% [Albright, 1985; Jooma et al., 1984; Raimondi and Tomita, 1983]. Most infants with brain tumors have hydrocephalus. Precraniotomy shunting will improve the infant’s condition, but unfortunately provides an entry for malignant cells into the peritoneal cavity [Raimondi and Tomita, 1983]. Although in recent years the mortality associated with surgery has been reduced because of advances in surgery and anesthesia, the morbidity in this age group remains high [DiRocco et al., 1993]. Despite these caveats, surgery is curative in some patients. Choroid plexus papillomas, teratomas, and cerebellar astrocytomas that can be completely excised are associated with a high cure rate. Even in patients in whom the tumor cannot be removed entirely, repeated surgery may be useful at recurrence. Thus the child with a low-grade supratentorial astrocytoma may have surgery and then be followed longitudinally by CT or MRI. In many situations, these children may be monitored for several years before evidence

A

of recurrence. If the child’s tumor does recur before 3 years of age, repeated surgery, rather than radiation, may still be the treatment of choice. Thus radiation may be delayed until the child’s brain is better able to tolerate this therapy (Fig. 71-46). Even in cases of malignant tumors such as medulloblastomas and ependymomas, the ability to achieve a gross total resection is the single most important indicator of survival [Duffner et al., 1993; 1996a]. In infants with malignant brain tumors, postoperative therapy must be provided. Standard radiation is poorly tolerated by the developing brain and consequently the total dose of radiation is usually decreased by 10% to 20%. This reduction in radiation may be inadequate for tumor control [Deutsch, 1982]. Unfortunately, despite this reduction in radiation dose, young children may still develop treatmentinduced mental retardation, vasculopathy, leukoencephalopathy, endocrinopathies, and second malignancies (Fig. 71-47). Several investigators have explored the concept of treating infants with brain tumors with postoperative chemotherapy in an effort to delay or eliminate radiation [Van Eys et al., 1985]. The largest published study of this approach, Baby POG, opened in 1986 [Duffner et al., 1993]. By closure in 1990, 198 children had been entered. Subsequent group-wide studies, Children’s Cancer Group 9921 and Baby POG 2, had 299 and 330 children enrolled, respectively. European investigators have also been using postoperative chemotherapy with or without delayed radiation in children less than 3 years of age with brain tumors. Unfortunately, much of these data are not yet in press. Results vary depending on tumor type.

B

FIGURE 71-46. A, CT of a male neonate demonstrating a large low-grade astrocytoma. B, Same patient at 2 years of age. There has been no progression of the tumor since surgery. No other treatment was given.

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in those children with gross total resection, survival was 61%. There was a significant difference in survival according to age less than 2 years versus 2 to 3 years, that is, 30% versus 58.8%, and in those with a gross total resection 37.5% versus 87.5%. The difference between the two groups, other than age, was that children younger than 2 years received chemotherapy for 2 years and then were irradiated, whereas older children received chemotherapy for 1 year and were irradiated. The results of this study strongly suggest that although radiation can be delayed safely for 1 year, it cannot be delayed for 2 years. In contrast, the French Society of Pediatric Oncology treated 73 children younger than 5 years with ependymomas with postoperative chemotherapy including cycles of procarbazine plus carboplatin, cisplatin plus etoposide, and vincristine plus cyclophosphamide. Radiation was planned only for relapse. Of interest, no complete or partial responses were identified. The 4-year progression-free survival was 22%, whereas the overall survival was 59%. Forty percent of patients were alive without receiving radiation. Prognostic factors included gross total resection and supratentorial location [Grill et al., 2001].

CEREBRAL PRIMITIVE NEUROECTODERMAL TUMORS

FIGURE 71-47. A 4-year-old patient who developed a severe radiation vasculopathy after radiation for a chiasmatic glioma at 15 months of age. Patient developed bilateral carotid occlusions with subsequent development of moyamoya pattern on serial angiograms.

MEDULLOBLASTOMAS Sixty-two children younger than 3 years of age with medulloblastomas were treated on Baby POG [Duffner et al., 1993]. Response rates to two cycles of cyclophosphamide and vincristine were high, that is, 48%. Five-year overall survivals were 42%. In those children with a gross total resection, however, survivals were 62%, and in the best prognostic group, that is, gross total resection and no metastases at diagnosis, survival was 69%. Moreover, those children with a gross total resection and no metastases at diagnosis were treated with reduced neuraxis radiation, that is, 2400 cGy with 5000 cGy to the tumor bed and still had excellent survivals, affirming the chemosensitivity of these tumors. Whether eliminating radiation entirely in a subset of children will provide equivalent results, awaits the results of the second Baby POG and Children’s Cancer Group infant studies.

EPENDYMOMAS Forty-eight children younger than 3 years with ependymomas were treated on Baby POG, [Duffner et al., 1998b]. Response rates to two cycles of cyclophosphamide and vincristine were 48%. The overall survival was 40.5%, but

Infants and young children with cerebral primitive neuroectodermal tumors have not done well compared with their older counterparts. In the first Baby POG study, the 5-year event-free survival was only 25% and 5-year survival was 27%. Among children with pineoblastomas, all died with widespread dissemination [Duffner et al., 1993; 1995a]. The French SFOP study of 25 children younger than 5 years with supratentorial embryonal tumors had similarly disappointing results. Twenty-four of 25 children relapsed with a median time of 5.5 months, and the 2-year disease-free survival was 4%. This group had been treated with postoperative chemotherapy consisting of cycles of carboplatin, procarbazine, cisplatin plus etoposide, and vincristine plus cyclophosphamide. A better prognosis was found in those with gross total resection (50% versus 8% 1-year event-free survival) and in those with hemispheric location [MarecBerard et al., 2002].

MALIGNANT GLIOMAS Whereas most infants and very young children have a significantly worse prognosis than older children with the same tumor pathology, malignant gliomas may be the exception. The first Baby POG study had 18 children younger than 3 years of age with malignant gliomas, including glioblastoma multiforme, anaplastic astrocytoma, and “malignant glioma.” Of the 10 children evaluable for neuroradiologic response following two cycles of cyclophosphamide and vincristine, there were six partial responses, that is, more than 60%. Survivals at 5 years were 50% and have remained stable. Of most interest, four children were not irradiated after 24 months of chemotherapy and none have developed recurrent disease [Duffner et al., 1996b]. Although the data from Baby POG 2 have not yet been published, infants with malignant gliomas also fared well.

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RHABDOID TUMORS One of the most challenging brain tumors in infancy are the atypical teratoid/rhabdoid tumors. These tumors were not diagnosed as separate entities on Baby POG 1, and were likely included in the medulloblastoma grouping. Thirty-six patients younger than 3 years with atypical teratoid/rhabdoid were treated on Baby POG 2 with a postoperative chemotherapy regimen composed of the Baby POG 1 chemotherapy regimen with dose intensification. Results were extremely poor, with all children dying, 31 of disease and 5 of complications from treatment [Strother et al., 2004]. Similarly poor results were reported in 9 children treated with a different postoperative intensive chemotherapy regimen with and without radiation. All died, with a mean survival of 10 months [Reinhardt et al., 2000].

Summary When reviewing responses to treatment protocols, Collins’ rule should be remembered. Tomita and McLone [1985] in a large review of children with malignant tumors during the first 24 months of life found that recurrence did not occur beyond the period of risk indicated by Collins’s rule (see earlier) among patients with medulloblastomas, ependymomas, and primitive neuro-ectodermal tumors. However, among patients with astrocytomas, 50% of deaths occurred after the period of risk. Although there have been advances in survival rates of older children with certain forms of brain tumors in the past 20 years, this improvement has not occurred to the same extent in very young children. Even within specific tumor types, children younger than 3 years of age have fared worse than older children. Not only do they respond poorly to standard therapy, but they are also at greater risk for treatment-induced neurotoxicity. The ultimate goal of prolonged postoperative chemotherapy is to eliminate radiation in those children who have no evidence of residual disease after completion of chemotherapy. Whether this is possible is currently unknown. It has become increasingly clear that although some tumors, such as ependymomas, may respond transiently to chemotherapy, radiation is necessary in most individuals for tumor control.

SPINAL CORD TUMORS Neoplasms of the spinal cord are less common than those found intracranially. The accepted ratio of intracranial/intraspinal neoplasms for adults is 5:1, whereas for children, depending on the histology of the tumor, the ratio varies from 20:1 to 5:1 [Reimer and Onofrio, 1985]. The literature sugests a 10:1 ratio of adults to children for astrocytomas and 20:1 to 3:1 for ependymomas of the spinal cord [Kopelson et al., 1980]. Because of their relative rarity, there are few series of pediatric spinal cord tumors reported in the literature [PascualCastroviejo, 1990]. The large reported series in children are those of Hamby [1944], Matson [1969], and a report from the People’s Republic of China [Cheng, 1982]. The Chinese report a much higher incidence of dysembryoplastic neoplasia (i.e., dermoids, epidermoids, teratomas, and chordomas) than is reported in the Western series.

Box 71-2 COMMON MISTAKEN DIAGNOSES IN CHILDREN WITH SPINAL CORD TUMORS Discitis Functional incontinence “Growing pains” Guillain-Barré syndrome Muscular dystrophy Peripheral neuropathy

Scoliosis Spondylitis Torticollis Transverse myelitis Trauma

Spinal cord tumors are most commonly found in the thoracic spinal cord followed by location in the cervical, thoracolumbar, and lumbosacral areas. Thus the divisions having the largest number of segments are areas associated with the highest incidence of tumor.

Clinical Characteristics Signs and symptoms of spinal cord neoplasms can be insidious and misleading. History is often vague, and early in the course of the disease there may be a paucity of clinical signs. Consequently, a high incidence of erroneous diagnoses occurs, as well as a long delay from onset of symptoms until a definitive diagnosis is made (Box 71-2). Complaints may be nonspecific or so nondirected that the physician does not consider spinal cord disease. Common complaints are extremity weakness, abnormalities of gait, or pain in the extremities, back, or even periumbilical region [Baysefer et al., 2004; Murovic and Sundaresan, 1992; Robertson, 1992]. Unfortunately, consideration of a spinal cord mass may not enter the differential diagnosis until there is considerable progression or a spinal cord sensory level becomes obvious. In young children, because enuresis is common, a history of changing patterns of continence may not be elicited. In the very young, who are not bowel or bladder trained, sphincter abnormalities may be over-looked. A clue to the presence of a neurogenic bladder is incontinence of urine associated with crying or straining at stool. Loss of rectal tone is a common finding in pa-tients with spinal cord tumors. An abnormality suggesting a neoplasm of the cervical cord is torticollis [Kiwak et al., 1983]. Changes in posture, nonspecific complaints of back pain, or even unexplained abdominal pain may be associated with disease of the spinal cord. Pain may be classified as root, spinal, or tract in origin. Pain is more often dull, aching, burning, and diffuse, rather than sharp. Sharp pain is uncommon and results from either infiltration of the root entry zone or from swelling of the spinal cord with distortion of the root. Spinal pain refers to epidural or bony involvement adjacent to the tumor. This form of pain is usually dull and aching. Tract pain is vague and burning, whereas paresthesias suggest involvement of the dorsal columns [Epstein and Epstein, 1982]. Classic signs of a sensory level with or without a Brown-Séquard syndrome (i.e., symptoms associated with hemisection of the cord) are rarely encountered. Any pain accentuated by either Valsalva’s maneuvers, such as sneezing, coughing, or straining at stool, or by straight leg raising should be evaluated. These maneuvers, by stretching the meninges, may cause root irritation in a patient with compressive disease of the spinal canal.

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Subtle physical findings may be mild scoliosis, discrepancy in foot or leg length, or vasomotor changes in the lower extremities. Findings of hyperreflexia, clonus, and Babinski’s responses suggest disease of the corticospinal tracts. Proprioceptive, vibratory loss, or a sensory level, no matter how subtle, should raise suspicion of intraspinal pathology.

Diagnostic Studies Unlike plain films of the skull, x-rays films of the vertebral column may yield considerable diagnostic information. Radiographs should be obtained in the anteroposterior, lateral, and, for the cervical spine, oblique projections. An increase in the interpedicular distance may suggest a longstanding intramedullary process (Fig. 71-48). Destructive changes of bone are more frequently associated with metastatic disease. Distortion or widening of the neuroforamina may be observed with extramedullary tumors, such as neurofibromas or metastatic disease to the spinal canal (Fig. 71-49). With slowly growing intraspinal tumors, the changing forces of an asymmetrical spinal lesion may alter vertebral growth in such a manner as to cause scoliosis. Bony abnormalities may be associated with a paravertebral soft tissue mass. Diagnosis is confirmed by neuroimaging. MRI with gadolinium is the procedure of choice. MRI can visualize the entire length of the cord in the sagittal diameter. By this method, intramedullary masses can be readily separated from extramedullary lesions. Further, unlike myelography, MRI readily identifies intramedullary cysts (Fig. 71-50) [Berger et al., 1986; Norman et al., 1983]. Other diagnostic considerations include the use of cystometrograms and cystourethrograms. These techniques help to evaluate bladder function and may confirm the presence of a neurogenic bladder. Electromyography is rarely of

FIGURE 71-49. MRI in the sagittal plane demonstrating an extramedullary neurofibroma displacing the spinal cord posteriorly.

FIGURE 71-50. A 6-month-old patient with a large hydromyelic cavity. The cyst, which was not demonstrated by CT, is easily visualized by MRI.

FIGURE 71-48. A 6-year-old male with myxopapillary ependymoma of the cauda equina. L5 spine demonstrates thinning of the pedicle and widening of the interpedicular distance.

much diagnostic use, although it helps to separate lower motor neuron unit disease from upper motor neuron unit disease and may help to establish the level of the lesion. In the presence of a suspected compressive lesion of the spinal cord, lumbar puncture must be performed judiciously. Protein content is invariably elevated. Froin’s syndrome, clotting of cerebrospinal fluid after its removal, is attributed to marked elevation of cerebrospinal fluid protein. This syndrome usually signifies a complete block of the cerebrospinal fluid pathways between the lumbar thecal sac and the subarachnoid space above the area of the block. Cerebrospinal fluid pressure may be variable—either unobtainable or elevated. In an effort to prevent precipitous paraplegia, cerebrospinal fluid examination should be undertaken only

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TABLE 71-4 Tumors of the Spinal Cord INTRAMEDULLARY

EXTRAMEDULLARY

Astrocytomas Cystic Noncystic Ependymomas Myxopapillary Well-differeniated Oligodendrogliomas

Neurofibromas Dysembryoblastic Dermoids Epidermoids Teratomas Lipomas Meningiomas Arachnoid cysts Metastatic Neuroblastoma Sarcoma Lymphoma

when preparations are made for a subsequent, immediate decompressive laminectomy. In these situations, time is very important. A rare observation has been the association of spinal cord tumors with increased intracranial pressure and papilledema [Celli et al., 1993]. The etiology for the papilledema has never been fully elucidated [Schijman et al., 1981]. In all likelihood, this association reflects a combination of decreased absorption of cerebrospinal fluid either secondary to hemorrhage within the tumor or as a result of a marked increase in cerebrospinal fluid protein. It is speculated that elevated protein may obstruct the arachnoid villi and axillary sleeves of the spinal roots, thereby limiting reabsorption of cerebrospinal fluid [Ucar et al., 1976].

Types of Tumors Extramedullary Tumors Traditionally, tumors of the spinal canal are divided into extramedullary and intramedullary masses (Table 71-4). Extramedullary masses erode the bony vertebral column, present asymmetrically, and involve those sensory and motor tracts placed laterally within the substance of the spinal cord parenchyma. These lesions are likely to represent metastases from sarcomatous or soft tissue masses, such as neuroblastoma, or may represent a more benign neurofibroma. Patients with neurofibromatosis may have scalloping of the posterior aspects of the bodies of the vertebrae. If scalloping of the vertebrae is found over one or two segments rather than multiple segments, an intraspinal tumor should be considered. Extensive scalloping is more likely associated with dural ectasia. Dumbbell lesions, consisting of neurofibromas presenting both inside and outside the neuroforamina, are occasionally encountered. These tumors can be cured surgically. Reticulum cell sarcomas, lymphomas, neuroblastomas, and other sarcomatous lesions usually present in the context of neoplasms found elsewhere in the body [Lewis et al., 1986]. In the spinal cord, they occur epidurally and present as compressive lesions. In some cases, metastatic lesions to the spinal canal can be treated with either radiation or chemotherapy without the need for decompressive laminectomy [Young et al., 1980]. Sarcomas may be quite radio-

FIGURE 71-51. Hairy patch overlying the spinal cord of a child with spinal dysraphism.

sensitive, whereas neuroblastomas are less responsive. Meningiomas are rare in children, except in cases of neurofibromatosis 2 [MacCollin and Mautner, 1998]. Dysembryoplastic lesions are observed in the younger child. The findings of teeth, bones, or calcification on x-ray film should suggest a dermoid. These findings may be associated with a sinus tract leading from the surface and extending intraspinally. The presence of sinus tracts has been associated with recurrent meningitis. As with dermoids, tumors usually occur in the lumbosacral midline region, although they may occur anywhere in the spinal column, and may be associated with spina bifida, sacral dimple, port-wine nevus, or excessive clumps of coarse hair (Fig. 71-51). At surgery, the tract extends to the conus. Nerve roots of the cauda equina are often enmeshed in the fatty tumor with varying degrees of neurologic abnormalities. The serpiginous nature of these fatty tumors may make surgery difficult. Despite this problem, with or without surgery, patients often remain relatively stable with little progression of symptoms.

Intramedullary Tumors Thirty-five percent of pediatric intraspinal tumors are intramedullary. Most intramedullary tumors in children are either astrocytomas or ependymomas. Astrocytomas are more common in younger children, whereas ependymomas are seen more often in adults [Houten and Weiner, 2000]. The mean duration of symptoms may vary from 1 day to 4 years [Reimer and Onofrio, 1985]. Astrocytomas present as a mass extending over multiple segments of the cord or the entire length of the spinal cord. They may be partially cystic [Epstein and Farmer, 1991]. Cysts are more common at the caudal end of the lesion and

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FIGURE 71-53. T2-weighted MRI signal revealing the extent of a myxopapillary ependymoma in a 12-year-old female.

FIGURE 71-52. A 12-year-old child with glioblastoma of the spinal cord. Parents refused postoperative therapy. He developed extensive leptomeningeal dissemination throughout the brain and spinal cord.

may occur in 40% of intramedullary astrocytomas. The cystic component is readily identified by MRI. Because these tumors expand and compress normal tissue, they are more likely to produce slowly progressive signs rather than sudden interruption of neurologic function. Astrocytomas of the spinal cord have hamartomatous features, consequently their natural history may be quite prolonged. Thus some have recommended a wide decompression with aspiration of cystic contents and bulk removal of the tumor [Epstein and Farmer, 1991; Matson, 1969]. In the presence of a gross total resection, no further therapy is needed [Nadkarni and Rekate, 1999]. Long-term survival of 90% with limited morbidity has been reported. Even in the face of dissemination, radiation can provide long-term survivals [Merchant et al., 2000). In contrast, high-grade astrocytomas of the spinal cord have a poor prognosis, often disseminating widely throughout the neuraxis (Fig. 71-52) [Epstein and Farmer, 1990]. The median survival of these tumors, despite therapy, is up to 12 months. They require, at a minimum, radiation. Ependymomas are less common than astrocytomas. Ependymomas of the spinal cord are classified into two types: well-differentiated cellular or well-differentiated myxopapillary tumors. The myxopapillary tumor is more

likely to involve the conus and cauda equina, whereas the more cellular tumors are found in the substance of the spinal cord. As with astrocytomas, treatment consists of laminectomy with decompression and attempt at total removal. Complete removal is the treatment of choice, resulting in cure [Nadkarni and Rekate, 1999]. In some cases a gross total resection is impossible due to the risks of severe morbidity. The response and need for radiation in both forms of this tumor are controversial. Some favor radiation for patients with subtotally resected cellular ependymomas of the spinal cord [Gilhuis et al., 2003]. The myxopapillary ependymoma is difficult to remove without causing neurologic deficits. As a result, limited resection followed by radiation has been recommended [Merchant et al., 2000] (Fig. 71-53). If a gross total resection can be achieved, however, no further therapy is needed [Gilhuis et al., 2003]. In general, the prognosis for ependymomas of the spinal cord is better than for astrocytoma, with 5-year survival rates of 72% to 100% [Epstein and Farmer, 1990].

Management Surgery After clinical suspicion and confirmation by neurodiagnostic procedures, surgical exploration and removal of tumor should be considered. In all cases, regardless of etiology and the extent of defect, surgical decompression is recommended. The spinal cord is resilient. In general, recovery depends on the length and duration of symptoms. Any evidence of compression of long tract motor or sensory function through the spinal cord limits hope for recovery.

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The first report of a patient successfully treated with surgery for a neoplasm involving the spinal cord was by Gowers and Horsley [1888]. In the intervening 100 years there have been marked advances in neurodiagnosis and neurosurgical technology. These changes have resulted in improvements in survival rates. The bipolar coagulating forceps, first used in 1940, permits the surgeon to effectively remove intrinsic tumor without blood loss [Greenwood, 1963]. In 1976 the introduction of the dissecting microscope further enhanced the surgeon’s ability to preserve small spinal cord vessels around a tumor [Yasargil et al., 1976]. More recently, the introduction of the ultrasonic surgical aspirator (CUSA system) and laser surgery has helped to minimize intraoperative trauma caused by traction and blunt dissection. The use of intraoperative ultrasonography has aided in defining solid neoplasm from associated intratumoral or extratumoral cysts. Cystic non-neoplastic lesions tend to occur at the rostral or caudal ends of a tumor, are smooth walled, and expand the cord symmetrically. Conversely, tumor cysts are asymmetrical, not smooth walled, and tend to be small. It has also been suggested that ultrasound is useful in planning myelotomies. Ultrasound allows exposure of the tumor at its most voluminous portion, thereby helping to minimize damage to functional neural tissue. Ultrasonography has also been helpful in differentiating astrocytomas from ependymomas of the spinal cord [Raghavendra et al., 1984]. Astrocytomas are relatively isodense and asymmetrical and exhibit heterogeneous signals presumably as a result of calcification or tumor cysts. Conversely, ependymomas are uniformly echogenic and expand symmetrically in a rostral caudal fashion. A tissue plane can be readily identified in ependymomas, whereas in astrocytomas tissue planes tend to blend into normal tissue. Furthermore, Epstein and Farmer [1991] suggested that a persistent abnormal signal will encourage tumor removal at a point at which direct inspection is unclear, which permits more radical resection of tumors previously viewed as inoperable. In the past, surgical cautery and its associated transmitted heat and movement through tumor adjacent to normal spinal cord led to the destruction of functional tissue and significant morbidity and, as such, prevented significant debulking. In skilled hands the use of the laser and the ultrasonic surgical aspirator (CUSA system) coupled with the operating microscope allow destruction of tumor while preserving normal tissue [Epstein and Farmer, 1991]. Ultrasonic dissection using the CUSA system limits tissue fragmentation to 1 mm from the vibrating tip. Successful myelotomies from the upper cervical segment to the lumbar region with and without associated cysts have been associated with complete cure without reliance on other adjuvant forms of therapy. At surgery, avoidance of damage to normal tissue can be aided by continuous monitoring of somatosensory evoked potentials. Changes may suggest reversible trauma or traction to the cord at surgery [Grundy, 1983]; however, the use of intraoperative evoked responses continues to remain controversial. During surgery, a loss of temporary signal without clinical correlation or neurologic deficit is frequently reported. The surgeon is often faced with a decision to either terminate the procedure for fear of inflicting irreversible neurologic deficit or continue in an effort to obtain maximum debulking [Epstein and Farmer, 1991]. Several

studies, however, have suggested that monitoring somatosensory evoked potentials is beneficial [Kearse et al., 1993; Nadkarni and Rekate, 1999; Stechison et al., 1995].

Adjuvant Management Radiation is recommended for subtotally resected spinal cord tumors; however, even this approach is not without controversy. Some have suggested that the cystic astrocytomas that occur over multiple segments in the spinal cord may be hamartomatous rather than neoplastic. As such, longterm survival can be expected with or without radiation. Conversely, the long-term survival of most patients with astrocytomas is worse than for patients with ependymomas. Many suggest radiation of all subtotally resected intramedullary tumors, regardless of histology. Recommended radiation doses to the lesion range between 2500 and 5000 cGy in 180 to 200 cGy fractions with a margin of 2 to 3 cm [Kopelson et al., 1980]. The volume to be irradiated should be local, with a margin of one or two vertebral bodies [O’Sullivan et al., 1994]. Furthermore, some suggest that radiation may improve preoperative deficits and lead to improved functional results.

Chemotherapy There are only limited reports of the use of chemotherapy in low-grade astrocytomas of the spinal cord [Balmaceda, 2000]. Most commonly, varying combinations of carboplatin and vincristine have been used. Two of three such studies reported complete responses with durable remissions (although one patient was 30 years old) [Bouffet et al., 1997; Foreman et al., 1998; Lowis et al., 1998]. There is more experience with high-grade astrocytomas. “Eight in one” was not found to be better than CCNU and vincristine [Allen et al., 1998]. However, several reports of more intensive chemotherapy including one of high-dose chemotherapy followed by autologous bone marrow transplantation with and without radiation produced either complete responses or stable disease [Finlay, 1996; Lowis et al., 1998; Weiss et al., 1997]. The experience with chemotherapy in ependymomas of the spinal cord is exceedingly limited. More research needs to be done in this area, particularly for very young children with intramedullary tumors that have not been completely resected.

Complications The main complications after treatment of spinal cord tumors are orthopedic. Depending on the extent of the laminectomy and the degree of instability that results from removal of the posterior elements of the vertebral column, significant orthopedic abnormalities may occur. Radiationassociated arachnoiditis or myelopathy also contributes to orthopedic abnormalities. Location of the tumor, age, dose, volume of radiation, and extent of surgery influence the degree of deficit [Fraser et al., 1977; Marks and Adler, 1982; Peschel et al., 1983]. Non-neurologic complications are kyphoscoliosis and, after radiation, limited growth of the vertebral column (Fig. 71-54). The recognition of the dynamic forces that occur in the growing spine has led many to seek a more conservative approach to treatment. The use

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matically increased the incidence of bone marrow remission, but approximately 50% of patients developed CNS relapse [Evans et al., 1970]. The introduction of CNS prophylaxis using intrathecal methotrexate reduced this complication to 25% of patients; later the use of cranial radiation therapy in addition to intrathecal methotrexate decreased CNS leukemia to 10% [Holland, 1976]. CNS complications of leukemia relate either to failure of therapy or to adverse effects of this therapy. If CNS leukemia were not prevented, multiple sites in the CNS might become directly involved, including the meninges, brain parenchyma, dural sinuses, and nerve roots. Complications of the disease and treatment include cerebrovascular accidents, infection, and leukoencephalopathy.

Meningeal Leukemia

FIGURE 71-54. Severe kyphoscoliosis secondary to spinal surgery and radiation for a cervical cord astrocytoma.

of microsurgical techniques has, to some extent, limited extensive laminectomies. Postoperative bracing and physical therapy can help retard but not prevent the development of significant orthopedic abnormalities [Raimondi et al., 1976; Reimer and Onofrio, 1985]. Neurologic complications after surgical treatment may be flaccid or spastic paraplegia or quadriplegia and bowel or bladder incontinence. Decubitus ulcers, pathologic fractures, and dislocated hips may occur because of loss of trophic neurologic input. Although treatment may be curative, morbidity can be significant. Skilled and continuous rehabilitative care is necessary to maximize the quality of life in such patients. In conclusion, the prognosis for patients with spinal cord tumors is much better than that for the child with an intracranial tumor. Surgical intervention may delay the growth and progression of these tumors. In the more aggressive tumors, surgery, coupled with judicious use of radiotherapy, has been associated with long-term survival or cure. Unfortunately, morbidity is quite significant. The insidious nature of spinal cord tumors, their relative rarity, and their lack of clinical specificity continue to challenge the most astute neurologic clinicians.

NEUROLOGIC COMPLICATIONS OF LEUKEMIA Leukemia Leukemia is the most common malignancy in childhood. In the 1960s, the use of systemic chemotherapy in the treatment of children with acute lymphoblastic leukemia dra-

Infiltration of the superficial arachnoid membrane is the first stage of meningeal leukemia. Leukemic cells are found in the trabeculae of the arachnoid and walls of veins at a time when cells are not commonly identified in the cerebrospinal fluid. In grade II meningeal leukemia, the superficial arachnoid becomes more extensively involved, and the deep arachnoid membrane is infiltrated by tumor cells. The cerebrospinal fluid is consistently contaminated by leukemic cells. Malignant cells penetrate deeply into the Virchow-Robin spaces, but the parenchyma is protected by the pial-glial membrane. In grade III meningeal leukemia, the pial-glial membrane is destroyed and leukemic cells enter the parenchyma. At this stage, there is extensive leukemic involvement of both superficial and deep arachnoid, as well as invasion of the cerebrospinal fluid [Price and Johnson, 1973]. Patients with meningeal leukemia may develop communicating hydrocephalus, presumably secondary to collections of leukemic cells in the subarachnoid space over the surface of the cortex and in the basal cisterns. These cells, by prohibiting or delaying the resorption of cerebrospinal fluid through the arachnoid villi back into the venous system, cause hydrocephalus and increased intracranial pressure [Pierce, 1962]. The child with leptomeningeal disease consequently develops signs and symptoms of increased intracranial pressure, such as headache, early morning vomiting, irritability, papilledema, and nuchal rigidity [Pinkerton and Chessells, 1984]. The association of fever with meningismus may mimic bacterial meningitis. Lumbar puncture reveals increased pressure, pleocytosis, increased protein, and decreased glucose. Blast cells may be identified on cytocentrifugation but in some cases, morphology may be atypical or cell numbers low. In general, high cerebrospinal fluid pressure correlates with high cell counts. Protein elevation is seen in approximately 50% of patients, although values rarely exceed 100 mg/dL. Cerebrospinal fluid glucose has been reported to be less than half the blood glucose level in 60% of patients, but of interest, there is no correlation with cellular response [Pierce, 1962]. Leukemic infiltration of cranial nerves is another typical presenting sign of leptomeningeal disease. Cranial nerves II, VI, VII, and VIII are most commonly involved. Ophthalmic complications of leukemia are found in approximately 9% of children. Involvement of the optic nerve by leukemic infiltration is but one cause of visual problems in patients with leukemia [Ridgway et al., 1976; Weaver et al., 1986].

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Although loss of vision is usually due to infiltration of the optic nerve, retinal bleeding and infiltration of the retina, iris, and orbit are also found. Rarely, leukemic infiltration in the subarachnoid space bathing the visual cortex may lead to cortical blindness [Ha et al., 1980]. Cranial nerve VI paresis is usually a nonlocalizing sign of increased intracranial pressure. However, leukemic infiltration of the nerve may also occur. Facial paresis may occur from infiltration of cranial nerve VII anywhere along its course. Disease may be found intracranially, in the internal auditory meatus, in the middle ear, or at the stylomastoid foramen. At times, facial paresis secondary to leukemic infiltration may be misdiagnosed as a Bell’s palsy [Murthy et al., 2002]. Vestibular dysfunction may relate to involvement of the membranous labyrinth by tumor or blood. Sensorineural deafness results from damage either to the intracranial portion of cranial nerve VIII as it enters the pons or from involvement of the end organ. Hearing loss may occur from either mechanism or as a complication of therapy. In addition, conductive deafness occurs when the middle ear is affected by the leukemic process. The complaint of a numb chin, even with no other findings, suggests infiltration of the mentalis nerve.

Dural Sinus Thrombosis Dural sinus thrombosis is a rare complication of CNS leukemia. It may occur while the child is in remission. Sagittal sinus thrombosis may be the cause of increased intracranial pressure in children with acute lymphoblastic leukemia in the absence of cerebrospinal fluid pleocytosis. The etiology is obscure but may be related to leukemic infiltration of the dural sinus or secondary to chemotherapy, such as L-asparaginase [David et al., 1975; Ganick et al., 1978].

Stroke Hemorrhagic and ischemic strokes occur in 4% of children with acute lymphoblastic leukemia [Packer et al., 1985]. The majority occur within the first year after diagnosis or when the child is no longer responsive to therapy. Hemorrhage commonly develops secondary to thrombocytopenia, disseminated intravascular coagulation, or hematologic toxicity associated with chemotherapy. Patients with low platelet counts and minor head trauma are also at risk for epidural and subdural hematomas, which are readily identified by CT. Patients may occasionally have CNS hemorrhage at diagnosis. Hemorrhage may occur in patients who have a rapid increase of leukocytes to levels of more than 100,000/mm3. Tendency to hemorrhage appears to be related to the increased viscosity of the blood. Disproportionately high hemoglobin and platelet counts are identified in some patients. With the increased packed cell volume and increased viscosity, cerebroleukostasis and massive hemorrhage follow. Hemorrhage can also develop secondary to expanding leukemic collections within the arachnoid that compress blood vessels. Vascular perfusion of surrounding brain is consequently reduced, leading to ischemic damage, necrosis, and intracerebral hemorrhage [Price and Johnson, 1973]. Patients with elevated white blood cell count levels may also develop thrombotic stroke. More commonly, the

FIGURE 71-55. Axial CT demonstrating an intracerebral hemorrhage secondary to L-asparaginase.

cerebrovascular accident is a complication of therapy. The major causative chemotherapeutic agent is L-asparaginase (Fig. 71-55) [Priest et al., 1980]. Typically, thrombotic stroke occurs at the end of induction and presents either as an acute venous sinus thrombosis with seizures and coma or as focal arterial thrombosis. The latter is associated with focal seizures and focal neurologic deficit. L-Asparaginase produces either thrombotic or hemorrhagic stroke, in part because of its tendency to prolong plasma clotting time, lower concentrations of factors IX and XI, depress levels of antithrombin 3, protein C, plasminogen, and produce hypofibrinogenemia [Priest et al., 1980]. Pretreatment with fresh frozen plasma is recommended by some authors [Feinberg and Swenson, 1988]. Other predisposing conditions for stroke in children with acute lymphoblastic leukemia are dehydration and CNS infection. Bacterial or viral sepsis may produce disseminated intravascular coagulation and thrombotic stroke. This condition may mimic a diffuse metabolic encephalopathy, albeit with focal features. The diagnosis may be obscure because the initial area of thrombosis may be in the brain, whereas the systemic manifestations of disseminated intravascular coagulation may not appear for 24 to 48 hours. Fungal meningitis, especially aspergillosis, has been associated with secondary arterial strokes [Packer et al., 1985].

Hypothalamic Syndrome Hypothalamic infiltration by leukemic cells leads to a syndrome characterized by hyperphagia, headache, vomiting, and increased intracranial pressure. This syndrome was first reported in 1954. Patients with acute lymphoblastic leukemia developed sudden weight gain and voracious appetite. Before CNS prophylaxis, this complication occurred in 15% to 25% of patients with CNS recurrence. Evidence of hypothalamic infiltration dramatically decreased after CNS prophylaxis became routine. Presumably, infiltration of leukemic cells into the ventromedian nucleus of the hypo-

Cohen and Duffner / Tumors of the Brain and Spinal Cord

thalamus (satiety center) and the lateral hypothalamus (feeding center) leads to uncontrolled increase in appetite and obesity. Patients with this complication are frequently in bone marrow remission [Greydanus et al., 1978]. Recognition that an increase in appetite and weight gain may represent CNS disease rather than a side effect of steroid therapy may lead to earlier intervention.

Seizures The incidence of seizures in a population of children with acute lymphoblastic leukemia ranges from 4% to 13%. Approximately two thirds do not have an obvious etiology. Identified etiologies are leukemic infiltration, venous or arterial thrombosis, rapid cell lysis, hemorrhage due to thrombocytopenia, infection, drug complications, or leukoencephalopathy [Ochs et al., 1984]. The majority of seizures are partial simple seizures with or without secondary generalization. Absence seizures and partial complex seizures are rare. Patients often have seizures during therapy but approximately half the children are in remission; the others have a history of prior meningeal leukemia with or without bone marrow relapse. Seizures have been reported in children within a week following intrathecal methotrexate, of which 50% in one study had prior meningeal leukemia [Maytal et al., 1995]. Seizures may also occur acutely in the presence of intrathecal methotrexate (<2%). Seizures may occur as isolated events or in the face of methotrexate chemical meningitis, a syndrome characterized by fever, headache, dizziness, back pain, nausea, and vomiting. Because methotrexate interferes with dihydrofolate reductase and the reduction of tetrahydrobiopterin, this reaction may secondarily decrease the availability of γ-aminobutyric acid, an inhibitory neurotransmitter, leading to increased seizure susceptibility. Methotrexate is known to be associated with the development of leukoencephalopathy and seizures, especially in patients who have previously received cranial irradiation or in those who have CNS leukemia. CT scans in these patients may reveal evidence of leukoencephalopathy (i.e., ventriculomegaly, calcification, hypodense areas) [Peylan-Ramu et al., 1978]. More recently, intravenous methotrexate, when given frequently and in high doses, has caused leukoencephalopathy in nonirradiated children without CNS disease. In addition to methotrexate-induced complications, seizures may occur with administration of cisplatin due to the development of syndrome of inappropriate antidiuretic hormone, resulting in hyponatremia [Mead et al., 1982]. Another agent, vincristine, may cause the syndrome of inappropriate antidiuretic hormone release with resulting seizures, but seizures have also been reported 5 to 6 days following vincristine when there were no metabolic derangements [Johnson et al., 1973]. L-Asparaginase increases the risk of seizures as well, especially in the presence of hemorrhagic stroke. Metabolic causes of seizures include hyponatremia, hypoglycemia, hypocalcemia, and hypomagnesemia. Narcotics and antiemetics, used commonly in this population, can also lower the seizure threshold. The evaluation of the child with leukemia and seizures should include assessment of electrolytes, glucose, coagulation studies, and lumbar puncture for cytology, protein, glucose, and bacterial, fungal, and viral cultures. MRI, mag-

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netic resonance venography, and arteriography should also be performed. The choice of anticonvulsants is problematic for those children still on chemotherapy. Drug-drug interactions may affect the levels of chemotherapy agents as well as anticonvulsants. For example, both phenobarbital and phenytoin displace methotrexate from plasma proteins that then increases the risk of methotrexate neurotoxicity. In addition, because anticonvulsants are given on a daily basis and chemotherapy is given in cycles, dose adjustments can be very difficult. Another issue with anticonvulsants is their effect on white blood counts, platelets, and liver function. Carbamazepine, for example, commonly causes leukopenia and valproic acid may cause thrombocytopenia, especially in the face of viral infections. Valproic acid, phenytoin, and carbamazepine all have been reported to cause hepatotoxicity. For those children receiving cranial irradiation, phenytoin should be avoided because of the association with erythema multiforme and Stevens-Johnson syndrome [Delattre et al., 1988]. Treating a child with leukemia and seizures may be problematic, making it difficult to know whether hematologic or hepatic abnormalities reflect the leukemia, the chemotherapy, or the anticonvulsants. The newer anticonvulsants such as gabapentin and levetiracetam are not metabolized in the liver and have limited hematologic and hepatic toxicity. As such, they are better choices for these children.

Chemotherapy-Associated Myelopathy Myelopathy has been reported following intrathecal methotrexate, particularly in children with meningeal disease. It has also been reported, however, in children without CNS leukemia. Cytosine arabinoside has also been implicated in causing myelopathy, even in the absence of methotrexate. Prior radiation to the spinal cord as well as total dose and frequency of drug administration are risk factors [Dunton et al., 1986]. Patients present with weakness or paralysis, a sensory level and loss of bowel and bladder function occurring either immediately or within a short time following chemotherapy. The thoracic cord is primarily affected. There have also been reports of ascending paralysis and death that have occurred as late as 5 weeks following therapy. Just as concerning are cases of progressive paraplegia occurring months after completion of intrathecal therapy [Hahn et al., 1983; McLean et al., 1994; Watterson et al., 1994]. The pathology associated with cytosine arabinoside myelopathy is microvacuolization without inflammation while methotrexate-associated myelopathy has been associated with white matter necrosis and sparing of gray matter [Watterson et al., 1994]. A syndrome that resembles poliomyelitis has also been reported, with destruction of anterior horn cells [Reznik, 1979]. Evaluation includes MRI of the spine and cerebrospinal fluid examination. There is an increase in cerebrospinal fluid protein in approximately half the patients. Elevation in myelin basic protein has been reported to be predictive of future myelopathy [Bates et al., 1985]. The prognosis is poor, with most children dying or remaining permanently paraplegic. There is no effective treatment.

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Spinal Cord Compression Spinal cord compression, an unusual complication of acute lymphoblastic leukemia, occurs in less than 1% of patients [Pui et al., 1985]. It is three times more common in myelogenous than lymphoid leukemia [Lo et al., 1985]. Compression may develop secondary to tumor infiltration. As in other causes of spinal cord compression, patients may have back pain, progressive weakness of lower extremities, and urinary and fecal incontinence. Sensation is generally affected. Diagnosis is often delayed or not recognized in patients treated for acute lymphoblastic leukemia because these symptoms are erroneously believed to be due to neuropathy from chemotherapy rather than secondary to spinal cord disease. Vincristine may cause weakness of the lower extremities and reflex changes, and prednisone may cause proximal muscle weakness and polyuria [Allen, 1978]. Furthermore, complaints of leg pain may be presumed secondary to bone involvement rather than root infiltration [Sullivan, 1963]. The conus medullaris syndrome, characterized by fecal and urinary incontinence with loss of sensation over S2, S3, and S4 dermatomes in the absence of motor weakness, has rarely been reported in acute lymphoblastic leukemia. This syndrome relates to leukemic infiltration of the sacral cord, although it may also be secondary to hemorrhage. Infiltration of the cauda equina by leukemic cells produces a syndrome similar to that of the conus medullaris but distinguished clinically by the presence of asymmetrical weakness or paralysis before sphincter involvement [Peturrson and Boggs, 1981]. The usual site of cord compression is in the thoracic or lumbar region. The lesion is generally epidural and should be readily demonstrated by MRI. Cerebrospinal fluid protein is usually elevated, at times reaching levels of 1000 mg/dL [Peturrson and Boggs, 1981]. Intramedullary lesions, characterized by perivascular cuffing and diffuse myelitis, are much less common. In these cases the picture may be confused with transverse myelitis. Treatment must be instituted as soon as possible. Local radiation in a dose of 3000 cGy and high-dose dexamethasone are recommended. Laminectomy is rarely necessary because of the sensitivity of the leukemic cells to radiation [Pui et al., 1985]. Results of treatment are generally good, with rapid response to therapy. Another cause of spinal cord compression is epidural or subdural hematoma in patients who receive lumbar punctures in the presence of thrombocytopenia. In suspected cases, CT or MRI of the affected area will demonstrate blood in the epidural or subdural space. Early evacuation is necessary to prevent permanent neurologic residual.

Cryptococcal meningitis is seen in patients with leukemia and other forms of cancer. India ink preparations are positive in 50% of patients. Culture and examination for cryptococcal antigen confirm the diagnosis. Therapy includes systemic amphotericin B in combination with 5-flucytosine. Brain abscess is suggested by the presence of focal neurologic findings and low-grade fevers. Diagnosis of a bacterial brain abscess is made by MRI or CT with a characteristic ringenhancing lesion. Cultures may reveal bacterial involvement with either aerobic or anaerobic bacteria. In the presence of pulmonary lesions, Aspergillus, Mucor, Candida, and Nocardia brain abscesses are more likely (Fig. 71-56). The CT appearance of abscess in fungal disease is usually a poorly circumscribed, low-density area without a capsule [Hara et al., 1984]. Treatment is sulfamethoxazole (Bactrim) for Nocardia and amphotericin for fungi (see Chapter 70) [Pizzo, 1981]. Viral encephalitis in patients with leukemia is usually caused by herpes simplex, varicella-zoster, and rubeola. Toxoplasma gondii also has a predilection for the CNS. In addition to evidence of CNS involvement characterized by seizures, focal motor deficits, and cranial neuropathies, patients may have more widespread involvement affecting lung, heart, liver, and spleen. There have been several reports of an atypical form of measles encephalitis in children with acute lymphoblastic leukemia who are in remission. Mortality is high, and the diagnosis may be difficult to establish [Campbell et al., 1977]. Previously children with leukemia commonly had cerebrospinal fluid reservoirs placed in an effort to facilitate drug administration. Unfortunately, these reservoirs were foreign bodies and were a nidus for infection [Machado et al., 1985].

LONG-TERM EFFECTS OF CENTRAL NERVOUS SYSTEM THERAPY As more children with CNS neoplasia survive their disease, the long-term effects of therapy become increasingly

Infection Bacterial meningitis is surprisingly uncommon in children with leukemia, which in part relates to the early administration of antibiotics in children with suspected infections. Symptoms such as headache, meningismus, and disorientation should suggest the possibility of bacterial meningitis. Cerebrospinal fluid must be evaluated for the different bacterial, viral, and fungal agents. Meningitis secondary to Listeria monocytogenes is suggested by the presence of gram-positive rods in the cerebrospinal fluid. Appropriate therapy includes intravenous ampicillin and gentamicin.

FIGURE 71-56. Gross pathologic section of a patient with acute lymphoblastic leukemia who developed CNS aspergillosis.

Cohen and Duffner / Tumors of the Brain and Spinal Cord

relevant. Most studies concerning the late effects of treatment have centered on cranial irradiation in children with leukemia and brain tumors. Chemotherapy is associated with more severe acute toxicity, and the long-term effects have been less well studied than those of radiation [Duffner, 2004a; 2004b].

Radiation The most common of the early delayed effects of radiation therapy on the cerebrum is the somnolence syndrome. Somnolence associated with anorexia, apathy, and headache occurs 6 to 8 weeks after radiation, with symptoms lasting from 4 to 14 days. Symptoms generally resolve without mental or physical sequelae. First recognized by Druckman in 1929, this syndrome was then reported again in 1973 by Freeman and co-workers, who described the somnolence syndrome in children irradiated for acute lymphoblastic leukemia [Freeman et al., 1973]. A severe form of the early delayed effect of radiation was reported by Lampert and Davis in 1964. This condition is a rapidly progressive syndrome of ataxia, cranial neuropathies, focal motor signs, nystagmus, and death developing over days to weeks after the termination of radiation therapy. Pathology reveals demyelination within the field of radiation therapy, as well as pronounced microglial and astrocytic proliferation [Lampert and Davis, 1964].

Radiation Necrosis One of the late delayed effects of radiation therapy is radiation necrosis. Radiation necrosis is estimated to occur in 5% of patients between 6 months and 2 years after completion of treatment. Risk increases with total dose and fraction size. Symptoms range from memory loss, dementia, personality change, and agitation to those of recurrent tumor, especially increased intracranial pressure. The pathology is primarily vascular, affecting the endothelium of small arteries and arterioles and leading to thrombosis and ischemia. White matter is also selectively involved with loss of myelin. Differentiating radiation necrosis from recurrent brain tumors is sometimes difficult because both may be associated with elevation in cerebrospinal fluid protein, focal EEG slow wave activity, an avascular mass on angiography, and presence of a mass lesion with a decreased attenuation coefficient and variable enhancement on CT [Marks et al., 1981; Martins et al., 1977]. MRI patterns vary, including a single lesion at or near the site of the original tumor, multiple lesions, subependymal lesions, or lesions remote from the original tumor. Single-photon emission CT and, more reliably, positron emission tomography now offer the potential of distinguishing radiation necrosis from recurrent tumors. However, the ability of positron emission tomography to distinguish these is only 43% [Thompson et al., 1999]. Magnetic resonance spectroscopy may also be useful in differentiating tumor recurrence from radiation necrosis. Patients with postradiation necrosis are more likely to have reduced N-acetylaspartate but preserved choline peaks compared with patients with tumor recurrence in which choline is increased [Usenius et al., 1995]. The incidence of radionecrosis has increased with the use of stereotactic radiosurgery, gamma knife, and brachytherapy.

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The course of radiation necrosis varies, ranging from spontaneous resolution to stabilization to progression. Steroids are used to decrease acute edema. Others have suggested anticoagulation. Additional agents being studied include pentobarbital, desferoxamine, and pentoxifylline. Surgery is indicated in those with significant mass effect [Glass et al., 1984].

Moyamoya Syndrome Moyamoya syndrome, a form of late-onset radiation vasculopathy, is a syndrome of basilar stenotic and occlusive disease occurring in the large arteries of the circle of Willis, the terminal parts of the internal carotid artery, and the proximal portions of the middle cerebral and anterior cerebral arteries. Symptoms include transient ischemic attacks, seizures, motor weakness, dementia, and frank strokes. The stenosis is gradual, leading to the development of an extensive collateral circulation. The patient at greatest risk of developing moyamoya syndrome is the child with neurofibromatosis 1 who is younger than 5 years of age and who has been irradiated to the hypothalamic-chiasmatic region with doses greater than 50 Gy. The treatment for this condition is encephaloduroarteriosynangiosis. A segment of the scalp artery is placed on the surface of the brain in order to improve collateral flow. If successful, no further deterioration will occur [Bitzer and Topka, 1995; Kestle et al, 1993; Omura et al, 1997].

Radiation Myelopathy Radiation myelopathy may occur as a transient phenomenon 6 weeks to 6 months following radiation. This is a temporary condition characterized by L’Hermitte’s sign (i.e., electrical buzzing sensations in the limbs and body brought on by movement of the neck) with transient demyelination of the posterior columns and lateral spinothalamic tracts. A much more serious form of radiation myelopathy is the delayed form that occurs months to years following radiation therapy. Patients develop acute or progressive paraplegia or quadriplegia, a sensory level, and loss of bowel and bladder function [Liu et al., 2001]. Radiation myelopathy correlates with total dose (>6000 cGy) and fraction size (>200 cGy). Pathology reflects demyelination and vascular changes including endothelial thickening, vasculitis, telangiectasia, and fibrinoid necrosis. MRI initially reveals spinal cord edema with ring enhancement, but over time spinal cord atrophy develops. Treatment includes steroids for acute edema. Anticoagulation has also been proposed to prevent further damage to the endothelium of small blood vessels [Liu et al., 2001]. Prognosis is poor.

Disturbances in Intellectual Function in Children with Leukemia The long-term effects of cranial radiation therapy on intellectual function were initially studied in children with acute lymphocytic leukemia who had previously received cranial irradiation as part of CNS prophylaxis. Although cranial radiation therapy is not routinely given to standard-risk children today, there is a large population of long-term survivors who are experiencing significant sequelae. The emphasis on

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children with leukemia, rather than children with brain tumors, reflects their better overall prognosis, as well as the larger numbers of children with acute lymphocytic leukemia available for study. In addition, because children with CNS leukemia were excluded from many of these studies, effects of treatment could be readily differentiated from the effects of primary CNS disease. A large, retrospective study of children with acute lymphocytic leukemia found that children who had been irradiated for CNS prophylaxis had significantly lower mean full-scale intelligence quotients than children treated with either intrathecal methotrexate alone or intravenous plus intrathecal methotrexate. Less than 15% of the irradiated patients exceeded the average intelligence quotients, whereas more than 55% from the other two groups had intelligence quotients higher than 100. Furthermore, irradiated children did worse on both wide-range achievement tests and on tests of neuropsychologic function [Rowland et al., 1984] (Fig. 71-57). In other studies, specific deficits in math, visuomotor function, and spatial processing have been recognized. In addition many children have distractibility and attention deficit disorder. Of interest, reading and language abilities are typically preserved [Copeland et al., 1985]. Risk factors include young age at radiation, feminine gender, and CNS relapse. Prospective longitudinal studies have revealed progressive deterioration, with intelligence quotients scores still falling a decade following treatment [Cousens et al., 1988; Fletcher and Copeland, 1988; Kato et al., 1993; Longeway et al., 1990; Mulhern et al., 1987]. The role of chemotherapy in treatment-induced cognitive decline is being reevaluated. Whereas earlier studies suggested that intravenous and/or intrathecal methotrexate was not associated with leukoencephalopathy (unless the child had been irradiated and/or had CNS disease), it is now increasingly accepted that even in the absence of these risk factors, high-dose frequently administered methotrexate

FIGURE 71-57. Full-scale intelligence quotient related to CNS treatment. IT, intrathecal; IV, intravenous; RT, radiation. (From Rowland et al., 1984.)

may produce leukoencephalopathy and cognitive disorders [Mahoney et al., 1998].

Disturbances in Intellectual Function in Children with Brain Tumors Concerns over the potential long-term effects of CNS radiation on children with brain tumors began to surface in the 1980s, as the number of survivors began to increase. Retrospective studies from that decade documented significant intellectual difficulties in children irradiated for brain tumors [Bamford et al., 1976; Broadbent et al., 1981; Duffner et al., 1983b; Raimondi and Tomita, 1979c]. Speculation centered on whether the poor intelligence quotients scores were due to the presence of hydrocephalus, the tumor, or the treatment. In an effort to assess the role of hydrocephalus, intelligence quotients of children with cerebellar astrocytomas treated with surgery alone were compared with children with medulloblastoma treated with surgery and postoperative radiation and chemotherapy. Medulloblastomas and cerebellar astrocytomas, because of their location in the posterior fossa, are both associated with obstructive hydrocephalus secondary to ventricular outflow obstruction. Thus the major difference between the two groups of patients was the postoperative radiation and chemotherapy. Results of this study revealed that only 11% of children with medulloblastomas had intelligence quotients higher than 90, whereas 62% of the patients with cerebellar astrocytomas had intelligence quotients above 90. This study implicated postoperative radiation and chemotherapy as the cause of the intellectual impairment; hydrocephalus was not believed to be a factor [Hirsch et al., 1979]. Subsequent reports confirmed these results [Kun et al, 1983; Mulhern and Kun, 1985]. Although hydrocephalus is not considered a risk factor, several others have been identified as increasing the likelihood of postradiation cognitive disorders. The most important risk factor is age at cranial irradiation. Children irradiated before 3 to 5 years of age have significantly greater intellectual impairment than older children, whereas children irradiated after the age of 8 years are likely spared the most severe deterioration [Packer et al., 1989; Spunberg et al., 1981]. Learning disabilities are almost universal regardless of age. Of great interest was a prospective study performed by Mulhern and colleagues [1989] in which very young children with brain tumors were treated with postoperative chemotherapy and delayed radiation. Only 25% of children had scores in the normal range before any treatment. Thus although radiation damages intellectual function in the very young child, many children may be abnormal before therapy. Another important risk factor is the volume of radiation. Ellenberg and associates [1987] prospectively studied the intelligence of patients treated for brain tumors and compared those who had received no radiation, local radiation, or whole brain radiation. Children who received wholebrain radiation had a significant decline in intelligence quotients following cranial radiation therapy, whereas children who received local or no cranial radiation therapy remained stable. Others have also found that intellectual dysfunction is more likely in children treated with whole-brain radiation rather than radiation to the posterior fossa alone [Kun et al., 1983].

Cohen and Duffner / Tumors of the Brain and Spinal Cord

The dose of radiation is also an important risk factor. Although a safe dose of cranial irradiation has not been defined, children who were irradiated for acute lymphoblastic leukemia in doses of 1800 to 2400 cGy did not demonstrate the severe intellectual sequelae seen in children treated with more than 3600 cGy to the brain. It is important to note, however, that in three different studies reducing the dose of cranial radiation therapy in children with acute lymphocytic leukemia from 2400 to 1800 cGy did not improve intelligence quotient scores [Jankovic et al., 1994; MacLean et al., 1995; Rodgers et al., 1991]. In contrast, studies in which the dose of radiation to the neuraxis in children with brain tumors was reduced have generally found improved scores, for example, full-scale intelligence quotient equal to 76.9 with 25 Gy compared with 63.7 with 35 Gy [Grill et al., 1999]. A Children’s Oncology Group study, however, in which children were treated with 2400 cGy craniospinal radiation and chemotherapy found declines in intelligence quotient of 15 to 20 points [Packer et al., 2002]. The site of tumor is also important. Children who have tumors located primarily in the posterior fossa are less likely to be intellectually impaired before treatment than children whose tumors are located either in the supratentorial region or the midline of the brain. After radiation treatment, deterioration may occur regardless of site, but because patients with supratentorial tumors have significantly lower intelligence quotients at baseline than children with posterior fossa tumors, their decline may place them in the frankly abnormal range [Ellenberg et al., 1987]. Several reports have cited hypothalamic and thalamic involvement as being associated with cognitive abnormalities, especially those tumors involving the anterior third ventricle. Patients with pineal region tumors have also been reported to have disorders of memory, visuomotor problem-solving and visuospatial attention [Giglio et al., 2000]. The only chemotherapeutic agent that has been clearly identified as a risk factor for treatment-induced dementia has been methotrexate. Children treated with radiation and intrathecal methotrexate for medulloblastoma in one study, for example, had mean intelligence quotients of only 74.6 2 years after radiation compared with studies by Packer and colleagues [1989] and Jannoun and Bloom [1990], in which irradiated children not treated with methotrexate had scores of 91 and 92, respectively [Riva et al., 1989]. Finally, perioperative morbidity is increasingly recognized as a poor prognostic factor [Chapman et al., 1995; Kao et al., 1994]. Perioperative complications including neurologic deficits, meningitis, shunt infections, and the need for repeat surgery have been correlated with cognitive deficits. The “posterior fossa syndrome” (cerebellar mutism), in particular, has been associated with long-term cognitive decline. A recent report from the Children’s Oncology Group found a 24% incidence of posterior fossa syndrome in a group of children with medulloblastomas. As such, long-term cognitive problems for a large group of survivors can be anticipated [Robertson et al., 2002]. This may become more important as attempts at achieving gross total resections are likely to increase in the future. Prospective studies of children with brain tumors have revealed that intellect may continue to decline over several years. During the first year after radiotherapy, results are inconsistent. However, when follow-up extends to 4 years,

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progressive deterioration in intellectual functioning is found. Cognition has continued to decline progressively over a 10-year period [Hoppe-Hirsch et al., 1990]. In addition, even children with normal intelligence quotients may have significant learning problems, including attentional difficulties and visual perception problems [Duffner et al., 1985a; Packer et al., 1989].

Disturbances In Endocrine Function Several groups of investigators have studied the endocrine status of children treated for acute lymphocytic leukemia. These studies demonstrated that levels of growth hormone obtained within 1 to 3 days after a 3-week course of cranial radiation therapy are lower than levels before cranial radiation therapy and, as such, an immediate suppressive effect on the hypothalamic-pituitary axis has been suggested [Dacou-Voutetakis et al., 1977]. The total dose of radiation appears to influence hypothalamic-pituitary function. Doses of less than 2400 cGy may be associated with normal growth hormone response to arginine stimulation, but not to insulin stimulation. In contrast, patients who receive more than 2400 cGy of radiotherapy may have abnormalities of growth hormone release after arginine and insulin stimulation. The theoretical basis for this disparity is that insulin-induced hypoglycemia may produce effects directly on the hypothalamus, whereas arginine stimulation may directly stimulate the pituitary gland. Because the pituitary gland itself is relatively radiation resistant, radiation in low doses may produce growth hormone deficiency resulting primarily from hypothalamic damage. Higher doses of radiation may affect both pituitary and hypothalamic function [Dickinson et al., 1978]. The incidence of biochemical growth hormone deficiency increases if the total dose of radiation is given in larger fractions over a shorter time. Children who receive 2400 cGy of radiation over 2 weeks in 10 fractions experience greater toxicity than children receiving the same dose given in 20 fractions over 4 weeks [Shalet et al., 1976; 1977]. Growth hormone deficiency is not related solely to cranial radiation therapy because it may also be found in children with acute lymphocytic leukemia treated with chemotherapy alone. Children with acute lymphocytic leukemia who were identified as being growth hormone deficient following cranial radiation therapy were initially thought to grow normally. When these children were reassessed after puberty, the irradiated children had shorter adult heights than nonrradiated children, presumably due to their inability to undergo a pubertal growth spurt [Brecher et al, 1992; Uruena et al, 1991; Voorhess et al., 1986]. Risk factors for growth failure in children with acute lymphocytic leukemia are radiation treatment at a young age, feminine gender, and early development of puberty. The effects of chemotherapy are less severe than those caused by radiation. Because of the much larger doses of cranial radiation therapy administered to children with brain tumors, the risk for endocrine dysfunction is greater than in children with leukemia. Retrospective studies have demonstrated that children with brain tumors treated with cranial radiation therapy are at high risk for the development of growth hormone deficiency. It has been suggested that a minimum dose of 2500 to 2900 cGy delivered to the hypothalamic-

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pituitary axis may produce growth hormone deficiency in children with brain tumors. Most studies have documented that approximately 80% to 90% of children who have received cranial radiation therapy for brain tumors will develop growth hormone deficiency [Duffner et al., 1985b; Shalet et al., 1978; Wara et al., 1977]. Most growth hormone– deficient children with brain tumors do not grow normally. The reasons for growth failure are multifactorial. Although growth hormone deficiency is a major consideration, another factor is the effect of radiation on the epiphyseal centers in the vertebrae. Shalet and co-workers [1987] reported that radiation of the spine of a child 1 year of age will lead to an absolute loss of height of 9 cm, whereas children irradiated at age 10 years will lose 5 cm. In addition to poor spinal growth, many children develop precocious puberty. Although they have an early growth spurt, they ultimately have short stature. Shalet and co-workers have shown a correlation between age at radiation and onset of puberty, with the earliest onset in those irradiated between 3 and 6 years [Shalet et al., 1988]. The presence of hypothyroidism also adversely affects growth. Finally, the poor nutrition of some children on long-term chemotherapy may contribute to growth failure. Prospective studies have demonstrated that biochemical growth hormone deficiency begins in some patients as early as 3 months after completion of radiation therapy. Furthermore, the number of patients with growth hormone deficiency increases during the first year after treatment [Duffner et al., 1985b]. Growth hormone deficiency does not appear to be reversible because children have been reported to be growth hormone deficient as long as 8 years after radiation therapy [Duffner et al., 1983a]. Growth deceleration may begin 6 months after completion of radiation and may closely parallel the onset of biochemical growth hormone deficiency. Unless growth deceleration is recognized and treated, clinical growth failure may be permanent (Fig. 71-58). Of interest, some children with brain tumors are growth hormone deficient but continue to grow normally. Explanation for the continued growth in these children is unknown. Growth hormone deficiency in irradiated patients may be a result of reduced production of growth hormone (pituitary)

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or deficiencies in growth hormone–releasing factor (ventromedian nucleus of the hypothalamus). Even children who receive radiation to the posterior fossa alone may become growth hormone deficient. Because the anterior limit of the radiation port to the posterior fossa does not include the pituitary gland but does include the ventromedian nucleus of the hypothalamus, it has been suggested that the etiology for some cases of radiation-induced growth hormone deficiency is hypothalamic in origin. Administration of growth hormone–releasing factor produces an elevation in growth hormone levels in some children whose growth hormone deficiency is secondary to cranial radiation therapy. Thus cranial radiation therapy appears to affect growth hormone levels, in part, by damaging hypothalamic growth hormone– releasing factor–secreting neurons [Lustig et al., 1985]. Several investigators have successfully treated radiationinduced growth hormone–deficient children with exogenous growth hormone [Romshe et al., 1984; Shalet et al., 1981]. Unfortunately, although children with brain tumors may respond well for the first year of treatment, others have suggested that a normal growth rate cannot be maintained over a 3-year treatment period [Winter and Green, 1985]. These results are in contrast to other reports in which growth acceleration has been maintained with growth hormone treatment. Growth hormone–releasing factor may also have potential therapeutic value because it causes an increase in growth hormone levels [Lustig et al., 1985]. The long-term efficacy of treatment with both growth hormone and growth hormone–releasing factor needs to be established in larger numbers of patients. Even if growth hormone treatment were effective, normal growth would be unobtainable in children who have abnormal vertebral body growth or in those with precocious puberty. As a result, some investigators have tried to reduce the dose of radiation to the spine, and others have attempted to delay puberty with gonadotropinreleasing hormone analogs [Adan et al., 2000]. Thyroid dysfunction is the next most common endocrinopathy after growth hormone deficiency in children following craniospinal radiation [Hirsch et al., 1979; Larkins and Martin, 1973]. Because the radiation port to the cervical spine includes the thyroid gland, primary hypothyroidism FIGURE 71-58. Abnormal growth in a patient with medulloblastoma treated with radiation and surgery. Patient had documented growth hormone deficiency. The patient’s height fell from the 30th percentile to the 5th.

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may develop after spinal radiation. The addition of chemotherapy raises the incidence of hypothyroidism from 20% to 69% [Livesey and Brook, 1989]. Giving hyperfractionation rather than standard radiation therapy reduced the incidence of hypothyroidism from 62% to 14% in a group of children with medulloblastoma, despite the fact that adjuvant chemotherapy was given to both groups [Chin et al., 1997; Ricardi et al., 2001]. Children who receive large doses of radiation to the hypothalamic-pituitary axis may also develop secondary or tertiary hypothyroidism, that is, low thyroid-stimulating hormone level in the presence of a low thyroxine level. Children who have a low normal thyroxine level in the presence of elevated thyroid-stimulating hormone (compensated hypothyroidism) should be placed on thyroid replacement even when they are clinically euthyroid because of an increased incidence of thyroid cancer in these patients. Because hypothyroidism may contribute to the child’s learning difficulty and may also adversely affect linear growth, prompt recognition and treatment are necessary. Gonadal function in children with brain tumors has not been studied nearly as well as other endocrinopathies. Radiation to the spine may affect the ovaries. In one study, 35% of girls treated with spinal radiation had evidence of ovarian dysfunction. This problem is compounded when adjuvant chemotherapy is used. Although spinal irradiation does not adversely affect male gonadal function, certain chemotherapeutic agents may be extremely toxic. In particular, cyclophosphamide has a primary effect on the Leydig cells. Although most men do not require androgen replacement, they may develop oligozoospermia or even azoospermia. Gynecomastia and gonadal dysfunction have been reported in adolescent boys treated with combination chemotherapy for Hodgkin’s disease [Sherins et al., 1978]. In general, prepubertal patients tend to be more resistant to adverse effects of radiation and chemotherapy on gonadal function, whereas 70% of postpubertal girls may develop oligomenorrhea and 30% of males may have low testosterone levels [Constine et al., 1993; Moshang and Grimberg, 1996]. These findings suggest that gonadal dysfunction in longterm survivors will need to be studied in much greater detail before definitive statements can be made [Clayton et al., 1988].

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FIGURE 71-59. CT features of leukoencephalopathy (i.e., calcification, hypodense areas, increased sulci).

Leukoencephalopathy Leukoencephalopathy was first described in children with leukemia and was attributed primarily to treatment with intrathecal methotrexate. Recently, MRI evaluations of children treated only with cranial irradiation for brain tumors have identified leukoencephalopathy in these patients as well. CT scans of affected children are characterized by enlarged ventricles, hypodense areas, and areas of calcification (Fig. 71-59) [Peylan-Ramu et al., 1978]. Typical MRI abnormalities include increased ventricular and sulcal size, with hyperintensity in the periventricular region that stops abruptly at the gray matter–white matter junction. Periventricular hyperintensity is symmetrical and scalloped in appearance (Fig. 71-60). The abnormalities have been graded by Zimmerman and co-workers as ranging from 0, in which there is no evidence of periventricular hyperintensity, to 4, in which there are diffuse white matter abnormalities with increased T2-weighted signals extending

FIGURE 71-60. MRI of leukoencephalopathy characterized by periventricular hyperintensity extending to the gray matter–white matter junction.

from the ventricular lining to the cortical medullary junctions. Intermediate grades range from a pencil-thin continuous line of hyperintensity surrounding the ventricles to a periventricular halo [Zimmerman et al., 1986]. The clinical correlates of CT and MRI leukoencephalopathy are dementia, seizures, and focal motor signs. Leukoencephalopathy is characterized by diffuse, reactive astrocytosis with multiple noninflammatory necrotic foci [Price and Jamieson, 1975]. Mineralized cellular debris is commonly found. Necrotic areas are found in more severe

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cases and are typically located in the subcortical white matter of the frontoparietal cortex. In addition to white matter changes, mineralizing microangiopathy and dystrophic calcification have been found, presumably an effect of radiation and chemotherapy [Price and Birdwell, 1978]. The lesion usually involves the lenticular nucleus with or without additional involvement of the cerebral cortex. Calcification and necrosis are present in adjacent neural tissue. Unlike subacute leukoencephalopathy, mineralizing microangiopathy preferentially affects gray matter, especially the putamen and cerebral cortex. It is presumed to be due to small vessel injury secondary to cranial irradiation. The typical distribution is in the border zones of the anterior, middle, and posterior cerebral arteries. Microangiopathy generally begins in the lenticular nuclei, spreading to the cerebral cortex and finally the cerebellar cortex [Price and Birdwell, 1978]. In 1978, methotrexate was implicated as causing leukoencephalopathy in children with leukemia [PeylanRamu et al., 1978]. Leukoencephalopathy is particularly likely to develop in children with CNS leukemia and increases with the number of CNS relapses. The addition of radiation further compounds the problem, raising the incidence of leukoencephalopathy to almost 100% [Duffner et al., 1984]. Recently leukoencephalopathy has also been identified in nonirradiated children with acute lymphoblastic leukemia who did not have CNS leukemia. As the dose and frequency of methotrexate administration have increased, so has the likelihood of methotrexate-induced leukoencephalopathy. Intrathecal and intraventricular routes of methotrexate have been most commonly associated with leukoencephalopathy. Patients with CNS leukemia and patients with brain tumors commonly have alterations in cerebrospinal fluid dynamics secondary to either communicating or obstructive hydrocephalus. When methotrexate is administered either intraventricularly or via the lumbar route to these patients, clearance of methotrexate is slowed or blocked, producing elevated levels of methotrexate for prolonged periods causing subependymal spread of drug into surrounding brain [Shapiro et al., 1973]. Because the toxicity of methotrexate is related not only to its peak level but also to prolonged duration of exposure, children with abnormal cerebrospinal fluid dynamics are more likely to develop leukoencephalopathy. The intraventricular and intrathecal routes of administration of methotrexate should be used only in patients with leptomeningeal disease after cerebrospinal fluid flow studies have demonstrated no abnormalities [Duffner et al., 1984].

Second Malignancies The oncogenic potential of radiation is increasingly significant as more patients survive their primary tumors. Even low doses of radiation are known to produce secondary malignancies. Children who received low-dose cranial irradiation for tinea capitis had an increased risk of malignant and benign neoplasms of the head and neck compared with control subjects. The most striking increase was in brain tumors, particularly meningiomas, as well as parotid and thyroid tumors [Albert et al., 1966]. Moderate- and high-dose radiation may also be associated with second malignancies. There are several reports of children with acute lymphoblastic leukemia treated with

FIGURE 71-61. T1-weighted MRI in a 16 year old with a right frontal parietal meningioma. Fourteen years previously, the patient had been treated with cranial radiation therapy and chemotherapy for acute lymphocytic leukemia.

moderate-dose cranial radiation therapy who later developed brain tumors [Chung et al., 1981] (Fig. 71-61). Similarly, a variety of brain tumors have been reported after high-dose radiation treatment for primary brain tumors in children. The interval between treatment of the first tumor and development of the second tumor has ranged from 5 to 26 years. Second tumors include meningiomas, glioblastomas, and astrocytomas. Second malignancies tend to be biologically aggressive, are poorly responsive to treatment, and tend to occur at the site of the original tumor or in locations remote from the original tumor but within the radiation port [Bachman and Ostrow, 1978; Pearl et al., 1980]. Chemotherapy can also cause second malignancies. The alkylating agents as well as topoisomerase inhibitors are carcinogenic. There have been reports of infants treated with postoperative chemotherapy for CNS neoplasms who have developed leukemia and myelodysplastic syndrome [Duffner et al., 1998a]. Because these agents are among the most effective chemotherapeutic agents for brain tumors, more such patients are likely to be reported. Non-CNS malignancies may also develop after treatment for brain tumors. Because children with medulloblastomas, primitive neuroectodermal tumors, and some spinal cord tumors receive radiation to the cervical cord, the thyroid gland is irradiated. Cases of thyroid carcinoma have occurred in such children 7 to 18 years after initial irradiation [Roggli et al., 1979]. Because survival time is increasing for all of these brain tumors, the incidence of thyroid carcinoma will likely increase.

Recommendations Recognition of the risk factors of young age, dose, and volume of radiation has led to changes in the treatment approach to children with brain tumors. As noted throughout this chapter, therapy is being modified to reduce neurotoxicity. For example, very young infants with malignant

Cohen and Duffner / Tumors of the Brain and Spinal Cord

brain tumors are now treated with prolonged postoperative chemotherapy in an attempt to delay radiation treatment and limit radiation damage to the developing brain. Volume of radiation has been reduced, where possible, by using adjuvant chemotherapy in tumors such as germinomas. Threedimensional conformal radiation to the tumor bed is now being studied in babies with medulloblastomas and children with ependymomas. Radiation to the craniospinal axis has been eliminated in children with nonmetastatic ependymomas and reduced in dose for some children with medulloblastoma. These studies have as their primary objective the reduction of neurotoxicity while maintaining survival. Until such time as less toxic therapies are available, certain procedures should be part of the routine follow-up of children treated for brain tumors. Those treated with cranial radiation therapy, with or without accompanying chemotherapy, should have baseline intelligence quotients and achievement tests (when age appropriate). When the child is of school age, reports from the school on academic performance should be obtained. Follow-up intellectual assessments are recommended 1 year after completion of cranial radiation therapy and then yearly for at least 5 years. Audiograms should be obtained routinely because children may have hearing loss resulting from previous radiation or chemotherapy. Communication among the family, psychologist, school, and physician is essential to provide the best possible learning experience for the child. Because many of these children will be long-term survivors, an appropriate program of remedial education is important to maximize quality of life. Endocrinopathies, which develop as a consequence of treatment, are potentially treatable. Therefore testing of endocrine function should be part of the follow-up of all children with brain tumors. Previous measurements of growth should be reviewed and routine assessments of longitudinal growth with sitting and standing heights made at frequent intervals. Current recommendations are to begin growth hormone therapy 2 years following diagnosis in children who have had growth deceleration. Most authors no longer recommend growth hormone stimulation tests in this population [Albertsson-Wikland et al., 1987; Clarson and Del Maestro, 1999; Romshe et al., 1984]. In those children with precocious puberty or those in whom puberty is advancing rapidly, gonadotropin-releasing hormone analogs are recommended. Failure to diagnose and treat growth hormone deficiency before the patient has epiphyseal fusion will lead to irreversible growth failure. Baseline thyroid testing, including thyroxine and thyroid-stimulating hormone, should be performed and repeated every 6 months for at least 5 years after completion of treatment. Assessment of gonadotropin function is indicated if the child does not exhibit signs of pubertal development by the appropriate age. In children with midline brain tumors, including those involving the diencephalon and pineal region, endocrine evaluations including levels of plasma cortisol, prolactin, and gonadotropins should be performed at 6-month intervals. Secondary oncogenesis is a serious potential complication of treatment. The physician must be aware that second primary tumors may develop intracranially or extracranially. Children who have received spinal radiation must be closely monitored for the possible development of thyroid carcinoma. If a neoplasm occurs in an unusual location, a second

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primary tumor rather than tumor recurrence should be considered. Because the second tumor may have a different pathology and respond to surgical excision, repeat explorative surgery and aggressive debulking should be considered. Recognition of the long-term complications of CNS therapy is important because some are amenable to treatment and others may be prevented by judicious monitoring of administration of drugs and radiation. Careful monitoring can occur only if the physician is aware of the potential adverse effects of treatment. Until newer methods of treatment with fewer long-term side effects are found, awareness of possible consequences of treatment and early intervention, when possible, can help maximize the quality of life of children with brain tumors.

NEW THERAPEUTIC APPROACHES Historically, the traditional approaches of surgery, radiation, and chemotherapy have yielded notable but limited results. Success has not been without its cost because morbidity to long-term survivors has become increasingly more apparent. Better methods of chemotherapy, improved methods of drug delivery, and imaginative treatment modalities currently available in the laboratory are awaiting clinical studies. Monoclonal antibodies directed against tumor-associated antigens should be available in the future. These antibodies can be used as homing devices and, when attached to a specific chemotherapeutic payload, deliver drug agents directly to the tumor. Monoclonal antibodies targeted with a radioactive label, by attaching to specific tumor antigens, may recognize tumor in unrecognized sanctuaries. This recognition provides the potential for diagnosis of recurrence at a time when the tumor burden is small. In theory, monoclonal antibodies should have considerable clinical application; however, there are several problems yet to be resolved, including antigenic modulation (i.e., a reverse loss of antigenic expression on the surface of cells), multiple antigenic sites, immunoselection, and the development of blocking factors in the presence of natural killer cells or macrophages [Ross et al., 2004; Vulfovich and Saba, 2004]. An increasing understanding in the mechanisms of cell signaling over the past decade has led to development of a new class of drugs. Agents that interfere with cell signaling have the potential of limiting cell proliferation, angioinvasion, and stromal invasion, and in promoting apoptosis. Increasing interest in protein kinase inhibitors has raised the hope that effective molecular options of treatment may soon be available. Several of these agents have shown success in the treatment of non-CNS tumors [Noble et al., 2004]. Two such agents are getfitinib (Irressa) and imatinib (Gleevec): both alter tyrosine kinase signaling activity. Getfitinib alters epidermal growth factor tyrosine kinase signaling. Imatinib inhibits platelet-derived growth factor signaling. Getfitinib has shown limited success in trials involving CNS metastasis. This agent is also being studied as a potential radiation sensitizer. The effect of imatinib to date has been most profound in chronic myelogenous leukemia. A host of other agents involved in inhibiting the tyrosine kinase family of proteins are currently under investigation [Dancey and Freidlin, 2003; Stea et al., 2003; Wong and Witte, 2004].

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Other molecular approaches involve phase I and II trials using farnesyl transferase inhibitors. Farnesylation is prominently involved in the activation of ras oncogenes. The proteins encoded by these oncogenes are involved in signaling cellular growth, differentiation, and apoptosis. RAS genes encode G-proteins responsible for initiating the reproductive events characterizing the cell cycle. Of interest is the observation that neurofibromin; the gene product mutated or altered in neurofibromatosis type 1 is prominently involved in the upstream regulation of RAS proteins. Transferrin receptors have been found to be preferentially expressed in proliferating tissues as opposed to normal brain and may represent a potentially useful target site for transferrin toxic conjugates. Transferrin is a naturally occurring protein and, unlike monoclonal antibodies, is not subject to immune reaction. Anti-transferrin receptor ricin immunotoxins have been used in vitro against glioblastomas in an attempt to obviate the immune responses identified with monoclonal antibodies [Zovickian et al., 1987]. Carrier systems using ricin, abrin, diphtheria toxin, and Pseudomonas organisms have been studied in experimental systems but have not been reported in large phase I trials [Weaver and Laske, 2003]. Liposomes and polymers are lipophilic compounds that can carry drugs, radionuclides, toxins, or other materials readily into the CNS. Liposomes are lipid vesicles that can be made from naturally occurring synthetic phospholipids, which are biodegradable and relatively nontoxic. They can be manufactured in sizes ranging from 0.3 to 10 mg and require no chemical binding. Small size offers the advantage of prolonged circulation time and greater likelihood of reaching interstitial spaces. Biodegradable wafers are being developed that release tumoricidal agents at a predicted rate [DiMeco et al. 2002]. For instance, drugs can be incorporated into albumin microspheres that can be implanted into a tumor. The drug is then released via diffusion. The rate of release can be achieved by modifying the structure of the wafer. Intra-arterial delivery of drugs is used in an effort to overcome the problems of the blood-brain barrier and to reduce systemic effects. These techniques allow large amounts of drug to be infused directly into the tumor. The basic assumption of regional perfusion is that higher drug concentration leads to greater cell kill, which, in turn, leads to improved tumor response. The advantage of intra-arterial over intravenous administration depends on the fraction of cardiac output flowing through the infused artery and the fraction of drug cleared from the systemic circulation during a single pass. The greater the amount of drug removed during the first pass, the greater the benefit of regional perfusion [Chen and Gross, 1980; Eckman et al., 1974]. If most of a drug such as BCNU or cisplatin administered intra-arterially is extracted during the first pass, large amounts of drug can be delivered with limited concern about systemic, hematologic, or hepatic effects. Techniques are being developed to circumvent the limited ability of chemotherapeutic agents to penetrate the blood-brain barrier. The blood-brain barrier, although disrupted in many tumors, may be intact in the brain-adjacent tumor. This is the region of the brain where the microenvironment of the nervous system is the most inaccessible. Systemic chemotherapy in the absence of an intact blood-brain barrier readily enters the

center of a tumor but is excluded from the margins of the tumor and the brain-adjacent tumor because of an intact blood-brain barrier. Seizure, hypertension, hypercapnia, and hyperosmotic agents all have a transient ability to transiently alter the blood-brain barrier. Bradykinin is a nonapeptide that plays a central role in inflammation and host defense against injury. Receptors for these agents are upregulated in regions of tissue damage or injury. The result is increased vascular permeability in cerebral vasculature as well as other areas of the body. In phase I trials bradykinins and their receptor agonists have been found to enhance permeability of selective agents in the region of the brainadjacent tumor [Elliott et al., 1996, Inamura et al., 1994]. Pro-drugs are substances that must be transformed in vivo to exert their pharmacologic effects. For example, cytosine arabinoside must be phosphorylated in vivo in the target cell to the triphosphate that is the active moiety. Direct administration of the active moiety is of no clinical use because of poor intercellular transport. Attachment of a prodrug to a carrier has the potential to bypass inactivating sites of the agent in question [Bodor, 1984]. Temozolomide is an example of a pro-drug used in treatment trials. This alkylating agent is an analog of dacarbazine, an antimelanoma drug used in the 1970s. The drug is metabolized to a triazene, its active ingredient. The drug’s action is to form DNA adducts by methylation in the O6 position of guanine, thereby hindering DNA replication [Friedman et al., 1995]. Techniques are being developed to enhance chemosensitivity by decreasing the development of drug resistance. Understanding drug resistance depends on knowledge of pharmacokinetics, ability of neoplastic cells to incorporate and retain cytotoxic agents, the ability to attain effective drug concentration by preventing metabolic degradation, and the ability to prevent drug-induced damage to DNA or other parts of the cytosol. Tumors may acquire resistance to drugs by activation of transporter enzymes, such as the multiple-drug–resistant transporter protein. The multipledrug–resistant gene encodes for the P170 glycoprotein. This gene has been found in both normal and tumor tissues and is believed to encode for a normally protective protein that acts to eliminate natural toxins found in food; therefore, one would expect that the multiple-drug–resistant gene would be operant in transporting those agents that are isolated from naturally occurring sources such as plants, microorganisms, and fungi. This group includes antibiotic agents, such as actinomycin D; doxorubicin; daunorubicin; the mitotic inhibitors, such as vincristine and vinblastine; and epidophyllotoxin. All of these agents are heterocyclic, have large molecular size, and are lipophilic. Calcium channel blockers (e.g., nifedipine, verapamil, calmodulin inhibitors) have been used to circumvent multiple-drug resistance. Metallothionein, another transporter gene, codes for a protein that facilitates the clearance of heavy metals from the cell, such as platinum, copper, and zinc. Resistance to nitrosoureas is believed to be the result of the attempt of an affected cell to repair damaged DNA. The cytotoxicity of alkylating agents develops through the formulation of covalent bonds between reactive alkyl groups and cellular molecules. Formation of DNA-DNA crosslengths results in inactivation of DNA with subsequent inhibition of DNA synthesis and ultimately death of the cell. O6-alkylguanine-DNA alkyltransferase is believed to

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mediate repair of DNA damage. Saturation of the enzyme by O6-methylguanine is one mechanism being explored to potentiate alkylating toxicity. Another mechanism of drug resistance is the presence of increased cellular levels of glutathione or glutathione S-transferase, which act to decrease the alkylating effect. Depletion of intracellular reduced glutathione by enzyme inhibitors and saturation of the glutathione S-transferases by nontoxic substrates have the therapeutic potential of modifying the reparative effect of these enzymes. Butathionine sulfoximine acts by inhibiting the synthesis of glutathione and therefore results in depletion of this agent in brain and extraneural tissues. The diuretic ethacrynic acid has a high substrate affinity for glutathione S-transferase and may act as a transferase inhibitor [Phillips, 1991]. Topoisomerase-2 is another enzyme that is believed to confer resistance to alkylators by enhancing the repair of DNA interstrand crosslengths. This enzyme is a nuclear one that may act to facilitate access of enzymes and other proteins involved in the repair of DNA interstrand breaks. As with the glutathione system, understanding the mechanism of action of topoisomerase may lead to ways of inhibiting the activity of this enzyme, thus potentiating drug activity [D’Arpa and Liu, 1989].

FUTURE DIRECTIONS Since the mid-1990s, despite the increasing interest of neurologists, radiation oncologists, and hematologists/ oncologists in the treatment of children with cancer of the nervous system, there has been limited overall change in prognosis. In fact this view extends, unfortunately, to all cancers. A report from the National Center for Health Statistics covering the years 1970 to 1994 indicates that all deaths from cancer have remained the same or have slightly decreased. Despite decades of basic science and clinical efforts focused on improving treatment, the overall results of the war on cancer must be judged a qualified failure. Fortunately, in a select group of cancers, such as leukemia, Hodgkin’s disease, Wilms’ tumor, and certain CNS tumors, improvements in survival have been noted. Reflecting on the overall state of cancer treatment, Bailar and Gornik [1997] have suggested that a more promising approach to cancer control may be a national commitment to prevention in addition to a focus on funding for research and treatment. The preceding rather pessimistic view is tempered by the development of new approaches that emphasize chemotherapy screening, virology, immunology, and more recently, molecular genetics. The increased interest in cancer prevention is the result of more attention being placed on the role of the environment and nutrition in initiating oncogenesis. There is now acceptance that genetic damage is central to oncogenesis. As pointed out in the preceding section the knowledge that has been accumulating since 2000 concerning the events occurring at the genomic level that lead to proliferation and differentiation is rapidly being applied to the clinic. Two different groups of genes, one group that is dominant and the other recessive, are implicated in the development of cancer. These groups have provided hints about specific molecular function and in turn the mechanisms that initiate

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and promote neoplasia. Dominant oncogenes imply that inheritance of a single mutant allele is sufficient to overcome the effects of the corresponding normal allele, thereby allowing the expression of a malignant phenotype. Recessive oncogenes or tumor suppressor genes, when present on one allele, are associated with orderly regulation of the cell cycle. However, these genes, when deleted or mutated, may be associated with the development of malignancy. Both copies of the gene from a chromosome pair must be absent to cause malignancy. Consistent with the recessive nature of this process, a single mutation may be ineffective. It is only with the second mutation in a given gene’s malignant allele partner that malignancy emerges. Thus, a heterozygous cell may function perfectly normally, whereas a cell that has a double mutation of an allelic pair may lose the ability to suppress the development of a tumor. This is called loss of heterozygosity. The types of experiments that enable identification of these two classes of oncogenes [Bishop, 1991; Marshall, 1991] include the analysis of chromosomal translocations, site-directed mutagenesis, and introduction of amplified DNA into transgenic animals with subsequent characterization of inherited kinships. These techniques have resulted in the identification of more than 60 dominant oncogenes. Recessive oncogenes were hinted at by cell fusion studies that indicated that fusion of a normal cell with a transformed cell suppressed malignancy [Bishop, 1991]. More recently, analysis of restriction fragment length polymorphisms in multiple tumors has identified several homozygous gene defects that are candidates for tumor suppressor genes [Marshall, 1991; Pihan and Doxsey, 1999]. It seems likely that malignancies occur as the result of interaction between dominant and recessive genes. Although many oncogenes have been identified, only a few have been sporadically associated with CNS neoplasia. The epidermal growth factor receptor gene has been recognized in up to 40% of malignant gliomas, and c-myc amplification has been found in medulloblastomas [Eberhart et al., 2004]. Tumor suppressor genes have been identified on the long arm of chromosome 17 in neurofibromatosis and on the long arm of chromosome 13 in retinoblastoma. Loss of markers that contain the site of the p53 gene on the short arm of chromosome 17 has been found in medulloblastomas and astrocytomas. Mutations in tumor suppressor genes responsible for retinoblastoma and type I neurofibromatosis are more likely to occur on the paternal than on the maternal chromosome, suggesting that germ cell mutations in the paternal line are a reflection of the increasing risk of mutation for spermatocytes. Identification of the retinoblastoma gene has provided the most information regarding the inherited tendency of cancer. In retinoblastoma, a defect in tumor suppressor genes is inherited on one allele of chromosome 13. The normal remaining allele is inactivated by an epigenetic event, with resultant loss of both tumor suppressor genes. The recessive loss of both alleles, one through the germline and the other autosomally, results in the dominant expression of the tumor. A dominant pattern of inheritance arises from the likelihood that the uninherited normal allele containing the retinoblastoma gene will be lost or inactivated in at least one cell, which subsequently will grow into a tumor. Thus the loss of heterozygosity for the retinoblastoma gene provides for a

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dominant phenotypic expression [Knudson, 1971; Marshall, 1991]. Oncogenes code for relatively small peptides that are involved in the cellular mechanisms that govern cell growth and proliferation. These proteins may act at the surface of the cell, convey signals from receptors to the cytosol, or code for proteins that orchestrate nuclear functions. Proto-oncogenes are considered normal components of the cell that act to regulate orderly cell division. When activated by viruses, ionizing radiation, gene amplification, deletion, or loss of tumor suppressors, these genes may induce unregulated cell growth. For the most part, three biologic mechanisms have been described for proto-oncogenes. The first mechanism involves phosphorylation of proteins, primarily at serine, threonine, and tyrosine residues. Protein tyrosine kinases have been the most widely studied and implicated in oncogenesis. Abnormal phosphorylation directed by oncogenes may cause malignant or premalignant transformation. For example, excessive phosphorylation of tyrosine may disrupt the binding of components of the cytoskeleton to the inner surface of the plasma membrane. This disruption may lead to changes that transform cells. It is unknown how this change relates to normal versus malignant, uncontrolled mitosis. Other oncogenes produce groups of protein that bind to guanosine triphosphate. These proteins transduce exogenous signals at the cell surface into cytoplasmic effects. Disruption of orderly guanosine triphosphate activity is thought to disrupt the regulation of cell division in response to exogenous signals [Tanabe et al., 1985]. A number of protooncogenes have been identified that encode nuclear proteins involved in genomic transcription. Oncogenes that affect DNA binding have gene products that relate directly to DNA or DNA-associated nuclear proteins [Donner et al., 1982]. The protein products of these oncogenes are believed to deregulate nuclear mitosis, the activity of which excites excessive mitosis. The result of excessive deregulation may be malignant transformation. The preceding functions, for the most part, are autocrine. Paracrine functions involve growth factors and growth factor receptors. For instance, platelet-derived growth factors are stored in platelets and released when blood vessels are damaged, stimulating the proliferation of fibroblasts. These factors, as well as other cytokines, play a role in tissue repair, in the phosphorylation of intracellular proteins, and in tyrosinespecific protein kinase activity. It is believed that the mitogenic effect of exogenous growth factor, such as platelet-derived growth factor, activates intercellular growth factor receptors and elicits a cytoplasmic signal protein. The activated signal protein influences nuclear oncogenes, which produce DNA protein. These proteins then act to enhance or suppress one or more of the nuclear regulators of mitosis. This cascade of events leading to cell growth and neoplasia may begin in a paracrine fashion in which the cell of interest is stimulated by one cytokine or another. Growth factor receptors acting on the surfaces of the cell, when stimulated by cytokines, activate intracellular components, which in turn initiate processes that may either upregulate or downregulate mitosis. The foregoing suggests that in their natural state, oncogenes are relatively quiescent and control mitosis in an orderly manner. When regulation of an oncogene is disturbed, cell division becomes disorderly and derepressed.

By directing the activity of protein products that act on the plasma membrane, the cytoplasm, and the nucleus, oncogenes may play a major role in the promotion and orderly control of cell division. The process of cell division is complicated. Its timing must be carefully controlled and coordinated. This mechanism depends on rapid synthesis of many cellular structures. Presumably, many different kinds of oncogenes exist to regulate this ongoing process of cell division and replication [Pihan and Doxsey, 1999]. Identification of oncogenes associated with various neoplasms suggests that in the future determining the malignant potential of the specific neoplasm may be possible. This capability may allow classification of neoplasms based on pathogenesis rather than on morphology alone. Further knowledge of an oncogene may allow development of inhibitors of that gene product. For instance, if a malignant tumor were associated with the production of a growth factor such as the epidermal growth factor receptor on the surface of the cells, a monoclonal antibody directed toward the cell surface receptor might be considered. The current wisdom is that the malignant phenotype, rather than resulting from one genetic event, is the byproduct of the cumulative effects of multiple genetic insults. This model of progressive clonal evolution in tumor cells has been most studied in colorectal cancer [Vogelstein et al., 1988]. Similar approaches in the adult help to define an order for the progressive dedifferentiation of astrocytomas into glioblastomas. Astrocytomas, characterized primarily by hypercellularity, are associated with an allelic loss on the short arm of chromosome 17 in the area of the p53 mutation. Astrocytomas have also been associated with overexpression of the platelet-derived growth factor receptors. The anaplastic astrocytoma, in addition to hypercellularity, is characterized by cellular pleomorphism, mitosis, and vascular proliferation. These changes have been associated with allelic loss on the long arm of chromosome 13 in the region of the retinoblastoma mutation, allelic loss on the short arm of chromosome 9 in the area of genes that code for interferon, and an allelic loss on the long arm of chromosome 19 in the region of DNA repair genes. Necrosis, in addition to the aforementioned histologic features, characterizes the glioblastoma. About 60% to 90% of glioblastomas are associated with allelic losses on both the long and short arms of chromosome 10, suggesting that multiple genes within this chromosome may be responsible for the invasive features of glioblastoma. In addition, in glioblastomas that occur de novo rather than dedifferentiating from astrocytomas, there has been identified a high incidence of amplification of the epidermal growth factor receptor [Furnari et al., 1996]. Biologic response modifiers are being explored as an alternative to chemotherapy. These agents are being considered in conjunction with or as independent modalities to augment the host immune response to evoke an antineoplastic effect. Adoptive immunotherapy is that technique in which T cells have been stimulated in vitro with host tumor cells to augment suppressed immune surveillance activity. Tumor infiltrating lymphocytes are an extension of this approach in which lymphocytes at the margin of the tumor are enhanced and reinjected into the patient. Theoretically those cells that are present at the edge of the tumor may be the most immunogenic and therefore the most cyto-

Cohen and Duffner / Tumors of the Brain and Spinal Cord

toxic. These cells have a 100-fold greater anaplastic activity than lymphocytic activated killer cells [Rosenberg et al., 1986]. Other techniques using cytokines such as interleukin1 and interleukin-2, tumor necrosis factor, and interferon have been used nonspecifically to heighten and augment the immune responsiveness of neoplastic cells. Unfortunately, clinical trials reporting the effectiveness of this approach have yet to be reported [Antonia et al., 2004; Martindale, 2003]. Attenuated retroviruses containing the herpes simplex thymidine kinase gene have been used to infect rapidly growing cells. These cells when exposed to antiviral agents such as ganciclovir have the potential to destroy replicating cells while preserving normal tissues. This approach is undergoing phase II trials in systemic cancers and to a limited extent in CNS tumors. There is also the potential for using antisense technologies to downregulate the expression of specific oncogenes and chemorepair genes. Other techniques available in tissue culture and animal models have suggested that the normal genetic makeup of a cell can be reconstituted using transfection techniques to replace absent tumor suppressor genes. Although much of the foregoing has yet to make a clinical impact, these techniques offer the hope of providing cures at the cellular level while maintaining the integrity of normal tissue, thereby preserving a good quality of life. Current research suggests that the treatments of tomorrow will be increasingly molecular, with the potential of reducing the need for mutilating surgery, radiation, or highly toxic chemotherapy. REFERENCES Aarsen FK, Van Dongen HR, Paquier PF, et al. Long-term sequelae in children after cerebellar astrocytoma surgery. Neurology 2004;62;1311. Adan L, Sainte-Rose C, Souberbielle JC, et al. Adult height after growth hormone (GH) treatment for GH deficiency due to cranial irradiation. Med Pediatr Oncol 2000;34:14. Al-Mefty O, Al-Rodhan NR, Phillips RL, et al. Factors affecting survival of children with malignant gliomas. Neurosurgery 1987;20:416. Albert RE, Omran AR, Brauer EW, et al. Follow-up study of patients treated by x-ray for tinea capitis. Am J Pub Health 1966;56:2114. Albertsson-Wikland K, Lannering B, Marky I, et al. A longitudinal study on growth and spontaneous growth hormone (GH) secretion in children with irradiated brain tumors. Acta Paediatr Scand 1987;76:966. Albright AL. Brain tumors in neonates, infants, and toddlers. Contemp Neurosurg 1985;7:1. Albright AL, Wisoff JH, Zeltzer P, et al. Prognostic factors in children with supratentorial (nonpineal) primitive neuroectodermal tumors. Pediatr Neurosurg 1995;22:1. Allen JC. The effects of cancer therapy on the nervous system. J Pediatr 1978;93:903. Allen JC. Controversies in the management of intracranial germ cell tumors. Brain tumors in children. Neurol Clin 1991;9:441. Allen JC, DaRosso RC, Donahue B, et al. A phase II trial of preirradiation carboplatin in newly diagnosed germinoma of the central nervous system. Cancer 1994;74:940. Allen JC, Epstein F. Medulloblastoma and other primary malignant neuroectodermal tumors of the CNS: The effect of age and extent of disease on prognosis. J Neurosurg 1982;57:446. Allen JV, Avivner S, Yates AJ, et al. Treatment of high-grade spinal cord astrocytoma of childhood with “8-in-1” chemotherapy and radiotherapy: A pilot study of CCG-945. J Neurosurg 1998;88:215. Allison RR, Schulsinger A, Vongtama V, et al. Radiation and chemotherapy improve outcome in oligodendroglioma. Int J Radiat Oncol Biol Phys 1997;37:399. Andler W, Roosen K, Clar HE. Pre- and post-operative evaluation of hypothalamo-pituitary function in children with craniopharyngiomas. Acta Neurochir 1979;45:287.

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Weaver M, Laske DW. Transferrin receptor ligand-targeted toxin conjugate (Tf-CRM107) for therapy of malignant gliomas. J Neurooncol 2003;65:3. Weaver RG Jr, Chauvenet AR, Smith TJ, et al. Ophthalmic evaluation of long-term survivors of childhood: acute lymphoblastic leukemia. Cancer 1986;58:963. Weiss E, Klingbiel T, Kortmann RD, et al. Intraspinal high-grade astrocytoma in a child—Rationale for chemotherapy and more intensive radiotherapy? Childs Nerv Syst 1997;13:108. White PT, Ross AT. Inanition syndrome in infants with anterior hypothalamic neoplasms. Neurology 1963;13:974. Winter RJ, Green OC. Irradiation-induced growth hormone deficiency: Blunted growth response and accelerated skeletal maturation to growth hormone therapy. J Pediatr 1985;106:609. Wolff JE, Sajedi M, Brant R, et al. Choroid plexus tumours. Br J Cancer 2002;87:1086. Wong S, Witte ON. The BCR-ABL story: Bench to bedside and back. Ann Rev Immunol 2004;22:247. Yasargil MG, Antic J, Laciga R, et al. The microsurgical removal of intramedullary spinal hemangioblastomas: Report of twelve cases and a review of the literature. Surg Neurol 1976;6:141. Yasargil MG, Curcic M, Kis M, et al. Total removal of craniopharyngiomas: Approaches and long-term results in 144 patients. J Neurosurg 1990;73:3. Young JL, Miller RW. Incidence of malignant tumors in U.S. children. J Pediatr 1975;86:254. Young RF, Post EM, King GA. Treatment of spinal epidural metastases: Randomized prospective comparison of laminectomy and radiotherapy. J Neurosurg 1980;53:741. Zeller WJ, Ivankovic S, Habs M, et al. Experimental chemical production of brain tumors. Ann N Y Acad Sci 1982;381:250. Zeltzer PJ, Boyett J, Finlay L, et al. Prognostic factors for survival in high risk primitive neuroectodermal tumors (PNETs) in children: Report from the Children’s Cancer Group CCG-921. Proc ASCO 1993;12:415. Zimmerman RA, Bilaniuk LT, Bruno L, et al. Computed tomography of cerebellar astrocytoma. Am J Roentgenol 1978;130:929. Zimmerman RD, Fleming CA, Lee BCP, et al. Periventricular hyperintensity as seen by magnetic resonance: Prevalence and significance. AJNR Am J Neuroradiol 1986;7:13. Zovickian J, Johnson VG, Youle RJ. Potent and specific killing of human malignant brain tumor cells by an anti-transferrin receptor-ricin immunotoxin. J Neurosurg 1987;68:850.

CHAPTER 72

Cerebrovascular Disease Gabrielle Aline deVeber

PEDIATRIC STROKE—OVERVIEW Stroke is defined as the sudden occlusion or rupture of cerebral arteries or veins resulting in focal cerebral damage and clinical neurologic deficits. Forms of stroke due to vascular occlusion are arterial ischemic stroke and cerebral sinovenous thrombosis. In arterial ischemic stroke, arterial occlusion is usually due to thromboembolism and results in an arterial infarct. In cerebral sinovenous thrombosis, occlusion of the cerebral veins or venous sinuses may result in a venous infarct or in no parenchymal damage. In either arterial or venous infarction, if the infarct does not contain visible hemorrhage it is called a bland infarct. A bland infarct can become a hemorrhagic infarct, occurring when there is bleeding into the area of infarction. Forms of stroke due to vascular rupture are called hemorrhagic stroke and are primarily intracerebral and subarachnoid hemorrhage. Fundamental developmental differences in children and adults make the recognition and treatment of children with stroke challenging. First, stroke in children is relatively rare, frequently resulting in a lack of recognition and delay in diagnosis. Second, the etiologies of stroke in children are legion, and no single risk factor predominates. Multiple risk factors are often present in individual patients. As a result, complex etiologic investigations are often necessary. Third, there have been only limited research studies of medical therapy for childhood stroke. Current treatments for children are therefore necessarily based on therapies used in adult stroke patients; biologic plausibility and safety data in pediatric patients are very limited. There are important maturational differences in the coagulation, cerebrovascular, and neurologic systems of infants and children compared with adults that limit the applicability of research performed in adult stroke patients to pediatric patients with stroke. During the past several years, a number of clinical and basic research studies have increased our understanding of childhood stroke. Population-based clinical studies have resulted in an increased awareness of the frequencies and outcomes of various types of stroke. Prospective cohort studies have demonstrated the feasibility and safety of several antithrombotic therapies in children with stroke. Advances in neuroimaging and in genetic and other laboratory testing techniques have led to an appreciation of a wider spectrum of stroke subtypes and risk factors. The purpose of this chapter is, first, to provide a basic understanding of the processes involved in childhood stroke; second, to provide an overview of the epidemiology, investigation, and treatment of pediatric stroke; and, third, to provide a practical clinical approach to the child with stroke. Several comprehensive reviews on the topic of childhood stroke have been published in the form of review articles

[Ball, Jr., 1994; Broderick et al., 1993; deVeber, 2002; Kirkham, 1994; Lynch et al., 2002; Nagaraja et al., 1994; Nelson and Lynch, 2004; Rivkin and Volpe, 1996; Trescher, 1992] and reference texts [Andrew et al., 2000; Lasjaunias and Terbrugge, 1997; Roach and Riela, 1995]. For this chapter, a comprehensive review of the literature was conducted searching Medline from 1966 to 2004 using combinations of the key words child, infant, and neonate combined with the terms stroke, cerebrovascular disease, cerebral thrombosis or embolism, cerebral ischemia, and sinus thrombosis. Basic references were supplemented with additional references located through the bibliographies of listed articles. All articles were graded by quality of evidence related to study design as levels I to V, according to previously described criteria [Cook et al., 1995]. Very few clinical treatment trials of childhood stroke were identified that qualified for the classification of levels I to III. Prospective cohort studies were classified as level IV. Retrospective case series were classified as level V. Complete reference lists of the level V studies, which constitute the overwhelming majority, are available on request. Chapter 17 in this book covers neonatal stroke.

Incidence of Pediatric Stroke Nearly one fourth of strokes in the “young” (i.e., <40 years of age) [Kerr et al., 1993] occur in children. Cerebrovascular disorders are among the top ten causes of death in children, with rates highest in the first year of life. The 1998 U.S. mortality rate for stroke was 7.8/100,000 in children 0 to 1 year of age and was increased in males compared with females and in blacks compared with whites [Murphy, 2000]. Stroke-related mortality in children younger than 1 year of age may have decreased in the past 2 decades [Fullerton et al., 2003]. In the past three decades, the reported incidence rates for pediatric stroke have increased. Previously, reported rates for combined ischemic and hemorrhagic pediatric stroke in the U.S. were 2.5 to 2.7 per 100,000 children per year (0.63 to 1.2 for ischemic stroke and 1.5 to 1.9 for hemorrhagic stroke) [Broderick et al., 1993; Schoenberg et al., 1978]. More recently, an analysis of stroke diagnostic codes in the National Hospital Discharge Survey (NHDS) estimated the incidence of pediatric stroke as 10.7 per 100,000 children per year (2.9 for ischemic stroke and 7.8 for hemorrhagic stroke) [Lynch et al., 2002]. In the city of Dijon, France, the incidence of pediatric stroke was reported as 13 per 100,000 children per year (7.91 for ischemic stroke and 5.11 for hemorrhagic stroke). In Canada, in a prospective population-based registry the estimated incidence of ischemic stroke was at least 1.8 per 100,000 (1.2 for arterial

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ischemic stroke and 0.67 for cerebral sinovenous thrombosis); hemorrhagic strokes were not assessed [deVeber and Canadian Paediatric Ischemic Stroke Study Group, 2000; deVeber et al., 2001]. In Victoria, Australia, the incidence of cerebral sinovenous thrombosis in children excluding neonates was estimated at 0.34 per 100,000 children per year [Barnes et al., 2004]. The proportion of hemorrhagic versus ischemic stroke in childhood remains to be clarified; two of the above studies reported that hemorrhagic stroke is more frequent [Broderick et al., 1993; Schoenberg et al., 1978] whereas three studies reported that ischemic stroke is more frequent [Giroud et al., 1995; Lanthier et al., 2000; Lynch et al., 2002]. At least two factors likely are responsible for the increased incidence rates. The widespread availability of more sensitive diagnostic tests including computed tomography (CT) and magnetic resonance imaging (MRI) scanning has increased the detection rate for pediatric stroke [Venkataraman et al., 2004; Warach and Baron, 2004; Wiznitzer and Masaryk, 1991]. These tests have also resulted in the identification of a milder spectrum of stroke than previously identified. Second, more effective treatments have increased survival of patients with certain previously lethal primary pediatric diseases that predispose to stroke. Infants and children with a history of prematurity, congenital heart disease, sickle cell disease, and leukemia, for example, now have longer life expectancies, during which time they remain at risk for stroke from the primary disease and its treatments. Ischemic strokes are likely still underdiagnosed in infancy and childhood, particularly cerebral sinovenous thrombosis, because of a lack of clinical suspicion and failure to use appropriate diagnostic tests.

The socioeconomic impact of stroke is considerable. In adults, the lifetime cost of a first stroke per person is estimated to be $228,030 for subarachnoid hemorrhage, $123,565 for intracerebral hemorrhage, $90,981 for ischemic stroke, and $103,576 averaged across all stroke subtypes [Taylor et al., 1996]. On average, developed countries spend 3% of health-care dollars on stroke [Evers et al., 2004]. The economic impact of childhood stroke has not been reported, but because many more decades of disability frequently result, the burden of illness per individual will inevitably be great.

ARTERIAL ISCHEMIC STROKE Pathophysiology Arterial Circulation: Anatomy and Physiology The brain receives its arterial supply via two principal systems: the anterior circulation, consisting of the paired carotid arteries and the posterior circulation, consisting of the paired vertebral arteries, which join to form the basilar artery (Figs. 72-1 to 72-3). The anterior and posterior communicating arteries link these two systems to form the circle of Willis. The major cerebral arteries arising from the circle of Willis are the paired anterior, middle, and posterior cerebral arteries. The anterior and middle cerebral arteries are the major branches of the internal carotid artery, and the posterior cerebral arteries are the major branches of the vertebrobasilar system. Small perforator branches arise from the stem of the anterior, middle, and posterior cerebral

FIGURE 72-1. Lateral view of the cerebral arteries detailing the branches of the anterior and middle cerebral arteries.

Callosomarginal artery Pericallosal artery Posterior parietal artery

Angular artery Posterior temporal artery

Ascending frontoparietal artery

Anterior choroidal artery

Frontopolar artery Anterior cerebral artery Middle cerebral artery

Posterior communicating artery Internal carotid artery

Ophthalmic artery

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FIGURE 72-2. Anteroposterior view of the cerebral arteries. Posterior parietal artery Ascending frontoparietal artery

Collosomarginal artery Pericallosal artery

Lateral lenticulostriate arteries

Frontopolar artery Medial lenticulostriate arteries

Angular artery

Posterior temporal artery

Middle cerebral artery

Anterior cerebral artery

Internal carotid artery

FIGURE 72-3. The vertebral-basilar artery system.

Posterior cerebral arteries Posterior cerebral artery Superior cerebellar arteries Posterior inferior cerebral artery

Vertebral artery

Anterior inferior cerebellar arteries Basilar artery Vertebral arteries

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arteries to supply the deep central brain structures, in particular the basal ganglia, thalami, and internal capsules.

Mechanisms of Thromboembolism Thrombosis arising within cerebral arteries can result from primary disorders of the cerebral arteries or from acquired or congenital prothrombotic states. Under physiologic circumstances, the endothelial lining of the arteries provides an anticoagulant surface that helps to maintain blood in a fluid phase. In situations of low flow, including the normal venous system, the coagulation system plays an increased role in thrombosis, resulting in a predominance of fibrin-rich thrombi. However, in arterial systems including arterial thrombotic stroke, the relative predominance of coagulation activation (fibrin-rich thrombi) or platelet activation (platelet-rich thrombi) is more variable and depends on flow rates, shear stresses, and other factors. When the arterial wall is damaged, as a result of the presence of inflammation or a breach in the endothelial lining, the arterial wall becomes thrombogenic, and thrombosis develops through several mechanisms. The exposure of flowing blood to arterial wall inflammation (as with vasculitis) or to exposed collagen and tissue factors (as with dissection) activates platelets and fibrin clot formation via the coagulation system. The coagulation system is also active in the formation of thrombosis in situations of blood stasis or slow blood flow—for example, arterial occlusion or severe stenosis, In situations of rapid arterial blood flow with “shear” forces, the platelet system becomes activated and promotes formation of platelet-rich thrombi. Agerelated differences in both platelet and coagulation activity exist in neonates compared with older children [Carcao et al., 1998; Israels et al., 2001; Roschitz et al., 2001]. Embolic sources for arterial thrombotic stroke in childhood include structural disorders of the heart, aorta, and cerebral arteries. These abnormalities result in cardiogenic embolism or artery-to-artery embolism. A further mechanism is the presence of right-to-left intracardiac shunting that results from ventricular or atrial septal defects, patent foramen ovale, and postoperative residual right-to-left shunts following Fontan and other cardiac surgical procedures. The shunt may be predominantly left to right, but intermittently with Valsalva or other maneuvers may become right to left, during which time a conduit for paradoxical embolism exists. This right-to-left shunting allows systemic venous thrombi to reach the cerebral circulation. Clots of venous origin or intracardiac clots tend to be primarily fibrin-rich thrombi as a result of activation of the coagulation system.

Mechanisms of Infarction In arterial thrombotic stroke, the severity of cerebral tissue damage and the resultant neurologic impairments are a function of many factors. These include (1) the duration of ischemia, related to the timing and adequacy of restoration of perfusion; (2) the volume and functional components of the brain structures supplied by the involved cerebral artery; (3) the maturational status of the brain; (4) the availability of collateral arterial blood supply; and (5) the concurrent metabolic demands of the ischemic brain tissue. Additional cerebral damage results from early recurrent infarcts. The extent of impairment in the delivery of substrates is directly

related to the duration of vascular occlusion and the adequacy of collateral blood flow supplying the ischemic area. Neuronal damage following arterial occlusion can be reversible or irreversible depending on the severity of ischemia and the rate of neuronal metabolic activity. In transient ischemic attacks, the clinical deficit is usually extremely brief, typically lasting less then 1 hour. In more recent definitions of transient ischemic attacks, no permanent parenchymal lesion is seen by MRI, confirming that the damage is fully reversible [Albers et al., 2002]. In an arterial infarct, the clinical deficit lasts longer, frequently persisting for more than 24 hours, and results in a radiographically confirmed infarct conforming to a vascular territory and appropriate to the neurologic syndrome. In arterial ischemic stroke, there is a central core zone, which represents irreversibly damaged brain, and a surrounding penumbral zone, which represents partially ischemic and potentially viable brain tissue [Schlaug et al., 1999]. The eventual volume of the ischemic infarct is the result of the balance between the rate of delivery of oxygen and glucose and the metabolic activity of the brain, particularly in the penumbra. Cell death in the core or the penumbra occurs with a combination of two major mechanisms, acute necrosis and apoptosis (delayed cell death). In the penumbra, clinical factors that increase the discrepancy between cerebral metabolic rate and the delivery of oxygen and glucose result in additional tissue injury and cell death. Although the core of an infarct is considered irreversibly damaged within several hours of onset, there is the real potential to salvage tissue within the penumbra. Cells in the penumbra are selectively vulnerable to secondary insults, leading to further cell death and enlargement of the stroke. Aggressive and early specialized care of the child during the first 48 hours after initiation of the ischemic infarct can salvage cerebral tissue, resulting in a smaller volume of infarction. Optimization of cerebral perfusion, tissue oxygenation, and metabolic balance requires careful attention to clinical parameters including blood pressure, abnormal blood glucose levels, and the presence of seizures and fever. Because autoregulation is disturbed in the damaged tissue within an evolving infarct, the peri-infarct area remains extremely vulnerable to decreased cerebral blood flow in the presence of decreased blood pressure. Cerebral perfusion is a direct function of the mean arterial pressure, intracranial pressure, and vascular resistance and is age-related [Volpe, 2001a]. In adults, the cerebral blood flow is 50 mL per 100 grams of brain tissue per minute. In term neonates, cerebral blood flow is estimated to be approximately 40% of the adult value [Altman et al., 1988]. In children younger than 3 years of age, the cerebral blood flow is around 30 to 50 mL per 100 gm, whereas in children from 3 to 10 years of age these rates significantly increase to about 100 mL per 100 gm of brain tissue per minute. During the late teen years, cerebral blood flow rates again diminish to adult levels. Studies utilizing CT quantitative perfusion have found that the global cerebral blood flow represents 10% to 20% of the global cardiac output for the first 6 months of life, peaks at approximately 55% by 2 to 4 years of age, and stabilizes at approximately 15% by 7 to 8 years of age [Wintermark et al., 2004]. Blood pressure and oxygen and carbon dioxide concentrations alter the degree of vasodilation and vasoconstriction of the cerebral arteries,

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and hence cerebral perfusion through autoregulation. The extent of autoregulation has not been well studied in the pediatric population; however, in the newborn, autoregulation is normally present between mean arterial blood pressures of 25 and 50 mm Hg [Volpe, 2001a]. The metabolic effects of focal brain ischemia are regional hypoxia and depletion of the high-energy compound adenosine triphosphate, as well as carbohydrate stores. The baseline metabolic rate of cerebral tissue is increased relative to that of other body tissues, and there is a relative paucity of energy stores in the brain [Trescher, 1992]. The cerebral metabolic rate for oxygen is 3.5 mL per 100 grams of brain per minute. Since virtually no oxygen reserve is available, rapid loss of neuronal function results if the oxygen supply is interrupted. Brain glucose reserve is slightly greater, allowing survival of brain tissue for up to 90 minutes if adequate oxygen is supplied. In the newborn, lactate can be used as a substrate for the production of energy, but this capability is lost quickly. When regional hypoxia develops during ischemia, there is a shift from oxidative metabolism to glycolysis. Glucose is metabolized to lactate, which accumulates and results in acidosis, which in turn exacerbates hypoxic injury. Seizures, by increasing the neuronal metabolic rate, dramatically increase the extent of neuronal damage occurring during ischemia. Important functional and anatomic differences between the cerebral arterial and the sinovenous systems result in differing features of thrombotic occlusion. In arterial ischemic stroke, for example, the infarcted brain is a zone of reduced arterial and venous pressure, and delayed recanalization with reperfusion does not relieve the ischemic damage, in contrast to the situation in cerebral sinovenous thrombosis. Through basic research studies utilizing animal models of stroke, including ischemia-reperfusion injury, exciting information has recently become available about the chain of events that occur in ischemic stroke [Hou and MacManus, 2002]. Additional insights into the timing of mechanisms of stroke have been gained from the application of advanced neuroimaging techniques, including diffusion-weighted MRI. The concept of a neurotoxic cascade of events initiated by acute hypoxia or ischemia has evolved. This neurotoxic biochemical cascade produces permanent cell death over a period of hours (necrosis) to days (apoptosis) following the insult. Accumulation of extracellular glutamate and activation of glutamate receptors play major initiating roles in this cascade, which then involves the accumulation of cytosolic calcium and the activation of multiple calcium-mediated deleterious intracellular events. This neurotoxic cascade, which evolves over many hours, potentially can be arrested by interventions even if instituted after termination of the initial insult. The mechanisms of acute and programmed cell death including apoptosis are further discussed in Chapter 64 of this text. Neuronal salvage medications aim to minimize neuronal damage at a cellular level by blocking these auto-destructive processes and thereby increasing the viability of the penumbral area. In rodent models, new agents have been found to block excitotoxicity of N-methyl-D-aspartate (NMDA) receptors, reduce stroke size, and improve neurologic outcome following middle cerebral arterial occlusion [Aarts et al., 2002], although clinical trials have not shown similar neuroprotection. Among the potential neuroprotective interventions for the immature brain, leading candidates

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include mild hypothermia, the inhibition of free radical production, and free radical scavengers. Promising clinical data are now available in human infants about the safety of the use of mild hypothermia, and efficacy data are being pursued [Battin et al., 2001]. Immature animal stroke models involving temporary vascular occlusion simulate human ischemia-reperfusion in arterial ischemic stroke and provide a potential means for the development of treatment directed at the inflammatory cascade and apoptosis, events associated with reperfusion injury. These and additional, more recent areas of research, including inhibition of nitric oxide and free-radical formation, the use of iron chelating agents, and the potential role of hypoxia-inducible factors and mediators of caspase activity, growth factors, hypothermia, and administration of magnesium sulfate, have been reviewed [Ashwal and Pearce, 2001]. Other models of vaso-occlusive stroke have been developed, particularly neonatal rodent models. Combined with the use of recent neuroimaging techniques, these can study the events associated with ischemic injury in immature and developing juvenile brains [Qiao et al., 2004]. However, animal models relevant to arterial ischemic stroke in children beyond the neonatal period would need to combine features of cerebral vasculopathies, disordered coagulation, and triggering factors, which underlie most strokes in childhood. Further work and the development of more mature pediatric animal models are necessary to help us understand the effect of stroke on the developing brain. It has long been held that increased plasticity of neurons and of neuronal pathways in the developing brain could provide increased resistance to damage and increased recovery in the young infant and child with arterial ischemic stroke. However, there has been little data from human studies to address this theory. Some animal studies have documented that the neonatal rodent brain has a decreased tolerance to the effects of ischemia compared with the adult brain [Yager and Thornhill, 1997]. Studies of neonatal, juvenile, and adult rat models have found that brain damage from hypoxic ischemic insult is most severe in 1- and 3-week-old animals, followed by those that were 6 months old. The 6- and 9-week-old groups had significantly less injury than the other three age groups, indicating that the neonatal brain may be more susceptible and that the younger juvenile brain may be relatively protected compared with the adult brain. Similar findings were reported in studies of temporal lobe cortical injury in neonatal, juvenile, and adult rats [Kolb and Cioe, 2003; Kolb et al., 2000]. However, studies of intellectual outcome following stroke in humans have reported conflicting results. Some studies suggest that intellectual outcomes following stroke are best when the stroke occurs either in early infancy or late childhood compared with the occurrence of stroke in early childhood [Bates et al., 1999; Goodman and Yude, 1996]. Recent studies reported that neuropsychologic recovery was better in children older than 1 year of age and worse in infants younger than 1 year age at the time of stroke [Lansing et al., 2004; Max, 2004].

Vascular Patterns Vascular patterns of arterial ischemic stroke can be classified as large- or small-vessel territory infarcts. Occlusion of large-caliber cerebral arteries results in classic peripheral,

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A

B

FIGURE 72-4. Large-vessel arterial infarct in the right middle cerebral artery (MCA) territory associated with “transient cerebral arteriopathy” of childhood in an 11-year-old female presenting with hemiparesis. A, T2-weighted MRI shows right middle cerebral artery (MCA) infarct maximally involving the cortex. B, Conventional angiogram shows irregular stenosis in the proximal right MCA. (B, Courtesy of Division of Neuroradiology, Hospital for Sick Children, Toronto, Ontario, Canada.)

FIGURE 72-5. CT scan shows large-vessel arterial infarct of unknown etiology in the left middle cerebral artery territory in a newborn female presenting with seizures on day 2 of life. (Courtesy of Dr. Laurence Friedman, Children’s Hospital at Chedoke McMaster, Ontario, Canada.)

wedge-shaped infarcts involving the cerebral cortex and subjacent white matter in characteristic vascular distributions (Figs. 72-4A and 72-5). Anastamoses at the level of the circle of Willis and through smaller vessels in the leptomeninges can provide collateral blood flow following occlusion of large arteries. In peripheral areas of the brain, at the junction of the areas supplied by the anterior, middle, and posterior cerebral arteries, are so-called watershed zones.

Watershed infarctions result when these areas are maximally damaged during global hypoperfusion and to a lesser extent during hypoxia. In the presence of fixed vascular stenosis of the cerebral arteries, global hypoperfusion causes focal infarction. An unusual form of multiple small, “deep” watershed infarcts involving hemispheric white matter has been observed in children with moyamoya disease and occlusion of the distal internal carotid artery. These infarcts appear at the border-zones between penetrating cerebral arterial branches and the perforator arteries arising from the stem of the major cerebral arteries. Occlusion of small-caliber perforator arteries produces infarcts several millimeters to several centimeters in diameter, similar to lacunar infarcts described in adults (Figs. 72-6A and B and 72-7). Such infarcts are concentrated in deep central brain structures, including the basal ganglia and brainstem, that are in the territory of the perforator arteries that arise from the most proximal portions of the anterior, middle, and posterior cerebral arteries. Perforator arteries are functionally classified as end-arteries because they lack vascular anastomoses and collateral supply does not exist. As a result, occlusion of these arteries is more likely to result in permanent infarction. Small-vessel territory infarcts, although small in size, can result in severe clinical manifestations because of the densely concentrated functional pathways located in deep central areas, including the internal capsule. In children with perforator artery territory infarcts, the infarcts tend to be larger “macro-lacunar” infarcts, compared with those in adults, and are probably related to differing mechanisms of occlusion. In adults, lipohyalinosis of the small arteries results in occlusion of individual and distal small artery branches. In childhood, perforator arteries become occluded at their origin off of the stem of the proximal middle, anterior, or posterior cerebral artery, due either to thrombotic occlusion or to inflammation of the wall of

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A

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B

FIGURE 72-6. Small-vessel arterial infarct of unknown etiology in a 10-month-old male. A, T2-weighted MRI shows right caudate and putamen infarct. B, Same patient 4 months after stroke, residual left hemiparesis with left hand fisting is seen. (Courtesy of Division of Neuroradiology, Hospital for Sick Children, Toronto, Ontario, Canada.)

the large arteries, as in post-varicella angiopathy and transient cerebral arteriopathy of childhood [Askalan et al., 2001; Chabrier et al., 1998]. In population-based studies, arterial infarcts are in the small-vessel distribution in approximately 20% of neonates and in 50% of older infants and children. In both populations, the strokes occur more frequently in the left than in the right hemisphere [deVeber and Canadian Paediatric Ischemic Stroke Study Group, 2000].

Clinical Features In children with acute arterial ischemic stroke, the recognition of cerebral infarction often is delayed beyond 24 hours because of the lack of public and physician awareness, which is related to the low incidence of arterial ischemic stroke. In one study, the time from clinical onset to first medical contact averaged 28.5 hours, and the time to diagnosis of stroke averaged 35.7 hours [deVeber, 2002]. In

children, hemiparesis may be erroneously attributed to migraine, focal seizure, focal encephalitis, or demyelination because of their similar presentations and the increased familiarity of physicians with these conditions in childhood. More subtle symptoms or signs are even less likely to be attributed to stroke, particularly in young infants and children who are unable to verbalize these complaints. To further confuse the issue, seizures at the onset of stroke are relatively frequent in children [Delsing et al., 2001], compared with adults [Trescher, 1992; Yang et al., 1995], and stroke may be incorrectly diagnosed as a postictal Todd’s paresis. Children with hypoglycemia also can present with focal neurologic deficits mimicking stroke [Kossoff et al., 2001]. The presenting clinical features of arterial ischemic stroke are age-related. The clinical presentation of stroke occurring in later infancy or childhood is typically an acute neurologic event heralded by hemiparesis with or without seizures. Seizures, fever, headache, and lethargy occur more com-

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Risk Factors

FIGURE 72-7. MRI (T2-weighted) shows left small-vessel arterial infarct not seen on CT in a 5-year-old male who had recurrent episodes of right hemiparesis 6 months after chickenpox and was diagnosed with plasminogen deficiency. (Courtesy of Dr. Laurence Friedman.)

monly in younger children than in older children [Trescher, 1992]. Dystonia is more common in children with basal ganglia infarction than in adults [Demierre and Rondot, 1983]. Although the majority of children with arterial ischemic stroke present with a single episode of focal neurologic deficit, transient ischemic attacks, frequently followed by a stroke, are increasingly recognized in children and infants. The definitions of transient ischemic attack and arterial ischemic stroke are undergoing revision. In the past, these entities were defined solely by the duration of deficit (less than 24 hours for transient ischemic attack and 24 hours or more for arterial ischemic stroke). In reality, a neurologic deficit lasting less than 24 hrs is associated with CT or MRI evidence of an infarct in 2% to 50% of adults. Thus, transient ischemic attack has been recently re-defined as “a brief episode of neurologic dysfunction caused by focal brain or retinal ischemia, with clinical symptoms typically lasting less than one hour, and without evidence of acute infarction.” The presence of persistent clinical signs, regardless of duration, or characteristic imaging abnormalities then defines infarction—that is, stroke [Albers et al., 2002]. In children, the differentiation of transient ischemic attack from other causes of brief neurologic deficits can be challenging. However, the development of a clinical deficit that is sudden and maximal at onset, or the presence of cerebral artery stenosis on conventional angiography or magnetic resonance angiography (MRA) suggests a probable thromboembolic etiology. The importance of identifying transient ischemic attacks is that they are frequently followed by stroke, and urgent antithrombotic treatment is advisable.

Risk factors for arterial ischemic stroke in children differ significantly from those in adults, in whom arteriosclerosis is the leading cause of stroke [deVeber, 2003]. Children are less likely than adult stroke patients to have identifiable risk factors and more likely to have infectious or inflammatory disorders underlying the stroke [Kerr et al., 1993]. In children with stroke, approximately half are previously well [Ganesan et al., 2003]. The reported frequency of identifiable risk factors in children with arterial ischemic stroke beyond the newborn period varies widely across studies, depending on the population of children, criteria for risk factors, and extensiveness of etiologic investigations. In single center tertiary care studies, risk factors are definable in 78% to 90% of children [Chabrier et al., 2000; Ganesan et al., 2003; Lanthier et al., 2000]. In a prospective populationbased study, a primary risk factor for cerebral infarction was definable in 72% of children with arterial ischemic stroke [deVeber and Canadian Paediatric Ischemic Stroke Study Group, 2000]. One important risk factor was cardiac disease in 24%. Stroke accompanied cardiac surgery in 20% and catheterization in 17% of these children and occurred spontaneously in 63%. Other risk factors in older children included prothrombotic or hematologic disorders (12%), dissection (7%), moyamoya disease (8%), post-varicella angiopathy (7%), and other vasculopathies (5%). Multiple risk factors frequently were present in individual patients. Another institutional study of risk factors for childhood arterial ischemic stroke reported anemia in 40%, and elevated homocysteine levels or homozygosity for the t-MTHFR mutation in 21% of children [Ganesan et al., 2003]. Trauma and previous varicella zoster infection also were frequently seen. Mechanisms of stroke in another institutional study of 59 children were arteriopathy in 53%, cardioembolic in 12%, and systemic disease in 14% [Chabrier et al., 2000]. In this study, dissection (20%) and transient cerebral arteriopathy (25%) were frequently noted, likely due to the consistent use of and referral for angiography. In 22% of children, no mechanism was identified. The cause of stroke in some children is obvious—for example, those children with a known structural cardiac disorder or sickle cell disease. Clinical features obtained from the history and physical examination can suggest less obvious etiologies. A recent head or neck injury suggests dissection. A varicella infection in the previous 12 months should lead to consideration of post-varicella angiopathy. A history of head or neck irradiation, especially when focused on the optic chiasm predisposes to postradiation vasculopathy. Migraine, oral contraceptive use, and amphetamine or cocaine use all predispose to infarction. The risk of ischemic stroke is increased in young women using oral contraceptives, including low-estrogen preparations [Gillum et al., 2000]. A family history of stroke, heart attack, lipid problems, leg clots, or lung clots at young ages suggests a hereditary coagulation or lipid disorder. Physical examination may provide additional clues, including head or neck bruits, cardiac murmurs, and skin lesions of tuberous sclerosis, neurofibromatosis, or Fabry’s disease. The interaction of genes with other known risk factors in childhood stroke is being explored [Kirkham, 2004]. Single gene disorders with a significant predisposition to stroke

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include sickle cell disease, homocystinuria, Menkes’ disease, and neurofibromatosis. In children with sickle cell disease, additional gene polymorphisms are associated with different patterns of infarction (small vessel only, large vessel territory with or without small vessel, no strokes) [Hoppe et al., 2004]. The probability of identifying the cause of arterial ischemic stroke depends on the thoroughness of investigation. An underlying predisposing condition should be sought, because children may remain at risk for recurrent thromboembolic events and adverse outcomes are linked to the type and number of risk factors [Chabrier et al., 2000; Lanthier et al., 2000]. Stroke may be the initial manifestation of serious undiagnosed diseases, including heart disease, systemic lupus erythematosus, diabetes, and cancer. Of particular importance is the identification of children with inherited coagulation abnormalities, because treatment for secondary prevention and genetic counseling are available. Additional risk factors for childhood arterial ischemic stroke will undoubtedly be identified over time. Box 72-1 lists the most common causes of arterial ischemic stroke. In the following section, the most important disorders causing arterial ischemic stroke in the pediatric age group are briefly reviewed.

Cardiac Disorders The most common identifiable cause of childhood ischemic stroke is complex congenital heart disease. Congenital and acquired (endocarditis, cardiomyopathy) cardiac disorders are present in 12% to 28% of older infants and children with arterial ischemic stroke [Chabrier et al., 2000; Ganesan et al., 2003; deVeber and Canadian Paediatric Ischemic Stroke Study Group, 2000]. Thrombi formed in the heart can embolize to the cerebral circulation. Prosthetic heart valves are an important source of emboli. In the presence of an atrial or ventricular septal defect, intermittent right-to-left intracardiac shunting allows systemic venous clots to reach the cerebral circulation. In approximately half of the children with congenital heart disease and stroke, the stroke occurred in relation to the time when cardiac surgery or catheterization procedures were performed. The frequency of stroke following cardiac surgery in children has been recently estimated as 1 in 250 to 1 in 400 procedures [Domi et al., 2002; Menache et al., 2002]. However, following the Fontan procedure, the frequency of immediate or delayed stroke ranged from 3% to 19% [Monagle and Karl, 2002]. Stroke following cardiac catheterization in children is reported to occur in 1 in 600 to 700 procedures [Liu et al., 2001]. Small insignificant intracardiac septal defects, including patent foramen ovale, have been established as risk factors for paradoxical embolism and stroke in young adults [DiTullio et al., 1992]. The Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS), confirmed that patent foramen ovale is more prevalent among patients with cryptogenic stroke and that treatment with aspirin (acetylsalicylic acid) is associated with a low risk of recurrent stroke in the absence of an associated atrial septal aneurysm [Mas et al., 2001]. Prothrombotic disorders apparently combine with patent foramen ovale in the genesis of stroke in such patients [Pezzini et al., 2003; Rodriguez and Homma, 2003]. Echocardiography should be performed in all children with arterial ischemic stroke of undetermined cause. Agitated saline to

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establish the presence of patent foramen ovale and transesophageal echocardiography increase the sensitivity of testing. These additional echocardiographic techniques should be considered in children with arterial ischemic stroke, especially in children older than 7 years in whom transthoracic echocardiography may have insufficient resolution.

Infection Fever and nonspecific or nasopharyngeal viral infections frequently are present in children presenting with cerebral infarction. In one recent study, fever was present in nearly 50% and leukocytosis in 26% of children, although specific infectious agents were infrequently identified [Ganesan et al., 2003]. Arterial or venous stroke has been identified in 5% to 12% of children with bacterial meningitis; however, strokes occur in as many as 75% of infants with meningitis in the first year of life [Chang et al., 2003; Chiu et al., 1995; Silverstein and Brunberg, 1995]. Local inflammation of the meninges with thrombophlebitis of cerebral vessels is the primary mechanism. Meningitis should be considered in children with arterial ischemic stroke and fever, and selected cerebrospinal and serum studies assessing for bacterial, tuberculous, and viral meningitis may be indicated. Pediatric stroke has been reported in the following specific infectious disorders: mycoplasma, cat scratch fever, Rocky Mountain spotted fever, Lyme disease, cryptococcus, Japanese encephalitis, coxsackievirus B4 and A9, influenza A, enterovirus, varicella, HIV (human immunodeficiency virus), parvovirus B19 and X, and chlamydia [Guidi et al., 2003]. HIV infection is increasingly recognized as a risk factor for multiple infarcts and cerebral aneurysms. In a recent series, these lesions were found on screening MRI scans in 2.6% of children with HIV and were frequently asymptomatic [Kleinschmidt-DeMasters and Gilden, 2001; Patsalides et al., 2002; Visudtibhan et al., 1999].

Prothrombotic Disorders Prothrombotic disorders are abnormalities of the coagulation system, fibrinolytic system, endothelial cells, or platelets, which lead to a reduced threshold for pathologic thrombus formation. Inherited or acquired coagulation system disorders have been identified in 50% to 68% of newborns and 20% to 50% of children presenting with arterial ischemic stroke [Barnes and deVeber, 2004; Bonduel et al., 1999; deVeber et al., 1998; Golomb et al., 2001; Gunther et al., 2000]. Acquired prothrombotic states are more frequent than congenital prothrombotic states in children with arterial ischemic stroke [Bonduel et al., 1999; deVeber et al., 1998]. The most frequently reported abnormalities include factor V Leiden deficiency, prothrombin G20210A mutation, elevated lipoprotein(a) and homocysteine levels, protein C deficiency, and antiphospholipid antibodies. In contrast to most prothrombotic states, which primarily promote venous thrombosis, the prothrombin G20210A mutation is more frequently associated with arterial thrombosis, including arterial ischemic stroke, than with venous thrombosis in children [Young et al., 2003]. Recently, anticardiolipin antibodies at modestly increased levels (less than 45 GPL [immunoglobulin G phospholipid] units) have been found not to predict recurrent stroke or transient ischemic attack in

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Box 72-1 DISORDERS CAUSING ISCHEMIC STROKE Intravascular Hematologic Disorders Hemoglobinopathies (sickle cell anemia) Immune thrombocytopenic purpura Thrombotic thrombocytopenic purpura Thrombocytosis Polycythemia Leukemia or other neoplasm Acquired Prothrombotic States Prothrombotic medications (oral contraceptives and L-asparaginase) Pregnancy and the postpartum period Lupus anticoagulant Anticardiolipin antibodies Lipoprotein abnormalities Congenital or Acquired Prothrombotic States Antithrombin III deficiency Protein S deficiency Protein C deficiency Plasminogen deficiency Congenital Prothrombotic States Factor V Leiden gene defect Methyltetrahydrofolate reductase Prothrombin gene defect Metabolic Disorders Hyperhomocysteinemia Hyperlipidemia Lipoprotein-a elevation Vascular Vasculitis Primary angiitis of the CNS Meningitis Systemic lupus erythematosus Polyarteritis nodosa Takayasu’s arteritis Rheumatoid arthritis Dermatomyositis Inflammatory bowel disease Drug abuse (cocaine, amphetamines) Systemic Vascular Disease Early atherosclerosis Diabetes

Ehlers-Danlos syndrome Pseudoxanthoma elasticum Homocystinuria Fabry’s disease Vasculopathies Post-varicella angiopathy* Transient cerebral arteriopathy* Arterial fibromuscular dysplasia Moyamoya disease Post-radiation vasculopathy Vasospastic Disorders Migraine Ergot poisoning Vasospasm with subarachnoid hemorrhage Trauma Brain herniation and arterial compression Post-traumatic arterial dissection Intra-oral trauma Carotid ligation (e.g., ECMO) Arteriography Embolic Congenital Heart Disease Complex congenital heart defect Ventricular/atrial septal defect Aortic or mitral stenosis Coarctation Patent foramen ovale Patent ductus arteriosus Acquired Heart Disease Rheumatic heart disease Prosthetic heart valve Bacterial endocarditis Cardiomyopathy and myocarditis Atrial myxoma Cardiac rhabdomyoma Dysrhythmia Trauma Amniotic fluid/placental embolism Fat or air embolism Foreign body embolism Cardiac catheterization

*Likely inflammatory and can be classified as focal vasculitis. CNS, central nervous system; ECMO, extracorporeal membrane oxygenation.

children, at least with current antithrombotic treatment [Lanthier et al., 2004]. The presence of some prothrombotic states does increase the risk of stroke recurrence in older children, although not in neonates. In a German collaborative study of Caucasian children, stroke recurrence risk was significantly increased

in children with familial protein C deficiency or increased lipoprotein (a) levels [Strater et al., 2002]. Children with prothrombotic disorders usually have additional “triggering” risk factors at the time of arterial ischemic stroke [Barreirinho et al., 2003; Strater et al., 2002]. Coagulation testing should be performed in any child with arterial ischemic stroke,

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including children with other identified risk factors. Children should be tested off anticoagulants if possible. Transient abnormalities in coagulation testing occur for several weeks or longer after the formation of a clot. Testing parents, if the abnormality is a hereditary coagulation abnormality, or retesting the child several months later or both, should confirm abnormal results on samples taken within several weeks of the stroke.

53% to 59% [Chabrier et al., 2000; Ganesan et al., 2003]. A classification system for arteriopathies associated with arterial ischemic stroke in childhood has been developed recently [Sébire et al., 2004]. Because the presence of vasculopathy increases the risk for arterial ischemic stroke recurrence nearly threefold, cerebrovascular imaging to detect arterial disorders is important [Askalan et al., 2001; Lanthier et al., 2004; Strater et al., 2002].

Hematologic Disorders

DISSECTION AND OTHER PHYSICAL INJURIES

Sickle cell disease is the most common hematologic disorder associated with cerebrovascular disease. About 25% of patients with sickle cell disease develop cerebrovascular complications that include overt arterial ischemic stroke, subclinical small-vessel occlusive arterial ischemic stroke, and subarachnoid or intracranial hemorrhage [Pegelow, 2001]. Stroke is the cause of death in 10% of children with sickle cell disease [Manci et al., 2003]. Thrombotic stroke occurs as part of the thrombotic crisis or as the result of a progressive cerebral vasculopathy resembling moyamoya disease. Strokes are ischemic in 75% and hemorrhagic in 25% of cases; prior to the mid-teen years hemorrhage is rare. Aneurysms are rare in children with moyamoya disease associated with sickle cell disease with an incidence of only 1.5% [Satoh et al., 1988]. Transcranial Doppler studies are a noninvasive means of following the large-vessel vasculopathy and determining stroke risk in these patients [Adams et al., 1992, 1998]. A randomized, controlled trial has documented that long-term transfusion therapy to reduce the levels of hemoglobin S to less than 20% to 30% reduces the risk of primary stroke in high-risk individuals [Adams et al., 1998]. Since publication of the STOP study in 1998, annual rates of admissions for first stroke for Californian children with sickle cell disease have declined from 0.88 per 100 person-years during 1991 through 1998 to 0.50 in 1999 and 0.17 in 2000 [Fullerton et al., 2004]. In children with sickle cell disease and moyamoya disease, EDAS (encephaloduroarteriosynangiosis) surgery has been used with promising results [Fryer et al., 2003]. Recently, nocturnal hypoxemia has been identified as a significant predictor of stroke in children with sickle cell disease [Kirkham et al., 2001]. Other therapies are under investigation, and hydroxyurea has shown efficacy in the prevention of recurrent stroke in a recent randomized, controlled trial [Ware et al., 2004]. The role of anticoagulant and antiplatelet agents remain unclear but should be considered, especially when large-vessel vasculopathy or prothrombotic abnormalities and recurrent stroke co-exist [Wolters et al., 1995]. Non-sickle cell anemias may be associated more frequently with arterial ischemic stroke than previously recognized and were observed in more than 25% of children with arterial ischemic stroke in one series [Ganesan et al., 2003]. Iron-deficiency anemia also is frequently associated with stroke, particularly in older infants [Hartfield et al., 1997]. The underlying pathophysiology explaining this relation has not been established. Platelet disorders including thrombocytosis can be associated with arterial ischemic stroke.

Dissection of the carotid or vertebral arteries occurs in 8% to 20% of children with arterial ischemic stroke [Chabrier et al., 2003; Fullerton et al., 2001; Rafay et al., 2002]. In children, dissection can result from intra-oral trauma, mechanical injuries to the neck including external manipulation, or physical exertion, or can occur spontaneously [Chabrier et al., 2003; Rafay et al., 2002]. Headache is a prominent presenting feature in 50% to 75% of children. With current medical therapy, recurrent transient ischemic attacks or strokes are documented in 8% to 19% of children with large-vessel dissection, and recurrent dissection in other arteries occurs in up to 20% of children with dissections involving the anterior circulation [Chabrier et al., 2003; Fullerton et al., 2001; Rafay et al., 2002]. As in adults, initial treatment usually consists of anticoagulation using unfractionated heparin or low-molecular-weight heparins, followed by 3 to 6 months of Coumadin therapy. However, even in adults uncertainty regarding optimal treatment exists, and a randomized, controlled trial assessing aspirin or anticoagulants is needed [Beletsky et al., 2003]. The risk of recurrence and period of endothelial disruption are maximal in the first several weeks from onset. Therefore, a switch from anticoagulant to aspirin therapy may be feasible earlier than is the current practice, especially in patients in whom follow-up vascular imaging indicates rapid resolution of arterial wall abnormalities. Post-radiation vasculopathy manifests with progressive large-vessel stenosis and transient ischemic attacks or strokes beginning several years after irradiation of optic chiasm gliomas or other sellar or suprasellar region tumors in children (Fig. 72-8). Younger children with increased doses of radiation are particularly susceptible [Omura et al., 1997]. MRI findings of arterial wall thickening and contrast enhancement have been described in this condition [Aoki et al., 2002]. No specific therapy halts the progression of postradiation vasculopathy, although disease progression may spontaneously diminish over time. Cerebral arteries at the base of the brain, particularly the posterior cerebral artery, are susceptible to extrinsic mechanical compression and occlusion. In childhood, this mechanism is observed when intracranial pressure is markedly increased by impending herniation, such as with head trauma, severe diffuse hypoxic ischemic injury, and hydrocephalus.

Arteriopathies In older infants and children with arterial ischemic stroke, vascular imaging reveals specific arteriopathic disorders in

POSTVARICELLA ANGIOPATHY Postvaricella angiopathy occurring weeks or months after uncomplicated varicella is probably underdiagnosed. In school-aged children with arterial ischemic stroke, there is a

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FIGURE 72-8. Nine-year-old female with optic glioma irradiated 3 years earlier and post-radiation vasculopathy with recurrent bilateral artery-to-artery embolic arterial infarcts. A and B, T2-weighted MRI shows multiple bilateral infarcts. C, MR angiogram shows obvious right and subtle left middle cerebral artery stenosis. (Courtesy of Dr. Laurence Friedman.)

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threefold increase in preceding varicella infection compared with published population rates, and varicella-associated arterial ischemic stroke accounts for nearly one third of childhood arterial ischemic strokes [Askalan et al., 2001]. Varicella-associated arterial ischemic stroke has characteristic features, including basal ganglia infarction and self-resolving unilateral stenosis of the distal internal carotid or proximal anterior, middle, or (less frequently) posterior cerebral arteries (Fig. 72-9; also see Fig. 72-7) [Askalan et al., 2001]. Elevated cerebrospinal fluid antibody titers to varicella-zoster virus rarely are found [Ueno et al., 2002]. In adults, viral particles or antigens have been detected in the cytoplasm and nuclei of smooth muscle cells from the wall of affected cerebral arteries

[Eidelberg et al., 1986; Linnemann and Alvira, 1980; Reshef et al., 1985]. In a 4-year-old female who died of progressive stroke secondary to postvaricella angiopathy, postmortem examination revealed a zoster antigen-positive giant cell arteritis involving the left middle cerebral artery [Berger et al., 2000]. A second case of clinical postvaricella stroke showed lymphocytic arteritis, without evidence of varicella virus, affecting cerebral small vessels in a surgical specimen after decompressive surgery in a 4-year-old male [Hayman et al., 2001]. The most likely mechanism is that the virus is activated in the trigeminal ganglion and spreads along the trigeminal nerve fibers innervating the internal carotid artery and proximal cerebral arteries [Kleinschmidt-DeMasters and Gilden, 2001].

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FIGURE 72-9. Postvaricella angiopathy in a 4-year-old male presenting with hemiparesis and speech loss 3 months following chickenpox. A, Initial MRI shows a “macro-lacune” involving left basal ganglia. B, Initial angiogram shows normal lumen diameter with abnormal striae in the stem (arrow) of the left middle cerebral artery (MCA). C, Followup angiogram 8 weeks later shows stenosis in MCA stem (arrow) at the site of the prior abnormality. D, Repeat angiogram after another 10 months shows persistence without progression of MCA stem (arrow) stenosis. (Courtesy of Derek Armstrong, Division of Neuroradiology, Hospital for Sick Children, Toronto, Ontario, Canada.)

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VASCULITIS Central nervous system vasculitis in childhood may be primary, termed isolated or primary angiitis of the central nervous system, or secondary to a variety of conditions, including infections, collagen vascular diseases, systemic vasculitides, and malignancies [Benseler and Schneider, 2004]. Systemic vasculitides that can affect the cerebral arteries include Kawasaki’s disease, Henoch-Schohnlein purpura, Polyarteritis nodosa, Wegener’s granulomatosis, and Takayasu’s arteritis [Belostotsky et al., 2002; Berman et al., 1990; Morales et al., 1991; Morfin-Maciel et al., 2002; von Scheven et al., 1998]. Connective tissue diseases, including systemic lupus erythematosus, Behçet’s syndrome, dermatomyositis, mixed connective tissue disease, Sjögren’s syndrome, and inflammatory bowel disorders, can also cause central nervous system vasculitis in childhood [Benseler and Schneider, 2004; Graf et al., 1993]. Takayasu’s arteritis in childhood is rare and presents with progressive stenosis and occlusion of extracranial arteries near their origin from the aorta [Morales et al., 1991]. Although systemic lupus erythematosus is often associated with arterial ischemic stroke, vasculitis as the etiology for

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stroke is rare [Devinsky et al., 1988]. Isolated angiitis of the central nervous system (IACNS) in childhood has been recently reviewed and classified [Lanthier et al., 2001]. In children, the large, medium-sized, and small vessels can be involved, at times overlapping in individual cases. Histopathologic findings range from a granulomatous to nongranulomatous, primarily lymphocytic process. The aggressive form of IACNS as seen in adults is rare in children. The diagnosis is suspected when progressive, irregular arterial narrowing occurs in the absence of other etiologies (Fig. 72-10). Brain or leptomeningeal biopsy is usually required for confirmation. Transient cerebral arteriopathy is a unilateral monophasic vasculitis that is frequently recognized in children with arterial ischemic stroke. Transient cerebral arteriopathy is presumed but not proven to represent a form of focal selflimited vasculitis and may well be the most common type of arteriopathy in children with arterial ischemic stroke [Chabrier et al., 1998; Shirane et al., 1992]. The angiographic appearance includes unilateral irregular stenosis involving the distal part of the internal carotid and proximal segments of the anterior cerebral artery (A1 segment), the

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FIGURE 72-10. Progressive, presumed vasculitis of the vertebrovascular system in a 4-year-old male with pontine infarction. A, Initial MRI shows pontine infarct. B, Initial angiogram demonstrates basilar artery occlusion (arrow) with normal vertebral arteries. C. Although the clinical course had not changed, follow-up angiogram 4 months later shows presumed vasculitis involving the distal right vertebral artery (arrow). D, Again, although the clinical course had not changed, a repeat angiogram after the child was on steroid therapy for 5 months shows progression of the presumed vasculitis involving the cervical portion of the vertebral artery (arrow). Biopsy was not performed. (Courtesy of Derek Armstrong, Division of Neuroradiology, Hospital for Sick Children, Toronto, Ontario, Canada.)

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middle cerebral artery (M1 segment), or the posterior cerebral artery (P1 segment) (see Fig. 72-4B) [Chabrier et al., 1998; Shirane et al., 1992]. Unilateral infarcts located in the basal ganglia and internal capsule are typical features. The average age at onset is 5 years. The natural history includes stabilization or regression of the lesions on angiographic follow-up, with progression of stenosis limited to the initial 3 to 6 months after presentation with arterial ischemic stroke. Serologic markers of vasculitis are rarely seen. The most plausible pathophysiologic mechanism underlying transient cerebral arteriopathy is a transient acute vasculitis induced by viral infection. When varicella infection precedes the onset of arterial ischemic stroke by less than 12 months, transient cerebral arteriopathy is termed postvaricella angiopathy. A worsening of arterial lesions detected on MRA at 6 to 12 months, compared to detection at 3 to 6 months, argues in favor of a chronic cerebral vasculitis [Sébire et al., 2004]. Transient cerebral arteriopathy has been included in the spectrum of IACNS, although this is controversial, and predictors distinguishing this condition from

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progressive IACNS have been defined [Benseler et al., 2003]. Enteroviral infection also has been associated with transient cerebral arteriopathy [Ribai et al., 2003]. Because vasculitis can involve medium-sized and small vessels that are not well visualized with current MRA techniques, conventional angiography is usually indicated in children with arterial ischemic stroke of unclear etiology. Laboratory tests for vasculitis include the erythrocyte sedimentation rate, complement studies (C3 and C4), rheumatoid factor, antinuclear antibodies, and cerebrospinal examination for pleocytosis. In children with bilateral or distal arterial lesions considered to be possible IACNS, a leptomeningeal and cortical biopsy should be considered to confirm the diagnosis prior to committing to long-term immunosuppressant therapy.

Moyamoya Disease and Moyamoya Syndrome Moyamoya disease should be distinguished from moyamoya syndrome. Moyamoya disease refers to a specific disease described primarily in the Asian population and characterized

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FIGURE 72-11. Moyamoya disease in a developmentally delayed 13-year-old male with left hemiparesis and chorea on the right. A, Anterior and middle cerebral arteries are occluded, and a prominent vascular pattern is evident in the basal ganglia. B, Lateral projection of same patient.

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by progressive idiopathic stenosis and eventual occlusion of the large cerebral arteries involving the circle of Willis. In response to the stenosis, an abnormal network of small collateral vessels develops creating the “puff of smoke” appearance on the angiogram (Fig. 72-11). Moyamoya syndrome includes the angiographic pattern typical of moyamoya disease but occurs secondary to a variety of slowly progressive, occlusive cerebral vasculopathies, such as sickle cell disease and postradiation vasculopathy. A variety of genetic syndromes are associated with moyamoya syndrome, including Down syndrome, neurofibromatosis, and Williams’ syndrome. Conventional angiography is the definitive method of diagnosis. The clinical course consists of recurrent transient ischemic attacks and strokes and progressive cognitive decline. Recurrent infarcts and rapid disease progression are more frequently seen in moyamoya disease presenting prior to age 6 years [Kim et al., 2004]. In contrast to other forms of childhood arterial ischemic stroke, the neurologic events in children with moyamoya disease are frequently related to hyperventilation and breath-holding and appear to have a vasoreactive mechanism responsive to acid-base balance, not simply thromboembolic mechanisms [Mikulis et al., 2004]. Over time, moyamoya disease can remain stable but more typically follows a progressive course with severe motor impairment and intellectual deterioration [Suzuki and Kodama, 1983]. The natural history of moyamoya disease may be less devastating than previously suggested. Hemorrhage is relatively rare in children with moyamoya disease compared with adults [Yoshida et al., 1993]. No specific medical therapy has been found to halt the progression of this disorder, although calcium channel blockers and acetazolamide have been used. Antithrombotic therapy for the prevention of recurrent thromboemboli has not been evaluated but should be considered, as for any other cerebral vasculopathy. Three surgical revascularization procedures have been used to manage this disease: anastamosis of the superficial temporal artery to the cerebral artery (“direct” revascularization), encephalomyosynangiosis, and encephaloduroarteriosynangiosis (“indirect” revascularization). In pial synangiosis, the superficial temporal artery is sutured to the pia mater under microscopic visualization [Ueki et al., 1994]. No clinical trials com-

paring surgical to nonsurgical management have been conducted. The goal of surgical intervention is to promote development of collateral circulation to the brain, thereby decreasing the risk of stroke, transient ischemic attacks, seizures, and progressive cognitive decline. These surgical techniques are increasingly utilized in the early stages of moyamoya disease with apparently minimal morbidity, and follow-up angiography and perfusion studies demonstrate excellent postoperative establishment of collateral circulation and increased perfusion of ischemic areas of the brain in the majority of patients. In a single center study, 271 pial synangiosis procedures were performed in 143 children, of whom 16 were Asian. In follow-ups ranging from 1 to 17 years, recurrent strokes or transient ischemic attacks were seen in 11 children more than 30 days following surgery and in only 9 children less than 30 days following surgery [Scott et al., 2004].

Migraine Children with stroke due to migraine have been rarely reported [Feucht et al., 1995; Nezu et al., 1997; Santiago et al., 2001]. The distribution of arterial ischemic stroke is predominantly in the posterior circulation in children with migrainous stroke. When there is an established history of migraine prior to the stroke and a clear migraine headache at the time of the stroke, the causative association is relatively clear. Migraine with aura is a predictor of stroke risk, and in adults migrainous stroke recurs in as many as 15% per year [Rothrock, 1993]. Children frequently develop migraine headache following brain injury, including stroke, and in such cases migraine is likely a result of rather than a cause of the stroke.

Metabolic Vasculopathies Homozygous homocystinuria predisposes to arterial and venous thrombosis, including cerebral infarcts. Thromboembolic manifestations can precede the ocular and other physical features of the disease [Bodensteiner et al., 1992]. For homozygous homocystinuria, plasma amino acid assays are an adequate diagnostic screen. More subtle forms of hyperhomocysteinemia have been found in up to one fifth of

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children with arterial ischemic stroke and may play an important pathogenic role [Cardo et al., 2000; Ganesan et al., 2003]. Because hyperhomocysteinemia has a prothrombotic effect, it should be considered even in the absence of a vasculopathy as a possible risk factor for arterial ischemic stroke. Measurement of plasma homocysteine using pediatric normal values is necessary for this diagnosis [Vilaseca et al., 1997]. An oral methionine loading test with pre- and post-methionine plasma homocysteine levels increases the sensitivity of plasma homocysteine testing. In Fabry’s disease, caused by alphagalactosidase deficiency, multiple lacunar cerebral infarcts occur in affected males during the teenage and early adult years. Diagnostic tests for Fabry’s disease include examination of the skin for angiokeratoma and testing for increased levels of urinary ceramide trihexoside and decreased levels of leukocyte alpha-galactosidase activity. Children with MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis and strokelike episodes) present with episodes of nausea, vomiting, headaches, seizures, hemiparesis and cortical blindness. Areas of infarction not conforming to typical vascular distributions are found, usually in the occipital regions [Mudd et al., 1985]. Whether the mechanism for these infarcts includes vascular occlusion has not been established [Michelson and Ashwal, 2005]. However, because focal cortical hyperperfusion is seen in single photon emission computed tomography (SPECT) studies during the strokelike episodes, a more likely explanation is that regional neuronal hyperexcitability results in marked depletion of energy compounds with resultant metabolic infarction [Iizuka et al., 2002]. Elevated serum and cerebrospinal fluid levels of lactate and pyruvate are suggestive of MELAS syndrome, and testing for specific genetic mutations is now available. Children with hyperlipidemia can suffer from stroke [Glueck et al., 1982]. Hypercholesterolemia has been found in up to 9% of children with stroke [Ganesan et al., 2003]. Fasting serum cholesterol, triglycerides, and high-density and low-density lipoprotein fractions should be obtained in any child with idiopathic arterial ischemic stroke. Normal age-related values for these tests are available [Muhonen and Lauer, 1996]. Transient viral or bacterial infections, which involve vasculitis and vascular occlusion in the brain, can trigger idiopathic childhood ischemic stroke on the basis of genetic predisposition [Zou et al., 2002].

Radiographic Features

MRI is far superior to CT because it avoids bone artifact. MRI is also more sensitive than CT in detecting hemorrhagic conversion of infarcts [Kidwell et al., 2004]. Modifications of MRI that have improved early detection and specificity of the diagnosis of infarct include diffusionweighted imaging, perfusion-weighted imaging, and proton spectroscopic imaging [Groenendaal et al., 1995; Warach and Baron, 2004]. Recent MRI studies suggest that MRI can predict the volume of ischemic tissue that will progress to infarction and can detect cerebral microbleeds—a risk factor for intracranial hemorrhage [Schlaug et al., 1999; Warach and Baron, 2004]. In children, in whom the differential diagnosis for acute focal deficits is more extensive than in adults, the improved sensitivity of MRI compared to CT in the first 24 hours after arterial ischemic stroke suggests that if a single radiographic study is to be done in suspected acute arterial ischemic stroke, the initial study should be MRI when it is available.

Magnetic Resonance Angiography MRA can be performed at the same time as MRI and adds valuable information regarding the status of the cerebral arteries. Because time-of-flight MRA visualizes the flow of blood within vessels rather than the structure of the vessels, it is prone to certain artifacts, which must be considered when interpreting the findings. MRA is able to adequately visualize flow in the major cerebral arteries at the level of the circle of Willis (see Fig. 72-8C). When specifically planned, MRA can also image flow in the extracranial carotid and vertebral arteries at sites prone to dissection [Koelfen et al., 1993, 1995; Wiznitzer and Masaryk, 1991]. With continued improvement and refinement, MRA is becoming a realistic noninvasive alternative to conventional angiography, particularly in the pediatric population [Husson and Lasjaunias, 2004]. Recently MRA has been found to correlate well with conventional angiography in children with ischemic stroke [Ganesan et al., 1999; Husson et al., 2002]. However, MRA is less sensitive to the flow effects of diseases involving the medium-sized or small vessels in children, and it also overestimates the degree of vascular stenosis [Ganesan et al., 1999; Husson et al., 2002]. Gadolinium-enhanced MRA and MRA on high-field (3 Tesla) MRI machines reduce the risk of flow-related artifacts and “pseudo-occlusion” seen with regular time-of-flight MRA techniques [Nederkoorn et al., 2003].

Computed Tomography

Conventional Angiography

CT of the brain is often normal within the first 12 hours after ischemic stroke [Ball, Jr., 1994]. In children, CT findings of arterial ischemic stroke are similar to those in adults (see Fig. 72-5). Bland infarcts appear as low-density lesions in a vascular territory distribution; hemorrhagic infarcts have additional high-density components. Contrast enhanced CT spiral angiography is a new technique that shows great promise for noninvasive vascular imaging.

Conventional angiography is still considered to be the definitive method of visualizing the extra and intracranial vasculature (see Figs. 72-4B, 72-9, 72-10, and 72-11), despite the increasing availability and value of MRA. With current time-of-flight technique, MRA does not visualize small or medium-sized cerebral arteries reliably, compared with conventional angiography. Specific signs of cerebrovascular disease may be well defined only with conventional angiography, including the “string” and “double lumen” signs of dissection and the “string of beads” seen in vasculitis. Because different management strategies may result from these specific diagnoses, if expertise in pediatric angiography is available, conventional angiography should be performed in children with arterial ischemic stroke in whom

Magnetic Resonance Imaging MRI is more sensitive than CT for detecting early, small, and multiple infarcts [Ameri and Bousser, 1992; Fiebach et al., 2002] (see Fig. 72-7). In the brainstem and cerebellum,

deVeber / Cerebrovascular Disease

a specific etiology has not been determined. In recent studies comparing MRA to conventional angiography in 72 children with arterial ischemic stroke, MRA detected all largeartery lesions but overestimated stenosis and missed small-artery abnormalities in 34% of children [Ganesan et al., 1999; Husson et al., 2002; Husson and Lasjaunias, 2004]. Conventional angiography showed abnormalities in four of nine (44%) patients with normal MRA results. There are no data assessing the rate of major complications following angiography in children with arterial ischemic stroke; however, clinical experience suggests that they are extremely rare. In adults, since the advent of digital subtraction angiography, the use of conventional angiography in routine clinical practice settings is associated with a 0.5% rate of major complications [Johnston et al., 2001].

Other Neuroimaging Modalities MR perfusion and single photon emission computed tomography (SPECT) scanning are methods that can detect areas of hypoperfusion that may be present prior to tissue infarction [Shahar et al., 1990]. These techniques provide perfusion information that can be helpful in assessing cerebrovascular reserve in children with severe arterial vasculopathy. Doppler imaging of the carotid arteries and transcranial Doppler imaging provide valuable dynamic information regarding flow patterns through cerebral arteries and can assist in the detection of large-vessel vasculopathy. The value of transcranial Doppler imaging in children with sickle cell disease in predicting the risk of future stroke has been established [Abboud et al., 2004]. Doppler studies, including transcranial Doppler imaging, require expert interpretation because normal values in children differ from those in adults.

Treatment The treatment of stroke in children has been directed towards stabilizing systemic factors, management of the underlying causes, and prevention of extension or recurrence of thrombotic occlusion of cerebral arteries.

Antithrombotic Therapies Antithrombotic therapeutic options for arterial ischemic stroke include unfractionated heparin, low-molecular-weight heparin, aspirin, Coumadin, and thrombolytic therapy [Andrew and deVeber, 1999; Monagle et al., 2004]. No randomized, controlled trials have assessed antithrombotic treatments in children with arterial ischemic stroke. Many of the antithrombotic treatment approaches increasingly used in children with cerebrovascular disease have been adapted from studies in adults. Evidence from randomized, controlled trials in children with arterial ischemic stroke is needed. The optimal treatment of children with arterial ischemic stroke using antithrombotic agents can be expected to differ from that of adults, because there are important differences in etiology as well as profound age-dependent differences in the hemostatic system [Andrew et al., 1992], the cerebral vasculature, and the brain [Altman et al., 1988; Roach and Riela, 1995]. These features influence both the pathophysiology of the thrombotic processes and the response to anticoagulant therapy.

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In neonates with arterial ischemic stroke, the risk of recurrent arterial ischemic stroke appears to be less than 5%, suggesting that no antithrombotic treatment is required in the majority of cases [deVeber and Canadian Paediatric Ischemic Stroke Study Group, 2000; Kurnik et al., 2003]. However, data now clearly indicate that “no treatment” is not an acceptable option for older children with arterial ischemic stroke, in whom the risk of recurrence is up to 51% when no aspirin or antiplatelet agents are given, nearly double the risk for children treated with these agents [Lanthier et al., 2004]. The use of antithrombotic therapy appears to be increasing for pediatric arterial ischemic stroke beyond the newborn period. In a recent population-based study, 55% of children with arterial ischemic stroke received one or more treatments including unfractionated heparin, low-molecularweight heparin, aspirin and/or Coumadin [deVeber and Canadian Paediatric Ischemic Stroke Study Group, 2000]. There was a wide variability in indications for and choice of anticoagulants. Accumulating experience with antithrombotic and anticoagulant treatment in children suggests that these agents can be safely used in children with arterial ischemic stroke [Burak et al., 2003; deVeber and Canadian Paediatric Ischemic Stroke Study Group, 2000; Ng W et al., 2002; Strater et al., 2001], although their efficacy and proper dose still need to be established by controlled trials. The use of thrombolytic agents in children with arterial ischemic stroke, however, has been rare, and the risks are as yet unknown. Antithrombotic treatment guidelines for childhood stroke have been published [Andrew and deVeber, 1999; Monagle et al., 2004; Nowak-Gottl et al., 2003; Paediatric Stroke Working Group, 2004] and reviewed [deVeber, 2005]. The choice of antithrombotic agents in subgroups of children with arterial ischemic stroke is related to the perceived relative roles of platelets and the coagulation system in the initial and future recurrent thrombus formation, that are in turn dependent on the underlying mechanism of stroke. Damage to the arterial intima in dissection, cardiac embolism, venous thrombosis with paradoxical embolism, the presence of prothrombotic abnormalities, and the presence of extremely severe stenosis with slow flow likely promote thrombosis via activation of the coagulation system proportionately more than platelets, and these conditions are frequently treated with anticoagulation, at least for the first days or weeks after initial arterial ischemic stroke. However, idiopathic stroke or the presence of a moderate vascular stenosis that occurs with most vasculopathies is likely to involve platelets in the formation of thrombus, in which case antiplatelet agents are more appropriate. In individual children, the risks of recurrence or progression of cerebral thromboembolism should be balanced against the risks of treatment, particularly bleeding. If arterial ischemic stroke is associated with initial hemorrhage, hypertension, or other risks to anticoagulants, for example, antithrombotic therapy may not be feasible.

HEPARIN Heparin, a large heterogeneous polysaccharide complex, functions as an anticoagulant by inhibiting specific enzymes in the coagulation pathway, which in turn prevents clot ex-

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tension or new clot formation. The major effect of heparin is to potentiate the antithrombin activities of the natural inhibitor antithrombin (AT) by catalyzing its ability to inactivate specific coagulation enzymes, in particular thrombin [Hirsh et al., 1998]. Lower amounts of heparin anticoagulation are needed in children to produce the same anticoagulant effect as in adults [Andrew et al., 1994]. In adults, heparin has been the standard therapy for acute anticoagulation following stroke in situations in which there is a high risk of extension or recurrence of thromboembolic stroke, including acute cardioembolic stroke due to nonvalvular atrial fibrillation, and arterial dissection [Albers et al., 2001; Sandercock et al., 1993]. The results of the International Stroke Trial, in which over 19,000 adults with stroke were randomized to aspirin or heparin or both or neither showed that adults with stroke treated with heparin have significantly fewer recurrent strokes compared with aspirin; however, this benefit is offset by increased risk of cerebral hemorrhage [International Stroke Trial Collaborative Group, 1997]. There have been no large-scale trials of heparin in children with arterial ischemic stroke, but increasing clinical experience suggests that children can be treated along the same lines as adult patients with reasonable safety [deVeber and Canadian Paediatric Ischemic Stroke Study Group, 2000; Monagle et al., 2004]. A decision to use acute anticoagulation in a child with arterial ischemic stroke rests on two questions: What is the likelihood of extension of an infarction or of a second infarction from an embolus that might be prevented by treatment? What is the risk of inducing a hemorrhage because of anticoagulation? Much like the situation in adults, heparin should be considered in children thought to have a high risk of recurrence and a low risk of secondary hemorrhage. Heparin is commonly used in children for deep vein thrombosis and pulmonary embolism [Monagle et al., 2004]. For anticoagulation for acute or recurrent arterial ischemic stroke, a heparin bolus is usually not given in order to limit the risk of converting a bland infarct to a hemorrhagic infarct. Instead, heparin is given at maintenance doses of 28 units/kg/hour in infants and 20 units/kg/hour in children older than 1 year of age. For older children, the adult dose of 18 units/kg/hour is used. During the maintenance treatment, the dose must be carefully monitored and adjusted according to the activated partial thromboplastin time. The target activated partial thromboplastin time is 60 to 85 seconds or 1.5 to 2 times the baseline value [Andrew et al., 1994]. A nomogram for dose adjustment of standard heparin in children is presented in Box 72-2 [Monagle et al., 2004]. The activated partial thromboplastin time does not reflect the anticoagulant effect of heparin in certain circumstances, such as the presence of a nonspecific inhibitor, which prolongs the activated partial thromboplastin time, or the presence of elevated Factor VIII levels, which shortens the activated partial thromboplastin time. Heparin levels are more accurate but more difficult to obtain. Therapy is usually given for 5 to 7 days, depending on the clinically assessed risk of clot extension or recurrence [Andrew and deVeber, 1999]. Adverse effects of heparin include the risk of hemorrhage, the risk of osteoporosis after long-term courses of therapy, and thrombocytopenia. Children rarely bleed when

Box 72-2 PROTOCOL FOR SYSTEMIC HEPARIN ADMINISTRATION AND DOSAGE ADJUSTMENT FOR PEDIATRIC PATIENTS I. Loading dose: No loading dose is usually given for stroke. II. Initial maintenance dose: 28 U/kg/hr for infants younger than 1 year. III. Initial maintenance dose: 20 U/kg/hr for children older than 1 year. IV. Adjust heparin dose to maintain activated partial thromboplastin time for 60 to 85 seconds (assuming that this reflects an anti-factor Xa level of 0.30 to 0.70): APTT BOLUS HOLD (seconds) (U/kg) (min) <50 50 0 50-59 0 0 60-85 0 0 86-95 0 0 96-120 0 30 >120 0 60

% RATE CHANGE +10% +10% 0 –10% –10% –15%

REPEAT APTT 4 hr 4 hr next day 4 hr 4 hr 4 hr

V. Obtain blood for APTT 4 hours after initial administration and 4 hours after every change in the infusion rate. VI. When APTT values are therapeutic, check CBC and APTT levels daily. APPT, activated partial thromboplastin time; CBC, complete blood count. From Michelson AD, Bovill E, Andrew M. Antithrombotic therapy in children. Chest 1995;108:506S. Reproduced with permission.

treated with heparin for deep vein thrombosis or pulmonary embolism [Andrew et al., 1994]. Heparin-induced thrombocytopenia occurs in less than 4% of children [Newall et al., 2003]. When heparin-induced thrombocytopenia occurs, heparinoid or danaproid are alternative anticoagulants.

Low-Molecular-Weight Heparins Low-molecular-weight heparins are molecular subcomponents of the larger compound, unfractionated heparin. They offer several advantages over unfractionated heparin, including reproducible pharmacokinetics [Massicotte et al., 1996], subcutaneous injection, minimal monitoring, and increased safety, with similar efficacy compared with unfractionated heparin in studies of adults. Adults with arterial infarcts who are treated with low-molecular-weight heparin within 48 hours of onset may have a better outcome [Kay et al., 1995]. More recent clinical trials in adults with arterial ischemic stroke have found that survival and disability rates are nearly identical for low-molecular-weight heparin and aspirin [Bath et al., 2001], and the former was therefore not recommended for the routine management of adults with ischemic stroke [Bath et al., 2001]. Low-molecular-weight heparin has become established as the first choice for acute anticoagulant therapy in children. Advantages over standard heparin include a better safety profile, ease of administration (twice-daily subcutaneous injections), and simplicity of monitoring (once weekly or monthly anti-factor Xa levels are usually adequate). In studies of pediatric patients treated for systemic clots with low-molecular-weight heparin, no significant hemorrhagic complications occurred in 100 children [Massicotte et al.,

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1996]. Data supporting the safety of low-molecular-weight heparin for acute pediatric arterial ischemic stroke has been published [Burak et al., 2003; deVeber and Canadian Paediatric Ischemic Stroke Study Group, 2000; Ng et al., 2002a; Strater et al., 2001] and treatment of children with cerebral sinovenous thrombosis with low-molecular-weight heparin also appears to be safe [deVeber et al., 2001]. Indications for either standard or low-molecular-weight heparin in children with arterial ischemic stroke include arterial dissection, coagulation disorders, and a high risk of embolism, such as from the heart in the presence of some congenital and acquired disorders [Andrew and deVeber, 1999; Roach and Riela, 1995]. Acute anticoagulation also seems reasonable for treatment of a child with progressing neurologic deficit not due to cerebral hemorrhage during the initial evaluation of a new cerebral infarction [Roach and Riela, 1995]. The recent recommendations of the American Academy of Chest Physicians (AACP) include the use of initial low-molecularweight or unfractionated heparin at full treatment doses for 5 to 7 days in children with nonhemorrhagic arterial ischemic stroke until dissection or cardiac clot have been excluded [Monagle et al., 2004]. Pediatric stroke guidelines published in the United Kingdom suggest initial aspirin therapy followed by anticoagulation if dissection or cardiac clot are found on investigations [Paediatric Stroke Working Group, 2004].

Box 72-3 PROTOCOL FOR SUBCUTANEOUS ENOXAPARIN THERAPY TO MAINTAIN AN ANTI-XA LEVEL 4 TO 6 HOURS POST-DOSE OF 0.5 TO 1.0 U/ML FOR PEDIATRIC PATIENTS I. Initial maintenance dose: 1.5 mg/kg/dose q12h for infants younger than 2 months of age. II. Initial maintenance dose: 1.0 mg/kg/dose q12h for infants 2 months of age or older and children. III. Adjust low-molecular-weight heparin dose to maintain an anti-Xa level of 0.5 to1.0 U/mL. AntiFactor Xa Level* < 0.35

Hold Next Dose?

Dose Change

No

Increase by 25% Increase by 10% No

0.35-0.49 No 0.5-1.0

No

1.1-1.5

No

1.6-2.0

3h

> 2.0

Until antiDecrease factor by 40% Xa = 0.5 U/mL

Decrease by 20% Decrease by 30%

Repeat AntiFactor Xa 4 h after next dose 4 h after next dose Next day, then 1 wk later, then monthly Before next dose Before next dose, then 4 h after next dose Before next dose; if not <0.5 U/mL, repeat q12h

Note: Enoxaparin has an anti-factor Xa level of 110 U/mg. Adapted from Monagle P, Michelson AD, Bovill E, Andrew M. Antithrombotic therapy in children. Chest 2001;119(1 Suppl):344S–370S.

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Low-molecular-weight heparins used in children include Lovenox, (Rhone-Poulenc) and Reviparin. Lovenox is given to children subcutaneously at doses of 1 mg/kg every 12 hours (or in infants 2 months of age or younger, 1.5 mg/kg every 12 hours) [Massicotte et al., 1996]. Reviparin dosing for infants and children weighing more than 5 kg is 100 units/kg every 12 hours. Anti-factor Xa levels are used for monitoring low-molecular-weight heparins because the activated partial thromboplastin time does not reflect their activity. The therapeutic range for anti-factor Xa levels is 0.5 to 1.0 units/mL in a sample drawn 4 to 6 hours after the subcutaneous dose. Once therapeutic levels are attained, a weekly check on the antifactor Xa level is usually sufficient. The initial dosage and nomogram for adjusting the dosage of enoxaparin, the most commonly used low-molecular-weight heparin, are presented in Box 72-3. Low-molecular-weight heparin can be administered using a subcutaneous catheter, which is replaced weekly, further reducing the number of needles required. Because this compound is cleared via the kidneys, its use in patients with renal failure requires close monitoring.

ASPIRIN AND OTHER ANTIPLATELET AGENTS Aspirin inhibits platelet aggregation by inhibiting the production of thromboxane A2 within platelets. Thromboxane A2 is the principal determinant of the aggregating activity of platelets. The traditional role of aspirin in arterial ischemic stroke has been as an agent for the secondary prevention of recurrent stroke following transient ischemic attack or stroke. In adults, aspirin reduces recurrent stroke by approximately 25% [Albers et al., 2001; Sandercock et al., 1993]. There appears to be a modest benefit from immediate aspirin therapy in acute ischemic stroke [Bousser, 1997; International Stroke Trial Collaborative Group, 1997;]; for longer-term stroke prevention, aspirin is equivalent to warfarin [Mohr et al., 2001]. No clinical trials assessing the efficacy of aspirin for stroke in childhood have been performed. However, aspirin at doses of 1 to 5 mg/kg/day has been found to be safe in children following arterial ischemic stroke [Strater et al., 2001]. The recommended dosage is 1 to 5 mg/ kg/day. Grouping the dosage into every-other-day scheduling is feasible because of the prolonged effect of the medication on platelet function. Side effects of aspirin are usually mild and include gastric upset, easy bruising and, extremely rare at this dose, hemorrhagic complications. Because of the previous association of Reye’s syndrome and aspirin at antipyretic dosages (40 to 60 mg/kg/day) [Hall, 1990], there has been a reluctance to prescribe aspirin for small children. The antiplatelet dosage of 3 to 5 mg/kg/day is less than 10% of the antipyretic doses at which Reye’s syndrome occurred, and to date no case of Reye’s syndrome has been reported at these doses. Because of the concern about Reye’s syndrome, however, precautions such as annual influenza vaccination and reduction of aspirin dosage during febrile illnesses should be observed. Other antiplatelet drugs used in adults for stroke prevention include ticlopidine and clopidogrel (Plavix), both of which are thienopyridines. Both drugs selectively inhibit ADP-induced platelet aggregation via inhibition of the P2Y12 receptor [Ito et al., 1992; Savi et al., 1996]. These agents may offer additional benefit over aspirin alone

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[CAPRIE Steering Committee, 1996]. Use of these medications has been limited in children; however, clopidogrel, at doses of approximately 1 mg/kg/day, is currently being used for stroke in children unable to take aspirin [Hune et al., 2004].

WARFARIN Warfarin and other coumarin anticoagulants reduce the activity of vitamin K–dependent coagulation factors in a dose-dependent manner. Although they may not reduce established clot, they do help prevent further clot formation. The anticoagulant effect occurs in 36 to 72 hours after beginning daily administration. Warfarin is used in adults for the secondary prevention of stroke in situations in which aspirin therapy has failed or is predicted to be insufficient, including nonvalvular atrial fibrillation. The Warfarin Aspirin Recurrent Stroke Study (WARSS) recently reported that warfarin and aspirin are equivalent for the prevention of recurrent stroke in adults [Mohr et al., 2001]. However, a 30% risk reduction (P = 0.02) was found for warfarin compared with aspirin in nonhypertensive patients with cryptogenic stroke and with infarcts located in the cerebral convexity, or in the convexity plus a deep ispilateral infarct, and in those patients whose infarct was “large and deep,” beyond the size boundaries usually considered examples of lacunar infarction (macro-lacunes) [Mohr, 2004]. The latter subtypes of stroke most closely correspond to childhood arterial ischemic stroke, and the implication of this finding is that warfarin may be superior to aspirin for preventing recurrent arterial ischemic stroke in children. The risk of hemorrhage in children appears to be low [Ng et al., 2002b]. The risk of hemorrhage in adults with stroke is increased in the presence of persistent hypertension and advanced age, factors that are rarely or not applicable to children with stroke. A randomized, controlled trial assessing aspirin compared with anticoagulants in pediatric stroke is under development. In children with cerebrovascular disorders, the major uses of warfarin treatment include long-term treatment for congenital or acquired heart disease, severe hypercoaguable states, arterial dissection, and recurrent arterial ischemic stroke or transient ischemic attack while the patient is taking aspirin. An international normalized ratio of 2.0 to 3.0 is appropriate for most children on warfarin; for children with mechanical heart valves, the international normalized ratio should be 2.5 to 3.5. A nomogram for dose adjustment is shown in Box 72-4 [Monagle et al., 2004]. Because of low levels of Vitamin K in breast milk, safe dosing of warfarin is very difficult in breast-fed infants. Older children may be resistant to oral anticoagulants because of impaired absorption or an excessive amount of Vitamin K in total parenteral nutrition formulas. Experience with long-term anticoagulation to prevent cerebral infarction in children is limited, and there is an additional concern about giving anticoagulants to an active child who may be prone to minor injuries through normal activities. The concern that active children may have an increased risk of hemorrhage due to trauma seems to be largely unfounded, although it is recommended that these children avoid activities that carry an especially high risk of injury (e.g., contact sports). Nevertheless, warfarin is the most effective means of prolonged anticoagulation in children, and clinical experience suggests that warfarin can be used with reasonable safety.

Box 72-4 PROTOCOL FOR ORAL ANTICOAGULATION THERAPY TO MAINTAIN AN INR BETWEEN 2 AND 3 FOR PEDIATRIC PATIENTS I. Dose 1: If the baseline INR is 1.0 to 1.3: Dose = 0.2 mg/kg orally II. Guidelines for loading doses 2-4: INR 1.1-1.4 1.5-1.9 2.0-3.0 3.0-3.5 >3.5

Action Repeat loading dose 50% of loading dose 50% of loading dose 25% of loading dose Hold until INR <3.5; then restart at 50% less than the previous dose

III. Long-term oral anticoagulation dose guidelines: INR 1.1-1.4 1.5-1.9 2.0-3.0 3.1-3.5 >3.5

ACTION Increase by 20% of dose Increase by 10% of dose No change Decrease by 20% of dose Check INR daily until INR <3.5; then restart at 20% less than the previous dose

INR, international normalized ratio. From Michelson AD, Bovill E, Andrew M. Antithrombotic therapy in children. Chest 1995;108:506S. Reproduced with permission.

THROMBOLYTIC AGENTS Thrombolytic agents include recombinant tissue-type plasminogen activator (t-PA), urokinase, prourokinase, and streptokinase. These agents act by converting endogenous plasminogen to plasmin, with the goal of dissolving existing thrombus and recanalizing the occluded blood vessel. A high rate of hemorrhagic complications has limited their use in the past.The use of intravenous t-PA in adults with arterial ischemic stroke has been approved by the U.S. Food and Drug Administration for treating acute ischemic stroke within 3 hours of onset of symptoms, based on the randomized, controlled trial reporting a 30% reduction in death and disability with this therapy [The National Institute of Neurologic Disorders and Stroke rt-PA Stroke Study Group, 1995]. In subsequent trials involving more than 5000 adults with stroke, similar outcome rates have been achieved by following the strict NINDS protocol; however, mortality rates are increased when protocol violations occur, including tPA administration after the 3-hour window [Meschia et al., 2002]. Intra-arterial prourokinase (proUK) given 3 to 6 hours after stroke symptom onset has been assessed in clinical trials in adults. This approach, which delivers an increased concentration of thrombolytic drug to the occlusive thrombus, has been associated with a recanalization rate of 66% for the proUK group compared with 18% for the control group in a randomized, controlled trial (P < 0.001). The clinical outcome was also improved at 90 days with recombinant proUK despite an increased frequency of early symptomatic intracranial hemorrhage [Furlan et al., 1999]. The risk of symptomatic intracranial hemorrhage was increased in the presence of acute hyperglycemia [Kase et al., 2001]. Literature reviews and prospective cohort studies of children with extracranial thrombosis treated with throm-

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bolytic agents have shown that although thrombus resolution was achieved in 80% of patients, minor bleeding (not requiring transfusion therapy) was found in over 50% in a pooled literature analysis [Leaker et al., 1996] and in approximately 25% in cohort studies [Leaker et al., 1996]. These bleeding rates suggest that thrombolytic agents should be used with caution in children, particularly because the presence of cerebral infarction would be predicted to increase the risk of intracranial hemorrhage. Recently a low-dose tPA regimen (10% of the standard tPA dose) was assessed in 17 children with systemic thrombosis [Wang et al., 2003]. This regimen was associated with thrombus resolution in approximately 70% of children with “acute” thromboses but required longer duration of therapy than standard tPA dosing. Thrombolytic agents have not been evaluated in children with arterial ischemic stroke, although several case reports have now been published [Carlson et al., 2001; Cognard et al., 2000; Gruber et al., 2000; Noser et al., 2001]. Theoretically, thrombolytic agents have the potential to be effective as an acute therapy for children with arterial ischemic stroke. However, there are significant concerns about their safety because of unique features of children and childhood arterial ischemic stroke, in particular, the lack of confidence in the diagnosis of arterial ischemic stroke very early in the course. There is a much wider differential diagnosis for acute-onset neurologic deficit in a child with a normal early CT scan than in an adult. Given the risks of intracranial hemorrhage observed in adults who receive thrombolysis when CT shows early signs of the infarct, the risk for bleeding complications of treatment is likely to be unacceptably high in infants and children with CT signs of established arterial ischemic stroke. Clinical trials evaluating the efficacy of thrombolytic agents in pediatric arterial ischemic stroke are not feasible as yet because of the frequent delay in diagnosis of arterial ischemic stroke in children and the lack of safety data. As the availability of urgent MRI and clinical awareness of pediatric arterial ischemic stroke increase, early diagnosis of this disorder is becoming feasible. Safety studies of tPA in children who arrive at the hospital within the time window for thrombolysis are currently enrolling patients. However, until safety data are available, thombolytic agents as initial stroke therapy in young children with arterial ischemic stroke should be considered potentially dangerous.

Nonantithrombotic Therapies ACUTE SUPPORTIVE AND NEUROPROTECTIVE CARE Children with suspected acute stroke should be stabilized promptly and transferred for further management to an institution that can offer specialized pediatric neurovascular care [Hutchison et al., 2004; Paediatric Stroke Working Group, 2004]. Because autoregulation of the cerebral vasculature is impaired during acute stroke, careful supportive therapy, including blood pressure and fluid management, is mandatory. Serum glucose should be carefully monitored because hyperglycemia is known to exacerbate the size of the infarct whereas hypoglycemia will also worsen the effects of stroke [Baird et al., 2003; Yager and Thornhill, 1997]. Maintenance of low-to-normal body temperature is important because hyperthermia exacerbates ischemic brain damage, whereas

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hypothermia is known to protect against brain damage, including in neonates with hypoxic ischemic encephalopathy [Gluckman et al., 2005; Krieger and Yenari, 2004; Rutherford et al., 2005; Volpe, 2001b]. In adults with stroke, induced hypothermia is feasible but is associated with serious side effects including hypotension, cardiac arrhythmia, and pneumonia [Olsen et al., 2003]. The early use of antiepileptic drugs in children with seizures associated with arterial ischemic stroke is important in order to prevent recurrent seizures that may increase the eventual infarct volume [Wirrell et al., 2001]. Development of malignant cerebral edema within the infarct zone and intracranial hypertension in the first week after acute arterial ischemic stroke may require treatment with intravenous mannitol and hypertonic saline. No beneficial effects of steroids have been demonstrated in adults or children with stroke.

NEUROPROTECTIVE AGENTS The chain of events occurring at a cellular level in ischemic injury and leading to neuronal death after stroke suggests several potential neuroprotective treatment strategies. In animal studies, several neuroprotective agents given within 6 to 12 hours after stroke onset have been associated with a reduction in infarct volume [Ginsberg and Pulsinelli 1997]. A combination of fibrinolytic and neuroprotective treatments also has been shown to reduce infarct size in animals [Lapchak and Zivin, 2003]. Despite the completion of many human trials, neuroprotective agents have yet to show convincing benefits in adults with arterial ischemic stroke. Whether such agents can be applied to the pediatric stroke population in the future remains to be determined. Unfortunately, irreversible neuronal changes will likely occur before treatment can be initiated in most children with arterial ischemic stroke unless early diagnosis is made. In addition, the effect of such medications on normal maturation and learning processes will require evaluation prior to treatment trials in pediatric patients.

IMMUNOSUPPRESSANT THERAPY In patients with proven vasculitis or suspected IACNS and, in consultation with rheumatology colleagues, immunosuppressive agents such as prednisone or cyclophosphamide may be indicated (see Chapter 73).

TRANSFUSION THERAPY For children with sickle cell disease and stroke, long-term transfusion is effective for primary stroke prevention in patients with large-vessel vasculopathy [Adams et al., 1998]. During exchange transfusion it is important to guard against large fluid shifts, as this may increase infarct size.

NEUROSURGICAL PROCEDURES The use of intracranial pressure monitoring in patients with large-arterial ischemic strokes who have significant cerebral edema is controversial. In patients with large strokes, a decreasing level of consciousness and midline shift are indicators of impending herniation. In the latter situation, emergency decompressive hemicraniectomy can be a life-saving

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procedure and is associated with good outcomes in young stroke patients [Gupta et al., 2004]. Hemicraniectomy is currently being assessed in adults in a multicenter randomized, controlled trial [Hofmeijer et al., 2003; Schwab et al., 1998]. Early experience with hemicraniectomy in children with progressive edema has been promising. Additional neurosurgical procedures in children with arterial ischemic stroke include revascularization techniques for moyamoya disease; in some patients. Evacuation of hematomas associated with infarction may be necessary to reduce local, compressive mass effects.

INTERVENTIONAL NEURORADIOLOGIC TECHNIQUES Intra-arterial thrombolysis has been discussed in a previous section. More aggressive interventional angiographic techniques, including angioplasty, clot retrieval, and stenting of cerebral arteries, are now available for adults with arterial ischemic stroke, and these remain largely unproven and carry significant risks. Their extension to the management of children with arterial ischemic stroke may not be feasible or safe. The smaller caliber and thinner walls of cerebral arteries in children may place them at increased risk for complications from these techniques, such as thrombosis, rupture, and dissection. In addition, long-term complications following these maneuvers, as the cerebral vasculature develops over many decades, are unknown and present additional concerns. Consecutive cohort safety studies are not yet available for pediatric arterial ischemic stroke but are a necessary precursor to the use of these techniques in children.

REHABILITATION THERAPY Rehabilitation therapies for adults with stroke are gaining an increasing base of evidence. For motor deficits, evidence now supports task-specific approaches and constraint-induced therapy as being more effective than traditional approaches that focus on impairment [Teasell and Kalra, 2004].

Constraint-induced therapy has been shown in a randomized, controlled trial to be effective in children with congenital hemiplegia [Taub et al., 2004]. Botulinum A (botox) injection is an option that is increasingly used for temporary relief of limb hypertonia associated with dystonia or spasticity in children with arterial ischemic stroke. Evidence for this approach is available in populations of children with cerebral palsy and adults with stroke [Bhakta et al., 2000; Fehlings et al., 2000]. Systematic studies assessing speech, occupational, physical, and psychologic therapies in pediatric arterial ischemic stroke are urgently needed. Given the frequency of potentially modifiable neurologic impairments and the known risk of increasing clinical deficits as the child matures, early and aggressive rehabilitation therapy initiated during acute hospitalization for children with persistent deficits is recommended [Paediatric Stroke Working Group, 2004]. Compared with adult stroke victims, infants and young children have additional rehabilitation considerations, including greater complexity of feeding dysfunction and speech therapy, ongoing modification of rehabilitation as the child grows and develops age-related skills, and the potential for ongoing recovery over longer periods of time. Hemiatrophy of affected limbs can create orthopedic problems such as leg length discrepancy and scoliosis. In addition, learning and behavioral deficits unique to this population are common and require intervention by specialized pediatric rehabilitation and education teams. Parents may need encouragement to avoid “overprotection” and to treat the affected child as normally as possible.

SPECIALIZED STROKE CARE Given the lack of clinical trials and evidence-based treatments of pediatric arterial ischemic stroke, its relative infrequency, and the proven benefit of specialized stroke care in adults, referral to tertiary care centers with expertise in the management of childhood arterial ischemic stroke should be made when feasible. In the care of the child with arterial ischemic stroke, a team approach including pediatric neurol-

Box 72-5 LITERATURE SUMMARY OF OUTCOME IN CHILDREN WITH ARTERIAL ISCHEMIC STROKE Author, Year Isler et al., 1984 Dusser, 1986

Study N Death Normal (Mean FU) 87 (30 y) 44

Lanska, 1991 — Broderick et al., 1993 7 Ganesan et al., 1999 39 de Schryver et al., 2000 37 (7 y) deVeber, 2000b 126 deVeber, 2000 660 Lanthier et al., 2000 51 Delsing et al., 2001 31 (3.5 y) Steinlin et al., 2004

18 (7 y)

Neurologic Deficits

Seizures

Recurrent Stroke

Predictors of Poor Outcome — “Symptomatic” stroke — — Large infarct volume —

— —

10% 18%

90% >82%

50% 29%

20% —

— 14% 5% 11% NA 10% 16% 13%

17% — 32% 41% 33% 34% 35% 29%

83% — 63% 59% 66% 56% 49% 58%

19% — — 24% 13% 10% 4%

— — — 27% 11% 19% 16% 22%

2

2

78% handicap 72% handicap

3

Multiple RFs ↓LOC, Sz, large MCA infarct Combined cortical and subcortical infarcts

N, number of patients in study; FU, follow-up period; LOC, level of conciousness; Sz, seizures; MCA, middle cerebral artery; neuropsych, neuropsychologic deficits; Rf, risk factors.

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ogists, pediatric hematologists, and other subspecialists is important in order to appropriately individualize investigations and therapy [Paediatric Stroke Working Group, 2004].

Outcome In general, children are observed to recover a greater degree of function and for longer periods of time than adults with the same type of arterial ischemic stroke. The published literature on outcome following pediatric arterial ischemic stroke is summarized in Box 72-5. Following childhood arterial ischemic stroke, the most frequently reported neurologic impairment is hemiparesis (see Fig. 72-6B). However, less obvious residual deficits, including speech and other cortical deficits and subtle problems in learning, socialization, and behavior, also occur and contribute to a reduced quality of life in children with stroke [De Schryver et al., 2000; Friefeld et al., 2004; Steinlin et al., 2004]. Recently, verbal learning and memory have been found to be significantly decreased in children following stroke [Lansing et al., 2004; Max, 2004; Nass and Trauner, 2004]. Younger age at stroke (less than 12 months) was associated with worse outcomes than older age at stroke (more than 12 months) and, in contrast to adults, verbal learning and memory deficits were similar for right and left hemisphere lesions. Movement disorders such as dystonia after basal ganglia infarction have been documented to develop more frequently in children compared with adults, and these can become disabling [Kwak and Jankovic, 2002; Nardocci et al., 1996]. Older studies reported residual neurologic deficits in over 75% of infants and children. [Eeg-Olofsson and Ringheim, 1983; Higgins et al., 1991; Satoh et al., 1988, 1991; Schoenberg et al., 1978]. In more recent population-based studies following neonatal arterial ischemic stroke, a normal outcome was reported in 50% of patients at 9 months’ average follow-up interval. The remaining patients had a seizure disorder or neurologic deficit [deVeber and Canadian Paediatric Ischemic Stroke Study Group, 2000]. In children in whom arterial ischemic stroke occurred beyond the neonatal period, outcomes include death in 5% to 13%, neurologic deficits in 56% to 63% of survivors (which are severe in about half), and no neurologic deficit in 29% to 34% [Delsing et al., 2001; deVeber et al., 2000]. Death is related to the underlying infarct in approximately half of the children. Mechanisms of death in adults with arterial ischemic stroke are time-related [Derouesne et al., 1993]. Transtentorial herniation, the main cerebral cause of death, occurs mainly in the first week and is related to large infarcts. The improved outcome reported in more recent studies of childhood arterial ischemic stroke may reflect the detection of milder forms of stroke enabled by MRI, an increasing trend to use of antithrombotic therapy for this condition, and sources of bias inherent in retrospective study design, which may overestimate abnormal outcome. Another important study design factor is the duration of follow-up interval. The emergence of later neurologic deficits, including subtle learning problems, as the child develops emphasizes the need for longer-term studies over many years in order to accurately define outcome. Factors predicting poor outcome in childhood arterial ischemic stroke include age younger than 12 months, presentation with an altered level of consciousness or seizures,

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and infarcts occupying more than 10% of intracranial volume [Delsing et al., 2001; Ganesan et al., 2000; Lansing et al., 2004; Max, 2004]. For both neonates and older children with arterial ischemic stroke, the worst outcome is predicted by the presence of bilateral infarction or of infarction involving both the internal capsule and the cortical middle cerebral artery territory [Golomb et al., 2003; Mercuri et al., 2004]. Neonates having an abnormal background EEG also have worse outcomes [Mercuri et al., 1999]. The likelihood of adverse outcomes following arterial ischemic stroke in neonates and children appears to be increased when prothrombotic abnormalities are defined. Elevated factor VIII (greater than 150 IU per dL and Ddimer levels (greater than 500 ng per mL) at diagnosis have been associated with worse outcomes in neonates and children with thrombotic disorders including stroke [Goldenberg et al., 2004]. In neonates with arterial ischemic stroke the presence of prothrombotic abnormalities, especially factor V Leiden, has been associated with worse outcome [Mercuri et al., 2001]. The reported risk of recurrent stroke or transient ischemic attack in older infants and children ranges from 7% to 35% [deVeber et al., 2000; De Schryver et al., 2000; Chabrier et al., 2000; Isler, 1984; Lanthier et al., 2000, 2004]. In children not treated with antithrombotic therapies, recurrence approaches 50% [Lanthier et al., 2004]. Recurrence is highly correlated with certain etiologies of arterial ischemic stroke, including the presence of an underlying vasculopathy and multiple risk factors [Chabrier et al., 2000; Lanthier et al., 2004].

SINOVENOUS THROMBOSIS Pathophysiology Sinovenous Circulation: Anatomy and Physiology The venous drainage of the brain is achieved by a network of cerebral veins and sinuses (Fig. 72-12). Cerebral sinuses are external to the brain and are enclosed between two layers of fibrous dura mater, the outermost layer being attached to bone along bony suture lines. Because of their rigid attachments, sinuses tend to have a fixed open lumen, and cerebral venous drainage is passive [Capra and Anderson, 1984]. The caliber of sinuses is unresponsive to changes in systemic blood pressure. These factors, combined with the lack of valves in the cerebral veins and sinuses, result in slow flow and the potential for flow reversal. This is in contrast to venous flow in limb veins, in which mechanical pumping action exerted on limb veins by muscle activity, combined with the presence of valves, encourages forward venous flow. Compensating in part for these factors is the effect of gravity when the head is in the upright position. The superior sagittal sinus is the principal site of the absorption of cerebrospinal fluid. This process occurs as the cerebrospinal fluid is absorbed into “arachnoid granulations,” highly vascular structures that protrude across the walls of the sagittal sinus into the subarachnoid space and that drain into the venous system. In sagittal sinus thrombosis or sinus hypertension, the arachnoid granulations become nonfunctional, resulting in communicating hydrocephalus [Bousser and Russell, 1997].

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Tumors and Vascular Disorders of the Nervous System / 72 FIGURE 72-12. Lateral view of the cerebral veins.

Superior sagittal sinus

Frontal cerebral vein

Rolandic vein of Trolard

Parietal ascending vein

Inferior sagittal sinus

Straight sinus

Internal cerebral vein

Thalamastriate veins

Vein of Galen

Descending temporal occipital vein Basal vein of Rosenthal Communicating vein of Labbe` Transverse sinus

The principal “superficial venous system” of the brain is provided by cortical veins that drain into the superior sagittal sinus. In most individuals, the superior sagittal sinus empties predominantly into the right lateral sinus (with transverse and sigmoid sinus portions) and the jugular vein. The “deep venous system” includes the inferior sagittal sinus and the paired internal cerebral veins, which join to form the vein of Galen and the straight sinus. This deep system drains predominantly into the smaller-caliber left lateral sinus and jugular vein system [Woodhall, 1936] (see Fig. 72-12). Anteriorly, the paired cavernous sinuses communicate with the jugular system via the petrosal sinuses.

tions (e.g., L-asparaginase) clearly increase clotting risk (Fig. 72-13). Prothrombotic abnormalities play a relatively more important role in promoting venous thrombosis than arterial thrombosis. Mechanical distortion of the major dural sinuses along the bony suture lines occurs during calvarial molding during the birth process [Newton and Gooding, 1975].

Mechanisms of Thromboembolism Different factors mediate thrombosis in cerebral sinovenous thrombosis compared with arterial ischemic stroke. In septic cerebral sinovenous thrombosis, a bacterial infection adjacent to the sinuses spreads directly into the sinus, provoking thrombophlebitis. In nonseptic cerebral sinovenous thrombosis, the exact mechanism that initiates thrombosis is not always evident. Platelets appear to play a minimal role in venous thromboembolism, in contrast to the situation in arterial ischemic stroke. There is a relative absence of thrombomodulin in the lining of cerebral sinuses, which may further increase the tendency to thrombosis [Lin et al., 1994]. Because of relatively slower blood flow, the initial formation and subsequent propagation of thrombus may be more likely to occur in cerebral venous channels than in cerebral arteries. Dehydration is a potent risk factor for cerebral sinovenous thrombosis because of hemoconcentration and impaired laminar flow. Inherited or acquired specific coagulation abnormalities including prothrombotic medica-

FIGURE 72-13. Sagittal T1-weighted MRI shows superior sagittal sinus thrombosis in an 11-year-old male with non-Hodgkins lymphoma following L-asparaginase chemotherapy. (Courtesy of Division of Neuroradiology, Hospital for Sick Children, Toronto, Ontario, Canada.)

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A

B

C

D

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FIGURE 72-14. Nine-month-old female with sinovenous thrombosis after dehydration with iron deficiency anemia. A, CT scan without contrast enhancement shows high-density clot within the internal cerebral veins and straight sinus and right thalamic venous infarct (bland). B and C, Axial and coronal CT scans with contrast enhancement show left cerebellar venous infarct and left lateral sinus thrombus with dural enhancement (“empty triangle”sign). D, MR venography scan (coronal) confirms left transverse sinus thrombosis and nonvisualization of the internal sinovenous system (internal cerebral veins and straight sinus). (Courtesy of Manohar Shroff, Division of Neuroradiology, Hospital for Sick Children, Toronto, Ontario, Canada.)

Mechanisms of Infarction Occlusion of cerebral venous structures initiates a rise in cerebral venous pressure, which, when sudden and severe, results in increased intracranial pressure either diffusely or regionally in the cerebral territory drained by the thrombosed veins. Local tissue pressure elevation results in marked edema as a result of transudation of fluid across

venous or capillary channels. Parenchymal lesions can be transient and reversible, likely representing acute focal edema, or permanent, representing tissue infarction (Fig. 72-14A). The increased pressure across capillary channels also accounts for an increased rate of hemorrhagic conversion of infarcts compared with that found in arterial ischemic stroke (Fig. 72-15). Tissue infarction results when the regional increased tissue pressure exceeds the regional arterial

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Tumors and Vascular Disorders of the Nervous System / 72

Galen or both may produce thalamic infarction, at times bilateral (see Fig. 72-14A) or intraventricular hemorrhage. However, the site of cerebral sinovenous thrombosis, location of cerebral venous infarction, and type of clinical deficit do not follow the highly correlated patterns seen in arterial ischemic stroke.

Clinical Features

FIGURE 72-15. CT scan without contrast enhancement shows bilateral hemorrhagic venous infarcts due to cerebral sinovenous thrombosis in a 5-week-old infant male with gastroenteritis and dehydration. (Courtesy of Dr. Laurence Friedman, Children’s Hospital at Chedoke-McMaster, Ontario, Canada.)

perfusion pressure. Venous infarction is more likely to occur with total occlusion of the sinus or venous lumen, in particular if the entry point of cerebral veins is occluded, and with more rapid rates of occlusion when pial venous collaterals cannot rapidly compensate for the obstruction of venous flow (see Fig. 72-14B and C) [Bousser and Russell, 1997]. Diffusion-weighted imaging studiesof evolving venous infarction demonstrate that initially areas of restricted diffusion (cytotoxic edema) appear to correlate with evolving venous infarction [Carvalho et al., 2001; Forbes et al., 2001]. Unlike the situation in arterial ischemic stroke, early increased diffusion changes are potentially reversible [Ducreux et al., 2001]. When the superior sagittal sinus is occluded, diffusely increased intracranial pressure results from venous congestion as well as from impaired cerebrospinal fluid absorption and a superimposed communicating hydrocephalus. In contrast to cerebral arterial ischemia, in venous occlusion the affected brain is a zone of prolonged increased venous pressure. As a result, delayed recanalization of the obstruction to venous drainage days and possibly weeks after the initial occlusion can potentially relieve circulatory congestion. At the same time, the low pressure and slower blood flow in the sinovenous system compared with the arterial circulation increases the potential for thrombus propagation throughout the sinovenous system. Accordingly, the role of antithrombotic treatment for cerebral sinovenous thrombosis can be expected to differ from that used for arterial ischemic stroke [Tsao et al., 1999].

Vascular Patterns of Cerebral Sinovenous Thrombosis Bilateral cortical infarcts, often hemorrhagic, are typical of sagittal sinus thrombosis. Deep venous thrombosis involving the internal cerebral veins, straight sinus or vein of

The clinical features of cerebral sinovenous thrombosis may be subtle or overshadowed by concomitant diffuse neurologic syndromes—for example, in a critically ill child with hypoxia or meningitis. Clinical features are age-related. In general, diffuse neurologic signs and seizures at presentation are frequent and focal signs are rare. Typically, the clinical features of cerebral sinovenous thrombosis are subtle and develop gradually over many hours, days, or occasionally, over many weeks. Neonates and infants less than 1 year of age constitute approximately half of pediatric patients with cerebral sinovenous thrombosis [deVeber et al., 2001; Carvalho et al., 2001]. Males are affected up to twice as frequently as females [Carvalho et al., 2001]. Infants present with seizures, lethargy or jitteriness, with an absence of focal signs [Barron et al., 1992; Carvalho et al., 2001; deVeber et al., 2001; Rivkin et al., 1992]. Seizures occur in over three fourths of neonates compared to nearly half of older infants and children. Hemiparesis is present in only 6% of neonates and 20% of older infants and children [deVeber et al., 2001]. External signs including dilated scalp veins, prominent anterior fontanel, and eyelid swelling have been reported in infants with severe cerebral sinovenous thrombosis [Hartmann et al., 1987] but are rare. Older infants and preschool-age children frequently present with fever, vomiting, and seizures and, occasionally, focal signs. Older children can present with signs and symptoms suggestive of “idiopathic intracranial hypertension,” including headache, papilledema, abducens palsy, and altered levels of consciousness. This clinical presentation is especially frequent when the superior sagittal sinus is the site of thrombosis. Seizures and focal signs including hemiparesis may be superimposed [Barron et al., 1992; deVeber et al., 2001]. Children beyond the neonatal period with cerebral sinovenous thrombosis in the Canadian Registry presented with seizures in 48%, headache in 54%, papilledema in 22%, altered consciousness in 49% and focal neurologic signs in 53% [deVeber et al., 2001]. Recently, a series of 11 children with idiopathic intracranial hypertension were found to have underlying cerebral sinovenous thrombosis, and this study included four children with only lateral sinus thrombosis [Reul et al., 1997]. Clinically unsuspected cerebral sinovenous thrombosis has been found in 25% of children with idiopathic intracranial hypertension undergoing angiography [Ameri and Bousser, 1992], emphasizing the need for a high degree of clinical suspicion. In adults with idiopathic intracranial hypertension, stenosis of the lateral sinuses has been documented in over 90% of patients; however, whether these sinus abnormalities represent the cause of intracranial hypertension or are secondary compression of sinus channels by mass effect is not known [Farb et al., 2003a].

deVeber / Cerebrovascular Disease

Risk Factors Traditionally, cerebral sinovenous thrombosis was classified into “septic” and “non-septic” etiologies. Septic cerebral sinovenous thrombosis is defined as thrombosis of venous sinuses associated with head and neck infections such as otitis media, mastoiditis, and sinusitis, has dramatically decreased in incidence but still accounts for 18% of cases of pediatric cerebral sinovenous thrombosis [deVeber et al., 2001]. Risk factors are definable in most children and are frequently multiple. In a prospective population-based study (n = 160), risk factors consisted of prothrombotic disorders in 41% of children, dehydration in 25%, systemic infection in 9%, head and neck infection in 18%, other head and neck disorders in 12%, hematologic disorders in 12%, malignancy in 8%, and cardiac disease in 5%. The majority of cancer patients had had L-asparaginase treatment. Multiple risk factors were present in 65% of patients, with 40% having more than three [deVeber et al., 2001]. Risk factors are age-related. Dehydration is especially common in neonates with cerebral sinovenous thrombosis (see Fig. 72-15). Hematologic disorders, including anemia and structural cardiac disease, predominate in older infants. Iron deficiency anemia has been increasingly reported in older infants with cerebral sinovenous thrombosis and may be an important risk factor [Belman et al., 1990; Hartfield et al., 1997; Meena et al., 2000; Sébire et al., 2005]. Head and neck infections are present in nearly one third of preschoolage children with cerebral sinovenous thrombosis. Chronic systemic diseases are an underlying risk factor in approximately 60% and are clustered in the older age groups. These include systemic lupus erythematosus, nephrotic syndrome, inflammatory bowel disease, hematologic disorders, underlying cardiac disease, and malignancy [deVeber et al., 2001]. The mechanism for sinovenous thrombosis in most chronic diseases is that of an acquired prothrombotic state. For example, nephrotic syndrome causes renal loss of antithrombin, resulting in an acquired antithrombin deficiency, and systemic lupus erythematosus may be associated with a lupus anticoagulant. Acute illnesses, including sepsis and dehydration, are present in nearly one third of children with cerebral sinovenous thrombosis. In older children, head trauma or cranial surgery may damage the dural sinuses, leading to cerebral sinovenous thrombosis [Muthukumar, 2004; Sousa et al., 2004]. In one study of 131 children with head injury requiring a cranial CT scan, cerebral sinovenous thrombosis was found in 8 patients (6.1%) [Stiefel et al., 2000]. In another study, head trauma was the etiology in 9 of 19 children with cerebral sinovenous thrombosis [Huisman et al., 2001]. Prothrombotic disorders have been reported in 20% to 80% of pediatric patients with cerebral sinovenous thrombosis [deVeber et al., 1998, 2001; Ganesan et al., 1996; Riikonen et al., 1996; Vielhaber et al., 1998]. These figures exceed estimates in adults, in whom the incidence is 15% to 21% [Deschiens et al., 1996; Zuber et al., 1996]. In children with cerebral sinovenous thrombosis, acquired prothrombotic states are more frequent than congenital prothrombotic disorders. In the largest study to date, 56% of 149 pediatric patients with cerebral sinovenous thrombosis who underwent systematic coagulation testing had prothrombotic ab-

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normalities, compared with only 21% of controls [Heller et al., 2003]. However, another smaller case-control study showed that there was no increase in thrombophilic markers in children with cerebral sinovenous thrombosis compared with controls, except in children with otherwise idiopathic cerebral sinovenous thrombosis [Kenet et al., 2004]. Factor V Leiden, anticardiolipin antibody, elevated lipoprotein (a), activated protein C resistance, and protein C, protein S, and antithrombin deficiencies are the most frequent abnormalities [deVeber et al., 2001; Ganesan et al., 1996; GouaultHeilman et al., 1994; Heller et al., 2003; Martinelli et al., 1996; Riikonen et al., 1996; Vielhaber et al., 1998]. Both hyperhomocystinemia and an excess of homozygotes for the thermolabile variant of the methylene tetrahydrofolate reductase (MTFHR) gene compared to control populations have been reported in children and adults with cerebral sinovenous thrombosis [Bonduel et al., 1999; Buoni et al., 2001; Carhuapoma et al., 1997; Vielhaber et al., 1998]. In children, the prothrombotic abnormality acts as a predisposing risk factor, with additional triggering factors usually present [Heller et al., 2003].

Radiographic Features The radiographic features and diagnostic pitfalls of pediatric cerebral sinovenous thrombosis have been reviewed [Shroff and deVeber, 2003]. The radiographic diagnosis of cerebral sinovenous thrombosis in infants and children is challenging. The location of cerebral sinovenous thrombosis can include any combination of sinuses or veins. However, thrombosis in the superficial system, including the superior sagittal sinus and lateral sinus, predominate (see Fig. 72-13). In the Canadian Registry, thrombosis was located in the superficial system in 86% of infants and children and in the deep system in 38%; nearly half of infants and children (49%) had multiple sinuses or veins involved [deVeber et al., 2001]. Parenchymal lesions such as bland or hemorrhagic venous infarcts are present in nearly half of children with cerebral sinovenous thrombosis (see Figs. 72-14 and 72-15). In the Canadian Registry, 41% had venous infarcts, which were bland in one third and hemorrhagic in two thirds of patients. A small number of patients had transient lowdensity parenchymal lesions [deVeber et al., 2001]. Radiographic diagnosis has significantly improved in recent years with refinements in CT venography, MRI and MR venography (see Fig. 72-14D) [Casey et al., 1996; Dormont et al., 1994; Lewin et al., 1994; Yuh et al., 1994]. However, cerebral angiography may still be required to confirm the diagnosis when CT and MRI findings are inconclusive.

COMPUTED TOMOGRAPHY CT performed with and without contrast administration can occasionally suggest the diagnosis of cerebral sinovenous thrombosis. However, CT misses the diagnosis in 10% to 40% of patients and underestimates the extent of sinus involvement and the presence of infarcts [Ameri and Bousser, 1992; Barron et al., 1992; Bousser and Russell, 1997; Jacewicz and Plum, 1990]. In the Canadian Registry, the diagnosis was missed in 16% of CT scans [deVeber et al., 2001]. CT can also yield false positive results [Hamburger et al., 1990]

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Tumors and Vascular Disorders of the Nervous System / 72

particularly in neonates in whom the increased hematocrit, lower density of unmyelinated brain, and slower venous flow combine to produce a high-density triangle in the torcular area mimicking the “dense triangle” sign [Davies and Slavotinek, 1994; Kriss, 1998; Ludwig et al., 1980]. In addition, subdural hemorrhage layering along the dural walls of the sinuses can be difficult to distinguish from intraluminal thrombus unless high quality coronal images are obtained. Signs of cerebral sinovenous thrombosis on a noncontrast CT include the “filled triangle” or dense triangle signs and the “cord” sign, which represent hyperdense thrombus in sinovenous channels (see Fig. 72-14A). On contrastenhanced CT, an empty triangle or “delta” sign represents bright contrast enhancement of the dura surrounding a sinovenous clot (see Fig. 72-14C). Multislice contrastenhanced CT with the capability of submillimeter slices and excellent multiplanar reformations (CT venography) have significantly improved the ability to diagnose cerebral sinovenous thrombosis; however, the increased radiation dose required for CT venography is a concern.

open fontanel, ultrasound provides an inexpensive noninvasive means of screening for and monitoring the course of cerebral sinovenous thrombosis, but its use has not been systematically assessed. Recent ultrasound techniques, including “power Doppler,” are specifically designed to determine blood flow and have improved the ability of ultrasound to diagnose cerebral sinovenous thrombosis [Bezinque et al., 1995; Dean and Taylor, 1995]. The power Doppler technique measures the energy of moving red blood cells instead of the velocity and direction of flow and is more sensitive for identifying flow in slow-flow states [Tsao et al., 1999]. The major limitation of Doppler ultrasound is in the evaluation of lateral venous sinuses when there is incomplete occlusion, because residual flow may be mistaken for normal flow [Bezinque et al., 1995; Govaert et al., 1992]. In infants, regular cranial ultrasound can be useful to monitor the presence and severity of centrally located intracranial hemorrhage associated with cerebral sinovenous thrombosis.

MAGNETIC RESONANCE IMAGING

Angiography is used in the diagnosis of cerebral sinovenous thrombosis when other techniques cannot confirm the diagnosis, or before intravascular intervention. Classic angiographic findings are similar to those in adults. Partial or complete lack of filling of cerebral veins or sinuses is diagnostic [Ameri and Bousser, 1992]. Angiographic signs that suggest cerebral sinovenous thrombosis include the presence of enlarged collateral veins, delayed venous emptying, reversal of normal venous flow direction, abnormal (broken or corkscrew-like) cortical veins, and regionally or globally delayed venous emptying [Ameri and Bousser, 1992]. Even with angiography, failure to scrutinize the venous phase can result in missing the diagnosis [Scotti et al., 1974], and the distinction between normal left lateral sinus hypoplasia and cerebral sinovenous thrombosis can be difficult [Ameri and Bousser, 1992]. Angiography may cause local thrombosis at the site of catheter insertion, particularly in small infants; however, it is an important alternative to consider when other techniques fail to clarify the diagnosis. In the Canadian Registry, conventional angiography was performed in fewer than 10% of children [deVeber et al., 2001].

The absence of radiation and the ability to visualize both absent flow and the presence of thrombus, clot progression and resolution over time, and associated parenchymal lesions have made MRI the diagnostic study of choice in cerebral sinovenous thrombosis [Ameri and Bousser, 1992; Jacewicz and Plum, 1990; Macchi et al., 1986; Medlock et al., 1992; Zimmerman et al., 1992]. On parenchymal MRI, thrombus appears as an increased signal on T1-weighted and T2weighted images in a cerebral vein or dural sinus. However, slow flow, turbulent flow, angled flow, or flow-related enhancement may produce an increased signal that can mimic intraluminal thrombus. Determining the age of the thrombus may be possible, according to the signal characteristics of the clot [Macchi et al., 1986]. In the subacute phase, a thrombus typically appears as increased signal on T1- and T2-weighted images. MR venography is frequently used to evaluate the cerebral sinovenous system. The 2-dimensional time-of-flight technique has provided increased diagnostic sensitivity compared with parenchymal MRI techniques. However time-of-flight venography depends on flow signal characteristics and is therefore subject to artifacts. It is associated with “flow gap” artifacts in the transverse sinus in up to 30% of normal adults [Ayanzen et al., 2000]. These artifacts are particularly problematic in the smaller, nondominant transverse sinus. In these situations, particularly common in neonates, confirmatory CT venography may be required. A gadolinium-enhanced MR venography technique is now available [Liang et al., 2001; Takano et al., 1999]. This technique involves the injection of a gadolinium bolus, followed by the acquisition of MR images triggered by the arrival of the gadolinium bolus at the vessel of interest. Gadolinium-enhanced MR venography has proved to be superior to conventional time-of-flight venography [Farb et al., 2003b].

ULTRASOUND In unstable, ventilated neonates and young infants, MR venography can be difficult to perform. In the presence of an

CONVENTIONAL ANGIOGRAPHY

Treatment Antithrombotic Therapies The treatment of cerebral sinovenous thrombosis in childhood has been strongly influenced by the results of clinical trials in adults because atherosclerosis is not a factor in either age group. Four randomized, controlled trials in adults with cerebral sinovenous thrombosis have reported variable findings. Three of these trials reported a statistically and clinically significant increase in survival and improved neurologic outcome in patients treated with anticoagulants [Einhaupl et al., 1991; Maiti and Chakrabarti, 1997; Nagaraja D et al., 1995]. The fourth trial failed to demonstrate a difference in outcome with anticoagulant treatment; however, this study was underpowered, given the high proportion of patients with good outcomes on placebo [de Bruijn and Stam, 1999]. A meta-analysis of these four trials showed that heparin reduces death and disability with a “number needed to treat”

deVeber / Cerebrovascular Disease

of 7 patients to prevent death. However the published metaanalysis excluded a trial published only in abstract form (Maiti and Chakrabarti, 1997) and a trial that used only CT for the diagnosis (Nagaraja et al., 1995). The combined results from the remaining two randomized, controlled trials showed only a strong trend toward efficacy [Stam et al., 2003]. All of the above trials showed that heparin was safe in adults with cerebral sinovenous thrombosis, including those with initial cerebral hemorrhage [Nagaraja et al., 1995]. These results are supported by large cohort studies that reported an improved outcome in adults with cerebral sinovenous thrombosis, including those with initial hemorrhage, who were treated with heparin therapy with no increase in hemorrhagic complications [Ameri and Bousser, 1992; Milandre et al., 1989; Preter et al., 1996]. The safety of anticoagulation therapy in children with cerebral sinovenous thrombosis has been established in several studies [deVeber et al., 1998, 2001; Dix et al., 2000; Nagaraja et al., 2002; Streif et al., 1999]. Currently anticoagulants are being used in the majority of childhood cerebral sinovenous thrombosis patients without significant hemorrhagic complications [deVeber et al., 1998]. Recent guidelines recommend anticoagulation for neonates without major hemorrhage and for children with cerebral sinovenous thrombosis [Monagle et al., 2004; Paediatric Stroke Working Group, 2004]. For neonates with cerebral sinovenous thrombosis, unfractionated heparin or low-molecular-weight heparin given for 7 days, followed by low-molecular-weight heparin alone for 6 to 12 weeks, should be considered. For older infants and children, unfractioned heparin or low-molecular-weight heparin given for 7 days, followed by Coumadin for 3 to 6 months, is a treatment option based on the practice in adults. If significant intracerebral hemorrhage is associated with initial cerebral sinovenous thrombosis, the use of anticoagulants in children is controversial because of scant pediatric safety data in this situation. The clinical trials data in adults with cerebral sinovenous thrombosis indicating the safety of anticoagulants for hemorrhagic cerebral sinovenous thrombosis are reassuring. If anticoagulants are not used because of hemorrhage or other risks, early (e.g., 5 days) repeated venous imaging is indicated to assess for propagation of the initial thrombus, in which case anticoagulants are usually indicated. In children with cerebral sinovenous thrombosis in whom there is progression of thrombosis in spite of maximal systemic anticoagulation, systemic or intra-clot thrombolytic therapy may be an option and has been used with apparent success in many adults and in several children with cerebral sinovenous thrombosis [Griesemer et al., 1994; Higashida et al., 1989; Roach and Riela, 1995; Wong et al., 1987]. However, a recent Cochrane review found no randomized, controlled trials of thrombolytic treatment in adults with cerebral sinovenous thrombosis and recommended a controlled trial including patients with predictors of poor outcome [Ciccone et al., 2004]. Until more is known about the risk/benefit ratio, thrombolytic therapy should be used only in exceptional circumstances in children with cerebral sinovenous thrombosis.

Nonantithrombotic Therapies Septic cerebral sinovenous thrombosis requires antibiotics and, in certain cases, surgical removal and drainage of the infection, such as mastoidectomy. Treatment of prolonged,

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increased intracranial pressure following cerebral sinovenous thrombosis consists of repeat lumbar punctures for removal of excess cerebrospinal fluid, acetazolamide, and, in resistant cases, lumboperitoneal shunting. During prolonged periods of increased intracranial pressure, careful monitoring of the visual fields, in particular the central scotoma, is necessary in order to avoid permanent visual loss. Optic nerve fenestration may be required in situations in which visual field deficits are increasing.

Outcome In adults with cerebral sinovenous thrombosis, the long-term outcome appears to be favorable. A retrospective study of 77 adults with cerebral sinovenous thrombosis (80% of whom had received anticoagulant therapy after diagnosis) reported neurologic sequelae in only 15% [Preter et al., 1996]. A recent international study of 624 adults with cerebral sinovenous thrombosis with a median follow-up of 16 months reported a normal outcome in 57%, minor or mild impairments in 30%, moderate impairments in 3%, severe handicap in 2%, and death in 8.3% [Ferro et al., 2004]. Overall, the mortality rate is reported to be 6% to 30% and predictors of death or disability include presentation with stupor, coma and intracranial hemorrhage, and thrombosis of the deep cerebral venous system [Ferro et al., 2004; Mehraein et al., 2003]. Symptomatic recurrence of cerebral sinovenous thrombosis (12%), usually in the first year, and pulmonary embolism (11%) occurred in adult patients with cerebral sinovenous thrombosis [Bousser and Russell, 1997; Preter et al., 1996]. The outcome of pediatric cerebral sinovenous thrombosis has been assessed in several cohort studies. In one study utilizing standardized outcome assessments, 63% of 38 consecutive infants and children surviving cerebral sinovenous thrombosis were normal at a mean follow-up of 1.7 years, and the remainder had a mild or moderate neurologic deficit [deVeber et al., 2000]. In a recent study of 17 children with cerebral sinovenous thrombosis, neurologic death occurred in 5 children. The 12 surviving children were followed for a mean of 2.5 years; normal outcomes were demonstrated in 8 children, motor disability in 1, cognitive loss in 2, and reduced quality of life in 3 [De Schryver et al., 2004]. In another study of 27 neonates and children, only 11 of 31 patients had a normal outcome, 17 had residual deficits, and 2 patients died [Carvalho et al., 2001]. In a population-based prospective study of 160 infants and children from the Canadian Pediatric Ischemic Stroke Registry (mean follow-up, 1.6 years) 65% were normal, 35% had a neurologic deficit, 20% had seizures and 9% died [deVeber et al., 2001]. Six of the 7 children who died did not receive anticoagulant therapy. Predictors of death or abnormal neurologic outcome included presentation with venous infarcts or seizures. In the Registry, nearly 25% of children showed an increased severity of neurologic deficits developing over time, reinforcing the need for long-term follow-up. In addition, 13% of children developed recurrent cerebral or systemic thrombosis [deVeber et al., 2001]. In these studies, because one third to one half of the children were treated with anticoagulants, the natural history cannot be extrapolated. In older infants and children with cerebral sinovenous thrombosis, persistent intracranial hypertension is well recognized and may not be influenced by the use of anticoagulants [Higgins et al., 2003].

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In adults, recanalization rates on serial neuroimaging have been shown to be maximal 4 months after diagnosis during anticoagulation therapy [Baumgartner et al., 2003]. Recanalization has also been correlated with improved outcome [Strupp et al., 2002]. The rate and extent of recanalization following cerebral sinovenous thrombosis in children has not been established. Recanalization of cerebral sinovenous thrombosis as early as 2 weeks after the onset of clinical symptoms has been reported [Macchi et al., 1986].

HEMORRHAGIC STROKE Hemorrhagic stroke involves the rupture of normal cerebral blood vessels, as seen in a bleeding diathesis or the rupture of abnormal blood vessels, (e.g., aneurysm or vascular malformation). The result is the extravasation of blood into the brain’s parenchyma or the subarachnoid space. Two major types of hemorrhagic stroke reflect the anatomic site of

Box 72-6 DISORDERS CAUSING HEMORRHAGIC STROKE Vascular Congenital Vascular Anomalies Arteriovenous malformation Venous angioma Cavernous malformation Hereditary hemorrhagic telangiectasia Intracranial aneurysm Coarctation with intracranial aneurysm Vasculopathies Ehlers-Danlos syndrome type IV Moyamoya Pseudoxanthoma elasticum Sickle cell disease Intravascular Hematologic Disorders Immune thrombocytopenic purpura Thrombotic thrombocytopenic purpura Hemophilic states Congenital serum C2 deficiency Liver dysfunction with coagulation defect Vitamin K deficiency Factor deficiencies Systemic Disease Systemic hypertension Vasculitis Drug abuse (cocaine, amphetamines) Hemolytic-uremic syndrome Trauma Child abuse Angioplasty Penetrating intracranial trauma

bleeding and are classified as intracerebral hemorrhage and subarachnoid hemorrhage. Both conditions can occur together—for example, as the result of rupture of an arteriovenous malformation or aneurysm. The most common underlying causes of hemorrhagic stroke are listed in Box 72-6.

General Features Important differences exist between pediatric ischemic stroke and pediatric hemorrhagic stroke. A specific cause is more likely to be found for hemorrhagic stroke than for ischemic stroke, and the causes are entirely different in the two conditions [Schoenberg et al., 1978]. In contrast to ischemic stroke, definitive treatment for hemorrhagic stroke frequently requires neurosurgical intervention. Compared with arterial ischemic stroke, hemorrhagic stroke is associated with an increased mortality but improved neurologic recovery in survivors. Among children with hemorrhagic stroke, subarachnoid hemorrhage is infrequent compared with intracerebral hemorrhage [Giroud et al., 1995; Lanthier et al., 2000]. In one study of 56 children with hemorrhagic stroke, 68% had intracerebral hemorrhage, 25% had subarachnoid hemorrhage and 8% had intraventricular hemorrhage [Blom et al., 2003]. In these children, underlying causes for hemorrhagic stroke included arteriovenous malformations (23); aneurysms (5); hematologic disorders (9); hematologic malignancies, vasculitis, and meningitis (2 each); and Menkes’ disease and pinealoma (1 each). In this study, the outcome from hemorrhagic stroke was systematically assessed; 25% had no physical or cognitive deficits at a mean follow-up of 10 years. Death directly related to the hemorrhage occurred in 13 children. In survivors, recurrent hemorrhage was noted in 9 children and was fatal in 3 children. Six children developed long-term seizures. Of 31 survivors, 15 had no physical impairment, 11 had hemiparesis, and 3 had ataxia. Cognitive deficits were found in 15 (50%), despite normal mean IQ scores, and included aphasia in 2 patients. Reduced self-esteem and emotional, behavioral, and other health problems were present in the majority and were increased, compared with normative data on quality of life from American and Dutch populations. Children and their parents reported these latter problems at similar rates [Blom et al., 2003]. Additional studies of hemorrhagic stroke in childhood have found a similar distribution of etiologies and outcomes [Lanthier et al., 2000]. Intraventricular hemorrhage, which should be considered separately from intracerebral hemorrhage, is rare beyond the newborn period and is associated with rupture of vascular malformations and aneurysms as well as with sinus thrombosis and bleeding diatheses. The surgical treatment of hemorrhagic stroke in children has been summarized in two excellent reviews [Punt, 2004; Smith et al., 2002]. The remainder of this chapter is divided into four sections. The sections deal separately with the principal clinical subtypes of hemorrhagic stroke in children—intracerebral (intraparenchymal) hemorrhage, subarachnoid hemorrhage, and traumatic intracranial hemorrhage. In the fourth section, specific vascular disorders underlying hemorrhagic stroke, including vascular malformations, aneurysms, and other vascular disorders, are reviewed.

deVeber / Cerebrovascular Disease

Intracerebral Hemorrhage Pathophysiology Hemorrhage into intracerebral compartments occurs when cerebral arteries or veins rupture. Usually the site of rupture is the medium-sized or smaller branches of the major cerebral arteries distal to their entry point into the brain, where vascular malformations tend to exist. The resulting hematoma mechanically disrupts neuronal structures, causing focal damage. The presence of blood products and damage to the blood-brain barrier promotes cerebral edema, resulting in relatively severe initial neurologic deficits and seizures. When large, a hematoma and the associated cerebral edema can act as a mass lesion, resulting in increased intracranial pressure and focal brain herniation. In particular, in the posterior fossa, hemorrhage may require urgent neurosurgical evacuation in order to prevent fatal brainstem compression. In one series, the location of intracerebral hemorrhage was left hemisphere in 11 cases, right hemisphere in 14, basal ganglia in 5, and cerebellar in 8 [Blom et al., 2003].

Clinical Features In older children, intracerebral hemorrhage typically presents with a severe headache, focal signs, rapid decrease in consciousness, and seizures. Smaller bleeds may have a more subtle presentation—for example, sudden onset of minor focal neurologic signs. If the posterior fossa is the site of hemorrhage, dysconjugate gaze, ataxia, and rapid deterioration to coma are typical. In a large series in Texas of 68 children with nontraumatic cerebral hemorrhage, clinical presentations included seizures in 37%, hemiparesis in 16%, irritability in 9%, and coma in only 2 children [Al Jarallah et al., 2000].

Risk Factors In children with nontraumatic intracerebral hemorrhage, risk factors are evident in 85% to 90% and include congenital vascular anomalies in 43% to 62% [Al Jarallah et al., 2000; Lanthier et al., 2000]. Compared with adults, children are less likely to have a generalized cerebral vasculopathy such as congophilic angiopathy or hypertensive vasculopathy underlying parenchymal hemorrhage. However, hemorrhage does occur in the setting of acquired vasculopathies including moyamoya disease, cerebral vasculitis, and metabolic or genetic vasculopathies and in adolescents abusing sympathomimetic drugs [Forman et al., 1989; Levine et al., 1990]. Compared with adults, intracerebral hemorrhage in children is more likely to result from a bleeding diathesis due to inherited hemophilic or thrombocytopenic disorders [Eyster et al., 1978; Roach and Riela, 1995]. These disorders have been found in 32% of children with intracerebral hemorrhage [Al Jarallah et al., 2000] and include hemophilia, thrombocytopenia, liver failure, leukemia, and warfarin therapy. Bleeding from cerebral lesions, including brain tumors and arterial or venous infarcts (see Fig. 72-15), are an important cause of pediatric intracerebral hemorrhage. In one series, 13% of children with intracerebral hemorrhage had brain tumors as the source of their bleeding [Al Jarallah

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et al., 2000]. In some children, intracerebral hemorrhage is of unclear origin. Conventional angiography should be performed in all older infants and children with intracerebral hemorrhage of unclear origin, because more than 50% will have a definable etiology [Al Jarallah et al., 2000; Zhu et al., 1997].

Outcome Following cerebral hemorrhage, normal neurologic outcome was present in 50% of the 68 children reported in the Texas series, with death in 9% and neurologic sequelae in the remainder [Al Jarallah et al., 2000]. These sequelae included hemiparesis (25%), aphasia (7%), seizures (10%), and hydrocephalus (5%).

Subarachnoid Hemorrhage Pathophysiology The subarachnoid space exists between the pial lining of the brain and the next external layer of leptomeninges, the arachnoid. Normally this space is filled with cerebrospinal fluid. The cerebral arteries forming the circle of Willis and the major branches of these arteries reside in the subarachnoid space, with medium-sized and smaller branches leaving this space as they enter the brain’s parenchyma. If the site of cerebral artery rupture is the proximal major arteries at the circle of Willis, as is the case in most aneurysms, or from arteriovenous malformations over the surface of the cerebral hemisphere, the majority of bleeding occurs into the subarachnoid space surrounding the brain. Following subarachnoid hemorrhage, the presence of blood and breakdown products of erythrocytes in the subarachnoid space frequently results in vasospasm in the cerebral arteries, which can be severe enough to cause secondary ischemic infarction. A communicating or noncommunicating hydrocephalus can result from adhesions at the outflow foramina of the fourth ventricle at the base of the brain, or in the arachnoid granulations where cerebrospinal fluid is absorbed.

Clinical Features In children with subarachnoid hemorrhage, a severe headache with meningeal signs and signs of increased intracranial pressure are typical. Low-grade fever and leukocytosis occasionally are present. Children with vein of Galen malformations may present with abrupt subarachnoid hemorrhage and focal signs. In patients with subarachnoid hemorrhage, retinal examination may reveal subhyaloid retinal hemorrhages. CT detects subarachnoid hemorrhage in most patients acutely, but over the first few days becomes less likely to detect blood. Nonradiographic means of diagnosis of subarachnoid hemorrhage include lumbar puncture, with immediate detection of xanthochromia, and bloody cerebrospinal fluid without reduction or clearing of blood over the duration of the spinal fluid collection. Cerebrospinal fluid glucose may be reduced in subarachnoid hemorrhage. Definitive treatment for subarachnoid hemorrhage depends on finding the source of the hemorrhage and varies according to the type of lesion as discussed later in the fourth section “Specific Vascular Disorders Underlying Hemorrhagic Stroke.”

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Risk Factors The principal causes of subarachnoid hemorrhage are the rupture of vascular malformations and aneurysms. In children, subarachnoid hemorrhage is more frequently attributable to aneurysms (mycotic or congenital) than to arteriovenous malformations [Blom et al., 2003; Sedzimir and Robinson, 1973]. In the setting of acute or subacute subarachnoid hemorrhage, if the initial angiogram does not reveal the cause, repeat angiography is usually indicated several weeks or months later because vasospasm, thrombosis, or hemorrhage impinging on the vascular anomaly can result in the lesion’s being missed. The diagnostic ability of MR angiography was recently compared with conventional angiography in 19 children with subarachnoid hemorrhage and underlying arteriovenous malformations or aneurysms [Fasulakis and Andronikou, 2003]. There was excellent correlation in the detection of arteriovenous malformations; conventional angiography was superior to MR angiography in demonstrating arterial anatomy, except in identification of lesions in the anterior and posterior communicating arteries, when MRA was superior.

Outcome The outcome in children with subarachnoid hemorrhage is not well established. In general, children with a depressed level of consciousness or coma at presentation have a poorer outcome than those with retention of normal consciousness [Higgins et al., 1991].

Traumatic Intracranial Hemorrhage Head trauma, accidental or nonaccidental, is the commonest overall cause of intracranial hemorrhage (as distinct from hemorrhagic stroke) in childhood and, with the exception of inflicted trauma due to child abuse, is usually obvious as a risk factor. Traumatic hemorrhage can occupy any of the classic intracranial compartments: epidural, subdural, subarachnoid, intracerebral, and intraventricular. Intracerebral hemorrhage due to trauma may be associated with a single or several large focal contusions at the site of blunt trauma or may consist of multiple small hemorrhagic foci throughout the white matter, as in diffuse axonal injury. Traumatic subarachnoid hemorrhage can result from the direct rupture of small subarachnoid vessels or can occur as a complication of post-traumatic dissection of cerebral arteries. In infants, unexplained subdural and other intracranial hemorrhage, particularly when bilateral, should raise suspicion of inflicted trauma. The “shaken baby syndrome” has been assessed in a large cohort study [Morad et al., 2002]. In 75 infants aged 2 to 48 months with shaken baby syndrome, neuroimaging findings included subdural hemorrhage in 94%, cerebral edema in 44%, subarachnoid hemorrhage in 16%, vascular infarction in 12%, intracerebral hemorrhage in 8%, contusion in 8%, and epidural hemorrhage in one child. In 75% of these children, retinal hemorrhages were present and were correlated in severity with the intracranial hemorrhages. Extreme vigilance when treating any infant with intracranial hemorrhage consistent with trauma is necessary because of the frequent absence of external signs of trauma and the difficulty in making a diagnosis of shaken baby syndrome [Committee

on Child Abuse and Neglect, 1997]. Head trauma is covered in greater detail in Chapter 63.

Specific Vascular Disorders Underlying Hemorrhagic Stroke The most important types of vascular disorders, including vascular malformations and aneurysms, and their unique clinical and radiographic features, treatments, and outcomes are briefly reviewed here. Several excellent comprehensive reference texts and reviews covering this topic have been published [Humphreys et al., 1996; Lasjaunias and Terbrugge, 2006; Roach and Riela, 1995].

Vascular Malformations Vascular malformations are classically divided into four types, based on the caliber and histologic structure of component blood vessels: arteriovenous malformations, cavernous malformations, venous angiomas, and capillary telangiectasias [Russell and Rubenstein, 1989]. Capillary telangiectasias are an infrequent cause of hemorrhagic stroke and are usually associated with neurocutaneous disorders, which are described in Chapter 31.

ARTERIOVENOUS MALFORMATIONS True arteriovenous malformations consist of an admixture of arteries and veins and can range from several millimeters to several centimeters in size. Development of an arteriovenous malformation results from failure of the formation of the capillary bed between primitive arteries and veins in the brain during the first trimester of fetal life. The incidence of arteriovenous malformations in children is 1 in100,000, and approximately 10% to 20% of all arteriovenous malformations become symptomatic during childhood [Menovsky and van Overbeeke, 1997]. The initial signs of an unruptured arteriovenous malformation include seizures, headaches, and, with large hemispheric arteriovenous malformations, gradually progressive neurologic deficit. In approximately 80% of patients, the initial manifestation is hemorrhage, in the form of either a warning leak or a catastrophic acute intracerebral or subarachnoid hemorrhage [Humphreys et al., 1996]. The probability of a first hemorrhage is 2% to 4% per year, with a recurrence risk as high as 25% by 5 years [Fults and Kelly, 1984]. Familial occurrence has been reported [Yokoyama et al., 1991]. CT with contrast enhancement or MRI can demonstrate an arteriovenous malformation (Fig. 72-16). However, conventional angiography is required in the planning stages of therapy. Definitive treatment of arteriovenous malformations consists of surgical resection or interventional neuroradiologic techniques employing balloon or coil occlusion of the larger feeding vessels [Burrows et al., 1987]. Successful surgical resection confers immediate protection against recurrent hemorrhage. However, in a recent study, among 36 children with arteriovenous malformations treated with surgical resection, the recurrence rate of bleeding from an arteriovenous malformation was 5.5% at follow-up (mean, 9 years) as a result of an undetected residual nidus [Andaluz et al., 2004]. Radiosurgery is an increasingly available option.

deVeber / Cerebrovascular Disease

A

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B

FIGURE 72-16. Large hemispheric arteriovenous malformation (AVM) in an 8-year-old child presenting with seizures. A, CT scan with contrast enhancement of right frontal mass. B, MRI (T1-weighted) shows multiple flow voids in the AVM. C, MRI (flow-sensitive sequence) shows flow in abnormal blood vessels within the AVM. (Courtesy of Karel Ter Brugge and Division of Neuroradiology, Hospital for Sick Children, Toronto, Ontario, Canada.)

C In smaller lesions, focused gamma knife or proton beam irradiation can obliterate the lesion. A recent study of 31 children treated with this modality reported that in arteriovenous malformations that received at least 18 Gy there was a 10-fold increase in the obliteration rate (63%) compared with arteriovenous malformations that received a lower dose. Lesions smaller than 3 cm3 were associated with a sixfold increased obliteration rate (53%) compared with lesions larger

than 3 cm3 (8%), but arteriovenous malformation volume was not a statistically significant predictor of response (P = 0.09) [Smyth et al., 2002]. The resolution of vascular lesions with radiosurgery is delayed by 1 to 2 years, during which time the patient remains at risk for rupture of the malformation [Loeffler et al., 1990]. In one study, 4 of 53 patients treated with radiosurgery for arteriovenous malformations had subsequent hemorrhages; it is interesting that all occurred more

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than 2 years after treatment [Levy et al., 2000]. In one study, the cumulative post-treatment hemorrhage rate after stereotactic radiation treatment after stereotactic radiation treatment was reported as 3.2% per patient per year in the first year and 4.3% per patient per year over the first 3 years [Smyth et al., 2002]. However, in another study the annual bleeding rate was 1.5% [Shin et al., 2002].

VEIN OF GALEN MALFORMATION Vein of Galen aneurysmal malformation is an important form of arteriovenous malformation in infancy. It consists of a highpressure vascular communication between branches of the major cerebral arteries and the vein of Galen (Fig. 72-17) and results from fistulous connections that develop near the embryonic choroidal plexuses of the 20- to 40-mm embryo. In early infancy, patients typically present with progressive high-output congestive heart failure or failure to thrive, or both, due to the large circulatory shunt into the arteriovenous malformation. In later infancy hydrocephalus can occur. Bleeding is a relatively rare presentation. In recent studies, a more favorable outcome has been reported than was previously observed and was related to an improved understanding of the pathophysiology and improved methods of endovascular therapy. In one study, 52% of 27 children undergoing endovascular treatment had no or only minor developmental delay [Fullerton et al., 2003]. In another large series of 120 infants, 83% were carefully selected for endovascular embolization treatment [Lasjaunias et al., 1996]. Death occurred in all infants in whom the treatment was conservative (i.e., no embolization therapy), and in 9% of those undergoing embolization treatment, giving an overall case mortality rate of 26%. Of the 65% with complete

A

FIGURE 72-17. Vein of Galen malformation in a 3-month old infant presenting with cardiac failure. MRI scan (T1-weighted) shows low-signal flow void within the dilated vein of Galen. (Courtesy of Karel Ter Brugge and Division of Neuroradiology, Hospital for Sick Children, Toronto, Ontario, Canada.)

obliteration of the lesion, only 8.5% had severe permanent sequelae. (In this series the treatment consisted of transarterial embolization via the femoral artery with intralesional injection of N-butyl cyanoacrylate.)

B

FIGURE 72-18. Cavernous malformation in an 18-year-old male presenting with seizures. A, CT scan with contrast enhancement of “mulberry” type lesion. B, MRI scan (T1-weighted) shows characteristic dark signal rim. (Courtesy of Karel Ter Brugge and Division of Neuroradiology, Hospital for Sick Children, Toronto, Canada.)

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Microsurgical techniques utilizing staged surgical procedures have been utilized [Moodie et al., 1983]. However, large, more recent studies assessing surgical treatment are not available. Ventricular shunting is no longer recommended because it is associated with complications and poor neurologic outcome and exacerbates the complex hydrodynamic problems that exist in infants with vein of Galen malformations [Zerah et al., 1992].

CAVERNOUS MALFORMATIONS Cavernous malformations are dense collections of thinwalled blood vessels distinct from the surrounding brain parenchyma (Fig. 72-18). Since the advent of MRI scanning, cavernous malformations are more frequently diagnosed, and they are often asymptomatic. When they are symptomatic, the initial clinical presentation in pediatric patients is approximately one third each with seizures, focal neurologic signs, and intracerebral hemorrhage [Simard et al., 1986]. The risk of hemorrhage is less than 0.25% per person per year [Del Curling et al., 1991]. Unlike hemorrhage resulting from arteriovenous malformations or aneurysms, life-threatening hemorrhage is rare. Familial occurrence of cavernous malformations [Malik et al., 1992] has been frequently reported. In the familial form, lesions tend to be multiple and may have a greater propensity to hemorrhage than nonfamilial cavernous malformations. Retinal cavernous malformations are seen in the familial form. Cavernous malformations have recently been linked to abnormalities in the long arm of chromosome 7 [Sahoo et al., 1999]. Conventional angiography results in cavernous malformations are typically normal. However, cavernous malformation may be associated with other vascular malformations, particularly venous angiomas [Rogner, 1976]. Because of the low risk for bleeding, unruptured cavernous malformations are often managed expectantly, with surgical resection reserved for those patients who have seizure disorders refractory to medical management [Roach and Riela, 1995; Punt, 2004].

VENOUS ANGIOMAS Venous angiomas are one of the most common types of vascular anomalies but rarely become symptomatic unless they are combined with other vascular malformations [Sarwar and McCormick, 1978]. In isolated venous angioma, hemorrhage is rare, and seizures without hemorrhage are more frequently the presenting clinical sign [Roach and Riela, 1995]. MRI and MR angiography can best demonstrate venous angiomas [Awad et al., 1993] and detect associated parenchymal or vascular lesions. Angiography indicates a caput medusae pattern consisting of a main venous trunk with a cluster of tributary veins (Fig. 72-19) [Agnoli and Hildebrandt, 1985]. Conservative management of isolated venous angiomas is usually recommended, because removal can increase neurologic deficits, presumably due to residual venous congestion in the brain drained by the angioma.

Aneurysms Approximately 1% to 2% of aneurysms become symptomatic during childhood. Aneurysms in children are frequently associated with other vascular lesions or chronic disorders.

FIGURE 72-19. Venous angioma of the cerebellum of a 6-year-old male presenting with migraine headache. CT scan with contrast enhancement shows characteristic “caput medusae” feeding the draining vein. (Courtesy of Karel Ter Brugge and Divisionof Neuroradiology, Hospital for Sick Children, Toronto, Ontario, Canada.)

Most aneurysms in childhood are saccular and are believed to arise from a focal congenital weakness of the elastic and muscular layers in the cerebral arteries (Fig. 72-20) [Ahlsten et al., 1985; Khoo and Levy, 1999; Rogner, 1976]. Aneurysms tend to rupture in infants younger than 2 years of age and children older than 10 years [Adner et al., 1969] and are twice as common in males as in females [Ostergaard, 1991], in contrast to the preponderance of females in adults with aneurysms. Aneurysms occurring in children younger than 2 years of age are located predominately in the anterior and middle cerebral arteries and internal carotid artery and are larger than 1 centimeter [Crisostomo et al., 1986]. Older children and adolescents have a high proportion of aneurysms at the internal carotid artery bifurcation, with an incidence of around 16%, compared to 4% seen in adults [Khoo and Levy, 1999]. Giant (larger than 10 centimeters) aneurysms are found in 20% to 50% of pediatric cases, and are particularly common in infants [Kasahara et al., 1996]. In children, aneurysms involve the posterior circulation in 20%, nearly three times more frequently than in adults [Khoo and Levy, 1999]. Clinical presentation is usually with acute subarachnoid hemorrhage, frequently associated with intracerebral or intraventricular hemorrhage. Early warning signs are often missed in children and include previous headache or local compressive syndromes such as cranial nerve palsies. Giant aneurysms may manifest clinically with compressive features related to their location. Many systemic and vascular diseases are associated with aneurysms, including systemic arteriovenous malformation, coarctation of the aorta, EhlersDanlos syndrome, polycystic kidney disease, and moyamoya disease. Familial occurrence of aneurysms is well described

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A

B

FIGURE 72-20. Saccular aneurysm of the left anterior cerebral artery manifesting with subarachnoid hemorrhage. A, CT without contrast enhancement shows high-density blood throughout the subarachnoid spaces. B, CT spiral angiogram shows left anterior cerebral artery aneurysm. C, Conventional angiogram confirms aneurysm. (Courtesy of Karel Ter Brugge and Division of Neuroradiology, Hospital for Sick Children, Toronto, Ontario, Canada.)

C and is frequently associated with multiple aneurysms in each family member. MRI and MR angiography can provide good visualization of aneurysms, but angiography is more sensitive and more specific [Ross et al., 1990]. Children with aneurysms may have an increased rebleeding rate compared with adults [Wojtacha et al., 2001]. Because of the risk of early recurrent hemorrhage, surgery the first week after subarachnoid hemorrhage is considered the treatment of choice but may need to be delayed in patients with severe subarachnoid hemorrhage and unstable clinical status [Kassell et al., 1990]. Conservative measures before surgery aimed to decrease the risk of recurrent hemorrhage include sedation,

adequate analgesia, prophylaxis against seizures, and prevention of hypertension. The risk of early vasospasm and ischemic infarction, particularly frequent in large subarachnoid hemorrhages, mitigates maintenance of adequate blood pressure, including volume loading. Nimodipine prevents vasospasm in adults but has not been evaluated in children. Acquired aneurysms are most frequently the result of bacterial endocarditis. In this condition, there is embolization of infected material into cerebral arteries, which results in mycotic aneurysm formation. These aneurysms may be detected on MR or conventional angiography or may manifest with subarachnoid or intracerebral hemorrhage.

deVeber / Cerebrovascular Disease

Bleeding is the first sign of a mycotic aneurysm in one fourth of cases [Brust et al., 1990]. Surgical resection of such aneurysms, although technically difficult, may be necessary to prevent this complication. Post-traumatic aneurysms may be an under-recognized condition in children [Ventureyra and Higgins, 1994]. In children with cerebral artery dissection, pseudoaneurysms also may be rarely associated with subarachnoid or intracerebral hemorrhage.

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CHAPTER 73

Neurologic Manifestations of Rheumatic Disorders of Childhood Nina Felice Schor, Robert Sheets, Ilona S. Szer, and Stephen Ashwal

The rheumatic disorders of childhood are composed of a wide variety of conditions ranging from simple arthritis to complex multisystem autoimmune diseases. The presence and the degree of nervous system impairment vary widely depending on the diagnosis and course of the disorder. Manifestations of neurologic disease may precede the onset of any other symptoms or occur much later. Classification of the chronic rheumatic disorders has changed, as shown in Box 73-1 [Petty et al., 2004]. The types of autoantibodies found in rheumatic diseases are outlined in Table 73-1. Neurologic manifestations of rheumatic disorders can arise in both primary and secondary fashion [Benseler and Schneider, 2004]. That is, the antibodies or cellular immune elements responsible for the underlying disease can directly attack and injure or can cause the malfunction of nerves, muscle, brain, spinal cord, and sensory organs. On the other hand, innocent bystander effects of such rheumatic disease accompaniments as the hypercoagulable state, inflammation of the blood vessel wall, and immune complex deposition and side effects of medications used in the treatment of rheumatic disease also take their toll on the nervous system. These neurologic signs and symptoms are often multifactorial in origin, and their treatment may involve approaches to the proximate underlying disease and the more distal symptomatic manifestations. Rheumatic disease underlies a small but tangible fraction of neurologic syndromes of childhood. For example, vasculitis of infectious or rheumatic origin accounts for approximately 4% of childhood stroke [Williams et al., 1997]. Rheumatic disease should be considered as a possible etiologic factor in neurologic syndromes of childhood when these syndromes are accompanied by persistent fever, weight loss, myalgias, arthralgias, meningeal signs, or multiple nonanatomically contiguous neurologic deficits [Carvalho and Garg, 2002].

CHRONIC ARTHROPATHIES The key neurologic and laboratory findings in chronic arthropathies are summarized in Table 73-2 [Tan, 1986].

Juvenile Idiopathic Arthritis The neurologic manifestations and sequelae of juvenile idiopathic arthritis ( previously described as juvenile rheumatoid arthritis) and its treatment vary greatly with the subtype of arthritis. Children with pauciarticular or polyarticular disease have only rarely been diagnosed with central nervous system disease, but approximately 20% of those with pauciarticular and 5% of those with polyarticular disease

develop uveitis [Rosenberg, 2002]. In contrast, only 1% of children with systemic onset disease develop uveitis [Rosenberg, 2002]. Approximately 6% of children with systemic arthritis develop nervous system symptoms that most often involve the central nervous system.

Neurologic Manifestations of Systemic Juvenile Idiopathic Arthritis ACUTE ENCEPHALOPATHY WITH OR WITHOUT SEIZURES The most common form of acute encephalopathy in children with systemic juvenile idiopathic arthritis is macrophage activation syndrome. Symptoms include unremitting fever, rheumatoid rash, seizures, encephalopathy, hepatosplenomegaly, and lymphadenopathy, as well as cardiac, pulmonary and renal failure. Laboratory studies indicate varying degrees of cytopenia, low albumin, elevated D-dimer, and elevated ferritin and lactate dehydrogenase. Elevated liver enzymes as well as triglycerides are common. The sedimentation rate may fall [Ravelli, 2002]. Initial reports of this catastrophic complication implicated the use of acetylsalicylic acid, indomethacin, and gold, but the macrophage activation syndrome has occurred after ingestion of many nonsteroidal anti-inflammatory drugs including sulfasalazine and in the context of no drug intake [Bray and Singleton, 1994]. Immediate treatment with steroids is associated with resolution in most cases. In steroid-resistant cases, cyclosporin A has been effective [Mouy et al., 1996]. In one series of patients, acute hepatic dysfunction, metabolic alterations (including hyponatremia), intracranial hemorrhage, and acute encephalopathy have been described with and without disseminated intravascular coagulation [Hadchouel et al., 1985]. Clinical features are suggestive of a Reye-like syndrome, although cerebral edema, hyperammonemia, and hepatic microvascular fatty infiltration have not been observed. Elevated cerebrospinal fluid protein and cell count were common. These patients demonstrated generalized electroencephalographic slowing, and the neurologic symptoms in five of seven children were attributable to a metabolic encephalopathy associated with hyponatremia. These five children responded well to high-dose corticosteroids. The remaining two children died from disseminated intravascular coagulation [Hadchouel et al., 1985]. In another series of children with systemic juvenile idiopathic arthritis without disseminated intravascular coagulation, an acute encephalopathy associated with generalized and focal seizures, altered states of consciousness, abnormal ictal and interictal electroencephalogram, and moderate elevation of cerebrospinal fluid protein and cells has been reported [Lang

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Box 73-1 CLASSIFICATION OF THE RHEUMATIC DISORDERS OF CHILDHOOD Juvenile Idiopathic Arthritis (Chronic Arthropathies) Systemic arthritis (systemic-onset JRA) Oligoarthritis, persistent or extended (pauciarticularonset JRA) Polyarthritis, rheumatoid factor–negative (polyarticularonset JRA) Psoriatic arthritis (not previously classified as JRA) Enthesitis-related arthritis (previously classified as spondyloarthritis) Undifferentiated arthritis Arthritis Associated with Infectious Agents Acute rheumatic fever Lyme disease Reiter’s syndrome

et al., 1974]. Perivascular infiltrates of inflammatory cells within the brain parenchyma have been documented in several children with acute encephalopathy. In one patient, cerebrospinal fluid immune complexes were associated with parenchymal perivascular mononuclear cell infiltrates, suggesting an autoimmune basis of this complication [O’Connor et al., 1980]. Two reports have been published in which there was an association of true Reye syndrome with chronic administration of acetylsalicylic acid in several patients with juvenile idiopathic arthritis when acetylsalicylic acid was the drug of choice for the treatment of chronic childhood arthritis [Silverman et al., 1983; Young et al., 1984]. No reports of Reye syndrome in children with juvenile idiopathic arthritis have emerged since the use of acetylsalicylic acid in children has declined in the United States; furthermore, this complication has not been reported with the use of newer nonsteroidal anti-inflammatory drugs such as naproxen.

NEUROPATHIES Connective Tissue Disorders Systemic lupus erythematosus Juvenile dermatomyositis Scleroderma Mixed connective tissue disease Sjögren’s syndrome Primary Vasculitic Disorders Necrotizing Vasculitis Polyarteritis nodosa Kawasaki disease Microscopic polyangiitis Cogan’s syndrome Leukocytoclastic Vasculitis Henoch-Schönlein purpura Hypersensitivity vasculitis Granulomatous Vasculitis Churg-Strauss syndrome Wegener’s granulomatosis Primary angiitis of the central nervous system Necrotizing sarcoid granulomatosis Sarcoidosis Giant Cell Arteritis Temporal arteritis Takayasu’s arteritis Miscellaneous Vasculitic Disorders Behçet’s disease Miscellaneous Disorders Thrombotic thrombocytopenic purpura Erythromelalgia JRA, juvenile rheumatoid arthritis. Modified from Cassidy JT, Petty RE. Textbook of pediatric rheumatology, 4th ed. Philadelphia: WB Saunders, 2001.

Motor and sensory neuropathies have been reported in children but are far more common in adults. As such, mononeuritis multiplex, the most common neuropathy in adults with rheumatoid arthritis, is seldom if ever present in children. Neuropathologic studies of adult rheumatoid arthritis patients with peripheral neuropathy have demonstrated vasculitis involving both the leptomeninges and the underlying parenchyma with infarction of adjacent neuronal tissue. The TABLE 73-1 Autoantibodies in Pediatric Rheumatic Diseases ANTIBODY

CLINICAL FINDING

ANA

97% SLE, but also positive in MCTD, SSc, 10-85% JDMS, 20-88% JRA, SS, and 2-5% of controls 30-70% SLE, rarely in other CTDs 30% SLE MCTD, also in SLE 25% SLE, 75% SS 10% SLE, 40% SS 50% SLE, >90% DILS 44-98% CREST syndrome 27% SSc >90% Wegener’s granulomatosis 10% Wegener’s granulomatosis, 70% CSS, 75% UC, 20% Crohn’s disease, 30% SLE 20% polyarticular JRA, 50% SS; 10-30% SLE, MCTD Correlates with thromboembolic risk in SLE Correlates with thromboembolic risk in SLE, malignancy; variable in many other diseases

Anti-ds-DNA Anti-Sm Anti-RNP Anti-SSA/Ro Anti-SSB/La Anti-histone Anti-centromere Anti-Scl-70 Anti-c-ANCA Anti-p-ANCA RF A LAC aCL

aCL, anticardiolipin antibody; ANA, antinuclear antibody; c-ANCA, cytoplasmic staining antineutrophil cytoplasmic antibody; CREST, calcinosis, Raynaud’s, esophageal dysmotility, sclerodactyly, telangiectasia; CSS, Churg-Strauss syndrome; CTD, connective tissue disease; DILS, drug-induced lupus syndrome; ds-DNA, double-stranded (native) DNA; JDMS, juvenile dermatomyositis, JRA, juvenile rheumatoid arthritis; LAC, lupus anticoagulant; MCTD, mixed connective tissue disease; p-ANCA, perinuclear staining antineutrophil cytoplasmic antibody; RF A, rheumatoid factor A; RNP, ribonucleoprotein; SLE, systemic lupus erythematosus; Sm, Smith; SS, Sjögren’s syndrome; SSc, systemic scleroderma; UC, ulcerative colitis. Adapted from Okano Y. Rheum Dis Clin North Am 1996;22:709; Moder KG. Mayo Clin Proc 1996;71:391; and Bylund DJ, McCallum RM. Vasculitis. In: Henry JB, ed. Clinical diagnosis and management by laboratory methods. Philadelphia: WB Saunders, 1996.

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TABLE 73-2 Key Neurologic and Laboratory Findings in the Chronic and Reactive Arthropathies DISEASE

NEUROLOGIC FINDINGS

LABORATORY FINDINGS

Systemic juvenile idiopathic arthritis

Encephalopathy, seizures, macrophage activation syndrome (Reye-like syndrome), neuropathies Myasthenia gravis, myopathy, neuropathy, seizures, cognitive changes Chorea, personality changes, seizures

Elevated WBC and ESR, anemia, DIC, elevated CSF protein and cell count, marked increase in ferritin and LDH Elevated ESR, microcytic anemia, melena

Inflammatory bowel disease Acute rheumatic fever Lyme disease

Early infection: aseptic meningitis, headache, chorea, cranial nerve palsies, late neuroborreliosis myelitis, MS-like symptoms, subtle encephalopathy, radiculopathy, mononeuritis multiplex

Positive ASO titers, elevated ESR and CRP, abnormal ECG Positive IgG Lyme titer by ELISA, protein by Western blot in serum, positive PCR in CSF

ASO, antistreptolysin O; CRP, c-reactive protein; CSF, cerebrospinal fluid; DIC, disseminated intravascular coagulation; ECG, electrocardiogram; ELISA, enzyme-linked immunosorbent assay; ESR, erythrocyte sedimentation rate; IgG, immunoglobulin G; LDH, lactate dehydrogenase; MS, multiple sclerosis; PCR, polymerase chain reaction; WBC, white blood cell count.

resulting axonal neuropathy may be associated with demyelination caused by vascular occlusion of the vasa nervorum [Peyronnard et al., 1982].

MOOD DISTURBANCES Reports of psychologic studies of children with juvenile idiopathic arthritis remain uncertain about both the relative frequency of psychologic disorders and the relation of age and severity of arthritis to psychologic symptoms [Baildam et al., 1995; Ungerer et al., 1988]. Premorbid family dynamics, specifically maternal personality, may contribute to subsequent psychologic disorders in the child with juvenile idiopathic arthritis [Vandvik and Eckblad, 1991]. Depression and difficulty with concentration may be secondary to drug interventions, including nonsteroidal antiinflammatory drugs and sulfasalazine.

MYOSITIS Approximately 33% of children with juvenile idiopathic arthritis have mild elevations of creatine kinase without weakness [Rachelefsky et al., 1976]. Proximal muscle weakness and biopsy-confirmed myositis are extremely rare, although intermittent myalgias are common, especially in systemic juvenile idiopathic arthritis. Myositis has been localized with magnetic resonance imaging (MRI) in a patient with myalgias and elevated muscle enzymes in systemic juvenile idiopathic arthritis [Miller et al., 1995]. Of note, children with Duchenne’s muscular dystrophy, paraplegia, poliomyelitis, and cerebral palsy may have skeletal changes, such as apparent overgrowth of the epiphysis, periarticular osteoporosis, and joint-space narrowing, similar to juvenile idiopathic arthritis [Richardson et al., 1984].

Neurologic Manifestations of Polyarticular Juvenile Rheumatoid Arthritis MYELOPATHY Many children with polyarticular or systemic onset juvenile rheumatoid arthritis develop neck stiffness secondary to

cervical arthritis. Lateral cervical flexion radiographs may document fusion of the posterior vertebral processes of C2 and C3 followed by fusion of the entire cervical spine. The child with cervical spine fusion is usually able to flex the neck but has severe limitation of cervical extension and rotation. Unlike classic rheumatoid arthritis of adulthood, cervical myelopathy associated with atlantoaxial dislocation is highly unusual.

NEUROPATHOLOGIC ABNORMALITIES OF THE CENTRAL NERVOUS SYSTEM Neuropathologic studies of children with systemic onset juvenile idiopathic arthritis who have had neurologic complications are rare. Investigations of adults with classic rheumatoid arthritis complicated by central nervous system disease document the presence of rheumatoid nodules in the cranial and spinal dura, falces, leptomeninges, parenchyma, and choroid plexus [Kim, 1980]. Because adult-type (i.e., polyarticular) rheumatoid arthritis is relatively uncommon in children, these manifestations have not been reported but may occur in older children with seropositive (rheumatoid factor–positive) juvenile idiopathic arthritis who have the same disease as their adult counterparts.

Management of Juvenile Idiopathic Arthritis The treatment of juvenile idiopathic arthritis is dictated by the subtype of the disease. Pauciarticular juvenile idiopathic arthritis is usually managed with either nonsteroidal antiinflammatory drugs, such as naproxen and tolmetin sodium, or steroid intra-articular joint injection. Iridocyclitis usually responds successfully to topical ophthalmic corticosteroids. Polyarticular juvenile idiopathic arthritis is initially treated with nonsteroidal anti-inflammatory drugs; however, the risk of chronic inflammation of multiple joints may require the use of second-line agents such as methotrexate. If methotrexate fails, a tumor necrosis factor-alpha blocking drug, such as etanercept or infliximab is used. Systemic juvenile idiopathic arthritis may be managed with nonsteroidal anti-inflammatory drugs alone but often requires steroids for control of systemic symptoms. Second-line drugs

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such as methotrexate are often needed to control arthritis [Cassidy and Petty, 2001]. Once again, etanercept or infliximab are used for disease poorly responsive to prednisone and methotrexate [Quartier et al., 2003]. High-dose methylprednisolone, intravenous immunoglobulin, and cyclophosphamide have been used in recalcitrant disease [Shaikov et al., 1992; Silverman et al., 1994; Uziel et al., 1996]. Antitumor necrosis factor-alpha therapies paradoxically have been associated with worsening of or even emergence of new cases of multiple sclerosis [Sicotte and Voskuhl, 2001]. Because of the chronic nature of juvenile idiopathic arthritis, some children have psychological problems, including depression, anger, adjustment disorders, and troubles with peer and family relations. Counseling of the patient and family is beneficial [Baildam et al., 1995; Quirk and Young, 1990]. In addition, the importance of physical and occupational therapy cannot be overemphasized [Rhodes, 1991].

photophobia, and blurred vision. Prompt attention is required, and treatment with topical ophthalmic corticosteroids usually clears the inflammation. More recent studies and speculation have focused on the inverse situation; that is, the modulation of gastrointestinal inflammation by the nervous system and its chemical messengers [Anton and Shanahan, 1998; Murch, 1998]. It has become clear that both macrophages and lymphocytes bear receptors for various neuropeptides and central nervous system–relevant cytokines, growth factors, and hormone-regulating factors. Furthermore, substance P has emerged as an important mediator, not only of sensory signaling but also of mucosal inflammation. Finally, the absence of significant pain in patients with severe inflammatory bowel disease and consequent mucosal erosion has been linked to altered cortical localization of pain perception as determined by positron emission tomography [Anton and Shanahan, 1998].

Neonatal-Onset Multisystem Inflammatory Disease (NOMID) or Chronic Infantile Neurologic Cutaneous and Articular (CINCA) Syndrome

ARTHRITIS ASSOCIATED WITH INFECTIOUS AGENTS

This unusual disorder, which mimics systemic juvenile idiopathic arthritis, has its onset during the first year of life, whereas systemic onset juvenile idiopathic arthritis is a disease of toddlers and children. Clinical manifestations include hectic fever, intermittent rash, lymphadenopathy, hepatosplenomegaly, uveitis, cognitive and developmental delay, chronic meningitis, hydrocephalus, seizures, papilledema, and deforming arthropathy with periosteal changes and bony overgrowth [De Cunto et al., 1997]. In addition, children with this disorder may develop hearing loss, seizures, transient hemiplegia, cerebral atrophy, and an open fontanel, and the electroencephagram results may be abnormal. Long-term prognosis is poor [Prieur, 2000].

Enthesitis-Related and Undifferentiated Syndromes Although primarily an intestinal disorder, inflammatory bowel disease may present with arthritis and neurologic symptoms. Published studies indicate that approximately 3% of children with inflammatory bowel disease had neurologic involvement during the course of the disease, including one child with myasthenia gravis and others with myopathy, peripheral neuropathy, venous sinus thrombosis, recurrent strokes, myelopathy, cranial neuropathy, seizures, headache, confusional states, meningitis, and syncope [Bridger et al., 1997; del Rosario et al., 1994; Lossos et al., 1995]. A syndrome has been described that includes ileocolonic lymphoid nodular hyperplasia, mild enterocolitis, and developmental delay with autistic features [Wakefield et al., 1998]. Recent reports and reviews have suggested that this disorder is associated with detection of measles virus in the intestinal mucosa of these children [Martin et al., 2002]. Causality has not been demonstrated [Murch et al., 2004]. Other than inflammatory bowel disease, the enthesitis-related syndromes have not been described with neurologic findings. Patients with inflammatory bowel disease, psoriatic arthritis, and other enthesitis-related arthritides may develop inflammation of the uveal tract. These patients may experience acute episodes of uveitis with eye redness, pain,

Acute Rheumatic Fever Acute rheumatic fever is an inflammatory illness that follows group A beta-hemolytic streptococcal pharyngitis. The syndrome affects the heart valves, joints, central nervous system, skin, and subcutaneous tissues. Common clinical manifestations include migratory polyarthritis, fever, carditis, and, less frequently, Sydenham’s chorea, subcutaneous nodules, and erythema marginatum. The modified Jones criteria, which were last revised in 1992, are used to confirm the diagnosis of acute rheumatic fever and call for the presence of a combination of two major and one minor criteria or one major and two minor criteria, as well as antibody evidence of preceding streptococcal infection (Box 73-2). In the case of isolated Sydenham’s chorea, demonstration of preceding streptococcal infection may not always be possible, and in these cases is not a requirement for the diagnosis of acute rheumatic fever [Dajani et al., 1992].

Clinical Characteristics of Sydenham’s Chorea Involuntary, distal, purposeless rapid movements; hypotonia; weakness; and emotional lability characterize Sydenham’s chorea. It may be associated with other manifestations of rheumatic fever, or “pure” chorea may appear as the sole manifestations of the disease. Isolated chorea represents 20% to 30% of acute rheumatic fever cases and occurs long after the pharyngitis has resolved, which makes the association with streptococcal infection difficult to demonstrate. Indeed, laboratory evidence of preceding streptococcal infection could not be demonstrated in 35% of children with Sydenham’s chorea [Ayoub and Wannamaker, 1966]. Although the onset may be explosive, Sydenham’s chorea may develop slowly and insidiously. Chorea may be misdiagnosed as an emotional disorder or as tics with irritability and decreased attention span. Chorea may also be confused with a central nervous system degenerative process, but this is more common in adults than in young children. In adolescents, chorea occurs almost exclusively in females and may, on rare occasions, be associated with hemichorea or hemiparesis. The hemiparesis, which may be the initial manifestation of the disorder, has an unusual form

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Box 73-2 JONES CRITERIA FOR DIAGNOSIS OF ACUTE RHEUMATIC FEVER (REVISED 1992) Major* Carditis: Murmur consistent with aortic regurgitation or mitral insufficiency; echocardiogram findings without significant auscultatory findings are not adequate Chorea: May be the only manifestation; proof of prior streptococcal infection in only 80% Erythema marginatum: Rare manifestation; never on the face; transient and migratory Migratory polyarthritis: Almost always migratory, involving larger joints, responds within 48 hours to aspirin and usually resolves in 1 month Subcutaneous nodules: Rare manifestation; nontender, on extensor surfaces, usually over elbows, wrists, knees, occipital region, or spinous processes Minor Fever: Usually greater than 39° C Arthralgia: Consider if arthritis not present Prolonged PR interval: Does not correlate with the development of carditis Elevated erythrocyte sedimentation rate or C-reactive protein Adapted from Dajani et al. and The Special Writing Group. Guidelines for the diagnosis of rheumatic fever. Jones Criteria, 1992 update. JAMA 1992; 268:2069. *Prior episodes of acute rheumatic fever are not criteria; if a patient has had a prior attack of acute rheumatic fever, a new attack may be difficult to diagnose on the basis of changing carditis. In this setting, proof of recent streptococcal infection and either one major or one minor criterion may allow a presumptive diagnosis. Proof of recent streptococcal infection is necessary, except for isolated chorea.

of flaccidity combined with hypotonia and slow relaxation of deep tendon reflexes. Choreiform movements are abrupt and erratic without being rhythmic or repetitive, and usually subside during sleep. Face, hands, and feet are most commonly affected; facial movements include grimacing, frowning, grinning, and pouting. Children commonly are unable to sustain prolonged hand contraction, resulting in the “milkmaid” sign. In other patients, emotional lability, personality changes, restlessness, hyperactivity, irritability, and episodes of anger and tearfulness may herald the onset of chorea. Occasionally, typical “spooning” is observed with hyperextension of the hands [Stollerman, 1985]. Choreiform movements usually subside in 2 to 4 months but may persist for 1 year or more. Chorea and arthritis do not usually accompany each other in acute rheumatic fever; however, carditis frequently develops as the chorea is improving. Rarely, acute rheumatic fever may be accompanied by other neurologic problems such as meningoencephalitis, encephalitis [Benda, 1948], seizures [Goldenberg et al., 1992], pseudotumor cerebri [Mitkov, 1961], papilledema [Chun et al., 1961], diplopia [Schieken et al., 1973], central retinal occlusion [Ling et al., 1969], transient intellectual loss [Gatti and Rosenheim, 1969], and acute psychosis [Wertheimer, 1961]. Combined, these complications occur in 3% to 5% of all patients.

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Chorea, obsessive-compulsive disorder, tic disorder, and Tourette syndrome may all have a common autoimmune pathway. It has been reported that some children with chorea have obsessive-compulsive disorder, and that the obsessivecompulsive disorder resolves before or simultaneously with the resolution of the chorea [Swedo et al., 1993, 1998]. Additionally, an increased prevalence of obsessive-compulsive disorder has been noted in children with tics and Tourette syndrome. An increased prevalence of antineuronal antibodies, as well as increased levels of antistreptococcal antibodies, has been reported in all four of these diseases. It has been shown that in patients with chorea, obsessivecompulsive disorder, or tic disorder, there is an increased incidence of the histocompatability locus antigen marker D8/17, which has been reported more frequently in rheumatic fever patients [Allen et al., 1995; Murphy et al., 1997; Swedo, 1994; Swedo et al., 1997]. The acronym PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) has been suggested for some of these conditions in which there is a combination of behavioral problems, obsessive-compulsive behavior, and tics when associated with an antecedent group A betahemolytic streptococcal infection [Garvey et al., 1998]. Some studies refute the connection between group A betahemolytic streptococcal infection and obsessive-compulsive disorder with tics, citing evidence that although children with Sydenham’s chorea have behavioral difficulties, they do not have an increased incidence of obsessive-compulsive disorder [Faustino et al., 2003]. Inattention was the most common behavioral disturbance found during the acute episodes in children with Sydenham’s chorea.

Laboratory Findings in Sydenham’s Chorea Laboratory studies include serologic documentation of antecedent streptococcal infection with an antistreptolysin-O titer, demonstration of a prolonged PR interval on electrocardiogram, elevated C-reactive protein or erythrocyte sedimentation rate, and leukocytosis. Although throat culture may show group A beta-hemolytic streptococci, an elevated or increasing antistreptolysin-O titer is required. An elevated anti-DNase-B increases the sensitivity of an antistreptolysin-O titer alone from 80% to 95% and may be necessary, especially in isolated chorea, in which sensitivity may only be 65%. To exclude other conditions manifesting with chorea, patients may need additional diagnostic studies, including serum ceruloplasmin, thyroxine, calcium, and antinuclear antibody titers. In patients with Sydenham’s chorea, electroencephalograms may demonstrate diffuse paroxysmal features and generalized or posterior slowing [Ganji et al., 1988]. Cerebrospinal fluid examinations and neuroimaging are rarely necessary. Of interest is the finding of antineuronal antibodies in the cerebrospinal fluid of patients with chorea [Swedo, 1994]. The specificity of these antibodies is not well known, and they are frequently documented in patients with central nervous system lupus [Bluestein, 1997]. A 3-year-old child with chorea was reported as having the first example of a persistently abnormal MRI, showing a cystic abnormality in the caudate and putamen [Emery and Vieco, 1997]. Subsequent longitudinal radiologic studies of patients with Sydenham’s chorea demonstrated that

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although the majority of patients with this disorder have a normal brain MRI, those with abnormalities during the symptomatic period often continue to demonstrate these same abnormalities when the disease is clinically quiescent or resolved [Faustino et al., 2003]. Most patients with MRI abnormalities demonstrate abnormal signal intensity or cystic changes in the caudate nuclei; subcortical foci and multiple peripheral white matter foci of abnormal signal have also been reported [Emery and Vieco, 1997; Faustino et al., 2003; Robertson and Smith, 2002].

Pathology of Central Nervous System Involvement Neuropathologic findings in acute rheumatic fever are rare. Rheumatic proliferative endarteritis is limited to the small cortical and meningeal vessels with spotty patches of gray matter degeneration [Halbreich et al., 1976].

Treatment of Sydenham’s Chorea All patients with acute rheumatic fever, including those whose only manifestation is chorea, should receive a 10-day course of penicillin or erythromycin. Prophylaxis with penicillin or sulfadiazine should be started immediately and continued at least until adulthood because of frequent reinfection and the risk of rheumatic heart disease with subsequent streptococcal pharyngitis. More specifically, when residual valvular disease exists, prophylaxis should continue for at least 10 years after the last episode and at least until age 40. If there is no residual valvular disease, the duration of treatment beyond 10 years or into adulthood is not clearly defined. When Sydenham’s chorea is diagnosed and there is no valvular disease, the duration of prophylaxis should be at least 5 years or until age 21, whichever is longer [Dajani et al., 1995]. Children who develop chorea as the sole manifestation of acute rheumatic fever during the initial episode of illness have an approximate 50% risk of developing rheumatic heart disease with subsequent infection [Aron et al., 1965]. In addition, studies have suggested that in certain choreaprone patients, recurrence of Sydenham’s chorea may follow either undetectable streptococcal infection or another infectious trigger [Berrios et al., 1985]. Sydenham’s chorea has been treated successfully with chlorpromazine, haloperidol [Shenker et al., 1973], phenobarbital, diazepam, valproic acid [Daoud et al., 1990], and corticosteroids [Green, 1978]. In mild cases, cyproheptadine may be effective. Other agents, such as clonidine, pimozide [Shannon and Fenichel, 1990], and corticosteroids [Faustino et al., 2002] may be beneficial in refractory cases. Complete recovery can be expected within 2 to 6 months, although some children may have residual motor, visuomotor, or cognitive dysfunction and a variety of neuropsychiatric manifestations [Bird et al., 1976; Faustino et al., 2002; Leonard et al., 1993; Stehbens and MacQueen, 1972; Swedo et al., 1989]. In some children with Sydenham’s chorea, atlantoaxial subluxation may occur during the acute episode of chorea, with symptoms of neck stiffness, decreased mobility, and pain [Coster and Cole, 1990]. In such patients, differentiating this complication from juvenile rheumatoid arthritis may require further clinical and laboratory evaluation and specific orthopedic intervention. In rare instances, recur-

rences of chorea may occur in patients without evidence of rheumatic cardiac involvement decades after the childhood onset of symptoms [Gibb and Lees, 1989].

Lyme Disease Lyme disease is an important cause of neurologic symptoms in children. The illness follows a tick bite and occurs in endemic areas during the summer months. The clinical course of Lyme disease is marked by stages similar to the course of syphilis, another spirochetal infection. The early stage begins with the tick bite and includes a flulike illness and the appearance of an oval, expanding rash at the site of the tick bite. At this stage, systemic infection with Borrelia burgdorferi may be documented by culture. Within several weeks, the patient may develop early neurologic manifestations, which most commonly include facial nerve palsy and aseptic meningitis but can also include other cranial neuropathies or transverse myelitis and can represent direct invasion of the organism into cerebrospinal fluid [Huisman et al., 1999]. Acute sinovenous thrombosis with consequent pseudotumor cerebri has been reported as well [Ansari et al., 2002]. The illness resolves spontaneously, but the resolution may be hastened by antibiotic treatment (amoxicillin or erythromycin in children younger than 9 years old and tetracycline in children age 9 years or older for 10 to 30 days). Weeks to months later, the patient who was not treated with antibiotics may develop episodic arthritis of the large joints, primarily the knee. Characteristically, the knee becomes acutely effused, but not particularly tender or hot. The often dramatic joint swelling lasts for several days and resolves but returns multiple times if treatment with antibiotics is not started. The diagnosis may be confirmed after the first few weeks with a positive serum IgG titer against B. burgdorferi. Western blotting may be used to confirm the diagnosis if the titer is equivocal [Steere, 1989]. Polymerase chain reaction amplification of the B. burgdorferi genome in the cerebrospinal fluid is available as well [Ansari et al., 2002]. Years after the acute infection, some patients develop late neuroborreliosis. In children, this rare complication may manifest as a subtle encephalopathy with stuttering and memory disturbances. Adults may develop a multiple sclerosis–like illness, optic neuritis, seizures, and chronic meningitis. The diagnosis of late neuroborreliosis is confirmed by the demonstration of an elevated intrathecal IgG titer compared with serum titer. Treatment with intravenous ceftriaxone for 1 month to penetrate the blood-brain barrier is indicated, but the response is variable. There is no evidence that treatment lasting longer than 4 weeks is of additional benefit [Bingham et al., 1995; Logigian et al., 1990; Szer et al., 1991].

CONNECTIVE TISSUE DISORDERS The key neurologic and laboratory findings in connective tissue disorders are summarized in Table 73-3 [Tan, 1986].

Systemic Lupus Erythematosus Systemic lupus erythematosus is the second most common chronic rheumatic illness of children after juvenile idio-

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TABLE 73-3 Key Neurologic and Laboratory Findings in Connective Tissue Diseases DISEASE

NEUROLOGIC FINDINGS

LABORATORY FINDINGS

SLE

Encephalopathy, chorea, seizures, aseptic meningitis, psychosis, behavioral or cognitive dysfunction, headaches, strokes, neuropathy, myelitis Seizures, blurred vision, bulbar palsy, optic neuritis, trigeminal neuropathy Same as SLE Encephalopathy, optic neuritis, aseptic meningitis, recurrent paresis, myelopathy, neuropathy, autonomic dysfunction

Elevated ANA, low C3 and C4, pancytopenia, hematuria, proteinuria, autoantibodies, LAC, elevated aCL

Scleroderma: coup-de-sabre deformity Mixed connective tissue disease Sjögren’s syndrome

Elevated ANA and rheumatoid factor Same as SLE plus elevated anti-RNP, elevated CK Positive ANA, rheumatoid factor, antibodies to SSA/Ro and SSB/La

aCL, anticardiolipin antibody; ANA, antinuclear antibody; C3, third component of complement; C4, fourth component of complement; CK, creatine kinase; LAC, lupus anticoagulant; RNP, ribonucleoprotein; SLE, systemic lupus erythematosus.

pathic arthritis. At the time of initial presentation, approximately 3.5% of patients with systemic lupus erythematosus are younger than 10 years of age, and 28% are younger than 19 years of age. Approximately 80% of patients are female. Revised criteria for the classification of systemic lupus erythematosus, developed by the American College of Rheumatology (Box 73-3), call for the presence of at least 4 of 11 specific criteria, including a positive test for antinuclear antibody. The antinuclear antibody alone is not sufficient to establish the diagnosis. It must be associated with multiorgan involvement. Arthritis, arthralgia, fever, and photosensitive rash are the most common initial complaints, with renal, cardiac, and neurologic involvement responsible for chronic disability. Lymphadenopathy, hepatosplenomegaly, pleural and pericardial effusions, pulmonary infiltrates, pericarditis, abdominal pain, and even peritonitis may be present at the time of initial evaluation [Cassidy and Petty, 2001; Szer and Jacobs, 1992].

Box 73-3 REVISED CRITERIA FOR THE CLASSIFICATION OF SYSTEMIC LUPUS ERYTHEMATOSUS (1982) Seizures or psychosis Serositis: Pleuritic pain, friction rub, effusion, or pericarditis Arthritis: Two or more peripheral joints Nephritis: Proteinuria > 500 mg/day or cellular casts Malar rash Oral or nasal ulcers Discoid lupus rash Photosensitive rash Antinuclear antibody: In the absence of a drug known to be associated with drug-induced lupus syndrome Hematologic disorder: Leukopenia <4000/mm on two or more occasions, or hemolytic anemia with reticulocytosis, or thrombocytopenia <100,000/mm in the absence of offending drugs, or lymphopenia <1500/mm on two or more occasions Autoantibody: Anti-ds-DNA, anti-Sm, false-positive serologic test for syphilis, positive LAC, elevated aCL aCL, anticardiolipin antibody; ds-DNA, double-stranded DNA; LAC, lupus anticoagulant; Sm, Smith. Adapted from Tan EM, et al. Arthritis Rheum 1982;25:1271; and Hochberg MC. Arthritis Rheum 1997;40:1725.

Renal disease occurs in 60% to 80% of children. It may range from an active urinary sediment to clinical renal disease with varying degrees of involvement, including nephrotic syndrome and acute or chronic glomerulonephritis. In addition to an abnormal urinalysis, low serum complement levels, and high antibodies to double-stranded DNA, patients have a decreased glomerular filtration rate and abnormal renal biopsy. Management of systemic lupus erythematosus is highly individual. Patients with minor organ disease are treated with relatively benign interventions, and children with major organ involvement who are at risk for organ failure are treated aggressively. A thorough evaluation of the extent and intensity of internal organ inflammation and injury dictates the subsequent choice of therapy. In general, acute worsening of organ-specific symptoms should be prevented, because each exacerbation may result in cumulative damage. The prognosis for children with systemic lupus erythematosus has improved dramatically, with an estimated 10-year survival of 85% [Cassidy and Petty, 2001; Szer and Jacobs, 1992; Takei et al., 1997].

Neurologic Manifestations Estimates of nervous system involvement in childhood systemic lupus erythematosus range from 20% to 45% [Parikh, 1995; Quintero-Del-Rio and Van Miller, 2000; Sibbitt, 2002; Steinlin et al., 1995]. Early reports in children with systemic lupus erythematosus suggested that central nervous system involvement was the second most common cause of death. More recently, the outcome of children with central nervous system lupus appears favorable, with most showing recovery [Parikh et al., 1995; Steinlin et al., 1995].

SEIZURES Approximately 10% of children with systemic lupus erythematosus develop generalized and occasionally focal motor seizures [Parikh et al., 1995; Steinlin et al., 1995]. Seizures usually occur during the first year of illness and may be the initial manifestation of systemic lupus erythematosus, but they may occur at any stage. In patients with advanced renal disease, seizures may be secondary to hypertension, uremia, and electrolyte disturbances. Hypertensive encephalopathy may be the presenting symptom of systemic

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lupus erythematosus in children. After immunosuppressive treatment has begun, opportunistic infections of the central nervous system and cerebral edema may cause seizures. Electroencephalography may show multifocal paroxysmal sharp-wave or slow-wave activity or, in rare instances, focal abnormalities. Quantitative electroencephalograms may show relatively specific changes [Ritchlin et al., 1992].

NEUROPSYCHIATRIC LUPUS Neuropsychiatric symptoms associated with childhood systemic lupus erythematosus include depression, emotional lability, confusion, headache, anxiety, personality changes, acute psychosis, and progressive dementia. It is estimated that approximately 25% of children with lupus will develop such symptoms; of these patients, approximately 20% to 30% will manifest them as the first symptom of the disease [Parikh et al., 1995; Steinlin et al., 1995]. Depression generally occurs early in the illness, whereas psychosis is observed in later stages. Depression typically is associated with reaction to the serious nature of the disease, to the stress of repeated hospitalizations, and to adolescent concerns about body image and peer rejection. Memory loss, disorientation, impaired cognitive function, and symptoms suggestive of an affective disorder with unusual elation or irritability have also been observed [Silber et al., 1984]. Preexisting psychiatric disorders may be exacerbated during the course of systemic lupus erythematosus [Sergent et al., 1975]. Although they may prove beneficial, antidepressant or antianxiety agents have unpredictable side effects. Acute emotional disturbances may be severe, but the ultimate prognosis may be excellent [Parikh et al., 1995; Steinlin et al., 1995]. In patients who are receiving chronic, intensive therapy for systemic lupus erythematosus, neuropsychiatric lupus can be difficult to distinguish from steroid psychosis. Serum and cerebrospinal fluid studies may be helpful in making this distinction, but in some cases, only close observation of the response to an increase in corticosteroid dose or substitution with cyclophosphamide may crystallize the differential diagnosis [Schor, 2000].

30% of patients who present with neurologic symptoms [Herd et al., 1978]. Systemic lupus manifestations often occur within 1 year of onset; rarely, a prolonged latent interval may ensue after the onset of chorea [Parikh et al., 1995; Steinlin et al., 1995]. Approximately 50% of children with lupus chorea develop other central nervous system manifestations, including seizures and neuropsychiatric disturbances. Chorea has also been associated with thromboembolic disease and elevated anticardiolipin antibody [Besbas et al., 1994].

REYE-LIKE SYNDROME A Reye-like syndrome associated with acetylsalicylic acid treatment of systemic lupus erythematosus has been recognized [Hansen et al., 1985]. Salicylate hepatocellular injury appears to be relatively common in patients with rheumatic disorders, but its relation to Reye’s syndrome has raised the possibility of some other etiologic relation between salicylate therapy, various rheumatic disorders, and idiopathic Reye’s syndrome. This syndrome has not been seen with other nonsteroidal anti-inflammatory agents.

CEREBROVASCULAR DISEASE

Headaches are common in children and adolescents with systemic lupus erythematosus [Parikh et al., 1995; Steinlin et al., 1995]. Headache usually occurs during exacerbation of systemic symptoms and frequently is associated with other neurologic symptoms. Unless objective neurologic symptoms are present, the diagnostic workup may yield few abnormalities, although evaluation for a hypertensive encephalopathy should be considered [Parikh et al., 1995; Steinlin et al., 1995]. Most patients will respond to increased dosages of corticosteroids. In a prospective study of adult patients with systemic lupus erythematosus, it was found that vascular headache developed in 26% of adult patients, and muscle contraction headache in 40% [Vazquez-Cruz et al., 1990].

Although it is unusual for a cerebrovascular syndrome to be the initial manifestation of systemic lupus erythematosus, approximately 3% of children develop cerebrovascular occlusive disease that results in hemiplegia, aphasia, or sensory and visual impairments [Parikh et al., 1995; Steinlin et al., 1995]. Most of these patients have serious renal, cardiac, pulmonary, or hematologic disease with hypertension or thrombocytopenia. Even if there is recurrent hemiplegia, significant recovery may occur. Antiphospholipid antibody has been associated with thrombosis in systemic lupus erythematosus, especially when lupus anticoagulant is present [Levy et al., 2003]. Alternatively, thrombotic or thromboembolic disease may be due to a vasculopathy with or without autoimmunity, atheromatous disease, valvular disease, or vasculitis [Bruyn, 1995; West, 1994]. Additionally, in adults it has been reported that elevated homocysteine levels increase the risk of atherothrombotic events [Petri et al., 1996]. A recent case report indicates that perivenous inflammation with secondary calcification may occur in systemic lupus erythematosus. This postmortem finding was preceded by computed tomography (CT) and MRI evidence of foci of breakdown of the blood-brain barrier, calcifications, and a clinical picture consistent with focal vascular dysfunction and diffuse encephalopathy [Matsumoto et al., 1998]. Multifocal cerebral dysfunction with patchy areas of altered signal intensity on MRI have been interpreted as acute vascular lesions associated with pulse steroid therapy in patients with systemic lupus erythematosus. This syndrome responds well to substitution of cyclophosphamide for pulse methylprednisolone, and, as such, it is imperative that it be promptly recognized [Tabata et al., 2002].

CHOREA

HYPERTENSIVE ENCEPHALOPATHY

Chorea occurs in perhaps 5% of children with systemic lupus erythematosus and is the initial symptom in 25% to

Headache, seizures, coma, and focal ischemic central nervous system injury have been reported as manifestations

HEADACHE

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of hypertensive encephalopathy associated with lupus nephritis [Cassidy et al., 1977]. Although the mechanism of this encephalopathy is unknown, controlling blood pressure and treatment with corticosteroids frequently result in substantial neurologic improvement.

CRANIAL NERVE, BRAINSTEM, AND SPINAL CORD DYSFUNCTION Ophthalmoplegia, ptosis, diplopia, facial numbness, vertigo, sensorineural hearing loss [Hisashi et al., 1993], vocal cord paralysis [Teitel et al., 1992], and ataxia have been described in children with systemic lupus erythematosus. Brainstem involvement is usually observed in conjunction with other nervous system symptoms such as chorea and seizures [Gold and Yahr, 1960]. Approximately 6% of children with systemic lupus erythematosus manifest visual symptoms, which include blurred vision, sudden blindness, and field loss [Brandt et al., 1975]. Retinal hemorrhages, cotton wool exudates, papilledema, optic neuritis, and cytoid bodies have all been reported [Cassidy et al., 1977; Hackett et al., 1974]. Retinal artery occlusion may also occur, with resulting transient or permanent visual loss. Papilledema associated with pseudotumor cerebri caused by either the disease or corticosteroid therapy has also been reported [Green et al., 1995]. If papilledema is present, the possible presence of increased pressure or a mass lesion should be assessed before lumbar puncture is performed [Brandt et al., 1975; Carlow and Glaser, 1974]. Patients with either retinal artery occlusion or papilledema should be treated with high doses of corticosteroids after elimination of structural or occlusive cerebrovascular disease. Transverse myelopathy that causes both paraplegia and sensory loss as the initial or late neurologic manifestations of systemic lupus erythematosus has been reported [Andrianakos et al., 1975; Meislin and Rothfield, 1968]. Other studies in adults have shown an association with antiphospholipid antibodies [Kovacs et al., 1993]. Early treatment with high doses of corticosteroids alone or in combination with cyclophosphamide has been used, but improvement was variable [Berlanga et al., 1992; Boumpas et al., 1990; Chan and Boey, 1996; Propper and Bucknall, 1989].

CENTRAL NERVOUS SYSTEM INFECTIONS Infection of the central nervous system in children with systemic lupus erythematosus is relatively rare [Cassidy and Petty, 2001; Fish et al., 1977; Walravens and Chase, 1976]. Bacterial meningitis, opportunistic bacterial infection, and fungal meningitis (aspergillosis, nocardiosis, and cryptococcosis) have been reported. Brain abscess may be difficult to differentiate from a multifocal vasculitis, but differentiation may be facilitated by using serial CT scans and angiography. Multiple abscesses of the central nervous system may be relatively silent; if suspected, broadspectrum antimicrobial or antifungal therapy should be instituted after appropriate cultures are obtained.

LUPUS ASEPTIC MENINGITIS The syndrome of lupus aseptic meningitis, accompanied by a sterile cerebrospinal fluid lymphocytic pleocytosis, may be

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manifested by nuchal rigidity, fever, and headache and may occur early in childhood lupus. This syndrome has been reported in association with nonsteroidal anti-inflammatory drugs and trimethoprim-sulfamethoxazole use [Escalante and Stimmler, 1992]. Clinical manifestations and cerebrospinal fluid abnormalities may persist for several weeks before resolving spontaneously. Therapy with corticosteroids may improve this condition, but the data are inconclusive because of the self-limited course [Canoso and Cohen, 1975; Keefe et al., 1974].

PERIPHERAL NERVOUS SYSTEM INVOLVEMENT Involvement of the peripheral nervous system occurs in approximately 5% of children with systemic lupus erythematosus. Peripheral neuropathies with symptoms consisting of paresthesias, numbness, and distal weakness are usually relatively mild in severity and course, although severe forms of acute lumbosacral plexopathies have been reported [Bailey et al., 1956; Jacob, 1963]. Neuropathy manifesting as either mononeuritis multiplex or acute demyelinating polyneuropathy may occur at any time during systemic lupus erythematosus, may recur, and generally worsens when central nervous system involvement is greater. Polyradiculoneuropathy may mimic Guillain-Barré syndrome in children; however, this pattern is extremely rare [Norris et al., 1977; Robson et al., 1994].

MYOPATHY Myositis is rare in systemic lupus erythematosus, although myalgias and generalized weakness are common. Myositis can be distinguished from corticosteroid-related myopathy by demonstrating elevated levels of muscle enzymes, electromyography consistent with myopathic and fibrillation activity, and lack of vacuolization in muscle biopsies. One case report demonstrated pyridostigmine-responsive myasthenia gravis complicating childhood systemic lupus erythematosus [Nishimura et al., 1997]. Although children with myasthenia gravis may have circulating serum antinuclear antibodies, clinical systemic lupus erythematosus is highly unusual.

DRUG-INDUCED LUPUS SYNDROME. Many drugs have been reported to induce a lupus-like syndrome in children and adults [Rubin, 1997]. In general, this disorder is milder than spontaneous systemic lupus erythematosus and occurs with equal frequency in males and females [Totoritis and Rubin, 1985]. Arthritis, pneumonitis, and pericarditis are common, whereas rashes and alopecia are less frequent. Hepatosplenomegaly, lymphadenopathy, and acute pancreatitis may occur in some patients; renal disease appears less often [Rubin, 1997]. Procainamide, hydralazine, and isoniazid are the three drugs that have most commonly induced this syndrome. These drugs share a primary amine or hydrazine portion that is acetylated by the N-acetyl transferase system of the liver in two different phenotypic expressions [Rubin, 1997]. The risk of a druginduced syndrome appears to be much greater in the “slow” acetylators than in the “fast” acetylators. Antiepileptic drugs and phenothiazines have also been associated with a drug-induced lupus syndrome. Anti-

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epileptic drugs reported to cause this disorder in children include phenytoin, ethosuximide, carbamazepine, and trimethadione [Rubin, 1997; Singsen et al., 1976]. Although children receiving these drugs are usually asymptomatic, approximately 20% of them produce antinuclear antibodies; these children commonly have normal immunoglobulin and serum complement levels and remain free of a clinical lupus-like syndrome. Antiepileptic medication therefore may be continued [Singsen et al., 1976]. Among patients in whom antiepileptic drugs have been discontinued, the presence of antinuclear antibodies may remain for several years. Recurrent seizures in patients whose initial seizures were well controlled suggest a drug-induced lupus-like syndrome. Moreover, when increasingly higher drug doses produce increased seizure activity, an antinuclear antibody study is appropriate. Although the antinuclear antibody is positive in both systemic and drug-induced systemic lupus erythematosus, specific antihistone antibodies are associated with drug-induced disease, whereas anti-double-stranded DNA tends to be elevated in systemic lupus erythematosus. Discontinuing or substituting other antiepileptic drugs dramatically reduces seizure activity in some patients. Only rarely will corticosteroids be necessary for seizure control. Drug-induced systemic lupus erythematosus has been associated with etanercept therapy in a child with juvenile idiopathic arthritis [Lepore et al., 2003].

Laboratory Findings Laboratory features of systemic lupus erythematosus commonly include a positive antinuclear antibody titer, low C3 and C4 levels, leukopenia, direct Coombs-positive hemolytic anemia, hematuria, and proteinuria. Abnormal autoantibodies may include antibody to double-stranded DNA, Sm (Smith), RNP (ribonucleoprotein), Ro (or SSA), La (or SSB), and anticardiolipin. In addition, there may be a paradoxical prolongation of the partial thromboplastin time because of antiphospholipid antibodies. Antibodies to antiphospholipid may also produce a biological false-positive rapid plasma reagin (RPR) or VDRL (Venereal Disease Research Laboratories). In adults a strong correlation between MRI changes and the presence of a positive lupus anticoagulant or anticardiolipin antibody exists, but there is no clear correlation with neuropsychiatric disease [Ishikawa et al., 1994; Manco-Johnson and Nuss, 1995; Molad et al., 1992; Toubi et al., 1995]. Pediatric case reports have also been published showing some correlation between disease and antiphospholipid antibodies as demonstrated by one of these tests [Steinlin et al., 1995; von Scheven et al., 1996]. Elevated lupus anticoagulant (LAC) appears to confer a significant increased risk of arterial or venous thrombotic events [Galli et al., 2003]. Anticardiolipin IgG fraction and anti-ß2-glycoprotein I antibodies may also correlate, but their association is less certain [Galli et al., 2003]. Several mechanisms explaining the pathogenesis of central nervous system lupus have been reported [Bruyn, 1995]. In most patients with documented central nervous system lupus, evidence of immune-mediated abnormalities cannot be found, suggesting multifactorial causes of central nervous system disease. Interestingly, one study found that approximately 75% of observed neurologic events were

attributed to metabolic, hematologic, or infectious factors rather than to the primary disease process [Kaell et al., 1986]. Serum complement and autoantibody levels may remain normal. The cerebrospinal fluid is often benign, and imaging modalities are of little value unless there is an ischemic event [Hirohata et al., 1985; Szer and Jacobs, 1992]. However, cerebrospinal fluid examination is often necessary to rule out infectious causes. In support of a diagnosis of immune disease, studies of cerebrospinal fluid immunoglobulin production have documented elevations of IgG, IgG/albumin ratio, and the cerebrospinal fluid IgG index and the presence of oligoclonal IgG, suggesting accelerated central nervous system IgG synthesis. Further support for immune-mediated disease may be found in the relatively high incidence of antineuronal and antiribosomal P antibody in some children with systemic lupus erythematosus [Reichlin, 2003; Silverman, 1996; West et al., 1995]; however, antiribosomal P was not found to be sensitive for neuropsychiatric manifestations of systemic lupus erythematosus in another series [Press et al., 1996]. In addition, endothelial or vascular injury may be a complement-mediated immunologic insult, because the choroid plexus has been reported as the deposition site of complement and immune complexes; cerebrospinal fluid C4 also appears to be reduced [Hadler et al., 1973; Sher and Pertschuk, 1974]. In addition, cerebrospinal fluid anti-double-stranded DNA complexes and lymphocytotoxic antibodies have been documented in central nervous system lupus [Bluestein, 1997; Carr et al., 1975]. Serial cerebrospinal fluid C4 complement levels may help to distinguish between neuropsychiatric symptoms caused by corticosteroids and those caused by systemic lupus erythematosus. A serial decrease in C4 complement level suggests increased disease activity rather than a drug-induced phenomenon. More recent studies demonstrate moderate levels of interleukin-6 in neuropsychiatric systemic lupus erythematosus. The significance of this finding must be interpreted with caution because significantly high levels of interleukin-6 may be found in central nervous system infection [Tsai et al., 1994]. At present, cerebrospinal fluid findings cannot reliably confirm the diagnosis of neuropsychiatric symptoms associated with central nervous system lupus. False-positive elevation of antistreptococcal antibody titers can occur in lupus chorea and may incorrectly result in the diagnosis of Sydenham’s chorea unless antinuclear antibody titers are obtained. Serum complement is decreased in lupus chorea, but cerebrospinal fluid complement, antidouble-stranded DNA antibody titers, and immunoglobulin synthesis have not been studied [Kukla et al., 1978]. In adults, a significant correlation exists between chorea and the presence of antiphospholipid antibodies [Asherson et al., 1987]. This association has also been reported in children [Besbas et al., 1994]. In patients with transverse myelopathy, cerebrospinal fluid analysis may demonstrate increased protein concentration, decreased glucose, and a monocytic pleocytosis [Al-Husaini and Jamal, 1985].

Neurodiagnostic Testing Neuroimaging with either CT or MRI scans is essential for evaluating the patient with systemic lupus erythematosus who is suspected of having intracranial disease [Carette

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A

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B

FIGURE 73-1. A, CT scan of a 14-year-old female with systemic lupus erythematosus, isolated seizures, depressed affect, and intellectual impairment. Cortical atrophy is prominent. B, T1-weighted MRI in sagittal plane of same patient, demonstrating mild enlargement of the frontoparietal sulci, indicative of atrophy. (A, Courtesy of Dr. Joseph Thompson, and B, Courtesy of Dr. David B. Hinshaw, Jr., Department of Neuroradiology, Loma Linda University Children’s Hospital.)

FIGURE 73-2. MRI of a 15-year-old female with systemic lupus erythematosus who developed seizures, depression, generalized weakness, and severe membranous nephritis. Proton density–weighted axial MR image through the high frontal region shows multiple bright cortical lesions (arrows; more lesions are visible than those marked). The lesions represent acute microinfarctions that result from small segmental leptomeningeal and parenchymal artery thromboses. With gadolinium, these microinfarctions tend to enhance in the subacute phase. (Courtesy of Dr. Joseph Thompson, Department of Neuroradiology, Loma Linda University Children’s Hospital.)

FIGURE 73-3. MRI of a 9-year-old female with systemic lupus erythematosus who had fever, leukopenia, abdominal pain, worsening headache, and cardiomyopathy. A T2-weighted axial image through the centrum semiovale above the lateral ventricles shows multiple bright white matter foci (largest labeled with arrow) and intrafalcial hemorrhage (arrowheads). No cortical lesions are discerned. Focal T2 lengthening is somewhat nonspecific as to whether it results from demyelination, microvascular infarction, edema, or more probably a combination of these. Cerebral falx hemorrhage is characterized by a black appearance on T2-weighted images of deoxyhemoglobin and bright adjacent methemoglobin or serum. (Courtesy of Dr. Joseph Thompson, Department of Neuroradiology, Loma Linda University Children’s Hospital.)

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et al., 1982; Provenzale et al., 1994]. Such studies may show atrophy (Fig. 73-1), infarction (Fig. 73-2), low-density lesions in the cerebral white matter (Fig. 73-3) [Isshi et al., 1994], or hemorrhage [Aisen et al., 1985; Kovacs et al., 1993]. MR angiography or venography may detect sinovenous thrombosis [Steinlin et al., 1995]. Cerebral angiography may be helpful in further differentiating arterial thrombotic from embolic disease but may be normal in children because small vessel arterial changes may not be demonstrable [Jones et al., 1975]. MRI has been used to detect myelopathy in a child as young as 5 years of age [Vieira et al., 2002]. Single-photon emission computed tomography (SPECT) is a sensitive tool for demonstrating diffuse and multiple perfusion abnormalities in children and adults with central nervous system events (Fig. 73-4). Unfortunately, the usefulness of SPECT is limited. It is not specific for central nervous system lupus, and longitudinal assessment with this modality correlates poorly with clinical status [Szer et al., 1993].

Treatment of Neurologic Manifestations Treatment of the neurologic complications seen in children with systemic lupus erythematosus can be categorized as follows.

Treatment of generalized symptoms requires controlling the underlying inflammatory disorder, correcting metabolic or systemic abnormalities such as hypertension, and administering specific symptom-directed medications such as antiepileptic drugs for the treatment of seizures; analgesic medications for headache; antidepressants, sedatives or tranquilizers, or antipsychotic agents for specific psychiatric symptoms; and dopamine blocking agents for the treatment of chorea. Commonly used antiepileptic drugs in children with seizures associated with systemic lupus erythematosus include phenobarbital, phenytoin, diazepam, lorazepam, valproate, and carbamazepine. Antiepileptic drug use should not be prolonged unnecessarily; discontinuation should be considered when the primary disease is well controlled. In moderate doses, corticosteroids do seem to have beneficial effects in studies of adults with mood or cognitive disorders, suggesting that these are often secondary to neuropsychiatric disease [Carbotte et al., 1995]. However, corticosteroids have also been associated with a variety of behavioral and mood disorders and with psychosis, although the mechanism of this toxic response is unknown. Treatment of lupus chorea with haloperidol, chlorpromazine, valproate, or corticosteroids is usually successful in conjunction with treatment of the underlying disorder.

FIGURE 73-4. Representative single-photon emission CT study of a 14-year-old male with systemic lupus erythematosus and acute onset of optic neuritis and transverse myelitis. The study was done immediately after the onset of central nervous system symptoms and shows bilateral cerebral hemisphere decreased perfusion defects in the right frontal region (white arrow) and in the right basal ganglia (black arrow) compatible with antecedent ischemia. (Courtesy of Dr. M.T. Parisi, Department of Radiology, Children’s Hospital of Los Angeles.)

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Treatment of central nervous system infection depends on the infectious agent causing the central nervous system disease. The infection will necessitate a diminution of the immunosuppressive therapy until the infection is controlled. Evaluation for central nervous system infection may be indicated in patients in whom the history or clinical examination suggests systemic infection that may have spread to the central nervous system or in patients in whom no definite explanation for their central nervous system symptoms can be determined. A high index of suspicion for fungal infection must be maintained. MRI and cerebrospinal fluid examination provide the most accurate and sensitive methods for such an evaluation. Anticoagulation may be considered in patients with ischemic cerebrovascular insults who have antiphospholipid antibodies, because there is a significant risk for recurrent thrombotic episodes [Bruyn, 1995; Khamashta et al., 1995]. Agents used in adults have included acetylsalicylic acid, heparin, and warfarin. In adults, prevention of recurrent venous thrombosis may require doses of warfarin with an international normalized ratio of 2 to 3 [Meroni et al., 2003]. It is unclear, even in studies of adults with arterial thromboembolic disease, if anticoagulation is effective, even with a higher international normalized ratio [Brey et al., 2003]. Because of the small number of children with systemic lupus erythematosus with such events, it is unlikely that controlled clinical studies will be completed. Given the nature of children’s activities and the reports of hemorrhage in children without systemic lupus erythematosus but with a lupus-type anticoagulant [Becton and Stine, 1997], it might be suspected that the risk of serious or life-threatening hemorrhage would be greater than in adults. Various alternative regimens have been recommended in children [Ravelli and Martini, 1997; Silverman, 1996]. Steroids have not been found to alter the pathology of antiphospholipid manifestations. It is imperative that patients with hypertension and thrombocytopenia do not receive anticoagulants because of the potential risk of central nervous system hemorrhage. Patients on long-term steroid therapy for systemic lupus erythematosus who also require anticoagulation must be monitored for the increased risk of gastrointestinal bleeding. Immunosuppressive therapy with corticosteroids has proved to be the mainstay of treatment for patients with neuropsychiatric symptoms or symptoms associated with vasculitis [Hammer and Saltissi, 1986; Sanna et al., 2003]. High-dose steroids have also been used for the treatment of coma, seizures, chorea, and transverse myelitis [Chan and Boey, 1996; Eyanson et al., 1980; Harisdangkul et al., 1995; West, 1994]. Adverse neuropsychiatric effects, such as psychosis or vacuolar myopathy, seen with high doses or chronic administration of corticosteroids are unusual [Wysenbeek et al., 1990]. Cytotoxic agents such as mycophenolate [Buratti et al., 2001; Contreras et al., 2004; Kapitsinou et al., 2004] or cyclophosphamide are used in patients with serious renal or neurologic disease. Candidates for such treatment include those who have evidence of diffuse proliferative glomerulonephritis and those with central nervous system lupus or myelopathy who are refractory to corticosteroids. Because there are no prospective controlled trials comparing different immunosuppressive and cytotoxic modalities in the

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various central nervous system lupus disorders, it is difficult to feel confident about a specific therapeutic regimen [Berlanga et al., 1992; Neuwelt et al., 1995; Propper and Bucknall, 1989]. Whereas mycophenolate is increasingly being used in steroid-resistant major organ disease and diffuse proliferative lupus nephritis, there are no data about the effectiveness of azathioprine or mycophenolate in central nervous system lupus.

Central Nervous System Pathology Neuropathologic studies of childhood and adult systemic lupus erythematosus are rare, and available reports document a variety of abnormalities. Foci of acute cortical and cerebellar encephalomalacia with neuronal loss and demyelination have been described [Gold and Yahr, 1960; Smith et al., 1994]. Postmortem examination reports of adults who have died from central nervous system lupus have documented diffuse microthrombi and demyelination [Hanly et al., 1992]. Vascular changes have also included vasculitis. Proliferative intimal changes, fibrinoid degeneration, and perivascular inflammation in cerebral arterial vessels have been reported in older studies, but have rarely been observed in recent investigations, suggesting that therapy may have altered the pathologic findings. These vascular changes are less frequent in children than in adults [Walravens and Chase, 1976]. Segmental small artery involvement with leptomeningeal and parenchymal thrombosis may occur, as well as venous sinus thrombosis [Falko et al., 1979; Steinlin et al., 1995]. These individuals have both occlusion and recanalization of vessels without changes in the media and adventitia, suggesting that the cerebrovascular lesions in systemic lupus erythematosus may result from processes acting at the endothelial-blood interface [Smith et al., 1994]. Intravascular coagulation and occlusion may be the primary mechanisms responsible for microinfarction [Falko et al., 1979]. More recent neuropathologic studies in adults implicate platelet thrombi, possibly mediated by antiphospholipid antibodies [Ellison et al., 1993]. Other studies, which do not document vascular involvement, suggest a role for antineuronal antibody-mediated damage in adults with systemic lupus erythematosus [Bluestein, 1997; Kuroe et al., 1994]. A review of the histopathologic studies of lupus patients with chorea rarely indicated abnormalities of the basal ganglia [Kuroe et al., 1994], but there were other central nervous system changes in these patients, such as microinfarction [Kovacs et al., 1993; Penn and Rowan, 1968]. Some neuropathologic studies of patients with peripheral neuropathies have revealed, although rarely, focal areas of necrosis in small arteries supplying nerve bundles, as well as perivascular inflammatory changes, fibrinous exudates, and thrombus formation. Adult patients with myelopathy exhibited large spinal cord infarcts, spinal cord subdural hematoma, and subpial leukomyelopathy [Provenzale and Bouldin, 1992].

Scleroderma Scleroderma in children occurs in two clinically distinct forms: localized and systemic. Localized scleroderma is further subdivided into morphea, generalized morphea, linear

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scleroderma, and coup-de-sabre lesions. Coup-de-sabre lesions present as linear sclerodermatous changes of the head or oral cavity. Because there may be underlying central nervous system changes, this form of scleroderma is the most important neurologic finding in children. Systemic scleroderma is subdivided into progressive systemic sclerosis and a generally milder syndrome termed CREST (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) [Lehman, 1996]. Localized scleroderma is a chronic disorder that generally is not associated with systemic symptoms, except for the coupde-sabre deformity. Local sequelae of linear scleroderma may include linear growth abnormalities when the process causes joint limitations secondary to local scarring. There have been very rare reports of localized scleroderma progressing to systemic scleroderma [Cassidy and Petty, 2001]. Progressive systemic sclerosis in childhood is a multisystem disease manifesting with progressive hardening of the skin and subcutaneous tissues, with involvement of the gastrointestinal tract, joints, heart, lungs, and kidneys [Uziel et al., 1995]. Children tend to have fewer signs and laboratory parameters of vascular disease compared with adults [Vancheeswaran et al., 1996], but generally the disease is the same [Kornreich et al., 1977; Martinez-Cordero et al., 1993]. Raynaud’s phenomenon, severe cardiac and pulmonary disease with congestive heart failure, pulmonary interstitial fibrosis, pulmonary vascular sclerosis, and renal sclerosis with acute renal failure contribute significantly to the mortality associated with this disorder. Although the two disorders may be difficult to differentiate clinically, the CREST syndrome is generally thought to be milder than progressive systemic sclerosis and carries a more favorable prognosis. Systemic sclerosis may have all of the features of the CREST syndrome but is characterized by more severe internal organ involvement [Cassidy and Petty, 2001]. Skin biopsy is diagnostic, demonstrating increased thickness and density of the dermal collagen beneath the epidermis, with scattered foci of perivascular mononuclear cell infiltrate and no evidence of immune complex deposition in any affected organs, including the kidney. Radiographic assessment often demonstrates subcutaneous calcinosis, joint effusions, and diminished esophageal peristalsis. Pulmonary function studies reveal decreased lung diffusion capacity, and echocardiography may document pericardial effusion or pulmonary hypertension.

Neurologic Manifestations Children with the coup-de-sabre form of localized scleroderma are at risk for central nervous system involvement [Appenzeller et al., 2004]. Progressive facial and scalp lesions may be associated with seizures, blurred vision, diplopia, and contralateral weakness. Vasculitis of small and medium-sized cerebral vessels ipsilateral to the skin lesions has been documented by angiography. A case study with neuropathology has suggested that this may not be a form of central nervous system vasculitis but rather a neurocutaneous syndrome with vascular dysgenesis [Chung et al., 1995]. Periarticular muscle atrophy, common in children with systemic scleroderma, may be attributed to both disuse and subtle myopathic involvement. Muscle biopsy demonstrates findings of a mixed neuromyopathy with group atrophy, suggesting vascular neuropathic involvement as one of the

mechanisms associated with the primary disease [Clements et al., 1978]. Despite elevation of creatine kinase activity in 33% of patients with scleroderma, muscle atrophy is rare [Dabich et al., 1974], but clinical weakness is frequent, particularly during the early inflammatory phase of the illness. MRI may be useful in the localization of suspected muscle disease in patients with scleroderma [Olsen et al., 1996]. Children with progressive systemic sclerosis generally do not have primary central nervous system involvement, although cerebral hemorrhage secondary to thrombocytopenia has been reported [Gordon and Silverstein, 1970; Kornreich et al., 1977]. Although neurologic manifestations have been reported rarely in adults with scleroderma, some reviewers [Cerinic et al., 1996; Hietaharju et al., 1993] have argued that these manifestations may be more common than originally believed and include neuropsychiatric symptoms, bulbar palsy, optic neuritis, trigeminal neuropathy, mononeuritis multiplex, and polyneuropathy. There is no consensus regarding treatment of these complications. Of interest is a recent study that demonstrated cerebral hypoperfusion on SPECT scans in half of the neurologically asymptomatic adults with progressive systemic sclerosis [Nobili et al., 2002]. This hypoperfusion is hypothesized to be the result of a noninflammatory microangiopathy that has its origins in endothelial cell damage and dysfunction.

Laboratory Findings Laboratory evaluation should include determination of antinuclear antibody titers, immunoglobulins, erythrocyte sedimentation rate, rheumatoid factor, and creatine kinase activity. A mild elevation of serum immunoglobulins may be present, and there may be markers of inflammation. Patients with progressive systemic sclerosis may have antibodies to DNA topoisomerase 1 (Scl-70) or RNA polymerase I, II, or III (RNAPs). Patients with the CREST syndrome may have an anticentromere antibody. Approximately 27% of children with progressive systemic sclerosis have Scl-70 antibodies [Vancheeswaran et al., 1996], compared with 14% to 77% of adults, whereas an uncertain number of children with the CREST syndrome have anticentromere antibody, compared with 44% to 98% of adults [Okano, 1996].

Treatment Treatment of progressive systemic scleroderma is largely supportive, and management of the underlying disease is often not successful. Initial management includes a course of corticosteroids to improve weakness associated with myopathy. D-Penicillamine was initially reported as beneficial for skin fibrosis but generally has not been associated with improvement [Murray and Laxer, 2002]. There has been anecdotal support for the use of steroids and methotrexate in combination for the treatment of linear scleroderma [Uziel et al., 2000]. Raynaud’s phenomenon should be treated with calcium channel blockers such as nifedipine or amlodipine. Gastrointestinal symptoms may be relieved by bethanechol chloride, Reglan, or cisapride [Pope, 1996]. Occupational and physical therapy is the mainstay of treatment and is aimed at maintaining and improving joint mobility that is impaired secondary to scarring.

Schor, Sheets, Szer, and Ashwal / Neurologic Manifestations of Rheumatic Disorders of Childhood

Mixed Connective Tissue Disease Mixed connective tissue disease is characterized by a combination of signs and symptoms of systemic lupus erythematosus, scleroderma, and dermatomyositis/polymyositis, with specific serologic association of antibodies reactive with the ribonuclease-sensitive component of extractable nuclear antigen (anti-RNP) and speckled pattern antinuclear antibody [Oetgen et al., 1981]. Some children progress to a systemic sclerosis pattern [Kotajima et al., 1996], whereas others follow a course typical of mild systemic lupus erythematosus. Clinical features include Raynaud’s phenomenon as the initial manifestation, followed by polyarthritis, fever, rash, thickening of subcutaneous tissues, hepatosplenomegaly, myositis, and cardiomyopathy. Secondary Sjögren’s syndrome may produce parotitis and keratoconjunctivitis sicca (dry eyes). Erythrocyte sedimentation rate and rheumatoid factor are often elevated. Evaluation may demonstrate decreased esophageal motility, diminished tear production, keratoconjunctivitis demonstrated by slit-lamp examination, abnormal parotid sialography, pulmonary effusion demonstrated by chest radiography, and abnormal pulmonary function tests.

Neurologic Characteristics Proximal muscle weakness, increased creatine kinase activity, myopathic electromyograms, and muscle biopsy are consistent with inflammatory myositis. In one study, asymptomatic children with mixed connective tissue disease had abnormalities detectable on electromyography and biopsy of proximal muscles [Singsen et al., 1980]. Seizures, headache, increased cerebrospinal fluid protein content, and aseptic meningitis have been reported in children with mixed connective tissue disease [Oetgen et al., 1981]. In the original 1972 description of 25 patients, of whom at least 4 were children, none had neurologic symptoms [Sharp et al., 1972]. A follow-up study of 14 of the original cohort indicated myositis as the only neurologic finding in 5 adults. The only surviving child was asymptomatic; the other three died of non-neurologic causes [Nimelstein et al., 1980]. Two additional children have been described with neurologic manifestations [Graf et al., 1993]. The first had an internal carotid artery occlusion and stroke with eventual recovery without evidence of antiphospholipid antibody. The second child had a large intracerebral hematoma and died. Postmortem examination found fibrinoid necrosis of intracerebral capillaries. Trigeminal neuralgia has been observed in adults but has not been reported in children [Sharp, 1975]. Studies of adults have indicated a significant incidence of neuropsychiatric symptoms [Bennet and O’Connell, 1980]. Additionally, an adult with recurrent optic neuropathy and transverse myelopathy has been reported [Flechtner and Baum, 1994], as well as another adult with myelopathy [Mok and Lau, 1995].

Treatment Treatment of mixed connective tissue disease depends on disease manifestations. For disease with mild organ involvement, hydroxychloroquine may be adequate. For more severe organ system involvement or significant myositis, cortico-

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steroids may be necessary. As there are few long-term studies that clarify the prognosis and best therapy, treatment is empirical [Mier et al., 1996; Tiddens et al., 1993]. Methotrexate, azathioprine, and cyclophosphamide have been used, similar to therapy for systemic lupus erythematosus.

Sjögren’s Syndrome Sjögren’s syndrome is a chronic autoimmune disorder in which lymphocytic infiltration of the salivary, lacrimal, and other exocrine glands leads to keratoconjunctivitis sicca, xerostomia, and recurrent inflammation of the salivary glands. Primary Sjögren’s syndrome is extremely rare in children, but the secondary form, preceding, accompanying, or following systemic lupus erythematosus, juvenile idiopathic arthritis, mixed connective tissue disease, juvenile dermatomyositis, or scleroderma is more frequent [Nikitakis et al., 2003]. Characteristic laboratory findings include hypergammaglobulinemia, positive antinuclear antibody, antiSSA, anti-SSB, and classic rheumatoid factor [Anaya et al., 1995]. Confirmation of the diagnosis is obtained by labial salivary gland biopsy, demonstrating periductal lymphocytic infiltration [Cassidy and Petty, 2001]. The Schirmer test, sialogram, and salivary scintiphotography support the diagnosis [Chudwin et al., 1981]. Several children with primary Sjögren’s syndrome and neurologic involvement have been reported. A 10-year-old female with optic neuritis and severe central nervous system disease has been described [Berman et al., 1990], as well as an 18-year-old female with aseptic meningitis and small infarctions in both temporal regions and in the right posterior parietal region [Gerraty et al., 1993]. In addition, a 17-year-old female has been described with bilateral carotid and vertebral artery occlusions who was treated with surgical bypass [Nagahiro et al., 1996]. A 9-year-old female who was eventually diagnosed with Sjögren’s syndrome developed recurrent paresis with associated nonenhancing lucencies of the left internal capsule and subcortical white matter in the right temporo-occipital regions on CT. MRI confirmed the CT findings and exhibited multiple regions of increased signal intensity on T2-weighted images in the internal capsule and subcortical and periventricular white matter [Ohtsuka et al., 1995]. She developed a rapidly increasing paresis that resulted in quadriplegia but responded fairly well to corticosteroids. T2-weighted images on MRI indicated diffuse swelling of the cervical cord and increased signal intensity from the first cervical to the seventh thoracic vertebra [Ohtsuka et al., 1995]. In adult patients with Sjögren’s syndrome and biopsy-documented inflammatory vascular disease, both central nervous system and peripheral nervous system involvement have been reported in 25% to 66% of patients [Alexander, 1992]. Neurologic manifestations in these patients consisted of focal and diffuse brain disease, including seizures, cognitive and behavioral disorders, acute encephalopathy, aseptic meningitis, and forms of progressive myelopathies. Peripheral nervous system involvement included motor and sensory neuropathies and carpal tunnel syndrome [Malinow et al., 1985; Molina et al., 1985]. Further study of these patients revealed one or more cerebrospinal fluid abnormalities in 16 of 21 patients, including increased protein content, pleocytosis, elevated IgG levels, elevated IgG index,

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increased oligoclonal bands, and abnormal cerebrospinal fluid/serum glucose ratios [Malinow et al., 1985]. Because classification criteria for Sjögren’s syndrome vary, it is difficult to interpret the frequency of neurologic symptoms in adults [Alexander, 1992]. MRI may indicate subcortical or periventricular lesions in the white matter in up to 80% of adult patients [Alexander, 1992]. Although the pathogenesis of Sjögren’s syndrome is unknown, it has been suggested that the anti-Ro (anti-SSA) antibody may play an immunopathologic role in central nervous system disease [Alexander, 1992].

Treatment Hydroxychloroquine and supportive care are the mainstays of treatment of non-neurologic manifestations of Sjögren’s syndrome [Fox, 1992]. Immunosuppressive management with corticosteroids is needed for significant neurologic manifestations [Anaya et al., 1995; Ostuni et al., 1996]. If there is progressive neurologic disease, cyclophosphamide in addition to corticosteroids has been used successfully [Alexander, 1992]. Long-term prognosis in children with and without neurologic disease is unclear [Anaya et al., 1995; Ostuni et al., 1996].

PRIMARY VASCULITIC DISEASES Vasculitis may be either primary or secondary to a multisystem disorder. Because the causes of vasculitic disorders remain unknown, classification of the vasculitides is difficult. (In Box 73-1, the vasculitides are organized by pathologic type.) Size and location of the affected vessels may aid in identifying specific disorders. Alternatively, because many of these disorders have distinct clinical patterns of involvement, the diagnosis is often established on clinical grounds with the aid of specific laboratory tests, which help rule out other disorders and confirm the diagnosis.

Although multiple etiologies have been proposed to explain the development of vasculitis, the formation of circulating immune complexes and the production of antiendothelial antibodies are the most commonly accepted theories [Conn, 1990; Kissel, 1989]. In the immune complex model, deposition of circulating antigen-antibody complexes in the vascular wall causes activation of the complement system and release of chemotactic substances that attract circulating polymorphonuclear leukocytes. Leukocytic infiltration of the vascular wall and phagocytosis of immune complexes result in the release of intracellular enzymes that cause localized vascular injury. Activation of the coagulation and kallikrein-kinin systems further contributes to the development of this type of vascular tissue damage. In the antiendothelial cell antibody model, viral infections or the underlying inflammatory disease process may alter the endothelial cell so that a specific antigen site precipitates antibody formation [Cines, 1989; Conn, 1990]. However, the presence of other factors such as tumor necrosis factor, interleukin-1, and interferon gamma appears necessary to sensitize the endothelial cells so that lysis can occur when these cells are exposed to antiendothelial cell antibodies. Once endothelial injury occurs, altered vascular tone causes localized contraction and vasospasm, which presumably happens in conjunction with the release of vasoconstrictor substances such as prostaglandins and calcium, or possibly as the result of inhibition of the release of endothelium-derived relaxing factor [Miller and Burnett, 1990]. The key neurologic findings in the vasculitides are listed in Table 73-4.

Necrotizing Vasculitis The disorders classified as necrotizing vasculitis include polyarteritis nodosa, microscopic polyangiitis, Kawasaki disease, and Cogan’s syndrome. They are characterized by fibrinoid necrosis of small and medium-sized muscular arteries.

TABLE 73-4 Key Neurologic and Laboratory Findings in Childhood Vasculitides DISEASE

NEUROLOGIC FINDINGS

LABORATORY FINDINGS

Polyarteritis nodosa

Headache, encephalopathy, stroke, seizures, neuropathies Aseptic meningitis, focal neurologic findings Neurosensory hearing loss Encephalopathy Headache, encephalopathy, stroke, seizures, various peripheral neuropathies, coma, intracranial hemorrhage Encephalopathy, intracranial hemorrhage, meningitis Headache, encephalopathy, seizures, stroke, myelopathy Obstructive hydrocephalus, seventh nerve palsy, meningitis, seizures, peripheral neuropathies Blindness, encephalopathy, headache Headache, stroke, syncope, visual loss Headache, meningitis, psychiatric disorders, encephalopathy, pseudotumor cerebri, brainstem signs

Elevated WBC, ESR, positive HBsAg and c-ANCA Coronary aneurysms, thrombocytosis None Elevated IgA in 50%, hematuria, melena Eosinophilia, eosinophils on skin biopsy, p-ANCA

Kawasaki disease Cogan’s syndrome Henoch-Schönlein purpura Churg-Strauss syndrome Wegener’s granulomatosis Primary angiitis of the CNS Sarcoidosis Temporal arteritis Takayasu’s arteritis Behçet’s disease

c-ANCA Elevated ESR Noncaseating granuloma Elevated ESR Elevated ESR and factor VIII–related antigen Elevated ESR

c-ANCA, cytoplasmic staining antineutrophil cytoplasmic antibody; CNS, central nervous system; ESR, erythrocyte sedimentation rate; HBsAg, hepatitis B surface antigen; IgA, immunoglobulin A; p-ANCA, perinuclear staining antineutrophil cytoplasmic antibody; WBC, white blood cell count.

Schor, Sheets, Szer, and Ashwal / Neurologic Manifestations of Rheumatic Disorders of Childhood

Polyarteritis Nodosa Polyarteritis nodosa occurs principally in older children and adolescents. Classic polyarteritis nodosa is characterized by unexplained fever, arthralgias, calf discomfort, abdominal pain, recurrent pulmonary infection, renal disease with hypertension, fatigability, weight loss, malar rash, and purpura. Severe kidney impairment and marked hypertension occur early in the course of the disease. Diffuse glomerulonephritis or necrotizing arteritis is found in renal biopsy material. Mesenteric arteritis and resultant bowel wall infarction may lead to gastrointestinal hemorrhage [Bakkaloglu et al., 2001; Maeda et al., 1997]. Laboratory evaluation reveals leukocytosis, anemia, increased sedimentation rate, abnormal urinalysis, and evidence of nephrosis and nephritis, in the absence of complement consumption, antinuclear antibodies, and rheumatoid factor [Ozen et al., 1992]. Patients with polyarteritis nodosa may have circulating antineutrophil cytoplasmic antibodies [Bakkaloglu et al., 2001], elevated factor VIII–related antigen [Ates et al., 1994], and positive serology for hepatitis B surface antigen [Guillevin et al., 1995]. In addition, an association with preceding streptococcal infection has been noted [David et al., 1993; Hoyne and Steiner, 1940]. Angiography may demonstrate aneurysmal dilation of the medium-sized mesenteric, celiac, or renal arteries (Fig. 73-5A). Before corticosteroid therapy, progressive neurologic, renal, and cardiovascular involvement led to a mortality rate of 80% to 90%. Currently, the use of

A

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corticosteroids and cytotoxic agents has dramatically reduced the mortality rate to as low as 5% [Bakkaloglu et al., 2001; Maeda et al., 1997]. Unfortunately, polyarteritis nodosa often follows a chronic course characterized by periods of exacerbations despite aggressive immune suppression [Maeda et al., 1997]. Postmortem studies of pediatric patients with arteritis demonstrate necrotizing angiitis accompanied by polymorphonuclear infiltration of small and medium-sized arteries [Ford and Siekert, 1965].

Neurologic Manifestations Approximately one fourth of patients with polyarteritis nodosa demonstrate neurologic manifestations during their lifetimes [Dillon, 1997]. Seizures frequently accompany polyarteritis nodosa and generally appear early in the illness, become more difficult to control as the disease becomes chronic, and may culminate in episodes of status epilepticus in terminally ill patients. Headache, disturbances of higher cortical function, and affective disorders commonly precede the onset of seizures. This finding suggests central nervous system vasculitis in addition to vasculitis of the internal organs and skin. Cerebrospinal fluid is usually normal, and the presence of blood strongly suggests a ruptured cerebral microaneurysm [Peal et al., 1946]. Commonly reported electroencephalographic abnormalities include diffuse and focal paroxysmal activity and background slowing. Cerebral angiography may indicate segmental narrowing of small and medium-sized vessels and occasional microaneurysmal

B

FIGURE 73-5. A, Renal arteriogram of a child with polyarteritis nodosa demonstrating segmental vasculitis, microaneurysmal dilation, and focal hypoperfusion. B, Cerebral angiogram demonstrating segmental narrowing of posterior communicating and posterior cerebral arteries and small branch occlusions in the middle cerebral artery distribution. (Courtesy of Dr. Joseph Thompson, Department of Neuroradiology, Loma Linda University Children’s Hospital.)

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dilation. Biopsy of the superficial temporal artery is not recommended because only 11% of patients have demonstrable arteritis in the external carotid circulation [Goder, 1956]. Polyarteritis nodosa may manifest with sudden onset of visual field defects, hemiparesis, or increased intracranial pressure. These symptoms tend to occur only in patients with a protracted course. Visual loss associated with proliferative retinitis and fundal hemorrhages may occur independently or accompanying increased intracranial pressure [Fager et al., 1951; Magilavy et al., 1977]. Nystagmus, ophthalmoplegia, diminished corneal reflexes, and ataxia rarely are reported [Ford and Siekert, 1965]. The sudden onset of stroke in a patient with polyarteritis nodosa requires complete assessment of the cerebral circulation initially with MRI and MR angiography, followed by cerebral angiography in selected patients. Although angiography may initially be normal, evidence of segmental arterial narrowing may be demonstrated within several weeks of the central nervous system event (see Fig. 73-5B). Pathology indicates necrotizing angiitis, ruptured microaneurysms of the superficial and deep arteries, subarachnoid hemorrhage, and encephalomalacia caused by ischemia or infarction. Aseptic meningitis with spinal fluid lymphocytosis and normal protein concentration has also been reported in childhood forms of polyarteritis nodosa. Bacterial meningitis is an uncommon complication in children, despite the use of immunosuppressive agents. Neuropsychiatric symptoms are uncommon in polyarteritis nodosa despite the diffuse cerebral arteritis [Ford and Siekert, 1965]. Extremely ill patients may develop organic psychosis, a progressive confusional state, and variable states of consciousness that are associated with renal insufficiency. Depression is unusual in the stable patient. Children with polyarteritis nodosa often experience diffuse myalgia; however, myositis is rarely diagnosed clinically, although it is demonstrated in approximately 11% of postmortem studies. There may be an accompanying increase of creatine kinase activity or evidence of myopathy indicated by electromyography [Blau et al., 1977; Magilavy et al., 1977]. Muscle biopsy may reveal necrotizing arteritis with fibrinoid necrosis and perivascular inflammation. A myopathic pattern is demonstrated in approximately 50% of children with polyarteritis nodosa who undergo electromyography. Peripheral neuropathy responds well to corticosteroids. Mononeuritis multiplex is the most common and typically early neurologic feature of adult polyarteritis nodosa [Nadeau, 2002]. Sensory and motor nerve conduction velocities are decreased in childhood polyarteritis nodosa. Pathologic studies of the peripheral nervous system reveal fulminant arteritis with thrombotic occlusion of small and mediumsized arteries with accompanying profound nerve infarction and demyelination. Myelopathy occurs rarely and usually only in patients who suffer from chronic disease [Carr and Bryer, 1993]. Microscopic polyangiitis is a subgroup of polyarteritis nodosa and is rarely seen in children [Ozen, 2004]. There is frequent pulmonary hemorrhage, and all patients have glomerulonephritis. They are frequently perinuclear staining antineutrophil cytoplasmic antibody (p-ANCA) positive due

to myeloperoxidase antibody. Peripheral neuropathy is less common than in polyarteritis nodosa.

Treatment Corticosteroids are the mainstay of treatment. Children whose disease follows a chronic course or who develop catastrophic events should be treated with cyclophosphamide both to avoid side effects associated with the use of chronic steroids and to provide greater immune suppression [Lhote and Guillevin, 1995]. Poorer prognosis has been associated with significant central nervous system disease, renal insufficiency, gastrointestinal disease, and cardiomyopathy. Aggressive treatment with high-dose intravenous corticosteroids and cyclophosphamide should be considered for such patients. Plasmapheresis has not been found to be of benefit [Lhote and Guillevin, 1995]. Overall 5-year survival has improved from 10% before corticosteroid use to about 80% in adults, and perhaps even higher in children [Lhote and Guillevin, 1995].

Kawasaki Disease Kawasaki disease is characterized by aneurysms largely limited to the coronary arteries, although aneurysms have been reported in multiple vessels as well [Burns and Glodé, 2004]. Kawasaki disease is diagnosed by the presence of fever of at least 5 days’ duration and four of the following five criteria: (1) bilateral nonpurulent conjunctival injection; (2) changes in the mucosa of the oropharynx, including injected or dry, fissured lips or strawberry tongue; (3) changes in the peripheral extremities, including edema, erythema of hands or feet, and desquamation; (4) rash, which may be polymorphous, but not vesicular; and (5) unilateral cervical lymphadenopathy [Burns and Glodé, 2004]. Prognosis has been excellent since the use of intravenous immunoglobulin and acetylsalicylic acid, with immediate clinical improvement in the majority of children and a decreased rate of coronary artery aneurysmal formation from 20% to 25% to less than 8%. However, myocardial infarction, dysrhythmias, and sudden death were reported in 1% of patients [Melish, 1996].

Neurologic Manifestations Although pronounced irritability, lethargy, and aseptic meningitis are quite common, other neurologic manifestations are rare [Melish, 1981]. With the exception of a single case report [Engel et al., 1995], cerebral aneurysms have not been demonstrated in infants with Kawasaki disease. This contrasts with polyarteritis nodosa, in which cerebral aneurysms have been reported. In patients who present with an out-of-hospital cardiac arrest secondary to coronary artery involvement, an anoxic encephalopathy may occur. Postmortem examination of children with Kawasaki disease have failed to reveal prominent cerebrovascular involvement. Major findings have included leptomeningeal thickening, mild endarteritis, and periarteritis.

Treatment Treatment of Kawasaki disease consists of acetylsalicylic acid, 80 to 100 mg/kg per day in four divided doses, until the

Schor, Sheets, Szer, and Ashwal / Neurologic Manifestations of Rheumatic Disorders of Childhood

patient has been afebrile for about 3 to 7 days, followed by 3 to 5 mg/kg per day in a single dose and continued until inflammatory markers have returned to normal, the thrombocytosis has resolved, and no coronary artery disease exists on followup echocardiogram at 4 to 6 weeks. During the acute stage, intravenous immunoglobulin, 2 g/kg as a single dose over 12 hours, is recommended early in the course and preferably before the 10th day [Melish, 1996; Shulman et al., 1995]. The use of corticosteroids in Kawasaki disease is controversial because of one early report of an associated increased frequency of coronary artery aneurysms. This report was not confirmed by others, and children with Kawasaki disease who have failed intravenous immunoglobulin therapy have successfully received corticosteroids [Wright et al., 1996].

Cogan’s Syndrome Cogan’s syndrome has been reported rarely in children [Ndiaye et al., 2002]. Although vasculitis may be diffuse, the characteristic features are vertigo, deafness, photophobia, and interstitial keratitis. Eye and ear involvement may precede other systemic symptoms by years. Aortitis and aortic valve insufficiency may also be present [Cassidy and Petty, 2001], along with arthralgia, myalgia, anorexia, episcleritis and/or uveitis, and fever. The noncardiac features generally respond well to corticosteroid therapy, but the aortic valve disease may require surgical replacement of the valve [Olfat and AlMayouf, 2001]. Neurologic symptoms have been described in adults [Bicknell and Holland, 1978].

LEUKOCYTOCLASTIC VASCULITIS Leukocytoclastic vasculitis is a necrotizing vasculitis. Pathologic changes indicate polymorphonuclear leukocytes and necrosis in the walls of small arteries. Nuclear debris is also found in the vessel walls. These changes are seen most commonly in Henoch-Schönlein purpura, systemic lupus erythematosus, and hypersensitivity vasculitis.

Henoch-Schönlein Purpura Henoch-Schönlein purpura is characterized by palpable purpura, petechiae, or ecchymotic rash, typically found over the buttocks and the lower extremities. It is often associated with large joint arthritis, cramping abdominal pain, fever, peripheral edema, and renal involvement, with a median age of onset of about 6 years [Cassidy and Petty, 2001; Szer, 1996]. Henoch-Schönlein purpura is a common, self-limited illness lasting from about 1 to 3 months. Recurrences may occur over 1 to 2 years. Laboratory tests are usually normal except for microscopic hematuria and guaiac-positive stools. Approximately 50% of patients have elevated IgA levels. Skin, renal, and gastrointestinal biopsies demonstrate leukocytoclastic vasculitis with polymorphonuclear cells within the vessel walls and deposition of IgA, complement, and properdin.

Neurologic Characteristics Central nervous system complications have been reported in 1% to 8% of children and are secondary to hypertension, renal failure, and vasculitis. Headache, seizures, altered states

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of consciousness, cerebral vasculitis, intracranial hemorrhage, spastic paralysis, and chorea occur in some patients [Belman et al., 1985; Chen et al., 2000; Østergaard and Storm, 1991; Ritter et al., 1983]. A diffuse encephalopathy in association with or without hypertension has been reported [Belman et al., 1985]. Although the pathogenesis of central nervous system symptoms has not been clearly defined, it has been suggested that IgA immune-complex deposition initiates arteriolar inflammation [Østergaard and Storm, 1991]. Peripheral nervous system complications previously reported include lesions of the femoral, sciatic, and facial nerves; Guillain-Barré syndrome; and isolated mononeuropathies, including mononeuritis multiplex [Bulun et al., 2001; Ritter et al., 1983]. Peripheral nerve dysfunction is believed to result from metabolic disturbances, vasculitis, immune mechanisms, and mechanical compression or entrapment. These peripheral nervous system complications are usually self-limited and resolve with treatment of the underlying disorder and of the specific neurologic symptom (e.g., seizures, chorea, headache).

Management There is consensus regarding the management of arthritis with nonsteroidal anti-inflammatory drugs and painful cutaneous edema with steroids. Supportive care is required for children who develop massive gastrointestinal bleeding or who become dehydrated or hypertensive [Szer, 1996]. Highdose steroids and plasmapheresis have been used anecdotally for severe central nervous system disease with success [Bulun et al., 2001; Chen et al., 2000; Eun et al., 2003].

Hypersensitivity Angiitis Hypersensitivity, or allergic, angiitis is an acute necrotizing inflammation of blood vessels similar to Henoch-Schönlein purpura. Unlike the latter, however, recurrent attacks are uncommon. The disorder may be acute and rapidly fatal and may be caused by a hypersensitivity reaction to various drugs, infections, or serums [Cassidy and Petty, 2001; Farooki et al., 1974]. Among adults manifesting similar clinical symptoms, decreased serum complement and cryoglobulinemia have been reported [Cassidy and Petty, 2001]. The occurrence of neurologic complications in the various forms of hypersensitivity angiitis appears to be rare because the cerebral vessels tend to be spared.

GRANULOMATOUS ANGIITIS Granulomatous angiitis represents a category of systemic necrotizing arteritis manifested by extravascular granulomatous nodules, which consist of a central area of fibrinoid degeneration with surrounding eosinophils and epithelioid and giant cells [Farooki et al., 1974]. Although ChurgStrauss syndrome (allergic granulomatosis), Wegener’s granulomatosis, and primary angiitis of the central nervous system are the primary forms of this type of vasculitis, necrotizing sarcoid granulomatosis and sarcoidosis also are discussed in this section because of their granulomatous pathology [Cassidy and Petty, 2001].

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Churg-Strauss Syndrome Churg-Strauss syndrome, also known as allergic granulomatosis, is associated clinically with asthma, fever, eosinophilia, cardiac failure, renal damage, and peripheral neuropathy [Sehgal et al., 1995]. Criteria established by the American College of Rheumatology require the presence of four of the following seven findings: (1) asthma, (2) eosinophilia, (3) history of allergy, (4) mononeuropathy or polyneuropathy, (5) pulmonary infiltrates that are migratory, (6) paranasal sinus abnormality, and (7) extravascular eosinophils on biopsy [Masi et al., 1990]. Approximately 21% of patients are children [Farooki et al., 1974]. The vasculitis is manifested by fibrinoid necrosis of the media of small arteries and veins, with arterial and capillary involvement. Neurologic involvement appears to be limited to the peripheral nervous system; no reported central nervous system involvement has been observed in children, except for a case report of a 13-year-old female who presented with chorea and associated MRI changes [Kok et al., 1993]. Mononeuritis multiplex or symmetric polyneuropathy is found in 65% to 80% of adult patients. Symptoms are due to a vasculitis of the vasa nervorum. Central nervous system involvement in adults tends to occur late in the course of the disease. Intracranial and subarachnoid hemorrhage, convulsions, and psychosis have been reported. Cranial nerve involvement and optic neuritis also have been described [Acheson et al., 1993; Liou et al., 1994; Sehgal et al., 1995; Tervaert and Kallenberg, 1993]. The treatment of Churg-Strauss syndrome is essentially the same as the therapy for polyarteritis nodosa, and most patients respond well to corticosteroids. Cyclophosphamide has been used for steroid-resistant cases, but usually is not necessary [Lhote and Guillevin, 1995].

Wegener’s Granulomatosis A necrotizing granulomatous vasculitis of the small vessels in the upper and lower respiratory tract and the kidneys characterizes Wegener’s granulomatosis. Symptoms frequently include fever, malaise, rhinorrhea, epistaxis, chronic sinusitis, nasal obstruction, pharyngeal ulcers, parenchymal pulmonary lesions, and chronic glomerulonephritis. The most common laboratory abnormality is a cytoplasmic staining antineutrophil cytoplasmic antibody due to anti-PR3 antibodies found in about 90% of patients [Cassidy and Petty, 2001]. Children are rarely affected. The cause of this disorder is unknown. Of 17 children with Wegener’s granulomatosis, 3 had neurologic complications manifested by peripheral neuropathy [Orlowski et al., 1978]. In a more recent review of 23 children, the course was similar to that described in adults except that there was more frequent subglottic stenosis and nasal septal deformity. Central nervous system involvement occurred in 17% of patients and peripheral nervous system involvement in 9% [Rottem et al., 1993]. Two patients had multiple cranial nerve palsies and two had seizures. Cerebral vasculitis has been reported in individual case reports [Haas et al., 2002; von Scheven et al., 1998]. Keratitis, optic nerve granuloma, proptosis, orbital pseudotumor [Wardyn et al., 2003], laryngitis with accompanying aphonia, spasticity, proximal muscle weakness, and dimin-

ished deep tendon reflexes have been described [Drachman, 1963; Moorthy et al., 1977]. In contrast to children, approximately 10% of adults with Wegener’s granulomatosis had central nervous system involvement, and about 44% had peripheral nervous system involvement [Cruz and Segal, 1997].

Treatment Prednisone and daily oral cyclophosphamide are often considered the treatments of choice and have lowered the previous mortality rate of up to 100% to the current survival rate of greater than 90% [Langford, 2003]. Pulse cyclophosphamide, intravenous immunoglobulin, trimethoprimsulfamethoxazole, cyclosporin A, and methotrexate also have been reported to have variable success in inducing remission [Calabrese et al., 1995; Georganas et al., 1996; Jayne and Lockwood, 1996; Reinhold-Keller et al., 1996; Sneller et al., 1995; Stegeman et al., 1996].

Primary Angiitis of the Central Nervous System Primary angiitis of the central nervous system, also called granulomatous angiitis, is characterized by granulomas in 80% of cases. Numerous case reports have been published in the last decade. Clinical criteria require a history or finding of an acquired neurologic deficit associated with angiographic or histopathologic demonstration of vasculitic changes, exclusion of other etiologies, and no evidence of systemic disease [Calabrese, 1995]. It is increasingly recognized as the cause of otherwise unexplained cerebral ischemic episodes in the young [Dillon, 1997] and has been mistaken on occasion for Rasmussen’s encephalitis [Derry et al., 2002]. Clinical features include headache, confusion, nausea, altered mental status, focal neurologic deficits, and progressive intellectual deterioration. Primary angiitis of the central nervous system may occur in children as young as 2 years of age and has an equal sex distribution [Barron et al., 1993; Matsell et al., 1990]. Clinical manifestations of primary central nervous system angiitis correlate with the size of the affected vessels. Patients with small vessel disease tend to present with headache, focal seizures, or progressive behavioral or multifocal neurologic impairment. In contrast, patients with mediumsized or large vessel disease tend to present with acute ischemic stroke or transient ischemic attack [Benseler and Schneider, 2004; Lanthier et al., 2001]. In both groups, cranial nerve abnormalities have been described, including diplopia, blurred vision, nystagmus, dysarthria, and pupillary abnormalities. Hemiparesis and language disorders have been observed in approximately 50% of patients. Seizures, spinal cord abnormalities, cerebral hemorrhage, fever, and weight loss also have been reported [Calabrese, 1995]. Laboratory studies reveal elevated erythrocyte sedimentation rate, elevated cerebrospinal fluid protein concentration, and moderately increased monocytosis with increased pressure [Calabrese et al., 1992; Sabharwal et al., 1982]. However, normal acute phase reactants and spinal fluid have been reported in children [Benseler and Schneider, 2004]. Cerebral angiography documents small- and medium-sized vessel occlusion or segmental narrowing with saccular aneurysms and areas of infarction. Neuropathologic studies

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indicate segmental necrotizing granulomatous vasculitis diffusely affecting the parenchymal and leptomeningeal vessels of the cortex but not the subcortical areas of the brain [Hankey, 1991; Sabharwal et al., 1982]. Patients with small vessel disease are more likely to demonstrate multifocal, hyperintense lesions on T2-weighted MRI with normal cerebrospinal fluid, erythrocyte sedimentation rate, and cerebral angiograms. Those with medium-sized or large vessel disease often demonstrate infarcts on CT and MRI and are more likely than those with small vessel disease to have abnormal cerebrospinal fluid studies, erythrocyte sedimentation rates, and angiograms (Fig. 73-6) [Lanthier et al., 2001]. The course of this disorder fluctuates, and, although initial studies reported that 90% of patients died within a year of onset, it is clear from more recent studies that this disease has a broad spectrum and that the prognosis is much better [Benseler and Schneider, 2004; Calabrese, 1995]. In general, the prognosis for patients with small vessel disease tends to be better than that for patients with stroke due to large vessel disease [Lanthier et al., 2001]. Therapeutic use of corticosteroids, with or without cyclophosphamide, is indicated and should be instituted early in the course of disease [Barron et al., 1993; Lanthier et al., 2001].

A

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The disease in a subgroup of patients seems to follow a benign course termed benign angiopathy of the central nervous system. These patients tend to be young women who have a sudden onset of symptoms and near-normal cerebrospinal fluid studies and whose disease often remits after a monophasic course. Unfortunately, some of these patients progress years later to serious and even lethal disease [Calabrese, 1995]. Although most of these patients have been adults, two pediatric patients who experienced complete recovery have been described [Calabrese and Mallek, 1988].

Necrotizing Sarcoid Granulomatosis Necrotizing sarcoid granulomatosis, first described in 1973, is clinically and pathologically intermediate between sarcoidosis and Wegener’s granulomatosis [Kwong et al., 1994]. It consists of a necrotizing granulomatosis and vasculitis similar to that found in Wegener’s granulomatosis, with noncaseating granulomas resembling those of sarcoidosis. The condition has been reported in children with multifocal neurologic disease and retinal angiitis. In one child, progressive asymmetric lower limb weakness associated with urinary retention, and diagnosed as an acute myelitis and polyneuritis, responded to treatment with corticosteroids

B

FIGURE 73-6. A 4-year-old male with primary angiitis of the central nervous system who had a 2-month history of seizures, chorea, left hemiparesis, and dysarthria; he improved significantly with intravenous immunoglobulin and corticosteroids. A, Time-of-flight MR angiogram partitioned for the right distal internal carotid artery shows prominent segmental supraclinoid internal carotid artery narrowing (arrowheads). B, Lateral right internal carotid digital subtraction arteriogram shows residual segmental narrowing, significantly improved after 2 days of steroid therapy. (Courtesy of Dr. Joseph Thompson, Department of Neuroradiology, Loma Linda University Children’s Hospital, Loma Linda, CA.)

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[Beach et al., 1980]. A more recent review discussed the previous reported cases, defined the vasculitic features, and differentiated childhood sarcoidosis from familial granulomatous arteritis with arthritis, uveitis, and fever [Kwong et al., 1994]. Findings reported in this disease are similar to those in sarcoidosis and include disc edema and retinal periphlebitis responsive to corticosteroid therapy. Necrotizing sarcoid granulomatosis usually responds to corticosteroids and does not require cytoxic therapy. No significant reports of neurologic involvement have been made [Heinrich et al., 2003]. The extent of this disorder in children and the degree of neurologic involvement are unknown.

Sarcoidosis Sarcoidosis is a chronic, multisystem granulomatous disease of unknown etiology that is rare in children. Interestingly, sarcoidosis in older children is indistinguishable from adult sarcoidosis, but younger children (younger than 4 years) tend to have different clinical manifestations. In the early onset form, the children tend to present in infancy to preschool years [Fink and Cimaz, 1997]. This form is characterized by relatively painless, boggy polyarthritis with well-preserved range of motion. Uveitis and cutaneous sarcoid lesions are usually present, but pulmonary involvement is rare. Older children tend to present with pulmonary symptoms, hilar adenopathy, fatigue, weight loss, anorexia, headache, fever, and parotid enlargement [Kwong et al., 1994; Pattishall and Kendig, 1996]. This form of sarcoidosis is characterized by hilar and paratracheal adenopathy with interstitial infiltrates, hypercalciuria, leukopenia, and eosinophilia. An elevated erythrocyte sedimentation rate and the presence of elevated serum immunoglobulins further support the diagnosis. Pulmonary function study results are abnormal in most older patients. Noncaseating granulomas obtained from mediastinal or peripheral lymph node biopsies are found in 90% of patients. Musculoskeletal findings in several children with sarcoidosis have included joint pain with effusions and palpable muscle masses; on biopsy, these muscle masses consist of noncaseating granulomas. Neurologic findings include obstructive hydrocephalus with noncaseating granulomas throughout the central nervous system, transient cranial nerve VII palsies, and myelopathy. There are reports of optic nerve and orbital involvement, pituitary and hypothalamic lesions, meningitis, and seizures [Cohen-Gadol et al., 2003; Lee et al., 1998; Leiba et al., 1996; Monfort-Gourand et al., 1996; Pattishall and Kendig, 1996]. In adults about 5% of patients with sarcoidosis have neurologic involvement. Central nervous system findings include meningeal, parameningeal, hypothalamic, and pituitary sarcoid infiltration. Adults have presented with symptoms of an apparent intracranial or intramedullary spinal cord tumor. Furthermore, peripheral neuropathies, including postnuclear cranial neuropathies, are associated with sarcoidosis [Scott, 1993]. It appears that the neurologic symptoms are different in children than in adults. Seizures are the most common central nervous system manifestation. Cranial nerve palsy and hypothalamic dysfunction are also frequent. About 25% of patients present with a central nervous system mass lesion [Baumann and Robertson, 2003].

Two reports of intramedullary spinal cord lesions studied by MRI and subsequent biopsy indicate that patchy contrast enhancement and increased T2-weighted signal intensity almost always occurred in sarcoid lesions of the spinal cord. These two relatively small cohorts of patients with nonneoplastic spinal cord lesions differed from one another with regard to the question of whether there was significant expansion of the spinal cord in the region of sarcoid involvement [Cohen-Gadol et al., 2003; Lee et al., 1998]. Treatment of the early-onset form of sarcoidosis has been anecdotal and has consisted of corticosteroids, azathioprine, methotrexate, or, occasionally, cyclophosphamide [Fink and Cimaz, 1997]. Therapy of late-onset or adult-type sarcoidosis depends on whether the arthritis is acute, chronic, or relapsing. Nonsteroidal anti-inflammatory drugs have been used for indolent disease, as well as for acute attacks. More painful episodes have been successfully managed with colchicine. Attacks unresponsive to colchicine have often responded to corticosteroids. Chronic disease unresponsive to nonsteroidal anti-inflammatory drugs has responded to low-dose, alternate-day steroids or methotrexate [Sequeira, 1997].

GIANT CELL ARTERITIS Temporal Arteritis Classic giant cell arteritis (temporal arteritis) most often affects men older than 50 years of age [Nordborg et al., 1995]. A recent report of temporal arteritis in a 9-year-old Haitian female with a past medical history remarkable for sensorineural hearing loss; an initial presentation with monocular blindness and a tortuous superficial temporal artery and a temporal artery biopsy study consistent with giant cell arteritis; and a disease course that included a systemic illness with encephalopathy most consistent with polyarteritis nodosa makes it clear that this disorder can occur in childhood [Bert et al., 1999]. Headache, scalp tenderness, visual disturbances, and jaw claudication appearing in association with an elevated sedimentation rate suggest the diagnosis. Biopsy of the superficial temporal artery reveals giant cell perivascular inflammatory infiltrates [Small, 1984]. Hemiparesis, vertigo, hearing loss, brainstem strokes, seizures, oculomotor disorders, and peripheral neuropathies have been reported. Optic neuritis is the most common problem. The superficial temporal, vertebral, ophthalmic, and posterior ciliary arteries are frequently involved. The internal and external carotid and central retinal arteries are less commonly affected, but occlusion of the ophthalmic or central retinal artery can lead to blindness. Intracranial arterial involvement has been documented, although it is rare [Small, 1984]. Myelopathy, transient ischemic attacks, and cerebral infarctions have been reported in adults with temporal arteritis. It is unclear whether the latter two disorders are due to the underlying condition or the patient’s age [Caselli and Hunder, 1993]. Before the case report of Bert and colleagues [1999], juvenile temporal arteritis was regarded as a different and even uncommon clinical entity than adult-type temporal arteritis. Two children, 7 and 8 years of age, initially developed unilateral nodules of the temporal arteries without systemic or neurologic symptoms [Lie et al., 1975].

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Studies of these lesions failed to demonstrate the classic giant cells but instead revealed perivascular lymphoid hyperplasia with eosinophilia. Occlusion of the temporal artery lumen with thrombus formation and diffuse intimal thickening and focal disruption of the internal elastic lamina and media were observed. This disorder demonstrates a form of non–giant cell granulomatous inflammation of the temporal artery; it is distinct from classic temporal arteritis of adults [Lie et al., 1975]. A more recent review included an additional case report of this syndrome [Lie, 1995].

Takayasu’s Arteritis Takayasu’s arteritis, a form of arteritis involving the aorta and its branches, has been reported in children as young as 5 months of age. Onset occurs before 16 years of age in 25% to 30% of patients [Morales et al., 1991], and a recent postmortem study from India demonstrated a mean age at death of 22.6 ± 10.2 years [Sharma et al., 1998]. In children, the abdominal aorta and its branches are more commonly affected than the aortic arch. The clinical course is variable. Most patients come to medical attention in the prepulseless stage with nonspecific symptoms of fever, fatigue, dyspnea, anorexia, and arthralgia. The obstructive phase of the illness is characterized by aneurysmal dilation and stenosis of the aorta or pulmonary arteries. Because the abdominal aorta is involved in young children, initial symptoms may include abdominal pain or mass, congestive heart failure, and occlusive vascular disease of the abdominal organs or lower extremities [Gronemeyer and Demello, 1982]. Symptoms of claudication, pulselessness, carotid hypersensitivity, and cerebrovascular involvement have been reported in children [Pantell and Goodman, 1981]. Hypertension caused by renal artery stenosis occurs in approximately 70% of patients. Hypertensive encephalopathy has been reported in two children with renal artery stenosis [Millar et al., 1996]. One review noted that neurologic symptoms in childhood are quite rare, but that adults may develop carotid thromboembolic disease, cerebral hypertension, subclavian steal syndrome, or hypersensitivity of the carotid sinus [Tervaert and Kallenberg, 1993]. A review of 26 children emphasized that hypertension, constitutional symptoms, gastrointestinal pain, and heart failure were fairly common. In addition, 50% of patients had significant headache, 12% had convulsions, and 8% developed hemiplegia [Morales et al., 1991]. Another review of 24 patients found similar findings except for a lack of neurologic symptoms [Jain et al., 2000]. In one small study, of patients who succumbed to Takayasu’s arteritis, 20% had seizures and 10% had hemiplegia [Sharma et al., 1998]. All of these patients had hypertension as the presenting feature of their disease. A lymphocytic and plasma cell inflammatory infiltrate in the media and adventitial large vessels occurs in the presence of few giant cells during the active phase of the disease. Subsequently, necrosis and thrombosis occur with accompanying fibrosis, and then narrowing of the arterial lumen. Treatment with corticosteroids and other immunosuppressive agents improves the long-term prognosis, but most immunosuppressive drugs provide little improvement over corticosteroids [Hoffman, 1996]. Significant improve-

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ment has been made with the use of bypass grafts and angioplasty [Hoffman, 1995; Kohrman and Huttenlocher, 1986].

MISCELLANEOUS VASCULITIC DISORDERS Not all vasculitic disorders can be classified in the previously noted categories of polyarteritis—leukocytoclastic, granulomatous, and giant cell vasculitides. As many as one third of all primary vasculitic diseases of childhood are categorized as idiopathic or “polyangiitis overlap syndrome” [Cassidy and Petty, 2001]. Other diseases, such as Behçet’s syndrome, do not fit any of these categories.

Behçet’s Disease Behçet’s disease is rare in children [Cassidy and Petty, 2001; Rakover et al., 1989], usually having its onset in the second decade of life. This rarity has led some authors to postulate that juvenile Behçet’s disease may differ from adult Behçet’s disease in pathogenesis [Koné-Paut et al., 1998]. One study of juvenile Behçet’s disease placed the onset of this disorder at or around age 7 [Krause et al., 1999]. The classic clinical triad of Behçet’s disease consists of recurrent oral and genital ulcerations and recurrent uveitis [Schor, 2000]. The uveitis tends to be a panuveitis with retinal vasculitis [Tugal-Tutkun and Urgancioglu, 2003]. The following criteria have been proposed for the diagnosis of Behçet’s disease: the presence of recurrent aphthous stomatitis and two of the following: (1) recurrent genital ulcers, (2) uveitis or retinal vasculitis, (3) erythema nodosum or pustules, or (4) pathergy (the appearance of a pustular skin lesion after skin puncture) [International Study Group for Behçet’s Disease, 1992]. Central nervous system manifestations are reported in as many as 66% of adult patients during the course of the illness. One study found that the prevalence of neurologic manifestations other than headache was much higher in their cohort of patients with childhood Behçet’s disease (26.3%) than in their adult counterpart (3.8%) [Krause et al., 1999]. Three forms of central nervous system involvement have been reported in adults and children: (1) diffuse involvement associated with an acute meningoencephalitis, organic psychosis, or dementia; (2) brainstem or spinal cord involvement, with cranial nerve palsies, hemiparesis, and ataxia; and (3) thrombosis of the dural sinuses and intracranial veins manifesting with signs of intracranial hypertension such as headache and papilledema [Davis et al., 1986; Wechsler, 1992]. The central nervous system symptoms occur as isolated recurrent events that evolve slowly [Bahabri et al., 1996; Devlin et al., 1995; Fujikawa and Suemitsu, 1997; Rosenberger et al., 1982]. MRI with or without gadolinium enhancement and SPECT have demonstrated central nervous system involvement in adult patients [Erdem, 1993; Mizukami et al., 1992; Wechsler et al., 1993], although both techniques underestimate the frequency of brain lesions in adults and children. In a study of seven children and one adult with Behçet’s disease, all patients demonstrated hypoperfusion, especially in the basal ganglia and frontal and temporal cortex, on 99mTc-HMPAO SPECT scanning [Nobili et al., 2002].

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Neuropathologic studies demonstrate lymphocytic meningitis, vasculitis with perivascular cuffing, and thrombosis of arterioles, venules, veins, and dural venous sinuses. Although the etiopathogenesis of Behçet’s disease is unknown, the intraocular fluid of patients with Behçet’s disease– associated uveitis, but not that of other uveitis patients, harbors T cells specific for non-peptide prenyl pyrophosphate antigens. This finding suggests that perhaps an autoimmune attack on a specific antigen underlies susceptibility to Behçet’s disease [Verjans et al., 2002]. Treatment remains controversial, although early treatment with high doses of corticosteroids appears beneficial [Cassidy and Petty, 2001; O’Duffy and Goldstein, 1976]. Ten children were reviewed recently in whom thalidomide was used successfully in some resistant cases, with good improvement in oral and genital ulcerations [Kari et al., 2001]. In patients with intracranial venous or dural sinus thrombosis, heparinization may be beneficial [Wechsler et al., 1992]. Immunosuppressive agents have been used for the central nervous system manifestations of the disease [Zelenski et al., 1989].

MISCELLANEOUS DISORDERS Thrombotic Thrombocytopenic Purpura Rapid onset of thrombocytopenia, severe microangiopathic hemolytic anemia, renal disease, neurologic symptoms, and fever characterizes thrombotic thrombocytopenic purpura [Amorosi and Ultmann, 1966]. Neurologic symptoms in children with thrombotic thrombocytopenic purpura are generally acute and include seizures, confusional states, coma, headache, visual loss, aphasia, and hemiparesis [Lawlor et al., 1997]. Central nervous system symptoms usually persist, unlike the intermittent fluctuating course observed in adults [Thompson et al., 1992]. Retinal hemorrhage is frequent. There have been rare reports of thrombotic thrombocytopenic purpura occurring with systemic lupus erythematosus [Chak et al., 2003]. Thrombotic occlusion may occur in any tissue and may involve the central nervous system, peripheral nervous system, or skeletal muscles. Cerebrospinal fluid examination results are normal in most patients, and electroencephalographic changes are nonspecific. MRI, MR angiography, cerebral angiography [Rinkel et al., 1991; Wijdicks, 1994], and CT scans may reveal evidence of arterial occlusion. A recent study of 12 adult patients with thrombotic thrombocytopenic purpura [Bakshi et al., 1999] demonstrated acute MRI abnormalities in 75%, most commonly reversible posterior leukoencephalopathy and edema associated with hypertension. Ischemic strokes, sometimes multiple in the same patient, were seen in 25% of the patients in this study, and many were complicated by secondary hemorrhage into the area of infarction. Half of the strokes were in the posterior cerebral artery territory, and in general, patients with stroke or primary hematoma (1 patient in this series) had an unfavorable long-term outcome. Pathologically, amorphous hyaline material occluding small cerebral arteries is usually seen and is indistinguishable from that found in the heart and kidneys. Cerebral gray matter contains many vascular lesions [Silverstein, 1968]. Previously, only 10% of children with thrombotic

thrombocytopenic purpura survived for more than 1 year despite aggressive intervention with heparin, intravenous corticosteroids, whole blood transfusion, dextran infusion, and splenectomy. Plasma exchange transfusion has been beneficial for some children, decreasing the mortality to very low levels [Byrnes and Khurana, 1977; Lawlor et al., 1997]. It has been suggested that plasma exchange removes pathogenic substances and supplies other factors that may be deficient in patients with thrombotic thrombocytopenic purpura [Lawlor et al., 1997]. Decreased levels of protease activity with the presence of Von Willebrand factor–protease inhibitors contribute to the bleeding diathesis in this condition [Horton et al., 2003].

Erythromelalgia and Erythermalgia Erythromelalgia, a rare disorder, consists of intense, asymmetric burning sensations with associated erythema and elevated temperature in the extremities [Mandell et al., 1977]. The transient episodes may last for minutes, hours, or even days. Because of the intense pain and discomfort, patients often do not walk or use their hands. Patients find relief by immersing their hands or feet in ice water. One form of the disorder is associated with thrombocythemia (a fixed increase in the number of platelets). Blood pressure and peripheral pulses are normal during the symptomatic phase. In older patients, this condition has been associated with hypertension, systemic lupus erythematosus, diabetes mellitus, and myeloproliferative diseases. A defect in prostaglandin metabolism was postulated after many patients reported relief of symptoms after using acetylsalicylic acid [Jorgensen and Sondergaard, 1978]. This so-called secondary erythromelalgia has no parallel in childhood [Drenth et al., 1994]. Primary erythromelalgia or “erythermalgia” is a more rare, chronic, symmetric, burning sensation that occurs in children and adults. It is not reliably responsive to medication [Davis et al., 2000], although some patients have responded well to amitriptyline, sodium nitroprusside, regional anesthetic blockade, and gabapentin [Chan et al., 2002; Harrison et al., 2003; McGraw and Kosek, 1997; Rauck et al., 1996]. Regional nerve block has also been used to control pain [Harrison et al., 2003]. Histopathology reveals no consistent vasculitic changes, and erythermalgia is not associated with thrombocythemia [Drenth et al., 1994]. Some studies have demonstrated autonomic and small sensory fiber axonal neuropathy in patients with this disorder [Chan et al., 2002; Davis et al., 2000; Harrison et al., 2003]. The differential for this disorder includes Raynaud’s phenomenon and reflex sympathetic dystrophy, but it can usually be distinguished from these conditions by its unique clinical appearance and the relief provided by ice water immersion. In one report, a child with a syndrome resembling erythermalgia was found to have growth hormone deficiency and remission of symptoms with growth hormone replacement therapy; this has raised the question of whether a disorder involving the insulin-like growth factor family of trophic factors and receptors is involved [Cimaz et al., 2001]. Familial instances of erythermalgia have facilitated localization of the gene for susceptibility to this condition to chromosome 2q31-32 [Drenth et al., 2001].

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CHAPTER 74

Normal Muscle V. Venkataraman Vedanarayanan and Owen B. Evans, Jr.

Movement is one of the ultimate expressions of the nervous system and totally depends on the contraction of skeletal muscle. As an organ, skeletal muscle is the largest structure of the body and has other functions besides voluntary movement and the generation of force. This chapter reviews the embryology, anatomy, function, and metabolism of muscle and the common diagnostic procedures used for its study.

EMBRYOLOGY AND DEVELOPMENT Primitive cells, which are called premyoblasts, are the precursors of muscle in the embryonic paraxial mesoderm. The mesoderm gives rise to segmentally arranged somites. Craniofacial muscles arise rostral of the first somite. Discrete condensations of mesenchymal cells, called dermatomyotomes and located in the dorsomedial somite, give rise to the axial muscles, and condensations from the lateral somite give rise to the limb muscles (Fig. 74-1) [McLennon, 1994]. Connective tissue and tendons arise from the somatopleural mesoderm, somites, and neural crest. Premyoblasts express the paired box transcription factors Pax-3 and Pax-7 and respond to Wnts and sonic hedgehog signals from surrounding embryonic tissues to activate Myf-5 and MyoD myogenic genes [Pownall et al., 2002]. These committed cells, myoblasts, migrate to the myotome. The myoblasts divide rapidly within the first several weeks of pregnancy, after a quantal cell cycle under the influence of fetal growth factors. The primordial cells stream ventrally and penetrate between the ectoderm and somatopleura. As the cells migrate, they split and recombine such that individual muscles are formed from several adjacent myotomes. In the limb bud, the cells coalesce into dorsal and ventral masses. The maturation of premyoblasts to myoblasts begins with the cessation of DNA synthesis. The postmitotic myoblasts elongate and begin attachment and fusion with other myoblasts end to end to form a long and slender primary myotube (Fig. 74-2). The process is facilitated by the appearance of several fetal adhesion molecules on the surface of the myoblast [Schnorrer and Dickson, 2004]. Secondary and tertiary myotubes are formed from side-to-side fusion of myoblasts to existing myotubes and require innervation for the process. Satellite cells provide nuclei to the polar ends of the elongating myotube. Individual muscles begin to form after the initial myotubes appear and the ingrowth of innervation. In the absence of innervation, maturation beyond primary myotubes does not occur, and the muscle develops abnormally. At about 4 weeks’ gestation, the contractile proteins appear and polymerize to form myofilaments, which are produced predominantly in the polar region of the myotube. By

the fifth week, the myofilaments aggregate to form the myofibrils, with simultaneous formation of characteristic striations. A microscopic cross-section of the muscle fiber at this stage reveals a tubular structure, with the contractile proteins located around the periphery of the fiber and the center containing the nuclei. The basic shape of an anatomic muscle is apparent by 7 weeks. Movement begins simultaneously with innervation at 8 weeks. In the latter stages of early fetal development, neuron sprouting is intense. Initially, individual mammalian muscle fibers are multiply innervated. Between 16 and 25 weeks’ gestation and in association with secondary myotube formation, all but one synapse is eliminated. There is constant denervation and reinnervation as neuromuscular interaction forms physiologic innervations of the motor units. Multiple motor neurons compete for innervation. Competition weakens some synapses and strengthens others, so that ultimately a single input prevails. This process of synaptic elimination is stimulated by local factors produced by muscle [Wyatt and Balice-Gordon, 2003]. Several growth factors and receptors appear on the cell surface to facilitate integration of nerve terminals to the muscle cell. The fetal (g) form of the acetylcholine receptor is present until 31 weeks’ gestation, after which only the adult type (e) is found. Rhythmic movements that are spinally mediated start shortly after innervation. Most of the fetal membrane proteins that promote growth and differentiation, including the major histocompatibility gene products [Kaparti et al., 1988], are not present on normal mature muscle. At about 16 weeks’ gestation, the nuclei begin migrating to the subsarcolemmal position. Most muscle fibers achieve the histologic features of mature muscle by 25 weeks, although a few continue to have central nuclei. At this stage, the fibers are rounded and loosely arranged within the prominent endomysium. The characteristic polygonal crosssectional shape becomes apparent after birth. Distinctive muscle fiber types (see next section) develop after innervation. Primitive fibers, typed as IIc, are undifferentiated and are believed to be precursors of the mature fibers: types I, IIa, and IIb [Landon, 1982]. The myosin in type IIc fibers is immunologically distinct from that of other fiber types [Thornell et al., 1984]. Type I fibers appear at about 18 weeks and are smaller than type II fibers until after birth, when they become somewhat larger. Most muscle fibers in the 20- to 26-week-old fetus are type IIc fibers. Type IIa and IIb fibers appear during the last month of gestation. Only a small percentage of type IIc fibers persist after birth. Differentiation into distinct fiber types is determined by neural influences and causes the biochemical and physiologic diversity of mature fibers. Calcineurin, a Ca2+calmodulin–regulated phosphatase, plays a critical role in

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Neuromuscular Disorders / 74 m nt

A

d s nc

B

C

FIGURE 74-1. Cross-section of 28-day fetus at the 21 to 28 somite stage. Early limb buds are apparent. d, Dermatome; m, myotome; nc, notochord; nt, neural tube; s, sclerotome.

the differentiation of physiologic properties in the muscle fiber [Matlin et al., 2001]. Continuous firing of motoneurons causes an increase in intracellular calcium, which activates calcineurin. Activated calcineurin binds and dephosphorylizes nuclear transcription factors, which are translocated to the nucleus and effect gene expression for slow-twitch fiber phenotype. Sporadic motor neuron firing decreases intracellular calcium and deactivates calcineurin. The absence of activated transcription factors in the nucleus results in fasttwitch fibers. Without innervation, muscle fibers atrophy and undergo cell death. Similarly, spinal motor neurons become nonviable without innervating muscle, so that muscle and neuronal development are ultimately interdependent [McLennon, 1994]. Satellite cells are one of several stem cell types found in muscle and have many features of premyoblasts, although the exact origins are unknown [Chen and Goldhamer, 2003]. These mononuclear muscle cells lie beneath the basement membrane of mature muscle fibers. Subsequent growth and elongation of embryonic muscle fibers depend on fusion of satellite cells for new nuclei. Satellite cells are abundant in fetal muscle, compose 1% to 5% of the total nuclei of

D FIGURE 74-2. Development of the muscle fiber. A, Premyoblasts. B, Myoblast fusion. C, Myotube. D, Muscle fiber.

mature muscle, and diminish with aging. They are the primary stem cell for regeneration of injured muscle and are capable of forming not only individual muscle fibers but also complete muscle fascicles [Alameddine et al., 1989; Anderson, 2000; Shultz, 1985]. The subsequent growth and strength of muscle after birth depend on functional demand, sex, age, training, and other factors. Enlargement of a muscle results from hypertrophy of muscle fibers rather than from growth of new fibers. Large muscles with a greater workload, such as the quadriceps, have greater cross-sectional diameters of muscle fibers than do other muscles, such as the diaphragm. There is no difference in fiber growth in males and females until puberty, when a noticeable increase appears in males. Training increases the cross-sectional diameter of the muscle fiber, and disuse decreases the diameter. Muscle atrophy associated with aging is caused by loss of muscle fibers, rather than by fiber atrophy, and a decrease in satellite cells to regenerate injured muscle. Muscle is quite malleable and is under a number of neuronal, hormonal, and usage influences that determine muscle function and contractile properties [Pette, 2001]. FIGURE 74-3. Morphology of muscle. en, Endomysium; ep, epimysium; f, fascicle; mf, muscle fiber; p, perimysium.

mf p

f

ep

en

Vedanarayanan and Evans / Normal Muscle

This plasticity of muscle results in changes in fiber type distribution, contractile proteins, calcium uptake of the sarcoplasmic reticulum, and altered energy metabolism.

Sarcomere The most striking feature of skeletal muscle on microscopic examination is the characteristic striations (“striated” muscle), which are especially prominent under polarized light. The striations are caused by the difference in the refractive index of the contractile proteins that are in phase with each other in the myofibrils. A repeating unit is called the sarcomere, which comprises interdigitating myofilaments and is bounded by the Z line (Fig. 74-4). The sarcomere has a length of about 2.5 to 3.0 μm and a diameter of 1.0 μm. The Z disk anchors the thin filaments of actin that extend into each adjacent sarcomere and are located in the I band. The M line bisects the sarcomere and also divides the A band, which is formed by an array of thick filaments composed of myosin. The area within the A band in which the thin and thick filaments do not overlap is called the H band. A refers to anisotropic and I refers to isotropic in reference to the refractile indexes under polarized light.

ANATOMY AND STRUCTURE Morphology The muscle as an organ comprises all the individual anatomic muscles. Each anatomic muscle has an origin and an insertion on the skeleton and bridges one or more bony articulations. Contraction of the anatomic muscle thus causes movement across a joint. The anatomic muscle is enclosed within a thick sheet of connective tissue called the epimysium. Separating the muscle into individual fascicles is the perimysium, which is contiguous with the epimysium. Within the perimysium are the nutrient blood vessels, intramuscular nerves, and muscle spindles (Fig. 74-3). The confluence of the perimysial and epimysial connective tissue forms the tendons at either end of the muscle belly. The muscle fascicle, which is bounded by perimysial connective tissue, is a wedge-shaped structure comprising several hundred individual muscle fibers. Surrounding each muscle fiber is a network of fine connective tissue, called the endomysium. The terminal axons and a rich capillary network reside within the endomysium. Within the muscle fiber are large groups of myofibrils, which contain myofilaments. Myofilaments are made of contractile proteins. Although a muscle may have almost any shape, all muscles are composed of almost identical muscle fibers. Muscle architecture can be specialized for force production or excursion, depending on the number of muscle fibers arranged in parallel or series, respectively. A muscle fiber, or muscle cell, is a multinucleated, long, tubular structure that varies in diameter from 10 to 20 μm in the infant to about 50 to 70 μm in the adult. Fiber length varies considerably, depending on the size of the muscle and whether the fibers are arranged in series or in parallel orientation, and can be several centimeters in length and can span the entire muscle.

Z

Z

S

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Contractile and Sarcomeric Proteins The two major proteins involved in muscle contraction are actin and myosin, which jointly interact with adenosine triphosphate to convert chemical energy to mechanical work. The actin system is complex. The actin molecule has four major domains surrounding a cleft containing adenosine triphosphate or adenosine diphosphate and is tightly bound to a divalent cation [Pollard, 1993]. There are at least 48 classes of actin-binding proteins. The thin filaments are composed of two chains of about 400 polymerized actin molecules arranged in a double helix (Fig. 74-5). The actin molecule has a molecular weight of about 42,000 daltons and is rich in 3-methyl histidine, a unique amino acid found exclusively in muscle. The actin molecule is the same in both fast and slow skeletal muscle fibers. α-Actinin is a major component of the Z disk and plays a role in the binding or cross-linking of actin to other cytoskeletal structures [Critchley, 1993]. Capping proteins anchor the barbed end of actin to the Z line [Cooper et al., 1993]. Mutation in the α-actin gene has been associated with congenital myopathy

M

Z

A

I

Z

H

FIGURE 74-4. Sarcomere. A sarcomere extends from Z line to Z line. The thick filaments are made up of myosin and occupy the A band. The thin filaments are made up of actin and make up the I band. The H band is the area in which the thick and thin filaments do not overlap. The M line anchors the thick filaments.

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Neuromuscular Disorders / 74 H

S1 S2

M

A

Tm

Tp

FIGURE 74-5. Contractile proteins. Myosin (M) is located in the thick filaments and is composed of two heavy chains (H) and four light chains located in the head region. The myosin head is divided into two parts: S1 and S2. The thin filaments are composed of actin (A), tropomyosin (Tm), and troponin (Tp).

with excess thin myofilaments and nemaline myopathy [Nowak et al, 1999]. The mechanochemical myosin molecule is a complex protein with a molecular weight of about 500,000 daltons. The myosin molecule consists of at least six polypeptides with two heavy chains and four light chains. The contractile properties of a muscle fiber are related to myosin. Myosin heavy chains are different for type I, IIa, and IIb fibers. The two heavy chains form a double helix that extends along the tail of the molecule. The light chains are of the following three types: two alkali dissociated and one phosphorylated. The light chains are different for type I and II fibers but are the same for IIa and IIb fibers. The structure of myosin is hexameric, composed of two heavy, two alkali dissociated, and two phosphorylated chains. There are nine isoforms of the myosin heavy chain: I, IIA, IIB, IID/X, IIA, α, neonatal, embryonic, and extraocular. The various isoforms of the heavy and light chains create a spectrum of isomyosins that are specific for fast-twitch skeletal muscle, slow-twitch skeletal muscle, cardiac muscle, smooth muscle, brain, and platelets [Whalen, 1985]. Embryonic and neonatal muscle contains distinct sets of isomyosins. Skeletal muscle isomyosins are determined by neural influences (see earlier discussion). “Pure” muscle fibers contain a single myosin heavy chain isoform. “Hybrid” fibers contain more than one myosin isoform, as in muscle fibers transitioning from one fiber type to another during reinnervation. The maximal force, velocity, and power produced by muscle fibers are determined to a large extent by the properties of myosin isoforms [Lutz and Lieber, 2002]. At one end, the myosin molecule evaginates to form globular heads. The myosin head is called the S2 region and is attached to the heavy chains. The S2 region is flexible at either end [Huxley, 1982]. One of each type of light chain is associated with the globular heads. The LC1 (light chain 1), or P light chain, somehow modulates the contractile response by specific phosphatase and kinase and exists as P1 and P2 isoforms [Westwood et al., 1984]. The cross-links between actin and myosin occur at the globular heads during excitation. Thus, the myosin molecule is a bipolar structure, with the heavy chains of the tail ordered along the backbone of the thick filament and the heads projected from the side.

The heads have a repeating helical arrangement that forms about three cross-bridges per repeating unit [Harrington and Rodgers, 1984]. C proteins exist as several isoforms and can be seen as cross-stripes on the A band on electron microscopy [Fishman, 1993]. The function of C proteins is unknown but is probably regulatory of cross-bridge movements. Actin and myosin have an inherent affinity, and troponin and tropomyosin are regulatory proteins that enable the actin-myosin interaction to be controlled by the calcium ion [Grabarek et al., 1990]. Tropomyosin is another helical structure, comprising two long filaments that reside within the groove of the actin chains [Smillie, 1993]. There are at least two isoforms of tropomyosin. Fast-twitch skeletal muscle contains both α and β isoforms; slow-twitch muscle contains only β-tropomyosin [Heeley et al., 1985]. Because of the close association with actin, tropomyosin probably also has a structural role. The troponin molecules are located periodically along tropomyosin and comprise three subunits. Troponin T anchors troponin to tropomyosin. Troponin C binds calcium, which induces a conformational change of the protein and results in activation of actomyosin adenosine triphosphatase, which causes contraction [Gergeley et al., 1993]. Troponin I inhibits actomyosin adenosine triphosphatase. The contraction of striated muscle is regulated by the troponin (Tn) complex, which acts as a Ca2+ sensor. Ca2+ binding to the regulatory sites of troponin C (TnC) strengthens the interaction of TnC with troponin I (TnI) and weakens the inhibitory activity of TnI for actin and the affinity of troponin T (TnT) for tropomyosin (Tm). Tm then moves toward the groove of the helical actin filament, switching on the myosin active site, which leads to muscle contraction. Tn binds to actin-Tm in the absence of Ca2+, and the changes in interactions among these thin filament components in the presence of Ca2+ promote strong binding of myosin to actin [Gomes et al., 2002]. Mutations of sarcomeric genes for troponin T1 and tropomyosin are some of several causes of nemaline myopathy [WallgrenPettersson, 2002] and cardiomyopathies [Gomes et al., 2004]. Titin, the largest known protein of about 3 to 3.7 megadaltons constitutes about 10% of myofibrillary proteins and is important for maintaining tension during stretch and recentering the sarcomere after relaxation [Tskhovrebova and Trinick, 2003]. Opposing molecules of titin span the sarcomere. The NH2 termini of the titin molecules attach to the Z disk, attaching myosin to the Z disk. The COOH ends extend and overlap in the M band, interconnecting myosin and actin and providing elasticity to the sarcomere. Associated binding proteins with titin in the Z disk include α-actinin, telethonin, and obscurin [Sanger and Sanger, 2001]. Mutations of the telethonin gene cause limb girdle muscular dystrophy type 2G [Moreira et al., 2000]. Calpain, another titin-binding protein, has been associated with limb girdle muscular dystrophy type 2A [Sorimachi et al., 2000]. Nebulin is another large filament of the skeletal muscle sarcomere. The COOH terminus is attached to the Z disk, and the NH2 terminus projects into the I band. Nebulin is closely associated with actin, and although its function is unclear, it may be that of a “ruler” determining the length of the thin filaments [Wang, 1993]. Nebulin is one of several Z-disk proteins that has been associated with nemaline myopathy [Pelin et al., 1999].

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reticulum during muscle activation. Calcium adenosine triphosphatase pumps calcium back into the sarcoplasmic reticulum during relaxation. Calsequestrin is a calciumbinding protein that increases the capacity of calcium in the sarcoplasmic reticulum [Franzini-Armstrong, 1999]. Some patients with myasthenia gravis, especially associated with thymoma, have anti–skeletal muscle antibodies to ryanodine receptor antigens, as well as to titin [Skeie et al., 2003; Zhang et al., 1993]. Autosomal-dominant and autosomalrecessive mutations of the ryanodine receptor gene (RYR) cause central core disease [Ferreiro et al., 2002] and central core disease with rods [Scacheri et al., 2000]. Other features seen on microscopic examination of muscle are nuclei and the sarcoplasm and its organelles. Normally, nuclei are located beneath the sarcolemma, and each muscle fiber has thousands of nuclei. The sarcoplasm contains many of the elements found in the cytoplasm of other tissues. Most important are the mitochondria, which are located primarily in the intramyofibrillary space near the Z line and adjacent to the A bands. Numerous glycogen granules and fat droplets are located in the same areas.

Sarcotubular System A major constituent of muscle fiber is the sarcotubular system (Fig. 74-6). The sarcolemma is the plasma membrane of the muscle cell and is surrounded by the basement membrane and endomysial connective tissue. The sarcolemma is an excitable membrane and shares many properties with the membrane of the neuron. The T tubules are contiguous with the sarcolemma and extend into the interior of the muscle fiber as a tubular system in communication with the sarcolemma. Depolarization of the sarcolemma is propagated throughout the interior of the muscle fiber through this system [Peachey, 1985]. The T tubules project into the interior of the muscle fibers in the area of the junction of the I band and A band, where they come in immediate contact with a second tubular system within the sarcoplasm called the sarcoplasmic reticulum. The T tubule bounded on either side by the sarcoplasmic reticulum is a triad. The sarcoplasmic reticulum forms a fine plexus around the myofibrils. Excitation of the sarcolemma and T tubules causes release of calcium from the sarcoplasmic reticulum and initiation of contraction by the myofilaments. Several important proteins are associated with the junction of the T tubules and the sarcoplasmic reticulum. The voltage sensors of the T-tubule calcium channels are regulated by dihydropyridine receptors. Ryanodine receptors mediate the calcium release of the sarcoplasmic

Cytoskeletal Proteins The structural integrity of the muscle is maintained against the physical forces of contraction exerted on the sarcolemma membrane by an intricate system of cytoskeletal proteins

pm

T

m

sr

tr

FIGURE 74-6. Sarcotubular system. The drawing illustrates a myofibril of one sarcomere and the associated membrane systems. m, Mitochondrion; pm, plasma membrane; sr, sarcoplasmic reticulum; T, T tubule; tr, triad.

Sg

FIGURE 74-7. Sarcolemma-associated cytoskeletal structures. Dystroglycan (Dg) consists of α-Dg associated with merosin ( M) and β-Dl, which binds to dystrophin (D). Syntropin (S) is bound to the C-terminal region of dystrophin. The sarcoglycan complex (Sg) consists of four transmembrane subunits: α, β, γ, and δ attached to the sarcolemma (Sl). (Modified from Duggan DJ, Gorospe JR, Fanin M, et al. Mutations in the sarcoglycan genes in patients with myopathy. N Engl J Med 1997;336:618).

M Dg

SI

D S

A

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TABLE 74-1 Muscle Proteins and Human Genetic Disease PROTEIN

LOCATION

DISEASE

Plasma Membrane Dystrophin α-Sarcoglycan β-Sarcoglycan γ-Sarcoglycan δ-Sarcoglycan Dysferlin Caveolin-3

Xp21 DMD 17q12-q21 4q12 13q12 5q33-34 2p13 3p25

BMD, DMD LGMD-2D LGMD-2E LGMD-2C LGMD-2F LGMD-2D, Miyoshi’s myopathy LGMD-1C

Extracellular Matrix α2-Laminin Collagen VI

6q2 21q22

Merosin-deficient CMD Ullrich’s CMD, Bethlem’s myopathy

Sarcoplasmic Calpain-3 TRIM32 Myotubularin Desmin Plectin

15q15.1 9q31-34 Xq28 11q21-23 8q24-qter

LGMD-2A LGMD-2H Myotubular myopathy Desmin-related myopathy Epidermolysis bullosa simplex with late-onset muscular dystrophy

Glycosylation Related Fukutin FKRP POMGnT1

9q31-33 19q1 1p32-34

POMT1

9q34

Fukuyama CMD LGMD-D2, CMD-1C Muscle-eye-brain CMD (O-mannose β-1,2-N-acetylglucosaminyl transferase) Walker-Warburg CMD (O-mannosyltransferase-1)

Sarcomeric Proteins Titin Myotilin Telethonin Actin Tropomyosin-3 Tropomyosin-2 Nebulin Slow troponin T Ryanodine receptor (RYR1)

2q 5q22-34 17q11-12 1q42 1q21-23 9p13 2q21-22 19q13 19q13.1

LGMD-2J LGMD-1A LGMD-2G Nemaline myopathy Nemaline myopathy Nemaline myopathy Nemaline myopathy Nemaline myopathy Central core disease, central core disease with rods

Nuclear Proteins Emerin Lamin A/C

Xq28 1q11-21

EDMD LGMD-1B

BMD, Becker muscular dystrophy; CMD, congenital muscular dystrophy; DMD, Duchenne muscular dystrophy; EDMD, Emery-Dreifuss muscular dystrophy; LGMD, limb girdle muscular dystrophy. Adapted from Vainzof M, Zatz M, 2003.

(Fig. 74-7). These proteins, through a complex pattern of arrangement, anchor the internal structure of the muscle to the basement membrane. Advances in techniques of molecular biology have led to identification and characterization of several of these proteins (Table 74-1).

Dystrophin The identification and characterization of dystrophin led to understanding the role of cytoskeletal proteins in providing strength and stability to the muscle membrane. Dystrophin is a large protein molecule of about 427 kilodaltons and is composed of 3,685 amino acids. It constitutes 0.01% of total muscle protein and 5% of the sarcolemmal cytoskeletal proteins [Hoffman et al., 1987]. The protein has the shape of a rod, is about 150 nm long, and is arranged as an

antiparallel holdimer. It is abundant at the myotendinous junction [Samitt and Bonilla, 1990] and at the postsynaptic membrane of the neuromuscular junction [Byers et al., 1991]. Immunocytochemical studies have localized dystrophin to the cytoplasmic surface of the sarcolemma [Bies et al., 1992]. Dystrophin with two other structural proteins, spectrin and vinculin, are located at the sites of attachment of sarcomeres to the cytoplasmic membrane overlying both the I bands and M lines [Porter et al., 1992]. These findings demonstrate that dystrophin forms an integral part of a muscle’s cytoskeleton and links the contractile apparatus to the sarcolemma. There is no difference in the expression of dystrophin in fast- and slow-twitch muscle fibers or in intrafusal muscle fibers [Zubrzycka-Gaarn et al., 1988]. Dystrophin has a binding site for the filamentous form of actin at the 5′ end or domain. The central rod domain

Vedanarayanan and Evans / Normal Muscle

contains a number of repeats and demonstrates homology with spectrin and gives the molecule a flexible rod-shaped structure [Pons et al., 1990]. The rod domain is highly conserved in vertebrates, and antibodies against the human dystrophin rod domain cross-react with amphibian and other vertebrate species [Sherratt et al., 1992]. The third domain is rich in cysteine [Suzuki et al., 1992], and the fourth domain, the carboxy terminus, binds with the dystrophin–glycoprotein complex [Ervasti and Campbell, 1991]. The dystrophinglycoprotein complex consists of dystroglycans (α and β), the sarcoglycans (α, β, γ, δ, ε), sarcospan, the syntrophin, and dystrobrevin [Crawford et al., 2000]. The peripheral members of the complex include neuronal nitric oxide synthase, caveolin, laminin, and merosin [Watkins et al., 2000]. Even though the RNA levels of these proteins are normal in patients with dystrophin deficiency, the protein expression is reduced. The deficiency of these proteins contributes further to the pathologic effects of dystrophin deficiency [Chen et al., 2000]. The gene coding for the protein dystrophin is located on the short arm of the X chromosome near the region Xp21. The dystrophin gene is the largest gene identified so far, covering more than 2.5 megabases (Mb), and contains at least 79 exons [Gutmann and Fischbeck, 1989]. The large size of the gene is responsible for the high rate of mutation in this gene. A 14-kilobase dystrophin messenger RNA is expressed in skeletal, cardiac, and smooth muscle cells. Smaller amounts are expressed in the brain. Isoforms of dystrophin, which are smaller in size, are expressed in nearly all tissues examined. Deficiency of the brain isoform of dystrophin, Dp 140 and Dp 71, is associated with cognitive handicaps. Dystrophin in the brain is important in maintaining synaptic plasticity and participates in cellular signaling pathways involved in modeling synapses [Blake and Kroger, 2000]. Dystrophin isoform Dp 260 is expressed in retina alone [Pillers et al., 1999]. The most important function of dystrophin is to provide mechanical support and structural integrity to the sarcolemma [Lapidos et al., 2004]. Dystrophin is part of the linkage system from the actin cytoskeleton out through the sarcolemmal membrane and basal lamina to the extracellular matrix. Through its linkage to the neuronal nitric oxide synthase, it has a role in regulation of blood flow through muscle during exercise [Sander et al., 2000]. Dystrophin within the dystrophin–glycoprotein complex participates in intracellular signaling. It plays a role in regulation of calcium-dependent kinases in the cell by interacting with calmodulin [Anderson et al., 1996]. Alteration in calcium signaling in dystrophin-deficient muscles plays a major role in altering the normal maturation process of regenerating and developing muscle fibers [Chen et al., 2000]. Deletions or abnormalities of the dystrophin gene cause a deficiency or absence of dystrophin, resulting in the Xlinked Duchenne’s and Becker’s muscular dystrophies.

Dystrophin–Glycoprotein Complex Biochemical investigation of dystrophin led to the discovery of a large oligomeric complex of glycoprotein localized in the sarcolemma. This dystrophin–glycoprotein complex binds the muscle cytoskeleton to a component of the

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extracellular matrix, laminin [Campbell and Kahl, 1989; Ervasti et al., 1990]. The dystrophin–glycoprotein complex consists of cytoskeletal, transmembrane, and extracellular components and is composed of two subgroups of protein complexes: the dystroglycans and sarcoglycans. The dystroglycan complex consists of a transmembrane and an extracellular component encoded by a single messenger RNA. The synthesized protein undergoes glycosylation as it passes from endoplasmic reticulum to the sarcolemmal membrane. The α-dystroglycan is a heavily glycosylated protein located on the extracellular side of the sarcolemmal membrane. It plays an active role in basement membrane assembly. It binds to β-dystroglycan (transmembrane component) with its carboxy-terminal region on the intracellular side. The dystroglycan complex plays a pivotal role in linking the cytoskeleton to the extracellular matrix. The dystroglycan complex also plays an important role in normal migration of neurons in the cerebral cortex [Martin and Freeze, 2003; Michele and Campbell, 2003]. The assembly and integration of these proteins occur in the presence of dystrophin; in its absence, these proteins may not be degraded, properly assembled, or integrated into the sarcolemma [IbraghimovBeskrovnaya et al., 1992]. No primary mutations in dystroglycans have been identified in human disease. Defective glycosylation of α-dystroglycans causes congenital muscular dystrophies with brain involvement: Fukuyama’s congenital muscular dystrophy, muscleeye-brain disease, Walker-Warburg syndrome, limb girdle muscular dystrophy type 2I [Grewal and Hewitt, 2003]. The sarcoglycan complex consists of α-sarcoglycan (adhalin), β-sarcoglycan, γ-sarcoglycan, and δ-sarcoglycan [Bonnemann et al., 1995]. The sarcoglycan genes α, β, and γ are located on 17q12-21, 4q12, and 13q12 chromosomes, respectively. Expression of α- and γ-sarcoglycan is limited to skeletal and cardiac muscles [Yamamoto et al., 1994]. The sarcoglycans form a tetrameric complex in the Golgi apparatus and then transition to the sarcolemma as a completely assembled structure. The sarcoglycans consist of a single transmembrane domain, a small intracellular domain, and a large extracellular domain, and their molecular weight ranges from 35 to 50 kilodaltons. The sarcoglycan complex, which is composed of α-, β-, γ-, and δ-sarcoglycan, is part of the dystrophin-associated glycoprotein complex and acts as a link between the extracellular matrix and the cytoskeleton, confers structural stability to the sarcolemma, and protects muscle fibers from mechanical stress during muscle contraction. Mutations in any of the sarcoglycan genes cause destabilization of the complex, produce a decrease in the amount of all sarcoglycan proteins, and cause the different forms of limb girdle muscular dystrophy [Matsumara et al., 1992; Straub and Campbell, 1997]. The diseases associated with sarcoglycan gene mutations (α-sarcoglycan [SGCA], limb girdle muscular dystrophy type 2D; β-sarcoglycan [SGCB], limb girdle muscular dystropy type 2E; γ-sarcoglycan [SGSG], limb girdle muscular dystrophy type 2C; δ-sarcoglycan [SGCD], limb girdle muscular dystrophy type 2F) are rare disorders in the general population but represent a sizable proportion of all muscular dystrophies with normal dystrophin (about 10% to 20% of cases). Limb girdle muscular dystrophy type 2D is the most frequent sarcoglycanopathy, followed by types 2C and 2E, whereas the most rare is type 2F [Boito et al., 2003].

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The measurement of α-sarcoglycan is a useful screening test to look for sarcoglycan gene mutations in patients with muscular dystrophy [Duggan et al., 1997].

Utrophin Initially described as dystrophin-related protein or dystrophinlike protein, utrophin is an autosomally encoded protein. It is smaller in size than dystrophin, and it has been localized to the sarcolemmal postsynaptic membrane at the neuromuscular junction and myotendinous junction in the mature muscle fiber [Khurana et al., 1991]. At the neuromuscular junction, it is preferentially concentrated at the acetylcholine receptor–rich crests. Utrophin is present in all tissues tested so far. In the brain, it is localized at the inner plasma face of astrocytic foot processes at the abluminal aspect of the blood-brain barrier [Khurana et al., 1992] Utrophin has a similar amino acid sequence as the carboxy terminus of dystrophin, and it copurifies with α-sarcoglycan. The gene coding for utrophin is localized to the long arm of human chromosome 6, at 6q24. The transcription of utrophin occurs preferentially at the nuclei close to the neuromuscular junctions (subsynaptic nuclei). The transcription of utrophin gene is regulated by growth factors released from neurite, such as heregulin, a neurite-associated growth factor that is a member of the neuregulin family of growth factors. In muscles, growth factors increase the transcription of acetylcholine receptor, sodium channels, and utrophin [Fishbach and Rosen, 1997]. In dystrophin-deficient states, utrophin content is increased and localizes to sarcolemma as well. A number of approaches to upregulate the expression of utrophin in muscles are being explored as treatment for Duchenne’s muscular dystrophy.

Dysferlin Dysferlin is a 237-kilodalton protein composed of 2,080 amino acids. It has a single transmembrane segment at the carboxy terminus. The protein is anchored at the sarcomere by the carboxy terminus, and the rest of the protein is intracytoplasmic. It is distributed at the sarcolemma, similar to dystrophin and the dystrophin–glycoprotein complex. However, the protein is not associated with dystrophin and the dystrophin–glycoprotein complex. The dysferlin protein is coded by a gene located in chromosome 2 p13. The gene is relatively large and spans 150 kilobases. It is composed of 55 exons and is expressed in skeletal and cardiac muscles and placenta. A shorter transcript of 3.5 kilobases is expressed in all regions of the brain. Proteins with homology to dysferlin are seen in other tissues. Fer-1 is present in testes and is required for maturation of spermatozoa. Otoferlin, with 55% homology to dysferlin, is expressed in the inner hair cells. Myoferlin, with 68% homology, is present in the lungs, placenta, heart, and cytoplasm and nuclear membranes of skeletal muscles [Bansal et al., 2003]. The ferlin family of cytoplasmic proteins has motifs that are homologous to so-called C2 domains. The C2 domains are typically found in proteins that function in signal transduction or in membrane trafficking, such as protein kinase C and synaptotamins [Anderson et al., 1999]. These domains interact with multiple targets, including calcium, phospholipids, and other proteins, to mediate signaling

events for membrane fusions [De Luna et al., 2004; Rizo and Sudhof, 1998]. The clinical disorders with deficiency, such as distal myopathy of Miyoshi and limb girdle muscular dystrophy type 2B, occur from defects in processes of membrane trafficking or fusion [Bajaoui et al., 1995; Liu et al., 1998; Takahashi et al., 2003].

Caveolin Caveolae are flask-shaped plasma membrane invaginations that participate in membrane trafficking, sorting, transport, and signal transduction. They are abundant in fibroblasts, adipocytes, endothelial cells, and smooth and striated muscle cells. Caveolin, a family of 21- to 24-kilodalton proteins, is a major constituent of the caveolae. Caveolins form the protein scaffolding upon which the specific proteins and lipids interacting with it are concentrated. Caveolin-3 is expressed in muscles. The human caveolin-3 gene maps to chromosome 3p25, and it codes for a protein of 150 amino acids. The caveolin protein is localized to the sarcolemmal membrane on immunocytochemical studies [Betz et al., 2001]. Mutations in the caveolin-3 gene produce autosomaldominant limb girdle muscular dystrophy type 1C, hyperCKemia, and hereditary rippling muscle disease [Carbone et al., 2000]. The mutant gene produces marked reduction in the caveolin-3 protein, consistent with the dominantly inherited disorder [Cagliani et al., 2003].

Merosin (Laminin-a2) Laminin-α2 is a major component of laminin in the basal lamina of postnatal muscle. It is also expressed in cardiac muscle, pancreas, lung, kidney, adrenal gland, skin, testis, meninges, choroid plexus, and brain. Expression of the laminin-α2 gene occurs in cells of mesenchymal origin. The gene for laminin-α2 is localized to chromosome 6q22-23 [Vuolteenaho et al., 1994]. The mature myofiber laminin is a heterodimer composed of laminin-α2, -β1, and -γ1. The laminin interacts with sarcolemma through the dystrophin– glycoprotein and vinculin–integrin complexes. It interacts with basal lamina and extracellular matrix through perlecan, nidogen, and a series of other proteins. Developing and embryonic myofibers express different isoforms of laminin. The laminin isoform expression changes to the α2 isoform from the α1 isoform at the time of birth. Mutations of laminin-α2 in children manifest as congenital muscular dystrophy, complete absence of muscle merosin, and abnormalities of cerebral deep white matter [Jones et al., 2001; Philpot et al., 1995]. Prenatal diagnosis can be made by immunostaining the chorionic villus sample for merosin [Yamamoto et al., 2004].

Intermediate Filaments Intermediate filaments are cytoskeletal proteins measuring between 10 and 12 nm in thickness [Omary et al., 2004]. Their size is intermediate between actin and the thicker myofilaments such as myosin. Intermediate filaments are seen in cells derived from all three embryonic lineages. Desmin, vimentin, nestin, and lamin are expressed in muscle. Desmin is the major intermediate filament in skeletal muscle. It is also expressed in cardiac and certain smooth

Vedanarayanan and Evans / Normal Muscle

muscles. Desmin is located at the Z band beneath the sarcolemma and is denser at the myotendinous junction [Tidball, 1992]. Desmin is involved with the alignment of sarcomeres with one another and the plasma membrane. It may play a role in the functional and spatial relationship between the nucleus and plasma membrane, and it is presumed to regulate myogenesis because it is more strongly expressed in immature myofibers [Fuchs and Weber, 1994; Gallanti et al., 1992]. Desmin is a 53-kilodalton protein organized in three domains. The highly conserved central α-helical core of 310 amino acids is flanked by a nonhelical amino-terminal head and carboxy-terminal tail. The core is formed of four helical rods: A1, A2, B1, and B2. The desmin polypeptide chains are intertwined in a coiled-coil fashion into a homodimer [Geisler and Weber, 1982]. The desmin filaments interact with other filaments and other proteins to form a crosslinking network, which attaches to membranes. A gene located on chromosome 2q35 encodes the desmin protein [Viegas-Pequignot et al., 1987]. Mutations of the desmin gene result in the desmin-related myopathies, also known as myofibrillar myopathies, and cardiomyopathies [Dalakas et al., 2000, Goldfarb et al., 2004]. Vimentin is an intermediate filament that is also expressed in immature muscle cells during myogenesis. After the postnatal period, its expression in muscle is primarily in regenerating and immature cells [Bornemann and Schmalbruch, 1993]. It is also expressed in tumors of rhabdoid origin. Nestin is a protein that is expressed with desmin in developing muscle cells [Sjoberg et al., 1994]. Postnatally, the protein is found with desmin in regenerating muscle fibers in patients with dystrophic and inflammatory myopathies. Plectin, a cytoskeletal linker protein for desmin and keratin organization in muscle and skin, is a large protein (more than 500 kilodaltons) that is expressed in a wide variety of tissues, including muscle and skin. It has a highaffinity binding site for intermediate filaments at its COOH– terminus. The amino terminus has an actin-binding site, and this site shares similarities with the actin-binding domains of α-actinin, dystrophin, and utrophin. Plectin provides mechanical strength to tolerate the forces of physical stress. Plectin is encoded by a gene localized to 8q24 and has 32 exons [Liu et al., 1996]. Deficiency of plectin has been identified as the cause of recessive epidermolysis bullosa with congenital muscular dystrophy [Whiche, 1998]. Other important cytoskeletal proteins include tubulins and anchor proteins. Microtubules formed from tubulins and other intermediate filaments play an important role in maintaining the cytoplasmic architecture. Anchor proteins link the cytoskeletal proteins to the plasma membrane. Tropomodulin is an integral component of the cytoskeletal structure in the postsynaptic region of the neuromuscular junction [Sussman et al., 1993].

Nuclear Membrane–Related Proteins: Emerin and Lamin A/C Emerin is a protein associated with the inner nuclear membrane. It is attached to the inner nuclear membrane by

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its carboxy terminus and extends into the nucleoplasm. Emerin is composed of 254 amino acids and is coded by gene on the X chromosome. Emerin is important in the organization of nuclear membrane during cell division [Fairley et al., 1999]. Mutation of this gene causes X-linked Emery-Dreifuss muscular dystrophy [Haraguchi et al., 2004]. Lamins are major components of the nuclear lamina, which is the major structural framework of nuclei in eukaryotic cells. In humans, two forms of type A (A and C) and B (B1 and B2) are present. Lamins have the helical rod portion and nonhelical portions at the amino and carboxy termini. Lamins differ from other intermediate filaments by the presence of a nuclear localization signal close to their carboxy terminus. The lamins interact with themselves, lamin-associated proteins, and chromatin. The lamins play a role in DNA replication, chromatin organization, spatial arrangement of nuclear pores, nuclear growth, and mechanical stability of the nucleus [Loewinger and McKeon, 1988; Maniotis et al., 1997]. Mutations in the lamin A (A and C) cause autosomal-dominant Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy with conduction defects, and Dunnigan-type familial partial lipodystrophy [Benedetti and Merlini, 2004; van der Kooi et al., 2002].

MUSCLE FIBER TYPES A single action potential of the neuron causes a transient contraction of the muscle fibers of a motor unit, which is called the muscle twitch. The action potential has a duration of about 5 milliseconds, and the onset of contraction occurs about 2 milliseconds after the muscle membrane action potential begins. However, the duration of the muscle fiber contraction varies with the fiber type. Some fibers have rapid twitch times of 5 to 10 milliseconds and are called fasttwitch fibers. Other fibers have slow contraction times of 50 to 100 milliseconds and are called slow-twitch fibers. Another characteristic of fast-twitch fibers is a relative sensitivity to fatigue and repetitive stimulation. Such fibers often have a grossly pale appearance because they have less myoglobin and mitochondria (“white” muscle). Slow-twitch fibers are resistant to fatigue and have more myoglobin and mitochondria (“red” muscle). Clinical use commonly divides human muscle fibers into types I and II [Dubowitz and Brook, 1973]. Type I fibers have slow-twitch characteristics and are rich in mitochondria and substrates for aerobic (oxidative) metabolism. They are slightly smaller than type II fibers and have a less welldeveloped sarcoplasmic reticulum and T-tubule systems. Type II fibers have fast-twitch characteristics and are rich in glycogen and other substrates and enzymes needed for anaerobic (glycolytic) metabolism. Type II fibers can be subdivided into type IIa and IIb fibers. Type IIb fibers are the prototype for the type II fibers, whereas type IIa fibers are intermediate, with both oxidative and glycolytic properties. Type I fibers are generally found in muscles needed for sustained tonic contraction, such as the antigravity muscles of the limbs and trunk. Type I fibers have a more luxurious capillary blood supply. Type II fibers are usually found in muscles concerned with rapid, forceful movement. Table 74-2 summarizes the properties of muscle fiber types. Division of

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muscle fibers into three basic types is probably an oversimplification. There is a continuum of physiologic properties dependent on the innervation of the motor neuron, which contributes to the plasticity of muscle to adapt to a variety of demands [Buchthal and Schmalbruch, 1980]. The biochemical characteristics of the fiber types can be visualized using histochemical reactions. Type I fibers manifest a strong reaction when stained for the mitochondrial enzymes: succinic dehydrogenase and nicotinamide-adenine dinucleotide (reduced form) transreductase. Nicotinamideadenine dinucleotide (reduced form) transreductase is also found in abundance in sarcoplasmic reticulum. Myosin adenosine triphosphatase activity can also be used to differentiate fiber types because of the relative abundance of myosin adenosine triphosphatase in type II fibers. Preincubation at various pH levels provides different staining characteristics to various muscle fibers. Type II fibers have an alkali-stable, acid-labile adenosine triphosphatase, whereas type I fibers have the opposite characteristic. Table 74-3 summarizes the histologic and histochemical properties of the muscle fiber types. All muscle fibers of a motor unit are of a single type. Most of the physiologic, metabolic, and morphologic properties of the muscle fiber depend on innervation from the anterior horn cell. Small α motor neurons innervate type I fibers, and large α motor neurons innervate type II fibers. Reinnervation by the axons of another anterior horn cell alters the muscle fiber properties so that they are identical to the fibers of the donor motor unit [Buller et al., 1960]. The clinical significance of this phenomenon is fiber-type grouping that occurs with reinnervation and can be detected by electromyography and muscle histochemistry. The fibers of a motor unit are normally distributed randomly over several millimeters in the muscle. When a muscle fiber loses its innervation, reinnervation from adjacent, intact axons changes its fiber type. The fiber type can also be altered by changing the characteristics of its innervation [Edgerton et al., 1985], especially its frequency and the quantity of impulses. Pro-

longed tonic stimulation to a type II fiber can induce type I histochemical characteristics in it [Pette and Vrborá, 1985]. The plasticity of muscle, which alters its characteristics to match changing patterns of innervation, makes the muscle system the most adaptable organ.

FUNCTION Motor Unit Contraction of a muscle fiber is initiated by depolarization of its anterior horn cell, which is the final common pathway for all cortical and spinal influences that affect movement. Depolarization of the anterior horn cell membrane is propagated along its axon in the peripheral nerve. At the nerve terminal, axon twigs run parallel within the muscle fascicle to the muscle fibers and innervate the fibers at the neuromuscular junction. Each anterior horn cell innervates about 50 to 200 muscle fibers, depending on the muscle. The anterior horn cell, its peripheral axon, and the innervated muscle fibers compose the motor unit and can be considered a functional unit of the muscle. The muscle fibers within the motor unit are not contiguous but are scattered fairly randomly. In the rat, the motor unit is dispersed over 8% to 76% of the cross-sectional area of the muscle, with some clustering of a few fibers in the motor unit territory [BodineFowler et al., 1990]. When the anterior horn cell discharges, all the muscle fibers innervated by that anterior horn cell contract almost simultaneously. The finer and more coordinated the movement of a muscle, the fewer the fibers in the motor unit. Eye muscles and some hand muscles may have 30 to 50 fibers in the motor unit, whereas some back muscles have hundreds. In general, the larger the muscle, the larger the size of the motor units [McComas, 1991]. For example, there are about 100 fibers per motor unit in the intrinsic muscles of the hand, 200 in the extensor digitorum brevis, and 900 in the larger muscles.

TABLE 74-2 Characteristic Features of Muscle Fiber Types I

IIa

IIb

Metabolic Features Glycolytic metabolism Myoglobin content Mitochondria content Sarcoplasmic-reticulum-calcium pump capacity Adenosine triphosphatase activity

Oxidative High High Moderate Slow

Oxidative High High High Fast

Glycolytic Low Low High myosin isozyme Fast

Physiologic Features Twitch speed Twitch duration Fatigue resistant

Slow Long Yes

Fast Short Intermediate

Fast Short No

Morphologic Features Capillary supply Sarcoplasmic reticulum Size Appearance Other names

Rich Intermediate Intermediate Red Red, slow oxidative

Intermediate Rich Small Red Fast oxidative

Poor Rich Large White White, fast glycolytic

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TABLE 74-3 Histochemical Reactions of Human Muscle

Myosin ATPase, pH 9.4 Myosin ATPase, pH 4.6 Myosin ATPase, pH 4.3 Actomyosin ATPase NADH-TR Succinic dehydrogenase α-Glycerophosphate dehydrogenase (menadione linked) Phosphorylase Periodic acid–Schiff stain Oil red O stain

I

IIa

IIb

Light Dark Dark Light Dark Dark Light Light to intermediate Light to intermediate Dark

Dark Light Light Dark Intermediate Intermediate Dark Dark Light Light

Dark Intermediate Light Intermediate Light Light Dark Dark Light Light

ATPase, adenosine triphosphatase; NADH-TR, nicotinamide-adenine dinucleotide (reduced form) transreductase.

syndome by reducing the quantal release of acetylcholine [Newsome-Davis, 2004]. Acetylcholine is synthesized from acetyl coenzyme A and choline and exists in a reserve compartment that is not readily available for release and in a mobilization compartment of vesicles. Each synaptic vesicle contains a quantum of about 10,000 acetylcholine molecules. The vesicles are attached to the active zone of the presynaptic membrane. Fifty to 300 vesicles fuse with a nerve terminus depolarization. The process of vesicle formation, fusion, and release is a complex system involving many proteins [Ruff, 2003]. Acetylcholine combines with specific acetylcholine receptors located on the postsynaptic membrane of the muscle sarcolemma. There are about 15,000/μm2 receptors in the junctional fold concentrated at the tops of the secondary folds. The acetylcholine receptor is a transmembrane glycoprotein with a molecular weight of 250,000 daltons and is composed of four subunits: α, β, δ, and γ [Momoi and Lennon, 1982]. The muscle acetylcholine receptor monomer is constructed with two α subunits and one of each of the other subunits in order: α1, γ, δ, β1 [Lindstrom, 2003]. The acetylcholine receptor monomer

Neuromuscular Transmission The neuromuscular junction is formed by specialized portions of the nerve and muscle plasma membrane, which are separated by the synaptic cleft (Fig. 74-8). The area on the muscle is the end plate and is located near the center of the muscle at the end-plate zone. The synaptic knob is the terminal dilation of the nerve axon and contains synaptic vesicles of acetylcholine. The motor neuron action potential is propagated down the motor nerve by saltatory conduction. Na+ channels at the nodes of Ranvier produce current. Within the muscle, the motor nerve fiber branches into terminal fibers that individually innervate muscle fibers within the motor unit. The nerve terminals are unmyelinated, and the membrane excitability is maintained by both K+ and Na+. Antibodies to the K+ antigen cause acquired neuromyotonia, such as Isaac’s syndrome [Newsome-Davis et al., 2003]. Depolarization of the nerve terminus opens voltage-gated calcium channels at the synaptic knob. As calcium enters the nerve ending, exocytosis of the synaptic vesicles occurs, releasing acetylcholine. Antibodies directed against the voltage-gated calcium channels causes Lambert-Eaton

FIGURE 74-8. Neuromuscular junction. bm, Basement membrane; da, distal axon; jf, junctional folds; pm, plasma membrane; sc, synaptic cleft; tk, terminal knob.

da

bm

pm

sc

tk

jf

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contains two acetylcholine-binding sites and the cationspecific channel, whose opening is regulated. The receptor is barrel shaped, traverses the sarcolemma, and projects above its surface. The subunits are arranged around the central channel-like staves (Fig. 74-9) [Kistler et al., 1982]. The acetylcholine receptors are anchored to dystrophin-related protein complexes and connected to the cytoskeleton by dystrophoglycans and sarcoglycan protein complexes. The structure and function of the acetylcholine receptor are remarkably similar in all species studied. Congenital myasthenic syndromes are caused by genetic mutations of the receptor and other synapse structures, whereas myasthenia gravis is caused by antibodies to receptor proteins. The binding of two acetylcholine molecules with the α subunits of the receptor causes a conformational change in the M2 portion of α-helical structures of each of the five subunits. This change results in a rotational realignment of the helices to open the center of the receptor for a few milliseconds and thereby alter the sodium and potassium permeability by opening ion channels. Increased ion conductance across the sarcolemma causes a localized depolarization of the muscle end plate. A single quantum of acetylcholine interacting with the end plate causes a miniature end-plate potential insufficient to engender a propagated membrane discharge. When depolarization of the terminal axon occurs, 50 to 300 acetylcholine quanta are released. Sufficient interactions between acetylcholine molecules and receptors cause the summation of potentials to reach the threshold potential for the end plate. Thus, an end-plate potential is achieved, and the depolarization is propagated along the sarcolemma and T tubules. Depolarization of the end plate is a statistical phenomenon; given sufficient numbers of acetylcholine molecules and receptors, an interaction will probably occur, followed by depolarization [Katz and Miledi, 1972]. Interference with the release of acetylcholine or a reduction in the number of receptors lessens the likelihood of successful neuromuscular transmission.

Excitation–Contraction Coupling The major function of muscle is generating movement or force by contraction. This function is accomplished through a series of events called excitation–contraction coupling, which is the linkage of the electrical and mechanical properties of muscle. Depolarization of the T tubules at the triad ␣

␤ ␦

␥ ␣

FIGURE 74-9. Acetylcholine receptor. The receptor projects above the plasma membrane and is composed of five subunits arranged around the central ion channel.

is sensed by dihydropyridine (a calcium-channel blocker) receptors, which are associated with charged molecules within the tubular membrane. Movement of these charged molecules, which can be inhibited by dantrolene [Hui, 1983], causes a conformational change in the “feet,” which are structures that bridge the membranes of the T tubules and sarcoplasmic reticulum [Peachey, 1985]. Calsequestrin is a major protein of the sarcoplasmic reticulum that binds calcium and is located close to the sarcoplasmic reticulum calcium efflux channels in register with the “feet” processes [Stadhouders, 1990]. Interaction of these membrane structures at the triad causes the release of calcium from the sarcoplasmic reticulum into the sarcoplasm. During tetany, calcium concentrations decrease in the sarcoplasmic reticulum and increase in the sarcoplasm [Somlyo et al., 1981]. This release of calcium is critical for the mechanics of muscle contractions. Calcium-binding proteins in the sarcoplasm, including calmodulin [Kennelly et al., 1989] and parvalbumin [Heizmann et al., 1990], are essential for regulation of the contractile proteins. Contraction of muscle is brought about by contractile proteins. These proteins have different forms (isoforms), and the presence of a specific isoform within the fiber determines some of the contraction properties of the muscle. The isoforms are similar but have slightly different properties, such as calcium-binding capacity and adenosine triphosphatase activity. Every fiber is capable of synthesizing all isoforms of the contractile proteins, but the precise composition of isoforms within a muscle fiber depends on the many complex mechanisms that coordinate gene expression and the neural influences that ultimately control fiber typing (see earlier discussion). When it is released by the sarcoplasmic reticulum, calcium binds with calmodulin; the complex acts as a second messenger that activates the myosin light chain troponin C kinase [Kennelly et al., 1989]. This reaction causes an unmasking of a myosin-binding site by displacing troponin I and tropomyosin. The myosin head swings away from the backbone of the thick filament at the hinge area of the S2 region [Horowits et al., 1989]. The myosin head then attaches to actin at an angle, and the hydrolysis of adenosine triphosphate causes the myosin head to swivel to a more acute angle, moving the chains toward one another (Fig. 74-10). Repetition of this event causes shortening of the sarcomere [Vale and Milligan, 2000]. Each attachment, swivel, and reattachment shortens the muscle about 1%, or about 14 nm [Ford et al., 1977]. Myosin hydrolyzes adenosine triphosphate slowly unless combined with actin. Each stroke of the myosin–actin cross-bridge attachment consumes one molecule of adenosine triphosphate: adenosine triphosphate binding to myosin, dissociation of actin and myosin, adenosine triphosphate hydrolysis, reassociation of actin and myosin, and release of hydrolysis products. The rate of stroke cycling and therefore the contraction velocity are dependent on the myosin adenosine triphosphatase isoform [Pollack, 1996]. The exact mechanism of the phase transition that brings about muscle contraction is still not fully known [Brooks, 2003]. The entire process constitutes excitation–contraction coupling. The tension generated by a muscle is directly proportional to the number of cross-links between the myosin heads of thick filaments and the actin of the thin filaments as

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A

B

A

B

C

FIGURE 74-11. Schematic diagram of myofilament orientation within the sarcomere. Cross-sections illustrate the relationships of the thick and thin filaments. A, A band. B, H band. C, I band.

C

FIGURE 74-10. Myosin head movement. During contraction, the myosin head swivels from its resting position (A), toward actin (B). With hydrolysis of adenosine triphosphate, the orientation of the head closes to a more acute angle, propelling the thin filament to slide (C).

determined by length–tension relationships [Pollack and Sugi, 1984]. On cross-section, each myosin heavy chain is surrounded by six actin light chains. This geometric array is found in the area of the sarcomere where there are overlapping myofilaments, as in the A band (Fig. 74-11). The more foreshortened the sarcomere, the more cross-links between the filaments. However, only the thin filaments occur in the I band. Each muscle has a length at which it generates maximum force and at which the greatest interaction between actin and myosin occurs [Hoxley, 1996; Lieber, 1986]. Evidence suggests that contraction of a muscle occurs by heavy and light myofilaments sliding toward one another. When a muscle contracts, the distance between the Z lines decreases at the expense of the I and H bands. The A band

remains unchanged (Fig. 74-12). During stretch, the I band increases in length as the actin filament arrays slide in the direction opposite of the myosin filament arrays; thus, the distance between Z lines increases. This sliding is produced by the formation and breakage of the cross-links between actin and myosin. Neuromuscular transmission is terminated by calcium sequestering within the synaptic knob. Muscle contraction is terminated when the T tubules repolarize; this causes reaccumulation of calcium within the sarcoplasmic reticulum, using a pump that depends on adenosine triphosphate [Peachey, 1985]. Unlike the nerve and muscle plasma membrane, the contraction process has no refractory period. As long as calcium is free in the sarcoplasm and adequate energy stores exist, the muscle will stay contracted. Muscle can stay contracted without excitation of the membrane system, and energy is required for the reuptake of calcium into the sarcoplasmic reticulum. Failure of calcium reuptake from the sarcoplasm when energy stores are depleted inhibits relaxation of the muscle. This mechanism causes rigor mortis and the cramping during exercise found in energy-deficiency disorders, such as McArdle’s disease.

Z

Z

Z

Z

FIGURE 74-12. Sliding filament mechanism of muscle contraction. The thick and thin filaments slide toward one another during contraction, causing the distance between the Z lines to shorten.

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NEURAL CONTROL OF MUSCLE CONTRACTION

γ Efferent System

The sarcomere is the contracting unit of muscle. Whole muscle contraction force is proportional to the number of sarcomeres contracting in parallel, whereas whole muscle contraction velocity is proportional to the number of sarcomeres acting in series [Lieber, 1986]. This interaction generally applies to the muscle fiber and to the architecture of muscle. The more fibers in parallel, the more force is generated by contraction. The longer the muscle fiber, the more sarcomeres are in series and the greater the contraction velocity.

The γ efferent system plays a major role in controlling muscle contraction by its effects on the muscle spindle. The muscle spindle is a specialized sensory organ located within the perimysial connective tissue (Fig. 74-13). It is an encapsulated structure containing 2 to 10 small muscle fibers (intrafusal fibers) and special sensory nerve endings. The intrafusal fibers comprise nuclear bag fibers, nuclear chain fibers, and an intermediate type of fiber. Each has distinct ultrastructural and histochemical characteristics [Barker et al., 1972]. The intrafusal fibers of the spindle are arranged in parallel with the extrafusal fibers of the muscle. The sensory endings are of two types [Scalzi and Price, 1972]. The primary endings (annulospiral) are supplied by large, myelinated, rapidly conducting Ia afferent fibers and end in a spiral or cagelike arrangement around nuclear bag fibers. These endings are sensitive to both stretch of the spindle and the velocity of stretch. Secondary endings of group II sensory nerves terminate in a variety of endings, including cylindrical, flat, and annulospiral or ring-shaped endings, mostly on nuclear chain fibers [Schroder et al., 1989]. Secondary endings are sensitive to the stretch of the spindle. The fusimotor fibers compose as much as 30% of the total number of ventral root fibers. Most are γ efferents, although a few are β efferents [Barker et al., 1972]. Multiterminal plate endings (i.e., flower-spray) are located on nuclear bag fibers from myelinated γ efferents and probably cause dynamic innervation. Trail endings, however, primarily innervate nuclear chain fibers and arise from smaller myelinated and unmyelinated fibers. Trail fibers supply static innervation. The afferent fibers of primary endings synapse directly on the anterior horn cells, which supply the extrafusal fibers of the same muscle. The secondary ending afferents probably synapse on motor neurons of other muscles [Scalzi and Price, 1972]. Stretch of a muscle causes distortion of the primary endings and generates a signal to the motor neuron to cause contraction. This signal is the mechanism of the deep tendon reflex. If the muscle were shortened, spindle discharge would decrease, causing muscle relaxation; therefore, spindles serve as a feedback mechanism to maintain muscle length and tone. The γ efferent system operates in concert with the α motor neuron to effect movement [van der Meulen et al., 1972]. Stimulation of the γ motor neuron causes stretching of the nuclear bag fibers, distortion of the primary endings, and reflex stimulation of the α motor neuron, as discussed previously. The γ motor neurons are regulated by several descending tracts, whose main purpose is to maintain the sensitivity to stretch throughout muscle contraction so that different muscle groups can adjust to the needs of postural control. The other major sensory innervation of muscle is the Golgi tendon organ [Stuart et al., 1972], which is a netlike structure located around the tendon fascicles supplied by fast-conducting myelinated afferent fibers. The output causes stimulation of inhibitory internuncial neurons, which, in turn, synapse on α motor neurons. The sensory organ is arranged in series with the muscle and thus is more sensitive to changes in muscle force than to changes in

Motor Unit System The motor unit consists of a single lower motor neuron and the muscle fibers it innervates. The motor unit is the final common pathway of the motor system [Miles, 1994]. The following two control mechanisms are used by the nervous system in generating muscle contraction force: (1) the orderly recruitment of motor units, and (2) the regulation of firing rates of active motor neurons [De Luca, 1985]. There is a rank order of recruitment within a motor neuron pool, so that increasingly larger motor units are recruited for increasing demands of force. Smaller motor units are recruited initially [Henneman, 1985]. Similarly, the rate of discharge of motor units is proportional to the degree of force generated. Current information indicates that the firing rates of motor neurons are not controlled individually, but that the nervous system controls the firing rate of motor neuron pools to modulate force generation. This mechanism has been termed common drive [De Luca, 1985]. In general, the recruitment of additional motor units is more important in generating force and power than modulating firing rates [Brooks, 2003]. Motor unit recruitment is the process by which different motor units are activated to produce a specific degree and type of muscle force [Petajan, 1991]. In the graded generation of force, the lower force threshold, slow-twitch motor units are recruited first. Increasing force output increases the firing rate of these first recruited motor neuron pools in fine gradations. Further force generation requires recruitment of large motor neurons with higher force threshold, fast-twitch motor units. This recruitment causes a 5- to 10-fold increase in the graded force. Normally, a motor unit discharges up to rates of 5 to 15 Hz before an additional neuron is recruited. The firing rate of the fastest firing motor unit divided by the number of recruited neurons is normally less than five (e.g., three neurons firing at a rate of 15 Hz). When this recruitment ratio is greater than 10 (e.g., two neurons firing at a rate of 20), it suggests a loss of motor units. At maximal exertion, there is fusion of contractions of the slow-twitch motor units. Because of the short twitch duration of the large motor units, they may not achieve contraction fusion with voluntary effort [De Luca et al., 1982]. During normal activity, slow-twitch motor units discharge more frequently and are active more often than fast-twitch motor units [Hennig and Lomo, 1985]. Changes in the firing rate and the number of motor units recruited for a given muscle contraction are under a variety of controls, including the γ afferents, Golgi tendon organs, and Renshaw cells that facilitate or disfacilitate neurons to produce a graded contraction.

Vedanarayanan and Evans / Normal Muscle get gep

II

Ia

cap

nbf ncf

FIGURE 74-13. Muscle spindle. cap, Capsule; get, γ efferent with trail ending; gep, γ efferent with plate ending; II, type II afferent with flowerspray ending; Ia type Ia efferent with annulospiral ending; nbf, nuclear bag fiber; ncf, nuclear chain fiber.

length. Excessive stretch produces an inhibitory influence on the α motor neurons.

MUSCLE METABOLISM Muscle contraction requires a relatively large amount of energy. The immediate source of this energy is derived from the hydrolysis of adenosine triphosphate, which is synthesized by phosphorylation of adenosine diphosphate. Energy for the formation of adenosine triphosphate is derived from metabolism. At rest, this energy can be stored in the form of phosphocreatine. When needed at the time of exercise, phosphocreatine is hydrolyzed by creatine kinase to form adenosine triphosphate from adenosine diphosphate. After depletion of phosphocreatine stores, muscle metabolism increases to maintain adenosine triphosphate stores. At rest, high-energy phosphate compounds are produced from the metabolism of available fats and glucose [Hultman, 1995]. Increased lipid supply inhibits glycolysis and carbohydrate use. Excess glucose can be metabolized directly

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from the circulation or stored as glycogen until needed. With maximal exertion, phosphocreatine and muscle glycogen are the fuels for energy production. Above 60% maximal exertion, type II fibers are preferentially recruited, and carbohydrates are the preferred fuel after a normal meal. Fat utilization is increased with starvation or a high fat intake before exercise. At exercise intensities below 60%, fat is the major fuel corresponding to the recruitment of type I fibers. In the presence of oxygen, each mole of glucose is converted to 2 mol of pyruvate, which is further oxidized through the citric acid cycle and electron transport chain. For each mole of glucose oxidized, 36 mol of adenosine triphosphate are generated (38 mol from glycogen). In the absence of oxygen, glucose is metabolized to lactic acid. For each mole of glucose consumed, 2 mol of lactic acid are produced, with only 2 mol of adenosine triphosphate. The yield from a glucose unit derived from glycogen under anaerobic conditions is 3 mol of adenosine triphosphate. Tremendous amounts of lactic acid can be generated from breakdown of stored glycogen during brief efforts of anaerobic metabolism, as demonstrated in short sprints and other maximal exertion exercises. There is a constant relationship among force, phosphate concentrations, and pH [Weiner et al., 1990]. As energy is expended, phosphocreatine concentrations decrease, phosphate increases, and pH decreases. The adenosine triphosphate concentration remains stable [Kushmerick, 1995]. Thus, fatigue is relative to the degree of acidosis and free phosphate concentrations. A lactate–proton cotransport system is important for reducing the accumulation of lactate and H+ within the muscle [Juel, 1997]. Recovery from fatigue parallels the normalization of these metabolic parameters [Boska et al., 1990]. Lipids can be used, giving a relatively higher yield of adenosine triphosphate per mole of lipid consumed. Mobilizing lipids for energy consumption is a slower process than mobilizing carbohydrates. Activities that require endurance or prolonged effort are associated with higher lipid metabolism. Training increases the vascular perfusion of muscle and oxygen delivery and increases energy production by aerobic metabolism. Training also increases the capacity of the electron transfer system, oxidative phosphorylation, and the lactate–proton cotransport system [Juel, 1997]. Training increases lactate clearance in the muscle by increasing muscle oxidation of lactate and increasing the lactate transporter protein, monocarboxylate transporter [Dubouchaud et al., 2000]. In general, muscle metabolism is quite plastic and adapts relatively rapidly to altered functional requirements. Muscle has metabolic functions besides energy production. Muscle protein anabolism and catabolism are controlled by many factors in the inverse relationship. The major factors that promote protein synthesis and muscle growth are exercise, amino acid availability, and insulin [Kimball et al., 2002; Wolfe, 2002]. In the adult male, muscle represents about 40% of body weight. It is a vast storehouse for protein, amino acids, fat, and glycogen. Muscle metabolism is intimately involved with metabolism of other tissues, especially the liver. Most lactate in the body is produced from resting muscle. The cell-to-cell lactate shuttle hypothesis suggests that lactate is an intermediate metabolite rather than an end product. It is produced by

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many tissues, especially muscle, and is used as an energy source in the heart and other highly oxidative tissues and as a precursor of glucose in liver gluconeogenesis (Cori’s cycle). Similarly, during fasting or other stresses, muscle releases amino acids, lactate, and other precursors for use by the liver during gluconeogenesis. There is clinical evidence that children with chronic hypoglycemia, as is found in the glycogen storage diseases, have secondary muscle degradation from the chronic muscle catabolism that provides the amino acids necessary for gluconeogenesis [Slonim et al., 1983].

CLINICAL LABORATORY TESTS Modern investigation of muscle disease includes clinical biochemistry and immunology, electromyography, muscle biopsy pathology, molecular genetics, imaging of muscle, and other modalities [Younger and Gordon, 1996].

Clinical Biochemistry Several muscle sarcoplasmic enzymes are used in the clinical evaluation of muscle disease. These enzymes are released from the muscle fiber when damaged. Of these enzymes, aldolase and creatine kinase are used most commonly, especially the latter. Creatine kinase exists as several isozymes, including M and B. BB is found almost exclusively in brain tissue, whereas MM is found almost exclusively in muscle and heart tissue. MB is found in several tissues. Determination of creatine kinase isozymes is helpful in differentiating brain from muscle disease but not muscle from heart disease [Vainzof et al., 1985]. Creatine kinase is not found in the liver or erythrocytes. The normal range of creatine kinase enzyme activity in the blood varies with age, gender, and daily activities. In an inactive male, however, this range may rise to two to three times that of the upper limits. After vigorous extended activity, such as running a marathon or a similar effort, plasma creatine kinase activity may approach 10 times that of normal [Brown et al., 1982]. Elevation of plasma creatine kinase also occurs after trauma, seizures [Wyllie et al., 1985], electroconvulsive therapy [Taylor et al., 1981], and injections. Myopathic disorders cause muscle breakdown and release of creatine kinase and other enzymes into the bloodstream. Increased activities of these enzymes are suggestive, but not diagnostic, of myopathic disease. Creatine kinase can also be mildly elevated in neuropathic diseases. Other enzymes released include transaminases, lactate dehydrogenase, carbonic anhydrase III, and pyruvate kinase. None is as useful as creatine kinase. Serum myoglobin also correlates with muscle breakdown [NorregaardHansen and Hein-Sorensen, 1982]. Other biochemical methods that have been used in investigating muscle disease include measuring urinary excretion of creatine and 3-methyl histidine. Their clinical application has not been commonly accepted for various reasons.

Electromyography Electromyography is the recording of electrical activity by a needle electrode of action potentials of muscle fibers firing singly or in groups near the electrode [Daube, 1991]. Sev-

eral techniques can be used to study specific features of muscle. The most common is the coaxial needle study. The needle has a central active electrode, which forms the core of the coaxial needle. A surrounding cylinder is insulated from the core and serves as the reference electrode. The needle is inserted into the muscle and records electrical depolarization of the surrounding muscle membranes. The motor unit potential can be visualized on a cathode-ray oscilloscope and is usually amplified through a loudspeaker for auditory analysis. Electromyographic abnormalities are not specific for a given clinical entity but allow for widespread sampling and an indication of the type of neuromuscular disease present [Wilbourn, 1993]. The electromyography study has three aspects. The first aspect is the recording of activity during insertion of the needle electrode. The insertional activity is a reflection of the mechanical damage caused by the needle. Inserting the needle electrode or adjusting the needle usually causes a brief, spontaneous discharge of the surrounding muscle fibers. Abnormal activity on insertion, such as prolonged discharges or activation of spontaneous trains of discharges, indicates disease. The second part of clinical electromyography is recording the spontaneous resting properties of the muscle. Normally, muscle is electrically silent during rest. End-plate noise can be recorded if the needle is placed near the end-plate zone. End-plate noise is generated by miniature end-plate potentials and single fiber discharges produced by needle irritation [Shahani and Young, 1985]. Spontaneous activities, such as fibrillations, positive sharp waves, fasciculations, or others, usually indicate underlying disease, most commonly neuropathic disorders. Spontaneous repetitive discharges are found in various neuropathic and myopathic disorders, such as the myotonias. The third part of electromyography is recording motor unit potentials to evaluate the electrical properties of muscle during contraction. The motor unit potential usually has two or three phases and is 5 to 15 milliseconds in duration. The voltage usually does not exceed 5 mV. With a primary muscle disease, a frequent finding is brief, small-amplitude, polyphasic potentials. With chronic neuropathic disease, a common finding is prolonged, large-amplitude, polyphasic potentials. With graded contraction, an increase in the firing rate of individual motor units occurs. Further effort causes an increase in the number of recruited motor units and is proportional to the degree of muscle contractions. Thus, motor units are recruited in response to the degree of effort, and there is a recruitment order of motor units that is relatively fixed [Henneman et al., 1974]. Analysis of the interference pattern can be useful in the diagnosis of neuromuscular disease [Sanders et al., 1996]. At maximal effort, individual motor unit potentials cannot be distinguished (full interference). In primary muscle disease, in which all muscle fibers are similarly affected, a greater number of fibers is needed to perform a given amount of work. Thus, there is an increase in the number of motor units needed to perform the given amount of work. This increase is noticeable with mild effort, and it causes the phenomenon of early recruitment. Conversely, with denervation, in which there is a reduction in the number of motor units, the recruitment pattern is decreased, and thus full interference is not possible.

Vedanarayanan and Evans / Normal Muscle

Single-fiber electromyography is a technique for studying the characteristics of neuromuscular transmission and the localized organization of muscle fibers within a motor unit [Sanders et al., 1996]. A special needle electrode is introduced into the muscle at multiple sites. The number of single muscle fiber action potentials belonging to one motor unit recorded in a given area gives a quantitative measure of the fiber density. Recording from two fibers of the same motor unit enables one to measure “jitter,” or the mean consecutive difference in time between the firing of the two fibers, which is usually between 10 and 55 milliseconds. An increase in jitter is commonly observed with defects of neurotransmission. Single-fiber electromyography also detects blocking when the second fiber fails to discharge, which is the basis for the decremental response during repetitive stimulation in patients with myasthenia gravis. Other electrodiagnostic methods are also useful in evaluating myasthenic disorders and peripheral neuropathies. These subjects are discussed in other chapters.

Muscle Biopsy Muscle biopsy is the definitive test for diagnosing specific muscle diseases and is indicated in the child with suspected neuromuscular disease; however, muscle biopsy is less likely to yield diagnostic findings if creatine kinase and electromyography readings are normal. Muscle biopsy may not be diagnostic early in the course of an illness when the abnormalities are scant and a sampling error can mask the pathologic condition. The pathologic condition may also escape diagnosis late in the course of a disease if the muscle is so altered that no distinguishing features exist (“end-stage” muscle). The method of muscle biopsy has been reviewed in detail elsewhere [Dubowitz and Brook, 1973]. It can be performed by either an open biopsy or a needle biopsy technique [Heckmatt et al., 1984]. Either method is relatively simple and can be performed on an outpatient basis. The muscle chosen for biopsy should be one affected clinically but not severely. To obtain optimal results, the material must be handled by experienced technicians and interpreted by those familiar with neuromuscular diseases. Routine histologic stains often used in evaluating a muscle biopsy include the hematoxylineosin stain, modified Gomori trichrome stain, periodic acid– Schiff stain for glycogen, and oil red O or Sudan black stain for lipid. The hematoxylin-eosin stain is used most often for evaluating muscle fibers, nuclei, and other cellular constituents. The trichrome stain is used especially for evaluating connective tissue, intramuscular nerves, and certain features of the muscle fiber, such as mitochondria. Other histologic stains are often used for special purposes. Histochemistry often reveals the most significant information. Adenosine triphosphatase reactions are used to determine fiber typing. The random distribution of the fiber type on the adenosine triphosphatase reaction is a major feature of normal muscle. Normally, there are about equal

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numbers of type I, IIa, and IIb fibers, although up to 50% of a single type can be found in some muscles [Dubowitz and Brook, 1973]. Oxidative stains and the periodic acid–Schiff stain also reflect fiber typing (see Table 74-3). The oxidative reactions that include succinic dehydrogenase and nicotinamine-adenine dinucleotide transreductase are helpful in identifying mitochondria and the sarcotubular system. Many other histochemical reactions facilitate the study of specific diseases, such as the myophosphorylase reaction that aids in diagnosis of McArdle’s disease. Figure 74-14 illustrates the major histologic and histochemical features of muscle. Immunohistochemistry is becoming increasingly important for the study of normal and diseased muscle. The absence of dystrophin on immunohistochemical staining of muscle tissue is diagnostic of Duchenne’s and related muscular dystrophies. Certain congenital myopathies can be classified based on immunohistochemical staining of other cytoskeletal proteins [Duggan et al., 1997; Philpot et al., 1995; Wallgren-Pettersson et al., 1995]. Electron microscopy is rarely needed for accurate diagnosis, but it is often necessary in disorders of the mitochondria and to determine the ultrastructure of central cores, nemaline rods, and other inclusions in congenital myopathy [Younger and Gordon, 1996].

Muscle Imaging Ultrasonography, computed tomography, and magnetic resonance imaging are used in the diagnosis and management of patients with neuromuscular disease [Clague et al., 1995]. Ultrasonography is a cost-effective method for localization of diseased muscle for biopsy purposes. It is useful for imaging dystrophic muscle [Heckmatt and Dubowitz, 1988]. Magnetic resonance imaging is particularly useful for the diagnosis of inflammatory muscle disease. Inflammation is easily identified and can be distinguished from other causes of weakness [Stonecipher et al., 1994].

Molecular Genetics Techniques for mapping and sequencing the human genome have brought about an entirely new approach to the diagnosis of human neuromuscular disease [Nawrotzki et al., 1996]. High deletion frequencies, unstable tandem repeat sequences, genomic duplications, and triplet repeat expansions are common abnormalities that enable a molecular genetic diagnosis to be made for such diseases as Duchenne’s and Becker’s muscular dystrophy, some forms of limb girdle dystrophy, myotonic muscular dystrophy, congenital muscular dystrophy, and many others (see Table 74-1). Often the defective gene product, such as dystrophin in the X-linked dystrophies, can be measured or visualized in muscle samples for diagnostic purposes. Similarly, a number of mitochondrial diseases can be diagnosed from analysis of mitochondrial DNA [Younger and Gordon, 1996].

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Neuromuscular Disorders / 74 FIGURE 74-14. Muscle histology and histochemistry. Serial sections are stained as follows: A, Hematoxylin and eosin. B, Modified Gomori trichrome. C, Myosin adenosine triphosphate, pH 9.4. D, Myosin adenosine triphosphate, pH 4.6. E, Myosin adenosine triphosphate, pH 4.3. F, Nicotine-adenine dinucleotide transreductase. G, Succinic dehydrogenase. H, Myophosphorylase. I, Periodic acid–Schiff stain.

A

B

C

D

E

F

G

H

I

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CHAPTER 75

Anterior Horn Cell and Cranial Motor Neuron Disease Anne M. Connolly and Susan T. Iannaccone

Anterior horn cells (a motor neurons), located in the anterior gray masses of the cord, are found at every cord segment and are concentrated in the cervical and lumbosacral enlargements. Morphologic differentiation of the anterior horn cells is most evident from 12 to 14 weeks’ gestation [Vassilopoulos and Emery, 1977]. There is a period of normal differentiation followed by programmed cell death [Fidzianska and Rafalowska, 2002; Yachnis et al., 1998] Anterior horn cells are clustered into medial and lateral cell divisions (Fig. 75-1). The medial group is subdivided into ventromedial and dorsomedial components. The ventromedial component innervates the superficial larger muscles, and the dorsomedial component innervates the small, deep muscles adjacent to the spine. The lateral cell mass is also subdivided into groups. The ventrolateral group innervates extensor muscles, and the centrodorsal group innervates flexor muscles [Romanes, 1951]. Because these groups of neurons are located in a relatively small region, deleterious influences harm cells from more than one group, and weakness may be widespread. The motor neurons in the nuclei of the cranial nerves are homologous to spinal cord anterior horn cells. Therefore, pathologic mechanisms that compromise the cranial motor neurons may initiate symptoms and signs that mimic anterior horn cell dysfunction. Atrophy, severe weakness, and fasciculations without sensory deficit are signs of anterior horn cell disease. When sensory function is impaired in conjunction with anterior horn cell disease, dysfunction of adjacent tracts of the spinal cord or the peripheral nerves must be present.

CONGENITAL DEFECTS Diastematomyelia Diastematomyelia is an abnormal division of the spinal cord, usually almost equally, by a septum of variable caudalrostral length (Fig. 75-2). The mesodermal septum is composed of fibrous tissue, bone, cartilage, or a mixture of these. The septum traverses the neural canal, thus splitting the spinal cord, and is usually anchored posteriorly on the dura or bony neural arch [Moes and Hendrick, 1963]. The neural tube forms a closed cavity when normal maturation occurs during the first fetal month. The tube becomes distended, the dorsal surface (roof) becomes permeable, and fluid flows into the adjacent space; this space develops into the subarachnoid space. The point of failure of the developmental process that results in diastematomyelia is still not completely understood.

Surgical manipulation of the chick embryo shows it is possible to produce a chick with diastematomyelia by intraspinal grafting of a somite. Transplanted quail cells may form a septum between the dorsal surface (roof) and floor, dividing the neural tube into two parts. However, in some chicks, the same experiment leads to the chick host eliminating quail cells, and in some, spina bifida is produced. This finding suggests that spontaneous diastematomyelia may be the consequence of abnormal gastrulation, the process by which the two early germ layers convert to three distinctive germ layers [Klessinger and Christ, 1996]. When diastematomyelia is present, the mesodermal septum commonly compromises the anterior horn cell column and subsequently causes muscle atrophy, decreased or absent deep tendon reflexes, and moderate-to-severe weakness of the distal muscles of the legs and feet. This weakness is often the patient’s first complaint. Involvement is usually bilateral. Deformities of the feet, particularly talipes equinovarus, commonly occur. Atonic bladder with urinary retention or incontinence may occur. Cutaneous lesions over the spine often accompany the condition; these lesions include sacrococcygeal sinus, lipoma, hypertrichosis, soft tissue swelling, myelomeningocele, and pigmented nevi or hemangiomas over the lower spine [James and Lassman, 1964]. Because of its location, the septum transects nerve fibers as they cross from one side of the spinal cord to the other. These fibers transmit pain and temperature sensations. Therefore, pain and temperature perception may be impaired. Superficial sensation (light touch) may also be affected. When the septum is wide enough or laterally placed, corticospinal tract compromise may be evidenced by upper motor unit symptoms and signs. Radiography, computed tomography (CT), or magnetic resonance imaging (MRI) usually demonstrates the septum; the deposition of calcium, which may be delayed for years, facilitates identification [Bruhl et al., 1990; Harwood-Nash and McHugh, 1990; Thron and Schroth, 1986]. More recently, diastematomyelia has been diagnosed prenatally with ultrasound and MRI (Fig. 75-3), allowing earlier intervention [Allen and Silverman, 2000; Sonigo-Cohen et al., 2003]. The septum is usually located in the lower thoracic and lumbar areas but may be present as high as the cervical vertebra [Balci et al., 2002; Cowie, 1951] One patient with involvement of the basicranium has been described [Pfeifer, 1991]. Spina bifida occulta or tethered cord may be associated [Guthkelch and Hoffmann, 1981]. Kyphoscoliosis or scoliosis may accompany the other characteristic findings. Intersegmental laminar fusion occurring with spina bifida at or adjacent to the level of fusion should suggest the diagnosis of diastematomyelia [Hilal et al., 1974]. Diastematomyelia has been associated with

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Flexor muscles of extremities Extensor muscles of extremities Lateral groups

Medial groups

Small deep muscles of spine and trunk Large superficial muscles of spine and trunk

FIGURE 75-1. The a motor neurons located in the anterior horn of the spinal cord (anterior horn cells) are clustered in a specific pattern. The medial cell groups are associated with muscles of the spine and trunk. The lateral cell groups are associated with muscles of the extremities.

epidermoid cysts and syrinx [Sheehan et al., 2002] or teratoma [Hader et al., 1999]. Because these may not occur at the same level, imaging of all levels is indicated.

Symptoms, particularly pain, may be prevented or significantly ameliorated by surgery [Kim et al., 1994; Meacham, 1967; Schijman, 2003]. Clinical and radiographic correlations suggest three subsets of patients with diastematomyelia: those with associated tethered cord, those with midline cutaneous stigmata, and those with meningocele or meningomyelocele [Schijman, 2003]. Excision of the mesodermal septum, including all portions attached to the anterior dural surface, and subsequent laminectomy are indicated in all but those with very severe associated meningomyelocele. Neurologic deficits may remain [Kim et al., 1994]. Failure to remove the septum almost always results in scoliosis.

Syringomyelia

FIGURE 75-2. The spinal cord is cleaved by a central or paracentral mesodermal septum. The cord is usually separated asymmetrically. The mesodermal septum may become calcified and thus readily identifiable with radiographic techniques.

Syringomyelia is a slowly progressive cavity formation within the spinal cord, medulla oblongata, or both that is associated with gliosis. When the medulla is involved, the condition is called syringobulbia. Cavity formation usually occurs in the cervical and lumbar cord segments. On crosssection, the destruction occurs in the area of the anterior white commissure, interrupting crossing fibers of the lateral spinothalamic tracts, with resultant bilateral loss of temperature and pain sensation (Fig. 75-4). Superficial sensation is normal because fiber tracts associated with this function are located dorsally and do not cross the cord. Dissociation of sensation occurs when there is concurrent preservation of light touch perception and decrease or absence of pain and temperature perception. The anterior horn cells are affected only after the lesion has reached significant proportions. Although the lesion is virtually always bilateral, involvement is usually asymmetric early in the course of the dis-

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Lateral corticospinal tract

Lateral spinothalamic tract FIGURE 75-4. The anterior white commissure is often compromised in syringomyelia. Severing the crossing fibers from the lateral spinothalamic tracts results in bilateral loss of pain and temperature sensation. Enlargement of the lesion often leads to disruption of the anterior horns.

A

B

FIGURE 75-3. Coronal T2-weighted fetal magnetic resonance images (A) 26 weeks’ gestation and (B) 3 months of age show the subdivision into two asymmetric cords (white arrows) and the hyposignal bony spur (black arrows) at the level of the diastematomyelia.

ease. The long tracts, including the corticospinal tracts, are not affected until after the cavitary lesion has become very large. Involvement of the sympathetic nervous system neurons in the cervical cord may cause Horner’s syndrome.

Chiari I malformations are often accompanied by syringomyelia or hydromyelia [Gillespie et al., 1986; Inoue et al., 2003; Isu et al., 1990, 1992]. The association of Chiari I malformation with syringomyelia is poorly understood [Gillespie et al., 1986; Iqbal et al., 1992]. In one set of monozygotic twins, both had syringomyelia, but they were discordant for Chiari I malformation [Tubbs et al., 2004]. Other congenital structural abnormalities, including basilar impression, Klippel-Feil syndrome, cervical ribs, and scoliosis, may be associated with syringomyelia [Berke and Magee, 1976; Isu et al., 1990, 1992; Jaeger et al., 1997]. The earliest clinical presentation of syringomyelia may be isolated congenital scoliosis or kyphosis. MRI studies of these infants indicate that 31% have spinal cord abnormalities, including syringomyelia (3 of 41), diastematomyelia (5 of 41), and tethered cord (12 of 41) [Suh et al., 2001]. Incomplete closure of the neural tube during the fourth week of gestation is the likely cause of congenital syringomyelia. The normal pattern of cell differentiation causes an inner clustering of spongioblastic cells, which subsequently form glial tissue, and an outer clustering of neuroblastic cells, which subsequently form neurons and their processes. Congenital syringomyelia may result from delayed differentiation of the spongioblastic cells, with ensuing cavitation and gliosis [Leyden, 1876]. Another theory cites a possible congenital structural defect of the hindbrain reminiscent of the one that leads to myelomeningocele and the Chiari deformity. Gardner reported many instances in which the foramen of Magendie was sealed by a membrane [Gardner, 1960]. Clear fluid appeared to accumulate between the syrinx and the fourth ventricle. Failure of the foramen to form an adequate passageway for the fluid during gestation may cause distention of the syrinx and fourth ventricle. Although these findings occasionally may reflect hydromyelia, it is more likely that the pathophysiologic defect is an abnormal intramedullary vascular pattern. The vessels appear to be susceptible to occlusion; thus, infarction or hemorrhage is likely to occur and cause cavitation [Netsky, 1953]. This vascular compromise may come as a result of intermittent compression from increased pressure [Levine, 2004]. Another explanation for syringomyelia evolved from a questionnaire designed to determine whether a high number

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of mothers of patients with syringomyelia had experienced difficult labor [Williams, 1977]. An unexpectedly high number of patients had undergone forceps delivery. The number of instances in which the patient with syringomyelia was the firstborn was also significantly increased. It was suggested that, as a result of birth injury, the tonsils descend through the foramen magnum and cause arachnoiditis. This mechanism may only be relevant for infants who already have a Chiari malformation [Newman et al., 1981]. The difference in fluid pressure between cranial and spinal compartments may lead to ongoing insidious descent of the tonsils, resulting in communicating syringomyelia. Recent animal models to study syringomyelia have focused on post-traumatic models. These models have very high syrinx formations when an excitotoxic agent is added to the traumatic injury. In the rat model, fluid enters the syrinx from the subarachnoid space through perivascular spaces. There is more flow in the perivascular spaces at the levels of the syrinx [Brodbelt et al., 2003a, 2003b, 2003c; Yang et al., 2001a]. Patients with syringomyelia have limited abilities to monitor pain and temperature. Trophic ulcers of the fingers are often present. Weakness of the limbs is often profound because the cervical and lumbosacral enlargements bear the brunt of the cavitation and gliosis. Muscle atrophy is often first appreciated in the distal small hand muscles. Deep tendon reflexes are either difficult to elicit or absent. Fasciculations are visible in muscles of the shoulder, elbow, and hip. Cervical syringomyelia has been accompanied by papilledema. Elevated intracranial pressure may be present and results from hydrocephalus, mass lesions, or obstruction of the foramina of Luschka and Magendie [Alpers and Comroe, 1931]. Rarely, syringomyelia may be acquired from tumors or infections of the spinal cord. These acquired types are unusual in infants and young children. Trauma may be a more common cause of acquired syringomyelia in older children and adults [Schurch et al., 1996; Silver, 2001]. Intramedullary cord tumors may cause signs and symptoms similar to those of syringomyelia and prove confounding [Gillespie et al., 1986; Madsen and Scott, 1993; Williams and Timperley, 1977]. Differentiation between syringomyelia and intramedullary tumors should be possible with modern imaging techniques. Spinal fluid dynamics and constituents are usually normal in syringomyelia, although the fluid may be xanthochromic, and flow may be obstructed. The Valsalva maneuver, which accompanies coughing, straining, and postural changes, may increase pressure and grossly exaggerate findings associated with cysts in the cord. The transient increased pressure may enhance the formation of syringomyelia and syringobulbia [Bertrand, 1973; Levine, 2004]. MRI appears to be the most sensitive method in the detection of syringomyelia [Gillespie et al., 1986; Iqbal et al., 1992]. Management of syringomyelia accompanied by Chiari I malformation consists of posterior fossa decompression, which is beneficial in almost 75% of such patients [Vaquero et al., 1990].

Hydromyelia Hydromyelia is a congenital deformity resulting from distention of the central canal, which in turn compresses the

surrounding cord structures, including the anterior horn cells. The clinical findings are similar to those in syringomyelia. Hydromyelia or syringomyelia is found in more than 50% of patients with Chiari I malformations [Menezes, 1991]. Hydromyelia is found most frequently in the cervical and lumbar cord enlargements. The pathologic distention may involve the cord throughout its entire length. The hydromyelic cavity is lined with ependymal cells, in contrast to the glial cell lining of the syrinx [Levine, 2004]. Although the cause of hydromyelia is unknown, its association with Chiari I malformation is well established [Wisoff, 1988]. The lack of patency in the foramina of the fourth ventricle may underlie the distention of the central canal [Gardner, 1965; Lassman et al., 1968]. However, cerebrospinal fluid protein content differs from that of the hydromyelic segment, and the measured pressure in the syrinx is higher than that of cerebrospinal fluid at rest. As with syringomyelia, erect position, cough, or strain may transiently elevate the cerebrospinal fluid pressure, causing an increase in fluid in the syrinx [Levine, 2004]. Hydromyelia develops in about one fourth of patients with posttraumatic cord injuries and is more likely to develop if there is more than 14 degrees of kyphosis or more than 25% stenosis [Abel et al., 1999]. Current therapeutic approaches in patients with Chiari I malformations are similar to those used in patients with syringomyelia and include posterior fossa decompression with or without duraplasty [Munshi et al., 2000].

SPINAL MUSCULAR ATROPHIES The history of the spinal muscular atrophies began in the 1890s when Guido Werdnig, a retired battalion physician who was working at the Institute of Anatomy and Physiology of the Central Nervous System at the University of Vienna, gave a lecture entitled “On a Case of Muscular Dystrophy with Positive Spinal Cord Findings” [Groger, 1990]. In 1891, he published the paper entitled “Two Early Infantile Hereditary Cases of Progressive Muscular Atrophy Appearing as Dystrophy, but on a Neurotic Basis.” The next year, Professor Johann Hoffmann of Heidelberg University coined the term spinal muscular atrophy, in German spinale muskelatrophie [Hoffmann, 1892a]. Together, their papers presented a complete picture of the clinical and pathologic aspects of infantile spinal muscular atrophies: onset during the first year of life, occurrence in siblings with normal parents, progressive floppiness and weakness, hand tremor, and death from pneumonia in early childhood. Moreover, Hoffmann talked about “progressive” and chronic (“chronische”) types of spinal muscular atrophies [Hoffmann, 1892a, 1892b, 1896]. In the tradition of German neurology of the late 19th century, both conducted postmortem examinations on their patients and described the striking atrophy of the ventral roots on gross examination. They correlated this finding with the histologic appearance of the anterior horns, which were lacking in the usual number of motor neurons, and with a pattern of atrophy in muscle fibers [Iannaccone et al., 1990]. For the next 50 years, confusion reigned in the nosology of spinal muscular atrophies. Some of this confusion stemmed from the teaching of Hermann Oppenheim, an

Connolly and Iannaccone / Anterior Horn Cell and Cranial Motor Neuron Disease

influential neurologist at the turn of the 20th century [Iannaccone et al., 1990]. In 1900, he published a paper in German “… und Localisierte Atonie der Muskulatur [Myatonie] …” that was translated into English unfortunately as “amyotonia” [Oppenheim, 1900]. His patients most likely had spinal muscular atrophies, but he claimed that some of them improved with time, unlike the patients of Hoffmann and Werdnig [Greenfield and Stern, 1928]. During the first part of the 20th century, then, many floppy infants were labeled with amyotonia congenita or Oppenheim’s amyotonia, when specific diagnostic tests, such as electromyography or biopsy, were unavailable for clarification. With the birth of myology as a subspecialty of neurology in the 1950s, muscle biopsy came into widespread use, and it became apparent that not all floppy infants had the same disease. Only then did discussion begin about whether all congenital disease of the anterior horn cell should be called spinal muscular atrophies. Beginning with Byers and Banker, the classification of spinal muscular atrophies according to severity was used to facilitate prognostication [Byers and Banker, 1961]. The relationship between age of onset and severity was supported by Dubowitz’s observations [Dubowitz, 1964]. As a result of international collaboration [Dubowitz, 1995; Munsat, 1991b], most pediatric neurologists now use the following nomenclature: spinal muscular atrophy type I, for onset of symptoms before age 6 months; spinal muscular atrophy type II, for onset between 6 and 18 months; and spinal muscular atrophy type III, for onset after age 18 months (Table 75-1). The three types may be subdivided on the basis of mortality or highest motor milestone achieved. For example, patients with type I spinal muscular atrophy are almost never able to sit without support [Iannaccone et al., 1993]. In fact, most patients with spinal muscular atrophy of any type can never pull themselves to sitting position or roll over at any age. Patients with type I spinal muscular atrophy and onset before 3 months of age have the highest mortality rate (90%), whereas those with onset after age 3 months may survive to adulthood, albeit with severe motor handicap. Patients with type III spinal muscular atrophy often are independently ambulatory at least for part of their life and often have a normal life expectancy [Russman et al., 1992]. On the other hand, the distribution of the three types is such that most spinal muscular atrophy patients have type I, with decreasing incidence for types II and III, respectively. In other words, the incidence is highest for type I, followed by type II; type III has the lowest incidence. Considering the relative mortality rates, it is not surprising that the highest prevalence is for spinal muscular atrophies types II and III.

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Spinal Muscular Atrophy Type I Synonyms for spinal muscular atrophy type I are infantile onset spinal muscular atrophy and Werdnig-Hoffmann disease. Spinal muscular atrophy type I is the most severe form of the disease, beginning at birth or in the first few months of life and frequently resulting in death from respiratory failure before 2 years of age. These infants have severe weakness of the limbs and intercostal muscles. There is a paucity of spontaneous movement at the shoulder and

FIGURE 75-5. This patient with spinal muscular atrophy type I, or Werdnig-Hoffmann disease, is severely affected and required a gastric feeding tube. There is little or no movement of the shoulders, whereas the fingers and toes remain active. The typical posture of flexion of the knees and abduction of the legs at the hips is evident. The weakness of the intercostal muscles, coupled with relatively normal diaphragmatic contractions, results in marked chest deformity.

TABLE 75-1 Clinical Features of Spinal Muscular Atrophy (SMA) Linked to the SMN Gene SMA TYPE

ONSET OF WEAKNESS

HIGHEST FUNCTION

MORTALITY

SMA I SMA II

<6 mo 6–18 mo

Most nonsitters; few sitters Most sitters; few walkers

SMA III

18 mo

Many walkers

>90%; few survive to second decade Variable; most survive to second or third decade Many with normal life expectancy

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Neuromuscular Disorders / 75

hip girdle. In contrast, there is some antigravity movement in the hands and feet (Fig. 75-5). The only spontaneous movement of the extremities may be that of the fingers and toes. Frequently, hand movement is characterized by a fine tremor called polyminimyoclonus. Often the infant assumes a frog-leg position, with the legs externally rotated, abducted, and flexed at the hips and knees. Typically, slight elbow flexion occurs, and the hands are held at chest level. There is often a narrowed thorax with a pectus excavatum deformity and flaring of the lower ribs (bell-shaped chest). These deformities are caused by weak intercostal muscles countered by diaphragmatic muscle contraction. Affected infants have diaphragmatic or “paradoxical” breathing pattern. Evidence of upper cranial nerve motor dysfunction is rare (i.e., cranial nerves III, IV, V, VI, and VII). Weakness of the tongue and accompanying fasciculations are commonly observed. However, the examiner must carefully distinguish fasciculations from normal movements during crying. The tongue should be examined at rest, in the mouth. Atrophy of the tongue may be manifest as scalloping of the border (see Fig. 2-6). Deep tendon reflexes are usually absent, whereas sphincter tone and sensation remain intact. There is a striking discrepancy between the infant’s high level of social interaction and lack of motor skills. Such infants tire quickly during feeding and, if breast-fed, may begin to lose weight before it is evident that they are not taking in appropriate calories. Their respiratory insufficiency exacerbates this fatigue and makes them susceptible to aspiration. Any minor upper respiratory tract infection may quickly become a life-threatening pneumonia. Bilateral eventration or paralysis of the diaphragm may be a presenting manifestation before the loss of deep tendon reflexes or the detection of muscle weakness [Bove and Iannaccone, 1988; McWilliam et al., 1985; Mellins et al., 1974]. Paralysis of the diaphragm, either unilateral or bilateral, before the age of 3 months is the most common presenting complaint in spinal muscular atrophy with respiratory distress (SMARD1). At the time of disclosure of diagnosis to the family, it is important to counsel them about the high risk for death from pneumonia [Samaha et al., 1994]. It is also important to review management, considering the possible need for nasogastric feedings and airway clearance. Parents should be taught how to handle a severely floppy infant and be provided with appropriate seating for feeding and for automobile travel. Most specialty clinics teach parents to provide prophylactic chest percussion therapy and advise full immunization against influenza, respiratory syncytial virus, and pneumonia. Intervention with ventilatory support has been provided for some patients on an individual basis. Longterm survival under such circumstances is rare and requires constant monitoring, although new technology makes mobility, even with ventilators, feasible [Wang et al., 1994].

Spinal Muscular Atrophy Type II Synonyms for spinal muscular atrophy type II include juvenile spinal muscular atrophy, intermediate spinal muscular atrophy, and chronic spinal muscular atrophy [Dubowitz, 1996; Hausmanowa-Petrusewicz, 1978]. Weakness and hypotonia are the rule, although patients usually achieve normal milestones up to 6 to 8 months of age. The

lower extremities tend to be more involved than the upper extremities, so that failure to walk is a typical chief complaint. Patients may be thought to have a paraparesis and occasionally have clubfoot deformity. The pattern of deep tendon reflexes may be variable, with preservation in muscle groups that are fairly strong. Minipolymyoclonus may be prominent in these infants. The movements are intermittent, irregular, and of small amplitude. Distal muscles, particularly of the fingers, are primarily affected. No movements are evident during relaxation or sleep. Fatigue, stress, and self-consciousness increase the amplitude. The pathophysiologic origin of these movements is not known, although fasciculations of the intrinsic hand muscles may participate. These movements do not occur in myopathic processes [Spiro, 1970]. Many patients with type II are able to sit without support if placed in position; rarely, some are able to stand or walk with aid. The age at death is quite variable, from 7 months to 7 years [Byers and Banker, 1961] or in the third decade [Guinter et al., 1977]. The eldest patient in one prospective study died at age 72 years [Russman et al., 1996].

Spinal Muscular Atrophy Type III The mildest form of spinal muscular atrophy is type III and is also called Wohlfart-Kugelberg-Welander syndrome and mild spinal muscular atrophy [Kugelberg and Welander, 1954, 1956]. It usually presents in late childhood or adolescence as a proximal neurogenic muscular atrophy that may be confused with limb girdle muscular dystrophy [Furukawa et al., 1968; Lunt et al., 1989; Topaloglu et al., 1989; Zerres and Rudnik-Schoneborn, 1995]. Frequently, patients have elevated serum creatine kinase levels [Kugelberg, 1975]. This syndrome is distinguished from Werdnig-Hoffmann disease by later onset and long survival [Kugelberg and Welander, 1954, 1956]. It is distinguished from amyotrophic lateral sclerosis by the benign course and absence of any involvement of corticospinal tracts. Spinal muscular atrophy type III patients may have a waddling gait, with lumbar lordosis, genu recurvatum, and a protuberant abdomen. Deep tendon reflexes may or may not be elicited but are never pathologically hyperactive. In one report, six of eight children were able to stand without aid between 1 and 2 years of age; however, only two of the eight were eventually able to walk without assistance [Byers and Banker, 1961]. The prognosis for continued independent ambulation can be correlated with age of onset of weakness [Zerres et al., 1997a]. If onset is before 2 years of age, the patient is likely to stop walking by age 15, whereas if onset occurs later than 2 years, it is highly likely that ambulation will be possible into the fifth decade [Russman et al., 1996]. A large, prospective clinical study found little or no progression of weakness over several years in patients with type II or III [Russman et al., 1992]. The authors suggested that spinal muscular atrophy may not be a neurodegenerative disease, but new information indicates that this conclusion was wrong [Bromberg and Swoboda, 2002]. Scoliosis is the most serious orthopedic problem experienced [Schwentker and Gibson, 1976]. Neuropathologic findings include loss of anterior horn motor neurons [Byers and Banker, 1961; Greenfield and Stern, 1928; Walsh et al., 1987]. Dicarboxylic aciduria was

Connolly and Iannaccone / Anterior Horn Cell and Cranial Motor Neuron Disease

reported in one infant with classic Werdnig-Hoffmann disease [Harpey et al., 1990; Kelley and Sladky, 1986], but the significance of such findings is unclear. Acidosis in some cases may be secondary to chronic malnutrition and loss of glycogen reserves in the context of extremely low muscle bulk. However, there is now concern that a subpopulation of spinal muscular atrophy patients may have a primary metabolic disturbance that must be identified before beginning experimental therapy, such as with histone deacetylase inhibitors [Brichta et al., 2003; Sumner et al., 2003; Tein et al., 1995]. Hexosaminidase A deficiency represents an interesting, albeit rare, variant of late-onset spinal muscular atrophy [Johnson et al., 1982, 1983]. This syndrome is discussed in more detail in the sections on GM2 gangliosidosis and on hexosaminidase variants and neuromuscular syndromes. Epidemiologic studies always indicated an autosomalrecessive mode of inheritance [Zellweger et al., 1969] and nearly equal sex distribution, with a slight predominance in males [Hausmanowa-Petrusewicz et al., 1984], but apparent autosomal-dominant transmission is a rare occurrence [Jansen et al., 1986]. Several families have been described in which the co-occurrence of spinal muscular atrophy and amyotrophic lateral sclerosis was documented [Appelbaum et al., 1992; Shaw et al., 1992]. Linkage of autosomal recessive spinal muscular atrophy to chromosome 5q11.2-13.3 was reported by Gilliam and associates [Gilliam et al., 1990]. This international consortium studied families with evidence of recessive transmission only, although they were able to document phenotypic heterogeneity within families [Brzustowicz et al., 1990; Muller et al., 1992; Munsat et al., 1990]. Melki and colleagues reported the occurrence of major deletions at 5q11.2-13.3 in patients with severe spinal muscular atrophy (Werdnig-Hoffmann phenotype), compared with patients with mild spinal muscular atrophy (WohlfartKugelberg-Welander phenotype) who had no deletions or smaller deletions [Melki et al., 1990]. Clinical evidence suggests that early-onset spinal muscular atrophy represents a spectrum of disease, a finding consistent with a single gene locus [Iannaccone et al., 1991; Melki et al., 1994]. Thus, the most common form of spinal muscular atrophy is an autosomal-recessive disorder [Hoffmann, 1900a, 1900b] linked to the 5q11 locus [Brzustowicz et al., 1990; Lefebvre et al., 1995; Melki et al., 1990; Muller et al., 1992; Roy et al., 1995]. Mutations occur in as many as 98% of children with spinal muscular atrophy, and mutation analysis has replaced electrodiagnostic studies and muscle biopsy in primary diagnosis of this disease. Deletions occur with less frequency among patients with mild spinal muscular atrophy than among those with type I [Gilliam et al., 1990; Melki et al., 1994; Rudnik-Schoneborn et al., 1996]. Most spinal muscular atrophy cases are associated with deletions or mutations in exons 7 and 8 of the telomeric copy of the spinal muscular atrophy gene (called SMN1), although cases of small deletions or mutations in other parts of the gene have also been reported. The centromeric copy of SMN (called SMN2) is a disease-modifying gene. The number of copies correlates with the type or severity of disease; mild cases tend to have more copies than severe cases [Burghes, 1997; Campbell et al., 1997; Gilliam et al., 1990]. SMN protein, found in structures called gems, was absent from motor neurons of infants with type I disease. Protein

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was present in type II or III disease but in decreased amounts compared with controls [Lefebvre et al., 1997]. These findings suggest that the severity of disease is proportional to the loss of SMN protein [Zerres et al., 1997b] and that a correlation between the SMN protein level and the disease state has been established [Lefebvre et al., 1997; Zerres et al., 1997b]. Patients with type I or II spinal muscular atrophy have reduced amounts of SMN protein compared with normal controls; this decrease ranges from 5% to 100% [Lefebvre et al., 1997]. Type III patients have normal amounts of intracellular SMN protein. SMN protein level and disease severity are most likely a consequence of SMN2 gene copy number [Burghes, 1997; Coovert et al., 1997; Lefebvre et al., 1997]. In addition, motor unit counts appear to correspond with SMN2 copy counts [Swoboda et al., 2005]. All patients have at least one copy of SMN2 because complete loss of all SMN genes appears to be an embryonic lethal lesion [DiDonato et al., 1999; Monani et al., 2000]. SMN1 produces full-length SMN messenger RNA. SMN2 expresses dramatically reduced full-length and abundant levels of transcript lacking exon 7 (Δ7-SMN) [Gavrilov et al., 1998]. The protein product of SMN2 differs from normal full-length SMN protein in sequence and function [Monani et al., 1999] because the SMN2 gene has a single base-pair change in exon 7 producing truncated messenger RNA transcript. A single nucleotide difference (C-to-T transition in exon 7) in SMN2 causes exon 7 skipping and a transcript that encodes for a less stable protein [Monani et al., 1999; Lorson, 1999, 2000]. Several studies demonstrated that the C to T change on the +6 position of exon 7 results in exon skipping of SMN2 during its transcription [Cartegni, 2002; Lemaire, 2002]. The gene product of SMN1 forms a large complex with other proteins called Gemin2, Gemin4, Gemin5, Gemin6, and Gemin7 [Pellizzoni et al., 2002]; this complex interacts with spliceosomes [Fischer et al., 1997; Liu et al., 1997; Strasswimmer et al., 1999]. There have been only a few studies to date that have investigated SMN protein [Coovert et al., 1997; Lefebvre et al., 1997] and RNA expression [Gavrilov et al., 1998; Gennarelli et al., 1995; Patrizi et al., 1999] in spinal muscular atrophy patients. Patients produced two to three times more Δ7-SMN compared with full-length SMN messenger RNA expression [Gavrilov et al., 1998; Gennarelli et al., 1995; Patrizi et al., 1999]. A number of studies investigated the relationship between SMN2 gene copy number and disease severity, suggesting that the number of SMN2 copies is directly related to a mild spinal muscular atrophy phenotype. Animal models for spinal muscular atrophy recently became available for therapeutic studies [Schmalbruch and Haase, 2001]. Mice have only one SMN gene, and the knockout Smn–/– mouse dies in utero before implantation. Heterozygotes (Smn+/–) had an SMA phenotype, but it was mild despite a 50% reduction in SMN protein level. Two groups constructed SMN2 transgenic mice and crossed them with Smn+/– to produce a knockout mouse with the human SMN2 gene, the Smn–/– SMN2 mouse [Hsieh-Li et al., 2000; Monani et al., 2000]. Littermates demonstrated a range of phenotypes similar to that seen in humans with spinal muscular atrophy types I, II, and III. Furthermore, the severity of the phenotype was inversely proportional to the

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number of SMN2 copies (and therefore the amount of SMN protein), exactly as seen in human subjects. The importance of SMN protein in producing the disease phenotype has been reinforced by the finding that an A2G missense mutation modulates the mouse phenotype [Monani et al., 2003]. In other words, increasing the presence of SMN protein, even abnormal protein, may be a reasonable therapeutic strategy. A concurrent strategy is to examine many compounds for their ability to alter splicing and to produce full-length protein in vitro using cells from patients or from Smn mice [Zerres et al., 1997b]. Frugier and associates cross-bred three mice: one with a transgene expressing Cre recombinase controlled by the neuron specific enolase promoter, the Smn+/– mouse, and finally one homozygous for Smn exon 7 being flanked by loxP recombination sites [Frugier et al., 2000]. This cross-breeding produced the SmnF7/– NSE-Cre mouse that expresses Smn exon 7 deletion in neurons only [Salah et al., 2002]. Both animal models are being used to test drugs and compounds for their effect on SMN protein production in vivo. The largest class of compounds to upregulate SMN messenger RNA ratios are histone deacetylase inhibitors [Andreassi et al., 2001; Jarecki et al., 2002]. Histone deacetylase inhibitors include the following drugs: valproic acid, commonly used as an antiepileptic in children; hydroxyurea; sodium butyrate; and sodium vanadate. Butyrate, a histone deacetylase inhibitor, can induce transcriptional activation of a number of genes and induce cellular differentiation as histone acetylation levels increase. Butyrate was found to induce γ-globin expression through changes in histone acetylation [McCaffrey et al., 1997; Pace et al., 2002]. Chang and colleagues have treated the Smn–/– SMN2 mouse with sodium butyrate [Chang et al., 2001]. Survival in the treated group was significantly improved. There was elevation of exon 7 containing SMN protein in treated animal tissues including motor neurons. Experiments using sodium butyrate in lymphoid cell lines from spinal muscular atrophy patients showed an increased number of full-length SMN transcripts. Sodium butyrate increased the amount of exon 7 containing SMN protein in spinal muscular atrophy lymphoid cell lines. Mercuri and colleagues reported a significant improvement in functional strength in a short pilot trial of phenylbutyrate in children with spinal muscular A atrophy [Carducci et al., 2001; Mercuri et al., 2004].

electromyography. Evidence of acute denervation such as fibrillation potentials is common. Infants may exhibit spontaneous rhythmic firing of motor units, whereas electromyographic patterns of patients with long-standing disease often display pseudomyotonic volleys [Hausmanowa-Petrusewicz et al., 1987; Hausmanowa-Petrusewicz and Jozwik, 1986]. There usually is also evidence of reinnervation in the form of large polyphasic motor units and increased recruitment. Measurement of motor nerve conduction velocities in infants may be difficult because of the small-sized limbs and short distance between stimulus and recording electrodes. Examination usually documents either normal conduction velocities or, occasionally, faster conduction velocities than expected [Moosa and Dubowitz, 1976]. Normal sensory conduction velocities have been found in the sural or median nerves of patients in all three groups and in patients with juvenile proximal hereditary muscular atrophy [Schwartz and Moosa, 1977]. If there is profound muscle atrophy, it may be difficult to interpret responses to nerve stimulus. Conventional diagnostic criteria mandate that the diagnosis of spinal muscular atrophy (in the absence of an identifiable gene mutation) must be accompanied by normal motor and sensory nerve conduction velocities. Ultrasonography of the muscles is usually abnormal and has been used as a screening test for neurogenic atrophy in patients with mild clinical disability [Kamala et al., 1985].

Clinical Laboratory Tests The diagnostic evaluation for spinal muscular atrophy has changed since the discovery of the survival motor neuron gene. The diagnosis now can begin with blood DNA analysis for mutations in this gene [Parano et al., 1996; RudnikSchoneborn et al., 1996]. For infants who have mutations, no further evaluation is necessary. If mutations cannot be identified, a more traditional approach may be necessary for diagnosis. This approach includes measurement of serum muscle enzymes, electrodiagnosis with nerve conduction velocities and electromyography, and muscle biopsy. As already stated, B serum levels of the muscle enzyme creatine kinase may or may not be elevated, although it usually is normal in spinal muscle atrophy types I and II. The electrodiagnostic characteristics that accompany anterior horn cell impairment are often readily detectable by

FIGURE 75-6. Infantile spinal muscular atrophy: biceps muscle from a 3-month-old infant. A, Fascicles with atrophic muscle fibers (AF) and fascicles with atrophic and normal fibers. (Trichrome stain, ×160.) B, Ultrastructural appearance showing small fibers, sarcomere disruption (SD), and degenerating fiber (DF) (×7000). (Courtesy of Dr. Stephen A. Smith.)

Connolly and Iannaccone / Anterior Horn Cell and Cranial Motor Neuron Disease

However, it is not as reliable or specific as other diagnostic tests. Muscle biopsy should indicate neurogenic atrophy or evidence of reinnervation (Fig. 75-6). The affected fibers are smaller in diameter than normal, and fat tissue is more abundant between the fiber bundles. Disproportionate preservation of large, rounded fibers in the denervated fasciculi is common [Byers and Banker, 1961]. This is frequently called the infantile pattern of neurogenic atrophy. From mid-childhood, one may see angular fibers indicating acute denervation and type grouping indicating reinnervation. Fidzianska described three types of muscle cells found in a study of muscle tissue taken from seven children with spinal muscular atrophy: normal cells, small cells with a large central nucleus appearing as older myoblasts, and cells resembling myotubes containing a common basement membrane [Fidzianska, 1976]. The latter two types were believed to represent arrested maturation rather than atrophy. Nonspecific changes such as fiber size disproportion may occur, possibly as a result of sampling error [Bove and Iannaccone, 1988]. In such a case, repeat biopsy of another muscle or at a later age may suggest more typical evidence of neurogenic atrophy. Many fibers reveal a loss of filaments from their myofibrils, a change typical of denervation atrophy. Other atrophic fibers contain clumps of thin filaments frequently seen in young myoblasts, suggesting either active regeneration or cessation of maturation [Shafiq et al., 1967]. However, no changes in the muscle spindles have been reported.

FIGURE 75-7. This patient with juvenile proximal hereditary muscular atrophy (Kugelberg-Welander disease) has generalized weakness. Marked weakness and atrophy of the shoulder girdle are present. Lumbar lordosis, as well as abdominal protuberance related to abnormal weakness, is common.

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Imaging of the central nervous system (CNS) is done infrequently. The brain should have normal structure. Anomalies of the CNS may occur with motor neuron disease but not with spinal muscle atrophy that is linked to the 5q locus. Variants of spinal muscle atrophy are discussed in a later section.

Management Because there is no effective therapy for spinal muscle atrophy [Dubowitz, 1996; Eng et al., 1984], management consists of preventing or treating the complications. Complications of severe weakness include restrictive lung disease, poor nutrition, orthopedic deformities, immobility, and psychosocial problems (Fig. 75-7). Restrictive lung disease results from weakness of intercostal muscles and diaphragm causing hypoventilation and weak cough. Aggressive prophylaxis against pneumonia may include assisted cough, chest percussion therapy, and intermittent positive-pressure breathing. Patients require assistance to maintain good pulmonary toilet even when not experiencing an acute infection and may require intervention to prevent progressive atelectasis [Bach, 1994; Bach and Alba, 1990, 1991]. Risk for pneumonia increases as forced vital capacity decreases and may occur even without significant change in limb or trunk strength. Oxygen therapy should be contraindicated except in the context of acute infection. Patients with restrictive lung disease develop retention of CO2 before hypoxia, and administration of oxygen may cause death from apnea secondary to suppression of the respiratory drive. It is helpful to monitor blood gases on a regular basis along with the forced vital capacity. When CO2 retention occurs, noninvasive ventilation, either positive or negative pressure, during sleep may be helpful and restorative. Recent studies indicate that noninvasive ventilation can improve quality of life, prolong survival, and decrease morbidity in patients with restrictive lung disease, including spinal muscular atrophy patients [Birnkrant et al., 1998; WallgrenPettersson et al., 2004]. Other technology is also available to improve airway clearance, including insufflators-exsufflators and intermittent P ventilation [Finder et al., 2004; Miske et al., 2004; Toussaint et al., 2003]. Poor nutrition often occurs as a result of a weak suck, unprotected airway, or easy fatigability. A feeding evaluation can be done by a team of occupational therapists and dietitians. Recommendations may include adjusting the feeding schedule, positioning, or food textures to maximize caloric intake. The child should be examined during a modified barium swallow using several food textures, including liquid, semiliquid, soft, and solid food. If aspiration occurs, a gastrostomy may be recommended. In some cases, supplemental gastrostomy feedings may be indicated in the absence of aspiration because the child cannot take in enough by mouth before fatiguing. Scoliosis is the most serious orthopedic problem among patients with spinal muscular atrophy. Nonwalkers tend to develop spinal deformities earlier than walkers. Most curves are thoracolumbar in location. Spinal orthoses usually do not prevent or retard scoliosis; however, they may help patients sit. Surgical correction should be undertaken only after careful consideration because patients should be in

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good health at the time, and they will experience no further linear growth after spine surgery [Schwentker and Gibson, 1976]. Vigorous preoperative and postoperative physical therapy is required to prevent loss of strength or function after spinal fusion, as well as respiratory complications. Marked improvement in the degree of scoliosis is often possible after fusion or instrumentation, with associated improvement in vital capacity, sitting, balance, and comfort [Aprin et al., 1982; Daher et al., 1985a; Piasecki et al., 1986]. Patients who do not undergo correction of scoliosis typically experience progressive deformity with discomfort, inability to position, and further decompensation of pulmonary functions. Walking may occasionally be facilitated by lightweight orthoses for the legs, although for spinal muscle atrophy type I or II patients, it may be a temporary skill [Russman et al., 1996; Wilkins and Gibson, 1976]. Power chairs should be prescribed as close to the second birthday as possible to provide some independent mobility at an appropriate developmental age [Siegel and Silverman, 1984]. Because children with spinal muscle atrophy often have high cognitive function [Whelan, 1987], they easily learn how to maneuver a joystick. The motor speed can be adjusted as needed, and the parents should be encouraged to set consistent limits for behavior. As the child grows, pneumatic lifts, special mattresses, and bath accessories are beneficial for many patients. An in-home occupational therapy consult will ensure that the patient receives appropriate equipment. School-aged children may benefit from a full-time aide who can help with toileting and feeding and maintain the respiratory and physical therapy regimens during the school day. Parents can be encouraged to seek resources for such help and to communicate freely with school district officials to provide their child with an education that will maximize academic abilities.

KENNEDY’S DISEASE Kennedy’s disease, or spinal and bulbar muscular atrophy, was first described in 1968 [Kennedy et al., 1968]. It is a rare motor neuron disease that causes proximal weakness, bulbar weakness with dysphagia and aspiration, asymmetric or symmetric facial weakness, and gynecomastia. Age of onset is variable, and clinical diagnosis may not be possible until gynecomastia develops after the fourth decade. Inheritance is X-linked. Fischbeck and colleagues localized the gene in 7 families to Xq12-22 [Fischbeck et al., 1986]. Subsequently, the human androgenic receptor gene (hAR) was localized to Xq11-12, and examination of hAR in spinal and bulbar muscular atrophy patients demonstrated that there was an abnormal expansion of exon 1 to more than twice normal size [Choi et al., 1993]. The expansion was found to be caused by CAG repeats, normally numbering 15 to 31 in hAR, but numbering more than 40 in the spinal and bulbar muscular atrophy mutation [Belsham et al., 1992; La Spada et al., 1991, 1994]. Although clinical and genetic diagnosis is usually established in the fourth of fifth decade of life when weakness is present, the earliest symptoms may be present in the second decade of life and include gynecomastia, muscle cramps, and fatigue [Sperfeld et al., 2002]. This weakness is slowly progressive and involves bulbar musculature, including a weak, atrophic tongue. There are no signs of spinal cortical tract dysfunction; deep tendon reflexes are diminished or normal. Fasciculations and cramps in limb muscles are common. Hypesthesia and decreased vibratory sense are present in about half of patients. There may be mild elevation of muscle enzymes, but electrodiagnostic study and muscle biopsy are indicative of motor neuron disease. Once the clinical phenotype is recognized in a patient, diagnosis may be confirmed by mutation analysis in a blood sample.

TABLE 75-2 Rare and Atypical Forms of Spinal Muscular Atrophy (SMA) Not Linked to the SMN Gene NAME

GENE/INHERITANCE

CLINICAL

REFERENCES

Scapuloperoneal SMA

AD; 12q24.1-q24.31

DeLong and Siddique, 1992; Isozumi et al., 1996

Spinal SMA 2

AR or X-linked

Pontocerebellar hypoplasia with SMA (PCH I)

AR

Distal infantile SMA with diaphragm paralysis (SMARD1) Distal hereditary motor neuropathy, Jerash type X-linked infantile SMA with arthrogryposis SMA, congenital nonprogressive, of lower limbs

AR; 11q13.2-q13.4 Immunoglobulin-γ–binding protein-2 (IGHMBP2) AR; 9p21.1-p12

Congenital absence of muscles; progressive weakness of scapuloperoneal, distal, and laryngeal muscles Onset 1 year; proximal more than distal Onset 0–6 mo; progressive CNS hypotrophic cerebellum and brainstem; absent dentate nucleus; neuronal loss in basal ganglia; cortical atrophy Onset 1–2 mo; diaphragmatic paralysis; death <3 mo

Xp11.3-q11.2 AD; 12q23-24

AD, autosomal dominant; AR, autosomal recessive; CNS, central nervous system.

Onset 6–10 yr; legs involved first then hands Onset birth or infant; contractures; death <2 yr Late walking proximal and distal weakness; mild knee contractures; pes equinovarus

Nevo et al., 1998 Barth, 1993; Chou, 1993; Chou et al., 1990; Gorgen-Pauly et al., 1999; Rudnik-Schoneborn et al., 2003; Ryan et al., 2000 Grohmann et al., 2003; Mellins et al., 1974; Rudnik-Schoneborn et al., 2004 Christodoulou et al., 2000; Middleton et al., 1999 Greenberg et al., 1988; Kobayashi et al., 1995 Fleury and Hageman, 1985

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TABLE 75-3 Distal Hereditary Motor Neuropathy (HMN) or Distal Spinal Muscular Atrophy (SMN) NAME

GENE/INHERITANCE

CLINICAL

HMN 1

AD

HMN 2

AD; HSPB8 (HSP22); 12q24 (same gene mutated in Charcot-Marie-Tooth disease 2L) AD; 7p14; glycyl transfer RNA synthetase (allelic with Charcot-Marie-Tooth disease 2D); GARS protein (aminoacyl transfer RNA synthetase)

Onset 2–40 yr; symmetric weakness; no upper motor neuron signs Onset 14–35 yr; weak toe extensors (Irobi et al., 2004b; Timmerman et al., with progression to complete 1992) paralysis of distal leg muscles in 5 years

HMN 5

HMN 5B

HMN 7

HMN + vocal cord (2)

Distal SMA, X-linked

Onset of weakness is in hands with mean age 17 yr; lower extremity involved in 50% after 2 yr; slowly progressive AD; 11q13; BSCL2 protein; seipin Onset in hands with mean onset age (allelic to Beradinelli-Seip 15 yr (range, 2–40 yr); slow congenital lipodystrophy, type 2, progression over decades with and SPG-17—Silver’s syndrome) lower extremity involvement in 95% AD; 2q14 Onset second decade with voice or gait disorder; slow progression but vocal cord paralysis can lead to respiratory failure AD: 2p13; dynactin 1 Early adult onset with respiratory failure with vocal cord paralysis; progressive; hands and then feet X-linked; Xq13.1-q21 Onset 1–10 yr; very slow

INVESTIGATORS

(Christodoulou et al., 1995; Ellsworth et al., 1999) (Irobi et al., 2004a; Windpassinger et al., 2004)

(Boltshauser et al., 1989; Young and Harper, 1980) (Puls et al., 2003)

(Takata et al., 2004)

AD, autosomal dominant; SPG, spastic paraplegia.

RARE AND ATYPICAL FORMS OF SPINAL MUSCULAR ATROPHY Molecular genetics have allowed specific identification of several atypical forms of spinal muscular atrophy that may occur distally or proximally (Tables 75-2 and 75-3). Scapuloperoneal spinal muscular atrophy was first described clinically by Emery and co-workers before the identification of the SMN gene, and Mawatari recognized sporadic and Xlinked cases [Emery et al., 1968; Mawatari and Katayama, 1973]. More recently, a clinically similar syndrome with onset in the first decade of life and slow progression has been linked to chromo-some 12 with autosomal-dominant inheritance [DeLong and Siddique, 1992; Isozumi et al., 1996]. In progressive bulbar paralysis of childhood, or FazioLonde disease, motor neurons in cranial nerve nuclei may be progressively impaired and decreased in number, with resultant progressive bulbar paralysis and little or no accompanying anterior spinal cord involvement [Gomez et al., 1962]. Although the condition may be genetically transmitted [Fazio, 1892; Londe, 1893, 1894], sporadic cases are more common [McShane et al., 1992; Suresh and Deepa, 2004]. Age of onset varies and may be as early as 3 years. Bulbar paralysis is only one facet of progressive motor neuron disease in many of these patients, and pathologic study confirms widespread degenerative changes in the brainstem. Morphologic involvement of anterior horn cells has been demonstrated despite the absence of clinical signs [Alexander et al., 1976]. Involvement of the anterior horn cells in the cervical and upper thoracic cord segments is often asso-

ciated with demonstrable loss of neurons in other locations, including decreased neuronal population in the dentate nucleus. Of the cranial nerves, cranial nerve VII is almost always affected. Cranial nerve XII is usually affected pathologically, and clinical manifestations are apparent in the early-onset patients. The nuclei of cranial nerves III, IV, VI, and X may also be involved. Clinical impairment of extraocular movement is rare. Juvenile-onset bulbospinal muscular atrophy associated with deafness [Brown-Vialetto-Van Laere syndrome) manifests late in the first decade or in the second decade [Brown, 1894; Van Laere, 1966; Vialetto, 1936]. Bulbar impairment is indicated by dysarthria, dysphagia, and facial diplegia [Gallai et al., 1981; Summers et al., 1987]

MÖBIUS’ SYNDROME First described in 1898 by Thomas, Möbius’ syndrome is a congenital, static condition manifested by facial palsy (often bilateral) and involvement (usually bilateral) of cranial nerve VI [Thomas, 1898]. The lower face is usually less involved than the upper face. Impaired lateral rectus muscle contraction results in unopposed medial rectus muscle action, with resultant convergence (Fig. 75-8). Conjugate eye movements in the vertical plane are usually present, although ptosis may also be present. Dysfunction of other cranial nerves, including cranial nerves V, X, XI, and XII, often accompanies the abnormalities of cranial nerves VI and VII. Associated absence of the pectoral muscles may occur. The clinical findings are correlated with failure of

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FIGURE 75-8. Patient with Möbius’ syndrome who has bilateral weakness of cranial nerves VI and VII. Recurrent swallowing impairment resulted in multiple episodes of pneumonitis, which necessitated tracheostomy.

development or degeneration of the involved cranial nerve motor cells. Several gene loci have been identified, and the nomenclature now refers to Möbius’ syndromes 1, 2, and 3 (Table 75-4). Möbius’ syndrome has also been associated with exposure to cocaine or misoprostol in utero [de Muelenaere, 1999; Goldberg et al., 2001; Kankirawatana et al., 1993; Leong and Ashwell, 1997; Marques-Dias et al., 2003; Pastuszak et al., 1998; Shepard, 1995; Vargas et al., 2000]. Although the differential diagnosis includes non–motor neuron involvement, including supranuclear or myopathic conditions such as facial scapulohumeral dystrophy, myotubular myopathy, or myotonic dystrophy, other clinical features usually distinguish Möbius’ syndrome from these.

AMYOTROPHIC LATERAL SCLEROSIS Amyotrophic lateral sclerosis represents a spectrum of motor system degeneration involving the corticospinal and corticobulbar pathways and motor neurons associated with the cranial nerves and anterior horn cells of the spinal cord. Onset may be as early as adolescence, although most cases present after the fourth decade of life. Dysfunction of upper and

lower motor neurons produces clinical manifestations of both spasticity and muscular atrophy. Amyotrophic lateral sclerosis is inherited in about 10% of cases as an autosomal-dominant disorder with increasing penetrance after 50 years of age [Emery, 1991]. Sporadic and familial amyotrophic lateral sclerosis are clinically indistinguishable. Familial amyotrophic lateral sclerosis has been studied to understand pathogenesis. Multiple genes or gene loci have now been identified in familial amyotrophic lateral sclerosis (Table 75-5). The most common, superoxide dismutase (SOD), a gene that encodes a cytosolic Cu/Znbinding superoxide dismutase, is causative in amyotrophic lateral sclerosis type 1 [Deng et al., 1993; Rosen et al., 1993]. The role of superoxide dismutase in controlling free radical tissue levels made it a logical choice as a candidate gene in familial amyotrophic lateral sclerosis. Superoxide is known to be cytotoxic, but the accumulation of superoxide by an inhibition of superoxide dismutase may be exacerbated by activation of excitatory neurotransmitters, such as glutamate [Coyle and Puttfarcken, 1993]. However, this initial concept of pathogenesis has not been confirmed because humans studies show that amyotrophic lateral sclerosis severity is independent of enzyme activity, and neither the SOD1 knockout nor the SOD1-overexpressing wild-type mice develop weakness [Shibata, 2001]. Instead, severity of weakness in SOD1 mutant mice is related to transgene copy number. Mice with high copy numbers develop progressive weakness and motor neuron loss resulting in death [Borchelt et al., 1998; Shibata, 2001]. This toxic gain of function may be caused by either a gain of oxidative function or gain of abnormal protein-protein interactions [Liochev and Fridovich, 2003]. There are three well-recognized amyotrophic lateral sclerosis syndromes with onset in the first two decades of life (see Table 75-5). Amyotrophic lateral sclerosis type 2 is due to mutations in the Alsin gene (ALS2) [Hadano et al., 2001; Yang et al., 2001b]. This gene, which has sequence homology to guanosine triphosphatase regulatory proteins, bears mutations that predict truncation of the protein and loss of function. Children present in the first decade of life with spasticity involving face and limbs and may develop a pseudobulbar affect. Symptoms are very slowly progressive with difficulty walking after 40 years of age. An allelic condition, progressive lateral sclerosis with onset in infancy, has also been associated with mutations in this gene [Eymard-Pierre et al., 2002; Gros-Louis et al., 2003]. The second juvenile-onset form of amyotrophic lateral sclerosis is type 4, an autosomal-dominant inherited distal motor neuronopathy with pyramidal symptoms [Chance et al., 1998]. Symptoms begin in the second decade of life

TABLE 75–4 Genetic Forms of Möbius’ Syndrome NAME

GENE LOCI

INHERITANCE /OMIM

ASSOCIATED FEATURES

INVESTIGATORS

MBS 1 MBS 2

13q12.2-q13 3q21-q22

AD; 157900 AD; 601471

CN IV; arthrogryposis; mental retardation Asymmetric CN VII; no ophthalmoplegia; incomplete penetrance Asymmetric, bifacial weakness; variable hearing loss; reduced penetrance

(Parkes, 1999; Slee et al., 1991) (Kremer et al., 1996)

MBS 3 AD, autosomal dominant; CN, cranial nerve.

AD; 604185

(Verzijl et al., 1999)

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TABLE 75–5 Genetic Forms of Amyotrophic Lateral Sclerosis (ALS) NAME

GENE/LOCI/PROTEIN

INHERITANCE

ONSET

INVESTIGATORS

ALS 1

SOD1/21q22.1/Cu/Zn-binding superoxide dismutase ALS2/2q33/alsin 18q21 9q34/senataxin 15q15 16q12 20p13 VAPB/20q13 9q21-22 22q12/neurofilament heavy chain 12q12/peripherin

AD

Adult

(Rosen, 1993)

AR AD AD AR AD AD AD AD Unknown Unknown

Child Adult Child Child Adult Adult Adult Adult Adult Adult

(Hadano et al., 2001; Yang et al., 2001b) (Hand et al., 2002) (Blair et al., 2000; Chen et al., 2004) (Hentati et al., 1998) (Ruddy et al., 2003; Sapp et al., 2003) (Sapp et al., 2003) (Nishimura et al., 2004) (Hosler et al., 2000) (Al-Chalabi et al., 1999) (Gros-Louis et al., 2004)

ALS 2 ALS 3 ALS 4 ALS 5 ALS 6 ALS 7 ALS 8 ALS-FTD*

*ALS with frontotemporal dementia. AD, autosomal dominant; AR, autosomal recessive; SOD, superoxide dismutase.

with difficulty walking, and examination shows both upper and lower motor neuron involvement. Electrophysiology confirms localization to the level of the anterior horn cell [Rabin et al., 1999]. The clinical course has a slow progression with a normal life span. Recently causative mutations in the senataxin gene (SETX) have been demonstrated. Although the precise function is unknown, the Senataxin gene has homology to genes involved in RNA processing [Chen et al., 2004]. The third form of amyotrophic lateral sclerosis with childhood onset is type 5, localized to chromosome 15q15.1q21.1, and is recessively inherited. No specific gene has been identified. This form of juvenile amyotrophic lateral sclerosis has been described in multiple ethnic groups from North Africa, South Asia, and Europe. There are two clinical subtypes. Onset for both is in the second decade of life. Type 1 affects arms more than legs, and bulbar symptoms develop late. Type 2 has much more spasticity and much more prominent involvement in legs and may be a form of familial spastic paraparesis [Hentati et al., 1998].

BENIGN CONGENITAL HYPOTONIA When examining tone in infants and young children, both axillary and appendicular tones are assessed. Infants with CNS injury often demonstrate decreased axial tone but increased appendicular tone after the first months of life. However, in the first months, tone in both areas may be decreased in these infants. In contrast, children with hypotonia secondary to disorders of spinal cord (spinal muscular atrophy), nerve, neuromuscular junction, or myopathy usually maintain low axial and appendicular tone and have clear weakness throughout infancy and childhood. The initial reports of children with “benign congenital hypotonia” cited 17 infants with hypotonia with no apparent weakness at birth or in first months of life. Eight improved completely by 10 years, and the other nine improved but had definite muscle weakness or marked ligamentous laxity at follow-up. All eight children who recovered had deep tendon reflexes when initially examined, although three had reflexes that were difficult to elicit [Walton, 1957]. Although

there was no clinical evidence of muscular dystrophy, infantile spinal muscular atrophy, mental deficiency, or upper motor neuron disease clinically in these children, diagnostic studies at that time were limited. Only two had muscle biopsies, with hematoxylin and eosin staining only [Walton, 1957]. Children with “benign hypotonia” may have various conditions, including nonprogressive congenital myopathies identified with more detailed testing [Spagnoli et al., 1985; Thompson, 2002]. Because some of these disorders have clinical or hereditary implications, making these specific diagnoses is important. Other children with hypotonia in infancy without weakness may have cognitive difficulties later [Dubowitz, 1968; Shuper et al., 1987; Zellweger, 1983]. Thus, some suggest that this diagnosis be eliminated or replaced with the term central hypotonia because the prognosis is not necessarily benign. The cause in those children without a neuromuscular diagnosis is likely related to improper modulatory influences on the gamma loop from the CNS. As the brain matures, typical motor deficits may develop that are consistent with a diagnosis of cerebral palsy. The condition may be accompanied by cognitive deficit [Dubowitz, 1968]. In short-term follow-up to age 3 years, 44% of 36 children still had hypotonia and gross motor delay, and a small number had speech delay [Shuper et al., 1987]. One follow-up of 25 children with a clinical diagnosis of benign congenial hypotonia demonstrated that by age 6 to 8 years, these children still had inferior gross motor performance for coordination and strength compared with 26 healthy controls [Parush et al., 1998]. Thus, the clinician must be wary of making the diagnosis of benign congenital hypotonia because of the large differential diagnosis, which includes infantile spinal muscular atrophy and congenital myopathies [Thompson, 2002; Zellweger, 1983]. Follow-up examination to determine whether the appendicular tone increases or stays low and whether weakness becomes apparent is critical to deciding which children should have more detailed diagnostic studies [Thompson, 2002; Zellweger, 1983]. It is also possible that some children with congenital hypotonia without persistent weakness have variable degrees of ligament laxity [Carboni et al., 2002; McGrory et al., 1997].

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ARTHROGRYPOSIS MULTIPLEX CONGENITA Arthrogryposis multiplex congenita, a syndrome manifesting at birth, is characterized by multiple, fixed contractures of large joints. The pathologic features of arthrogryposis cover a broad spectrum [Banker, 1985, 1986, 1994]. General and genetic classifications have been proposed [Hall, 1997]. Fetal hypokinesia or restricted movement in utero of any cause will result in congenital contractures. Congenital anomalies of the brain are common (e.g., hydrocephalus, hydranencephaly, microcephaly) [Hageman et al., 1987; Hennekam et al., 1991] and may be accompanied by anomalies of other organs [Vlaanderen et al., 1991]. Inheritance of anterior horn cell arthrogryposis, when determinable, is most often autosomal recessive. However, autosomal-dominant transmission has been reported [Fleury and Hageman, 1985]. Anterior horn cell arthrogryposis results from a marked decrease of the anterior horn cell population in the cervical and lumbar spinal cord enlargements. More than 90% of patients with arthrogryposis have anterior horn cell–related disease [Adams et al., 1988; Banker, 1985]. Most affected infants hold their arms rotated inwardly; elbow position varies. The forearms are held pronated, with ulnar deviation at the wrists. The hands are flexed, and the fingers are curled tightly. The thighs are usually externally rotated and flexed at the hips. There is either flexion or extension of the knees, but the feet are almost always positioned in an equinovarus deformity (Fig. 75-9). The limbs are slender (Fig. 75-10); conversely, the joints appear greatly enlarged (Fig. 75-11).

FIGURE 75-9. This 6-month-old male has the neurogenic form of arthrogryposis. The marked deformities of the ankles and feet are evident. There are flexion contractures of the wrists, elbows, and knees.

FIGURE 75-10. This patient with anterior cell arthrogryposis has had a number of orthopedic procedures. Marked scoliosis and generalized muscle wasting, particularly of the shoulder girdle, are clearly demonstrated.

FIGURE 75-11. Close-up view of the knees of the patient in Figure 75-10. The knee joints, although of normal size, appear relatively enlarged because of the marked muscle wasting.

Connolly and Iannaccone / Anterior Horn Cell and Cranial Motor Neuron Disease

The patella may be very small or absent. Other abnormalities may include inguinal hernias, cleft palate, scoliosis, ankylosis of the temporomandibular joint, and cardiac malformations [Drachman and Banker, 1961]. Passive movement of the affected joints is possible, but only a small range is present. Deep tendon reflexes are not elicitable, and electromyographic examination confirms electrical abnormalities consistent with anterior horn cell impairment. The few available pathologic studies of the involved muscles revealed markedly decreased bulk [Drachman and Banker, 1961] or even absence [Adams et al., 1988]. Hip contractures develop from unopposed contraction of the iliopsoas muscles. Muscle spindles are normal. Few pathologic alterations are evident in endomysial connective tissue, but perimysial connective tissue may be decidedly increased. One affected member each in two sets of identical twins has been reported [Drachman and Banker, 1961]. Children with arthrogryposis associated with anterior horn cell disease present in infancy and may demonstrate autosomal recessive, sporadic, or X-linked inheritance. The genetically defined syndromes are described in Table 75-2. Pathologic features of arthrogryposis multiplex congenita associated with anterior horn cell dysfunction were studied in infants from two families. These infants had flexed elbows, extended wrists, acute flexion of the knee and hip joints, and bilateral talipes equinovarus [Hooshmand et al., 1971; Pena et al., 1968]. Postmortem examination documented nodular fibrosis of the anterior spinal roots along the entire length of the spinal cord and absence of myelin and axis cylinders. Central chromatolysis was evident in a few anterior cells; the morphologic changes were believed to be secondary to the anterior root lesions. The voluntary muscle exhibited neurogenic muscular atrophy. Identification of muscle tissue in some areas was impossible because of extensive replacement by fat [Pena et al., 1968]. A rare form of lethal arthrogryposis multiplex congenita related to abnormal Schwann cell development was reported [Charnas et al., 1988]. Contractures have accompanied neonatal myasthenia gravis, although anticholinesterase therapy does not improve them [Holmes et al., 1980; Smit and Barth, 1980]. Prenatal diagnosis has been done using ultrasound [Bonilla-Musoles et al., 2002; Stoll et al., 1991]. Newborns with arthrogryposis may have myotonic dystrophy [Sarnat et al., 1976]. The lower extremities are predominantly involved. These infants often have loose, wrinkled skin and a paucity of subcutaneous tissue. Neck muscle weakness precludes normal neck flexion. Serum creatine kinase activity may be elevated. Diagnosis can be confirmed by blood DNA analysis, which reveals an expansion of the triplet repeat in the myotonic dystrophy gene. Considering the differential diagnosis, it is not surprising that muscle pathology varies greatly in arthrogryposis patients. All of the congenital myopathies have been associated with arthrogryposis, including central core disease, nemaline myopathy, and centronuclear myopathy, as well as congenital muscular dystrophy [Moerman et al., 1985; Quinn et al., 1991; Schmalbruch et al., 1987]. Selective distal arthrogryposis is more likely to be caused by specific muscle mutations [Sung et al., 2003a, 2003b]. Administration of anesthesia during surgical intervention may be complicated by malignant hyperthermia, especially in

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children with muscular dystrophy or central core disease [Baines et al., 1986]. Kuskokwim disease, named for the river delta on which the original cases were diagnosed, is a form of arthrogryposis in Alaskan Eskimos [Petajan et al., 1969]. Multiple contractures of the joints, commonly of the knees and ankles, characterize the disease. The primary pathologic process is associated with the connective tissue. There is no indication of myopathy, neuropathy, or motor cell disease. The disease manifests in the first decade of life and is transmitted as an autosomal-recessive trait. Contractures at the elbows and knees may be seen during the first few months of life. Accompanying internal tibial torsion and profound planovalgus occur. Flexion hip contractures are also present. The deep tendon reflexes are usually elicitable in the biceps and Achilles tendons but are frequently absent in the triceps and quadriceps tendons. Although one infant had a small cataract at 3 years of age, cataracts are uncommon in adults. Radiographic examinations have revealed cysts in the proximal long bones of several patients. Other patients have had pigmented nevi and diminished corneal reflexes. This form of arthrogryposis may be associated with webbed-neck or Klippel-Feil deformity and with anomalies of the genitourinary system [Beckerman and Buchino, 1978]. New information describing genes that control development of limb buds suggests that abnormalities in transcription factors may be theoretically responsible for some cases of arthrogryposis [Nelson et al., 1996; Roberts and Tabin, 1994]. In such cases, there would be no evidence of muscle or nerve disease, but muscle development in the limbs may be severely defective or absent (amyoplasia) [Sells et al., 1996]. To date, no such mutations have been found. On the other hand, mutations in contractile proteins, such as tropomyosin 2 and troponin I, have been shown to cause amyoplasia or distal arthrogryposis [Sung et al., 2003a, 2003b]. Orthopedic procedures performed on patients with arthrogryposis often provided sufficient alignment and stability of the legs to allow independent ambulation [Bennett et al., 1985; Fisher et al., 1970; Guidera and Drennan, 1985]. Nonsurgical casting and manipulation methods introduced by Penseti have replaced early surgical approaches in children with clubfoot deformity [Ponseti, 1998] but require careful follow-up and compliance to be successful [Dobbs et al., 2004]. Talectomy before walking ability is acquired is rarely done currently but may prove beneficial in severe clubfoot deformity [Joseph and Myerson, 2004]. Scoliosis may be a prominent problem and may require surgical correction [Daher et al., 1985b]. Some improvement in arm and hand function is usually possible with physical therapy and exercise. Anesthesia for these patients requires special consideration [Baines et al., 1986; Oberoi et al., 1987; Oda et al., 1990]. Otolaryngologic management may be necessary for poor suck reflex, omega-shaped epiglottis, airway compromise, achalasia, and micrognathia [Laureano and Rybak, 1990].

INFECTIOUS DISEASES Poliomyelitis Poliomyelitis is a viral disease of motor neurons caused by poliovirus. Nonparalytic poliomyelitis is the most common

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form of the disease. From a clinical standpoint, it is largely indistinguishable from other meningoencephalitides. About 25% of patients reported in one series had nonparalytic poliomyelitis, 50% had spinal poliomyelitis, about 12% had bulbar poliomyelitis, and 10% had bulbospinal involvement [Auld et al., 1960; Lepow and Spence, 1965]. Three immunologically different types of virus that do not produce cross-immunity have been isolated as causing poliomyelitis; infection with a specific type results in permanent immunity to that type. In many countries, immunization with killed-virus and attenuated live-virus vaccines has effectively ended the large-scale epidemics of the disease that previously occurred in the summer and early fall. Transmission of the virus is from human to human, primarily through secretions of the upper respiratory tract or through fecal contamination. In the United States, a few cases have occurred in adults whose immune status had diminished with time or in siblings not yet immunized; transmission could be traced to a child recently immunized with live vaccine. Onset is indicated by signs of malaise, which are usually accompanied by muscular pains or stiffness. Headaches occur frequently, and symptoms of upper respiratory tract infection are common in children. The patient may experience some degree of nuchal rigidity and a low-grade fever as the disease progresses. Muscular tightness then becomes noticeable, primarily in the hamstring, thigh, and neck. Poliomyelitis characterized by a triad of fever, nuchal rigidity, and spasm of the back muscles may affect infants who are younger than 1 year of age [Abramson and Greenberg, 1955]. Spinal involvement is more common than bulbar involvement in infants. The course of the disease may range from slowly progressive to fulminating; the more rapid the progression, the more severe the eventual involvement. The anterior horn cells are the prime target of the virus, and motor weakness is the hallmark of the clinical pattern. In most cases, the weakness is asymmetric. The incidence of quadriplegia and trunk muscle compromise is greater after the first year of life. Bulbar involvement is life threatening, resulting in embarrassment of the respiratory, autonomic, and circulatory centers of the brainstem and in profound weakness of the muscles of respiration and swallowing [Auld et al., 1960; Baker et al., 1950]. Poliomyelitis has occurred in utero on numerous occasions and can result in death during the neonatal period [Pugh and Dudgeon, 1954].

Clinical Laboratory Tests Evidence of pleocytosis with mononuclear cells and a normal or slightly elevated protein concentration can usually be obtained through spinal fluid examination. Polymorphonuclear cells may become prevalent early in the course of the disease. The spinal fluid glucose content is usually normal. Direct analysis of cerebrospinal fluid for virus DNA makes diagnosis rapid and accurate.

Management Treatment is supportive. Mechanical ventilation and support of circulation may be required in the presence of bulbar symptoms. Prolonged rehabilitation is generally the rule after patients have recovered from the acute stage of polio, and

permanent motor deficits are common. Postpolio syndrome may begin two or more decades after the illness and is associated with progressive loss of strength and atrophy of an already affected limb. Its cause is unknown [Munsat, 1991a].

Other Viruses Causing Polio-like Paralysis Although poliovirus immunization has led to marked reduction of this form of anterior horn cell disease, it is clear that many other viruses, including Epstein-Barr virus [Wong et al., 1999], enterovirus 71 [Hayward et al., 1989], ECHO (enteric cytopathogene human orphan) virus type 4 [Kopel et al., 1965], and coxsackievirus [Grist, 1962; Jarcho et al., 1963] are capable of causing a “polio-like syndrome.” Most recently, West Nile virus has also been demonstrated to cause producing flaccid paralysis that localizes by examination, imaging, and electrophysiologically to the anterior horn cell [Solomon and Willison, 2003].

West Nile Poliomyelitis West Nile virus is a single-strand RNA flavivirus that is transmitted between Culex mosquitoes and birds, with incidental infections developing in humans. It is endemic to Africa, the Middle East, and Southwest Asia. An epidemic in New York City in 1999 has led to the virus spreading across North America [Asnis et al., 2000, 2001]. There is a 5- to 15-day incubation period, and infection through blood productions has been documented [Pealer et al., 2003]. Most infections are asymptomatic, with 20% of affected patients developing a mild febrile illness. Symptomatic infections are more common in adults older than 50 years but have been described in children. Systemic features include fever, nausea, vomiting, and headache, and meningoencephalitis is present in 63%. Cerebrospinal fluid studies find elevated protein, normal glucose, and pleocytosis [Petersen and Marfin, 2002]. Children with West Nile virus infection have less severe illnesses [Hayes and O’Leary, 2004]. Neurologic involvement develops in between 1 in 140 and 1 in 320 infections [Horga and Fine, 2001]. Weakness over days may be associated with encephalopathy. The weakness may involve the face and may be asymmetric involving a single limb. Sensory examination is normal, and electrophysiologic studies indicate normal conduction velocities but small compound muscle action potentials and asymmetric denervation changes [Al-Shekhlee and Katirji, 2004; Flaherty et al., 2003; Leis et al., 2002]. MRI changes are not uniformly present but may include cauda equina enhancement, spinal cord parenchymal signal abnormalities, and parenchymal or leptomeningeal signal changes in the brain [Heresi et al., 2004; Jeha et al., 2003]. Although most patients well studied electrophysiologically have localization to the anterior horn cells, a demyelinating, Guillain-Barré– like picture has also been described [Ahmed et al., 2000]. Although neurologic manifestations are less common in children, encephalitis and aseptic meningitis developed in two hospitalized children in the original outbreak [Horga and Fine, 2001]. The polio-like illness has been described in a single child [Heresi et al., 2004]. Pathologic features include perivascular and leptomeningeal inflammation, microglial nodules, and neurono-

Connolly and Iannaccone / Anterior Horn Cell and Cranial Motor Neuron Disease

phagia, involving the temporal lobes and brainstem in patients with meningoencephalitis [Kelley et al., 2003]. In patients with polio-like illness, similar findings are present in the spinal cord [Kelley et al., 2003; Sampson et al., 2003]. Diagnosis is confirmed by demonstrating rising immunoglobulin M titer to the virus. Although this test is sensitive, antibodies to West Nile virus may cross-react with dengue or St. Louis encephalitis, so that positive results should be confirmed using reverse-transcriptase polymerase chain reaction [Horga and Fine, 2001].

A

C

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Transverse Myelitis Associated with Immune-Mediated Processes, Infection, or Both Transverse myelitis associated with infection or associated immune-mediated processes is usually viral in origin, although other microorganisms may be involved. Many of the clinical characteristics of the infectious myelitides are similar, thus allowing for a general discussion. The thoracic area of the cord is most often affected. The illness begins acutely and progresses quickly for 1 to 2 days. Early manifestations of spinal cord dysfunction may follow

B

FIGURE 75-12. Magnetic resonance imaging findings in a child with transverse myelitis. Sagittal (A) and axial (B) T2-weighted images of the cervical cord demonstrate diffuse hyperintense signal from the obex to T4. C, Gadolinium-enhanced sagittal T1-weighted image demonstrates patchy enhancement of the cord over the same area.(From Andronikou S, Albuquerque-Jonathan G, Wilmshurst J, et al. MRI findings in acute idiopathic transverse myelopathy in children. Pediatr Radiol 2003;33:624.)

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or be accompanied by fever, lethargy, malaise, and myalgia. Paresthesias of the legs are common. Back pain at the segmental level of the involved cord frequently occurs. Anterior horn cell disruption in the cervical or lumbar enlargements causes symptoms and signs of lower motor unit dysfunction in the arms and legs. The permanency of the weakness is not predictable from its characteristics. The sequence of involvement most often exhibited is weakness and even flaccidity of the legs with subsequent loss of rectal and bladder sphincter control. Sensory impairment usually extends to the segmental level of motor impairment. The transitional zone between the involved and uninvolved areas may be the site of dysesthesias and hyperalgesia. Deprivation of autonomic innervation below the cord lesion causes loss of sweating. Recovery may be evident within a week of onset; more commonly, improvement may not occur for several weeks or months, if it occurs at all. Unfortunately, flaccidity in limbs innervated caudal to the spinal segment interruption may slowly transform into spasticity after several weeks. Consonant with the appearance of spasticity, hyperreflexia associated with ankle clonus and extensor toe signs may occur. Aggressive corticosteroid therapy may be beneficial. Examination of cerebrospinal fluid usually reveals pleocytosis with a high percentage of lymphocytes. Protein content is usually normal, but a slight increase may occur when the rootlets or peripheral nerves are compromised. Glucose concentration is usually normal. Electromyographic examination may be normal or may demonstrate anterior horn cell dysfunction in the involved cord segments. MRI may depict the degree and extent of the lesion, with T2-weighted images indicating hyperintensity and patchy enhancement with gadolinium (Fig. 75-12) [Andronikou et al., 2003; Awerbuch et al., 1987]. Importantly, the severity of MRI involvement does not correlate with the severity of presentation or outcome [Andronikou et al., 2003]. Numerous viral and other infections, as well as other agents and processes, including immune-mediated phenomena that are associated with inflammation, have been implicated in transverse myelitis and accompanying anterior horn cell involvement. They include acquired multiple sclerosis [Rust, 2000], immune deficiency syndrome [Barakos et al., 1990], infectious mononucleosis [Clevenbergh et al., 1997; Grose and Feorino, 1973; Grose et al., 1975; Junker et al., 1991; Tsutsumi et al., 1994], mumps [Benady et al., 1973; Caksen and Ustunbas, 2003; Nussinovitch et al., 1992; Venketasubramanian, 1997], Mycoplasma pneumoniae infection [Candler and Dale, 2004; Francis et al., 1988; Parisi and Filice, 2001], rabies vaccination [Harrington and Olin, 1971; Label and Batts, 1982], smallpox vaccination [Shyamalan et al., 1964], rubella, rubeola, small pox [Booss and Davis, 2003], and varicella.

TRAUMA-RELATED ANTERIOR HORN CELL DISEASE Incomplete or total transection of the spinal cord may follow birth trauma, falls, motor vehicle crashes, or blows to the spinal column. Neurologic dysfunction, reflected in diverse functional impairment, may result. Fractures or dislocations of the vertebrae are often present. The pattern of clinical involvement is determined by the areas of anatomic disruption. Therefore, signs and symptoms of corticospinal

tract, posterior column, and lateral spinothalamic tract interruption may be present. Limb weakness, consonant with the segmental level of injury, and loss of deep and superficial sensations below that level are seen. Compromise of bladder function is common. Findings characteristic of anterior horn cell dysfunction are evident in the limbs as a sequel to spinal cord trauma in the cervical or lumbosacral enlargements. Neurologic impairment resulting from trauma localized to the anterior horn cell column is unlikely unless the anterior spinal artery is the primary site of injury. Trauma accompanying delivery, particularly in a breech presentation, usually affects the middle and lower cervical segments of the spinal cord [Abroms et al., 1973]. Radiographic documentation of dislocation or fracture of the spinal column is rare. Although flaccidity is present at birth, spasticity of the legs may gradually develop. The distribution of weakness in the arms and hands is variable. The pattern may be such that bilateral Erb’s paralysis is erroneously diagnosed. The combination of compromise of the small muscles of the hands and paresis of the legs should suggest spinal cord involvement rather than brachial plexus injury. Development of pectus excavatum in these patients results from unopposed diaphragmatic respiration by the intercostal muscles. The abdominal muscles are frequently weak, and protrusion of the abdomen occurs. Impairment of bladder function with resultant urinary retention followed by infection may become a major problem. Depending on the level of involvement, Horner’s syndrome may be present. Decreased or absent perspiration below the segmental levels innervated by the upper thoracic nerves may alter temperature homeostasis, resulting in hyperthermia that may prove life threatening if the ambient temperature is high. Providing an air-conditioned environment may be obligatory for these infants. Although motor vehicle crashes are the most common cause of traumatic spinal cord injury in infants and children, etiologies vary by age [Cirak et al., 2004]. Children 2 to 9 years of age had injuries caused most commonly by falls, and children 10 to 14 years of age had sports injuries as the most common cause [Cirak et al., 2004]. In neonates, many reports corroborate the relatively high risk for middle or lower cervical cord trauma during breech delivery when there is hyperextension of the head. In one report, complete transection of the cervical cord occurred in 21% of the 88 patients reviewed. None of the infants delivered by cesarean section sustained spinal cord injury [Abroms et al., 1973]. Other causes of spinal cord injury in the neonatal period, including ischemia, are common associated problems [Ruggieri et al., 1999]. Unfortunately, no specific treatment exists, although physical and occupational therapy may be helpful.

VASCULAR CONDITIONS Anterior Spinal Artery Occlusion The anterior spinal artery originates where the vertebral arteries meet and traverses the anterior median sulcus over the entire course of the spinal cord. The radicular arteries are

Connolly and Iannaccone / Anterior Horn Cell and Cranial Motor Neuron Disease

divided into anterior and posterior radicular arteries. Blood from the anterior radicular arteries that enter with the nerve roots between the third cervical and third lumbar segments flows into the anterior spinal artery (Fig. 75-13). The anterior spinal artery is then further separated into several sulcal branches that pierce the central gray matter, perfuse the anterior horn cells, and then form numerous small penetrating vessels that supply the white matter of the anterior and lateral columns. Because the penetrating branches of the anterior spinal artery are end arteries, their occlusion results in infarction of the anterior half of the spinal cord. The anatomic relationship between the two posterior spinal arteries provides a much different vascular pattern for the posterior cord than the anterior spinal arteries do for the anterior cord. The posterior circulation has a more extensive collateral system. Therefore, occlusion of the posterior spinal arteries usually does not cause severe clinical dysfunction. Steegman reported the clinical effects of obstruction of anterior spinal artery circulation [Steegman, 1952]. Occlusion of the anterior spinal artery often results from arteriosclerotic vascular disease in adults, a condition uncommon in children. However, certain childhood pathologic conditions may lead to similar obstruction of blood flow. Trauma and infectious conditions are among the most common causes of anterior spinal artery insufficiency in children [Blennow and Starck, 1987; Goebel and Muller, 1977]. Other causes include embolism from cardiac disease and thrombosis from hypercoagulable states [Oller-Navarro et al., 1979]. Compromise of blood circulation in rhesus monkeys occurring inferior to the first lumbar vertebra causes the

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development of a lesion that expands from the central gray matter toward the periphery [Fried and Aparicio, 1973]. The most devastated areas of infarction are found in the third and sixth lumbar segments. The region superior to the experimental ligation is relatively unaffected. The central gray matter is entirely infarcted. In the lesions that are associated with the greatest degree of destruction, only a thin rim of the peripheral white matter is preserved. In lesions that are less extensive, the neighboring circumferential white matter is disrupted. This occasional survival of the peripheral white matter and the lateral area of the anterior horn may result from perfusion from pial plexus vessels and vasa corona, both receiving blood supplies from the posterior spinal arteries. As much as 50% of the outer rim of white matter may receive its circulation from these sources [Fried and Aparicio, 1973]. Clinical findings associated with anterior spinal artery occlusion depend on the level at which the artery is occluded [Steegman, 1952]. Obstruction of the anterior spinal artery near its inception from the two vertebral arteries initiates brainstem compromise. Clinical findings may be unilateral but are usually bilateral. Loss of pain and temperature sensation and spastic quadriplegia occur and are commonly associated with some loss of superficial sensation inferior to the involved segmental level. Ischemia or infarction of the cervical spinal cord causes flaccid paralysis of the arms because of disruption of the anterior horn cells in the cervical enlargement. Weakness, muscle atrophy, and absence of deep tendon reflexes in the legs follow occlusion of the anterior spinal artery in the region of the lumbar enlargement.

Posterior spinal artery

Anastomosing arterial plexus

Dorsal nerve root

Posterior branch of radicular artery Spinal nerve

Lateral corticospinal tract

Radicular artery

Lateral spinothalamic tract Anterior branch of radicular artery

Anterior corticospinal tract Anterior spinothalamic tract Sulcal artery Anterior spinal artery

FIGURE 75-13. The anterior spinal artery supplies most of the anterior spinal cord as well as the lateral column area of the cord (darkly shaded area). Some areas of the cord are supplied by both the anterior and posterior circulation (light-gray shaded area); there is variation among individuals. The anterior horn cells and lateral spinothalamic tracts rely on the anterior spinal artery for blood supply.

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Temperature and pain perception are often affected in the legs. Pain and temperature perception can be lost while superficial sensation remains intact (dissociation of sensation) in the presence of certain lesions below the medulla because of the anatomic arrangement. The myelinated tracts subserving temperature and pain sensations cross in the anterior white commissure of the spinal cord; in this area of intersection, they are subject to damage when anterior spinal artery obstruction occurs. However, the tracts responsible for superficial sensation ascend in the cord without crossing and thus are not at risk when the anterior spinal artery is occluded. Bladder function is impaired with occlusion of the anterior spinal artery, and dysfunction may become the most difficult treatment problem. Return of automatic and occasionally voluntary bladder function may occur after several weeks. Tumors and congenital vascular malformations are among the conditions that must be considered in the differential diagnosis of anterior spinal artery interruption in children. Vascular syndromes of the spinal cord may be seen in association with coarctation of the aorta [Darwish et al., 1979; Owens and Swan, 1963; Servais et al., 2001]. During corrective surgery, blood flow must be maintained from the proximal to the distal portions of the aorta. Surgical anastomosis requires removal of the stenotic section of the aorta and establishment of an adequate anastomosis. One and occasionally two radicular arteries in the thoracic region originate in the aorta; they in turn provide blood flow for the anterior spinal artery through radicular branches. If the radicular artery is cut or clamped for a significant period during surgery, clinical findings of anterior spinal artery compromise may develop [Weenink and Smilde, 1964]. Sensory impairment may initially be severe after ischemia induced during surgery but tends to relent in the first few postoperative weeks; unfortunately, the motor deficits often remain. The deficits appear to mirror anterior horn cell dysfunction. This pattern may reflect the fact that the anterior horn cells are in the region of greatest oxidative metabolic dependency in the spinal cord [Dodson and Landau, 1973]. The anterior spinal artery syndrome has been reported with coarctation of the aorta in children who have not had surgical correction [Weenink and Smilde, 1964].

Spinal Cord Vascular Anomalies Although arteriovenous malformations of the spinal cord are rare, symptoms during the first two decades of life develop in 20% of patients [Rodesch et al., 2004]. Of the 30 children in one large series, 21 presented with hemorrhage. In 11 of these, hematomyelia developed, and in 10, the hemorrhage was subarachnoid. Twenty of the 30 children had nidustype arteriovenous malformations, and 10 had fistulous type (Fig. 75-14). The fistulous-type shunts were divided into microarteriovenous and macroarteriovenous fistulas. Five of the six with macroarteriovenous fistulas had hereditary hemorrhagic telengiectasia [Rodesch et al., 2004]. Infarction is accompanied by pain in the back or abdomen; the loss of strength and sensation in the legs may develop gradually or suddenly. The lower extremities become flaccid over the next 12 to 24 hours, and bladder control ceases [Buchanan and Walker, 1941]. During the next few weeks, the leg flaccidity grad-

FIGURE 75-14. Angiogram of 11-year-old child with nidus-type arteriovenous malformation located at thoracic level 4. The lesion (asterisk) is supplied by a radiculomedullary artery (arrowheads), participating in the continuity of the anterior spinal axis (open arrows). The nidus drains through a radicular vein (arrows) toward the upper thoracic epidural plexuses. (From Rodesch G, Hurth M, Alvarez H, et al. Angio-architecture of spinal cord arteriovenous shunts at presentation. Clinical correlations in adults and children. The Bicetre experience on 155 consecutive patients seen between 1981–1999. Acta Neurochir [Wien] 2004;146:217.)

ually relents, only to be replaced by spasticity. Priapism, which may be intractable, may occur. Imaging studies and surgical exploration demonstrate a large mass of pulsating vessels in the spinal canal. Despite anterior horn cell compromise, concurrent impairment of the corticospinal and spinothalamic tracts results in a clinical picture primarily of loss of temperature and pain perception and of upper motor unit dysfunction manifested by acute flaccidity that evolves into spasticity after several weeks. Lumbar puncture reveals normal cerebrospinal fluid pressure. The cerebrospinal fluid may be xanthochromic. Normal cerebrospinal fluid flow is often obstructed, with resultant marked elevation of protein content. Myelography may not faithfully depict the extent of the lesion. Angiography or magnetic resonance angiogram may be necessary for adequate visualization of the arteriovenous malformation [Pattany et al., 2003; Tobin and Layton, 1976]. Based on angiography, three types of lesions have been described: single coiled vessel, glomus, and juvenile. CT and MRI may

Connolly and Iannaccone / Anterior Horn Cell and Cranial Motor Neuron Disease

be most useful in delineating the vascular lesions. The relative benefit of surgery is determined by such factors as residual damage, number of feeding vessels, and extent and pattern of the abnormal vessels within the mass. ACKNOWLEDGMENT We would like to thank Dr. Alan Pestronk of the Neuromuscular Disease Center, Washington University School of Medicine, St. Louis, MO. (World Wide Web URL: http://www.neuro.wustl. edu/neuromuscular/.)

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CHAPTER 76

Peripheral Neuropathies Stephen A. Smith and Robert Ouvrier

Disorders of peripheral nerves may be considered acute or chronic, divided by the type of peripheral nerve involved (primarily motor, sensory, or autonomic), or classified as acquired or hereditary. Some neuropathies are radicular in distribution. Pathologically, neuropathies are demyelinating or axonal, depending on whether the main disruption involves the axon or the myelin supported by the Schwann cell. This chapter discusses neuropathies occurring in children, and categorization is by disease.

ANATOMY The peripheral nervous system is made up of cranial nerves III through XII, the spinal roots, the nerve plexuses, the peripheral nerves, and the autonomic ganglia. (The autonomic nervous system is addressed separately and is not discussed in this chapter.) Neuronal cell bodies subserving the nerves in the peripheral nervous system reside in the brainstem, anterior horn cells of the spinal cord, intermediolateral cell column where the autonomic system originates, and the dorsal root ganglia for afferent sensory function. Peripheral nerves innervate all skeletal muscles through large myelinated nerve fibers. Sensory input from skin, joints, and muscles is transmitted through a combination of unmyelinated and myelinated nerve fibers from the periphery to the central nervous system (CNS). The outer connective tissue sheath of a peripheral nerve, the epineurium, encases bundles of nerves in fascicles. Each fascicle has a sheath termed the perineurium. Myelinated and unmyelinated nerve fibers surrounded by collagenous fibers, the endoneurium, are present in fascicles (Fig. 76-1). Peripheral nerves are very vascular, with arteries and arterioles in the epineurium, arterioles in the perineurium, and primarily capillaries in the endoneurium. The venous system is similarly represented. Fetal nerve is initially unmyelinated, with multiple nerve fibers contained within single Schwann cell investments. By 20 weeks of gestation, there are many more Schwann cells, and myelin is beginning to form [Davison et al., 1973]. The biochemical composition of the peripheral nerve becomes more complicated after 20 weeks. Myelination continues after birth. The perineurium creates a diffusion barrier responsible for the maintenance of endoneurial homeostasis. The perineurium matures relatively late during human peripheral nerve development [Pummi et al., 2004]. Evaluation of peripheral nerve diseases includes obtaining a clear history of the distribution and rate of progression of the condition; conducting an appropriate examination; obtaining an electromyogram with nerve conduction velocities, amplitudes, and latencies plus indicated muscle needle

electrode study; and often performing a sural nerve biopsy. Many peripheral neuropathies are familial, and other family members may need to be studied.

Facial Nerve Paralysis (Bell’s Palsy) Acute dysfunction of cranial nerve VII caused by lesions of the facial nerve nucleus in the pons or axial or extra-axial facial nerve is called Bell’s palsy. The result is partial or complete paralysis of the upper and lower face muscles. Bell’s palsy most often results from edema and inflammation of the nerve as it traverses the facial canal within the temporal bone. Cranial nerve VII is a complex nerve that has motor, sensory, and autonomic components (Fig. 76-2). The nonmotor functions of the facial nerve are mediated by parasympathetic afferent fibers, which innervate lacrimal and salivary glands; efferent fibers, which subserve taste; and other fibers that mediate the auditory reflex. Motor functions are subserved by somatic afferent fibers innervating muscle fibers of facial movement. Lesions of the facial nerve nucleus and nerve distal to the nucleus result in paralysis of upper (forehead) and lower facial muscles. Because bihemispheral pathways from the motor cortex extend to the facial nerve nuclei subserving frontalis and orbicularis oculi muscles, a lesion in one cerebral hemisphere causes facial weakness confined strictly to the lower face and spares forehead muscles. This condition is termed central facial nerve palsy. It is important to ascertain whether facial paralysis is due to upper or lower motor unit involvement before the diagnosis of Bell’s palsy is considered. When forehead muscles are involved, a lower motor lesion of the facial nerve or peripheral facial nerve palsy is present.

Clinical Features The incidence of Bell’s palsy is 2.7 per 100,000 below the age of 10 years and 10.1 per 100,000 during the second decade of life [Katusik et al., 1986]. Female and male incidence is equal. Ear pain near the mastoid process is the first manifestation of impending facial nerve involvement half of the time. Unilateral inability to close the eyelid and maintain normal facial movement is the initial indication of motor involvement. Facial weakness develops rapidly over several hours to 3 days, resulting in paresis to complete paralysis. Bell’s palsy commonly follows an upper respiratory tract infection, indicating possible postinfectious demyelination. Drinking and eating are impaired because of the inability to close the mouth on the involved side. Depending on the site of facial nerve involvement (Table 76-1; see Fig. 76-2), lacrimation may be decreased and taste distorted.

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A

B

FIGURE 76-1. Normal sural nerve in an infant. A, Low-power view showing part of the perineurium surrounding a nerve fascicle and unmyelinated and myelinated nerve fibers (×1980). B, Higher-power view showing multiple unmyelinated nerve fibers invested by Schwann cells and individual myelinated fibers with Schwann cell investment (×10,800).

Sensory

Facial nerve nucleus in pons

1.

Somatic motor Autonomic motor

2.

n atio

Petrosal nerve

S a li v

a ti

on

s Ta

t

expr e

Chorda tympani

c ial

Stapedius muscle and nerve

Fa

4.

e

ssion

Geniculate ganglion

3.

L

Internal auditory meatus

rim ac

Tympanic membrane

5. 6.

Styloid foramen

FIGURE 76-2 Schematic pathway of the facial nerve (cranial nerve VII). (Modified from Haymaker W. Bing’s local diagnosis in neurological diseases, 15th ed. St Louis: Mosby, 1969; Rasmussen AT. The principal nervous pathways. New York: Macmillan, 1951; and Swaiman KF, Wright FS. Pediatric neuromuscular diseases. St Louis: Mosby, 1979.)

Taste sensation is evaluated by alternately applying solutions of sugar and salt to the anterior edge of the tongue on the involved side while holding the tongue with a piece of gauze. The tongue should not be retracted during the exam-

ination because the solutions will intermix. Lacrimation may be reduced on the ipsilateral side. However, if the parasympathetic pathways of lacrimation are intact, excessive tearing can occur from corneal irritation. Diminished lacri-

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TABLE 76-1 Clinical Localization of Facial Nerve Lesions ANATOMIC SITE*

FACIAL MOVEMENT

LACRIMATION

TASTE

SALIVATION

HYPERACUSIS

Nucleus (1) Pons to internal auditory meatus (2) Geniculate ganglion (3) Ganglion to stapedius nerve (4) Stapedius nerve to chorda tympani (5) Below chorda tympani (6)

Defective Defective Defective Defective Defective Defective

Normal Defective Defective Normal Normal Normal

Normal Normal Defective Defective Defective Normal

Normal Defective Defective Defective Defective Normal

Present Present Present Present Absent Absent

*Numbers refer to Figure 76-2.

mation may be determined by hooking filter paper over both lower eyelid margins and observing decreased wetting of the paper on the involved side over 5 minutes (Schirmer test). Stapedius nerve function is evaluated by audiologic study. The differential diagnosis of facial paralysis includes trauma, acute and chronic infections of the inner ear, herpes simplex infection, herpes zoster infection, Mycoplasma pneumoniae infection [Klar et al., 1985], Epstein-Barr virus infection [Andersson and Sterner, 1985], and Lyme disease (Borrelia species infection) (Box 76-1). Hypertension may be responsible for an acute facial paresis resembling Bell’s palsy [Lloyd et al., 1966]. Melkersson-Rosenthal and Möbius’ syndromes have facial paralysis. Guillain-Barré syndrome, motor neuron disorders, myasthenia gravis, various myopathies, leprosy, and Tangier disease may cause facial paresis. In rare circumstances, Bell’s palsy can present bilaterally in children, although one side is usually more involved than the other. The more-affected side usually is paralyzed first, and the less-involved side by the next day. Bilateral facial nerve palsy is often associated with Guillain-Barré syndrome. Bilateral, congenital facial paralysis, usually in conjunction with ophthalmoplegia involving cranial nerve VI, presents in the newborn as Möbius’ syndrome. The condition is the result of aplasia or hypoplasia of cranial nerves and nuclei VI and VII [Jaradeh et al., 1996]. Muscles innervated by other cranial nerves may be involved. Arthrogryposis may be present. Mental retardation may be diagnosed later. Möbius’ syndrome may be sporadic or inherited as a dominant condition linked to chromosomes 13q12.2-13 or 3q [Kremer et al., 1996; Nishikawa et al., 1997]. Differential diagnosis includes traumatic delivery with skull fracture and injury to the nerve in the facial canal, sacral pressure on the facial nerve during delivery, or pressure over the parotid area from forceps application with nerve compression. Möbius’ syndrome may be related in some instances to maternal ingestion of ergotamine in early pregnancy [Smets et al., 2004]. Simple asymmetry of facial expression when infants and children cry is common. A rare syndrome, the cardiofacial syndrome, referred to as Cayler’s syndrome, is due to congenital hypoplasia of the depressor anguli oris causing the asymmetric crying facies syndrome. Unilateral partial lower facial weakness is noted in infants when smiling or crying. The syndrome is associated with congenital heart disease [Caksen et al., 1996; Cayler et al., 1971; Nelson and Eng, 1972; Punal et al., 2001]. Anomalies of the head and neck, heart, skeleton, genitourinary tract, and CNS accompany the syndrome [Lin et al., 1997]. Cardiofacial syndrome links to chromosome 22q11.2, including in one infant with-

out cardiac involvement and in another with hypoparathyroidism [Giannotti and Mingarelli, 1994; Lindsay et al., 1995; Stewart and Smith, 1997]. Frameshift mutation of the EYA1 gene has been described [Shimasaki et al., 2004]. Most children with asymmetric crying facies are otherwise normal.

Laboratory Findings Uncomplicated facial palsy that resolves relatively quickly does not need detailed evaluation. Palsy that persists or seems atypical requires study. Evaluation for infection is appropriate, but peripheral leukocyte and differential counts and erythrocyte sedimentation rate are usually normal. Cerebrospinal fluid studies may show pleocytosis and blood-brain barrier alterations in Lyme disease (Borrelia species infection) [Roberg et al., 1991]. Imaging of the cranium is performed to exclude skull fracture, osteomyelitis, mastoiditis, increased intracranial pressure, calcification, and osteopetrosis. Magnetic resonance imaging (MRI) has been used in adults to predict the outcome of acute facial nerve palsy during the first few days after onset of symptoms [Kress et al., 2004]. The time to recovery from onset may increase from 6 to 14 weeks if enhancement on postcontrast images is present [Yetiser et al., 2003]. MRI can be used in children to find rare tumors invading the facial nerve [Koerbel el al., 2003]. Small lesions inside the temporal bone and at the cerebellopontine angle can be detected using gadolinium-enhanced MRI [Becelli et al., 2003]. Electrodiagnostic techniques may be useful in assessing the severity of facial nerve involvement and predicting the outcome. These studies include determination of nerve conduction velocity [Langworth and Taverner, 1963], detection of the level or threshold of response to stimulation [Campbell et al., 1962; Devi et al., 1978], nerve conduction latencies, and electrical stimulation of the tongue [Peiris and Miles, 1965]. Serial studies may be helpful [Fisch, 1984]. Nerve degeneration can be detected electrically by 72 hours after onset of paralysis. Because Bell’s palsy may be a component of a more widespread disease affecting other cranial and peripheral nerves, obtaining a complete electromyographic evaluation and extremity nerve conduction velocities is sometimes helpful [Bueri et al., 1984].

Treatment and Prognosis The prognosis for recovery in children is good [Singhi and Jain, 2003]. Most children do not need drug therapy

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Box 76-1 FACIAL WEAKNESS IN CHILDHOOD Congenital, Structural Chiari malformation Depressor anguli oris muscle absence (cardiofacial syndrome) Inner ear or facial nerve malformations Möbius’ syndrome Syringobulbia Genetic Facioscapulohumeral dystrophy Familial cranial neuropathy (recurrent) Fazio-Londe disease Myasthenia gravis (non–immune mediated) Myotonic dystrophy Nemaline myopathy Infectious, Inflammatory Basilar meningitis Bell’s palsy Epstein-Barr infection (infectious mononucleosis) Guillain-Barré syndrome Miller-Fisher syndrome Mycoplasma pneumoniae infection Lyme disease (Borrelia species infection) Otitis media and mastoiditis Parotitis Poliomyelitis Ramsay Hunt syndrome (herpes zoster) Sarcoidosis Trichinosis Tuberculosis Trauma, Nerve Compression Forceps pressure during delivery Cleidocranial dysostosis Histiocytosis X Hyperostosis cranialis interna Increased intracranial pressure Petrous bone fracture Pressure from maternal sacrum Metabolic Conditions Hyperparathyroidism Hypothyroidism Idiopathic infantile hypercalcemia Osteopetrosis Neoplasms Brainstem glioma Parotid gland tumors Vascular Arterial hypertension Vascular syndromes of the cranial nerves Other Idiopathic cranial neuropathy Melkersson-Rosenthal syndrome Multiple sclerosis Myasthenia gravis (immune mediated) Myasthenia gravis (transient neonatal)

[Salman and MacGregor, 2001]. A number of drugs have been used, particularly steroids. Surgical decompression has been recommended in some patients when progressive paralysis and thus nerve degeneration occur [Jenkins et al., 1985]. Prednisone is the most widely used drug; it is given in high dosage for 1 week, followed by tapering the second week. It should be started within 1 week of disease onset. The degree to which steroid therapy can alter the natural history of Bell’s palsy is unknown, although it appears to be more helpful in completely paralyzed than paretic individuals [Wolf et al., 1978]. Most children recover completely without treatment. Recovery usually begins within 2 to 4 weeks, reaching its maximum within 6 to 12 months. Wetting solutions to maintain corneal moisture and an eye patch for protection may be needed when the child cannot close the eye.

Recurrent Facial Paralysis Recurrent unilateral facial paralysis indicates the need to exclude a neoplasm or vascular malformation. The Melkersson-Rosenthal syndrome is a rare cause of recurrent facial nerve paralysis [Graham and Kemink, 1986; Rogers, 1996]. It is a dominant syndrome with incomplete penetrance linked to chromosome 9p11. Onset is usually before 16 years of age. This syndrome consists of recurrent unilateral or bilateral facial paralysis accompanied by orofacial edema manifested as a fissured, reddish-brown appearance of swollen lips or facial edema. Fissured tongue (lingua plicata) is present in up to half of patients. Facial nerve decompression may be recommended.

BRACHIAL PLEXUS Nerve roots from the fifth cervical through the first thoracic nerves form the three primary trunks of the brachial plexus. Once formed, they divide promptly into anterior and posterior divisions (Fig. 76-3). The posterior divisions join to form the posterior cord, which gives rise to the upper and lower subscapular, thoracodorsal, axillary, and radial nerves. The anterior divisions of the fifth, sixth, and seventh nerves form the lateral cord, and the anterior divisions of the eighth cervical and first thoracic nerves form the medial cord. The lateral cord subsequently gives rise to the musculocutaneous nerve and a branch to the coracobrachialis. The medial cord gives rise to the ulnar, medial antebrachial cutaneous, and medial brachial cutaneous nerves. Additional branches from the lateral and medial cords unite to form the median nerve.

Injury Birth-related brachial plexus injuries occur in 0.5 to 1 of 1000 live births. Although traditionally thought to be associated with excessive traction to the affected extremity during breech delivery or traction to the head and neck during vertex delivery [Adler and Patterson, 1967], brachial plexus injuries can occur in the absence of fetal trauma [Ouzounian et al., 1997]. A recent study found that half of cases of Erb’s palsy occur in normal-sized infants without trauma at delivery [Graham et al., 1997]. Brachial plexus injury is observed often in infants with shoulder dystocia [Greenwald et al.,

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Roots Tr. Div

Long thoracic nerve C5,C6 Serratus anterior Posterior cord Medial cord

Cord

C5 C6 C7 C8 T1

Dorsal scapular C5—rhomboid Suprascapular nerve C5, C6—supraspinatus; infraspinatus Lateral cord Lateral pectoral C5-C7—pectoralis major (clavicular portion) Axillary nerve C5, C6—deltoid, teres minor Musculocutaneous nerve C5-C7—biceps; brachialis; coracobrachialis

Medial pectoral—pectoralis major (sternal portion) Medial brachial cutaneous Medial antebrachial cutaneous

Roots

Radial nerve C5-C8 (light blue) Extensors of forearm, wrist, and fingers; supinator

Tr. Div Cord

Median nerve C5-T1 (dark blue) Medial head C8, T1—adductor pollicis brevis; opponens pollicis; flexor pollicis longus; I and II lumbricals Lateral head C5-C7—flexor carpi radialis; palmaris longus; flexor digitorum sublimis and profundus (II, III); pronator teres

Ulnar nerve C7-T1 (white) Intrinsic muscles of the hand; hypothenar eminence; flexor carpi ulnaris; flexor digitorum profundus IV and V FIGURE 76-3. Relationship of the brachial plexus to peripheral nerves of the shoulder and arm. Note the formation of the brachial plexus from nerve roots of spinal segments C5 to T1. The brachial plexus is divided into roots, trunks, divisions, and cords. The origin of the peripheral nerves and their muscle innervations are listed. The median nerve has a lateral head from the lateral cord (C5, C6, C7) and a medial head from the medial cord (C8, T1). The ulnar nerve also arises from the medial cord, whereas the radial nerve comes directly from the posterior cord.

1984; Rossi et al., 1982; Tada et al., 1984], although other studies question this assumption [Ecker et al., 1997; Graham et al., 1997]. Birth-related brachial plexus injury is associated with clavicle fracture in 10% of cases and humerus fracture in 10%. The most common brachial plexus injury is Erb’s palsy, which composes 80% to 90% of newborn brachial plexus injuries. Damage to the fifth and sixth cervical nerves or the upper trunk of the brachial plexus results in paralysis of the upper arm. The infant with this condition typically lies with the humerus adducted and internally rotated with the elbow extended, forearm pronated, and wrist flexed. The deltoid, biceps, brachialis, supinator, and extensors of the wrist and finger muscles are paralyzed (Fig. 76-4). The biceps and radioperiosteal reflexes are absent. Unless there has been avulsion of nerve roots, recovery occurs in part, if not completely. It is important to protect the arm and brachial plexus from further injury by pinning the forearm in a sleeve sling in front of the chest. Two to three weeks later, passive range of motion is appropriate to prevent contracture of the shoulder. Although quick recovery may be observed, complete recovery may take many months. Good return of hand and arm function by 6 months is a good prognostic sign [DiTaranto et al., 2004].

Surgery for newborn brachial nerve lesions is becoming more popular, especially when electrophysiologic and neuroimaging data indicate primary injury to the plexus and no nerve root evulsion. Primary nerve reconstruction followed by appropriate tendon transfers provides return of function in select patients [Piatt, 2004; Tonkin et al., 1996]. Injury to the lower trunk of the plexus, involving the eighth cervical nerve and first thoracic nerve, is known as Klumpke’s paralysis. This condition is rare, composing less than 1% of newborn brachial plexus injuries [al-Qattan et al., 1995]. Weakness of the forearm extensors, flexors of the wrist and fingers, and intrinsic muscles of the hand occurs. Horner’s syndrome is often present as a result of involvement of the sympathetic fibers accompanying the first thoracic nerve. The elbow is typically flexed, the forearm is supinated, the wrist is extended, and a clawlike deformity of the hand with hyperextension of the wrist and fingers is present. The triceps reflex may be diminished, and the grasp reflex is usually absent. As with Erb’s palsy, protection of the plexus initially, followed by passive rangeof-motion therapy, in this instance to the wrist and fingers, is appropriate during recovery. The most severe newborn brachial plexus injury occurs when all three trunks of the brachial plexus are involved.

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hand. The outlook for recovery after complete brachial plexus injury is poorer than with isolated upper or lower trunk injury because of the larger distribution of involvement and the usually greater severity of nerve injury. In this circumstance, nerve roots have often been avulsed or nerves in the plexus divided by severe stretching. In up to 10% to 20% of newborn brachial plexus injuries, bilateral involvement is present. Rare instances of brachial neuritis have been reported in children and may be associated with diphtheria-pertussis-tetanus vaccinations [Martin and Weintraub, 1973].

Inherited Conditions

FIGURE 76-4. Erb’s palsy caused by birth injury. The arm position is characteristic. The arm is adducted, with the humerus internally rotated, elbow extended, forearm pronated, and wrist flexed. The fingers are not involved. (Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School, Minneapolis, MN.)

Total brachial plexus involvement is present 10% of the time in newborn injuries. The arm hangs limply from the shoulder with no muscle movement. This is associated with tendon areflexia and decreased sensation over the arm and

A

Recurrent inherited brachial plexus neuritis, referred to as hereditary neuralgic amyotrophy and carried on chromosome 17q24-q25 as a dominantly inherited condition [Guillozet and Mercer, 1973; Wiederholt, 1974], is typically diagnosed in childhood. This recurrent syndrome manifests with pain and is followed by brachial plexus innervated muscle weakness, often including facial paresis. The long thoracic nerve is involved, with scapular winging present. Lumbar plexus involvement may be noted. Tendon reflexes are reduced. Residual weakness may develop after exacerbations. Autonomic nerves are affected [Dunn et al., 1978]. Short stature, hypotelorism, small face and palpebral fissures, prominent epicanthal folds, and syndactyly are part of the syndrome. Axonal loss is demonstrated by electrophysiologic testing. The condition is believed to be an immune complex disease that causes damage to blood vessel walls. In most instances, recovery occurs spontaneously, and there is no specific treatment [Rubin, 2001]. Hereditary neuropathy with liability to pressure palsies may present in children. This autosomal dominantly inherited condition due to a deletion involving the PMP22 gene carried on chromosome 17p11.2-p12 may cause recurrent brachial neuropathy. The condition is painless, demyelination is corroborated electrophysiologically, and recovery is common [Windebank et al., 1995].

B

FIGURE 76-5. Sural nerve biopsy from a 14-year-old male with acute inflammatory demyelinating polyradiculoneuropathy. A, Part of a nerve fascicle demonstrating demyelinating nerve fibers (arrows) and perivascular infiltration (arrowhead) (×1180). B, Perivenular lymphocytic infiltrate (arrow) (×1560).

Smith and Ouvrier / Peripheral Neuropathies

INFLAMMATORY NEUROPATHIES Acute Inflammatory Demyelinating Polyradiculoneuropathy (Guillain-Barré Syndrome) Acute inflammatory demyelinating polyradiculoneuropathy is commonly known as Guillain-Barré syndrome (see Chapter 72). It is an inflammatory, demyelinating disorder of spinal nerve roots and peripheral nerves of acute to subacute onset. Activated cellular and humoral immune mechanisms, induced by an antecedent, presumably viral infection, trigger inflammation and demyelination [Arnason and Soliven, 1993; Asbury et al., 1969; Brechenmacher et al., 1987; Cook and Dowling, 1981; Hartung et al., 1995a; Honavar et al., 1991; Prineas, 1981]. Cytomegalovirus, Epstein-Barr virus, M. pneumoniae infection, vaccinia virus, and Campylobacter jejuni bacterial diarrhea are recognized causes of prodromal illness preceding acute inflammatory demyelinating polyradiculoneuropathy [Hartung et al., 1995b; Kuwabara, 2004; Winer et al., 1988]. An antecedent infectious disease is recognized in 65% of cases 3 days to 6 weeks before the onset of symptoms caused by demyelination [Beghi et al., 1985; Hartung et al., 1995b]. The resultant neuropathy is predominantly motor [Guillain et al., 1916] and is typically accompanied by mild sensory loss and sensory ataxia. Severe sensory deficit is rare [Dawson et al., 1988]. Autonomic involvement occurs in children and may be quite severe for some [Hodson et al., 1984].

Pathology Demyelination and mononuclear cell infiltration of peripheral nerve may be found on nerve biopsy [Honavar et al., 1991; Prineas, 1981]. Varying degrees of edema, endoneurial lymphocytic cell infiltration, and segmental demyelination occur (Fig. 76-5). Macrophage invasion of Schwann cells can be seen ultrastructurally [Brechenmacher et al., 1987]. Spinal roots and proximal and distal nerves display focal and perivenular lymphocytes and macrophages [Hall et al., 1992]. In addition to demyelination, axonal degeneration may be found [Feasby et al., 1993] or may even predominate (acute motor axonal neuropathy) [HaferMacko et al., 1996]. Complement-fixing antibodies to peripheral nerve myelin may be demonstrated in some cases [Koski et al., 1987], but not all patients with acute inflammatory demyelinating polyradiculoneuropathy have immunoglobulin deposits on myelin sheaths [Honavar et al., 1991]. Cerebrospinal fluid protein is elevated within the first week, accompanied by a lack of inflammatory cellular response, with usually less than 10 lymphocytes/mm3.

Clinical Characteristics The overall incidence of acute inflammatory demyelinating polyradiculoneuropathy is 1 to 2 per 100,000 each year; in the population younger than 18 years, the incidence is 0.8 per 100,000 each year [Beghi et al., 1985]. The incidence rate for males is 1.5 times that for females [Koobatian et al., 1992]. Muscle pain may be the initial manifestation of the disease in children, involving the anterior and posterior thighs, buttocks, and lower back [Ropper and Shahani, 1984].

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Pain and paresthesias after infection are quickly followed by symmetric, progressive weakness of extremity and facial muscles. Bladder dysfunction, mental alterations, headache, ataxia, and meningismus may be accompanying features. Tendon reflexes are diminished or lost. The disease may progress for days to several weeks before plateauing, and then improves over a period of months. Weakness may proceed rapidly with complete paralysis, including bulbar paralysis developing within 24 hours of onset. Ventilatory support may be necessary even early in the course of the illness. Eighty percent of patients make an excellent recovery. Autonomic involvement may produce blurred vision, cramping abdominal pain, postural hypotension, cardiac dysrhythmia, and bladder and bowel incontinence. These symptoms may occur transiently in the course of predominantly motor and sensory involvement. Electrophysiologic evaluation usually provides evidence for peripheral nerve demyelination often accompanied by changes indicative of axonal involvement. Distal motor and F wave latencies are prolonged to more than 150% of normal. Nerve conduction velocities are reduced to 70% below normal. Compound motor action potentials are reduced with prolonged terminal dispersions, these being the most common electrophysiologic findings in children [Bradshaw and Jones, 1992]. Children younger than 10 years of age have greater slowing of motor nerve conduction velocities than children older than 10. More profound slowing corresponds to high antibody levels against peripheral nerve myelin during the first week of illness [Rudnicki et al., 1992]. In cases in which the pathologic change is one of mainly axonal degeneration, nerve conduction studies reveal normal or mildly slow conduction with diminished amplitude of compound muscle action potentials. The youngest reported patients are neonates. A 4-month-old child presented with advancing hypotonia [Carroll et al., 1977]. Several other children younger than 6 months of age have been reported. The rate of progression, degree of impairment, and time for improvement vary greatly; however, recovery does not continue after 2 years from onset [Ropper, 1986]. Poor prognosis is related to the need for ventilation and failure to improve after 3 weeks of reaching peak deficit [Winer et al., 1985]. The mortality rate approaches 5% in adults but should be negligible in children; 10% to 15% of adults remain permanently disabled [Arnason, 1984].

Management Because prognosis is usually excellent for spontaneous recovery, the mainstay of treatment is supportive. Mechanical ventilation may be needed, and careful attention to nutritional, fluid, and electrolyte balance is necessary. When paralyzed and ventilated, children are still mentally alert. They need psychologic support from parents and caregivers. The ordeal may be very frightening. Plasmapheresis may be effective if started within 7 days of illness onset [French Cooperative Group, 1987; Greenwood et al., 1984; Guillain-Barré Syndrome Study Group, 1985; Osterman et al., 1984; Smith and Hughes, 1992]. If patients lose the ability to walk unaided, have significant reduction in respiratory capacity, or have bulbar insufficiency, plasmapheresis or intravenous immune globulin

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therapy is indicated. Although most plasmapheresis studies have been performed on adults, a study on children demonstrated shortened recovery time in 5 of 6 children aged 5 to 15 years [Lamont et al., 1991]. A retrospective study documented faster recovery of independent ambulation in 9 children who received plasmapheresis, compared with 14 who did not receive plasmapheresis [Epstein and Sladky, 1990]. Intravenous immune globulin is more convenient in small children and shortens the course of illness [Kleyweg et al., 1988; Sladky, 2004]. In adults, intravenous immune globulin given during the first week is at least as effective as plasmapheresis and may be of greater efficacy [van der Meché et al., 1992]. There is no documented benefit to using both therapies [Bril et al., 1996; Hughes et al., 1996]. Corticosteroids, thought to be of little value, may improve outcome in combination with intravenous immune globulin.

Chronic Inflammatory Demyelinating Polyradiculoneuropathy Chronic inflammatory demyelinating polyradiculopathy was the cause of polyneuropathy in 8.8% to 11.6% of children in two series of childhood polyneuropathy [Ouvrier and McLeod, 1988; Sladky et al., 1986]. A low frequency of antecedent events is described. Precipitous onset of weakness accompanied by sensory loss and diminished tendon reflexes is typical [Nevo et al., 1996; Simmons et al., 1997]. Pain and cranial neuropathies are uncommon. Progressive weakness for 2 months is required for the diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy, although one of five affected children reach their nadir by this time [Simmons et al., 1993]. For some children, a monophasic disease progresses beyond 2 months, and for others, relapses are common.

Pathology Cerebrospinal protein is elevated with a normal cell count. Slowed conduction velocities, prolonged distal latencies,

A

and temporal dispersion are present electrophysiologically. Sural nerve biopsy, if performed, shows demyelination, remyelination, and usually a lymphocytic inflammatory infiltrate. Onion bulb formation indicates chronicity of the condition (Fig. 76-6).

Management Patients, including children, improve with therapy [Colan et al., 1980; Gorson et al., 1997; Nevo et al., 1996; Sladky et al., 1986; Uncini et al., 1991], which most often begins with intravenous immune globulin or, less commonly, plasmapheresis. Plasmapheresis combined with prednisone or prednisone alone has also been used. Sustained recovery is expected with treatment [Simmons et al., 1997], and even without treatment, most children eventually improve.

HEREDITARY NEUROPATHIES About 70% of chronic neuropathies seen in children are hereditary. In Dyck’s classification of these conditions [Dyck, 1984], the broad categories of hereditary motor, hereditary sensory and autonomic, and hereditary motor and sensory neuropathies are subdivided on the basis of clinical, genetic, and (rarely) biochemical characteristics. The main basis for inclusion in one of these three groups is whether the peripheral motor, peripheral sensory, or both are mainly affected. The peripheral motor neuropathies are called the spinal muscular atrophies in other classifications and are described in Chapter 75. The original Dyck classification of the hereditary motor and sensory neuropathies did not allow for the inclusion of autosomal and X-linked recessive forms of hereditary motor and sensory neuropathy types I and II. Nor could it have included the striking recent advances in the understanding of the molecular biology of these disorders. Because the question of classification is in flux, a modified version of Dyck’s classification is included in Tables 76-2 and 76-3.

B

FIGURE 76-6. Sural nerve biopsy from a 5-year-old female with chronic inflammatory demyelinating polyradiculoneuropathy. A, Demyelination of two nerve fibers (arrows) with lymphocytes (L) located nearby (×6100). B, Partial demyelination of a nerve fiber surrounded by redundant Schwann cell elements, including excessive basement membrane. This process represents early onion bulb formation, which develops as the disease progresses (×8400).

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TABLE 76-2 Subclassifications of Charcot-Marie-Tooth (CMT) Syndrome DISORDER (OMIM NO.)

INHERITANCE

CHROMOSOMAL LOCUS

PATHOLOGIC MECHANISM

HISTOPATHOLOGIC FEATURES

CMT 1A (118220)

AD

Chromosome 17, 1.5-Mb duplication at 17p11.2-12

DNA duplication, PMP 22 protein

Sheath hypertrophy, onion bulb formation

CMT 1B (118200)

AD

1q21-23

Duffy linked, myelin Similar to CMT 1A or protein P0 mutation more severe

CMT 1C CMT 1D

AD AR

16p13.1-p12.1 10q21.1-q22.1

CMT 1E (118300)

AD

17p11.2

LITAF missense EGR2/KROX20 mutation PMP22 mutation

CMT 1F

AR, AD

8p21

NEFL mutation

CMT 1

AR

Unknown

CMT X1 (302800)

X-linked AD

Xq13.1

Fewer classic onion bulbs; basal lamina bulbs more frequent; tomacula present Connexin 32 (gap Demyelination and junction protein axonal degeneration; [GJB1] mutation); minimal hypertrophy; NB GJB1 and P0 MNCVs lower than mutations have also normal but faster than been found in CMT CMT 1A 2 patients.

CMT X2 (302801)

X-linked AR

Xp22.2

Unknown

CMT X3 (302802)

X-linked AR

Xq26

Unknown

CMT 2A (118210)

AD

1p35-36

CMT 2B

AD

3q13-q22

CMT 2B1 (605588)

AR

1q21.2-3

Kinesin family Axonal degeneration member gene 1B (KIF1B) mutation; mitofusin 2 (MFN2) RAB7 missense Large and small fiber loss LMNA missense

CMT 2B2 (605589)

AR

19q13.3

Unknown

Linked to chromosome 12

Unknown

CMT 2C (606071) CMT 2D (601472)

AD

7p15

GARS mutation

CMT 2E (607684) CMT 2F (606595)

AD AD

8p21 7q11-q21

CMT 2G (607706)

AR

8q13-q21.1

NEFL gene mutation HSPB1/ HSP27; small heat-shock protein GDAP1 missense

CMT 2H (607731)

AR

8q21.3

GDAP1 missense

CMT 2I (607677)

AD

1q22, 8q21.3

CMT 2J (607736)

AR

1q22

MPZ (P0) mutation GDAP1 missense MPZ (P0) mutation

CLINICAL FEATURES Distal weakness; mild functional impairment; slowing of NCVs Similar to CMT 1A or more severe (see Dejerine-Sottas syndrome)

Associated with sensorineural deafness Early onset, severe; is confused with Dejerine-Sottas syndrome Early onset, similar to CMT 1A but more complex X-linked: absence of male-to-male transmission; females mildly affected; males more severely affected than in CMT 1A Rare X-linked: only 1 family affected; females very mildly affected As for CMT X2 but 2 families studied Normal NCVs; later onset than CMT 1A Single kindred; sensory features Confined to a small Moroccan pedigree Confined to a small inbred Costa Rican pedigree Severe, including respiratory failure and vocal weakness Clinically similar to CMT 2A; spinal atrophy Few kindreds

Several kindreds, some severe with vocal weakness Pyramidal features; single Tunisian kindred Late onset Sensory and pupillary abnormalities continued

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TABLE 76-2, cont’d Subclassifications of Charcot-Marie-Tooth (CMT) Syndrome DISORDER (OMIM NO.)

INHERITANCE

CHROMOSOMAL LOCUS

PATHOLOGIC MECHANISM

HISTOPATHOLOGIC FEATURES

CMT 2K (607831)

AR

8q13-q21.1

GDAP1 missense

CMT 3 (145900) (Dejerine-Sottas syndrome)

AR, AD

19q13.1, 17p11.2, 1q22 (a number of specific allelic variants have been reported)

Periaxin (PRX), Hypomyelination; basal PMP22, MPZ (P0), lamina onion bulb EGR2 formation; MNCVs < 10 m/sec

CMT 4A (214400)

AR, occasionally AD

8q13-q21.1

GDAP1 mutation

Axonal degeneration

CMT 4B1 (601382)

AR

11q22

CMT 4B2 (604563)

AR

11p15

CMT 4C (601596)

AR

5q32

MTMR2 gene mutation MTMR 13 (SBF2) mutation KIAA1985 mutation

Congenital hypomyelination; excessive myelin out-folding; onion bulbs; slow NCVs

CMT 4D (601455) Lom type

AR

8q24.3

NDRG1 mutation

CMT 4E (605253)

AR

10q21-22

CMT 4F (145900)

AR

19q13

EGR2 (Krox20 mouse homolog) mutation Periaxin (PRX)

CMT 5 (600631)

AD

Not known; linkages excluded Unknown at chromosomes 1, 3, 7, 10, 17

Axonal degeneration

CMT intermediate A (608340)

AR

8q13-q21.1

GDAP1 mutation

Intermediate NCVs

CMT intermediate AD B (606482) CMT intermediate AD C (608323) CMT intermediate AD D (607791) Hereditary neuropathy with liability to pressure palsies (HNPP) (162500)

19p13.2-p12

Unknown

1p35

Unknown

1q22-q23

MPZ (P0) mutation

Chromosome 17, 1.5-Mb deletion at 17p11.2-12

Roussy-Lévy syndrome (180800)

Chromosome 17, 500-Kb partial duplication at 17p11.2; 1q22-q23

DNA deletion (or Presence of tomaculous Acute onset of weakness missense mutation) changes on biopsy and sensory loss affecting PMP 22 with uncompacted following nerve protein synthesis myelin; mild slowing trauma; often the of MNCVs, but functional deficit is conduction block may temporary, returning be present to baseline levels over time; may be episodic PMP22 or MPZ (P0) Similar features to CMT mutation 1A but with associated gait ataxia and tremor; in later life may suffer neuropathic foot ulcers

CLINICAL FEATURES Single Moroccan kindred Clinically severe; infantile onset; global delay; cranial and spinal nerve involvement (shares features with severe CMT 1A, especially in the tetrasomic homozygous variants) Early and severe onset; complete distal (to elbows and knees) paralysis by teens; often nonambulatory Clinically mild to severe; early distal weakness and pes cavus; cranial nerve signs; confined to small pedigrees; glaucoma in CMT 4B2 Closed gypsy pedigree; associated with deafness See CMT 3 (Dejerine-Sottas syndrome) Two families; pyramidal features; marked leg cramps; late onset Two Turkish families; mixed axonal and demyelinating features; fairly mild Two unrelated families

AD, autosomal dominant; AR, autosomal recessive; MNCV, motor nerve conduction velocity; NCV, nerve conduction velocity. Data from Auer-Grumbach and Strasser-Fuchs, 1998; Chance, 2001; Murakami et al., 1996; Ouvrier, 1996; Vance et al., 2000; and the National Institutes of Health On-line Mendelian Inheritance in Man database.

Smith and Ouvrier / Peripheral Neuropathies

TABLE 76-3 Hereditary Sensory and Autonomic Neuropathies TYPE

INHERITANCE

COMMENTS

I II III IV

Autosomal dominant Autosomal recessive Autosomal recessive Autosomal recessive

Linked to 9q22.1-22.3 — Riley-Day syndrome Possibly due to TRKA receptor defect

V

Possibly autosomal recessive —

Other

— —

Note: The term CMT 3 should be reserved for hereditary neuropathies in which hypomyelination is the dominant feature. This would include congenital hypomyelinating neuropathy, Dejerine-Sottas syndrome, and congenital amyelinating neuropathy.

Hereditary Motor and Sensory Neuropathy Hereditary motor and sensory neuropathy types I and II are often referred to as Charcot-Marie-Tooth disease. CharcotMarie-Tooth disease is characterized by weakness of the extremities and foot deformities, including pes cavus and permanently flexed “hammer” toes. Variable loss of sensation is present. This condition is also referred to as peroneal muscular atrophy because of characteristic muscle wasting and weakness in legs early in the course of the illness. The distinction between types I and II is discussed later. Charcot-Marie-Tooth disease is present throughout the world, with an estimated prevalence of up to 40 per 100,000. In most countries, hereditary motor and sensory neuropathy type I is three or four times more common than type II disease.

Type I Hereditary motor and sensory neuropathy type I is a heterogeneous disorder causing a progressive motor and sensory demyelinating neuropathy. It is a dominantly inherited disorder with onset in the first or second decade of life. In

A

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certain families, the defective gene maps to chromosome 1 [Chance et al., 1990; Lebo et al., 1990], where it has been found to cause mutations of myelin protein zero (P0), the most abundant protein in peripheral myelin [Hayasaka et al., 1993]. Much more commonly, the defective gene links to the short arm of chromosome 17 in the region 17p11.2 [Middleton-Price et al., 1990; Raeymakers et al., 1989; Vance et al., 1989]. In most type I families, affected members have a 1.5 million base-pair tandem DNA duplication at that site [Hallam et al., 1992; Lupski et al., 1991; Raeymakers et al., 1991]. This region contains the gene for the myelin protein PMP22, increased amounts of which may lead to excessive or faulty production of myelin. Rare cases of hereditary motor and sensory neuropathy type I have been due to point mutations of the PMP22 gene. The disease carried on chromosome 17 is designated type Ia, and the condition carried on chromosome 1 is called type Ib. Although cases of hereditary motor and sensory neuropathy types Ia and Ib caused by point mutations tend to be more severely affected than cases caused by the duplication on chromosome 17, the frequent exceptions to the rule make it difficult to separate these subtypes on clinical or neurophysiologic grounds. Cases of autosomal-dominant hereditary motor and sensory neuropathy type I exist in which no abnormalities of the PMP22 or MPZ gene can be demonstrated. Hereditary motor and sensory neuropathy type Ic is due to mutations of the LITAF gene, whereas type Id is due to EGR2 mutation and type If is due to mutation in the neurofilament light-chain gene. There is also a “spinal” form of Charcot-Marie-Tooth disease, known as distal spinal muscular atrophy, in which degeneration of specific anterior horn cells leads to a clinical picture similar to hereditary motor and sensory neuropathy type I or II but without any sensory nerve involvement.

PATHOLOGY The peripheral nerves in hereditary motor and sensory neuropathy type I are often easily palpated because they are hypertrophied as a result of excessive Schwann cell and

B

FIGURE 76-7. Sural nerve biopsy from a 15-year-old female with hereditary motor and sensory neuropathy type I, the hypertrophic form of Charcot-Marie-Tooth disease. A, Demyelination and axonal disruption are noted (×17,400). B, Typical onion bulb formation with a myelinated nerve fiber surrounded by redundant Schwann cell investments, basement laminae, and collagen (×10,100).

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fibroblast activity. This situation creates redundant wrappings of Schwann cell investments around nerve fibers accompanied by excessive collagen deposition, known as onion bulbs [Thomas et al., 1974]. Sural nerve biopsies disclose a loss of myelinated fibers, especially the large myelinated fibers. With advancing age, there is progressive reduction in the myelinated fiber density, an increased number of fibers undergoing demyelination, and increased frequency of onion bulb formations [Low et al., 1978]. In this setting, onion bulb formations are the result of repeated episodes of demyelination and remyelination (Fig. 76-7). Some loss of axonal neurotubules and filaments may eventually be observed, indicating that, although demyelination is predominant, some axonal degeneration is part of the disease process and is responsible for the progression of the weakness and wasting [Nordborg et al., 1984].

CLINICAL CHARACTERISTICS The disease is typically recognized during the first decade of life or in early adolescence, but it may be evident even at birth. A large variation in the age of onset and severity of disease among individuals in the same family has sometimes been observed [Birouk et al., 1997; Hagberg and Lyon, 1981]. Early onset, although uncommon, usually results in greater disability later in life than that seen in individuals with later onset, who are often able to ambulate and work until old age. The disease presents with distal lower extremity muscle wasting and weakness, accompanied by development of pes cavus. Progressive weakness of the tibialis anterior and peroneal muscles, which are more involved clinically than the tibialis posterior muscle, is associated with the development of the high arch of the foot or pes cavus. The hammer toe deformities occur as the long toe extensors attempt to make up for the foot dorsiflexor (tibialis anterior) atrophy and weakness. Gradual loss of sensation is noted, especially loss of proprioception, which causes unsteady gait in darkness and a positive Romberg sign. Vibration and big toe position sense are both diminished. Tendon reflexes are usually lost early at the ankle and later at the knee. Muscle wasting and weakness slowly spread proximally, so that atrophy of the medial rectus muscle and distal rectus femoris in the quadriceps group becomes apparent. Classically, the leg assumes a storklike appearance, with little motor function remaining, but this is rare in children with hereditary motor and sensory neuropathy type I. As the lower extremities become more involved, atrophy of the hand intrinsic muscles with accompanying weakness is recognized, which leads to difficulty with fine motor skills, including writing. Distal sensory loss soon becomes evident in the upper extremities. Kyphosis and scoliosis develop in about 10% of cases. Variability of expression among families makes it difficult to describe a uniform rate of change. Typically, younger age of clinical recognition and more rapid progression in a parent are associated with similar expression in affected children. Some individuals require wheelchair assistance because of severe muscle weakness. Much more commonly, patients remain ambulatory, often assisted by leg braces or corrective foot surgery at the end of the second decade or in the third decade. The condition is compatible with normal longevity.

CLINICAL NEUROPHYSIOLOGY Motor and sensory conduction velocity is within the “demyelinating” range and is thus less than 60% of normal values in infants; in patients older than 3 years, it is less than 38 m/second in all peripheral nerves. Conduction velocity changes little with increasing age, but there is a progressive reduction in the amplitude of the evoked muscle action potential, indicating axonal loss [Roy et al., 1989].

GENETICS Hereditary motor and sensory neuropathy types Ia through If are dominantly inherited. In addition, autosomal recessive [Gabreels-Festen et al., 1992; Harding and Thomas, 1980] and X-linked forms of a similar disorder exist [Hahn et al., 1990; Rozear et al., 1987]. Autosomal-recessive forms, which are designated Charcot-Marie-Tooth disease type 4, tend to have an earlier onset and a higher incidence of ataxia, complete areflexia, and kyphoscoliosis than dominant types. Several recessive varieties have been cloned or linked to specific chromosomal regions, such as in inbred Tunisian (chromosome 8q13-21) [Ben Othmane et al., 1993], Bulgarian (chromosome 8q24) [Kalaydjieva et al., 1996], and Algerian (chromosome 5q23-33) [Kessali et al., 1997] families. Another form with florid myelin sheath changes, known as hereditary motor and sensory neuropathy with focally folded myelin or congenital dysmyelinating neuropathy, has been linked to chromosome 11q23. Even this latter condition, however, is heterogeneous. Charcot-Marie-Tooth disease type 4B1 is due to mutations of the myotubularin gene, whereas type 4B2 is due to a mutation of the SBF2 gene. The classification of Charcot-Marie-Tooth disease and related disorders has become complex and confused and is likely to remain so because of the ever-expanding list of gene mutations that are continuing to be discovered. A recent classification is shown in Table 76-2.

MANAGEMENT Treatment is supportive. Early in the course of the disease, strengthening exercises for the feet and legs with active stretching of the feet may be beneficial, although there is no objective evidence for this. Typically, the hind foot can be dorsiflexed well beyond 90 degrees, but tightness in the plantar fascia may inhibit normal forefoot dorsiflexion as the pes cavus deformity becomes more pronounced. Special attention to stretching of the forefoot in late childhood and early adolescence may be of considerable benefit in helping maintain gait without footdrop. Using polypropylene anklefoot orthoses to stabilize the feet and correct the footdrop reduces the likelihood of falling. The lightweight polypropylene orthoses slip conveniently into supportive shoes and can be covered by socks. In adolescence, orthopedic surgery on the foot to reduce the pes cavus deformity and eliminate footdrop by fusing the ankle bones together may be helpful. After such stabilizing surgery, some adolescents have been able to resume strenuous activities, such as water skiing and tennis. Involvement of the wrist and hand may call for the use of special adaptive devices for the hands, such as cock-up

Smith and Ouvrier / Peripheral Neuropathies

splints or specially adapted writing instruments, communicators, and utensils. It is hoped that as the genes causing the various forms of Charcot-Marie-Tooth disease are isolated and their gene products identified, more specific therapies will become available.

Type II Hereditary motor and sensory neuropathy (Charcot-MarieTooth disease) type II is heterogeneous and is usually dominantly inherited. Autosomal recessive and X-linked forms of the disorder are known and will be discussed further [Hahn et al., 1990; Harding and Thomas, 1980; Rozear et al., 1987]. Hereditary motor and sensory neuropathy type II does not link to chromosome 17 [Loprest et al., 1992]. The known gene mutations and linkages for type II are shown in Table 76-2. In general, onset of clinical manifestations tends to be later in dominantly inherited hereditary motor and sensory neuropathy type II than in type I. Muscle atrophy and weakness are milder and more prominent than sensory deficits compared with the type I disorder. Otherwise, the clinical course of type II disease is similar to that found in type I. The pathology is marked by axonal degeneration. Nerve hypertrophy and palpable nerve enlargement are not present. The onion bulb formation typical of type I disease is rarely seen. In one variant, focally enlarged myelinated axons with aggregations of neurofilaments have been described [Goebel et al., 1986]. In addition to the focal accumulation of intraaxonal neurofilaments in the myelinated fibers, similar structures have been seen without axonal enlargement in the nonmyelinated axons. Similar structures have been noted in fibroblasts and endothelial cells in muscle and skin. Whether these intra-axonal filaments describe a different disease process is unknown. Nerve conduction velocities are low normal to slightly reduced. A rather severe form of hereditary motor and sensory neuropathy type II, which is usually of autosomal-recessive inheritance, was designated hereditary motor and sensory neuropathy of neuronal type with onset in early childhood. Two large series of such patients were reported [GabreelsFesten et al., 1991; Ouvrier et al., 1981]. The disorder accounts for up to 5% of childhood chronic neuropathies. The features of the disorder include sporadic occurrence or evidence of autosomal-recessive or, less commonly, autosomal-dominant inheritance. In addition, onset of weakness within the first 5 years of life, rapid progression of weakness to almost complete paralysis below the elbows and knees by the second decade, moderate sensory changes in most cases, clinical electrophysiologic studies consistent with an axonal degenerative polyneuropathy, and histologic studies indicating neuronal (axonal) atrophy and degeneration of peripheral motor and sensory neurons are noted. Cerebrospinal fluid is usually normal. The condition advances rather rapidly, so that most patients are nonambulatory by the middle to late teens. The chromosomal localization of this group of disorders is not yet known.

Congenital Axonal Types Some infants are born with arthrogryposis secondary to an axonal neuropathy. This condition is often a nonprogres-

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sive disorder, presumably secondary to some intrauterine insult. It is not clear whether these disorders are hereditary. Cases have been described in which infants a few weeks old have presented with rapidly progressive respiratory distress leading to death or permanent ventilatory support within the first year of life [Appleton et al., 1994; Vanasse and Michaud, 1992]. In these cases, clinical electrophysiologic and histopathologic examinations have been consistent with a form of spinal muscular atrophy affecting the diaphragm and distal muscles preferentially. In others, investigations have suggested the presence of an axonal neuropathy. Mutations of the gene encoding the immunoglobulin mu binding protein (IGHMBP2) cause these disorders.

Type III (Dejerine-Sottas Disease) and Hypomyelinating Neuropathies Hypomyelinating neuropathies are disorders in which Schwann cells are, to a variable extent, incapable of forming normal myelin. Histopathologically, they are characterized by the presence of thin myelin sheaths, often with few or poorly compacted myelin lamellae, and by the presence of onion bulbs, which are often large and made up of thin lamellae and basal lamina remnants. The most extreme form of hypomyelinating neuropathy, in which the patient is severely affected at birth by a condition resembling congenital spinal muscular atrophy, is sometimes termed congenital amyelinating neuropathy [Charnas et al., 1988; Karch and Urich, 1975; Kasman et al., 1976; Palix and Coignet, 1978; Seitz et al., 1986]. In this group, arthrogryposis is common, presumably because of lack of limb movements in utero. Because of respiratory problems and swallowing difficulties, these infants usually die when very young. Nerve conduction velocity is either unrecordable or extremely low. Peripheral nerve histopathologic examination reveals no (amyelination) or very little myelin and virtually absent onion bulbs. Such cases probably represent examples of the extreme end of the spectrum of clinical and pathologic severity resulting from myelin protein mutations. Dejerine-Sottas disease (hereditary motor and sensory neuropathy type III) pathologically is associated with hypomyelination. In most cases, hypotonia, delay in developmental milestones, or both are noted within the first year of life. The onset of walking is often delayed beyond the second year, but most hereditary motor and sensory neuropathy type III toddlers eventually do walk, although coordination is never fully normal. Ataxia is present in all patients and is probably due to a proprioceptive deficit. Distal weakness, more marked in the lower limbs, is present early. Proximal weakness and deformity of the hands and feet are not common in early childhood. Both become increasingly more obvious with advancing age, so that by the second decade, proximal weakness is the rule. Deep tendon reflexes are usually absent. Clinical enlargement of nerves, with the median and other peripheral nerves feeling thicker than a pencil, is present in most hereditary motor and sensory neuropathy type III patients by the end of the first decade or earlier. By the time adequate testing can be performed, moderate-to-severe sensory loss is present in most patients. By comparison, such sensory loss is rarely seen in

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hereditary motor and sensory neuropathy type I cases. Scoliosis often occurs early and tends to progress. Nerve conduction velocities are typically lower than 10 m/second, probably because of loss of saltatory conduction. Prognosis is variable [Guzzetta et al., 1982]. Some patients clearly deteriorate over the first two decades [Tyson et al., 1997], but most patients whom we have been able to follow have experienced little change over many years, except for the progression of limb deformities and scoliosis [Ouvrier et al., 1987]. Many, perhaps most, cases of congenital hypomyelinating neuropathy and Dejerine-Sottas syndrome are the result of myelin protein mutations. The (dominant) heterozygous PMP22 and myelin P0, as well as homozygous myelin P0, mutations have been reported to cause the Dejerine-Sottas phenotype [Tyson et al., 1997; Valentijn et al., 1995; Warner et al., 1996]. In addition, homozygous inheritance of the chromosome 17p11.2 -12 duplication (in which the patient has four copies of the PMP22 gene), compound heterozygous states involving a deletion and a point mutation of the PMP22 gene [Gonnaud et al., 1995], and a case of apparent homozygosity for hereditary motor and sensory neuropathy type II [Sghirlanzoni et al., 1992] caused by a myelin P0 mutation [Taroni et al., 1996] have all been associated with the Dejerine-Sottas phenotype. There is probably also a rare autosomal-recessive form. The complexity of the genetics of the Dejerine-Sottas syndrome makes it important to study such cases and their families before genetic counseling is given. In addition to the preceding studies, two remarkable cases of recovery from a congenital hypomyelinating neuropathy were reported [Ghamdi et al., 1997; Levy et al., 1997].

Types IV to VII The term hereditary motor and sensory neuropathy type IV was applied by Dyck to Refsum’s disease but is not widely used. Dyck designated patients with spastic paraplegia, who had abnormalities in quantitative testing of sensation, of sensory nerve conduction, and of histometric evaluation of sural nerve, as well as a pattern of autosomal-dominant inheritance, as cases of hereditary motor and sensory neuropathy type V. Harding and Thomas [1984] reported 25 cases of peroneal muscular atrophy with pyramidal features. In contrast to Dyck and colleagues [1975], these authors believed that peroneal muscular atrophy with pyramidal features is a separate disorder from hereditary spastic paraplegia but that it also demonstrates heterogeneity. The combination of hereditary motor and sensory neuropathy with optic atrophy was designated hereditary motor and sensory neuropathy type VI by Dyck and colleagues [1975]. First described by Vizioli [1879], this rare condition may be transmitted by autosomal-dominant or autosomal-recessive inheritance [Ippel et al., 1995]. The combination of a neuropathy with familial retinitis pigmentosa, first reported by Massion-Verniory and associates [1946] from Belgium, was designated hereditary motor and sensory neuropathy type VII by Dyck and colleagues [1975]. In the original family, a 34-year-old male rather abruptly developed visual and gait difficulties that worsened over the next 9 years. Two of his sisters had pigmentary retinopathy without evidence of neuropathy. Cerebrospinal fluid protein was elevated. A nerve biopsy was unhelpful. Cases of this combination are

rare and, to the authors’ knowledge, have not been reported in childhood.

X-Linked Forms X-LINKED DOMINANT FORMS (X-LINKED DOMINANT CHARCOT-MARIE-TOOTH DISEASE) About 10% of hereditary motor and sensory neuropathies are transmitted by X-linked inheritance. The cardinal features of X-linked dominant hereditary motor and sensory neuropathy are as follows: 1. A pattern of inheritance consistent with X-linked transmission, as indicated by absence of male-to-male transmission, a tendency for females to be less severely affected than males, or demonstration of genetic linkage with X chromosome markers, as well as absence of the DNA duplication seen on chromosome 17 in hereditary motor and sensory neuropathy type Ia patients 2. Onset of symptoms within the first or second decade 3. Progressive wasting and weakness of distal limb musculature, more marked in affected males than females, and with more severe involvement, especially of the hands, in males with X-linked hereditary motor and sensory neuropathy than males with hereditary motor and sensory neuropathy type Ia 4. Median nerve motor conduction velocity usually between 30 and 40 m/second 5. Presence of some obligate carrier females with nerve conduction velocities varying in a range from 25 m/second to normal 6. Histopathologic features predominantly of axonal degeneration and regeneration but with some evidence of segmental demyelination in sural nerve biopsies

Clinical Manifestations The clinical features of X-linked hereditary motor and sensory neuropathy are broadly similar to those of hereditary motor and sensory neuropathy type Ia, but the disease is more severe in X-linked hereditary motor and sensory neuropathy males and less severe in females than in hereditary motor and sensory neuropathy type Ia. Gait difficulties are usually the first manifestation. Wasting of leg muscles and subsequently of the intrinsic muscles of the hands is more marked in X-linked hereditary motor and sensory neuropathy males than females and more obvious than in males with hereditary motor and sensory neuropathy type Ia. The patellar reflexes are retained in about 50% of affected females but only in 10% of males. The ankle jerks are absent in most cases [Nicholson and Nash, 1993]. Sensory loss is present in more than 75% of affected adult men and women. Clinical hypertrophy of nerves is not a feature. Despite the presence of the condition, few adults with the disorder are sufficiently disabled to interfere with work until age 50 or 60 years. Affected males often require canes to stabilize their gait when elderly, but they are not often wheelchair bound.

Clinical Neurophysiology Motor nerve conduction velocities in X-linked hereditary motor and sensory neuropathy males tend to be lower than

Smith and Ouvrier / Peripheral Neuropathies

normal but faster than those in typical hereditary motor and sensory neuropathy type I cases. Nicholson and Nash [1993] found a mean median motor nerve velocity of 31 m/second in a group of 20 X-linked hereditary motor and sensory neuropathy males from two kindreds, compared with a mean median motor nerve conduction velocity of 45 m/second in 32 affected females. The histopathologic findings on sural nerve biopsy have been variable. Biopsies in patients with proven connexin mutations demonstrate a mixture of demyelination and axonal degeneration. Fiber loss and regenerative cluster formation are evident in transverse sections but with some onion bulb formation. Rarely there are marked changes of chronic demyelination.

Genetics As an X-linked dominant condition, expression is more severe in affected males than affected females. Fathers transmit the gene to all of their daughters but none of their sons. Affected females transmit the gene to half their sons and half their daughters. Thus, fewer males are affected than females. The gene is localized to the DXYS1 region at Xq13.1 on the proximal long arm of the X chromosome near the centromere [Bergoffen et al., 1993b; Fischbeck et al., 1986]. More recently, it was recognized that the gene for the gap junction protein (connexin 32) was located in the same chromosomal segment. Direct sequencing of the connexin 32 gene has revealed mutations in individuals with X-linked Charcot-Marie-Tooth disease [Bergoffen et al., 1993a]. There is remarkable variability in the connexin 32 mutations, with mostly different mutations in tested patients with X-linked hereditary motor and sensory neuropathy [Scherer et al., 1995]. Connexin 32 is normally expressed in myelinated peripheral nerve and appears to be localized mainly at the nodes of Ranvier and Schmidt-Lanterman incisures. It is postulated that connexin 32 may form intracellular gap junctions that connect the folds of Schwann cell cytoplasm, allowing transfer of ions, nutrients, and other small molecules around and across the compact myelin to the innermost myelin layers, perhaps also providing indirect sustenance to the axon as well [Bergoffen et al., 1993a].

X-LINKED RECESSIVE FORMS X-linked recessive inheritance of a condition resembling hereditary motor and sensory neuropathy type II has also been reported. The specific characteristics of these disorders are poorly defined.

Hereditary Sensory and Autonomic Neuropathies Type I Hereditary sensory and autonomic neuropathy type I is a dominantly inherited disorder, usually evident in the second or third decade of life [Dyck, 1984]. The condition is mapped to 9q22.1-22.3 [Nicholson et al., 1996]. The disorder is caused by mutations of the SPTLC1 gene encoding serine palmitoyl transferase [Dawkins et al., 2001]. In some instances, genetic analysis has indicated that a similar disease may be inherited as an autosomal-recessive

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condition rather than as the typical dominantly inherited condition with variable expression [Kondo et al., 1974]. Characteristically, the patient experiences lightning-like pains and develops perforating ulcers of the feet. Cutaneous sensation and tendon reflexes are lost in the lower extremities [Berginer et al., 1984]. Pes cavus, hammer toes, and peroneal muscular weakness develop. Variability of disease expression is so great that some affected relatives may be asymptomatic, but 100% penetrance is evident by the age of 30 years, as reported in the large kindred by Nicholson and colleagues [1996]. Spontaneous amputations of the distal limbs have occurred. Pathologic studies from such individuals have demonstrated nerve degeneration and bone necrosis [Teot et al., 1985]. As individuals advance into adulthood, the loss of all peripheral sensory modalities, except those of the face, has been reported [Nance and Kirby, 1985]. Hereditary deafness is an associated feature [Fitzpatrick et al., 1976; Nicholson et al., 1996]. Increased immunoglobulin A levels were found in members of three unrelated families [Whitaker et al., 1974]. In a separate family, both immunoglobulin A and G levels rose as the disease progressed [Iwabuchi et al., 1976]. Sural nerve biopsy reveals marked loss of myelinated nerve fibers, especially large myelinated fibers, and loss of unmyelinated nerve fibers [Danon and Carpenter, 1985]. Treatment is limited and is generally preventive. Protection of the feet from injury by wearing appropriate shoes and avoiding jumping and falling is important. Meticulous attention to proper toenail trimming and treatment of plantar ulcers are other important measures. If conservative efforts fail, amputation of affected extremities is necessary [Gwathmey and House, 1984].

Type II Hereditary sensory and autonomic neuropathy type II occurs as a congenital sensory neuropathy that seems to be recessively inherited [Ohta et al., 1973]. In addition to loss of pain and temperature sensation, affected children have great difficulty recognizing objects by touch. Recurrent infections are common in the digits, and fractures may occur. As the disease progresses, mutilation of fingers and toes occurs. Nerve biopsies reveal a marked decrease in myelinated fibers of all calibers, as well as of unmyelinated fibers. There are possibly several subtypes of this disorder, one of which is thought to be nonprogressive [Ferrière et al., 1992].

Type III Hereditary sensory and autonomic neuropathy type III is otherwise known as familial dysautonomia or the Riley-Day syndrome (see Chapter 85).

Type IV Hereditary sensory and autonomic neuropathy type IV is a congenital recessively inherited sensory neuropathy usually associated with mental retardation [Dyck, 1984]. Anhidrosis is a feature of the condition [Gillespie and Perucca, 1960; Pinsky and DiGeorge, 1966; Swanson, 1963; Vassalla et al., 1968]. Rosemberg and associates [1994] summarized the findings in 32 cases, 16 sporadic and 16 from seven kindreds. Of the 16 sporadic cases, parental consanguinity was present in four. The condition is similar to hereditary sen-

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sory and autonomic neuropathy type II except for the sweating deficit and possibly the preservation of fungiform papillae on the tongue. Oral lacerations and self-mutilation are particularly prominent, leading to infection and scarring of the tongue, lips, and gums and sometimes to osteomyelitis of the jaw. The condition differs from hereditary sensory and autonomic neuropathy type III in that overflow tears are preserved in type IV and excessive sweating is a feature of dysautonomia. The anhidrosis leads to episodes of apparently unexplained fevers and hyperthermia, particularly in infancy, which are often associated with febrile convulsions. The incidence and degree of mental retardation are apparently higher than in hereditary sensory and autonomic neuropathy type II, although normal intellect has been reported. Although often attributed to episodes of hyperthermia, mental disability occurs in the absence of overt episodes of the latter. When measured, intelligence quotients have varied from 41 to 78, the majority being in the 60 to 92 range. Microcephaly is sometimes described [Rosemberg et al., 1994]. Decreased cerebrospinal fluid levels of substance P were found in four patients with hereditary sensory and autonomic neuropathy type IV. This reduction may be a secondary effect of the loss of primary sensory neurons, which might in turn be the result of a prenatal deficiency of nerve growth factor [Iwanaga et al., 1996]. The long-term prognosis is poorly defined but, in the authors’ experience, rather unsatisfactory. Chronic infections, particularly of the bones and joints, cause multiple hospitalizations and deformities. Death before the age of 4 years occurs in about 20% of cases [Rosemberg et al., 1994], usually secondary to hyperthermia or sepsis. This disorder is of autosomal recessive inheritance. Indo and associates [1996] reported four unrelated patients with consanguineous parents who had deletion, splice, and missense mutations of TRKA, a receptor tyrosine kinase for nerve growth factor. Mouse models lacking TRKA indicate diminished responses to painful stimuli and develop skin ulcerations, missing digits, and corneal opacities. They also demonstrate deficits in cholinergic basal forebrain projections to the hippocampus and cortex [Smeyne et al., 1994]. The striking similarity of these mouse models to human hereditary sensory and autonomic neuropathy type IV suggests that a deficit in TRKA is responsible for this disorder, which also explains the cognitive difficulties.

Type V Individuals with hereditary sensory and autonomic neuropathy type V do not perceive pain or temperature normally, but other sensory modalities are relatively well preserved [Dyck et al., 1983; Low et al., 1978]. Strength and deep tendon reflexes are normal, as are conventional nerve conduction studies. Nerve biopsy discloses absence of small myelinated fibers but preservation of the large ones. These findings explain the preservation of tendon reflexes and the normal nerve conduction studies.

Other Inherited Sensory Neuropathies Several entities have been described that do not fit into the preceding categories. These include sensory neuropathy in association with spasticity [Cavanagh et al., 1979], skeletal

dysplasia [Axelrod et al., 1983], keratitis [Donaghy et al., 1987], growth hormone deficiency [Liberfarb et al., 1993], ichthyosis and anterior chamber syndrome [Quinlivan et al., 1993], deafness, and ovarian agenesis [Linssen et al., 1994]. In addition, two different types of sensory neuropathy have been described in Navajo children [Appenzeller et al., 1976; Johnsen et al., 1993]. Most of these conditions appear to be of autosomal-recessive inheritance, but an X-linked sensory neuropathy was described by Jestico and colleagues [1985].

Acquired Sensory Neuropathy Acquired sensory neuropathies are rare in childhood. Roach and colleagues [1985] reported self-injurious behavior in a 2-year-old child with a sensory neuropathy after organophosphate ingestion. A delayed sensory neuropathy resulting from chlorpyriphos (another organophosphate) was reported in 14- and 15-year-old siblings by Kaplan and colleagues [1993]. Sensory neuropathy of acute or subacute onset has been reported after administration of excessive doses of pyridoxine [Albin et al., 1987; Schaumburg et al., 1983]. Acute sensory neuropathy is a monophasic disorder characterized by the rapid onset of generalized paresthesia, ataxia, and areflexia associated with a severe, mainly proprioceptive sensory defect. The site of the lesion is thought to be at the dorsal root ganglion and is probably mediated by an autoimmune response. Fernandez and colleagues [1994] described such a case in a 9-year-old male. Leprosy may be associated with sensory neuropathy, which presents even in childhood, but the neuropathy is usually patchy or thermally distributed. Associated clinical features, coupled with family history, usually make diagnosis easy once suspicion is aroused [Sabin and Thomas, 1984]. It is exceptional for amyloidosis to present before the age of 15 years. Diagnosis is readily apparent on sural nerve biopsy [O’Connor et al., 1984].

FRIEDREICH’S ATAXIA Friedreich’s ataxia is an autosomal-recessive disease characterized by slowly progressive ataxia commencing in childhood. The ataxia affects all motor functions, and the gait disturbance eventually requires use of a wheelchair, usually in the second decade of life. Intellect is preserved. Skeletal deformities of pes cavus, hammer toes, and kyphoscoliosis are typical. Cardiomyopathy is often present. A sensory neuropathy resulting from progressive degeneration of dorsal ganglion cells with “dying back” of their central and peripheral axons is the principal cause of disease progression [Lamarche et al., 1984]. This process results in an alteration in sensory nerve potentials and conduction [Dunn, 1973; Oh and Halsey, 1973]. Motor nerve conduction velocities remain typically in the low-normal range at the time when sensory conduction velocities are markedly impaired. These findings are in addition to those of the spinal cord posterior column and corticospinal tract degeneration. A loss of myelinated nerve fibers, particularly of large caliber, is seen in peripheral sensory nerves. Axonal degeneration, with some secondary demyelination in the later stages, is the predominant finding in nerve biopsies. When strict diagnostic criteria are applied, all cases of Friedreich’s ataxia are inherited by autosomal-recessive

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transmission [Barbeau, 1976]. The Friedreich’s ataxia locus was linked to chromosome 9 in typical families [Chamberlain et al., 1988]. Subsequent testing of late-onset and Acadian cases, as well as of families with early-onset ataxia with retained tendon reflexes, also indicated linkage homogeneity [Chamberlain et al., 1989; De Michele et al., 1994; Keats et al., 1990; Klockgether et al., 1993; Palau et al., 1995]. In 1996, Campuzano and colleagues identified the responsible gene X25 in the critical region on chromosome 9q13 [Campuzano et al, 1996]. The gene encodes a 210–amino acid protein, frataxin, the function of which is currently unknown. Most Friedreich’s ataxia patients (98%) are homozygous for an unstable GAA trinucleotide in the first intron of X25, but a few (about 1%) have point mutations of the frataxin gene. It is thought that the triplet GAA expansion causes disease by suppressing frataxin gene expression, which, in some way, causes spinal cord, heart, and pancreatic degeneration. This is the first autosomal-recessive disease in which a triplet repeat expansion has been demonstrated. Further studies have shown that virtually all patients with typical Friedreich’s disease, Acadian Friedreich’s disease, late-onset Friedreich’s disease, and early-onset ataxia with retained tendon reflexes carry two copies of the GAA triplet expansion. Cases with larger GAA expansions tend to have earlier onset and are more likely to demonstrate additional manifestations of the disease, such as optic atrophy, hearing loss, and possibly cardiomyopathy (see Chapter 57) [Montermini et al., 1997].

GIANT AXONAL NEUROPATHY Giant axonal neuropathy was first described in 1972 by Berg and colleagues in a 6-year-old female as a slowly progressive peripheral neuropathy resembling Friedreich’s ataxia [Berg et al., 1972]. With reports of four more children, it became clear that this disorder is a generalized one of increased, abnormal cytoplasmic microfilaments involving a number of body tissues, including Schwann cells, fibroblasts, and vascular endothelium [Carpenter et al., 1974; Igisu et al., 1975; Koch et al., 1977; Ouvrier et al., 1974]. Axons are swollen with densely packed neurofilaments. The initial descriptions of children younger than 9 years of age noted the presence of unusually kinky hair (Fig. 76-8). Parental consanguinity was recorded for six involved children, suggesting autosomalrecessive inheritance [Donaghy et al., 1988; Gambarelli et al., 1977; Igisu et al., 1975; Ouvrier et al., 1974]. Reports of siblings with the disease further suggested recessive inheritance [Jones et al., 1979; Takebe et al., 1981]. The responsible gene, gigaxonin, located on chromosome 16q24 [Bomont et al., 2000], is a cytoskeletal protein that may play a role in neurofilament architecture. Progressive gait disturbance, kinky hair, long curly eyelashes, a prominently high forehead, and variable CNS involvement, including optic atrophy, abnormal ocular motility, mental retardation, and spasticity, are hallmarks of the condition [Dooley et al., 1981; Fois et al., 1985; Kirkham et al., 1980]. Leukoencephalopathy on brain imaging studies may be accompanied clinically by deterioration of cognitive function [Stollhoff et al., 1991]. As the disease advances, motor function declines. Not all systems are equally affected; for example, some wheelchairbound children retain normal mental capacity [Boltshauser

FIGURE 76-8. A 6-year-old male with giant axonal neuropathy. Note his kinky hair and need to grasp a finger for support because of gait unsteadiness. Ankle-foot orthoses counteract footdrop.

et al., 1977; Pfeiffer et al., 1977]. Rapid progression of the sensory motor neuropathy leads to early death. Abnormal electroencephalograms and visual, auditory, and somatosensory-evoked potentials have been recorded [Majnemer et al., 1986]. Nerve conduction studies provide evidence of axonal neuropathy. Thickened, distal axons distended by an increased number of neurofilaments accompanied by axonal loss constitute the peripheral nerve pathologic findings [Asbury et al., 1972; Carpenter et al., 1974]. Other pathologic descriptions note the presence of cytoplasmic microfilaments in Schwann cells, endothelial cells, perineurial cells, endoneurial fibroblasts, and melanocytes (Fig. 76-9) [Bonerandi et al., 1981; Klymkowsky and Plummer, 1985; Prineas et al., 1976]. Skin biopsy may demonstrate accumulation of microfilaments in endothelial cells, melanocytes, and fibroblasts [Takebe and Koide, 1981]. Neurofilaments that accumulate in sural nerve have the same protein composition as normal neurofilaments [Ionasescu et al., 1983; Pena, 1982]. One newborn with hypotonia had axonal swelling in peripheral nerves and distal degeneration of long spinal cord tracts without involvement of the cerebral cortex or brainstem [Kinney et al., 1985]. Severe cerebellar degeneration and optic atrophy clinically were demonstrated at postmortem examination to be caused by degeneration and gliosis of the optic nerves and tracts [Thomas et al., 1987]. Ultrastructurally, the hair has characteristic longitudinal grooves [Treiber-Held et al., 1994].

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ciated with diminished tendon reflexes in an infant exhibiting regression of milestones is a clear sign of the disorder. Urinary retention may become a problem as the disease advances. Hypothalamic failure results in diabetes insipidus and hypothyroidism. The autonomic nervous system is affected, with decreased tearing and poor temperature regulation clinically apparent. One infant presented unusually early in the neonatal period with hypertonia, axonal spheroids on biopsy, and mineralization of the basal ganglia observed by imaging studies and at postmortem examination [Venkatesh et al., 1994]. MRI indicates cerebellar atrophy and cerebellar hyperintensity on T2-weighted images [Tanabe et al., 1993], corresponding to marked loss of cerebellar neurons and astrogliosis found at postmorterm examination. The MRI changes are characteristic early in the course of the disease and may aid in diagnosis. Children with infantile neuroaxonal dystrophy do not survive beyond their preschool years. Later-onset forms of neuroaxonal dystrophy have been reported. Central, peripheral, and autonomic neurons and nerve fibers contain spheroids of varying sizes with a predilection for involvement of sensory nerves [Itoh et al., 1993]. Sural nerve biopsy displays periodic acid–Schiff stain–positive, ballooned axons, the spheroids that contain mitochondria, glycogen-like granules, dense bodies, vesicles, and electron lucent material (Fig. 76-10) [Shimono et al., 1976]. Membranotubular and granulovesicular profiles are found ultrastructurally in spheroids [Malandrini et al., 1995]. Peripheral nerve lesions mimic those found in the CNS [Duncan et al., 1970; Martin and Martin, 1972]. Biceps muscle biopsy may FIGURE 76-9. Nerve biopsy from a child with giant axonal neuropathy displaying one myelinated and one unmyelinated fiber (b and d, respectively) with excessive tubules. Fibers c and e show axons composed largely of tightly packed neurofilaments (×12,000). Inset, ×22,000. (From Prineas JW, Ouvrier RA, Wright RG, et al. Giant axonal neuropathy: A generalized disorder of cytoplasmic microfilament formation. J Neuropathol Exp Neurol 1976;35:458.)

In summary, giant axonal neuropathy presents in early infancy or early childhood with hypotonia, distal weakness, diminished tendon reflexes, gait disturbance if the child is already walking, and kinky hair. Electromyographic findings demonstrate an axonal, motor sensory neuropathy; sural nerve examination reveals numerous large, swollen axons distended by neurofilaments. Numerous other body cells, including Schwann cells and fibroblasts, also contain the filamentous inclusions, indicating that this is a disease associated with abnormal cytoskeleton proteins. The defective gene is gigaxonin. This disorder is recessively inherited.

INFANTILE NEUROAXONAL DYSTROPHY (SEITELBERGER’S DISEASE) Infantile neuroaxonal dystrophy is a progressive central and peripheral nervous system disorder characterized pathologically by the presence of axonal spheroids. Onset of symptoms is recognized between ages 1 and 2 years. Loss of mental and motor milestones denotes the regressive nature of the condition. Seizures typically develop. Progressive motor sensory neuropathy causes loss of sensation in particular with subsequent limb mutilation. Hypotonia asso-

FIGURE 76-10. Sural nerve biopsy from a child with neuroaxonal dystrophy ultrastructurally displaying a spheroid containing mitochondria, membranotubular profiles, granulovesicular inclusions, dense bodies, and vesicles (×15,000).

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be useful for diagnostic purposes, revealing axonal spheroid bodies in intermuscular nerve fibers, neuromuscular junctions, and motor nerve endings [Miike et al., 1986]. Early muscle biopsy may require an intense ultrastructural investigation of presynaptic neurons at the neuromuscular junction to demonstrate dystrophic axons [Wakai et al., 1993]. Immunohistochemistry of spheroids is positive for ubiquitin and negative for β-tubulin and β-amyloid. Lack of reactivity to tubulin in spheroids suggests that loss of microtubules may be part of the mechanism in the formation of axonal spheroids [Moretto et al., 1993]. Activation of the ubiquitin system is an attempt of the neuron to remove abnormal proteins. The morphologic findings of infantile neuroaxonal dystrophy are remarkably similar to those reported in α-N-acetylgalactosaminidase deficiency [Wolfe et al., 1995].

more striking. Loss of bladder filling sensation correlates with duration of diabetes and poor blood sugar control. It is clear that careful clinical and electrophysiologic follow-up is required to monitor altered peripheral and autonomic nerve function in childhood-onset diabetes mellitus. In another study comparing diabetic and nondiabetic children, both motor and sensory peripheral nerve abnormalities were related to poor blood sugar control as measured by hemoglobin A1c and duration of diabetes [Fiçicioglu et al., 1994]. These results emphasize the importance of metabolic control and duration of diabetes in the pathogenesis of diabetic neuropathy. The findings suggest that peripheral neuropathy is common in young, insulin-dependent diabetic patients. Because nerve function tests are easy to conduct and are sensitive, they may help to achieve better metabolic control and prevent diabetic complications.

METABOLIC NEUROPATHIES

Uremic Neuropathy

Diabetes Mellitus

Uremic neuropathy is rarely diagnosed in children. When recognized, it is characterized by burning sensations in the feet and a symmetric motor sensory neuropathy with progressive muscle weakness. Motor nerve and sensory nerve conduction velocities are decreased early in the course of the disease, often before clinical symptoms appear [Di Paolo et al., 1982]. In particular, the proximal 1a sensory and motor nerve conduction velocities are significantly slowed early, compared with distal values in uremic neuropathy [Panayiotopoulos and Lagos, 1980]. The H-reflex response latency can be used to detect early changes in some patients [Knoll and Dierker, 1980]. Parathyroid hormone levels have been correlated with early peripheral nerve conduction delays in some instances [Di Paolo et al., 1982], but not in others [Aiello et al., 1982]. The facial nerve is a sensitive indicator of uremic neuropathy [Mitz et al., 1984]. In vitro inhibition of tubulin 6s polymerization by uremic toxins suggests a mechanism for initiating uremic neuropathy [Braguer et al., 1986]. The plasma of uremic patients contains high concentrations of middle molecules in the 300 to 1500 dalton range, which cause toxic effects [Babb et al., 1981]. A b4-2 peak correlates with the neuropathy [Faguer et al., 1983]. The predominant change in the peripheral nerve is a demyelinating neuropathy, but some individuals experience a progressive axonal neuropathy with secondary segmental demyelination. An acute axonal neuropathy is rarely observed [Said et al., 1983]. In the more rapidly progressive neuropathies, ischemic changes related to accelerated hypertension and possibly to septicemia may be etiologically related to rapid progression [McGonigle et al., 1985]. Biotin therapy has been recommended for patients with advanced renal failure before the neuropathy becomes manifest [Yatzidis et al., 1984].

It has been known for a long time that 10% of children with insulin-dependent diabetes mellitus have symptoms and signs caused by peripheral neuropathy associated with diabetes [Gamstorp et al., 1966]. These bilaterally symmetric changes, especially in the lower extremities, include mild distal weakness, loss of touch and pain sensation, and decreased ankle tendon reflexes. Despite good management of diabetes, impaired nerve function occurs. In a large prospective study of nerve conductions and autonomic nervous system function in diabetic children, slowed sensory nerve conduction velocities and impaired autonomic function were present in 25% of children at the time of diagnosis [Solders et al., 1997]. Follow-up measurements of nerve conduction velocities and parasympathetic function (R-R variations) 2 years later indicated deterioration from baseline of sensory and motor nerve conductions and autonomic nerve function. The degree of deterioration correlated with blood sugar control. After 3 years of diabetes, all motor and sensory nerve conduction times were slowed [Hyllienmark et al., 1995]. By contrast to the electrophysiologic changes, only 4% of children at onset of diabetes have symptoms or signs suggestive of neuropathy despite early nerve conduction slowing. In another approach to peripheral nerve function, vibration perception threshold was measured in diabetic males. Compared with age-matched control subjects, impaired vibration perception was present in diabetic males in the absence of clinical symptoms of peripheral or autonomic neuropathy [Olsen et al., 1994]. Mildly impaired autonomic nervous system function is found in 30% to 50% of children with diabetes when measured soon after diagnosis [Donaghue et al., 1996; Verrotti et al., 1995]. The percentage involved does not change over 3 years [Donaghue et al., 1996]; abnormalities are not related to age, duration of diabetes, or degree of blood sugar control. Heart rate variation during Valsalva maneuver and a maximum-to-minimum ratio of 30:15 are the most sensitive indexes to detect autonomic abnormalities in children [Verrotti et al., 1995]. Further, asymptomatic diabetic children have diminished sensation of bladder filling [Barkai and Szabó, 1993]. If cardiovascular autonomic dysfunction is present in addition, loss of bladder filling sensation is even

Acute Intermittent Porphyria Acute intermittent porphyria, a rare inborn error of metabolism inherited on an autosomal-dominant basis, is caused by defects in the gene encoding hydroxymethylbilane synthase on the long arm of chromosome 11. There is a marked increase of δ-aminolevulinic acid, porphobilinogen, uroporphyrin, and coproporphyrin in the urine. δ-Aminolevulinic

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acid synthetase activity is typically increased in body tissues. Although the disease has occurred within the first decade of life, it typically presents after puberty. Gene carriers are at risk for developing potentially fatal neurogenic attacks if exposed to precipitating factors [Wassif et al., 1994]. Axonal damage observed both on sural nerve biopsy [Defanti et al., 1985] and postmortem examination suggests that the neuropathy is primarily axonal [Yamada et al., 1984]. Acute, severe, colicky abdominal pain is a typical manifestation of an acute episode accompanied by CNS and peripheral nervous system impairment. Peripherally, motor weakness is most striking, but sensory impairment may also occur. A flaccid paralysis resembling Guillain-Barré syndrome has been observed. The proximal muscles may be more involved than distal muscles when weakness occurs. Reflexes are often diminished or absent. The motor cranial nerves, particularly cranial nerves III, VII, and X, may be involved. Urinary retention or incontinence occurs. Centrally, mental changes consisting of confusion, delirium, and hallucinations may develop. Autonomic function involving the sympathetic and parasympathetic nervous systems may be affected. Typically the symptoms remit with resolution of the episode, but parasympathetic dysfunction has been detected during remission and when the patient is otherwise asymptomatic [Laiwah et al., 1985]. Barbiturates and other antiepileptic drugs may trigger attacks. No successful treatment has been described. Lead poisoning and GuillainBarré syndrome must be considered in the differential diagnosis.

Vitamin Deficiency Thiamine, or vitamin B1, is a water-soluble vitamin that serves as a coenzyme in carbohydrate metabolism. Classic thiamine deficiency in children causes peripheral neuropathy, encephalopathy, and high-output cardiac failure [Debuse, 1992]. Infantile beriberi disease has been described in infants born to mothers with thiamine deficiency. Symptoms consist of anorexia, vomiting, and lethargy occurring within the first 3 months of life as a result of vasoconstriction, hypotension, and severe metabolic acidosis. The infant may be pale, puffy, and listless on examination. Cranial nerve dysfunction has been noted, with ptosis, optic atrophy, and laryngeal paralysis causing a hoarse cry. Cardiac enlargement with heart failure has also been found. A thiamine-dependent state has also been described [Mandel et al., 1984]. Treatment allows for reversal of symptoms with or without sequelae [Román, 1994].

Congenital Pernicious Anemia Two forms of pernicious anemia in children are associated with peripheral neuropathy. One occurs as a congenital disease or an early-onset disease in children [Heisel et al., 1984]. Congenital pernicious anemia occurs before age 5 years as a result of a vitamin B12 deficiency caused by isolated absence of gastric intrinsic factor. There is adequate gastric-free acid and a normal gastric mucosa. The patient has a macrocytic anemia, a decreased serum vitamin B12 level, a lack of intrinsic factor in the gastric juice, but an otherwise normal gastric acid content and gastric mucosa.

There is an absence of the antibodies to the parietal cell and intrinsic factor. Select infants with this form of pernicious anemia have been reported to have neuropathies. There may be a delay in acquiring motor milestones and growth failure. Treatment is with parenteral vitamin B12 and results in recovery to normal hemoglobin levels in 4 to 6 weeks. A later-onset form of pernicious anemia resembles that seen in adults. This form is histamine-fast achlorhydria associated with gastric mucosal atrophy and the presence of antibodies to parietal cells and intrinsic factor in the serum. These children may experience a variety of endocrinologic disorders. Pathologic changes develop in the spinal cord and less commonly in the peripheral nerve and brain. Infants who are breast-fed by strictly vegetarian mothers or who have undiagnosed pernicious anemia are at risk for developing a megaloblastic anemia because of a deficiency of vitamin B12. A loss of acquired milestones with seeming neurologic regression occurs [Higginbottom et al., 1978]. Cystathioninuria, glycinuria, methylmalonic aciduria, 3hydroxy propionic aciduria, and formic aciduria may develop. Inadequate tissue availability of vitamin B12 results in increased concentrations of methylmalonic acid and homocysteine caused by inhibition of methylmalonyl-coenzyme A mutase and methionine synthase, respectively. It can be prevented by supplementing the vegetarian mother’s diet with vitamin B12 (cobalamin).

Abetalipoproteinemia Abetalipoproteinemia, known as Bassen-Kornzweig syndrome, is characterized by progressive ataxic neuropathy, retinitis pigmentosa, steatorrhea, hypolipidemia, deficiency of fat-soluble vitamins, and acanthocytosis [Bassen and Kornzweig, 1950; Selimoglu et al., 2001]. The onset of symptoms in this autosomal-recessive disorder occurs between early childhood and the late teen years. Apoprotein B, required for synthesis and structural integrity of chylomicrons and low-density and very-low-density lipoproteins, is missing in plasma because of lack of synthesis [Salt et al., 1960]. The result is absence of lipoproteins. Intestinal fat absorption is absent from birth and results in a progressive deficiency of fat-soluble vitamins A, D, E, and K. Many of the clinical problems of the syndrome are due to vitamin E deficiency, and treatment with vitamin E is recommended [Miller and Lloyd, 1982]. Sensory neuropathy exists with reduced amplitude responses [Lowry et al., 1984].

Pathology Degeneration of posterior columns, spinal cerebellar pathways, and cerebellum caused by vitamin E deficiency [Mino, 1993] is the major pathologic change. Loss of anterior horn cells is found in the spinal cord. Posterior column degeneration leads to abnormal somatosensoryevoked potentials [Brin et al., 1986]. Sural nerve biopsy indicates decreased numbers of large myelinated fibers and clusters of regenerating fibers [Wichman et al., 1985]. The posterior fundus of the eye exhibits a loss of photoreceptors, loss or attenuation of pigment epithelium, and preservation of submacular pigment epithelium, with an excessive accumulation of lipofuscin [Cogan et al., 1984]. Macrophagelike pigmented cells invade the retina.

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Clinical Characteristics The most significant neurologic finding is a progressive ataxia that may be present as early as 2 years of age but certainly by age 6 years. Generalized weakness, ptosis, and extraocular muscle weakness develop. The lower cranial nerves may be involved, with facial and tongue weakness plus twitching movements. A progressive peripheral sensory neuropathy causing hypesthesia, hypalgesia, and proprioceptive loss is associated with absent tendon reflexes. Generalized muscle weakness and wasting may be severe. Intestinal malabsorption produces bulky, foul stools and leads to a delay in normal growth.

Clinical Laboratory Tests The most significant finding is the inborn absence of the major apoprotein of low-density plasma lipoproteins [Lange and Steck, 1984], leading to an abnormal serum and red-cell lipid profile, along with spiny erythrocytes or acanthocytosis. Fatsoluble vitamin deficiency is typically present. The electroretinogram may be nonrecordable because of the pigmentary retinopathy [Judisch et al., 1984]. There are wide variations in the appearance of the acanthocytes. Erythrocyte membrane phospholipids and cholesterol are increased [Iida et al., 1984].

Management High doses of vitamin E provide clinical amelioration and electrophysiologic improvement with increased evoked motor unit potentials and improved nerve conduction velocities [Brin et al., 1986; Hegele and Angel, 1985; Runge et al., 1986]. In addition to large doses of oral vitamin E therapy, a low-fat diet and supplements of the other fatsoluble vitamins are recommended. If these dietary changes are started early enough, the progressive retinopathy can most likely be prevented.

α-Lipoprotein Deficiency (Tangier Disease) Tangier disease is an uncommon familial disorder of lipoprotein metabolism notable for the absence of normal highdensity lipoprotein from plasma and the accumulation of cholesterol esters in multiple organs. Extremely low plasma cholesterol levels are present. Physical examination indicates patches of yellow-orange lymphoid tissue in the tonsils and pharynx and hepatosplenomegaly. Yellow patches are present on the surface of the liver, and liver biopsy specimens contain cholesterol esters. Fiberscopic rectal examination documents orange-brown spots present throughout the rectum. Foam cells are present in the lymphoid tissue of both the pharynx and rectal mucosa, and rectal mucosal biopsy is recommended for diagnostic purposes [Tarao et al., 1984]. Widespread storage of lipid material by the reticuloendothelial system is present, and foamy histiocytes can be easily found [Dechelotte et al., 1985]. Onset is between 2 and 67 years of age [Pietrini et al., 1985].

Clinical Characteristics Recurrent neuropathy occurs in children with fluctuating asymmetric sensory involvement mostly in the lower

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extremities, sometimes accompanied by progressive development of weakness of both distal and proximal muscles. Complaints of numbness and tingling in the distal extremities are early symptoms, followed by signs of the neuropathy and weakness. A dissociated loss of pain and temperature sensation may occur. More severe forms of neuropathy have been described in older individuals, suggesting more than one type of neuropathic involvement [Marbini et al., 1985; Pietrini et al., 1985]. Facial diplegia may develop. Hand atrophy occurs. Sural nerve biopsy in more severely affected individuals indicates a reduction of smaller myelinated and unmyelinated fibers, with an abundance of abnormal non– membrane-bound vacuoles in the Schwann cells, fibroblasts, macrophages, and perineurial cells [Gibbels et al., 1985].

Biochemistry Tangier disease is characterized by low levels of apo-A-1 and high-density lipoproteins. A higher than normal amount of pro-apo-A-1 lipoprotein is present in Tangier disease, but there is no deficiency of the converting enzyme activity to mature apo-A-1 [Bojanovski et al., 1984]. The turnover rate from pro-apo-lipoprotein to mature apo-lipoprotein may be abnormal [Edelstein et al., 1984]. In normal circumstances, high-density lipoproteins bind to monocytes at the cell surface, and the lipoprotein is internalized and subsequently resecreted without significant degradation. Conversely, high-density lipoproteins bind to Tangier monocytes more actively, and when internalized, they are found in secondary lysosomes; that is, when they are resecreted, most of the high-density lipoprotein is degraded. At least one of the abnormal mechanisms in this disease is apparently the abnormal cellular metabolism of high-density lipoproteins in Tangier monocytes [Schmitz et al., 1985]. Another biochemical abnormality demonstrated in Tangier disease is a significant reduction of endoneurial sodium, potassium adenosine triphosphatase, and magnesium adenosine triphosphatase activities demonstrated in six sural nerve biopsies from patients with the condition [Sutherland and Pollock, 1984]. All these patients had either mononeuropathy multiplex or a progressive axonal neuropathy. The reduced level of the adenosine triphosphatase activity may relate to altered endoneurial lipid metabolism and impaired axoplasmic flow.

Management Treatment by restriction of dietary fat may be one way to reduce the accumulation of the cholesterol esters in the reticuloendothelial system [Herbert et al., 1978], possibly resulting in clinical improvement.

Krabbe’s Disease (Globoid Cell Leukodystrophy) Galactosylceramide lipidosis, known as Krabbe’s disease or globoid cell leukodystrophy, is an autosomal-recessive neurodegenerative disorder that presents most often in infants 3 to 5 months of age (see Chapter 27). Deficiency of galactosylceramide β-galactosidase results from mutations and heterogeneous deletions in the galactocerebrosidase gene on chromosome 14q31 [Luzi et al., 1995; Rafi et al., 1995; Tatsumi et al., 1995]. The clinical profile is a highly irritable infant with spasticity, optic atrophy, intellectual

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delay, and polyneuropathy. The disease leads to a loss of milestones, microcephaly, severe failure to thrive, and progressive demyelinating peripheral neuropathy with slowed conduction velocities with prolonged latencies. Hyperacusis is part of the irritability. Cerebrospinal fluid protein is elevated. Average age of death is 13 months. An earlier, neonatal onset is associated with failure to thrive, infantile spasms, and hemiplegia [Hagberg, 1984]. A small number of patients have later-onset forms of the condition, up to age 50 years [Rafi et al., 1995], causing spasticity, motor polyneuropathy, dysarthria, and optic atrophy [Loonen et al., 1985]. The central and peripheral manifestations are due to abnormalities in the metabolism of myelin with accumulation of galactosylceramide, which causes an infiltration of macrophages that subsequently transform into globoid cells in the brain [Suzuki, 1984]. The peripheral neuropathy is characterized by uniform marked slowing of conduction velocities [Miller et al., 1985]. Hypomyelination is noted pathologically in infantile Krabbe’s disease. Segmental demyelination is more important in later-onset globoid cell leukodystrophy and can be demonstrated on sural nerve biopsy. Ultrastructurally, curvilinear lamellar cytoplasmic inclusions are present in Schwann cells and histiocytes creating the globoid cell. Krabbe’s disease may present initially as a peripheral neuropathy. A 13-year-old with scoliosis and pes cavus displayed distal leg weakness and sensory loss. Electrophysiologic nerve study indicated demyelinating neuropathy. Four years later, spasticity developed, and the diagnosis was established [Marks et al., 1997].

Metachromatic Leukodystrophy Metachromatic leukodystrophy is a recessively inherited disease affecting children and adults (see Chapter 27). The basic disorder is a failure of the catabolism of sulfatide, the sulfate ester of galactose cerebroside. This lipid is a component of the myelin membrane and is probably also a component of neuronal membranes [McKhann, 1984]. The storage of metachromatic material in Schwann cell lyso-

FIGURE 76-11. Sural nerve biopsy from a child with metachromatic leukodystrophy demonstrating sulfatide storage (arrows) in a Schwann cell and degeneration of the axon in myelinated nerve fiber (×17,400).

somes and macrophages associated with segmental demyelination is well recognized in the late infantile, juvenile, and adult forms (Fig. 76-11) [Luijten et al., 1978]. Given the abnormal storage of lipid in the central and peripheral nervous system, a combination of upper and lower motor neuron disease is recognized clinically. Nerve conduction velocities are slowed, and the latencies of evoked potentials are prolonged. Sensory nerve conduction velocities are generally delayed earlier and more severely than are motor nerve conduction velocities [Takakura et al., 1985]. Clinically, in the infantile form of metachromatic leukodystrophy, the infant acquires normal milestones until 1 to 2 years of age and then begins to exhibit signs of the disease. An unsteady gait is an early sign, accompanied by loss of language, intellectual deterioration, and later, spasticity. The juvenile form of the disease occurs after several years of age, again with gait disturbance followed by intellectual deterioration. Given the greater variability of presentation in the adult form, dementia may be the initial presentation without other obvious neurologic deficits. The disease can be suspected when evoked potentials are delayed and peripheral nerve conduction velocities are slowed [Wulff and Trojaborg, 1985]. Bone marrow transplantation has shown some promise for at least delaying the progression of the late infantile and juvenile forms of metachromatic leukodystrophy [Bayever et al., 1985; Krivit et al., 1990; Lipton et al., 1986]. Followup studies indicate arrest of CNS disease but not of peripheral neuropathy.

Refsum’s Disease (Heredopathia Atactica Polyneuritiformis) Refsum’s disease is a recessively inherited condition caused by a deficiency in phytanic acid oxidase activity, allowing the accumulation of phytanic acid in body tissues. Anorexia, ataxia, ichthyosis, and sensorineural hearing loss were originally described [Refsum, 1946; Refsum et al., 1949] (see Chapter 29). Malabsorption and steatorrhea may be present early [Mandel et al., 1992]. In the classic form of the disease, clinical characteristics can be divided into three groups. Congenital abnormalities, such as skeletal deformities unrelated to the level of phytanic acid, constitute one group. Retinitis pigmentosa, which develops slowly, is another clinical group, unrelated to the plasma phytanic acid level. A third group of lesions includes the neuropathy, rash, and cardiac dysrhythmias, which can deteriorate or improve according to plasma phytanic acid level [Gibberd et al., 1985]. The sensorimotor neuropathy is of the chronic hypertrophic demyelinating type with very reduced nerve conduction velocity and raised cerebrospinal fluid protein levels. Exacerbations of the neuropathy and rash can be precipitated by a low calorie intake, with mobilization of phytanic acid from adipose tissue. Patients with Refsum’s disease lack the ability to degrade phytanic acid to pristanic acid and carbon dioxide. This defect can be analyzed in fibroblasts [Skjeldal et al., 1986]. The gene responsible for the metabolic defect codes for phytanoyl–coenzyme A hydroxylase. Serial plasma exchanges to reduce the level of phytanic acid have been correlated with significant clinical improvement, in particular of the neuropathy and cerebellar ataxia [Hungerbeuhler et al., 1985].

Smith and Ouvrier / Peripheral Neuropathies

When this is combined with a diet low in phytanic acid, clinical improvement, which correlates with a lowered serum phytanic acid level, can be sustained. An infantile form of Refsum’s disease is recognized as a result of excessive phytanic acid storage. Pigmentary retinopathy is again observed, along with hypotonia, severe hearing impairment, and severe developmental delay [Weleber et al., 1984]. Facial dysmorphism and hepatomegaly have also been described [Budden et al., 1986]. Two patients had intracranial hemorrhage secondary to a vitamin K–responsive clotting defect, and both had steatorrhea. The affected infant may have protracted diarrhea and low serum cholesterol level. There is an absence of the normal hepatic peroxisomes [Van den Branden et al., 1986] compared with the adult form of Refsum’s disease in which peroxisomes and fibroblasts are not diminished [Beard et al., 1985]. The plasma of patients with the infantile, but not adult, form of Refsum’s disease contains increased amounts of pipecolic acid and at least two abnormal bioacids [Poulos et al., 1984]. Cultured skin fibroblasts demonstrate a marked increase in the concentration of the long-chain fatty acid hexacosanoic acid [Poulos and Sharp, 1984]. Infantile Refsum’s disease appears to share several biochemical features with the cerebrohepatorenal syndrome (Zellweger’s disease) and adrenoleukodystrophy. Both the patients with infantile Refsum’s disease and patients with Zellweger’s disease have a deficiency in phytanic acid oxidase activity, and all three are considered neonatal peroxisomal disorders [Aubourg et al., 1986; Poulos et al., 1985].

Chédiak-Higashi Syndrome Chédiak-Higashi syndrome produces albinism with abnormal pigmentation of the hair and skin, pancytopenia, susceptibility to infection, and an increased risk for lymphoreticular malignancy. Psychomotor retardation, seizures, and muscular weakness have been described. Leukocytes contain characteristic peroxidase-positive granules. Axonal sensory neuropathy with loss of myelinated nerve fibers in sural nerve biopsy is associated with the syndrome [Misra et al., 1991]. In more advanced neuropathy, abnormal granules are present in Schwann cells [Lockman et al., 1967]. Spinocerebellar degeneration has been observed and is often associated with features of parkinsonism [Pettit and Berdal, 1984]. Muscle biopsy in advanced disease indicates neurogenic muscular atrophy secondary to the peripheral neuropathy. In addition, acid phosphatase–positive granules, indicating abnormal lysosomes, are found in normalappearing muscle fibers. These correspond ultrastructurally to autophagic vacuoles containing glycogen particles and membranous structures [Uchino et al., 1993]. These findings indicate that Chédiak-Higashi syndrome is a generalized lysosomal disorder. The defective gene has been localized to chromosome 1q42-44 [Barbosa et al., 1997].

TOXIC NEUROPATHIES Diphtheria Diphtheria is an uncommon disease in the Western hemisphere because most individuals are immunized with

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diphtheria-pertussis-tetanus vaccine. The disease occurs in unimmunized children and in adults who have lost immunity. An exotoxin produced by the Corynebacterium diphtheriae infection in the throat produces cardiomyopathy and neuropathy. A systemic radiculoneuropathy with onset 1 to 16 weeks after infection marked by sensory loss may develop [Gaskill and Korb, 1946]. Clinically, blurred vision and swallowing difficulties mark the onset of diphtheric neuropathy. A generalized motor sensory demyelinating polyneuropathy with distal, symmetric involvement is recognized [Créange et al., 1995]. Lower cranial nerves are affected. Proximal and distal muscle weakness and muscle tenderness are present. Proprioceptive modalities are altered in the lower extremities. Spinal fluid protein may be elevated with or without pleocytosis. Recovery is usually complete within several months [Buzzi, 1982]. The exotoxin may produce a localized effect on pharyngeal and palatal muscles secondary to nerve involvement adjacent to the infection. Complete recovery is anticipated.

Neuropathy of Serum Sickness Serum sickness is a systemic illness resulting from hypersensitivity to an injected foreign protein, such as tetanus or diphtheria antisera, producing encephalomyelitis, neuropathy, or brachial plexus neuropathies [Igbal and Arnason, 1984; McCombe and Pender, 1991]. Fever, joint swelling, abdominal pain, diarrhea, and cutaneous eruptions develop within days of receiving foreign protein. Deposition of antigen–antibody complexes is associated with disease.

Botulism See Chapter 78.

Antibiotic-Induced Neuropathy A number of antibiotic, antifungal, and antituberculous drugs have been known to cause peripheral neuropathy in a small percentage of cases. For example, chloramphenicol can cause mild, primarily sensory peripheral neuropathy after long-term use at relatively high doses. Nitrofurantoin may produce a polyneuropathy of sudden onset on rare occasion. Isoniazid causes an axonal neuropathy responsive to pyridoxine therapy in 1% to 2% of patients. The primarily sensory neuropathy begins with paresthesias. Ethambutol, an antituberculous drug, occasionally causes a sensory neuropathy associated with optic neuritis.

Pyridoxine-Induced Polyneuropathy Pyridoxine taken in large doses can cause a sensory neuropathy with paresthesias, diffuse sensory loss, sensory ataxia, and autonomic dysfunction [Albin et al., 1987; Schaumburg et al., 1983]. Strength is intact. Sural nerve biopsy documents marked loss of large myelinated nerve fibers [Santoro et al., 1991]. Recovery may be incomplete. A chronic neuropathy from lower-dose ingestion has similar and milder symptoms and a better prognosis [Dordain and Deffond, 1994]. There is a dose-dependent relationship to the development of neuropathy [Berger et al., 1992]. Most reports in the literature concern adults; however, a report of

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an 18-year-old with pyridoxine-dependent seizures describes onset of sensory neuropathy by 2 years of age as a result of 2 g/day of pyridoxine therapy for seizure control. The neuropathy did not progress from age 2 to 18 years. Electrophysiologic studies indicate a pure sensory neuronopathy [McLachlan and Brown, 1995].

distal muscle weakness is noted. In select protocols treating germ cell tumors in children and using cisplatin as one therapeutic agent, the incidence of neuropathy was very low [Göbel et al., 1989; Hartmann et al., 1988]. High-tone hearing loss was noted, which may be due to the combination of cisplatin and etoposide.

Nitrous Oxide–Induced Polyneuropathy

Vaccine-Induced Polyneuropathy

Severe myeloneuropathy and macrocytic anemia associated with a low vitamin B12 level are reported after prolonged exposure to nitrous oxide [Stacy et al., 1992]. Vitamin B12 supplementation alone does not result in improvement, but the addition of methionine does arrest the progression of neuropathy. Chronic nitrous oxide exposure inhibits methionine synthetase activity, which remains suppressed after nitrous oxide exposure has ended, underscoring the need for treatment with methionine. Continuous exposure to nitrous oxide for longer than 3 hours causes neuropathy, especially in vitamin B12–deficient individuals [LouisFerdinand, 1994].

The diphtheria-pertussis-tetanus vaccine may produce a peripheral neuropathy, probably because of the tetanus toxoid component. The influenza, or 1976 swine flu, vaccine allegedly caused Guillain-Barré syndrome, but this has been questioned by reevaluation of the statistical evidence on which the initial allegation rested.

Chemotherapeutic Agent–Induced Neuropathy Peripheral neuropathy may develop after the use of chemotherapeutic agents to treat neoplasms. Sensorimotor peripheral neuropathy may develop after high-dose cytosine arabinoside therapy manifested pathologically by axonal degeneration and scattered destruction of myelin sheaths [Borgeat et al., 1986]. The neuropathy is marked by dysesthesias, muscle aching, and progressive weakness. Cytosine arabinoside neuropathic pain may respond to carbamazepine [Malapert and Degos, 1989]. In 1% of patients treated with high-dose cytosine arabinoside, demyelinating polyneuropathy develops, resulting in quadriparesis and need for ventilatory support [Openshaw et al., 1996]. In addition to peripheral neuropathy, brachial plexus neuropathy has been observed with high-dose cytosine arabinoside [Scherokman et al., 1985]. Adenine arabinoside has also been reported to cause a sensory neuropathy with pain and tingling in the feet [Lok et al., 1984]. Combination therapy with cancer chemotherapeutic agents may induce peripheral neuropathy. Vincristine is perhaps the best known chemotherapeutic agent, causing peripheral neuropathy and, less commonly, autonomic and cranial nerve neuropathy [Shapiro and Young, 1984]. Tingling sensations, absent reflexes (particularly at the heels), distal weakness, and impaired vibration and superficial sensation develop secondary to vincristine use. Vincristine neuropathy is most profound in children with hereditary motor and sensory neuropathy type I and is associated with incomplete recovery after discontinuation of the drug. Neuropathy is less severe in hereditary motor and sensory neuropathy type II with better recovery of nerve function after drug use is discontinued [Igarashi et al., 1995]. Vincristine should be avoided in hereditary motor and sensory neuropathy type I [Graf et al., 1996]. Cisplatin may cause profound axonal loss in peripheral nerves, producing a sensory neuropathy. Paresthesias and numbness occur months after initiating cancer therapy with this agent. Proprioception is also impaired, with diminished vibration and joint position sensation. Occasionally, mild

Heavy-Metal Neuropathy Lead toxicity may cause a motor and to a lesser extent sensory neuropathy. Lower extremities are particularly affected in children. Axonal neuropathy is demonstrated electrophysiologically and pathologically. Chelation therapy with penicillamine or ethylenediaminetetra-acetic acid may be indicated, and slow recovery is anticipated with elimination of lead exposure. Lead levels can be measured. Coproporphyrin is elevated. Other presentations include colic and pallor. Encephalopathy may be present with or without neuropathy, and weakness is typical of lead poisoning, which can be caused by both organic and inorganic forms of the heavy metal. Organic tetra-alkyl derivatives are fat soluble and easily cross the blood-brain barrier. They produce an encephalopathy without neuropathy in both adults and children. The inorganic salts produce alterations that are age dependent. In infants and children, inorganic lead poisoning usually causes an encephalopathy, whereas in adults, a neuropathy is produced. Abdominal pain, constipation, anemia, and neuropathy are the typical clinical features. The anemia is usually microcytic and hypochromic, with basophilic stippling of the red cells. Children may also have an iron-deficiency anemia. Slowing of nerve conduction occurs in children environmentally exposed to lead, who are otherwise asymptomatic [Schwartz et al., 1988]. Current concern is raised for developmental problems in children exposed to continuous, low-level lead in the environment. In lead poisoning, inhibition of erythrocyte aminolevulinic acid occurs, leading to an increase in aminolevulinic acid, which is detectable in the urine when the blood lead level reaches 40 to 50 mg/dL. In adults, the most common exposure is industrial, but in children, the ingestion of old, lead-based paint or chewing on paint chips causes the intoxication. Obviously, removing the source of the lead is most important, and a chelating agent may be of value. Rare instances of arsenic poisoning, usually purposely perpetrated against an individual, have been reported, producing an axonal, primarily sensory neuropathy. Exposure may be by overdose, producing a subacute neuropathy, or may be more chronic, causing a slowly progressing neuropathy. Environmental exposure from industrial waste is associated with skin pigmentation, palmar and plantar keratosis, gastrointestinal symptoms, liver disease, and peripheral neuropathy [Mazumder et al., 1992].

Smith and Ouvrier / Peripheral Neuropathies

Mercury poisoning was described in Minamata Bay in Japan. The poisoning resulted from industrial discharge of short-chain alkyl mercury compounds, which were picked up by microorganisms and subsequently entered the food chain, concentrated in fish and shellfish. Organic mercury poisoning in children produces acrodynia, or pink disease, consisting of generalized erythema, especially of the hands, feet, and face, with swelling of the hands and feet. Stomatitis, loss of teeth, increased perspiration, and irritability are present. Elemental mercury is absorbed from a saturated atmosphere of mercury vapor, leading to subacute exposure. Several patients with predominantly axonal motor neuropathy resulting from vapor exposure have been recorded [Ross, 1964; Swaiman and Flagler, 1971]. Chronic exposure results in sensory and motor neuropathy, encephalopathy, and autonomic dysfunction. Chronic exposure may produce a subclinical neuropathy detected electrophysiologically [Zampollo et al., 1987]. Removing the source of mercury is important, and chelation therapy may be of value. Accidental ingestion of rat poison or insecticides containing thallium causes an acute or subacute syndrome of gastrointestinal disturbance and neuropathy. A sensory and motor axonal severe peripheral neuropathy with abdominal pain, nausea, vomiting, and alopecia is typical. One transplacental case is known. If death does not ensue, recovery is usually complete [Desenclos et al., 1992; Rangel-Guerra et al., 1990]. Thallium was banned in the United States as a rodenticide in 1972.

Critical Illness Polyneuropathy Critical illness polyneuropathy occurs in patients with sepsis and multiple organ failure. Initially reported in adults with severe systemic illnesses in intensive care units [Bolton et al., 1986], it is often first recognized when it proves difficult to wean the patient from mechanical ventilation. The accompanying signs of generalized weakness, muscle wasting, and depressed reflexes may be difficult to detect or may be misinterpreted in the intensive care setting. The differential diagnosis includes paraparesis or tetraparesis secondary to spinal cord lesions, prolonged neuromuscular blockade, steroid- or relaxant-induced myopathy, acute necrotizing myopathy, hypophosphatemia, toxic (including nitrous oxide) and thiamine deficiency neuropathies, the asthma-amyotrophy (Hopkins) syndrome, and Guillain-Barré syndrome. These can be eliminated by systematic investigation by imaging, serum creatine kinase and phosphate levels, clinical neurophysiologic studies, and, if doubt persists, nerve and muscle biopsies. In typical cases of critical illness polyneuropathy, nerve conduction and histopathologic studies confirm widespread axonal degeneration with extensive muscle denervation. The condition has been reported in childhood secondary to sepsis associated with severe asthma [Sheth and Bolton, 1995], sepsis accompanying brain contusion or craniectomy [Petersen et al., 1999], status epilepticus, cardiac surgical complications, and hemorrhagic shock encephalopathy syndrome. It has occurred with complications of bone marrow transplantation [Banwell et al., 2003]. A similar condition may follow severe burns. Treatment is mainly supportive, but therapy with intravenous immune globulins, given within 24 hours of the

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CHAPTER 77

Inflammatory Neuropathies John T. Sladky and Stephen Ashwal

Although children and adults with peripheral neuropathies exhibit similar clinical and electrophysiologic features, the incidence and nature of the underlying disorders responsible for peripheral nerve diseases in children and adults are widely divergent. Perhaps the most salient difference is that most peripheral nerve diseases in children are immune mediated and potentially treatable. Table 77-1 shows a broad categorical breakdown of the etiologies for neuropathy in a group of 249 children evaluated over 12 years at a tertiary pediatric referral center. Acquired inflammatory neuropathies were the most frequently occurring peripheral nerve diseases in this group of patients, followed by the genetically determined neuropathies. Table 77-2 illustrates a more specific classification of the acquired immune-mediated neuropathies seen in this group. Acute and chronic inflammatory demyelinating neuropathies were the most common cause of neuropathy in the inflammatory subgroup. Some children with collagen vascular diseases developed neuropathy as a complication of rheumatoid arthritis, systemic lupus erythematosus, or mixed connective tissue disease. Necrotizing vasculitis selectively affecting the peripheral nervous system was also seen. The category of “other immune/infectious disorders” included children with graft-versus-host disease after bone marrow transplantation [Adams et al., 1995; Perry et al., 1994] and children who developed a chronic immune demyelinating polyneuropathy-like presentation in the course of primary Lyme disease. Although children with human immunodeficiency virus infection and acquired immune deficiency syndrome were frequently evaluated for neurologic complications, only one adolescent developed an associated peripheral neuropathy [Leger, 1992], presumably as a complication of treatment. Inflammatory neuropathies, by virtue of their frequency and potential to respond to therapeutic intervention, are important to consider when evaluating children with peripheral nerve disease. As noted earlier, Guillain-Barré syndrome constitutes the most common variety of acquired immune-mediated neuropathy in childhood. The pathologic manifestations of Guillain-Barré syndrome are protean, with immunologictargeted antigens resulting primarily in segmental demyelination or axonal degeneration. The clinical manifestations of the disease are determined by the nature of the pathology and the populations of axons that come under immunologic attack. Although the salient clinical feature of Guillain-Barré syndrome is weakness, any organ system that relies on peripheral nerve for reporter or executive functions may be affected by the illness. It is reasonable to conceptualize this syndrome as an inhomogeneous spectrum of clinical features with specific constellations of clinical characteristics clustering in distinct patterns, permitting definitions of subcategories of Guillain-Barré syndrome.

ACUTE INFLAMMATORY DEMYELINATING POLYNEUROPATHY Epidemiology Acute inflammatory demyelinating polyneuropathy, one of several discrete varieties of Guillain-Barré syndrome, accounts for about 90% of the disease in North America and Western Europe. It is the most common paralytic illness affecting children in countries with established immunization programs. The incidence of Guillain-Barré syndrome has been estimated in population-based studies to be between 0.25 and 1.5 cases per 100,000 children younger than 16 years [Rantala et al., 1994]. Based on these estimates, about 400 to 600 children per year would be diagnosed with Guillain-Barré syndrome in the United States [Prevots et al., 1997]. Similar data have been reported from Canada [McLean et al., 1994], England, Europe, and the Scandinavian countries [Farkkila et al., 1991; Korinthenberg et al., 1996]; Latin America [Asbury and Cornblath, 1990; Hart et al., 1994; Korinthenberg and Monting, 1996; Molinero et al., 2003; Olive et al., 1997]; and Taiwan [Hung et al., 1994]. Both sexes are affected, although most pediatric series have noted a slight male preponderance.

Diagnostic Criteria As part of a nationwide program to evaluate the possible relation of swine-flu immunization to Guillain-Barré syndrome, diagnostic criteria were developed under the sponsorship of the National Institute of Neurological Disorders and Stroke and were later modified after analysis of data from several multicenter treatment trials [Asbury and Cornblath, 1990]. Boxes 77-1 and 77-2 provide summaries of the consensus statement describing the clinical characteristics necessary to diagnose Guillain-Barré syndrome along with those features, including electrophysiologic testing and laboratory measurements, that mitigate for or against the diagnosis.

Clinical Features The clinical presentation of Guillain-Barré syndrome is similar in children and adults [Bradshaw and Jones, 1992; Kleyweg et al., 1989; Korinthenberg and Monting, 1996; Rantala et al., 1991; Sakakihara et al., 1991; Sarada et al., 1994; Sladky, 2004] Although there is considerable variability in the nature of the initial symptoms, the overall pattern of the evolution of the clinical syndrome and the ultimate severity of disability usually conform to a triphasic model: (1) onset and progression of symptoms and signs that reach a nadir, followed by (2) a plateau phase and

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TABLE 77-1

TABLE 77-2

Etiologies of Neuropathy in 249 Children (1980–1992)

Causes of Inflammatory and Immune Neuropathy in 112 Children

CATEGORY

PATIENTS (%)

DIAGNOSIS Immune and inflammatory disorders Genetically determined disorders Other causes of neuropathy

45 42 13

Data from unpublished observations of John T. Sladky, MD.

Guillain-Barré syndrome Chronic inflammatory demyelinating polyneuropathy Cases associated with collagen vascular disease Other immune and infectious disorders

PATIENTS (%) 58 31 7 4

Data from unpublished observations of John T. Sladky, MD.

Box 77-1 CLINICAL AND LABORATORY FEATURES IN THE DIAGNOSIS OF GUILLAIN-BARRÉ SYNDROME

Box 77-2 CONSENSUS ELECTROPHYSIOLOGIC FEATURES SUPPORTIVE OF A DIAGNOSIS OF MULTIFOCAL DEMYELINATING NEUROPATHY OF GUILLAIN-BARRÉ SYNDROME

From Asbury AK, Cornblath DR. Assessment of current diagnostic criteria for Guillain-Barré syndrome. Ann Neurol 1990;27:S21.

From Asbury AK, Cornblath DR. Assessment of current diagnostic criteria for Guillain-Barré syndrome. Ann Neurol 1990;27:S21.

finally (3) recovery that takes place over weeks or months. The initial phase is generally relentless and rapid. Between 50% and 75% of patients develop maximal weakness within 2 weeks, and 90% to 98% by 4 weeks [Asbury and Cornblath, 1990; Korinthenberg and Monting, 1996; Italian Guillain-Barré Study Group, 1996]. In several series describing the natural history of the disorder, in both adults

Sladky and Ashwal / Inflammatory Neuropathies

and children, the mean duration of the progressive phase was in the range of 10 to 12 days. A small number of patients continue to progress for longer than 4 weeks. This latter group overlaps to some degree with patients diagnosed with chronic inflammatory demyelinating polyneuropathy. The duration of the plateau phase is similar to that of the progressive phase, averaging 10 to 12 days but ranging from several days to 4 weeks [Italian Guillain-Barré Study Group, 1996]. Patients who develop severe axonal degeneration have a prolonged plateau phase and tend to have more severe residual weakness [Cornblath, 1990]. In a series primarily of adult patients, about half recovered within 6 months, and more than 80% by 24 months [Italian GuillainBarré Study Group, 1996]. A multicenter study of 175 children with Guillain-Barré syndrome has reported similar findings [Korinthenberg and Monting, 1996]. At the height of the disease, 26% of patients remained able to walk, but 16% required artificial ventilation. The median time from onset of symptoms to first recovery was 17 days, to walk unaided 37 days, and to be free of symptoms 66 days. The population in this study was heterogeneous, with many children receiving some form of treatment including plasmapheresis, intravenous immune globulin, and corticosteroids. A large number of children have a relatively benign course, and a smaller group a more severe and protracted course of their disease. At 6 months’ follow-up evaluation, 98 of 106 children were free of symptoms, and the others were able to walk unaided. As in series of adult patients, the maximum degree of disability at clinical nadir appears to be the most powerful predictive factor for incomplete recovery. In the past, there has been debate about whether the natural history of Guillain-Barré syndrome in children is more benign or comparable to that among adults. Advocates have positioned themselves on both sides of the question. The argument may ultimately be unresolvable because of the absence of large prospective controlled treatment trials in children compared with adults with Guillain-Barré syndrome. There are only a few case series that include descriptions of the natural course of this syndrome in untreated children with consistent end-point measures. Two benchmark studies in adults are the North American Treatment Trial and the French Plasmapheresis Treatment Trial. Table 77-3 summarizes some of the presenting complaints seen in a series of 49 children hospitalized with TABLE 77-3 Clinical Features in 49 Children Younger than 18 Years with Guillain-Barré Syndrome FEATURE

PREVALENCE

Age Male-to-female ratio Weakness Pain Ataxia Paresthesias Shortness of breath

7.1 years (mean) 1.2:1 73% 55% 44% 18% 4%

Data from unpublished observations of John T. Sladky, MD. Two patients had findings consistent with Miller Fisher syndrome.

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TABLE 77-4 Clinical Grading Scale from the U.S. Guillain-Barré Syndrome Plasmapheresis Trial

From the Guillain-Barré Syndrome Study Group. Neurology 1985;35:1096.

Guillain-Barré syndrome. Not surprisingly, weakness was the most common initial complaint. Pain, particularly in the back and lower extremities, was also a prominent feature. A history of difficulty with balance early in the course of the illness was elicited in almost half of the children. The classic triad, characteristic of the Miller Fisher variant of GuillainBarré syndrome (ataxia, ophthalmoparesis, and areflexia), was present in only two children. All children had evidence of progression. Maximal disability was quantitated according to the 1985 Guillain-Barré Syndrome Study Group grading scale (Table 77-4). At the time of maximal neurologic deficit, 25% of children were able to ambulate 5 meters without assistance (grade 2). Another 11 children (22%) reached a nadir of grade 3 (unable to walk 5 meters without assistance). The largest group of children (39%) were bed or wheelchair confined (grade 4), and 7 children (14%) required mechanical ventilatory assistance (grade 5). There were no fatalities. Autonomic dysfunction was present in 14 children (28%) and included labile hypertension in 9 children and urinary or bowel incontinence in 6 children. The duration of symptoms in children with Guillain-Barré syndrome requiring hospitalization varies in the reported studies. The incidence of admission to pediatric intensive care units for treatment of respiratory failure or other serious medical problems (e.g., infection) or for plasmapheresis ranges between 17% and 68%, with the average length of stay about 11 days [Jansen et al., 1993]. The average duration for mechanical ventilation ranges from 17 to 22 days. The mean duration of hospitalization is also quite variable, ranging from 12 to 84 days [Jansen et al., 1993; Jones, 1996]. Time to independent walking reported in a multicenter study in Western Europe [Korinthenberg and Monting, 1996] was somewhat shorter than in other pediatric series, which reported durations of 43 days [Lamont et al., 1991] or 52 days [Epstein and Sladky, 1990]. The European study was a questionnaire-based survey that included children from community hospitals along with tertiary referral centers, which the authors thought may represent a less severely affected population. In addition, many of these children received therapies, including corticosteroids, intravenous immune globulin, and plasmapheresis. Autonomic dysfunction has been reported in 12.5% to 25% of children with Guillain-Barré syndrome [Bradshaw and Jones, 1992; Hung et al., 1994] and is similar to that in adults [Ropper, 1994; Zochodne, 1994]. Symptoms are usually intermittent and include postural hypotension, supra-

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ventricular tachycardia, bradycardia, and fluctuating blood pressure. Gastrointestinal complaints are numerous and related to impaired swallowing, gastroesophageal dysmotility, pseudo-obstruction, and constipation. Urinary retention also occurs, and the potential need for catheterization and bladder decompression should be considered in children with more severe symptoms during the acute phase of the illness. On rare occasions, cardiac arrest secondary to autonomic dysfunction has been observed in children with GuillainBarré syndrome [Bos et al., 1987; Briscoe et al., 1987]. Although acute inflammatory demyelinating polyneuropathy is often regarded as an entity in which motor symptoms predominate, pain is a common symptom, occurring in up to 79% of children [Bradshaw and Jones, 1992; Nguyen et al., 1999; Sladky, 2004] and 72% of adult patients [Pentland and Donald, 1994]. Pain is among the initial manifestations of Guillain-Barré syndrome in roughly 60% of

children. The types of pain are protean and include paresthesias, dysesthesias, axial and radicular pain, meningismus, myalgia, joint pain, and visceral discomfort. Pain intensity on admission appears to correlate poorly with the degree of initial neurologic disability and is not predictive of prognosis [Moulin et al., 1997]. Patients may also present with or develop pain in a variety of clinical settings, such as the intensive care unit or pediatric ward, or during the more chronic phase of the disease when in rehabilitation or at home. Back and leg pain usually resolves over the first 8 weeks, but dysesthetic extremity pain may persist longer in 5% to 10% of patients despite motor recovery. Moderate-to-severe pain requires aggressive treatment. In a recent study of adult patients with Guillain-Barré syndrome, 75% required oral opioid analgesics, and 29% received parenteral morphine to provide adequate pain relief [Hahn, 1996]. Despite aggressive therapy, most adults with

TABLE 77-5 Variants of Immune-Mediated Acute and Chronic Demyelinating and Axonal Disorders Seen in Children GUILLAIN-BARRÉ SYNDROME SUBTYPE

DESCRIPTION

REFERENCES*

Acute inflammatory demyelinating polyneuropathy (AIDP)

Acute onset of ascending weakness and hyporeflexia with elevated CSF protein and EMG showing demyelinating neuropathy; triphasic course usually with good recovery Acute onset of ascending weakness and hyporeflexia with elevated CSF protein and EMG showing axonal involvement with reduction of CMAP; triphasic course usually with poor or limited recovery Clinical syndrome similar to AIDP or AMSAN; elevated CSF protein; electrophysiologic and histopathologic evidence of degeneration strictly limited to sensory axons Acute onset of ophthalmoplegia, hyporeflexia, and ataxia with elevated CSF protein and subsequent recovery Acute onset of multiple cranial nerve palsies (usually bilateral VII and sparing of II) with elevated CSF protein, slowing of motor conduction velocities and recovery Acute onset of sensory loss, areflexia, elevated CSF protein, slowing of motor conduction velocities and recovery Acute onset of multiple dysautonomic symptoms with limited or no motor involvement, CSF protein elevation, and good recovery Subacute or indolent onset of weakness and hyporeflexia with elevated CSF protein and EMG showing demyelinating neuropathy; symptoms persist for > 8 weeks and may remain chronic or become progressive Acute or subacute onset of weakness and hyporeflexia with elevated CSF protein and EMG showing demyelinating neuropathy; symptoms persist for > 8 weeks and follow a chronic relapsing course Subacute or indolent onset of weakness and hyporeflexia with elevated CSF protein and EMG consistent with an axonal neuropathy; symptoms follow a chronic course; sural nerve biopsy is normal Acute onset of weakness and hyporeflexia with elevated CSF protein and EMG showing demyelinating neuropathy accompanied by encephalopathic and brainstem symptoms that may have a protracted course

Hung et al., 1994; Jones, 1996, 2000; Korinthenberg and Monting, 1996

Acute motor and sensory axonal neuropathy (AMSAN)

Acute motor axonal neuropathy (AMAN)

Miller Fisher syndrome Polyneuritis cranialis

Acute sensory neuropathy Acute pandysautonomia Chronic inflammatory demyelinating polyneuropathy

Chronic inflammatory relapsing demyelinating polyneuropathy

Chronic inflammatory axonal polyneuropathy

Guillain-Barré syndrome with encephalopathic features

*References listed are for pediatric case series if available. CMAP, compound motor unit action potentials; CSF, cerebrospinal fluid; EMG, electromyography;

Alma, 1998; Chowdhury, 2001; Currie et al., 1990; Reisin et al., 1993

Griffin et al., 1995; Ho et al., 1995, 1997b; Lu et al., 2000; Paradiso et al., 1999 Hughes et al., 1999; Jones, 2000; Sladky, 2004; Willison and O’Hanlon, 1999 McFarland, 1976; Morosini et al., 2003; Polo et al., 1992 Sahashi et al., 1985; Seneviratne et al., 2002; Wilmshurst et al., 1999 Chistiansen and Brodersen, 2003; Fagius et al., 1983; Low, 1994; Nass and Chutorian, 1982; Zochodne, 1994 Connolly, 2001; Korinthenberg, 1999; Nevo, 1998; Ryan et al., 2000

Connolly, 2001; Gorson and Chaudhry, 1999; Hahn, 1998; Hahn et al., 1996a; Hughes, 1994; Nevo, 1998; Ryan et al., 2000; Said, 2002; Sladky et al., 1986 Chin et al., 2004; Feasby, 1990; Hughes, 1994; Uncini et al., 1991

Bradshaw and Jones, 2001; Brashear et al., 1985; Feasby et al., 1990; Gamstorp, 1974; Maier et al., 1997; Nadkarni and Lisak, 1993; Uncini et al., 1991

Sladky and Ashwal / Inflammatory Neuropathies

grade 4 or 5 disease severity reported that their pain was inadequately treated. Few data regarding pain symptoms in children with this syndrome have been published. The principles of pain management for Guillain-Barré syndrome patients have been well described [Moulin et al., 1997; Pentland and Donald, 1994].

Clinical Variants of Guillain-Barré Syndrome Several clinical forms of Guillain-Barré syndrome have been characterized (Table 77-5). Some of the more clearly defined entities are discussed in this section.

Acute Motor and Sensory Axonal Neuropathy Whether acute motor and sensory axonal neuropathy is distinct from the more common acute inflammatory demyelinating polyneuropathy or part of a continuum of disease remains a topic for ongoing discussion. The initial clinical presentations in these disorders are virtually identical; however, children and adults with acute motor and sensory axonal neuropathy with a severe extent of axonal degeneration are more likely to have incomplete recovery. The electrophysiologic hallmark of this syndrome is the decrement or absence of sensory and motor action potential amplitudes with only minimal slowing of nerve conduction velocities commensurate with the degree of axonal loss. In most instances, pathologic evaluation of the peripheral nervous system from patients within the spectrum of GuillainBarré syndrome illnesses reveals evidence of endoneurial inflammation with both primary demyelination and axonal degeneration [Berciano et al., 1993]. Either process can predominate in an individual patient, within a particular peripheral nerve, or in a nerve segment [Berciano et al., 1997]. The mechanism through which the immune system targets specific constituents of the peripheral nervous system remains poorly understood. It is clear that the immune response can be remarkably specific in isolating predominantly myelin-related epitopes, those associated with axolemma, or an admixture of both [Griffin et al., 1996a, 1996b; Hughes et al., 1999]. There have been a number of studies attempting to associate the presence of circulating immunoglobulin directed against specific ganglioside moieties with specific Guillain-Barré syndrome–related entities. For the most part, there has been only limited correlation between the targeted antigens and the syndrome phenotype. The strongest associations have been reported in Miller Fisher syndrome with an immune response to GQ1B [Hughes et al., 1999; Saida, 1996]. Reisin and colleagues [1993, 1996] reported a series of 44 children with an acute axonal form of Guillain-Barré syndrome. These patients initially had severe reduction in the amplitude of compound motor action potentials (<10% of lower limit of normal) and after 2 weeks of illness had diffuse, severe denervation on needle electrode examination. Compared with patients with compound motor action potentials that were greater than 10% of normal, they were more likely to require assisted ventilation (60% versus 6.2%), were more frequently quadriplegic at the peak of their disability (80% versus 18.7%), and required longer periods to improve one functional grade (mean, 63.6 days versus 16.6 days) and to become ambulatory (mean, 156 versus 17.6 days).

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Acute Motor Axonal Neuropathy Although there may have been earlier recognition of this unique form of Guillain-Barré syndrome, the first clear and detailed description of acute motor axonal neuropathy resulted from studies of clustered outbreaks of the disease in rural regions of northern China. The clinical presentation of the disease is similar to that of acute inflammatory demyelinating polyneuropathy or acute motor and sensory axonal neuropathy but is distinguished by the discrete involvement of motor axons with sparing of sensory axons [Lu et al., 2000]. Electrophysiologic hallmarks of the disease are normal sensory nerve conduction studies and diminished compound motor action potential amplitudes, with normal, or nearly so, motor conduction velocities [McKhann et al., 1991]. Diffuse denervation is present during needle electromyography. Histopathologic examination reveals normal-appearing sensory nerves with degeneration of motor axons within motor nerve roots and motor fibers in the peripheral nervous system [Griffin et al., 1995, 1996a, 1996b; Ho et al., 1995, 1997a; Lu et al., 2000; McKhann et al., 1993]. Just as acute inflammatory demyelinating polyneuropathy and acute motor and sensory axonal neuropathy have been found to occur after gastrointestinal infection with Campylobacter jejuni, the association in acute motor axonal neuropathy is even stronger. Patients who develop acute motor axonal neuropathy in northern China typically come from rural areas where the ability to purify communal drinking water is often limited or nonexistent. Paradiso and colleagues made similar observations in a series of children with Guillain-Barré syndrome who were treated in Buenas Aires [Paradiso et al., 1999]. The patients with acute motor axonal neuropathy constituted 30% of children with Guillain-Barré syndrome with a high incidence of evidence of prior infection with C. jejuni.

Miller Fisher Syndrome Ophthalmoplegia, ataxia, and areflexia characterize this Guillain-Barré syndrome variant described originally in adults in 1956 [Arakawa et al., 1993; Bradshaw and Jones, 1992; Eggenberger et al., 1993; Jones 2000; Sladky, 2004; Wong, 1997]. The incidence of Miller Fisher syndrome is probably 2% to 4% in children with Guillain-Barré syndrome-like illnesses (see Table 77-5) [Bradshaw and Jones, 1992; Jones 2000; Sladky, 2004]. Cerebrospinal fluid protein elevation is seen in virtually all patients, and in most patients, complete recovery occurs. Brainstem auditory-evoked potentials have demonstrated peripheral and central auditory conduction defects in children [Wong, 1997] Of interest are recent investigations demonstrating antibodies against the ganglioside GQ1b that recognize similar epitopes from specific C. jejuni strains [Jacobs et al., 1997a]. Cross-reactivity with the GQ1b ganglioside, which is present in cranial and other peripheral nerves, may in part account for the restricted involvement seen in patients with Miller Fisher syndrome [Willison et al., 1993, 1999]. This is in contrast to the classic form of Guillain-Barré syndrome in which molecular mimicry has been described between anti-GM1 antibodies and C. jejuni [Ang et al., 2001; Carpo et al., 1998; Kuroki et al., 2001]. Successful treatment with intravenous immune globulin has been reported in a 3-year-old boy with Miller Fisher syndrome [Arakawa et al., 1993].

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Neuromuscular Disorders / 77

Polyneuritis Cranialis

Differential Diagnosis

Polyneuritis cranialis can occur in children, and it manifests with the acute onset of multiple cranial nerve palsies (usually bilateral VII and sparing of II) with elevated cerebrospinal fluid protein, slowing of motor conduction velocities, and good recovery [Lyu et al., 2004; Polo et al., 1992, 2002]. Bilateral facial weakness, dysphonia, and dysphagia are typical symptoms. Evidence suggests some association with cytomegalovirus infection. Visser studied 20 cytomegalovirus-associated Guillain-Barré syndrome patients, comparing the findings with earlier established data of C. jejuni-related Guillain-Barré syndrome patients, and found that they were significantly younger, initially had a severe course indicated by a high frequency of respiratory insufficiency, and often developed cranial nerve involvement and severe sensory loss [Visser et al., 1996]. This finding was in contrast to patients with C. jejuni infection, which was more commonly associated with an acute inflammatory demyelinating polyneuropathy phenotype. Enhancement of multiple cranial nerves seen with postcontrast magnetic resonance imaging (MRI) has also been documented, but clinical symptoms and electrodiagnostic studies reflected abnormalities caused by some, but not all, of the enhancing cranial nerves [Fulbright et al., 1995; Morosini et al., 2003].

A variety of other peripheral and occasionally CNS disorders can be confused with Guillain-Barré syndrome. These are outlined in Box 77-3, and the reader is referred to the specific chapters that discuss these conditions.

Guillain-Barré Syndrome with Central Nervous System Manifestations Although rare, Guillain-Barré syndrome with central nervous system (CNS) manifestations is reasonably well described in both adults and children [Bradshaw and Jones, 2001; Gamstorp 1974; Maier et al., 1997; Nadkarni and Lisak, 1993; Okumura et al., 2002]; however, the incidence, severity, neuroimaging, and pathologic characterization of Guillain-Barré syndrome immune-mediated or toxic encephalopathy in children remains elusive. Maier and colleagues reported on 13 postmortem examinations of adult patients with Guillain-Barré syndrome whose death ranged from 1 day to 12 months from the onset of neurologic symptoms. CNS pathologic findings were predominantly secondary to injury to spinal nerve roots and cranial nerves. Evidence of primary inflammation was present, especially within the spinal cord, medulla, and pons, with clusters of mononuclear cells around small vessels. Although features of primary demyelination were identified in the peripheral nervous system in 12 of 13 patients, it was not detected in the CNS in any patients. Nadkarni and Lisak [1993] reported a 28-year-old patient with acute Guillain-Barré syndrome who developed bilateral optic neuritis and extensive CNS white matter lesions on MRI. This illness was associated with Mycoplasma pneumoniae infection and suggested some degree of overlap with acute disseminated encephalomyelitis. It was hypothesized that certain infections might have a shared epitope that targets both the peripheral nervous system and CNS. The finding of abnormal central conduction using somatosensory evoked potentials in children with Guillain-Barré syndrome and Miller Fisher syndrome supports the possibility that CNS involvement may also occur in children. It is likely that such involvement in young children, particularly if there is severe generalized weakness with or without respiratory failure, may be clinically difficult to detect.

Clinical Laboratory Evaluation The diagnosis of Guillain-Barré syndrome is based on clinical features. Confirmatory laboratory studies include cerebrospinal fluid examination, electrophysiologic testing, and occasionally MRI to look for enhancement in spinal roots after contrast administration.

Box 77-3 DIFFERENTIAL DIAGNOSIS OF GUILLAIN-BARRÉ SYNDROME Cerebral Bilateral strokes Hysteria Cerebellar Acute cerebellar ataxia syndrome (multiple etiologies) Posterior fossa structural lesion Spinal Compressive myelopathy Transverse myelitis Anterior spinal artery syndrome Peripheral nerve Toxic neuropathy Drugs: amitriptyline, dapsone, glutethimide, hydralazine, isoniazid, nitrofurantoin, nitrous oxide, incrusting Toxins: acrylamide, glue sniffing, fish toxins, heavy metals (lead, arsenic, mercury, thallium), insecticides, N-hexane and other solvents, organophosphates Critical illness neuropathy Diphtheria Tick paralysis Porphyria Neuromuscular Junction Botulism Myasthenia gravis Neuromuscular-blocking agents Muscle Diseases Acute viral myositis Acute inflammatory myopathies (polymyositis, dermatomyositis) Metabolic myopathies (multiple types) Periodic paralysis Modified from Evans OB. Guillain-Barré syndrome in children. Pediatr Rev 1986;8:69; and Jones HR. Childhood Guillain-Barré syndrome: Clinical presentation, diagnosis, and therapy. J Child Neurol 1996;11:4.

Sladky and Ashwal / Inflammatory Neuropathies

Cerebrospinal Fluid A characteristic laboratory finding supporting the diagnosis of Guillain-Barré syndrome is albuminocytologic dissociation or a disproportionate elevation of cerebrospinal fluid protein in the absence of significant evidence of inflammation (i.e., >10 mononuclear cells/mm3 of cerebrospinal fluid) after the first week of symptoms of the disease. The presence of significant cerebrospinal fluid pleocytosis (>50 mononuclear cells/mm3) or the presence of polymorphonuclear leukocytes in the cerebrospinal fluid should raise doubt about the diagnosis of Guillain-Barré syndrome [Asbury and Cornblath, 1990; Jones 1996]. Elevation of cerebrospinal fluid protein includes both albumin and immunoglobulin moieties. This feature of the illness is due to breakdown of the blood-nerve barrier within the subarachnoid space surrounding spinal nerve roots. Cerebrospinal fluid protein elevation may not be detectable early in the course of Guillain-Barré syndrome in about 20% of children. If sites of inflammation within the course of the peripheral nervous system are distal to the intraspinal roots, protein elevation within cerebrospinal fluid may be minimal. In most reported pediatric series, the increase in cerebrospinal fluid protein has been in the range of 80 to 200 mg/dL (normal being less than 40 mg/dL) [Briscoe et al., 1987; Epstein and Sladky, 1990; Jones, 1996, 2000; Rantala et al., 1991].

Electrophysiologic Testing The pathologic hallmark of Guillain-Barré syndrome is multifocal, immune-mediated demyelination within spinal roots and peripheral nerves [Asbury et al., 1969]. The electrophysiologic correlate is the presence of multifocal slowing of nerve conduction or conduction block [Alma et al., 1998; Cros et al., 1996; Hadden et al., 1998; Vriesendorp et al., 1995]. In the case of acute inflammatory demyelinating polyneuropathy, the task of the clinical electrophysiologist is to demonstrate electrophysiologic evidence of multifocal demyelination in sensory and motor peripheral nerves indicative of an acquired, inflammatory disorder. This task requires demonstrating asymmetric slowing of nerve conduction along the course of peripheral nerves, disparate conduction velocities among comparable nerve segments, or the presence of conduction block. Asymmetric slowing along the course of a peripheral nerve might be manifest as disproportionate prolongation of the distal motor latency compared with the degree of conduction slowing in a more proximal nerve segment. Alternatively, markedly prolonged F-wave or H-reflex latencies in the face of reasonably normal distal motor latency and nerve conduction velocity in the limb are indicative of slowing of conduction in proximal nerve segments or spinal roots. Conduction block and temporal dispersion of proximally evoked compound motor action potentials are also features of multifocal segmental demyelination in peripheral nerves and are indicative of an acquired inflammatory demyelinating neuropathy. Box 77-2 includes the revised consensus criteria of electrodiagnostic features considered supportive of the diagnosis of GuillainBarré syndrome [Asbury and Cornblath, 1990]. Application of a form of these criteria in recent studies resulted in 60% of adult patients with Guillain-Barré syndrome fulfilling the

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criteria for polyneuropathy at the first examination (mean time interval, 6 days since disease onset) [Meulstee and van der Meche, 1995].

Magnetic Resonance Imaging Because the differential diagnosis includes transverse myelitis, a possibility that is underscored when weakness is confined to the lower extremities and the child is complaining of back pain, spinal MRI studies may occasionally need to be performed as part of the diagnostic evaluation. Several observers have noted marked gadolinium enhancement of the cauda equina and lumbar nerves that is indicative of an inflammatory process confined to dorsal and ventral spinal nerve roots [Baran et al., 1993; Bertorini et al., 1995; Crino et al., 1994]. Conspicuous nerve root enhancement in some studies appeared to correlate with pain, Guillain-Barré syndrome disability grade, and duration of recovery [Gorson et al., 1996]. Nerve root enhancement was also 83% sensitive in the diagnosis of acute Guillain-Barré syndrome and was present in 95% of typical cases; it is potentially useful in patients in whom the electrophysiologic abnormalities are equivocal.

Pathologic Findings The pathologic findings of Guillain-Barré syndrome are confined predominantly to spinal nerve roots and peripheral nerves [Asbury et al., 1969]. The pathogenesis of the disorder is immune orchestrated with macrophage-mediated demyelination of sensory and motor axons within the peripheral nervous system [Hafer-Macko et al., 1996b; Hartung et al., 1996; Hughes et al., 1999]. There is also evidence that epitopes expressed on axolemma may also be a target for immune attack and result in concomitant axonal degeneration that commonly accompanies the demyelinating process [Hafer-Macko et al., 1996b; Hartung et al., 1999; Hughes et al., 1999]. It is likely that both myelin–Schwann cell and axonal surface epitopes are immunologically targeted to variable degrees during the active phase of GuillainBarré syndrome, resulting in the spectrum of clinical manifestations of the disease. The typical pathogenic mechanism in Guillain-Barré syndrome involves macrophages insinuating themselves under the myelin sheath at the node of Ranvier or between myelin lamellae and stripping myelin from the underlying axon [Hafer-Macko et al., 1996b; Hartung et al., 1996, 2002; Hughes et al., 1992, 1999; Kiefer et al., 2001; Steck et al., 1998]. Documenting the early events in the immune-mediated attack on the peripheral nervous system is, for obvious reasons, difficult in humans. The early pathologic changes have been characterized in a laboratory model, experimental allergic neuritis, a nearly homologous disorder to Guillain-Barré syndrome. Experimental allergic neuritis can be induced in laboratory rodents immunized with constituents of peripheral nerve myelin or with transfer of activated T cells from animals with the disease (Fig. 77-1) [Rostami, 1997]. A different pattern of injury has been described (Fig. 77-2) in acute motor axonal neuropathy related to Campylobacter species infection. In these patients, macrophages have again been found to interrupt axoglial tight junctions at nodes of Ranvier and attack and

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Neuromuscular Disorders / 77

FIGURE 77-1. Cross-section through a sciatic nerve from a Lewis rat during the acute phase of experimental allergic neuritis. There is a large collection of mononuclear cells within the endoneurium during this acute phase of the illness (bounded by arrows) (×250). (Courtesy of John Sladky, MD.)

FIGURE 77-2. Cross-section through a sciatic nerve from a Lewis rat during the acute phase of experimental allergic neuritis. Note that there are several demyelinated axons (some indicated with asterisks) and thinly myelinated axons in the early stages of remyelination. Large-caliber myelinated axons demonstrating splitting and fragmentation of myelin lamellae in the early stage of macrophage-mediated demyelination are present (arrows) (×650). (Courtesy of John Sladky, MD.)

destroy the motor axon, sparing the circumferential myelin, which then secondarily breaks down [Griffin et al., 1995, 1996a, 1996b; Hafer-Macko et al., 1996a; McKhann et al., 1993]. This process results in a relatively pure motor syndrome without evidence of primary demyelination on histopathologic examination or electrophysiologic testing [Griffin et al., 1995, 1996a, 1996b; Hafer-Macko et al., 1996a; McKhann et al., 1993]. The sequence of events that engenders autoimmune neuromuscular disorders such as Guillain-Barré syndrome is incompletely understood. Dalakas [1995] emphasized that several sequential steps are required to orchestrate autoimmunemediated tissue injury. The first is breaking of tolerance in which molecular mimicry, cytokine stimulation, or superantigens, individually or in concert, activate T cells to recognize autoantigens. The second requires antigen recognition by T-cell receptors and antigen processing through the class I

or II major histocompatibility complexes. This second step is modulated by costimulatory factors, such as B7 and B7-binding proteins, and intercellular adhesion molecule-1. The activated T cells must then gain access to their targeted autoantigens. In the peripheral nervous system, they must traverse the blood-nerve barrier, usually through a pathway of adhesion molecules including selectins and leukocyte integrins and their counter-receptors on endoneurial vascular endothelial cells. Finally, activated T cells and autoantibodies enter the endoneurium along with macrophages and bind targeted epitopes on Schwann cells, axons, or both, resulting in tissue injury and phagocytosis [Dalakas, 1995, 1999a, 1999b; Hartung et al., 2001, 2002; Hughes et al., 1999]. The presence of proinflammatory and anti-inflammatory cytokines acts to modulate the intensity of the autoimmune attack on endoneurial contents. Nerve fibers in peripheral nerves are relatively protected from systemic immune responses and inflammatory reactions by the specialized endoneurial, endothelial, and perineural barriers [Dalakas, 1995; Hartung et al., 2001, 2002; Hughes et al., 1999]. Compared with peripheral nerve trunks, there are more macrophage-like cells and more permeable blood vessels in the dorsal root ganglia and spinal roots that are preferred sites for the inflammatory response in experimental allergic neuritis. As noted earlier, experimental allergic neuritis can be induced by immunization with either myelin proteins or fragments of the proteins. P0 and P2 proteins have been most consistently used to induce this Guillain-Barré syndrome model; a similar but less inflammatory, more chronic demyelinating neuropathy can be induced in rabbits with the glycolipid galactocerebroside [Harvey et al., 1987]. In myelin protein–induced experimental allergic neuritis, CD4+ helper T-cell responses are sufficient to transfer full-blown disease, but antibodies of undefined specificity may also play a part. In rabbit galactocerebroside neuritis, antibodies are probably more important and are directed predominantly against a haptenic group including galactose. A small proportion of patients with Guillain-Barré syndrome and chronic immune demyelinating polyneuropathy show T-cell responses to P0 or P2, which may mark important pathogenetic reactions. In addition, some patients with Guillain-Barré syndrome and chronic immune demyelinating polyneuropathy have antibodies to gangliosides, including for instance the most abundant peripheral nerve ganglioside, GM1, which may also be important. In particular, patients with acute severe GuillainBarré syndrome and marked axonal degeneration often have immunoglobin G antibodies to GM1 and GD1b, whereas patients with Miller Fisher syndrome are characterized by antibodies to GQ1b. Autoimmune responses to neural antigens have become useful diagnostically in some diseases and probably indicate important pathogenetic mechanisms. In inflammatory demyelinating neuropathy, macrophagemediated demyelination is probably targeted by both antibody and T-cell-mediated autoimmune responses. The nature of the autoantigen and the relative importance of Tversus B-cell responses are likely to vary depending on the nature of the initial immunologic stimulus. Antecedent events associated with the subsequent development of Guillain-Barré syndrome have been infection, immunization, drugs [Awong et al., 1996], trauma, or parturition. It is likely that many of the reported associations

Sladky and Ashwal / Inflammatory Neuropathies

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TABLE 77-6 Infectious Agents Associated with Guillain-Barré Syndrome INFECTIOUS AGENT

REFERENCES

Borrelia burgdorferi Brucellosis Campylobacter species Cytomegalovirus Epstein-Barr virus Enteroviral infections Hantavirus Hepatitis virus Herpes virus Measles Mumps Mycoplasma Rocky Mountain spotted fever Typhoid fever

Bouma et al., 1989; Horneff et al., 1993; Lopez de Munain et al., 1990; Mancardi et al., 1989; Shapiro, 1998 Al-Eissa et al., 1996; Berciano et al., 2003; Garcia et al., 1989; Namiduru et al., 2003 Griffin et al., 1993; Hadden and Gregson, 2001; Hughes, 2004; Rees et al., 1995b Jacobs et al., 1997c, 1998; Yuki, 2001 Hadden et al., 2001; Hughes et al., 1999; Jacobs et al., 1998 Alexander et al., 1994; McMinn et al., 2001; Mori et al., 2000; Usui et al., 1974 Esselink et al., 1994; Rabaud et al., 1995 Murthy, 1994; Ono et al., 1994; Tabor, 1987; Tsukada et al., 1987 Dowling and Cook, 1981; Jacobs et al., 1997c; Merelli et al., 1992; Ormerod and Cockerell, 1993 Coe, 1989; Lidin-Janson et al., 1972; Murthy, 1994; Phillips, 1972 Duncan et al., 1990; Ghosh, 1967; Murthy, 1994 Ang et al., 2002; Jacobs et al., 1998; Kusunoki et al., 2001; Meseguer et al., 1998 Toerner et al., 1996 Aldrey et al., 1999; Berger et al., 1986; Chanmugam and Waniganetti, 1969; Donoso, 1988; Ozen et al., 1993

are purely coincidental. The relations between several common infections and immunizations and Guillain-Barré syndrome that seem relatively solid are summarized in Table 77-6. Some of the more well-established infections include cytomegalovirus [Jacobs et al., 1997c], Epstein-Barr virus [Grose et al., 1972; Jacobs et al., 1998] and other herpes viruses [Dowling et al., 1981], hepatitis [Tabor, 1987], and Mycoplasma species infections [Susuki et al., 2004; Thomas et al., 1993]. Of the acute viral infections that have been implicated as possible antecedent events, only cytomegalovirus and Epstein-Barr virus have been found, using serologic markers, to be statistically related to subsequent Guillain-Barré syndrome illnesses [Jacobs et al., 1998; Winer et al., 1988]. The subgroups of Guillain-Barré syndrome—acute inflammatory demyelinating polyneuropathy, acute motor and sensory axonal neuropathy, and acute motor axonal neuropathy—have all been associated with antecedent or coincident systemic infection with Campylobacter species [Hadden and Gregson, 2001; Hughes, 2004; Jacobs et al., 1997b; McCarthy et al., 2001; MelendezVasquez et al., 1997; Rees et al., 1995a; Toyka, 1999]. Controversy exists concerning the oral polio vaccine and its relation to Guillain-Barré syndrome. In 1993, the Institute of Medicine found that the evidence favored acceptance of a causal relationship between oral polio vaccine and GuillainBarré syndrome [Ismail et al., 1998; Stratton et al., 1994], although other epidemiologic studies have found no such correlation [Rantala et al., 1994]. This issue is discussed further in Chapter 91.

Treatment Immunomodulating strategies for the treatment of GuillainBarré syndrome can include agents to interrupt the autoimmune process at several stages from T-cell activation to macrophage-mediated tissue injury [Hahn, 1997; Hughes et al., 1999; Saida, 1996]. There is reasonable evidence that it is possible to blunt the severity of tissue injury by interfering with the autoimmune process at multiple levels, including interventions that (1) block or interfere with antigen recognition or T-cell activation, (2) blunt costimulatory pathways and cytokine activity, (3) impair access of activated cells and autoantibodies to target tissues, (4) selectively elim-

inate activated lymphocyte subpopulations through cytotoxic T-cell receptor ligands, (5) interrupt macrophage targeting or lysosomal activity at antigen recognition sites in the endoneurium, and (6) interfere with effector proteases that mediate cytoskeletal injury [Deretzi et al., 1999; Gabriel et al., 1997; Hartung et al., 2000; Hughes et al., 1998; Jung et al., 1995; Kiefer et al., 2001; Laura et al., 2002; Redford et al., 1997; Stoll, 2002; Yu et al., 2002; Zou et al., 1999, 2000, 2002]. The mechanisms by which plasmapheresis and intravenous immune globulin administration act in Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy are not entirely understood. It is likely that the primary effect of plasmapheresis is to remove circulating antibody directed toward peripheral nerve antigens. The predominant effect of intravenous immune globulin is speculative. High-dose intravenous immune globulin administration may act by binding anti-idiotypic antibodies, absorbing complement, or down-regulating B-cell–mediated antibody production. Other actions that may also play a role include blockade of activated receptors, enhancement of suppressor cell activity, and interference with lymphocyte proliferation (Thornton and Griggs, 1994). Both of these therapies also down-regulate production of proinflammatory cytokines, which play an important role in enhancing the severity of the immune-mediated injury [Aarli, 2003; Creange et al., 1996; Jander et al., 2001; Lisak et al., 1997; Sharief et al., 1999; Stoll, 2002]. There are no definitive, prospectively derived data to indicate that treatment of children with Guillain-Barré syndrome with plasmapheresis or intravenous immune globulin is efficacious. Nevertheless, several limited studies indicate that both treatments may be effective for this disorder [Abd-Allah et al., 1997; Baskin et al., 1996; Epstein and Sladky, 1990; Gurses et al., 1995; Jansen et al., 1993; Kanra et al., 1997; Khatri et al., 1990; Lamont et al., 1991; McKhann, 1990; Shahar and Leiderman, 2003; Singhi et al., 1999; Sladky, 2004; Vajsar et al., 1994]. Evidence in large prospective trials of plasmapheresis and intravenous immune globulin involving predominantly adults has confirmed that both treatment modalities reduce morbidity associated with Guillain-Barré syndrome and that they are comparable in efficacy [French Cooperative Group on Plasma

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Neuromuscular Disorders / 77

Exchange in Guillain-Barré Syndrome, 1987; Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group, 1997]. Both modalities appear to reduce the duration of the disease and improve the neurologic outcome [Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group, 1997]. In addition, the Guillain-Barré Syndrome Study Group documented that treatment with high-dose intravenous corticosteroids was not only ineffective but also likely to be harmful in adults with Guillain-Barré syndrome [Guillain-Barré Syndrome Steroid Trial Group, 1993]. In a subsequent study by these same investigators, plasmapheresis and intravenous immune globulin were found to be comparable in efficacy, and these two treatments in combination were not superior to either treatment alone in adults with Guillain-Barré syndrome [Plasma Exchange/ Sandoglobulin Guillain-Barré Syndrome Trial Group, 1997)]. Subsequent studies have examined the benefit of performing two, four, or six plasmaphereses in patients with varying degrees of severity of Guillain-Barré syndrome [French Cooperative Group on Plasma Exchange in Guillain-Barré Syndrome, 1987]. The conclusions of this study recommended that patients with mild Guillain-Barré syndrome on admission receive two cycles of plasmapheresis, whereas patients with moderate or severe forms would benefit from two additional exchanges. More than four exchanges did not enhance the pace or completeness of recovery.

Plasmapheresis Available data on treatment of children with Guillain-Barré syndrome are derived from small, nonrandomized series

using, for the most part, historical controls (Table 77-7). One of these studies looking at treatment and control groups that were reasonably well matched in terms of demographic characteristics and disease severity indicated that plasmapheresis significantly shortened the time required for nonambulatory patients to regain independent ambulation from 60 to 24 days [Epstein and Sladky, 1990]. This observation has been confirmed by other studies in at least 50 pediatric patients [Jansen et al., 1993; Khatri et al., 1990; Lamont et al., 1991]. In adult studies, plasmapheresis was particularly effective when started within 7 days of the onset of symptoms. Similar observations have been noted in several of the studies of children with severe Guillain-Barré syndrome [Jansen et al., 1993]. Rantala and colleagues [1995] have suggested that certain factors increase the risk for respiratory failure in children with Guillain-Barré syndrome and that, if present, early treatment with plasmapheresis or intravenous immune globulin is warranted. In this study, signs and symptoms predictive of respiratory failure included (1) onset of symptoms of Guillain-Barré syndrome within 8 days after a preceding infection, (2) presence of cranial nerve involvement, and (3) cerebrospinal fluid protein level greater than 800 mg/L during the first week of illness [Rantala et al., 1995]. Plasmapheresis appears to be safe in children but is limited to some degree by size constraints of the patient and the availability of a technically trained staff and appropriately sized equipment. Children as young as 8 months of age have been treated [Delgado, 1996], and the reported morbidity associated with plasmapheresis in children is minimal [Epstein and Sladky, 1990; Jansen et al., 1993]. Potential

TABLE 77-7 Results of Treatment with Plasmapheresis or Intravenous Immune Globulin in Children with Guillain-Barré Syndrome*

REFERENCE

NO. OF PATIENTS IMPROVED/ TREATED

TIME TO WALKING: TREATMENT GROUP (DAYS)

TIME TO WALKING: CONTROL GROUP (DAYS)

Plasmapheresis Niparko et al., 1989

Not stated/15

NA

NA

Epstein and Sladky, 1990 Khatri et al., 1990 Lamont et al., 1991 Jansen et al., 1993 Hernandez Gonzalez et al., 1993 Hammersjö, 1995

9/9 10/11 5/6 8/8 3/5 0/11

24 NA 17 NA NA —

60 NA 43 NA NA —

Intravenous Immune Globulin Shahar et al., 1997

25/26

NA

NA

Reisin et al., 1996

0/13

NA

NA

Vallee et al., 1993 Vajsar et al., 1994

12/13 9/10

12 NA

51 NA

Goodhew et al., 1996 Abd-Allah et al., 1997 Kanra et al., 1997

7/7

NA

NA

Not stated/75

NA

NA

OTHER COMMENTS

All patients were in ICU with ventilatory assistance 14 control GBS patients At 6 months, 9 of 11 were normal 18 control GBS patients Lower GBS scores in treatment group Cardiac arrest in 1 patient — 20 patients able to walk within 1 week of IVIG Not improved, particularly those with low CMAP 8 control GBS patients Time to improve 2 GBS scores was 17 days in IVIG group and 48 days in plasmapheresis group IVIG treatment similar to plasmapheresis Mean time to improve 1 clinical grade 20.8 days in IVIG group, 64.2 days in controls

*Only reports with at least five pediatric patients are included in this table. CMAP, compound motor unit action potential; GBS, Guillain-Barré syndrome; ICU, intensive care unit; IVIG, intravenous gamma globulin; NA, not available.

Sladky and Ashwal / Inflammatory Neuropathies

complications include hemorrhage, hypotension, transfusion reactions, transmitted infections, septicemia, hypocalcemia, arrhythmias, cardiac arrest, and local tissue injury. There have been no reported deaths caused by plasmapheresis in children.

Intravenous Immunoglobulin Similar results have also been reported in trials of intravenous immune globulin in children with Guillain-Barré syndrome [Abd-Allah et al., 1997; al-Qudah, 1994; Kanra et al., 1997; Reisin et al., 1996; Shahar et al., 1997] and are summarized in Table 77-7. Shahar and colleagues, in an open prospective multicenter study of 26 children with severe Guillain-Barré syndrome, concluded that intravenous immune globulin was effective and safe in severe childhoodonset disease and considered it the initial treatment of choice [Shahar et al., 1997]. They administered a total dose of 2 g/kg on 2 consecutive days and found marked and rapid improvement in 25 children (improvement by 1 to 2 disability grade scales within 2 weeks of treatment). Twenty were able to walk independently by 1 week, and one could be weaned off ventilatory support. Eighteen children recovered by 2 weeks. The rest recuperated in 4 months, including a child who was artificially ventilated for 4 weeks. AbdAllah and colleagues compared a group of seven children treated with intravenous immune globulin with another cohort of eight children treated with plasmapheresis and found that intravenous immune globulin was equally effective [Abd-Allah et al., 1997]. They reviewed data on 74 previously treated pediatric patients and also concluded that intravenous immune globulin should be considered the initial choice of treatment.

Critical Care Management Despite the dramatic therapeutic advances made during the past two decades, Guillain-Barré syndrome remains a serious disorder that requires careful management, particularly for patients who develop respiratory failure or lose the ability to swallow and maintain nutrition. The mortality rate for adults with Guillain-Barré syndrome remains at 5% to 8% [Hahn, 1996]. Within industrialized countries, the mortality from Guillain-Barré syndrome in children is virtually zero. For reasons incompletely understood, the mortality in countries with more limited resources remains in the range of 10% [Molinero et al., 2003]. Several articles, predominantly focusing on adult patients with Guillain-Barré syndrome, have reviewed selected aspects of care in the critical-care setting [Fulgham and Wijdicks, 1997; Hahn, 1996; Henderson et al., 2003; Hughes, 1992, 1998; Hughes et al., 2003b; Kieseier et al., 2004; Ng et al., 1995; Ropper, 1994; Zochodne et al., 1996]. By definition, children with Guillain-Barré syndrome who require intensive care unit care admission are the most severely affected. In addition to paralysis and respiratory failure, which is the usual reason for admission to the intensive care unit, attendant concerns include secondary infection, gastrointestinal dysfunction, urinary obstruction, and the risk for pulmonary embolism. Other dysautonomic symptoms, including hypertension and hypotension, volume loss caused by excessive perspiration, and cardiac dysrhythmias,

1929

may also complicate the course [Ropper, 1994; Zochodne, 1994]. Additional care must be taken with children concerning their fragile nutrition and hydration status. Intravenous hyperalimentation frequently is required, and occasionally, in long-term severely compromised patients, percutaneous gastrostomy is necessary. Many of these severely affected children also have marked dysesthetic symptoms, and adequate pain control is essential. Attention to the stress of illness on the family and awareness of the problems attendant with the loss of verbal and nonverbal forms of communication, particularly in children, are critical in the successful management of these patients [Khatri and Pearlstein, 1997; Manners and Murray, 1992; McDouall and Tasker, 2004; Mikati and DeLong, 1985; Moulin et al., 1997; Nguyen et al., 1999; Pentland and Donald, 1994; Roca et al., 1998; Ropper and Shahani, 1984]. In GuillainBarré syndrome, as in other acute debilitating disorders, the early implementation of a comprehensive rehabilitation program, preferably within the intensive care unit for severely affected patients, will prevent many secondary complications of the disease.

Prognosis Most series indicate that the prognosis for children who develop Guillain-Barré syndrome is generally excellent and probably better than that for older age groups [Briscoe et al., 1987; Cole and Matthew, 1987; Kleyweg et al., 1989; Korinthenberg and Monting 1996; Ortiz Corredor et al., 2003; Rantala et al., 1991; Sladky, 2004; Vajsar et al., 2003]. Opinion in the literature is not unanimous, and dissenting viewpoints argue that the clinical course and prognosis are similar in children and adults [Kleyweg et al., 1989]. In the group of 49 children listed in Table 77-3, 80% achieved complete functional recovery within 6 months of the onset of illness. About 20% had mild residual neurologic deficits, including mild weakness in the facial or lower extremity muscles and decreased deep tendon reflexes [Barbara Martin, M.D., personal communication]. Similar findings, as reviewed earlier in this chapter, were reported from a retrospective international multicenter study of 175 children with Guillain-Barré syndrome [Korinthenberg and Monting 1996]. A limitation in our ability to draw definitive conclusions regarding the prognosis of Guillain-Barré syndrome in children is the absence of prospectively defined, systematically collected clinical data. The numbers of children included in individual published studies are small, which contributes to the variable fashion in which these limited observations are interpreted. The consensus in the literature is that children will do at least as well if not better than older patients with Guillain-Barré syndrome [Jones, 2000; Korinthenberg and Monting, 1996; Sladky, 2004]. This opinion is reinforced by several nonprospective studies looking at treatment in which children recover faster after plasmapheresis or intravenous immune globulin administration than published recovery rates in adults [Epstein and Sladky, 1990; Jansen et al., 1993; Jones 2000; Korinthenberg and Monting 1996; Lamont et al., 1991; Reisin et al., 1996; Sladky, 2004]. These studies are not directly comparable and need to be interpreted with caution; however, there is emerging consensus that prognosis in childhood

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Box 77-4 RESEARCH CRITERIA FOR THE DIAGNOSIS OF CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY

Sladky and Ashwal / Inflammatory Neuropathies

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Box 77-4 RESEARCH CRITERIA FOR THE DIAGNOSIS OF CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY CONT’D

From the Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. Research criteria for the diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Neurology 1991;41:617.

Guillain-Barré syndrome is good and may be enhanced with developing treatment modalities.

CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY Chronic inflammatory demyelinating polyneuropathy is an immune-mediated polyneuropathy of more than 2 months’ duration. Criteria for the diagnosis of this condition were developed in 1991 by an ad hoc subcommittee of the American Academy of Neurology and are listed in Box 77-4. These criteria were developed for research purposes and may be somewhat restrictive for general clinical practice. They provide, however, helpful benchmarks for evaluating patients with suspected chronic inflammatory demyelinating polyneuropathy. Chronic progressive and relapsing subtypes have been described.

Epidemiology The true incidence of this disorder in children is unknown and probably unlikely to come to light. Although it represents the most common acquired, potentially treatable chronic neuropathy in childhood, it is nonetheless rare. Ascertaining the incidence of this disease in the pediatric population is further complicated by its propensity for mimicking genetically determined neuropathies, except that the often anticipated history of dominant transmission in the kinship is lacking. Because many children affected with this disorder respond well to immunosuppressive therapy, it is critical to consider this disease in the differential diagnosis of any child with chronic neuropathy, particularly when there are features of demyelination and when evidence for a hereditary pattern cannot be elicited [Connolly, 2001; Korinthenberg, 1999; McLeod et al., 1999; Nevo, 1998; Rodriguez-Casero et al., 2003; Ryan et al., 2000; Sladky, 1996].

Clinical Features The clinical features of chronic inflammatory demyelinating polyneuropathy are protean, and diagnosis can be difficult. It can present as an indolently progressive, predominantly motor neuropathy and closely resemble hereditary motor and sensory neuropathy type I, including several genotypic variants [Carter et al., 2004]. Active demyelination may be confined to proximal nerve segments, and electrophysiologic testing may be most compatible with an axonal neuropathy, with the disease masquerading as hereditary motor

and sensory neuropathy type II. It has been reported to present in infancy with extremely slow nerve conduction velocity measurements resembling hereditary motor and sensory neuropathy type III disease [Sladky, 1996]. It may also present with features of sensory ataxia and can mimic Friedreich’s ataxia. Alternatively, the clinical manifestations may include any combination of these presentations. In some children, the disease presentation is more typical, with the distinct onset of neuropathic symptoms in a previously healthy child, a negative family history with normal examination of both parents, and confirmatory laboratory studies. This scenario is usually the exception, and the likelihood of diagnosing children with more subtle presentations of chronic inflammatory demyelinating polyneuropathy is directly related to the persistence and expertise of the neurologist evaluating such patients. In summary, the disease may present in any age group, the rate of progression may be subacute to indolent, and it may affect selective populations of peripheral nerve axons and interrupt function of any organ system that relies on peripheral nerve function for feedback or regulatory input. There have been several series reporting the clinical, electrophysiologic, histopathologic, and prognostic features in children with chronic inflammatory demyelinating polyneuropathy [Connolly, 2001; Hattori et al., 1998; Korinthenberg, 1999; Nevo et al., 1996; Simmons et al., 1997a, 1997b; Sladky, 1996]. As one might predict, there are divergent observations among individual reports, presumably as a consequence of relatively small numbers in each series. Looking at the papers in aggregate, several common themes emerge. First, like adults with chronic inflammatory demyelinating polyneuropathy, the clinical course and response to treatment are variable. Similarly, children may present with a subacute course or a more subtle indolent progression of symptoms. Lower extremity weakness is the most common presenting complaint, whereas sensory symptoms are relatively uncommon. Areflexia is the rule. Second, the pace of progression of the initial symptoms may be subacute, over 2 to 3 months, or may exhibit a more protracted course. On some occasions, the initial temporal progression of the disease may be so indolent as to mimic genetically determined neuropathies. Those with a more rapid pace of onset of their chronic inflammatory demyelinating polyneuropathy may have a better likelihood of responding to treatment and a more benign outcome. Third, electrophysiologic testing is a useful diagnostic tool and will, in most cases, confirm the acquired nature of the neuropathy. These tests, however, have only limited predictive value regarding prognosis. Fourth, chronic inflam-

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Neuromuscular Disorders / 77

matory demyelinating polyneuropathy is an eminently treatable disease in children. Therapeutic outcomes fall roughly into three categories. Most children initially improve in response to treatment with corticosteroids. About half the children with chronic inflammatory demyelinating polyneuropathy have a monophasic course and are able to be weaned from steroids, albeit, in many cases, over a protracted period of time. The balance become refractory to steroid treatment and require alternative immunosuppressants or suffer one or more relapses. Most of this group will respond to immunosuppressant therapies, and many achieve remission. A small fraction of children with chronic inflammatory demyelinating polyneuropathy may become refractory to aggressive immunotherapy and become dependent on chronic immunosuppression or sustain severe, widespread peripheral nerve injury with substantial residual neurologic disability. Like the situation in Guillain-Barré syndrome, the prognosis for children with chronic inflammatory demyelinating polyneuropathy is more favorable than among adults.

Laboratory Evaluation Although there are persuasive arguments to the contrary, it is sometimes useful to look at Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy as different ends of the spectrum of the same disease. In that context, the similarities between the disorders are more striking than the differences. Like the children with the more fulminant Guillain-Barré syndrome, children with chronic inflammatory demyelinating polyneuropathy may evidence pathognomonic features of multifocal demyelination on electrophysiologic testing. These features have been reviewed extensively [Albers et al., 1989; Connolly 2001; Hattori et al., 1998; McCombe et al., 1987; Simmons et al., 1997b]. Sensory and motor nerve conduction studies are the most useful and practical way to assess the physiologic properties of saltatory conduction in large-caliber myelinated fibers. Such data may be useful in distinguishing inherited from acquired disorders. However, none of the electrophysiologic measures are, in themselves, absolute discriminators. Excluding those rare kinships with steroid-responsive inherited demyelinating neuropathy [Bird et al., 1991; Dyck et al., 1982c], some children with typical hereditary motor and sensory neuropathy type I may demonstrate dispersion of proximal evoked compound motor action potentials and conduction block. Conversely, some children with chronic inflammatory demyelinating polyneuropathy may have electrophysiologic characteristics that suggest a genetically determined disease. When the clinical history is suggestive of an acquired disorder and electrophysiologic testing is compatible with an axonal neuropathy, cerebrospinal fluid examination may be helpful in demonstrating an elevated protein concentration typical of demyelinating neuropathies. Measurement of circulating antibodies to myelin protein constituents is rarely useful in children. Contrast-enhanced MRI may indicate blood-nerve barrier breakdown caused by spinal nerve root inflammation [Bertorini et al., 1995; Crino et al., 1993; Kuwabara et al., 1997]. Nerve biopsy may be necessary to assist in discriminating acquired from sporadic or recessively transmitted genetic disorders [GabreelsFesten et al., 1993]. Because de novo mutations can result in the appearance of a sporadic disorder, testing for an abnor-

mality in the more common gene mutations associated with hereditary motor and sensory neuropathy type I phenotype may establish a diagnosis and define implications for prognosis and genetic counseling. Finally, when the clinical and laboratory data remain inconclusive, including clinical and electrophysiologic examination of family members, a therapeutic trial of immunosuppressive therapy may be warranted.

Pathologic Findings The most characteristic histopathologic features on nerve biopsy of patients with chronic inflammatory demyelinating polyneuropathy are loss of myelinated axons, particularly larger-caliber axons; evidence of segmental demyelination and remyelination; and regional variability in the severity of fiber loss and inflammation [Baba et al., 1993; GabreelsFesten et al., 1993; Matsumuro et al., 1994; Sladky et al., 1986]. The presence of inflammatory cells and selective fascicular variability in the expression of pathologic abnormalities are the only characteristics helpful in distinguishing an acquired from a genetically determined disorder [GabreelsFesten et al., 1993]. The presence of thinly remyelinated internodes, segmental demyelination and remyelination, and onion bulb formations (indicative of chronicity) may be seen in any chronic demyelinating neuropathy. Specific features of inflammation (i.e., mononuclear cellular infiltrates) are present in a minority of biopsies from children and infants with chronic inflammatory demyelinating polyneuropathy. Most children with chronic inflammatory demyelinating polyneuropathy demonstrate evidence of subperineurial and endoneurial edema and an increased number of inflammatory cells dispersed within the endoneurium [Sladky et al., 1986]. Discrete perivascular collections of inflammatory cells around epineurial or endoneurial vessels are relatively rare. Teased fiber preparations demonstrating isolated demyelinated internodes or random variability in internodal length and myelin thickness are also highly suggestive of a multifocal inflammatory demyelinating process (Fig. 77-3). Electron microscopy may confirm these features and demonstrate fragmentation of myelin sheaths with splitting of myelin lamellae and intralamellar insinuation of macrophages ingesting internodal myelin. Immunocytochemical testing may be helpful to confirm activated lymphocytic subpopulations within the endoneurium and demonstrate expression of class I and II major histocompatibility complex markers on Schwann cell surfaces in areas of active demyelination. Similar findings have been reported in Guillain-Barré syndrome as well [Asbury et al., 1969; Hughes et al., 1992]. More recently, circulating antibodies to myelin-related gangliosides have been reported and associated, for the most part loosely, with specific Guillain-Barré syndrome subtypes. However, antibodies to any of these candidate myelin autoantigens were not significantly more frequent in patients with chronic inflammatory demyelinating polyneuropathy than in controls or other groups studied. In addition, serologic evidence of C. jejuni or cytomegalovirus infection was not detected. The ability to make a conclusive diagnosis from a biopsy specimen in a multifocal process such as chronic inflammatory demyelinating polyneuropathy is limited by the problem of sampling error. Because only a finite amount of tissue is removed, pathognomonic histopathologic features may not be

Sladky and Ashwal / Inflammatory Neuropathies

FIGURE 77-3. Teased fiber preparation of osmicated axons from a patient with chronic immune demyelinating polyneuropathy. Sequential internodes along the course of an individual myelinated axon are shown. (Individual nodes of Ranvier are indicated with arrowheads.) The random variability in internodal length and myelin thickness is pathognomonic for a multifocal demyelinating process and could be seen in chronic immune demyelinating polyneuropathy or during the recovery stage in Guillain-Barré syndrome (×75). (Courtesy of John Sladky, MD.)

present in the sample obtained for pathologic inspection. This situation is of particular concern in chronic inflammatory demyelinating polyneuropathy, in which inflammation with secondary axonal injury may be confined to proximal nerve segments. A biopsy specimen from a sural nerve site well “downstream” from the area of active inflammation may indicate only evidence of wallerian degeneration of distal axons below the level of primary injury.

Treatment Several therapeutic modalities have been found to be effective in the management of chronic inflammatory demyelinating polyneuropathy, including corticosteroids, plasmapheresis, intravenous immune globulin, and other immunosuppressive agents [Baba et al., 1993, 1996; Barnett et al., 1998; Berger et al., 2003; Brannagan, 2002; Brannagan et al., 2002; Choudhary and Hughes, 1995; Comi et al., 2003; Connolly, 2001; Dalakas, 2002, 2004a, 2004b; Dyck et al., 1982a, 1982b, 1985a, 1985b, 1986, 1994; Good et al., 1998; Gorson et al., 2004; Gorson et al., 1998; Hahn et al., 1996a, 1996b; Hodgkinson et al., 1990; Hughes et al., 2003a; Kissel, 2003; Mahattanakul et al., 1996; Mendell et al., 2001; Meriggioli and Rowin, 2000; Molenaar et al., 1997; Mowzoon et al., 2001; Vallat et al., 2003; van Doorn and Ruts, 2004]. However, there are few data comparing the relative efficacy of these treatments [Choudhary and Hughes, 1995; Choudhary et al., 1995b]. It remains unclear which treatment should be a first-line regimen in the treatment of chronic inflammatory demyelinating polyneuropathy.

1933

In patients with suspected or definite chronic inflammatory demyelinating polyneuropathy, initial treatment with prednisone at a dose of 2 mg/kg/day for 6 to 8 weeks has been successful. Most previously untreated children with the disease demonstrate substantial functional improvement within that time frame [Baba et al., 1996; Connolly, 2001; Korinthenberg, 1999; Nevo, 1998; Sladky, 1996]. Lack of significant clinical improvement in this setting implies that (1) the child cannot metabolize prednisone to an active form, (2) the child will not respond well enough to corticosteroids to justify potential long-term side effects, or (3) the child does not have chronic inflammatory demyelinating polyneuropathy. A small number of individuals are unable to metabolize prednisone to an active form. In prednisone nonresponders who also are not demonstrating other clinical signs of steroid effects after 6 to 8 weeks of treatment (i.e., cushingoid facies and weight gain), this possibility should be entertained and methyl prednisolone substituted before discarding corticosteroid therapy. Patients nonresponsive to corticosteroids can be tapered off medication over several weeks. In steroid-responsive individuals, it is desirable to gradually reduce the dosage schedule over 6 months to an alternate-day dose of about 1 mg/kg/day or a dose of 30 mg on alternate days in children weighing more than 30 kg. A cumulative daily dose of 0.5 mg/kg is considered to pose little significant risk for opportunistic infection, osteopenia, or cataract formation. This regimen can be slowly reduced over the next 4 to 6 months. About half the children will remain in remission after treatment is discontinued. In a pilot study involving a small group of patients, pulsed highdose dexamethasone (six cycles at 40 mg/day for 4 days every 28 days) has been reported in adults to be an alternative effective treatment [Molenaar et al., 1997]. Although most children with chronic inflammatory demyelinating polyneuropathy initially respond to corticosteroids, some become refractory or require unacceptably high doses to maintain stable function. Human intravenous immune globulin or plasmapheresis is the next alternate therapeutic option to consider in such patients [Barnett et al., 1998; Gay et al., 1986; Hahn, 2000; Hahn et al., 1996a, 1996b; Kiprov et al., 2003; Tanaka, 1998; Vedanarayanan et al., 1991; Walk et al., 2004]. Intravenous immune globulin has the advantage of permitting treatment at home using visiting nursing teams if the child has exhibited no untoward reactions to an initial course of treatment in the hospital. In older children who are large enough to establish adequate peripheral venous access for plasmapheresis, the procedure can be initiated on an outpatient basis. The choice between therapies depends more on logistical and technical factors than on the inherent superiority of one or the other modality. A small number of children become refractory to these treatments as well and will require more potent immunosuppressive agents to maintain remission. Again, there are no data to guide the clinician as to which immunosuppressant will be best for an individual patient. It is probably wisest to begin with an agent with which the treating physician has the most experience. Clinicians have been inclined to avoid cyclophosphamide and azathioprine in the past because of the potential risk for developing future malignancies. However, there are probably only small differences in the risk for this late complication among different chemotherapeutic agents. Methotrexate is not commonly helpful in chronic

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Neuromuscular Disorders / 77

inflammatory demyelinating polyneuropathy, but it is worth consideration because it can be given orally on a weekly basis and is associated with few complications when serum levels are carefully monitored. Cyclosporine can be useful in treating selected refractory cases of chronic inflammatory demyelinating polyneuropathy [Barnett et al., 1998; Jongen et al., 1988; Mahattanakul et al., 1996; Ryan et al., 2000]. This agent is given orally at an initial dose of 3 to 5 mg/kg twice a day. It is generally a safe drug if renal function and serum levels are carefully followed.

Prognosis The prognosis in children is generally favorable [Ryan et al., 2000; Simmons et al., 1997b; Sladky, 1996; Sladky et al., 1986]. About 50% respond well to corticosteroids and remain in remission after treatment is discontinued. Another 25% to 30% respond to additional treatment modalities and require a prolonged course of treatment. The long-term prognosis in this group of patients remains uncertain. A small number of children respond poorly to all treatment strategies or, more typically, become refractory to treatment or develop significant side effects to protracted immunosuppression and suffer substantial neurologic disability [Connolly, 2001; Nevo, 1998; Nevo et al., 1996; Pollard, 1994, 2002; Ryan et al., 2000; Simmons et al., 1997a, 1997b].

OTHER IMMUNE-MEDIATED NEUROPATHIES IN CHILDREN Table 77-8 summarizes some of the other types of immunemediated peripheral neuropathies that have been observed in children. These occur relatively infrequently and are usually associated with evidence of other systemic symptoms [Tan et al., 2003]. Although peripheral nerve disorders are described as being relatively frequent in patients with human immunodeficiency virus infection, many of the affected children have been identified based on electrodiagnostic criteria and often have little clinical evidence of peripheral nerve involvement [Floeter et al., 1997]. Many of these children are also receiving multiple drugs, and it is likely that peripheral neuropathy in this population is, in some cases, a side effect of treatment rather than a complication of infecTABLE 77-8 Immune-Mediated Neuropathies Other than Guillain-Barré Syndrome and Chronic Immune Demyelinating Polyneuropathy in Children IMMUNE DISORDER Bone marrow transplantation Collagen vascular diseases (juvenile rheumatoid arthritis, lupus erythematosus, mixed connective tissue disease) Human immunodeficiency virus infection Lyme disease Peripheral nerve vasculitis Data from unpublished observations of John T. Sladky, MD.

NO. OF PATIENTS (TOTAL OF 10) 4 3 1 1 1

tion. Inflammatory neuropathy, often with electrophysiologic evidence of demyelination, can occur in the course of graft-versus-host disease after bone marrow transplantation [Adams et al., 1995; Amato et al., 1993; Imrie et al., 1994; Openshaw, 1997; Sladky, 1996]. There are a number of reports associating Borrelia burgdorferi infection with peripheral neuropathy, especially chronic inflammatory demyelinating polyneuropathy. Most of these reports have involved older individuals. Chronic peripheral neuropathy including chronic inflammatory demyelinating polyneuropathy developing in the course of active Lyme disease is rare in childhood [Belman et al., 1993]. As in the case of many associations, a causal relationship between chronic inflammatory demyelinating polyneuropathy and neuropathy may be inferred, but not proved. Finally, vasculitis confined to peripheral nerves and presenting as mononeuritis multiplex is extremely uncommon [Mok et al., 2001] but can occur in children and may respond well to corticosteroids or other immunosuppressant modalities [Bulun et al., 2001]. REFERENCES Aarli JA. Role of cytokines in neurological disorders. Curr Med Chem 2003;10:1931. Abd-Allah SA, Jansen PW, Ashwal S, et al. Intravenous immunoglobulin as therapy for pediatric Guillain-Barré syndrome. J Child Neurol 1997;12:376. Adams C, August CS, Maguire H, et al. Neuromuscular complications of bone marrow transplantation. Pediatr Neurol 1995;12:58. Albers JW, Kelly JJ Jr. Acquired inflammatory demyelinating polyneuropathies: Clinical and electrodiagnostic features. Muscle Nerve 1989;12:435. Aldrey JM, Fernandez-Rial A, Lopez-Gonzalez FJ, et al. Guillain-Barré syndrome as first manifestation of typhoid fever. Clin Infect Dis 1999;28:1171. Al-Eissa YA, Al-Herbish AS. Severe hypertension: An unusual presentation of Guillain-Barré syndrome in a child with brucellosis. Eur J Pediatr 1996;155:53. Alexander JP Jr, Baden L, Pallansch MA, et al. Enterovirus 71 infections and neurologic disease—United States, 1977-1991. J Infect Dis 1994;169:905. al-Qudah AA. Immunoglobulins in the treatment of Guillain-Barré syndrome in early childhood. J Child Neurol 1994;9:178. Alma TA, Chaudhry V, Cornblath DR. Electrophysiological studies in the Guillain-Barré syndrome: Distinguishing subtypes by published criteria. Muscle Nerve 1998;21:1275. Amato AA, Barohn RJ, Sahenk Z, et al. Polyneuropathy complicating bone marrow and solid organ transplantation. Neurology 1993;43:1513. Ang CW, De Klerk MA, Endtz HP, et al. Guillain-Barré syndrome– and Miller Fisher syndrome–associated Campylobacter jejuni lipopolysaccharides induce anti-GM1 and anti-GQ1b antibodies in rabbits. Infect Immun 2001;69:2462. Ang CW, Tio-Gillen AP, Groen J, et al. Cross-reactive antigalactocerebroside antibodies and Mycoplasma pneumoniae infections in Guillain-Barré syndrome. J Neuroimmunol 2002;130:179. Arakawa Y, Yoshimura M, Kobayashi S, et al. The use of intravenous immunoglobulin in Miller Fisher syndrome. Brain Dev 1993;15:231. Asbury AK, Arnason BG, Adams RD. The inflammatory lesion in idiopathic polyneuritis. Its role in pathogenesis. Medicine 1969;48:173. Asbury AK, Cornblath DR. Assessment of current diagnostic criteria for Guillain-Barré syndrome. Ann Neurol 1990;27:S21. Awong IE, Dandurand KR, Keeys CA, et al. Drug-associated GuillainBarré syndrome: A literature review. Ann Pharmacother 1996;30:173. Baba M, Ogawa M, Matsunaga M. Treatment of chronic inflammatory demyelinating polyneuropathy (CIDP). Rinsho Shinkeigaku 1996;36:1336. Baba M, Takada H, Tomiyama M, et al. Chronic inflammatory demyelinating polyneuropathy in childhood. No To Shinkei 1993;45:233. Baran GA, Sowell MK, Sharp GB, et al. MR findings in a child with Guillain-Barré syndrome. AJR Am J Roentgenol 1993;161:161.

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CHAPTER 78

Diseases of the Neuromuscular Junction Gil I. Wolfe and Richard J. Barohn

Both acquired and inherited disorders of the neuromuscular junction occur in childhood. As with adults, the most common neuromuscular junction disorders are autoimmune and respond to immunosuppressive therapy. These include myasthenia gravis and the rarer Lambert-Eaton myasthenic syndrome. A number of genetically determined disorders of neuromuscular transmission, the congenital myasthenic syndromes, are unique to childhood and are discussed later in this chapter. Botulism, a toxin-mediated disorder of the neuromuscular junction, most commonly occurs in infancy. All neuromuscular junction disorders have the ability to produce generalized weakness and fatigability with a propensity for oculobulbar involvement. Electrophysiologic studies detect an impairment of neuromuscular transmission in most of these disorders [Harper, 1996]. Before the various neuromuscular junction disorders are described, normal relevant physiology is reviewed.

THE NEUROMUSCULAR JUNCTION Familiarity with the pathophysiology, diagnosis, and treatment of neuromuscular junction disorders requires a fundamental understanding of normal neuromuscular transmission (Fig. 78-1). Acetylcholine is the natural neurotransmitter of the neuromuscular junction. It is synthesized and stored in vesicles in the motor nerve terminal [Drachman, 1978; Miller, 1985]. Each vesicle contains a quantum (about 10,000 molecules) of neurotransmitter. At rest, individual vesicles spontaneously release their quantum of acetylcholine at special release sites on the presynaptic membrane. The released neurotransmitter migrates and binds to acetylcholine receptors (AchRs) located on the postsynaptic membrane, producing a transient increase in the permeability of sodium and potassium ions. The local endplate depolarization that results is known as a miniature endplate potential. It has been hypothesized that miniature endplate potentials help to maintain resting muscle tone by producing a perpetual background of cholinergic stimulation [Liu and Erickson, 1994]. Miniature endplate potentials are dwarfed by the larger depolarizations that occur when nerve action potentials arrive at the presynaptic terminal. The nerve action potentials rapidly depolarize the presynaptic membrane. Depolarization produces an influx of calcium ions into the motor terminal, leading to exocytosis of a large number of acetylcholine vesicles (150 to 200 quanta). The resulting postsynaptic depolarization is termed an endplate potential. Because of a physiologic safety factor, the endplate potential is normally sufficient to generate an action potential along the muscle membrane. Propagation of this muscle action

potential leads to a cascade of events that drives muscle contraction. The amplitude of the endplate potential is directly related to the number of acetylcholine molecules that bind to their receptors. Normally an adequate number of neurotransmitterreceptor interactions occurs to produce a muscle action potential [Miller, 1985]. As discussed later, the immunologic defect in myasthenia gravis directly reduces this safety margin, and muscle weakness ensues. Neuromuscular transmission is rapid, taking only milliseconds to complete the entire sequence. The process is terminated by diffusion of acetylcholine from the synapse and its rapid hydrolysis by acetylcholinesterase [Liu and Erickson, 1994]. By 20 weeks of gestation, the structure of the neuromuscular junction is well established, with further refinement of the postsynaptic membrane continuing until term [Sanes and Jessell, 2000]. Clustering of AchR in utero depends on muscle-specific receptor tyrosine kinase (MuSK) and rapsyn. Both the AchR and MuSK have been implicated as postsynaptic targets of the immune system in myasthenia gravis [Hoch et al., 2001]. Other neuromuscular junction antigens targeted by plasma factors are likely to be discovered in the future (Plested et al., 2002).

AUTOIMMUNE MYASTHENIA GRAVIS Myasthenia gravis is the best understood autoimmune disease of the nervous system [Vincent et al., 2001]. The immune-mediated nature of myasthenia gravis was suspected as early as 1960 when Simpson speculated that it was an autoimmune disease with antibodies directed against the skeletal muscle AchR. A series of breakthroughs in the 1970s confirmed Simpson’s hypothesis. Lindstrom and colleagues [1976a; Patrick and Lindstrom, 1973] developed the animal model of experimental autoimmune myasthenia gravis by immunizing rabbits and rats with highly purified AchR from the electric organ of the eel. Not only did the animals develop weakness and respiratory insufficiency in about 3 weeks, but they also responded to anticholinesterase medications and demonstrated typical decremental responses on repetitive nerve stimulation [Seybold et al., 1976]. These animals also had high anti-AchR antibody titers in serum. Subsequently, these titers were found in the serum of myasthenia gravis patients [Lindstrom et al., 1976b]. Engel and co-workers [Engel and Arahata, 1987; Engel et al., 1977b] localized both the immunoglobulin G (IgG) antibody and complement to the myasthenia motor endplate. This finding implied that circulating IgG antibody directed against the AchR became bound to the postsynaptic

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Neuromuscular Disorders / 78 FIGURE 78-1. Diagram of the neuromuscular junction. At top, a nerve action potential arrives at the motor terminal and produces rapid depolarization. The depolarization initiates an influx of calcium ions into the motor axon, which leads to synchronized fusion of vesicles containing acetylcholine (Ach) with the presynaptic membrane. Released Ach molecules diffuse across the synapse, bind to their postsynaptic receptors, and generate a localized endplate potential (EPP). If the EPP reaches threshold, the muscle membrane undergoes an increase in sodium conductance, with subsequent generation of a muscle action potential. Propagation of the muscle action potential through the muscle fiber culminates in a cascade of events that drive contraction. Neuromuscular transmission is terminated by diffusion of Ach from the synapse and its rapid cleavage by acetylcholinesterase (AchE).

Nerve action potential

Ca2+ Calcium entry

AchE

Ach release Muscle action potential

Receptor

Na+

Muscle contraction

membrane and activated the terminal complement sequence (C5b-9), or membrane attack complex, which resulted in lysis of the AchR with subsequent degeneration. Elevated membrane attack complex levels have been demonstrated in the plasma of patients with myasthenia gravis [Barohn and Brey, 1993]. Anti-AchR antibody has also been found to block neuromuscular transmission and accelerate turnover of AchR crosslinked by IgG [Drachman, 1978]. As a result of this process, the postsynaptic membrane becomes simplified, with decreased junctional folds [Engel et al., 1976]. In addition, the neuromuscular blockade is passively transferred by injecting animals with IgG from myasthenia gravis patients [Toyka et al., 1977]. The same phenomenon occurs when an infant born to a mother with myasthenia gravis exhibits symptoms at birth, so-called neonatal myasthenia gravis [Papazian, 1992]. The AchR is a large protein consisting of five subunits, and the antibody response in myasthenia gravis and experimental autoimmune myasthenia gravis is polyclonal. The portion of the protein primarily responsible for inducing antibodies that produce the disease is debated. Although the existence of a main immunogenic region in the alpha subunit has been promoted [Tzartos and Lindstrom, 1980], other investigators have challenged this evidence [Lennon and Greismann, 1989]. It is possible that if the most pathogenic determinants of the AchR can be identified, a more rational and specific immune therapy can be designed [Krolick et al., 1994]. The process that initiates the immune-mediated neuromuscular junction dysfunction is still unknown. The thymus gland may play a role, inasmuch as 75% of myasthenia gravis patients who undergo thymectomy have thymic

pathologic findings; 15% are tumors of the thymus, and the remainder consist of lymphoid hyperplasia [Castleman, 1966]. Lymphocytes in the thymus and peripheral blood appear to be sensitized to muscle in myasthenia gravis patients [Sommer et al., 1990, 1991]. Muscle-like myoid cells are found in the thymus gland, and thymus tissue from myasthenia gravis patients with and without thymoma is enriched in AchR-reactive T cells [Kao and Drachman, 1977; Wekerle et al., 1975]. The close association of lymphocytes and myoid cells in the thymus, along with some stimulus causing the disruption of immune tolerance, may lead to the autoimmune response. There may be a hereditary predisposition to develop myasthenia gravis because there is an increased incidence of certain human leukocyte antigens in various myasthenia gravis populations [Behan, 1980; Compston et al., 1980].

Clinical Features Myasthenia gravis has a prevalence of approximately 125 cases per million population [Drachman, 1994]. Approximately 11% to 24% of all patients with myasthenia gravis experience disease onset in childhood or adolescence [Millichap and Dodge, 1960; Simpson, 1958]. There is a slight female predominance of 3:2 at those ages but a male predominance in older age groups. The disease can arise at any age, but peaks are observed in the third and sixth decades. Myasthenia gravis is characterized by weakness and fatigability of ocular, bulbar, and extremity striated muscles. The ocular manifestations are ptosis and diplopia, whereas the bulbar manifestations are dysarthria, dysphagia, and

Wolfe and Barohn / Diseases of the Neuromuscular Junction

dyspnea. Proximal muscles tend to be weaker than distal extremity muscles. Symptoms of myasthenia gravis tend to worsen with stress, with exertion, and as the day progresses. These temporal symptoms, however, may be difficult to elicit in many patients. Myasthenic crisis, characterized by respiratory weakness and the inability to handle secretions or swallow, may punctuate a more stable clinical course in some children. The best data on the natural history of myasthenia gravis are from Grob and co-workers [1987], who carefully studied more than 1400 patients between 1940 and 1985. Some of the key points from their work are as follows: • Most patients present with ocular symptoms. Initial symptoms were ocular in 53% (ptosis in 25%, diplopia in 25%, blurred vision in 3%); leg, arm, face, neck, or trunk weakness in 20%; bulbar symptoms in 16% (difficulty swallowing in 6%, slurred or nasal speech in 5%, difficulty chewing in 4%, dyspnea in 1%); and generalized fatigue in 9%. • Most patients exhibit progression of the disease. One year after onset, the disease was purely ocular in 40%, generalized in 35%, confined to the extremities in 10%, and bulbar or oculobulbar in 15%. However, myasthenia gravis remained purely ocular in only 14% over the entire follow-up period. Therefore, 86% of patients eventually progress to generalized involvement. • If a patient with ocular myasthenia gravis is going to develop general symptoms, this occurs relatively early. Of the patients who presented with purely ocular disease, 56% progressed to generalized disease by 6 months, 78% by the first year, 85% by the second year, and 92% by the third year. • Mortality statistics for myasthenia gravis have fallen dramatically over time. Between 1940 and 1957, the mortality rate was 31%, whereas between 1966 and 1985, the mortality rate was 7%. The two primary reasons for this reduced mortality rate were the improvement in intensive respiratory care and the introduction of corticosteroids. Death from myasthenia gravis is an uncommon event in current practice.

Clinical Classification Osserman [1958] classified myasthenia gravis patients according to disease severity. The most commonly used modification of the original classification is as follows: • • • •

Group I: ocular Group IIA: mild generalized Group IIB: moderate-to-severe generalized Group III: acute, severe, developing over weeks to months • Group IV: late, severe with marked bulbar involvement The Osserman classification has several shortcomings, including the vague descriptive terminology and lack of distinctions between some of the groups. For instance, differentiating between mild and moderate generalized disease may be difficult. The scheme also fails to include a category for patients in remission. Other myasthenia gravis classifications have been developed to more clearly dif-

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Box 78-1 MYASTHENIA GRAVIS FOUNDATION OF AMERICA (MGFA) CLASSIFICATION SYSTEM Class I: Any ocular muscle weakness; there may be weakness of eye closure. All other muscle strength is normal. Class II: Mild weakness affecting muscles other than ocular muscles; there may also be ocular muscle weakness of any severity. IIa. Predominantly affecting limb, axial muscles, or both. There may also be lesser involvement of oropharyngeal muscles. IIb. Predominantly affecting oropharyngeal, respiratory muscles, or both. There may also be lesser or equal involvement of limb, axial muscles, or both. Class III: Moderate weakness affecting muscles other than ocular muscles; there may also be ocular muscle weakness of any severity. IIIa. Predominantly affecting limb, axial muscles, or both. There may also be lesser involvement of oropharyngeal muscles. IIIb. Predominantly affecting oropharyngeal, respiratory muscles, or both. There may also be lesser or equal involvement of limb, axial muscles, or both. Class IV: Severe weakness affecting muscles other than ocular muscles; there may also be ocular muscle weakness of any severity. IVa. Predominantly affecting limb, axial muscles, or both. There may also be lesser involvement of oropharyngeal muscles. IVb. Predominantly affecting oropharyngeal, respiratory muscles, or both. There may also be lesser or equal involvement of limb, axial muscles, or both. Class V: Defined as intubation, with or without mechanical ventilation, except when used during routine postoperative management. The use of a feeding tube without intubation places the patient in class IVb.

ferentiate between mild, moderate, and severe disease states and to include remission as a separate category [Barohn and Jackson, 1994; Mohan et al., 1994]. A task force of the Myasthenia Gravis Foundation of America developed a new classification system (Box 78-1) that is more descriptive and provides better distinction between classes [Barohn, 2003; Jaretzki et al., 2000].

Categories of Myasthenia Gravis in Childhood Autoimmune myasthenia gravis in children is most commonly divided into neonatal transient and juvenile types. Neonatal transient myasthenia gravis occurs in infants of myasthenic mothers. Placental transfer of anti-AchR antibody or immunocytes results in transient impairment of neuromuscular transmission in the neonate [Barlow, 1981; Donaldson et al., 1981]. Findings such as a weak suck or cry, ptosis, dysphagia, generalized weakness, decreased spontaneous movement, and respiratory distress are usually present in the first few hours of life but may not be evident until the third day [Millichap and Dodge, 1960]. Hypotonia

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Neuromuscular Disorders / 78

may be the primary manifestation. The disorder usually resolves in the first 4 weeks but may persist for months [Branch et al., 1978; Desmedt and Borenstein, 1977]. The severity of the disorder in the infant is not correlated with the degree of maternal involvement. A prior history of neonatal myasthenia gravis in a sibling is the only predictive factor. Fortunately, only 10% to 15% of infants born to myasthenic mothers develop the disorder [Ahlsten et al., 1992; Fraser and Turner, 1953; Namba et al., 1970]. Prior thymectomy or remission of disease in the mother does not prevent development of neonatal transient myasthenia gravis [Elias et al., 1979; Geddes and Kidd, 1951]. Careful monitoring of pregnant women with myasthenia gravis is critical because there is a 40% chance of disease exacerbation during pregnancy and a 30% risk in the puerperium. The perinatal mortality rate is approximately 68 per 1000 births, five times the risk in uncomplicated pregnancies [Plauche, 1991]. Juvenile myasthenia gravis represents the childhood onset of autoimmune myasthenia gravis seen in adults. The onset is usually after 10 years of age, and disease manifestations appear before puberty in half the cases. Onset before 1 year of age is exceptional [Andrews et al., 1993; Fenichel, 1978; Geh and Bradbury, 1998]. Juvenile myasthenia gravis is more common in girls, but a large proportion of cases in boys is prepubertal [Anlar et al., 1996; Batocchi et al., 1990; Rodriguez et al., 1983]. In one study, predominance was in girls at a rate of 1.3:1 in prepubertal cases, in comparison with 1.8:1 in peripubertal and 14:1 in postpubertal cases [Andrews et al., 1993]. As with adults, ptosis is the most common clinical finding, frequently accompanied by ophthalmoparesis (Fig. 78-2). Ptosis was unilateral at onset in one third of patients with juvenile myasthenia gravis but subsequently spread to the other eye in nearly 90% of cases [Afifi and Bell, 1993]. Facial and oropharyngeal weakness, other common findings, lead to dysarthria, dysphagia, and difficulty chewing. Facial weakness without ocular involvement is an unusual but recognized presentation of juvenile myasthenia gravis [Kini, 1995]. Extremity weakness can occur and is usually most prominent proximally. Bulbar weakness, characterized by slow chewing, dysphagia, nasal

FIGURE 78-2. Ptosis of the right eyelid in a young woman with juvenile myasthenia gravis. A hypertropia of the left eye is also present.

dysarthria, and weak cough, develops in up to 75% of patients [Rodriguez et al., 1983]. Respiratory failure from either diaphragmatic or intercostal muscle weakness or airway compromise related to bulbar dysfunction produces myasthenic crisis, an exacerbation severe enough to endanger the patient’s life. As in adults, the disease may be generalized at onset, but isolated ocular involvement is a more common presentation, followed by generalization at a later time. However, children with ocular myasthenia gravis appear more likely than adults to remain with purely ocular involvement and not progress to generalized disease. As many as 85% of adults with ocular myasthenia gravis later develop generalized disease [Evoli et al., 1988; Weinberg et al., 1994]. In children, this percentage is closer to 50% to 75% [Afifi and Bell, 1993; Andrews, 2004]. In children of Chinese descent, pure ocular myasthenia gravis is the predominant disease type and has been linked to certain human leukocyte antigen types [Chan-Lui et al., 1984; Hawkins et al., 1989]. Myasthenia gravis is frequently associated with other diseases, specifically those with an immune etiology. The most common associations are with rheumatoid arthritis, thyroid disease, systemic lupus erythematosus, and diabetes mellitus [Afifi and Bell, 1993; Millichap and Dodge, 1960; Rodriguez et al., 1983]. Nonimmune disorders associated with juvenile myasthenia gravis include epilepsy in 3% to 13% [Rodriguez et al., 1983; Snead et al., 1980] and various forms of neoplasia, particularly thymoma and, later in life, breast carcinoma. Thymoma cases in juvenile myasthenia gravis, present in fewer than 5% of children with myasthenia gravis [Rodriguez et al., 1983], are rare in comparison with adult cases and are found mainly in children with onset of myasthenia gravis in adolescence [Andrews, 2004].

Neurologic Examination On examination, it is important to determine whether ptosis is present. Normally the upper eyelid should be positioned at least 1 mm above the pupil. Observing for upper eyelid fatigue in sustained upward gaze can be helpful, but this phenomenon is often not present and may be difficult to assess in children. Any restriction of ocular motility is documented, as is whether the patient has diplopia in primary position, on horizontal gaze to the right or left, or on vertical gaze. Testing for weakness in the orbicularis oculi muscle is crucial but often overlooked. Many patients with symptomatic myasthenia gravis have bilateral weakness of this muscle group. Strength should also be tested in the lower facial muscles (blowing out cheeks against resistance) and in the tongue. Attention to speech patterns may disclose a nasal dysarthria. It is important to check for neck flexion and extension weakness because those muscle groups are frequently involved. Testing of extremity strength should include proximal and distal muscle groups in the arms and legs. Proximal limb muscles tend to be more affected than distal muscles. In rare cases, however, patients with myasthenia gravis may demonstrate a tendency for weakness in distal muscle groups, especially finger extensors [Nations et al., 1997]. Symptoms and signs can be quantified by using a validated myasthenia gravis scoring system and activities of

Wolfe and Barohn / Diseases of the Neuromuscular Junction

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TABLE 78-1 Quantitative Myasthenia Gravis Scale

From Barohn RJ, McIntire D, Herbelin L, et al. Reliability testing of the quantitative myasthenia gravis score. Ann N Y Acad Sci 1998;841:769.

TABLE 78-2 Myasthenia Gravis Activities of Daily Living Scale

From Wolfe GI, Herbelin L, Nations SP, et al. Myasthenia gravis activities of daily living profile. Neurology 1999;52:1487.

daily living scale (Tables 78-1 and 78-2). The activities of daily living score is correlated with the objective quantitative myasthenia gravis score [Wolfe et al., 1999]. A Myasthenia Gravis Foundation of America task force has recommended that the quantitative myasthenia gravis score be used as an outcome measure for therapy trials in myasthenia gravis [Barohn, 2003; Jaretzki et al., 2000]. The

scales are readily administered to adolescents as young as 15 years of age [Barohn et al., 1998].

Clinical and Laboratory Tests In most instances, the clinician can be confident about the diagnosis of myasthenia gravis on the basis of abnormalities

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revealed through the neurologic history and examination. However, one or more tests are usually performed to confirm the clinical diagnosis.

Edrophonium (Tensilon) Test The intravenous administration of up to 10 mg of edrophonium is often the first diagnostic test performed in the evaluation of a potential myasthenia gravis patient. However, the edrophonium test has a number of pitfalls. The most common mistake is that the physician performing the test does not have an objective parameter to measure before and after edrophonium administration. The most useful parameter is the degree of ptosis in each eye. The best indication of a positive test result is a significant increase in the palpebral fissure aperture or the opening of a completely ptotic eye. If no ptosis is present, the edrophonium test result may be difficult to interpret even in clear-cut cases of myasthenia gravis. If the patient has a severe restriction of extraocular movement and edrophonium dramatically improves the motility, the test result is considered positive. However, subjective diplopia may not resolve unless edrophonium corrects alignment for both eyes, which is rare. Significant improvement in dysarthria or in swallowing is another indication of a positive edrophonium test result. A mild improvement in limb strength or in subjective well-being is not sufficient for claiming a positive result. In addition, a positive edrophonium test result is not specific because transient subjective improvement is reported in other neuro-

Baseline

Resp (#) 1 2 3 4 5

NPamp (%chg) 0.0 . –13.5 –25.1 –27.2 –27.4

NParea (%chg) 0.0 0.0 –20.2 –32.9 –36.7 –36.7

Resp (#) 1 2 3 4 5

NPamp (%chg) 0.0 0.0 –3.6 –4.9 –6.4 –6.1

NParea (%chg) 0.0 0.0 –6.1 –7.3 –7.2 –8.1

logic disorders, such as motor neuron disease and peripheral neuropathy [Oh and Cho, 1990]. The edrophonium test is performed in a straightforward manner. First, 1 mL (10 mg) of edrophonium is drawn up into a 1-mL tuberculin syringe. The edrophonium is often injected directly into a vein (usually antecubital), but in smaller children, a “butterfly” intravenous line can be started, connecting the tuberculin syringe directly to the intravenous catheter. In children weighing less than 30 kg, the total delivered dose should not exceed 0.1 mg/kg. For children weighing more than 30 kg, a total dose up to 0.2 mg/kg may be given, not to exceed 10 mg. Initially, a test dose of 0.01 mg/kg is injected. If after 30 to 60 seconds the patient experiences no side effects from the drug (fasciculations, sweating, nausea), further aliquots of 0.01 to 0.02 mg/kg are injected, not exceeding the total dose suggested. When the drug is injected into an intravenous catheter, catheter flushes with saline are needed with each aliquot. Children are more likely than adults to experience nausea, and so an emesis basin should be available. More serious side effects, such as bronchospasm or lightheadedness caused by bradycardia, are quite uncommon, but atropine should be readily available. When either side effects or a positive response is obtained, no further edrophonium need be given. The mean dose of edrophonium needed to produce a positive response was 3.3 mg (±1.6 mg standard deviation) for ptosis and 2.6 mg (±1.1 mg standard deviation) for oculomotor dysfunction in a survey of 83 adult patients [Kupersmith et al., 2003].

5.0 mV

A

2 ms Immediately post 10 sec exercise

B

FIGURE 78-3. Repetitive stimulation of the ulnar nerve at 3 Hz, recorded in the adductor digiti minimi. A, Baseline; there is an abnormal amplitude decrement of 27%. B, Immediately after 10 seconds of exercise, the decrement has resolved, demonstrating postexercise facilitation. NPamp, negative peak amplitude; NParea, negative peak area; Resp, response.

Wolfe and Barohn / Diseases of the Neuromuscular Junction Baseline

NPamp (%chg) 0.0 0.0 –7.1 –8.5 –10.1 –6.0

NParea (%chg) 0.0 0.0 –9.2 –12.6 –15.9 –14.0

Resp (#) 1 2 3 4 5

NPamp (%chg) 0.0 0.0 –9.1 –13.9 –12.6 –9.1

NParea (%chg) 0.0 0.0 –10.5 –17.6 –19.4 –15.8

Immediately post-exercise

Resp (#) 1 2 3 4 5

NPamp (%chg) 0.0 0.0 2.3 1.3 3.4 7.0

NParea (%chg) 0.0 0.0 0.3 0.2 –0.8 2.8

2 min post-exercise

Resp (#) 1 2 3 4 5

NPamp (%chg) 0.0 0.0 –11.0 –18.6 –16.6 –19.2

NParea (%chg) 0.0 0.0 –12.6 –18.7 –16.9 –19.2

B

5.0 mV

A

Resp (#) 1 2 3 4 5

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2 ms 1 min post-exercise

C

4 min post-exercise

E

Resp (#) 1 2 3 4 5

NPamp (%chg) 0.0 0.0 –15.1 –23.0 –23.0 –24.7

NParea (%chg) 0.0 0.0 –16.1 –24.1 –23.9 –26.1

D

Immediately post 10 sec exercise

F

Resp (#) 1 2 3 4 5

NPamp (%chg) 0.0 0.0 –9.6 –13.1 –12.4 –12.2

NParea (%chg) 0.0 0.0 –12.5 –16.8 –15.3 –15.0

FIGURE 78-4. Repetitive stimulation (RS) of the ulnar nerve at 3 Hz, recorded in the adductor digiti minimi. At baseline (A), there is only a borderline decrement at response 4. Immediately after exercise (B), there is no decrement, but a 12% to 14% decrement develops 1 minute (C) after exercise, and this worsens at 2 and 4 minutes (D and E), demonstrating postexercise exhaustion. After 10 seconds of brief exercise (F), the decrement improves. NPamp, negative peak amplitude; NParea, negative peak area; Resp, response.

If a patient has ptosis, it is crucial that the palpebral fissure aperture be measured and its size recorded before and after edrophonium administration. In most children a placebo injection before edrophonium is likely unnecessary. In patients with less objective findings that do not enable easy measurement, edrophonium should likely not be given in the first place. Thus a placebo injection is rarely useful. In infants and younger children who are too uncooperative to monitor for a brief time, longer acting neostigmine may be favored over edrophonium. The intramuscular dose is 0.15 mg/kg and intravenous dose 0.05 mg/kg [Andrews, 2004]. Intravenous use can be hazardous because of severe muscarinic side effects [Wolfe et al., 1997]. A positive response is generally evident by 15 minutes and is most obvious after 30 minutes. Positive results on edrophonium or neostigmine testing are seen in up to 90% of juvenile myasthenia gravis cases [Afifi and Bell, 1993]. It is a good idea to have injectable atropine available in the case of severe side effects whenever neostigmine is used.

Electrophysiologic Testing REPETITIVE STIMULATION The classic electrophysiologic demonstration of a neuromuscular junction transmission defect is the documentation of a decremental response of the compound muscle action potential to repetitive stimulation of a motor nerve [Oh, 1988]. The decrement results from failure of some muscle fibers to reach threshold and contract when successive volleys of acetylcholine vesicles are released at the neuromuscular junction. Failure to reach the threshold endplate potential to achieve muscle contraction is called blocking. The percentage decreases in amplitude and area are calculated between the first compound muscle action potential produced by a train of stimuli and each successive potential. In most laboratories, five or six responses are obtained at 2 or 3 Hz, and the maximal percentage decrement can be measured at the fourth or fifth response. A decrement exceeding 10% is considered a positive result of a repetitive stimulation study (Fig. 78-3).

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In some patients a decremental response can be demonstrated at baseline. However, often a brief period of exercise (usually 1 minute) is necessary to elicit fatigue in the neuromuscular junction so that the decrement can be observed. This phenomenon of postexercise exhaustion usually occurs at 2 to 4 minutes after exercise (Fig. 78-4). In addition, postexercise facilitation, or an improvement in the decrement, can sometimes be observed immediately (within seconds) after brief exercise (see Fig. 78-3). Repetitive stimulation is typically first recorded in a distal thenar or hypothenar muscle after the median or ulnar nerve, respectively, is stimulated. If no decrement is observed, repetitive stimulation can be performed on a proximal limb muscle (i.e., trapezius, deltoid, or biceps) or on a facial muscle (orbicularis oculi). An arm board is used to immobilize the hand muscles. False-positive results are more of a problem in proximal limb muscles because of motion artifact. Because repetitive stimulation is a reflection of the integrity of neuromuscular junction transmission, a decrement is more often observed in clinically weak muscles. Thus, even if a patient has generalized myasthenia gravis and if there is only facial and proximal limb weakness, a decrement in a hand muscle is unlikely. In a patient with pure ocular myasthenia gravis a decrement may not be present in the orbicularis oculi unless that muscle is found to be weak on examination. As with the edrophonium test, repetitive stimulation does not have to be performed on every patient with myasthenia gravis if the diagnosis is certain according to the clinical findings and a positive finding of anti-AchR antibody. A protocol for repetitive stimulation of the ulnar nerve recording over the adductor digiti minimi is as follows: • Apply electrodes and immobilize the patient’s hand. • Obtain a normal baseline compound muscle action potential and increase to supramaximal intensity. • If there is a small compound muscle action potential amplitude at baseline, screen for Lambert-Eaton myasthenic syndrome before doing repetitive stimulation (see later discussion). • After establishing a stable baseline compound muscle action potential, give five shocks at 3 Hz. • If there is no decrement, exercise the hand by having the patient spread the fingers for 1 minute. Repeat repetitive stimulation immediately after exercise and 1, 2, 3, 4, and 6 minutes after exercise. • If there is a decrement after exercise (postexercise exhaustion), briefly exercise the muscle again for 10 seconds and repeat repetitive stimulation at 3 Hz. If the decrement improves, this indicates postexercise facilitation. • If there is a marked decrement at baseline to 3-Hz repetitive stimulation (>20%), exercise for only 10 seconds and repeat repetitive stimulation immediately. If the decrement improves, this is also postexercise facilitation. In this case, the protocol for demonstrating postexercise exhaustion described previously is optional. A decremental response is more likely present in a proximal muscle than in a distal muscle. In the series by Stalberg and Sanders [1981], a decrement in a distal muscle was

A

1.0 ms/d

B

FIGURE 78-5. Recruited single-fiber electromyogram of the extensor digitorum communis muscle. The single-fiber needle is inserted in the muscle with the patient extending the digit so that action potentials from at least two muscle fibers from the same motor unit are recorded (A). A trigger is placed on the initial potential under the arrow. Because both potentials are from the same motor unit, the second potential (under the arrowhead) appears at approximately the same time in relation to the triggered potential. One hundred successive acquisitions are obtained (B). The degree of variability in the time that the second potential occurs in the successive pairs is the jitter, measured as the mean consecutive difference. In this normal pair, the mean consecutive difference is 14.3 microseconds (normal <35 microseconds).

Wolfe and Barohn / Diseases of the Neuromuscular Junction

reported in 38% of patients, whereas a decrement in proximal muscles occurred in 64%. Similar findings have been described by other authors [Oh et al., 1992; Vial et al., 1991]. In a study of 27 juvenile myasthenic patients, Afifi and Bell [1993] found that the chance of finding a decrement was doubled to 66% by including proximal muscles. In children with generalized disease at onset, 80% demonstrated a decrement when proximal muscles were studied. In ocular myasthenia gravis, decrements are less common, occurring in 20% to 50% of patients [Evoli et al., 1988; Stalberg and Sanders, 1981]. Repetitive stimulation at faster rates (i.e., 20 or 50 Hz) is usually not performed unless there is con-cern about Lambert-Eaton myasthenic syndrome, a rare condition in children.

1

2

A

SINGLE-FIBER ELECTROMYOGRAPHY Conventional electromyography is rarely helpful in the diagnosis of myasthenia gravis in children. Single-fiber electromyography, however, is a more sensitive measure of neuromuscular transmission than is repetitive stimulation and can be considered in selected children. In myasthenia gravis, the time required for the endplate potential at the neuromuscular junction to reach threshold is extremely variable. The measurement of this variability in the endplate potential rise time is known as jitter. The jitter value, calculated in microseconds, is the most important piece of data obtained from single-fiber electromyographic study. Everyone, including healthy individuals, has some degree of jitter (Fig. 78-5). Myasthenic patients have increased jitter values (Fig. 78-6). In addition, blocking occurs in myasthenic patients if a muscle fiber’s endplate potential never reaches threshold and depolarization does not occur. The frequency of blocking, expressed as a percentage, is also determined with single-fiber electromyography. In healthy individuals, the percentage of blocking is zero (see Fig. 78-6). Single-fiber electromyography is undoubtedly the most sensitive test for myasthenia gravis in adults. It is abnormal in 94% of patients with generalized myasthenia gravis and 80% of those with ocular myasthenia gravis [Oh et al., 1992]. However, single-fiber electromyography has several disadvantages. It is a tedious and lengthy study that requires considerable patient cooperation and is poorly tolerated by many children. Stimulated single-fiber electromyography can be performed with the patient under sedation, requires less patient cooperation, and may be preferred for children, although it is still a lengthy procedure [Jabre et al., 1989]. An abnormal result of a single-fiber electromyographic study is not specific for myasthenia gravis because increased jitter commonly occurs as a result of other neuromuscular diseases, such as motor neuron disease, peripheral neuropathy, and many myopathies [Oh, 1988]. Fortunately, it is seldom necessary to perform single-fiber electromyography to diagnose myasthenia gravis in children. It is likely most useful in children who present difficult diagnostic dilemmas and who otherwise have normal results of laboratory studies for myasthenia gravis. Single-fiber electromyographic abnormalities may be seen in 12% to 33% of first-degree relatives of patients with juvenile myasthenia gravis [Anlar et al., 1995; Stalberg et al., 1976].

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1.0 ms/d

B

FIGURE 78-6. Recruited single-fiber electromyogram from the extensor digitorum communis in a patient with myasthenia gravis. Three muscle fiber potentials from the same motor unit are recorded (A), and 100 successive recordings are captured (B). The arrow identifies the triggered potential. The degree of jitter for potential 1 is 270 microseconds and for potential 2 it is 187 microseconds (normal <35 microseconds). In addition, potential 1 demonstrates blocking in 50% of the acquisitions (two of these instances are indicated by the closed circles in B).

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Antibody Testing ANTI-AchR ANTIBODIES Finding anti-AchR antibody in the serum of a suspected myasthenia gravis patient is the most specific and definitive finding for supporting the diagnosis. When the anti-AchR antibody assay yields positive results, it can be argued that no other diagnostic studies for myasthenia gravis are needed. Most hospitals and medical centers do not run the assay inhouse, but the test is commercially available through a number of reference laboratories. It generally takes 1 week to receive the results from the reference laboratory. Thus, the clinician who is initially making the diagnosis is often in the position of performing the edrophonium and electrophysiologic tests while awaiting the results of the study. Anti-AchR antibody levels are not elevated in all patients with myasthenia gravis. The assay is most informative in adults with generalized myasthenia gravis; it is positive in 85% of such patients [Drachman, 1994; Lindstrom et al., 1976b; Oh et al., 1992; Vincent and Newsom-Davis, 1985]. Only 50% of patients with ocular myasthenia gravis, however, have a measurable anti-AchR antibody. Children represent another group of myasthenia gravis patients whose results are often antibody negative. In one study, only 56% of prepubertal children with autoimmune juvenile myasthenia gravis were seropositive [Andrews et al., 1993], in comparison with 82% who had peripubertal onset of the disease. All 15 children with onset after puberty were seropositive. Similarly, seropositivity was more common in females with onset of juvenile myasthenia gravis after 11 years of age [Anlar et al., 1996]. Seronegativity was more common in pure ocular forms, mild disease, and remission [Afifi and Bell, 1993; Andrews et al., 1993; Anlar et al., 1996]. Only 13% of patients with generalized myasthenia gravis at the time of antibody testing were seronegative [Andrews et al., 1993]. These serologic data support the view that sex and hormonal status influence disease frequency and anti-AchR antibody levels in juvenile myasthenia gravis [Andrews et al., 1993]. Because congenital myasthenic syndromes and seronegative autoimmune myasthenia gravis manifest in early childhood, it is often difficult to differentiate these disorders when the family history is negative [Andrews et al., 1993]. Fluctuating weakness or disease severity and good responses to pharmacologic therapy favor an autoimmune basis [Anlar et al., 1996]. The most common anti-AchR antibody test is the binding radioimmunoassay with bungarotoxin, measured in nanomoles per liter. The upper limit of normal level varies among reference laboratories (usually between 0.03 and 0.5 nmol/liter) [Lennon, 1982]. Other assays that block bungarotoxin binding to AchR (“blocking” assay) or that reduce the density of AchR on cultured human myotubes (modulating antibody assay) are also commercially available [Howard et al., 1987]. These additional assays may be useful in patients with suspected myasthenia gravis whose tests yielded negative results with the standard binding assay [Howard et al., 1987]. Anti-AchR antibodies can also be detected using human rhabdomyosarcoma cell lines [Tami et al., 1994; Voltz et al., 1991], but these are still primarily research laboratory assays. Anti-AchR antibody titers are poorly correlated with myasthenia gravis severity [Roses et al., 1981]. Although

the titer may fall in some patients as the clinical condition improves, antibody titers in general do not guide therapeutic decisions. Indeed, myasthenia gravis patients in clinical remission may still have elevated titers, but this is not an indication to continue immunosuppressive therapy.

ANTI-MuSK ANTIBODIES Since 2001, IgG from 40% to 70% of seronegative patients with generalized myasthenia gravis has been found to bind to the extracellular domain of MuSK [Hoch et al., 2001; McConville et al., 2004; Sanders et al., 2003]. Marked female predominance with mean age at onset in the fourth decade has been a typical finding [Evoli et al., 2003; Sanders et al., 2003], although Evoli and associates encountered a child with disease onset at age 6 years, and two patients from the initial series presented before age 10 [Hoch et al., 2001]. A child with severe bulbar involvement beginning at age 9 years has also been encountered with this antibody. Patients with anti-MuSK myasthenia gravis often have prominent oculobulbar involvement [Scuderi et al., 2002] or neck, shoulder, and respiratory involvement [Sanders et al., 2003] that is more refractory to conventional treatment. Anti-MuSK antibodies appear to be rare in pure ocular myasthenia gravis and only as recently as 2004 were identified in patients who also were seropositive for antiAchR antibody [Ohta et al., 2004]. It has been hypothesized that anti-MuSK antibodies impede agrin-mediated clustering of AchR and disrupt normal postsynaptic architecture, but this hypothesis has been placed into question by initial studies on human intercostal muscle; therefore, the pathogenesis remains unclear [Selcen et al., 2004]. Testing for anti-MuSK antibodies is commercially available.

STRIATED MUSCLE ANTIBODIES Antibodies to striated muscle in patients with myasthenia gravis were discovered before anti-AchR antibodies. These antibodies can be directed against a number of striated muscle proteins, including myosin, actin, α-actinin, titin, and tropomyosin. It is generally believed that if anti–striated muscle antibodies are present in a myasthenia gravis patient, they should raise suspicion for thymoma, because they are reported in up to 84% of patients with thymoma [Limburg et al., 1983]. However, this high a frequency has not been duplicated in all series [Mohan et al., 1994], and the antibody has limited specificity, being present in one third of patients without thymoma [Limburg et al., 1983]. The absence of anti–striated muscle antibodies also does not exclude a thymoma. Thus, the predictive value of this assay may be overemphasized [Lanska, 1991]. From an adult perspective, anti-titin antibodies have been suggested as a marker for more severe disease in patients with myasthenia gravis onset after age 40 and demonstrated a better correlation with disease severity than did anti-AchR antibodies [Romi et al., 2000].

Treatment Most patients with juvenile myasthenia gravis who require maintenance therapy are treated with anticholinesterase

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agents with or without a variety of immunosuppressive medications. Pyridostigmine is recommended as an initial intervention [Snead et al., 1980]. As with the adult form of the disease, corticosteroids and other immunosuppressive medications have been useful [Engel, 1984], although few randomized, controlled clinical trials have been conducted for any myasthenia gravis population. Thymectomy plays an important role in treating older children at most centers. Plasmapheresis [Pinching et al., 1976] and intravenous gamma globulin [Arsura, 1989] are generally reserved for patients with more refractory disease or for those in myasthenic crisis. Plasmapheresis is also used to maximize function before thymectomy. Short-term supportive care and anticholinesterase agents are usually adequate for neonatal transient myasthenia gravis. Management for the different types of childhood myasthenia gravis is reviewed in the following sections.

Neonatal Myasthenia Gravis Neonates with transient myasthenia gravis are at risk of respiratory and bulbar dysfunction. If there is no significant respiratory or swallowing impairment, medications are not necessary. In more severe cases, oral pyridostigmine is given in syrup form (60 mg/5 mL) at a recommended daily dose of 7 mg/kg. The dose should be divided during the day and given 30 minutes before feedings. For neonates unable to swallow, intramuscular injections of pyridostigmine should be given. To convert from oral doses, 1 mg of intramuscular pyridostigmine is equivalent to 30 mg orally. Intramuscular neostigmine is an alternative but has more muscarinic side effects. Treatment for 4 to 6 weeks is usually all that is required.

Juvenile Myasthenia Gravis ACETYLCHOLINESTERASE INHIBITORS In juvenile myasthenia gravis, the aggressiveness of management should be in accordance with disease severity. In general, management attempts should first focus on pyridostigmine. A total daily dose up to 7 mg/kg a day is delivered in five to six divided doses [Wolfe et al., 1997]. Older children can use 60-mg tablets that can be split in half as needed. Typical doses in older children and adults are 60 mg three to five times a day. If symptoms are poorly controlled on a pyridostigmine dose exceeding 300 mg/day, it is likely necessary to add immunomodulating therapy. Prolonged-release pyridostigmine is also available (Mestinon TS, 180 mg). However, because of variable absorption, difficulty adjusting doses, and increased side effects, many clinicians discourage use of this preparation. Although weakness, which is a nicotinic receptor side effect that results from pyridostigmine use, is relatively uncommon, muscarinic side effects occur frequently. The most common of these are gastrointestinal cramps and diarrhea. These symptoms can limit the amount of pyridostigmine that a patient can tolerate. Oral hyoscyamine sulfate, glycopyrrolate, atropine, and over-the-counter loperamide can be prescribed on an as-needed basis or prophylactically with selected pyridostigmine doses to minimize these side effects.

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If a child with juvenile myasthenia gravis is hospitalized and cannot take oral pyridostigmine, intravenous pyridostigmine can be substituted. This situation arises most often if a myasthenic patient is admitted for surgery unrelated to the myasthenia gravis and is not permitted to take oral fluids or medications. The general rule is that intravenous pyridostigmine is given at one thirtieth the dose of oral pyridostigmine. Thus, 60 mg of oral pyridostigmine is equivalent to 2 mg given intravenously. The frequency of administration can remain the same. A second scenario is the critically ill myasthenic patient who is unable to swallow or requires mechanical ventilation for crisis. However, it is accepted practice in this setting to withhold all pyridostigmine, simplifying airway management by avoiding cholinergic overstimulation. Once the patient has improved with other therapeutic interventions and bed rest, oral pyridostigmine can be resumed. Pyridostigmine is usually not the deciding factor in withdrawing patients from the ventilator and resolving myasthenic crisis.

THYMECTOMY When a child’s symptoms can no longer be controlled by anticholinesterase agents alone, a decision must be made regarding whether to pursue thymectomy or immunosuppressive therapy. In 1939, Blalock and co-workers reported the remission of generalized myasthenia gravis in a 21-yearold woman after removal of the cystic remains of a necrotic thymic tumor. Since then, thymectomy, with or without the presence of thymoma, has gained widespread acceptance as a treatment for myasthenia gravis. Thus, thymectomy was the first attempt at “immunotherapy” for myasthenia gravis and continues to be one of the most common treatments for the disease. There is a general consensus that patients between puberty and 60 years of age with generalized myasthenia gravis benefit from thymectomy [Lanska, 1990; Rowland, 1987]. However, randomized studies of thymectomy that control for medical therapy have never been conducted. A critical review of the largely retrospective literature continues to raise questions about the ability of the procedure to induce remission or produce clinical improvement [Lanska, 1991; McQuillen and Leone, 1977]. The use of thymectomy in very young children, in itself, is controversial because of concerns for a subsequent impairment in immune protection or an enhanced risk of cancer. A review of incidental thymectomy and thymectomy as treatment for myasthenia gravis in young children, however, did not reveal a consistent association between thymectomy and these proposed risks in children older than 1 year [Seybold, 1998]. In a survey that included 56 neurologists with expertise in myasthenia gravis, lower age limits for thymectomy ranged from 1 year to puberty, the median being 7.5 years [Lanska, 1990]. In an evidence-based practice parameter from the American Academy of Neurology, Gronseth and Barohn [2000] analyzed retrospective, controlled, nonrandomized studies of thymectomy in myasthenia gravis. A total of 28 studies published between 1953 and 1998 were identified. The effect of surgery was broadly favorable in most series. However, the benefit of surgery was generally small. For example, the median relative rate favoring surgery over

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nonoperative treatment for achieving remission was 2.1 (a modest gain in view of the fact that the median remission rate in the nonthymectomized groups was 10%). Other median relative rates were 1.6 for asymptomatic status, 1.7 for improvement, and 1.1 for survival. Patient subgroup analysis indicated that only patients with myasthenia gravis who had moderate weakness or greater (Osserman group IIB) exhibited a significant improvement after thymectomy in comparison with control subjects. Of importance was that the modest benefits ascribed to thymectomy were confounded by baseline differences between the operative and nonoperative groups as well as by limited thymic resections performed in a significant percentage of the patients. No study included blinded assessments. As a result, the authors expressed uncertainty as to whether claims of improved myasthenia gravis outcomes were a result of thymectomy or related to differences in baseline characteristics between operative and nonoperative groups. The authors concluded that thymectomy be considered a treatment option in patients without thymoma [Gronseth and Barohn, 2000]. To address this uncertainty, an international prospective, single-blinded, randomized trial controlling for medical therapy is being organized for nonthymomatous myasthenia gravis [Wolfe et al., 2003]. Thymectomy has been widely used for the treatment of juvenile myasthenia gravis, resulting in a higher likelihood of remission when performed early in the disease course than did no operative treatment [Seybold, 1998]. In the largest study, 85 (57%) of 149 patients with juvenile myasthenia gravis underwent thymectomy. Of the thymectomized patients, 42 (49%) entered remission and another 25 (29%) improved clinically [Rodriguez et al., 1983]. In contrast, only 34% of patients who did not undergo thymectomy entered remission. Remission rates were 260 per 1000 person-years in the first year after thymectomy, falling to 95 per 1000 person-years over the next year after surgery [Rodriguez et al., 1983]. After 3 years, the remission rate decreased to 20 per 1000 person-years, similar to the spontaneous remission rate. Favorable predictors for postoperative remission included surgery during the first year after disease onset, bulbar symptoms, absence of ocular or generalized involvement, onset of symptoms between ages 12 and 16 years, and the presence of other autoimmune disorders [Rodriguez et al., 1983]. Sex of the child or thymic pathologic findings did not appear to influence remission rates. Histologic findings of the thymus were normal in 16%, hyperplastic in 78%, and neoplastic in 3%. Other series suggest that the clinical benefit from thymectomy may not be realized for as long as 7 to 10 years [Mulder et al., 1989]. Adams and co-workers [1990] reported that, of 24 patients with juvenile myasthenia gravis who underwent thymectomy, 16 entered complete remission and 7 experienced improvement. Of 12 black children with juvenile myasthenia gravis who underwent thymectomy, 6 entered remission and 4 experienced much improvement in follow-up periods ranging from 1 to 10 years [Lakhoo et al., 1997]. These favorable clinical responses and the low rates of morbidity and mortality from thymectomy in childhood cases bolster its widespread use [Batocchi et al., 1990; Ryniewicz and Badurska, 1977; Youssef, 1983], prompting some investigators to consider the procedure at the onset of generalized symptoms [Adams et al., 1990]. Clinical

improvement after thymectomy has been observed regardless of whether there is a reduction in circulating anti-AchR antibody levels [Oosterhuis et al., 1985]. Transsternal thymectomy remains the preferred surgical technique [Younger et al., 1987], although transcervical and infra-axillary video-assisted approaches have been used [Cooper et al., 1988; Mack et al., 1996; Papatestas et al., 1975]. There is some evidence to support the view that the more extensive the resection, the better the long-term results [Jaretzki, 1997]. After a “maximal” thymectomy approach that included both transcervical and transsternal incisions, life-table analyses demonstrated an 81% remission rate at 7.5 years [Jaretzki and Wolff, 1988]. Comparative remission rates for transcervical approaches have been in the range of 30% to 45% at 7 years [Jaretzki et al., 2003], and approximately 50% at 6 years after either an extended transsternal or a video-assisted thoracoscopic procedure that includes a transverse cervical incision [Mantegazza et al., 2003]. It should be noted that remission rates in surgical series are often unexpectedly high. Definitions of remission, as well as its duration, vary between studies, and the retrospective determination of these outcomes is certainly open to bias [Gronseth and Barohn, 2000; Jaretzki, 1997]. Transcervical and video-assisted thoracoscopic procedures offer advantages from a cosmetic and postoperative recovery standpoint. Thoracoscopic procedures have been found to reduce the length of hospital stay and patient care costs in comparison with open thoracic surgery [Hazelrigg et al., 1993]. The presence of a thymoma is, of course, the one absolute indication for thymectomy. All newly diagnosed myasthenia gravis patients must undergo computed tomography or magnetic resonance imaging of the chest with contrast medium to look for evidence of a thymoma. Up to 25% of thymic tumors may not be detected on routine chest radiographs [Batra et al., 1987]. Although there is a consensus among neurologists that thymectomy should be considered in all but the youngest children with generalized myasthenia gravis whose disease is not controlled by anticholinesterase agents alone, there is less enthusiasm for the procedure in isolated ocular myasthenia gravis. Response to thymectomy was lacking in a report of 12 patients with anti-MuSK antibodies, 5 with typical myasthenia gravis findings and 7 with proximal neck/shoulder or respiratory muscle weakness but without ocular involvement [Sanders et al., 2003]. Further studies of patients with anti-MuSK antibodies are needed to better guide treatment decisions. Nevertheless, work to date suggests that thymic tissue in the population with anti-MuSK antibodies does not demonstrate morphologic abnormalities and that thymectomy does not produce significant clinical improvement for these patients [Lauriola et al., 2004]. In several reviews, authors have discussed the preoperative management of patients with myasthenia gravis who undergo thymectomy, including the use of intravenous immune globulin or plasmapheresis to reduce the risk of perioperative complications [Dillon, 2004; Huang et al., 2003; Juel, 2004].

CORTICOSTEROIDS Despite its many potential side effects, prednisone is considered by many physicians to be the most effective oral

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immunosuppressive agent for the treatment of myasthenia gravis. Although corticosteroids can potentially suppress the immune system in a variety of ways, the exact explanation for the beneficial response in myasthenia gravis is unknown. However, prednisone can reduce anti-AchR antibody titers, and this may be correlated with clinical improvement [Tindall, 1980]. Typically, oral prednisone is initiated at 1.5 to 2 mg/kg daily. If clinical improvement occurs in the first 4 weeks, the patient can be switched immediately to an alternate-day dose of 1.5 to 2 mg/kg [Warmolts and Engel, 1972]. Longer daily regimens must be followed by a slower alternate-day gradual withdrawal. If corticosteroid therapy is initiated at moderate to high doses, an improvement is usually apparent in 2 to 3 weeks [Johns, 1984; Pascuzzi et al., 1984]. However, in some patients, daily dosing may be necessary for 2 to 3 months before there is clinical improvement. The main concern when initiating prednisone therapy at these doses is the transient worsening that occurs in one third to one half of patients [Badurska et al., 1992; Johns, 1984; Miller et al., 1986; Pascuzzi et al., 1984]. The mechanism may involve a direct effect of corticosteroids to impair neuromuscular junction function [Miller et al., 1986]. In one study, 8.6% of patients who experienced transient worsening required intubation [Pascuzzi et al., 1984]. In another report, 3 of 20 children started on corticosteroids developed respiratory failure [Badurska et al., 1992]. Thus, an advised practice is to admit patients with myasthenia gravis to the hospital for 5 to 7 days when high-dose prednisone therapy is initiated. During this time, bulbar function and forced vital capacity are monitored daily. If the patient remains stable over this interval, he or she can be safely discharged with a prescription for oral prednisone. The therapeutic efficacy of prednisone in adult myasthenia gravis has been clearly demonstrated [Johns, 1984; Pascuzzi et al., 1984]. In a study of 116 patients, prednisone produced pharmacologic remission (asymptomatic on medication) in 28%, marked improvement in 53% (minor symptoms and return to activities of daily living), moderate improvement in 15% (functional limitations), and no improvement in only 5% [Pascuzzi et al., 1984]. The mean time needed to achieve maximum prednisone benefit was 5.5 months (range, 2 weeks to 6 years). This study also made clear the disappointing fact that only 14% of patients were able to discontinue prednisone treatment and maintain improvement. Similar response rates have been reported in children [Andrews, 2004]. It is noteworthy that a retrospective analysis suggested that prednisone reduces the incidence of disease generalization at 2 years in patients presenting with pure ocular myasthenia gravis [Kupersmith et al., 2003]. Only 7% of such patients receiving prednisone developed generalized disease, in comparison with 36% receiving only pyridostigmine or no medication. Similar observations were made from two smaller retrospective series [Mee et al., 2003; Monsul et al., 2004]. After significant improvement is observed, there should not be a rush to withdraw the prednisone. Most patients remain on alternate-day doses of prednisone for at least 6 to 8 months. Premature withdrawal of prednisone is a common management error. When the withdrawal is begun, it is best to proceed slowly by reducing the dose no faster than 5 mg

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every 2 weeks. When the patient’s dose has been reduced to 20 mg every other day, withdrawing at an even slower rate is advisable. Although an attempt should be made for the patient to withdraw fully from prednisone, it is not uncommon for patients to require low-dose therapy (5 to 10 mg every other day) for many years or indefinitely. Prior thymectomy does not appear to influence the outcome of steroid withdrawal [Miano et al., 1991]. The side effects of corticosteroids are well appreciated and significant. Children should be closely monitored for cataracts, hypertension, diabetes mellitus, weight gain, growth retardation, and cognitive or affective disturbance [Drachman, 1994; Massey, 1997; Pascuzzi et al., 1984; Andrews, 2004]. Adverse effects of corticosteroids on early stages of bone mineralization and development are also of concern, emphasizing the need for “steroid-sparing” strategies in children whose disease is refractory to gradual withdrawal.

AZATHIOPRINE Azathioprine (Imuran), an antimetabolite that blocks cell proliferation and inhibits T lymphocytes, has been used more frequently because of the side effects associated with corticosteroids. Most reports describe its use in adults. It is used most often in patients who have a relapse while taking prednisone or who have been taking prednisone for lengthy periods in the hope that the steroid dose can be decreased or eliminated. Azathioprine is commonly used as a first-line immunosuppressive agent instead of prednisone in Europe [Hohlfeld et al., 1988; Mantegazza et al., 1988; Matell, 1987; Myasthenia Gravis Clinical Study Group, 1993]. Retrospective studies of azathioprine therapy have demonstrated that 70% to 90% of patients with myasthenia gravis experience improvement [Hohlfeld et al., 1988; Mantegazza et al., 1988; Matell, 1987; Mertens et al., 1981; Myasthenia Gravis Clinical Study Group, 1993], regardless of whether it is used as a first- or second-line immunosuppressive drug. However, the response is slow, ranging up to 12 months or more. In a double-blind study, the use of oral prednisolone was compared with prednisolone plus azathioprine. Patients receiving azathioprine had fewer relapses, longer remissions, and fewer side effects with less weight gain [Palace et al., 1998]. At 3 years, 63% of patients receiving azathioprine had completely withdrawn from prednisolone, in comparison with 20% who had received prednisolone alone. However, the beneficial effect of azathioprine was not statistically documented until month 18 of the study. Thus, if a patient already taking pyridostigmine is quite weak and a rapid response is required, azathioprine is not a practical choice. Azathioprine may be used in combination with plasmapheresis in children whose disease is refractory to other management modalities [Carter et al., 1980]. Azathioprine is reported to lower anti-AchR antibody levels [Mantegazza et al., 1988]. Azathioprine is supplied as a 50-mg, dumbbell-shaped tablet that can be easily broken in half. The initial dose of azathioprine in children should be no more than 25 to 50 mg daily for 1 week. If there are no systemic side effects, the dose is increased to a target level of 2 to 3 mg/kg/day. Although azathioprine is generally well tolerated, there are three important and limiting side effects [Kissel et al.,

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1986]: (1) Approximately 10% of patients have an idiosyncratic systemic reaction within the first several weeks of therapy that consists of fever, abdominal pain, nausea, vomiting, and anorexia. Such patients feel as if they have the flu. When the drug is stopped, the symptoms resolve quickly. If such a patient is rechallenged, the symptoms invariably recur. (2) In addition, patients can develop leukopenia and hepatotoxicity. Blood counts and hepatic enzymes need to be monitored monthly. If the white blood cell count falls below 4000 cells/mm3, it is advisable to decrease the dose. If it falls below 3000 cells/mm3, medication should be temporarily withheld until the cell count returns to normal. Similarly, medication should be temporarily withheld if there is evidence of hepatocellular dysfunction. Although the patient can be rechallenged after the laboratory values return to normal, toxicity often recurs, requiring discontinuation of the drug. (3) Late development of malignancy after long-term use of azathioprine is of theoretical concern [Andrews, 2004].

CYCLOSPORINE Cyclosporine (Sandimmune, Neoral) is an accepted option for immunosuppressive therapy in adult myasthenia gravis. Data on its use in juvenile myasthenia gravis are not available, although it is frequently used in pediatric transplant recipients. Cyclosporine inhibits helper T lymphocytes and allows the expression of suppressor T lymphocytes. It blocks the production and secretion of interleukin-2 by helper T cells. Cyclosporine was subjected to randomized, doubleblinded, placebo-controlled trials in myasthenia gravis [Tindall et al., 1987, 1993]. These studies demonstrated that cyclosporine was more effective than placebo in improving myasthenia gravis when a quantitative myasthenia gravis scale was used as the primary efficacy measure. In addition, cyclosporine lowered anti-AchR antibody levels. Corticosteroid doses could be reduced after cyclosporine was initiated [Tindall et al., 1993]. The onset of clinical benefit for cyclosporine is 1 to 2 months. This is somewhat faster than azathioprine and slower than prednisone. Doses for cyclosporine range between 3 and 6 mg/kg/day. The drug is usually given in two divided doses rather than as a single dose, to reduce potential nephrotoxicity. Cyclosporine is available as 25- or 100-mg capsules or as an oral solution (100 mg/mL). Side effects include hirsutism, tremor, gum hyperplasia, paresthesias, and hepatotoxicity. Hypertension and nephrotoxicity are the main limitations to therapy. More than one fourth of adult patients taking cyclosporine experience increases in serum creatinine levels between 30% and 70% above baseline levels [Ciafaloni et al., 2000]. Blood pressure, renal function, and trough plasma cyclosporine levels are monitored monthly.

MYCOPHENOLATE MOFETIL Mycophenolate mofetil (MM, CellCept) is the latest immunosuppressive agent to enter common practice at myasthenia gravis centers, having exhibited initial promise in several uncontrolled, open-label series demonstrating favorable responses in two thirds of adult patients [Chaudhry et al., 2001; Ciafaloni et al., 2001]. Benefits have included

improved functional status and a corticosteroid-sparing effect. According to a retrospective analysis of 85 patients in which Myasthenia Gravis Foundation of America postintervention classifications were used, 73% achieved pharmacologic remission, minimal manifestation status, or improvement with mycophenolate mofetil [Meriggioli et al., 2003]. Patients with severe weakness (Myasthenia Gravis Foundation of America class IV) were less likely to respond. Mycophenolate mofetil had a relatively rapid onset of action, with improvement observed at a mean of 9 to 11 weeks and maximal improvement by approximately 6 months. In some subjects, however, the initial response was delayed up to 40 weeks. The most common adult dosing regimen is 1 gram by mouth twice daily, although doses up to 3 grams a day have been used. It is used in the pediatric transplant population at doses 600 mg/m2 twice daily. Children with body surface areas greater than 1.5 m2 are dosed at 1 gram twice daily. Mycophenolate mofetil blocks inosine monophosphate dehydrogenase, which results in selective inhibition of B and T lymphocyte proliferation by blocking purine synthesis. It is routinely used in allogeneic transplant recipients and has been well tolerated in the population with myasthenia gravis. Main side effects are diarrhea, vomiting, increased risk for infection, and leukopenia, which is relatively uncommon. Complete blood counts are checked weekly for the first month and then less frequently. Long-term safety for mycophenolate mofetil is still in question, but malignancy rates do not appear higher in the transplant population. With its more rapid onset of action and favorable side-effects profile, mycophenolate mofetil is replacing azathioprine as the firstline “steroid sparer” in many myasthenia gravis centers and is being studied in two multicenter, randomized, controlled trials.

CYCLOPHOSPHAMIDE The use of cyclophosphamide (Cytoxan), a nitrogen mustard alkylating agent that blocks cell proliferation, is mainly reserved for patients with refractory myasthenia gravis. Reported use is limited. In one study, 42 adults had been treated with cyclophosphamide; 23 were also taking prednisone [Perez et al., 1981]. At the time of the retrospective data analysis, 25 of the 42 patients had become asymptomatic, and 12 were in complete remission and had discontinued all medications. Of 10 children with juvenile myasthenia gravis, 8 improved when cyclophosphamide was added to regimens that included azathioprine and corticosteroids [Badurska et al., 1992]. In a randomized, placebo-controlled, double-blinded study, monthly intravenous pulses of cyclophosphamide, 500 mg/m2, were given to 23 adult myasthenia gravis patients with severe, refractory disease or steroid-related side effects [De Feo et al., 2002]. At month 12, the group receiving cyclophosphamide had significantly improved muscle strength on the Quantitative Myasthenia Gravis Scale. At both 6 and 12 months, steroid doses were significantly lower for the patients receiving cyclophosphamide. Similarly, impressive therapy responses were seen in three adult patients with refractory disease who received high-dose (50 mg/kg) intravenous cyclophosphamide for 4 days, followed by “rescue” with granulocyte colony-

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stimulating factor [Drachman et al., 2003]. Marked improvement in strength without disease recurrence over several years was observed. The high rate and severity of toxicity are the drawbacks for cyclophosphamide. In one study, alopecia occurred in 75%, leukopenia in 35%, and nausea and vomiting in 25% [Perez et al., 1981]. The increased risk of bladder and lymphoreticular malignancy with prolonged administration of cyclophosphamide should be of particular concern. As a result, cyclophosphamide should be considered only in the most refractory cases of juvenile myasthenia gravis.

PLASMAPHERESIS Plasma exchange was first used for myasthenia gravis in 1976 [Pinching et al., 1976] and is employed primarily in the shortterm, acute management of severe disease, including crisis, and in readying weak patients for thymectomy [Behan et al., 1979; Campbell et al., 1980; Dau et al., 1977; Rowland, 1980]. Plasmapheresis removes anti-AchR antibodies from the circulation of patients with myasthenia gravis, and improvement is measured in several days, rather than weeks for corticosteroids and months for immunosuppressive agents. Two other circumstances in which plasmapheresis is considered include the treatment of severely weak patients admitted for initiation of prednisone therapy and a chronic intermittent therapy in patients with refratory disease. Plasmapheresis has been lifesaving in some children [Snead et al., 1980]. In general, a course of plasmapheresis consists of four to six exchanges in which approximately 50 mL of plasma per kilogram of the patient’s weight are removed at each treatment. Decisions regarding the number of exchanges and total amount removed are largely driven by the status of the patient, including clinical response and tolerability of the hemodynamic shifts from the procedure. Improvement is often seen within 48 hours after the first or second exchange. Treatments are usually administered every other day or on no more than 2 of 3 consecutive days, so that a full course is completed in 7 to 10 days [Andrews, 2004]. The main limitations of plasmapheresis are (1) intravenous access, because a double-lumen catheter is required in younger children; (2) complications, including pneumothorax, hypotension, sepsis, and pulmonary embolism; (3) expense of the procedure; and (4) the relatively brief clinical benefit, which persists for only a few weeks.

INTRAVENOUS IMMUNE GLOBULIN Intravenous immune globulin is increasingly used by neurologists for various immune-mediated neuromuscular diseases, including myasthenia gravis. In an analysis of eight published retrospective studies, a response rate to intravenous immune globulin of 73% was derived, with clinical responses seen in 4 to 5 days [Arsura, 1989]. The effect can persist for several weeks to several months. A randomized, double-blinded, placebo-controlled trial of intravenous immune globulin in generalized myasthenia gravis was initiated but was terminated before an adequate number of subjects could be enrolled, and the trial was underpowered [Wolfe et al., 2002]. In the open-label intravenous immune globulin extension, favorable trends in

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quantitative strength and electrophysiologic outcome measures were seen in patients who had initially received placebo, which was consistent with qualitative improvement seen in prior reports. In a Cochrane Database review, data from four randomized controlled trials of intravenous immune globulin that enrolled 147 subjects were analyzed [Gajdos et al., 2003]. No significant efficacy difference was observed between intravenous immune globulin and either plasma exchange or methylprednisolone in disease exacerbations [Gajdos et al., 1997]. Although no studies have focused on the pediatric population, children and adolescents have responded favorably to intravenous immune globulin [Andrews, 2004]. The initial dose of intravenous immune globulin is usually 2 grams/kg. This can be given over 2 to 5 days. When given over the shorter interval, the infusion runs nearly continuously. A common practice is to then schedule two or three subsequent infusions of 0.4 to 1 gram/kg at 2- to 4-week intervals. Patients are then reevaluated to determine whether further treatments are needed. Advantages of intravenous immune globulin over plasma exchange include the relative ease of administration and the favorable side effects profile in both children and adults. Headache, transient flulike symptoms, and hyperactivity are the adverse events most common to the pediatric population [Andrews, 2004]. Patients who suffer migraine are prone to develop a severe headache related to aseptic meningitis. The

Box 78-2 DRUGS THAT MAY WORSEN MYASTHENIA GRAVIS OR INTERFERE WITH NEUROMUSCULAR TRANSMISSION Antibiotic agents Aminoglycosides Erythromycin Tetracycline Penicillins Sulfonamides Fluoroquinolones Clindamycin Lincomycin Anesthetic agents Neuromuscular blocking agents Lidocaine Procaine Antiepileptic drugs Phenytoin Mephenytoin Trimethadione Cardiovascular drugs Beta blockers Procainamide Quinidine Rheumatologic drugs Chloroquine D-Penicillamine Miscellaneous Iodinated contrast Chlorpromazine Corticosteroids Lithium

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Neuromuscular Disorders / 78

outbreak of hepatitis C in relation to some intravenous immune globulin products [Schiff, 1994] has been controlled with improved donor screening and sterilization techniques. Major complications are observed in up to 5% of adults, including cardiovascular, cerebrovascular, and deep venous thrombotic events; congestive heart failure; and acute nephrotoxicity [Brannagan et al., 1996; Go and Call, 2000; Steg and Leflowitz, 1994; Tan et al., 1993].

Drugs to Avoid Children with myasthenia gravis, like adults with myasthenia gravis, are sensitive to nondepolarizing neuromuscular blocking agents. Intermediate-acting nondepolarizing blockers such as atracurium and vecuronium should be used with care [Baraka, 1992]. It is advisable to administer small increments of these agents, with neuromuscular monitoring as a guide [Brown et al., 1990]. Other commonly used drugs known to exacerbate myasthenia gravis or interfere with neuromuscular transmission are listed in Box 78-2. Of these agents, aminoglycoside antibiotics are perhaps the agents that most commonly affect neuromuscular transmission, and they should be used in patients with myasthenia gravis only when there are no reasonable alternatives.

LAMBERT-EATON MYASTHENIC SYNDROME Lambert-Eaton myasthenic syndrome is an acquired autoimmune disorder of neuromuscular junction transmission in which the defect is in the presynaptic nerve terminal. Lambert and co-workers [1956] and Eaton and Lambert [1957] are credited for defining the syndrome, including the electrophysiologic abnormalities seen on routine electromyography. Elmqvist and Lambert [1968] then found that the neuromuscular junction defect resulted from inadequate presynaptic release of acetylcholine. An immune-mediated basis for Lambert-Eaton myasthenic syndrome was suspected when the disease was passively transferred from the purified IgG of patients to mice [Lang et al., 1981]. At about the same time, it was found that the number of voltage-gated calcium channels is reduced in the motor nerve terminal [Fukunga et al., 1982]. A number of investigators have subsequently provided data as evidence that the Lambert-Eaton syndrome IgG is directed at voltage-gated calcium channels [Kim and Neher, 1988; Lang et al., 1989; Sher et al., 1989]. This action inhibits the influx of calcium into the motor nerve terminal. As a result, the number of quanta of acetylcholine vesicles released with each action potential that reaches the nerve terminal is decreased.

Clinical Features Lambert-Eaton myasthenic syndrome is characterized by fatigability and weakness in a limb-girdle distribution [Mareska and Gutmann, 2004; O’Neill et al., 1988]. Unlike patients with myasthenia gravis, these patients may note that the weakness is worse soon after awakening and lessens later in the day. Although exercise can transiently improve strength, persistent exertion causes fatigue. Cranial nerve and respiratory involvement are less common than in

myasthenia gravis. Up to 50% of patients have a mild degree of ptosis, diplopia, dysphagia, and dysarthria. Patients also have autonomic involvement, including dry mouth and eyes, impotence, blurred vision, and orthostasis. On examination, there is a limb-girdle pattern of weakness, and deep tendon reflexes are reduced or absent. In some patients, improvement in strength or the reflex response can be demonstrated after a few seconds of voluntary contraction. This reaction is called postexercise facilitation of reflexes and was observed in 44% of 16 patients in one study [Odabasi et al., 2002]. A malignancy is present in approximately 50% of adult patients with Lambert-Eaton myasthenic syndrome. The tumor is usually a small cell carcinoma of the lung; other malignancies include renal cell carcinoma and hematologic tumors. Lambert-Eaton myasthenic syndrome can be the presenting manifestation of a small cell carcinoma and can precede the detection of the tumor by months. Seventy percent of men with Lambert-Eaton myasthenic syndrome and only 25% of women with Lambert-Eaton myasthenic syndrome have a malignancy. Lambert-Eaton myasthenic syndrome is only rarely described in children. The first report was about a 10-yearold boy with leukemia [Dahl and Sato, 1974]. The literature contains only a handful of cases in which the patient is younger than 15 years [Argov et al., 1995; ChelmickaSchorr et al., 1979; Shapira et al., 1974; Tsao et al., 2002], often in association with a lymphoproliferative disorder. A congenital case of Lambert-Eaton myasthenic syndrome not diagnosed until age 4 years has been reported [Bady et al., 1987].

Clinical Laboratory Tests A diagnosis of Lambert-Eaton myasthenic syndrome is often first suggested by findings on nerve conduction studies and repetitive stimulation. Edrophonium may produce mild improvement in strength, but its results do not differentiate Lambert-Eaton myasthenic syndrome from myasthenia gravis. The classic electrophysiologic triad of LambertEaton myasthenic syndrome is (1) low-amplitude compound muscle action potential that increases dramatically after brief exercise, (2) decremental response at low rates of repetitive stimulation (2 to 5 Hz), and (3) incremental response at high rates (20 to 50 Hz) of repetitive stimulation [Oh, 1988]. These electrophysiologic features are illustrated in Figure 78-7. The diagnosis of Lambert-Eaton myasthenic syndrome often becomes apparent first in the electromyography laboratory when, in the process of performing routine motor nerve conduction studies, diffusely small-amplitude compound muscle action potentials are found. At this point, it is useful to conduct the Lambert-Eaton myasthenic syndrome screen test. After the baseline compound muscle action potential amplitude is obtained (e.g., in the adductor digiti minimi), the patient is asked to spread the fingers apart against resistance for 10 seconds. Then the single nerve stimulation is immediately repeated and the compound muscle action potential recorded. In Lambert-Eaton myasthenic syndrome there is a dramatic, often greater than 100% increase in the compound muscle action potential amplitude and area. The physiologic effect of either brief exercise or tetanic stimulation produces enough influx of

Wolfe and Barohn / Diseases of the Neuromuscular Junction

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FIGURE 78-7. Repetitive stimulation of the ulnar nerve, recorded in the adductor digiti minimi in a patient with Lambert-Eaton myasthenic syndrome. A, Low-frequency (3-Hz) repetitive stimulation elicited a 32% decrement. B, After 10 seconds of exercise (brief exercise test), the compound motor action potential demonstrated a 220% increment over baseline. C, High-frequency repetitive stimulation elicited a 195% increment. (From Katz J, Wolfe GI, Bryan WW, et al. Acetylcholine receptor antibodies in the Lambert-Eaton myasthenic syndrome. Neurology, 1998;50:470.)

calcium into the presynaptic terminal to overcome the underlying defect in quantal release. Incremental responses consistent with Lambert-Eaton myasthenic syndrome should be at least 100%. Normal individuals can have incremental responses as great as 40% [Oh, 1989]. Single-fiber electromyography indicates increased jitter in Lambert-Eaton myasthenic syndrome, but this does not differentiate the disease from myasthenia gravis. Antibody testing for Lambert-Eaton myasthenic syndrome is now available in select laboratories. In a study of 72 patients ranging from 16 to 80 years of age, 92% were seropositive for antibodies to P/Q-type voltage-gated calcium channel [Motomura et al., 1996]. In contrast, only 33% were seropositive for anti-N-type voltage-gated calcium channel antibodies. All patients with anti-N-type voltage-gated calcium channel antibodies were also seropositive for anti-P/Q-type voltage-gated calcium channel antibodies. Lennon and co-workers [1995] found that all patients with Lambert-Eaton myasthenic syndrome who had a diagnosis of cancer had anti-P/Q-type voltagegated calcium channel antibodies, in comparison with 91% of such patients without cancer [Lennon et al., 1995]. Nakao and colleagues [2002] found that of 110 patients with Lambert-Eaton myasthenic syndrome, 85% had anti-P/Qtype voltage-gated calcium channel antibodies and that seronegative patients were less likely to have small cell carcinoma (12% versus 70% of the seropositive population). Anti-N-type voltage-gated calcium channel antibodies were present in only 49% of patients with Lambert-Eaton myasthenic syndrome. These results support the notion that anti-P/Q-type voltage-gated calcium channel antibodies are primarily responsible for the presynaptic defect in LambertEaton myasthenic syndrome. Children with P/Q-type

voltage-gated calcium channel antibodies and typical features of Lambert-Eaton myasthenic syndrome were first reported as recently as 2002 [Tsao et al., 2002]. On occasion, adult patients with Lambert-Eaton myasthenic syndrome also have anti-AchR antibodies in the serum [Katz et al., 1998].

Treatment As in the adult form of the disorder, clinical improvement in childhood Lambert-Eaton myasthenic syndrome has been observed with anticholinesterase agents [Dahl and Sato, 1974], prednisone [Chelmicka-Schorr et al., 1979], and guanidine hydrochloride [Bady et al., 1987; ChelmickaSchorr et al., 1979]. As expected, treatment guidelines are mostly drawn from reports of adult patients. In general, a trial of pyridostigmine is the first intervention, although it is often of limited benefit. Ideally, drugs that increase the release of acetylcholine vesicles should be tried. Guanidine hydrochloride is the oldest drug in this group and has been beneficial in some Lambert-Eaton myasthenic syndrome patients [Cherington, 1976]. However, the side effects of guanidine are prohibitive and include bone marrow depression, renal failure, gastrointestinal distress, ataxia, hypotension, paresthesias, confusion, dry skin, and atrial fibrillation. One report suggested that lower doses of guanidine not exceeding 1000 mg daily, combined with pyridostigmine, may be more tolerable [Oh et al., 1997]. 3,4-Diaminopyridine increases the duration of the presynaptic action potential by blocking the outward potassium efflux. This effect indirectly prolongs the activation of voltage-gated calcium channel and increases calcium entry in nerve terminals. In clinical trials, 3,4-diaminopyridine improves strength and compound muscle action potential

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amplitudes in patients with Lambert-Eaton myasthenic syndrome [McEvoy et al., 1989; Sanders et al., 1993]. Most patients tolerated the drug with only minor side effects. Unfortunately, 3,4-diaminopyridine is available only as an investigational agent in the United States. There are surprisingly few clinical studies on immunosuppressive therapy in Lambert-Eaton myasthenic syndrome. Newsom-Davis and Murray [1984] reported that plasmapheresis, corticosteroids, and azathioprine can be effective in both neoplastic and nonneoplastic LambertEaton myasthenic syndrome. Other reports describe the effectiveness of intravenous immune globulin in a small number of Lambert-Eaton myasthenic syndrome patients [Bird, 1992; Rich et al., 1997]. Muscle strength improved in a placebo-controlled crossover trial of intravenous immune globulin in nine patients with Lambert-Eaton myasthenic syndrome [Bain et al., 1996]. The improvement peaked 2 to 4 weeks after infusion and was associated with a significant decline in voltage-gated calcium channel antibody titers. A sustained response to cyclosporine was reported in two children who had only limited responses to intravenous immune globulin and plasmapheresis [Tsao et al., 2002]. A Cochrane Database review of Lambert-Eaton myasthenic syndrome treatment concluded that randomized, controlled trials of 3,4-diaminopyridine and intravenous immune globulin demonstrated improved muscle strength scores and compound muscle action potential amplitudes [Maddison and Newsom-Davis, 2003]. In general, the regimens and doses for the immunotherapies outlined for myasthenia gravis can be applied to Lambert-Eaton myasthenic syndrome.

CONGENITAL MYASTHENIC SYNDROMES Congenital myasthenic syndromes compose a heterogeneous group of relatively uncommon childhood diseases that present a diagnostic challenge to the clinician. The estimated prevalence is 1 to 2 per million. Some forms are life threatening, whereas others produce only mild weakness and are treatable [Engel, 1990; Shillito et al., 1993]. Therefore, an accurate diagnosis is necessary for rational therapy. Unlike myasthenia gravis and Lambert-Eaton myasthenic syndrome, the congenital myasthenic syndromes are not autoimmune; antibody determinations are negative, and immunosuppressive therapy is not effective. Although clinical and electrophysiologic data may suggest congenital myasthenic syndrome, specialized microelectrode analysis of neuromuscular transmission, ultrastructural studies of the neuromuscular junction, biochemical skeletal muscle assays, and molecular analysis are necessary to make a precise diagnosis [Engel, 1993; Engel et al., 1998; Harper, 2004]. These genetically determined disorders all compromise in some way the safety factor that normally preserves the integrity of neuromuscular transmission, either directly or through secondary alterations at the neuromuscular junction [Engel, 1994]. The earliest report of a congenital myasthenic syndrome was in 1937 by Rothbart, who described four brothers who developed a myasthenic condition before the age of 2 years. Bowman [1948] coined the term congenital myasthenia to describe the condition of an infant who had normal parents and whose myasthenic symptoms persisted into childhood.

Box 78-3 CLASSIFICATION OF THE CONGENITAL MYASTHENIC SYNDROMES Presynaptic defects Paucity of synaptic vesicles and decreased quantal release Congenital myasthenic syndromes with episodic apnea (choline acetyltransferase deficiency) Lambert-Eaton syndrome–like form Synaptic defects Endplate acetylcholinesterase deficiency Postsynaptic defects Primary acetylcholine receptor deficiency Reduced receptor expression as a result of acetylcholine receptor mutations Reduced receptor expression as a result of rapsyn mutations Reduced receptor expression with plectin deficiency Primary acetylcholine receptor kinetic abnormality with or without acetylcholine receptor deficiency Slow-channel syndrome Fast-channel syndrome Sodium-channel mutations

By 1972, 97 familial cases of early-onset myasthenia had been documented [Bundey, 1972]. Forty-one had presented before 2 years of age. Using refined techniques, Engel and co-workers [1977a] subsequently described three forms of congenital myasthenic syndrome: endplate acetylcholinesterase deficiency [Engel et al., 1977a], slow-channel syndrome [Engel et al., 1982], and impaired resynthesis or vesicular packaging of acetylcholine [Mora et al., 1987], also known as familial infantile myasthenia [Greer and Schotland, 1960; Robertson et al., 1980]. Work by Engel’s group has identified other forms of congenital myasthenic syndrome related to kinetically abnormal or deficient AchRs [Engel et al., 1997]. Box 78-3 summarizes the syndromes that have been characterized to this point [Harper, 2004].

Clinical Features Most patients with congenital myasthenic syndrome present in the first 2 years of life, with many becoming symptomatic in the neonatal period or in early infancy [Misulis and Fenichel, 1989; Shillito et al., 1993]. However, clinical involvement may not occur until adolescence or adulthood, particularly in the slow-channel syndrome. Symptoms in familial infantile myasthenia can be episodic or worsen with fever and emotional stimuli. There is considerable variation between families and even siblings sharing the same type of congenital myasthenic syndrome, which confounds the clinical definition and classification of these disorders [Misulis and Fenichel, 1989; Vincent et al., 1981]. Typical clinical findings in congenital myasthenic syndrome include feeding difficulty, respiratory dysfunction, ophthalmoparesis, ptosis, hypotonia, and limb fatigability. Symptoms may worsen with crying or physical activity in the neonatal period [Engel, 1994]. The attainment of developmental milestones, as well as progression and regression of symptoms, should be carefully documented.

Wolfe and Barohn / Diseases of the Neuromuscular Junction

Response to various pharmacologic challenges may assist in defining the syndrome. A positive family history is obviously suggestive of congenital myasthenic syndrome, but a negative family history does not exclude autosomal-recessive inheritance, incomplete penetration, or a new mutation.

Clinical Laboratory Tests Preliminary testing should include nerve conduction studies and needle electromyography. These studies often yield normal results, but repetitive motor action potential discharges to a single electrical stimulus suggest acetylcholinesterase deficiency or slow-channel syndrome [Engel, 1993]. Lowfrequency repetitive nerve stimulation usually reveals a decrement in weak muscles and should be performed at baseline and after exercise. To exclude autoimmune myasthenia or myasthenic syndrome, antibodies against AchR, skeletal muscle, and calcium channels should be assayed. Routine muscle biopsy for light microscopy and electron microscopy may yield normal results or reveal nonspecific abnormalities such as type 1 fiber predominance or type 2 fiber atrophy. Small groups of atrophic fibers and vacuolar changes near the endplate are seen in slow-channel syndrome. Although the specialized, intensive testing required for definitive diagnosis is available in only a handful of tertiary centers, routine clinical data can be very helpful in classifying patients. Table 78-3 summarizes distinctive clinical and electrodiagnostic features of the various forms of congenital myasthenic syndrome. Specialized studies include microscopic and ultrastructural examination of muscle specimens to assess synaptic vesicle content, acetylcholinesterase assay, AchR abundance, and destructive postsynaptic changes that may reflect cholinergic overactivity [Engel and Ohno, 2002]. Microelectrode electrophysiologic studies on intercostal or anconeus muscle biopsies can localize the process to a presynaptic, synaptic, or postsynaptic defect and can define factors responsible for the impairment in neuromuscular transmission. Miniature endplate potential amplitude and frequency, endplate potential amplitude, the number and probability of quanta released by nerve impulses, and quantal content are determined. Patch clamp recording of individual AchRs defines the amplitude and duration of single currents to determine kinetic abnormalities of the receptor. A number of developments since the mid-1990s have accelerated the molecular characterization of these disorders. These include the identification of the complementary DNA sequence for the various subunits of the AchR and acetylcholinesterase, improved resolution of patch clamping techniques in human intercostal muscle to allow recording of single-channel currents, and the ability to study mutant neuromuscular junction proteins in engineered mammalian systems [Engel and Ohno, 2002]. If the evaluation demonstrates features consistent with a defect in a candidate gene or protein, molecular analysis follows. If a mutation is found, genetically engineered models of the mutant molecule can be used to confirm the pathogenicity and further define the properties of the mutation. This approach has led to the discovery of more than 100 mutations combined in various subunits of the AchR, acetylcholinesterase, and choline acetyltransferase [Ohno and Engel, 2000].

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Presynaptic Defects Three major types of presynaptic defects have been identified: congenital myasthenic syndrome with episodic apnea related to disturbances in acetylcholine resynthesis, paucity of synaptic vesicles with reduced quantal release, and a Lambert-Eaton myasthenic syndrome–like form of congenital myasthenic syndrome.

Disturbances in Acetylcholine Resynthesis Patients with defective acetylcholine resynthesis have distinctive, sudden episodes of generalized and bulbar weakness with apnea precipitated by infections, fever, vomiting episodes, or emotional stimuli. Some infants present at birth with hypotonia and bulbar and respiratory weakness necessitating mechanical ventilation; others are normal at birth and do not experience apneic episodes until childhood. Ptosis, poor suck, feeble cry, and generalized weakness may be present early, but there is little or no extraocular involvement. Affected infants often demonstrate spontaneous improvement after several weeks and by adolescence may appear normal except for easy fatigability with exercise [Engel, 1990; Shillito et al., 1993]. Episodic crises may occur at any age, however, potentially leading to respiratory failure and death in infancy and early childhood [Conomy et al., 1975; Gay and Bodensteiner, 1990]. A family history of “sudden infant death syndrome” in older siblings is not uncommon [Ohno et al., 2001]. Apneic episodes become less frequent and severe as the child grows older. Decremental responses are typical on lowrate repetitive stimulation in presynaptic congenital myasthenic syndromes [Albers et al., 1984; Lecky et al., 1986; Vincent et al., 1981], at times occurring only after exercise [Engel, 1980; Hart et al., 1979]. In milder cases, prolonged repetitive stimulation at rates of 10 to 15 Hz may be necessary to demonstrate neuromuscular transmission failure [Harper, 2004]. The progressive decrement seen with prolonged stimulation is more severe and recovers more slowly (over 10 to 15 minutes) than in autoimmune myasthenia gravis or congenital myasthenic syndrome related to AchR deficiency and sodium channel defects. These patients closely resemble those described in earlier reports of “familial infantile myasthenia” [Greer and Schotland, 1960; Misulis and Fenichel, 1989], but this term should be avoided because all congenital myasthenic syndromes are familial and most manifest in the neonatal period. On microelectrode studies, miniature endplate potentials are normal at rest but decrease abnormally on repetitive stimulation over several minutes, which is consistent with a defect in acetylcholine resynthesis. Later studies established that mutations in the CHAT gene encoding endplate choline acetyltransferase, the rate-limiting enzyme in resynthesis of acetylcholine from choline and acetyl coenzyme A, are responsible [Ohno et al., 2001]. Low doses of anticholinesterases improve muscle strength in these patients and should be available in intramuscular form (neostigmine) for episodic crises [Engel, 1994]. Installation of apnea monitors is advised, as is training of family members in hand-assisted ventilatory devices. Nutritional support and aggressive treatment of underlying infections are important during crises [Harper, 2004]. 3,4-Diaminopyridine may produce transient benefit but over time can exacerbate symptoms when

x (most mutations)

x

Autosomal Episodic dominant apnea inheritance triggered by stressors

x (in severe cases)

x (in severe cases)

x

x

x (in severe cases)

x

x

x

x

x

x

x

x x

x

x

Neonatal Skeletal Delayed Prominent Repetitive Progressive Marked Decrement hypotonia deformities pupillary neck, wrist CMAPs decrement increment repairs and light and finger after single with (>200%) with AchE respiratory responses extensor stimulus prolonged with highinhibitors insufficiency weakness exercise or frequency repetitive repetitive stimulation stimulation

AchE, acetylcholinesterase; AchR, acetylcholine receptor; CMAPs, compound muscle action potentials; CMS, congenital myasthenic syndrome; LEMS, Lambert-Eaton myasthenic syndrome.

Fast-channel CMS

Slow-channel CMS

Postsynaptic Primary AchR deficiency

Synaptic AchE deficiency

Presynaptic Choline acetyltransferase deficiency LEMS-like form

CMS Syndrome

Distinctive Clinical and Electrodiagnostic Features of Congenital Myasthenic Syndromes

TABLE 78-3

x

x

x

Clinical Clinical improvement worsening with AchE with AchE inhibitors inhibitors

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Wolfe and Barohn / Diseases of the Neuromuscular Junction

acetylcholine stores are depleted [Harper, 2004; Palace et al., 1991].

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Paucity of synaptic vesicles with reduced quantal release clinically resembles autoimmune myasthenia gravis with symptoms beginning in infancy in the one documented case [Walls et al., 1993]. Slow-rate repetitive stimulation revealed a decrement that repaired after exercise. There was a marked reduction in quantal release in response to nerve impulses, and morphologic studies documented a reduction in density of synaptic vesicles. The molecular basis for this disorder is unknown, and whether it relates to defective axonal transport of vesicle constituents or impaired recycling is unclear. Anticholinesterase medications produced modest benefit.

1977a; Hutchinson et al., 1993]. Recessive mutations in the COLQ gene, which encodes the triple-stranded collagenic tail of acetylcholinesterase, have been identified in affected patients [Ohno et al., 2000]. The ColQ tail is responsible for anchoring catalytic subunits of acetylcholinesterase to the basal lamina of the postsynaptic membrane. Neuromuscular transmission appears to be impaired by the small size of nerve terminals, an endplate myopathy resulting from cholinergic overstimulation, and by densensitization/ depolarization block of AchRs [Engel and Ohno, 2002]. Treatment is difficult, inasmuch as the condition is refractory or worsens with anticholinesterase agents [Harper, 2004]. Medications that enhance neurotransmitter release from the nerve terminal, such as 3,4-diaminopyridine, would likely have a similar effect. Ephedrine may produce subjective improvement [Milone and Engel, 1996].

Lambert-Eaton Myasthenic Syndrome-like Form

Postsynaptic Defects

The Lambert-Eaton myasthenic syndrome–like syndrome shares the electrophysiologic signature of autoimmune Lambert-Eaton myasthenic syndrome discussed previously, with greater than 100% facilitation on high-frequency stimulation [Albers et al., 1984; Maselli et al., 2001]. Infants present with severe hypotonia and respiratory insufficiency [Harper, 2004]. There are no significant morphologic alterations, and synaptic vesicle density appears normal. Defective P/Q-type voltage-gated calcium channels or impaired vesicle release mechanisms may be responsible. Anticholinesterase agents, guanidine, and 3,4-diaminopyridine may provide some benefit.

Postsynaptic defects represent the most common forms of congenital myasthenic syndrome (Box 78-4). These disorders arise predominantly from a variety of AchR subunit mutations that either enhance or reduce their response to neurotransmitter. Although phenotypes vary, postsynaptic defects tend to be less severe than other forms of congenital myasthenic syndrome and, at times, respond more favorably to pharmacologic therapy. Muscle AchR is a transmembrane structure composed of five homologous subunits: two alpha, one beta, one delta, and one gamma subunit in the fetal form that is replaced by an epsilon subunit in the adult AchR. On the basis of extensive studies, two major kinetic abnormalities of the AchR have been described: slow-channel and fast-channel syndromes [Engel and Ohno, 2002]. Primary AchR deficiency, which may be accompanied by kinetic abnormalities, and congenital myasthenic syndrome related to perijunctional sodium channel mutations round out the postsynaptic defects.

Paucity of Synaptic Vesicles

Synaptic Defects Endplate Acetylcholinesterase Deficiency The initial description of acetylcholinesterase deficiency was in 1977 [Engel et al., 1977a] and was followed by several reports of either sporadic cases or autosomal-recessive pedigrees [Engel et al., 1981; Hutchinson et al., 1993; Walls et al., 1989]. Symptoms begin in the neonatal period with ptosis, poor suck, feeble cry, and generalized moderate to severe weakness. Motor milestones are delayed. Lordosis and scoliosis are prominent features. Ophthalmoparesis is variable, seen in about half of patients [Engel, 1990, 1994]. Pupillary light responses may also be abnormally sluggish. Decremental responses are seen on repetitive stimulation. Multiple motor action potential discharges may follow a single stimulus on routine nerve conduction studies, a characteristic but nonspecific finding that is also seen in slow-channel syndrome and in the setting of excessive anticholinesterase use [Shillito et al., 1993]. Acetylcholinesterase deficiency can be differentiated from slow-channel syndrome by a test in which cholinesterase inhibitors are administered: The number and size of the repetitive discharges after a single stimulus increases in slow-channel syndrome but does not change in the setting of acetylcholinesterase deficiency [Harper, 2004]. The primary abnormality is deficient acetylcholinesterase activity at the endplate on cytochemical and immunocytochemical studies, resulting in prolonged miniature endplate potential and endplate potential durations [Engel et al.,

Slow-Channel Congenital Myasthenic Syndrome The slow channel syndrome was first described by Engel and co-workers in 1982. Whereas most forms of congenital myasthenic syndrome demonstrate recessive inheritance, the majority of slow-channel syndromes result from dominant gain-of-function mutations [Harper, 2004]. These mutations prolong channel opening events and slow the decay of endplate currents, which result in cationic overload in muscle fibers and an endplate myopathy with fixed weakness [Gomez et al., 1997; Milone et al., 1997]. Onset of symptoms varies considerably, ranging from infancy to adulthood [Shillito

Box 78-4 LOCALIZATION OF DEFECT IN 134 PATIENTS WITH CONGENITAL MYASTHENIC SYNDROMES [ENGEL AND OHNO, 2002] Type of Congenital Myasthenic Syndromes Presynaptic Synaptic Postsynaptic No identified defect

Number of Cases 1 (8%) 23 (17%) 96 (72%) 4 (3%)

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et al., 1993], although late onset is more typical of this syndrome than for other forms of congenital myasthenic syndrome. Clinical findings also vary, although there is a propensity for early cervical, scapular, wrist, and finger extensor weakness that helps to distinguish the syndrome. Ptosis and ophthalmoplegia are less prominent. Lower extremities may be less involved than upper extremities [Engel, 1990]. Weakness in most patients is slowly progressive. Decremental responses up to 40% and increased jitter are seen on electrophysiologic testing. Repetitive potentials to single stimuli are characteristic of both weak and strong muscles and are best seen at rates below 0.2 Hz, inasmuch as at higher stimulation rates, the second potential is often of very small amplitude [Oosterhuis et al., 1987]. Cholinesterase inhibitors increase the number and amplitude of the repetitive responses in slow-channel syndrome but not in endplate acetylcholinesterase deficiency; this difference helps distinguish these two forms of congenital myasthenic syndrome. Specialized electrophysiologic studies on intercostal muscle have shown normal or slightly reduced miniature endplate potential amplitudes and normal quantal content of the endplate potential but prolonged decay time of the miniature endplate potential and endplate potential. Although it was suspected earlier, it was not until 1992 that prolonged open time of the AchR was clearly demonstrated to account for the slowed decay of endplate currents [Engel et al., 1993]. On exposure to acetylcholine, the abnormal AchRs have prolonged activation, resulting in abnormally slowed decay of endplate potential. Spontaneous openings of the AchR are also observed. This change in kinetic activity produces cationic overloading and an endplate myopathy with loss of junctional folds and AchRs, widening of synaptic space, and other morphologic alterations [Engel and Ohno, 2002]. These changes, in addition to the depolarization block that occurs when prolonged endplate potentials extend beyond the refractory period of muscle fibers, compromise neuromuscular transmission. A number of dominant mutations in the alpha, beta, and epsilon subunits of AchR have been described in slowchannel syndrome. Autosomal recessive mutations in the epsilon subunit have also been described [Croxen et al., 2002]. Not surprisingly, acetylcholinesterase inhibitors and 3,4-diaminopyridine worsen the condition. The worsening with acetylcholinesterase inhibitors can help distinguish slow-channel syndrome from autoimmune myasthenia gravis and all other forms of congenital myasthenic syndrome except for endplate acetylcholinesterase deficiency. Quinidine at doses of 200 mg two to three times a day and fluoxetine at doses of 80 to 160 mg per day have improved clinical and electrophysiologic measures in a small number of patients [Harper and Engel, 1998; Harper et al., 2003]. These two agents partially correct for prolonged AchR activation episodes in cell cultures expressing mutated receptors and clinically have demonstrated both short-term and long-term improvement of weakness. Quinidine may be problematic because of drug allergies, and fluoxetine is often better tolerated.

Fast-Channel Congenital Myasthenic Syndrome More recently described are the less common fast-channel syndromes. These are related to recessive loss-of-function

mutations of the AchR. Common features of these postsynaptic syndromes are rapid decay of endplate currents, brief channel activation episodes, and reduced probability of channel opening in response to acetylcholine, which result in reduced miniature endplate potential amplitudes [Engel and Ohno, 2002]. A variety of kinetic abnormalities have been described in the fast-channel syndromes in relation to mutations in the alpha and epsilon subunits of the AchR. The syndromes result from a mutant subunit allele that dominates the clinical phenotype combined with a null or missense mutation on the second allele. Phenotypic severity varies from a disabling congenital myasthenic syndrome related to low-affinity channels [Uchitel et al., 1993] to a mild syndrome associated with gating abnormalities. Typical patients present in infancy to early childhood with ptosis, opthalmoparesis, bulbar symptoms, and exertional limb weakness [Harper, 2004]. Decrements are present at slow rates of repetitive stimulation that can repair with exercise, high-frequency stimulation, and anticholinesterases. A static or slowly progressive course is usually observed. As would be predicted, fast-channel syndromes respond favorably to 3,4-diaminopyridine combined with anticholinesterases, because these agents enhance AchR activation by either increasing quantal release or reducing acetylcholine degradation in the synapse [Engel and Ohno, 2002].

Primary Acetylcholine Receptor Deficiency AchR deficiency states have most commonly been linked to homozygous or heterozygous recessive mutations of AchR subunits. Most mutations have involved the epsilon subunit [Engel et al., 1996]. This propensity may arise because null mutations of other subunits are lethal, whereas the fetal gamma subunit can partially compensate for the absence of the epsilon subunit. In addition, the epsilon subunit gene may be more susceptible to DNA rearrangements. The mutations reduce AchR density; in addition, some mutations produce minor kinetic abnormalities. Recessive mutations in the gene that encodes rapsyn, a protein synthesized by muscle that, through agrin and muscle-specific kinases, mediates the clustering of AchRs on the postsynaptic membrane, have also been associated with congenital myasthenic syndrome [Burke et al., 2003; Maselli et al., 2003; Ohno et al., 2002]. A single case report of reduced AchR counts associated with myopathy has been described with plectin deficiency [Banwell et al., 1999]. Disease severity in AchR deficiency states, whether from receptor subunit or rapsyn mutations, is variable, with onset occurring between the neonatal period and childhood [Harper, 2004]. Ptosis, ophthalmoplegia, and generalized hypotonia and weakness are typical. Epsilon subunit mutations generally produce milder manifestations [Engel et al., 2003]. Fixed weakness and skeletal anomalies, including high-arched palate and facial dysmorphism, are observed. In most cases, there is a nonprogressive course or even improvement with age. Repetitive stimulation at slow rates demonstrates a decrement in most but not all patients that repairs with anticholinesterases. In more severe cases, the decrement may worsen with stimulation frequencies above 10 Hz. Ultrastructural studies demonstrate increased numbers of endplate regions over an increased span of muscle fibers [Engel and Ohno, 2002]. Junctional folds

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appear to be preserved, although some endplates are small and simplified. There is a notable reduction in the density and numbers of AchRs. As with fast-channel forms of congenital myasthenic syndrome, anticholinesterases and 3,4-diaminopyridine may provide benefit [Harper, 2004].

Sodium-Channel Congenital Myasthenic Syndrome Sodium-channel congenital myasthenic syndrome was described in a single patient who harbored two recessive mutations in the skeletal muscle-sodium channel gene SCN4A [Tsujino et al., 2003]. Expression of the mutation in a human cell line exhibited enhanced fast inactivation of the sodium channel, thereby decreasing the safety margin of neuromuscular transmission by increasing the size of the endplate potential needed to generate a muscle action potential. Weakness began at birth with ptosis and bulbar and skeletal involvement. Brief exacerbations of bulbar and respiratory symptoms lasting no longer than 30 minutes persisted into early adulthood. Routine repetitive stimulation studies were normal. Decrements were seen only after stimulation for periods longer than 1 minute at rates of 10 to 50 Hz. The drop in compound motor action potential amplitude repaired rapidly within several minutes, a faster repair than that seen in choline acetyltransferase deficiency [Harper, 2004].

BOTULISM Botulism is caused by a toxin produced by Clostridium botulinum, a gram-positive anaerobic organism found commonly in soil and agricultural products [Cherington, 1990, 2004; Glatman-Freedman, 1996]. Eight immunologically distinct toxins have been identified; most human cases are caused by type A, B, or E. After binding irreversibly to receptors on presynaptic nerve terminals, the botulinum toxin is translocated across the membrane and blocks the calcium-dependent release of acetylcholine [Gutierrez et al., 1994]. The action of the toxin appears independent of calcium entry. Impaired release of acetylcholine results in failed neuromuscular transmission. Damage to nerve terminals may be permanent, resulting in a prolonged clinical recovery believed to be dependent on the formation of new neuromuscular junctions. Three forms of botulism exist, the most common being the form that occurs in infants.

Classic Botulism The classic form of botulism almost always follows ingestion of food contaminated by previously formed toxin [Cherington, 1998]. The stereotypical presentation features the development of bulbar symptoms, including blurred vision, diplopia, ptosis, dysarthria, and dysphagia, within 12 to 36 hours after ingestion of the contaminated food. A descending pattern of weakness and, in some cases, respiratory paralysis follows. Antitoxins have not clearly improved outcome, but supportive care measures have improved survival rates, and nearly full recovery is expected for surviving patients.

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Infantile Botulism Infantile botulism was first described in 1976 [Pickett et al., 1976] and has since become the most frequently reported form of botulism. It is also a common cause of hypotonia in this age group [Gay and Bodensteiner, 1990]. An interesting observation is that most reported cases in the United States occur in California, Pennsylvania, and Utah, states with high counts of C. botulinum spores in the soil [Cherington, 1990]. In infantile botulism, spores of C. botulinum are ingested and then germinate and propagate in the gastrointestinal tract, producing toxin in vivo. Consumption of honey and corn syrup has been associated with infantile botulism, but in most cases, the source of infection is not evident [Glatman-Freedman, 1996; Spika et al., 1989]. Infantile botulism typically manifests in infants between 6 weeks and 9 months of age and is heralded by the onset of severe constipation [Cherington, 1990; Gay and Bodensteiner, 1990]. A descending paralysis with cranial nerve paralysis, poor suck, feeble cry, and reduced facial expressions ensues and is followed by limb weakness [Wilson et al., 1982]. The child appears hypotonic, with ptosis, decreased extraocular motility, sluggish pupillary light responses, facial diplegia, weak suck, and a reduced gag response. Deep tendon reflexes and spontaneous bowel sounds are reduced. There is usually no associated fever. Both respiratory and autonomic compromise may occur, with the disease progressing over several days to a week. Although the presentation is often quite typical, the diagnostic approach should be tailored to exclude other possible etiologies, including systemic infection, tick paralysis, organophosphate poisoning, Guillain-Barré syndrome, congenital myopathies, and autoimmune and congenital myasthenic conditions. Electrophysiologic studies support a presumptive diagnosis of botulism while results of the bacteriologic studies are awaited. Sensory nerve conduction studies are normal. Compound muscle action potential amplitudes are normal to reduced, and motor conduction velocities are preserved. Repetitive stimulation study results confirm a presynaptic defect in neuromuscular transmission. Decremental responses are variably seen on slow rates of repetitive stimulation, but increments are present at rapid rates (20 to 50 Hz). An incremental response at rapid rates was the most distinctive finding in one study, observed in 92% of cases [Cornblath et al., 1983]. The increment averaged 73%. Post-tetanic facilitation is also seen in Lambert-Eaton myasthenic syndrome, but the facilitation is particularly prolonged in botulism, persisting up to 20 minutes [Gutierrez et al., 1994]. On needle electromyography, fibrillation potentials are seen in approximately 50% of affected infants, and short-duration, low-amplitude motor units in more than 90% [Cornblath et al., 1983]. Diagnosis is confirmed by isolation of the organism or toxin in stool samples. Toxin isolation is accomplished by the mouse neutralization test, usually performed at state health departments [Cherington, 1990]. Polymerase chain reaction assays have been developed but are not routinely available. In infantile botulism, the toxin is only rarely found in the serum [Cherington, 1990]. Treatment of infantile botulism is supportive; complete recovery requires several weeks to months. Case fatality rates of hospitalized patients in the United States are below

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5% [Glatman-Freedman, 1996; Wilson et al., 1982]. Nasogastric or parenteral nutrition is needed if the child is unable to drink or eat. Mechanical ventilation may also be required. Aminoglycosides and other agents that impair neuromuscular transmission should be used with extreme caution. The length of hospitalization averages 4 weeks, but some infants may require supportive care for as long as 5 months [Wilson et al., 1982].

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CHAPTER 79

Muscular Dystrophies Diana M. Escolar and Robert T. Leshner

Muscular dystrophies are progressive, inherited skeletal muscle disorders resulting in muscle degeneration and loss of strength. This heterogeneous group of disorders has been further characterized at the clinical and molecular level since the 1980s, giving rise to the many unique forms of muscular dystrophies known today. The time of clinical onset of these disorders ranges from the neonatal period to late adulthood. The distribution of predominant muscle weakness can help identify six major phenotypes [Emery, 2002]: • Duchenne-like, involving shoulder and pelvic girdle, neck flexors muscle with calf hypertrophy. • Emery-Dreifuss–type with scapulohumeral peroneal distribution. • Limb-girdle (pelvic and shoulder). • Fascioscapulohumeral peroneal involvement. • Distal muscle involvement (distal myopathy). • Oculopharyngeal, as seen in oculopharyngeal muscular dystrophy, with involvement of these muscles plus shoulder and limb girdle. The congenital forms of muscular dystrophies are generalized. The mode of inheritance in muscular dystrophies can be autosomal dominant, autosomal recessive, or X-linked. The underlying molecular defects responsible for these disorders are very diverse, including extracellular matrix proteins (laminin-2, collagen VI), transmembrane- and sarcolemmaassociated proteins (dystrophin, sarcoglycans, caveolin-3, α5 and α7 integrins, dysferlin), cytoplasmatic proteases (calpain-3), cytoplasmatic proteins associated with organelles and sarcomeres (titin, fukutin, telethonin), and nuclear membrane proteins (lamin, emerin). The molecular characterization of the different muscular dystrophies since the 1990s has helped increase the understanding of the sarcolemmal organization and underlying muscle biology responsible for the normal structure and maintenance of the normal sarcolemma. Figure 79-1 depicts an updated version of the muscle membrane. Binding relationships among proteins have turned out to be more complex than once thought, and the specific relation of these proteins, as well as the presence of phosphorylation sites, provides the basis for the pathophysiology that has been associated with these disorders. Disorders caused by mutations of these proteins are listed in the figure. In view of the widely variable manifestation of the muscular dystrophies, the broad spectrum of other organs that might be involved in addition to muscle (i.e., myotonic dystrophies), and the diverse group of proteins that can cause these disorders, it seems that the only common feature among them is the characteristic pathologic changes in muscle that allows characterization of these disorders as a

“dystrophy,” although at times these features can be very mild. An updated molecular-based classification of the muscular dystrophies is presented in Table 79-1. Many of these disorders first manifest clinically in adulthood and are not covered in detail in this chapter. The most common muscular dystrophy in children is Duchenne muscular dystrophy, and it is the main focus of this chapter. Extensive investigations of this disorder have shed light on the pathophysiology of other muscular dystrophies, especially those related to the dystrophin-associated glycoprotein complex (DGC), and so most of these features are discussed only in the Duchenne muscular dystrophy section.

DYSTROPHINOPATHIES Dystrophinopathies are a group of muscular dystrophies resulting from mutations in the dystrophin gene, located on the short arm of the X chromosome in the Xp21 region [Baumbach et al., 1989]. Of these, Duchenne muscular dystrophy is the most common dystrophinopathy resulting from complete absence of the dystrophin gene product, the subsarcolemmal protein dystrophin. Its allelic variant, Becker muscular dystrophy, is rarer. Becker muscular dystrophy is a consequence of different types of mutations in the same gene (in-frame mutations) that result in decreased quantity or decreased quality of the dystrophin protein, giving rise to a disease with varied severity and time of onset, ranging from childhood to adulthood. Whereas Duchenne muscular dystrophy typically manifests before age 4 years, Becker muscular dystrophy can be asymptomatic for many decades.

Duchenne Muscular Dystrophy History In a communication to the Royal Medical and Chirurgical Society of London in December 1851 (published in the Transactions of the Society the following year), Edward Meryon, an English physician, described in considerable detail a disease affecting eight males in three families. He was particularly impressed by the predilection for male members and its familial nature and by the fact that the progressive muscle wasting and weakness resulted from a disease of muscle and not the nervous system. He described meticulous histologic studies that revealed no abnormality of the spinal cord or nerves, but in muscle tissue he observed extensive “granular degeneration” and, in particular, that the sarcolemma was broken down and destroyed. He appears to

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Neuromuscular Disorders / 79

Extracellular Basement membrane proteins Collagen VI

Laminin-2 (merosin)

(Bethlem Ulrich syndrome)

(MDC1A)

Agrin ␣–dystroglycan

(LGMD 2C-F) Sarcoglycans ␤ ␥ ␣ ␦

sarcospan

Integrins ␣7 ␤1

␤

Caveolin-3 (LGMD 1C) Dysferlin (LGMD 2B)

Grb2

Filamin 2 ␣-dystrobrevin

nNOS

NH2

P

P

P nNOS

␤1 P

Syncolin

(LGMD 2I) FKRP(MDC 1C)

(ITGA7)

␣1

Syntrophins Calmodulin Dystrophin (DMD/BMD)

COOH

P

Calpain-3

(LGMD 2H)

(LGMD 2A)

P

Trim32

(LGMD 2G) COOH

Telethonin Myotilin

(LGMD 1A)

Golgi

Intracellular

(LGMD 2J) Titin

F-Actin filaments

LaminA/C Emerin (LGMD 1B) (DMD) Nucleus

NH2 FIGURE 79-1. Diagram of the muscle membrane as known today, illustrating association of dystrophin-glycoprotein complex linkage to contractile proteins, extracellular matrix proteins, and other proteins with signaling properties (syntrophins, Grb2). It also illustrates the multiple phosphorylation sites in the 3′ end of dystrophin, dystrobrevin, and dystroglycans. Diseases associated with defect in individual proteins are also listed in parentheses. BMD, Becker muscular dystrophy; DMD, Duchenne muscular dystrophy; ITGA7, integrin α7; LGMD, limb-girdle muscular dystrophy; MDC1A, merosin-negative congenital muscular dystrophy; MDC1C, merosin-positive congenital muscular dystrophy; nNOS, neuronal nitric oxide synthetase. See also Color Plate.

have been the first physician to make a detailed clinical, genetic, and pathologic study of the disorder several years before Guillaume-Benjamin Duchenne [Emery, 1993]. Later, in 1868, Duchenne, a French neurologist and student of electrical stimulation of muscle, described a syndrome characterized by muscular paralysis associated with muscle hypertrophy that resulted from accumulation of large amounts of fat and connective tissue in muscle. Duchenne described the first instrument capable of procuring muscle for biopsy and analysis, and his description of pseudohypertrophic, X-linked muscular dystrophy bears his name. The discovery of the molecular defect in this disorder constitutes the first example of reverse cloning. Restriction fragment length polymorphisms were used to track the cosegregation of the disease phenotype with DNA markers within a family. The initial cloning of the Duchenne dystrophy gene occurred in 1985 and 1986 [Kunkel et al., 1985; Monaco et al., 1985; Ray et al., 1985], followed by isolation of the DNA clones complementary to the Duchenne dystrophy gene [Burghes et al., 1987; Cross et al., 1987; Monaco et al., 1986]. These complementary DNA clones, which were made from RNA transcripts from the Duchenne gene, contain the coding sequences or exons in the Duchenne

gene. Subsequently, the protein product of the human Duchenne muscular dystrophy locus was identified through the use of polyclonal antibodies directed against fusion proteins containing two distinct regions of the Duchenne muscular dystrophy locus’s complementary DNA. This protein was named dystrophin [Hoffman et al., 1987a].

Molecular Pathogenesis Duchenne muscular dystrophy is a relentlessly progressive skeletal muscle disorder caused by a genetic mutation in the X-linked dystrophin gene, resulting in absence of a critical protein, dystrophin [Hoffman et al., 1987a, 1988; Koenig et al., 1987]. The dystrophin gene includes 86 exons (including seven promoters linked to unique first exons), which make up only 0.6% of the gene; the rest consists of introns. The gene spans a genetic distance of more than 2.5 million base pairs and is the largest human gene isolated to date [Burmeister and Lehrach, 1986]. In more than 90% of males with the Duchenne muscular dystrophy genotype, there is an absence of dystrophin corresponding to an “out-of-frame” mutation that disrupts

Escolar and Leshner / Muscular Dystrophies

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TABLE 79-1 Classification of the Muscular Dystrophies DISEASE

GENE LOCUS

GENE PRODUCT

MODE OF INHERITANCE

Limb-Girdle Muscular Dystrophy (LGMD) Caused by Sarcolemma or Cytosolic Protein Defects Duchenne/Becker muscular Xp21 Dystrophin dystrophy LGMD1A 5q22 Myotilin LGMD1B 1q11-q21 Lamin A/C LGMD1C 3p25 Caveolin-3 LGMD1D 6q23 Not identified LGMD1E 7q Not identified LGMD1F 2q Not identified LGMD2A 15q15 Calpain-3 LGMD2B/Myoshi’s myopathy 2p13 Dysferlin LGMD2C 13q12 γ-Sarcoglycan LGMD2D 17q112 α-Sarcoglycan LGMD2E 4q12 β-Sarcoglycan LGMD2F 5q23 δ-Sarcoglycan LGMD2G 17q11 TCAP LGMD2H 9q31 TRIM32 LGMD2I 13q13 FKRP LGMD2J/Tibial muscular dystrophy 2q31 Titin

AD AD AD AD AD AD AR AR AR AR AR AR AR AR AR AR/AD

Congenital Muscular Dystrophies (CMDs) Secondary to Glycosylation Disorder Fukuyama’s muscular dystrophy 9q31-q33 Muscle-eye-brain disease 1p3 Walker-Warburg syndrome 9q34 MDC1A 6q22 MDC1B 1q42 MDC1C 19q13 MDC1D 22q12

Fukutin POMGnT1 glycosyltransferase POMT1 Laminin-2 (merosin) Not identified FKRP LARGE

AR AR AR AR AR AR AR

Other Congenital Muscular Dystrophies CMD with early rigid spine CMD with ITGA7 mutations Ullrich’s syndrome/Bethlem’s myopathy

Selenoprotein 1 Integrin α7 Collagen 6 A1, A2, and A3

AR AR AD

1p36 12q 21q22.3 (A1, A2) 2q37(A3)

XR

Muscular Dystrophies Secondary to Nuclear Envelope Defects (“Nuclear Envelopathies”) Emery-Dreifuss muscular dystrophy (EDMDX) Xq28 Emerin Emery-Dreifuss muscular dystrophy (EDMD1) 1q11-q23 Lamin A/C

XR AD/sporadic

Muscular Dystrophies Secondary to RNA Metabolism Defect Myotonic dystrophy 1 (DM1) 19q13 Myotonic dystrophy 2 (DM2) 3q21

DM ZFN9

AD AD

Muscular Dystrophies of Unknown Mechanism Facioscapulohumeral muscular dystrophy Oculopharyngeal muscular dystrophy

Not identified PABp2

AD AD

4q35 14q11.2-q13

AD, autosomal dominant; AR, autosomal recessive; MDC, merosin-negative congenital muscular dystrophy; XR, X-linked recessive.

normal dystrophin transcription [Gillard et al., 1989]. These mutations cause a premature stop codon and early termination of messenger RNA transcription. As a result, an unstable RNA is produced, undergoes rapid decay, and eventually leads to the production of nearly undetectable concentrations of truncated proteins. If the mutation maintains translational reading, an “in-frame” deletion, the Becker muscular dystrophy phenotype, with variably decreased amounts of abnormal molecular weight dystrophin, is present [Hoffman et al., 1988]. This reading frame hypothesis holds for over 90% of afflicted individuals and is commonly used both as a diagnostic confirmation of dystrophinopathies and for the differential diagnosis of Duchenne muscular dystrophy and Becker muscular dystrophy. Exceptions to these two typical situations occur in approximately 10% of patients. Out-of-frame deletions

affecting exons 3 to 7, 5 to 7, 3 to 6 or downstream at exons 51, 49 to 50, 47 to 52, 44, or 45 can result in a milder Becker muscular dystrophy phenotype. The most common explanation for the presence of at least some dystrophin in these patients is exon skipping, which occurs through alternative splicing [Nicholson et al., 1992; Patria et al., 1996]. In this form of Becker muscular dystrophy, the carboxy-terminus is always preserved [Arahata et al., 1991]. Exon skipping is also the underlying mechanism for the revertant fibers (muscle fibers exhibiting dystrophin staining in muscle biopsies) evident in about 50% of males with Duchenne muscular dystrophy [Winnard et al., 1995]. The limited expression of dystrophin results in a slower progression of muscle weakness than in the usual Duchenne phenotype [Arahata et al., 1989; Baumbach et al., 1989; Koenig et al., 1989; Malhotra et al., 1988]. A new therapeutic strategy in Duchenne muscular dystrophy is being developed on the basis of this

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natural finding, attempting to pharmacologically induce “exon-skipping” in Duchenne muscular dystrophy patients to allow for production of some quantity of dystrophin to ameliorate the phenotype (see therapeutic approaches). Another exception to the reading frame hypothesis might occur with large in-frame deletions in the 5′ end that extend to the middle of the rod domain (i.e., deletions of exons 3 to 31, 3 to 25, 4 to 41, and 4 to 18) [Nevo et al., 2003], as well as with small in-frame deletions of exons 3 to 13 [Muntoni et al., 1994] that cause the severe Duchenne muscular dystrophy phenotype. These small and large mutations affect another actin-binding domain in this N-terminus of dystrophin and therefore may have significant functional consequences, resulting in the worsened phenotype. Other mechanisms, such as unexpected effect of the deletion on splicing behavior, might also be implicated in determining the phenotypic outcome [Muntoni et al., 1994]. After the complete dystrophin complementary DNA was isolated [Koenig et al., 1987], it became evident that about 60% of patients with Duchenne and Becker muscular dystrophies manifest structural rearrangements of the deletion type [Darras et al., 1988; den Dunnen et al., 1987; Forrest et al., 1987; Koenig et al., 1987; Kunkel, 1986]. Deletions and, more rarely, duplications can happen almost anywhere in the dystrophin gene; however, two deletion hot spots are known. The most commonly mutated region includes exons 45 to 55 with genomic breakpoints (i.e., the end points of where the deletions actually occur) lying within intron 44. The second hot spot is located toward the 5′ end and includes exons 2 to 19 with genomic breakpoints commonly found in introns 2 and 7 [Beggs et al., 1990; den Dunnen et al., 1989; Nobile et al., 1995; Oudet et al., 1992]. The other 40% of patients have mutations that result from small mutations (point mutations resulting in frameshift or nonsense mutations) or duplications. The incidence of Duchenne muscular dystrophy is approximately 1 per 3300 male births [Brooks and Emery, 1977; Jeppesen et al., 2003]. Although the most common mode of inheritance is X-linked recessive (mother is a carrier), this disorder is associated with a high spontaneous mutation rate, which accounts for approximately 30% of cases [Brooks and Emery, 1977; Moser, 1984; Scheuerbrandt et al., 1986; van Essen et al., 1992]. Therefore, almost one third of males with Duchenne muscular dystrophy have no family history of muscular dystrophy. This mutation rate is estimated to be 10 times higher than for any other genetic disorder [Hoffman et al., 1992] because of the extremely large Duchenne gene size [Hoffman and Kunkel, 1989]. The 2.5 million base pairs constituting the gene (a full 1% of the X chromosome) provide a large target for random mutational events. Nonfamilial Duchenne muscular dystrophy patients might be the product of germinal mosaicism on the X chromosome (a mutation occurring before the birth of the mother) [Bakker et al., 1989; Bunyan et al., 1994; Lanman et al., 1987; Smith et al., 1999], in which case the mother is a Duchenne muscular dystrophy carrier, but no other family member is affected with Duchenne muscular dystrophy. Another possibility is that the mother or father has gonadal mosaicism: a new mutation in maternal or paternal germ cells in an unaffected father or mother whose other maternal cells (i.e., muscle, lymphocytes) are normal [Darras et al., 1988; Hurko et al., 1989; Lanman et al.,

1987]. This mother neither is an obligate carrier nor has the muscle characteristics of the Duchenne muscular dystrophy carrier. The remaining new mutations are partial gene duplications [Hu et al., 1989, 1990]. Because the genetic defect is an X-linked recessive trait, dystrophinopathies are expressed primarily in boys and young men. However, females may manifest symptoms of Duchenne muscular dystrophy if they also exhibit skewed X-inactivation, wherein the abnormal X chromosome is expressed in an excessively abnormal proportion [Kinoshita et al., 1990; Lesca et al., 2003; Pena et al., 1987; Yoshioka et al., 1986]. Females with both Duchenne muscular dystrophy and Turner’s syndrome have been described. This rare combination arises because the single X chromosome contains a mutant gene [Bjerglund Nielsen and Nielsen, 1984; Ferrier et al., 1965; Lescaut et al., 2004].

GENOTYPE/PHENOTYPE CORRELATION There is no simple relationship between the size of the deletion and the resultant clinical disease. For example, large deletions, which may involve nearly 50% of the gene, have been described in patients with Becker muscular dystrophy [England et al., 1990], whereas deletions of small exons, such as exon 44, typically results in classic Duchenne muscular dystrophy. The central and distal rod domains seem to be almost dispensable functionally; some deletions in this region are associated with a syndrome characterized only by myalgia and muscle cramps or by an isolated increase in creatine kinase [Beggs et al., 1991; Gospe et al., 1989]. This finding has been reported in patients with inframe deletions in exons 32 to 44, 48 to 51, or 48 to 53, all of whom had normal or near normal dystrophin concentrations [Melis et al., 1998]. The effect of the genetic mutations on the phenotype depends on whether it does or does not disrupt the reading frame (reading frame hypothesis) and on specific essential signaling or binding sites in the dystrophin protein that might be affected by the mutation. Good correlation is generally found between the severity of the phenotype and the effect of the deletion on the reading frame: Deletions that disrupt the reading frame result in a severe phenotype, whereas in-frame deletions are associated with a milder disease course [Gillard et al., 1989]. These assumptions hold true for about 90% of the cases in which mutations are in the rod domain of the dystrophin protein. Rare exceptions to this rule exist, mainly resulting from frameshift mutations in the 5′ region of the gene (in particular, deletions involving exons 3 to 7) which are associated with a milder phenotype than expected [Malhotra et al., 1988]. When mutations arise in the 5′ region of the gene, especially in the first 13 exons of the dystrophin gene, one third of them have a phenotype different from that theoretically expected [Muntoni et al., 1994]. Affected patients can have a severe clinical phenotype despite the presence of a small in-frame deletion, or they can have a mild phenotype with an out-of-frame deletion. In the first case, a Duchenne phenotype is associated with in-frame deletions of exon 5, of exon 3, and of exons 3 to 13. In the second case, an intermediate Duchenne muscular dystrophy or Becker phenotype is seen with out-of-frame deletions involving not only the usual exons 3 to 7 but also 5 to 7 and 3 to 6 [Muntoni et al., 1994]. Because of this, a high

Escolar and Leshner / Muscular Dystrophies

proportion of patients with a deletion in the 5′ end of the gene have a phenotype that is not predictable on the basis of the effect of the deletion on the reading frame. Very large chromosomal deletions, such as the Xp21 chromosomal microdeletion syndrome, cause multisystem disorders along with the Duchenne muscular dystrophy phenotype [Francke et al., 1985]. The Leiden database (http://www.dmd.nl/) is a useful resource for phenotype/genotype correlation in situations in which genetic testing and phenotype do not appear to be clearly correlated.

Pathophysiology DYSTROPHIN PROTEIN The normal dystrophin gene creates a 14-kilobase dystrophin messenger RNA that encodes 3685 amino acids, producing a 427-kD protein called dystrophin. Dystrophin localizes to the subsarcolemmal region in skeletal and cardiac muscle and constitutes 0.002% of total muscle protein [Hoffman et al., 1987a, 1987b; Knudson et al., 1988]. Dystrophin binds to the cytoskeletal actin and to the cytoplasmic tail of the transmembrane DGC protein β-dystroglycan and thus forms a link from the cytoskeleton to the extracellular matrix (see Fig. 79-1). Dystrophin contains 3685 amino acids and is separated into four domains: the N-terminus, the rod domain, a cysteinerich area, and the C-terminus [Koenig et al., 1987]. The N-terminus consists of the first 240 amino acids and provides an F-actin binding site at three distinct regions with α-actinin homology. The rod region is a succession of 25 triple-helical repeats similar to spectrin and contains about 3000 residues, including four proline-rich regions that may act as hinges. Another F-actin binding site is located near the middle of the dystrophin rod domain but with significantly lower affinity than the N-terminus site [Rybakova et al., 1996]. A cysteine-rich area with amino acids 3080 to 3360 has a WW domain that binds to the protein β-dystroglycan, an essential protein through which dystrophin links to other integral membrane components of the DGC [Ozawa, 1995; Ozawa et al., 1995]. The site at which dystrophin binds to βdystroglycan extends to the first half of the carboxy-terminal domain (C-terminus) [Watkins et al., 2000]. The C-terminus comprises the last 420 amino acids and has homology to utrophin and dystrobrevin. This area contains many potential phosphorylation sites and also binds to syntrophins at exon 74 and possibly to dystrophin-associated glycoproteins [Rybakova et al., 1996]. Dystrophin is organized in costamers and is present in greater amounts at myotendinous and neuromuscular junctions than in other muscle areas. In the heart, it is also associated with T tubules. In smooth muscle, it is discontinuous along membranes, alternating with vinculin. Besides the full dystrophin protein just described, seven different dystrophin transcripts can be identified. These transcripts have different promoter regions and initial exons. The N-terminus region is excluded in smaller dystrophins, but the C-terminus region is found in all seven dystrophin transcripts. The transcripts are specific to cell types. Three full-length isoforms have the same number of exons but are derived from three independent promoters in brain, muscle,

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and Purkinje cerebellar neurons. The best characterized of these transcripts is the previously described muscle protein, expressed not only in skeletal muscle but also in cardiac muscle, smooth muscle, and retina. A cortical 427-kDa transcript is found in cortical postsynaptic densities, retina, and skeletal muscle [Boyce et al., 1991]. A Purkinje cell 427-kDa transcript is found in the cerebellum [Gorecki et al., 1992]. There is also a retinal 260-kDa transcript, a brain and kidney 140-kDa transcript, and a Schwann cell 116-ka protein resulting from transcription beginning on exon 56 [Byers et al., 1993]. A glial 71-kDa transcript resulting from transcription beginning at exon 63 can be found in glia, viscera, and cardiac muscle [Rapaport et al., 1992]. The presence or absence of these seven dystrophin transcripts in Duchenne muscular dystrophy depends on the location and size of deletion in the dystrophin gene, which determines phenotypic expression.

PRIMARY AND SECONDARY (DOWNSTREAM) EVENTS An important concept that has evolved is that muscle cell death in the muscular dystrophies (by apoptosis and necrosis) is conditional and reflects a propensity that varies between muscles and changes with age [Rando, 2001b]. The fact that adjacent muscle groups in Duchenne muscular dystrophy can be completely normal and others are undergoing active necrosis not only supports this concept but also argues against the concept of inevitability. If endogenous biochemical mechanisms alter the ability of a muscle cell to live or die while the genetic and biochemical defects remain constant, then pharmacologic modulation of these pathways should result in successful therapies for Duchenne muscular dystrophy and other muscular dystrophies [Rando, 2001b]. Whereas dystrophin deficiency is the primary cause of Duchenne muscular dystrophy, multiple secondary pathways are responsible for the progression of muscle necrosis, abnormal fibrosis, and failure of regeneration that results in a progressively worsening clinical status. Since the mid1990s, hypothesis-driven research has dissected several abnormal pathways involved in muscular dystrophy progression. There is ample literature establishing evidence of oxidative radical damage to myofibers [Baker and Austin, 1989; Haycock et al., 1996a, 1996b; Murphy and Kehrer, 1986; Rando et al., 1998], inflammation [Cai et al., 2000; Kissel et al., 1993; Lagrota-Candido et al., 2002; McDouall et al., 1990; Nahirney et al., 1997; Porter et al., 2002; Shaw et al., 1996; Spencer et al., 2000; Spencer and Tidball, 2001], abnormal calcium homeostasis [Baker and Austin, 1989; De Luca et al., 2002; Leijendekker et al., 1996; Murphy and Kehrer, 1986; Pulido et al., 1998; Ruegg et al., 2002; Wrogemann and Pena, 1976], myonuclear apoptosis [Adams et al., 2001; Rando, 2001b; Sandri et al., 1995, 1997, 1998a, 1998b, 2001; Smith et al., 2000; Spencer et al., 1997; Tews, 2002; Tews and Goebel, 1997; Tindall et al., 1987], and abnormal fibrosis and failure of regeneration [Bernasconi et al., 1995, 1999; D’Amore et al., 1994; Iannaccone et al., 1995; Luz et al., 2002; Melone et al., 2000; Morrison et al., 2000; Murakami et al., 1999; Passerini et al., 2002; Rando, 2001b; Yamazaki et al., 1994]. This evidence has been validated by cross-sectional genomewide approaches that allow an overall analysis of multiple defective mechanisms in Duchenne muscular dystrophy

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[Chen et al., 2000; Porter et al., 2002]. The increasing understanding of these events has led to the discovery of potential pharmacologic targets designed to reverse, stop, or slow down muscle damage and progression of disease, even if the primary genetic defect cannot at present be repaired. Thus, it is important to understand these mechanisms as the basis of present and future therapies for this otherwise fatal disease.

Mechanical Membrane Fragility Dystrophin is a link between the intracellular cytoskeleton and the extracellular matrix. The carboxy-terminal of dystrophin is attached to the sarcolemma, the surface membrane of striated muscle cells [Arahata et al., 1988; Bonilla et al., 1988; Watkins et al., 1988; Zubrzycka-Gaarn et al., 1988], binding to β-dystroglycan [Jung et al., 1995] and, through this, to other dystrophin-associated glycoproteins [Ervasti and Campbell, 1991]. When dystrophin is lost, disconnection of the link between contractile proteins to βdystroglycan results in loss of β-dystroglycan and DGC from sarcolemma, expressed as reduced α-sarcoglycan immunoreactivity. The location of dystrophin supported the original idea of fragile membranes in Duchenne muscular dystrophy and Becker muscular dystrophy, with membrane gaps that allow leakage of cytoplasmic components, such as creatine kinase, and the influx of excessive Ca2+. Initially, it was thought that the main function of dystrophin was to provide mechanical reinforcement to the sarcolemma and thereby protect it from the mechanical stress of muscle contraction [Petrof et al., 1993]. Indeed, dystrophin is a load-bearing element, and deficiency in dystrophin leads to muscle membrane fragility and aberrant mechanotransduction [Kumar et al., 2004]. In the absence of dystrophin, there is disruption to normal force transmission and greater stress placed on myofibrillar and membrane proteins, leading to muscle damage [Lynch, 2004], especially during lengthening (eccentric) contractions, during which a muscle contracts against a mechanical force pulling in the opposite direction [Lynch et al., 2000]. The consequent muscle membrane fragility and abnormal permeability characteristics allow increased Ca2+ influx intracellularly [Mallouk and Allard, 2000; Mallouk et al., 2000] and initiate some aspects of the pathologic cascade of events that result in muscle necrosis and fibrosis [Ruegg and Gillis, 1999; Ruegg et al., 2002]. However, it does not appear that Ca2+ enters the cell through a “broken” membrane.

Abnormal Permeability to Calcium and Chronic Increase of Intracellular Calcium Although the theory of increased membrane microdisruptions with subsequent increased Ca2+ permeability cannot be refuted, there is accumulating evidence that abnormal Ca2+ handling may be related to direct dystrophin regulation of mechanosensitive transient receptor potential channels [Vandebrouck et al., 2002b; Yeung and Allen, 2004], as well as abnormal Ca2+ intracellular cycling [Doran et al., 2004; Dowling et al., 2004; Woods et al., 2004]. Several nifedipine-insensitive, voltage-independent Ca2+ channels might be involved in the initial abnormal Ca2+ entry. This new evidence is extremely important, because modulation of these channels could be new therapeutic targets. Although there is concordant evidence of increased

Ca2+ influx to the cell, there is no consensus on an overall increase in resting intracellular Ca2+ concentration [Gillis, 1996]. As explained later, not only are Ca2+ currents increased, but release of Ca2+ from the sarcoplasmic reticulum appears to be decreased, and many Ca2+ buffering proteins are abnormal, so that the overall intracellular Ca2+ concentration at rest might be difficult to measure. One line of evidence involves abnormal function of “stretch-activated” and “stretch-inactivated” Ca2+ channels, a subfamily of the transient receptor potential channels [Clapham, 2003]. These stretch-activated channels are abnormally active under mechanical stimulation in mdx (murine model of Duchenne muscular dystrophy) myotubes and result in an increase in intracellular Ca2+ [Mallouk and Allard, 2000; Vandebrouck et al., 2002a, 2002b]. In addition, there is evidence that a large number of these channels, when subjected to mild mechanical stress, irreversibly shift to a stretch-inactivated channel form [Franco and Lansman, 1990] that remains open at rest and allows a chronic increase of calcium currents [Franco-Obregon and Lansman, 2002]. Accumulation of abnormally active Ca2+ leak channels over time results in a gradual loss of Ca2+ homeostasis and eventual cell death [Alderton and Steinhardt, 2000]. This increase of Ca2+ current might also be initiated by other types of Ca2+ permeable, growth factor–activated channels. The latter are normally localized in the cytoplasm of skeletal muscle, and translocate to the plasma membrane only under insulin-like growth factor 1 and possibly other growth factor stimuli [Iwata et al., 2003]. In dystrophic muscle, these channels are abnormally increased in the sarcolemma and seem to be directly involved with the increased in intracellular Ca2+ and abnormal creatine kinase efflux seen during mechanical stress of dystrophic muscle membrane [Iwata et al., 2003]. The increase in intracellular Ca2+ further increases the translocation of cytoplasmic growth factor–activated channels to the membrane, with subsequent increase of intracellular Ca2+ in a vicious cycle. Of practical importance is that blockade of these stretchactivated channels has been achieved by the nonselective transient receptor potential blockers gadolinium and mycin, as well as by the selective cationic transient receptor potential blocker GsMTx4 (spider venom toxin) and has resulted in normalization of intracellular calcium and muscle force generation ex vivo in mdx mouse muscle [Yeung et al., 2003, 2005]. Furthermore, treatment of mdx mice with oral streptomycin resulted in decreased muscle necrosis, which is suggestive of its possible use in clinical trials [Yeung et al., 2005]. Forced expression of the full length and mini-dystrophin protein in dystrophin-deficient So18 skeletal myotubes also rectified steady-state levels of subcellular concentrations of Ca2+ and of Ca2+ transients [Marchand et al., 2001, 2004]. The L-type, voltage gated Ca2+ channels appear to be abnormal in the absence of dystrophin, as it was demonstrated that the Ca2+ currents in response to an action potential were much smaller in mdx mice than in normal control subjects. A disrupted direct or indirect linkage of dystrophin with these channels may be crucial for proper excitationcontraction coupling to initiate Ca2+ release from the sarcoplasmic reticulum. This linkage seems to be fully restored in the presence of mini-dystrophin [Friedrich et al., 2004]. Calcium cycling within the dystrophic muscle cell is also altered in mdx mice. Although the subsarcolemmal Ca2+

Escolar and Leshner / Muscular Dystrophies

concentration might be elevated [Mallouk et al., 2000], release of Ca2+ by the sarcoplasmic reticulum in response to an action potential is much decreased in this model [Plant and Lynch, 2003; Woods et al., 2004] and might contribute to abnormal activation-contraction coupling and subsequent muscle weakness. The Ca2+ buffering system in dystrophin myotubes is equally affected. A key luminal Ca2+-binding protein, sarcalumenin, is affected in mdx skeletal muscle, which results in an abnormal shuttling of Ca2+ between the Ca2+-uptake sarco-endoplasmic reticulum Ca2+-adenosine triphosphatase and calsequestrin and might indirectly amplify the Ca2+ leak channel-induced increase in cytosolic Ca2+ levels [Dowling et al., 2004]. Abnormal intracellular Ca2+ levels result in abnormal activation of Ca2+-activated proteases (e.g., calpain) with subsequent abnormal degradation of intracellular proteins that likely contribute to the abnormal functioning of the leak channels [Turner et al., 1993]. There is evidence that exercise worsens the abnormalities in calcium homeostasis in mdx [Fraysse et al., 2004]. This finding is not surprising because it is well known that excessive exercise by individuals with Duchenne muscular dystrophy may be deleterious and exacerbate muscle weakness [Allen, 2004; Ansved, 2003].

Abnormal Immunologic Response In normal skeletal muscle, contraction-induced damage is followed by an inflammatory response involving multiple cell types that subsides over several days. This transient inflammatory response is a normal homeostatic reaction to muscle damage. In contrast, a persistent inflammatory response is observed in dystrophic skeletal muscle that leads to an altered extracellular environment that includes an increased presence of inflammatory cells (i.e., macrophages) and elevated levels of various inflammatory cytokines (i.e., tumor necrosis factor α, transforming growth factor β). Therefore, the signals that lead to successful muscle repair in healthy muscle may promote muscle wasting and fibrosis in dystrophic muscle. Evidence supporting the role of the immune system in promoting muscle pathology in Duchenne muscular dystrophy, as well as the active role of cytotoxic T cells and myeloid cells in the pathophysiology of progressive muscle necrosis and fibrosis in Duchenne muscular dystrophy and mdx mice, has accumulated since the mid-1990s [Spencer and Tidball, 2001]. More recently, genome-wide approaches investigating the gene expression profile of Duchenne muscular dystrophy and mdx mouse muscles have revealed that an abnormal immunologic response is induced very early and is maintained at a low level in Duchenne muscular dystrophy patients and mdx mice from early in the neonatal period [Chen et al., 2000; Porter et al., 2003a]. Microarray experiments conducted longitudinally in mdx mice have allowed identification of abnormally increased cytokines and their receptors within the muscle cells, which implies that the dystrophic muscle might contribute to abnormal chemotaxis [Porter et al., 2002, 2003a]. These cytokine pathways could be new therapeutic targets. Several pathways are involved in abnormal immune response in Duchenne muscular dystrophy. First, invasion of antigen-presenting cells activate cytotoxic and helper T cells [Banchereau and Steinman, 1998; Hart, 1997]. These release interleukin-2 that initiates polyclonal expansion of cytotoxic T

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cells [Gussoni et al., 1994; Spencer et al., 1997, 2001], which in turn mediates muscle necrosis by perforin-mediated [Cai et al., 2000; Spencer et al., 1997, 2001] and cytokine-mediated (tumor necrosis factor α and transforming growth factor β) killing mechanisms [Isenberg et al., 1986; Lundberg et al., 1995; Morrison et al., 2000; Spencer et al., 2000; Tews and Goebel, 1996]. Another pathway is through circulating dermal dendritic cells, which are abundant in Duchenne muscular dystrophy muscle [Chen et al., 2000] and through CD4+ cells, which in turn activate (through interleukin-2) CD8+ cells. Finally, another immune pathway starts by the invasion of muscle by myeloid cells, including macrophages, neutrophils, eosinophils, and mast cells [Arahata and Engel, 1988; Cai et al., 2000; Gorospe et al., 1994b; McDouall et al., 1990]. Most of these can kill target cells by liberating cytokines (tumor necrosis factor α; macrophage inflammatory protein 1αβ, RANTES), and by generating high concentrations of oxidative radicals. Mast cells can also promote muscle fibrosis [Gorospe et al., 1994a; Granchelli et al., 1996]. Muscle cells might become autoreactive as they liberate tumor necrosis factor α and could be an additional source of antigen-presenting cells [Behrens et al., 1998]. Many of these specific pathways are known to be blocked by prednisone, including induction of the transcription of I B (inhibitor), which keeps nuclear factor κβ in the inactive state; decreased production of proinflammatory cytokines; and induction of genes that inhibit cyclooxygenase-2, adhesion molecules, and other inflammatory mediators.

Abnormal Signaling Functions Although the mechanical theory remains an important one and is well documented [Kumar et al., 2004], there is accumulating evidence that the DGC complex has important muscle cell–signaling functions, and its integrity is essential for muscle cell viability [Rando, 2001a]. These functions include transmembrane signaling (through β-dystroglycan), docking of signal transduction molecules (e.g., caveolin-3) and interaction with or regulation of other transmembrane complexes (e.g., integrins). A review of this line of evidence is beyond the scope of this chapter; the interested reader is referred to an excellent published summary [Rando, 2001a]. The absence of dystrophin causes extensive abnormalities and disruption of the DGC, in which sarcoglycans, neuronal nitric oxide synthetase [Rando, 2001b], and other members of the DGC lose their association with the sarcolemma. Many of the putative signaling cascades and molecules associated with this complex are known to regulate the balance between pro- and anti-apoptotic pathways [Rando, 2001a]. In addition to direct regulation of apoptosis, the defective DGC signaling might alter the metabolic pathways necessary to modulate cell susceptibility to injury. Of these important pathways that are clearly involved in Duchenne muscular dystrophy pathogenesis and that lead to cell death when disrupted, those involving oxidative radical metabolism [Baker and Austin, 1989; Haycock et al., 1996b; Kumar and Boriek, 2003; Ragusa et al., 1997; Rando, 2002; Spencer et al., 2001] and intracellular Ca2+ regulation are of particular interest because they could be targets of pharmacologic modulation. In addition, mechanical stretch has been demonstrated to abnormally activate the classic nuclear factor κβ pathway (in a Ca2+- independent manner) in the mdx mouse, resulting in increased expression of inflam-

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matory cytokines interleukin-1β and tumor necrosis factor α, which precedes the onset of muscular dystrophy [Kumar and Boriek, 2003]. The “vascular” theory of Duchenne muscular dystrophy pathogenesis was supported in the past by morphologic evidence in Duchenne muscular dystrophy and mdx mouse muscle fiber group necrosis, which occurred very early in the disease, presumably secondary to ischemia. Indeed, more recent findings indicate that the mislocalization and reduction of neuronal nitric oxide synthetase in dystrophic muscle affects smooth vessel vasodilation in response to alpha-adrenergic stimuli during exercise [Thomas et al., 2003], and results in muscle ischemia [Sander et al., 2000]. Dystrophin-associated α-syntrophin appears to be essential for the membrane localization of neuronal nitric oxide synthetase [Thomas et al., 2003].

Abnormal Fibrosis and Muscle Regeneration Fibrosis (excessive deposition of endomysial and perimysial extracellular matrix) is a phenomenon known to be secondary to chronic muscle inflammation and fiber degeneration in Duchenne muscular dystrophy [Porter et al., 2002]. However, the amount of fibrosis in Duchenne muscular dystrophy seems disproportionate in relation to the clinical severity in the earlier stages of the disease, which raises the hypothesis that an abnormal fibrotic process might be directly related to the absence of dystrophin and might occur in parallel to (as well as after) muscle necrosis and degeneration. In fact, there is enough evidence that both enhanced fibrinogenesis and decreased fibrinolysis [von Moers et al., 2005] are implicated in the development of muscle fibrosis in Duchenne muscular dystrophy. There is a clear increase in expression of the fibrogenic cytokine transforming growth factor β1 in muscle of Duchenne muscular dystrophy patients [Bernasconi et al., 1995] and in serum samples of individuals with Duchenne muscular dystrophy [Bernasconi et al., 1999]. Moreover, preclinical studies in mdx mice have revealed that transforming growth factor β1 levels are also significantly elevated in the diaphragm, the muscle in this model that better mimics human skeletal muscle pathology [Hartel et al., 2001; Iannaccone et al., 1995; Morrison et al., 2000; Passerini et al., 2002; Porter et al., 2002]. Similar findings of abnormal cytokine levels and fibrosis early in the disease process are found in the golden retriever model of Duchenne muscular dystrophy [Passerini et al., 2002]. The level of messenger RNA transcript for transforming growth factor β1 was found to be increased in mononucleated cells around areas of fiber necrosis in 6- and 9-week-old mdx mice but not in 12-week-old mdx mice [Gosselin et al., 2004]. These findings indicate a role of transforming growth factor β1 during the early stages of fibrogenesis in dystrophic diaphragmatic muscle. Transforming growth factor β1 induces organ fibrosis by increasing extracellular matrix synthesis [Gosselin et al., 2004] and by simultaneously inhibiting matrix-degradation proteases such as matrix metalloproteases, especially matrix metalloprotease 1 [Herbst et al., 1997; von Moers et al., 2005]. Another abnormal fibrotic pathway in Duchenne muscular dystrophy relates to an increase in levels of platelet-derived growth factor and its receptors, which have an important modulating role in the active stage of tissue destruction, as well as initiation and promotion of muscle fibrosis [Zhao et al.,

2003]. Of concern is that fibroblasts in Duchenne muscular dystrophy appear to have a paracrine function inhibiting satellite cell growth [Melone et al., 2000], in which case abnormal fibrosis would directly decrease muscle regeneration. Temporal gene expression profiling studies in Duchenne muscular dystrophy have demonstrated that inflammatory and profibrinogenic pathways predominate in the presymptomatic stages of the disease, whereas the acute activation of transforming growth factor β and failure of metabolic pathways occur later in the disease [Chen, 2005]. In hind limb mdx muscle, inflammation, proteolysis, and extracellular matrix upregulation and fibrosis are initiated very early in the course of the disease, represent a substantial component of the transcriptional response at that early age, and are tightly coordinated [Porter et al., 2003b]. Pharmacologic blockade of these pathways may have promising therapeutic implications, especially in symptomatic subjects [De Luca et al., 2005; Porter et al., 2002].

Clinical Characteristics The natural history of untreated Duchenne muscular dystrophy follows a predictable course. However, the disease course can be modified with aggressive pharmacologic (corticosteroids) and rehabilitation treatments. The following sequence of events occurs in treated and untreated patients with Duchenne muscular dystrophy but at a much later age in the former. The disease is present in infancy, with muscle fiber necrosis and a high serum creatine kinase enzyme level; however, clinical manifestations are typically not recognized until the child is 3 years of age or older. This “therapeutic window” has been previously underemphasized; however, it lends itself to the development of early therapeutic interventions to prevent or delay the onset of symptoms secondary to advanced muscle degeneration. Walking often begins later than in normal children, and affected children experience more falling than expected. Gait abnormality often becomes apparent at 3 to 4 years of age, prompting clinical evaluation. Muscle weakness is present initially in neck flexor muscles, with power being less than antigravity. As a result, the child needs to turn on his side when getting up from a supine position on the floor, which is the initial sign of the Gowers maneuver (Fig. 79-2). Hypertrophy of calf muscles typically occurs, often being very prominent by age 3 or 4 years (Fig. 79-3). Hypertrophy of other muscles may also develop, especially involving the vastus lateralis; infraspinous; deltoid; and, less frequently, the gluteus maximus, triceps, and masseter muscles. Muscle mass is usually decreased in later stages in the pectoral, peroneal, and anterior tibial muscles. Hip girdle muscles are affected earlier than shoulder girdle muscles. Because of weakness of the hip extensor muscles that act as “shock absorbers” when weight is placed on one leg, these patients tend to rock from side to side when walking, which produces a waddling gait. Anterior hip rotation caused by muscle weakness results in increased lumbar lordosis, which is necessary to keep the center of balance stable, with shoulders lined up over hips, knees, and ankles. The preschooler has difficulty rising from the floor, turning 45, then 90, and finally 180 degrees (depending on the

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FIGURE 79-2. Boy with Duchenne muscular dystrophy demonstrates the sequence of maneuvers that constitute Gowers’ sign. The child pushes off the floor with all four extremities, then prepares to push up by moving his hands along the floor closer to the feet, and finally places the hands on the thighs and pushes up to the erect position. The maneuver is necessary primarily because of marked weakness of the hip extensors.

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prevent deterioration in muscle strength from disuse. When ambulation is no longer possible—usually near the end of the first decade in untreated Duchenne muscular dystrophy and about 3 to 10 years later in steroid-treated Duchenne muscular dystrophy—a wheelchair is required. Contractures become more pronounced in the lower extremities and soon involve the shoulders. Kyphoscoliosis may develop after ambulation is lost. Maintaining an erect posture with long leg braces or a stander after ambulation is lost may help prevent scoliosis. Proper wheelchair sizing, solid seating, and solid back support are important. Both manual and power wheelchairs are useful. Cardiac and respiratory involvement often occurs in this later disease stage. Adolescent patients manifest increasing weakness and are unable to perform routine tasks with their arms, hands, and fingers. The head may progressively flex forward as extensor neck muscles lose strength. Lower facial muscles may be involved in the advanced phase.

PULMONARY INVOLVEMENT

FIGURE 79-3. Pseudohypertrophy of the gastrocnemius muscles is usually profound. The large muscle mass is secondary to replacement of normal muscle with adipose and collagen tissue.

degree of neck flexor weakness), and placing the hands on the floor to get up. Later, the complete Gowers sign (see Fig. 79-2) is exhibited. The patient assumes a locked-leg, buttocks-first position, followed by pushing off the floor with the hands, literally pushing the trunk erect by bracing the arms against the anterior thighs. The maneuver is necessary because of pronounced weakness of the hip muscles, predominantly the gluteus maximus, and is present by age 5 or 6 years. As muscle deterioration proceeds, climbing stairs becomes difficult, necessitating use of both hands on a railing or crawling on all four extremities. Distal muscles of the arms and legs exhibit weakness as the disease progresses. The patellar tendon reflex is often diminished early in the course of Duchenne muscular dystrophy. In contrast, the Achilles tendon reflex can usually be elicited for many years. Contractures of heel cords, necessitating vigorous, daily stretching, may be a major problem as early as 4 to 5 years of age in males with untreated Duchenne muscular dystrophy. Iliotibial bands and hip flexors also may become contracted because of the alteration in gait that results from the distribution of muscle weakness. If contractures are allowed to advance to a fixed equinovarus position, the patient walks on his toes and often falls. Locking of the knees to compensate for less-than-antigravity quadriceps strength with resultant genu recurvatum posture is common as the gastrocnemius muscles attempt to compensate for the quadriceps deficiency. Accelerated deterioration in strength and balance often results from intercurrent disease or surgically induced immobilization. If tendon release surgery is performed, immediate mobilization in a walking splint or cast is necessary to

Pulmonary function becomes compromised because of weakness of intercostal and diaphragmatic muscles and severe scoliosis, occurs later in the disease in nonambulatory patients, and is the primary cause of mortality in Duchenne muscular dystrophy. Delaying the time to reach nonambulatory status can have a significant impact on the development of scoliosis and respiratory function. This postponement can be achieved by the use of steroids [Moxley et al., 2005] (which prolongs ambulation) and the use of standers to keep children upright even when they are not walking [Galasko et al., 1995]. Use of mechanical ventilation and good pulmonary and cardiac care have increased survival [Gomez-Merino and Bach, 2002] to about 58% at age 25 years even in patients in some countries who have not been treated with steroids [Eagle et al., 2002]. Muscle weakness affects all aspects of lung function, including mucociliary clearance, gas exchange at rest and during exercise, and respiratory control during wakefulness and sleep [Gozal, 2000]. It is important to recognize that Duchenne muscular dystrophy is often associated with sleep-disordered breathing, which could be asymptomatic or only mildly symptomatic. Patients can have normal waking oxygen saturation and capillary blood gas levels and normal or near-normal forced vital capacity. Overnight polysomnography is useful for detecting abnormalities [Kirk et al., 2000].

CARDIAC INVOLVEMENT Children with Duchenne muscular dystrophy are at risk for cardiomyopathy, especially if they have deletion of exons 48 to 53 [Nigro et al., 1994]. Early screening for cardiomyopathy at ages 5 to 6 years and then again at 10 to 12 years with an electrocardiogram and echocardiogram allows detection of cardiomyopathy with impaired cardiac output, often before signs of heart failure are apparent. If heart failure occurs, rigorous intervention to improve cardiac function and output is necessary to prevent terminal cardiac failure. Mild degrees of cardiac compromise in Duchenne muscular dystrophy may occur in up to 95% of affected males [Melacini et al., 1996]. Chronic heart failure may

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affect up to 50% [Melacini et al., 1996; Wahi et al., 1971]. Sudden cardiac failure can occur, especially during adolescence. In one series of 19 patients, postmortem studies revealed that 84% had demonstrable cardiac involvement [Leth and Wulff, 1976]. Characteristic electrocardiographic changes include sinus tachycardia; tall R1 wave in lead V1; prominent Q wave in leads I, aVL, and V6 or in leads II, III, and aVF; increased QT dispersion; and possibly autonomic dysfunction [Danzig et al., 2003; Finsterer and Stollberger, 2003]. Initially, routine echocardiography yields normal findings. However, very early abnormalities in cardiac function can be detected with newer ultrasound techniques in children between the ages of 4 and 10 years [Giglio et al., 2003]. Some young children with Duchenne muscular dystrophy might exhibit regional wall motion abnormalities in areas of fibrosis [Melacini et al., 1996]. With spreading of fibrosis, left ventricular dysfunction and ventricular dysrhythmias can occur. In the final stages of the disease, systolic function may lead to heart failure and sudden death. Subclinical or clinical cardiac insufficiency is present in about 90% of patients with Duchenne muscular dystrophy or Becker muscular dystrophy but is the cause of death in only 20% of those with Duchenne muscular dystrophy and 50% of those with Becker muscular dystrophy [Finsterer and Stollberger, 2003; Melacini et al., 1996].

NEUROPSYCHOLOGIC INVOLVEMENT Males with Duchenne muscular dystrophy, overall, have an intelligence quotient (IQ) curve shifted to the left [Ogasawara, 1989]. The mean IQ score in one study was 83 (range, 46 to 134). However, other investigators have not been able to demonstrate a difference in overall IQ [Bushby et al., 1995; Felisari et al., 2000; Hinton et al., 2000; Roccella et al., 2003]. It has become evident that certain cognitive areas are more affected than others in patients with Duchenne muscular dystrophy: namely, verbal memory [Hinton et al., 2000]. Genotype/phenotype studies have revealed that deletions localized in central and 3′ parts of the gene are preferentially associated with mental impairment, some of these directly affecting the regulatory and coding sequences for the three central nervous system-specific carboxyterminal isoforms [Giliberto et al., 2004]. Another study of 137 males with Duchenne muscular dystrophy/Becker muscular dystrophy confirmed these findings, demonstrating that all patients with deletions upstream of the 5′ end of the gene were mentally normal, whereas all patients with mental retardation or autism had deletions containing the 3′ end of the gene. Some researchers have found average intelligence [Sollee et al., 1985] but difficulties with immediate memory [Wicksell et al., 2004]. Specifically, children with Duchenne muscular dystrophy have poor performance on measures of story recall, digit span, and auditory comprehension. This profile indicates that verbal working memory skills are selectively impaired in Duchenne muscular dystrophy, and this could contribute to poor academic achievement [Hinton et al., 2001]. Morphologic changes in the central nervous system have been reported; however, the results of brain postmortem examination and, more recently, brain imaging studies have been inconsistent. Although many investigators have found no pathologic or radiologic brain abnormalities

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in Duchenne muscular dystrophy, others, using positron emission tomographic scanning, have reported hypometabolism in the cerebral and cerebellar hemispheres [Bresolin et al., 1994; Rae et al., 1998]. Pathologic studies have revealed mild-to-striking abnormalities, including neuronal loss, heterotopias, gliosis, neurofibrillary tangles, Purkinje cell loss, dendritic abnormalities (length, branching, and intersections), disordered architecture, astrocytosis, and perinuclear vacuolation [Anderson et al., 2002]. There is some evidence that patients with Duchenne muscular dystrophy who have identifiable brain abnormalities, especially mild brain atrophy, also have cognitive impairment [Septien et al., 1991], but these findings have not been confirmed by other investigators [al-Qudah et al., 1990]. Overall, there is no firm evidence that an abnormality of the brain, either gross or histologic, is common in patients with Duchenne muscular dystrophy, and a correlation between abnormality and intellectual impairment has yet to be clearly established [Anderson et al., 2002].

OTHER ORGAN INVOLVEMENT Males with Duchenne muscular dystrophy can have an early abnormality in gastric motility caused by deranged regulatory mechanisms and later the result of smooth muscle involvement. Symptoms can include megacolon, volvulus, abdominal cramping, and malabsorption [Borrelli et al., 2005]. In the era before steroids and ventilation, death usually occurred late in the second decade of life (median age of 18 years), and only 25% of males with Duchenne muscular dystrophy lived beyond 21 years of age [GardnerMedwin, 1970]. This natural history has changed [Eagle et al., 2002], and in current studies, researchers are trying to characterize the impact of steroid treatment, age at start of treatment, noninvasive ventilation, rehabilitation, scoliosis surgery, and pulmonary care on the quality of life and survival of patients with Duchenne muscular dystrophy.

FEMALE DUCHENNE MUSCULAR DYSTROPHY CARRIERS AND MANIFESTING CARRIERS Female carriers are heterozygous with a normal dystrophin gene on one X chromosome and a mutant gene on the other. More than 90% of female carriers are asymptomatic. However, female carriers may manifest various degrees of muscle weakness because random inactivation of one X chromosome, according to the Lyon hypothesis, may leave more than half of mutant X chromosomes operant in muscle cells (skewed X-inactivation). When more than half the X chromosomes in a given muscle fiber express a mutant gene for Duchenne muscular dystrophy, the muscle fiber is prone to degeneration. The number of potentially abnormal muscle fibers in a given muscle determines whether that muscle displays weakness. The degree of strength from one muscle to another may vary from normal strength to significant weakness. In the presence of muscle fiber degeneration resulting from a burden of more than half mutant X chromosomes in muscle nuclei, muscle fiber degeneration is followed by regeneration. The new fiber, formed from fused myoblasts, may have less than half or more than half mutant X chromosomes and be susceptible to degeneration. Overall,

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individual muscle groups may express less than normal strength but with time either become stronger or weaker or stay the same. Each muscle responds separately. The tendency in muscles with a high percentage of mutant X chromosomes is that with remodeling of the muscle through cycles of degeneration and regeneration, there is an increase in the number of normal X chromosomes but not necessarily a parallel increase in dystrophin content [Pegoraro et al., 1995]. Immunohistochemical and immunoblot analysis of muscle biopsies in these female carriers reveals a mosaic of dystrophin-normal and dystrophin-abnormal muscle fibers [Minetti et al., 1991]. Signs and symptoms of female dystrophinopathy include muscle weakness, myopathic muscle biopsy specimens, elevated levels of creatine kinase enzymes, and partial absence of dystrophin in the muscle [Hoffman et al., 1992]. This absence is seen in about one fifth of Duchenne muscular dystrophy carriers [Hoogerwaard et al., 1999a]. Search for female dystrophinopathy should be initiated in women with elevated creatine kinase enzyme levels and muscle weakness, even in the absence of a Duchenne muscular dystrophy-positive family history [Hoffman, 1996]. Female patients with Duchenne muscular dystrophy and severe weakness and absence of muscle dystrophin are affected when chromosomal translocation has taken place, allowing expression of an abnormal Duchenne muscular dystrophy gene. The female Duchenne muscular dystrophy phenotype resembling the male Duchenne muscular dystrophy phenotype is occasionally present with Turner’s syndrome. Duchenne muscular dystrophy carriers appear to have an increased incidence of cardiomyopathy. Different studies have revealed an incidence of asymptomatic cardiomyopathy in 8% to 48% among adult Duchenne muscular dystrophy carriers [Grain et al., 2001; Hoogerwaard et al., 1999a, 1999b] and in 0% to 15% among Duchenne muscular dystrophy carrier girls younger than 16 years [Nolan et al., 2003].

Diagnosis CLINICAL LABORATORY TESTS The serum creatine kinase level is the most valuable and universally used diagnostic enzyme indicator of Duchenne dystrophinopathy. Levels of creatine kinase, the muscle isoenzyme, are greatly elevated, typically from 10,000 to 30,000 times normal, early in the disease. Gaps in the sarcolemma allow efflux of the enzyme into the circulation. Serum creatine kinase levels can vary greatly with activity and decrease as muscle mass is lost with disease progression. There is no correlation between the serum creatine kinase level and clinical severity in Duchenne muscular dystrophy, and the use of creatine kinase levels as a surrogate marker of treatment response is not well supported. Because of the leakage of intracellular muscle proteins, other muscle isoenzyme levels also increase in the circulation. These include lactate dehydrogenase, alanine aminotransferase, and, to a lesser degree, aspartate aminotransferase, all usually tested routinely as markers of liver function in normal children. It is not unusual that pediatricians embark in extensive unnecessary liver studies before it is realized that

these are muscle isoenzymes and their abnormal levels parallel that of creatine kinase. This occurrence is more common in Becker muscular dystrophy because these patients might not have any muscle symptoms for decades [Korones et al., 2001; Lin et al., 1999; Tay et al., 2000; Zamora et al., 1996].

GENETIC TESTING Genetic test for Duchenne muscular dystrophy and Becker muscular dystrophy is widely available, especially for the deletions in the two hot spots of the gene. The screening of only 19 exons by multiplex polymerase chain reaction identifies about 98% of all deletions [Beggs et al., 1990]. Southern blot analysis of these samples can frequently predict whether the deletion, when in the rod domain, will shift the reading frame, and thus is conclusive for Duchenne muscular dystrophy or Becker muscular dystrophy. This technique is very effective for the molecular diagnosis of common deletions (60% of patients); however, it cannot be used to identify duplications or to establish genotype in female carriers. Other diagnostic approaches, such as quantitative polymerase chain reaction [Abbs and Bobrow, 1992; Yau et al., 1996] or multiplex amplifiable probe hybridization [White et al., 2002] might be used for carrier diagnosis. With more recent technology, it is possible to screen the entire dystrophin gene for the specific molecular defects responsible in the other 40% of patients with Duchenne muscular dystrophy and Becker muscular dystrophy in whom a genetic abnormality has not been detected. These techniques include a protein truncation test [TufferyGiraud et al., 1999a, 1999b], single-condition amplification/ internal primer sequencing [Mendell et al., 2001] and denaturing high-performance liquid chromatography followed by sequencing, which enables the detection of small mutations in nearly all the 79 exons [Bennett et al., 2001]. In a large series with single-condition amplification/internal primer sequencing, deletions of one or more exons were found in 66% of probands, which was consistent with the frequency of deletions in the previously reported literature. Point mutations were found in 18%, including premature stop codons in 13% and missense mutations in 4% of the total mutations. Frameshift mutations were found in 3% of patients. Fourteen subexonic mutations were also found, and these included nonsense mutations in 9 (64%); missense mutations in 3 (21%), and frameshift mutations in 2 (14%). This testing modality might be more sensitive for detecting deletions than is multiplex polymerase chain reaction. Of the 45 deletions detected, 3 (7%) either were undetected or would have been undetected by that technique [Dent et al., 2005]. Duplications were detected in 6% of patients, and no disease-causing mutation was identified in 7% of the evaluated patients [Dent et al., 2005]. There are few commercial laboratories offering gene sequencing at present, but these methods will become routinely available for diagnosis of suspected dystrophinopathy patients, as well as for carrier detection and prenatal diagnosis.

MUSCLE BIOPSY Histologic study reveals fiber size variation, degenerating and regenerating fibers, clusters of smaller fibers, endo-

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is less distinct than expected. Oxidative histochemistry is maintained. Absence of immunoreactivity for dystrophin with monoclonal antibodies against the C-terminal, rod domain, and N-terminal are necessary for accurate diagnosis of Duchenne muscular dystrophy (Fig. 79-5). Quantitative dystrophin analysis by immunoblot is more accurate for diagnosis than is immunostaining, with levels of dystrophin being less than 5% of normal in Duchenne muscular dystrophy patients. On electron microscopic study, gaps in the sarcolemma with preservation of the basement lamina are seen in non-necrotic fibers (Figs. 79-6 and 79-7).

Management

FIGURE 79-4. Biceps muscle biopsy sample from a 2-year-old child with Duchenne muscular dystrophy, revealing dark, opaque fibers, variable fiber size, and excessive connective tissue (large arrows). A basophilic, regenerating fiber is identified by the small arrow. (Hematoxylin and eosin staining; ×390.)

mysial fibrosis, and a few scattered lymphocytes. Large, opaque fibers distinguished by intense staining with the modified Gomori trichrome are prominent (Fig. 79-4). As the disease progresses and degeneration exceeds regeneration, a decrease in the number of muscle fibers is apparent, with replacement of muscle with fat and connective tissue. Fiber typing with adenosine triphosphatase histochemistry

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Children with Duchenne muscular dystrophy and Becker muscular dystrophy are best cared for in a multidisciplinary setting, in which physicians (neurologists, psychiatrists, orthopedic surgeons, cardiologists, and pulmonary medicine), physical and occupational therapists, nutritionists, exercise physiologists, and social workers can work together for the overall well-being of the child and the family. Parents of the patient with Duchenne dystrophinopathy should be kept informed on a timely basis about the expected clinical course, the need for regular evaluations, and available treatment programs, including clinical trials, for their participation. Initial counseling is with parents, but as the patient becomes older, he or she should be involved directly with team members. For example, an explanation of how muscles function and the concept of weakness are im-

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FIGURE 79-5. Immunocytochemical staining for dystrophin with a monoclonal antibody (DYS 2) reacting to muscle protein dystrophin. This antibody recognizes a distal portion of the dystrophin molecule that represents the last 17 amino acids of the carboxy-terminus on the dystrophin gene. A, Control muscle exhibiting normal dystrophin localization to the sarcolemma, demonstrated with peroxidase staining (×230). B, Muscle from a 5-year-old male with Duchenne muscular dystrophy, devoid of sarcolemmal staining for dystrophin except for one recombinant fiber in the center of the field (×260).

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FIGURE 79-6. Electron micrograph of a speciment from a 6-year-old child with Duchenne muscular dystrophy, revealing sarcolemmal (plasma cell wall) disruption (arrows) with redundant basement membranes (×10,800).

FIGURE 79-7. Longitudinally oriented, plastic-embedded resin section from a 2-year-old child with Duchenne muscular dystrophy. Note the vesicular muscle nucleus with prominent nucleoli (arrowhead) and satellite cell (arrow) adjacent to a mildly vesicular muscle nucleus. A capillary, fibroblasts, and prominent endomysial connective tissue are present. (Toluidine blue staining; ×2400.)

portant. Many children with Duchenne muscular dystrophy have known for a long time before they are told about their disease that they “were different” and not as athletic as their peers, which frequently causes serious self-esteem issues. Interacting with playmates and school peers and adjusting to a nonambulatory life are key adjustments that must be made. It may be necessary for appropriate team members to contact school authorities or even participate in school team meetings to educate teachers and peers on how to support the child with Duchenne muscular dystrophy and yet let the child be as independent as possible. Support groups for the family, siblings, and patient and special camps should be made available, and participation in them should be encouraged.

PHARMACOLOGIC TREATMENT Daily prednisone stabilizes or improves the strength of children with Duchenne muscular dystrophy and it is the only demonstrated treatment for this disease [Moxley et al., 2005]. Drachman and associates [1974] first reported a beneficial

effect of prednisone in an open trial of 2 mg/kg/day. This finding was duplicated in other open-design trials [Brooke et al., 1987; DeSilva et al., 1987] and subsequently, through the collaboration of the Clinical Investigation of Duchenne Dystrophy investigators, in double-blinded placebo-controlled trials [Fenichel et al., 1991; Griggs et al., 1993; Mendell et al., 1989]. The most effective dose is 0.75 mg/kg/day. There is a dose-response effect, the lower effective dose being 0.3 mg/kg/day [Mendell et al., 1989]. Effects on strength are seen as soon as 10 days after treatment starts, with a peak at 3 months and then a stabilization period [Griggs et al., 1991]. In a 3-year follow-up study, improvement was maintained in children who were kept on doses of at least 0.5 and 0.6 mg/kg/day [Fenichel et al., 1991]. It is hoped that long-term monitoring of these patients will confirm continuous benefit in muscle strength and respiratory function. Children with Duchenne muscular dystrophy treated with prednisone from an early age usually remain ambulatory into their teens, have a lower incidence of scoliosis [Alman et al., 2004; Biggar et al., 2004] and of contractures [Yilmaz et al., 2004], and maintain normal or near-normal respiratory function [Angelini et al., 1994; Biggar et al., 2004; Campbell and Jacob, 2003; Merlini et al., 2003]. Daily deflazacort yields a similar benefit in strength with decreased incidence of weight gain, but it carries an increased rate of asymptomatic cataract formation [Angelini et al., 1994; Biggar et al., 2001; Bonifati et al., 2000; Campbell and Jacob, 2003; Mesa et al., 1991; Moxley et al., 2005]. Weight gain and cushingoid features, two common side effects of prednisone, although somewhat less, also occur more frequently in children treated with deflazacort in comparison with placebo. The suggested dosage is 0.9 to 1.2 mg/kg/day. However, this drug is not available in the United States; therefore, U.S. patients must import the drug from other countries. This medication should be recommended only for patients with Duchenne muscular dystrophy who are already overweight before treatment and in a more advanced stage of the disease. Lower dosage regimens, including alternate-day corticosteroids and treatment for the first 10 days of the month, have not demonstrated sustained efficacy [Fenichel et al., 1991; Sansome et al., 1993]. Other immunosuppressive medications have produced mixed results. Whereas azathioprine yields no benefit [Griggs et al., 1993], there is uncontrolled evidence that cyclosporine is efficacious in managing Duchenne muscular dystrophy [Mendell et al., 1995; Sharma et al., 1993]. In spite of the fact that prednisone remains the only drug that has been proved effective in 80% of children with Duchenne muscular dystrophy, this therapy has not become the standard of care for treatment of this disease because of its feared significant side effects. An American Academy of Neurology Practice Parameter paper on the use of steroids in treating Duchenne muscular dystrophy [Moxley et al., 2005] and a Cochrane Database review of all trials [Manzur et al., 2004] support the use of corticosteroids for Duchenne muscular dystrophy. Clearly, the benefits of steroids outweigh the risks. There is accumulating evidence that treatment should start as soon as the diagnosis is made [Dubowitz et al., 2002; Kinali et al., 2002; Merlini et al., 2003]. However, early steroid treatment is associated with significant decrease in linear growth. A pilot study of 10 mg/kg given over 2 consecutive days of the week (Friday and Saturday)

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demonstrated that males with Duchenne muscular dystrophy had improved muscle strength and function while maintaining linear growth and did not have an increase in their basal metabolic index in comparison with males with untreated Duchenne muscular dystrophy [Connolly et al., 2002]. A larger trial is ongoing. Such a dosage regimen, if proven equally effective, could encourage physicians and parents to start treatment earlier. With the standard treatment of daily prednisone, the most common side effects are increased appetite with weight gain, irritability, hirsutism, cushingoid facies, and decreased linear growth [Moxley et al., 2005]. The most serious side effects of prednisone (e.g., diabetes, hypertension, ulcers, and infections) are extremely rare in this population. The effect of steroids on bone metabolism and subsequent osteoporosis is difficult to discern, because baseline osteoporosis might be present secondary to decreased activity [Aparicio et al., 2002; Bianchi et al., 2003; Larson and Henderson, 2000]. A study of deflazacort in children with Duchenne muscular dystrophy revealed that treated patients had better bone density than did untreated patients [Biggar et al., 2004]. However, other studies have yielded opposite results [Bianchi et al., 2003], leaving this an area for further research [Biggar et al., 2005]. Children with Duchenne muscular dystrophy who are treated with prednisone or deflazacort should be supplemented orally with calcium and vitamin D. There is no consensus regarding the need for monitoring bone density with dual-energy x-ray absorptiometric scans, inasmuch as the relationship of decreased Z scores and the incidence of fractures in this population (and the general population) has not been established. There is no indication for treatment of asymptomatic children with Duchenne muscular dystrophy who have osteoporosis. However, in the setting of spontaneous pathologic fractures and osteoporosis, treatment with alendronate or similar drugs could be offered, although the safety of these drugs has not been proven in children [Biggar et al., 2005]. Obesity is often a major problem in patients with Duchenne muscular dystrophy, even if steroids are not used. For uncertain reasons, children with Duchenne muscular dystrophy may gain excessive weight, which often becomes apparent before ambulation is lost. The obesity becomes more prominent after the patient can no longer walk. Boredom, diminished physical activity, and depression may lead to inappropriate food intake [Zanardi et al., 2003], and rigorous measures are required to forestall weight gain. Obesity reduces the period of walking capability, hastens scoliosis, and fosters respiratory and cardiac insufficiency. Therefore, if steroid treatment is prescribed, these patients need to follow a strict dietary caloric intake to prevent excessive weight gain. A diet high in proteins, fresh fruits, and vegetables and low in fat and carbohydrates is ideal. A nutritionist should be part of the medical team of a patient with Duchenne muscular dystrophy who receives continuous steroid treatment. Experience suggests that the patient and the entire family must embrace these healthier eating habits to avoid excessive weight gain. Obesity in the parents is a bad prognostic factor for the child’s compliance with diet. The mechanism of action of prednisone in Duchenne muscular dystrophy is not entirely known and likely involves immunosuppressive actions, gene transcription

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regulation, and modulation of intracellular calcium [Kissel et al., 1993; Liu and Sun, 1996; Passaquin et al., 1998; Ruegg et al., 1998, 2002; St-Pierre et al., 2004; Wershil et al., 1995] and might prevent exercise-induced apoptosis [Lim et al., 2004] and thus prevent some muscle damage related to exercise. Other immunosuppressive and other pharmacologic treatments have undergone limited investigation. Cyclosporine (5 mg/kg/day) produced improvement in strength tested on an isolated muscle [Sharma et al., 1993]. The anabolic steroid oxandrolone was tried in a randomized trial, and there was a trend toward improvement of muscle strength as a secondary, but not primary, outcome measure (quantitative isometric muscle force) [Fenichel et al., 2001]. A randomized, controlled, blinded trial of creatine monohydrate and glutamine supplementation in ambulant Duchenne muscular dystrophy patients (aged 5 to 11) also yielded negative findings based on manual muscle testing (primary outcome). However, there were consistent and clear trends toward improvement in isometric muscle strength in the older patients with creatine and increase in function in the younger children with creatine and glutamine [Escolar et al., 2005]. Other studies have demonstrated increases in muscle strength and body mass index with creatine in Duchenne muscular dystrophy [Tarnopolsky et al., 2004; Walter et al., 2000]. No significant side effects were seen with doses of 5 grams/day for at least 6 months [Escolar et al., 2005]. In an attempt to repair mutant dystrophin genes in vivo, gentamicin, an aminoglycoside antibiotic that binds the ribosome and causes “read-through” of premature stop codon (nonsense) mutations, was tried first in the mdx murine model of Duchenne muscular dystrophy [Barton-Davis et al., 1999] and then in a clinical trial on four patients with Duchenne muscular dystrophy or Becker muscular dystrophy [Wagner et al., 2001]. Although the mdx experiments revealed positive dystrophin measurements in about 15% of previously dystrophin-negative muscle fibers, the investigators were unable to duplicate this finding in humans. Efforts with similar but more potent drugs are ongoing. Other approaches involving gene repair mechanisms are being evaluated in experimental models. These include delivery to dystrophin-deficient cells of RNA-DNA oligonucleotides that target the specific mutation and cause it to revert to the normal sequence (chimeraplasts) [Rando et al., 2000] and the delivery of antisense RNA molecules to dystrophindeficient cells so that semifunctional dystrophin can be produced [Errington et al., 2003; Gebski et al., 2003; Lu et al., 2003; Mann et al., 2001; Wells et al., 2003]. This method forces the cell-splicing machinery to skip the dystrophin gene exon that contains the gene mutation, which results in the full translation of dystrophin messenger RNA (minus the mutant exon) into an “in-frame” semifunctional dystrophin protein. These antisense oligonucleotides are small molecules and could be systemically delivered, which makes them an exciting prospect for effective therapy. Preclinical studies involving delivery of functional minidystrophin genes to replace the missing dystrophin, through adeno-associated viral vectors, are also in progress. In this model, dystrophin can be produced, the immune response can be prevented, and there is evidence of improved function and amelioration of pathology [Wang et al., 2000] in young and older animals [DelloRusso et al., 2002; Hartigan-

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O’Connor et al., 2001; Scott et al., 2002]. A last hurdle was crossed when systemic delivery of an adeno-associated virus type 6 vector with a mini-dystrophin gene was achieved in the older mdx mouse [Gregorevic et al., 2004]. This approach is expected to move toward the clinical phase by 2010. Results of myoblast transfer and other stem cell approaches are not encouraging [Partridge, 2002]. Myoblast transplantation was attempted in children with Duchenne muscular dystrophy with no success [Miller et al., 1997; Munsat, 1990; Neumeyer et al., 1998], although they were effective in mdx mice [Huard et al., 1994].

RESPIRATORY CARE With the progression of muscle weakness, loss of respiratory muscle strength, with ensuing ineffective cough and decreased ventilation, leads to pneumonia, atelectasis, and respiratory insufficiency in sleep and during wakefulness [Gozal, 2000]. These complications are generally preventable with careful monitoring and assessments of respiratory function. Patients with Duchenne muscular dystrophy should have routine immunizations by a primary care physician, as recommended for well children by the American Academy of Pediatrics. In addition, these patients should receive the pneumococcal vaccine and an annual influenza vaccine. The older ambulatory patients with Duchenne muscular dystrophy should undergo annual spirometry. Once the child can no longer walk and if either the forced vital capacity falls below 80% of predicted or the child is 12 years of age, or both, the child should be seen twice a year by a physician specializing in pediatric respiratory care [Finder et al., 2004]. Patients in more advanced stages of the disease who require mechanically assisted airway clearance therapy or mechanically assisted ventilation should see a pulmonologist every 3 to 6 months. Routine evaluations at these visits should include oxyhemoglobin saturation by pulse oxymetry, spirometry, and measures of inspiratory and expiratory pressures and peak cough flow [Bach et al., 1997]. Maintaining good pulmonary toilet is essential; hence, these patients should be taught strategies to improve airway clearance and how to employ these techniques early and aggressively. The use of assisted cough technologies should be recommended when peak cough flow is less than 270 liters/minute or when the maximal expiratory pressures are less than 60 cm H2O, or both [Finder et al., 2004]. Patients with Duchenne muscular dystrophy have an increased risk for sleep apnea, nocturnal hypopnea, and hypoxemia. Treatment of these problems with noninvasive nocturnal ventilation can significantly increase the quality of life [Baydur et al., 2000; Vianello et al., 1994]. A polysomnographic study with continuous CO2 monitoring is the best way to assess the need for ventilatory support. Pulse oximetry, especially during the waking state, is suboptimal. Decisions regarding long-term ventilation, either invasive or noninvasive, should involve the patient, caregivers, and medical teams. Physicians have a legal and ethical responsibility to disclose treatment options and must avoid using their own perceptions of quality of life as the main factor in deciding whether to offer this type of information [Gibson, 2001]. End-of-life decision-making should be discussed earlier, with all possible information available to the patient [Hilton et al., 1993].

REHABILITATION Unfortunately, no large prospective studies have been conducted to evaluate the role of physical therapy, stretching exercises, use of braces, and types of physical activity in Duchenne muscular dystrophy, and so the scientific evidence to support solid recommendations is poor.

Exercise On the basis of the preclinical data in the mdx murine model of Duchenne muscular dystrophy, there is a general consensus that high-resistance exercises, especially those involving eccentric contractions (e.g., weight lifting), are damaging to the muscle cell membrane and should be avoided [Ansved, 2003; Petrof, 1998]. However, a sedentary life is equally damaging [McDonald, 2002]. Furthermore, another line of evidence in mdx mice indicates that sustained, nonresistive activity might produce a histochemical shift of the muscle cells toward fatigue resistance with benefits in activity and fatigability measures [Carter et al., 1995; Hayes et al., 1993; Petrof, 1998]. Therefore, active nonresistive exercises are encouraged. Swimming is perhaps the best sport for these children and is usually recommended. Keeping an active life style will also prevent excessive weight gain, especially if the child is taking steroids. Regular periods of daily walking for several hours enhance maintenance of strength and retard contracture formation. Swivel walkers may be used to provide lowenergy ambulation and improve the quality of life [Sibert et al., 1987]. Both the nature and degree of activity should be modified so that fatigue does not remain after a night’s sleep. Wheelchair games can be played when ambulation is lost. Children confined to bed because of intercurrent disease, injury, or surgery require physical therapy, including range-of-motion exercises, with return to more active exercise, including walking, as soon as possible; if such exercise is not resumed, patients may lose the capacity to ambulate. In the event of leg fractures, walking casts should be used as soon as possible [Siegel, 1977].

Contractures Contractures of the Achilles tendons and, later, of other joints is common. With early hip girdle weakness, anterior rotation of the hips and posterior displacement of the shoulders to keep the center of gravity perpendicular to the ground through the shoulders, hips, and ankles occur. When this happens, there is excessive force in the gastrocnemius musculature that ultimately shortens the heel cord tendons. Active range-of-motion exercises supplemented by passive stretching are important for preventing contractures. Nighttime stretching orthoses (similar to the static ankle-foot orthoses but with a hinge at the ankle and adjustable straps) are useful and should be recommended at age 5 to 6. A standing board tilted up 20 degrees may be used for 20 minutes twice per day to provide constant stretching of the Achilles tendons. Keeping the heel cords stretched through vigorous passive stretching by parents and physical therapists helps the patient maintain better gait mechanics. This program requires stretching of the tensor fascia lata, hamstrings, knee flexors, and ankle plantar flexors. If strenuous stretching is not effective, surgical release of tight heel cords may be beneficial [Do, 2002], even if both the quadriceps and gastrocnemius muscle groups have

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Once the scoliotic curve reaches 30 degrees, it progresses with age and growth [Yamashita et al., 2001a]. Failure to repair scoliosis in Duchenne muscular dystrophy can result in increased hospitalization rates, worsening of pulmonary function, and poor quality of life [Finder et al., 2004; Yamashita et al., 2001b]. In fact, monitoring vital capacity may help determine the relative need for surgical stabilization of the spine [Rideau et al., 1984]. Surgical intervention should be undertaken when lung and cardiac function are satisfactory (with best recovery when the forced vital capacity exceeds 40%). However, there are no absolute contraindications to scoliosis surgery that are based on pulmonary function [Finder et al., 2004]. Surgery is usually scheduled once the Cobb angle measured on scoliosis films is between 30 and 50 degrees [Brook et al., 1996]. Immobilization attendant to surgical intervention for scoliosis may adversely affect the patient’s residual strength if proper physical therapy is not provided.

CARDIAC MANAGEMENT

FIGURE 79-8. Orthotic devices stabilize the position of the feet in relation to the ankles after Achilles tenotomy and are temporally helpful and necessary to help maintain position.

less-than-antigravity in strength. In the latter case, long leg bracing can be offered to keep some ambulation after contractures are corrected. Mobilization in a walking cast immediately after surgery is essential for preventing loss of strength. Temporary bracing after surgery is necessary for optimal results after tenotomy procedures (Fig. 79-8). The iliotibial bands may also tighten because of the broadbased gait used to maintain stability. Hip flexors may become contracted when ambulation is still present as a result of the anterior rotation of the hips or, later, because of sitting for prolonged periods in a wheelchair. Hip flexion contractures may benefit from surgical release, followed by application of long leg braces. Resection of the tensor fascia lata (Rideau procedure) may be beneficial for some patients [Do, 2002].

Scoliosis Nearly all patients with Duchenne muscular dystrophy develop scoliosis after losing independent ambulation. The use of solid seat and back inserts in properly fitted wheelchairs is helpful in preventing scoliosis by keeping truncal posture erect. For some patients, long leg braces can be fitted to allow braced upright daily standing to prevent curvature. Baseline back radiographs to document the degree of curvature if scoliosis begins to develop should be obtained for comparison with future films. The use of steroids— perhaps because it prolongs ambulation beyond the growth spurt of early teenage years—delays or prevents scoliosis, even if the child is eventually unable to walk [Alman et al., 2004; Yilmaz et al., 2004].

The mechanism of muscle damage discussed previously appears to be the same for cardiac muscle degeneration. In Duchenne muscular dystrophy and Becker muscular dystrophy, the left posterobasal and lateral walls are more extensively affected, with sparing of the left and right atria and the right ventricle [Finsterer and Stollberger, 2003]. The conduction system does not appear to be involved until there is advanced fibrosis; however, most cardiac deaths occur secondary to left ventricular cardiac failure [Corrado et al., 2002]. Two families with promoter and exon 1 involvement presenting with X-linked dilated cardiomyopathy enabled the discovery of a novel regulatory element, DEM2, which appears to be involved with the expression of dystrophin in the heart [Bastianutto et al., 2002]. Although electrocardiographic abnormalities are common in Duchenne muscular dystrophy, the best correlation of cardiac involvement with prognosis is measuring left ventricular dysfunction with echocardiography [Corrado et al., 2002]. Guidelines for the study of cardiac involvement in Duchenne muscular dystrophy [Bushby et al., 2003; Finsterer and Stollberger, 2003] recommend that Duchenne muscular dystrophy patients undergo electrocardiography and echocardiography at the time of diagnosis and then be screened every 2 years up to age 10 and subsequently every year. Early, preventive use of angiotensin-converting enzyme inhibitors and, later, β blockers may be needed and should be considered [Bushby et al., 2003; Finsterer and Stollberger, 2003].

GENETIC COUNSELING Duchenne muscular dystrophy and Becker muscular dystrophy are inherited in an X-linked recessive manner, and the risk to siblings of a patient depends on the carrier status of the mother. Female carriers have a 50% chance of transmitting the Duchenne muscular dystrophy mutation in each pregnancy. Sons who inherit the abnormal gene are affected, whereas daughters who inherit it are carriers. Male patients with Duchenne muscular dystrophy do not reproduce. However, male patients with Becker muscular dystrophy and X-linked dilated cardiomyopathy may reproduce. All their

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daughters are carriers, but none of the sons inherits his father’s dystrophin mutation. Prenatal testing for fetuses at risk is possible. Until the molecular genetics of Duchenne muscular dystrophy and Becker muscular dystrophy were understood, diagnosis of maternal and female sibling carriers was based on pedigree analysis and indirect assays. These included serum creatine kinase determinations [Griggs et al., 1985; Milhorat and Goldstone, 1965], the occasional finding of histologic abnormalities in muscle obtained from carriers [Maunder-Sewry and Dubowitz, 1981], and in vitro muscle ribosomal protein synthesis [Ionasescu et al., 1971a, 1971b, 1980]. Today, the specific molecular characterization of a patient makes genetic counseling easier. If a specific mutation is found in a child with Duchenne muscular dystrophy or Becker muscular dystrophy, genetic testing of the mother or sister for the exact mutation determines whether she is or is not a carrier; appropriate counseling for future pregnancies can be performed. When DNA analysis in the patient is not informative, muscle biopsy of a fetus can be used for diagnosis [Kuller et al., 1992]. Study of muscle from male fetuses with Duchenne muscular dystrophy reveals morphologic changes by the second trimester, especially greater muscle nuclear size in comparison with fetuses of the same gestational age [Vassilopoulos and Emery, 1977]. Immunoreaction for dystrophin is absent. When a deletion or specific mutation in the Duchenne muscular dystrophy/ Becker muscular dystrophy gene has been demonstrated in another family member, the deletion may be detected in fetal tissue or earlier by chorionic villus sampling. This means that intrauterine diagnosis is possible by the seventh week of gestation in male embryos suspected of being affected. A genetic counselor is an essential part of the multidisciplinary team that diagnoses and monitors patients with Duchenne muscular dystrophy. The genetic counselor should give the family a full explanation of the X-linked recessive inheritance pattern of Duchenne muscular dystrophy, and molecular genetic testing should be made available to the patient and other family members as necessary.

DRUG PRECAUTIONS Use of anticholinergic drugs and ganglionic blocking agents should be avoided because of their tendency to decrease muscle tone. Patients with Duchenne muscular dystrophy may be susceptible to malignant hyperthermia, and proper evaluation and preparation before administration of general anesthesia are recommended [Heiman-Patterson et al., 1986]. Cardiotoxic drugs, such as halothane, should not be used, and caution is advised in inducing general anesthesia [Smith and Bush, 1985].

EMOTIONAL AND BEHAVIORAL ABNORMALITIES Dysthymic disorder and major depressive disorder can occur in children with Duchenne muscular dystrophy, especially during adolescence [Fitzpatrick et al., 1986; Witte, 1985]. An affected child’s preoccupation with self and subsequent withdrawal may lead many families to seek counseling. Depression may develop in a patient who has lost an older sibling or close friend with Duchenne muscular dystrophy. Depression is often associated with intellectual limitation, which may induce low tolerance for frustration. Psychologic

evaluation and counseling may be necessary. Neuropsychologic screening for intellectual deficits and behavioral problems is ideally conducted at time of school entry and should be repeated in preadolescence. Appropriate follow-up with the family and school officials is important. Mothers identified as carriers of Duchenne muscular dystrophy may suffer from feelings of guilt and require psychologic support [Nereo et al., 2003]. Depression is also common among parents and should be recognized [Abi Daoud et al., 2004]. End-of-life care, including home mechanical ventilation, may be appropriate [Hilton et al., 1993].

Becker Muscular Dystrophy A “late-onset X-linked muscular dystrophy” was reported by Becker and Kiener in 1955. Like Duchenne muscular dystrophy, Becker muscular dystrophy is an X-linked recessive condition with mutation at Xp21. When the dystrophin reading frame is not shifted, there is no stop codon, and dystrophin is present but in reduced amounts. Distal rod deletions involving exons 45 to 48 result in a relatively high level of dystrophin, whereas N-terminus deletions are associated with low levels of dystrophin, perhaps as low as 10% of normal. The distal rod in-frame deletions result in a moderate Becker phenotype. A more severe Becker phenotype is associated with N-terminus deletions. The most severe phenotype, resembling Duchenne muscular dystrophy with the presence of minimal dystrophin, results from carboxyterminus deletions. Further discussion of molecular genetics is found under Duchenne Muscular Dystrophy. At times, routine immunohistochemistry studies might demonstrate normal dystrophin in patients with increased creatine kinase and only mild or no muscle weakness. In these patients, immunostaining for neuronal nitric oxide synthetase has been found useful, revealing complete absence in 3 patients who were later found to have in-frame deletions in the common rod domain exons (in these cases 48, 45 to 51, and 47 to 53) that were consistent with Becker muscular dystrophy [Torelli et al., 2004]. In one family, deletion of exon 48 was demonstrated in five members (a 4-year-old female and four male relatives, aged 8 to 58), all of whom had normal muscle strength. These individuals by definition have Becker muscular dystrophy but represent one end of the clinical spectrum. This finding means that molecular genetic studies alone cannot be used for counseling purposes [Morrone et al., 1997]. With in-frame deletions in the proximal third of the rod domain involving exons 13 to 17, the clinical manifestation is cramps and myalgia. In this particular Becker phenotype, immunoreactivity over the sarcolemma for dystrophin often appears normal. Creatine kinase levels in Becker muscular dystrophy are usually between 2000 and 20,000 U/liter but may be in the normal range for mildly affected male patients. Because these patients can be asymptomatic for decades, it is not uncommon that they receive misdiagnoses of a liver disorder when routine laboratory testing indicates elevated transaminase levels (aspartate aminotransferase and alanine aminotransferase), which are, in reality, muscle isoenzymes, abnormally elevated in parallel with the creatine kinase serum levels. These children might undergo several liver biopsies, with repeated normal results, before a creatine kinase level is measured and a diagnosis of Becker muscular

Escolar and Leshner / Muscular Dystrophies

dystrophy is established after further testing is performed [Tay et al., 2000; Zamora et al., 1996]. Muscle biopsy histologic findings are similar to those in Duchenne muscular dystrophy, but findings are less pronounced. The sarcolemmal gaps displayed ultrastructurally in Duchenne muscular dystrophy are not as readily seen in Becker muscular dystrophy. When monoclonal antibodies are directed to separate regions of dystrophin, immunoreactivity over the sarcolemma has a variety of staining patterns, ranging from intact to absent with one or more antibodies [Jay et al., 1993]. Becker muscular dystrophy is present in 3 to 6 per 100,000 male births [Gardner-Medwin, 1970]. The onset of Becker muscular dystrophy usually occurs after age 7 years and often in the second decade. Ambulation is typically maintained beyond age 30. Pseudohypertrophy, proximal hip weakness resulting in Gowers’ sign, and electrocardiographic abnormalities associated with Duchenne muscular dystrophy are also common in Becker muscular dystrophy (Fig. 79-9). A few patients with earlier onset Becker muscular dystrophy have the same phenotype as patients with Duchenne muscular dystrophy but prove later, with muscle dystrophin and molecular genetic testing, to have Becker muscular dystrophy [Hoffman, 1991]. A number of children and adolescents with Becker muscular dystrophy experience calf pain or muscle cramps after exercise, which may be the initial symptom [Samaha and Quinlan, 1996]. In other individuals, strength may be nearly normal, but vigorous exercise produces severe cramps and occasionally rhabdomyolysis [Figarella-Branger et al., 1997]. A few teenagers with Becker muscular dystrophy initially have heart failure caused by a dilated cardiomyopathy before weakness is recognized. Sudden cardiac failure caused by heart block may occur in Becker muscular dystrophy. Early-onset

FIGURE 79-9. This 14-year-old male with Becker muscular dystrophy manifests moderate pseudohypertrophy of the calf muscles and wasting of the muscles of the shoulder girdle.

1987

cardiomyopathy with mild muscle weakness is associated with muscle promoter and exon 1 deletion. The likelihood of intellectual retardation, although greater than that in the general population, is less than that in Duchenne muscular dystrophy. However, mental retardation (IQ range, 60 to 68) and psychiatric disturbance in the absence of muscle weakness have been reported in Becker muscular dystrophy [North et al., 1996]. Therapeutic suggestions and measures appropriate for Duchenne muscular dystrophy are applicable at some point for Becker muscular dystrophy. This approach includes the use of prednisone in the more severely affected patients. Patients with Becker muscular dystrophy may be predisposed to malignant hyperthermia, and appropriate precautions should be taken when general anesthesia is necessary [Breucking et al., 2000; Kleopa et al., 2000].

Chromosome Xp21 Microdeletion Syndromes The Xp21 microdeletion syndromes are a series of syndromes that include Duchenne muscular dystrophy, Aland’s eye disease, adrenal hypoplasia, glycerol kinase deficiency, retinitis pigmentosa (RP3), mental retardation (MRX1), and ornithine transcarbamylase deficiency. The combination of these conditions led to the discovery of the Duchenne muscular dystrophy gene on Xp21 [Francke et al., 1985].

LIMB-GIRDLE MUSCULAR DYSTROPHIES The limb-girdle muscular dystrophies (LGMDs) are a diverse group of disorders characterized by progressive muscle weakness, usually affecting the large muscles around the shoulder and pelvic girdles. However, as specific phenotypes corresponding to individual causative mutations have been characterized, the distribution of weakness around the limb-girdles has been found not universal, and some forms of LGMD affect distal muscles and can be confused with the most common phenotype of a neuropathy. These disorders are caused by a multiplicity of genes encoding proteins involved in all aspects of muscle cell biology. Initial classification of these disorders were based on the mode of inheritance, and were divided into autosomal-dominant (type 1: LGMD1), autosomal-recessive (type 2: LGMD2), and X-linked. With the discovery of causative genes in these three categories, each new entity was given a nominal letter, which resulted in the confusing and unpractical denomination of LGMD1A to 1F and LGMD2A to 2K. To date, there are 6 autosomaldominant forms and 11 autosomal-recessive forms. Most loci defined by linkage have been identified, with the exception of LGMD1D to 1F, which are not included in the classification table. The majority of cases of LGMD are autosomal-recessive. Autosomal-dominant forms are found only in a few families, except for LGMD1B, which is the autosomal-dominant form of Emery-Dreifuss muscular dystrophy. An integrated classification taking into account the type and localization of the proteins has been proposed [Emery, 2002]. The age at onset and the key clinical findings are added to this classification scheme in this chapter to provide a clinical-biochemical classification more useful to the practitioner evaluating these disorders. This classification is presented in Table 79-2. Many of these syndromes are

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TABLE 79-2 Clinical and Biochemical Classification of the Limb-Girdle Muscular Dystrophies (LGMDs)

PROTEINS

PROPOSED PROTEIN FUNCTION

NOMENCLATURE

Sarcolemma Associated γ-Sarcoglycan α-Sarcoglycan β-Sarcoglycan δ-Sarcoglycan

Stabilize DGC at the sarcolemma δ and γ bind γ-filamin Signaling

Caveolin-3

Dysferlin

AGE AT ONSET

KEY CLINICAL FINDINGS

MODE OF INHERITANCE

LGMD2C LGMD2D LGMD2E LGMD2F

Infancy to young adult

AR

Variable proportion in different countries worldwide

Concentration of signaling molecules/biogenesis of T tubules

LGMD1C

Childhood (age 5)

AD

Uncommon, but worldwide

Membrane repair

LGMD2B

Teens to early 20s

Variable in severity from DMD to BMD phenotype Dilated cardiomyopathy in δ-sarcoglycan Calf hypertrophy, increased CK, rippling muscle disease May manifest with distal or proximal weakness Biopsy reveals inflammation Worsens with steroids

AR

Relatively common Worldwide

Anchors basal lamina in extracellular matrix Bridges cells with extracellular matrix through integrins

Bethlem’s myopathy

Neonatal to adulthood

Proximal weakness, atrophy, distal contractures

AD

Rare

Regulates nuclear factor κβ/Iκβα in protection from apoptosis Binds titin Cleaves γ-filamin Glycosylation of α-dystroglycan

LGMD 2A

Infancy to young adult

AR

Relatively common in many countries

LGMD 2I

Birth to adulthood

AR

Commonest LGMD in many countries

LGMD2K

Infancy

Atrophic disease, early Achilles contractures, and trunk muscle involvement Calf hypertrophy, common cardiac and respiratory involvement Mild muscle hypertrophy, microcephaly, mental retardation, normal brain MRI

AR

Rare: described in Turkish and British families

Binds α-actinin, γ-filamin and bundles α-actin

LGMD 1A

Teens to young adult. Anticipation?

AD

Rare

Telethonin (Z line)

Substrate for titin kinase

LGMD 2G

9 to 15 years

AR

Rare: described only in Brazil

Titin

Specifies sarcomeric structure Has intrinsic kinase activity

LGMD 2J

Childhood

AR

Rare: described only in Finland

Extracellular Matrix Collagen 6A1, A2, and A3

Proteins with Enzymatic Activity Calpain-3 (cytosolic)

Fukutin-related protein (Golgi apparatus)

Protein O-mannosyl- Glycosylation of transferase (POMT) α-dystroglycan 1 (endoplasmic reticulum) Sarcomeric Proteins Myotilin (z-line)

Dysarthria, tight Achilles tendons, 50% cardiomyopathy Proximal weakness and footdrop Calf hypertrophy or atrophy, cardiomyopathy Allelic with Finnish tibial myopathy, more severe, high CK level

FREQUENCY

AD, autosomal dominant; AR, autosomal recessive; BMD, Becker muscular dystrophy; CK, creatine kinase; DGC, dystrophin-associated glyprotein complex; DMD, Duchenne muscular dystrophy.

extremely rare; only a few affected families have been described in the literature, and so these rarer forms are not reviewed in detail in this chapter [see Laval and Bushby,

2004, for a recent review]. In this classification, proteins causing solely a congenital muscular dystrophy phenotype have been purposefully excluded because those are better

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classified as listed later in Table 79-4 and described in the later section on congenital muscular dystrophies. The pathophysiology of the syndromes caused by defects of sarcolemmal proteins, as part of the DGC, is similar to that described for dystrophinopathies. In contrast, other LGMDs have distinct pathophysiologic mechanisms. For example, dysferlin deficiency causes abnormal muscle membrane repair, whereas calpain-3 deficiency involves abnormal regulation of anti-apoptotic pathways and likely abnormal cytoskeletal remodeling.

calpain-3 was in relation to its abnormal activation in Duchenne muscular dystrophy secondary to increased levels of intracellular Ca2+. Type 2A was the first form of LGMD identified that is caused by deficiency of a nonstructural protein; this deficiency emphasizes the role of abnormal molecular signaling as the basis for muscle cell degeneration that has been discussed before for Duchenne muscular dystrophy.

Limb-Girdle Muscular Dystrophy 1C: Caveolinopathy

The gene responsible for LGMD2A (CAPN3) is located at chromosome region 15q15.1-q21.1 [Chiannilkulchai et al., 1995] and consists of 24 exons extending over a genomic region of 50 kilobases [Richard et al., 1995]. It is expressed as a 3.5-kilobase transcript, a 94-kDa translated protein. More than 140 different mutations have been reported, including different nonsense, splice site, frameshift, or missense calpain-3 mutations, most of which are “unique” mutations [Saenz et al., 2005]. In addition, several ethnic groups have unique mutations that co-segregate with the disease [CankiKlain et al., 2004; Chae et al., 2001; Chrobakova et al., 2004; Cobo et al., 2004; Fanin et al., 2004; Jia et al., 2001; Kramerova et al., 2004; Passos-Bueno et al., 1999]. In a large series, it was found that 87% of mutant alleles are concentrated in seven exons (exons 1, 4, 5, 8, 10, 11, and 21) and 61% correspond to only eight mutations, which indicates the regions to which future molecular analysis could be restricted [Fanin et al., 2004]. In patients in Brazil, most mutations are found in exons 1, 2, 4, 5, 11, and 22 [Zatz et al., 2003]. However, other investigators have not found the same deletion pattern [Saenz et al., 2005], which suggests that these hot spots could be related to confounder mutations in the area. Mutations can be homozygous or compound heterozygous. Homozygous null-null mutations appear to confer the most severe phenotype, in terms of earlier wheelchair need, whereas a heterozygous missense mutation confers a milder phenotype [Saenz et al., 2005]. Calpain-3 is a muscle specific protein that belongs to the calpain family of proteins. This protein has many unique features and is considered a “modulator protease.” Several lines of evidence suggest that calpain-3 is mostly in an inactive state in muscle and needs a signal to be activated. Activated calpain-3 has several relationships with important cytoskeleton proteins. Some of its substrates include titin and filamin C [Taveau et al., 2003]. The interaction of calpain-3 with these cytoskeletal proteins may modulate remodeling during myofibrillogenesis by affecting scaffolding of titin for sarcomere assembling [Kramerova et al., 2004], and by cleaving filamin C and inhibiting its regulation of sarcoglycan assembly [Guyon et al., 2003]. There is also evidence that when calpain-3 is activated, its proteolytic activity leads to disruption of the actin cytoskeleton. Thus, calpain-3 appears to be a cytoskeleton modulator with an important role in muscle maturation [Spencer et al., 2002]. Other pathogenic hypotheses are proposed to explain why mutations in this gene might cause muscular dystrophy. Calpain-3 could have a protective effect and be involved in muscle detoxification preventing degradation of the muscle fiber [Zatz et al., 2003]. It may also play a role in intracellular signaling pathways and its deficiency might be associated with myo-

Caveolins are small transmembrane proteins with intracellular domains that undergo extensive oligomerization to form membrane complexes known as caveolae. Skeletal muscle disorders result from mutations on chromosome 3p25 in the gene that encodes caveolin-3, which interacts with neuronal nitric oxide synthase and the dystrophinassociated protein complex via the intracellular portion of β-dystroglycan [Song et al., 1996; Tang et al., 1996]. During muscle differentiation, caveolin-3 is associated with developing T tubules [Parton et al., 1997]. In the original reports of caveolinopathy, the disorders resulted from heterozygous changes in the membrane-spanning domain, which produced an autosomal-dominant LGMD phenotype [Minetti et al., 1998]. The clinical features of subsequently reported cases have been heterogeneous, and too few cases have been reported to define a predominant phenotype. Symptoms can begin in childhood with slowly progressive weakness. Calf hypertrophy is present, and creatine kinase levels are elevated 4- to 20-fold. Other families may manifest only elevated serum creatine kinase levels (hypercreatine kinaseemia) and postexertional myalgia and cramping, which may also begin in the first decade [Herrmann et al., 2000; Merlini et al., 2002]. Caveolin-3 mutations have been defined in autosomal-dominant rippling muscle disease [Betz et al., 2001], and severe rippling muscle symptoms have been reported in two unrelated patients with homozygous caveolin-3 mutations [Kubisch et al., 2003]. A single case of distal myopathy has been described [Tateyama et al., 2002]. The broad spectrum of clinical symptoms and the possibility that spontaneous or germline mutations produce simplex cases frequently raise the possibility of caveolinopathy. The postulated dominant negative effect of a number of caveolin-3 mutations leads to a substantial or complete loss of caveolin3 immunoreactivity, allowing for screening with immunohistochemical techniques [Carbone et al., 2000; Herrmann et al., 2000].

Limb-Girdle Muscular Dystrophy 2A: Calpainopathy Calpainopathy is a relatively frequent, childhood-onset LGMD that was fully characterized, and the molecular and biochemical abnormalities were described, in 1995 [Chiannilkulchai et al., 1995; Richard et al., 1995]. This type has been reported as the most frequent autosomalrecessive LGMD in several series [Chae et al., 2001; Dincer et al., 1997; Richard et al., 1997; Topaloglu et al., 1997]. The abnormal protein, calpain-3, is a nonlysosomal intracellular, muscle-specific, Ca2+-activated neutral protease [Johnson, 1990]. Before recogition of this new LGMD, the focus on

Molecular Pathogenesis

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nuclear apoptosis by deregulation of the Iκβα/nuclear factor κβ pathway [Baghdiguian et al., 1999]. The majority of the LGMD2A mutations appear to affect domain-domain interaction, which may be critical in the assembly and activation of the multidomain calpain-3 [Jia et al., 2001]. Under normal circumstances, calpain-3 undergoes rapid autocatalytic activity after translation, [Taveau et al., 2003]. During the short time (less than 5 minutes in muscle cultures) that the protein is present, it is in a resting state, unless it is activated by signaling mechanisms [Rey and Davies, 2002]. The autocatalytic activity resides in a Ca2+-sensitive region between domains II and III of the protein. In the 20% to 40% [Fanin et al., 2003; Saenz et al., 2005] of patients with genetically proven LGMD2A, in which Western blots fail to reveal any protein abnormality, the mutations are in these autocatalytic regions (R490Q, R489Q, R490W missense mutations), resulting in a reduced autocatalytic activity by lowering the Ca2+ sensitivity [Fanin et al., 2003].

Clinical Manifestations LGMD2A has a characteristic phenotype in about 64% of the genetically confirmed patients. Interfamilial and intrafamilial variability is not uncommon [Zatz et al., 2003]. The age at onset of symptoms is between 2 and 49 years; the mean age at presentation is 14 (±8) years [Saenz et al., 2005]. The disease causes symmetric weakness of the pelvic and shoulder girdle muscles. There is preferential involvement of the posterior compartment of the thighs and posterior superficial calves that can be seen clinically and by computed tomographic or magnetic resonance imaging (MRI) studies. Facial, oculomotor, and cardiac muscles are not affected. Scapular winging can be observed early [Beckmann and Bushby, 1996]. Contractures, if present, occur late in the disease and do not extend into the spine [Beckmann and Bushby, 1996]. Most patients become unable to walk about 25 years after symptom onset. The creatine kinase level is 5- to 20-fold elevated. However, occasional patients (reported in Brazil) have normal creatine kinase levels, and so this should not be an exclusion criterion. Cognition is not impaired. The clinical phenotype can be confused with that of LGMD2I (fukutin-related protein gene [FKRP]) or facioscapulohumeral muscular dystrophy because of the presence of scapular winging. However, the distribution of weakness and the muscle MRI findings are very characteristic and distinct from those of these two disorders [Mercuri et al., 2005].

Diagnosis Diagnosis of a calpainopathy is based on a typical phenotype, a muscle biopsy sample revealing Western blot abnormalities, and genetic testing indicating two mutations on two alleles. The combination of a typical phenotype with an abnormal Western blot result in muscle biopsy samples (at least two abnormal bands) increases the probability that an affected patient has a calpainopathy to 90% [Saenz et al., 2005]. However, if one of these variables is missing, the probability is reduced to about 75% [Saenz et al., 2005]. False-negative reports with Western blots in 20% to 40% of these patients indicates that genetic sequencing has to be

pursued when a calpainopathy is clinically suspected on the basis of the typical phenotype [Fanin et al., 2003; Saenz et al., 2005]. Muscle pathologic findings are positive for necrosis, regeneration, altered myofibrillar architecture, increased numbers of centrally placed nuclei, fibrosis, fiber type I predominance, and normal immunoreactivity for dystrophin and αsarcoglycan. Muscle biopsy samples in preclinical cases have exhibited an unusual pattern of isolated fascicles of degenerating fibers in an almost normal muscle. This pattern has not been seen in patients early in the disease course who are affected by other forms of LGMD, which suggests that a peculiar pattern of focal degeneration occurs early in calpainopathy, independently of the type of mutation or the amount of calpain-3 in the muscle [Vainzof et al., 2003]. Western blot analysis of muscle calpain-3 can reveal total, partial, or no deficiency, with no relation between protein expression and severity of phenotype [Saenz et al., 2005; Zatz et al., 2003]. Secondary reduction of calpain-3 can be seen in other conditions, specifically dysferlinopathies and LGMD2I secondary to FKRP deficiency [Vainzof et al., 2000a].

Limb-Girdle Muscular Dystrophy 2B: Dysferlinopathy Mutations in the dysferlin gene on chromosome 2p13 cause distinct phenotypes of muscular dystrophy: LGMD type 2B (LGMD2B), Miyoshi’s myopathy, and distal anterior compartment myopathy, which are known by the term dysferlinopathies. This form represents 1% of recessive LGMD and about 33% of distal LGMD. Although the distributions of weakness in Miyoshi’s myopathy and LGMD2B are different (distal and proximal, respectively), both syndromes manifest in the late teens, progress slowly, and are associated with high serum creatine kinase levels. Moreover, identical mutations can give rise to both phenotypes in the same family; therefore, environmental or other factors might contribute to the differential expression of muscle weakness [Kawabe et al., 2004].

Molecular Pathogenesis Molecular pathogenesis is an autosomal-recessive LGMD that is caused by mutations in the dysferlin gene on chromosome 2p13 [Bashir et al., 1996; Passos-Bueno et al., 1996a, 1996b]. In humans, the dysferlin gene encompasses 55 exons spanning more than 150 kilobases of genomic DNA [Aoki et al., 2001]. The dysferlin gene encodes a 230-kDa protein with widespread expression in tissues such as skeletal muscle, cardiac muscle, the kidneys, the placenta, the lungs, and the brain. Although dysferlin is expressed most abundantly in skeletal and cardiac muscles, there is no evidence for cardiac muscle dysfunction in dysferlindeficient patients. Immunohistochemical studies revealed that in skeletal muscle, dysferlin is located at the plasma membrane, as well as in cytoplasmic vesicles [Bansal et al., 2003]. The pathogenesis of this class of muscular dystrophy is distinct in that the defect lies in the maintenance, not the structure, of the plasma membrane. Histopathologic and immunohistochemical studies in these patients reveal absence of dysferlin [Matsuda et al., 1999]. In addition, a

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very active inflammatory and degenerative process is characteristic in this disease and can lead to a misdiagnosis of polymyositis. However, the immune response is different, with macrophages being more common than T cells; the presence of perivascular and interstitial infiltrate consisting of CD8+ and CD4+ cells, but no B cells; and overexpression of major histocompatibility complex class I on muscle fibers [Gallardo et al., 2001]. These findings differ from polymyositis but are closely similar to those in SJL/J mice (murine model of dysferlin deficiency); this emphasizes a direct relationship between absence of dysferlin and immune system abnormalities in muscle [Confalonieri et al., 2003], perhaps in response to an inefficient muscle membrane repair and regenerative system [Cenacchi et al., 2005]. Ultrastructural studies provide evidence for the abnormal membrane repair mechanism when dysferlin is absent. Electron microscopy studies demonstrate prominent aggregations of small vacuoles, likely derived from the Golgi apparatus in the subsarcolemmal region, consisting of empty, swollen cisternae. The sarcolemma has multiple small gaps and microvillus-like projections. The basal lamina is thick and has focal duplications, thus having a multilayered appearance [Cenacchi et al., 2005; Selcen et al., 2001]. These alterations are seen mostly over plasmalemmal defects. Characteristic of this disorder is the presence of one to several layers of small vesicles just beneath the sarcolemma as proof of a defective resealing mechanism that fails to repair the sarcolemma [Cenacchi et al., 2005].

Clinical Presentation There are two common phenotypes, LGMD2B and Miyoshi’s myopathy, both manifesting in the second decade of life [Takahashi et al., 2003]. Two other phenotypes, distal anterior compartment type and scapuloperoneal type, also exist and are seen especially early in the clinical course [Ueyama et al., 2002]. Patients undergo normal early developmental milestones without weakness in childhood and development of slowly progressive muscle weakness and wasting starting in adolescence [Mahjneh et al., 2001]. The LGMD2B phenotype is a predominantly proximal muscular dystrophy. Affected individuals have onset of pelvic girdle muscle weakness, with lower limbs abducted and externally rotated and hyperlordosis as a result of hip muscle weakness. The anterior muscles of the distal legs and distal arms are relatively normal in these patients, even at the later stages of the disease. In contrast, the Miyoshi myopathy phenotype is a predominantly distal muscular dystrophy with early involvement of the posterior compartments of the lower limb; a common early symptom is the inability to stand on tiptoes. These patients manifest hyperextension of the lower limbs caused by weakness of the quadriceps and gastrocnemius muscle. As a result, physical examination reveals extensive wasting of the distal posterior muscles of the leg and, later, of the thigh [Ueyama et al., 2002]. Although previously described mainly in Japan, Miyoshi’s myopathy has been increasingly recognized in Western countries. Ten years after the onset of the disease, pronounced gait abnormalities are present in both the LGMD2B and the Miyoshi myopathy phenotypes: The foot leaves the ground with a double flexion of the knee and the hip. At this stage, upper extremity weakness is also evident and at times has a distal

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pattern. Laboratory evaluation demonstrates markedly increased serum creatine kinase levels. There is no specific treatment for this disorder, and the management is in the realm of rehabilitation medicine. Anklefoot orthosis can improve gait when footdrop is pronounced. Despite the pronounced inflammatory response in muscle biopsy samples, steroids are not beneficial and might worsen the disorder.

Diagnosis Diagnosis of dysferlinopathy is based on the absence of dysferlin expression on immunoblots or cryostat sections and on exclusion of dystrophinopathy, sarcoglycanopathy, calpainopathy, and calveolinopathy, because dysferlin deficiency is rarely secondary in other myopathies. However, severe reduction of dysferlin expression is seen only in Miyoshi’s myopathy or LGMD2A [Anderson et al., 2000]. The diagnosis of dysferlinopathy can also be made by measuring dysferlin expression in peripheral blood mononuclear cells by immunoblot analysis, which has excellent correlation with muscle biopsy findings [Ho et al., 2002]. This test is available commercially.

Limb-Girdle Muscular Dystrophies 2C, 2D, 2E, 2F: Sarcoglycanopathies The sarcoglycanopathies are a family of autosomal recessive disorders that often manifest with an early and severe phenotype. The four sarcoglycans constitute a tetrameric complex of membrane proteins that contributes to the stability of the plasma membrane cytoskeleton and facilitates the association of dystrophin with the dystroglycans. The four sarcoglycan genes (α, β, γ, and δ) are related to each other structurally and functionally, but each has a discrete chromosomal location. Mutations in each gene may produce partial or complete loss of the entire complex [Nigro et al., 1996b]. Patients with sarcoglycanopathies were initially distinguished from children with a severe Duchenne-like presentation who proved dystrophin positive and in whom autosomal-recessive inheritance was likely [Zatz et al., 1989]. The term severe childhood autosomal recessive muscular dystrophy was used to describe the condition of these children; some of them were later found to have a deficiency of a 50-kDa dystrophin-associated protein, the gene for which was localized to chromosome 13q12, the locus for γsarcoglycan [Azibi et al., 1993; Matsumura et al., 1992]. Sister proteins were identified [Mizuno et al., 1994], and the phenotypes associated with sarcoglycanopathies broadened to include less severely involved children. Mutations in each of the four sarcoglycans are found worldwide. In outbred populations such as those in Europe, North America, and Brazil, the relative frequencies of symptomatic mutations of the four genes are, from highest to lowest, α, β, γ, and δ in an 8:4:2:1 ratio [Duggan et al., 1997]. In other populations, this ratio may vary. A founder mutation Thr151Arg in β-sarcoglycan has been identified in the Indiana Amish community [Duclos et al., 1998]. Specific mutations of γ-sarcoglycan cause the majority of cases of LGMD among Gypsies and persons in northern Africa [Merlini et al., 2000; Noguchi et al., 1995], and a specific mutation of δ-sarcoglycan is seen in a relatively higher

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frequency in African-Brazilians [Nigro et al., 1996a; Vainzof et al., 1999]. Although the worldwide epidemiology of sarcoglycanopathies has not been extensively studied, data obtained in northern Italy suggest an incidence of 5.6 per million [Fanin et al., 1997]. Before a child is evaluated for sarcoglycanopathy, a primary dystrophinopathy must be excluded. Fewer than 5% of males with a Duchenne/Becker phenotype have a sarcoglycanopathy or other limb girdle muscular dystrophy. Young females with a Duchenne/Becker phenotype are nearly as likely to be carriers of a dystrophinopathy as to have an alternative diagnosis [Hoffman and Clemens, 1996]. The majority of dystrophin-positive children presenting with an early-onset Duchenne-like phenotype have a sarcoglycanopathy [Duggan et al., 1996; Vainzof et al., 1999]. In contrast, only about 10% of patients with a more benign phenotype evolving in adolescence or young adulthood manifest a sarcoglycanopathy. Immunostaining of muscle with antisarcoglycan antibodies is the standard screening for new cases of sarcoglycanopathy. Muscle biopsy samples from patients with primary dystrophinopathy reveal reduced sarcoglycan immunoreactivity. Therefore, both dystrophin and sarcoglycan immunostaining must be performed on the same muscle tissue. The finding of normal dystrophin staining and deficiency in immunostaining of any of the sarcoglycans suggests that a sarcoglycan mutation is present. Many laboratories perform immunostaining only for α-sarcoglycan, relying on a reduction or absence of immunoreactivity to reflect a mutation in any of the four sarcoglycans. Because the entire sarcoglycan complex tends to be affected as a unit in response to mutations in any of the four components, this is usually adequate. However, staining with antibodies to all four sarcoglycans can provide clues regarding the protein that reflects the primary mutation. This information helps direct DNA testing for definitive diagnosis of the specific sarcoglycan mutation. On occasion, immunoreactivity of components within the sarcoglycan complex appears normal in the presence of a documented reduction in immunostaining of another component [Higuchi et al., 1998; Vainzof et al., 2000b]. γ-Sarcoglycanopathy in particular may produce a marked reduction in γ-sarcoglycan immunoreactivity with relatively good preservation of α- and δ-sarcoglycan staining [Nowak et al., 2000; Vainzof et al., 1996]. The pathophysiology of sarcoglycanopathies relates to that of dystrophinopathies, discussed in detail in the preceding section and is not covered here.

γ-Sarcoglycanopathy (Limb-Girdle Muscular Dystrophy 2C) The gene for γ-sarcoglycan is found on chromosome 13q12. It codes for a 35-kDa protein expressed predominantly in skeletal muscle. In addition to its role as a stabilizer of the dystrophin-associated complex, γ-sarcoglycan binds γfilamin/filamin C [Noguchi et al., 1995]. Minor expression in smooth muscle occurs as well [Barresi et al., 2000]. The most common γ-sarcoglycan mutation is the deletion of a single thymidine residue, del52IT [Noguchi et al., 1995], that originated in northern Africa as a founder mutation. This mutation produces a truncated protein. However, the clinical severity is variable even within families, ranging

from a Duchenne-like to a mild Becker phenotype [McNally et al., 1996a, 1996b]. The mean age at symptom onset is 5 years. The distribution of weakness is most notable in the glutei and thigh adductors. Upper extremity weakness usually begins in the periscapular muscle and later involves the deltoid and biceps muscles. In contrast to Duchenne muscular dystrophy, the quadriceps tends to be spared and is usually as powerful as the hamstrings. Calf and tongue muscle hypertrophy is common. Cardiac problems occur late in the disease, with evidence of right ventricular hypertrophy on electrocardiograms and asymptomatic ventricular dysfunction [Melacini et al., 1999]. Cognition is normal. Mild sensorineural hearing loss may evolve. Loss of independent ambulation occurs at mean age of 16 years (range, 10 to 37 years). Orthopedic problems include progressive lordosis. Surgical stabilization of the spine is rarely needed. Laboratory studies reveal gross elevations of creatine kinase level, usually more than 10-fold normal. Muscle biopsy samples yield dystrophic findings of degeneration and regeneration and occasional foci of inflammation. Immunostaining of sarcoglycans with a dystrophin-immunostaining control sample is the diagnostic procedure of choice. Patients with γ-sarcoglycan can have near-normal α-sarcoglycan immunostaining, which yields a false-negative muscle biopsy result [Nowak et al., 2000].

α-Sarcoglycanopathy (Limb-Girdle Muscular Dystrophy 2D) α-Sarcoglycan is encoded on chromosome 17q21. The 50-kDa protein originally called adhalin is expressed only in skeletal and cardiac muscle. Most mutations are missense in the extracellular domain [Piccolo et al., 1995]. Worldwide, α-sarcoglycanopathy is the most common of the sarcolycan disorders, accounting for over 50% of patients [Hayashi and Arahata, 1997]. The Arg787Cys missense mutation is the most common, accounting for a third of all cases of α-sarcoglycanopathy [Carrie et al., 1997]. Null mutations are associated with total absence of αsarcoglycan and often confer a severe phenotype with onset of symptoms in the first 3 years of life [Duggan et al., 1997]. Onset of motor problems occurs between 2 and 15 years; earlier onset is predictive of more rapid deterioration and low or absent α-sarcoglycan. In patients with late onset, ambulation may be preserved for decades. Occasional patients manifest a high creatine kinase level in the absence of weakness. The distribution of weakness, atrophy, and hypertrophy is similar to that described for γ-sarcoglycan, but the quadriceps tends to be involved in patients with severe, early-onset disease. The phenotype varies from a severe Duchenne phenotype to a mild Becker phenotype. Early scapular weakness is common. Symptomatic cardiomyopathy is rare, although evidence of cardiac dysfunction is present in about 30% of patients [Melacini et al., 1999]. Cognition is normal. Serum creatine kinase levels are high, usually over 5000 IU. Small therapeutic trials of corticosteroids have been conducted, with reports of benefits similar to those seen in steroid-treated Duchenne muscular dystrophy patients [Connolly et al., 1998].

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β-Sarcoglycanopathy (Limb-Girdle Muscular Dystrophy 2E) β-Sarcoglycan is coded on chromosome 4q12. It is a 43-kDa protein that is expressed not only in skeletal and cardiac muscle but also in brain and kidney tissue. Worldwide, it accounts for about 25% of reported cases of sarcoglycanopathy. However, certain populations have a much higher incidence of β-sarcoglycan mutations, including the Indiana Amish. The clinical spectrum is similar to that described for the γ- and α-sarcoglycanopathies, with onset occurring between age 3 years and the mid-teens and faster progression with earlier onset. Independent walking is often lost between the ages of 10 and 15 and nearly always by age 25. Muscle hypertrophy is prominent in the calves. Symptomatic cardiomyopathy is rarely seen. Creatine kinase levels are approximately 5000 IU. Muscle biopsy specimens usually reveal absence of all sarcoglycan immunostaining, and there is occasional reduction of dystrophin immunostaining as well. A knockout mouse model of β-sarcoglycanopathy has been developed, and attempts at gene transfer have been initiated [Dressman et al., 2002].

δ-Sarcoglycanopathy (Limb-Girdle Dystrophy 2F) The gene for δ-sarcoglycanopathy in chromosome region 5q33-q34 codes for a 35-kDa protein localized to the subsarcolemmal region of skeletal and cardiac muscle. It is the rarest of the sarcoglycanopathies. Missense and nonsense mutations are reported, as is a frameshift mutation that produces a premature truncation of protein found in affected Brazilian families [Nigro et al., 1996a]. The clinical phenotype is universally severe, with onset of symptoms occurring between 2 and 10 years of age and progression to full-time wheelchair use by the mid-teens. Most patients do not survive their second decade. A dilated cardiomyopathy may occur with or without skeletal myopathy [Politano et al., 2001; Tsubata et al., 2000].

Limb-Girdle Muscular Dystrophy 2I: Fukutin-Related Protein Gene Deficiency LGMD2I is a newly characterized LGMD, whose causative gene was discovered in 2001 [Brockington et al., 2001b]. Since then, it has become apparent that this is one of the most common forms of LGMD, representing from 11% [Zatz et al., 2003] to 19% [Krasnianski et al., 2004; Walter et al., 2004] of all cases of LGMD in different series.

Molecular Pathogenesis The disease is caused by a mutation in the fukutin-related protein gene in chromosome 19q13.3 [Brockington et al., 2001a]. The most common mutation is a single point (826C>A) missense mutation in one allele (>90%) causing a Leu276Ileu (C826A) [Brockington et al., 2001b]. Disease severity correlates with a mutation on the second allele; consequently, patients with homozygous mutations causing a Leu276Ileu exhibit a less severe phenotype [Brockington et al., 2002; Mercuri et al., 2003]. Patients heterozygous for this mutation usually have a second heteroallelic mutation

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on the other allele [Walter et al., 2004]. This disorder is allelic to congenital muscular dystrophy with muscle hypertrophy and a normal central nervous system (merosinpositive congenital muscular dystrophy type [MDC1C]) [Brockington et al., 2001a]. FKRP is a ubiquitous protein with highest levels in skeletal muscle, heart, and placenta tissue. FKRP localizes to rough endoplasmic reticulum and has glycosyltransferase activity [Matsumoto et al., 2004]. FKRP and fukutin are targeted to the medial Golgi apparatus through their Ntermini and transmembrane domains [Esapa et al., 2002]. Together with fukutin, FKRP appears to be involved in the initial steps of O-mannosylglycan synthesis of αdystroglycan [Matsumoto et al., 2004].

Clinical Manifestations Age at onset ranges from 0.5 to 27 years; 61% of patients present before age 5 years. Patients present with either a Duchenne muscular dystrophy phenotype (heterozygous mutations) or, with a later onset, milder limb-girdle syndrome (homozygous mutations). The clinical course varies, usually involving weakness and wasting of the shoulder girdle muscles and proximal extremities, with significant calf hypertrophy, and elevated serum creatine kinase levels, ranging from 5- to 70-fold increases. There is a characteristic predilection for muscles of the lower extremities, with weakness of hip flexion and adduction, knee flexion, and ankle dorsiflexion being more predominant [Fischer et al., 2005]. Other clinical manifestations have been described, including exercise-induced myalgia in addition to weakness and isolated myalgia, cramps, elevated serum creatine kinase levels, and dilated cardiomyopathy without muscle weakness [Krasnianski et al., 2004]. In some series, most patients presented with muscle pain and myoglobinuria as the earliest symptoms [Walter et al., 2004]. Cardiac and respiratory involvement are relatively common in the heterozygous, earlier presentation cases, occurring in about 30% of patients, and at times while they are still ambulatory [Mercuri et al., 2003; Poppe et al., 2003].

Diagnosis Methods for genetic sequencing of the FKRP gene from peripheral blood are commercially available, and so diagnosis can be confirmed. Muscle biopsy samples reveal characteristic dystrophin changes, with muscle fiber size variation, muscle fiber necrosis and regeneration, and mild increase in connective tissue. The most consistent abnormality is secondary abnormal laminin-2 immunostaining. Most patients also have a marked decrease in immunostaining of muscle αdystroglycan and a reduction in its molecular weight on Western blot analysis [Brockington et al., 2001a, 2001b]. MRI of muscle demonstrates a distinct and consistent pattern of muscular involvement in LGMD2I that is correlated with the pattern of muscle weakness in these patients. Predominant weakness of shoulder adduction and internal rotation, elbow flexion, hip flexion and adduction, knee flexion, and ankle dorsiflexion, independent of the individual disease duration and the level of clinical severity, are corroborated by the findings on muscle MRI analysis

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[Fischer et al., 2005]. This pattern is very similar to that of LGMD2A (calpain-3 deficiency) but distinct from dysferlinopathies, sarcoglycanopathies, and dystrophinopathies. In LGMD2I, marked hyperintense signal changes on T1weighted images can be seen in the adductor and posterior thigh muscles that clearly exceed the changes in the abductor and anterior thigh muscles. Hypertrophy of the gracilis and sartorius muscle seems to be a frequent finding. Furthermore, the degree of signal abnormalities in affected muscles mirrors the degree of muscle weakness in individual patients [Fischer et al., 2005].

Management There is no specific treatment for this disorder, and its management does not differ from other muscular dystrophies. There is no evidence of a response to steroids or other pharmacologic treatments. Cardiac and respiratory function need to be evaluated at diagnosis, with follow-up frequency determined from the baseline measurements and clinical evolution.

Limb-Girdle Muscular Dystrophy 1A, 2G, and 2J: Sarcomeric Protein Deficiencies Limb-Girdle Muscular Dystrophy 1A (Myotilinopathy) LGMD1A was the first autosomal-dominant limb-girdle dystrophy to be linked to a specific gene locus. Initial clinical observations of the co-segregating of two rare diseases, muscular dystrophy and Pelger-Huët syndrome [Schneiderman et al., 1969], in a kindred were followed years later by linkage studies localizing the gene to chromosome region 5q31-q33 [Yamaoka et al., 1994] and the discovery of the first of several missense mutations in the gene coding for the sarcomeric protein myotilin [Hauser et al., 2002]. Myotilin localizes to the Z-disk and interacts with αactinin and F-actin, efficiently cross-linking thin filaments. This protein also interacts with other filaments, including filamin C. In vitro studies suggest that the expression of myotilin in muscle cells is tightly regulated to become active in the later stages of in vitro myofibrillogenesis, when preassembled myofibrils begin to align. Thus, myotilin appears to have an indispensable role in stabilization and anchorage of the thin filaments that may be needed for correct Z-disk orientation [Salmikangas et al., 2003]. The mutations observed in LGMD1A do not disrupt binding of myotilin to α-actinin but result in Z-disk streaming. Myotilin has been implicated in other diseases, including a causal role in some cases of myofibrillar myopathy [Selcen and Engel, 2004; Selcen et al., 2004] and a secondary role in central core disease and nemaline myopathy [Schroder et al., 2003]. Missense mutations underlie the pathophysiology in the initially reported family and the seven additional families expressing this disorder. Patients in the initial kindred had symptoms of proximal weakness in young adulthood, with a mean age at onset of 27 [Hauser et al., 2000]. A suggestion of anticipation has been reported with a reduction in age at onset by 13 years from one generation to the next, an observation uncommon in diseases not caused by nucleotide

repeat expansions. About half of patients with LGMD1A develop nasal dysarthria. Ankle contractures are common. Progression of the disease is slow, and ambulation is maintained for decades. Creatine kinase level elevations from 2to 10-fold are common. Electrodiagnostic study findings are consistent with a myonecrotic myopathy. Cardiac involvement occurs in about half of the patients but is rarely debilitating. Muscle biopsies reveal Z-line streaming, muscle fiber degeneration, fiber splitting, and central nucleation. Rimmed autophagic vacuoles are reported [Hauser et al., 2002]. Establishing the diagnosis in new patients is challenging. Immunostaining of myotilin is normal. A history of slowly progressive limb-girdle weakness with a family history consistent with autosomal-dominant transmission may be obtained, but the incidence of spontaneous mutation is unknown. The findings of heel cord contracture, nasal dysarthria, mild-to-moderate elevation of creatine kinase level, and muscle biopsy findings of Z-line streaming and autophagic vacuoles should increase clinical suspicion. Mutation analysis of the myotilin gene is needed for a definitive diagnosis.

Limb-Girdle Muscular Dystrophy 2G (Telethonin) Telethonin is a small 19-kDa sarcomeric protein expressed in skeletal and cardiac muscle [Valle et al., 1997]. Its gene maps to chromosome region 17q11-q12, the candidate site to which samples from members of a Brazilian family with an early-onset LGMD phenotype had mapped [Moreira et al., 1997]. Subsequent studies of this and three other Brazilian families confirmed mutations of the telethonin gene [Moreira et al., 2000]. Telethonin has been implicated in myofibrillar assembly [Mason et al., 1999]. It is phosphorylated by the serine kinase domain of titin and may serve to cap titin in the Z-disk [Knoll et al., 2002]; telethonin is also known as T-CAP. Patients with telethonin mutations have not been recognized outside Brazil. The onset of symptoms has occurred between 9 and 15 years of age. Weakness is mainly proximal, but of the 13 patients described, 7 had prominent distal weakness with lower extremity atrophy and footdrop. Paradoxically, six patients evidenced calf hypertrophy. Only one patient has remained independently ambulatory after age 43. Five of 9 of these original 13 patients studied for cardiac abnormality had mild cardiomyopathy. Creatine kinase levels were elevated 3- to 30-fold in all patients early in their disease. Muscle biopsy revealed degenerating and regenerating muscle fibers and rimmed vacuoles (an unusual finding for LGMD but not for distal myopathy syndromes) [Moreira et al., 1997]. Patients can be screened with immunohistochemical techniques through the use of antitelethonin antibodies. Mutation analysis is simplified because the telethonin gene contains only two exons.

Limb-Girdle Muscular Dystrophy 2J (Titin) Titin is a giant structural protein of the sarcomere with a molecular weight of over 3800 kDa. It is the largest human protein and forms the third filament system in striated muscle along with actin and myosin. Single titin molecules

Escolar and Leshner / Muscular Dystrophies

span half sarcomeres from Z-disks to M-lines in skeletal and cardiac muscle. Titin contributes to sarcomere assembly and passive tension of myofibrils and serves sensor and signaling functions [Granzier and Labeit, 2004; McElhinny et al., 2004]. Titin serine kinase phosphorylates telethonin, another sarcomeric protein that is implicated in LGMD2G. Mutations in the titin gene on chromosome 2q31 most often produce autosomal-dominant tibial muscular dystrophy, a distal muscular dystrophy of mid-adult life with prominent involvement of the tibialis anterior and toe extensor muscles [Hackman et al., 2002]. This disorder is most commonly seen in persons of Finnish descent. Patients with mutations causing truncated titins have autosomaldominant familial dilated cardiomyopathy without skeletal muscle disease [Gerull et al., 2002]. Homozygous mutations have produced an adult-onset limb-girdle disorder, LGMD2J [Hackman et al., 2003]. Severe calpain-3 deficiency is seen in patients with LGMD2J and may be an important downstream pathway [Haravuori et al., 2001]. A review of 207 patients heterozygous for the specific C-terminal M-line titin mutation illustrated variability of clinical expression, including one child with infantile-onset generalized weakness and one with onset of a LGMD phenotype at age 6 [Udd et al., 2005].

X-LINKED SYNDROMES McLeod’s cardiomyopathy is a dilated cardiomyopathy with limited findings for myopathy linked to chromosome Xp21.1 as a recessive condition involving Kx membrane transport protein. Muscle weakness is mild. Central nervous system involvement includes chorea, seizures, and cerebral and caudate nucleus atrophy [Malandrini et al., 1994]. Acanthocytosis is present, and erythrocytes have abnormal expression of Kell blood group and Kx surface antigens. Creatine kinase levels tend to be high. Another X-linked dilated cardiomyopathy, known as Barth’s syndrome, is linked to chromosome Xp28. Tafazzin protein, which belongs to a superfamily with acyl transferases involved in phospholipid synthesis, is abnormal. Onset occurs in infancy. Motor development is delayed. Recurrent neutropenia and early infections, including pyodermia, are present. Ventricular hypertrophy with endocardial fibroelastosis is present. The creatine kinase level is normal. Muscle is mildly myopathic. In the endocardium, abnormal mitochondria are found with concentric cristae. Urinary organic acids 3-methylglutaconic acid, 3-methylglutarate, and 2-ethylacrylic acid are excreted. Early death in childhood from cardiac failure or sepsis may happen. Other patients exhibit gradual improvement in cardiac funcion, motor development, and resolving infections. X-linked vacuolar myopathy is expressed pathologically with excessive autophagic vacuoles and granular material in the basement membrane. It is located on chromosome Xq28 near the Emery-Dreifuss locus as a recessive condition. Onset occurs in early childhood with weakness proximally and at the ankles. Progression of the disease is slow. The creatine kinase level is elevated 2 to 10 times normal.

1995

EMERY-DREIFUSS MUSCULAR DYSTROPHY Overview Emery-Dreifuss muscular dystrophy was recognized as a distinct phenotype in the mid-1960s [Emery and Dreifuss, 1966]. Emery-Dreifuss muscular dystrophy is characterized by a clinical triad of early contractures, muscle wasting and weakness in a humeroperoneal distribution, and cardiomyopathy. Considerable phenotypic variability exists regarding age at onset and rate of progression. X-linked transmission and autosomal-dominant transmission are recognized.

Molecular Biology Both X-linked and autosomal-dominant Emery-Dreifuss muscular dystrophy result from mutations in genes coding for nuclear envelop proteins. The X-linked form of EmeryDreifuss muscular dystrophy is caused by mutations of the STA gene located at Xq28 which encodes a 34-kDa ubiquitously expressed nuclear envelop protein, emerin [Bione et al., 1994]. Of mutations producing X-linked EmeryDreifuss muscular dystrophy, 95% are null mutations associated with a complete absence of emerin in skeletal muscle, as well as in smooth muscle, skin fibroblasts, leukocytes, and exfoliative buccal cells. A mosaic pattern is seen in female carriers, and the diagnosis of X-linked EmeryDreifuss muscular dystrophy in males and identification of female heterozygotes is therefore possible with immunohistochemical studies of muscle and more easily accessed tissue [Emery, 2000; Manilal et al., 1997]. Autosomal-dominant Emery-Dreifuss muscular dystrophy and autosomal-recessive Emery-Dreifuss muscular dystrophy (a single reported case [Raffaele Di Barletta et al., 2000]) result from mutations of the LMNA gene located on 1q21, which encodes two nuclear envelope proteins, lamins A and C [Bonne et al., 1999]. Lamins A and C are alternatively spliced products of the same gene and constitute part of the nuclear lamina; they interact with chromatin and other proteins of the inner nuclear membrane, including emerin [Gruenbaum et al., 2003]. Mutations of the lamins A and C genes that produce the autosomal-dominant EmeryDreifuss muscular dystrophy phenotype are missense mutations that allow translation of full-length lamins A and C. Immunostaining of lamins A and C is therefore not reliable for confirmation of the diagnosis of autosomal-dominant Emery-Dreifuss muscular dystrophy [Emery, 2000]. The diagnosis of lamin A or C disorders requires DNA sequencing or mutation scanning [Bonne et al., 2000, 2003; Brown et al., 2001]. The Emery-Dreifuss muscular dystrophy phenotype and its variants have focused attention on the importance of nuclear envelope proteins [Nagano and Arahata, 2000], but the pathophysiologic mechanisms of the diseases remain conjectural.

Clinical Features Although X-linked Emery-Dreifuss muscular dystrophy and autosomal-dominant Emery-Dreifuss muscular dystrophy usually share a similar phenotype, wide clinical variation with poor genotype-phenotype correlation has been documented in both X-linked Emery-Dreifuss muscular dystrophy and

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autosomal-dominant Emery-Dreifuss muscular dystrophy [Bonne et al., 2000; Fujimoto et al., 1999; Muntoni et al., 1998]. Inter- and intrafamilial phenotypic variability may exist in patients sharing identical mutations. The onset of contractures occurs early in the disease, in the first or second decade, and often precedes clinically significant weakness. Contractures are most prominent at the elbows, Achilles tendons, and posterior cervical muscles [Emery, 1989] (Figs. 79-10 and 79-11). Upper extremity contractures often precede axial and lower extremity deformities. The arms are held in a semiflexed position (Fig. 79-12). The feet are set in talipes equinus, often in association with toe walking. Posterior cervical contractures preclude full neck flexion (Fig. 79-13; see also Fig. 79-11). Contractures usually remain disproportionate to the degree of weakness [Emery, 2000] and may be the major factor in functional impairment. Muscle weakness is relatively mild and slowly progressive. The distribution of motor deficits is humeroperoneal with upper extremity weakness (in biceps, triceps, and spinatus muscles)

A

FIGURE 79-10. Sixteen-year-old male with X-linked Emery-Dreifuss muscular dystrophy. This male exhibits significant humeral atrophy, elbow flexion contractures, and neck hyperextension secondary to neck extensor contractures. Facial muscles are spared.

B FIGURE 79-12. Seven-year-old male with autosomal-dominant Emery-Dreifuss muscular dystrophy. The presenting symptom was mild weakness; however, elbow flexor contractures (A) and mild neck extension contractures (B) were obvious on examination, as depicted in this photograph.

FIGURE 79-11. Same male with X-linked Emery-Dreifuss muscular dystrophy. Significant neck extensor contractures severely limit neck flexion.

occurring earlier than leg weakness (in tibialis anterior and peroneal muscles). Pseudohypertrophy is not seen, and its absence helps clinically differentiate X-linked Emery-Dreifuss muscular dystrophy from dystrophinopathy (Becker muscular dystrophy). Cardiac symptoms may include palpitations, syncope, and diminished exercise tolerance. Supraventricular dysrhyth-

Escolar and Leshner / Muscular Dystrophies

mias, atrioventricular conduction block, ventricular dysrhythmias, and restrictive or dilated cardiomyopathy may evolve. The risk of ventricular dysfunction and dysrhythmias is greater in autosomal-dominant than in X-linked Emery-Dreifuss muscular dystrophy [Becane et al., 2000; Bonne et al., 2003], but symptomatic cardiomyopathy may occur in women heterozygous for null emerin mutations. Cardiac symptoms usually evolve after the second decade. Phenotypic variability in emerin deficiency relates to the age at onset and disease progression in X-linked EmeryDreifuss muscular dystrophy. A broad spectrum of phenotypes has been discovered for mutations of the lamin A or C gene. Skeletal and cardiac myopathy without early contracures characterizes autosomal-dominant LGMD1B (see Fig. 79-13). Disorders of peripheral nerve, including an autosomal-recessive axonal form of Charcot-Marie-Tooth syndrome (type 2B1) and an autosomal-dominant peripheral neuropathy, are seen in other lamin A or C mutations [De Sandre-Giovannoli et al., 2002]. Dunnigan-type familial partial lipodystrophy [Shackleton et al., 2000] and generalized lipoatrophy with insulin resistance [Caux et al., 2003] have been reported. Autosomal-dominant Hutchinson-Gilford progeria [De Sandre-Giovannoli et al., 2003] and atypical Werner’s syndrome [Chen et al., 2003] are more recent additions to the spectrum of laminopathies.

Management Treatment is largely based on symptoms. The high incidence of cardiac dysfunction mandates early and regular cardiology evaluations. Mothers and sisters of males with X-linked Emery-Dreifuss muscular dystrophy should also receive cardiology consultation. Orthopedic interventions may be helpful in addressing limb contractures. In the late stage of Emery-Dreifuss muscular dystrophy, respiratory aids, including cough-assistive devices and noninvasive nocturnal respiratory support, may be helpful.

FIGURE 79-13. Mother of the male in Figure 79-12. She was asymptomatic, and her condition was undiagnosed; however, her neck extensor contractures are obvious, as depicted in this picture of her attempting to flex her neck.

1997

FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY Overview Facioscapulohumeral muscular dystrophy was described by Landouzy and Dejerine in 1885. This disease is inherited as an autosomal-dominant disorder with high penetrance and variable expression. Ten percent to 30% of cases represent new mutations [Zatz et al., 1995]. Prevalence is estimated at 1 per 20,000. Clinical signs and symptoms are usually present before age 20 years and are manifested by weakness of the facial muscles, fixators of the scapula, and dorsiflexors of the ankle. Severity is highly variable. Although skeletal muscle symptoms dominate the clinical picture, other systems are often involved, which implies a more widespread developmental/degenerative process.

Molecular Genetics Facioscapulohumeral muscular dystrophy maps to chromosome 4q35 [Wijmenga et al., 1993]. More than 95% of patients with facioscapulohumeral muscular dystrophy have a reduced number of 3.3-kilobase tandem repeat sequences termed D4Z4. The D4Z4 repeat region lies within a region of telomeric heterochromatin. There is no known gene within or telomeric to the D4Z4 repeat region, and the molecular biology underlining skeletal muscle and systemic abnormalities remains conjectural. An inverse correlation exists between the D4Z4 size and disease severity [Zatz et al., 1995]. Abnormal restriction enzyme EcoRI fragments are 34 kilobases or smaller (i.e., fewer than 10 repeats) [Upadhyaya et al., 1997]. The largest deletions have been associated with severe, congenital-onset facioscapulohumeral muscular dystrophy [Brouwer et al., 1994, 1995]. A large deletion with a 10- to 13-kilobase remaining DNA fragment usually produces symptoms by 16 years of age, and these may be severe. In some instances, this may be a new mutation. An intermediate deletion with a remaining DNA fragment greater than 16 kilobases is associated with large families expressing the dominantly inherited condition beginning between ages 8 and 22 years. Small deletions are usually found in kindreds with disease of later onset, usually from 15 to 23 years. In these families, a few individuals carrying the small deletion phenotypically appear normal, which is suggestive of nonpenetrance. Possible mechanisms by which truncation of the D4Z4 repeat sequences produces facioscapulohumeral muscular dystrophy include altered interactions with transcription factors or chromatin modifiers at the nuclear envelope. Shortening of the D4Z4 repeat sequence may also allow position effect variegation (a change in the expression of a gene adjacent to heterochromatin) [Winokur et al., 1994]. The possibility of de-repression of silent genes or pathologic maintenance of genes in a transcriptionally active state after expression should have been downregulated is supported by studies demonstrating upregulation of the expression of genes that lie immediately upstream of the D4Z4 repeats [Tsien et al., 2001]. Commercially available testing of chromosome 4q35 is the most specific and sensitive diagnostic test for facioscapulohumeral muscular dystrophy. Subtelomeric translocations between chromosomes 4q35 and 10q26 occur

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relatively frequently in the general population and may complicate molecular diagnosis. A D4Z4 deletion results in disease if the deletion occurs on chromosome 4, but deletions on chromosome 10 have no clinical significance. Detection of a deletion in an individual with a 4;10 translocation must be interpreted with caution [van der Maarel et al., 1999; van Deutekom et al., 1996]. In 5% of facioscapulohumeral muscular dystrophy patients a 4q35 deletion is not identified, which suggests that at least one additional genetic disorder, designated facioscapulohumeral muscular dystrophy 1B, produces the facioscapulohumeral muscular dystrophy phenotype [Yamanaka et al., 2004].

ogy of the footdrop. Axial paraspinal muscle weakness may result in marked lumbar lordosis, especially in patients with childhood-onset facioscapulohumeral muscular dystrophy. Motor deficits are slowly progressive. Some patients report long periods of clinical stability punctuated by abrupt stepwise loss of power in restricted muscle groups. Asymmetry of weakness and muscle atrophy is the rule and may be striking. Most patients remain functionally independent throughout life. About 20% of facioscapulohumeral mus-

Clinical Features Clinical diagnostic criteria have been established by the facioscapulohumeral muscular dystrophy consortium [Tawil et al., 1998]. They specify autosomal-dominant inheritance; bifacial weakness; and weakness of the scapular stabilizer muscles, ankle dorsiflexor muscles, or both. Supporting criteria include asymmetry of motor deficits (a finding far more common in facioscapulohumeral muscular dystrophy than any other muscular dystrophy); sparing of deltoid, neck flexor, and calf muscles; and involvement of wrist extensors and abdominal muscles. Hearing loss involving high frequencies and retinal vasculopathy (Coats’ disease) are additional supportive findings. Exclusion criteria include eyelid ptosis, extraocular muscle weakness, skin rash, elbow contractures, cardiomyopathy, sensory loss, neurogenic changes documented in muscle biopsy, and myotonia or neurogenic motor unit potentials documented on needle electromyography. Weakness is usually first appreciated in the facial muscles. Patients have difficulty with puckering the lips, whistling, sipping through a straw, or blowing up balloons because of weakness of the orbicularis oris muscle. Most patients have a transverse smile and limited facial expression. Weakness of the orbicularis oculi is usually asymptomatic, but the examiner can appreciate it by observing incomplete burying of the eyelashes with forced eyelid closure and the ease with which the closed eyelids can be pried apart. A history of sleeping with the eyes open may be offered by a parent or spouse. Facial weakness may not be symmetric (Figs. 79-14 and 79-15). Weakness of scapular fixation is evidenced by scapular winging accentuated by arm elevation in a forward plane (Fig. 79-16). The scapulae ride high on the back, producing the illusion of hypertrophied trapezius muscles (Fig. 79-17). Arm abduction is impaired in the presence of normal power and bulk of the deltoid muscles. Wasting of the biceps and triceps with preservation of deltoid and forearm muscles yields a “Popeye” configuration to the arms. Wasting of the clavicular head of the pectoral muscles produces a reversal of the axillary folds with a deep upward slope. Weakness of lower abdominal muscles may result in a “potbelly” when standing and a positive Beevor sign (cephalad movement of the umbilicus with neck flexion) when the patient lies supine. Lower extremity weakness is usually first evident in the ankle dorsiflexors, with compromised heel walking or overt footdrop. Atrophy is most prominent in the tibialis anterior muscle. Preservation or hypertrophy of the extensor digitorum brevis muscle clinically excludes a neurogenic etiol-

FIGURE 79-14. Marked facial weakness of this patient with facioscapulohumeral muscular dystrophy leads to a smooth, unlined, relatively inanimate face. The patient is attempting to blow her cheeks outward without success.

FIGURE 79-15. Marked facial weakness in patient with facioscapulohumeral muscular dystrophy, manifesting with asymmetric orbicularis oculi weakness and incomplete eyelid closure (inability to bury the eyelashes).

Escolar and Leshner / Muscular Dystrophies

cular dystrophy patients (usually those with early disease onset) eventually require a wheelchair. Life expectancy is normal. Men appear to be more severely affected than women, and greater penetrance of the disorder has been documented in male patients [Zatz et al., 1998]. Sensorineural hearing loss is frequently documented, especially in children presenting before 10 years of age [Takeya et al., 1990; Voit et al., 1986] but can often be asymptomatic.

1999

Retinal vasculopathy with telangiectasia and retinal detachment (Coats’ disease) may develop [Fitzsimons et al., 1987; Gurwin et al., 1985; Padberg et al., 1995]; regular ophthalmology evaluations are warranted. Congenital onset of facioscapulohumeral muscular dystrophy has been associated with mental retardation and epilepsy in children with the largest D4Z4 deletions (EcoRI fragment size of 10 kilobases; i.e., fewer than 10 repeats). The congenital-onset, or infantile, phenotype is severe and rapidly progressive, accompanied by sensorineural hearing loss and Coats’ disease [Fitzsimons et al., 1987; Small, 1968; Taylor et al., 1982]. Marked shoulder and pelvic girdle weakness is present before 6 years of age, with loss of ambulation by 15 years. The condition may be mistaken for Möbius’ syndrome. Profound weakness of facial, including extraocular, muscles is typical (Fig. 79-18).

Laboratory Findings Creatine kinase determinations are either normal or slightly elevated; creatine kinase levels exceeding five times the laboratory norms are suggestive of an alternative diagnosis. Genetic testing has largely replaced electrodiagnostic and muscle biopsy evaluations in persons with suspected facioscapulohumeral muscular dystrophy. Electromyographic studies of moderately weak muscles reveal brief, lowamplitude motor unit potentials consistent with myopathy; sparse fibrillations reflecting muscle fiber necrosis are also present. However, the needle electromyographic examination may be normal in clinically powerful muscles. Neurogenic motor units are virtually never seen and, if present, should raise the possibility of another disorder, such as

FIGURE 79-16. Patient with facioscapulohumeral muscular dystrophy exhibits extreme wasting of the muscles responsible for scapular stabilization.

FIGURE 79-17. Patient with facioscapulohumeral muscular dystrophy exhibits scapular high-riding on the back as a consequence of abnormal scapular fixation, giving the appearance of hypertrophied trapezius muscles.

FIGURE 79-18. The early-onset or infantile form of facioscapulohumeral muscular dystrophy, manifesting with incomplete eyelid closure and lack of facial expression.

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X-linked spinal and bulbar muscular atrophy. Muscle biopsy findings are often nonspecific, with occasional small angular fibers, necrotic fibers, and regenerating fibers. A modest increase in the percentage of hypertrophy type II muscle fibers may be seen. Foci of inflammatory cells in a perivascular or endomysial distribution are commonly encountered and on occasion may lead to a pathologic misdiagnosis of polymyositis [Rothstein et al., 1971].

Treatment There is no definitive treatment for facioscapulohumeral muscular dystrophy. Results of therapeutic trials of corticosteroids [Rose and Tawil, 2004] and the β-adrenergic agonist albuterol [Kissel et al., 2001] have been disappointing. A larger trial of albuterol is currently in progress. Footdrop is best managed with ankle-foot orthoses. Orthopedic scapular fixation may improve upper extremity function [Bunch and Siegel, 1993; Twyman et al., 1996] but the gain may be short-lived. Muscle strengthening exercises may be of some benefit for preserving power in relatively unaffected muscle groups. Severe weakness of the orbicularis oculi may predispose to corneal injury; artificial tears can be helpful.

OCULOPHARYNGEAL MUSCULAR DYSTROPHY The earliest description of oculopharyngeal muscular dystrophy is credited to Taylor [1915], who described the combination of ptosis and pharyngeal palsy, key findings of the disorder, in related family members. Oculopharyngeal muscular dystrophy typically manifests after 50 years of age [Brais et al., 1995]. Many affected individuals of FrenchCanadian descent are traced to a single ancestor from France [Barbeau, 1966]. Oculopharyngeal muscular dystrophy is recognized in the fourth to sixth decades by onset of ptosis, partial extraocular muscle paresis, dysphagia, and tongue weakness. Weakness of the proximal upper and lower extremity muscles slowly develops. The creatine kinase level may be normal or mildly elevated. Progressive oculopharyngeal dysfunction is described in Greek siblings, aged 11 and 14 years, both of whom had rimmed vacuoles; one was found to have cytoplasmic and intranuclear tubulofilamentous inclusions 25 nm in diameter on muscle biopsy [Rose et al., 1997]. Another childhoodonset oculopharyngeal syndrome manifested with intestinal pseudo-obstruction [Amato et al., 1995]. These may be examples of recessively inherited conditions similar to dominantly inherited oculopharyngeal muscular dystrophy. Progressive ophthalmoplegia in a child should be interpreted with caution. Most likely, this is secondary to a mitochondrial disorder, rather than a muscular dystrophy [Rowland et al., 1997].

tractures. Signs and symptoms are evident in the neonatal period or the first few months of life. Serum creatine kinase levels are usually elevated. Muscle biopsy abnormalities suggestive of a myopathic or dystrophic process, including variation in muscle fiber size, necrotic and regenerating fibers, and an increase in endomysial connective tissue, establish a working diagnosis of congenital muscular dystrophy (Fig. 79-19). Delineation of a precise diagnosis requires integration of muscle and systemic findings, immunostaining or Western blot of extracellular proteins, and DNA testing when available. The congenital muscular dystrophy syndromes are divided into those associated with brain and eye malformations (syndromic congenital muscular dystrophy) and those without (nonsyndromic or “classic” congenital muscular dystrophy). Within this broad classification, considerable phenotypic variation exists, and clinical differences may be more quantitative than qualitative. However, evidence supports genetically distinct bases for the different congenital muscular dystrophy subgroups. The summed incidence of all forms of congenital muscular dystrophy is approximately 1 per 21,500 [Mostacciuolo et al., 1996].

Nonsyndromic (Classic) Congenital Muscular Dystrophy Merosin-Negative Congenital Muscular Dystrophy Merosin-negative congenital muscular dystrophy (MDC1A) is the most common of the congenital muscular dystrophy disorders and accounts for about 50% of cases of nonsyndromic congenital muscular dystrophy (Table 79-3). Patients with complete absence of merosin present as hypotonic infants. Limb weakness is usually more prominent than bulbar or respiratory impairment, but feeding difficulties including aspiration [Philpot et al., 1999], and ventilatory insufficiency necessitating respiratory support may occur [Fardeau et al., 1996]. Most patients achieve independent sitting, but few stand or walk unassisted. Multiple

CONGENITAL MUSCULAR DYSTROPHY The congenital muscular dystrophies are a heterogeneous group of autosomal-recessive disorders characterized by hypotonia, weakness, and variable degrees of muscle con-

FIGURE 79-19. Muscle biopsy from an infant with congenital muscular dystrophy. Note the fiber size variation, muscle necrosis (arrow), and regenerating fibers (arrowheads) surrounded by increased endomysial connective tissue. (Hematoxylin and eosin staining; ×300.)

Escolar and Leshner / Muscular Dystrophies

2001

TABLE 79-3 Nonsyndromic (Classic) Congenital Muscular Dystrophies (CMDs) DISEASE

GENE LOCUS

PROTEIN PRODUCT

TESTING

CMD with complete merosin deficiency (MDC1A) CMD with secondary merosin deficiency (MDC1B) CMD type 1C (MCD1C) CMD with integrin α7 mutations CMD with early rigid spine Ullrich’s CMD with collagen 6 mutations

6q22-q23 LAMA2 (merosin gene) 1q42

Laminin α2 chain (merosin)

Immunostaining

Unknown

—

Fukutin-related protein Integrin α7 SEPN1 (Selenoprotein) COL6A1, COL6A2, COL6A3

DNA testing available Research Research Research

19q13.3 12q13 1p36-p35 21q22.3 2q37

joint contractures may be present at birth or develop in infancy or early childhood. Weakness tends to be stable or slowly progressive (Fig. 79-20). Most patients exhibit normal brain structure and cognitive development. Focal cortical dysplasia of the occipital lobes occurs in some cases with concurrent intellectual impairment [Taratuto et al., 1999], but the extensive neuronal migration abnormalities characteristic of patients with syndromic congenital muscular dystrophy is not seen. Epilepsy occurs frequently even in patients with normal intellect [Pegoraro et al., 1998]. Virtually all merosin-negative congenital muscular dystrophy patients have characteristic white matter lesions on MRI scans most prominent on T2-weighted images.

FIGURE 79-20. A 3-year-old male with congenital muscular dystrophy getting up from a sitting position by using a modified Gowers maneuver. Note the generalized, proximal weakness, which is greater than distal weakness.

These findings may not be evident at birth but invariably develop by age 6 months. White matter abnormalities involve the centrum semiovale and spare the corpus callosum, internal capsule, cerebellum, and brainstem [Caro et al., 1999]. The MRI findings are consistent with abnormal water distribution in the white matter that results from disruption of the blood-brain barrier secondary to merosin deficiency in cerebral vasculature [Villanova et al., 1997]. Serum creatine kinase levels are usually elevated in the neonatal period in excess of 1000 U/liter but tend to decrease over years. Electrodiagnostic studies yield nonspecific myopathic findings on needle electromyography. Nerve conduction studies reveal slowing of conduction velocity, which is consistent with demyelinating polyneuropathy [Gilhuis et al., 2002]. Muscle biopsy samples demonstrate changes consistent with a dystrophic process, including adipose tissue replacement and connective tissue proliferation. In addition, inflammatory changes may be striking enough to suggest a diagnosis of infantile polymyositis [Pegoraro et al., 1996]. Merosin is the heavy α2 chain of laminin 2 (LAMA2). The laminins are heterotrimeric proteins that influence cell adhesion, growth, and migration. LAMA2 is expressed in the basement membrane of muscle fibers, Schwann cells of intramuscular nerves and at neuromuscular junctions. LAMA2 promotes myotube stability and inhibits apoptosis [Vachon et al., 1996]. Absence of immunohistochemical staining for the laminin α2 chain on snap frozen muscle biopsy tissue provides confirmation of the diagnosis of merosin deficiency. The merosin (LAMA2) gene located on chromosome 6q22 contains 64 exons with mutations distributed through a large coding sequence of 9.5 kilobases, which makes routine mutation screening impractical at present. Partial merosin deficiency has been reported in rare patients with a benign childhood- or adult-onset LGMD phenotype [Allamand et al., 1997]; routine immunohistochemical staining for LAMA2 is therefore suggested in evaluating patients with both congenital muscular dystrophy and LGMD phenotypes. Prenatal diagnosis of merosin-deficient congenital muscular dystrophy is possible by direct mutation analysis of chorionic villus biopsy material, but because of the lack of predictable hot spots of mutation, linkage analysis is a more commonly used approach. Direct immunostaining of trophoblasts from chorionic villus samples with laminin α2 chain antibodies provides an additional method for prenatal diagnosis.

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Merosin-Positive, Nonsyndromic Congenital Muscular Dystrophies Patients with nonsyndromic congenital muscular dystrophy who express merosin are a heterogeneous group. A small percentage of patients have mutations of the LAMA2 gene and may present with an LGMD or mild congenital muscular dystrophy phenotype. The majority of patients with normal merosin expression or partial merosin deficiency presenting with a congenital muscular dystrophy phenotype have other genetic disorders that do not link to the region of chromosome 6q; their clinical course is similar to but usually milder than that of merosin-negative children. The distribution of weakness and contractures is comparable. Patients lack the cerebral white matter MRI abnormalities seen in merosin-negative patients.

Congenital Muscular Dystrophy Type 1C Caused by Fukutin-Related Protein Deficiency MDC1C usually manifests at birth or in the first few weeks of life with hypotonia and leg muscle hypertrophy. Creatine kinase values are greatly increased (1000 to 10,000 IU/liter). Children follow a regressive course that may include cardiomyopathy. Routine histochemical analysis of muscle biopsy specimens does not differentiate these patients from children with merosin-negative congenital muscular dystrophy. Immunohistochemical staining reveals partial merosin deficiency and severely reduced α-dystroglycan. In addition, reduced molecular weight of α-dystroglycan on Western blot indicates defective glycosylation, which is important in the pathophysiology of MDC1C. The genetic defect maps to chromosome 19q13.3 and the gene coding for fukutinrelated protein. The spectrum of this protein deficiency therefore includes the milder limb-girdle phenotype LGMD2I and a congenital muscular dystrophy phenotype [Brockington et al., 2001a, 2002]. DNA testing is commercially available.

Congenital Muscular Dystrophy with Integrin α7 Deficiency This rare disorder was discovered during analysis of muscle biopsy specimens from 117 patients with unclassified congenital myopathy and congenital muscular dystrophy phenotypes. Three patients evidenced integrin α7 deficiency on muscle immunohistochemistry profiles, which was correlated with three different mutations in the integrin α7 deficiency gene on chromosome 12q13 [Hayashi et al., 1998]. Another study of 210 patients with undefined myopathy indicates that secondary deficiencies of this type of congenital muscular dystrophy also occur, complicating the diagnostic significance of this protein [Pegoraro et al., 2002].

Congenital Muscular Dystrophy with Early Rigid Spine Syndrome Development of axial paraspinal muscle contractures produces the rigid spine syndrome in a number of congenital myopathies and muscular dystrophies including EmeryDreifuss muscular dystrophy. A distinct phenotype-genotype correlation was defined in consanguineous families of

Moroccan, Turkish, and Iranian descent [Moghadaszadeh et al., 2001]. The gene for rigid spine syndrome in these patients mapped to chromosome region 1p35-p46, coding for a selenoprotein (SEPN1) known to be expressed in skeletal muscle. In another American family presenting a phenotype of infantile hypotonia, prominent cervical muscle weakness, and early spinal rigidity and scoliosis, linkage to the chromosome 1p rigid spine syndrome locus was proved [Flanigan et al., 2000]. Restrictive lung disease often complicates rigid spine syndrome and mandates close observation for nocturnal hypoventilation and early institution of noninvasive respiratory support.

Ullrich’s Congenital Muscular Dystrophy and Bethlem’s Myopathy Ullrich’s congenital muscular dystrophy is characterized by infantile onset of weakness, hypotonia, and early findings of severe proximal joint contractures in the face of striking hyperlaxity of distal joints [Furukawa and Toyokura, 1977]. Other orthopedic findings may include congenital hip dislocation, prominent calcanei, and transient kyphosis. Progressive flexion contractures of the wrists, fingers, and ankles may replace distal limb laxity. The disease is slowly progressive. Although some youngsters acquire independent ambulation, weakness and orthopedic deformities lead to full-time wheelchair use. Involvement of chest wall and diaphragm muscles often necessitates nocturnal ventilatory assistance, but cardiac function is usually unaffected. Serum creatine kinase levels are usually normal or slightly elevated. Muscle biopsy samples demonstrate nonspecific myopathic or dystrophic changes of degenerating and regenerating muscle cells with increased endomysial connective tissue. Collagen 6 immunostaining of muscle basal lamina and endomysial connective tissue is severely reduced or absent [Higuchi et al., 2003]. Ullrich’s congenital muscular dystrophy is caused by autosomal-recessive mutations in any of three collagen genes [Vanegas et al., 2002; Zhang et al., 2002]. Collagen 6 is composed of three different α peptide chains. The α1 and α2 chains are encoded by two genes (COL6A1 and COL6A2) located head to tail at chromosome 21q22.3 [Heiskanen et al., 1995]. The gene for COL6A3 maps to locus 2q37. Collagen 6 is an extracellular matrix protein expressed in nearly all connective tissues. The phenotype of Ullrich’s congenital muscular dystrophy merges with that of Bethlem’s myopathy, originally described as a benign myopathy with autosomal dominant inheritance [Bethlem and Wijngaarden, 1976]. The clinical manifestation is far more variable than that of Ullrich’s congenital muscular dystrophy. The onset of signs and symptoms of proximal weakness is usually in early childhood, manifesting by difficulty climbing stairs and running. Gowers’ sign is often present. In more severe cases, findings may be present in the neonatal period with mild hypotonia, foot deformities, congenital torticollis, or arthrogryposis. Unlike the progressive contractures in Ullrich’s syndrome, the neonatal arthrogryposis seen in patients with Bethlem’s myopathy tends to improve spontaneously. Weakness is usually nonprogressive. However, contractures may develop late in the first decade, often localized to the ankles, elbow flexors

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and finger flexors. In other patients, the clinical presentation is delayed until the fourth decade. Dominant mutations in any of the collagen 6 genes may produce the Bethlem’s myopathy phenotype or a clinical picture of Ullrich’s congenital muscular dystrophy [Jobsis et al., 1999]. The family history is helpful in determining whether the disorder has been transmitted as an autosomal-dominant or -recessive trait, but de novo mutations and parental germline mosaicism may complicate this assessment. Immunostaining for collagen 6 is usually normal in Bethlem’s myopathy; therefore, DNA studies of the COL6A genes are necessary for definitive diagnosis [Lampe et al., 2005]. Management of Ullrich’s congenital muscular dystrophy and Bethlem’s myopathy is symptomatic. Aggressive physical therapy and surgical intervention address contractures. Severely affected children need active mobilization, and standing frames are often helpful. Nocturnal ventilatory support is often required [Wallgren-Pettersson et al., 2004]. The combination of restrictive lung disease and progressive orthopedic deformity in severely affected children make the timing of surgical interventions critical.

Syndromic Congenital Muscular Dystrophy There are three clinically defined congenital muscular dystrophies (Table 79-4) with associated brain malformations. The genes and protein products of these disorders are involved in glycosylation of extracellular muscle and brain protein. All three diseases arise from mutations in known or putative glycosyltransferase enzymes and share a common feature of a hypoglycosylated form of α-dystroglycan in skeletal muscle. Brain pathology is characterized by neuronal migration past a defective glial limiting membrane into the subpial space, which produces a developmental anomaly termed the cobblestone complex. It is appreciated that deficiency of fukutin-related protein seen in MDC1C and LGMD2I does not result in pathologic neuronal migration.

Fukuyama’s Congenital Muscular Dystrophy Fukuyama’s congenital muscular dystrophy is one of the most common autosomal-recessive diseases and the second most common form of muscular dystrophy in Japan, where the carrier frequency is estimated at 1 per 90 [Toda et al., 2000]. The disease is uncommon outside of Japan. Hypotonia and generalized muscle weakness are usually present before 9 months of age, and 50% of affected infants manifest a poor suck and weak cry. Facial weakness and a tented upper lip are frequent findings. Calf hypertrophy is present in 50% of patients. Gross motor milestones are severely delayed. Affected children often achieve independent sitting but never gain independent ambulation. Contractures are not marked at birth but develop by 1 year of age and involve the

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hips, knees, ankles, and elbows. Mental retardation is often severe, with IQ scores ranging from 30 to 50. Seizures occur in 40% of affected children. Ocular abnormalities are common but not universal and include myopia, cataracts, optic disc pallor, and retinal detachment. Most children have a rapid deterioration in motor abilities after the age of 6 years, and death occurs in early adolescence. Laboratory studies reveal consistent elevations of creatine kinase levels. Electrodiagnostic studies reveal myopathic potentials on needle electromyography; nerve conduction velocities are normal. Brain imaging studies and postmortem studies reveal brain malformations, including polymicrogyria, pachygyria, and agyria of the cerebrum and cerebellum (type II cobblestone lissencephaly), with a lack of the normal lamination of the cerebral cortex. There is a paucity of cortical gyrations in the temporal and occipital regions. Fukuyama’s congenital muscular dystrophy is caused by mutations of chromosome 9q31 on the gene coding for fukutin, a protein localized to the basement membrane of muscle. The protein is also found in fetal but not in postnatal neurons. The most common mutation is a 3-kilobase retrotransposon, which is suggestive of a founder effect [Kobayashi et al., 1998]. Fukutin deficiency is associated with decreased immunostaining for α-dystroglycan and merosin with preservation of the dystrophin-related complex [Hayashi et al., 2001]

Muscle-Eye-Brain Disease Approximately 30 patients have been reported with this disorder, the majority from Finland. The clinical picture is dominated by neonatal hypotonia, profound developmental delay with psychomotor retardation, and ocular abnormalities. Affected children may attain independent ambulation by age 4 years. Some acquire limited language skills. Motor abilities decline late in the first decade in association with the development of contractures and spasticity. Visual failure is in the form of severe myopia, followed by retinal degeneration and cataracts. Seizures are common. Central nervous system dysgenesis includes cobblestone lissencephaly type II, frontal pachygyria, and occipital micropolygyria. There is severe disorganization of the cerebral and cerebellar cortices [Haltia et al., 1997]. The associated myopathy may be overshadowed by central nervous system and ocular abnormalities. However, creatine kinase levels are increased, especially after the first year of life, and electromyography studies indicate myopathic abnormalities. The muscle-eye-brain disease gene localizes to chromosome region 1p32-p34 [Cormand et al., 2001] and codes for loss of function mutations in O-mannose β1,2-N-acetylglucosaminyltransferase. DNA testing for at-risk families is available.

TABLE 79-4 Syndromic Congenital Muscular Dystrophies (CMDs) DISEASE

GENE LOCUS

PROTEIN PRODUCT

TESTING

Fukuyama’s CMD Muscle-eye-brain disease (POMGnT1) Walker-Warburg syndrome (POMT1)

9q31 1q32-34 9q34.1

Fukutin O-mannoside β1,2-N-acetylglucosaminyl-transferase O-mannosyltransferase 1

DNA testing available DNA testing available DNA testing available

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Walker-Warburg Syndrome Unlike Fukuyama’s congenital muscular dystrophy and muscle-eye-brain disease, Walker-Warburg syndrome does not have an ethnic predominance. The clinical stigmata are dominated by the most severe brain malformations seen in any congenital muscular dystrophy syndrome, including lissencephaly type II, hydrocephalus, occipital encephalocele, fusion of the cerebral hemispheres, absence of the corpus callosum, and hypoplasia of the cerebellum and brainstem. Ocular findings have included congenital cataracts, microphthalmia, buphthalmus, and Peter’s anomaly. At birth, affected children are blind, markedly hypotonic, and poor feeders. Myopathy is manifest by mild elevations of creatine kinase level and variable abnormalities on muscle biopsy samples. All affected infants manifest profound psychomotor retardation, and the median length of survival is only 4 months. Clinical similarities in muscle-eye-brain disease and Walker-Warburg syndrome cause debate as to whether they are separate entities or a spectrum of a single autosomal recessive disorder. Detection of a distinct gene locus on chromosome 9q34.1 coding for protein O-mannosyltransferase 1 in 6 of 30 patients with WalkerWarburg syndrome favors classifying this condition as a separate disease. Only limited DNA testing is available for at-risk families.

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CHAPTER 80

Congenital Myopathies Jonathan B. Strober

The congenital myopathies are a group of disorders characterized by their histopathologic findings on muscle biopsy. The discovery of this heterogeneous group grew out of the ability to investigate abnormal muscle by histochemical techniques introduced in the 1950s and 1960s [Jungbluth et al., 2003]. Since then, electron microscopy, proteomics, and genomics have expanded the understanding of these conditions, as well as complicated physicians’ ability to create a simple classification schema. The majority of these conditions manifest at or shortly after birth with hypotonia, static or nonprogressive muscle weakness, normal to decreased deep tendon reflexes, and delays in reaching milestones [Riggs et al., 2003; Taratuto, 2002]. They can also become manifest in late childhood or adulthood. Patients may have a mildly progressive course or may even be asymptomatic when presenting later in life [Riggs et al., 2003]. The serum creatine kinase level is typically normal or mildly elevated, and electromyography often reveals a myopathic pattern: namely, short, small-action potentials with rapid recruitment. A muscle biopsy is usually necessary to classify the condition and improve the clinician’s ability to prognosticate for the patient and family. The findings commonly seen in the biopsy include type I fiber predominance or hypotrophy, or both, with the absence of fiber necrosis and other evidence of chronic degeneration, such as endomysial fibrosis and fatty infiltration, findings typically seen in muscular dystrophies. Protein aggregation, often of defective proteins, then allows for final classification. Overall, there are no cures for these conditions, but supportive care is important for quality of life and longevity. The more common and better known congenital myopathies are central core disease, nemaline myopathy, and myotubular myopathy. These are discussed in this chapter, along with some of the rarer disorders that have been described.

CENTRAL CORE DISEASE Central core disease was the first congenital myopathy described by Magee and Shy [1956]. It was named from the round delineated areas, typically within type I muscle fibers, that are devoid of oxidative enzyme activity [Jungbluth et al., 2003; Quinlivan et al., 2003; Taratuto, 2002].

Clinical Features In addition to the hypotonia, muscle weakness (which typically affects the pelvic girdle), and developmental delay, children often present with skeletal deformities such as scoliosis, congenital hip dislocation, and pes cavus [Jungbluth et al.,

2003; Quinlivan et al., 2003; Taratuto, 2002]. Facial weakness can also be present, is usually mild, and may be seen only in the inability to bury the eyelashes completely [De Cauwer et al., 2002; Jungbluth et al., 2003]. It mainly manifests in infancy or early childhood, although it can appear later in life or even never. The weakness tends to be static or slowly progressive. Many patients are eventually able to walk, and some families may report muscle cramping [Jungbluth et al., 2003]. It is allelic with malignant hyperthermia [Quinlivan et al., 2003]. The serum creatine kinase level tends to be normal to mildly elevated.

Pathology Muscle biopsy specimens from patients with central core disease demonstrate type I fiber predominance, with cores seen in the center of many type 1 fibers that extend throughout a large part of the fiber’s length [Jungbluth et al., 2003; Taratuto, 2002]. The cores are most easily seen when stained with the nicotinamide adenine dinucleotide–tetrazolium reductase technique [Riggs et al., 2003]. The 1995 diagnostic criteria created by the European Neuromuscular Centre include the presence of cores, which are central, although they may be eccentric or multiple, and well demarcated, visible with oxidative stains and affecting only type 1 fibers [De Cauwer et al., 2002]. Histologic diagnosis also requires distinctive electron microscopy and a type 1 fiber predominance. Corelike lesions can also be seen with denervation and are called targetoid lesions or targets if they are trilayered [Goebel, 2003]. Various proteins have been found to accumulate within cores (Table 80-1), and this often helps differentiate central core disease from mini-core disease, which is discussed later.

Genetics Central core disease is most commonly an autosomal-dominant condition with variable penetrance; however, sporadic cases have been reported [Jungbluth et al., 2003; Riggs et al., 2003; Taratuto, 2002]. It has been mapped to chromosome region 19q12-p13.1 [Fananapazir et al., 1993; Haan et al., 1990; Monnier et al., 2000; Tilgen, et al., 2001], which is also associated with malignant hyperthermia. This locus is linked to a ryanodine receptor (RYR1), which is a ligand-gated release channel for calcium [McCarthy et al., 2000], mediating calcium release after sarcolemma depolarization [Taratuto, 2002]. Mutations in this gene can give rise to malignant hyperthermia, central core disease, or both and account for almost 80% of cases of central core disease [Taratuto, 2002]. There are three regions on the RYR1 gene where mutations have been found. The majority of lesions are

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found in regions 1 and 2, which reside in the myoplasmic foot domain [Tilgen et al., 2001]. Mutations have more recently been reported in region 3, which is located in the highly conserved transmembrane C-terminal region. A mutation in this region has been found in a French family with a severe form of the disease with malignant hyperthermia and cores and rods in muscle fibers on biopsy [Monnier et al., 2000]. Central core disease has also been reported with hypertrophic cardiomyopathy, but not malignant hyperthermia, and found to result from a mutation in β-myosin heavy gene [Fananapazir et al., 1993].

MULTI-MINI-CORE DISEASE Multi-mini-core disease is histologically similar to central core disease; however, there are many significant differences. It was first described by Engel and associates in 1971 and is characterized by multiple small areas of sarcomeric disorganization lacking oxidative activity [Ferreiro and Fardeau, 2002].

Clinical Features There are four phenotypic groups identified, all of which are characterized by approximately normal creatine kinase levels, myopathic findings on electromyography, and no cardiac involvement [Ferreiro and Fardeau, 2002]. Patients typically present at birth or within the first 18 months of life. The classic form, or first group, manifests with severe neonatal hypotonia; predominant axial muscle weakness, especially in neck flexors; delayed motor development; severe scoliosis; and significant respiratory involvement. Its characteristics are similar to those of congenital muscular dystrophy with early rigidity of the spine (RSMD1) [Jungbluth et al., 2003]. Limb joint hyperlaxity and myopia have been found in many of the patients [Ferreiro and Fardeau, 2002; Taratuto, 2002]. The second group, or ophthalmoplegia form, consists of the typical findings plus variable ophthalmoplegia and often severe facial weakness. The third group manifests with early onset and arthrogryposis, and the fourth group is characterized by slow progression and hand amyotrophy.

Pathology There are several pathologic differences between central core and mini-core disease. In multi-mini-core disease, the lesions tend to have poorly defined boundaries and are short; thus, longitudinal muscle sections must be evaluated to help differentiate the two conditions. Mini-cores are found in both fiber types, as opposed to just type 1 fibers in central core disease [Ferreiro and Fardeau, 2002], and contain different proteins (see Table 80-1) [Goebel, 2003].

Genetics These disorders are mostly autosomal recessive, but many sporadic cases have been reported [Jungbluth et al., 2003]. Recessive mutations have been found in the RYR1 gene in patients with group 3 disease [Jungbluth et al., 2002] and in one family with distal weakness and amyotrophy [Ferreiro et al., 2002a]. Patients with the classic form have been found to have recessive mutations in the selenoprotein N gene

TABLE 80-1 Protein Accumulation in Core Disease Central Core Disease Actin α-Actin α1-antichymotrypsin β-Amyloid precursor protein β2-Microglobulin Caveolin Desmin Dysferlin Dystrophin

Gelsolin Myosin (slow) Neural cell adhesion molecule Nebulin Tau Tubulin Ubiquitin Utrophin Vimentin

Mini-Core Disease αB-crystallin Desmin γ-Filamin/filamin 2C Myozenin/calsarcin Telethonin Adapted from Goebel HH. Congenital myopathies at their molecular dawning. Muscle Nerve 2003;27:527.

[Ferreiro et al., 2002b] and in the RSMD1 gene [Moghadaszadeh et al., 2001]. Selenoprotein N is a glycoprotein found in the endoplasmic reticulum, expressed mostly in fetal tissues and in dividing cells [Petit et al., 2003].

NEMALINE MYOPATHY Nemaline myopathy was the second congenital myopathy to be reported. Its classification system has undergone a dramatic change as a result of advances in molecular genetics, and six different clinical forms can be identified [Goebel, 2003].

Clinical Features The severe congenital form manifests with no spontaneous movements or respirations at birth and may be associated with contractures and congenital fractures [WallgrenPettersson and Laing, 2000]. The fetal akinesia sequence has been reported to be associated with intrauterine onset [Lammens et al., 1997]. High-arched palate [Taratuto, 2002], cardiomyopathy, and ophthalmoplegia have also been associated with this form [Wallgren-Pettersson and Laing, 2000]. Children affected with the intermediate congenital type are able to breathe and move at birth, but during early childhood they become unable to breathe independently and typically cannot sit or walk [Wallgren-Pettersson and Laing, 2000]. Contractures tend to develop early. The typical form manifests in early childhood with proximal weakness, especially in neck flexors, in association with facial, bulbar, and respiratory weakness [Wallgren-Pettersson and Laing, 2000]. Distal involvement can occur later, but affected children are able to reach their milestones, albeit delayed, and have a slowly progressive or even nonprogressive course [WallgrenPettersson and Laing, 2000]. The mild childhood or juvenile form is similar to the classic form without facial weakness [Goebel, 2003]. There is also an adult-onset form and other, less common forms that may manifest with an unusual distribution of weakness [Wallgren-Pettersson and Laing, 2000].

Strober / Congenital Myopathies

Pathology Nemaline myopathy is histopathologically characterized through the use of the Gomori trichrome technique by red staining “rods” that are predominantly subsarcolemmal [Jungbluth et al., 2003], although they can be intermyofibrillar or intranuclear and are reactive to α-actin [Taratuto, 2002]. They are associated with the Z-disk and often are in continuity with the Z-lines [Jungbluth et al., 2003; Riggs et al., 2003]. They have a similar lattice structure and are composed of filaments. There is no correlation between the amount of rods seen and the severity of the condition [Jungbluth et al., 2003; Taratuto, 2002]. The rods can be seen solely in type I fibers or in both fiber types and measure 2 to 7 mm in length [Riggs et al., 2003]. These findings are typically in conjunction with type 1 fiber predominance or type 1 fiber hypotrophy, or both.

Genetics Currently, five filament encoding genes have been found to carry mutations. The rods have been found to be morphologically the same among all types [Goebel, 2003]. The most common mutations have been found in the α-actin and nebulin genes. α-Actin gene mutations, which account for 10% to 20% of cases [Taratuto, 2002], are frequently reported in the severe cases [Wallgren-Pettersson and Laing, 2001], although the presentation in patients with these mutations is heterogeneous [Agrawal et al., 2004]. Autosomal-dominant and -recessive forms have also been described [Nowak et al., 1999]. The α-actin gene is at chromosome 1q42.1 [Goebel, 2003; Taratuto, 2002], and most cases are sporadic [Agrawal et al., 2004]. Nebulin gene mutations have also been reported in the severe congenital form [Wallgren-Pettersson et al., 2002]. The nebulin gene is located on chromosome region 2q21.2-q22 [Pelin et al., 1999]. Mutations are usually recessive and are associated with the typical form [Jungbluth et al., 2003; Wallgren-Pettersson and Laing, 2003]. The first genetic locus to be reported in nemaline myopathy is in the slow α-tropomyosin gene, found on chromosome region 1q21-q23 [Laing et al., 1992, 1995]. It, along with β-tropomyosin, are actin-related skeletal muscle fiber proteins [Goebel, 2003]. α-Tropomyosin gene mutations [Laing et al., 1995] and, less frequently, β-tropomyosin gene mutations are located on 9p13.2-p13.1 [Donner et al., 2002] and have been reported in the mild form. The often fatal infantile autosomal-recessive type has been associated with a mutation in the troponin T1 gene on chromosome 19q13.4 in an Amish population [Johnston et al., 2000]. Troponins are a component of the actin filaments [Goebel, 2003]. Finally, an autosomal-dominant phenotype consisting of muscle slowness and proximal muscle weakness with associated corelike lesions on muscle biopsy was found in a Dutch family [Gommans et al., 2002] and has been linked to chromosome region 15q21-q23 [Gommans et al., 2003]. However, no disease-associated mutations in the αtropomyosin-1 gene, which is located within the critical region, could be found.

Management Nemaline myopathy is the only myopathy in this group with a possible treatment apart from supportive care. L-Tyrosine

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has been reported to improve certain clinical aspects of patients with this condition [Wallgren-Pettersson and Laing, 2003]. Tyrosine treatment appears to diminish drooling and increase appetite and physical activity level. These symptoms returned on cessation of the supplement and were again controlled with reinstituting the treatment. Tyrosine is a nonessential amino acid required in the synthesis of catecholamines, which possibly helps explain the benefits seen from supplementation. Several trials evaluating the benefits of tyrosine in patients with nemaline myopathy are currently in progress.

CENTRONUCLEAR/MYOTUBULAR MYOPATHY Myotubular (centronuclear) myopathy is likely the most severe of all the congenital myopathies, and the majority of cases are X-linked autosomal-recessive [Taratuto, 2002]. Pathologically, there are numerous centrally located nuclei in muscle fibers, which appear similar to the myotube, the immature stage of the muscle fiber [Goebel, 2003]. It is this appearance that led to the name myotubular myopathy [Spiro et al., 1966], and later centronuclear myopathy [Sher et al., 1967].

Clinical Features Respiratory failure typically leads to death within the first year of life [Taratuto, 2002] and often necessitates ventilatory dependence [Bertini et al., 2004]. Milder forms with the development of spontaneous breathing have been reported [Barth and Dubowitz, 1998]. Associated conditions include polyhydramnios, reduced to absent fetal movements, severe hypotonia, and limited extraocular movements [Jungbluth et al., 2003; Taratuto, 2002]. It appears to be a nonprogressive condition; however, affected infants do not exhibit progress in motor developmental milestones [Jungbluth et al., 2003]. Female carriers are usually asymptomatic [Taratuto, 2002], although they can develop early limb-girdle weakness with secondary kyphoscoliosis. Facial weakness and dysarthria can develop. These findings are more likely caused by an abnormal expression or distribution of myotubularin, the abnormal protein leading to this condition, rather than by X-inactivation [Sutton et al., 2001]. Other clinical courses have been described. Patients with onset during late infancy or childhood present with weakness that includes the extraocular muscles, hypotonia, and delayed achievement of milestones [Riggs et al., 2003]. Other patients present in adulthood with mild-to-moderate lower extremity weakness.

Pathology Muscle nuclei, which normally are peripherally placed, are found displaced centrally in a large number of muscle fibers in patients with this disorder. Perinuclear halos—areas with absence of myofilaments—often surround these central nuclei [Jungbluth et al., 2003]. As with the other myopathies in this category, type 1 fiber predominance is usually seen with type 1 fiber hypotrophy. Central nuclei can be seen in just type 1 fibers or in both fiber types [Riggs et al., 2003]. Although the disorder has been named after the similar

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appearance that muscle fibers seen on biopsy samples have to fetal myotubes, studies have demonstrated the presence of mature myofibrillar proteins [Jungbluth et al., 2003].

TABLE 80-2 More Common Causes of Fiber Size Disproportion Congenital myopathies Muscular dystrophies Mitochondrial myopathies Arthrogryposis multiplex congenita Peripheral neuropathies

Genetics The severe form of this disorder tends to arise from mutations in the myotubularin gene on chromosome Xq28 [Laporte et al., 1996] and likely accounts for up to 80% of X-linked cases [Laporte et al., 2000]. Myotubularin is a tyrosine phosphatase [Laporte et al., 1996] that dephosphorylates phosphatidylinositol-3-phosphate, a second messenger, and exerts its effects during myogenesis by regulating cellular levels of this lipid [Taylor et al., 2000]. Most mutations lead to absence or inactivation of myotubularin [Bertini et al., 2004]. Eight other forms of myotubularin have been reported [Goebel, 2003], and mutations in one have been found in patients with one of the demyelinating forms of Charcot-Marie-Tooth disease [Bolino et al., 2000; Houlden et al., 2001]. Autosomal-dominant forms, which tend to be milder and manifest later in life, and autosomal-recessive forms, with variable manifestation from mild generalized weakness with external ophthalmoplegia to early onset with severe proximal muscle weakness, have also been reported in myotubular myopathy [Jungbluth et al., 2003].

FIBER TYPE DISPROPORTION MYOPATHY Case reports of patients with presentations similar to the congenital myopathies and the finding of type 1 fibers being at least 12% smaller than type 2 fibers were published in the 1960s and 1970s [Clarke and North, 2003]. The term congenital fiber type disproportion was then coined by Brooke [1973]. However, since then, these pathologic findings have been reported in the other congenital myopathies and in myotonic dystrophy, other myopathies, neuropathies, and central nervous system disorders [Clarke and North, 2003; Imoto and Nonaka, 2001; Taratuto, 2002] (Table 80-2). This condition should therefore be diagnosed only through exclusion, if at all.

Clinical Features Overall, children with a diagnosis of this condition tend to have proximal and limb-girdle static weakness in association with myopathic facies and high-arched palate [Clarke and North, 2003]. Most cases have a mild-to-mod-

Spinal muscular atrophy Cerebral malformations Spinocerebellar degeneration Perinatal asphyxia Globoid cell leukodystrophy

Adapted from Clarke NF, North KN. Congenital fiber type disproportion—30 years on. J Neuropathol Exp Neurol 2003;62:977.

erate course, although severe cases have been reported. There is often a positive family history of this condition, but the disease can also be sporadic.

OTHER STRUCTURAL CONGENITAL MYOPATHIES Many other forms of congenital myopathy have been reported over the years as resulting from abnormal structural arrangements seen on biopsy (Table 80-3). Some have emerged as a result of the presence of intracytoplasmic inclusions or aggregates of filaments, whereas others have been characterized by vacuolated areas. As knowledge of the proteins involved in muscle structure and function increases, investigators have been able to determine the underlying etiology for some of these conditions. Cases of congenital myopathy with unusual inclusions previously reported include zebra bodies, which are a nonspecific finding in muscle at the myotendinous junction and in extraocular muscles; cylindric spirals; caps; and reducing bodies, which have also been observed in a congenital myopathy with rigid spine [Taratuto, 2002]. Several other myopathies that contain inclusions are described as follows.

Desminopathies Desmin is a 52-kDa chief intermediate filament of skeletal and cardiac muscle [Dalakas et al., 2000] that has been found to accumulate in a group of myopathies known as myofibrillar myopathies [Taratuto, 2002]. These aggregates appear as cytoplasmic, sarcoplasmic, and spheroid bodies and can also be seen as granulofilamentous material [Goebel, 2003; Taratuto, 2002]. Several structural desminrelated myopathies have also been discovered and include αB-crystallinopathy, hereditary inclusion body myopathies, and possibly hyaline body myopathy [Goebel and Fardeau, 2002].

TABLE 80-3 Congenital Myopathy Genetics CONGENITAL MYOPATHY

INHERITANCE

LOCUS

PROTEIN

Myotubular myopathy Central core Nemaline myopathy

XR AD AD (NEM1) AR (NEM2) AR AD AD and AR

Xq28 19q13.1 1q21-q23 2q21.2-q22 19q13.4 9p13.2-p13.1 1q42.1

Myotubularin Skeletal muscle ryanodine receptor α-Tropomyosin Nebulin Troponin T1 β-Tropomyosin α-Actin, skeletal muscle

(Actinopathy)

AD, autosomal dominant; AR, autosomal recessive; XR, X-linked recessive.

Strober / Congenital Myopathies

Clinical Features Desminopathies typically manifest with distal muscle weakness. Cardiac conduction defects may be present, as may a cardiomyopathy [Taratuto, 2002]. When a cardiomyopathy was present, granulofilamentous material was seen on muscle biopsy [Goebel, 2003]. Peripheral neuropathy can accompany these features as well, and giant axons resulting from neurofilament accumulation are seen on nerve biopsy [Goebel, 2003]. The protein aggregates of desmin, which have been found to be hyperphosphorylated [Goebel, 2003], are typically surrounded by areas lacking oxidative enzymes [Taratuto, 2002]. Autosomal-dominant and -recessive types have been reported [Goebel and Fardeau, 2002; Taratuto, 2002]. The desmin gene maps to chromosome 2q35 [ViegasPequignot et al., 1989]. A desmin knockout mouse develops normally but becomes afflicted with an early skeletal and cardiac myopathy accompanied by vascular disease [Goebel, 2003].

αB-Crystallinopathy A French family with a clinical picture suggestive of a desminopathy and accompanied by small lens opacities was found to have a mutation on chromosome 11 in a gene encoding αB-crystallin [Goebel and Fardeau, 2002], a protein that co-aggregates with desmin [Goebel, 2003]. αB-crystallin is a small heat shock protein the acts as a chaperone protein that participates in the breakdown of intracellular proteins outside of the lysosome [Goebel, 2003]. Therefore, mutated αB-crystallin would naturally lead to protein accumulation. αB-crystallin has been found in many tissues, including skeletal muscle, and lens tissue and in cardiocytes [Goebel, 2003].

Hyaline Body Myopathy Hyaline body myopathy, which was known as myofibrillar lysis myopathy [Goebel and Fardeau, 2002], is characterized by non–membrane-bound subsarcolemmal aggregation of dense, disorganized filaments in continuity with myosin staining, also known as hyaline bodies [Goebel and Anderson, 1999; Taratuto, 2002]. These bodies are usually seen in 10% to 30 % of type 1 fibers, exhibit myosin immunoreactivity, and stain intensely with acid myosin adenosine triphosphatase [Goebel and Anderson, 1999]. Children affected with this disorder typically present with mild, nonprogressive scapuloperoneal weakness and atrophy early in life [Goebel and Anderson, 1999; Taratuto, 2002]. Most cases are sporadic, but autosomal-dominant and -recessive forms have been described [Goebel and Fardeau, 2002; Taratuto, 2002].

Myosin-Related Myopathy Two disorders have so far been linked to mutations in the genes encoding myosin heavy chains. The first is in a Swedish family with a progressive myopathy and rimmed vacuoles, tubulofilamentous aggregates, and mini-core–like lesions. This condition was once called hereditary inclusion body myopathy type 3 and now is known as type 1c [Goebel, 2003]. The gene is on chromosome 17 and encodes for myosin

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heavy chain IIa. Hereditary cardiomyopathies have also been associated with mutations in cardiac myosin heavy chains.

Fingerprint Body Myopathy Fingerprint body myopathy was first described by Engel and colleagues in 1972 and manifests with early onset, limb and trunk weakness, and delayed motor development [Riggs et al., 2003]. Fingerprint bodies are identified on electron microscopy as subsarcolemmal inclusions of osmiophilic lamellae that resemble fingerprints [Goebel and Anderson, 1999; Riggs et al., 2003]. There is one case report of a pair of siblings with proximal muscle weakness and susceptibility to malignant hyperthermia who were found to have central cores in conjunction with fingerprint bodies [Stojkovic et al., 2001]. No mutations in the RYR1 gene were found. Fingerprint bodies have been reported in other muscle disorders, such as myotonic dystrophy [Tomé and Fardeau, 1973], a patient with Marfan’s syndrome and slowly progressive weakness [Jadro-Santel et al., 1980], and oculopharyngeal muscular dystrophy, as well as other myopathies and neurodegenerative disorders [Riggs et al., 2003; Stojkovic et al., 2001]. They have also been found in fetal muscle, which suggests that these bodies may be transient structures of developmental significance, which could account for their infrequent occurrence in these conditions [Ambler et al., 1987].

Tubular Aggregate Myopathies Tubular aggregates are basophilic deposits made up of fascicles of parallel tubules possibly derived from the sarcoplasmic reticulum [Riggs et al., 2003]. They have been reported to be seen in up to 98% of muscle fibers on biopsy in a family with slowly progressive weakness of the iliopsoas, deltoid, triceps, and sternocleidomastoid muscles. This condition is inherited in an autosomal-dominant fashion [Goebel and Anderson, 1999]. However, like fingerprint bodies, tubular aggregates have been reported in many other neurologic conditions, such as periodic paralyses; myalgic syndromes, in which the aggregates were in type 2 fibers; and familial myopathies, in which they were seen in both fiber types [Riggs et al., 2003].

Vacuolar Myopathy Families have been reported with what appears to be Xlinked mental retardation, cardiomyopathy, and a vacuolar myopathy [Goebel and Anderson, 1999; Muntoni et al., 1994]. Affected males developed proximal and axial muscle weakness in their teens and a cardiomyopathy in their 20s. They all had moderate-to-severe cognitive impairment. Creatine kinase values were moderately elevated, and muscle biopsy specimens revealed severe vacuolar changes in association with many fibers’ having internal nuclei. REFERENCES Agrawal PB, Strickland CD, Midgett C, et al. Heterogeneity of nemaline myopathy cases with skeletal muscle alpha-actin gene mutations. Ann Neurol 2004;56:86. Ambler MW, Neave C, Entwistle R. Fingerprint inclusions in normal fetal muscle. Acta Neuropathol (Berl) 1987;73:185.

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Barth PG, Dubowitz V. X-linked myotubular myopathy—A long-term follow-up study. Eur J Paediatr Neurol 1998;2:49. Bertini E, Biancalana V, Bolino A, et al. 118th ENMC International Workshop on Advances in Myotubular Myopathy. 26-28 September 2003, Naarden, The Netherlands. (5th Workshop of the International Consortium on Myotubular Myopathy). Neuromuscul Disord 2004;14:387. Bolino A, Muglia M, Conforti FL, et al. Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2. Nat Genet 2000;25:17. Brooke MH. Congenital fiber type disproportion. In: Kakulas BA, ed. 2nd International Congress on Muscle Disease, November 22-29, 1971. Perth, Australia: Excerpta Medica, 1973;147. Clarke NF, North KN. Congenital fiber type disproportion—30 years on. J Neuropathol Exp Neurol 2003;62:977. Dalakas MC, Park KY, Semino-Mora C, et al. Desmin myopathy, a skeletal myopathy with cardiomyopathy caused by mutations in the desmin gene. N Engl J Med 2000;342:770. De Cauwer H, Heytens L, Martin JJ. Workshop report of the 89th ENMC International Workshop: Central Core Disease, 19th-20th January 2001, Hilversum, The Netherlands. Neuromuscul Disord 2002;12:588. Donner K, Ollikainen M, Ridanpaa M, et al. Mutations in the beta-tropomyosin (TPM2) gene—A rare cause of nemaline myopathy. Neuromuscul Disord 2002;12:151. Engel AG, Angelini C, Gomez MR. Fingerprint body myopathy, a newly recognized congenital muscle disease. Mayo Clin Proc 1972;47:377. Engel AG, Gomez MR, Groover RV. Multicore disease. A recently recognized congenital myopathy associated with multifocal degeneration of muscle fibers. Mayo Clin Proc 1971;46:666. Fananapazir L, Dalakas MC, Cyran F, Cohn G, Epstein ND. Missense mutations in the beta-myosin heavy-chain gene cause central core disease in hypertrophic cardiomyopathy. Proc Natl Acad Sci U S A 1993;90:3993. Ferreiro A, Fardeau M. 80th ENMC International Workshop on Multi-Minicore Disease: 1st International MmD Workshop. 12-13th May, 2000, Soestduinen, The Netherlands. Neuromuscul Disord 2002;12:60. Ferreiro A, Monnier N, Romero NB, et al. A recessive form of central core disease, transiently presenting as multi-minicore disease, is associated with a homozygous mutation in the ryanodine receptor type 1 gene. Ann Neurol 2002a;51:750. Ferreiro A, Quijano-Roy S, Pichereau C, et al. Mutations of the selenoprotein N gene, which is implicated in rigid spine muscular dystrophy, cause the classical phenotype of multiminicore disease: Reassessing the nosology of early-onset myopathies. Am J Hum Genet 2002b;71:739. Goebel HH. Congenital myopathies at their molecular dawning. Muscle Nerve 2003;27:527. Goebel HH, Anderson JR. Structural congenital myopathies (excluding nemaline myopathy, myotubular myopathy and desminopathies): 56th European Neuromuscular Centre (ENMC) sponsored International Workshop. December 12-14, 1997, Naarden, The Netherlands. Neuromuscul Disord 1999;9:50. Goebel HH, Fardeau M. Desmin—Protein surplus myopathies, 96th European Neuromuscular Centre (ENMC)–sponsored International Workshop held 14-16 September 2001, Naarden, The Netherlands. Neuromuscul Disord 2002;12:687. Gommans IM, Davis M, Saar K, et al. A locus on chromosome 15q for a dominantly inherited nemaline myopathy with core-like lesions. Brain 2003;126(Pt 7):1545. Gommans IM, van Engelen BG, ter Laak HJ, et al. A new phenotype of autosomal dominant nemaline myopathy. Neuromuscul Disord 2002;12:13. Haan EA, Freemantle CJ, McCure JA, et al. Assignment of the gene for central core disease to chromosome 19. Hum Genet 1990;86:187. Houlden H, King RH, Wood NW, et al. Mutations in the 5 region of the myotubularin-related protein 2 (MTMR2) gene in autosomal recessive hereditary neuropathy with focally folded myelin. Brain 2001;124(Pt 5):907. Imoto C, Nonaka I. The significance of type 1 fiber atrophy (hypotrophy) in childhood neuromuscular disorders. Brain Dev 2001;23:298. Jadro-Santel D, Grcevic N, Dogan S, et al. Centronuclear myopathy with type I fibre hypotrophy and “fingerprint” inclusions associated with Marfan’s syndrome. J Neurol Sci 1980;45:43. Johnston JJ, Kelley RI, Crawford TO, et al. A novel nemaline myopathy in the Amish caused by a mutation in troponin T1. Am J Hum Genet 2000;67:814.

Jungbluth H, Muller CR, Halliger-Keller B, et al. Autosomal recessive inheritance of RYR1 mutations in a congenital myopathy with cores. Neurology 2002;59:284. Jungbluth H, Sewry CA, Muntoni F. What’s new in neuromuscular disorders? The congenital myopathies. Eur J Paediatr Neurol 2003;7:23. Laing NG, Majda BT, Akkari PA, et al. Assignment of a gene (NEMI) for autosomal dominant nemaline myopathy to chromosome I. Am J Hum Genet 1992;50:576. Laing NG, Wilton SD, Akkari PA, et al. A mutation in the alpha tropomyosin gene TPM3 associated with autosomal dominant nemaline myopathy NEM1. Nat Genet 1995;10:249. Lammens M, Moerman P, Fryns JP, et al. Fetal akinesia sequence caused by nemaline myopathy. Neuropediatrics 1997;28:116. Laporte J, Biancalana V, Tanner SM, et al. MTM1 mutations in X-linked myotubular myopathy. Hum Mutat 2000;15:393. Laporte J, Hu LJ, Kretz C, et al. A gene mutated in X-linked myotubular myopathy defines a new putative tyrosine phosphatase family conserved in yeast. Nat Genet 1996;13:175. Magee KR, Shy GM. A new congenital non-progressive myopathy. Brain 1956;79:610. McCarthy TV, Quane KA, Lynch PJ. Ryanodine receptor mutations in malignant hyperthermia and central core disease. Hum Mutat 2000;15:410. Moghadaszadeh B, Petit N, Jaillard C, et al. Mutations in SEPN1 cause congenital muscular dystrophy with spinal rigidity and restrictive respiratory syndrome. Nat Genet 2001;29:17. Monnier N, Romero NB, Lerale J, et al. An autosomal dominant congenital myopathy with cores and rods is associated with a neomutation in the RYR1 gene encoding the skeletal muscle ryanodine receptor. Hum Mol Genet 2000;9:2599. Muntoni F, Catani G, Mateddu A, et al. Familial cardiomyopathy, mental retardation and myopathy associated with desmin-type intermediate filaments. Neuromuscul Disord 1994;4:233. Nowak KJ, Wattanasirichaigoon D, Goebel HH, et al. Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy. Nat Genet 1999;23:208. Pelin K, Hilpela P, Donner K, et al. Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy. Proc Natl Acad Sci U S A 1999;96:2305. Petit N, Lescure A, Rederstorff M, et al. Selenoprotein N: An endoplasmic reticulum glycoprotein with an early developmental expression pattern. Hum Mol Genet 2003;12:1045. Quinlivan RM, Muller CR, Davis M, et al. Central core disease: Clinical, pathological, and genetic features. Arch Dis Child 2003;88:1051. Riggs JE, Bodensteiner JB, Schochet SS Jr. Congenital myopathies/dystrophies. Neurol Clin 2003;21:779. Sher JH, Rimalovski AB, Athanassiades TJ, Aronson SM. Familial centronuclear myopathy: A clinical and pathological study. Neurology 1967;17(8 Pt 1):727. Spiro AJ, Shy GM, Gonatas NK. Myotubular myopathy. Persistence of fetal muscle in an adolescent boy. Arch Neurol 1966;14:1. Stojkovic T, Maurage CA, Moerman A, et al. Congenital myopathy with central cores and fingerprint bodies in association with malignant hyperthermia susceptibility. Neuromuscul Disord 2001;11:538. Sutton IJ, Winer JB, Norman AN, et al. Limb girdle and facial weakness in female carriers of X-linked myotubular myopathy mutations. Neurology 2001;57:900. Taratuto AL. Congenital myopathies and related disorders. Curr Opin Neurol 2002;15:553. Taylor GS, Maehama T, Dixon JE. Inaugural article: Myotubularin, a protein tyrosine phosphatase mutated in myotubular myopathy, dephosphorylates the lipid second messenger, phosphatidylinositol 3-phosphate. Proc Natl Acad Sci U S A 2000;97:8910. Tilgen N, Zorzato F, Halliger-Keller B, et al. Identification of four novel mutations in the C-terminal membrane spanning domain of the ryanodine receptor 1: Association with central core disease and alteration of calcium homeostasis. Hum Mol Genet 2001;10:2879. Tomé FM, Fardeau M. “Fingerprint inclusions” in muscle fibres in dystrophia myotonica. Acta Neuropathol (Berl) 1973;24:62. Viegas-Pequignot E, Li ZL, Dutrillaux B, et al. Assignment of human desmin gene to band 2q35 by nonradioactive in situ hybridization. Hum Genet 1989;83:33. Wallgren-Pettersson C, Donner K, Sewry C, et al. Mutations in the nebulin gene can cause severe congenital nemaline myopathy. Neuromuscul Disord 2002;12:674.

Strober / Congenital Myopathies Wallgren-Pettersson C, Laing NG. Report of the 70th ENMC International Workshop: Nemaline myopathy, 11–13 June 1999, Naarden, The Netherlands. Neuromuscul Disord 2000;10:299. Wallgren-Pettersson C, Laing NG. Report of the 83rd ENMC International Workshop: 4th Workshop on Nemaline Myopathy,

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22–24 September 2000, Naarden, The Netherlands. Neuromuscul Disord 2001;11:589. Wallgren-Pettersson C, Laing NG. 109th ENMC International Workshop: 5th workshop on nemaline myopathy, 11th-13th October 2002, Naarden, The Netherlands. Neuromuscul Disord 2003;13:501.

CHAPTER 81

Metabolic Myopathies Ingrid Tein

UTILIZATION OF BIOENERGETIC SUBSTRATES IN EXERCISE Defects of energy metabolism may profoundly disrupt the function of muscle and other highly energy-dependent tissues, such as those of the brain, nerves, heart, kidneys, liver, and bowel. The limits of energy utilization in skeletal muscle are set by the adenosine triphosphatases (ATPases), which couple muscle contraction (myosin ATPase) and ion transport (calcium and sodium, potassium ATPases) to the hydrolysis of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) and inorganic phosphate [Kushmerick, 1995]. ADP and inorganic phosphate, in turn, activate energy-producing reactions that regenerate ATP. Without this, ATP stores would be exhausted in seconds. The substrates that are used to replenish ATP are determined by the intrinsic properties of these fuels and by the intensity and duration of exercise that modulates fuel selection [Astrand and Rodahl, 1986; Gollnick, 1985]. The creatine kinase reaction and anaerobic glycogenolysis are the major anaerobic sources of ADP phosphorylation. Increases in ADP and adenosine monophosphate (AMP) that occur in strenuous exercise are buffered primarily by the coupled adenylate kinase (myokinase), adenylate deaminase (myoadenylate deaminase) reactions. Anaerobic glycogenolysis and phosphocreatine hydrolysis support rates of muscle energy production that are twofold to fourfold higher than those supported by oxidative metabolism [Sahlin, 1986]. Anaerobic energy is crucial for rapid bursts of exercise and for fueling the transition from rest to exercise. The acceleration to high rates of energy production occurs instantly for ATP, in less than a second for phosphocreatine, and within seconds for anaerobic glycogenolysis. In contrast, maximal oxidative power requires from 3 minutes (with glycogen as the oxidative substrate) to 30 minutes (for peak fatty acid oxidation). Anaerobic fuels are rapidly depleted and lead to the accumulation of metabolic end products such as protons and inorganic phosphates that promote fatigue. If exercise needs to be sustained for more than a few minutes, then oxidative phosphorylation is necessary and provides the most abundant source of ATP synthesis. Glycogen is the major endogenous oxidative fuel of skeletal muscle, whereas blood glucose and free fatty acids are the major exogenous fuels. A small percentage of muscle energy needs are supplied by amino acids, predominantly branched-chain amino acids, which are oxidized to a limited extent. Oxidative metabolism provides higher yields of ATP per mole of substrate, rising from 2 to 36 for glucose and from 3 to 37 per glycosyl unit of glycogen metabolized anaerobically rather than oxidatively. Furthermore, the metabolic end

products of oxidative metabolism, namely, carbon dioxide and water, are easily removed from working muscle and do not promote fatigue. The most abundant and critical fuel for the support of prolonged, moderate exercise is lipid. Carbohydrate stores in the form of muscle and hepatic glycogen and blood glucose (derived mainly from hepatic glycogenolyis) are limited and can support high-intensity exercise for only 1 to 2 hours. However, carbohydrate, particularly muscle glycogen, is critical for normal oxidative metabolism. Glycogen supports a peak rate of oxidative phosphorylation that is about twofold greater than that for fat. Although this process is incompletely understood, it may be based on a requirement for glycogen-derived pyruvate to support optimal function of the tricarboxylic acid cycle [Gibala et al., 1997; Sahlin et al., 1990, 1995]. The proportion of carbohydrate in relation to lipid oxidation increases progressively as the intensity of the aerobic exercise increases until carbohydrate is the exclusive fuel of maximum oxidative metabolism [Sahlin, 1986; van Loon et al., 2001]. Glycogen is also able to accelerate to maximal oxidative power output more rapidly than are other fuels [Haller and Vissing, 2002; Sahlin, 1986]. Third, the molar ratio of ATP produced to oxygen consumed is higher for glycogen (6.17) and glucose (5.98) than for fatty acids (5.61) [Rennie and Edwards, 1981]. The importance of this point lies in the fact that peak oxygen utilization in healthy humans is limited by oxygen delivery [Saltin, 1988]. The combustion of fuels in oxidative metabolism involves the generation of reducing equivalents in β-oxidation, glycolysis, and the tricarboxylic acid cycle that are oxidized through the respiratory chain, in which the phosphorylation of ADP is coupled to the reduction of molecular oxygen to water. Normal oxidative metabolism requires a highly integrated physiologic support system to regulate the flow of oxygen from the lungs to the respiring muscle mitochondria, as well as to functional mitochondria, that can efficiently extract the available oxygen from blood. Muscle oxygen utilization in oxidative phosphorylation may increase 50-fold or greater from rest to peak exercise. This increase is achieved by increases in the level of oxygen extraction from oxyhemoglobin in red blood cells and in the rate of delivery of oxygenated blood to working muscle by the circulation. The primary source of energy for resting muscle is derived from fatty acid oxidation [Felig and Wahren, 1975]. At rest, glucose utilization accounts for 10% to 15% of total oxygen consumption [Wahren, 1977]. Both slow- and fast-twitch fibers have similar levels of glycogen content at rest [Essen, 1978]. The choice of the bioenergetic pathway in working muscle depends on the type, intensity, and duration of exercise [Essen, 1977; Gollnick et al., 1974] but also on diet and physical conditioning [DiMauro and Haller, 1999]. In

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the first 5 to 10 minutes of moderate exercise, high-energy phosphates are used first to regenerate ATP. This period is followed by muscle glycogen breakdown, which is indicated by a sharp rise in lactate during the first 10 minutes. Blood lactate levels then drop as muscle triglycerides and bloodborne fuels are used [Felig and Wahren, 1975; Lithell et al., 1979]. After 90 minutes, the major fuels are glucose and free fatty acids. During 1 to 4 hours of mild-to-moderate prolonged exercise, muscle uptake of free fatty acids increases approximately 70%, and after 4 hours, free fatty acids are used twice as much as carbohydrates. Symptoms in muscle energy defects are directly related to a mismatch between the rate of ATP utlilization (energy demand) and the capacity of the muscle metabolic pathways to regenerate ATP (energy supply). This energy supply/ demand mismatch impairs energy-dependent processes that power muscle contraction (resulting in weakness and exertional fatigue), mediate muscle relaxation (muscle cramping, tightness), and/or maintain membrane ion gradients necessary for normal membrane excitability (fatigue, weakness) and muscle cell integrity (muscle pain, injury, myoglobinuria).

In metabolic myopathies, the specific metabolic mediators of premature fatigue, cramping, pain, and muscle injury are complex and vary among the different metabolic disorders. Disorders of glycogen, lipid, or mitochondrial metabolism may cause two main clinical syndromes in muscle: (1) acute, recurrent, reversible muscle dysfunction with exercise intolerance and acute muscle breakdown or myoglobinuria (with or without cramps), such as phosphorylase, phosphorylase b kinase, phosphofructokinase, phosphoglycerate kinase, phosphoglycerate mutase, and lactate dehydrogenase among the glycogenoses, and carnitine palmitoyltransferase II, very-long-chain acyl-coenzyme A (CoA) dehydrogenase (VLCAD), trifunctional protein, short-chain L-3-hydroxyacylCoA dehydrogenase (SCHAD) deficiency among the disorders of fatty acid oxidation, and complex II and coenzyme Q10 deficiencies among the mitochondrial disorders; and (2) progressive weakness, such as acid maltase, debrancher enzyme, brancher enzyme, and aldolase enzyme deficiencies among the glycogenoses; long-chain acyl-CoA dehydrogenase (LCAD), VLCAD, trifunctional protein, glutaric aciduria type II, and short-chain acyl-CoA

Box 81-1 HERITABLE CAUSES OF MYOGLOBINURIA I. Biochemical abnormality known A. Glycolysis/glycogenolysis 1. Phosphorylase deficiency [McArdle, 1951]* 2. Phosphofructokinase deficiency [Layzer et al., 1967; Tarui et al., 1965] 3. Phosphoglycerate kinase deficiency [DiMauro et al., 1981a]* 4. Phosphoglycerate mutase deficiency [DiMauro et al., 1981b]* 5. Lactate dehydrogenase deficiency [Kanno et al., 1980]* 6. Phosphorylase b kinase deficiency [Abarbanel et al., 1986] 7. Debrancher deficiency [Brown, 1986] 8. Aldolase A deficiency [Kreuder et al., 1996]* B. Fatty acid oxidation 1. Carnitine palmitoyltransferase II deficiency [DiMauro and DiMauro, 1973]* 2. Long-chain acyl-CoA dehydrogenase deficiency [Roe, cited in Stanley, 1987] 3. Very long-chain acyl-CoA dehydrogenase deficiency [Ogilvie et al., 1994] 4. Medium-chain acyl-CoA dehydrogenase deficiency [Ruitenbeek et al., 1995] 5. Short-chain L-3-hydroxyacyl CoA dehydrogenase deficiency [Tein et al., 1991]* 6. Trifunctional enzyme deficiency [Dionisi-Vici et al., 1991]* 7. Medium-chain 3-ketoacyl CoA thiolase deficiency [Kamijo et al., 1997]* C. Pentose phosphate pathway 1. Glucose-6-phosphate dehydrogenase deficiency [Bresolin et al., 1989]*

D. Purine nucleotide cycle 1. Myoadenylate deaminase deficiency [Hyser et al., 1989] E. Respiratory chain 1. Complex I deficiency [de Lonlay-Debeney et al., 1999]* 2. Coenzyme Q10 deficiency [Ogasahara et al., 1989] 3. Complex II and aconitase deficiencies [Haller et al., 1991]* 4. Complex III deficiency (cytochrome b deficiency) [Andreu et al., 1999] 5. Complex IV deficiency (cytochrome oxidase deficiency) (Keightley et al., 1996]* 6. Multiple mitochondrial DNA deletions [Ohno et al., 1991]* II. Biochemical abnormality incompletely characterized A. Impaired long-chain fatty acid oxidation [Engel et al., 1970]* B. Impaired function of the sarcoplasmic reticulum (?) in familial malignant hyperthermia (predisposition in central core disease, Duchenne muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy, myotonia congenita, Schwartz-Jampel syndrome, King-Denborough syndrome)* C. Abnormal composition of the sarcolemma in Duchenne and Becker muscular dystrophies [Bonilla et al., 1989; Hoffman et al., 1989; Medori et al., 1989]* III. Biochemical abnormality unknown A. Familial recurrent myoglobinuria* B. Repeated attacks in sporadic cases*

Modified from Tein I, DiMauro S, Rowland LP. In: Rowland LP, DiMauro S, eds. Handbook of clinical neurology, vol 18 (62). Myopathies. Amsterdam: Elsevier Science, 1992;553. *Etiologies that have been documented to cause recurrent myoglobinuria beginning in childhood.

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dehydrogenase (SCAD) deficiencies and plasmalemmal carnitine transporter (OCTN2) defect among the fatty acid oxidation defects; and mitochondrial enzyme deficiencies such as complex I, cytochrome oxidase deficiency, multiple mitochondrial DNA (mtDNA) deletions, and mtDNA depletion syndrome (Box 81-1). Progressive weakness and recurrent myoglobinuria can also occur together in a given disorder (e.g., LCAD, VLCAD, SCHAD, trifunctional protein, and severe carnitine palmitoyltransferase II deficiencies among the fatty acid oxidation defects, as well as multiple mtDNA deletions and coenzyme Q10 deficiency).

MYOGLOBINURIA Myoglobinuria is a clinical syndrome, not just a biochemical state [Rowland, 1984]. In the alert patient, myalgia and limb weakness are the most common presenting symptoms. Urine color is usually brownish rather than red, and the urine tests positive for both albumin and heme (a concentration of at least 4 μg/mL). There are few or no red blood cells. Myoglobin can be identified by immunochemical methods. Concentrations of the sarcoplasmic enzymes, including serum creatine kinase, are usually elevated to more than 100 times normal. Less frequent features include hyperphosphatemia, hyperuricemia, hypocalcemia, or hypercalcemia. If renal failure occurs, serum potassium and calcium levels may rise. If the patient is comatose or if the presenting disorder is one of acute renal failure, there may be no muscle symptoms or signs. Under these conditions, the diagnosis can be made if (1) there is renal failure and (2) the serum content of sarcoplasmic enzymes is 100 times normal. The potentially life-threatening hazards of an attack of myoglobinuria include renal or respiratory failure and cardiac dysrhythmias. The etiologies of heritable myoglobinuria in adults differ from those in children. In a study of 77 adult patients aged 15 to 65 years, Tonin and associates [1990] identified the enzyme abnormality in 36 patients (47%) as follows: carnitine palmitoyltransferase deficiency in 17 patients; glycolytic defects in 15 patients (including phosphorylase in 10, phosphorylase b kinase in 4, and phosphoglycerate kinase in 1); myoadenylate deaminase in 3; and combined carnitine palmitoyltransferase and myoadenylate deaminase deficiencies in 1. In contrast, in 100 cases of recurrent childhood-onset myoglobinuria, cases have been diagnosed biochemically in a lower percentage of affected children (24%): 16 had carnitine palmitoyltransferase deficiency, 1 had SCHAD deficiency, and 7 had various glycolytic defects (2 had phosphorylase deficiency, 1 had phosphoglycerate kinase deficiency, 3 had phosphoglycerate mutase deficiency, and 1 had lactate dehydrogenase deficiency) [Tein et al., 1990b]. These children could be divided into two groups: a type I exertional group, in which exertion was the primary precipitating factor (56 cases), and a type II toxic group, in which leukocytosis and infection and/or fever were the primary precipitants (37 cases). The type II toxic childhood-onset group was distinguished from the type I exertional childhood-onset and adult-onset groups by the etiologies, which were limited to fatty acid oxidation defects, as well as its slight female predominance, which was in contrast to the marked male predominance in the latter two groups. The type II toxic group was further

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distinguished by the earlier age at onset of myoglobinuria, the presence of a more generalized disease (e.g., ictal bulbar signs, seizures, encephalopathy, developmental delay), and a higher mortality rate. Currently, the most common etiology for recurrent myoglobinuria in both adults and in children is carnitine palmitoyltransferase II deficiency [Tein et al., 1992].

GLYCOGENOSES Only glycogenoses affecting skeletal muscle, alone or in association with other tissues, are discussed in this section (Fig. 81-1) [DiMauro and Bresolin, 1986]. Molecular genetic analysis has led to the cloning of genes encoding the

(Lysosome)

Epinephrine exercise Cyclic AMP

Acid maltase

II

(Ca2+)

Protein kinase

Glucose

Phosphorylase b kinase VIII Phosphorylase a Phosphorylase b

Glycogen

IV

V–VI UDPG

PLD III Glucose-1-P I Blood glucose

Glucose-6-P Fructose-6-P ATP ADP

VII Fructose-1, 6-P Glyceraldehyde-3-P (2) 3-P-Glyceroyl phosphate (2)

2 ADP 2 ATP

IX 3-Phosphoglycerate (2) X 2-Phosphoglycerate (2) Phosphoenol pyruvate (2)

2 ADP 2 ATP Pyruvate (2) XI Lactate (2) FIGURE 81-1. Scheme of glycogen metabolism and glycolysis. Roman numerals refer to glycogenoses resulting from defects of the following enzymes: I, glucose-6-phosphatase; II, acid maltase; III, debrancher; IV, brancher; V, muscle phosphorylase; VI, liver phosphorylase; VII, phosphofructokinase; VIII, phosphorylase b kinase; IX, phosphoglycerate kinase; X, phosphoglycerate mutase; XI, lactate dehydrogenase. ADP, adenosine diphosphate; AMP, adenosine monophosphate; ATP, adenosine triphosphate; P, phosphate; PLD, phosphorylase-limit-dextrin, D; UDPG, uridine diphosphate glucose. (From DiMauro S, Miranda AF, Sakoda S, et al. Metabolic myopathies. Am J Med Genet 1986;25:635-651.)

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TABLE 81-1 Chromosomal Assignment of Human Genes Encoding Glycogenolytic and Glycolytic Enzymes ENZYME

SUBUNIT OR ISOZYME

CHROMOSOME

REFERENCE

Acid maltase Phosphorylase b kinase

— α (M) α (L) β γ M L B — M P L M A M B M H

17q23→q25 Xq12→q13 Xp22.2→p22.1 16q12→q13 7p12-q21 11q13 14q21→q22 10, 20p11.2 1p21 1(cen→q32) 10p 21q22.3 16q22-q24 Xq13 7 10 11 12

Engel and Hirschhorn, 1994 Francke et al., 1989 Davidson et al., 1992 Francke et al., 1989 Jones et al., 1990 Lebo et al., 1984 Newgard et al., 1986; Billingsley et al., 1994 Newgard et al., 1988; Rao et al., 1992 Yang-Feng et al., 1992 Vora et al., 1982 Vora et al., 1983b Van Keuren et al., 1986 Kukita et al., 1987 Meera Khan et al., 1971 Edwards et al., 1989 Junien et al., 1982 Boone et al., 1972 Chen et al., 1973

Phosphorylase Debrancher Phosphofructokinase Aldolase A Phosphoglycerate kinase Phosphoglycerate mutase Lactate dehydrogenase

Modified from DiMauro S, Tsujino S. Nonlysosomal glycogenoses. In: Engel AG, Franzini-Armstrong C, eds. Myology, vol 2. New York: McGraw-Hill, 1994;1554. A, the isoform of phosphoglycerate kinase present in all tissues except spermatogenic cells; B, brain; H, heart; L, liver; M, muscle; P, platelets.

enzymes involved in most glycogenoses, as well as their chromosomal localization (Table 81-1). All are autosomal recessive in inheritance with the exception of phosphoglycerate kinase, which is X-linked recessive, and phosphorylase b kinase, which may be either. In the glycogenoses, fixed weakness is the primary manifestation in deficiencies of acid maltase, debrancher, aldolase, and brancher enzymes, whereas exercise intolerance with cramps, myalgia, and recurrent myoglobinuria are the primary manifestations in deficiencies of phosphorylase kinase, phosphorylase, phosphofructokinase, phosphoglycerate kinase, phosphoglycerate mutase, β-enolase, and lactate dehydrogenase [DiMauro and Lamperti, 2001].

Pathophysiology The immediate source of energy for contraction and relaxation is provided by the hydrolysis of ATP. Oxidative phosphorylation provides the largest contribution of energy overall, whereas anaerobic glycolysis plays a relatively minor role, limited primarily to conditions of sustained isometric contraction when blood flow and oxygen delivery to exercising muscles are drastically reduced. The dynamic form of exercise, such as walking or running, depends primarily on aerobic glycolysis. Therefore, the pathophysiology of glycogenoses relates more to the impairment of aerobic than anaerobic glycolysis [Lewis and Haller, 1986; Lewis et al., 1991]. Which energy substrates are used by muscle for aerobic metabolism depends on the type, intensity, and duration of exercise, as well as on physical conditioning and diet. During intense exercise (close to maximal oxygen uptake [VO2max], in dynamic exercise or maximal force generation in isometric exercise), energy is derived from anaerobic glycolysis, particularly when there is a burst of activity with rapid acceleration to maximal exercise [DiMauro and Tsujino, 1994]. During low-intensity exercise (below 50% VO2max), the primary sources of energy are blood glucose and free fatty acids. At higher intensities, the proportion of energy

derived from carbohydrate oxidation increases, and glycogen becomes an important fuel. At 70% to 80% of VO2max, the critical energy source is provided by the aerobic metabolism of glycogen, and fatigue occurs when glycogen stores are exhausted [DiMauro and Tsujino, 1994]. Individuals with defective glycolysis/glycogenolysis are most vulnerable during the initial stages of intense exercise, and they must rest soon after beginning exercise because of muscle cramps. However, if they continue to exercise at low intensity, they are able to continue for a longer time. This is known as the second-wind phenomenon and has been attributed to a metabolic switch from carbohydrate to fatty acid utilization [Felig and Wahren, 1975] and to increased circulation with increased availability of blood glucose from hepatic glycogenolysis [Haller et al., 1985]. A decrease in ATP levels could first cause muscle contracture. In theory, a more severe depletion could lead to myoglobinuria [Rowland, 1984], although this has not been proved. The forearm ischemic exercise test developed by McArdle [1951] is a useful test for the detection of enzymatic defects in the nonlysosomal glycogenolytic and glycolytic pathways. This test can be performed in cooperative children as young as 6 years of age. A catheter is placed in a superficial antecubital vein, and basal lactate and ammonia levels are obtained without stasis. A sphygmomanometer cuff is then placed above the elbow and inflated above arterial pressure. The patient is asked to rhythmically squeeze another rolled-up cuff to well above 120 mm Hg for 1 minute of exercise. This test requires constant encouragement from the observer because significant discomfort can occur even in healthy control subjects. The test should be discontinued if the patient develops an acute cramp, because myonecrosis or a compartment syndrome or both may occur in an individual with a glycolytic disorder [Lindner et al., 2001; Meinck et al., 1982). After 1 minute of exercise, the cuff around the arm is deflated, and blood samples are sequentially obtained 1, 3, 5, 7, 10, and 15 minutes afterward. In healthy subjects, there is a fourfold to sixfold

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increase of lactate concentrations over baseline, with the peak occurring 1 to 2 minutes after the exercise, and then a decline to baseline values by 15 minutes. This pattern is paralleled by a similar fivefold or more increase in ammonia concentrations, which generally peak 2 to 5 minutes after the exercise in individuals with normal myoadenylate deaminase activity. In healthy subjects, venous ammonia and lactate concentrations are linearly related [Sinkeler et al., 1985]. In individuals with a defect in glycolysis/ glycogenolysis, there is an insufficient rise in lactate (less than twofold), with a compensatory and exaggerated increase in ammonia, which also indicates sufficient effort on the part of the individual. This exaggerated rise in ammonia is attributable to high cellular levels of ADP, which result from a combination of blocked glycogenolysis/ glycolysis and absence of cellular acidosis. An insufficient lactate rise has been demonstrated in deficiencies of phosphorylase, debrancher enzyme, phosphofructokinase, phosphoglycerate kinase, phosphoglycerate mutase, and lactate dehydrogenase but not in acid maltase or phosphorylase b kinase deficiency. The major limitation of this test is that the rise of venous lactate in individuals who do not have a defect in this pathway is highly dependent on the patient’s ability and willingness to exercise. Therefore, patients in whom lactate levels are low, because of either poor effort or placement of the venous catheter in other than the median cubital vein, exhibit proportionally blunted ammonia responses. In view of the potential risk of myoglobinuria, alternatives to the traditional ischemic forearm test have been described. One of these uses sustained, intense (70% of maximal voluntary contraction) isometric handgrip exercise [Hogrel et al., 2001]. However, this form of testing is as ischemic as the use of a blood pressure cuff, inasmuch as the intramuscular pressure in isometric contractions of more than 50% of maximal voluntary contraction completely occludes muscle blood flow. Therefore, any reduction in the incidence of muscle contractures depends on shortening the duration of the test, which is also effective in minimizing contractures in the traditional ischemic forearm test. An alternative nonischemic forearm test involves 30 maximal handgrip contractions in 1 minute without a blood pressure cuff [Kazemi-Esfarjani et al., 2002]. The degree of increases in lactate and ammonia concentrations in control subjects and the diagnostic sensitivity in patients were similar to those in the ischemic exercise test. However, in contrast to the ischemic tests, the retained oxidative capacity helps protect individuals from contractures or significant pain [Kazemi-Esfarjani et al., 2002].

Glycolytic/Glycogenolytic Defects Acid Maltase Deficiency CLINICAL FEATURES Acid maltase deficiency (glycogenosis type II) results in three very different clinical presentations [DiMauro and Lamperti, 2001]: (1) A severe generalized disease of infancy described by Pompe [1932] that is invariably fatal before 2 years of age as a result of respiratory weakness and cardiac failure. This infantile form (Pompe’s disease) manifests with diffuse hypotonia and weakness in the first weeks or months of life and is associated with macroglossia, massive cardio-

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megaly, and moderate hepatomegaly. (2) A juvenile variant that affects exclusively muscle, with onset in childhood. It causes severe proximal, truncal, and respiratory muscle weakness, usually leading to death in the second or third decade. (3) A milder, adult-onset variant simulating limbgirdle dystrophy or polymyositis. In adult acid maltase deficiency a slowly progressive myopathy begins in the third or fourth decade with early ventilatory insufficiency. Affected adults often complain of headache upon waking, caused by sleep hypercapnia. Slonim and co-workers [2000] described a subgoup of patients who have the neonatal onset and the muscle morphologic features of the infantile form, but their condition differs from typical Pompe’s disease in that the heart is not involved and survival is longer.

LABORATORY TESTS In all forms of acid maltase deficiency, there is an increase in serum creatine kinase concentration. Electromyographic studies reveal myopathic abnormalities and may also demonstrate fibrillation potentials, positive waves, complex repetitive discharges, and myotonic discharges [DiMauro and Lamperti, 2001]. These are more frequently demonstrated in the paraspinal muscles. The electrocardiogram demonstrates characteristic, although not specific, changes, including a short PR interval, giant QRS complexes, and signs of biventricular hypertrophy in infantile acid maltase deficiency. In adults, there is markedly reduced vital capacity.

PATHOLOGY In infantile acid maltase deficiency, glycogen accumulation is evident in all tissues, most notably the heart. There is significant involvement of the anterior horn cells of the spinal cord, leading to severe weakness and fasciculations, and of brainstem nuclei. Glycogen accumulation in Schwann cells is seen in peripheral nerve biopsy specimens. There is vacuolar myopathy on muscle biopsy samples in all three forms of acid maltase deficiency [DiMauro et al., 1992]. In the infantile form, all muscle fibers contain many vacuoles, which often coalesce into a lacework pattern and contain periodic acid–Schiff stain–positive, diastase-digestible material and stain positively for acid phosphatase. Electron microscopic study reveals excess glycogen within lysosomal vacuoles and free in the cytoplasm.

INHERITANCE The three forms of acid maltase deficiency are allelic disorders that are transmitted as autosomal recessive traits. The gene encoding acid maltase is located on chromosome 17. Acid maltase activity can be measured in cultured amniocytes for the purposes of prenatal diagnosis.

BIOCHEMISTRY AND MOLECULAR GENETICS Although the enzyme defect is generalized and can be documented in lymphocytes [Shanske and DiMauro, 1981] or in cultured skin fibroblasts, biochemical measurement of acid maltase in muscle establishes the diagnosis. It is not entirely clear why symptoms are confined mainly to muscle in the childhood and adult forms. However, differences in

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clinical expression may in part relate to the amounts of residual activity [Mehler and DiMauro, 1977; Reuser et al., 1987; Van Der Ploeg et al., 1988]. Also, genetic heterogeneity has been demonstrated. In a study of 14 patients, Martiniuk and colleagues [1990a, 1990b] found that messenger RNA was lacking in 5 of 10 cases of infantile acid maltase deficiency and was present in all four adult cases, although it was shorter in two cases. The defective lysosomal enzyme, α-glucosidase, is encoded by a gene on chromosome 17 [D’Ancona et al., 1979; Solomon et al., 1979; Weil et al., 1979], and more than 55 mutations have been identified in patients with the three variants [DiMauro and Lamperti, 2001]. The correlation between genotype and phenotype is hard to establish because of the frequent compound heterozygosity. However, there is good correlation between the severity of the mutation and the severity of the clinical phenotype. Therefore, deletions and nonsense mutations are usually associated with the infantile variant, whereas “leaky” mutations, such as the IVS1 (–13T>G) splice site mutations, are associated with the adult-onset variant [Hirschhorn, 1995]. Childhood acid maltase deficiency is often the result of compound heterozygosity [Huie et al., 1998], but it has also been associated with at least one homozygous, apparently specific mutation [Adams et al., 1997].

TREATMENT Trials with lysosome-labilizing agents and activators of glycogenolysis have been unsuccessful in Pompe’s disease [DiMauro et al., 1992]. The use of an acid maltase precursor containing phosphorylated, N-linked, high-mannose carbohydrate chains, which is efficiently taken up by cultured muscle cells from patients, may be more promising [Van Der Ploeg et al., 1988]. Enzyme replacement also looks promising, particularly for patients with childhood- and adult-onset acid maltase deficiency. Recombinant human αglucosidase obtained from the milk of transgenic rabbits and injected into knockout mice lacking acid maltase fully corrected the enzyme defect in all tissues except brain tissue [Bijvoet et al., 1999]. Amalfitano and associates [2001] reported the results of a phase I/II open-label study of recombinant human α-glucosidase administered intravenously twice weekly in three infants with infantile acid maltase deficiency. The results of more than 250 administrations revealed that recombinant human α-glucosidase was generally well tolerated. Steady decreases in heart size and maintenance of normal cardiac function for more than 1 year were observed in all three infants. These infants lived past the critical first birthday and also exhibited improvements in skeletal muscle function. In another study of lateonset acid maltase deficiency, three patients (aged 11, 16, and 32 years)—all wheelchair dependent and two ventilator dependent with a history of deteriorating pulmonary function—received 3 years of treatment with weekly intravenous infusions of recombinant α-glucosidase from rabbit milk; they exhibited stabilized pulmonary function and reported less fatigue [Winkel et al., 2004]. The youngest and least affected patient demonstrated significant improvement of skeletal muscle strength and function and, after 72 weeks of treatment, could walk without support. There have also been promising gene therapy results both in vitro and in vivo using E1-deleted recombinant adenovirus encoding human

α-glucosidase. Transduction of the viral construct into enzyme-deficient human fibroblasts in culture resulted in a dose-dependent return of acid maltase activity, which was localized within lysosomes [Pauly et al., 1998]. Equally encouraging results were obtained by injecting a similar viral construct into the pectoral muscle of acid maltasedeficient Japanese quails, which are an avian model of acid maltase deficiency [Tsujino et al., 1998]. Individuals with childhood or adult acid maltase deficiency may require ventilatory assistance. A high-protein diet has improved strength and respiratory function in some but not all patients [DiMauro et al., 1992; Slonim et al., 1983].

Phosphorylase b Kinase Deficiency CLINICAL FEATURES Phosphorylase b kinase deficiency (glycogenosis type VIII) may be divided into four clinical syndromes [DiMauro and Tsujino, 1994]. These can be differentiated by inheritance and tissue distribution as follows: • Liver disease that is usually benign, begins in infancy or childhood, and is characterized by hepatomegaly, abnormal liver function tests, gross motor delay, failure to thrive, and fasting hypoglycemia [Willems et al., 1990]. Inheritance is X-linked recessive, encoded by a gene in chromosome region Xp22.2-p22.1, or, on occasion, autosomal recessive. The defect is expressed in liver and erythrocytes [Van der Berg and Berger, 1990]. Burwinkel and co-workers [1998] described eight new mutations in the gene encoding the liver isoform of the phosphorylase b kinase alpha subunit and the phenotypic consequence in patients with X-linked liver glycogenosis. • Liver and muscle disease characterized by childhood-onset hepatomegaly, fasting hypoglycemia, and nonprogressive myopathy. This disease is autosomal recessive and caused by mutations in the beta subunit encoded by a gene in chromosome region 16q12-q13. • Myopathy that appears to be X-linked recessive [DiMauro and Lamperti, 2001]. Most patients have childhood- or adolescent-onset exercise intolerance with cramps and weakness in exercising muscles; six patients have been reported with exercise-induced pigmenturia [Abarbanel et al., 1986; Carrier et al., 1990]. Two molecular defects have been identified in the muscle isoform of the alpha subunit, including a nonsense mutation [Wehner et al., 1994] and a splice-junction mutation that causes skipping of one exon [Bruno et al., 1998]. • Fatal infantile cardiomyopathy, which may be autosomal recessive [Mizuta et al., 1984; Servidei et al., 1988a].

LABORATORY FEATURES The resting serum creatine kinase level is variably increased in most patients. The electromyogram may appear normal or may reveal nonspecific myopathic changes. Muscle biopsy specimens may be normal or contain subsarcolemmal accu-

Tein / Metabolic Myopathies

mulations of glycogen, located primarily in type 2B fibers. The phosphorylase stain is normal. There are pools of free, normal-looking glycogen particles on electron microscopic studies [DiMauro and Tsujino, 1994].

BIOCHEMISTRY AND MOLECULAR GENETICS Phosphorylase b kinase participates in glycogen metabolism regulation by acting on the two main enzymes involved in glycogen synthesis and degradation: glycogen synthetase and phosphorylase [Heilmeyer, 1991]. Phosphorylase b kinase converts phosphorylase from the less active “b” form to the more active “a” form and simultaneously converts glycogen synthetase from a more active, dephosphorylated form to a less active, phosphorylated form. Thus, when glycogen synthesis is turned on, glycogen degradation is turned off, and vice versa. Phosphorylase b kinase is a multimeric enzyme composed of four different subunits (alpha, beta, gamma, and delta) [DiMauro and Tsujino, 1994]. The alpha and beta subunits are regulatory, the gamma subunit is catalytic, and the delta subunit is identical to calmodulin and confers calcium sensitivity to the enzyme [DiMauro and Lamperti, 2001]. In addition, there are two isoforms for the alpha subunit (muscle and liver) that are encoded by genes on the X chromosome. The two isoforms for the gamma subunit (muscle and testis) and the beta subunit are encoded by autosomal genes. Glycogen is normal or moderately increased in patients with myopathy, and the phosphorylase b kinase activity is absent or markedly decreased [DiMauro and Tsujino, 1994]. It is not easy to account for the tissue specificity in the different clinical variants. Two distinct genes have been identified. One gene (PHKA1) is on the proximal long arm at chromosome Xq13, which encodes a muscle isozyme; the other gene (PHKA2) is on the distal short arm of the X chromosome at Xp22.2-p22.1, which encodes a nonmuscle isozyme, and is in the same region to which the gene for Xlinked liver glycogenosis resulting from phosphorylase b kinase deficiency has been mapped [Willems et al., 1991]. Tissue-specific isozymes may be the result of alternative RNA splicing. DiMauro and Tsujino [1994] suggested that mutations in tissue that specifically expressed exons of the beta subunit [Harmann et al., 1991] could explain the apparently autosomal-recessive forms of myopathy and fatal infantile cardiomyopathy.

TREATMENT Although there is no specific therapy for phosphorylase b kinase deficiency, a high-protein diet may be helpful.

Phosphorylase Deficiency CLINICAL FEATURES Myophosphorylase deficiency (type V glycogenosis, or McArdle’s disease) is a rare disease but an important cause of recurrent myoglobinuria. Exercise intolerance generally starts in childhood, but overt episodes of muscle cramping and myoglobinuria develop later in adolescence. Brief isometric contraction (e.g., as in lifting heavy objects) and less intense but sustained dynamic exercise (e.g., as in

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climbing stairs) are the two primary precipitants. Approximately 50% of affected patients experience episodes of muscle necrosis and myoglobinuria after exercise, 27% of whom develop acute renal failure. Although there is usually complete functional recovery after the episode of myoglobinuria, about one third of patients have fixed mild proximal weakness greater than distal weakness, which is more commonly seen in older patients [DiMauro and Bresolin, 1986]. The diagnosis is usually made in the second or third decade of life. There may be a marked variation in the severity of symptoms. In some, progressive weakness may begin late in life (the sixth decade) with no history of cramps or pigmenturia [DiMauro and Bresolin, 1986; Pourmand et al., 1983]. The cumulative effect of recurrent muscle damage over the years may explain the appearance of fixed weakness in older individuals. In contrast, there have been four unique childhood cases with severe generalized muscle and respiratory weakness documented at or soon after birth with death in infancy [DiMauro and Hartlage, 1978; DiMauro and Tsujino, 1994; Milstein et al., 1989]. One hypotonic 1-year-old infant has been described with repeated episodes of hyper–creatine kinase–emia during febrile episodes [Ito et al., 2003].

LABORATORY DATA Between episodes of myoglobinuria, the serum creatine kinase is variably increased in 93% of cases. This serves as a feature differentiating phosphorylase b kinase deficiency from carnitine palmitoyltransferase deficiency, in which the resting creatine kinase is generally normal. Electromyography between episodes of myoglobinuria demonstrates fibrillations, myotonic discharges, and positive waves in up to 50% of patients, which are suggestive of mild myopathy [DiMauro and Tsujino, 1994]. There is a lack of cytoplasmic acidification on phosphorus 31 nuclear magnetic resonance (31P-NMR) spectroscopy during aerobic or ischemic exercise, as well as an abnormally steep drop in the phosphocreatine/inorganic phosphate ratio [Argov and Bank, 1991; Ross et al., 1981].

INHERITANCE There is an unexplained, marked male predominance despite the autosomal-recessive pattern of inheritance. The muscle isoform gene has been localized to chromosome 11 [Lebo et al., 1984]. The appearance of the disease in two families with apparent autosomal-dominant transmission [Chui and Munsat, 1976; Schimrigk et al., 1967] may be explained on the basis of subsequent generations of homozygotes and manifesting heterozygotes, in whom the residual activity was below a critical threshold [Papadimitriou et al., 1990; Schmidt et al., 1987]. In a third family, Tsujino and associates [1993a] demonstrated that the affected mother was a compound heterozygote carrying two different point mutations in the phosphorylase gene, the unaffected father was heterozygous for a third point mutation, and the three affected children were compound heterozygotes.

MUSCLE BIOPSY There may or may not be focal accumulations of glycogen between myofibrils and in the subsarcolemmal regions on

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Neuromuscular Disorders / 81

periodic acid-Schiff stain. The phosphorylase stain [Takeuchi and Kuriaki, 1955] reveals no staining in muscle fibers, in contrast to normal staining of the smooth muscle in the walls of intramuscular vessels. DiMauro and Tsujino [1994] pointed out that a positive histochemical reaction may be seen in McArdle’s disease under the following two conditions: (1) when there are regenerating fibers and (2) when there is residual enzyme activity. A false-positive reaction in regenerating fibers results from expression of a different isozyme in immature muscle cells [DiMauro et al., 1978; Sato et al., 1977]. Accumulation of normal-looking glycogen beta particles under the sarcolemma and between myofibrils and myofilaments may be seen on electron microscopy [DiMauro and Tsujino, 1994].

BIOCHEMICAL CONSIDERATIONS Phosphorylase (α-1,4-glucan orthophosphate glycosyl transferase) initiates glycogen breakdown by removing 1,4glucosyl residues phosphorolytically from the outer branches of the glycogen molecule with liberation of glucose-1-phosphate until the peripheral chains have been shortened to approximately four glucosyl units. The debranching enzyme catalyzes the further breakdown. The combined action of these two enzymes degrades glycogen to glucose-1-phosphate (approximately 93%) and glucose (approximately 7%). Muscle phosphorylase exists as an active phosphorylated alpha form and a less active dephosphorylated beta form. The muscle phosphorylase activity is undetectable in most or up to 10% of normal residual activity in affected patients [DiMauro and Tsujino, 1994]. Glycogen accumulation is moderate (about twofold) or normal. The glycogen structure is normal. There is no immunologically detectable enzyme protein in muscle by sodium dodecylsulfate polyacrylamide gel electrophoresis, immunoblot, and enzyme-linked immunosorbent assay in the majority of patients [McConchie et al., 1991; Servidei et al., 1988b]. Normal mature human muscle has a single phosphorylase isozyme, whereas cardiac muscle and brain have three different isozymes on polyacrylamide gel electrophoresis: (1) a minor, slow-migrating isozyme identical to muscle phosphorylase and representing about 13% of total activity in the heart and 8% in the brain; (2) a major, fastmigrating brain isozyme representing 58% of total activity in the heart and 64% in the brain; and (3) an intermediate band (29% of total activity in the heart and 28% in the brain), which is a hybrid of the muscle and brain isozymes [Bresolin et al., 1983]. Lack of the muscle isozyme should therefore cause partial defects in the heart and brain. A defect of the brain isozyme would be expected to cause heart and brain involvement [DiMauro and Tsujino, 1994].

PATHOPHYSIOLOGY The pathophysiology of exercise intolerance in McArdle’s disease involves a combination of interconnected factors related to impaired ATP production from both aerobic and anaerobic glycolysis. The decrease of ATP generated during anaerobic glycolysis may selectively affect muscle ATPases [James et al., 1996], including Na+/K+-ATPase. This inhibition, together with a decrease in Na+/K+ pump numbers, may lead to excessive increases in levels of blood and

extracellular potassium, which are typically seen during exercise in McArdle’s disease [Haller et al., 1998a]. These changes can, in turn, explain the sarcolemmal inexcitability during repetitive neural stimulation [Dyken et al., 1967]. Furthermore, the lack of lactic acid production and intracellular acidification during exercise alters the equilibrium of the creatine kinase reaction, resulting in an exaggerated rise of ADP during exercise. The excessive intracellular ADP is converted to AMP, inosine monophosphate, ammonia, and adenine nucleotide degradation products, including inosine, hypoxanthine, and uric acid [Mineo et al., 1987]. Premature fatigue may result from impaired excitationcontraction coupling, mediated by excessive accumulation of ADP [Lewis and Haller, 1991a]. Oxidative metabolism is also affected in McArdle’s disease, because the block in glycogenolysis impairs production of pyruvate, which is a major anaplerotic substrate for the Krebs cycle [Sahlin et al., 1995]. In patients with McArdle’s disease, oxygen extraction and maximal oxygen uptake are decreased; these can be partially restored by administration of intravenous glucose [Haller et al., 1985].

MOLECULAR GENETICS The three phosphorylase isozyme genes have been cloned, sequenced, and localized to different chromosomes [Billingsley et al., 1994; Lebo et al., 1984; Newgard et al., 1986, 1988; Rao et al., 1992] (see Table 81-1). Tsujino and associates [1993a] identified three different point mutations in the muscle isozyme gene: a C-to-G mutation in codon 49 of exon 1 (converting an arginine molecule to a stop codon), a G-to-A mutation in codon 204 of exon 5 (converting a glycine molecule to a serine molecule), and an A-to-C mutation in codon 542 of exon 14 (converting a lysine molecule to a threonine molecule). In an analysis of 32 patients, 15 were homozygous for the first mutation, and 12 were compound heterozygotes [Tsujino et al., 1993a]. More than 30 mutations have been identified in the muscle isozyme gene, which will facilitate carrier identification [DiMauro and Lamperti, 2001; DiMauro and Tsujino, 1994; Tsujino et al., 1993a, 1994a, 1994b, 1994c]. These include missense, nonsense, and splicejunction mutations. The most common mutation in Europe and North America is the Arg49Stop, which accounts for 81% of the alleles in British patients [Bartram et al., 1993] and 63% of alleles in a survey of U.S. patients [El-Schahawi et al., 1996]. The high frequency of this mutation, on at least one allele, has facilitated molecular diagnosis in blood samples from patients with suspected McArdle’s disease. However, it is important to realize that the frequency of different mutations varies in different ethnic groups. The frequency of the Arg49Stop mutation appears to decrease from north to south in Europe from 81% of alleles in the United Kingdom [Bartram et al., 1993] to 56% in Germany [Vorgerd et al., 1998] and 32% in Italy [Martinuzzi et al., 1996]. To date, there has been no clear genotype:phenotype correlation in McArdle’s disease. For example, the common homozygous Arg49Stop mutation was also present in an infant with the fatal myopathic variant [Tsujino et al., 1993a] and in a child who died of sudden infant death syndrome [El-Schahawi et al., 1997]. This lack of clear correlation between genotype and phenotype was also documented in a study of 54 Spanish patients with McArdle’s disease from

Tein / Metabolic Myopathies

40 unrelated families [Martin et al., 2001]. One possible explanation for increased severity of clinical manifestation would be the presence of additional gene defects, such as myoadenylate deaminase deficiency [Rubio et al., 1997; Tsujino et al., 1995a].

TREATMENT A key therapeutic strategy has been the attempt to bypass the metabolic block by providing the muscle with glycolytic substrates [DiMauro and Tsujino, 1994]. The oral administration of glucose or fructose to raise the blood glucose concentration has been helpful but has resulted in weight gain. Glucagon injections were impractical and yielded inconsistent results. Although exercise tolerance was increased by raising the serum free fatty acid concentration through the use of fat emulsions, fasting, and the administration of norepinephrine or heparin, more practical regimens such as a high-fat, lowcarbohydrate diet have not been effective [DiMauro and Bresolin, 1986]. An alternative strategy was to supply branched-chain amino acids, which are taken up, rather than released, by tissue of patients with McArdle’s disease during exercise [Wahren et al., 1973]. Slonim and Goans [1985] demonstrated an improvement of muscle endurance and strength in a patient with weakness after institution of a highprotein diet. Direct administration of branched-chain amino acids to six patients, however, resulted in an impairment rather than an improvement of bicycle exercise capacity in five of the six patients, possibly because of a lowering of free fatty acid levels by the amino acids [MacLean et al., 1998]. In contrast, aerobic training in four McArdle’s patients improved peak cycle exercise capacity, circulatory capacity, and oxygen uptake [Haller et al., 1998b]. Vitamin B6 is another potential therapeutic aid, inasmuch as overall body stores of pyridoxal phosphate are depleted in McArdle’s disease because of the lack of enzyme protein to which pyridoxal phosphate is bound [Haller et al., 1983]. One patient experienced a beneficial effect with vitamin B6 supplementation [Phoenix et al., 1998] but further studies need to be done. In addition, oral creatine monohydrate supplementation in a placebo-controlled crossover trial involving nine patients was demonstrated to alleviate symptoms and increase patients’ capacity for ischemic, isometric forearm exercise [Vorgerd et al., 2000]. Another strategy has been the ingestion of sucrose before exercise to increase the availability of glucose [Vissing and Haller, 2003]. In a single-blind, randomized, placebo-controlled crossover study, 12 patients were studied. Ingestion of sucrose before exercise improved exercise tolerance and sense of well-being. Finally, a first-generation adenoviral recombinant containing the full-length human myophosphorylase complementary DNA has been efficiently transduced into phosphorylasedeficient sheep myoblasts and human myoblasts, resulting in restoration of phosphorylase activity [Pari et al., 1999].

Debrancher Deficiency CLINICAL FEATURES Debrancher deficiency (glycogenosis type III) is characterized by childhood-onset liver dysfunction with hepatomegaly, growth failure, fasting hypoglycemia, and infrequently

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hypoglycemic seizures. Spontaneous resolution may occur around puberty with normal adult liver function [Smit et al., 1990], although cirrhosis and liver failure may develop later [Fellows et al., 1983]. The myopathy tends to appear late in the third or fourth decade in 70% of cases and involves primarily distal leg and intrinsic hand muscles. It is slowly progressive and rarely incapacitating. Childhood onset was documented in 7 of 22 patients. Two patients had exercise intolerance, cramps, and premature fatigue [Murase et al., 1973; Ozand et al., 1967], and five others had diffuse weakness and wasting, growth failure, and gross motor delay [Badurska et al., 1970; Slonim et al., 1982]. Myoglobinuria was reported in one case [Brown, 1986]. Enzymatic deficiency was documented in the muscle of 16 patients, 11 of whom had no weakness [Moses et al., 1986]. However, in view of the young ages of these patients (2 to 27 years), it is possible that clinical myopathy developed later. Peripheral neuropathy has also been documented [Moses et al., 1986]. Although clinical cardiomyopathy is infrequent, cardiac involvement has been demonstrated in most patients with myopathy [Brunberg et al., 1971; Miller et al., 1972; Moses et al., 1989]. Of interest, Cleary and associates [2002] reported consistent facial features in seven patients with glycogenosis type III, which included midfacial hypoplasia with a depressed nasal bridge and a broad upturned nasal tip, indistinct philtral pillars, and blow-shaped lips with a thin vermillion border. In addition, younger patients had deep-set eyes. Several children had clinical problems such as persistent otitis media or recurrent sinusitis.

LABORATORY DATA Administration of glucagon or epinephrine in the fasting state does not increase blood glucose levels, which indicates liver involvement [DiMauro and Tsujino, 1994]. All patients with myopathy have an increase in serum creatine kinase levels. The electromyogram has characteristics of myopathy but may also demonstrate fibrillation activity, and the nerve conduction velocities are frequently decreased [Brunberg et al., 1971; Moses et al., 1986]. Evidence of left ventricular or biventricular hypertrophy may be seen on the electrocardiogram and echocardiogram [Brunberg et al., 1971; Moses et al., 1989; Smit et al., 1990].

INHERITANCE There is a male predominance. The gene has been assigned to chromosome 1p21 [Yang-Feng et al., 1992]. Prenatal diagnosis can be made by a qualitative assay on the basis of persistence of the abnormal polysaccharide in cultured amniocytes exposed to a glucose-free medium [Yang et al., 1990].

PATHOLOGY A severe vacuolar myopathy, which contains periodic acidSchiff stain–positive material that is digested by diastase, is seen on muscle biopsy. This myopathy corresponds to large pools of free and apparently normal glycogen particles seen on electron microscopic studies [DiMauro and Tsujino, 1994]. Excessive glycogen is also seen in skin biopsy specimens [Sancho et al., 1990], cultured muscle [Miranda et al., 1981], endomyocardial biopsy specimens [Olson et al.,

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1984], intramuscular nerves [Powell et al., 1985], and Schwann cells and axons of sural nerve [Ugawa et al., 1986], and brain tissue [Hug and Schubert, 1966].

BIOCHEMISTRY The debrancher enzyme is a single 160-kDa polypeptide with two distinct catalytic functions. After digestion of glycogen to four glucosyl units by phosphorylase, the residual stubs are removed by the debrancher enzyme in two steps, a transferase and a glucosidase, which are located in different domains of the polypeptide [Bates et al., 1975]. On the basis of enzymatic and immunologic assays, debrancher deficiency has been classified into three groups [Chen et al., 1987; Ding et al., 1990]: (1) common type IIIA, characterized by lack of both transferase and glucosidase activity and lack of cross-reacting material in both muscle and liver; (2) less frequent type IIIB, characterized both by lack of enzymatic activities and by a lack of or marked decrease in cross-reacting material in liver, with sparing of the muscle and heart; and (3) type IIIC, characterized by the selective loss of transferase activity in both liver and muscle and the presence of cross-reacting material.

MOLECULAR GENETICS Human debrancher complementary DNA has been isolated and sequenced [Yang et al., 1992]. A number of mutations have been described in glycogenosis type IIIa [Okubo et al., 1996, 1999, 2000; Parvari et al., 1998; Shaiu et al., 2000; Shen et al., 1996, 1997] and in glycogenosis type IIIb [Shen et al., 1996]. It is interesting to note that most patients with the type IIIb variant have mutations in exon 3 of the debrancher gene, which are expected to result in truncated proteins [Shen et al., 1996]. Whereas the overall incidence of type III glycogenosis in the U.S. is about 1 in 100,000 live births, it is unusually frequent among Jews of north African descent in Israel (prevalence, 1 per 5400; carrier prevalence, 1 per 35) [Parvari et al., 1997]. Another ethnic group with a high prevalence of glycogenosis type III—1 per 3600, with a carrier frequency of 1 per 30—are individuals from the Faroe Islands [Santer et al., 2001].

TREATMENT Fasting hypoglycemia should be avoided in infants and young children with debrancher deficiency through the implementation of frequent feedings and nocturnal gastric glucose infusions and uncooked cornstarch [Fernandes, 1990]. A marked improvement after institution of a high-protein diet overnight for 6 months was documented in a 7-year-old child with severe weakness and wasting [Slonim et al., 1982]. However, a 6-month high-protein diet had no significant effect on an adult with myopathy and distal wasting [DiMauro and Tsujino, 1994].

Phosphofructokinase Deficiency CLINICAL FEATURES Muscle phosphofructokinase deficiency (glycogenosis type VII) has been reported in fewer than 40 patients [Rowland

et al., 1986]. Exercise intolerance with cramps and compensated hemolysis are the main clinical features. Fixed weakness of late adult onset was prominent in three patients. Myoglobinuria has been documented in 10 of 25 patients. Six children have been reported with early severe myopathy, with or without contractures [Amit et al., 1992; DiMauro and Tsujino, 1994]. One male also had a cardiomyopathy and died at 21 months of age [Amit et al., 1992]. None of the infantile cases had hemolysis, which is suggestive of different molecular etiologies. Other associated multisystem signs in infants or very young children have included seizures, cortical blindness, corneal opacifications, and cardiomyopathy [DiMauro and Lamperti, 2001]. Four patients had hemolysis without myopathy; two of these patients had normal or only mildly decreased muscle activity and about half-normal erythrocyte phosphofructokinase activity. This finding was attributed to instability of the muscle-specific subunit of phosphofructokinase [Etiemble and Kahn, 1976; Kahn et al., 1975]. Minor clinical differences from McArdle’s disease include more common reports of nausea and vomiting during exercise-induced crises of myalgia, cramps, and weakness and lesser frequency of attacks of myoglobinuria [DiMauro and Lamperti, 2001]. Considering that phosphofructokinase deficiency blocks both the metabolism of muscle glycogen and blood glucose, Haller and Vissing [2004] studied five indiiduals with muscle phosphofructokinase deficiency and 29 patients with McArdle’s disease during continuous cycle exercise. They found that no phosphofructokinase-deficient patient developed a spontaneous second-wind phenomenon under conditions that consistently produced one in patients with McArdle’s disease and concluded that the ability to metabolize blood glucose was critical to the development of a typical spontaneous second-wind phenomenon.

LABORATORY DATA The serum creatine kinase concentration is usually increased in patients with muscle disease. Hemolysis is indicated by an increased serum bilirubin level and moderate reticulocytosis [DiMauro and Tsujino, 1994]. Most patients have an increase in uric acid. The electromyogram may appear normal or myopathic. 31P-NMR spectroscopy reveals a pattern different from that obtained in McArdle’s disease, because in phosphofructokinase deficiency, as well as in other defects of distal glycolysis, glycolytic intermediates accumulate in muscle as phosphorylated monoesters and can be detected as a distinct spectral peak [Argov and Bank, 1991].

INHERITANCE The gene encoding the muscle (M) subunit is located on chromosome 1 [Vora et al., 1982].

MUSCLE BIOPSY Diagnosis can be made from a negative histochemical phosphofructokinase stain [Bonilla and Schotland, 1970]. The definitive diagnosis comes from the biochemical analysis but only if the muscle specimen is snap-frozen at the time of biopsy, because phosphofructokinase is highly labile and its activity declines rapidly in specimens kept at room temperature or on wet ice, which is why partial phosphofructo-

Tein / Metabolic Myopathies

inase deficiencies with residual activities above 10% or 20% of normal should be considered skeptically [DiMauro and Lamperti, 2001]. An important feature differentiating this condition from McArdle’s disease is the presence of an abnormal polysaccharide in some cases, particularly older patients [Hays et al., 1981]. This abnormal polysaccharide has the characteristics of polyglucosan and stains intensely with the periodic acid-Schiff reaction but is resistant to diastase digestion, and, ultrastructurally, it is composed of finely granular and filamentous material, similar to the storage material seen in branching enzyme deficiency and in Lafora’s disease [DiMauro and Lamperti, 2001].

BIOCHEMISTRY Phosphofructokinase (ATP:D-fructose-1-phosphotransferase) is a tetrameric enzyme under the control of three structural loci that encode three distinct subunits: M (muscle), L (liver), and P (platelet) [Vora, 1983; Vora et al., 1983a]. The three subunits have variable expression in different tissues. Mature human muscle expresses only the M subunit, whereas erythrocytes express both the M and L subunits, thereby containing five isozymes. In the typical form of phosphofructokinase deficiency, genetic defects of the M subunit cause total lack of activity in muscle and partial enzyme deficiency in erythrocytes, in which the homotetramer L4 is responsible for the residual activity. Other tissues, such as liver, that express predominantly the L subunit are not affected.

PATHOPHYSIOLOGY The functional consequences of phosphofructokinase deficiency are similar to those observed in McArdle’s disease and are related to the inability of muscle to generate pyruvate [DiMauro and Tsujino, 1994]. With the ischemic exercise test, the venous lactate levels fails to rise [Tarui et al., 1965). However, phosphofructokinase deficiency differs signific-antly from phosphorylase deficiency by the inability of phosphofructokinase-deficient muscle to use glucose. Because of this inability, maximal oxygen uptake has been increased by increasing free fatty acid availability [Haller and Lewis, 1991]. Exercise intolerance is not decreased by glucose administration, which is potentially harmful because it reduces the concentration of free fatty acids and ketones. This problem explains why high-carbohydrate meals exacerbate exercise intolerance in patients with phosphofructokinase deficiency, a situation referred to as the out-of-wind phenomenon [Haller and Lewis, 1991]. The excessive exercise-induced degradation of muscle purine nucleotides likely accounts for the hyperuricemia present in phosphofructokinase-, phosphorylase-, and debrancherdeficient patients [Mineo et al., 1987]. Finally, in phosphofructokinase deficiency, as in McArdle’s disease, exercise triggers increases in heart rate, cardiac output, and blood flow, which are exaggerated in relation to the muscle’s capacity to use oxygen [Lewis et al., 1991].

MOLECULAR GENETICS The genes encoding the M, P, and L subunits have been assigned to chromosomes 1, 10, and 21 (see Table 81-1)

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[Van Keuren et al., 1986; Vora et al., 1982, 1983b]. The M subunit complementary DNA has been isolated and sequenced [Nakajima et al., 1987], and evidence for tissuespecific alternative messenger RNA splicing has been documented [Nakajima et al., 1990]. At least 20 mutations responsible for muscle phosphofructokinase deficiency have been identified [DiMauro and Lamperti, 2001; DiMauro et al., 1995; Sherman et al., 1994; Tsujino et al., 1994d]. Raben and Sherman [1995] tabulated 15 disease-inducing mutations of the muscle phosphofructokinase gene and several polymorphisms. These included splicing defects, frameshifts, and missense mutations in patients from six different ethnic backgrounds, supporting of genetic heterogeneity of the disease. This disorder appeared to be particularly prevalent among individuals of Ashkenazi Jewish descent. The most frequent mutation in these patients was an exon 5 splicing defect, which accounted for approximately 68% of the mutant alleles. Patients in whom muscle phosphofructokinase deficiency is diagnosed in the United States have been of Ashkenazi Jewish origin, and the several mutations identified in them differ from those described in the non-Ashkenazi Italian and Japanese patients [DiMauro et al., 1995].

TREATMENT Glucose is not an alternative substrate in phosphofructokinase deficiency. A high-protein diet may be beneficial, although this has not been tried [DiMauro and Tsujino, 1994]. A 2-year-old male with the severe infantile form of phosphofructokinase deficiency, including arthrogryposis multiplex congenita, respiratory insufficiency, slowed motor nerve conduction velocities, and abnormal electroencephalographic patterns had a significant improvement in strength, electromyographic features, and electroencephalographic patterns on the ketogenic diet [Swoboda et al., 1997]. Unfortunately, the child died of complications of pneumonia at 35 months.

Phosphoglycerate Kinase Deficiency CLINICAL FEATURES Phosphoglycerate kinase deficiency (glycogenosis type IX) manifests with nonspherocytic hemolytic anemia and dysfunction of the central nervous system [Boivin et al., 1974; Valentine et al., 1960]. Neurologic problems have included behavioral abnormalities, mental retardation, seizures, and strokes. In hemizygous male patients, the severe hemolytic anemia manifests soon after birth with jaundice, splenomegaly, and hemoglobinuria. Childhood mortality has been reported in four members of one family [Valentine et al., 1960]. Heterozygous females may be normal or may have mild chronic hemolytic anemia. Myopathic features have included myopathy in males [DiMauro et al., 1981a, 1983a; Morimoto et al., 2003; Rosa et al., 1982; Tonin et al., 1993] with exercise intolerance, cramps, and myoglobinuria. Twenty phosphoglycerate kinase variants with reduced phosphoglycerate kinase activity have been identified; myopathy was present in eight of these variants [Tsujino et al., 1995b].

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LABORATORY DATA Myopathic patients demonstrate an inconsistent increase in resting serum creatine kinase level.

INHERITANCE Phosphoglycerate kinase is located on the long arm of the X chromosome (see Table 81-1). The defect is expressed in fibroblasts, and prenatal diagnosis is possible [DiMauro and Tsujino, 1994].

MUSCLE BIOPSY Periodic acid–Schiff stain for glycogen illustrated mildly increased levels in one patient. Electron microscopic studies demonstrated glycogen accumulation in all patients [DiMauro and Tsujino, 1994].

BIOCHEMISTRY Human phosphoglycerate kinase is a single polypeptide encoded on the X chromosome for all tissues except spermatogenic cells [DiMauro and Tsujino, 1994]. The complete amino acid sequence of normal human phosphoglycerate kinase has been determined [Huang et al., 1980a, 1980b], and mutations have been identified. Patients with hemoglobinuria and those with myopathy demonstrate genetic heterogeneity in enzyme activities. Phosphoglycerate kinase mutant genes associated with myopathy have been named Creteil [Rosa et al., 1982], New Jersey [DiMauro et al., 1983a], Alberta [Tonin et al., 1993], Hamamatsu [Sugie et al., 1989], Shizuoka [Fujii et al., 1992], and North Carolina [Tsujino et al., 1994e]. Because phosphoglycerate kinase is a monomer, there are no tissuespecific isoforms with the exception of phosphoglycerate kinase 2, which is confined to spermatogenic cells; therefore the defect should be expressed in all tissues. In three patients with myopathy, phosphoglycerate kinase was documented to be significantly decreased in erythrocytes, leukocytes, platelets, fibroblasts, and muscle culture [DiMauro et al., 1983a; Rosa et al., 1982; Tonin et al., 1993].

PATHOPHYSIOLOGY It is difficult to explain the lack of clinical myopathy in many patients with hemolytic anemia and conversely, the selective involvement of muscle in other patients [DiMauro and Tsujino, 1994]. However, one patient with phosphoglycerate kinase Shizuoka has been described with chronic hemolysis and myoglobinuria [Fujii et al., 1992], and a second patient has been described with hemolytic anemia, central nervous system dysfunction, and myopathy [Sugie et al., 1994]. Systematic correlation of molecular genetic, biochemical, and clinical data in future patients may provide insight into the explanation for the striking clinical heterogeneity of phosphoglycerate kinase deficiency [Tsujino et al., 1995b].

MOLECULAR GENETICS A full-length complementary DNA for the normal phosphoglycerate kinase gene on the X chromosome has been isolated [Michelson et al., 1983], and genetic heterogeneity

has been documented [Tonin et al., 1993]. Seven missense mutations and one splice-junction mutation have been identified in eight patients, three of whom had myopathy [Fujii et al., 1992; Morimoto et al., 2003; Tsujino et al., 1994e, 1995b]. The testicular isozyme, phosphoglycerate kinase 2, is encoded by a gene on chromosome 19 [DiMauro and Lamperti, 2001].

Phosphoglycerate Mutase Deficiency CLINICAL FEATURES Phosphoglycerate mutase deficiency (glycogenosis type X) has been reported in four men and two women [DiMauro et al., 1981b; DiMauro and Tsujino, 1994]. Exercise intolerance, cramps, and myoglobinuria are the main clinical features.

LABORATORY DATA Four patients demonstrated an increase in serum creatine kinase concentration between attacks. Results of electromyographic and nerve-conduction studies were normal.

MUSCLE BIOPSY A variable increase in the periodic acid–Schiff stain reaction has been demonstrated on histochemical examination, and electron microscopic studies have confirmed mild glycogen accumulation in most cases [DiMauro and Tsujino, 1994].

BIOCHEMISTRY Phosphoglycerate mutase catalyzes the conversion of 3-phosphoglycerate to 2-phosphoglycerate and is very active in normal human muscle [DiMauro et al., 1981b, 1982]. The glycogen concentration in muscle was normal in four patients and moderately increased in two [DiMauro and Tsujino, 1994]. Insufficient in vitro lactate production has been demonstrated in three patients during anaerobic glycolysis [DiMauro et al., 1981b; Servidei and DiMauro, 1989]. The residual phosphoglycerate mutase activity varied from 2.1% to 6% of normal. Human phosphoglycerate mutase is a dimeric enzyme that consists of different proportions of a slow-migrating muscle (MM) isozyme, a fast-migrating brain (BB) isozyme, and an intermediate hybrid (MB) form in different tissues [Omenn and Cheung, 1974; Omenn and Hermodson, 1975]. The electrophoretic pattern of normal adult human muscle phosphoglycerate mutase reveals a marked predominance of the MM band, with only faint BB and MB bands [DiMauro et al., 1981b, 1982; Omenn and Cheung, 1974; Omenn and Hermodson, 1975]. The only other tissues containing substantial amounts of the M subunit are heart and sperm, although there is no evidence of cardiomyopathy or male infertility in phosphoglycerate mutase deficiency [DiMauro and Lamperti, 2001]. In cardiac muscle, the MM isozyme predominates, although all three bands are seen [DiMauro et al., 1981b; Omenn and Hermodson, 1975]. In most other tissues, such as those of the brain, liver, leukocytes, and erythrocytes, BB is the only isozyme present on electrophoresis of PGAM-BB [Omenn and Cheung, 1974; Omenn and Hermodson, 1975].

Tein / Metabolic Myopathies

PATHOPHYSIOLOGY Normal lactate production was demonstrated in one patient during maximal aerobic exercise [Kissel et al., 1985]. 31 P-NMR studies revealed exercise-induced accumulation of phosphorylated monoesters and mild intracellular acidosis [Argov et al., 1987].

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encoding lactate dehydrogenase-H has been assigned to chromosome 12 [Chen et al., 1973]. Five mutations have been described that lead to muscle lactate dehydrogenase deficiency [DiMauro et al., 1995; Maekawa et al., 1990, 1991, 1994].

Branching Enzyme Deficiency

MOLECULAR GENETICS

CLINICAL FEATURES

A full-length ccomplementary DNA [Shanske et al., 1987] and the genomic clone for phosphoglycerate mutase-M [Tsujino et al., 1989] have been isolated and sequenced, and the gene has been localized to chromosome 7 [Edwards et al., 1989]. Tsujino and associates [1993b] identified three distinct point mutations in five patients with phosphoglycerate mutase-M deficiency. A full-length complementary DNA has been identified for phosphoglycerate mutase-B [Sakoda et al., 1988]. The gene has been localized to chromosome 10 [Junien et al., 1982].

Branching enzyme (brancher) deficiency (glycogenosis type IV) manifests in infancy as a rapidly progressive disease dominated by liver dysfunction with hepatosplenomegaly and cirrhosis, with death from hepatic failure or gastrointestinal bleeding by 4 years of age [DiMauro and Tsujino, 1994]. Other clinical features include hypotonia, muscle wasting, and contractures [Fernandes and Huijing, 1968; Zellweger et al., 1972]. Cardiomyopathy has also been documented in several affected children [Farrans et al., 1966; Servidei et al., 1987]. Isolated myopathy has been reported in six patients, three siblings with delayed motor development and chronic proximal weakness [Reusche et al., 1992], a child with myopathy and hepatic involvement [Bruno et al., 1999], and two adults in whom proximal weakness had started at 26 and 49 years of age [Bornemann et al., 1996; Ferguson et al., 1983]. Schroder and co-workers [1993] reported a case of juvenile type IV glycogenosis with total brancher deficiency in skeletal muscle and liver in a male patient who presented with severe myopathy, dilated cardiomyopathy, heart failure, dysmorphic features, and subclinical neuropathy and who died at age 19 of sudden cardiac death. Alegria and associates [1999] reported hydrops fetalis as a presenting manifestation of glycogenosis type IV. The infant was delivered by cesarean section at 34 weeks and had generalized edema, severe hypotonia, and arthrogryposis of the lower limbs at birth and died at 4 days of age. Cox and colleagues [1999] reported three sibling fetuses who were documented to have type IV glycogenosis by pathologic and biochemical studies and who had onset of hydrops, limb contractures, and akinesia early in the second trimester. This disease has considerable clinical heterogeneity. Brancher deficiency has been identified in the leukocytes of two Israeli patients with adult polyglucosan body disease [Lossos et al., 1991]. Adult polyglucosan body disease has been described in approximately 15 patients and is characterized by progressive upper and lower motor neuron involvement, sensory loss, sphincter problems, neurogenic bladder, and, in some cases, dementia [Bruno et al., 1993; Cafferty et al., 1991].

Lactate Dehydrogenase Deficiency CLINICAL FEATURES Lactate dehydrogenase deficiency (glycogenosis type XI) has been reported in two young men with exercise intolerance and recurrent myoglobinuria [Bryan et al., 1990; Kanno et al., 1980]. It has also been reported in an asymptomatic woman through blood screening [Maekawa et al., 1984]. In addition to muscle symptoms, three affected Japanese women suffered from dystocia, which necessitated cesarean sections, and a few patients had dermatologic problems [Kanno et al., 1995]. Takayasu and colleagues [1991] reported a 16-year-old Japanese female who had desquamating erythematosquamous lesions primarily on the extensor surface of the extremities. The epidermis of the diseased skin and scalp hair follicles were virtually devoid of lactate dehydrogenase activity.

LABORATORY DATA The forearm ischemic exercise test demonstrated an abnormally low increase in venous lactate, in contrast to an excessive increase in pyruvate, in all three patients studied. The muscle biopsy specimen was normal in one patient [Bryan et al., 1990].

BIOCHEMISTRY Lactate dehydrogenase is a tetrameric enzyme composed of two subunits, M (or A) and H (or B), which result in five isozymes, the two homotetramers, M4 and H4, and the three hybrid forms. The M subunit-containing isozymes predominate in skeletal muscle. The H subunit-containing isozymes predominate in heart and other tissues [DiMauro and Tsujino, 1994].

MOLECULAR GENETICS The gene encoding lactate dehydrogenase-M has been assigned to chromosome 11 [Boone et al., 1972]. The gene

LABORATORY DATA Carbohydrate tolerance tests and the response of blood glucose to glucagon or epinephrine are normal in affected patients with liver disease [DiMauro and Tsujino, 1994]. The serum creatine kinase concentration is inconsistently increased. Echocardiography revealed cardiac dilatation and impaired shortening of the left ventricular ejection fraction in one patient [Servidei et al., 1987]. Sensorimotor axonopathy has been demonstrated in patients with adult polyglucosan body disease [Bruno et al., 1993; Cafferty et al., 1991].

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INHERITANCE

BIOCHEMISTRY

Prenatal diagnosis is possible in fibroblasts and amniocytes [Brown and Brown, 1989].

Biochemical assays revealed a profound reduction in muscle and red blood cell aldolase levels and a decrease in the thermostability of the residual enzyme [Kreuder et al., 1996]. The enzyme is a tetramer of identical 40,000-Da subunits. Vertebrates have three aldolase isozymes that are distinguished by their electrophoretic and catalytic properties [Charlesworth, 1972].

MUSCLE BIOPSY Muscle biopsy demonstrates deposits of basophilic, intensely periodic acid–Schiff stain–positive material, which is only partially sensitive to diastase digestion. Electron microscopy reveals storage material consisting of filamentous and finely granular material often associated with normal-looking glycogen beta particles [DiMauro and Tsujino, 1994]. The abnormal polysaccharide is found in skin, liver, muscle, heart, and the central nervous system. In adult polyglucosan body disease, polyglucosan bodies have been found in both gray and white matter in the processes of neurons and astrocytes. In sural nerve biopsies, the bodies are in the axoplasm primarily of myelinated fibers and in Schwann cells [Cafferty et al., 1991].

BIOCHEMISTRY Branching enzyme catalyzes the last step in glycogen biosynthesis by attaching a short glucosyl chain in an α-1,6-glucosidic link to a naked peripheral chain of nascent glycogen [DiMauro and Tsujino, 1994]. The polysaccharide that accumulates has peripheral chains that are longer than normal and fewer branching points than does normal glycogen.

MOLECULAR GENETICS Several mutations have been identified in patients with different clinical presentations [Bao et al., 1996; Bruno et al., 1999]. One of these, Tyr329Ser, was present in seven patients with adult polyglucosan body disease [Lossos et al., 1998].

TREATMENT A number of strategies have been used, including administration of glucagon; long-term use of steroids; a highprotein, low-carbohydrate diet; and administration of fungal α1,4-glucosidase and α-1,6-glucosidase. These strategies have been ineffective [DiMauro and Tsujino, 1994]. Liver transplantation was thought to be beneficial in 10 children [Selby et al., 1991], although one child developed intractable cardiomyopathy 2 years after transplantation [Sokal et al., 1992].

Aldolase A Deficiency (Glycogenosis Type XII) CLINICAL FEATURES This disorder was discovered in 1996 in a 4-year-old male who presented with episodic exercise intolerance and weakness after febrile illnesses [Kreuder et al., 1996]. This boy was considered to have myoglobinuria even though his highest serum creatine kinase concentration was 6480 U/liter (normal, <60 U/liter). He also had proximal muscle wasting with weakness and episodes of nonspherocytic hemolytic anemia and jaundice.

MOLECULAR GENETICS The aldolase A gene has been mapped to chromosome region 16q22-q24, and two pseudogenes were found on chromosomes 3 and 10 [Kukita et al., 1987; Serero et al., 1988]. The patient described by Kreuder and colleagues [1996] was found to be homozygous for a germline mutation in which a negatively charged glutamic acid is changed to a positively charged lysine at residue 206, a residue that is highly conserved within the subunit interface region.

FATTY ACID OXIDATION DISORDERS Historical Background Fatty acid oxidation disorders are an important group of diseases because they potentially are rapidly fatal and are a source of major morbidity. They manifest with a spectrum of clinical disorders, including recurrent myoglobinuria; progressive lipid storage myopathy; neuropathy, progressive cardiomyopathy; recurrent hypoglycemic hypoketotic encephalopathy, or Reye-like syndrome; seizures; and mental retardation. All of the currently known conditions are inherited as autosomal-recessive traits. Thus, there is frequently a family history of sudden infant death syndrome in siblings. Early recognition and prompt institution of therapy, appropriate preventive measures, and, in certain cases, specific therapy may be lifesaving and may significantly decrease long-term morbidity, particularly with regard to central nervous system sequelae. There are at least 20 recognized defects in fatty acid oxidation, most of which have been diagnosed since 1990. With the significant advances in bioedical technology, there has been a rapid increase in the number of subsequently diagnosed cases. For example, in a study of 410 consecutive neonatal blood-spot cards in a northern English population for the most common mutation for MCAD deficiency (substitution of a guanine for an adenine at base pair 985 in the MCAD gene), the data suggested a heterozygote carrier state of 1 per 68 for this particular mutation, with a projected homozygote frequency of approximately 1 per 18,500 births [Blakemore et al., 1991; Gregersen et al., 1991]. The incidence for MCAD deficiency was even higher, at 1 per 8930 live births, in a more recent survey from the Pennsylvania neonatal screening program, in which diagnosis by tandem mass spectrometry was followed by confirmation through molecular analysis for several common mutations [Ziadeh et al., 1995]. The delay in recognition of these disorders can be attriuted to three major factors. First, fatty acid oxidation does not play a major role in energy production until relatively

Tein / Metabolic Myopathies

late in fasting. Thus, affected individuals may remain clinically asymptomatic until they experience periods of fasting beyond 12 hours or prolonged exercise. In a number of cases, the acute decompensation may be precipitated by an intercurrent infection with fasting, vomiting, and shivering thermogenesis. Second, results of routine laboratory tests, such as that for urinary ketones, may not demonstrate the defect in fatty acid oxidation, unless the blood and urine samples are obtained at the time of the acute episode. If they are obtained after the child has received intravenous glucose therapy or has recovered from the acute illness, the defect may be missed. Thirdly, there has been a rapid expansion in the methods for identifying defects in fatty acid oxidation. For example, methods to identify abnormal fatty acid metabolites in the urine through gas chromatography/mass spectrometry have been available only since the mid-1970s. The identification of certain characteristic organic acid profiles in urine specimens taken during the acute episode has been seminal in the diagnosis of the probable site of defect.

Fasting Adaptation

Endothelium

Blood

Plasma membrane

Fats constitute the most important and efficient fuel for oxidative metabolism and are the largest reserve of fuel in the body. Because liver glycogen stores are depleted within a few hours of a meal, and because there are no reserve stores of protein in the body, fatty acids become the predominant substrate for oxidation quite early in fasting [Stanley, 1987]. In adults, fatty acids provide approximately 80% of caloric requirements after a 24-hour period of fasting; this proportion increases to 94% during more prolonged fasting. Fatty acids serve three major functions. First, the partial oxidation of fatty acids by the liver produces

Muscle

Palmitate (albumin)

5

9

Palmitate carnitine

There are several reasons for an increased risk of problems with fasting adaptation in infants and young children [Aynsley-Green, 1982; Bier et al., 1977; Pildes et al., 1973]. First, because of the large ratio of surface area to body mass, basal energy needs in the infant are high so as to maintain body temperature. Shivering thermogenesis, which maintains body temperature, is highly dependent on efficient fatty acid oxidation. Second, infants have a larger brain in comparison with body size. The developing brain is highly dependent on glucose and has a high rate of metabolism [Hale and Bennett, 1992]; therefore, infants and children exhibit even earlier activation of fatty acid oxidation with hyperketonemia within 12 to 24 hours of fasting. Third, there is a lower activity of several key enzymes involved in energy production in the infant than in the older child and

Mitochondrial matrix Palm-carnitine CoA

6

7

3

2 VLDL Carnitine

Increased Susceptibility of the Child

CoA

TG

1

ketones, which are an important auxiliary fuel for almost all tissues and particularly for the brain. Because the bloodbrain barrier prevents the direct use of long-chain fatty acids by the brain, ketones provide an important mechanism with which to spare glucose oxidation and proteolysis during prolonged fasting [Cahill, 1970]. Second, fatty acids serve as a major fuel for cardiac and skeletal muscle. During mildto-moderate prolonged exercise and during rest, muscle depends primarily on fatty acid oxidation [Essen, 1978; Felig and Wahren, 1975; Gollnick et al., 1974]. Third, the high rates of hepatic gluconeogenesis and ureagenesis needed for maintaining fasting homeostasis are sustained by the production of energy (ATP), reducing equivalents, and metabolic intermediates derived from fatty acid oxidation [Hale and Bennett, 1992].

Outer Inner mitochondrial mitochondrial membrane membrane Palm-carnitine

Lipid droplet

4

Palm-CoA Carnitine

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Palm-CoA Carnitine 8

Myristoyl-CoA

Acetyl CoA FADH2 NADH + H+

FIGURE 81-2. Schematic representation of long-chain fatty acid metabolism in muscle. Bloodborne substrates are represented by fatty acids bound to albumin and by triglycerides in the form of verylow-density lipoproteins (VLDL). Endogenous lipid stores are triglycerides (TG) in lipid droplets. Enzymes or enzyme complexes are indicated by circled numbers adjacent to or within the membrane to which they are bound: 1, lipoprotein lipase; 2, intracellular neutral triglyceride, diglyceride, and monoglyceride lipase; 3, triglyceride synthetic pathway; 4, palmitoyl (Palm)-coenzyme A (CoA) synthetase; 5, CPT I; 6, carnitineacylcarnitine translocase; 7, carnitine palmitoyltransferase II; 8, beta oxidation pathway; 9, active transport system for carnitine. FADH2, flavin adenine dinucleotide, reduced form; H+, hydrogen ion; Mit, mitochondrial; NADH, nicotinamide adenine dinucleotide, reduced form. (From DiMauro S, Tonin P, Servidei S. In: Rowland LP, DiMauro S, eds. Handbook of clinical neurology, vol 18, Myopathies. Amsterdam: Elsevier Science, 1992;479–526.)

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adult, which leads to further impairment of the infant’s ability to maintain glucose homeostasis [Pagliara et al., 1973].

Normal Pathway of Fatty Acid Oxidation The pathway of mitochondrial fatty acid oxidation is outlined in Figure 81-2 [DiMauro et al., 1992]. Free fatty acids are liberated from adipocytes during fasting and are transported to other tissues either as triglyceride-rich lipoproteins or bound to serum albumin [Stremmel et al., 1986]. Once across the plasma membrane, short-chain (e.g., four-carbon) and medium-chain (e.g., eight-carbon) fatty acids of fewer than 10 carbon atoms are able to cross the outer and inner mitochondrial membranes as free acids to enter the mitochondrial matrix. They are then activated into their CoA esters for ensuant intramitochondrial beta oxidation. The mitochondrial membrane is impermeable to long-chain (e.g., 16-carbon) fatty acids. Therefore, long-chain fatty acids diffuse or are transported to the outer mitochondrial membrane and to the endoplasmic reticulum, where they are activated by conversion to their CoA thioesters by longchain acyl-CoA synthetase [Schulz, 1985]. The inner mitochondrial membrane is impermeable to CoA and its derivatives. Therefore, the long-chain acyl-CoA must first be converted into its acylcarnitine form (e.g., palmitoylcarnitine), with release of free CoA by carnitine palmitoyltransferase I, which is located on the inner side of the outer mitochondrial membrane [Murthy and Pande, 1987]. The palmitoylcarnitine is then translocated across the inner mitochondrial membrane by carnitine-acylcarnitine translocase [Pande, 1975]. In the mitochondrial matrix, palmitoylcarnitine in the presence of free CoA is then converted back to palmitoyl-CoA and carnitine by carnitine palmitoyltransferase II on the inner side of the inner mitochondrial membrane. There are four sequential steps in mitochondrial beta oxidation, which is composed of chain length–specific enzymes. Until recently, it was held that the complete intramitochondrial oxidation of long-chain fatty acids required a minimum of nine enzymes, including the three genetically distinct acyl-CoA dehydrogenases (short-, medium-, and long-chain) [Ikeda et al., 1983], at least two enoyl-CoA hydratases (crotonase and long-chain enoyl-CoA hydratase) [Fong and Schulz, 1981], two L-3-hydroxyacyl-CoA dehydrogenases (short- and long-chain) [El-Fakhri and Middleton, 1982], and two 3-ketoacyl-CoA thiolases (acetoacetyl-CoA thiolase and generalized 3-ketoacyl-CoA thiolase) [Middleton, 1975]. Further characterization has revealed the presence of an additional VLCAD enzyme [Izai et al., 1992; Kelley, 1992] and of a trifunctional enzyme, which combines the activities of the long-chain enoyl-CoA hydratase, long-chain L-3-hydroxyacyl-CoA dehydrogenase (LCHAD), and the long-chain thiolase enzymes [Carpenter et al., 1992; Hashimoto, 1992; Luo et al., 1993]. The trifunctional protein is a heterocomplex of four alpha and four beta subunits, which are encoded by two nuclear genes. The alpha subunit contains the long-chain enoyl-CoA hydratase and LCHAD activities, and the beta subunit contains the long-chain 3-ketoacyl-CoA thiolase activity [Kamijo et al., 1993]. There are two different biochemical phenotypes of trifunctional protein deficiency [Jackson et al., 1992; Kamijo et al., 1994]. The first includes deficiency of all three

enzyme activities of the trifunctional protein, with loss of both alpha and beta subunits documented by immunoblotting studies. The second has isolated LCHAD deficiency with preservation of the long-chain enoyl-CoA hydratase and 3-ketoacyl-CoA thiolase activities and normal amounts of alpha and beta subunit proteins. With each complete cycle of intramitochondrial beta oxidation, a two-carbon fragment is cleaved, and an acetylCoA moiety is released. Most tissues, such as those of muscle and the heart, oxidize acetyl-CoA for energy production through the tricarboxylic acid cycle. In liver, approximately 90% of the hepatic acetyl-CoA is converted into ketones via the coordinated action of acetyl-CoA acetyltransferase, β-hydroxy-β-methylglutaryl-CoA lyase, and βhydroxybutyrate dehydrogenase [Reed and Lane, 1975]. The ketones are then exported for final oxidation by other tissues, such as brain.

Alternative Pathways for Fatty Acid Metabolism Mitochondrial beta oxidation accounts for the majority of fatty acid oxidation under normal circumstances. The peroxisome may contribute up to 20% of total cellular fatty acid oxidation, under conditions of prolonged fasting, through omega oxidation, which leads to the formation of dicarboxylic acids [Krahling et al., 1978]. The specific pattern of dicarboxylic acids in serum or urine may be useful in the identification of specific inborn errors of fatty acid oxidation. When there is an impairment in mitochondrial beta oxidation, three additional mechanisms may be important. These include the deacylation of CoA by thioesterases and the conjugation of acyl groups to glycine and to carnitine [Kolvraa and Gregersen, 1986; Roe et al., 1985]. Measurement of acylcarnitines and acylglycines is also diagnostically useful in the identification of genetic defects in fatty acid oxidation [Baretz et al., 1976; Millington, 1986; Rinaldo et al., 1988].

Clinical and Biochemical Features of Identified Defects Common Features of Fatty Acid Oxidation Disorders Hale and Bennett [1992] suggested that there are at least four clinical and laboratory features that should lead the clinician to suspect a genetic defect in fatty acid oxidation: (1) acute metabolic decompensation in association with fasting, (2) chronic involvement of tissues highly dependent on efficient fatty acid oxidation (e.g., heart, muscle, and liver), (3) recurrent episodes of hypoketotic hypoglycemia, and (4) alterations in the quantity of total carnitine or in the percentage of esterified carnitine in plasma and tissue.

METABOLIC DECOMPENSATION IN ASSOCIATION WITH FASTING Children with fatty acid oxidation defects are most prone to decompensation, within the context of depleted glycogen and glucose reserves, during conditions that place stress on the fatty acid oxidation pathway for fuel generation. These conditions include prolonged exercise (particularly after 1 hour of mild-to-moderate aerobic exercise), fasting, infection with vomiting, and cold-induced shivering thermogenesis.

Tein / Metabolic Myopathies

In cold exposure, ketogenesis is stimulated in normal individuals [Johnson et al., 1961], and shivering, which is an involuntary form of muscle activity, also depends on longchain fatty acid oxidation [Bell and Thompson, 1979]. After an overnight fast, affected children are most likely to be found comatose in the early morning hours. During infection, there may be an added problem with vomiting and decreased oral intake. Children may also present with a Reye-like syndrome. Infants and younger children are at greater risk during fasting because of their decreased abilities to adapt to fasting. Prolonged fasting for an infant younger than 1 year is 6 to 10 hours, in comparison with 12 hours for a child between 1 and 4 years of age [Hale and Bennett, 1992].

INVOLVEMENT OF FATTY ACID OXIDATION–DEPENDENT TISSUES Tissues such as skeletal muscle, heart, and liver have high energy demands and are therefore dependent on efficient fatty acid oxidation. When there is a defect in hepatic ketogenesis, glucose becomes the only available fuel and thus becomes rate limiting under conditions of fatty acid oxidation stress when glycogen and glucose stores have been depleted. As a result, free fatty acids, which are liberated during fasting and cannot be metabolized because of the block, may be stored in the cytosol as triglycerides. This situation produces a progressive lipid storage myopathy with weakness; hypertrophic or dilatative cardiomyopathy, or both; and a fatty liver. Increased content of short- or medium-chain fatty acids and, in particular, their dicarboxylic metabolites, from compensatory omega oxidation, may cause a variety of secondary biochemical abnormalities, including an impairment of gluconeogenesis, beta oxidation, and the citric acid cycle [Corkey et al., 1988; Tonsgard, 1986; Tonsgard and Getz, 1985], leading to a further decrease in cellular ATP production. In addition, in the long-chain fatty acid oxidation disorders, which may have recurrent episodes of acute muscle breakdown or myoglobinuria (e.g., carnitine palmitoyltransferase II, VLCAD, and trifunctional enzyme deficiencies), the accumulation of long-chain fatty acids and long-chain acylcarnitines may have detergent-like actions on muscle membranes. Excessive amounts of palmitoyl-CoA and palmitoylcarnitine have detergent properties on isolated canine myocytic sarcolemmal membranes and potentiate free radical–induced lipid membrane peroxidative injury in ischemia [Mak et al., 1986]. Long-chain acylcarnitines also activate calcium channels in cardiac [Inoue and Pappano, 1983; Spedding, 1985] and smooth muscle myocytes [Spedding, 1985; Spedding and Mir, 1987]. They may thus potentiate the increase in cytosolic calcium associated with arrhythmogenesis, as seen in ischemic myocardium [Lee et al., 1987].

HYPOKETOTIC HYPOGLYCEMIA The pattern of hypoketotic hypoglycemia reflects the accelerated rate of glucose utilization that occurs when fatty acids cannot be used as fuels and ketone bodies are not generated to spare glucose/glycogen stores. An increase in the ratio of serum free fatty acids to ketones from the normal 1:1 to greater than 2:1 therefore suggests a block in beta oxidation.

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ALTERATIONS IN PLASMA AND TISSUE CONCENTRATIONS OF CARNITINE In most cases of intramitochondrial beta oxidation defects, the total carnitine concentration is decreased (<50% or normal), and the acylcarnitine fraction is increased (>50% esterified; normal is 10% to 25% in the fed state and 30% to 50% in the fasting state) [Hale and Bennett, 1992]. In the intramitochondrial beta oxidation disorders, the excessive acyl-CoAs that accumulate proximal to the metabolic block may be converted into acylcarnitines by chain length–specific carnitine acyltransferases [Bremer, 1983]. These acylcarnitines, when filtered through the kidneys, compete with free carnitine at the renal tubular reabsorptive site. Because the longer chain– length acylcarnitines have an increasingly higher affinity for the carnitine transporter than does free carnitine [Stanley et al., 1991], the free carnitine is excreted, which leads to a decrease in free carnitine in the serum. In the case of the high-affinity plasmalemmal carnitine transporter OCTN2 defect, the total carnitine is markedly reduced (e.g., <5% of normal) and the esterified fraction is normal [Tein et al., 1990a] because the transport defect, which is also expressed in kidney, leads to a decreased renal threshold for carnitine reabsorption.

Additional Laboratory Findings During acute catabolic crises, other biochemical derangements may be present. A modest hyperammonemia (100 to 200 μmol/liter) accompanied by threefold to fivefold elevations of liver transaminases may be documented during the Reye-like syndrome manifestation [Hale and Bennett, 1992]. In acute myoglobinuria, there are marked increases in the concentrations of sarcoplasmic enzymes, including that of serum creatine kinase, which may rise higher than 100,000 IU/liter (normal, <250 IU/liter). The serum concentrations of amino acids (especially taurine), creatinine, potassium, phosphate, and urate may also be increased [Tein et al., 1990b]. These changes may have deleterious renal and cardiac effects, thereby further exaggerating the damage [Knochel, 1976]. Lactic acidosis may also be present during the acute catabolic episodes. This presence may reflect either poor tissue perfusion or inhibition of critical enzymes, such as pyruvate carboxylase, by accumulated metabolites [Corkey et al., 1988]. Urine organic acid screening may demonstrate unusual or excessive amounts of organic acids, which may be diagnostic of a specific block in beta oxidation.

Specific Features of Individual Genetic Defects For most of the defects in fatty acid oxidation—with the exeption of MCAD, carnitine uptake (OCTN2) defect, classic late-onset carnitine palmitoyltransferase II, VLCAD, LCHAD, α-electron transfer flavoprotein (α-ETF) and ETFcoenzyme Q deficiencies, and 3-hydroxy-3-methylglutaryl (HMG)-CoA lyase deficiency—fewer than 25 cases have been reported in the literature, although more cases may have been diagnosed. Thus, the clinical and laboratory characteristics presented here are based on a review of these cases and are summarized in Table 81-2 [Rinaldo et al., 2002; Tein, 1995, 2000a]. There are several differentiating features. In the defects involving the transport of fatty acids into the mitochondria (carnitine uptake defect, carnitine palmitoyltransferase I,

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TABLE 81-2 Clinical Features Associated with Specific Genetic Defects of Fatty Acid Oxidation

DEFICIENCY

FASTING DISORDER

TISSUE INVOLVED

HYPOKETOTIC HYPOGLYCEMIA

ALTERED CARNITINE

DICARBOXYLIC ACIDS

REYE-LIKE SYNDROME

SUDDEN INFANT DEATH SYNDROME

LCFAUD CUD CPT I TRANS

+ + + +

+ + + +

+ + + +

NR NR NR NR

NR + + +

NR NR NR +

CPT II (mild)

+/−

NR

+

NR

NR

NR

CPT II (severe)

+

+

+

NR

+

+

VLCAD/LCAD

+

+

+

+

+

+

Trifunctional/ LCHAD

+

+

+

+

+

+

Dienoyl-CoA reductase

NR

NR

+

NR

NR

NR

MCAD SCAD

+ +

+ +/−

+ +

+ +

+ NR

+ +

SCHAD

+

+

+

+

NR

+

ETF and ETF-Qo

+

+

+

+

NR

+

HMG-CoA lyase

+

Liver Heart, muscle Kidney Heart, muscle, (myoglobinuria) Muscle, myoglobinuria, pancreatitis Heart, muscle, myoglobinuria, liver Heart, muscle, myoglobinuria, liver Heart, muscle, myoglobinuria, liver, neuropathy, pancreatitis, retinopathy Muscle, dysmorphic features, brain, (heart) (Myoglobinuria) Muscle, brain, dysmorphic features, heart Heart, muscle, myoglobinuria liver Muscle, heart, kidney, brain, dysmorphic features Brain, pancreatitis

+

+

+

+

+?

CoA, coenzyme A; CPT, carnitine palmitoyltransferase; CUD, carnitine uptake defect; ETF, electron transfer flavoprotein; HMG, β-hydroxy-β-methylglutaryl; LCAD, long-chain acyl-CoA dehydrogenase; LCHAD, long-chain L-3-hydroxyacyl-CoA dehydrogenase; LCFAUD, long-chain fatty acid uptake defect; MCAD, medium-chain acyl-CoA dehydrogenase; NR, no case yet reported; Qo, coenzyme Q oxidoreductase; SCAD, short-chain acyl-CoA dehydrogenase; SCHAD, short-chain L-3-hydroxyacylCoA dehydrogenase; TRANS, carnitine acylcarnitine translocase; trifunctional, long-chain enoyl-CoA hydratase + long-chain L-3-hydroxyacyl-CoA dehydrogenase + longchain 3-ketoacyl-CoA thiolase; VLCAD, very-long-chain acyl-CoA dehydrogenase. Modified from Tein I. Fatty acid oxidation and associated defects. In American Academy of Neurology Proceedings, 1995. Madison, WI: Omnipress, 1995, 269:9–38.

carnitine-acylcarnitine translocase, carnitine palmitoyltransferase II), there is generally not an associated abnormal dicarboxylicaciduria. However, this has been reported in one case of severe infantile carnitine palmitoyltransferase II deficiency [Elpeleg et al., 1993] and, on one occasion, during an acute metabolic decompensation in an individual with infantile carnitine palmitoyltransferase I deficiency who presented with recurrent Reye-like syndrome [Poll-The et al., 1992]. The carnitine uptake (high-affinity carnitine transporter OCTN2) defect, carnitine palmitoyltransferase I, and carnitine acylcarnitine translocase defects involve both skeletal and cardiac muscle and manifest in infancy or early childhood. The carnitine uptake defect is characterized by a progressive hypertrophic or dilatative cardiomyopathy, or both, which pathologically resembles endocardial fibroelastosis [Tripp et al., 1981]. Of importance is that this defect is exquisitely responsive to high-dose oral carnitine supplementation, which reverses the cardiomyopathy [Stanley et al., 1991; Tein et al., 1990a]. Renal tubular acidosis has been documented in one case of carnitine palmitoyltransferase I deficiency [FalikBorenstein et al., 1992]. Classic adult carnitine palmitoyl-

transferase II deficiency is characterized by adolescent-onset recurrent episodes of acute myoglobinuria precipitated by prolonged exercise or fasting, in which power between episodes is normal and in which lipid accumulation in muscle is present only under conditions of fasting and prolonged exercise [DiMauro and Papadimitriou, 1986]. Fasting ketogenesis is generally normal in this condition, although it may be delayed, and there is no fixed cardiomyopathy, although dysrhythmias secondary to hyperkalemia and hypocalcemia may occur during the acute myoglobinuric crises. Statistically speaking, classic carnitine palmitoyltransferase II deficiency is the most common cause for recurrent myoglobinuria in children and in adults [Tein et al., 1990b; Tonin et al., 1990]. Several cases of severe infantile carnitine palmitoyltransferase II deficiency have been described as manifesting with recurrent Reye-like syndrome; hepatomegaly with hypoketotic hypoglycemia and elevated liver aminotransferase concentration; cardiomegaly with cardiac dysrhythmias and elevated serum creatine kinase concentration; and evidence of lipid storage in the heart, skeletal muscle, liver, and kidney [Demaugre et al., 1991; Elpeleg et al., 1993; Hug et al., 1991]. In these cases, the

Tein / Metabolic Myopathies

activity of carnitine palmitoyltransferase II in cultured skin fibroblasts was less than 10% of control values, in contrast to the 25% residual activity documented in classic carnitine palmitoyltransferase II deficiency [Demaugre et al., 1991], which may explain the differences in severity of the clinical phenotype. In addition to the high-affinity plasmalemmal carnitine transporter OCTN2 defect, there is another plasma membrane fatty acid oxidation disorder: long-chain fatty acid transport/ binding defect [Al-Odaib et al., 1998]. This defect in the active transport of long-chain free fatty acids across the plasma membrane has been described in two young males who presented with acute liver failure accompanied by hyperammonemia, hyperbilirubinemia, coagulopathy, and mild encephalopathy, with no evidence of cardiac or skeletal myopathy, and who required liver transplantation. One boy had documented hypoketotic hypoglycemia. The uptake of oleic acid (C18:1) in skin fibroblasts from the patients was lower than in control subjects. The features that were atypical for a fatty acid oxidation defect included the absence of fatty liver with low concentrations of long-chain free fatty acids and elevated carnitine concentrations in liver homogenate, caused by defective transport of long-chain free fatty acids. The intramitochondrial beta-oxidation defects (SCAD, MCAD, LCAD, VLCAD, ETF, ETF-coenzyme Q, SCHAD, medium-and short-chain L-3-hydroxyacyl-CoA dehydrogenase (M/SCHAD), trifunctional/LCHAD, medium-chain 3-ketoacyl-CoA thiolase, 2,4-dienoyl-CoA reductase, HMGCoA synthase, HMG-CoA lyase deficiencies) share many features, although there are differentiating characteristics. Those cases previously attributed to LCHAD deficiency are known to be related to a defect in the trifunctional enzyme that combines the activities of the long-chain enoyl-CoA hydratase, LCHAD, and long-chain 3-ketoacyl-CoA thiolase enzymes [Hashimoto, 1992; Sims et al., 1995], although isolated LCHAD deficiency appears to be more common than trifunctional protein deficiency [Rinaldo et al., 2002]. A number of previously diagnosed cases of LCAD deficiency are believed to be attributable instead to VLCAD deficiency [Aoyama et al., 1995b; Ogilvie et al., 1994; Yamaguchi et al., 1993]. Cardiac involvement (cardiomegaly, cardiomyopathy) is more commonly found in the long-chain defects (e.g., LCAD, VLCAD, trifunctional) [Glasgow et al., 1983; Hale et al., 1985, 1990a, 1990b; Strauss et al., 1995; Tein et al., 1995], although it has also been documented in one case of SCHAD deficiency [Tein et al., 1991] and one case of SCAD deficiency [Tein et al., 1999a]. Cardiomyopathy has been documented in 17 of 24 reported cases of trifunctional enzyme deficiency with presumed or proved marked deficiency of the LCHAD component [Tein et al., 1995]. Chronic skeletal muscle weakness is seen in all of the intramitochondrial beta oxidation defects but less commonly in MCAD [Stanley et al., 1990] and HMG-CoA lyase deficiency [Gibson et al., 1988]. A unique case of SCAD deficiency has been reported in a 13-year-old-female with progressive external ophthalmoplegia, ptosis, cardiomyopathy, and multi-core myopathy [Tein et al., 1999a]. Additional cases of SCAD deficiency with multi-core myopathy have since been identified. Recurrent myoglobinuria has been reported with LCAD [Hale et al., 1990a], VLCAD [Ogilvie et al., 1994], trifunctional [Dionisi-Vici et al., 1991;

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Tein et al., 1995], and SCHAD deficiencies [Tein et al., 1991]. A first episode of myoglobinuria has also been described in an adult with MCAD deficiency [Ruitenbeek et al., 1995]. All intramitochondrial enzyme defects demonstrate hepatic dysfunction at the time of catabolic decompensation. Persistent dysfunction has been documented in trifunctional enzyme [Hagenfeldt et al., 1990], severe carnitine palmitoyltransferase II [Elpeleg et al., 1993], and LCAD/ VLCAD [Hale et al., 1985] deficiencies. Of importance is that isolated LCHAD deficiency in children may also be associated with severe illness in the heterozygous mother during pregnancies with affected fetuses who have a common mutation (G1528C, E474Q) in one or both alleles [Ibdah et al., 1998b; Sims et al., 1995; Tein, 2000b; Treem et al., 1996; Wilcken et al., 1993]. The maternal illnesses include the acute fatty liver of pregnancy syndrome; the syndrome of hypertension or hemolysis, elevated liver enzymes, and low platelets (HELLP); and hyperemesis gravidarum. In acute fatty liver of pregnancy syndrome, the mother may suffer fulminant liver failure and die. In both syndromes, there is microvesicular fatty infiltration of the maternal liver. In addition to the recurrent episodes of myoglobinuria, trifunctional protein/LCHAD deficiency may manifest with progressive pigmentary retinopathy [Tyni et al., 1998, 2004] and motor-sensory neuropathy [Spiekerkoetter et al., 2004]. Thus, the myoneuropathic variant of trifunctional protein/ LCHAD deficiency may mimic the spinal muscular atrophy phenotype. There appear to be three major phenotypes of trifunctional protein/LCHAD deficiency with variable overlap: a hepatic form with Reye-like syndrome that is associated with acute fatty liver of pregnancy syndrome; a neonatal cardiomyopathic form; and a less common, milder, myoneuropathic form. These phenotypes appear to be correlated with specific genotypes [Ibdah et al., 1998a, 1999; Isaacs et al., 1996; Sims et al., 1995]. Maternal complications in pregnancy are not limited to carriers of LCHAD mutations. Patients with deficiencies of carnitine palmitoyltransferase I, MCAD, and SCAD were also born to mothers who developed liver disease during their pregnancies [Innes et al., 2000; Matern et al., 2001; Nelson et al., 2000; Walter, 2000]. Therefore, all infants born after pregnancies that are complicated by acute fatty liver of pregnancy or HELLP syndrome should be considered at risk for having a defect in beta oxidation. SCAD deficiency is a clinically heterogeneous disorder in which the clinical phenotype varies from fatal metabolic decompensation, including intermittent metabolic acidosis and neonatal hyperammonemia, to infantile-onset lipid storage myopathy with failure to thrive, developmental delay, hypotonia, seizures, and hyperreflexia [Bhala et al., 1995] to more subtle later onset progressive myopathy, including multi-core myopathy [Tein et al., 1999a], to asymptomatic states [Ribes et al., 1998]. The characteristic metabolites of ethylmalonic and methlysuccinic acids in SCAD deficiency may also result from the presence of one of two relatively common variants of SCAD (625G>A and 511C>T) that predispose to excessive ethylmalonic acid production. These variants may represent disease susceptibility variations when occurring in combination with other genetic or environmental factors or both, especially fever [Corydon et al., 2001; Gregersen et al., 1998].

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Multiple acyl-CoA dehydrogenase deficiency or glutaric acidemia type II is caused by defects of the ETF or ETFubiquinone oxidoreductase, which are nuclear encoded proteins through which electrons from flavoprotein acyl-CoA dehydrogenases, dimethylglycine dehydrogenase, and sarcosine dehydrogenase enter the respiratory chain [Frerman and Goodman, 1989]. These cases can be divided into three groups, each consistent within a family, and have been designated as (1) neonatal onset with congenital anomalies, (2) neonatal onset without anomalies, and (3) mild or later onset. Patients in the first two groups are sometimes said to have severe multiple acyl-CoA dehydrogenase deficiency and the third group to have a mild form of this deficiency. Patients with the neonatal onset form and congenital anomalies are often premature, presenting within the first 24 to 48 hours after birth with severe hypoglycemia, hypotonia, hepatomegaly, metabolic acidosis, and an odor similar to that of sweaty feet. Affected infants may have enlarged kidneys and facial dysmorphism (e.g., high forehead, low-set ears, hypertelorism, hypoplastic midface), rocker-bottom feet, muscular defects of the anterior abdominal wall, and anomalies of the external genitalia (hypospadius, chordee). Most of these patients die within the first week after birth. In others, congenital anomalies are not documented, but renal cysts are found at postmortem examination. Affected infants without congenital anomalies usually develop hypotonia, tachypnea, hepatomegaly, hypoglycemia, metabolic acidosis, and a “sweaty foot” odor within the first few days after birth, many in the first 24 hours. The few infants with this form who have survived beyond the first week of life, as a result of prompt diagnosis and treatment, have died within a few months, usually of severe cardiomyopathy. A few other infants have been hypoglycemic in the neonatal period, have later developed typical Reye-like episodes, and have survived longer. The late-onset glutaric acidemia type II is extremely variable in age at manifestation and course of the disease. One infant presented at 7 weeks of age with intermittent episodes of vomiting, hypoglycemia, and acidosis, whereas another patient was asymptomatic during childhood and presented in adulthood with episodic vomiting, hypoglycemia, hepatomegaly, and proximal myopathy. Some individuals have had progressive lipid storage myopathy with carnitine deficiency. SCHAD deficiency has been only rarely reported. It is also now known as M/SCHAD deficiency, given its broader chain length specificity [Kobayashi et al., 1996]. Three distinct clinical and biochemical phenotypes have been described. One female presented with recurrent myoglobinuria, myopathy, cardiomyopathy, and hypoketotic hypoglycemic encephalopathy and died at 16 years of age [Tein et al., 1991]. SCHAD activity was deficient in muscle but not in cultured skin fibroblasts, although these fibroblasts demonstrated marked microvesicular steatosis when cultured in a glucose-free medium to simulate fasting stress [Renaud et al., 2002]. Other tissues were not examined enzymatically. A second phenotype manifesting with ketotic hypoglycemia and SCHAD deficiency was described in isolated mitochondria from cultured skin fibroblasts, but no other tissues were studied [Bennett et al., 1996]. A third group of patients presented with hepatic involvement and steatosis; SCHAD activity was deficient in liver but normal in muscle and fibroblasts [Bennett et al., 1999]. Mutation

analysis of the SCHAD gene in these patients has been inconclusive, which suggests that other proteins in addition to M/SCHAD may be necessary for enzymatic activity and that these proteins may have a tissue-specific distribution. Apparent disease-causing mutations have been described in a patient with fulminant hepatic failure who required transplantation [O’Brien et al., 2000]. Only one patient with 2,4-dienoyl-CoA reductase deficiency in muscle and liver has been reported; that patient presented with neonatal hypotonia, microcephaly, a small ventricular septal defect, and dysmorphism and died at 4 months of age of respiratory acidosis; biventricular hypertrophy was evident at postmortem examination [Roe et al., 1990]. The clinical significance of the biochemical abnormalities therefore cannot be confirmed until additional patients have been identified. In addition, one patient with medium-chain 3-ketoacyl-CoA thiolase deficiency has been described in a Japanese male neonate who died at 13 days of age after presenting at 2 days of age with vomiting, dehydration, metabolic acidosis, liver dysfunction, and myoglobinuria [Kamijo et al., 1997]. There are several disorders of ketone body production. Deficiency of HMG-CoA lyase, which is also active in the metabolism of leucine, manifests with hypoketotic hypoglycemia, hyperammonemia, and acidosis [Mitchell and Fukao, 2001]. Succinyl-CoA:3-keto-acid CoA transferase (SCOT) functions in conjunction with mitochondrial acetoacetyl-CoA thiolase to generate ketones in extrahepatic tissues. SCOT deficiency manifests as persistent ketonuria in the first 1 to 2 years of life, whereas acetoacetyl-CoA thiolase deficiency manifests with variable clinical symptoms and exaggerated ketoacidosis in response to minor physiologic stresses [Fukao et al., 1995, 1997; Kassovskabratinova et al., 1996; Pretorius et al., 1996]. HMG-CoA synthetase deficiency has been reported in a child who presented with fasting hypoketotic hypoglycemia [Thompson et al., 1997].

Differentiating Laboratory Features Analysis of the fatty acid intermediates in the serum or urine of affected children may suggest the site of defect, depending on the chain-length specificity and the species type of the intermediates. Identification of these intermediates often requires specialized biomedical technology, which may necessitate referral to specialized metabolic laboratories. Particularly useful are the assessment of plasma total and free carnitine, serum acylcarnitines, urine acylcarnitines and urine acylglycines, and organic acids. These intermediates may be absent at times when the child is metabolically stable and receiving adequate supplies of glucose, because this state would reduce the stress on the fatty acid oxidation pathway. They are best detected in the serum and urine of children during acute catabolic crises or during times of fasting. Specific intermediates characteristic for individual defects are listed in Table 81-3 [Tein, 1995].

Carnitine Fatty acid oxidation disorders are associated with a decrease in plasma total carnitine concentration (<30 μmol/liter; normal, 40 to 60 μmol/liter). The carnitine uptake defect has

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TABLE 81-3 Laboratory Features Associated with Genetic Defects of Fatty Acid Oxidation

DEFICIENCY

LEVELS OF CARNITINE Total

UNIQUE OR SPECIFIC METABOLITES Free

Acyl-Carnitine

Acyl-Glycine

Organic Acids

LCFAUD CUD CPT I TRANS CPT II (mild) CPT II (severe) VLCAD/LCAD Trifunctional

Low Very low Normal/high Low Low Low Low Low

Low Low High Very low Very low Very low Low Low

NR NR NR Long-chain Long-chain Long-chain Long-chain Long-chain

NR NR NR NR NR NR NR NR

Dienoyl-CoA reductase MCAD

Low

Low

Decadienoyl

NR

NR NR NR(+) NR NR + Adipic, suberic, sebacic Adipic, suberic, sebacic; 3-hydroxy intermediates NR

Low

Low

Octanoyl

SCAD

Low

Low

Butyryl

Suberyl, hexanoyl, phenylpropionyl Butyryl

SCHAD

Low

Low

NR

NR

ETF and ETF-Qo

Low

Low

Suberyl, hexanoyl, butyryl, isovaleryl

HMG-CoA lyase

Low

Low

Octanoyl, glutaryl, butyryl, isovaleryl 3-Methylglutaryl

?

Adipic, suberic, sebacic Adipic, suberic, sebacic; ethylmalonic; methylsuccinate Adipic, suberic, sebacic; 3-hydroxy intermediates Adipic, suberic, sebacic; glutaric; ethylmalonic 3-Hydroxy-3-methylglutaric; 3-methyl-glutaconic; 3-methyl-glutaric, adipic; 3-hydroxy- isovaleric

CoA, coenzyme A; CPT, carnitine palmitoyltransferase; CUD, Carnitine uptake defect; ETF, electron transfer flavoprotein; HMG, β-hydroxy-β-methylglutaryl; LCAD , long-chain acyl-CoA dehydrogenase; LCFAUD, long-chain fatty acid uptake defect; MCAD, medium-chain acyl-CoA dehydrogenase; NR, no case yet reported; Qo, coenzyme Q oxidoreductase; SCAD, short-chain acyl-CoA dehydrogenase; SCHAD, short-chain L-3-hydroxyacyl-CoA dehydrogenase; TRANS, carnitine acylcarnitine translocase; trifunctional, long-chain enoyl-CoA hydratase + long-chain L-3-hydroxyacyl-CoA dehydrogenase + long-chain 3-ketoacyl-CoA thiolase; VLCAD, very long-chain acyl-CoA dehydrogenase. Modified from Tein I. Fatty acid oxidation and associated defects. In American Academy of Neurology Proceedings, Seattle, 1995. Madison, WI: Omnipress, 1995;269;9–38.

the lowest concentrations, which are usually less than 5% of control values [Stanley et al., 1991]. In the intramitochondrial beta oxidation defects, the plasma total carnitine concentrations vary between 10% and 50% of normal. In carnitine palmitoyltransferase I deficiency, in contrast, the total plasma carnitine concentration may be normal or increased because the esterification of palmitate to carnitine is defective [Stanley et al., 1992]. In most fatty acid oxidation defects, with the exception of the carnitine uptake and carnitine palmitoyltransferase I defects, there is an increase in the ratio of esterified carnitine to total carnitine. This increase reflects the esterification to carnitine of the excessive acyl-CoAs that accumulate proximal to the block in beta oxidation. Estimates of the amount of acylcarnitines are based on the difference between the free and total carnitine measurements. Under normal conditions, the esterified carnitine is 10% to 25% of total in the fed state and 30% to 50% of total in the fasting state [Hale and Bennett, 1992]. The carnitine esters can be further separated on the basis of the acid insolubility of long-chain acylcarnitine esters [Hale and Bennett, 1992]. Increased amounts of long-chain acylcarnitines are found in defects of long-chain fatty acid oxidation [Glasgow et al., 1983]. Further separation and identification of the individual acylcarnitine esters have been facilitated by fast atom bombardment-tandem mass spectrometry and isotopic exchange high-performance liquid chromatography [Kerner and Bieber, 1983; Millington et al., 1992]. Profiles of specific serum acylcarnitines have been useful in the

diagnosis of certain defects (e.g., octanoyl-carnitine in MCAD deficiency) [Millington, 1986]. They are particularly helpful in the diagnosis of long-chain fatty acid oxidation disorders because they overcome the problem of the renal threshold effect, whereby long-chain acylcarnitines are selectively reabsorbed at the renal carnitine transporter site at the expense of free carnitine. This limits the urinary excretion and detection of long-chain acylcarnitines. Serum acylcarnitine measurements also overcome the problem of the poor solubility of long-chain fatty acids in urine. A novel approach that has been successfully applied to skin fibroblasts for the diagnosis of various fatty acid oxidation defects involves probing the beta oxidation pathway by incubating the cells in the presence of a stable, isotopically labeled long-chain fatty acid and then analyzing the produced acylcarnitine intermediates by tandem mass spectrometry [Nada et al., 1995a, 1995b]. This method has also been used for the successful prenatal diagnosis of MCAD and VLCAD deficiencies in cultured amniocytes [Nada et al., 1996].

Dicarboxylic Acids Dicarboxylic acids (adipic, suberic, and sebacic acids) are found in all identified intramitochondrial beta oxidation defects [Gregersen et al., 1982a]. Hale and Bennett [1992] pointed out that there are several limitations to the value of these compounds in the recognition of fatty acid oxidation defects:

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• These dicarboxylic acids may be found in children receiving certain formulas containing medium-chain triglycerides or in children who are seriously ill (e.g., with diabetic ketoacidosis) [Mortensen and Gregersen, 1982]. They are also found in children who are receiving certain medications that interfere with fatty acid oxidation, such as valproic acid [Mortensen, 1981]. In each of these cases, however, the amount of ketones exceeds the amount of dicarboxylic acids, whereas in the intramitochondrial fatty acid oxidation defects, the amount of dicarboxylic acids equals or exceeds the amount of ketones when the children are fasting. • These dicarboxylic acids are not present when children are not catabolic, are well and eating regularly, or are receiving intravenous glucose at rates in excess of normal hepatic glucose production rates. Under these conditions, there is a reduction in dependence on fatty acid oxidation and the production of fatty acid metabolites. • Increased concentrations of dicarboxylic acids in the urine are generally not seen in the disorders involving the transport of fats into the mitochondria. Therefore, a fatty acid oxidation defect can be suspected in the presence of an excess of dicarboxylic acids relative to ketones, but the absence of dicarboxylic acids does not necessarily exclude a defect. The site of defect may be suggested by the organic acid pattern. For example, children with LCAD/VLCAD deficiency excrete primarily medium- and long-chain saturated dicarboxylic acids, in contrast to children with trifunctional enzyme deficiency, who excrete almost equimolar amounts of the saturated and the 3-hydroxydicarboxylic acids [Hale et al., 1990a, 1990b]. However, toxic reactions with acetaminophen and intrinsic liver disease may also manifest with urinary excretion of 3-hydroxy compounds [Pollitt, 1990]. Further advances in stable-isotope dilution mass spectrometry have improved the ability to quantify metabolites in very small amounts [Gregersen et al., 1986] in plasma or urine. Acylglycines that are consistently excreted in small quantities in the urine do not appear to have the same limitations of dicarboxylic acids. Useful glycine metabolites therefore have been identified for several defects, including MCAD, SCAD, ETF, and ETF-coenzyme Q oxidoreductase deficiencies [Rinaldo et al., 1988].

Diagnostic Approaches and Screening Methods History and Physical Examination The key to investigation of these patients is a thorough history and a careful clinical examination. The presentation may be either acute and recurrent or more chronic and slowly progressive. The more typical presentation is the acute one in which the child has a history of decreased oral intake during the preceding 24 to 36 hours, followed by increasing lethargy and progressive obtundation or coma. The important initial investigations in a comatose child should include serum glucose and urine ketone measurements. Determination of urine ketones may be complicated because ill children are often dehydrated and have con-

centrated urine that may demonstrate a relatively spurious elevation in ketones. A blood glucose level above 3.3 mmol/ liter (60 mg/dL) and accompanied by large amounts of urinary ketones tends to rule out a fatty acid oxidation disorder. However, a blood glucose level lower than 3.3 mmol/ liter with trace or small amounts of urine ketones suggests the possibility of a fatty acid oxidation disorder and warrants further investigation. Most important, samples from the acute presentation, particularly before intravenous glucose therapy, should be saved for the determination of total and free serum carnitine, serum acylcarnitines, serum free fatty acids and ketones, urine organic acids, acylglycines, and acylcarnitines. With normal fatty acid oxidation, the ratio of serum free fatty acids to ketones is 1:1. In the event of a block in fatty acid oxidation, this ratio increases to greater than 2:1 and is therefore useful as an initial screen. The serum and urine specimens during the acute episode can also be used to assess the integrity and hormonal regulation of the biochemical pathways involved in glucose homeostasis.

Total Carnitine Measurement The differentiation among the carnitine uptake defect, carnitine palmitoyltransferase I, and the intramitochondrial defects on the basis of total and free plasma carnitine concentrations has been previously discussed.

Urinary Organic Acids It is crucial to obtain urine specimens during the acute catabolic episode, before intravenous glucose is administered, because production of fatty acid metabolites ceases quickly during normoglycemia. The chain length and species type of the organic acids help identify the specific site of fatty acid oxidation block.

Fasting Studies If the important samples have not been taken during an acute catabolic event, a fasting study may be considered in order to distinguish a fatty acid oxidation defect from the other etiologies of hypoglycemia. However, if a fasting study is to be undertaken, it must be done under carefully controlled hospital conditions with continuous monitoring and by physicians who are knowledgeable with regard to hypoglycemia, hypopituitarism, hyperinsulinism, and fatty acid oxidation disorders. It is thought by some authorities that fasting studies should not be performed in children with fatty acid oxidation disorders, because diagnostic fasting may precipitate an acute metabolic crisis, leading to further morbidity or death. It has been suggested instead that loading tests with carnitine or phenylpropionate can be used to aid in diagnosis. Hale and Bennett [1992] outlined advantages and disadvantages of each method. The specific advantages of a fasting study are the following: • The duration of fasting tolerance can be determined under carefully controlled conditions. This control may provide useful information regarding the long-term management of the affected patient and provide guidelines for the prevention of hypoglycemia.

Tein / Metabolic Myopathies

• The full spectrum of abnormal fasting adaptation can be studied through the assessment of a number of laboratory parameters, including hormonal measurements. • The time to precipitation of acute clinical decompensation can be documented. As previously emphasized, the cardinal risk is the precipitation of an acute catabolic crisis that leads to morbidity and death. It is preferable instead to collect the appropriate samples during an acute catabolic event that the child has suffered. The primary advantage of loading tests and the measurement of specific metabolites is their safety. The disadvantages are that (1) they are useful only in certain fatty acid oxidation defects (e.g., MCAD deficiency) and thus a negative test result does not exclude all fatty acid oxidation defects, and (2) they do not evaluate the spectrum of fasting adaptation. The purpose of the fasting study is to identify the defective metabolic pathway through an analysis of temporal

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changes in substrates (glucose, free fatty acids, lactate, ketones), metabolites (carnitine, dicarboxylic acids), and relevant hormones (growth hormone, cortisol, insulin). The fast should be promptly terminated when the child demonstrates the first symptoms or has a blood glucose level of less than 3.3 mmol/liter (60 mg/dL). If at this point there is a deficient ketogenic response in the presence of a significant dicarboxylic aciduria, and if the ratio of serum free fatty acids to ketones is greater than 2:1, there is strong presumptive evidence of a defect in the fatty acid oxidation pathway.

Other Studies Once presumptive evidence of a defect in fatty acid oxidation has been established, the clinical picture in combination with an analysis of serum acylcarnitines, urinary organic acid profiles, and urinary acylglycines may suggest a specific site of defect and the chain-length specificity of the defect (e.g., short-, medium-, or long-chain). Further investigations to identify the specific site of defect are discussed next.

TABLE 81-4 Enzymatic and Molecular Characterization of Fatty Acid Oxidation Disorders DEFICIENCY

ASSAY

GENE

CHROMOSOME LOCATION

PROTEIN AND MOLECULAR CHARACTERIZATION; REFERENCES

CUD (OCTN2 transporter)

SLC22A5

5q33.1

Wu et al., 1998; Tamai et al., 1998; Lamhonwah and Tein, 1998

CPT I, liver

Carnitine uptake in cultured skin fibroblasts, lymphoblasts, myoblasts Fibroblasts, muscle, liver

CPT1A

11q13

TRANS

Fibroblasts

SLC25A20

3p21.31

CPT II

Fibroblasts, muscle, liver

CPT2

1p32

VLCAD

Fibroblasts, muscle

ACADVL

17p11.2-p.11.1

LCAD Trifunctional/LCHAD

Fibroblasts, muscle, liver Fibroblasts, muscle, liver

ACADL HADHB/HADHA

2q34-q35 2p23

Dienoyl-CoA reductase MCAD

Muscle, liver Fibroblasts, liver, leukocytes

DECR1 ACADM

8q21.3 1p31

SCAD

Fibroblasts, muscle, liver

ACADS

12q22-qter

SCHAD ETF

HADHSC

4q22-q26

ETF/Qo HMG-CoA lyase

Fibroblasts, muscle, (liver) Fibroblasts α-Subunit β-Subunit Fibroblasts Fibroblasts, liver, leukocytes

Esser et al., 1993; Britton et al., 1995; Yamazaki et al., 1996 Indiveri et al., 1990, 1991; Palmieri et al., 1996 Woeltje et al., 1990; Finocchiaro et al., 1991; Taroni et al., 1993; Gellera et al., 1994; Verderio et al., 1995 Kelley, 1992; Izai et al., 1992; Strauss et al., 1995; Aoyama et al., 1995a, 1995b; Andresen et al., 1996a, 1996b Indo et al., 1991b Carpenter et al., 1992; Luo et al., 1993; Uchida et al., 1992; Jackson et al., 1992; Kamijo et al., 1993, 1994; Sims et al., 1995; Strauss, 1997 Helander et al., 1997 Kelly et al., 1987; Strauss et al., 1990; Gregersen et al., 1991; Blakemore et al., 1991 Finocchiaro et al., 1987; Naito et al., 1989; Corydon et al., 1996; Gregersen et al., 1996 Vredendaal et al., 1996

ETFA ETFB ETFDH HMGCL

15q23-q25 19q13.3 4q32.qter 1pter-p33

Finocchiaro et al., 1988; Indo et al., 1991a Finocchiaro et al., 1993 Goodman et al., 1992 Mitchell et al., 1993; Roberts et al., 1994

HMG-CoA synthase

Liver

HMGCS2

1p13-p12

Bouchard et al., 2001; Mascaro et al., 1995

CoA, coenzyme A; CPT, carnitine palmitoyltransferase; CUD, Carnitine uptake defect; ETF, electron transfer flavoprotein; HMG, β-hydroxy-β-methylglutaryl; LCAD, long-chain acyl-CoA dehydrogenase; LCFAUD, long-chain fatty acid uptake defect; LCHAD, long-chain L-3-hydroxyacyl-CoA dehydrogenase; MCAD, medium-chain acyl-CoA dehydrogenase; OCTN2, an organic cation/carnitine transporter; Qo, coenzyme Q oxidoreductase; SCAD, short-chain acyl-CoA dehydrogenase; SCHAD, short-chain L-3-hydroxyacyl-CoA dehydrogenase; TRANS, carnitine acylcarnitine translocase; trifunctional, long-chain enoyl-CoA hydratase + long-chain L-3-hydroxyacyl-CoA dehydrogenase + long-chain 3-ketoacyl-CoA thiolase; VLCAD, very long-chain acyl-CoA dehydrogenase. Modified from Tein I. Fatty acid oxidation and associated defects. In American Academy of Neurology Proceedings, Seattle, 1995. Madison, WI: Omnipress, 1995;269:9–38.

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FATTY ACID OXIDATION STUDIES Provided the defect is expressed in cultured skin fibroblasts, a useful screening tool is the measurement of the oxidation rates of [1–carbon 14]–labeled palmitate (C16), octanoate (C8), and butyrate (C4) in the fibroblasts to establish the chain-length specificity of the defect [Rhead, 1990]. Another screening test useful for suggesting an underlying defect in fatty acid oxidation is to culture skin fibroblasts in a glucose-free medium, which will simulate fasting and exacerbate microvesicular steatosis in the fibroblasts expressing a genetic defect in fatty acid oxidation [Renaud et al., 2002]. Another method for quantitative acylcarnitine profiling by electrospray ionization–tandem mass spectrometry in human skin fibroblasts with unlabeled palmitic acid as substrate has revealed pathognomonic acylcarnitine profiles in a variety of short-, medium- and long-chain fatty acid oxidation defects [Okun et al., 2002]. In addition, this method delineates different variants of MCAD deficiency, such as mild and classic. A rapid method for acylcarnitine profiling with stable isotopically labeled palmitate and intact mitochondria prepared from homogenates of fresh muscle biopsy specimens, which reduces the delay in diagnosis related to tissue culture, has also been described [Tyni et al., 2002].

ENZYMATIC ASSAYS Depending on the suspected site of defect, a direct enzymatic assay may then be performed for the specific enzyme (Table 81-4) [Tein, 1995]. These assays can be performed in cultured skin fibroblasts or in muscle biopsy specimens for carnitine palmitoyltransferase I, carnitine palmitoyltransferase II, SCAD, LCAD, SCHAD, and trifunctional enzyme deficiencies, among others. However, certain of these defects may be tissue specific, such as muscle SCHAD deficiency [Tein et al., 1991], in which case the defect is expressed in muscle biopsy specimens and not in fibroblasts and therefore may be missed unless the affected tissue is examined. Carnitine acylcarnitine translocase deficiency [Pande et al., 1993] and MCAD deficiency can be measured in cultured skin fibroblasts. Evidence for a defect in ETF or ETF-coenzyme Q relies on demonstration of a combined deficiency in the activities of the SCAD, MCAD, and LCAD enzymes. Carnitine palmitoyltransferase II deficiency has been rapidly diagnosed prenatally by enzyme assay in 10 mg of chorionic villus sampling at the 11th week of gestation in combination with haplotyping with polymorphic markers linked to the carnitine palmitoyltransferase II gene [Vekemans et al., 2003].

CARNITINE UPTAKE STUDIES For the carnitine uptake defect, diagnosis is confirmed by in vitro studies of carnitine uptake in cultured skin fibroblasts. This study demonstrates negligible uptake of carnitine in the homozygous patients, thereby precluding the calculation of Km and Vmax values [Tein et al., 1990a; Treem et al., 1988]. This finding supports the concept that primary carnitine deficiency is caused by a defect in the specific high-affinity, low-concentration, carrier-mediated OCTN2. Heterozygotes demonstrate normal Km values but reduced Vmax values,

ranging from 13% to 44% of control values [Stanley et al., 1991; Tein et al., 1990a]. This suggests that heterozygotes have a reduced number of normally functioning transporters. This is the most sensitive study for detection of the carrier state because serum carnitine concentrations in the heterozygotes may be normal. Negligible carnitine uptake has also been demonstrated in the cultured lymphoblasts [Tein and Xie, 1996] and myoblasts [Pons et al., 1997] of affected children.

MOLECULAR STUDIES Molecular characterization of the specific defects include Western blotting to determine whether the defects are positive for cross-reacting material, suggestive of a kinetic deficiency, or whether they are negative for cross-reacting material, suggestive of a decrease in the production of the affected enzyme. Western blotting has also been used in the determination of the amounts of the alpha and beta subunits of ETF [Finocchiaro et al., 1990]. A number of the enzymes (e.g., carnitine palmitoyltransferase I, carnitine palmitoyltransferase II, VLCAD, LCAD, SCAD, MCAD, trifunctional enzymes) and transporters (e.g., high-affinity OCTN2) have been cloned (see Table 81-4). This cloning has led to the discovery of specific mutations resulting in the defective activity, which has given rise to the development of specific molecular probes. These probes can be used for the precise and rapid detection of certain specific defects. Specific mutations have been documented for carnitine palmitoyltransferase II [Taroni et al., 1993; Verderio et al., 1995], VLCAD [Andresen et al., 1996a, 1996b; Souri et al., 1996; Strauss et al., 1995], MCAD [Blakemore et al., 1991; Gregersen et al., 1991], SCAD [Corydon et al., 1996; Gregersen et al., 1996; Naito et al., 1990], trifunctional enzyme [Sims et al., 1995; Strauss, 1997], and OCTN2 defects [Lamhonwah et al., 2002], among others. The types of mutations may include missense mutations, small amino acid deletions and insertions, truncating mutations, nonsense mutations, out-of-frame deletions and insertions, and splice-site mutations [Gregersen et al., 2001]. The most straightforward application of mutation analysis is to confirm the diagnosis in suspected patients, particularly in the context of family studies and for prenatal/preimplantation analysis.

Treatment Because of the small number of patients in any given institution, it is difficult to systematically evaluate any single treatment regimen. However, the mainstay of therapy is the avoidance of precipitating factors, particularly prolonged fasting. General treatment strategies are discussed next.

Avoidance of Precipitating Factors Avoidance of precipitating factors, such as prolonged fasting, prolonged aerobic exercise (>30 minutes), and cold exposure leading to shivering thermogenesis, is key. Prolonged fasting is 6 to 10 hours for the infant younger than 1 year and 12 hours for the child between 1 and 4 years of age. In the event of progressive lethargy, obtundation, or an inability to take oral feedings because of vomiting, the child should be taken immediately to the emergency room for

Tein / Metabolic Myopathies

intravenous glucose therapy. Intravenous glucose should be provided at rates sufficient to prevent fatty acid mobilization (8 to 10 mg/kg/minute of glucose) [Hale and Bennett, 1992]. This regimen should be continued until the catabolic cascade has been reversed and the child is able to take oral feedings again. It is wise to avoid prolonged exercise (i.e., >30 minutes) because during this time there is increased fat mobilization. A high-carbohydrate load before exercise is advisable with a rest period and a repeat carbohydrate load at 15 minutes. Avoidance of cold exposure is essential.

High-Carbohydrate, Low-Fat Diet In general, it is advisable to institute a high-carbohydrate, low-fat diet with frequent feedings throughout the day that would be commensurate with the nutritional needs at the child’s age. This goal is best achieved with the aid of a dietitian, aiming toward approximately 70% to 75% of calories from carbohydrate sources, 15% from protein, and approximately 10% to 15% from fat. Monitoring of essential fatty acid levels is important to ensure that the child is receiving adequate essential fatty acids, which may necessitate supplementation. Augmentation of the diet with essential fatty acids (at 1% to 2% of total energy intake) is often used to reduce the risk of essential fatty acid deficiency [Gillingham et al., 1999; Solis and Singh, 2002; Uauy et al., 1989]. Flaxseed, canola, walnut, or safflower oil can be used for this purpose. An older child should have three regular meals per day with three equidistantly scheduled intermeal snacks, including a bedtime snack. In younger children, oral or nasogastric tube administration of an appropriate formula is indicated. In HMG-CoA lyase deficiency, a high-carbohydrate, lowfat, low-protein diet with leucine restriction should be implemented [Gibson et al., 1988].

Uncooked Cornstarch To delay the onset of fasting overnight, the nightly institution of uncooked cornstarch, in doses similar to those used in the treatment of glycogen storage disease (1 to 2 grams per kilogram of body weight per day as a single nighttime dose), will prolong the postabsorptive state and delay fasting [Dionisi-Vici et al., 1991]. Cornstarch provides a sustained-release source of glucose, thereby preventing hypoglycemia and lipolysis [Fernandes and Smit, 2001]. Cornstarch is usually initiated at 8 months of age, when pancreatic enzymes are first able to function at full capacity for appropriate absorption [Hayde and Widhalm, 1990]. The initial recommended dose is generally 1.0 gram/kg/day, which can be gradually increased to 1.5 to 2.0 grams/kg/day by age 2 years as needed [Fernandes and Smit, 2001]. Specific measures for individual fatty acid oxidation disorders include the following: • Medium-chain triglyceride oil: Medium-chain triglyceride oil as a nutritional source could be useful in long-chain fatty acid oxidation disorders because the medium-chain fatty acids would circumvent the block in long-chain fatty acid oxidation and thereby facilitate ATP production from the remainder of the

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patent fatty acid oxidation pathway. The mediumchain triglyceride oil could be started at a dosage of 0.5 gram/kg/day divided in three daily doses and could be increased up to 1 or 1.5 grams/kg/day as tolerated. The major side effect is diarrhea. The usefulness of this approach, however, may be limited because excess medium-chain triglyceride would ultimately be stored as long-chain fats in adipocytes. The success of medium-chain triglyceride oil supplementation in LCHAD deficiency has been variable [Tein et al., 1995]. When a high percentage of energy from fat is provided by medium-chain triglyceride oil, patients are at risk for essential fatty acid deficiency, and their diet should therefore be supplemented with essential fatty acids (1% to 2% of total energy intake) [Solis and Singh, 2002]. • Riboflavin: Certain cases of the multiple acyl-CoA dehydrogenase deficiencies (e.g., ETF or ETF-coenzyme Q–linked deficiencies) are responsive to riboflavin supplementation [Gregersen et al., 1982b]. The dosage is approximately 50 mg three times a day for infants and young children and 100 mg three times a day for older children. • Carnitine: The essential indication for carnitine therapy is the OCTN2 defect, which is characterized by carnitine-responsive cardiomyopathy and very low plasma and tissue concentrations of carnitine (generally <5% of normal) [Stanley et al., 1991; Tein et al., 1990a]. There was a dramatic improvement in the cardiomyopathy and myopathy in all 22 patients treated with high-dose oral carnitine supplementation within the first few weeks, as well as a reduction of heart size toward normal within a few months of therapy. In addition, three children with significant failure to thrive before therapy demonstrated a marked improvement in growth after therapy [Tein et al., 1990a]. Of 19 patients treated with carnitine therapy for 5 to 20 years, 18 continue to be healthy [Cederbaum et al., 2002; Stanley et al., 1991]. Thus, in the OCTN2 defect, high-dose oral L-carnitine supplementation at 100 mg/kg/day in four divided daily doses is critical and lifesaving, significantly reversing the pathology in this otherwise progressive and lethal disease. Furthermore, in children in whom the condition is prospectively diagnosed at birth, early carnitine therapy from birth has been demonstrated to prevent the development of the clinical phenotype [Lamhonwah et al., 2002]. In the intramitochondrial beta oxidation defects with secondary carnitine deficiency, the results of carnitine therapy have been highly variable and insufficiently evaluated. Theoretically, carnitine has been given to limit the intracellular concentrations of potentially toxic acyl-CoA intermediates within the cell through transesterification and to thereby liberate CoA, which is a critical intracellular cofactor [Hale and Bennett, 1992]. However, there has been no objective prospective study to prove that carnitine administration has had a beneficial effect. In one study of a patient with MCAD deficiency, Stanley and colleagues [1990] demonstrated that the associated carnitine deficiency was not the cause of the defect in fatty acid oxidation, as indi-

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Neuromuscular Disorders / 81

cated by the lack of effect of carnitine replacement on fasting ketogenesis. After 3 months of oral carnitine therapy, this patient had no increase in plasma ketones and continued to become ill and hypoglycemic after 14 hours of fasting. Furthermore, there is increasing evidence to suggest that carnitine administration may have deleterious effects in the long-chain fatty acid oxidation disorders. In these disorders, there is an accumulation of long-chain acyl-CoAs proximal to the metabolic block, which on esterification become longchain acylcarnitines. Excessive palmitoylcarnitine may have detergent effects on membranes and arrhythmogenic effects as previously discussed [Inoue and Pappano, 1983; Lee et al., 1987; Mak et al., 1986; Spedding, 1985; Spedding and Mir, 1987]. This field warrants further investigation.

SPECIFIC THERAPIES FOR LCHAD/TRIFUNCTIONAL PROTEIN DEFICIENCY Oral prednisone has led to a dramatic reversal of the limbgirdle myopathy and marked reduction in the episodic myoglobinuria in one male with the myoneuropathic form of LCHAD deficiency [Tein et al., 1995]. Several children with LCHAD deficiency who had asssociated pigmentary retinopathy were documented to have a deficiency of the n-3-polyunsaturated fatty acid docosahexaenoic acid, and subsequent supplementation with docosahexaenoic acid led to some improvement in visual function [Gillingham et al., 1997; Harding et al., 1999]. Furthermore, the daily oral administration of a cod liver oil extract containing high amounts of docosahexaenoic acid led to a marked clinical and electrophysiologic recovery of the progressive peripheral sensorimotor axonopathy in one male with the myoneuropathic form of LCHAD deficiency [Tein et al., 1999b].

TRIHEPTANOIN Use of the anaplerotic odd-chain triglyceride triheptanoic acid has been reported to be of value in the therapy for longchain fatty acid oxidation defects [Roe et al., 2002]. In three patients with VLCAD deficiency fed controlled diets in which the fat component was switched from medium-length even-chain triglycerides to triheptanoin, this treatment led rapidly to clinical improvement that included the resolution of chronic cardiomyopathy, myoglobinuria, and muscle weakness for more than 2 years in one child and of myoglobinuria and weakness in the others. This finding warrants further investigation.

Genetics and Presymptomatic Recognition All known fatty acid oxidation disorders are inherited as autosomal-recessive conditions. Therefore, screening for other affected siblings is important because institution of preventive measures is relatively simple, and without treatment, morbidity and mortality are significant. Although screening of family members after identification of an affected individual is of benefit to the family, this approach fails to identify individuals who do not belong to this high-risk group. One approach to screening would be to evaluate populations that are considered at risk for a fatty acid oxidation defect, such as those manifesting with sudden infant death syndrome, “near-miss” sudden infant death syndrome, and Reye’s syndrome. Bennett and co-workers [1987] demon-

strated that the incidence of dicarboxylic aciduria in an acutely ill pediatric population is approximately 1 per 12,000 and that in most cases the organic acid pattern was consistent with a defect in fatty acid oxidation. In another study of 7058 dried filter-paper blood spot specimens obtained at postmortem examination by electrospray tandem mass spectrometric analysis of acylcarnitine profiles from infants with unexplained causes of death, there were 23 cases of MCAD deficiency, 9 cases of VLCAD deficiency, 8 cases of glutaric acidemia type II, 6 cases of carnitine palmitoyltransferase II/ translocase deficiencies, 4 cases of severe carnitine deficiency, and 4 cases of LCHAD/trifunctional protein deficiency [Chace et al., 2001]. More recently, specific molecular probes have been used to screen for one of the more common defects, MCAD deficiency. In one study, through use of the specific molecular probe for the gene mutation found in more than approximately 60% of children in the United Kingdom with MCAD deficiency (A985G point mutation), Blakemore and associates [1991] examined 410 consecutive neonatal bloodspot cards in a northern English population. The data suggested that the carrier state for this mutation is 1 in 68, which would correspond to a frequency of approximately 1 in 18,500 births for the homozygous MCAD-deficient state in this particular population group. Tandem mass spectrometry has made screening possible for most fatty acid oxidation defects on the basis of the profiling of acylcarnitines in blood spots [Rinaldo and Matern, 2000]. The inclusion of fatty acid oxidation disorders in screening programs is highly desirable to prevent morbidity and mortality, implement preventive measures and treatment strategies, and to contain the cost of care of affected patients. For example, the incidence for MCAD deficiency was 1 per 8930 live births in a survey from the Pennsylvania neonatal screening program, obtained through tandem mass spectrometry, followed by confirmation through molecular analysis for several common mutations [Ziadeh et al., 1995].

MITOCHONDRIAL ENCEPHALOMYOPATHIES Although all of the mitochondrial myopathies that are expressed in muscle are at potential risk for the development of myopathy and exercise intolerance, the specific defects in which acute episodes of myoglobinuria have been documented to date include defects of complexes I, II, III, and IV activities, as well as multiple mtDNA deletions and coenzyme Q10 deficiency. Chapter 28 is dedicated to the detailed discussion of the individual mitochondrial disorders; therefore, the following sections serve to summarize and highlight the key clinical, morphologic, biochemical, genetic, and physiologic features of this group of disorders.

Historical Considerations In 1962 the concept of mitochondrial disease was first introduced when Luft and colleagues [1962] reported a young Swedish woman who suffered from severe hypermetabolism that was not caused by thyroid dysfunction. Muscle biopsy revealed abnormal mitochondria, and biochemical investigation revealed loose coupling of oxidation and phosphorylation in isolated muscle mitochondria. In the 1960s and

Tein / Metabolic Myopathies

1970s, investigation of muscle biopsy specimens led to the recognition of different patterns of mitochondrial changes [Shy and Gonatas, 1964; Shy et al., 1966]. In 1963 the modification of the Gomori trichrome stain by Engel and Cunningham [1963] allowed identification of abnormal deposits of mitochondria as ragged-red fibers. In the 1970s and 1980s, systematic biochemical investigation led to a rational biochemical classification of mitochondrial diseases into five main groups. With advances in mitochondrial genetics, which contain their own DNA (mtDNA), a genetic classification has subsequently been proposed on the basis of nuclear or mitochondrial inheritance or both.

Morphologic Considerations Although the finding of ragged-red fibers or ultrastructural alterations of mitochondria in muscle biopsy specimens suggests the possibility of a mitochondrial disorder, there are important limitations, as pointed out by DiMauro [1993]: • In nonmitochondrial disorders, such as muscular dystrophies, polymyositis, and some glycogenoses, ragged-red fibers, or ultrastructural mitochondrial abnormalities in which they likely represent secondary changes, may be present. • Conversely, in many primary mitochondrial diseases, such as enzyme defects in metabolic pathways other than the respiratory chain (e.g., the pyruvate dehydrogenase complex, carnitine palmitoyltransferase, beta oxidation, and fumarase deficiencies), ragged-red fibers are not present. In addition, there are defects of the respiratory chain, such as the form of Leigh’s syndrome secondary to cytochrome c oxidase (COX) deficiency, in which ragged-red fibers tend not to be present. Although ragged-red fibers are most often present in transfer RNA encoding mtDNA defects (which affect the respiratory chain), protein coding defects, such as the syndrome of neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) and Leber’s hereditary optic neuropathy, have only subtle mitochondrial changes, without ragged-red fibers [Uemura et al., 1987]. Furthermore, the appearance of ragged-red fibers may also depend on the stage of the disease and on the threshold effect (the percentage of mutant mtDNA). Succinate dehydrogenase and COX stains are two other useful histochemical stains. Ragged-red fibers are often COX-negative, although not all COX-negative fibers are ragged-red fibers [DiMauro, 1993]. COX-negative ragged-red fibers are seen in patients with progressive external ophthalmoplegia and mtDNA deletions and in the syndrome of myoclonus and epilepsy with raggedred fibers (MERRF). They are not seen in the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS), in which COX-positive raggedred fibers are usually present. There may be increased numbers of mitochondria (pleoconial myopathy), increased size (megaconial myopathy), disoriented or rarefied cristae, or osmiophilic or paracrystalline inclusions [DiMauro, 1993] on electron microscopic samples. The paracrystalline inclusions are deposits of mitochondrial creatine kinase [Stadhouders et al., 1990]. Lipid or glycogen storage may also be documented on muscle biopsy, signifying a defect of terminal oxidation [Jerusalem et al., 1973].

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Clinical Considerations The prevalence of mtDNA-related disorders has only been estimated. In northeastern England, mtDNA defects were the cause of disease in 6.57 per 100,000 adults of working age [Chinnery et al., 2000]. Overall, it was estimated that 12.48 per 100,000 individuals in the adult and child population either had mtDNA disease or were at risk of developing mtDNA disease. In western Sweden, the incidence of mitochondrial diseases overall was 1 per 11,000 preschool children [Darin et al., 2001]. Certain mtDNA mutations are relatively common, such as the A3243G MELAS mutation in northern Finland, which was estimated to occur in 16.3 per 100,000 in the adult population [Majamaa et al., 1998]. These prevalence rates support the conclusion that mitochondrial diseases are among the most common metabolic disorders, at least in northern Europe [Vu et al., 2002]. Mitochondrial diseases are clinically heterogeneous. There may be variation in the age at onset, course, and distribution of weakness in pure myopathies [DiMauro, 1993]. Additional features may include exercise intolerance and premature fatigue. In clinical classification, there has been controversy between the “lumpers” and the “splitters.” Originally, three specific clinical syndromes were described: Kearns-Sayre, MERRF, and MELAS syndromes, each resulting from three distinct mutations in mtDNA. All three share the features of short stature, dementia, sensorineural hearing loss, lactic acidosis, and ragged-red fibers [DiMauro, 1993]. Mitochondria and mtDNA are ubiquitous, which explains why every tissue in the body can be affected by mtDNA mutations. The most common presenting clinical features include short stature, sensorineural hearing loss, migraine headaches, ophthalmoparesis, myopathy, axonal neuropathy, diabetes mellitus, hypertrophic cardiomyopathy, and renal tubular acidosis. Additional features may include strokelike episodes, seizures, myoclonus, retinitis pigmentosa, optic atrophy, ataxia, and gastrointestinal pseuo-obstruction. In the case of mtDNA mutations, there may be a diverse spectrum of associated syndromes, even in a single pedigree, because of heteroplasmy and the threshold effect, whereby different tissues harboring the same mtDNA muttion may be affected to different degrees or not at all. Furthermore, the same mutation can cause different syndromes (e.g., the T8993G mutation can cause either NARP or maternally inherited Leigh’s syndrome), and different mutations can cause the same phenotype (e.g., A3243G mutation, single deletion, and multiple deletions of the mtDNA can all cause progressive external opththalmoplegia) [Moraes et al., 1993; Vu et al., 2002]. Thus, the diagnosis of mtDNA-related disorders often requires a careful synthesis of the clinical history, signs, mode of inheritance, laboratory data, neuroradiologic findings, exercise physiology, muscle biopsy findings, biochemistry profile, and molecular genetics.

Biochemical Classification Mitochondrial encephalomyopathies can be classified into five groups [DiMauro, 1993] according to the area of mitochondrial metabolism specifically affected: (1) defects of transport, (2) defects of substrate utilization, (3) defects of

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Neuromuscular Disorders / 81 Carbohydrates Cytosol

Glycolysis

Fatty acids

Amino acids

Pyruvate

Pyruvate Amino acids Transaminase AcetyI CoA

Fatty acids

␤-Oxidation Citrate

Oxaloacetate Malate

␣Ketoglutarate Mitochondrion

Fumarate Succinate

2H

Succinyl Coenzyme A

2H

2H

2H Complex I

NADH

FMN

FeS

FeS

FeS

FeS

CoQ

Complex II FAD

FeS

FeS

Complex III Cyt b1

Cyt ba

FeS

Complex IV Cyt c1

Cyt c

Cyt a

Cyt a3

O2

FeS

Complex V ADP P1

ATP Pi

FIGURE 81-3. Scheme of mitochondrial metabolism. ADP, adenosine diphosphate; ATP, adenosine triphosphate; CoA, coenzyme A; CoQ, coenzyme Q; Cyt, cytochrome; FAD, flavin adenine dinucleotide; FeS, nonheme iron-sulfur protein; FMN, flavin mononucleotide; NADH, nicotinamide adenine nucleotide, reduced; Pi, inorganic phosphate. (From DiMauro S, DeVivo DC. Diseases of carbohydrate, fatty acid, and mitochondrial metabolism. In: Siegel GJ, Agranoff BW, Albers W, et al., eds. Basic neurochemistry: Molecular, cellular, and medical aspects, 4th ed. New York: Raven Press, 1989;647.)

the Krebs cycle, (4) defects of the respiratory chain, and (5) defects of oxidation/phosphorylation coupling (Fig. 81-3) [DiMauro and De Vivo, 1989]. Limitations of this classification scheme relate to the respiratory chain defects that can result from genetic defects of mtDNA, which are usually heteroplasmic, and to deletions of mtDNA or point mutations in transfer RNA, which affect mtDNA translation as a whole and may lead to multiple respiratory chain defects.

Genetic Classification Mitochondria are the only subcellular organelles with their own DNA (mtDNA) [Nass and Nass, 1963] that are capable of synthesizing a vital set of proteins. Human mtDNA is a small (16.5-kilobase), circular, double-stranded molecule that has been completely sequenced [Anderson et al., 1981]. It encodes 13 structural proteins, all of which are subunits of respiratory chain complexes, as well as two ribosomal RNAs and 22 transfer RNAs needed for translation. Human mtDNA has a number of unique features [DiMauro, 1993]:

• Its genetic code differs from that of nuclear DNA. • It is subject to spontaneous mutations at a higher rate than is nuclear DNA. • It contains no introns and is therefore tightly packed with information. • It is transmitted by maternal inheritance. • Its repair mechanisms are less efficient than those of nuclear DNA. • It is present in hundreds or thousands of copies per cell. In the formation of the zygote, mtDNA is contributed only by the oocyte [Giles et al., 1980]. Therefore, a mother carrying an mtDNA mutation passes it on to all her children, but only her daughters will transmit it to their progeny. If there is a mutation in some mtDNA in the ovum or zygote, this may be passed on randomly to subsequent generations of cells, some of which will receive primarily or exclusively mutant genomes (mutant homoplasmy); others will receive few or no mutant genomes (normal or wild type of homoplasmy); and still others will receive a mixed population of mutant and wild-type mtDNAs (heteroplasmy).

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Maternal inheritance and heteroplasmy have several important implications [DiMauro, 1993]:

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• At cell division, the proportion may shift in daughter cells (mitotic segregation), leading to a corresponding phenotypic change. This shift explains the age-related, and even tissue-related, variability of clinical features frequently observed in mtDNA-related disorders. • Subsequent generations will be affected at a higher rate than in autosomal-dominant diseases.

• Inheritance of disease is maternal, as in X-linked traits, but both sexes are equally affected. • Phenotypic expression of an mtDNA mutation will depend on relative proportions of mutant and wildtype genomes; a minimum critical number of mutant genomes is necessary for expression (threshold effect). The threshold for disease is lower in tissues that are highly dependent on oxidative metabolism, such as brain, heart, skeletal muscle, retina, renal tubule, and endocrine gland tissue. Therefore, these tissues are especially vulnerable to the effects of pathogenic mutations in mtDNA.

The critical number of mutant mtDNA needed for the threshold effect may vary, depending on the specific vulnerability of the tissue to impairments of oxidative metabolism. It may also vary according to the vulnerability of the same tissue over time, which may increase with age [Moraes et al., 1991a; Ozawa, 1995; Wallace et al., 1988b]. A current

Parkinsonism, Aminoglycoside-induced deafness MELAS, Myoglobinuria

LS, MELAS, Multisystem disease

Myopathy, PEO

Cardiomyopathy

Cardiomyopathy, ECM

PEO, LHON, MELAS, Myopathy, Cardiomyopathy, Diabetes and deafness

V

12s

F

P

ECM, LHON, Myopathy, Cardiomyopathy, MELAS and Parkinsonism

T

16S Cyt b

LHON

Cardiomyopathy ECM

L1 Myopathy, Cardiomyopathy, PEO Myopathy, MELAS

Cardiomyopathy, LHON

LS, MELAS ND5

ND2

LS, Ataxia Chorea, Myopathy PEO

ECM PEO

W A N C Y

L2 S2 H COI

Myoglobinuria, Motor neuron disease, Sideroblastic anemia PPK, Deafness, MERRF/MELAS

LHON, MELAS Diabetes, LHON + Dystonia

ND6

I Q M

Myopathy, Lymphoma

Myopathy PEO

E ND1

S1 D

ND4

ND3 A8 K

Myopathy, Multisystem disease, Encephalomyopathy

Diabetes and deafness LHON, Myopathy, LHON + Dystonia

ND4L

COII

Cardiomyopathy, Myoclonus

Cardiomyopathy, ECM, PEO, Myopathy, Sideroblastic anemia

A6

COIII

R LHON

G

Progressive myoclonus, epilepsy and optic atrophy NARP,MILS, FBSN

Cardiomyopathy PEO, MERRF, MELAS, Deafness

Cardiomyopathy, SIDS, ECM LS, ECM, Myoglobinuria

FIGURE 81-4. Morbidity map of the human mitochondrial genome as of January 1, 2004. See also Color Plate. In the map of the 16,569-kilobase mitochondrial DNA, differently shaded areas represent the protein-coding genes for the seven subunits of complex 1 (ND1 to ND4, ND4L, ND5, ND6), the three subunits of cytochrome oxidase (COX), cytochrome b (Cyt b), and the two subunits of adenosine triphosphate synthetase (A8, A6) (red); the 12S and 16S ribosomal RNAs (12S, 16S) (dark blue), and the 22 transfer RNAs identified by one-letter codes and by L1, L2, S1, and S2 for the corresponding amino acids (light blue). Diseases caused by mutations that impair mitochondrial protein synthesis are named in blue; diseases caused by mutations in protein-coding genes are named in red. ECM, encephalomyopathy; FBSN, familial bilateral striatal necrosis; KSS, Kearns-Sayre syndrome; LHON, Leber’s hereditary optic neuropathy; LS, Leigh’s syndrome; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes; MERRF, myoclonus, epilepsy with ragged-red fibers; MILS, maternally inherited Leigh’s syndrome; NARP, neuropathy, ataxia, retinitis pigmentosis; PEO, progressive external opththalmoplegia; PPK, palmoplantar keratoderma; SIDS, sudden infant death syndrome. (From DiMauro S. Mitochondrial diseases. Biochim Biophys Acta 2004;1658:83, Fig. 3; modified from DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. New Engl J Med 2003;348:2660, Fig. 3. Copyright ” 2003 Massachusetts Medical Society. All rights reserved.)

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Neuromuscular Disorders / 81

morbidity map of the human mitochondrial genome is shown in Figure 81-4 [DiMauro, 2004]. Although the mtDNA-encoded peptides are functionally important, they represent only a small proportion of the total mitochondrial protein. Of the approximately 80 proteins that make up the respiratory chain, only 13 are encoded by mtDNA. Complexes I, III, IV, and V contain some subunits encoded by mtDNA: seven for complex 1 (ND1-ND4, ND4L, ND5, and ND6), one for complex III (cytochrome b), three for complex IV (COX I to COX III), and two for complex V (ATPase 6 and ATPase 8) [DiMauro, 2004]. In contrast, complex II, coenzyme Q, and cytochrome c are encoded exclusively by nuclear DNA. Thus, the majority of mitochondrial proteins are encoded by nuclear DNA. The nuclear DNAencoded proteins are synthesized in the cytoplasm and then imported into mitochondria. This transport of proteins requires a complex series of post-translational events and translocation machinery. This series involves synthesis of larger precursors in the cytosol, amino terminal leader peptides, which function as address signals and recognize specific mitochondrial membrane receptors. This synthesis is followed by translocation across the mitochondrial membrane and cleavage of the

TABLE 81-5 Genetic Classification of Mitochondrial Diseases Defects of mtDNA Single-deletions (usually sporadic) Duplications or duplications/deletions (maternal transmission) Point mutations (maternal transmission) Structural genes Transfer RNA genes Defects of Nuclear DNA (Mendelian Transmission) Mutations in genes encoding enzymes or translocases Defects of substrate transport Defects of substrate utilization Defects of the respiratory chain Defects of oxidation/phosphorylation coupling Defects of mitochondrial protein importation Defects of intergenomic dialogue Multiple deletions of mtDNA Depletion of mtDNA From Vu TH, Hirano M, DiMauro S. Mitochondrial diseases. Neurol Clin North Am 2002;20:810. mtDNA, mitochondrial DNA.

TABLE 81-6 Genetic and Biochemical Classification of the Mitochondrial Diseases GENOME

GENE

mtDNA

[mtDNA]

BIOCHEMISTRY

CLINICAL PHENOTYPE

Single deletion

Decreased protein synthesis

tRNA tRNALys Other tRNAs ATPase 6

Decreased protein synthesis Decreased protein synthesis Decreased protein synthesis Decreased ATP synthesis

ND1, ND4, ND6 ND1, ND4 Cytochrome b COX III

Decreased complex I

Kearns-Sayre syndrome; ocular myopathy; Pearson’s syndrome MELAS syndrome MERRF syndrome Multiple phenotypes Neurogenic muscle weakness, ataxia, retinitis pigmentosa (NARP)/maternally inherited Leigh’s syndrome Leber’s hereditary optic neuropathy

Decreased complex I Decreased complex III Decreased complex IV

Myopathy† Myopathy† Myopathy†

NDUF SDHA BCSIL SURF1 SCO1 SCO2 COX 10 COX 15 ATP 12 TP

Decreased complex I Decreased complex II Decreased complex III Decreased complex IV Decreased complex IV Decreased complex IV Decreased complex IV Decreased complex IV Decreased complex V Decreased _

Leigh’s syndrome Leigh’s syndrome GRACILE Leigh’s syndrome Hepatoencephalomyopathy Cardioencephalomyopathy Nephroencephalomyopathy Cardioencephalomyopathy Fatal infantile multisystemic disease Mitochondrial neurogastrointestinal encephalomyopathy Autosomal-dominant PEO-plus‡ Autosomal-dominant PEO-plus‡ Autosomal-dominant/recessive PEO-plus‡ Hepatocerebral syndrome Myopathy; spinal muscular atrophy Barth’s syndrome Autosomal-dominant optic atrophy

Leu(UUR)

Nuclear DNA

ANT1 Twinkle POLG dGK TK2 TAZ OPA1

Multiple deletions* Multiple deletions* Multiple deletions* Multiple deletions* Depletion* Depletion*

Decreased protein synthesis Decreased protein synthesis Decreased protein synthesis Decreased protein synthesis Decreased protein synthesis Decreased cardiolipin Decreased mitochondrial motility

*[mtDNA] indicates changes of mtDNA secondary to nuclear DNA mutations (defects of intergenomic signaling). † Mutations in cytochrome b and COX genes can also cause multisystemic diseases. ‡ “Plus” refers to proximal weakness, neuropathy, psychiatric disorders, and parkinsonism. ATP, adenosine triphosphate; ATPase, adenosine triphosphatase; COX, cytochrome c oxidase; GRACILE, growth retardation, aminoaciduria, cholestasis, lactic acidosis, and early death; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes; MERRF, myoclonus, epilepsy associated with ragged-red fibers; mtDNA, mitochondrial DNA; PEO, progressive external ophthalmoplegia; tRNA, transfer RNA. From DiMauro S. Mitochondrial diseases. Biochim Biophys Acta 2004;1658:81.

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leader peptides with assembly of mature peptides at their final intramitochondrial location [Schatz, 1991]. Therefore, the genetic classification of mitochondrial diseases must take into account defects of nuclear DNA or mtDNA and defects of communication between the two genomes (Table 81-5) [Vu et al., 2002]. The corresponding biochemical defects and the disease phenotypes arising from mutations in the currently recognized nuclear and mitochondrial genes are summarized in Table 81-6 [DiMauro, 2004].

Physiologic Considerations Standard exercise physiology tests, such as cycle ergometers or treadmills, can be used to detect alterations of oxidative metabolism [Haller et al., 1989; Lewis and Haller, 1991b]. Maximal oxygen uptake is the most useful indicator of a patient’s capacity for oxidative metabolism [DiMauro, 1993]. Typical physiologic responses in patients with defects in oxidative metabolism are as follows [Haller et al., 1989, 1991; Taivassalo et al., 2003]: • The increase of cardiac output during exercise is greater than normal in relation to the rate of oxidative metabolism. In a study of 40 patients with mitochondrial myopathies who engaged in maximal cycle exercise, the increase in cardiac output relative to oxygen uptake (VO2) (15.0 ± 13.6; range, 3.3 to 73) was found to be exaggerated in comparison with control subjects (5.1 ± 0.7). • Oxygen extraction per unit of blood remains almost unchanged from rest to maximal exercise. In patients during maximal cycle exercise, the mean peak systemic arteriovenous oxygen difference was 7.7 ± 3.5 mL/dL (range, 2.7 to 17.6), in comparison with control subjects, whose values were 15.2 ± 2.1 mL/dL. This problem leads to a gross mismatch between oxygen transport and utilization. • Ventilation is normal at rest but increases excessively in relation to oxygen uptake. In patients during maximal cycle exercise, the increase in ventilation in relation to VO2 (mean peak ventilation/VO2 = 65 ± 24; range, 21 to 104) was exaggerated in comparison with control subjects (ventilation/VO2 = 41.2 ± 7.4). • The level of venous lactate, which is usually elevated at rest, increases excessively in relation to workload and oxygen uptake. Furthermore, during maximal cycle exercise in 40 patients with mitochondrial myopathies, the mean peak work capacity (0.88 ± 0.6 [watts]/kg) and oxygen uptake (VO2 = 16 ± 8 mL/kg/ minute) were significantly lower (P < 0.01) than in control subjects (mean work capacity, 2.2 ± 0.7 W/kg; VO2 = 32 ± 7 mL/kg/minute), but the patient range was broad (mean work capacity, 0.17 to 3.2 W/kg; VO2 = 6 to 47 mL/kg/minute) [Taivassalo et al., 2003]. The investigators concluded that the degree of exercise intolerance in mitochondrial myopathies was correlated directly with the severity of impaired muscle oxidative phosphorylation, as indicated by the peak capacity for muscle oxygen extraction. The exaggerated circulatory and ventilatory responses to exercise were a direct consequence of the level of

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impaired muscle oxidative phosphorylation and increased exponentially in relation to increasing severity of oxidative impairment. Aerobic forearm exercise provides an easily performed screening test that sensitively detects impaired oxygen use and accurately assesses the severity of oxidative impairment in patients with mitochondrial myopathy and exercise intolerance. In a study of 13 patients with mitochondrial myopathy and exercise intolerance, the exercise venous oxygen tension (PO2) paradoxically rose from 27.2 ± 4.0 mm Hg to 38.2 ± 13.3 mm Hg, whereas the oxygen tension fell from 27.2 ± 4.2 mm Hg to 24.2 ± 2.7 mm Hg in healthy subjects [Taivassalo et al., 2002]. The range of elevated venous oxygen tension during forearm exercise in the patients (32 to 82 mm Hg) was correlated closely with the severity of oxidative impairment as assessed during cycle exercise. Impaired oxygen extraction by exercising muscles can also be detected by near-infrared spectroscopy, which measures the degree of deoxygenation of hemoglobin [Bank et al., 1998]. Mitochondrial function in muscle in vivo can be evaluated quantitatively with 31P-NMR [Radda et al., 1995]. The ratio of phosphocreatine to inorganic phosphate can be measured in muscle at rest, during exercise, and during recovery. In patients with mitochondrial dysfunction, ratios of phosphocreatine to inorganic phosphate are lower than normal at rest, decrease excessively during exercise, and return to baseline values more slowly than normal [Argov and Bank, 1991].

Defects of Mitochondrial DNA Defects in Mitochondrial Protein Synthesis MITOCHONDRIAL DNA REARRANGEMENTS: SINGLE DELETIONS AND DUPLICATIONS Single deletions of mtDNA have been associated with three conditions that are usually sporadic [DiMauro and Hirano, 2003a]: (1) Kearns-Sayre syndrome, a multisytem disorder; (2) progressive external ophthalmoplegia, with or without proximal limb weakness, which is often compatible with a normal life span; and (3) Pearson syndrome, a rapidly fatal disorder of infancy characterized by sideroblastic anemia and exocrine pancreas dysfunction. Duplications of mtDNA can occur in isolation or together with single deletions and have been documented in patients with Kearns-Sayre syndrome or with diabetes mellitus and deafness [DiMauro, 2004]. Duplications and duplications/ deletions are rare and are usually transmitted by maternal inheritance.

Kearns-Sayre Syndrome The clinical criteria for diagnosing Kearns-Sayre syndrome are (1) onset before age 20; (2) progressive external opththalmoplegia; (3) pigmentary retinopathy; and (4) at least one of the following: heart block, cerebellar ataxia, or a cerebrospinal fluid protein level above 100 mg/dL. Other relatively common but nonspecific features include dementia, sensorineural hearing loss, and multiple endocrine abnormalities (short stature, diabetes, hypoparathyroidism) [DiMauro, 1993]. Ragged-red fibers and variable COX-negative fibers

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are seen on muscle biopsy. The prognosis is poor despite pacemaker placement. The course is progressively downhill, with death by the third or fourth decade. Renal tubular acidosis [Eviatar et al., 1990; Goto et al., 1990a] and Lowe’s syndrome [Moraes et al., 1991b] are unusual clinical variants. A few overlapping cases, such as two children with Kearns-Sayre syndrome and strokelike episodes [Zupanc et al., 1991], have been described. The genetic basis of Kearns-Sayre syndrome is attributable to mtDNA deletions in the great majority of cases [Holt et al., 1989; Moraes et al., 1989].

Sporadic Progressive External Opththalmoplegia with Ragged-Red Fibers Sporadic progressive external opththalmoplegia with raggedred fibers is a clinically benign condition characterized by adolescent- or young adult–onset ophthalmoplegia, ptosis, and proximal limb weakness, which is slowly progressive and compatible with a relatively normal life span. The muscle biopsy reveals ragged-red fibers and COX-negative fibers. Approximately 50% of patients with progressive external opththalmoplegia have mtDNA deletions [Moraes et al., 1989]. The family history is negative. In terms of therapy, one woman with adult-onset chronic progressive external ophthalmoplegia, ptosis, mild proximal weakness, and muscle mtDNA deletion was treated with 7 months of oral lipoic acid; she demonstrated an increase in brain energy availability and skeletal muscle performance, as illustrated by in vivo 31P-NMR spectroscopy [Barbiroli et al., 1995].

DELETIONS OF MITOCHONDRIAL DNA: MOLECULAR BIOLOGY Deletions of mtDNA range from approximately 2 to 8.5 kilobases and are confined primarily to an 11-kilobase region [DiMauro, 1993]. Regardless of clinical presentation, 30% to 40% of all deletions are identical. They span 4977 base pairs from the ATPase 8 gene to the ND5 gene [Holt et al., 1989; Shoffner et al., 1989; Tanaka et al., 1989]. These deletions can be divided into two main classes [Mita et al., 1990]. The distribution and relative abundance of mtDNA deletions in different tissues appear to determine the clinical phenotype [DiMauro, 1993].

MITOCHONDRIAL DNA POINT MUTATIONS Point mutations have been identified in mtDNA from a variety of disorders, most of which are maternally inherited and multisystemic, although some are sporadic and tissue specific. Two of the more common syndromes among the maternally inherited encephalomyopathies are the MERRF and MELAS syndromes. Syndromes associated with transfer RNA mutations may be multisystemic, affecting vision (optic atrophy, retinitis pigmentosa, cataracts), hearing (sensorineural hearing loss), the endocrine system (short stature, diabetes mellitus, hypoparathyroidism), the heart (hypertrophic cardiomyopathies, cardiac conduction blocks), the gastrointestinal tract (exocrine pancreatic dysfunction, intestinal pseudo-obstruction, gastroesophageal reflux), and the kidneys (renal tubular acidosis).

MERRF Syndrome MERRF syndrome is characterized by myoclonus, seizures, mitochondrial myopathy, and cerebellar ataxia. Less com-

mon signs include dementia, optic atrophy, spasticity, hearing loss, and peripheral neuropathy. Inheritance is maternal; however, expression depends on the percentage of mutant mtDNA. The highly specific, although not exclusive, point mutation is an A8344G in the transfer RNALys gene of mtDNA [Shoffner et al., 1990]. This facilitates identification of patients independent of the severity of their clinical phenotype. Genetic heterogeneity is suggested by the absence of the mutation in four patients with typical MERRF syndrome [Hammans et al., 1991; Zeviani et al., 1991]. Other identified mutations in the transfer RNALys gene that have been associated with MERRF syndrome are the T8356C and G8363A point mutations [DiMauro, 2004]. In one patient with MERRF syndrome, a mutation has been identified in a different transfer RNA: G611A in the transfer RNAPhe gene [Mancuso et al., 2004a]. Onset may occur in childhood or in adulthood, and the course may be slowly progressive or rapidly downhill. Wallace and associates [1988b] suggested that there may be a hierarchy of vulnerability of different organs in which the brain suffers first, followed by muscle and heart. However, there may be variations among patients in the sequence of organ involvement [Lombes et al., 1989; Tsairis et al., 1973]. Muscle biopsy reveals ragged-red fibers, although exceptions occur [Hammans et al., 1991]. There are two populations of mitochondria: those that have normal COX activity and immunoreactivity for subunit II and those with decreased COX activity and COX II immunoreactivity [Lombes et al., 1989]. Neuropathologic findings include neuronal loss and gliosis, affecting in particular the dentate nucleus and inferior olivary complex, with some dropout of Purkinje cells and neurons of the red nucleus. There is pallor of the posterior columns of the spinal cord [DiMauro, 1993]. Muscle biochemistry profiles have revealed variable defects of complex III [Berkovic et al., 1989; Morgan-Hughes et al., 1982], complexes II and IV [Berkovic et al., 1989], complexes I and IV [Wallace et al., 1988b], or complex IV alone [Lombes et al., 1989]. Combined partial defects of all complexes with subunits encoded by mtDNA have been suggested by studies in which investigators used human cell lines completely devoid of mtDNA (rho0 cells) [Chomyn et al., 1991; King and Attardi, 1989]. There is no specific therapy, although coenzyme Q10 appeared to benefit a mother and daughter with the MERRF mutation [Wallace et al., 1991].

MELAS Syndrome MELAS is a clinical syndrome that is characterized by (1) strokelike episodes (computed tomography or magnetic resonance imaging provides evidence of focal brain abnormalities); (2) lactic acidosis, ragged-red fibers, or both; and (3) at least two of the following: dementia, focal or generalized seizures, recurrent headache, or vomiting [Ciafaloni et al., 1992; Pavlakis et al., 1984]. In one series, onset was before 15 years of age in 62% of patients, and hemianopia or cortical blindness was the most common manifestation [Ciafaloni et al., 1992]. Inheritance is maternal, and there is a highly specific, although not exclusive, point mutation at nucleotide 3243 in the transfer RNALeu(UUR) gene of mtDNA [Goto et al., 1990b; Kobayashi et al., 1990]. Other point mutations have also been described. Cerebrospinal fluid protein levels were abnormally increased in approximately

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50% of patients [Ciafaloni et al., 1992]. Basal ganglia calcifications were demonstrated in 6 of 22 patients and dilatative or hypertrophic cardiomyopathy in 4 [Ciafaloni et al., 1992]. Ragged-red fibers are usually but not always seen on muscle biopsy specimens [Ciafaloni et al., 1992]. Mitochondrial accumulations have been demonstrated in smooth muscle cells of intramuscular vessels [Sakuta and Nonaka, 1989] and of brain arterioles [Ohama et al., 1987] and in epithelial cells and blood vessels of the choroid plexus [Ohama and Ikuta, 1987]. Muscle complex I deficiency has been demonstrated in many cases [Kobayashi et al., 1987; Koga et al., 1988]; however, multiple defects involving complexes I, III, and IV have also been demonstrated [Ciafaloni et al., 1992]. Because the number of mutant genomes is lower in blood than in muscle [Ciafaloni et al., 1992], the mutation may not be detectable in blood cells from some patients in whom it is detectable in muscle. The prognosis in patients with the full syndrome is poor. Therapeutic trials have included corticosteroids [Shapira et al., 1975] and coenzyme Q10 [Yamamoto et al., 1987]. In some patients with severe lactic acidosis, the use of dichloroacetate to lower serum lactate levels has led to significant biochemical [De Stefano et al., 1995] or clinical improvement [D. C. De Vivo, personal communication, 1992] [Saijo et al., 1991]; however, this has not occurred in all cases. Furthermore, peripheral neuropathy is an important complication of chronic dichloroacetate therapy [Spruijt et al., 2001].

Defects of Protein-Coding Genes In this category, two syndromes are more common. The first syndrome has two phenotypic manifestations, NARP and maternally inherited Leigh’s syndrome, and the second syndrome is Leber’s hereditary optic neuropathy.

ATPASE 6 MUTATION ATPase 6 mutation is a maternally inherited disorder that manifests with either Leigh’s syndrome or developmental delay, retinitis pigmentosa, dementia, seizures, ataxia, proximal weakness, and sensory neuropathy and is caused by a point mutation at nucleotide 8993 within the ATPase 6 gene [Holt et al., 1990]. The severity of disease manifestation appears to correlate with the percentage of mutant mtDNA. When the degree of heteroplasmy is moderate (around 70%), the clinical expression is NARP, a subacute or chronic disease of young adults, but when the degree of heteroplasmy is very high (about 90%), the clinical expression is a rapidly progressive encephalopathy of infancy or childhood, Leigh’s syndrome [Tatuch et al., 1992]. Maternally inherited Leigh’s syndrome is a more severe infantile encephalopathy with characteristic symmetric lesions in the basal ganglia and the brainstem. There are two recognized mutations, namely, T8993G and T8993C, with the T-to-G mutation being both clinically and biochemically more deleterious than the T-to-C change [Vazquez-Memije et al., 1998].

LEBER’S HEREDITARY OPTIC NEURORETINOPATHY Leber’s hereditary optic neuropathy is characterized by onset, usually between 18 and 30 years of age, of acute or subacute loss of vision resulting from severe bilateral optic atrophy.

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There is a marked male predominance [Newman and Wallace, 1990]. The classic ophthalmologic features include circumpapillary telangiectatic microangiopathy and pseudoedema of the optic disc. Associated features may include cardiac conduction abnormalities (pre-excitation syndrome), cerebellar ataxia, hyperreflexia, and peripheral neuropathy. About a dozen different mtDNA point mutations in structural genes have been associated with Leber’s hereditary optic neuropathy, but only three appear to be pathogenic even when present in isolation. A homoplasmic G-to-A transition at nucleotide 11778, which causes the replacement of a highly conserved arginine residue by histidine at position 340 of the ND4 protein of complex 1, was first described in 11 American pedigrees [Wallace et al., 1988a]. Another point mutation was found in which a G-to-A transition at nucleotide 3460 in the ND1 gene was identified in three Finnish families [Huoponen et al., 1991]. A third pathogenic mutation, namely, T14484C in ND6 has been identified [Carelli, 2002]. All three mutations affect genes of complex I. Predominance of affected men (approximately 50% of male patients but only approximately 20% of female patients have optic atrophy) has been attributed to the influence of the nuclear gene on the X chromosome [DiMauro, 1993]. Complex I deficiency was demonstrated in platelets from four affected members of an Australian family in which the molecular genetic defect was not documented [Parker et al., 1989]. Interestingly, point mutations in mtDNA protein-coding genes often escape the rules of mitochondrial genetics in that they affect single individuals and single tissues and most commonly involve skeletal muscle [DiMauro et al., 2003]. For example, patients with exercise intolerance, myalgia, and occasionally recurrent myoglobinuria may have isolated defects of complex I, complex III or complex IV, caused by pathogenic mutations in genes encoding ND subunits, COX subunits, and, in particular, cytochrome b [Andreu et al., 1999]. The lack of maternal inheritance and the involvement of muscle alone would suggest that the mutations arose de novo in myogenic stem cells after germ layer differentiation (“somatic mutations”) [DiMauro, 2004].

Diseases Caused by Mutations in Nuclear DNA There are numerous disorders caused by mutations in nuclear DNA, not only because most respiratory chain subunits are nucleus-encoded but also because the correct structure and functioning of the respiratory chain requires a series of steps, all of which are under the control of nuclear DNA. These steps include the following [DiMauro, 2004]: • Nuclear factors are needed for the proper assembly of respiratory chain complexes. Mutations in these ancillary proteins have been associated with numerous disorders, particularly Leigh’s syndrome. • The integrity and replication of mtDNA require nuclear DNA–encoded factors, and there has been rapid progress in the understanding of the molecular basis of disorders of intergenomic signaling, such as syndromes associated with multiple mtDNA deletions and mtDNA depletion.

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• Hereditary defects in the complex machinery involved in the transport of nuclear DNA–encoded proteins from the cytoplasm into the mitochondria have been documented. • The respiratory chain is embedded in the lipid bilayer of the inner mitochondrial membrane. Alterations of this lipid milieu can lead to disease, as seen in Barth’s syndrome, in which there is altered synthesis of cardiolipin. • Mitochondria move around the cell, divide by fission, and fuse with one another. Disorders of motility can cause disease, as seen in autosomal dominant optic neuropathy.

Defects of Substrate Transport The carnitine uptake defect and carnitine palmitoyltransferase deficiency were discussed earlier.

Defects of Substrate Oxidation Defects in beta oxidation have already been discussed. Within pyruvate metabolism, pyruvate may be converted to acetyl-CoA by the pyruvate dehydrogenase complex. Defects of the pyruvate dehydrogenase complex can affect each of three catalytic components—E1 (pyruvate decarboxylase), E2 (dihydrolipoyl transacetylase), or E3 (dihydrolipoyl dehydrogenase)—as well as the regulatory component, pyruvate dehydrogenase–phosphatase, which activates it and the protein X–lipoate component. The most common enzyme defect, E1 (pyruvate decarboxylase), is composed of two subunits that are encoded by a gene on the X chromosome at Xp22.1-p22.2 [Brown et al., 1989] and two beta subunits that are encoded by a gene on chromosome 3 [Ho et al., 1988]. The E1 defects are caused by mutations in the E1-alpha gene, which is X-linked. This particular E1 defect can manifest in three ways, with a graded spectrum from most to least severe [Robinson, 1995] as follows: • A neonatal form with onset in the first days or weeks of life and death usually before 6 months of age. This is characterized by hypotonia, seizures, episodic apnea and lethargy, failure to thrive, and severe lactic acidosis, with frequent agenesis of the corpus callosum. • An infantile form with onset before 6 months of age, which is characterized by psychomotor delay, hypotonia, seizures, episodic apnea and lethargy, ophthalmoplegia, optic atrophy, ataxia, and mild to moderate lactic acidosis, with death usually by 3 years of age. The neuropathologic findings are characteristic of Leigh’s syndrome. • A benign form with mild developmental delay and with episodes of intermittent ataxia or exercise intolerance, which is found only in male patients and appears to respond to thiamine administration. Because of the central importance of the pyruvate dehydrogenase complex in central nervous system metabolism, the E1-alpha mutations can manifest in both male and female patients. Most defects in the E1-alpha gene are de novo mutations. In male patients, the defects are either missense mutations or mutations that affect only the 3′ end

of the coding sequence. In female patients, deletions and insertions that completely nullify one allele are more common. The remaining defects of the pyruvate dehydrogenase complex are extremely rare [Robinson, 1995]. The E2 and protein X-lipoate defects result in severe psychomotor retardation. The E3 lipoamide deydrogenase defect leads to deficient activity in the pyruvate dehydrogenase complex and in the alpha-ketoglutarate and branched-chain keto-acid dehydrogenase complexes. Pyruvate dehydrogenase phosphatase deficiency has been documented in three patients with Leigh’s disease and a fourth with unremitting lactic acidemia. Alternatively, pyruvate may be converted to oxaloacetate by pyruvate carboxylase. Pyruvate carboxylase deficiency has three major manifestations [Robinson, 1995]. In the simple (A) form, which has been documented in the Algonkianspeaking American Indian population, onset occurs in the first few months of life with a mild to moderate lactic acidemia and delayed development, leading to severe mental retardation and often death in childhood. In the more complex (B) form, which occurs in patients in France and the United Kingdom, the onset is soon after birth with a severe lactic acidemia accompanied by hyperammonemia, citrullinemia, and hyperlysinemia. Death usually occurs before 3 months of age. In a single case (C), the manifestation was mild and consisted only of episodic acidosis with no pyschomotor retardation. There is good evidence to suggest that patients in group A have some residual pyruvate carboxylase activity, whereas those in group B have no activity at all.

Defects of the Krebs Cycle Defects in the Krebs cycle include alpha-ketoglutarate dehydrogenase, fumarase, and aconitase deficiency. Aconitase deficiency has been described in an individual who had exercise intolerance and myoglobinuria, as well as complex II deficiency [Haller et al., 1991].

Defects of the Respiratory Chain: Mutations in Genes Encoding Subunits or Ancillary Proteins of the Respiratory Chain Defects of the respiratory chain may be caused by defects of nuclear DNA or mitochondrial DNA. As previously mentioned, mtDNA encodes only 13 subunits of the respiratory chain, whereas nuclear DNA encodes all subunits of complex II, most subunits of the other four complexes, as well as coenzyme Q10 and cytochrome c. The following syndromes are presumed to be caused by nuclear DNA defects. Direct “hits” are mutations in genes encoding respiratory chain subunits, which includes subunits of complex I [Triepels et al., 2001] and of complex II [Bourgeron et al., 1995]. Most of these have been associated with autosomal recessive forms of Leigh’s syndrome. Indirect “hits” are mutations in genes encoding proteins that are not themselves components of the respiratory chain but are required for the proper assembly and function of the respiratory chain complexes. Examples of such ancillary proteins are best demonstrated by mendelian defects of COX (complex IV). Mutations in five ancillary proteins, SURF1, SCO2, SCO1,

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COX10, and COX15, have been associated with COXdeficient Leigh’s syndrome [Sacconi et al., 2003; Tiranti et al., 1998; Zhu et al., 1998] or other multisystemic fatal infantile disorders, in which encephalopathy is associated with cardiomyopathy [Antonicka et al., 2003; Papadopoulou et al., 1999] (SCO2, COX15), nephropathy [Valnot et al., 2000] (COX10), or hepatopathy [Valnot et al., 1999] (SCO1). Mutations in a complex III assembly protein, BCSIL, have been associated with Leigh-like syndromes [de Lonlay et al., 2001] and with the lethal infantile disorder of growth retardation, aminoaciduria, cholestasis, iron overload, lacticacidosis, and early death (GRACILE) [Fellman, 1992; Visapaa et al., 2002]. There is also a newly recognized defect of complex V, caused by mutations in the assembly protein ATP12, that is associated with congenital lactic acidosis and a fatal infantile multisystemic disease involving the brain, liver, heart, and muscle [De Meirleir et al., 2004]. This is an important field of research from both theoretic and practical points of view as identification of mutations allows prenatal diagnosis. Furthermore, in certain cases there are potentially novel approaches to future therapy, such as copper administration to infants with mutations in SCO2, a protein involved in copper homeostasis in complex IV, as suggested by studies in cultured human cells [Jaksch et al., 2001; Salviati et al., 2002a].

COMPLEX I DEFICIENCY Reduced nicotinamide adenine dinucleotide (NADH)coenzyme Q reductase is the largest complex of the respiratory chain. It contains 46 different polypeptides (7 encoded by mtDNA) and several nonprotein components, including flavin mononucleotides, eight nonheme iron-sulfur clusters, and phospholipid [Hatefi, 1985; DiMauro, 2004]. Three main clinical syndromes have been characterized: • A fatal infantile multisystem disorder characterized by severe congenital lactic acidosis, psychomotor delay, diffuse hypotonia and weakness, cardiomyopathy, and cardiorespiratory failure, which leads to death in the neonatal period [Moreadith et al., 1984; Robinson et al., 1986]. The enzymatic defect is multisystemic. Therapeutic trials with biotin, thiamine, carnitine, and the ketogenic diet have proved unsuccessful [Moreadith et al., 1984]. Some subunits may be encoded by genes on the X chromosome [Day and Scheffler, 1982]. • Myopathy with exercise intolerance, followed by fixed weakness. This form can start in childhood or adulthood and is usually accompanied by lactic acidosis at rest, which may be exaggerated by exercise [Morgan-Hughes et al., 1988]. In view of the tissue specificity of this disorder, it is possible that one or more of the nuclear DNA-encoded complex I subunits may exist as tissue-specific isoforms. Therapy with riboflavin was of benefit to one patient with weakness [Arts et al., 1983]. • Mitochondrial encephalomyopathy (excluding MELAS syndrome) with onset in childhood or adulthood. This form can have multiple combinations of ophthalmoplegia, seizures, dementia, ataxia, sensorineural hearing loss, pigmentary retinopathy,

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sensory neuropathy, and involuntary movements [Morgan-Hughes et al., 1988]. Because many cases were reported before systematic analysis of mtDNA, this heterogeneous group may include patients with nuclear DNA and others with mtDNA defects [DiMauro, 1993]. Pitkanen and Robinson [1996] demonstrated that complex I deficiency leads to the increased production of superoxide radicals and thereby to the induction of manganese superoxide dismutase, which produces hydrogen peroxide. Hydrogen peroxide in the presence of high free iron levels would generate excessive hydroxyl radicals in these cells that could then cause damage to DNA, lipids, and proteins and would be likely to contribute to the severe symptoms, morbidity, and mortality observed in affected patients.

COMPLEX II DEFICIENCY The clinical spectrum has included encephalomyopathy in five patients [DiMauro, 1993] and myopathy in two [Garavaglia et al., 1990; Haller et al., 1991]. One patient had exercise intolerance, exertional myoglobinuria, and a lack of succinate dehydrogenase stain on muscle biopsy [Haller et al., 1991]. Another patient had associated aconitase deficiency [Haller et al., 1991].

COENZYME Q10 DEFICIENCY Exercise intolerance and slowly progressive weakness of axial and proximal limb muscles, with sparing of facial and extraocular muscles, were described in two sisters [Ogasahara et al., 1989]. Autosomal–recessive inheritance was suggested by the family history. Both patients had episodes of myoglobinuria in association with seizures or intercurrent infections. Excessive lipid and mitochondria in type I fibers were documented on muscle biopsy. Biochemical analysis suggested a muscle- (5% normal) and likely brain-specific isozyme defect of coenzyme Q10. Replacement therapy improved both brain and muscle function. It is now apparent that primary coenzyme Q10 deficiency can cause three major syndromes: a predominantly myopathic disorder with recurrent myoglobinuria, a predominantly encephalopathic disorder with ataxia and cerebellar atrophy, and a generalized form [Lamperti et al., 2003]. It is possible that the different manifestations reflect mutations in different biosynthetic enzymes, but this remains to be documented [DiMauro, 2004]. The diagnosis is crucial in view of the significant clinical response to the coenzyme Q10 supplementation.

COMPLEX III DEFICIENCY Complex III is composed of 11 subunits, which include two high-molecular weight core proteins, the apoprotein of cytochrome b (encoded by mtDNA), the apoprotein of cytochrome c1, and a nonheme iron-sulfur protein known as the Rieske protein [Hatefi, 1985]. A complex III block impairs use of both nicotinamide adenine dinucleotide- and flavin adenine dinucleotide-linked substrates. There is heterogeneity in the clinical manifestations. Patients can be divided into two major groups: those with multisystem disease

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(encephalomyopathy) and those with tissue-specific defects, such as myopathy or cardiomyopathy. Among the multisystem group, a fatal infantile form was described in a child who had severe lactic acidosis; hypotonia; complex III deficiency in muscle, heart, kidney, and liver tissue; and a 75% decrease of cytochrome b in muscle [Birch-Machin et al., 1989]. Later onset encephalomyopathies (childhood to adult life) have manifested with a variable spectrum of weakness, short stature, dementia, sensorineural deafness, pigmentary retinopathy, ataxia, sensory neuropathy, and pyramidal signs [Kennaway, 1988; Morgan-Hughes et al., 1985]. The myopathic manifestation is characterized by exercise intolerance with premature fatigue and hyperpnea and is often associated with fixed weakness [Kennaway, 1988; MorganHughes et al., 1985]. Tissue specificity is suggested by the presence of normal complex III activity in fibroblasts and lymphoid cells of one patient with pure myopathy [DarleyUsmar et al., 1986]. Menadione (vitamin K3) and ascorbate (vitamin C) have been used as treatment strategies [Eleff et al., 1984]. In one young woman with myopathy [DarleyUsmar et al., 1983], this treatment resulted in prompt clinical improvement [Argov et al., 1986; Eleff et al., 1984]. This treatment, however, proved ineffective in two other patients, including an infant with encephalomyopathy [Przyrembel, 1987] and an adult with myopathy [Reichmann et al., 1986]. Another phenotype of complex III deficiency has been described in one patient with an unusual form of facioscapulohumeral muscular dystrophy [Slipetz et al., 1991]. The cardiomyopathic symptoms caused by complex III and reducible cytochrome b deficiency in the myocardium were documented in one infant with a rare fatal histiocytoid cardiomyopathy [Papadimitriou et al., 1984]. This defect proved to be tissue-specific to heart tissue.

COMPLEX IV DEFICIENCY COX catalyzes the transfer of reducing equivalents from cytochrome c to molecular oxygen. The generated energy sustains a transmembrane proton-pumping activity. The COX complex contains two copper atoms and two unique heme A iron porphyrins as redox centers, which are bound to a multisubunit protein frame that is embedded in the inner mitochondrial membrane [DiMauro, 1993]. The apoprotein is composed of 13 polypeptides. The three largest subunits (I, II, and III) perform both catalytic and proton-pumping activities and are encoded by mtDNA. The 10 smaller subunits (IV, Va, Vb, VIa, VIb, VIc, VIIa, VIIb, VIIc, and VIII) are encoded by nuclear DNA [Kadenbach et al., 1983]. The full-length cDNAs of all the subunits of human COX have been elucidated [DiMauro et al., 1990; Koga et al., 1990]. The clinical manifestations can be divided into a myopathic form and a multisystemic form, which is dominated by encephalopathy [DiMauro et al., 1990]. There are two forms of myopathy. Both manifest soon after birth with severe diffuse weakness, respiratory distress, and lactic acidosis, although they have different outcomes. The fatal infantile myopathy is often accompanied by associated renal disease with DeToni-Fanconi syndrome and results in death before 1 year of age. Autosomal recessive inheritance is suggested by pedigree analysis, and immunocytochemical studies have documented a selective defect of COX subunit VIIa in four patients [Tritschler et al., 1991]. In addition, an infan-

tile myopathy with associated cardiomyopathy is not thought to be genetically related to the fatal infantile myopathy [Hart and Chang, 1988; Zeviani et al., 1986]. The benign infantile myopathy manifests with severe weakness and, frequently, a need for ventilator assistance and gavage feedings in early life. Subsequently, there is spontaneous improvement and a return to normal by 2 or 3 years of age [DiMauro et al., 1983b]. There is a lack of both subunit VIIa and subunit II on muscle immunocytochemistry profiles in the benign form, with a spontaneous recovery toward normal COX activity both histochemically and biochemically [DiMauro et al., 1983b]. It is postulated that the defect most likely involves a nuclear DNA–encoded COX subunit that is tissue specific and developmentally regulated and that corrects as the mature isozyme is expressed [DiMauro, 1993]. COX deficiency is the most common biochemical cause of Leigh’s syndrome (subacute necrotizing encephalomyelopathy) [Van Coster et al., 1991]. Leigh’s syndrome is a devastating encephalopathy of infancy or childhood (rarely of adulthood). It is characterized by psychomotor regression, usually beginning at 1 year of age, with ataxia, optic atrophy, ophthalmoplegia, nystagmus, tremor, dystonia, pyramidal signs, and respiratory abnormalities. The classic pathologic findings consist of focal, symmetric areas of necrosis in the thalamus, brainstem, and posterior columns of the spinal cord, which are spongiform lesions characterized by cystic cavitation, vascular proliferation, neuronal loss, and demyelination [DiMauro, 1993]. There may be increased numbers of mitochondria in muscle on electron microscopic study. Involvement of nuclear DNA has been confirmed by fusion experiments [Miranda et al., 1989]. Inheritance is autosomal recessive. Patients with Leigh’s syndrome have a generalized but partial defect of COX activity [DiMauro, 1993]. This defect is expressed in fibroblasts in most patients, making possible prenatal diagnosis from chorionic villi sampling [Ruitenbeek et al., 1988]. COX deficiency has also been documented in the muscle biopsy specimens of two unrelated cases of Alpers’ disease [Prick et al., 1983].

COMPLEX V DEFICIENCY Complex V or ATP synthase converts the transmembrane proton gradient generated in the respiratory chain into chemical energy by synthesizing ATP from ADP and inorganic phosphate. The complex consists of a membrane portion, F0, and a catalytic portion, F1, which are joined by a stalk. It is composed of 12 to 14 subunits, two of which (subunits 6 and 8) are encoded by mtDNA [Hatefi, 1985]. Two phenotypes have been described. One was in a 17-year-old male with a multisystem syndrome of weakness, ataxia, retinopathy, dementia, and peripheral neuropathy [Clark et al., 1983]. The other was a 37-year-old female with congenital, slowly progressive myopathy, ragged-red fibers, and intramitochondrial paracrystalline inclusions [Schotland et al., 1976].

COMBINED DEFECTS OF THE RESPIRATORY CHAIN Combined defects of the respiratory chain are often caused by defects in mtDNA but can also be caused by defects of nuclear DNA. Potential mechanisms include (1) mutations of regulatory genes controlling more than one complex,

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(2) mutations of subunits shared by two or more complexes, (3) mutations affecting the milieu of the complexes, and (4) defects of mitochondrial protein importation affecting subunits of multiple complexes [DiMauro, 1993].

myopathy or hepatopathy [Moraes et al., 1991a; Vu et al., 1998].

DEFECTS OF OXIDATION/PHOSPHORYLATION COUPLING

Multiple deletions of mtDNA were documented in an Italian family with an autosomal-dominant disease characterized by progressive external opththalmoplegia, cataracts, hearing loss, exercise intolerance, proximal and respiratory muscle weakness, and early death with lactic acidosis and raggedred fibers documented on muscle biopsy [Servidei et al., 1991; Zeviani et al., 1989]. Other families with autosomal dominantly inherited progressive external opththalmoplegia have also been described [Cormier et al., 1991; Zeviani et al., 1990]. Associated multisystemic features have included mental retardation, tremor, ataxia, and peripheral neuropathy [Zeviani et al., 1990]. Other abnormalities have included hypoparathyroidism and hypodensities of the basal ganglia, centrum ovale, and brain peduncle documented by computed tomographic scan [Cormier et al., 1991]; nystagmus; and abnormal electroencephalographic findings [Iannaccone et al., 1974]. There were different clinical and family histories in two sets of Japanese brothers [Ohno et al., 1991; Yuzaki et al., 1989] whose parents were apparently asymptomatic. In one family, the brothers had ptosis but no ophthalmoplegia, myopathy, optic atrophy, or peripheral neuropathy [Yuzaki et al., 1989]. In the other family, the brothers suffered from recurrent myoglobinuria precipitated by exercise, fasting, or alcohol intake but had no ptosis or ophthalmoplegia [Ohno et al., 1991]. Muscle biochemistry demonstrated combined defects of the respiratory chain in one family [Servidei et al., 1991], complex I deficiency in another [Cormier et al., 1991], and normal respiratory chain enzymes in the patients with myoglobinuria [Ohno et al., 1991]. Four of these conditions have been characterized at a molecular level. Mutations in the gene encoding one isoform of adenine nucleotide translocator (ANT1) have been documented in some, but not all, patients with autosomaldominant progressive external opththalmoplegia [Kaukonen et al., 2000]. Mutations in the gene for thymidine phosphorylase (TP) lead to an autosomal-recessive multisystemic syndrome, named MNGIE (mitochondrial neurogastrointestinal encephalomyopathy) [Nishino et al., 1999, 2000]. Both types of mutations affect the mitochondrial nucleotide pools and may have similar pathogenic mechanisms. Mutations in the Twinkle gene, which is a helicase, are associated with autosomal dominant progressive external opththalmoplegia [Spellbrink et al., 2001]. Finally, mutations in the gene encoding polymerase γ (POLG) may lead to either autosomal-dominant or autosomal recessive progressive external opththalmoplegia, which is occasionally associated with psychiatric symptoms or parkinsonism [Mancuso et al., 2004b; VanGoethem et al., 2001].

Luft’s disease (nonthyroidal hypermetabolism) or loose coupling of oxidation/phosphorylation has been reported in two patients with sporadic cases: a Swedish woman [Luft et al., 1962] and a Jordanian woman [DiMauro et al., 1976; Haydar et al., 1971]. The clinical manifestation was that of onset in adolescence with fever, heat intolerance, profuse perspiration, polyphagia, polydipsia, and resting tachycardia with exercise intolerance and mild-to-moderate weakness. Myopathic changes were documented on electromyography, and muscle biopsy demonstrated numerous ragged-red fibers with greatly enlarged mitochondria, many of which contained osmiophilic inclusions. The possibility that Luft’s disease may be the result of a nuclear DNA defect is suggested by the lack of evidence for maternal inheritance, apparent muscle specificity of the disease, and lack of mtDNA deletions [Moraes et al., 1989].

Defects of Mitochondrial Protein Importation Mitochondrial proteins that are synthesized in the cytoplasm are given mitochondrial targeting signals that direct their entry into mitochondria. Transport across outer and inner membranes requires a series of factors, including docking protein, chaperonins, and proteases. In addition, it involves unfolding and refolding of the protein to be translocated [Okamoto et al., 2002]. Several mutations in targeting sequences that prevent individual proteins from reaching their destination have been documented. At least two disorders have been associated with mutations in components of the transport machinery. One is an X-linked disease, the deafnessdystonia syndrome (Mohr-Tranebjaerg syndrome), which is characterized by neurosensory hearing loss, dystonia, cortical blindness and psychiatric symptoms. It is caused by mutations in the TIMM8A gene, which encodes the deafnessdystonia protein (DDP1), an intermembrane space component of the transport machinery [Roesch et al., 2002]. The second is an autosomal-dominant form of hereditary spastic paraplegia caused by mutations in the chaperonin HSP60 [Hansen et al., 2002].

Defects of Intergenomic Signaling For its function and replication, mtDNA is highly dependent on numerous factors encoded by nuclear genes. Mutations in these genes cause mendelian disorders that are characterized by qualitative or quantitative alterations of mtDNA [Hirano et al., 2001; Suomalainen and Kaukonen, 2001]. Qualitative alterations of mtDNA include autosomal-dominant or autosomal-recessive multiple deletions of mtDNA, which are usually accompanied clinically by progressive external ophthalmoplegia plus a variety of other signs and symptoms [Hirano and DiMauro, 2001]. Quantitative alterations of mtDNA include severe or partial expression of mtDNA depletion, which is usually characterized clinically by congenital or childhood forms of autosomal-recessively inherited

MULTIPLE MITOCHONDRIAL DNA DELETIONS

DEPLETION OF MITOCHONDRIAL DNA Depletion of mtDNA has been described in a number of patients and can be divided into those with severe depletion and those with partial depletion [Boustany et al., 1983; Moraes et al., 1991a; Tritschler et al., 1992]. Clinical manifestation has been variable in severe mtDNA depletion. The

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spectrum has included different combinations of diffuse myopathy in the first weeks of life, necessitating ventilator support; liver disease; renal dysfunction with glycosuria, phosphaturia, and generalized amino aciduria (DeToniFanconi-Debre syndrome); seizures with evidence of hypsarrhythmia; and, in rare cases, progressive external opththalmoplegia, with death between 3 and 9 months of age. All patients had severe lactic acidosis and ragged-red fibers in muscle. One family history was suggestive of autosomal-recessive inheritance [Boustany et al., 1983]. In each case, mtDNA depletion was observed only in the affected tissues. In children with partial mtDNA depletion, the primary feature was myopathy, with onset between 5 and 12 months of age and death between 11 months and 3 years of age. Serum lactate levels were normal. Muscle biochemistry demonstrated combined defects of respiratory chain complexes containing mtDNA-encoded subunits, such as complexes I, III, and IV, which were more severe in patients with severe depletion. A male with normal early growth and development until 1 year of age, followed by a severe progressive neuromuscular disorder resembling spinal muscular atrophy, lost his ability to walk at 3 years of age and subsequently received a diagnosis of mtDNA depletion syndrome. An initial muscle biopsy at 21/2 years of age was consistent with denervation, but there were no deletions in exons 7 and 8 of the survival motor neuron gene on DNA analysis [Pons et al., 1996]. Thus, mtDNA depletion is usually characterized clinically by congenital or childhood forms of autosomal recessively inherited myopathy or hepatopathy [Moraes et al., 1991a; Vu et al., 1998]. Although skeletal muscle and liver seem to be the main target tissues, other tissues are often affected in both conditions, including kidney (renal tubular acidosis) and the central nervous system. Central nervous system involvement often simulates spinal muscular atrophy, and mtDNA depletion should be considered in children with the spinal muscular atrophy phenotype but without mutations in the SMN gene [Mancuso et al., 2002, 2003]. The decrease in mtDNA is documented by densitometry of Southern blot analysis and confirmed by immunocytochemistry with anti-DNA antibodies and by in situ hybridization [Andreeta et al., 1991; Moraes et al., 1991a; Tritschler et al., 1992]. In severe cases, depletion of muscle mtDNA varies between 83% and 98%, and in less severe cases, it varies between 66% and 92%. Mutations in two genes, both of which are involved in mitochondrial nucleotide homeostasis, have been associated with mtDNA depletion syndromes, even though they do not explain all cases. Mutations in the gene encoding thymidine kinase 2 (TK2) are frequently documented in patients with the myopathic mtDNA depletion syndrome [Mancuso et al., 2002; Saada et al., 2001]. Mutations in the gene encoding deoxyguano-sine kinase (dGK) predominate in patients with hepatic or multisystemic mtDNA depletion syndromes [Mandel et al., 2001; Salviati et al., 2002b].

Alterations of the Lipid Milieu of the Inner Mitochondrial Membrane An example of this etiology is provided by Barth’s syndrome, an X-linked recessive disorder characterized by mitochondrial myopathy, cardiomyopathy, growth retarda-

tion, and neutropenia [Barth et al., 1999]. This disorder is caused by mutations in the tafazzin (TAZ) gene, which encodes a family of proteins (“tafazzins”) that are homologous to phospholipid acyltransferases [Bione et al., 1996]. Analysis of phospholipids in target tissues from patients with Barth’s syndrome and TAZ mutations revealed decreased cardiolipin in all tissues from patients with genetically proven Barth’s syndrome [Schlame et al., 2002, 2003]. The cardiolipin was selectively affected, whereas the other phospholipid levels were normal.

Alterations of Mitochondrial Motility or Fission Mitochondria are dynamic organelles that are propelled within the cell by energy-requiring dynamins along cytoskeletal microtubular rails [Boldogh et al., 2001]. Mutations in a gene (OPA1) that encodes a dynamin-related guanosine triphosphatase have been associated with an autosomaldominant form of optic atrophy resulting in early-onset blindness [Alexander et al., 2000; Delettre et al., 2000]. Morphologically, mitochondria were clumped together rather than uniformly distributed in the cytoplasm of monocytes from these patients.

Differential Diagnosis of Lactic Acidemia The ratio of lactate to pyruvate in the blood is a helpful indicator of the underlying problem and may help to direct further investigations. A ratio of lactate to pyruvate below 25, which is considered to be in the normal range, suggests a defect of either pyruvate dehydrogenase or one of the gluconeogenic enzymes, whereas a consistently elevated ratio of lactate to pyruvate, particularly one of 35 or greater, suggests a pyruvate carboxylase (type A) deficiency or a respiratory chain defect [Robinson et al., 1987, 1989].

MYOADENYLATE DEAMINASE DEFICIENCY Clinical Presentation Myoadenylate deaminase deficiency is detected in 1% to 3% of all muscle biopsy samples and may be characterized by exercise-related myalgia and cramps [Sabina, 1993]. However, the pathogenetic significance of this defect is controversial because (1) in patients with unexplained myopathy, symptoms are generally mild, ill-defined, and often subjective and (2) more than 50% of patients had either well-defined myopathies, such as Duchenne or Becker muscular dystrophy, McArdle’s disease, spinal muscular atrophy, or amyotrophic lateral sclerosis. Therefore, Fishbein [1985] divided myoadenylate deaminase into the following two forms: (1) a primary (hereditary) myoadenylate deaminase deficiency characterized by myopathy alone with exercise intolerance, myalgia, and cramps; very low residual activity (<1% of normal); and lack of cross-reacting material in muscle and (2) a secondary (acquired) myoadenylate deaminase deficiency associated with well-defined myopathies or neuromuscular disorders in which there is higher residual activity and detectable cross-reacting material. Isolated myoadenylate deaminase deficiency may manifest with recurrent myoglobinuria [Baumeister et al., 1993; Tonin et al., 1990].

Tein / Metabolic Myopathies

Laboratory Tests The resting serum creatine kinase level is usually normal but may increase after exercise. The forearm ischemic exercise test demonstrates a normal rise in venous lactate but no rise in ammonia or inosine monophosphate. The electromyogram may appear normal or may demonstrate nonspecific myopathic features.

Pathology Muscle biopsy specimens are usually normal; however, decreased myoadenylate deaminase activity can be detected by histochemical staining [Fishbein et al., 1980].

Biochemistry and Molecular Genetics There are three tissue-specific subunits: M (muscle), L (liver), and E (erythrocyte), which are under separate genetic control. Adult human muscle contains almost exclusively the M homotetramer. AMP deaminase converts AMP to inosine monophosphate and ammonia. The complementary DNA and gene of muscle AMP deaminase have been cloned, sequenced, and localized to chromosome 1p13-p21 [Gross, 1994; Sabina et al., 1990], and a C34T mutation leading to recurrent myoglobinuria has been identified [Baumeister et al., 1993]. The AMP deaminase-1 gene maps to chromosome 1p21-p13 [Morton et al., 1989]. ACKNOWLEDGMENTS Part of the work described here was supported by an operating grant from the Heart and Stroke Foundation of Ontario (T-5424) and the physicians of Ontario, Canada, through the Physicians’ Services Incorporated Foundation. Ingrid Tein is a recipient of a Detweiler Travelling Fellowship from the Royal College of Physicians and Surgeons of Canada.

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CHAPTER 82

Inflammatory Myopathies Anthony A. Amato and John T. Kissel

The inflammatory myopathies are a heterogeneous group of disorders all characterized pathologically by inflammation in skeletal muscle with resulting muscle fiber damage and subsequent clinical weakness. There are two major categories of inflammatory myopathy—idiopathic and infectious (Box 82-1). Although several types of muscular dystrophy may be associated with inflammation (e.g., facioscapulohumeral dystrophy), these disorders are traditionally excluded from classifications of inflammatory myopathy because they result from a fundamental genetic defect. The classic idiopathic inflammatory myopathies are usually considered autoimmune diseases, although a genetic predisposition may exist for many of these diseases based on inherited human leukocyte antigen haplotypes. As a group, the inflammatory myopathies are the most common acquired myopathies of childhood. The infectious myositides are the most prevalent conditions worldwide, with acute viral myositis clearly the most common variety in North America and Europe. The idiopathic varieties are relatively uncommon, with a combined incidence (including adult cases) of approximately 1 in 100,000 [Dalakas, 1991; Medsger et al., 1970]. There are three major forms of idiopathic inflammatory myopathy—dermatomyositis, polymyositis, and inclusion body myositis, with dermatomyositis by far the most common form in childhood [Pachman, 1994]. Polymyositis is relatively uncommon in children and is usually seen as an overlap syndrome with other connective tissue disorders. Inclusion body myositis is exclusively a disease of adulthood and therefore is not discussed here.

IDIOPATHIC INFLAMMATORY MYOPATHIES Although clinicians frequently conceptualize the idiopathic inflammatory myopathies as a single entity (e.g., polymyositis is dermatomyositis without the rash), the disorders are clinically, histologically, and pathogenetically distinct. Banker and Victor [1966] first reported the unique vascular changes of juvenile dermatomyositis and highlighted the involvement of organs other than muscle and skin. Subsequent immunologic and pathologic observations have confirmed a differing pathophysiology for these disorders. Although there have been occasional reports of siblings or parent/child cases of both dermatomyositis and polymyositis, most cases are sporadic.

Dermatomyositis Clinical Features Juvenile dermatomyositis can present at any age, including infancy, although most cases occur between ages 5 and

14 years [Medsger et al., 1970]. Females are affected more commonly than males. Onset of weakness is typically over weeks to a few months, although fatigue, muscle aches and stiffness, decreased activity, and fever can precede the onset of weakness by months. More acute, fulminate onset (over days) or an indolent, slowly progressive course (sometimes lasting a year) also has been described [Kissel et al., 1991; Pachman, 1994, 1995; Tymms and Webb, 1985]. Weakness typically affects the neck flexors and shoulder and pelvic girdle muscles first, so that the child may have difficulty getting up from the floor, riding a bicycle, running, climbing steps, or raising the arms above the head. Distal weakness is usually present, although not as severe as in proximal muscles. Complete sparing of distal strength should always lead the clinician to suspect another diagnosis, particularly one of the dystrophies. Dysphagia occurs in approximately one third of patients, and rarely individuals will also have chewing

Box 82-1 THE INFLAMMATORY MYOPATHIES I. Idiopathic A. Juvenile dermatomyositis B. Polymyositis C. Inclusion body myositis D. Myositis as overlap syndrome 1. Mixed connective tissue disease 2. Scleroderma 3. Systemic lupus erythematosus 4. Rheumatoid arthritis 5. Sjögren’s syndrome E. Other inflammatory myopathies 1. Eosinophilic myositis 2. Focal nodular myositis 3. Sarcoid myopathy II. Infectious A. Viral myositides 1. Influenza 2. Human immunodeficiency virus 3. Others (coxsackievirus, parainfluenza, mumps, measles, adenovirus, herpes simplex, cytomegalovirus, hepatitis B, Epstein-Barr virus, respiratory syncytial virus, echovirus, and possibly arboviruses) B. Parasitic myositis 1. Trichinosis 2. Toxoplasmosis 3. Cysticercosis C. Bacterial myositis D. Fungal myositis

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difficulties, dysarthria, and speech delay because of oropharyngeal involvement. The rash frequently precedes the muscle symptoms and often provides the most important clue to diagnosis [Bowyer et al., 1986; Crowe et al., 1982; Sontheimer, 1999]. Skin changes typically involve the fingers and periorbital regions first, although any area may be involved. A purplish discoloration of the eyelids (heliotrope rash) with periorbital edema and extension onto the cheeks and forehead is typical (Fig. 82-1). On the hands, the periungual regions become erythematous and scaly, with dilated capillary loops in the nailbeds (Fig. 82-2). Papular, erythematous, scaly lesions over the knuckles (Gottron’s sign) are characteristic, with similar lesions occurring on the elbows, knees, and malleoli. A more macular, erythematous rash may appear on the face, neck, and anterior chest (V sign) or on the shoulders and upper back (shawl sign). Subcutaneous calcifications, which do not occur in adult cases, occur in 30% to 70% of childhood cases. The calcinosis tends to develop over pressure

FIGURE 82-1. An 8-year-old male with juvenile dermatomyositis has a mild, erythematous rash over the cheeks, nasal bridge, and eyelids with mild periorbital edema. (Photo courtesy Albert Tsao, MD.)

points (e.g., buttocks, knees, elbows) and occurs more commonly when the diagnosis has been delayed or the treatment inadequate [Bowyer et al., 1983; Pachman, 1995]. The lesions typically appear as painful, hard nodules that erupt through the skin in severe cases. Occasional patients have the characteristic rash but never develop weakness [Euwer and Sontheimer, 1993; Stonecipher, 1993].

ASSOCIATED MANIFESTATIONS Although involvement of organs other than muscle and skin has become less common with the advent of effective immunosuppressive therapies, some children will develop clinical manifestations in addition to weakness and rash on the basis of the underlying vasculopathy. About 50% will have electrocardiographic abnormalities, including conduction defects and dysrhythmias, and pericarditis, myocarditis, and congestive heart failure can occur [Askari, 1984; Haupt and Hutchins, 1982; Tymms and Webb, 1985]. Pulmonary function tests may demonstrate restrictive defects and reduced diffusion capacity even in patients with no pulmonary symptoms [Pachman, 1994]. Approximately 10% of patients, particularly those with antibodies to histidyl transfer ribonucleic acid synthetase (Jo-1), develop frank interstitial lung disease or bronchiolitis obliterans and organizing pneumonia [Love et al., 1991; Targoff, 1994]. Vasculopathic involvement of the gastrointestinal tract can result in malabsorption, mucosal ulceration, perforation, and hemorrhage. Dysphagia and delayed gastric emptying caused by inflammatory involvement of the alimentary skeletal and smooth muscles are more common. Arthralgias are common, but true arthritis occurs mainly in children with an “overlap” connective tissue disorder (see later). Ophthalmic involvement on the basis of vascular changes in the retina and conjunctiva can occur [Pachman, 1995]. Renal compromise is rare and results from acute tubular necrosis in the setting of myoglobinuria after fulminant muscle necrosis [Rose et al., 1996]. In contrast to adult dermatomyositis patients, no definitive increased incidence of malignancy has been demonstrated in children [Callen, 1994; Sigugeirsson et al., 1992].

Laboratory Features The laboratory evaluation of patients with inflammatory myopathy should include muscle enzyme analysis, electrodiagnostic studies, and muscle biopsy. Muscle imaging studies can indicate areas of inflammation in affected muscles but are seldom useful in making a diagnosis [Fraser et al., 1991; Hernandez et al., 1993].

Serologic Studies

FIGURE 82-2. Close-up view of the fingers of a 17-year-old female with juvenile dermatomyositis. The cuticles are thickened, cracked, and irregular; there are dilated capillary loops at the nail base, especially in the first finger.

Creatine kinase is the most reliable, sensitive, and specific marker for muscle destruction. The creatine kinase level is elevated in more than 90% of patients sometime during the course of the disease, with levels up to 50 times normal [Amato et al., 1996; Dalakas, 1994a; Tymms and Webb, 1985]. Creatine kinase levels often do not correlate with weakness and can be normal even in children with significant weakness. Rarely, serum aldolase can be elevated when the serum creatine kinase is normal. Serum myo-

Amato and Kissel / Inflammatory Myopathies

globin, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase can also be elevated but provide no additional information to the creatine kinase. Erythrocyte sedimentation rate is normal or mildly elevated and does not correlate with severity. Antinuclear antibodies occur in 25% to 50% of patients, most commonly in those with overlap syndromes. Myositis-specific antibodies are associated with specific human leukocyte antigen haplotypes and can be demonstrated in a minority of patients (usually adults) with inflammatory myopathy. There have been few reports of these antibodies in childhood dermatomyositis, and their role in the pathogenesis of the inflammatory myopathies is unclear [Love et al., 1991; Plotz et al., 1995]. Although these antibodies provide some information about prognosis [Joffe et al., 1993; Miller, 1993; Targoff, 1994], their value in managing patients is limited. The only exception is the Jo-1 antibody, which is commonly present in patients with interstitial lung disease. In these Jo-1–positive patients, the interstitial lung disease is often more refractory to treatment, and may require the initiation of therapy with prednisone and a second-line immunosuppressive agent (see “Treatment” later). The presence of interstitial lung disease is also a contraindication to the use of methotrexate, which can itself cause interstitial pulmonary fibrosis.

ELECTROMYOGRAPHY

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MUSCLE BIOPSY Every child suspected of having dermatomyositis should undergo muscle biopsy before therapy is instituted. A characteristic histologic feature is perifascicular atrophy, which occurs in 90% of childhood cases and is relatively specific for dermatomyositis (Fig. 82-3). Traditional teaching has been that the perifascicular small fibers represent the residuals of ischemic damage [Carpenter et al., 1976], but recent evidence suggests that other factors may be involved [Greenberg and Amato, 2004]. Dermatomyositis is clearly associated with a microvasculopathy with capillary loss, and the earliest demonstrable histologic abnormality is deposition of C5b-9 complement membrane attack complex around small blood vessels (as well as immunoglobulin M and other complement components, including C3 and C9) [Emslie-Smith and Engel, 1990; Kissel et al., 1986]. These findings have led to the hypothesis that complement-mediated necrosis of small blood vessels leads to reduced capillary density and ischemic damage of muscle fibers. Supporting this view is the finding that inflammatory cells in dermatomyositis biopsies are predominantly perivascular and perimysial in location (Fig. 82-4). Electron microscopy reveals small intramuscular arterioles and capillaries with endothelial hyperplasia, microvacuoles, and cytoplasmic inclusions.

Pathogenesis

Electromyography is indispensable in demonstrating that the patient’s weakness is myopathic in origin and in determining which muscle to biopsy in patients with mild weakness [Mastaglia and Laing, 1996]. Typical electromyographic features include increased spontaneous activity with fibrillation potentials, positive sharp waves, and occasionally pseudomyotonic and complex repetitive discharges, as well as small-duration, low-amplitude, polyphasic motor unit potentials, which recruit early but at normal frequencies. The amount of spontaneous activity generally reflects the ongoing disease activity.

Dermatomyositis is believed to be an autoimmune, humorally mediated microangiopathic disorder. The vascular deposits of immunoglobulin M, C3, and membrane attack complex suggest that the primary immunologic event in dermatomyositis is generation of an antibody directed against antigens located within the walls of intramuscular blood vessels. According to this traditional hypothesis, the microangiopathy then leads to ischemic damage to muscle fibers. The triggers that initiate the immunologic events are uncertain, however, and the putative vascular antigens are unknown. It is also not known whether the complement deposition results from activation of the direct or indirect complement

FIGURE 82-3. Bicep biopsy from a patient with dermatomyositis showing characteristic perifascicular atrophy with relative sparing of the central fascicle (ATPase stain, pH 4.6, ×200).

FIGURE 82-4. Muscle biopsy from a patient with juvenile dermatomyositis showing striking focus of perivascular inflammation in a perimysial blood vessel (modified Gomori trichrome, ×400).

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cascade or if it is an epiphenomenon, unrelated to the main cause of the capillary destruction [Greenberg and Amato, 2004]. Gene expression studies on muscle biopsies have suggested increased expression of type 1 interferons in patients with dermatomyositis as well as perivascular, perimysial, and endomysial plasmacytoid dendritic cells (primary producers of type 1 interferons) [Greenberg et al., 2005]. This finding suggests that the innate immune system may also be involved in the pathogenesis of dermatomyositis.

Treatment Although corticosteroids are generally regarded as the most effective therapy for dermatomyositis, there is controversy surrounding the best route of administration, dosing regimen, duration of therapy, and parameters to monitor during therapy [Amato and Griggs, 2003a]. There have been no controlled trials to examine these issues, although retrospective studies have demonstrated that prednisone reduces morbidity and improves strength and function [Adams and Plotz, 1995; Chwalinska-Sadowska and Madykowa, 1990; Dalakas, 1994a; Joffe et al., 1993; Oddis, 1994].

CORTICOSTEROIDS Prednisone is the usual first line of treatment for dermatomyositis. Short courses of intravenous methylprednisolone (Solu-Medrol) (20 to 30 mg/kg/day or every other day for 3 to 5 days) may be the best way to initiate therapy in severely affected individuals, especially because this therapy may prevent calcinosis [Callen et al., 1994; Laxer et al., 1987]. A more traditional regimen involves oral therapy (1 to 2 mg/kg/day) given as a single morning dose. After 3 to 6 weeks of daily prednisone, the dosage can usually be switched directly to an alternate-day regimen at the same dose, although occasional patients will require persistent daily therapy. The high dose is maintained while strength is carefully monitored. Although the creatine kinase level can sometimes be useful in monitoring response, it should never be the primary determinant when therapeutic decisions are made. Patients should be evaluated at least monthly during this phase of treatment. When the child’s strength has returned to normal or improvement has reached a plateau (usually within 4 to 6 months), the prednisone can be tapered at a rate no faster than 5 mg every 2 to 4 weeks. If an exacerbation occurs during the tapering, the prednisone dose is increased

back to its original level and again given daily. When strength has recovered, the prednisone taper can be resumed. Although occasional patients will require daily dosing, or even split daily doses to maintain adequate disease control, alternate-day dosing is preferred because it is associated with fewer side effects. Most patients (approximately 80%) improve with therapy, with approximately two thirds having a complete response [Amato et al., 1996; Pachman, 1995]. Because most patients require therapy for 1 to 2 years to achieve remission, limiting the side effects of prednisone is an important part of management [Boumpas et al., 1993]. Patients should be started on a low-sodium, lowcarbohydrate, high-protein, low-calorie diet to limit weight gain and reduce the risk of hypertension. Calcium supplementation (1000 to 1500 mg/day) and vitamin D reduce the risk of osteoporosis, as does physical therapy with axial exercise as tolerated by the patient’s weakness. Baseline determination of bone density through dual-energy x-ray absorptiometry scanning is indispensable in diagnosing and following osteoporosis in this population. Exercise also reduces the risk of steroid myopathy [Escalante et al., 1993]. Blood pressure, serum glucose and potassium levels, and ocular status (for cataracts and glaucoma) should be assessed periodically. Hip pain in a child on prednisone must be investigated aggressively because avascular necrosis is an uncommon but devastating development in these individuals. Growth retardation and delayed puberty can occur with prolonged therapy. Although the rash usually responds along with the muscle response, occasional patients require separate treatment for their skin changes. Hydroxychloroquine, chloroquine, topical steroids, topical tacrolimus, and sunscreen have been used to treat the rash when weakness is mild or not apparent [Euwer and Sontheimer, 1993; Sontheimer, 1999; Stonecipher, 1993]. Treatment of calcinosis is more difficult. Colchicine, probenecid, warfarin, and phosphate buffers have been used with only limited success [Pachman, 1994]. Surgery may be indicated, but the lesions may recur or worsen despite surgery.

OTHER AGENTS Patients who respond poorly to steroids, relapse repeatedly as prednisone is tapered, or develop intolerable side effects are candidates for alternative therapy (Table 82-1). Methotrexate is probably the drug of choice in children, although there are no prospective, controlled studies to guide its use.

TABLE 82-1 Steroid-Sparing Immunosuppressive Therapy for Inflammatory Myopathies AGENT

ROUTE

DOSE

SIDE EFFECTS

MONITOR

Methotrexate

Cyclosporine

PO IV PO IV PO

10-20 mg/m2/wk 1-3 mg 1-2 mg/kg/day 50-75 mg/m2 0.5-7.5 mg/kg/day

IVIG

IV

2 g/kg over 2 days

Hepatotoxicity, leukopenia, alopecia, stomatitis, neoplasia Same Leukopenia, cystitis, alopecia, infections, neoplasia Same, nausea and vomiting Renal toxicity, hypertension, hirsutism, hepatotoxicity, infection, gum hyperplasia Fevers, chills, diaphoresis, aseptic meningitis, headache, hypotension, leukopenia

LFTs, CBC Same CBC, urinalysis Same BP, BUN, Cr, LFTs, drug levels BP, BUN, Cr

Cyclophosphamide

BP, blood pressure; BUN, blood urea nitrogen; CBC, complete blood count; Cr, creatinine; IV, intravenous; LFTs, liver function tests; PO, orally; IVIG, intravenous immunoglobulin.

Amato and Kissel / Inflammatory Myopathies

In a retrospective series, approximately 75% of children refractory to prednisone improved with methotrexate therapy [Cagnoli et al., 1991; Joffe et al., 1993; Miller et al., 1992b]. Methotrexate must be used with caution because of side effects, including alopecia, stomatitis, oncogenicity, infection, interstitial lung disease, and bone marrow, renal, and liver toxicity. Pulmonary function tests, blood counts, and liver functions must be monitored. Azathioprine, mycophenolate mofetil, cyclophosphamide, and cyclosporine have also been used in refractory patients (see Table 82-1) [Amato and Barohn, 1997; Amato and Griggs, 2003a]. On the basis of a double-blind, placebo-controlled study suggesting benefits in 15 adult dermatomyositis patients, intravenous immunoglobulin has become an important component of the treatment of dermatomyositis [Dalakas et al., 1993]. Although originally used only for refractory cases, it is finding increasing use as both a steroid-sparing agent and a primary agent because of its low incidence of long-term side effects. Treatment is usually initiated at a dose of 2 g/kg given slowly over 2 to 5 days with repeat infusions at variable intervals (usually every 2 to 6 weeks) for at least 3 months [Thornton and Griggs, 1994]. Patients should have an immunoglobulin A level checked before therapy because patients with low immunoglobulin A levels may have antiimmunoglobulin A antibodies, which can cause anaphylactic reactions. Flulike symptoms (i.e., headaches, myalgias, fever, chills, and nausea) may occur in as many as 50% of patients during the infusions but are usually mild. Rash, aseptic meningitis, transient leukopenia, renal failure, and stroke have been described rarely. A controlled trial of plasmapheresis and leukopheresis demonstrated no improvement with either modality in dermatomyositis [Miller et al., 1992a].

Polymyositis Polymyositis, although common in adults, is relatively rare in children as an isolated entity [Amato and Griggs, 2003b; Dalakas and Hohlfeld, 2003, Hoogendijk et al., 2004; Van der Meulen et al., 2003]. In one epidemiologic study, juvenile dermatomyositis was 10 to 20 times more common than polymyositis [Hanissian et al., 1982]. When polymyositis does occur in children, it is often in the setting of an “overlap” condition with features of another connective tissue disorder [Pachman, 1994; Rider and Miller, 1994]. Because of the absence of the rash, the diagnosis is often delayed compared with dermatomyositis.

Clinical Features As in dermatomyositis, patients typically present after weeks to months of neck flexor and symmetric proximal greater than distal arm and leg weakness. Muscle pain and tenderness are common. Dysphagia occurs in approximately one third of patients secondary to oropharyngeal and esophageal involvement. Mild facial weakness occasionally may be demonstrated. Sensation and tendon reflexes are usually preserved. As in adults, in children, other organs, most notably the heart and lungs, can be involved, although the incidence appears to be less than in adults. Congestive heart failure or conduction abnormalities and interstitial lung disease are found in rare patients, the latter more commonly in patients

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FIGURE 82-5. Scleroderma/dermatomyositis overlap syndrome in a 16-year-old male. There is tapering of the digits with a scaly, erythematous rash over the interphalangeal joints and tightness and thinning of the skin.

with serum anti–Jo-1 antibodies [Love et al., 1991]. Polyarthritis has been reported in as many as 45% of polymyositis patients at the time of diagnosis.

OVERLAP SYNDROMES In children, polymyositis more frequently occurs as part of an overlap syndrome, where the myositis is associated with another connective tissue disorder, than as an isolated entity. The common overlap syndromes associated with polymyositis (and often dermatomyositis) include scleroderma, mixed connective tissue disease, Sjögren’s syndrome, systemic lupus erythematosus, polyarteritis nodosa, and rheumatoid arthritis [Rider and Miller, 1994]. Involvement of the skin, joints, kidneys, eyes, and salivary glands is identical to that seen for each disorder in isolation (Fig. 82-5), and the serologic abnormalities are also similar. Weakness in these patients is not always due to myositis because disuse and type 2 fiber atrophy from chronic steroid treatment of the underlying condition can also result in muscle weakness. In these individuals, it is crucial to document the nature of the muscle involvement with serologic and electromyographic studies and often muscle biopsy. The prognosis is often related to the underlying disorder, and treatment may have to be modified based on the associated condition.

Laboratory Features Laboratory evaluation in polymyositis is similar to that in dermatomyositis. Unlike dermatomyositis, the serum creatine kinase is essentially always elevated in polymyositis. The serum creatine kinase level can be helpful in monitoring response to therapy but only in conjunction with the physical examination. Positive antinuclear antibodies are present in approximately 30%. Muscle-specific antibodies have been reported to be more common in polymyositis than dermatomyositis [Love et al., 1991; Plotz et al., 1995; Targoff, 1994]. Close analysis of these reports, however, indicates that the muscle histopathology in many of the antibody-positive cases does not demonstrate the typical pathologic features of polymyositis (e.g., there is usually no invasion of non-necrotic muscle fibers by CD8+ T-lympho-

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2003a]. The role of intravenous immunoglobulin in polymyositis is less clear than in dermatomyositis and should probably be reserved for refractory cases. Treatment of patients with an overlap syndrome is occasionally dictated more by the degree of joint, kidney, or skin involvement than by the muscle disease. Although the majority of patients with polymyositis respond to therapy, the response is often less robust and less sustained than in dermatomyositis. Fewer patients (approximately 20%) attain a complete remission, so that more long-term therapy, along with its associated side effects from medications, is frequently required. Unfortunately, no prospective studies have examined in detail the long-term prognosis of these patients.

FIGURE 82-6. Muscle biopsy from a patient with polymyositis revealing endomysial inflammation surrounding and occasionally invading (top right) individual non-necrotic muscle fibers (hematoxylin and eosin stain, ×500).

cytes). [Greenberg et al., 2002; Miller et al., 2002; Mozaffar et al., 2000]. In some cases, the biopsies are more suggestive of a microangiopathic disorder similar to that seen in dermatomyositis. Electromyography is similar to that in dermatomyositis, with a myopathic picture of increased spontaneous activity, small polyphasic motor units, and early recruitment.

MUSCLE BIOPSY The pathologic findings of polymyositis are distinct from dermatomyositis and reflect basic differences in the underlying pathophysiology [Amato and Griggs, 2003b; Dalakas and Hohlfeld, 2003; Van der Meulen et al., 2003]. Biopsies are characterized by variability in fiber size, with scattered necrotic and regenerating fibers, and endomysial inflammation, with invasion of non-necrotic muscle fibers by CD8+ cytotoxic/suppressor T cells and macrophages (Fig. 82-6) [Arahata and Engel, 1984; Engel and Arahata, 1984]. The invaded (and some noninvaded) fibers express major histocompatibility complex class 1 antigen, which is not present on normal fibers [Emslie-Smith et al., 1989]. The vascular changes of dermatomyositis are not seen.

Pathogenesis Polymyositis results from a human leukocyte antigenrestricted, antigen-specific, cell-mediated immune response against muscle fibers. The T-cell receptors of the muscleinvading T cells have an oligoclonal pattern of gene rearrangement, suggesting that the immune response is antigen specific [Mantegazza et al., 1993]. The antigen against which the immune response is generated and the trigger for the autoimmune attack are not known. Although speculation has centered around a viral infection triggering the immune response, viral antigens and genomes have not been identified in the muscle fibers of patients with polymyositis [Leff et al., 1992; Plotz et al., 1995].

Treatment The treatment of children with polymyositis does not differ in any substantive way from that of dermatomyositis. Corticosteroids are the mainstay of treatment, with secondary agents used as indicated by the response [Amato and Griggs,

Congenital Inflammatory Myopathy Over the past three decades, there have been scattered reports of infants with “congenital inflammatory myopathy” or “infantile myositis” [Kinoshita et al., 1980, 1986; Nagai et al., 1992; Roddy et al., 1986; Shevell et al., 1990; Thompson, 1982]. The disorder is characterized by perinatal hypotonia and generalized weakness with elevated serum creatine kinase levels, myopathic electromyography, and striking inflammation on muscle biopsy. In one case of welldocumented congenital myositis [Roddy et al., 1986], the child was later diagnosed as having Prader-Willi syndrome. Most of the other patients did not improve with corticosteroid therapy, and it is likely that many of these cases had a form of muscular dystrophy with secondary inflammation. Inflammation on biopsy is not specific for a primary inflammatory myopathy and can be demonstrated in Duchenne, facioscapulohumeral, dysferlin-related, and Fukuyama-type muscular dystrophies; Walker-Warburg syndrome; and the Occidental type of congenital dystrophy with hypomyelination and laminin alpha-2 deficiency [Olney and Miller, 1983; Pegoraro et al., 1996]. The diagnosis of inflammatory muscle disease should be made with extreme caution in infants and only after the various dystrophies have been carefully considered.

Other Idiopathic Inflammatory Myopathies Several other extremely rare inflammatory myositides have been described in children. Eosinophilic myositis has been described in several children with peripheral eosinophilia and focal eosinophilic infiltration in isolated muscles [Agrawal and Giesen, 1981; Kaufman et al., 1993; Nagar and BarZiv, 1993]. The reported cases in children may differ from those in adults in occasionally being a focal rather than diffuse myositis, occurring without a drug or toxin exposure, and sometimes resolving without treatment. The condition usually occurs as a part of the hypereosinophilic syndrome. Focal nodular myositis, as the name implies, is also a focal disorder associated with mononuclear infiltration in individual muscles causing the subacute onset of focal pain, swelling, and weakness [Flaisler et al., 1993]. Some patients go on to develop generalized polymyositis. Improvement has been reported after surgical excision of the mass but can also occur spontaneously. A myositis with noncaseating granulomas can occur in sarcoid myopathy, a condition that may respond partially to prednisone [Banker, 1994].

Amato and Kissel / Inflammatory Myopathies

INFLAMMATORY MYOPATHY ASSOCIATED WITH INFECTIONS Although myositis can occur after a wide variety of bacterial, parasitic, fungal, or viral infections, the viral myositides (especially those caused by influenza), toxoplasmosis, and trichinosis are the disorders most likely to be encountered by the clinician.

Influenza Myositis Influenza A, B, and rarely C are common upper respiratory tract pathogens. Acute infection is commonly associated with myalgias when fever and other constitutional symptoms are present. The myalgias are presumably caused by the systemic release of cytokines, although a true myositis can develop [Hays and Gamboa, 1994].

Clinical Features As respiratory symptoms subside, pain, swelling, and muscle tenderness herald the onset of myositis [Hays and Gamboa, 1994; Mejlszenkier et al., 1973; Ruff and Secrist, 1982]. The pain can be so severe as to interfere with the child’s ability to walk or perform routine activities, and muscle swelling and induration may be present. Weakness can be profound and myoglobinuria has been reported [Christianson et al., 1990]. The symptoms are self-limited, lasting less than 1 week, although rare patients have recurrent symptoms associated with different influenza types [Ruff and Secrist, 1982].

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OTHER VIRAL MYOSITIDES Acute viral myositis is not specific for influenza infection, and similar syndromes can complicate infections with coxsackievirus, parainfluenza, mumps, measles, adenovirus, herpes simplex, cytomegalovirus, hepatitis B, Epstein-Barr virus, respiratory syncytial virus, echovirus, and possibly arboviruses [Hays and Gamboa, 1994]. Like influenza, the myositis associated with these viruses is usually self-limited and requires only supportive therapy. Acute and convalescent viral titers (3 or 4 weeks after infection), as well as blood, stool, urine, and throat cultures, can be useful in identifying the responsible virus but seldom add to the management of the muscle symptoms. An inflammatory myopathy has also been described with infection by human immunodeficiency virus. This disorder usually develops in patients with acquired immune deficiency syndrome but can also occur in early human immunodeficiency virus infection. It has been reported exclusively in adults, although human immunodeficiency virus-infected children are also at risk. The presentation is similar to that of polymyositis with subacute progressive, symmetric proximal weakness, an elevated creatine kinase level, and myopathic electromyography. The disorder must be distinguished from zidovudine (AZT) myotoxicity, human immunodeficiency virus–wasting syndrome, and other disorders that can complicate human immunodeficiency virus infection [Dalakas, 1994b; Illa et al., 1991].

Trichinosis Trichinosis, the most common parasitic disease of skeletal muscle, is caused by the nematode Trichinella spiralis, which is ingested in inadequately cooked meat (usually pork). Most infected patients are asymptomatic.

Laboratory Features

Clinical Features

The creatine kinase level is usually elevated, often markedly so, whereas it is typically normal in uncomplicated influenza infection. Electromyography reveals features of an active necrotizing myopathy. Muscle biopsy is rarely indicated but indicates scattered necrotic and regenerating fibers, with occasional interstitial inflammatory cells. Influenza virus has only occasionally been isolated on culture of the muscle specimen [Hays and Gamboa, 1994].

Two to 12 days after ingestion, the larval form of the nematode disseminates through the bloodstream and invades the muscles [Davis et al., 1976]. Patients develop fever, headache, abdominal pain, diarrhea, generalized myalgias, and weakness during the acute systemic reaction. Periorbital edema, ptosis, subconjunctival hemorrhage, and an erythematous urticarial or petechial rash are also often present. Myalgias and weakness peak in the third week of the infection but can last for months. Severe disease can be complicated by myocarditis, pneumonitis, and central nervous system infection.

PATHOGENESIS The mechanism of muscle injury in these patients is unclear. Although muscle damage may result from direct attack of the virus on muscle, electron microscopy has not revealed viral particles in the muscle biopsies, and viral cultures are rarely positive for influenza [Farrell et al., 1980]. An immune-mediated attack on muscle triggered by the virus is another possible mechanism for muscle injury.

TREATMENT The disorder is usually self-limited, and treatment is supportive, with bed rest, hydration, and acetaminophen or nonsteroidal anti-inflammatory drugs.

Laboratory Features Most patients have a marked eosinophilic leukocytosis and elevated serum creatine kinase level. Serum antibodies against T. spiralis can be demonstrated 3 to 4 weeks after infection. Electromyography demonstrates the typical features of an inflammatory myopathy. In the early stage of infection, muscle biopsy reveals infiltration of the muscle by eosinophils and polymorphonuclear leukocytes. With more chronic infection, mononuclear inflammatory cells are more common [Gross and Ochoa, 1979]. Larvae, cysts with focal calcification, fibrosis, and granulomas may be observed months after the initial infection (Fig. 82-7).

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infection, although once the organisms have become encysted in muscle no medication is effective. Clindamycin is also an effective agent and can be used in place of sulfadiazine. The duration of therapy is variable and depends on the severity of the illness.

Cysticercosis

FIGURE 82-7. Muscle biopsy from a patient with trichinosis documenting encysted larvae of the Trichinella organism (modified Gomori trichrome, ×550). (Photo courtesy Jerry Mendell, MD.)

Treatment Thiabendazole (25 mg/kg twice daily to a maximum dose of 3 g/day) is the drug of choice for killing the larvae and adult nematode, with 7 days usually an adequate course of therapy. Thiabendazole is not effective against the encysted larvae, and mebendazole may be a better agent in this regard. Because a Herxheimer-like reaction can develop after degeneration of the larvae, concurrent prednisone administration is beneficial (2 mg/kg/day for several weeks). The majority of patients respond quickly to treatment.

Toxoplasmosis Toxoplasmosis is caused by the protozoon Toxoplasma gondii. The common mode of infection is through the ingestion of food, usually undercooked meat, contaminated with oocysts or cysts containing bradyzoites of the organism. The cysts mature and enter the bloodstream and lymphatics to invade other organs. Exposure to the organism is common worldwide, although symptomatic infection usually occurs in immunocompromised patients. Skeletal muscle involvement can occur in isolation or as part of more generalized infection [Banker, 1994].

Clinical and Laboratory Features In most patients, symptoms are mild and nonspecific, including fever, malaise, fatigue, and myalgias. Patients with more severe disease have lymphadenopathy, hepatosplenomegaly, uveitis, pneumonia, myocarditis, rash, or meningoencephalopathy. Weakness develops in those with significant muscle involvement [Gherardi et al., 1992; Pollock, 1979]. The serum creatine kinase level is elevated, and the typical myopathic picture is evident on electromyography. Muscle biopsy may reveal cysts containing the organism, along with inflammation and giant cells. The diagnosis is confirmed through serologic studies indicating immunoglobulin M reactivity to the organism.

Treatment A combination of pyrimethamine and sulfadiazine or trisulfapyrimidines is the treatment of choice for the primary

Cysticercosis is caused by the tapeworm Taenia solium, another organism usually transmitted through eating undercooked meat. Although central nervous system infection usually dominates the clinical picture, with focal neurologic deficits, seizures, and encephalopathy, skeletal muscles can also be involved. Weakness, myalgias, muscle tenderness, and muscle pseudohypertrophy are accompanied by an elevated creatine kinase level and eosinophilia [Banker, 1994; Sawney et al., 1976]. The biopsy is characterized by fibrosis, inflammation with eosinophils, giant cells, and encysted organisms. Praziquantel (50 mg/kg/day in three divided doses for 2 weeks) is effective against central nervous system infection, but its efficacy in muscle is less clear. Albendazole (15 mg/kg/day in divided doses for 8 days) also has been used. Niclosamide and paromomycin are useful for treating the adult worms, and corticosteroids suppress the inflammatory reaction against degenerating parasites.

Bacterial Infections Pyomyositis refers to the multifocal abscesses associated with bacterial infection of the muscle. Although bacterial infections are more common in developing countries, they are being seen with increasing frequency in developed countries as a result of human immunodeficiency virus infection and intravenous drug abuse [Antony and Kerodle, 1996; Hsueh et al., 1996; Rodgers et al., 1993]. Muscle pain, tenderness, and fever are the initial symptoms, most commonly affecting the quadriceps, glutei, and deltoids. Most patients have a neutrophilic pleocytosis, elevated erythrocyte sedimentation rate, and normal or elevated serum creatine kinase level. Blood cultures are usually negative early in the infection until the patient becomes septic. Ultrasound, computed tomography, and magnetic resonance imaging of muscle can be useful in localizing abscesses for diagnostic needle aspiration. The most common organisms are Staphylococcus aureus, streptococci, Escherichia coli, Yersinia organisms, and Legionella organisms [Akman et al., 1996; Collazos et al., 1996; O’Neill et al., 1996]. Pyomyositis usually arises as an extension of infection from adjacent tissues or via hematologic spread of the organisms. Early in the illness, the infection may respond to appropriate antibiotics, although more severe infections require incision and drainage.

Fungal Myositides Fungal infection of the muscles is very uncommon and usually occurs in an immunosuppressed adult patient. Candidiasis is the most common fungal myositis and almost always is associated with disseminated disease [Arena et al., 1981; Jarowski et al., 1978]. Diffuse muscle pain, tenderness, weakness, fever, and a papular erythematous rash are evident but may be obscured by other systemic involvement.

Amato and Kissel / Inflammatory Myopathies

Muscle biopsy demonstrates infiltration of the muscle by hyphal and yeast forms of the organism, inflammation, and hemorrhagic necrosis. Myositis has also been reported complicating cryptococcal infection, sporotrichosis, actinomycosis, and histoplasmosis [Halverson et al., 1985; Heffner, 1993; Wrzolek et al., 1990]. REFERENCES Adams EM, Plotz PH. The treatment of myositis. How to approach resistant disease. Rheum Clin North Am 1995;21:179. Agrawal BL, Giesen PC. Eosinophilic myositis: An unusual cause of pseudotumor and eosinophilia. JAMA 1981;246:70. Akman I, Ostrov B, Varma BK, et al. Pyomyositis: Report of three patients and review of the literature. Clin Pediatr 1996;35:397. Amato AA, Barohn RJ. Idiopathic inflammatory myopathies. Neurol Clin 1997;15:615. Amato AA, Gronseth GS, Jackson CE, et al. Inclusion body myositis: Clinical and pathological boundaries. Ann Neurol 1996;40:581. Amato AA, Griggs RC. Inflammatory myopathies. Curr Opin Neurol 2003a;16:569. Amato AA, Griggs RC. Unicorns, dragons, polymyositis and other mythical beasts. Neurology 2003b;61:316. Antony SJ, Kerodle DS. Nontropical pyomyositis in patients with AIDS. J Natl Med Assoc 1996;88:865. Arahata K, Engel AG. Monoclonal antibody analysis of mononuclear cells in myopathies. I. Quantitative of subsets according to diagnosis and sites of accumulation and demonstration and counts of muscle fibers invaded by T cells. Ann Neurol 1984;16:193. Arena AP, Perlin M, Brahman H, et al. Fever, rash, and myalgias of disseminated candidiasis during antifungal therapy. Arch Intern Med 1981;141:1233. Askari AD. Inflammatory disorders of muscle: Cardiac abnormalities. Clin Rheum Dis 1984;10:131. Banker BQ. Other inflammatory myopathies. In: Engel AG, Franzini-Armstrong C, eds. Myology, 2nd ed. New York: McGraw-Hill, 1994. Banker BQ, Victor M. Dermatomyositis (systemic angiopathy) of childhood. Medicine (Baltimore) 1966;45:261. Boumpas DT, Chrousos GP, Wilder RL, et al. Glucocorticoid therapy for immune-mediated diseases: Basic and clinical correlates. Ann Intern Med 1993;119:1198. Bowyer SL, Blane CE, Sullivan DB. Childhood dermatomyositis: Factors predicting functional outcome and development of dystrophic calcification. J Pediatr 1983;103:882. Bowyer SL, Clark RAF, Ragsdale CG, et al. Juvenile dermatomyositis: Histologic findings and pathogenic hypothesis for the associated skin changes. J Rheumatol 1986;13:753. Cagnoli M, Marchesoni A, Tosi S. Combined steroid, methotrexate, and chlorambucil therapy for steroid resistant dermatomyositis. Clin Exp Rheumatol 1991;9:658. Callen JP. Relationship of cancer to inflammatory muscle diseases: Dermatomyositis, polymyositis, and inclusion body myositis. Rheum Dis Clin North Am 1994;20:943. Carpenter S, Karpati G, Rothman S, et al. The childhood type of dermatomyositis. Neurology 1976;26:952. Christianson JC, San Joaquin VH. Influenza-associated rhabdomyolysis in a child. Pediatr Infect Dis J 1990;9:60. Chwalinska-Sadowska H, Madykowa H. Polymyositis-dermatomyositis: 25 year follow-up of 50 patients—Disease course, treatment, prognostic factors. Mater Med Pol 1990;22:213. Collazos J, Fernandez A, Martinez E, et al. Pneumococcal pyomyositis. Case report, review of the literature, and comparison with classic pyomyositis caused by other bacteria. Arch Intern Med 1996;156:1470. Crowe WE, Love KE, Levinson JE, et al. Clinical and pathogenetic implications of histopathology in childhood polydermatomyositis. Arthritis Rheum 1982;25:126. Dalakas MC. Polymyositis, dermatomyositis, and inclusion body myositis. N Engl J Med 1991;325:1487. Dalakas MC. How to diagnose and treat the inflammatory myopathies. Semin Neurol 1994a;14:137. Dalakas MC. Retrovirus-related muscle disease. In: Engel AG, Franzini-Armstrong C, eds. Myology, 2nd ed. New York: McGraw-Hill, 1994b.

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Dalakas MC, Illa I, Dambrosia JM, et al. A controlled trial of high dose intravenous immunoglobulin infusions as treatment for dermatomyositis. N Engl J Med 1993;329:1993. Dalakas MC, Holhfeld R. Polymyositis and dermatomyositis. Lancet 2003;362:971. Davis MJ, Cilo M, Platitakis A, et al. Trichinosis. Severe myopathic involvement with recovery. Neurology 1976;26:37. Emslie-Smith AM, Arahata K, Engel AG. Major histocompatibility complex 1 antigen expression, immunolocalization of interferon subtypes, and T cell–mediated cytotoxicity in myopathies. Hum Pathol 1989;20:224. Emslie-Smith AM, Engel AG. Microvascular changes in early and advanced dermatomyositis: A quantitative study. Ann Neurol 1990;27:343. Engel AG, Arahata K. Monoclonal antibody analysis of mononuclear cells in myopathies. II: Phenotypes of autoinvasive cells in polymyositis and inclusion body myositis. Ann Neurol 1984;16:209. Escalante A, Miller L, Beardmore TD. Resistive exercise in the rehabilitation of polymyositis/dermatomyositis. J Rheumatol 1993;20:1340. Euwer RL, Sontheimer RD. Amyopathic dermatomyositis: A review. J Invest Dermatol 1993;100:124S. Farrell MK, Partin JC, Bove KE, et al. Epidemic influenza myopathy in Cincinnati in 1977. J Pediatr 1980; 96:545. Flaisler F, Blin D, Asencio G, et al. Focal myositis: A localized form of polymyositis? J Rheumatol 1993;20:1414. Fraser DD, Frank JA, Dalakas M, et al. Magnetic resonance imaging in idiopathic inflammatory myopathies. J Rheumatol 1991;18:1693. Gherardi R, Baidrimont M, Lionnet F, et al. Skeletal muscle toxoplasmosis in patients with acquired immunodeficiency syndrome. Ann Neurol 1992;32:535. Greenberg SA, Bradshaw EM, Pinkus GS, et al. Interferon α/β-mediated innate mechanisms in dermatomyositis. Ann Neurol 2005;57:664. Greenberg SA, Sanoudou D, Haslett JN, et al. Molecular profiles of the inflammatory myopathies. Neurology 2002;59:1170. Greenberg SA, Amato AA. Uncertainties in the pathogenesis of DM. Curr Opin Neurol 2004;13:356. Gross B, Ochoa J. Trichinosis: Clinical report and histochemistry of muscle. Muscle Nerve 1979;2:394 Halverson PB, Lahiri S, Wojno WC, et al. Sporotrichal arthritis presenting as granulomatous myositis. Arthritis Rheum 1985;28:1425. Hanissian AS, Masi AT, Pitner SE, et al. Polymyositis and dermatomyositis in children: An epidemiologic and clinical comparative analysis. J Rheumatol 1982;9:390 Haupt HM, Hutchins GM. The heart and conduction system in polymyositis-dermatomyositis. Am J Cardiol 1982;50:998. Hays AP, Gamboa ET. Acute viral myositis. In: Engel AG, Franzini-Armstrong C, eds. Myology, 2nd ed. New York: McGraw-Hill, 1994. Heffner RR. Inflammatory myopathies. A review. J Neuropathol Exp Neurol 1993;52:339. Hernandez RJ, Sullivan DB, Chenevert TL, et al. MR imaging in children with dermatomyositis: Findings and correlations with clinical and laboratory findings. Am J Roentgenol 1993;161:359. Hoogendijk JE, Amato AA, Lecky BR, et al. Workshop report. 119th ENMC international workshop: Trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis. Naarden, The Netherlands, October 10-12, 2003. Neuromusc Disord 2004;14:337. Hsueh PR, Hsiue TR, Hsieh WC. Pyomyositis in intravenous drug abusers: Report of a unique case and review or the literature. Clin Infect Dis 1996;22:858. Illa I, Nath A, Dalakas MC. Immunocytochemical and virological characteristics of HIV-associated inflammatory myopathies: Similarities with seronegative polymyositis. Ann Neurol 1991;29:474. Jarowski CI, Fialk MA, Murray HW, et al. Fever, rash, and muscle tenderness. A distinctive clinical presentation of disseminated candidiasis. Arch Intern Med 1978;138:544. Joffe MM, Love LA, Leff RL. Drug therapy of idiopathic inflammatory myopathies: Predictors of response to prednisone, azathioprine, and methotrexate and a comparison of their efficacy. Am J Med 1993;94:379. Kaufman LD, Kephart GM, Seidman RJ, et al. The spectrum of eosinophilic myositis: Clinical and immunopathologic studies of three patients, and a review of the literature. Arthritis Rheum 1993;36:1014.

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Kinoshita M, Nishina M, Koya N. Ten years follow-up study of steroid therapy for congenital encephalomyopathy. Brain Dev 1986;8:281. Kinoshita M, Iwasaki Y, Wada F, et al. A case of congenital polymyositis—A possible pathogenesis of “Fukuyama type congenital muscular dystrophy.” Clin Neurol 1980;20:911. Kissel JT, Halterman RK, Rammohan KW, et al. The relationship of complement-mediated microvasculopathy to the histologic features and clinical duration of disease in dermatomyositis. Arch Neurol 1991;48:26. Kissel JT, Mendell JR, Rammohan KW. Microvascular deposition of complement membrane attack complex in dermatomyositis. N Engl J Med 1986;314:331. Laxer RM, Stein LD, Petty RE. Intravenous pulse methylprednisolone treatment of juvenile dermatomyositis. Arthritis Rheum 1987;30:328. Leff RL, Love LA, Miller FW, et al. Viruses in idiopathic inflammatory myopathies. Absence of viral candidate genomes in muscle. Lancet 1992;339:1192. Love LA, Leff RL, Fraser DD, et al. A new approach to the classification of idiopathic inflammatory myopathy: Myositis-specific autoantibodies define useful homogeneous patient groups. Medicine 1991;70:360. Mantegazza R, Andreetta F, Bernasconi P, et al. Analysis of T cell receptor of muscle-infiltrating T lymphocytes in polymyositis: Restricted V alpha/beta rearrangements may indicate antigen-driven selection. J Clin Invest 1993;91:2880. Mastaglia FL, Laing NG. Investigation of muscle disease. J Neurol Neurosurg Psychiatry 1996;60:256. Medsger TA Jr, Dawson WN, Masi AT. The epidemiology of polymyositis. Am J Med 1970;48:715. Mejlszenkier JD, Safran AP, Healy JJ, et al. The myositis of influenza. Arch Neurol 1973;29:441. Miller FW. Myositis-specific antibodies. Touchstones for understanding the inflammatory myopathies. JAMA 1993;270:1846. Miller FW, Leitman SF, Cronin ME, et al. Controlled trial of plasma exchange and leukopheresis in polymyositis and dermatomyositis. N Engl J Med 1992a;326:1380. Miller LC, Sisson BA, Tucker LB, et al. Methotrexate treatment of recalcitrant childhood dermatomyositis. Arthritis Rheum 1992b;35:1143. Miller T, Al-Lozi MT, Lopate G, et al. Myopathy with antibodies to the signal recognition particle: Clinical and pathological features. J Neurol Neurosurg Psychiatry 2002;73:420. Mozaffar T, Pestronk A. Myopathy with anti-Jo-1 antibodies: Pathology in perimysium and neighbouring muscle fibres. J Neurol Neurosurg Psychiatry 2000;68:472. Nagai T, Hasgawa T, Saito M, et al. Infantile polymyositis: A case report. Brain Dev 1992;14:167. Nagar H, Bar-Ziv Y. Focal eosinophilic myositis: Unusual cause of a tumour on the chest wall. Eur J Surg 1993;159:187. Oddis CV. Therapy of inflammatory myopathy. Rheum Dis Clin North Am 1994; 20:899.

Olney RK, Miller RG. Inflammatory infiltration in Fukayama type congenital muscular dystrophy. Muscle Nerve 1983;6:75. O’Neill DS, Baquis G, Moral L. Infectious myositis. A tropical disease steals out of its zone. Postgrad Med 1996;100:193. Pachman LM. Inflammatory myopathy in children. Rheum Dis Clin North Am 1994;20:919. Pachman LM. Juvenile dermatomyositis. Pathophysiology and disease expression: Pediatr Rheumatol 1995;42:1071. Pegoraro E, Mancias P, Swerdlow SH, et al. Congenital muscular dystrophy with primary laminin 2 (merosin) deficiency presenting as inflammatory myopathy. Ann Neurol 1996;40:782. Plotz PH, Rider LG, Targoff IN, et al. Myositis: Immunologic contributions to understanding cause, pathogenesis, and therapy. Ann Intern Med 1995;122:715. Pollock JL. Toxoplasmosis appearing to be dermatomyositis. Arch Dermatol 1979;115:736. Rider LG, Miller FW. New perspectives on the idiopathic inflammatory myopathies of childhood. Curr Opin Rheumatol 1994;6:575. Roddy SM, Ashwal S, Peckham N, et al. Infantile myositis: A case diagnosed in the neonatal period. Pediatr Neurol 1986;2:241. Rodgers WB, Yodlowski ML, Mintzer CM. Pyomyositis in patients who have the human immunodeficiency virus. Case report and review of the literature. J Bone Joint Surg 1993;75:588. Rose MR, Kissel JT, Bickley LS, et al. Sustained myoglobinuria: The presenting manifestation of dermatomyositis. Neurology 1996;47:119. Ruff RL, Secrist D. Viral studies in benign acute childhood myositis. Arch Neurol 1982;39:261. Sawney BB, Chopra JS, Banerji AK, et al. Pseudohypertrophic myopathy in cysticercosis. Neurology 1976;26:270 Shevell M, Rosenblatt B, Silver K, et al. Congenital inflammatory myopathy. Neurology 1990;40:1111. Sigugeirsson B, Lindelöf B, Edhag, et al. Risk of cancer in patient with dermatomyositis or polymyositis. N Engl J Med 1992;326:363. Sontheimer RD. Cutaneous features of classic dermatomyositis and amyopathic dermatomyositis. Curr Opin Rheum 1999;11:475. Stonecipher MR. Cutaneous changes of dermatomyositis in patients with normal muscle enzymes: Dermatomyositis sine myositis? J Am Acad Dermatol 1993;28:951. Targoff IN. Immune manifestations of inflammatory disease. Rheum Dis Clin North Am 1994;20:857. Thompson CE. Infantile myositis. Dev Med Child Neurol 1982;24:307. Thornton CA, Griggs RC. Plasma exchange and intravenous immunoglobulin treatment of neuromuscular disease. Ann Neurol 1994;35:260. Tymms KE, Webb J. Dermatomyositis and other connective tissue diseases: A review of 105 cases. J Rheumatol 1985;12:1140. Van der Meulen MFG, Bronner M, Hoogendijk JE, et al. Polymyositis: A diagnostic entity reconsidered. Neurology 2003;61:316. Wrzolek MA, Sher JH, Kozlowski PB, et al. Skeletal muscle pathology in AIDS: An autopsy study. Muscle Nerve 1990;13:508.

CHAPTER 83

Channelopathies: Myotonic Disorders and Periodic Paralysis Richard T. Moxley III and Rabi Tawil

The term channelopathies has been extended to include disorders affecting all organ systems, but this chapter focuses on channelopathies of skeletal muscle. The initial identification of channelopathies of skeletal muscle began with a number of diseases associated with mutations in the genes for specific channels, including the channels for chloride [Davies and Hanna, 2003; Fahlke et al., 1997a, 1997b; George et al., 1993; Jurkat-Rott and Lehmann-Horn, 2004; Koch et al., 1992; Meyer-Kleine et al., 1995; Zhang et al., 1996], sodium [Cannon, 1996, 2001; Fournier et al., 2004; Lehmann-Horn and Rudel, 1996; Ptacek, 1997; Ptacek et al., 1993], calcium [Greenberg, 1997; McCarthy and Mackrill, 2004], and potassium [Cannon, 2002; Choi et al., 2004; Donaldson et al., 2004; Sanguinetti and Spector, 1997] ions. Periodic symptoms are typical for most channelopathies and occur in disorders other than muscle diseases. For example, familial migraine and hereditary episodic ataxia result from mutations in the calcium channel. These two diseases have joined a growing list of disorders, including familial hypokalemic periodic paralysis, malignant hyperthermia, central core disease, and Lambert-Eaton myasthenic syndrome, that are also calcium channelopathies

Box 83-1 GENERAL CLASSIFICATION OF THE CHANNELOPATHIES SEEN IN CHILDREN: MYOTONIAS AND PERIODIC PARALYSES Myotonic disorders of unknown mechanism Myotonic dystrophy type 1 (DM1) Myotonic dystrophy type 2 (DM2) Chloride channel myotonias Autosomal-dominant myotonia congenita (Thomsen’s disease) Autosomal-recessive myotonia congenita (Becker’s disease) Sodium channel myotonias Without periodic paralysis Acetazolamide-responsive myotonia Myotonia fluctuans With periodic paralysis Paramyotonia congenita Paramyotonia congenita with hyperkalemic periodic paralysis Hyperkalemic periodic paralysis with myotonia Possible sodium or potassium channel abnormality with periodic paralysis Calcium channel abnormality with periodic paralysis Possible calcium channel abnormality with periodic paralysis

[Greenberg, 1997]. This chapter limits its discussion to the disorders listed in Box 83-1 and refers the reader to the preceding references for discussion of other channelopathies.

THE MYOTONIC DYSTROPHIES: MYOTONIC DYSTROPHY TYPE 1 OF STEINERT AND MYOTONIC DYSTROPHY TYPE 2 (PREVIOUSLY TERMED PROXIMAL MYOTONIC MYOPATHY) The myotonic dystrophies represent a group of dominantly inherited, multisystem (eye, heart, brain, endocrine, gastrointestinal tract, uterus, skin) diseases that share the core features of myotonia, weakness, and early-onset cataracts (younger than 50 years). Table 83-1 summarizes myotonic dystrophy types 1 and 2. Clinicians considered myotonic dystrophy to be a single disease up until the later part of the 1990s. Steinert and colleagues described the disorder clearly in the early 1900s, and that description is still valid [Harper, 2001]. After the discovery of the gene defect responsible for myotonic dystrophy of Steinert in 1992 [Brook et al., 1992; Fu et al., 1992; Mahadevan et al., 1992] DNA testing revealed a group of patients with dominantly inherited myotonia, proximal greater than distal weakness, and cataracts who were previously diagnosed as having myotonic dystrophy but who after testing lacked the gene defect responsible for myotonic dystrophy of Steinert. Subsequent clinical studies of kindreds with patients having these characteristics led to the use of new diagnostic labels for these patients, myotonic dystrophy type 2 [Thornton et al., 1994] and proximal myotonic myopathy (PROMM) [Ricker et al., 1994a]. Later studies demonstrated that many of the families identified as having myotonic dystrophy type 2 or PROMM had the same disease, a disorder that results from an unstable four nucleotide repeat expansion [CCTG] on chromosome 3 [Liquori et al., 2001]. This disease is similar to, but distinct from, classic myotonic dystrophy of Steinert. It is referred to as myotonic dystrophy type 2 [Day et al., 1999, 2003; Thornton et al., 1994]. The existence of different types of myotonic dystrophy has created a need to develop a diagnostic classification. To address this need, the International Myotonic Dystrophy Consortium developed a new nomenclature and guidelines for deoxyribonucleic acid (DNA) testing [IDMC, 2000]. Myotonic dystrophy of Steinert, the classic form of myotonic dystrophy that results from an unstable trinucleotide repeat expansion on chromosome 19, is now termed myotonic dystrophy type 1 (DM1). Patients with the clinical picture of myotonic dystrophy type 2/proximal myotonic

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TABLE 83-1 Myotonias Due to Unstable Nucleotide Repeat Expansion CLINICAL FEATURES

MYOTONIC DYSTROPHY OF STEINERT (MYOTONIC DYSTROPHY TYPE 1, [DM1])

MYOTONIC DYSTROPHY TYPE 2 (PROXIMAL MYOTONIC MYOPATHY—DM2)

Inheritance Gene defect

Dominant Chromosome 19; CTG expansion affecting a protein kinase; repeat size ranges from 50 to >2000; normal 5-37 repeats

Age of onset

Broad range of ages (infancy to adulthood), with infant onset in most severe cases Face, eyes, forearm, hands, and legs, with generalized weakness and hypotonia in affected infants Primarily affects hand and forearm muscles and tongue; occasionally affects respiratory muscles and smooth muscle, such as intestine or uterus; myotonia improves with heat and exercise; myotonia results from a decrease in chloride channel protein Myotonia worsened by rest and cold; myotonia is relatively constant in severity and muscles affected

Dominant Chromosome 3; CCTG expansion affecting the zinc finger 9 protein gene; repeat sizes vary from 78 >11,000; normal <78 repeats Broad range of ages (late childhood to late adulthood)

Myopathy Myotonia

Provocative stimuli Therapy for symptoms

Bracing; cataract removal; monitoring dysrhythmias and respiratory insufficiency; pacemaker; antimyotonia therapy (mexiletine); avoid depolarizing muscle relaxants, opiates, and barbiturates with surgery for all of these myotonic disorders

myopathy (DM2), who have positive DNA testing for the unstable four nucleotide repeat expansion on chromosome 3, are now classified as having DM2. Patients with myotonia, proximal greater than distal weakness, and early onset cataracts with negative DNA testing for DM1 and DM2 are classified as having the “PROMM syndrome” or as having possible DM3 or as having an unclassified form of myotonic dystrophy [Meola and Moxley, 2004]. Reliability of DNA testing to establish the diagnosis of or to exclude DM1 is close to 100% [Harper, 2001]. However, caution is necessary in excluding the diagnosis of DM2. DNA testing methodology used in the recent past to screen for DM2 may have failed to detect as many as 20% of affected individuals [Day et al., 2003]. It will be necessary to use the more sensitive DNA testing methodologies for DM2 [Bachinski et al., 2003; Day et al., 2003] to rule out this disorder. Patients need to undergo this more sensitive DNA testing before a care provider raises the possibility that the individual has another form of myotonic dystrophy, such as DM3 and so on.

Mild; thighs, hips, neck flexors, occasional calf muscle hypertrophy Mainly in hands and thighs; varies; frequently hard to detect; pain occurs sometimes with and without myotonia; myotonia improves with repeated contractions; myotonia results from a decrease in chloride protein Myotonia worsened by rest but varies in severity, occasionally being absent on clinical examination; hand grip and thigh stiffness are usual sites Cataract removal; occasional need for pacemaker; antimyotonia therapy often not necessary (mexiletine); monitor carefully during and after surgery for muscle rigidity and rhabdomyolysis

A

Myotonic Dystrophy Type 1 Clinical Features and Subclassification DM1 is a multisystem, autosomal dominantly inherited, highly variable muscle disease with an incidence of 1 in 8000 individuals (see Table 83-1) [Harper, 2001; Moxley, 2003]. In childhood it presents as a severe congenital form or in a milder form in early school years. The congenital form presents at birth with respiratory failure, poor feeding, generalized hypotonia, clubfoot deformity, and an increased risk of intracerebral hemorrhage and eventration of the diaphragm [Harper, 2001]. During gestation there are often reduced fetal movements and a history of polyhydramnios. There is an increased frequency of placenta previa and miscarriage [Harper, 2001; Rudnik-Schoneborn and Zerres,

B FIGURE 83-1. Mother with mild-to-moderate myotonic dystrophy with her two children, both of whom have the congenital form of myotonic dystrophy (upper panel). Father and son both have mutations in the gene for the skeletal muscle sodium channel and have the acetazolamideresponsive form of sodium channel myotonia (lower panel).

Moxley and Tawil / Channelopathies: Myotonic Disorders and Periodic Paralysis

2004], and not uncommonly a failed labor may require urgent cesarean section. During the perinatal period, infants with congenital myotonic dystrophy may require continuous ventilator support, and those remaining ventilator dependent beyond 4 weeks of age have a poor prognosis for survival [Campbell et al., 2004; Harper 2001]. During the first 2 years of life, children with congenital myotonic dystrophy are at increased risk for aspiration pneumonitis and difficulties with feeding. Mental retardation and learning disabilities are common in congenital myotonic dystrophy. Determining the degree of cognitive deficit requires careful evaluation because these patients have marked facial weakness and are unable to speak and communicate well until mid to late childhood. There is also an increased incidence of hearing loss [Harper, 2001]. These problems complicate results of neuropsychologic testing. The upper panel of Figure 83-1 shows a mother with two daughters, both of whom have congenital myotonic dystrophy. Both children have delayed ability to speak and cognitive impairment. Their mother has mild ptosis, minimal grip myotonia, and minimal distal weakness. She is fully employed and has no cognitive impairment. This mother has the classic adultonset form of myotonic dystrophy [Harper, 2001; Moxley, 2003]. The later childhood-onset form usually is evident from nonmuscular manifestations of the disease, such as intellectual deficiency, difficulty with speech or hearing, clumsiness, or rarely with a cardiac dysrhythmia or postoperative apnea [Harper, 2001; Moxley, 2003; Sabovic et al., 2003]. An increased sensitivity to sedative medications, especially barbiturates and opiates, occurs in DM1 and occasionally muscle stiffness/myotonia worsens during general anesthesia [Harper et al., 2004; Moxley, 2003]. Cardiac arrhythmias are more common complications for the adult-onset forms of DM1 [Bhakta et al., 2004; Harper, 2001]. However, other nonmuscular manifestations, such as gastrointestinal hypomotility with chronic constipation, and intermittent urinary tract symptoms, such as urgency or frequent urination, are common in childhood myotonic dystrophy [Harper, 2001; Harper et al., 2004].

Genetics DM1 results from an unstable trinucleotide expansion in the 3′ untranslated region of a gene on chromosome 19 that codes for a serine/threonine protein kinase, DMPK [Brook et al., 1992; Fu et al., 1992; Mahadevan et al., 1992]. The function of this kinase, DMPK, remains unclear. The cause of the unstable CTG repeat expansion is also unknown. Recent research suggests that premutations arise from the upper normal range of CTG sizes and become pathologically enlarged within a few generations [Abbruzzese et al., 2002; Martorell et al., 2001]. More recent investigation demonstrates that mitomycin C can enhance enlargement of pathologically expanded repeats and promote enlargement of normal repeats [Pineiro et al., 2003]. Inhibitors of replication also modulate instability of the CTG repeat in the DM1 gene in cultured cells [Yang et al., 2003]. These observations raise the possibility that environmental/external factors may influence the development of pathologic enlargement of CTG repeats at the DM1 locus. The normal size of the [CTG]n repeats ranges from 5 to 37 repeats.

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Children with the congenital form of DM1 have expansions typically greater than 1500 repeats [Harley et al., 1993; Lavedan et al., 1993; Redman et al., 1993; Tsilfidis et al., 1992]. Moderately affected adults with DM1 have [CTG]n sizes ranging from 300 to 1000 repeats, and mildly affected individuals have expansions from 50 to 200 repeats. The unstable expansion of the DM1 gene provides an explanation for the well-described phenomenon of anticipation, that is, the earlier onset of more severe manifestations of disease in successive generations. Figure 83-1 emphasizes the phenomenon of anticipation in that the mother who has mild-to-moderate DM1 has had two children with severe congenital DM1.

Pathophysiology There are no examples of point mutations in the DMPK gene locus that have caused the clinical picture of DM1. There is evidence in a recently described mouse model of DM1 that certain disease manifestations may result largely from the CTG repeat expansion alone [Mankodi et al., 2000] without requiring either the presence of or disturbance of the DMPK gene or flanking genes. The molecular pathomechanism of DM1 appears in large part to result from a toxic effect of the abnormally expanded mRNA that accumulates in the nuclei of target tissues [Mankodi and Thornton, 2002; Mankodi et al., 2003; Ranum and Day, 2002; Timchenko et al., 2002]. The abnormal mutant transcripts contain expansions of CUG repeats that interfere with the normal regulation of splicing of specific premessenger ribonucleic acids. Accumulation in muscle nuclei of this expanded mRNA interrupts the production of important proteins, such as the insulin receptor and the skeletal muscle chloride channel. Investigations of muscle biopsies from DM1 patients have discovered abnormal splicing of the insulin receptor [Savkur et al., 2001] and the skeletal muscle chloride channel [Charlet et al., 2002; Mankodi et al., 2002]. The previously mentioned transgenic mouse model of DM1 also demonstrates a defect in splicing and offers a means to examine the pathophysiologic alterations that occur [Mankodi et al., 2000, 2002]. Studies of the transgenic DM1 mouse model demonstrate that the myotonia results from a severe decrease in chloride conductance that is associated with a marked deficiency of normal chloride channel protein. The severity of the defect in production of the chloride channel relates directly to the size of the CUG repeat in the transgene and to its level of expression [Mankodi et al., 2002]. Clues as to how the accumulations of expanded ribonucleic acid lead to the defect in splicing of specific premRNAs have come from studies of muscleblind knockout mouse models of DM1 [Kanadia et al., 2003] and from studies of muscleblind staining in muscle biopsies from DM1 patients [Mankodi et al., 2003]. Disruption of the muscleblind 1 gene in mice leads to muscle, eye, and RNA splicing abnormalities that are characteristic of DM1 [Kanadia et al., 2003]. The double-stranded RNA binding nuclear regulatory factor, muscleblind, binds to CUG repeats in the intranuclear accumulations containing the abnormally expanded DM1 mRNA, and only proteins in the muscleblind family are recruited to these foci [Mankodi

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et al., 2003]. A deficiency of muscleblind or at least an improper distribution of this nuclear regulatory protein occurs in DM1 and appears to be an important contributor to the defect in splicing and the disease manifestations. The cause of the muscle wasting and weakness remains a mystery. In the DM1 mouse model the mice do not develop muscle wasting or significant weakness. In patients there are hormonal abnormalities, including testosterone deficiency, insulin resistance, hyperinsulinemia, and altered release of growth hormone, which may contribute to muscle wasting due to deficient anabolism; but, to date, therapeutic trials restoring or exceeding physiologic levels of these hormones have failed to reverse the weakness and wasting [Harper, 2001; Moxley et al., 2004].

nuclei, scattered angular fibers, pyknotic nuclear clumps, and type 1 fiber atrophy. Creatine kinase levels may be normal or elevated and are not of primary value in the diagnosis.

Treatment

Identification of the abnormal expansion of [CTG]n repeats in the DMPK gene on chromosome 19 establishes the diagnosis of DM1. Electromyography to detect myotonia is helpful in older children, but myotonia may be absent in infancy or in early childhood. Slit-lamp examination to identify the typical iridescent, spokelike posterior capsular cataracts is helpful. Muscle biopsy is not necessary to diagnose DM1 but may be useful to exclude other disorders. Careful examination of the mothers of patients with suspected congenital DM1 is more useful than a muscle biopsy. The biopsy in adults indicates prominent central

With the discovery of the gene defect in DM1, it is possible to perform both prenatal and perinatal genetic counseling. Analysis of the DNA isolated from amniocytes or chorionic villus samples can predict the delivery of affected infants and the severity of illness [Harley et al., 1993; Harper, 2001; Redman et al., 1993]. Treating patients with congenital myotonic dystrophy involves ventilatory support, use of a feeding tube, and bracing for clubfoot deformities when present (Fig. 83-2) [Harper, 2001; Harper et al., 2004]. Figure 83-2 shows the molded plastic orthosis that helps treat foot deformity later in childhood. Speech problems and abdominal pain may improve with antimyotonia treatment. Mexiletine is sometimes helpful in alleviating some of the symptoms, especially in later childhood or adolescence when patients may have recurrent dislocation of the mandible and pain and muscle spasm in the masseter muscles. Electrocardiographic monitoring is necessary on a regular basis, particularly during treatment with mexiletine to search for covert dysrhythmias. Treatment should be coordinated with the child’s school to ensure that cognitive deficiencies and hearing deficits are monitored. The increased risk for cardiac dysrhythmia and apnea after administration of general anesthesia for surgery

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Clinical Laboratory Tests

FIGURE 83-2. An example of the plastic, molded foot orthosis that is useful in the treatment of clubfoot deformity in congenital myotonic dystrophy.

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requires overnight hospitalization with monitoring. Apnea can develop several hours after a patient has been extubated [Harper et al., 2004; Moxley, 2003]. No specific limitation on physical activity is necessary during childhood provided the child has gained sufficient strength and coordination to carry out activities requested in the school environment.

Myotonic Dystrophy Type 2 (Formerly Proximal Myotonic Myopathy) Clinical Features DM2/PROMM typically appears in adult life and has variable manifestations, such as early-onset cataracts (younger than 50 years), varying grip myotonia, thigh muscle stiffness, and muscle pain, as well as weakness (hip flexors, hip extensors, or long flexors of the fingers) [Day et al., 1999, 2003; Meola, 2000; Moxley et al., 2002; Ricker et al., 1994a, 1995; Schoser et al., 2004; Thornton et al., 1994]. These complaints often appear between 20 and 50 years of age, and patients as well as their care providers ascribe them to overuse of muscles, “pinched nerves,” “sciatica,” arthritis, or fibromyalgia. Younger patients may complain of stiffness or weakness when running up steps. The muscle pain has no consistent relationship to exercise or to the severity of myotonia found on clinical examination. The pain, which tends to come and go without obvious cause, usually fluctuates in intensity and distribution over the limbs. It can last for days to weeks. This pain seems qualitatively different from the muscle and musculoskeletal pain that occurs in patients with DM1. Early in the presentation of DM2 there is only mild weakness of hip extension, thigh flexion, and finger flexion. Myotonia of grip and thigh muscle stiffness vary from minimal to moderate severity over days to weeks. Direct percussion of forearm extensor and thenar muscles is the most sensitive clinical test for myotonia in DM2. Myotonia of grip is sometimes prominent and often has a jerky quality that seems to differ from that in DM1 and the nondystrophic myotonias. Myotonia is often less apparent in DM2 compared with patients with DM1. In cases of late-onset DM2, myotonia may only appear on electromyographic testing after examination of several muscles [Day et al., 2003; Ricker et al., 1995]. Facial weakness is mild in DM2 as is muscle wasting in the face and limbs. Weakness of neck flexors is frequent. Trouble arising from a squat is common, especially as the disease progresses. Calf muscle hypertrophy occasionally is prominent [Ricker et al., 1994a, 1995; Thornton et al., 1994]. Other manifestations, such as excessive sweating, hypogonadism, glucose intolerance, cardiac conduction disturbances, and cognitive/ neuropsychologic alterations may also occur and worsen over time [Day et al., 1999, 2003; Meola et al., 1999, 2003]. At present there is no evidence of a congenital form of DM2 [Day et al., 2003]. However, there is evidence of anticipation, with earlier onset of more prominent symptoms, in studies of parent-child pairs [Schneider et al., 2000]. When symptoms occur in childhood, they typically are transient and relate to grip myotonia in the hands and thighs. Proximal weakness, muscle pain, cataracts, and

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occasional cardiac dysrhythmias usually do not develop until mid or late adult life [Ricker et al., 1995; Thornton et al., 1994].

Genetics DM2 results from an unstable four nucleotide repeat expansion, CCTG, in intron 1 of the zinc finger protein 9 gene on chromosome 3q21 [Bachinski et al., 2003; Liquori et al, 2001, 2003; Ranum et al., 1998]. The cause for the unstable expansion is unknown. The size of the CCTG repeat appears to increase over time in the same individual, and, like DM1, it is a dynamic gene defect [Day et al., 2003]. The size of the CCTG repeat in normal leukocyte DNA is less than 75 repeats [Day et al., 2003; Liquori et al., 2001]. The size in DM2 ranges from 75 to over 11,000 repeats [Day et al., 2003; Liquori et al., 2001]. The gene mutation responsible for DM2 appears to have arisen from a northern European founder [Bachinski et al., 2003; Liquori et al., 2003].

Pathophysiology The molecular pathomechanism leading to the manifestations of DM2 is believed to be similar to that in DM1 and relates to a toxic effect of the abnormally expanded RNA that accumulates in the muscle nuclei [Mankodi and Thornton 2002; Mankodi et al., 2003; Ranum and Day, 2002; Timchenko et al., 2002]. There is no apparent relationship between the putative functions of the zinc finger protein 9 gene at 3q21 and the DM1 gene at 19q13.3 or their gene products [Liquori et al., 2001]. Flanking genes are not similar for the DM2 and DM1 loci. A toxic effect of the ribonucleic acid made from the unstable, abnormally expanded, nucleotide repeats in the DM2 and DM1 genes is likely to serve as the common mechanism for their disease manifestations. Both DM2 and DM1 have intranuclear accumulations of abnormally expanded ribonucleic acid, and both have ribonuclear foci that bind the nuclear regulatory protein, muscleblind [Mankodi et al., 2003]. Muscleblind is necessary for the muscle cell to produce the proper type of chloride channel. Abnormal splicing of the skeletal muscle chloride channel [Mankodi et al., 2002] and insulin receptor [Savkur et al., 2001, 2004] occurs in both DM2 and DM1, and DM2 and DM1 produce a severe deficiency of chloride channel protein on immunostaining of muscle biopsies from the patients [Mankodi et al., 2002]. Sequestering of muscleblind and thwarting of its normal function appears responsible for the abnormal splicing. The cause for the weakness in DM2 is unclear. Patients with DM2, in contrast to patients with classic DM1, usually have only mild muscle wasting. However, there is an uncommon, adult-onset variant of DM2, termed proximal myotonic dystrophy [Udd et al., 1997] that causes severe wasting of proximal arm and thigh muscles as the illness progresses. Patients with the proximal myotonic dystrophy variant of DM2 have the identical CCTG repeat expansion at 3q21 that occurs in patients with DM2 [Bachinski et al., 2003]. The reason for the severe muscle wasting in this variant compared with DM2 patients is unknown. Whether individuals with proximal myotonic dystrophy [Udd et al., 1997] share an underlying mechanism responsible for

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muscle wasting that is similar to the mechanism in DM1 remains to be established. If the pathomechanism of muscle wasting in this variant of DM2 is the same as DM1, what cellular mechanism limits the loss of muscle in DM2?

Clinical Laboratory Tests Leukocyte DNA testing is available for DM2. DNA testing methodology used in the recent past to screen for DM2 may have failed to detect as many as 20% of affected individuals [Day et al., 2003]. It is necessary to use the more sensitive DNA testing methodologies for DM2 [Bachinski et al., 2003; Day et al., 2003; Jakubiczka et al., 2004; Sallinen et al., 2004] to rule out this disorder. Patients need to undergo this more sensitive DNA testing before considering the possibility that the individual has another form of myotonic dystrophy. Slit-lamp examination to detect early cataract formation and electromyography, especially of the first dorsal interosseous, anterior tibialis, and anterior thigh muscles, are useful. Grip myotonia varies in severity and may be absent. Some patients have an elevation (twofold to fourfold) in creatine kinase and gamma glutamyltransferase levels. Patients with elevated creatine kinase values may have greater postoperative complications [Ricker et al., 1995]. A recent comparison of muscle biopsy findings in DM2 with those in classic DM1 indicates that there is less severe atrophy of fibers in DM2, and that in DM2 there are subgroups of very small type 2 fibers and nuclear clumps [Vihola et al., 2003]. Both DM2 and DM1 display abundant central nuclei on their biopsies [Day et al., 2003; Harper, 2001; Vihola et al., 2003], but it appears that DM2 is predisposed to type 2 fiber atrophy and DM1 to type 1 fiber atrophy [Schoser et al., 2004b; Vihola et al., 2003].

Treatment In general the management of DM2 is similar to that of DM1, but there is less need for supportive care, such as bracing, scooters, or wheelchairs. Cataracts require monitoring, and serial monitoring with an electrocardiogram (ECG) is necessary to check for covert dysrhythmia. Disturbances

in cardiac rhythm are less frequent in DM2, but abnormalities do occur [Day et al., 2003; Moxley et al., 2002]. Hypogonadism and insulin resistance need monitoring as in DM1. Myotonia tends to be less marked and less troublesome in DM2, but in specific circumstances antimyotonia therapy is helpful, especially if muscle stiffness is frequent and persistent. Cognitive difficulties also occur in DM2 as in DM1 but become manifest in adult life and appear to be associated with decreased cerebral blood flow to frontal and anterior temporal lobes [Meola et al., 1999] and decreased brain volume [Akiguchi et al., 1999; Chang et al., 1998; Flachenecker et al., 2003]. The changes are less severe than in DM1. Their etiology is unknown but may relate to the toxic effect of intranuclear accumulations of abnormally expanded RNA. Management of these brain symptoms is similar to that for DM1. A frequent and difficult problem in DM2 is the peculiar muscle pain described earlier. The exact mechanism underlying the pain is unknown, and there is no wellestablished, effective treatment. Carbamazepine or mexiletine along with nonsteroidal anti-inflammatory medications ameliorate this pain in some patients.

Autosomal-Dominant and Autosomal-Recessive Myotonia Congenita Thomsen’s disease (autosomal-dominant myotonia congenita) and Becker’s disease (autosomal-recessive myotonia congenita) represent two forms of chloride channelopathies (Table 83-2). The chloride channelopathies that produce myotonia as their primary symptom resemble the sodium channel disorders without periodic paralysis and may resemble mild forms of DM1 and DM2. Other causes of muscle stiffness or poor coordination, including central nervous system diseases affecting the frontal lobes, brainstem, and cerebellum, require initial consideration but are rarely confused with these channelopathies.

Clinical Features Generalized painless myotonia is the major clinical symptom in dominant and recessive forms of chloride channel

TABLE 83-2 Chloride Channel Myotonias CLINICAL FEATURES Inheritance Gene defect Age of onset Myopathy Myotonia Provocative stimuli Therapy for symptoms

AUTOSOMAL-DOMINANT MYOTONIA CONGENITA OF THOMSEN Dominant Chromosome 7; mutation in skeletal muscle chloride channel Infancy to early childhood Muscle hypertrophy frequent; no myopathy, although variants uncommonly develop weakness Generalized stiffness, especially after rest; improves with exercise; prominent myotonia of eye closure, but not paradoxical myotonia Prolonged rest or maintenance of the posture Exercise; antimyotonia therapy (e.g., mexiletine); Achilles’ tendon stretching helps prevent need for heel cord–lengthening surgery

AUTOSOMAL-RECESSIVE GENERALIZED A MYOTONIA OF BECKER Recessive Chromosome 7; mutation in skeletal muscle chloride channel Late childhood, occasionally starts earlier or begins in teens Occasional muscle wasting and weakness can occur late; hypertrophy of muscles frequently occurs in legs Generalized stiffness, especially after rest; transient weakness is prominent after complete relaxation for several minutes; myotonia occurs in eyes; no paradoxical myotonia Prolonged rest or maintenance of the same posture Exercise; especially avoiding prolonged rest; antimyotonia therapy (e.g., mexiletine); transient weakness does not improve after mexiletine

Moxley and Tawil / Channelopathies: Myotonic Disorders and Periodic Paralysis

myotonia congenita. Symptoms develop in the first or second decade of life. Myotonic stiffness occurs with sudden physical exertion after a period of rest. Repeated muscle contractions ameliorate the stiffness. This response is the “warm-up phenomenon,” which helps distinguish chloride channel myotonia congenita from certain forms of sodium channel myotonia that display increasing muscle stiffness with repeated contractions, a paramyotonic response. DM1 and DM2, like chloride channel myotonia, demonstrate the typical warm-up response. In contrast to Thomsen’s disease, patients with autosomalrecessive myotonia congenita have transient muscle weakness. The transient weakness appears for a few seconds during the initial attempt at a specific movement after a period of inactivity [Zwarts and VanWeerden, 1989]. Muscle strength improves to normal after several strong contractions [Baumann et al., 1996; Zwarts and VanWeerden, 1989]. Patients have prominent muscle hypertrophy, especially in the legs in both the autosomal-dominant and autosomalrecessive forms of myotonia congenita. Tendon reflexes, cerebellar function, sensation, and strength are normal. Myotonia is present in the grip on eye closure, and there is a lid lag. If patients lie supine for 5 to 10 minutes and suddenly arise, generalized myotonic stiffness in the proximal and paraspinous muscles becomes apparent.

Genetics Point mutations in the gene for the skeletal muscle chloride channel cause both autosomal-dominant [Fahlke et al., 1997a; Grunnet et al., 2003; Koch et al., 1992; Pusch, 2002; Pusch et al., 1995] and autosomal-recessive [Koch et al., 1992; Pusch, 2002; Zhang et al., 1996] forms of myotonia congenita. Autosomal-dominant myotonia congenita (Thomsen’s disease) may vary considerably in age of onset and severity of myotonia [Duno et al., 2004; Koty et al., 1996]. It is possible to screen for known point mutations in the chloride channel gene on chromosome 7 [Abdalla et al., 1992], but this genetic testing for the more than 60 mutations is not routinely available.

Pathophysiology Electrophysiologic studies in myotonic goats [Lipicky and Bryant, 1993] and human muscle tissue from patients with autosomal-dominant and autosomal-recessive [Koch et al., 1992; Rudel et al., 1994] myotonia congenita demonstrate a decreased chloride conductance. The decreased chloride conductance across the transverse tubular system renders the muscle membrane hyperexcitable, which leads to afterdepolarization and repetitive firing, creating clinical myotonia. Both autosomal-dominant myotonia congenita (Thomsen’s disease) and generalized autosomal-recessive myotonia congenita (Becker’s disease) involve mutations at the same locus [George et al., 1993; Koch et al., 1992]. Current models for the chloride channel indicate that two subunits combine to form a double-barreled entry gate for chloride ions and a single outflow channel [Duffield et al., 2003; Fahlke et al., 1997a, 1997b; Jentsch et al., 2002; Pusch, 2002; Saviane et al., 1999]. Dominant mutations affect the common outflow channel (slow flow channel) and

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recessive mutations require involvement of the two faster flow entry gates [Duffield et al., 2003]. The model proposes that involvement of only one entry gate does not cause clinical disease. Recessive mutations cause a pathologic reduction in chloride current because both fast gates undergo blockade, and dominant mutations cause pathologically reduced current because they affect the slower, common exit channel for chloride ions. The variations in the clinical severity of certain very rare dominantly inherited forms chloride channel myotonia, such as “myotonia levior” [Ryan et al., 2002; Wu et al., 2002], and “fluctuating myotonia” [Wagner et al., 1998], are interesting, and point to limitations in our current version of the model as explanation for the clinical spectrum of findings. A more recent report further emphasizes the limitation of the model. This report describes two unrelated families with the Becker recessive form and two unrelated families with the Thomsen dominant form of myotonia congenita, all of whom have a common R894X mutation [Duno et al., 2004]. The dominant family with the most severe phenotype expressed twice the expected amount of the R894X mRNA allele. These findings suggest that allelic variation may be an important modifier of disease progression in myotonia congenita. The model for the chloride channel also does not provide an explanation for the transient weakness that is a prominent clinical feature in generalized autosomal recessive (Becker’s myotonia) myotonia congenita. Its cause remains to be discovered.

Clinical Laboratory Tests Evaluation of patients with suspected myotonia congenita should include consideration of other myotonic disorders, such as DM1, DM2, paramyotonia congenita, sodium channel myotonias of other types, and chondrodystrophic myotonia (Schwartz-Jampel syndrome) (see Table 83-2). DM1 patients typically have facial and distal muscle weakness. DNA analysis reveals an abnormal expansion of [CTG]n repeats in the DMPK gene on chromosome 19. Patients with DM2 have an abnormal expansion of [CCTG]n repeats in the zinc finger 9 protein gene on chromosome 3. Patients with chondrodystrophic myotonia (Schwartz-Jampel syndrome) have typical dysmorphic features, dwarfism, and distinctive myotonic discharges on electromyography, which are neurogenic in origin. Distinguishing patients with chloride channel myotonia, either autosomal-dominant or autosomal-recessive forms, from those with sodium channel myotonic disorders is difficult. Both cause myotonic stiffness and muscle hypertrophy, especially in the legs. One distinguishing feature of sodium channel myotonia is the paradoxical myotonia of the eyelids that develops with repeated forceful eye closure. Figure 83-3 shows the response to looking up and down and to eye closure in a patient with DM1. The patient in Figure 83-4 has sodium channel myotonia, exhibiting lid lag and persisting myotonia after forceful closure of the eyes. If this patient repeats the forceful closure of his eyes, his myotonia worsens. Persistent myotonia of the eyelids also occurred in this patient’s son. In contrast, patients with autosomaldominant and autosomal-recessive forms of chloride channel myotonia exhibit warm-up after repeated contractions. Patients with chloride channel myotonia do not have a

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Neuromuscular Disorders / 83 FIGURE 83-3. Sequential photographs of the mother with myotonic dystrophy in Figure 83-1 looking up, looking down, and closing her eyes (upper panel). Sequential photographs of the father with acetazolamideresponsive sodium channel myotonia in Figure 83-1 looking up, looking down, and closing his eyes (lower panel).

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worsening of myotonic stiffness or paralysis after prolonged exposure of muscle to cold. To search for cold-induced paralysis, it is necessary to soak the hand or forearm muscles in cold water (15° C) for 15 to 20 minutes. If there is weakness with exercise after this cold exposure, this strongly favors sodium channel myotonia rather than chloride channel disease. The subsequent section on sodium channel myotonia briefly describes the laboratory evaluation of the sodium channelopathy disorder, hyperkalemic periodic paralysis. In that section the use of provocative testing using potassium loading as a diagnostic test is discussed. Sodium

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F channel myotonic disorders are typically “potassium sensitive.” An elevation in extracellular potassium markedly worsens myotonia in sodium channelopathies but not in chloride channel myotonia.

Treatment Antimyotonia treatment with mexiletine is often helpful [Ceccarelli et al., 1992]. Before initiating treatment with mexiletine, a baseline ECG is necessary to identify patients with unsuspected cardiac conduction abnormalities. Side effects of

Moxley and Tawil / Channelopathies: Myotonic Disorders and Periodic Paralysis

mexiletine, which are usually mild and dose related, include dysgeusia, light-headedness, and diarrhea. Tocainide, another lidocaine derivative similar to mexiletine, was another useful alternative [Kwiecinski et al., 1992], but it is no longer available. Isolated reports suggest that carbamazepine may be a readily available alternative antimyotonia medication for myotonia congenita [Berardinelli et al., 2000; Sheela, 2000]. Children with moderately severe myotonia develop heel cord shortening and contractures at their elbows. If these contractures do not respond to stretching and other physical therapy exercises, it is appropriate to initiate antimyotonia treatment even when patients do not complain of stiffness.

Acetazolamide-Responsive Sodium Channel Myotonia and Myotonia Fluctuans Two disorders that mimic myotonia congenita and are forms of sodium channel myotonia without periodic paralysis include acetazolamide-responsive sodium channel myotonia and myotonia fluctuans (Table 83-3). The discovery that hyperkalemic periodic paralysis and paramyotonia congenita result from mutations in the gene for the skeletal muscle sodium channel [Cannon, 2002; LehmannHorn and Jurkat-Rott, 1999; Ptacek and Bendahhou, 2001] has led to further investigations that have identified a group of patients with myotonia without episodic weakness, whose myotonia is worsened by potassium intake and who have mutations in the gene for the skeletal muscle sodium channel [Lerche et al., 1993; Ptacek et al., 1992, 1994b; Ricker et al., 1990, 1994b; Trudell et al., 1987]. This section reviews two of these disorders, acetazolamide-responsive myotonia [Ptacek et al., 1994b; Trudell et al., 1987] and myotonia fluctuans [Ricker et al., 1990, 1994b], which resembles chloride channel myotonia. A review of two other rare nondystrophic myotonic disorders caused by mutations in the sodium channel, myotonia permanens and chronic myotonia [Lerche et al., 1993], is not included. The reader is referred to the reports describing these uncommon disorders.

Clinical Features Acetazolamide-responsive sodium channel myotonia often initially presents to the pediatrician rather than the neurologist with common complaints, such as clumsiness causing

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frequent falls, a lazy eye, growing pains, back muscle spasm, or stridor. Parents may observe that after prolonged crying an infant or young child will have “their eyes stuck.” This is a manifestation of paradoxical eyelid myotonia that develops with repeated bouts of forceful closure of the eyes during crying. Myotonia is most apparent in the face, eyes, and larynx in very young patients. Stiffness in the hands, proximal limb muscles, and paraspinous muscles is more apparent in middle childhood. Muscle hypertrophy, especially in the legs, is frequent. Cerebellar function, sensory testing, tendon reflexes, and muscle strength are normal. Grip and percussion myotonia, as well as lid lag, are present. The severity of these complaints varies both in affected individuals within the same kindred and between kindreds. Episodes of painful muscle spasm occur in some patients, usually during or immediately after exercise. Pain is not common in most myotonic disorders. Acetazolamide-responsive sodium channel myotonia and DM2 are exceptions. The clinical findings in myotonia fluctuans are similar to those described previously for acetazolamide-responsive sodium channel myotonia, with one important additional finding. The severity of the muscle stiffness fluctuates to a greater degree in this illness. On “good days” the myotonia can vanish. The fluctuating myotonia also has an interesting relationship to prolonged exercise. A phenomenon termed exercise-induced delayed-onset myotonia occurs [Ricker et al., 1990]. Patients report that after a period of rest following vigorous exercise, if they resume exercise “at the wrong time,” severe muscle stiffness may develop. The time interval between the period of rest and the resumption of exercise is critical. If it is only a few minutes or an hour or more, stiffness does not occur. During the intermediate time interval, the fluctuation and provocation of severe myotonia happen. The myotonic symptoms in both acetazolamide-responsive sodium channel myotonia and myotonia fluctuans tend to persist throughout a patient’s lifetime. Some individuals note a lessening in severity in mid to late adulthood. This finding may represent only an adjustment to the illness and a decrease in physical activity.

Genetics Acetazolamide-responsive sodium channel myotonia results from a mutation in the gene for the skeletal muscle sodium

TABLE 83-3 Sodium Channel Myotonias without Periodic Paralysis CLINICAL FEATURES

ACETAZOLAMIDE-RESPONSIVE SODIUM CHANNEL MYOTONIA

Inheritance Gene defect

Dominant Chromosome 17; mutation in skeletal muscle sodium channel

Age of onset Myopathy Myotonia

First decade Rare Face, paraspinal muscles, paradoxical myotonia of eyelids, grip limbs; varies in severity and often there is pain with myotonia Fasting, cold, oral potassium, infection

Dominant Chromosome 17; mutation in skeletal muscle sodium channel First or second decade Rare; muscle hypertrophy common Face, limbs, eyelids; frequently fluctuates in severity, especially after exercise Exercise-rest-exercise, oral potassium

Acetazolamide, mexiletine; avoid high-potassium diet; monitor during and after surgery for rigidity and rhabdomyolysis

Mexiletine; avoid high-potassium diet; monitor during and after surgery for rigidity and rhabdomyolysis

Provocative stimuli Therapy for symptoms

MYOTONIA FLUCTUANS

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channel [Ptacek et al., 1994b] as does myotonia fluctuans [Ricker et al., 1994b]. The mutations in these two disorders of the sodium channel are not identical. Two separate mutations produce myotonia fluctuans [Ricker et al., 1994b]. Both disorders are autosomal dominant.

Pathophysiology Both of these nondystrophic sodium channel myotonic disorders worsen with an elevation in extracellular potassium. The myotonic stiffness can totally disable a patient under these circumstances. The specific mechanism by which the fluctuation in severity of myotonia occurs remains unclear, but it may relate in part to hormonal fluctuations. The levels of insulin, corticosteroids, and other hormones may exert an important influence on extracellular potassium levels [Lehmann-Horn et al., 1994; Ricker et al., 1994b].

Clinical Laboratory Tests Routine DNA testing is not available; however, several research laboratories screen for known mutations in the gene for the sodium channel in selected patients. The remainder of the laboratory evaluation is as described previously for chloride channel myotonia.

Treatment Acetazolamide often controls myotonic stiffness and pain in acetazolamide-responsive sodium channel myotonia [Ptacek et al., 1994b]. This treatment usually ameliorates the muscle pain. Annual ultrasound of the abdomen is useful to detect early formation of kidney stones, which are the major complication of acetazolamide [Tawil et al., 1993]. Dysesthesia and dysgeusia are common side effects. Attacks of severe muscle spasm and pain often improve with cyclobenzaprine. Patients undergoing surgery require monitoring during and after the procedure for signs of worsening muscle stiffness. Maintaining plasma potassium levels between 3.8 and 4.2 mEq/L helps to decrease perioperative muscle stiffness. Stress, muscle tissue damage, and bleeding all elevate plasma potassium levels and worsen myotonia. Postoperatively, intravenous diazepam or lorazepam may be

necessary to decrease myotonic stiffness, especially if patients are unable to take medications by mouth. Mexiletine is an effective alternative to acetazolamide, and, if necessary, these drugs can be used in combination. The management of myotonia fluctuans is similar to that of acetazolamide-responsive sodium channel myotonia. Careful attention to the pattern and timing of exercise helps to decrease episodes of severe muscle stiffness. Intraoperative and postoperative monitoring is important, as noted previously.

PERIODIC PARALYSES This section focuses on those disorders listed in Tables 83-4 and 83-5, which are associated with periodic paralyses, including channelopathies affecting the sodium, potassium, and calcium channels in skeletal muscle. The general classification of the periodic paralyses is as primary (inherited) or secondary (acquired) forms and as to the change in serum potassium level, such as hyperkalemic or hypokalemic. Paralytic attacks may last from less than 1 hour to several days. Weakness can be localized or generalized. Tendon reflexes decrease or disappear during attacks. Muscle fibers become unresponsive to either direct or indirect electrical stimulation. The generalized attacks of weakness usually begin in proximal muscles and spread to distal ones. Respiratory and cranial muscles tend to be spared but occasionally may become paralyzed. Rest after exercise tends to provoke weakness in the muscles that have undergone the exercise, but continued mild exercise may abort attacks. Exposure to cold may provoke weakness in certain sodium channel-related forms of periodic paralysis. Complete recovery usually occurs after attacks. Permanent weakness and irreversible pathologic changes sometimes occur. Disorders that cause periodic weakness in otherwise normal individuals are uncommon. In patients with a clear autosomal-dominant family history and in whom the serum potassium level indicates a clear increase or decrease during the paralytic attack, the diagnosis of a specific type of periodic paralysis is obvious. However, on many occasions a patient has an episode of weakness at home or arrives late in the attack or after recovery. Some patients have relatively

TABLE 83-4 Sodium Channel Myotonias with Periodic Paralysis CLINICAL FEATURES

PARAMYOTONIA CONGENITA

Inheritance Gene defect

Dominant Chromosome 17; mutation in skeletal muscle sodium channel First decade Very rare Especially paradoxical myotonia of the eyelids, and grip Cold exposure followed by exercise leads to focal paralysis; occasionally exercise provokes stiffness, but cold does not cause weakness Mexiletine, mild exercise, keep patient warm

Age of onset Myopathy Myotonia Provocative stimuli

Therapy for symptoms

PARAMYOTONIA CONGENITA WITH HYPERKALEMIC PERIODIC PARALYSIS

HYPERKALEMIC PERIODIC PARALYSIS WITH MYOTONIA

Dominant Chromosome 17; mutation in skeletal muscle sodium channel First decade Rare Especially paradoxical myotonia of the eyelids, and grip Oral potassium load, rest after exercise mainly in morning (hyperkalemic weakness), cold exposure followed by exercise (focal paralysis) Mild exercise, thiazides, mexiletine

Dominant Chromosome 17; mutation in skeletal muscle sodium channel First decade Infrequent Especially paradoxical myotonia of the eyelids Rest after exercise, cold, oral potassium Thiazides, acetazolamide, sodium restriction

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TABLE 83-5 Channelopathies with Hypokalemic Periodic Paralysis

CLINICAL FEATURES

ANDERSEN’S SYNDROME: PERIODIC PARALYSIS WITH CARDIAC CALCIUM CHANNEL DYSRHYTHMIA PERIODIC PARALYSIS

SODIUM CHANNEL PERIODIC PARALYSIS

POTASSIUM CHANNEL PERIODIC PARALYSIS

Inheritance

Dominant

Dominant

Dominant

Dominant

Gene defect

Chromosome 17; affects Kir2.1 potassium channel

Age of onset

Chromosome 1; affects skeletal muscle calcium channel First to third decade

First or second decade Typical; also short Moderately common stature; dysmorphic late; vacuoles features; prolonged frequently seen on QT interval on biopsy electrocardiogram; ventricular dysrhythmias No No Rest after exercise, High-carbohydrate oral glucose meals, rest after exercise, cold, emotional stress/ excitement Mild exercise, glucose, Acetazolamide, high sodium intake, dichlorphenamide, acetazolamide, potassium, dichlorphenamide spirolactone

Chromosome 17; affects skeletal muscle sodium channel First to third decade

Chromosome 11; affects MiRP2 subunit of potassium channel Second to third decade

Not yet determined

Not yet determined

No High-carbohydrate meals, rest after exercise, cold, emotional stress/ excitement Acetazolamide, dichlorphenamide, potassium, spirolactone

No Usually by strenuous exercise followed by rest. Less consistent provocation after high carbohydrate intake Acetazolamide

Myopathy

Myotonia Provocative stimuli

Therapy for symptoms

mild attacks, and diagnostic laboratory findings or clues from physical examination are not present. Some patients with inherited forms of periodic paralysis have other medical problems, and these coexisting problems may complicate the history and findings as the care provider attempts to develop a differential diagnosis. Certain general guidelines are useful to consider. The hereditary forms of periodic paralysis manifest symptoms within the first two decades of life, and on initial evaluation there is usually no difficulty distinguishing the cause of the weakness from the cause of weakness in patients with cerebral dysfunction, spinal cord disease, nerve root damage, or neuromuscular transmission failure. Muscle weakness, fatigue, or gait instability caused by illnesses involving the central nervous system, nerve roots, or neuromuscular junction become manifest during exercise. This contrasts with symptoms of periodic paralysis, which virtually never develop during exercise. Occasionally there is a lack of clear-cut family history or clinical findings to identify autosomal dominant inheritance. If other family members have symptoms, molecular genetic testing can assist in confirming the diagnosis. Ultimately, however, some children need to undergo provocative testing with potassium loading, cold exposure, and glucose loading to establish a diagnosis.

Hyperkalemic Periodic Paralysis Clinical Features Table 83-4 outlines the major clinical and diagnostic features of hyperkalemic periodic paralysis, as well as important issues in management. All three forms are transmitted

PERIODIC PARALYSIS WITH THYROID DISEASE Sporadic—occasionally dominant Unknown

Third decade (males 20:1) Infrequent

No High-carbohydrate meals, rest after exercise, acetazolamide Propranolol, restoration of euthyroid state, oral potassium, spironolactone

as autosomal dominant with high penetrance in both sexes [Cannon, 2002; Lehmann-Horn and Jurkat-Rott, 1999; Moxley, 2000; Ptacek, 1998]. Attacks begin in childhood and are usually brief, being shorter and more frequent than attacks in hypokalemic periodic paralysis. The attacks can occur with or without myotonia and in certain families hyperkalemic paralysis occurs in combination with coexisting paramyotonia congenita [Cannon, 2002; Lehman-Horn and Jurkat-Rott, 1999; Moxley 2000; Ptacek, 1998]. At the onset of an attack, myalgia may develop. Patients with hyperkalemic periodic paralysis plus myotonia frequently develop muscle stiffness and prominent paradoxical myotonia of the eyelids during attacks. Similar symptoms occur in patients with hyperkalemic periodic paralysis in association with paramyotonia congenita. Most patients with hyperkalemic attacks manifest signs of myotonia and notice increasing muscle tension, especially in the paraspinous muscles.

Genetics All clinical variants of hyperkalemic periodic paralysis result from mutations in the gene for the skeletal muscle sodium channel [Barchi, 1995; Cannon, 1997, 2002; Lehmann-Horn and Jurkat-Rott, 1999; Lehmann-Horn et al., 1994; Miller et al., 2004; Ptacek et al., 1993, 1994a], but the exact mutation can differ despite the fact that clinical symptoms are indistinguishable.

Pathophysiology In hereditary primary hyperkalemic periodic paralyses with and without myotonia, the net movement of potassium is

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opposite of that which occurs in hereditary hypokalemic periodic paralysis. There is an enhanced urinary excretion of potassium, a decrease in serum sodium concentration and in urinary excretion of sodium, and a decrease or unaltered serum chloride level [Moxley, 1994]. These findings are consistent with the egress of potassium and entry of sodium into muscle cells during attacks. During attacks of weakness in both hyperkalemic periodic paralysis and in paramyotonia congenita, there is an abnormally increased sodium conductance leading to depolarization of the muscle [Lehmann-Horn et al., 1994]. Patients with hyperkalemic periodic paralysis have a strong diurnal sensitivity to attacks of weakness, which occur primarily in the morning [Ricker et al., 1989]. This sensitivity may relate to circulating factors, such as glucocorticoids and beta-adrenergic hormones. Interestingly, salbutamol and metaproterenol, both beta-adrenergic drugs, are capable of increasing muscle strength during attacks [Lehmann-Horn et al., 1994; Ricker et al., 1989].

Clinical Laboratory Tests The primary laboratory evaluation involves monitoring of serum electrolytes during attacks to identify hyperkalemia or hypokalemia and monitoring the ECG to search for any evidence of dysrhythmia or other conduction disturbance, such as the ECG changes that occur in Andersen-Tawil syndrome. A dominant family history helps to limit additional laboratory testing to search for secondary forms of hyperkalemia, which might lead to muscle weakness. Laboratory evaluation for secondary hyperkalemic weakness should include a search for hormonal disturbances, such as insulin deficiency or adrenal insufficiency, or toxic effects of medications, such as beta-adrenergic antagonists, alphaadrenergic agonists, digitalis intoxication, or the use of succinylcholine. In patients not observed during a spontaneous attack of weakness, it may be necessary to perform provocative testing with oral potassium loading or exercise followed by potassium challenge [Moxley, 2000].

Treatment Attacks of weakness in hyperkalemic periodic paralysis are seldom severe enough to require emergency room evaluation. Oral glucose hastens recovery. Severe attacks usually respond to 2 g/kg of glucose by mouth and 15 to 20 units of crystalline insulin subcutaneously. Occasionally, severe attacks may fail to respond to these treatments. Calcium gluconate, 0.5 to 2 g intravenously, is sometimes effective, as is the inhalation of beta-adrenergic agents, such as metaproterenol, every 15 minutes for three doses. Preventive treatment includes avoidance of fasting, exposure to cold, and overexertion. A prudent consumption of frequent meals high in carbohydrate content is helpful. Diuretics that promote kaluresis, such as hydrochlorothiazide and carbonic anhydrase inhibitors, are the primary therapies.

Paramyotonia Congenita Clinical Features Symptoms develop usually during the first decade of life and have a predilection for facial, lingual, neck, and hand mus-

cles (see Table 83-4) [Lehmann-Horn and Jurkat-Rott, 1999; Moxley, 2000]. Attacks of increased muscle stiffness followed by paralysis occur on exposure to cold followed by exercise. The hallmark clinical sign is paradoxical myotonia or paramyotonia, that is, stiffness that worsens with repeated muscle contraction. This sign is most prominent in the muscles of eye closure. Clinical myotonia may be restricted to the eye muscles and not be apparent in grip or after percussion.

Genetics Mutations in the gene for the skeletal muscle sodium channel in several locations cause paramyotonia congenita [Cannon, 2002; Lehmann-Horn and Jurkat-Rott, 1999; Miller et al., 2004; Ptacek, 1998], but they tend to fall into the following two general groups: (1) those in the S3-S4 segments in domain 4 near the extracellular surface of the membrane; and, (2) those in the cytoplasmic loop between domains 3 and 4. Patients with paramyotonia congenita associated with hyperkalemic periodic paralysis have mutations in the cytoplasmic loop between domains 3 and 4 [Bouhours et al., 2004; Lehmann-Horn and Jurkat-Rott, 1999; Ptacek, 1998]. There is considerable variation in the severity of symptoms both within and between kindreds, and this variation does not correlate closely with the exact mutation [Lehmann-Horn and Jurkat-Rott, 1999; Mohammadi et al., 2003]. One recent report indicates that the combined form of hyperkalemic periodic paralysis and paramyotonia congenita, with the severe phenotype beginning in infancy, involves a specific mutation, methionine substitution at codon 704 (T704M) [Brancati et al., 2003]. More studies are necessary to establish this phenotype-genotype correlation.

Clinical Laboratory Tests Standardized testing using immersion of the hand and forearm in cold water for 15 minutes followed by exercise is effective in provoking paramyotonic stiffness and paralysis in most patients [Moxley, 2000; Ricker et al., 1990]. Most cooperative children can tolerate this testing. If no clear evidence of cold-induced muscle stiffness and weakness is apparent, further laboratory testing as indicated previously under hyperkalemic periodic paralysis and as noted under laboratory tests for chloride channel myotonia may be necessary. DNA analysis to search for known mutations in the gene for the sodium channel is available in selected research laboratories and in the future may become routinely available.

Pathophysiology As in hyperkalemic periodic paralysis caused by sodium channel dysfunction, paramyotonia congenita also has increased sodium conductance and excessive depolarization of the muscle membrane [Cannon, 2002; Bouhours et al., 2004; Lehmann-Horn and Jurat-Rott, 1999]. The electrophysiologic defect in hyperkalemic periodic paralysis and paramyotonia congenita differs. This difference is apparent in the response of forearm muscle to cooling and exercise. In hyperkalemic periodic paralysis, cooling of forearm muscle followed by forceful contractions leads to mild

Moxley and Tawil / Channelopathies: Myotonic Disorders and Periodic Paralysis

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FIGURE 83-4. Patient has acetazolamide-responsive sodium channel myotonia. The patient appears in Figure 83-1 with his father, who is also shown in Figure 83-3. Sequential photographs of the patient before and after forced closure of the eyes. Myotonia appears and worsens after repeated eye closure (e.g., paramyotonia).

weakness, but muscle fibers do not display the marked depolarization observed in the muscle of patients with paramyotonia congenita. Treatment with tocainide, which is effective in paramyotonia congenita, does not reduce the mild weakness provoked by cooling and exercise in hyperkalemic periodic paralysis, in contrast to its beneficial protective effect on forearm muscle strength in paramyotonia congenita [Rudel et al., 1994]. In paramyotonia congenita, exercise after exposure to cold provokes muscle stiffness and occasionally prolonged paralysis. More research is necessary to clarify the mechanism of cold-induced weakness in paramyotonia and its variation within individuals in the same and different kindreds.

Treatment Mexiletine is usually effective in preventing attacks of coldinduced weakness. Tocainide is also effective, but is no longer available. Patients having the combination of paramyotonia congenita plus hyperkalemic periodic paralysis require additional treatment with either a thiazide diuretic or acetazolamide.

Hypokalemic Periodic Paralysis Hypokalemic periodic paralysis is an autosomal-dominant disorder caused most commonly by mutations in a skeletal muscle calcium channel gene [Fouad et al., 1997; JurkatRott et al., 1994, 1998; Ptacek et al., 1994a]. A clinically identical form of hypokalemic periodic paralysis can also result from specific mutations of the same skeletal muscle sodium channel associated with hyperkalemic periodic paralysis [Bulman et al., 1999; Jurkat-Rott et al., 2000; Struyk et al., 2000].

Clinical Features Attacks of hypokalemic periodic paralysis usually have their onset in the first or second decade, and about 60% of patients are affected before the age of 16 years [Engel et al., 1965; Lapie et al., 1997; Lehmann-Horn et al., 1994; Moxley, 1994; Shy et al., 1961]. Initially, attacks tend to be infrequent but eventually may recur daily. Diurnal fluctuations in strength

may develop so that patients demonstrate greatest weakness during the night or early morning hours and gradually gain strength as the day passes. During major attacks, the serum potassium level decreases but not always to below normal. There is urinary retention of sodium, potassium, chloride, and water [Lehmann-Horn et al., 1994; Moxley, 1994]. Oliguria or anuria develops during such attacks, and patients tend to be constipated. Sinus bradycardia and ECG signs of hypokalemia appear when the serum potassium falls below normal. Usually during the fourth and fifth decades of life, attacks become less frequent and may cease. However, repeated attacks may leave the patient with permanent residual weakness [Dalakas and Engel, 1983; Dyken et al., 1969; Griggs et al., 1970; Odor et al., 1967].

Genetics Familial hypokalemic periodic paralysis results from mutations in the gene for the skeletal muscle voltage-gated calcium channel on chromosome 1 and typically affects the dihydropyridine receptor [Jurkat-Rott et al., 1994; Lapie et al., 1997; Ptacek et al., 1994a; Sillen et al., 1997]. The mutations affect segment S4 of domains 3 and 4 [Lapie et al., 1997]. The prevalence of familial hypokalemic periodic paralysis is approximately 1 in 100,000 [Lapie et al., 1997; Lehmann-Horn et al., 1994]. The symptoms are more severe in males, as is the case in hyperkalemic periodic paralysis. About 10% of hypokalemic periodic paralysis results from specific mutations of the skeletal muscle sodium channel gene [Miller et al., 2004].

Pathophysiology In hereditary hypokalemic periodic paralysis, the muscle fiber develops reduced excitability and an increased sodium conductance that, unlike sodium channel forms of periodic paralysis, cannot be prevented by application of the sodium channel blocker tetrodotoxin [Lehmann-Horn et al., 1994; Moxley, 1994]. The in vitro electrophysiologic behavior of muscle fibers with sodium channel mutations associated with hypokalemic periodic paralysis appears to be similar to those with mutated calcium channels [Cannon, 2002].

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The precise mechanism by which the skeletal muscle calcium channel permits this inexcitability of the muscle fiber remains unknown.

Clinical Laboratory Tests Evaluation of serum electrolytes and ECG during attacks of weakness is essential to diagnosis and treatment. Muscle biopsy is usually not necessary but may reveal vacuoles, especially in patients with fixed weakness [Lehmann-Horn et al., 1994]. In patients not observed during attacks of weakness, it may be necessary to undertake careful provocative testing. This testing requires hospitalization and continuous monitoring of the ECG as indicated in previously published protocols [Moxley, 1994, 2000]. Occasionally, hypokalemic paralysis develops from acquired, secondary causes. Causes for secondary hypokalemic weakness include hypokalemia in association with hyperthyroidism, beta-adrenergic stimulation, excessive insulin, alkalemia, barium poisoning, poor potassium intake (e.g., alcoholics, anorexia nervosa), excessive potassium excretion (e.g., diarrhea, laxative abuse, profuse sweating during athletic training), and renal loss of potassium (e.g., renal tubular acidosis, osmotic diuresis, and medication use, such as large doses of penicillin antibiotics) [Moxley, 1994].

Treatment Acute attacks may respond to oral potassium chloride (0.2 to 0.4 mmol/kg) repeated at 15- to 30-minute intervals [Moxley, 1994]. Monitoring ECG and serum potassium levels and muscle strength helps determine the frequency of these doses. Milder attacks resolve spontaneously, and mild exercise of the weakened muscles speeds recovery. If a patient has a severe attack and is unable to swallow or is vomiting, cautious intravenous infusion of potassium may be necessary. Treating physicians should keep in mind that a patient’s serum potassium levels do not represent a total body deficit of potassium but rather a temporary intracellular shift. Therefore potassium replacement formulas tend to overestimate the replacement needs and result in potentially dangerous hyperkalemia. Preventive therapy for attacks of hypokalemic weakness is usually needed. A low-sodium (2 to 3 g/day) and lowcarbohydrate (60 to 80 g/day) diet, avoidance of exposure to cold and overexertion, and supplemental doses of potassium chloride (2.5 to 7.5 g as a 10% solution) taken two to four times daily are preventive measures that may help [Moxley, 1994]. However, no convincing data are available to indicate that oral potassium chloride prevents attacks. Acetazolamide in divided doses usually abolishes attacks of weakness in most patients when taken daily [Griggs et al., 1970; Lehmann-Horn et al., 1994; Moxley, 1994]. Dichlorphenamide is another carbonic anhydrase inhibitor that is useful as preventive treatment if acetazolamide proves ineffective [Dalakas and Engel, 1983; Lehmann-Horn et al., 1994; Moxley, 1994; Tawil et al., 2000]. Both of these carbonic anhydrase inhibitors produce a metabolic acidosis, and despite their kaluretic action and their tendency to lower serum potassium levels, they appear to act on skeletal muscle to stabilize potassium flux, especially during insulin stimu-

lation [Corbett et al., 1984]. Side effects are as described in the section on hyperkalemic periodic paralysis. There are rare familial cases of hypokalemic periodic paralysis in which acetazolamide exacerbates attacks of weakness [Torres et al., 1981]. This weakness appears to be a consistent but not universal feature of hypokalemic periodic paralysis families carrying sodium channel mutations [Cannon, 2002; Venance et al., 2004]. In these families, triamterene or spironolactone may control the attacks.

Myotonic Chondrodystrophy: Schwartz-Jampel Syndrome The Schwartz-Jampel syndrome is diagnosed in early childhood by the presence of myotonia, short stature, masklike facies, muscle pseudohypertrophy, skeletal dysplasia with bone and joint abnormalities, and growth retardation [Aberfeld et al., 1965; Cao et al., 1978; Schwartz and Jampel, 1962]. This classic form of Schwartz-Jampel syndrome is proposed as type 1A [Giedion et al., 1997] and is linked to chromosome 1p34-p35 [Fontaine et al., 1996; Nicole et al., 1995]. The perlecan, a large heparin sulfate proteoglycan, is involved in Schwartz-Jampel syndrome causation. Mutations in the perlecan gene (HSPG2) are associated with Schwartz-Jampel syndrome [ArikawaHirasawa et al., 2002]. The defective protein that is encoded leads to abnormal cartilage development and anomalous neuromuscular activity [Ho et al., 2003]. A similar Schwartz-Jampel syndrome, type 1B, is recognizable at birth with more pronounced bone dysplasia. A more severe form of the syndrome, designated type 2, manifests at birth with increased mortality and bone dysplasia. More severe skeletal abnormalities and feeding difficulties are present [Al Gazali et al., 1996]. The presence in neonates of chondrodysplasia; congenital bowing of shortened femora and tibiae; and facial manifestations consisting of a small mouth, micrognathia, and pursed lips should suggest the diagnosis of Schwartz-Jampel syndrome [Spranger et al., 2000]. Death resulting from respiratory complications may occur in type 2. A second locus appears to be responsible for this severe neonatal type of Schwartz-Jampel syndrome [Brown et al., 1997]. In typical Schwartz-Jampel syndrome, range of motion at joints becomes progressively restricted, which may be due to unchecked myotonia. Although carpal tunnel syndrome is rare in childhood, it does occur with some frequency in Schwartz-Jampel syndrome [Van Meir and De Smet, 2003]. Malignant hyperpyrexia may occur, complicating orthopedic surgical procedures [Seay and Ziter, 1978]. Mental retardation is present in 25% of affected children, and developmental language disorder and attention-deficit disorder may be present [Paradis et al., 1997]. Severe microcephaly has been reported [Pinto-Escalante et al., 1997]. Serum creatine kinase activity is mildly increased. Striking high-frequency potentials associated with myotonia are demonstrated electrophysiologically. Electrical silence does not occur during rest, during general anesthesia, or after curarization [Taylor et al., 1972]. Muscle biopsy demonstrates myopathic findings [Brown et al., 1975; Huttenlocher et al., 1969]. Computed tomography of muscles reveals difuse high attenuation in sternocleidomastoid muscles and low attenuation in the paraspinal, quadriceps, sartorius, soleus,

Moxley and Tawil / Channelopathies: Myotonic Disorders and Periodic Paralysis

and gastrocnemius muscles [Iwata et al., 2000]. Somatosensoryevoked potentials are delayed [Singh et al., 1997], although visual and brainstem auditory-evoked potentials and nerve conduction velocities are normal. Phenytoin administration increases range of motion through relaxation of myotonia. Carbamazepine treatment also reduces myotonia [Topaloglu et al., 1993]. Early initiation of treatment tends to lessen skeletal malformations [Squires and Prangley, 1996].

Periodic Paralysis with Cardiac Arrhythmia: Andersen-Tawil Syndrome Clinical Features Andersen syndrome [Bendahhou et al., 2003; Donaldson et al., 2003; Miller et al., 2004; Tristani-Firouzi et al., 2002] or, as recently recognized, Andersen-Tawil Syndrome [Bendahhou et al., 2003], is a rare inherited disorder characterized by periodic paralysis, long QT syndrome, ventricular dysrhythmias, and skeletal developmental abnormalities. The early reports of this disorder raised the possibility of hyperkalemia during attacks of weakness, but as more specific identification of kindreds with AndersenTawil syndrome has occurred, it is apparent that the disorder is a variant of hypokalemic periodic paralysis [Bendahhou

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et al., 2003; Donaldson et al., 2003; Miller et al., 2004; Tristani-Firouzi et al., 2002]. Patients with this type of hypokalemic weakness have dysmorphic features, such as short stature, clinodactyly, and microcephaly, as well as ventricular dysrhythmias (Fig. 83-5). Attacks of weakness develop during the first or second decade [Andersen et al., 1971; Fukuda et al., 1988; Gould et al., 1985; Klein et al., 1963; Kramer et al., 1979; Levitt et al., 1972; Lisak et al., 1972; Sansone et al., 1997; Stubbs, 1976; Tawil et al., 1994; Yoshimura et al., 1983]. The attacks of limb weakness can vary from mild, resembling those in the sodium channel form of hyperkalemic periodic paralysis, to severe, resembling the typical calcium channel form of hypokalemic periodic paralysis. The major difference is that occasionally the episodes of weakness are associated with syncopal attacks and rarely sudden death. The cardiac arrhythmias and extrasystoles improve with an elevation in extracellular potassium, while hypokalemia tends to aggravate the cardiac dysrhythmias. In carriers of the potassium channel mutation, Kir2.1, associated with Andersen-Tawil syndrome, 64% had attacks of weakness, 71% had long QT intervals, and 78% had dysmorphic features [Tristani-Firouzi et al., 2002]. Cardiac symptoms can be provoked by digitalis; are refractory to disopyramide phosphate, propranolol, and phenytoin; and may respond to imipramine [Sansone et al., 1997; Tawil et al., 1994].

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FIGURE 83-5. Facial appearance of a teenager with Andersen’s syndrome (hyperkalemic periodic paralysis with cardiac dysrhythmias), the hands of his mother, who also has mild dysmorphic features of Andersen’s syndrome, and the electrocardiograph (ECG) in this teenage patient demonstrating the typical dysrhythmia. During attacks of generalized weakness in which the serum potassium level rises above 5 mEq/L, the ECG in this patient typically returns to normal. (From Sansone V et al., 1997; and Tawil R et al., 1994. Copyright 1994 Wiley-Liss, Inc., a Wiley Company. Reproduced with permission of John Wiley & Sons, Inc.)

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Genetics One of the responsible mutations involves the gene encoding the inward-rectifying potassium channel Kir2.1 [Ai et al., 2002; Andelfinger et al., 2002; Plaster et al., 2001]. Autosomaldominant inheritance occurs with variable severity within families [Bendahhou et al., 2003; Donaldson et al., 2003; Miller et al., 2004; Tristani-Firouzi et al., 2002]. Aside from the individuals with known mutations in the Kir2.1 gene, approximately 40% of cases with the clinical features of Andersen-Tawil syndrome have unknown mutations [Donaldson et al., 2004].

Pathophysiology The 21 different mutations thus far identified in 30 kindreds with Andersen-Tawil syndrome appear to affect channel function through heterogeneous mechanisms [Donaldson et al., 2004]. These include (a) reduced activation of the channel due to altered binding of membrane-associated phosphatidylinositol 4,5 bisphosphate [Donaldson et al., 2003] and (b) mutated channels co-assembled and co-localized to the muscle membrane, with normal channels causing a dominant negative effect on their function [Bendahhou et al., 2003]. Other gene mutations that cause Andersen-Tawil syndrome likely share a common pathway or function with Kir2.1 or facilitate the activity of this ion channel.

Clinical Laboratory Tests Periodic monitoring of the ECG is important to identify covert dysrhythmias. DNA testing as it becomes available will also be very helpful in establishing the diagnosis [Donaldson et al., 2004]. Muscle biopsy may help to distinguish patients with Andersen-Tawil syndrome from those with other myopathic disorders, especially various congenital myopathies. Provocative testing with potassium may be necessary. Patients with Andersen’s syndrome are potassium sensitive [Sansone et al., 1997; Tawil et al., 1994], and occasionally more detailed provocative testing may be necessary [Moxley, 1994].

Treatment Acetazolamide in doses used to treat sodium channel forms of hyperkalemic periodic paralysis is sometimes effective in preventing attacks of weakness. Dichlorphenamide may provide an effective alternative if acetazolamide fails [Tawil et al., 2000]. Cardiac dysrhythmias are less frequent if serum potassium is permitted to range from 4 to 4.4 mEq/L. However, this elevation in potassium may be difficult to achieve because it is typically not feasible with the use of carbonic anhydrase inhibitors. Occasionally, patients require the use of a spironolactone diuretic in combination with a carbonic anhydrase inhibitor to achieve a slightly higher serum potassium. Management of the cardiac dysrhythmia is best handled by a cardiologist. It is typically difficult to control.

Thyrotoxic Periodic Paralysis Clinical Features Attacks of thyrotoxic periodic paralysis are unusual in the first decade or early in the second decade of life but tend to

develop in the late teens and during the 20s. It is much more frequent in Asians and males; 95% of cases are sporadic [Moxley, 1994; Ober, 1992; Resnick et al., 1969]. Cardiac problems, including sinus tachycardia, atrial fibrillation, supraventricular tachycardia, and ventricular fibrillation, can occur [Moxley, 1994; Ober, 1992; Resnick et al., 1969].

Pathophysiology Pathophysiology of thyrotoxic periodic paralysis remains a mystery, but it is clear that the hyperthyroid state is an essential factor in mediating the hypokalemia and attacks of weakness [Moxley, 1994]. Patients have attacks only when they are hyperthyroid, and attacks cannot be precipitated by insulin and carbohydrate administration once patients become euthyroid in contrast with patients with hereditary hypokalemic periodic paralysis [Moxley, 1994; Ober, 1992]. Even after patients have become euthyroid and symptom free, paralytic attacks recur if the patient experiences a relapse into a thyrotoxic state or if hyperthyroidism is produced again with exogenous thyroid hormone [Moxley, 1994; Ober, 1992; Okihiro and Nordyke, 1966]. Hyperthyroidism alters plasma membrane permeability to sodium and potassium and increases responsiveness to catecholamines, probably through an increase in the sodium potassium adenosine triphosphatase in skeletal muscle [Ewart and Klip, 1995; Norgaard and Kjeldsen, 1991]. However, hypokalemia does not appear to be the primary regulator of weakness in thyrotoxic periodic paralysis because some patients regain their strength in the presence of persistent hypokalemia [Shayne and Hart, 1994; Yeung and Tse, 1974]. Moreover, a degree of hypokalemia sufficient to provoke a paralytic attack in a hyperthyroid patient may have no effect when that same patient is euthyroid [Ober, 1992], emphasizing that the relationship between hypokalemia and thyrotoxic periodic paralysis is complex. The fact that propranolol can prevent paralytic attacks at a level of hypokalemia, which in the same individual typically precipitates weakness [Ober, 1992; Yeung and Tse, 1974], raises additional questions about the specific role of changes in serum potassium in the etiology of thyrotoxic periodic paralysis.

Genetics The gene defect responsible for thyrotoxic hypokalemic periodic paralysis remains unclear. One recent report described an R83H mutation in the potassium channel gene, KCNE3 [Dias da Silva et al., 2002] in a man who developed symptoms with the onset of Graves’ disease. The mutation was found in two of three descendants. Three more recent reports have failed to confirm this observation. One study of 97 Chinese men with thyrotoxic periodic paralysis compared the genetic findings in this group to those in 77 Graves’ disease patients without periodic paralysis and to 100 normal males [Kung et al., 2004]. None of the men with known thyrotoxic periodic paralysis had mutations in the calcium channel, sodium channel, or potassium channel genes previously reported to be associated with periodic paralysis. Another study describes an analysis of the entire coding sequence of KCNE3 gene in 79 Chinese patients with thyrotoxic periodic paralysis and compared their findings with those from 111 men with thyrotoxicosis without periodic paralysis [Tang et al., 2004]. No mutations were found in the

Moxley and Tawil / Channelopathies: Myotonic Disorders and Periodic Paralysis

KCNE3 gene. A third report describes genetic studies in 19 Chinese men with thyrotoxic periodic paralysis and compared them to evaluations in 48 thyrotoxic patients and 32 normal individuals [Ng et al., 2004]. No mutations were found in the calcium or sodium channel genes previously reported to cause hypokalemic periodic paralysis. Despite the close similarity between familial autosomal-dominant hypokalemic periodic paralysis and thyrotoxic periodic paralysis, there does not appear to be a common genetic basis for these disorders.

Clinical Laboratory Tests Measurement of thyroid function tests and the ECG are essential in establishing the diagnosis and in directing treatment. Other aspects of clinical laboratory evaluation are as described for familial hypokalemic periodic paralysis.

Treatment Treatment consists of antithyroid therapy until the patient achieves the euthyroid state. Preventive measures should be undertaken after treatment of the acute attack as described for primary familial hypokalemic periodic paralysis. Pro-

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pranolol is often effective in preventing attacks in thyrotoxic periodic paralysis [Ober, 1992; Yeung and Tse, 1974]. One recent report has emphasized the importance of propranolol as an initial treatment and has suggested caution about the use of potassium replacement [Tassone et al., 2004]. Acetazolamide is ineffective and may worsen or precipitate symptoms in thyrotoxic hypokalemic periodic paralysis and should be avoided [Moxley, 1994]. In general, beta-blocking drugs are helpful to use throughout the early stages of management until the patient becomes euthyroid.

MYOTONIC-LIKE DISORDERS AFFECTING PERIPHERAL AND CENTRAL NERVOUS SYSTEM OR THE BASEMENT MEMBRANE OF NEUROMUSCULAR JUNCTION AND CARTILAGE This section briefly considers those disorders that have myotonic-like skeletal muscle manifestations but have their primary defect in nonmuscle tissues. These disorders include Schwartz-Jampel syndrome [Aberfeld et al., 1965; Ho et al., 2003; Pascuzzi, 1991; Schwartz and Jampel, 1962], hereditary familial episodic ataxia type 1 [Brunt and

TABLE 83-6 Disorders of Central and Peripheral Nervous System Causing Myotonic-like Muscle Contractions CLINICAL FEATURES

STIFF PERSON SYNDROME

Inheritance Gene defect

Acquired Associated with elevated titers of antibodies against glutamic acid decarboxylase, the rate limiting enzyme for synthesis of γ-aminobutyric acid, the major inhibitory neurotransmitter in the brain. A subgroup of patients have antiamphiphysin autoantibodies of paraneoplastic origin Early to late adulthood Emotional stress and startle provoke sudden episodic muscle spasms; predominantly affects spinal and lower extremity muscles; females more than males 2:1; paraneoplastic variant occurs with breast cancer

Age of onset Main findings

ACQUIRED GENERALIZED PERIPHERAL NERVE HYPEREXCITABILITY

HEREDITARY FAMILIAL EPISODIC ATAXIA TYPE 1

Acquired Associated with autoantibody-mediated or autoimmune-associated disorders that have antibodies against voltage-gated potassium channels; also associated with certain toxins, e.g., timber rattlesnake venom

Autosomal dominant Chromosome 12p13; mutations identified in voltage-gated potassium channel gene, KCNA1

Childhood to late adulthood Infancy or childhood Muscle twitching, cramps, stiffness, delayed Episodic brief attacks (seconds to muscle relaxation after contraction, minutes) of ataxia, dysarthria, and spontaneous carpal or pedal spasm occurs; rippling muscles (myokymia) hyperhydrosis common; one third have occur; muscle hypertrophy, joint distal paresthesias contractures, skeletal deformity, and postural abnormalities may develop Myotonia Electromyography during the muscle Delayed muscle contractions and Electromyography usually reveals spasms indicates normal motor units spontaneous snakelike muscle movements ongoing myokymic discharges that discharge in a pattern of occur in association with myokymic even in the absence of clinical spasmodic reflex myoclonus; affects and/or neuromyotonic discharges on signs of myokymia or delayed agonist and antagonist muscles electromyography; these discharges persist muscle contraction; simultaneously; transcranial magnetic during sleep and general anesthesia but neuromyotonic discharges also stimulation demonstrates enhanced disappear following curare blockade occur motor cortex excitability Provocative stimuli Emotional stimuli; sudden noise; Exercise or muscle contraction (voluntary Strenuous exercise, emotional stress, gentle skin stimulation or electrically evoked) sudden limb movement, startle, and elevated body temperature or local elevation of temperature (hot bath, hair dryer) Therapy for symptoms Symptomatic treatment with Symptomatic treatment with carbamazepine Symptomatic treatment with γ-aminobutyric acid-enhancing and phenytoin; plasma exchange or carbamazepine and phenytoin agents (benzodiazepines, valproate, intravenous immunoglobulin infusions as vigabatrin, tigabine, gabapentin, short-term treatment; long-term baclofen; immunotherapy immunotherapy (corticosteroids, other); (corticosteroids, other); treat specific toxins or other associated plasmapheresis, periodic intravenous diseases immunoglobulin infusions

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van Weerden, 1990; Gancher and Nutt, 1986], acquired generalized peripheral nerve hyperexcitability [Gamstorp and Wohlfart, 1959; Hart, 2000; Hart et al., 2002; Isaacs, 1961], and stiff person syndrome [Dalakas et al., 2000; Koerner et al., 2004; Moersch and Woltman, 1956; Murinson et al., 2004]. Table 83-6 summarizes their characteristics and treatments. Schwartz-Jampel syndrome and episodic ataxia type 1 occur early in childhood, whereas acquired generalized peripheral nerve hyperexcitability, which usually presents in adults, occasionally has an onset in childhood or adolescence. Stiff person syndrome presents almost exclusively in adults, but in principle the underlying pathophysiologic process can occur in children. Clinical features, especially the characteristics of the muscle contractions and the associated electromyographic findings, distinguish the myotonic-like disorders from the primary myotonic diseases and the periodic paralyses. Below are highlights of the clinical findings and comments about treatment that complement the information provided in Table 83-6.

Schwartz-Jampel Syndrome Clinical Features The phenotype of Schwartz-Jampel syndrome has considerable variability. Severe forms appear in infancy and milder forms usually develop manifestations between 2 and 3 years of age [Ho et al., 2003; Pascuzzi, 1991]. Patients have a short neck, protuberant abdomen, and sparse subcutaneous tissue. Joint contractures develop, along with a typical facial appearance (small palpebral fissures, pursed lips, low hairline, and low-set ears). The abnormal facies becomes increasingly prominent with age. The bony abnormalities, such as pectus carinatum, kyphoscoliosis, pes planus, hip dysplasia, platybasia, and flattened small vertebrae often are apparent early in the disease. Patients have a stooped posture with their shoulders flexed forward. Muscle hypertrophy and hirsutism are common. Orthopedic consultation may precede neurologic evaluation, and comments by a radiologist about the spinal x-ray appearance may point to the diagnosis of Schwartz-Jampel syndrome. On neurologic examination the combination of action and percussion myotonia, hyporeflexia, typical facies and body appearance, and electromyographic evidence of continuous muscle fiber activity (high frequency discharges occurring both at rest and exacerbated by muscle contraction) is diagnostic for Schwartz-Jampel syndrome. The electromyographic findings differ from classic myotonic discharges that disappear at rest, have a lower frequency, and wax and wane [Huttenlocher et al., 1969; Taylor et al., 1972]. Local infusion of curare abolishes continuous discharges in some patients [Cadilhac et al., 1975; Edwards and Root, 1982; Taylor et al., 1972]. This finding supports the hypothesis that the electrical discharges are neural or neuromuscular junction mediated [Arikawa-Hirasawa et al., 2002].

Genetics Genetic heterogeneity accompanies the phenotypic variability in Schwartz-Jampel syndrome [Arikawa-Hirasawa et al., 2002; Brown et al., 1997; Fontaine et al., 1996; Giedion et al., 1997; Nicole et al., 2000] as indicated in Table 83-6.

One type of Schwartz-Jampel syndrome (type 1A and type 1B) is linked to chromosome 1p34-36 [Al Gazali et al., 1996; Arikawa-Hirasawa et al., 2002; Fontaine et al., 1996; Giedion et al., 1997; Brown et al., 1997; Nicole et al., 2000] and the other (Schwartz-Jampel syndrome type 2) is not linked to this locus [Brown et al., 1997]. Mutations in the perlecan gene (HSPG2) are responsible for most cases of Schwartz-Jampel syndrome [ArikawaHirasawa et al., 2002; Nicole et al., 2000]. Perlecan is a large heparan sulfate proteoglycan and is a component of the basement membrane [Brown et al., 1997; Costell et al., 1999; Friedrich et al., 1999; Iozzo et al., 1994]. Evidence supports the hypothesis that a deficiency of perlecan causes Schwartz-Jampel syndrome and that complete absence of perlecan causes a severe neolethal condition, SilvermanHandmaker disorder [Arikawa-Hirasawa et al., 2001, 2002].

Pathophysiology The electrophysiologic evidence noted earlier that suggests that the hyperexcitability of nerve-muscle transmission in Schwartz-Jampel syndrome relates to alterations at the neuromuscular junction secondary to a deficiency of perlecan. Recent evidence indicates that perlecan is a key molecule for localizing acetylcholine esterase at the synapse of the neuromuscular junction [Arikawa-Hirasawa et al., 2002; Peng et al., 1999]. Studies of muscle biopsies of Schwartz-Jampel syndrome patients demonstrate nonspecific alterations in muscle fibers on typical histochemical staining but have weak immunostaining of perlecan with domain-specific antiperlecan antibodies [Arikawa-Hirasawa et al., 2002]. It seems likely that a deficiency of perlecan at the neuromuscular junction in Schwartz-Jampel syndrome allows sufficient but altered regulation of neuromuscular transmission. This alteration in turn leads to continuous muscle fiber activity and myotonic-like muscle contractions. Absence of perlecan in contrast may not permit sufficient neuromuscular transmission and in turn accounts for the rapid demise of the patient and the lack of clinical signs of myotonic-like muscle contractions.

Treatment Therapy in Schwartz-Jampel syndrome is supportive and focuses on specific symptoms and potential complications. Orthopedic consultation and physical and occupational therapy are necessary to treat the bony deformities and contractures. Carbamazepine (20 mg/kg/day in infants [Squires and Prangley, 1996; Topaloglu et al., 1993] and 600 mg of extended release twice daily in older children [Ho et al, 2003]) is effective in controlling the myotonia and continuous muscle fiber activity. Procainamide is another potential antimyotonia treatment [Huttenlocher et al., 1969] and phenytoin may provide a modest benefit [Edwards and Root, 1982; Taylor et al., 1972]. Response to other antimyotonia drugs, such as mexiletine, has not been reported. Some patients require nasal bilevel positive airway pressure for obstructive sleep apnea [Cook and Borkowski, 1997] and some benefit from levator aponeurosis surgery [Cruz et al., 1998]. Anesthesiology consultation before surgery is prudent, since difficulty with intubation [Cook and Borkowski, 1997] and malignant hyperthermia [Ho et al., 2003; Seay and Ziter, 1978] are potential complications.

Moxley and Tawil / Channelopathies: Myotonic Disorders and Periodic Paralysis

Hereditary Familial Episodic Ataxia Type 1 Clinical Features The classic description of episodic ataxia type 1 includes the appearance of sudden episodes of cerebellar ataxia, lasting a few minutes, often provoked by startle, and beginning in childhood [Brunt and van Weerden, 1990; Gancher and Nutt, 1986]. Some patients display prominent myokymia [Hanson et al., 1977; Vaamonde et al., 1991; Van Dyke et al., 1975]. However, recent clinical studies demonstrate that there is considerable phenotypic variation in episodic ataxia type 1 [Eunson et al., 2000; Kinali et al., 2004; Klein et al., 2004]. Some patients have grip myotonia, muscle stiffness, limited jaw opening, contractures (elbows and ankles), muscle hypertrophy, and kyphoscoliosis [Kinali et al., 2004], a clinical picture that resembles the childhood form of Schwartz-Jampel syndrome. Some individuals within a kindred only display seizures and have no episodes of ataxia or muscle stiffness [Eunson et al., 2000]. In contrast, one report describes a patient with prolonged episodes (10 to 12 hours in duration) of painful muscle stiffness triggered by fever and exertion associated with wrist flexion, thumb adduction, and myokymia in the periorbital muscles [Klein et al., 2004]. Ataxia was not a feature of these episodes. Dysarthria and double vision along with swelling of the feet occurred at the onset of attacks in this patient [Klein et al., 2004]. Tendon reflexes may be diminished, normal, or hyperactive. Electromyographic studies reveal continuous myokymic discharges and occasional neuromyotonic discharges [Gutmann and Gutmann, 2004]. Nerve conduction is normal. Usually the clinical picture and the family history of a dominantly inherited episodic disorder confirm the diagnosis.

Genetics and Pathophysiology Episodic ataxia type 1 links to mutations in the KCNA1 gene on chromosome 12p13 that encodes the Shaker-type potassium channel subunit hKv1.1 [Litt et al., 1994]. There are at least five mutations associated with episodic ataxia type 1 [Eunson et al., 2000; Kinali et al., 2004; Klein et al., 2004; Rea et al., 2002]. Recent evidence suggests that the specific molecular defect and the phenotype vary with the location of the mutation [Imbrici et al., 2003; Klein et al., 2004; Rea et al., 2002]. Mutations that cause typical episodic ataxia type 1 (V4041, I177N) or neuromyotonia (P244H) alone are associated with altered kinetics of the potassium channel [Imbrici et al., 2003; Rea et al., 2002]. A mutation (R417stop) that causes a severe medicationresistant form of episodic ataxia type 1 impairs both tetramerization of the R417stop with the wild type of hKv1.1 subunits and the membrane targeting of the heterotetramers. Two other mutations (T226R, A242P) that lead to a severe phenotype of episodic ataxia type 1, including seizures, produce a combination of defects in channel assembly, membrane trafficking, and abnormal channel kinetics [Rea et al., 2002]. Another mutation, which involves a single nucleotide change at position 785 T>C, causes prolonged (10 to 12 hours), painful episodes of stiffness triggered by fever and exertion. These clinical findings [Klein et al., 2004] are similar to those in patients with antibody-mediated acquired

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generalized peripheral nerve hyperexcitability [Hart et al., 2002], and have led the investigators to hypothesize that the 785 T>C mutation causes channel dysfunction similar to that in the autoimmune disorder [Klein et al., 2004]. Further research is necessary to establish phenotype-genotype relationships.

Treatment Therapy is symptomatic. Reducing opportunities for stress, startle, and overexertion lessen the frequency of episodes. Physical therapy and orthopedic consultation are helpful in patients with contractures. Acetazolamide may reduce episodes of ataxia, but carbamazepine is necessary to control muscle stiffness and myokymia [Klein et al., 2004]. Phenytoin can also ameliorate myokymia and stiffness [Kinali et al., 2004].

Acquired Generalized Peripheral Nerve Hyperexcitability Clinical Findings Acquired generalized peripheral nerve hyperexcitability represents a heterogeneous group of disorders that have included diagnoses such as Isaacs’ syndrome, crampfasciculation syndrome, and neuromyotonia [Gutmann and Gutmann, 2004; Hart, 2000; Hart et al., 2002; NewsomDavis et al., 2003]. Autoimmune, toxic, degenerative, and hereditary forms are included in the classification [Hart et al, 2002]. The core clinical symptoms are muscle twitching, exercise triggered muscle cramps, and muscle stiffness [Hart et al., 2002]. Delayed relaxation after muscle contraction (pseudomyotonia) occurs less commonly (36%) [Hart et al., 2002]. Acquired generalized peripheral nerve hyperexcitability is very uncommon in childhood. In a recent series of 42 patients, only 3 patients were younger than 20 years of age (5, 10, and 15 years of age) [Hart et al., 2002]. One of these patients developed symptoms in early childhood and went untreated for many years. He had growth retardation and presented for evaluation in a wheelchair with severe muscle stiffness and cramps that had been mistaken for spasticity. Patients typically have normoactive or diminished tendon reflexes, and approximately one third have sensory complaints. Excessive sweating is common (50%), but specific alterations of the autonomic nervous system are not. At the time of presentation most patients have muscle overactivity affecting the legs alone or legs and trunk combined [Hart et al., 2002]. Electromyography reveals spontaneous firing of motor units as doublet, triplet, or multiple discharges that have a high burst frequency (40 to 400 Hz) and in more than 90% of cases, the discharges occur at irregular intervals of 1 to 30 seconds [Hart, 2000]. Voluntary contractions or electrically evoked contractions often provoke prolonged after-discharges. Abnormal spontaneous activity can occur without visible myokymia. These discharges disappear after blockade of neuromuscular transmission and lessen or disappear in some patients after epidural anesthesia or proximal nerve block [Hart, 2000]. These findings support the hypothesis that the spontaneous discharges result from peripheral nerve hyperactivity [Hart, 2000; Hart et al., 2002].

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Pathophysiology Immune-related diseases, such as myasthenia gravis, diabetes mellitus, and rheumatoid arthritis, are more frequent in acquired generalized peripheral nerve hyperexcitability as is lung cancer. Approximately 40% of patients have antibodies to the voltage-gated potassium channel [Hart et al., 2002], and these antibodies appear to have a central role in the pathophysiology [Arimura et al., 2002; Hart et al., 2002; Tomimitsu et al., 2004]. Studies of cultured cell lines incubated with patient sera indicate there is antibodymediated suppression of outward-gated potassium current [Arimura et al., 2002; Tomimitsu et al, 2004]. Recent in vitro investigations using neuronal cell lines indicate that the reduction in potassium currents by antibodies to the voltagegated potassium channel is independent of added complement; however, F(ab′)2 fragments isolated from patient sera significantly reduce potassium currents. These findings make it likely that cross-linking of the voltage-gated potassium channels by divalent antibodies is an important mechanism in reducing the potassium current [Tomimitsu et al., 2004]. Other circulating factors cause acquired generalized peripheral nerve hyperexcitability, such as timber rattlesnake envenomation [Gutmann and Gutmann, 2004]. The venom enters the circulation, causing generalized myokymia involving the face and extremities. Symptoms abate within hours of administering antivenin therapy [Gutmann and Gutmann, 2004].

Treatment Carbamazepine and phenytoin are the primary symptomatic medications for the neuromyotonia and usually control symptoms of muscle overactivity [Hart, 2000]. In refractory cases or in the initial management of severe cases, plasma exchange [Hart, 2000; Hayat et al., 2000; Newsom-Davis et al., 2003] or immune globulin infusion [Alessi et al., 2000; Hart, 2000; Newsome-Davis et al., 2003] may produce rapid resolution of symptoms. Prednisone and azathioprine may prove useful for long-term treatment, as well as other immunosuppressive agents [Hart, 2000; Newsom-Davis et al., 2003], but long-term controlled trials are necessary to confirm this clinical impression.

Stiff Person Syndrome Clinical Findings Stiff person syndrome is a rare neurologic disorder with autoimmune features. Its primary manifestation is progressive, severe muscle rigidity or stiffness, most prominently affecting the spine and lower extremities [Dalakas et al., 2000; Murinson et al., 2004; Rakocevic et al., 2004]. Occasionally the muscle stiffness may resemble myotonia with a delay in relaxation, but the typical manifestations in skeletal muscle are readily distinguished from true myotonia. In stiff person syndrome there is an insidious onset of muscular rigidity in limb and axial musculature [Dalakas et al., 2000]. The stiffness is most prominent in the abdominal and thoracolumbar muscles and causes difficulty in turning and bending. Electromyographic recordings demonstrate

that there is continuous co-contraction of agonist and antagonist muscles, and the patient is unable to relax. Episodic muscle spasms that may occasionally resemble myotoniclike contractions are superimposed on this rigidity and are precipitated by unexpected noises, tactile stimuli, or emotional stress. These manifestations occur in the absence of any other neurologic disease or underlying chronic pain syndrome that might produce prolonged muscle rigidity and spasms. Many patients have an elevated titer of antibodies to glutamic acid decarboxylase antibodies, and they often have diabetes or other autoimmune diseases [Dalakas et al., 2000; Koerner et al., 2004; Lohmann et al., 2003; Murinson et al., 2004; Rakocevic et al., 2004]. Uncommonly, in perhaps 5% of stiff person syndrome patients there is a paraneoplastic origin for the illness associated with antibodies against amphiphysin [Petzold et al., 2004]. Stiff person syndrome is rare in children. One recent study of 116 stiff person syndrome patients with elevated levels of glutamic acid decarboxylase antibodies included only 1 teenage patient; the remaining 115 patients were older than 30 years of age [Murinson et al., 2004]. In an earlier study of 20 selected patients the average age was 41.2 years [Dalakas et al., 2000], and in another recent report of 16 patients with stiff person syndrome the ages ranged from 37 to 62 years, with a median age of 52 years [Rakocevic et al., 2004].

Pathophysiology Electromyographic investigations in patients with stiff person syndrome disclose the presence of low-frequency firing of normal motor units, especially in the muscles of the trunk, which increases for seconds or minutes to a dense pattern during a spontaneous or provoked muscle spasm [Koerner et al., 2004; Martinelli et al., 1996; Meinck et al., 1995]. These bursts of electrical activity are highly variable in location, duration, and intensity. Investigators have described a stereotyped motor response to stimulation of peripheral nerves in stiff person syndrome patients that consists of a sequence of one to three synchronous myoclonic bursts, 60 to 70 milliseconds after median nerve stimulation, followed by tonic decrescendo activity over a number of seconds [Meinck et al., 1995]. They call this response spasmodic reflex myoclonus, and have used it to explain certain aspects of the pathophysiology of stiff person syndrome. They speculate that the stiffness is a fragment of spasms and that both are due to a common neuronal mechanism of abnormal regulation of interneurons in the spinal gray matter [Meinck et al., 1995]. Other studies support this mechanism and suggest an important role for motor cortex hyperexcitability in stiff person syndrome [Koerner et al., 2004; Martinelli et al., 1996]. The most recent study using transcranial magnetic stimulation methodology points out that the elevation of glutamic acid decarboxylase antibodies directly correlates with the enhanced cortical excitability and that γaminobutyric acid–mimetic medications reduce intracortical facilitation [Koerner et al., 2004]. These observations suggest a clear role for glutamic acid decarboxylase antibodies in mediating the stiffness and muscle spasms. However, the precise pathophysiologic role of glutamic acid decarboxylase antibodies in stiff person syndrome requires further investigation [Dalakas et al., 2001b].

Moxley and Tawil / Channelopathies: Myotonic Disorders and Periodic Paralysis

One recent study of 16 adults with stiff person syndrome notes that there is no correlation between the glutamic acid decarboxylase antibody titers in serum or cerebrospinal fluid and the severity of disease [Rakocevic et al., 2004]. The authors emphasize that an elevation of glutamic acid decarboxylase antibodies serve as an excellent marker for stiff person syndrome, but monitoring their titers during the course of the disease may not have practical value. Another recent study stresses the importance of establishing an appropriate threshold elevation of glutamic acid decarboxylase antibodies before making a diagnosis of stiff person syndrome [Murinson et al., 2004] because nonaffected individuals, such as some diabetic people, may have modest elevations of glutamic acid decarboxylase antibodies. This study also notes that elevation of glutamic acid decarboxylase antibodies do not correlate with the age or duration of stiff person syndrome [Murinson et al., 2004]. It is interesting to note that two children born to two different mothers with stiff person syndrome had high titers of glutamic acid decarboxylase antibodies for the first 24 months of life, and having reached the ages of 6 and 8 years have not had any manifestations of stiff person syndrome [Nemni et al., 2004]. Clinical criteria remain the benchmark for the diagnosis of stiff person syndrome [Chang and Lang, 2004].

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CHAPTER 84

Endocrine Disorders of the Hypothalamus and Pituitary Qing Dong and Stephen M. Rosenthal

Through integrated neural and hormonal signaling, the hypothalamus and pituitary regulate a broad range of physiologic processes, including statural growth, sexual maturation, lactation, metabolic actions ascribed to adrenal (glucocorticoid) and thyroid hormones, appetite, and water balance. Each of these physiologic processes involves hypothalamic/pituitary regulation of a variety of target tissues, which in turn, regulate hypothalamic/pituitary function through feedback loops. Although a comprehensive endocrine approach to abnormalities of any of these physiologic loops or axes requires consideration of disorders intrinsic to the hypothalamus/pituitary or intrinsic to the target tissues, this chapter will focus on those disorders specifically caused by endocrine abnormalities of the hypothalamus and pituitary. An overview of hypothalamic/pituitary anatomy and physiology is followed by a review of endocrine disorders of these structures grouped by principal signs and symptoms.

ANATOMIC AND PHYSIOLOGIC ASPECTS The hypothalamus, the ventral part of the diencephalon, is an evolutionarily conserved region of the mammalian brain. The hypothalamus is separated by the third ventricle and connected to the pituitary by the hypophysial stalk. The hypothalamus functions as the primary control center for a variety of physiologic processes, integrating neural and hormonal signaling. Hypothalamic nuclei are not welldemarcated regions; however, these cell groups in the walls of the third ventricle possess specific physiologic functions [Pansky et al., 1988]. The supraoptic and paraventricular nuclei produce arginine vasopressin (also known as antidiuretic hormone) and oxytocin. Paraventricular nuclei and arcuate nuclei release thyrotropin-releasing hormone, corticotropin-releasing hormone, somatostatin, growth hormone-releasing hormone, gonadotropin-releasing hormone, and dopamine into the hypophysial portal circulation to regulate the synthesis and release of anterior pituitary hormones. In addition, hypothalamic neurons that regulate appetite and energy balance are also located in the paraventricular and arcuate nuclei of the hypothalamus, such as pro-opiomelanocortin and neuropeptide Y and agouti-related protein–expressing neurons [Cone et al., 2003]. The pituitary (hypophysis) is housed in the sella turcica, and, as noted, is attached to the hypothalamus by the hypophysial stalk. The stalk, also called the infundibulum, is a collective term for the median eminence (the most inferior extension of the tuber cinereum), and the infundibular stalk (a hollow process extending from the tuber cinereum to the

posterior hypophysis). The stalk serves as an anatomic and functional link between the hypothalamus and the pituitary. The optic chiasm is situated directly anterior to the pituitary stalk (Fig. 84-1). The pituitary itself is small, weighing an average of about half a gram, and is divided into the anterior lobe (adenohypophysis), the posterior lobe (neurohypophysis), and a vestigial intermediate lobe. Six hormones—growth hormone, thyroid-stimulating hormone, adrenocorticotropin hormone, follicle-stimulating hormone, luteinizing hormone, and prolactin—are synthesized and stored in the anterior lobe from well-differentiated distinct cell types (somatotrophs, thyrotrophs, corticotrophs, gonadotrophs, and lactotrophs). However, some cell types, such as mammosomatotrophs, can express multiple hormones (prolactin and growth hormone). The neurohypophysis synthesizes, stores, and secretes arginine vasopressin and oxytocin [Cone et al., 2003]. The blood supply in the hypothalamic-pituitary-portal system allows bidirectional hypothalamic-pituitary hormonal interaction. The superior hypophysial arteries from the internal carotid arteries form a primary plexus in the median eminence. These vessels travel down to the anterior pituitary as the major blood supply. The hypothalamicpituitary-portal circulation carries the hypothalamicreleasing and hypothalamic-inhibiting hormones to the adenohypophysis. Retrograde blood flow within the internal capillary plexus (gomitoli) derived from the stalk branches of the superior hypophysial arteries provides local hormonal feedback to the hypothalamus. The blood supply for the posterior pituitary gland is derived from the inferior hypophysial arteries, in turn, derived from the internal carotid arteries [Bergland and Page, 1979; Stanfield, 1960]. Organogenesis of the hypothalamus and the pituitary is a complex process. The alar plates from the myelencephalon form the lateral walls of the diencephalon. During brain development the hypothalamic sulcus divides the alar plates into dorsal and ventral regions. The hypothalamus, as part of the lower and ventral portion of the alar plates, differentiates into hypothalamic nuclei that serve as control centers for life-sustaining physiologic processes. The pituitary, however, develops from two distinct areas. The adenohypophysis derives from the oral ectoderm (Rathke’s pouch), and the neurohypophysis is a downward extension of the diencephalon [Sadler, 1990]. Since the mid 1990s, significant progress has been made in our understanding of the molecular events that regulate embryogenesis of the adenohypophysis. Bone morphogenic protein-4 and fibroblast growth factor-8 are critical for anterior pituitary gland development. In addition, differentiation of anterior pituitary cell types requires a spatiotemporally regulated cascade of homeodomain transcription factors. Several

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Neuroendocrine and Autonomic Nervous System Disorders / 84 FIGURE 84-1. Coronal (A) and sagittal (B) T1-weighted images of normal hypothalamus/pituitary in an 8-year-old female by MRI. Note the location of the pituitary stalk, and the intense bright signal from the posterior pituitary (bright spot) in the sagittal view.

A

B

pituitary-specific transcription factors, such as Lhx3/Lhx4 (LIM homeobox-3 and -4), Rpx (Rathke’s pouch homeobox, also known as Hesx1), Pitx (pituitary homeobox), Prop-1, Pit-1, and Sox3, are important determinants of pituitary cell lineages. Mutations in these transcription factors can lead to either isolated or combined pituitary hormone deficiencies with or without detectable anatomic abnormalities [Cohen and Radovick, 2002; Dattani et al., 1998, 2000; Rizzoti et al., 2004].

HYPOTHALAMIC/PITUITARY DISORDERS OF PUBERTAL DEVELOPMENT Normal Physiology of Puberty and Adrenarche Puberty is the transitional period between the juvenile state and adulthood, characterized by attainment of secondary sex characteristics and reproductive capability. The control center of puberty is composed of hypothalamic gonadotropinreleasing hormone neurosecretory neurons (pulse generator) located in the medial basal hypothalamus [King et al., 1985]. Puberty is not a sudden event but rather reflects a milestone on a continuum that begins before birth. The gonadotropinreleasing hormone pulse generator becomes pulsatile by midgestation, and remains active in early infancy until about 6 months of age in males and 12 to 24 months in females [Grumbach, 2002]. Between late infancy and the onset of puberty, the gonadotropin-releasing hormone pulse generator becomes relatively quiescent as a consequence of an as yet poorly defined central nervous system (CNS) inhibitory mechanism. After a quiescent period of approximately 10 years, the gonadotropin-releasing hormone pulse generator is disinhibited, leading to increased amplitude and frequency of luteinizing hormone and follicle-stimulating hormone secretion resulting in increased sex steroid production (principally estradiol and testosterone) and attainment of physical puberty [Grumbach, 2002].

Adrenarche refers to the prepubertal rise of adrenal androgen precursors, in particular dehydroepiandrosterone and its sulfated form, as a consequence of maturation of the zona reticularis of the adrenal cortex. Dehydroepiandrosterone can be peripherally converted to testosterone, thus adrenarche is clinically typified by mild androgenic effects, such as a change in body odor and the appearance of axillary and pubic hair and acne. The mechanisms that regulate adrenarche are not well understood. Adrenache is independent of the maturation of the hypothalamic-pituitarygonadal axis, preceding the onset of puberty by about 2 years [Miller, 1999]. The normal age of onset of secondary sexual characteristics (defined as 2.5 standard deviations on either side of the mean, or where approximately 99% of the population falls) is 6 to 13 years in females and 9 to 14 years in males. The appearance of secondary sexual characteristics, acceleration of growth, and the capacity of reproduction are hallmarks of puberty. The development of puberty is characterized by sequential events that are specific for each sex. In females, secondary sexual characteristics include breast development, the appearance of pubic and axillary hair, maturation of the labia, and estrogenization of the vaginal mucosa. The development of pubic and axillary hair is influenced by androgens produced in both the adrenal cortex (adrenarche) and the ovary. Menarche usually occurs 2 to 3 years after initiation of breast development. The pubertal growth spurt, which normally occurs in the early stages of puberty for females, can result in a gain in height of 25 cm or more. In males, puberty begins with testicular enlargement (≥2.5 cm in longest dimension) followed by the appearance of sexual hair and phallic enlargement. The growth spurt occurs during midpuberty, which results in an average 28 cm gain in height [Grumbach and Styne, 2003]. General abnormalities of puberty include sexual precocity and delayed or arrested puberty, each with a broad differential diagnosis. Although pubertal disorders can arise from defects at the level of the hypothalamus, pituitary, or

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gonads, the focus of this discussion is on hypothalamic and pituitary causes of sexual precocity and delayed puberty.

Sexual Precocity Sexual precocity is usually defined as the development of secondary sexual characteristics before 7 years of age in females [Herman-Giddens et al., 1997], and before 9 years of age in males. In all cases thus far described, sexual precocity results from an increase in circulating sex steroids. An endocrine approach to the differential diagnosis of sexual precocity would include consideration of exogenous and endogenous sources of these steroids. Endogenous causes include the gonads and adrenal cortex, either of which may inappropriately secrete sex steroids as the result of a primary process intrinsic to these tissues, or secondary to a circulating stimulatory factor. As previously noted, this chapter focuses only on hypothalamic/pituitary causes of sexual precocity. Precocious puberty (sometimes referred to as true or central precocious puberty) is defined as early puberty specifically resulting from premature reactivation of the gonadotropin-releasing hormone pulse generator. Precocious puberty is most commonly idiopathic but can result from a broad range of abnormalities, including CNS tumors, hamartoma of the tuber cinereum, congenital malformations, subarachnoid cysts, CNS infection, irradiation, and trauma. The incidence of precocious puberty is significantly higher in females. In studies of females with precocious puberty, idiopathic precocious puberty ranges from 63% to 74% [Cisternino et al., 2000; Pescovitz et al., 1986]. In contrast, precocious puberty is idiopathic in only 6% of males with this condition [Pescovitz et al., 1986]. Idiopathic precocious puberty is a diagnosis of exclusion and it is thus essential to search for underlying neurologic causes. Tumors involving in the posterior hypothalamus, such as glioma, germinoma, and teratoma can cause precocious puberty. Most of these tumors are thought to trigger early puberty by interfering with mechanisms that normally inhibit the gonadotropin-releasing hormone pulse generator. Few luteinizing hormone/ follicle-stimulating hormone–secreting adenomas have been reported in adults, [Demura et al., 1977; Sassolas et al., 1988]; however, they are extremely rare in children [Tashiro et al., 1999]. Hamartoma of the tuber cinereum, a congenital malformation, can cause central precocious puberty. Hamartomas are small lesions (4 to 25 mm), may be sessile or pedunculated, and usually do not enlarge with time (Fig. 84-2). Histologically, they appear to be composed of normal brain tissue and contain gonadotropin-releasing hormone secretory neurons, which may serve as an “ectopic pulse generator” [Mahachoklertwattana et al., 1993]. In some hypothalamic hamartomas, the production of transforming growth factor α can initiate early puberty by activating the normal gonadotropin-releasing hormone pulse generator [Jung et al., 1999]. Hamartomas of the tuber cinereum are often associated with gelastic (laughing) seizures. Ectopic human chorionic gonadotropin–secreting tumors in the CNS (and elsewhere), for example, hypothalamic germinomas, can cause sexual precocity in males [Sklar et al., 1981]. Such patients do not have pituitary gonadotropindependent precocious puberty in that they do not have

FIGURE 84-2. Hamartoma of the tuber cinereum in a 3-year-old female by MRI. Note a small (6 × 6 mm), pedunculated and isointense hypothalamic mass in the sagittal view. The patient had midpubertal breast development, and an advanced bone age of 6 years at a chronologic age of 3 years.

premature reactivation of the hypothalamic gonadotropinreleasing hormone pulse generator. Rather, the ectopic human chorionic gonadotropin interacts with the luteinizing hormone/human chorionic gonadotropin receptor on testicular Leydig cells, resulting in increased testosterone secretion and virilization. In females, ovarian estrogen secretion requires both luteinizing hormone and folliclestimulating hormone. Thus, ectopic secretion of human chorionic gonadotropin alone causes sexual precocity almost exclusively in boys [Grumbach and Styne, 2003]. The accurate diagnosis of precocious puberty and its cause requires detailed history, physical examination, hormonal testing, and imaging studies of the CNS. Idiopathic precocious puberty is often familial. The occurrence of early breast and pubic hair development is often seen in females with precocious puberty, and testicular enlargement and other signs of virilization are seen in males with precocious puberty. Hormonal analysis demonstrates increased amplitude and frequency of luteinizing hormone and follicle-stimulating hormone pulsatile secretion, resulting from increased pulsatile secretion of gonadotropinreleasing hormone. This finding can be demonstrated either by serial sampling of luteinizing hormone and folliclestimulating hormone or by single luteinizing hormone/ follicle-stimulating hormone measurements using highly sensitive immunochemiluminescent assays. Dynamic testing using gonadotropin-releasing hormone or a gonadotropinreleasing hormone agonist is also routinely used to diagnose precocious puberty. Magnetic resonance imaging (MRI)

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with particular attention to the hypothalamic-pituitary area should be carried out in any child diagnosed with precocious puberty.

Management If a CNS lesion that causes precocious puberty is identified, an appropriate treatment plan for that lesion should be developed. Previously, treatment of hamartomas of the tuber cinereum was principally surgical. However, such treatment carried a significant risk of morbidity and mortality [Rosenfeld et al., 2001; Valdueza et al., 1994]. A long-term follow-up study demonstrated an excellent response to gonadotropin-releasing hormone agonist without surgical resection [Mahachoklertwattana et al., 1993]. Rarely, after treatment of CNS disorders causing precocious puberty, the rapid progression of pubertal development is reversed or arrested. More commonly, once puberty has been initiated, it will often continue despite intervention to address a primary CNS disorder. Such patients require treatment to suppress the hypothalamic-pituitary-gonadal axis. Stateof-the-art treatment consists of administration of a gonadotropin-releasing hormone agonist, which desensitizes pituitary gonadotropin-releasing hormone receptors, leading to suppression of the hypothalamic-pituitarygonadal axis [Breyer et al., 1993]. This treatment is commonly given by a monthly depot intramuscular injection. Long-term studies demonstrate resumption of normal puberty after discontinuation of gonadotropin-releasing hormone agonist [Feuillan et al., 2001].

Delayed or Arrested Puberty Delayed puberty may be defined in males by the absence of testicular enlargement by 14 years of age, and in females by the absence of breast development by 13 years of age. The differential diagnosis of delayed puberty can be divided into three major categories: constitutional delay in growth and development, hypogonadotropic hypogonadism, and hypergonadotropic hypogonadism. Constitutional delay in growth, the most common cause of delayed puberty, is a normal variant, and is thought to result from a prolonged quiescent period of the gonadotropin-releasing hormone pulse generator. Such patients often have a family history of delayed puberty and have delayed skeletal maturation without evidence of endocrinopathy or other organic diseases. Hypergonadotropic hypogonadism, which indicates a defect at the level of the gonads, is not reviewed in this section. Hypogonadotropic hypogonadism indicates a defect at the level of the hypothalamus or pituitary, and may result from a variety of CNS disorders that can lead to delayed or absent puberty. Hypogonadotropic hypogonadism can be congenital or acquired, can occur alone or in association with multiple hypothalamic and pituitary hormone deficiencies, and may be organic or functional in etiology.

Isolated Congenital Hypogonadotropic Hypogonadism The most common form of isolated gonadotropin deficiency is Kallmann’s syndrome (olfactory-genital-dysplasia), which occurs in 1 in 10,000 males and 1 in 50,000 females

[Rugarli and Ballabio, 1993]. Considerable genetic heterogeneity exists for Kallmann’s syndrome. Classic Kallmann’s syndrome is transmitted in an X-linked or autosomaldominant fashion with variable penetrance, characterized by hypogonadotropic hypogonadism and anosmia/hyposmia. Some patients may also have unilateral renal agenesis, synkinesia (mirror movements), and pes cavus. Mirror movements occur in 85% of patients with classic Kallmann’s syndrome, associated with bilateral hypertrophy of the corticospinal tract [Krams et al., 1999]. Mutations in the KAL1 gene account for half of males with X-linked hypogonadotropic hypogonadism [Hardelin et al., 1993] and 5% of sporadic cases [Georgopoulos et al., 1997]. The KAL1 gene resides close to the pseudoautosomal region of the X-chromosome. The cause in females is unknown. The concurrence of anosmia/hyposmia and hypogonadism may reflect disruption of comigration of gonadotropin-releasing hormone and olfactory neurons from the olfactory placode into the hypothalamus during early embryonic development [Wray et al., 1989]. Lack of correlation between genotype and phenotype has been described in Kallmann’s syndrome. For instance, within the same family, one patient may have normal gonadal function and anosmia, whereas another may have hypogonadism and a normal sense of smell. However, isolated gonadotropin deficiency with normal sense of smell is rare. Another form of X-linked hypogonadotropic hypogonadism is associated with adrenal hypoplasia congenita due to defects of DAX1 (dose-sensitive sex reversal adrenal hypoplasia congenita–associated gene on the X chromosome). DAX1 encodes a transcription factor that appears to play key developmental roles in the hypothalamus, pituitary, gonad, and adrenal cortex. Males with DAX1 mutations who survive adrenal failure in infancy and early childhood can present with hypogonadotropic hypogonadism. Rarely, a mild mutation may present in adulthood with mild adrenal insufficiency and incomplete pubertal development. Females homozygous for a DAX1 nonsense mutation can present with isolated hypogonadotropic hypogonadism [Kalantaridou and Chrousos, 2002]. In addition, mutations in the ß subunits of follicle-stimulating hormone and luteinizing hormone have been reported in association with primary amenorrhea and hypogonadism [Kalantaridou and Chrousos, 2002]. Isolated hypogonadotropic hypogonadism on an autosomal basis is also found in patients with mutations in genes encoding the gonadotropin-releasing hormone receptor [Kalantaridou and Chrousos, 2002] and GPR54, a G protein–coupled receptor [Colledge, 2004; de Roux et al., 2003; Seminara et al., 2003]. Isolated gonadotropin deficiency also occurs in association with Prader-Willi syndrome and Laurence-Moon-Biedl syndrome [Crino et al., 2003; Hashimoto and Kumahara, 1979].

Hypogonadotropic Hypogonadism Associated with Multiple Hypothalamic/Pituitary Hormone Deficiencies Hypogonadotropic hypogonadism can also present in combination with other hypothalamic/pituitary hormone deficiencies. Human mutations of pituitary transcription factors known to cause delayed puberty include Prop-1 and Lhx3. Prop-1 (prophet of Pit-1) is a paired-like homeo-

Dong and Rosenthal / Endocrine Disorders of the Hypothalamus and Pituitary

domain transcription factor expressed only in the anterior pituitary. Combined pituitary hormone deficiencies caused by mutations in Prop-1 occur with an incidence of about 1 in 8000 births. Patients with mutations in Prop-1 have combined pituitary hormone deficiencies, which may include deficiencies of growth hormone, prolactin, thyroid-stimulating hormone, and gonadotropins. Such patients have hypogonadotropic hypogonadism in association with short stature and hypothyroidism [Wu et al., 1998]. Lhx3 is a LIM-type homeodomain protein. Mutations in Lhx3 have been associated with anterior pituitary hypoplasia and complete deficits of growth hormone, prolactin, thyroidstimulating hormone, and gonadotropins. Lhx3 mutations are also associated with decreased range of motion in the cervical spine [Netchine et al., 2000]. Other genetic factors that lead to delayed puberty include mutations of prohormone convertase-1, leptin, and leptin receptor genes. A defect in prohormone convertase-1 has been found to disrupt gonadotropin-releasing hormone processing and results in hypogonadotropic hypogonadism and obesity associated with impaired processing of insulin and proopiomelanocortin. Mutations in leptin and the leptin receptor are associated with a similar clinical picture of hypogonadotropic hypogonadism, hyperinsulinemia, and obesity [Beier and Dluhy, 2003; Kalantaridou and Chrousos, 2002]. Congenital midline defects of the CNS, such as septo-optic dysplasia, empty sella syndrome, and Rathke’s cyst are often associated with hypothalamic/pituitary dysfunction, which may include hypogonadotropic hypogonadism. The genetics of septo-optic dysplasia and its related pituitary hormone deficiencies are reviewed in detail in the section on hypothalamic/ pituitary disorders of statural growth. Numerous CNS lesions can lead to hypogonadotropic hypogonadism, including CNS tumors (primarily third ven-

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tricular), CNS infection, invasive diseases, cranial irradiation, and trauma. These CNS disorders often present with combined anterior and posterior pituitary hormone deficiencies. CNS tumors of the sella and parasellar region associated with multiple hypothalamic/pituitary hormone deficiencies include craniopharyngioma, pituitary adenomas, optic and hypothalamic gliomas, and germ cell tumors. Delayed or arrested puberty is the second most common presenting symptom of CNS tumors after headache. Craniopharyngiomas, the most common tumor of the sella and parasellar region in children, are slow-growing, spaceoccupying tumors (Fig. 84-3). Most patients present before their teenage years with headache, visual loss, and multiple hypothalamic/pituitary hormone deficits. Pituitary adenomas in children usually present as microadenomas with pituitary hormone hypersecretion. Nonsecreting adenomas in children are rare and are usually macroadenomas. Prolactinoma is the most common pituitary adenoma in the pediatric population and is frequently associated with delayed or arrested puberty. Nonsecreting macroadenomas also can cause delayed puberty, at least in part, through elevation of prolactin as a consequence of stalk compression [Kunwar and Wilson, 2001]. Cranial irradiation to the third ventricular area may also be associated with hypogonadotropic hypogonadism.

Functional Hypogonadotropic Hypogonadism Reproductive capability is intimately linked to nutritional and metabolic homeostasis. Chronic systemic disease, malnutrition, hypothyroidism, hypercortisolism, poorly controlled diabetes mellitus, and anorexia nervosa are known to cause delayed or arrested pubertal development as a consequence of hypogonadotropic hypogonadism. Functional gonadotropin deficiency may be associated with marijuana use and may occur in some female athletes and ballet dancers. In general, weight loss to less than 80% of ideal weight may result in functional gonadotropin deficiency.

Evaluation of Delayed or Arrested Puberty As part of an initial evaluation, basal gonadotropin levels (luteinizing hormone, follicle-stimulating hormone) should be measured. Elevated gonadotropins indicate primary ovarian or testicular failure, whereas low or normal gonadotropins indicate either constitutional delay or hypogonadotropic hypogonadism. A gonadotropin-releasing hormone stimulation test is often useful in distinguishing patients with constitutional delay from those with hypogonadotropic hypogonadism. If hypogonadotropic hypogonadism is strongly suspected, further evaluation to identify a specific etiology should be undertaken. An important aspect of the physical examination is evaluation of the sense of smell. Any patient with proven hypogonadotropic hypogonadism should have a thorough evaluation of all hypothalamic/pituitary hormones and should undergo an MRI with particular focus on the third ventricular area.

Management FIGURE 84-3. Craniopharyngioma in a child by MRI. Note a large suprasellar mass elevating the floor of the third ventricle.

Once the etiology of delayed or arrested puberty has been established, an appropriate treatment plan can be designed.

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For constitutionally delayed pubertal development, shortterm (3 to 6 months) sex steroid replacement may be useful to induce maturation of the gonadotropin-releasing hormone pulse generator. Permanent hypogonadotropic hypogonadism requires long-term sex hormone replacement. Testosterone for males can be administrated either by intramuscular injection or topically. Long-term hormonal therapy for females includes the use of estrogen and progestin cycling.

DISORDERS OF PROLACTIN SECRETION Normal Biochemistry and Physiology of Prolactin Prolactin was identified in humans in the early 1970s after the lactogenic acitivity of growth hormone was blocked by growth hormone antiserum. Prolactin is a 199–amino acid peptide synthesized in lactotroph cells, which constitute 15% to 25% of functioning anterior pituitary cells. Prolactin has homology to growth hormone and placental lactogen in its structure and function. Regulation of prolactin secretion is distinct from that of other anterior pituitary hormones. Prolactin is the only pituitary hormone that is predominantly regulated by the hypothalamus through an inhibitory mechanism mediated by dopamine via the hypothalamic-pituitary portal circulation. Other inhibitory factors include transforming growth factor β and endothelin-1, thought to act via paracrine mechanisms. Stimulatory factors include thyrotropin-releasing hormone, oxytocin, and vasoactive intestinal polypeptide. The principal physiologic functions of prolactin are enhanced mammary gland development during pregnancy and lactation. Prolactin may be increased through physiologic and pathologic mechanisms. Physiologic stimuli include pregnancy, lactation, stress, sleep, and exercise. Pathologic causes of hyperprolactinemia include prolactinomas, injury to the hypothalamic-pituitary stalk secondary to tumors or other CNS disease (infiltration, granuloma, irradiation, infection, trauma), a variety of systemic disorders, including chronic renal failure and cirrhosis, and a variety of drugs ranging from dopamine receptor blockers and dopamine synthesis inhibitors to oral contraceptives.

Clinical Features and Management of Hyperprolactinemia The principal clinical feature of hyperprolactinemia, regardless of the cause, is galactorrhea, which may be unilateral or bilateral. Other clinical features may include delayed or arrested puberty, amenorrhea in females, and gynecomastia in males. Prolactinoma is the most common tumor of the pituitary, comprising about 50% of anterior pituitary adenomas. Most prolactinomas are less than 1 cm in diameter, such as microprolactinomas, and normally do not cause significant mass effects. However, with macroprolactinoma, headache and visual disturbance can be the first presenting symptoms. Rarely, patients with macroprolactinoma present with hydrocephalus, cranial nerve palsies, and seizures [Colao et al., 1998]. If a prolactinoma is diagnosed, therapeutic options include medical management with dopamine agonists, sur-

gery, and adjunctive radiotherapy. Although medical management is often considered the principal intervention, numerous reports indicate that microprolactinomas can be removed surgically, though with variable recurrence rates. Macroprolactinomas are less likely to be cured surgically and often require chronic dopamine agonist treatment. Adjunctive radiotherapy has been considered beneficial in some patients with macroprolactinoma. The skill and experience of the surgeon clearly play a role in determining the optimal treatment and outcome.

HYPOTHALAMIC/PITUITARY DISORDERS OF GLUCOCORTICOID PRODUCTION The hypothalamic-pituitary-adrenal axis is responsible for glucocorticoid production by the zona fasciculata of the adrenal cortex. Adrenocorticotropic hormone is produced by pituitary corticotrophs in response to stimulation by hypothalamic corticotropin-releasing hormone. Adrenocorticotropic hormone increases adrenal production of cortisol, the principal glucocorticoid, by a cyclic adenosine monophosphate-dependent mechanism. Cortisol, in turn, regulates the production of both corticotropin-releasing hormone and adrenocorticotropic hormone through negativefeedback loops. An intact hypothalamic-pituitary-adrenal axis is essential for general homeostasis, including regulation of blood pressure and glucose, and for response to stress. Hypersecretion of pituitary adrenocorticotropic hormone leads to Cushing’s disease, whereas inadequate production of corticotropin-releasing hormone/adrenocorticotropic hormone causes adrenal glucocorticoid insufficiency.

Adrenocorticotropic Hormone Excess Excessive production of adrenocorticotropic hormone from the pituitary arises either from corticotrophin-releasing hormone overproduction or from a primary adrenocorticotropic hormone–producing adenoma (Cushing’s disease). The first sign of Cushing’s disease in a growing child is often impaired linear growth [Mindermann and Wilson, 1995]. Other classic signs and symptoms of Cushing’s disease include excessive weight gain (central obesity), buffalo hump, plethora, “moon facies,” acne, striae, hypertension, hirsutism, fatigue, pubertal delay or arrest, bruising, and headache [Devoe et al., 1997; Magiakou et al., 1994, 2002]. Usually, at the time of diagnosis, adrenocorticotropic hormone–producing adenomas are significantly smaller than other pituitary adenomas (Fig. 84-4). These tumors are usually not well demarcated and are often less than 10 mm in diameter (microadenoma). The diagnosis of Cushing’s disease can pose significant challenges. Endogenous hypercortisolism is either adrenocorticotropic hormone dependent or adrenocorticotropic hormone independent. Of the adrenocorticotropic hormone– dependent causes, a pituituary adenoma (Cushing’s disease) is most common. A less common adrenocorticotropic hormone–dependent cause is ectopic adrenocorticotropic hormone production associated with a variety of extrapituitary neoplasms. Adrenocorticotropic hormone–independent causes of hypercortisolism are rare in the pediatric

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FIGURE 84-4. Adrenocorticotropic hormone–secreting pituitary adenoma in a 15-year-old female by MRI. A crescent-shaped hypodense area is indicated in the coronal view (A). A 3 × 2-mm hypodense nodule in the inferior aspect of the pituitary is indicated by the arrow in the sagittal view (B).

A

B

population. Biochemical evidence of hypercortisolism can be demonstrated by 24-hour urine collections for free cortisol. Patients with hypercortisolism will demonstrate loss of normal diurnal variation in plasma cortisol and adrenocorticotropic hormone. A single midnight serum cortisol value has been reported to effectively distinguish Cushing’s syndrome from a pseudo-Cushing condition (e.g., exogenous obesity, depression, stress) [Papanicolaou et al., 1998]. The main challenge in the differential diagnosis of Cushing’s syndrome is distinguishing Cushing’s disease from ectopic adrenocorticotropic hormone production. In general, patients with Cushing’s disease experience suppression of cortisol and adrenocorticotropic hormone with dexamethasone administration (20 μg/kg every 6 hours for 2 days). However, up to 20% of patients with Cushing’s disease do not suppress under these conditions. An MRI of the hypothalamic/pituitary area should be obtained if Cushing’s disease is suspected, although small adenomas may not be visualized [Devoe et al., 1997; Magiakou et al., 1994]. Transsphenoidal resection of pituitary adenomas has emerged as the treatment of choice for Cushing’s disease [Devoe et al., 1997]. Due to small size, some of these tumors are difficult to identify intraoperatively. The recurrence rate after surgery is about 15% to 25% even in the hands of skilled neurosurgeons. Radiotherapy can be effective for unsuccessful transsphenoidal surgery [Estrada et al., 1997]. Other therapeutic options for recurrent Cushing’s disease include repeated pituitary exploration, bilateral adrenalectomy, and the use of pharmacologic agents that directly impair cortisol synthesis and secretion.

Adrenocorticotropic Hormone Deficiency Secondary adrenal insufficiency is defined as hypocortisolism as a consequence of adrenocorticotropic hormone deficiency. Secondary adrenal insufficiency can be isolated or occur as part of multiple hypothalamic/pituitary deficien-

cies; such deficiencies can be idiopathic or associated with structural malformations or various CNS diseases as previously discussed in the section on gonadotropin deficiency. Chronic suppression of corticotropin-releasing hormone and adrenocorticotropic hormone by long-term glucocorticoid therapy can also result in secondary adrenal insufficiency. Isolated adrenocorticotropic hormone deficiency is a rare cause of secondary adrenal insufficiency, due to either corticotropin-releasing hormone deficiency or a primary decrease in adrenocorticotropic hormone production by corticotrophs. Clinical presentation is highly variable. Neonatal onset of isolated adrenocorticotropic hormone deficiency usually presents with sudden, severe episodes of hypoglycemia, sometimes with seizure and coma. Neonates may also present with prolonged cholestatic jaundice. Death may occur if treatment is not initiated promptly. More than 70% of these patients have a loss of function mutation in the TPIT gene, which encodes a transcription factor that is specifically expressed in corticotrophs and is required for expression of pro-opiomelanocortin, the precursor of adrenocorticotropic hormone. Other genetic factors leading to isolated adrenocorticotropic hormone deficiency remain to be elucidated. As noted, adrenocorticotropic hormone deficiency can be associated with multiple hypothalamic/ pituitary hormone deficiencies. The genetic basis of some forms of combined pituitary hormone deficiencies has been elucidated. As previously noted, mutations in Prop-1 can present with growth hormone, prolactin, thyroid-stimulating hormone, gonadotropin, and adrenocorticotropic hormone deficiencies [Agarwal et al., 2000]. Adrenocorticotropic hormone deficiency is also found in patients who have mutations in the Lhx4 gene, which is closely related to Lhx3 as described in the section on delayed puberty. Mutations in either Lhx3 or Lhx4 can also lead to deficiencies in both growth hormone and thyroid-stimulating hormone [Machinis et al., 2001]. CNS tumors involving the third ventricular area, such as craniopharyngioma, germinoma, and astro-

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cytoma can cause multiple pituitary deficiencies, including adrenocorticotropic hormone deficiency. In addition, adrenocorticotropic hormone deficiency with other pituitary hormone deficiencies can be seen in a variety of CNS disorders, including infection, invasive disease, irradiation, congenital malformation, and trauma. Long-term glucocorticoid therapy, for example, in patients with chronic inflammatory and autoimmune diseases, will often suppress the hypothalamic-pituitary-adrenal axis. Cortisol (hydrocortisone) replacement is based on studies of the cortisol secretory rate in the pediatric population [Kerrigan et al., 1993; Linder et al., 1990; Metzger et al., 1993]. During periods of significant stress, such as febrile illness and surgery, such patients are routinely managed with a temporary increase in glucocorticoids (given orally or parenterally) at doses up to 50 mg/m2/day of hydrocortisone.

HYPOTHALAMIC/PITUITARY DISORDERS OF STATURAL GROWTH Statural growth is a complex process influenced by multiple factors. Endocrine regulation of growth postnatally stems from hormones produced in the hypothalamus and the pituitary, including growth hormone–releasing hormone, somatostatin, growth hormone, thyrotropin-releasing hormone, thyroid-stimulating hormone, corticotropin-releasing hormone, and adrenocorticotropic hormone. Inadequate thyrotropin-releasing hormone/thyroid-stimulating hormone and excessive corticotropin-releasing hormone/adrenocorticotropic hormone/cortisol lead to suboptimal linear growth, as discussed in other sections of this chapter. Abnormal statural growth related to either growth hormone deficiency or growth hormone excess (gigantism) is discussed in this section. Human growth hormone is synthesized, stored, and secreted by somatotrophs in the lateral regions of the adenohypophysis. Human growth hormone is a single-chain peptide hormone composed of 191 amino acids. Pulsatile growth hormone secretion is regulated by two hypothalamic regulatory peptides: growth hormone–releasing hormone and somatostatin, which in turn are regulated by multiple neurotransmitters and neuropeptides. For instance, ghrelin, a 28–amino acid peptide secreted from oxyntic cells in the stomach fundus and duodenum, increases growth hormone secretion by either increasing growth hormone–releasing hormone in the hypothalamus, or by directly stimulating growth hormone in the pituitary. Other hormones that affect growth hormone secretion include glucocorticoids, thyroid hormones, and sex steroids. Although acute glucocorticoid administration stimulates growth hormone secretion, chronically elevated glucocorticoids inhibit growth hormone, as seen in Cushing’s disease and during chronic administration of glucocorticoids. Sex steroids (estradiol and testosterone) stimulate growth hormone secretion, contributing to a pubertal rise in growth hormone. In addition, growth hormone levels are decreased in hypothyroidism. The growth-promoting effects of growth hormone are mediated principally through endocrine, autocrine, and paracrine production of insulin-like growth factors. Growth hormone also has direct effects on lipid metabolism and glucose regulation [Rosenfeld and Cohen, 2002].

Growth Hormone Deficiency The incidence of growth hormone deficiency is estimated to be as high as 1:3480 in the United States [Lindsay et al., 1994]. Children with congenital growth hormone deficiency are of normal size at birth. However, after approximately 6 months of life, growth failure becomes apparent when linear growth becomes growth hormone dependent. Usually, children with growth hormone deficiency are short and cherubic with a dolllike appearance. Approximately 10% to 20% of growth hormone–deficient patients present with severe hypoglycemia in addition to short stature. In the neonatal period, hypoglycemia and microphallus strongly suggest growth hormone deficiency. Abnormalities can occur at any level of the growth hormone-releasing hormone/growth hormone–insulin-like growth factor-I axis, but the majority of these abnormalities occur at the hypothalamic/pituitary level. In fact, most patients with growth hormone deficiency (80% to 90%) are growth hormone–releasing hormone deficient, and are capable of secreting growth hormone in response to exogenous growth hormone–releasing hormone. As with gonadotropins or adrenocorticotropic hormone, a deficiency of growth hormone may be isolated or associated with other hypothalamic/ pituitary hormone abnormalities. Growth hormone deficiency may be idiopathic, genetic, associated with a variety of CNS disorders (midline developmental defect syndrome, tumors, infection, irradiation, and trauma) and may occur in association with significant emotional deprivation. Isolated growth hormone deficiency is rarely due to a growth hormone gene deletion. Mutations in the homeobox gene Rpx/Hesx1 are associated with septo-optic dysplasia, also known as de Morsier’s syndrome, a common midline malformation. This syndrome is characterized by the classical triad of optic nerve hypoplasia, midline malformations (such as agenesis of the corpus callosum and absence of the septum pellucidum), and pituitary hypoplasia with consequent panhypopituitarism. Mutations in Rpx/Hesx1 also can cause isolated growth hormone deficiency. However, more commonly, these mutations found in pituitary transcription factors cause multiple hormonal deficiencies and congenital midline defects. The phenotypes of mutations in Rpx/Hesx1 gene are highly variable, ranging from isolated growth hormone deficiency without any midline defects to the complete spectrum of the disease with panhypopituitarism [Thomas et al., 2001]. Evaluation of a child with suspected growth hormone deficiency includes a thorough history, physical examination, and careful review of growth charts and laboratory studies. Severe neonatal hypoglycemia is suggestive of growth hormone deficiency. Most children with growth hormone deficiency will have not only short stature but also a subnormal height velocity with relative preservation of weight and head circumference. The diagnosis of growth hormone deficiency is often difficult to make with a single blood test in view of the pulsatile nature of growth hormone secretion. Growth hormone–dependent insulin-like growth factor-I and insulinlike growth factor–binding protein-3 levels and provocative tests of growth hormone secretion have been widely used to evaluate growth hormone status. If a diagnosis of growth hormone deficiency is made, it is essential to evaluate all anterior and posterior pituitary hormones and to obtain a cranial MRI with particular attention to the third ventricular area.

Dong and Rosenthal / Endocrine Disorders of the Hypothalamus and Pituitary

The primary treatment of children with growth hormone deficiency is recombinant synthetic growth hormone. Typically, growth hormone is administered as a daily subcutaneous injection. Some children with growth hormone deficiency on the basis of growth hormone–releasing hormone deficiency have been successfully treated with growth hormone–releasing hormone. Adequacy of treatment is determined by assessment of growth velocity and serum insulin-like growth factor-I and insulin-like growth factor–binding protein-3 levels. Recent studies demonstrate beneficial effects of continued growth hormone treatment (at lower doses) after final height is reached in adolescents with permanent growth hormone deficiency. Growth hormone treatment is occasionally associated with side effects, such as increased intracranial pressure, hyperglycemia, and slipped femoral capital epiphysis.

Growth Hormone Excess Growth hormone excess can lead to tall stature (gigantism) in children who have open epiphyses and acromegaly in adolescents who have closed epiphyses. Gigantism is a rare condition caused by growth hormone oversecretion primarily due to increased growth hormone production from the pituitary [Abe and Ludecke, 1999; Kunwar and Wilson, 1999]. Growth hormone–producing adenomas constitute up to 10% of pituitary adenomas [Kunwar and Wilson, 2001]. Ectopic growth hormone–releasing hormone overproduction is a rare cause of growth hormone excess [Thorner et al., 1982]. In addition, McCune-Albright syndrome can present with gigantism. The constitutively active G proteins in somatotrophs can result in a rise in cyclic adenosine monophosphate, leading to increased growth hormone secretion in patients with McCune-Albright syndrome [Cuttler et al., 1989; Geffner et al., 1987]. Accelerated longitudinal growth and acromegalic features (enlarged head, large hands and feet, big tongue, and broad nose) are the most prominent signs of growth hormone excess. In girls, menstrual irregularity is common. Mass effect of the tumor can cause impaired vision and headache due to increased intracranial pressure. Some patients may also have hyperprolactinemia as a result of an adenoma from somatolactotrophs. A diagnosis of pituitary gigantism is made by demonstrating nonsuppressible growth hormone in response to glucose infusion in association with elevated insulin-like growth factor-I and insulin-like growth factor–binding protein3 levels. Usually, cranial MRI will reveal a pituitary mass. The goal of treatment in growth hormone–secreting adenomas is normalization of growth hormone and insulinlike growth factor-I levels. Transsphenonoidal surgery has resulted in a greater than 80% cure rate. If surgery is unsuccessful, somatostatin analogs, growth hormone antgonists, and dopamine agonists can be used; radiotherapy may be beneficial.

HYPOTHALAMIC/PITUITARY DISORDERS OF THYROID FUNCTION Normal Thyroid Physiology Under regulation by the hypothalamus and pituitary, the thyroid gland produces thyroxine and triiodothyronine,

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which have broad effects on metabolism, general growth, and central nervous system development [Anderson et al., 2000]. Embryonic development of the hypothalamicpituitary-thyroid axis begins during the first trimester, marked by significant concentrations of thyrotropin-releasing hormone in the hypothalamus, the median eminence, and the supraoptic tract. The thyroid gland forms as an invagination of endoderm at the base of the tongue and descends along the midline to its final position anterior to the second to fourth tracheal cartilage rings [Fisher and Brown, 2000]. Maturation of the human hypothalamicpituitary-thyroid axis is a complex process involving ontogenesis of hypothalamic thyrotropin-releasing hormone, pituitary thyroid–stimulating hormone, and thyroid hormone secretory processes, as well as maturation of their respective receptors, and of pituitary iodothyronine monodeiodinase enzyme activities [Fisher and Brown, 2000]. Thyroid-stimulating hormone is a heterodimeric glycoprotein consisting of α and β subunits. The α subunit is common to thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, and human chorionic gonadotropin, whereas the β subunit confers specificity. Thyroid-stimulating hormone acts on the thyroid gland to stimulate thyroid hormone synthesis and secretion. Thyroidstimulating hormone is negatively regulated by thyroid hormones and positively regulated by thyrotropin-releasing hormone. Thyroid hormone signaling is mediated by specific nuclear receptors that regulate the expression of target genes at the levels of transcription and protein synthesis [Anderson et al., 2000]. More than 90% of circulating thyroxine and triiodothyronine are bound to thyroid-binding proteins (thyroid-binding globulin, transthyretin, and albumin) [Refetoff, 1989]. Thyroxine serves largely as a prohormone that is peripherally converted to the more potent triiodothyronine [Anderson, et al., 2000].

Central Hypothyroidism Central (hypothalamic/pituitary) hypothyroidism is rare in comparison with primary hypothyroidism, and may be congenital or acquired. Signs and symptoms associated with hypothyroidism may arise insidiously and are often nonspecific. In the neonatal period, newborns may have lethargy, hypotonia, hypothermia, or prolonged jaundice. Untreated hypothyroidism during infancy and early childhood can result in developmental delay, mental retardation, and poor statural growth. Presenting symptoms in older children include weight gain, subnormal height velocity, constipation, cold intolerance, hoarse voice, dry skin, and lethargy. Congenital thyroid-stimulating hormone deficiency occurs in 1:50,000 to 1:150,000 newborns [Fisher, 2002]. Underlying etiologies include isolated thyroid-stimulating hormone deficiency, developmental defects of the hypothalamus and pituitary, and familial panhypopituitarism. Patients with congenital thyroid-stimulating hormone deficiency are usually not detected by neonatal screening for hypothyroidism because most programs are designed to screen for hyperthyrotropinemia that accompanies the more primary hypothyroidism. Isolated thyroid-stimulating hormone deficiency is usually autosomal recessive. Mutations in the thyroid-stimulating hormone β subunit prevent formation of the active

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thyroid-stimulating hormone heterodimer [Hayashizaki et al., 1989, 1990; Karges et al., 2004; McDermott et al., 2002]. Thyroid-stimulating hormone deficiency in combination with other pituitary hormone deficiencies is frequently seen in patients with HESX1, PIT1, and PROP1 mutations. As described previously in sections on disorders of statural growth and puberty, these genes are pituitary transcription factors critical for pituitary development. In addition, isolated central hypothyroidism can result from a loss-of-function mutation in the thyrotropin-releasing hormone receptor [Collu et al., 1997]. Acquired central hypothyroidism may result from CNS insults including tumors invading the third ventricular area, irradiation, infection, and trauma. Acquired central hypothyroidism is usually associated with multiple hypothalamic/ pituitary hormone deficiencies. With respect to laboratory assessment of thyroid function, it is critical to recognize that normal ranges vary significantly with age [Nelson et al., 1993]. In particular, thyroidstimulating hormone and free thyroxine are relatively high in newborns in comparison with older infants, children, and adolescents. The principal goals of treating central hypothyroidism are prevention of mental retardation and growth impairment. Thus, thyroxine replacement should be instituted promptly after diagnosis of hypothyroidism, regardless of etiology.

Central Hyperthyroidism Most cases of hyperthyroidism in the pediatric population are autoimmune and thyroid-stimulating hormone independent. Central hyperthyroidism as a consequence of a pituitary thyroid-stimulating hormone–secreting adenoma is exceedingly rare [Tolis et al., 1978]. Such patients may have a prominent local mass effect of the tumor, such as loss or partial loss of vision from optic atrophy, and may have hydrocephalus. Other signs and symptoms of hyperthyroidism such as agitation, tall stature, goiter, tremor, and palpitation are also manifested in central hyperthyroidism.

␣-MSH

Appetite and energy balance are regulated by a complex network in which the hypothalamus serves as the central processing unit for hormonal, nutritional, and neuronal input from both peripheral tissue and higher brain centers. In humans it is well known that hypothalamic damage (e.g., from a tumor, surgery, trauma, or radiation) can lead to hypothalamic obesity [Bray and Gallagher, 1975]. These patients present with excessive weight gain without response to caloric restriction or exercise [Bray et al., 1981]. Traditionally, the ventromedial hypothalamus has been viewed as the “satiety” center because damage to the ventromedial hypothalamus can cause hyperphagic obesity. In contrast, the lateral hypothalamus has been viewed as the “feeding” center because its disruption leads to hypophagia and weight loss [Flier and Maratos-Flier, 1998]. Insights into mechanisms of hypothalamic obesity derive from advances in our understanding of hypothalamic control of appetite regulation and energy balance (Fig. 84-5). Energy storage and appetite are regulated at the hypothalamus through signaling by leptin, an anorexigenic hormone secreted by adipocytes, and by insulin. Both leptin and insulin stimulate anorexigenic and inhibit orexigenic pathways in the hypothalamus. In the anorexigenic pathway, leptin and insulin maintain expression of pro-

Anorexigenic MC4R

AgRP NPY

Orexigenic

Leptin

Insulin

PYY

Ghrelin

Adipocytes

Pancreas

Small intestine and the colon

Stomach

Long-term signals

HYPOTHALAMIC DISORDERS OF APPETITE REGULATION AND ENERGY BALANCE

Paraventricular nucleus lateral hypothalamic area

Arcuate nucleus POMC

Biochemically, patients with central hyperthyroidism have elevated concentrations of thyroid-stimulating hormone in the context of elevated thyroxine and triiodothyronine. If a pituitary adenoma is not identifiable on imaging studies, rare selective pituitary triiodothyronine resistance should be considered. Surgical removal of the tumor is the treatment of choice for thyroid-stimulating hormone–secreting pituitary adenoma. However, the treatment of selective pituitary triiodothyronine resistance remains a therapeutic challenge.

Short-term signals

Y1R

Food intake Energy balance

FIGURE 84-5. Hormonal regulation of food intake and energy balance in the hypothalamus. The dashed lines indicate inhibitory effects and the solid lines with arrows indicate stimulatory effects. Long-term signals affecting body fat mass include leptin and insulin, whereas short-term signals determining meal initiation and termination include peptide YY3-36 and ghrelin. α-MSH, α-melanocyte–stimulating protein; AgRP, agouti-related protein; MC4R, melanocortin-4 receptor; NPY, neuropeptide Y; POMC, pro-opiomelanocortin; PYY, peptide YY3-36; Y1R, Y1 subtype of the neuropeptide Y receptor.

Dong and Rosenthal / Endocrine Disorders of the Hypothalamus and Pituitary

opiomelanocortin in the arcuate nuclei within the ventromedial hypothalamus, and pro-opiomelanocortin–derived α-melanocyte–stimulating hormone activates the melanocortin-4 receptor in the paraventricular nuclei and the lateral hypothalamic area. This melanocortin signal is appetite suppressing and leads to decreased food intake. In addition, leptin and insulin inhibit neuropeptide Y and agouti-related protein within the arcuate nuclei, both of which are appetitestimulating peptides [Schwartz et al., 2003]. Neuropeptide Y decreases pro-opiomelanocortin expression through the neuropeptide Y1 receptor. Agouti-related protein is an inverse agonist for melanocortin-4 receptor, thus antagonizing the interaction of α-melanocyte–stimulating hormone and the melanocortin-4 receptor and leading to increased food intake [Korner and Leibel, 2003]. Short-term signals that affect appetite and determine meal initiation and termination are derived from gut hormones, such as ghrelin (secreted by oxyntic cells in the stomach fundus) and peptide YY3-36 secreted by endocrine L cells in the distal small bowel and colon). Ghrelin signals hunger and increases food intake by stimulating ghrelin receptors on hypothalamic neuropeptide Y and agouti-related proteinexpressing neurons [Cummings et al., 2002]. In contrast, peptide YY3-36 signals satiety and decreases food intake by inhibiting neuropeptide Y/agouti-related protein–expressing neurons via the neuropeptide Y2 receptor and by decreasing ghrelin levels [Batterham et al., 2002, 2003]. Both long-term and short-term hormonal signals are received in the arcuate nuclei, constituting the afferent system of the feedback loop for appetite and energy balance. Through the paraventricular and lateral nuclei, these signals are transmitted into a complex and less wellunderstood efferent system that controls appetite and energy balance. The autonomic system plays a critical role in regulating energy expenditure. It is known that the ventromedial hypothalamus has direct neuronal projections to spinal cord that regulate sympathetic outflow. Activation of the sympathetic nervous system results in increased energy expenditure, such as increased local heat production and increased lipolysis. In addition, the ventromedial hypothalamus has projections to the dorsal motor nucleus of the vagus that innervate the gastrointestinal system. Disinhibition of vagal firing by ventromedial hypothalamus lesions is associated with relative insulin hypersecretion and subsequent increased energy storage [Lustig, 2002]. Examples of monogenic obesity are those caused by mutations in either pro-opiomelanocortin or melanocortin-4 receptor. In the former, two patients have been reported with loss-of-function mutations in pro-opiomelanocortin, leading to defective synthesis of adrenocorticotropic hormone and α-melanocyte–stimulating hormone [Krude et al., 1998, 2003]. Both patients have red hair, adrenal insufficiency, hyperphagia, and morbid obesity. In the latter, heterogeneous mutations in melanocortin-4 receptor have been found in 2.5% of obese children, representing the most common genetic defects in human obesity [Farooqi et al., 2000; Vaisse et al., 2000]. Congenital leptin deficiency and leptin receptor abnormalities are extremely rare monogenic forms of morbid obesity. Only two United Kingdom families of Pakistani origin [Farooqi et al., 2002; Montague et al., 1997], one Canadian family of Pakistani origin [Gibson et al., 2004],

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and one Turkish family [Licinio et al., 2004] with mutations in the leptin gene have been described thus far. The first three children reported were born to two consanguineous Pakistani families [Farooqi et al., 2002]. They had normal birth weight but became hyperphagic in infancy and developed severe obesity with undetectable levels of leptin. Exogenous administration of leptin induced sustained weight loss due to loss of fat mass in these patients. Similar results were observed in three adults who have congenital leptin deficiency [Licinio et al., 2004]. Leptin replacement in these adults resulted in profound weight loss, increased physical activity, and resolution of insulin resistance and hypogonadism. Homozygous mutation of the leptin receptor is also associated with severe childhood obesity. These patients have early onset of morbid obesity associated with high levels of leptin. In addition, they have absent pubertal development and reduced levels of both thyrotropin and growth hormone [Clement et al., 1998]. As previously noted, hypothalamic obesity is frequently seen in children with hypothalamic insults such as brain tumor, surgery, irradiation, or trauma. Approximately 50% of children with craniopharyngioma develop hypothalamic obesity. Other tumors, such as germinoma, optic glioma, prolactinoma, hypothalamic astrocytoma, also are associated with hypothalamic obesity. These patients usually have unrelenting weight gain after tumor removal or radiotherapy without documented excessive food intake [Harz et al., 2003]. Other risk factors associated with hypothalamic obesity include dose of hypothalamic irradiation (>51 Gy), and associated hypothalamic endocrinopathy (growth hormone deficiency, hypothyroidism, adrenocorticotropic hormone deficiency, precocious or delayed puberty, and diabetes insipidus) [Lustig et al., 2003]. A recent report indicates that reduced physical activity rather than increased energy intake is primarily responsible for obesity in patients with craniopharyngioma [Harz et al., 2003]. In patients with hypothalamic obesity and apparent insulin hypersecretion, the somatostatin agonist octreotide has been found to decrease or stabilize body weight [Lustig et al., 1999].

HYPOTHALAMIC/PITUITARY DISORDERS OF WATER BALANCE Under normal circumstances plasma osmolality is maintained within a relatively narrow range (280 to 295 mOsm/kg). This homeostasis requires adequate water intake regulated by an intact thirst mechanism and appropriate free water excretion by the kidneys, mediated by appropriate secretion of vasopressin (arginine vasopressin), that is, antidiuretic hormone [Robertson, 2001]. Arginine vasopressin is produced in the magnocellular neurons in the paraventricular and supraoptic nuclei of the hypothalamus. Axons from these neurons project through the pituitary stalk and terminate in the posterior pituitary gland [Robertson, 2001]. A gene on chromosome 20p13 encodes both arginine vasopressin and its carrier protein, neurophysin II. Arginine vasopressin and neurophysin II are synthesized as a single polypeptide, cleaved within neurosecretory granules, reassembled into an arginine vasopressin/neurophysin II complex, and secreted [Rutishauser et al., 2002]. Arginine

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vasopressin exerts its antidiuretic action by binding to the X chromosome–encoded V2 vasopressin receptor (V2R), a G protein–coupled receptor on the basolateral membrane of renal collecting duct epithelial cells. After V2 vasopressin receptor activation, increased intracellular cyclic adenosine monophosphate mediates shuttling of the water channel aquaporin-2 to the apical membrane of collecting duct epithelial cells, resulting in increased water permeability and antidiuresis [Schrier and Cadnapaphornchai, 2003]. Arginine vasopressin secretion is regulated mainly by changes in plasma osmolality and in effective circulating volume [Robertson, 2001]. Osmoreceptors in the hypothalamus stimulate secretion of arginine vasopressin when plasma osmolality increases by as little as 1% in healthy individuals. Arginine vasopressin levels are normally low and do not increase until plasma osmolality exceeds 280 mOsm/kg [Robinson and Verbalis, 2003]. Arginine vasopressin secretion is also regulated by changes in blood volume. Baroreceptors in the systemic venous circulation, right side of the heart, and left atrium (“low pressure” areas), as well as in the systemic arterial systems of the carotid sinus and aortic arch (“high pressure” areas) signal the hypothalamus via the vagus and glossopharyngeal nerves, respectively. These baroreceptors become activated when stretched by increases in intravascular volume, leading to inhibition of arginine vasopressin secretion. In addition, a variety of other factors affect arginine vasopressin secretion. Arginine vasopressin is stimulated by pain, stress, and a variety of drugs and is inhibited by multiple factors [Robinson and Verbalis, 2003]. Adequate water intake, governed by an intact thirst mechanism, is regulated by hypothalamic osmoreceptors located near vasopressinergic neurons. Clinical disorders of water balance are common, and abnormalities in many steps involving arginine vasopressin secretion and responsiveness have been described [Robertson, 2001]. The focus of this section is on the principal hypothalamic/pituitary disorders of water balance, diabetes insipidus, and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion.

Diabetes Insipidus Diabetes insipidus may result from a deficiency of arginine vasopressin or from nephrogenic causes [Baylis and Cheetham, 1998; Robinson and Verbalis, 2003; Verbalis, 2003]. Nephrogenic diabetes insipidus may be congenital, resulting from inactivating mutations in the V2 vasopressin receptor gene or from autosomal-recessive or autosomaldominant lesions in the aquaporin-2 gene, or acquired, resulting from a variety of conditions including some forms of primary renal disease, obstructive uropathy, hypokalemia, hypercalcemia, sickle cell disease, and a variety of drugs including lithium and demeclocycline [Baylis and Cheetham, 1998; Morello and Bichet, 2001; Robinson and Verbalis, 2003; Verbalis, 2003]. Prolonged polyuria of any cause can result in some degree of nephrogenic diabetes insipidus secondary to a reduction of tonicity in the renal medullary interstitium and a subsequent decrease in the gradient necessary to concentrate the urine. Central diabetes insipidus is rarely congenital and more frequently acquired. Congenital central diabetes insipidus

may be caused by hypothalamic structural malformations and through both autosomal-dominant and autosomalrecessive mutations in the arginine vasopressin/neurophysin II gene. Of the latter, the autosomal-dominant causes are more common and are thought to be a consequence of heterozygous mutations in the arginine vasopressin/ neurophysin II gene, which lead to misfolding of the precursor arginine vasopressin/neurophysin II protein [Rutishauser et al., 2002]. The dominant negative effect is thought to occur as a consequence of the misfolded precursor protein that accumulates in the endoplasmic reticulum of vasopressinergic neurons, ultimately resulting in death of these neurons and gliosis [Robinson and Verbalis, 2003; Rutishauser et al., 2002]. In such patients, clinical diabetes insipidus usually develops several months to years after birth. A rare autosomal-recessive form of central diabetes insipidus has been reported in association with a mutation in the arginine vasopressin/neurophysin II gene, resulting in a biologically inactive arginine vasopressin [Willcutts et al., 1999]. Acquired forms of diabetes insipidus occur in association with a variety of disorders in which there is destruction or degeneration of vasopressinergic neurons. Etiologies include primary tumors (e.g., craniopharyngioma germinoma) or metastases, infection (meningitis, encephalitis), histiocytosis, granuloma, vascular disorders, and autoimmune disorders (lymphocytic infundibuloneurohypophysitis) [Baylis and Cheetham, 1998; Robinson and Verbalis, 2003; Verbalis, 2003]. Acquired diabetes insipidus may occur in association with trauma and surgery. Idiopathic diabetes insipidus is a diagnosis of exclusion, and one that is made with decreasing frequency concurrent with improved sensitivity of CNS MRI imaging and of cerebrospinal fluid and serum tumor markers [Maghnie et al., 2000; Mootha et al., 1997]. The principal presenting sign of diabetes insipidus is polyuria, which in addition to deficiency or impaired responsiveness to arginine vasopressin, may result from an osmotic agent (e.g., hyperglycemia in diabetes mellitus) or from excessive water intake (primary polydipsia). Hypernatremia usually does not occur if patients have an intact thirst mechanism, adequate access to fluids, and no additional ongoing fluid losses (e.g., diarrhea). Infants with diabetes insipidus, in addition to polyuria and polydipsia, may be irritable and have fever of unknown origin, growth failure secondary to inadequate caloric intake, and hydronephrosis. Older children may also have nocturia and enuresis. Diabetes insipidus may not be apparent in patients with coexisting untreated anterior pituitary-mediated adrenal glucocorticoid insufficiency, because cortisol is required to generate a normal free water loss [Robinson and Verbalis, 2003]. A diagnosis of diabetes insipidus can be made if screening laboratory studies reveal serum hyperosmolality concurrent with urine that is inappropriately dilute. However, because most patients with diabetes insipidus do not have hyperosmolality and hypernatremia, as noted above, a standardized water deprivation test is useful to distinguish diabetes insipidus from primary polydipsia. Urine osmolality of greater than 750 mOsm/kg after 7 to 8 hours of water deprivation is thought to exclude diabetes insipidus [Baylis and Cheetham, 1998]. Urine osmolality in the 300-

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to 750-mOsm/kg range may indicate partial diabetes insipidus [Baylis and Cheetham, 1998]. If diabetes insipidus is suspected, a plasma sample should be obtained for arginine vasopressin radioimmunoassay. Arginine vasopressin or a synthetic analog (desmopressin) should then be administered to distinguish arginine vasopressin deficiency from arginine vasopressin unresponsiveness. Once a diagnosis of central diabetes insipidus is made, a brain MRI with particular attention to the third ventricular area should be obtained. An absent posterior pituitary “bright spot” is seen in virtually all patients with central diabetes insipidus. Under normal circumstances a posterior pituitary bright spot is seen on T1-weighted images due to stored arginine vasopressin in neurosecretory granules (see Fig. 84-1). In patients with diabetes insipidus as a consequence of an autosomal-dominant mutation in the arginine vasopressin/neurophysin II gene, a posterior pituitary bright spot may be seen in the early stages of the disease [Robinson and Verbalis, 2003]. In central diabetes insipidus patients with an absent posterior pituitary bright spot, an otherwise normal MRI warrants close followup with cerebrospinal fluid tumor markers and cytology, serum tumor markers, and serial contrast-enhanced brain MRIs for early detection of an evolving occult hypothalamic-stalk lesion [Mootha et al., 1997]. In addition to treating a primary disease causing central diabetes insipidus, the drug of choice for most patients with arginine vasopressin deficiency is desmopressin. This arginine vasopressin analog has markedly reduced pressor activity in comparison with native arginine vasopressin, has a prolonged half-life, and can be administered orally, intranasally, or by subcutaneous injection.

Syndrome of Inappropriate Antidiuretic Hormone Secretion SIADH is characterized by the inability to excrete a free water load, with inappropriately concentrated urine, and resultant hyponatremia, hypo-osmolality, and natriuresis [Bartter and Schwartz, 1967; Baylis, 2003; Robinson and Verbalis, 2003]. Following from the original criteria established by Bartter and Schwartz [1967], a diagnosis of SIADH is made when the following occur: (1) plasma hypoosmolality (<275 mOsm/kg); (2) less than maximally dilute urine (urine osmolality >100 mOsm/kg); (3) euvolemia (secondary to regulatory adaptations); (4) natriuresis; (5) normal renal function; and (6) no evidence of thyroxine or cortisol deficiency. Whereas most patients with SIADH have inappropriately measurable or elevated levels of plasma arginine vasopressin relative to plasma osmolality, 10% to 20% of patients with SIADH do not have measurable arginine vasopressin levels. This finding may reflect issues of assay sensitivity or may indicate a syndrome resembling SIADH, such as the recently described nephrogenic syndrome of inappropriate antidiuresis associated with an activating mutation in the X-linked G protein–coupled V2 vasopressin receptor and unmeasurable circulating levels of arginine vasopressin [Feldman et al., 2004]. Euvolemia in chronic SIADH is an important distinguishing factor in the evaluation of a patient with serum hypo-osmolality and has a bearing on treatment issues, as is discussed subsequently. Euvolemia in chronic SIADH is thought to represent an adaptation to water overload. This

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adaptation is mediated, in part, at the cellular level through depletion of intracellular electrolytes (potassium) and organic osmolytes [Robinson and Verbalis, 2003]. The loss of brain solutes is thought to allow effective regulation of brain volume during chronic hyponatremia and SIADH. Natriuresis, thought to be mediated in part through secretion of atrial natriuretic peptide, also contributes to volume regulation in chronic SIADH [Cogan et al., 1988]. Cerebral salt wasting, associated with some intracranial diseases (e.g., subarachnoid hemorrhage), is often considered in the differential diagnosis of SIADH. However, the hypo-osmolality, hyponatremia, and natriuresis in cerebral salt wasting are associated with volume contraction, which distinguishes this disorder from the euvolemic condition of SIADH [Robinson and Verbalis, 2003]. A large number of disorders and conditions are associated with SIADH, and can be grouped into five categories: (1) disorders of the CNS, including infection, trauma, cerebrovascular accident, tumors (nonarginine vasopressin producing), hydrocephalus, neonatal hypoxia; (2) a variety of pulmonary disorders (e.g., pneumonia, asthma); (3) nonCNS tumors with ectopic production of arginine vasopressin (e.g., bronchogenic carcinoma, lymphoma; (4) a large variety of drugs (e.g., phenothiozines, tricylic antidepressants); and (5) general surgery (mechanism not well understood) [Baylis, 2003; Robinson and Verbalis, 2003]. Therapy for SIADH includes treatment of the underlying disorder (or discontinuation of an offending drug) and fluid restriction. Replacement of lost body sodium may also be necessary but usually can be achieved through normal dietary salt intake. Severe hyponatremia (serum sodium <120 mEq/L) may be associated with CNS abnormalities, including seizures, and may require treatment with hypertonic (3%) intravenous sodium chloride solution. Concurrent use of a diuretic, such as furosemide, may be indicated when volume expansion is severe. Other therapeutic approaches include the use of agents that induce nephrogenic diabetes insipidus, such as demeclocycline and lithium, although both are contraindicated, particularly in younger pediatric patients, because of untoward side effects. Urea has been used as an osmotic diuretic in pediatric SIADH [Huang et al., 2004]. A variety of nonpeptide V2 vasopressin receptor antagonists are currently in clinical trials [Verbalis, 2002]. If SIADH and hyponatremia are acute (<48 hours), it is thought that hyponatremia can be corrected quickly. However, if SIADH and hyponatremia are chronic (>48 hours), overzealous treatment can result in CNS damage, including central pontine myelinolysis [Robinson and Verbalis, 2003]. Brain solute loss, although an important regulatory mechanism in chronic SIADH, may predispose to the development of central pontine myelinolysis with rapid correction of serum osmolality. It is generally recommended that plasma sodium be corrected to a “safe” level of approximately 120 to 125 mEq/L at a rate of no greater than 0.5 mEq/L per hour with an overall correction that does not exceed 12 mEq/L in the initial 24 hours and 18 mEq/L in the initial 48 hours of treatment [Robinson and Verbalis, 2003]. REFERENCES Abe T, Ludecke DK. Recent primary transnasal surgical outcomes associated with intraoperative growth hormone measurement in acromegaly. Clin Endocrinol (Oxf) 1999;50:27.

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CHAPTER 85

Disorders of the Autonomic Nervous System: Autonomic Dysfunction in Pediatric Practice Christopher J. Mathias

The autonomic nervous system supplies and influences every organ in the body with a network of efferent pathways whose activities depend on a number of factors (Fig. 85-1). These include afferent information from various sources, cerebral and spinal cord integration, and local factors in target organs. The peripheral effector pathways consist of the sympathetic and parasympathetic nervous systems, in addition to the enteric nervous system. Dysfunction of the autonomic nervous system in childhood may occur for a variety of reasons; these include developmental abnormalities in the neonate that result in clinical presentation at birth, genetic disorders that manifest later in childhood, and the many causes of generalized or localized dysfunction as observed in adults. Autonomic disorders in children, as in adults, cover many disciplines; dysfunction may be a complication of various diseases and thus can pose particular challenges. At different stages in children, specific aspects linked to developmental changes may need to be considered. This chapter, based predominantly on adult clinical practice, provides an emphasis on disorders occurring in childhood. There are brief descriptions also of adult autonomic disorders, which are of relevance because this information may have implications for genetic advice and for screening of children.

ANATOMIC, PHYSIOLOGIC, AND BIOCHEMICAL BASIS OF AUTONOMIC NERVOUS SYSTEM FUNCTION The development of the autonomic nervous system has been well described in recent reviews [Ashwal, 1999; Hammil and La Gamma, 2002]. The effector components of the autonomic nervous system develop in the basal plate of the spinal cord and in the neural crest. In the third week of gestation, the neural plate begins to fuse and the neural tube is closed by the fourth week. Neural crest cells migrate as the neural tube fuse; crest cells in cephalic regions detach and migrate before the neural tube has closed. These cells undergo modification and differentiate to form the sympathetic and parasympathetic nervous systems. The sympathetic nervous system, in the thoracolumbar portion of the spinal cord, is formed from neural crest cells from the sixth somite to the posterior end of the neural crest. By the fifth week of gestation, primitive sympathetic ganglia appear, and later other preganglionic fibers pass through the paravertebral ganglia without synapsing, forming the splanchnic nerves that innervate the viscera. Preganglionic parasympathetic fibers arise from neural crest cells in the diencephalon and cranial part of the mes-

encephalon (III cranial nerve), rhombencephalon (migrating cranially to form cranial nerves VII, IX, and X), and the second to fourth sacral segments of the developing spinal cord (parasympathetic supply to the pelvic viscera). Pupils, salivary glands, heart, gastrointestinal tract, and lungs become innervated from the fifth to the seventh week. In the 10th week, cardiac conducting fibers have appeared. Development of the enteric nervous system is from three different regions—the neural crest, vagal trunk, and sacrum—with neuroblasts first detected in the 24th week. A variety of intrinsic and extrinsic factors affect the development of the autonomic nervous system, and these are both intrinsic and extrinsic. Genes, growth factors, and neurotrophins control various stages, and each may be critical at different development phases. These factors may in part be responsible for genetic and familial disorders, which include Hirschsprung’s disease; Riley-Day syndrome; dopamine beta hydroxylase deficiency; hereditary, sensory, and autonomic neuropathies; and tumors affecting sympathoadrenal tissue. The autonomic nervous system is essentially an effector (efferent) system that often operates in the form of a reflex arc. The sympathetic outflow is connected with major nuclei in the hypothalamus, midbrain, and brainstem and descends through the cervical spinal cord, where axons synapse in the intermediolateral cell mass. From the thoracic and upper lumbar spinal segments, myelinated axons emerge in white rami and synapse in paravertebral ganglia, which are some distance from target organs. The major ganglionic neurotransmitter is acetylcholine. Postganglionic fibers, which are unmyelinated, rejoin the mixed nerve through the gray rami and innervate target organs, except for the adrenal medulla, which has only a preganglionic supply. The neurotransmitter at postganglionic sites is predominantly noradrenaline, although sympathetic cholinergic fibers (with acetylcholine as the transmitter) supply sweat glands. There are complex pathways in neurotransmitter formation, release, and function, as illustrated with the catecholamines (Fig. 85-2). Many neurons have multiple neurotransmitters, which may be nonadrenergic and noncholinergic (Fig. 85-3). Vasoactive intestinal polypeptide is co-secreted with acetylcholine, which explains the inability of atropine to block all the effects of parasympathetic stimulation. Neuropeptide Y may be coreleased with noradrenaline, accounting for why alphaadrenoceptor blockers may not completely prevent the effects of sympathetic neural stimulation. The autonomic nervous system, despite the multiplicity of neurotransmitters and neuromodulators, however, selectively controls responses in specific regional vascular territories and organs, making it a highly complex but precisely regulated and integrated system.

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SYMPATHETIC NERVOUS SYSTEM

Eye

II

PARASYMPATHETIC NERVOUS SYSTEM

Mesencephalon

Medulla oblongata

Tear and salivary glands

Superior cervical ganglion Stellate ganglion

IX, VII X Vagus n. Lung

Cervical

Pons

Celiac ganglion

Liver Stomach

Thoracic

Heart

Adrenal medulla Interior mesenteric ganglion

Sacral

Large intestine, rectum

Lumbar

Pancreas Small intestine

Superior mesenteric ganglion

Bladder

Sympathetic trunk

Reproductive organs FIGURE 85-1. Parasympathetic and sympathetic innervation of major organs. (From Janig, 1989.)

Tyrosine – TH

Dopa DDC

DA SYMPATHETIC NERVE TERMINAL

MAO DA D␤H

NA + –

NA

Uptake 1

+

– ␤␣ 2

NA

SYNAPTIC CLEFT EFFECTOR CELL

D␤H

␤

␣1

Uptake 2 COMT

FIGURE 85-2. Schema of some pathways in the formation, release, and metabolism of noradrenaline from sympathetic nerve terminals. Tyrosine is converted into dihydroxyphenylalanine (dopa) by tyrosine hydroxylase (TH). Dopa is converted into dopamine (DA) by dopa decarboxylase (DDC). In the vesicles DA is converted into noradrenaline (NA) by dopamine β-hydroxylase (DβH). Nerve impulses release both DβH and NA into the synaptic cleft by exocytosis. NA acts predominantly on alpha1-adrenoceptors (α1) but has actions on beta-adrenoceptors (β) on the effector cell of target organs. It also has presynaptic adrenoceptor effects. Those acting on alpha2 adrenoceptors inhibit NA release; those on beta-adrenoceptors stimulate NA release. NA may be taken up by a neuronal (uptake 1) process into the cytosol, where it may inhibit further formation of dopa through the rate-limiting enzyme TH. NA may be taken into vesicles or metabolized by monoamine oxidase (MAO) in the mitochondria. NA may be taken up by a higher capacity but lower affinity extraneuronal process (uptake 2) into peripheral tissues, such as vascular and cardiac muscle and certain glands. NA is also metabolized by catechol-O-methyltransferase (COMT). NA measured in plasma is the overspill not affected by these numerous processes. (Adapted from Mathias, 2004.)

Mathias / Disorders of the Autonomic Nervous System GANGLIA

TARGET ORGAN

Parasympathetic

ACh

ACh Glands Smooth muscle Heart

Sympathetic

ACh

NA

ACh

ACh Sweat glands

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diabetes mellitus (Table 85-1). Drugs are a major cause of autonomic dysfunction (Table 85-2). An intermittent autonomic abnormality occurs in neurally mediated syncope and the postural tachycardia syndrome. Table 85-3 provides examples of autonomic disorders in which localized deficits affect specific organs.

Blood vessels Heart

CLINICAL FEATURES OF AUTONOMIC DYSFUNCTION

ACh

Adrenal medulla

FIGURE 85-3. Outline of the major transmitters at autonomic ganglia and postganglionic sites on target organs supplied by the sympathetic and parasympathetic efferent pathways. The acetylcholine receptor at all ganglia is of the nicotinic subtype. Ganglionic blockers such as hexamethonium thus prevent both parasympathetic and sympathetic activation. Atropine, however, acts only on the muscarinic (ACH-m) receptor at postganglionic parasympathetic and sympathetic cholinergic sites. The co-transmitter is also indicated. NA, noradrenaline. (Adapted from Mathias, 1998.)

The parasympathetic outflow consists of cranial and sacral efferents. Cranial efferents accompany cranial nerves III, VII, IX, and X and supply the eye, lacrimal and salivary glands, heart and lungs, and gastrointestinal tract with associated structures, down to the level of the colon. The sacral outflow supplies the urinary tract and bladder, the large bowel, and reproductive system. Cerebral and spinal parasympathetic nuclei have specific control, for example, the Edinger-Westphal nucleus in pupillary control and Onuf’s nucleus in the second and third sacral segments in urinary sphincter function. Most parasympathetic ganglia are close to target organs, and acetylcholine is the major transmitter at ganglia and at postganglionic sites. Each sensory pathway has the capability to influence autonomic activity, as has been described in relation to autonomic control of blood pressure. The major baroreceptor afferents in the carotid sinus and aortic arch relay information to the brain through cranial nerves IX (glossopharyngeal) and X (vagal). Receptors in the heart and lungs (cardiopulmonary baroreceptors), skin, muscle, and viscera also influence blood pressure. Their role may be unmasked in tetraplegic subjects with cervical cord lesions above the spinal sympathetic outflow, where the peripheral sympathetic and cranial parasympathetic nervous systems function independently of the brain. The major cerebral centers concerned with autonomic regulation include the insula, amygdyla, hypothalamus, midbrain (Edinger-Westphal nucleus and locus ceruleus), and brainstem (nucleus tractus solitarius and vagal nuclei). A combination of neuroimaging and physiologic studies indicates that a variety of cerebral areas, in different situations and in response to different stimuli, influence autonomic function (Benarroch, 2002; Critchley et al., 2001a, 2001b; Spyer, 2002).

CLASSIFICATION OF AUTONOMIC DISORDERS IN CHILDREN Autonomic disorders may be primary, in which no cause has been determined, or secondary to specific diseases, such as

Disorders of the autonomic nervous system can result in a wide spectrum of clinical manifestations (Table 85-4). Sympathetic adrenergic failure results in orthostatic (postural) hypotension and ejaculatory failure (in the postpubertal male), whereas sympathetic cholinergic failure causes anhidrosis. The reverse, sympathetic overactivity may result in hypertension, tachycardia, and hyperhidrosis. Parasympathetic failure causes a fixed heart rate, an atonic urinary bladder, a sluggish large bowel, and erectile failure; overactivity can result in bradycardia and even cardiac arrest. The clinical features depend on the extent of the lesion, the associated disease, and the ensuing functional deficit. Some disorders are recognized at birth, such as the RileyDay syndrome (familial dysautonomia), in which there usuTABLE 85-1 Outline Classification of Autonomic Failure PRIMARY Acute/Subacute Dysautonomias Pure pandysautonomia Pandysautonomia with neurologic features Pure cholinergic dysautonomia Chronic Autonomic Failure Syndromes Pure autonomic failure Multiple system atrophy (Shy-Drager syndrome) Autonomic failure with Parkinson’s disease SECONDARY Congenital Nerve growth factor deficiency Hereditary Hereditary sensory and autonomic neuropathies Riley-Day syndrome (familial dysautonomia) Congenital insensitivity to pain with anhidrosis Familial amyloid neuropathy Dopamine β-hydroxylase deficiency Metabolic Diabetes mellitus Chronic renal failure Chronic liver disease Alcohol-induced Inflammatory Guillain-Barré syndrome Transverse myelitis Infections Bacterial tetanus Viral human immunodeficiency infection Neoplasia Brain tumors, especially of third ventricle or posterior fossa Paraneoplastic, to include adenocarcinomas of lung and pancreas Trauma Spinal cord lesions DRUGS, CHEMICALS, POISONS, TOXINS (also see Table 85-2) By their direct effects By causing a neuropathy Adapted from Mathias, 2003.

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TABLE 85-2

TABLE 85-4

Drugs, Chemicals, Poisons, and Toxins Causing Autonomic Dysfunction

Some Clinical Manifestations of Autonomic Dysfunction

Decreasing Sympathetic Activity Centrally Acting Clonidine Methyldopa Moxonidine Reserpine Barbiturates Anesthetics Peripherally acting Sympathetic nerve endings (guanethidine, bethanidine) Alpha-adrenoceptor blockade (phenoxybenzamine) Beta-adrenoceptor blockade (propranolol) Increasing Sympathetic Activity Amphetamines Releasing noradrenaline (tyramine) Uptake blockers (imipramine) Monoamine oxidase inhibitors (tranylcypromine) Beta-adrenoceptor stimulants (isoprenaline) Decreasing Parasympathetic Activity Antidepressants (imipramine) Tranquilizers (phenothiazines) Antidysrhythmics (disopyramide) Anticholinergics (atropine, probanthine, benztropine) Toxins (botulinum) Increasing Parasympathetic Activity Cholinomimetics (carbachol, bethanechol, pilocarpine, mushroom poisoning) Anticholinesterases Reversible carbamate inhibitors (pyridostigmine, neostigmine) Organophosphorous inhibitors (parathion, sarin) Miscellaneous Alcohol, thiamine (vitamin B1) deficiency Vincristine, perhexiline maleate Thallium, arsenic, mercury Mercury poisoning (pink disease) Ciguatera toxicity Jellyfish and marine animal venoms First dose of certain drugs (prazosin, captopril) Withdrawal of chronically used drugs (clonidine, opiates, alcohol) Adapted from Mathias CJ. Disorders of the autonomic nervous system. In: Bradley WG, Daroff RB, Fenichel GM, Jankovic J, eds. Neurology in clinical practice, 4th ed. Philadelphia: Butterworth-Heinemann, 2004;2406.

TABLE 85-3 Examples of Localized Autonomic Disorders Horner’s syndrome Holmes-Adie pupil Crocodile tears (Bogorad’s syndrome) Gustatory sweating (Frey’s syndrome) Reflex sympathetic dystrophy Idiopathic palmar or axillary hyperhidrosis Chagas’ disease (Trypanosoma cruzi)* Surgical procedures† Sympathectomy (regional) Vagotomy and gastric drainage procedures in “dumping” syndrome Organ transplantation (heart, lungs) *

Listed here because it specifically targets intrinsic cholinergic plexuses in the heart and gut. Surgery also may cause other localized disorders, such as Frey’s syndrome after parotid surgery.

†

Cardiovascular Postural hypotension Lability of blood pressure Tachycardia Sudomotor Hypohidrosis or anhidrosis Gustatory sweating Heat intolerance

Supine hypertension Paroxysmal hypertension Bradycardia Hyperhidrosis Hyperpyrexia

Alimentary Xerostomia Gastric stasis Constipation

Dysphagia Dumping syndromes Diarrhea

Urinary Nocturia Urgency; retention

Frequency Incontinence

Sexual Erectile failure Retrograde ejaculation Eye Pupillary abnormalities Alacrima

Ejaculatory failure

Ptosis Abnormal lacrimation with food ingestion

ally is a history of consanguinity in parents of Ashkenazi Jewish origin. Vasovagal syncope frequently presents in teenage years. In familial amyloid polyneuropathy, symptoms often occur in adulthood. In later years, after the age of 50, a number of neurodegenerative disorders such as multiple system atrophy present; in this particular disorder, there is no familial or known genetic link, which is important to the family of such patients. There may be sex preponderance; vasovagal syncope and the postural tachycardia syndrome are more common in females. A detailed history is essential and must include drug medication and previous exposure to chemical substances. The history should include gestational details, including the use of drugs taken during pregnancy. In secondary autonomic disorders the features of the underlying or associated disorder need consideration because they may exacerbate autonomic manifestations. Individual assessments are necessary, especially of their psychologic state, in certain forms of vasovagal syncope, also known as emotional syncope. The clinical findings may be confined to an area or an organ or may involve an entire system or systems. Impairment of the parasympathetic supply to the iris musculature occurs in the Holmes-Adie pupil; in essential hyperhidrosis, only the palms and soles may be affected. In generalized disorders a cardinal feature often is orthostatic (postural) hypotension (Fig. 85-4). This feature is defined as a decrease in systolic blood pressure of more than 20 mm Hg, or a fall in diastolic blood pressure of more than 10 mm Hg, while standing or during head-up tilt to 60 degrees for at least 3 minutes (Schatz et al., 1996). A variety of symptoms accompany the fall in blood pressure (Bleasdale-Barr and Mathias, 1998, Mathias et al., 1999) (Table 85-5). These depend on the rapidity and degree of fall in blood pressure, the extent to which compensatory factors come into play,

Mathias / Disorders of the Autonomic Nervous System 60-DEGREE HEAD-UP TILT 150

180

60-degree head-up tilt

0 180

60-degree head-up tilt

0 Autonomic failure

0

and the underlying disorder. Many factors influence orthostatic hypotension (Table 85-6). Stimuli in daily life such as food ingestion and mild exercise (Figs. 85-5 and 85-6) can lower supine blood pressure and unmask or exaggerate orthostatic hypotension (Mathias et al., 1991; Smith et al., 1993). The effect of drugs should be considered. Determination of the mechanisms contributing to orthostatic hypotension is of importance in management.

TABLE 85-5 Some of the Symptoms Resulting from Orthostatic Hypotension and Impaired Perfusion of Various Organs Cerebral Hypoperfusion Dizziness Visual disturbances Blurred—tunnel Scotoma Graying out—blacking out Color defects Loss of consciousness Cognitive deficits Muscle Hypoperfusion Paracervical and suboccipital (“coat hanger”) ache Lower back/buttock ache Subclavian Steal-like Syndrome Renal Hypoperfusion Oliguria Spinal Cord Hypoperfusion Nonspecific Weakness, lethargy, fatigue Falls Adapted from Mathias, 2003.

150

Heart rate (bpm)

Blood pressure (mm Hg) (Portapres II)

Normal

2133

FIGURE 85-4. Blood pressure and heart rate before, during, and after head-up tilt in a normal subject (upper panel), and in a patient with autonomic failure (lower panel). In the normal subject, there is no fall in blood pressure during head-up tilt, unlike a subject with autonomic failure in whom blood pressure falls promptly and remains low with a blood pressure overshoot on return to the horizontal. In this subject, there is only a minimal change in heart rate despite the marked blood pressure fall. In each subject, continuous blood pressure and heart rate was recorded with the Portapres II monitor. (Adapted from Mathias, 2005.)

0

INVESTIGATION OF AUTONOMIC DYSFUNCTION Autonomic activity may be measured directly or indirectly. Sympathetic nerve activity can be recorded using the electrophysiologic technique of microneurography or biochemically by measuring plasma noradrenaline and adrenaline levels using spillover techniques (Esler et al., 2003; Wallin, 2002). Each has its limitations. Some are invasive and measurements in a particular territory may not reflect activity in the whole body or other regions than from where the measurements are made. In clinical practice, functional effects are measured with systems- and organdirected investigations (Mathias and Bannister, 2002a) (Table 85-7). Testing always should be in combination with the clinical history and examination. The main objectives of investigation are:

TABLE 85-6 Factors That May Influence Orthostatic Hypotension Speed of positional change Time of day (worse in the morning) Prolonged recumbency Warm environment (hot weather, hot bath) Raising intrathoracic pressure—micturition, defecation, or coughing Water ingestion* Food and alcohol ingestion Physical exertion Physical maneuvers and positions (bending forward, abdominal compression, leg crossing, squatting, activating calf muscle pump)** Drugs with vasoactive properties *This raises blood pressure in autonomic failure. † These maneuvers usually reduce the postural fall in blood pressure in neurogenic causes of orthostatic hypotension, unlike the others. Adapted from Mathias, 2003.

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Neuroendocrine and Autonomic Nervous System Disorders / 85 FIGURE 85-5. Twenty-four-hour noninvasive ambulatory blood pressure profile, showing systolic (dark circles) and diastolic (dark squares) blood pressure and heart rate at intervals through the day and night. A, Normal. The changes in a normal subject with no postural fall in blood pressure; there was a fall in blood pressure at night while asleep, with a rise in blood pressure on waking. B, Patient with autonomic failure. The marked falls in blood pressure usually are the result of postural changes, either sitting or standing. Supine blood pressure, particularly at night, is elevated. Getting up to micturate causes a marked fall in blood pressure (at 0300 hours). There is a reversal of the diurnal changes in blood pressure. There are relatively small changes in heart rate, considering the marked changes in blood pressure. (From Mathias and Bannister, 2002b. Reprinted with permission of Oxford University Press.)

A Blood pressure (mm Hg)

200 Systolic

In bed

Diastolic

150

100

50 0

Heart rate (bpm)

150

75

0 09

11

13

15

17

19

21

23

01

03

05

07

Sample time/24 h

B Blood pressure (mm Hg)

200 Systolic

Diastolic

150

100

50 In bed 0

Heart rate (bpm)

150

75

0 09

11

13

15

17

19

21

23

01

03

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Sample time/24 h

1. To assess if autonomic function is normal or abnormal. 2. If the latter, to ascertain the degree of autonomic dysfunction with an emphasis on the site of lesion and functional deficit. 3. To determine the underlying or associated disease because this disease will need concurrent treatment with management of autonomic dysfunction. Investigation of the autonomic nervous system ideally should utilize noninvasive techniques that are safe, reproducible, and patient friendly so that they can be used for initial screening and if needed for repeat testing to deter-

mine disease progression and the effects of therapy. This comforting approach is of importance in young children. Different autonomic laboratories are unlikely to have similar equipment and an identical set of procedures, despite attempts to standardize such approaches. High specificity and sensitivity, although desirable, may not be achievable or practical, and the findings must be considered in the context of a wide variety of factors, including the patient’s ability to cooperate while being tested. The effect of drugs is another confounding factor, because some have effects directly or indirectly on autonomic function. Finally, the results must be linked with the relevant clinical symptoms and signs. Difficulties mainly arise in mild or moderate cases with

Mathias / Disorders of the Autonomic Nervous System

FIGURE 85-6. Supine systolic and diastolic blood pressure before and after a standard meal in a group of normal subjects (stippled area) and in a patient with autonomic failure. Blood pressure does not change in the normal subjects after a meal taken while lying flat. In the patient, there is a rapid fall in blood pressure to levels around 80/50 mm Hg, which remains low while in the supine position over the 3-hour observational period. (From Mathias and Bannister, 2002b. Reprinted with permission of Oxford Univeristy Press.)

140 130

Systolic and diastolic blood pressure (mm Hg)

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120 Control subjects 110 100 90 80 70 60 50 Autonomic failure 40

0

Meal

–30 –15

0

15

30

45

60

90

120

180

Time (min)

questionable autonomic involvement, unlike patients with definite abnormalities.

Cardiovascular System A postural fall in blood pressure, especially if consistently more than 20 mm Hg systolic, or less in the presence of symptoms, warrants further investigation. Head-up tilt often is used as the postural stimulus, especially when the neurologic deficit or severe hypotension makes it difficult for the patient to stand (see Fig. 85-3). In some, orthostatic hypotension may be unmasked by exercise (Smith and Mathias, 1995) because vasodilatation in skeletal muscle is not appropriately counteracted by autonomic reflexes. Food ingestion also may be a provoking factor (Mathias et al., 1989), presumably because of splanchnic vasodilatation not compensated for by vasoconstriction in other regions. Nonneurogenic causes of orthostatic hypotension also must be considered (Table 85-8). The same may occur with drugs that cause vasodilatation, even if this usually is only a minor side effect. Both blood pressure and heart rate can be accurately measured using noninvasive techniques, many of which are automated and provide a printout at preset intervals. Intermittent ambulatory recordings over a 24-hour period using small computerized devices are of particular value, especially at home to determine the effects of various stimuli in daily life (see Fig. 85-5). They may be of value in determining the beneficial effects of therapy in different situations. Beat-by-beat measurement of blood pressure and heart rate is essential in neurally mediated syncope when the changes in blood pressure often are rapid and would be missed because of the slow response time of most noninvasive sphygmomanometers; furthermore they may be

independent of changes in heart rate. The Finometer, Portapres, and CNS Taskforce machines enable noninvasive and beat-by-beat blood pressure and heart rate recordings with a finger cuff and provide a reliable measure of change in blood pressure (Wieling and Karemaker, 2002). Screening investigations help determine the site and extent of the cardiovascular autonomic abnormality. With these tests, cooperation is an essential component, which may be difficult to ensure, especially in younger children. The responses to the Valsalva maneuver during which intrathoracic pressure is raised depend on the integrity of the entire baroreflex pathway. Changes in heart rate alone, even in the absence of blood pressure recordings, provide a useful guide. Some patients may, however, raise mouth pressure without necessarily raising intrathoracic pressure, resulting in a falsely abnormal response. Stimuli that raise blood pressure, such as isometric exercise (by sustained hand grip for 3 minutes), the cold pressor test (immersing the hand in ice slush for 90 seconds), and mental arithmetic (using serial-7 or serial-17 subtraction), activate different afferent or central pathways, which then stimulate the sympathetic outflow. The heart rate responses to postural change, deep breathing (sinus dysrhythmia; see Fig. 85-5), and hyperventilation assess cardiac vagal efferent pathways. Additional investigations may be needed to determine factors causing or contributing to orthostatic hypotension and syncope. These include determining the responses to food ingestion and exercise. To assess postprandial hypotension, the cardiovascular responses to a balanced liquid meal containing carbohydrate, protein, and fat are determined while supine, with comparisons of the blood pressure response to head-up tilt before the meal and 45 minutes later (Mathias et al., 1991) (see Fig. 85-6). To evaluate exerciseinduced hypotension, responses are obtained during graded

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TABLE 85-7

TABLE 85-8

Outline of Investigations in Autonomic Dysfunction

Examples of Non-neurogenic Causes of Orthostatic Hypotension

Cardiovascular Physiologic

Biochemical

Pharmacologic

Endocrine Sudomotor

Gastrointestinal Renal Function and Urinary Tract

Sexual Function Respiratory Eye and Lachrymal Function

Head-up tilt (60 degrees)*; standing*; Valsalva’s maneuver* Pressor stimuli* (isometric exercise, cold pressor, mental arithmetic) Heart rate responses—deep breathing,* hyperventilation,* standing,* head-up tilt,* 30:15 R-R interval ratio Liquid meal challenge Exercise testing Carotid sinus massage Plasma noradrenaline: supine and head-up tilt or standing; urinary catecholamines; plasma renin activity and aldosterone Noradrenaline: alpha-adrenoceptors, vascular Isoprenaline: beta-adrenoceptors, vascular and cardiac Tyramine: pressor and noradrenaline response Edrophonium: noradrenaline response Atropine: parasympathetic cardiac blockade Clonidine—alpha2-adrenoceptor agonist: noradrenaline suppression; growth hormone stimulation Central regulation thermoregulatory sweat test Sweat gland response to intradermal acetylcholine, quantitative sudomotor axon reflex test, localized sweat test Sympathetic skin response Videocine fluoroscopy, barium studies, endoscopy, gastric emptying studies, lower gut studies Day and night urine volumes and sodium/potassium excretion Urodynamic studies, intravenous urography, ultrasound examination, sphincter electromyography Penile plethysmography Intracavernosal papaverine Laryngoscopy Sleep studies to assess apnea and oxygen desaturation Pupil function, pharmacologic and physiologic Schirmer’s test

*Indicates screening autonomic tests used in the author’s London unit. Adapted from Mathias and Bannister, 2002b. Reprinted with permission of Oxford University Press.

incremental supine exercise using a bicycle ergometer with measurement of postural responses before and after exercise (Smith and Mathias, 1995) (Fig. 85-7). Measurement of plasma catecholamine levels may provide valuable information about the site of lesion. Thus in postganglionic lesions, as observed in acute sympathetic failure and adults with pure autonomic failure, the supine basal level of plasma noradrenaline is low, indicating a distal lesion. This finding differs from that in patients with central lesion (as in the adult with multiple system atrophy), in whom supine levels often are within the normal range (Fig. 85-8). In both groups, however, there is an attenuation or lack of rise in plasma noradrenaline levels during head-up

Low Intravascular Volume Blood/plasma loss Fluid/electrolyte deficiency Diminished intake Loss from gut Loss from kidney Endocrine deficiency

Hemorrhage, burns, hemodialysis Anorexia nervosa Vomiting, ileostomy losses, diarrhea Salt-losing nephropathy, diuretics Adrenal insufficiency (Addison’s disease)

Cardiac Insufficiency Myocardial Myocarditis Impaired ventricular filling Atrial myxoma, constrictive pericarditis Impaired output Aortic stenosis Vasodilatation Endogenous

Exogenous

Hyperpyrexia Hyperbradykininism Systemic mastocytosis Varicose veins Drugs that are vasodilators Alcohol Excessive heat

Adapted from Mathias, 2003.

tilt, indicating impairment of sympathetic neural activity. However, in patients with high spinal cord lesions who also have preganglionic lesions, basal plasma noradrenaline and adrenaline levels are low and do not rise with postural change (Mathias et al., 1975). There is a rise (but only moderately above the basal levels of normal subjects) during severe hypertension accompanying autonomic dysreflexia (Mathias et al., 1976) that differentiates these patients from pheochromocytoma in which paroxysmal hypertension often is associated with elevated plasma noradrenaline or adrenaline levels. Extremely low or undetectable levels of plasma noradrenaline and adrenaline with elevated plasma dopamine levels occur in sympathetic failure caused by deficiency of the enzyme dopamine β-hydroxylase, which converts dopamine into noradrenaline (Mathias and Bannister, 2002b). Plasma levels of this enzyme are undetectable, but this situation may occur in 10% of normal individuals and is not diagnostic of the disorder. Immunohistochemical studies confirm the absence of the enzyme in tissues such as skin. Many techniques capitalize on applying the advances of modern technology, as demonstrated with the study of cardiovascular autonomic function. These include techniques for the noninvasive measurement of cardiac function and blood flow in various regions (Chandler and Mathias, 2002; Puvi-Rajasingham et al., 1997), a variety of computer and spectral analytic techniques that assess heart rate (Parati et al., 2002), and methods (some invasive) that measure total body and regional noradrenaline spillover in the heart, splanchnic, renal, and brain circulation (Esler et al., 2003; Lambert et al., 1997). Techniques to visualize sympathetic innervation of cardiac tissue include radionuclide 123metaiodobenzylguanidine (Hakusui et al,. 1994, Mantysaari et al., 1996), and positron emission tomography scanning with 6-[18F]fluorodopamine (Goldstein et al,. 1997). These

Mathias / Disorders of the Autonomic Nervous System Exercise

FIGURE 85-7. Changes in systolic blood pressure during supine bicycle exercise at three incremental levels (25, 50, and 75 watts) in normal subjects (controls) and patients with multiple system atrophy (MSA) and pure autonomic failure (PAF). The bars indicate standard error of the mean. Unlike controls in whom there is a rise, there is a fall in blood pressure in both MSA and PAF. Blood pressure returns rapidly to the baseline in controls, unlike in the two patient groups in whom it takes almost 10 minutes. All remained horizontal during and for 10 minutes postexercise. (From Smith et al., 1995b.)

75 W 50 W

25 W

Change in systolic blood pressure (mm Hg)

40 Controls MSA PAF

30

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20 10 0 –10 –20 –30 – 40

0

3

6

9

Post 2

Post 5

Post 10

Time (min)

techniques have a role in the clinical research setting, mainly in adults, and some are applied to the clinical investigation of cardiovascular autonomic function. In the majority of autonomic disorders affecting the circulation, physiologic testing using head-up postural challenge, a series of pressor tests, Valsalva’s maneuver, deep breathing, and hyperventilation is often adequate for screening purposes. Depending on the disorder, additional tests may be needed, such as food and exercise challenge, ocular massage, and appropriate biochemical and pharmacologic studies.

Sweating The thermoregulatory sweating response is tested by elevating body temperature by 10° C, with either a heat cradle or hot water bottles and a space blanket. This process tests the integrity of central pathways, from the hypothalamus to the sweat glands. Sweating is assessed using powders such as Ponceau red, which turns from a pale pink to vivid red on exposure to moisture. In autonomic failure, the thermoregulatory sweating response is lost, and additional tests are needed to distinguish between central and peripheral lesions. In postganglionic lesions, the sudomotor and pilomotor response to intradermal acetylcholine is lost. Various measures can be used, including the quantitative sudomotor axon reflex test. Intradermal pilocarpine assesses the function of sweat glands directly. In dopamine βhydroxylase deficiency syndrome, sympathetic cholinergic function and sweating is preserved, providing a clue to selective impairment of sympathetic noradrenergic function. In gustatory sweating, spicy foods, cheese, or substances containing tyramine are ingested to provoke sweating (Fig. 85-9).

The sympathetic skin response measures electrical potentials from electrodes on the foot and hand and provides a measure of sympathetic cholinergic activity to sweat glands. The sympathetic skin response can be induced by stimuli that are physiologic (inspiratory gasps, loud noise, or touch) or electrical (median nerve stimulation) (Cariga et al., 2001a, 2001b; Nicotra et al., 2004). In peripheral autonomic disorders, such as pure autonomic failure and pure cholinergic dysautonomia (Fig. 85-10), the sympathetic skin response is a reliable marker of sympathetic cholinergic function. However, this reliability depends on the presence or absence of the response, rather than latency and amplitude, which are highly variable (Magnifico et al., 1998).

Gastrointestinal Tract Video or cinefluoroscopy is of value in assessing swallowing and the presence of oropharyngeal dysphagia. A barium swallow, meal, and follow-through are helpful in suspected upper gastrointestinal disorders, although alternative investigation by endoscopy provides the opportunity for biopsy. Caution should be exercised when there is suspected widespread cholinergic involvement and colonic stasis. Esophageal manometry is of value in disorders of motility and esophagogastric function. Several methods (radioisotope methods and scintigraphic scanning) are available to determine gastric motility noninvasively. When bacterial overgrowth is a suspected cause of diarrhea, a therapeutic trial with broad-spectrum antibiotics, such as neomycin or tetracycline, may be used along with investigations such as jejunal aspiration and the C14 glycocholate test. In the adult with chronic primary autonomic failure, such as multiple system atrophy and pure autonomic failure (Maule et al.,

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Neuroendocrine and Autonomic Nervous System Disorders / 85

600 Supine Tilt

Noradrenaline (pg/mL)

500 400 300 200 100 0

Controls

MSA

PAF

*

*

DβH Defn-1

DβH Defn-2

*

*

FIGURE 85-8. Plasma noradrenaline, adrenaline, and dopamine levels (measured by high-pressure liquid chromatography) in normal subjects (controls), patients with multiple system atrophy (MSA) or pure autonomic failure (PAF), and two individual patients with dopamine β-hydroxylase (DβH) while supine and after head-up tilt to 45 degrees for 10 minutes. The asterisk indicates levels below the detection limits for the assay, which are less than 5 pg/mL for noradrenaline and adrenaline and less than 20 pg/L for dopamine. Bars indicate ± SEM. (From Mathias and Bannister, 2002b. Reprinted with permission of Oxford University Press.)

600

Adrenaline (pg/mL)

500 400 300 200 100 0

Controls

MSA

PAF

DβH Defn-1

DβH Defn-2

Controls

MSA

PAF

DβH Defn-1

DβH Defn-2

600

Dopamine (pg/mL)

500 400 300 200 100 0

2002), Helicobacter pylori infection is common and may contribute to gastric dysfunction; whether this occurs in children is unclear. Small bowel manometry and telemetric devices are of value in separating myopathic from neuropathic disorders of the gut. The measurement of transit time and proctologic function are used to investigate lower bowel disorders causing diarrhea, constipation, and fecal incontinence.

Urinary Tract Nocturnal polyuria can be assessed by separate day and night measurement of urine volume. Measurements of urine osmolarity and the concentration of sodium and potassium may be helpful. When the urinary bladder is involved, an intra-

venous pyelogram and micturating cystometrogram may be needed. Urodynamic measurements are valuable in defining the function of the bladder musculature and sphincter mechanisms. Measurement of postmicturition residual volume (e.g., by ultrasound) is of particular importance. It may be high when the urinary bladder is involved; this residual may cause urinary infection, which should be detected early and promptly treated. In some, such as patients with spinal cord lesions, particular care must be provided because recurrent infections, along with calculi, may cause chronic renal failure.

Respiratory System Respiratory rate and arterial blood gases should be measured to determine the degree of hypoxia, especially during

Mathias / Disorders of the Autonomic Nervous System

A

2139

B

FIGURE 85-9. Gustatory sweating induced by food in a subject recovering from an acute pandysautonomia. On contact with moisture, the pale powder, hardly visible in A, turns a vivid red, with sweat dripping down the neck (as observed in B). (From Mathias, 1996. ©1996. Reproduced with permission from The McGraw-Hill Companies.)

A

B

CONTROL

PURE AUTONOMIC FAILURE Right hand

Right hand

100 ␮V 500 ␮V

Right foot

Right foot 1 sec PURE CHOLINERGIC DYSAUTONOMIA Right hand

1 sec DBH DEFICIENCY

500 ␮V

Right foot 1 sec

Right hand 500 ␮V

Right foot

1 sec

FIGURE 85-10. A, The sympathetic skin response (in microvolts) from the right hand and right foot of a normal subject (control) and a patient with dopamine β-hydroxylase (DβH) deficiency. B, The sympathetic skin response could not be recorded in two patients, one with pure autonomic failure and the other with pure cholinergic dysautonomia. (From Magnifico et al., 1998. Reprinted with kind permission of Springer Science and Business Media.)

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sleep in patients with apneic episodes. Indirect and direct laryngoscopy detects laryngeal abductor paresis.

Eye Various pharmacologic preparations administered locally help determine the degree of sympathetic or parasympathetic involvement of pupils. Lacrimal secretion can be tested by Schirmer’s test, and damage from deficient secretion can be assessed using rose bengal instillation followed by slit-lamp examination.

Skin The flare response is elicited by intradermal injection of histamine. A positive response is indicated by local swelling and redness. Absence of pain, piloerection, and flare are typical in autonomic dysfunction.

Miscellaneous Additional nonautonomic investigations may be needed to determine the cause of the disorder or associated complications. Computed tomographic scans and magnetic resonance imaging (MRI) of the brain help in assessing basal ganglia, cerebellar, and brainstem involvement. Positron emission tomography scanning has provided valuable information in adults with central autonomic disorders, such as multiple system atrophy (Brooks, 2002). In suspected peripheral nerve involvement, electrophysiologic studies together with sural nerve biopsy are indicated. In amyloidosis, a rectal or renal biopsy may be diagnostic; the latter is indicated if there is renal involvement. Genetic testing is helpful in familial amyloid polyneuropathy. To exclude adrenal insufficiency, a short or long Synacthen test should be performed. In patients with localized lesions, specific investigations to determine the cause may be warranted. In Horner’s syndrome, for example, investigations may include brain neuroimaging to exclude a midbrain or medullary hemorrhage, bronchoscopy, and radiography to exclude an apical bronchial neoplasm, and carotid artery angiography to assess lesions of the internal carotid artery. Measurement of plasma cortisol, plasma renin activity, and plasma aldosterone levels is useful in certain cases. In Addison’s disease and adrenocortical failure, basal plasma renin levels are markedly elevated, whereas plasma aldosterone is low or absent. In diabetic autonomic neuropathy, there may be low levels of both plasma renin and aldosterone, which contribute to hyperkalemia.

MANAGEMENT OF ORTHOSTATIC HYPOTENSION Orthostatic hypotension may cause considerable disability. In some children, as in dopamine β-hydroxylase deficiency, it may be the reason for inability to exercise. In others there is the potential risk of serious injury. In non-neurogenic orthostatic hypotension, the underlying problem may need to be resolved rapidly because it may be an indicator of substantial blood or fluid loss or of a serious underlying disorder, such as adrenal insufficiency (Table 85-9).

TABLE 85-9 Some of the Approaches Used in the Management of Orthostatic Hypotension Caused by Autonomic Failure NONPHARMACOLOGIC MEASURES To be avoided Sudden head-up postural change (especially on waking) Prolonged recumbency Straining during micturition and defecation High environmental temperature (including hot baths) “Severe” exertion Large meals (especially with refined carbohydrate) Alcohol Drugs with vasodepressor properties To be introduced Head-up tilt during sleep Small frequent meals High salt intake Judicious exercise (including swimming) Body positions and maneuvers To be considered Elastic stockings Abdominal binders Water ingestion PHARMACOLOGIC MEASURES Starter drug—fludrocortisone Sympathomimetics—ephedrine, midodrine Specific targeting—octreotide, desmopressin, erythropoietin Adapted from Mathias, 2003.

Approaches to therapy may include reducing fluid loss, replacing blood and fluids, correcting the endocrine deficiency, improving cardiac function, and preventing vasodilatation. In some patients with neurogenic orthostatic hypotension, treatment may be highly effective, as in dopamine β-hydroxylase deficiency; in the majority, however, cure is less likely. The management depends on the pathophysiologic processes and primary disease responsible. It should be emphasized that the management of associated non-neurogenic factors (such as those resulting from fluid and blood loss), also is essential because they can considerably exacerbate neurogenic orthostatic hypotension. Nonpharmacologic measures are an essential component of management, even when drugs are used. Because no single drug can effectively mimic the actions of the sympathetic nervous system, a multipronged approach is needed (Table 85-10), which includes factors to avoid, institute, and consider. Even in young children, increasing awareness of the many factors that lower blood pressure is important. These include simple measures such as avoiding rapid postural change, especially in the morning when getting out of bed, because the supine blood pressure often is lowest at this time, in those in whom nocturnal polyuria reduces extracellular fluid volume. Prolonged bed rest and recumbency, especially postoperatively, should be avoided. Head-up tilt at night is beneficial and may reduce salt and water loss by stimulating the renin-angiotensin-aldosterone system or by activating other hormonal, neural, or local renal hemodynamic mechanisms, which reduce recumbency-induced diuresis. When head-up tilt is impractical or the degree of tilt achieved inadequate, nocturnal polyuria and nocturia can be reduced with the antidiuretic agent desmopressin (Mathias and Young, 2003; Mathias et al., 1986). Straining during micturition and bowel movement should be avoided. In hot weather there

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lower limb elastic stockings and abdominal binders (Tanaka et al., 1997). Each has its limitations and may increase susceptibility to orthostatic postural hypotension when not in use. Tachypacing with an implanted cardiac pacemaker is of no benefit in the management of neurogenic orthostatic hypotension except in the rare situation when bradycardia also occurs (Bannister et al., 1986, Sahul et al., 2004). This result occurs because raising heart rate without increasing venous return does not elevate cardiac output and therefore does not raise blood pressure. Recent observations indicate that ingestion of 500 mL of water raises supine blood pressure substantially in older adults (Jordan et al., 2000) and raises supine blood pressure and improves orthostatic hypotension in primary autonomic failure (Cariga et al., 2001a; Young and Mathias, 2004) (Fig. 85-11). Drugs to raise blood pressure are needed in some patients, in addition to the nonpharmacologic measures described above. They act in various ways (see Table 85-10). In autonomic failure, enhanced blood pressure responses usually occur to pressor and vasodepressor agents; the former may result in severe hypertension, especially when supine, whereas vasodepressor substances may cause marked hypotension. Although there is no evidence of a mineralocorticoid deficiency in primary autonomic failure, a valuable starter drug is fludrocortisone, in a low dose of 0.1 or 0.2 mg at night. Low-dose fludrocortisone reduces the inability to retain salt and water, especially when recumbent, and increases the sensitivity of blood vessels to pressor substances. In low doses it is less likely to induce side effects such as ankle edema and hypokalemia. If nocturnal polyuria is not reduced by head-up tilt, fludrocortisone can be effectively combined with desmopressin, a vasopressin-2 receptor agonist with potent antidiuretic but minimal direct pressor activity. A dosage of 5 to 40 mg intranasally or 100 to 400 mg orally at night reduces the diuresis but when used without fludrocortisone does not prevent nocturnal natriuresis. These trials have been performed mainly in chronic autonomic failure. Smaller doses (usually 5 to 10 mg only) are used in postganglionic lesions (such as pure autonomic

TABLE 85-10 Outline of the Major Actions by Which a Variety of Drugs May Reduce Orthostatic Hypotension. Reducing salt loss/plasma volume expansion Mineralocorticoids (fludrocortisone) Reducing nocturnal polyuria V -receptor agonists (desmopressin) 2 Vasoconstriction—sympathetic On resistance vessels (ephedrine, midodrine, phenylephrine, noradrenaline, clonidine, tyramine with monoamine oxidase inhibitors, yohimbine, L-dihydroxyphenylserine) On capacitance vessels (dihydroergotamine) Vasoconstriction—nonsympathomimetic V1 receptor agents—terlipressin Ganglionic nicotinic-receptor stimulation Anticholinesterase inhibitors Preventing vasodilatation Prostaglandin synthetase inhibitors (indomethacin, flurbiprofen) Dopamine receptor blockade (metoclopramide, domperidone) Beta2-adrenoceptor blockade (propranolol) Preventing postprandial hypotension Adrenosine receptor blockade (caffeine) Peptide release inhibitors (somatostatin analog: octreotide) Increasing cardiac output Beta blockers with intrinsic sympathomimetic activity (pindolol, xamoterol) Dopamine agonists (ibopamine) Increasing red cell mass Erythropoietin Adapted from Mathias, 2003.

may be elevation of body temperature if thermoregulatory mechanisms, such as sweating, are impaired; this elevation may further increase vasodilatation and worsen orthostatic hypotension. Ingestion of alcohol or large meals, especially those containing a high carbohydrate content, may cause postprandial hypotension and aggravate postural hypotension. Various physical maneuvers such as leg crossing, squatting, sitting in the knee-chest position, and abdominal compression, are of value in reducing orthostatic hypotension (Wieling et al., 1993). Consideration should be given to introducing means to prevent venous pooling during standing. These include PAF SUBJECT

Continuous finger blood pressure (mm Hg)

160 140 Water 120 100 80 60 40 20 0 –5

0

5

10

15

20 25 30 Time (min)

35

40

45

50

55

FIGURE 85-11. Changes in blood pressure before and after 500 mL distilled water ingested at time “0” in a patient with pure autonomic failure (PAF). Blood pressure is measured continuously using the Portapres II monitor. (From Cariga and Mathias, 2001. ©The Biochemical Society. Reproduced with permission.)

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failure) because they appear to be more sensitive to the drug than in patients with central lesions (such as multiple system atrophy). Plasma sodium must be monitored to exclude hyponatremia and water intoxication. These can be reversed by stopping the drug and withholding water, but a diuresis then ensues, which may enhance orthostatic hypotension. Sympathetic failure is a feature of neurogenic orthostatic hypotension and sympathomimetics often are used with fludrocortisone. Drugs that mimic the activity of noradrenaline, either directly or indirectly, include ephedrine and midodrine. Ephedrine acts both directly and indirectly, and is of value in central and incomplete autonomic lesions, including multiple system atrophy. A dose of 15 mg three times daily initially can be increased to 30 or 45 mg three times daily, although central side effects (loss of appetite and insomnia) may limit use of the higher doses. In severe peripheral sympathetic lesions (as in pure autonomic failure), it may have minimal or no effects. Drugs that act directly on alpha-adrenoceptors include midodrine, which is converted to the active metabolite, desglymidodrine (Low et al., 1997). The ergot alkaloid dihydroergotamine acts predominantly on venous capacitance vessels, but its effects are limited by its poor absorption; high oral doses (5 to 10 mg three times daily) may be needed. In individuals with a precise biochemical deficit, such as in dopamine β-hydroxylase deficiency, agents can be given that bypass deficient enzyme systems and result in appropriate neurotransmitter replacement (Fig. 85-12). The amino acid L-threo-3,4-dihydroxyphenylserine is directly converted by dopa-decarboxylase into noradrenaline. Whether this occurs intra- or extraneuronally (or both) is unclear. It may be of value in the management of orthostatic hypotension in primary autonomic failure (Kaufmann et al., 2003; Mathias et al., 2001a). Some drugs act through pre- and postsynaptic alpha2adrenoceptor mechanisms although they have limited application in practice. The alpha2-adrenoceptor agonist clonidine, which lowers blood pressure mainly through a CH2 TYROSINE HO

HO

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central reduction in sympathetic outflow, also acts on peripheral postsynaptic alpha2-adrenoceptors, and may raise blood pressure in the presence of pressor supersensitivity. Yohimbine blocks presynaptic alpha2-adrenoceptors, which normally suppress release of noradrenaline and should theoretically benefit in incomplete sympathetic lesions, as observed in single-dose studies. Recently the acetylcholinesterase inhibitor pyridostigmine has been reported to raise blood pressure when given in single doses (Singer et al., 2003). Their value in long-term management is not known. In adults the management of orthostatic hypotension, especially with drugs, may cause supine hypertension, may occur in chronic autonomic failure, and may be worsened by treatment. It is unclear if this is a problem in children. It may occasionally result in cerebral hemorrhage, aortic dissection, myocardial ischemia, or cardiac failure. This effect may be a greater problem with certain drug combinations, such as tyramine (which releases noradrenaline) and monoamine oxidase inhibitors (such as tranylcypromine and moclobemide), which prolong its actions. Supine hypertension may increase symptoms of cerebral ischemia during subsequent postural change, probably through an unfavorable resetting of cerebral autoregulatory mechanisms. To prevent these problems, head-up tilt, omission of the evening dose of vasopressor agents, a prebedtime snack to induce postprandial hypotension, and even nocturnal use of short-acting vasodilators have been suggested. To overcome the problems with lability of blood pressure, a subcutaneous infusion pump (as in the control of hyperglycemia with insulin in diabetes mellitus) has been used in adults, infusing the short-acting vasoconstrictor, noradrenaline. Previous studies with a pilot device had been successful, but with a number of practical problems, including the difficulty of accurate monitoring of blood pressure without an intra-arterial catheter. Some of these problems have been overcome (Oldenberg et al., 2001). This may benefit the severely hypotensive patient refractory to the combination of nonpharmacologic and conventionally administered drug therapy.

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FIGURE 85-12. Biosynthetic pathway in the formation of adrenaline and noradrenaline. The structure of DL-DOPA is indicated on the right. It is converted directly to noradrenaline by dopa decarboxylase, thus bypassing dopamine β-hydroxylase. (From Mathias et al., 1990. Reprinted with permission of Oxford University Press.)

Mathias / Disorders of the Autonomic Nervous System

A variety of drugs have been used in adults, sometimes with success. They include the prostaglandin synthetase inhibitors, indomethacin and flurbiprofen. They may act by blocking vasodilatory prostaglandins, by causing salt and water retention through their renal effects, or both. They have potentially serious side effects, however, such as gastrointestinal ulceration and hemorrhage. The dopamine antagonists metoclopramide and domperidone may be of value when an excess of dopamine is contributory. Beta-adrenoceptor blockers, such as propranolol, may be successful when orthostatic hypotension is accompanying tachycardia; the combination of blocking beta2adrenoceptor vasodilatation and beta1-adrenoceptor–induced tachycardia may account for the benefit. Beta-adrenoceptor blockers with high intrinsic sympathomimetic activity, such as pindolol, may raise blood pressure and probably increase cardiac output, but may cause cardiac failure. Various therapeutic approaches have been used to reduce severe postprandial hypotension. Caffeine, which blocks vasodilatory adenosine receptors, has been used in a dose of 250 mg (the equivalent of two cups of coffee). The prodrug L-dihydroxyphenylserine, presumably through adrenoceptorinduced vasoconstriction, reduces postprandial hypotension in primary autonomic failure (Freeman et al., 1996). The somatostatin analog octreotide, which inhibits release of a variety of gastrointestinal tract peptides, including those with vasodilatory properties, has been successfully used to prevent postprandial hypotension; it also may partly reduce postural and exercise-induced hypotension (Smith et al., 1995b). It does not enhance nocturnal (supine) hypertension (Alam et al., 1995). The need for subcutaneous administration is a drawback. Exercise-induced hypotension may respond to octreotide or midodrine (Schrage et al., 2004). Anemia may occur in some subjects with primary autonomic failure and dopamine β-hydroxylase deficiency; it may be associated with renal impairment in diabetes mellitus and primary amyloidosis. Erythropoietin, which raises red cell mass and hemoglobin concentration, reduces orthostatic hypotension in such circumstances (Hoeldtke and Streeten, 1993).

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other neurologic features, in which the peripheral nerves often are affected. The precise causes are unclear and may include viral infections, with immunologic damage as a contributory factor. The prognosis in the pandysautonomias is variable, with complete recovery in some. Pure cholinergic dysautonomia mainly affects children and young adults (Hopkins et al., 1974; Inander et al., 1982; Takayama et al., 1987; Tomashevsky et al., 1972). Symptoms of parasympathetic failure include blurred vision, dry eyes, xerostomia, dysphagia involving mainly the lower esophagus, constipation, and urinary retention. Symptoms of sympathetic cholinergic failure are anhidrosis and a tendency to hyperthermia. The signs include dilated pupils, raised heart rate, dry and hot skin, a distended abdomen, and a palpable urinary bladder. Orthostatic hypotension is absent, as sympathetic vasoconstrictor function is not impaired. Only cholinergic muscarinic synapses are affected. There is a response to cholinomimetic agents, such as bethanechol, indicating preservation of postsynaptic cholinergic receptor function and suggesting a presynaptic lesion. A barium meal examination must be avoided because it will be retained in the colon (Fig. 85-13). The prognosis is good if complications are avoided. Recovery of cholinergic function is unlikely. The differential diagnosis in pure cholinergic dysautonomia includes the effects of anticholinergic drugs, poisons, and toxins. In jimsonweed (Datura stramonium) seed poisoning, there are similar autonomic features, along with additional features including hallucinations, hyperreflexia, and clonic jerking movements; recovery usually

DESCRIPTION OF AUTONOMIC DISORDERS Primary Autonomic Failure In autonomic disorders the etiology is unknown and there is no clear association with either specific lesions or known diseases. The acute-subacute dysautonomias are relatively rare, unlike the chronic forms of primary autonomic failure that occur mainly in adults (Mathias, 2004). The latter consists of pure autonomic failure in which only the autonomic nervous system is affected, unlike multiple system atrophy, in which there are additional neurologic deficits. The latter is a neurodegenerative disorder that mainly occurs older than the age of 55 and is sporadic in nature with no familial or hereditary component.

Acute or Subacute Dysautonomias There are three forms of dysautonomia: pure cholinergic dysautonomia, pure pandysautonomia (with both sympathetic and parasympathetic failure), and pandysautonomia with

FIGURE 85-13. Retention of barium in the colon of a patient with acute cholinergic dysautonomia 3 months after barium ingestion. Attempts to dislodge the barium failed. She needed a laparotomy, with partial colectomy. (From Mathias, 1996. ©1996. Reproduced with permission from The McGraw-Hill Companies.)

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occurs in a few days (Mikolich et al., 1975). A variant of botulism, botulism B, which spares motor pathways and appears to preferentially affect the cholinergic system, has been described; in such cases, however, there is substantial recovery within 3 months (Jenzer et al., 1975; Merz et al., 2003). In the pandysautonomias there is sympathetic and parasympathetic involvement that may occur with other neurologic features (Kanda et al., 1990; Young et al., 1975). In addition to cholinergic features, as described earlier, there are manifestations of sympathetic failure. Postural hypotension is often a major problem. The symptoms and clinical features, therefore, are more extensive and the investigation additionally indicates postural hypotension, diminished pressor responses, and an abnormal Valsalva maneuver. The degree of autonomic impairment varies from case to case; in those with neurologic deficits, electrophysiologic studies are often suggestive of a peripheral neuropathy and abnormal features are seen on nerve biopsy. The cerebrospinal fluid protein levels may be elevated. The prognosis in the pandysautonomias is variable; in some patients there may a substantial recovery, whereas in others, as with pure cholinergic dysautonomia, recovery may be minimal. These disorders may have an immunologic basis, and intravenous immunoglobulin has been used with success in some (Heafield et al., 1996; Smit et al., 1997); currently there is no clear evidence in favor of such an approach. The management consists of supportive therapy. Postural hypotension often impedes rehabilitation and usually calls for a combination of nondrug and drug therapy. Hyperthermia should be prevented. Adequate fluid intake and nutrition is important, particularly if there is a paralytic ileus. The investigation of dysphagia must not include the use of barium because this can result in deposition in the large bowel; a recent patient needed, in due course, a hemicolectomy with a colostomy. Blurred vision can be prevented with low-dose pilocarpine eyedrops. Artificial tears, such as hypromellose, are needed to prevent ocular complications. Artificial saliva is helpful. Cholinomimetics such as bethanechol and carbachol, which can be given either orally or parenterally to improve bowel and bladder activity, are helpful. The prognosis in the early stages largely depends on establishing an early diagnosis and on supportive management to prevent complications. As children grow, there may be new problems, as in males when they reach adulthood and experience erectile and ejaculatory dysfunctions.

Secondary Autonomic Failure Hereditary Sensory and Autonomic Neuropathies There are a number of hereditary autonomic disorders that are characterized by additional sensory involvement (Hilz, 2002) and have been classified into predominantly five types. Some, such as type III, the Riley-Day syndrome, can be diagnosed at birth. Types II, IV, and V appear in infancy or early childhood and type I in adulthood. There are varying autonomic abnormalities. In types I and IV, anhidrosis is a feature, being severe in the latter (congenital insensitivity to pain with anhidrosis). In type II, there is episodic hyper-

hidrosis, as in types II and V, but with fever, bladder, and gastrointestinal dysfunctions, tonic pupils, and apnea. A variety of autonomic abnormalities occur in type III, as described later. Autonomic investigation should include the intradermal histamine flare response, with an impaired response common in these disorders. There are other autonomic disorders with overlapping features, some of which may be related to nerve growth factor deficiency (Anand et al., 1991). Anhidrosis may be an integral component of some of the hereditary sensory and autonomic neuropathies (Houlden et al., 2001) or may be congenital and without other features (Cevoli et al., 2002).

Riley-Day Syndrome (Familial Dysautonomia) Because there are a number of familial autonomic disorders (including familial amyloid polyneuropathy and dopamine β-hydroxylase deficiency), the Riley-Day syndrome probably is a more appropriate designation. It is an autosomal-recessive disorder predominantly affecting autonomic and sensory neurons (Axelrod, 2002; Mahloud et al., 1970). The parents usually are normal; it occurs mainly in Ashkenazi Jews and there is a strong history of consanguinity. In a newborn infant, absent fungiform papillae, lack of corneal reflexes, decreased deep tendon reflexes, and a diminished response to pain in a child of Ashkenazi Jewish extraction should point to the diagnosis. An abnormal intradermal histamine skin test (with an absent flare response) and pupillary hypersensitivity to cholinomimetics would confirm the diagnosis. The chromosome abnormality is linked to 9Q31 and there is a mutation in the gene IK-BKAP in 99% of cases; there is sufficient sensitivity to genetic probe to ascertain whether the fetus is affected (Anderson et al., 2001; Blumenfeld et al., 1993). A variety of symptoms, resulting from both autonomic underactivity and overactivity may occur. These include a labile blood pressure (with hypertension and postural hypotension), parasympathetic abnormalities (with periodic vomiting, dysphagia, constipation, and diarrhea), and urinary bladder disturbances. Neurologic abnormalities, associated skeletal problems (scoliosis), and renal failure previously contributed to a poor prognosis. The ability to anticipate complications and provide adequate support and therapy has resulted in a number of children reaching adulthood. The clinical manifestations are variable and are usually present from birth, with additional features appearing with increasing age. These include a labile blood pressure with postural hypotension and impaired responses to pressor stimuli. Hypertension, however, may also occur (Fig. 85-14). There may be episodes of sweating and blotchy erythema, sometimes at mealtimes and when patients are excited. Excretion of homovanillic acid (a metabolite of dopamine) and vanillylmandelic acid (a metabolite of noradrenaline) is reduced. Plasma dopamine β-hydroxylase levels may be low. Parasympathetic abnormalities include periodic vomiting, dysphagia (which may be associated with impaired motility in the lower third of the esophagus), constipation, and diarrhea. Urinary bladder control is often disturbed. The eyes are affected with diminished tear secretion, and there is hypersensitivity of the pupil to cholinomimetics such as dilute methacholine or pilocarpine. There is sensory

Mathias / Disorders of the Autonomic Nervous System

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FIGURE 85-14. Twenty-four-hour noninvasive ambulatory blood pressure profile, showing systolic (dark circles) and diastolic (dark squares) blood pressure and heart rate at intervals through the day and night in a subject with the Riley-Day syndrome (familial dysautonomia). There is considerable lability of blood pressure, with hypotension and hypertensive episodes. (Adapted from Mathias, 1996. ©1996. Reproduced with permission from The McGraw-Hill Companies.)

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involvement. Corneal hypesthesia may lead to corneal ulceration and scar formation. Other sensory system abnormalities include an abnormal taste sensation and a pale, smooth tongue because of lack of fungiform papillae. The prognosis depends on anticipating complication and on supportive therapy. The average life expectancy has been steadily rising; before 1960, some 50% of these patients died before the age of 5 years. Many now reach adulthood, with 50% reaching the age of 30 years. Many lead independent lives and some have married and had normal offspring. In the past, many would have been dead by the early second decade. Death is often sudden and may be the result of a cardiorespiratory arrest. Cardiac pacemakers may be of value. A prolonged Q-T interval in the electrocardiograph is seen in one third of patients; it is unclear if this predisposes them to cardiac dysrhythmias. Renal failure can occur in older children and adults. The management of patients includes control of blood pressure, which can be difficult because of its lability. Impaired thermoregulation can occur with extremes of temperature and requires appropriate therapy. Reduced food intake because of periodic vomiting and impaired gastroesophageal motility may impair growth and result in anemia; a gastrostomy is often helpful. There are a wide variety of neurologic disturbances, in addition to those affecting impaired sensation. Gait disturbances are common and scoliosis frequently occurs with increasing age. There may be a range of psychometric abnormalities.

Congenital Insensitivity to Pain with Anhidrosis This is an autosomal-recessive disorder characterized by anhidrosis, recurrent episodic fever, and absence of afferent neurons causing pain insensitivity and self-mutilation (Swanson, 1963). It occurs in Greek, Italian, Arabic, Bedouin, Japanese, Pakistani, and Indian families; there is consanguinity in about 50%. The chromosomal abnormality is linked to 1q21-22 and the abnormal gene is NTRK1, with multiple mutations involving the NTRK1/tyrosine kinase

domain of the nerve growth factor receptor (Indo et al., 1996; Mardy et al., 1999).

Familial Amyloid Polyneuropathy In familial amyloid polyneuropathy, symptoms occur in the adult. However, the diagnosis has considerable implications for children. Sensory, motor, and autonomic abnormalities result from deposition in peripheral nerves of mutated amyloid protein, mainly produced in the liver. Motor and sensory neuropathy often begins in the lower limbs. Classification of familial amyloid polyneuropathy is based on the chemical and molecular nature of the constituent proteins and not on clinical presentation. There are various forms: transthyretin (TTR30) FAP, FAP Ala 60 (Irish/Appalachian), and FAP Ser 84 and His 58. The cardiovascular system, gut, and urinary bladder can be affected at any stage. The disease relentlessly progresses but at a variable speed. There is increasing evidence of differences in autonomic dysfunction in the various mutations resulting in familial amyloid polyneuropathy. There may be dissociation of autonomic symptoms from functional deficits; this dissociation is of importance because evaluation of cardiovascular autonomic abnormalities may be essential in preventing morbidity and mortality especially during hepatic transplantation. Currently this is the only way to reduce levels of variant transthyretin and its deposition in nerves. Thus it appears to prevent progression and may reverse some neuropathic features. It may be of greater value if performed before substantial nerve damage, or cardiac deposition, occurs. Genetic testing for familial amyloid polyneuropathy is of value although the potentially damaging aspects of a positive test in children need to be considered. In the adult, light chain amyloid deposition results in autonomic dysfunction (Reilly and Thomas, 2002). In this form, amyloid is derived from monoclonal light chains, secondary to multiple myeloma, malignant lymphoma, or Waldenström’s macroglobulinemia. There appear to be no genetic implications.

Neuroendocrine and Autonomic Nervous System Disorders / 85

Dopamine β-Hydroxylase Deficiency This disorder has been described in nine patients, two who are siblings (Deinum et al., 2004; Gomes et al., 2003; Mathias and Bannister, 2002a). Presentation often is in childhood, although an autonomic disorder was not considered until they became teenagers, when orthostatic hypotension was first recognized. Whether the symptoms become more prominent, or are easier to detect, at this time is unclear. The clinical features indicate sympathetic adrenergic failure with sparing of sympathetic cholinergic and parasympathetic function (Man in’t Veld et al., 1987; Mathias et al., 1990; Robertson et al., 1986). Sweating is preserved and urinary bladder and bowel functions are normal; in one of the males erection was possible but ejaculation was difficult to achieve. The diagnosis may be made from basal levels of plasma catecholamines because noradrenaline and adrenaline levels are undetectable while dopamine levels are elevated. The enzymatic defect is highly specific, with the sympathetic nerve pathways and terminals otherwise intact, as has been demonstrated by both electron microscopy and preservation of muscle sympathetic nerve activity using microneurography. These subjects, therefore, are a unique model of superselective sympathetic adrenergic failure. In six patients, several different mutations of the dopamine β-hydroxylase gene, leading to truncated proteins or an altered sequence in certain regions have been described (Deinum et al., 2004; Kim et al., 2002); one of the mutations, a splice site variant, was common in five. Absence of dopamine β-hydroxylase in plasma, without the functional deficit seen in these patients, also may occur, through a locus in the 5′ flanking region of the dopamine β-hydroxylase gene (Deinum et al., 2004) Treatment is with the prodrug L-dihydroxyphenylserine (see Fig. 85-12), which has a structure similar to noradrenaline except for a carboxyl group that is acted on by the enzyme dopa decarboxylase, which is widely distributed, thus transforming it into noradrenaline. This transformation reduces orthostatic hypotension and has resulted in remarkable improvements in their ability to lead active lives. In those with anemia, there is a favorable response to erythropoietin (Gomes et al., 2003); the cause of low erythropoietin and anemia is unclear and may be related to noradrenergic failure.

vagus, with characteristic features of cardiac vagal denervation (Watkins and Edmonds, 2002). This may occur in conjunction with partial preservation of the cardiac sympathetic and may predispose diabetic patients, many of whom have ischemic heart disease, to sudden death from cardiac dysrhythmias. The type of diabetes may influence the neuropathy; in type 2 diabetes sympathetic neuropathies seem to occur more frequently than parasympathetic impairment (Sundqvist et al., 1998). In those with sympathetic failure, orthostatic hypotension may be enhanced by insulin. Awareness of hypoglycemia, which depends on autonomic activation, is diminished. There may be involvement of the gastrointestinal tract (gastroparesis diabeticorum and diabetic diarrhea), the urinary bladder (diabetic cystopathy), and in the male, impotence. Sudomotor abnormalities include gustatory sweating. Damage to other organs may occur through non-neuropathic factors and compound the problems caused by the neuropathy. Other than maintaining normoglycemia, there is no known means to prevent and reverse the neuropathy except possibly by pancreatic transplantation. Atropine 0.6 mg IV

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Diabetes Mellitus Impairment of the autonomic nervous system can result in a variety of abnormalities, especially in older, long-standing adult diabetics on insulin therapy (Watkins, 1998). Whether autonomic neuropathy occurs in children is not entirely clear. However, the early onset of microvascular complications has been reported in single cases (Hamilton et al., 2004) and a recent study reported that nearly a third of young patients had profound neuropathy (Tesfaye et al., 2005) and within a short time frame a fourth developed neuropathy. The probability of autonomic involvement thus remains higher than previously considered (Perkins and Bril, 2005). In the adult with diabetic autonomic neuropathy, morbidity and mortality are considerably higher than in those without a neuropathy. It initially often involves the

FIGURE 85-15. A, The effect of disconnecting the respirator (as required for aspirating the airways) on the blood pressure (BP) and heart rate (HR) of a recently injured tetraplegic patient (C4-5 lesion) in spinal shock, 6 hours after the last dose of intravenous (IV) atropine. Sinus bradycardia and cardiac arrest (also observed on the electrocardiograph) were reversed by reconnection, intravenous atropine and external cardiac massage. B, The effect of tracheal suction, 20 minutes after atropine. Disconnection from the respirate and tracheal suction did not lower either heart rate or blood pressure. (A, from Frankel et al., 1975; B, from Mathias, 1976.)

Mathias / Disorders of the Autonomic Nervous System

Spinal Cord Lesions Autonomic dysfunction affecting various systems occurs in spinal cord lesions and injuries because the entire sympathetic and the sacral sympathetic outflow is from the spinal cord (Mathias and Frankel, 2002). The level of completeness of lesion determines the degree of dysfunction. In children spinal cord damage can result from a variety of causes—trauma (causing spinal cord transaction), syringomyelia, and transverse myelitis. There can be varying degrees of autonomic involvement, depending on the site and extent of the lesion. The disturbances affect the cardiovascular, thermoregulatory, gastrointestinal, urinary, and reproductive systems (Mathias and Frankel, 2002). In the majority of cases, there may be both autonomic underactivity and at times overactivity, which can pose special problems. In recently injured tetraplegics, the basal supine level of blood pressure usually is lower than normal (Mathias et al., 1979). This condition depends on a number of factors, including complicating trauma and drug therapy. The lower levels of blood pressure appear secondary to diminution in sympathetic nervous activity, which normally accounts for about 20% of vascular tone. It is unlikely that skeletal muscle paralysis alone is the explanation because tetraplegics, due to poliomyelitis, often have normal or even higher levels of blood pressure. The basal heart rate, especially in high lesions, also can be low, reflecting a relative increase in cardiac vagal activity in the absence of other neural and humoral adrenergic stimuli to the heart. This imbalance is likely to contribute to bradycardia and even cardiac arrest at times, especially in high lesions that depend on artificial respiration (Fig. 85-15). It can be a particular problem during tracheal suction, which stimulates vagal and glossopharyngeal afferents to reflexively increase vagal efferent activity (Mathias, 1976). Normally this is opposed

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by factors that raise heart rate and that include the pulmonary inflation vagal reflex and sympathoneuronal activity. Bradycardia effectively is prevented by atropine, emphasizing that the efferent limb of the reflex is the cardiac vagus. Knowledge of these mechanisms is important because the prevention of hypoxia, care during tracheal suction, and, if necessary, the use of maintenance atropine or even a temporary demand pacemaker, may be critical in the early phases when high lesions need respiratory support. The return of isolated spinal cord activity, with skeletal muscle spasms and spinal autonomic reflexes, in cervical and high thoracic lesions, may cause considerable lability in blood pressure. In the early stages of rehabilitation, movement from the horizontal to the upright position can result in pronounced orthostatic hypotension (Fig. 85-16) with symptoms resulting from organ hypoperfusion (see Table 85-5). Symptoms include cervical pain, in the “coat hanger” region (Cariga et al., 2002b). Loss of consciousness may occur, although this is more frequent in the early stages of rehabilitation and in chronic lesions after prolonged recumbency. With frequent postural changes and time, along with drugs such as ephedrine if needed, the blood pressure decrease with head-up change is reduced. Importantly, there is greater tolerance to lower levels of blood pressure; this tolerance may be related to the increasing ability of the cerebral circulation to autoregulate in the face of a low perfusion pressure. In the later stages, additional factors that aid blood pressure recovery during postural change include activation of the reninangiotensin-aldosterone system and the initiation of spinal sympathetic reflexes. Spinal sympathetic reflex activity may be induced by stimuli below the level of lesion resulting from visceral, skeletal muscle, or cutaneous stimulation. There may be a widespread increase in autonomic activity, mainly beneath the level of the lesion. In high lesions (above T6), this may result in autonomic dysreflexia. In this syndrome, blood 150

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FIGURE 85-16. Blood pressure and heart rate measured continuously with the Portapres II monitor in a patient with a high cervical spinal cord lesion. There is a fall in blood pressure because of impairment of the sympathetic outflow disrupted in the cervical spine. Heart rate rises because of withdrawal of vagal activity in response to the rise in pressure. (From Mathias, 2005.)

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BP (mm Hg)

FIGURE 85-17. Blood pressure (BP), heart rate (HR), intravesical pressure (IVP), and plasma noradrenaline (NA) and adrenaline (A) levels in a tetraplegic patient before, during, and after bladder stimulation induced by suprapubic percussion of the anterior abdominal wall. The rise in BP is accompanied by a fall in heart rate as a result of increased vagal activity in response to the rise in blood pressure. Level of plasma NA (open histograms), but not A (filled histograms) rises, suggesting an increase in sympathetic neural activity independently of adrenomedullary activation. (From Mathias and Frankel, 2002.)

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sympathetic ganglia (hexamethonium), adrenoreceptors (phenoxybenzamine, prazosin, and terazosin) (Vaidyanathan et al., 1998). Agents that act indirectly on the target organs, such as glyceryltrinitrate and nifedipine, dilate blood vessels to lower blood pressure. Propantheline bromide, which blocks muscarinic cholinergic receptors, can prevent sweating. The abnormalities arising from disordered sudomotor function and cutaneous vascular function predispose such patients to abnormal body temperature regulation. Hyperthermia can occur because of the inability to vasodilate and to sweat appropriately, whereas the reverse, hypothermia, may occur especially in high lesions because of the inability to vasoconstrict and to increase heat production because of impaired shivering thermogenesis (Fig. 85-18). Measurement of core temperature, as with a low-reading rectal thermometer, is critical because axillary and oral temperature measurements may be misleading. Gastrointestinal dysfunction is common. In high lesions, paralytic ileus may occur in the early stages of shock and cause abdominal distention and meteorism, which reduces

pressure is elevated; there is constriction of blood vessels (arterial and venous) below the level of the lesion, reducing peripheral blood flow and causing cold limbs, and a rise in levels of plasma noradrenaline but not adrenaline (Fig. 85-17). Sometimes evacuation of the urinary bladder and lower bowel, penile erection, and skeletal muscle spasms occur; these are components of the “mass reflex” described by Head and Riddoch (1917). Above the lesion there is usually dilatation of blood vessels with flushing over the face and neck, along with sweating. These episodes may be severe and prolonged, causing a throbbing headache and excessive perspiration above the lesion and, at times, death because of intracerebral hemorrhage. It is important to determine the cause of autonomic dysreflexia and rectify it; sometimes this is not possible and maneuvers and drugs are needed, especially to reduce hypertension (Hickey et al., 2004; McGinnis et al., 2004). These approaches may involve blocking afferent activity to the cord (lignocaine into the bladder), diminishing spinal autonomic activity (a spinal anesthetic), centrally acting drugs (clonidine) or drugs that act on 110

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FIGURE 85-18. Fall in central temperature (measured as rectal temperature) and heart rate in a recently injured tetraplegic in a temperate climate. Hypothermia is ideally monitored by a low reading rectal thermometer or tympanic temperature, as a measure of core temperature. It may be missed, as indicated in this case initially, if oral temperature alone is recorded. (From Pledger, 1962. Reproduced with permission and copyright © of the British Editorial Society of Bone and Joint Surgery.)

Mathias / Disorders of the Autonomic Nervous System

diaphragmatic improvement; additionally, there are associated problems with nutrition and fluid balance. Bowel atony in the early stages is followed by a return of function with reflex activation by distention of the bowel. This can be used in reconditioning of large bowel function. The same applies to the urinary bladder; in the early stages catheterization is needed, preferably with intermittent catheterization, but with return of reflex function and a neurogenic bladder training is often successful. The sequelae of disturbed urinary bladder function, especially with a discoordinated bladder (detrusor contraction against a contracted sphincter), include autonomic dysreflexia; in some patients this may lead to hydronephrosis, recurrent urinary infections, and ultimately, renal failure. Abnormalities in sexual function usually are not of relevance to children with high spinal cord lesions. Penile erection may occur reflexively, as part of autonomic dysreflexia, during cutaneous stimulation of the glans penis, such as before urethral catheterization.

Infectious Diseases A combination of autonomic underactivity and overactivity may occur in disorders associated with bacterial, viral, or parasitic illness. In the Guillain-Barré syndrome, tachycardia and hypotension may alternate with bradycardia and hypertension. There are differences between the axonal and myelinated forms of the Guillain-Barré syndrome (Asahina et al., 2001). Autonomic disturbances contribute to both morbidity and mortality. The precise mechanisms are unclear and the possibilities should be anticipated because appropriate drugs may be needed. Cardiovascular disturbances of a similar nature may occur in tetanus, especially in those who suffer muscle paralysis and are on assisted respiration. In acquired immunodeficiency syndrome, a cardiovascular and gut neuropathy has been reported (Craddock et al., 1987).

Drugs, Chemicals, and Toxins A variety of drugs, chemicals, heavy metals, and toxins may cause or contribute to autonomic dysfunction through their recognized pharmacologic effects, such as the sympatholytic agents (see Table 85-3), or by other actions (such as causing a neuropathy) (Tonkin and Frewin, 2002). A side effect of a drug may cause clinical problems when used in high dosage or over a prolonged period (such as the anticholinergic effects of antidepressants), or when deficits are unmasked or induced in susceptible individuals. Examples are the ability of pressor agents to cause severe hypertension in autonomic failure because of denervation supersensitivity (Polinsky, 2002). Drugs such as vincristine, by causing an autonomic neuropathy, may induce autonomic dysfunction independently of their pharmacologic properties. In some cases the relationship may be obvious, although there are situations in which it may be less so. Examples include the beta-adrenoceptor blockers such as atenolol for treatment of gestation hypertension; this drug may cause bradycardia in the fetus and newborn infant (Shifferli and Caldeyro-Barcia, 1973). Certain drugs taken by mothers who are breast-feeding have the potential, through secretion in breast milk, to affect the infant. In children undergoing

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organ transplantation, cyclosporine can increase sympathetic neural activity (Scherrer et al., 1990); this effect may be a contributory factor to hypertension, which is common in transplantees. Children are more likely than adults to accidentally ingest toxins and poisonous substances that can impair the autonomic nervous system. Increased parasympathetic activity may result from mushroom poisoning, whereas the reverse, decreased parasympathetic activity, may occur after ingestion of atropine-like substances. These include the shining black berries of deadly nightshade (Atropa belladonna), the seed of the thorn apple (jimsonweed or D. stramonium) and various parts of henbane (Hyoscyamus niger) (Cooper and Johnson, 1984).

Neurally Mediated Syncope Intermittent dysfunction of the autonomic nervous system is a common cause of syncope and presyncope, once cardiac and nonautonomic neurologic causes have been excluded (Mathias et al., 2001b). In neurally mediated syncope, there may be increased cardiac parasympathetic activity resulting in bradycardia (the cardioinhibitory form), diminished sympathetic vasoconstrictor activity resulting in hypotension (the vasodepressor form), or a combination of the two. Cardiac vagal tone is considerably greater (vagotonia) in children and may be a contributory factor to their death in certain situations. Stimulation of facial receptors triggering an associated vagal response, for instance, may be responsible for apnea and cardiac arrest when a child falls even into a shallow pool of cold water. In those children with near death experiences, there often is an exaggerated cardiac response to ocular compression (Kahn et al., 1983). It is essential in children to exclude disorders with a prolonged Q-T interval, such as the RomanoWard and Jervell and Lange-Nielsen syndromes. There are three major causes of neurally mediated syncope. These include vasovagal syncope, in the young, carotid sinus hypersensitivity, especially in patients older than 50 years, and miscellaneous causes, often referred to as situational syncope.

Vasovagal Syncope Vasovagal syncope probably is the most common form of neurally mediated syncope. There are three forms: cardioinhibitory, vasodepressor, and mixed form (Fig. 85-19). The history often provides an important clue. Episodes may begin in the very young; there may be sudden collapse and seizures due to anoxia, hence the use of the abbreviation RAS that may indicate reflex anoxic syncope, reflex anoxic seizures, or even reflex asystolic syncope (Stephenson, 1990). It may be, because of the greater degree of vagotonia in children, that the cardioinhibitory form is more common. A cardiac demand pacemaker often is of value in such cases. Another cluster occurs around the teenage years, with fainting often associated with a postural component especially while standing still, such as at assembly. There may be a clear provoking factor that includes blood, needles, or pain. Sometimes even the sight of a needle or mention of venipuncture may induce an attack. In those presenting as teenagers, there often is a strong family history, which in some studies also has been associated with friends of the patient (Camfield and Camfield, 1990; Mathias et al., 1998,

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Neuroendocrine and Autonomic Nervous System Disorders / 85 FIGURE 85-19. Blood pressure (blue shading) and heart rate (blue line) with continuous recordings from the Portapres II monitor in a patient with the mixed (cardioinhibitory and vasodepressor) form of vasovagal syncope. (From Mathias, 2005.)

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2001). Whether this indicates an acquired or genetic predisposition or both, is unclear. In some with vasovagal syncope, recurrent attacks may be the result of pseudosyncope, which can cause considerable difficulties in diagnosis and management (Mathias et al., 2001b). The investigation of vasovagal syncope in older children includes tilt-table testing, often with a provocative stimulus, which in recent studies has included venipuncture and even pseudovenipuncture (Mathias et al., 2001b). In the mixed form, when the role of bradycardia is not clear and a cardiac demand pacemaker is being considered, an atropine test is often useful. Atropine elevates heart rate and if with repeat head-up tilt hypotension is reduced with fewer or no symptoms, this result favors the beneficial effect of cardiac pacing. A lack of effect suggests that vasodepression is the key component and that a pacemaker is unlikely to be of benefit. There is, however, unpredictability in inducing an episode with head-up tilt tests, and this has led to combining additional physiologic and pharmacologic stimuli to induce an attack (El Badawi and Hainsworth, 1994). These include lower body negative pressure, or drugs such as isoprenaline, GTN, and adenosine. Such testing may result in false positives. The management of vasovagal syncope includes reducing or preventing exposure to precipitating causes, although these may be unclear. In some, especially with phobias, cognitive behavioral psychotherapy is needed. A combination of nonpharmacologic approaches should include a high-salt diet, fluid repletion, exercise especially to strengthen lower limb muscles, measures that activate the sympathetic nervous system such as sustained hand grip, the use of the calf muscle pump to prevent pooling, and various maneuvers that range from leg crossing to simulating the tying of shoelaces (Brignole et al., 2004; Cooper et al., 2002; Mathias and Young, 2004; van Dijk et al., 2000). The ideal in such patients when they have symptoms suggestive of an oncoming attack is to sit and lie, head down, if needed, with legs upright. Drugs are used especially when there is a low supine blood pressure and nonpharmacologic measures alone are not successful. They include low-dose fludrocortisone and sympathomimetics such as ephedrine and midodrine. The 5-hydroxytryptamine uptake release inhibitors have been used with varying success in adults. There appears to be a limited role for beta blockers. In the cardio-

0

inhibitory form, a cardiac demand pacemaker may be of value (Benditt, 1999). The long-term prognosis is favorable, and in many young subjects the frequency of attacks is reduced after the third decade.

Carotid Sinus Hypersensitivity Carotid sinus hypersensitivity is a disease of adults, rarely diagnosed before the age of 50 (McIntosh et al., 1993); the incidence increases with advancing age. It is more common than previously thought and may be the cause of unexplained falls. The provocative stimulus of carotid sinus massage should be performed in the laboratory when upright, which is when there is a greater dependence on autonomic activity (Mathias et al., 1991). In carotid sinus hypersensitivity a cardiac pacemaker often is of benefit. The disorder is not familial and there are no genetic implications.

Miscellaneous Causes There are a variety of situations, often referred to as situational syncope, that can cause bradycardia and hypotension, again by mechanisms similar to those observed in vasovagal syncope. These findings may occur in high spinal cord injuries, especially in tetraplegic patients on artificial respirators, where increased vagal activity not opposed by sympathetic activity may result from tracheal stimulation (see Fig. 85-17). The first-dose hypotensive effect of certain drugs may be neurally mediated via the Bezold-Jarisch reflex. In otherwise normal adults, intermittent syncope has been reported with swallowing (in some associated glossopharyngeal neuralgia) (Deguchi and Mathias, 1999), and during pelvic and rectal examination. In some cases instrumentation, even during anesthesia, may result in cardiac arrest. Micturition- and defecation-induced syncope has been reported mainly in adults, as has laughter-induced and cough syncope. Syncope may occur in trumpet blowers and weight lifters. Changes in intrathoracic pressure may contribute, as in cough- and laughter-induced syncope, trumpet blowing, and voluntary syncope (“fainting lark”). The fainting lark is due to a combination of the Valsalva maneuver and gravity (lowering blood pressure with hyperventilation causing hypocapnea and cerebral vasoconstriction) (Fig. 85-20). Fainting is induced by squatting, overbreathing, standing up suddenly, and blowing

Mathias / Disorders of the Autonomic Nervous System

FIGURE 85-20. Finger arterial blood pressure at heart level, end tidal carbon dioxide concentration (ETCO2), and middle cerebral artery blood flow velocity in a normal subject during squatting and hyperventilating, followed by standing and straining. There is a rapid fall in blood pressure and the subject can readily lose consciousness. This phenomenon is the basis of the “fainting lark” as used by children. (From Wieling and van Lieshout, 2002. Reprinted with kind permission of Springer Science and Business Media.)

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against a closed glottis (Howard et al., 1951). It may be selfinduced and has been reported in mentally retarded children (Gastaut et al., 1982). In children, increased vagal activity and vagotonia may contribute to their being more susceptible to bradycardia. This susceptibility may explain why the young are more prone to cardiac arrest and sudden death during blunt impact to the chest during sports activities; the precise cause of “commotio cordis” is unclear and the

possibility of excessive vagal activity in the presence of apnea remains likely (Maron et al., 1995).

Transient Orthostatic Hypotension Instantaneous or transient orthostatic hypotension has been described in children with normal autonomic function, who have appropriate vasoconstrictor responses to gravitational

FIGURE 85-21. Blood pressure and heart rate measured (noninvasively) continuously before, during, and after 60-degree head-up tilt (by the Portapres II monitor) in a normal subject and in a subject with two different autonomic disorders: with pure autonomic failure (PAF) and the postural tachycardia syndrome (PoTS). (From Mathias, 2002.)

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stimuli (Stewart, 2002; Tanaka et al., 1999). This response may be an exaggeration of the initial transient fall in blood pressure described in normal adults (Wieling and Karemaker, 2002). There may be a greater proportion of young with the chronic fatigue syndrome with this transient change, which may cause dizziness; impaired cerebral hemodynamics may contribute, but does not explain all the findings (Tanaka et al., 2002)

Postural Tachycardia Syndrome Symptoms of orthostatic intolerance (light-headedness and other manifestations of cerebral hypoperfusion), often with palpitations and without orthostatic hypotension are the hallmark of the postural tachycardia syndrome (Low et al., 2001). The symptoms occur on standing and during even mild exertion. Investigations exclude orthostatic hypotension and autonomic failure; during postural challenge the heart rate increases by more than 30 beats per minute or rises above 120 beats per minute (Fig. 85-21). In the adult it has been predominantly observed in young females between 20 and 50 years of age. Whether the same criterion of heart rate change with head-up posture should apply in children needs consideration (Stewart et al., 1999). There are similarities between postural tachycardia syndrome and various syndromes, including those initially described by Da Costa and by Lewis (also known as soldier’s heart or neurocirculatory asthenia). There is an association with mitral valve prolapse, chronic fatigue syndrome, and deconditioning after prolonged bed rest and microgravity during space flight. In a family with identical twins, a genetic basis with a defect in the noradrenaline transporter system has been described, which accounted for the raised basal noradrenaline levels; mutation of the gene encoding the noradrenaline transporter was thought to be responsible (Shannon et al., 2000). In some it appears to follow a viral infection, raising the possibility of immunologically mediated autonomic neuropathy. Investigations indicate predominantly lower limb autonomic denervation affecting vascular and sudomotor function (Jacob et al., 2000; Schondorf and Low, 1993; Streeten, 1990). Venous pooling may be a problem (Streeten et al., 1998). Antibodies to autonomic ganglia have been observed in some patients and are related to the autonomic deficits (Vernino et al., 2000). There is a strong association with the joint hypermobility syndrome (Ehler-Danlos type III) (Gazit et al., 2003). Psychogenic components need to be evaluated, especially when hyperventilation is thought to contribute. In postural tachycardia syndrome, the symptoms may warrant use of drug approaches similar to those used for orthostatic hypotension, and include fludrocortisone and midodrine. Correcting hypovolemia and contributory factors (such as hyperventilation) is important. Beta blockers, especially those that are cardioselective, may reduce tachycardia. As in neurally mediated syncope, use of nonpharmacologic measures should be introduced. With time, some recover spontaneously. The complications of associated disorders, such as the joint hypermobility syndrome, need to be addressed.

“Localized” Autonomic Disorders There are many autonomic disorders affecting single organs or specific systems. Examples of these are listed in Table 85-4.

The lacrimal glands have a rich autonomic innervation. Alacrima may occur as part of a generalized autonomic disorder. “Crocodile” tears may result from aberrant reinnervation of the lacrimal gland with fibers from the salivary glands. The mechanisms are similar to gustatory sweating, due to aberrant connections between nerves to salivary and facial sweat glands. Triple A (Allgrove) children have alacrima, achalasia, and adrenal failure (Allgrove et al., 1978). The disorder is autosomal recessive, with mutations of the ALADIN gene, along with other neurologic and autonomic deficits (Houlden et al., 2002). The Holmes-Adie pupil is characteristically dilated and sluggishly responsive to light but responds to near vision, hence the descriptive term near-light dissociation. It results from parasympathetic denervation, probably of the ciliary ganglia, with supersensitivity of the iris musculature to locally applied cholinomimetics. The term Holmes-Adie syndrome is used when associated with absent tendon reflexes; this probably is due to involvement of dorsal root ganglia, accounting for the absent H reflex on electrophysiologic testing. Some patients have areas of anhidrosis, although they often complain of hyperhidrosis that is likely to be compensatory in nature (Ross’ syndrome). Others may have cardiovascular autonomic deficits, a chronic dry cough, and diarrhea (Kimber et al., 1998). Although considered benign, in some adults the disorder may be progressive, with baroreceptor reflex dysfunction causing labile hypertension and orthostatic hypotension. The disorder is not familial. In Horner’s syndrome, there is partial ptosis and a small pupil as the sympathetic fibers to the face are affected. It may result from a lesion along the course of the facial sympathetic supply, in the brain, spinal cord, the upper thoracic ganglia, or postganglionic efferents that follow the vasculature. Although it causes few, if any, symptoms, it may be a harbinger of a serious disorder. In essential (primary) hyperhidrosis there is excessive palmar, plantar, and sometimes whole-body hyperhidrosis. There is no peripheral neural abnormality; whether hypothalamic dysfunction or altered behavioral responses are the mechanisms causing hyperhidrosis is unclear. There is a familial component in some (Kaufmann et al., 2003). The treatment of hyperhidrosis, especially of localized areas (Kaufmann et al., 2003) such as the palms and face, includes percutaneous endoscopic transthoracic sympathectomy, with bilateral ablation of ganglia between T2 and T4; compensatory hyperhidrosis affecting the trunk and lower limbs may occur postoperatively that in some patients may be worse than the original complaint. Injection of botulinum toxin, especially into small areas such as the palm, face, and axillae, has been successful but needs to be repeated and long-term benefits are unknown (Naumann et al., 1997a, 1997b; Tugnoli et al., 2002). In reflex sympathetic dystrophy (chronic regional pain syndrome type 2), there is debate about whether features such as sweating and vascular changes have an autonomic basis (Schott, 1998); in some these abnormalities are relieved by sympatholytic (guanethidine) blockade. Localized disorders of the gut include Hirschsprung’s disease. In Chagas’ disease (after infection with Trypanosoma cruzi), the intrinsic autonomic ganglia in the esophagus, colon, and heart are specifically targeted, probably by an immunologic process. Various surgical procedures may be complicated by autonomic dysfunction, an example

Mathias / Disorders of the Autonomic Nervous System

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sympathetic failure due to an inability to synthesize noradrenaline from dopamine because of a deficiency of dopamine beta-hydroxylase. Q J Med, New Series 1990;278:617. Mathias CJ, Christensen NJ, Corbett JL, et al. Plasma catecholamines, plasma renin activity and plasma aldosterone in tetraplegic man, horizontal and tilted. Clin Sci Molec Med 1975;49:291. Mathias CJ, Christensen NJ, Corbett JL, et al. Plasma catecholamines during paroxysmal neurogenic hypertension in quadriplegic man. Circ Res 1976;39:204. Mathias CJ, Christensen NJ, Frankel HL, Spalding JMK. Cardiovascular control in recently injured tetraplegics in spinal shock. Q J Med, New Series 1979;48:273. Mathias CJ, da Costa DF, Fosbraey P, et al. Cardiovascular, biochemical and hormonal changes during food induced hypotension in chronic autonomic failure. J Neurol Sci 1989;94:255. Mathias CJ, Deguchi K, Bleasdale-Barr K, Kimber JR. Frequency of family history in vasovagal syncope. Lancet 1998;352:33. Mathias CJ, Deguchi K, Schatz I. Observations on recurrent syncope and presyncope in 641 patients. Lancet 2001b;357:348. Mathias CJ, Frankel H. Autonomic disturbances in spinal cord lesions. In: Mathias CJ, Bannister R, eds. Autonomic failure. A textbook of clinical disorders of the autonomic nervous system, 4th ed. Oxford: Oxford University Press, 2002;494. Mathias CJ, Fosbraey P, da Costa DF, et al. The effect of desmopressin on nocturnal polyuria, overnight weight loss and morning postural hypotension in patients with autonomic failure. BMJ 1986;293:353. Mathias CJ, Holly E, Armstrong E, et al. The influence of food on postural hypotension in three groups with chronic autonomic failure: Clinical and therapeutic implications. J Neurol Neurosurg Psychiatry 1991;54:726. Mathias CJ, Mallipeddi R, Bleasdale-Barr K. Symptoms associated with orthostatic hypotension in pure autonomic failure and multiple system atrophy. J Neurol 1999;246:893. Mathias CJ, Senard J, Braune S, et al. L-threo-dihydroxphenylserine (L-threo-DOPS; droxidopa) in the management of neurogenic orthostatic hypotension: A multi-national, multi-centre, dose-ranging study in multiple system atrophy and pure autonomic failure. Clin Auton Res 2001a;11:235. Mathias CJ, Young TM. Plugging the leak—The benefits of the vasopressin-2 agonist, desmopressin in autonomic failure. Clin Auton Res 2003;13:85. Mathias CJ, Young TM. Water drinking in the management of orthostatic intolerance orthostatic hypotension, vasovagal syncope and the postural tachycardia syndrome. Eur J Neurol 2004;11:613. Maule S, Lombardo L, Rossi C, et al. Helicobacter pylori and gastric function in primary autonomic neuropathy. Clin Auton Res 2002;12:193. McGinnis KB, Vogel LC, McDonald CM, et al. Recognition and management of autonomic dysreflexia in pediatric spinal cord injury. J Spinal Cord Med 2004;27 (Suppl 1):S61. McIntosh SJ, Lawson J, Kenny RA. Clinical characteristics of vasodepressor, cardioinhibitory and mixed carotid sinus syndrome in the elderly. Am J Med 1993;95:203. Merz B, Bigalke H, Stoll G, Naumann M. Botulism type B presenting as pure autonomic dysfunction. Clin Auton Res 2003;13:337. Mikolich JR, Paulson GW, Cross CJ. Acute anti-cholinergic syndrome due to Jimson seed ingestion: Clinical and laboratory observation in six cases. Ann Intern Med 1975;83:321. Naumann M, Flachenecker P, Brocker E-B, et al. Botulinum toxin for palmar hyperhidrosis. Lancet 1997a;349:252. Naumann M, Zellner M, Toyka KV, Reiners K. Treatment of gustatory sweating with botulinum toxin. Ann Neurol: 1997b;42:973. Nicotra A, Asahina M, Mathias CJ. Skin vasodilator response to local heating in human chronic spinal cord injury. Eur J Neurol 2004;11:835. Oldenburg O, Mitchell AN, Nurnberger J, et al. Ambulatory norepinephrine treatment of severe autonomic orthostatic hypotension. J Am Coll Cardiol 2001;37:219. Perkins BA, Bril V. Early vascular risk factor modification in type 1 diabetes. N Engl J Med 2005;352:408. Parati G, Di Rienzo M, Omboni S, Mancia G. Computer analysis of blood pressure and heart rate variability in subjects with normal and abnormal autonomic cardiovascular control. In: Mathias CJ, Bannister R, eds. Autonomic failure. A textbook of clinical disorders of the autonomic nervous system, 4th ed. Oxford: Oxford University Press, 2002;211. Pledger HG. Disorders of temperature regulation in acute traumatic paraplegia. J Bone Joint Surg 1962;44B:110.

Mathias / Disorders of the Autonomic Nervous System Polinsky RJ. Neuropharmacological investigation of autonomic failure. In: Mathias CJ, Bannister R, eds. Autonomic failure. A textbook of clinical disorders of the autonomic nervous system, 4th ed. Oxford: Oxford University Press, 2002;232. Puvi-Rajasingham S, Smith GDP, Akinola A, Mathias CJ. Abnormal regional blood flow responses during and after exercise in human sympathetic denervation. J Physiol 1997;505:481. Reilly MM, Thomas PK. Amyloid polyneuropathy. In: Mathias CJ, Bannister R, eds. Autonomic failure. A textbook of clinical disorders of the autonomic nervous system, 4th ed. Oxford: Oxford University Press, 2002;410. Robertson D, Goldberg MR, Onrot J, et al. Isolated failure of autonomic noradrenergic neurotransmission. Evidence for impaired betahydroxylation of dopamine. N Engl J Med 1986;314:494. Sahul ZH, Trusty JM, Erickson M, et al. Pacing does not improve hypotension in patients with severe orthostatic hypotension—A prospective randomized cross-over pilot study. Clin Auton Res 2004;14:255. Schatz IJ, Bannister R, Freeman RL, et al. Consensus statement on the definition of orthostatic hypotension, pure autonomic failure and multiple system atrophy. Clin Auton Res 1996;6:125. Scherrer U, Vissing SF, Morgan BJ, et al. Cyclosporine-induced sympathetic activation and hypertension after heart transplantation. N Engl J Med 1990;323:693. Schondorf R, Low PA. Idiopathic postural tachycardia syndrome: An attenuated form of acute pandysautonomia? Neurology 1993;3:132. Schott GD. Interrupting the sympathetic outflow in causalgia and reflex sympathetic dystrophy. A futile procedure for many patients. BMJ 1998;316:792. Schrage WG, Eisenach JH, Dinenno FA, et al. Effects of midodrine on exercise-induced hypotension and blood pressure recovery in autonomic failure. J Appl Physiol 2004;97:1978. Shannon JR, Flatten NL, Jordan J, et al. Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency. N Eng J Med 2000;342:541. Shifferli PY, Caldeyro-Barcia R. Effects of atropine and beta-adrenergic drugs on the heart rate of the human fetus. In: Boreus LO, ed. Fetal pharmacology. New York: Raven Press, 1973;259. Singer W, Opfer-Gehrking TL, McPhee BR, et al. Acetylcholinesterase inhibition: A novel approach in the treatment of neurogenic orthostatic hypotension. J Neurol Neurosurg Psychiatry 2003;74:1294. Smit AAJ, Hardjowijono MA, Wieling W. Are portable folding chairs useful to combat orthostatic hypotension? Ann Neurol 1997;42:975. Smith GDP, Alam M, Watson LP, Mathias CJ. Effects of the somatostatin analogue, octreotide, on exercise induced hypotension in human subjects with chronic sympathetic failure. Clin Sci 1995a;89:367. Smith GDP, Bannister R, Mathias CJ. Post exercise dizziness as the sole presenting symptom in autonomic failure. Br Heart J 1993;69:359. Smith GDP, Mathias CJ. Postural hypotension enhanced by exercise in patients with chronic autonomic failure. Q J Med 1995;88:251. Smith GDP, Watson LP, Pavitt DV, Mathias CJ. Abnormal cardiovascular and catecholamine responses to supine exercise in human subjects with sympathetic dysfunction. J Physiol (Lond) 1995b;484:255. Spyer KM. Central nervous control of the cardiovascular system. In: Mathias CJ, Bannister R, eds. Autonomic failure. A textbook of clinical disorders of the autonomic nervous system, 4th ed. Oxford: Oxford University Press, 2002;45. Stephenson JBP. Fits and faints. In: Clinical and Developmental Medicine No 109. Oxford, Mac Keith Press, Blackwell, 1900. Stewart JM. Transient orthostatic hypotension is common in adolescents. J Pediatr 2002;140:418. Stewart JM, Gewitz MH, Weldon A, Munoz J. Patterns of orthostatic intolerance: The orthostatic tachycardia syndrome and adolescent chronic fatigue. J Pediatr 1999;135:218. Streeten DH. Pathogenesis of hyperadrenergic orthostatic hypotension: Evidence of disordered venous innervation exclusively in the lower limbs. J Clin Invest 1990;86:1582.

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CHAPTER 86

Disorders of Micturition and Defecation Bhuwan P. Garg

DISORDERS OF MICTURITION Micturition is an intricate function that results from a coordinated activity of the muscles of the urinary bladder and urethral sphincter. Knowledge, particularly of normal mechanisms, is accruing primarily from animal studies. Volitional and automatic functions are integrated [Bradley, 1986]. The automatic activities are controlled by the autonomic nervous system. In infants, autonomic control is primary, and as development proceeds, voluntary control over micturition is exerted. Voiding is frequent and largely uninhibited for the first 16 months of life. However, recent studies have found that there is cortical arousal in response to a full bladder even in newborns [Yeung et al., 1995]. Voiding frequency gradually decreases, and between 1 and 2 years of age, the child becomes aware of the sensation of a full bladder. By 2 years of age, children begin to retain their urine for brief periods, although most children cannot willfully initiate voiding. By 3 years of age, diurnal control is established, and most children acquire nocturnal control by age 4 years. By 5 years of age, 85% of children have achieved complete bladder control [Himsel and Hurwitz, 1991]. Bowel control precedes bladder control with the sequence of control as follows: (1) nocturnal bowel control, (2) diurnal bowel control, (3) diurnal bladder control, and (4) nocturnal bladder control [Perlmutter, 1985]. Toilet training is necessary for achieving continence. As a general rule children are ready for toilet training when they can appreciate the sensation of voiding and recognize a wet or soiled diaper. Similarly, ability to largely remain dry through an afternoon nap is a sign that a child is ready to stop wearing a diaper at night. Toilet training is a complex process and includes not only the recognition of an urge to void but also the ability to undress, void, wipe, dress again, flush, and wash hands [Stadtler et al.,1999]. Isolated day wetting or wetting both day and night is urinary incontinence. Nocturnal enuresis, or more commonly enuresis (derived from the Greek word enourein, “to void urine”), is usually used to denote bedwetting only in sleep. In nocturnal enuresis there is a mismatch between the nocturnal bladder capacity and the amount of urine produced during the night, as well as an inability of the child to wake up in response to a full bladder. In one study of micturition habits of healthy children, 12% of boys and 7% of girls at 7 years of age and 0.3% of boys and 0.6% of girls at 17 years of age reported bedwetting [Hellström et al., 1995]. In another study, daytime urinary incontinence (at least once a month) occurred in 6.3% of first graders and 4.3% of fourth graders. Bedwetting (at least once a month) was reported in 7.1% and 2.7%, respectively. In first graders, fecal incontinence was present in 9.8% and in fourth graders in 5.6%. Daytime

urinary incontinence was strongly associated with fecal incontinence [Soderstrom et al., 2004]. Micturition is primarily a parasympathetic function; the sympathetic nervous system is involved in determining bladder capacity and urine storage. Voluntary control of the external sphincter, periurethral muscles, and abdominal muscles is effected through conventional pathways of the corticospinal connections. Knowledge of the specific mechanisms of normal micturition remains incomplete, thereby frustrating efforts directed toward precise diagnosis and management.

Anatomy and Embryology The urinary bladder, a hollow viscus, receives urine from the kidneys through the two ureteral orifices and discharges urine through a solitary urethral orifice [Elbadawi, 1996]. The mucous membrane of the bladder is lined by transitional epithelium, which is supported by an underlying loose submucous coat. A three-layer muscular coat of smooth muscle fibers forms the bulk of the bladder wall. There are inner longitudinal, middle circular, and outer longitudinal layers of muscle fibers (i.e., detrusor muscle). The inner longitudinal layer is the thinnest. The middle circular layer, strongest of the three layers, forms a ring ventrally around the internal urethral orifice. The outer longitudinal layer ventrally forms a collar-like structure called the collare vesicae; around the bladder neck this structure is called the nodus vesicae [Dorschner et al., 1994]. The detrusor muscle is bilaterally innervated and functions as a syncytium [Zimmern et al., 1996]. Gap-type junctions (electrical synapses) occur frequently; axoaxonal-type synapses are also present. Stretch receptors are arranged in series with the detrusor muscle fibers [Bradley, 1986]. The urinary bladder originates from the enlarged terminal portion of the hindgut (the cloaca), which forms during the early somite stage. Ventrally the entodermal cloacal lining is in direct contact with the surface ectoderm, forming the cloacal membrane. During the fourth to seventh weeks of gestation, the cloaca subdivides into an anterior primitive urogenital sinus and a posterior anorectal canal. This subdivision is accomplished by the caudad growth of the urorectal septum. The entrance of the mesonephric ducts into this primitive urogenital sinus divides the sinus into two portions—the vesicourethral canal above and the definitive urogenital sinus below. The urinary bladder and the upper portion of the urethra are formed from the vesicourethral canal. Therefore the epithelial lining of the bladder is derived from the embryonic entoderm. Some controversy exists regarding the origin of the epithelium of the trigone of the bladder, which may be partially of mesodermal origin. The detrusor muscle arises from the visceral mesoderm.

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Nerve Supply The urinary bladder has two chief sources of nerve supply— the autonomic nervous system, primarily concerned with impulses of involuntary nature, and the cerebrospinopudendal pathway, which subserves volitional control. The pathways that provide cerebral control of the detrusor neurons have been delineated with horseradish peroxidase and immunohistochemical techniques. In the rat the urinary bladder appears to be innervated by axons from the caudal

Cerebrocortical micturition control

Path 1

Brainstem center

Path 2

Reticulospinal tracts

Detrusor muscle fibers

Bladder sensory nerves

Pelvic nerves FIGURE 86-1. Paths 1 and 2. (Redrawn from Bradley, 1986.)

portion of the nucleus laterodorsalis tegmenti, which connects with the medial frontal cortex [Sakanaka et al., 1983]. The projections in the rat appear to be ipsilateral and also extend to the ipsilateral septal area; the latter area is involved with emotional and motivational activities [Bradley, 1986]. In humans the cerebrocortical areas concerned with pudendal and detrusor activation are located in the medial aspect of the area immediately anterior to the rolandic fissure [Haldeman et al., 1982a; 1982b]. Bradley [1986] has divided the various neural interconnections into loops (paths). Path 1 is a bidirectional pathway between brainstem and cerebral cortex that includes connections to subcortical nuclei (e.g., thalamus, basal ganglia, and amygdaloid nucleus) (Fig. 86-1). Path 2, which is also bidirectional, is traversed by ascending impulses from the detrusor muscle to the brainstem detrusor nucleus and by descending impulses from the brainstem detrusor nucleus to the sacral spinal cord (see Fig. 86-1). Path 3 comprises the following: (1) afferent axons from the detrusor muscle and periurethral striated muscle that impinge on the sacral pudendal nucleus and (2) efferent motor axons that originate in the sacral pudendal nucleus and terminate in the striated sphincter muscles (Fig. 86-2). Path 4 consists of supraspinal (path 4a) and segmental (path 4b) portions. Path 4a comprises the following: (1) a sensory pathway that traverses the posterior columns and (2) an efferent motor pathway that originates in the motor cortex and connects with the sacral alpha motor and gamma motor neurons (Fig. 86-3). The afferent portion of path 4b comprises the following: (1) sensory fibers originating in the striatedmuscle spindles of the periurethral area and (2) the axons that travel upward to connect with the sensorimotor cortex. The efferent portion of path 4b comprises the following: (1) the alpha motor fibers that issue from the alpha motor neurons in the sacral cord and innervate the periurethral striated muscle and (2) the gamma motor fibers that originate in the gamma motor neurons in the anterior horn of the spinal cord and innervate the muscle spindle fibers in the periurethral striated muscle (Fig. 86-4). Three other minor pathways have been described, which include proximal urethra to detrusor muscle, periurethral striated muscle to detrusor (which inhibits contraction), and sacral afferents to the lumbar cord that cause excitation of lumbar efferents to the pelvic ganglia, which in turn inhibit synaptic transmission in the pelvic ganglia [Bradley, 1986]. Paths 1 and 4a provide for cortical control or modification of the detrusor and pudendal pathways. Path 2 provides for brainstem control of the detrusor pathways. Path 3 provides for segmental control of pudendal pathways. Path 4b is a conventional pathway that contains alpha motor neuron, gamma motor neuron, and axonal connections with the sensorimotor and motor cortex and striated muscle of the periurethral area. The spinal cord detrusor nucleus is located in the region of the parasympathetic nerve cells at S3 in the intermediolateral cell column. S2 and S4 also contribute to the nerve supply (Fig. 86-5) [Saper, 1995]. The axons from these cell bodies, after traversing the ventral roots, form the pelvic nerve that innervates the detrusor muscle; both ipsilateral and contralateral innervation occurs. The sympathetic motor nerve supply to the bladder originates in the cell bodies of the intermediolateral column

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FIGURE 86-2. Paths 3 and 4b. (Redrawn from Bradley, 1986.)

Detrusor sensory axons

Sensory axons from periurethral striated muscles Detrusor nucleus

Pudendal nucleus

Pudendal motor axons

pathetic fibers innervate the trigone region of the bladder [Chai and Steers, 1996; Wein and Barrett, 1992]. The cerebrospinopudendal pathway subserves volitional control of micturition. The pudendal nerve arises from the pudendal nucleus (Onuf’s nucleus), which is located in the anterior horn cell column of S3 and S4 (see Fig. 86-5). The nerve innervates the external urethral sphincter, as well as the accessory urethral and perineal muscles. The pudendal nucleus is innervated through the pyramidal tract from the upper motor neuron cells situated on the medial surface of the frontal lobe anterior to the rolandic fissure (the paracentral lobule). Somatic afferent impulses, which are transmitted in the pudendal nerve, enter the dorsal roots of S2 to S4.

Motor cortex

Pathophysiology Sensory pathway

Pyramidal tract

Sacral spinal cord FIGURE 86-3. Paths 4a and 4b. (Redrawn from Bradley, 1986.)

of the spinal cord extending from T11 to L2. The preganglionic nerve fibers from these cell bodies synapse in the sympathetic ganglia of the hypogastric plexus and emerge as postganglionic fibers in the hypogastric nerve. These sym-

Most children with lower urinary tract dysfunction suffer from neurologic compromise [Fidas et al., 1987; Sensirivatana et al., 1987]. The micturition reflex is primarily a brainstem reflex and requires intact brainstem reticular formation pathways to the spinal cord (reticulospinal tracts), although other portions of the brain exert significant influence on the micturition reflex. Important areas of brain control of micturition include the frontal sensorimotor cortex (medial surface anterior to the rolandic fissure), the midbrain, and the dorsal tegmental area of the pons (brainstem detrusor motor nucleus); they exert either a facilitatory or an inhibitory effect on the micturition reflex [Carpenter and Sutin, 1983; Chai and Steers, 1996; Wein and Barrett, 1992]. The precise role of the thalamus, hypothalamus, limbic system, and basal ganglia remains largely unknown, although the general contributions of these regions have been partially delineated. The activities in the cerebral cortex, basal ganglia, anterior hypothalamus, and anterior midbrain inhibit the reflex detrusor contraction that is induced by

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Neuroendocrine and Autonomic Nervous System Disorders / 86 To sensorimotor cortex

Pyramidal tract

FIGURE 86-4. Path 4b. (The pyramidal tract actually descends on the same side as the ascending tract to the sensorimotor cortex.) (Redrawn from Bradley, 1986.)

Muscle spindle ory fi Sens

bers

fibers Gamma motor

Alpha m

otor f ibers

Periurethral striated muscle

bladder filling. Although connections between the cerebellum and urinary bladder have been established and possible cerebellar influence on micturition hypothesized [Bradley, 1986], little specific information is available concerning this relationship. The brainstem detrusor motor nucleus is located in the caudal portion of the dorsal tegmental area of the pons rostral to the nucleus locus ceruleus [Tohyama et al., 1978]. Two projections emanate from this nucleus—one to the lateral hypothalamic area and one to the sacral spinal cord [Saper, 1995]. Bilateral lesions involving the pontine tegmentum, resulting in an inability to empty the bladder and urinary retention, have been described [Manente et al., 1996]. Detrusor muscle and the striated urethral sphincter muscles act in a complex reciprocal manner during bladder filling and voiding. Concurrent relaxation of the striated muscles of the internal and external urethral sphincters and contraction of detrusor muscle results in voiding. Reverse interaction results in bladder filling. The stretch receptors in the detrusor muscle are activated by bladder filling and initiate the micturition reflex [Bradley, 1986]. Some of these stretch receptor-initiated impulses travel in the pelvic nerve afferents, which synapse with the pudendal neurons in the sacral cord (path 3; see Fig. 86-2). Impulses inhibit the pudendal neurons, with resultant

relaxation of the striated muscles of the internal and external urethral sphincters. Other afferents are directed over a long pathway to the brainstem pudendal nucleus; from there they travel down the reticulospinal tract to terminate on the sacral detrusor neurons, with resultant muscle contraction (path 2). The voluntary control of the urethral sphincter is mediated through path 4a, which originates in the neurons of the corticospinal tract (pyramidal tract) in the medial anterior frontal cortex. The axons of the pyramidal tract terminate on the pudendal neurons in the sacral cord and by effecting activity in path 4b exert voluntary control over the sphincter muscle (cerebrospinopudendal pathway) [Nakagawa, 1980]. Tonic activity in the pudendal nerves innervating the urethral sphincter maintains closure of the sphincter during both waking and sleeping states. The muscle stretch receptors in the sphincter-striated muscle modulate and maintain this tonic activity. Commanding the patient to contract the sphincter provides a test for evaluating these neural connections. Because the innervation of the urethral and anal sphincter is the same for purposes of analysis, anal sphincter monitoring is useful for assessing urethral sphincter function. An anourethral reflex has also been described [Shafik, 1992]. Urethral sphincter function may also be assessed electromyographically by examination of the pelvic floor muscles [Siroky, 1996].

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2161

From brainstem reticular formation

To brainstem reticular formation

Pudendal nerve stretch receptors in external sphincter

Pelvic nerve stretch receptors in detrusor muscle

Dorsal horn Detrusor nucleus

Ventral horn Pudendal nucleus

Pudendal nerve to external sphincter Pelvic nerve to detrusor muscle FIGURE 86-5. Input-output relationships of conus medullaris. Recurrent inhibition pathways are observed in the pelvic motor nerves. (Redrawn from Bradley, 1986.)

The frontal lobes exert some voluntary control over the detrusor muscle. The integrity of this pathway can be readily demonstrated by the ability of the patient to suppress the detrusor reflex contraction on command during micturition and cystometric examination. Pathologic compromise of this pathway results in detrusor hyperreflexia, which is characterized during the cystometric examination by the reaction of a detrusor reflex at a low-volume threshold; the reflex cannot be interdicted volitionally by the patient. The impair-

ment may be so subtle that the clinical manifestations may be evident only on postural change or during walking. Bilateral pathologic involvement of the pyramidal tract, usually in the spinal cord, results in impaired volitional control of the urethral sphincter; therefore the urethral sphincter may undergo inappropriate relaxation, or increased sphincter activity may occur during detrusor contraction. This imbalance is termed detrusor-urethral sphincter dyssynergia [Hinman, 1980].

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Box 86-1 MICTURITION DISORDERS: SITES OF DYSFUNCTION Upper motor neuron unit lesions Frontal and parietal lobes Limbic system and hypothalamus Basal ganglia Brainstem Cerebellum Spinal cord Lower motor neuron unit lesions Afferent (sensory) pathways Efferent (motor) pathways Preganglionic Postganglionic Muscle fibers Detrusor vesicle outlet structural alterations

Box 86-2 FUNCTIONAL CLASSIFICATION OF URINARY INCONTINENCE A. Impaired urine storage 1. Detrusor dysfunction a. Hyperreflexia b. Increased tone c. Decreased elasticity 2. Altered outflow resistance a. Incompetent sphincter b. Structural abnormalities B. Impaired bladder emptying 1. Detrusor dysfunction a. Hypotonicity b. Areflexia 2. Increased outflow resistance a. Sphincter dyssynergia b. Structural abnormalities Anatomic and functional classifications of the disorders of micturition, including incontinence, are provided in Boxes 86-1 and 86-2.

Patient Evaluation History A detailed history is essential in eliciting clues regarding onset and the site of pathologic involvement in disorders of micturition. The presence or absence of incontinence or change in urinary habits must be ascertained. Frequency, urgency, force of the urinary stream, urinary volume, pattern of incontinence, and associated discomfort are crucial aspects of the history. Questioning a child concerning these symptoms requires patience and imagination. Allowing the child to describe the urinary dysfunction, with particular emphasis on the sensations associated with urination and the procedures and sensations associated with initiating and terminating micturition, may be crucial to ascertaining the correct diagnosis. One should suspect children who void by the Valsalva or Credé maneuver. In infants, whether the infant has to strain to void, the number of diapers changed, and the interval between changes must be determined.

Chronic genital dermatitis despite frequent diaper changes may indicate constant dribbling and a neurogenic bladder. Intact afferent and efferent connections to the detrusor muscle are prerequisites for instigation of the desire to void. Lesions in the afferent pathways from the bladder result in an absence of the desire to void. Sensations of imminent micturition and of ongoing micturition indicate that the requisite sensory pathways are intact. Lesions of the efferent pathways to the bladder lead to a dysfunction of micturition in the presence of a normal desire to void. In this situation, structural obstruction to the flow of urine must be excluded. In spinal cord lesions the level of injury determines the symptom complex. In lesions of the spinal cord at or below T10, the sensation of suprapubic fullness is generally preserved [Bauer, 1992]. If the lesion is rostral to T6, autonomic overactivity may be present and manifested by bradycardia, chills and diaphoresis, piloerection, paroxysmal hypertension, headache, and suffusion of the head and neck. This overactive autonomic response is the result of exaggerated reflex sympathetic activity in the isolated spinal cord. Plasma catecholamine concentrations are elevated, and peripheral sympathetic activity is increased. Circumstances surrounding the initiation and termination of urination provide further evidence of the type of neural lesion involved. The abrupt urge to void, with resultant sudden micturition, signifies an incomplete suprasegmental lesion. When the lesion is complete, the patient has no warning and no sensation associated with reflex micturition. In peripheral motor lesions involving injury of S2 to S4 segments (conus medullaris lesions), bladder pressure must be increased with the use of the abdominal muscles, and/or the bladder must be manually compressed to effect voiding. In this instance, micturition may cease when the patient discontinues straining or applying pressure to the abdominal wall. In suprasegmental lesions a momentary, involuntary interruption of the urinary stream may occur. If the patient can volitionally interrupt and resume urination, the efferent pathway may be presumed to be intact. Nocturnal enuresis is defined as persistent nighttime bedwetting beyond 5 years of age because 85% of children are urinary bladder continent by this age. Nocturnal enuresis has an uneven age and sex distribution; more boys than girls have this complaint at corresponding ages [Mattsson, 1994; Rushton, 1995]. Sleep polygraphic studies suggest immaturity of the central nervous system (CNS) inhibition of micturition reflex in sleep in enuretic children [Robert et al., 1993]. In a child who never achieved complete bladder control, the enuresis is said to be primary. Secondary enuresis is bedwetting after a dry period, indicating successful urinary bladder control. A few children, more females than males, exhibit daytime giggle micturition (enuresis risoria), which should be distinguished from stress incontinence [Elzinga-Plomp et al., 1995]. Diurnal or nocturnal enuresis occurring beyond the expected age of urinary control requires systematic evaluation. In enuretic children any associated impairment of sensory or motor function, particularly of the legs and perianal areas, should be carefully delineated because of the possibility of cord involvement. When present, incontinence should be categorized. Frequency of urination, urgency with a need to rush to the bathroom, and urge incontinence (often accompanied by a squatting posture in girls) usually indicate an overactive

Garg / Disorders of Micturition and Defecation

bladder. The likely mechanism in this instance is uninhibited detrusor contractions during bladder filling. Infrequent voiding may be due to a hypocontractile and distended bladder. Weak urinary stream, difficulty in initiating urination, or necessity to strain during micturition should lead to a suspicion of overactive sphincter, dysfunctional voiding, and structural obstruction. Urge syndrome is the most common voiding dysfunction in children [Saedi and Schulman, 2003]. Overflow incontinence, relatively rare in childhood, may accompany involvement of central or peripheral motor mechanisms. Loss of urine when lifting objects, coughing, or walking indicates stress incontinence, which may result from a peripheral motor lesion compromising either the detrusor muscle or the muscles of the pelvic floor. Abrupt, uncontrolled voiding is associated with neurologic lesions, such as those involving the cerebral hemispheres or the suprasegmental areas of the spinal cord.

Neurologic Examination The classic neurologic conceptualization of disease resulting from either upper or lower motor neuron unit involvement is inadequate for evaluating problems of micturition. Effects of CNS lesions vary widely because these lesions, depending on location, have significant inhibitory or facilitatory influences on micturition. Other confounding factors associated with these lesions are chronic infection and bladder distention, which lead to alterations in detrusor muscle contractility and neuronal excitability; these changes must be differentiated from primary neurologic conditions. Uninhibited neurogenic bladder may occur with bilateral involvement of the medial frontal lobe areas (e.g., superior sagittal sinus thrombosis). Frequency and urgency of urination are increased; bladder sensation is preserved. As the bladder fills, the detrusor contracts and increases intravesical pressure. The bladder may become so contracted that a minute quantity of urine induces micturition. Ultimately, automatic micturition develops [Saper, 1995]. Suprasegmental lesions of the spinal cord above the lumbar segments are accompanied by urgency, incontinence, increased frequency, and nocturia. The neurologic examination should be directed at excluding focal or progressive spinal cord lesions. The cutaneous area over the spine should be scrutinized for

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midline abnormalities that may indicate underlying congenital malformations. The spine should be evaluated for tenderness and scoliosis. Skeletal muscle spasticity, hyperreflexia, clonus, and extensor toe signs accompany suprasegmental lesions. Muscle atrophy, muscle weakness, and decreased or absent deep-tendon reflexes accompany lower motor neuron unit lesions originating in the lumbosacral cord; associated sensory changes are often evident. Syndromes of the epiconus, conus medullaris, and cauda equina are distinguishable by clinical findings and are summarized in Table 86-1 [Wright, 1982]. When the epiconus (L4, L5, S1, and S2) is involved, profound motor involvement of the lower legs and feet occurs [Saper, 1995]. External rotation and dorsiflexion of the thigh are most affected. Abduction at the hip, flexion at the knee, and flexion and extension at the ankle are also involved. The Achilles tendon reflex is absent. When the conus medullaris (S3 to Coc1) is involved (conus syndrome), paralytic bladder incontinence and, usually, bladder distention occur [Bauer, 1992; Saper, 1995]. Bowel incontinence is also present. There is loss of perianal sensation consonant with impairment of the lower sacral (S3 and S4) and coccygeal cord segments. Rectal sphincter reflex (anal wink) is absent, and denervation of the voluntary anal sphincter causes loss of anal sphincter tone. No motor abnormalities of the legs and feet occur. The Achilles tendon reflex is uninvolved. In a study of traumatic conus lesions, the prognosis was somewhat better than has been widely appreciated [Taylor and Coolican, 1988]. In the cauda equina syndrome, there is involvement of nerve roots from spinal segments L3 to Coc1. It may be difficult to distinguish cauda equina from conus lesions. All forms of sensibility are involved. Spontaneous pain, especially in the perineum over the sacrum and bladder, may dominate the clinical pattern [Saper, 1995]. Peroneal weakness, including footdrop, may occur. Fibrillary twitching in affected muscles is common. When preferential interruption of motor innervation occurs, detrusor contraction is greatly compromised, although bladder sensation is preserved (motor paralytic bladder).

Clinical Laboratory Tests Studies are chosen to clarify the nature of the bladder dysfunction [Borzyskowski, 1996]. Urinalysis and urine

TABLE 86-1 Differentiating Features of Lower Spinal Cord Lesions EPICONUS L4-S2

CONUS MEDULLARIS S3-COC1

CAUDA EQUINA L3-COC1 ROOTS

Reflexes

Achilles tendon reflex absent

Bladder and rectal symptoms

Small, contracted “spastic” bladder, loss of voluntary control with incontinence Variable

Usually sudden and bilateral Usually mild, symmetric motor dysfunction; fasciculations may be present Bilateral, symmetric saddle distribution; dissociation of sensory loss may be present Achilles tendon reflex may be diminished Paralytic, distended bladder and patulous anus, incontinence

Usually gradual and unilateral Asymmetric, marked motor dysfunction; fasciculation uncommon

Sensory

Variable Considerable motor dysfunction in the lower extremities (see text for details) Disturbances in L4-S2 segments

Onset Motor

Pain

Absent or symmetric bilateral mild pain in perineum or thighs

Asymmetric, saddle distribution; may be unilateral; no dissociation of sensation Patellar and Achilles tendon reflexes may be absent Paralytic, distended bladder and patulous anus, incontinence; involvement late and less severe Radicular pain; asymmetric, unilateral pain that may be severe and prominent

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culture, blood urea nitrogen, and serum creatinine are necessary studies. Results of these tests may indicate primary renal or other non-neurologic conditions. Ultrasonography of the kidneys and bladder has been of great value in rapidly assessing structural changes. In one series of children studied with ultrasonography, 32% of 74 children with voiding problems had one or more of the following: thickened detrusor muscle; large bladder capacity with or without residual urine; fecal impaction; suspected bladder neck obstruction, which later required internal urethrotomy; or small bladder capacity [Maizels et al., 1987]. A wide bladder neck anomaly has been recognized as a common cause of incontinence in children [Murray et al., 1987]. Abnormal cystic masses, bladder diverticula, and other structural abnormalities may be recognized; however, interpretation may occasionally be difficult and lead to erroneous diagnoses [Vick et al., 1983]. Urodynamic study of the free-flow curve provides valuable data without invasive instrumentation or an extensive urodynamic study. If the free-flow curve is normal and there is no residual urine, a significant voiding abnormality, whether functional or anatomic in origin, is unlikely [Griffiths and Scholtmeijer, 1984]. Study methods particularly adapted to children and norms for children have been developed [Di Scipio et al., 1986; Pompino and Hoffmann, 1983]. Video urodynamic studies of children with grossly intact neurologic function often reveal detrusor dysfunction and abnormal sphincter activity [Webster et al., 1984]. Computer-monitored voiding studies can provide useful information concerning detrusor muscle function and allow categorization of the dysfunction [van Mastrigt and Griffiths, 1986]. Urodynamic evaluation and follow-up care are important in the diagnosis and optimal management of many children with micturition problems [Churchill et al., 1987]. Plain radiographs of the lumbosacral area, intravenous pyelography, and a voiding cystourethrogram all provide further information. Bladder prolapse, with the bladder neck situated below the upper margin of the pubic symphysis, has been described as a urographic radiologic sign of urethral sphincter denervation in children with myelodysplasia [Zerin et al., 1990]. Conventional invasive urologic examinations, now less commonly required because of modern imaging techniques, should be performed when other examinations have not provided sufficient data [Ewalt and Bauer, 1996; Walther and Kaplan, 1979]. Detrusor muscle function can be evaluated by cystometry if other methods are insufficient. A slow-fill cystometrogram triggers bladder contraction after dilatation with instilled fluid. Detrusor tone, reflex threshold, sensation, and volitional ability to inhibit detrusor contraction can be assessed. Reflex abnormalities of the detrusor (i.e., hyperreflexia, hyporeflexia, or areflexia) may be documented [Bauer, 1992; Rushton, 1995]. Voiding cystourethrography and other radiologic techniques provide useful additional information [Bisset et al., 1987; Lebowitz, 1985]. Although infrequently performed, percutaneous stimulation of the sacral roots can be performed, in conjunction with transducer placement in the bladder, to monitor peripheral reflex pathways. Intact preganglionic pathways to the bladder are necessary for optimal detrusor response after percutaneous stimulation. Currently, sacral-evoked responses are used to evaluate these pathways, typically by

determining the latency of the bulbocavernosus reflex [Vodusek, 1996; Wein and Barrett, 1992]. Testing of the postganglionic pathways is more complex. The effect of percutaneous stimulation is assessed, as well as the detrusor contraction in response to direct electrical stimulation applied through a cystoscope and the intravesical pressure response to bethanechol chloride [Chai and Steers, 1996; Ewalt and Bauer, 1996; Wein and Barrett, 1992]. Muted or absent response to percutaneous and direct electrical stimulation and denervation hypersensitivity to bethanechol suggest impaired postganglionic pathways. Lack of a con-

Box 86-3 SELECTED DIFFERENTIAL DIAGNOSIS OF NEUROLOGICALLY INDUCED DISORDERS OF MICTURITION AND DEFECATION Congenital malformations Caudal regression syndrome Diastematomyelia Diplomyelia Hydromyelia Myelodysplasia Myelomeningocele Sacral agenesis Spondylosis Syringobulbia Syringomyelia Tethered cord Infectious and inflammatory conditions Acute disseminated encephalomyelitis (postvaccinal, postinfectious) Adhesive arachnoiditis of the spinal cord Anterior horn cell infection (e.g., coxsackie, poliomyelitis) Guillain-Barré syndrome Herpes zoster Suppurative infection of the spine with extension to the cord (e.g., tuberculosis) Transverse myelitis Vascular conditions Anterior spinal artery occlusion or hemorrhage Hematomyelia Sagittal sinus thrombosis Spinal cord arteriovenous malformation Spinal cord epidural hemorrhage Metabolic conditions Diabetes mellitus Traumatic conditions Birth injury (e.g., spinal cord traction) Spinal anesthesia complications Spinal cord injury (e.g., crush injury, stab injury) Vertebral fracture or dislocation with spinal cord disruption Tumors Cauda equina tumor (e.g., teratoma, lipoma) Cerebral tumors (e.g., parasagittal meningioma) Sacrococcygeal mass (e.g., teratoma, lipoma, dermoid) Spinal cord tumor (e.g., ependymoma, lymphoma) Demyelinating diseases Devic’s disease Multiple sclerosis

Garg / Disorders of Micturition and Defecation

tractile response to direct stimulation and lack of denervation hypersensitivity may indicate myopathic detrusor changes, which result from bladder overdistention or infection.

Patient Evaluation Differential Diagnosis Nocturnal enuresis is the most common disorder of micturition in childhood. Neurologic disease must be excluded in any child who either does not develop or subsequently loses urinary continence. Box 86-3 presents a list of differential diagnoses in disorders of micturition. Several dysfunctional voiding syndromes without associated neurologic dysfunction (non-neurogenic voiding disorders) have been described and respond to a variety of therapeutic interventions [Homsy, 1994; Jayanthi et al., 1997; Yang and Mayo, 1997]. Chronic constipation may sometimes be associated with urinary incontinence in children [Loening-Baucke, 1997].

Management Individuals with impaired bladder and bowel control report a low self-concept and low self-esteem with lower perceived quality of life on several domains and have greater difficulty in creating new social relationships [Hicken et al., 2001; Moore et al., 2004]. Precise diagnosis is required for a systematic and effective therapeutic approach. Neurogenic bladder dysfunction must be countermanded so that urinary control and normal renal function are allowed to continue [Chandra, 1995]. The goals of treatment are to preserve renal function, prevent urinary infection, and promote urinary continence in older children [Fernandes et al., 1994]. Optimal neurogenic therapy prevents infections (Table 86-2). Patients require regular monitoring. Medications commonly employed in treating bladder dysfunction are listed in Table 86-2. Hyperreflexic bladder, the result of impairment of suprasegmental governance of the detrusor muscle, is associated with increased resting bladder tone, uncontrollable bladder contraction with incontinence, frequency and urgency of urination, and diminished bladder volume. Therapeutic measures are directed at these cardinal features [Chua et al., 1996; Sakakibara et al., 1996; Wyndaele, 1995].

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Administration of anticholinergic drugs decreases contractility. Therapy with propantheline bromide is often effective. Oxybutynin may be used in some children [Kaplinski et al., 1996; Mizunaga et al., 1994; Palmer et al., 1997]. Trials with new anticholinergic agents demonstrate promise [Hehir and Fitzpatrick, 1985; Mazur et al., 1995; Otto-Unger, 1985]. Unfortunately, anticholinergic therapy may be associated with urinary retention and an increase in residual urine; therefore residual urine volume should be estimated and urinary output monitored. Intermittent catheterization may prove necessary if retention occurs [Cass et al., 1984]. Credé’s or Valsalva’s maneuver may sometimes be sufficient to completely empty the bladder [Bauer, 1992]. Renal rupture after the Credé maneuver has been described [Reinberg et al., 1994]. Drugs that augment the noradrenergic system appear to facilitate continence; in addition, drugs that depress or block dopamine activity may produce urinary incontinence. Dopamine agonists and specific catecholamine agents may prove valuable in managing urinary incontinence [Ambrosini, 1984]. A sympathomimetic agent is used if detrusor muscle hypertonicity rather than uninhibited detrusor reflex contractions exists. Management is usually initiated with imipramine hydrochloride. The child (and parents) should be instructed concerning the features of urinary retention. Difficulty in initiating micturition; failing to completely empty the bladder, which leads to urinary retention; and dribbling incontinence are characteristic of detrusor hyporeflexia or areflexia. Bladder capacity is usually significantly increased. Management in this instance is directed toward increasing effective intravesicular pressure and decreasing bladder outlet resistance. Credé’s or Valsalva’s maneuver, as well as intermittent catheterization, may be used to empty the bladder. Cholinergic stimulation (e.g., with bethanechol chloride) should be used with caution because it may aggravate urinary dysfunction in such patients. Neurogenic bladder outlet obstruction may respond to alpha-adrenergic blocking agents. Alpha-blocker therapy with doxazosin also has been used succesfully to reduce postvoid residual urine volume in children with complex neuropathic and non-neuropathic voiding dysfunction [Cain

TABLE 86-2 Drugs Used in Neurogenic Bladder Dysfunction BLADDER DYSFUNCTION Impaired Urine Storage Decreased bladder capacity

Decreased outflow resistance Impaired Bladder Emptying Increased bladder capacity Increased outflow resistance Modified from Bauer, 1992.

DRUG

ACTION

USUAL MINIMUM DOSE PER DAY (mg/kg)

USUAL MAXIMUM DOSE PER DAY (mg/kg)

Propantheline Oxybutynin Flavoxate Dicyclomine Terodiline Phenylpropranolol Ephedrine Imipramine

Anticholinergic Anticholinergic Direct muscle action Anticholinergic Calcium antagonist Sympathomimetic Sympathomimetic Complex

1 0.4 6 1 12.5 5 1 1.4

2 0.8 9 2 25 mg/day 7.5 3 2.4

Bethanechol Phenoxybenzamine Dantrolene

Cholinergic Sympatholytic Direct muscle action

2 0.6 1

3 1.5 8 to 10

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et al., 2003]. The phentolamine test can be used to predict which patients are likely to benefit from phenoxybenzamine therapy [Smey et al., 1980]. Use of oral baclofen may be of limited benefit in a few patients. It probably relaxes the external sphincter and may be used as an adjunct. Intravesical medications may be used in children who either cannot tolerate or have poor and inadequate response to oral therapy [Greenfield and Fera, 1991; Kato et al., 1991]. Intrathecal baclofen has also been used [Frost et al., 1989]. Botulinum A toxin injection into the external urethral sphincter has been used for the treatment of detrusor-sphincter dyssynergia in patients with spinal cord injury [Schurch et al., 1997]. Newer drugs with both anticholinergic and calcium antagonist properties, such as terodiline, are being used in children [Langtry and McTavish, 1990]. An understanding of the role of serotonin (5-HT4) receptors in urinary bladder function may also lead to the development of newer drugs [Hegde and Eglen, 1996]. Functional bladder-sphincter dyssynergia may be successfully treated by using electromyographic biofeedback with exercises, which consist of alternate tensing and relaxing lower pelvic muscles [Libo et al., 1983]. Other biofeedback training programs have also been effective in managing children with probable non-neurogenic bladder disturbances [Hellström et al., 1987; Jerkins et al., 1987]. Mechanical compression (Credé’s or Valsalva’s maneuver), intermittent self-catheterization [Bauer, 1992; Cass et al., 1984; Chai et al., 1995], and various surgical techniques may be of value. Clean, intermittent catheterization has been widely used in children, but its use and effectiveness in infants have only recently been recognized. Early implementation of this method helps preserve renal function, especially in children with myelodysplasia. It may be used in combination with anticholinergic drugs in infants [Baskin et al., 1990; Joseph et al., 1989; Lapides et al., 1972]. Surgical techniques include transurethral incision of the external urethral sphincter, urinary stream diversion operations, implantation of an artificial urinary sphincter [Khoury and Churchill, 1987; Light, 1985; Simeoni et al., 1996], bladder augmentation [Krishna et al., 1995], bladder replacement [Hensle and Burbige, 1985; King et al., 1987], free autogenous muscle transplantation [Hakelius et al., 1984], and differential sacral nerve root rhizotomy and electrical stimulation [Sindou et al., 1994; Tanagho et al., 1989]. Nonsurgical therapies should be exhausted before surgical therapy is undertaken. Early intervention may sometimes be necessary to preserve normal function or avoid progressive dysfunction, especially in children with spinal dysraphism [Bauer, 1992; Keating et al., 1988]. Several incontinent products are available for use in children with urinary incontinence. [Sanders, 2002]

DISORDERS OF DEFECATION Defecation is the conscious act of emptying the bowel, and continence is the ability to control defecation voluntarily. Fecal soiling is the presence of stool in the underwear independent of whether an organic or anatomic lesion is present. Fecal incontinence is fecal soiling when there is an organic or anatomic lesion such as meningomyelocele or other neuromuscular disorders, anal malformations, anal

surgery, or traumatic lesions [Loening-Baucke, 1996]. Reflex neuromuscular mechanisms and the anatomy of the rectum, anus, and sphincters contribute to anal continence in a normal child. Bowel control usually precedes bladder control in children [Perlmutter, 1985]. Conscious bowel control is achieved at 28 months of age on average [Brazelton, 1962]. Toilet training is a complex multistep process as mentioned in the preceding discussion.

Anatomy and Embryology The rectum and anal canal are derived from the primitive anorectal canal and originate from entoderm and ectoderm, respectively. The muscular anal sphincters are mesodermal in origin. The pelvic diaphragm, formed by the levator ani muscles, demarcates the anal canal from the rectum. The anal canal proceeds dorsocaudally through the levator ani muscles to the anus and is surrounded by the internal and external anal sphincters. The ringlike internal anal sphincter is a thickening of the circular muscle of the rectum. The external anal sphincter, which envelops the internal sphincter, is elliptic in outline and is divided into three portions. The deep division is separated from the internal sphincter by strands of the longitudinal coat, whose fibers also interdigitate partially with those of the levator ani. The superficial division is the principal part. It is attached to the coccyx dorsally and to the central tendon ventrally. The subcutaneous division surrounds the anus and has no bony attachments. The course of the rectum is aligned at an approximate 90-degree angle to the axis of the anal canal. The sharp angular bend favors anal continence. The pelvic floor is formed from the levator ani muscles, which elevate the anorectal junction and thrust it anteriorly during contraction. The resultant straightening of the path between the anal canal and rectum facilitates defecation. Fecal continence is the result of the interrelationships among the two anal sphincters and the levator ani muscles [Rao, 1996, 1997].

Nerve Supply In a simplistic sense, the sympathetic nervous system modulates rectal filling, and the parasympathetic system controls bowel emptying. Activation of the parasympathetic system results in contraction of the sigmoid and rectal smooth muscles with concomitant relaxation of the internal sphincter. Activation of the sympathetic system causes the reverse pattern—relaxation of the sigmoid and rectum and contractions of the internal sphincter [Rao, 1996, 1997]. Innervation of the rectum parallels that of the bladder; the previous discussion of bladder neuroanatomy should be reviewed for further information. Pudendal nucleus cells (S2 to S4) are located in the region of parasympathetic nerve cells, give rise to the pudendal nerve, and innervate the external anal sphincter. Sympathetic innervation is derived primarily from L1 and L2 through the hypogastric plexus and innervates the internal anal sphincter. The anal canal contains numerous sensory nerve endings. Light touch, pain, and temperature sensations are transmitted to the sacral cord through the pudendal nerves, where they are distributed through conventional sensory pathways

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and also participate in path 3, which was described in the discussion on bladder innervation. The neural circuitry for defecation is complex. Some afferent impulses travel through the pudendal nerve to the spinal cord and then ascend to the cerebrum, which exerts voluntary control. Motor impulses (efferent) arising in the cerebrum descend by way of the lateral columns and reach the T6 to T12 motor neurons and initiate abdominal muscle contraction. This contraction increases intraabdominal pressure and secondarily exerts pressure on the rectum. Distention of the rectal ampulla causes the sensation of fullness in the perineum. Increasing distention causes awareness that defecation is imminent. Sensory information is also provided by the numerous free endings and by the extensive myenteric plexus in the rectum. Pararectal nerve stimulation and stretching of the sensory nerve endings in the levator ani muscles (especially the puborectalis muscle) may also contribute to the urge to defecate. In the initial (involuntary) phase of defecation, fecal material reaches the rectum as a result of the peristaltic movement originating in the sigmoid colon. The elevation in rectal pressure, which results from fecal matter pushing against the anorectal ring (puborectalis muscle), results in the urge to defecate. The next phase consists of volitional contraction of the abdominal muscles, followed by an increase in abdominal pressure and simultaneous relaxation of rectal sphincters, causing defecation. Interaction of tone and reflex activity is essential in the physiology of continence. Reflex and voluntary contractions of the puborectalis muscle and internal and external sphincters are important components of continence during sleep and waking. Because of the intricate relationship of the sphincters, determining their contribution to maintenance of resting pressure is difficult; however, the resting pressure appears primarily to be the result of contraction of the internal sphincter [Pemberton and Kelly, 1986]. Incontinence occurs when the pressure induced by the peristaltic movement in the distal rectum overcomes the anorectal pressure. There are three types of incontinence— true incontinence, partial incontinence, and overflow incontinence [Wright, 1982]. Deficient anorectal muscles (e.g., imperforate anus) or impaired neuromuscular function results in true incontinence. There may be insufficient anorectal pressure or impaired sensation of peristaltic movement and bowel distention. Fecal soiling is the result of partial incontinence because the final stage of defecation is inadequate and is followed by continuing passage of small amounts of stool. Overflow incontinence, not a true form of incontinence, results from chronic fecal impaction and leakage of liquid feces through the dilated anorectal ring.

Patient Evaluation History Fecal incontinence is the usual complaint of patients seeking help. It is essential to determine whether bowel control was lost after it had been achieved or whether bowel control was never present. The age at onset, frequency, related circumstances (e.g., time of day, association with sleep, behavioral

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aspects), and alterations in bowel habits, stool mass, stool color, and stool consistency should be established. Overall integrity of afferent and efferent pathways may be evaluated by further questioning. Inquiries should be designed to ascertain whether rectal sensation, including pressure of fecal volume and need to defecate, as well as the ability to differentiate between passage of flatus and feces, is present. Similarly, efferent function can be evaluated by questions related to volitional inhibition of defecation. Fecal incontinence is unlikely to be due to spinal cord disease in the absence of urinary symptoms or neurologic abnormalities in the lower limbs.

Neurologic Examination Because the neural pathways are similar, neurologic evaluation of bowel incontinence parallels that described for disorders of micturition. In lesions above the sacral cord (suprasegmental lesions), voluntary control over the sphincter ani is lost. Sphincter tone is increased, and fecal retention occurs, leading to chronic fecal impaction and consequent soiling. During rectal examination the patient should be able to contract and relax the sphincter on request. Sphincter tone is often increased and contracted with suprasegmental lesions [Wright, 1982]. Paralysis of the sphincter ani accompanies sacral cord disturbance. The anus is patulous, the anal sphincter reflex is lacking, and the patient is unable to contract the sphincter on command. In contrast with bladder function, the extent of preservation or return of anal and rectal sensation in conus medullaris lesions is important in achieving bowel control. The involuntary passage of flatus is a distressing symptom in such patients if they cannot distinguish it from feces for which sensory input is essential [Taylor and Coolican, 1988]. Further information on the examination of the patient with lower cord and cauda equina lesions can be found in the section on urinary incontinence.

Clinical Laboratory Tests Proctoscopy and fiberoptic studies of the lower bowel are efficient methods of excluding the presence of structural abnormalities. Barium enema studies are sometimes necessary as are defecography studies, which visually monitor the functional events during defecation [Mezwa et al., 1993]. Special studies include anal sphincter electromyography [Lewis and Rudolph, 1997; Rao, 1996, 1997; Shafik, 1992]. Denervation potentials indicate a recent lower motor neuron process. Pudendal nerve terminal motor latency is especially useful when neuropathy is suspected. Overall electrodiagnostic studies are helpful in the evaluation of fecal incontinence, although less so in very young children [Cheong et al., 1995]. A manometric study may also be useful [Rao, 1996]. The correlation between the clinical findings and the manometric assessment of sphincters in response to rectal distention has often been thought to be poor; recent reevaluation suggests otherwise [Rao and Patel, 1997]. Computed tomography allows imaging of the puborectal muscle and external sphincters and identification of associated anomalies [Ikawa et al., 1985; Kohda et al., 1985]. Sacral ratios less than 0.52 correlate well with spinal cord anomalies and with unfavorable prognosis in children with anorectal

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malformations. Sacral ratio is determined by dividing the distance from the lowest point of the sacrum (or of the coccyx, if present) to the line joining the two posterior iliac spines by the distance from that latter line to the line joining the upper limits of the iliac crests [Torre et al., 2001].

Differential Diagnosis Bowel dysfunction is produced by the conditions listed in Box 86-3. Lumbosacral defects may be associated with reduced or absent external sphincter function, which is demonstrated by sphincter electromyography. Denervation potentials or reduced large-amplitude potentials may be observed. In Hirschsprung’s disease, manometric studies demonstrate an absence of the rectoanal inhibitory reflex; that is, the internal sphincter fails to relax in response to a transient rectal distention. The relaxation wave is absent. The most common cause of bowel incontinence is encopresis, which is not associated with neurologic dysfunction. Encopresis is fecal incontinence without organic cause for more than a month in children 4 years of age or older. Males outnumber females 3.5 to 1 [Bellman, 1966]. The cardinal feature of encopresis is withholding of stools: This condition is often not recognized by parents. Neurogenic and other organic conditions causing bowel dysfunction must be excluded [Loening-Baucke, 1996; Nolan and Oberklaid, 1993].

Management Assessment of contributing factors, including psychosocial milieu, anorectal examination, and appropriate neurologic evaluation, is necessary for adequate management. Therapeutic approaches include dietary, behavioral, pharmacologic, and surgical methods [Wald, 1986]. Education is important in achieving good outcome [King et al., 1994]. Dietary measures to harden stools may be attempted for some patients. The stools can then be evacuated by manual pressure over the abdomen and by straining of the abdominal muscles. Some children may perceive the urge to defecate when the stools are bulkier, which can be achieved by using stool-bulking agents (e.g., Metamucil). High-fiber diet may be appropriate in some cases. Rectal suppositories (bisacodyl) or a saline enema may empty the rectum before it fills and cause reflex relaxation of the internal sphincter. This approach may prevent soiling in some children. Excessive flatus and soiling may also be controlled by avoiding certain foods, such as legumes, and by giving attention to strict dietary and bowel habits. Antegrade colonic enemas have been used in children who have failed usual medical treatment [Griffiths and Malone, 1995; Squire et al., 1993]. Biofeedback training [Owen-Smith and Chesterfield, 1986], behavior modification [Whitehead et al., 1986], muscle training, and medications are often beneficial [Scharli, 1987]. New devices to control both fecal and urinary incontinence have shown promise [Numanoglu, 1987]. Surgical intervention may be considered if conservative treatment fails [Bass and Yazbeck, 1987; Chen and Zhang, 1987; Kottmeier et al., 1986; Peña, 1994]. Artificial anal sphincter, gracilis muscle transposition, and dynamic graciloplasty have also been used with good outcome in children who fail medical management [Baeten et al., 1995; Han et al., 1995; Wong et al., 1996].

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CHAPTER 87

Poisoning and Drug-Induced Neurologic Diseases Laurence E. Walsh and Bhuwan P. Garg

Many substances are potential nervous system toxins. Manufactured and naturally occurring agents, including pharmaceutical compounds and recreational drugs, may be ingested, inhaled, injected, or absorbed, with a subsequent deleterious effect on a child’s central or peripheral nervous system. Effects may be acute, subacute, or chronic and occur in adolescents, young children, infants, or fetuses. Neurologic dysfunction may be isolated or part of a systemic derangement. Poisonings are common. In 2003, nearly 2.4 million cases of poisoning were reported to the nation’s poison control centers, 93% of which occurred at home [Watson et al., 2004]. Of these, 1.58 million involved persons younger than 20 years of age, and 1.24 million (or 52% of all poisoning victims) were children younger than 5 years [Watson et al., 2004]. Intoxication is the second most common injury (behind falls) in children younger than 48 months [Agran et al., 2003]. Data from other countries suggest similar demographics [Andiran and Sarikayalar, 2004]. Neurotoxins are among the most commonly encountered toxins, although they less commonly are the culprits in children younger than 6 years [Watson et al., 2004]. Poisonings and drug-induced neurologic disease may mimic infection, trauma, neoplasm, psychiatric illness, or metabolic disorders. Intoxications should be considered in the differential diagnosis of a child with an unexplained change in sensorium, seizures, ataxia, involuntary movements, muscle weakness, or autonomic dysfunction. Prompt recognition and management of intoxication reduce both mortality and morbidity in most cases. Neurotoxins may have more long-term cognitive sequelae. Unfortunately, studies of low-level environmental exposures often suffer from imperfect control of confounding factors [Mink et al., 2004; Weiss et al., 2004]; this situation may limit conclusions that may be drawn from these studies. Most childhood poisonings are accidental [Nhachi and Kasilo, 1994; Singh et al., 1995; Watson et al., 2004]. The most common agents implicated in children younger than 6 years are cosmetics, personal care products, and household cleaning solutions. Important factors contributing to accidental poisonings include parental factors, such as improper medicinal or chemical storage, lapses in child monitoring, and ignorance of poison control methods. Likewise, children may be noncompliant, may mistake a potential toxin for food, may imitate parental medication-taking behavior, or simply may be curious. One unusual example was that of an 11-year-old male who ingested 35% hydrogen peroxide solution. Although H2O2 exposure may result in irreversible cerebral injury, his magnetic resonance imaging (MRI) test demonstrated bilateral posterior reversible diffusion

restriction; he later made a full recovery [Cannon et al., 2003]. Failure of “childproof” containers was cited in 18% of poisonings in one study [Brayden et al., 1993]. Adolescents and preadolescents are at risk for recreational drug and solvent abuse. The rate of substance abuse by preteens in the United Kingdom approaches 5% [McArdle, 2004]. Poisoning occurs deliberately in suicide attempts, child abuse, and other attempts to harm a child. In a 2002 Polish study, 14% of poisonings in children younger than 15 years were intentional (including self-inflicted) [Kotwica and Czerczak, 2002]. Two thirds of suicide victims younger than 19 years in the United Kingdom use selfpoisoning [Camidge et al., 2003]. In Hong Kong, poisoning is implicated in 15% to 20% of murders and suicides in the general population [Chan et al., 2003]. These high percentages of nonaccidental poisoning deaths compared with the United States may reflect differences in firearm regulation. Among the pediatric population, those at highest risk for abuse are infants and preschoolers; teenagers have the highest risk for suicide [McClure, 1994; McClure et al., 1996]. Abuse of alcohol and other recreational drugs may predict suicide attempts, although the method may involve neither [Hawton and Fagg, 1992, 1993]. Common suicide methods identified recently in teenagers include hanging, exhaust inhalation, and overdose on medications, including paracetamol, benzodiazepines, and tricyclic antidepressants [Andiran and Sarikayalar, 2004; Ghazi-Khansari and Oreizi]. Pesticides, herbicides, and caustic agents may also be used; fatalities caused by ingestion of such agents may be the result of suicidal intent rather than accidental exposure more often in adolescents than in adults [Andiran and Sarikayalar, 2004; Klein-Schwartz and Smith, 1997; Thompson et al., 1995]. Poisoning as a result of child abuse usually occurs in conjunction with a background of other, separate injuries. Still, poisoning may occur in isolation or within a more cryptic history of unexplained illnesses; this is especially evident in Munchausen’s syndrome by proxy [Chadwick, 1997]. A diagnosis of Munchausen’s syndrome by proxy suggests the secondary gain of medical contact as motive; it is sometimes difficult to differentiate Munchausen’s syndrome by proxy from other causes of nonaccidental injury. The incidence of nonaccidental poisoning in the British Isles is more than 2.8 per 100,000 children younger than 1 year each year and more than 0.5 per 100,000 children younger than 16 years each year [McClure et al., 1996]. Methods reported include forced ingestion of antiepileptic drugs, opioids, and caustics, as well as various other agents [Gotschlich and Beltran, 1995; McClure et al., 1996]. Unfortunately, escalation of Munchausen’s syndrome by proxy often occurs, with suffocation a frequent terminal event [Chadwick, 1977; McClure et al.,

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1996]. One instructive case of Munchausen’s syndrome by proxy was that of an 11-year-old female with a history of cyclic vomiting. Investigation eventually revealed arsenic poisoning by her mother [Embry, 1987]. Conversely, some children and adults present with complaints of symptoms that are believed to be the result of a toxic exposure, but for which no toxin is identified. In these cases, symptoms often are vague; litigation is common (30%); and the patients or families do not easily accept refutation of the alleged exposure [Leikin et al., 2004]. Finally, chemical agents have been used as weapons against groups of people. Although their use in battle is not new, recent events have raised concern over covert use of chemical agents to attack civilian populations. In the 1994 Matsumoto nerve agent terrorist attack using sarin, 58 of 600 exposed people required hospital admission, and 7 died. The most common symptom was miosis. Central nervous system (CNS) effects and transient cardiomyopathy also occurred [Okudera, 2002]. The U.S. Department of Health and Human Services has published a brief guide to toxidromes associated with likely covertly used chemical weapons [Patel et al., 2003]. Clinical trials, preclinical studies, anecdotal reports, and epidemiologic data have contributed to our understanding of neurotoxins [Erinoff, 1995; Fray and Robbins, 1996; Indulski and Lutz, 1996; Kurz et al., 1995]. Detailed discussion of antiepileptic drugs and immunization side effects is omitted here; these topics are covered in other chapters.

EMERGENCY EVALUATION AND MANAGEMENT Management of the poisoned child requires skilled immediate stabilization of the patient and appropriate corrective and supportive therapy. It requires also that the physician review the history and examine the child carefully for clues that may suggest poisoning or drug effects. Discovery of such evidence is not always easy, and a high index of suspicion is necessary. Three fourths of all poisonings are by ingestion. Although cosmetics and household cleaning solutions are ingested, medications account for most deaths [Litovitz et al., 1995; Watson et al., 2004]. Careful physical examination helps to establish the cause of the child’s distress and guide therapy. Neurologic findings may result from the drug or toxic agent itself or from CNS hypoxia or ischemia caused by a generalized disturbance of circulation and respiration. Systemic abnormalities that occur after various types of intoxication may include cardiac dysrhythmias, gastrointestinal disturbances, and varying degrees of metabolic acidosis. Dysrhythmias, including marked degrees of bradycardia with cyanide or physostigmine intoxication, may be clues to the identity of the toxic agent and signal the need for emergency treatment. Cardiac conduction abnormalities, such as prolonged QT interval with phenothiazine overdose and widened QRS interval with tricyclic antidepressants, quinine, or quinidine overdose, may be present. Gastrointestinal complications, including severe diarrhea and vomiting, may occur with lithium, mercury, phosphorus, arsenic, mushroom, and organophosphate poisoning. Metabolic acidosis with a large anion gap may result from intoxication with cyanide, methyl alcohol, ethylene glycol, propylene glycol, and salicylates [Gardner et al., 2004].

BOX 87-1 SUGGESTED GENERAL MANAGEMENT OF SUSPECTED INTOXICATIONS AND POISONING 1. Establish patent airway, adequate respirations, pulse, and systemic perfusion; monitor level of consciousness and urine output. 2. Establish intravenous access. 3. Administer oxygen, glucose, and naloxone as necessary, especially in patients with acute alteration of mental status. 4. Obtain pertinent history and perform careful physical examination, specifically looking for entry sites for envenomation, needle tracks, or other evidence of agent entry (e.g., nasal mucosa, mouth, genital orifices); examine for systemic signs of intoxication, including fever, abnormal vital signs, excessive tearing or salivation, odor, skin and nailbed color, hyperhydrosis or anhydrosis, trauma, or hemorrhages. 5. Perform age-appropriate neurologic examination, including mental status examination and cranial nerve, speech, motor, cerebellar, muscle stretch reflex, and sensory evaluations. Observe patient for posture and gait. 6. Obtain laboratory studies, such as a chemistry profile, including serum glucose and electrolyte levels, blood pH, complete blood count, urine and serum toxicologic studies (for specific agents when indicated), and drug levels if suggested by history or physical examination. 7. Prevent further absorption or maximize elimination of the toxic agent using gastric lavage or activated charcoal only when indicated [Zimmerman, 2004]. 8. Administer specific antidote when indicated. 9. Obtain electrocardiogram and, when indicated, neuroimaging studies (e.g., CT, MRI), electroencephalogram, and cerebrospinal fluid for examination. 10. Monitor closely; reassess the child frequently.

Finally, steps should be taken to protect the child from future exposures. Appropriate general management steps are outlined in Box 87-1; details may be found in several recent references [Arena, 1985; Banner et al., 1994; Chan et al., 1993; Goetz, 1985; Gosselin et al., 1984; Haddad and Winchester, 1983; Leikin and Osterhoudt et al., 2004; Paloucek, 1995; POISINDEX, 2005; Zimmerman, 2003]. Therapy for specific toxidromes is discussed with the individual agents.

Testing The value of routine toxicologic testing in cases of possible intoxications is debated in the literature. The low sensitivity of specific tests and the inability to test for all possible agents, medicolegal concerns, and cost effectiveness have fueled arguments that routine testing should be limited [Bond, 1995]. Ideally, history and physical examination narrow the list of possible exposures and direct specific toxicologic testing. However, young children may not provide adequate

Walsh and Garg / Poisoning and Drug-Induced Neurologic Diseases

history, and poisoned children sometimes present with unfamiliar or atypical clinical features [Lifshitz et al., 1997]. These situations may require a more extensive search for the toxic agent. Toxicologic screening methods have other limitations as well. Most are not designed specifically for use in children, although modified panels or pediatric protocols are available [Badcock and Zoanetti, 1996]. Many physicians are unaware of the agents actually identified by the blood and urine panels available at their institutions. A standard screen for drugs of abuse may detect barbiturates, benzodiazepines, opioids, amphetamines, cocaine metabolites (benzoylecgonine), phencyclidine palmitate, and marijuana metabolites (tetrahydrocannabinol) by immunoassay, but other drugs, such as lysergic acid diethylamide, may remain undetected [Bond, 1995]. Other broad drug screens may detect phenothiazines, tricyclic antidepressants, ethanol or other volatile substances, and sympathomimetic amines. Urine screens for drugs of abuse may detect two to nine agents (e.g., tetrahydrocannabinol, cocaine, opioids, amphetamines, barbiturates, benzodiazepines, methamphetamines, phencyclidine palmitate, tricyclic antidepressants in Diagnostix kits). Other commercially available screens include EMIT (Behring Diagnostics, San Jose, California), Abuscreen (Roche Diagnostic Systems, Basel, Switzerland), and others. Thin-layer chromatography and ultraviolet spectroscopy are also popular, but older tests, including crude spot tests, are still available. The sensitivity of the screens and the need for subsequent confirmation (i.e., by high-performance liquid chromatography) depend on the methods used. Likewise, routine urine screens for heavy metals may identify only arsenic, mercury, and lead. Results from some screens may be obtained in less than 1 hour, but broad screens may require 24 hours for results; specific tests may require a week [Pathology and Laboratory Medicine, 1994]. Hair sample–based toxicologic testing has become increasingly popular and overcomes many limitations of other modalities. The test is minimally invasive, does not rely on dilution methods, and gives historical information. Use of a wide variety of substances can be determined from hair samples, including drugs of abuse, haloperidol, antidepressants, sympathomimetics, and heavy metals [Hoffman and Nelson, 2001; Leikin, 1995]. The primary cocaine metabolite, benzoylecgonine, and acidic, polar drugs are difficult to identify reliably in hair samples, and the test is probably not appropriate for acute toxicity testing situations, although in the case of cocaine, qualitative and semiquantitative analysis of more chronic use can be demonstrated [Katikaneni et al., 2002; Stephens et al., 2004]. In a prospective pediatric emergency department study, using urine gas chromatography–mass spectrometry drug screens, the best clinical predictors of poisoning were odor on the child’s breath, symptoms and signs consistent with poisoning, and poison actually on the child’s clothing [Hwang et al., 2003]. Positive predictive values for these three variables were 100%, 92%, and 86%, respectively.

Other Ancillary Testing Ancillary testing is directed by specific clinical findings. Electroencephalography is important to exclude subtle or subclinical seizures in intoxicated patients who display

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altered mental status. Neuroimaging studies have at least three roles. First, in the acutely intoxicated child or teenager, a head computed tomography (CT) scan may be required if there is suspicion of concomitant trauma or hemorrhage. Second, brain MRI findings may explain a patient’s neurologic findings when clinical history and other laboratory studies do not. As neuroimaging of an increasing number of poisoned children and adults has occurred, a couple of recurring MRI patterns have become evident. Agents that cause hypoxic injury, including cellular respiratory poisons, may result in an MRI picture of bilateral symmetric cortical and subcortical gray matter injury, although white matter changes occur as well [Halavaara et al., 2002; Kim et al., 2003; Rachinger et al., 2002]. Medications used for immunosuppression and those that cause hypertension or changes in blood-brain barrier permeability may contribute to a characteristic neuroradiographic pattern of bilateral posterior reversible leukoencephalopathy (so-called posterior reversible leukoencephalopathy syndrome) [Renard et al., 2004]. Third, the increasing use of diffusion-weighted MRI sequences and apparent diffusion coefficient calculations (apparent diffusion coefficient mapping) often provides a method to delineate early cerebral injury.

Neurologic Examination Examination of a poisoned child includes initial and serial assessment of neurologic status; this assessment guides clinical management, predicts prognosis, and often identifies the offending agent. Assessment of mental status is important because several poisons, medications, and recreational drugs may be associated with affective symptoms and may also cause acute changes in sensorium such as irritability, other affective symptoms, delirium, coma, lethargy, and seizures. Although psychotropic or analgesic medications have the greatest potential to cause these effects, antihistamines and other routinely used pediatric medications are common culprits [Bassett et al., 1996]. Environmental and biologic toxins may likewise cause change in sensorium, although more often in younger children. More chronic effects include dementia, subtle learning difficulties, and apparent psychiatric illness. Agents that cause seizures or changes in sensorium are listed in Box 87-2. Cranial nerve examination may reveal specific toxininduced syndromes. Decreased visual acuity or changes in color perception may suggest anticholinergic or cardiac glycoside toxicity, respectively. Papilledema reflects increased intracranial pressure and may suggest pseudotumor cerebri, or benign intracranial hypertension, caused by systemically administered steroids, excessive vitamin A intake, or use of outdated tetracyclines. Visual impairment and a macular cherry red spot has been reported in association with dapsone poisoning. The patient had concomitant peripheral neuropathy, and the macular changes were considered secondary to toxic retinal damage [Abhayambika et al., 1990]. Pupillary dysfunction may be caused by medication use, abuse of street drugs, and exposure to various environmental or biologic toxins [Leikin and Paloucek, 1995; Slamovits and Glaser, 1990]. Nystagmus is common in intoxications, especially with antiepileptic agents; bradykinetic extraocular movements follow exposure to antidopaminergic

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BOX 87-2 SELECTED AGENTS THAT CAUSE CHANGES IN SENSORIUM OR SEIZURES Medications Allopurinol Antiarrhythmics Antibiotics Anticholinergic agents Antidepressants Antiepileptic drugs Antifungal agents Antihistamines Antihypertensives Antineoplastics Antiparasitic agents Antipsychotics Antitubercular drugs Antiviral agents Anxiolytics Baclofen [Chen et al., 2003] Benzodiazepines β-Agonists β-Blockers [Gleiter and Deckert, 1996] Bismuth subgallate Bromides [Frances et al., 2003] Bromocriptine Camphor Carbinols Castor oil Chloral hydrate Cholinergic agents Cisapride Clomiphene Cocaine Colchicine [Goldbart et al, 2000] Cyclobenzaprine Dantrolene Dextromethorphan Disulfiram Diuretics Erythropoietin Glutethimide, zolpidem Granisetron, nabilone Guaifenesin Hallucinogens Hydrogen peroxide [Cannon et al., 2003] Immunomodulators Isotretinoin Ketamine Levodopa Levothyroxine Lithium Lovastatin Muromonab-CD3 [Thaisetthawatkul et al., 2001] Nabilone Narcotics Niacin (acute) Nitrous oxide Nonsteroidal anti-inflammatory drugs, salicylates [Easley and Altemeier, 2000; Hesslinger et al., 1996] Omeprazole (acute) Steroids

Sucralfate Sulfasalazine Sumatriptan Sympathomimetics, stimulants Vitamin A Industrial Toxins Acrylamide Alcohols (ethanol, isopropanol, methanol) Aluminum compounds Ammonium chloride (toilet bowl cleaners) Antifreeze components Boric acid (antiseptics, insecticides) Camphor Carbon monoxide Cyanide Ethylene oxide Formaldehyde Gasoline Heavy metals Hexachlorophene Metaldehyde (snail bait, fire starters) Naphthalene Organophosphate insecticides Rodenticides Solvents Zinc, manganese [Mergler et al., 1994] Biologic Toxins Baneberry (Actaea species) Box jellyfish (sea wasp) Box thorn (Lycium halmifolium) Buckeye (Aesculus species) Copperhead, cottonmouth, some rattlesnake venom Corn lily (Helleborus species) Daphne Death Camus (Zigadenus species) Foxglove (Digitalis purpurea) Ginkgo nuts [Miwa et al., 2001] Hyoscyamus niger Jimson weed (Datura stramonium) Lupine Marijuana (Cannabis sativa) Mayapple (Podophyllum peltatum) Mescaline, peyote Methcathinone Morning glory (Ipomoea purpurea, Rivea corymbosa) Mushrooms (especially Amanita muscaria, Pantherina, Psilocybe, Panaeolus, Copelandia, and Gymnopilus species) Nutmeg Oleander Peony, Paeonia species (high doses in medicinal preparations) Potato (leaves, stems, immature tubers) Shellfish (domoic acid poisoning) Shigella toxin [Lahat et al., 1990] Solanum species (Jerusalem cherry or ornamental pepper, black nightshade)

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BOX 87-2 SELECTED AGENTS THAT CAUSE CHANGES IN SENSORIUM OR SEIZURES, CONT’D Star fruit [Chan et al., 2002] Star of Bethlehem, Indian tobacco (Lobelia inflata)

Strychnine (“slang nut”) [Katz et al., 1996] Tobacco (nicotine, acute)

medications, and extraocular muscle paresis is an important indicator of botulism poisoning [Glaser and Bachynski, 1990]. Loss of the blink reflex and facial paresis may occur as part of a generalized encephalopathy, such as in profound narcotic intoxications, or occur in isolation, such as in botulism or vincristine-induced neuropathy. Acute hearing loss resulting from poisoning is uncommon but may be caused by aminoglycoside use, toxicity, or overdose of nicotine or lithium. Vestibular dysfunction is one of the most common presenting symptoms of drug-induced neurologic syndromes, including those caused by exposure to antiepileptic drugs, antibiotics, and metals [Mount et al., 1995; Wood et al., 1996]. Vestibular dysfunction should be differentiated from vagally mediated “dizziness,” although both may result from intoxications. Isolated toxin-induced disorders of the pharyngeal and neck musculature (e.g., loss of ability to swallow in clostridial toxidromes) are rare, but dysgeusia is not; the latter occurs commonly with use of lithium-containing preparations. Table 87-1 lists toxins that cause cranial nerve deficits. Motor weakness may be due to poisoning of the anterior horn cells, peripheral nerves, neuromuscular junction, or muscles. Proximal myopathies (e.g., caused by steroid use) or distal motor neuropathies (e.g., caused by metal ex-

posure) should be differentiated from infectious, inflammatory, metabolic, and degenerative processes. Profound weakness may occur with use of depolarizing agents and neuromuscular blockers. Rigidity may result from either central or peripheral disinhibition (Boxes 87-3 to 87-5) [Katz et al., 1996; Reeves et al., 1996]. Extrapyramidal disorders may be caused by exposure to environmental toxins but are also well-recognized side effects of many medications (Box 87-6). Drugs implicated most frequently in movement disorders are antipsychotics and related agents, calcium channel antagonists, CNS stimulants, antidepressants, antiepileptic drugs, antiparkinsonian drugs, and lithium [Jimenez-Jimenez et al., 1997; Kerrick et al., 1995]. With severe intoxications, the cardiovascular effects of many of these medications overshadow the acute neurologic symptoms. Antibiotics, antidepressants, and some antineoplastic drugs may cause myoclonus (Box 87-7) [Chow et al., 2003]. Ataxia may be due to cerebellar or peripheral nerve dysfunction (Box 87-8). Cerebellar dysfunction may also manifest as nystagmus, scanning speech, hypotonia with pendular reflexes, dyssynergy, dysmetria, or dysdiadochokinesis [DeJong, 1967; Findley, 1996]. Tremor is common in several intoxications (Box 87-9).

TABLE 87-1 Selected Agents Causing Cranial Nerve Deficits CRANIAL NERVE DEFICIT

MEDICATIONS

INDUSTRIAL TOXINS

BIOLOGIC TOXINS

General Olfactory Optic nerve and retina

Methotrexate, vincristine Levodopa Antibiotics, phenothiazines [Glaser, 1990], antineoplastics, cyclosporine, disulfiram (retrobulbar neuritis), isoniazid, minoxidil, quinines, valproic acid Botulinum A toxin, bretylium, antiepileptics, interferon Antihistamines, anticholinergics, nortriptyline barium, bromides, carbamazepine, cocaine, cyclobenzaprine, glutethimide, sertraline, sympathomimetics

Organic mercury, ethylene glycol — Cyanide, methanol, lead, thallium, organic mercury, hexachlorophene

Cobra venom — Lathyrus

—

Clostridium botulinum toxin

Ethylene glycol, benzene, cyanide

Black nightshade (Solanum nigrum), box thorn (Lycium halmifolium), lupine, morning glory, potato (leaves, stems, immature tubers), tetrodotoxin (puffer fish, others), water hemlock (Cicuta species), mescaline, peyote — Ciguatera toxin (red snapper, farmraised salmon)

Extraocular Muscles Mydriasis

Miosis Dysgeusia Auditory

Buspirone, cholinergics, narcotics — Dipyridamole, disulfiram, selegiline, Dimethyl sulfoxide ethambutol, lithium, nedocromil tocainide Antibiotics, especially aminoglycosides, Carbon monoxide, cyanide, ` antifungals, antineoplastics, lithium methanol, solvents, mercury (acute), nonsteroidal (organic) anti-inflammatory drugs and salicylates, quinine antiarrhythmics, angiotensin-converting enzyme inhibitors, danazol, dantrolene, dapsone, antidepressants, digoxin, dimenhydrinate, diuretics, vitamin A

Tobacco (acute), lathyrus

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BOX 87-3 SELECTED AGENTS ASSOCIATED WITH MYOPATHIES Amphetamine Amiodarone Barium β-Blockers Caffeine Chloroquine, hydroxychloroquine Cimetidine Clofibrate Cocaine Colchicine Corticosteroids: prednisone Cromolyn sodium Cyclosporine Diltiazem Doxepin D-Penicillamine Ethanol Etretinate Heroin Hydrogen peroxide Licorice Lovastatin Minoxidil Niacin Phencyclidine palmitate (PCP) Procainamide Propylthiouracil Pyrithioxine Quinolones, penicillin, nalidixic acid Salicylates Sulfasalazine Tiopronin Vincristine, paclitaxel Zidovudine

Common Toxidromes The neurologic examination may indicate poisonings and drug intoxications that fit clinically into one of several toxidromes resulting from a predominant neurotransmitter derangement or disruption of one arm of the autonomic nervous system [Babe and Serafin, 1996; Brown and Taylor, 1996; Haddad and Winchester, 1983; Hoffman and Lefkowitz, 1996; Leikin and Paloucek, 1995; Reisine and Pasternak, 1996; Sanders-Bush and Mayer, 1996]. The major toxidromes include the following: anticholinergic, cholinergic, sympathomimetic, serotonergic, antihistaminic, and narcotic/sedative-hypnotic syndromes. The anticholinergic syndrome is readily recognizable. Features may be divided into peripheral muscarinic signs, including tachycardia, dry skin and mucous membranes, dilated pupils, decreased gastrointestinal motility, urinary retention, and fever, and central anticholinergic signs, including confusion, disorientation, agitation, hallucinations, incoordination, ataxia, and frank psychosis (“mad, hot, dry, and blind”). The anticholinergic toxidrome is caused by atropine, belladonna alkaloids, plants (jimson weed), antihistamines, low-potency phenothiazines, and antidepressants, especially tricyclic antidepressants. The

BOX 87-4 SELECTED AGENTS CAUSING PERIPHERAL NEUROPATHY Medications Amiodarone Amitriptyline (acute polyradiculopathy) Antibiotics: nitrofurantoin, chloramphenicol, quinolones, aminoglycosides, polymyxin B Antineoplastic agents: vinca alkaloids, paclitaxel, procarbazine (mixed), cisplatin, cytosine arabinoside Antiparasitic agents: metronidazole, chloroquine, hydroxychloroquine [Gupta et al., 2003] Antitubercular agents [Lewin and McGreal, 1993] Colchicine Dapsone (distal motor neuropathy) [Abhayambika et al., 1990] Digitoxin Disulfiram Ethanol Ethionamide Hydralazine Interferons (sensory) Nitrous oxide Phenytoin, fosphenytoin Pyridoxine (sensory) [Parry and Bredesen, 1985] Streptokinase (Guillain-Barré syndrome) [Taylor et al., 1995] Thalidomide (sensory) Industrial Toxins Acrylamide (sensory) Carbon monoxide Chlorophenoxy herbicides (sensory) Dinitrophenols Ethylene oxide (mixed motor, sensory) [Crystal et al., 1988; Schaumburg and Berger, 1993] Heavy metals Organophosphate pesticides Solvents Biologic Toxins Cyanide (cassavism) Diphtheria Lathyrus Podophyllum (ingestion) Stonefish (Scorpaenidae) Additional references: Le Quintrec and Le Quintrec, 1991; Dyck and Thomas, 1993; Leikin and Paloucek, 1995; Patel et al., 2003; REPROTOX, 2005.

tricyclic antidepressants may also be associated with a depressed level of consciousness, seizures, and cardiac dysrhythmias. Cholinergic toxidromes, which include both muscarinic and nicotinic effects, are produced by organophosphate insecticides, carbamate insecticides, nicotine, physostigmine, and their congeners. Consciousness may be extremely depressed, and the patient may be comatose with respiratory depression; pinpoint pupils; widespread fasciculations; salivation, lacrimation, urination, and defecation (SLUD syndrome); bronchoconstriction; pulmonary edema; hypotension or hypertension; and bradycardia.

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BOX 87-5 SELECTED AGENTS ASSOCIATED WITH PARALYSIS AND MUSCULAR RIGIDITY Paralysis Medications and Industrial Toxins Aminoglycoside antibiotics β-Blockers Chloroquine (with color vision shift) Cholinesterase inhibitors: neostigmine, pyridostigmine D-Penicillamine Pesticides: organophosphates, carbamates Pyrithioxine Trimethadione Biologic Toxins Cobra venom Poison hemlock (Conium maculatum) Scorpion fish (Scorpaenidae) Snake venom, ticks, botulinum toxin Star of Bethlehem (Hippobroma longiflora) Sweet pea (Lathyrus odoratus) Tetrodotoxin (puffer fish, blue-ringed octopus, others) Muscular Rigidity Black widow spider venom (Latrodectus mactans) [Reeves et al., 1996] Strychnine (Strychnos nux vomica, “slang nut”) [Katz et al., 1996] Tetanus toxin

BOX 87-7 SELECTED AGENTS ASSOCIATED WITH MYOCLONUS Medications Antibiotics (β-lactams) Antidepressants [Bak et al., 1995] Antineoplastics: busulfan, chlorambucil Carbamazepine, vigabatrin [Neufeld and Vishnevska, 1995] Clozapine [Bak et al., 1995] Levodopa [Bak et al., 1995] Lidocaine Lithium [Bak et al., 1995] Lorazepam (preterm infants) [Reiter and Stiles, 1993] Methaqualone Morphine [Jacobsen et al., 1995] Nitroprusside Piperazine [Conners, 1995] Industrial Toxins Camphor Chlorophenoxy herbicides Gasoline Biological Toxins Buckeye (Aesculus species) Lupine Shellfish (domoic acid poisoning)

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BOX 87-6 SELECTED AGENTS ASSOCIATED WITH PARKINSONISM AND OTHER ACUTE EXTRAPYRAMIDAL REACTIONS Medications Amiodarone Anticholinergic agents: benztropine Antidepressants (including selective serotonin reuptake inhibitors) [Eisenhauer and Jermain, 1993] Antiepileptic drugs Antifungal agents Antihistamines Antipsychotics and related drugs (including “novel” agents) [Buzan, 1996; Lindstrom et al., 1995] Bethanechol Bupropion (acute) Buspirone Captopril (acute) Clonazepam Diazoxide Digoxin (chorea) Estrogen (chorea) Heroin Ketamine Levodopa Lithium (chorea) 1-Methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) Metronidazole (oculogyric crisis) Narcotics Ofloxacin (Tourette-like syndrome) [Thomas and Reagan, 1996] Reserpine Stimulants Sulfasalazine (chorea) Vinblastine Industrial Toxins Carbon monoxide Metals: manganese, thallium, aluminum [Normandin et al., 2002] Methanol Trichloroethylene Biologic Toxins Arthrinium mycotoxin [He et al., 1995] Seizures may occur. Young children, however, may not display typical peripheral cholinergic signs and symptoms [Lifshitz et al., 1997; Patel et al., 2003]. Sympathomimetic, or stimulant, toxidromes occur with ingestion (sometimes at subtherapeutic doses) of amphetamines, methylphenidate, xanthines (caffeine), ephedrine and related agents, nicotine, and cocaine. Signs range from restlessness, anorexia, and insomnia to euphoria and, in severe cases, seizures [Conway et al., 1990; Rivkin and Gilmore, 1989]. Mydriasis is present, and increased motor activity and tremor may also occur. Although serotonergic side effects have been noted with several drugs (isoniazid, tranylcypromine, and L-tryptophan in combination with monoamine oxidase inhibitors), the proliferation of newer, relatively selective, serotonin re-

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BOX 87-8 SELECTED TOXIC CAUSES OF ATAXIA Medications Acetohexamide Amiodarone Anticholinergic agents Antidepressants, including selective serotonin reuptake inhibitors Antiepileptic drugs Antihistamines Antimicrobials, antifungals Antineoplastics Antiparasitics [Conners, 1995; Lewin and McGreal, 1993] Baclofen Buspirone Dextromethorphan Disulfiram Ethanol Fenfluramine Lithium Lysergic acid diethylamide (LSD), phencyclidine palmitate (PCP) Mexiletine Sedatives, narcotics Industrial Toxins Aluminum compounds Butyl alcohol Carbon monoxide Carbon tetrachloride Ethylene glycol Formaldehyde Gasoline Manganese Metaldehyde (snail bait, fire starters) Paradichlorobenzene (moth repellent, diaper pail deodorant) Rodenticides: aluminum phosphide, sodium monofluoroacetate Solvents Biologic Toxins Belladonna, hyoscyamine Buckeye (Aesculus species) Mayapple (Podophyllum peltatum) Mescaline, peyote Podophyllum (ingested) Poison hemlock (Conium maculatum) uptake inhibitors used to treat depression, obsessivecompulsive disorder, and headache has fostered new interest in this toxidrome. Onset is often sudden. Central manifestations of this syndrome include confusion, myoclonus, tremor, ataxia, hyperreflexia, and fever; peripheral findings consist of sweating, facial flushing, trismus, and diarrhea [Sternbach, 1991]. Antihistaminic agents can be divided into histamine1 and histamine2 blockers. Both may cause significant CNS side effects at therapeutic doses, although the degree to which they do so is agent specific. Older histamine1 blockers, such as

BOX 87-9 SELECTED AGENTS ASSOCIATED WITH TREMOR Medications Aluminum compounds Aminophylline, theophylline Amiodarone Antiepileptic drugs Antihistamines Chlorambucil Ciprofloxacin Cyclosporine, tacrolimus (FK-506) Dextromethorphan Digitoxin, lidocaine Fenfluramine Levothyroxine Lithium Nortriptyline Piperazine Sympathomimetics, stimulants Industrial Toxins Carbon tetrachloride Fluoride Metaldehyde (snail bait, fire starters) Organic mercury Pyrethrins [Miyamoto et al., 1995] Rodenticides: aluminum phosphide Biologic Toxins Hyoscyamine Mescaline, peyote Star of Bethlehem, Indian tobacco (Lobelia inflata) Tobacco (nicotine) chlorpheniramine, act at both central and peripheral histamine1 receptors, monoaminergic receptors, and muscarinic receptors. They cause sedation and delirium, the latter especially in children, and subtle cognitive deficits [Gengo, 1996]. They may also have significant toxicity, including movement disorders and autonomic dysfunction related to their antagonism of dopaminergic, β-adrenergic, serotonergic, and muscarinic receptors. With overdose, ataxia and seizures may supervene. Agents such as terfenadine and clemastine are less likely to cause CNS toxicity as a result of more histamine1 selectivity and less CNS penetration [Babe and Serafin, 1996]. However, toxicity may be delayed by several days because of slower CNS penetration. Histamine2 blockers, such as cimetidine, ranitidine, and newer agents, tend not to have significant antihistaminic side effects (except cimetidine) in children at therapeutic doses. At high doses, mental status changes predominate, especially with cimetidine. The opioid-induced toxidrome, which is readily diagnosable and treatable by administration of naloxone, includes CNS depression with coma, pinpoint pupils, muscle flaccidity, respiratory depression, and bradycardia. All opioid-derived agents may cause this syndrome. Sedative-barbiturate toxidromes are manifested primarily by lethargy or more profound depression and respiratory depression, miotic pupils, and generalized hypotonia with areflexia and ataxia. Signs and symptoms may be pro-

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gressive, especially in intoxication with longer-acting agents, such as phenobarbital. In the absence of administration of a specific antidote, such as naloxone for opioids or flumazenil for benzodiazepines, differentiation between causative agents may prove difficult on clinical grounds.

including school attendance, improves [Stulemeijer et al., 2005].

Chronic Fatigue Syndrome and Related Disorders

Toxic effects of several specific agents deserve additional discussion. Although there is much overlap in toxicity among various poisons and therapeutically used medications (see preceding discussion of toxidromes), individual classes of toxins, and in some cases individual agents, may have unique effects and specific remedies.

Fatigue is a common complaint in both adult and pediatric medicine. It may take the form of simple “lack of energy” or present as a more pervasive syndrome attended by an “infectious” prodrome and a host of somatic symptoms, including weakness, malaise, and sleep, appetite, and emotional or neuropsychiatric disturbances. This cluster of symptoms has been codified as chronic fatigue syndrome. The disorder is marked by extreme, disabling fatigability of longer than 6 months’ duration, lasting an average of 2 to 3 years, but usually with eventual full recovery. In a cohort of Chicago primary care adolescent patients the rate of chronic fatigue syndrome was 4.4% [Mears et al., 2004]. Diagnostic criteria have been developed, although the disorder’s heterogeneity is recognized [Farrar et al., 1995]. Putative etiologies for chronic fatigue syndrome are numerous. Postinfectious and postviral causes have been explored most thoroughly, although there is little direct evidence of an association between infection and chronic fatigue syndrome. In one study an apparent infection rate of 72% in chronic fatigue syndrome patients yielded a proven infection rate of only 7% [Salit, 1997]. Other contributing factors included trauma, surgery, antecedent stressful events, and allergies. Psychiatric factors are also suggested [Huibers et al., 2004]. Allergies have been implicated as a result of findings of possible but inconsistent immunologic alterations in chronic fatigue syndrome patients, a 65% rate of positive allergy history in chronic fatigue syndrome patients, and anecdotal reports of chronic fatigue syndrome onset after immunizations [Farrar et al., 1995; Salit, 1997]. Rigorous evaluation of the cohort of Salit revealed no correlation between chronic fatigue syndrome and exposure to animals, raw milk, meat, cigarette smoking, or foreign travel [Salit, 1997]. Neurobehavioral abnormalities in children are also ascribed frequently to allergies or “environmental toxins.” Some models for testing the causal relationship in adults exist but are applicable only in individual assessments, and the field is in its infancy [Weiss, 1994]. There are no largescale studies of toxic causes for childhood behavioral disorders. A systematic approach to a child in whom there is concern for such a causal exposure begins with a careful history and physical examination to discern any evidence of exposure to known toxins. Temporal and spatial aspects of the history may be especially important. Other possible causes, including psychosocial factors, should be investigated as well. Results of this evaluation should direct any subsequent testing. Elimination of the putative offending agent (or removal of the child from the environment) should be an option, but disruption of the child’s life is a significant consideration in cases in which there is little evidence of environmental toxic exposure. Cognitive behavioral therapy has been associated with improvement in chronic fatigue syndrome symptoms in adolescents and adults. Although relapse of some symptoms is common, functional outcome,

SPECIFIC AGENTS

Poisons and Environmental Toxins Biologic Toxins Biologic toxins include snake, tick, insect, and fish toxins, botanical toxins, and bacterial toxins (e.g., diphtheria, tetanus, botulism). Botanical poisonings are especially common among children; whereas most are mild and result from ingestion of easily accessible houseplants, other botanical poisonings may have more serious consequences (see Table 87-1 and Boxes 87-2 and 87-4 to 87-9) [Krenzelok et al., 1996]. See also reviews by Hardin and Arena [1974], Kunkel [1983], and Langford and Boor [1996]. Snake venoms, which in the United States are primarily from rattlesnakes and copperheads, are strong neurotoxins. In addition to the local effects of envenomation, there are systemic symptoms of fever, nausea, vomiting, diarrhea, and tachycardia, as well as altered blood coagulation. Neurotoxins affect the neuromuscular junction, causing paralysis of the diaphragm and the intercostal and limb muscles and, more rarely, altered states of consciousness and convulsions. There is controversy concerning the use of local incisions, fasciotomy, application of ice packs, and steroids. Exercise hastens absorption of venom. Intravenous administration of specific antivenoms is recommended [Grant et al., 1997; Hawgood, 1996; Podgorny, 1983]. The occurrence of the various envenomations depends partially on regional fauna. In New South Wales, Australia, the percentage of poisoning from envenomation range from 3.1% (females aged 15 to 19 years) to 84.1% (males aged 5 to 9 years) [Lam, 2003]. Tick paralysis is an infrequent but treatable cause of acute paralysis or ataxia caused by neurotoxins from Dermacentor andersoni (wood tick), Dermacentor variabilis (dog tick), Amblyomma americanum (Lone Star tick), Amblyomma maculatum, Ixodes scapularis (black-legged tick), and Ixodes pacificus (western black-legged tick) [Centers for Disease Control and Prevention, 1996a]. Although most prevalent in states west of the Rocky Mountains, tick paralysis also occurs in the southeastern and northeastern United States. Small children are most likely to be paralyzed. The scalp and neck at the hairline are the most common sites for attachment of the gravid tick, which produces a neurotoxin that prevents liberation of acetylcholine at the neuromuscular junction [Swift and Ignacio, 1975]. Within 5 to 6 days after tick attachment, the child develops restlessness and irritability, followed within 24 hours by progressive ataxia and difficulty walking or by symmetric ascending flaccid paralysis with loss of deep tendon reflexes. Removal of the tick in the early stage of the disease

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leads to reversal of the clinical manifestations within 24 hours, whereas failure to remove the tick may result in progressive bulbar paralysis and death. Insect repellents, especially permethrin-containing products applied to children’s clothing, may be used as a preventive measure. Botulinum toxin blocks presynaptic release of acetylcholine and causes neuromuscular junction blockade. Infection with Clostridium botulinum spores results in three different clinical syndromes. Food-borne botulism occurs after ingestion of food, which is frequently home cooked and canned, that is contaminated with C. botulinum. Nonacidic canned vegetable products and soups are frequently implicated, and recent reports also implicate dairy products as a source of botulism poisoning [Aureli et al., 1996; Townes et al., 1996]. There are prominent gastrointestinal symptoms of diarrhea and vomiting, followed by rapidly developing progressive paralytic disease associated with visual blurring and diplopia, dysphagia, dysarthria, and subsequent weakness of extremities and intercostal muscles. Antitoxin is effective only if given early [Cherington, 1974]. Infantile botulism, which occurs almost exclusively in the first months of life, can be a severe paralytic disease affecting the limbs, trunk, bulbar musculature, and cranial nerves. It is preceded almost universally by a history of severe constipation without other gastrointestinal symptoms. This illness has been reported in clusters in both California and Pennsylvania, but it has also been observed in isolated instances throughout the United States and in some instances has been related to the ingestion of honeycontaining botulinum spores [Glatman-Freedman, 1996; Johnson et al., 1979; Midura, 1996]. Wound botulism, the rarest form of botulism, is both a local infection of contaminated wounds and a systemic intoxication. It can produce a paralytic illness that may be indistinguishable clinically from the disorder produced by food-borne botulism. The most common cause of wound botulism in the United States is secondary to intravenous drug abuse [Centers for Disease Control and Prevention, 1996b]. Rarely, wound botulism may result from small intranasal or septal abscesses in nasal cocaine abusers. Botulism mimicking Guillain-Barré syndrome has been reported [Griffin et al., 1997].

Insecticides Organophosphate and carbamate insecticides account for most childhood insecticide exposures. Fortunately, most childhood exposures do not result in poisoning. Fewer than 10% of the 8500 insecticide exposures reported to 16 regional poison control centers in 1983 were symptomatic or associated with more than minor symptoms [Veltri and Litovitz, 1984]. A later nine-state study from 1999 to 2002 confirmed that even with active community spraying programs, symptomatic exposure was rare. In that study, 133 cases were reported among a population of 118 million people. Of these cases, 29 resulted from a single incident in which a mosquito-control truck inadvertently sprayed a malathion-containing product during a softball game. Only one person, who survived, had severe toxicity [Patel et al., 2003]. However, these agents are acetylcholinesterase inhibitors, which may result in serious cholinergic signs. Toxins can be absorbed through the skin and gastrointestinal tract,

but most childhood poisonings are the result of ingestion. Signs of acute intoxication occur usually within 12 to 24 hours but can develop in minutes after an acute exposure, indicating severe intoxication and a medical emergency. Salivation, lacrimation, bronchoconstriction, wheezing, and increased pulmonary secretions are all muscarinic manifestations. Peripheral nicotinic signs include muscle weakness, decreased respiratory effort, and muscle fasciculations. CNS signs are anxiety, restlessness, confusion, headache, slurred speech, ataxia, and generalized seizures. Opsoclonus has been reported with diazinon poisoning in an adult [Liang et al., 2003]. With low-dose organophosphate exposure, muscarinic signs predominate, but in more severe acute intoxication, the nicotinic and CNS signs appear. Nicotinic effects appear to mediate delayed peripheral toxicity. With longer-acting agents, such as chlorpyrifos (Dursban), recovery is protracted and possibly incomplete [Sherman, 1995]. Rarely a myopathy may complicate the picture [Marrs, 1993; Rusyniak and Nanagas, 2004]. A scoring system called Acute Physiology and Chronic Health Evaluation II (APACHE II) has been applied to adults with organophosphate poisoning and has indicated high predictive value for intensive care unit admission and subsequent mortality [Lee and Tai, 2001]. Cholinesterase levels may be used to predict subsequent weaning of mechanical ventilation in surviving patients. Treatment includes decontamination, general supportive therapy, and administration of specific antidote, including atropine and pralidoxime or obidoxime, the oximes being cholinesterase reactivators [Mortensen, 1986]. Prompt decontamination protects both the patient and attendant healthcare workers [Stacey et al., 2004]. The dose of atropine for children younger than 12 years is 0.02 to 0.05 mg/kg, followed by maintenance doses of 0.02 to 0.05 mg/kg repeated every 10 to 30 minutes (maximum dose, 1 to 2 mg) until cholinergic signs are reversed. For children older than 12 years, the adult dose of atropine (1 to 2 mg) may be used. Because pralidoxime does not cross the blood-brain barrier, atropine must be continued in addition to pralidoxime to reverse central and muscarinic receptor overstimulation. The response to antidote virtually confirms the diagnosis suggested by the history of exposure and the characteristic acute cholinergic symptoms, although intermediate (1 to 4 days after exposure) and delayed effects are not influenced by atropine or oxime therapy [Marrs, 1993]. These delayed effects are not seen generally in insecticides available in the United States and Europe, and it is thought that the delayed central effects are mediated not by cholinergic mechanisms but rather by direct phosphorylation of neuronal structures [Marrs, 1993]. A newer therapeutic agent, liposome encapsulating organophosphorus hydrolase, has demonstrated promise in the laboratory, raising the median lethal dose of paraoxon beyond that provided by pralidoxime and atropine combined [Petrikovics et al., 2004]. Endosulfan, a chlorinated hydrocarbon, may pose a chronic and endemic threat to children with repeated exposure. Acute intoxication causes respiratory distress, gagging, vomiting, diarrhea, agitation, convulsions, ataxia, and coma in severe cases. Fatal status epilepticus occurs, and endosulfan-related fatalities occurred in Sri Lanka in 1998 before the agent was banned that year [Roberts et al., 2003]. Dewan and associates reported recurrent convulsions and

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several deaths in a rural area of India due to wheat flour being stored in containers previously used for endosulfan storage [Dewan et al., 2004]. Amitraz, a formamidine pesticide, has side effects similar to clonidine overdose (CNS depression, miosis, bradycardia, hypotension, emesis, and hyperglycemia). With adequate support, death is rare [Aydin et al., 2002].

Nerve Agents Nerve agents are chemically related to organophosphate insecticides but are far more potent [Newmark, 2004]. A single drop of VX on the skin may kill a person. Childhood exposure would likely be as result of deliberate attack with nerve agents. They are divided into two classes: G agents and V agents. Tabun (GA), Sarin (GB), and Soman (GD), are clear, tasteless, and colorless, and mostly odorless. Tabun and Soman may have a slightly fruity odor, but this property is not clinically useful. VX is amber and oily but also odorless and tasteless. All may exert their effects within seconds to minutes depending on route of exposure. Onset after cutaneous exposure may be delayed up to 18 hours. Management, as with insecticide poisoning, rests on decontamination; airway, breathing, and cardiovascular stabilization; and specific antidotes as described previously [Rotenberg and Newmark, 2003; Smythies and Golomb, 2004]. The Centers for Disease Control and Prevention maintain a web site outlining exposure and management information for these agents (http://www.atsdr.cdc.gov/ MHMI/mmg166.html) [Patel et al., 2003].

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attempted within 30 to 60 minutes after ingestion; subsequently, activated charcoal or cholestyramine speeds gastrointestinal excretion of lindane. Prevention of lindane poisoning is easier than its treatment. Permethrin 5% preparations may be safer in infants and young toddlers. Repeated exposures within 7 days and increased topical absorption (e.g., with open wounds or after a hot bath) enhance toxicity. Finally, pediculicidal preparations available in the United States contain 1% lindane; lindane 0.3% preparations have been effective in other nations [Surber and Rufli, 1995].

INSECT REPELLENTS The most effective general insect repellent currently in use is diethyltoluamide (permethrin is more effective against ticks), a compound available in many topical preparations. Although increasing the diethyltoluamide concentration up to 75% increases its efficacy, preparations containing more than 20% diethyltoluamide are likely to cause neurotoxicity, and most products for children contain 8% to 10% diethyltoluamide [Brown and Herbert, 1997]. Children using compounds with as little as 20% diethyltoluamide may suffer seizures (8 to 48 hours after exposure), ataxia, and tremor [Oransky et al., 1989; Sudakin, 2003]. There is some evidence, in fact, that there is no absolutely safe level of diethyltoluamide exposure for children [Briassoulis et al., 2001].

Metals

LINDANE

LEAD

Lindane (1,2,3,4,5,6-hexachlorocyclohexane) is a topical pediculicide used commonly throughout the world. Its use has been associated with significant neurotoxicity, especially in infants. Lindane passes easily into the CNS; brain levels may greatly exceed blood levels [Fischer, 1994]. Acute lindane neurotoxicity manifests usually as generalized seizures. Mental status changes and extrapyramidal movements may occur as well. Onset of symptoms after topical use occurs within a few hours, with generally complete resolution within 48 hours. Although topical lindane poisoning in young adults is reported, it most commonly results from inappropriate or excessive use of the medication in children [Boffa et al., 1995; Fischer, 1994; Forrester et al., 2004]. Occupational exposure may result in chronic lindane poisoning manifesting as emotional changes, muscle jerking, and alteration of the electroencephalogram [Aks et al., 1995]. Accidental ingestion of lindane is usually reported in toddlers. This situation appears to result from parental misunderstanding of application instructions. High levels may be attained quickly, and vomiting and seizures result, although vomiting and ocular pain are common [Forrester et al., 2004]. Myonecrosis may occur with blood lindane levels exceeding 0.6 g/mL, whereas blood levels in excess of 1.2 g/mL may be fatal [Aks et al., 1995]. Treatment of acute topical exposure is supportive, with control of seizures necessary. Barbiturates or benzodiazepines are the antiepileptic drugs of choice; phenytoin should be avoided because it may exacerbate lindaneinduced seizures [Aks et al., 1995]. Gastric lavage may be

Acute lead poisoning is rare. The syndrome of acute lead encephalopathy in children with pica who ate lead paint chips from peeling paint and plaster in older dwellings consisted of listlessness, drowsiness, and irritability, followed by seizures and signs and symptoms of acutely increased intracranial pressure. Severe cerebral edema resulting from acute lead encephalopathy often resulted in significant neurologic sequelae. Use of lead-based paints for indoor use was banned in the United States in 1978, with a consequent decrease in lead toxicity since. Chronic lead exposure as a result of ingestion of lead paint, inhalation of automobile exhaust fumes, or inhalation of industrial pollutants may result in high levels of blood lead and is the more common form of intoxication today. Lead poisoning is defined as a blood lead level of greater than 10 μg/dL, although this threshold is undergoing critical reappraisal as perhaps too liberal [Lidsky and Schneider, 2003; Wilken et al., 2004]. Most children with lead poisoning are asymptomatic. A lead concentration of 25 μg/dL or higher in blood is reported to be associated with learning problems and neurobehavioral effects [Bellinger, 1995; Bellinger et al., 1991; Landrigan et al., 1975; LaPorte and Talbott, 1978; Winneke et al., 1990, 1996]. Measurement of full-scale intelligence may be relatively insensitive in detecting the deleterious effects of chronic lead exposure in children; subtests measuring visual motor and reaction performance skills appear to be more sensitive. Some authorities recommend treatment with ethylenediaminetetraacidic acid for children who have even mildly elevated

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lead levels (i.e., greater than 25 μg/dL) [American Academy of Pediatrics, 1995; Piomelli et al., 1984; Trachtenbarg, 1996]. A newer oral chelation agent, meso 2,3-dimercaptosuccinic acid, has been approved recently and used for children with blood lead levels greater than 45 μg/dL [Berlin, 1997]. Acute lead encephalopathy at any blood lead level constitutes a life-threatening emergency and should be managed accordingly [American Academy of Pediatrics Committee on Drugs, 1995].

MERCURY Mercury poisoning can result from both inorganic and organic mercury exposure. The former can occur acutely after accidental ingestion of an antiseptic solution containing mercury. Chronic poisoning may follow prolonged use of mercury-containing teething powders, repeated applications of ammoniated mercury ointment to the skin, or application of mercury-containing antiseptics to the oral mucosa. Acute inorganic mercury poisoning results primarily in severe gastrointestinal problems without neurologic symptoms, whereas chronic or subacute mercury toxicity is manifested by the development of coarse tremor, irritability, and peripheral neuropathy. Symptoms of acrdynia, now mainly of historical interest, include irritability and signs of profound peripheral neuropathy. Organic mercury poisoning has occurred as a result of ingestion of fish (contaminated by mercury-polluted water), grain (contaminated by mercurial fungicides), or pork (contaminated by feeding pigs mercury fungicide–treated grain) [Cranmer et al., 1996; Zepp et al., 1974]. Minamata disease occurred in people who ate fish from mercury-contaminated waters and exemplified the danger of organic mercury bioamplification as it ascends the food chain [Bigham and Vandal, 1996]. The symptoms and signs of organic mercury poisoning include ataxia, peripheral neuropathy, choreoathetosis, visual loss, confusion, and coma [Patel et al., 2003]. Subclinical mercury neurotoxicity has been demonstrated as well in occupational exposures, using visual-evoked potentials and electromyography [Urban et al., 1996]. Dimercaprol and 2,3-dimercaptosuccinic acid effectively chelate and remove mercury from the tissues but do not necessarily reverse the clinical manifestations. Heavy-metal poisoning may also cause a peripheral neuropathy, although this is rare in children. Ingestion of elemental mercury, such as from a broken thermometer, does not usually cause mercury poisoning; however, Koyun and colleagues reported serious mercury intoxication in three unrelated teenagers after exposure to a broken manometer [Koyun et al., 2004]. Despite chelation therapy, one patient died. Although other heavymetal poisoning is usually associated with industrial exposure affecting workers, poisoning may also occur in children. Smelting operations may release large amounts of lead, zinc, cadmium, and arsenic into the surrounding environment [American Academy of Pediatrics Committee on Drugs, 1997]. Perhaps no topic concerning mercury has resulted in as much controversy as an alleged link between thimerosal and autism. In such debates, causal links are difficult to prove, and often even more difficult to disprove once suggested. Most peerreviewed literature does not support an association beyond coincident timing of vaccines and manifestations of autism.

Furthermore, historical evidence (e.g., Minamata disease) reveals a different developmental neuropathology regarding mercury poisoning [Nelson and Bauman, 2003].

THALLIUM Thallium was once used as treatment for night sweats in tuberculosis and topically for ringworm in children (with mortality rates reported as high as 5%) [Dyck and Thomas, 1993]. The primary modern sources of thallium are rodenticides and insecticides. Ingestion may be accidental or intentional. Thallium poisoning presents with the clinical triad of abdominal pain, alopecia, and mixed peripheral neuropathy. Although there may be gastritis and hepatic injury, abdominal pain is usually secondary to peripheral neuropathy [Burnett, 1990]. Alopecia occurs suddenly after a 2- to 3-week delay and is associated with an acneiform rash over the nose, cheeks, and nasolabial folds [Dyck and Thomas, 1993]. The neuropathy is both demyelinating and axonal. Other neurologic effects of thallium include cranial neuropathies involving optic and oculomotor nerves, CNS depression, dementia, delirium, and seizures. CNS levels of thallium may continue to rise for at least a few days after the initial exposure [Sharma et al., 2004]. Cardiovascular involvement includes hypertension and myocardial damage, with shock and death occurring in massive doses [Sharma et al., 2004]. In adults, acute exposure to as little as 1 g of thallium may be fatal; 5 mg/kg is toxic in children [Burnett, 1990; Patel et al., 2003]. Additional clues to diagnosis of thallium poisoning include the presence of painful distal glossitis, Mees’ lines, and black thallium deposits at the base of abnormally tapered hairs [Feldman and Levisohn, 1993]. Cerebrospinal fluid protein may be elevated as well. Thallium crosses the placenta and may affect the fetus.

ARSENIC Chronic arsenic poisoning is well recognized. Although intentional poisoning captures the imagination, accidental exposure through the workplace or environmental contamination poses a larger public health problem. Because inorganic arsenic poses a greater threat of acute poisoning than does the less toxic organic arsenic, most severe accidental poisonings occur by contamination of water supply [Abernathy et al., 2003]. Acute poisoning manifests with nausea and vomiting, abdominal pain, and diarrhea, together with cutaneous and neurologic findings [Ratnaike, 2003]. Severe inorganic arsenic poisoning also results in encephalopathy in older children [Patel et al., 2003]. Reports describe endemic chronic arsenic intoxication within entire families and towns resulting from contamination of the local water supply or from chronic dust exposure [Gerr et al., 2000]. In these epidemics, children are affected with the typical keratoderma and distal peripheral neuropathy and may also be mentally retarded [Das et al., 1995; Foy et al., 1992–1993; Mazumder et al., 1992]. Other acute cutaneous findings may include facial edema, transient flushing, conjunctival hemorrhage, and maculopapular rash in intertriginous areas. Mees’ lines may be found several months after exposure [Uede and Furukawa, 2003]. Unlike thallium, arsenic typically does not cause alopecia [Rusyniak et al., 2002].

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Heavy-metal exposure, including cadmium, lead, arsenic, mercury, and thallium, may occur from intake of medicinals. Ernst and Coon provide a review of such metal toxicity in traditional Chinese medicines [Ernst and Coon, 2001].

Solvents Isopropyl alcohol poisoning most commonly results from the ingestion of common household “rubbing alcohol.” Isopropyl alcohol vaporizes readily and is rapidly absorbed through the lungs. Alcohol sponging for fever reduction, especially in a poorly ventilated room, can result in intoxication and coma. Ingestion of as little as 20 mL can produce symptoms [McFadden and Haddow, 1969]. Peak serum levels are reached in about 1 hour, with adverse initial symptoms, primarily gastrointestinal complaints, occurring within 30 minutes after ingestion. CNS effects include headache, confusion, dizziness, ataxia, stupor, and deep coma, which may be caused partially by the formation of acetone during metabolism [Mydler et al., 1993]. Hypotension and hypothermia may occur. The diagnosis is suggested by history, characteristic odor on the patient’s breath, and the presence of large amounts of ketones in the urine without significant metabolic acidosis. Urine toxicology may be revealing [Mydler et al., 1993]. Treatment is primarily supportive. Intermittent or continuous gastric lavage has been suggested, but use of syrup of ipecac is contraindicated; charcoal may be beneficial [Leikin and Paloucek, 1995]. Intoxication has also been reported with benzyl alcohol, which was used as an antibacterial agent and a preservative in saline solution. This form of intoxication, called the gasping syndrome, was reported after the administration of saline solutions as intravenous flushes in small, preterm infants [American Academy of Pediatrics Committee on Drugs, 1997; Gershanik et al., 1982]. The infusion of small amounts of flush solutions containing 0.9% benzyl alcohol may cause severe metabolic acidosis, encephalopathy, respiratory depression with gasping, and death. Intoxication from other sources of benzyl alcohol (i.e., as a preservative in medications other than saline) is unlikely. Children may suffer from clinically significant environmental exposure to solvents. This exposure may occur especially in areas with little child labor protection, resulting in occupational exposure [Saddik et al., 2003].

Other Nonpharmacologic Compounds A patient presented after ingesting matchstick heads, of which potassium chlorate is the major component, in coma; his MRI indicated bilateral symmetric deep gray matter and temporal lobe hyperintensity on T2-weighted images. He recovered after hyperbaric oxygen therapy and supportive care [Mutlu et al., 2003].

Drugs of Abuse Cocaine Cocaine abuse has reached epidemic proportions, especially among young adults. Lifetime incidence of cocaine use is 15% among high school seniors and more than 20% among

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college students. There is a suggestion of a decrease in cocaine use, although the same may not be true of crack cocaine. Almost 1 in 20 high school seniors have tried crack cocaine [O’Malley et al., 1991]. Cocaine, a stimulant alkaloid, is derived from the leaves of the shrub Erythroxyline cocoa. Cocaine inhibits reuptake of norepinephrine, dopamine, and serotonin. Acute toxicity, manifested by tremors, diaphoresis, tachycardia, cardiac dysrhythmias, vasoconstriction, and hypertension, is probably the result of cocaine’s effect on norepinephrine reuptake. Behavioral effects are most likely caused by its actions on the dopaminergic system. Cocaine use results in an enhanced sense of well-being, increased alertness and excitement, and apparent enhancement of the reward response. These effects are followed by anxiety, depression, exhaustion, and sometimes paranoid psychosis. Addiction follows continued use. Stroke, intracranial hemorrhage, and seizures have been reported [Levine et al., 1990; Mody et al., 1988; Sloan et al., 1991; Walsh and Garg, 1997]. Infants and children passively exposed to cocaine may have similar complications; however, some have disputed these effects [Wurtzel et al., 1988]. Increased cerebral blood flow velocity has been found in infants exposed to cocaine [Van de Bor et al., 1990].

Narcotics Data regarding numbers of established narcotic users in childhood are scanty; a great percentage of narcotic users never come to the attention of poison control centers. High school students are among the population at risk, as are children younger than 5 years of age who reside with adults who are narcotic abusers. Narcotics such as morphine, heroin, hydromorphone (Dilaudid), levorphanol (Dromoran), meperidine (Demerol), and methadone share the toxic properties of the opiate group, but the onset and duration of toxic signs vary after ingestion. Opiate users may also be simultaneously exposed to multiple other toxic agents, which are either adulterants of the opiates or are taken concurrently. The signs and symptoms of acute opiate poisoning most commonly follow rapid intravenous administration and include apnea, circulatory collapse, convulsions, and cardiopulmonary arrest. The less severely poisoned patient experiences varying degrees of CNS depression, ranging from drowsiness to profound coma, miotic pupils, and respiratory depression. Narcotic poisoning in younger children more commonly results from ingestion of various analgesics, such as meperidine, codeine, oxycodone (Percodan), and pentazocine (Talwin). Ingestion of a large dose, whether accidental or iatrogenic, of the antidiarrheal medication diphenoxylate (Lomotil), which also contains atropine, may result in signs of opiate toxicity with CNS and respiratory depression, as well as signs of atropine overdose, such as facial flushing, tachycardia, dry mouth, hyperpyrexia, and agitation [Brunton, 1996; POISINDEX, 2005]. Treatment of opiate intoxication includes administration of naloxone, a specific and highly effective opiate antagonist, and maintenance of respiration and circulation. The initial dose of naloxone is 0.01 mg/kg; if there is no response, the dose can be increased up to 10-fold, to 0.1 mg/kg. Naloxone can be given intravenously, intramuscularly, or

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even through an endotracheal tube, with effects lasting 30 to 45 minutes. Constant monitoring of the patient is required, with repeated doses of naloxone administered as needed in addition to supportive care. Nanan and associates reported the case of a 14-year-old female with intentional morphine sulfate overdose and leukoencephalopathy involving the corpus callosum, centrum semiovale, and cerebellar white matter [Nanan et al., 2000]. The MRI findings were not explained adequately by hypoxicischemic injury, and a drug-induced neurotoxicity was suggested. Other cases of severe neurotoxicity resulting from polypharmacy are reported [Nebelsieck, 2004]. Injected heroin also has been reported to produce a spongiform leukoencephalopathy [Robertson et al., 2001]

Cannabis Cannabis usually is taken recreationally by inhalation (smoking marijuana cigarettes) or ingestion. The active compound is tetrahydrocannabinol. Tetrahydrocannabinol intoxication produces psychomotor slowing acutely, short-term memory loss, analgesia, and appetite stimulation. Coma has been reported in children ingesting cannabis-laced cookies. Cannabis ingestion should be considered in cases of coma, especially when associated with conjunctival hyperemia, pupillary dilation, and tachycardia and when there is no other obvious cause [Boros et al., 1996]. Tetrahydrocannabinol acts through the CB1 receptor [Iverson, 2003]. Interestingly, anandamide, an endogenous ligand for the CB1 receptor, has been implicated in the “runner’s high” [Sparling et al., 2003]. Long-term biologic sequelae of cannabis use are ill defined. Dependency may occur, as may apparently reversible mild cognitive impairment. Psychosocial consequences may be more severe.

γ-Hydroxybutyrate γ-Hydroxybutyrate is a schedule I sedative-hypnotic drug. Although it is used volitionally as a recreational drug, its most infamous use is when it is given surreptitiously as a “date-rape” drug. There is suggestion in the literature that its sedative effects may be reversed by physostigmine, but no conclusive data exist [Caldicott and Kuhn, 2001; Traub et al., 2002].

Volatile Solvents and Propellants Hydrocarbon-based solvents are frequently used by adolescents for their euphoria-producing effects. The compounds commonly in use include various glues, rubber and model airplane cements, typewriter correction fluids, gasoline, lighter fluids, and aerosols [Doring et al., 2002]. Neurologic effects develop within minutes and last several hours, with an initial excitatory stage of euphoria, mental confusion, ataxia, and dysarthria, followed by lethargy, sleep, and coma. Cerebellar dysfunction and sensorimotor neuropathy from chronic gasoline sniffing have been reported [Prockop, 1979; Prockop et al., 1974; Young et al., 1977]. Permanent cognitive impairment and CT evidence of diffuse atrophy of the cerebral hemispheres, cerebellum, and brainstem have also been documented [Hormes et al., 1986]. More sequelae occur with abuse of leaded gasoline [Cairney et al., 2004].

One MRI series demonstrated cerebral atrophy, white matter hyperintensity on T2-weighted images, and hypointensity involving the basal ganglia and thalami on T2-weighted images, as well as focal enhancement. Although a correlation was found between the degree of neurologic impairment and extent of white matter disease, no correlation was seen between radiographic evidence of damage to subcortical gray structures and clinical findings [Caldemeyer et al., 1996].

Nitrous Oxide Nitrous oxide abuse is governed by access and therefore is rare in children. Neurotoxicity is related to nitrous oxide’s ability to interfere with the cobalamin cofactor of methionine synthetase. Neurologic toxicity, which occurs after months of daily use, presents as subacute combined degeneration of the spinal cord [Seppelt, 1995].

Hallucinogens Phencyclidine, also known as angel dust or PCP, is a readily available drug of abuse that is commonly inhaled or ingested. The clinical syndrome of phencyclidine palmitate toxicity includes euphoria and a “high” appearance, at times with violent behavior associated with extreme muscular rigidity and Herculean displays of muscle strength. Vertical and horizontal nystagmus is common, along with marked pupillary dilation. Instead of excitation, the intoxicated patient may manifest a syndrome of catatonic rigidity, opisthotonus, dystonic posturing, stupor or profound fluctuations in the level of consciousness, seizures, and myoclonus. Extreme elevations of blood pressure are common. Intracranial hemorrhage has been reported [Bessen, 1982; Boyko et al., 1987]. The phencyclidine palmitate–intoxicated patient should be sedated, especially if agitated or seizing, cooled for extreme degrees of hyperthermia, and treated for systolic hypertension with hydralazine or diazoxide [Kulberg, 1986]. Gastric lavage is helpful in removing ingested but unabsorbed drug. Urinary acidification promotes drug excretion. Lysergic acid diethylamide remains a potent and frequently abused hallucinogen. Lysergic acid diethylamide intoxication results in acute personality changes, hallucinations, and feelings of depersonalization. Acute panic reactions, or “bad trips,” may occur with neurologic signs of excitation, including ataxia, tremors, diaphoresis, convulsions, and, with severe toxicity, coma and respiratory arrest. Most of the milder cases resolve spontaneously; there is no specific antidote or treatment for lysergic acid diethylamide poisoning other than general support and sedation. Finally, coma has been reported in children ingesting cannabis-laced cookies. Cannabis ingestion should be considered in cases of coma, especially when associated with conjunctival hyperemia, pupillary dilation, and tachycardia and when there is no other obvious cause [Boros et al., 1996].

Amphetamines Amphetamines such as dextroamphetamine, benzedrine, and methamphetamine cause clinically similar effects,

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including a sense of well-being and decreased fatigue. With increasing doses, acute paranoid psychosis may develop, with mania, hyperactivity, and severe sympathomimetic effects, including mydriasis, flushing, diaphoresis, and tachycardia. Convulsions are rare. Cerebral vasculitis, cerebral infarction, and intracranial hemorrhage have been reported with amphetamine use [Delaney and Estes, 1980; Matick et al., 1983; Rothrock et al., 1988]. Gastric lavage is useful in elimination of the toxin. Severe agitation or seizures may be treated with intravenous benzodiazepines; hallucinations may also be treated with haloperidol. Hyperthermia should be treated aggressively; diazoxide or nitroprusside may be indicated for severe hypertension. Adverse effects of medicinal amphetamine use are discussed later in this chapter.

“Ecstasy” 3,4-Methylenedioxymethamphetamine (commonly known as ecstasy) continues to be a popular drug of abuse. Its primary mode of action is to both stimulate and block reuptake of serotonin (5-hydroxytryptamine) [Parrott, 2002]. It also has lesser effect on other monoaminergic neurotransmitters. Taken at dance parties called raves, it promotes a feeling of closeness and heightens sensory experience. It also causes euphoria. Acutely, it commonly causes serotonergic symptoms of confusion, hyperkinesis, and increased body temperature. These symptoms may be exacerbated by conditions that may prevail at raves: overcrowding, high ambient temperature, and coincident use of other stimulants. Rarely these symptoms can develop into a full-blown serotonergic syndrome and a medical emergency. Once the acute effects wear off, depressive symptoms resulting from monoaminergic depletion occur. There are both laboratory animal and human data suggesting subsequent serotonergic axonal damage [Parrott, 2002].

Ethanol Ethanol is abused increasingly often by children; acute alcohol intoxication and even chronic alcoholism have become serious problems in children as young as 10 years of age. The signs of acute alcohol intoxication are familiar, but a pediatrician confronted with a child who exhibits incoordiation, ataxia, wide mood swings, impaired awareness, and gastrointestinal distress may not consider the diagnosis. Profound CNS depression follows ingestion of large amounts of alcohol. Alcohol withdrawal syndromes are rare in children. Alcohol intoxication may occur in mixed substance abuse. Accidental alcohol intoxication has also been reported in young children drinking attractively packaged and flavored mouthwashes. These mouthwashes have a significant ethanol content (14.2% to 26.9%) [Selbst et al., 1985], as do a variety of medicinal preparations, including cough medicines, decongestants, and teething preparations [Pruitt, 1984]. Chronic ethanol exposure in pregnant women causes fetal alcohol syndrome, as well as lesser fetal alcohol effects (see later discussion); some studies have suggested radiographically demonstrable brain injury in infants born to pregnant women consuming large amounts of alcohol [Holzman et al., 1995; Mattson et al., 1994]. Alcohol abuse may have a relationship to teenage suicide [Esposito-

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Smythers and Spirito, 2004]. Alcohol intoxication may increase the risk for suicidal attempts acutely. Its longterm disruptive influence on the young person’s life also may lead to further depressive symptoms and subsequent suicidal behavior.

Barbiturates Barbiturate poisoning in small children is usually the result of accidental ingestion, whereas barbiturate poisoning in teenagers is often seen in suicide attempts. Barbiturate intoxication produces confusion and varying degrees of sedation and coma; lesser amounts may result in ataxia. Respiratory depression, flaccid areflexia, miotic pupils, and absent brainstem reflexes occur with more severe poisoning. Although barbiturates are absorbed rapidly, gastric lavage should be used within 1 hour of ingestion. Activated charcoal is also indicated in the management of barbiturate poisoning; the half-life of longer-acting barbiturates is shortened by repeated doses of activated charcoal administered over 3 to 4 days. Urine alkalinization and forced diuresis enhance the clearance of barbiturates. Because there are no antidotes to barbiturates and the use of stimulant drugs is contraindicated, the prime consideration in the treatment of the child with barbiturate intoxication is respiratory and circulatory support. Renal function monitoring is necessary because renal failure may be a consequence of hypotension and shock. Hemodialysis is of unproved value but may benefit severely intoxicated patients. Barbiturates are an uncommon cause of reflex sympathetic dystrophy [Falasca et al., 1994; Botella et al., 1996].

Other Medications Benzodiazepines Intoxication with benzodiazepines is common because of their ready availability. These compounds produce depression and sedation at low doses and confusion, somnolence, and coma at higher doses. Respiratory depression and hypotension may occur. The combination of benzodiazepines and other CNS depressants is potentially fatal. Treatment consists of supportive care and administration of flumazenil, a specific benzodiazepine antagonist. An optimal dose is not defined, but an initial dose of 0.01 to 0.02 mg/kg (maximum dose, 0.125 mg) is suggested; repeated doses or continuous infusion may be necessary. Flumazenil-induced convulsions may occur in individuals with chronic benzodiazepine use [Leiken and Paloucek, 1995; Perry and Shannon, 1996].

Other Sedatives Chloral hydrate, ethchlorvynol (Placidyl), methaqualone, and glutethimide (Doriden) are sedatives that can cause severe intoxication with CNS depression. With mild intoxication, the child may be lethargic, confused, and ataxic; with severe intoxication, profound hypotonia, coma, and ophthalmoplegia may occur. Glutethimide in particular is associated with prolonged periods of unconsciousness. Careful attention must be given to respiratory support, which may be

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prolonged, and premature weaning must be avoided [Nicholson, 1983]. Glutethimide and its metabolites persist in the blood because they recirculate from fat stores and undergo enterohepatic circulation, resulting in reabsorption from the gastrointestinal tract; however, there is a poor correlation between plasma levels of glutethimide and clinical effects. Activated charcoal and resin hemoperfusion have been used in patients who have not responded to standard supportive measures. There are no specific antidotes for these sedative agents, although methylene blue is used to treat glutethimideinduced methemoglobinemia. Despite its notoriety as a teratogen, the hypnotic agent thalidomide has been used in many infectious and inflammatory conditions, including human immunodeficiency virus– related complications, leprosy, graft-versus-host disease, and lupus erythematosus. Although it typically causes limb and craniofacial birth defects, fetal thalidomide exposure can also cause congenital cranial neuropathies. Its effects suggest a toxic neural cristopathy. Postnatally, thalidomide acts as a potent neurotoxin, causing a potentially severe and often prolonged, if not permanent, sensory neuropathy [Alexander and Wilcox, 1997; Forsyth et al., 1996; Haslett et al., 1997; LeQuesne, 1993; Rodier et al., 1997].

Antipsychotic Agents (Neuroleptics) Major tranquilizers include phenothiazines and related compounds, as well as butyrophenones, which are associated with a variety of serious neurologic complications, including sedation, acute dystonic reactions, akathisia, pseudoparkinsonism, withdrawal, emergent dyskinesia, tardive dyskinesia, and neuroleptic malignant syndrome. Newer antipsychotic agents include clozapine, sertindole, olanzapine, and risperidone and reportedly have fewer neurologic side effects [Caroff et al., 2002]. Acute intoxication in a young child usually results in a confusional state or depressed level of consciousness. Acute dystonic reactions, often observed in children after a single dose of phenothiazine or haloperidol, may manifest as an oculogyric crisis or sudden dystonic posturing of the head and neck, including opisthotonus, retrocollis, torticollis, facial grimacing, and tongue thrusting. These acute reactions are not necessarily dose related and are usually readily reversed with the intravenous administration of 25 to 50 mg of diphenhydramine. Miosis, coma, hypothermia or hyperthermia, and hypotension may occur after ingestion of a large dose of either phenothiazines or butyrophenones. Respiratory depression suggests the ingestion of additional agents, such as narcotics [Knight and Roberts, 1986]. Akathisia, an internal feeling of restlessness, is a doserelated neurologic complication of neuroleptic treatment and is thought to be rare in children [Sachdev, 1995]. It is one of the most distressing adverse effects of neuroleptic use but usually responds to treatment with anticholinergic drugs or blockers. Neuroleptic malignant syndrome is a rare complication of neuroleptic drug therapy and is characterized by fever, muscular rigidity, autonomic dysfunction, and altered sensorium with waxing and waning of consciousness. The patient may be in a catatonic-like stupor and may be mute. In children, neuroleptic malignant syndrome occurs during therapy with neuroleptics, as well as after accidental phenothiazine inges-

tion [Klein et al., 1985b]. Myoglobinuria and acute renal failure may supervene. Treatment consists of intensive supportive care with monitoring of vital signs, aggressive fluid management, and in selected cases dantrolene administration [Caroff and Mann, 1993; Tueth, 1994]. Although reported more often in association with older antipsychotic medications, neuroleptic malignant syndrome occurs also with newer agents such as clozapine, albeit possibly with less dramatic clinical and laboratory findings [Sachdev et al., 1995]. A clinical presentation of confusion, myoclonus, hyperreflexia, diaphoresis, and diarrhea progressing to fever, coma, and rigidity that improved over 10 days with bromocriptine and aggressive intensive care unit care was seen in a young woman taking risperidone and fluvoxamine [Reeves et al., 2002].It was thought that this may not have been neuroleptic malignant syndrome but rather serotonin syndrome. Tardive dyskinesia after chronic phenothiazine or haloperidol use is extremely rare in children [Singer, 1986]. The propensity to develop tardive dyskinesia may be related to the patient’s underlying neural substrate, as found in a recent study. Juckel and colleagues [1995], using auditory event–related potentials, demonstrated an association between a small P300 evoked potential and subsequent tardive dyskinesia. The newer “novel” antipsychotics, such as clozapine, risperidone, olanzapine, and sertindole, have clinically significant pharmacologic activity at multiple receptors and fewer typical antidopaminergic side effects such as acute parkinsonism, akathisia, and tardive movement disorders [Baldessarini, 1996; Casey, 1996a; Krebs, 1995; Lindstrom et al., 1995; Schooler, 1996]. Clozapine, in particular, appears to be associated with less bradykinesia and akathisia than haloperidol, although not necessarily less tremor [Kurz et al., 1995]. Acute extrapyramidal effects have been seen in children after an overdose of 100 mg of clozapine [Goetz et al., 1993; POISINDEX, 2005]. Confusion, lethargy, and ataxia have also been reported in children. Although clozapine-associated seizures have been reported at doses of 250 mg/day, the prevalence of seizures is higher (5%) in adults taking 600 to 900 mg/day [Haller and Binder, 1990; Tueth, 1994]. Myoclonus has also been reported at higher doses [Bak et al., 1995]. Extrapyramidal side effects (acutely, dystonia) and tardive dyskinesia are reported infrequently with risperidone [Buzan, 1996; Daniel et al., 1996; Faulk et al., 1996]. Olanzapine appears to have an extrapyramidal side-effect profile intermediate between that of the older antipsychotics and its newer cousins [Casey, 1996b].

Antidepressants Tricyclic antidepressants, such as amitriptyline, imipramine, and desipramine, have been associated with acute toxicity and significant morbidity and mortality. Acute encephalopathy occurs within 4 hours of ingestion and includes ataxia, hallucinations, and nystagmus. Somnolence occurs subsequently, and tremor or myoclonus may occur. Cardiac conduction abnormalities, including tachycardia, heart block, atrial fibrillation, and ventricular flutter, are the most common and serious non-neurologic results of tricyclic intoxication [Pimentel and Trommer, 1994]. Dry mouth, palpitations, and tachycardia occur as typical anticholinergic effects. Death may occur as a result of progressive coma,

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seizures, and cardiac conduction defects. In acute poisoning, activated charcoal with a cathartic may be helpful; lavage may be attempted if fewer than 6 hours have passed since ingestion. Up to 2 mg of physostigmine administered intravenously may awaken a comatose patient but should be avoided in patients with bradycardia. Keeping the blood pH slightly alkaline (e.g., 7.5) helps in the treatment of tachyarrhythmias. A prolonged QRS interval is a good predictor of seizures and cardiac dysrhythmias in acute intoxication with tricyclics, but serious CNS depression may occur with relatively normal QRS intervals [Boehnert and Lovejoy, 1985]. Amoxapine, a newer tricyclic antidepressant, also frequently induces seizures when taken in toxic amounts, but unlike the other drugs of this class, it does not seriously alter the electrocardiogram [Rogol et al., 1984]. Selective serotonin reuptake inhibitors are some of the most frequently used medications in the United States at the present time. Such popularity stems from their broad range of efficacy and relatively favorable side-effect profile. Although cases of selective serotonin reuptake inhibitor toxicity have increased as a result of this wide availability, serious neurotoxicity is limited generally to accidental ingestions or intentional overdoses, especially in combination with other medications or drugs of abuse [KleinSchwartz and Anderson, 1996; Lavin et al., 1993; Litovitz et al., 1995]. Paradoxic behavioral reactions and selective sertonin re-uptake inhibitor–induced hyperkinetic movement disorders are perhaps the most likely adverse neurologic effects. In a review of 469 selective serotonin reuptake inhibitor intoxication cases in adults, a more severe serotonergic syndrome, with coma or convulsions, occurred in 2.4% and 1.9%, respectively [Isbister et al., 2004]. Of note, of the five different selective serotonin reuptake inhibitors involved, citalopram had relative QTc prolongation, although its clinical significance was unclear. In a study of isolated accidental fluoxetine ingestion of 20 mg or more in 120 children younger than 6 years, 96% were asymptomatic. Sedation and vomiting were the only side effects reported in symptomatic children [Baker and Morgan, 2004]. Recently, a neonatal withdrawal syndrome including neonatal convulsions has been described in newborns whose mothers were taking selective serotonin reuptake inhibitors during the pregnancy [Sanz et al, 2005].

Lithium Lithium carbonate, used for the treatment of bipolar depression in adults, is effective in the treatment of certain behavioral and affective disorders in children [Goetting, 1985]. Most cases of lithium intoxication occur during the course of prolonged therapy. The typical patient has apathy, drowsiness, nystagmus, tinnitus, dysarthria, ataxia, coarse muscle tremors, vomiting, and diarrhea. Choreiform movements, dystonic posturing, and cogwheel rigidity may occur. Severity of symptoms correlates well with the serum lithium concentration. Seizures and coma indicate severe toxicity (i.e., serum lithium level, >3.0 mmol/L). Treatment of acute poisoning should include induction of emesis or gastric lavage. However, because of the slow excretion of lithium, symptoms may progress despite cessation of the medication. There is no specific treatment other than attention to fluid balance and support. Sodium chloride administration en-

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hances urinary excretion, particularly if the patient is hyponatremic. Peritoneal dialysis or hemodialysis is used in cases of clinically severe intoxication with serum lithium levels greater than 3 mmol/L [Tueth, 1994]. Prolonged hemodialysis may be necessary to prevent a rebound in serum lithium concentration [Sansone and Ziegler, 1985].

Salicylates and Acetaminophen Salicylates are present in a myriad of medicinal preparations ranging from aspirin tablets to oil of wintergreen and longused Chinese medicinal oils [Chan et al., 1995; Chan, 1996]. Poisoning has been reported with all forms through both oral and topical routes [Abdel-Magid and el-Awad Ahmed, 1994]. Absorption rate depends on the preparation. Neurologic, hepatic, and pulmonary toxicity occurs in concert with other metabolic derangements [Bari, 1995]. Symptom onset in acute intoxications is within a few hours. Salicylates directly affect the CNS and cause central hyperventilation with respiratory alkalosis. Poisoning of the Krebs cycle and increased skeletal muscle metabolism result in increased oxygen consumption, increased carbon dioxide production, and metabolic acidosis. Salicylates also contribute directly to this acidosis. Mortality is related to brain salicylate concentration; respiratory decompensation and subsequent worsening acidosis facilitate salicylic acid passage into the CNS [Yip et al., 1994]. Severe intoxication is more likely in children younger than 4 years. Chronic toxicity occurs after several days of use and may be more difficult to discern sometimes because of symptoms of the patient’s underlying illness. CNS disturbances occur in up to 60% of patients and include lethargy, coma, and convulsions; however, the predominant toxicity with chronic salicylism is pulmonary edema [English et al., 1996; Yip et al., 1994]. Poisoning also may result from chronic excessive use of bismuth subsalicylate (Pepto-Bismol). The combination of typical signs of chronic salicylate toxicity and radiopaque bismuth precipitate seen on radiographs of the abdomen suggests the diagnosis [Hearney et al., 1996; Vernace et al., 1994]. Failure to recognize and aggressively treat salicylate poisoning contributes to morbidity and mortality. Supportive therapy and aggressive measures to speed elimination of salicylates from the body are the mainstays of treatment. Fluid diuresis coupled with urinary alkalinization is used in milder cases; more severe poisonings may require blood alkalinization. This alkalinization and early hemodialysis may be life saving in severe intoxications [Yip et al., 1994]. Activated charcoal is beneficial, but the advantage of multipledose over single-dose regimens is not proved [Cienki et al., 1995]. Hypoglycemia may complicate salicylate poisoning. Intravenous fluids should contain at least 5% glucose; 10% glucose solutions should be used in young children with documented hypoglycemia or mental status changes. Aspirin tablets may form bezoars within the stomach; these provide a reservoir for prolonged salicylate absorption and may require dilutional catharsis. Unlike salicylates, acetaminophen (and paracetamol) appears not to have a recognizable primary toxic effect on the brain. CNS effects result from acetaminophen-induced liver failure. Hepatic coma and life-threatening cerebral edema may be present in severe acute overdoses, although

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peak symptoms may not occur until 1 to 3 days after ingestion [Leikin and Paloucek, 1995]. Early lack of symptoms does not exclude a potentially fatal ingestion, and need for therapy is directly related to dose and measured acetaminophen blood level. Conservative estimates of the acute pediatric toxic dose are 140 to 150 mg/kg, but many authors use doses of 200 mg/kg, up to an adult toxic dose of about 7.5 g [Anker and Smilkstein, 1994]. Home ipecac administration for this and other suspected poisonings once was considered standard of care; however, the current American Academy of Pediatrics recommendation is to not have ipecac in the home [American Academy of Pediatrics Committee on Injury, Violence, and Poison Prevention, 2003; Bond, 1995; Shannon, 2003;]. Gastric lavage is effective if performed within 1 hour after ingestion. Activated charcoal should be given up to 4 hours after ingestion. If dosage at or above toxic range is suspected, N-acetylcysteine should be started; efficacy of oral versus intravenous therapy is debated. A 4-hour postingestion blood acetaminophen level is compared with a standard nomogram to determine the need to continue N-acetylcysteine therapy [Brandwene et al., 1996]. N-acetylcysteine coupled with a molecular absorbant recirculating system, if started early, may allow hepatic regeneration and obviates the need for liver transplantation [Koivusalo et al., 2003]. After ingestion of extended-release acetaminophen preparations, a second blood acetaminophen level should be obtained 4 to 6 hours after the first (but at least 8 to 12 hours after ingestion) [Cetaruk et al., 1997; Leikin and Paloucek, 1995].

Stimulants Stimulant medications, such as dextroamphetamine, pemoline, and methylphenidate, used for the treatment of attention-deficit–hyperactivity disorder may produce increased activity and varying dyskinesias, including motor tics and chorea [Jimenez-Jimenez et al., 1997; Nakamura et al., 2002; Stork and Cantor, 1997]. Some children receiving methylphenidate may develop Tourette’s syndrome, but a recent study of males with attention-deficit–hyperactivity disorder and Tourette’s syndrome demonstrated that tics increased reversibly with stimulant use [Castellanos et al., 1997].

Theophylline Theophylline and aminophylline, commonly used for treating apnea of prematurity and asthma, may cause neurologic symptoms as a result of either accidental ingestion or therapeutic error. Although theophylline concentrations higher than 20 mg/L are believed to be toxic, and clinical toxicity with nausea, vomiting, tachycardia, and agitation followed by seizures is more common when theophylline levels are greater than 30 to 40 mg/L, some children suffer lesser side effects with levels above 12 to 15 mg/L [Barr et al., 1994]. Gastrointestinal symptoms do not necessarily precede the onset of seizures, and seizures may occur with serum theophylline concentrations as low as 25 mg/L, although they are more common when concentrations exceed 50 mg/L [Gal et al., 1980; Jira et al., 1996]. Treatment of theophylline toxicity is supportive. Although activated charcoal absorbs the drug well within the gastrointestinal tract,

hemoperfusion is considered the definitive treatment. Peritoneal dialysis has been used successfully in neonates and infants [Colonna et al., 1996; Jira et al., 1996]. Ipecac should be avoided. Seizures may be difficult to control but should be treated initially with benzodiazepines [Leikin and Paloucek, 1995]. Status epilepticus associated with increased theophylline levels carries a risk for increased morbidity over status epilepticus in general [Dunn and Parekh, 1991]. This risk may be secondary to theophylline-induced decreased cerebral blood flow or to increased risk for hypoxia due to underlying pulmonary disease.

Atropine and Related Alkaloids Many drugs with anticholinergic properties, such as atropine, may produce an acute anticholinergic syndrome if taken in excess (see previous toxidrome discussion). Examples of drugs with significant anticholinergic properties include atropine, scopolamine, and local mydriatics, such as cyclopentolate (Cyclogyl) and tropicamide (Mydriacyl); a few antihistaminics, such as diphenhydramine and tripelennamine; gastrointestinal antispasmodics, such as dicyclomine (Bentyl) and propantheline (Pro-Banth-ıne); and older tricyclic antidepressants. The scopolamine-containing transdermal patches used for the prevention of motion sickness are a novel way to administer excessive amounts of scopolamine to children. The transdermal patch was developed primarily for adults and contains 1.5 mg of scopolamine, which can produce toxic psychosis in children and should be used with caution [Klein et al., 1985a; Lewis et al., 1994]. These patches also are used in some developmentally disabled children (e.g., with cerebral palsy) to decrease drooling. Poisoning may also occur after ingestion of plants containing belladonna alkaloids (Atropa belladonna, also known as deadly nightshade). Recreational abuse of such plants (e.g., tea made with Brugmansia [Angel’s trumpet] and Datura species) in teenagers has been reported, although seizures or fatalities resulting from drinking the prepared tea appear unlikely [Isbister et al., 2003; Patel et al., 2003]. Supportive measures are the mainstay of therapy. Physostigmine may be used but may precipitate cholinergic toxicity, including seizures and bradyarrhythmias, and its use requires availability of adequate supportive therapy for these potential complications [Kulig and Rumack, 1983]. Physostigmine (0.5 mg intravenously) is administered slowly in children; it may be repeated every 10 minutes for a maximum total dose of 2 mg.

Drugs Used in Organ Transplantation Organ transplantation may result in severe neurologic complications. Severe neurologic sequelae may occur in 10% to 15% of children who undergo hematopoietic stem cell transplantation [Faraci et al., 2002]. In a large Italian study, risk factors were allogeneic donor, presence of graft-versus-host disease, and use of total brain irradiation.

Cyclosporine Cyclosporine, a potent immunosuppressant, is being used increasingly in solid organ transplantation [de Groen et al., 1987; Lee and Vacanti, 1996]. It probably is implicated most

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in neurologic sequelae of transplantation drugs [Faraci et al., 2002]. Neurotoxicity, nephrotoxicity, and hypertension are complications of cyclosporine therapy. Cyclosporine is lipophilic, a property that allows it relatively easy access to the CNS. The most common side effects of cyclosporine on the nervous system are headache, confusion, and seizures, but cortical blindness, hemiparesis, ataxia, and tremor are also reported [Adams et al., 1987; Boon et al., 1988; Garg et al., 1993; Ghalie et al., 1990; Miller, 1996; Reece, 1991; Soy et al., 1995; Trzepacz et al., 1993]. A syndrome of encephalopathy, seizures, and cerebral white matter changes has also been described. The white matter changes are more prominent in the parieto-occipital areas and resemble posterior reversible encephalopathy syndrome [Miller, 1996; Truwit et al., 1991; Nishie et al., 2003]. Marchiori and associates reported a case of cyclosporine-associated posterior reversible encephalopathy syndrome and reversible opsoclonus in a teenager after orthotopic liver transplantation [Marchiori et al., 2004]. These complications seem to be reversible but may require a decrease in the cyclosporine dose. Side effects are usually associated with high levels of cyclosporine. Other factors that exacerbate cyclosporine toxicity include hypertension, fever, hypomagnesemia, hypocholesterolemia, aluminum overload (especially in patients undergoing renal transplantation), and concurrent methylprednisolone treatment [Bhatt, 1988; de Groen, 1987; Thompson et al., 1984; Trzepacz et al., 1993].

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relationship of these side effects is unclear, although increased toxicity has been noted with concomitant use of agents that increase tacrolimus delivery to the small intestine (e.g., metoclopramide) [Backman et al., 1994; Trzepacz et al., 1993; Prescott et al., 2004]. MRI may indicate white matter change, but reversibility may be predicted by apparent diffusion coefficient mapping [Shimono et al., 2003; Furukawa et al., 2001].

Antibiotics Chloramphenicol Chloramphenicol has been associated with the development of a reversible optic neuritis, demonstrable clinically and by visual-evoked potentials, in patients with cystic fibrosis who undergo long-term treatment with chloramphenicol [Leikin and Paloucek, 1995; Leitman et al., 1964; Spaide et al., 1987].

Nitrofurantoin Polyneuropathy is a known complication in patients treated over prolonged periods with nitrofurantoin, particularly in the presence of impaired renal function. Patients have ascending sensory and motor polyneuropathy associated with increased spinal fluid protein [Spring et al., 2001].

OKT3 OKT3 is a murine monoclonal anti–pan-T-cell antibody of the immunoglobulin G2a isotype. OKT3 has been used extensively as an immunosuppressant agent in acute cellular allograft rejection or graft-versus-host disease [Norman, 1989]. The target of OKT3 is CD3, a 17- to 20-kDa molecule found on mature T cells that is selectively removed during treatment with this monoclonal antibody. OKT3 blocks both the generation and function of cytotoxic T cells. The half-life of injected OKT3 is about 18 hours [Fung, 1991; Norman, 1989]. A picture of aseptic meningitis with fever, photophobia, cephalgia, and cerebrospinal fluid pleocytosis has been described with OKT3 use [Adair et al., 1991; Emmons, 1986; Martin et al., 1988]. Other complications have included cerebral edema, seizures, cerebritis, and tremor [Capone and Cohen, 1991; Garg et al., 1993; Thomas et al., 1987; Trzepacz et al., 1993].

Tacrolimus (FK-506) Tacrolimus, or FK-506, is used primarily to prevent organ rejection in liver transplant recipients [Diasio and LoBuglio, 1996; Lee and Vacanti, 1996]. Like cyclosporine, it inhibits interleukin-2 and is thought to act by inhibiting T-cell activation. Serum levels of tacrolimus are altered significantly by multiple drugs, including cyclosporine, methylprednisolone, metoclopramide, some antiepileptic drugs, and various antifungal agents. Tacrolimus has clinical toxicity similar to that of cyclosporine. At serum levels greater than 3 ng/mL, delirium has been reported [Trzepacz et al., 1993]. Other neurologic side effects include dysphasia, seizures, and tremor. The dose

Aminoglycosides Aminoglycosides are potentially ototoxic. Recent data suggest that susceptibility to aminoglycoside-induced ototoxicity is associated with a mitochondrial mutation (nucleotide 1555) [Usami et al., 1997]. Symptoms may arise not only from oral or parenteral administration of the drugs but also after wound irrigation. A myasthenic-like syndrome accompanied by generalized muscle weakness, which is partially antagonized by neostigmine, may result from the administration of aminoglycosides such as streptomycin, neomycin, kanamycin, bacitracin, colistin, and gentamicin. This reaction usually occurs in association with the simultaneous administration of a neuromuscular blocking agent (e.g., succinylcholine, D-tubocurarine, decamethonium bromide). This neuromuscular blocking effect is especially pronounced when these antibiotics are placed in the pleural or abdominal cavities, with resultant rapid absorption and high plasma levels. These antibiotics may also cause a transient clinical deterioration in patients with myasthenia gravis [Kaeser, 1984].

β-Lactam Antibiotics The β-lactam antibiotics are a diverse group of medications with potential for myriad systemic and neurologic side effects. Seizures caused by the penicillins, cephalosporins, and carbapenems result from the inhibition of γ-aminobutyric acid receptors [Asensi et al., 1993; Sunagawa and Nouda, 1996]. Movement disorders and change in sensorium may occur also. Effects may be magnified in a child with an altered blood-brain barrier.

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Antiviral Agents Anti–human immunodeficiency virus drugs have prolonged the lives of many patients with acquired immune deficiency syndrome. They have also been associated with significant neurotoxicity. Use of two older agents, dideoxycytidine and dideoxyinosine, as well as a newer reverse transcriptase inhibitor, stavudine, has been associated with peripheral neuropathy [Brew and Currie, 1993; Mueller, 1997]. So far, therapy with protease inhibitors has not demonstrated significant neurotoxicity, but only preliminary data are available [Mueller, 1997]. Anticytomegalovirus agents (acyclovir, ganciclovir, and foscarnet) have some CNS side effects, such as alteration in consciousness or seizures, but they are usually overshadowed by neurologic sequelae of concomitant systemic toxicity (i.e., myelosuppression and nephrotoxicity).

Antineoplastic Drugs Use of chemotherapeutic agents has produced striking improvement in the outcome of childhood malignant disease and is associated with a number of neurologic complications in children and adults [Armstrong and Gilbert, 2004].

Vinca Alkaloids Vincristine and vinblastine are potent antineoplastic agents with variable degrees of neurotoxicity, some of which is reversible. Impaired nutrition appears to increase susceptibility to vincristine toxicity. Greater neurotoxicity is also related to higher concentrations of drug per dose and increased frequency and duration of therapy. Some degree of symmetric peripheral neuropathy, with areflexia involving early and consistent loss of Achilles tendon reflexes, slapping gait, muscle atrophy, and leg weakness, develops frequently, even with customary doses of vincristine. Numbness and tingling paresthesias in hands and feet are common with preserved cutaneous sensation, although the child may complain of hand clumsiness before the onset of footdrop [Tuxen and Hansen, 1994]. Muscle cramps are also a frequent symptom of vincristine-associated motor neuropathies, occurring in both proximal and distal distributions [Haim et al., 1991]. Cranial nerve palsies may also occur with involvement of cranial nerves II to VIII and X. The most common ocular findings are variable degrees of ophthalmoparesis and ptosis. Autonomic dysfunction is another aspect of vincristine neurotoxicity, with colicky abdominal pain, paralytic ileus and constipation (in 33% to 46% of patients), and bladder atony (Christensen et al., 1994; Tuxen and Hansen, 1994). Generalized seizures and inappropriate secretion of antidiuretic hormone are additional but rare complications of vincristine treatment [Sandler et al., 1969; Shurin et al., 1982]. Vincristine’s peripheral neurotoxic effects may be potentiated by itraconazole [Ariffin et al., 2003; Kamaluddiin et al., 2001]. Vinorelbine has the potential to cause similar neurotoxic effects but, possibly because of its greater selectivity for mitotic rather than axonal microtubules, does so less often [Tuxen and Hansen, 1994]. Vincristine also causes a necrotizing myopathy [Le Quintrec and Le Quintrec., 1991]. Especially with concomitant steroid therapy, a combined myoneuropathy picture may develop [Bradley et al., 1970; DeAngelis et al,

1991]. Improvement usually ensues with completion of therapy.

Methotrexate Myelopathy, headache, vomiting, nuchal rigidity with aseptic meningitis, truncal ataxia, tremor, paraplegia, delirium, and somnolence have been described as complications of both intrathecal and systemic therapy with methotrexate. Meningoencephalopathy can occur as late as several months after completion of methotrexate therapy. Scattered subcortical intracerebral calcifications may result from large cumulative doses of intravenous methotrexate, and concurrent administration of cytosine arabinoside may increase the risk for this complication [McIntosh et al., 1977]. The most devastating effect of methotrexate therapy, originally thought to be related to a combination of a high dose of intrathecal methotrexate and CNS irradiation, is a subacute and usually progressive leukoencephalopathy. A characteristic pattern of decreased density of periventricular white matter is evident on CT or as increased periventricular signal on T2-weighted MRI. Clinical manifestations include mental deterioration with dementia, seizures, and focal neurologic deficits. This complication may occur between 3 and 9 months after high-dose methotrexate therapy. An immediate and fatal necrotizing leukoencephalopathy has been reported in association with an inadvertent, more than 50-fold intrathecal overdose of methotrexate [Ettinger, 1982]. Leukoencephalopathy can occur with intravenous methotrexate therapy plus cranial irradiation without intrathecal administration of the methotrexate [McIntoshet al., 1977; Price and Jamieson, 1975; Weiss et al., 1974; Shuper et al., 2002]. Animal studies suggest that concomitant administration of steroids may play a role in this neurotoxicity [Mullenix et al., 1994]. In addition, underlying disease may potentiate methotrexate toxicity. Miller and Wilkinson describe 79% to 93% reduction in local cerebrospinal fluid clearance of intraventricularly administered methotrexate in three individuals with carcinomatous meningitis [Miller and Wilkinson, 1989]. Improvement also has been reported in a single report using a combination of high-dose folinic acid and aminophylline [Jaksic et al., 2004]. L-Asparaginase L-Asparaginase

therapy may produce changes in mentation, somnolence, and electroencephalogram slowing [Moure et al., 1970; Tuxen and Hansen, 1994]. Intracranial thrombosis or hemorrhage and peripheral arterial thrombosis with headache, obtundation, hemiparesis, and seizures have also been recognized as complications in 1% to 2% of children receiving L-asparaginase [Priest et al., 1982]. The associated coagulation disorder is thought to be secondary to L-asparaginase–induced decrease in antithrombin III level [Kieslich et al., 2003]. Despite this, it is not yet clear that L-asparaginase–related cerebrovascular thrombosis responds to replacement of factors, or that it is resistant to low-molecular-weight heparin therapy.

Platinum Agents Ototoxicity is a common complication of cisplatin therapy; peripheral sensory neuropathy may also occur with dys-

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esthesias and paresthesias, diminished reflexes, decreased vibratory and light touch sensation, and sensory ataxia [Cavaletti et al., 1996; Thompson et al., 1982; Steeghs et al., 2003; Markman, 2003]. Although retinal toxicity is reported in adults, it is rare in children and may be associated with abnormal renal function [Hilliard et al., 1997]. Autonomic neuropathy is rare. Oxaliplatin has similar neurotoxic potential; carboplatin appears somewhat less toxic to the nervous system [Tuxen and Hansen, 1994]. Possible neuroprotectant agents that may minimize this neurotoxicity include calcium channel antagonists, thiol compounds, adrenocorticotropic hormone analogs, and neurotropic factors [Cavaletti et al., 1996].

Cytosine Arabinoside Cytosine arabinoside has been associated with transient paraplegia after intrathecal administration. In childhood acute myelogenous leukemia, patients given intrathecal and intravenous cytosine arabinoside have exhibited progressive ascending paralytic disease, with onset delayed up to 6 months after treatment, accompanied by spinal cord demyelination [Dunton et al., 1986]. Cytosine arabinoside may also cause cerebellar ataxia, change in sensorium (the latter at high doses), and rarely peripheral neuropathy or brachial plexopathy [Tuxen and Hansen, 1994].

Cyclophosphamide and Ifosfamide Cyclophosphamide and ifosfamide both may cause CNS toxicity (10% to 30% incidence in the case of the latter) [DiMaggio et al., 1994; Tuxen and Hansen, 1994]. This toxicity is manifest as mental status changes, seizures, and ataxia. Cranial neuropathies are also possible. In the case of ifosfamide, toxicity may be evident within 2 hours after infusion is begun and may continue for 1 to 3 days after a 5-day course of therapy [Pratt et al., 1989; Nicolao and Giometto, 2003; Rieger et al., 2004]. It is more likely to occur in the face of common concomitants of malignancy, including hepatic or renal dysfunction, hypoalbuminemia, acidosis, or prior CNS abnormality. Improvement has been reported with methylene blue administration [Raj et al., 2004; Orbach et al., 2003].

Other Agents Used in Cancer Chemotherapy Fludarabine, cladribine, and pentostatin are newer purine analogs that are used currently more often in adults than in children. They carry potential for fatal neurotoxicity at higher-than-recommended doses; at the recommended dosage, each carries a 15% risk for (usually reversible) neurotoxicity [Cheson et al., 1994]. Finally, as cytokines find increasing roles in cancer chemotherapy, their neurotoxicity is becoming more evident. Evidence is strongest for interferon and interleukin2. Interferon therapy has been associated with frontal lobe dysfunction (decreased executive functions, transient aphasia), migraine, parkinsonism and akathisia, and peripheral neuropathy. Conversely, interleukin-2 use has been linked to neurobehavioral changes ranging from lethargy to delirium. The mechanism of neurotoxicity is unclear, although it is postulated that they circumvent the bloodbrain barrier through a poorly understood mechanism.

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Quantification of the degree of toxicity awaits prospective studies [Forman, 1994; Margolin, 1994].

Steroids Neurologic complications of steroid therapy include delirium, cortical atrophy, pseudotumor cerebri, and steroid myopathy. More subtle neurobehavioral effects of steroids, especially anabolic and androgenic steroids used (and abused) by athletes, are catalogued elsewhere [Lukas, 1996; Pope and Katz, 1994]. Brain atrophy (ascertained by neuroimaging studies) and pseudotumor cerebri related to steroids occur primarily in children receiving prolonged corticosteroid treatment, the latter at times after drug withdrawal. There does not appear to be any relationship between pseudotumor cerebri and the disorder for which steroids were being administered. Autonomic neuropathy has also been reported [Rosener et al., 1996]. Proximal myopathy may be a common complication of steroid therapy. Onset may be insidious, and it may occur after only a short duration (<14 days) of steroid therapy. Although often mild, myopathy may occur in up to 60% of patients treated with steroids [Batchelor et al., 1997].

Radiographic Contrast Agents Metrizamide, a contrast agent for myelographic procedures, may cause a transient encephalopathy manifested by confusional state, hallucinations, myoclonus, and asterixis. There is evidence that metrizamide reaches the intracranial subarachnoid space in these patients [Junck and Marshall, 1983]. Headache is common after metrizamide myelography. The incidence of seizures is 0.1%; many of the reported seizures have occurred in patients with a history of seizures [Torvik and Walday, 1995]. Rare transient adverse effects of metrizamide include paraparesis, loss of reflexes, blindness, speech disturbances, and diplopia. Cerebrospinal fluid pleocytosis and clinical evidence of aseptic meningitis may occur after metrizamide myelography [Junck and Marshall, 1983; DiMario, 1985]. Seizures have also been reported with diatrizoate meglumine (Hypaque) [Karl et al., 1994]. Newer nonionic contrast agents, including iohexol and iodixanol, appear to have less risk, although similar side effects have been reported anecdotally [Torvik and Walday, 1995]. Symptoms occur 2 to 12 hours after injection and may last 24 to 72 hours. Iophendylate (Pantopaque), an oily contrast agent that is used occasionally for myelography, may induce acute and chronic meningeal reactions. The acute reaction consists of headache, fever, meningismus, and cerebrospinal fluid pleocytosis and is usually self-limited. Patients with adhesive arachnoiditis from chronic inflammation may have back pain and signs and symptoms of lumbar and sacral root dysfunction within several months of myelography. Complete removal of any residual iophendylate after myelography is recommended as a preventive measure. Systemic or intrathecal corticosteroid therapy may be beneficial.

ADVERSE DRUG REACTIONS Adverse drug reactions affecting the nervous system are not necessarily a result of accidental ingestions, inappropriate

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dosage, or therapeutic error but may occur during the course of therapy. Such reactions may be due to (1) vehicle or method of medication preparation, (2) method of drug administration, (3) pharmacogenetic susceptibility, (4) drug interactions, (5) developmental immaturity, (6) underlying disease, or (7) idiosyncrasy or exaggeration of the normal pharmacologic action of drugs.

Propylene glycol has been commonly used as a drug solubilizer for various medications, including vitamins and certain parenteral drug products such as phenytoin and diazepam. CNS and respiratory depression, hypotension, and cardiac dysrhythmias may result from intravenous injection of products containing propylene glycol. Otherwise unexplained CNS depression in small children has occurred after large doses of oral vitamin D–containing propylene glycol for treatment of vitamin D–deficiency rickets [Pruitt et al., 1985].

with winging of the scapula accompanied by weakness or pain in the shoulder. Neonatal sciatic nerve palsy has resulted from umbilical artery injections with subsequent vasoconstriction of the umbilical artery and vasospasm of the hypogastric and inferior gluteal arteries. The injection of hypertonic sodium bicarbonate or 50% glucose solutions may produce this effect [San Augustin et al., 1962]. Paraplegia has also occurred as a complication of umbilical artery catheterization, with flaccid paralysis of the lower extremities and profound sensory deficit, presumably resulting from ischemic injury to the spinal cord. With the advent of therapeutic botulinum toxin injections to treat myriad neuromuscular problems, there is potential for inadvertent regional effects of neuromuscular blockade. In one report, botulinum toxin injections administered to alleviate adductor spasticity produced prolonged urinary retention [Schnider et al., 1995]. Finally, intramuscular injection of phenytoin may lead to sterile abscess. It is hoped that the introduction of fosphenytoin will eliminate this complication.

Technique of Drug Administration

Pharmacogenetic Susceptibility

Intramuscular injections of medications, particularly into the buttocks, may result in peripheral nerve injury, especially in infants and small children. Sciatic neuropathy may result from a buttock injection when the needle is directed inadvertently into the sciatic nerve; this injection error may occur more easily in a small, struggling infant. Sciatic neuropathy has occurred after intramuscular administration of penicillin, promethazine, chlorpromazine, and vitamin K [Gilles and Matson, 1970]. The clinical syndrome classically occurs within 12 hours after an injection presumably has been given in the upper outer quadrant of the buttock. The child complains of pain and tingling paresthesia in the buttock and down the back of the leg to the lateral margin of the foot. The pain and dysesthesias may be so severe that the child refuses to walk. Within weeks, footdrop and calf muscle atrophy develop, with decreased sensation over the lateral aspect of the foot and diminished Achilles tendon reflex. Before the institution of aggressive rehabilitation and neurolysis, only 30% to 60% of children had good recovery. This figure now approaches 100%, although lack of electrical activity and muscle strength in innervated muscles portend a less favorable outcome [Villarejo and Pascual, 1993]. Because of this complication, the recommended site for intramuscular injections in infants and children is the lateral or anterolateral aspect of the upper thigh. Injections into the lateral or anterolateral aspect of the thigh, however, are not entirely free of complications. Repeated intramuscular injections into this area may result in fibrosis and contracture of the quadriceps muscle with loss of knee flexion. In addition, these children have palpable cords of connective tissue in the thighs, with associated atrophy and dimpling of the overlying skin and subcutaneous tissue. Affected patients usually have been given repeated injections of antibiotics for the treatment of serious illnesses in the neonatal period [Norman et al., 1970]. Progressive fibrosis involving the deltoid muscle has been reported in children after repeated injections in the upper arm. Deltoid muscle injury and fibrosis may result in progressive abduction contracture of the arm at the shoulder,

Adverse reactions to some drugs may be related to individual genetic variation rather than to the drug itself. Sex, race, and ethnicity influence drug response and metabolism [Matthews, 1995]. Although isoniazid poisoning is known to occur after excessive doses of the drug, adverse reactions, including toxic psychosis, seizures, and peripheral neuropathy, may also occur in genetically susceptible individuals on conventional therapeutic doses of isoniazid. Such individuals are slow inactivators of isoniazid, a genetically transmitted autosomal recessive trait. These slow isoniazid inactivators are also predisposed to phenytoin intoxication when given both isoniazid and phenytoin simultaneously. Impaired parahydroxylation of phenytoin, another genetically determined defect in drug metabolism, is another cause of unexplained phenytoin toxicity manifested by nystagmus, ataxia, and mental clouding. This autosomal-dominant trait results in the accumulation of unmetabolized phenytoin, with marked elevation of serum phenytoin concentrations despite the use of conventional dosages of the drug. Idiosyncratic reactions to both phenytoin and carbamazepine were linked previously to defective microsomal epoxide hydrolase, although more recent studies have not confirmed this association [Davis et al., 1995; Gaedigk et al., 1994; Green et al., 1995]. Pseudocholinesterase deficiency, an autosomal recessive trait, results in abnormal reactions to succinylcholine manifested by prolonged muscle relaxation with profound weakness and apnea. The adverse response follows the administration of therapeutic doses of succinylcholine during surgery. Individuals with this disorder have an atypical plasma cholinesterase that hydrolyzes succinylcholine at markedly reduced rates, with resultant persistent elevation of plasma succinylcholine concentrations. Patients with acute intermittent porphyria and some of the other genetically determined disorders of porphyrin metabolism (e.g., variegate porphyria and hereditary coproporphyria) have recurrent attacks of severe abdominal pain. Presumably these attacks are related to autonomic and pe-

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ripheral neuropathy that, in addition to delirium, coma, and seizures, may be precipitated by several drugs, including antiepileptic drugs, sulfonamides, griseofulvin, barbiturates, and other sedative hypnotic agents. Malignant hyperthermia is an inherited disorder precipitated by the administration of halothane, isoflurane, and muscle relaxants such as succinylcholine, decamethonium, gallamine, and D-tubocurarine [Nelson and Flewellen, 1983]. The clinical syndrome is characterized by the rapid development of tachycardia, cardiac dysrhythmias, muscle fasciculations, muscular rigidity, and high fever after agent administration. Myoglobinuria, elevation of blood creatine kinase and potassium levels, and severe metabolic acidosis are prominent laboratory findings. Complications include swelling, pain, necrosis of skeletal muscle, renal failure, disseminated intravascular coagulation, and encephalopathy. Pretreatment with dantrolene is effective in preventing the clinical syndrome. The prophylactic oral dose in children is 4 to 8 mg/kg per day divided into four doses for 1 to 2 days preceding anesthetic administration; the time between the last dose and induction of anesthesia should be 3 to 4 hours for oral dosing and 75 minutes for intravenous administration, the latter at a dose of 2.5 mg/kg [Leikin and Paloucek, 1995]. Emergency administration of dantrolene, discontinuation of the inciting drug, and vigorous supportive care are effective treatment measures for individuals who appear to be developing the clinical disorder. Other potentially at-risk individuals include children with central core disease, those with muscular dystrophies such as Duchenne’s muscular dystrophy, and a group of children with a unique constellation of unusual physical features resembling those seen in Noonan’s syndrome, including short stature, thoracic kyphosis, lumbar lordosis, hypoplastic mandible, low-set ears, webbed neck, down-slanting palpebral fissures, and cryptorchidism [King and Denborough, 1973; Online Mendelian Inheritance in Man, 1997]. The halothanecaffeine contracture test on muscle biopsy tissue is the most specific test for laboratory confirmation of the disorder; however, it is not always diagnostic in children younger than 5 years.

Drug Interactions The administration of one drug may alter the pharmacologic activity of another by changing the hepatic metabolism of the second drug or by interfering with its protein binding or renal clearance. For example, addition of felbamate alters the metabolism of phenytoin, carbamazepine, and valproic acid and usually requires reduction in their doses by as much as one third. Other such antiepileptic drug interactions are discussed in Chapter 49. Likewise, concurrent administration of erythromycin in patients taking cimetidine or carbamazepine produces CNS toxicity with confusion, slurred speech, delirium, hallucinations, and coma despite doses of cimetidine that are not usually intoxicating [Caroff and Mann, 1993].

Developmental Immaturity Sulfisoxazole (Gantrisin) was implicated in the pathogenesis of kernicterus in preterm infants [Silverman et al., 1956]. This finding remains one of the clearest examples of iatro-

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genic neurologic disease related to the adverse effect of a drug and an immature hepatic enzyme system. The sulfonamide given to these infants competed with bilirubin for albumin binding sites, displacing the bilirubin and allowing free unconjugated bilirubin to diffuse into the brain with subsequent kernicterus. Salicylates, caffeine, sodium benzoate, and oxacillin may similarly displace bilirubin from albumin with increased risk for kernicterus. Another similar form of drug-induced neonatal jaundice and kernicterus was related to the administration of large doses of two synthetic, water-soluble vitamin K analogs (e.g., menadione sodium diphosphate, menadione sodium bisulfate) for the prevention of hemorrhagic disease in the newborn [Lucey and Dolan, 1959]. A variety of analgesic drugs administered to the mother may affect the newborn, causing significant degree of sedation, hypotonia, poor suck, and decreased Moro response. In addition, tranquilizing agents, such as phenothiazines administered during labor to reduce the requirement of maternal analgesic medications, may produce lethargy. Neonatal withdrawal syndromes have been related to chronic maternal use of various sedative-hypnotics, barbiturates, and opiates, including heroin, morphine, hydromorphone, methadone, codeine, pentazocine, propoxyphene (Darvon), ethchlorvynol (Placidyl), hydroxyzine hydrochloride (Atarax), and desmethylimipramine [TERIS, 2005; Webster, 1973]. In the case of heroin-using mothers, 40% to 80% of at-risk infants display withdrawal or abstinence syndromes. These are manifested by irritability, hypertonicity, vomiting, diarrhea, sneezing, poor suck, shrill cry, jitteriness, tremors, and, rarely, seizures [Alroomi, 1988; Lam et al., 1992; Zuckerman et al., 1995]. Onset is most often 24 hours to 7 days postpartum (depending on the narcotic used) and appears to be less evident in preterm infants. The latter observation may be attributed to either decreased fat stores or receptor immaturity in preterm infants [Zuckerman et al., 1995]. The syndrome usually lasts about 3 weeks but may be more prolonged. The treatment of choice is paregoric, using one of a number of titration schedules; alternatively, phenobarbital may be used. Duration of treatment is individualized, but 10 to 30 days’ duration is common [Kendall, 1995]. Magnesium sulfate used for the treatment of toxemia may produce neonatal respiratory depression, lethargy, diminished tone, and absent reflexes. Such infants usually have significant elevation of magnesium above the upper normal level of 2.9 mg/dL; the severity of the neurologic disorder correlates well with the serum magnesium level. Chronic use of tranquilizers and psychotropic agents during pregnancy may have adverse effects on the fetus and newborn. An association between neuroleptic use and neonatal behavioral abnormalities has been noted, often after large maternal doses [Hammond and Toseland, 1970; Levy and Wisniewski, 1974; Tamer et al., 1969; TERIS, 2005]. The abnormalities closely resemble the extrapyramidal signs seen in patients taking these agents, with prominent rigidity, hypertonia, and tremor. The symptoms resolve gradually but may persist for months. This association has been reported for chlorpromazine, haloperidol, and perphenazine, among others [Handal et al., 1995; Sexson and Barak, 1989]. Neonates born to mothers treated during pregnancy with the antidepressant clomipramine may develop significant

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lethargy, hypotonia, and respiratory irregularity, which only gradually subside within the first weeks of life [Ostergaard and Pedersen, 1982]. There is mounting evidence that maternal selective serotonin re-uptake inhibitor use during pregnancy may result in a withdrawal syndrome in neonates [Lanz et al, 2005]. This syndrome has been reported with paroxetine and may relate to the pharmacokinetics of the various selective serotonin reuptake inhibitor agents. The clinical picture is one of an encephalopathy, with jitteriness and hyperreflexia starting within the first day of life. Infants are described as hypotonic, but tone may be variable. Seizures and respiratory distress may occur, requiring aggressive intervention. Neonates suspected of selective serotonin re-uptake inhibitor withdrawal should be monitored in a neonatal intensive care unit. Although the symptoms usually resolve over several days, they can last up to a month [Herbst and Gortner, 2003]. Among the risk factors associated with the development of intraventricular hemorrhage is the maternal use of aspirin. The incidence of intraventricular hemorrhage appears significantly higher in preterm infants exposed to aspirin compared with those not exposed [Rumack et al., 1981]. Coagulation defects have been noted in infants born to mothers who had received antiepileptic medications. Intracranial, abdominal, or thoracic hemorrhage may occur, and these infants should be carefully monitored. Although vitamin K administration reverses the clotting abnormalities, critical reappraisal of data in maternal-fetal pairs receiving enzyme-inducing antiepileptic drugs has suggested that the actual number of infants at risk for serious bleeding is smaller than previously suggested [Hey, 1999; Kaaja et al., 2002; Montouris et al., 1979]. Finally, many additional substances find their way into the neonate through breast milk. Assessment of risk is inexact. A rough estimate of level of exposure may be obtained by consideration of the milk-to-plasma ratio of the possible toxin, metabolic alteration of the drug by maternal organs (including the breast), correlation of feeding schedule and agent half-life, and pharmacokinetics of the agent in the infant [Bailey and Ito, 1997]. Although convincing studies are limited, a few agents have demonstrated toxicity when introduced through breast-feeding, although longterm sequelae of these exposures are unknown. The incidence of neonatal hypotonia correlated with polychlorinated biphenyl levels in the breast milk of the infants’ mothers [Huisman et al., 1995; Rogan et al., 1986, 1988]. Isolated cases of adverse effects on breast-fed newborns have also been reported with phenobarbital, primidone, carbamazepine, clemastine, and ergots. If the mother is still actively using cocaine postpartum, breast-feeding is contraindicated [Kendall, 1995]. In the absence of reassuring data, a recent review suggested avoidance of drugs of abuse, ethanol, antineoplastic agents, gold, iodine, and lithium [Bailey and Ito, 1997]. Although lead and mercury are both found in breast milk, the prevailing concentrations are much lower than for maternal blood. They probably pose little risk to the breastfed infant [Dorea, 2004].

Underlying Disease The pharmacokinetics of a drug may be altered by a child’s underlying disease. Impaired renal clearance increases the

ototoxic potential of kanamycin, gentamicin, and colistin and the peripheral neurotoxicity of nitrofurantoin (Macrodantin) and related drugs. Similarly, lactam antibioticinduced myoclonus and generalized tonic-clonic seizures occur more frequently in renal patients and in those who are neurologically abnormal [Asensi et al., 1993; Grondahl and Langmoen, 1993; Keskin and Konkol, 1993]. Severe chronic constipation with functional megacolon or congenital aganglionic megacolon increases the likelihood of water intoxication as a complication of enemas with tap water or hypotonic solutions. Functional megacolon is a recognized complication in psychiatric and neurologic patients, although its causes in this population are heterogeneous [Fehlow et al., 1995]. Patients with colon dilation, associated with severe chronic constipation, have an increased absorptive surface and decreased peristaltic function and thus absorb large amounts of hypotonic fluids after administration of these enemas [Ziskin and Gellis, 1958]. Patients may develop headache, vomiting, decreased awareness, coma, and convulsions. After the administration of hypertonic enemas, especially those containing large amounts of sodium phosphate and biphosphate, patients with megacolon may develop tetany, coma, and convulsions from hypernatremia, hyperphosphatemia, and severe hypocalcemia. Use of hypertonic contrast media may increase the risk for stroke in patients with sickle cell disease because of increased sickling [Zagoria, 1994]. Alternate strategies, such as use of low-osmolality contrast agents or substitution of MRI or magnetic resonance angiography where appropriate, may be considered [Allison et al., 1994; Hunter et al., 1994].

Neuroteratology A variety of adverse effects on the fetus may occur as a result of administration of drugs during pregnancy. The effects of these drugs depend on the timing of administration; the dose, distribution, and metabolism in maternal tissues; placental transfer; and subsequent concentration and distribution of the drug in fetal tissues. Brain development, including phases of neuronal proliferation and migration, arborization and synaptogenesis, and myelination, represents a long period of developmental vulnerability [Rodier, 2004]. Assessment of neuroteratogenic effects of a given agent is difficult. Teratogenic risk is frequently underestimated or overestimated. Improved methods of ascertainment are being developed, including mathematic models and models derived from animal studies [Leroux et al., 1996; Slikker, 1994; Zhang et al., 1995]. Sparse data and confounding factors limit conclusive recommendations. Discussion is limited to agents in which a neuroteratogenic effect seems likely based on human data or in which animal data reflect a likely human scenario (i.e., in the case of some antineoplastic agents). Omitted here is discussion of agents in which massive animal exposures to agents are associated with teratogenicity but for which there are no supporting human data, as well as agents described as possible behavioral teratogens without either strong statistical support or corresponding structural anomalies (Table 87–2). Fetal ethanol exposure is the most common preventable chemical cause of mental retardation in the United States.

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TABLE 87-2 Selected Human Neuroteratogens DRUG/TOXIN

EFFECT ON NERVOUS SYSTEM

REFERENCE

Aminoglycoside antibiotics Antiepileptic drugs: oxazolidinediones (trimethadione), phenytoin, valproic acid, carbamazepine

Cranial nerve VIII damage (10%–15%) CNS malformations, mental retardation, developmental delay, microcephaly, neural tube defect; spina bifida (1%-2%)

Cisplatin Chloroquine, hydroxychloroquine, quinine

Cranial nerve III Hydrocephalus, optic nerve hypoplasia, cranial nerve VIII damage (10%-15%) CNS hemorrhage, infarction Mental retardation, microcephaly, optic nerve hypoplasia, midline CNS malformations Mental retardation, developmental and behavioral disabilities, dyscoordination, microcephaly, CNS midline malformations and migrational errors Cranial malformations, mental retardation

Hanson, 1996; Warkany, 1979 Adams et al., 1990; Feldman et al., 1977; Gladstone et al., 1992; Hanson, 1986, 1996; Omtzigt et al., 1992; REPROTOX, 2005 REPROTOX, 2005 Dannenberg et al., 1983; Hanson, 1996; Nishimura and Tanimura, 1976 Heier et al., 1991; REPROTOX, 2005 Gulba, 1996; Hanson, 1996

Cocaine Coumarin anticoagulants Ethanol (dose related)

Folic acid antagonists (aminopterin, methotrexate) Hyperthermia Ionizing radiation (>200 Gy) Lead Maternal diabetes mellitus Organic mercury Solvents: gasoline, xylene, toluene (as substances of abuse) Retinoids, vitamin A Thiouracil, propylthiouracil (PTU), iodine-131 Undertreated maternal phenylketonuria Vinyl chloride

Neural tube defect, migrational errors, Möbius’ syndrome CNS malformation, microcephaly Learning disabilities Caudal regression, holoprosencephalyarhinencephalia CNS malformation, microcephaly Caudal regression malformation, CNS malformations, mental retardation Holoprosencephaly, neural tube defect, microcephaly, posterior fossa cysts, cranial nerve palsies (II, III, VII) Mental retardation (congenital hypothyroidism) Mental retardation (>90% in untreated mothers) CNS malformation

The 1985 Household Survey on Drug Abuse sponsored by the National Institute on Drug Abuse suggested that 60.9% of women of childbearing age (between 15 and 44 years of age; 34 million of the about 56 million women in this age group) were current (meaning within the past month) users of alcohol. By 1990, this figure was reduced to 50.8%, or about 30.5 million women [Adams et al., 1989; Khalsa and Gfroerer, 1991]. In a survey of 19,991 pregnant women, 0.8% to 3.1% reported “binge” drinking sometime during pregnancy, most before 6 weeks of gestation [Gladstone et al., 1997]. Alcohol consumed during pregnancy is associated with increased risk for fetal abnormalities. There is an estimated 6% risk that an alcoholic mother will have a child with fetal alcohol syndrome; the risk is 70% for subsequent offspring. This number compares with a risk of 1.9 per 1000 in the general population [Abel and Sokol, 1987]. Although most studies suggest that significant risk to the fetus occurs with maternal ethanol consumption of about two drinks a week or a few “weekend binges” during pregnancy, there is no defined “safe” threshold consumption value. Cardinal features of fetal alcohol syndrome are (1) prenatal and postnatal growth deficiency; (2) CNS anomalies, usually involving microcephaly and mental retardation, with irritability and restlessness in infants; and (3) craniofacial anomalies that

Hanson, 1996; Swayze et al., 1997

Hanson, 1996 Graham et al., 1988; Hanson, 1996; Layde et al., 1980 Hanson, 1996; Leikin and Paloucek, 1995 Dietrich et al., 1987; Hanson, 1996; Winneke, 1996 Barr et al., 1981; Hanson, 1996 Hanson, 1996; Leikin and Paloucek, 1995; Matusmoto et al., 1965 Hanson, 1996; Arnold et al., 1994; Pearson et al., 1994 Hanson, 1996 Cheron et al., 1981; Hanson, 1996 Hanson, 1996 Leikin and Paloucek, 1995

include short palpebral fissures, frontonasal alterations, midface hypoplasia with flat midface, thin upper lip, hypoplastic maxilla, and sometimes hypoplastic mandible [Jones, 1996; Swayze et al., 1997; TERIS, 2005]. Partial morphologic expression of alcohol effect is sometimes referred to as alcohol-related birth defects or fetal alcohol effects. Long-term follow-up suggests that patients with fetal alcohol syndrome continue to have growth retardation, craniofacial anomalies, and cognitive and behavioral problems in school. Children with fetal alcohol syndrome had lower weight, shorter length, and smaller head circumference at 3 years of age [Day et al., 1991]. Decrease in intelligence quotient at 4 and 7 years of age has been reported [Streissguth et al., 1989, 1990]. Antiepileptic medications are also teratogens. Although it is difficult to separate the effects of epilepsy and antiepileptic drugs in the production of fetal abnormalities, phenytoin administered to pregnant women is associated with a specific fetal malformation syndrome of facial and digital anomalies, growth deficiency, and mental deficiency [Hanson and Smith, 1975; Jones, 1996; Online Mendelian Inheritance in Man, 2005; Phelan et al., 1982]. Carbamazepine, trimethadione, and valproic acid are also teratogenic [Feldman et al., 1977; Jones, 1996; TERIS, 2005]. Neural

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tube defects occur in about 1% to 2% of valproate- or carbamazepine-exposed fetuses [Jones, 1996]. There may also be more subtle effects of valproic acid [Koch et al., 1996]. Maternal folic acid supplementation may reduce the risk for antiepileptic drug–associated neural tube defects. Isotretinoin (Accutane), a vitamin A analog used to treat acne, is a recently identified teratogen. It produces a characteristic pattern of malformation involving craniofacial, cardiac, thymic, and CNS structures. The CNS malformations include hydrocephalus, posterior fossa defects, and focal cortical abnormalities. The syndrome is thought to relate to isotretinoin’s ability to interfere with neural crest cell development [Coberly et al., 1996; Hanson, 1996; Lammer et al., 1985]. Although the evidence is strongest for the agents listed in Table 87-2, suggestive animal or human data support the teratogenicity of other substances. These substances include antineoplastic medications, including azacitidine, carmustine, and etoposide [Rosen et al., 1990; Takahashi et al., 1986; Thompson et al., 1974]; polychlorinated biphenyls [Huisman et al., 1995; Jacobson and Jacobson, 1997; Winneke et al., 2002]; and less conclusively, manganese (in manganese-based contrast agents), ribavirin, and combinations of tobacco and caffeine [Misselwitz et al., 1995; Nehlig and Debry, 1994; TERIS, 2005]. Severe intrauterine methylmercury exposure may result in mental retardation, visual and hearing deficits, and a cerebral palsy–like picture. Stable low-level maternal exposure to mercury also appears to have neuropsychologic consequences at least into early school age [Grandjean et al., 2003; Mendola et al., 2002]. The U.S. National Research Council has concluded that 0.1 g/kg body weight per day probably is a safe level of methylmercury exposure for maternal-fetal pairs [Mahaffey, 2000]. Finally, prenatal exposure to cocaine may have both short- and long-term CNS sequelae. Although the existence of a consistent dysmorphic “syndrome” in cocaine-exposed neonates is debated, congenital urogenital malformations are linked more firmly to prenatal cocaine exposure [Zuckerman et al., 1995]. Infants and children may be exposed to cocaine through transplacental transfer, breast-milk ingestion, and passive inhalation [Bateman and Heagarty, 1989; Chasnoff et al., 1986; Shannon et al., 1989]. The potential public health impact of prenatal cocaine exposure is not trivial. In the 1985 Household Survey on Drug Abuse sponsored by the National Institute on Drug Abuse, 3.5% of women of childbearing age reported cocaine use in the preceding month [Khalsa and Gfroerer, 1991]. Although this figure had dropped to 0.5% by 1990, current data do not support this apparent trend. The percentage of pregnant women testing positive for cocaine metabolites in one innercity clinic in Atlanta was 5% of those who consented to testing [Khalsa and Gfroerer, 1991; Lindsay et al., 1997]. Another study from Toronto produced a self-reported rate of cocaine use among pregnant women of 1.1% in the control group (11% in an ethanol-binge group) [Gladstone et al., 1997]. Screening based on self-reporting (and possibly on urine testing) underestimates cocaine use [Kline et al., 1997]. Finally, neonatal and meconium cocaine testing yielded positive results in 0.25% to 0.6% in “lowprevalence” rural populations [Little et al., 1996; O’Connor et al., 1997]. Infants exposed to cocaine prenatally have intrauterine growth retardation and reduced head circumference [Little

and Snell, 1991; Little et al., 1996; Napiorkowski et al., 1996; Zuckerman et al., 1989]. Sharp waves and spikes may be seen in the neonatal electroencephalogram, and there is maturational delay in the brainstem auditory-evoked response in neonates exposed prenatally to cocaine [Doberczak et al., 1988; Salamy et al., 1990]. Maternal cocaine use has been associated with intracranial hemorrhage and antenatal or perinatal cerebral infarction [Chasnoff et al., 1986; Dusick et al., 1991]. Effects on neurobehavioral performance in 3-week-old infants after intrauterine cocaine exposure have also been reported recently [Tronick et al., 1996]. Infants are frequently irritable and tremulous with a high-pitched cry and sometimes hypertonia and hyperreflexia [Dempsey et al., 2000]. Poor feeding, abnormal sleep patterns, inappropriate response to stimulation, and difficulties with state regulation may also be present [Griffith et al., 1988; Madden et al., 1986]. Long-term follow-up data are limited, but there is a suggestion that cocaine-exposed children at 3 years of age are highly distractible with poorly developed verbal, language, and motor skills despite average test scores; microcephaly persists [Freier et al., 1991; Griffith et al., 1990; Zuckerman et al., 1995]. Two prospective studies addressed this issue further. One revealed dose-dependent abnormalities on standardized neonatal behavioral tests; the other demonstrated deficits in prenatally exposed children’s ability to attend to a computer vigilance task but revealed no effect on academic achievement or classroom behavior through age 6 years [Martin et al., 1996; Richardson et al., 1996].

CONCLUDING REMARKS AND ADDITIONAL SOURCES Fifty years ago, more than 400 children in the United States died each year as a result of poisoning. From a stack of index cards and other informal efforts grew our current system of regional and local poison control centers. The American Association of Poison Control Centers compiles Toxic Exposure Surveillance System data from regional centers in the United States. This effort, combined with educational efforts by the American Academy of Pediatrics and the National Association of Medical Examiners’ Pediatric Toxicology (PedTox) Registry and local poison control center public and professional education, has reduced pediatric poison-related deaths in this country to less than 50 children each year [Burda and Burda, 1997; Hanzilck, 1996]. Other nations have similar programs and results. New information concerning poisoning and drug effects on the nervous system appears rapidly. Because no text chapter can incorporate this burgeoning body of knowledge, the following section lists several other sources for current toxicology information. Internet URLs are current as of early 2005. The sites have links to other sites involving specific subtopics.

Internet Sites Poison Control Centers (United States) American Association of Poison Control Centers: http://www.aapcc.org/

Walsh and Garg / Poisoning and Drug-Induced Neurologic Diseases

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CHAPTER 88

Neurologic Disorders Associated with Cardiac Disease Cecil D. Hahn and Adré J. du Plessis

Congenital heart disease is recognized in approximately 0.5% to 1.25% of live births [Rosenthal, 1998]. Of approximately 40,000 infants born yearly in the United States with some form of congenital heart disease, about one half have critical congenital heart disease that will require surgical intervention in the first year of life [Benson, 1989; Castaneda et al., 1974; Castaneda et al., 1989]. It is therefore not surprising that children with congenital heart disease and its complications constitute one of the largest inpatient populations in most major pediatric centers. Neurologic injury is one of the most common extracardiac complications of congenital heart disease, and the morbidity of this injury tends to be prolonged. Consequently, the child neurologist is increasingly faced with diagnostic and management decisions for affected children. The predominant cause of acquired neurologic dysfunction in this population is mediated by cerebral hypoxiaischemia or reperfusion injury. This result occurs primarily because of the nervous system’s exquisite dependence on a consistent and responsive supply of oxygen and metabolic substrate. In children with congenital heart disease, cerebral hypoxia-ischemia or reperfusion injury may be mediated by global hypoperfusion (e.g., cardiac arrest) and focal vasoocclusive insults (e.g., cardiogenic stroke). The major advances in management of congenital heart disease in recent decades have changed the mechanisms and manifestations of hypoxic-ischemic brain injury in these infants. In earlier years, neurologic complications of congenital heart disease were related in large part to the effects of right-to-left shunting and chronic cyanosis [Berthrong and Sabiston, 1951; Cottrill and Kaplan, 1973; Martelle and Linde, 1961; Phornphutkul et al., 1973; Terplan, 1976; Tyler and Clark, 1957a, 1957b]. With the development in 1953 of cardiopulmonary bypass, the ability to provide extracorporeal circulatory support facilitated the development of open-heart surgery. However, for the ensuing 2 decades, the surgical options for complex lesions were limited by the small size of the infant’s heart and the constricted surgical field. Repeated palliative procedures were often necessary until growth of the infant allowed definitive procedures to be performed. During this delay of the final repair, infants remained exposed to cumulative brain injury from chronic hypoxia, polycythemia, and right-to-left shunts, as well as from the effects of repeated cardiopulmonary bypass and surgery [Newburger et al., 1984]. The next major advance in the surgical management of congenital heart disease occurred in the early 1970s with the development of low-flow cardiopulmonary bypass and deep hypothermic circulatory arrest. These techniques allowed the reduction of blood flow or complete circulatory arrest during critical phases of the operation, thereby clearing the

surgical field of blood and cannulas and exposing small and complex lesions for repair. A prerequisite for low-flow cardiopulmonary bypass and deep hypothermic circulatory arrest was the development of techniques such as deep hypothermia that effectively suppress cellular metabolism and oxygen requirements and “prepare” vital organs for the marked decrease in oxygen delivery. These developments have been pivotal in allowing definitive anatomic repair in ever-younger infants. As a result, neonatal heart repair has become commonplace in many major centers. These techniques are largely responsible for the dramatic increase in survival of infants with congenital heart disease, particularly those with lesions that are more complex. The impact of these advances on the incidence of neurologic morbidity in infants undergoing cardiac surgery unfortunately has not paralleled the decrease in mortality. Instead, these surgical advances have heightened concerns about the neurologic outcome of these children [Limperopoulos et al., 1999, 2000]. Although cardiac repair in the newborn has reduced exposure to earlier risk factors such as chronic hypoxia, there has been a paradoxical increase in other forms of neurologic morbidity. First, severe heart lesions may be associated with profound hemodynamic shock and acidosis in the newborn period. These previously lethal conditions have become amenable to early correction, and the long-term neurologic consequences of such early-life hemodynamic disturbances are beginning to emerge in survivors. Second, the techniques responsible for increasing survival (i.e., low-flow cardiopulmonary bypass and deep hypothermic circulatory arrest) have their own inherent risks for neurologic injury. Consequently, the striking increase in survival of infants with severe congenital heart disease has been accompanied by the emergence of a population in whom cardiac morbidity has been replaced by chronic, often lifelong, neurodevelopmental dysfunction. This chapter reviews the neurologic complications of cardiac surgical interventions and considers inherited and acquired conditions with combined neurologic and cardiac dysfunction unrelated to surgery.

NEUROLOGIC COMPLICATIONS OF CARDIAC SURGERY The advance of neonatal heart repair into the earliest days of the newborn period has had a significant impact on the neurologic complications in this population. First, the shorter period before cardiac correction has decreased the brain’s exposure to the deleterious effects of an uncorrected cardiovascular anatomy (e.g., chronic hypoxia). Second, the marked circulatory and metabolic changes intrinsic to many

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neonatal cardiac operations now occur more frequently in patients with a structurally and functionally immature cerebral vasculature. The increased vascular fragility and tenuous autoregulatory function of the immature brain have prompted increasing concern about hemorrhagic (e.g., germinal matrix– intraventricular hemorrhage) and ischemic (e.g., periventricular leukomalacia) injury occurring in the perioperative period of neonatal cardiac surgery. Children undergoing cardiac surgery are at risk for brain injury before, during, and after the operative procedure. The residual neurologic deficits are likely the cumulative result of insults sustained during these periods. Insults that occur during earlier phases may render the cerebral vasculature and parenchyma vulnerable to injury in subsequent phases. Despite this complex interplay of potential injurious mechanisms and the difficulty of delineating the precise role of insults in these different phases, this chapter considers the preoperative, intraoperative, and postoperative mechanisms separately.

Mechanisms of Neurologic Injury in Cardiac Surgical Patients

BOX 88-1 INTRAOPERATIVE DETERMINANTS OF GLOBAL CEREBRAL OXYGEN DELIVERY AND USE Factors That Decrease Cerebral Oxygen Use Hypothermia Drugs (e.g., barbiturates) After hypoxia or ischemia Factors That Decrease Cerebral Oxygen Supply Cerebral perfusion pressure decreases Deep hypothermic circulatory arrest or low-flow cardiopulmonary bypass Nonpulsatile perfusion Disturbed autoregulation Increased central venous pressure Oxygen-carrying capacity decreases Hemodilution Oxygen delivery decreases Increased oxyhemoglobin affinity (i.e., hypothermia and alkalosis)

Intraoperative Mechanisms The principal cause of perioperative neurologic dysfunction is hypoxic-ischemic or reperfusion injury. The ability to identify imminent hypoxia-ischemia in the individual patient has been limited by a lack of reliable techniques for the intraoperative measurement of cerebral blood flow and oxygenation. Near-infrared spectroscopy is a promising technique that has provided important insights in animal and human studies [du Plessis et al., 1995c; Sakamoto et al., 2001, 2004; Wardle et al., 1998]. The potential mechanisms for the development of hypoxic-ischemic or reperfusion injury are multiple and include global (Box 88-1) and focal insults (Box 88-2). In adults undergoing cardiac surgery, the predominant form of brain injury is embolic, resulting when atheromatous debris dislodged from the aorta enters the arteriosclerotic cerebrovascular bed. Conversely, in the young infant undergoing open-heart surgery, the cerebral hypoxicischemic or reperfusion insults are primarily mediated by global hypoperfusion. This notion is supported by the neuropathologic features at postmortem examination, which correspond in topography to other forms of global hypoxicischemic or reperfusion injury. Specifically, cortical laminar necrosis, periventricular leukomalacia, and parasagittal injury are seen; focal infarctions occur less commonly [Bozoky et al., 1984; Terplan, 1973, 1976]. The lesions are likely acquired for the most part during periods of low or absent blood flow required for open-heart surgery. A multitude of complex, dynamic, and interrelated phenomena simultaneously may affect cerebral oxygen delivery and demand (see Box 88-1) during the core cooling, low- or no-flow bypass, and rewarming phases of deep hypothermic cardiac surgery. The precise role and contribution of each of these phenomena in the ultimate neurologic outcome in individually affected infants are unclear. In essence, the anesthetist-perfusionist team assumes control of the complex autoregulatory systems that normally maintain the delicate balance between cerebral oxygen supply and use. Guidelines for this external regulation of cerebral oxygen supply and demand are based

BOX 88-2 POTENTIAL MECHANISMS FOR FOCAL INTRAOPERATIVE VASO-OCCLUSIVE INSULTS Embolic Insults From bypass circuit Synthetic debris Platelet emboli Air emboli From surgical field Fat emboli Air emboli Platelet emboli From venous system Systemic veins after deep hypothermic circulatory arrest Pulmonary veins after bypass Thrombotic Insults Arterial: possible inflammatory vascular changes Venous: increased central venous pressure on theoretical parameters of safety for techniques, such as duration of circulatory arrest and depth of hypothermia. There has been intense research into techniques that reduce the risk of intraoperative hypoxia-ischemia. Clinical trial data have provided important insights into strategies that optimize intraoperative cerebral oxygen delivery. A randomized clinical trial of deep hypothermic circulatory arrest versus low-flow bypass in 171 infants with transposition of the great arteries found that circulatory arrest was associated with higher perioperative morbidity [Newburger et al., 1993] and worse developmental outcome at ages 1, 4, and 8 years [Bellinger et al., 1997, 1999, 2003]. As a result, current bypass strategies favor the maintenance

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FIGURE 88-1. Aneurysmal dilatations (arrows) in the cerebral microvasculature after cardiopulmonary bypass. (From Moody D, Bell M, Challa VR, et al. Brain microemboli during cardiac surgery or aortography. Ann Neurol 1990;28:477-486. Copyright © 1990 Wiley-Liss, Inc., a Wiley Company. Reproduced with permission of John Wiley & Sons, Inc.)

of low blood flow during surgery, and they minimize circulatory arrest times. Another area of controversy has been the approach to acid-base management. Both the more alkalotic alpha-stat strategy and the more acidotic pH-stat strategy have theoretical advantages. The alpha-stat approach is based on the natural alkaline shift in tissue that accompanies hypothermia, and it is thought to optimize enzyme function at low temperatures. Conversely, the pH-stat technique uses the addition of carbon dioxide to counter this alkaline shift, and it is used to enhance tissue oxygen delivery. The more hypercarbic perfusate increases cerebral perfusion and increases oxygen release in tissues by countering the increased oxygen-hemoglobin affinity associated with hypothermia. A randomized clinical trial comparing these two pH management strategies found that infants managed by the pH-stat strategy had less perioperative morbidity and a shorter time to recovery of electrocortical activity [du Plessis et al., 1997]. In many centers, the pH-stat strategy has become the preferred method of acid-base management in infants undergoing cardiopulmonary bypass. Another area of investigation has been the management of hematocrit during infant cardiopulmonary bypass. Hemodilution is widely used in adult cardiopulmonary bypass to improve blood flow in the microcirculation. However, the benefits of improved perfusion are countered by the reduced oxygen-carrying capacity of blood. A randomized clinical trial of different hematocrit levels in infants undergoing hypothermic cardiopulmonary bypass found that hemodilution was associated with greater perioperative hemodynamic instability and worse psychomotor development at 1 year of age [Jonas et al., 2003]. Vaso-occlusive insults play a lesser role in intraoperative brain injury during infant cardiac surgery. Cardiopulmonary bypass and the surgical field may generate particulate (e.g., platelet, synthetic, fat) (Fig. 88-1) or gaseous (e.g., air)

emboli [Boyajian et al., 1993; Fish, 1988; Moody et al., 1990; Padayachee et al., 1987]. Young infants commonly develop a post-bypass systemic inflammatory syndrome [Kirklin et al., 1983; Westaby, 1987], with systemic vascular injury manifesting with marked edema. This syndrome is related to the relatively large blood volume required for priming bypass pumps and the prolonged exposure of this blood to artificial surfaces. The elevated levels of cytokines (i.e., interleukins-6, -8, and -10; tumor necrosis factor-α; and endothelin-1) measured in bypass blood may mediate vascular and cellular injury [Bando et al., 1998; Elliott, 1999; Elliott and Finn, 1993; Jansen et al., 1992; Journois et al., 1996; Kirklin et al., 1983; Millar et al., 1993; Steinberg et al., 1993]. Ultrafiltration of blood during or after cardiopulmonary bypass reduces cytokine levels and excess free plasma water [Gaynor, 2003]. Ultrafiltration has been associated with improved postoperative hemodynamics [Bando et al., 1998] and improved myocardial function [Chaturvedi et al., 1999; Davies et al., 1998], but a significant long-term benefit has not been demonstrated. It is not known whether the beneficial effects of ultrafiltration result primarily from a reduction in postoperative cytokine levels or from hemoconcentration. The possible contribution of this systemic inflammatory response to intraoperative brain injury has received limited attention, and its importance remains uncertain.

Perioperative Mechanisms In the preoperative and early postoperative periods, circulatory and oxygenation derangements may be severe. A detailed understanding of this complex cerebrovascular pathophysiology is essential for effective prevention of perioperative brain injury in this population. Infants with complex heart lesions may present with shock, hypoxemia, and acidosis before surgery. After open-heart surgery, significant

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Cortical Gray Matter • Seizures • Coma

Stroke • Arterial • Venous

Deep Gray Matter • Dyskinesias

Spinal Cord • Transverse myelopathy • Anterior horn cell loss

FIGURE 88-2. Diagram of the neuraxis demonstrates the different levels at which neurologic injury may occur during the intraoperative and perioperative periods in children undergoing cardiac surgery.

Cerebral White Matter • Periventricular leukomalacia

Plexus • Brachial • Lumbar

Peripheral Nerve • Traction/pressure • Cold injury

Neuromuscular Junction • Prolonged blockade • “Critical illness”

Muscle • Necrotizing myopathy • Steroid myopathy

Preoperative Neurologic Complications cardiopulmonary dysfunction can complicate the early postoperative course. The brain’s vulnerability to this systemic hemodynamic instability may be further accentuated by postoperative disturbances in cerebral vasoregulation [du Plessis et al., 1995b; O’Hare et al., 1995; Rodriguez et al., 1995]. Perioperative and intraoperative injury to the nervous system may occur at any or multiple levels of the neuraxis (Fig. 88-2). However, the clinical diagnosis of neurologic dysfunction at the bedside of these critically ill infants may be complicated by the subtle manifestations of cerebrovascular injury and further obscured by the widespread use of sedating or paralyzing medications. These confounding factors have delayed the accurate diagnosis of perioperative brain dysfunction and limited the formulation of rational management strategies.

Neonatal Cerebrovascular Disease The leading cause of neurologic injury in the newborn infant is mediated by cerebrovascular disturbances. The most important factors predisposing to this form of brain injury are vascular immaturity (structural and functional) and systemic hemodynamic instability. In the premature infant, this cerebrovascular vulnerability manifests as hemorrhagic or ischemic injury (i.e., intraventricular-periventricular hemorrhage and periventricular leukomalacia). Compared with the newborn population overall, the prevalence of cerebrovascular injury is increased among infants with congenital heart disease [Glauser et al., 1990a; Leviton and Gilles, 1974]. This vulnerability is related to the intrinsic circulatory disturbances associated with congenital heart disease and the increasingly immature infants rescued by modern cardiac surgery.

Hahn and du Plessis / Neurologic Disorders Associated with Cardiac Disease

Congenital heart disease prolongs the risk period for this maturity-dependent injury. The incidence of antenatal cerebrovascular injury is increased [van Houten et al., 1996], and the risk extends into later gestation than for the overall population of newborn infants. In term infants with congenital heart disease, cranial ultrasound studies revealed a 59% incidence of cerebral abnormalities; the most common lesions were cerebral atrophy (41%), linear echodensities of the deep gray matter (20%), intraventricular hemorrhage (16%), and parenchymal echodensities (16%) [van Houten et al., 1996]. Brain lesions of antenatal origin are most common in coarctation of the aorta and ventricular septal defect. Term infants with these cardiac lesions occurring in combination had a 70% incidence of an abnormality at birth identified by cranial ultrasound [van Houten et al., 1996], possibly because of disturbed intrauterine cerebral perfusion because of limited flow through the preductal aorta. Cranial ultrasound studies performed preoperatively and postoperatively in a cohort of infants undergoing cardiac surgery identified a 24% incidence of new lesions after cardiac surgery, with new hemorrhagic lesions in 6% of cases [Krull et al., 1994]. Preoperative and postoperative magnetic resonance imaging (MRI) of 24 term newborns with congenital heart disease undergoing open-heart surgery confirmed the importance of preoperative and intraoperative contributions to neurologic injury. Preoperative elevations in brain lactate were seen in 53% of newborns by magnetic resonance (MR) spectroscopy. Periventricular leukomalacia was present in 16% of newborns before surgery and developed in another 48% of newborns after surgery. New postoperative infarctions were seen in 19%, and new intraparenchymal hemorrhages were seen in 33% of patients. Overall, new postoperative lesions or worsening of preoperative lesions occurred in 67% of patients [Mahle et al., 2002]. Another study using MRI and MR spectroscopy in 10 newborns with transposition of the great arteries revealed preoperative brain injury in 4, and age-adjusted levels of lactate were higher in the patients with heart disease compared with controls, confirming the larger study of Mahle [Miller et al., 2004].

Diagnosis of Preoperative Cerebrovascular Injury The accurate diagnosis of cerebrovascular lesions before cardiopulmonary bypass and cardiac surgery correlates with the potential for extending or consolidating reversible tissue injury during the procedure. The induced hemodynamic and coagulation changes required during open-heart surgery may extend hemorrhagic and ischemic lesions, as well as cause hemorrhagic transformation of a bland infarct. One MRI study comparing the preoperative and postoperative appearance of asymptomatic intracranial hemorrhage in neonates with congenital heart disease demonstrated increased hemorrhage in 43%, decreased hemorrhage in 26%, and no change in 30% of patients [Tavani et al., 2003]. Other than this study, the overall paucity of prospective data has hampered the formulation of guidelines for the diagnosis and management of preoperative hemorrhagic or ischemic brain lesions. Until such data become available, a reasonable approach is to obtain preoperative brain ultrasound scans for infants with birth weights less than 1500 grams, hemodynamic compromise sufficient to cause metabolic acidosis, neurologic dysfunction,

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coagulation disturbances, or certain cardiac lesions at particular risk, such as hypoplastic left heart syndrome, with its inherent hemodynamic instability [Glauser et al., 1990a], and coarctation of the aorta, with its increased prevalence of intracranial vascular malformations and hypertension [Volpe, 2001; Young et al., 1982]. Infants with focal neurologic deficits suggestive of stroke (e.g., preoperative focal seizures) are best evaluated by computed tomography (CT) or MRI if their medical conditions allow transport.

Management of Preoperative Cerebrovascular Injury Recent cerebrovascular injury in infants awaiting cardiac surgery presents a difficult management dilemma. The timing and management of cardiac surgery in children with acute cerebrovascular injury should aim to balance the risks of extending brain injury during cardiac surgery with the hemodynamic instability of uncorrected heart disease. These decisions are influenced by the severity of cardiac dysfunction, the nature of the brain lesion, and the anticipated complexity of the operation. Informed management guidelines are limited by the lack of prospective outcome data. The optimal timing of surgery in the newborn infant with intraventricular-periventricular hemorrhage presents a dilemma similar to that confronting clinicians using extracorporeal membrane oxygenation [Rudack et al., 1994; von Allmen et al., 1992]. Minor subependymal hemorrhages are at minimal risk for extension and should not delay surgery. Conversely, in infants with intraventricular or intraparenchymal vaso-occlusive stroke (with its tenuous penumbral region), cardiopulmonary bypass should be delayed for a week or longer, provided the cardiovascular status of the child remains stable. Hemorrhagic transformation is a concern, particularly after large, major arterial strokes, venous thrombosis, and infected emboli (discussed later). Prospective studies are needed to better define these issues.

Early Postoperative Neurologic Complications As many as 25% of children undergoing open-heart operations demonstrate neurologic dysfunction in the early postoperative period [Ferry, 1987, 1990; Newburger et al., 1993]. These early postoperative neurologic complications are often transient, and they were previously considered to be of little long-term consequence. However, some studies have demonstrated that these early complications may be associated with long-term adverse outcomes [Bellinger et al., 1995]. As the long-term significance of these early complications emerges, neurologists will be called on more frequently to evaluate and treat these conditions.

Delayed Recovery of Consciousness Excessive delay in the recovery of consciousness after cardiac surgery, anesthesia, and sedation is a frequent postoperative complication. The standard diagnostic guidelines [Plum and Posner, 1985] for the evaluation of altered mental status should be applied to these patients. The precise mechanism of this complication remains unclear in most patients. Ultimately, many of these infants demonstrate features compatible with cerebral hypoxic-ischemic or reperfusion injury. However, because intraoperative events specific

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for hypoxic-ischemic or reperfusion injury are often lacking, other potentially reversible causes should be excluded, including postoperative hepatic or renal impairment with accumulation of toxic metabolites and impaired metabolism or excretion of sedating drugs. Prolonged use of neuromuscular blocking agents for ventilatory management may be associated with delayed recovery of motor function [Gooch et al., 1991; Partridge et al., 1990; Waitling and Dasta, 1994], and in severe cases, the situation may mimic impaired consciousness. Neuromuscular blockade may be excluded with a bedside peripheral nerve stimulator or with nerve conduction studies. A significant minority of infants develops postoperative seizures, which may recur serially and are often clinically silent [Newburger et al., 1993]. In the absence of other causes for persistent loss of consciousness, such occult seizures or a prolonged postictal state should be considered.

Seizures Seizures are among the most common manifestations of neurologic dysfunction after infant open-heart surgery. Past series have reported clinical seizures in up to 15% of infants in the early postoperative period [Ehyai et al., 1984; Miller et al., 1995; Newburger et al., 1993], whereas clinically silent, electrographic seizures were detected by continuous electroencephalographic (EEG) monitoring in up to 20% of infants [Helmers et al., 1997]. Later studies from large pediatric cardiac surgery centers reported widely disparate postoperative seizure rates of 1.2% to 17.7% [Clancy et al., 2003; Menache et al., 2002]. Risk factors for postoperative seizures include the use of deep hypothermic cardiac arrest (rather than low-flow bypass), prolonged deep hypothermic circulatory arrest times, presence of a ventricular septal defect, and preexisting genetic conditions [Clancy et al., 2003; Helmers et al., 1997]. The recent decline in seizure incidence observed in some centers may be attributable to refinements in extracorporeal perfusion support, such as the minimization of circulatory arrest in favor of low-flow bypass and the adoption of a pH-stat strategy. Two forms of early postoperative seizures may be distinguished: seizures with a readily identifiable cause and seizures without an identified cause. The usual causes of seizures should be excluded, particularly reversible causes such as hypoglycemia and electrolyte disturbances. Cyclosporin toxicity is a common cause of seizures in heart transplant recipients [Menache et al., 2002].

EEG seizures

Epilepsy

Clinical seizures

Rare

24

48 72 Postoperative hours

96

FIGURE 88-3. Diagram of the circumscribed postoperative susceptibility period for electroencephalographic (EEG) and clinical seizures.

POSTPUMP SEIZURES In previous years, most postoperative seizures did not have a clearly identified cause. The frequency of these cryptogenic postoperative seizures, widely known as postpump seizures, appears to be decreasing. Postpump seizures tend to have certain characteristic clinical features, and they are confined almost exclusively to young infants. Conversely, postoperative seizures in older infants and children are usually associated with an identifiable cause. Postpump seizures often are assumed to reflect intraoperative hypoxicischemic or reperfusion injury; however, they differ from other hypoxic-ischemic or reperfusion (e.g., birth asphyxia) seizures in several ways. First, the onset of postpump seizures (including EEG seizures) is typically delayed until 24 to 48 hours postoperatively. This delay is significantly later than postasphyxial seizures, which often manifest within the first 12 hours after birth. Second, the long-term outcome after these seizures [Bellinger et al., 1995] is markedly better than the 50% incidence of adverse neurologic outcomes seen after postasphyxial seizures [Andre et al., 1990; Bergman et al., 1983; Volpe, 2001]. The temporal predilection for postpump seizures is relatively circumscribed to a window of several days (Fig. 88-3). During this period, seizures tend to recur, and status epilepticus commonly develops. After several days, the tendency for further seizures decreases rapidly. The clinical manifestations of postpump seizures may be subtle, especially in infants on sedating or paralyzing drugs. Behavioral changes may be confined to paroxysmal changes in autonomic function and pupillary size. Convulsive activity, when evident, is often focal or multifocal. Bedside electroencephalography helps distinguish true epileptic phenomena from other behavioral or autonomic changes [Mizrahi, 1987; Scher and Painter, 1990]. The ability of electroencephalography to detect clinically occult seizure activity helps guide therapy with antiepileptic drugs. Highly focal EEG abnormalities may reflect an underlying stroke, indicating the need for neuroimaging. The therapeutic approach to postpump seizures is best dictated by their typical clinical course. After reversible causes such as hypoglycemia, hypomagnesemia, and hypocalcemia [Lynch and Rust, 1994; Satur et al., 1993] have been excluded, antiepileptic therapy should commence. In view of the tendency toward repeated seizures and status epilepticus, the initial goal is rapid achievement of therapeutic antiepileptic levels by an intravenous route. Most postoperative seizures are controlled by standard antiepileptic drug regimens used in infants. Careful cardiorespiratory monitoring is essential when using potentially cardiotoxic antiepileptic drugs during the postoperative period, when myocardial dysfunction or dysrhythmias are prevalent. In infants with established myocardial dysfunction, cautious administration of phenobarbital is advisable, whereas preexistent conduction disturbances, particularly bradyarrhythmias, necessitate careful monitoring of phenytoin therapy [Cranford et al., 1978]. The apparently circumscribed window of susceptibility for these postpump seizures and the rarity of subsequent epilepsy allow successful early withdrawal of antiepileptic agents, often before hospital discharge.

Hahn and du Plessis / Neurologic Disorders Associated with Cardiac Disease

PROGNOSIS The prognosis for postoperative seizures depends on the underlying cause. Postpump seizures without an obvious cause were previously considered benign, transient events. However, a significant association between postoperative seizures and worse neurodevelopmental outcome and MRI abnormalities has been demonstrated in a large, prospective study [Bellinger et al., 1995; Rappaport et al., 1998]. Although epilepsy is a rare sequel to typical postpump seizures [Ehyai et al., 1984], the West syndrome has been described in occasional survivors of intractable postoperative seizures [du Plessis et al., 1994a]. The long-term outcome of infants with an identified cause for their postoperative seizures is related to the specific cause. The prevalence of developmental brain anomalies is increased in infants with congenital heart disease (discussed later). Seizures in infants with brain dysgenesis are associated with an almost universally poor long-term outcome, and epilepsy is a common complication. Stroke in young infants commonly manifests with seizures. The overall risk for subsequent epilepsy in these infants ranges from 20% to 30% [Lanska et al., 1991; Yang et al., 1995], and it is related to the age at stroke and the post-stroke latency to first seizure. Specifically, the risk for later epilepsy is lowest when stroke occurs in the newborn infant [Levy et al., 1985] and when seizures are an early manifestation of stroke [Yang et al., 1995]. These features should be considered when planning maintenance antiepileptic drug therapy.

Movement Disorders For almost 4 decades, movement disorders have been a dreaded complication of deep hypothermic cardiac surgery [Barrat-Boyes, 1990; Bergouignan et al., 1961; Bjork and Hultquist, 1962; Brunberg et al., 1974; Chaves and ScaltsasPersson, 1988; Curless et al., 1994; DeLeon et al., 1990; Donaldson et al., 1990; Huntley et al., 1993; Medlock et al., 1993; Robinson et al., 1988; Wical and Tomasi, 1990; Wong Latency period

Severity of dyskinesia

2–7 days

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et al., 1992]. Choreoathetosis is the most frequently reported dyskinesia after cardiac surgery, but a spectrum of movement disorders, including oculogyric crises [du Plessis et al., 1994b], akathisia, and parkinsonian syndromes [Straussberg et al., 1993] may be encountered. These dyskinesias are likely underdiagnosed and underreported, making the true incidence difficult to ascertain; however, in reported case series, the incidence of postoperative choreoathetosis has ranged from 0.5% [Wessel and du Plessis, 1995] to 19% [Brunberg et al., 1974]. Despite the relative infrequency of this complication, these postoperative movement disorders are often dramatic, frequently intractable, and ultimately debilitating. Severe forms are associated with substantial mortality. Postoperative choreoathetosis has a fairly stereotypic presentation and clinical course (Fig. 88-4). The involuntary movements are preceded in most cases by a latent period of 2 to 7 days, during which neurologic recovery from surgery is unremarkable. The dyskinesia is almost invariably heralded by subacute changes in mental status, including often severe insomnia and irritability. These mental status changes are soon followed by “restlessness” progressing to frankly abnormal involuntary movements. The dyskinesia usually commences in the distal extremities and orofacial muscles and progresses proximally to involve the girdle muscles and trunk. In severe cases, violent ballismic thrashing may develop. The dyskinesia is present during wakefulness, becomes more noticeable during distress, and resolves during the brief and fitful periods of sleep. An oromotor apraxia may become prominent, disrupting oral feeding and expressive language. Parents and caretakers often develop concerns about “blindness” in these infants, because they appear not to look at or show signs of recognizing familiar faces. This problem rarely is caused by blindness and instead results from a supranuclear ophthalmoplegia or oculomotor apraxia, with loss of voluntary gaze. Reflex extraocular movements and optokinetic nystagmus remain spared. Over the course of days to a week, the involuntary movements intensify and then plateau over 1 to 2 weeks. This period is

Deterioration period

Plateau period

Recovery period

3–7 days

Days–weeks

Severe 6 months–2 years Die

Delirium Insomnia Apraxia eyes mouth Usual postoperative recovery

Persistent unchanging dyskinesia

Dyskinesia distal to proximal

Abnormal (90%)

Mild days–6 months No dyskinesia ? normal Time

FIGURE 88-4. Diagram of the time course and evolution of postoperative dyskinesia.

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followed by a recovery phase that is more variable in duration, depending on the severity of the initial dyskinetic syndrome. Most cases of mild dyskinesia tend to resolve completely within days to weeks; by 6 months, none of these children exhibits involuntary movements. The quality of their voluntary movements and cognitive abilities has not been studied in detail. In survivors of severe postoperative dyskinesia, the involuntary movements may gradually improve for up to 2 years, after which the chances for further meaningful recovery are unlikely. Diagnosis of these postoperative hyperkinetic syndromes is essentially clinical. Adjunctive neurodiagnostic techniques have been useful only insofar as they exclude other disorders. Neuroimaging studies, including CT and MRI, have indicated nonspecific and nonfocal changes, the most common picture being one of diffuse cerebral atrophy [Medlock et al., 1993; Robinson et al., 1988; Wong et al., 1992]. Single-photon emission computed tomography (SPECT) functional brain imaging studies have found a high incidence of cortical and subcortical perfusion defects, even in the absence of structural defects detected using CT or MRI [du Plessis et al., 1994b]. The EEG pattern is usually normal or demonstrates diffuse slowing. The involuntary movements are not associated with ictal changes. Postmortem examination studies in these patients are limited and the inconsistent neuropathologic changes have not elucidated the mechanisms of injury [Chaves and ScaltsasPersson, 1988; Kupsky et al., 1995]. The characteristic features of focal or global hypoxic-ischemic or reperfusion insults are typically absent. The basal ganglia do not exhibit infarction, and the topography of the selective neuronal loss and gliosis (i.e., in the external globus pallidus) is uncharacteristic of hypoxic-ischemic or reperfusion injury occurring at normothermia [Kupsky et al., 1995]. However, an animal model of deep hypothermic circulatory arrest [Johnston et al., 1995; Redmond et al., 1994] has suggested that when hypoxic-ischemic or reperfusion injury occurs at deep hypothermia, the topography and evolution of injury may be modified. In this model, selective neuronal necrosis is prominent in the globus pallidus. The prognosis of these conditions depends largely on their initial severity. Based on the severity and persistence of the dyskinesias, two forms of postpump choreoathetosis may be distinguished: a mild, transient form and a severe, persistent form [Wong et al., 1992]. In the mild, transient form, involuntary movements are confined to the distal extremities or face, and they tend to resolve over several weeks to months in virtually all cases [du Plessis et al., 2002]. However, a significant minority of these children has persistent disturbances in gait, fine motor function, and language. In contrast, children with severe postpump choreoathetosis invariably have a much less favorable course. Their involuntary movements persist long after the onset, and they have pervasive disturbances in behavior and cognition, frequently meeting the criteria for mental retardation [du Plessis et al., 2002]. These severe cases are associated with a mortality rate approaching 40% because of respiratory complications such as aspiration pneumonia, massive caloric consumption, and infection [Wong et al., 1992]. Dyskinesias have also been associated with the use of fentanyl and midazolam, widely used postoperative anal-

gesics and sedatives. These medication-associated forms of movement disorder have a good prognosis, with less prominent sensorium changes and mild involuntary movements that resolve over days to weeks [Bergman et al., 1991; Lane et al., 1991; Petzinger et al., 1995]. The effective management of postoperative dyskinesias, both preventive and symptomatic, remains a frustrating challenge. Prevention of these disorders is limited by the current lack of a discernible mechanism of injury. However, certain preventable risk factors have been identified in retrospective studies. Children at particular risk tend to be older than 9 months at the time of surgery, have cyanotic congenital heart disease with systemic-to-pulmonary collaterals from the head and neck and, during surgery, have shorter cooling periods before attenuation of intraoperative blood flow [Wong et al., 1992]. These guidelines have been incorporated into the surgical management protocol at Children’s Hospital, Boston. In patients with correction of heart lesions at earlier ages, close attention to systemic-topulmonary collaterals, more gradual cooling, and decreased use of deep hypothermic circulatory arrest have resulted in a marked decline in the incidence of postoperative dyskinesia [Wessel and du Plessis, 1995]. Acute and long-term management of these postoperative dyskinesias has remained frustrating. No agents reliably control the adventitious movements while preserving alertness. In the acute phase, essential management goals should be amelioration of the agitated delirium, protection of the airway, and anticipation of the skin breakdown and increased nutritional demands. General measures against the profound irritability should include a decrease in the level of external (e.g., noise, light) and internal (e.g., pain) stimuli. Sedation should be used judiciously, and it should aim to restore the fragmented sleep-wake cycle. During the acute phase, mild dyskinesias can be managed by sedating agents alone, such as benzodiazepines and chloral hydrate. Despite the generally refractory nature of severe movement disorders, a cautious trial with more specific antidyskinetic agents is a reasonable approach. If the child’s hemodynamic status is stable, a trial of haloperidol may be warranted. This agent should be started at low doses (0.025 mg/kg/day, given in divided doses three times daily) and gradually increased while monitoring closely for cardiodepressant effects of dopamine blockade. If sedation becomes evident without a clear decrease in involuntary movements or if myocardial depression develops, these agents should be replaced by more specific sedating agents, such as clonazepam. The often-prominent oromotor dyskinesia impairs feeding and predisposes to aspiration. Nasogastric or even gastrostomy tube feedings may be necessary to meet the high caloric demands of the constant involuntary movements. Equally exasperating has been the pursuit of long-term pharmacologic control of residual dyskinesias. A wide spectrum of medications effective against other forms of hyperkinetic movement disorders has been tried, including dopamine receptor antagonists (e.g., phenothiazines, butyrophenones), dopamine-depleting agents (e.g., reserpine, tetrabenazine), dopamine agonists (L-dopa), γ-aminobutyric acid agents (e.g., benzodiazepines, barbiturates, baclofen), and other agents, including valproic acid, carbamazepine, phenytoin, diphenhydramine, and chloral hydrate. The efficacy of these agents for movement control has been

Hahn and du Plessis / Neurologic Disorders Associated with Cardiac Disease

modest at best and often occurs at the expense of excessive sedation. The benefit-risk ratio of several of these agents is further compromised by their risks for cardiac dysfunction and the development of secondary dyskinesias (e.g., tardive dyskinesias).

Spinal Cord Injury Spinal cord injury is a rare complication of cardiac surgery in infants and children, and it is most commonly [Puntis and Green, 1985] seen after aortic coarctation repair, occurring in 0.4% [Brewer et al., 1972] to 1.5% [Lerberg et al., 1982; Pennington et al., 1979] of patients. During aortic surgery, spinal cord injury results from a watershed type of hypoxicischemic or reperfusion insult. In the spinal cord, end-zone or watershed territories of arterial supply are located transversely at the lower thoracic level and longitudinally between the supply territories of the anterior and posterior spinal arteries. Transverse ischemia at the thoracic level is the usual form of cord injury seen after coarctation repair. Clamping of the aorta distal to the subclavian arteries renders the distal cord vulnerable to ischemia for several reasons. First, perfusion to the distal cord depends on a highly variable, inconsistent collateral supply. Second, aortic cross-clamping may precipitate hypertension that increases cerebrospinal fluid pressure and further decreases perfusion pressure to the lower cord. Transverse cord ischemia manifests as postoperative paraplegia with pyramidal features, with or without a thoracolumbar sensory level and bladder and bowel dysfunction. The longitudinal cord syndrome is rare and is mediated by systemic hypotension, as occurs with birth asphyxia [Sladky and Rorke, 1986] or with cardiac defects [Rousseau et al., 1993]. Injury is maximal in the ventral gray matter columns, with selective anterior horn cell loss. Unlike the predominant pyramidal features of transverse cord ischemia, longitudinal cord injury causes a prominent lower motor neuron syndrome, with acute and long-term hypotonia and weakness with decreased or absent reflexes; posterior column sensory function is relatively spared. Some authorities have advocated intraoperative monitoring of spinal cord function during coarctation surgery by using somatosensory-evoked potentials [Guerit et al., 1997; Laschinger et al., 1983, 1988]. However, this technique evaluates posterolateral spinal pathways rather than the more vulnerable anterior horn cells, and consequently, it has not been universally adopted [Laschinger et al., 1988]. Strategies for the prevention of this complication have been investigated in experimental models and adults undergoing aortic aneurysm surgery [Coles et al., 1983; Colon et al., 1987; Lange et al., 1997; Laschinger et al., 1984, 1987; Nylander et al., 1982; Robertson et al., 1986]. In infants and children, the relatively low prevalence of aortic coarctation and the rare occurrence of intraoperative spinal injury have limited the design of prospective clinical trials for prevention.

Peripheral Neuromuscular Injury The often prolonged periods of immobility during and after cardiac procedures expose the peripheral nervous system to pressure and traction injuries. The child with congenital heart disease also is at risk for toxic metabolic injury to the peripheral nerve, neuromuscular junction, and muscle.

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PLEXOPATHIES Plexopathies, particularly brachial, can occur after cardiac procedures [Kent et al., 1994; Lederman et al., 1982]. The brachial plexus is vulnerable to traction injury during the intraoperative retraction of a sternal thoracotomy incision; this form of plexopathy is more common in older patients. Cardiac catheterization, particularly newer interventional techniques such as radiofrequency ablation of aberrant conduction pathways and the placement of devices to occlude septal defects, may require prolonged shoulder hyperabduction in the sedated patient. This treatment may result in traction injury, usually to the lower brachial plexus. The patient presents in the postcatheterization period with weakness in the wrist and finger extensors and the intrinsic muscles of the hand, occasionally associated with Horner’s syndrome. Because the lesion is usually neurapraxic, it usually improves over time [Dawson and Fischer, 1977]. Conversely, upper plexus lesions most commonly result from direct injury or extravasated blood associated with indwelling central venous catheters in the neck vessels. The clinical manifestation of such upper brachial plexus injuries depends on the precise level of injury but most commonly involves the abductors and external rotators of the shoulder. Prognosis for recovery from these direct traumatic lesions is more guarded. Catheterization by using the femoral vessels in the inguinal region may be complicated by a localized hematoma or false aneurysm formation. The compressive and inflammatory effects of extravasated blood may injure the lumbar plexus (with retroperitoneal hematomas) or the femoral nerve and its branches (with inguinal hematomas). Although these neuropathies may be acutely debilitating, recovery is usually complete [Kent et al., 1994].

MONONEUROPATHIES Pressure palsies may develop at a variety of dependent sites, most commonly the peroneal and ulnar nerves. Phrenic nerve injury is another relatively common complication of hypothermic cardiac surgery. This form of injury results in diaphragmatic paralysis and should be considered in the evaluation of any child with postoperative ventilator dependence. The precise mechanism of injury is often unclear, but it is thought to reflect direct cold injury from ice packed around the heart or inadvertent transection of the nerve as it courses alongside the heart [Dunne et al., 1991; Mok et al., 1991; Watanabe et al., 1987]. The diagnosis may be established by ultrasound or fluoroscopy of the diaphragm or by bedside phrenic nerve conduction and diaphragmatic electromyography [Bolton, 1993; Swenson and Rubenstein, 1992]. In most cases, the phrenic nerve palsies are transient and presumably neurapraxic in origin. Less commonly, phrenic palsies are permanent and require diaphragmatic plication or rarely require diaphragmatic pacing [WeeseMayer et al., 1992].

POLYNEUROPATHY AND MYOPATHY Several reports [Gooch et al., 1991; Waitling and Dasta, 1994] have described a prolonged neuromuscular syndrome emerging after withdrawal of nondepolarizing neuro-

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muscular blocking drugs. Agents such as vecuronium and pancuronium are commonly used to facilitate postthoracotomy ventilatory management. Patients with renal and hepatic failure appear to be at increased risk for developing this syndrome. Administration of acetylcholinesterase inhibitors may result in improved strength, but this effect is unpredictable and usually transient. The neuropathology of this syndrome is highly variable, ranging from an axonal motor neuropathy to myopathic changes [Danon and Carpenter, 1991; Subramony et al., 1991]. The neuropathy associated with neuromuscular blockers may be difficult to distinguish clinically from “critical illness polyneuropathy” [Sheth and Bolton, 1995]. This syndrome occurs in patients with sepsis and multiorgan failure, conditions that may complicate congenital heart disease and surgery. Prolonged neuromuscular blockade may be complicated by an often severe myopathy. The risk of this form of myopathic complication is increased when neuromuscular blocking agents and high-dose steroids are used together [Hirano et al., 1992]. This combination of drugs is often used after cardiac transplantation. Unlike the neuropathies described previously, muscle weakness associated with these myopathic syndromes is usually maximal in proximal muscles. Tendon reflexes are reduced or absent, and sensory function is preserved. Two forms of myopathy may complicate neuromuscular blockade: an acute necrotizing myopathy and an acute myosin-deficiency myopathy [Al-Lozi et al., 1994; Hirano et al., 1992]. These myopathies may be distinguished by electromyography, which demonstrates markedly increased spontaneous activity in the necrotizing variety that is not seen in the myosin-deficiency myopathy. Muscle biopsy indicates a severe myofiber necrosis or, in the latter condition, relative preservation of myofibers with deficiency of myosin relative to actin filaments.

Delayed Postoperative Neurologic Complications The delayed neurologic manifestations of cardiac surgery may be considered in two categories. First, there are the developmental and cognitive deficits that emerge later in children who have suffered transient acute postoperative neurologic complications such as seizures and choreoathetosis. For example, although epilepsy is a rare sequel to postpump seizures, these infants are at higher risk for longterm neurodevelopmental deficits [Bellinger et al., 1995]. The second category of delayed neurologic manifestations includes those that develop ab initio remote from surgical procedures. Two specific manifestations, stroke and headache, are the focus of this section.

operative, and early postoperative periods, most cardiogenic strokes occur remote from surgery. The overall annual incidence of childhood stroke ranges from 2.5 [Schoenberg et al., 1978] to 7.9 per 100,000 children [Giroud et al., 1995] each year. Congenital heart disease remains the leading known risk factor for stroke in childhood; it occurs in 25% to 30% of cases [Lanska et al., 1991; Riela and Roach, 1993; Schoenberg et al., 1978]. Risk factors for cardiogenic stroke in earlier years (e.g., polycythemia, right-to-left shunt) have decreased with the surgical correction of heart lesions in early infancy [Berthrong and Sabiston, 1951; Cottrill and Kaplan, 1973; Martelle and Linde, 1961; Phornphutkul et al., 1973; Terplan, 1976; Tyler and Clark, 1957a, 1957b]. Postmortem examination studies from earlier decades described cerebrovascular ischemic lesions in up to 20% of children with congenital heart disease [Berthrong and Sabiston, 1951; Terplan, 1976]. The prevalence of stroke in the modern era of cardiac surgery is unknown because of the lack of neuropathologic studies. In patients who survive cyanotic congenital heart disease into adulthood, the risk for stroke persists and likely increases. One study found a stroke incidence of 1 case per 100 patient-years for patients with cyanotic congenital heart disease who were older than 18 years [Ammash and Warnes, 1996]. Similar to earlier studies in children [Cottrill and Kaplan, 1973; Linderkamp et al., 1979], the strongest risk factor for stroke in this cyanotic population was microcytosis. The proposed mechanism is a procoagulant shift resulting from an increased blood viscosity caused by the microcytic erythrocytosis. The major physiologic and anatomic risk factors for stroke, including the three elements of Virchow’s triad (i.e., altered vascular surface, stasis [du Plessis et al., 1995a; Rosenthal et al., 1995a, 1995b], and hypercoagulability [Cromme-Dijkhuis et al., 1990; Komp and Sparrow, 1970; Linderkamp et al., 1979], commonly exist in children with

Cerebral vein thrombosis

Cerebral arterial embolus

Paradoxical embolus

Central venous hypertension

Stroke Stroke in the child with congenital heart disease is predominantly thromboembolic in origin. Less commonly, arteriopathic or stenotic lesions of the intracranial vasculature may be seen in patients with certain congenital heart lesions.

THROMBOEMBOLIC CARDIOGENIC STROKE Although thromboembolic stroke may complicate congenital heart disease at any time in the preoperative, intra-

Cardioembolic

Systemic vein thrombosis FIGURE 88-5. The three broad mechanisms of cardiogenic stroke: cardioembolic (i.e., intracardiac embolic source), paradoxical (i.e., systemic venous embolic source), and cerebral vein thrombosis.

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congenital heart disease. The presence of paradoxical vascular pathways between the systemic venous system and the cerebral arteries constitute a further major risk factor for cardiogenic stroke. In broad terms, cardiogenic stroke may be mediated by three mechanisms (Fig. 88-5). First, arterial emboli may emanate from an intracardiac embolic source (i.e., cardioembolic stroke). Second, emboli may arise from a systemic venous or right heart source and bypass the pulmonary circulation through a right-to-left shunt (i.e., paradoxical embolic stroke). Cerebral venous thrombosis may result from a combination of central venous hypertension, venous stasis, and polycythemia. In earlier postmortem examination reports, venous thrombosis was the most common form of cerebral vaso-occlusive lesion [Cottrill and Kaplan, 1973]. Although most strokes occur beyond the early postoperative period, certain features of open-heart surgery and the immediate postoperative period predispose patients to stroke and warrant brief review. During the intraoperative period, embolic and thrombotic mechanisms may predispose patients to cerebral vaso-occlusive disease. Particulate and gaseous emboli originating from the cardiopulmonary bypass apparatus or surgical field bypass the normal pulmonary filtration system during cardiopulmonary bypass and enter the systemic circulation directly [Boyajian et al., 1993; Moody et al., 1990; Padayachee et al., 1987; Solis et al., 1975]. Improvements in bypass circuits, particularly the replacement of bubble oxygenators by membrane oxygenators, have decreased the incidence of macroembolic injury [Nussmeier and McDermott, 1988]. The impact of these advances on the incidence of microvascular injury [Fish, 1988] is unclear. The often-marked inflammatory response triggered by the extensive and prolonged exposure between bypass blood and artificial surfaces [Kirklin et al.,

1983; Millar et al., 1993; Steinberg et al., 1993] is known to trigger complex cascades, including endothelial–leukocyte interactions [del Zoppo, 1994; Elliott and Finn, 1993; Feuerstein et al., 1994; Lucchesi, 1993]. The resulting microvascular dysfunction may predispose to intravascular thrombosis or thromboembolism, manifesting with vaso-occlusive brain injury. In the early postoperative period, several factors predispose to cardiogenic stroke. First, vascular stasis may result from localized areas of low flow within the heart [du Plessis et al., 1995a; Rosenthal et al., 1995a, 1995b] or global ventricular dysfunction. Prolonged postoperative immobility predisposes to systemic venous stasis and thrombosis. Transient pulmonary hypertension is common after cardiopulmonary bypass, elevating venous pressure and decreasing the rate of blood flow through the right heart chambers and central veins. Injury to native tissue or the presence of prosthetic tissue alters vascular surfaces in contact with the circulation. A number of these stroke risk factors may apply after the Fontan procedure, the most common final operation for congenital heart disease with a single-ventricle physiology [Day et al., 1995; Dobell et al., 1986; du Plessis et al., 1995a; Hutto et al., 1991; Mathews et al., 1986; Rosenthal et al., 1995a, 1995b]. In this procedure, venous blood returning to the right atrium is redirected to the pulmonary arterial system, bypassing the single ventricle, which then serves as the pump for systemic perfusion. Consequently, right atrial pressure is often elevated, slowing flow through this chamber and the central veins supplying it. The procoagulant effect of this slow venous flow is further enhanced by the use of a prosthetic “tunnel” or baffle within the atrium to redirect flow. These factors combine to predispose to thrombus formation within the right atrium and central veins. In

A

B

FIGURE 88-6. Recurrent strokes after a Fontan procedure for congenital heart disease with single-ventricle physiology with persistent or recurrent thrombus in the pulmonary artery stump. A, The echocardiogram shows a thrombus (arrow) in the proximal, blind-ending stump of the ligated main pulmonary artery. AAo, arch of aorta; LV, left ventricle; PV, pulmonary valve. B, Computed tomographic brain scan with contrast demonstrates a recurrent stroke (arrow) in the right middle cerebral artery distribution. This stroke occurred 14 months after an initial large, left-sided stroke despite therapeutic levels of anticoagulation. It was presumably caused by an embolus from the persistent or recurrent pulmonary artery thrombus in A.

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the fenestrated Fontan modification, a right-to-left interatrial defect is created in the baffle or tunnel. This fenestrated modification, which has markedly reduced the mortality of the Fontan operation, essentially connects the thrombogenic right atrium to the cerebral arterial supply. Another potential area of thrombus formation after the Fontan procedure results when the main pulmonary artery is ligated, leaving a blind-ending low flow stump. Thrombi in this location (Fig. 88-6A) are capable of generating emboli directly into the aorta and cerebral circulation (see Fig. 88-6B). Retrospective studies of patients after the Fontan procedure confirm the increased stroke risk, with a prevalence ranging from 2.6% [du Plessis et al., 1995a] to 8.8% [Day et al., 1995]. This risk for stroke after the Fontan operation persists for up to 3 [du Plessis et al., 1995a] to 15 years [Rosenthal et al., 1995b] after the procedure. Stroke therapies may be considered in broad terms as rescue or preventive strategies. Rescue strategies aim to limit the extent of stroke by salvaging injured but potentially viable brain. Rescue therapies include thrombolytic agents [del Zoppo et al., 1988; Mori et al., 1988] or agents directed at limiting the injurious biochemical cascades triggered by hypoxic-ischemic or reperfusion insults [Gerlach et al., 1995; Vannucci, 1990]. Because these rescue therapies are confined to experimental and adult trials, they are not discussed further here. Preventive therapies for stroke may be primary (i.e., treatment of high-risk patients to prevent a first stroke) or secondary (i.e., aimed at preventing stroke recurrence) [Anderson, 1991]. A universally accepted approach for the primary or secondary prevention of cardiogenic stroke in children is lacking. For the most part, the guidelines in current clinical practice are based on the adult stroke experience. However, many aspects of stroke prophylaxis in adults are still in dispute, and the mechanisms and long-term consequences of stroke differ markedly in children compared with adults. These issues emphasize the need for prospective therapeutic trials for the prevention of stroke in congenital heart disease. Widely accepted indications for primary stroke prophylaxis in congenital heart disease include children with prosthetic heart valves, dilated cardiomyopathy, or intracardiac thrombus identified by echocardiogram. Stroke prophylaxis should also be considered in patients with combined risk factors such as elevated right atrial pressure, intracardiac prosthetic material, right-to-left shunt, and prolonged bed rest. Because post-Fontan patients have a number of these risk factors, many centers use prophylactic antithrombotic agents after this operation. Although low-dose aspirin is most commonly used, the optimal agent and duration of treatment are unclear. Some patients with critical end-stage heart disease have been supported by mechanical circulatory support devices that serve as a bridge to heart transplantation. These devices may be extracorporeal membrane oxygenation or intracardiac devices used to augment ventricular function. The prolonged interface between circulating blood and prosthetic material predisposes the patient to thrombus formation and stroke. The theoretical risk of stroke in children on these support devices has not been studied in any detail; consequently, the optimal prophylactic anticoagulation strategy has not been established. Secondary stroke prevention with anticoagulant therapy is controversial, particularly in the early period after stroke

[Pessin et al., 1993]. The aim of secondary prophylaxis is to balance the risks of recurrent embolism and hemorrhagic transformation of a bland infarction. Unfortunately, the magnitude of these risks is unknown for childhood cardiogenic stroke. In adults with stroke after myocardial infarction, the risk of recurrent cerebral embolism is approximately 1% per day during the first 2 weeks [Anderson et al., 1992; Cerebral Embolism Study Group, 1984, 1987; Cerebral Embolism Task Force, 1989], whereas the risk for spontaneous hemorrhagic transformation of the infarct may be as high as 20% to 40% [Hart and Easton, 1986; Hart et al., 1995]. The risk of significant clinical deterioration is higher when hemorrhagic transformation occurs in the anticoagulated patient [Okada et al., 1989; Sherman et al., 1992]. Certain broad guidelines have emerged for the use of anticoagulation after acute stroke. Overall, 70% of strokes that ultimately undergo hemorrhagic transformation do so within the first 48 hours after the onset of cerebral infarction [Sherman et al., 1992]. Large infarcts are at greater risk for secondary hemorrhage, particularly when an entire cerebral lobe or more than 30% of a hemisphere are involved [Okada et al., 1989; Sherman et al., 1992; Yatsu et al., 1988]. Other risk factors for bleeding into stroke include uncontrolled systemic hypertension, stroke due to septic emboli (see Fig. 88-9), and cerebral venous thrombosis. The risk of hemorrhagic complications may be decreased by newer low-molecular-weight heparin preparations. Initial experience with these agents in children at risk for thrombosis is encouraging, but full evaluation awaits a randomized clinical trial [Massicotte et al., 1996]. Long-term administration of these agents through a subcutaneous catheter may facilitate home therapy for children at risk for stroke. Seizures are a common manifestation of childhood stroke, particularly in the young infant [Clancy et al., 1985; Lanska et al., 1991; Levy et al., 1985]. The combination of antiepileptic and antithrombotic therapies may result in important drug interactions. Phenobarbital and carbamazepine tend to decrease the anticoagulant effect of warfarin (Coumadin), necessitating higher warfarin doses, whereas phenytoin may increase or decrease this effect. The coagulation profile should be followed closely, particularly after discontinuation of antiepileptic agents, when excessive anticoagulation may occur.

ARTERIOPATHIC STROKE Various forms of progressive stenotic or occlusive vasculopathy involving the intracranial circulation have been reported in patients with congenital heart disease. Although these conditions are not usually related to cardiac surgery, they are discussed here because they should be included in the differential diagnosis of stroke in congenital heart disease. Several cardiac lesions have been associated with intracranial arteriopathy, and they may be grouped into two broad categories: conotruncal defects and obstructive lesions of the aorta or pulmonary arteries. In one report, five patients with congenital heart disease who developed repeated strokes and seizures had moyamoya disease [Lutterman et al., 1998]. This slowly obliterative angiopathy involves the supraclinoid internal carotid artery and the anterior and middle (more than the posterior) cerebral arteries. Moyamoya disease results from progressive intimal thickening and the develop-

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ment of extensive collateral vessels [Suzuki and Kodama, 1983]. This syndrome most commonly manifests with repeated transient ischemic attacks and seizures. Over months to years, affected children develop progressive motor deterioration, mental retardation, and epilepsy. Coarctation of the aorta has also been associated with other neurovascular lesions, such as aneurysms [Orsi et al., 1993] of the circle of Willis and spinal arteries [Ling and Bao, 1994], and arteriovenous malformations [LeBlanc et al., 1968; Shearer et al., 1970; Tomlinson et al., 1992; Young et al., 1982]. Children with aortic coarctation who develop hypertension may be particularly vulnerable to intracranial hemorrhage from these intracranial vascular defects. After coarctation repair, patients who develop stroke symptoms (particularly when referable to the posterior circulation) should be evaluated for a subclavian steal syndrome [Saalouke et al., 1978]. The vasculopathy originally described in Williams’ syndrome was confined to stenosis of the supravalvar aortic region. The arterial luminal narrowing is more widespread than previously recognized, with reports describing involvement of the carotid, vertebral, and intracranial arteries. There have been several reports of stroke in patients with Williams’ syndrome [Ardinger et al., 1994; Kaplan, 1995; Soper et al., 1995]. Histopathologically, this multifocal intracranial arteriopathy is characterized by medial fibroelastic dysplasia, hypertrophied smooth muscle cells, and disorganized elastin fibers. This angiopathy is thought to result from a deficiency of elastin in the vessel media, caused by deletion of the elastin gene [Ewart et al., 1993]. Two older patients (i.e., 18 and 22 years) with Williams’ syndrome have been described as having moyamoya disease [Kawai et al., 1993; Soper et al., 1995]. However, the histopathology of moyamoya disease [Graham, 1992] differs from that of Williams’ syndrome, exhibiting predominant fibrocellular thickening of the intima rather than the medial changes seen in Williams’ syndrome. The relationship between the various angiopathic syndromes

FIGURE 88-7. T1-weighted magnetic resonance imaging of the brain of a 3-week-old infant with transposition of the great arteries who developed postoperative seizures after an arterial switch operation. The scan shows cerebral dysgenesis in the form of agenesis of the corpus callosum (arrows) and a small cerebellar vermis.

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seen in patients with congenital heart disease needs further study.

Headache Intracranial mechanisms of headache are mediated by stimulation of nerve endings in the dura and blood vessels by processes as diverse as inflammation and tension or pressure. Because many of the physiologic changes capable of stimulating these structures (e.g., vasodilation, intracranial hypertension) occur in congenital heart disease, it is not surprising that headaches are a common complication of congenital heart disease. For example, decreased cerebral oxygen delivery and hypercarbia can cause vasodilation. Elevated cerebral venous pressure may cause headaches by venous distention and, if sustained, by causing communicating hydrocephalus due to impaired cerebrospinal fluid absorption [Rosman and Shands, 1978]. Headaches are particularly common in adolescent and adult survivors of earlier palliative procedures, in whom progressive pulmonary hypertension, central venous hypertension, and polycythemia develop over time. Certain surgical procedures (i.e., Fontan and Glenn operations) are prone to central venous hypertension and are commonly complicated by headaches. In patients with venous hypertension and polycythemia, the development of headaches may herald dural vein thrombosis. The intensity and frequency of headaches associated with progressive polycythemia tend to parallel the rising hematocrit and to respond to erythropheresis. Headache is the most common initial complaint in the often subtle clinical presentation of brain abscess [Aicardi, 1992b]. Consequently, a diagnosis of brain abscess must be excluded before the direct measurement of cerebrospinal fluid pressure when doing a lumbar puncture in congenital heart disease patients with papilledema. Sudden-onset, severe headaches should always raise concern about the

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possibility of subarachnoid hemorrhage, particularly in patients with infective endocarditis [Bohmfalk et al., 1978; Jones and Sieker, 1989] and in hypertensive patients with coarctation of the aorta [LeBlanc et al., 1968; Shearer et al., 1970; Tomlinson et al., 1992; Young et al., 1982].

NEUROLOGIC COMPLICATIONS UNRELATED TO CARDIAC SURGERY A substantial proportion of the neurologic morbidity complicating childhood heart disease is unrelated to the acute or chronic effects of cardiac surgery. The mechanisms and manifestations of neurologic dysfunction in these cases depend on the associated form of heart disease: structural congenital heart disease; inherited disease of the heart, brain, and muscle; and acquired heart disease. Considerable neurologic morbidity is associated with extracorporeal membrane oxygenation (ECMO).

INFECTIVE ENDOCARDITIS Neurologic injury complicates infective endocarditis in 20% to 40% of patients [Francioli, 1991; Saiman et al., 1993]. The neurologic manifestations of infective endocarditis are protean and include meningitis, brain abscess, seizures, and most commonly, cerebrovascular injury. Systemic embolization occurs in up to 50% of patients with infective endocarditis [Lutas et al., 1986; Pelletier and Petersdorf, 1977; Roy et al., 1976], with as many as 65% of embolic events targeting the brain, usually the middle cerebral artery territory [Pruitt et al., 1978]. Several factors have been identified that increase the risk for dissemination of septic emboli [Pruitt et al., 1978]: endocarditis caused by Staphylococcus aureus or Candida albicans; vegetations on the mitral (25%) more than the aortic (10%) valve (Fig. 88-8), particularly the anterior mitral leaflet; vegetations exceeding 10 mm; and the first 2 to 4 weeks after the initiation of antibiotic treatment. Cerebrovascular complications are the most common form of neurologic injury, and they are the most lethal

Structural Congenital Heart Disease The nonoperative neurologic complications of structural congenital heart disease may be developmental or have an infectious cause. Dysgenetic disorders often manifest in infancy, whereas infectious complications tend to occur later.

Cerebral Dysgenesis The prevalence of dysgenetic brain lesions is increased among children with congenital heart disease, ranging from 10% to 29% in postmortem examination studies [Glauser et al., 1990b; Jones, 1991; Miller and Vogel, 1999; Terplan, 1976]. Cerebral dysgenesis should be considered in any child with congenital heart disease and unexplained neurologic dysfunction (Fig. 88-7). The prevalence of dysgenetic brain lesions appears to be particularly increased among patients with certain cardiac lesions [Glauser et al., 1990b; Jones, 1991; Terplan, 1976]. For example, a range of cerebral dysgenesis, from microdysgenesis to gross malformations such as holoprosencephaly, has been described at postmortem examination in infants with the hypoplastic left heart syndrome [Glauser et al., 1990b]. Clinically, these dysgenetic lesions may manifest in the newborn period with seizures, alterations in level of consciousness, and abnormalities in motor tone. Conversely, the lesions may remain clinically occult until later infancy and childhood, when they manifest with developmental delay, epilepsy, and cerebral palsy. Diagnosis is best confirmed by MRI of the brain. The increasing availability and resolution of neuroimaging likely will delineate more clearly the association between congenital heart disease and brain dysgenesis.

A

Infectious and Parainfectious Complications Congenital heart disease is a known risk factor for infective endocarditis and brain abscess. Although earlier corrective surgery and modern antibiotic therapy have been associated with a marked decline in the incidence of these potentially devastating infectious complications, they continue to occur in children with congenital heart disease.

B FIGURE 88-8. The echocardiogram demonstrates the aortic valve during systole (A) and diastole (B). Vegetations on the valve leaflets are indicated by arrows. AAo, aortic arch; LV, left ventricle.

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B

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C

FIGURE 88-9. Cerebral hemorrhagic infarction in a 16-year-old boy with bacterial endocarditis. A, Echocardiogram of the aortic (AO) root demonstrates vegetations on the aortic valve leaflets (arrows). LA, left atrium. B, Computed tomography (CT) of the brain shows large area of hemorrhage in the right occipitoparietal region several days after the development of seizures. C, Follow-up CT of the brain 3 months later shows a large residual area of encephalomalacia in the right occipitoparietal region.

[Pruitt et al., 1978]. Cerebrovascular lesions are at particular risk for bleeding when mediated by infected emboli, whether into an infarct or through a mycotic aneurysm. For these reasons, anticoagulant therapy is contraindicated in children with infective endocarditis who develop neurologic symptoms [Pruitt et al., 1978].

CEREBRAL MYCOTIC ANEURYSMS Cerebral mycotic aneurysms are an infrequent but often lethal complication of infective endocarditis. Although mycotic aneurysms complicate only 1.2% to 5% of cases of infective endocarditis, the overall mortality of this lesion approaches 60% [Bohmfalk et al., 1978]. Two thirds of cerebral mycotic aneurysms occur at the more distal bifurcations, particularly the middle cerebral artery. The remaining aneurysms are more centrally located at the branches of the circle of Willis [Corr et al., 1995]. Angiographic studies have determined that multiple aneurysms are present in approximately 30% of patients [Corr et al., 1995]. The clinical presentation is highly variable, with features ranging from those of sudden catastrophic hemorrhage (Fig. 88-9), a mass lesion, or an embolic lesion. Presentation and outcome depend primarily on the location and integrity of the aneurysm. The mortality rate for patients with intact aneurysms is about 30%, and it increases to 90% if the aneurysm ruptures [Bohmfalk et al., 1978; Jones and Sieker, 1989]. Aneurysms that leak rather than rupture are associated with a sterile meningeal syndrome with elevations of spinal fluid protein and of red and white blood cell counts. Mycotic aneurysms should be excluded in all cases of infective endocarditis complicated by severe headaches, “sterile” meningitis, strokelike events, or cranial nerve abnormalities. The screening technique of choice is highresolution, contrast-enhanced CT, because it is capable of identifying the presence of cerebral hemorrhage and the location of mycotic aneurysms. The definitive diagnostic test remains four-vessel angiography. Current MR angio-

graphy techniques remain insensitive to aneurysms smaller than 5 mm [Huston et al., 1994]. Management of mycotic aneurysms is complex and includes medical and surgical approaches [D’Angelo et al., 1995; Elowiz et al., 1995; Utoh et al., 1995]. A 6-week course of antimicrobial therapy directed at the organism responsible for the underlying endocarditis should be completed. Hereafter, follow-up angiography is indicated to assess the response to treatment and to detect enlarging or new aneurysms [Corr et al., 1995]. Subsequent treatment is based on these angiographic findings. When angiograms are repeated after a full course of appropriate antimicrobial therapy, complete resolution of the aneurysms is seen in 33% to 50%, whereas 17% to 30% exhibit a decrease in size [Bingham, 1977; Corr et al., 1995]. In 17%, there is no change in size [Corr et al., 1995]; in 20%, the aneurysms enlarge [Bingham, 1977]. Despite a full course of treatment, new aneurysms may develop in up to 10% of cases [Bingham, 1977]. Up to 50% of patients have full clinical recovery of their neurologic deficits after a 6-week course of treatment [Corr et al., 1995]. Indications for surgical intervention remain controversial [Wilson et al., 1982] but include the presence of single or multiple aneurysms distal to the first middle cerebral artery bifurcation that persist, enlarge, or bleed despite appropriate antibiotic therapy [Corr et al., 1995; Scotti et al., 1996]. The usual surgical approach to these aneurysms is direct excision or clip application, but endovascular procedures [Scotti et al., 1996] have been used to manage selected, severe cases of deep or distal mycotic aneurysms.

BRAIN ABSCESS Brain abscess is a rare condition in childhood [Ghosh et al., 1988]. However, among children diagnosed with brain abscess, almost one half had congenital heart disease [Aebi et al., 1991]. In children with congenital heart disease, brain abscess is rare before the age of 2 years, with a peak

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incidence between 4 and 7 years of age [Kagawa et al., 1983]. The risk is highest in cyanotic congenital heart disease; earlier studies reported that brain abscess develops in 2% to 6% of patients [Shu-yuan, 1989]. The risk for brain abscess is highest in children with polycythemia and rightto-left shunts [Tyler and Clark, 1957a], particularly tetralogy of Fallot [Aebi et al., 1991]. The incidence, morbidity, and mortality rates of brain abscess in congenital heart disease are inversely correlated with circulating arterial oxygenation [Shu-yuan, 1989]. Infants with higher oxygen saturations are less likely to develop brain abscess and more likely to recover. During periods of systemic illness and dehydration, polycythemia may critically disturb cerebral microvascular perfusion, with subsequent localized areas of ischemia. A right-to-left shunt allows organisms to bypass the pulmonary filtration system and to gain direct access to the brain. In areas of necrosis, organisms breach the disrupted blood-brain barrier, passing into necrotic areas to form focal septic cerebritis that may evolve to frank cerebral abscess. The recent marked decrease in incidence of brain abscess among children with congenital heart disease likely results from a number of factors, including earlier corrective surgery, decreased exposure to polycythemia and hypoxia, and more aggressive rehydration. Clinical manifestations of brain abscess are determined by the degree of intracranial hypertension, focal neurologic injury, and sepsis. The location of the abscess influences the neurologic presentation. Seventy-five percent of brain abscesses are supratentorial. Posterior fossa abscesses are less common but more dangerous because they often remain clinically silent until the onset of rapid deterioration from

tonsillar herniation and brainstem compression (Fig. 88-10). Cerebral abscesses are multifocal in about 20% of patients. The manifestation of brain abscess is usually subtle, with the exception of seizures, and the course is slowly progressive. The most common presenting features are headache and vomiting [Aicardi, 1992a]. Up to 75% of patients are afebrile and have minimal peripheral leukocytosis. Diagnosis of brain abscess is best established by contrast-enhanced CT or MRI scan. On CT, brain abscess appears as an area of hypodensity with contrast ring enhancement. The lesion is often surrounded by marked cerebral edema. After brain imaging has excluded significant mass effect, cerebrospinal fluid should be obtained. Typically, results suggest elevated levels of protein but only mild leukocytosis (see Chapter 68). Optimal management of brain abscess remains controversial [Dodge and Pomeroy, 1992]. Surgery by direct resection or CT-guided aspiration is still considered the definitive first-line treatment in many centers. Advances in antibiotic therapy and neuroimaging surveillance have allowed a more conservative approach [Berg et al., 1978; Rosenblum et al., 1980]. This approach remains controversial, but it may prove effective in early cases of focal cerebritis without rapid progression. Whether combined with surgery or not, high-dose antibiotic therapy should be maintained for at least 6 weeks. Initial antimicrobial management should be directed at the most common causative organisms (i.e., mixed aerobic and anaerobic streptococci and staphylococci) [Ghosh et al., 1988]. Third-generation cephalosporins used in combination with anti-staphylococcal and anaerobic agents have largely superseded earlier antibiotic regimens. Subsequent

FIGURE 88-10. T1-weighted magnetic resonance imaging reveals multiple brain abscesses in the cerebellum and fourth ventricle of an infant with cyanotic congenital heart disease. A, Coronal view. B, Sagittal view.

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antibiotic treatment should be guided by microbial culture results. In immunosuppressed patients (e.g., after cardiac transplantation), other lower-virulence organisms, fungi (e.g., Aspergillus), and parasites (e.g., Toxoplasma) should be considered. Because the clinical presentation of brain abscess may closely resemble stroke in up to 30% of patients [Kurlan and Griggs, 1983], it has been suggested that children with cyanotic congenital heart disease and a strokelike presentation should be managed with antibiotic therapy until a brain abscess is excluded [Kurlan and Griggs, 1983]. Diagnostic and therapeutic advances have reduced the mortality of brain abscess from 40% [Kagawa et al., 1983] to 10% [Dodge and Pomeroy, 1992]. However, in survivors, the prevalence of neurologic sequelae has remained largely unchanged at about 35% to 45% [Aebi et al., 1991; Dodge and Pomeroy, 1992]. Epilepsy may develop, often years later, in up to 30% of survivors [Aebi et al., 1991].

Inherited Disorders of Heart, Muscle, and Nervous System Combined cardiac and neurologic dysfunction may develop in certain inherited disorders of metabolism and neuromuscular disorders. Certain chromosomal disorders may have prominent cardiac and nervous system malformations. This discussion is confined to the more common of these rare syndromes. Diagnostic and therapeutic approaches to these conditions are discussed in more detail elsewhere in this textbook.

Inborn Errors of Metabolism Cardiac dysfunction may be a prominent feature, and it is often the cause of death of patients with several inherited metabolic disorders [Lyon et al., 1996]. The inheritance of these conditions is usually recessive (autosomal, rarely X-linked) or mitochondrial. The cardiac dysfunction results from a hypertrophic or dilated cardiomyopathy resulting from myocardial infiltration or energy failure rather than from a primary structural lesion. The cardiac involvement in these conditions manifests clinically with myocardial failure, valvular insufficiency, dysrhythmias, or coronary insufficiency (in storage disorders) with myocardial ischemia. Neurologic manifestations may be due primarily to the underlying enzyme defect, or it may result from global or focal cerebral hypoperfusion caused by diminished cardiac output.

Disorders of Energy Production MITOCHONDRIAL FATTY ACID OXIDATION DEFECTS Conditions caused by mitochondrial fatty acid oxidation defects include a group of autosomal recessive disorders that may manifest with combined cardiac and neurologic dysfunction (see Chapters 23 and 28). These conditions manifest with several clinical syndromes, including recurrent metabolic crises, depressed mental status, and ataxia. Primary systemic carnitine deficiency results from a defect in carnitine transport, and it is the only disorder of carnitine

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metabolism with prominent cardiomyopathic features. Children with long-chain acyl-CoA dehydrogenase (LCAD) deficiency commonly develop a hypertrophic or dilated cardiomyopathy owing to myocardial fat deposition. Infants with the neonatal-onset form of multiple acyl-CoA dehydrogenase deficiency (glutaric aciduria type II) may present with dysmorphic features, a “sweaty feet” odor, and a severe, often catastrophic illness within the first days of life. Neuronal loss and gliosis lead to caudate and putaminal atrophy [Chow et al., 1989], with a prominent ataxic and dyskinetic syndrome. The cardiomyopathy in this condition is severe and usually lethal within weeks to months.

DISORDERS OF OXIDATIVE PHOSPHORYLATION Disorders of oxidative phosphorylation result from enzyme defects in pyruvate metabolism and the mitochondrial electron transport chain. Brain and muscle are the most commonly involved systems. Cardiac dysfunction may be prominent, with the presenting features related to the age at onset. In young infants, a rapidly progressive and usually fatal hypertrophic cardiomyopathy develops, whereas older patients with later-onset cardiac involvement are more likely to develop dysrhythmias and conduction defects [Guenthard et al., 1995]. Patients with certain respiratory chain enzyme defects, such as complex I (i.e., NADH CoQ reductase) [Rustin et al., 1994] and complex IV (i.e., cytochrome c oxidase) [Zeviani and Van Dyke, 1986] deficiencies (often in combination) [Nagai et al., 1993] are more prone to cardiac dysfunction. Complex III (i.e., reduced CoQ-cytochrome c reductase) deficiency may cause an isolated cardiomyopathy. Cytochrome c oxidase deficiency may manifest in the newborn or young infant as a severe, rapidly fatal condition or as a benign, reversible form. Initially, the benign form may be indistinguishable from the lethal form; the lactic acidemia may be more severe in the benign form [DiMauro et al., 1990]. Because infants with the benign form may recover fully with supportive management, an aggressive approach is warranted until the clinical distinction becomes evident. Kearns-Sayre syndrome usually is associated with complex I or IV deficiencies, and it causes retinal degeneration and chronic progressive external ophthalmoplegia. Cardiac involvement results in atrioventricular heart block, with syncopal spells or sudden death occurring between late childhood and adulthood.

Storage Disorders of the Heart and Nervous System GLYCOGEN STORAGE DISEASES Among the different forms of glycogen storage disease, combined cardiac and neurologic dysfunction is largely confined to the early-infantile form of type II glycogen storage disease caused by acid maltase (acid α-glucosidase) deficiency (see Chapter 25). Later-onset type II glycogen storage disease manifesting after age 2 years is not associated with cardiac dysfunction. Glycogen deposition in the earlyinfantile form causes macroglossia, a hypertrophic cardiomyopathy, and a rapidly progressive diffuse skeletal myopathy. In the nervous system, glycogen deposition is confined to the anterior horn cells of the spinal cord and brainstem [Martin et al., 1973], sparing cerebral cortical neurons.

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The progressive obstructive cardiomyopathy and respiratory weakness caused by myopathy and anterior horn cell involvement usually culminate in cardiorespiratory death before 1 year of age.

LYSOSOMAL STORAGE DISEASES Lysosomal storage diseases are slowly progressive conditions in which the clinical manifestations of hypertrophic or dilated cardiomyopathy are delayed until well after the typical features (e.g., coarse facial features, hepatomegaly, corneal clouding) and neurodegeneration are established. Patients with the mucopolysaccharidoses may develop myocardial thickening, valvular dysfunction, coronary insufficiency, and pulmonary hypertension. Refsum’s disease results from a deficiency of phytanic acid oxidase with abnormal storage of phytanic acid. Cardiac dysfunction is confined to a later-onset form of Refsum’s disease and manifests with atrioventricular conduction defects and bundle branch block, progressive cardiac failure, and sudden death. Cardiac complications tend to develop late, after the typical features of retinitis pigmentosa, peripheral polyneuropathy, cerebellar ataxia, and sensorineural deafness are established.

Inherited Neuromuscular Disorders with Cardiac Complications X-LINKED MUSCULAR DYSTROPHIES The dystrophinopathies of Duchenne and Becker may be complicated by a dilated cardiomyopathy that usually manifests years after the skeletal muscle syndrome becomes established. Severe and rapidly progressive cardiac deterioration may occur in Duchenne’s dystrophy because of papillary muscle dysfunction with subsequent valvular (particularly mitral) incompetence, cardiac (mainly atrial) dysrhythmias, and myocardial fibrosis. Another X-linked condition, Emery-Dreifuss muscular dystrophy, manifests with slowly progressive humeral-peroneal muscle weakness and wasting with prominent, early contractures. Cardiac dysfunction caused by atrial flutter, fibrillation, and permanent atrial inexcitability is a frequent cause of death that may be prevented by cardiac pacing.

MYOTONIC DYSTROPHY Myotonic dystrophy is an autosomal-dominant condition that involves multiple tissues, including skeletal, smooth, and cardiac muscle. Although myocardial dystrophy is usually mild in this condition, severe cardiac conduction defects may develop, causing dysrhythmias and heart block.

FRIEDREICH’S ATAXIA Friedreich’s ataxia is an autosomal recessive disorder caused by a GAA trinucleotide repeat expansion in the FXN gene encoding the protein frataxin, which is involved in mitochondrial iron metabolism [Durr et al., 1996]. The frataxin deficiency seen in Friedreich’s ataxia causes mitochondrial iron accumulation, resulting in toxic free radical generation and oxidative cellular injury. Years after their neurologic diagnosis is established, patients with Friedreich’s ataxia frequently develop a hypertrophic cardiomyopathy, which

may progress to a hypokinetic dilated cardiomyopathy, which carries a particularly poor prognosis. Pathologic Q waves on electrocardiography may identify patients who are more likely to develop the hypokinetic dilated cardiomyopathy [Casazza and Morpurgo, 1996]. Clinical trials of the free radical scavenger idebenone have demonstrated modest improvement in the cardiomyopathy but no improvement in neurologic function [Buyse et al., 2003; Mariotti et al., 2003].

Chromosomal Disorders Involving the Heart and Brain Combined structural cardiac defects and cerebral dysgenesis may be prominent in certain chromosomal disorders. Approximately 40% of children with trisomy 21 have congenital heart disease, typically endocardial cushion defects. The most common cardiac lesions in trisomies 13 and 18 are ventricular septal defects and patent ductus arteriosus. A spectrum of chromosome 22 deletion syndromes [Morrow et al., 1995] has been delineated. The phenotypic similarities have led to the acronym CATCH-22 spectrum (i.e., cardiac defect, abnormal facies, thymic hypoplasia, cleft palate, hypocalcemia, chromosome 22q11 deletions) [Demczuk et al., 1995; Driscoll, 1994; Lindsay et al., 1995; Morrow et al., 1995; Shprintzen et al., 1992]. This spectrum includes the DiGeorge syndrome and velocardiofacial (Shprintzen’s) syndrome, both of which may manifest initially with hypocalcemic seizures and subsequently manifest neurologic or cognitive disturbances [Moss et al., 1995]. A second genetic locus for DiGeorge syndrome and velocardiofacial syndrome (DGS2) has been identified on chromosome 10p [Bartsch et al., 2003; Daw et al., 1996]. The most common cardiac defects in DiGeorge syndrome are interrupted aortic arch type B, truncus arteriosus, and tetralogy of Fallot. Features typical of the velocardiofacial syndrome include cleft palate or velopharyngeal insufficiency and a typical facial appearance (Fig. 88-11), with a broad, prominent nose and retrognathia. Ventricular septal defects and tetralogy of Fallot are the most common structural defects in the velocardiofacial syndrome, and developmental brain lesions include a small posterior fossa and vermis and small cystic lesions adjacent to the frontal horns of the lateral ventricle. Developmental and learning disabilities are conspicuous features of the velocardiofacial syndrome. The mean IQ is 70, with a marked discrepancy between verbal and performance IQ [Moss et al., 1995]. Hearing and speech impairment is often striking. During childhood, a peculiar and inappropriately blunt affect emerges [Golding-Kushner et al., 1985], and adults with this syndrome appear at increased risk for psychotic illness [Pulver et al., 1994; Shprintzen et al., 1992]. The most common cardiac lesions seen in patients with Williams’ syndrome are supravalvar aortic stenosis, peripheral pulmonary stenosis, and ventricular or atrial septal defects. These patients are prone to neurologic dysfunction [Ardinger et al., 1994; Chapman et al., 1995; Kaplan, 1995; Soper et al., 1995] and usually have obvious cognitive impairment; the average IQ is approximately 55. This impairment is further compounded by learning and social disabilities. Gross motor, fine motor, and oromotor dysfunctions are common, as are visuospatial and constructional difficulties [Chapman et al., 1995]. Children with Williams’ syndrome may present with stroke because of an intracranial

Hahn and du Plessis / Neurologic Disorders Associated with Cardiac Disease

FIGURE 88-11. Facial features of a female with velocardiofacial syndrome include the typical elongated face and broad nasal bridge. (From Jones KL, ed. Smith’s recognizable patterns of human malformation, 4th ed. Philadelphia: WB Saunders, 1988:225.)

arteriopathy [Ardinger et al., 1994; Kaplan, 1995; Soper et al., 1995].

Acquired Heart Disease Acquired heart disease in children for the most part has an infectious or para-infectious origin. Among the more common forms of infectious cardiac disease associated with neurologic dysfunction are viral myocarditis and rheumatic carditis, both of which predispose patients to the generation of emboli and focal cerebral ischemia. In viral myocarditis, ventricular dilation and hypokinesia predispose to thrombus and embolus formation. In rheumatic carditis with valvular disease, bland emboli from vegetations and septic emboli from secondary infective endocarditis may compromise the cerebral circulation. Because these complications were discussed earlier, this section focuses on the other major neurologic complication of rheumatic fever: Sydenham’s chorea.

Rheumatic Heart Disease Sydenham’s chorea, the major neurologic complication of acute rheumatic fever [Special Writing Group, 1992], was in

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earlier years the most common form of acquired chorea in childhood [Eschel et al., 1993]. For several decades, there has been a global decline in the incidence of rheumatic fever and in the incidence of chorea as a complication of rheumatic fever [Eschel et al., 1993]. Possible reasons for this decline are an alteration in the virulence or epitopes of rheumatogenic streptococci and a decrease in antigen crossreactivity with the basal ganglia. However, outbreaks of rheumatic fever in the United States [Ayoub, 1992] and elsewhere [Karademir et al., 1994] have again focused attention on this condition. Chorea complicates rheumatic fever in only 10% to 25% of patients [Eschel et al., 1993]. Chorea may emerge 1 week to 8 months after the onset of rheumatic fever and then persist for 1 to 6 months [Eschel et al., 1993]. Sydenham’s chorea is rare in children younger than 3 years, and it occurs more commonly in females than in males. In some patients, chorea may be the only clinical manifestation of rheumatic fever. The onset of this disorder is often subtle, and the abnormal movements tend to be preceded by psychologicemotional symptoms such as anxiety, emotional lability, distractibility, the emergence or exacerbation of attentiondeficit–hyperactivity disorder, obsessive-compulsive symptoms, and sleep disturbances [Swedo, 1994; Swedo and Kiessling, 1994]. Occasionally, the onset of psychologicemotional prodrome and dyskinesia may be explosive. The motor activity that at first is described as “fidgety” soon becomes choreiform, evolving from initial brief, myocloniclike proximal muscle jerks to more complex and writhing distal movements. The handgrip often has a rippling character due to inconsistently sustained finger pressure (i.e., milkmaid’s grip). The chorea may be asymmetric, and in some cases, pure hemichorea develops. Muscle hypotonia and mild-to-moderate weakness are often present. Patients may have difficulty initiating and sustaining spontaneous motor activity. Speech and oral motor activity are often affected; an explosive dysarthria may develop, evolving in severe cases to complete mutism. These symptoms usually begin to subside after about 2 to 6 months, but they may recur in the setting of subsequent illnesses, particularly streptococcal infections, pregnancy (i.e., chorea gravidarum), or oral contraceptive use. The diagnosis of acute rheumatic fever is based on specific (Jones) criteria [Special Writing Group, 1992], which may be major or minor, depending on their diagnostic importance. A patient with two major criteria or with one major and two minor criteria has a high probability of having rheumatic fever. The major criteria are carditis, polyarthritis, chorea, erythema marginatum, and subcutaneous nodules. The minor criteria are based on clinical features (e.g., fever, arthralgia, previous rheumatic fever) or laboratory features (e.g., acute-phase reaction, elevated erythrocyte sedimentation rate, leukocytosis, C-reactive protein, prolonged PR interval on electrocardiogram). Additional laboratory findings, such as an elevated anti-streptolysin O titer or positive throat cultures for group A β-hemolytic streptococci, may be helpful. The diagnosis of chorea is purely clinical. Despite the causal relationship to streptococcal infection, the onset of chorea is often delayed. Consequently, serologic evidence of streptococcal disease may be absent in 25% of patients. Rheumatogenic strains of group A streptococci contain particular (M-type) proteins

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that share antigenic determinants with neurons in the basal ganglia, particularly in the caudate and subthalamic nuclei. Autoantibodies against these neurons (i.e., antineuronal antibodies) have been detected in up to 90% of patients in some studies [Swedo, 1994; Swedo et al., 1997]. Because this condition is seldom fatal, neuropathologic data are limited. However, neuronal loss with vascular and perivascular inflammatory changes has been described in the caudate, putamen, and frontoparietal cortex. The topography of these earlier neuropathologic findings has been supported by MRI [Giedd et al., 1995; Heye et al., 1993] and SPECT [Heye et al., 1993]. These techniques have also demonstrated disturbances in the blood-brain barrier with localized edema, presumably resulting from vasculitis [Heye et al., 1993]. Current management of the chorea includes dopamineblocking agents such as haloperidol, given as 0.5 to 1 mg twice daily for 2 to 6 months and then gradually withdrawn. Other agents used include carbamazepine and valproic acid [Aicardi, 1992b; Swedo et al., 1993]. These drugs often diminish the intensity of the chorea, but they fail to completely control it. In severe cases, prednisone has been used with limited success. Prophylaxis against group A streptococcal infections with penicillin or monthly intramuscular benzathine penicillin is recommended because even asymptomatic future infections may precipitate recurrence of chorea. The high incidence of antineuronal antibodies [Swedo, 1994; Swedo and Kiessling, 1994] and anticardiolipin antibodies [Diniz et al., 1994; Figueroa et al., 1992] in these patients has led to trials of plasmapheresis and intravenous immunoglobulin therapy; results from these studies are not yet available.

carotid) are ligated as part of the procedure. The right common carotid artery has been reconstructed after termination of extracorporeal membrane oxygenation.

Extracorporeal Membrane Oxygenation

Extracorporeal membrane oxygenation may injure the brain through multiple mechanisms that promote ischemic or hemorrhagic injury. Carotid ligation causes an immediate reduction in blood flow to the ipsilateral middle cerebral artery, which may be only partially restored by collateral flow from the anterior communicating artery, from the posterior circulation through circle of Willis, and from the external carotid artery. This reduced flow may cause direct ischemia, and it may interfere with cerebral autoregulation, rendering that hemisphere vulnerable to systemic hypotension. Jugular vein ligation can result in cerebral venous hypertension, which may predispose to venous infarction. Systemic heparinization increases the risk of intracranial hemorrhage, which may be primary or result from hemorrhagic transformation of an ischemic lesion. Extracorporeal membrane oxygenation causes elevated levels of inflammatory cytokines, which may contribute to the development of periventricular leukomalacia [Fortenberry et al., 1996; Kinney and Back, 1998].

Extracorporeal membrane oxygenation has been used for some time in tertiary centers to support children with severe respiratory failure. More recently, extracorporeal membrane oxygenation has been used to support children with severe cardiac failure due to congenital or acquired heart disease. The short-term benefit of extracorporeal membrane oxygenation is well demonstrated, with multicenter reports of 83% survival rates among infants with a predicted mortality rate of greater than 80% [Stolar et al., 1991]. Extracorporeal membrane oxygenation may be performed through a venovenous or, more commonly, a veno-arterial circuit. Venovenous extracorporeal membrane oxygenation provides oxygenation for respiratory failure, whereas veno-arterial extracorporeal membrane oxygenation provides oxygenation and circulatory support for cardiac failure. In both veno-venous and veno-arterial circuits, venous blood is drained from the right atrium through a catheter placed in the right internal jugular vein. After oxygenation, removal of carbon dioxide, and rewarming, the blood is pumped by a nonpulsatile flow into the right atrium through the second lumen of a double-lumen catheter (i.e., veno-venous circuit) or to the aortic arch through a catheter in the right common carotid artery (i.e., veno-arterial circuit). Systemic heparinization is required to prevent clotting in the extracorporeal membrane oxygenation circuit. The rostral segments of the cannulated vessels (i.e., jugular vein and, in veno-arterial extracorporeal membrane oxygenation, the right common

Indications Extracorporeal membrane oxygenation is indicated for pulmonary failure that is refractory to treatment but potentially reversible (e.g., meconium aspiration syndrome, congenital diaphragmatic hernia, persistent pulmonary hypertension, sepsis, respiratory distress syndrome), for potentially reversible cardiac disease (e.g., cardiomyopathy), because of an inability to wean off cardiopulmonary bypass after cardiac surgery, and as a bridge to cardiac transplantation.

Contraindications Absolute contraindications to extracorporeal membrane oxygenation include gestational age of less than 34 weeks (because of excessive morbidity and mortality related to intracranial hemorrhage), birth weight less than 2000 grams (because of limitations of cannula size), any uncontrollable coagulopathy or bleeding, and a preexisting grade III intraventricular hemorrhage or periventricular hemorrhagic infarction. Relative contraindications include preexisting grade I or II intraventricular hemorrhage, other intracranial hemorrhage, cerebral infarction, and sepsis, which increases the risk for intracranial hemorrhage [Cilley et al., 1986; Kim and Stolar, 2000; Sell et al., 1986].

Mechanisms of Neurologic Injury

Neurologic Complications Intracranial hemorrhage and infarction are the primary neurologic complications of extracorporeal membrane oxygenation. The overall risk of hemorrhage or infarction is between 25% and 50%, whereas 10% to 20% of infants experience severe hemorrhage or infarction [Volpe, 2001]. The most common sites of hemorrhage are intraventricular and posterior fossa. Cerebral ischemia may be global or focal, or it

Hahn and du Plessis / Neurologic Disorders Associated with Cardiac Disease

may manifest as periventricular leukomalacia [Jarjour and Ahdab-Barmada, 1994; Kinney and Back, 1998]. Clinical and electrographic seizures are common among neonates treated with extracorporeal membrane oxygenation, with a reported incidence of 20% to 70% [Kim and Stolar, 2000]. However, the risk for subsequent epilepsy is low. Sensorineural hearing impairment is reported in 4% to 15% of neonates after extracorporeal membrane oxygenation, but many of these deficits resolve over time [Desai et al., 1997; Hofkosh et al., 1991; Schumacher et al., 1991]. Reports of neurocognitive outcome after extracorporeal membrane oxygenation indicate that 10% to 29% of extracorporeal membrane oxygenation neonates have developmental quotients less than 70, with smaller infants at the greatest risk for developmental delays [Hamrick et al., 2003; Revenis et al., 1992].

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Terplan KL. Brain changes in newborns, infants and children with congenital heart disease in association with cardiac surgery. Additional observations. J Neurol 1976;212:225. Tomlinson F, Piepgras D, Nichols D, et al. Remote congenital cerebral arteriovenous fistulae associated with aortic coarctation. J Neurosurg 1992;76:137. Tyler R, Clark DB. Cerebrovascular accidents in patients with congenital heart disease. Arch Neurol Psychiatry 1957a;77:483. Tyler R, Clark DB. Incidence of neurologic complications in congenital heart disease. Arch Neurol Psychiatry 1957b;77:17. Utoh J, Miyauchi Y, Goto H, et al. Endovascular approach for an intracranial mycotic aneurysm associated with infective endocarditis. J Thorac Cardiovasc Surg 1995;110:557. van Houten J, Rothman A, Bejar R. High incidence of cranial ultrasound abnormalities in full-term infants with congenital heart disease. Am J Perinatol 1996;13:47. Vannucci R. Current and potentially new management strategies for perinatal hypoxic-ischemic encephalopathy. Pediatrics 1990;85:961. Volpe JJ. Neurology of the newborn. Philadelphia: WB Saunders, 2001:482. von Allmen D, Babcock D, Matsumoto J, et al. The predictive value of head ultrasound in the ECMO candidate. J Pediatr Surg 1992;27:36. Waitling S, Dasta J. Prolonged paralysis in intensive care unit patients after use of neuromuscular blocking agents: A review of the literature. Crit Care Med 1994;22:884. Wardle SP, Yoxall CW, Weindling AM. Cerebral oxygenation during cardiopulmonary bypass. Arch Dis Child 1998;78:26. Watanabe T, Trusler GA, Williams WG, et al. Phrenic nerve paralysis after pediatric cardiac surgery. Retrospective study of 125 cases. J Thorac Cardiovasc Surg 1987;94:383. Weese-Mayer DE, Hunt CE, Brouillette RT, et al. Diaphragm pacing in infants and children. J Pediatr 1992;120:1. Wessel DL, du Plessis AJ. Choreoathetosis. In: Jonas RA, Newburger JW, Volpe JJ, eds. Brain injury and pediatric cardiac surgery. Boston: Butterworth-Heinemann, 1995:353. Westaby S. Organ dysfunction after cardiopulmonary bypass: A systemic inflammatory reaction by the extracorporeal circuit. Intensive Care Med 1987;13:89. Wical B, Tomasi L. A distinctive neurologic syndrome after profound hypothermia. Pediatr Neurol 1990;6:202. Wilson W, Giuliani E, Danielson G, et al. Management of complications of infective endocarditis. Mayo Clin Proc 1982;57:162. Wong PC, Barlow CF, Hickey PR, et al. Factors associated with choreoathetosis after cardiopulmonary bypass in children with congenital heart disease. Circulation 1992;86:118. Yang J, Park Y, Hartlage P. Seizures associated with stroke in childhood. Pediatr Neurol 1995;12:136. Yatsu F, Hart R, Mohr J, et al. Anticoagulation of embolic strokes of cardiac origin: An update. Neurology 1988;38:314. Young R, Liberthson R, Zalneraitis E. Cerebral hemorrhage in neonates with coarctation of the aorta. Stroke 1982;13:491. Zeviani M, Van Dyke D. Myopathy and fatal cardiopathy due to cytochrome c oxidase deficiency. Arch Neurol 1986;43:1198.

CHAPTER 89

Interrelationships between Renal and Neurologic Diseases and Therapies Robert S. Rust and Raymond W. M. Chun

Diseases of the kidneys were among the first to be productively investigated with regard to pathophysiology, including deleterious effects secondarily produced on the nervous system by renal demise. Nearly 200 years ago, Richard Bright inaugurated this study as part of his great pioneering investigations of the correlation between disease manifestations and morbid anatomy [Bright, 1831]. The spectrum of neurologic disturbances that can result from renal failure has expanded considerably since the time of Bright. Fortunately, increased understanding of these consequences has engendered the development of strategies and treatments that prevent or ameliorate many of these neurologic abnormalities. The effects of kidney disease and treatments on the nervous system function constitute the initial and major portion of this chapter. Heritable metabolic diseases are usefully classified on the basis of whether their predominant renal system effects are on the entire nephron or on only a portion (i.e., proximal tubule, distal tubule, or distal nephron). Most of the other systemic diseases that may acutely or chronically affect both the nervous and renal system function are vascular, inflammatory, or toxic processes. These various diseases that affect the nervous and renal systems are reviewed in the second section of this chapter. Greater detail is provided for diseases not considered in detail in other sections of this book. A small number of primarily neurologic diseases produce renal dysfunction or injury. They are largely neuroendocrinologic (i.e., inappropriate antidiuretic hormone secretion, cerebral salt wasting, diabetes insipidus, dysautonomia). Renal injury may also be produced by neurologic drugs, by myoglobinuric muscle diseases, or as the consequences of a neurogenic bladder. Central hypertension may produce both dysfunctional renal responses and renal injury. Treatments for some neurologic diseases must be modified in the presence of renal dysfunction. These various associations are the subject of the final section of this chapter.

RENAL DISEASES SECONDARILY AFFECTING THE NERVOUS SYSTEM Acute Renal Failure Acute renal failure is a common problem. It occurs in as many as 4% of all hospital admittances in the United States or nearly 20% of those requiring critical care management [Schrier et al., 2004]. The two most important potential morbidities of acute renal failure are neurologic and renal. The most significant

renal morbidity is the development of chronic renal failure. Risk for chronic renal failure is strongly influenced by the nature and severity of the underlying cause of acute renal failure. The morbidity of acute renal failure in newborns is greater if it occurs as a manifestation of hypoxic-ischemic injury with multiorgan failure (end-stage renal disease) and ensuing blood pressure instability [Andreoli, 2004]. The causes of neonatal acute renal failure are predominantly prerenal, particularly hypoxemic or asphyxial forms of hypoxic-ischemic stress. It usually results in a biphasic course of oliguria followed by diuresis. Sudden severe ischemia due to hemorrhage or cardiopulmonary arrest may produce multiorgan failure including not only kidney but also brain. The associated pattern of brain injury involves encephaloclastic injury to all cell types within the parasagittal watershed regions of the cerebral cortex or within the brainstem. Renal cortical necrosis may occur. In such situations, protective cardiovascular reflexes preserve glomerular filtration in preference to some other organ systems [Schrier et al., 2004], but where possible these reflexes preserve cerebral perfusion at the cost of reducing renal perfusion. Reflexes designed to achieve hierarchal selection of flow to preserve cardiopulmonary and neurologic function work best in situations of hypoxemia or asphyxia, especially if partial and prolonged, but not in instances of sudden severe ischemic collapse. The management of some of the important diseases that produce acute renal failure in children—those that have independent effects on the nervous system—are reviewed in the next section of this chapter. Many reviews of what is currently known about the benefits and risks of various medications and renal replacement strategies employed to treat acute renal failure are available [Hoste and Kellum, 2004; Schrier et al., 2004; Van Biesen et al., 2003; Williams, et al., 2002]. Few resources for optimal management of acute renal failure are available in developing nations, a situation that has necessitated circumscribed and adaptive application of often inadequate treatment strategies [Naicker, 2003]. Because the site of renal physiologic dysfunction determines selection of therapeutic interventions, it is important to be aware of diagnostic clues concerning the level at which initial renal dysfunction occurs [Andreoli, 2004; Moghal et al., 1998; Schrier and Wang, 2004; Stapleton et al., 1987]. Neurologic decompensation in association with acute intrinsic renal failure occurs with (1) fluid and electrolyte disturbances, (2) accumulation of toxins (e.g. uremia, medications), or (3) hypertension. Neurologic abnormalities secondary to acute renal failure may occur in patients who have normal blood urea nitrogen and creatinine levels. The likelihood, severity, and nature of

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the neurologic decompensation resulting from acute renal failure are functions of the rate and severity of uremia and oliguria, metabolic balance of the whole organism, and intake (alimentary or parenteral) of free water, salt, and protein [Mahoney and Arieff, 1982]. Acute onset of severe renal failure is more likely to cause neurologic dysfunction because slower development of renal failure permits compensatory mechanisms to blunt the effects of uremia, hypertension, or electrolyte disturbances. The likelihood that partial degrees of renal failure will engender neurologic dysfunction is determined by the concurrent metabolic state of the organism: the loads of solute, electrolytes, protein catabolites, and other potentially deleterious substances with which the nephron is expected to deal. These loads determine the likelihood that intrinsic renal adaptive capacity will be exceeded and that some ensuing neurotoxic combination of uremia, high anion gap acidosis, hyperkalemia, or hypertension will be achieved.

Water Intoxication Neurologic abnormalities associated with water intoxication may arise in acute oliguric/anuric renal failure as well as in many other settings. The kidney’s capacity to excrete from water in dilute urine is the chief mechanism for prevention of water intoxication. In acute renal failure this homeostatic mechanism is lost and neurologic dysfunction develops hours to days after the onset of renal failure, depending on initial water balance and the rate of additional free water intake. Individuals with sodium values as low as 120 to 125 mEq/L often remain asymptomatic. Symptoms become more prevalent once the serum sodium has fallen below 120 mEq/L. Signs and symptoms of water intoxication may include headache, nystagmus, nausea, vomiting, diaphoresis, weakness, generalized tremulousness, ankle clonus, and the development of muscular irritability with coarse fibrillary twitching. Mental status changes range from apathy to progressive anxious restlessness, through agitation, confusion, or forgetfulness, to obtundation [Bhananker et al., 2004; Riggs, 2002]. It is possible that underlying predilections to migraine, anxiety, or other neurologic conditions may influence the symptomatic expression of water intoxication. The rate of deterioration in neurologic function ranges from gradual to rapid; the course ranges from linear to stepwise, and the severity ranges from mild to severe. Children are at particularly high risk for the development of sudden decompensation due to brain edema at higher serum sodium concentration than adults because they usually have higher brain:skull ratios than adults. The immature brain often reaches adult size by 6 years of age, whereas adult skull size may not be achieved until 16 years of age [Moritz and Ayus, 2002]. Because of this vulnerability, the outcome of children whose water intoxication is overlooked may be worse than that for adults with similar duration and degree of excessive free water retention. Systemic aspects of water intoxication include cardiovascular compromise or pulmonary edema. These complications further jeopardize brain function owing to impaired oxygenation, provision of glucose, and removal of toxic metabolites of brain metabolism. Hyponatremia may result in seizures, increasing cerebral energy demand, and the rate at which toxic

byproducts of metabolism accumulate. Brain edema may develop and increase intracranial pressure, further impairing cerebral circulation. The edema is due to osmotically mediated flow across the blood-brain barrier, diluting extracellular electrolytes and then intracellular electrolytes. If hyponatremia associated with neurologic decompensation remains uncorrected, convulsions, coma, and death due to brain herniation or complications of generalized convulsions may follow in quick succession. The mortality rate for severe hyponatremia with associated cerebral edema may be greater than 50% [Baran and Hutchinson, 1984]. Under experimental conditions, the increase in brain water required to produce neurologic symptoms is about 3%, with an associated decrease in concentration of intracellular cations estimated to be 20% [Dodge et al., 1960]. Cerebral edema per se is unlikely to be the cause of many of the early neurologic signs and symptoms of water intoxication because these can be produced under experimental conditions without cerebral edema and because cerebral edema in isolation does not necessarily produce a similar constellation of signs and symptoms [Crawford and Dodge, 1964; Gutman et al., 1967; Kennedy et al., 1964; Wakim, 1969b]. It is far more likely that these abnormal findings are due to abnormal membrane excitability, enzymatic activity, or synaptic function. Similar findings develop in children with cystic fibrosis and heat prostration who are in a sodium-depleted state [Barbero and Sibinga, 1964]. Because correction of intracellular potassium concentration lags several hours behind that of sodium and because symptoms persist during this interval, it has been concluded by some authorities that dilution of intracellular potassium concentrations plays a more important direct role in neurologic dysfunction than sodium dilution. The water shifts that dilute intracellular potassium, however, are likely due to dilution of sodium—first in the intravascular and then in the interstitial brain compartments and finally the intracellular milieu [Dila and Pappius, 1972; Dodge et al., 1960]. Brain edema likely accounts for progressive headache and some of the focal signs of advanced water intoxication, including hemiparesis, ataxia, cranial nerve palsies, rigidity, and progressive obtundation [Riggs, 2002]. Treatment of hyponatremia in the patient with acute renal failure must be suited to the particular circumstances of the individual patient. Fluid restriction in early stages may be adequate for mild hyponatremia but can be dangerous if cerebral perfusion is compromised. Maintenance of circulation often requires judicious administration of isotonic or even hypertonic saline solutions. Dialysis may be necesary [Bhananker et al., 2004; Riggs, 2002]. The rate of sodium correction is a particularly important consideration. Excessively rapid correction poses the danger for development of central pontine myelinolysis. In children, it is recommended that correction at the rate of approximately 1 mEq/L/hour be achieved until the patient becomes alert and seizure free, plasma sodium becomes 125 to 130 mEq/L, or serum sodium level is increased by 20 to 25 mEq/L, whichever occurs first. If seizures persist or there are signs of increased intracranial pressure (especially if these signs are worsening), the sodium concentration may be corrected at a rate of 4 to 8 mEq/L for 1 hour (if tolerated) or until seizures stop. Assuming that total body water comprises 50% of body mass, administration of 1 mL/kg of 3%

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NaCl solution will increase plasma sodium by approximately 1 mEq/L [Moritz and Ayus, 2002].

Hyperkalemia During the first 48 hours of anuric acute renal failure from prerenal causes there is loss of as much as 70% to 80% of renal outer medullary potassium secretory channel and 35% to 40% of the activity of potassium channel inducing factor. Cardiac and pulmonary manifestations of hyperkalemia generally precede and are greater threats for survival than neurologic ones. Cardiac dysfunction is usually the earliest and most ominous clinical sign of hyperkalemia. Cardiac instability or arrest is virtually diagnostic of hyperkalemia in the setting of acute renal failure. Electrocardiography is an earlier and more sensitive indicator of the progressive effects of hyperkalemia that portend cardiac failure and should be performed promptly and monitored or repeated as indicated if hyperkalemia is suspected. In many cases of reversible acute renal failure, plasma potassium concentration peaks at about 48 hours and returns to normal in about 7 days. However, during the first 48 hours, it is critical to monitor and, if necessary, bind or redistribute existing potassium while at the same time preventing further intake. Rare instances of hyperkalemia of acute renal failure presenting as a neurologic sign (e.g., paralysis) rather than cardiac decompensation have been described [Cumberbatch and Hampton, 1999]. Elevation of serum potassium concentration reflects a complex set of equilibria. Factors include the degree of displacement of potassium from the intracellular compartment as the result of acidemia and the state of dilution or concentration of body fluids (the balance of free water intake and output). Hyperkalemia may provoke smooth or striated muscle weakness owing to lowered membrane resting potentials, delayed depolarization, rapid repolarization, or slowed cardiac and peripheral nerve conduction velocities [Chantler, 1988]. Correction of metabolic acidosis with infusion of calcium or glucose, insulin, and in some instances administration of an ∃-2 stimulant such as salbutamol may shift the circulating potassium excess to safer intracellular loci [Kemper et al., 1996]. Management may involve the use of ion exchange resins or dialysis.

Uremic Encephalopathy Uremia is an extremely complicated, and as yet incompletely characterized, metabolic state that results from the failure of renal mechanisms for (1) regulation of fluid and electrolyte balance, (2) excretion of protein catabolites and other potentially toxic substances, and (3) endocrine regulation [Bergstrom, 1985]. It occurs when glomerular filtration rate has declined to less than 10% of normal. It is fatal if untreated. Most patients with acute uremia have experienced proportional injury to tubular and glomerular systems. Bicarbonate wasting occurs but is in part compensated for by the retention of nonchloride anions, such as sulfate and phosphate. The result is high anion gap acidosis with normal or increased serum potassium concentration. Sodium and chloride levels remain normal unless free water excretion is impaired. Brain edema is uncommon in uremic encephalopathy because most of the osmotically active

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molecules that accumulate in uremia are small molecules that equilibrate readily across the blood-brain barrier [Dettori et al., 1982; Mahoney and Arieff, 1983; Smogorzewski, 2001]. Occurrence and degree of uremic encephalopathy correlate poorly with renal function as measured by degree of blood urea nitrogen or creatinine abnormality. Disturbances of endocrine function occur in uremia, with possible elevations, especially in chronic renal failure, of parathyroid hormone, insulin, growth hormone, glucagons, thyrotropin, prolactin, luteinizing hormone, or gastrin. Elevated concentrations of parathyroid hormone, associated particularly with cases of uremic decompensation of chronic renal failure, may activate second-messenger systems that alter cellular calcium hemostasis, the balance of which is viewed by many observers as a central element of the metabolic crisis that produces uremic encephalopathy [Arieff and Armstrong, 1980; D’Hooge et al., 2003; Fraser, 1992]. Parathyroid hormone concentration elevations have been clearly linked to the reduction of mental status and electroencephalographic (EEG) abnormalities associated with uremic encephalopathy [Cooper et al., 1978; Fraser, 1992; Guisado et al., 1975; Moe and Sprague, 1994; Smits et al., 1983]. In chronically uremic patients, EEG abnormalities and mental and psychiatric manifestations may improve with parathyroidectomy or chemical suppression of parathyroid function [Cogan et al., 1978]. Exogenous toxins, infectious and inflammatory disturbances, and particularities of glomerulotubular dysfunction may also play variable roles in exacerbating uremic encephalopathy but are not essential predisposing features for uremic encephalopathy. Numerous lines of evidence suggest the considerable importance of disturbances of calcium homeostasis, membrane excitability, and neurotransmitter function as central functional abnormalities of uremic encephalopathy [Biasoli et al., 1984; Moe and Sprague, 1994]. It appears likely that some combination of effects produced by the presence of low-molecular-weight, fast-acting toxic solutes that are not excreted in renal failure are responsible for these disturbances. Among the dozens of unexcreted solutes that might produce such effects are urea, creatinine, hippuric acid, polyamines, polypeptides, guanidino compounds, acetoin, myoinositols, sulfates, aliphatic and aromatic amines, phenols, purines, indoles, glucuronates, spermine, DLhomocysteine, orotate, and glycine [Arieff et al., 1976; D’Hooge et al., 2003; Lubash et al., 1964; Ludwig et al., 1968; Morgan and Morgan, 1966]. These compounds have different capacities for the penetration of nervous tissues and may also have effects on blood vessels, membranes, enzymes, neurotransmitters, or receptors. Many of these potentially toxic chemicals, so quietly and efficiently removed by the normal kidney, are less efficiently removed from circulation by dialysis. It has long been known that cerebral rates of utilization of glucose, oxygen, and high-energy phosphate compounds fall in uremic encephalopathy, apparently because of reduced demand rather than energy failure. To some extent this may be a protective adaptation [Mahoney et al., 1984; Scheinberg, 1954; Van den Noort et al., 1970], although it is possible that the reduction is due in part to failure of synaptic transmission. It is not as yet known whether this global reduction masks regional or focal excesses of

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utilization (in conjunction, for example, with focal seizure activity or “twitch-myoclonus”) or whether some aspects of this reduction may injure rather than protect brain. Observed reduction in activity of the pentose phosphate shunt, an important source of reducing equivalents for maintenance of myelin and other synthetic tasks, may represent compensatory reduction of a temporarily dispensable energy expenditure. On the other hand, reduced flux in this pathway interferes with the maintenance of myelin. Interestingly, the uremic reduction in overall cerebral metabolic rate is not accompanied by reduction in cerebral blood flow, suggesting an unusual and as yet unexplained form of energy supplydemand uncoupling [Heyman et al., 1951; Scheinberg, 1954]. “Uremic” synaptosomal preparations have diminished activity of the metabolic pumps associated with Na+/K+ and Ca2+ adenosine triphosphatases and disturbances not only in calcium but also in cellular magnesium and potassium homeostasis. Evidence suggests that creatinine and acidic derivatives of guanidine metabolism (e.g., methyl guanidine and guanidinosuccinic acid) inhibit physiologic responses to γ-aminobutyric acid and glycine, disturb synaptic transmission in the CA1 region of the hippocampus, and elevate excitatory tone of certain neuronal populations. Guanidino compounds, phenol, and spermine, among the first uremic small molecules to have been proven to exert definable deleterious effects on brain, alter various membrane ionic conductances by means of voltage- or ligand-gated channels. These include the N-methyl-D-aspartate receptor complex, which variously enhances inward calcium or outward potassium currents [D’Hooge et al., 2003]. Sufficient concentrations of some of these various smallmolecule compounds are capable of engendering clonic seizures under experimental conditions, and it is possible that they are responsible for such classic manifestations of uremic encephalopathy as uremic “twitch-myoclonus.” Uremic myoclonus has also been associated with elevation of cerebrospinal fluid phosphate to concentrations in excess of 3.8 mg/mL, perhaps reflecting a particular sensitivity of the brainstem reticular formation to this chemical [Chadwick and French, 1979; Freeman et al., 1962]. Hypercalcemia (see later) is a known cause of myoclonic encephalopathy with seizures and dysarthria. Hypophosphatemia may also contribute to development of seizures in some patients [Rivera-Vazquez et al., 1980]. Toxicity of guanidinosuccinic acid is more marked in the post-hypoxic state [Torremans et al., 2004], owing to the generation of superoxides and hydroxyl free radicals that have been found to produce glial cell death under experimental conditions [Hiramatsu, 2003]. It is of interest that many of the small molecules associated with uremia may play important positive roles in normal brain, perhaps as free-radical scavengers. Factors that may account for toxicity of these same molecules during renal failure likely include loss of closely regulated and carefully compartmentalized concentrations and enhanced transformation of nontoxic and metabolically useful ones into toxic molecules. An important example of this is free radicalstimulated transformation of arginosuccinic acid into guanidinosuccinic acid [Cohen, 2003]. The generation of that toxic intermediate is enhanced in proportion to urea concentration [Aoyagi, 2003].

The complex state of uremia includes other pertinent and as yet incompletely understood or characterized metabolic and neurotransmitter disturbances, including the possible rise of glycine concentration in critical locations and fall in γ-aminobutyric acid concentrations in others. Uremic disturbance of tryptophan metabolism results in accumulation of kynurenine neurotransmitters that may provoke seizures, alter consciousness, or produce neuronal injury or cell death [Topczewska-Bruns et al., 2002]. Older data concerning uremic depression of metabolism of nucleotides, catecholamines, and amino acids involved in neurotransmitter synthesis [Fraser et al., 1985; Minkoff et al., 1972] may remain pertinent. Uremia may disturb the transport of amino and organic acids that activate excitatory or inhibitory synapses [Arieff et al., 1978; Biasioli et al., 1986; Deferrari et al., 1981; Fishman, 1970; Fishman and Raskin, 1967]. Pathologic studies of uremic encephalopathy suggest variable degrees of generalized neuronal degeneration. In some instances, perivascular necrosis and demyelinative changes are discerned. Abnormalities may be emphasized in cerebral cortex, subcortical and brainstem nuclei, or cerebellum. In persons dying of acute uremic encephalopathy, Alzheimer type II astrocytes may be found [Norenberg, 1994]. Subdural hemorrhages are found in less than 3% of cases of chronic renal failure with uremia [Fraser and Arieff, 1997]. Although uremic encephalopathy occurs in patients without a preceding history of serious renal disease, the majority of the 16,000 to 20,000 cases that occur in the United States annually occur in some of the more than 200,000 patients who are on chronic dialysis for end-stage renal disease. It is therefore important in caring for patients with chronic renal disease to be aware of the risk of this. Care should be taken before diagnoses such as for depression or frustration with chronic disease are used to explain behavioral changes. In patients with new-onset renal failure associated with uremia, an even wider differential diagnosis must be entertained as possible causes for neurologic deterioration. Difficulty may arise in instances in which new-onset renal disease with uremia pursues an indolent but subacutely progressive course. In each of these various groups, it must also be remembered that neurologic signs may precede definite clinical or biochemical evidence of renal failure. Acute uremic encephalopathy produces deterioration of higher cortical function at a rate that varies from slowly progressive to fulminant. The earliest characteristic changes, often subtle or insidious, include inattention, indecisiveness, irritability, and diminished intellectual agility. These changes may be improperly ascribed to depression. They are often more apparent to caregivers than to the patient. They may be overlooked in children or may be falsely ascribed to uncooperativeness and irritability. Standardized assessment of vigilance with digit span or serial subtraction may be useful in following patients at risk. A peculiar dyspraxic hesitancy of speech is a common and distinctive clue, usually dyspraxia without dysnomia or other associated aphasia [Martinez et al., 1978; Raskin and Fishman, 1976a, 1976b]. Lethargy, somnolence, anorexia, nausea, vomiting, pruritus [Zucker et al., 2003] and disturbance of the sleep-wake cycle are other common early manifestations. Episodic

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confusion, disinterest in surroundings, or impairment of recent memory may develop, interspersed with more lucid intervals. Occasionally, especially in persons with fulminant renal failure, acute agitation, delirium, psychosis, coma, or catatonia suggests the presence of uremic encephalopathy [Souheaver et al., 1982]. In such instances, effects of an intoxicating drug (e.g., corticosteroids, propranolol, cimetidine, levetiracetam, phenobarbital, or tricyclic antidepressants) must be excluded [Stenback and Haapanen, 1967]. Uremic encephalopathy may produce signs suggestive of Wernicke-Korsakoff syndrome. The development of tremor is a particularly reliable early sign of uremic encephalopathy and should prompt careful mental status evaluation. Both action (e.g., ataxic) and postural tremors of irregular amplitude may occur. Asterixis in persons with renal failure is another important sign of uremic encephalopathy but is seen in other metabolic encephalopathies that impair attentiveness [Adams and Foley, 1949, 1953]. The asterixic flap is not an active movement but appears to occur because patients fail to maintain voluntary motor extension of the wrists or feet. The rapidity of the flap does not, however, resemble the slower relaxation of effort seen with inattention. Central inhibition of sustained motor neuron activity has also been proposed in explanation, and the phenomenon has been called a variety of “negative myoclonus.” Similar impersistence is observed with sustained eye closure or forced smiling [Adams, 1964; Tyler, 1964, 1965]. Truncal asterixis also occurs and may be so severe that it mimics epileptic drop attacks [Young and Shahani, 1986]. With progressive obtundation, encephalopathy becomes less intermittent and a wider variety of neurologic dysfunction is displayed. Along with more severe disturbances of orientation, memory, cognition, and judgment, primitive reflexes (e.g., snout, root, grasp) may emerge. Transient loss of hearing or vision (uremic amaurosis) may occur. Either may persist for several days. Visual loss may result from either optic nerve or cortical dysfunction, possibly owing to edema. The localization is readily ascertained by the absence or presence of the pupillary light reflex [Tyler, 1968]. Abducens palsy only occasionally complicates uremia. It is far more common in hypertensive encephalopathy. Seizures, usually generalized tonic-clonic, occur in 20% to 40% of children with uremic encephalopathy, typically at the time of onset of renal failure. They are especially common in cases in which renal failure is fulminant, as is seen in acute glomerulonephritis and other causes. Seizures are seldom the only sign of uremia. Their occurrence may, however, presage an ensuing rapid decline in renal function with multiple manifestations. In acute renal failure they are more commonly brief generalized motor than focal motor seizures. Epilepsia partialis continua may develop in some cases. Seizures occurring in the later stages of acute uremia generally signify the development of other complications such as infection or electrolytic disturbances during the diuretic phase of resolving acute renal failure or as consequences of overzealous dialysis. Muscle twitching or fasciculation, especially in the distal extremities, is common in acute renal failure. Some patients report that such activity is preceded by distal extremity muscle ache or cramping. Multifocal uremic stimulussensitive myoclonus that Adams termed twitch-convulsive

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often emerges as uremic stupor develops [Tyler, 1968, 1976]. Restless leg phenomenon is not uncommon in uremic encephalopathy. Tetany (i.e., tonic muscle irritability, carpopedal spasm, Trousseau sign) may develop in uremia and may not respond to calcium supplementation [Tyler, 1968]. Choreoathetosis and even hemiballism may be observed. Moderate to severe motor weakness (including alternating hemiplegia) may follow. In patients with chronic renal failure/end-stage renal disease, acute weakness must be distinguished from preexisting changes related to neuropathy or hyperparathyroidism (see later). Hyperkalemia must be excluded. Rarely, signs of autonomic failure are noted [Levitan et al., 1982], some of which may be manifestations of uremic neuropathy [Yildiz et al., 1998]. Longtract signs may be present and are often asymmetric and changeable. If coma deepens without treatment of uremia, progressive brainstem failure leading to death often follows [Chadwick and French, 1979; Dinapoli et al., 1966; Locke et al., 1961; Raskin and Fishman, 1976a; Schreiner, 1959; Stark, 1981]. No distinctive pathologic process has been identified in such cases [Olsen, 1961]. In the patient with new-onset renal disease, uremic encephalopathy must be distinguished from many other causes of acute encephalopathy, particularly if renal failure develops after inflammatory, infectious, cardiovascular, metabolic, or other diseases known to produce neurologic abnormalities whether or not renal failure develops. In the patient with known renal disease, the acuteness of uremic deterioration usually sets it apart from slower-onset neurologic deteriorations to which chronically dialyzed patients are also subject (see later). It may be more difficult in patients with chronic renal failure to clinically distinguish uremic encephalopathy from encephalopathy due to water intoxication or hypertension. It is frequently difficult to ascertain exactly what metabolic stresses have provoked uremic encephalopathic decompensation in the patients with chronic renal disease. Among the influences or alternative diagnostic considerations that must be excluded are treatable conditions such as infection, endocrinopathy, vitamin deficiency states, or dialysis-related complications. Any question of increased intracranial pressure suggested by focal neurologic signs and symptoms of increased intracranial pressure must urgently be investigated and, if found, treated. Given the complexity of the biochemical changes associated with uremic encephalopathy, great care must be taken to detect and fix readily correctable metabolic perturbations such as disturbances of sodium, potassium, phosphate, magnesium, and glucose. It should also be recognized that neurologic improvement may lag behind adequate correction of readily measurable metabolic parameters. Some abnormalities (e.g., emotional and intellectual) may respond quickly to dialysis, whereas others (e.g., motor and sensory) respond more slowly, persisting for an uncomfortable interval [Grushkin et al., 1972]. This latency may be related to the inefficiency of dialysis in the clearance of unmeasured toxic intermediates. Drug screening, electroencephalography, evoked potentials, brain imaging, bacterial cultures, and lumbar puncture may be indicated in individuals with uremic encephalopathy to detect alternative or related diagnoses. In acute uremia,

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the electroencephalogram usually demonstrates generalized irregular but bisynchronous low-voltage slowing, particularly in patients whose blood urea nitrogen level is in excess of 60 mg/dL. The severity of these changes and prevalence of associated paroxysms roughly correlate with the further degrees of blood urea nitrogen elevation and degree of clinical encephalopathy. Slow alpha-dominant rhythm with occasional theta bursts and characteristic prolonged bursts of bisynchronous slow-sharp activity or spike and wave may be found. Bilateral spike discharges may accompany myoclonic jerks, and generalized electroconvulsive discharges in association with generalized convulsive seizures may also occur, possibly more commonly in patients with hypomagnesemia. Photomyoclonus and photic driving may be present. Rarely, the electroencephalogram may be normal despite uremic encephalopathy [Raskin and Fishman, 1976a]. Bursts of high voltage 12- to 13-Hz vertex sharp activity may be seen in drowsiness, spindles may be absent in stage 2 sleep, and high-voltage slow bursts may occur with wakening. EEG abnormalities may persist for quite some time, especially in patients with chronic renal failure for whom many months of dialysis may be required before restoration of a normal EEG pattern is seen. Deteriorations in blood urea control or other indications of transient worsening of renal function may be associated with transient intrusion of diffuse delta and theta waves, generalized spike-wave discharges, or heightened sensitivity to photic stimulation [Kiley et al., 1976]. Infrequently, brain imaging in acute uremic encephalopathy may disclose subdural hemorrhage. Some patients manifest a gyriform increase in T2-weighted signal or similar abnormalities on magnetic resonance imaging (MRI) of parietal and occipital subcortical areas, changes that reverse with treatment and must be distinguished from changes suggesting hypertensive encephalopathy (see later). Generally, brain imaging is not of much practical value in straightforward uremic encephalopathy [Schmidt et al., 2001]. In uremic encephalopathy in individuals with preceding chronic renal failure, scans may indicate changes due to either atrophy or corticosteroid treatment–related pseudoatrophy. However, the scans of such persons are often normal. Elevated lumbar cerebrospinal fluid pressure may be found in cases of uremic encephalopathy and usually resolves with dialysis. The decision to perform a lumbar puncture must be carefully weighed in individuals with severe encephalopathy given the risk for herniation. It is far from clear that lumbar puncture increases risk for herniation, but the performance of such a procedure represents a risk that is avoidable. Even without urgent performance of that test, appropriate broad-spectrum antibiotic therapy for possible infectious causes of deterioration can be undertaken. Cultures of blood and dialysate should be obtained when indicated, and lumbar puncture can be performed if still needed once it is clear that the risk of herniation has declined. Cerebrospinal fluid protein concentration may be elevated, and pleocytosis may be found. In such cases an underlying infectious cause, such as human immunodeficiency virus, can be sought. However, these changes may occur without identification of any treatable process and may be related to uremic alteration of blood-brain barrier function. The primary treatment of uremic encephalopathy is dialysis, with scrupulous attention to water balance, electrolytes,

blood pressure, and ventilation. Consideration must in some cases be given to parathyroidectomy or chemical parathyroid suppression. Response to dialysis may be rapid or may require many days [Locke et al., 1961]. Fixed deficits may develop, especially when uremic encephalopathy is complicated by hypertension or central nervous system (CNS) hemorrhage. Excessive or too rapid dialysis must be avoided because rapid shifts in water or solutes in various compartments may lead to alternative forms of neurologic decompensation. Seizures should suggest reevaluation for hypertension, electrolyte or water imbalance, infection, or intoxication (commonly penicillin or a phenothiazine). Persistent seizures should be treated with antiepileptic drugs. Phenytoin, phenobarbital, and carbamazepine have been the most frequently employed antiseizure medicines in this setting, in part because of the considerable familiarity with the safe and effective use of such drugs in renal failure and dialysis. Phenytoin should be used cautiously. Uremia may increase phenytoin hepatic clearance while at the same time hypoalbuminemia may increase free phenytoin concentration owing to diminished protein binding. These effects often balance one another, but not invariably. It is wise to frequently assess free phenytoin concentrations in patients with uremic encephalopathy and seizures.

Hypertensive Encephalopathy The designation hypertensive encephalopathy is generally reserved for hypertensive patients with alteration of consciousness and diffuse or multifocal CNS dysfunction in whom there is no better or more complex etiologic explanation [Chester et al., 1978]. Malignant hypertension as a cause of the neurologic abnormalities of hypertensive encephalopathy can arise in association with a number of underlying illnesses. The causes of malignant hypertension in children vary according to age [Chantler, 1986]. Within the first month of life, two thirds of cases are related to renovascular thrombosis (spontaneous or associated with asphyxia, cyanotic heart disease, disseminated intravascular coagulopathy, or umbilical artery catheterization). Nearly 20% of cases are due to CNS disturbances, and approximately 8% are caused by tumors (e.g., Wilms’ tumor, neuroblastoma) or coarctation. Malignant hypertension is rare in neonates, although it may arise as the consequence of renal failure or congenital adrenal hyperplasia [Spoudeas et al., 1993]. It is also not uncommon in infants 1 to 12 months of age. When it does occur in the first year of life, it carries high risk of morbidity and mortality, owing to the severity of the illnesses that typically underlie pressure elevation at this young age. These include aortic coarctation and polycystic kidneys (each accounting for about one third of such cases in young patients), nephritis (16%), and hemolytic-uremic syndrome (7%). The remaining cases are due to causes such as tumors that generate Cushing’s syndrome (e.g., neuroblastoma, corticotropin-secreting ganglioneuroblastoma), high doses of adrenocorticotropic hormone used to treat infantile spasms, and various forms of renovascular disease. No cases of socalled central (primarily CNS-mediated) hypertension were described in the Boston Children’s Hospital series of cases of malignant infantile hypertension [Ingelfinger, 1982].

Rust and Chun / Interrelationships between Renal and Neurologic Diseases and Therapies

In children older than 1 year of age, roughly two thirds of cases are caused by inflammatory or infectious parenchymal renal disease. These include hemolytic-uremic syndrome, acute glomerulonephritis, and collagen vascular diseases (particularly systemic lupus erythematosus). Renal or aortic vascular abnormalities such as renal artery stenosis, kidney malformations (multicystic or dysplastic kidneys), and tumors (Wilms’ tumor, neuroblastoma, pheochromocytoma) account for the remaining one third in most centers. Renal graft rejection may be the most frequently encountered cause of hypertensive encephalopathy in centers that perform many kidney transplants, however. Immunosuppression employed in such cases may increase risk for acute hypertension even without graft rejection [Primavera et al., 2001; Proulx et al., 1993; Still and Cottom, 1967; Stocker et al., 2003; Zangeneh et al., 2003]. More than 40% of patients with malignant hypertension develop significant neurologic complications, including encephalopathy. In early reports, one or another of these neurologic complications were lethal in 20% of patients, particularly cerebral thrombosis or hemorrhage [Schottstaedt and Sokolow, 1953]. Although the fatality rate has undoubtedly declined, fatalities still occur, especially as the result of intracranial hemorrhage [Schwartz et al., 1995]. The risk for hypertensive encephalopathy is related to both the rapidity and severity of blood pressure increase from any given baseline [Dinsdale, 1983; Healton et al., 1982]. Thus, risk is higher in acute renal failure caused by acute glomerulonephritis or hemolytic-uremic syndrome than it is in essential hypertension or chronic renal failure/ end-stage renal disease. Acute glomerulonephritis or hemolytic-uremic syndrome should be suspected in any child older than 1 month of age with unexplained hypertensive encephalopathy, even when initial laboratory findings are minimal [Hoyer et al., 1967]. Some inflammatory illnesses that cause acute hypertensive renal failure in children, such as hemolytic-uremic syndrome, may have direct effects on the CNS beyond those provoked by severe hypertension (see later). Generalized severe headache is almost universal with severe hypertension. Seizures and visual loss are other common early manifestations of hypertensive encephalopathy [Wright and Mathews, 1996]. Headache develops hours to days after the initiating blood pressure crisis and may be accompanied by lethargy, projectile vomiting, meningismus, or edema of the eyelids and ankles. Papilledema is present in only one third of childhood cases of hypertensive encephalopathy. Retinal arteriolar spasm is a far more characteristic and important sign [Bar and Savir, 1982; McGregor et al., 1986]. Evidence of ischemic infarction of nerve fibers (white exudate or cotton-wool spots) is another important funduscopic indication [Pickering, 1968]. The earliest signs in newborns and infants include irritability, lethargy, and hypotonia. Encephalopathy develops after 12 to 36 hours of headache and is heralded in most children by seizures, more commonly generalized than focal [Dedeoglu et al., 1996; Trompeter et al., 1982]. In virtually all cases of hypertensive encephalopathy with seizures, systolic and diastolic blood pressures are more than four standard deviations above the mean for age. Status epilepticus may further elevate systolic and diastolic blood pressures in more than 10% of cases.

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Elevation of blood pressure by four standard deviations above the mean for age should in no case, however, be ascribed to seizures alone [Proulx et al., 1993]. Seizures without persistently associated mental status changes occasionally occur as the sole initial clinical manifestation of hypertensive encephalopathy [Dinsdale, 1983]. Infants without hypertensive encephalopathy may exhibit opisthotonos, fever, and unresponsiveness. The level of consciousness in older children consists of fluctuating confusion, irritability, and restlessness that may progress to coma. Muscle twitching and myoclonus may occur. Focal neurologic signs occur in various combinations of aphasia, scotomas (retinal, optic nerve, or cortical), cranial neuropathy (especially abducens or facial nerves), and focal motor weakness (especially hemiparesis). In severe cases, rapidly progressive brainstem failure may precede death unless effective treatment is initiated [Jellinek et al., 1964; Lindfors-Lonnkvist and Jakobsson, 1994; Zangeneh et al., 2003]. Hypertension-associated occipital blindness with additional features such as headache, lethargy, transient motor deficits, confusion, visual hallucination, and convulsive seizures (generalized more commonly than focal) constitute a syndrome that has been termed reversible posterior leukoencephalopathy [Hinchey et al., 1996; Kwong et al., 1987; Saatci and Topaloglu, 1994; Sebire et al., 1995]. This clinically distinctive subcategory of hypertensive encephalopathy was first described in individuals receiving immunosuppression with cyclosporine. It occurs most commonly, however, in children or adults who develop acute hypertension in the setting of either acute or chronic nephrotic conditions. Nephrotoxic (e.g., acyclovir) or cytotoxic (e.g., cyclosporine) drugs or treatment with high doses of methylprednisolone enhance risk, especially in patients receiving excessive fluid loads [Ikeda et al., 2001]. Cytotoxic drugs may enhance risk for reversible posterior leukoencephalopathy because they compromise the blood-brain barrier. The respiratory distress of fluid-overloaded patients may increase risk because of elevation of venous “back-pressure” of the cerebral venous circulation. Attention has been drawn to the development of MRI changes consistent with reversible posterior leukoencephalopathy in the hemisphere contralateral to predominantly hemiconvulsive seizures, suggesting that seizures themselves may have a role in the genesis and evolution of reversible posterior leukoencephalopathy [Obeid et al., 2004]. Brain imaging in reversible posterior leukoencephalopathy usually illustrates fairly symmetric and extensive abnormalities within 24 hours of clinical onset that are more apparent on MRI than on computed tomography (CT). With MRI, T2-weighted bright and T1-weighted dark abnormalities usually are due to edema rather than infarction and tend to be located in the posterior parietal/occipital cortical ribbon and especially the subadjacent white matter. Similar changes may be found in the frontal or temporal lobes, basal ganglia, brainstem, or cerebellum, representing more generalized changes of hypertensive encephalopathy. Gradient-echo techniques may demonstrate characteristic petechial hemorrhages [Kandt et al., 1995; Weingarten et al., 1994]. Because the parieto-occipital changes of reversible posterior leukoencephalopathy involve both gray and white

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matter in children, the designation occipital-parietal encephalopathy is favored by some investigators [Pavlakis et al., 1997]. In some instances, clinical and radiographic changes of reversible posterior leukoencephalopathy or of hypertensive encephalopathy do not resolve for days to as many as 8 weeks after control of hypertension. Reduction of dosage of medications such as cytotoxic or immunosuppressive agents may be required in persistent cases [Dedeoglu et al., 1996; Hinchey et al., 1996; Primavera et al., 2001]. The clinical findings and radiographic changes of reversible posterior leukoencephalopathy are virtually identical to those found in the syndrome of cyclosporine neurotoxicity (see later). In cases that promptly resolve after correction of blood pressure with medications or dialysis, the most likely pathogenesis is edema from hypertensive encephalopathy. Edema may be exacerbated by effects of cyclosporine on blood-brain barrier permeability [Lopez-Garcia et al., 2004; Primavera et al., 2001] rather than by any direct toxic effect of cyclosporine on brain. Intracranial hemorrhage is more typically associated with cyclosporine-induced than other forms of hypertensive encephalopathy, probably potentiated by cyclosporine-induced thrombocytopenia [Schwartz et al., 1995]. Changes resembling reversible posterior leukoencephalopathy develop in a minority of patients who have had long-term dialysis followed by administration of interferon alfa in preparation for renal transplantation. Some of these individuals have chronic hepatitis C infection. Focal clinical features of hypertensive encephalopathy are not always transient. Aphasia, optic nerve scotomas, and hemiparesis may indicate the occurrence of brain, cranial nerve, or brainstem infarction. Unilateral infarction of some portion of the anterior optic pathways is especially characteristic. Infarction may be more common in patients who have had long-standing unrecognized hypertension. It also occurs in those who experience hypotensive episodes as the result of overly aggressive management of blood pressure elevation [Sebire et al., 1995]. It is as yet unclear if infarctions are due to vasculopathy or to impairment of blood flow related to edema and hypotension. Information concerning the pathologic changes that occur in hypertensive encephalopathy is scant. Perivascular edema (with or without microhemorrhages) and swelling of astrocytes and myelin have been described [Lumsden, 1970]. The exact nature of the pathophysiology of hypertensive encephalopathy is not fully understood, but two major theories are advocated. An older view states that encephalopathy is the result of excessive cerebral vasoconstrictive autoregulation, stimulated to protect cerebral microvascularity from high pressure. This reduction of microcirculatory flow is believed to compromise capillary integrity and result in edema, vascular necrosis, microinfarction, and petechial hemorrhages. This sequence has been demonstrated in experimental models [Adams and Foley, 1953; Byrom, 1954; Finnerty, 1972; Myers et al., 1960]. A newer hypothesis suggests that hypertensive encephalopathy is actually the result of failure of cerebral autoregulation. In this model the vasoconstrictive threshold is exceeded and transudative perivascular edema develops, which may then compress the regional microvasculature. This process, perhaps in combination with back-pressure related to venous hypertension, may then result in proliferative endarteritis of retinal and cerebral arterioles with

focal ischemic fibrinoid necrosis, petechial hemorrhages, and parenchymal microhemorrhages [Dinsdale, 1983; Goldby and Beilin, 1976; Gulliksen et al., 1983]. Loss of autoregulation, significantly impairing vascular compensation to intercurrent hypotensive episodes, may render the individual vulnerable to infarction in areas of vascular watershed across the parasagittal and deep gray regions of the cerebral hemispheres. Neither theory has been proved, although experimental and clinical observations have been advanced supporting both. Although it is known that hypertension is necessary, it is not known whether it is sufficient to cause hypertensive encephalopathy or whether other inciting circumstances are required. Regardless of the initial event, microinfarction, edema, and loss of autoregulation do occur, necessitating caution in blood pressure reduction and manipulation of cardiac output because rapid changes may result in acute cerebral infarction [Healton et al., 1982]. Generally, intact cerebral autoregulatory mechanisms are capable of blunting systolic arterial pressure elevations as high as 200 mm Hg in adolescents and adults [Harper, 1966; Strandgaard et al., 1973]. These mechanisms can adapt to even greater pressures in patients with chronic hypertension [Lassen and Agnoli, 1972; Strandgaard et al., 1973]. On the other hand, children with chronic renal disease may experience particularly acute and severe episodes of hypertension. This vulnerability is ascribed to chronic volume expansion, renovascular constriction that results in increased plasma renin and angiotensin II, and increased vascular responsiveness to angiotensin II owing to increased plasma Na+/K+ adenosine triphosphatase inhibitor [de Wardener and MacGregor, 1988]. The upper limits of vascular autoregulation in the newborn are more uncertain than in older individuals, and little is known about cerebrovascular autoregulation in young children in a hypertensive state [Fraser and Arieff, 1988]. Autoregulatory responses become more complex when metabolic homeostasis is disturbed. Both acidosis and carbon dioxide accumulation prompt cerebral arteriolar dilatation and may permit higher pressure to be conveyed to the delicate microcirculation of the brain, perhaps lowering the pressure threshold for decompensation. This effect is best illustrated by the fact that only moderate blood pressure elevation is required to produce hypertensive encephalopathy in some children with acute pulmonary edema. Abnormalities observed with magnetic resonance perfusion imaging support the concept that vasodilatation is an important aspect of vulnerability to hypertensive encephalopathy [Jones et al., 1997]. There is no clear explanation for the occipital preponderance of MRI-deprived changes in brain appearances, although it seems likely that there are physiologic or anatomic differences in the blood vessels or associated blood-brain barrier in posterior brain regions [Kandt et al., 1995]. Acute hypertension, severe headache, and encephalopathy progressing over several days is highly suggestive of hypertensive encephalopathy, particularly if there is funduscopic evidence of arteriolar spasm and/or ischemic infarction of nerve fibers. Inflammatory vasculitides (especially systemic lupus erythematosus) associated with a chronic hypertensive state often produce similar retinal changes even without hypertensive encephalopathy. Acute

Rust and Chun / Interrelationships between Renal and Neurologic Diseases and Therapies

hypertensive encephalopathy associated with acute dependent edema and hematuria suggests the possibility of acute post-streptococcal glomerulonephritis. Diagnoses such as eclampsia, complications of immunosuppression, or acetaminophen-induced hepatorenal failure will be suggested by the clinical setting [Hinchey et al., 1996; Saatci and Topaloglu, 1994]. When appropriate, structural CNS lesions (tumor, hemorrhage, or stroke) should be excluded by unenhanced brain imaging because the presence of such lesions may influence blood pressure management. In some cases it is difficult to exclude ischemic brain injury without serial imaging. Cerebral hemorrhage in hypertensive encephalopathy is usually petechial. In the preadolescent patient, any large brain hemorrhage is more likely the cause than the result of hypertension, except in patients with cyclosporine-induced thrombocytopenia [Schwartz et al., 1995]. Multiple infarctions are sometimes found in association with hypertensive encephalopathy. It may be important in some cases to exclude CNS infection by lumbar puncture. Both opening pressure and protein may be elevated in hypertensive encephalopathy, but cell count should be normal. The electroencephalogram is usually slow, resembling that of uremic encephalopathy. It may identify subclinical seizures. Focal EEG abnormalities may suggest infarction or subdural, intraparenchymal hemorrhages or tumor. However, focal clinical or EEG abnormalities may also be detected in hypertensive encephalopathy or uremic encephalopathy without identifiable structural lesions [Dinsdale, 1983]. Prompt remission with control of blood pressure is the most important confirmation of hypertensive encephalopathy [Healton et al., 1982; Hinchey et al., 1996; Kandt et al., 1995]. Medications employed in the management of blood pressure in children are shown in Table 89-1. Selection, utilization, side effects, and detailed dosage considerations for these medications fall outside the scope of this chapter. All patients should initially be managed as if cerebral edema is present. The fundamental steps include elevation of the head of the bed by 30 degrees and careful attention to free water balance. Further decisions about treatment depend on etiology. Unless hypertension is very severe, drug therapy should not be undertaken until space-

TABLE 89-1 Antihypertensive Medications Useful in Children MEDICATION

ROUTE

Diazoxide Hydralazine Labetalol Sodium nitroprusside Captopril Chlorothiazide Furosemide Hydralazine Minoxidil Nifedipine Prazosin Propranolol Spironolactone

IV bolus IV/IM IV IV PO PO PO PO PO PO PO PO PO

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occupying CNS lesions (stroke, tumor, hemorrhage) and the brittle dysautonomia of Guillain-Barré syndrome are excluded. Other important etiologic considerations for acute encephalopathy include intoxication, acute pulmonary edema, acute pancreatitis, and endocrine or metabolic diseases. Rarely, an acute anxiety reaction with hypertension and pseudoencephalopathy must be excluded. A careful history and examination should determine the selection of appropriate laboratory tests. If severe blood pressure elevation and the threat of permanent CNS injury (e.g., rapidly progressive visual loss) are present, blood pressure should be treated medically [Thien et al., 1979]. Care should be taken not to reduce the mean arterial pressure lower than the lower limit of cerebral blood flow autoregulation. Below this level, maximal autoregulatory vasodilatation fails to prevent cerebral ischemia and permanent nervous system injury may result [Brown et al., 1987; Graham, 1975; Hulse et al., 1979; Sebire et al., 1995]. Predicting this lower limit is difficult given agerelated variation, as well as the fact that chronic hypertension may reduce the vasodilatory capacity of arterioles and thus raise the mean pressure at which decompensation occurs. Within these limits for blood pressure reduction, aggressive treatment is likely to be well tolerated except in the setting of increased intracranial pressure and dysautonomia, as in Guillain-Barré syndrome. The risk for neurologic sequelae (blindness, coma, pyramidal tract injury) from iatrogenic hypotension is related not only to the severity but also to the duration of hypotension [Franklin, 1984]. In most patients with childhood-accelerated hypertension, aggressive and safe blood pressure reduction can be achieved with intravenous sodium nitroprusside. This highpotency, brief-duration agent provides the considerable advantage of momentary titration to the responses of the individual patient. Sustained use in renal failure carries the risk of intoxication. Labetalol is another useful intravenous medication, but the longer duration of action is disadvantageous or even dangerous if hypotension develops. In patients with less severe elevations of blood pressure, hydralazine or nifedipine may be used [Kandt et al., 1995; Trompeter et al., 1982]. Captopril is a particularly useful agent in patients with renin-dependent hypertension (essential, renovascular, hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura–related). Diazoxide is the medication most commonly associated with untoward hypotensive reduction of blood pressure with deleterious consequences. Large-bore venous access should be secured in every patient against the possibility of sudden hypotension, whatever therapeutic approach is undertaken. The appropriate medication choice and the dosage for use in the newborn are not well defined. Sodium nitroprusside may pose a greater risk for intoxication, and both methyldopa and reserpine may cause profound sedation. Acute management of severe cerebral edema may involve mechanical hyperventilation, osmotic agents, or corticosteroids. In such instances, placement of an intracranial pressure monitor should be considered, especially with hyperventilation, because this action is associated with risk for reflexive cerebral capacitance vessel vasoconstriction that may worsen cerebral and brainstem perfusion defects. Osmotic agents may accumulate in acute renal failure and

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should be carefully dialyzed. Some patients respond slowly to treatment or develop permanent deficits, particularly visual and motor ones [Hulse et al., 1979]. Antiepileptic medications should be administered to children with acute, persistent seizures, but chronic anticonvulsant therapy is seldom required. Chronic hypertension carries a significant risk for seizures, cerebral thrombosis/hemorrhage, subarachnoid hemorrhage, and Bell’s palsy even if acute hypertensive encephalopathy does not occur [Schottstaedt and Sokolow, 1953]. Some adults develop a subacute progressive hypertensive encephalopathy with pathologically identifiable changes in the deep cerebral microvasculature [Fisher, 1998]. It is unclear whether chronic hypertension or multiple episodes of acute blood pressure elevation produce similar changes in children. A number of antihypertensive medications may impair intellectual function of children and adults. Of particular importance are methyldopa, reserpine, propranolol, and clonidine. These changes may be due in part to sedation (usually transient), sleep disturbance, or depression [Light, 1980].

COMPLICATIONS OF CHRONIC RENAL FAILURE The prevalence of chronic renal failure is 18 per 1 million children. End-stage renal disease is present in 1.5 per 1 million children [Leumann, 1976]. All of the neurologic complications observed in acute renal failure may occur as complications of chronic renal failure, particularly during acute uremic or hypertensive decompensations. However, other subacute forms of neurologic dysfunction not encountered in acute renal failure are characteristically observed in chronic renal failure and especially end-stage renal disease (defined as a glomerular filtration rate below 2.9 mL/minute/m2, the level at which dialysis is required to maintain homeostasis) [Nissenson et al., 1977]. Chronic renal failure may be complicated by one of two different types of dementia. The first of these disorders is observed in young children with renal failure manifesting in infancy and is termed congenital uremic encephalopathy. The development of this dementia is independent of dialysis and is accompanied by microcephaly and severe growth failure. A second type of dementia, termed progressive dialysis encephalopathy, is found in dialyzed adolescent and adult patients with end-stage renal disease. Other complications of dialysis, chronic renal failure, and end-stage renal disease include headache, dialysis disequilibrium syndrome, dialysis-associated seizures, Wernicke’s encephalopathy, cerebral hemorrhage, uremic neuropathy, and various neurologic complications of transplantation.

Congenital Uremic Encephalopathy Severe chronic uremia (glomerular filtration rate ≤ 10% of normal) developing in the first year of life carries a very high risk for ensuing subacute progressive encephalopathy [Foley et al., 1981; Valanne et al., 2004]. Most of these infants have inherited forms of nephrosis, particularly congenital nephrosis of the Finnish type. It is possible that some of the neurologic abnormalities noted in these infants are independently inherited developmental abnormalities or due to

the prenatal metabolic effects of nephrosis. The appearance of abnormalities may appear after a latent interval. Early provision of dialysis has not prevented development of congenital uremic encephalopathy. Some children with genetically determined congenital nephroses have worse neurologic outcomes than others. There is emerging evidence concerning coexpression of defective enzymes in brain and kidney that may account for abnormal development and function of both organs. An important research priority remains that of discovering whether the neurologic abnormalities of congenital nephroses are (1) the inexorable result of unpreventable heritable neurodevelopmental defects or the effects of prenatal toxicity of the uremic state, or (2) whether and to what extent they may be due to postnatal course and treatment of the congenitally nephrotic child. Older studies have tended to group all individuals with infantile onset of severe renal failure (those that survive the neonatal period) together for follow-up studies without consideration of varied genetic causes that are now appreciated. These studies have proved that more than two thirds of such children manifested seizures and developmental arrest in the first year of life, followed in the second year by developmental regression with acquired microcephaly [Polinsky et al., 1980, 1987; Sedman et al., 1984]. By several years of age, 60% to 80% have epilepsy (focal or generalized), as well as moderate-to-severe motor, cognitive, language, and psychosocial delay [McGraw et al., 1986; Rotundo et al., 1982]. By comparison, studies from the same era found that at least 90% of children who developed end-stage renal disease after early infancy enjoyed normal psychomotor development even if assessed after far greater durations of illness and dialysis [Rasbury et al., 1983]. Despite careful attention to nutrition and metabolic parameters, the linear growth of the majority of children with infantile-onset end-stage renal disease is retarded. More than two thirds of these children have acquired microcephaly. Craniosynostosis develops in a small number. Neurologic abnormalities include varied degrees of ataxia, choreoathetosis, facial myoclonus, hypotonicity, weakness, and hyperreflexia. If language develops, it is often compromised by dysarthria and lingual apraxia [Polinsky et al., 1987]. Most children with congenital uremic encephalopathy die within the first few years of life, often from progressive bulbar failure [Rotundo et al., 1982]. No evidence exists that renal transplantation reverses or even arrests progression of congenital uremic encephalopathy. Improved neurologic function with dialysis remains a reliable way to distinguish acute infantile uremia with encephalopathy from congenital nephrosis with progressive uremic encephalopathy that does not manifest improvement [McGraw et al., 1986]. Inexorable decline in neurologic function and somatic growth despite careful attention to metabolic parameters is so characteristic that the diagnosis of congenital progressive uremic encephalopathy can usually be made on clinical grounds. The electroencephalogram initially indicates generalized slowing in either form of encephalopathy, but in the congenital progressive form the EEG organization deteriorates in a fashion parallel to observed neurologic deterioration despite treatment, with the development of paroxysmal sharp, rhythmic slow, or polyspike-wave discharges. The EEG findings improve in infantile uremia with encephalopathy in a fashion that

Rust and Chun / Interrelationships between Renal and Neurologic Diseases and Therapies

roughly parallels improvement in the clinical capacities of the appropriately treated infant. These characteristic paroxysms resemble those observed in older children and adults with progressive dialysis encephalopathy [Guisado et al., 1975; Jacob et al., 1965]. Brain imaging of infants with progressive uremic encephalopathy due to congenital nephrosis usually reveals brain atrophy [Baluarte et al., 1977; McGraw and Haka-Ikse, 1985], although pseudoatrophy due to the concurrent use of corticosteroids in many of these children makes interpretation of scans difficult until encephalomalacia is fairly advanced. Pathologic examination of the brain of children with congenital nephrotic syndromes has confirmed that sulcal widening and enlarged ventricles are the result of neuronal loss greatest in the cerebral cortex, brainstem sensory nuclei, and reticular formation [Papageorgiou et al., 1982]. The volume loss is compounded by wallerian degeneration in the subcortical and brainstem fiber pathways. Most children with congenital nephrosis have inherited the severe Finnish type. It is an autosomal recessive condition due to mutations in both nephrin gene (NPHS1) alleles. Many of these children are born a month or so before term and have low birth weight, microcephaly, ascites, edema, and massive proteinuria. Suspicion of this condition is raised by the detection of persistent elevation of amniotic fluid α-fetoprotein without evidence for neural tube defects. The severity of the Finnish type of congenital nephrosis has led to termination of some pregnancies [Overstreet et al., 2002]. Many infants with Finnish type congenital nephrosis die in the first few weeks or months of life. This genetic defect results in structural and functional abnormalities of the podocyte foot processes and slit-diaphragm structures of the developing kidney [Finn, 2003; Pollak, 2003; Valanne et al., 2004]. These infants lack expression in kidney of nephrin and have diminished kidney expression of synaptopodin and GLEPP1, proteins that are crucial to the assembly of the kidney podocyte and associated structures. It has recently been discovered that these proteins are also expressed in neurons. Their function in the nervous system is as yet uncertain, although they may play a role in synaptic plasticity [Deller et al., 2000, 2002, 2003; Mundell et al., 1997; Mundell and Kelly, 1998]. Some children with congenital nephrosis have corticosteroid-resistant focal segmental glomerulosclerosis. Often, these children also have neurologic abnormalities. This form of congenital nephrosis occurs as the result of mutations of both podocin gene (NPHS2) alleles. The relationship among nephrin, podocin, αactinin-4 (ACTN4) and other genes whose proteins are coexpressed in kidney and brain to the poor neurologic development in many children with severe congenital renal disease remains unclear. Diminished expression of these various proteins is also found in renal conditions such as minimal change disease, which is not associated with neurologic abnormalities. In addition to genetic conditions that affect kidney structure, metabolic conditions such as type 1 carbohydrate-deficient glycoprotein disease may produce the phenotype of congenital renal failure with abnormal growth and neurologic dysfunction [Drouin-Garraud et al., 2001]. Galloway-Mowat, arthrogryposis, renal dysfunction, and cholestasis (ARC), and progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome are among the heterogenous collection of phenotypes

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with early-onset nephropathy associated with various neurologic abnormalities. The Galloway-Mowat phenotype includes children with microcephaly, cerebellar atrophy or hypoplasia, and nephrosis due to focal segmental glomerulosclerosis that may not become clinically apparent until several years of age. End-stage renal disease may not develop until near the end of the first decade of life [Shiihara et al., 2003]. Certain potentially deleterious but preventable postnatal influences on neurologic development in children with congenital or early childhood chronic renal failure have been identified. These include aluminum toxicity, vascular accidents, chronic uremia, hypertension, malnutrition, circulatory disturbances, and psychosocial deprivation [Arieff and Armstrong, 1980; Chantler et al., 1981; Cogan et al., 1978; Elzouki et al., 1994]. ALUMINUM TOXICITY. Until recently, almost all infants with severe early-onset renal disease have received high doses of aluminum-containing phosphate binders indicated for the treatment of hyperphosphatemia that is the result of secondary hyperparathyroidism [Polinsky et al., 1980; Randall, 1983]. Aluminum is now known to be toxic, especially in the setting of hyperparathyroidism. Aluminum exposure has been identified in epidemiologic studies as a significant risk factor for encephalopathy in patients with end-stage renal disease at any age. Progressive dementia has been demonstrated in industrial aluminum exposure. Aluminum was proposed as a cause of Alzheimer’s disease, although evidence has appeared increasingly unconvincing [Crapper et al., 1973, 1976]. It has been suggested, on the basis of limited information, that the known neurotoxicities of aluminum are due to alteration of cellular repair mechanisms, derangement of neurotransmitter or energy metabolism, or deleterious affects on vascular reactivity [Polinsky and Gruskin, 1984; Starkey, 1987; Wilson and Fearon, 1984]. It has also been suggested that aluminum may serve as an adjuvant for the toxic effects of other circulating toxins. It may alter membrane (e.g., blood-brain barrier) characteristics, permitting greater access of toxins to the CNS. Sources of aluminum have included water (used in dialysate or commercially prepared infant formula), intravenous solutions, and parenteral medications, and especially the aluminum salts administered to control hyperphosphatemia [McGraw et al, 1986; Milliner et al., 1985; Sedman et al., 1985]. Bladder irrigation with alum as a treatment for hemorrhagic cystitis has resulted in acute encephalopathic deterioration of patients with chronic renal failure [Perazella and Brown, 1993]. Infants with congenital uremic encephalopathy have been found to have serum, bone, and brain concentrations of aluminum that exceed control values by up to 25-fold [Andreoli et al., 1984; Freundlich et al., 1985; Nathan and Pedersen, 1980]. Serum levels of aluminum do not correlate directly with degree of putative neurotoxicities observed in a given individual [Sedman et al., 1984]. Infants were at high risk for aluminum toxicity because of one or more of the following: (1) the total daily aluminum salt doses calculated for infants on a weight basis have been far higher than the total daily doses administered to older patients with end-stage renal disease (>100 mg/kg/day); (2) gut absorption and brain penetration by aluminum may be greater in infants, especially if they

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have hyperparathyroidism; and (3) cow’s milk and infant formulas enriched in phosphate have prompted the use of higher doses of aluminum-containing phosphate binders [Polinsky et al., 1987]. Management of infantile chronic renal failure without the use of aluminum salts has greatly diminished the prevalence of progressive nephrotic encephalopathy. In one study, infants managed without these salts who receive vigorous nutritional and psychosocial support have demonstrated markedly improved neurologic outcome by 4 years of age. Neurologic examinations of such children may indicate only hypotonia. Microcephaly is found in approximately one third, brain atrophy in 20%, developmental delay in 20%, and neuropathy in less than 15% [Elzouki et al., 1994]. On the other hand, congenital uremic encephalopathy has developed in some infants who have never received aluminum-containing phosphate binders. STROKES. Vascular accidents may cause acquired neurologic injuries in children with congenital nephroses. At 6 to 11 years of age, 50% of brains of children who have onset of nephrosis in the first year of life have vascular border zone abnormalities, mostly mild, suggesting prior ischemic brain injury. A smaller percentage has large artery territory or basal ganglia infarcts, and some have brain atrophy. The presence of lesions suggesting vascular territory infarctions appears to correlate with history of pretransplantation hemodynamic crises and with greater duration of management by dialysis before renal transplantation [Valanne et al., 2004]. Attention devoted to ensuring hemodynamic stability in infants undergoing dialysis for chronic renal failure and early consideration of transplantation may improve outcome. MALNUTRITION. Head circumference is a reliable index of brain injury in malnourished infants with congenital uremic encephalopathy [Winick et al., 1971]. That severe encephalopathy does not develop in most patients with malabsorption syndromes despite poor somatic growth suggests that factors other than nutrition are of greater importance in producing this vulnerability to poor brain growth in children with congenital uremic encephalopathy [McGraw and Haka-Ikse, 1985]. Tube feedings and special formulas have improved growth but do not appear to prevent congenital uremic encephalopathy. Nutritional disorders are difficult to dissociate from the metabolic and endocrine dysfunction of chronic renal failure. Recent information suggests that vitamin B12 deficiency with abnormality of methionine metabolism and hyperhomocystinuria may contribute to neurologic abnormalities [Herrmann and Knapp, 2002]. Renal osteodystrophy and hyperparathyroidism, routinely found in patients with congenital renal failure, have long been appreciated as factors of importance in developmental and growth delay. Osteodystrophy may secondarily impair gross motor function but does not explain the significant delay exhibited by these patients in other areas of development. ENDOCRINOPATHY. Hyperparathyroidism and either hypercalcemia or hypocalcemia may directly injure the nervous system [Seyahi et al., 2004]. Uremia with hyperparathyroidism is associated with slowing of the EEG and may increase brain calcium to the extent that cerebral calcification results. This calcification is found in the subcortex

and basal ganglia in children, rather than the cortical and hypothalamic calcification more typical of adults with endstage renal disease. Parathyroid hormone excess may directly affect neurotransmission in brain [Smits et al., 1983]. Studies in animals and human adults have found that encephalopathy may be prevented or ameliorated with parathyroidectomy [Akmal et al., 1984; Mahoney and Arieff, 1983]. Poor somatic growth in congenital chronic renal failure has been ascribed in part to hypothalamicpituitary dysfunction [Schmitz and Moller, 1983]. It has been found that normalization of parathyroid hormone leads to acceleration of growth velocity and “catch-up” growth in children with chronic renal failure [Waller et al., 2003]. Some patients with congenital onset of chronic renal failure have fulminant deterioration in neurologic function at some point in their course. Often, this deterioration occurs in association with infection, severe metabolic decompensation, or after surgery, including renal transplantation [Griswold et al., 1983]. In such patients, CNS infection, hemorrhage, electrolyte disturbances, intoxications, and hypertension must be excluded.

COMPLICATIONS OF DIALYSIS Dialysis is efficacious in the remediation or prevention of acute uremic encephalopathy in patients with severe renal failure and is also beneficial in the treatment of uremic peripheral neuropathy and of some cases of acquired deafness [Mitschke et al., 1975]. Dialysis is associated with many potential complications of greater or lesser significance. Many are neurologic, including headache, dialysis disequilibrium syndrome, thiamine and carnitine deficiencies, intracranial hemorrhage, and progressive dialysis encephalopathy. Dialysis complications are three times as common during the first four dialysis sessions than later [Rosa et al., 1980]. Problems related to the preparation of dialysis fluids are now seldom encountered. When they do occur, they tend to manifest as seizures or decline in mental status. Once such improperly prepared fluids are identified, a satisfactory outcome may be achieved after gradual correction with properly prepared dialysate even after severe hypernatremia [Borrego Dominguez et al., 2003]. Prevalences of complications of dialysis vary from common to rare. Headache (2% to 25%) or cramps (15% to 50%) are common. Exceedingly rare complications in children include Wernicke’s encephalopathy and dialysisassociated amyloidosis [Lopez and Collins, 1968; Rosa et al., 1980]. The incidence of many complications has decreased markedly in the past decade, particularly dialysis disequilibrium syndrome. Episodic hypertension is a common concern in dialysis and may be associated with hypertensive encephalopathy, brain hemorrhage, severe headache, and pulmonary edema. It is caused by extracellular fluid accumulation between dialysis sessions and the secretion of large amounts of renin, especially during and immediately after dialysis sessions. Hemodialyzed patients (especially blacks) may develop encephalopathy with hypertension related to acute pancreatitis [Avram, 1977].

Rust and Chun / Interrelationships between Renal and Neurologic Diseases and Therapies

Headache The frequency of dialysis-associated headache is unclear, with various reports suggesting figures between 2% and 70% of patients with chronic renal failure/end-stage renal disease [Antoniazzi et al., 2002; Bana and Graham, 1976; Goksan et al., 2004; Rosa et al., 1980]. There is no reliable information concerning the frequency of headache in children who undergo dialysis. Mild-to-moderate headache is not uncommonly reported by older children. Criteria for diagnosis have been established by the International Headache Society and require headache related to dialysis to begin during hemodialysis and terminate within 24 hours of onset [Antoniazzi et al., 2003]. It is likely that dialysis headache is prompted by water and electrolyte shifts or by other aspects of dialysis disequilibrium (see later). Risk can be reduced by adjustment of dialysis parameters, including the use of sodium modeling programs during dialysis rather than administering a constant concentration of dialysate sodium [Sadowski et al., 1993]. Dialysis headache may share some of the mechanisms of water-deprivation headache [Blau et al., 2004]. Patients with higher predialysis systolic and diastolic blood pressure may be at greater risk for headache, as well as those who experience dialysis-related hypotension or weight loss [Antoniazzi et al., 2002; Goksan et al., 2004]. Our experience suggests that at least half the children who experience dialysis-associated headaches have historical evidence for a migrainous disorder, although their worst headaches may develop only with dialysis. Family history, occurrence of throbbing hemicrania, and relief with sleep support the diagnosis of migraine. Migrainous dialysis headache develops after several hours of dialysis, usually with bilaterally throbbing pain, but pain may have a viselike or dull quality. Headache is known to respond to administration of ergot or butalbital and rest [Bana and Graham, 1976]. Various other analgesics have been employed, including dipyrone [Antoniazzi et al., 2002]. There is as yet no information on the risks and benefits of triptans in this setting. Children or adolescents who do not have a history of migrainous headaches may also develop headaches of mild to moderate severity after 3 to 4 hours of dialysis. These headaches often respond to acetaminophen with or without butalbital. Headache can result from readily detectable metabolic abnormalities (e.g., hypernatremic cellular dehydration or water intoxication), which must in some instances be excluded. Hypertension or subdural hemorrhage should be considered when headache is more severe or persistent, particularly if obtundation or new focal neurologic signs are present [Raskin and Fishman, 1976b]. Subdural hemorrhage associated with anticoagulation is a rare but important complication of dialysis. It causes progressive headache and obtundation, often with focal neurologic signs. Use of wornout cellulose acetate dialysis membranes has been blamed for an outbreak of postdialysis headache and, in some instances, loss of hearing or vision (with corneal opacity) [Hutter et al., 2000].

Dialysis Disequilibrium Syndrome Dialysis disequilibrium syndrome is a variable but distinctive mixture of neurologic symptoms and signs that are

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particularly likely to occur in the early phases of a dialysis program [Kiley, 1984]. In the early days of dialysis, disequilibrium syndrome occurred in nearly 10% of adults and more than 30% of children [Grushkin et al., 1972; Tyler and Tyler, 1984]. The most common manifestations are irritability or restlessness, fatigue, headache, nausea, blurred vision, muscle cramps, and, in some instances, twitching. Hypertension, tremulousness, vomiting, disorientation, agitated delirium, seizures, visual loss, elevated intraocular pressure, papilledema, and asterixis are sometimes seen [Kennedy et al., 1964; Peterson and Swanson, 1964]. Wernicke’s encephalopathy has been reported rarely. Coma may develop, and death may occur from central herniation [Milutinovich et al., 1979]. EEG changes are usually limited to variable degrees of background slowing. The syndrome is particularly likely to occur with recently initiated dialysis, utilization of rapid dialysis protocol, or dialysis with ultrafiltration [Kerr, 1980; Raskin and Fishman, 1976b; Tyler, 1968; Young et al., 1988]. The onset may be from 3 to 4 hours after initiation or as late as 20 hours after the completion of a dialysis session. Intellectual dysfunction, psychiatric symptoms, and visual abnormalities are usually self-limited, lasting for several hours. These problems may, in some instances, persist for several days. It is likely that subtle and unrecognized intellectual dysfunction occurs not infrequently in the early stages of dialysis as a manifestation of mild dialysis disequilibrium syndrome. Dialysis with rapid correction of hyponatremia has been blamed for one case of fatal pontine myelinolysis [Loo et al., 1995]. The term osmotic demyelination has been applied to some patients who experience deterioration of neurologic function after dialysis and are found to have hypointense abnormalities on T2-weighted MRI in the region of the pons. These changes may be found also in some patients with dialysis-associated seizures or mild disturbances of consciousness. Repeat scans usually demonstrate the rapid and complete disappearance of these changes, the imaging characteristics of which are consistent with edema. It is likely that many individuals with dialysis disequilibrium have merely developed transient dialysis-related brain edema rather than demyelination [Tarhan et al., 2004]. Dialysis removes osmotically active molecules from blood more rapidly than they can diffuse out of the brain. This movement results in an osmotic gradient that provokes net flow of water into the brain, resulting in cerebral edema, increased intracranial pressure, and encephalopathy [Arieff et al., 1973; Wakim, 1969a, 1969b]. These deleterious osmotic gradients were ascribed to effects of urea (“reverse urea syndrome”) because dialysis disequilibrium syndrome did not appear to develop when nonuremic patients were dialyzed [Kennedy et al., 1963; Kleeman et al., 1962; Peterson and Swanson, 1964], but studies failed to provide convincing evidence of a significant urea gradient [Pappius et al., 1967; Wakim, 1969a]. Urea enters the brain at a very slow rate, but the use of a urea-containing dialysate has failed to prevent edema. Another theory suggested that osmotic activity is the result of retention within the brain or nonurea “middle molecules” or “idiogenic osmoles” [Arieff et al., 1973]. The fall in cerebrospinal fluid pH that may occur during dialysis was cited as indirect evidence for the accumulation of osmotically active organic acid and amine

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“middle molecules” in the CNS of patients with chronic renal failure [Arieff et al., 1978]. Another study found no evidence for any additional contribution by “idiogenic osmoles” to dialysis-induced cerebral edema [Silver et al., 1992]. Short echo-time magnetic resonance spectroscopy has documented changes in cerebral concentration of myoinositol, choline-containing compounds, and water in brain during dialysis. These changes were greater in gray matter than in white matter [Michaelis et al., 1996]. Modifications in dialysis protocols have significantly reduced the frequency of dialysis disequilibrium. These modifications have included changes in dialysis priming, increased dialysate salt concentration, inclusion of colloids such as mannitol and albumin, limitation of dialysis to 10% of blood volume, and more gradual initial reduction of blood urea nitrogen to the range of 70 to 80 mg/dL. The most important element in preventing dialysis disequilibrium is early diagnosis and dialysis so that profound azotemia (blood urea nitrogen ≥ 200 mg/dL) is rarely encountered [Arieff et al., 1978; Port et al., 1973]. If dialysis disequilibrium is severe, mannitol administration may be beneficial. The use of mannitol must be carefully coordinated with dialysis to ensure that the mannitol and mobilized fluid are removed from the circulation with appropriate speed. Seizures due to dialysis disequilibrium are usually transient.

Dialysis-Associated Seizures Dialysis-associated seizures occur in 7% to 10% of children (newborn to 21 years) with end-stage renal disease. Most are generalized tonic-clonic seizures that occur during or shortly after dialysis [Swartz et al., 1983]. They are more commonly associated with hemodialysis (8% to 9%) than peritoneal dialysis (0% to 4%) [Grushkin et al., 1972] and are likely due to chemical or osmotic disequilibria. The risk for dialysis-associated seizures is as high as 29% in children with a history of seizures [Glenn et al., 1992]. Other risk factors are young age, malignant hypertension, or encephalopathy due to uremia, dialysis disequilibrium, or congenital uremic encephalopathy [Swartz et al., 1983]. Seizures are more likely to occur during the early phases of a dialysis program when solute changes are the greatest. Increased risk with hemodialysis may be related to more rapid clearance of electrolytes and other osmotically active solutes by this method than by peritoneal dialysis [Glenn et al., 1992]. The frequency of dialysis-associated seizures in older children and in children who have undergone dialysis for more than 2 months may be accounted for by the greater likelihood of hemodialysis in those groups [Glenn et al., 1992; Polinsky et al., 1980]. Severe azotemia (blood urea nitrogen > 200 mg/dL), hypocalcemia (<6 mg/dL), hypomagnesemia (<1 mg/dL), anemia (hemoglobin < 5 mg/dL), hypertonicity, acidosis, and hypoxemia also increase the risk for dialysis-associated seizures [Swartz et al., 1983]. MRI abnormalities suggesting edema in the pons, as well as in extrapontine locations, may be present and resemble changes seen in dialysis disequilibrium syndrome [Tarhan et al., 2004]. The electroencephalogram may indicate frontal intermittent rhythmic delta and diffuse slowing with prominent photic activation [Watemberg et al., 2002]. These changes have been interpreted by some as representing the

presence of old structural injury perhaps related to ischemic watershed infarction [Watemberg et al., 2002]. The efficacy of antiepileptic drugs in treating or preventing dialysisassociated seizures is poorly defined. The use of readily dialyzable medications may increase the risk for dialysisassociated seizures because these drugs are removed at the same time that the dialytic metabolic stress may induce seizures.

Vitamin and Cofactor Deficiencies The B vitamins are water soluble, and most are readily dialyzable. A single dialysis session may reduce plasma thiamine concentration by as much as 40% [Lasker et al., 1963]. Patients with end-stage renal disease are therefore at risk for thiamine deficiency, which may present as confusion progressing rapidly to obtundation or coma. Associated findings may include chorea, visual loss, ophthalmoparesis, ataxia, myoclonus, or seizures. It has been estimated that this deficiency may account for as many as one third of all cases of unexplained acute encephalopathy in chronically dialyzed adults [Hung et al., 2001a, 2001b]. It is somewhat surprising that symptomatic thiamine deficiency has been reported only rarely in children, probably because stores of thiamine accumulated before the development of renal disease are only gradually depleted and considerable effort is expended by parents and caregivers to ensure good nutrition. Wernicke’s encephalopathy has been described in a child undergoing dialysis who demonstrated the characteristic triad of ophthalmoplegia, encephalopathy, and ataxia [Faris, 1972]. Adult cases usually develop in the wake of prolonged malnutrition [Raskin and Fishman, 1976a]. Prompt recognition and treatment are important. Response to intravenous thiamine may confirm the diagnosis [Hung et al., 2001b]. Pyridoxine-deficiency seizures have been described in a child treated with peritoneal dialysis [Joshioka et al., 1984]. Deficiency of vitamin B12 may, in turn, provoke abnormal methionine metabolism. Hyperhomocystinuria is an important indicator of vitamin B12 deficiency. If found, it is associated with higher risk for preeclampsia, neural tube defects in offspring, atherosclerotic arterial disease (large and peripheral vessels), stroke, and venous thrombosis [Herrmann and Knapp, 2002]. Supplementation with B vitamins is routine to avoid these various complications [Kopple and Swendseid, 1975]. Dialysis may also result in depletion of serum carnitine; the possible clinical significance of this effect requires more investigation [Bartel et al., 1982].

Intracranial Hemorrhage The incidence of subdural hematoma among children is unknown but is probably less than 10% [Grushkin et al., 1972]. Replacement of generalized with regional anticoagulation minimizes the risk of this serious complication. Subdural hematoma must be considered in renal patients with persistent drowsiness, headache, or vomiting, and particularly in those with persistent focal neurologic signs (typically hemiparesis) or meningismus. Signs and symptoms may fluctuate or progressively worsen [Bechar et al., 1972; Leonard and Shapiro, 1975].

Rust and Chun / Interrelationships between Renal and Neurologic Diseases and Therapies

Progressive Dialysis (Aluminum) Encephalopathy (Dementia) A progressive and lethal dementia affecting patients with endstage renal disease and manifesting dyspraxia and multifocal seizures at the onset was first described by Alfrey and associates in 1972. The entity quickly assumed epidemic proportions and caused considerable consternation in dialysis patients and their physicians [Mahurkar et al., 1973]. Aluminum exposure was the result of utilization of dialysate water purified with aluminum sulfate techniques and from the utilization of aluminum hydroxide as a phosphate binder [Dunea, 2001]. A largely unheeded warning of the potential toxicity of aluminum had been offered in 1970 [Berlyne et al., 1970], but the flurry of research that followed Alfrey’s report of the clinical syndrome greatly enhanced recognition of the public health threat posed by this metal. In the early stages, aluminum dementia must be distinguished from each of the many treatable forms of encephalopathy associated with chronic uremia (see earlier), including various metabolic disequilibria. It is especially important to consider thiamine deficiency, a condition for which all end-stage renal disease patients are at risk and which may present as confusion progressing rapidly to encephalopathy or coma (see earlier discussion). The chronically poor development and gradual decline of patients with congenital uremic encephalopathy is usually readily distinguishable from the abrupt deterioration of function that occurs early in aluminum dementia. Acquired speech dyspraxia is especially difficult to distinguish from the severe speech and language problems characteristically found in individuals with Finnish-type congenital renal failure.

Milder Forms of Encephalopathy Neuropsychologic studies of adults have consistently documented subtle forms of cortical dysfunction in some patients with chronic renal failure, particularly low verbal IQ. Ability to concentrate may be reduced by even moderate azotemia [Teschan et al., 1983]. Little systematic information is available concerning subtle intellectual dysfunction and learning disability in children with end-stage renal disease. However, abnormalities of performance IQ, short-term visual and auditory memory, attention span, memory, and speed of decision making have been documented. The risk for such problems is greatest if end-stage renal disease developed in early childhood (particularly during the first year of life) or if the disease is of very long duration [Crittenden et al., 1985; Fennell et al., 1984; Osberg et al., 1982; Polinsky et al., 1980]. Subtle intellectual and behavioral abnormalities that are responsive to dialysis have been detected in older [Grushkin et al., 1972] but not all [Fennell et al., 1986] studies. Evaluation of speech performance requires consideration of the high prevalence of depression, emotional stress, and hearing abnormalities in patients with chronic renal failure and exclusion of the confounding effects of prior developmental dysmaturity and chronic hospitalization. Sensorineural hearing abnormalities may be present in as many as half of patients with end-stage renal disease [Bergstrom and Thompson, 1983; Mirahmadi and Vaziri, 1980]. Drugs used

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for treatment of end-stage renal disease and its complications may provoke encephalopathy (see later). Seizures may interfere with school performance. The electroencephalogram must be interpreted cautiously because up to half of children with end-stage renal disease have bursts of spikeand-wave activity without evidence of clinical seizures [Foley et al., 1981]. Poor intellectual function should lead to identification and scrupulous correction of metabolic abnormalities. Moderate uremia may result in disturbances ranging from mild encephalopathy to mild chronic delirium or psychosis [Richet and Vachon, 1966]. In some patients, intellectual dysfunction, deafness, and neuropathy (see later discussion) unresponsive to optimal dialysis may improve after successful transplantation [Brown et al., 1987; Fennell et al., 1984; Mitschke et al., 1975]. Hypophosphatemia (especially serum phosphate < 1.0 mg/dL) is associated with delirium. A combination of aluminum binders, dialysis, and poor diet (often the consequence of anorexia in patients with chronic renal failure) may also provoke mental status changes. Neurologic dysfunction ranging from confusion to nonketotic hyperosmolar coma may occur as the result of using dialysate with a high glucose concentration.

Uremic Neuropathy (Neuropathy of Chronic Renal Failure) Peripheral neuropathy, first reported more than 40 years ago [Hegstrom et al., 1962], occurs in some patients with advanced chronic renal failure. Asbury and colleagues [1963] provided the earliest detailed description. Somatic and autonomic nerves may be involved [Jedras et al., 2001]. Risk for neuropathy is not limited to any particular etiologic category of chronic renal failure. As with other neurologic complications, duration and severity of chronic renal failure (e.g., degree of loss of glomerular filtration) are the most important determinants of occurrence and severity of neuropathy [Jurcic et al., 1998]. In patients with congenital or early childhood onset of chronic renal failure, clinical manifestations of neuropathy have been detected as early as 8 years of age [Oh et al., 1978]. However, few welldocumented childhood cases have been reported [Patten, 1984]. Although the term uremic neuropathy is commonly employed, the pathogenesis is complex and incompletely understood; and it may be preferable to refer to the condition as neuropathy of chronic renal failure. Onset of this condition is usually insidious. It is not known how early in the course of the development of neuropathy that electrophysiologic abnormalities can be detected. Subclinical nerve conduction slowing is a not uncommon finding of patients with end-stage renal disease [Ackil et al., 1981; Arbus et al., 1975]. Electrophysiologic abnormalities consistent with neuropathy are ultimately detectable in as many as two thirds of adults with long-standing chronic renal failure, whether or not dialysis has been initiated [Hassan et al., 2003]. Occasionally, the onset of neuropathy is fulminant, suggesting the possibility of a nonuremic etiology [Asbury et al., 1963; Kondo et al., 1997]. Males are more likely to manifest sensorimotor uremic neuropathy than females and may develop somatic neuropathy in association with uremia of milder degree and briefer

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duration, but females are more likely to manifest autonomic neuropathy [Asbury et al., 1963; Jedras et al., 2001; Versaci et al., 1964]. A “restless legs” syndrome is among the most common presenting complaints of sensorimotor neuropathy, associated with an unpleasant sensation of “crawling skin” or a “dull ache” of legs that is worse in the evening. Dysesthesias tend to be relieved by leg movement. More convenient and sustained relief may be achieved with clonazepam [Callaghan, 1966]. Pruritus, which is complained of by as many as two thirds of patients who have had long-term dialysis for end-stage renal disease, may also be a sign of neuropathy in some cases. Likelihood is greatest in individuals who also complain of paresthesias, many of whom are found to have neurophysiologic symptoms and additional clinical evidence of neuropathy [Jedras et al., 1998]. Loss of deep tendon reflexes (especially the ankle jerk), diminished vibratory sensation, and weakness of great toe extension are among the earliest signs of uremic neuropathy [Tenckhoff et al., 1965]. Paradoxical heat sensation, the tendency to identify a low-temperature stimulus as “hot,” is also a sensitive early sign of uremic polyneuropathy. This phenomenon appears to correlate not only with the degree of cold hypesthesia but also with the serum creatinine level [Yosipovitch et al., 1995]. As with other neuropathic forms of weakness, distal wasting of muscle is an important clinical sign that distinguishes neuropathic from myopathic causes of weakness. Early in the course of illness it may be difficult to discern either because wasting may be masked by obesity (due to inactivity, excessive caloric intake, or steroid use) or by excessive dependent fluid retention (due to inactivity, fluid shifts, or autonomic dysfunction). Fully developed uremic neuropathy is a distal, symmetric polyneuropathy that involves both sensory and motor modalities in a length-dependent fashion. Greatest abnormality is detected in functions subserved by large, long peripheral nerve fibers. The legs are usually more severely affected than the arms [Bakke, 1970; Nielsen, 1971a, 1971b]. In most patients, uremic neuropathy so closely resembles nutritional, diabetic, or alcoholic neuropathies as to be clinically indistinguishable. Diminished sensitivity to all sensory modalities in a glove-stocking distribution gradually develops. Pressure palsies, to which chronic renal failure/neuropathic renal disease patients are particularly subject, may alter the expected distribution of abnormalities [Bolton et al., 1971]. Other forms of dysesthesia, nocturnal calf cramps, distal weakness, and atrophy may develop and vary considerably in severity [Callaghan, 1966; Tyler, 1976]. In adolescents and adults with dialysis for end-stage renal disease, sudomotor changes and postural hypotension are common consequences of autonomic neuropathy if it develops [Yildiz et al., 1998]. It is unknown how frequently autonomic neuropathy develops in children [Bach et al., 1979]. Successful renal transplantation may simultaneously and rapidly reverse both sympathetic and parasympathetic autonomic dysfunction that has developed in adult patients with endstage renal disease [Yildiz et al., 1998]. Hearing loss, common in end-stage renal disease, may be the result of uremic axonal neuropathy, although other incompletely cleared endogenous or administered ototoxic substances may contribute to this and other neuropathic abnormalities. Uremic anemia might also contribute to the development of deafness [Shaheen et al., 1997].

Typical electrophysiologic abnormalities include slow motor nerve conduction velocities with reduced distal latencies and compound muscle action potentials of greater degree in the median, peroneal, and tibial nerves than in the ulnar nerves. Widespread reduction of sensory nerve conduction velocities and action potentials is found. Abnormalities of somatosensory-evoked potentials (including N9, N13, and N20 latencies and amplitudes) are commonly encountered, as are findings suggesting central and peripheral axonopathy. Abnormal leg F-waves, foot vibration detection thresholds, and sural nerve sensory action potential amplitude are among the most sensitive diagnostic tests for uremic neuropathy [Hassan et al., 2003; Jurcic et al., 1998; Makkar and Kochar, 1994]. If available, Von Frey hairs are excellent devices for assessment of peripheral nerve dysfunction. Quantitative assessment of vibratory sensation with a large tuning fork or especially a vibrometer (Somedic AB, Sweden) may be as sensitive as nerve conduction velocity testing in diagnosing uremic neuropathy. The persistence of apprehension of vibration of the tuning fork is assessed against the examiner’s apprehension of this sensation (e.g., placing a finger beneath the joint of the great toe, the tuning fork above it). The vibrometer may be the most sensitive approach other than Von Frey hairs, although the findings of vibrometer testing do not entirely overlap with those identified by nerve conduction testing [Hilz et al., 1995]. Electrophysiologic evidence for phrenic nerve dysfunction is found in a majority of patients with uremic neuropathy and can be predicted by the prolonged peroneal nerve conduction velocities [Zifko et al., 1995]. Sex differences do not exist for electrophysiologic manifestations of parasympathetic (e.g., electrocardiographic RR interval variation) autonomic testing, although males more frequently manifest abnormal sympathetic skin responses [Jedras et al., 1998, 2001]. Changes found on biopsy are often more severe than anticipated on the basis of the conduction velocity results [Jennekens et al., 1971]. Pathologic features of uremic neuropathy are similar to those seen in other nutritional or toxic neuropathies and include primary axonopathy with secondary segmental demyelination and remyelination, all emphasized in distal portions of large, long nerve trunks. Muscle biopsy may indicate loss of type-2 fibers [Appenzeller et al., 1971; Dyck et al., 1971; Savazzi et al., 1980]. The mechanisms of nerve injury are unknown. They are not related to urea or creatinine concentrations and, except for “burning feet,” do not involve deficiencies of vitamins or magnesium. Failure of certain energy-dependent axonal/ perikaryonal functions, including ion pumps, axoplasmic transport, and neurofilament synthesis, have been alleged as causes of axonopathy [Bakke, 1970; Dyck et al., 1971; Nielsen, 1973]. Because “middle molecules” are removed more efficiently by peritoneal dialysis and because peripheral neuropathy is less common in peritoneal dialysis than in hemodialysis, deleterious effects of these compounds have been implicated. Sugar alcohols that accumulate in chronic renal failure (e.g., myoinositol) may also play a role [Oh et al., 1978]. Diminished occurrence of neuropathy in children managed without aluminum salt exposure suggests that aluminum may have played a role in uremic neuropathy [Elzouki et al., 1994].

Rust and Chun / Interrelationships between Renal and Neurologic Diseases and Therapies

After renal transplantation, some patients develop neuropathy as a manifestation of graft-versus-host disease [Kondo et al., 1997]. Burning dysesthesia of the feet was formerly more common than at present and was likely due to dialysisinduced depletion of thiamine [Bolton, 1980]. Some patients with end-stage renal disease develop combined system degeneration owing to vitamin B12 deficiency [Kondo et al., 1997]. With vitamin B supplementation, these latter two causes of neuropathy have become rare. Many patients with uremic neuropathy become stable or slowly improve with long-term hemodialysis, although little if any improvement is seen after a single dialysis pass [Laaksonen et al., 2002]. Mild neuropathy may remit, but severe neuropathy seldom does. It is possible that increased hours of dialysis or initiation of peritoneal dialysis may provide benefit in some severe cases [el Aklouk et al., 2004]. Worsening of electrophysiologic but not clinical manifestations of neuropathy may be detected in patients who have had more than 10 years of hemodialysis [Jurcic et al., 1998]. Successful renal transplantation usually, but not invariably, leads to complete amelioration of neuropathy in 6 to 12 months, even in patients with severe neuropathy [Hodson, 1983; Nielsen, 1974a]. Improvement of motor conduction velocity can be documented within days [Oh et al., 1978] or months [Nielsen, 1974b] of transplantation. Sympathetic and parasympathetic autonomic dysfunctions remit fairly promptly after successful transplantation [Yildiz et al., 1998]. Femoral neuropathy is a rare complication of the transplant surgery itself [Probst et al., 1982; Yazbek et al., 1985]. The potential ameliorative effects of erythropoietin administration are under investigation [Hassan et al., 2003].

Uremic Myopathy (Myopathy of Chronic Renal Failure) Weakness is a common and important source of morbidity in patients with chronic renal failure, especially those on longterm renal dialysis. The limitations that weakness may place on normal activities may produce one of the most significant negative impacts of chronic renal disease on quality of life. Untoward weight gain from a variety of causes may occur in renal patients and produce a vicious cycle of weaknessengendered inactivity, inactivity-engendered weight gain, and weight-related exacerbation of weakness. The effects of this cycle and its associated rate of functional decline may be worsened by mood disturbance or by such frequently encountered intermittent causes of exacerbation of muscular weakness such as hypokalemia. In individuals with chronic advanced renal failure or endstage renal disease, corticosteroids, uremic neuropathy (see later), or uremic osteodystrophy may also contribute to weakness. Corticosteroid myopathy tends to have a much more acute onset than uremic myopathy. The particularly abrupt and severe onset of so-called acute care myopathy may occur in patients with chronic renal failure. The wide variety of other conditions that may cause acute weakness must also be considered in patients with chronic renal disease with rapidly worsening weakness, including toxic, infectious, or inflammatory diseases of muscle [Berretta et al., 1986; Chazan et al., 1970]. Chronic and progressive muscular weakness may be the secondary consequence of uremic neuropathy, which has

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already been considered. Uremic vasculopathy is another cause of secondary myopathy of smooth or striated muscles. Vascular myopathy is a necrotic process that has been ascribed to severe hyperparathyroidism with calcification of blood vessels. This process may result in impaired muscle capillary oxygen transfer [Bardin, 2003; Goodhue et al., 1972]. As with many other myopathic conditions, proximal leg weakness is the predominant finding of the deleterious consequences of uremic vasculopathy on striated muscle function. Secondary hyperparathyroidism and the associated hyperphosphatemia contribute to this vascular calcification, which may involve the coronary arteries and produce coronary vascular disease, the “silent killer” of uremic patients. It has been suggested that excessive use of calcium-containing phosphate binders may increase the likelihood of uremic vasculopathy [Bardin, 2003]. Utilization of calcium-free and (for reasons noted earlier) aluminum-free phosphate binders is likely an important advance in the avoidance of not only renal osteodystrophy but also uremic vascular myopathy. Caution may need to be taken in the use of vitamin D derivatives as well because they may enhance hypercalcemia [Bardin, 2003]. Pelvic girdle myopathy may also develop despite the absence of significant vascular changes on biopsy or evidence of other processes noted earlier that may produce weakness. As with uremic neuropathy, the pathogenesis of the myopathy of chronic renal failure is complex and as yet incompletely understood. It may involve such disparate mediators as “uremic toxins,” abnormalities of vitamin D metabolism, malnutrition, carnitine depletion, muscular energy failure, impaired protein synthesis or amino acid metabolism, hypophosphatemia, or impaired biochemical function of sarcolemma. In uremic neuropathy the most striking finding in sampled muscle is moderate atrophy involving fast-twitch (type II) muscle fibers to a greater extent than slow-twitch (type I) fibers. Severe but nonspecific ultrastructural abnormalities may also be found with electron microscopy of human biopsy specimens, and milder degrees of type II atrophy may be found in muscle biopsy specimens of uremic patients who do not have clinical myopathy. Recent detailed reviews of uremic myopathy are available [Bardin, 2003; Campistol, 2002].

COMPLICATIONS OF TRANSPLANTATION The quality of life, including certain aspects of neurologic function, of patients with end-stage renal disease is generally improved after transplantation. Dialysis-associated complications are avoided, and neuropathy usually improves. Higher cortical functions may also improve, including memory, concentration, vigilance, and even intelligence [Fennell, et al., 1986; Rasbury et al., 1983]. Transplantation improves head growth and psychomotor development of some children with end-stage renal disease [Kohaut et al., 1985; So et al., 1987]. Survival has improved with donor-related but not cadaver transplantation [Vollmer et al., 1983]. Transplantation is not helpful in some diseases that affect both the nervous system and the kidney, such as Fabry’s disease or oxalosis. Two major forms of encephalopathy (congenital uremic encephalopathy and progressive dialysis encephalopathy),

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once well established, do not improve after transplantation [Fennell and Rasbury, 1980]. For reasons noted earlier, the prevalence of progressive dialysis encephalopathy has been sharply reduced. It has not been clear why patients with congenital nephroses exhibit poor development, although emerging data suggest ischemic brain injury may play a role and that transplantation may reduce the risk for this complication. A recent study considered 33 children aged 6 to 11, most of whom had Finnish-type congenital nephrosis, who underwent prior successful transplantation for end-stage renal disease before 5 years of age. It was found that more than half of these children had brain imaging evidence for cerebrovascular border zone ischemia, whereas a smaller number had evidence for major arterial territory infarctions. It appeared that the longer the latency to transplantation for individuals with severe congenital nephrosis, the more likely that they would manifest changes suggesting brain ischemia. Clinical histories of hemodynamic crises were documented in approximately 40% of these cases; and within the limits of the study, there was no clear evidence that prematurity, perinatal complications, or sepsis accounted for the imaging abnormalities [Valanne et al., 2004]. Transplantation entails risk for a particular set of neurologic complications. These complications can be divided into those related to graft failure and those related to immunosuppression. Immunosuppressive complications can further be divided into those related to the immunosuppressed state (in combination with chronic antigenic stimulation by the graft) and those related to immunosuppressive drugs [Ram Prasad et al., 1987].

Graft Failure or Rejection A characteristic rejection encephalopathy with seizures occurs in children [Bates et al., 1986; Fine et al., 1971]. Rejection encephalopathy is clinically indistinguishable from hypertensive encephalopathy [Gross et al., 1982]. It is always important to check serum magnesium levels in patients with a recent or long-term kidney graft who manifest seizures because magnesium stores may be low in the pretransplantation epoch and after transplantation tubular reabsorption of magnesium may initially be inadequate despite maintenance of adequate glomerular filtration rate [Heering et al., 1996].

Infection Infection is uncommon during the first month after transplantation. There is no evidence of difference in infection risk with immunosuppression due to either cyclosporine or tacrolimus [Woo et al., 1997]. When early infection does occur, it is usually fulminant bacterial infection by Staphylococcus aureus or by gram-negative organisms. After the first month, subacute and chronic meningoencephalitides or abscesses are more likely to develop. The pathogens are usually opportunistic organisms, such as Listeria, Toxoplasma, Cryptococcus, or Aspergillus. Infection with pneumococci, mycobacteria, Pneumocystis, Nocardia, Histoplasma, Candida, or Mucor occurs less commonly [Barmeir et al., 1981; Cohen and Raps, 1995; Hodson et al., 1978; Rifkind et al., 1967; Rubin et al., 1981; Tilney et al.,

1982]. Of these, the agents that may present late (6 months or more after transplantation) tend to be Nocardia or Toxoplasma. Listeria and Toxoplasma gondii are the most common causes of meningoencephalitis in transplant recipients. Fever is not necessarily prominent. Listeria should be suspected if profound cerebrospinal fluid monocytosis is found [Holden et al., 1980; Lechtenberg et al., 1979]. Toxoplasma infection may produce myocardial involvement, and clinical features closely resemble systemic cytomegalovirus infection (see later discussion) [Schmidt et al., 1995]. Brain abscess, which develops in slightly more than 1% of kidney transplant patients, is most often caused by Nocardia but may also be due to infection with Aspergillus or Listeria [Lechtenberg et al., 1979; Rubin et al., 1981]. Characteristic febrile pulmonary involvement may distinguish these and other opportunistic agents (e.g., Gemella, Ochroconis gallopavum) that may cause brain abscess from tumor [Murray et al., 1975; Rifkind, 1967; Selby et al., 1997; Wang et al., 2003]. Disseminated histoplasmosis may present in a myriad of ways, particularly as mass lesions of the brain or spinal cord. Cerebrospinal fluid may be normal; and, as with other fungal infections, biopsy may be necessary to confirm the diagnosis [Livas et al., 1995]. Cryptococcal or candidal septic-metastatic mycotic encephalitis may occur [Schwechheimer and Hashemian, 1995]. Cerebral or rhinocerebral aspergilloma has had a very poor outlook [Cuccia et al., 2000], but with early diagnosis the combination of surgical removal and aggressive antifungal therapy is occasionally curative [Mrowka et al., 1997]. Cerebral cysticercosis produces ring-enhancing lesions in transplant recipients and should be considered in the southwestern United States and in many developing countries as well as in migrants from such endemic areas [Gordillo-Paniagua et al., 1987]. These various opportunistic agents carry a mortality of 46% to 86%. They are often difficult to diagnose, with brain abscess presenting in many instances as personality change or withdrawal. Given the gravity of these infectious conditions, early biopsy of brain lesions should be considered. Treatment usually involves discontinuation of immunosuppression and reinstitution of dialysis [Selby et al., 1997; Wang et al., 2003]. Viral pathogens include Epstein-Barr, herpes simplex, and varicella-zoster viruses [Peterson and Ferguson, 1984]. The risk for cytomegalovirus infection is increased by both cyclosporine and tacrolimus [Woo et al., 1997]. EpsteinBarr virus may cause particularly malignant lymphoproliferative mononucleosis with encephalopathy and can lead to fatal multisystem failure. Acyclovir treatment with termination of immunosuppression may be lifesaving. Cytomegalovirus has been associated with systemic infection, encephalitis, retinitis, polyneuropathy, transverse myelitis, and graft loss [Bale et al., 1980; Chow, 1986; Fiala et al., 1975; Schneck, 1965; Spitzer et al., 1987]. Hepatitis C virus not uncommonly infects dialyzed patients with end-stage renal disease prior to transplantation. In such preinfected patients, few observable effects are noted either before or after transplantation with immunosuppression. However, infection with hepatitis C virus acquired during or after transplantation may provoke with

Rust and Chun / Interrelationships between Renal and Neurologic Diseases and Therapies

unusual rapidity a fulminant hepatitis with or without cirrhosis. Hepatic encephalopathy develops in as many as half of these cases. Discontinuation of azathioprine, as well as in some cases cyclosporine and prednisolone, may be required to improve the ascites, jaundice, and encephalopathy. In some instances, discontinuation may be tolerated without change in graft function [Ok, 1998]. Progressive multifocal leukoencephalopathy and spongiform encephalopathy have been described in adult transplant recipients but not in children [ZuRhein and Varakis, 1974]. Pneumocystis is the most common protozoal cause of CNS infection after transplantation. Other rare pathogens include Leishmania, Strongyloides, Sporothrix, and Schistosoma [Gullberg et al., 1987; Tsanaclis and de Morais, 1986]. Tuberculosis is always a consideration, especially when no other pathogen is identified. Evaluation of cerebrospinal fluid should always be carefully considered in transplant recipients with otherwise unexplained lethargy.

Tumor Renal transplant recipients have a 1.6% to 24% risk for malignancy, typically skin cancer (Kaposi sarcoma or malignant melanoma) or non-Hodgkin’s malignant lymphoma [Penn, 1979; Tyler and Tyler, 1984]. Lymphoproliferative disorders are far more common in children than in adults who have received renal allografts and constitute the majority of neoplasms for which these children are at risk [Novello and Fine, 1982; Schneck and Penn, 1970]. The risk for reticulum cell sarcoma is increased 35-fold by transplantation [Hoover and Fraumeni, 1973]. Any of these forms of malignancy can involve the CNS. The risk for CNS glioma is also markedly increased after renal transplantation. The occurrence of these tumors may be related to reduced immune surveillance, chronic graft-related antigenic stimulation, oncogenic viruses (e.g., Epstein-Barr virus), or oncogenic effects of immunosuppressive drugs. Cyclosporine, azathioprine, and prednisone all appear to increase the risk of lymphoma [van Diemen-Steenvoorde et al., 1986; Wilkinson et al., 1989]. In a high percentage of the childhood transplant recipients who develop lymphoma, the neoplasm remains confined to the CNS. However, it is very rapidly progressive and poorly responsive to standard therapy for non-Hodgkin’s lymphoma or acyclovir. Reduction or cessation of immunosuppression may be beneficial in some lymphoproliferative cases, but in most instances even this makes little difference to the grim outlook for this condition [Dean et al., 1997; Mirra et al., 1981]. Diagnosis may be difficult because changes observed on scans may resemble those produced by abscess or by such drugs as asparaginase or peg asparagase (Bushara and Rust, 1997). Persistent space-occupying lesions are more likely to be tumor than opportunistic abscess in patients without pulmonary infection or fever. The thrombotic changes induced by such compounds as asparaginase are transient and do not enhance with administration of a contrast agent. In some cases, tumors and abscesses coexist [Schneck and Penn, 1970], and biopsy is frequently indicated. Precious stereotaxic biopsy material is best analyzed with a combination of immunocytochemistry and polymerase chain reaction. Benign polyclonal immune cell infiltrates

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may obscure tiny clones of malignant cells unless great care is taken in analyzing the specimen [Dean et al., 1997].

Stroke Massive cerebral hemorrhages have been reported after renal transplantation [Schwechheimer and Hashemian, 1995]. The risk for vascular calcification in brain and in heart, the “silent killer” of adult uremic patients, is likely influenced by the complex interactions of hyperparathyroidism, hyperphosphatemia, osteodystrophy, and use of calciumcontaining phosphate binders and of vitamin D derivatives [Bardin, 2003].

Drugs Drug-related complications include hypertension, immunosuppression, oncogenesis, and direct neurotoxicity. Hypertension severe enough to result in hypertensive encephalopathy may result from corticosteroid or cyclosporine therapy. This complication usually occurs shortly after transplantation; acute graft rejection or renal artery thrombosis must be excluded [Fine et al., 1970; Hodson et al., 1978]. Immunosuppressive and oncogenic effects of drugs have already been considered. Cyclosporine, perhaps because it has been in use the longest, is the calcineurin inhibitor most commonly cited as producing neurologic side effects, including paresthesias, neuralgia, peripheral neuropathy, ataxia, tremor, stupor, coma, confusion, insomnia, psychosis, hallucinations, sympathetic overactivation, headaches, or seizures [Arns 1994; Peces et al., 1996; Shah et al., 1984]. One or more of these neurologic side effects are experienced by 10% to 38% of patients who receive cyclosporine [Beckstein, 2000]. In most instances the side effects disappear with dose reduction. The association of cyclosporine with reversible posterior leukoencephalopathyassociated seizures, stupor, and other findings has been considered in a previous section. The substrate for encephalopathy may include cyclosporine-induced vascular endothelial injury [Teshima et al., 1996]. There is recent evidence that tacrolimus, a more potent immunosuppressant than cyclosporine, may also have an even greater tendency to engender neurotoxicities of the same variety associated with cyclosporine use [Parvex et al., 2001; Primavera et al., 2001]. Either cyclosporine or tacrolimus may engender seizures or make it more difficult to control epilepsy in renal transplant recipients. Tacrolimus has been associated with a post-transplantation encephalopathy that includes MRI-discernible changes in both gray and white matter. This syndrome may subside without discontinuation of tacrolimus. A similar condition arose with sirolimus. It is not as yet known exactly what role the various drugs employed to prevent rejection of an implanted kidney play in these peculiar syndromes [Parvex et al., 2001]. Enzyme-inducing antiepileptic drugs may reduce expected serum levels of calcineurin-inhibiting immunosuppressive drugs. Corticosteroids such as methylprednisolone employed for graft-versus-host disease prophylaxis may produce headache, psychosis, bone demineralization, or spinal cord compression owing to extradural fat accu-

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mulation. Corticosteroids may interfere with myelination of the early developing brain [Lee et al., 1975; Polinsky et al., 1987]. Tacrolimus, an inhibitor of cytokine and T-cell function, may provoke tremor, headache, hyperkalemia, insomnia, confusion, lethargy, neuropathy, or hypertension. Administration of the CD3 monoclonal antibody orthoclone OKT3 to prevent renal allograft rejection may variously provoke headache, fever, vomiting, a flulike syndrome, hypotension, seizure, or aseptic meningitis in as many as one third of patients. These changes may be severe and include obtundation or coma. Prompt investigation should exclude such alternative causes as CNS infection [Beaman et al., 1985; Capone and Cohen, 1991; Fernandez et al., 1993; Morris, 1999; Shihab et al., 1993]. OKT3-related encephalopathy has been associated with a cytokine release syndrome that involves elevation of concentrations of several CSF cytokines, including tumor necrosis factor and interleukin-6. Cerebral infarction may occur. Brain edema may develop and lead to brain herniation and death [Agarwal et al., 1993; Reiss et al., 1993; Shihab et al., 1993a, 1993b]. OKT3 may produce a state of akinetic mutism [Pittock et al., 2003], transient hemiparesis [Osterman et al., 1993], or blindness or optic disc swelling with abducens palsies due to increased intracranial pressure [Strominger et al., 1995].

DISEASES AFFECTING BOTH KIDNEY AND NERVOUS SYSTEM These illnesses can be divided into four general categories: (1) inflammatory/vascular, (2) infectious, (3) toxic or metabolic, and (4) an increasing number of heritable disorders associated with static anomalies of brain and kidney. The inflammatory/vascular illnesses that are considered first in this section include thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, and other thrombocytopenic microangiopathies. In addition, the hepatorenal syndrome, Henoch-Schönlein syndrome, and familial amyloidosis are reviewed. Systemic lupus erythematosus, polyarteritis nodosa, and Wegener’s granulomatosis are examples of other illnesses that produce inflammatory changes in both nervous and renal systems. The details of these illnesses are covered in Chapter 73.

Thrombotic Thrombocytopenic Purpura Thrombotic thrombocytopenic purpura was first described by Moschcowitz in 1925 [Baehr et al., 1936], who noted that the combination of fever, hemolytic anemia, renal failure, and neurologic dysfunction could result from widespread hyaline thrombosis of small blood vessels. Subsequently, many hundreds of cases labeled thrombotic thrombocytopenic purpura have been reported. Formerly, clinical diagnosis required at least two major (thrombocytopenia, Coombs-negative microangiopathic anemia, or neurologic dysfunction) and two minor (fever, renal dysfunction, or circulating thrombi) manifestations [Bukowski, 1982]. In many cases (unlike hemolytic-uremic syndrome), there is associated fever at onset. Hemolytic-uremic syndrome was first described by Gasser and colleagues in 1955. At that time it was usually fatal. Onset typically occurred in early childhood with

Coombs-negative thrombocytopenic microangiopathic hemolytic anemia and irreversible acute renal failure that usually required dialysis. The outlook for survival has greatly improved, owing to therapeutic advances. However, hemolyticuremic syndrome remains a leading cause of acute renal failure in North American children. It accounts for 7% of cases of hypertension in children younger than 12 months of age [de Chadarevian and Kaplan, 1978; Gianantonio et al., 1973; Lieberman et al., 1966]. The microangiopathic pathologic similarities to thrombotic thrombocytopenic purpura were recognized from the start. Kidney tropism without prominent neurologic abnormalities, onset before 10 years of age, and absence of associated fever were the common findings that permitted most cases of hemolyticuremic syndrome to be readily distinguished from thrombotic thrombocytopenic purpura [Silverstein, 1968]. It became clear, however, that a minority of cases thought to be hemolytic-uremic syndrome (because kidney manifestations predominated) presented after 10 years of age whereas other cases with a predominant phenotype closely resembling thrombotic thrombocytopenic purpura occurred in small children. A recent retrospective pathologic study has demonstrated that thrombotic thrombocytopenic purpura and hemolyticuremic syndrome are pathologically distinct entities. In cases severe enough to prove fatal, thrombotic thrombocytopenic purpura–associated thrombi are platelet rich and are found in heart, pancreas, kidney, adrenal, and brain, in decreasing order of severity. Hemolytic-uremic syndrome– associated thrombi are fibrin/red cell rich and tend largely to be confined to the kidney [Hosler et al., 2003]. Other studies have found that thrombotic thrombocytopenic purpura thrombi are found in the brains and kidneys of 50% to 75% of individuals with fatal thrombotic thrombocytopenic purpura. These thrombi contained von Willebrand factor multimers. It has long been recognized that patients with thrombotic thrombocytopenic purpura have ultra-large von Willebrand factor multimers in circulation [Bell et al., 1991; Berkowitz et al., 1979; Chow et al., 1998). Brain thromboses of thrombotic thrombocytopenic purpura occur in small arterioles, capillaries, and venules and are associated with microinfarction. Small petechial hemorrhages may be widely scattered in gray matter [Adams, 1964]. Remarkable recent progress in the characterization of the pathogenesis of thrombotic thrombocytopenic purpura has explained the reasons that thrombotic thrombocytopenic purpura–associated thrombi differ from those of hemolyticuremic syndrome. These advances have also provided diagnostic tests that reliably designate most heritable thrombotic thrombocytopenic purpura cases, as well as most individuals with acquired (autoimmune) thrombotic thrombocytopenic purpura [Raife, 2003]. On the basis of recent advances, thrombotic microangiopathies have been reclassified, as is shown in Table 89-2. Other as yet incompletely understood symptomatic thrombotic microangiopathies with a thrombotic thrombocytopenic purpura–like phenotype—conditions that tend to afflict adults and have predominantly neurologic manifestations—are now considered under their own headings in the new classification scheme for thrombotic microangiopathies. Hemolytic-uremic syndrome constitutes a family of illnesses including at least one heritable (congenital) form,

Rust and Chun / Interrelationships between Renal and Neurologic Diseases and Therapies

TABLE 89-2 Thrombotic Microangiopathies

From MacWhinney JB, Packer JT, et al. Thrombotic thrombocytopenic purpura in childhood. Blood 1962;19:181.

as well as cases that are subclassified as atypical and symtomatic hemolytic-uremic syndrome. It is of interest to note that the prevalence of thrombotic microangiopathies appears to be increasing. In part, this increase is accounted for by the development of new symptomatic forms, such as that related to bone marrow transplantation. Population-based studies have found that the prevalence of hemolytic-uremic syndrome substantially increased in the decade of the 1980s [Martin et al., 1990; Tarr et al., 1989). More recently, an increase in prevalence of the acquired forms of thrombotic thrombocytopenic purpura has been discerned, an increase that is out of proportion to the development of novel provocations such as bone marrow transplant [Tsai and Shulman, 2003]. When considered against the background of increasing prevalence over the past 40 years of other autoimmune diseases in industrialized nations (e.g., juvenile rheumatoid arthritis, asthma, systemic lupus erythematosus, multiple sclerosis in women), it seems that some common set of influences is disturbing the development of immunoregulation and tolerance. Current research on the genetic and immunoexperiential factors that determine the competence of immunoregulatory T cells is likely to prove relevant to these worrisome observations. Recent elegant studies have established the association of many cases of thrombotic thrombocytopenic purpura are due to congenital or acquired defects in the function of the zinc-dependent metalloproteinase ADAMTS13. This metalloproteinase is synthesized in liver. It is responsible for cleaving von Willebrand factor multimers. If properly cleaved, small multimers are capable, under highly regulated conditions, of binding to glycoprotein complexes Ib/IX/V and IIb/IIIa on the surface of platelets. Binding induces changes in platelet conformation from normal “clumping-resistant” globular form to an elongated form in which platelets tend readily to clump [Siedlecki et al., 1996]. The IIb/IIIa site, which in normal-sized multimers requires activation by circulating mediators or by sheer forces, may be particularly important in regulating platelet adhesiveness. Ultra-large von Willebrand multimers persist in circulation if the plasma activity of ADAMTS13 is reduced to less than 5% of normal. Cleavage of the ultra-large multimers is a critical antithrombotic regulatory function that reduces and regulates Ib/IX/V and IIb/IIIa platelet receptor binding affinity. Without cleavage the large fragments are prothrombotic, tending to bind to platelets without appro-

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priate activating signals. The ensuing platelet conformational change results in platelet clumping in arterioles and capillaries [Fujikawa et al., 2001; Furlan et al., 1997; Tsai et al., 1997; Zheng et al., 2001]. ADAMTS13 is not the only inducer of multimer cleavage. Calprins, leukocyte elastases, cathepsin G, plasmin, streptokinase, urokinase, and tissuetype plasminogen activator are others. These highly active substances are sequestered or inhibited under normal conditions and therefore play no role in physiologic von Willebrand factor cleavage. Severe deficiency of ADAMTS13 is considered diagnostic of the acute idiopathic form of thrombotic thrombocytopenic purpura [Hovinga et al., 2004]. However, this deficiency is not found in all patients with a thrombotic thrombocytopenic purpura phenotype. In a series of 396 consecutive patients with various thrombotic microangiopathies, severe ADAMTS13 deficiency was found in 17% of the total. Moreover, it was found in at least 60% of congenital or acute idiopathic (sporadic) thrombotic thrombocytopenic purpura cases. It was not found in any of the 130 patients with hemolytic-uremic syndrome or in the 14 patients with hematopoietic stem cell transplantation– associated thrombotic microangiopathy. Severe ADAMTS13 deficiency was not invariably associated with microvascular platelet clumping and/or other cardinal features of thrombotic microangiopathies [Hovinga et al., 2004]. Certain generalizations about the clinical aspects of thrombotic thrombocytopenic purpura can be stated. Thrombotic thrombocytopenic purpura is slightly more common in females than in males (ratio 3:2). Although the peak incidence is in the third decade, it may occur in neonates and young children [Kennedy et al., 1980]. Cases occurring in adults are likely mostly acquired thrombotic thrombocytopenic purpura, whereas those in neonates or young children are most likely congenital thrombotic thrombocytopenic purpura. The old observation that tendency to recur cannot be predicted on either a clinical or laboratory basis remains true [Meacham et al., 1952]. Signs and symptoms of acute thrombotic thrombocytopenic purpura usually evolve quickly and quite noticeably over 7 to 10 days. Skin purpura is the initial manifestation in more than 90% of patients. Fever usually develops early in the course of the illness. Hemorrhage (retinal, choroidal, nasal, gingival, gastrointestinal, and genitourinary), pallor, abdominal pain, arthralgia, or pancreatitis may also develop. Neurologic findings are seen in most cases and include fatigue, confusion, headache, and varying degrees of dysfunction of vision or language. Significant laboratory findings include microangiopathic hemolytic anemia, thrombocytopenia, elevated lactate dehydrogenase, proteinuria, and microscopic hematuria. Cerebrospinal fluid chemistry, cell counts, and pressure are usually normal [Adams, 1964]. Other findings commonly associated with disseminated intravascular coagulopathy are not usually found. MRI of brain is often normal. Single-photon emission tomographic images may indicate diminished cerebral blood flow [Fiorani et al., 1995]. At the time of original description, thrombotic thrombocytopenic purpura was almost 100% fatal. The outlook for thrombotic thrombocytopenic purpura has considerably improved, but fatalities still occur in 10% to 40% of welltreated cases [Bukowski, 1982; Rock et al., 1991]. It is not

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clear whether the improved survival is the result of more efficacious specific therapies or the improvement in techniques for supporting patients during the acute stage of illness. To some extent the improved survival rates may reflect the inclusion of milder forms of illness that were formerly overlooked. Monotherapy with corticosteroids appears beneficial in milder cases, and these drugs may be valuable adjuvants when plasma exchange is undertaken in more severe cases. Response to plasmapheresis and plasma infusion is often so prompt and dramatic as to suggest that these treatments are the most important factors in the greatly improved outlook for the thrombotic thrombocytopenic purpura family of illnesses [Bukowski, 1982; Ridolfi and Bell, 1981; Rock et al., 1991]. Remarkably, only a minority of patients who recover from thrombotic thrombocytopenic purpura manifest any significant permanent organ damage [Tsai, 2003]. As has been suggested, plasma exchange may be more efficacious treatment than plasma infusion. In a controlled, prospective, double-blind crossover multicenter thrombotic thrombocytopenic purpura treatment trial [Rock et al., 1991], at least 80% survival was found for plasma exchange, compared with 60% survival for patients randomized to plasma infusion. A more recent report [Lawlor et al., 1997] suggests that the benefits of plasma exchange are related to infusion of larger volumes of plasma or better clearance of toxins, antibodies, multimers, or immune complexes compared with plasma infusion. Plasma infusions carry risk for transmission of infections, including hepatitis and possibly human immunodeficiency virus. Most thrombotic thrombocytopenic purpura patients have been treated with seven or eight exchanges (requiring blood from 200 or more donors), after which at least 60% of patients who had a more severe form of thrombotic thrombocytopenic purpura experienced relapse [Bell et al., 1991]. Most cases of thrombotic thrombocytopenic purpura are monophasic, but 11% to 28% of patients experience one or more recurrence. In some instances, chronic thrombotic thrombocytopenic purpura develops [Bell et al., 1991; Rock et al., 1991; Tsai and Shulman, 2003]. Relapses occur weeks to years after initial remission. For severe or recurrent cases, plasmapheresis and plasma infusion are useful, but the combination of both (plasma exchange) using fresh-frozen platelet-poor plasma appears to be the most beneficial form of therapy, sometimes in combination with corticosteroids [Moake et al., 1984; Moake, 1990]. Plasmapheresis may remove the large von Willebrand factor multimers and circulating antibodies, whereas infused fresh-frozen plasma may contribute ADAMTS13 and circulating antioxidants (e.g., prostacyclin) and may also dilute ADAMTS13inhibiting IgG. THROMBOTIC THROMBOCYTOPENIC PURPURA– LIKE THROMBOCYTOPENIC MICROANGIOPATHY SYMPTOMATIC OF OTHER ILLNESSES. The thrombotic

thrombocytopenic purpura phenotype and other forms of thrombocytopenic microangiopathy may develop in association with the various categories shown in Table 89-2. Inflammatory vasculitic diseases (e.g., rheumatoid arthritis, polyarteritis nodosa, systemic lupus erythematosus, Sjögren’s syndrome, HELLP syndrome) constitute one important category. Thrombocytopenic micoangiopathy with or without a thrombotic thrombocytopenic purpura

phenotype may also develop in association with neoplasia (particularly lymphoma) or chemotherapy. Thrombocytopenic micoangiopathy associated with hematopoietic stem cell transplantation is yet another category. Remaining cases could be classified as (1) thrombocytopenic micoangiopathy with other conditions (endocarditis, during puerperium, factor H deficiency), (2) thrombocytopenic micoangiopathy due to drugs or poisons (i.e., sulfa, ticlopidine, cyclosporine, iodine, birth control pills, various other drugs and poisons), and the inevitable (3) thrombocytopenic micoangiopathy “not otherwise specified” [Hovinga et al., 2004; Remuzzi and Bertani, 1988; Teshima et al., 1996].

Hemolytic-Uremic Syndrome Hemolytic-uremic syndrome is a Coombs-negative thrombocytopenic microangiopathy the onset of which is typically in early childhood. Two thirds of all cases occur in children younger than 3 years of age, and few cases occur after 5 years of age [Gianviti et al., 2003]. Hemolytic-uremic syndrome may occur in the neonate and occasionally occurs in adults, especially in the elderly. Manifestations tend to be much more focal than those of thrombotic thrombocytopenic purpura. In addition to microangiopathic hemolytic anemia, the characteristic and serious finding is that of acute renal failure, which is usually severe. If there are neurologic manifestations, they are usually mild. As has been noted, however, there is an area of clinical overlap between hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura. Thrombotic thrombocytopenic purpura occasionally occurs in neonates, and hemolytic-uremic syndrome occasionally occurs in adults, especially the elderly. Hemolytic-uremic syndrome in the elderly may have a different pathogenesis from childhood cases because the disease of the elderly tends not to respond well to therapies that are effective in childhood cases [Blackall and Marques, 2004; Karlsber et al., 1997]. The venerable Drummond scheme [Drummond, 1985] of hemolytic-uremic syndrome classification has been greatly revised (Table 89-3) to more accurately subclassify the illness according to current understanding of the varied pathogenic bases on which hemolytic-uremic syndrome may arise. The new classification includes a “classic congenital” category and retains but redefines the “postinfectious,” and “familial” categories. The postinfectious TABLE 89-3 Classification of Hemolytic-Uremic Syndrome FORMER

CURRENT

Classic infantile (D+) Postinfectious (D+ or D−) Familial

Classic infantile (D+) Postinfectious (D+ only) D+ familial D− familial H-factor positive subgroup H-factor negative subgroup Sporadic D+ subgroup D− subgroup Subdivided into sporadic or familial categories Subdivided into sporadic or familial categories

Immunologic Secondary Endocrine

Rust and Chun / Interrelationships between Renal and Neurologic Diseases and Therapies

category is now restricted to individuals who manifest prodromal diarrhea (D+), despite the fact that some individuals without prodromal diarrhea harbor the same enteric Shiga-toxin–producing Escherichia coli bacteria that provoke the prodromal diarrhea in most postinfectious cases [Gianviti et al., 2003]. Familial cases are divided into those that do (D+) or do not (D–) have prodromal diarrhea. The former immunologic category is termed sporadic and is subdivided into D+ or D– subgroups. The former secondary and endocrine categories have been redistributed into the familial or sporadic groups depending on whether there is evidence for inheritance of the hemolytic-uremic syndrome predilection. The primary event in the pathogenesis of hemolyticuremic syndrome is damage to vascular endothelium, especially within the kidney. This mechanism may be shared by all categories of hemolytic-uremic syndrome, although it has been most thoroughly investigated and is now best understood for the postinfectious cases. Most of the children with postinfectious hemolytic-uremic syndrome harbor gastrointestinal Shiga-toxin–producing Escherichia coli. The Shiga toxin (verocytotoxin) elaborated by these bacteria enters the circulation and produces most of the ensuing injury in the vasculature of the kidney. The reason for this tropism is not entirely clear, nor is the age-related predilection, although both may be due to age-related expression of particular receptors in the kidney tubules (see later). Other causes of endothelial injury that results in hemolytic-uremic syndrome have been identified in children and especially in elderly adults with hemolytic-uremic syndrome and include cytotoxic drugs and systemic inflammatory illnesses. The pathology of hemolytic-uremic syndrome is predominantly that of thrombotic microangiopathy that tends particularly to involve the capillary subendothelial space of the kidney. As has been noted, hemolytic-uremic syndrome– associated thrombi differ from those of thrombotic thrombocytopenic purpura in that they are fibrin/ erythrocyte-rich [Hosler et al., 2003] and do not contain von Willebrand factor multimers. Whereas thrombotic thrombocytopenic purpura thrombi are widespread, hemolytic-uremic syndrome thrombi are largely restricted to the renal microvasculature, particularly in children younger than 5 years of age [Blackall and Marques, 2004; Chow et al., 1998; Hosler et al., 2003]. In older children and adults, necrotizing arterial thrombosis may predominate. Direct injury to the glomerular endothelium has been observed in some patients [Remuzzi and Bertani, 1988]. Deficiency of ADAMTS13 activity is not a feature of hemolytic-uremic syndrome [Tsai, 2003; Tsai and Lian, 1998; Tsai et al., 2000]. Indeed, young children with Shigatoxin–producing Escherichia coli–associated hemolyticuremic syndrome may have elevated rates of ADAMTS13 cleavage of von Willebrand factor multimers, producing smaller than normal von Willebrand factor multimers. Enhanced cleavage may be due to greater availability of von Willebrand factor ADAMTS13 receptor sites. This availability may itself result from abnormal unfolding of the multimer receptor site areas owing to increased sheer stress to the von Willebrand factor multimers in the vicinity of hemolytic-uremic syndrome thrombi [Tsai, 2002]. Red blood cell fragmentation occurs in hemolytic-uremic

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syndrome [Tsai, 2002], in part explaining the erythrocyte enrichment of hemolytic-uremic syndrome thrombi. Fibrin deposition in clots has been explained, in Shiga-toxinproducing E. coli–related hemolytic-uremic syndrome cases, by activation of both prothrombin peptide F1+2 and D-dimer increase before the microangiopathic stage of Shiga-toxin–producing E. coli–associated hemolytic-uremic syndrome [Chandler et al., 2002]. Classic infantile hemolytic-uremic syndrome is the second largest category of hemolytic-uremic syndrome, accounting for approximately 10% of all hemolytic-uremic syndrome cases. These infants have a febrile prodrome with diarrhea but negative bacterial blood cultures. Viral cultures may also be negative, although echoviruses or coxsackieviruses, adenoviruses, and human immunodeficiency virus have been isolated in some instances. It is possible that viruses produce endothelial injury in the kidney vasculature, although currently there is little information concerning pathogenesis of classic infantile hemolytic-uremic syndrome. This type of hemolytic-uremic syndrome tends to be mild and to have a relatively good prognosis. Postinfectious hemolytic-uremic syndrome is the largest hemolytic-uremic syndrome category. This group accounts for as many as 46% to 68% of all hemolytic-uremic syndrome cases [Gianviti et al., 2003; Martin et al., 1990]. The category that formerly bore this name included cases with or without a diarrheal prodrome. In the current scheme, only cases manifesting diarrhea are included and most cases are associated with Shiga-toxin–producing E. coli. In nearly 50% of Shiga-toxin–producing E. coli infections, the organism is E. coli O157:H7. However, other serotypes may be found, including E. coli O26 (25%), E. coli O111 (11%), E. coli O145 (11%), and E. coli O103 (6%). Other E. coli serotypes (O55, O86, O118, and O120) together account for less than 1% of postinfectious hemolytic-uremic syndrome cases [Gianviti et al., 2003]. Other pathogens associated with the development of postinfectious hemolytic-uremic syndrome include viruses (echoviruses, adenoviruses, human immunodeficiency virus, or coxsackieviruses) or bacteria (Salmonella, Shigella, Streptococcus, or Yersinia). Some of these bacteria, particularly Shigella, elaborate verotoxin. The association of gastrointestinal E. coli O157-H7 with hemolytic-uremic syndrome, as well as with some cases of hemorrhagic colitis was first published in 1982 [Cimolai and Carter, 1991; Joh, 1997; Martin et al., 1990]. The implicated E. coli O157-H7 bacterial strains elaborate both an adhesion intimin and two verocytotoxins (VT-1 and VT-2, also known as Shiga toxins). The former mediates attachment of the ingested organism to colonocytes. The VT-2 verocytotoxins mediate attachment to circulating polymorphonuclear leukocytes, cells that, in turn, distribute the toxins throughout the body but particularly to the kidney [Te Loo et al., 2000]. The binding to leukocytes is of relatively low affinity, permitting reattachment to cell surfaces, particularly those of the kidney [Te Loo et al., 2001]. It is of interest that in several cases in adults with a thrombotic thrombocytopenic purpura rather than hemolyticuremic syndrome phenotype there has been an associated E. coli O157:H7 infection [Kovacs et al., 1990]. The E. coli VT-2 verocytotoxin has been found to cause not only renal endothelial injury but also cerebral microcirculatory endo-

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thelial injury in piglets [Richardson et al., 1987; Tzipori et al., 1988]. This experimental model may include aspects that are pertinent to hemolytic-uremic syndrome and others that are pertinent to thrombotic thrombocytopenic purpura and suggests that there remains an area of pathophysiologic overlap between these two conditions. It has been determined that as many as 82% of the household contacts of a child with postinfectious hemolyticuremic syndrome also have verocytotoxin bound to their polymorphonuclear leukocytes, but despite this fact they are often asymptomatic. It is therefore hypothesized that an additional mediator is necessary for the development of postinfectious hemolytic-uremic syndrome, now presumed to be a lipopolysaccharide [Seigler et al., 2001]. The fact that the use of an antimotility agent increases the risk for hemolytic-uremic syndrome suggests the possibility that prolonged contact of organism with colonocytes or with inflammation-associated polymorphonuclear leukocytes may play an important role in pathogenesis [Joh, 1997]. It is also known that administration of antibiotics such as trimethoprim-sulfamethoxazole to children with E. coli O157–associated diarrhea may increase the risk for hemolytic-uremic syndrome [Joh, 1997; Wong et al., 2000]. The significance of this observation with regard to pathogenesis of hemolytic-uremic syndrome remains unclear. C3 complement levels are low in approximately half of all D+ hemolytic-uremic syndrome cases, suggesting that activation of the alternative complement pathway occurs in postinfectious hemolytic-uremic syndrome. Postinfectious hemolytic-uremic syndrome tends to occur in the midsummer [Palomeque Rico et al., 1993]. It tends to be a much more severe illness than the classic infantile hemolytic-uremic syndrome and has a much more guarded prognosis. Undercooked hamburger appears to be a major vehicle for food-borne E. coli O157:H7 outbreaks in children, suggesting an epizootic reservoir [Riley et al., 1983]. Familial (atypical) hemolytic-uremic syndrome is defined clinically by the occurrence of hemolytic-uremic syndrome in two or more family members. The first description of familial hemolytic-uremic syndrome was provided in 1956, although the careful studies of Kaplan and associates made a considerable additional contribution in 1975 [Kaplan et al., 1975]. There are both autosomal-dominant and autosomal-recessive forms of familial hemolytic-uremic syndrome. The pathophysiology of familial hemolyticuremic syndrome is less well understood than that of postinfectious hemolytic-uremic syndrome. Familial cases that lack a diarrheal prodrome are termed D– familial hemolytic-uremic syndrome. These cases are further classified according to whether there is an identifiable defect in factor H expression. Ten to 20 percent of either familial or sporadic D– cases are associated with mutations in a region of chromosome 1 that encodes the expression of various complement regulatory proteins. Some familial cases are found to have heritable deficiencies of the third component of complement (C3), others of complement factor H [Noris et al., 1999; Warwicker et al., 1998]. Individuals with either of these deficiencies tend to have hemolytic-uremic syndrome of greater than average severity. A missense mutation in the gene that encodes factor H expression has been identified in

some cases of familial hemolytic-uremic syndrome [Warwicker et al., 1998] with subsequent demonstration that there is genetic heterogeneity in affected individuals. It has further been demonstrated that mutations of this same gene may be associated with either familial or sporadic (defined by the absence of family history) varieties of D– hemolyticuremic syndrome [Perez-Caballero et al., 2001]. Factor H is a fluid phase regulator of activation of the alternative complement pathway, a pathway that plays a critical role in regulation of the discernment of host from foreign tissues. Some of the various missense mutations associated with hemolytic-uremic syndrome result in abnormalities in the carboxyl terminal of factor H, a region that is important for binding to C3b complement and cell surface polyanionis. It is hypothesized that early procoagulant activation occurs, as in diarrheal cases, because of endothelial cell injury. Dysregulation of the alternative complement pathway, due to the abnormal binding function of factor H, then prolongs the abnormal procoagulant state. Patients with hemolytic-uremic syndrome usually have normal levels of factor H with normal or low levels of complement or the C3 complement constituent [Noris et al., 1999; Richards et al., 2002]. A normal factor H level does not exclude the presence of mutation of the factor H gene. It is not yet clear how many D– hemolytic-uremic syndrome cases have demonstrable factor H gene abnormalities. One extensive recent literature review of severe hemolyticuremic syndrome cases found reports of factor H gene abnormality in less than 15% of nondiarrheal cases requiring renal transplant. There is an inverse association between C3 levels and disease severity and outcome in both D+ and D– hemolytic-uremic syndrome [Fortin et al., 2004; Fremeaux-Bacchi et al., 2004; Rodriguez et al., 2004]. Although hemolytic-uremic syndrome occurs in individuals with specific abnormalities of the carboxyl terminus of factor H, complete absence of this factor in pigs, mice, and humans leads to mesangiocapillary glomerulonephritis rather than hemolytic-uremic syndrome [Alexander et al., 2005]. Sporadic hemolytic-uremic syndrome has replaced the former “immunologic” hemolytic-uremic syndrome category and includes cases of hemolytic-uremic syndrome associated with a fall in C3 component. These cases are subdivided into D+ or D– forms based on the presence or absence of diarrhea and other clinical features. As is noted earlier, very low C3 is a negative prognostic indicator for hemolytic-uremic syndrome. Some individuals with D+ sporadic hemolytic-uremic syndrome are found to harbor gastrointestinal Shiga-toxin–producing Escherichia coli infections [Gianviti et al., 2003], whereas other individuals classified as D– sporadic hemolytic-uremic syndrome are found to have factor H deficiency [Warwicker et al., 1998]. The most important associated underlying illnesses for sporadic D– hemolytic-uremic syndrome are vasculitic and inflammatory illnesses such as Henoch-Schönlein syndrome, systemic lupus erythematosus, scleroderma, polyarteritis nodosa, and Wegener’s granulomatosis. Individuals with these underlying illnesses may, in some instances, develop thrombocytopenic microangiopathies with a thrombotic thrombocytopenic purpura phenotype. In many instances these diseases produce rapidly progressive vas-

Rust and Chun / Interrelationships between Renal and Neurologic Diseases and Therapies

culitic glomerulonephritis rather than the peculiar glomerulopathy of hemolytic-uremic syndrome. Other provocations include malignant hypertension, kidney radiation, bone marrow transplantation, medications employed for immunosuppression (cyclosporine, tacrolimus, methylprednisolone), snake venom or diethylene glycol intoxication, and cancer chemotherapy drugs such as mitomycin. Endocrine causes of hemolytic-uremic syndrome include pregnancy and oral contraceptives [Goldstein et al., 1979; Habib et al., 1958]. Tacrolimus-associated hemolytic-uremic syndrome, for which renal transplant patients are at risk, tends to arise in adults rather than children. It is representative of the generalization that hemolytic-uremic syndrome in adults tends to be more severe and difficult to treat than hemolyticuremic syndrome in children that tends to afflict adults. It occurs slightly more often in men than women and has a mean onset at about 40 years of age or about 7 months after transplant. It is not dose related. Nearly 45% of cases improve with various mixtures of anticoagulation, antiplatelet agents, dialysis, and plasma exchange. Tacrolimus is usually replaced with cyclosporine, although in some instances an initial dose reduction of tacrolimus has been tried. Graft loss occurs in 25% of cases. Without successful retransplantation, all of these individuals die. Even with transplantation, approximately one third die. If there is associated liver failure, 60% die [Lin et al., 2003]; and these cases can be further subdivided between the sporadic or inherited forms of hemolytic-uremic syndrome, depending on whether there is a family history or demonstrated factor H or factor H gene defect. CLINICAL ASPECTS OF HEMOLYTIC-UREMIC SYNDROME. Most diarrhea-associated (D+) hemolytic-

uremic syndrome cases are preceded by days to weeks of varying degrees of abdominal pain, vomiting, diarrhea, and hematochezia. Abdominal pain may be severe and fever may be quite high. Children with a D– presentation who have a prodromal respiratory illness have a distinctly worse prognosis than those with a D+ presentation. Microangiopathic Coombs-negative hemolytic anemia and acute renal failure with microscopic hematuria and proteinuria (1 to 2 g/dL) abruptly mark the onset of hemolytic-uremic syndrome in nearly all patients. Leukocytosis may accompany this phase of illness, and elevated concentrations of α1 and β2 microglobulins may be found in the urine. Neurologic manifestations of hemolytic-uremic syndrome—most commonly behavioral changes, motor seizures, stroke and varying degrees of encephalopathy— are seen in 30% to 40% of patients. Blindness, ataxia, hemiparesis, and decerebrate rigidity have also been reported [Kaplan et al., 1971; Martin et al., 1990; Sheth et al., 1986]. The occurrence of neurologic abnormalities predicts a worse outcome with enhanced risk for end-stage renal disease or death [Garg et al., 2003]. It is not always clear whether such neurologic changes are the result of cerebral microangiopathy or are secondary to metabolic disturbances and hypertension. MRI of brain may disclose focal areas of infarction with swelling and, in some cases, hemorrhage, especially in such areas as the internal capsule and deep gray nuclei [Jeong et al., 1994]. Children in whom neurologic signs develop are more likely to die or to have residual hypertension or chronic renal dysfunction [Palomeque Rico et al.,

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TABLE 89-4 Clinical Features Suggesting HUS Rather than TTP as Cause of Thrombocytopenic Microangiopathy Age younger than 10 years No other plausible explanation Preceding diarrhea or colitis, pulmonary infiltrates, or respiratory disease Absence of associated fever Evidence for renal dysfunction Oliguria or anuria Hypertension (>140/90 mm Hg) Serum creatinine > 3.5 mg/dL Need for dialysis HUS, hemolytic-uremic syndrome, TTP, thrombotic thrombocytopenic purpura. Adapted from Tsai HM. Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. J Am Soc Nephrol 2003;14:1072.

1993; Sheth et al., 1986]. Clinical features suggestive of hemolytic-uremic syndrome are noted in Table 89-4. TREATMENT. Investigations have been undertaken concerning the efficacy of administering preparations containing inert adsorptive surfaces that are capable of binding circulating verocytotoxin, thereby preventing attachment to endothelial surfaces where they can engender injury. SYNSORB-pk ingestion was among the first approaches tried [Joh, 1997] but appears to have been abandoned. Other preparations are undergoing evaluation [Armstrong et al., 1995]. Improved supportive therapy, including transfusion, dialysis, and careful management of fluids, electrolytes, and hypertension, has reduced mortality from 50% half a century ago to what is variously estimated as 0% to 30% mortality, with recent pooled data suggesting roughly 10% [Garg et al., 2003; Gianantonio et al., 1973; Kaplan et al., 1976]. Adult mortality is much higher, probably because adult hemolytic-uremic syndrome more often occurs as a complication of much more severe systemic illnesses than are encountered in childhood hemolytic-uremic syndrome cases. Therapeutic options include anticoagulation, administration of antiplatelet or antioxidant agents, thrombolysis (streptokinase), plasmapheresis/plasma exchange, or infusions of plasma, prostacyclin, or gamma globulin [Arenson and August, 1975; Beattie et al., 1981]. None of these various approaches has well-established efficacy (beyond that achieved by excellent supportive care). Plasma manipulations appear to be less beneficial in hemolytic-uremic syndrome than in thrombotic thrombocytopenic purpura [Misiani et al., 1982; Moake, 1991; Powell, et al., 1984]. Trials of gamma globulin are in progress, and preliminary results are promising. Although it is undertaken in some adults with hemolytic-uremic syndrome, anticoagulation in childhood cases entails a certain risk in an illness that is frequently complicated by both bleeding and hypertension. Moreover, it does not appear to be beneficial even when combined with administration of oral antiplatelet agents. It is probably contraindicated [Proesmans et al., 1980]. Hemolytic-uremic syndrome–associated renal failure usually persists for several weeks. Dialysis is required in 30% to 50% of patients and is indicative of a poorer prognosis [Blaker et al., 1978; Ekberg et al., 1977; Garg et al., 2003; Martin et al., 1990]. Renal transplantation is

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necessary in severe hemolytic-uremic syndrome, amounting to approximately 25% of all childhood cases. Considerable interest is attached to the identification of reliable prognostic factors identifiable very early in the course of hemolyticuremic syndrome. Such factors should be of importance in stratifying treatment groups for assessment of efficacy of various therapies and might permit aggressive novel strategies to be initiated early in the course of disease for cases with the poorest prognosis. A review of 387 childhood cases of hemolytic-uremic syndrome has greatly contributed to this important objective. Among these cases, 68% of 276 tested were found to have Shiga-toxin–producing Escherichia coli–related hemolytic-uremic syndrome. Age at onset, leukocyte count, and evidence for CNS involvement did not predict time to recovery. However, the combined absence of prodromal diarrhea and Shiga-toxin–producing Escherichia coli infection was associated with poorer outcome. Only 34% of individuals who lacked both features recovered normal renal function as compared with 65% to 76% of those who did have one or both features [Gianviti et al., 2003]. For 118 cases in a study of postdiarrheal hemolyticuremic syndrome with kidney transplantation, the recurrence rate was only 0.8%, causing graft loss in that single case. For 63 reported transplanted nondiarrheal hemolyticuremic syndrome cases without factor H deficiency, 21% demonstrated recurrence with graft loss, whereas nearly 30% of seven transplanted nondiarrheal cases with factor H gene mutations demonstrated recurrence. In some transplanted cases without factor H deficiency or genetic defect, low C3 levels enhance risk for recurrence with graft loss. Disappointing as these statistics might be, they are better than the recurrence risk for heritable adult hemolytic-uremic syndrome, which is about 60% for both autosomal-recessive and autosomal-dominant forms [Loirat and Niaudet, 2003]. Adult hemolytic-uremic syndrome cases, constituting a tiny minority of all hemolytic-uremic syndrome cases, tend to result from a different pathogenesis than most childhood cases and may not be as responsive to therapies that are effective in children [Blackall and Marques, 2004; Karlsberg et al., 1977].

Vasculitic Diseases with Neurologic-Renal Presentations Extended consideration of these various inflammatory disorders is to be found in Chapter 73.

Hepatorenal Syndrome Hepatorenal syndrome is a widely accepted but controversial designation for the functional, potentially reversible renal failure that occurs in patients with various forms of liver failure [Bataller et al., 1998; Van Roey and Moore, 1996]. It is divided into two types, each with established diagnostic criteria [Arroyo et al., 1996]. Type 1 includes patients whose rapidly deteriorating renal function with hyponatremia and hyperkalemia develops in association with acute severe hepatic dysfunction (from various causes) or severe hepatic cirrhosis (chiefly alcoholic). It is usually fulminant and carries a high risk for death. Encephalopathy

develops in most type 1 cases. Type 2 includes patients that manifest the combination of less severe liver and renal disease. Encephalopathy is less common in type 2 cases. Some form of hepatorenal syndrome develops in as many as 20% of patients who are in their first year of acute or subacute hepatic failure. It occurs in 40% of those who have experienced at least 5 years of chronic hepatic failure. Cases of type 1 hepatorenal syndrome are rare in childhood. Half of all such cases occur in the wake of acute viral hepatitis with hepatic failure. It may also occur after other causes of liver failure (native or graft), particularly if portal hypertension is present and has produced gastrointestinal bleeding [Evans et al., 1995]. Liver necrosis (sometimes centrilobular) and fatty infiltration of liver may be found [Shida et al., 1996]. Some cases occur after liver transplantation for children who had chronic liver disease due to biliary atresia. One case has been reported in a 3-year-old child with α1-antitrypsin deficiency. This child died with hepatorenal syndrome after developing hemorrhagic shock and encephalopathy, disseminated intravascular coagulopathy, metabolic acidosis, and nonketotic hypoglycemia [Shida et al., 1996]. Severe hepatorenal syndrome may also develop in children with hereditary fructose intolerance [Ali et al., 1993], with Wilson’s disease, with liver malignancy, with autoimmune hepatitis, after shunting procedures for bleeding varices [Evans et al., 1995], or after administration of medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) or minocycline [Arroyo et al., 1983; Boudreaux et al., 1993]. Spontaneous bacterial peritonitis may provoke the hepatorenal syndrome. The understanding of the pathophysiology of hepatorenal syndrome is incomplete, and the available theories remain controversial. Renal failure probably occurs as the result of severe renal cortical arterial and arteriolar vasoconstrictive ischemia. Some believe that this is in response to the release hepatic substances that variously provoke vasoconstriction or vasodilation. Some believe that vasopressin, reninangiotensin, or catecholamines may provoke intense selective vasoconstriction with ensuing renal failure [Neuschwander-Tetri, 1994]. Doppler ultrasonography has demonstrated increased renal vascular resistance in as many as 40% of patients with nonazotemic liver disease [Maroto et al., 1994; Sacerdoti et al., 1993]. Renal dysfunction subsequently develops in more than half of these at-risk individuals, half of whom in turn develop hepatorenal syndrome [Platt et al., 1994]. An inverse correlation has been observed between plasma-activated cytokine levels and improvement in renal function after treatment of hepatorenal syndrome with liver transplantation [Burke et al., 1993]. In patients who develop encephalopathy, it has been found that the cerebral circulation is also compromised by intense selective cerebral vasoconstriction [Better, 1983]. It is not known why the sustained vasoconstrictive sympathetic response may be so selective for vessels subserving kidney and brain circulation, whereas capacitance vessels in many other vascular beds dilate. Increased renal secretion of regional vascular modulators may enhance the vasoconstriction and produce additional deleterious effects on glomerular capillary ultrafiltration [Nijima, 1977; Van Roey and Moore, 1996]. Systemic hypotension frequently accompanies the onset of hepatorenal syndrome and may be due to

Rust and Chun / Interrelationships between Renal and Neurologic Diseases and Therapies

the opening of portosystemic shunts with resulting splanchnic bed dilation, accompanied by blood pooling in that and possibly in other portions of the systemic circulation. That hepatorenal syndrome may develop in children with septic or hemorrhagic shock suggests the importance of such vasoactive mediators as endotoxin, thromboxane A2, or other prostaglandins that may alter circulatory balance [Henriksen, 1995; Shida et al., 1996]. Precipitation of hepatorenal syndrome by the administration of NSAIDs ingested by patients with cirrhosis has been regarded as evidence for the importance of prostaglandins in the maintenance of renal vascular tone when the liver is failing (Arroyo et al., 1983). Because of this presumed drug effect, many have thought it wiser to avoid these agents in patients with the hepatorenal syndrome. Some have proposed inadequate renal synthesis of vasodilating prostaglandin E2 despite normal or increased renal thromboxane A2 synthesis, and severe activation of endogenous vasoconstrictors is the cause of ischemic renal failure in hepatorenal syndrome [Laffi et al., 1997]. Whether the liver elaborates substances that provoke a dysfunctional “hepatorenal reflex” or fails to produce a much-needed counterregulatory substance, it is probable that failing liver cannot adequately clear circulating vasoactive substances (such as the false neurotransmitter octopamine or various cytokines) or other vascular regulatory substances from the circulation [Fischer and Baldessarini, 1971; Shida et al., 1996]. The performance of large-column paracentesis without compensatory replacement of plasma volume may contribute to the occurrence or severity of the hepatorenal syndrome. The initial renal response to the hepatorenal syndrome is hypermineralocorticoid (i.e., oliguric with retention of both water and salt). Salt wasting may supervene if acute tubular necrosis develops as a result of the intense vasoconstriction. The poor response of the oliguric phase of hepatorenal syndrome to volume expansion or exogenous vasodilators is among the reasons that some have questioned the primacy of renal cortical vasoconstrictive ischemia as the cause of renal failure. Clinical features of hepatorenal syndrome include ascites, jaundice, and low arterial blood pressure despite increased plasma volume. Hepatomegaly is usually not present. A preexisting poor nutritional state is not uncommon. Laboratory findings often include hyponatremia, hyperkalemia, low urinary sodium clearance, low plasma but high urine osmolarity, high plasma renin activity, increased plasma norepinephrine, and moderately increased blood urea nitrogen and creatinine. Patients who develop acute encephalopathy with hepatorenal syndrome, probably due to severe cerebral vasoconstriction, may be found to have extensive symmetric ischemic brain injury suggestive of parasagittal infarction [Shida et al., 1996]. Most patients with type 1 hepatorenal syndrome are adults. Data on children with this condition are limited. Until recently, all age groups with hepatorenal syndrome had the same generally poor outlook, including a mortality rate of 80% to 95% depending on etiology [Van Roey and Moore, 1996]. Treatment has of necessity involved correction of hepatic failure and support. Some patients have responded to renal transplantation or performance of a shunt procedure to relieve the ascites that is found in 75% of patients with hepatorenal syndrome [Iwatsuki, 1973; Van

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Roey and Moore, 1996]. Resolution of renal dysfunction has required correction of hepatic dysfunction either by liver regeneration or by liver transplant. Coagulopathy must be corrected. It has been found that treatment with agonists of the vasopressin V(1) and α-adrenergic receptors, if combined with plasma expansion, may reverse both type 1 and 2 hepatorenal syndrome and improve survival. Current research is focusing on the best way to use the various novel drugs that work at these receptor sites [Barada, 2004]. Without effective treatment, patients with hepatorenal syndrome manifest progressive vascular pooling and edema, declining plasma oncotic pressure and blood pressure, and worsening circulatory failure. The outcome of this progressive failure is death. Before transplantation and other interventions, most patients with type 1 hepatorenal syndrome lived less than 2 weeks. Those with type 2 survived for 6 to 12 months. A wide variety of drug and circulating volume treatments aimed at reversing the systemic vasodilation and renal or cerebral vasoconstriction have failed or resulted in only modest improvement in survival. Misoprostol, a prostaglandin E1 analog, has been touted as a treatment for hepatorenal syndrome, as well as for a wide variety of other toxic or inflammatory forms of hepatic or renal disease [Davies et al., 2001]. The use of systemic vasoconstrictors (terlipressin, ornipressin) with albumin has resulted in recovery of renal function in many patients or recovery of sufficient degree and duration of function to permit liver transplantation or a hepatic shunt procedure to be performed [Moreau, 2002; Ortega et al., 2002]. Liver transplantation has greatly improved survival rate [Restuccia et al., 2004]. However, the limited availability of grafts and the hesitancy to use them in the setting of a grave disease associated with so many predisposing medical conditions have limited the usefulness of this option. Transjugular intrahepatic portosystemic shunts have promise in management of hepatorenal syndrome [Angeli, 2004]. Among patients who experience hepatic recovery or have successful liver transplantation, approximately 7% develop end-stage renal disease [Gonwa et al., 1991].

Amyloidosis Amyloidoses are divided into the heredofamilial (primary) and those that are the secondary (reactive) groups. Primary amyloidoses comprise a heterogeneous collection of conditions, many of which are rare and restricted to particular mutations shared by small isolated communities of individuals [Benson, 2003]. Identification of the specific gene defect underlying a particular family amyloidosis is of importance for selection of therapy, prognostication, and genetic counseling [Benson, 2003]. Reactive amyloidoses are associated with a wide variety of provocative circumstances, most of which are encountered only in adults. These include inflammatory arthritides or vasculitides, dialysis, and myeloma-associated immunoglobulin light chain deposition. Table 89-5 lists selected amyloid-related disorders. Many forms of heredofamilial amyloidosis are chiefly cutaneous or do not involve the neurologic and renal systems. However, progressive nephrosis and neurologic disease (CNS tissues, nerve, or muscle) are among the most common manifestations

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TABLE 89-5 Selected Heredofamilial (Primary) Amyloidoses Type I (transthyretin methionine-30 amyloidosis) Type II (Indiana-type amyloidosis) Type III (Danish cardiac-type amyloidosis) Type IV (Iowa-type amyloidosis) Type V (amyloid cranial neuropathy with lattice corneal dystrophy, amyloidosis due to mutant gelsolin, Finnish-type amyloidosis, Meretoja-type amyloidosis) Type VI (Icelandic-type amyloidosis) Type VII (oculoleptomeningeal-type amyloidosis, Ohio-type amyloidosis) Type VIII (familial renal/visceral amyloidosis; systemic non-neuropathic amyloidosis; Ostertag-type amyloidosis; German-type amyloidosis) Type IX (familial cutaneous lichen amyloidosis; primary cutaneous amyloidosis; lichen amyloidosis, familial; primary localized cutaneous amyloidosis) Amyloidosis of gingiva and conjunctiva, with mental retardation (Hornova-Dlurosova syndrome)

of either primary or secondary amyloidoses. Cardiac and gastrointestinal abnormalities are also common. Dysfunction in these various organ systems are the consequence of serositis and vasculitis associated with deposition of the insoluble betapleated sheet fibrils (low-molecular-weight peptides) that were long ago misnamed amyloid. Arterial and arteriolar wall deposition in affected organ systems is more common than capillary or venous. Of the 24 amyloid proteins associated with disease in humans, 7 produce neurologic disease. Their genetic loci are shown in Table 89-6. As can be seen, most patients present in mid or late adulthood with dementia or stroke and many have little or no renal abnormality. Amyloid-β precursor protein may account for some aspects of the progressive dementia seen in Alzheimer’s disease and Down syndrome, although this assertion remains controversial. CNS amyloid deposition in such individuals results in amyloid angiopathy that may produce visual disturbances (small or large, TABLE 89-6 Genetic Loci of Amyloid Proteins Associated with Human Central Nervous System Disease PRECURSOR Gelsolin

CHROMOSOME

AMYLOID PROTEIN

9

AGel

Transthyretin

18

ATTR

Cystatin C

20

Acys

Prion protein

20

AprPsc

Aβ precursor

21

Aβ

ABri precursor

13

ABri

ADan precursor

13

ADan

DISEASE Familial amyloidosis, Finnish type Meningovascular amyloidosis HCHWA-Icelandic type Creutzfeldt-Jakob disease, kuru, GerstmannSträussler-Scheinker disease, fatal familial insomnia Alzheimer’s, Down syndrome Familial British dementia Familial Danish dementia

irregular, poorly reactive pupils; internal ophthalmoplegia; blindness), nerve deafness, bland or hemorrhagic cerebral infarction, dementia, seizures, polyneuropathy, weakness, or muscle wasting [Benson, 2002; Revesz, 2003; Rousset et al., 2000; Suhr et al., 2003]. The precursor protein is expressed in kidney and is a low concentration constituent of normal urine. The concentration of this soluble protein increases in certain forms of renal tubulopathy associated with a variety of metabolic diseases. Autosomal dominant familial amyloidotic polyneuropathy (type I amyloidosis) is most likely to occur in Portuguese, Spanish, Majorcan, Swedish, or Japanese kindreds. More than 80 identified missense mutations in the transthyretin gene produce variant transthyretins that account for various disease manifestations [Date et al., 1997; Falk et al., 1997; Uyama et al., 1997]. One of the mutations (Val121Ile) is found in about 3% of American blacks. This condition may present as lower extremity polyneuropathy at some point between the second and fourth decades of life. Individuals may develop fatal meningovascular angiopathy associated with early loss of short-term memory and in the advanced state with cerebral hemorrhage. Subsequently, hearing loss, autonomic or craniofacial polyneuropathy, ataxia, and pyramidal tract signs may be noted. Individuals with this condition may have abnormalities of kidney, liver, heart, gastrointestinal system, lungs, skin, and ovaries [Benson, 2002; Rousset, et al., 2000]. Treatment with early liver transplantation may improve neurologic manifestations, but cardiac and renal function may deteriorate somewhat after transplantation of liver [Suhr, 2003]. Chronic uremia may induce oxidative endothelial vascular damage that facilitates amyloid deposition and worsens the vasculopathy of various organ systems that this disease promotes [Sakashita et al., 2001]. A Hungarian variety of transthyretin gene mutation tends to be clinically restricted to the nervous system. Severe meningocerebrovascular changes are associated with memory disturbance, psychomotor deterioration, ataxia, hearing loss, migrainous headaches with vomiting and episodic disorientation, tremor, and nystagmus. Motor decline is associated with the development of pyramidal signs. Sleep disturbances and facial tics may be found. Peripheral nerve, heart, and kidney function are usually normal despite amyloid deposition, and vision remains normal [Garzuly et al., 1996]. Another autosomal dominant amyloidosis is termed hereditary cerebral (Icelandic type, type VI) amyloidosis. Mutations of codon 68 of cystatin C gene on chromosome 20 result in production of ACys. Affected normotensive Icelandic young adults have presented with hemorrhagic strokes that may recur or cause death. These are due to the particular tendency for the formation of heavy amyloid deposits on small arteries or arterioles of brain, although vessels of the kidney, spleen, lymph nodes, salivary glands, and seminal vesicles may be involved. Individuals who do not develop strokes may experience progressive middle-age onset of dementia [Olafsson et al., 1996]. Finnish-type (type V) amyloidosis is the result of mutations in the chromosome 9 gene that encodes gelsolin, a regulatory protein. This condition also occurs in Danish and Czech kindreds. There is disturbance of amyloid genesis but also of fusin proteolysis. The pathway that is involved with

Rust and Chun / Interrelationships between Renal and Neurologic Diseases and Therapies

this disturbance is responsible for the production of Pme117-encoded fibrils, which are precursors for the biogenesis of melanosomes [Huff et al., 2003]. Individuals with this condition may have droopy-appearing eyes and protruding lips. Peculiar corneal “lattice” deposits may be seen. Neurologic abnormalities include peripheral or cranial neuropathy and progressive vasculopathy of blood vessels subserving brain, spine, and sensory ganglia. Homozygous Finnish-type amyloidosis due to the ASN187 gelsolin mutation produces severe nephrotic syndrome. This syndrome may progress to end-stage renal disease owing to heavy glomerular deposits of gelsolin-derived amyloid, especially in tubular epithelium [Maury, 1993]. Among individuals of Middle Eastern ancestry, especially Sephardic Jews and Armenians, familial Mediterranean fever is the most important cause of secondary (AA) amyloidosis. This autosomal-recessive condition is common in the Middle East, with disease prevalence as high as 1:2600 and gene frequency as high as 1:50 in the Near Middle East. At least 30 different mutations of the MEFV gene on chromosome 16p13.3 have been linked to this disease [Aldea et al., 2004]. Typical recurrent manifestations develop between 4 months and 16 years of age and if untreated persist throughout life. They include short attacks of fever, abdominal or unilateral chest pain, erysipelas-like erythema, organomegaly, and serositis (pleuritic and arthritic). Without adequate treatment secondary amyloidosis often develops, especially when there is a family history of amyloidosis. Affected persons are at risk of amyloidotic renal failure and neurologic complications. The risk for these eventualities is reduced by as much as 95% if chronic colchicine therapy is undertaken after early diagnosis [Aldea et al., 2004; Hojberg and Mertz, 1995]. If amyloidosis does develop, the 5-year risk for chronic renal failure ranges from 50% (type I amyloidosis) to greater than 80% (type II amyloidosis). Schönlein-Henoch purpura and polyarteritis nodosa may develop, as well as symptomatic thyroid and gastrointestinal amyloid deposition. Neurologic manifestations result either from CNS vasculitis or secondary to chronic renal failure [Kavukcu et al., 1995; Rawashdeh and Majeed, 1996; Saatci et al., 1993, 1997; Tinaztepe et al., 1993]. A severe form of autosomal-dominant familial secondary amyloidosis has been described in Spain, wherein intermittent bouts of joint pain occur. Progressive AA-associated renal failure may develop and is unresponsive to colchicine. All patients with this condition are heterozygotes for the newly described H4784 MEFV gene mutation. It is currently uncertain whether this condition ought to be classified with familial Mediterranean fever or with the newly described group of inherited autoinflammatory periodic syndromes seen in association with other gene mutations including TNFRSFIA and CIAS1/PYPAF1/NALPO3 [Aldea et al., 2004]. There are a number of additional secondary or reactive forms of amyloidosis. One that has clinical similarities to Portuguese familial amyloidosis is Muckle-Wells syndrome. Like familial Mediterranean fever, it is an AA amyloidosis. Presentation may be in the second decade with corticosteroidresistant nephrotic syndrome. Neurologic abnormalities include bilateral inner ear deafness and recurrent urticaria.

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Other findings are arthralgia, aphthosis, amyloid goiter, and skeletal abnormalities. Skin and joint abnormalities respond to immunosuppressive therapies including cyclophosphamide [Andrade et al., 1969; Berthelot et al., 1994; Black, 1969; Fuger et al., 1992; Muckle and Wells, 1962; Schwarz et al., 1989; Throssell et al., 1996]. Various chronic infectious or inflammatory conditions can provoke secondary amyloidosis. Examples include juvenile rheumatoid arthritis, systemic lupus erythematosus, granulomatous bowel disease, Takayasu’s disease, tuberculosis, leprosy, osteomyelitis, and inadequately treated chronic suppurative infections such as subacute bacterial endocarditis. Hematuria, proteinuria, abnormal urinary sediment, diminished renal function, or hypertension may indicate the development of renal amyloidosis. However, such manifestations are not uncommonly the result of infectious glomerulonephritis or the administration of nephrotoxic drugs [Herbert et al., 1995; Kavukcu et al., 1995; Sieniawska et al., 1996; Tinaztepe, 1995]. A wide range of neurologic abnormalities may be seen in individuals with one or another of these secondary amyloidoses. Vasculopathy may result in neurologic consequences due to bland or infectious cardiogenic emboli, cerebral amyloid angiopathy, Takayasu’s disease, or hypertensive encephalopathy [Sousa et al., 1993]. Close collaborative investigation and management of such complex patients by pediatric neurologists and nephrologists, rheumatologists, and infectious disease specialists is of great value in arriving at an accurate diagnosis. Decreased urinary excretion of glycosaminoglycans may be a marker for renal involvement in the amyloidoses. This finding is thought to be the result of (1) diminished number of functioning nephrons, (2) diminished glycosaminoglycans synthesis in functioning glomeruli, and (3) trapping of glycosaminoglycans by amyloid fibrils [Tencer et al., 1997]. The test may also prove valuable in the screening of patients with chronic inflammatory disorders, particularly those that affect the kidney and nervous system.

Metabolic Diseases Producing Generalized Nephron and Neurologic Dysfunction Both acute and chronic generalized nephron dysfunction may result from metabolic diseases that have primary effects on both the kidney and nervous system. Diseases that are most likely to result in encephalopathy are those that produce the combination of a catabolic and acute renal failure. Under such conditions the metabolic perturbation worsens more rapidly and often achieves greater severity. Systemic diseases that can provoke encephalopathy even without renal failure (e.g., sepsis, burns, fever, ethylene glycol, lactic acidosis, or ketoacidosis) produce more fulminant, severe, and difficult-to-treat nervous system dysfunction when renal failure also occurs or was previously present. Therapeutic interventions undertaken in encephalopathic patients who have renal failure must be carried out with scrupulous attention to cerebrovascular dynamics because cardiac output is often low and cerebral autoregulation is often compromised. Administration of fluids or alkali may in some instances have deleterious effects on cerebral blood flow that must be considered.

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Selective Tubular Dysfunction Many inherited diseases and intoxications produce characteristic patterns of renal tubular acidosis in association with neurologic abnormalities; glomerular function is usually preserved in these diseases. Renal tubular acidosis is generally characterized by hyperchloremia and reduced plasma bicarbonate and is further divided into proximal (bicarbonate wasting) or distal (defective acid excreting) renal tubular varieties. Selective tubular dysfunction itself produces far fewer clinical manifestations than are observed in uremia. In many instances the neurologic dysfunction is more apparent than the associated renal dysfunction, which is often overlooked. The quite straightforward process of detecting and characterizing the renal tubular abnormality is often helpful in diagnosing the cause of observed neurologic dysfunction. Unfortunately the important diagnostic clues provided by selective tubular dysfunction may be overlooked because the renal defect itself may produce few signs or symptoms. Important examples of diseases that produce neurologic TABLE 89-7 Heritable Nervous System Diseases with Proximal Renal Tubular Acidosis/Fanconi Syndrome Amyloidosis (familial) Carbonic anhydrase deficiency type II Cystinuria Galactosemia Glycogen storage disease I Hartnup disease Hereditary fructose intolerance Lowe (oculocerebrorenal) syndrome Lysinuric protein intolerance Methylmalonic aciduria Nephropathic cystinosis Nephrosialidosis Primary mitochondrial cytopathies Pyruvate carboxylase deficiency Sjögren’s syndrome Tyrosinemia type I Wilson’s disease

TABLE 89-8 Diseases with Nervous System Dysfunction and Distal Renal Tubular Acidosis Carnitine palmitoyltransferase deficiency Chronic active hepatitis Cryoglobulinemia Fabry’s disease Glycogen storage disease type I Hashimoto’s thyroiditis Hereditary fructose intolerance* Leprosy Lysinuric protein intolerance* Neuraxonal dystrophy Primary biliary cirrhosis Primary hyperparathyroidism Sickle cell anemia Sjögren’s syndrome* Systemic lupus erythematosus Type IV distal renal tubular acidemia Wilson’s disease* *Also may cause proximal renal tubular acidosis/Fanconi syndrome.

dysfunction in association with proximal renal tubular acidosis are listed in Table 89-7. Those associated with distal renal tubular acidosis are listed in Table 89-8. Intense scrutiny is being paid to the molecular genetics and mechanisms of these various conditions, resulting in a rapidly evolving increase in understanding and a rich banquet of clinical and scientific data. Only a brief review can be provided here. Additional information can be obtained through the Online Mendelian Inheritance in Man (OMIM) available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM.

Proximal Renal Tubular Acidosis The function of the proximal tubule depends on maintenance of an electrical gradient across the tubular epithelium. The gradient requires low intracellular as compared with extracellular sodium concentration. As in the nervous system, the gradient is maintained by Na+-K+ adenosine triphosphatase pumps located in the basolateral membrane. It is clear that excessive generalized loss of solutes in urine produces a form of proximal renal tubular acidosis termed the de Toni-Debré-Fanconi (“renal” Fanconi, hereinafter Fanconi) syndrome. Associated serologic abnormalities suggest the presence of proximal renal tubular acidosis and the combination of these laboratory data with clinical findings may designate the presence of a particular underlying metabolic disorder. A history of polyuria, polydipsia, and dehydration may be found if renal Fanconi syndrome is severe, although within the context of the early recognition of the diseases considered in this section such a history is uncommon. Febrile illnesses in infantile presentations may worsen dehydration. Detection of the characteristic urinary pattern of elevation of the concentrations of multiple amino acids, glucose, phosphate, bicarbonate, calcium, and protein is an especially convenient method of confirming proximal renal tubular acidosis. Characteristically, urine is often dilute despite the elevated concentrations of various solutes owing to a concentrating defect that is secondary to hypokalemia. Additional findings in most cases include stable but mildly reduced level of serum bicarbonate (15 to 20 mEq/L) and appropriate urine acidity on an early morning void (pH > 5.3) [McSherry, 1981]. Further diagnostic clues include normal anion gap acidosis, hypophosphatemia, and hypomagnesemia. Hypokalemia and bicarbonaturia worsen after administration of alkali. Renal Fanconi syndrome may occur as a primary familial disorder. Of greater importance in this chapter is the secondary form of renal Fanconi syndrome that may occur in the setting of various heritable metabolic disorders (see Table 89-7), which also manifest neurologic abnormalities in addition to and not directly dependent on the presence of Fanconi syndrome. Indeed, in most of these metabolic conditions, Fanconi syndrome tends to be mild to moderate. In some of these diseases, most commonly nephropathic cystinosis, disease tends to progress to chronic renal failure. Almost all of these heritable metabolic conditions are autosomal recessive. The exceptions discussed in this section are X-linked recessive Lowe syndrome and maternally inherited mitochondropathies. Secondary renal Fanconi syndrome may also result from endocrinopathies, intoxications, and various other disorders.

Rust and Chun / Interrelationships between Renal and Neurologic Diseases and Therapies

Obviously, any disease that causes severe generalized proximal renal tubular acidosis, including familial Fanconi syndrome, may result in neurologic abnormalities when severe disturbances of potassium, glucose, or acid-base balance occur. This is particularly the case when poorly compensated chronic renal failure or end-stage renal disease develops. The occurrence of seizures in a patient with proximal renal tubular acidosis may be due to hypocalcemia or hypomagnesemia [Heering et al., 1996]. Some neurologic problems may be worsened by a proximal renal tubular leak. Carnitine loss in infantile renal Fanconi syndrome has been associated with poor muscle development and abnormal intramuscular lipid deposition. Hypokalemic muscle weakness is an important potential complication of alkali or thiazide treatment of proximal renal tubular acidosis from any cause. Individuals with inherited hyperkalemic periodic paralysis who have Fanconi syndrome may be vulnerable to an attack of their condition owing to those same interventions. NEPHROPATHIC CYSTINOSIS. Nephropathic cystinosis, caused by a defective lysosomal membrane transport protein, is the most common identifiable cause of renal Fanconi syndrome in children. This autosomal recessive condition occurs almost exclusively in white individuals. The defective gene has been mapped to a 1-cM region of chromosome 17p13. Continued work, including the cloning of the responsible gene and studies of immortalized proximal tubule cells expressing the defect, should provide important information concerning the biology of lysosomal transport proteins [Jean et al., 1996; McDowell et al., 1996; Peters et al., 1997; Racusen et al., 1995; Stec et al., 1996]. Nephropathic cystinosis is one of the only lysosomal diseases for which there is effective therapy. Treatment is aimed at preventing the pathogenic accumulation of free intracellular cystine in various tissues, including kidney, cornea, thyroid, muscle, and brain [Gahl, 1997]. Cystine is a known nephrotoxin. Exposure of rat kidney slices or isolated tubule cells to cystine deimethylester is a commonly employed model of renal Fanconi syndrome. This compound accumulates in renal tubules and reduces the rate of mitochondrial respiration in association with decline in transporter activity, impaired glutamate-dependent mitochondrial oxygen consumption, and diminished concentrations of intracellular potassium and adenosine triphosphate [Foreman et al., 1995]. At present, diagnosis is usually established with the demonstration of elevated free cystine in polymorphonuclear white cells. This method also permits diagnosis of the heterozygous carrier state. Linkage studies should soon become the diagnostic method of choice. In the infantile form of cystinosis, biochemical evidence for proximal tubule cell dysfunction is usually detectable within the first few months of life. If untreated, frank renal failure usually develops within the first decade of life [Racusen et al., 1995]. The course of renal deterioration after the development of Fanconi syndrome is similar to that observed in other severely nephropathic diseases. Nephrocalcinosis and the formation of calcium oxalate stones are frequent occurrences in nephropathic cystinosis, related in part to supplementation of these patients with phosphate and alkalinizing agents [Theodoropoulos et al., 1995]. Evidence that cysteamine (or phosphocysteamine) administered in doses ranging from 33 to 51 mg/kg per day (or

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from 1.3 to 1.95 g/m2 body surface area per day) significantly delays the onset of renal failure has prompted approval of this drug by the U.S. Food and Drug Administration for treatment of nephropathic cystinosis [van’t Hoff and Gretz, 1995; Wu et al., 1995]. Although treatment is quite expensive, it delays the even greater expense and multiple complications of renal transplantation [Soohoo et al., 1997]. It may provide other benefits, including longer life expectancy. The potential efficacy of this drug is of further significance in that kidney transplantation does not prevent progressive injury because of the underlying disease to various organs, including the transplanted kidney [Almond et al., 1993]. Before renal transplantation was available, it was thought that neurologic abnormalities occurred only as consequences of renal dysfunction. With the prolonged survival that renal transplantation affords, it has become clear that the infantile and juvenile forms may be associated with visual, intellectual, and motor abnormalities that result from cystine accumulation in the eye (cornea, conjunctiva, retina) or brain (choroid plexus, cortex). Accumulation in the cornea causes progressive keratopathy. Recurrent corneal erosions may prove troublesome [Elder and Astin, 1994]. Cysteamine supplementation to deplete cystine does not influence the course of corneal keratopathy [Thoene, 1995]. Other neurologic consequences develop at various ages from childhood to adulthood. They may include headache; autonomic abnormalities (heat intolerance, hyperthermia, abnormal sweating); poor vision and deficient visual memory; short, raspy, repetitive speech; tremor; pyramidal or extrapyramidal motor defects; and weakness [Gahl et al., 1988; Jonas et al., 1987; Levine and Paparo, 1982]. Selective impairment of visual processing, such as inability to mentally rotate figures, is a frequent finding despite the typically normal intelligence and primary sensory function of these patients. Abnormality of tactile recognition with astereognosis has been discerned in some patients. These higher cortical deficits must be considered in the educational planning for children with this disorder. These subtle deficits are the likely basis of some of the school difficulties experienced by children with nephropathic cystinosis. In some instances the general level of intelligence may be slightly below that of parents or siblings. Intellectual deficits may be static or slowly progressive [Ballantyne et al., 1997; Colah and Trauner, 1997; Scarvie et al., 1996; Williams et al., 1994]. Some patients experience much more severe and strikingly progressive neurologic complications. Cystinosisrelated encephalopathy is an entity characterized initially by manifesting cerebellar and pyramidal signs, with ensuing mental deterioration, and then development of pseudobulbar or bulbar palsy with a prominent swallowing disorder. Adults with nephropathic cystinosis may have strokelike episodes with coma and hemiplegia. In either of these clinical groupings, abnormalities may be discerned in MRI images [Broyer et al., 1996; Van Lierde et al., 1994]. These abnormalities correspond to demonstrable pathologic changes within the nervous system, which include nonobstructive hydrocephalus; calcification of the basal ganglia, periventricular zone, and internal capsule; and demyelination of the internal capsule and brachium pontis. Evidence suggests that cysteamine may reverse cystinosis-related

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Systemic Diseases and Their Effect on the Nervous System / 89

encephalopathy, improve the radiologic appearance of brain, and prevent paroxysmal episodes [Broyer et al., 1996]. As has been noted in the section on uremic myopathy, approximately one fourth of patients with long-standing nephropathic cystinosis develop distal lipid inclusion myopathy and perhaps all such patients have subclinical electrophysiologic abnormalities. This result may be the direct effect of cystine toxicity, although carnitine deficiency and other potential causes may also contribute. It remains unclear whether replenishment of muscle carnitine with oral supplementation is beneficial [Gahl et al., 1993]. Patients with cystinosis-related myopathy develop weakness and wasting of small hand muscles, facial weakness, and muscular dysphagia. However, they retain sensation and tendon reflexes. Distal motor unit potentials may have reduced amplitude and duration, and biopsies may indicate a vacuolar myopathy of lysosomal origin [Charnas et al., 1994]. Cystine depletion with cysteamine has been advocated [Vester et al., 2000]. One case of anesthetic-induced malignant hyperthermia has been reported in a child with cystinosis, possibly related to myopathic changes [Purday et al., 1995]. Additional heritable diseases that may result in a combination of neurologic and renal manifestations are listed in Table 89-9.

Neurologic Drugs That May Affect Renal Function Some drugs commonly used in the management of neurologic diseases may produce disturbances of renal function TABLE 89-9 Syndromes with Kidney Malformation and Neurologic Disease SYNDROME (INHERITANCE)

KIDNEY

NEUROLOGIC

Bardet-Biedl (AR) Beckwith/Wiedemann (Sp) Cat’s eye Cockayne’s (AR) Fanconi pancytopenia (AR) Fraser’s (AR) Johanson-Blizzard Joubert’s Klippel-Feil (Sp) Meckel-Gruber (AR) Melnick-Fraser (AD) MURCS Orofaciodigital I Pallister-Hall (Sp) Partial trisomy 10S Rubinstein-Taybi Schinzel-Giedion Short-rib polydactyly II Townes’ Triploidy/mixoploidy Trisomy 9 mosaic Trisomy 18 Tuberous sclerosis (AD) Turner’s Zellweger’s (AR)

CGN/HTN RD/RT RA RD/HTN RH/RD RA RD/HN RC RD RD RH/RD RA PCK RD RD RD HN RD/PCK RH/HN RD/PCK D HN/PCK T RD/HTN RC

MR/V MR MR/V MR/D/A/PN MR/CN/D MR MR/D CbD CN/NT/CD NT/M D CD/D MR/M/HC/E T/M/NE MR/M MR MR/D/E CD/M D MR/M/NT/HC MR/M/NT MR/M/NT/HC MR/T/MR/E MR/D MR/M

A, ataxia; AD, autosomal-dominant; AR, autosomal recessive; CbD, cerebellar dysplasia; CD, cervical dysplasia; CGN, congenital glomerulonephritis; CN, cranial neuropathy; D, deafness; E, encephalopathy; HC, hydrocephalus; HN, hydronephrosis; HTN, hypertension; M, central nervous system migrational abnormalities; MR, mental retardation; MURCS, müllerian duct renal and cervical vertebral defects; NT, neural tubule defects; PCK, polycystic kidneys; PN, peripheral neuropathy; RA, renal agenesis; RC, renal cysts; RD, renal dysplasia; RH, renal hypoplasia; Sp, sporadic; T, tumors; V, visual abnormalities.

TABLE 89-10 Neurologic Medications That May Produce Renal Dysfunction Acetazolamide (PRTA/S/Postrenal failure) Amphetamines (ARF/AIN) Analgesics/NSAIDs (PRTA/F/DRTA/Prerenal failure) Carbamazepine (ARF/AIN) Cimetidine (ARF/AIN) Indomethacin/NSAIDs (ARF/AIN/PN) Phenobarbital (ARF/AIN) Phenytoin (ARF/AIN) AIN, acute interstitial nephritis; ARF, acute renal failure; DRTA, distal renal tubular acidosis; F, renal Fanconi; NSAIDs, nonsteroidal anti-inflammatory drugs; PN, papillary necrosis; PRTA, proximal renal tubular acidosis; S, seizures.

TABLE 89-11 Drugs/Toxins Affecting Nervous System and Kidney DRUG

NEUROLOGIC

RENAL

Analgesics Arsenic Burn toxin Cadmium Chromium “Ecstasy” Ethylene glycol Gallium Indium Lead Lithium Mercury Mycotoxin Pentazocine Tellurium Tetracycline Thallium Toluene Xylitol

E/H E/H/PNM E E/S/PNM E E/S E B/PNM E/S/PNM E/PNM E/D E/M E E/D/H E Ps E/S/GBS E/L/S/D/Ps E/S

PRTA/F/DRTA PRTA/CRF PRTA PRTA/F ARF/CRF ARF ARF/CRF ARF/CRF ARF/CRF PRTA/F DRTA PRTA/F PRTA DRTA ARF/CRF PRTA/F PRTA/F/DRTA PRTA < DRTA ARF/CRF

ARF, acute renal failure; B, blindness; CRF, chronic renal failure; D, delirium; DRTA, distal renal tubular acidosis; E, encephalopathy; F, renal Fanconi; GBS, Guillain-Barré syndrome; H, headache; L, long-tract signs; M, myopathy; PNM, peripheral neuropathy and/or myopathy; PRTA, proximal renal tubular acidosis; Ps, pseudotumor; S, seizures.

that range from mild transient effects on the regulation of free water clearance to severe parenchymal kidney injury. Important effects of selected neurologic drugs on renal function are summarized in Tables 89-10 and 89-11. It is well known that carbamazepine and oxcarbazepine produce hyponatremia in appreciable minorities of treated individuals. Prevalence with carbamazepine treatment is approximately 5% [Brewerton and Jackson, 1994]. Serum sodium concentrations in the 126- to 135-mM/L range are found in 18% to 25% of oxcarbazepine-treated children. They are less than 125 mM/L in no more than 3%. Symptomatic hyponatremia is found in 2% or less. No aspects of age, sex, or dose were predictive of risk for hyponatremia in either of two retrospective studies [Borusiak, 1998; Holtmann et al., 2002]. However, a study of institutionalized patients with intellectual disabilities found that more than 40% of those treated with carbamazepine had (largely asymptomatic) hyponatremia as compared with only about 5% of those who were not treated with this drug. Possible correlation of hyponatremic risk with higher carbamazepine levels was suggested [Kelly and Hillery, 2001].

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The mechanism of hyponatremia with either of these drugs is in doubt. Although the syndrome of inappropriate secretion of antidiuretic hormone was formerly thought to explain the effect [Van Amelsvoort et al., 1994], it has recently been shown that this is not the case for carbamazepine. In patients with carbamazepine-associated hyponatremia, there is no compensatory rise in arginine vasopressin to a water load and there is a fall in free water clearance in response to declining serum sodium concentration. Alternative explanations include induction of enhanced renal response to normal circulating concentrations of antidiuretic hormone. Clinical manifestations of hyponatremia are rare in children treated with either carbamazepine or oxcarbazepine [Flegel and Cole, 1977; Holtmann et al., 2002]. There is some evidence that co-treatment with demeclocycline or doxycycline may alleviate carbamazepine-associated hyponatremia when it is necessary to use the drug [Boutros et al., 1995; Brewerton and Jackson, 1994]. Combinations of oxcarbazepine with furosemide [Siniscalchi et al., 2004] or carbamazepine with thiazide diuretics [Ranta and Wooten, 2004] may result in acute hyponatremic encephalopathy. Lamotrigine use in children with centrally mediated diabetes insipidus has been found to induce hyponatremia owing to change in desmopressin requirements [Mewasingh et al., 2000]. Acetazolamide may provoke a selective form of proximal renal tubular acidosis manifested by bicarbonate wasting without generalized proximal tubular dysfunction [Leaf et al., 1954]. Phenytoin, on the other hand, may inhibit the secretion of antidiuretic hormone, resulting in diabetes insipidus [Dousa and Hechter, 1970; Fichman and Bethune, 1968]. Phenytoin-induced lupus may, in turn, produce lupus-related nephropathy. Prolonged ethosuximide administration was associated with development of quite severe lupus in one individual. In addition to kidney dysfunction, this individual manifested cerebral abnormalities, an unusual development in drug-induced lupus. Weight loss, pancreatitis, and arthritis also occurred. Some authorities have discerned provocation of flares of preexisting lupus with initiation of ethosuximide treatment [Casteels et al., 1998]. Rarely, oral or parenteral barbiturates may cause nontraumatic rhabdomyolysis with ensuing acute tubular dysfunction. Distal renal tubular acidosis with hyperkalemia (type IV distal renal tubular acidosis) may be caused by lithium or by indomethacin [Perez et al., 1975; Steele and Edwards, 1971]. Clinically significant nephrogenic diabetes insipidus develops in 20% to 30% of patients receiving long-term lithium carbonate therapy and may not be entirely irreversible. Subtler defects are found in more than 60% of chronically treated patients [Bucht and Wahlin, 1980]. NSAIDs may diminish renal perfusion because of selective inhibition of cyclooxygenase-2 with the occasional result of hyperkalemic renal failure [Brater, 1999]. There is considerable evidence that phenacetin and, to a lesser extent, aspirin, acetaminophen, and other NSAIDs are potentially nephrotoxic. Several forms of “analgesic nephropathy” have been described, particularly slowly progressive renal papillary necrosis, demonstrable on renal CT scans. There have been instances of acute or chronic interstitial nephritis associated with the use of NSAIDs. Likelihood of nephropathy is greater in individuals using analgesic com-

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binations containing caffeine and/or codeine or individuals combining several different analgesics to achieve pain relief [Elseviers and De Broe, 1999]. Acetaminophen nephrotoxicity may be augmented by the co-administration of herbal remedies such as echinacea, kava, meadow sweet, or willow [Abebe, 2002]. Analgesic nephropathy is rare before 30 years of age. It has been suggested that nitric oxide-releasing NSAIDs may be devoid of nephrotoxicity. Indeed, it has been suggested that these NSAIDs may actually ameliorate kidney function [Fiorucci et al., 2001]. NSAIDs may blunt the response to antihypertensive agents [Brater, 1999]. In healthy individuals there is little evidence that aspirin used alone in therapeutic doses carries any significant risk for irreversible kidney injury. In individuals with glomerulonephritis, cirrhosis, chronic renal insufficiency, or children with congestive heart failure, short-term courses of aspirin have on occasion provoked reversible renal failure. Aspirin intoxication (>300 mg/kg) poses considerable risk for acute renal failure, and doses of more than 500 mg/kg may prove lethal [D’Agati, 1996]. Aspirin and other analgesic medications may produce hyperkalemia that is proportional to the degree and duration of renal failure [Lieberman et al., 1985]. Tricyclic drugs may interfere with the action of some antihypertensive medications and may provoke urine retention. Nifedipine may worsen the edema of renal failure. Other drugs commonly employed for management of neurologic diseases can cause acute interstitial nephritis and include phenytoin, phenobarbital, carbamazepine, cimetidine, amphetamine, and interferon alfa [Sawaishi et al., 1992; Verrotti et al., 2000]. Phenobarbital appears even over several years of administration to pose a much smaller threat to kidney tubules than does valproate or carbamazepine [Verrotti et al., 2000]. Rarely, carbamazepine may cause membranous glomerulonephropathy or induce an acute hypersensitivity reaction with ensuing acute renal failure [Ray-Chaudhuri et al., 1989]. It is possible to assess whether renal injury is occurring by measurement of several urinary lysosomal hydrolases, N-acetyl glucosaminidase and βgalactosidase. Valproic acid has direct effects on renal tubular ammonia metabolism, accelerating glutamine uptake, ammoniagenesis, and production of alanine, lactate, and pyruvate. These effects appear to be related to stimulation of renal tubular mitochondrial glutamine transport, increased flux of glutamate to malate, and/or reduction of the flux of pyruvate oxidation and carboxylation. In this manner, increased renal ammoniagenesis may combine with valproate-related inhibition of hepatic ureagenesis [Hjelm et al., 1986] to produce the hyperammonemia that is observed in some children with therapeutic serum valproate concentrations [Warter et al., 1983]. Liver enzyme levels remain normal [Gougoux and Vinay, 1988; Martin et al., 1987], and the only clear symptom may be sedation at the ammonia peak, especially after a high-protein meal [Gidal et al., 1997]. Chronic valproate administration may result in proximal renal tubular dysfunction [Gougoux and Vinay, 1989; Ponchaut et al., 1989; Verrotti et al., 2000]. Under experimental conditions, the observable reduction in glutathione (kidney > liver) associated with increased malondialdehyde concentration suggests that lipid peroxidation may play an important role in the development of tubular dysfunction [Raza et al., 1997]. Renal valproate toxicity appears to be a

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very gradual process that is both time and dose (i.e., “area under the dose/time curve”) dependent. Long-term treatment with the combination of valproate and phenobarbital is particularly likely to produce this tubular dysfunction because larger doses of valproate are required to maintain therapeutic serum concentrations. The development of tubulopathy may be suspected in patients who require unexpected increases in valproic dosage after long intervals of stable dosing to maintain a desirable serum level. An additional clue is the development of proteinuria of a modest degree. It is typically reversible after valproate discontinuation. Carbamazepine poses a smaller, although definite, risk to tubules than does valproate [Verrotti et al., 2000]. Acyclovir may result in acute renal failure; and although this drug has a high therapeutic index, high plasma concentrations increase the risk for this consequence. Coadministration of cephalosporins, which compete for tubular excretion, may increase the nephrotoxic risk of acyclovir administration. With acyclovir-associated renal failure, neurologic deterioration may follow, owing to accumulation of toxic substances as a consequence of renal failure, including high serum and CNS concentrations of acyclovir [Da Conceicao et al., 1999]. In renal transplant patients, the signs and symptoms of acyclovir-associated encephalopathy correlate poorly with acyclovir serum levels [de Knegt et al., 1995; Schwartz et al., 1995].

Drug Therapy in Renal Disease Renal dysfunction may have significant effects on drug disposition, including many drugs commonly administered to treat neurologic complications of renal disease [Bennett et al., 1987]. Renal dysfunction may affect drug binding, hepatic biotransformation, or renal clearance either of the drug or its metabolites. Drug binding (especially of acidic drugs) may be affected by poor nutrition, by protein loss, or by the competition with the weak organic acids that accumulate in uremia. Biotransformation may be affected by changes in free fraction or, as is the case with phenytoin, by unknown mechanisms. Renal clearance is of little importance for some drugs but of great importance for others (e.g., barbiturates, levetiracetam, gabapentin, toxic metabolites of nitroprusside). Drug penetration into the CNS or systemic clearance may be altered in renal failure. These issues are the subject of several excellent reviews [Asconape and Penry, 1982; Reidenberg, 1977; Tyler, 1975]. Some of the most important problems are considered in the following sections. DRUG-INDUCED ENCEPHALOPATHY IN RENAL FAILURE. Encephalopathy is the most common con-

sequence of pharmacologic changes with renal failure, with manifestations ranging from subtle intellectual impairment to confusion, delirium, or coma. Hallucination and agitation should always suggest the possibility of intoxication in a patient with renal failure. Severe drug-related encephalopathy may closely resemble uremic encephalopathy, with seizures, myoclonus, and asterixis. Drugs most commonly implicated are antibiotics, antihistamines, antihypertensives, and neuropsychiatric medications [Richet et al., 1970]. Cyproheptadine may produce psychosis in patients with

TABLE 89-12 Drugs That May Produce Unexpected* Encephalopathy in Individuals with Renal Failure Antibiotics (penicillin G†, ticarcillin, aminoglycosides) Antiepileptic drugs (barbiturates, benzodiazepines) Antihistamines (cyproheptadine†, diphenhydramine) Antihypertensives (prazosin) Neuropsychiatric (chlorpromazine, haloperidol, phenothiazines) *Within normal “therapeutic window” ranges of serum concentration. † Described in children. Data from Berger et al., 1977; Chin et al., 1986; McAllister et al., 1978; and Taclob and Needle, 1976.

renal failure [Berger et al., 1977; McAllister et al., 1978]. Other commonly encountered drugs that produce encephalopathy in renal failure are listed in Table 89-12. Although a careful drug history is often of greater importance in ascertaining the deleterious drug than the symptom pattern or serum levels, some clinical findings are relevant. Agitation, emotional lability, and anticholinergic signs suggest antihistamines or neuroleptics. Anticholinergic effects may include life-threatening cardiorespiratory impairment. Myoclonus may result from penicillins, chelated aluminum, cyclosporine, nitroprusside, tricyclic antidepressants, phenothiazine, or meperidine. Prominent, recurrent seizures suggest penicillin toxicity. Established “toxic levels” of medications may not always represent reliable guides in renal failure where unmeasured toxic metabolites may accumulate. Therefore, trial withdrawal of expendable or especially toxic medications may be necessary. Recovery from medication effects may require weeks to months, as has been shown for phenothiazine and prazosin [Bloomer et al., 1967; Chin et al., 1986; Taclob and Needle, 1976]. ANTISEIZURE DRUGS. Seizures are common problems in children with renal disease. Most are brief and selflimited, resulting from transient, correctable metabolic disturbances (usually calcium, magnesium, sodium, or glucose) or acute hypertension. Management generally involves exclusion of a serious precipitating cause (e.g., CNS infection, hemorrhage, thrombosis, hypertensive crisis) and correction of metabolic disturbances. However, some individuals with renal disease experience prolonged seizures or develop epilepsy and require acute or chronic treatment with antiseizure medications. Treatment of prolonged seizures is based on seizure type [Rosenbloom and Upton, 1983]. Diazepam, phenobarbital, and phenytoin are the most commonly employed drugs. Acute short-term treatment may be accomplished by administration of loading doses without longer-term administration if clearance is low. Longer-term or even chronic treatment with an antiseizure medication must be undertaken where risk for seizure recurrence is high. Such usage is guided by medication level, known pharmacokinetics and pharmacodynamics of the antiseizure medication, the extent to which these are likely to be altered at a given level of reduction of renal creatinine clearance or by dialysis, and the degree of hepatic dysfunction. Children with chronic renal failure who are at greater risk for seizure recurrence include those with potential seizure foci as suggested by clinical, imaging, or EEG abnormality. The EEG abnormalities of greatest concern are focal slowing and an active focus of spike

Rust and Chun / Interrelationships between Renal and Neurologic Diseases and Therapies

discharge. These findings are of greatest concern if the focus corresponds to observed clinical semiology of seizures. Other groups with high risk for recurrence are children with epilepsy or underlying diseases known to provoke seizures. Renal failure mandates adjustment of dosages and/or dosing intervals of many antiseizure medications. The effects of chronic renal failure on drug disposition are greatest for phenytoin [Letteri et al., 1971]. Protein binding of phenytoin may decrease by as much as threefold in uremia or nephrotic syndrome owing to hypoalbuminemia and the presence of competitive or noncompetitive inhibitors of binding (uremic or dialysis related). Conversely, the steady-state plasma concentration for a given dose of phenytoin also decreases by twofold to threefold as the result of an increase in the apparent volume of distribution and shortened half-time of elimination [Asconape and Penry, 1982]. It is particularly important to monitor carefully the phenytoin levels in patients with renal failure because the nonlinear kinetics of this drug, which are difficult to manage even without renal failure, are much more likely to produce subtherapeutic or supertherapeutic levels in patients with renal failure. It is best to rely on published tables predicting free phenytoin concentrations as a function of serum creatinine in choosing a dosage [Reidenberg and Affrime, 1973] and to titrate dosage adjustments on the basis of free phenytoin levels. It should also be noted that enzyme-multiplied immunoassays for total phenytoin are unreliable in uremic serum [McDonald and Kabra, 1980; Sirgo et al., 1984]. Dosing intervals should be 8 hours or less because administration of larger, less-frequent doses may produce toxic symptoms as a result of the high free fraction. Hemodialysis has little effect on serum phenytoin concentration. In fact, heparinization for dialysis may displace bound phenytoin, resulting in transient toxicity [Steele et al., 1979]. Chronic phenytoin therapy may aggravate renal osteomalacia, but the same effect is produced by most, if not all, of the other antiepileptic drugs—especially when administered in combination. Although few good studies are available, valproic acid is probably subject to pharmacokinetic changes similar to phenytoin when administered to patients with renal failure [Bruni et al., 1980]. The efficacy of dialysis in removing this drug is incompletely characterized [Orr et al., 1983]. However, the toxicity of valproate is generally quite low and the drug can be effective in controlling myoclonic and generalized uremic seizures [Asconape and Penry, 1982]. Theoretical considerations favor its use for seizures associated with cyclosporine therapy and renal graft rejection [Hillebrand et al., 1987]. Phenobarbital elimination depends in part on the glomerular filtration rate and urine pH, but there are surprisingly few data on the disposition of this drug in renal failure [Rust et al., 1989]. Over the short term, renal failure usually has little effect on serum phenobarbital levels [Fabre et al., 1966]. Long-term phenobarbital therapy in severe renal disease may require dosage reduction. Postdialysis doses are usually necessary because this drug is readily dialyzed, especially by hemodialysis. Doses should be adjusted according to postdialysis plasma levels. Pentobarbital, on

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the other hand, is poorly dialyzable. Primidone may prove toxic in renal failure and requires careful serum monitoring, particularly of the upstream intermediate, phenyl-ethylmalonic acid (PEMA). Carbamazepine bioavailability and clearance are unlikely to be greatly affected by renal disease but have not been well studied. Reliable information regarding clearance by dialysis is lacking. The glucuronide metabolites of the new antiepileptic drug, oxcarbazepine, may accumulate in patients with severe renal dysfunction, but the concentration of the active monohydroxy derivative is less likely to do so. Additional studies are required [Lloyd et al., 1994; Rouan et al., 1994]. Ethosuximide has not been well studied, but it is seldom used in patients with renal disease. It is likely to be readily dialyzable. As much as 90% of circulating levetiracetam is excreted in the urine—more than two thirds unchanged and the remainder as an inactive metabolite. It is not liver metabolized; hence, in patients with renal failure, dosage must be modified in a fairly linear fashion in accordance with the degree of decline in creatinine clearance. Approximately two thirds of zonisamide elimination is accomplished by the kidneys, either unchanged or as a glucuronide conjugate. Renal clearance of this drug also diminishes in an approximately linear relationship with diminished creatinine clearance. With severe renal failure (creatinine clearance < 20 mL/minute), zonisamide accumulation may result in serum concentrations approximately one third greater than otherwise anticipated. In assessing for this eventuality, it must be borne in mind that the very long elimination time of this drug means that steady-state elevation will not be achieved for a considerable interval after introduction or dose modification. Lamotrigine inactivation is the result of hepatic conjugation with ensuing elimination of the predominantly 2-N-glucuronate adduct. At least 94% of elimination of this metabolite is renal; hence, accumulation occurs with renal failure. The mean plasma half-life of the drug is greater than 40 hours in renal failure as compared with 26 hours in patients who do not have renal or hepatic failure. Approximately 20% of the plasma concentration is removed by 4 hours of dialysis. The mean half-life is approximately 13 hours with hemodialysis but 57 hours without hemodialysis. These data suggest that, after normal initial dosing, increments should be half or less as great as would be employed without renal (or hepatic) failure with careful monitoring of predialysis and postdialysis trough concentrations. Given the prolonged upward dosage titration necessary to avoid allergy to this medication, its use in patients with renal failure may be a complicated undertaking. It has been suggested that lamotrigine (Lamictal) may elevate risk for renal stones by twofold to fourfold as compared with expected risk. Gabapentin is not appreciably metabolized so that elimination is achieved almost entirely as unchanged drug in urine. Hence, there is a linear inverse relation of steady-state concentration to clearance. The usual elimination half-life of 5 to 7 hours is increased to a mean of 132 hours for creatinine clearance less than 30 mL/minute without dialysis or to approximately 50 hours in end-stage chronic renal failure with thrice-weekly dialysis. Published dosage tables for renal failure in adults receiving hemodialysis are available.

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Individuals with creatinine clearance in the 30- to 60-mL/ minute range usually require somewhat less than half of the expected daily maintenance doses (400 to 1400 mg/day as compared with 900 to 3600 mg/day), and the doses should again be cut in half (200 to 700 mg/day) if creatinine clearance is 15 to 29 mL/minute. Doses for individuals whose clearance is less than 15 mL/minute can be reduced linearly in proportion to fraction by which clearance is further reduced as compared to 15 mL/minute (i.e., dosage for clearance of 7.5 mL/minute is half that of 15 mL/minute). Approximate supplementary doses for adults after hemodialysis range, without regard to creatinine clearance, from 125 (total daily dose up to 700 mg/day) to 350 mg (total daily dosage > 700 mg/day). This treatment must be individualized, adjusted on the basis of peak and trough levels of gabapentin. Benzodiazepines (especially clonazepam) are useful in controlling uremic myoclonus [Chadwick and French, 1979; Stark, 1981] and may not require dosage alteration for acute administration in renal failure, although protein binding may be reduced. Diazepam and lorazepam require reduction more often than clonazepam. Diazepam is not readily dialyzable. Little information is available concerning the dialysis of other benzodiazepines [Asconape and Penry, 1982]. These drugs may accumulate with repeated administration and produce encephalopathy or even myoclonus [Taclob and Needle, 1976]. Lidocaine may be useful in the treatment of uremic status epilepticus, but only limited information is available [Da Conceicao et al., 1999; Raskin and Fishman, 1976b]. OTHER NEUROLOGIC DRUGS. A number of other medications commonly used in the therapy of neurologic disease should be administered with caution in patients with renal failure. Acyclovir doses must be carefully adjusted in patients with renal insufficiency, including acyclovirprovoked renal insufficiency [Da Conceicao et al., 1999]. Both aspirin and acetaminophen require longer interdose intervals in renal failure. Aspirin should not be administered when the glomerular filtration rate is less than 10 mL/ minute. Both of these analgesic drugs are readily cleared by dialysis. Acetazolamide is entirely eliminated by renal mechanisms. The dosage should be reduced for renal failure and avoided in end-stage renal disease and in patients with acidosis, hypokalemia, or urolithiasis (all of which may be worsened by its administration). Tricyclic drugs are not dialyzed well but usually do not require dosage changes in renal failure. They may have beneficial effects, increasing appetite and weight in endstage renal disease. β Blockers and calcium-channel blockers are not readily cleared by dialysis. Dosage may require adjustment in severe renal failure. Haloperidol is not well dialyzed and may provoke hypotension in patients with renal failure. Lithium is a dialyzable drug that requires a longer interdose interval in renal failure. It should be avoided in patients with renal disease because of potential aggravation of renal tubular acidosis or provocation of nephrogenic diabetes insipidus or chronic interstitial fibrosis. Considerably greater detail concerning the management of drugs pertinent to neurologic and other forms of medical practice in children with renal failure is available in several recent reviews [Veltri et al., 2004].

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Wolfsdorf JI, Laffel LM, et al. Metabolic control and renal dysfunction in type I glycogen storage disease. J Inherit Metab Dis 1997;20:559. Wong CS, Jelacic S, et al. The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med 2000;342:1930. Woo M, Przepiorka D, et al. Toxicities of tacrolimus and cyclosporin A after allogeneic blood stem cell transplantation. Bone Marrow Transplant 1997;20:1095. Woodrow G, Harnden P, et al. Acute renal failure due to accelerated hypertension following ingestion of 3,4-methylenedioxymethamphetamine (“ecstasy”). Nephrol Dial Transplant 1995;10:399. Wright RR, Mathews KD. Hypertensive encephalopathy in childhood. J Child Neurol 1996;11:193. Wu BL, Austin MA, et al. Deletion of the entire NF1 gene detected by the FISH: Four deletion patients associated with severe manifestations. Am J Med Genet 1995;59:528. Yager C. Galactitol and galactonate in red blood cells of galactosemic patients. Mol Genet Metab 2003;80:283. Yazbeck S, Larbrisseau A, et al. Femoral neuropathy after renal transplantation. J Urol 1985;134:720. Yildiz A, Sever MS, et al. Improvement of uremic autonomic dysfunction after renal transplantation: A heart rate variability study. Nephron 1998;80:57. Yokoyama K, Hayashi H, et al. Renal lesion of type Ia glycogen storage disease: The glomerular size and renal localization of apolipoprotein [see comments]. Nephron 1995;70:348. Yoshida Y, Machigashira K, et al. Immunological abnormality in patients with lysinuric protein intolerance. J Neurol Sci 1995;134:178. Yosipovitch G, Yarnitsky D, et al. Paradoxical heat sensation in uremic polyneuropathy. Muscle Nerve 1995;18:768. Young JB, Ahmed-Jushuf IH, et al. The role of EEG monitoring and immobilization in dialysis encephalopathy. Dial Transpl 1988;17:15. Young RR, Shahani BT. Asterixis: One type of negative myoclonus. Adv Neurol 1986;43:137. Yuce A, Coskun T, et al. Type I glycogenosis with renal tubular dysfunction (presentation of two cases). Turk J Pediatr 1993;35:201. Zangeneh F, Young WF Jr, et al. Cushing’s syndrome due to ectopic production of corticotropin-releasing hormone in an infant with ganglioneuroblastoma. Endocr Pract 2003;9:394. Zhang X, Jefferson AB, et al. The protein deficient in Lowe syndrome is a phosphatidylinositol-4,5-bisphosphate 5-phosphatase. Proc Natl Acad Sci U S A 1995;92:4853. Zhao Q, et al. Detrimental effects of the ketogenic diet on cognitive function in rats. Pediatric Res 2004;55:368. Zheng X, Chung D, et al. Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura. J Biol Chem 2001;276:41059. Zifko U, Auinger M, et al. Phrenic neuropathy in chronic renal failure. Thorax 1995;50:793. Zimmerman BG, Gisslen J. Pattern of renal vasoconstriction and transmitter release during sympathetic stimulation in presence of angiotensin and cocaine. J Pharmacol Exp Ther 1968;163:320. Zucker I, Yosipovitch G, et al. Prevalence and characterization of uremic pruritus in patients undergoing hemodialysis: Uremic pruritus is still a major problem for patients with end-stage renal disease. J Am Acad Dermatol 2003;49:842. ZuRhein GM, Varakis J. Letter: Progressive multifocal leukoencephalopathy in a renal-allograft recipient. N Engl J Med 1974;291:798.

CHAPTER 90

Neurologic Disorders Associated with Gastrointestinal Diseases, Nutritional Deficiencies, and Fluid-Electrolyte Disorders Yitzchak Frank and Stephen Ashwal

The association between the gastrointestinal (GI) tract and the nervous system is reciprocal. The central nervous system (CNS) depends on the GI system for a constant supply of glucose, the absorption and metabolism of a variety of other nutrients and vitamins required for normal brain function, and the removal of toxic metabolic wastes. The GI tract has an elaborate system of neurons and neural connections: the enteric nervous system, which controls motility, sphincter tone and activity, hormone secretion, and GI circulation. Although this system is partially independent, it has motor and sensory sympathetic and parasympathetic connections to the CNS [Goyal and Hirano, 1996]. Therefore, diseases of the GI tract and liver may cause neurologic abnormalities (e.g., hepatic encephalopathy), whereas neurologic abnormalities affecting the CNS or the enteric nervous system may give rise to GI abnormalities (e.g., achalasia, esophageal reflux, megacolon). A significant number of GI disorders have neurologic manifestations or complications. Some of these are nutritional, related to malabsorption, and some are related to the toxic effects of waste products (e.g., ammonia). Other complications are not related to either of these (e.g., inflammatory bowel disease) and involve immunologic responses related to the underlying disease, genetic factors, vascular abnormalities, or infectious agents. In patients with celiac disease, complications that can develop include cerebellar ataxia, myelopathy, or cerebral, brainstem, and peripheral nerve abnormalities. In patients with Whipple’s disease, possible complications include cognitive and psychiatric manifestations, supranuclear gaze palsy, upper motor neuron dysfunction signs, hypothalamic dysfunction, cranial nerve abnormalities, seizures, ataxia, and sensory deficits. Neurologic abnormalities in inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis) can be related to vascular changes, epilepsy, chronic inflammatory polyradiculoneuropathy, or myasthenia gravis. In patients with hepatitis C, neurologic abnormalities can develop because of vasculitis associated with hepatitis C virus–related cryoglobulinemia. Neurologic abnormalities in persons with GI disease also can be a consequence of vitamin B1, nicotinamide, vitamin B12, vitamin D, or other nutritional deficiencies. In some cases, onset of the neurologic manifestations may precede appearance of the GI abnormalities. The first part of this chapter reviews neurologic complications of the most common GI and liver diseases. GI manifestations of enteric nervous system abnormalities are discussed for some of the common motility disorders. These manifestations are more comprehensively reviewed, as are the anatomy and physiology of the enteric nervous system, in Chapter 85. Several excellent reviews on this topic are

available [Camilleri and Bharucha, 1996; Costa and Brookes, 1994; Ghezzi, 2001; Goyal and Hirano, 1996; Perkin, 1998; Quigley, 1997; Singaram, 1996; Skeen, 2002]. The second part of the chapter reviews disorders associated with malnutrition, vitamin deficiencies, and fluid and electrolyte disturbances.

Neurologic Complications of Common Gastrointestinal and Liver Diseases DISORDERS ASSOCIATED WITH GASTROINTESTINAL DISEASES Episodic Gastrointestinal Disease Cyclic Vomiting Syndrome and Recurrent Abdominal Pain Cyclic vomiting syndrome, described first by Gee [1882], is manifested by recurrent bouts of vomiting lasting for hours or days, which can cause dehydration, hypochloremic alkalosis, and ketosis [Abu-Arafeh and Russell, 1995]. The time of onset, during the day or night, and the duration of the episodes tend to be stereotypic for the affected person. Abdominal pain, weakness, and fever may be present, as well as pallor, skin blotching, and other autonomic features [Fleisher, 1997], and the patient may become drowsy and lethargic. Variable intervals of normal health between episodes are characteristic. Cyclic vomiting and recurrent abdominal pain (including abdominal migrane) are classified under childhood functional GI disorders [RasquinWeber, 1999]. The condition usually occurs in early childhood but can start later and usually resolves before adulthood [Fleisher and Matar, 1993]. Cyclic vomiting syndrome may affect up to 1.9% of school-aged children [Abu-Arafeh, 1995]. It causes a high degree of medical morbidity, with 50% of affected patients requiring intravenous rehydration and experiencing academic disruption. Complications of cyclic vomiting include esophagitis, which may be caused by the continued vomiting, hematemesis, electrolyte depletion, and hypertension [Fleisher, 1995]. The physiology of vomiting involves a number of systems at the level of the medulla including the area postrema and the nucleus tractus solitarius, all finally projecting to a central pattern generator for vomiting that controls the sequence of events during emesis. It receives efferent innervation from chemoreceptors in the area postrema in the floor of the fourth ventricle that are sensitive to different stimuli from

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vagal GI fibers, the vestibulo-ocular system, and the cortex. Vomiting, therefore, can be a result of GI, autonomic, or cerebral dysfunction secondary to tumors, hydrocephalus, toxins, hormonal changes, familial dysautonomia, or migraine [Johns, 1995]. Similarly, the treatment of vomiting differs according to the mechanism or underlying disorder. For instance, some of the antiemetics work through an effect on the vagal complex [Hornby, 2001]. Considerations in the differential diagnosis of cyclic vomiting syndrome include GI obstruction (i.e. malrotations, internal hernias, webs, atresias), inborn errors of metabolism such as urea cycle defects (e.g., ornithine transcarbamylase deficiency), organic acidemias (e.g., methylmalonicacademia), porphyria, fatty acid oxidation defects, and disorders of carbohydrate metabolism. The diagnosis is therefore not complete until established causes of cyclic vomiting syndrome have been investigated [Bu, 1998; Stein, 2001]. Other children have recurrent abdominal pain lasting for hours, with or without headaches, nausea, and vomiting. Some clinical and physiologic overlap exists among cyclic vomiting syndrome, abdominal migraine, and migraine headaches [Bu, 1999]. Exact pathophysiology is unknown, but mitochondrial DNA mutations, ion channelopathies, and excessive hypothalamic-pituitary-adrenal axis activation have been suggested [Bu, 2000]. Abnormal autonomic balance also has been suggested [Bu, 1999]. Recurrent abdominal pain has been referred to as abdominal migraine [Axon et al., 1991; Bentley et al., 1995; Fleisher and Matar, 1993; Symon and Russell, 1986]. A history of migraine headache in first-degree relatives is common [Symon and Russell, 1995]. An electroencephalographic pattern seen with migraine, consisting of posterior temporo-occipital delta slowing, was recorded in a patient with cyclic vomiting during an episode [Jernigan and Ware, 1991]. It also has been suggested that cyclic vomiting may be a manifestation of abdominal epilepsy [Lanzi et al., 1983], although good evidence to prove the existence of such a specific type of epilepsy is lacking. Treatment of cyclic vomiting is with fluid and electrolyte replacement and treatment of esophagitis. Lorazepam has antiemetic and anxiolytic properties. Pharmacologic therapy includes antiemetic agents. Commonly used are chlorpromazine, butyrophenones, and metoclopramide. Serotonin (5-hydroxytryptamine-3) receptor antagonists such as ondansetron have been used recently as antiemetics for cyclic vomiting syndrome. Phenothiazines, butyrophenones, metoclopramide (Reglan), or trimethobenzamide (Tigan) may be effective as antiemetics but may cause extrapyramidal side effects. Prophylactic therapy with propranolol has been reported [Forbes and Withers, 1995]. At times, antiepileptic drugs, such as phenobarbital or valproic acid, may be of benefit. Prophylactic therapy with amitriptyline and with cyproheptadine was found to be effective in small, noncontrolled studies [Anderson, 1997], although treatment with tricyclic antidepressants was more effective in patients who had functional vomiting [Prakash, 1999]. Propranolol [Forbes, 1995], atenolol, and antiepileptic drugs including phenytoin and barbiturates [Gokhale, 1997] have been used. Trials of motilin agonist (erythromycin) have been performed [Vanderhoof, 1995]. Sumatriptan, a 5-hydroxytryptamine-1 agonist, may be effective when used early at the beginning of a cyclic vomiting syndrome episode [Huang, 1997].

Anatomic Disorders Gastroesophageal Reflux Gastroesophageal reflux occurs when an incompetent lower esophageal sphincter allows entry of gastric contents and acid into the esophagus, with the potential for aspiration and development of esophagitis [Hillemeier, 1996]. Some patients also may have a hiatal hernia [Mittal and Balaban, 1997]. Gastroesophageal reflux is common in infants and generally resolves spontaneously within the first year of life as the lower esophageal sphincter mechanism matures. Conservative management in these children involves thickened feedings and positional treatment. The reflux is considered a disease—gastroesophageal reflux disease—when it becomes symptomatic or causes pathologic consequences. Gastroesophageal reflux disease can be primary or secondary. Secondary gastroesophageal reflux disease is associated with a number of genetic syndromes, chromosomal anomalies, and esophageal atresia and also is seen in neurologically impaired children including those with myopathies [Berezin, 1988; Henry, 2004]. Therefore, in children in whom the etiology of gastroesophageal reflux is not established, evaluation for a neurologic cause should be considered. Apnea in most preterm infants is unrelated to gastroesophageal reflux [Poets, 2004]. Factors contributing to the frequent occurrence of gastroesophageal reflux with neurologic conditions include esophageal muscle weakness, hypotonia, incoordination of the swallowing mechanism, scoliosis, and immobility. Symptoms of gastroesophageal reflux include pain, discomfort, irritability, and vomiting. Anemia and recurrent aspiration pneumonia also may occur. Respiratory symptoms resulting from reflux, aspiration, and laryngospasm that cause apnea, cyanosis, and stiffening may be confused with seizures [Bray, 1977]. A relation among hiatal hernia, gastroesophageal reflux, and dystonic neck posture, described by Sandifer, was reported by Kinsbourne in 1964. The dystonic posture consists of extension and rotation of the neck. Other investigators have suggested that the dystonic posture allows for better peristalsis and clearance of acid from the distal esophagus [Puntis et al., 1989]. The same workers, however, could not reproduce these findings in two children with gastroesophageal reflux without dystonia or in normal adult controls. The diagnosis of gastroesophageal reflux is made by upper GI contrast studies, endoscopy and esophageal manometry, and esophageal pH monitoring. Esophageal pH monitoring demonstrates intermittent periods of pH reduction, which indicates reflux of acid gastric contents into the distal esophagus [Hillemeier, 1996]. Esophageal manometry may demonstrate decreased sphincter pressure and reduced peristaltic activity. A barium swallow study of the upper intestinal tract also should be performed to determine the presence of other anatomic or functional abnormalities that may mimic reflux. In children whose symptoms are not ameliorated by being placed in an upright sitting position during and after feeding or by being given thickened feedings, medications that enhance GI motility (e.g., metoclopramide) may be beneficial [Cucchiara, 1996; Hillemeier, 1996; Jung, 2001]. In addition, antacids and the reduction of gastric acid production with histamine receptor type 2 antagonists such as cimetidine or ranitidine or proton

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pump inhibitors may be efficacious. The use of cisapride in childhood gastroesophageal reflux has been discontinued. These therapies are less effective in decreasing respiratory symptoms such as apnea in children with underlying neurologic disorders [Bagwell, 1995; Jolley et al., 1980; Smith et al., 1992]. In children with reflux refractory to aggressive medical treatment, fundoplication may be beneficial [Bagwell, 1995]. Indications for surgery include an established esophageal stricture, associated anatomic defect, and failure of medical therapy, or apneic spells secondary to documented reflux [Spitz, 2003]. A large proportion of children who undergo fundoplication for treatment of gastroesophageal reflux are helped by the operation [Bourne, 2003; Norrashidah, 2002]. Children with neurologic impairment tend to benefit from fundoplication, but they are at greater risk for postoperative complications (12% to 20%), are more likely to require gastrostomy tube placement, and are at greater risk for the development of recurrent reflux than are normal children [Bagwell, 1995; Pearl et al., 1990; Smith et al., 1992].

Hirschsprung’s Disease The enteric nervous system controls and modulates intestinal motility, sensation from the gut, mucosal secretion, and blood flow. It is a complex network of neurons within the wall of the intestine that originate in the neural crest. Neurocristopathies are a group of diverse disorders that result from defective growth, differentiation, and migration of the neural crest cells [Bolande, 1997]. Hirschsprung’s disease is a neurocristopathy with defective migration of neural crest cells to the colonic submucosa and failure to form enteric ganglia in the hindgut, resulting in aganglionic megacolon—the absence of the parasympathetic ganglion cells in the submucosal and myenteric plexuses of the gut, leading to narrowed distal segment and distention of the proximal portion of the bowel. A hypothesis for the pathogenesis of Hirschsprung’s disease is that the migration of neuroenteric ganglion cells from the neural crest to the most distal part of the gut is incomplete, because the migrating neural crest cells confront a genetically determined segmental abnormal microenvironment in the colon [Sullivan, 1996]. The diagnosis is made by the absence of ganglion cells in a rectal biopsy. Increased acetylcholinesterase in the same segment also can be found. Hirschsprung’s disease has an incidence of 1 in 5000 live births. It has been described in conjunction with several syndromes, including Down syndrome, Smith-Lemli-Opitz syndrome, familial piebaldness, Goldberg-Shprintzen syndrome, Haddad’s syndrome, and Waardenburg’s syndrome, and with agenesis of the corpus callosum and other neurologic abnormalities [Kaplan, 1983; Shahar, 2003]. The Goldberg-Shprintzen syndrome includes the combination of unusual facial features (hypertelorism, cleft palate, and maxillary deficiency) and Hirschsprung’s disease [Goldberg and Shprintzen, 1981; Yomo et al., 1991]. Mental retardation and epilepsy also are associated with this syndrome [Tanaka et al., 1993]. Computed tomography (CT) scanning demonstrates diffuse cerebral atrophy. This syndrome may be a manifestation of abnormal neuronal migration, because the parasympathetic ganglia involved in Hirschsprung’s disease

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and the connective tissues of the face and affected oropharyngeal structures all are derived from the neural crest. Patients with Waardenburg’s syndrome, which consists of dysmorphic facial features, partial or total heterochromia iridis, piebaldism of the skin or hair, and congenital deafness affecting one or both ears, also may have Hirschsprung’s disease. Again, the embryonal defect may be a neural crest migration defect [Mallory et al., 1986]. Hirschsprung’s disease also may occur in Haddad’s syndrome, the combination of congenital alveolar hypoventilation requiring continuous mechanical ventilation in the neonate [Stern et al., 1981] and short-segment Hirschsprung’s disease. The existence of familial cases suggested that genetic factors are involved in the etiology of some cases of Hirschsprung’s disease. The inheritance pattern was thought to be multifactorial or autosomal dominant. Recent genetic studies identified a number of genes that may be involved in the disease, including the tyrosine kinase receptor Ret, endothelin-B receptor, and endothelin-3 genes [Chakravarti, 1996; Edery et al., 1994]. In addition, mutations have been found in the gene encoding the glial cell line–derived neurotrophic factor [Wartiovaara, 1998], a factor that promotes the migration of neural crest stem cells in culture [Iwashita, 2003]. Recently, abnormalities of the L1CAM gene, a member of the immunoglobulin gene family of neural cell adhesion molecules localized at Xq28, have been described in cases of Hirschsprung’s disease (and other idiopathic intestinal pseudo-obstruction syndromes) with X-linked hydrocephalus [Bott, 2004; Parisi, 2002; Okamoto, 2004].

Intestinal Pseudo-obstruction Intestinal pseudo-obstruction is manifested by the clinical features of intestinal obstruction in the absence of mechanical blockage [Scott, 1996]. Infants with this condition do not have an anatomic-pathologic diagnosis (e.g., Hirschsprung’s disease). Box 90-1 lists some of the common causes of intestinal pseudo-obstruction in children. Acute pseudo-obstruction (paralytic ileus) usually occurs postoperatively or secondary to the use of medications, including anticholinergic agents, phenothiazines, tricyclic antidepressants, narcotics, and certain antiepileptic drugs, particularly benzodiazepines and barbiturates. Chronic pseudo-obstruction may be due to a variety of abnormalities of the intestinal musculature (chronic myopathic intestinal pseudo-obstruction), such as muscular dystrophies [Barohn et al., 1988], myotonic dystrophies [Brunner et al., 1992], and disorders of intestinal innervation (chronic neuropathic intestinal pseudo-obstruction), including X-linked recessive neuronal forms [Auricchio et al., 1996]. Other syndromes associated with pseudo-obstruction include the POLIP (polyneuropathy, ophthalmoplegia, leukoencephalopathy, and intestinal pseudo-obstruction) syndrome, a familial, possibly autosomal-recessive, chronic neuropathic intestinal pseudo-obstruction that accompanies a progressive severe neuronal disease manifested by external ophthalmoplegia, ptosis, severe sensory and motor peripheral neuropathy, and neuronal hearing loss, without CNS or cognitive involvement [Faber et al., 1987; Steiner et al., 1987]. Postmortem examination in three cases revealed degenerative neuronal changes with eosinophilic intranuclear inclusion bodies and

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Box 90-1 CAUSES OF INTESTINAL PSEUDO-OBSTRUCTION IN CHILDREN I. Acute A. Postoperative B. Electrolyte disturbances C. Medication effects D. Acute infections or toxins II. Chronic A. Disorders of the myenteric plexus 1. Primary disorders of the myenteric plexus a. Developmental abnormalities 1) Neuronal immaturity and developmental abnormalities b. Aganglionosis 1) Hirschsprung’s disease 2) Segmental aganglionosis 2. Familial visceral neuropathies—multiple subtypes 3. Systemic disorders affecting the myenteric plexus a. Infectious—Chagas’ disease, cytomegalovirus infection, infectious mononucleosis, zoster b. Neurologic disorders—familial dysautonomia c. Endocrine disorders—diabetes mellitus d. Gastrointestinal disorders—malabsorption syndromes B. Disorders of intestinal smooth muscle 1. Primary disorders of smooth muscle a. Familial visceral myopathy—various inherited forms b. Sporadic childhood visceral myopathies 2. Systemic disorders affecting visceral smooth muscle a. Muscular and myotonic dystrophies b. Hypothyroidism c. Connective tissue disorders—systemic lupus erythematosus, polymyositis/dermatomyositis C. Small intestinal diverticulosis 1. With myopathic changes 2. With neuropathic changes Modified from Scott RB. Motility disorders. In: Walker WA, Durie PR, Hamilton JR, et al, eds. Pediatric gastrointestinal disease. St. Louis: Mosby, 1996.

it has not yet been clarified whether some of the pathologic features described for intestinal neural dysplasia are the result, rather than the cause, of impaired motility [Kapur, 2003]. The clinical manifestation of intestinal pseudo-obstruction is recurrent episodes of bowel obstruction without a mechanical obstructive cause. Symptoms and signs include poor feeding, vomiting, abdominal distention, megacolon, and constipation. Evaluation for pseudo-obstruction requires excluding structural, mechanical, and pharmacologic causes, followed by additional studies to evaluate motor activity and motility, including barium contrast studies of the GI tract, breath hydrogen determination, scintigraphy, and manometric studies [Scott, 1996; Vargas et al., 1988].

Intussusception Intestinal intussusception with invagination of the gut into its distal segment is the most common cause of bowel obstruction in children between 2 months and 5 years of age. Presenting signs and symptoms are typically abdominal, but encephalopathy with irritability, lethargy, obtundation, or coma has been described. Impairment of mental status can precede the appearance of GI symptoms and signs [Pumberger, 2004]. Brainstem reflexes usually are normal, but extreme miosis may occur. Muscle tone and deep tendon reflexes may be decreased [Goetting et al., 1990; Hoisington et al., 1993]. Neurologic symptoms resolve after surgical reduction. The pathophysiology of this disorder is unknown; on the basis of an apparent response to naloxone, it has been suggested that pain may cause endorphin release, which accounts for miosis, hypotonia, hyporeflexia, and a generalized cortical depression that also could mask the abdominal pain [Tenenbein and Wiseman, 1987]. Alternatively, endotoxin release from intestinal mucosa may act as a CNS depressant [Conway, 1993].

Malabsorption Syndromes A variety of well-known GI disorders are associated with malabsorption syndromes that can cause selected nutritional, biochemical, and vitamin deficiencies. Neurologic involvement in children is seen in some of these disorders. Various biochemical deficiencies, including vitamin E and vitamin B12 deficiency, that can occur as a result of GI disorders are reviewed later in this chapter.

Celiac Disease demyelination in the myenteric plexus and the peripheral nervous system, possibly secondary to axonal atrophy. Cranial nerves and spinal roots were less severely involved, and neurons in the brainstem and spinal cord were intact [Simon et al., 1990]. Abnormal intestinal innervation can be the result of intestinal neuronal dysplasia. Evidence from animal models suggests that intestinal neuronal dysplasia is an entity caused by a genetic defect [Puri, 2004]. It also may exist in humans, in isolation or as a part of Hirschsprung’s disease. Animal studies, however, have demonstrated histologic evidence that chronic intestinal obstruction can induce different degrees of enteric nervous system dysplasia [Galvez, 2004]. Therefore,

Celiac disease is a malabsorption disorder characterized by permanent gluten intolerance. It is a common disorder with a prevalence of about 1%, caused by an inappropriate immune response to the gliadin component in dietary gluten [Dieterich, 1997]. Exposure to gluten perpetuates an enteropathy, leading to malabsorption with chronic diarrhea, weight loss, and abdominal distention. The small intestinal mucosa is abnormal, and jejunal biopsy demonstrates various degrees of villous atrophy, absence of surface mucosa, and crypt hyperplasia. Abnormalities of humoral and cell-mediated immunity suggest that celiac disease is an immunologic disorder [Walker-Smith, 1996]. Anti–tissue transglutaminase anti-

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body assay, an enzyme-linked immunoabsorbent assay, has been used clinically as a serologic screening test for celiac disease. Similarly, antiendomysial, antigliadin, and antireticulin immunoglobulin A antibodies are associated with celiac disease and can be used for serologic screening and monitoring, along with a duodenal biopsy. A large percentage of patients with celiac disease have the gene encoding HLA DQ2, and some have the HL A DR4 DQ8 gene [Hadjivassiliou et al, 1998; Skeen, 2002]. Treatment is by exclusion of gluten from the diet, resulting in healing of the enteropathy and normalization of small bowel function. Gluten sensitivity also can be present in the absence of any symptoms or with neurologic abnormalities but without strictly defined celiac disease, which means that gluten sensitivity constitutes a large spectrum of disease [Fasano et al, 2001; Hadjivassiliou et al, 1998]. Studies report the development of neurologic or psychiatric problems in 10% to 50% of adults with celiac disease. These problems include most commonly ataxia [Luostarinen, 1999; Hadgivassiolou, 1996; Kieslich, 2001] but also depression, seizures, migraine, dementia, and, rarely, peripheral neuropathy or myopathy [Albers et al., 1989; Collin and Maki, 1994; Collin et al., 1991; Gobbi et al., 1992; Holmes, 1996]. Celiac disease occurs in 9% or more of patients with idiopathic cerebellar ataxia, in comparison with 2% of the healthy Finnish population. Patients can present with gait or limb ataxia, and/or dysarthria, oculomotor, sensory or bladder dysfunction [Hadjivassiliou, 2004; Luostarinen et al, 2001]. Because antigliadin antibodies are nonspecific, their presence in persons with ataxia may not necessarily prove the existence of gluten sensitivity [Hadjivassiliou, 2003; Willis, 2002]. Still, patients with idiopathic cerebellar ataxia should be evaluated for the possibility of gluten sensitivity. Children with the disease are typically irritable. Seizures occur in 3.5% to 5.5% of patients with celiac disease [Holmes, 1996]. Neuropathy, manifested by paresthesias, numbness, reduced tendon reflexes, sensory ataxia, and weakness, usually occurs late in the disease, in adults with severe steatorrhea [Kaplan et al., 1988]. Nerve conduction velocity studies and nerve biopsies provide evidence of distal axonopathy. The neuropathy is believed to result from vitamin deficiency. Similarly, myopathy is a rare complication of celiac disease in childhood. CT may demonstrate cerebral calcifications, as well as cerebral and cerebellar atrophy. Specific syndromes of occipital calcifications and epilepsy and cerebellar degeneration with or without epilepsy have been described in childen with celiac diseaese [Arroyo et al., 2002; Gobbi, 1992; Gordon, 2000; Labate et al., 2001]. Screening of patients with Down syndrome using immunoglobulin A (IgA) antiendomysium antibodies, IgA antigliadin antibodies, and total IgA level revealed that a high prevalence of these patients are positive for antiendomysium antibodies (1 in 14). In other studies, the prevalence of celiac disease in people with Down syndrome ranges from 1 in 6 to 1 in 14 [Zachor et al., 2000]. Neurologic disease may be the presenting sign of celiac disease [Finelli et al., 1980; Hardoff et al., 1980; Luostarinen, 1999]. In addition, celiac disease may be present in a significant number of patients with neurologic disease of unknown etiology [Hadjivassiliou, 1996]. Twenty percent of a group of children with biopsy-confirmed celiac disease were prospectively assessed for neurologic disease and were

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found on CT or MRI study to have white matter lesions, which may be the result of vascular or inflammatory demyelination [Kieslich, 2001]. Neuropathologic findings described in an adult patient with celiac disease who manifested a pancerebellar syndrome consisted of cerebellar and basal ganglia cell loss and fibrillary gliosis [Finelli et al., 1980]. Abnormalities also have been described in the cortex, spinal cord, and muscle [Steinberg and Frank, 1993]. The neuropathologic findings in patients with Down syndrome include degenerative changes and evidence of an autoimmune mechanism including inflammation and demyelination. The pathogenesis of CNS or peripheral nervous system dysfunction in gluten enteropathy is not clear. Malabsorption with abnormalities of vitamins B12, B6, D, and E and folic acid, as well as hypocalcemia and hypokalemia, has been implicated [Ventura et al., 1991]. Although these abnormalities may cause neurologic changes and should be looked for in patients with celiac disease and neurologic abnormalities, evidence indicating that the neurologic complications are secondary to malabsorption is lacking in most patients. It has been suggested that the pathogenesis of neurologic abnormalities in celiac disease may be due to a vasculitis that involves the vascular endothelium. Biopsyconfirmed CNS vasculitis and a case of a stroke with CNS vasculitis were documented in association with celiac disease [Ozge, 2001; Rush, 1986]. The syndrome of occipital calcification reported with celiac disease may be the result of autoimmune endothelial inflammation [Gobbi, 1992]. In addition, occasional occurrence of cerebrospinal fluid oligoclonal bands and the presence of inflammatory necrosis, myelin loss, and prominent lymphocytic infiltration suggest an inflammatory immunomediated mechanism [Ghezzi, 2001]. Childhood stroke in association with celiac disease also has been reported [Goodwin, 2004]. CT study of the brain of a 3-year-old female with recurrent episodes of transient left arm weakness, ataxia, and prior history of recurrent diarrhea that subsided after reducing milk intake revealed a low-density enhancing lesion in the right caudate nucleus and two additional lesions, all of which were consistent with infarction. Results of antiendomesial IgA antibodies were positive, antitransglutaminase antibodies were elevated at over 200 U/mL, and duodenal biopsy confirmed the diagnosis of celiac disease. The authors of that report suggest that tissue transglutaminase may be important to the maintenance of vascular endothelial integrity [Kim, 2002]. The enzyme is present in the brain, most abundant in the caudate, putamen, and substantia nigra, and antiendomysial antibody has been reported to immunofluoresce with cerebral vasculature [Pratesi, 1998]. These findings may provide an explanation for the occurrence of vascular abnormalities, demyelination, and stroke in celiac disease. A gluten-free diet or vitamin supplementation has not been found to reverse the CNS abnormalities, although improvement may follow gluten restriction in some patients with peripheral neuropathy or myopathy [Hardoff et al., 1980; Kaplan et al., 1988; Wills, 2000; Wills and Unsworth, 2002]. In a follow-up study of children with celiac disease, a greater frequency of symptoms was found in the group on an unrestricted diet [Bardella et al., 1994]. Neurologic complications, specifically epilepsy with cerebral calcifications, occurred only in patients who were not on a gluten-free diet.

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Short Bowel Syndrome Short bowel syndrome is a malabsorption syndrome that follows resection of a significant portion of the small bowel, usually for a congenital anomaly, necrotizing enterocolitis in the neonate, inflammatory bowel disease, or ischemic injury. The degree of malabsorption is related to the underlying cause for surgical resection, but the extent of bowel resection does not necessarily predict long-term outcome. If the malabsorption prevents normal growth on even specialized enteral feedings, then the child may require central intravenous hyperalimentation until bowel adaptation occurs. Eventual transition to full enteral feedings, however, is not possible in all children with short bowel syndrome who require intravenous nutrition. An unusual complication of this syndrome is an encephalopathy that affects infants and is associated with hyperchloremic acidosis and increased blood and urine lactate. The encephalopathy has been attributed to elevated blood and presumably cerebral lactate concentrations [Gurevitch et al., 1993]. Early recognition, treatment with an intestinal antibiotic, and appropriate adjustment of enteral feedings facilitate correction of the hyperchloremic acidosis and recovery.

Inflammatory Bowel Disease Inflammatory bowel disease, including Crohn’s disease (regional enteritis) and ulcerative colitis, primarily affect young adults and occur infrequently in children. In 15% to 25% of affected persons, the disease starts in childhood [Kim, 2004]. The incidence of inflammatory bowel disease in Wisconsin children was found to be 7.05 per 100,000. The incidence of Crohn’s disease was more than twice the rate of ulcerative colitis [Kugathasan et al, 2003]. Crohn’s disease is a chronic, inflammatory process that can affect any region of the GI tract but mostly affects the small bowel in a discontinuous fashion [Hyams, 1996]. Inflammation involves all layers of the bowel in Crohn’s disease. Ulcerative colitis is a chronic relapsing inflammatory disease involving the mucosa of the colon and rectum in a continuous manner [Kirschner, 1996]. The etiology of both diseases remains unknown, although they likely are of immune origin. Patients complain of diarrhea, rectal bleeding, abdominal pain, vomiting, and weight loss. The pathogenesis of inflammatory bowel disease is complex and involves a reaction to a putative persistent intestinal infection, defective mucosal barrier to luminal antigens, and a dysregulation of the immune response to ubiquitous antigens [Ghezzi, 2001]. Therapy is with anti-inflammatory agents, corticosteroids, and supportive nutritional management [Justinich and Hyams, 1994]. The increased understanding of the immunologic processes involved with inflammatory bowel disease has resulted in the increase of therapeutic agents used to treat the disease [Stein et al, 2001]. Extraintestinal manifestations occur in about 25% to 35% of patients with either disease. Neurologic manifestations are rare, occurring in about 3% of patients with inflammatory bowel disease, and are dominated by CNS vascular complications, including arterial occlusion, arteritis, and encephalopathy [Lloyd-Still and Tomasi, 1989; Lossos et al., 1995; Mezoff et al., 1990]. Seizures, focal neurologic

deficits, and psychiatric disorders also are seen [Elsehery, 1997], as are myelopathy, myopathy, and myasthenia gravis. Peripheral neuropathy and disturbed autonomic functions occur infrequently in patients with long-standing Crohn’s disease [Lindgren et al., 1991; Nemni et al., 1987]. Radiologic findings include arterial occlusion, sagittal sinus thrombosis, and cerebral arteritis. Increased T2 signal in the white matter on MRI scans appears in 40% to 50% of patients with inflammatory bowel disease [Geissler, 1995; Hart, 1998]. In a majority of patients, the onset of neurologic symptoms is within the first 5 to 6 years after the onset of inflammatory bowel disease symptoms [Lossos et al., 1995]. Because bowel fistulas to nearby organs are a complication of Crohn’s disease, spinal infiltration can occur. Although rare, it is a serious complication of Crohn’s disease and must be considered in every patient with significant back pain with or without obvious neurologic signs [Hershkowitz et al, 1990; Maggiore et al, 2004]. A comorbidity of Crohn’s disease and multiple sclerosis also has been reported [Beaugerie, 1997; Kimura et al, 2000]. The pathophysiology of the neurologic manifestations in patients with Crohn’s disease is unknown but may have a dysimmune basis, affecting cell-mediated and humoral immunity and inflammatory mechanisms. Elevated factor V and VIII levels and decreased antithrombin-3 have been found in inflammatory bowel disease. Children with inflammatory bowel disease and neurologic complications may have a family history of collagen-vascular disease (see Chapter 73).

Enteric Infections Enteric bacterial and viral infections that cause primary CNS infection are reviewed in Chapters 68 and 69. A variety of systemic viral and bacterial infections, however, may cause an encephalopathy resulting from the presence of endotoxins or electrolyte and fluid disturbances (Chapter 89). Some of the more well-recognized entities are reviewed here. Seizures and encephalopathy in infants with enteric infections and diarrhea can be caused by hyponatremia or hypernatremia. Hyponatremia may cause brain swelling because sodium and chloride ions cross the brain capillaries slower than water does. Treatment consists of rehydration with adequate sodium salts and avoidance of more dilute fluids [Finberg, 1986]. Hypokalemia can accompany diarrhea and may have neuromuscular manifestations, including hypotonia, diminished bowel sounds, weakness, lethargy, abdominal distention, and, in severe cases, rhabdomyolysis and myoglobinuria. Neuromuscular manifestations become more prominent with serum potassium levels lower than 3 mEq/liter. Severe hypokalemia occurs more frequently in children younger than 24 months and in infants receiving dextrose-containing intravenous fluids without electrolyte replacement and is related to the type of rehydration therapy [Chhabra et al., 1995]. The exact mechanism by which hypokalemia causes muscle weakness is still unclear, but hypokalemia has been demonstrated in experimental models to change the resting membrane potential, limit increases in blood flow in exercising muscles, and cause a reduction in muscle glycogen content.

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Escherichia coli Infection An outbreak of Escherichia coli hemorrhagic colitis in 1990 in Japan was associated with neurologic abnormalities, including generalized seizures, impaired consciousness, urinary incontinence, nystagmus, phrenic nerve palsy, action tremor, and vertigo. The neurologic manifestations were believed to be secondary to bacterial endotoxins [Hamano et al., 1993]. Additional similar cases have been described [Ephros et al., 1996].

Campylobacter jejuni Infection Campylobacter jejuni, a frequently identified bacterial cause of gastroenteritis, has been associated with Guillain-Barré syndrome and encephalopathy [Duret et al., 1991; Nasaralla et al., 1993; Rees et al, 1995]. The incubation period for infections due to this organism usually is 24 to 72 hours but can be longer. Nonspecific prodromal symptoms of fever, myalgia, and headaches occur, and the diarrhea is typically watery but may become bloody. In approximately 30% to 40% of affected persons, Guillain-Barré syndrome develops following C. jejuni infection. Some evidence suggests that Guillain-Barré syndrome in these patients may be a more severe variant of the disease, with a more frequent need for ventilatory support and greater residual disability [Hughes et al, 1997; Rees et al, 1995]. C. jejuni infection with antibodies to GM1 and GD1b gangliosides are associated with a severe, pure motor form of Guillain-Barré syndrome. Crossreactivity between neural antigens and C. jejuni may be one of the mechanisms by which Guillain-Barré syndrome is triggered [Rees et al., 1993]. An oral killed whole-cell vaccine is being tested [Scott, 1997].

Infant Botulism Botulism can be acquired by ingesting contaminated food containing the toxin produced by the bacteria, and through wound infection. Infant botulism and other forms of the disease also have been described [Cherington, 2004]. Botulinum neurotoxin is the neuromuscular poison that is responsible for the disease botulism. The same toxin is being used as a treatment for an expanding list of disorders. Infant botulism, caused by the release of toxins (either type A, B, or E) from the bacterium Clostridium botulinum, occurs in young infants and is manifested by constipation, cranial nerve deficits, pupillary involvement, generalized hypotonia and weakness, and loss of deep tendon reflexes [Arnon, 1992; Clay et al., 1977; Cochran and Appleton, 1995; Hatheway, 1995]. The toxin blocks acetylcholine release by impairing calcium influx associated with membrane depolarization and causes an acute reversible motor unit disease. Affected infants have a history of lethargy, irritability, poor feeding, constipation, and generalized weakness of 12 hours to 7 days’ duration. Examination may reveal ophthalmoplegia with sluggish pupillary responses and abnormal function of cranial nerves VII, IX, X, and XI. Other signs of autonomic dysfunction include delayed gastric emptying and a paralytic ileus. In moderate or severe cases of infant botulism, progressive respiratory failure occurs, with many patients requiring prolonged periods of mechanically assisted ventilation. Cardiovascular symptoms are absent.

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Repetitive nerve stimulation studies document an unusual incremental response, and electromyography demonstrates a distinctive pattern consisting of brief small motor unit potentials. Treatment is supportive, focusing primarily on the need to maintain adequate ventilation and nutrition in a critical care setting.

Shigellosis Shigellosis is an acute bacterial enteritis caused by Shigella bacteria and is characterized by intestinal and extraintestinal symptoms. Neurologic manifestations of dysentery caused by Shigella organisms are common and include convulsions, meningismus, lethargy, confusion, headache, and infrequently an encephalopathy, with hallucinations, delirium, or mutism [Selimoglu et al., 1995]. Neurologic abnormalities may appear before the onset of diarrhea and other GI symptoms [Ashkenazi et al., 1989]. Although seizures and encephalopathy usually are benign and rarely recur or have permanent sequelae [Ozturk et al., 1996], cases of severe fatal encephalopathy have been described [Sandyk and Brenna, 1983]. CT may demonstrate cerebral edema [Perles et al., 1995]. Convulsions occur in 12% to 45% of hospitalized patients with culture-proven shigellosis and are most common in children between 6 months and 4 years of age [Ashkenazi et al., 1983; Daoud et al., 1990]. In a large series, convulsions in a majority of the cases were generalized and lasted less than 10 minutes, and approximately 25% of the children had a history of previous febrile seizures [Ashkenazi et al., 1987]. In another study of 55 children with Shigella organism– associated convulsions who were followed for 6.9 to 14.1 years, none had subsequent nonfebrile seizures, and only 2 had subsequent febrile seizures [Lahat et al., 1990]. Therefore, chronic antiepileptic drug therapy usually is not indicated [Ozturk et al., 1996]. The mechanisms responsible for the neurologic complications of shigellosis have not been clearly elucidated. Some manifestations, especially seizures, may be related to fever, whereas others may not. Neurologic manifestations likely are not related to production of Shiga toxin [Ashkenazi et al., 1990]. A study from Bangladesh of 863 patients with diarrhea documented that clinical features of fever, severe dehydration, hypoglycemia, hyponatremia, or meningitis were present in 92% of the patients in whom a seizure was witnessed and in 92% of the patients who were unconscious [Kahn, 1999]. These findings suggested to the study authors that a majority of the cases of seizures or loss of consciousness were not related to Shiga toxin. At postmortem examination in three patients with Shigella organism–related fatal encephalopathy, areas of necrosis were present throughout the brain; in one patient, pontine hemorrhages and demyelination were present [Sandyk and Brenna, 1983]. Studies in a mouse model of shigellosis demonstrated that local production of tumor necrosis factor-α and interleukin-1b in the brain may play a role in enhanced seizures in the animals infected with Shigella dysenteriae [Nofech-Mozes et al., 2000]. Other studies found that nitric oxide, induced by S. dysenteriae, and corticotropin-releasing hormone may be involved in enhancing the susceptibility to seizures caused by Shigella [Balter-Seri, 1999; Yuhas, 2004].

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Rotavirus Infection Enteric rotavirus infection causing gastroenteritis with concomitant afebrile seizures has also been described in infants [Lin et al., 1996; Tsai and Cho, 1996]. Seizures did not recur in these patients, and no long-term antiepileptic therapy was prescribed. Transient abnormalities on the electroencephalogram (EEG) also have been reported. The occurrence of exanthems in 4% of patients with rotavirus infection suggests the possibility of generalized viremia. It is possible, therefore, that the virus invades the CNS by a hematogenous route [Contino et al., 1994]. Direct inoculation of three strains of rotavirus, including human rotavirus strain 2, into monkey brain caused a neurologic syndrome including transient paresis, with pathologic evidence of viral invasion of the CNS.

Other Gastrointestinal Conditions Whipple’s Disease Whipple’s disease is a multisystem chronic granulomatous disease caused by the bacillus Tropheryma whippelii [Marth and Raoult, 2003]. The first case was reported by G. H. Whipple in 1907. It is described primarily in middle-aged adults (in males more often than in females) but can occur in childhood [Tan et al., 1995] and is manifested clinically by weight loss, steatorrhea, malabsorption, fever, arthritis, lymphadenopathy, and cardiac abnormalities. It involves mostly the small intestine. The diagnosis is based on the presence of periodic acid–Schiff–positive macrophages in duodenal or lymph node biopsy in patients with systemic involvement. Electron microscopy demonstrates gram-positive bacilli (T. whippelii) within the intestinal lamina propria. Periodic acid-Schiff-positive macrophages have been identified in body tissues including the CNS. Increased protein and lymphocytic pleocytosis are detected in the cerebrospinal fluid of patients with the disease. Polymerase chain reaction studies have helped identify the T. whippelii organism [Relman et al, 1992] and have a high sensitivity and specificity. Attempts to culture the organism occasionally are successful. Gene sequencing of T. whippelii isolated from the cerebrospinal fluid of a patient diagnosed with Whipple’s disease demonstrated a condensed genome with a lack of key biosynthetic pathways and a reduced capacity for energy metabolism [Bentley, 2003]. CNS abnormalities are found in 20% to 40% of the patients. In addition, cerebrospinal fluid polymerase chain reaction assay results are positive in 67% of patients with Whipple’s disease without neurologic symptoms [von Herbay et al, 1997]. Signs of CNS infection include progressive dementia, supranuclear ophthalmoplegia, seizures, myoclonus and ataxia, and hypothalamic abnormalities including insomnia [Alba et al., 1995; Jovic and Jovic, 1996; Manzel, 2000]. Recurrent stroke-like episodes have been described, with multiple enhancing lesions on T2-weighted MRI. [Peters, 2002]. Oculomasticatory myorhythmia, possibly caused by brainstem tegmental abnormalities, is a movement disorder nearly unique to patients with Whipple’s disease [Schwartz et al., 1983]. It consists of rhythmic convergence of the eyes and synchronous contractions of the eyelids, jaw, face, and neck with characteristics resembling spinal myoclonus.

Review of the 84 cases of CNS Whipple’s disease revealed that 80% of the patients had systemic signs [Louis et al., 1996]. Cognitive changes were frequent (71%), and 47% of the patients with cognitive changes also had psychiatric signs. Oculomasticatory myorhythmia and oculofacialskeletal myorhythmia, pathognomic for CNS Whipple’s disease, were present in 20% of patients and were always accompanied by a supranuclear vertical gaze palsy. The possibility of CNS Whipple’s disease should be entertained in the setting of unexplained systemic symptoms and neurologic signs (supranuclear vertical gaze palsy, rhythmic myoclonus, dementia with psychiatric symptoms, or hypothalamic manifestations), and in patients with such findings, small bowel biopsy should be considered. CT and MRI demonstrate intracranial focal abnormalities, including low-density focal lesions in the pontine tegmentum and temporal lobe [Halperin et al., 1982; Schnider et al., 1995] and cortical and subcortical atrophy. In a pediatric patient with Whipple’s disease, white matter lesions initially appeared as areas of very low signal intensity on T1-weighted images and hyperintensity on proton densityweighted and T2-weighted images and indicated slight peripheral enhancement on delayed contrast-enhanced T1weighted images. MRI studies performed 3 and 5 months after antibiotic therapy demonstrated that the lesions had decreased in size and no longer enhanced [Duprez, 1996]. MRI features of single lesions may mimick a low-grade glioma [Lohr, 2004]. Neurologic abnormalities can be present without evidence of GI disease [Adams et al., 1987; Halperin et al., 1982; Jovic and Jovic, 1996; Schwartz et al., 1983]. Without treatment, the natural evolution of the disease is always fatal. It responds to antibiotics that cross the blood-brain barrier (such as parenteral penicillin with streptomycin, followed by oral trimethoprim-sulfamethoxazole) given for 1 year, with continuous monitoring of clinical signs and results of cerebrospinal fluid polymerase chain reaction assay [Alba et al., 1995]. Antibiotics, although effective for treating other systemic symptoms, may not affect the progression of neurologic complications [Adams et al., 1987; Halperin et al., 1982; Ratnaike, 2000]. CNS relapse usually is resistant to therapy. Antibiotics can be discontinued only when the results of cerebrospinal fluid polymerase chain reaction assay are negative. Appropriate therapy instituted earlier in the course of the disease is associated with a better neurologic outcome.

Porphyria The porphyrias are a group of metabolic diseases characterized by abnormalities of porphyrin metabolism resulting from deficiencies in enzymes participating in their biosynthesis, the critical prosthetic group for numerous hemoproteins [Tefferi et al., 1994]. Accumulation of the heme precursor δ-aminolevulinic acid and other photoreactive byproducts, the porphyrins, is associated with neurologic manifestations, cutaneous photosensitivity, and dermatopathic manifestations [Bont et al., 1996; Ellefson and Ford, 1996; Lockwood, 1995]. Clinical manifestations may be neurovisceral or cutaneous, and patients may present with acute attacks or cutaneous lesions or both. Porphyrias are classified as erythropoietic or hepatic, depending on the primary enzyme defect.

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Acute intermittent porphyria has an autosomal dominant pattern of inheritance [Schreiber, 1995]. This form of the disease is due to a mutation in the gene encoding porphobilinogen deaminase. Expression of symptoms ranges from mild to severe, and acute episodes of neuropathic porphyrias can progress to paralysis and life-threatening respiratory failure. During an acute attack, measurement of urinary porphobilinogen is the most reliable laboratory test and the method of choice for establishing a diagnosis. DNA mutation analysis is needed to confirm the diagnosis of acute intermittent porphyria [Kauppinen, 2002) and provides 95% sensitivity and approximately 100% specificity [Kauppinen, 2004]. Presentation in childhood is rare [Parsons et al., 1994]. Ten percent of children with DNA-verified acute intermittent porphyria followed prospectively had a clinical attack by the age of 15 years, but symptoms may be vague and of short duration, and urinary δ-aminolevulinic acid and porphobilinogen may be elevated only slightly [Hultdin, 2003]. Neurologic manifestations include abdominal pain, psychosis, and neuropathy [Suarez et al., 1997]. Abdominal pain, the most common complaint, likely results from an underlying autonomic neuropathy with dilatation of the bowel [Gupta and Dolwani, 1996]. Symptoms and signs of neuropathy and cerebrospinal fluid findings may develop acutely, resembling those of Guillain-Barré syndrome [Barohn et al., 1994]. Electrodiagnostic studies indicate axonal polyradiculopathy or neuropathy. Weakness may be asymmetric. CNS manifestations include neuropsychiatric symptoms [Crimlisk, 1997], seizures [Bylesjo et al., 1996], and focal abnormalities such as aphasia, hemiparesis, visual field abnormalities, [King and Bragdon, 1991], cortical blindness, and occipital brain lesions [Kupferschmidt, 1995]. MRI may demonstrate multiple high-signal-intensity abnormalities in the white matter on T2-weighted images [Bylesjo, 2004]. In a case study, a patient with an acute intermittent porphyria attack manifested by abdominal pain and seizures had bilateral lesions on T2-weighted images, especially on fluid-attenuated, inversion recovery (FLAIR) images, which completely resolved with clinical improvement [Utz, 2001]. The MRI abnormalities resemble those seen in patients with the posterior reversible encephalopathy syndrome [Celik, 2002]. The pathophysiology of the porphyric neuropathy is unknown but may relate to neurotoxicity of elevated δ-aminolevulinic acid [Albers, 2004]. Similarly, the pathophysiology of seizures may relate to intrinsic epileptic character of some of the porphyrins or to metabolic abnormalities such as hyponatremia [Solinas, 2004]. Treatment is primarily symptomatic and includes a highcarbohydrate diet, as well as prevention and treatment of water and electrolyte disorders that result from inappropriate antidiuretic hormone production. Long-term management consists of genetic counseling and avoidance of medications (e.g., barbiturates, phenytoin, sulfonamides, chloroquine) that precipitate acute attacks. Of the new antiepileptic drugs, lamotrigine has been reported to precipitate porphyric symptoms, whereas gabapentin has been used successfully to treat seizures in patients with acute intermittent porphyria [Gregersen et al., 1996; Krauss et al., 1995; Tatum and Zachariah, 1995].

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NEUROLOGIC DISORDERS ASSOCIATED WITH HEPATOBILIARY DISEASES Diseases of the liver may be associated with neurologic abnormalities, more commonly with CNS dysfunction, and less commonly with a disruption of the peripheral nervous system. Major neurologic syndromes discussed in this section are hepatitis, hepatic encephalopathy, Wilson’s disease, acquired hepatocerebral degeneration (non-Wilsonian), Reye’s syndrome, and bilirubin encephalopathy-kernicterus [Jones and Weissenborn, 1997; Lewis and Howdle, 2003; Lockwood, 2002; Raskin and Rowland, 1995; Rothstein and Herlong, 1989; Steinberg and Frank, 1993; Victor and Rothstein, 1992]. This section does not address some of the more specific conditions that affect the liver and the brain, including congenital hyperammonemia, galactosemia, and Zellweger’s (cerebrohepatorenal) syndrome, because they are discussed elsewhere in the text. Other neurobehavioral manifestations of liver disease are pruritus in patients with cholestasis, and profound fatigue in patients with chronic cholestasis [Jones, 1995], which also may be associated with altered cerebral neurotransmitter function.

Hepatitis Encephalitis, myelitis, Guillain-Barré syndrome, and polymyositis are infrequent complications of hepatitis A and B [Peters, 1989]. Similarly, hepatitis C virus infection may be associated with extrahepatic syndromes including those affecting the nervous system [Ghezzi, 2001]. Guillain-Barré syndrome infrequently complicates hepatitis [Tabor, 1987; Zimmerman and Lowry, 1947]. The co-occurrence of these disorders reported in the older literature may have represented cases of infectious mononucleosis or cytomegalovirus infection, both of which are capable of causing Guillain-Barré syndrome and hepatitis. Guillain-Barré syndrome has been reported to occur during the preicteric, icteric, or posticteric phase of the disease, although most patients have clinically apparent hepatitis at the time of onset of their polyneuritis. Circulating immune complexes containing hepatitis B antigens have been detected in serum and cerebrospinal fluid of adult patients at the height of neurologic symptoms, but it is unclear whether this finding is due to intrathecal synthesis or whether it reflects blood-brain barrier dysfunction [Penner et al., 1982; Peters, 1989; Tsukada et al., 1987]. The pattern of recovery appears similar to that in patients with Guillain-Barré syndrome associated with other etiologic disorders. Other neurologic syndromes associated with viral hepatitis include mononeuritis, auditory neuritis, and seizures. Polymyositis can rarely occur [Mihas et al., 1978]. Clinical peripheral neuropathy is uncommon, but abnormal nerve conduction velocities have been reported [Chari et al., 1977]. The pathophysiology of peripheral nervous system abnormalities associated with hepatitis C may include vasculitis of the epineurial nerves [Heckermann, 1999 Khella, 1995]. The CNS also may be involved, with symptoms and signs including drowsiness, pyramidal signs, and myoclonus. Progressive encephalopathy, encephalomyelitis, and white matter

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abnormalities have been described [Heckermann, 1999]. Hepatitis C virus antibodies have been found in the cerebrospinal fluid [Propst, 1997]. The pathophysiology of CNS involvement is, similarly, vasculitis associated with hepatitis C virus-related cryoglobulinemia. Interferon-a, steroids, and plasmapheresis were reportedly effective in some cases [Propst, 1997].

encephalopathy in patients with liver disease include upper GI tract bleeding, usually from esophageal varices; excessive protein intake; use of diuretics, narcotics, sedatives, and hepatotoxic drugs; infections; constipation; hypovolemia and hypoxia. The etiology of hyperammonemia in children also includes disorders involving the urea cycle enzymes (Chapter 24).

Hepatic Encephalopathy

Clinical Signs and Symptoms

Hepatocellular failure may be complicated by the behavioral syndrome of hepatic encephalopathy characterized by an altered state of consciousness, abnormal mental status, and neurologic abnormalities [Butterworth, 1996]. Hepatic encephalopathy can complicate most liver diseases, whether acute, subacute, or chronic, and can occur with or without portosystemic shunting. Its symptoms and signs are related to the rapidity with which hepatic failure develops, and to its severity. It occurs frequently in patients with liver failure, although less often in affected children. Between 10% and 50% of patients with cirrhosis and/or portosystemic shunt will experience an episode of hepatic encephalopathy at some point during their illness. Clinically, hepatic encephalopathy can be classified as one of three types—chronic portosystemic encephalopathy, cirrhosis with a precipitant, and acute liver failure [Sherlock, 1977]. Hepatic encephalopathy occurring in a patient with cirrhosis may be either acute or chronic. The acute form usually is associated with a clearly identifiable precipitating factor and usually resolves when the precipitating factor is removed or corrected. Chronic portosystemic encephalopathy occurs in patients with chronic liver disease in association with the presence of a large portosystemic shunt, which may occur spontaneously when portal vein hypertension induces extensive portal collateral circulation or may be surgically created [Gonzales et al., 1990; Mutchnick et al., 1974]. Portal vein blood bypasses the impaired liver, which normally acts as a detoxification site, and drains directly into the systemic circulation to produce the cerebral intoxication. Hepatic encephalopathy also can occur when patients with underlying hepatic cirrhosis experience precipitating events that depress hepatocellular or cerebral function or increase intestinal nitrogenous material. Precipitating factors include oral protein load, GI bleeding, electrolyte imbalance, infection with consequent deteriorated liver function, and constipation [Basile, 1991].

The hallmark of hepatic encephalopathy is mental status change, including cognitive defects in orientation, memory, affect, perception, attention, and judgment, and deterioration of the level of consciousness [Kalra and Murali, 1986]. The earliest changes are subtle psychiatric and behavioral changes and mild impairments of intellectual function apparent to the patient’s family and close friends, which reflect bilateral forebrain, parietal, and temporal dysfunction [Jones, 1997]. Sleep disturbances are a common early sign [Cordoba, 1998]. Initially, verbal ability is relatively well preserved. Later, performance both in work and at school deteriorates, motor functions become impaired, and consciousness decreases. Symptomatic hepatic encephalopathy is traditionally graded into four stages, with derangement of consciousness progressing from drowsiness to stupor and coma:

Etiology The most common cause of hepatic encephalopathy in the pediatric age group is fulminant viral hepatitis, accounting for 50% to 75% of cases. Other causes include ingestions of drugs and toxins such as paracetamol (acetaminophen), high-dose salicylate therapy, parenteral hyperalimentation, and ingestion of isoniazid, rifampicin, halothane, αmethyldopa, azathioprine, erythromycin, sodium valproate, or tetracycline [Alonso et al., 1995; Bhaduri and Mieli Vergani, 1996; Kalra and Murali, 1986]. In addition, chronic end-stage liver disease caused by biliary atresia, α1antitrypsin deficiency, autoimmune chronic active hepatitis, Wilson’s disease, and Reye’s syndrome also may cause a hepatic encephalopathy. Factors that precipitate hepatic

Grade I: Altered sleep cycle, altered affect (euphoria or belligerence, mild confusion, loss of spatial orientation) Grade II: Drowsy, responding to simple commands Grade III: Stuporous, responding only to painful stimuli Grade IV: Unresponsive to pain, decorticate or decerebrate posturing The neurologic examination may demonstrate pyramidal tract dysfunction including hypertonia, hyperreflexia, and extensor plantar responses, later changing to hypotonia when coma develops, and early parkinsonian syndrome, which may include hypomimia (i.e., masked facies), muscular rigidity, bradykinesia, monotony of speech, dyskinesia, and Parkinson’s disease–like tremor [Spahr, 2000]. Other signs are ataxia, action tremor, dysarthria, and asterixis, a characteristic flapping tremor that consists of frequent involuntary flexion-extension movements of the hand associated electrophysiologically with periods of complete electrical silence in muscles. Asterixis can be elicited by having the patient extend the arms with dorsiflexion of the wrist, which elicits a “flap” [Rio et al., 1995]. Seizures are uncommon, occurring in 10% to 30% of patients [Decell et al., 1994]. Focal neurologic abnormalities may be findings [Cadranel, 2001], as can cerebral and retinal visual abnormalities [Miyata, 1988; Eckstein, 1997]. Cerebral edema is a frequent complication in late-stage hepatic encephalopathy in patients with acute liver failure and may be the cause of death. It is rarely seen in patients with encephalopathy resulting from chronic liver disease [Yanda, 1988]. Clinical signs are those of increased intracranial pressure and include dilated and sluggishly reactive pupils, respiratory changes, and increased muscle tone with decerebrate posturing. Hepatic encephalopathy also can occur after the surgical placement of a portosystemic shunt. Symptoms and signs are similar to those of hepatic encephalopathy from other

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causes, but the occurrence of spastic paraparesis also has been described [Pantel et al, 1968b; Reskin et al., 1984]. On histopathologic examination, evidence of myelopathy with degeneration of the anterior and lateral corticospinal tracts is seen. Some patients without liver disease who undergo portocaval shunting may have favorable neuropsychologic outcomes. In a study of portal vein obstruction without liver disease, 42 children were studied up to 24 years after surgery that had been performed between 2 and 14 years of age [Alagille et al., 1986]. Two control groups composed of children who had undergone other abdominal surgical procedures and children with portal vein obstruction that was not shunted also were studied. Serum ammonia levels were higher in the children with portosystemic shunts but little difference in scholastic achievement was found. Visual memory and spatial-temporal tests indicated slightly worse results in the portocaval shunt group. Findings on neurologic examination and EEG were similar in all groups.

Laboratory Tests The diagnosis of hepatic encephalopathy is established clinically. No consistent correlation has been found between any specific laboratory test and the severity of symptoms caused by hepatic encephalopathy. Results of liver function tests usually are abnormal, but derangements may not be as drastic as expected from findings on the examination. Arterial blood ammonia may be elevated and correlates to some degree with the clinical state and the rate of ammonia uptake and metabolism by the brain, although the level does not correlate with the severity of encephalopathy [Kramer, 2000]. Cerebrospinal fluid glutamine concentration is more specific than blood ammonia and correlates better with the stage of hepatic encephalopathy. Neuropsychologic tests provide useful information, especially in patients with subclinical hepatic encephalopathy that would otherwise be overlooked.

Electrophysiologic Studies The EEG is characteristic, although not specific, and correlates with clinical staging of hepatic encephalopathy. In the early stages, it demonstrates progressive slowing of the alpha rhythm, mixed with theta activity. With further clouding of consciousness, slower delta frequencies occur. As with other metabolic encephalopathies, triphasic waves may be present and are seen at a late stage of encepahopathy and usually carry a poor prognosis. These waves may, however, not be seen in young children [Sherlock, 1977]. Occasionally, triphasic waves occur before encephalopathy is clinically evident; this finding is useful in the differential diagnosis. Subsequently, wave amplitude decreases, and finally, cerebral activity ceases altogether. Brainstem and somatosensory evoked potential latencies are delayed [Chu, 1997; Jones, 2001; Kullmann et al., 1995; Sexana,, 2001], although the role of evoked potentials in patients with varying degrees of hepatic encephalopathy remains unclear.

Neuroimaging CT scans may demonstrate cortical atrophy or cerebral edema, but findings may be normal early in the course of

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hepatic encephalopathy. Abnormalities detected by MRI in adults with non-Wilsonian chronic hepatic failure demonstrate increased signal in basal ganglia regions and in the anterior pituitary on T1-weighted images without corresponding abnormalities on T2-weighted images [Ballauff et al., 1994; Pujol et al., 1991; Weissenborn et al., 1995]. Significant abnormalities have not been demonstrated in the cerebral cortex or cerebellum. The MRI appearance does not correlate with laboratory indices of hepatic function, with histologic liver diagnosis, or with neurologic status at the time of MRI acquisition [Brunberg et al., 1991]. MR spectroscopy typically indicates depletion of myoinositol, preservation of N-acetylaspartate, and elevations in glutamine [Laubenberger et al, 1997].

Neuropathology The neuropathologic characteristics of hepatic encephalopathy were initially described by Fredrichs in his “Treatise on Liver Disease” [1860] and later confirmed by Adams and Foley [1953]. The pathologic hallmark of hepatic encephalopathy in patients with cirrhosis and with portosystemic shunts is the presence of Alzheimer type II astrocytes, found in many brain regions, including the cortex and the lenticular, lateral thalamic, dentate, and red nuclei [Lockwood, 2001]. Although not specific to hepatic encephalopathy [Adams and Foley, 1952], these hypertrophic astrocytes are commonly found in the brains of patients who die with cirrhosis and portosystemic shunting, develop shortly after the onset of hepatic encephalopathy, and are related to the duration of coma; the neuropathologic changes are reversible [Sherlock, 1977; Norenberg, 1987]. Other significant parenchymal neuropathologic abnormalities are not present. In acute fulminant hepatic failure, the major finding is the presence of cerebral edema.

Pathophysiology A major determinant causing hepatic encephalopathy is the metabolic effects of products toxic to the brain [Treem, 1996]. Such products, such as those related to bacterial action on proteins in the large intestine, normally are metabolized by the liver. In the presence of parenchymal liver disease or portosystemic shunting, these toxins accumulate in the extracellular fluid and reach the brain. In addition, the blood-brain barrier may be damaged in patients with liver failure, resulting in an increased permeability and increased access of such substances to the brain. Ammonia is regarded as the most likely toxin [Butterworth, 1987], although patients with hepatic encephalopathy may have normal blood ammonia levels. Multiple other agents have been implicated in the pathogenesis of hepatic encephalopathy, including short-chain fatty acids, mercaptans, false neurotransmitters, and γ-aminobutyric acid (GABA), a predominant CNS inhibitor. The relation between ammonia and hepatic encephalopathy is based on the following [Gabuzda, 1952]: (1) ammonia levels in serum and cerebrospinal fluid are elevated in hepatic failure; (2) a correlation exists between the degree of hyperammonemia and the depth of coma; (3) levels of glutamine and α-ketoglutarate (metabolites of ammonia) are elevated in the brain and cerebrospinal fluid of patients with hepatic encephalopathy; (4) hepatic encephalopathy results in

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neuropathologic damage (Alzheimer type II astrocytes) similar to that found in patients with congenital hyperammonemia caused by inherited defects of urea cycle enzymes or in animal models of hepatic portocaval encephalopathy [Cooper and Plum, 1987; Zieve, 1981]; and (5) the most effective treatments for hepatic encephalopathy involve lowering ammonia concentration. Ammonia is produced in the intestinal tract by bacterial breakdown of ingested protein, transported to the liver by the hepatic portal vein, and converted to urea by the urea cycle enzymes; the urea is then excreted by the kidneys. Regardless of the etiology of elevated plasma ammonia levels, brain ammonia concentrations generally are increased in hepatic coma. This elevation may be due to increased permeability of the blood-brain barrier, allowing ammonia to more freely diffuse into the brain. This situation results in an ammonia-induced encephalopathy, although arterial ammonia levels are near normal or normal, and explains the emergence of toxin hypersensitivity as liver disease progresses [Lockwood, 1991]. In the brain, ammonia normally is detoxified by astrocytes, combining with α-ketoglutarate to form glutamic acid, which then forms glutamine, leading to elevated glutamine levels in the cerebrospinal fluid in cases of hepatic encephalopathy [Fraser and Arieff, 1985]. Elevated cerebrospinal fluid glutamine levels may be more specific than blood ammonia levels for hepatic encephalopathy. In addition, conversion of ammonia to glutamine requires ATP, and because of reduced ATP availability, slowing of the tricarboxylic cycle may occur. Several mechanisms have been proposed to explain the neurotoxic action of ammonia, including modification of blood-brain barrier transport, effects on glucose metabolism and brain energy production, disruption of amino acid profiles in the brain (particularly glutamate), and alteration of the chloride pump and normal neuronal membrane physiology [Shields, 1992]. As previously discussed, however, hyperammonemia alone cannot explain the severity of hepatic encephalopathy[Kalra and Murali, 1986; Sherlock, 1977]. GABA, a principal neurotransmitter, is synthesized by intestinal bacteria. It is the major inhibitory neurotransmitter in the human brain. Increased GABA-mediated neurotransmission is known to cause impaired consciousness and psychomotor dysfunction. A few lines of evidence, some from studies in animal models, support the hypothesis that increased GABA-mediated neurotransmission contributes to the manifestations of hepatic encephalopathy [Basile, 1991; Jones, 1994]. Both increased GABA release and enhanced activation of the GABA receptor complex have been demonstrated [Albrecht, 1999]. GABA levels are markedly elevated in patients with fulminant hepatic failure and correlate well with the stage of encephalopathy [Ferenci et al., 1983]. Elevated plasma levels may be due to defective hepatic clearance by GABA transaminase. With impaired blood-brain barrier function, GABA accumulates postsynaptically, resulting in neuronal membrane inhibition. In a rabbit model, development of hepatic encephalopathy was associated with increased plasma levels of GABA, increased blood-brain barrier permeability, increased brain GABA and benzodiazepine binding sites, and a pattern of neuronal activity similar to that induced by drugs that activate the GABA neurotransmitter system [Schafer and Jones, 1982].

Similarly, patients who died with chronic liver disease and encephalopathy were found to have an increased density of brain GABA receptors, suggesting that symptoms were related to increased sensitivity of brain to GABAergic (mediated by GABA) neural inhibition [Jones and Schafer, 1986]. It was postulated that a combination of chronic lowgrade glial edema and potentiation of the effect of GABA on the CNS by ammonia may be responsible for many of the symptoms of hepatic encephalopathy [Basile, 1997; Haussinger, 2002; Lewis, 2003]. In addition, benzodiazepine receptor ligands ameliorated both the behavioral depression and visual-evoked response abnormalities in the thioactamide-induced rat model of hepatic encephalopathy, suggesting involvement of the GABA/benzodiazepine receptor complex [Gammal et al., 1990]. Benzodiazepines can act at the type A GABA (GABAA) receptor complex, and increased concentrations of endogenous benzodiazepines are found in the brain in liver failure [Basile, 1994]. Increased sensitivity of the brain of patients with cirrhosis to an exogenously administered benzodiazepine has been demonstrated [Jones, 1997]. Some patients with hepatic encephalopathy improve after administration of the GABAA receptor antagonist flumazenil. Plasma levels of amino acids, short-chain free fatty acids, and substance P also are elevated in hepatic encephalopathy. False neurotransmitters, such as octopamine, are elevated in the brain and cerebrospinal fluid. Thus, it is possible that hepatic encephalopathy may be mediated by the synergistic actions of a number of agents, including ammonia, GABA, and mercaptans [Treem, 1996]. Neurotransmitters other than GABA may be involved in the pathogenesis of hepatic encephalopathy. These include glutamate, dopamine, serotonin, and opioid systems.

Therapy Hepatic encephalopathy is reversible with medical treatment and is directed at removal or correction of any precipitating factors, reduction of absorption of nitrogenous substances from the intestinal tract, and reduction of increased portosystemic shunting [Jones, 1997]. Most effective therapies are based on reducing the ammonia concentration and treating various complications, including infections, renal and cardiovascular dysfunction, and bleeding secondary to ruptured varices, hypersplenism, or clotting factor deficiencies [Riordan and Williams, 1997]. Therapy also is effective for portosystemic encephalopathy but much less so for fulminant hepatic failure. Ammonia production can be reduced by decreasing dietary protein, treating constipation, controlling GI tract bleeding, and reducing the bacterial content of the intestinal tract. Ammonia also can be removed from the gut by the osmotic action of nonabsorbable disaccharides such as lactulose. Lactulose is metabolized in the lower intestinal tract to lactic acid, reduces local pH (to 5.5), and inhibits growth of colonic organisms and the formation of ammonia. Ammonia is converted to the ammonium ion (NH4) and is then excreted in the stool [Sherlock, 1987]. The resulting decrease in ammonia concentration is associated with improvements in mental status and correction of EEG abnormalities. Complications of lactulose therapy include dehydration and hypernatremia. Reduction of gut ammonia also can be achieved

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using antibiotics, such as neomycin, that are active against urease-producing bacteria. The efficacy of neomycin is similar to that of lactulose [Conn et al., 1977]. Treatments aimed at reversing the neurotransmitter defects, including the use of flumazenil, are still experimental. The imidazobenzodiazepine flumazenil, a benzodiazepine receptor antagonist, is a selective, high-affinity, competitive antagonist of central benzodiazepine receptors on the GABAAbenzodiazepine receptor complex. It competes with high specificity with benzodiazepine receptor agonist ligands (for example, diazepam) for binding to those receptors. It is useful for the component of hepatic encephalopathy related to the effects of natural benzodiazepine receptor agonists. Flumazenil given as an intravenous bolus injection improved clinical and electrophysiologic signs of hepatic encephalopathy; some evidence suggests that it reduced the severity of hepatic encephalopathy [Ferenci, 1996; Gooday, 1995; Jones, 1990] Management of acute severe cerebral edema involves restriction of intravenous fluids, use of hyperosmolar agents (e.g., mannitol, 3% normal saline), and in selected patients, intubation and hyperventilation [Murphy et al., 2004; Yanda, 1988;]. Cerebral edema is best controlled with mannitol (0.25 to 0.5 g/kg) infused rapidly over 20 minutes every 4 to 6 hours. Higher doses may cause a hyperosmolar state and result in decreased cerebral perfusion. Usually three to six doses are sufficient; prolonged use is not recommended. Intracranial pressure monitoring, although involving some risk, may in certain clinical situations be of value in assessing the effects of treatment and progression of the disease. Mannitol is contraindicated in patients with hepatorenal syndrome [Kalra and Murali, 1986]. A role for liver transplantation in fulminant hepatic failure has emerged over the past decade [Liu et al., 2003; Schafer and Shaw, 1989].

Prognosis The prognosis for hepatic encephalopathy has not changed significantly over the past two decades, despite improvement in intensive medical support [Bustamante et al., 1999]. The 1-year survival rate is 40%, and the 3-year survival rate is 15%. Fulminant hepatic failure carries a mortality rate of 75%, and severe hepatic coma is associated with a substantial risk of permanent neurologic disability. On the other hand, the encephalopathy in patients who recover from acute liver failure can resolve without residual neurologic sequelae because, in most cases, brain structural lesions are reversible.

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impairments of visuospatial functioning, attention, and psychomotor speed [Weissenborn, 2001]. The neurophysiologic technique of critical flicker frequency was suggested to be an effective test of minimal hepatic encephalopathy [Kircheis, 2002]. This test establishes the frequency at which a flashing light appears to stop flashing and becomes continuous (fusion frequency). This finding suggests that hepatic encephalopathy represents a continuum, with variable degrees of impairment. Minimal hepatic encephalopathy has an impact on the patient’s quality life; accordingly, appropriate treatment should be given [Groeneweg, 1998; Weissenborn, 2001]. Treatment of minimal hepatic encephalopathy is similar to treatment of overt hepatic encephalopathy, with dietary protein restriction and lactulose treatment. The prognostic significance of this condition is not clear [Amodio, 1999; Hartmann, 2000].

FULMINANT LIVER FAILURE Fulminant liver failure is said to occur when hepatic encephalopathy occurs within 1 to several weeks of the first manifestation of liver disease [Bernuau, 1993]. Rapid loss of hepatocellular function favors the development of cerebral edema and raised intracranial pressure, which can lead to brain ischemia as a result of compression of cerebral vasculature, and to brainstem herniation. Raised intracranial pressure due to cerebral edema can contribute to neurologic deficits. Agitation and seizures are additional findings. Ammonia concentration higher than that usually associated with hepatic encephalopathy in cirrhotic patients can occur and may be responsible for symptoms of neurotoxicity such as psychomotor agitation, muscle twitching, mania, delirium, or seizures, especially in children. The higher ammonia concentrations also may contribute to the pathogenesis of cerebral edema and raised intracranial pressure by promoting increased conversion of glutamate to the organic osmolyte glutamine in astrocytes. From 70% to 80% of the patients with fulminant hepatic failure that progress to stage IV encephalopathy have cerebral edema. The mortality rate is high at 80% to 90% [Alper, 1998], although hepatic structure, histologic characteristics, and function can be completely restored in survivors [Yanda, 1988]. Survival rates have been improving, because many of the patients are receiving liver transplants [Bismuth, 1996; Hassanein, 1997]. Management includes monitoring for hypoglycemia and increased intracranial pressure and treatment as indicated [Donovan, 1992; Lidofsky, 1992] and maintenance of adequate cerebral perfusion pressure.

MINIMAL HEPATIC ENCEPHALOPATHY

COGNITIVE ABNORMALITIES IN CHILDREN WITH LIVER DISEASE

Patients with cirrhosis of the liver are frequently cognitively impaired, even though they do not have evidence of overt encephalopathy. Minimal hepatic encephalopathy was known in the past as subclinical hepatic encephalopathy and refers to chronic liver disease in patients who are believed to be clinically non-encephalopathic but in fact have signs of cognitive impairment. Findings on the routine neurologic examination are normal, but application of psychometric and electrophysiologic tests discloses abnormal brain function [Groeneweg et al, 2000; Schmerus and Hamster, 1998]. Common findings on cognitive testing include

Children with end-stage liver disease have cognitive delays relative to developmental gains made by children with cystic fibrosis or healthy children. Cognitive abnormalities are related to the age at onset and severity of disease [Stewart et al., 1991, 1992]. Nonverbal intelligence is affected more than verbal intelligence. Patients with intellectual impairment have an earlier onset and longer duration of illness, poorer nutritional status, and greater degree of vitamin E deficiency [Stewart et al., 1988]. When examined 1 year after transplantation, older children were more likely to have impairments of cognitive and social function [Stewart et al.,

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1989]. With longer follow-up periods (up to 5 years), cognitive abilities remained unchanged, but gross motor function was better, and patients’ behavior as judged by parental perceptions improved [Zitelli et al., 1988].

NEUROLOGIC COMPLICATIONS OF LIVER TRANSPLANTATION Liver transplantation usually results in improved brain function in patients with hepatic encephalopathy, including a significant improvement in cognitive functioning, but patients do not return to normal, suggesting that hepatic encephalopathy is not completely reversible [Moore, 2000]. Neurologic complications also may arise after transplantation in a large percentage of patients [Blanco et al., 1995; Patchell, 1994]. Seventeen of 52 (33%) patients who underwent 56 orthotopic transplantation procedures had serious postoperative neurologic complications [Adams et al., 1987]. These complications included encephalopathy, seizures, involuntary movements, cortical blindness, brachial plexopathy, and peripheral neuropathy [Appleton et al., 1989; Estol et al., 1989a, 1989b; Garg et al., 1993]. Etiologic factors include air embolism, graft-versus-host reactions, coagulopathy-associated cerebral hemorrhage, seizures or central pontine myelinolysis resulting from severe electrolyte and metabolic changes, cerebral infarction resulting from perioperative hypotension, and meningoencephalitis or cerebral abscess resulting from opportunistic infection. Drug-induced neurologic disorders also may occur. A common complication that occurs in 25% of patients, mostly within the first week after transplantation, is seizures [Adams et al., 1987]. Epileptiform activity seen on EEG is more frequent in patients who die than in survivors [Wszolek et al., 1991]. In one study, 21 patients who had seizures were found at postmortem examination to have combinations of the following: ischemic or hemorrhagic strokes in 18 patients, central pontine myelinosis in 5, and CNS infection in 5 [Estol et al., 1989a]. Multiple metabolic abnormalities were a contributing factor to the onset of seizures. Immunosuppression may lead to opportunistic infections in the months after liver transplantation [Shields, 1992]. The most common organisms causing CNS infection include Listeria monocytogenes, Cryptococcus neoformans, disseminated Nocardia organisms, and disseminated Aspergillus organisms. Chronic dementia can be caused by progressive multifocal leukoencephalopathy. Cyclosporine is an effective immunosuppressive agent, but it may have adverse effects on the CNS [Appleton et al., 1989]. It has been reported to cause a syndrome of encephalopathy without papilledema, cortical blindness, and seizures with white matter lesions that are sometimes hemorrhagic and are predominantly but not exclusively posterior [DeGroen et al., 1987; Rubin and Kang, 1987]. CT demonstrates nonenhancing areas of hypoattenuation, and MRI indicates T2 prolongation in these regions [Truwit et al., 1991]. A disorder of speech and language including mutism, dysarthria, and speech apraxia, with elements of aphasia, also has been described as a complication of orthotopic liver transplantation and may be related to cyclosporine therapy [Bird et al., 1990; Bronster et al., 1995; Stein et al., 1992]. Concurrent high-dose methylprednisolone treatment, hypertension, and possibly other metabolic abnormalities may be contributing factors to

encephalopathy and seizures in such patients. Low total serum cholesterol also has been reported in some of these patients [Truwit et al., 1991]. Suggested mechanisms relating cholesterol to the cyclosporine-induced CNS toxicity include interference of cyclosporine with the transport of cholesterol and other lipids into the brain and an increase in cyclosporine concentration in lipoprotein particles resulting from low cholesterol levels, thereby increasing the brain uptake of cyclosporine. Symptoms and signs, as well as radiographic findings, are reversed after discontinuation or reduction in the dose of cyclosporine. Other neurologic complications of liver transplantation include central pontine myelinolysis, especially with significant serum sodium changes. Careful monitoring of electrolytes in patients undergoing liver transplantation in the perioperative period is recommended [Estol et al., 1989a]. Increased intracranial pressure with reduced cerebral perfusion can occur during or within hours after liver transplantation, and therapy with mannitol may be necessary [Keays et al., 1991]. Chronic inflammatory demyelinating polyradiculoneuropathy or sensorimotor neuropathy has been reported after liver transplantation [Taylor et al., 1995] but is rare and has been tentatively linked to the use of immunosuppressive medications. A recent decrease in the incidence of neurologic complications after liver transplantation has been described and attributed to the immediate withdrawal of cyclosporine at the onset of a change in mental status or dysarthria and improvement in intraoperative and postoperative management [Stein et al., 1992].

Reye’s Syndrome Reye’s syndrome is an uncommon syndrome characterized by an acute encephalopathy with fatty infiltration of various organs including the liver, kidney, and heart [Belay et al., 1999; Casteels-Van Daele et al., 2000; DeVivo, 1985; Glasgow and Middleton, 2001]. The syndrome typically is associated with viral illnesses such as influenza B and varicella, as well as salicylate therapy. Studies have established an increased risk for Reye’s syndrome after aspirin use; in general, salicylates should be avoided in children [Hurwitz et al., 1985]. Some metabolic conditions (e.g., carnitine deficiency, organic acidurias, medium chain acyl-coenzyme A [CoA] dehydrogenase deficiency) can cause recurrent Reyelike syndrome. Therefore, patients with recurrent episodes should be evaluated for evidence of an underlying metabolic disorder (see Chapters 23 through 26 on metabolic disorders). Patients with Reye’s syndrome have abnormalities of mitochondrial function that cause a variety of metabolic derangements of carbohydrates, amino acids, fatty acids, clotting factors, ammonia, lactate, and acid-base balance. Insufficient energy availability to the brain results in massive cytotoxic edema [DeVivo, 1985]. Clinical presentation involves an antecedent viral infection followed by vomiting and marked changes in sensorium that may start with a hyperexcitable stage and progress to lethargy and coma with decorticate posturing. The latter symptoms are secondary to increased intracranial pressure and central herniation as a result of brain edema [Reye et al., 1963]. Clinical staging systems, consisting of four or five stages, have been reported and are based on the cephalo-

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caudal progression of brainstem dysfunction secondary to increased intracranial pressure [Lovejoy et al., 1974] or on EEG criteria [Aoki and Lombroso, 1973]. Reported laboratory abnormalities include marked elevations of hepatic transaminases, prolongation of the prothrombin time, hyperammonemia, hypoglycemia, increases in plasma fatty acid levels, elevation of plasma lactate, and reduced phosphorus concentrations [DeVivo, 1985; Lockwood, 1995; Tonsgard et al., 1982]. Neuroimaging, MR spectroscopy, and single-photon emission computed tomography studies have been reported in several patients with Reye’s syndrome, most of whom suffer severe sequelae [Kinoshita et al., 1996; Kreis et al., 1995; Ozawa et al., 1997]. The gross pathologic abnormalities described by Reye and colleagues [1963] consisted of “cerebral swelling, a slightly enlarged, firm, and uniformly bright-yellow liver, and pallor and slight widening of the renal cortex.” Microscopic liver pathologic findings include microvesicular fatty infiltration, glycogen depletion, depleted Golgi membranes, proliferation of peroxisomes, and distorted mitochondria. Similar abnormalities of mitochondria together with lipid droplet accumulation and glycogen depletion have been seen in muscle biopsy specimens. Brain histopathologic examination demonstrates similar changes in mitochondria and abnormalities of myelin, as well as generalized cerebral edema. Biochemical studies demonstrate decreased activity of mitochondrial enzymes. The most important therapeutic measure is reduction of intracranial pressure with intravenous mannitol or furosemide and hyperventilation (with carbon dioxide tension maintained at approximately 25 mm Hg). In selected patients, hypothermia or high-dose barbiturates can be used to control intracranial pressure elevations. Continuous measurements of intracranial pressure are helpful in monitoring the effects of therapy. Additional supportive treatments include the use of hypertonic glucose solution (15% to 20%) with intravenous insulin, fluid restriction, maintaining electrolyte balance and serum osmolality below 320 mOsm/L, correction of clotting factors, and fever reduction [Trauner, 1990]. Decompressive craniotomy may be beneficial in selected patients. Exchange transfusions, once popular in the 1970s and 1980s, are no longer used, provided that intracranial pressure is monitored and can be controlled by other conventional treatments.

Prognosis Initial reports suggested that Reye’s syndrome was associated with a high mortality rate, particularly in those patents with grade IV or V EEG abnormalities [Van Caillie et al., 1977]. Currently, the prognosis is much improved if the condition is recognized early and treated aggressively. Cognitive, neurologic, and psychological deficits that are frequently subtle but lasting can be found in some survivors [Meekin et al., 1999]. An international perspective reviewing etiologic and epidemiologic aspects of Reye’s syndrome has been published [Stumpf, 1995].

Hepatolenticular Degeneration: Wilson’s Disease Wilson’s disease is a rare defect of copper metabolism manifesting in late childhood or adolescence, with an autosomal-

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recessive pattern of inheritance [Pleskow and Grand, 1996]. Its manifestations are due to the toxic effects of copper deposition in various organs, including the brain, liver, kidneys, and corneas [Loudianos and Gitlin, 2000]. Copper is needed as a catalyst for numerous biologic processes, mainly those involving the utilization of oxygen. Mutations of genes that code for copper-transporting ATPase enzymes constitute the molecular basis for Wilson’s and Menkes’ diseases. Wilson’s disease is characterized by excessive deposition of copper in the liver as a result of deficiency in biliary copper secretion, and subsequently throughout the body, mainly in the CNS and kidney, resulting in liver disease and in neuropsychiatric disease [El Youssef, 2003]. As with Menkes’ disease, the Wilson’s disease gene product has characteristics of a copper-transporting ATPase. It is located on 13q14 and encodes a copper-transporting ATPase [Schilsky, 1996]. It may serve a function in the export of copper from cells, whereas the Menkes’ disease gene product has a role in the import of copper [Tanzi et al., 1993]. Another gene, the MURRI gene, also may be important for biliary copper excretion. [Wijmenga, 2004]. Ceruloplasmin functions in the enzymatic transfer of copper to copper-containing enzymes, such as cytochrome oxidase. Reduced activity of this enzyme has been reported in patients with Wilson’s disease [Shokeir and Shreffler, 1969]. Liver disease can occur in the form of hepatitis and cirrhosis. Neurologic manifestations are gradual in onset and include cognitive abnormalities; dementia; movement disorders, including tremors of the hand or head, whole-body dystonia and rigidity, or other parkinsonian features; ataxia; and occasionally seizures [Lockwood, 1995; Steinberg and Frank, 1993]. Three subsets of patients with Wilson’s disease have been recognized [Oder, 1993]: (1) pseudoparkinsonian patients, with dilatation of the third ventricle, who have signs of bradykinesia, rigidity, cognitive impairment, and an organic mood syndrome; (2) pseudosclerosis patients, with focal thalamic lesions, who exhibit ataxia, tremor, and reduced functional capacity; and (3) dyskinesia patients, with focal abnormalities of the putamen and globus pallidus, who exhibit dyskinesia, dysarthria, and an organic personality syndrome. Psychiatric symptoms often correlate with the severity of the neurologic disturbances [Akil, 1991; Dening, 1989, 1990] In children, deterioration in school achievement and the development of abnormal behavioral or conduct disorders begin insidiously and progress slowly [Lingam et al., 1987]. Neurologic manifestations have been reported in children as young as 6 years of age, although traditionally, children younger than 10 years have the hepatic form of the disease and children older than 10 years have neurologic involvement, [Jones, 2000; Lingam et al., 1987; Scheinberg and Sternlieb, 1984; Walshe and Yealland, 1992]. Psychiatric disorders are common and include mania, psychosis, depression, and even schizophrenia. All patients with neurologic and psychiatric manifestations develop corneal Kayser-Fleischer rings, areas of granular brown pigmentation encircling the cornea caused by copper deposition in Descemet’s membrane, which can be visualized by slit-lamp examination of the cornea. Diagnosis is based on clinical and biochemical data [Sternleib, 1993]. In a patient with neurologic signs, a diag-

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nosis of Wilson’s disease can be made if Kayser-Fleischer rings are present and the ceruloplasmin concentration is less than 20 mg/dL. From 80% to 90% of patients with the disease have low serum ceruloplasmin concentration (less than 20 mg/dL). Other findings include increased urinary copper excretion and elevated liver copper concentration. Serum ceruloplasmin levels are low, and 24-hour urinary excretion is increased [Pleskow and Grand, 1996]. Liver biopsy and examination using radioactive 64Cu or 67Cu can be performed to study hepatic copper levels and metabolism. Neuroimaging abnormalities are common in patients with Wilson’s disease. CT scan abnormalities reported in 60 patients with Wilson’s disease included ventriculomegaly (found in 73% of the patients), cortical atrophy (in 63%), brainstem atrophy (in 45%), hypodensities in the basal ganglia (in 45%), posterior fossa atrophy (in 10%), and no abnormalities (in 18%) [Williams and Walshe, 1981]. More recent studies have confirmed these CT observations [van Wassenaer–van Hall et al., 1996], and extended them to MRI [King et al., 1996]. MRI is more sensitive than CT in detecting abnormalities [Nazer, 1993]. CT findings are abnormal in 50% of asymptomatic patients. Cranial CT and MRI abnormalities other than brain atrophy can be reversed with chelation therapy [Roh, 1994]. Using positron emission tomography, changes in dopaminergic metabolic markers correlate with structural MRI changes but not with clinical symptoms [Westermark et al., 1995]. Proton MR spectroscopy in neurologically symptomatic patients with Wilson’s disease indicates reduced N-acetylaspartate-to-creatine ratios and can determine the degree of neuronal loss in these patients [Van Den Heuvel et al., 1997]. Neuropathologic examination reveals diffuse copper deposition, atrophy of the caudate and putamen, neuronal loss, and Alzheimer type II astrocytes with cortical and basal ganglia demyelination [Yarze, 1992]. Abnormalities of the white matter and cerebral cortex occur in approximately 10% of cases [Brewer, 1992]. Copper concentrations in affected and unaffected regions of the brain are similar. Treatment is directed at reducing systemic copper levels with a low-copper diet and with several anticopper medications. The four drugs currently used include (1) zinc, which blocks intestinal absorption of copper, (2) penicillamine and (3) trientine, both of which are chelators that increase urinary excretion of copper, and (4) tetrathiomolybdate, which forms a tripartite complex with copper and protein and can block copper absorption from the intestine or render blood copper nontoxic [Brewer, 1995; Ferenci, 2004]. Zinc is considered by some investigators to be the therapeutic agent of choice for maintenance therapy, for treatment of the presymptomatic patient from the beginning, and for treatment of the pregnant patient because of its efficacy and lack of toxicity [Brewer, 1995; Czlonkowska et al., 1996]. For patients with mild liver failure, combined treatment with trientine and zinc is effective [Brewer, 1995; Dahlman et al., 1995]. Trientine gives a strong, fast, negative copper balance, and zinc induces hepatic metallothionein, which sequesters hepatic copper. For patients with neurologic disease, tetrathiomolybdate is now preferred by some groups of investigators to penicillamine [Brewer et al., 1994; Schilsky, 1996]. Tetrathiomolybdate provides rapid, safe control of copper levels. Patients who receive penicillamine are at great risk of serious permanent neurologic worsening [Brewer, 1995] or side

effects of this drug, which include rash, bone marrow suppression, immune complex disorders, nephrotic syndrome, optic neuropathy, and loss of taste. Pyridoxine should be given concurrently in those patients receiving penicillamine. Most of the psychiatric manifestations and cognitive abnormalities usually respond to copper chelation therapy [Dening, 1990; Lang, 1990; Lingam et al., 1987]. MRI abnormalities also may remit after treatment [Takahashi, 1996]. When patients with neurologic and psychiatric manifestations are diagnosed late in the course of the disease, some psychiatric dysfunction may remain. In selected patients, primarily those with fulminant hepatitis or chronic hepatic insufficiency with or without neurologic symptoms, liver transplantation may be successful [Bellary et al., 1995; Chen et al., 1997; Schilsky et al., 1994]. Patients with neurologic Wilson’s disease in the absence of hepatic insufficiency also may have clinical improvement [Bax et al., 1998]. Case reports of patients who underwent liver transplantation for Wilson’s disease demonstrated an increase in ceruloplasmin level, disappearance of the Kayser-Fleischer ring, and normalization of urinary copper excretion. Neuropsychiatric abnormalities, as well as MRI abnormalities, tend to remit [Geissler, 2003; Stracciari, 2000], although not always [Kassam, 1998].

Acquired Hepatocellular Degeneration and Hepatic Myelopathy Alpers’ syndrome, described first by Alpers in 1931, is a heterogeneous group of disorders affecting young children manifested by progressive neurologic degeneration with seizures, brain atrophy with neuronal necrosis, and sometimes liver disease. It is discussed in detail in Chapter 59.

Bilirubin Encephalopathy: Kernicterus Bilirubin is the end product of the catabolism of heme, the major source of which is circulating hemoglobin. Bilirubin is transported in plasma bound to albumin and converted in the liver to an excretable conjugated form. Conjugated bilirubin is then excreted into the bile, transported to the small intestine, further degraded by intestinal bacteria, and excreted in the stool. Physiologic hyperbilirubinemia occurs in the first week of life as a result of increased bilirubin load to the liver and decreased bilirubin-conjugating capacity. A number of disorders in the newborn period, however, may lead to much higher concentrations of unconjugated bilirubin [Yao and Stevenson, 1995]. These include hemolytic diseases of the newborn caused by blood group incompatibility (but also some hemoglobinopathies), hemorrhage, polycythemia, inherited or acquired defects of conjugation, and hypothyroidism. Some evidence suggests that bilirubin is injurious to neurons, particularly in its unconjugated form [Shapiro, 2003]. Acidosis and hypoalbuminemia facilitate the neurotoxicity of bilirubin and increase the risk of kernicterus. Bilirubin anions can bind to phospholipid. Bilirubinphospholipid complexes are lipophilic, allowing bilirubin to move across the blood-brain barrier. Such mobility is increased when the blood-brain barrier is disrupted (e.g., with sepsis, asphyxia, or meningitis). In the full-term infant

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with marked hyperbilirubinemia secondary to hemolytic disease, a clear correlation can be established between the occurrence of kernicterus and the maximal recorded level of serum bilirubin [Maisels and Newman, 1995; Newman and Maisels, 1992; Penn et al., 1994]. In the preterm infant, kernicterus has occurred without marked hyperbilirubinemia [Watchko and Claassen, 1994]. These infants are more likely to have acidosis, asphyxia, hypothermia, or sepsis. A distinctive regional topography and selective susceptibility of specific neurons to kernicterus have been described [Levine, 1988; Notter and Kendig, 1985]. In the brain, the bilirubin anion–phospholipid complex can attach to and destroy cellular membranes, thereby affecting multiple enzyme systems and organelles, particularly mitochondria, with resulting disturbances in mitochondrial respiration and oxidative phosphorylation, glycolysis, glycogen synthesis, citric acid cycle function, cyclic adenosine monophosphate synthesis, amino acid and protein metabolism, DNA synthesis, lipid metabolism, myelination, and synthesis and transport of neurotransmitters [Brann et al., 1987; Schiff et al., 1985; Wennberg et al., 1991]. The neuropathologic features of acute bilirubin encephalopathy consist of bilirubin staining followed by neuronal necrosis [Connolly and Volpe, 1990; Turkel, 1990]. Brain bilirubin staining and injury are selective. The regions most commonly stained by bilirubin are the basal ganglia, hippocampus, cranial nerve VIII nuclei and tracts, other brainstem and cerebellar nuclei, and the anterior horn cells of the spinal cord. The cerebral cortical neurons are mildly involved [Hayashi et al., 1991]. Early neuronal changes consist of swollen granular cytoplasm and disruption of neuronal and nuclear membranes, followed by neuronal loss with prominent astrocytosis. Distribution of neuronal injury is similar to that of the bilirubin staining. Little staining but severe neuronal loss occurs in Purkinje cells, especially in the preterm infant. The sequence of acute bilirubin encephalopathy consists of three phases: (1) stupor, hypotonia, and poor sucking and feeding in the first days of life; (2) hypertonia, particularly in the extensor muscle groups, with backward arching of the neck or back (retrocollis-opisthotonos); (3) hypotonia, usually appearing after the first week of life [Van Praagh, 1961; Volpe, 1995]. A minority of infants with kernicterus may not demonstrate neurologic abnormalities in the neonatal period. Chronic bilirubin encephalopathy is manifested by auditory impairment, in most cases a high-frequency bilateral hearing loss [Hung, 1989]; extrapyramidal abnormalities (e.g., chorea, dystonia, or ballismus), which may fluctuate; and gaze abnormalities, which usually affect vertical gaze. Although affected children may manifest hypotonia and motor developmental delay, characteristic features may not become apparent until after 1 year of age. Severe intellectual deficits are encountered less commonly. In some patients, onset may be delayed for several years before development of a movement disorder [Scott and Jankovic, 1996; Volpe, 1995]. Determination of blood bilirubin, albumin, and pH levels may give an indication of the risk of kernicterus. Brainstem auditory-evoked response testing provides early detection of bilirubin neurotoxicity, demonstrating prolonged conduction times between waves I, III, and V [Nwaesei et al., 1984; Ozcelik et al., 1997; Perlman et al., 1983]. MRI may show

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high-intensity lesions in the globus pallidus on T2-weighted imaging [Martich Kriss et al., 1995; Yokochi, 1995]. The essential aspect of bilirubin encephalopathy management is the detection of the infant at risk for brain injury caused by bilirubin. Exchange transfusion is the treatment of choice for hyperbilirubinemia when urgent intervention is necessary [Yao and Stevenson, 1995]. Phototherapy refers to the exposure of the infant to light with high-energy output near the maximum absorption peak of bilirubin. This procedure exposes the bilirubin circulating in superficial capillaries to the light and stimulates photoisomerization of bilirubin to a form that is water soluble and can be excreted in bile without conjugation.

Hepatotoxicity of Antiepileptic Medications Hepatotoxicity is one of the more alarming side effects of antiepileptic drugs and is reviewed in Chapter 49. Considered here is sodium valproate toxicity, because of all antiepileptic drugs, it has been most commonly associated with fatal toxicity. The pattern of occurrence in affected children suggests that the risk is highest in those younger than 2 years of age, on multiple antiepileptic drugs, with metabolic disorders, or with severe seizure disorders accompanied by mental retardation and organic brain diseases [Dreifuss et al., 1989; Willmore et al., 1991]. A Reye-like syndrome associated with valproic acid treatment also has been described [Gerber et al., 1979]. Sodium valproate therapy can be associated with decreased carnitine levels or with true carnitine deficiency. Carnitine is synthesized from dietary amino acids and has a role in longchain fatty acid metabolism. Measurement of carnitine levels in patients who take carnitine, especially as one of multiple antiepileptic medications, is warranted, and carnitine supplements may be useful, although data are limited [Coulter, 1991].

Hepatic Tumors Tuberous sclerosis is a disorder of autosomal-dominant inheritance characterized by seizures, mental retardation, and multiple hamartomas in many organ systems, including skin, brain, heart, kidneys, retina, and liver (see Chapter 31). Hamartomas of the liver (usually multiple) can occur in children with tuberous sclerosis and are more common in females (5:1) than in males and increase in incidence with age. They usually are benign and do not produce symptoms of hepatic dysfunction. On ultrasound studies, they appear as areas of increased echogenicity in comparison with the surrounding hepatic parenchyma [Jozwiak et al., 1992]. Brain metastasis from hepatocellular carcinoma is rare and occurs in less than 2% of patients [Tanabe et al., 1994].

Disorders of Nutrition, Including Fluid-Electrolyte Disturbances OVERVIEW Malnutrition remains a worldwide problem affecting a large number of children, and disorders of nutrition remain the most common environmental insult affecting the developing nervous system. Worldwide, the incidence of malnutrition in

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children decreased over the past decade, but it is estimated that still nearly 149 million children are undernourished [Bhan et al., 2005]. In the United States, less than 1% of all children have chronic malnutrition. Nevertheless, the incidence of malnutrition in some groups (e.g., children in homeless shelters or in rural areas) approaches 10% [Grigsby, 2003]. Studies of hospitalized children also suggest that as many as 25% of patients have some form of acute protein-energy malnutrition, and that 27% have chronic protein-energy malnutrition. Based on a national U.S. Census Bureau survey, 11.1% of all U.S. households (34.9 million people) in 2002 were categorized as “food insecure” because of lack of resources [http://www.frac.org/html/hunger_in_the_us/hunger_index.ht ml]. Approximately 9.4 million of affected persons lived in households in the worst circumstances and experienced outright hunger. People living in 1 in 10 households (9.7%) with incomes below 185% of the federal poverty line also experienced hunger. Disorders of nutrition include both states of undernutrition related to protein-energy malnutrition and deficiencies of vitamins, micronutrients, and minerals. The most common and clinically significant micronutrient deficiencies in children and women of childbearing age throughout the world include deficiencies of iron, iodine, folate, vitamin D, and vitamin A. In this second part of the chapter, some of the conditions that affect the developing nervous system are reviewed. Several excellent reviews discuss various aspects of the effects of undernutrition on brain development [Grantham-McGregor and Ani, 2001; Levitsky and Strupp, 1995; Olness, 2003; Uauya et al., 2001], cognition [Gorman, 1995; GranthamMcGregor, 1995], and behavior [Schurch, 1995]. Another aspect of malnutrion relates to the fact that a high prevalence of epilepsy is frequent among children in developing countries [Hackett and Iype, 2001]. It is likely that any of numerous vitamin, micronutrient, and electrolyte abnormalities of various causes might be a contributing factor in the pathogenesis of epilepsy in children with malnutrition. Conversely, the occurrence of epilepsy may have a detrimental effect on future development. In addition, still other, poverty-related factors in both developed and developing countries, as well as the AIDS pandemic, maternal depression, and the solely institutional care received by many malnourished infants and children, may affect long-term cognitive and behavioral outcomes [Richter, 2003].

PROTEIN-ENERGY MALNUTRITION The World Health Organization (WHO) defines malnutrition as “the cellular imbalance between supply of nutrients and energy and the body’s demand for them to ensure growth, maintenance, and specific functions” [Grigsby, 2003]. Kwashiorkor and marasmus are two forms of protein-energy malnutrition that have been described; the distinction between these entities is based on the presence (kwashiorkor) or absence (marasmus) of edema. Kwashiorkor is a chronic protein deficiency with adequate carbohydrate and often adequate caloric intake. Children are edematous, with swollen faces, ascites, hepatomegaly, and hair and skin depigmentation. If the condition is left untreated, death occurs as a result of infection or hepatic or cardiac failure. Kwashiorkor usually occurs in the latter part of the first to third years of life [Bhan et al., 2005].

Marasmus, a deficiency in both energy (i.e., calories) and protein, is characterized by extreme emaciation, growth failure, alternating apathy and irritability, and eventually obtundation and death. In most affected children, this disorder develops within the first year of life. Because the developing brain reacts differently from the adult brain to severe chronic nutritional deficiencies, the risk for long-term irreversible anatomic, biochemical, and functional disorders is greater. These changes can be associated with intellectual and behavioral deficiencies that persist throughout life [Galler et al., 1986; Klein, 1980; Lloyd-Still, 1976].

Anatomic and Biochemical Effects of Undernutrition Animal studies demonstrate that protein-calorie undernutrition in early life, during the accelerated period of brain development, can affect morphologic, physiologic, and biochemical maturation of the brain [de Souza, 2004; Marichich, 1979; Pinos, 2004; Rotta, 1999; Singh, 1999; Winick, 1976], as measured by growth parameters, synaptic development, myelination, and neurotransmitter levels. Early studies at the beginning of the last century demonstrated that undernutrition early in life had dramatic effects on brain growth. Undernourished animals had increased brain water content, decreased myelination and brain lipid content, and decreased cerebral cortical volume but no significant reductions in the total number of cells compared with age-matched control animals [Donaldson, 1911; Sugita, 1918]. These and later studies suggested that the primary effect of protein-energy deprivation is on the replication and growth of cells (rather than as a destructive process) and is strongest on those elements most actively proliferating during the insult [Dobbing, 1964, 1972; Dobbing and Sands, 1971; Dodge et al., 1975; Winick and Noble, 1966]. That is, the mammalian brain is most vulnerable to malnutrition during the period when the brain is growing most rapidly; consequently, those structures that develop postnatally, such as the cerebrum, hippocampus, and cerebellum, are the most susceptible to permanent morphologic changes [Levitsky and Strupp, 1995]. An alternative hypothesis is that the maximum period of critical vulnerability occurs when specific neurons are undergoing organizational development earlier in life, implying greater susceptibility prenatally than postnatally. The parameters of undernutrition may differ in various studies, and other factors definitely play a role and may modify the effect of undernutrition [Rajanna, 1987]. Although evidence exists for a causal relationship between severe early malnutrition and effects on brain development and functions, many variables are involved, including the duration of undernutrition, prenatal versus perinatal effects, time and extent of rehabilitation, the effects of lack of environmental stimulation, and early or late effects. The outcome also may depend on the quality of the subsequent environment [Grantham-McGregor, 1995]. Some animal studies suggest that the anatomic effects of early undernutrition may persist even if the animals are rehabilitated [Warren, 1988] Box 90-2 lists some of the major neuropathologic abnormalities resulting from malnutrition described in animal experimental studies (see Levitsky and Strupp [1995] for a comprehensive review). Morphometric analysis of specific areas of cerebral cortex and of selected subcortical nuclei by

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BOX 90-2 NUTRITION AND BRAIN DEVELOPMENT Effects of Malnutrition on the Developing Brain Reduction in brain volume Sparing of cortical neurons Increased cell packing Disruption of cortical pyramidal cells Reduction in cortical dendritic spines Decrease in width of cortical neurons Decreased dendritic branching in cortex Reduced number of cortical glial cells Reduced number of cortical synapses Reduced number of synaptic reactive zones Effects of Restoring Nutrition on Reversibility of Brain Lesions Increase in brain weight and volume: “catch-up” head growth Prolongation of period of mitotic activity Prolongation of period of protein synthesis Reversal of cell packing Reduced cortical glial cell density Persistence of reduced number of cortical dendrites and synaptic spines Persistence of reduced myelination Increase in number of mitochondria in neurons Increase in synaptic density Modified from Levitsky DA, Strupp BJ. Malnutrition and the brain: Changing concepts, changing concerns. J Nutr 1995;125:2212S.

Diaz-Cintra and colleagues [1981, 1984, 1990] suggests specific differences in the responses of selected neurons to undernutrition. For example, in the visual cortex of the protein-deprived rat, changes in the developmental pattern of the pyramidal cells of layer V differ from those in layers II and III [Diaz-Cintra et al., 1990]. Pregnant rats subjected to severe protein restriction from the fourth day of gestation give birth to litters that average a 15% decrease in the number of brain cells [Patel et al., 1973]. The reduction is most marked in the areas adjacent to the lateral ventricles and in the cerebellum [Guthrie and Brown, 1968; Shimada et al., 1977]. A similar decrease in cerebral protein has been reported [Zamenhof and Guthrie, 1977]. Activity of rat brain lactate dehydrogenase and of other brain enzymes is affected by food deprivation [Swaiman and Wolfe 1970; Swaiman et al., 1970]. Reductions in protein and calorie intake during the suckling period in rats produced a 10% to 30% reduction in brain weight, with a corresponding decrease in DNA [Fishman et al., 1971; Winick and Noble, 1966]. The major cellular change appears to involve oligodendroglial cells. These cells are reduced in number in both the cortex and the white matter, and their maturation is delayed [Bass et al., 1970]. No significant reduction in the number of neurons in the cerebral cortex is likely, although the number of neurons in the cerebellum, particularly granule cells, may be reduced [Clos et al., 1977]. In undernourished preweanling animals, the reduction of DNA content in the cerebellum is considerably greater than in the cerebrum [Chase et al., 1969]. This difference likely is secondary to the rapid proliferation of cerebellar neurons after birth in the rat. The effects of

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undernutrition on cell number are greatest when a nutritional insult is prolonged from early intrauterine life through the period of lactation, which results in a 60% reduction in cell number in human infants by the time of weaning [Winick, 1970]. Studies in Rhesus monkeys disclosed no effect on brain growth when the mother was adequately nourished during gestation and the infant was protein restricted at birth [Portman et al., 1987]. Myelination is another parameter of brain development that is easily measured in undernourished animals. Cholesterol, which is found in all membranes, is decreased in proportion to total lipids [Dobbing, 1964]; however, greater reductions occur in lipids, such as cerebrosides, that are found predominantly in myelin [Culley and Mertz, 1965]. Proteolipid protein, which also is a myelin constituent, is reduced disproportionately in comparison with other proteins and lipids [Benton et al., 1966]. The chemical composition of myelin from brains of undernourished animals does not differ markedly from that in control animals [Fishman et al., 1971]. Even with prolonged starvation in postnatal life, changes in the amount of myelin are not large. For example, in animals starved from birth to 21 days of age, total myelin quantity was reduced to only 86.5% of that in the control animals. In animals starved from birth to 53 days of age, myelin quantity was 71% of that in age-matched control animals [Fishman et al., 1971]. It is possible that the reduction in myelination is secondary to a reduction in the total number of oligodendroglial cells. Reductions in both RNA and protein in the cerebral cortex of undernourished rats are greater than reductions in DNA. This finding suggests that the impairment in cell growth exceeds the reduction in cell number [Bass et al., 1970]. Levels of gangliosides also are a measure of cell size; these lipids are greatly reduced in undernourished piglets [Dickerson et al., 1971]. Cragg [1972] observed that the number of synapses in the cortex of undernourished rats was decreased. This reduction does not correspond with the general reduction in synaptic transmitters, however. For example, in the undernourished rat brain, serotonin is increased [Resnick and Morgane, 1984], acetylcholine is unchanged [Wiggins et al., 1984], and area-to-area variability in norepinephrine is apparent [Wiggins et al., 1984]. The major aspects of the anatomic and biochemical changes associated with severe protein-calorie malnutrition in animals have been observed in malnourished children. Brain weights are reduced, water content is increased, and a definite reduction in myelin is present that correlates with the length of starvation [Fishman et al., 1969]. DNA content also is reduced in the cerebrum and cerebellum and is related to a reduction in cell number, particularly of oligodendroglial cells [Winick and Rosso, 1969a, 1969b; Winick et al., 1970]. Animals may recover from periods of undernutrition as evidenced by normalization of brain weight and biochemical indices [Dobbing et al., 1971; Winick et al., 1968]. If the period of undernutrition persists during the entire period of cell replication, however, a deficit in cell numbers persists, regardless of the diet provided thereafter [Fish and Winick, 1969; Swaiman et al., 1970]. This deficit is indicated by reduced brain DNA in later life. Briefer insults ending before the age of 21 days in the rat (a period in which cell division is still programmed to occur in the rat brain)

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produce no permanent defects once the animal is re-fed [Culley and Lineberger, 1968; Winick and Noble, 1966]. Evidence in humans is less direct, but measurements of somatic growth and head size suggest that the length of the insult during development is an important factor in the production of permanent effects in humans as well [Chase and Martin, 1970; Hoorweg and Stanfield, 1976]. Physical growth also is decreased after long periods of kwashiorkor later in childhood [Bowie et al., 1980; Pereira et al., 1979]. At age 1 year, human preterm infants who were malnourished in utero, born small for gestational age, or undernourished in early extrauterine life had smaller head circumferences and poorer performances on the Bayley Infant Development scales than corresponding measurements in children of the same gestational age with normal birth weights who were undernourished in early extrauterine life [Georgieff et al., 1985]. This finding suggests that in animals and humans, a combination of intrauterine and extrauterine malnutrition produces the greatest effect on brain weight, chemical composition, and function. The existence of a single common pathway by which lack of protein and calories affects growth of the nervous system is unlikely. It is certain, however, that for there to be significant effect on brain development, the insult occurs during a period of rapid nervous system growth or at a point when cell-cell interconnections are developing.

Effects of Protein-Calorie Undernutrition As suggested earlier, the duration of the undernourished state and the time at which undernutrition occurs have complex effects on long-term cognitive function in children. These effects have been reviewed in detail, and the reader is referred to several sources [Gorman, 1995; GranthamMcGregor, 1995]. ACUTE EFFECTS ON BEHAVIOR AND COGNITION.

Severely malnourished children demonstrate marked behavioral changes during the acute stages of malnutrition [Grantham-McGregor, 1995]. Apathy, reduced activity, decreased interest in and exploration of the environment, reduced stress responses, and impaired cognition all are well characterized. Brief postnatal insults lasting less than 4 to 5 months do not appear to have a permanent effect on mental function [Chase and Martin, 1970]. Starvation over a considerable period does have an effect on behavior and intelligence. Separating the effects of undernutrition from other variables, however, has made it difficult to categorize and quantify the nature and magnitude of deficits attributable to undernutrition. Numerous studies have demonstrated that the intellectual function, academic achievement, and behavior of persons malnourished for long periods differ from those in age-matched control subjects or in siblings in the same family [Cabak and Najdanvic, 1965; Cravioto et al., 1966; Galler et al., 1983; Grantham-McGregor, 1995; Ivanovic, 2000; Stoch and Smythe, 1976; Udani, 1992]. The environments in which malnourished children are reared, however, are almost always suboptimal. Overcrowding, poor education, lack of parental stimulation, and poverty are variables that cannot be confidently evaluated even in sibling studies. TREATMENT. The only treatment of undernutrition is adequate food intake. An adequate protein and calorie intake certainly ends the acute insult, but it is not clear whether caloric supplements always improve growth and function.

The use of dietary supplements, both in utero and during the suckling period, was attempted on several occasions with variable results [Herrera et al., 1980; Joos et al., 1983; Klein et al., 1976; Susser and Stein, 1980]. First, many of the supplements were not used or were used improperly [Beaton and Ghassemi, 1982]. Second, improved nutrition cannot compensate for the other problems of poverty, such as lack of parental interest and overcrowding. Third, it is not certain when improvement ceases or if differences between supplemented and control populations will be of less importance later in life. For example, the study of undernourished children in Bogata, which used both nutritional supplementation and environmental stimulation in different treatment groups, found that nutritionally supplemented children at 18 months of age had benefited in all tested aspects of development except language. At 36 months of age, however, the children’s language skills also had benefited compared with those in nonsupplemented children of the same age. By contrast, the effects of early environmental stimulation lessened with age [Waber et al., 1981]. Nutritionally supplemented populations and their malnourished control subjects have now been followed for up to 9 years. The effects have been positive but small [Grantham-McGregor, 1987]. All facets of neurologic function do not need to recover in parallel. Celedon and DeAndraca [1979] reported that with feeding at the end of a period of protein-calorie undernutrition, psychomotor development improved, but the benefit was limited predominantly to social language and fine motor coordination. Gross motor coordination did not demonstrate any improvement during the 5 months in which the affected children received treatment. Other studies indicated the positive effects of psychosocial stimulation or relatively well-structured home environments during the recovery period [Beardslee et al., 1982; Cravioto and Arrieta, 1979; Grantham-McGregor et al., 1980]. In studies performed in underfed populations in New York City, no differences were disclosed in two groups—one supplemented and one eating the usual diet—using the Bayley Mental and Motor scales. These mothers, however, were supplemented only during pregnancy and not during lactation [Susser and Stein, 1980].

DISORDERS ASSOCIATED WITH VITAMIN DEFICIENCIES OR EXCESSES Vitamins are organic compounds required by mammals in small amounts to sustain normal metabolism. They must be supplied from exogenous sources because they cannot be synthesized endogenously. The chemical structure, physiologic properties, and metabolic function of vitamins are quite diverse. In some instances, vitamins act as cofactors in defined enzymatic reactions; in others, they function by interacting with specific intracellular receptors in target organs or as reducing agents [Snodgrass, 1992]. The existence of vitamins became known through the study of disorders produced by vitamin deficiency in diets [Rosenfeld, 1997]. The almost complete eradication of nutritional vitamin deficiency disorders in developed countries marks one of the major advances in human health, but nutritional vitamin deficiency remains a public health problem in several developing countries and among the poor and aged worldwide. In addition, it is now estimated that about 40%

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of the United States population consumes vitamin supplements, increasing the risk of hypervitaminosis [Meyers et al., 1996]. Clinical manifestations affecting the CNS and peripheral nervous system occur in most nutritional vitamin deficiency states. They also may occur in diseases affecting vitamin absorption, metabolism, and excretion. Iatrogenic vitamin deficiency has been associated with parenteral nutrition, chronic dialysis, and drug administration. An increasing number of inborn errors of metabolism, in which mutations lead to protein alterations that require pharmacologic rather than physiologic amounts of a vitamin, have been documented. These vitamin dependency states, although relatively rare, present a challenge to the clinician, because only through their recognition and the prompt initiation of specific therapy can severe neurologic consequences be prevented (Table 90-1). Ingestion or administration of excessive amounts of some vitamins also may cause neurologic abnormalities and other signs of intoxication.

Vitamin A (Retinol) Vitamin A is the generic term for a group of fat-soluble compounds that possess the biologic activity of retinol (vitamin A1) [Goodman, 1984]. This activity includes important physiologic roles in retinal function, growth and differentiation of epithelial tissue, bone growth, reproduction, embryonic development, and enhancement of the immune system [Snodgrass, 1992]. Physiologic functions of vitamin A are mediated through different forms of the compound. Retinol, the alcohol, serves as the transport molecule; retinal, the aldehyde, is active in the formation of visual pigments; and retinoic acid may be the active metabolite in the growth, maintenance, and differentiation of body tissues. Retinol esters function as storage material. Vitamin A is necessary for the adaptation of the retinal rods and cones to dim light [O’Brien, 1982]. Rhodopsin, formed from the combination of the protein opsin and 11cis-retinal, is the photosensitive pigment of the rods. After absorption of a photon of light, rhodopsin undergoes

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transformational changes through a series of intermediary steps that ultimately leads to the development of a retinal action potential [Stryer, 1986]. Retinol also has an important role in maintaining epithelial cell integrity by stimulating mucus production. Deprived of adequate amounts of retinol, goblet mucous cells disappear and epidermal basal cells proliferate, resulting in keratinization. The absence of normal mucous secretions promotes irritation and infection. Animal work has suggested that vitamin A is required during early pregnancy and development [Zile, 2001]. In addition, major anatomic brain abnormalities occur in the absence of vitamin A [Maden, 1998]. Vitamin A and retinoids may play a role in CNS function. High levels of cellular retinol-binding protein type 1 immunoreactivity and an increased number of nuclear retinoid receptors were found in the CNS of the adult rodent. The vitamin and its derivatives, the retinoids, have been implicated in the synaptic plasticity of the hippocampus and in cognitive functions [Etchamendy, 2003]. Stored retinol esters are a dietary source of vitamin A. Carotenoids, pigmentary compounds present in all photosynthetic plant tissue, provide another major dietary source [Simpson and Chichester, 1981]. These retinol esters are hydrolyzed to retinol in the intestinal lumen and within the brush border of intestinal cells. Absorption mediated by cellular retinol-binding proteins depends on the presence of absorbable fat and bile and is considerably reduced in conditions associated with steatorrhea and other chronic diarrheas [Chytil and Ong, 1987]. Vitamin A is stored in the liver as retinol ester. In the plasma, retinol is bound to a specific retinol-binding protein that binds to specific cell surface sites [Ong, 1985]. The absorption, distribution, and metabolic fate of retinoic acid differ from those of retinol. The recommended daily dietary requirement (i.e., the dietary reference intake) for vitamin A 500 μg/day is for infants younger than 1 year of age and 600 to 900 μg/day for children and adolescents. Under normal conditions, the liver concentration of retinol ester approximates 100 to 300 μg/g, and the normal plasma retinol concentration is 30 to 70 μg/dL.

TABLE 90-1 Vitamin Dependency Disorders VITAMIN

DISORDER

DEFECTIVE ENZYME(S)

Thiamine

Lactic acidemia Maple syrup urine disease Glutaricacidemia type I Glutaricacidemia type II Hartnup’s disease Infantile convulsions Homocystinuria Cystathioninuria Gyrate atrophy of retina (ornithinemia) Inherited transcobalamin II deficiency Methylmalonicacidemia Homocystinuria with methylmalonicaciduria Congenital folate malabsorption Dihydrofolate reductase deficiency Formiminotransferase deficiency Methylenetetrahydrofolate reductase deficiency

Pyruvate carboxylase, pyruvate dehydrogenase Branched-chain dehydrogenase complex Glutaryl-CoA dehydrogenase Multiple acyl-CoA dehydrogenase — — Cystathionine synthase Cystathionase Ornithine-delta-aminotransferase — Methylmalonic-CoA mutase Methyltetrahydrofolate reductase, methylmalonyl-CoA mutase — Dihydrofolate reductase Formiminotransferase Methylenetetrahydrofolate reductase

Riboflavin Niacin Pyridoxine

Cobalamin Folate

CoA, coenzyme A

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Vitamin A Deficiency Dietary vitamin A deficiency continues to be a major cause of infantile blindness in some developing countries [Kello, 2003; Sommer, 1989; Sommer et al., 1981] and may be infrequently seen in developed countries [Rodrigues, 2004]. Reported estimates of the prevalence of inadequate vitamin A intake in several countries ranged from 32% to 68% [Calloway et al., 1993]. In one series, 11.6% of children had reduced blood concentrations [Wetherilt et al., 1992]. It is estimated that between 100 and 140 million children are vitamin A deficient and that an estimated 250,000 to 500,000 vitamin A–deficient children become blind every year, half of them dying within 12 months of losing their sight [WHO, 2004]. In developed countries, vitamin A is among the essential nutrients most likely to be ingested in marginal amounts by the poor. Signs and symptoms of vitamin A deficiency also occur in patients with steatorrhea and other forms of chronic diarrhea, hepatic and pancreatic disease, chronic infections, and hypermetabolic states (e.g., hyperthyroidism) [Abernathy, 1976; Main et al., 1983; Roos and Van Der Blij, 1985]. Clinical manifestations of vitamin A deficiency include night blindness (nyctalopia), corneal and conjunctival dryness (xerophthalmia), appearance of yellow patches on the bulbar conjunctivae (Bitot’s spots), corneal ulcerations and scarring, and, if untreated, irreversible amblyopia [Sommer et al., 1980]. Keratinization of the skin and epithelial lining of the respiratory and urinary tracts leads to increased susceptibility to infection. Pseudotumor cerebri [Abernathy, 1976; Kasarkis and Bass, 1982; Lucidi et al., 1993; Roos and Van Der Blij, 1985] and facial nerve palsy [Sillman et al., 1985] also have been reported. Because serum retinol levels are maintained for months at the expense of hepatic stores, low serum retinol concentrations imply that hepatic stores have been depleted. Clinical manifestations of deficiency may appear when the plasma concentration falls below 20 μg/dL. Clinical manifestations of deficiency should be treated with 6 to 15 mg of retinol (20,000 to 50,000 IU of vitamin A) per day for 4 to 5 days, followed by 0.6 to 1.5 mg per day for 1 to 2 months. In conditions interfering with intestinal vitamin absorption, aqueous preparations should be administered intramuscularly. Treatment initiated before the occurrence of corneal scarring leads to rapid and complete recovery. Benign intracranial hypertension can occur with hypovitaminosis A and E [Lucidi, 1993]. A deficit in spatial learning and memory task was found in adult rats following 12 weeks of vitamin A–free diet, with this cognitive deficit fully reversed when vitamin A was restored in the diet. A reduction in the size of hippocampal nuclei of CA1 region in the vitamin-deficient rats, compared with rats fed with a vitamin A–sufficient diet, also has been reported. These findings suggest that vitamin A has a role in learning and memory processes [Cocco, 2002].

Vitamin A Intoxication In the United States, about 10 to 15 cases of adult vitamin A toxicity are reported each year [Meyers et al., 1996]. This poisoning is due in part to increased vitamin A consumption because of its antioxidant properties [van Poppel and van

den Berg, 1997]. Human sensitivity to excessive amounts of vitamin A is variable and more common in infants and children. Acute toxicity may occur after ingestion of 300,000 IU of vitamin A. Signs of chronic toxicity usually appear after the administration of 2500 IU/kg per day but may result after ingestion of smaller dosages [Bendich and Langseth, 1989]. Ingestion of such quantities of vitamin A is common in the treatment of acne or among megavitamin faddists [Lippe et al., 1981; Shaywitz et al., 1977]. Hepatitis may precipitate manifestations of toxicity [Hatoff et al., 1982]. The molecular basis of vitamin A toxicity is not known. Acute toxicity is characterized by headache, vomiting, diplopia, papilledema (bulging fontanel in infants), stiff neck, and abducens nerve palsies caused by increased intracranial pressure (benign intracranial hypertension). In chronic exposure, manifestations of increased intracranial pressure may be preceded or accompanied by painful fissures at the corners of the mouth, a pruritic desquamating dermatitis, tender hyperostoses of the long bones and skull, limitations of joint motility, hepatomegaly, and failure to gain weight. Diagnosis is established from the dietary history and characteristic clinical findings. The plasma retinol concentration usually exceeds 100 to 600 μg/dL. Radiographs of the limbs may reveal periosteal new bone formation, metaphyseal cupping, and increased metaphyseal density. The uptake of technetium-99m polyphosphate is increased on bone scans. Removal of vitamin A from the diet invariably leads to resolution of symptoms and signs of toxicity within several days.

Vitamin A Teratogenesis Retinoic acid is essential for both embryonic and adult growth, activating gene transcription by means of specific nuclear receptors. It is generated, through a retinaldehyde intermediate, from retinol. Evidence from several animal models indicates that retinoic acid participates in the regulation of the anterior-posterior axis of the hindbrain, the dorsal-ventral axis of the spinal cord, and certain genderspecific segments of the spinal cord [McCaffery et al., 2003]. Inappropriately high concentrations of retinoic acid result in abnormal development of cerebellum and hindbrain nuclei. Teratogenic effects with vitamin A toxicity during pregnancy include hydrocephalus, microcephaly, retinal and optic nerve defects, microtia or anotia, and conotruncal heart defects [Lammer et al., 1985]. Women should be warned preconceptionally about excessive intake of vitamins, especially products containing large amounts of vitamin A, including topical vitamin A derivatives (tretinoin) for acne and age-related skin damage, oral vitamin A derivatives for severe cystic acne (isotretinoin), and psoriasis (etretinate) [Steegers Theunissen, 1995; Swain and Kaplan, 1995]. Some evidence also suggests that low vitamin A levels during brain development interact with susceptibility genes to alter brain development, probably by epigenetic regulation that alters gene expression throughout adult life and may contribute to the development of schizophrenia [Mackay-Sim et al., 2004]. Induction between neural crestderived, retinoic acid-producing mesenchyme, the anterior neural tube, and the anterior surface epithelium of the embryo guides regional differentiation and pathway

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formation during forebrain development. Furthermore, at least two mouse mutations—in the genes encoding Pax-6 and Gli-3—are known to cause peripheral malformations and specifically disrupt neural crest–mediated, retinoic acid– dependent induction and differentiation in the forebrain. These observations suggest that induction might provide a common target for genes that alter morphogenesis of peripheral structures. Disruption of retinoic acid signaling could potentially affect forebrain development, which might influence the numbers or cellular properties of neurons and circuits, possibly reflected in the aberrant forebrain function that characterizes schizophrenia [LaMantia, 1999].

Thiamine (Vitamin B1) Thiamine functions as a cofactor in oxidative decarboxylation and transketolation reactions [Davis and Leke, 1983]. Thiamine pyrophosphate, the physiologic active form, is an essential cofactor in the oxidative decarboxylation of pyruvate to acetyl-coenzyme A (CoA); α-ketoglutarate to succinyl-CoA; and the α-keto derivatives of isoleucine, leucine, and valine to their corresponding branched-chain CoA derivatives (see Chapters 23 and 28). Thiamine pyrophosphate also is the cofactor for the transketolase reaction in the hexose monophosphate shunt that provides pentose for nucleotide synthesis. In addition, thiamine has roles in cerebral metabolism, in which it is present as both a diphosphate and a triphosphate. Although the precise molecular basis of the nervous system function of thiamine is not known, experimental studies have implicated this factor in fatty acid synthesis [Volpe and Marasa, 1978], neuronal membrane transport [Voorhees et al., 1977], neuromuscular transmission [Waldehind, 1978], and axonal conduction [Schoffeniels, 1983]. Thiamine is readily available in meats, grains, and vegetables but is destroyed by heat. It is actively transported across the small intestine by a saturable process, limiting the amount that can be absorbed. In the blood, thiamine is bound to protein, predominantly albumin. Its transport into the CNS and cerebrospinal fluid is controlled by a ratelimiting process involving a specific membrane-bound phosphatase [Spector, 1976]. Excesses of the vitamin are excreted in the urine. The requirement for thiamine depends on the metabolic rate and is increased when carbohydrates are the major energy source. The recommended daily dietary reference intake is 0.3 to 0.4 mg in infants younger than 1 year of age and 0.6 to 1.2 mg in older children and adolescents, amounts readily available in normal diets.

Thiamine Deficiency Historically, clinical manifestations of dietary thiamine deficiency (beri-beri) occurred in populations in which polished rice formed the major dietary staple [Carpenter and Sutherland, 1995]. Signs of deficiency still occur in alcoholics and the aged, populations that use thiamine less effectively. Beri-beri also has been reported after ingestion of large amounts of raw freshwater fish, shellfish, and bracken foods that contain thiaminase-1, an enzyme promoting thiamine decomposition [Murata, 1965], and large quantities of tea, which contains another thiamine antagonist [Vimokesant

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et al., 1974]. An infantile form of beri-beri has been reported in breast-fed infants of thiamine-deficient mothers [Rao and Subrahmagam, 1964] and in infants fed a soybean formula in which the thiamine was presumably heat inactivated during preparation [Cochrane et al., 1961]. Early symptoms of thiamine deficiency are not specific and include apathy, fatigue, mental sluggishness, depression, anorexia, and abdominal discomfort. More prolonged and severe deficiency is associated with signs of peripheral neuropathy, nerve and muscle tenderness, and cardiomyopathy [Tojo et al., 1993]. Hoarseness caused by laryngeal nerve paralysis is a classic sign. Ptosis, optic atrophy, and encephalopathic features are other possible findings. As the deficiency persists, increased intracranial pressure, meningismus, seizures, and coma may progress rapidly to a fatal outcome from either neurologic or cardiac failure. Vitamin B1 deficiency also can cause Wernicke-Korsakoff syndrome. This syndrome usually is seen in adults with chronic alcoholism, pancreatitis, or carcinoma of the stomach or esophagus but also is found in children, in whom it is underdiagnosed. In a collected series of pediatric Wernicke’s encephalopathy cases, 41.9% of patients were diagnosed at postmortem examination. The original patients with Wernicke’s encephalopathy had a clinical triad comprising ocular abnormalities, mental status changes, and ataxia, but many of the patients do not present with this classic triad. In a review of a series of children and adolescents with this condition, only 6 of 30 presented with the Wernicke’s encephalopathy clinical triad at the onset of their disease [Vasconcelos, 1999]. The most common symptom was mental state change, occurring in 82% of patients, followed by ocular signs (e.g., ophthalmoplegia, nystagmus, ptosis) in 68% and ataxia in 21%. CT abnormalities included hypodensities in the basal ganglia and medial thalami, whereas MRI demonstrated abnormalities in all tested patients manifested by increased signal in T2-weighted images and contrast enhancement of the basal ganglia, medial thalami, mammillary bodies, or periaqueductal gray matter. The most frequently underlying disorder in this series was malignancy. Symptoms of thiamine deficiency also can be seen in patients with GI disease who have malabsorption or vomiting and in patients on total parenteral nutrition [Hahn, 1998; Ming, 1990]. Single photon emission computed tomography in Wernicke’s encephalopathy may reveal bilateral frontal and frontotemporal hypoperfusion and right basal ganglia hypoperfusion [Celik, 2004]. In children, MRI may be helpful in establishing the diagnosis of Wernicke’s encephalopathy by demonstrating diencephalic and mesencephalic signal abnormalities on T2-weighted images and, in some patients, enhancement of the mammillary bodies and the floor of the hypothalamus [Coe et al., 2001; Ming et al., 1998; Sparacia et al., 1999] Infantile beri-beri is characterized by vomiting, aphonia, abdominal distention, diarrhea, cyanosis, tachycardia, and convulsions. Death may occur suddenly. In less fulminant, more chronic depletions, infants fail to grow, and subsequently edema, oliguria, constipation, cardiomegaly, and hepatomegaly typically develop [Cochrane et al., 1961]. Neuropathologic features of beri-beri are fairly characteristic and consist of nerve cell degeneration, endothelial hyperplasia, and petechial hemorrhages localized to the periventricular gray matter around the third ventricle, sylvian

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aqueduct, fourth ventricle, and mammillary bodies [Cochrane et al., 1961]. Peripheral nerves manifest patchy areas of demyelination. Diagnosis of thiamine deficiency depends primarily on suspicions raised by the dietary history and the presence of typical clinical manifestations. Determining serum thiamine concentrations is not of practical value. Urinary excretion of less than 120 μg of thiamine per gram of creatinine suggests thiamine deficiency. An increase of 25% or more in red cell ketolase activity after the addition of thiamine pyrophosphate also is characteristic of deficiency. Clinical response to the administration of thiamine is the best confirmatory test. Oral administration of 10 to 50 mg of thiamine daily will reverse clinical symptoms in a few weeks. Serious life-threatening neurologic manifestations or congestive heart failure should be treated with the parenteral administration of 5 to 20 mg of thiamine.

Thiamine Dependency Pyruvate dysmetabolism disorders are among the varied causes of lactic acidosis [Evans, 1986]. Thiamine pyrophosphate is an essential cofactor in pyruvate decarboxylation. Several patients with documented thiamine-responsive lacticacidemia have been described [Duran and Wadman, 1985]. The age at onset of symptoms varies, ranging from the immediate postnatal period to 8 years. Mental retardation and episodic neurologic abnormalities, including intermittent ataxia, choreoathetosis, and hypotonia with areflexia, occur. Pyruvate carboxylase deficiency has been confirmed in one patient by liver biopsy, and a partial deficiency of the pyruvate dehydrogenase complex was confirmed in two others by enzymatic assay of cultured skin fibroblasts. Biochemical abnormalities normalized and episodic neurologic symptoms subsided after administration of pharmacologic amounts of thiamine (20 to 2400 mg per day). In view of the potential benefits, therapy with thiamine in pharmacologic amounts should be attempted in all patients with persistent lacticacidemia believed to be secondary to a primary metabolic defect. (See Chapters 23, 25, 28, and 81 for further discussion of the role of thiamine in metabolic diseases.) Thiamine also is important in other inborn errors of metabolism, including a form of thiamine-dependent maple syrup urine disease and subacute necrotizing encephalomyelopathy (Leigh’s disease) (see Chapter 23). A syndrome of thiamine-dependent megaloblastic anemia, sensorineural deafness, and diabetes mellitus also has been described [Haworth et al., 1982; Viana and Carvalho, 1978]. The finding that thiamine (20 to 25 mg per day) corrects the megaloblastic anemia was serendipitous. In one patient, it was possible to discontinue insulin use after the initiation of thiamine treatment. Hearing impairment was not reversible. The basis of the response to the thiamine in this syndrome is not known.

Riboflavin (Vitamin B2) Two coenzymes, flavin mononucleotide and flavin adenine dinucleotide, are the physiologically active forms of riboflavin. These nucleotides play a vital role in a variety of mitochondrial oxidation-reduction reactions involving flavoproteins, including amino acid oxidase, xanthine

oxidase, glutathione reductase, and nitric oxide synthase [Neims and Helerman, 1970; Stuehr and Griffith, 1992]. Riboflavin is widely distributed in plant and animal tissues. Phosphorylation of riboflavin to flavin mononucleotide occurs in the intestinal mucosa through a reaction catalyzed by the cytosolic enzyme flavokinase, and both riboflavin and flavin mononucleotide are absorbed into the circulation [Jusko and Levy, 1975]. The upper limit of absorption is approximately 25 mg per dose. Only small amounts of riboflavin are stored, and unused riboflavin is excreted in the urine and feces. In the plasma, riboflavin and flavin mononucleotide are bound to protein, predominantly albumin. In tissues, riboflavin is converted to flavin mononucleotide in a reaction catalyzed by flavokinase. Flavin mononucleotide is subsequently converted to flavin adenine dinucleotide in a reaction catalyzed by flavin adenine dinucleotide pyrophosphorylase and then transported into the mitochondria. The recommended dietary reference intake for riboflavin is 0.3 to 0.4 mg in infants younger than 1 year of age and 0.5 to 1.8 mg in older children and adolescents.

Riboflavin Deficiency Symptomatic riboflavin deficiency invariably occurs in association with deficiencies of other vitamins [Hoppel and Tandler, 1990]. Early symptoms include sore throat and angular stomatitis. Glossitis, cheilosis, seborrheic dermatitis of the face, and dermatitis over the trunk and limbs develop later. Other late effects include a normochromic, normocytic anemia with associated reticulocytopenia. A neuropathy characterizes the neurologic deficit. Diagnosis rests primarily on suspicions raised by the dietary history and presence of characteristic symptoms. Serum riboflavin concentration determinations are of no practical value; urinary excretion rates below 30 μg per 24 hours suggest riboflavin depletion. The activity of the flavin-dependent erythrocyte glutathione reductase before and after flavin adenine dinucleotide activation is a good index of riboflavin status [Prentice and Bates, 1981]. Riboflavin in dosages of 5 to 10 mg per day readily reverses the manifestations of riboflavin deficiency.

Riboflavin Dependency RIBOFLAVIN-DEPENDENT GLUTARICACIDEMIA TYPE I Glutaryl-CoA dehydrogenase deficiency type I is an autosomal-recessive error of metabolism characterized by early acquired macrocephaly, severe mental retardation, seizures, progressive choreoathetosis, and dystonia associated with glutaricaciduria and 3-hydroxyglutaric-aciduria [Goodman et al., 1977; Stutchfield et al., 1985] (see Chapter 23). Neuropathologic features include severe symmetric destruction of the putamen and lateral margins of the caudate nuclei [Leibel et al., 1980]. The content of GABA in the basal ganglia and substantia nigra is markedly decreased, presumably because GABA synthetase is inhibited by glutaric acid [Bennett et al., 1986; Christensen and Brandt, 1978]. The activity of glutaryl-CoA dehydrogenase, an enzyme for which riboflavin is a cofactor, is deficient in leukocytes, cultured skin fibroblasts, and amniotic cells. The severity of the clinical manifestations, biochemical abnor-

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malities, and amount of residual enzymatic activity vary considerably. Administration of riboflavin in pharmacologic dosages (200 to 300 mg per day) has led to clinical improvement and decreased the urinary excretion of glutaric acid in some patients [Brandt et al., 1979; Leibel et al., 1980; Stutchfield et al., 1985].

RIBOFLAVIN-DEPENDENT GLUTARICACIDEMIA TYPE II Glutaricacidemia type II is characterized biochemically by nonketotic hypoglycemia, metabolic acidosis, and the accumulation and urinary excretion of a number of organic acids derived from saturated acyl-CoA esters, including C6 to C10 dicarboxylic acids and ethylmalonic, isobutyric, butyric, hexanoic, and glutaric acids. This organic aciduria is a direct consequence of a defect in the acyl-Co vitamin A dehydrogenase complex, which consists of several distinct acyl-CoA dehydrogenases, electron transfer flavoprotein, and electron transfer protein:ubiquinone oxidoreductase. The acyl-CoA dehydrogenase complex functions in the transfer of electrons from fatty acids and some branched-chain keto acids to coenzyme Q in the mitochondria [Gregerson, 1985]. In most cases the disorder is due to deficiency of electron transfer protein or electron transfer protein:ubiquinone oxidoreductase. Considerable phenotypic variability in the clinical manifestations and quantitative pattern of urinary organic acids exists with this disorder. In the newborn, the illness is characterized by rapidly progressing respiratory difficulties, a “sweaty-feet” odor, convulsions, and severe metabolic acidosis without ketosis and leads to a fatal outcome in the first days or weeks of life [Przyrembel et al., 1976; Sweetman et al., 1980]. Some patients have dysmorphic clinical features and other congenital anomalies. Glutaricaciduria dominates in this form of the disease, although the other organic acids also are present in the urine. Administration of riboflavin is not beneficial in these patients. A later-onset glutaricaciduria type II (ethylmalonicadipicaciduria) manifests in older infants and children with repetitive episodes of acute encephalopathy, hepatomegaly, metabolic acidosis, and hypoglycemia, resembling Reye’s syndrome [Gregerson et al., 1982; Mantagos et al., 1974]. Administration of riboflavin in pharmacologic dosages (300 mg per day in three equal doses) has resulted in dramatic metabolic improvement during the acute episode in such patients and appears to reduce the frequency of subsequent episodes. In adolescents and young adults, ethylmalonic-adipicaciduria has been associated with a syndrome characterized by episodic symptoms of fatigue, lethargy, mild jaundice, hypoglycemia, and hepatomegaly precipitated by febrile illnesses or pregnancy [Dusheiko et al., 1979; Harpey et al., 1983]. In one such patient, prolonged periods of coma associated with protracted hypoglycemia occurred [Dusheiko et al., 1979]. In another, mild symptoms had occurred during the last trimester of several pregnancies and were associated with decreased fetal movements. One stillborn infant and six infants who died in the first month of life had been born to the affected patient before glutaricacidemia type II was diagnosed. After diagnosis, administration of riboflavin (20 mg per day) during the woman’s ninth pregnancy led to

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symptomatic improvement and an increase in fetal movements [Harpey et al., 1983]. Riboflavin supplementation was continued for several months after birth, and the infant did well. Ethylmalonic-adipicaciduria also may be associated with a progressive lipid storage myopathy, which responded dramatically to administration of riboflavin 100 mg and carnitine 3 g per day [Brivet et al., 1991; DeVisser et al., 1986].

Niacin (Vitamin B3) The pyridine nucleotides nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate are the physiologically active forms of niacin (nicotinic acid), which is present in nucleotides in the form of an amide (nicotinamide) [Henderson, 1983]. These nucleotides function in a variety of oxidation-reduction reactions. The reduced nucleotides are subsequently reoxidized by flavoproteins [White, 1982]. Cellular nicotinamide-adenine dinucleotide and nicotinamide-adenine dinucleotide phosphate, found in a variety of foods, function as the dietary source of niacin. After ingestion, the nucleotides are hydrolyzed in the small intestine to niacin and nicotinamide by the mucosal enzyme nicotinamide-adenine dinucleotide glycohydrolase, a ratelimiting step in absorption. The released niacin and nicotinamide are then transported across the intestine by passive diffusion [Bernofsky, 1980]. The absorbed niacin is rapidly converted to nicotinamide adenine dinucleotide in erythrocytes, and in the liver, nicotinamide adenine dinucleotide glycohydrolases subsequently release nicotinamide for transport to other tissues, where it is reconverted into nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate. Tryptophan is an important secondary dietary source of nicotinic acid [Horwitt et al., 1981]. Nicotinic acid is synthesized from tryptophan in a series of reactions through kynurenine, 3-hydroxy anthranilate, and quinolinate. Approximately 1 mg of nicotinic acid is derived from 60 mg of dietary tryptophan. That symptomatic niacin deficiency (pellagra) occurs predominantly in populations in which corn, which has a low content of tryptophan, serves as the major dietary staple attests to the importance of the substance as a dietary source of niacin. The minimum amount of dietary niacin required to prevent symptomatic deficiency is 4.4 mg/1000 kcal. The recommended daily dietary reference intake for niacin is 2 to 4 mg/day niacin in children younger than 1 year of age and 6 to 16 mg/day in older children and adolescents.

Niacin Deficiency The clinical manifestations of niacin deficiency (pellagra) are characterized by the triad of dermatitis, diarrhea, and dementia [Spivais and Jackson, 1977]. Cutaneous manifestations begin with an erythematous dermatitis on the hands; the forehead, neck, and feet are subsequently involved. Hyperpigmentation, desquamation, and scarring ultimately develop. Stomatitis, enteritis, recurrent diarrhea, and excessive salivation are the GI manifestations. CNS manifestations include headache, dizziness, insomnia, depression, and memory impairment. In severe cases, delusions, hallucinations, and

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dementia can occur. Motor and sensory peripheral nerve abnormalities also occur. Pellagra, caused by nicotinic acid deficiency, is seen mostly in relation to poverty and malnutrition and chronic alcoholism. Encephalopathy manifested by irritability, insomnia, and later hallucinations and delusions, followed by loss of consciousness and myoclonus, developed in an adult alcoholic patient with pellagra treated with B-complex vitamin tablets that did not contain niacin. The neurologic symptomatology resolved after treatment with nicotinic acid [Pitsavas, 2004]. The diagnosis rests predominantly on the dietary history, clinical findings, and a response to physiologic amounts of niacin. Measurement of urinary excretion of methylated metabolites of nicotinic acid is sometimes helpful in confirming the diagnosis.

Niacin Dependency Hartnup’s disease is a disorder of autosomal-recessive inheritance characterized by impairment of neutral amino acid transport by the kidneys and small intestine (see Chapter 23). A diagnostic feature is a striking neutral hyperaminoaciduria. Reduced intestinal absorption and increased renal excretion of tryptophan may lead to a reduced availability of this amino acid for niacin synthesis. Pellagra-like clinical features, including intermittent ataxia, psychotic behavior, and photosensitive skin rash, have been reported. Several reports document clinical but not biochemical improvement after daily administration of 50 to 300 mg of nicotinamide [Henderson, 1958; Herson and Rodnight, 1960].

Pyridoxine (Vitamin B6) Vitamin B6 is the generic term for three naturally occurring pyridine derivatives—pyridoxine (an alcohol), pyridoxal (an aldehyde), and pyridoxamine (an amine) [Fowler, 1985]. Pyridoxal phosphate, the physiologically active form, functions as a cofactor for more than 50 enzymatic reactions, including the decarboxylation, transamination, and racemization of amino acids and reactions in the metabolism of tryptophan, sulfur-containing amino acids, and hydroxyamino acids. Several important interactions between pyridoxine and therapeutic drugs also have been identified [Bauernfeind and Miller, 1987]. Vitamin B6 enhances the peripheral decarboxylation of levodopa, thereby reducing its therapeutic effectiveness. Isonicotinic acid hydrazide (isoniazid) acts as a potent inhibitor of pyridoxal kinase by combining with pyridoxal phosphate. Pyridoxine also interacts with cycloserine and hydralazine, and penicillamine promotes pyridoxine urinary excretion. Pyridoxine, pyridoxal, and pyridoxamine are present in meats, liver, cereals, soybeans, and vegetables. Because all three compounds are degraded by heat, ultraviolet light, and oxidation, considerable losses may occur during food preparation. All three compounds are absorbed from the intestine by passive diffusion. In the blood, they are bound to proteins and hemoglobin. After passive uptake by the liver, they are converted to pyridoxal phosphate by the hepatic enzyme pyridoxal kinase. Plasma concentrations reflect concentrations in the liver [Lumeng et al., 1980]. The principal excretory product is pyridoxic acid, which is excreted in the urine after its formation in a reaction catalyzed by the hepatic

enzyme aldehyde oxidase. Some unmetabolized pyridoxal also is excreted in the urine. The requirement for pyridoxine increases with the amount of protein in the diet. The recommended daily dietary reference intake of pyridoxine is 0.1 to 0.3 mg in infants younger than 1 year of age and 0.5 to 1.7 mg in older children and adolescents.

Pyridoxine Deficiency Clinical manifestations of vitamin B6 deficiency affect the nervous system, skin, and blood. Neurologic abnormalities include seizures in infants and peripheral neuropathy in adolescents [Snodgrass, 1992]. In infants fed a formula deficient in pyridoxine, irritability, exaggerated startle responses, and generalized seizures developed [Coursin, 1954]. The convulsions may be a consequence of decreased brain concentrations of GABA, which is synthesized from glutamate in a reaction catalyzed by pyridoxal-dependent glutamic acid dehydrogenase [Kurleman et al., 1991; Lott et al., 1978]. Pyridoxine deficiency also leads to decreased brain concentrations of norepinephrine and serotonin [Lovenberg et al., 1962]. Cutaneous manifestations include a seborrheic dermatitis (predominantly about the eyes, nose, and mouth), glossitis, and stomatitis. Microcytic, hypochromic anemia is the characteristic hematologic abnormality. The diagnosis of pyridoxine deficiency rests predominantly on the correlation of the dietary history, characteristic clinical findings, and prompt response of clinical symptoms with the administration of physiologic amounts of pyridoxine. An increase in the urinary excretion of the tryptophan metabolite xanthurenic acid after an oral load of tryptophan (100 mg/kg) serves as a possible confirmatory laboratory test.

Pyridoxine Dependency Pyridoxine dependency is associated with an autosomalrecessive error of metabolism characterized by a severe neonatal (or prenatal) seizure disorder with the onset of generalized convulsions in the newborn period that is responsive to pharmacologic amounts of pyridoxine [Gospe, 2002; Haenggeli et al., 1991]. Seizures usually begin within the first hours of life, but their recognition may be delayed. An intrauterine onset also has been reported [Bejsovec et al., 1967]. Pyridoxine-dependent epilepsy is diagnosed clinically, but potentially more common presentations, with later onset and atypical features, widen the spectrum [Pearl and Gibson, 2004]. A majority of affected patients are mentally retarded [Burd, 2000] and may have other neuropsychiatric abnormalities [Baynes et al., 2003]. The EEG is severely abnormal, demonstrating a variety of abnormal paroxysmal patterns, including hypsarrhythmia [Mikati et al., 1991]. Cessation of seizures and normalization of the EEG occur promptly after the parenteral administration of pyridoxine (50 to 100 mg intravenously). Lifelong administration of pharmacologic amounts of pyridoxine (5 to 300 mg/kg per day) is necessary to prevent recurrence of convulsions [Haenggeli et al., 1991]. Neurologic damage usually can be prevented when appropriate therapy is initiated promptly. The molecular basis of this disorder is not known. A mutation leading to defective binding of pyridoxal phosphate to

Frank and Ashwal / Neurologic Disorders Associated with Gastrointestinal Diseases/Nutritional Disorders

glutamate decarboxylase, essential for GABA synthesis, has been suggested [Bonner et al., 1960]. No gene locus has been confirmed; the pathophysiology may involve alterations in pyridoxal phosphate transport, binding to glutamate decarboxylase, or other pyridoxal phosphate–dependent pathways [Pearl and Gibson, 2004]. An instability of plasma albumin pyridoxal binding also has been implicated [Heeley et al., 1978]. Pyridoxine dependency is also associated with one of the subtypes of homocystinuria (see Chapter 23). Recently, much interest has been focused on the role of B6 and hyperhomocystinuria, particularly in relation to cerebrovascular disease and neuropsychiatric disorders in adults. No definite evidence exists for short-term benefit from vitamin B6 in improving mood (depression, fatigue, and tension symptoms) or cognitive functions in adult patients [Malouf and Grimley, 2003], or for secondary prevention of stroke [Schwammenthal and Tanne, 2004]. Pyridoxine dependency also has been demonstrated in some patients with cystathioninuria. Deficient activity of cystathionase catalyzes the cleavage of cysteine to αketobutyrate and leads to cystathioninuria [Frimpter, 1965]. Cystathioninuria has been detected in patients suffering from retardation, seizures, nephrogenic diabetes insipidus, and diabetes mellitus; however, because cystathioninuria also is found in unaffected people, a causal association between the metabolic defect and clinical symptoms has not been substantiated [Nyhan, 1984]. Pyridoxal phosphate is a cofactor in the cystathionase reaction, and a dramatic reduction in the cystathioninuria occurs after administration of pyridoxine in pharmacologic dosages (up to 100 mg per day) in most instances [Pascal et al., 1975]. Another disorder associated with pyridoxine dependency involves ornithine metabolism. Ornithinemia (gyrate atrophy of the retina and choroid) and ornithinuria resulting from a deficiency in the activity of ornithine-delta-aminotransferase, for which pyridoxal phosphate is a cofactor, are associated with the autosomal-recessive syndrome of gyrate atrophy of the retina and choroid [Simell and Takki, 1973]. A variety of genetic mutations account for the disorder [Brody et al., 1992]. This disorder usually manifests with night blindness between the ages of 5 and 10 years and is gradually progressive, leading to blindness by the fourth decade of life. The name gyrate atrophy is derived from the early appearance of peripheral atrophic lesions of the retina that resemble cerebral gyri. The funduscopic abnormality, also progressive, eventually is characterized by retinitis pigmentosa and optic nerve atrophy. Although weakness is not a prominent symptom, type II muscle fibers are atrophic, and tubular aggregates are found in muscle biopsy specimens [Sipila et al., 1979]. Plasma ornithine concentrations are 10 to 20 times normal, and urinary ornithine excretion reaches 0.5 to 10 mmol per day. L-ornithin-2-oxoacid aminotransferase activity in cultured skin fibroblast from affected patients ranges from 0 to 5.7% of normal control subjects [O’Donnell et al., 1978]. Pharmacologic dosages of pyridoxine (500 to 1000 mg per day) substantially reduce the elevated plasma ornithine concentrations and appear to prevent further visual deterioration [Berson et al., 1981; Hayasaka et al., 1982; Weleber and Kennaway, 1981]. Penicillamine administration in persons with mild pyridoxine dependency can result in clinical symptoms [Swaiman and Milstein, 1970].

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Pyridoxine Intoxication Chronic pyridoxine intoxication produces a progressive axonal sensory neuropathy in experimental animals and human adults. Daily oral administration of 300 mg/kg of pyridoxine to adult beagles produced widespread neuronal degeneration in dorsal root ganglia [Krinke et al., 1980]. Smaller but still excessive amounts (50 to 200 mg per day) administered over longer periods produced a reversible axonal sensory neuropathy without demonstrable pathologic results in the dorsal root ganglia [Phillips et al., 1978; Windeback et al., 1985]. In the human adult, clinical manifestations of a sensory neuropathy occurred after the ingestion of 2 to 6 g per day for several months [Schaumburg et al., 1983]. Nerve conduction studies and histologic examination of sensory nerve biopsies limited the pathologic origin to sensory nerve axonal degeneration. Partial, gradual recovery followed cessation of pyridoxine ingestion. Subsequent reports indicated that sensory neuropathy could result from the ingestion of only 200 mg of pyridoxine per day [Berger and Schaumburg, 1984; Parry and Bredesen, 1985]. The molecular basis for the sensory neuropathy is unknown. A similar syndrome has not been reported in the pediatric age group.

Cobalamin (Vitamin B12) Vitamin B12 is a generic term for organometallic compounds (cobalamins) in which a cobalt atom with a complex side chain is situated within a corrin ring [Davis, 1985]. The cobalamins are further differentiated by attachments to the cobalt atom. Hydroxycobalamin, methylcobalamin, and deoxyadenosylcobalamin have been isolated from mammalian tissue. Hydroxycobalamin is the major cobalamin in blood. Methylcobalamin and adenosylcobalamin function as cofactors in enzymatic reactions. Cyanocobalamin, a stable compound formed as an artifact of isolation, can be used in therapy because it is readily convertible to hydroxycobalamin. Methylcobalamin is a cofactor for cytoplasmic methionine synthase, the enzyme that catalyzes the transfer of a methyl group from 5-methyltetrahydrofolate in the remethylation of homocysteine to methionine. Deoxyadenosylcobalamin is a cofactor for mitochondrial methylmalonyl-CoA mutase, the enzyme that catalyzes the isomerization of methylmalonylCoA to succinyl-CoA. Cobalamins can be synthesized only by certain microorganisms. Stored cobalamins in meats and dairy products provide the predominant dietary source for humans. Vitamin B12 absorption is a complex mechanism requiring several steps. Ingested cobalamin binds to intrinsic factor, a glycoprotein formed by gastric parietal cells, in the upper small intestine [Donaldson, 1981]. The cobalamin–intrinsic factor complex subsequently interacts with specific receptors on ileal brush border cells, where the complex is dissociated and free cobalamin is absorbed into the circulation. In blood, vitamin B12 is bound to several carrier proteins, the transcobalamins. Transcobalamin II is the predominant carrier protein for newly absorbed cobalamin, and the transcobalamin II–cobalamin complex is preferentially delivered to the liver, bone marrow, and other proliferating cells [Allen, 1976]. At the target tissue, the transcobalamin IIcobalamin complex attaches to specific surface receptors and subsequently is transported into the cells by pinocytosis.

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Within the cell, proteolytic lysosomal enzymes degrade the carrier protein and release free cobalamin into the cytoplasm. Adenosylcobalamin is formed within mitochondria from hydroxycobalamin. The trivalent cobalt atom of hydroxycobalamin is successively reduced to monovalent cobalamin in enzymatic reactions catalyzed by reductase enzymes, and adenosylcobalamin is formed from monovalent cobalamin through a reaction catalyzed by adenosyltransferase. The recommended daily dietary reference intake for vitamin B12 is 0.4 to 0.5 μg in infants younger than 1 year of age and 0.9 to 2.4 μg for older children and adolescents.

Cobalamin Deficiency Symptomatic cobalamin deficiency, although rare in childhood, can occur as a consequence of inadequate dietary intake, congenital or acquired intrinsic factor deficiency, removal of the vitamin from the intestine by bacteria or parasites, malabsorptive states resulting from surgical resection [Banerji and Hurwitz, 1971] or chronic disease [Pant et al., 1968a], or an inherited disease of the specific ileal receptor [Matthews and Linnell, 1982]. Vitamin B12 deficiency has been described primarily in adults, presumably because of the prolonged duration between surgery and the onset of neurologic symptoms [Williams et al., 1969]. Manifestations of cobalamin (vitamin B12) deficiency are hematologic (pernicious anemia), GI, neurologic, and psychiatric [Carmel, 2003; Healton et al., 1991]. Characteristically, all of these systems are involved, but neurologic disease can occur in the absence of anemia or macrocytosis [Green and Kinsella, 1995; Lindenbaum et al., 1988]. The underlying biochemical abnormality associated with B12 deficiency is thought to be due to a defect in one of the two cobalamin-dependent enzymes, methionine synthase and methylmalonyl-CoA mutase [Beck, 1988]. Neurologic manifestations are caused by predominantly white matter degenerative lesions in the brain, spinal cord, and peripheral nerves and include optic neuropathy, progressive cerebellar ataxia, myelopathy, peripheral neuropathy, and gaze limitation. Most patients with pernicious anemia with neurologic dysfunction present with a mixed myelopathic-neuropathic picture. A description of “subacute combined degeneration” after partial gastrectomy was provided by Knox and Delamore [1960]. This entity involves degenerative changes in the posterior and lateral columns without proliferative glial changes. Degenerative changes in the cerebral white matter also may occur [Adams and Kubic, 1944; Pant, 1968a]. Clinical manifestations, seen primarily in adults, include paresthesias of the feet and fingers, disturbed vibratory and proprioceptive senses, and spasticity, caused by involvement of the peripheral nerves and spinal cord. Cognitive abnormalities include slow mentation, dementia, confusion, memory changes, and psychiatric symptoms including depression, acute psychosis, and manic and schizophrenic states [Lindenbaum et al., 1988]. Diffuse leukoencephalopathy is present on MRI, and a decrease in signs of subacute combined degeneration and neuropsychiatric abnormalities is observed after methylcobalamine therapy [Ahn, 2004; Healton, 1991; Lindenbaum et al., 1988; Morita, 2003; Williams et al., 1969]. MRI has been useful in detecting lesions in the spinal cord, brainstem, and cerebellum that appear as high-signal-intensity areas on T2-

weighted images that can resolve with B12 treatment [Katsaros et al., 1998]. Inadequate cobalamin ingestion occurs predominantly in infants exclusively breast-fed by strictly vegetarian mothers [Cornejo et al., 2001; Grattan Smith et al., 1997; Higginbottom et al., 1978; Kuhne et al., 1991]. Two forms of intrinsic factor deficiency (pernicious anemia) occur in the pediatric age group [Arthur, 1972]. Congenital pernicious anemia is an inherited disorder in which intrinsic factor deficiency is not associated with other structural or functional gastric abnormalities, and antibodies to intrinsic factor are not detected. Symptoms usually begin before the age of 3 years. Juvenile pernicious anemia has characteristics similar to those of adult pernicious anemia—in both, the intrinsic factor deficiency is associated with gastric atrophy, achlorhydria, antibodies to intrinsic factor or gastric parietal cells, and other endocrinopathies. The juvenile form usually becomes symptomatic late in childhood or early in adolescence. A familial disorder in which cobalamin deficiency results from an impairment of transport across the specific ileal receptor also has been well documented [Grasbeck et al., 1960; Mackenzie et al., 1972]. An infant with mild symptoms of vitamin B12 deficiency secondary to the failure of the release of cobalamin into the cytoplasm from lysosomes also has been described [Rosenblatt et al., 1985]. Developmental regression is the presenting symptom in most infants with cobalamin (vitamin B12) deficiency. A review of findings in six infants with nutritional B12 deficiency noted a consistent clinical pattern of irritability, anorexia, failure to thrive, marked developmental regression, and poor brain growth [Graham et al., 1992]. A recent report of 14 infants documented feeding difficulties, failure to thrive, hypotonia, seizures, microcephaly, and developmental delay with an unfavorable outcome, often with early death or significant neurologic impairment in survivors [Biancheri et al., 2001]. Cerebral white matter atrophy was detected by MRI in a majority of patients. Waking EEG exhibited epileptiform abnormalities, and a high incidence of seizures was reported in these cases. Increased latency of evoked responses and/or prolongation of central conduction time were the most significant neurophysiologic abnormalities. Irritability and lethargy may rapidly progress to coma. Mental retardation and signs of peripheral neuropathy [Renault et al., 1999] are common. Encephalopathy, seizures, and microcephaly were described in another infant with megaloblastic anemia, caused by a subclinical pernicious anemia of the mother [Korenke, 2004]. Involuntary movements are characteristic neurologic abnormalities in infants with B12 deficiency. In the case of an exclusively breast-fed infant of a vitamin B12–deficient mother, symptoms and signs consisted of abnormal vigilance and a movement disorder. MRI of the brain demonstrated atrophy, or reduced brain volume, and a delay in myelination. Proton magnetic resonance spectroscopy revealed accumulation of lactate in the white and gray matter, suggesting an abnormality of oxidative energy metabolism [Horstmann, 2003]. In other infants with cobalamin deficiency caused by maternal cobalamin deficiency, abnormal movements developed a few days after the start of cobalamin therapy [Ozer, 2001]. The explanation for the timing of the onset of abnormal movements in these children is not clear. These abnormal movements were described as a com-

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bination of tremor and myoclonus and were treated with clonazepam. A case report of three infants with cobalamin deficiency and cognitive regression noted the onset of a movement disorder consisting of tremor and myoclonus, particularly involving the face, tongue, and pharynx, that appeared 48 hours after the initiation of treatment with intramuscular cobalamin [Grattan Smith et al., 1997]. Other neurologic symptoms subsided and the movements slowly abated 3 to 6 weeks after initiation of treatment. In general, vitamin B12 deficiency caused by maternal pernicious anemia needs to be considered in the differential diagnosis in infants with neurologic disease, especially if they have megaloblastic anemia. In older children, paresthesias, ataxia, hyperreflexia with a Babinski sign, ankle clonus, and distal loss of vibratory and position sense are common. These neurologic abnormalities likely result from deficient methionine synthase activity with deficiency of S-adenosylmethionine [Hall, 1990; Surtees, 1993]. Sensory ataxia, along with megaloblastic anemia and skin hyperpigmentation, was described in a young male patient with low serum B12 level and a family history of megaloblastic anemia. Spinal MRI demonstrated extensive demyelination of the posterior columns along the entire length of the cord. Treatment with cobalamin resulted in complete remission and normalization of the MRI appearance [Facchini, 2001]. Exposure to nitrous oxide, used during anesthesia, can be a precipitating factor for increased neurologic and other abnormalities in infants with megaloblastic anemia, because nitrous oxide depletes cobalamin [Felmet, 2000]. Macrocytic, megaloblastic anemia results from failure of erythrocytes to mature. Giant megakaryocytes and enlarged polymorphonuclear leukocytes are present in the peripheral smear. Characteristics of this anemia are similar to those of the macrocytic anemia secondary to folate deficiency: Cobalamin deficiency leads to a functional folate deficiency, because methyltetrahydrofolate cannot be demethylated to its active tetrahydrofolate form. Serum vitamin B12 concentration in this anemia is below 100 pg/mL (normal, 140 to 700 pg/mL). Methylmalonic acid is excreted in the urine. The amount of labeled vitamin B12 excreted in the urine after the ingestion of 1 to 2 μg of cobalt-57- or cobalt60-labeled cyanocobalamin, followed by the intramuscular administration of 1 mg of unlabeled vitamin B12 (the Schilling test), is useful in assessing vitamin B12 absorption. Repeating the test with the addition of orally administered intrinsic factor will differentiate between pernicious anemia and other absorption defects. Cobalamin neuropathy, in conjunction with low levels of cerebrospinal S-adenosylmethionine and abnormal myelination in inherited disorders affecting cobalamin and folate metabolism, also has been reported [Metz, 1993]. On rare occasions, neurologic complications of anorexia nervosa caused by vitamin B12 deficiency have been observed [Patchell et al., 1994]. Intramuscular injection of 1 to 5 μg of cobalamin results in prompt hematologic improvement and serves as a confirmatory test. Oral administration of 1000 μg of cobalamin at monthly intervals prevents recurrent deficiency; 1000 μg given at weekly intervals is suggested for the treatment of neurologic deficits.

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Cobalamin Dependency Transcobalamin II deficiency is an autosomal-recessive disorder characterized by failure to thrive, hypotonia, megaloblastic anemia, and recurrent infection [Hitzig et al., 1974]. Oral ulcerations and glossitis develop. The serum cobalamin concentration is normal despite the absence of transcobalamin II, the carrier protein for newly absorbed cobalamin. Oral or parenteral administration of cobalamin (1000 μg per week) results in remission of the clinical manifestations. When affected, other cobalamin-dependent enzyme pathways cause methylmalonicacidemia or homocystinuria with methylmalonicacidemia (see Chapter 23).

Vitamin B12 and Cognitive Functioning Because animal products are the only source of vitamin B12, infants breast-fed by mothers with low intakes of these products and children who do not consume them are at risk for vitamin B12 deficiency [Black, 2003]. Greater than two thirds of school-aged children from rural Kenya experience vitamin B12 deficiency [Siekmann et al., 2003], suggesting that the worldwide prevalence of B12 deficiency in developing countries may be substantial. Most research examining the relation between B12 deficiency and cognitive functioning in children is limited to case studies of infants of mothers with pernicious anemia or vegan mothers [Black, 2003] or those who were on a macrobiotic diet (containing no meat or dairy products) during infancy and childhood. As recently reviewed, several studies have found delays in motor and language development, poorer cognitive performance, and delays in reaction time on neuropsychologic tests of perception, memory, and reasoning, along with academic problems including lower academic performance, lower teacher ratings, more attentional problems, and more delinquent behavior in children with B12 deficiency [Black, 2003; Bryan, 2004].

Vitamin C (Ascorbic Acid) Vitamin C is a generic term for compounds that have the biologic activity of ascorbic acid [Englehard and Seifters, 1986; Levine, 1986]. Ascorbic acid, a six-carbon compound that is structurally related to glucose, can be synthesized by most vertebrates, but in humans and a few animals the last enzyme involved in ascorbate synthesis is missing. Ascorbic acid is reversibly oxidized in the body to dihydroascorbic acid, a compound that retains full vitamin C activity. Vitamin C functions as a reducing agent in a variety of hydroxylation reactions, providing electrons to metalcontaining enzymes to maintain the metal in the reduced form that is necessary for optimal activity. Known functions include the conversion of proline to hydroxyproline in collagen synthesis, the hydroxylation of lysine in carnitine synthesis, and the hydroxylation of dopamine to norepinephrine. Vitamin C also has a role in the synthesis of serotonin, several peptide hormones, and acetylcholine receptors [Block and Levine, 1991]. Ascorbic acid is available from fruits, vegetables, and potatoes. It is destroyed by heat, oxidation, and alkali but is stable in acid. Ascorbic acid is readily absorbed through the intestinal tract by simple diffusion, and its plasma concen-

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tration varies with the amount of intake. An active transport system in the choroid plexus maintains brain and cerebrospinal fluid ascorbic acid concentrations within a relatively narrow range [Spector and Lorenzo, 1973]. The recommended daily dietary reference intake for vitamin C is 40 to 50 mg for infants younger than 1 year of age and 15 to 75 mg for older children and adolescents. Consumption of ascorbic acid above the recommended daily allowance leads to increases in plasma concentrations and body stores, but because the renal threshold for ascorbic acid approximates 1.5 mg/dL, ingestion of amounts greater than 100 mg per day merely results in increased urinary excretion.

Vitamin C Deficiency Symptomatic vitamin C deficiency (scurvy) is now quite rare but still occurs [Ratanachu-Ek et al., 2003]. In some developing countries, vitamin C deficiency has been reported in approximately 30% of children younger than 2 years of age and in 40% of women [Villalpando et al., 2003]. Even in developed countries, inadequate intake of vitamin C, defined as intake below two thirds of recommended values, has been reported in children [Serra-Majem et al., 2001]. In the United States, a study examining prevalence rates of vitamin C deficiency between 1984 and 1994 in adult and pediatric populations found that mean intakes and serum levels of vitamin C were normal but that vitamin C deficiency and depletion were common, occurring in 5% to 17% and 13% to 23%, respectively, of respondents [Hampl et al., 2004]. Infants fed exclusively cow’s milk or unsupplemented evaporated milk formulas were the most prone to the development of scurvy [Grewar, 1959]. Occasional instances of scurvy in children with peculiar dietary habits continue to be reported [Douglas et al., 1973; Ellis et al., 1984]. Such habits have been observed in children with developmental delay [Weinstein et al., 2000], as well as those with autism [Monks et al., 2002]. Little correlation exists between clinical manifestations of vitamin C deficiency and known molecular functions on the vitamin. The onset of symptoms is delayed for 4 to 9 months after the initiation of a deficient diet. Initial manifestations include irritability, tachypnea, anorexia, and pallor. The most striking subsequent manifestations are a consequence of musculoskeletal pain and a hemorrhagic diathesis [Akikusa et al., 2003; Ratanachu-Ek et al., 2003; Weinstein et al., 2000]. Bone pain leads to decreased voluntary movement, especially of the lower limbs (pseudoparalysis). Infants prefer to lie immobile in the supine position, with the hips partially flexed and externally rotated (pithed-frog position). Attempts at examination and passive movement cause considerable pain. Petechial hemorrhages secondary to capillary fragility appear in the skin, initially surrounding hair follicles, and at the gums and may lead to frank purpura. Subarachnoid and subdural hemorrhages may occur. Extraocular muscle palsy may result from intraocular hemorrhage. Radiographs of the long bones, especially around the knee, reveal characteristic abnormalities, including thinning of the cortex, rarefaction of the epiphyses, and trabecular atrophy. Epiphyseal separation may occur. During healing, the subperiosteal hemorrhages, not visualized in the acute stage, become calcified, and the healing bone assumes a characteristic dumbbell shape.

Plasma ascorbate levels reflect current intake rather than body stores. Leukocyte ascorbic acid concentrations below 30 mg/dL suggest depleted stores. Daily administration of 100 to 200 mg of ascorbic acid for 10 days leads to rapid reversal of clinical symptoms [Ratanachu-Ek et al., 2003]. Bone abnormalities resolve completely within a few months.

Transient Neonatal Tyrosinemia Transient tyrosinemia is present in 0.2% to 10% of neonates and may persist for several months [Goldsmith, 1983]. It is more common in preterm infants and least common in breast-fed term neonates. Although the molecular basis of the disorder has not been fully elucidated, a combination of excessive protein intake and relative deficiency of the activity of the enzyme hydroxyphenylpyruvate oxidase likely is responsible. Ascorbic acid facilitates the activity of this hydroxylation enzyme. Lethargy, feeding difficulties, hypotonia, and prolonged jaundice have been associated with tyrosinemia, although many infants are asymptomatic. Mild mental retardation may be a long-term sequela [Mamunes et al., 1976; Menkes et al., 1972]. In addition to hypertyrosinemia, the blood concentration of phenylalanine is increased in affected neonates, and urinary excretion of tyrosine and some of its metabolites is also increased. A reduction of daily protein intake to 2 to 3 g/kg usually corrects the hypertyrosinemia. In some infants, additional supplementation with ascorbic acid (100 to 400 mg per day) produces a dramatic response.

Vitamin D Vitamin D is the generic term for a group of steroid compounds that function in the regulation of calcium and phosphate homeostasis by promoting the absorption of calcium and phosphorus from the intestine, enhancing calcium resorption by the kidney in conjunction with the parathyroid hormone, and mobilizing calcium from the bone [Bell, 1985; Henry and Norman, 1984]. Vitamin D2 (calciferol) is derived from the plant sterol ergosterol, and vitamin D3 (cholecalciferol) is derived from 7-dehydrocholesterol in skin. Calciferol and cholecalciferol are derived from respective provitamins by a nonenzymatic photochemical reaction activated by ultraviolet light, which results in the cleavage of the B-sterol ring to form a diene bridge. In humans, the metabolic fate and physiologic properties of vitamin D2 and of vitamin D3 are similar. 7-Dehydrocholesterol normally is present in the skin and is converted to cholecalciferol by solar ultraviolet radiation. Under optimal exposure to sunlight, dietary supplementation of vitamin D is not necessary because cholecalciferol is transported to the liver and stored. The active form of vitamin D is calcitriol (1,25dihydroxycholecalciferol), which is formed from cholecalciferol by two successive hydroxylations. The initial hydroxylation to calcidiol 25-hydroxycholecalciferol occurs in the liver, and the second hydroxylation to calcitriol occurs in the kidney. The activity of the kidney mitochondrial hydroxylase, which catalyzes the second hydroxylation, is stimulated by parathyroid hormone and increases with deficiencies of vitamin D, calcium, and phosphate. Dietary vitamin D and vitamin D3 are absorbed from the small

Frank and Ashwal / Neurologic Disorders Associated with Gastrointestinal Diseases/Nutritional Disorders

intestine. Bile is essential for absorption. After absorption, the vitamin, bound to a lipoprotein complex, is transported in lymph chylomicrons to the liver, where it is stored before its hydroxylation to calcidiol. Calcidiol is the major circulating form of vitamin D in the blood. Calcitriol is hydroxylated to 1,24,25-trihydroxycalciferol by a renal hydroxylase that also hydroxylates 25-hydroxycalciferol to 24,25-dihydroxycalciferol. These compounds have less vitamin D activity than calcitriol and probably represent excretory compounds excreted in the bile. The recommended daily dietary reference intake for vitamin D is 5.0 μg cholecalciferol for infants younger than 1 year of age and 5 to 15 μg for older children and adolescents. Reports of nutritional rickets among U.S. children less than 18 years of age published between 1986 and 2003 found that the average age of children with rickets ranged from 4 to 54 months of age; that approximately 83% were black; and that 96% were breast-fed, and among those who were breast-fed, only 5% of records indicated vitamin D supplementation during breast-feeding [Weisberg et al., 2004]. In 1963, the American Academy of Pediatrics (AAP) recommended 400 IU of vitamin D per day for all infants and children [Greer, 2004]. In response to the 1997 Institute of Medicine recommendations, however, and after reports of increasing nutritional rickets in certain populations, the AAP in 2003 changed the dietary reference intake dose to 200 IU for all infants and children. In making these recommendations, several issues were considered, including the following: (1) Vitamin D deficiency is more than rickets, which is the final stage of the deficient state among growing children; (2) adequate sunlight exposure cannot be determined exactly; (3) ultraviolet B light exposure in childhood carries a risk for later development of skin cancer; and (4) intake of vitamin D-fortified food intake in older children and adolescents has been decreasing [Greer, 2004].

Vitamin D Deficiency Symptomatic vitamin D deficiency can occur as a consequence of inadequate dietary intake [Edidin et al., 1980; Ladhani et al., 2004], inadequate exposure to sunlight, malabsorption states, chronic hepatic or renal disease, or administration of antiepileptic drugs, or from the chronic effects of severe burn injury [Klein et al., 2004]. Even in “dairy states” such as Wisconsin, vitamin D deficiency can occur, particularly in infants who were breast-fed and did not receive vitamin supplementation [Mylot et al., 2004]. Vitamin D deficiency remains the major cause of rickets among young infants in most developing countries because breast milk is low in vitamin D and its metabolites and because social and religious customs or climatic conditions often prevent adequate ultraviolet light exposure [Pettifor, 2004]. Also, mothers who are vitamin D–deficient in pregnancy are likely to be deficient postnatally, and their infants, especially if breast-fed, are at higher risk of vitamin D deficiency [Thompson et al., 2004]. Over the past several decades, antiepileptic drugs have been associated with rickets in children and osteomalacia in adults, but reports were primarily in institutionalized persons [Pack et al., 2004]. Studies in ambulatory adults and children taking antiepileptic drugs do not reveal rickets or osteomalacia but do report alterations of bone mineral metabolism and density and increased fracture rates. Anti-

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epileptic drugs that induce the cytochrome P-450 enzyme system are most commonly associated with bone abnormalities, and data suggest that valproate, an enzyme inhibitor, also may affect bone metabolism [Pack et al., 2004]. Limited information is available on the newer antiepileptic drugs and the risk of developing rickets. Patients who are institutionalized are more vulnerable because of added factors including reduced physical activity and reduced exposure to light. Prophylactic supplementation with vitamin D is advised in such institutionalized patients chronically treated with antiepileptic drugs. Clinical manifestations predominantly affect the bone, leading to rickets in children and osteomalacia in adults. The bone abnormalities in rickets are secondary to inadequate mineralization of osteoid tissue. Craniotabes, or thinning of the inner table of the skull, is an early manifestation in infants. Rickets is further characterized by epiphyseal enlargements at the wrists, ankles, and costochondral junctions; bending of the shafts of long bones; scoliosis; and kyphosis. Neurologic manifestations are characterized by tetany, which occurs when the metabolic abnormality leads to hypocalcemia. Symptoms are not present in latent tetany, but elicitation of Chvostek’s, Trousseau’s, and Erb’s signs constitutes evidence of increased neuromuscular irritability. Latent tetany is usually associated with serum calcium concentrations between 7 and 7.5 mg/dL. Manifest tetany, characterized by symptomatic carpopedal spasm, laryngospasm, or convulsions, usually is associated with serum calcium concentrations below 7 mg/dL. Vitamin D deficiency also causes muscle weakness and muscle aches and pains in both children and adults. Recent research has demonstrated that a large number of children and adults have deficient levels of vitamin D [Holick, 2003]. These patients may present with persistent musculoskeletal pain [Plotnikoff, 2003]. Limb-girdle muscle weakness secondary to vitamin D deficiency also has been recently reported [van der Heyden et al., 2004]. Hypocalcemia, elevated alkaline phosphatase, and low 25-hydroxycalciferol are found in patients receiving chronic antiepileptic therapy [Alderman, 1994]. Seizures can recur because of the hypocalcemia [Ali, 2004]. As reported in a recent study, the volume of the posterior fossa in children with rickets is significantly smaller than in normal children, and a significant number of them have a Chiari I malformation [Tubbs, 2004]. The diagnosis of rickets is confirmed by radiologic examination. Wrist radiographs are best for early diagnosis and demonstrate the characteristic widened, frayed, concave distal ends of the ulna and radius. The distance between the ends of these long bones and the carpal bones is increased, because the large rachitic metaphysis is not calcified. Plasma alkaline phosphatase level is elevated, and the serum phosphorus concentration usually is below 4 mg/dL. The serum calcium concentration may be normal or reduced. Daily administration of 0.2 to 0.5 μg of calcitriol leads to healing, demonstrable on radiographs within 2 to 4 weeks. In tetany, calcium supplementation also is necessary.

Vitamin D Dependency VITAMIN D-DEPENDENT RICKETS TYPE I Vitamin D-dependent rickets type I is transmitted as an autosomal-recessive trait and is characterized by hypotonia,

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weakness, failure to thrive, tetany, and convulsions in the first year of life [Rassmussen and Anast, 1983]. The disorder is caused by deficient activity of the renal 1-hydroxylase that catalyzes the synthesis of calcitriol from calcidiol. Bone radiographs are indistinguishable from those of vitamin D deficiency. The serum alkaline phosphatase level is elevated, and the phosphorus concentration is normal or low. Hypocalcemia is common. The serum calcidiol concentration is normal, but the calcitriol concentration is reduced. Treatment with pharmacologic dosages of vitamin D (vitamin D3, 5000 to 40,000 units per day; calcitriol, 1 to 3 μg per day) reverses the manifestations of rickets and permits normal growth.

Vitamin D Intoxication Symptoms of vitamin D intoxication develop 1 to 3 months after excessive intake of the vitamin. Clinical manifestations include irritability, hypotonia, polydipsia, polyuria, and constipation. Hypertension with retinopathy, aortic stenosis, corneal and conjunctival clouding, and nephropathy occur in chronic cases. Laboratory findings include hypercalcemia, hypercalciuria, and metastatic calcifications on radiographs of long bones. Treatment consists of discontinuing vitamin D ingestion and decreasing calcium intake.

Tocopherol (Vitamin E) Vitamin E is the generic term for a group of fat-soluble compounds that function as scavengers of free radicals, protecting polyunsaturated fatty acids in subcellular organelles from oxidation by free radicals generated in normal metabolic reactions or by toxic compounds. α-Tocopherol is the most important of these compounds and is widely distributed in foods, especially vegetable oils. Absorption of vitamin E depends on the intestinal digestion and absorption of fat and the presence of bile. Once absorbed, the vitamin enters lymph channels and, in chylomicrons and very-lowdensity lipoproteins, is transported to the blood, where it equilibrates with plasma lipoproteins. It is stored predominantly in adipose tissue. Tissue stores will provide a source for the vitamin for long periods. Blood levels reflect recent dietary intake and absorption rather than body stores. The recommended daily dietary reference intake of vitamin E is 4 to 5 mg of α-tocopherol equivalents for infants younger than 1 year of age and 6 to 7 mg for older children and adolescents.

Vitamin E Deficiency Vitamin E deficiency occurs predominantly in disorders associated with either chronic fat malabsorption (e.g., cystic fibrosis, celiac disease, chronic cholestatic hepatobiliary disorders including biliary atresia, short bowel syndrome, inflammatory bowel disease) or a deficiency of plasma lipoproteins (e.g., abetalipoproteinemia) [Gordon, 2000; Kayden, 1993; Koenig, 2003; Perkin, 1998; Sokol, 1990]. A neurologic degenerative syndrome associated with selective vitamin E deficiency not associated with fat malabsorption also has been documented [Harding et al., 1985; Krendel et al., 1987]. Infants are born in a state of relative vitamin E deficiency, with plasma α-tocopherol levels below 5 μg/mL (11.6 μmol/L) [Merck, 2005]. The smaller and more premature the infant,

the greater the deficiency. Vitamin E deficiency in preterm infants persists during the first few weeks of life and can be attributed to limited placental transfer of vitamin E, low tissue levels at birth, relative dietary deficiency in infancy, intestinal malabsorption, and rapid growth. As the digestive system matures, vitamin E absorption improves, and blood vitamin E levels rise. In children and adults, malabsorption generally underlies vitamin E deficiency. Genetic abnormality in the transport of vitamin E also can play a role. Clinical manifestations of vitamin E deficiency include progressive weakness, ataxia, ophthalmoplegia, loss of position and vibratory sense, neuropathy, dystonia, and in some instances, especially in abetalipoproteinemia, progressive visual impairment associated with retinitis pigmentosa [Aparicio et al., 2001; Koenig, 2003; Roubertie et al., 2003; Sokol, 1990]. Children with cystic fibrosis and low plasma α-tocopherol levels are at greater risk for long-term neurocognitive impairments unless the deficiency is treated with vitamin E supplementation [Koscik et al., 2004]. Neuropathologic features include cerebellar atrophy and loss of nerve cell bodies in the third and fourth cranial nerve nuclei and axonal dystrophy (e.g., swollen, dystrophic axons, spheroids) in the posterior columns, Clarke’s column, and dorsal and ventral spinocerebellar tracts of the spinal cord [Rosenblum et al., 1981]. Premature lipofuscin accumulation in dorsal horn and peripheral nerve Schwann cell cytoplasm also has been reported [Werlin et al., 1983]. Nerve conduction studies [De Schepper et al., 1997] and brainstem evoked responses [Vaisman et al., 1996] also may be abnormal in some patients with vitamin E deficiency. Early deficiency may not produce neurologic abnormalities. In children with chronic cholestasis and vitamin E deficiency, however, a slowly progressive neuromuscular disease with ataxia, dysmetria, dysarthria, areflexia, loss of vibratory sensation, and ophthalmoplegia, impaired vision, and a pigmentary retinopathy may develop [Guggenheim et al., 1982; Kayden, 1993; Satya-Murti et al., 1986]. The neuropathologic findings are similar to those in animals with experimental vitamin E deficiency and include posterior column degeneration; selective loss of peripheral nerve largecaliber, myelinated axons; and spheroids in the gracile and cuneate nuclei [Rosenblum et al., 1981]. Muscle histochemical studies demonstrate cytoplasmic inclusions and occasional necrotic fibers. Normal dosages of vitamin E for 6 to 14 months improved the neurologic disease in some but not all patients [Guggenheim et al., 1982]. Children with protein energy malnutrition and neurologic signs involving posterior column, spinocerebellar, retinal, and peripheral nerve deficits due to vitamin E deficiency can undergo significant improvement with supplementation [Kalra et al., 2001; Patients with a familial disorder of vitamin E absorption, manifested by a normal absorption of vitamin E normally but an inability to conserve plasma α-tocopherol in verylow-density lipoproteins, had a neurologic syndrome resembling Friedreich’s ataxia—ataxia, cerebellar signs, dysarthria, extensor plantar responses, pes cavus and scoliosis, absence of deep tendon reflexes in the lower extremities, and impaired proprioception [Gordon, 2001; Hamida, 1993]. The disease is genetically recessive and has been mapped to chromosome 8. It is suggested that patients presenting with a syndrome suggesting Friedreich’s ataxia should have vitamin E levels measured.

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Measurement of serum lipid concentrations documents most instances of vitamin E deficiency. The normal lower limit for adolescents is 5 mg/mL and is lower for younger children [Farrell et al., 1978]. Because vitamin E is bound to lipoproteins in the plasma, the ratio of vitamin E to total serum lipid concentration reflects vitamin E status more accurately in hyperlipidemic states. Limits of normal for this ratio of total tocopherol to total lipid are 0.8 mg/g in adolescents and 0.6 mg/g in infants and children. Serum vitamin E concentrations do not accurately reflect vitamin E states in patients with abetalipoproteinemia. In patients with abetalipoproteinemia, dietary supplementation with vitamin E (100 to 200 mg/kg per day) before the age of 1 year prevented the development of retinopathy and prevented, stabilized, or improved the neurologic disorder [Muller et al., 1977]. The neurologic function of children with vitamin E deficiency associated with chronic cholestasis also was significantly improved by large oral dosages (up to 10 mg/kg per day) or intramuscular injection of α-tocopherol (0.8 to 2.0 IU/kg per day) [Lemonnier et al., 1990; Perlmutter et al., 1987; Sokol et al., 1985]. Mutation of the gene for a-tocopherol transfer proteins, on chromosomal locus 8q13, an autosomal-recessive disorder, causes isolated vitamin E deficiency with ataxia (ataxia with vitamin E deficiency [AVED]) and responds to treatment with vitamin E [Federico, 2004; Mariotti, 2004]. Other neurologic abnormalities observed with these mutations include spasticity and retinitis pigmentosa. A male with vitamin E deficiency ataxia improved after treatment with vitamin E supplementation, but progressive dystonia developed subsequently [Roubertie, 2003].

Biotin (Vitamin H) Biotin is a cofactor for four carboxylation enzymes: pyruvate carboxylase, acetyl-CoA carboxylase, propionyl-CoA carboxylase, and 3-methylcrotonyl carboxylase [Bartlett et al., 1985]. These enzymes all are involved in carbon chain elongation reactions: pyruvate carboxylase in gluconeogenesis, acetyl-CoA carboxylase in fatty acid synthesis, propionyl-CoA carboxylase in propionate metabolism, and 3-methylcrotonyl carboxylase in leucine catabolism. In these reactions, biotin is linked to a lysine residue of the apoenzyme, in a reaction catalyzed by the enzyme holocarboxylase synthetase, to form the functional carboxylase holoenzyme. Biotin is present in low concentrations in numerous foods [Roth, 1981]. The enzyme biotinidase cleaves biotin from biocytin (biotin-lysine) and from larger biotinyl peptide fragments formed in the degradation of the carboxylase, thereby allowing for biotin reuse. Biotin-synthesizing bacteria in the small intestine also are a major nutritional source. Biotin is absorbed through the intestine by active transport mechanisms [Said et al., 1990]. In the blood, it is bound to proteins. It is excreted in the urine and feces. The recommended daily dietary reference intake is 5 to 6 μg for neonates and infants younger than 1 year of age and 8 to 25 μg for older children and adolescents.

Biotin Deficiency Symptomatic biotin deficiency resulting from inadequate dietary intake is quite rare. Two children with symptomatic

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biotin deficiency associated with the ingestion of large quantities of raw albumin, which contains avidin (a glycoprotein that binds biotin so effectively that its intestinal absorption is prevented), have been described [Scott, 1958; Sweetman et al., 1981]. Biotin deficiency also has been reported as a consequence of parenteral hyperalimentation and chronic hemodialysis [Mock et al., 1981; Yatzidis et al., 1984]. Clinical manifestations of biotin deficiency include a generalized, scaly, erythematous rash resembling seborrheic dermatitis; alopecia totalis; anorexia; severe metabolic acidosis; and neurologic manifestations that include developmental delay or dementia, seizures, progressive ataxia, and hearing loss. In the neonate and young infant, the clinical manifestations may evolve rapidly, with vomiting, failure to thrive, hypotonia, and severe metabolic acidosis leading to coma and death, before other manifestations are evident. Characteristic laboratory findings in addition to the metabolic acidosis include a specific organic aciduria; 3-methylcrotonylglycine, 3-hydroxyisovaleric acid, 3-hydroxypropionic acid, or 2-methylcitric acid may be detected in the urine. Symptoms and signs are rapidly reversed by the administration of 5 to 10 mg of biotin. Changes in biotin levels in some children on antiepileptic drug therapy with carbamazepine, phenytoin, or phenobarbital have been described. The clinical significance of such changes remains unknown [Mock, 1998].

Biotin Dependency The neurologic complications associated with biotin dependency, such as biotin-dependent propionicacidemia, biotin-dependent holocarboxylase synthetase deficiency (neonatal multiple carboxylase deficiency) and biotinidase deficiency (late-onset multiple carboxylase deficiency), are discussed in detail in Chapter 23.

Vitamin K Vitamin K is a fat-soluble vitamin essential for the biosynthesis of several blood clotting factors, including prothrombin (factor II), proconvertin (factor VII), plasmaconverting factor (Christmas factor, factor IX), and Stuart factor (factor X) [Corrigan, 1981; Olsen, 1984; Sutor, 2003]. Vitamin K1 (phylloquinone), found in chloroplasts of plant leaves and in many vegetable oils, and vitamin K2, comprising a series of compounds (menaquinones) in which the phytyl chain in vitamin K1 has been replaced by a side chain containing 2 to 13 phytyl units, are synthesized predominantly by a gram-positive bacterium. Vitamin K3 (menadione) is a synthetic compound with properties similar to those of phylloquinone. Vitamin K acts as an essential cofactor for hepatic microsomal enzyme systems, which convert the biologically inactive precursors of prothrombin, proconvertin, and plasma thromboplastin components to the active compounds participating in the events necessary for normal blood clotting. In this process, vitamin K converts residues of phytic-bound glutamic acid in each of the precursors into γcarboxyglutamyl residues. This conversion activates the blood clotting proteins by allowing them to bind calcium

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ions. The calcium-carboxyglutamyl proteins subsequently are bound to phospholipid surfaces. In the process of γ-carboxylation of the glutamate residues, vitamin K quinone is converted to the 2,3-epoxide. An enzyme-dependent salvage mechanism for the regeneration of the active vitamin K catalyzed by the hepatic enzyme epoxide reductase is blocked by warfarin therapy. The recommended daily dietary reference intake for vitamin K is 2.0 to 2.5 μg for infants younger than 1 year of age and 30 to 75 μg for older children and adolescents. Such amounts are readily available when average diets are supplemented by the menaquinones produced by intestinal bacteria. Vitamin K is absorbed through the small intestine. Bile salts and pancreatic secretions are necessary for optimal absorption. Once absorbed, vitamin K is incorporated into chylomicrons, transported to the liver, and bound to verylow-density lipoproteins, through which it is transported to other tissues.

Vitamin K Deficiency Vitamin K deficiency results in a hemorrhagic diathesis known as hemorrhagic disease of the newborn. The newborn is particularly susceptible because vitamin K stores are deficient, and because factor II, IV, VII, IX, and X concentrations characteristically are only 50% of normal. These concentrations continue to decline for 48 to 72 hours after birth but subsequently increase slowly as a result of the absorption of dietary vitamin K and the initiation of synthesis by bacterial flora in the intestine. Breast-fed infants are particularly prone to development of the disorder, because the vitamin K content of breast milk is low. Hemorrhagic disease of the newborn can occur early (i.e., within the first 2 to 3 days of life) or late (between weeks 2 and 12) [Aydinli et al., 1998; Bor et al., 2000; Zipursky, 1999]. It is estimated that the median incidence of hemorrhagic disease of the newborn in developed countries is 7 per 100,000 births; it likely is much higher in developing countries [Victora and Van Haecke, 1998]. Presenting complaints in a recent study of the late form of the disease were seizures (in 91% of the patients), drowsiness (in 82%), poor sucking (in 64%), vomiting (in 46%), fever (in 46%), pallor (in 46%), acute diarrhea (in 27%), and irritability and high-pitched cry (in 18%); findings on examination included tense or bulging fontanel (in 73%), anisocoria (in 36%), weak neonatal reflexes (in 18%), and cyanosis (in 18%) [Aydinli et al., 1998]. Location of intracranial hemorrhage includes the following: intracerebral 91%, subarachnoid 46%, subdural 27%, and intraventricular 27%. At follow-up evaluation after periods ranging from 6 to 48 months, only three (27%) infants remained neurologically normal; seizures (in 73%), severe psychomotor retardation (in 46%), cerebral palsy (in 46%), microcephaly (in 46%), and hydrocephalus (in 27%) were observed in the remainder. Vitamin K deficiency may occur in children with severe developmental disabilities [Yoshikawa et al., 2003]. Infection, use of antibiotics, and elemental nutrition are risk factors for vitamin K deficiency in severely disabled children, and vitamin K intake with enteral nutrition might be marginal. Intracranial hemorrhage, the most serious neurologic consequence, rarely occurs without hemorrhage into other tissues. Hemorrhagic disease in the newborn is now rare

because of the routine prophylactic administration of vitamin K on the first day of life but may occur in newborn infants and in older children in association with conditions impairing fat absorption and parenteral alimentation and after the chronic administration of broad-spectrum antibiotics, which sterilize the intestinal tract. Laboratory studies indicate prolonged prothrombin and partial thromboplastin times with normal platelet counts and fibrinogen concentrations. Parenteral administration of 1 mg vitamin K usually is recommended, although 0.25 μg is sufficient in most instances. When vitamin K deficiency is associated with chronic disease, 1 to 5 mg of vitamin K1 should be administered parenterally at weekly intervals. Vitamin K may play a role in development of the CNS. Recently a congenital deficiency of vitamin K-dependent coagulation factors associated with CNS anomalies has been described [Puetz et al., 2004]. Vitamin K deficiency in the embryo secondary to maternal malabsorption has been suggested to cause severe malformations similar to those occurring with warfarin embryopathy and other related conditions [Menger et al., 1997]. It also has been demonstrated that vitamin K–dependent carboxylase expression is temporally regulated in a tissue-specific manner, with high expression in the CNS during early embryonic stages; a wide distribution of the novel vitamin K-dependent growth factor, Gas6, also was demonstrated [Tsaioun, 1999]. Studies with animals also support a role for vitamin K in the biosynthesis of sphingolipids, raising the possibility that vitamin K could be involved in major cellular events such as cell proliferation, differentiation, and survival [Carrie et al., 2004]. Taken together, these results suggest a possible role of vitamin K in nervous system development.

Folate (Vitamin M) In the past 2 decades, recognition of the importance of folates in the developing nervous system has been increasing, based on its relation to formation of the neural tube (Chapter 19), its role in several of the pediatric neurotransmitter diseases (Chapter 30), and its role in cerebrovascular injury related to stroke risk and hyperhomocystinemia (Chapters 17 and 72). The folates, a group of pteridine compounds composed of pteroic acid linked to a variable number of glutamate residues, have a fundamental role in cell growth and division [Stover, 2004]. Fully reduced methyltetrahydrofolate, formed from other folates in a reaction catalyzed by the enzyme dihydrofolate reductase, is the active cofactor. Known functions of folate include one-carbon transfer reactions in de novo purine synthesis and in the synthesis of methionine from homocysteine, serine from glycine, and deoxythymidylic acid from deoxyuridylic acid. Folate also is a cofactor in the conversion of formiminoglutamic acid to glutamic acid in the degradation of histidine. Dietary folates consist predominantly of folate polyglutamates. During the process of absorption and transport across the jejunum, most polyglutamates are hydrolyzed to the monoglutamate, which is subsequently reduced and methylated to methyltetrahydrofolate [Halstead, 1980]. After absorption, methyltetrahydrofolate is rapidly transported to tissues and stored in the liver. Considerable liver methyltetrahydrofolate is excreted in the bile and resorbed in the

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small intestine. In the plasma, folates are transported either as the free form or loosely bound to protein. A specific folate-binding protein, which is found in low concentration in normal serum, is present in increased concentration in folate deficiency. A different folate-binding protein with a high affinity for methyltetrahydrofolate is present in umbilical cord blood, accounting for the preferential uptake of folate by the fetus, even in folate-depleted mothers. The choroid plexus also contains a folate-binding protein with a high affinity for methyltetrahydrofolate, reflecting the dependency of the CNS on methyltetrahydrofolate because of a low concentration of dihydrofolate reductase [Levitt et al., 1971; Spector and Lorenzo, 1975]. Methyltetrahydrofolate and other folate derivatives are excreted in the urine. Some folate is resorbed by the renal tubule. The recommended dietary reference intake for folate is 2.0 to 2.5 μg for infants younger than 1 year of age and 30 to 75 μg for older children and adolescents. During pregnancy, lactation, and other conditions characterized by rapid cell division (e.g., hemolytic anemia), the folate requirement can increase to 400 μg per day.

Folate Deficiency Inadequate dietary intake is rarely the sole cause of folate deficiency but can occur in populations fed exclusively wellboiled foods or in infants for whom goat’s milk, which is deficient in folate, forms the major dietary staple. Folate deficiency more commonly results from conditions associated with increased folate requirements or diseases associated with abnormalities of folate absorption, use, or excretion. Pregnancy, prematurity, and diseases characterized by increased cell turnover (e.g., hemolytic anemia) are conditions associated with an increased folate requirement. The preterm infant is especially prone to develop this deficiency because the folate stores (normally formed during the third trimester) are inadequate, rapid growth is taking place, and renal tubular conservation mechanisms are not fully developed [Landon and Hey, 1974; WorthingtonWhite et al., 1994]. Malabsorption defects and hepatic disease may interfere with folate absorption. Several drugs, including phenytoin, phenobarbital, oral contraceptives, and cycloserine, impede folate absorption and use [Waxman et al., 1970]. Methotrexate, trimethoprim, and triamterene specifically inhibit dihydrofolate reduction, preventing methyltetrahydrofolate synthesis [Winick et al., 1992]. A progressive megaloblastic anemia, irritability, diarrhea, and failure to gain weight are the clinical manifestations of folate deficiency in infants. A possible association between human immunodeficiency virus I (HIV) in children with folate deficiency presenting with neurologic symptoms of delayed development, developmental regression, seizures, hypotonia or spastic quadriplegia, and basal ganglia calcifications also has been reported [Habibi et al., 1989]. No single laboratory test is optimal for the documentation of folate deficiency. Megaloblastic anemia is associated with a low reticulocyte count. Nucleated erythrocytes may be present in peripheral blood. Neutropenia and thrombocytopenia also may be present. Vitamin B12 deficiency must be excluded because prolonged treatment with folic acid may reverse the megaloblastic anemia of vitamin B12 deficiency without affecting the neurologic abnormalities. The serum

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folate concentrations (normal, 5 to 12 ng/mL) and total red cell content (normal, 150 to 600 ng/mL) are low. The red cell content is a better measure of folate status than is the serum concentration. Formiminoglutamic acid is excreted in the urine, especially after an oral loading dose of histidine. Because the megaloblastic anemia improves within 72 hours, parenteral administration of 200 μg of folic acid can be used as a diagnostic test. Treatment with 2 to 5 mg of folic (pteroylglutamic) acid for 3 to 4 weeks usually is sufficient to reverse the clinical manifestations of deficiency. Disorders associated with cerebral folate deficiency recently have been reviewed [Ramaekers and Blau, 2004] and also are discussed in depth in Chapter 30.

Folate Deficiency and Neural Tube Defects The mechanisms that underlie the relation between folate and neural tube defects have yet to be determined [Stover, 2004]. Folate-responsive neural tube defects are believed to result from impaired maternal and/or fetal folate metabolism, with the involved pathways being either deoxythymidine monophosphate (dTMP) or methionine synthesis. These metabolic disruptions can be overcome by elevating maternal folate levels. Proposed mechanisms for folate-responsive neural tube defects as reviewed by Stover [2004] include accumulation of homocysteine, decreased rates of DNA synthesis due to impaired dTMP synthesis, and elevations in the S-adenosylhomocysteine/methionine ratio. Some evidence indicates that homocysteine can react with and oxidize proteins and also bind to the N-methyl-D-aspartate (NMDA) receptor, but direct evidence that homocysteine inhibits closure of the neural tube is lacking. Impaired dTMP synthesis also has been proposed to affect cell proliferation or migration during the critical period of neural tube closure. Finally, increases in the Sadenosylhomocysteine/methionine ratio that result from impaired homocysteine remethylation can affect DNA methylation density and alter the expression of genes that are critical for the formation of the neural tube. The best evidence from human studies indicates that impairments in the homocysteine remethylation pathway, or in other affected methionine-dependent methylation reactions for which homocysteine serves as a marker, can impair normal embryonic development [Stover, 2004]. Moderate maternal hyperhomocysteinemia increases risks for neural tube defects. Recommendations that all women capable of becoming pregnant should consume 400 μg of folic acid per day from supplements or fortified foods were made in the early 1990s, and subsequently the U.S. Food and Drug Administration (FDA) mandated the addition of folic acid to enriched cereal grain products. These changes have had a dramatic effect on improving folate status in this high-risk group and in reducing the incidence of neural tube defects [Hague et al., 2003]. Of additional concern is that increased maternal plasma homocysteine concentrations during pregnancy have been associated with the occurrence of diseases associated with placental vascular thrombosis—in particular, pre-eclampsia and placental abruption, conditions that are well know to potentially cause perinatal brain injury. Since 1963, evidence from various studies has supported an association between antiepileptic drug and congenital malformations in the offspring of women with epilepsy [Oguni and Osawa, 2004]. Exposure to antiepileptic drug treatment

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in utero occurs in 1 of every 250 newborns. The absolute risk of major malformations in these infants is approximately 7% to 10%—approximately 3% to 5% higher than in the general population. In part, these teratogenic effects are related to folate deficiency [Lindhout et al., 1994]. Additional risk factors include high maternal daily dosage or serum concentrations of antiepileptic drug, polytherapy, and generalized seizures during pregnancy. Other factors that may contribute to the risk include concomitant diseases such as diabetes mellitus, occupational exposure to teratogens, excessive prepregnancy weight, and various nutrient deficiencies [Yerby, 2003]. Adverse pregnancy outcomes include neural tube defects and also congenital heart malformations, facial clefts, hypospadias, and growth and mental retardation [Lindhout et al., 1994]. Valproate and carbamazepine have been associated specifically with the development of neural tube defects. Data concerning the risk for congenital malformations associated with the newer antiepileptic drugs—gabapentin, felbamate, lamotrigine, leve-tiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide—are still limited. Several pregnancy registries for women taking antiepileptic drugs have been established. It is unclear whether the protective effect of folate supplementation is comparable for women with epilepsy and for pregnant women who do not have epilepsy and who are not on antiepileptic drugs. Despite uncertainty about the efficacy of periconceptional folate supplementation in women with epilepsy, it is recommended that folate supplementation be used (0.4 to 4 mg) [Lindhout et al., 1994; Morrell, 1998; Pennell, 2004; Yerby, 2003].

Hyperhomocysteinemia and Stroke Hyperhomocysteinemia is an important risk factor for vascular disease, including stroke [Schwammenthal and Tanne, 2004]. Homocysteine is a metabolite of methionine, an essential amino acid derived from dietary protein. It is metabolized by one of two pathways: remethylation into methionine, catalyzed by the vitamin B12–dependent enzyme methionine synthase, or trans-sulfuration to cysteine and glutathione by folate dependent methylenetetrahydrofolate reductase. A role for homocysteine in the pathogenesis of atherosclerosis was first suggested in 1969; this possibility was based on observation of extensive atherosclerotic changes in two children with hyperhomocysteinemia and homocysteinuria [McCully, 1963]. Mechanisms that have been suggested for the atherothrombotic potential of homocysteine include endothelial dysfunction through oxidative damage (vascular toxicity), increased oxidation of low-density lipoprotein, stimulation of smooth muscle cell proliferation, prothrombotic effects, and impaired thrombolysis [Schwammenthal and Tanne, 2004]. Whether treatment of hyperhomocystinuria with B complex vitamins including folate reduces the risk of recurrent stroke remains somewhat controversial [Kaplan, 2003]. Results of the Vitamin Intervention for Stroke Prevention study (VISP) found that moderate reduction of total homocysteine after nondisabling cerebral infarction had no effect on recurrent stroke or coronary events [Toole, 2004]. Despite the absence of a treatment effect, however, a consistent association among baseline concentration, vascular risk, and the probability of stroke was found [Schwammenthal and Tanne, 2004].

The role of hyperhomocysteinemia in pediatric stroke is reviewed in Chapter 72 and in several recent studies [Cardo et al., 1999, 2000]. A higher prevalence of hyperhomocysteinemia and the nucleotide 677 cytosine-to-thymidine point mutation (677C>T) polymorphism was observed among 21 children with stroke than among 28 children without stroke (28.6% versus 14.3%) [Cardo et al., 2000]. Total plasma homocysteine levels were significantly increased in children aged 2 months to 15 years with stroke compared with reference values. Significant negative correlations also were found between total plasma homocysteine levels and folate and cobalamin levels. Overall, the studies demonstrated that the 677C>T genotype is a strong factor for predisposition to hyperhomocysteinemia and recurrent risk of stroke that also might be prevented with folate supplementation. The authors of these studies suggested that systematic screening for hyperhomocysteinemia should be included in protocols that investigate the etiology of stroke in children and that antiepileptic treatment in children with stroke may be responsible for the mild hyperhomocysteinemia observed in some patients [Cardo et al., 1999]. It also is suggested that dietary supplementation with folate may be of benefit in children with stroke and in those taking antiepileptic drugs.

Folate Dependency CONGENITAL FOLATE MALABSORPTION SYNDROMES Specific folate absorption defects have been described in several infants [Jebnoun et al., 2001; Malatack et al., 1999; Poncz and Cohen, 1999; Steinschneider et al., 1990]. In affected infants, selective deficiency occurs in the transport of folates in the intestinal tract and across the blood-brain barrier [Zittoun, 1995]. In addition to failure to thrive, diarrhea, and megaloblastic anemia, affected patients have CNS abnormalities of variable severity. Neurologic defects range from learning disability to profound mental retardation, seizures, progressive athetosis, and peripheral neuropathy. Basal ganglia calcifications may develop during adolescence. The megaloblastic anemia but not the progression of neurologic abnormalities responded to folate supplementation (10 to 40 mg/day of folic acid); parenteral administration was necessary in some patients [Jebnoun et al., 2001; Steinschneider et al., 1990]. Parenteral therapy with folinic acid, a reduced folate derivative more readily transported across the blood-brain barrier, decreased the CNS deficit and elevated the folate concentration in one patient [Steinschneider et al., 1990]. The variability in clinical presentation and responsiveness to folate therapy suggests that different genotypic mutations are involved.

METHYLENE-TETRAHYDROFOLATE REDUCTASE DEFICIENCY Methylene-tetrahydrofolate reductase deficiency is the most common of the folate-dependent enzymatic disorders [Fattal-Valevski et al., 2000; Fowler, 1998; Haworth et al., 1993; Zittoun, 1995]. Symptoms are primarily neurologic and have included limb weakness, lack of coordination, paresthesias, and memory lapses, along with developmental delay, marked hypotonia, seizures, microcephaly, apnea, and coma and, rarely, schizophrenic syndromes.Vascular disease

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also may occur. Hematologic abnormalities are not observed. Low levels of folate in serum, red blood cells, and cerebrospinal fluid associated with homocystinuria are constant.

GLUTAMATE FORMIMINOTRANSFERASE DEFICIENCY Formiminotransferase catalyzes the conversion of Nformiminoglutamic acid to glutamic acid, the final step in histidine catabolism. Several children in whom an excessive urinary excretion of formiminoglutamic acid suggested glutamate formiminotransferase deficiency have been reported [Fowler, 1998; Hilton et al., 2003]. This autosomal-recessive disorder is the second most common inborn error of folate metabolism and is presumed to be due to defects in the bifunctional enzyme glutamate formiminotransferasecyclodeaminase. Two clinically and biochemically distinct syndromes emerge from these descriptions. In one, mild neurologic deficits (e.g., mild mental retardation, learning disabilities, attention-deficit disorder, hypotonia, clumsiness) are associated with massive urinary formiminoglutamic acid excretion, normal serum folate concentrations, and normal hematologic studies. In some of these patients, folate administered either orally as folic acid or intramuscularly as tetrahydrofolate decreased formiminoglutamic acid excretion [Fowler, 1998; Niederwieser et al., 1974; Perry et al., 1975]. In the other syndrome, severe mental retardation, diffuse cerebral atrophy, and increased serum folate concentrations and formiminoglutamic acid urinary excretion were associated with a partial deficit of formiminotransferase activity in liver biopsy specimens or erythrocytes. One of these children had a folate-responsive megaloblastic anemia [Zittoun, 1995].

FOLATE-DEPENDENT DIHYDROFOLATE REDUCTASE DEFICIENCY Several patients with a suspected deficiency of dihydrofolate reductase, the enzyme catalyzing the reduction of folate derivatives to methyltetrahydrofolate, have been described [Fowler, 1998; Tauro et al., 1976; Walters, 1967]. The family history suggested that this enzyme defect may result in abortion or stillbirth. The patients first required treatment for failure to thrive and a severe megaloblastic anemia in early infancy. Mental retardation of variable degree was subsequently observed. The hematologic abnormality responded to the intramuscular administration of folinic acid (100 μg to 6 mg per day). Because therapy was delayed and intermittent, whether the neurologic deficit could have been prevented is not clear. Some investigators have suggested that the neurologic deficits seen in these patients may be due to reduced levels of S-adenosylmethionine [Bottiglieri and Hyland, 1994].

DISORDERS ASSOCIATED WITH MICRONUTRIENT DEFICIENCIES Iron Deficiency Overview About 25% of the world’s children younger than 3 years of age have iron deficiency anemia, with higher rates in de-

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veloping countries; when iron deficiency without anemia is considered, rates are even higher [Black, 2003]. The WHO estimates that worldwide, 2 billion persons have anemia and up to 5 billion persons are iron deficient [WHO, 1992]. The estimated prevalence of iron deficiency in the United States, according to the 2002 Centers for Disease Control and Prevention report, is greatest in toddlers 1 to 2 years of age (7%) and in adolescent and adult females 12 to 49 years of age (9% to 16%) [From the Centers for Disease Control and Prevention, 2002]. The prevalence of iron deficiency is approximately twice as high among non-Hispanic black and Mexican-American females (19% to 22%) as it is among non-Hispanic white females (10%). Dietary deficiency is the most common cause of iron depletion in infants and children. Breast-feeding for less than 6 months’ duration, the use of non–iron-fortified infant formula, the introduction of cow’s milk before the age of 1 year, and a diet deficient in iron all are proven risk factors [Yager and Hartfield, 2002]. Iron is necessary for hemoglobin synthesis, and iron deficiency leads to reduced oxygen-carrying capacity and can have an impact on immunity, growth, and development. Clinical effects of iron deficiency include anemia, weakness, failure to thrive, and breath-holding spells [Leung and Chan, 2001]. Iron deficiency results in decreased heme proteins, iron-containing enzymes, and reactions in which iron is involved as a cofactor. Consequently, changes in nucleic acid biosynthesis, oxidative respiration and mitochondrial function, detoxification of metabolic byproducts, and catecholamine metabolism occur [Yager and Hartfield, 2002]. The brain is sensitive to dietary iron depletion and repletion and reacts to changes by means of homeostatic regulatory mechanisms regulated by the blood-brain barrier in response to iron status [Beard et al., 2001; Bryan et al., 2004]. Brain tissue is overall very rich in iron, with concentrations differing according to brain region and stage of development [Youdim and Yehuda, 2000]. Some areas of the brain that are important for cognition—such as the cortex, hippocampus, and striatum—are more sensitive to iron deficiency than others. Iron affects myelination during development and is an important cofactor for dopaminergic, serotoninergic, and noradrenergic neurotransmitter synthesis [Bryan et al., 2004]. Studies in rats have found that iron deficiency results in a reduction of dopamine D2 receptor densities and inadequate dopamine reuptake [Ashkenazi et al., 1982], suggesting that alterations in frontal cortical dopamine levels may be associated with deficits in executive function, attention, perception, memory, motivation, and motor control [Beard, 2003]. Evidence of CNS structural abnormalities in children with iron deficiency anemia is limited [Grantham-McGregor and Ani, 2001; Yager and Hatfield, 2002]. Auditory-evoked brainstem responses have suggested impaired myelin synthesis, based on prolongation of the central conduction time [Roncagliolo et al., 1998]. Other studies have found that children who received treatment for iron deficiency anemia also have longer P100 latencies on visual-evoked potential testing compared with control subjects, again suggesting that iron deficiency anemia alters myelination [Algarin et al., 2003]. The relation of iron deficiency and cognitive development in children has received much attention in the past 3 decades

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and has been recently reviewed [Bryan et al., 2004; Gordon, 2003; Grantham-McGregor and Ani, 2001]. Studies have found a correlation between hemoglobin concentrations and cognitive performance or school achievement scores, especially in iron-deficient persons [Sungthong et al., 2002]. Children with iron deficiency anemia early in life demonstrate lower academic performance during their school years, even after the anemia had been treated. Comparisons of iron-deficient, anemic, and nonanemic children have demonstrated that anemic children perform more poorly on tests assessing development, cognitive performance, and school achievement in areas such as mathematics [Halterman et al., 2001]. Longitudinal studies examining associations between iron status in children younger than 2 years of age and later measures of cognitive performance suggest that early anemia, even if treated, is associated with impaired long-term development [Bryan et al., 2004; Lozoff et al., 2000]. A Cochrane Review examined the impact of iron therapy in children younger than 3 years of age with iron deficiency anemia and found positive and negative correlations [Logan et al., 2001]. Several clinical trials also have examined whether iron supplementation in children younger than 3 is beneficial. About half of the studies found improved cognitive performance [Black, 2003]. In the trials in which improvement was observed, mental and motor development and language skills were better and lessening of symptoms such as wariness and irritability was reported. Evidence is scarce regarding the efficacy of short-term iron supplementation on the cognitive development of anemic children younger than 2 years of age, or of longer-term treatment to help anemic children catch up with nonanemic children in development level [Bryan, 2004]. Studies in developing countries, however, have found a beneficial effect of longerterm treatment of anemic older children [Idjradinata and Pollitt, 1993; Stoltzfus et al., 2001]. The results of nine randomized, controlled trials in children older than 2 years and in adolescents recently have been summarized and demonstrated inconsistent findings [Bryan, 2004; GranthamMcGregor and Ani, 2001]. Overall, although little evidence exists for the efficacy of short-term iron supplementation in children younger than 2 years of age, reasonable evidence suggests a beneficial effect of longer-term iron supplementation on the cognitive performance of older children. A detailed discussion of these studies is beyond the scope of this chapter but is presented in the review by GranthamMcGregor and Ani [2001]. Currently, no practice guidelines have been published on screening for iron deficiency or use of iron supplementation to prevent cognitive or behavioral defects. The foregoing findings must be tempered by an appreciation of the ongoing controversy regarding the relative effects that micronutrient deficiencies such as iron are responsible for a majority of observed impairments that occur. As reviewed by Pollit [2000], (1) studies of protein-energy malnutrition suggest that environmental factors can moderate the relation between early nutritional insult and later developmental disadvantage; (2) profound developmental changes can occur after the age of fastest brain growth when the environment changes and the child’s basic needs are met without interruption; (3) no data are available to suggest that the observed delays of cognition reported for children in

middle or late childhood, who were iron deficient as infants, were not a result of familial variables; and (4) documentation is lacking that the cerebral alterations produced by experimentally induced iron-deficiency anemia in rat models are the reasons for cognitive delays of children.

Specific Neurologic Effects of Iron Deficiency Three neurologic problems have been associated with iron deficiency: stroke, breath-holding spells, and benign intracranial hypertension [Yager and Hartfield, 2002].

STROKE Stroke occurring in association with iron deficiency has been reported in both children and adults [Belman et al., 1990; Bruggers et al., 1990]. In some children, an antecedent viral infection was reported [Hartfield et al., 1990], whereas in others, congenital heart disease in conjunction with venous thrombosis also was present [Cottrill et al., 1973]. Several mechanisms have been proposed to explain the association between iron deficiency anemia and stroke and include (1) development of thrombocytosis due to loss of iron regulation of platelet production; (2) development of a hypercoagulable state consequent to increased blood viscosity from the microcytic, poorly deformable red blood cells resulting from the iron deficiency, with increased risk of venous thrombosis; and (3) development of anemic hypoxia, which has been associated with transient hemiplegia and cerebellar infarcts [Yager and Hartfield, 2002].

BREATH-HOLDING SPELLS Breath-holding episodes also have been associated with iron deficiency and can occur in up to 27% of affected children [Colina et al., 1995; Daoud et al., 1997]. Autonomic dysregulation resulting in vagally mediated cardiac arrest or bradycardia has been proposed [Holowach and Thurston, 1965], as have the effects of anemia on reducing oxygencarrying capacity. Iron-deficient children also are known to be more irritable; presumably, this may increase the likelihood of an event. Treatment with iron supplementation has been shown to significantly reduce or eliminate the risk of recurrence [Daoud et al., 1997].

BENIGN INTRACRANIAL HYPERTENSION Iron deficiency as a cause of benign intracranial hypertension has been recognized for more than a century [Yager and Hartfield, 2002]. It is most common in young females. Although the underlying mechanism is unknown, it has been proposed that tissue hypoxia leads to increased capillary permeability and development of brain edema or abnormalities in cerebrovascular hemodynamics that increase cerebral blood flow, leading to increased intracranial pressure. Depletion of iron-containing enzymes also may contribute to the development of cerebral edema. Several studies report that benign intracranial hypertension due to iron deficiency is reversible with iron supplementation [Tugal et al., 1994].

Frank and Ashwal / Neurologic Disorders Associated with Gastrointestinal Diseases/Nutritional Disorders

IODINE DEFICIENCY Iodine deficiency is the most preventable cause of mental retardation in the world [Black, 2003]. It is a major problem that affects children in geographic areas in which iodine is depleted from the soil, primarily mountainous regions, such as the Himalayas and Andes, and in flood plains. A 1996 WHO report estimates that 2.2 billion persons are at risk for iodine deficiency [WHO, 1996]. People consuming iodinedeficient foods grown in these areas become iodine deficient unless iodine can be consumed from external sources [Bryan, 2004]. Public health measures such as use of iodized salt, injections of iodinated oil, and oral iodine supplementation have been effective in preventing congenital hypothyroidism and the associated mental retardation [Stanbury, 1994]. Iodine is required for synthesis of the thyroid hormones triiodothyronine (T3) and thyroxine (T4), which are necessary for skeletal growth and for growth and development of the brain [Reavley, 1998]. Iodine deficiency in utero results in fetal hypothyroidism and irreversible neurologic and cognitive deficits manifested as cretinism, characterized by mental retardation, primitive reflexes, visual problems, facial deformities, stunted growth, and impaired motor function [Halpern, 1994]. In addition to cognitive delays, primitive reflexes, and pyramidal signs, features of myxedematous cretinism include severe growth retardation, dry skin, and electrocardiographic abnormalities [Black, 2003]. Chronic hypothyroidism also can have ongoing effects across all ages, and affected persons can have epilepsy, motor dysfunction, dementia, depression, and disorders of vigilance, visuomotor planning, and abstract thinking [Bryan, 2004]. Patients who are most severely affected are those who have congenital cretinism and postnatal hypothyroidism that extends into childhood and adulthood. Summaries of studies on the effects of iodine deficiency on cognitive development and the effects of iodine supplementation have recently been published [Black, 2003; Bryan, 2004]. A meta-analysis of 18 studies completed by Bleichrodt and Born [1994] indicated a general loss of 13.5 IQ points in chronically iodine-deficient populations compared with non–iodine-deficient groups. Another study found that children with mild hypothyroidism had deficits in spelling and reading compared with control subjects [Huda et al., 1999]. Some studies indicate that children with goiter perform significantly less well on tests of nonverbal reasoning ability, whereas other studies have found no difference between groups on measures of general intelligence [Bryan, 2004]. One difficulty with comparing children on the basis of the presence of goiter is that no clear relation between goiter and the degree of hypothyroidism has been described. A number of studies have used other biomarkers of iodine deficiency, such as urinary iodine status, which has been found to correlate with cognitive performance studies [van den Briel et al., 2000]. Randomized iodine supplementation trials from iodinedeficient areas found that children whose mothers were supplemented before conception or early in pregnancy have better developmental outcomes than those in children born to unsupplemented mothers. Clinical trials also have examined the impact of iodine supplementation on cognitive performance of infants and children in iodine-deficient areas

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[Black, 2003]. The results have been inconsistent. Most studies were performed in iodine-deficient populations, and about half of the studies found positive effects on mental performance [Bryan, 2004]. In some studies, improvements in mental performance were seen only in those children who also had an improved iodine status [Bryan, 2004]. In studies in which cognitive improvement was not detected, problems with study design or other factors may have been present [Bryan, 2004]. In a recent longitudinal follow-up study of school-age children, all of whom received iodine, those whose mothers received iodine before the third trimester had better scores on a measure of psychomotor performance than corresponding scores in children whose mothers received iodine later in pregnancy or who received iodine at age 2 years [O’Donnell et al., 2002]. The effects of postnatal iodine deficiency on children’s cognitive performance are less clear than the effects of prenatal iodine deficiency. As noted by Black [2003], universal salt iodization is a public health priority for women of childbearing age to protect their unborn children from the severe consequences of hypothyroidism. In geographic regions in which iodine deficiency is common, but iodized salt is either not consumed or unavailable, iodized oil can be used. Although iodine supplementation reduces the incidence of goiter in children, the impact on their cognitive development requires further investigation.

ZINC DEFICIENCY Zinc deficiency remains a serious health problem worldwide, affecting developed as well as developing countries. Zinc deprivation during periods of rapid growth negatively affects cognitive function, growth, and development [Gibson, 1998; Oken and Duggan, 2002; Rivera et al., 2003; Salgueiro et al., 2004]. Zinc deficiency has been demonstrated in animal models to affect cognitive development by decreasing activity, increasing emotional behavior, and impairing memory and the capacity to learn [Bhatnagar and Taneja, 2001]. Zinc has a critical role in the function of several structural, regulatory, and catalytic proteins [Hambidge, 2000; McCall et al., 2000]. Zinc is known to play an important molecular role in processes of gene replication, activation, and repression, as well as in DNA transcription and translation and protein synthesis [Bryan et al., 2004; Walsh et al., 1994]. Prompted by early reports of birth defects in the offspring of zinc-deficient rats in the 1980s, more recent investigations have examined the effects of zinc deficiency. Zinc may be an important modulator of neuronal excitability, because it is present in high concentrations in the synaptic vesicles of “zinc-containing” neurons in the forebrain, and it also plays important roles in myelination and GABA and glutamate release. Zinc also is important for neurogenesis, neuronal migration, and synaptogenesis, and its deficiency could interfere with neurotransmission and neurophysiologic development [Bhatnagar and Taneja, 2001]. Zinc also is involved in the metabolism of thyroid hormones and receptor function and transport of other hormones that could influence the CNS. Indirectly, zinc deficiency may affect cognitive performance through its interactions with other nutrients [Bryan et al., 2004. Because iron and zinc are most bioavailable from many of the same foods and their absorption

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is inhibited by many of the same dietary substances, iron and zinc deficiencies often occur simultaneously [Bryan et al., 2004]. Zinc also is known to affect vitamin A metabolism, and zinc deficiency might thereby contribute to the consequences of vitamin A deficiency. Biologic measures of zinc status, such as plasma and hair zinc concentrations, are imperfect indicators of functional impairment due to zinc deficiency, and response to randomized trials of zinc supplementation conducted in zincdeficient populations has been an important means to examine the consequences of zinc deficiency [Black, 2003]. Supplementation trials among nutritionally deficient infants have demonstrated beneficial effects of zinc on growth, diarrhea and pneumonia morbidity, and on mortality. A majority but not all of the zinc supplementation studies in pregnant women, infants, and toddlers have shown improved activity and motor development [Bentley et al., 1997; CastilloDuran et al., 2003; Sazawa et al., 1996; Tamura et al., 2003]. Zinc supplementation trials have resulted in alteration in fetal neurobehavior, better motor development in infants of very low birth weight, more vigorous and functional activity in malnourished infants and toddlers, and improved neuropsychologic functions in school-aged children. Although evidence from supplementation trials in infants and toddlers suggests that zinc deficiency may compromise early motor development, the evidence linking zinc deficiency to cognitive development is inconclusive [Black, 2003, 1998]. Several randomized trials of zinc supplementation measuring cognitive development in school-aged children have found mixed results [Black, 2003]. In two studies, however, one from China [Penland et al., 1997] and one involving Mexican-American children from Texas [Penland et al., 1999], found improved neuropsychologic performance, particularly in reasoning, in zinc-supplemented children. Additional studies will be needed to determine the indications for zinc supplementation, the correct populations that require treatment, the optimal intensity and duration of treatment, and how this should be combined with treatment for other micronutrient deficiencies.

Fluid and Electrolyte Abnormalities Fluid and electrolyte abnormalities may cause severe acute injury that results in long-term neurologic and developmental sequelae, particularly in children. This section reviews the more common clinically encountered conditions [Gullans and Verbalis, 1993] and their effect on the developing nervous system. Aspects of the neurologic complications of renal disease are extensively reviewed in Chapter 89. Management of fluid and electrolyte disorders is reviewed in standard textbooks of pediatrics [Behrman et al., 1996; Hoekelman et al., 1997; Oski et al., 1994; Rudolph et al., 1996] and elsewhere [Jospe and Forbes, 1996; Mahalanabis and Snyder, 1996; Meyers, 1994]. Other reviews have considered fluid and electrolyte disorders in neurologic [Riggs, 2002], neurosurgical [Andrews, 1994], or pediatric surgical patients [Filston, 1992]; in patients with bacterial meningitis [Brown and Feigin, 1994]; in children with other critical care illnesses [Khilnani, 1992]; after anesthesia in the perioperative and postoperative periods [Gold, 1992]; and in the neurologically impaired patient [Parobek and Alaimo, 1996].

In addition, new technologies, such as proton MR spectroscopy, which allows measurement of myoinositol, a key brain osmol [Haussinger et al., 1994], or diffusion-weighted imaging, which determines early water movement after injury [Nomura et al., 1994], may allow better understanding of many of the common fluid and electrolyte disorders (also see Chapter 89).

SODIUM, WATER, AND CHLORIDE ABNORMALITIES Sodium and Water The regulation of sodium and water metabolism is closely integrated. Sodium is the principal cation in the extracellular fluid and, through its osmotic properties, determines extracellular volume. Sodium content depends on dietary intake, intestinal absorption, and renal and extrarenal (e.g., in sweat or feces) excretion. The kidneys play a pivotal role in sodium homeostasis. Sodium excreted in the glomerular filtrate is subsequently reabsorbed in the renal tubular system. An increased sodium load promotes an increase in glomerular filtration and a decrease in renal tubular sodium reabsorption, whereas a decreased sodium load leads to a decrease in glomerular filtration and an increase in tubular reabsorption of sodium. These processes are mediated through complex interactions of multiple hormones, including the cardiac hormone atrial natriuretic factor, the adrenal hormone aldosterone, and the hypophyseal antidiuretic hormone. Atrial natriuretic factor, stored in the atrial cardiocyte, is activated in response to volume expansion (e.g., sodium content excess), leading to an increase in glomerular filtration and renal tubular sodium excretion. Aldosterone promotes renal tubular sodium reabsorption. It is released from the adrenal medulla in response to the activation of angiotensin II by the stimulation of juxtaglomerular cells in afferent renal arterioles by small decreases in plasma volume (e.g., sodium content depletion). Extracellular sodium concentration is regulated primarily by antidiuretic hormone. Synthesized in the supraoptic nuclei of the hypothalamus and subsequently stored in synaptic vesicles in the posterior pituitary, antidiuretic hormone is released into the plasma in response to stimulation by hypothalamic osmoreceptors and promotes the reabsorption of water by the distal renal tubules.

Hyponatremia Hyponatremia may result from excessive sodium loss, excessive water intake or retention, a shift of water from cells to extracellular fluid, or a shift of sodium from extracellular fluid into cells (Table 90-2) [Berry and Belsha, 1990]. Combinations of mechanisms occur frequently. In the pediatric age group, hyponatremia most commonly results from either sodium loss or water retention. As hyponatremia develops, an associated reduction of plasma osmolality with a rapid shift of water into the brain occurs. Subsequent homeostatic mechanisms, including the shift of water into the cerebrospinal fluid and the shift of intracellular potassium and organic cations into the interstitial cerebral space, provide protection against fulminant cerebral edema [Fishman, 1974; Rymer and Fishman, 1973]. The neurologic effects of chronic hyponatremia reflect the

Frank and Ashwal / Neurologic Disorders Associated with Gastrointestinal Diseases/Nutritional Disorders

TABLE 90-2 Causes of Hyponatremia MECHANISM

SOURCE

Excessive NaCl loss

Gastrointestinal tract Skin Urinary tract

Excessive water intake

Oral Parenteral

Defective water excretion

Rectal Inappropriate antidiuretic hormone secretion

CAUSATIVE FACTOR/ DISORDER Diarrhea Cystic fibrosis Heat stress Salt-losing renal disease Adrenal insufficiency Diabetes mellitus Psychogenic Acute renal failure Therapeutic error Coma Tap water enema Anesthetic drugs Craniocerebral trauma Infection

electrolyte depletion of brain cells and may be secondary to the inhibition of transmitter release [Hajtha and Shersin, 1975] or abnormalities in energy metabolism [Fishman, 1974]. Symptomatic hyponatremia invariably develops only after the plasma sodium concentration has decreased below 120 mEq/L and involves the CNS. An alteration in mental status is the most common neurologic manifestation of hyponatremia and ranges in degree from mild confusion to coma. The severity of clinical manifestations depends on the degree of hyponatremia and the rapidity by which the sodium concentration has decreased. Mild symptoms are relatively nonspecific and include malaise, fatigue, listlessness, and muscle cramping. The rapid onset of severe hyponatremia may lead to confusion, disorientation, delirium, weakness, ataxia, and seizures, frequently followed by prolonged coma. Rare descriptions of rhabdomyolysis associated with hyponatremia exist [Rizzieri, 1995]. The treatment of symptomatic hyponatremia consists of the correction of serum osmolality by the intravenous administration of a hypertonic saline solution. The optimum rate for correction remains controversial [Oh and Carroll, 1992]. Excessively rapid correction may shrink the volume of adapted brain cells [Sterns et al., 1989] and has been implicated in the pathogenesis of central pontine myelinolysis, a fulminating demyelinative disorder of the body of the pons, clinically characterized by quadriparesis, pseudobulbar palsy, and the “locked-in” state [Arieff, 1981; Brunner et al., 1990; Pirazda and Ali, 2001; Sterns et al., 1986]. A 17-month-old infant with kwashiorkor and hyponatremia had a central pontine lesion on MRI with a clinical presentation of acute massive myoclonus [Tan, 2004]. Central pontine myelinolysis, as well as osmotic demyelination syndrome, may complicate the correction of hyponatremia. Osmotic demyelination syndrome is the term used to describe the combination of pontine and extrapontine myelinolysis [Martin, 2004]. Most cases of central pontine myelinolysis occur in alcoholics, about 20% occur after the correction of hyponatremia, and 17% occur in patients who underwent liver transplantation, in whom the disorder is attributed to treatment with the immunosuppressive medication cyclosporine [Lampl, 2002]. Osmotic demyelination

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syndrome, manifested clinically mostly as an altered level of consciousness and convulsions, can develop in patients with hyponatremia after hemodialysis. With this syndrome, MRI abnormalities are seen in the pons in most cases, and in the pons along with extrapontine sites in a minority. Prospective MRI studies demonstrated the development of characteristic pontine lesions in patients who recieived treatment for hyponatremia in relation to rapid correction of the hyponatremia (more than 12 mEq/liter per day) [Brunner et al, 1990]. Diffusion-weighted MRI identified pontine abnormalities within 24 hours of onset of symptoms [Ruzek, 2004]. The lesions usually resolved rapidly, suggesting that they represent edema rather than demyelination [Tarhan, 2004]. The correction of hyponatremia can cause central pontine myelinolysis or osmotic demyelination syndrome. Therefore, treatment should take into consideration a number of factors, including whether the hyponatremia is symptomatic, the patient’s volume status, and the severity and duration of the hyponatremia and hypo-osmolarity [Han, 2002].

Hypernatremia Hypernatremia, defined as an increase in serum sodium concentration above 150 mEq/L, may result from excessive sodium intake or retention, excessive water loss, a shift of water into cells, or a shift of sodium out of cells (Table 90-3). Hypernatremia can occur in association with increased, decreased, or normal body sodium content. In the pediatric age group, the loss of hypotonic fluid with gastroenteritis is among the more common causes of hypernatremia [Finberg, 1967, 1973; Finberg et al., 1963]. Neurologic manifestations of hypernatremia include restlessness and irritability, followed by lethargy, seizures, spasticity, and coma. Hypernatremia in a child was associated with transient thalamic signal changes [Hartfield et al, 1999]. Permanent neurologic sequelae are frequent because acute hypernatremia leads to cellular dehydration and brain shrinkage, which may be associated with venous thrombosis and subdural or parenchymal intracerebral hemorrhage [Arieff and Guisado, 1976; Korkmaz et al, 2000]. Permanent brain damage was reported in one third of children with severe TABLE 90-3 Causes of Hypernatremia MECHANISM Excess sodium intake

Water deficit

Water deficit in excess of sodium deficit

CAUSATIVE FACTOR/DISORDER Improperly mixed formula or rehydration solution Excessive sodium bicarbonate administration during resuscitation Saltwater drowning Diabetes insipidus Diabetes mellitus Excessive sweating Increased water loss Adipsia Inadequate water intake Diarrhea Osmotic diuretics Obstructive uropathy Renal dysplasia

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hypernatremia [Morris-Jones et al, 1967]. The production of “idiogenic osmols”—the amino acids taurine, glutamine, alanine, and aspartic acid, derived from the catabolism of intracellular protein—subsequently restores the quantity of intracellular water to near normal [Trachtman et al., 1988]. Treatment should be directed toward correcting the basic disease process whenever possible, preserving perfusion, and restoring normal sodium concentration. Excessively rapid restoration of the sodium concentration to normal in chronic hypernatremia may lead to cerebral edema and should be avoided. A rate of reduction of the serum sodium concentration by 10 to 15 mEq/L per day is recommended [Conley, 1990].

Chloride Chloride is the major anion in intracellular fluid and plays an important role in maintaining electrochemical neutrality in the extracellular fluid and blood plasma. Chloride input and output parallel those of sodium; chloride transport is predominantly passive along an electrochemical gradient created by sodium, although a site for the active transport of chloride in the thick ascending loop of Henle specifically blocked by furosemide has been established [Rochas and Kokko, 1973]. In most circumstances, alterations in plasma chloride concentrations parallel those of sodium and are most frequently observed in dehydration from diarrhea.

Hypochloremia Hypochloremia is associated with metabolic alkalosis and occurs as a consequence of excessive chloride loss or deficient intake [Roy, 1984]. Excessive loss may occur from the upper GI tract (e.g., vomiting, pyloric stenosis), the skin (e.g., cystic fibrosis), or the urine (e.g., administration of diuretics, Bartter’s syndrome). A rare congenital disorder characterized by a chloride-losing diarrhea also has been reported [Holmberg, 1986]. Chloride depletion also has resulted from the feeding of a chloride-deficient formula [Grossman et al., 1980; Roy and Arant, 1979]. Affected infants developed muscular weakness, delayed motor development, anorexia, and constipation associated with hypochloremic metabolic acidosis, hyponatremia, hypokalemia, hypoaldosteronuria, and microscopic hematuria. In a majority of affected infants, these symptoms and signs were associated with failure to thrive and microcephaly. Clinical and laboratory abnormalities disappeared promptly after the restoration of normal chloride intake, and on subsequent studies the children were normal at 4 to 5 years of age, except for persistent behavioral problems in a few [Hellerstein et al., 1985].

whereas the potassium concentration in the extracellular fluid varies, ranging from 3.5 to 5.5 mEq/L. Because extracellular fluid contains only 2% of the total body potassium and the potassium content of adipose tissue is negligible, total body potassium correlates closely with lean body mass. Dietary potassium is absorbed in the upper GI tract. Although some potassium is excreted in the feces and sweat, the kidney is the principal organ responsible for potassium balance. Because potassium filtered through the renal glomeruli is almost completely resorbed in the proximal tubules, urinary potassium excretion is principally a consequence of the amount of potassium secreted by the distal renal tubular system. This process is controlled by multiple interrelated factors, including electrochemical and concentration gradients between the distal tubular cells and the lumen, sodium-potassium adenosine triphosphatase pumps, and plasma aldosterone concentration [Giebish, 1980]. Acute changes in the ratio of intracellular to extracellular concentration of potassium are influenced by epinephrine and insulin, which promote potassium uptake by liver and muscle cells [Brem, 1990]. The neurologic manifestations of potassium disturbances involve mostly the peripheral nervous system and only rarely the CNS.

Hypokalemia Hypokalemia, defined as serum potassium concentrations less than 3.5 mEq/L, may result from decreased potassium intake, renal or extrarenal potassium loss, or a shift of plasma potassium into cells (Table 90-4). Clinical manifestations associated with hypokalemia include skeletal muscle weakness, areflexia, decreased intestinal peristalsis and paralytic ileus, and loss of the ability of the kidney to concentrate urine. Paralysis and death from respiratory failure can occur. Prolonged hypokalemia may lead to permanTABLE 90-4 Causes of Hypokalemia MECHANISM

CAUSATIVE FACTOR/DISORDER

Deficient intake

Protein-calorie malnutrition Parenteral nutrition Distal tubular acidosis Proximal tubular acidosis (Fanconi’s syndrome) Bartter’s syndrome Interstitial nephritis Pyelonephritis Diabetes mellitus Cushing’s syndrome Aldosteronism Drug administration (diuretic, aspirin, steroids) Hypomagnesemia Hypercalcemia Alkalosis Drugs (insulin, catecholamines) Parenteral nutrition Vomiting, diarrhea Fistula drainage Laxative abuse Ion-exchange resins Congenital alkalosis

Renal loss Renal disease

Extrarenal disease

Hyperchloremia Hyperchloremia occurs in several forms of metabolic acidosis and may be a consequence of bicarbonate loss from the GI or urinary tract, the administration of drugs (e.g., acetazolamide, ammonium chloride), or renal tubular acidosis.

POTASSIUM CONCENTRATION ABNORMALITIES Potassium is the principal intracellular cation; the intracellular potassium concentration approximates 150 mEq/L,

Shift (extracellular to intracellular) Extrarenal loss

Frank and Ashwal / Neurologic Disorders Associated with Gastrointestinal Diseases/Nutritional Disorders

TABLE 90-5 Causes of Hyperkalemia MECHANISM

CAUSATIVE FACTOR/DISORDER

Excessive intake

Potassium-containing salt substitutes Parenteral administration (excessive infusion, outdated blood) Gastrointestinal bleeding

Decreased renal excretion Renal disease Extrarenal causes

Shift (intracellular to extracellular)

Oliguric renal failure Chronic hydronephrosis Potassium-sparing diuretics Addison’s disease Congenital adrenal hyperplasia Diabetes mellitus Drugs (beta blockers, heparin) Rapid cell breakdown (trauma, infection, cytotoxic agents) Acidosis Freshwater drowning

ent impairment of renal function associated with vacuolar changes in the tubular epithelium that can persist even after potassium repletion. Treatment consists of the administration of potassium with serial monitoring of electrolytes.

Hyperkalemia Hyperkalemia, defined as a serum potassium concentration greater than 5.5 mEq/L, may result from excessive potassium intake or administration, decreased renal excretion, or a shift of potassium from the intracellular to the extracellular space (Table 90-5). Clinical manifestations primarily affect neuromuscular transmission and result from a reduction of action potentials toward threshold levels, leading to delayed depolarization, rapid repolarization, and slowing of conduction velocity. These responses lead to paresthesias, weakness, and ultimately flaccid paralysis. The heart is particularly vulnerable to hyperkalemia; serum concentration greater than 6.5 mEq/L must be considered a medical emergency because ventricular fibrillation and death may ensue rapidly. Emergency therapeutic measures include the rapid administration of sodium bicarbonate (up to 2 mEq/kg over 5 to 10 minutes) or of glucose and insulin (glucose in a dose of 0.5 g/kg and regular insulin in a dose of 0.3 unit/g, given over 2 hours). Intravenous calcium gluconate (a 10% solution in a dose of up to 0.5 mL/kg, given over 2 to 4 minutes) will counter the cardiac toxicity but must be accompanied by electrocardiographic monitoring. These emergency methods do not remove excess potassium and should be accompanied by cessation of all potassium intake and, if necessary, the use of an ion exchange resin (e.g., Kayexalate), hemodialysis, or peritoneal dialysis.

CALCIUM CONCENTRATION ABNORMALITIES Calcium is the fifth most abundant element in the body; approximately 99% of the body calcium content is in bone. Despite the large calcium reserve in bone, extracellular calcium concentration is maintained remarkably constant at approximately 5 mEq/L (10 mg/dL) under normal con-

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ditions. Approximately 40% of extracellular calcium is bound to protein, predominantly albumin; 10% is diffusible but complexed to anions such as citrate and phosphate; and the remaining 50% (2.5 mEq/L) is freely diffusible as calcium ions. The freely diffusible fraction is responsible for the physiologic effects of calcium in neuromuscular transmission, in which calcium functions as a coupling agent for excitation-transmission in the nervous system and excitationcontraction in muscle [Lynch, 1990; Rassmussen, 1986]. The absorption of calcium in the intestinal tract is mediated by an active carrier process [DeLuca and Schnoes, 1983], which is enhanced by vitamin D and parathyroid hormone. In addition to intestinal calcium absorption, plasma calcium concentration also is controlled through renal calcium reabsorption and bone resorption [Bushinsky and Monk, 1998]. Calcium absorption is increased in sarcoidosis, carcinomatosis, and multiple myeloma and is decreased by increased GI motility, with decreased bowel length, and in the presence of phytate, oxalate, and phosphate, which promote the formation of unabsorbable complexes. Diffusible calcium is excreted by the kidney. Almost 99% of the calcium filtered by renal glomeruli is resorbed. Renal calcium resorption is enhanced by 1,25-dihydroxyvitamin D and parathyroid hormone and is inhibited by thyrocalcitonin. Renal calcium excretion also is increased by osmotic diuretics, growth hormone, thyroid hormone, glucagon, metabolic acidosis, prolonged fasting, and prolonged physical activity. The cerebrospinal fluid concentration of calcium varies, ranging from 2 to 3 mEq/L, roughly approximating the diffusible fraction in the extracellular fluid. Transport of calcium into the cerebrospinal fluid is determined by a carriermediated transport process [Goldstein et al., 1979; Graziani et al., 1965].

Hypocalcemia Although hypocalcemia may occur at any age, it most commonly is observed in the neonatal period (Box 90-3) [Juan, 1977]. Relatively uncommon in breast-fed infants, it may occur in otherwise healthy, non–breast-fed newborns as a consequence of transient physiologic hypoparathyroidism and after ingestion of the relatively high phosphate load of cow’s milk for several days. Neonatal hypocalcemia also may occur in the first 36 hours of life, particularly in preterm infants born to mothers who have diabetes and in association with conditions leading to perinatal encephalopathy. Excessive secretion of thyrocalcitonin may cause persistent hypocalcemia in preterm infants [Tsang et al., 1973]. More persistent neonatal hypocalcemia also may be a consequence of maternal hypoparathyroidism or a manifesta-

Box 90-3 CAUSES OF HYPOCALCEMIA • • • • • • • •

Vitamin D deficiency Hypoparathyroidism Pseudohypoparathyroidism Hyperphosphatemia Magnesium deficiency Acute pancreatitis Alkalosis Rapid correction of acidosis

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tion of agenesis of the parathyroid glands (DiGeorge’s syndrome). In later life, hypocalcemia can occur in nutritional rickets, in chronic malabsorption states, during the treatment of dehydration as a manifestation of hypoparathyroidism or pseudohypoparathyroidism, and rarely as a consequence of chronic antiepileptic drug therapy. In the newborn, convulsions are the most characteristic manifestation of tetany. Laryngospasm with cyanosis and apneic episodes also may occur. Poor feeding, vomiting, and lethargy are frequent, nonspecific associated manifestations. Bradycardia with heart block is rarely observed. Treatment of neonatal symptomatic tetany consists of the slow intravenous administration of 10% calcium gluconate in a dose of 2 mL/kg. Concurrent monitoring of the cardiac rate to prevent excessive bradycardia is advised. The intravenous dose can be repeated at 6- to 8-hour intervals. In older children, clinical manifestations associated with symptomatic hypocalcemic tetany include paresthesias, stiffness, and cramping of limb muscles; stridor; and convulsions. Convulsions may be the sole clinical abnormality associated with hypocalcemia. Carpopedal spasms may occur spontaneously or be precipitated by hyperventilation or application of a constricting blood pressure cuff (Trousseau’s sign). Myotatic stretch reflexes are characteristically hyperactive, and the hyperirritability of peripheral nerves can be elucidated by observing muscle contraction after tapping of the peroneal nerve at the lateral margin of the knee (peroneal sign) or tapping of the facial nerve in front of the ear (Chvostek’s sign). Mental status abnormalities include irritability, anxiety, confusion, and psychosis. Calcifications of the basal ganglia are seen in patients with chronic hypoparathyroidism.

Hypercalcemia Hypercalcemia may result from hyperparathyroidism, vitamin D intoxication, hyperthyroidism, prolonged immobilization, malignancies (especially in bone), sarcoidosis, Williams’ syndrome, and the use of diuretics. Clinical manifestations include anorexia, nausea, vomiting, polydipsia and polyuria, and muscle weakness. Hypercalcemia has been associated with apnea in infants [Kooh and Binet, 1990]. Chronic hypercalcemia leads to nephrocalcinosis and renal failure.

MAGNESIUM CONCENTRATION ABNORMALITIES Magnesium, the fourth most abundant cation in the body, plays an important role in neuronal and muscle excitability and is essential for the normal activity of the various enzyme systems, including all those requiring adenosine triphosphate [Rude and Singer, 1981]. Almost all magnesium is located intracellularly, predominantly in bone, muscle, and liver; only 1% of the total body magnesium content is distributed in extracellular spaces. Under normal conditions, plasma magnesium concentrations range from 1.5 to 2.2 mEq/L. Magnesium is absorbed in the small intestine through an active transport process linked to calcium absorption and is excreted predominantly by the kidney. Most of the magnesium filtered by the renal glomeruli is resorbed in the

Box 90-4 CAUSES OF HYPOMAGNESEMIA • • • • • •

Malabsorption Hypoparathyroidism Renal tubular acidosis Diuretic therapy Primary aldosteronism Neonatal tetany

proximal tubules; only approximately 3% to 5% of filtered magnesium is excreted in the urine.

Hypomagnesemia Although cellular depletion of magnesium can occur without demonstrable hypomagnesemia [Montgomery, 1960], clinical manifestations of magnesium depletion usually are associated with hypomagnesemia (serum concentration of 1.3 mEq/L or less). Hypomagnesemia can occur in chronic diarrhea or vomiting, sprue, or celiac disease; with prolonged parenteral nutrition therapy; and in hypoaldosteronism (Box 90-4). Tetany that is clinically indistinguishable from hypocalcemic tetany is the most distinctive symptom of magnesium depletion, but muscle tremors, fasciculations, weakness, choreoathetosis or tremor, dysphagia, ataxia, vertigo, nystagmus, and mental changes including irritability and confusion also may occur [Fishman, 1965; Hamed and Lindeman, 1978; Langley and Mann, 1991]. Cardiac dysrhythmias may occur. Hypocalcemia resistant to vitamin D therapy caused by impaired parathyroid function [Rude et al., 1976] and hypokalemia caused by impaired renal potassium resorption [Shils, 1969] also have been reported. Because of the similarity between the neurologic manifestations of hypomagnesemia and those of hypocalcemia, it is important to assess both calcium and magnesium status in treating patients with these manifestations.

Hypermagnesemia Hypermagnesemia usually signifies impaired renal function. Clinical manifestations of hypermagnesemia rarely occur unless the serum magnesium concentration is greater than 4 mEq/L. Neuromuscular and cardiac symptoms and signs predominate. The neuromuscular manifestations are a consequence of decreased impulse transmission across the neuromuscular junction, decreased responsiveness of the postsynaptic membrane, and an increased threshold for axonal excretion [Mordes and Walker, 1978; Rude and Singer, 1981]. Hyporeflexia or areflexia may be observed with serum magnesium concentrations greater than 4 mEq/L, somnolescence at concentrations of 4 to 7 mEq/L, and paralysis at concentrations greater than 10 mEq/L. Cardiac conduction deficits characterized by prolonged P-R and R-T intervals and increased T wave amplitude are observed at serum concentrations of 5 to 10 mEq/L. Complete heart block and cardiac arrest in diastole may occur with serum concentrations greater than 15 mEq/L. Although rare, symptomatic hypermagnesemia can occur in patients with renal failure, Addison’s disease after excessive parenteral administration, or iatrogenic poisoning (Box 90-5). Hypermagnesemia has been reported in newborns after magnesium

Frank and Ashwal / Neurologic Disorders Associated with Gastrointestinal Diseases/Nutritional Disorders

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CHAPTER 91

Neurologic Complications of Immunization Claudia A. Chiriboga

Immunization programs are undoubtedly cost-effective public health measures that protect against infectious disease. Recommendations on immunization schedules are made by the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention to the Surgeon General. New recommendations of the ACIP are published in Morbidity and Mortality Weekly Report, and they are the standard of care for immunization practices (Table 91-1). Vaccination programs have proved successful in eradicating diseases worldwide. For instance, smallpox was eradicated in 1980, and a World Health Organization (WHO) vaccination program to eradicate poliomyelitis by the year 2000 has made steady progress, with cases decreasing from 4000 in 1994 to 600 in 2003. Efforts have been thwarted by mistrust of vaccines in Nigeria, where the government stopped vaccinating against polio because of unfounded fears that it caused sterilization. As of July 2004, Nigeria accounted for 78% of 440 polio cases worldwide. Vaccine mistrust is not just a problem in Third World countries. Increasingly, antivaccine movements are afoot in the United States and other industrialized countries. These types of movements have potential for harming children by not affording them needed protection against infections at a biologically vulnerable age. For instance, countries such as the United States that have strong antivaccine movements have rates of pertussis that are 10 to 100 times higher than rates in countries such as Hungary without such antivaccine movements, where levels of vaccination are very high [Gangarosa et al., 1998]. Antivaccine movements are fueled by ignorance, lack of scientific scrutiny of the Internet, anecdotal reports, and frustration among parents by the lack of well-defined causes to explain neurologic or TABLE 91-1 Schedule of Routine Immunization of Healthy Infants and Children RECOMMENDED AGE

IMMUNIZATIONS

Birth 2 months 4 months 6 months 12–15 months 4–6 years 11–12 years

HBV DTaP, HBV, HIB, OPV or eIPV DTaP, Hib, eIPV DTaP, HBV, Hib DTaP, Hib, MMR, eIPV, Var, PCV DTaP, MMR, eIPV DT, MMR, and Var if not given at or after 12 months

DT, diphtheria-tetanus; DTaP, pertussis vaccine combined with diphtheria and tetanus toxoids; eIPV, enhanced-potency trivalent inactivated polio vaccine; HBV, hepatitis B virus; Hib, Haemophilus influenzae type b; MMR, measles, mumps, and rubella vaccine; OPV, oral polio vaccine; Var, live-attenuated varicella vaccine.

developmental disorders (e.g., autism) that may temporally coincide with vaccination. The high rates of complications of earlier vaccines (e.g., rabies) may also contribute to this mistrust.

ASSESSING CAUSALITY Events that are temporally associated are not necessarily causally linked. Determining causal relationships between vaccinations and specific disorders with certainty is difficult. Among existing methods, the one least helpful in assessing causality is the case report, which relies on simple temporal associations that may easily have occurred by coincidence. For example, any exposure (e.g., vaccinations) that affects an entire population (e.g., children) is bound to be associated with an outcome, even a rare outcome, by simple chance. When the outcomes are common (e.g., developmental disorders), associations by chance are expected to occur and do not denote causality. Clinical trials and epidemiologic population-based studies are more robust in assessing links between vaccines and adverse outcomes. Clinical trials, not usually employed to assess vaccine safety and efficacy in the United States, compare adverse outcomes in an exposed (i.e., vaccinated) and unexposed (i.e., not vaccinated or vaccinated with a different preparation) group of randomly selected individuals. Findings resulting from such studies are valid, but they are limited by their relatively small sample size that precludes identifying associations with rare outcomes. Population-based studies are useful, especially if large, because they can assess even rare outcomes. The risks of adverse outcomes in one population can then be compared with risk among the nonvaccinated populations or rates of the naturally occurring disease. However, causality cannot be determined with certainty, only suspected, unless there is a biologic marker. Further complicating assigning causality is the administration of several vaccines at one time [Fenichel, 1999; Howe et al., 1997]. The U.S. Institute of Medicine was charged with undertaking the first reviews of vaccine-related complications, and it continues to review vaccine safety. Given the lack of a “smoking gun” to attribute causality and because absence of proof is not proof of absence, the Institute of Medicine takes into account level of proof and does not make determination based on lack of evidence. Instead, the literature is reviewed, biologic mechanisms are taken into account, and causality is classified into the following five levels of proof: (1) no evidence bearing on a causal relationship, (2) evidence is inadequate to accept or reject a causal relationship, (3) evidence favors rejection of a causal relationship, (4) evidence favors acceptance of a causal relationship, and

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BOX 91-1 TYPES OF VACCINES Whole-Killed Organisms Influenza Pertussis Poliomyelitis (i.e., inactivated polio vaccine) Rabies Live-Attenuated Viruses Measles Mumps Poliomyelitis (i.e., oral poliovirus vaccine) Rubella Varicella Influenza (i.e., nasal vaccine) Components of Organisms Acellular pertussis Haemophilus influenzae type b Pneumococcal conjugate Diphtheria Tetanus Recombinant Hepatitis B (5) evidence establishes a causal relationship [Institute of Medicine, 1991, 1993]. In determining causality, biologic mechanisms (formerly defined as biologic plausibility), should first be taken into account (i.e., whether there is a plausible mechanism by which the vaccine could cause the complication or disease in question). For example, a measles vaccine cannot elicit vaccineassociated polio. Next, the method of vaccine preparation should be considered. Four types of vaccines are available: vaccines composed of whole-killed organisms, vaccines composed of live-attenuated viruses, vaccines composed of components of organisms, and recombinant vaccines (Box 91-1). Adverse events should be congruent with the vaccine preparation. For example, vaccines made of components of organisms cannot cause the disease being vaccinated against, but live-attenuated viruses can do so in the right host (e.g., vaccine-associated polio).

VACCINE INJURY COMPENSATION PROGRAM The U.S. Vaccine Injury Compensation Program (VICP), effective since 1988, is a federal no-fault system designed to compensate individuals or families of individuals who have been injured by childhood vaccines. Vaccines covered under the VICP are diphtheria, tetanus, and pertussis (DTP, DTaP, DT, TT, or Td); measles, mumps, and rubella (MMR or any components); polio (OPV or IPV); hepatitis B; Haemophilus influenzae type b; varicella (chickenpox); rotavirus; and pneumococcal conjugate, whether administered individually or in combination. A table of injuries was established outlining known injuries to covered vaccines (Table 91-2). The injuries listed are presumed to be caused by the vaccine unless an alternate cause is established.

TYPES OF VACCINES Vaccines Composed of Whole-Killed Organisms Vaccines composed of whole-killed organisms were the first laboratory-produced vaccines. They provoke an antibody response that provides temporary immunity. Some vaccines made from whole-killed organisms may cause immunemediated disorders.

Inactivated Polio Vaccine The Salk inactivated polio vaccine (IPV) was licensed in 1955 and immediately led to a drop in the incidence of paralytic poliomyelitis. The Salk vaccine has been highly effective, with a 70% to 90% protection rate. It was replaced in 1963 by Sabin’s oral poliovirus vaccine (OPV), which resulted in polio eradication in the United States by 1979, the time of the last documented wild type poliovirus infection. Because OPV is prepared with a live-attenuated virus, it is associated with a low risk of eliciting polio in healthy individuals and a larger risk in immune-suppressed people (see “Vaccines Composed of Live-Attenuated Viruses”). An enhanced-potency trivalent polio vaccine (eIPV) was licensed in the United States in 1987, which was initially indicated for immunodeficient individuals. After a successful transition from OPV, eIPV has become the vaccine used to immunize children in the United States [CDC, 1997]. It is easier to administer, and it is not associated with vaccine-associated poliomyelitis.

Influenza Virus Vaccine Epidemic human influenza illness is caused by influenza A and B. Influenza A viruses are categorized into subtypes based on two surface antigens: hemagglutinin (H) and neuraminidase (N). New influenza virus variants result from changes in antigens (i.e., antigenic drift) due to point mutations arising during viral replication. Every year, a new influenza vaccine is developed to protect against the prevalent virus strains that are expected to appear in the United States the following winter. Each vaccine contains three influenza viruses: one A (H3N2) virus, one A (H1N1) virus, and one B virus. Two types of flu vaccines are available: the inactivated flu vaccine (discussed later) and the nasal-spray flu vaccine (i.e., live-attenuated influenza vaccine [LAIV]). The “flu shot” vaccine is prepared from inactivated flu virus and is approved for use in all high-risk groups. The LAIV is prepared from live, attenuated flu viruses that do not cause disease in humans. This nasal preparation is cold adapted to replicate best at 25° C, and it is temperature sensitive so that it cannot replicate in lower airways. LAIV was licensed for use in the United States in 2003 and is approved for use in healthy people 5 to 49 years of age who are not pregnant. Trials in children have found comparable efficacy and safety profile between inactivated flu vaccine and LAIV in children [Zangwill et al., 2003, 2004]. Annual vaccination against influenza with inactivated virus is recommended for both extremes of life: children age 6 to 23 months (as of 2002) and the elderly (>65 years). It is also recommended for people of all ages with chronic diseases.

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TABLE 91-2 National Childhood Vaccine Injury Act: Vaccine Injury Table VACCINE

ADVERSE EVENT*

TIME INTERVAL

Tetanus toxoid-containing vaccines (e.g., DTaP, DTP-Hib, DT; Td, or TT)

A. Anaphylaxis or anaphylactic shock B. Brachial neuritis C. Any acute complication or sequela (including death) of above events A. Anaphylaxis or anaphylactic shock B. Encephalopathy (or encephalitis) C. Any acute complication or sequela (including death) of above events A. Anaphylaxis or anaphylactic shock B. Encephalopathy (or encephalitis) C. Any acute complication or sequela (including death) of above events A. Chronic arthritis B. Any acute complication or sequela (including death) of above event A. Thrombocytopenic purpura B. Vaccine-strain measles viral infection in an immunodeficient recipient C. Any acute complication or sequela (including death) of above events A. Paralytic polio In a non-immunodeficient recipient In an immunodeficient recipient In a vaccine-associated community case B. Vaccine-strain polio viral infection In a non-immunodeficient recipient In an immunodeficient recipient In a vaccine-associated community case C. Any acute complication or sequela (including death) of above events A. Anaphylaxis or anaphylactic shock B. Any acute complication or sequela (including death) of above event A. Anaphylaxis or anaphylactic shock B. Any acute complication or sequela (including death) of above event A. Intussusception B. Any acute complication or sequela (including death) of above event

0–4 hours 2–28 days Not applicable

Pertussis antigen-containing vaccines (e.g., DTaP, DTP, P, DTP-Hib) Measles, mumps and rubella virus-containing vaccines in any combination (e.g., MMR, MR, M, R) Rubella virus-containing vaccines (e.g., MMR, MR, R) Measles virus-containing vaccines (e.g., MMR, MR, M)

Polio live virus-containing vaccines (OPV)

Polio inactivated-virus containing vaccines (e.g., IPV) Hepatitis B antigen–containing vaccines Vaccines containing live, oral, rhesus-based rotavirus

0–4 hours 0-72 hours Not applicable 0–4 hours 5–15 days Not applicable 7–42 days Not applicable 7–30 days 0-6 months Not applicable 0–30 days 0–6 months Not applicable 0–30 days 0–6 months Not applicable Not applicable 0–4 hours Not applicable 0–4 hours Not applicable 0–30 days Not applicable

*Information effective as of August 26, 2002; see http://www.hrsa.gov/osp/vicp/table.htm for full definition of each adverse event. No condition specified for compensation for Haemophilus influenzae type b, pneumococcal conjugated vaccine, rotavirus vaccine, or varicella vaccine. DT, diphtheria-tetanus vaccine; DTaP, acellular pertussis vaccine combined with diphtheria and tetanus toxoids; Hib, Haemophilus influenzae type b; IPV, inactivated polio vaccine; MMR, measles, mumps, and rubella vaccine; MR, mumps and rubella vaccine; OPV, oral polio vaccine; Td, tetanus and diphtheria toxoid; TT, tetanus toxoid.

GUILLAIN-BARRÉ SYNDROME Increased rates of Guillain-Barré syndrome (GBS) were reported to be associated with the swine vaccine of 1976, with rates of GBS among vaccinees found to exceed the background rate of less than 10 cases per 1 million persons vaccinated. However, subsequent influenza seasons studied have not found a significant increase risk of GBS after influenza vaccination [Hurwitz et al., 1981]. The Institute of Medicine has determined a causal relationship between GBS and influenza vaccination for 1976 but not for other years. Nevertheless, because individuals with a history of GBS have a substantially greater likelihood of subsequently experiencing GBS than individuals without such a history, it has been recommended that influenza vaccination be avoided among individuals with a history of GBS and who are known to have experienced GBS within 6 weeks of a previous influenza vaccination (http://www.cdc.gov/flu/ protect/vaccine.htm). Whether influenza vaccination truly

increases the risk for recurrence of GBS or is coincidental is unknown. Even if GBS were a true complication of influenza vaccination, the risk of GBS attributable to the vaccine would be only about 1 additional case per 1 million persons vaccinated, a figure that is substantially less than the risk for severe influenza, especially among high-risk individuals. No cases of GBS are reported in vaccinated children [Institute of Medicine, 2003].

MULTIPLE SCLEROSIS There is no evidence that influenza vaccination increases the risk of multiple sclerosis relapse. Several studies, including a double-blind clinical trial [Miller et al., 1997] and a cohort study [Confavreux et al., 2001], have failed to find an association between multiple sclerosis relapse and vaccination. Influenza vaccination does not induce relapse and should be used in affected individuals.

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BELL’S PALSY Higher rates of Bell’s palsy were reported after intranasal vaccination with inactivated influenza virus in a case-control study in Switzerland [Mutsch et al., 2004]. Such reports have not been replicated elsewhere.

Rabies Vaccine Rabies was the first manufactured vaccine to be used in humans. Early vaccines were grown in the central nervous system of animals and contained myelin basic protein [Hemachudha et al., 1987]. These vaccines, still in use in underdeveloped countries, have been associated with encephalomyelitis, polyradiculitis, and polyneuritis [Tullu et al., 2003]. The rabies vaccine licensed for use in the United States is prepared from rabies virus grown on human diploid cells, and it has an excellent safety record. Rare cases of an atypical GBS are the only reported reactions [Boe and Nyland, 1980].

Whole-Cell Pertussis Vaccine Before 1992, pertussis vaccination was composed of a suspension of formalin-inactivated Bordetella pertussis bacteria (i.e., whole-cell pertussis vaccine). A more purified acellular vaccine was subsequently introduced, and it is the primary vaccine in use (see “Acellular Pertussis Vaccine”). Whole-cell pertussis vaccine has been routinely combined with diphtheria and tetanus toxoids (DTwP). The endotoxin contained in the whole-cell vaccine causes fever and pain at the injection site. Whole-cell pertussis immunization also has been associated with seizures, especially febrile and hypotonic hyporesponsiveness in about 1 case per 1750 doses and with a rare (0 to 10.5 cases per 1 million doses administered) acute encephalopathy, characterized by persistent crying [Cody et al., 1981]. The Institute of Medicine review of combined pertussis vaccine (DwPT) concluded that the evidence, although not probative, was consistent with a causal relationship between DwPT and an acute encephalopathy in the children who experience a serious acute neurologic illness within 7 days after receiving DwPT vaccine [Institute of Medicine, 1994]. Several detailed reviews of available studies by a number of countries, including those by the U.S. Institute of Medicine, have concluded that the data did not support a causal relationship between DTwP and chronic nervous dysfunction [American Academy of Pediatrics, 1996; Cowan et al., 1993].

Vaccines Composed of Live-Attenuated Viruses Live-attenuated virus vaccines are intended to cause an asymptomatic infection. However, properly constituted vaccines can cause symptomatic infection and the expected complications of the natural disease. The immunity provided by live-attenuated virus vaccines is similar to that from natural diseases, and it may persist for life.

Measles: Rubeola Measles vaccinations have been in use since 1963. Before routine vaccinations, approximately 3 to 4 million cases of measles and 450 deaths occurred annually in the United

States, where no endemic measles currently exists. Most reported measles cases in the United States are imported. Occasionally, outbreaks have occurred in populations that refuse vaccination (e.g., communities in Utah and Nevada, Christian Scientist schools in Missouri and Illinois). To avoid outbreaks in adolescents, a second measles booster is recommended at 10 to 12 years of age [Wittler et al., 1991]. The licensed measles vaccine uses the Edmonton B measles virus attenuated by prolonged passage in chick embryo cell culture that is combined with mumps and rubella vaccines (MMR). Children who receive live-attenuated measles vaccines are expected to develop an asymptomatic case of measles. Some children develop fever, rash, and conjunctivitis in the second week after immunization (i.e., the incubation period is at least 5 days). Children with vaccine-induced measles can develop any of the known complications of natural infection. The main neurologic complication of measles immunization is a febrile seizure during the second week after immunization [Griffin et al., 1991]. In a large Danish study, MMR vaccination was associated with a transient increased rate of febrile seizures, but the risk difference was small, even among high-risk children. The rate of epilepsy, however, was not increased in such children compared with children who had febrile seizures of a different cause [Vestergaard et al., 2004]. Rare cases of measles encephalitis with neurologic sequelae have been reported to the VICP [Fenichel, 1982]. Isolated cases of subacute sclerosing panencephalitis, a chronic form of measles encephalitis, have been reported among measles vaccinees in countries where measles is endemic, suggesting prior subclinical measles infection [Bonthius, 2000]. Studies that have genetically characterized the viral material from brains of patients with subacute sclerosing panencephalitis have all reported wild type of measles sequences [Barrero et al., 2003; Jin et al., 2000]. Moreover, cases of subacute sclerosing panencephalitis in individuals who did not recall having measles all have identified the wild type of measles. In developed countries with scant or no endemic measles, subacute sclerosing panencephalitis has disappeared in tandem with the disappearance of measles [Bloch et al., 1985; CDC, 1982].

Mumps The mumps vaccine is administered with MMR vaccination. It is prepared by passage of the Jeryl Lynn strain of mumps virus in chick embryo cell culture. Mumps vaccine has eliminated natural mumps infection, including mumps encephalitis. No adverse neurologic events are associated with the mumps vaccine used in the United States. Aseptic meningitis has been associated with the mumps vaccine used in other countries that use a different viral strain [Arruda and Kondageski, 2001; Suigura and Yamada, 1991]. A total of 10 isolated cases of sensorineural deafness has been reported after immunization with MMR [Kaga et al., 1998; Stewart and Prabhu, 1993]. Three of these cases could be explained from other causes; the remaining cases were unexplained.

Rubella Earlier rubella vaccines that were grown in various animal kidneys were associated with high rates of neuropathy and

Chiriboga / Neurologic Complications of Immunization

arthritis. Since 1979, the rubella vaccine used in the United States is prepared from human diploid cells. The immunologic response it produces parallels that of the natural infection. Up to 25% of people receiving the current rubella vaccine may develop transient arthralgias and paresthesias. Other chronic illnesses that have been reported after rubella vaccination include painful limb syndrome, blurred vision, fibromyalgia, and fatigue [Morton-Kute, 1985; Tingle et al., 1985]. In 1991, the Institute of Medicine reviewed the available scientific evidence and determined it to be consistent with, but not probative of, a causal relationship between rubella vaccination and chronic arthritis in women [Institute of Medicine, 1991]. Studies designed to address this question have not identified an association between chronic arthritis and rubella vaccination [Ray et al., 1997; Slater et al., 1995]. Rubella virus vaccine has been highly successful and has nearly eradicated rubella embryopathy.

Oral Polio Vaccine Sabin’s OPV, introduced in 1963, was successful in eradicating polio in the United States. Because the greatest risk of contracting polio in the United States was vaccine associated (i.e., the risk of wild polio is nil), OPV has been replaced by an enhanced-potency trivalent IPV (eIPV). The overall risk for vaccine-associated paralytic poliomyelitis (VAPP) after OPV administration is approximately 1 case per 2.4 million doses distributed. Among immunocompetent persons, 82% of cases among vaccine recipients and 65% of cases among contacts occur after administration of the first dose. After administration of the first dose among immunocompetent children, 82% of cases occur among vaccine recipients, and 65% of cases occur among contact persons. The risk for VAPP is 1 case per 750,000 first doses of OPV distributed [Nathanson et al., 1979]. Immunodeficient patients, particularly those who have B-lymphocyte disorders that inhibit synthesis of immune globulins (i.e., agammaglobulinemia and hypogammaglobulinemia), are at greatest risk for VAPP (3200-fold to 6800-fold greater than the risk for immunocompetent OPV recipients) [Sutter and Prevots, 1994]. There is no scant evidence that administration of OPV or IPV increases the risk for GBS [Kinnunen et al., 1989]. A population-based study found that GBS in children was not associated with OPV vaccination, because no cases had developed within a month of the vaccination. Moreover, 70% of cases of GBS were preceded by an intercurrent infection [Rantala et al., 1984].

Varicella A live-attenuated varicella virus (Oka strain) vaccine was licensed in 1995 in the United States, and it is currently recommended for routine childhood immunization for susceptible children between 12 and 24 months of age [American Academy of Pediatrics, 2000]. It is safe and effective in normal and immunocompromised children, and it is being used to protect children with acute lymphocytic leukemia [White et al., 1991] and HIV-infected children (before immune suppression) [Levin et al., 2001]. The vaccine produces a mild case of chickenpox. Varicella vaccination can cause herpes zoster among vaccine recipients, but incidence rates of vaccine-associated herpes zoster are much

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lower (approximately 2.6 per 100,000 vaccine doses distributed [CDC, unpublished data, 1998]) than rates reported among immunocompetent children (<20 years) with natural varicella infection (68 per 100,000 person-years) [Guess et al., 1986]. Serious adverse events, such as encephalitis, ataxia, seizures, neuropathy, and death, have been reported in temporal association with varicella vaccine. In some cases, the wild type of varicella-zoster virus or another causal agent has been identified. In most cases, data are insufficient to determine a causal association.

Smallpox Eradicated in 1980, smallpox has again emerged as a potential risk in the wake of recent terrorist events because of its potential use as a biologic weapon. The United States has commissioned the manufacture of vaccinia vaccines in preparation for possible intentional release of smallpox among the populace. In case of an outbreak, individuals of all ages would be vaccinated. The smallpox vaccine currently is recommended only for high-risk personnel (i.e., laboratory workers and at-risk military personnel) and is contraindicated for children and individuals with cutaneous disorders and immune suppression [Wharton et al., 2004]. The smallpox vaccine is prepared from vaccinia, a live poxvirus that causes mild disease, including rash, fever, and aches. The main neurologic complication of smallpox vaccination is post-vaccinal encephalomyelitis [CDC, 2003]. Neuropathologic reports describe cerebral edema and perivenular and leptomeningeal inflammation, findings that are consistent with an immune-mediated response [Perdrau, 1928]. However, vaccinia has been cultured [Angulo et al., 1964], as well as antigen recovered from affected brains [Kurata, 1977]. A comprehensive review based on data collected before 1970 estimates the risk of postvaccinal encephalomyelitis to be at least 3 cases per 1 million primary vaccinations and vaccinia necrosum to be 1 case per 1 million primary vaccinations [Aragon et al., 2003]. The highest risk for developing postvaccinial encephalomyelitis was among infants younger than 1 year (risk ratio = 2.80, compared with vaccinees 1 year or older). The mortality rate among patients with postvaccinial encephalomyelitis was 29%, and among patients with vaccinia necrosum, it was 15%. Among revaccinees, the risk of postvaccinial encephalomyelitis was reduced 26-fold, the risk of generalized vaccinia was reduced 29-fold, and the risk of eczema vaccinatum was reduced 12-fold. Clinical trials of recombinant smallpox vaccine are being carried out. The recombinant smallpox vaccine was designed to be safer for patients with cutaneous disorders, and it is expected to be associated with a lower risk of postvaccinial encephalomyelitis. Compensation for smallpox vaccination complications are covered under a separate congressional act [Health Resources and Services Administration, 2003).

Component Vaccines Acellular pertussis vaccine and Haemophilus influenzae type b vaccine are made from components of the bacteria. Toxoids are composed of denatured bacterial toxins. Toxoids prevent disease but not infection.

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Acellular Pertussis Vaccine Since 1997, acellular pertussis vaccines have been recommended for initial vaccination of children beginning at 5 weeks of age [CDC, 1997]. Acellular pertussis vaccines contain substantially fewer proteins (five) and less endotoxin than whole-cell pertussis vaccines. Acellular pertussis vaccination is associated with fewer local adverse events and systemic adverse events compared with DwPT [Rosenthal et al., 1996]. Fewer rates of serious neurologic disorders are also reported [Geier and Geier, 2004]. In a large Canadian study, no encephalopathy could be identified attributable to acellular pertussis after the administration of more than 6.5 million doses of vaccines [Moore et al., 2004].

Haemophilus influenzae Type b Haemophilus influenzae type b (Hib) vaccines in use in the United States are based on Hib polysaccharide conjugated to a protein carrier, such as a tetanus toxoid (PRP-T), a meningococcal outer membrane protein (PRP-OMP), a diphtheria toxoid (PRP-D), or a diphtheria toxoid–like protein (PRPHbOC). The conjugation of PRP to the protein induces a T-cell-dependent immune response to the Hib polysaccharide. The vaccine is administered in the United States during infancy concomitantly with DTaP as repeated doses. Hypersensitivity to the vaccine components is the only contraindication to its administration. No neurologic adverse events have been attributed to the vaccine in the United States.

Pneumococcal Conjugated Vaccine The first conjugate pneumococcal vaccine was licensed in the United States in 2000. It is composed of purified capsular polysaccharide of seven serotypes of streptococcal pneumonia conjugated to a nontoxic strain of diphtheria toxoid. Pneumococcal conjugated vaccine is indicated for routine vaccination of children younger than 2 years. Before routine vaccination, Streptococcus pneumonia was responsible for invasive disease in 188 per 100,000 children younger than 2 years, accounting for 20% of all invasive pneumococcal disease. Rates of invasive disease have fallen 95% after vaccination. The vaccine produces local side effects, fever, and myalgias. No serious neurologic side effects have been attributed to pneumococcal conjugated vaccine.

Tetanus and Diphtheria Tetanus and diphtheria are toxoids that are produced by formalin inactivation of the toxins elaborated by the two organisms. Both have low rates of complications [Lloyd et al., 2003]. Tetanus toxoid is given alone to children and adults after injury or burn exposure. The only contraindication for either toxoid is a history of a neurologic or severe hypersensitivity reaction after a previous dose. GBS associated with tetanus toxoid has been reported in one child and one adult. The adult patient developed recurrent episodes of GBS after three doses of tetanus toxoid separated by many years and later developed chronic inflammatory demyelinating polyneuropathy without prior vaccination [Pollard and Selby, 1978].

Infants have been reported who developed brachial neuritis after DTP immunization, and in such cases, the tetanus toxoid has been implicated [Hamati-Haddad and Fenichel, 1997]. The Institute of Medicine had concluded that a causal relationship exists in adults between tetanus toxoid and brachial neuritis based on repeated reports (class III).

Recombinant Vaccines Recombinant vaccines are genetically engineered vaccines. Hepatitis B is the only recombinant vaccine in use.

Hepatitis B Vaccine Hepatitis B vaccine is prepared by introducing DNA coding for the hepatitis B surface antigen into yeasts for cloning. The original plasma-derived vaccine is also safe and effective, and it is still used elsewhere in the world. Multiple sclerosis has been temporally associated with hepatitis B vaccine. Initial reports occurred when hepatitis B immunization became mandatory for health care workers in France [Gout et al., 1997]. A few cases of GBS, Bell’s palsy, acute cerebellar ataxia, and brachial plexitis have been reported after use of the plasma-derived vaccine [Deisenhammer et al., 1994; Shaw et al., 1988]. Controlled studies found no association between hepatitis B vaccine with new-onset multiple sclerosis in adults [Ascherio et al., 2001; Verstraeten et al., 2001] or adolescents [Sadovnik and Scheifele, 2000] or with multiple sclerosis relapse [Confavreux et al., 2001]. The Institute of Medicine has determined that the evidence is insufficient to support a cause-and-effect association [Institute of Medicine, 1993].

COMBINATION VACCINES AND ADDITIVES Most vaccination preparations involve combination vaccines. Concerns have been raised that combination vaccines (e.g., MMR) or vaccine additives (e.g., thimerosal) could elicit specific developmental disorders of childhood.

Mumps, Measles, and Rubella Vaccine and Autism A major debate arose after publication of a small gastroenterology study in Britain of a link between the MMR vaccine and autism. The study of 12 patients found gastrointestinal complaints among patients with autistic regression, 8 of whom had been vaccinated with MMR as determined retrospectively [Wakefield et al., 1998]. The authors have since retracted their conclusion of a causal link with autism [Murch et al., 2004], but not before causing broad repercussions throughout Britain and the United States. Subsequently, several studies [Chen et al., 2004; Madsen et al., 2002; Verstraeten et al., 2001] have found that MMR is not associated with pervasive developmental delay or autistic regression. The Institute of Medicine has concluded after a careful review of existing studies that data do not support a causal relationship between MMR and autism [Institute of Medicine, 2004].

Chiriboga / Neurologic Complications of Immunization

Thimerosal-Containing Vaccines and Developmental Disorders of Childhood Thimerosal is an organic mercury compound preservative that has been in use since the 1930s. It was contained in more than 30 vaccines licensed and marketed in the United States, including some of the vaccines administered to infants for protection against diphtheria, tetanus, pertussis, Haemophilus influenzae type b, and hepatitis B. Thimerosal is metabolized to ethylmercury and thiosalicylate. Theoretical concerns were raised that cumulative exposure to ethylmercury, a known neurotoxin, could have developmental side effects [Thimerosal in vaccines, 1999]. In 1999, thimerosal was removed from vaccines to trace amounts (<3 μg). Several studies [Hviid et al., 2003; Verstraeten et al., 2001] have found no association between thimerosal-containing vaccines and autism. Subsequent ecologic studies reported that after discontinuation of thimerosal-containing vaccines, rates of autism remained unchanged or increased [Madsen et al., 2003]. The Institute of Medicine has concluded that thimerosal-containing vaccines are not associated with neurodevelopmental disorders, including autism, attention-deficit–hyperactivity disorder, and developmental delay [Institute of Medicine, 2004]. REFERENCES American Academy of Pediatrics. Varicella vaccine update. American Academy of Pediatrics Committee on Infectious Diseases. Pediatrics 2000;105;136-141. American Academy of Pediatrics. The relationship between pertussis vaccine and central nervous system sequelae: Continuing assessment. American Academy of Pediatrics Committee on Infectious Diseases. Pediatrics 1996;97:279-281. Angulo JJ, Pimenta-de-Campos E, de-Salles-Gomes LF. Postvaccinial meningo-encephalitis. Isolation of the virus from the brain. JAMA 1964;187:151–153. Aragon TJ, Ulrich S, Fernyak S, et al. Risks of serious complications and death from smallpox vaccination: A systematic review of the United States experience, 1963–1968. BMC Public Health 2003;3:3–26. Arruda WO, Kondageski C. Aseptic meningitis in a large MMR vaccine campaign (590,609 people) in Curitiba, Parana, Brazil, 1998. Rev Inst Med Trop Sao Paulo 2001;3:301–302. Ascherio A, Zhang SM, Hernan MA, et al. Hepatitis B vaccination and the risk of multiple sclerosis. N Engl J Med 2001;344:327–332. Barrero PR, Grippo J, Viegas M, et al. Wild-type measles virus in brain tissue of children with subacute sclerosing panencephalitis, Argentina. Emerg Infect Dis 2003;9:1333–1336. Bloch AB, Orenstein WA, Stetler HC, et al. Health impact of measles vaccination in the United States. Pediatrics 1985;6:524. Boe E, Nyland H. Guillain-Barré syndrome after vaccination with human diploid cell rabies vaccine. Scand J Infect Dis 1980;12:231–232. Bonthius DJ, Stanek N, Grose C. Subacute sclerosing panencephalitis, a measles complication, in an internationally adopted child. Emerg Infect Dis 2000;6:377–381. Centers for Disease Control and Prevention (CDC). Subacute sclerosing panencephalitis surveillance—United States. MMWR Morb Mortal Wkly Rep 1982;31:585–588. Centers for Disease Control and Prevention (CDC). Vaccination: Use of acellular pertussis vaccines among infants and young children: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 1997;46:1–25. Centers for Disease Control and Prevention (CDC). Smallpox vaccination and adverse reactions. Guidance for clinicians [Dispatch]. MMWR Morb Mortal Wkly Rep 2003;52(RR04):1–28. Chen W, Landau S, Sham P, et al. No evidence for links between autism, MMR and measles virus. Psychol Med 2004;34:543–553. Cody CL, Baraff LJ, Cherry JD, et al. Nature and rates of adverse reactions associated with DTP and DT immunizations in infants and children. Pediatrics 1981;68:650–659.

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Confavreux C, Suissa S, Saddier P, et al, for the Vaccines in Multiple Sclerosis Study Group. Vaccinations and the risk of relapse in multiple sclerosis. Vaccines in Multiple Sclerosis Study Group. N Engl J Med 2001;344:319–326. Cowan LD, Griffin MR, Howson CP, et al. Acute encephalopathy and chronic neurological damage after pertussis vaccine. Vaccine 1993;11:1371–1379. Deisenhammer F, Pohl P, Bösch S, et al. Acute cerebellar ataxia after immunisation with recombinant hepatitis B vaccine. Acta Neurol Scand 1994;89:462–463. Fenichel GM. Assessment: Neurologic risk of immunization. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 1999;52:1546–1552. Fenichel GM. Neurological complications of immunization. Ann Neurol 1982;12:119–128. Gangarosa EJ, Galazka AM, Wolfe CR, et al. Impact of anti-vaccine movements on pertussis control: The untold story. Lancet 1998;351:356–361. Geier DA, Geier MR. An evaluation of serious neurological disorders following immunization: A comparison of whole-cell pertussis and acellular pertussis vaccines. Brain Dev 2004;26:296–300. Guess HA, Broughton DD, Melton LJ, et al. Population-based studies of varicella complications. Pediatrics 1986;78:723–727. Gout O, Théodorou I, Liblau R, et al. Central nervous system demyelination after recombinant hepatitis B vaccination: Report of 25 cases. Neurology 1997;48 (Suppl 3):A424. Griffin MR, Ray WA, Mortimer EA, et al. Risk of seizures after measlesmumps-rubella immunization. Pediatrics 1991;88:881. Hamati-Haddad A, Fenichel GM. Brachial neuritis following routine childhood immunization for diphtheria, tetanus, and pertussis (DTP): Report of two cases and review of the literature. Pediatrics 1997;99:602–603. Hemachudha T, Griffin DE, Giffels JJ, et al. Myelin basic protein as an encephalitogen in encephalomyelitis and polyneuritis following rabies vaccination. N Engl J Med 1987;316:369–374. Health Resources and Services Administration (HHS). Smallpox Vaccine Injury Compensation Program: Administrative implementation. Interim final rule. Fed Regist 2003;68:70079–70106. Hurwitz ES, Schonberger LB, Nelson DB, et al. Guillain-Barré syndrome and the 1978–1979 influenza vaccine. N Engl J Med 1981;304:1557–1561. Howe CJ, Johnston RB, Fenichel GM. Detecting and responding to adverse events following vaccination: Workshop summary. In: Institute of Medicine Vaccine Safety Forum: Summary of two workshops. Washington, DC: National Academy Press, 1997. Hviid A, Stellfeld M, Wohlfahrt J, et al. Association between thimerosal-containing vaccine and autism. JAMA 2003;290:1763–1766. Institute of Medicine. Adverse effects of pertussis and rubella vaccines. Washington, DC: National Academy Press, 1991. Institute of Medicine. Adverse events associated with childhood vaccines: Evidence bearing on causality. Washington, DC: National Academy Press, 1993. Institute of Medicine. DPT vaccine and chronic nervous system dysfunction: A new analysis. Washington, DC: National Academy Press, 1994. Institute of Medicine. Immunization safety review: Influenza vaccine and neurological complications. Washington, DC: National Academy Press, 2003. Institute of Medicine. Immunization safety review: Vaccine and autism. Washington, DC: National Academy Press, 2004. Jin L, Beard S, Brown DWG, et al. Characterization of measles virus strains causing SSPE: A study of 11 cases. J Neurovirol 2002;8:335–344. Kaga K, Ichimura K, Ihara M. Unilateral total loss of auditory and vestibular function as a complication of mumps vaccination. Int J Pediatr Otorhinolaryngol 1998;43:73–75. Kinnunen E, Färkkilä M, Hovi T, et al: Incidence of Guillain-Barré syndrome during a nationwide oral poliovirus vaccine campaign. Neurology 1989;39:1036. Kurata T, Aoyama Y, Kitamura T. Demonstration of vaccinia virus antigen in brains of postvaccinial encephalitis cases. Jpn J Med Sci Biol 1977;30:137–147. Levin MJ, Gershon AA, Weinberg A, et al, for the AIDS Clinical Trials Group 265 Team. Immunization of HIV-infected children with varicella vaccine. J Pediatr 2001;139:305–310.

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Lloyd JC, Haber P, Mootrey GT, et al., for the VAERS Working Group. Adverse event reporting rates following tetanus-diphtheria and tetanus toxoid vaccinations: Data from the Vaccine Adverse Event Reporting System (VAERS), 1991–1997. Vaccine 2003;21:3746–3750. Madsen KM, Hviid A, Vestergaard M, et al. A population-based study of measles, mumps, and rubella vaccination and autism. N Engl J Med 2002;347:1477–1482. Madsen KM, Lauritsen MB, Pedersen CB, et al. Thimerosal and the occurrence of autism: Negative ecological evidence from Danish population-based data. Pediatrics 2003;112:604-606. Miller AE, Morgante E, Buchwald LY, et al. A multicenter, randomized, double-blind, placebo-controlled trial of influenza immunization in multiple sclerosis. Neurology 1997;48:312–314. Morton-Kute L. Rubella vaccine and facial paresthesias [Letter]. Ann Intern Med 1985;102:563. Moore DL, Le Saux N, Scheifele D, et al., Members of the Canadian Paediatric Society/Health Canada Immunization Monitoring Program Active (IMPACT). Lack of evidence of encephalopathy related to pertussis vaccine: Active surveillance by IMPACT, Canada, 1993–2002. Pediatr Infect Dis J 2004;23:568–571. Murch SH, Anthony A, Casson DH, et al. Retraction of an interpretation. Lancet 2004;363:7506. Mutsch M, Zhou W, Rhodes P, et al. Use of the inactivated intranasal influenza vaccine and the risk of Bell’s palsy in Switzerland. N Engl J Med 2004;350:896–903. Nathanson N, Martin JR. The epidemiology of poliomyelitis: Enigmas surrounding its appearance, epidemicity, and disappearance. Am J Epidemiol 1979;110:672–692. Perdrau JR. The histology of post-vaccinal encephalitis. J Pathol Bacteriol 1928;31:17–32. Pollard JD, Selby G. Relapsing neuropathy due to tetanus toxoid. J Neurol Sci 1978;37:113. Rantala H, Cherry JD, Shields WD, et al. Epidemiology of Guillain-Barré syndrome in children: Relationship of oral polio vaccine administration to occurrence. J Pediatr 1994;124:220–223. Ray P, Black S, Shinefield H, et al. Risk of chronic arthropathy among women after rubella vaccination. JAMA 1997;278:551–556. Rosenthal S, Chen R, Hadler S. The safety of acellular pertussis vaccine vs whole-cell pertussis vaccine: A postmarketing assessment. Arch Pediatr Adolesc Med 1996;150:457–460. Sadovnik AD, Scheifele DW. School-based hepatitis B vaccination programme and adolescent multiple sclerosis. Lancet 2000;355:549–550. Slater PE, Tirtsa B, Fogel A, et al. Absence of an association between rubella vaccination and arthritis in underimmune postpartum women. Vaccine 1995;13:1529–1532.

Shaw FE, Graham DJ, Guess HA, et al. Postmarketing surveillance for neurological adverse events reported after hepatitis B vaccination. Am J Epidemiol 1988;127:337–352. Stewart BJ, Prabhu PU. Reports of sensorineural deafness after measles, mumps, and rubella immunization. Arch Dis Child 1993;69:153–154. Sugiura A, Yamada A. Aseptic meningitis as a complication of mumps vaccination. Pediatr Infect Dis J 1991;10:209–213. Sutter RW, Prevots DR. Vaccine-associated paralytic poliomyelitis among immunodeficient persons. Infect Med 1994;11:426,429–430, 435–438. Thimerosal in vaccines: A joint statement of the American Academy of Pediatrics and the Public Health Service. MMWR Morb Mortal Wkly Rep 1999;48:563–565. Tingle AJ, Chantler JK, Pot KH, et al. Postpartum rubella immunization: Association with development of prolonged arthritis, neurological sequelae, and chronic rubella viremia. J Infect Dis 1985;152:606–612. Tullu MS, Rodrigues S, Muranjan MN, et al. Neurological complications of rabies vaccines. Indian Pediatr 2003;40:150–154. Vestergaard M, Hviid A, Madsen KM, et al. MMR vaccination and febrile seizures: Evaluation of susceptible subgroups and long-term prognosis. JAMA 2004;21:351–357. Verstraeten T, DeStefano F, Jackson L, et al. Risk of demyelinating disease after hepatitis B vaccination—West Coast, United States, 1995–1999. Paper presented at the 50th Annual Epidemic Intelligence Service Conference, Atlanta, GA, 2001. Wakefield AJ, Murch SH, Anthony A, et al. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet 1998;351:637–641. Wharton M, Strikas RA, Harpaz R, et al. Recommendations for using smallpox vaccine in a pre-event vaccination program. Supplemental recommendations of the Advisory Committee on Immunization Practices (ACIP) and the Healthcare Infection Control Practices Advisory Committee (HICPAC). MMWR Morb Mortal Wkly Rep 2004:52(RR-7):1–16. White CJ, Kuter BJ, Hildebrand CS, et al. Varicella vaccine (Varivax) in healthy children and adolescents: Results from clinical trials, 1987 to 1989. Pediatrics 1991;87:604–610. Wittler RR, Veit BC, McIntyre S, et al. Measles revaccination response in a school-age population. Pediatrics 1991;88:1024–1030. Zangwill KM, Greenberg DP, Chiu CY, et al. Safety and immunogenicity of a heptavalent pneumococcal conjugate vaccine in infants. Vaccine 2003;21:1894–1900. Zangwill KM. Belshe RB. Safety and efficacy of trivalent inactivated influenza vaccine in young children: A summary for the new era of routine vaccination. Pediatr Infect Dis J 2004;23:189–197.

CHAPTER 92

Pediatric Neurorehabilitation Medicine Ann H. Tilton and Maria B. Weimer

Within the scope of pediatric neurorehabilitation, distinct diseases can produce specific complications; these complications, however, can also occur in association with many other disorders. For example, spasticity from injury to the upper motor neuron unit can develop in many neurologic disorders in children. Several of these complications can be quite severe and potentially life-threatening—for example, autonomic dysreflexia, deep vein thrombosis, and heterotopic ossification. In this chapter the major conditions encountered in pediatric neurorehabilitation are reviewed, as well as complications seen in these and other common disorders. Additional information is available in several recently published reference texts [DeLisa and Gans, 2005; Dobkins, 2003; Lazar, 1998; Umphred, 2001].

COMMON CONDITONS CAUSING BRAIN INJURY IN CHILDREN Traumatic Brain Injury Traumatic brain injury is a common cause of morbidity and mortality in adults and children. The incidence of traumatic brain injury is 180 per 100,000 in the general population, with 70 per 100,000 considered moderate to severe brain injury (see Chapter 62). Childhood traumatic brain injury results in an estimated 3000 deaths, 29,000 hospitalizations, and 400,000 emergency department visits annually in the United States (children 0–14 years old) [Thurman, 2000, 2001]. Males and adolescents ages 15 to 24 represent the largest group of patients. Although a majority of persons with traumatic brain injury are considered mildly affected, symptoms nonetheless interrupt daily activities [Dombovy, 1997; Thompson and Irby, 2003]. The definition of mild, moderate, and severe head injury is classically based on the Glasgow Coma Scale score or the duration of post-traumatic amnesia (the lack of memory for ongoing events) [Thompson and Irby, 2003]. The Glasgow Coma Scale score examines three variables: eye opening, motor response, and verbal response. A score of 8 or less indicates severe injury, 9 to 12 moderate injury, and 13 to 15 mild head injury. Post-traumatic amnesia is considered to be mild if the duration is less than 24 hours, moderate if 1 to 7 days in duration, and severe if lasting 8 days or longer [Levin et al., 1982]. A complicating factor in determining the consequences of traumatic brain injury is that persons with preexisting behavioral or cognitive difficulty or with prior head injury, are more likely to have a traumatic brain injury [Dombovy, 1997; Luis and Mittenberg, 2002]. In children, the cause of traumatic brain injury is agedependent. Nonaccidental trauma is more common in children younger than 2 years of age. In children younger than 5 years of age, falls predominate, whereas motor vehicle and

bicycle accidents are more common in children ranging in age from 5 to 14 years [Goldstein and Levin, 1987]. The pathophysiology of traumatic brain injury involves a complex combination of forces that has been a subject of substantial debate [Drew and Drew, 2004]. Immediate injury to the brain is followed by metabolic derangements and secondary injury. In addition, there are direct impact injuries and injuries related to transitional forces from acceleration and deceleration. These forces may be linear or rotational. In the classic theory of coup-contrecoup injury, the hard surfaces of the skull cause contusional injury, and cavitation or vaporization of the brain also occurs as negative–pressure gradients form in the opposite poles. Shearing forces are responsible for diffuse axonal injury. In this setting, the patient may not demonstrate major abnormalities on neuroimaging yet clinically will have a very significant head injury with immediate loss of consciousness. The metabolic cascade that follows diffuse axonal injury progresses for hours and is responsible for the often-associated prolonged coma. Following head injuries, regardless of the mechanism, there is release of excitatory neurotransmitters that contribute to the injury [Dombovy, 1997]. The pathophysiology of traumatic brain injury is reviewed in detail in Chapter 62.

Medical Issues Although the acute issues are largely resolved before the patient is transferred for rehabilitation, there is still a need to ensure that all aspects of general medical care are provided. Patients with traumatic brain injury often have non-neurologic injuries that may be obscured by the patient’s inability to indicate discomfort. Bone scans have been helpful in detecting fractures that require orthopedic evaluation [Heinrich et al., 1994]. During the rehabilitation process, patients with traumatic brain injury are at risk for other complications of their injuries. Tone abnormalities and spasticity due to upper motor neuron lesions, as well as the development of deep vein thrombosis and heterotopic ossification, can develop and are a major focus of rehabilitation. Before discharge, repeat neuroimaging studies should be considered. This repetition provides follow-up of known abnormalities such as previous hemorrhage or diffuse axonal injury. Additionally, chronic subdural hematomas may develop and necessitate intervention if symptoms of increased intracranial pressure are present. A plateau in improvement may suggest the development of hydrocephalus that also requires surgical intervention and may affect long-term outcome.

Behavioral Aspects Children who have had a traumatic brain injury often have behavioral disturbances, even when their intelligence has

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not been affected, although in most individuals the behavioral abnormalities correlate with the severity of injury. Posttraumatic amnesia is helpful in gauging the probability of future behavioral problems. With post-traumatic amnesia of less than 1 week duration, permanent and more serious behavioral problems are less frequent than in patients in whom the duration of amnesia is longer. Frontal lobe injury commonly results in emotional dysregulation and cognitive abnormalities [Dombovy, 1997]. Frequently, motor recovery far exceeds behavioral recovery. Other psychiatric disorders have been described following head injury in children, including depression, mania, and anxiety. Agitation is an expected component of recovery and may be difficult to control. Providing structure and familiar surroundings is helpful as is frequently reorienting the patient to the environment, family members, and others. Close medical and rehabilitation supervision is critical in assessing and managing these problems. Medications most often prescribed by head injury specialists include betablockers, carbamazepine, and tricyclic antidepressants. Sedating medications such as the benzodiazepines and haloperidol are used much less frequently [Fugate et al., 1997]. Although stimulants are recommended in the setting of attention-deficit disorder, antipsychotic medications are not routinely recommended for children unless there is an established diagnosis of psychosis (although they are now more commonly being used) [Dombovy, 1997]. A major difficulty for many patients is memory loss. Families should be counseled that long-term memory is better preserved. Short-term memory is a significant issue in the rehabilitation setting and in the community as the patient tries to incorporate new information and strategies. Another wellrecognized cognitive problem is the onset or accentuation of an attention-deficit disorder following injury, a complication that can be improved with the use of stimulant medications such as methylphenidate. Use of these medications is reviewed in Chapter 36. Clonidine also has been employed and may have the additional benefit of evening sedation that will help with sleeping. There are few well-controlled studies to help guide clinicians in the optimal choices of medications to use for the different types of neuropsychiatric problems that occur in children with traumatic brain injury [Dombovy, 1997].

Post-traumatic Seizures A question that frequently arises is whether it is appropriate to continue antiepileptic drugs in children with head injuries. Recommendations in the literature address this issue in adults. If an individual does not have a seizure during the first week after injury, the risk of developing seizures approaches 1% (see Chapter 62). If a seizure is witnessed within the first week, the risk for lifetime occurrence increases to 25%. Structural lesions such as depressed skull fractures, open injuries, hematomas, and brain contusions also increase the risk [Dombovy, 1997]. Children overall do have a higher risk of early post-traumatic seizures than adults but nevertheless have a good prognosis for resolution of the seizures. Five percent of all children have a focal or major motor seizure in the first week after head trauma. The long-term risk of seizure recurrence is 17% within 4 years after injury [Rosman et al., 1979]. Data about adults support the recommendation that seizure prophylaxis does not need to be continued past the first

few weeks in individuals who remain seizure-free. One practice parameter addressed post-traumatic seizures in adults with severe traumatic brain injury and found that phenytoin prophylaxis was effective in decreasing the risk of early posttraumatic seizures but that prophylaxis with antiepileptic drugs was probably not effective in decreasing the risk of late posttraumatic seizures [Chang and Lowenstein, 2003]. It was recommended that additional investigations were needed to evaluate patients with milder forms of traumatic brain injury for the risk of epilepsy and the need for antiepileptic drugs. In addition, use of the newer antiepileptic drugs for the treatment of post-traumatic seizures, the role of the EEG, and the relevance of these findings to children were also reviewed. EEGs are helpful in identifying focal epileptiform abnormalities and, if they are present, use of carbamazepine and valproic acid should be considered if the decision to treat is recommended [Hauser, 1990].

Rehabilitation Approach Rehabilitation of children with traumatic brain injury is similar to that of adults. Therapy is focused on addressing functional skills and the use of strategies or retraining to perform daily living skills, as well as to advance mobility. Whereas the focus in adult patients is on reentering the workplace, the focus in children is on returning to school. An extensive team evaluation of children regarding motor needs along with behavioral, cognitive, and communication requirements is important as they make the transition from the rehabilitation facility to the home and school setting. School personnel need to be included in this transitional reentry process. Support and education of all persons involved in the patient’s life are vital, because the patient’s relationship with family and peers is frequently dramatically altered by the injury.

Prognosis Prognosis directly correlates with the severity of injury. Several factors have been cited as prognostic risk factors after major head injury in childhood. These include a posttraumatic vigilance disturbance for longer than 24 hours, a Glasgow Coma Scale score less than 7, increased intracranial pressure with cerebral perfusion pressure less than 50 mm Hg, age younger than 2 years at the time of the injury, physical abuse, and the development of posttraumatic epilepsy [Kirshblum et al., 2003].

Spinal Cord Injury The annual incidence of spinal cord injuries in the United States is estimated to be 30 to 40 new cases per million individuals. About 3% to 5% of cases each year occur in children younger than 15 years of age [Price et al., 1994]. The male-to-female ratio of patients is 4:1 in the general population, but in younger age groups the ratio is approximately 1.5:1 [Zidek and Srinuvasan, 2003]. Chapter 66 contains a detailed discussion of spinal cord injuries in children.

Etiology and Pathophysiology Motor vehicle accidents are the most frequent cause of spinal cord injury, although injuries associated with sports

Tilton and Weimer / Pediatric Neurorehabilitation Medicine

activities or related to violent behavior are becoming more common. There has been an increase in violent behaviors as a cause of spinal cord injury in children during the past 20 years from approximately 10% to more than 35% [Zidek and Srinuvasan, 2003]. Spinal cord injury without radiologic abnormality is uniquely seen in children usually younger than age 10 because of the flexibility of the ligaments and lack of stability of the spine. The most sensitive test in this setting is magnetic resonance imaging [Hamilton and Myles, 1992].

Clinical Evaluation Clinical evaluation of a patient with a suspected spinal cord injury is based on sensory and motor evaluation. Scores are generated by the responses elicited from 28 dermatomes for pinprick and dull and light touch based on a 3-point scale, with a motor strength grading of 10 key muscles bilaterally—5 in the upper extremities and 5 in the lower extremities on each side. The neurologic level is the most caudal level at which sensory and motor responses are evident bilaterally. The American Spinal Injury Association (ASIA) criteria provide international standards for neurologic classifications for spinal cord injuries based on levels A to E (Table 92-1). Key muscle groups, when injured and weak, are helpful in determining the level of spinal cord injury (Table 92-2). Additional information about using the neurologic examination to localize spinal cord injury is provided in Chapters 2 to 4. Outcome after spinal cord injury is based on the functional motor level. Other variables such as concomitant injuries, the patient’s medical history, and degree of home and social support also affect outcome. Regardless of whether damage to the spinal cord is complete or incomplete, TABLE 92-1 American Spinal Injury Association Classification of Spinal Cord Injury A Complete: No motor or sensory function preserved, including sacral segments S4-S5. B Incomplete: Sensory but no motor function below the neurologic level, including the sacral segments S4-S5. C Incomplete: Motor function is preserved below the neurologic level, and more than half of the key muscles have a muscle grade <3. D Incomplete: Motor function is preserved below the neurologic level, and at least half of the key muscles below the neurologic level have a muscle grade >3. E Motor and sensory functions are normal

TABLE 92-2 Key Muscle Groups for Determining the Spinal Level of Injury SPINAL LEVEL

KEY MUSCLES

C5 C6 C8 L2 L3 L5 S1

Elbow flexors Wrist extensors Finger flexors Hip flexors Knee extensors Long toe extensors Ankle plantar flexors

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the majority of recoveries occur during the first 6 months following injury [Yarkony, 1997]. Individuals with high cervical injuries (C1-C4) almost always require ventilatory support and adaptive equipment, such as sip-and-puff switches, mouth sticks, and head controls. A power wheelchair is needed in addition to a manual backup wheelchair. The patient with a C5 lesion has the capability of having functional arm flexion because of use of the biceps muscles. Therapists are active in strategies to increase independence and function that are often facilitated with orthotics. Children can be trained so that they can feed themselves and use communication devices. Control of a power wheelchair is possible with use of a joystick or other hand-held controls. A reclining wheelchair is helpful because of the need for pressure relief to prevent skin breakdown. In patients with a C6 spinal lesion, radial wrist extension expands functional use. Orthotics are important to improve tenodesis for independence. Children with a C6 lesion are often able to feed themselves and perform some dressing activities. Power wheelchairs are valuable, and manual wheelchairs can be independently propelled. Patients with injuries at the C7-C8 level have adequate arm extension and improved hand function, which is helpful for improving self-reliance. This functionality is critical for mobility and being able to transfer, as well as for bowel and bladder training programs. The ability to ambulate improves in patients with injury at lower levels [Yarkony, 1997]. The ASIA motor score has been used to predict ambulation as early as 1 month after injury [Waters et al., 1994]. If there is hip or knee extension of at least a trace or of poor quality, the potential for ambulation at 1 year is good. If patients demonstrate incomplete paraplegia below T12, they have a 20% chance of becoming a community ambulator using orthotic devices [Yarkony, 1997]. In some individuals, devices such as reciprocating gait orthoses may be helpful on a limited basis. Because of the high energy and time consumption needed for ambulation, weaker patients often prefer to use wheelchairs for community activities and reserve ambulation for shorter distances. It is difficult emotionally for the child and family to accept the loss of being able to walk independently. A wheelchair may be more acceptable to children, who often place a high priority on keeping up with friends, and they may tire of the limitations imposed by orthotic devices. Major concerns in the medical care of patients with spinal cord injury are spasticity, deep vein thrombosis, autonomic dysreflexia, and heterotopic ossification. Because of the significance they hold in the care of children with spinal cord injuries, they are discussed in detail later in this chapter. Other medical care issues that must be addressed include pulmonary function, hypercalcemia, bowel and bladder management, avoidance of pressure ulcers, and prevention of joint contractures and scoliosis. Pulmonary complications are seen acutely and also chronically. In patients with injury above the C3 level, apnea may occur and ventilatory support is required. With high cervical lesions, diaphragm function is partially or completely impaired and the intercostal muscles are needed to assist during inspiration. If the patient has an injury at the C6-C7 level, weaning from a ventilator is usually possible [Yarkony, 1997]. Hypercalcemia is seen in almost 25% of patients 1 to 12 weeks after injury and is due to bone resorption [May-

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nard, 1986]. Clinically, nausea, vomiting, and lack of appetite occur, and calcium levels frequently are higher than 12 mg/dL. Diuretics are commonly used to treat this problem [Meythaler et al., 1996; Tori and Hill, 1978]. Bladder dysfunction is another common complication, and anticipatory care of the problems associated with a neurogenic bladder is extremely important [Decter and Bauer, 1993; Zidek and Srinuvasan, 2003]. During the acute period of spinal shock, the bladder is atonic or hypotonic, a phenomenon that persists for the first 6 to 12 weeks after injury. As this resolves, bladder tone increases to a more spastic state. Uninhibited contractions are seen and detrusor sphincter dyssynergy is common. This lack of coordination results in decreased bladder emptying capacity, high intravesicular pressures, and damage to the upper urinary tract. Urodynamic evaluation is important, as is recognition that there will be a transition from spinal shock to spasticity. Initially, indwelling catheters are helpful but transition to a program of intermittent catheterization every 4 to 6 hours is much preferred once the patient is stable and is weaned from intravenous fluids. There are numerous advantages to intermittent catheterization, including the reduced risk of urinary tract infection. Colonization of the bladder is common but usually should not be treated unless the patient has symptoms of a urinary tract or systemic infection. Symptoms associated with a neurogenic bladder may benefit from treatment with anticholinergic medications such as oxybutynin (in children 1 to 5 years, 0.2 mg/kg orally two to four times daily; in children older than 5 years, 5 mg two to three times daily to a maximum of 15 mg/day) or imipramine (in children 6 to 12 years, 10 to 50 mg daily; in children older than 12 years, 10 to 75 mg/day). Botulinum toxin is used to alleviate increased bladder pressure related to sphincter dyssynergy [Dykstra and Sidi, 1990]. In patients who are unable to tolerate these medications or who have persistent bladder overdistention, high voiding pressures, or progressive upper urinary tract deterioration due to persistent vesicoureteral reflux or poor bladder emptying, urologic surgical procedures may be required. A bowel program should be instituted. Typically, this requires the use of glycerin suppositories every other day, digital stimulation, and administration of a stool softener and, at times, laxative agents. To prevent formation of sacral decubiti, which occur in approximately a third of patients, pressure relief is necessary, and the individual and family must be educated about the importance of avoiding this complication. As a consequence of muscle imbalance and orthopedic injuries that may accompany spinal cord injury, children are at high risk for scoliosis. If a child sustains a spinal injury before skeletal maturation occurs, the probability of developing scoliosis approaches almost 100%, with 70% of children requiring surgery [Dearoff et al., 1990]. Scoliosis needs to be radiographically monitored every 6 months and orthopedic consultation is recommended. Orthotics are often used when the spinal curve is less than 40 degrees, but spinal fusion is usually required once the child is skeletally mature (older than10 years of age) and the spinal curve is greater than 35 to 40 degrees [Massagli, 2000]. Another common concern that needs to be evaluated and treated is the pain that often accompanies spinal cord injury. This includes radicular pain, musculoskeletal pain, dys-

esthesias, and physical discomfort such as that related to wheelchair positioning. Multiple medications have been recommended, of which the most recent addition is gabapentin [Zidek and Srinuvasan, 2003].

Orthotics and Wheelchair Requirements Children with injuries below C6 often have recovery of hand function, and splints may not be necessary [Zidek and Srinuvasan, 2003]. However, wrist extension splints are recommended when there is extensor muscle weakness and if the patient is unable to do a pincer grasp. Adaptations include use of mobile arm supports and universal cuffs for activities of daily living skills. Walkers are helpful for lowerextremity weakness. A swivel walker provides a substantial amount of support in the trunk area and allows the patient to have a swivel gait but does limit the patient to a standing position. A parapodium walker provides truncal support and a swivel gait and also allows the patient to sit. The Louisiana State University (LSU) reciprocating gait orthosis can be used to provide a swing-through gait pattern in patients who have injury at a lower level (Fig. 92-1). It can be used on uneven surfaces but does require independent leg movements. Ankle-foot orthoses are appropriate for patients with paraplegia due to lesions below T6. It was reported that at least 10 degrees of hip extension and 5 to 10 degrees of ankle dorsiflexion are needed to utilize them appropriately. Ankle-foot orthoses are frequently used to assist ambulation in a child with an L5 or lower injury and also for support and positioning of the foot in patients with injuries at higher levels. There are substantial psychologic benefits for a child to be at eye level with peers. However, because of increased

FIGURE 92–1. The Louisiana State University (LSU) reciprocating gait orthosis.

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energy requirements needed for the use of complicated orthotics, children often choose to use the most efficient means of transportation, the manual or power wheelchair. A good wheelchair is expensive and often needs multiple modifications to meet current and anticipated needs of the patient. Typically, a manual wheelchair can be used by children when they reach 18 to 24 months of age, and a power wheelchair can be operated quite well by cognitively appropriate children as young as 24 months. A child with C6 level or lower injuries should be able to use a light manual wheelchair, whereas children or adults with injuries above C6 will require power wheelchairs for mobility.

deficits in patients with cerebral palsy [Nelson and Ellenberg, 1982]. Traditionally, subtypes of cerebral palsy are defined by the pattern of motor impairments that are the main focus as the clinician addresses patient independence. There are now more treatment options to address spasticity, dystonia, and other motor disorders. Certain deficits that affect motor development and influence rehabilitation occur more commonly in children with cerebral palsy [Russman et al., 1997]. The contribution to impairment by the underlying weakness in addition to the symptoms of tone abnormalities cannot be underestimated (Table 92-3).

Cerebral Palsy

Physical Therapy

Comprehensive rehabilitation of children with cerebral palsy integrates the contributions of multiple care providers, the educational and recreational setting, the family, and, most important, the child. The common goal is to maximize the functional and emotional independence of the child and facilitate the steps necessary to accomplish these goals. In clinical practice, cerebral palsy is often a term of convenience, defining a clinical condition [Nelson and Ellenberg, 1978]. Inherent in the diagnosis is that the disorder is static and not progressive. This statement is not to imply that the child’s clinical course is not changing, because for most children this evolves to meet new needs, demands, and associated complications. Chapter 20 reviews aspects of the epidemiology, etiology, diagnosis, and management of children with cerebral palsy. Recent studies have suggested that neurorehabilitation has the potential to affect subsequent brain development. Studies in animal models and humans have found that experience such as specific motor training before the age of 12 years results in increased cortical representation and differentiation [Farmer et al., 1991; Gingold and Iannaccone, 1998]. The developing nervous system may have greater capability for repair, or may possess alternative mechanisms related to innervation and plasticity. This has been suggested by studies that have found spontaneous resolution of motor

Physical therapy is required to improve muscle function and activities of daily living in children with cerebral palsy as well as other central nervous system disorders such as traumatic brain injury. Regular stretching of involved muscles to maintain full range of motion and prevention of contractures is necessary and, in addition to improving function, can reduce pain. Stretching of the relaxed muscle at least 1 minute every 12 hours is necessary for muscles to grow and preserve elasticity [Reimers, 1991]. Children with mild and moderate disabilities normally are active and want to move, and with parental education many range-of-motion exercises can be met by daily recreational activities [Russman, 1986]. However, impairments may lead to use of compensatory strategies that minimize movement of the affected joint. As a result, the muscles become overcontracted and relatively shorter. This problem is functionally magnified as the bones grow and may increase the potential for a fixed contracture. To minimize this potential, regular stretching of all affected limbs is recommended. Stretching can reduce the severity of tone for several hours, providing a short-term, but not longterm, antispasticity action. Physical therapy may encompass a regular exercise program, hydrotherapy, horseback riding, use of a handpropelled tricycle (Fig. 92-2), and other modalities, including cold, heat, biofeedback, and electrical stimulation. The intensity of physical therapy needed to maximize gains has

TABLE 92-3 Specific Motor and Functional Deficits in Children with Cerebral Palsy MOTOR DEFICIT

FUNCTIONAL DEFICIT

Loss of selective motor control

Impairment in the development of sequential motor skills with difficulty in individualizing and coordinating motor movements Persistent abnormal developmental reflexes interfere with appropriate movements Multiple treatments focus on decreasing tone to allow more functional growth and balance Orthotics and mobility devices may be required

Abnormal muscle tone influenced by abnormal body posture Imbalance between muscle agonists and antagonists Symptoms due to impaired balance

Adapted from Russman BS, Tilton A, Gormley ME Jr. Cerebral palsy: A rational approach to a treatment protocol, and the role of botulinum toxin in treatment. Muscle Nerve Suppl 1997;6:S181.

FIGURE 92–2. A hand-propelled tricycle used for exercise activities and mobility.

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been the subject of several studies. Bower and colleagues [2001] compared the effects of the usual amount of physical therapy to intensive therapy (1 hour per day, 5 days per week) in children between ages 3 and 12 years over a 6-month period. Differences in function or performance between groups were not found. Ankle-foot orthoses are commonly used to treat dynamic equinovarus foot deformities in children with cerebral palsy. Gait analysis studies have shown that ankle-foot orthoses can reduce ankle excursion and increase the dorsiflexion angle at foot strike but may not improve stride length or walking speed [Carlson et al., 1997]. Ankle-foot orthoses can also improve sit-to-stand transition in preambulatory children whose standing is impaired by equinovarus foot deformities [Wilson et al., 1997]. In patients with spastic diplegia, posterior balance is a major problem. If balance can be maintained while the patient leans forward, independent walking is possible. If anterior balance is also abnormal, crutches are required. If lateral balance is abnormal, a walker is usually necessary [Russman et al., 1997]. Children with spasticity frequently can walk better with a reverse walker, which offers increased speed while helping with posture [Gingold and Iannaccone, 1998]. Other equipment is also appropriate. Standing frames place the non–weight-bearing child in an appropriate position to help prevent contractures. Inhibitive or serial casting is used for immobilization or prolonged passive stretch. In a child with increased tone and contractures, frequent revision of the casts allows stretching of the contracture to the desired angle. Then the cast can be bivalved and used as a splint to prevent or slow the rate of recurrence. An anklefoot orthosis may be fabricated to maintain the new range of motion. Serial casting is now frequently used in conjunction with botulinum toxin to treat spasticity and associated contractures.

Treatment Planning Caregivers play a central role in the day-to-day management of children with motor impairment and should participate in each stage of goal setting, treatment planning, and plan modification. Additionally, the age of the child, the presence of coexistent conditions such as seizures or cognitive impairment, and the ability of the family to implement treatments at home, continue ongoing outpatient care, and manage the financial costs of care and other issues need to be balanced in determining the best treatment.

MEMBERS OF THE NEUROREHABILITATION TEAM Physical Medicine and Rehabilitation Physicians Physical medicine and rehabilitation physicians play an important role in the evaluation and management of children with acquired brain injury as well as those with disorders that are genetic or due to other conditions. These specialists provide integrated care in the treatment of neurologic and musculoskeletal disabilities and focus on the restoration of function in patients with problems ranging from simple physical mobility issues to those with complex cognitive

involvement [DeLisa and Gans, 2005]. When treating patients with severe physical problems, physiatrists often serve as leaders of an interdisciplinary team that may include medical professionals from multiple disciplines as well as allied health professionals such as physical and occupational therapists, speech pathologists, vocational counselors, psychologists, and social workers. The American Academy of Physical Medicine and Rehabilitation is the national medical society representing more than 7000 physical medicine and rehabilitation physicians; its website is http://www.aapmr.org/.

Child Neurologists Child neurologists frequently are actively involved in the care of children with rehabilitation needs, and in some centers the child neurologist functions as the primary neurorehabilitationist. Child neurologists frequently assist in the assessment of patients to help determine long-term prognosis, to determine whether patients may have epilepsy, and often to provide input into use of medications to manage some of the complications that infants and children with rehabilitation needs have. The Child Neurology Society is the national medical society representing more than 1500 child neurologists; its website is http://www.childneurologysociety.org/.

Physical Therapists Physical therapists are very active in the care of children with developmental issues and gross motor delays and have special skills in the selection and modification of orthotics and mobility devices [Campbell et al., 2000]. In addition to contributing emotional support and education of caregivers and patients, therapists emphasize the importance of regular stretching to maintain full range of motion and prevention of contractures. The American Physical Therapy Association (APTA) is the national professional organization representing more than 63,000 members; its website is www.apta.org.

Occupational Therapists Occupational therapists can help children with deficits in fine motor control, feeding, oral motor function, and activities of daily living. They can help to improve functional deficits related to dressing, eating, and upper extremity function and can also assist with modification of equipment to improve patients’ access to their environment [Neistadt and Crepeau, 1998; Pedretti and Early, 2001]. Occupational therapists have roles similar and complementary to those of physical therapists in care of the child younger than 3 years, in which the focus is mainly on family support and the child’s development of appropriate postural control and patterns of movement. The American Occupational Therapy Association is the national professional organization in the United States, with approximately 35,000 occupational therapists; its website is http://www.aota.org.

Speech Therapists and Audiologists Speech therapists and audiologists are important in ensuring the maximum independence of the child by developing communication skills, including both verbal skills and the use of alternative modalities [Owens et al., 2003]. Often children’s

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cognitive abilities are underestimated because of their inability to use traditional testing techniques. Communication boards, sign language, and computer modifications may offer new ways to communicate. Audiologic screening is important to ensure that hearing impairment is not an additional contributing factor to language delay. The American Speech-Language-Hearing Association is the national professional and scientific association of more than 115,000 speech-language pathologists, audiologists, and scientists in the United States and internationally; its website is http://www.asha.org/.

Other Team Members Psychologists can provide insight into the appropriate educational setting that a child needs and can help the child and family with counseling. Psychologists may address the impact that the diagnosis has on the family and the multiple transitions that the children experience as they become teenagers and young adults. The American Psychological Association, with more than 150,000 members, is the professional organization that represents psychology in the United States and internationally (http://www.apa.org/). The National Association of School Psychologists is another active organization of psychologists involved in the care of children (http://www.nasponline.org/). Social workers are important in identifying resources in the community to help with therapy, equipment, and funding. Music and recreational therapists utilize leisure activities and music to fulfill the therapeutic goals identified for the patient by the rehabilitation team. The National Association of Social Workers, the national organization of professional social workers, has more than 153,000 members; its website is http://www.naswdc.org/.

SELECTED ASPECTS OF NEUROREHABILITATION Autonomic Dysreflexia Autonomic dysreflexia is the acute and potentially lifethreatening syndrome of excessive and uncontrolled sympathetic output that occurs in patients with spinal cord injury at or above level T6. Correct and early recognition of this syndrome is critical to avoid the serious consequences inherent in the untreated disorder. Although the best treatment is prevention, if autonomic dysreflexia is addressed appropriately, it can be effectively managed.

Clinical Findings The estimated lifetime frequency of autonomic dysreflexia varies widely (from 19% to 70%) in patients with spinal cord injuries [Blackmer, 2003]. Symptoms include diffuse, pounding headache with associated nasal congestion, nausea, and sweating in areas above the spinal cord lesion. Hypertension is common and is associated with increased morbidity. When hypertension is present, patients may experience seizures, intracranial hemorrhage, cardiac and pulmonary complications, coma, and death [Blackmer, 2003]. In the practical management of patients with spinal cord lesions, blood pressure during the recovery phase after

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injury often is low (in the range of 90/60 mm Hg in adults). A pressure that is 20 to 30 mm Hg above baseline should be considered elevated [Blackmer, 2003]. Reports of “silent autonomic dysreflexia” have raised awareness that during routine bowel programs, substantial elevation in blood pressure may occur without other clinical symptoms [Kirshblum et al., 2003]. In some patients, autonomic dysreflexia may occur even if the level of spinal injury is below T6 [Krassioukov et al., 2003]. Virtually any noxious stimulus that occurs below the level of spinal injury may precipitate symptoms. Urinary tract infections and bladder dysfunction due to insufficient catheterization or catheter blockage are the most common stimuli, accounting for 75% to 85% of cases. Bowel distention is responsible for an additional 10% to 20% of cases [Lindan et al., 1980]. Pressure sores and ingrown toenails may also trigger autonomic dysreflexia; fractures, joint dislocations, and heterotopic ossification can also precipitate symptoms in patients with multiple traumas. Lower, extremely deep vein thrombosis, which may be asymptomatic, can be recognized by the swelling and redness that often accompany the disorder. A review of the patient’s medications is important to determine if sympathomimetics may be an additional contributing factor. Pregnant patients are also at risk for autonomic dysreflexia. During labor and delivery, approximately 85% to 90% of mothers with a lesion at T6 or above may suffer from these symptoms [Blackmer, 2003]. On occasion, autonomic dysreflexia may occur after an intramuscular injection, although this is relatively rare [Selcuk et al., 2004]. Autonomic dysreflexia occurs between 1 and 6 months after injury in patients with complete or incomplete tetraplegia [Helkowski et al., 2003], but it may occur as early as 7 to 31 days after acute cord transection, a point when even the deep tendon reflexes are still absent [Silver, 2000]. Autonomic dysreflexia often occurs after patients have been discharged to outpatient care. Anticipatory patient education is very important.

Pathophysiology Autonomic dysreflexia is associated with the preservation of normal spinal reflex mechanisms below the injury site. Any noxious afferent stimulus, such as a urinary tract infection, distended bladder, or even an ingrown toenail, generates a substantial and generalized sympathetic response. Vasoconstriction below the neurologic lesion follows, with a resultant elevation of blood pressure that stimulates the vascular baroreceptors. Normally, brainstem-mediated afferent inhibitory signals regulate this sympathetic response. However, in patients with spinal cord injury, inhibition of this sympathetic chain response is blocked. Unopposed parasympathetic output above the level of the lesion and the ensuing peripheral vasodilation trigger symptoms of headaches, flushing, sweating, and nasal congestion [Blackmer, 2003].

Treatment Understanding the etiology and providing education and anticipatory care underlie effective management of autonomic dysreflexia. If symptoms occur, early identification is

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important. The following approach to treatment [Blackmer, 2003] is recommended: 1. Sit the patient in the upright position. 2. Loosen any clothing or restrictive devices. 3. Monitor blood pressure every 2 to 5 minutes during the episode. 4. If no indwelling catheter is present, perform intermittent catheterization. 5. If an indwelling catheter is present, check for obstruction and irrigate the bladder. 6. If symptoms are present and systolic blood pressure is elevated, treat with antihypertensive pharmacologic agents. 7. If symptoms persist and the systolic blood pressure is elevated but less than 150 mm Hg in the “adult,” manually disimpact the bowel. If catheterization or disimpaction is attempted, the application of lidocaine jelly is important. 8. If symptoms persist, search for other precipitants. 9. If the patient is an outpatient, admit to evaluate for other etiologies. The choice of pharmacologic agent to control hypertension is unclear because randomized trials have not been performed. Nifedipine has been used in a bite-and-swallow technique; more recently, captopril also has been found to be of benefit [Esmail et al., 2002]. Education of the patient and family is helpful and effective. Information regarding recognition of the clinical symptoms and treatment of autonomic dysreflexia is crucial. Because children spend a substantial portion of their day at school, education of school personnel is beneficial.

Sialorrhea Sialorrhea, or drooling, in children older than 4 years of age, is considered pathologic; when it occurs in conjunction with developmental impairment and disability, it leads to further social isolation and barriers to the successful integration of the child in the home and school environment [Crysdale, 1989]. Between 10% and 37% of children with cerebral palsy have persistent drooling [Bachrach et al., 1998; Bothwell et al., 2002]. Studies of swallowing in cerebral palsy patients revealed incomplete lip closure, low suction pressure, and prolonged delay between the sucking stage and the stage in which foods are propelled into the gastrointestinal tract [Blasco and Allaire, 1992; Lespargot et al., 1993]. Affected children and caregivers often report this as a major source of anxiety. Associated difficulties can range from skin breakdown to life-threatening consequences secondary to aspiration. When families request assistance, the treating physician is faced with the need to find an effective treatment not associated with significant side effects. Although numerous approaches have been used individually and in combination to treat drooling, none have been universally successful. Behavioral programs and oral appliances have been employed but are not very effective [Harris and Purdy, 1987]. Anticholinergic drugs, such as glycopyrrolate, scopolamine, and benztropine, have been administered orally or transdermally to reduce formation of secretions [Brodtkorb et al., 1988]. The anticholinergic drugs have little selectivity for the parasympathetic receptor sites; as a

result, the majority of patients experience systemic side effects, including constipation, irritability, and urinary retention [Bachrach et al., 1998; Blasco and Stansbury, 1996; Mier et al., 2000]. More invasive treatment methods, such as irradiation of the parotid gland, are rarely used because of the secondary risk of malignancy. Surgical approaches have had variable results, with benefits in only two thirds of patients [Burton, 1991; Webb et al., 1995]. Botulinum toxin A has been used for the treatment of many neurologic disorders [Blitzer and Sulica, 2001; Yablon, 2001]. Its ability to chemodenervate at the neuroglandular junction has been recognized, and it has been used therapeutically for the treatment of hyperhidrosis and vasomotor rhinorrhea [Kim et al., 1998; Shaari et al., 1998; Wilkie and Broady, 1977]. Botulinum toxin A has been used recently for the treatment of sialorrhea based on a presumed similar mechanism of action. The duration of the clinical effect of botulinum toxin A at the neuromuscular junction is approximately 3 to 4 months. A longer duration of effect was reported at the glandular level [Jongerius et al., 2004; Suskind and Tilton, 2002]. Several studies have reported the successful use of botulinum toxin A for the treatment of drooling in children with cerebral palsy using injection into the submandibular or parotid glands alone or in combination with other agents [Bothwell et al., 2002; Jongerius et al., 2001, 2004; Suskind and Tilton, 2002]. In some studies the beneficial effects have lasted for up to 4 months [Jongerius et al., 2004] without serious side effects or disturbances of oral function [Jongerius et al., 2001, 2004; Suskind and Tilton, 2002].

Prevention of Deep Vein Thrombosis and Pulmonary Embolism Deep vein thrombosis and pulmonary embolism in children are rare but may have considerable morbidity and occasional mortality. The incidence in Canada of deep vein thrombosis in children is 5.3 per 10,000 hospital admissions [Andrew et al., 1994].

Clinical Findings Symptoms of deep vein thrombosis include pain, swelling, and discoloration in the affected extremity. Although it may occur spontaneously, one study demonstrated that 98% of children with deep vein thrombosis had an underlying disorder or predisposing factor [David and Andrew, 1993]. Of 308 children evaluated for venous thrombosis, the most common etiologies were indwelling catheter (21%), surgery (13%), trauma (8.8%), systemic lupus erythematosus (7.5%), infection (6.2%), tumor (5.8%), total parenteral nutrition (5.5%), and unknown (5.5%). Deep vein thrombosis in the upper venous system was usually due to central venous catheters, whereas deep vein thrombosis in the lower extremities was often related to non-catheter thrombotic complications. Children with spinal cord injury are at risk for developing deep vein thrombosis; in adolescents older than 15 years, the incidence was 10%, a percentage much lower than that reported in adults [Radecki and Gaebler-Spira, 1994]. A retrospective analysis of pulmonary embolism revealed an incidence of 78 per 100,000 in hospitalized adolescents

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[Bernstein et al., 1986]. The most common risk factors were oral contraceptive use (26%), recent trauma to the lower extremities without fracture (21%), and elective abortion (21%). Symptoms of pulmonary embolism include pleuritic pain, dyspnea, and cough. In children, pulmonary embolism results more often from cardiac emboli rather than from a peripheral vein; therefore, prophylactic placement of a caval filter is not necessary [McBride et al., 1994]. A ventilationperfusion scan should be obtained to evaluate children for the possibility of pulmonary embolism when clinical symptoms are present [David and Andrew, 1993]. Detection of deep vein thrombosis may be done with invasive techniques such as venous angiography or noninvasively with ultrasonography. Some authors consider that an angiographic study should be done for most pediatric patients with thrombotic complications [David and Andrew, 1993]. In a retrospective review of children clinically suspected of having deep vein thrombosis, only 18% of venograms demonstrated abnormalities indicative of deep vein thrombosis [Perlmutt and Fellows, 1983]. In a prospective study in children, it was concluded that only periodic venous duplex studies accurately diagnosed the disorder in patients with increased risk for deep vein thrombosis [Rohrer et al., 1996]. There are no studies comparing the sensitivity and specificity of duplex ultrasonography and venography in children [Andrew et al., 1994].

Treatment Treatment of thromboses in children may include heparin therapy followed by oral anticoagulant therapy or thrombolytic therapy followed by anticoagulants [David and Andrew, 1993]. This topic is reviewed in greater detail in Chapter 72. Heparin therapy should be started with a dose of 75 units/kg (maximum 5000 units) for 10 minutes followed by an infusion at 20 units/kg/hour [David and Andrew, 1993]. Approximately 4 to 6 hours after the initial dose, the activated partial thromboplastin time should be obtained to measure the effects of heparin. Except for patients with extensive thrombosis or pulmonary embolism, heparin therapy for 5 to 7 days is sufficient [David et al., 1995]. In children younger than 1 year of age, maintenance heparin requirements are 25% higher compared with older children [Andrew et al., 1994]. Anticoagulant (warfarin) therapy is initiated within the first 2 days of heparin therapy. The protocol for warfarin is a loading dose of 0.2 mg/kg/day (maximum 10 mg) for 2 consecutive days if the baseline international normalized ratio is 1.0 to 1.3; however, if liver dysfunction is present, the initial loading dose should be decreased to 0.1 mg/kg [Andrew et al., 1994]. Subsequent loading doses depend on the international normalized ratio. Heparin therapy is continued with warfarin until a stable therapeutic international normalized ratio is obtained. A protocol and guidelines advocating additional loading doses and long-term warfarin therapy to maintain an international normalized ratio of 2 to 3 have been proposed [Andrew et al., 1994]. The average daily dosing of warfarin and the intensity of laboratory observation are age-dependent. Additional factors affecting the required dosage depend on the nature of the underlying disorder. Warfarin may be discontinued after 3 months unless the thrombosis is recurrent or the underlying cause of the thrombosis is still present [David et al.,

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1995]. In such circumstances, the duration of warfarin therapy needs to be individualized. More recently, low-molecular-weight heparin therapy has been used for prophylaxis and treatment of deep vein thrombosis in children. For prophylaxis, the dosing of enoxaparin is 0.75 mg/kg subcutaneously every 12 hours for infants younger than 2 months of age and 0.5 mg/kg subcutaneously every 12 hours for children older than 2 months [Massicotte, 2001]. The dose for prophylactic reviparin is 30 units/kg every 12 hours in children younger than 3 months of age and 50 units/kg every 12 hours for children 3 months and older [Massicotte, 2001]. Target antifactor Xa levels are not needed for prophylaxis unless renal failure is present. Enoxaparin dosing for treatment of deep vein thrombosis is higher than that used to prevent its occurrence and is agedependent: 1.5 mg/kg every 12 hours for children younger than 2 months and 1 mg/kg every 12 hours for older children [Massicotte, 2001]. Reviparin dosing for children weighing more than 5 kg is 100 units/kg every 12 hours [Massicotte et al., 1997; Michelson et al., 1998]. There are no published data for the dosing of reviparin for children who weigh 5 kg or less [Massicotte, 2001]. Placement of a subcutaneous catheter may reduce local tissue trauma resulting from frequent subcutaneous dosing [Dix et al., 2000]. When children are receiving low-molecular-weight heparin therapy, antifactor Xa monitoring and dose recalculations are required as they grow and gain weight [Massicotte, 2001]. Target antifactor Xa levels are 0.5 to 1.2 units/ml. Monitoring is also necessary when an underlying disease may intermittently put a child at increased risk for bleeding, renal failure, or thrombocytopenia [Massicotte, 2001].

Heterotopic Ossification Heterotopic ossification indicates true bone formation in an atypical location such as soft tissue. It frequently occurs in patients with central nervous system insults, such as traumatic brain injury, cerebral anoxia, and spinal cord injury, but can occur after soft tissue trauma or surgical insults [Garland, 1991; Kluger et al., 2000]. Approximately 20% to 30% of adults with spinal cord injury will develop heterotopic ossification [Stover et al., 1991]. In one study of 643 pediatric patients, the incidence of heterotopic ossification was 5%, which included all central nervous system etiologies [Kluger et al., 2000]. In a separate 11-year prospective study of 145 comatose and head-injured children and adolescents, the incidence of heterotopic ossification was 15% [Mital et al., 1987]. Overall, the incidence is lower in children than in adults [Garland et al., 1989].

Clinical Findings The initial onset of symptoms of heterotopic ossification is variable. In one pediatric study, the average time of onset of symptoms after the initial insult was 4 months (range, 4 weeks to 20 months) [Kluger et al., 2000]. In another study, the peak onset was 2 months (range, 1 to 4 months) after the initial insult, irrespective of etiology [Garland, 1991]. Symptoms include pain, fever, swelling, erythema, and decreased joint mobility [Shehab et al., 2002]. These symptoms may mimic those of a septic joint or thrombophlebitis.

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FIGURE 92–4. Heterotopic ossification in formation.

FIGURE 92–3. Bone scan of heterotopic ossification demonstrating radionuclide uptake in the shoulder area where the ossification is located.

The most common locations for heterotopic ossification are the axial musculature and proximal limbs, but multiple areas may be affected [Garland, 1991]. In spinal cord injury, heterotopic ossification develops only in sites distal to the level of injury [Shehab et al., 2002]. Elevation of the alkaline phosphatase level is a sensitive indicator of heterotopic ossification and precedes radiologic findings of ectopic bone [Mital et al., 1987]. However, alkaline phosphatase levels, which are mildly elevated in children because of incomplete bone growth, may not be a reliable marker [Kluger et al., 2000]. Triple-phase bone scans appear to be the most sensitive method for detecting heterotopic ossification (Fig. 92-3). Radiographic abnormalities lag behind clinical symptoms and may not reveal heterotopic ossification for 4 to 6 weeks, in contrast with triple-phase bone scans on which such changes are evident much earlier [Freed et al., 1982]. This is shown in Figure 92-4, in which early formation of heterotopic ossification is depicted, and in Figure 92-5, which shows a mature heterotopic ossification.

FIGURE 92–5. Heterotopic ossification in the mature phase.

Pathophysiology Although the pathophysiology of heterotopic ossification is unknown, there does appear to be conversion of soft tissue mesenchymal cells to cells with the capability to form bone. This capability is thought to occur in response to multiple factors including local trauma, spasticity, variations in blood flow with stasis, and anoxia independent of the degree of mobility (i.e., complete immobilization to mobilization with physical therapy) [Kluger et al., 2000]. There appears to be a cumulative effect when local trauma is associated with a head injury, especially if surgery is required [Garland, 1991].

Tilton and Weimer / Pediatric Neurorehabilitation Medicine

Treatment Treatment modalities for heterotopic ossification include medication, radiation, and surgery. Salicylates at a daily dose of 60 mg/kg/day for a 6-week period, maintaining a drug level of 15 to 20 mg/100 mL, appear to be a safe and successful measure to avert recurrence of heterotopic ossification [Mital et al., 1987]. Salicylates prevent the continued development of heterotopic ossification when initiated early. Contraindications to salicylate therapy include kidney disease, coagulopathies, blood dyscrasias, and salicylate intolerance. Corticosteroids and indomethacin have been used in adults, but these medications have not been tried in children because of potential adverse effects in already fragile patients [Mital et al., 1987]. Because of the lack of adequate placebo-controlled studies, the use of biphosphates in treating heterotopic ossification has not been justified [Kluger et al., 2000]. Radiation therapy in children with recurrence of heterotopic ossification is not considered safe [Kluger et al., 2000]. Additional evidence points toward the benefit of an aggressive approach to spasticity, including the use of botulinum toxin and intrathecal baclofen [Kluger et al., 2000]. A debate exists as to the benefits and risks associated with manipulation of the affected area. One argument is that mobilization increases the inflammatory response and contributes to heterotopic ossification formation, whereas the opposing view is that manipulation does not affect heterotopic ossification formation but does maintain mobility. Manipulation under anesthesia is sometimes required and provides the necessary range of motion after the procedure [Garland, 1991]. Surgical excision is most favorable when the patient begins to demonstrate neurologic recovery and when the heterotopic ossification is a hindrance to rehabilitation [Mital et al., 1987]. It is important to recognize that to reduce the risk of recurrent surgical procedures, resections should not be performed until complete maturation of the heterotopic ossification occurs, which is usually 1 to 2 years after the initial manifestation (see Figs. 92-4 and 92-5) [Garland and Orwin, 1989; Kluger et al., 2000]. However, when heterotopic ossification severely impedes rehabilitation, earlier resection may be indicated, and in that setting salicylates are important for preventive therapy [Kluger et al., 2000].

Spasticity and Other Forms of Muscle Overactivity Brain or spinal cord injury may lead to the upper motor neuron syndrome, whose characteristic signs include paresis, loss of fine motor control, and muscle overactivity. The predominant forms of muscle overactivity include spasticity, clonus, flexor and extensor spasms, and co-contraction. In addition, rheologic changes in muscle occur, with prolonged distortion of the normal range of motion that may restrict motion further and complicate assessment and treatment. The combination of these findings varies with each individual and even within the same individual depending on activity, treatment, and other factors. Reduction of muscle overactivity may be beneficial to the patient, but the determination of whether to treat, what to treat, and how to treat muscle overactivity requires a comprehensive evaluation. Setting of realistic functional goals and involvement of the

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family and caregivers is very important for a successful outcome.

Spasticity Spasticity is defined as a velocity-dependent increase in resistance to passive stretch. In the clinic, spasticity is elicited when the examiner moves the limb passively through its range of motion; as the speed of the passive movement increases, there is increasing resistance or stiffness. For the patient engaged in normal activities at home, passive stretch may occur during transfers, dressing, and similar activities. Spasticity may interfere with such activities and therefore may become an appropriate object of treatment. On the other hand, some spasticity, especially in the lower limbs, may be useful to the patient—for example, providing limb stiffness for transfers when muscle control is lacking.

Flexor and Extensor Spasms Spasms of the flexor and/or extensor muscles can occur spontaneously or in response to stimuli. The exaggerated motor responses emanate from abnormal spinal cord circuitry as it is influenced by proprioceptive, nociceptive, and extraceptive input, as well as the descending inputs from the suprasegmental areas [Mayer, 1997]. Stimuli may be external, such as from tight clothing or excessive pressure against the arm of a wheelchair, and may be internal, such as from a full bladder, pressure sores, ingrown toenail, or heterotopic ossification. Spasms may affect an individual muscle, a small group of muscles, or an entire limb. Spasms are often painful and may last from seconds to minutes. They may interfere with the full range of daily functions, including sleep.

Co-contraction Co-contraction occurs when an antagonist is activated together with an agonist. Co-contraction is a normal feature of fine motor control but becomes pathologic when activated at inappropriate times or excessively. Patients with cocontraction move slowly and with effort and may have difficulty with full range of motion of limbs.

Rheologic Changes Changes in muscle plasticity or viscoelasticity, collectively called rheologic changes, may have a significant impact on muscle function. Immobilization or reduced range of motion can lead to muscle shortening and fibrosis, which together lead to a static contracture, or permanent shortening and stiffening of the muscle [Herman, 1970; Hufschmidt, 1985]. Contractures are among the most difficult consequences of muscle overactivity to treat, often requiring orthopedic intervention, physical therapy, and bracing. Avoidance of contracture is a major goal of treatment.

Treatment Planning for Muscle Overactivity Multiple factors must be considered in devising a treatment plan for muscle overactivity in children. The first consideration is whether to treat at all, since mild overactivity

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may not be disabling, and even moderately increased tone may be acceptable if it does not interfere with function, comfort, or care or is not predicted to lead to future orthopedic problems. In most cases, some form of treatment is appropriate. Factors that must be considered in devising a treatment plan include the distribution of overactivity (focal, regional, or global), degree of overactivity, coexistent conditions such as mental retardation or feeding difficulties, family involvement and abilities, physical and financial access to medical care, and social factors such as educational needs. For example, a child who lives many miles from a treatment center may not be a candidate for intrathecal baclofen, and a child who is going to school may not benefit from oral medications with cognitive side effects. A hierarchy of treatment goals may provide a framework in which to develop a treatment plan. One such hierarchy [Pierson, 1997] is as follows: • • • •

Reduce pain. Decrease decubiti and contracture formation. Promote safe and comfortable seating. Promote the plantigrade foot under the pelvis for gait, and the plantigrade hand under the shoulder for weight-bearing. • Promote motor control development. • Minimize cost, invasiveness, and required maintenance of treatment. With this hierarchy in mind, choices can be made among the available treatment options (Fig. 92-6). Such options [Tilton and Maria, 2001] include the following: • • • • • • • •

Physical and occupational therapy Orthotics and casting Oral medications Nerve and motor point blocks Botulinum toxin Selective dorsal rhizotomy Intrathecal baclofen Orthopedic interventions

Allied health Oral medication

Orthopedic surgery Defined goals Selective dorsal rhizotomy

Chemodenervation Intrathecal baclofen

FIGURE 92–6. Treatment options for a child with muscle overactivity. (Modified from Tilton AH, Maria BL. Consensus statement on pharmacotherapy for spasticity, J Child Neurol 2001;16:66-67.)

PHYSICAL AND OCCUPATIONAL THERAPY Physical therapy begins with stretching, which is an essential part of any spasticity treatment program. Stretching maintains range of motion and reduces the occurrence of contractures. Therapy programs may include motor retraining, sensory reintegration, and strengthening. Occupational therapy includes use of seating and standing devices, communication aids, and other adaptive equipment, as well as upper extremity training. Modalities employed by physical therapists and occupational therapists may include transcutaneous electrical stimulation, biofeedback, and use of heat and cold, as well as the more familiar types of equipment, including orthotics, braces, and casting. Efficacy of any of these techniques is variable, and few clinical trials have been conducted to assess their indications and efficacy. The duration of gains from such treatments is usually several months after treatment is stopped; benefits are not permanent for any intervention [Bower et al., 2001].

ORAL MEDICATIONS A wide variety of medications are used for reduction of muscle overactivity. The most common are diazepam and other benzodiazepines, dantrolene sodium, tizanidine, and baclofen. Sedation is a common side effect and is doselimiting. Because they have a global effect on tone, oral medications are most appropriate for a child with widespread muscle overactivity. The benzodiazepines act as postsynaptic γ-aminobutyric acid A (GABA-A) agonists. Diazepam is the most commonly used agent. A major component of its action is generalized relaxation [Marsh, 1965]. Double-blind, placebo-controlled studies of cerebral palsy have found significant improvement in spasticity, especially in younger children and in those children with athetosis [Denhoff, 1964; Engle, 1966; Holt, 1964; Pranzatelli, 1996]. Diazepam in combination with dantrolene has also been found to be superior to either medication used alone [Nogen, 1979]. Side effects include excessive somnolence, dizziness, mild weakness, and a withdrawal syndrome that may limit its use [Gracies et al., 1997]. Clorazepate and clonazepam also have demonstrated anti-spasticity action in adult studies, with sedation being a limiting factor with clonazepam [Gracies et al., 1997]. Clorazepate is less sedating, but studies of this medication in children with spasticity have not been conducted [Gracies et al., 1997] Baclofen is a pre-synaptic inhibitor of GABA-B. It is most effective for spinal cord lesions and less effective for spasticity of cerebral origin. A placebo-controlled, doubleblind crossover study of oral baclofen in children with cerebral palsy reported significant reduction in spasticity and improved use of extremities [Milla and Jackson, 1977; Pranzatelli, 1996]. Side effects of baclofen include central nervous system depression, confusion, and weakness. Dantrolene is a unique medication that acts directly on muscle, inhibiting calcium release from the sarcolemmal membrane causing uncoupling of excitation and contraction. Because of its peripheral action, it is less sedating than other centrally acting agents. Dantrolene’s side-effect profile has limited its use in children despite proven benefits in placebo-controlled studies of children with cerebral palsy [Haslam et al., 1974; Joynt and Leonard, 1980]. Side effects

Tilton and Weimer / Pediatric Neurorehabilitation Medicine

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TABLE 92-4 Oral Anti-Spasticity Medications DRUG

MECHANISM

DOSAGE

SIDE EFFECT

STUDIES

Baclofen Oral

GABA-B agonist inhibits at spinal cord level

2+ sedation, confusion, 2+ weakness, ± seizure control

DBPC (adult)

Clorazepate

Facilitates GABA

Clonazepam

Facilitates GABA

Diazepam

Facilitates GABA

Dantrolene

Interferes with skeletal muscle contraction by interruption of calcium release from sarcoplasmic reticulum Alpha-2 adrenergic agonist with presynaptic inhibition

2–7 yr, max 40 mg; 8–11 yr, max 60 mg; >12 yr, max 80 mg; divided tid to qid; increase q3days >9–12 yr, max 60 mg/day; >12 yr, max 90 mg/day; divided bid to tid; increase weekly <10 yr or 30 mg, max 0.1–0.2 mg/kg/day; >10 yr or 30 kg, max 20 mg/g/day; divided bid to tid; increase q3days <12 yr, 0.1–0.8 mg//kg/day; >12 yr, 6–30 mg/day divided tid to qid; increase weekly >5 yr, 12 mg/kg/day; divided bid to qid; adult max 400 mg/day; increase q4–7days

Tizanidine

0.2–0.3 mg/kg/day divided tid to qid; night dosing helpful for sleep; adult max 36 mg; increase weekly

DBPC (adult) 1–2+ sedation, 1–2+ weakness 3++ sedation, 2+ weakness

Open trial only

3+ sedation, 2+ weakness, dizziness

DBPC (child/adult)

1+ sedation, 3+ weakness, hepatotoxicity, GI complaints

DBPC (child/adult)

2++ sedation, 1+ weakness, hypotension

DBPC (adult)

DBPC, double-blind, placebo-controlled; GABA, γ-aminobutyric acid; GI, gastrointestinal.

include excessive weakness and gastrointestinal complaints. Hepatotoxicity was reported in 1% of patients. Monitoring of hepatic function should be considered in children taking dantrolene [Katz, 1988; Young and Delwaide, 1981]. Tizanidine is an alpha-2 agonist that inhibits the release of excitatory amino acids and facilitates the action of glycine at spinal and supraspinal levels. There have been numerous controlled studies in adults with spasticity of multiple etiologies, but controlled studies of tizanidine have not been performed in children [Lataste et al., 1994]. Side effects include dry mouth and sedation. Sedation can be beneficial when the medication is administered at bedtime in a child who has difficulty initiating sleep or who has spasms at night. Although tizanidine does not cause hypotension as often as clonidine, it may occasionally have this side effect. Caution should be exercised when using it with antihypertensive agents. Hallucinations have been reported with its use (Table 92-4) [Gracies et al., 1997].

NERVE AND MOTOR POINT BLOCKS A nerve block is a perineural injection targeting a motor nerve, whereas a motor point block is an intramuscular injection that targets individual branches near nerve terminals. A nerve block offers complete blockade and reduction in tone, whereas a motor point block gives a graded but highly variable response. Phenol and ethyl alcohol are commonly used for nerve and motor point blocks. Electrical stimulation is used to target the nerve or motor point. Because the injection requires precision and may be painful and stressful in children, an anxiolytic or sedation may be appropriate.

The duration of effect for motor blockade with phenol averages 4 to 8 months but is highly variable in individual patients [Yadav et al., 1994]. Painful dysesthesia is a known adverse effect, occurring most commonly when mixed nerves are targeted. A randomized, double-blind comparative trial of phenol and botulinum toxin type A for treatment of the sequelae of stroke produced similar efficacy but more ambulation-limiting dysesthesias in those receiving phenol [Kirazli et al., 1998].

BOTULINUM TOXIN Botulinum toxin is injected into overactive muscle, where it provides a dose-dependent reduction in tone for up to 3 months. The beneficial effect usually begins within 1 week after injection and the peak benefit occurs at 2 weeks. Electromyography may aid in site selection, better targeting, and dose reduction [Ajax et al., 1998]. Botulinum toxin is commercially available in the United States as Botox (serotype A) or Myobloc (serotype B). The two serotypes have different unit potencies, side-effect profiles, and dilution schedules. Both have been used in children with cerebral palsy, although serotype A has been used more extensively. Dosing guidelines have been suggested for botulinum toxin A (as Botox) for adult and pediatric patients. Adult recommendations are available for botulinum toxin B, but studies are ongoing for pediatric patients (Table 92-5) [Tilton, 2003]. Botulinum toxin can be used for reduction of focal spasticity. Its effects are localized but may extend beyond the injected muscle, probably through interruption of synergy

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TABLE 92-5 Dosing Guidelines for BTX-A (specifically Botox) DOSE

DOSING FACTORS

TOTAL DOSE

DILUTION

SITES

REINJECTION

Small muscles: 1–3 units/kg (pronators) Large muscles: 3–6 units/kg (hamstrings)

Muscle mass Degree of spasticity Number of muscles to be injected Prior response to injections Injector’s experience

Typical maximum dose: 12–15 units/kg 300 units (child); 400 units (adult) LD50 = 39 units/kg

100 units/mL or 100 units/2 mL; 0.9% Preservative-free saline

4–5 cm apart if possible; 1–2 sites/muscle; 0.5 mL max per site

≥3 months

Modified with permission from Tilton, A.H., Butterbaugh, G. Mental retardation and cerebral palsy. In: Noseworthy, JH, ed. Neurological Therapeutics: Principles and Practice, Vol 2. New York: Martin Dunitz, 2003;1617–1629.

TABLE 92-6 Optimal Candidate for Botulinum Toxin AGE

STRENGTH

LIMITATION OF MOVEMENT

MUSCLE INVOLVEMENT

1 to 6 yrs for lower extremity; ≥4 yrs for upper extremity; 5 to 15 yrs for hemiplegia (younger age recommendations are being studied)

Sufficient underlying strength to allow weakening of the injected muscles

Due to spasticity and not a fixed contracture; demonstrates some degree of selective motor control; has applications for care and comfort

Focal involvement of ≤4 muscle groups or specific muscle involvement with a generalized treatment approach

patterns that replace selected muscle control in the upper motor neuron syndrome. Tone reduction has been demonstrated repeatedly in children with cerebral palsy, but functional benefits have been more difficult to demonstrate [Edgar, 2000; Kirschner et al., 2001; Yablon, 2001]. This difficulty may be due to the inadequacy of current rating scales to measure the highly localized improvements associated with focal injections (Table 92-6). Side effects include development of localized muscle weakness, injection site discomfort, and mild flulike symptoms. Dry mouth has been reported more often for serotype B than for serotype A. Dysphagia is a common problem in the cervical dystonia population, but not in individuals receiving treatment for spasticity.

marginal ambulators [Lin, 1998; McLaughlin et al., 1998; Wright et al., 1998]. The side-effect profile of rhizotomy includes complications associated with the surgical procedure. Long-term concerns regarding the development of lordosis and scoliosis have been raised [Crawford et al., 1996]. The risk of developing a structural spinal deformity ranges from 24% to 36% for scoliosis and is 50% for lordosis for an average of 4 to 11 years after selective dorsal rhizotomy [Johnson et al., 2004; Turi and Kalen, 2000]. Although laminectomy and laminoplasty had no impact, older age, more severe neurologic impairment, and preexisting spinal deformity were reported to increase this risk [Johnson et al., 2004; Turi and Kalen, 2000].

SELECTIVE DORSAL RHIZOTOMY

INTRATHECAL BACLOFEN

Selective dorsal rhizotomy is a surgical procedure in which selected afferent fibers in the dorsal roots are dissected and cut in an attempt to reduce aberrant muscle spindle input believed to trigger muscle overactivity. Nerve rootlets from L1 to S2 are exposed and stimulated. Those rootlets exhibiting abnormal responses (40% to 60 % of the rootlets in the L4 to S1 distribution) are cut [Lazareff et al., 1999]. The operation may be appropriate in children with spastic diplegia, usually between the ages of 4 and 6, and in patients with pure spasticity, isolated leg movements, and good strength and trunk control [Engsberg et al., 1999]. Ability to walk after selective dorsal rhizotomy is best in children who are diplegic and who had good gait scores before the operation [Chicoine et al., 1996]. Intensive therapy is recommended after rhizotomy, including physical therapy 4 to 5 times a week and occupational therapy once or twice a week for 6 months to return motor function to preoperative levels. Randomized studies of selective dorsal rhizotomy have demonstrated improvement in tone and motor function, with evidence that the procedure may be most efficacious in

Intrathecal delivery of baclofen allows a much lower dose of drug than oral delivery, greatly reducing cognitive and systemic side effects [Gracies et al., 1997]. At the same time, the dose reaching the target in the spinal cord is much higher, resulting in better tone control. Intrathecal baclofen is delivered via a catheter, whose tip is placed in the intrathecal space, usually at the T11-T12 level. The pump containing the medication reservoir is implanted in the abdomen and is battery-powered and programmable via telemetry from a hand-held computer. The pump has a reservoir that stores enough medication for approximately 3 to 6 months and emits an audible alarm when the reservoir is low. It can be refilled percutaneously. Batteries must be replaced approximately every 7 years. Patients who benefit most from intrathecal baclofen therapy are those with generalized spasticity and lowerextremity weakness whose spasticity is interfering with function, comfort, or care and those with movement disorders and dystonia [Albright et al., 1991;Gilmartin et al., 2000; Van Schaeybroeck et al., 2000]. A catheter trial or

Tilton and Weimer / Pediatric Neurorehabilitation Medicine

bolus-screening dose may be used to gauge response, but this trial is not necessarily predictive of the functional benefit that may be achieved with continuous infusion. Likewise, the response to oral baclofen is not a predictor of the potential benefit from intrathecal baclofen. Adverse effects include weakness, nausea, vomiting, and hypotonia, as well as changes in urinary and bowel function. Human error in programming and equipment malfunction are potentially life threatening. Symptoms of an overdose are consistent with those seen in oral baclofen overdose: sedation leading to coma and respiratory compromise. Families must be trained to recognize symptoms of the withdrawal syndrome. Initially, mild symptoms include pruritus, nausea, and return of the pretreatment spasticity. Unrecognized, the syndrome may rarely advance to hyperthermia, severe spasticity, and seizures. Case reports have included rhabdomyolysis, multisystem organ failure, and death [Gilmartin et al., 2000; Green and Nelson, 1999]. As a precaution, families are prescribed Valium or Diastat as well as oral baclofen to have at home. If there is evidence of withdrawal, one of these medications is administered, and the patient is instructed to go immediately to the emergency department. Although aggressive use of benzodiazepines and oral baclofen may be helpful, recognition and return of the appropriate intrathecal baclofen dosage is essential for rapid recovery [Alden et al., 2002]. The withdrawal syndrome is sometimes confused with an intercurrent illness such as a urinary tract infection. An illness or noxious stimuli can increase spasticity and result in fever, but a catheter or pump malfunction must always be considered. Because of inherent risks, families must be fully committed to scheduled refilling of the pump.

ORTHOPEDIC SURGERY Surgery can be beneficial for selected patients to correct deformities induced by force imbalances across a joint [Morrissy and Weinstein, 2001]. Uncorrected deformities cause pain, interfere with mobility or care, and lead to subluxation. The most common deformity is an equinovarus deformity of the foot. Subluxation, or partial dislocation of the hip joints, is also frequent. Correction of equinovarus deformity is usually accomplished by tendon lengthening or by splitting the tendon and transferring the distal end of the lateral half to the cuneiform and cuboid bones, where it exerts a corrective pull across the joint. Hip joint dislocation correction involves multiple tenotomies and transfers of the thigh adductors, and in severe cases, femoral osteotomy. Surgery may also be helpful in correcting deformities of the knee and the upper extremities, depending on the degree of deformity in these joints. The best time to perform orthopedic procedures is after a child’s gait has matured, usually between the ages of 6 and 10 years [Renshaw et al., 1995]. It is preferable to perform all procedures at the same time to minimize postsurgical recovery and immobility. Postoperative physical therapy is essential to improve strength and range of motion.

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Tilton and Weimer / Pediatric Neurorehabilitation Medicine Mital M, Garber J, Stinson J. Ectopic bone formation in children and adolescents with head injuries: Its management. J Pediatr Orthop 1987;7:83. Morrissy R, Weinstein SL. Lovell and Winter’s Pediatric Orthopaedics. Philadelphia: Lippincott Williams & Wilkins, 2001. Neistadt ME, Crepeau E. Occupational Therapy. Philadelphia: Lippincott Williams & Wilkins, 1998. Nelson K, Ellenberg J. Children who “outgrew” cerebral palsy. Pediatrics 1982:69:529. Nelson KB, Ellenberg JH. Epidemiology of cerebral palsy. Adv Neurol 1978;19:421. Nogen AG. Effect of dantrolene sodium on the incidence of seizures in children with spasticity. Childs Brain 1979;5:420. Owens RE, Metz DE, Haas A. Introduction to Communication Disorders: A Life Span Perspective. In: Dragin SD, ed. Boston: Pearson Education, 2003. Pedretti L, Early MB. Occupational Therapy—Practice for Physical Dysfunction. St Louis: Mosby, 2001. Perlmutt L, Fellows K. Lower extremity deep vein thrombosis in children. Pediatr Radiol 1983;13:266. Pierson SH. Outcome measures in spasticity management. Muscle Nerve 1997;20:S36. Pranzatelli MR. Oral pharmacotherapy for the movement disorders of cerebral palsy. J Child Neurol 1996;11:S13. Price C, Makintubee S, Herndon W, et al. Epidemiology of traumatic spinal cord injury and acute hospitalization and rehabilitation charges for spinal cord injuries in Oklahoma, 1988-1990. Am J Epidemiol 1994;139:37. Radecki RT, Gaebler-Spira DJ. Deep vein thrombosis in the disabled pediatric population. Arch Phys Med Rehabil 1994;75:248. Reimers J. Clinically based decision making for surgery. In: Sussman MD, ed. The Diplegic Child: Evaluation and Management. Rosemont: American Academy of Orthopedic Surgeons, 1991. Renshaw TS, Green NE, Griffin PP, et al. Cerebral palsy: Orthopaedic management. J Bone Joint Surg 1995;77-A:1590. Rohrer MJ, Cutler BS, MacDougall E, et al. A prospective study of the incidence of deep venous thrombosis in hospitalized children. J Vasc Surg 1996;24:46. Rosman NP, Herskowitz J, Carter AP, et al. Acute head trauma in infancy and childhood. Pediatr Clin N Am 1979;26:707. Russman BS. Are infant stimulation programs useful ? Arch Neurol 1986;43:282. Russman BS, Tilton A, Gormley ME Jr. Cerebral palsy: A rational approach to a treatment protocol, and the role of botulinum toxin in treatment. Muscle Nerve Suppl 1997;6:S181. Selcuk B, Inanir M, Kurtaran A, et al. Autonomic dysreflexia after intramuscular injection in traumatic tetraplegia: A case report. Am J Phys Med Rehabil 2004;83:61. Shaari CM, Wu B, Biller HF, et al. Botulinum toxin decreases salivation from canine submandibular glands. Otolaryngol Head Neck Surg 1998;118:452. Shehab D, Elgazzar A, Collier B. Heterotopic ossification. J Nucl Med 2002;43:346.

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CHAPTER 93

Pain Management and Palliative Care John Colin Partridge

PAIN MANAGEMENT Pain has been defined as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” [International Association for the Study of Pain, 1979]. The stimulus can be thermal (heat or cold), chemical (acid or alkali), or mechanical (torsion, stretch, pinch, or prick). Nociception, or pain perception, is the series of electrochemical events following tissue damage or injury, excluding any emotional correlates of the noxious sensation. Acute pain occurs in a wide variety of pediatric medical encounters, and chronic pain in one form or another affects an estimated 15% to 20% of children [Goodman and McGrath, 1991]. Pain can be effectively relieved in 90% of patients; nevertheless, only 20% of patients achieve effective pain relief [Ferrel and Rhiner, 1991]. Many studies demonstrate that neonates, infants, and children can safely receive analgesia and anesthesia [Anand et al., 1999; Polaner, 2001; Shah and Ohlsson, 2002; Stevens et al., 2000; Taddio, 2002].

Historical Background Studies from the 1970s into the 1990s documented undertreatment of pediatric patients undergoing uncomfortable diagnostic (e.g., lumbar puncture) or major surgical procedures (e.g., amputations, nephrectomies, and atrial septal defect repairs) [Bauchner, 1991; Schechter, 1989; Schechter et al., 1986]. Despite an increased number of studies documenting adverse effects of pain over the past two decades, misinformation about pain and nociception in very young children and neonates prevailed until recently. Contrary to prevalent myths, newborn infants have the neurophysiologic basis necessary to experience and remember pain [Anand and Hickey, 1992; Grunau et al., 1994a, 1994b; Taddio et al., 1997]. Fortunately, pain assessment and attention to treatment of painful symptoms are now standards of care for patients of all ages [Joint Commission on Accreditation of Healthcare Organizations, 2001].

Physiology The physiology of pain perception has been reviewed [Anand and Carr, 1989]. Nociceptors present in mucosal membranes, cornea, subcutaneous tissue, bone and teeth, joints, and muscle detect noxious or potentially noxious thermal, chemical, and mechanical stimuli. A noxious stimulus is translated into electrical sensory nerve activity, and the sensory information is transmitted to the central nervous system via several fiber types: (1) A-beta (moderately myelinated, fast-conducting) fibers carry impulses

from pressure/position sensors; (2) A-delta (moderately myelinated, fast-conducting) fibers carry impulses from high-threshold mechanoreceptors and polymodal peripheral sensory neurons that respond to pressure and temperature; and (3) C-fibers (unmyelinated, slow-conducting) carry impulses from cutaneous and deep, low-threshold mechanoreceptors, chemoreceptors, and thermoreceptors. A-delta fibers carry sharp, spatially distinct pain signals, whereas C-fibers carry diffuse pain signals. A-beta fibers signal nonpainful touch and pressure that can compete with nociception. Peripherally, the sensory process can be influenced by local release of inflammatory mediators that sensitize neurons and recruit silent receptors, resulting in hyperalgesia. The majority of peripheral sensory neurons have cell bodies in the dorsal root ganglion, with some afferent input transmitted through the ventral root. Entering through the dorsal root, these fibers separate into A and C fiber bundles in the medial and lateral divisions of the dorsolateral fasciculus and form synapses within the laminae of spinal cord gray matter. Neurons within the laminae synapse with the peripheral sensory neurons and relay information via ascending tracts to various portions of the brain. The long ascending tracts make monosynaptic or polysynaptic reflex connections with lower motor neurons in the ventral horns and have projections to higher brain centers. In the brain, secondary neurons terminate in the medulla, midbrain, periaqueductal gray matter, hypothalamus, thalamus, and cortex. Sensory signals can be amplified by neuronal activation in the periphery or the spinal cord by inflammatory mediators (bradykinin, cytokines, catecholamines, and substance P) or they can be attenuated by competitive stimulation of A-beta fibers. Afferent impulses can be amplified in the spinal cord by substance P or neurokinin A or they can be attenuated by endogenous opioids (endorphins, dynorphins and enkephalins) and serotonergic, noradrenergic, cholinergic and GABA-ergic compounds. Opioid receptors, present in the spinal cord, limbic system, midbrain respiratory centers, and periphery, respond to stereospecific endogenous opioids to produce analgesia, as well as side effects (euphoria/dysphoria, respiratory depression, decreased gastrointestinal motility, bradycardia/tachycardia, and dependency). Several anatomic pathways also inhibit peripheral sensory input, including the cortex, thalamus, periaqueductal gray matter, medulla and dorsolateral funiculus via inhibitory effects of norepinephrine, endogenous opioids, GABA, and acetylcholine.

Developmental Differences Fetal stress responses to painful stimuli have been documented as early as 18 weeks of gestation, with peripheral,

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spinal, and suprapinal capacity for afferent pain transmission by 26 weeks [Klimach and Cooke, 1988]. At this age, newborns can mount behavioral, autonomic, and metabolic stress responses to tissue injury [Anand et al., 1987]. Neonates demonstrate characteristic facial expressions, aversive body movements, alterations in cardiac activity, and changes in their cry in response to painful stimuli [Fitzgerald and Anand, 1993]. Nociceptive nerve endings are fewer in number in children than in adults; therefore, tissue damage may be more significant before a pain response is elicited. Young infants may perceive pain more intensely than older children or adults because descending inhibitory pathways develop later than afferent excitatory pathways [Fitzgerald and Koltenburg, 1986; Franck et al., 2000]. Inadequately treated pain in premature infants is associated with adverse shortterm effects (e.g., more postoperative complications) [Anand and Hickey, 1992]; the accompanying physiologic changes (increased heart rate and blood pressure, cardiac variability, hypoxemia, changes in autonomic tone, increased venous pressure, increased cerebral blood flow and intracranial pressure) may augment risks of intraventricular hemorrhage or white matter injury in the immature brain [Low et al., 1992]. Inadequately treated repetitive pain in the developing brain may accentuate neuronal apoptosis [Bhutta and Anand, 2002], foster wind-up (in which unmodified afferent transmission enhances N-methyl-D-aspartate [NMDA] receptors and facilitates hyperalgesia) [Dickenson, 1995], foster hyperreactive pain responses to subsequent stimuli [Weisman et al., 1998], and cause long-term behavioral changes [Grunau et al., 1994a, 1994b; Taddio et al., 1997]. Use of opioids in the first week of life after perinatal TABLE 93–1 Responses to Painful Stimuli Behavioral Responses to Pain 1. Crying, whimpering 2. Facial expressions: brow bulge, eye squeeze, and deepening of the nasolabial folds 3. Active movement and attempts to withdraw from the painful stimulus a. Thrashing b. Tremulousness c. Limb withdrawal, flexion d. Bicycling e. Arching 4. Disorganized behavior; limp and flaccid 5. Flexor responses; leg withdrawal 6. Exaggerated reactivity 7. Changes in state a. Decrease in sleep periods b. Rapid changes in state cycles c. Decreased rapid eye movement (REM) sleep Physiologic/Autonomic Responses 1. Changes in heart rate and variability 2. Changes in respiratory rate and quality 3. Fluctuations in blood pressure 4. Decreased transcutaneous oxygen and carbon dioxide levels 5. Oxygen desaturation 6. Increased intracranial pressure 7. Palmar sweating 8. Pallor 9. Flushing 10. Pupillary dilation 11. Increased catabolic state

asphyxia has been found to increase the brain’s resistance to hypoxic-ischemic insults [Angeles et al., 2005].

Clinical Assessment Pain is a subjective and variable experience with no direct relation between “pain experience” and pain intensity or between physical pathology and pain intensity. Responses to pain vary widely, depending on gestational age, chronologic age, developmental state, initial behavioral state, prior experience of pain, and the ability to respond to and become habituated to sensory stimuli. There is no single uniform, standard technique for assessing pain in neonates or children. Biochemical responses to pain (elevations in cortisol, catecholamines, beta-endorphins, insulin, glucagon, renin-aldosterone, growth hormone, and prolactin) are rarely useful to clinicians. Infants and children demonstrate a variety of nonspecific but consistent behavioral, physiologic, and autonomic responses to pain (Table 93-1) [Anand and Carr,1989]. These signs have been used by clinicians to recognize pain in nonverbal infants and to quantitate severity of the pain experience. Self-report, usually by use of a linear analog scale, is regarded as most reliable but only for children who have the cognitive capacity to respond appropriately. Infants and preverbal children cannot self-report pain, quantify its severity, or inform providers as to the efficacy of analgesic treatments. For preverbal patients, pain assessment is best achieved using multidimensional scales including behavioral, physiologic, and autonomic responses (Table 93-2). Behavioral observational scales are used for pain assessment in neonates, children younger than 4 years of age, and cognitively impaired children. Neonatal scales used include the NIPS (Neonatal Infant Pain Scale), PIPP (Premature Infant Pain Profile), and pain assessment score sheet [Franck et al., 2000]. Toddlers and pre-school children who cannot effectively communicate pain quality or intensity can often use structured questioning or standardized semiquantitative pain assessment tools (poker chips in increasing numbers, cartoon drawings of faces, a pain thermometer, and colors or words) to consistently and reliably rate pain intensity. Children 8 years or older are able to effectively communicate pain intensity and quality using questionnaires or visual analog scales designed for adults. Behavioral assessment tools, such as FLACC (see Table 93-2), have been used to evaluate children with developmental delay who are at particular risk for acute or chronic undiagnosed or untreated pain [McGrath et al., 1999; Oberlander et al., 1999; VoepelLewis et al., 2002].

Management Pain should be regularly assessed and aggressively treated with nonpharmacologic methods and appropriate analgesic therapies. Effective pain management schemes use the simplest effective regimen, dose around the clock for on-going painful conditions, and tailor the regimen to fit individual patient needs. Oral medications are preferred whenever possible, and regular repeated doses should be ordered with appropriate dosing intervals. Additional medication should be made available on an as needed basis for breakthrough pain. Doses should be titrated according to the patient’s

Partridge / Pain Management and Palliative Care

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TABLE 93–2 Examples of Pain Assessment Scales for Differing Developmental Ages 1. Modified Neonatal Infant Pain Scale (NIPS)* PARAMETER Facial expression Cry Breathing pattern Arms Legs State of arousal Heart rate Oxygen saturation

Relaxed Grimace No cry Whimper Vigorous crying Relaxed Change in breathing Relaxed Flexed/extended Relaxed Flexed/extended Sleeping/awake Fussy Within 10% of baseline Within 11–20% of baseline >20% of baseline No additional oxygen needed to maintain saturation Additional oxygen needed to maintain saturation

FINDING

POINTS

Restful face, neutral expression Tight facial muscles, furrowed brow, chin, jaw Quiet, not crying Mild moaning, intermittent Loud scream, shrill, continuous (silent cry may be scored if intubated) Usual pattern for infant Irregular, faster than usual, gagging, breath holding No muscular rigidity, occasional random movements Tense, straight arms, rigid and/or rapid extension, flexion No muscular rigidity, occasional random movements Tense, straight legs, rigid and/or rapid extension, flexion Quiet, peaceful, sleeping or alert and settled Alert, restless and thrashing

0 1 0 1 2 0 1 0 1 0 1 0 1 0 1 2 0 1

2. FLACC Scale† CATEGORIES 0 Face

No particular expression or smile

Legs Activity Cry

Normal position or relaxed Lying quietly, normal position, moves easily No cry (awake or asleep)

Consolability

Content, relaxed

SCORING 1

2

Occasional grimace or frown, withdrawn, disinterested Uneasy, restless, tense Squirming, shifting back and forth, tense

Frequent to constant quivering chin, clenched jaw Kicking, or legs drawn up Arched, rigid or jerking

Moans or whimpers; occasional complaining Reassured by occasional touching, hugging or being talked to, distractible

Crying steadily, screams or sobs, frequent complaints Difficult to console or comfort

3. FACES Scale‡

0 No hurt

1 Hurts little bit

2 Hurts little more

3 4 Hurts Hurts even more whole lot

5 Hurts worst

4. Visual Analog Scale§ | 0 No pain

| 1

| 2

| 3

| | 4 5 Moderate pain

| 6

| 7

| 8

| | 9 10 Worst possible pain

5. Numerical Analog Scale|| If “0” is no pain and “10” is the worst possible pain, how would you rate your pain?

6. Verbal Descriptive Scale|| 0 = no pain; 1–3 = mild pain; 4–6 = moderate pain; 7–10 = worst possible pain *For preterm and term infants; scored on a 0-10 point system. † For infants 4 months of age to children 3 years of age. Each of the five categories—(F) Face; (L) Legs; (A) Activity; (C) Cry; (C) Consolability—is scored from 0 to 2, resulting in a total score between zero and 10. ‡ For children 3 to 11 years of age. § For children ≥7 years of age. || For children older than 11 years of age. Example 1, Neonatal Infant Pain Scale (NIPS), modified from Lawrence J, Alcock D, McGrath P, et al. The development of a tool to assess neonatal pain. Neonatal Netw 1993;6:59-66. Example 2, FLACC Scale, from Merkel SI, Voepel-Lewis T, Shayevitz JR, Malviya S. The FLACC: A behavioral scale for scoring postoperative pain in young children. Pediatr Nurs 1997;23:293-297. Example 3, FACES Scale, from Wong DL, Hockenberry-Eaton M, Wilson D, et al. Wong’s Essentials of Pediatric Nursing, 6th ed. St Louis: Mosby, 2001;1301.

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response, with close attention to the developmental changes in physiology and pharmacokinetics occurring between birth and childhood. A four-step approach to painful conditions, initially intended as a model for cancer pain management but applicable to other diseases, has been advocated by the World Health Organization [Schug et al.,1990]. Mild pain can be treated with cognitive techniques and weak analgesics (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs] and acetaminophen). For moderate pain, oral “weaker” opioids or combinations of opioids and NSAIDs or acetaminophen can be used. Severe pain requires more aggressive, parenteral opioids such as morphine or fentanyl. Intractable pain or unacceptable toxicities of pain management may require invasive interventions such as nerve blocks and intraspinal anesthetic infusions. A multimodal approach to pain relief allows drug synergy or potentiation and can reduce single drug doses, minimizing side effects [Galloway and Yaster, 2000]. Common side effects of opiates such as drowsiness, constipation, nausea, and pruritus should be treated prophylactically or when they occur without reducing analgesic doses. Sucrose (given orally as a 24% or 30% solution) is effective in reducing mild procedural pain (such as circumcision and immunizations) in neonates and infants; however, an association between poor neurodevelopmental outcomes and repeated sucrose analgesia has been reported [Johnston et al., 2002].

Anticipatory pain control (administering analgesics before to a painful procedure) can reduce hyperexcitability, diminish the total amount of drug required to treat pain, and prevent later behavioral changes. Nonpharmacologic techniques that may be effective include comfort measures (swaddling, pacifiers, contralateral tactile stimulation for newborns), soothing sounds, gentle handling and proper positioning, rest periods between procedures, reduced environmental stimuli, heat and cold, massage, transcutaneous electrical nerve stimulation, cognitive approaches, guided imagery, and distraction. Consultation with or referral to a multidisciplinary pain service may be indicated for unexpected pain duration, neuropathic pain, concerns about addiction, previous use of drugs or alcohol, or complicated family psychosocial issues.

Types of Pain Medication Aspirin, Acetaminophen, and Nonsteroidal Antiinflammatory Drugs Except for specific indications in rheumatologic diseases and for inhibition of platelet adhesion, aspirin is not commonly used as an analgesic in pediatrics because of its association with Reye’s syndrome. NSAIDs are most effective as preemptive agents or for treatment of mild-tomoderate pain of somatic origin. Acetaminophen is widely

TABLE 93–3 Dosage Guidelines for Analgesics DRUG Sucrose Acetaminophen

Ibuprofen Naproxen Aspirin

DOSE 0.2 ml of 30% solution 10–15 mg/kg Maximum daily dose: Infants, <75 mg/kg Neonates, >32 wks, 60 mg/kg Neonates, 28–32 wks, 40 mg/kg 6–10 mg/kg 5–6 mg/kg 10–15 mg/kg

Ketorolac 0.5 mg/kg Opioid Analgesics* Morphine Bolus: 0.1 mg/kg Infusion: Children, 0.03 mg/kg/hr Infants, 0.01–0.03 mg/kg/hr Term neonates, 0.005–0.02 mg/kg/hr Preterm neonates, 0.002–0.01 mg/kg/hr Oral immediate release: 0.3 mg/kg Oral sustained release: Infants 20-35 kg, 10–15 mg/kg Infants 35–50 kg, 15–30 mg/kg Oxycodone 0.1–0.2 mg/kg Methadone 0.1mg/kg Fentanyl Bolus: 0.5–1.0 μg/kg Infusion: Children, 0.05–2.0 μg/kg/hr Infants, 1–2 μg/kg/hr Term neonates, 0.05–2 μg/kg/hr Preterm neonates, 0.05–1 μg/kg/hr Hydromorphone Bolus: 0.02 mg/kg Infusion: 0.006 mg/kg/hr Oral: 0.04–0.08 mg/kg

INTERVAL (hr) 4

ROUTE PO PO, PR

6 8–12 4–6

PO PO PO

8

IV

2–4

IV

IV IV IV IV 3–4

PO

8–12 8–12 3–4 4–8 1–2

PO PO PO IV, PO IV

2–4 3–4

COMMENTS Optimal dose not established

Restricted use for anti-platelet or anti-inflammatory effect

No ceiling effect for severe pain

IV IV IV IV IV IV PO

*Initial doses and intervals. Adapted from Berde CB, Sethna NF. N Engl J Med 2004;347:1094-1103; Stevens B, Gibbons S, Franck LS. Pediatr Clin North Am, 2000;47:633-650; Holder KA, Patt RB. Pediatr Ann 1995;24:164-168; Tobias JD. Pediatr Clin North Am 2000;47:527-543.

Partridge / Pain Management and Palliative Care

used for minor pain and discomfort. Dosage guidelines for aspirin and other analgesics are summarized in Table 93-3. Because excess dosing can cause hepatic failure in infants and children, maximum daily doses are also listed. Other NSAIDs, most commonly ibuprofen and naproxen, have gained wide acceptance for pediatric use and are equally effective. For children who cannot tolerate oral dosing, ketorolac is available. NSAIDs provide a weak analgesia effect that tends to be more effective for pain that has an inflammatory component, as in postoperative pain. The concurrent use of NSAIDs can reduce opioid doses needed for effective pain management. The use of more than one NSAID concurrently offers little therapeutic advantage and increases the risk of side effects. NSAIDs used in conjunction with corticosteroids augment the risk of serious gastrointestinal complications.

Opioids Opioids are the mainstay of treatment of severe pain, operative procedures, postoperative pain relief, and management of chronic painful medical conditions in neonates and children [Berde and Sethna, 2002; Golianu et al., 2000; Stevens et al., 2000]. Opioids bind to brain and spinal cord opiate receptors to block neurotransmitter production. Mu-receptor agonists such as morphine, codeine, fentanyl, hydrocodone, and hydromorphone are effective for all pain intensities and are first-line choices for pain management. Agonist-antagonist drugs are not recommended because they have an analgesic ceiling, may precipitate withdrawal, and have limited routes of administration. Suggested guidelines for opiate-naïve patients are listed in Table 93-3. Because opiate-agonists have no therapeutic ceiling, doses should be adjusted to meet the patient’s individual needs. The overall safety and efficacy of opioids are well established. In children, as in adults, the risks of addiction after receiving opioids for pain are low [McCaffery and Pasero, 1999]; thus, clinicians should not hesitate to treat pain aggressively. However, increased risks for respiratory depression in infants younger than 6 months of age require close cardiorespiratory and saturation monitoring in settings in which emergent airway management is feasible. Fentanyl is the drug used most often for short procedures because of its rapid onset (1 to 2 minutes), peak effect (3 to 5 minutes), and short duration of action (2 to 4 hours). Morphine has a somewhat slower onset (5 minutes), with a peak response at 10 to 30 minutes, and longer duration of action (3 to 8 hours). Intravenous bolus or continuous infusions allow more rapid and reliable onset of analgesia that can be easily titrated and quickly reversed by narcotic antagonists. Patientcontrolled analgesia can be used in children (generally older than 7 years of age), but younger children should be under parent or nurse control. Opioids may also be administered subcutaneously, orally, rectally, transdermally, or intranasally. For some procedures, oral transmucosal fentanyl citrate provides an alternative for conscious sedation, although emesis is a frequent side effect. Rectal administration can be used when oral dosing is contraindicated; intramuscular injection should be used only as a last resort. Adverse effects of opioids include respiratory depression, sedation, vasodilation, hypotension, bradycardia (Fentanyl), muscle rigidity, urinary retention, ileus, seizures, and rigid

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chest (Fentanyl given rapidly). Tolerance may develop more rapidly with continuous infusions and with use of synthetic opioids [Arnold et al., 1990; Katz et al., 1994]. Characteristic withdrawal symptoms including irritability, hypertonicity, diaphoresis, fever, and emesis can occur when opioids are abruptly discontinued after several days’ exposure.

Procedural Sedation and Analgesia Most minor procedures that are minimally invasive can be performed using a mild analgesic and sedation. More uncomfortable procedures require deeper sedation appropriately performed by anesthesiologists, intensivists, or emergency physicians trained in advanced life-support and experienced in deep sedation techniques and monitoring. The American Academy of Pediatrics (AAP) has defined two levels of sedation less deep than general anesthesia [AAP, 2002]. Conscious sedation is a medically controlled state of depressed consciousness that: (1) allows protective reflexes to be maintained, (2) retains ability to maintain airway independently and continuously, and (3) permits appropriate response by the patient to physical stimulation or verbal commands. Deep sedation is a medically controlled state of depressed consciousness or unconsciousness from which the patient is not easily aroused, loses protective airway reflexes, and cannot maintain an airway or respond purposefully to physical stimulation or verbal command. Guidelines for sedating children undergoing therapeutic or diagnostic procedures have been reviewed by Krauss and Green [2000].

Analgesia Topical analgesia can reduce the discomfort of minor procedures or the local infiltration of anesthetic agents used for lumbar punctures, difficult intravenous cannulation, and suturing. Useful topical compounds when skin is intact include TAC (tetracaine, epinephrine, and cocaine), LET (lidocaine, epinephrine, and tetracaine), and EMLA (eutectic mixture of topical anesthetics, prilocaine and lidocaine). For brief procedures, ethyl chloride or fluoromethane can be used to cool the skin and provide a limited analgesic effect. For procedures involving deeper structures or prolonged painful interventions, local anesthetics or peripheral nerve blocks are required. For such procedures, fentanyl is preferred because of its faster onset, shorter duration, and lack of a histamineinducing effect; transmucosal fentanyl (lozenges or lollipops) offers procedural analgesia but often causes emesis. For procedures of longer duration, morphine and meperidine remain the preferable agents. For painful procedures, ketamine (given by the IM, IV, or enteral route) induces profound analgesia, sedation, and immobilization whereas spontaneous respiratory activity, airway tone, and protective reflexes are maintained. It may be the drug of choice for emergency procedures when the patient has not fasted. Side effects such as hallucinations, dreams, and dysphoria are seen less commonly in younger children than in adults.

Sedation Benzodiazepines are the most commonly used drugs for sedating children, particularly in pediatric intensive care

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units. Midazolam is the preferred drug for procedural sedation [McCaffery and Pasero, 1999]. It has a rapid onset of action (1 to 5 minutes), and a short half-life (1 to 12 hours). Given by the IV, IM, intratracheal, or enteral route, it provides potent sedation, some muscle relaxation, memory loss, and anxiolysis. Oral or intravenous routes are preferable for children; nasal administration causes an intense irritant response. As it has shorter duration than diazepam or lorazepam, it is a more appropriate choice for brief procedural sedation. Oral diazepam avoids the pain of intravenous injection and the variable absorption of intramuscular doses. For painful procedures, benzodiazepine sedation should be accompanied by opioid analgesia, and the patient should be monitored for hypoxia or respiratory depression. Midazolam can be reversed by flumazenil. Barbiturates are considered the sedatives of choice for diagnostic imaging in children older than 3 years of age, but they do not provide analgesia. Barbiturates lower the pain threshold, especially when pain is already present. Intravenous pentobarbital, rectal methohexital, and thiopental are the most extensively used drugs for procedural sedation. Chloral hydrate, an acceptably safe alternative sedative without analgesic efficacy, can be used for nonpainful procedures; the oral or rectal dose is 25 to 100 mg/kg (maximum dose, 2 g). Its use is largely restricted to sedation for electroencephalograms and diagnostic imaging in children younger than 3 years of age. Its extremely long half-life in neonates mitigates against repeated administration (Mayer et al., 1991), and other concerns have been raised because of potential carcinogenicity and genotoxicity in mice, even when given as a single low dose (Salmon et al., 1995). Given at subanesthetic doses, intravenous ultra-short-acting agents (etomidate, methohexital, propofol, remifentanil, and thiopental) can be used for procedural pain management, but they should be used only by practitioners experienced in dealing with the potential for oversedation or rapid swings in consciousness.

Types of Pain Neuropathic Pain A variety of neuromuscular and neurodegenerative diseases can cause both nociceptive pain (e.g., contractures or osteoarthritis) and neuropathic pain (e.g., nerve injury or entrapment) [Galloway and Yaster, 2000]. Neuropathic pain is difficult to treat with opioids and often requires multiple modalities for effective pain relief. Infiltration or compression of nerves by tumors responds to varying degrees to palliative radiation, steroids, surgical decompression, adjuvant drugs (tricyclic antidepressants, antiepileptics), neurolytic nerve blocks, epidural and intrathecal blocks, and opioids (which are often ineffective) [Galloway and Yaster, 2000]. Phantom pain after amputation may respond to preemptive regional anesthesia, antiepileptics, tricyclic antidepressants, calcitonin, topical agents, and intrathecal medication. Nerve trauma may be treated with injected local anesthetics, steroids, neurolysis, antiepileptics, tricyclics, or mexiletine. Neuropathies after chemotherapy can be treated with antiepileptics, tricyclics, or mexiletine. Tricyclic antidepressants (most commonly amitryptilene, doxepin, and sertraline) are used as adjuvants to inhibit nor-

epinephrine and serotonin uptake, thereby increasing neurotransmitter tone at the spinal cord level. Pain relief is achieved more quickly than the slower antidepressant effect of these drugs, with a response in 1 to 2 weeks. Given the quinidine-like effects of tricyclic antidepressants on cardiac conduction, baseline and periodic ECGs are recommended. Antiepileptic agents (carbamazepine and gabapentin) have been used to a limited extent in children to treat lancinating pain from peripheral nerve compression or injury and for peripheral neuropathies [Galloway and Yaster, 2000]. Mexiletine, an oral antiarrhythmic drug with potent analgesic effects, may be useful for neuropathic pain resistant to tricyclic antidepressants and antiepileptic medications. Because it also enhances the efficacy of other agents, it is generally used in combination with other drugs.

Pain in Children with Significant Neurologic Impairment Children with cerebral palsy or developmental delays experience pain, despite some reports of blunted pain responses or insensitivity to pain [Oberlander et al., 1999]. Patients with neurodevelopmental impairments have a variety of conditions or procedures that may cause pain, including splinting and casting, dislocations and joint contractures, spasticity, pressure sores, feeding tubes, constipation, diagnostic tests and specific treatments. Pain from spasticity and muscle spasms can be treated with diazepam, dantrolene, or oral baclofen. Oral analgesia is the least invasive method of administration and therefore the preferred route; intramuscular injections may be more painful in children with decreased muscle mass. Subcutaneous and transdermal administration can be used for chronic administration. Patients with neurologic impairment are more likely to have pain discounted or denied by caregivers and thus may have pain ineffectively treated. In patients too impaired to communicate their experience of pain, behavioral responses should be regarded as surrogate measures of pain and the pain treated appropriately. To avoid over- or undertreatment when self-report is uncertain, it is important to choose a measure appropriate to the individual patient that can be ascertained over time. For children with significant neurologic impairments, the need for analgesia for acute procedural pain must be balanced by the recognition that systemic opioids may have undesirable side effects, such as respiratory depression and constipation.

Migraine and Headache Symptomatic pain relief from headache can be obtained by oral, rectal, or intravenous routes and has been reviewed elsewhere [Annequin et al., 2000] (see Chapter 53). NSAIDs or weak analgesics can be given in adequate doses for mildto-moderate pain from tension headaches and migraine attacks. For intractable migraine, dihydroergotamine and sumatriptan have been used in preference to opioids, because of the potential for abuse or dependence in patients with recurrent attacks. The hallmark of effective control of migraine is treatment early in an attack. Intranasal administration of sumatriptan [Lewis et al., 2004] or possibly dihydroergotamine may be preferable because of the nausea and vomiting associated with some migraine headaches. The condition of children with tension headaches improves with

Partridge / Pain Management and Palliative Care

simple analgesia and relief of any precipitating stressors. Once a chronic pattern is established, cognitive-behavioral techniques such as biofeedback and relaxation therapy may help alleviate headaches.

Summary Relief of pain is one of the most important aspects of ethical medical care, especially in young children and children with neurologic handicaps who cannot communicate their experience of pain [Oberlander et al., 1999]. The success of nonpharmacologic means in reducing anxiety or fear should not dissuade physicians from giving pediatric patients appropriate analgesics.

PALLIATIVE CARE Over 50,000 children die each year in the United States from trauma, lethal congenital conditions, extreme prematurity, heritable disorders, and acquired illness [Catlin and Carter, 2002; Himelstein et al., 2004]. At least 500,000 children suffer life-threatening medical conditions that put them at high risk for not surviving into adulthood [Himelstein et al., 2004]. Nearly half of pediatric deaths occur in the hospital, and over 70% of deaths from chronic complex conditions are in hospital; of these, nearly half occur in intensive care settings [Feudtner et al., 2002]. Although children younger than 1 year of age have a higher death rate than any other pediatric age group [Behrman et al., 1996; Guyer et al., 1999], it is estimated that only 5000 to 7000 children (1% of dying children) receive hospice care or formal palliative care services. It is thought that another 10,000 to 15,000 children could benefit from hospice services [World Health Organization, 1998]. Currently, approximately 60% of deaths in pediatric intensive care units and nearly 75% of deaths in neonatal intensive care units follow limitation of care or withdrawal of life-sustaining treatments when therapy appears to offer no benefits or when quality of life appears unacceptable [Garros et al., 2003; Wall and Partridge, 1997]. Recent population-based studies have documented that 15% of pediatric hospital deaths are from neurologic or neuromuscular diseases [Feudtner et al., 2002]. Neuromuscular disorders cause 3% to 4% of childhood deaths in all age groups but account for 15% to 20% of deaths of children with complex chronic conditions. A variety of severe neurologic diagnoses fit into four broad categories of life-limiting conditions for which palliative care may be indicated (Box 93-1) [Dangel, 2002]. Deficiencies in provision of end-of-life care have been well documented [Wolfe et al., 2000] in other subspecialty fields. Some neurologists believe that they lack the training and experience required to manage the complex needs of dying children, to treat pain and other end-of-life symptoms, or to communicate bad news to young patients and their families.

Historical Background Palliative care as an adjunct to modern medical care began with the founding of St. Christopher’s Hospice by Cecily Saunders in 1967 [Saunders, 1988]. Whitfield later adapted

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Box 93-1 EXAMPLES OF NEUROLOGIC CONDITIONS THAT MAY BE APPROPRIATE FOR PEDIATRIC PALLIATIVE CARE Life-Threatening Conditions Curative treatment may be feasible but can fail. • Cancer • Meningitis • Encephalitis (herpes simplex virus) • Extreme prematurity Chronic Conditions Long periods of intensive treatment aimed at prolonging life and allowing participation in normal childhood activities are required, but premature death is still possible. • Neurofibromatosis • Tuberous sclerosis • Hydrocephalus • Muscular dystrophy and progressive neuropathies • Neurodegenerative diseases • Metabolic disorders with neurologic manifestations, including inborn errors of metabolism • Stroke, including moyamoya disease Progressive Conditions Treatment is exclusively palliative and commonly extends over many years. • Severe congenital myopathies • Spinal muscular atrophy • Anencephaly • Rachischisis • Intraventricular hemorrhage • Periventricular leukomalacia • Progressive metabolic disorders Nonprogressive Conditions Severe neurologic disability may cause weakness and susceptibility to health complications, but the patient may deteriorate unpredictably. • Unresponsive seizure disorders • Severe/high meningomyelocele • Central nervous system trauma • Hypoxic-ischemic encephalopathy • Chromosomal abnormalities with neurodevelopmental consequences (e.g., trisomy 13 or 18) • Holoprosencephaly or other severe brain malformations • Severe static encephalopathies with recurrent infections or symptoms difficult to control • Profound mental retardation models for care of adults to care of dying infants and their families, recommending changes in the intensive care environment [Whitfield et al., 1982]. Although the first pediatric hospices were started in 1982, it is only recently that widespread institution of pediatric palliative care has been recommended [American Academy of Pediatrics, 1996, 2000; World Health Organization, 1998]. Pediatric palliative care offers a cost-effective means to care for dying children [Pierucci et al., 2001]. It decreases

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the number of procedures that patients receive, increases the use of support services, shifts deaths to less-intensive settings, and increases the incidence of withholding or withdrawing aggressive measures [Pierucci et al., 2001]. Increasing emphasis on understanding patients’ and their families’ experience of death and dying can improve the care of critically ill children [Kirschbaum, 1990; Wolfe et al., 2000]. End-of-life care has more recently become a national focus for national quality improvement initiatives.

Definitions of Palliative Care Encompassing more than end-of-life care, palliative care embraces a philosophy of care that extends beyond and complements the aims of curing and healing children with life-limiting conditions. Dying pediatric patients (or their proxy decision-makers) have the same basic concerns as adults with terminal disease: (1) relief of pain and suffering, (2) avoiding inappropriate prolongation of dying, (3) achieving a sense of control, (4) relieving burdens, and (5) strengthening relationships with loved ones [Singer et al., 1999]. Typically provided by a multidisciplinary team, palliative care seeks to ensure the quality of living and of dying for the child for whom curative efforts are not (or are no longer) considered appropriate (Box 93-2) [Catlin and Carter, 2002]. The primary focus is to provide comprehensive, compassionate, and developmentally appropriate care that meets the physical, psychologic, emotional, social, and spiritual needs of the child as the disease progresses [American Academy of Pediatrics, 2000; Institute of Medicine, 1997; World Health Organization, 1998]. Additionally, palliative care optimally provides support and respite for parents during the illness, death, and bereavement in ways appropriate to their values, upbringing, religion, culture, and community. The intent is a decent or “good” death—free from avoidable distress and suffering for patients, families, and caregivers.

Box 93-2 INTERDISCIPLINARY TEAM FOR PALLIATIVE CARE • Primary care provider, community pediatricians, subspecialists • Pediatric registered nurses/case managers • Pediatric social worker • Child life therapist • Spiritual care counselor • Home health aides • Pediatric medical consultants • Physical/occupational therapists • Clinical pharmacist • Clinical dietitian • Volunteers • Insurers/payers • Other providers • Regional centers • Durable medical equipment companies • Community pharmacies

Components of Palliative Care Identifying the Need Whether providing primary care or subspecialty consultation, neurologists must learn when to address the palliative care needs of their patients and the family members. Children with neuromuscular diseases, and their family members, have a diverse range of medical, psychologic and emotional needs that differ from those of dying adults. Providers should learn to recognize when the need for palliative care is becoming more salient with neurodegenerative diseases and progressive neuropathies and when medical complications from a static encephalopathy impinge on the quality of life (e.g., aspiration in patients with spastic quadriplegia). Medical information about expected outcome and services should be appropriate for the child’s developmental age, current cognitive capacity, and emotional stage, as well as sensitive to the parents’ ability to accept their child’s clinical deterioration. Providers should allow time for the parents to nurture their child, while recognizing the difficult emotional stresses that parents face when seeing the acute change in their child’s condition or coming to grips with a certainty of neurologic compromise or death in the future. Providers should attempt to give parents—and when appropriate, children—some sense of control when they feel helpless and overwhelmed. Even when critically ill or dying, children benefit from being with and comforted by their parents. Although to an extent remaining strangers at the bedside [Rothman, 1991], physicians and nurses often become powerful and meaningful sources of support to parents [Meyer et al., 2002].

Transition in Goals of Care Palliative care for children does not need to be restricted to those expected to die soon when therapeutic interventions fail or are withdrawn. Some neurologic conditions are associated with a predictably shortened life span (e.g., trisomy 13 and 18, neurodegenerative diseases, anencephaly, severe hydrocephalus, and many inborn errors of metabolism), and the primary focus of care is limited to optimizing quality of life when a cure is not possible. Other diseases make prediction of life expectancy and quality of life more difficult (e.g., traumatic or hypoxic brain injury, some central nervous sytem or spinal tumors, congenital myopathies and neuropathies, muscular dystrophy, and storage diseases). Because it can be difficult to tell who will die early as a result of certain central nervous system and neuromuscular disease processes, it seems appropriate to offer palliative care to children with progressive conditions early, transitioning from curative efforts to palliative care as their condition worsens [Simpson Sligh, 1993]. Accordingly, palliative care efforts can and should coincide with therapies aimed to cure the disease or limit its progression. With children old enough to express their preferences, it is important to address future choices for care before neurologic status deteriorates to the extent that the child is no longer able to participate in health-care decisions. Parents must be given information necessary for decision making but must also understand the limits of the provider’s ability

Partridge / Pain Management and Palliative Care Therapy to modify disease (curative, life-prolonging, or palliative in intent)

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FIGURE 93-1. Model for transition to palliative care. (Adapted from Ferris et al., 2002).

End-of-life care Bereavement care Palliative care

Diagnosis

Illness continuum

Therapy to relieve suffering and/or improve quality of life

Acute life-threatening

Chronic

Death

Advanced life-threatening

to prognosticate treatment efficacy and outcome. Mention of palliative therapies, supportive care, or levels of non-intervention early in the course of a chronic or progressive life-threatening disease can soften the impact of nonintervention discussions later in the disease trajectory. An essential step is to clarify, and periodically reassess, the goals of continuing, rather than limiting, on-going interventions as the chances for cure lessen (Figure 93-1). Providers should facilitate the transition from curative or life-extending care to supportive efforts intended to improve quality of life. They may need to initiate discussions about changing treatment goals when parents have difficulty admitting that end-of-life care is needed [Callahan, 2000], particularly when parents have adapted to the demands of caring for children with life-threatening chronic conditions and to the diminished quality of life associated with many of these conditions (e.g., spinal muscular atrophy, unresponsive central nervous system tumors, and states of minimal consciousness). Acute brain injury (e.g., perinatal asphyxia and other sudden catastrophic deteriorations in neurologic status) can make the transition to palliative care difficult, because physicians often cannot offer clear prognostic certainty on survival or later neurodevelopmental functioning. With emergent conditions, there is often little time for difficult decisions or coping with complex emotions, and the transition from curative interventions to palliative care can seem abrupt [Frager, 1996; Sahler et al., 2000].

Levels of Care The shift in treatment goals, however, does not imply that ongoing medical interventions aimed at treating or curing the child’s disease (such as administration of blood products, oxygen, and antibiotics) must be abandoned, as they typically are in adult hospice care [Children’s Hospice International, 1989]. Some potentially beneficial treatments entail significant burdens, and it becomes important to clarify which specific measures will continue to be used as well as which level of nonintervention is most appropriate. An order proscribing all or selected resuscitative measures in the event of a cardiac or respiratory arrest (“Do not resuscitate” [DNR] or “Do not attempt resuscitation” [DNAR] order) is often the first step. This order represents a selective nonintervention order in the event of respiratory or cardiac arrest, not a half-hearted resuscitation (“slow code”) of a child deemed likely to die. When providers and

parents perceive that further medical therapy offers no benefit, that on-going interventions are inappropriate, or that the present quality of life is untenable, more extensive discussions about withholding or withdrawing specific lifesustaining therapies may be indicated [Wall and Partridge, 1997]. Withholding of life-sustaining measures involves an agreement not to institute specific medical measures that would otherwise be indicated. This level of nonintervention is usually reserved for children with a grim prognosis or whose quality of life would not be improved by more aggressive interventions. Such a level of nonintervention might be deemed appropriate for infants with trisomy 13 or 18, cerebral or spinal tumors, severe central nervous system malformations, or severe hydrocephalus. Interventions deemed futile are not required and should be discontinued [Paris et al., 1999]—for example in patients with brain death, anencephaly, lethal neuropathies and myopathies, and untreatable inborn errors of metabolism. Withdrawal of life-sustaining measures involves the discontinuation of medical interventions currently in use but deemed either futile or no longer appropriate to the child’s best interests, accepting the possibility that death may be hastened. Although ethically equivalent, withholding and withdrawing treatment often feels different at the bedside and can raise emotional responses in parents and providers. Whenever support is withheld or withdrawn, it is appropriate for the primary physician to discuss DNAR status with parents and the healthcare team before writing the order.

Communication Patterns of communication sensitive to the child’s developmental age and neurologic status and to the parents’ emotional state are critical to good palliative care for children. The degree to which the child can participate in decision making increases with older children (older than 7 years of age). The use of pictures, stories, toys, and music can help younger children communicate their preferences. On the other hand, infections of the nervous system, hypoxia-ischemia, neurodegenerative diseases, or traumatic brain injury can diminish an older child’s decision-making capacity. Whenever the child has the cognitive capacity to participate, it is important for providers to allow the child the time to express hopes, dreams, and fears [Back, 2003]. Discussions about treatment options should review the child’s current status, estimate the presumed disease

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Box 93-3 PROTOCOL FOR PALLIATIVE CARE COMMUNICATIONS— SPIKES: A PROTOCOL FOR DELIVERING BAD NEWS AND NEGOTIATING GOALS OF CARE

From Buckman R. Breaking bad news: A guide for health care professionals. Baltimore: Johns Hopkins University Press, 1992.

trajectory, characterize the quality of life that each treatment choice entails, and finally assist the child and parents in selecting which measures should and should not be carried out. The primary focus is to determine what is important to the child and the family—for example, longer life, freedom from pain, time with family members, specific desires, choice of environment and setting, and time to say goodbye. The next step is to devise a collaborative care plan that respects the patient’s emotional and spiritual needs, incorporates family values, and supports family involvement in health-care decisions. When time allows, such planning is best done by parents and primary care providers working together over a period of time, giving cognitively capable patients and parents time for questions, second-opinion consultations, talks among family members, reflection, deliberation, and informed decision making. Repeated discussions empower informed decision making and help minimize the guilt some parents feel about their decisions after their child dies. A structured approach can help physicians deliver difficult news and negotiate goals of care (Box 93-3). Critical aspects of the communication process include simple, direct, clear, and honest explanations that relate the expected outcomes of each treatment option without prejudicing or constraining the parents’ choices. It is important that the information neither overwhelms the parents nor leaves them in despair. Providers should avoid promising outcomes that they do not believe are feasible. Neurologists play a key role in communicating the expected neurologic outcome after a life-threatening illness; neurology consultation can help parents understand expected functional status when there is little chance for an acceptable outcome. To minimize the sense of giving up or abandoning their child, it is critical that parents understand that the goal of care is to do everything that should be done rather than everything that can be done.

Health-Care Decision Making Because children usually have no previously documented preferences for health-care decisions, parents and physicians must assess when the burdens of care are no longer in the best interests of the child. The first issue is to identify and involve those who will be making health-care decisions. To the level of their developmental capacity, older children themselves have the right to determine what quality of life

means to them, with support from their parents and physicians. Younger children necessarily depend on their parents as the predominant decision makers. Parents (or the competent adolescent) determine the quantity of information necessary for them to make an informed decision. If decisions seem not to reflect a full understanding of the disease, the goals of care, or expected outcomes, further discussions facilitate review of the information and reflection on treatment options. Decisions that do not concur with the provider’s choices should be respected when made in the child’s best interests. Advanced directives specifying care preferences of once-competent adults, or identifying proxy decision makers should an adult become incapacitated have no legal relevance in pediatric patients [Pierucci et al., 2001]. In general, parents are assumed to be the primary proxy decision-makers for young children; however, their discretion is not unlimited. When consensus is difficult to reach, ethics committee consultation can help clarify impediments to decision making. In rare situations in which parents’ judgment may be questionable or the child’s best interests remain uncertain, providers may need to advocate for the child or even refer to child welfare services. A process of guided autonomy can support the involvement of the child and the parents in treatment decisions while preserving some autonomy and minimizing the undue emotional strain of making decisions to limit care.

VEGETATIVE STATE A small proportion of children who survive critical illnesses continue for varying periods of time in a vegetative or a minimally conscious state. Although the exact incidence is unknown, an estimated 4000 to 10,000 infants and children in the United States live in this condition and present a special challenge to clinicians and ethicists alike [Ashwal et al., 1992]. Although there is no consensus about whether children in a vegetative state experience pain and suffering, it seems prudent to treat signs or symptoms in children in a vegetative state that may mimic or appear like pain and suffering. Decisions to withdraw or withhold life-sustaining measures should be made in collaboration with parents only when neurodiagnostic testing and a sufficient period of observation suggest there is no chance for a meaningful recovery [AAN Quality Standards Subcommittee, 1995]. Decisions to forego supportive care, especially those involving withholding fluids or hydration, remain controversial even when deemed appropriate responses to the child’s medical situation. Such decisions present complex emotional and ethical challenges to clinicians and family members [Carter and Leuthner, 2003].

Environment for Death and Dying Some parents may prefer continued care in the hospital, where skilled nursing and medical care offsets limitations to privacy and the inhospitable ambience of most in-patient settings. A private space for families to gather before and after the child’s death is recommended (e.g., a screen for privacy or, better, a separate comfort-care room) and should not impede nursing care or medical attention to pain and symptoms. Other in-patient options include transfer to a lower level of care or to a hospice, although some parents

Partridge / Pain Management and Palliative Care

may feel abandoned by changes in care providers late in the course of their child’s disease. Death at home is preferred by a significant number of children and parents [Pierucci et al., 2001]. Parents who opt for home care must be adequately supported in managing terminal care for the child outside the hospital. Plans for a death at home require a care provider skilled in managing pain and suffering and able to provide 24-hour coverage from discharge through the child’s death and the parents’ bereavement.

Support during Dying

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have primary care pediatricians or palliative care specialists manage other frequently encountered end-of-life symptoms such as dyspnea, anxiety, fatigue, fever, bleeding, nausea, skin breakdown, anorexia, dehydration, and constipation. Despite shared concerns for patient well-being, treatment of symptoms experienced by dying patients has been inconsistent [Partridge and Wall, 1997; Pierucci et al., 2001; Wolfe et al., 2000]. Attempts should be made to organize a care plan allowing death without suffering (either at home or in hospital) for any child in need, regardless of socioeconomic circumstances.

When death is near, providers can prepare parents for the child’s imminent death by envisioning expected changes in the child’s appearance, advising them as to likely timing, and assuring them that pain will continue to be aggressively treated. Parents usually choose to hold their dying child, and this choice should be facilitated and the parents’ well-being ensured as best as possible. Mention can be made of discussions that will be required after the child dies, such as autopsy or organ donation. Some families perceive organ donation as a positive aspect within the tragedy of their child’s death (e.g., after traumatic brain death or sudden infant death syndrome). In other cases, such as anencephalic infants, organ donation continues to pose difficult medicolegal issues for clinicians [Walters, 2001]. Overall support of a family when a child dies involves a balance between respect for privacy and close but noninvasive attention to the child’s and the family members’ needs. Neurologists caring for terminal patients can turn to primary care pediatricians, social workers, clergy, psychologists, psychiatrists, and other sources of support, as the parents’ adjustment dictates.

Developmental, Emotional, and Spiritual Concerns

Assessment and Treatment of Symptoms

Children are aware of dying and disease; they understand much more about death and dying than adults realize. Parents who sense that the child is aware of imminent death more often regret not having talked with the child than do parents who do not sense this awareness in the child, and typically parents who talk with a child about death do not regret doing so [Kreicbergs et al., 2004]. Children grieve as much as adults, although in different ways. Dying children may grieve their impending death, the loss of functional status, or the inability to participate in current or future events. They may worry about how family members will cope after their death. Dying children and their siblings do not need to be protected from death and dying as much as they need help making it understandable. When heritable neuromuscular disorders pose a future risk for affected siblings, particular care is necessary to deal with parents’ sense of guilt, parents’ and siblings’ grief, concerns about subsequent pregnancies, and family fears of illness in the future. In general, the grieving process should not be rushed. Providers should allow family members the opportunity to spend time grieving with their deceased child alone. In the immediate moment, there is a time to talk and a time to be silent; it may be helpful to celebrate their child’s life, recap the family’s experience, value their loss and their emotional responses, and help them contact other family members and friends. Parents should be offered access to religious observances, social services support, family support groups, or other measures to help them cope.

A primary focus of palliative care is the relief of distressing symptoms that detract from the child’s quality of life. Providers should discuss in advance symptom management to reassure patients and parents and to educate them about what may occur as the disease progresses. Providers should reevaluate the efficacy of pain and symptom management as the disease progresses. Some neurologists feel comfortable managing pain and other end-of-life symptoms and will follow the child throughout the course of the disease. Others may prefer to consult the primary care pediatrician or a pediatric palliative care specialist with expertise in symptom management. Pain should be aggressively treated with analgesics. When there is severe or unremitting pain at the end of life, terminal sedation with opioids is used to alleviate suffering, recognizing that opioids may suppress respiratory drive in debilitated patients and may thereby hasten death. The risk of death is justified because there is no alternative that alleviates suffering while lessening the risk of death [Fleischman, 1998]. Fears of addiction to opioids, the mainstay of pain management at the end-of-life care, on the part of providers or family members are unwarranted. Paralytics are not appropriate when life support is being withdrawn [Pierucci et al., 2001]. Anxiolytics may help terminal agitation and perhaps air hunger experienced in the terminal phases. Many neurologists are comfortable treating seizures, insomnia, and depression in dying patients but may prefer to

Care for a dying child requires candor, openness, and emotional availability to the child’s experience of illness and imminent death. Children need to understand death and dying in terms of their developmental age. Research indicates that they begin to understand it as a change of being by age 3 and as a universal fact of living by age 5 or 6 and have gained a concept of their personal mortality by age 8 or 9 [Himelstein et al., 2004]. Spirituality is one way that patients and families cope with death and dying whether or not they adhere to any specific religion. Approaches that respect the child’s spiritual nature at varying developmental stages allow providers to explore issues of love, hope, security, and loneliness and concepts of the legacy that the child will leave to surviving parents, siblings, friends, and schoolmates. Family routines and rituals add familiar structure and a sense of normality as the child’s medical condition worsens and should be encouraged whenever possible.

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Care of the Child with Neurologic Disorders / 93

Excluding children from the grieving process may foster a loss of trust or a sense of resentment. Attending the funeral can be a way in which children can participate in remembering and valuing the dead child. In some cases, psychologic counseling may be offered as a way to help parents and siblings work through the emotional trauma. Practice Sphere Physical concerns

Follow-up Conference Many physicians arrange a conference after the child’s death to see how the parents are coping and help them resume more normal functioning in the aftermath of the child’s death. A meeting can review postmortem examination results and

Area of Assessment Identify pain or other symptoms

Identify child and family’s fears and concerns

Address child and family’s fears and concerns honestly Assure child and family they will not be abandoned Address concerns of child’s siblings and extended family

Identify child’s coping and communication styles

Adjust care plan to meld with child and family’s coping and communication styles Communicate with child in a developmentally appropriate fashion Explain death concepts and developmental stages of death understanding

Discuss previous experiences with death, dying, other traumatic life events, or special issues such as substance abuse or suicidality

Modify care plan and choices on basis of child’s previous experiences Consider referring child and family to mental health professionals as needed

Assess resources for bereavement support

Make plan for follow-up of family after child’s death Assure family members they will not be abandoned

Perform a spiritual assessment (review child’s hopes, dreams, values, life meaning, view of role of prayer and ritual, beliefs regarding death)

Consider referring child to culturally appropriate spiritual care provider Offer to help explain child’s illness to spiritual provider, with family’s permission Allow time for child and family to reflect on life’s meaning and purpose

Identify decision makers

Include key decision makers Communicate decision-making information to entire team

Discuss illness trajectory

Provide information as necessary to make the subject understandable Establish consensus regarding illness trajectory Identify effect of illness on child’s functional capacity and quality of life Identify probable time until death

Identify goals of care

Establish whether goals are curative, uncertain, or primarily comfort Communicate goals to health care team

Think about issues regarding care or concerns near end of life

Create or disseminate medical plan (including do-notresuscitate orders as necessary), reflecting choices for specific interventions related to change in health status Provide anticipatory guidance regarding physical changes at time of or near death, whom to call, who will manage child’s symptoms

Establish means of communication and coordination with health care team

Identify care coordinator and route of contact that is always available Recruit new personnel as needed to achieve goals (such as hospice or palliative care specialists) Make plan-of-care information available to team

Establish child and family’s preferences for location of care

Assure child or family that stated goals of care can be achieved in preferred environment Create and disseminate plan for location of death, contacts at time of death, and pronouncement of death

Become familiar with child’s home or school environment

Create and disseminate care plan for all relevant environments Try to visit care sites such as school to provide education and support, if possible in partnership with community agencies

Address child’s current and future functional status

Order medical equipment such as wheelchair, suction, commode, or hospital bed for anticipated needs

Inquire about the financial burden child’s illness places on family

Offer assistance from social services, financial counselors, or other supports as available in the community

Psychosocial concerns

Spiritual concerns

Plan Create and disseminate pharmacologic and nonpharmacologic treatment plan Place emergency medications in the home Refer child to pain and palliative care specialists as needed

Advance care planning

Practical concerns

FIGURE 93–2. Essential elements in the approach to pediatric palliative care. (From Himelstein BP, Hilden JM, Boldt AM, Weissman D. Pediatric palliative care. N Engl J Med 2000 350;1752–1762. Copyright © Massachusetts Medical Society. All rights reserved.)

Partridge / Pain Management and Palliative Care

clarify aspects of the diagnosis, etiology, and end-of-life events; it can provide a measure of solace by demonstrating that providers remember their child and continue to care about the family. Often it is an opportunity to put to rest parents’ questions about “what might have been,” to minimize tendencies to blame themselves or their child’s providers, to detail the implications of heritable neurologic disorders for siblings or subsequent pregnancies, and to offer referrals to counseling or support groups.

Barriers to Palliative Care The remarkable success of medicine in treating many medical conditions can make it difficult to abandon attempts to cure the primary disease. Providers may overtly or tacitly encourage treatments with little or no hope of a favorable outcome, abandoning them only when death seems inevitable. In pediatrics, a late transition from curative to palliative care is a frequent problem. Some providers may conceive of palliative care as a second-string treatment regimen, to be offered and used only for patients who cannot be cured and only very near the end of life [Pierucci et al., 2001]. In many pediatric neurologic diagnoses, it is difficult to predict the course of the disease, which children will die from the disease, or the quality of life as the disease progresses. Parents’ recognition that death is inevitable often lags behind their understanding of the diagnosis. Both parents and providers may feel that the death of a child is inexplicable, unnatural, something that should not happen. Palliative care requires increased time and staff to provide for the many needs of the dying patient and of family members.

Summary When cure of a life-threatening disease is not expected, neurologists can offer children and their families other benefits: the best medical information on diagnosis, current status, and expected outcome; adequate analgesia and treatment of other symptoms; medical and emotional support; perspective and referrals; assistance in decision-making partnership; open discussion about ways to “optimize” the dying process; follow-up meetings; and opportunities/referrals for grief counseling. Palliative care offers many ways to improve children’s and families’ experience of end-of-life care (Figure 93-2). Neurologists should develop expertise in palliative care of children with life-threatening neurologic and neuromuscular conditions. When serving as a consultant, neurologists should work with primary pediatric providers and palliative care specialists to meet their patients’ needs for end-of-life care. With an interdisciplinary team approach and the use of medical technology only when benefits outweigh burdens, providers and parents ensure the best possible life while the child lives and a death that is comfortable, peaceful, and dignified. REFERENCES AAN Quality Standards Subcommittee. Practice parameters: Assessment and management of patients in the persistent vegetative state. Neurology 1995;45:1015. American Academy of Pediatrics Committee on Bioethics. Ethics and the care of critically ill infants and children. Pediatrics 1996;98:149.

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Fitzgerald M, Koltzenburg M. The functional development of descending inhibitory pathways in the dorsolateral funiculus of the newborn rat spinal cord. Brain Res 1986;389:261. Fleischman AR. Commentary: Ethical issues in pediatric pain management and terminal sedation. J Pain Symptom Manage 1998;15:260. Frager G. Pediatric palliative care: Building the model, bridging the gaps. J Palliat Care 1996;12:9. Franck LS, Greenberg CS, Stevens B. Pain assessment in infants and children. Pediatr Clin North Am 2000;47:487. Galloway KS, Yaster M. Pain and symptom control in terminally ill children. Pediatr Clin North Am, 2000;47:711. Garros D, Rosychuk RJ, Cox PN. Circumstances surrounding end of life in a pediatric intensive care unit. Pediatrics 2003;112:e371. Golianu B, Krane EJ, Galloway KS, et al. Pediatric acute pain management. Pediatr Clin North Am, 2000;47:559. Goodman JE, McGrath PJ. The epidemiology of pain in children and adolescents: A review. Pain 1991;46:247. Grunau RVE, Whitfield M, Petrie P, et al. Early pain experience, child and family factors, as precursors of somatization: A prospective study of extremely premature and full-term children. Pain 1994a;56:353. Grunau RVE, Whitfield M, Petrie J. Pain sensitivity and temperament in extremely low-birth-weight premature toddlers and preterm and full-term controls. Pain 1994b:58:341. Guyer B, Hoyert DL, Martin JA, et al. Annual summary of vital statistics—1998. Pediatrics 1999;104:1229. Himelstein BF, Hilden JM, Boldt AM, Weissman D. Pediatric palliative care. N Engl J Med 2004;350:1752. Holder KA, Patt RB. Taming the pain monster: Pediatric postoperative pain management. Pediatr Ann 1995;24:164. Howard RF. Current status of pain management in children. N Engl J Med 2003;290:2464. Institute of Medicine, Committee on Care at the End of Life. Approaching death: Improving care at the end of life. Washington, DC: National Academy Press,1997. Institute of Medicine. Field MJ, Behrman R, eds. When children die: Improving palliative and end-of-life care for children and their families. Washington, DC: National Academy Press, 2003. International Association for the Study of Pain, Subcommittee on Taxonomy. Pain terms: A list with definitions and notes on usage. Pain 1979;6:249. Joint Commission on Accreditation of Healthcare Organizations. Pain assessment and management standards—hospitals. Oakbrook Terrace, IL: Joint Commission Resources, 2001. Johnston CC, Filion F, Snider L, et al. Routine sucrose analgesia during the first week of life in neonates younger than 31 weeks’ postconceptional age. Pediatrics 2002;110:523. Katz R, Kelly HW, His A. Prospective study on the occurrence of withdrawal in critically ill children who receive fentanyl by continuous infusion. Crit Care Med 1994;22:763. Kirschbaum MS. Needs of parents of critically ill children. Dimens Crit Care Nurs 1990;9:344. Klimach VJ, Cooke RW. Maturation of the neonatal somatosensory evoked response in preterm infants. Dev Med Child Neurol 1988;30:208. Krauss B, Green SM. Sedation and analgesia for procedures in children. N Engl J Med 2000;342:938. Kreicbergs U, Valdimarsdottir U, Onelov E, et al. Talking about death with children who have severe malignant disease. N Engl J Med 2004;351:1175. Lawrence J, Alcock D, McGrath P, et al. The development of a tool to assess neonatal pain. Neonatal Netw 1993;122:59. Lewis D, Ashwal S, Hershey A, et al. Practice parameter: Pharmacological treatment of migraine headache in children and adolescents. Neurology 2005, in press. Mayer D, Hindmarsh KW, Sankaran K, et al. Chloral hydrate disposition following single dose administration to critically ill neonates and children. Dev Pharmacol Ther 1991;16:71. McCaffery M, Pasero C. Teaching patients to use a numerical pain-rating scale. Am J Nurs 1999;99:22. McGrath PJ, Rosmus C, Camfield C, et al. Behaviors caregivers use to determine pain in non-verbal cognitively impaired children. Dev Med Child Neurol 1999;40:340.

Merkel SI, Voepel-Lewis T, Shayevitz JR, Malviya S. The FLACC: A behavioral scale for scoring postoperative pain in young children. Pediatr Nurs 1997;23:293. Meyer EC, Burns JP, Griffith JL, et al. Parental perspective on end-of-life care in the pediatric intensive care unit. Crit Care Med 2002;30:226. Paris JJ, Singh J, Schreiber MD, et al. Unilateral do-not-resuscitate order in the neonatal intensive care unit. J Perinatol 1999;19:383. Partridge JC, Wall SN. Analgesia for dying infants whose life support is withdrawn or withheld. Pediatrics 1997;99:76. Pierucci RL, Kirby RS, Leuthner SR. End-of-life care for neonates and infants: The experience and effects of a palliative care consultation service. Pediatrics 2001;108:653. Polaner DM. Sedation-analgesia in the pediatric intensive care unit. Pediatr Clin North Am 2001;48:695. Rothman DJ. Strangers at the bedside: A history of how law and bioethics transformed medical decision making. New York: BasicBooks, Harper Collins, 1991. Sahler OJ, Frager G, Levetown M, et al. Medical education about end-of-life care in the pediatric setting: Principles, challenges, and opportunities. Pediatrics 2000;105:575. Salmon AG, Kizer KW, Zeise L, et al. Potential carcinogenicity of chloral hydrate—a review. J Toxicol Clin Toxicol 1995;33:115. Saunders CM, ed. St. Christopher’s in celebration: Twenty-one years at Britain’s first modern hospice. London: Hodder and Stoughton, 1988. Schechter NL, Allen DA, Hanson K. Status of pediatric pain control: A comparison of hospital analgesic usage in children and adults. Pediatrics 1986;77:11. Schechter NL. The undertreatment of pain in children: An overview. Pediatr Clin North Am 1989;36:781. Schug SA, Zech D, Dorr U. Cancer pain management according to WHO analgesic guidelines. J Pain Symptom Manage 1990;5:27. Shah V, Ohlsson A. The effectiveness of premedication for endotracheal intubation in mechanically ventilated neonates. A systematic review. Clin Perinatol 200;29:535. Simpson Sligh J. An early model of care. In: Armstrong-Dailey A, Zarbock Goltzer S, eds. Hospice care for children. New York, Oxford: Oxford University Press, 1993. Singer PA, Martin DK, Kelner M. Quality end-of-life care: Patients’ perspectives. JAMA 1999;281:163. Stevens B, Gibbins S, Franck LS. Treatment of pain in the neonatal intensive care unit. Pediatr Clin North Am 2000;47:633. Taddio A. Opioid analgesia for infants in the neonatal intensive care unit. Clin Perinatol 2002;29:493. Taddio A, Katz J, Ilersich AL, et al. Effect of neonatal circumcision on pain responses during subsequent routine vaccination. Lancet 1997;349:599. Tobias JD. Weak analgesics and nonsteroidal anti-inflammatory agents in the management of children with acute pain. Pediatr Clin North Am 2000;47:527. Voepel-Lewis T, Merkel S, Tait AR, et al. The reliability and validity of the Face, Legs, Activity, Cry, Consolability observational tools as a measure of pain in children with cognitive impairment. Anesth Analg 2002;95:1224. Wall SN, Partridge JC. Death in the intensive care nursery: Physician practice of withdrawing and withholding life support. Pediatrics 1997;99:64. Walters JW. Anencephalic infants as organ sources. Bioethics 1991;5:326. Weisman SJ, Bernstein B, Schechter NL. Consequences of inadequate analgesia during painful procedures in children. Arch Pediatr Adolesc Med 1998;152:147. Whitfield JM, Siegel RE, Glicken AD, et al. The application of hospice concepts to neonatal care. Am J Dis Child 1982;136:421. Wolfe J, Grier HE, Klar N, et al. Symptoms and suffering at the end of life in children with cancer. N Engl J Med 2000;342:326. Wong DL, Hockenberry-Eaton M, Wilson D, et al. Wong’s Essentials of pediatric nursing, 6th ed. St. Louis: Mosby, 2001. World Health Organization. Cancer pain relief and palliative care in children. Geneva: World Health Organization, 1998.

CHAPTER 94

Ethical Issues in Child Neurology David L. Coulter

The “task” of ethics in general is to understand how human beings should behave in regard to other persons and to society [Slote, 1995] or to understand what is right and what is wrong. The philosophical study of ethics is as old as civilization itself and parallels the growth and development of human society. Morality is understood as the set of generally accepted rules and guidelines for acceptable conduct in society. These social conventions about what is right and wrong constitute the “common morality” [Beauchamp and Childress, 1994]. Philosophical ethics can be thought of as the attempt to develop a rational basis for morality. Although ethics (as a form of philosophy) strives for universal truth, it is inextricably linked to the realities of the human societies whose morality it seeks to understand [Slote, 1995]. Distinguishing between “moral” and “ethical” behavior is often difficult [Bernat, 1994]. Perhaps moral behavior may be thought of as a personal attempt to conduct one’s life in conformity with the common morality, whereas ethical behavior may be thought of as a more theoretical or rational attempt to apply philosophical thinking to what is right and wrong. In other words, ethics is a systematic attempt to understand how to live and act morally in a social context. Ethics addresses all aspects of human behavior. Bioethics considers the interaction between biology and ethics. It is defined as “the systematic study of the moral dimensions of the life sciences and health care” and includes consideration of “the health-related and science-related moral issues in the areas of public health, environmental health, population ethics and animal care” [Reich, 1995]. Clinical ethics is a subcategory of bioethics that refers to the day-to-day moral decision making of those caring for patients [Callahan, 1995]. More specifically, clinical ethics refers to the identification, analysis, and resolution of moral problems that arise in the care of a particular patient [Jonsen et al., 1998]. Medical ethics is a subcategory of clinical ethics that refers to the moral behavior of physicians (and is thus distinguishable from nursing ethics, social work, and pastoral/spiritual ethics). Neuroethics is a new concept that cuts across most of these distinctions. As an area of bioethics, it considers the interaction between the neurosciences and ethics in all of the same areas of study as bioethics noted previously [Pfaff, 1983]. As a clinical discipline, it addresses the care of patients with neurologic disorders. As an area of medical ethics, it refers most directly to the moral behavior of neurologists and neurosurgeons. Thus, child neurologists interested in ethics need to be knowledgeable about the general approaches to ethics, the emerging scope of bioethics, and the more specific approaches to ethics in medicine, nursing, and other health-related disciplines.

This edition of this textbook on pediatric neurology is the first to include a chapter on ethics. Although many articles and books have been published on ethical topics of interest to child neurologists, few provide a systematic approach to ethics in child neurology. A recent collection of articles covered a number of important topics [Shevell, 2002], and a recent casebook presented a number of illustrative cases whose analyses illuminate many of the important ethical issues in child neurology [Freeman and McDonnell, 2001]. The best general, systematic resource on ethics in neurology is the classic text by Bernat [1994], but it mainly covers topics of interest in adult neurology. This chapter follows the general structure of Bernat’s book and seeks to apply its concepts specifically to the area of pediatric neurology. The goal of the chapter is to provide child neurologists interested in ethics with the tools they need to identify, analyze, and resolve moral problems they may encounter in the care of children and adolescents with neurologic disorders. The first part of this chapter covers the most significant theoretical approaches to ethics as they apply to child neurology. The second part considers the varied duties of the child neurologist caring for patients with morally problematic issues. The third part discusses several specific ethical problems in child neurology. The discussion of these specific problems is broadly conceptual to identify issues and raise questions whose answers will need to be elaborated in the context of caring for a particular patient and family.

THEORETICAL APPROACHES TO ETHICS Philosophy may be a search for truth, but the fact is that there is no one, true, universal approach to ethics. Physicians who want to act ethically should be aware of the several major ethical theories that compete for attention in contemporary medical practice. Two ethical theories in particular dominate thinking in Western philosophy. Utilitarianism is derived from the writings of Jeremy Bentham [Bentham, 1982] and John Stuart Mill [Mill, 1971]. Deontology is derived mainly from the writings of Immanuel Kant [Kant, 1959]. Elements of both theories persist in modern ethical approaches to clinical problems, usually in somewhat modified form. Most physicians will find themselves using utilitarian thinking on some occasions and deontologic thinking on other occasions, or using some combination of both when it is necessary to resolve an ethical dilemma in clinical practice. A number of other ethical approaches have been developed more recently and also deserve consideration. As a general statement, probably no one theory or approach is

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optimal in every case in medical practice. A skillful physician will recognize which approach is best suited to the challenges of a specific ethical situation.

Utilitarianism The essence of utilitarian theory is the idea that the morality of an action is determined mainly by its consequences: the morally right action is the one that produces the best result [Beauchamp and Childress, 1994]. Of course, the result of an action may be quite complex. An action that helps one person may harm another person. Withdrawing support from a child in a vegetative state undoubtedly harms the child, since it results in the child’s death, but the action may help the family grieve and may allow society to use limited medical resources to help other patients. The utility principle states that one should act to produce the best overall balance of positive and negative consequences of the act. This idea is embedded in the concept of balancing risks and benefits to achieve the best overall result. Utilitarian theory is often cited to justify actions that are most likely to increase happiness, but other desirable results are also possible. Individuals may wish to act in such a way so as to increase personal quality of life, enjoyment of and satisfaction with life, success in a preferred career, and general knowledge and understanding or to strengthen personal relationships. Lawyers and policymakers use the utility principle to produce the best overall balance of justice and fairness for society. Utilitarian thinking is almost intuitive in many aspects of ordinary life. Understanding this form of thinking is important because it may help avoid the potential pitfalls that can result from uncritical application of the theory. Perhaps the most familiar situation is the use of utilitarian theory to justify the killing of defective newborns [Kuhse and Singer, 1985]. Although theoretically logical, such arguments are morally repugnant to persons who apply a different moral standard based on some other approach to ethics. Another problem with utilitarian theory is its failure to protect minorities, which results from its emphasis on producing the most good for the majority. The needs of children with rare neurologic disorders can be overlooked if utilitarian thinking allocates scarce medical resources primarily to children with more common disorders.

Deontology Deontologic theory is based on the importance of “deon,” or duty. Duty is based more on the intentions that lead a person to act than on the outcomes or consequences of the action. Utilitarian thinking is mostly situational and depends on the specific aspects of a given situation; deontologic thinking strives to be more universal and to emphasize decisions that would apply in all relevant situations. Thus, Kant’s categorical imperative states that we should act only in a way that is consistent with a universal law or obligation [Kant, 1959]. Using people as means to an end implies that different actions (or reactions) are needed, depending on the end or outcome that is desired; therefore, the actions are not universally applicable. For this reason, deontologic thinking stipulates that we should treat all people as “ends” and not as means to an end. This could cause problems in thinking

about the morality of organ transplantation if the organ donor is thought of only as a means to the end of survival for the recipient. Clearly, deontologic thinking imposes a duty to respect the rights and value of the donor as much as those of the recipient because anyone could be either a donor or a recipient. Deontologic thinking emphasizes duties and obligations, but these may conflict. For example, physicians may have different and competing obligations toward patients, families, hospitals, insurance companies, and society. The attempt to describe duties leads to formulation of general or universal rules for moral action, but these rules may also conflict. Rules may be too abstract and impractical to apply to real-life situations. Deontologically based rules do not take into account the messiness of human relationships, a point that is essential to keep in mind when considering the ethics of care discussed later in this chapter.

Common Morality and Natural Law What are the universal rules that spring from deontologic thinking? Most Western philosophers would argue that these rules can be derived from the application of reason—from rational, logical thinking about the nature of human existence. The general argument is that “all rational persons would agree that these rules are essential to govern and guide the moral actions of individuals in a cohesive society” [Beauchamp and Childress, 1994]. Beauchamp and Childress [1994] describe the “common morality” as socially approved norms of human conduct that form the basis of ethical theory This common-sense understanding of what is needed for individuals to behave in society is not derived from theory but rather forms the basis for potentially competing theories. Natural law theory is an ancient approach to deriving universal rules through the application of reason [Simon, 1992]. For Thomas Aquinas, natural law sprang from man’s participation in God’s eternal law and was brought into being by the application to action of human intelligence and reasoning [May, 1991]. This application leads first to the principle that all things desire that which is good; therefore, good is to be pursued and evil is to be avoided. Good things are those to which man has a natural inclination, such as life (existence), social interaction, family life, and civil government. To pursue these good things, one should act fairly, love God, and love other persons. Secondary precepts or rules (such as the Ten Commandments) follow from these basic principles. Secular interpretations of natural law are as old as Aristotle and are still used in some forms of legal theory. Bernard Gert [2000] defined two sets of rules that he believed all rational persons would accept as natural and essential, without relying explicitly on natural law theory. Many of his rules are in fact similar to the Ten Commandments. Gert also emphasized that the rules are not absolute and that violations may be considered in specific circumstances. Beauchamp and Childress [1994] do not define any specific rules as part of their common morality, but they do define four principles that are not absolute and that need to be specified based on actual circumstances. Nonetheless, their four principles may be seen to correlate with the precepts of natural law:

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1. 2. 3. 4.

Do good (beneficence) Avoid evil (nonmaleficence) Act fairly (justice) Love one another (autonomy)

Whatever the source of the common morality, it is the basis for principlism, the ethical theory based on the application of principles to specific situations.

Principlism Principlism is an approach to ethical problems that is based on the application of the four principles of beneficence, nonmaleficence, justice, and autonomy. It is more of a practical guide than an abstract theory, and it has found widespread acceptance in a variety of settings [Beauchamp and Childress, 1994]. It was adopted explicitly in the Belmont Report, which forms the foundation for research ethics in the United States [Belmont Report, 1979]. Although principlism is perhaps the best known approach to clinical ethical problems, it is by no means the only approach. Understanding principlism is necessary to consider these alternative systems. The principle of autonomy has become pre-eminent in Western society, although it may be less prominent in Eastern societies that place a greater value on social harmony. Physicians need to keep this in mind when caring for patients from other cultures. An autonomous choice is one that is based on sufficient knowledge of the facts involved, the ability to understand the situation, and the independence to choose without undue influence from other people. An autonomous person can determine for himself what he thinks is best, and this principle states that other people should respect these choices even when they do not agree with or approve of them. Autonomy is the basis for the concept of informed consent, which requires that a patient has the capacity or competence to understand the issues, full disclosure of all of the information needed to make a decision, and freedom from any coercion that might influence the decision. In general, persons younger than 18 years of age are not considered to have the capacity to make fully autonomous choices, although their preferences should be considered and respected if possible. American law recognizes that persons 18 years of age and older are fully competent unless a judge has determined otherwise. This recognition is critically important for young adults with neurologic disorders that may affect their capacity to make fully autonomous decisions. If capacity is in doubt, the family will need to initiate legal proceedings to obtain guardianship when the person becomes 18 years old. A young adult (over 18 years) with a neurologic disorder that results in limited competence is unable to give informed consent, but his parents cannot give consent for him or her unless they have obtained guardianship. Failure to obtain guardianship when it is necessary can interfere seriously with medical treatment. The principle of beneficence encourages physicians to do good or to act in the best interest of the patient whenever possible. This principle can also be interpreted to suggest that physicians should seek to promote an optimal quality of life or satisfaction with life. Considerable debate exists about how to measure quality of life [Nordenfelt, 1994; Nussbaum and Sen, 1993; Schalock, 1996]. Objective measures are based on the judgments of others, whereas

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subjective measures are based on the opinions of the patient about what constitutes a satisfying life. In general, preference is given to subjective judgments when they can be known. The principle of nonmaleficence encourages physicians to avoid doing harm to patients and dates back to Hippocrates. It is related logically to the principle of beneficence. Both principles are considered when physicians attempt to strike a balance between providing a benefit for the patient (doing good) and not imposing a burden (avoiding harm). This balance may become especially problematic when the same action could produce both a good, or desired, effect, as well as a bad, or undesired effect. The classic example is prescription of sufficient medicine to reduce pain while knowing that it may also cause the patient to stop breathing. This problem is known as the “situation of double effect” [Beauchamp and Childress, 1994]. In Catholic moral theory (which contains the most explicit analysis of such situations), an action that causes double effects is morally justifiable only if it meets all of the following criteria: 1. The action itself is not morally wrong (such as killing). 2. The intent is to produce the good effect, even though the bad effect may be expected. 3. The good effect is not based on achieving the bad effect. 4. The benefit to be obtained is greater than the harm that might occur. This concept is admittedly difficult to apply in practice. Evaluation of each criterion may be arguable in a specific situation. Perhaps the best that can be expected is that physicians will make a good-faith effort to adhere to the principles involved and seek to obtain the optimal balance between benefit and harm for the patient and family. The principle of justice requires that equals be treated equally, but the basis for an equal distribution of resources may be arguable. Should resources be distributed according to need, effort, merit, contribution to society, or some other factor? Utilitarian, libertarian, communitarian, and egalitarian approaches have been proposed to answer this question [Beauchamp and Childress, 1994]. Rawls [1971] suggests that resources should be distributed to ameliorate the effects of life’s natural and social lotteries. It may be simply bad luck (“losing the lottery”) that a child is born with a disabling condition or is born into poverty. If the child is not responsible for this condition, then society should act to remedy the situation. According to this rule, unfair situations would presumably have priority over merely unfortunate situations. How many resources should be provided to those who have been unfairly deprived? The limits of this redistribution policy may be the extent to which it disables or impoverishes the rest of society [Veatch, 1986]. Jonsen and colleagues [1998] suggest that ethical issues can be analyzed by asking the following four questions (which are in fact practical applications of the four principles discussed previously): 1. What are the medical indications for treatment? (principle of beneficence) 2. What are the patient’s preferences? (principle of autonomy)

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3. What impact on the patient’s quality of life can be reasonably anticipated? (principle of beneficence) 4. What are the burdens and benefits that may affect the family and society? (principles of justice and nonmaleficence) The questions may be somewhat hierarchic, in the sense that medical indications and patient preferences are usually more important than potential social burdens, but physicians should not be too rigid about this. In fact, asking (and answering) these four questions in a particular case is an excellent way to make sure that the relevant issues are identified and evaluated. These issues can then be considered by the caregiving team, patient, and family. Resolution of the issues may vary from case to case, but at least everyone involved will be able to see how the decision was made.

Virtue or Character Ethics Virtue can be described as a trait that has moral or social value. According to Aristotle, virtuous behavior requires both the right motive and the right action. In other words, wanting (or intending) to do the right thing is not enough by itself. This idea is somewhat at variance with pure deontologic thinking, as described previously. In virtue theory, following a presumably universal rule is not necessarily a moral or virtuous act if it produces a bad result. Similarly, doing right for the wrong reason is not necessarily a moral or virtuous act if the motive itself was not virtuous. The catalog of virtues is not exhaustive and varies from one writer to another. Pellegrino and Thomasma [1993] suggest eight virtues that are necessary for sound medical practice: 1. 2. 3. 4. 5.

Fidelity to trust (trustworthiness) Compassion (understanding the patient’s feelings) Prudence (clinical judgment) Justice (in the sense of love and altruism) Fortitude (sustained courage in the face of difficulty or despair) 6. Temperance (balance in one’s life, perhaps also Osler’s sense of equanimity) 7. Integrity (personal honesty and wholeness) 8. Effacement of self-interest (putting the patient’s interests first) They argue that these eight virtues are necessary but not sufficient for physicians to practice ethically. Possessing these virtues provides evidence of good intent but they must be linked to ethical action. They suggest that principlism, although not specifically part of virtue theory, can provide a guide for virtue-based ethical action.

Ethics of Care Care-based ethical thinking is prominent in nursing practice but may be somewhat unfamiliar to physicians. It arose as somewhat of an alternative to deontologic, rule-based thinking that depends on adherence to more or less rigid principles. It also arose from feminist research studies comparing male and female approaches to ethical dilemmas. Gilligan [1982] found that males were more likely to look for rules to follow and to insist on adherence to these rules. Females

were more likely to look for some situation-based way to resolve a dilemma, taking into consideration the person’s feelings and significant relationships [Gilligan, 1982]. This “feminine” way is not exclusively reserved for women (or for nurses), of course. Rather, it provides an alternative and perhaps more subjective way to evaluate an ethical problem that is especially relevant when a rule-based approach seems to be inappropriate or unhelpful [Taylor and Watson, 1989]. Somewhat obviously, care-based ethics does not have any fixed rules. In fact, it challenges the idea that impartial or universal rules should guide ethical action. Instead, it looks at the particularity of the patient and the clinical situation and seeks to find answers that fit this unique case. Carebased ethics accepts the fact that emotions have important moral value and must be considered carefully. It also emphasizes the patient’s human relationships and the mutual interdependence of the patient, family, and all members of the caregiving team. A care-based approach to an ethical dilemma would say something like, “That can’t be the only possible ethical solution. There must be another way to resolve this problem that is acceptable to everyone here. We all want to do what’s best for the patient, so let’s think about what that means. Maybe we could start by understanding what the patient is feeling and by talking to the family. We should also talk about how we feel about all of this. Let’s brainstorm some ideas and think about what they would involve. Maybe we need to talk to some more people and get more information. If we keep working at it, we’ll find a way.” This approach will sound familiar to anyone who has been involved in difficult cases in the intensive care unit (ICU), which emphasizes the ubiquity and usefulness of this way of thinking in clinical practice. Perhaps an awareness of the sound ethical foundation of care-based ethics will also help clinicians give this way of thinking the respect it deserves.

Casuistry Casuistry, or case-based ethics, is another alternative to utilitarian or rule-based ethical approaches [Jonsen and Toulmin, 1988]. It rejects the very idea of a “moral calculus” that can be analyzed impartially, based on abstract concepts. Instead of a “top-down” approach based on pure theory, it takes a “bottom-up” approach based on the particularity of specific cases. Casuistry looks at specific cases and emphasizes points of agreement about those cases. It recognizes that moral intuition may be more important than adherence to principles. It is common knowledge that members of hospital ethics committees often agree on what needs to be done but cannot always say with clarity why they feel that way (or what ethical theory they relied on to make a particular judgment). This moral intuition may also reflect the influence of the “common morality” described previously. By looking at the particularities of a specific case, casuistry is also sensitive to contextual influences and individual differences. The method of casuistry is somewhat analogous to the method of case law used in the United States. One first identifies several key cases about which there is a consensus regarding the proper ethical approach. These are cases that have had careful scrutiny in the past and are still believed to be instructive. New cases are then compared with these key

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cases, selecting those past cases that have the greatest similarity to the current case. One then seeks to develop a consensus about how to resolve the current case, based on how these past cases were resolved. Each new case that is resolved in this way goes into the body of case experience, so that the consensus is revised and modified incrementally in the light of clinical experience. One can see that casuistry is very similar to what an experienced clinician does naturally, drawing on his or her experience in past cases to sort out the issues in a new case. One has to be careful about which past cases to consider and to what extent the decisions made in those cases apply to the current case. Experience in past cases may also be conflicting, and it may be difficult to sort out the similarities and differences compared with the current case. One also has to be careful about how much weight should be given to one past case compared with another past case. In a very real sense, every new case is different (as every clinician knows), but there is still much to be learned from past experience. Casuistry provides a sound ethical foundation for using this clinical experience in resolving ethical dilemmas.

Spirituality Spirituality is variously defined, but it can be understood as a belief system that focuses on intangible elements that impart vitality and meaning to one’s life [Koenig, 2002]. Because it is based on beliefs, or faith statements, it is not provable through logical argument. Spirituality in medicine is often based on religious beliefs [Sulmasy, 1997], but it need not be. As an expression of ultimate concern, it reflects the elements of our lives that are the most important and make life worth living. Most people have some spiritual beliefs that become prominent when their health is threatened; yet these beliefs are often not considered by physicians and other health-care providers. Physicians may anticipate that patients would have certain beliefs based on knowledge of their religious background [Numbers and Amundsen, 1998], but individual differences exist even within a religious tradition. A more direct understanding of the patient’s spirituality would be preferable. One approach to understanding the patient’s spirituality is the “three ways of looking” [Coulter, 2001]. The first look is to see the person subjectively as an individual human being. Compassion requires distance and objectivity [Pellegrino and Thomasma, 1993], but this first look requires closeness and subjectivity. It is an attempt to understand the patient’s spiritual beliefs. The second look is to recognize in the other person that which we know to be central to our own existence. With the second look, we can value in the patient that which we most value in ourselves. These values include living, freedom, tolerance, respect, happiness, and satisfaction with life. Physicians would then seek to protect for their patients the values that they would protect for themselves. The third look is more elusive and is an attempt to grasp through our relationship with another person the transcendence or divinity that is the basis of our spiritual existence. This third look comes when it is least expected, often in the vulnerability of a frustrating or challenging ethical situation. When we are open to it, it can provide insight, enrichment, and ethical guidance.

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The three ways of looking can be the basis for a spiritual approach to medical ethics. Three precepts can be identified: 1. Respect in others what I value in myself. This precept is similar to the principle of autonomy but is based on the mutuality of spiritual sharing between physician and patient. 2. Do the most loving thing possible. When we love in the patient what we love in ourselves, we will strive to do that which is best for all. Love—not just duty, convention, rules, or cost containment—is the basis for action. 3. Seek guidance from the source of my own and the other person’s being, through deep reflection, prayer, advice, or sharing. Thoughtful physicians often do this in difficult ethical situations but may not recognize the spiritual nature of these reflections. These precepts do not appear to depend on any specific religious tradition and should be applicable in all cultures and religions. One need not be religious to apply them to one’s practice. They avoid the relativity of accepting cultural practices at face value by providing a general structure for applying differing cultural beliefs to specific clinical situations. Spirituality cannot and must not be coerced or imposed on others, but physicians who are open to the role of spirituality in the lives of their patients may find these precepts useful in considering difficult ethical challenges.

ETHICAL RESPONSIBILITIES Child neurologists have duties as physicians, as pediatricians, and as neurologists. These categories overlap to some extent. Physicians in general have duties that are reflected in the Hippocratic Oath and the Code of Ethics of the American Medical Association (AMA). Pediatricians have duties as primary care physicians and as caregivers for minor children in a family context. Neurologists have duties as specialists to provide consultation and to maintain expertise in the field.

Duties as a Physician The AMA Code of Ethics is a document that has been revised over the years and includes opinions and statements on a variety of current issues. It incorporates the current version of the Principles of Medical Ethics [American Medical Association, 2001]: 1. A physician shall be dedicated to providing competent medical care, with compassion and respect for human dignity and rights. 2. A physician shall uphold the standards of professionalism, be honest in all professional interactions, and strive to report physicians deficient in character or competence, or engaging in fraud or deception, to appropriate entities. 3. A physician shall respect the law and recognize a responsibility to seek changes in those requirements which are contrary to the best interests of the patient. 4. A physician shall respect the rights of patients, colleagues, and other health professionals, and shall

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6.

7.

8. 9.

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safeguard patient confidences and privacy within the constraints of the law. A physician shall continue to study, apply, and advance scientific knowledge, maintain a commitment to medical education, make relevant information available to patients, colleagues, and the public, obtain consultation, and use the talents of other health professionals when indicated. A physician shall, in the provision of appropriate patient care, except in emergencies, be free to choose whom to serve, with whom to associate, and the environment in which to provide medical care. A physician shall recognize a responsibility to participate in activities contributing to the improvement of the community and the betterment of public health. A physician shall, while caring for a patient, regard responsibility to the patient as paramount. A physician shall support access to medical care for all people.

Additional guidance may be found in descriptions of the virtues needed for medical practice [Pellegrino and Thomasma, 1993]. These include the need for trustworthiness, compassion, empathy, prudent clinical judgment, altruism, fortitude, temperance, integrity, and primacy of the patient’s interest. Indeed, many of these virtues are implicit in the principles delineated by the AMA. Many professional societies have developed ethical codes or guidelines that are specific for their field. The websites of the American Academy of Pediatrics (www.aap.org), the American Academy of Neurology (www.aan.com), and the Child Neurology Society (www.childneurologysociety.org) may be consulted for the most up-to-date statements about the ethical responsibilities of members of these societies. Conflicts may arise in applying these principles during ordinary practice. For example, physicians should generally tell the truth, but what if truth-telling would appear to be harmful to the patient? There are no easy answers. The application of a care-based ethical approach may be useful in such situations. A carefully considered amount of information may be provided in such a way and in a particular context, taking into account the physician-patient relationship, so that all involved will understand the information being conveyed and be able to use it to benefit the patient. Consider this example: A 6-month-old infant is up for adoption and the agency wants an opinion about the child’s developmental potential. The child’s mother was an alcoholic, but the child does not meet criteria for a diagnosis of fetal alcohol syndrome. Should the agency be told that the child is at risk for alcohol-related neurodevelopmental delay (fetal alcohol effects), which could jeopardize the potential adoption and relegate the child to prolonged and potentially damaging foster care? Or should the physician accentuate the positive and simply say there is no evidence of fetal alcohol syndrome? How much truth needs to be told, and how certain can the physician be that others will be able to use the information for the benefit of the patient? Physicians are often called upon to write letters for patients. These letters may be used to secure benefits for the patient in school, work, or other settings. Letters may also be requested to assist the patient or family in obtaining

insurance coverage for tests or treatments, or in obtaining help with housing and utilities (heat, electricity, or telephone services). In general, physicians would seem to be required to do what is best for the patient, but what if this seems to conflict with a duty to respect the law and to do what is best for the community? Consider this example: A 17-year-old boy with KleinLevin syndrome has been difficult to treat but did best when he was involved in competitive sports in school. Unfortunately, his grades are now not good enough for him to participate in varsity football. Should the physician write a letter to the school principal stating that it is medically necessary for him to play football, even though this would violate the school’s rules about eligibility for sports? Or should the physician and the principal negotiate a way for the patient to obtain the benefit of vigorous exercise and competition in some other format? Physicians are often requested by insurance companies to prescribe older, cheaper drugs or to use generic products instead of new brand-name products. Indeed, in some insurance arrangements (such as full capitation), physicians may receive a financial benefit by limiting the cost of the patient’s care. Should a physician order expensive tests or prescribe expensive treatments anyway, if they are believed to be in the patient’s best interest? How much is a physician responsible for the overall cost of health care in society, and how should this responsibility be balanced against the responsibility to do what is best for the patient? Consider this example: A physician believes that atomoxetine would be a better choice to treat a child with attention-deficit-hyperactivity disorder instead of a stimulant drug such as methylphenidate or dextroamphetamine. However, Medicaid refuses to pay for atomoxetine unless the child has already failed a trial of stimulant drugs. Should the physician prescribe a generic stimulant and wait for the child to have adverse effects from it, or should the physician “shade the truth” in requesting Medicaid coverage for atomoxetine? Clearly, application of general principles of medical ethics to complicated clinical situations is anything but straightforward. Nonetheless, physicians should make a genuine effort to do the best they can. The requirement to make the patient’s interests paramount would appear to be the defining standard in most cases. In doubtful or difficult situations, consultation or discussion with one’s colleagues (either formally or informally) is probably a good idea.

Duties as a Pediatrician Many (but not all) child neurologists have trained as pediatricians and have some experience with the roles and responsibilities of a pediatrician. Most also have frequent contact with referring pediatricians who provide primary care for the patients seen in neurologic practice. The role of a pediatrician often involves primary care in the United States, but in other countries and other settings the pediatrician is a specialist who manages diseases involving other parts of the body. Child neurologists interact regularly with pediatric specialists involved in the care of children with complex disorders. Thus, there is an overlap between the duties of the child neurologist and the pediatrician that warrants some exploration.

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Primary care involves the longitudinal management of all of the health issues of the child and family and requires a commitment to being accessible, available, and capable. Effective primary care is compassionate, culturally competent, and comprehensive and includes coordination and oversight of all of the child’s health problems [Tonniges and Palfrey, 2004]. Most child neurologists do not provide this type of primary care. Many do, however, provide many of the same elements of care for children whose neurologic problems constitute the main health issues. These include older children and adolescents who are otherwise healthy but have ongoing neurologic problems, as well as patients with complex neurologic problems whose general health problems are fairly straightforward. Child neurologists have no obligation to take on this role and may confine their role to that of a consultant. Those who do take on this role would seem to have the same duties as those of a primary care physician listed above, except that their duties are limited to management of the child’s neurologic problems. All physicians who care for children (including pediatricians and child neurologists) have a duty to understand and respect the child’s status as a minor. This duty has two elements: one involves promoting the child’s emerging development into an adult, and the other involves protecting the child from harm. Promoting the child’s development involves an understanding of normal child development and helping the child succeed as much as possible. Child neurologists ordinarily monitor the child’s progress in school and provide whatever assistance is possible to secure special education and therapeutic resources needed to promote the child’s development. Although the primary responsibility rests with the parents and the school, the child neurologist should be available and capable of providing help when needed. Because children are not capable of making sound judgments about their own best interests, others must judge for them what is in their best interests. Social convention and the law generally recognize that parents are the best judge of what is in the child’s best interest, but this recognition is not absolute. A substantial body of law and regulation governs when and in what circumstances a parent’s rights may be superseded. Consideration of these laws and regulations is beyond the scope of this chapter [see Beauchamp and Childress, 1994; Bernat, 1994]. Child neurologists may be called upon to give an opinion about what medical care is in the child’s best interest. They may also be asked about whether they believe the child is capable of independent judgment. Persons who are 18 years old are usually assumed to be fully autonomous adults who are capable of giving informed consent for medical treatment. Many neurologic patients with significant intellectual disabilities are not capable, however; therefore, others must be designated as guardians for them. The child neurologist should be aware of what is involved in determining the need for guardianship and assist the patient and family in whatever way is appropriate. The United Nations [1990] has formulated a declaration on the rights of children, the Convention on the Rights of the Child, which contains 54 Articles that stipulate the rights of the child to life, safety, health, education, and a decent standard of living. Article 23 states that a mentally or physically disabled child should enjoy a full and decent life in con-

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ditions which ensure dignity, promote self-reliance, and facilitate the child’s active participation in the community. It further recognizes the rights of the disabled child to special care. Article 24 states that the child should have access to quality health services, including primary care, preventive health care, and treatment of health conditions. Although the Convention’s declaration is not legally binding, it provides a strong moral statement about the internationally accepted obligations of states to protect the best interests of all children. Awareness of this international consensus may be helpful to physicians who are advocating for children under their care.

Duties as a Neurologist Child neurologists are specialists or subspecialists and have duties that correspond to this role. They provide longitudinal care for children and adolescents with chronic neurologic disorders that includes corresponding duties that resemble those of primary care, as described previously. They also provide consultative opinions about diagnosis and treatment, both in outpatient and inpatient settings. As a consultant, the child neurologist has a duty to provide a fair, impartial, accurate, and (as much as possible) evidence-based statement about the facts of the case. The child neurologist’s principal role in evaluating ethical dilemmas is to clarify the facts. This is a critical role, because accurate data are essential for making sound ethical decisions [Coulter et al., 1988]. Indeed, poor or questionable ethical decisions are often due to inadequate specialized medical information regarding the diagnosis, treatment, and/or prognosis of a case. This problem is illustrated well in cases when the patient is in a vegetative state. Some may consider such a state permanent and hopeless after only a few weeks and seek to withdraw life-sustaining treatment. The child neurologist, acting as a consultant in such a case, would inform the family and caregivers about the published data suggesting that the vegetative state is not considered permanent until 3 months after an anoxic injury and 12 months after a traumatic brain injury [Multi-Society Task Force on PVS, 1994]. The family may be given some hope for possible recovery of consciousness before these time periods, which may call for continued treatment and rehabilitation. The role of an expert consultant has certain limitations. For the most part, child neurologists are experts in child neurology and not in ethics. The child neurologist should distinguish between opinions regarding the neurologic data and opinions regarding the ethical issues involved in cases that present ethical dilemmas. The child neurologist’s opinion about the ethical issues is one voice among many and is not necessarily the most important or determining opinion. Normally, the family’s opinion about the ethical issues is the most important. The views of the extended family and the family’s religious or faith community are often important. In many cases, the views of individuals who have had longterm, close and personal relationships with the patient (e.g., friends, personal attendants, or group home staff) also deserve consideration. Child neurologists, as well as other physicians and nurses involved in such cases, should be careful not to impose their own ethical opinions or attempt to override the expressed opinions of the patient’s family and friends.

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The child neurologist also has a duty to maintain expertise in the field. This is a duty that is shared with all medical specialists. Expertise is maintained through continuing education, which may involve reading journals, attending conferences, and discussing issues or cases with colleagues who may have more knowledge or experience regarding the issues in question.

Research Many child neurologists are involved in research, which carries additional ethical duties. One of the challenges for child neurologists involved in clinical research is to separate their ethical obligations as investigators from their ethical obligations as physicians responsible for treating patients who may be enrolled as subjects in the neurologist’s research study. This challenge is harder than it may seem. In the United States, research ethics is based on the Belmont Report [1979], which adopted the principles of autonomy, beneficence, and justice (see earlier discussion) as the basis of research ethics. In general, the researcher’s principal ethical obligation is to protect the rights and welfare of the research subject [Dunn and Chadwick, 1999]. Poorly designed research studies are inherently unethical because they are not likely to produce sound scientific results, and thus they place the patient-subject at risk for harm without the prospect of benefit. The researcher’s ethical obligation as an investigator to pursue well-designed scientific studies is secondary to his or her obligation to protect the subject involved in the research. When the research subject is also a patient, this means that the child neurologist-investigator’s clinical duties to the patient are ordinarily stronger than his or her duties to enroll subjects in the research study. In the United States, federally sponsored research is governed by the Code of Federal Regulations, which stipulates the roles and responsibilities of researchers and institutions involved in clinical research [see Dunn and Chadwick, 1999]. Researchers are required to obtain review and approval of the research study by a properly constituted Institutional Review Board for the Protection of Human Subjects in Research (IRB). Child neurologists involved in clinical research have legal and ethical obligations to follow these rules and regulations. In general, ethical issues in research should be considered when the study is being designed, not just at the end of the study when IRB review and approval are requested. The researcher should be knowledgeable about ethical issues in research. If the researcher has questions about ethical aspects of study design or protocol development, most IRBs will provide assistance. Building ethics into the study from the beginning will usually prevent problems later during the process of IRB approval, as well as during continuing review and oversight of the study.

ETHICAL PROBLEMS Personhood Critical ethical problems in child neurology often center on the question of personhood. Some authorities [Field and Behrman, 2004], consider this the most important problem

in bioethics. Indeed, the history of the concept of personhood can be traced to Plato and Aristotle [Mahowald, 1995]. This history includes many rich and varied discussions based on several key questions. Should all human beings be considered persons, in a moral sense, to whom ethical duties are owed? Or are some human beings (such as fetuses or infants with anencephaly) “nonpersons” who can be treated differently than “real persons”? Is personhood absolute or are there degrees of personhood, and thus degrees of ethical obligations? Can personhood be lost while human existence persists—for example, in a vegetative state? Are there reliable and valid criteria that one can use to determine whether a human being is a person? The capacity for rational thought is often considered to be what separates human persons from nonpersons, yet rationality may not be sufficient by itself. Plato, Aristotle, Augustine, Aquinas, and other classical philosophers emphasized the unity of reason and spirit, or soul [Mahowald, 1995]. Current religious and theologic arguments maintain this position by arguing that all human beings have a God-given soul, which confers moral personhood and that requires ethical respect. Berrigan wrote that the presence of God is most apparent when we are with those who are unable to respond to us [Berrigan, 2000]. Enlightenment philosophers such as Locke and Kant redefined the issue to emphasize self-consciousness, or the rational ability to have a concept of oneself as a unique being and thus to exercise autonomy or free will. This definition would suggest that human beings who do not have this ability may not be fully human persons in a moral sense. Modern thinkers have sought to identify criteria by which one may determine whether personhood is present. Fletcher [1979] identified a number of such criteria, including self-awareness, self-control, a sense of one’s history and future, the capacity to relate to others, and the ability to communicate. For Fletcher, IQ could be used as a surrogate measure of these abilities, so that an IQ below 20 meant that one was not a person. Utilitarian theory has been used to arrive at essentially the same position [Kuhse and Singer, 1985]. This position has been criticized on philosophical grounds [Byrne, 2000]. Hauerwas considered the question of developing criteria for personhood “fundamentally wrong-headed” because it ignores the real question, which is how others should relate to those who may not meet these criteria: “I suspect that we are human exactly to the extent we can reach out and provide care to those who have no right to it” [Swinton, 2004]. The question of what it means to be human can be considered from an anthropologic and historical perspective. Fernandez-Armesto [2004] identified six challenges to our understanding of human personhood: 1. The similarity between humans and nonhuman primates 2. The presence of “human” qualities (such as language or tool-making) in other animals 3. The indistinct boundary between modern humans (Homo sapiens) and prehistoric ancestors (such as Neanderthals) 4. The evolutionary mutability of all species 5. The problem of artificial intelligence and “humanoid” robots 6. The ability to modify the human genome by addlng or subtracting characteristics and abilities.

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Considering these challenges leads to the conclusion that the boundaries of what physicians consider “humankind” or human personhood, from an anthropologic perspective, are by definition necessarily indistinct [Fernandez-Armesto, 2004]. What does this mean for child neurologists? Many patients (such as infants with severe neurologic disabilities, children with profound intellectual disabilities, and adolescents in a persistent vegetative state) would not meet the criteria of personhood advocated by Fletcher. Are physicians’ ethical obligations to them any less than to other patients who are more obviously human persons, or do theories of justice require physicians to provide more compensatory resources to help them function more effectively in society [Veatch, 1986]? Theories of beneficence argue that physicians should attempt to promote and protect the patient’s quality of life as perceived by the patient, regardless of what physicians may think of it [Beauchamp and Childress, 1994]. From a clinical perspective, parents rarely regard their children with severe disabilities as nonpersons. Child neurologists, working together with parents and other caregivers, will want to focus on doing what is best for the child and family. Distinguishing between moral status and moral agency [Mahowald, 1995], physicians may conclude that patients whose moral status is questionable because of presumed limited personhood are still moral agents with human rights to whom those with greater moral status have ethical obligations as members of human society.

Euthanasia The challenge of euthanasia is one of the most important ethical issues in neurology and medicine today. Conventional thinking distinguishes between passive euthanasia (not doing something to preserve life) and active euthanasia (doing something to end life). Passive euthanasia is generally considered acceptable medical practice in some situations, whereas active euthanasia is not (and is illegal in most situations). However, this distinction may be vague and confusing in some cases. Legitimate and illegitimate applications of both passive and active euthanasia can be identified. In their discussion of the ethical principle of nonmaleficence, Beauchamp and Childress [1994] argue for recasting the distinction in terms of respect for autonomy and serving the patient’s best interests. They argue that in some carefully specified situations, physicians may legitimately assist patients in dying (active euthanasia) if the action responds to the patients’ wishes and serves their interests. Passive euthanasia (withdrawal of life-sustaining treatment) is often considered for persons who are in a persistent vegetative state (PVS). Consensus exists regarding the medical aspects of a vegetative state in children and adults [Multi-Society Task Force on PVS, 1994], but the ethical and legal issues are more contentious [Jennett, 2002]. With respect to children and adolescents, two questions arise: (1) What are the boundaries of the diagnosis of the vegetative state? (2) How confident can we be about the prognosis for patients in a vegetative state? The Multi-Society Task Force on PVS included representation from the Child Neurology Society and reviewed the literature to address these questions. The Task Force concluded that the concept of the vegetative state cannot be applied to preterm infants, and the diagnosis of a vegetative

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state is difficult to make before three months of life. An exception to this statement may be made for infants with true anencephaly who by definition are in a vegetative state. Caregivers are often confused when patients demonstrate subtle or minimal signs of responsiveness, which would suggest that the diagnosis of PVS is no longer accurate. Patients who demonstrate minimal but definite behavioral evidence of self or environmental awareness may be diagnosed instead as being in a minimally conscious state, which is distinct from the vegetative state. Diagnostic criteria exist for distinguishing between a minimally conscious state and a vegetative state in children [Ashwal and Cranford, 2002]. Data also exist regarding the prognosis for children and adolescents in a minimally conscious state or a vegetative state. It is possible to distinguish between a mobile (ability to lift the head, roll over, or sit) and an immobile minimally conscious state, but studies have found little difference in survival between children in either state [Strauss et al., 2000]. For children 3 years of age in a vegetative state or an immobile minimally conscious state, 12% to 18% had evolved to a state better than a minimally conscious state after 3 additional years. For children in a vegetative state from birth to 1 year of age, median survival was 4.2 years and life expectancy was 7.2 additional years. For adolescents still in a vegetative state 1 year after onset, median survival was 5.2 years and life expectancy was 10.5 additional years [Strauss et al., 1999]. Withdrawal of life-sustaining treatment (including nutrition and hydration) is generally considered legally and ethically appropriate for children and adults who are in a permanent vegetative state [Jennett, 2002]. This view has been challenged recently for Roman Catholics because of the statement by Pope John Paul II [2004], that the withdrawal of assisted (artificial) nutrition and hydration “has to be considered a genuine act of euthanasia by omission, which is morally unacceptable.” The Pope’s statement was not delivered under the doctrine of infallibility and thus is not binding in the strict sense. Catholic theologians consider it to represent an important opinion to be discussed carefully in the ongoing debate about the care of patients in a vegetative state [Shannon and Walter, 2004]. The legal and ethical standards for withdrawing life-sustaining treatment from patients in a minimally conscious state are much less clear, since such patients theoretically could feel pain and suffering [Ashwal and Cranford, 2002]. The concept of futility implies that a proposed treatment or course of action offers negligible potential for overall patient benefit, whether that potential is considered quantitatively in terms of the probability of success or qualitatively in terms of the expected impact on the patient’s quality of life. The question often arises when patients or families request treatment that caregivers do not believe is appropriate. Rather than focus on strict guidelines or policies to follow in such cases, physicians are encouraged to develop fair and transparent procedures for decision-making that encompass the views of all parties involved in these difficult situations [Shevell, 2002]. Voluntary active euthanasia is much more controversial than passive euthanasia [Smith, 1997]. Often called mercy killing or physician-assisted suicide, it is opposed by the American Medical Association and is illegal in all of the United States except in Oregon. On the other hand, it is legal

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in some countries, most visibly in The Netherlands, where it has recently been extended to include children younger than 12 years of age. Following Beauchamp and Childress [1994], many people wish to be able to exercise their autonomy rights and to choose death (with or without medical assistance) when this is a conscious, carefully considered, noncoerced, personal decision they make for themselves. Whether it is ever ethical for others to make this decision on behalf of nonautonomous persons (such as children and adolescents) is not at all clear (even in The Netherlands), and no convincing ethical argument has been advanced so far to support a consensus on this point.

Perfection and Neuroethics The attempt to create more perfect children is universal and perhaps understandable. Parents do not wish to create a child whom they believe to be imperfect [Murray, 1996]. Some deaf parents may wish to create a child whom others might consider imperfect because of deafness but whom they consider more perfect because of the child’s ability to participate in deaf society [Middleton et al., 2001]. Even parents who love and accept their child’s imperfections would likely still prefer to have those imperfections disappear if possible. In asking whether “the retarded suffer from being retarded,” Hauerwas [1986] argues that individuals project on them their own fears of what it would be like to have an intellectual disability and thus fail to imagine what living with such a disability is really like. Obversely, people desire perfection for their children because they value perfection in ourselves. The desire for perfection may be a relevant consideration when parents must make decisions about life-sustaining treatment for infants and young children faced with the prospect of lifelong severe disability. Often the child is still dependent on life-sustaining technology, which, if withdrawn, will result in the child’s death. The prognosis may be somewhat uncertain and likely to become clearer with time [Coulter, 1987]. Yet if the parents wait, the child’s medical situation may stabilize and no longer require life-sustaining technology. Parents who are relatively intolerant of imperfection (lifelong severe disability) may thus choose to withdraw life-sustaining treatment before the exact prognosis is clarified, rather than wait and lose the opportunity to choose. This situation is very difficult for the child neurologist caring for the patient, whose principal duties are to provide accurate data about diagnosis and prognosis and to support the family’s decision [Glass, 2002]. Although some observers think that parents may be making these choices earlier and withdrawing support more often than they did in the past, little or no published data are available to verify this observation or to explore why this might be true. Literature on the social and spiritual significance of disability [Eiesland, 1994; Vehmas, 2004] points out that individuals with disabilities often perceive their quality of life to be better than those without disabilities might expect. On the other hand, some contemporary philosophers argue that personhood is limited in the presence of severe disability, and withdrawal of life support is appropriate [Kuhse and Singer, 1985]. Perhaps child neurologists can do no more than be aware of these issues and discuss them with families who are faced with these difficult choices.

The issue of perfection is framed more starkly when considering what has been termed cosmetic neurology [Dees, 2004]. Chatterjee [2004] distinguished between the goal of medicine to treat disease and the goal to enhance quality of life by improving normal functions. Should drugs be prescribed to enhance strength, coordination, attention, learning, memory, mood, and affect in those who are neurologically normal? He identified four ethical dilemmas related to cosmetic neurology: 1. What degree of risk should be acceptable when enhancing normal brain function (when the alternative is normality)? 2. How does enhancement of normal brain function alter our views of what it means to be a person [as suggested by Fernandez-Armesto]? 3. Should enhancement of normal brain function be available to all or only to those who can afford it? 4. Are persons subject to coercion from employers and others who would value enhanced brain function and reward those who have it? Furthermore, if the advent of cosmetic neurology is inevitable, how will neurologists respond when their patients request it? Child neurologists will be faced with an additional ethical question: Should parents be able to request cosmetic neurology for their children? Clearly much ethical thought will be needed to address these questions. Cosmetic neurology is one aspect of what has been termed neuroethics. This is a new concept that incorporates the application of modern neuroscientific research to clinical problems and to general society. Related to this, the term neurotheology has been coined to encompass the application of neuroscientific research to understanding religious and spiritual experience [Joseph, 2002]. Functional neuroimaging now allows us to evaluate personal information such as personality traits, social and moral attitudes, individual preferences, deception, guilt, and thoughts [Farah and Wolpe, 2004]. The principal ethical challenges of these applications of neuroimaging relate to privacy, autonomy, and respect for the person. Another aspect of neuroethics is the use of new genetic knowledge to diagnose and treat neurogenetic disorders. Ethical issues in genetic diagnosis include stigma and privacy, whereas gene therapy raises ethical issues similar to those of cosmetic neurology [Avard and Knoppers, 2002]. Scientific progress is inevitable and desirable and the challenges of neuroethics will become even more important in the near future. All neurologists must be aware of these ethical challenges and become informed about appropriate responses as they are developed.

SYNTHESIS The child neurologist striving to do the right thing and to avoid doing the wrong thing will listen to many voices conveying a variety of messages. Some of these voices are internal and reflect the several theoretical approaches that provide a “best fit” for the patient’s problem. The neurologist’s mind will hear different ways of conceptualizing the problem, perhaps from an ethics of care or a utilitarian perspective or some other approach. Experience

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teaches that clinical ethics is not procrustean, that no theory or approach will fit every clinical situation. Every case is unique and provides lessons that can be stored away in memory and called upon another day. Drawing upon his or her knowledge about ethics derived from careful study, as well as the knowledge that can only come from having been at the bedside of many sick children over the years, the neurologist will struggle to derive a sense of harmony that will be helpful when a decision must be made. The child neurologist also listens to the external voices of others who are involved in the clinical situation. Foremost among them is the voice of the family. When love is present, families usually find a way to deal with whatever life hands them. It may not be the “right” way (the way others want them to take), but it is a way that works for them and deserves respect. At any given point in time most people are doing the best they can, given their skills and abilities and the pressures and limitations they face. When physicians seek to understand the situation from the family’s point of view, they may be able to help them do the best they can for themselves and for their child [Coulter, 2002]. The neurologist will also hear the voices of other patients and families he or she has treated and followed over the years, who were in a similar situation in the past and whose subsequent history speaks to the wisdom of decisions that were made [Freeman, 2004]. The child neurologist also will hear the voices of other caregivers involved in a particular case, especially those of the nurses who have a more intimate relationship with the patient and family. In some cases, the voices of long-time friends, pastoral ministers, and staff who have cared for the patient before the present situation arose will need to be heard and considered carefully. The soft but insistent voices of insurance administrators and utilization reviewers may also be audible. Synthesizing all of these arguments and perspectives is never easy and perhaps benefits most from a deep sense of humility. Reflecting on the lessons he had learned in a long and distinguished career as one of the foremost child neurologists in the United States, John Freeman concluded: “One lesson I believe I have learned is that decisionmaking should be a process, and the process for arriving at a decision is far more important than the decision arrived at. This process cannot be left solely to the family, or to relatives and friends, with their biases and prejudices, any more than it can be left solely to the physician. Physicians and families together must learn to work out a plan for the handicapped or potentially handicapped newborn—and likewise for the premature infant, for the person with late-stage Alzheimer’s disease, for the critically ill patient, and for individuals at both ends of life.” [Freeman, 2004] REFERENCES American Medical Association. Principles of medical ethics. Chicago: American Medical Association, 2001. Ashwal S, Cranford R. The minimally conscious state in children. Semin Pediatr Neurol 2002;9:19. Avard DM, Knoppers BM. Ethical dimensions of genetics in pediatric neurology: A look into the future. Semin Pediatr Neurol 2002;9:53. Beauchamp TL, Childress JF. Principles of biomedical ethics, 4th ed. New York: Oxford University Press, 1994. Bentham J. An Introduction to the principles of morals and legislation. New York: Methuen, 1982.

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Bernat JL. Ethical issues in neurology. Boston: Butterworth-Heinemann, 1994. Berrigan D. God is love. Noah Homes Newsletter 2000;Spring issue:2. Byrne P. Philosophical and ethical problems in mental handicap. New York: Palgrave, 2000. Callahan D. Bioethics. In: Reich W, ed. Encyclopedia of bioethics. New York: Simon and Schuster Macmillan, 1995. Chatterjee A. Cosmetic neurology: The controversy over enhancing movement, mentation and mood. Neurology 2004;63:968. Coulter DL, Murray TH, Cerreto M. Practical ethics in pediatrics. Curr Probl Pediatr 1988;18:139. Coulter DL. Neurological uncertainty in neonatal intensive care. N Engl J Med 1987;316:840. Coulter DL. Recognition of spirituality in health care: Personal and universal implications. J Religion Disability Health 2001;5:1. Coulter DL. The strength of families and individuals. J Religion Disability Health 2002;6:1. Dees RH. Slippery slopes, wonder drugs, and cosmetic neurology: The neuroethics of enhancement. Neurology 2004;63:951. Dunn CM, Chadwick G. Protecting study subjects in research. Boston: CenterWatch, 1999. Eiesland NL. The disabled god: Toward a liberatory theology of disability. Nashville, TN: Abingdon Press, 1994. Farah MJ, Wolpe PR. Monitoring and manipulating brain function: New neuroscience technologies and their ethical implications. Hastings Cent Rep 2004;34:35. Fernandez-Armesto F. Humankind: A brief history. New York: Oxford University Press, 2004. Field MJ, Behrman RE, eds, Ethical conduct of clinical research involving children. Washington, DC: National Academy Press, 2004. Fletcher J. Humanhood: Essays in biomedical ethics. Buffalo, NY: Prometheus Books, 1979. Freeman JF, McDonnell K. Tough decisions: Cases in medical ethics, 2nd ed. New York: Oxford University Press, 2001. Freeman JM. On learning humility: A thirty-year journey. Hastings Cent Rep 2004;34:13. Gert B. The relevance of moral theory to pediatric neurology. Semin Pediatr Neurol 2002;9:2. Gilligan C. In a different voice. Cambridge, MA: Harvard University Press, 1982. Glass KC. Ethical issues in neonatal intensive care: Perspectives for the neurologist. Semin Pediatr Neurol 2002;9:35. Hauerwas S. Suffering presence: theological reflections on medicine, the mentally handicapped, and the church. Notre Dame, IN: University of Notre Dame Press, 1986. Jennett B. The vegetative state: Medical facts, ethical and legal dilemmas. New York: Cambridge University Press, 2002. Jonsen AR, Siegler M, Winslade WJ. Clinical ethics: A practical approach to ethical decisions in clinical medicine, 4th ed. New York: McGrawHill, 1998. Jonsen AR, Toulmin S. The abuse of casuistry: A history of moral decision-making. Berkeley, CA: University of California Press, 1988. Joseph R, ed. Neurotheology: Brain, science, spirituality, religious experience. San Jose, CA: University Press, 2002. Kant I. Foundations of the metaphysics of morals. Indianapolis, IN: Bobbs-Merrill, 1959. Koenig HG. Spirituality in patient care: Why, how, when and what. Philadelphia: Templeton Foundation Press, 2002. Kuhse H, Singer P. Should the Baby Live? The problem of handicapped infants. New York: Oxford University Press, 1985. Mahowald M. The person. In: Reich W, ed. Encyclopedia of bioethics. New York: Simon and Schuster Macmillan, 1995. May WE. An introduction to moral theology. Huntington, IN: Our Sunday Visitor Publications, 1994. Middleton A, Hewison J, Mueller R. Prenatal diagnosis for inherited deafness—what is the potential demand? J. Genet Couns 2001;10:121. Mill JS. Utilitarianism. Indianapolis, IN: Bobbs-Merrill, 1971. Murray TH. The worth of a child. Berkeley, CA: University of California Press, 1996. Nordenfelt L, ed. Concepts and measurement of quality of Life in health care. Boston: Kluwer Academic, 1994. Numbers RL, Amundsen DW, eds. Caring and curing: Health and medicine in the western religious traditions. Baltimore: Johns Hopkins University Press, 1998. Nussbaum MC, Sen A, eds. The quality of life. Oxford: Clarendon Press, 1993.

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Pellegrino E, Thomasma D. The virtues in medical practice. New York: Oxford University Press, 1993. Pfaff DW, ed. Ethical questions in brain and behavior. New York: Springer-Verlag, 1983. Pope John Paul II. Joint statement on the vegetative state, 2004. www.vatican.va. Rawls J. A Theory of justice. Cambridge, MA: Harvard University Press, 1971. Reich W: Introduction. In: Reich W, ed. Encyclopedia of bioethics. New York: Simon and Schuster Macmillan, 1995. Schalock RL, ed. Quality of Life, Vol 1: Conceptualization and measurement. Washington, DC: American Association on Mental Retardation, 1996. Shannon TA, Walter JJ. Implications of the papal allocution on feeding tubes. Hastings Cent Rep 2004;34:18. Shevell MI, ed. Ethical issues in pediatric neurology. Semin Pediatr Neurol 2002;9:1. Shevell MI. Reflections on futility. Semin Pediatr Neurol 2002;9:41. Simon YR. The tradition of natural law. New York: Fordham University Press, 1992. Slote M. The task of ethics. In: Reich W, ed. Encyclopedia of bioethics. New York: Simon and Schuster Macmillan, 1995. Smith WJ. Forced exit. New York: Random House, 1997.

Strauss DJ, Ashwal S, Day SM, et al. Life expectancy of children in vegetative and minimally conscious states. Pediatr Neurol 2000;23:312. Strauss DJ, Shavelle RM, Ashwal S. Life expectancy and median survival time in the permanent vegetative state. Pediatr Neurol 1999;21:626. Sulmasy DP. The healer’s calling: A spirituality for physicians and other health care professionals. New York: Paulist Press, 1997. Swinton J, ed. Disabling society, enabling theology: Critical reflections of Stanley Hauerwas’ theology of disability. Binghamton, NY: Haworth Press, 2004. Taylor RL, Watson J, eds. They shall not hurt: Human suffering and human caring. Boulder, CO: University of Colorado Press, 1989. The Belmont Report. Ethical principles and guidelines for the protection of human subjects in research. Washington, DC: Federal Register Document 79-12065, 1979. The Multi-Society Task Force on PVS. Medical aspects of the persistent vegetative state. N Engl J Med 1994; 330:499(Part 1), 1572 (Part 2). Tonniges TF, Palfrey JS. The medical home. Pediatrics 2004;113:1471. United Nations. Convention on the Rights of the Child. New York: Office of the United Nations High Commissioner for Human Rights, 1990. Veatch RV. The foundations of justice: why the retarded and the rest of us have claims to equality. New York: Oxford University Press, 1986. Velmas S. Ethical analysis of the concept of disability. Ment Retard 2004;42:209.

CHAPTER 95

The Internet and Its Resources for the Child Neurologist Kenneth J. Mack and Steven M. Leber

The rapid explosion of the Internet has created a plethora of opportunities and challenges in the field of child neurology, both for practitioners and for patients and their families. Not only is clinical and scientific information more rapidly and universally available, but new forms of information now exist only because of the power of electronic communication. Libraries of all sorts are now literally at our fingertips, and clinical consultation and research collaboration with distant colleagues have never been easier. In this chapter, many of the potential applications of the Internet for pediatric neurology are reviewed. Obtaining and learning to use the new software and hardware require time and money, and some of the potential costs of the new methodologies are also noted. Just as the well-informed physician needs continuing medical education to keep pace with the rapid growth of clinical knowledge, he or she must invest time and energy in “continuing informatics education” to keep up with the explosion of computer methods available to assist in the care of patients. For those who are proficient in the use of computers and the Internet, the challenge will be to apply the methodology creatively to clinical practice. For others who find learning to use computers like trying to learn a new language well past the critical period, the challenge is simply to keep up with the changes. For still others around the world, access to the hardware required for any of these applica-tions is severely limited. The greatest challenge to all, however, may be in developing the wisdom and experience necessary to determine the quality of information being communicated.

THE INTERNET The Internet was initially established in the 1960s as a U.S. military communication system with the goal of providing a reliable communication system in the event of a nuclear war. Over time, multiple regional and academic connections were made to the initial network, and the Internet became a network of multiple computers. Currently, the Internet consists of hundreds of millions of connected computers all around the world. Similar to telephone services, no central organization is currently responsible for the entire Internet. The strength of this design is that it is nearly impossible for the Internet to break down. The disadvantage is that the Internet can seem poorly organized. In the previous edition of this book, this chapter focused on how to access the Internet. In the ensuing years, access has become almost trivial, and the Internet is now a tool used by most clinicians.

THE INTERNET’S POTENTIAL USEFULNESS Electronic Mail Electronic mail (e-mail) provides a connection between two computers on the Internet. Data, typically as text files such as letters, are sent from one computer to another. Other computer files, such as graphic files, audio files, video files, or even computer programs, can be attached to an e-mail message. For instance, if one wanted to confer with a colleague about an intriguing magnetic resonance scan or an unusual histologic specimen, he or she could scan the image into a file and then e-mail that file across the country or around the world within seconds. E-mail addresses are typically in the following form: [email protected] (e.g., [email protected]). Among the topdomain codes in the United States are edu (educational), com (commercial), gov (government), and org (organization). Outside of the United States, two-letter suffixes usually identify the country (e.g., uk for United Kingdom). An e-mail message can be sent to a central computer, which distributes the messages to everyone on a “mailing list.” Typically, mailing lists are organized by topics, so that there are separate mailing lists for child neurology, adult neurology, child psychiatry, epilepsy, and so forth (see Neurosciences on the Internet [http://www.neuroguide.com/ neurolist.html] for some). Most medical mailing lists are either “closed” or “monitored.” In closed lists, access is restricted (e.g., to physicians only). In monitored lists, the messages are screened by the system operator to decrease the probability that inappropriate messages are sent out in the mailings. Many lists now have a “digest” option, so that all the e-mail of a single day can be incorporated into a daily digest. This digest option significantly cuts down on the clutter in many e-mail inboxes. When using a mailing list, note that there are generally two mailing addresses. For instance, in the “Child-Neuro” mailing list, mail sent to [email protected] will go out to all the subscribers to the list [HernandezBorges et al., 1997; Mack and Leber, 1996]. In contrast, the e-mail address [email protected] is used to address the computer managing the Child-Neuro list and acts as a command—for example, to add a name (subscribe) to the list. Two issues of recurrent concern for physicians discussing individual patients in e-mail discussion groups are patient confidentiality and professional liability. As with case reports in published journals, anonymity is imperative when patients are discussed, and names and other identifying protected health information must be deleted when imaging studies are shared. Although breaches are possible in un-

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monitored lists, generally this has not been a problem for most groups. If potentially identifying information is shared (e.g., facial photographs), informed consent must be obtained. In situations in which patient databases are created for intraor inter-institutional studies, adequate security controls must be installed and anonymity maintained. The issue of liability for online consultation is quite complex and beyond the scope of this discussion, but many attorneys believe that advice provided online is similar to that given in phone consultation: When a physician advises another health care provider without establishing a direct doctor-patient contact or expecting payment for services, that physician is not held liable for the advice given [De Ville, 1996; Elliot and Elliot, 1996]. Even if the legal aspects of this issue become clarified as Internet law evolves, the question of quality of advice will remain. Many postings are unsigned, and the numerous “I treat disease X this way” postings, which may not be based on scientifically controlled trials, are certainly subject to legitimate caution, if not criticism. However, rigorously proved answers are not available for many of the questions pediatric neurologists pose, and this type of practical advice often is exactly what is being sought. Furthermore, although postings to e-mail lists are not subject to any direct peer-review prescreening, the ability of any reader to reply to the original message creates the possibility of a post facto review from clinicians with a broader diversity of expertise than might be found in the traditional two- or three-person review process used in journal publications. Mailing lists can also be useful in providing notification of publication of articles related to specified medical topics and subspecialties. For example, MDLinx (http://www.mdlinx.com/) has a variety of neurology and pediatric subspecialty mailing lists (including pediatric neurology), supplying brief summaries and links to entire articles. Amedeo (http://www.amedeo.com/) allows subscribers to choose particular areas of neurology and specific journals and then sends out regular lists of new publications, along with links to the articles in PubMed (see later). Both are free services.

USENET Groups USENET, the user’s network, is dedicated to topic-specific discussion groups. These are “bulletin boards” where anyone can post or place a message, and where others can read that message at their convenience, similar to postings on a “real” bulletin board. An initial comment and the responses it prompts are known as a thread. More than 10,000 news groups exist, arranged in a hierarchical fashion. At least 20 of these discuss neurology or neuroscience-related topics, and many are dedicated to particular diseases. USENET is an excellent forum for obtaining the opinion of people with an interest in a particular topic even when one has no way of knowing in advance who these “experts” may be. Because access is open to everyone, the nature and quality of the discussions vary considerably from group to group and thread to thread, but discussions that professionals might not find medically useful (e.g., many in the general medicine news group sci.med) can be quite educational in giving clinicians a glimpse of the concerns of patients and families

expressed outside the office setting. Similar discussion forums exist on private online services, such as America Online. Neurosciences on the Internet (http://www.neuroguide.com/ neuronews.html) lists many of these groups. Access to USENET can be through dedicated software called newsreaders (see http://users.rcn.com/kateshort/nnq/ nnewsreader.html for an overview) or through World Wide Web browsers (see later discussion). New users are urged to begin with the group news.announce.newusers.

World Wide Web Access to the Internet became available for people without a strong computer science background when browsers such as Mosaic, Netscape, and Internet Explorer became available. The World Wide Web (WWW) originated as a project to connect researchers in the high-energy physics community. Originally, the basic algorithm for the WWW was developed by researchers at CERN (the European Laboratory for Particle Physics in Switzerland) in 1989. This initial Web was a consortium of computer users who implemented a standardized, nonproprietary syntax termed hypertext markup language (HTML). HTML is a standardized method for including images, videos, and audio in documents that can be displayed on a variety of computers, including Apple Macintosh, IBM PCs, and UNIX-based computers [McEnery, 1995]. Later, an NSF-funded effort at the University of Illinois (National Center for Supercomputer Applications) developed Mosaic, a browser program that allows easy access to the large number of text, video, and audio files on the web. The web has its own specific jargon. A homepage is a virtual or computer home. Often a homepage contains links to other useful pages containing text or graphic files. These pages are connected by hypertext, a highlighted word or icon that allows one to switch to a new page, regardless of whether that page is on the same computer, in the same city, or across the world. In this way, the web can link a variety of information on a single topic from different information sources around the world. The name or location of a page is called its URL, or uniform resource locator. Most begin with the code http://, which stands for hypertext transfer protocol and tells the reading program the mode of access it will use to read the information on the page. This information is followed by a series of characters that specify the location of the host computer and of the file within that computer. Although URLs generally consist of almost unmanageably long lists of letters, web browsers have bookmark features that allow users to save URLs of interest for future reference. In addition to the multimedia and hypertext features, another use of the web involves its capacity for interaction: The reader can fill out forms, respond to questions, and run searches for specific information. Numerous web browsers are available. Among the more popular are Netscape and Microsoft Internet Explorer. Most are extremely easy to use, and all are in rapid evolution. In addition, numerous helper applications or plug-ins are being developed that expand the capacities of these browsers for audio, video, and interactivity, including three-dimensional virtual reality features. Many universities, private companies, and other groups are developing their own Intranets. These consist of Web-

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like pages and documents that are accessible via web browsers but only internally, and that are intended for intrainstitutional communication. These may be used for accessing medical records, laboratory data and radiographic images, patient schedules, and medical references; for listing telephone, paging, and e-mail directories; and for posting a wide variety of documents previously printed on paper, such as meeting minutes, call schedules, and practice parameters. Current physiologic data, such as blood pressure and intracranial pressure, can also be placed online in a format accessible from home or office by a physician with a web browser. Because information can flow both to and from the documents and because the documents can be linked to databases, online equipment and supply catalogs can be combined with ordering forms. Interactive intranets can be set up to schedule meetings by coordinating individual schedules. Furthermore, since intra-institutional USENETlike discussion groups can be set up, the need for faceto-face meetings may actually decrease.

Academy and Societal Web Sites The Child Neurology Society formed an Electronic Communication Committee to facilitate access to useful information on the Internet. In addition, a new Child Neurology Society website (http://www.childneurologysociety.org/) contains information about meetings, fellowship and job opportunities, practice parameters, society publications, a membership directory, and a variety of society business affairs. The Child Neurology Society can be contacted by e-mail at nationaloffi[email protected]. Before the completion of the Society’s website, a Child-Neuro website was organized (http://www-personal.umich.edu/~leber/c-n/) by the authors of this chapter in an attempt to consolidate useful Internet information of interest to child neurologists and parents of children with neurologic diseases. This site contains supplemental information of value to child neurologists, including listing of research studies seeking patients, research opportunities in child neurology, and patient education resources. The International Child Neurology Association has also developed a site (http://www.child-neuro.net/) for the field of child neurology. The American Academy of Child and Adolescent Psychiatry site (http://www.aacap.org/) is also worth visiting. The most innovative part of this site is its “Facts For Families,” a series of fact sheets for patients and their families on common clinical problems in the field, such as autism, tics, and depression. The American Academy of Pediatrics has a well-designed site (http://www.aap.org/) that features patient and professional information. This site includes information on “Professional Education” and includes other useful Internet resources for pediatrics. The American Academy of Neurology is aggressively expanding its website (http://www.aan.com/). Plans include having searchable text documents on the site, useful crosslisting of other sites, and academy information. One of the publications of the American Psychiatric Association site (http://www.psych.org/) is available online (Psychiatric News), as well as a continuing medical education program that includes text, audio, and graphic materials.

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Journal Sites Most journals are now available online. A few examples are listed in Table 95-1. An expanding number of journals allow online access to full articles and text, although a paid subscription (either personal or through a library) is usually required. Articles are generally available either in plain text format with links to figures or as print-format PDF files, which can be viewed with special readers, such as Adobe Acrobat Reader, available at no cost from http://www.adobe.com/ products/acrobat/readstep2.html. The Highwire Press (http://www.highwire.org/) of Stanford University is a leader in moving journals toward electronic publishing. Both abstracts and full-text articles are available. Online journals can make current medical and scientific information readily accessible to the third world, and the Health InterNetwork (http://www.healthinternetwork.net/) is leading efforts to provide this free of charge. The advantages of online journals include the ability to publish quickly and ease of access. Other potential advantages include search capabilities, forums for discussions of articles, links to related articles, and the ability to include supplemental resources and data too extensive to include in a print format. Furthermore, audio and video components can be included in publications without difficulty, which should be of tremendous utility to neurologists discussing language or movement disorders, for example.

Electronic Textbooks Electronic books are available both online and as purchasable CD-ROM volumes (see Table 93-1). Online Mendelian Inheritance in Man (OMIM) (http://www.ncbi.nlm.nih.gov/ entrez/query.fcgi?db=OMIM) is a federally funded project run through the National Center for Biotechnology Information that provides searchable information on human genes and genetic syndromes. It is based in part on McKusick’s excellent book on genetic syndromes [McKusick, 1998] but has the advantage of being continually updated. Clinical, historical, and genetic information, with hypertext links available to the abstracts of the cited references, is provided for a vast number of disorders. Currently, this is perhaps the single most useful site for a child neurologist. For example, if a neurologist sees a patient with ataxia and albinism, a search of OMIM reveal eight disorders in which this combination has been seen and describes the clinical and genetic features of each. Other useful book sites include online versions of the Physicians Desk Reference and the Merck Manual. More than 40 peer-reviewed topics in child neurology and many more topics in general neurology and other areas of medicine are contained in the electronic text “eMedicine” (http://www.emedicine.com/). The Neuromuscular Disease Center at Washington University (http://www.neuro.wustl.edu/neuromuscular/) is a comprehensive and up-to-date outline covering many aspects of neuromuscular disease in a searchable format. Neuropathology and Neuroanatomy on the Internet (http://www.neuropat. dote.hu/) features an online neuropathology atlas, as well as a tutorial on normal brain structures. A search of an online bookstore in early 1998 found eight neurology books available or soon-to-be available as CD-

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TABLE 95-1 Selected Websites of Interest to Pediatric Neurologists

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TABLE 95-1, cont’d Selected Websites of Interest to Pediatric Neurologists

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TABLE 95-1, cont’d Selected Websites of Interest to Pediatric Neurologists

CME, continuing medical education; NIH, National Institutes of Health. From McKusick VA, 1998.

ROMs. In contrast, a search in 2004 revealed nearly 2000. The computerized versions generally have an advantage over traditional texts in that they allow searches by keywords, phrases, chapter titles, authors, and so forth; have hyperlinks between topics and to images and references; and are frequently updated at minimal expense. In addition, they have the capacity for color images and multimedia files. For example, video is extremely useful in discussing movement disorders and eye movements. Many anatomy and radiology books also are available as CD-ROM editions. The Bookshelf (http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?db=Books), produced by the National Center for Biotechnology Information, is a collection of biomedical books, searchable by concept or keyword and linked to terms in PubMed abstracts. The site organizes the books into units of content rather than mirroring a textbook in print, and is designed so that the reader can begin browsing with a search on the PubMed link rather than reading a book sequentially from beginning to end. Once browsing the book page, it is possible to navigate around a whole unit of content.

Other Interesting Reference Sites It is estimated that the web consists of hundreds of millions of documents and resources. Trying to navigate to an area of interest is a formidable task. A wide variety of search engines, such as Google and Yahoo, are available to help with this task. These can either allow direct searches or searches via a hierarchical categorization of topics (known as web directories). One can prompt any of these search engines to provide website information on topics as diverse as medicine, gardening, space, and art. These search engines have simple interfaces and are easy to use, but also have advanced features (including the use of Boolean logic) that are worth spending a few minutes learning, allowing both more focused and more comprehensive searches. One of the most useful web functions is access to the MEDLINE database. The MEDLINE file contains bibliographic citations and author abstracts from more than 4800 current biomedical journals published in the United States and 70 other countries. The file contains more than 12 million records dating back to 1966. This database can be accessed through a variety of browsers. One such browser, PubMed (http://www.ncbi.nlm.nih.gov/PubMed/), was developed at the National Library of Medicine. It has been developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations

and linking to full-text journals at websites of participating publishers. It has the advantage of ease of use, a frequently updated database, and no charge to users. PubMed also allows access to OLDMEDLINE, which has 2 million citations of articles published between 1951 and 1965, as well as to new publications not yet indexed in MEDLINE. The Visible Human Project (http://www.nlm.nih.gov/ research/visible/visible_human.html) features a collection of images (cryopreserved, computed tomography, and magnetic resonance imaging) of an entire male and female [Lindberg and Humphreys, 1995]. Harvard University provides a whole brain atlas (http://www.med.harvard.edu/ AANLIB/home.html) that provides imaging examples of normal structures, as well as pathologic findings. Several excellent websites aim at teaching the neurologic examination using both text and video. NeuroLogicExam (http://medstat.med.utah.edu/neurologicexam/) and Neuroexam.com (http://www.neuroexam.com/) each use videos to illustrate various elements of a neurologic examination. The former also features helpful anatomic diagrams. A new site, PediNeuroLogicExam (http://medstat.med.utah.edu/ pedineurologicexam/) provides videos and text, demonstrating the changing examination as the child matures and the approach to examining the young patient. GeneralPediatrics.Com (http://www.generalpediatrics.com) is a compilation of Internet resources useful both to pediatricians and to parents. The explosion of research in pediatric neurology has made it difficult to keep up with genetic testing and research studies. Two sites, both sponsored by the National Institutes of Health, are exceptionally helpful. Gene Tests (http://www.genetests.org/), from the University of Washington, contains information about clinical and research tests available for genetic diseases, including where to send the specimens, as well as clinical summaries about some of the conditions. Clinical Trials (http://clinicaltrials.gov/), from the National Library of Medicine, provides information about federally and privately supported clinical research on human volunteers, including the purpose of the trial, inclusion and exclusion criteria, location, and contact information. For example, in September, 2004, input of “leukodystrophy” revealed 5 ongoing trials, and “epilepsy” (further restricted to trials in children), 27. Privately sponsored sites, such as Center Watch’s “Clinical Trials In Neurology” (http://www.centerwatch.com/patient/studies/ area10.html), also list trials seeking patients. Several directories of neurology and neuroscience sites provide excellent starting points in searching for informa-

Mack and Leber / The Internet and Its Resources for the Child Neurologist

tion. Two such directories are “Neurosciences on The Internet” (http://www.neuroguide.com/) and the Internet Handbook on Neurology (http://www.neuropat.dote.hu/ neurology.htm).

Clinical Decision-Making Software SimulConsult (http://simulconsult.com/) is a free, medicaldecision-support application developed by Dr. Michael Segal. It allows users to input information about a patient’s age, symptoms, age at which symptoms began, and laboratory findings and generates a differential diagnosis. It then suggests additional findings and laboratory tests that will be useful in reaching a diagnosis. The database used to generate this information is provided by a large peerreviewed community of experts and is being continually updated. Recently, Segal and his colleagues have also developed web-based tools to generate and share educational cases over the web (http://simulconsult.com/ neurologicalsyndromes/edu/). ISABEL (http://www.isabel.org.uk/) is a commercial, online clinical decision information system covering a broader spectrum of pediatrics, including pediatric neurology.

THE PROBLEMS In a recent editorial, concern was expressed that any “preprint” posted on the Internet (like those in the physics community) is “incomplete until it undergoes peer review” [Kassirer and Angell, 1995]. Certainly, anyone can post almost any item of information on the Internet, and currently there are no safeguards to ensure that the information is accurate. Some websites, like those for the journal Science or for the American Academy of Neurology, have high credibility because the postings have gone through some form of review. However, the quality of a web site on headaches cannot be controlled. Web sites cannot be deemed reputable simply because they are associated with a university department or patient organization. Physicians cannot trust an e-mail or a bulletin board posting, especially if such communications are unsigned or are signed by unknown individuals. Certainly, as when reading any journal article, the physician must be critical and take into account the source of that article or information. In the future, a few sites may distinguish themselves by their usability and accuracy in our field [Hernandez-Borges et al., 1997]. Codes of conduct for medical publishing on the Internet do exist, such as Health on The Net Foundations’s Code of Conduct (http://www.hon.ch/ HONcode/Conduct.html) and new methods are being assessed for measuring quality [Eysenbach and Diepgen, 1999]. Issues of payment and copyright arise when journals or academics place information on the Internet. The technology is available to restrict access to certain websites so that only (paying) members can enter. One can transfer credit card information, although this is generally not considered to be risk free. In terms of copyright, there is concern about how information is downloaded and reproduced by other individuals [Stern and Westenberg, 1995; Taubes, 1995]. The biggest problems for medical resources on the Internet seem not to be of a technical

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nature but rather of quality of information, accessibility, and appropriate reimbursement (e.g., for access to journal subscriptions).

A PATIENT EDUCATION RESOURCE The Internet and forums on private services (such as America Online) are rapidly becoming major sources of information for patients and their families. Websites, e-mail lists, and USENET groups dedicated to particular diseases provide a wealth of factual information, as well as contact with patients, families, and (less commonly) health care providers sharing similar interests. The Family Village (http://www.familyvillage.wisc.edu/) is an example of a website that attempts to catalog useful Internet information for families of patients with developmental disabilities. Some medical centers and departments are using the Web to advertise their particular areas of expertise to other clinicians and patients. Be aware, however, that these Internet resources provide excellent supplements to the information provided by the patient’s doctor but cannot substitute for it. The quality of information shared is variable, and rumors and word of purported treatments occasionally run wild. Sometimes, of course, some of these rumors contain truth, and the dissemination of this information is highly desired. Who is to determine truth or quality, however? An interesting development in the United States is that the Federal Trade Commission is starting to regulate promotions on the web and USENET for products and services claiming to help cure, treat, or prevent a variety of diseases. The problem lies not only in the lack of a peerreview type of process but also in limited physician involvement in many patient-centered discussion groups. These problems are hardly surprising, given time constraints, the absence of compensation for this type of work, and appropriate fears of misguiding patients and of contradicting their own physicians. Physicians interested in Internet resources for patients are often caught in a bind between trying to provide families with reliable information over the Internet, quelling rumors in the making, and returning patients to their best resources, their own doctors. These issues are likely to become even more significant in the future as Internet access becomes more universal and routine.

COMMUNICATING WITH PATIENTS VIA E-MAIL Although the actual office or hospital visit is the gold standard of medical care, many patients choose to interact with physicians via phone or fax. Typically, these interactions are for simple requests, such as prescription refills, but also can involve diagnostic, management, and triaging decisions. E-mail has the advantage to the physician and patient of avoiding the time-consuming and sometimes expensive “phone tag,” of allowing questions and responses to be formulated carefully in advance, and of providing documentation of the interaction for future reference and for the medical record. However, the use of e-mail raises concerns about breaches of confidentiality, the authenticity of the senders and recipients of e-mail, and the risk of

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missed e-mail messages. Guidelines have been developed to minimize the risks and maximize the benefit of e-mail [Bovi, 2003; Gerstle, 2004; Kane et al., 1998]. Unsolicited e-mail from patients unknown to the physician also poses potential moral and legal problems [Eysenbach, 2000]. Some of these problems may be addressed by the development of secure servers, web-based portals that “triage” patient messages [Gerstle, 2004; Katz et al., 2003]. Patients are given passwords, log into a web site as they might for online banking, and are notified by e-mail when a new message from their health-care provider waits for them on the web site. Messages coming into the doctor’s office via the web site are triaged in ways similar to incoming phone calls. The use of such a secure server has been found to increase the amount and, in the eyes of the physicians, the quality of communication between patients and providers but did not reduce the number of telephone calls, office visits, or missed appointments [Katz et al., 2003].

sicians’ personal schedules. Many of these tasks could also be performed with computer terminals located in examination rooms or on small laptops or tablet computers. The advantages of bigger screens are their usefulness in the display of anatomic images, as well as in multimedia displays that could be used in patient education. The Handheld Computing Center (http://aan.com/ pda.cfm) of the American Academy of Neurology aims to help the neurologist expand his or her understanding and use of handheld devices. A recent review of handheld computers [Al-Ubaydii, 2004] lists more likely uses, and calls attention to versions of PubMed (http://pubmedhh.nlm.nih.gov/nlm/ pubmed/index.html and http://archive.nlm.nih.gov/proj/ pmot/pmot.php) and evidenced-based medicine resources (www.infopoems.com), as well as many other resources, customized for PDAs. The review also discusses the security concerns brought about by the use of these devices.

PERSONAL DIGITAL ASSISTANTS

Telemedicine is a rapidly expanding set of applications in which electronic communication is applied directly to patient care. Still images, live video, audio, text, and quantitative data can be transmitted between physician and physician, physician and patient, imaging center and physician, and so forth. The methods are promising, but cost-effectiveness is not yet proved, and many legal and administrative issues need to be worked out before they gain widespread use. In addition to videoconferencing, which is gaining widespread use as an educational tool, pediatric neurologists are likely to see telemedicine applications evolve in several patient care areas in the coming decade:

Miniaturization has made it practical for the physician to carry a small, handheld computer into the examination room. The personal digital assistant (PDA) may soon be as necessary a piece of equipment as the reflex hammer, particularly as hospital and office medical records evolve from being paper-based to electronic and as connectivity between these handheld devices and hospital computers improves. Many medical programs for these PDAs already exist, and the variety of uses is likely to expand as use becomes routine and wireless connectivity becomes standard. As of 2002, more than one third of pediatricians used PDAs in their clinical practice [Carroll and Chistakis, 2004]. Patient encounters can be tracked, with automated access to demographic information and laboratory data on the main office or hospital computer. Prior records and laboratory values available at the bedside in a searchable fashion would be extremely helpful. Conversely, information obtained at the bedside can be entered into the main computer. This information can include charge entries, such as diagnoses and procedures, each with automated coding. Information entered at the bedside, such as vital signs, patient orders, and admission and progress notes, can become part of an electronic medical record or, as an intermediate step, can be printed out to become part of the paper chart. Entry of orders and progress notes may be faster and more complete if a word processing program with diagnosis-specific templates and menu selections is used (e.g., “headache” could lead to entries for location, frequency, quality, and positional dependence). In addition to information flow between PDAs and main computers, medical resources available at the bedside, such as practice parameters, medical references, and drug information, can also be a boon for both the doctor and patient. Other organizational tools can aid in patient management. These include applications to perform clinical calculations, to digitalize “scut lists,” to write prescriptions and communicate them online to the patient’s pharmacy, and to manage patient schedules and interface them with phy-

TELEMEDICINE

1. Electronic storage of patients’ medical records and laboratory data, with improved dissemination between specialists and primary caretakers 2. Transmission of radiology and pathology images from the sites where these images were created both to specialized interpreters (e.g., neuroradiologists and neuropathologists), and to the physicians (e.g., pediatric neurologists) caring for the patients 3. Transmission of these images in the opposite direction—attachment of relevant radiographic and even video images to electronic consultation letters and discharge summaries “may be worth a thousand words.” 4. Remotely accessible databases for research, teaching, and patient care (e.g., outcomes research, practice parameters) 5. Transmission of data from patients’ homes (e.g., remote electroencephalogram monitoring) 6. Consultations—perhaps the most important, and certainly the most challenging application. Both physician-to-physician and physician-to-patient consultations would expand on the telephone conversations now common and accepted. Allowing geographically separated physicians to discuss patients with specialists while looking at radiographic images or even live video of the patients themselves could allow more efficient triaging and improved

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recommendations for patient care. For patients in rural or other settings remote from specialty centers, at least limited pediatric neurology “office” evaluations could be performed without requiring traveling long distances. Similarly, one specialist could easily consult another, even in another country. Many obvious difficulties are associated with these types of consultations: 1. Neurologic examinations would, by necessity, be limited (e.g., inadequate evaluation of strength and tone), and the criteria by which these video visits could replace face-to-face evaluations need to be determined. 2. In a similar vein, although sound and image quality are rapidly improving, they are not consistently equivalent to personal examination, and the brief delays often associated with transmission can be annoying. 3. Although one goal of this type of consultation would be to lower health-care costs by improving centralization of specialty care, the initial costs of setting up such systems can be quite high. 4. The means by which a physician can bill for electronic consultations remain to be determined. 5. It remains to be proved that electronic consultations truly improve efficacy in a cost-effective manner. For example, two studies comparing television and telephone consultations found that the former took more time and was more expensive without any improvement in diagnostic accuracy, the number of tests requested, or referral rates [Dunn et al., 1977; Moore et al., 1975]. 6. Finally, numerous legal, liability, and privacy issues arise, particularly when care is being shared across state or even national boundaries. The issue of out-of-state licensing needs to be addressed when the physician and patient are in different locales. Malpractice liability becomes confusing when care is shared by physicians, particularly if different rules apply in different states. The confidentiality of medical records, whether video images transmitted electronically or patient databases, needs to be maintained and may be complicated by different privacy laws in different states.

WHAT DOES THE FUTURE HOLD? The question for our field is whether the Internet is something that can make our careers easier, more efficient, and more effective. From our personal standpoint, the answer is yes because specific programs or web sites are identifiable, can be used, and have been helpful. In a certain sense, the Internet is a fluid, expanding library of information. Since the last version of this chapter was published in 1999, geographically dispersed centers have begun pooling patient data for descriptions of rare disorders and for designing and managing trials; electronic medical records and radio-

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graphic data have become the norm; physicians have begun to use medical decision-making software after seeing a patient and before writing their consultation notes; and textbooks themselves are becoming continually updated, with online versions that include audio and video data and linkage to outside references and websites. It is likely that all of this information will become more portable as wireless, handheld computers become standard tools. As more information and programs are made available, the usefulness to the profession will increase. Certain organizations, such as the American Academy of Neurology and the Child Neurology Society, are trying to take the lead and help organize and review the information that is available. The best is yet to come. As child neurologists, the usefulness of the Internet should not be judged on what it contains now but what it will contain in the near future.

REFERENCES Al-Ubaydii M. Handheld computers. BMJ 2004;15:1181. Bovi AM; Council on Ethical and Judicial Affairs of the American Medical Association. Ethical guidelines for use of electronic mail between patients and physicians. Amer J Bioethics 2003;3:W43. Carroll AE, Chistakis, DA. Pediatricians’ use of and attitudes about personal digital assistants. Pediatrics 2004;113:238. De Ville KA. Internet listservers and pediatrics: Newly emerging legal and clinical practice issues. II. Pediatrics 1996;98:453. Dunn EV, Conrath DW, Bloor WG, et al. An evaluation of four telemedicine systems for primary care. Health Serv Res 1977;12:19. Elliot SJ, Elliot RG. Internet listservers and pediatrics: Newly emerging legal and clinical practice issues. Pediatrics 1996;97:399. Eysenbach G. Towards ethical guidelines for dealing with unsolicited patient emails and giving teleadvice in the absence of a pre-existing patient-physician relationship: Systematic review and expert survey. J Med Internet Res 2000;2:e1. (http://www.jmir.org/2000/1/e1/). Eysenbach G, Diepgen TL. Labeling and filtering of medical information on the Internet. Methods Inf Med 1999;38:80. Gerstle RS. E-mail communication between pediatricians and their patients. Pediatrics 2004;114:317. Hernandez-Borges AA, Pareras LG, Jimenez A. Comparative analysis of pediatric mailing lists on the internet. Pediatrics 1997;100:E8. Kane B, Sands DZ, for the AMIA Internet Working Group, Task Force on Guidelines for the Use of Clinic-Patient Electronic Mail. Guidelines for the clinical use of electronic mail with patients. J Am Med Inform Assoc 1998;5:104 (http://www.amia.org/pubs/other/email_guidelines.html). Kassirer JP, Angell M. The Internet and the journal. N Engl J Med 1995;332:1709. Katz SJ, Moyer CA, Cox DT, et al. Effect of a triage-based e-mail system on clinical resource use and patient and physician satisfaction in primary care. J Gen Intern Med 2003;18:734. Lindberg DA, Humphreys BL. Computers in medicine. JAMA 1995;273:1667. Mack KJ, Leber SM. Child neurology and the Internet. Pediatr Neurol 1996;15:283. McEnery KW. The Internet, World-Wide Web, and Mosaic: An overview. AJR Am J Roentgenol 1995;164:469. McKusick VA. Mendelian inheritance in man, 12th ed. Baltimore: John Hopkins University Press, 1998. Moore GT, Willemain RT, Bonanno R, et al. Comparison of television and telephone for remote medical consultation. N Engl J Med 1975;292:729. Stern EJ, Westenberg L. Copyright law and academic radiology: Rights of authors and copyright owners and reproduction of information. AJR Am J Roentgenol 1995;164:1083. Taubes G. Indexing the Internet. Science 1995;269:1354.

INDEX

Page numbers followed by b, f, or t denote boxes, figures, and tables, respectively.

A A band, 1839, 1839f, 1841, 1849, 1849f A wave in electroretinography, 245, 246f in intracranial pressure, 1515 AAMR Adaptive Behavior Scale (ABS), 805 Abasia, 1244, 1246 Abdominal migraine, 1191, 2285-2286 diagnostic criteria for, 1186b Abdominal muscles, testing of, 34t Abdominal pain, recurrent, 2285-2286 Abdominal protuberance, in spinal muscular atrophy, 1864, 1867f Abdominal reflexes, 19, 41 in Friedreich’s ataxia, 1249 Abducens nerve (CN VI) assessment of, 80 in newborn (term), 52 in older child, 20-22 injury or palsy of, 339 brain tumors and, 1694 hydrocephalus and, 429 intracranial pressure increase and, 1517 in meningeal leukemia, 1735-1736 in Möbius syndrome, 1870, 1870f Abduction of eye, 20-22, 21f, 21t A-beta fibers, in pain, 2373 Abetalipoproteinemia, 88t, 1247t, 1288, 1906-1907 clinical characteristics of, 1907 laboratory tests in, 1907 management of, 1907 pathology of, 1906 vitamin E in, 1907, 2316-2317 Abilify. See Aripiprazole Abrin, for tumor, 1746 Abscess(es) brain, 1588-1589 amebic, 1646-1649 in candidiasis, 1638, 1639f clinical characteristics of, 1588, 1588t computed tomography of, 173, 1588 with congenital heart disease, 2220 CSF analysis in, 1575t, 1588 CSF protein content with, 162t differential diagnosis of, 1588 diffusion-weighted imaging of, 187 EEG findings with, 1588 in leukemia, 1738 magnetic resonance imaging of, 174, 177f, 1588 pathogenesis and pathology of, 1588-1589 prognosis of, 1589 in systemic lupus erythematosus, 1811 treatment of, 1589 epidural cranial, 1589, 1589f diffusion-weighted imaging of, 187 spinal, 1539, 1589 Absence seizures, 984b, 1023-1029 atypical, 1024-1025, 1024t

Absence seizures continued automatisms in, 1024 calcium channel blockers for, 999-1000 childhood, 1025 classification of, 1024, 1024t clinical features of, 1023-1025 differential diagnosis of, 1025, 1025t disorders mimicking, 984b EEG findings in, 1024t, 1026, 1026f-1027f etiology of, 1025-1026 juvenile, 1025, 1029 myoclonic seizures with, 1074 pathophysiology of, 999-1000, 999f, 1026-1028, 1027f prognosis of, 1029 treatment of, 999-1000, 1023t, 1028-1029 typical, 1024-1025, 1024t Absence status epilepticus, 1093b, 1094 Absorption of drugs, 1105-1109 children’s physiology and, 1117-1118, 1117t extent of, 1105 rate of, 1105 Abuscreen, 2175 Abuse. See Child abuse Academic underachievement, in epilepsy, 1171-1172 Acadian ataxia, 1250, 1903 Acanthamoeba, 1646, 1650-1652. See also Granulomatous amebic encephalitis Acanthosis nigricans, Crouzon’s disease with, 447t, 448 Acatalasemia, 743t, 750 Acceleration injury, 1402, 1457 Accutane (isotretinoin), teratogenicity of, 364, 2198 Acellular pertussis vaccine, 2350 Acentric chromosomes, 528 Acentric fragments, 516 Acetaminophen dosage of, 2376t hepatotoxicity of, 2294 for migraine, 1193t, 1195 nephrotoxicity of, 2265 overuse of, and headache, 1195 for pain, 2376-2377 poisoning, 2189-2190 in renal failure, action and effects of, 2268 for tension headache, 1198 Acetazolamide for Andersen-Tawil syndrome, 2100 bioavailability of, 1106t and CSF formation, 155 for episodic ataxia type 1, 2103 formulations of, 1106t for hydrocephalus, 321, 430-431 for hypokalemic periodic paralysis, 2098 for idiopathic intracranial hypertension, 1200, 1522 and ketogenic diet, 1143 for moyamoya disease, 1773 for myoclonic seizures, 1075 Volume 1: pages 1–1180

Volume 2: pages 1181–2408

Acetazolamide continued for nonepileptic paroxysmal disorders, 1213t, 1297-1298 for paramyotonia congenita, 2097 pharmacokinetics of, 1106t in renal failure, action and effects of, 2268 routes of administration, 1106t for sinovenous thrombosis, 1787 Acetazolamide-responsive paroxysmal ataxia, 1213t-1214t, 1215, 1220 Acetazolamide-responsive sodium channel myotonia, 2092f, 2093-2094 clinical features of, 2093, 2093t, 2097f genetics of, 2093-2094, 2093t laboratory tests in, 2094 pathophysiology of, 2094 treatment of, 2093t, 2094 Acetyl coenzyme A (acetyl-CoA), 718 in ketogenesis, 1136-1138, 1137f Acetyl coenzyme A carboxylase, 723, 2317 Acetylcholine in neuromuscular transmission, 1847-1848, 1941, 1942f as neurotransmitter, 2129-2131, 2130f resynthesis of, disturbances in, 1959-1960 Acetylcholine receptor(s), 1848, 1848f, 1941, 1942f in congenital myasthenic syndromes, 1958-1959, 1961 in fast-channel syndrome, 1961-1962 in focal epilepsy, 1013 in myasthenia gravis, 1941-1942 antibodies against, testing for, 1949-1950 primary deficiency of, 1962 in slow-channel syndrome, 1961 Acetylcholinesterase endplate deficiency of, 1960 in neural tube defects, 370, 379 Acetylsalicylic acid, for Kawasaki disease, 1820-1821 Achilles reflex in Duchenne muscular dystrophy, 1978, 1984-1985, 1985f in older child, 18 in preterm infant, 56-57, 58t Achilles tendon xanthoma, in cerebrotendinous xanthomatosis, 1367 Achondroplasia, 459-461 clinical characteristics of, 460-461 genetics of, 443f, 459-460 management of, 461 megalencephaly with, 408 neurologic symptoms in, 460 sleep in, 1235 Acid maltase deficiency, 626-630, 698-699, 2027-2028 adult, 630, 698, 2027-2028 clinical manifestations of, 622t, 630, 2027 enzyme defect in, 622t glycogen structure in, 622t infantile, 626-628, 698-699, 2027-2028 biochemistry of, 626-627, 2027-2028

ii

Index

Acid maltase deficiency continued cardiac involvement in, 2223 clinical manifestations of, 622t, 627, 627f, 2027 enzyme defect in, 622t genetics of, 628, 2027-2028 glycogen structure in, 622t laboratory tests in, 627-628, 2027 management of, 628, 2028 pathology of, 626, 2027 juvenile, 630, 698, 2027 late infantile, 628-629, 698-699 biochemistry of, 629 clinical manifestations of, 622t, 628, 628f enzyme defect in, 622t glycogen structure in, 622t laboratory tests in, 629 management of, 629 microscopic findings in, 629, 629f Acid sphingomyelinase deficiency, 673-675 Acid-base management, in cardiac surgery, 2209 Acidemia(s) amino, 567, 570-585 cognitive and motor regression in, 826t isovaleric, 353-354, 353t, 588-589 clinical manifestations of, 588-589 laboratory tests in, 589 pathophysiology of, 586f, 588 treatment of, 589 methylmalonic, 350t-352t, 353-354, 353t, 587-588, 727 clinical manifestations of, 588 laboratory tests in, 588 pathophysiology of, 586f, 587 treatment of, 588 organic, 353-354, 567, 585-596 clinical features of, 350t-351t, 354 cognitive and motor regression in, 826t diagnosis of, 353t, 354 dystonia in, 1286 leukoencephalopathies, 1345, 1346t management of, 354 MRI findings in, 352t versus urea cycle disorders, 356 propionic, 353-354, 353t, 585-587, 586f clinical manifestations of, 587 diagnosis of, 587 treatment of, 587 Acidosis in hypoxic-ischemic injury, 290 in inborn errors of metabolism, 568 in intraventricular hemorrhage, 320, 320t lactic, 717-718 and autism, 917-918 differential diagnosis of, 2060 and encephalopathy, 354-355, 354f in malaria, 1658 in maple syrup urine disease, 577-579 in status epilepticus, 1093 thiamine therapy for, 2308 in mental retardation/developmental delay, 813b renal tubular, 2262-2264 distal, 2262, 2262t with hyperkalemia, 2265 proximal, 2262-2264, 2262t Aciduria(s) argininosuccinic, 603-604, 606-607 dicarboxylic, 721, 2043-2044 in spinal muscular atrophy type III, 1864-1865 glutaric, 361, 493, 2042 clinical features of, 350t-351t, 361 MRI findings in, 352t, 361 treatment of, 361 type 1, 593-595, 2308-2309

Aciduria(s) continued clinical manifestations of, 594 laboratory tests in, 594-595 MRI findings in, 594, 594f treatment of, 595 type 2, 594, 724 type II, 2309 3-hydroxy-3-methyl-glutaric, 353-354, 353t 3-hydroxyisobutyric, 595-596 3-methylglutaconic, 591-592 type I, 591-592 type II, 592 type III, 592 type IV, 592 mevalonic, 596 Aconitase deficiency, 2056 Acoustic immittance testing, 113-114 Acoustic meatus, 98-99 Acrania, 378 Acrocallosal syndrome, 385t, 464t Acrocentric chromosomes, 516 Acrocephalosyndactyly type 1. See Apert’s syndrome Acrocephalosyndactyly type 5. See Pfeiffer’s syndrome Acromegaly, 2121 Acroparesthesia, in Fabry’s disease, 669-670 Actigraphy, 1228-1229, 1229f Actin, 1839-1840, 1840f diseases associated with, 1842t in nemaline myopathy, 2017 Actinomyces, 1636-1637. See also Actinomycosis Actinomyces israelii, 1636-1637 Actinomycin C, for optic pathway tumors, 1703 Actinomycosis, 1636-1637 clinical characteristics of, 1637 CNS syndromes in, 1632t diagnosis of, 1632t, 1637 epidemiology of, 1636-1637 geographic distribution of, 1632t laboratory tests in, 1637 management of, 1632t, 1637 microbiology of, 1636-1637 myositis in, 2083 pathology of, 1636-1637 risk factors for, 1632t Actinopathy, genetics of, 2018t Action myoclonus, 1293 Action potential in EEG, 206-207 muscle, 1845-1846, 1941 Action tremor, 1290 Activated charcoal for acetaminophen toxicity, 2190 in lindane poisoning, 2184 for solvent poisoning, 2185 Activation, in autism therapy, 923 Activities of daily living scale, in myasthenia gravis, 1944-1945, 1945t Acupuncture, for tic disorders, 895 A-current potassium channel, 994 Acute cerebellar ataxia, 73, 1246-1247, 1296 causes of, 1246-1247 viral, 1597, 1598b, 1608-1609 evaluation of, 1247 incidence of, 1246 mean age at presentation, 1246 treatment of, 1247 Acute disseminated encephalomyelitis (ADEM), 90, 1351-1352, 1596 clinical features of, 1352 magnetic resonance imaging in, 176, 179f, 1352, 1352f pathology of, 1352 perfusion MRI in, 190 treatment of, 1352 Volume 1: pages 1–1180

Acute fatty liver of pregnancy, 724 Acute hemorrhagic leukoencephalitis, 1352-1354 Acute inflammatory demyelinating neuropathy (AIDP), 1922t Acute inflammatory demyelinating polyneuropathy. See Guillain-Barré syndrome Acute intermittent porphyria, 1905-1906, 2195, 2292 Acute lymphoblastic leukemia hypothalamic syndrome in, 1736-1737 seizures in, 1737 spinal cord compression in, 1738 stroke in, 1736 Acute motor and sensory axonal neuropathy (AMSAN), 1922t, 1923 Acute motor axonal neuropathy (AMAN), 1922t, 1923 Acute Physiology and Chronic Health Evaluation II (APACHE II), 2183 Acyclovir, 1603 for acute cerebellar ataxia, 1247 adverse effects of, 1605, 2265 for herpes simplex virus, 1605-1606 for human herpesviruses type 6, 7, and 8, 1610 nephrotoxicity of, 2265 in renal failure, action and effects of, 2268 toxicity of, 2192 for varicella-zoster virus, 1608-1609 Acyl-CoA dehydrogenase deficiency, 355, 717-718, 721, 723-725 clinical features of, 724-725 histopathology of, 718 long-chain, 724-725 medium-chain, 724 multiple, 724-725 short-chain, 724 very-long-chain (VLCAD), 724 Acyl-coenzyme A deficiency, 724 Acyl-coenzyme A oxidases deficiency of, 749 in fatty acid oxidation, 736f, 737, 2037f, 2038 Adams-Oliver syndrome, 422 ADAMTS13 defects, in thrombotic thrombocytopenic purpura, 2253 Adaptive behavior, 801 testing of, 804t, 805 Adaptive immunity, in spinal cord injury, 1531-1532 Adderall, for ADHD, 878t, 881 Addison’s disease, 2140 adrenoleukodystrophy with, 746t, 747 deficiency of, 2118-2120, 2140 adrenoleukodystrophy with, 746t, 747 Adduction of eye, 20-22, 21f, 21t Adductor brevis muscle, in gait, 71f Adductor longus muscle, in gait, 71f Adelaide-type craniosynostosis, 443f, 449 A-delta fibers, in pain, 2373 Adenine, 508, 508f Adenine arabinoside, neuropathy induced by, 1910 Adenoma(s) ACTH-secreting, 2118-2119, 2119f growth hormone-secreting, 2121 pituitary, 1707, 2117, 2121 thyroid-stimulating hormone-secreting, 2122 Adenoma sebaceum, 777, 779 Adenosine, in hypoxic-ischemic injury, 1501 Adenosine triphosphatase mutation, 2055 Adenosine triphosphate in exercise, 2023-2024, 2026-2027 in fatty acid oxidation, 1136

Volume 2: pages 1181–2408

Index Adenosine triphosphate continued in hypoxic-ischemic injury, 1471-1473, 1473f, 1501 in muscle biopsy, 1853 in muscle contraction, 1849, 1851, 2023 synthesis of, 717 Adenosylcobalamin, 2311-2312. See also Cobalamin (vitamin B12) Adenoviridae, 1595b, 1610 ADHD. See Attention-deficit hyperactivity disorder Adhesion molecules in malaria, 1657 in multiple sclerosis, 1347 in traumatic brain injury, 1461-1462 Adjacent 1 segregation, 528 Adjacent 2 segregation, 528 Adrenal androgens, prepubertal rise in, 2114-2115 Adrenal hypoplasia congenita, 2116 Adrenal insufficiency, 2118-2120, 2140 adrenoleukodystrophy with, 746t, 747 Adrenaline. See Epinephrine Adrenarche definition of, 2114 normal physiology of, 2114-2115 α-Adrenergic receptor agonist(s) α2, 944-945 for ADHD, 879t-880t, 882, 944-945 adverse effects of, 945 for autism, 927t clinical applications of, 944 clinical management of, 944-945 drug interactions of, 945 for intracranial hypertension, 1583 pharmacology of, 944 for hepatorenal syndrome, 2259 for micturition disorders, 2165 for neurocardiogenic syncope, 1211, 1211b for orthostatic hypotension, 2142 β-Adrenergic receptor antagonist(s) for ADHD, 880t and autonomic dysfunction, 2149 for chronic daily headache prevention, 1196t, 1197 for intracranial hypertension, 1583 for migraine prevention, 1194t for neurocardiogenic syncope, 1211-1212, 1211b for orthostatic hypotension, 2143 for thyrotoxic periodic paralysis, 2101 for vasovagal syncope, 2150 Adrenocorticotropic hormone (ACTH), 2118 adenomas secreting, 2118-2119, 2119f for autism, 925 deficiency of, 2118-2120, 2140 adrenoleukodystrophy with, 746t, 747 for early infantile epileptic encephalopathy, 268 excess of, 2118-2119 for infantile spasms, 1067-1070, 1068b for myoclonic seizures, 1075 Adrenoleukodystrophy diffusion-weighted imaging in, 187 hearing loss with, 103, 105t magnetic resonance imaging in, 176 neonatal, 361, 740-744 clinical and pathologic features of, 741-742 genetics of, 740t, 742 laboratory diagnosis of, 742-744, 743t prenatal diagnosis of, 744 treatment of, 744 vision loss with, 88t X-linked, 745-749 with Addison’s disease, 746t, 747 adolescent cerebral, 746, 746t adult cerebral, 746, 746t asymptomatic and presymptomatic, 746t, 747

Adrenoleukodystrophy continued biochemistry of, 746 childhood cerebral, 746, 746t, 747f classification of, 1345, 1346t clinical features of, 746 contiguous deletion syndrome of, 749 laboratory diagnosis of, 743t molecular basis of, 746 MRI findings in, 746, 747f, 749 pathogenesis of, 748 pathologic features of, 746 phenotypes of, 746, 746t versus Schilder’s disease, 1351 symptomatic heterozygotes in, 747-748 therapies of, 748-749 Adrenomyeloneuropathy, 745-749 with Addison’s disease, 746t, 747 clinical features of, 746-747 MRI findings in, 746-747 phenotypes of, 746, 746t Adult polyglucosan storage disease, 1369 Adverse drug reactions, 2193-2199. See also specific drugs developmental immaturity and, 2196-2197 method of preparation and, 2194 pharmacogenetic susceptibility to, 2194-2195 in renal failure, 2265-2268 technique of administration and, 2194 underlying disease and, 2197 Adversive seizures, 1042 African Americans, cerebral palsy in, 491-492 African sleeping sickness, 1662-1664 classification of, 1647t clinical characteristics of, 1647t, 1663-1664 diagnosis of, 1647t, 1663-1664 epidemiology of, 1662-1663 geographic distribution of, 1647t, 1662-1663 laboratory tests in, 1663-1664 management of, 1647t, 1664 microbiology of, 1662-1663, 1662f mode of infection, 1647t, 1662-1663 pathology of, 1647t, 1662-1663 risk factors for, 1647t Agalsidase alfa, for Fabry’s disease, 670 Agalsidase β, for Fabry’s disease, 670 Agammaglobulinemia, 1611, 1611f Ageusia, 143 Aging, mitochondrial damage in, 730 Agitation, in impaired consciousness, 1391 AGL gene, in debrancher deficiency, 630 Agnosia auditory, 822t clinical features of, 822t cortical localization of, 822t spatial, 822t tactile, 822t verbal auditory, 849, 907 in epileptiform disorders, 1055 visual, 822t Agouti-related protein, 2123 Agraphia, alexia with, 822t Agyria, 410, 411f, 413f, 416f. See also Lissencephaly Aicardi-Goutieres syndrome CSF analysis in, 163, 1354 neuroimaging in, 1353f, 1354 Aicardi’s syndrome, 83, 84f, 88t, 268, 385t polymicrogyria in, 422 AIDS. See Human immunodeficiency virus infection Airway management, in spinal cord injury, 1540 Airway obstruction, in sudden infant death syndrome, 1484 Akathisia neuroleptic agents and, 965t, 966, 2188-2189 postoperative, in cardiac surgery, 2213 Volume 1: pages 1–1180

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iii

Akinetic mutism, 1381 Alacrima, 2152 Alagille’s syndrome, genetics of, 556t, 557 Alanine-glyoxalate aminotransferase, 738-739 deficiency of, 750-751 Alar plates, 379-380, 379f, 383 ALARA (as low as reasonably possible), 170 Albendazole for cysticercosis, 1671 for echinococcosis, 1669 for gnathostomiasis, 1668 for microsporidiosis, 1654 for toxocariasis, 1665 Alberta Infant Motor Scale (AIMS), 805 Albinism hearing loss with, 105t ocular or oculocutaneous, 84-85 Albright’s hereditary osteodystrophy, versus McCune-Albright syndrome, 458-459 Albumin in CSF, 161-162 in Guillain-Barré syndrome, 1925 for hypoxic-ischemic injury, 1505 for intracranial hypertension, 1583 Albuterol, for facioscapulohumeral muscular dystrophy, 2000 Alcohol abuse/intoxication, 2187 and cerebral palsy, 493 and cleft lip/palate, 468 and holoprosencephaly, 396 and mental retardation, 800 and microcephaly, 402 for myoclonus dystonia, 1283 teratogenicity of, 402, 2197 Alcohol-related birth defects, 2197 Aldolase A deficiency, 2036 biochemistry of, 2036 clinical features of, 2036 genetics of, 2036 Aldosterone, 2324 Alemtuzumab, for multiple sclerosis, 1350 Alertness, of term infant, 47-48 Alexander’s disease, 1356-1360 adult-onset, 1357 biochemistry of, 1360 clinical features of, 1357 clinical studies of, 1357 genetics of, 1360 infantile-onset, 1357 juvenile-onset, 1357 magnetic resonance imaging in, 176 neuroimaging in, 1357, 1358f-1359f pathology of, 1357-1360 subclassification of, 1357 treatment of, 1360 Alexia with agraphia, 822t ALG1 gene, in congenital glycosylation disorder, 650t, 652 ALG2 gene, in congenital glycosylation disorder, 650t, 651 ALG3 gene, in congenital glycosylation disorder, 650t, 651 ALG6 gene, in congenital glycosylation disorder, 650t ALG8 gene, in congenital glycosylation disorder, 650t, 651 ALG9 gene, in congenital glycosylation disorder, 650t, 652 ALG12 gene, in congenital glycosylation disorder, 650t, 651 Alice in Wonderland syndrome, 1184, 1189, 1609-1610 Alkaline phosphatase, in heterotopic ossification, 2364 Alkalosis, in inborn errors of metabolism, 568

iv

Index

Alkyl-dihydroxyacetone phosphate synthase, 738, 750 Allele(s), 532 premutation, 559, 559t Allele-specific oligonucleotide (ASO) hybridization, 524 Allergic granulomatosis (Churg-Strauss syndrome), 1818t, 1822 Allergic neuritis, experimental, 1925-1926, 1926f Allescheriosis, 1640 clinical characteristics of, 1640 CNS syndromes in, 1632t diagnosis of, 1632t, 1640 geographic distribution of, 1632t laboratory tests in, 1640 management of, 1632t, 1640 risk factors for, 1632t Allopurinol for Chagas’ disease, 1662 for Lesch-Nyhan disease, 1286 Allopurinol testing, in ornithine transcarbamylase deficiency, 605 Almotriptan, for migraine, 1193t Alobar holoprosencephaly, 395f, 396-397 Alopecia, in developmental disorders, 835t Alpers, Bernard, 1326 Alpers’ disease, 726, 1326-1328, 2300 biochemistry of, 1327 clinical features of, 1326 EEG findings in, 1327 genetics of, 1327 history of, 1326 infantile, 1326 juvenile, 1326 laboratory tests in, 1326-1327 management of, 1328 neuroimaging in, 1326-1327 pathogenesis of, 1328 pathology of, 1327 prenatal, 1326 Alpers-Huttenlocher syndrome. See Alpers’ disease Alpha activity, in EEG abnormal slowing or suppression of, 209 in drowsy state, 221 newborn/neonatal gestational age younger than 28 weeks, 215 in seizures, 263, 264f αβ crystallin, in Alexander’s disease, 1360 11 α- [ C]methyl-L-tryptophan (AMT) positron emission tomography, 1154, 1161 Alpha-fetoprotein (AFP) in ataxia-telangiectasia, 1252, 1278 in neural tube defects, 370, 378 Alpha-satellite DNA, 516 Alphaviruses, 1611-1612 Alport’s syndrome, hearing loss with, 105t, 115 Alprazolam, 956t for anxiety disorders, 955-956 dosage of, 956t drug interactions of, 956t half-life of, 956t preparations of, 956t Alsin (ALS2) gene, in amyotrophic lateral sclerosis, 1871 Alström’s syndrome, 88t Alternate segregation, 528 Alternating hemiplegia (hemiparesis) of childhood, 1184, 1190, 1288 Aluminum toxicity, 2243-2244, 2246 Alveolar hypoventilation, central alveolar, 1231 Amantadine for dopa-responsive dystonia, 1283 for hyperkinetic disorders, 1290 for parkinsonism, 1293

Amaurosis, uremic, 2237 Amblyomma americanum, 2181 Amblyomma maculatum, 2181 Amblyopia, 77, 87-88 anisometropic, 87-88 deprivation, 87-88 strabismic, 87 Amebiasis, cerebral, 1646-1649 classification of, 1647t clinical characteristics of, 1647t, 1648-1649 diagnosis of, 1647t, 1648-1649 epidemiology of, 1646-1648 geographic distribution of, 1647t, 1648 laboratory tests in, 1648-1649 management of, 1647t, 1649 microbiology of, 1646-1648 mode of infection, 1646, 1647t pathology of, 1646-1648, 1647t, 1648 risk factors for, 1647t Amebic encephalitis, granulomatous Acanthamoeba, 1650-1652 classification of, 1647t clinical characteristics of, 1647t, 1651 diagnosis of, 1647t, 1651 epidemiology of, 1650-1651 geographic distribution of, 1647t laboratory tests in, 1651 management of, 1647t, 1651 microbiology of, 1650-1651 mode of infection, 1646, 1647t, 1650-1651 pathology of, 1647t, 1650-1651 risk factors for, 1647t Balamuthia mandrillaris, 1652-1653 classification of, 1647t clinical characteristics of, 1647t, 1652-1653 diagnosis of, 1647t, 1652-1653 epidemiology of, 1652 geographic distribution of, 1647t, 1652 laboratory tests in, 1652-1653 magnetic resonance imaging in, 1652, 1653f management of, 1647t, 1653 microbiology of, 1652, 1652f mode of infection, 1646, 1647t, 1652 pathology of, 1647t, 1652 risk factors for, 1647t Amebic infections, 1646-1653. See also specific infections classification of, 1647t clinical characteristics of, 1647t diagnosis of, 1647t geographic distribution of, 1647t management of, 1647t mode of infection, 1647t pathology of, 1647t risk factors for, 1647t Amebic keratitis, 1651 Amebic meningoencephalitis, primary, 1649-1650 causative agent of, 1649, 1649f-1650f classification of, 1647t clinical characteristics of, 1647t, 1649-1650 diagnosis of, 1647t, 1649-1650, 1650f differential diagnosis of, 1650 epidemiology of, 1649 geographic distribution of, 1647t, 1649 laboratory tests in, 1649-1650 management of, 1647t, 1650 microbiology of, 1649 mode of infection, 1646, 1647t, 1649 pathology of, 1647t, 1649, 1649f risk factors for, 1647t American Academy of Child and Adolescent Psychiatry website, 2401 Volume 1: pages 1–1180

American Academy of Neurology (AAN) practice parameters of for autism, 912-913 for global developmental delay, 799, 805, 806f for headache, 1187-1188, 1200-1201 for migraine, 1192 for mild traumatic brain injury, 1428 website of, 2401 American Academy of Pediatrics (AAP) guidelines for mild traumatic brain injury, 1428 website of, 2401 American Academy of Physical Medicine and Rehabilitation, 2360 American Association on Mental Retardation (AAMR), 799 American Medical Association Code of Ethics, 2391-2392 American Occupational Therapy Association, 2360 American Physical Therapy Association (APTA), 2360 American Psychological Association, 2361 American Sign Language (ASL), 115-116, 118 American Speech-Language-Hearing Association, 2361 American Spinal Injury Association (ASIA), 1533, 1533b, 1534f, 1546-1547, 2357, 2358t American trypanosomiasis, 1661-1662 autonomic dysfunction in, 2152 classification of, 1647t clinical characteristics of, 1647t, 1661-1662 diagnosis of, 1647t, 1661-1662 epidemiology of, 1661 geographic distribution of, 1647t, 1661 laboratory tests in, 1661-1662 management of, 1647t, 1662 mode of infection, 1647t, 1661 pathology of, 1647t risk factors for, 1647t Amino acid(s), 510-511, 717-718 classification, by side chains, 510, 510t in CSF, 154t, 163 large, neutral, for phenylketonuria, 574 metabolism of, 738-739 L-Amino acid decarboxylase deficiency, 359360, 360f, 762-763, 1288 clinical features of, 350t-351t, 360, 762-763, 763f Amino acid monomers, in lysosomal storage diseases, 660t D-amino acid oxidase, 738-739 5-Amino-4-imidazolecaroxamide ribosiduria (AICA), 350t-352t, 359 Aminoacidemia(s), 567, 569-585 cognitive and motor regression in, 826t Aminobisphosphonate, for fibrous dysplasia, 458 γ-Aminobutyric acid. See Gamma-aminobutyric acid (GABA) Aminoglycosides for bacterial meningitis, 1580t, 1581 and hearing loss, 110, 730, 2192 teratogenicity of, 2182t toxicity of, 2191 and vertigo, 133 δ-Aminolevulinic acid, in porphyria, 2292-2293 Aminophylline toxicity, 2190-2191 Aminopterin, teratogenicity of, 2197t Aminopyridine, for spinal cord injury, 1542 Aminothiol cysteamine, for cystinosis, 701 Amish community glutaric aciduria type 1 in, 594 Jackson-Weiss syndrome in, 448 Amish lethal microcephaly, 402t-403t

Volume 2: pages 1181–2408

Index Amitraz, 2183 Amitriptyline, 946 for ADHD, 878t adverse effects of, 946, 2189 for chronic daily headache prevention, 1196, 1196t for cyclical vomiting syndrome, 1217, 2286 for migraine prevention, 1194t, 1195 for nonepileptic paroxysmal disorders, 1213t pharmacology of, 946 toxicity of, 2189 Amlodipine, for Raynaud’s phenomenon, 1816 Ammonia elevated levels of. See Hyperammonemia in hepatic encephalopathy, 2295-2297 in Reye’s syndrome, 2299 Ammon’s horn, 991-992, 993f Amnesia post-traumatic, 2356 transient global, of childhood, 1190 Amniocentesis, 548-549 Amniotic fluid, odor of, 144-145 Amoxicillin for Lyme disease, 1588 for meningitis prophylaxis, 1584 AMPA receptor(s), 995 in hypoxic-ischemic injury, 297f, 301, 1474-1475, 1502 in inflicted neurotrauma, 1446 in status epilepticus, 1093 AMPA receptor antagonists, for hypoxicischemic injury, 1502 Amphetamine(s) abuse/poisoning, 2186-2187 mixed salts of for ADHD, 878t, 880-881, 939t, 941 dosage of, 939t, 941 labeled and off-labeled use of, 938t pharmacology of, 939t nephrotoxicity of, 2265 Amphotericin B for aspergillosis, 1638 for candidiasis, 1638 for coccidioidomycosis, 1634 for cryptococcosis, 1633 for histoplasmosis, 1636 for North American blastomycosis, 1634 for phycomycosis, 1640 for primary amebic meningoencephalitis, 1650 for South American blastomycosis, 1635 Ampicillin, for bacterial meningitis, 1580t Amplification, for hearing loss, 104, 116-117 Ampulla of semicircular canal, 98f Amyelinating neuropathy, congenital, 1899 Amygdala, corticomedial, 137f Amylo-1,4 → 1,6 transglucosidase deficiency, 631-633. See also Brancher enzyme deficiency Amylo-1,6-glucosidase deficiency, 630-631. See also Debrancher deficiency Amyloid polyneuropathy, familial, 2145, 2260, 2260t Amyloid proteins, 2260, 2260t Amyloid-β precursor protein, 2260, 2260t Amyloidosis, 2140, 2259-2261 dialysis-associated, 2244 of gingiva and conjunctiva, with mental retardation, 2260t hereditary cerebral, 2260-2261 heredofamilial (primary), 2259-2261, 2260t reactive (secondary), 2259-2261 Amylopectin, 632 Amyotonia congenita, 1863 Amyotrophic lateral sclerosis, 1870-1871 genetic forms of, 1870-1871, 1871t type 2, 1870, 1871t

Amyotrophic lateral sclerosis continued type 4, 1870-1871, 1871t type 5, 1871, 1871t Amyotrophy, hereditary neuralgic, 1892 Anabolism, muscle, 1852 Anal canal anatomy and embryology of, 2166 nerve supply of, 2166 Anal manometry, 2167 Anal sphincter(s), 2166 evaluation of, 2167-2168 Anal sphincter electromyography, 2167 Analgesia/analgesics, 2377 adverse effects of, 2265, 2377 for chronic daily headache, 1197 dosage guidelines for, 2376t fetal/neonatal effects of, 2196 in Guillain-Barré syndrome, 1923-1924 nephrotoxicity of, 2265 overuse of, and headache, 1195, 1197 for post-traumatic headache, 1199 procedural use of, 2377 in renal failure, actions and effects of, 2268 topical, 2377 in traumatic brain injury, 1428 Anaphase, 513, 514f-515f Anaplasma phagocytophilum, 1644-1645. See also Anaplasmosis, human Anaplasmosis, human, 1645 clinical characteristics of, 1641t, 1645 epidemiology of, 1641t geographic distribution of, 1641t incubation period of, 1641t laboratory tests in, 1641t, 1645 management of, 1641t mode of infection/vector, 1641t reservoir for, 1641t Anaplastic astrocytoma, 1718 genetics of, 1748 incidence of, 1719t in infants and very young children, 1725 survival rates with, 1689t, 1718 Anaplastic ependymoma incidence of, 1719t survival rates with, 1690t Anaplastic oligodendroglioma, survival rates with, 1689t Anarchic seizures, neonatal, 258 Andermann’s syndrome, 385t Andersen’s disease. See Brancher enzyme deficiency Andersen-Tawil syndrome, 2099-2100 clinical features of, 2095t, 2099, 2099f genetics of, 2095t, 2100 laboratory findings in, 2100 pathophysiology of, 2100 treatment of, 2095t, 2100 Androgens, prepubertal rise in, 2114-2115 Anemia(s) iron deficiency, 2321-2322 and benign intracranial hypertension, 2322 and breath-holding spells, 1205-1206, 2322 cognitive effects of, 2321 epidemiology of, 2321 neurologic effects of, 2322 and restless legs syndrome, 1233 and sinovenous thrombosis, 1783f, 1785 and stroke, 1766, 1769, 2322 megaloblastic, 2312-2313, 2319 pernicious, 1906, 2312-2313 Anencephaly, 378-379 antenatal diagnosis of, 378 clinical considerations in, 379 definition of, 378 differential diagnosis of, 378 epidemiology of, 378 Volume 1: pages 1–1180

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v

Anencephaly continued etiology of, 366-367 pathogenesis of, 364, 366, 378 pathology of, 378 Aneuploidy, 525, 546, 550-555 Aneurysm(s), 1793-1795 acquired, 1794-1795 cerebral mycotic, 2221 clinical presentation of, 1793-1794 familial occurrence of, 1793-1794 giant, 1793 neuroimaging of, 1794, 1794f post-traumatic, 1795 recurrent, 1794 rupture of, 1793 saccular, 1793, 1794f Angel dust (drug), 2187 Angelman’s syndrome, 558 autism in, 919 clinical features of, 557f diagnostic criteria for, 558t EEG findings in, 240 genetics of, 544f, 556t, 557-558, 558t, 920 Angiitis. See also Vasculitis granulomatous, 1821-1824 hypersensitivity, 1821 isolated, 1771-1772 primary, 1771, 1822-1823 clinical features of, 1822 laboratory findings in, 1818t, 1822-1823 MR angiography in, 1823, 1823f neurologic manifestations of, 1818t, 1822 treatment of, 1823 Angiofibroma, in tuberous sclerosis complex, 777, 778f, 779 Angiography, 171f, 195 in aneurysm, 1794f in arteriovenous malformation, spinal, 1878f in brain death, 1559, 1561 in brain tumors, 1696, 1696f in cavernous malformation, 1793 digital subtraction, 1561 in intracerebral hemorrhage, 1789 in intraventricular hemorrhage, 311-312 magnetic resonance. See Magnetic resonance angiography in polyarteritis nodosa, 1819-1820, 1819f in sinovenous thrombosis, 1786 in stroke, 1764f, 1770f-1773f, 1774-1775 in Sturge-Weber syndrome, 783 in subdural hematoma, 337 in traumatic brain injury, 1420 inflicted (child abuse), 1462 in vasculitis, 1772 Angiokeratoma in developmental disorders, 834t in Fabry’s disease, 669, 669f in Schindler-Kanzaki disease, 695 Angioma(s) cavernous, susceptibility-weighted imaging of, 191, 192f retinal, in Wyburn-Mason syndrome, 789-790 in Sturge-Weber syndrome, 782-783, 782f, 784 venous, 1793, 1793f Angiomatosis, encephalofacial. See SturgeWeber syndrome Angiomatosis retinae, 784 Angiomyolipoma, in tuberous sclerosis complex, 780 Angiostrongyliasis, 1667 classification of, 1647t clinical characteristics of, 1647t, 1667 diagnosis of, 1647t, 1667 epidemiology of, 1667 geographic distribution of, 1647t, 1667 laboratory tests in, 1667

vi

Index

Angiostrongyliasis continued management of, 1647t, 1667 microbiology of, 1667 mode of infection of, 1647t, 1667 pathology of, 1647t, 1667 risk factors for, 1647t Angiostrongylus, 1667. See also Angiostrongyliasis Angiostrongylus cantonensis, 1667 Angiotensin II, 2324 Anhidrosis, 2131 congenital insensitivity to pain with, 2145 Animal models of hypoxic-ischemic injury, 298-299 large animal, 298 small animal, 299 of intraventricular hemorrhage, 313, 313f-314f of neonatal seizures, 272 Aniridia, 83-84 Anisometropia, 87-88 Anisotropic diffusion, 184, 187 Ankle clonus, 40, 51 Ankle dorsiflexion, in preterm infant, 54f-55f Annual wormwood, for malaria, 1659 Anophthalmia, 387 Anosmia, 146 olfactory nerve function and, 19 specific, 146 Anotia, 108t Anoxic seizures generalized, 1210 reflex, 1203, 1206-1207, 1212 Anoxic-epileptic seizures, 1206 Antacids, for gastroesophageal reflux, 2286-2287 Antalgic gait, 74-75 Antegren (natalizumab), for multiple sclerosis, 1350 Anterior cerebral artery, 1760-1762, 1761f Anterior circulation, 1760-1762, 1761f-1762f Anterior fontanel, 436 closure of, 436-437, 437b, 437t intracranial pressure monitoring from, 1516 Anterior horn cell(s), 1846-1847, 1859 centrodorsal group of, 1859 dorsomedial group of, 1859 lateral group of, 1859, 1860f medial group of, 1859, 1860f ventrolateral group of, 1859 ventromedial group of, 1859 Anterior horn cell arthrogryposis, 1872-1873, 1872f Anterior horn cell disease, 814b, 1859-1879. See also specific diseases congenital, 1859-1862 infectious, 1873-1876 trauma-related, 1876 vascular, 1876-1879 Anterior lobe, 1241, 1242f Anterior neural ridge, 379, 379f Anterior olfactory nucleus, 137f Anterior segment dysgenesis, 83 Anterior spinal artery, 1876-1877, 1877f occlusion of, 1876-1878 Anterior spinal cord syndrome, 1538 Anterior tibialis muscle, in gait, 71f Antibiotics for bacterial meningitis, 1579-1582, 1580t for brain abscess, 1589 neuropathy induced by, 1909 for sinovenous thrombosis, 1787 toxicity of, 2191 Anticholinergic drugs for acute dystonic reactions, 1288 adverse effects of, 1289, 2178, 2191, 2362

Anticholinergic drugs continued for L-amino acid decarboxylase deficiency, 763 for chronic dystonia, 1288-1289 contraindicated in Duchenne muscular dystrophy, 1986 for dopa-responsive dystonia, 1283 for DYT1 dystonia, 1282 for glutaric aciduria type 1, 595 for kernicterus, 1284 for micturition disorders, 2164-2165, 2358 for neurocardiogenic syncope, 1211, 1211b for pantothenate kinase-associated neurodegeneration, 1285 for parkinsonism, 1293 for paroxysmal nonkinesigenic dyskinesia, 1297 in renal failure, encephalopathy induced by, 2266 for sialorrhea, 2362 in spinal cord injury, 1544 for tyrosine hydroxylase deficiency, 764 Anticholinergic syndrome, 947, 2178, 2191 Anticholinesterase inhibitors for congenital myasthenic syndromes, 1960 insecticides as, 2183 for Lambert-Eaton myasthenic syndrome, 1957 for myasthenia gravis, 1951 Anticoagulants for deep vein thrombosis, 1776, 2363 postoperative, in cardiac patients, 2218 for sinovenous thrombosis, 1786-1787 for stroke, 1775-1779 in systemic lupus erythematosus, 1815 teratogenicity of, 2197t Anticonvulsants. See Antiepileptic agents Antidepressant(s), 945-955. See also specific drugs and disorders for ADHD, 878t-879t, 882, 946 adverse effects of, 937, 2189 for autism, 924-925, 927t for chronic daily headache prevention, 1196, 1196t labeled and off-labeled use of, 938t for migraine prevention, 1194t, 1195 toxicity of, 2188-2189 tricyclic, 945-948. See also Tricyclic antidepressants Antidiuretic hormone, 2324 for cardiac arrest, 1498 and CSF formation, 155 in hepatorenal syndrome, 2258-2259 inappropriate secretion of, 1576, 1582, 2125 Antiemetics, for cyclical vomiting syndrome, 1191, 2286 Antiepileptic agents, 1002-1004, 1105-1126 for absence seizures, 1023t, 1028-1029 absorption of, 1105-1109 adverse reactions to, 1122-1125, 1176, 2264-2267, 2301 central nervous system, 1122-1123 gastric irritation, 1123 gastrointestinal, 1123 gingival hyperplasia, 1123-1124 increased seizures, 1124 management of, 1125 osteomalacia, 1124 weight gain, 1123 weight loss, 1123 for atonic seizures, 1023t attentional effects of, 1174-1175 for autism, 925, 927t, 1060 behavioral effects of, 1174-1177 bioavailability of, 1105, 1106t-1107t for bipolar affective disorder, 958, 960-964 cessation of, 986 Volume 1: pages 1–1180

Antiepileptic agents continued chorea induced by, 1279 for chronic daily headache prevention, 1196t, 1197 cognitive effects of, 1174-1177 for cyclical vomiting syndrome, 2286 in cysticercosis, 1671 cytochrome P450 system and, 1111, 1111t discontinuation of, 1126 benefits of, 1126 risks of, 1126 dosage of initial maintenance, 1107t-1109t loading, 1109, 1109t dose response or concentration response of, 1116-1117 drug interactions of, 1118, 2195-2196 elimination of, 1107t-1109t, 1110-1111, 1110f for febrile seizure prevention, 1085-1086 fetal/neonatal effects of, 2196 for focal seizures, 1049-1052 formulations of, 1106t-1107t, 1119-1120 for generalized tonic-clonic seizures, 10211023, 1023t generic formulations of, 1116 for glycine encephalopathy, 581-582 half-life of, 1110-1111 hepatotoxicity of, 2301 hypersensitivity to, 1124-1125 clinical features of, 1124-1125 pathogenesis of, 1125 patients at high risk for, 1125t prevention of, 1125 for idiopathic epilepsy, 1050 initiation of, 985 for juvenile myoclonic epilepsy, 1072-1073 with ketogenic diet, 1143 labeled and off-labeled use of, 938t for Landau-Kleffner syndrome, 1059 and learning disabilities, 856 for Lennox-Gastaut syndrome, 1032-1033 in leukemia, 1737 in lindane poisoning, 2184 lupus syndrome induced by, 1811-1812, 2265 in malaria, 1660 mechanism of action, 1002-1004, 1003f-1004f, 1118-1119, 1119t in meningitis, 1582 for mentally retarded patients, 815 metabolism of, 1107t-1109t, 1110-1111 for migraine prevention, 1193t-1194t, 1195 monitoring of, 1120-1122 for adverse effects, 1121 for drug concentrations, 1121-1122, 1122b for efficacy, 1120-1121 mood effects of, 1174-1175 for myoclonic seizures, 1023t, 1074-1075 exacerbation by/adverse effects of, 1030-1031, 1074t for neonatal seizures, 269-271 adjuvant, for acute cases, 270-271 adverse effects of, 271 chronic therapy with, 271 decision to initiate, 269-270 first-line, 269t, 270 in hypoxic-ischemic injury, 290-291 initial, in acute cases, 270 maturation-dependent effects of, 298 second-line, 269t, 270-271 uncoupling with, 270 nephrotoxicity of, 2264-2265 for neuronal ceroid lipofuscinosis, 703 optimal concentration of, 1117, 1117t, 1121-1122 for pain, 2378 for paroxysmal kinesigenic dyskinesia, 1297

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Index Antiepileptic agents continued pharmacodynamics of, 1116-1117 pharmacokinetics of characteristics of, 1106t-1109t, 1111-1116 children’s physiology and, 1117-1118, 1117t in infants and children, 1118 in neonates, 1118 principles of, 1105-1111 plasma concentration of, 1105, 1109, 1115, 1115f for postpump seizures, 2212 and potassium channels, 994 practical guide to, 1051t protein binding of, 1107t-1109t, 1109-1110, 1110f in renal failure, actions and effects of, 2266-2268 for Rett’s syndrome, 1321 routes of administration, 1106t-1107t, 1119 intranasal, 1119-1120 intravenous and intramuscular, 1119 rectal, 1119, 1120t selection of specific, 1125-1126 and sleep, 1234 for status epilepticus, 1098-1100 for Sturge-Weber syndrome, 784 symptomatic use of, 1004 in systemic lupus erythematosus, 1814 teratogenicity of, 364, 367, 2182t, 2197-2198, 2319-2320 testing of, procedures for, 1002 therapeutic range of, 1117, 1117t, 1121 for tic disorders, 896 tolerance to, 1117 for tonic seizures, 1023t in traumatic brain injury, 1427-1428, 1435 in uremic encephalopathy, 2238 and vision loss, 86 and vitamin D deficiency (rickets), 1124, 2315 volume of distribution, 1107t-1109t, 1109-1110 Antifungal agents, 1632t Antihistamine(s) for chronic daily headache prevention, 1196t, 1197 for migraine prevention, 1194t, 1195 in renal failure, encephalopathy induced by, 2266 Antihistaminic toxidrome, 2178, 2180 Antihypertensive agents, 2241-2242, 2241t for chronic daily headache prevention, 1196t, 1197 cognitive effects of, 2242 for intracranial hypertension, 1583 for migraine prevention, 1194t Antimony potassium tartrate, for schistosomiasis, 1674 Antioxidant(s), in hypoxic-ischemic injury, 301-302, 302f, 1503 Antiparallel strands, of DNA, 508 Antiparasitic agents, 1647t-1648t Antiphospholipid antibodies, in neonatal stroke, 332 Antiplatelet agents, for stroke, 1777-1778 Antipsychotic(s), 964-971 fetal/neonatal effects of, 2196 novel or atypical, 938t, 964, 968-971 adverse effects of, 968 common characteristics of, 968 dosage of, 967t monitoring of, 968 receptor activity of, 967t, 968 toxicity of, 2188 typical, 938t, 964-968 adverse effects of, 964-966 classification of, 964 common characteristics of, 964-966

Antipsychotic(s) continued extrapyramidal side effects of, 964, 965t representative, 965t Antipyretics, for febrile seizure prevention, 1085 Antiretroviral therapy, 1620, 1622 Antisense strand, in transcription, 511 Antistreptolysin-O, 1807 Antithrombin III, in neonatal stroke, 332 Antithrombotic therapies for arterial ischemic stroke, 1775-1779 for sinovenous thrombosis, 1786-1787 Antiviral chemotherapy, 1602-1603 toxicity of, 2192 Antley-Bixler syndrome, 451 clinical features of, 442t, 451 genetics of, 442t, 451 Anus, 2166 Anxiety disorder(s) with ADHD, 876 assessment in, 946-947 with mental retardation, 815 pharmacologic therapy for, 948-953, 955-957 prevalence of, 955 with Tourette syndrome, 890 vertigo with, 133 Anxiolytics, 955-957 Aortic coarctation, 1878, 2219 Apert’s syndrome, 444 clinical features of, 442t, 447-448, 464t genetics of, 442t, 443, 443f, 447, 447t, 452f, 464t hearing loss with, 108t Apgar score, 47, 48t Aphasia acquired EEG findings in, 236 epileptic (Landau-Kleffner syndrome), 917, 1047, 1055-1061 magnetoencephalography in, 195 arachnoid cysts and, 435 clinical features of, 822t conductive, 822t cortical localization of, 822t motor (Broca’s), 822t sensory (Wernicke’s), 822t Aphemia, 849 Apicomplexan infections, 1647t, 1654-1661. See also specific infections Apnea in brain death determination, 1553, 1556-1557, 1557t in cerebellar vermis hypoplasia, 390-391 in cranial birth injuries, 335 with gastroesophageal reflux, 2286 in inflicted neurotrauma, 1447-1448 in intraventricular hemorrhage, 320, 320t sleep. See Sleep apnea in spinal cord injury, 339 Apnea challenge test, 1557, 1557t Apoptosis in arterial ischemic stroke, 1762-1763 and cortical malformations, 400 in developing brain, 1404 in hypoxic-ischemic injury, 303f, 304, 1472-1473, 1473b, 1479, 1501-1502 in neonatal seizures, 271-272 in spinal cord injury, 1531 in traumatic brain injury, 1407 Appetite regulation, 2122-2123, 2122f disorders of, 2122-2123 Applied behavior analysis, 926 Apraxia(s) ataxia-oculomotor, 1277-1278 type 1, 1253 age of onset, 1248t genetics of, 1248t, 1253 Volume 1: pages 1–1180

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Apraxia(s) continued type 2, 1253 age of onset, 1248t genetics of, 1248t, 1253 clinical features of, 822t cortical localization of, 822t gait, 74 ideational, 822t ideomotor, 822t limb-kinetic, 822t Aprosencephaly, 385-386 Aqueductal stenosis with arachnoid cyst, 433 hydrocephalus in, 427-428, 429f, 433 ultrasound of, 169f Aquinas, Thomas, 2388 Arachidonic acid, in hypoxic-ischemic injury, 1479, 1505 Arachnodysplasia, megalencephaly with, 408 Arachnoid cyst(s), 433-436 clinical presentations of, 434-435 complications of, 433-435 distribution of, 433, 433t and epilepsy, 435 infratentorial, 433 intrasellar, 434 management of, 435-436 mechanism of formation, 433 and neuropsychiatric disorders, 435 posterior fossa, 433, 1709 radiologic findings of, 433-434, 434f sellar region, 434 spinal, 1539-1540 and subdural hematoma, 435 and subdural hygroma, 435 suprasellar, 433-434 supratentorial, 433 sylvian fissure/middle cranial fossa, 434 Arachnoid granulations, 1781 Arachnoid space, 1402, 1402f Archicerebellum, 1243 Architectural dysplasia, 425 Arenaviridae, 1595b, 1620 ARFGEF2 gene, and periventricular nodular heterotopia, 412t, 420 Arginase, deficiency of, 603, 607 Arginine, 511 L-arginine, for urea cycle disorders, 611 Arginine vasopressin (AVP) deficiency of, 2124 and sodium balance, 349, 350t in water balance, 2123-2124 Argininemia, 604, 607 treatment of, 604t Argininosuccinate acid, in urea cycle, 603-604, 604f Argininosuccinate acidemia, 604t Argininosuccinate lyase deficiency of, 603-604, 606-607 in urea cycle, 603, 604f Argininosuccinate synthetase deficiency of, 603, 605-606 in urea cycle, 603, 604f Argininosuccinic acidemia, 606-608 Argininosuccinic aciduria, 603-604, 606-607 ARHGEF6 gene, in mental retardation, 809, 809r Aripiprazole, 971 adverse effects of, 968, 971 clinical applications of, 971 clinical management of, 971 dosage of, 967t drug interactions of, 971 labeled and off-labeled use of, 938t for mentally retarded patients, 815 pharmacology of, 971 receptor activity of, 967t

viii

Index

Aristotle, 2390 Arm(s) in gait evaluation, 71-72 muscle testing in, 27 segmental innervation of, 25f, 30t Arm recoil, in preterm infants, 54f-55f Arnold-Chiari malformation. See Chiari II malformation Aromatic L-amino acid decarboxylase deficiency, 359-360, 360f, 762-763, 1288 clinical features of, 350t-351t, 360, 762-763, 763f Arousal, in EEG sleep patterns, 225 Arousal disorders, 1226t, 1235 in sudden infant death syndrome, 1484 Arrested puberty, 2116-2118 evaluation of, 2117 management of, 2117-2118 Arsenic poisoning, 1910, 2184 Artemisinin, for malaria, 1659 Arterial circulation, 1760-1762, 1760f-1761f Arterial dissection, and stroke, 1769 Arterial ischemic stroke age-dependent features of, 1765-1766 anatomy and physiology in, 1760-1762, 1760f-1761f angiography (conventional) in, 1764f, 1770f-1773f, 1774-1775 animal models of, 1763 antithrombotic therapies for, 1775-1779 arterial dissection and, 1769 arteriopathies and, 1769-1772 cardiac disorders and, 1767, 1776, 2210-2211 cell death/apoptosis in, 1762-1763 in children versus adults, 1759, 1766 clinical features of, 1765-1766 cognitive effects of, 1763 computed tomography of, 1774 definition of, 1759, 1766 Doppler studies of, 1775 epidemiology of, 1759-1760 epilepsy/seizures with, 1781 etiology of, 1766-1767, 1768b genetics of, 1766-1767 hematologic disorders and, 1769 versus hemorrhagic stroke, 1788 hypothermia in, 1763, 1779 immunosuppressive therapy in, 1779 incidence of, 1759-1760 infarction mechanisms in, 1762-1763 infection and, 1767 interventional radiologic techniques in, 1780 in leukemia, 1736, 1736f magnetic resonance angiography in, 1774 magnetic resonance imaging of, 1774 metabolic vasculopathies and, 1773-1774 migraine and, 1773 mortality rate for, 1781 motor effects of, 1765f, 1781 moyamoya disease and, 1769, 1772-1773 neonatal, 329-330, 330f neuronal salvage in, 1763 neuroprotective agents in, 1779 neuroprotective care in, 1779 neurosurgical procedures for, 1779-1780 neurotoxic biochemical cascade in, 1763 non-antithrombotic therapies for, 1779-1781 outcome of, 1780t, 1781 pathophysiology of, 1760-1765 perfusion MR of, 1775 postradiation vasculopathy and, 1769, 1770f prothrombotic disorders and, 1767-1769, 1781 radiographic features of, 1774-1775 recurrent, 1781

Arterial ischemic stroke continued rehabilitation in, 1780 risk factors for, 1766-1774 single-photon emission tomography of, 1775 socioeconomic impact of, 1760 specialized care in, 1780-1781 supportive care in, 1779 thromboembolic mechanisms in, 1762 transfusion therapy in, 1779 treatment of, 1775-1781 varicella-zoster virus and, 1608-1609, 1766, 1769-1770, 1771f, 1772 vascular patterns of, 1763-1765, 1764f-1766f vasculitis and, 1771-1772, 1772f Arteriopathic stroke, 1769-1772, 2218-2219 Arteriovenous malformation (AVM), 1790-1792 clinical features of, 1790 development of, 1790 incidence of, 1790 neuroimaging of, 1790, 1791f perfusion MRI of, 190-191 spinal cord, 1878-1879, 1878f and subarachnoid hemorrhage, 1790 treatment of, 1790-1792 in Wyburn-Mason syndrome, 789-790 Arthritis enthesitis-related, 1806 infectious agent-associated, 1804t, 1806-1808 in inflammatory bowel disease, 1806 juvenile idiopathic, 1803-1806, 1804t acute encephalopathy with or without seizures in, 1803-1804 counseling in, 1806 management of, 1805-1806 mood disturbances in, 1805 myelopathy in, 1805 myositis in, 1805 neuropathies in, 1804-1805 neuropathologic abnormalities in, 1805 polyarticular, neurologic manifestations of, 1805 systemic, neurologic manifestations of, 1803-1805, 1805t uveitis with, 88, 1803 in Lyme disease, 1808 in meningitis, 1573 psoriatic, 1806 Arthrogryposis anterior horn cell, 1872-1873, 1872f X-linked spinal muscular atrophy with, 1868t Arthrogryposis multiplex congenita, 67, 69, 1872-1873 clinical features of, 1872-1873, 1872f management of, 1873 pathologic features of, 1872-1873 prenatal diagnosis of, 1873 Arthropathies, chronic, 1803-1806, 1804t-1805t Arthropod-borne encephalitis virus, 1602t Articulation disorders of, 846b, 848-849 pure, 848 variability of, 848, 848f Artifacts, in EEG, recognition of, 205-206, 205f ARX gene in lissencephaly, 411f, 414-415 in mental retardation, 809, 809r Arylsulfatase A deficiency, 680-683 Arylsulfatase A pseudodeficiency, 681-682 Arylsulfatase B deficiency, 682-683, 690 Arylsulfatase C deficiency, 682-683 Ascorbic acid (vitamin C), 2313-2314 absorption of, 2313-2314 deficiency of, 2314 dietary sources of, 2313 physiologic functions of, 2313 recommended daily requirement for, 2314 Volume 1: pages 1–1180

Aseptic meningitis, 1596-1597, 1597b CSF analysis in, 162t, 1575t enterovirus, 1610-1611 epidemiology of, 1598, 1599f herpes simplex, 1604-1605 lupus, 1811 in polyarteritis nodosa, 1820 Ashkenazi Jews Canavan’s disease in, 1362-1363 DYT1 dystonia in, 1282 familial dysautonomia in, 2132, 2144 Gaucher’s disease in, 671-673 GM2 gangliosidoses in, 667-669 mucolipidosis type IV in, 698 Niemann-Pick disease in, 675 ASP syndrome, 374 L-asparaginase and seizures, 1737 and sinovenous thrombosis, 1785 and stroke, 1736, 1736f toxicity of, 2192 Aspartate/glutamate transport carrier deficiency, 603 Aspartoacylase deficiency, 592-593, 1362, 1364 Aspartylglucosaminidase deficiency, 692-693 Aspartylglycosaminuria, 692-693 clinical features of, 693 diagnosis of, 693 genetics of, 693 treatment of, 693 Asperger, Hans, 908-909 Asperger’s disorder, 908-909 versus autistic disorder, 909 clinical features of, 909 diagnostic criteria for, 909 epidemiology of, 911-912 genetics of, 918 neuroimaging in, 916 stimulant therapy for, 925 Aspergillosis, 1637-1638 causative agent of, 1637, 1637f clinical characteristics of, 1637-1638 CNS syndromes in, 1632t diagnosis of, 1632t, 1637-1638 epidemiology of, 1637 geographic distribution of, 1632t laboratory tests in, 1637-1638 in leukemia, 1738, 1738f in liver transplant patients, 2298 management of, 1632t, 1638 microbiology of, 1637 pathology of, 1637 in renal transplant patients, 2250 risk factors for, 1632t in transplant recipients, 1631 Aspergillus, 1637. See also Aspergillosis Aspergillus fumigatus, 1627f, 1637. See also Aspergillosis Asphyxia. See also Hypoxic-ischemic injury and cardiac arrest, in infants and older children, 1471 in inflicted neurotrauma, 1461 perinatal, 492 Aspirin adverse effects of, 1777, 2190, 2265 dosage of, 2376t fetal/neonatal effects of, 2196 and hearing loss, 110 nephrotoxicity of, 2265 for pain, 2376-2377 in renal failure, action and effects of, 2268 for stroke, 332, 1777-1778 toxicity of, 2190 and vertigo, 133 ASPM gene, and cortical malformations, 402t, 405

Volume 2: pages 1181–2408

Index Assisted reproductive technology, and intraventricular hemorrhage, 311-312 Astatic (atonic) seizures, 1023t, 1030-1031 Astereognosis, 26 Asterixis in hepatic encephalopathy, 2294 in renal failure, 2237 Astigmatism, 87 Astrocytoma(s), 1718-1722 age at diagnosis, 1693 anaplastic, 1718 genetics of, 1748 incidence of, 1719t in infants and very young children, 1725 survival rates with, 1689t, 1718 brainstem, 1716 cerebellar, 1712-1714 chemotherapy for, 1714 clinical characteristics of, 1712-1713 cystic, 1712 diagnosis of, 1713 distribution of, 1712 gross appearance of, 1712, 1712f histopathology of, 1712 incidence of, 1712 in infants and very young children, 1725 management of, 1713 microscopic appearance of, 1712 prognostic factors in, 1713-1714 radiation therapy for, 1713, 1714 surgery for, 1713, 1714 survival rates in, 1714 chemotherapy for, 1721 classification of, 1692, 1718 clinical characteristics of, 1719-1720 diagnosis of, 1720 diffuse, 1719 survival rates with, 1689t genetics of, 1719, 1720f, 1748 giant cell, 1708 management of, 1708 in region of foramen of Monro, 1708, 1708f with tuberous sclerosis, 1708, 1708f grading of, 1718 hypothalamic, 1700-1701 incidence of, 1692-1693, 1719t in infants and very young children, 1725, 1727f-1728f management of, 1720-1722 neuroimaging of, 1695f, 1720, 1720f not otherwise specified incidence of, 1719t survival rates with, 1689t pilocytic, 1718 age at diagnosis, 1693 hypothalamic, 1700 incidence of, 1687, 1719t survival rates with, 1689t, 1718 pineal region, 1704 prognostic factors in, 1721-1722 radiation therapy for, 1721 spinal cord, 1732-1734, 1733f supratentorial, 1718-1722 surgery for, 1720-1721 survival rates with, 1689t, 1718, 1721-1722 temporal course of, 1694 thalamic, 1700 Astroglioma, incidence of, 1687 Asymmetric crying facies, 52 Asynergia, 1244 Ataxia(s), 1244, 1246-1264, 1295-1296. See also specific types acetazolamide-responsive paroxysmal, 1213t1214t, 1215, 1220 acute cerebellar, 73, 1246-1247, 1296, 1597, 1598b

Ataxia(s) continued in Alpers’ disease, 1326 autosomal dominant inherited, 1254-1264, 1255t classification of, 1254 genetics of, 1254-1255, 1255t autosomal recessive inherited, 1248-1254, 1248t causes of, 1245b-1246b, 1246, 1295t treatable, 1247t viral, 1597, 1598b, 1608-1609 in celiac disease, 2289 clinical features of, 1295-1296 definition of, 1244, 1295 differential diagnosis of, 1246-1247, 1296 versus dystonia, 1281 episodic, 1262 associated with nystagmus, 1215 hereditary familial type 1, 2101t with myokymia, 1262 type 1, 1247t, 1255t, 1262, 2101t, 2103 type 2, 1247t, 1255t, 1262 type 3, 1255t, 1262 type 4, 1255t, 1262 etiology of, 1275, 1295t, 1296 hereditary, 1247-1264, 1295t age of onset, 1247-1248 classification of, 1247 clinical manifestations of, 1247-1248 diagnostic approach to, 1264 hereditary paroxysmal cerebellar, 1262 hereditary spastic, 1263 management of, 1247-1264 in mental retardation/developmental delay, 814b in poisoning/intoxication, 2177-2178, 2180b primary, 1296 secondary, 1296 sensory, 73 spinocerebellar, 1255-1264, 1286 in systemic lupus erythematosus, 1811 treatment of, 1296 Ataxia-oculomotor apraxia, 1277-1278 type 1, 1253 age of onset, 1248t genetics of, 1248t, 1253 type 2, 1253 age of onset, 1248t genetics of, 1248t, 1253 Ataxia-telangiectasia, 1251-1253, 1277-1278 age of onset, 1248t, 1251 clinical features of, 560t, 1251-1252, 1252f genetics of, 560t, 561, 1248t, 1252-1253, 1277 incidence of, 1252 laboratory findings in, 1252, 1278 pathology of, 1252, 1277 prevalence of, 1251 and risk of neoplasia, 1693 treatment of, 1253, 1278 tumors with, 1251-1252 vertigo in, 132 Ataxia-telangiectasia-like disorder, 1253 age of onset, 1248t genetics of, 1248t, 1253 Ataxic cerebral palsy, 499-500 Ataxin-1, 1256 Ataxin-2, 1257 Ataxin-3, 1257 Ataxin-10, 1259 Atelencephaly, 385 Atenolol and autonomic dysfunction, 2149 for chronic daily headache prevention, 1197 for migraine prevention, 1194t for neurocardiogenic syncope, 1211b Athetosis, 74, 1272t, 1281-1282 in cerebral palsy, 498-499, 1282 Volume 1: pages 1–1180

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ix

Atkins diet, 1135 Atlantoaxial dislocation, 1535 Atlantoaxial subluxation, in Sydenham’s chorea, 1808 Atlas (Jefferson) fracture, 1529f, 1530, 1535 ATM (ataxia-telangiectasia mutated) gene, 1252-1253, 1277 Atomoxetine, 943-944 for ADHD, 878t, 881, 939t, 943-944 adverse effects of, 944 clinical applications of, 943 clinical management of, 943-944 dosage of, 939t, 943-944 drug interactions of, 944 pharmacology of, 939t, 943 versus stimulants, 943 Atonic cerebral palsy, 499 Atonic diplegia, 499 Atonic seizures, 1030-1031 clinical features of, 1030 EEG findings in, 1031 etiology of, 1030 prognosis of, 1030 treatment of, 1023t Atovaquone, for babesiosis, 1661 Atovaquone-proguanil, for malaria, 1659 ATP1A2 gene, in infantile seizures, 1010 ATP7A gene, in Menkes’ disease, 1321-1323 ATPase binding cassette (ABC) proteins, in peroxisomes/peroxisomal disorders, 735, 746, 749 ATR gene, and cortical malformations, 402t, 405 Atrial natriuretic factor, 2324 Atropine for breath-holding spells, 1206 for insecticide poisoning, 2183 for myasthenia gravis, 1951 for reflex anoxic seizures, 1207 toxicity of, 2190 for vasovagal syncope, 2150 Attention, antiepileptic agents and, 1174-1175 Attention-deficit hyperactivity disorder, 871-883 α-adrenergic agents for, 879t-880t, 882, 944-945 adverse effects of, 945 clinical management of, 944-945 drug interactions of, 945 pharmacology of, 944 in adults, 883 antidepressants for, 878t-879t, 882, 946 arachnoid cysts and, 435 atomoxetine for, 878t, 881, 939t, 943-944 adverse effects of, 944 clinical management of, 943-944 dosage of, 939t, 943-944 drug interactions of, 944 pharmacology of, 939t, 943 behavior therapy for, 882 behavioral inhibition in, 871, 873f biofeedback programs for, 882-883 bupropion for, 879t, 953-954 cerebellum in, 875 classification of, 871 clinical neurophysiology of, 875 coexisting conditions with, 874, 876, 940-941 combined type, 871 complementary and alternative medicine for, 883 cortical structures in, 874 desipramine for, 878t, 882, 897 dexmethylphenidate for, 878t, 881 dextroamphetamine for, 878t, 880-881 diagnosis of, 871-872 controversies in, 872-874 criteria for, 871-874, 872b

x

Index

Attention-deficit hyperactivity disorder continued diagnostic evaluation of, 876-877 dopamine in, 875-876 EEG findings in, 877 with epilepsy, 1172, 1177 etiology of, 876 event-related potentials in, 875 genetic studies of, 876 hyperactive-impulsive type, 871, 872b imaging studies of, 877 functional, 875 structural, 874-875 inattentive type, 871, 872b laboratory studies in, 877 with mental retardation, 815 methylphenidate for, 877-881, 878t neurobiology of, 874-877 nonpharmacologic therapy for, 882-883 nonstimulant medications for, 881-882, 943-944 outcome of, 883 pharmacologic therapy for, 877-882, 878t880t, 939t, 940-945 prevalence of, 871 sleep disorders and, 874, 876-877, 942 sleep studies of, 877 stimulants for, 877-881, 878t, 897, 939t, 940-943 adverse effects of, 880, 937, 942-943 assessment for, 940-941 clinical management of, 940-942 dosage of, 939t, 941 “drug holidays” from, 941-942 drug interactions of, 943 initiation and titration of, 941 monitoring therapy with, 941-942 pharmacology of, 939t, 940 subcortical structures in, 874-875 symptom rating scales in, 871 with Tourette syndrome, 889-890, 897 treatment of, 877-883, 896t, 897, 939t, 940-945 with tuberous sclerosis complex, 778-779 venlafaxine for, 879t, 954 Atypical teratoid/rhabdoid tumor, 1709, 1729-1730 Audiologists, 2360-2361 Audiometry behavioral, 112-113, 112f-113f calibration of, 100 in meningitis, 1577 speech, 113 threshold in, shape of, 104, 112-113, 112f-113f Auditory agnosia, 822t verbal, 849, 907, 1055 Auditory nerve (CN VIII) assessment of, 108 in infant, 39 in newborn (term), 52 in older child, 24 imaging of, 114 in meningeal leukemia, 1735-1736 in poisoning/intoxication, 2177t Auditory neuropathy, 103, 106 Auditory pathways central, 99, 100f peripheral, 100f Auditory processing disorder, with ADHD, 876 Auditory seizures, 1042-1043 Auditory system, 97-102 anatomy of, 97-99, 98f-100f embryology of, 97-99 physiology of, 99-102

Auditory-evoked potentials, 242-244, 244f in autistic disorder, 244, 915-916 in brain death, 1562 in brain tumors, 1696, 1696f after cardiac arrest, 1493-1495 clinical applications of, 244 in coma, 1392 elicitation of, 243 in hearing loss, 101-102, 102f, 111, 114, 244 maturational changes in, 243-244 in meningitis, 1577 Aura with focal seizure, 1020-1021 with migraine, 1183-1184, 1184b, 1187-1189, 1188t Austin’s disease, 682-683 Autism Diagnostic Interview-Revised, 915 Autism Diagnostic Observation ScheduleGeneral, 915 Autism/autistic disorder, 905-928 age at diagnosis in, 912 age of onset versus age of recognition in, 911 animal models of, 921 antidepressants for, 924-925, 927t antiepileptic agents for, 925, 927t, 1060 versus Asperger’s disorder, 909 atypical, 909 behavioral and educational interventions in, 926-928 candidate genes in, 919-920 clinical features of, 906-908 clinical testing in, 915-916 cognitive theories of, 911 communication in, 906b, 907-908 “red flags” for, 913, 913b complementary and alternative medicine for, 925-926 cytogenetic studies of, 919 diagnostic criteria for, 905-908, 906b diagnostic evaluation and screening in, 912-915, 913b-914b DSM-IV classification of, 905, 906t EEG findings in, 1056-1057 entire-genome screening studies of, 919 epidemiology of, 911-912 epigenetics of, 920 epilepsy with, 917, 1056-1058 etiology of, 920-923 executive dysfunction in, 911 feeding disturbances in, 916 in fragile X syndrome, 918 functional MRI in, 911 gastrointestinal problems in, 916 genetic counseling in, 920 genetic studies of, methods for, 919-920 genetics of, 918-919 haloperidol for, 923-925, 927t, 966 hearing testing in, 244, 915-916 historical perspective on, 905 hyperactivity in, treatment of, 925 ICD-9 classification of, 905, 906t infantile, 905 lead level in, 916 medical comorbidities with, 916-918 medical evaluation in, 915-916 metabolic testing in, 916 mitochondrial disorders and, 917-918 neuroimaging in, 916 neuroleptic agents for, 923-924, 927t, 966 neuropathology of, 921-922 opiate antagonists for, 924, 927t pathophysiology of, 920-923 pharmacologic therapy for, 923-926, 927t and activation, 923 phenylketonuria and, 918 physical examination in, 915 Volume 1: pages 1–1180

Autism/autistic disorder continued practice parameter for, 912-913 prevalence of, 911-912 resources for families in, 928 risk factors for, 920-921 rules and rituals in, inflexibility of, 908 serotonin in, 922-923 serotonin reuptake inhibitors for, 924-925, 927t sleep disturbances in, 917 social interaction in, 906-907, 906b stimulant therapy in, 925, 927t, 940 tests of unproven value in, 916 theory of mind in, 911 in tuberous sclerosis complex, 778, 918-919 vaccines and, 923, 2185 weak central coherence in, 911 Autistic regression, 911, 917 with epileptiform EEG, 1056-1058, 1060t natural history of, 1057-1058 Autistic spectrum disorders, 905-928. See also Asperger’s disorder; Autism/autistic disorder; Childhood disintegrative disorder; Rett’s syndrome broader phenotype in, 905, 918 classification of, 905, 906t clinical features of, 905-911 diagnostic criteria for, 905-911, 906t diagnostic evaluation and screening in, 912-915, 913b-914b epidemiology of, 911-912 with epileptiform EEG, 1056-1058, 1059t Autoantibodies, in rheumatic disorders, 1804t Autoimmune disorders. See also specific disorders and chorea, 1279-1280 Automatisms, 1024, 1043 Autonomic dysreflexia, 2147-2148, 2361-2362 clinical findings in, 2361 pathophysiology of, 2361 treatment of, 2361-2362 Autonomic failure, pure, 2151f catecholamines in, 2138f sympathetic skin response in, 2137, 2139f Autonomic nervous system anatomy of, 2129-2131, 2130f biochemistry of, 2129-2131, 2130f-2131f disorders of, 2129-2153. See also specific disorders cardiovascular, 2135-2137 classification of, 2131, 2131t clinical features of, 2131-2133, 2132t description of specific, 2143-2153 drug-induced, 2131, 2132t, 2149 exercise testing in, 2135-2136, 2137f eye, 2140 gastrointestinal, 2137-2138 infectious, 2149 investigation of, 2133-2140, 2136t localized, 2131, 2132t, 2152-2153 primary, 2131, 2131t, 2143-2144 respiratory, 2138-2140 secondary, 2131, 2131t, 2144-2149 skin, 2140 in spinal cord injury, 2146f, 2147-2148, 2148f, 2361-2362 with spinal cord lesions, 2146f, 2147-2149, 2148f sweating response in, 2137, 2139f urinary tract, 2138 in pain response, 2374, 2374t physiology of, 2129-2131 Autonomously replicating sequence (ARS), 516 Autonomy, 2389 Autoregulation, 299, 1515, 1762-1763, 2240 Autoregulatory index, 1431 Autosomal dominant inheritance, 533, 533f Autosomal recessive inheritance, 532-533, 533f

Volume 2: pages 1181–2408

Index Autosomes, 516, 541 Avonex (interferon-β), for multiple sclerosis, 1349-1350 Avulsion, in brachial plexus injury, 340 Awareness, in consciousness, 1377 Axillary freckling, in neurofibromatosis type 1, 772f, 773 Axillary nerve, 28t Axonal disconnection, 1406-1407 Axonotmesis, in brachial plexus injury, 340 Azacitidine, teratogenicity of, 2198 Azathioprine for chronic inflammatory demyelinating polyneuropathy, 1933 for dermatomyositis, 2079 hepatotoxicity of, 2294 for Lambert-Eaton myasthenic syndrome, 1957 for mixed connective tissue disease, 1817 for myasthenia gravis, 1953-1954 for peripheral nerve hyperexcitability, 2105 for sarcoidosis, 1824 toxicity of, 2251 Azithromycin for babesiosis, 1661 for granulomatous amebic encephalitis, 1653 for primary amebic meningoencephalitis, 1650

B B cells, in multiple sclerosis, 1346, 1349 B wave in electroretinography, 245, 246f in intracranial pressure, 1515 B4GALT1 gene, in congenital glycosylation disorder, 650t, 652 B4GALT7 gene, in Ehlers-Danlos syndrome, 650t Babès, Viktor, 1660 Babesia, 1660, 1661f. See also Babesiosis Babesia divergens, 1660 Babesia microti, 1660 Babesiosis, 1660-1661 classification of, 1647t clinical characteristics of, 1647t, 1660-1661 diagnosis of, 1647t, 1660-1661, 1661f epidemiology of, 1660 geographic distribution of, 1647t, 1660 laboratory tests in, 1660-1661 management of, 1647t, 1661 mode of infection, 1647t, 1660 pathology of, 1647t risk factors for, 1647t Babinski reflex, 19, 43t, 51, 71 Back muscles, testing of, 34t Back pain lumbar puncture and, 158 spinal cord tumor and, 1730 Baclofen adverse effects of, 1289, 2367t for dystonia, 1282, 1289 for dystonic storm, 1281 for heterotopic ossification, 2365 intrathecal, 2368-2369 for kernicterus, 1284 for micturition disorders, 2165 for muscle overreactivity (spasticity), 2366, 2367t, 2368-2369, 2378 for myoclonus, 1295 for neuronal ceroid lipofuscinosis, 1332 for pantothenate kinase-associated neurodegeneration, 1285 for post-traumatic spasticity, 1434 in spinal cord injury, 1544

Baclofen continued for stiff person syndrome, 2106 for tic disorders, 896 Bacteremia, 1572 Bacterial endocarditis, and aneurysm, 1794 Bacterial infections, 1571-1591. See also specific infections and myopathy, 2082 and stroke, 1767 Bacteroides fragilis, 1589 Balamuthia mandrillaris, 1646, 1650, 16521653. See also Granulomatous amebic encephalitis Baller-Gerold syndrome, 450 clinical features of, 442t, 450 genetics of, 442t, 450 Ballism, 1272t, 1280 in cerebral palsy, 499 in Lesch-Nyhan disease, 1286 in pantothenate kinase-associated neurodegeneration, 1285 pathophysiology of, 1274-1275 Balloon cells, focal cortical dysplasia with, 403t, 410 Baltic myoclonus, 1254 Bannayan-Riley-Ruvalcaba syndrome, 408 Baraitser-Winter syndrome, 414-417 Barbiturate(s) abuse/intoxication, 2187 adverse effects of, 1425, 2180-2181, 2265 as antiepileptic agents in lindane poisoning, 2184 mechanism of action, 1003, 1004f in mentally retarded patients, 815 for cyclical vomiting syndrome, 2286 for febrile seizure prevention, 1085 fetal/neonatal effects of, 2196 for intracranial hypertension, 1422, 1426, 1521 nephrotoxicity of, 2265 for nonepileptic paroxysmal disorders, 1213t, 1214 for sedation, 2378 Bardet-Biedl syndrome, 88t, 389t Barium enema, 2167 Barium examination, contraindicated in pure cholinergic dysautonomia, 2143, 2143f Baroreceptors, 2130-2131 Barthel Index, 1546 Barth’s microlissencephaly syndrome, 403t, 405 Barth’s syndrome, 592, 728, 1995, 2060 Bartonella, 1590 Bartonella henselae, 1590 Bartonella quintana, 1590 Barx-1 gene, in craniofacial development, 438 Basal ganglia abnormalities, in developmental disorders, 840t in ADHD, 874-875 circuitry of, 1272-1274, 1273f-1274f embryology of, 383 in Fahr’s disease, 1286-1287, 1287f hypoxic-ischemic injury to, 285-287 clinical features of, 286-287 computed tomography of, 286, 286f diagnosis of, 286 magnetic resonance imaging of, 282, 286, 286f pathogenesis of, 285-286 ultrasound of, 286, 286f in movement disorders, 1272-1274 model of, 1274, 1275f pathophysiology of, 1274-1275 in Rett’s syndrome, 1317 Basal plates, 379-380, 379f Basal skull fracture, 1418 Base(s), DNA, 507-508 Volume 1: pages 1–1180

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xi

Base pairs, 508 Basilar artery, 1761f Basilar artery migraine, 131-132, 1189, 1189t Basilar impression, 461-462 clinical characteristics of, 461-462 diagnosis of, 462 management of, 462 Basilar membrane, 98, 99f Basket cells, 1241 Bassen-Kornzweig syndrome (abetalipoproteinemia), 88t, 1247t, 1288, 1906-1907 clinical characteristics of, 1907 laboratory tests in, 1907 management of, 1907 pathology of, 1906 vitamin E in, 1907, 2316-2317 Bat wing appearance, in glutaric aciduria, 594 Bathtub drowning, 1485 Battelle Developmental Inventory, 805, 1395-1396 Batten’s disease. See Neuronal ceroid lipofuscinosis Battered child syndrome, 1445. See also Child abuse Battle’s sign, 1408, 1461 Bayley Infant Neurodevelopmental Screener (BINS), 802t Bayley Scales of Infant Development, 802t, 805, 1396 Baylisascariasis, 1665-1666 classification of, 1647t clinical characteristics of, 1647t, 1665-1666 diagnosis of, 1647t, 1665-1666, 1666f epidemiology of, 1665 geographic distribution of, 1647t, 1665 laboratory tests in, 1665-1666 management of, 1647t, 1666 microbiology of, 1665 mode of infection, 1647t, 1665 pathology of, 1647t, 1665 risk factors for, 1647t Baylisascaris procyonis, 1665. See also Baylisascariasis Beagle model, of intraventricular hemorrhage, 313, 313f-314f Beare-Stevenson syndrome, 449 clinical features of, 442t, 449 genetics of, 442t, 447t, 449 Beaten copper appearance, in craniosynostosis, 453 Becker muscular dystrophy, 531, 1969, 1986-1987 cardiac involvement in, 1979, 1987, 2224 clinical features of, 1987, 1987f genetic counseling in, 1985-1986 genetic testing for, 1980 genetics of, 531, 1986 laboratory findings in, 1986-1987 management of, 1981, 1987 muscle biopsy in, 1987 neuropsychiatric involvement in, 1979 Becker nevus syndrome, 787t Becker’s disease, 2090-2093, 2090t clinical features of, 2090-2091, 2090t genetics of, 2090t, 2091 laboratory tests in, 2091-2092 pathophysiology of, 2091 treatment of, 2090t, 2092-2093 Beckwith-Wiedemann syndrome, 464t, 558t Bedwetting, 2157, 2162 Behavior adaptive, 801 testing of, 804t, 805 of older child, observation of, 17

xii

Index

Behavior continued school, assessment of, 7-15, 11f-12f, 13b, 14f-15f Behavior disorders antiepileptic agents and, 1174-1177 in Duchenne muscular dystrophy, 1986 in epilepsy, 987, 1055, 1171-1177 epilepsy surgery and, 1152 in malnutrition, 2304 in mental retardation, 815 in Sanfilippo syndrome, 688-689 in Tourette syndrome, 897 in traumatic brain injury, 1433-1434, 2355-2356 in tuberous sclerosis complex, 778-779 Behavior therapy for ADHD, 882 for autism, 926-928 Behavioral arrest seizures, 1039-1040, 1041f Behavioral audiometry, 112-113, 112f-113f Behavioral inhibition, in ADHD, 871, 873f Behçet’s disease, 1825-1826 diagnostic criteria for, 1825 laboratory findings in, 1818t neurologic manifestations of, 1818t, 1825-1826 treatment of, 1826 Behr’s syndrome, 1254 Belladonna for nonepileptic paroxysmal disorders, 1213t, 1214 toxicity of, 2191 Bell’s palsy, 1887-1890 acoustic immittance testing in, 114 bilateral, 1889 clinical features of, 1887-1889 differential diagnosis of, 1889, 1890t epidemiology of, 1887 herpes simplex virus and, 1604 incidence of, 1887 influenza vaccine and, 2348 laboratory findings in, 1889 in Möbius syndrome, 1870, 1870f, 1889 MRI findings in, 1889 prognosis of, 1889-1890 treatment of, 1889-1890 Bell-shaped chest, 67 in spinal muscular atrophy type I, 1864 Beneficence, 2389 Benign angiopathy of central nervous system, 1823 Benign childhood epilepsy with centrotemporal spikes, 1014, 1044-1045 Benign congenital hypotonia, 1871 Benign familial infantile seizures, 1010, 1045t Benign familial neonatal seizures, 266-267, 1009 EEG findings in, 267 genetics of, 266-267, 1009 incidence of, 266 onset of, 267 therapy for, 267 Benign familial neonatal-infantile seizures, 1009-1010 Benign focal epilepsies of childhood, 1044-1045 Benign idiopathic neonatal convulsions, 266 Benign myoclonic epilepsy of infancy, 1070t Benign myoclonus of early infancy, 1217 Benign neonatal convulsions, 266 as diagnosis of exclusion, 266 EEG findings in, 266 incidence of, 266 prognosis in, 266 therapy for, 266 Benign neonatal sleep myoclonus, 1299

Benign paroxysmal tonic upgaze, 1213t, 1215 Benign paroxysmal torticollis, 131, 1191, 1216, 1300-1301 Benign paroxysmal vertigo, 124-126, 130-131, 1191, 1213 treatment of, 1213, 1213t Benign positional molding, 438-441. See also Deformational plagiocephaly Benign rolandic epilepsy of childhood (BREC), 1014, 1040f, 1045t, 1151 Bentham, Jeremy, 2387-2388 Benzedrine, 877 Benzimidazole for Chagas’ disease, 1662 for echinococcosis, 1669 Benzodiazepine(s), 955-957, 956t abuse/intoxication, 2187 adverse effects of, 956-957, 2181 for amphetamine toxicity, 2187 as antiepileptic agents, 1111-1112 for absence seizures, 1029 for febrile seizures, 1084-1086 in lindane poisoning, 2184 mechanism of action, 1003, 1004f, 1119t for myoclonic seizures, 1075 for neonatal seizures, 270, 291 for status epilepticus, 1098t, 1099-1100 for anxiety disorders, 955-957 versus buspirone, 957 classification of, 955 clinical applications of, 955-956 clinical management of, 956 for cyclical vomiting syndrome, 1191 dosage of, 956t drug interactions of, 956t, 957 for dystonia, 1289 acute reactions, 1288 DYT1, 1282 myoclonus, 1283 half-lives of, 955, 956t for kernicterus, 1284 for Landau-Kleffner syndrome, 1059 for Lesch-Nyhan disease, 1286 for muscle overreactivity (spasticity), 2366 for myoclonus, 1294-1295 for neuroacanthocytosis, 1287-1288 for neuronal ceroid lipofuscinosis, 703, 1332, 1336 for pantothenate kinase-associated neurodegeneration, 1285 pharmacokinetics of, 1111-1112 pharmacology of, 956 for post-traumatic spasticity, 1434 preparations of, 956t in renal failure, action and effects of, 2268 for sedation, 2377-2378 and sleep, 1234 for tic disorders, 1298 toxicity of, 2181 for tremor, 1291 Benztropine, for sialorrhea, 2362 Benzyl alcohol poisoning, 2185 Benzyl alcohol preservative, and cerebral palsy, 493 Bereavement, 2383-2384 Beri-beri, 1906, 2307-2308 Beta activity, in EEG abnormal slowing or suppression of, 209 in drowsy state, 221-222 in infancy through adolescence, 219 Beta blockers for ADHD, 880t and autonomic dysfunction, 2149 for chronic daily headache prevention, 1196t, 1197 for intracranial hypertension, 1583 Volume 1: pages 1–1180

Beta blockers continued for migraine prevention, 1194t for neurocardiogenic syncope, 1211-1212, 1211b for orthostatic hypotension, 2143 in renal failure, action and effects of, 2268 for thyrotoxic periodic paralysis, 2101 for vasovagal syncope, 2150 Beta oxidation defects, 717-718, 721, 723-724 Beta-hydroxybutyrate (BHB) in ketogenesis, 1136-1138, 1137f ketogenic diet and, 1138-1139 Betaine for homocystinuria, 582f, 583 for methylmalonic acidemia, 588 Betamethasone, for intraventricular hemorrhage prevention, 323-324 Bethanechol for micturition disorders, 2165, 2165t for pandysautonomia, 2144 for scleroderma, 1816 Bethlem’s myopathy, 2002-2003 Beutler test, 619 Bezold-Jarisch reflex, 2150 BH4 (tetrahydrobiopterin) in CSF, 163 deficiency/disorders of, 360, 360f, 574-575, 759-761, 767 for phenylketonuria, 574 role in central nervous system, 759 in sepiapterin reductase deficiency, 763 Bicarbonate, in cerebrospinal fluid, 154, 154f, 154t Bicarbonate wasting, in uremia, 2235 Biceps muscle, testing of, 34t Biceps reflex in older child, 18, 19t in preterm infant, 56-57, 58t Bifunctional enzymes deficiency of, 749-750 in fatty acid oxidation, 736f, 737 Bile acid synthesis, 738 defects of, 743, 743t Bilirubin elevated levels of in cephalohematoma, 338 and cerebral palsy, 494 in CSF, 159 and hearing loss, 109t, 110 in kernicterus, 1284, 2300-2301 in subgaleal hematoma, 336, 338 toxicity of, 1284 Binet, Alfred, 800 Bioavailability, 1105 Biochemical reactions phase I, 1111 phase II, 1111 Bioethics, 2387 Biofeedback in ADHD, 882-883 in chronic daily headache, 1198 in defecation disorders, 2168 in micturition disorders, 2165 in migraine, 1192, 1192b Biologic clocks, and neonatal sleep patterns, 222 Biologic response modifiers, for tumors, 1748-1749 Biologic toxins, 2181-2182 Biopterin disorders, 574-575, 1283 clinical manifestations of, 574-575 diagnosis of, 575 treatment of, 575 Biotin (vitamin H), 2317 absorption of, 2317 deficiency of, 590-591, 723, 2317 clinical manifestations of, 590, 2317 diagnosis of, 590

Volume 2: pages 1181–2408

Index Biotin (vitamin H) continued etiology of, 590, 2317 laboratory findings in, 590, 2317 treatment of, 590-591, 730, 2317 dependency disorders of, 2317 physiologic functions of, 2317 recommended daily requirement for, 2317 Biotinidase deficiency, 590-591, 723, 730, 2317 Biotin-responsive multiple carboxylase deficiencies, 589-592 Biotransformation, 1111 in renal failure, 2266-2268 Bipolar affective disorder antiepileptic agents for, 958, 960-964 carbamazepine for, 961-962 diagnosis in children, controversy over, 957-958 gabapentin for, 937, 963 lamotrigine for, 962-963 lithium therapy for, 958-960 pharmacologic therapy for, 957-964 topiramate for, 963-964 with Tourette syndrome, 890 valproic acid for, 960-961 Bipolar recordings, in EEG, 204 Birth information, in neurologic history, 3 Birth injuries, 329, 334-341. See also specific injuries brachial plexus, 334, 340-341, 1890-1892 clinical presentation of, 335-341 cranial, 336-339 outcomes in, 338-339 cranial nerve, 339 deaths from, 334 definition of, 334 delivery mode and, 334-335 epidemiology of, 334 extracranial, 335-336 versus inflicted neurotrauma, 1460 intracranial, 337-339 laboratory testing in, 335 management, by diagnosis, 335-341 mechanical, 334 radiologic studies of, 335 risk factors for, 334-335 spinal cord, 339-340 Birth weight, 53 and intraventricular hemorrhage, 310-311, 311t, 321 and neurodevelopmental disability, 309 Bisacodyl, for defecation disorders, 2168 Bispectral Index Scale, 1392 Bisphosphonate(s) for fibrous dysplasia, 458 for heterotopic ossification, 2365 for McCune-Albright syndrome, 459 for osteogenesis imperfecta, 463 Bithionol, for paragonimiasis, 1674 Bitter taste, 141t, 142 Bladder anatomy of, 2157 control of, 2157 dysfunction of, 2157-2165 in anterior spinal artery occlusion, 1878 autonomic, 2138 classification of, 2162f differential diagnosis of, 2164, 2168b laboratory tests in, 2163-2164 management of, 2164-2165 neurologic examination in, 2163 pathophysiology of, 2159-2162 patient evaluation in, 2162-2164 patient history in, 2162-2163 radiographic evaluation of, 2164 in spina bifida, 372 in spinal cord injury, 1544, 2163, 2163t, 2358

Bladder continued embryology of, 2157 hyperreflexic, 2164 nerve supply of, 2158-2159, 2158f-2161f neurogenic, 2163-2164, 2358 treatment of, 2164-2165, 2165t overactive, 2162-2163 prolapse of, 2164 Blake’s pouch cyst, 392-393, 393f Bland infarct, 1759 Blastomyces dermatitidis, 1634. See also Blastomycosis, North American Blastomycosis North American, 1634 clinical features of, 1634 CNS syndromes in, 1632t diagnosis of, 1632t, 1634 geographic distribution of, 1632t management of, 1632t, 1634 risk factors for, 1632t South American, 1634-1635 clinical characteristics of, 1635 CNS syndromes in, 1632t diagnosis of, 1632t, 1635 geographic distribution of, 1632t, 1634 laboratory tests in, 1635 management of, 1632t, 1635 risk factors for, 1632t Blepharospasm, 1280 Blindfolded tandem gait, 125b, 126 Blindness. See also Vision loss cortical in Alpers’ disease, 1327 traumatic brain injury and, 1415 occipital, hypertension-associated, 2239 vitamin A deficiency and, 2306 Bloch-Sulzberger syndrome, 788-789. See also Incontinentia pigmenti Blocking, in neuromuscular transmission, 1947 Blood flow, cerebral in arterial ischemic stroke, 1762-1763 in brain death, measurements of, 1559-1562, 1559t, 1560f in coma, 1392-1393 in hypoxic-ischemic injury, 297, 299, 1504 after resuscitation, 1479-1480 intracranial pressure and, 1514-1516 in intraventricular hemorrhage, 310-311, 310b in meningitis, 1577 pressure passive, in preterm infants, 299, 310 in traumatic brain injury, 1406, 1430-1431 velocity of, Doppler measurement of, 1516 Blood oxygen level in functional MRI, 191 in perfusion MRI, 189 Blood pressure ambulatory profile of, 2134f, 2135 beat-by-beat measurement of, 2135 orthostatic changes in. See Orthostatic hypotension Blood urea nitrogen, in micturition disorders, 2163-2164 Blood-brain barrier and chemotherapy, 1699, 1699f disruption, in meningitis, 1576 Blood-CSF barrier, 155 Bloom’s syndrome, 561 clinical features of, 560t genetics of, 560t, 561 Bobble-head doll movement, 429, 434, 1302 Body rocking, 1219 Body temperature. See also Hyperthermia; Hypothermia in hypoxic-ischemic injury, 291, 304-305, 1500 in impaired consciousness/coma, 1391 Volume 1: pages 1–1180

Volume 2: pages 1181–2408

xiii

Body temperature continued in intracranial hypertension, 1521 regulation of, 1225 in traumatic brain injury, 1425 Bone disorders, craniofacial, 435b, 436, 455-466 Bone marrow transplantation for adrenoleukodystrophy, 748-749 for Hurler syndrome, 687 for lysosomal storage diseases, 663t, 664 for malignant gliomas, 1721 for mannosidosis, 692 for Maroteaux-Lamy syndrome, 690 for metachromatic leukodystrophy, 682 for mucopolysaccharidoses, 685 for osteopetrosis, 457 for Sly’s syndrome, 690 Bone morphogenetic proteins (BMPs), and neural tube development, 366 Bone scan, in heterotopic ossification, 2364, 2364f Bonnet-Dechaum-Blanc syndrome, 790 Bony labyrinth, 97, 98f, 114 Bony spine, 1527-1528, 1528f Bookshelf (on-line resource), 2404 Bordetella pertussis, 2348 Borrelia burgdorferi, 1587-1588. See also Lyme disease Borrelia garinii, 1587 Boston-type craniosynostosis, 450 clinical features of, 442t genetics of, 442t, 443f Botulinum toxin, 2182 adverse effects of, 2368 for dystonia, 1289 for heterotopic ossification, 2365 for hyperhidrosis, 2152 for kernicterus, 1284 for micturition disorders, 2165, 2358 for muscle overreactivity (spasticity), 2367-2368 optimal candidates for, 2368t for pantothenate kinase-associated neurodegeneration, 1285 for post-traumatic spasticity, 1434 for sialorrhea, 2362 for spinal cord injury, 1544 for tic disorders, 897 type A (Botox), 2367 dosing guidelines for, 2368, 2368t type B (Myobloc), 2367 Botulism, 1962-1963, 2182 B variant of, 2144 classic, 1962, 2182 infantile, 67, 1962-1963, 2182, 2291 neurologic examination in, 2175-2177 ptosis with, 88 wound, 1963, 2182 Bovine spongiform encephalopathy, 1598 Bowel control, 2157, 2166 Bowel dysfunction, 2166-2168 differential diagnosis of, 2167b, 2168 inflammatory. See Inflammatory bowel disease malabsorption, 2288-2290 management of, 2168 patient evaluation in, 2167-2168 in spina bifida, 372 in spinal cord injury, 2358 Brachial plexus, 28t, 1890-1892, 1891f inherited conditions of, 1892 Brachial plexus injury, 334, 340-341, 1890-1892 avulsion in, 340 axonotmesis in, 340 complete, upper, or lower, 340 differential diagnosis of, 341

xiv

Index

Brachial plexus injury continued evaluation for, 39 incidence of, 340, 1890 management of, 341, 1891 neuropraxia in, 340 neurotmesis in, 340 outcome of, 341, 1892 postoperative, in cardiac surgery, 2215 predisposing factors in, 340 subdural hematoma with, 337 types of, 340 Brachial plexus neuritis, 1892 Brachioradialis muscle, testing of, 34t Brachioradialis reflex in older child, 18, 19t in preterm infant, 56-57, 58t Brachium conjunctivum, 1242f, 1243 Brachium pontis, 1242f, 1243 Brachycephaly, 445, 1523 Brachytherapy, 1698 Bradley, Charles, 877 Bradycardia in intraventricular hemorrhage, 320, 320t in spinal cord injury, 1538 in sudden infant death syndrome, 1484-1485 Bradykinesia, 1282 definition of, 1291 etiology of, 1275-1276 in parkinsonism, 1291-1293 treatment of, 1293 Brain anatomy of, 1402, 1402f compliance of, 1513 developing, distinctions of injury to, 1404-1405 development of malnutrition and, 2302-2304, 2303b neonatal seizures and, 271-272 normal embryonic, 364-365, 364t electrical activity of, 206. See also Electroencephalography (EEG) pressure-volume relationships of, 1513, 1514f-1515f structural defects of. See also specific defects epidemiology of, 363 etiology of, 363-364, 364t neuroimaging of, 363 pathogenesis of, 363-364 vascular supply of, 1402 Brain abscess(es), 1588-1589 amebic, 1646-1649 in candidiasis, 1638, 1639f clinical characteristics of, 1588, 1588t, 2222 computed tomography of, 173, 1588, 2222 in congenital heart disease, 2220-2223, 2222f CSF analysis in, 162t, 1575t, 1588 differential diagnosis of, 1588 diffusion-weighted imaging of, 187 EEG findings with, 1588 headache with, 2219-2220 in leukemia, 1738 magnetic resonance imaging of, 174, 177f, 1588, 2222, 2222f pathogenesis and pathology of, 1588-1589 prognosis of, 1589 in systemic lupus erythematosus, 1811 treatment of, 1589, 2222-2223 Brain death, 1381-1382, 1381f, 1553-1565 age distribution of, 1555, 1555t ancillary neurodiagnostic studies in, 15581562 apnea in, 1556-1557, 1557t brainstem examination in, 1556 caloric stimulation in, 1553, 1554b cerebral perfusion in, 1559-1562, 1559t, 1560f

Brain death continued cerebral unresponsivity in, 1556 clinical examination in, 1556-1557 in comatose pediatric patient, 1563-1565, 1564f definition of Conference of Medical Royal College and Faculties, 1553 legal, 1554 discussion with family and staff in, 1564 EEG findings in, 238, 1553-1554, 1558-1559, 1563 epidemiology of, 1554-1556 etiologies of, 1555-1556, 1555t evoked potentials in, 1562 historical perspective on, 1553-1554 incidence of, 1554-1555, 1555f international guidelines for, 1553 neurologic evaluation in, 1556-1557 in newborns, 1562-1563 duration of observation in, 1562-1563 epidemiology of, 1562 neurodiagnostic testing in, 1563 organ donation in, 1565 outcome after diagnosis of, 1556 pediatric guidelines for, 1553-1554, 1555b President’s Commission guidelines for, 1553, 1554b Brain energy failure, in hypoxic-ischemic injury, 1471-1473, 1473f Brain injury. See also Perinatal trauma; Stroke, neonatal and chorea, 1279 neonatal, 329-341 traumatic. See Traumatic brain injury Brain isoenzyme of creatine kinase (BB-CK), in osteopetrosis, 457 Brain tumor(s), 1687-1730. See also specific types angiography in, 1696, 1696f causal inference in, criteria for, 1693 chemotherapy for, 1698-1699 blood-brain barrier and, 1699, 1699f cell-cycle specific versus cell-cycle nonspecific, 1699 testing of, 1699 classification of, 1691-1693, 1692t computed tomography of, 172f, 1695, 1695f CSF protein content with, 162t databases on, 1687, 1687f-1688f diagnosis of, 1694-1696 diffusion-weighted imaging of, 186-187 distribution by site, 1687, 1688f doublings of, 1696, 1697f EEG findings with, 1696 environmental factors and, 1693 epidemiology of, 1687, 1687f-1688f, 1689t-1691t, 1693 evoked potentials with, 1696, 1696f functional MRI of, 193-194 future directions in, 1747-1749 genetics of, 1693 headache with, 1200-1201, 1694, 1695f hearing loss with, 110 histology of, 1687-1691 histopathologic groupings of, 1691-1693 immunohistochemistry of, 1688-1691 incidence of, 1687, 1687f age-specific, 1719t in infants and very young children, 1724-1730, 1725f clinical characteristics of, 1725-1727, 1726f diagnosis of, 1727 distribution of, 1725 management of, 1728 radiation therapy for, 1728, 1728f-1729f Volume 1: pages 1–1180

Brain tumors continued intracranial pressure increase with, 1694 long-term effects of therapy for, 1738-1745 recommendations for, 1744-1745 magnetic resonance imaging of, 172f, 176-177, 180f-181f, 1695, 1695f magnetic resonance spectroscopy of, 183-184, 188f, 1696 management of general principles of, 1696-1699 log-kill hypothesis in, 1696 mass at diagnosis, 1696 midline, 1699-1707 neurofilament markers in, 1688-1691 new therapeutic approaches for, 1745-1747 nystagmus with, 92 perfusion MRI of, 189-190, 1696 physical findings with, 1200 positron emission tomography of, 196, 1696 proliferation antigens in, 1691 radiation therapy for, 1698 cognitive effects of, 1740-1741 endocrine effects of, 1741-1743, 1742f long-term effects of, 1739-1743 risk factors for, 1693 as secondary malignancy, 1744, 1744f seizures with focal, 1048, 1695 surgery for, 1153-1154 single-photon emission computed spectography of, 196, 1696 surgery for, 1697-1698 survival rates in, 1687, 1688f, 1689t-1691t by age group, 1693, 1694f temporal course of, 1694 type, by age at diagnosis, 1693, 1725 ventricular, 1707-1709 vertigo with, 132 vision loss with, 1694 Brainstem abnormalities, and sudden infant death syndrome, 1484 dysfunction of and eye movement, 22 and facial sensation, 23 examination, in brain death determination, 1556 hypoxic-ischemic injury to, 285-287 clinical features of, 286-287 diagnosis of, 286 magnetic resonance imaging of, 282 pathogenesis of, 285-286 in systemic lupus erythematosus, 1811 Brainstem auditory-evoked responses (BAERs), 101-102, 102f, 111, 114, 242-244, 244f in autistic disorder, 244, 915-916 in brain death, 1562 in brain tumors, 1696, 1696f after cardiac arrest, 1493-1495 in coma, 1392 in meningitis, 1577 Brainstem nuclei, in migraine, 1187, 1187f Brainstem release phenomena, 258 Brainstem tumors, 1687, 1716-1718 classification of, 1718 clinical characteristics of, 1717 computed tomography of, 1717, 1718f diagnosis of, 1716 in infants and very young children, 1725 magnetic resonance imaging of, 176, 180f, 1717, 1717f management of, 1717-1718 radiation therapy for, 1718 staging of, 1716 surgery for, 1717-1718 survival rates with, 1717

Volume 2: pages 1181–2408

Index Branched-chain fatty acids oxidation, 738 Branched-chain keto-acid dehydrogenase (BCKAD) deficiency, 352-353 Brancher enzyme deficiency, 631-633, 1369-1370, 2035-2036 biochemistry of, 632, 2036 clinical manifestations of, 622t, 631-633, 2035 enzyme defect in, 622t genetics of, 632-633, 2036 glycogen structure in, 622t laboratory tests in, 632, 2035 management of, 633, 2036 muscle biopsy in, 2036 pathology of, 632 Branchial arch(es), 437-438 Branchial arch malformation syndrome, 106 Bratton-Marshall test, 359 Breast assessment, in gestational age estimation, 53t, 57t Breast-fed infants drug exposure via, 2196-2197 flavor perception in, 145-146 smell perception in, 145 taste perception in, 141 vitamin B12 deficiency in, 2312 vitamin D deficiency in, 2315 vitamin K deficiency in, 2318 Breath-holding spells, 1203-1206, 1212 age of onset, 1203 anemia and, 1205 autonomic function and, 1205 cardiorespiratory control and, 1205 chemosensitivity and, 1204 classification by color change, 1203 clinical features of, 1203 clinical laboratory tests in, 1204 complications of, 1203 cyanotic, 1203-1205, 1212 EEG findings in, 240, 1204 frequency of, 1203 genetics of, 1205-1206 incidence of, 1203 iron deficiency and, 1205-1206, 2322 pallid, 1203, 1205, 1212 pathophysiology of, 1204-1205 polysomnography in, 1204-1205 REM sleep patterns and, 1204-1205 treatment for, 1206 Breathing disturbances, sleep-related, 1229-1231. See also Sleep apnea Breech presentation, and birth trauma, 334, 340 Bright, Richard, 2233 Bright light therapy, for delayed sleep phase syndrome, 1234 Brill-Zinsser disease, 1641t, 1643-1644 Broader autism phenotype, 905, 918 Broca’s aphasia, 822t Brodmann’s areas, 1241 Brown-Séquard syndrome, 1539 Brown-Vialetto-Van Laere syndrome, 1870 Browsers, Internet, 2400 Bruck’s syndrome, 463 Brudzinski’s sign, 1386, 1573, 1596-1597 Bruininks-Oseretsky Test of Motor Proficiency (BOTMP), 805 Bruits, intracranial, in infants, 38, 50 Bucket drowning, 1485-1486 Bulbar paralysis of childhood, progressive, 1869-1870 Bulbospinal muscular atrophy, juvenile-onset, 1870 Bunyaviruses, 1595b, 1603t, 1616 Buphthalmos, in neurofibromatosis type 1, 774, 774f

Bupropion, 953-954 for ADHD, 879t, 953-954 adverse effects of, 954 clinical applications of, 953 clinical management of, 954 dosage of, 953t, 954 drug interactions of, 954 labeled and off-labeled use of, 938t, 953 mechanism of action, 953 pharmacodynamics of, 953t pharmacokinetics of, 953t pharmacology of, 953 preparations of, 953t Burning feet, in uremic neuropathy, 2248-2249 BuSpar. See Buspirone Buspirone, 957 adverse effects of, 957 versus benzodiazepines, 957 clinical applications of, 957 clinical management of, 957 dosage of, 957 drug interactions of, 957 pharmacology of, 957 Buttock injections, adverse reactions to, 2194 Butyrophenones for cyclical vomiting syndrome, 2286 toxicity of, 2188-2189

C C wave in electroretinography, 245 in intracranial pressure, 1515 CA repeats, 519 CA3 pyramidal cells, 997-998, 998f Cachexia, in Farber’s disease, 677, 677f CACNA1H gene, in generalized epilepsy, 1011 Café au lait spots in Maffucci’s syndrome, 786 in McCune-Albright syndrome, 458 in mental retardation/developmental delay, 813b in neurofibromatosis type 1, 772-773, 772f Caffeine and migraine, 1195 nephrotoxicity of, 2265 for orthostatic hypotension, 2143 teratogenicity of, 2198 Cajal-Retzius cells, 398-399 Calcidiol, 2315. See also Vitamin D Calciferol, 2314. See also Vitamin D Calcifications basal ganglia in developmental disorders, 840t in Fahr’s disease, 1286-1287, 1287f intracranial computed tomography of, 171, 172f in toxoplasmosis, 1655, 1655f in Sturge-Weber syndrome, 783, 783f Calcineurin, in muscle development, 1837-1838 Calcitriol, 2314-2315. See also Vitamin D Calcium, 2327 abnormal concentrations of, 2327-2328 absorption of, 2327 CSF concentration versus plasma, 154t in Duchenne muscular dystrophy, 1974 in epilepsy, 208 extracellular concentration of, 2327 for hyperkalemia, 2235 in hypoxic-ischemic injury, 297f, 1473-1475, 1474f, 1502-1503 in muscle contraction, 1840, 1848-1850 in nephropathic cystinosis, 2263 in renal failure, 2244 in renal Fanconi syndrome, 2263 in spinal cord injury, 1542, 2357-2358 Volume 1: pages 1–1180

Volume 2: pages 1181–2408

xv

Calcium continued in status epilepticus, 1092-1093 in traumatic brain injury, 1405-1406 in uremic encephalopathy, 2235-2236 Calcium channel(s) depolarizing conductances in, 994 in Duchenne muscular dystrophy, 1974-1975 in epilepsy, 992-994, 1001 low-threshold (T-type), in absence seizures, 999-1000, 999f, 1028 as therapeutic target, 1002-1004, 1003f hyperpolarizing conductances in, 994 in immature brain, and seizure susceptibility, 1001 in Lambert-Eaton myasthenic syndrome, 1956-1957 in neuromuscular transmission, 1847-1848 in paroxysmal disorders, 1220 stretch-activated and stretch-inactivated, 1974 voltage-gated, 992-994, 994t Calcium channel blockers for absence seizures, 999-1000 for alternating hemiplegia of childhood, 1190, 1288 for cluster headache, 1199 for hypoxic-ischemic injury, 1502-1503 for migraine prevention, 1194t for moyamoya disease, 1773 for neuroprotection, in hypoxic-ischemic injury, 291 for Raynaud’s phenomenon, 1816 in renal failure, action and effects of, 2268 for spinal cord injury, 1542 Calcium channel periodic paralysis, 2095t Calcium gluconate for hyperkalemia, 2327 for hyperkalemic periodic paralysis, 2096 for hypermagnesemia, 2329 California encephalitis. See La Crosse encephalitis Caloric stimulation, 24, 123-124, 127b, 128, 1213, 1554b in brain death determination, 1553 in comatose patient, 1387 Calpain(s) in hypoxic-ischemic injury, 1475 in muscular dystrophy, 1840, 1988t, 1989-1991 Calpain-3, 1970f, 1979 diseases associated with, 1842t in limb-girdle muscular dystrophy, 1988t, 1989-1991 Calsequestrin, 1841, 1848 Calvarial vault reconstruction, 452-453 Campath-IH (alemtuzumab), for multiple sclerosis, 1350 Campylobacter jejuni, 2291 and Guillain-Barré syndrome, 1927, 1927t, 2291 and neuropathy, 1923-1924 Canavan, Myrtelle, 1360 Canavan’s disease, 592-593, 1360-1364 biochemistry of, 1362 clinical manifestations of, 593, 1360-1361 clinical studies of, 1361-1362 computed tomography in, 1361-1362 congenital type, 1361 diagnosis of, 593 genetics of, 1362-1363 infantile onset, 1361 juvenile variant, 1361 magnetic resonance imaging in, 176, 593, 593f, 1361f, 1362 pathology of, 1362, 1362f prenatal diagnosis of, 593, 1363 proton MR spectroscopy in, 182 subclassification of, 1360-1361 treatment of, 1363-1364

xvi

Index

Cancer. See also specific types and anatomic sites future directions in, 1747-1749 new therapeutic approaches in, 1745-1747 Cancer Chemotherapy National Service Center, 1698-1699 Candida, 1631, 1638. See also Candidiasis Candida albicans, 1638, 1639f Candida lusitaniae, 1638 Candida parapsilosis, 1638 Candida tropicalis, 1638 Candidiasis, 1638 causative agent of, 1638, 1639f clinical characteristics of, 1638, 1639f CNS syndromes in, 1632t diagnosis of, 1632t, 1638 geographic distribution of, 1632t laboratory tests in, 1638 in leukemia, 1738 management of, 1632t, 1638 myositis in, 2082-2083 in premature infants, 1631 in renal transplant patients, 2250 risk factors for, 1632t Cannabis, 2186-2187 Captopril for autonomic dysreflexia, 2362 for hypertension, 2241 Caput medusae pattern, 1793, 1793f Caput succedaneum, 48-49, 335, 1402f Carbachol, for pandysautonomia, 2144 Carbamate insecticides, 2182-2183 Carbamazepine, 961-962 absorption of, 1112, 1112f adverse effects of, 959t, 962, 1022, 1122-1124, 2264-2265 pharmacogenetics of, 2195 as antiepileptic agent, 1051t, 1112-1113 behavioral and cognitive effects of, 1175 for focal seizures, 1050 for generalized seizures, 1022, 1023t for idiopathic epilepsy, 1050 in leukemia, 1737 mechanism of action, 1002, 1003f, 1119t for neonatal seizures, 271 in systemic lupus erythematosus, 1814 testing of, procedures for, 1002 in traumatic brain injury, 1427, 1435 in uremic encephalopathy, 2238 autoinduction of, 1112-1113 baseline assessments for, 959t, 962 bioavailability of, 1106t, 1112 blood level of, 1051t in breast milk, 2196-2197 chorea induced by, 1279-1280 clinical applications of, 961 clinical management of, 962 dosage of, 962, 1022, 1051t, 1112-1113 initial maintenance, 1108t loading, 1109t drug concentration of, 1122 drug interactions of, 962, 1022, 2195-2196, 2218 for DYT1 dystonia, 1282 elimination of, 1108t, 1112-1113 for episodic ataxia type 1, 2103 exacerbation of myoclonic seizures by, 1031, 1074t extended-release, 961-962, 1022 for Fabry’s disease, 670 formulations of, 1106t hypersensitivity to, 1125 immediate-release, 961-962, 1022 labeled and off-labeled use of, 938t for Lesch-Nyhan disease, 1286 lupus syndrome induced by, 1811-1812

Carbamazepine continued metabolism of, 1108t monitoring of, 959t, 962, 1022 as mood stabilizer, 959t, 961-962 and myoclonus, 1295 for myotonia congenita, 2093 for myotonic dystrophy type 2, 2090 nephrotoxicity of, 2264-2265 for neuronal ceroid lipofuscinosis, 703 for nocturnal paroxysmal dystonia, 1235 for nonepileptic paroxysmal disorders, 1213t, 1214, 1297 optimal range of, 1117t for pain, 2378 for peripheral nerve hyperexcitability, 2105 pharmacokinetics of, 1106t, 1108t, 1112-1113 pharmacology of, 961-962, 1022 practical guide to, 1051t preparations of, 959t, 1051t, 1112, 1112f protein binding of, 1108t, 1112 in renal failure, action and effects of, 2267 for Rett’s syndrome, 1321 routes of administration, 1106t, 1119, 1120t for Schwartz-Jampel syndrome, 2099, 2102 and sleep, 1234 for Sydenham’s chorea, 1279, 2225 teratogenicity of, 367, 2197-2198, 2320 volume of distribution, 1108t, 1112 Carbamyl phosphate synthetase deficiency of, 603, 605, 718 treatment of, 604t, 605, 611-612 in urea cycle, 603, 604f Carbatrol. See Carbamazepine Carbidopa for biopterin disorders, 575 for Segawa’s disease, 762 for sepiapterin reductase deficiency, 763 for tyrosine hydroxylase deficiency, 764-765 Carbidopa-levodopa, 1288 for parkinsonism, 1293 for restless legs syndrome, 1233 Carbohydrate metabolism abnormalities of, 617-637 disorders of cognitive and motor regression in, 826t hypoglycemia with, 348t Carbon dioxide, in CSF formation, 154, 154f Carbon monoxide, in hypoxic-ischemic injury, 283 Carbon monoxide poisoning, diffusion-weighted imaging in, 187 Carbonic acid, in CSF formation, 154, 154f Carbonic anhydrase, in CSF formation, 154-155, 154f Carbonic anhydrase III, 1852 Carbonic anhydrase inhibitors and CSF formation, 155 for hypokalemic periodic paralysis, 2098 for idiopathic intracranial hypertension, 1200 Carboplatin for ependymoma, 1716, 1729 for optic pathway tumors, 1703 for pineal region tumors, 1705 for primitive neuroectodermal tumor, 1729 for spinal cord tumors, 1734 Carboxylase deficiencies, multiple, 589-592, 723, 1247t Cardiac arrest, 1471-1506 biochemical markers after, 1495 clinical outcome in, 1480-1482, 1481t prediction of, laboratory tests for, 1492-1497 delayed posthypoxic injury after, 1492 EEG findings after, 1493 endogenous defenses in, modulation of, 1501 epidemiology of, 1471 Volume 1: pages 1–1180

Cardiac arrest continued etiology of, 1471, 1472b, 1472t evoked potentials after, 1493-1495, 1494f hospital care in, 1498-1501 intracranial pressure in, 1498-1499 magnetic resonance spectroscopy after, 1495-1497, 1496f-1497f major disorders causing, 1482-1491 morbidity and mortality in, 1480-1482, 1481t neuroimaging after, 1495-1497 neurologic complications after, 1492, 1506 neurologic examination after, 1492-1493 post-ischemic seizures after, 1492 prehospital care in, 1497-1498 resuscitation for, metabolism and cerebral blood flow after, 1479-1480 sudden, in children and adolescents, 1491-1497 treatment for, 1497-1505 Cardiac arrhythmia, periodic paralysis with, 2095t, 2099-2100, 2099f Cardiac catheterization, and stroke, 1767 Cardiac surgery, neurologic complications of, 2207-2220 cerebrovascular, 1767, 2210-2211, 2216-2219 delayed postoperative, 2216-2220 delayed recovery of consciousness, 2211-2212 early postoperative, 2211-2216 hypoxic-ischemic injury, 2208-2209, 2208b, 2211-2212 mechanisms of, 2208-2210 intraoperative, 2208-2209, 2208b, 2210f perioperative, 2209-2210, 2210f movement disorders, 2213-2215 peripheral neuropathy, 2215-2216 preoperative, 2210-2211 seizures, 2212-2213, 2212f spinal cord injury, 2215 vaso-occlusive insults, 2209, 2209f Cardioembolic stroke, 2216f, 2217 Cardiofacial syndrome, 23, 1889 Cardiogenic stroke, 2216-2219 echocardiography of, 2217f epidemiology of, 2216 mechanisms of, 2216f, 2217 postoperative factors in, 2217-2218 prevention of, 2218 risk factors for, 2216-2217 Cardioinhibitory syncope, 2149 Cardiolipin, 728 Cardiomyopathy in Duchenne muscular dystrophy, 1978, 1980 in Friedreich’s ataxia, 1249 McLeod’s, 1995 in phosphorylase kinase deficiency, 2028 Cardiopulmonary bypass, 2207 vaso-occlusive insults in, 2209, 2209f Cardiopulmonary resuscitation, 1497-1498 metabolism and cerebral blood flow after, 1479-1480 Cardiovascular-mediated syncope, 1210 Care-based ethics, 2390-2391 Carmustine for primitive neuroectodermal tumors, 1723 teratogenicity of, 2198 Carnitine concentrations, in fatty acid oxidation disorders, 2039, 2040t, 2042-2044 for myoclonic seizures, 1075 Carnitine cycle, 721, 721f defects of, 355-356, 717-718, 721-723, 917-918 Carnitine palmitoyl transferase I deficiency, 718, 722-723 in myopathies, 2024-2025

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Index Carnitine palmitoyl transferase II deficiency, 355-356, 718, 721-723 clinical features of, 350t-351t histopathology of, 718 MRI findings in, 352t Carnitine supplementation, 730 for 3-methylcrotonyl-CoA carboxylase deficiency, 589 for fatty acid oxidation defects, 2047-2048 for glutaric aciduria type 1, 595 with hepatotoxic drugs, 2301 for isovaleric acidemia, 589 with ketogenic diet, 1144 for β-ketothiolase deficiency, 592 for methylmalonic acidemia, 588 for nephropathic cystinosis, 2264 for phenylketonuria, 574 for propionic acidemia, 587 for Rett’s syndrome, 1321 Carnitine uptake studies, 2046 Carnitine-acylcarnitine translocase deficiency, 722-723 Carotenoids, 2305 Carotid artery dissection, 1769 Carotid artery stenosis, in neurofibromatosis type 1, 775 Carotid sinus hypersensitivity, 2149-2150 Carotid sinus massage, 2150 Carpal tunnel syndrome, osteopetrosis and, 456 Carpenter’s syndrome, 444, 451 clinical features of, 442t, 451 genetics of, 442t, 451 Caspase-3, in hypoxic-ischemic injury, 304, 1501-1502 Caspofungin for aspergillosis, 1638 for candidiasis, 1638 for phycomycosis, 1640 Casuistry, 2390-2391 Catabolism, muscle, 1852 Catalase, peroxisomal, 735, 737 disorders of, 743t, 744 Cataplexy in narcolepsy, 1231-1232 in Niemann-Pick disease, 675-676 treatment of, 1232 Catapres. See Clonidine Cataract(s) in cerebrotendinous xanthomatosis, 1367 congenital, 82 galactokinase deficiency and, 620 galactosemia and, 82, 618-620 in developmental disorders, 838t in mental retardation/developmental delay, 812b in myotonic dystrophy type 2, 2089-2090 Catastrophic neonatal epilepsy syndromes, 266 CATCH-22 spectrum, 2224 Catecholamines, 2129, 2130f in autonomic dysfunction, 2136, 2138f in hepatorenal syndrome, 2258 β-Catenin, in megalencephaly, 408 Cathepsin A deficiency, 659, 694 Catheters for micturition disorders, 2165 for monitoring intracranial pressure, 1423, 1515-1516 in spinal cord injury, 2358 Cat-scratch disease, 1590 Cauda equina, 1528 injuries of, 1540 tumor of, 1731f, 1732 Cauda equina syndrome, 2163 Caudal regression syndrome, 374-375, 374f Caudate nucleus, 1272, 1273f in ADHD, 874

Caveolin, 1843-1844, 1970f, 1979 in limb-girdle muscular dystrophy, 1988t, 1989 Caveolin-3, 1969, 1970f diseases associated with, 1842t, 1844, 1988t in limb-girdle muscular dystrophy, 1988t, 1989 Cavernous angioma, susceptibility-weighted imaging of, 191, 192f Cavernous malformations, 1792f, 1793 Cavum septum pellucidum, 384f, 385 Cayler’s (cardiofacial) syndrome, 23, 1889 Cayman type ataxia, 1253-1254 age of onset, 1248t genetics of, 1248t, 1253-1254 CCNU for astrocytoma, 1721 intra-arterial delivery of, 1746 for medulloblastoma, 1711 for oligodendroglioma, 1724 for spinal cord tumors, 1734 CDKL5 gene, and lissencephaly, 415 Cefotaxime for actinomycosis, 1637 for bacterial meningitis, 1580t, 1581 for Lyme disease, 1588 Ceftazidime, for bacterial meningitis, 1580t Ceftriaxone for actinomycosis, 1637 for bacterial meningitis, 1580t, 1581 for brain abscess, 1589 for Lyme disease, 1588 Celexa. See Citalopram Celiac disease, 2288-2289 immunology of, 2288-2289 management of, 2289 neuropathology of, 2289 neuropsychiatric symptoms of, 2289 pathogenesis of, 2289 Cell cycle, 513-515 chemotherapy specificity in, 1699 Cell death. See also Apoptosis in arterial ischemic stroke, 1762-1763 in hypoxic-ischemic injury, 303f, 304, 1472-1473, 1473b, 1479, 1501-1502 in muscle development, 1838 in traumatic brain injury, 1407 Cellcept. See Mycophenolate mofetil Center Watch, 2404 Central Brain Tumor Registry of the United States (CBTRUS), 1687, 1688f, 1692 Central core disease, 2015-2016 clinical features of, 2015 genetics of, 2015-2016, 2018t pathology of, 2015 protein accumulation in, 2015, 2016t Central facial nerve palsy, 1887 Central herniation, 1389, 1410, 1518 Central hyperthyroidism, 2122 Central hypothyroidism, 2121-2122 Central hypotonia, 69, 1871 Central hypoventilation syndrome, 1231 Central nervous system normal embryonic development of, 364-365, 364t structural defects of, 363-469. See also specific defects Central pontine myelinolysis, 2298, 2325 Central sleep apnea, 1230f Central spine syndrome, 1538 Central transtentorial herniation, 1410 Central venous thrombosis, 329-330, 330f Centromeres, 516, 541-542, 543f Centronuclear myopathy, 2017-2018 clinical features of, 2017 genetics of, 2018 pathology of, 2017-2018 Volume 1: pages 1–1180

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Centrotemporal spikes, benign childhood epilepsy with, 1014, 1044-1045 Cephalocele(s). See Encephalocele(s) Cephalohematoma(s), 48-49, 335, 1402f in inflicted neurotrauma, 1452 outcome of, 338 plain radiography of, 335, 335f skull fracture with, 335-336 subdural hematoma with, 337 versus subgaleal hematoma, 335-336 ultrasound of, 335 Cephalosporin(s) for bacterial meningitis, 1581 for Lyme disease, 1588 Cerebellar astrocytoma(s), 1712-1714 chemotherapy for, 1714 clinical characteristics of, 1712-1713 cystic, 1712 diagnosis of, 1713 distribution of, 1712 gross appearance of, 1712, 1712f histopathology of, 1712 incidence of, 1712 in infants and very young children, 1725 management of, 1713-1714 microscopic appearance of, 1712 prognostic factors in, 1713 radiation therapy for, 1714 surgery for, 1713-1714 survival rates in, 1714 Cerebellar ataxia. See Ataxia(s) Cerebellar atrophy, versus cerebellar hypoplasia, 389 Cerebellar cognitive affective syndrome, 1246 Cerebellar dysarthria, 1244 Cerebellar gait, 72-73 Cerebellar hemangioblastoma, in von HippelLindau syndrome, 784 Cerebellar herniation syndromes, 1389-1390, 1403f Cerebellar hypoplasia, 389 versus cerebellar atrophy, 389 clinical features of, 389 conditions associated with, 389t, 390b lissencephaly with, 389t, 413-414, 413f, 464t sporadic nonsyndromic, 389 Cerebellar injury, hypoxic-ischemic, 285-287 magnetic resonance imaging of, 286 Cerebellar peduncles, 1242-1243, 1242f Cerebellar plate, 380 Cerebellar theory, of dyslexia, 856 Cerebellar tonsillar herniation, 453, 1403f, 1410, 1518, 1694 Cerebellar tumor(s) diagnosis of, 1695 magnetic resonance imaging of, 176-177, 181f Cerebellar vermis hypoplasia, 390-391 in Dandy-Walker syndrome, 391-393, 392f, 393 in Joubert’s syndrome, 390-391, 391f management of, 391 syndromes with, 389t, 390-391 Cerebellum, 1241-1246. See also Cerebellar entries in ADHD, 875 development of, 364t dysfunction of, 1244-1246. See also Ataxia(s) management of, 1247-1264 vertigo with, 132-133 function of, 1243-1244 assessment of in infant, 40 in older child, 19 in vestibular dysfunction (vertigo), 125 histology of, 1241, 1243f

xviii

Index

Cerebellum continued malformations of, 387-398. See also specific malformations in Rett’s syndrome, 1317 sensorimotor representation of, 1241-1242, 1244f structure of, 1241-1243, 1242f-1244f tumors of, 1687 Cerebral arteries, 1760-1762, 1761f-1762f Cerebral autosomal dominant arteriopathy subcortical infarcts and leukoencephalopathy (CADASIL), 1369 Cerebral blood flow in arterial ischemic stroke, 1762-1763 in brain death, measurements of, 1559-1562, 1559t, 1560f in coma, 1392-1393 in hypoxic-ischemic injury, 297, 299, 1504 after resuscitation, 1479-1480 intracranial pressure and, 1514-1516 in intraventricular hemorrhage, 310-311, 310b in meningitis, 1577 pressure passive, in preterm infants, 299, 310 in traumatic brain injury, 1406, 1430-1431 velocity of, Doppler measurement of, 1516 Cerebral contusion, 1402f, 1403, 1414 computed tomography of, 1414, 1414f in inflicted neurotrauma, 1457-1458, 1458f Cerebral cortex. See also Cortical entries in ADHD, 874 developmental malformations of, 398-425, 840t-841t. See also specific types of cell proliferation, 400-410 classification of, 398 epidemiology of, 400 epilepsy surgery for, 1152, 1155, 1163-1164 and focal seizures, 1048 MRI of, 1157, 1158f of neuronal migration, 410-420 organizational, 420-425 with severe microcephaly, 405 embryology of, 383, 398-400, 399f hyperexcitable, in migraine, 1187 neuronal populations of, 399 spreading depression, in migraine, 1187, 1187f Cerebral dysgenesis, with congenital heart disease, 2219f, 2220 Cerebral edema. See also Intracranial pressure, increased cytotoxic, 1513-1514, 1576 in diabetic ketoacidosis, 1523 diffuse, 1410-1411 galactosemia and, 619 in hepatic encephalopathy, 2294, 2297 hydrostatic, 1513-1514 in hypertensive encephalopathy, 2241-2242 in hypoxic-ischemic injury, 280 control of, 291 cortical or subcortical, 284, 284f parasagittal, 285 in inflicted neurotrauma, 1456-1457 malignant, 1417, 1417f in maple syrup urine disease, 352, 580 in meningitis, 1576 pathophysiology of, 1513-1514 severe, 1518, 1518f vasogenic, 1513-1514, 1576 in water intoxication, 2234 Cerebral hemisphere(s), 1241, 1242f embryology of, 383, 398-400, 399f Cerebral hemorrhage. See also Intraventricular hemorrhage

Cerebral hemorrhage continued CSF protein content with, 162t magnetic resonance imaging of, 177-178, 181f Cerebral infarction in arterial ischemic stroke, 1762-1765. See also Arterial ischemic stroke computed tomography of, 171, 171f, 174f, 1765 diffusion-weighted imaging of, 187, 189 EEG studies of, 228 extracorporeal membrane oxygenation and, 2225-2226 in hypertensive encephalopathy, 2241 in inflicted neurotrauma, 1454f, 1456f, 1458 large-vessel, 1763-1764, 1764f magnetic resonance angiography of, 188f, 189 magnetic resonance imaging of, 175, 177, 1764f-1766f in meningitis, 1583 periventricular hemorrhagic, 287 clinical features of, 287 diagnosis of, 287 pathogenesis of, 287 ultrasound of, 287, 288f recognition of, 1765 small-vessel, 1763-1765, 1765f-1766f Cerebral mycotic aneurysms, 2221 Cerebral palsy, 491-500 ataxic, 499-500 athetoid, 498-499, 1282 and chorea, 1279 choreoathetotic, 498-499, 1276 chorioamnionitis and, 493-494 classification of, 495-496 functional, 496 clinical characterization of, 491 clinical features of, 494-495 definition of, 491 developmental abnormalities and, 493 diagnosis of, 494-495 dystonic, 499, 1276, 1284 epidemiology of, 491-492 etiology of, 492-494, 492t evaluation of, 494, 495f extrapyramidal, 498-499 functional deficits in, 2359, 2359t hypotonic (atonic), 499 hypoxic-ischemic injury and, 279, 286, 292, 492-494 intraventricular hemorrhage and, 315, 320-323, 494 Little’s description of, 497 mixed, 500 motor function in, 1275, 2359, 2359t prognosis for, 500, 501f MRI findings in, 495, 495f multiple gestation and, 491 neonatal encephalopathy and, 492 neonatal stroke and, 492-493 neurologic impairments in, 491 pain in, 2378 pathogenesis of, 493-494 pathologic features of, 494 perinatal brain injury and, 492-493 periventricular leukomalacia and, 315, 322 physical therapy for, 2359-2360, 2359f postnatal brain injury and, 494 prenatal risk factors for, 492t, 493-494 in preterm infants, 491, 493 prevalence of, 491 progressive disorders misdiagnosed as, 823, 825t race/ethnicity and, 491-492 rehabilitation in, 2359-2360 sialorrhea in, 2362 spastic, 496-498 sleep in, 1234 Volume 1: pages 1–1180

Cerebral palsy continued specific syndromes of, 496-500 in term infants, 491 treatment planning in, 2360 ultrasound in, 322 ventriculomegaly and, 322 Cerebral perfusion in arterial ischemic stroke, 1762-1763 in brain death, measurements of, 1559-1562, 1559t, 1560f in hypoxic-ischemic injury, maintenance of, 290 intracranial pressure and, 1514-1516 in meningitis, 1577 Cerebral perfusion pressure definition of, 1424 in traumatic brain injury, 1424, 1430-1431 Cerebral salt wasting syndrome, in craniosynostosis, 454 Cerebral sinuses, 1781-1782, 1782f Cerebral venous thrombosis, 2216f, 2217 Cerebral ventricle(s), fourth, dilation, in DandyWalker syndrome, 391-392, 392f Cerebral visual impairment, 91-92 Cerebrocerebellum, 1243 Cerebrohepatorenal syndrome. See Zellweger’s syndrome Cerebrospinal fluid, 153-163 absorption of, 155, 426 analysis of, 159-163 in brain abscess, 1575t, 1588 in chronic inflammatory demyelinating neuropathy, 1894, 1930t in Guillain-Barré syndrome, 1925 in impaired consciousness/coma, 1390 in intracranial hypertension, 1200, 1519-1520 in intraventricular hemorrhage, 320 in meningeal leukemia, 1735 in meningitis, 156, 160-161, 162t, 1574-1575, 1575t in multiple sclerosis, 162-163, 1347-1348 in muscular tone disorders, 69 in Rett’s syndrome, 1316-1317 in spinal cord injury, 1537 in spinal cord tumor, 162t, 1731 in traumatic brain injury, 1420 in viral infections, 1600-1601, 1600t, 1602, 1602t appearance of, 159 bacterial infections of, 1572, 1574 cells/cell counts in, 159-160, 159t diagnostic sampling of, 156 complications of, 158-159 contraindications and cautions in, 156 and headache, 158-159 herniation after, 156 history of, 153 indications for, 156 and intracranial hypotension, 158-159, 158f needles for, 157, 157f normal pressures in, 157 patient positioning for, 156-157, 156f procedure for, 156-158 Queckenstedt test in, 157 slow flow in, methods for increasing, 157 tube collection in, 157-158 drainage, in traumatic brain injury, 1424-1425 excess of. See Hydrocephalus flow of, 155, 155f, 426, 426f formation of, 153-155, 154f, 426 maintenance of, 155 rate of, 155 function of, 156 glucose in, 160-161 immunologic testing of, 160, 162-163, 162f

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Index Cerebrospinal fluid continued microorganisms in, 160 neurometabolic studies of, 163 neurotransmitters in, 163 organic acid analysis of, 163 osmolality of, 154t protein content of, 160f, 160t, 161-162 as brain injury marker, 161-162 in neurologic disorders, in adults, 162t “sink action” of, 156 solute concentrations in, versus plasma, 153, 154t Tyndall’s effect in, 159 yellowish discoloration of (xanthochromia), 159-160 Cerebrotendinous xanthomatosis, 1367-1369 clinical features of, 1367 neuroimaging in, 1367 treatment of, 1367-1369 Cerebrovascular disease, 1759-1795. See also Stroke in cardiac patients, 2220-2221, 2221f postoperative, 2216-2219 preoperative, 2210-2211 and focal seizures, 1049 in systemic lupus erythematosus, 1771, 1810 Ceruplasmin, in Menkes’ disease, 1321-1322 Cervical nerve, 28t Cervical plexus, 28t Cervical spinal cord injury, 1527-1528 perinatal, 339 Cervical spine, 1527, 1528f Cervical traction, for spinal cord injuries, 1543-1544 Cervical vertebrae, fusion, in Klippel-Feil syndrome, 454-455 Cervicomedullary syndrome, 1538 Cesarean delivery and birth trauma, 335 and intraventricular hemorrhage, 324 in spina bifida, 370 Cestode infections, 1646, 1664, 1668-1671. See also specific infections classification of, 1648t clinical characteristics of, 1648t diagnosis of, 1648t geographic distribution of, 1648t management of, 1648t mode of infection, 1648t pathology of, 1648t risk factors for, 1648t C-fibers, in pain, 2373 Chagas’ disease, 1661-1662 autonomic dysfunction in, 2152 classification of, 1647t clinical characteristics of, 1647t, 1661-1662 diagnosis of, 1647t, 1661-1662 epidemiology of, 1661 geographic distribution of, 1647t, 1661 laboratory tests in, 1661-1662 management of, 1647t, 1662 mode of infection, 1647t, 1661 pathology of, 1647t risk factors for, 1647t Chain termination mutations, 531 Channelopathy(ies), 267 in paroxysmal disorders, 1220 with periodic paralysis, 2094-2105, 2094t-2095t of skeletal muscle, 2085-2105 Character ethics, 2390 Charcot-Marie-Tooth disease, 1897-1901 clinical characteristics of, 1897 congenital axonal, 1899 genetics of, 556t subclassifications of, 1895t-1897t, 1898 type I, 1897-1899

Charcot-Marie-Tooth disease continued clinical characteristics of, 1898 clinical neurophysiology of, 1898 genetics of, 1897-1898 management of, 1898-1899 pathology of, 1897-1898, 1897f type Ic, 1897 type Id, 1897 type II, 107, 728, 1899 type III, 1899-1900 type IV, 1900 type V, 1900 type VI, 1900 type VII, 1900 X-linked dominant, 1900-1901 clinical manifestations of, 1900 clinical neurophysiology of, 1900-1901 genetics of, 1901 X-linked recessive, 1901 CHARGE association, 83, 83f, 108t, 464t Checklist for Autism in Toddlers, 913 Chédiak-Higashi syndrome, 85, 1909 Chelating agents for hypoxic-ischemic injury, 301-302, 1504 for lead poisoning, 2184 for malaria, 1659 for mercury poisoning, 2184 for neuropathy, 1910 for spinal cord injury, 1543 Chemical irritation, 135-136 Chemical senses, 135-136. See also Smell; Taste Chemical shift, 178, 184f Chemical shift selective saturation (CHESS), 178 Chemical warfare, 2174 Chemotherapy. See also specific agents and disorders for brain tumors, 1698-1699 cognitive effects of, 1740-1741 intra-arterial delivery of, 1746 and leukoencephalopathy, 1743-1744, 1743f neuropathy induced by, 1910 new approaches in, 1746-1747 resistance to, 1746-1747 and secondary malignancies, 1744 teratogenicity of, 2198 toxicity of, 2192-2194 Chenodeoxycholic acid, for cerebrotendinous xanthomatosis, 1367-1369 Cherry-red macula in developmental disorders, 838t in galactosialidosis, 694 in GM1 gangliosidosis, 666 in mental retardation/developmental delay, 812b in Niemann-Pick disease, 674 in poisoning, 2175 in Tay-Sachs disease, 667, 667f Cherry-red spot myoclonus syndrome, 240, 692-694, 1072t, 1073-1074 Chest deformities, 67 Chest pain, in coccidioidomycosis, 1633 Chest physiotherapy, in spinal cord injury, 1544 Chiari I malformation, 375, 375t, 387-389 versus Chiari II type, 388 clinical characteristics of, 388-389 definition of, 387-388 hydromyelia with, 1862 magnetic resonance imaging of, 388, 388f management of, 389 pathophysiology of, 388 sleep-wake disorders with, 1227 syringomyelia with, 388-389, 1861-1862 Chiari II malformation, 375-376 with basilar impression, 461 Volume 1: pages 1–1180

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Chiari II malformation continued versus Chiari I type, 388 classification of, 375, 375t clinical characteristics of, 376, 376t with corpus callosum agenesis, 387 imaging of, 370 major features of, 375, 375f management of, 376 with myelomeningocele, 369-372, 375 pathophysiology of, 375-376 prevention of, 370 and sleep-wake disorders, 1227 type I, vertigo with, 132 type II, computed tomography of, 175f Chiari III malformation, 375, 375t, 388 Chiari IV malformation, 375, 375t Chicken pox. See Varicella-zoster virus Child abuse coma in, 1386 computed tomography in, 173, 176f, 1412, 1412f, 1447, 1447f, 1453f-1456f, 1456-1457, 1462-1463 diffusion-weighted imaging in, 187 hypoxic-ischemic injury in, 1489 intracranial hemorrhage in, 1790 versus osteogenesis imperfecta, 463-466, 1460 poisoning in, 2173-2174 traumatic brain injury in, 1411-1412, 1445-1464, 2355 acute presentation of, 1447-1448 autonomic and neuroendocrine responses in, 1461 biochemical markers in, 1461-1462 biologic factors in, 1446, 1446b versus birth trauma, 1460 cerebral contusions in, 1457-1458, 1458f cerebral injuries in, 1456-1457 chronic subdural effusions in, 1454f, 1455, 1455f clinical assessment and management of, 1460-1462 clinical features of, 1447-1449 computed tomography of, 1447, 1447f, 1453f-1456f, 1456-1457, 1462-1463 diagnosis of, 1462-1464 differential diagnosis of, 1458-1460 diffuse axonal injury in, 1457 epidural hematoma in, 1455-1456 extra-axial collections in, 1453-1456 extracranial injuries in, 1452-1453 factors associated with, 1463b versus falls, 1458-1460 general examination in, 1460-1461 historical perspective on, 1445 history of injuries in, evaluation of, 1463 incidence of, 1445 intracranial injuries in, 1453-1458 key questions in evaluation of, 1462b laboratory evaluation in, 1461-1462 lucid interval issues in, 1463 markers of, 1449b mechanical factors in, 1446, 1446b mechanisms of injury, 1446-1447 medicolegal issues in, 1463-1464 versus metabolic disorders, 1460 morbidity and mortality in, 1445 neuroimaging in, 1447, 1447f, 1463 neurologic examination in, 1461 ocular injuries in, 1450-1452 optic nerve sheath hemorrhage in, 1452 pathology of, 1449-1458, 1450f predisposition of immature neuraxis to, 1445-1446, 1446b radiographic evaluation of, 1462 retinal and optic nerve sheath differential in, 1452

xx

Index

Child abuse continued retinal hemorrhage in, 1412, 1412f, 1450-1452, 1450f-1451f sequelae of, 1448-1449 severity of, factors affecting, 1449b skull fracture in, 1452-1453, 1452f subacute or chronic presentation of, 1448 subarachnoid hemorrhage in, 1455 subdural hematoma in, 1447f, 1453-1455, 1453f-1456f subgaleal hematoma in, 1452, 1452f terminology in, 1445 timing of injuries in, 1463 Child Behavior Checklist, 871 in Tourette syndrome, 891 Child Development Inventory, 804t Child neurologists, 2360 ethical duties of, 2392-2394 Internet resources for, 2399-2407, 2402t-2404t Child Neurology Society, 2360 autism practice parameter of, 912-913 website of, 2401 Childhood Autism Rating Scale, 915 Childhood disintegrative disorder, 909 diagnostic criteria for, 909, 910b Children’s Coma Scale, 1383, 1383t Children’s Oncology Group, 1698 Chloral hydrate abuse/toxicity of, 2188 dosage of, 2378 for sedation, 206, 2378 Chloramphenicol for bacterial meningitis, 1581 neuropathy induced by, 1909 for rickettsial diseases, 1640 toxicity of, 2191 Chlordiazepoxide, for nonepileptic paroxysmal disorders, 1213t, 1214 Chloride abnormal concentrations of, 2326 in immature brain, and seizure susceptibility, 1001-1002 Chloride channel myotonia(s), 2085b, 2087, 2090-2093, 2090t versus sodium channel myotonia, 2091-2092 Chloroquine for amebiasis, 1649 for malaria, 1657, 1659 teratogenicity of, 2197t Chlorpheniramine, toxicity of, 2180 Chlorproguanil-dapsone, for malaria, 1659 Chlorpromazine anticholinergic effect of, 965t for cyclical vomiting syndrome, 2286 dosage of, 965t extrapyramidal effect of, 965t fetal/neonatal effects of, 2196 historical perspective on, 964 potency of, 965t preparations of, 965t sedative effect of, 965t for Sydenham’s chorea, 1808 Choanal atresia, in craniosynostosis, 444 Cholecalciferol, 2314. See also Vitamin D Cholesteatoma, 110 diffusion-weighted imaging of, 187-189 Cholesterol elevated levels of, and stroke, 1774 ketogenic diet and, 1144 Cholesterol biosynthesis defects, 361-362 clinical features of, 350t-351t, 361-362 MRI findings in, 352t treatment of, 362 Cholesteryl ester storage disorder, 683 Cholestyramine, for lindane poisoning, 2184

Choline-containing compounds (Cho), in proton MR spectroscopy, 179-180, 184f in hypoxic-ischemic injury, 282 Cholinergic dysautonomia, pure, 2143-2144 barium exam contraindicated in, 2143, 2143f clinical features of, 2143 differential diagnosis of, 2143-2144 sympathetic skin response in, 2137, 2139f treatment of, 2143 Cholinergic syndrome, 2178-2179 Chondrocranium, 436 Chondrodysplasia(s) clinical features of, 650t genetics of, 650t Chondroitin sulfate, 654 Chorda tympani nerve, 23, 97, 135f, 136, 143 Chorea, 1272, 1272t, 1276-1277 associated with brain injury, 1279 associated with systemic illness, 1279-1280 in ataxia-telangiectasia, 1277-1278 in cerebral palsy, 498-499 etiology of, 1276 familial benign hereditary, 1278 gait abnormalities with, 74 in Huntington’s disease, 1277 medication-induced, 1279, 1289 pathophysiology of, 1274-1275 primary, 1277-1278 secondary, 1278-1280, 1278t Sydenham’s, 1278-1279, 1806-1808, 2225-2226 in systemic lupus erythematosus, 1810, 1814 tardive, 1279, 1301-1302 treatment of, 1280 Chorea acanthocytosis. See Neuroacanthocytosis Choreiform, 1277 Choreoathetosis, 1282 in ataxia-telangiectasia, 1251 classification of, 1276 in kernicterus, 1284 in mental retardation/developmental delay, 814b paroxysmal dystonic, 1213-1214, 1296-1297 genetics of, 1214t of Mount and Reback, 1213-1214, 1296-1297 treatment of, 1213t, 1214 paroxysmal familial, 1296 paroxysmal kinesigenic, 1213-1215, 1213t, 1296-1297 etiology of, 1214-1215 genetics of, 1214-1215, 1214t treatment of, 1213t, 1214 paroxysmal nonkinesigenic, 1213-1214, 1297 postoperative, in cardiac surgery, 2213-2214 in uremic encephalopathy, 2237 Choreoathetotic cerebral palsy, 498-499, 1276 Chorioamnionitis and cerebral palsy, 493-494 and intraventricular hemorrhage, 311 and periventricular leukomalacia, 288 Choriocarcinoma, 1704 tumor markers and survival in, 1704t Chorionic villus sampling (CVS), 548-549 Chorioretinitis, in mental retardation/developmental delay, 812b Choroid plexus CSF secretion from, 153-155, 154f, 426, 426f intraventricular hemorrhage in, 314-315 Choroid plexus papilloma, computed tomography of, 172f Choroid plexus tumors, 1693, 1707-1708 hydrocephalus with, 428 in infants and very young children, 1725 management of, 1707-1708 neuroimaging of, 1707, 1707f prognostic factors in, 1707-1708 CHRNA4 gene, in focal epilepsy, 1013 CHRNB2 gene, in focal epilepsy, 1013 Volume 1: pages 1–1180

Chromatids, 541, 542f-543f Chromatin, 513, 515, 541-542, 542f Chromomeres, 516 Chromosome(s), 508, 509f, 513, 515-516, 541-561 abnormalities of, 524-529, 541, 545-561 cardiac and cerebral effects of, 2224-2225 clinical approach to, 547-549 common clues to, 548, 548t developmental impairment with, 548 incidence of, 548 and malignancy, 549 multiple congenital anomalies with, 548 nomenclature for, 529, 529t, 547, 547t prenatal diagnosis of, 537, 548-549 recurrent miscarriage with, 548 specific syndromes of, 549-561 acentric, 528 acrocentric, 516 analysis of, 520, 520f methods of, 543-545 classification of, 520 deletion of, 526, 529t, 546, 555-557, 555t-556t derivative, 525 dicentric, 528-529 duplication of, 526f, 527-528, 529t, 546, 555-557, 555t function of, 541-542 homologous, 516 identification of, 516 insertion of, 529 inversion of, 526-528, 527f, 529t, 546 long (q) arm of, 516, 541, 543f marker, 546-547 metacentric, 516 mutations of, 529 nondisjunction of, 525, 546 number of, 516, 517f, 541 abnormalities of, 524-525, 529, 546 pairing of, 514, 514f-515f rearrangements of, 525-529 balanced versus unbalanced, 525, 527 mechanisms of, 525-527 special types of, 527-529 ring, 526f, 529 short (p) arm of, 516, 541, 543f specialized regions of, 516 structure of, 509f, 515, 541-542, 542f-543f abnormalities of, 525-529, 555-561 submetacentric, 516 translocation of, 520f, 526f-527f, 528-529, 528f, 529t, 546 Chromosome 22 deletion syndromes, 2224 Chromosome breakage syndromes, 560t, 561 Chromosome painting, 544 Chromosome Xp21 microdeletion syndromes, 1987 Chronic fatigue syndrome, 2181 Chronic infantile neurologic cutaneous and articular (CINCA) syndrome, 1806 Chronic inflammatory axonal polyneuropathy, 1922t Chronic inflammatory demyelinating polyneuropathy, 1894, 1922t, 19311934 clinical features of, 1894, 1931-1932 CSF analysis in, 1894, 1930t diagnostic criteria for, 1930t electrophysiologic findings in, 1894, 1930t, 1932 epidemiology of, 1931 incidence of, 1931 laboratory findings in, 1930t, 1932 pathologic findings in, 1894, 1894f, 1932-1933, 1933f

Volume 2: pages 1181–2408

Index Chronic inflammatory demyelinating polyneuropathy continued prognosis of, 1933 treatment of, 1894, 1932-1933 Chronic inflammatory relapsing demyelinating neuropathy, 1922t Chronic regional pain syndrome, type 2, 2152 Churg-Strauss syndrome, 1822 laboratory findings in, 1818t neurologic manifestations of, 1818t, 1822 treatment of, 1822 Chvostek’s sign, 2328 Cimetidine drug interactions of, 2196 for gastroesophageal reflux, 2286-2287 nephrotoxicity of, 2265 for nonepileptic paroxysmal disorders, 1213t toxicity of, 2180 Cingulate herniation, 1403f, 1518-1519 Circadian rhythm, 1225 disorders of, 1225, 1226t, 1233-1235 and neonatal EEG sleep pattern, 222-223 Circle of Willis, 1760 Cirrhosis cognitive effects of, 2297-2298 galactosemia and, 620 with precipitant, 2294 in urea cycle disorders, 608 Cisapride, for scleroderma, 1816 Cisplatin for ependymoma, 1715-1716, 1729 and hearing loss, 110, 2193 intra-arterial delivery of, 1746 and neuropathy, 1910 for primitive neuroectodermal tumors, 1723, 1729 teratogenicity of, 2197t toxicity of, 2193 Cisternal puncture, 158 Citalopram, 948-953 for ADHD, 879t adverse effects of, 951-952, 2189 for autism, 924, 927t clinical applications of, 948-949 dosage of, 948t, 950 initiation and titration of, 950 labeled and off-labeled use of, 938t pharmacokinetics of, 948t, 949 preparations of, 948t Citrin deficiency, 603, 604f, 605-606, 605t Citrulline, in urea cycle, 603, 604f Citrullinemia, 603, 605-606 adult-onset, 603, 606 neonatal or childhood-onset, 606 treatment of, 604t, 606, 611-612 type 1/3, 606 type II, 603, 606 Citrullinuria, 605-606 Cladribine toxicity, 2193 Clarithromycin, for granulomatous amebic encephalitis, 1653 Clavicular fracture, perinatal, 334, 337 CLCN2 gene, in generalized epilepsy, 1011 Clean, intermittent catheterization, for micturition disorders, 2165 Clearance of drugs, 1110-1111 in renal failure, 2266-2268 Cleft brain. See Schizencephaly Cleft lip/palate, 466-469 disorders associated with, 464t-466t, 466 embryology of, 466 environmental factors in, 468 etiology of, 466 genetic factors in, 467, 467t hearing loss with, 108t incidence of, 466

Cleft lip/palate continued management of, 469 neurocognitive and neurobehavioral disorders with, 468-469 neurologic involvement in, 468 nonsyndromic, 466 speech and language functioning with, 468 Cleidocranial dysplasia, 459 associated anomalies with, 459 clinical features of, 459, 464t genetics of, 443f, 459, 464t Clemastine, in breast milk, 2196-2197 Climbing fibers, 1241, 1243f, 1244 Clindamycin, for babesiosis, 1661 Clinical decision-making software, 2405 Clinical ethics, 2387 Clinical Evaluation of Language Function (CELF), 805, 845 Clinical Linguistic and Auditory Milestone Scales (CLAMS), 805 Clinical only seizure, 259 Clinical Trials (on-line resource), 2404 Cloaca, 2157 Clock gene, 1225, 1236 Clofazimine, for leprosy, 1591 Clomipramine, 945t for ADHD, 878t for autism, 924-925, 927t for cataplexy, 1232 clinical applications of, 945-946 dosage of, 945t, 947 fetal/neonatal effects of, 2196 labeled and off-labeled use of, 938t for obsessive-compulsive disorder, 897, 945-946 pharmacokinetics of, 945t pharmacology of, 946 preparations of, 945t Clonazepam, 956t for absence seizures, 1029 adverse effects of, 271, 2367t for anxiety disorders, 955-956 bioavailability of, 1106t dosage of, 956t, 1108t drug interactions of, 956t elimination of, 1108t formulations of, 1106t half-life of, 956t for hyperekplexia, 1218 for hyperkinetic disorders, 1290 metabolism of, 1108t for muscle overreactivity (spasticity), 2366, 2367t for myoclonic seizures, 1023t, 1075 for myoclonus, 1295 for neonatal seizures, 268, 271 for neuronal ceroid lipofuscinosis, 1333 for nonepileptic paroxysmal disorders, 1213t, 1214, 1297 pharmacokinetics of, 1106t, 1108t preparations of, 956t protein binding of, 1108t in renal failure, action and effects of, 2268 for restless legs disorder, 1233, 2248 routes of administration, 1106t, 1120t for stiff person syndrome, 2106 for tic disorders, 896 for tremor, 1291 volume of distribution, 1108t Clonic seizures focal, 1040, 1041f neonatal, 258, 258t-259t, 260, 266-267 generalized, 1029 clinical features of, 1029 EEG findings in, 1029 etiology of, 1029 prognosis of, 1029 Volume 1: pages 1–1180

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xxi

Clonic status epilepticus, 1093b, 1094 Clonidine, 944-945 for ADHD, 879t, 882, 897, 943-945 adverse effects of, 945 for Asperger’s disorder, 925 for autism, 927t clinical applications of, 944 clinical management of, 944-945 drug interactions of, 943, 945 for intracranial hypertension, 1583 labeled and off-labeled use of, 938t for mentally retarded patients, 815 for migraine prevention, 1194t for orthostatic hypotension, 2142 pharmacology of, 944 for Sydenham’s chorea, 1808 for tic disorders, 896, 1298 Cloning, 521 Clopidogrel, for stroke, 1777-1778 Clorazepate adverse effects of, 2367t bioavailability of, 1106t formulations of, 1106t for juvenile myoclonic epilepsy, 1073 for muscle overreactivity (spasticity), 2366, 2367t for neuronal ceroid lipofuscinosis, 703, 1333 pharmacokinetics of, 1106t routes of administration, 1106t Close-lipped schizencephaly, 383, 384t, 422 Clostridium botulinum, 1962-1963, 2182, 2291 Clouding of consciousness, 1377 Cloverleaf skull malformation, 444, 447 in Pfeiffer’s syndrome, 449 Clozapine adverse effects of, 968, 2189 for autism, 924 Cluster headache, 1199 Cluttering, 848 Clutton’s joints, 1587 COACH syndrome, 391 Coagulation disorders, and stroke, 331-332, 331b, 1767-1769 Coagulation necrosis, in spinal cord injury, 1531, 1531f Coarctation of aorta, 1878, 2219 Coats’ disease, 1999-2000 Coaxial needle study, 1852 Cobalamin (vitamin B12), 2311-2313 absorption of, 2311-2312 and cognitive functioning, 2313 in cystathionine β-synthase deficiency, 582-583 deficiency of, 582f, 2312-2313 in dialysis patients, 2246 in methylmalonic acidemia, 586f, 587 neuroimaging in, 187, 2312-2313 in peripheral neuropathy, 1906, 2313 dependency disorders of, 2305t, 2313 for methionine synthase deficiency, 583 for methylmalonic acidemia, 588 recommended daily requirement for, 2312 Cobblestone complex lissencephaly, 389t, 416f, 417 Cobblestone cortex, 417 Cobblestone malformations antenatal diagnosis of, 418 clinical characteristics of, 417 genetic testing for, 417-418 genetics of, 412t, 417-418 management of, 418 MRI findings in, 416f Cocaine abuse/poisoning, 2185 teratogenicity of, 402, 2197t, 2198 as topical analgesia, 2377

xxii

Index

Coccidioides immitis, 1633. See also Coccidioidomycosis Coccidioidomycosis, 1633-1634 clinical characteristics of, 1633-1634 CNS syndromes in, 1632t diagnosis of, 1632t, 1633-1634 epidemiology of, 1633 geographic distribution of, 1632t, 1633 laboratory tests in, 1633-1634 management of, 1632t, 1634 microbiology of, 1633 pathology of, 1633 risk factors for, 1632t Cochlea anatomy of, 97-99, 98f-99f anomalies of, and hearing loss, 108 damage, in meningitis, 1577 emissions of, 101, 101f frequency selectivity of, 101 physiology of, 100-102 Cochlear duct, 97-98, 98f Cochlear implants, 104, 117 meningitis after, 1574 Cockayne’s syndrome clinical features of, 560t genetics of, 560t hearing loss with, 105t, 107 vision loss with, 88t Cocktail party syndrome, 849 Co-contraction, 2365 Codeine abuse/poisoning, 2186 fetal/neonatal effects of, 2196 nephrotoxicity of, 2265 for pain, 2377 Coding region, of gene, 511-512 Coding strand, in transcription, 511 Codon(s), 510-511, 511t Coefficient of inbreeding, 533 Coenurosis, 1671 classification of, 1648t clinical characteristics of, 1648t, 1671 diagnosis of, 1648t geographic distribution of, 1648t, 1671 management of, 1648t mode of infection, 1648t, 1671 pathology of, 1648t risk factors for, 1648t Coenzyme Q supplementation, 730 for myoclonic seizures, 1075 Coenzyme Q10 deficiency of, 2057 for MELAS, 2055 Coenzyme Q-cytochrome c oxidoreductase deficiency, 726 COG7 gene, in congenital glycosylation disorder, 650t, 652 Cogan’s syndrome, 1821 clinical features of, 389t laboratory findings in, 1818t neurologic manifestations of, 1818t, 1821 Cognition, 821 antiepileptic agents and, 1174-1177 antihypertensive agents and, 2242 arterial ischemic stroke, 1763 autistic disorder and, 911 cobalamin (vitamin B12) and, 2313 Duchenne muscular dystrophy and, 1979 epilepsy surgery and, 1152 epilepsy/epileptiform disorders and, 1055-1061, 1171-1177 febrile seizures and, 1081-1082 hepatic dysfunction and, 2297 intraventricular hemorrhage and, 323 iron deficiency and, 2321-2322 leukemia treatment and, 1739-1740

Cognition continued malnutrition and, 2304 in mental retardation/developmental delay, treatment for, 274 neonatal stroke and, 333 renal failure and, 2242, 2247 traumatic brain injury and, 1433-1434 zinc deficiency and, 2323-2324 Cognitive Assessment System, 805 Cognitive impairment, transient, 1055 Cognitive regression, 821-824 causes of, 825t-827t inherited metabolic, 826t-827t classification of, 822, 823t cortical localization of, 821, 822t diagnosis of, 821, 823-824, 824t-843t based on signs and symptoms, 828t epidemiology of, 821-823 frequency of, 822, 823t incidence of, 821-822 COLIA gene, in osteogenesis imperfecta, 462t, 463 Colitis, ulcerative, 2290 Collare vesicae, 2157 Collier’s sign, in hydrocephalus, 429 Collins’ rule, 1709 Collis horizontal suspension, 43t Collis vertical suspension, 43t Colloid bodies, 1517 Colloid cyst(s), 1708-1709 management of, 1709 of third ventricle, 1699, 1700f Coloboma, 83, 83f-84f in developmental disorders, 839t Color vision, assessment of, 79 Colorado tick fever virus, 1616 Coma, 1377-1397 brain death determination in, 1563-1565, 1564f. See also Brain death clinical evaluation of, 1385 definition of, 1378-1379 depth of, 1378-1379 diagnostic testing in, 1390 etiology of, 1383-1385, 1384b identification of, 1385 evaluation of, 1385-1388 general physical examination in, 1386 in hepatic encephalopathy, 2294 in herniation syndromes, 1388-1390 history of, 1385-1386 hyperammonemic, 356, 608, 611-613, 1390 in hypertensive encephalopathy, 2239 hypoglycemic, 348 in inflicted neurotrauma, 1448 monitoring of, 1392-1393 neurologic examination in, 1386-1388 neurophysiologic testing in, 1392 outcome measurement in, 1393-1395 pathophysiology of, 1383 prognosis of, 1395-1397 neurophysiologic studies of, 1396-1397 in nontraumatic injury, 1396 in traumatic injury, 1395-1396 rating scales for, 1382-1383, 1382t-1383t treatment of, 1390-1391, 1391b in uremic encephalopathy, 2237 versus vegetative state, 1378-1379 Coma depassé, 1553 Common drive, 1850 Common morality, 2387-2389 Commotio cordis, 1491, 2151 Communication, in autistic disorder, 906b, 907-908 “red flags” for, 913, 913b Comparative genomic hybridization (CGH), 521, 544-545 Volume 1: pages 1–1180

Competence, mental, 801 Complementary and alternative medicine (CAM) for ADHD, 883 for autism, 925-926 for chronic daily headache, 1197-1198 for migraine, 1192-1195, 1192b Complex febrile seizures, 1079-1080 Complex I deficiency, 725, 2057 Complex II deficiency, 725-726, 2057 Complex III deficiency, 726, 2057-2058, 2223 Complex inheritance, 535 Complex IV deficiency, 726, 2058 Complex partial seizures, 984b, 1037, 1043-1044 versus absence seizures, 1025, 1025t classification of, 1037, 1038b, 1042 disorders mimicking, 984b EEG findings in, 235f, 236 Complex partial status epilepticus, 1093b, 1094 Complex V deficiency, 726-727, 2058 Compliance, brain, 1513 Component vaccines, 2349-2350 Compound skull fracture, 1418 Comprehension, reading, 864-865 Comprehensive Test of Adaptive BehaviorRevised (CTAB-R), 805 Comprehensive Test of Nonverbal Intelligence (CTONI), 803t-804t Comprehensive Test of Phonological Processing in Reading (CTOPR), 864 Compulsion(s). See also Obsessive-compulsive disorder definition of, 889 Computed tomography, 167, 170-173 in Aicardi-Goutieres syndrome, 1353f, 1354 in Alexander’s disease, 1357, 1358f in Alpers’ disease, 1326-1327 of aneurysm, 1794f of arteriovenous malformation, 1790, 1791f of astrocytoma, 1720, 1720f in autonomic dysfunction, 2140 axial, 170 of brain abscess, 173, 1588, 2222 in brain death, 1561 of brain tumors, 172f, 1695, 1695f in infants and very young children, 1727, 1727f of brainstem tumors, 1717, 1718f in Canavan’s disease, 1361-1362 after cardiac arrest, 1495 of cavernous malformations, 1792f of cerebellar astrocytoma, 1713 of cerebral contusion, 1414, 1414f of cerebral infarction, 171, 171f, 174f, 1764f in cerebrotendinous xanthomatosis, 1367 of Chiari II malformation, 175f of choroid plexus tumor, 1707, 1707f contrast-enhanced, 172f, 173 coronal, 170-171 of craniopharyngioma, 1706 of craniosynostosis, 444, 451-452 in cytomegalovirus, 1606-1607, 1607f in defecation disorders, 2167-2168 of ependymoma, 1715 of epidural hematoma, 337, 337f in head trauma, 173, 176f in hearing loss, 114 helical, 170 in hepatic encephalopathy, 2295 in herpes simplex virus, 1604f, 1605, 1605f high density in, 171-172, 172f in HIV, 1622, 1622f of hydrocephalus, 429, 430f of hypoxic-ischemic injury, 282 central, 286, 286f cortical or subcortical, 284, 284f

Volume 2: pages 1181–2408

Index Computed tomography continued image composition in, 170 in impaired consciousness/coma, 1390 indications for, 167 of intracranial calcifications, 171, 172f of intracranial hemorrhage, 338, 338f isodensity in, 171 of leukoencephalopathy, 1743, 1743f low density in, 171, 171f before lumbar puncture, 156 in lymphocytic choriomeningitis virus, 1620f in malaria, 1659 in maple syrup urine disease, 577 of meningioma, 1708 in meningitis bacterial, 1575-1576 tuberculous, 1585-1586 multidetector or multislice, 170 of muscle, 1853 in neuronal ceroid lipofuscinosis, 1329t-1330t infantile, 1329t, 1331 juvenile, 1329t, 1335 juvenile-like variant, CLN9-deficient, 1330t, 1337 late infantile, classic, 1329t, 1332 in nonaccidental trauma, 173, 176f, 1412, 1412f non-contrast-enhanced, 172-173, 173f-176f of oligodendroglioma, 1724 in perinatal trauma, 335 of periventricular leukomalacia, 289, 289f of pineal region tumors, 1704 in poisoning, 2175 prenatal, 167 of primitive neuroectodermal tumor, 1723, 1723f radiation risk in, 170 of retinal hemorrhage, 1456f in second impact syndrome, 1417, 1417f in shaken-infant syndrome, 176f of sinovenous thrombosis, 1783f-1784f, 1785-1786 of skull fracture, 173, 176f, 336, 336f, 1417, 1417f in smell and taste disorders, 138 spinal, 195 of spinal cord injury, 339, 1535-1536, 1536f, 1545f of spinal cord tumor, 1731, 1731f in stroke, 1774 of subarachnoid hemorrhage, 338, 338f, 1412, 1413f of subdural hematoma, 337, 1413, 1413f, 1447f, 1453f-1456f of subdural hemorrhage, 173, 173f, 176f of subgaleal hematoma, 336, 336f in systemic lupus erythematosus, 1812-1814, 1813f technical developments in, 170 of thalamic tumor, 1700, 1700f of traumatic brain injury, 1418-1420, 1419t, 1431 inflicted (child abuse), 1447, 1447f, 1453f-1456f, 1456-1457, 1462-1463 mild, 1428-1429 in tuberous sclerosis, 173, 175f, 780f, 781, 782t of venous angioma, 1793f in viral infections, 1601-1602 Computed tomography cisternography, 172 Computed tomography myelography, 172, 195 Computer analysis, of electrographic data, 240-247 Computer resources. See Internet Concerta, for ADHD, 878t, 881 Concussion(s), 1403, 1414-1417 clinical symptoms of, 1415

Concussion(s) continued definition of, 1414 general management of, 1428-1430 grading scale for, 1429, 1429t labyrinthine, 131 repeated, 1415-1417 sports, 1415-1417 epidemiology of, 1415-1416 pathophysiology of, 1416, 1416f return to play guidelines in, 1429-1430, 1429t sequelae of, 1416-1417 symptomatology of, 1416 syndrome after, 1415, 1436 Conduct disorder, with epilepsy, 1173 Conduction aphasia, 822t Conductive hearing loss, 102-103 causes of, 102-103, 103b in developmental disorders, 836t in mental retardation/developmental delay, 813b pathology of, 106 tests of, 100 Confidentiality, of e-mail, 2399-2400 Confusion definition of, 1377-1378 in malaria, 1658 Confusional arousals, 1235 Confusional migraine, 1190-1191 Congenital anomalies. See also specific anomalies computed tomography of, 172-173, 175f evaluation for, 47 structural, 363-469 epidemiology of, 363 etiology of, 363-364, 364t neuroimaging of, 363 pathogenesis of, 363-364 Congenital disorders of glycosylation, 361, 647-653 CDG-Ia, 649, 650t CDG-Ib, 649-651, 650t CDG-Ic, 650t, 651 CDG-Id, 650t, 651 CDG-Ie, 650t, 651 CDG-If, 650t, 651 CDG-Ig, 650t, 651 CDG-Ih, 650t, 651 CDG-Ii, 650t, 651 CDG-IIa, 650t, 652 CDG-IIb, 650t, 652 CDG-IIc, 650t, 652 CDG-IId, 650t, 652 CDG-IIe, 650t, 652 CDG-IIf, 650t, 652 CDG-Ij, 650t, 651 CDG-Ik, 650t, 651-652 CDG-Il, 650t, 652 clinical features of, 350t-351t, 361, 389t, 649 defects or types in, 645 diagnosis of, 647-649 group I, 361, 645, 647 group II, 361, 645, 647 MRI findings in, 352t, 361 nomenclature for, 647 prenatal testing for, 649 specific types of, 649-653, 650t testing for, indications for, 652-653 transferrin isoforms in, 647-649 Congenital disorders of glycosylation (CDG), 361 clinical features of, 350t-351t, 361, 389t group I, 361 group II, 361 MRI findings in, 352t, 361 Congenital double athetosis-aconjunctival vascular plexus syndrome, 1251. See also Ataxia-telangiectasia Volume 1: pages 1–1180

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xxiii

Congenital heart disease (CHD) cerebrovascular risks in, 1767, 2210-2211, 2216-2219 epidemiology of, 2207 headache in, 2219 hearing loss in, 115 learning disabilities in, 855-856 management of, 2207 neurological complications of infectious and parainfectious, 2220-2223 non-surgery-related, 2220-2227 in surgical management, 2207-2220 Congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD), 787t Congruence concept, for epilepsy surgery, 1155-1156 Conklin, Hugh, 1131 Connective tissue disorder(s), 1804t, 1808-1818. See also specific disorders neurologic and laboratory findings in, 1809t Connors Rating Scales, 877 Conscious sedation, 2377 Consciousness brief loss of definition of, 1428 in mild traumatic brain injury, 1428-1429 clouding of, 1377 continuum of, 1377 definition of, 1377 operational, for newborns and infants, 1377 delayed recovery, after cardiac surgery, 2211-2212 dimensions of, 1377 impairment of, 1377-1397 with activated mental state, 1378 clinical evaluation of, 1385 diagnostic testing in, 1390 etiology of, 1383-1385, 1384b evaluation of, 1385-1388 general physical examination in, 1386 in hepatic encephalopathy, 2294 in herniation syndromes, 1388-1390 history of, 1385-1386 identification of cause, 1385 neurologic examination in, 1386-1388 outcome measurement in, 1393-1395 pathophysiology of, 1383 prognosis of, 1395-1397 neurophysiologic studies of, 1396-1397 in nontraumatic injury, 1396 in traumatic injury, 1395-1396 with reduced mental state, 1378-1379 treatment of, 1390-1391, 1391b rating scales for, 1382-1383, 1382t-1383t Constipation ketogenic diet and, 1143 in Rett’s syndrome, 1321 Consultand, 532 Contiguous deletion syndromes, 556-557, 749 Continuous traits, 535 Contra-coup injury, 1402, 2355 Contractile proteins, 1839-1840, 1840f Contracture(s) in Duchenne muscular dystrophy, 1978, 1984-1985 in Emery-Dreifuss muscular dystrophy, 1996f, 1997, 1997f muscular tone and, 66-67 Contrast agents in sickle cell anemia, risks of, 2197 toxicity of, 2194 Contusion(s) cerebral, 1402f, 1403, 1414 computed tomography of, 1414, 1414f in inflicted neurotrauma, 1457-1458, 1458f spinal, 1530

xxiv

Index

Conus medullaris syndrome, 1539, 2163 Convention on the Rights of the Child, 2393 Conversion reaction gait, 75 Convulsion(s). See also Epilepsy; Seizure(s) benign idiopathic neonatal, 266 benign neonatal, 266 benign neonatal familial, 266-267 Convulsive syncope, 1212 Copaxone (glatiramer acetate), for multiple sclerosis, 1349-1350 Copolymer-1 (glatiramer acetate), for multiple sclerosis, 1349-1350 Copper in Menkes’ disease, 1321-1326 in Wilson’s disease, 1291, 2299-2300 Copper histidine, for Menkes’ disease, 1325 Copper-zinc superoxide dismutase, in hypoxicischemic injury, 1503 Coprolalia, 1298 Copropraxia, 1298 Corencephalopathies, 823t Corn starch, uncooked, for fatty acid oxidation defects, 2047 Cornea anomalies of, 83, 88 development of, 83 Corneal clouding in developmental disorders, 838t-839t in mucolipidosis type IV, 697-698 Corneal opacity, 82-83, 82f Corneal reflex, 23 in comatose patient, 1388 in traumatic brain injury, 1409 Cornelia de Lange’s syndrome, 464t Coronal suture, 436, 436f, 437t Coronal synostosis, 445, 445f-446f, 1523 versus plagiocephaly, 441t Corpus callosotomy, 1075, 1164 Corpus callosum agenesis of, 383t, 385f other anomalies with, 387 with arachnoid cyst, 433 complete, 386 conditions featuring, 385t, 386b with Dandy-Walker syndrome, 392 with glycine encephalopathy, 580-581 and language disorders, 850 with osteopetrosis, 456 partial, 386 prenatal ultrasound of, 387 in Rett’s syndrome, 1317 tearing of, in inflicted neurotrauma, 1455f, 1457 Cortical auditory event-related potentials, 114 Cortical blindness in Alpers’ disease, 1327 traumatic brain injury and, 1415 Cortical deafness, 103 Cortical dysplasia focal with abnormal but non-neoplastic cells, 410 without abnormal cell types, 425 with balloon cells, 403t, 410 without balloon cells, 425 epilepsy surgery for, 1153 with neoplastic changes, 410 Cortical injury, hypoxic-ischemic, 284 clinical features of, 284 computed tomography of, 284, 284f diagnosis of, 284 magnetic resonance imaging of, 284 pathogenesis of, 284 Cortical malformations, 398-425. See also specific types in developmental disorders, 840t-841t and focal seizures, 1048

Cortical sensory function, assessment of, 25 Cortical spreading depression, in migraine, 1187, 1187f Cortical tubers, in tuberous sclerosis, 780f, 781 Cortical visual impairment, 85-87 structural cerebral anomalies causing, 86-87 Cortical-striatal-thalamic-cortical pathways, in Tourette syndrome, 893-894, 893f, 895f Corticomedial amygdala, 137f Corticosteroid(s) for acute disseminated encephalomyelitis, 1352 for acute hemorrhagic leukoencephalitis, 1354 adverse effects of, 1953, 1983 for African trypanosomiasis, 1664 for Behçet’s disease, 1826 for chronic inflammatory demyelinating polyneuropathy, 1932-1933 for Churg-Strauss syndrome, 1822 for Cogan’s syndrome, 1821 for cysticercosis, 2082 for dermatomyositis, 2078 for Duchenne muscular dystrophy, 1982-1983 for Guillain-Barré syndrome, 1894 for heterotopic ossification, 2365 for human T-cell lymphotropic virus type I, 1623 for intracranial hypertension, 1521, 1582 for intraventricular hemorrhage prevention, 311, 311t, 323-324, 323t for juvenile idiopathic arthritis, 1805 for Kawasaki disease, 1821 for Lambert-Eaton myasthenic syndrome, 1957 for MELAS, 2055 for meningitis bacterial, 1581-1582 tuberculous, 1586 for mixed connective tissue disease, 1817 for multiple sclerosis, 1349 for myasthenia gravis, 1952-1953 for polyarteritis nodosa, 1819-1820 for polymyositis, 2080 for primary angiitis, 1823 in renal transplant patients, complications with, 2251-2252 for sarcoidosis, 1824 for Schilder’s disease, 1351 for schistosomiasis, 1673 for scleroderma, 1816 for Sjögren’s syndrome, 1818 for stiff person syndrome, 2106 for Sydenham’s chorea, 1279, 1808 for systemic lupus erythematosus, 1815 for Takayasu’s arteritis, 1825 toxicity of, 2194 for trichinosis, 1667, 2082 for varicella-zoster virus, 1609 for viral infections, 1603 Cortisol, 2118 deficiency of, 2119-2120 excess of, 2118-2119 Cortisol replacement therapy, 2120 Corynebacterium diphtheriae, 1909 Cosmetic neurology, 2396 Costeff’s optic atrophy syndrome, 592 Cough syncope, 2150 Coup injury, 1402 Coup-contrecoup injury, 1402, 2355 Coup-de-sabre lesions, in scleroderma, 18151816 Cowden’s syndrome, 394, 408 Coxiella burnetii, 1640, 1644. See also Q fever Cranial base abnormalities, 435b, 459-466 Cranial epidural abscess, 1589, 1589f Volume 1: pages 1–1180

Cranial injuries, perinatal, 336-339 Cranial motor neuron disease, 1859-1879. See also specific diseases Cranial nerve(s). See also specific nerves assessment of in infant, 39 in newborn (term), 47, 51-52 in ocular motility testing, 80, 80f in older child, 19-25 in preterm infant, 59-60 in traumatic brain injury, 1409 damage, in meningitis, 1577 in Friedreich’s ataxia, 1248 in hydrocephalus, 429 in meningeal leukemia, 1735-1736 perinatal injuries to, 339 in poisoning/intoxication, 2175-2177, 2177t in spinal muscular atrophy type I, 1864 in systemic lupus erythematosus, 1811 tumors of, incidence of, 1719t Cranial neuralgias, 1184, 1198-1199 Cranial ultrasound. See Ultrasound Cranial vault, 436 evaluation of in infant, 38 in newborn (term), 48-50, 49f Craniocerebellocardiac dysplasia, 465t Craniocerebral erosion, 1436 Craniofacial anomalies. See also specific anomalies genetics of, 437-438, 439t-440t and sleep-wake disorders, 1227 Craniofacial development, 437-438 genetic mechanisms of, 437-438 neural crest in, 437-438 Craniopharyngioma(s), 1693, 1699, 1705-1707 clinical presentation of, 1706 cystic, 1706 diagnosis of, 1706 endocrinopathy with, 1706, 2117, 2117f, 2123 gross appearance of, 1705, 1705f incidence of, 1719t management of, 1706-1707 neuroimaging of, 1706, 1706f suprasellar, 1706 survival rates in, 1705 Craniorachischisis, 378 Craniosynostosis, 50, 441-454 Adelaide-type, 443f, 449 Boston-type, 442t, 443f, 450 classification of, 444-447, 444t clinical characteristics of, 443-444 cognitive outcomes in, 454 complications of, 454 evaluation of, 451-452 fibrillin-related, 450-451 fibroblast growth factor receptor-related, 443, 443f, 447-449, 447t historical perspective on, 441 intracranial pressure increase in, 453-454, 1523-1524 management of, 452-453 molecular testing in, 452, 452f MSX-related, 443, 450 neuroimaging of, 451-452 neuropathologic findings in, 444 nonsyndromic, 445, 447 pathogenesis of, 441-443 prevalence of, 444 primary, 441, 444-445 radiologic findings in, 444 reconstructive surgery for, 452-453 secondary, 443-445 syndromic, 442t, 443, 443f, 444-445 treatment goals in, 452 Twist-related, 437, 442t, 449-450

Volume 2: pages 1181–2408

Index Craniotubular bone-modeling disorders, 435b, 455-457 CRASH syndrome, 385t, 428 Creatine, in proton MR spectroscopy, 179-180, 184f Creatine kinase, 1852 in Becker muscular dystrophy, 1986-1987 in congenital muscular dystrophies, 2001 in congenital myopathies, 2015 in dermatomyositis, 2076-2077 in Duchenne muscular dystrophy, 1976, 1980 in facioscapulohumeral muscular dystrophy, 2000 in influenza myositis, 2081 in limb-girdle muscular dystrophy, 1990-1993 in phosphorylase kinase deficiency, 2028 in polymyositis, 2079 in spinal muscular atrophy, 1864 Creatine kinase BB, 1852 Creatine kinase M, 1852 Creatine kinase MB, 1852 Creatine kinase MM, 1852 Creatine monohydrate, for Duchenne muscular dystrophy, 1983 Creatinine, in micturition disorders, 2163-2164 Credé maneuver, urinary voiding by, 2162, 2165 Cree leukoencephalopathy, 1366 Cremasteric reflex, 19, 41 in Friedreich’s ataxia, 1249 CREST syndrome, 1816 Cretinism, 808, 2323 Creutzfeldt-Jakob disease, 1598 classic, 1598 EEG findings in, 234 variant, 1598 Cri du chat syndrome, 402 genetics of, 555t Crista of semicircular canal, 98f Critical illness polyneuropathy, 1911, 2216 Crocodile tears, 2152 Crohn’s disease, 2290 Crossed extensor reflex, 43t, 60 Crossing over, 514, 515f Crouzon’s disease, 444, 448 with acanthosis nigricans, 447t, 448 clinical features of, 442t, 448 genetics of, 442t, 443, 443f, 447t, 448 hearing loss with, 108t hydrocephalus in, 453 tonsillar herniation in, 453 Crying, assessment, in newborn (term), 52 Cryptococcosis causative agent of, 1631, 1633f clinical characteristics of, 1631-1633 CNS syndromes in, 1632t diagnosis of, 1631-1633, 1632t geographic distribution of, 1632t laboratory tests in, 1631-1633 in leukemia, 1738 in liver transplant patients, 2298 management of, 1632t, 1633 myositis in, 2083 in renal transplant patients, 2250 risk factors for, 1632t Cryptococcus neoformans, 1631, 1633f. See also Cryptococcosis Cryptogenic epilepsies, 981, 982t, 1046-1047 Cryptogenic infantile spasms, 1066 Cryptorchidism, in developmental disorders, 843t αβ-Crystallinopathy, 2019 CSF. See Cerebrospinal fluid CT. See Computed tomography CT number, 170 Culpepper, Nicholas, 1203 Culture(s), of CSF, 160

Currarino’s syndrome, 374, 374f Cushing response, 1410, 1518 Cushing’s disease, 1707, 2118-2119 clinical features of, 2118 diagnosis of, 2118-2119 treatment of, 2119 Cyanocobalamin, 2311. See also Cobalamin (vitamin B12) Cyanotic breath-holding spells, 1203-1205, 1212 Cyclical vomiting syndrome, 1184, 1186b, 1191, 1213t, 1216-1217, 2285-2286 age of onset, 1216 diagnosis of, 1217 differential diagnosis of, 2286 management of, 1217, 2286 physiology of, 2285-2286 prevalence of, 1216 triggering factors in, 1216-1217 Cyclobenzaprine, in spinal cord injury, 1544 Cyclogyl (cyclopentolate), toxicity of, 2191 Cyclooxygenase(s), in hypoxic-ischemic injury, 1479, 1505 Cyclopamine, and holoprosencephaly, 397 Cyclopentolate, toxicity of, 2191 Cyclophosphamide for cerebellar astrocytoma, 1714 for chronic inflammatory demyelinating polyneuropathy, 1933 for Churg-Strauss syndrome, 1822 for dermatomyositis, 2079 for ependymoma, 1715, 1729 for inflammatory myopathies, 2078t for juvenile idiopathic arthritis, 1806 for medulloblastoma, 1729 for mixed connective tissue disease, 1817 for myasthenia gravis, 1954 for pineal region tumors, 1705 for polyarteritis nodosa, 1820 for primary angiitis, 1823 for primitive neuroectodermal tumors, 1723, 1729 for sarcoidosis, 1824 for Sjögren’s syndrome, 1818 in stroke, 1779 toxicity of, 2193 for Wegener’s granulomatosis, 1822 Cyclosporine and autonomic dysfunction, 2149 for chronic inflammatory demyelinating polyneuropathy, 1933 for dermatomyositis, 2079 for Duchenne muscular dystrophy, 1983 for inflammatory myopathies, 2078t for Lambert-Eaton myasthenic syndrome, 1958 for myasthenia gravis, 1954 in renal failure, encephalopathy induced by, 2266 for renal transplant patients, 2250 in renal transplant patients, complications with, 2250-2252 for spinal cord injury, 1542 toxicity of, 2190-2191, 2212, 2298 and vision loss, 91-92 Cylert. See Pemoline Cyproheptadine for chronic daily headache prevention, 1196t, 1197 for cyclical vomiting syndrome, 2286 for migraine prevention, 1194t, 1195 in renal failure, encephalopathy induced by, 2266 for Sydenham’s chorea, 1808 Cyst(s). See also specific types and anatomic sites diffusion-weighted imaging of, 187 Volume 1: pages 1–1180

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xxv

γ-Cystathionase deficiency, 582f Cystathionine β-synthase deficiency, 582-583, 582f clinical manifestations of, 583 laboratory tests in, 583 pathophysiology of, 582-583 pyridoxine-responsive, 582-583 treatment of, 583 Cystathioninura, 2311 Cystatin C, 2260-2261, 2260t Cysteamine for cystinosis, 701, 2263-2264 for neuronal ceroid lipofuscinosis, 1328 Cystic encephalomalacia, computed tomography of, 284, 284f Cystic leukoencephalopathies, 1364-1366 Cysticercosis, 1669-1671, 2082 classification of, 1648t clinical characteristics of, 1648t, 1670-1671, 2082 diagnosis of, 1648t, 1670-1671 epidemiology of, 1669-1670 geographic distribution of, 1648t, 1670 laboratory tests in, 1670-1671 management of, 1648t, 1671 microbiology of, 1669-1670, 1669f mode of infection, 1648t, 1670 muscle biopsy in, 2082 neuroimaging in, 1670f, 1671 pathology of, 1648t, 1669-1670 in renal transplant patients, 2250 risk factors for, 1648t Cystinosis, 701 diagnosis of, 701 genetics of, 701 infantile, 701 juvenile, 701 management of, 701 nephropathic, 701, 2263-2264 Cystometrograms, 2164 of spinal cord tumor, 1731 Cystourethrograms, of spinal cord tumor, 1731 Cytochrome c oxidase in Alpers’ disease, 1327 deficiency of, 2223 in Menkes’ disease, 1324 Cytochrome oxidase deficiency, 717, 726 benign infantile, 726 clinical features of, 350t-351t, 726 fatal infantile, 726 infantile myopathic, 726 MRI findings in, 352t Cytochrome P450 system, in antiepileptic agent metabolism, 1111, 1111t Cytogenetics clinical, 524-529, 543-545 future of, 561 nomenclature in, 529, 529t, 547, 547t technology of, 520-521 Cytokine(s) in bacterial meningitis, 1572 in Duchenne muscular dystrophy, 1975-1976 in hepatorenal syndrome, 2258 in hypoxic-ischemic injury, 302-304, 1479 in intraventricular hemorrhage, 311, 313 in malaria, 1657 in oncogenesis, 1748 in periventricular leukomalacia, 288 in spinal cord injury, 1532 toxicity of, 2193 in viral infections, 1596 Cytomegalovirus (CMV), 1606-1607 clinical features of, 1606 congenital, 364, 1606-1607, 1607f diagnosis of, 1602, 1602t, 1606

xxvi

Index

Cytomegalovirus (CMV) continued and Guillain-Barré syndrome, 1606-1607, 1893, 1927t and hearing loss, 109, 115, 1606-1607 in HIV/AIDS, 1606, 1622 neuroimaging in, 1606-1607, 1607f and optic neuritis, 90, 90f outcome of, 1603t, 1606-1607 in renal transplant patients, 2250 transmission of, 1600, 1606 treatment of, 1606-1607 Cytoplasmic inheritance, 715 Cytosine, 508, 508f Cytosine arabinoside and myelopathy, 1737 and neuropathy, 1910 toxicity of, 2193 Cytoskeletal proteins, 1841-1845, 1841f, 1969, 1970f and human disease, 1842t, 1969, 1970f

D Daclizumab, for multiple sclerosis, 1350 Dandy-Walker malformation. See Dandy-Walker syndrome Dandy-Walker syndrome, 86, 391-393 associated features of, 392, 392t classic, 392t clinical course of, 393 clinical features of, 377t, 391-392 diagnostic criteria for, 392 differential diagnosis of, 392-393, 393f encephalocele in, 377, 377t with osteopetrosis, 456 treatment of, 393 ultrasound in, 169-170, 169f variants of, 392-393, 392t, 393f Danon’s disease, 621, 699-700 clinical features of, 699-700 diagnosis of, 700 genetics of, 661, 700 Dantrium, for stiff person syndrome, 2106 Dantrolene adverse effects of, 2366-2367, 2367t for malignant hyperthermia, 2195 for micturition disorders, 2165t for muscle overreactivity (spasticity), 2366-2367, 2367t, 2378 for post-traumatic spasticity, 1434 Dapsone, for leprosy, 1591 Dapsone poisoning, 2175 Darvon (propoxyphene), fetal/neonatal effects of, 2196 Date rape drug, 2186 Datura stramonium, 2143-2144 DAX1 gene, in hypogonadism, 2116 Daydreaming, versus absence seizure, 1025, 1025t Daytime giggle enuresis, 2162 DCX gene, in lissencephaly, 411f, 414-415 de Morsier’s syndrome, 84, 387. See also Septo-optic dysplasia de Toni-Debré-Fanconi syndrome, 2060, 2262-2264, 2263t. See also Fanconi syndrome, renal Deaf community, 119 Deafness, 104. See also Hearing loss X-linked progressive, 556t Deafness-dystonia syndrome, 727 Death, brain. See Brain death Death and dying bereavement after, 2383-2384 developmental, emotional, and spiritual concerns in, 2383

Death and dying continued environment for, 2382-2383 health-care decision making in, 2382 palliative care in, 2379-2385 support during, 2383 Debrancher deficiency, 630-631, 2031-2032 adult type, 631 biochemistry of, 630-631, 2032 childhood type, 631, 2031 clinical manifestations of, 622t, 631, 2031 enzyme defect in, 622t genetics of, 631, 2031-2032 glycogen structure in, 622t infantile type, 631 laboratory tests in, 631, 2031 management of, 631, 2032 pathology of, 630, 2031-2032 Decamethonium, and malignant hyperthermia, 2195 Deceleration injury, 1402, 1457 Decerebrate posturing, 1388 Decibels (dBs), 99-100 Decision-making software, 2405 Decoding, in reading, 864-865 Decompensation, metabolic, in fatty acid oxidation disorders, 2038-2039 Decompressive craniectomy, 1393, 1425-1426 criteria suggestive of potential benefit of, 1426t in intracranial hypertension, 1521 in traumatic brain injury, 1425-1426 Decorticate posturing, 1388 Deep brain stimulation for dyskinesia, 1290 for dystonia, 1283, 1289 for dystonic storm, 1281 for Lesch-Nyhan disease, 1286 for parkinsonism, 1293 for tic disorders, 897 for tremor, 1291 Deep cerebellar nuclei, 1241, 1242f Deep sedation, 2377 Deep tendon reflexes absent, in spinal cord injury, 339 assessment of in infant, 40, 45 in newborn (term), 50-51, 67 in older child, 17-19 in preterm infant, 56-57, 56f, 58t, 67 in Friedreich’s ataxia, 1249 types and segmental levels of, 18, 19t in uremic neuropathy, 2248 Deep vein thrombosis, 1783f, 1784, 2362-2364 clinical findings in, 2362-2363 diagnosis of, 2363 incidence of, 2362 treatment of, 1776, 2363 Deep venous system, 1782 Defecation anatomy of, 2166 definition of, 2166 disorders of, 2166-2169 differential diagnosis of, 2167b, 2168 laboratory tests in, 2167-2168 management of, 2168 neurologic examination in, 2167 patient evaluation in, 2167-2168 patient history in, 2167 in spinal cord injury, 2358 initial (involuntary) phase of, 2166 neural circuitry for, 2166 and syncope, 2150 Deferoxamine for hypoxic-ischemic injury, 301-302 for malaria, 1659 Defibrillators, 1491-1492 Volume 1: pages 1–1180

Deflazacort, for Duchenne muscular dystrophy, 1982 Deformational plagiocephaly, 438-441, 445 diagnosis of, 440-441 frontal, 438-440, 441t incidence of, 438 posterior, 438-440, 441t versus synostoses, 441t treatment of, 440-441 Degenerative disease(s), EEG findings in, 239-240 Dehydration in meningitis, 1576 in renal Fanconi syndrome, 2262 and sinovenous thrombosis, 1782, 1784f, 1785 Dehydroemetine, for amebiasis, 1649 Dehydroepiandrosterone, in puberty, 2114 Dejerine-Sottas disease, 1899-1900 Dekaban-Arima syndrome, 391 Delayed echolalia, 908 Delayed puberty, 2116-2118 evaluation of, 2117 management of, 2117-2118 Delayed sleep phase syndrome, 1233-1234 Deletion, genetic, 527-528, 529t, 530, 546, 555-557, 555t-556t Deletion 4p, 555t. See also Wolf-Hirschhorn syndrome Deletion 5p, 555t. See also Cri du chat syndrome Deletion 9p, 555t Deletion 13q, 555t Deletion 18p, 555t Deletion 18q, 555t Deletion terminal short arm chromosome 1, 555t Delinquency, with epilepsy, 1173 Delirium definition of, 1378 in malaria, 1658 Delis-Kaplan Executive Function System (D-KEFS), 804t Delta activity, in EEG in febrile seizures, 237 in hypoxic-ischemic injury, 238 intermittent, 209-210 frontal, 209-210 occipital, 209-210 newborn gestational age of 28 to 31 weeks, 212f-214f, 215-216 gestational age of 32 to 34 weeks, 214f, 216 gestational age of 38 to 42 weeks, 214f gestational age younger than 28 weeks, 211f, 213f, 215 polymorphic, 208f, 209 slowing of abnormal, 208f, 209-210 in children, 219-220 Delta brushings, 211f-214f, 215-216, 218 Delta-9-tetrahydrocannabinol, for tic disorders, 897 Deltoid muscle injury, in intramuscular injection, 2194 testing of, 34t Delusions, definition of, 1378 Demeclocycline, for hyponatremia prevention, 2264 Dementia, 821-823 in renal failure, 2242, 2246 Dementia infantalis, 909 Demerol. See Meperidine Demyelinating disorders classification of, 1345, 1345t immune-mediated, 1345-1354

Volume 2: pages 1181–2408

Index Demyelinating neuropathies, 1922t Demyelinating polyneuropathy acute inflammatory. See Guillain-Barré syndrome chronic inflammatory, 1894, 1894f, 1922t, 1931-1934 clinical features of, 1931-1932 CSF analysis in, 1930t diagnostic criteria for, 1930t electrophysiologic findings in, 1930t, 1932 epidemiology of, 1931 incidence of, 1931 laboratory findings in, 1930t, 1932 in liver transplant patients, 2298 pathologic findings in, 1932-1933, 1933f prognosis of, 1933 treatment of, 1932-1933 Denaturing gradient gel electrophoresis (DGGE), 523 Denaturing high-performance liquid chromatography (DHPLC), 523 Dental enamel pits, in tuberous sclerosis complex, 779 Dentate gyrus, 991-992, 993f, 997-998 in meningitis, 1578-1579 Dentate nuclei, 1241, 1242f lesions of, 1246 Dentatorubral-pallidoluysian atrophy, 1255t, 1262-1263, 1295 Denver Developmental Screening Test (DDST), 7 Denver Developmental Screening Test II (DDST II), 5f-6f, 7, 17, 802t, 805 Deontology, 2387-2388 Deoxyadenosylcobalamin, 2311. See also Cobalamin (vitamin B12) Deoxyhemoglobin in functional MRI, 191 in perfusion MRI, 189 Deoxypyridinoline, in Menkes’ disease, 1322 Deoxyribonucleic acid. See DNA Deoxyribose, 507 Depakene. See Valproic acid (valproate) Depakote. See Valproic acid (valproate) Depolarization, in EEG, 207-208, 996f, 997 Depolarizing conductances, 994 Deprenyl, for ADHD, 897 L-Deprenyl, for biopterin disorders, 575 Depressed skull fracture, 1417-1418 Depression in ADHD, 876 assessment in, 946-947 in Duchenne muscular dystrophy, 1986 in epilepsy, 1173 in Huntington’s disease, 1277 in juvenile idiopathic arthritis, 1805 pharmacologic therapy for, 945-955 in polyarteritis nodosa, 1820 in systemic lupus erythematosus, 1810 in Tourette syndrome, 890 in traumatic brain injury, 2356 Deprivation amblyopia, 87-88 Derivative chromosomes, 525 Dermacentor andersoni, 1642, 1642f, 2181 Dermacentor variabilis, 2181 Dermatan sulfate, 654, 683, 690 Dermatomyositis, 2075-2079 associated conditions in, 2076 clinical features of, 2075-2076, 2076f corticosteroids for, 2078 electromyography in, 2077 laboratory features of, 2076 muscle biopsy in, 2077, 2077f pathogenesis of, 2077-2078 serologic studies in, 2076-2077 treatment of, 2078-2079, 2078t

Dermatomyotomes, 1837, 1838f Desert fever, 1633 Desipramine for ADHD, 878t, 882, 897, 946 adverse effects of, 947, 2189 pharmacology of, 946 toxicity of, 2189 Desmethylimipramine, fetal/neonatal effects of, 2196 Desmin, 1845 diseases associated with, 1842t Desminopathies, 2018-2019 Desmopressin, for diabetes insipidus, 2125 Detrusor hyperreflexia, 2161 Detrusor muscle anatomy of, 2157, 2158f control of, 2161 embryology of, 2157 function of, 2160 innervation of, 2158-2159, 2158f radiographic evaluation of, 2164 Detrusor-urethral sphincter dyssynergia, 2161, 2165 Development infant, 37t older child, 17, 18f Developmental delay cerebral palsy and, 494-495 chromosomal abnormalities and, 548 definition of, 799 global, 799-817 AAN practice parameter for, 799, 805, 806f cognitive impairment in, pharmacologic treatment of, 274 consultation and follow-up in, 814-815 diagnosis of, 801-807 epidemiology of, 799-800 eye abnormalities in, 812b genetic testing in, 812 hair abnormalities in, 813b hearing abnormalities in, 813b imaging in, advances in, 807, 812-813 laboratory testing in, 811-814 metabolic acidosis in, 813b outcome and prognosis in, 274-275 patient evaluation in, 810-815 patient history in, 810-811 physical examination in, 811, 812b-814b risk factors for, 810, 810b seizures in, 812b, 813, 815 skin abnormalities in, 813b sleep disorders in, 274 vomiting in, 813b neonatal stroke and, 333 Sturge-Weber syndrome and, 783 Developmental disorders, 821-824 associated with abnormal head size, 830t-831t associated with abnormal movements, 829t associated with hair abnormalities, 835t associated with hearing abnormalities, 836t-837t associated with hepatomegaly, 832t associated with lower motor neuron abnormalities, 842t associated with MRI abnormalities, 840t-841t associated with ophthalmologic abnormalities, 838t-839t associated with skin abnormalities, 833t-834t causes of, 825t-827t inherited metabolic, 823, 826t-827t classification of, 822, 823t diagnostic evaluation of, 823-824, 824t-843t based on signs and symptoms, 823-824, 828t epidemiology of, 821-823 Volume 1: pages 1–1180

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xxvii

Developmental disorders continued frequency of, 822, 823t incidence of, 821-822 language, 845-851 misdiagnosed as cerebral palsy, 823, 825t pervasive, 905. See also Autism/autistic disorder Developmental reflexes, evaluation of in brain death determination, 1556, 1556t in infant, 42-44, 43t, 50 in preterm infant, 60-61, 60t Developmental tests, 801, 802t Dexamethasone for bacterial meningitis, 1581-1583 for hypoxic-ischemic injury, 1505 for intracranial hypertension, 1522, 1582, 1660 for intraventricular hemorrhage prevention, 323-324 for malaria, 1660 Dexedrine for ADHD, 878t, 941 dosage of, 941 Dexmethylphenidate for ADHD, 878t, 881, 939t dosage of, 939t pharmacology of, 939t Dextroamphetamine for ADHD, 878t, 880-881, 939t comorbid with tic disorders, 897 dosage of, 939t immediate release, 939t labeled and off-labeled use of, 938t for narcolepsy, 1232 pharmacology of, 939t sustained release, 939t toxicity of, 2190 Dextromethorphan, for glycine cleavage defects, 357, 582, 767 Diabetes insipidus, 2124-2125 acquired, 2124 central, 2124-2125 clinical features of, 2124 drug-induced, 2264-2265, 2268 holoprosencephaly and, 397 laboratory findings in, 2124-2125 MRI findings in, 2125 nephrogenic, 2124 treatment of, 2125 Diabetes mellitus autonomic dysfunction in, 2146 in Friedreich’s ataxia, 1249 peripheral neuropathy in, 1905, 2140 teratogenicity in, 2197t Diabetic ketoacidosis, cerebral edema in, 1523 Diagnostix, 2175 Dialysis cofactor deficiency in, 2246 complications of, 2244-2249 incidence of, 2244 prevalence of, 2244 headache in, 2245 intracranial hemorrhage in, 2246 seizures in, 2246 for urea cycle disorders, 611 vitamin deficiency in, 2246 Dialysis disequilibrium syndrome, 2244-2246 Dialysis encephalopathy, progressive, 2242, 2246 3,4-Diaminopyridine for fast-channel congenital myasthenic syndrome, 1961-1962 for Lambert-Eaton myasthenic syndrome, 1957-1958 Diaphragm paralysis, in spinal muscular atrophy, 1864, 1868t testing of, 34t

xxviii

Index

Diastat. See Diazepam, rectal Diastatic suture, 1418 Diastematomyelia, 373, 1859-1860, 1860f clinical characteristics of, 373, 1861 versus diplomyelia, 373 imaging of, 373, 373f, 1860-1861, 1861f type I, 373 type II, 373 Diazepam, 956t adverse effects of, 271, 2367t bioavailability of, 1106t dosage of, 956t drug interactions of, 956t for dystonia, 1289 for febrile seizures, 1084-1086 formulations of, 1106t half-life of, 956t in malaria, 1660 in meningitis, 1582 for muscle overreactivity (spasticity), 2366, 2367t, 2378 for neonatal seizures, 269t pharmacokinetics of, 1106t, 1111-1112 practical guide to, 1051t preparations of, 956t rectal, 1051t, 1085-1086, 1099, 1119, 1120t in renal failure, action and effects of, 2266, 2268 routes of administration, 1106t, 1119-1120, 1120t for sedation, 2378 in spinal cord injury, 1544 for status epilepticus, 1099-1100 for stiff person syndrome, 2106 for Sydenham’s chorea, 1808 in systemic lupus erythematosus, 1814 in traumatic brain injury, 1422 Diazoxide for glucose-6-phosphatase deficiency, 626 for hypertension, 2241 Dicarboxylic aciduria, 721, 2043-2044 in spinal muscular atrophy type III, 1864-1865 Dicentric chromosomes, 528-529 Dichloroacetate, for pyruvate dehydrogenase defects, 730 Dichlorphenamide for Andersen-Tawil syndrome, 2100 for hypokalemic periodic paralysis, 2098 Dichotic testing, of hearing, 113 Dicyclomine, for micturition disorders, 2165t Didanosine, 1603 for HIV infection, 1622 Dideoxycytidine toxicity of, 2192 Dideoxyinosone toxicity, 2192 Dideoxynucleoside triphosphates (ddNTPs), 522-524 Diencephalic syndrome, 1701, 1701f, 1727 Diencephalic tumors, 1709 Diencephalon, 380, 383 absence of, 385-386 Diethyltoluamide, 2184 Differential Ability Scales (DAS), 803t Differential diagnosis, in neurologic history, 3-4 Diffuse axonal injury, 1403, 1411 in inflicted neurotrauma, 1457 magnetic resonance imaging of, 1411, 1411f susceptibility-weighted imaging in, 191 Diffuse cerebral degeneration of infancy. See Alpers’ disease Diffuse progressive degeneration of gray matter. See Alpers’ disease Diffusion tensor imaging, 187, 189, 282-283, 807 preoperative, for epilepsy surgery, 1156-1157

Diffusion-weighted imaging, 184-189 in acute setting, 187 degree of diffusion in, factors in, 185-186 of hypoxic-ischemic injury, 282-283 of periventricular leukomalacia, 289 of stroke, 184-185, 189 Difluoromethylornithine, for African trypanosomiasis, 1664 DiGeorge syndrome, 2224 clinical features of, 466t genetics of, 443f, 466t, 556t Digit extensors, testing of, 34t Digit flexors, testing of, 34t Digital subtraction angiography, in brain death, 1561 Dihydroergotamine for cluster headache, 1199 for migraine, 2378 for orthostatic hypotension, 2142 Dihydrofolate reductase deficiency, folatedependent, 2321 Dihydrolipoyl dehydrogenase deficiency, 725 in maple syrup urine disease, 577-579 Dihydropteridine reductase (DHPR) deficiency, 574-575, 759, 761 Dihydropyridine receptors, 1841, 1848 Dihydroxyacetone phosphate acyltransferase, 738, 750 Dihydroxyphenylserine for dopamine beta-hydroxylase deficiency, 2142, 2142f, 2146 for orthostatic hypotension, 2143 Dilantin. See Phenytoin Dilapidated speech, 849 Dilaudid. See Hydromorphone Dimercaprol, for mercury poisoning, 2184 2,3-Dimercaptosuccinic acid for lead poisoning, 2184 for mercury poisoning, 2184 Dimethylglycine, for autism, 926 Diphenhydramine for acute dystonic reactions, 1288 for nonepileptic paroxysmal disorders, 1213t, 1214 toxicity of, 2191 Diphenoxylate toxicity, 2186 Diphtheria, 1909 Diphtheria toxin, for tumor, 1746 Diphtheria vaccine, 2350 Diphtheria-pertussis vaccine, and polyneuropathy, 1910 Diphyllobothriasis, 1668 classification of, 1648t clinical characteristics of, 1648t diagnosis of, 1648t epidemiology of, 1668 geographic distribution of, 1648t management of, 1648t, 1668 microbiology of, 1668 mode of infection, 1648t pathology of, 1648t, 1668 risk factors for, 1648t Diphyllobothrium latum, 1668. See also Diphyllobothriasis Diplegia atonic, 499 spastic, 498, 500 in Segawa’s disease, 762 Diploid number, 516 Diplomyelia, 373 versus diastematomyelia, 373 Diplopia, 20 with basilar artery migraine, 1189 with increased intracranial pressure, 1517 with myasthenia gravis, 1942-1943 Direct duplication, chromosomal, 529t Volume 1: pages 1–1180

Direct insertion, chromosomal, 529 Disability Rating Scale, 1394 Disequilibrium syndrome, in dialysis patients, 2244-2246 Disintegrative disorder, epileptiform, 1057, 1060t Disintegrative psychosis, 909 Disk herniation, 1528-1529 Dislocations, in muscle overreactivity, 2369 Disopyramide, for neurocardiogenic syncope, 1211b Disruptive disorders, with mental retardation, 815 Disseminated intravascular coagulation in bacterial meningitis, 1578-1579, 1582 in juvenile idiopathic arthritis, 1803 Distal hereditary motor neuropathy, 1868t-1869t Distribution volume, 1109-1110 Diuretic(s). See also specific drugs for hydrocephalus, 321, 430-431 for intracranial hypertension, 1522, 1583 loop, and CSF formation, 155 Divalproex sodium. See Valproic acid Diving reflex, 1486 Dizziness, 123. See also Vertigo DLXL-6 gene, in craniofacial development, 438 DNA, 507-509 alpha-satellite, 516 double helix of, 508, 509f, 541 function of, 508-509, 541-542 low copy repeats of, 518, 525-527, 525f malnutrition and, 2303 mitochondrial, 519, 715-717, 716f, 716t, 2050-2053 defects of, 728-729, 2053-2055 deletions of, 2053-2054 multiple, 2059 depletion syndrome of, 727-728, 2059-2060 duplications of, 2053-2054 point mutations of, 728-729, 2054 affecting protein-coding L genes, 728-729 affecting synthetic genes, 729 rearrangements of, 728, 2053-2054 mutations of (polymorphisms), 518-519, 529-531 noncoding, 518, 541-542 nuclear, defects of, 722-728, 2055-2056 recombinant, 522 repair of, disorders of, 560t, 561 repetitive, 518-519 replication of, 508-509, 516 disorders of, 560t, 561 errors in, 530 satellite, 518-519 structure of, 507-508, 508f-509f, 541, 542f DNA arrays, 524, 807 DNA bases, 507-508, 508f DNA clones, 521 DNA histogram, 1691 DNA methylation analysis, 524 DNA polymerases, 508-509, 509t DNA sequence analysis, 522-523 DNA viruses, 1595, 1595b DNAR (do not attempt resuscitation), 2381 DNR (do not resuscitate), 2381 Docosahexaenoic acid, for peroxisomal disorders, 744 Doll’s-eye reflex, 52, 60, 126, 1387 Domperidone, for orthostatic hypotension, 2143 Donepezil for Down syndrome, 274 for tic disorders, 897 Doose’s syndrome, 1030 L-dopa. See Levodopa Dopa-decarboxylase deficiency, 762-763

Volume 2: pages 1181–2408

Index Dopamine in ADHD, 875-876 in autonomic assessment, 2136, 2138f in basal ganglia, 1273-1274 CSF analysis for, 163 deficiency of, 759-767 L-ADD defects and, 359-360, 360f, 762-763 neurologic symptoms of, 759 patient approach in, 767 secondary, 766 in restless legs disorder, 1233 in Rett’s syndrome, 1320 in Tourette syndrome, 894, 895f Dopamine beta-hydroxylase deficiency, 765, 2136-2137, 2138f-2139f, 2143, 2146 clinical presentation of, 2146 diagnosis of, 2146 treatment of, 2142, 2142f, 2146 Dopamine monooxygenase, in Menkes’ disease, 1322, 1324 Dopamine receptor agonist(s) for L-amino acid decarboxylase deficiency, 763 for dopa-responsive dystonia, 1283 for micturition disorders, 2165 for Parkinson’s disease, 1292-1293 for postoperative movement disorders, 2214 for restless legs syndrome, 1233 for tic disorders, 897 for tyrosine hydroxylase deficiency, 764-765 Dopamine receptor antagonist(s), 964-968 adverse effects of, 964-966 for autism, 923-924 classification of, 964 common characteristics of, 964-966 extrapyramidal side effects of, 964, 965t for orthostatic hypotension, 2143 for postoperative movement disorders, 2214 representative, 965t for tic disorders, 896 Dopamine receptor genes (DRD) in ADHD, 876 in Tourette syndrome, 893 Dopamine transporter (DAT), in ADHD, 875-876 Dopa-responsive dystonia, 761-762, 1282-1283 autosomal dominant, 762, 1283 autosomal recessive, 764-765, 1283 with diurnal variation, 1215, 1282 clinical features of, 1215 genetics of, 1214t, 1215 neurophysiology mechanism in, 1215 treatment of, 1213t, 1215 Doppler ultrasound, 168, 170 transcranial in brain death, 1560-1561 in coma, 1393 of sinovenous thrombosis, 1786 of stroke, 1775 Dormant interneuron hypothesis, 272 Dorsal cleft formation, 364t Dorsal cyst, with holoprosencephaly, 397-398 Dorsal raphe nuclei, in migraine, 1187 Dorsal scapular nerve, 28t Double helix, of DNA, 508, 509f, 541 Double lumen sign, in angiography, 1774 Down syndrome, 551-553 arachnoid cysts in, 435 autism with, 919 celiac disease in, 2289 clinical features of, 552-553, 552f genetics of, 525, 546, 551-552 hearing loss in, 108, 108t life expectancy in, 553 management of, 553

Down syndrome continued mental retardation in, 808 muscle tone in, 69, 552 olfactory dysfunction in, 146-147 pharmacologic treatment in, 274 prenatal diagnosis of, 549, 551 sleep in, 1235 Doxacurium, in traumatic brain injury, 1422 Doxepin for neuronal ceroid lipofuscinosis, 703 pharmacology of, 946 Doxorubicin, for pineal region tumors, 1705 Doxycycline for hyponatremia prevention, 2264 for Lyme disease, 1588 for Mycoplasma pneumoniae infection, 1590 for rickettsial diseases, 1640 for Rocky Mountain spotted fever, 1643 for scrub typhus, 1644 DPAGT1 gene, in congenital glycosylation disorder, 650t, 651 DPM1 gene, in congenital glycosylation disorder, 650t, 651 Dravet’s syndrome, 1012-1013 Dromoran. See Levorphanol Drooling (sialorrhea), 2362 Drop attacks, 1023t, 1030-1031, 1074 Drotrecogin alfa, in bacterial meningitis, 1582 Drowning, 1485-1488 cold-water, 1486 definition of, 1485 dry, 1486 epidemiology of, 1485-1486 fresh versus salt water, 1486 morbidity and mortality in, 1485 pathophysiology of, 1486 prevention of, 1488 prognosis in, 1486-1488 secondary, 1485 wet, 1486 Drowsy patterns, in EEG, 220f, 221-222 Drug abuse, 2173, 2185-2191. See also specific drugs testing for, 2174-2175 Drug disposition in children, 1117-1118, 1117t Drug holidays, in stimulant therapy, 941-942 Drug interactions, 2195. See also specific drugs Drug-induced neurologic diseases, 2173-2199. See also specific drugs and diseases Drusen, 1517 DTDST gene, in chondrodysplasia, 650t Duane’s syndrome, 52, 455 Dubowitz’s syndrome, 464t Duchenne, Guillaume-Benjamin, 1969-1970 Duchenne muscular dystrophy, 1969-1986 calcium in, 1974-1975 abnormal permeability to, 1974-1975 intracellular, chronic increase in, 1974-1975 cardiac involvement in, 1978-1979, 1985, 2224 clinical characteristics of, 1976-1980, 1977f-1978f contractures in, 1978, 1984-1985 diagnosis of, 1980-1981 drug precautions in, 1986 electron microscopy in, 1981, 1981f emotional and behavioral abnormalities in, 1986 exercise in, 1984 exon skipping in, 1971-1972 female carriers of, 1979-1980, 1985-1986 fibrosis and muscle regeneration in, 1976 gastrointestinal involvement in, 1979 gene therapy for, 1983-1984 genetic counseling in, 1985-1986 genetic testing in, 1980 Volume 1: pages 1–1180

Volume 2: pages 1181–2408

xxix

Duchenne muscular dystrophy continued genetics of, 531, 535, 1970-1972 genotype/phenotype correlation in, 1972-1973 Gowers’ maneuver in, 1976-1978, 1977f hip girdle strength in, 1976-1978 historical perspective on, 1969-1970 immunologic response in, 1975 incidence of, 1972 laboratory tests in, 1980 management of, 1981-1986 manifesting carriers of, 1979-1980 mechanical membrane fragility in, 1974 molecular pathogenesis of, 1970-1972 multidisciplinary approach in, 1981 muscle biopsy in, 1980-1981, 1981f muscle hypertrophy in, 1976, 1978f muscle necrosis in, 1973-1974 neuropsychiatric involvement in, 1979 obesity in, 1983 orthotic devices in, 1984-1985, 1985f pathophysiology of, 1973-1976 pharmacologic treatment of, 1982-1984 primary and secondary events in, 1973-1974 pulmonary involvement in, 1978, 1984 reading frame hypothesis of, 1970-1972 rehabilitation in, 1984-1985 respiratory care in, 1984 scoliosis in, 1978, 1985 signaling functions in, 1975-1976 therapeutic window in, 1976 utrophin in, 1844 vascular theory of, 1976 Dumbbell lesions, 1732 Duplex Doppler ultrasound, 168, 170 Duplication, genetic, 526f, 527-528, 529t, 530, 546, 555-557, 555t Dura, 1402, 1402f and craniosynostosis, 442-443 Dural sinus thrombosis diffusion-weighted imaging in, 187 intracranial hypertension with, 1522, 1522f in leukemia, 1736 susceptibility-weighted imaging in, 191 Duret’s hemorrhages, 1410 Duty(ies) as ethical concept, 2388 of neurologist, 2393-2394 of pediatrician, 2392-2393 of physician, 2391-2392 Dwarfism. See also Achondroplasia microcephalic osteodysplastic primordial, 403t, 405 Dynamic brain scintigraphy, 1559 Dynamic contrast-enhanced susceptibilityweighted perfusion imaging, 189 Dysarthria, cerebellar, 1244 Dysautonomia(s) acute or subacute, 2143-2144 familial (Riley-Day syndrome), 143, 1901, 2132, 2144-2145 blood pressure profile in, 2144, 2145f clinical features of, 2144-2145 genetics of, 2144 management of, 2145 prognosis of, 2145 pure cholinergic, 2139f, 2143-2144 barium exam contraindicated in, 2143, 2143f clinical features of, 2143 differential diagnosis of, 2143-2144 sympathetic skin response in, 2137, 2139f treatment of, 2143 Dyschromatopsia, brain tumor and, 1694 Dysdiadochokinesis, 19, 1244, 1296

xxx

Index

Dysembryoplastic neuroepithelial tumors, 1693, 1722, 1732 Dysferlin, 1844, 1970f, 1979 diseases associated with, 1842t, 1844 in limb-girdle muscular dystrophy, 1989, 1991-1992 Dysgeusia, 143 in poisoning/intoxication, 2177, 2177t Dysgraphesthesia, 26 Dyskinesia paroxysmal, 1214, 1297 exertion-induced, 1297-1298 pontocerebellar hypoplasia with, 394 postoperative, in cardiac surgery, 2213-2214, 2213f tardive, 1288, 1301-1302 haloperidol and, 966 neuroleptic agents and, 965t, 966, 968, 1301-1302 symptoms of, 1302 treatment of, 1302 treatment of, 1290 in Wilson’s disease, 2299 Dyskinetic gait, 73-74 Dyslexia, 855-867 characteristics of, 855 cognitive theories of, 856-857 compensatory systems in, 858 computation and component systems in, 858-859, 859f diagnosis of, 863-866, 864b educational accommodations in, 867 epidemiology of, 855 with epilepsy, 1172 etiology of, 855-856 functional brain imaging in, 857 functional MRI in, 857-863, 858f-860f, 862f genetics of, 855 historical perspective on, 855 identification and localization in, 857-858, 858f intelligence testing in, 865 laboratory tests in, 866 magnetoencephalography in, 195, 861 neurobiologic studies of, 857 neurologic examination in, 866 outcome of, 866 phonologic model of, 856-857, 867 physical examination in, 866 plasticity in, 859-861, 860f positron emission tomography in, 857 pre-reading and reading assessment in, 864-865 prevalence of, 855 reading skill trajectory in, 855, 856f treatment of, 866-867 Dysmetria, 1244 ocular, 1246 Dysmyelinating disorders, 1354-1360 classification of, 1345, 1345t Dysmyelinating neuropathy, congenital, 1898 Dysosmia, 146 Dysostosis multiplex, 684, 685f Dysphagia, autonomic dysfunction in, 2137-2138 Dysphonia, spasmodic, 1280 Dyspraxia versus phonologic programming disorder, 848-849 verbal, 849 Dysprosody clinical features of, 822t cortical localization of, 822t Dysreflexia, autonomic, 2147-2148 Dyssomnia(s), 1225-1226, 1226t circadian rhythm, 1225, 1226t extrinsic, 1225, 1226t intrinsic, 1225, 1226f

Dyssynergia cerebellaris myoclonica (Ramsay Hunt syndrome), 109, 1254, 1295, 1608-1609 Dystonia, 1272, 1272t, 1280-1290 acute, neuroleptic agents and, 965-966, 965t, 966 associated movement disorders, 1281-1282 in ataxia-telangiectasia, 1251 causes of, 1281t in cerebral palsy, 499, 1276, 1284 classification of, 1276, 1280-1281 deafness with, syndrome of, 727 definition of, 1280 diagnosis of, 1281 dopa-responsive, 1282-1283 autosomal dominant, 762, 1283 autosomal recessive, 764-765, 1283 with diurnal variation, 1215, 1282 clinical features of, 1215 genetics of, 1214t, 1215 neurophysiology mechanism in, 1215 treatment of, 1213t, 1215 DYT1 (Oppenheim’s), 1282 DYT5. See Dystonia, dopa-responsive DYT8, 1283 DYT10, 1283 DYT12, 1283-1284 etiology of, 1276 in Fahr’s disease, 1286-1287 focal, 1276, 1280 gait abnormalities in, 74 generalized, 1280 genetics of, 1280-1281 hyperkinetic, treatment of, 1290 in kernicterus, 1284 in Lesch-Nyhan disease, 1285-1286 medication-induced, 1288 in mental retardation/developmental delay, 814b multifocal, 1280 myoclonus, 1283 in neuroacanthocytosis, 1287-1288 neurosurgery for, 1289 in organic acidemias, 1286 in pantothenate kinase-associated neurodegeneration, 1284-1285 paroxysmal nocturnal, 1213-1214, 1235, 1297-1298 pathophysiology of, 1274-1275 prevalence of, 1276 primary, 1280, 1282-1284 psychogenic, 1284 secondary, 1284-1286 segmental, 1280 in spinocerebellar ataxia, 1286 in stroke, 1766, 1781 tardive, 1288, 1301-1302 task-specific, 1280 treatments for, 1288-1290 Dystonia musculorum deformans, 1282 Dystonia-plus syndromes, 1281 Dystonic cerebral palsy, 498-499 Dystonic neck posture, with gastroesophageal reflux, 2286 Dystonic paroxysmal choreoathetosis, 1213-1214, 1296-1297 genetics of, 1214t of Mount and Reback, 1213-1214, 1296-1297 treatment of, 1213t, 1214 Dystonic storm, 1281 Dystonic tremor, 1280-1281, 1290 Dystroglycan, 1841f, 1843-1844 diseases associated with, 1843 Dystrophin, 653-654, 1843, 1969, 1970f, 1973 deficiency of, 1843 Volume 1: pages 1–1180

Dystrophin continued diseases associated with, 1842t, 1843, 1969-1987, 2224. See also Becker muscular dystrophy; Duchenne muscular dystrophy function of, 1843 gene for, 1843 isoforms of, 1843 structure of, 1843, 1973 transcripts of, 1973 Dystrophin-glycoprotein complex, 1843-1844, 1969 composition of, 1843

E Ear(s), 97-102 anatomy of, 97-99, 98f-100f anomalies of, and hearing loss, 106, 108, 108t embryology of, 97-99 external, anatomy of, 97 in gestational age estimation, 53t, 57t imaging of, 114 inner, anatomy of, 97-98, 98f middle effusions of, and hearing loss, 97, 106, 109 external, 97 function of, 100 pressure in, equalization of, 97 physiology of, 99-102 reconstructive surgery on, 117 Ear drum, 97 Early infantile epileptic encephalopathy, 266, 268-269 versus early myoclonic encephalopathy, 260, 260t, 268-269 EEG findings in, 268 etiology of, 268 incidence of, 268 prognosis in, 268 seizure type in, 268 therapy for, 268 Early myoclonic encephalopathy, 266-268, 1070t versus early infantile epileptic encephalopathy, 260, 260t, 268-269 EEG findings in, 267 metabolic causes of, 267-268 outcome in, 268 seizure types in, 267 therapy for, 268 East African sleeping sickness, 1663 Eastern equine encephalitis, 1603t, 1612 Ebendazole, for microsporidiosis, 1654 Echinococcosis, 1668-1669 classification of, 1648t clinical characteristics of, 1648t, 1669 diagnosis of, 1648t, 1669 epidemiology of, 1668 geographic distribution of, 1648t, 1668 laboratory tests in, 1669 management of, 1648t, 1669 microbiology of, 1668 mode of infection, 1648t, 1668 pathology of, 1648t, 1668 risk factors for, 1648t Echinococcus, 1668. See also Echinococcosis Echinococcus granulosa, 1668-1669 Echinococcus multilocularis, 1668-1669 Echocardiography of cardiogenic stroke, 2217f in Duchenne muscular dystrophy, 1985 in muscular tone disorders, 69 in stroke patients, 1767

Volume 2: pages 1181–2408

Index Echolalia, 1298 delayed, 908 immediate, 908 Ecstasy (drug), 2187 Eczema, in developmental disorders, 833t Edema cerebral. See Cerebral edema pulmonary, intracranial pressure and, 1518 Edinger-Westphal nucleus, 2130 Edrophonium test in Lambert-Eaton myasthenic syndrome, 1956 in myasthenia gravis, 1946-1947 Education, of hearing impaired, 117-118 Edward’s syndrome (trisomy 18), 464t, 525, 546, 549, 551 clinical features of, 551, 551f management of, 551 Edwin Smith Surgical Papyrus, 153 EEG. See Electroencephalography (EEG) Efavirenz, for HIV infection, 1622 Effexor. See Venlafaxine EFHC1 gene, in generalized epilepsy, 1011 Eflornithine, for African trypanosomiasis, 1664 Ehlers-Danlos syndrome clinical features of, 650t genetics of, 650t hemorrhagic stroke in, 1795 progeroid variant of, 654 Ehrlichia, 1644. See also Ehrlichiosis Ehrlichia chaffeensis, 1644-1645. See also Ehrlichiosis, human monocytic Ehrlichia ewingii, 1641t, 1644-1645 Ehrlichiosis, 1644-1645 human monocytic, 1644-1645 clinical characteristics of, 1641t, 1644-1645 epidemiology of, 1641t geographic distribution of, 1641t incubation period of, 1641t laboratory tests in, 1641t, 1645, 1645f management of, 1641t mode of infection/vector, 1641t, 1644-1645 reservoir for, 1641t Ejaculatory failure, 2131 Electrical shock, 1490-1491 Electrical status epilepticus, 1057 during sleep, 1174, 1234 Electrical-only seizure, 259 Electrocardiography in Duchenne muscular dystrophy, 1979, 1985 in hyperkalemia, 2235 in muscular tone disorders, 69 Electroclinical seizure, 259, 1094 Electrodecremental response, 233 Electrodes, in EEG, 204 application of, 204 arrays or montages of, 204 International 10-20 System of, 204 names and numbers of, 204 placement of, 204 Electroencephalography (EEG), 203-247 abnormal patterns in, 225-236 neurophysiologic basis of, 207-208 abnormal slowing or suppression in, 208-210, 208f in ADHD, 877 in Alpers’ disease, 1327 artifact recognition in, 205-206, 205f bipolar recordings in, 204 in brain abscess, 1588 in brain death determination, 238, 1553-1554, 1558-1559, 1563 in brain tumors, 1696 in breath-holding spells, 240, 1204 calibration in, 204 after cardiac arrest, 1493 in central nervous system infections, 238-239

Electroencephalography (EEG) continued computerized analyses of, 203, 240-247, 264-265 in convulsive syncope, 1212 in degenerative diseases, 239-240 digital, 240 dominant frequency/rhythm in, 218-219, 219f drowsy patterns in, 220f, 221-222 duration of, 206 electrodes in, 204 application of, 204 arrays or montages of, 204 International 10-20 System of, 204 names and numbers of, 204 placement of, 204 epileptiform, 231-236, 984, 991, 996f in absence seizures, 1024t, 1026, 1026f-1027f in atonic seizures, 1031 autistic regression with, 1056-1058, 1059t autistic spectrum disorders with, 10561058, 1059t in benign focal seizures, of childhood, 1044-1045 clinical seizure association of, 231-232 in clonic seizures, 1029 cognitive symptoms with, 1055-1061 electrodecremental response in, 233 focal patterns in, 234-235 focal periodic discharges in, 236-237, 237f in focal seizures, 1037-1042, 1038b, 1040f-1041f generalized patterns in, 233-234 generalized periodic discharges in, 234 in generalized tonic-clonic seizures, 1021 hypsarrhythmia in, 233-234, 234f, 10651066, 1066f-1067f interictal background in, 232, 260 in juvenile myoclonic epilepsy, 1071f, 1072 language impairment with, 1055-1056 multiple independent spike foci in, 236, 236f occipital spikes in, 235 outcome prediction for, 232-233 photoconvulsive response in, 1019-1020, 1020f in progressive myoclonic epilepsies, 1073, 1073b repeat studies of, 231 rolandic spikes in, 234-235, 235f, 1014 secondary bilateral synchrony in, 234 sharp-wave and slow-wave complex, 233 slowing of activity in, 210, 231 spike or sharp-wave discharges in, 207-208, 231 spike-and-wave patterns in, 232f, 233 in status epilepticus, 1097-1098 subclinical, 232 synchronizing mechanisms in, 996f, 997-998, 998f temporal spikes and sharp waves in, 235-236, 235f in tonic seizures, 1030, 1030f evoked-potential, 241-247 in febrile seizures, 237-238, 1080-1081 filter settings in, 205 functional imaging with, 241 in glycine encephalopathy, 239f, 240, 580 in head trauma, 238 in headache assessment, 238 in hepatic encephalopathy, 2295 in herpes simplex virus, 238-239, 1601, 1605 in HIV, 239, 1622 in hypertensive encephalopathy, 2241 hyperventilatory response in, 220-221, 220f, 1026 Volume 1: pages 1–1180

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xxxi

Electroencephalography (EEG) continued in hypoxic-ischemic injury, 238 in impaired consciousness/coma, 1390, 1392 in infancy through adolescence, 218-222 in infantile spasms, 1065-1067, 1066f-1067f input terminal one/two in, 204 instrumental control settings in, 204-205 instrumentation for, 204 interpretation of, 203 in ketogenic diet studies, 1140-1141 in La Crosse encephalitis, 1601, 1616 lambda waves in, 220 in Landau-Kleffner syndrome, 222, 1047, 1055-1056 in language disorders, 850 in Lennox-Gastaut syndrome, 233, 1032, 1032f, 1055 in malaria, 1659 maturational patterns in, 210-222 in measles virus, 238-239, 1617 in mesial temporal sclerosis, 1046 monitoring strategies in, 240-247 mu or central rhythm in, 219 in neonatal hypoglycemia, 348 in neuronal ceroid lipofuscinosis infantile, 1331 juvenile, 1335 juvenile-like variant, CLN9-deficient, 1337 late infantile, classic, 1332 neuronal networks in, 207 neurophysiologic basis for, 206-210 newborn, 210-218 abnormal patterns in, 225-236, 226f-227f, 227t analysis of, guidelines for, 225 in benign neonatal convulsions, 266 in benign neonatal familial convulsions, 267 burst-suppression (paroxysmal) pattern in, 226, 226f, 267-268, 283 continuity/discontinuity in, 212f-214f, 215-218 in early infantile epileptic encephalopathy, 268 in early myoclonic encephalopathy, 267 focal abnormalities in, 227f, 228, 261-262 focal periodic patterns in, 230-231, 230f frontal sharp transients in, 217 gestational age and, 210, 211f-214f gestational age of 28 to 31 weeks, 212f-214f, 215-216 gestational age of 32 to 34 weeks, 214f, 216-217 gestational age of 34 to 37 weeks, 217 gestational age of 38 to 42 weeks, 214f, 217-218 gestational age younger than 28 weeks, 211f, 213f, 215 in hypoxic-ischemic injury, 238, 283 invariant pattern in, 226, 227f isoelectric pattern in, 226, 226f lateralized abnormalities in, 228, 228f multifocal, sharp wave pattern in, 226, 226f, 261-262, 261f-262f normalization in, 225 ontogeny of features in, 213-215 prognosis assessment in, 225-228, 226f-227f, 227t reactivity to stimulation in, 216-217 regional changes in, 210, 213f-214f in seizures, 228-230, 228f-229f, 260-265, 261f-264f, 274 sleep patterns in, 214f, 217-218, 222-223, 223f spikes and sharp waves in, 231 in stroke, 334

xxxii

Index

Electroencephalography (EEG) continued sulcal-gyral development and, 210, 211f-212f synchrony/asynchrony in, 211f, 213f-214f, 215-218, 226f in nonepileptic paroxysmal disorders, 240 nonepileptiform patterns in, abnormal, 237 normal variations in, significance of, 210-222 notations and annotations in, 206 paper speed in, 205 in pediatric neurointensive care, 241 photic stimulation in, 216, 221, 221f, 233, 1019-1020, 1020f physiologic noncerebral channels in, 205 in poisoning, 2175 polarity localization in, 204 posterior occipital transients in, 221, 224f in postoperative seizures, 2212, 2212f potential fields in, 207 practice parameters for, 203-204 preoperative, for epilepsy surgery, 1156 in preterm infants, 53t, 54, 210-217 proper skills and techniques for, 203 recording techniques in, 204 referential recordings in, 204 in reflex anoxic seizures, 1206 in Rett’s syndrome, 240, 910, 1316-1317 in Reye syndrome, 240 sedation for, 206 sensitivity settings in, 204-205 settings for, 203, 206 sleep patterns in, 222-225, 1225, 1226f arousal in, 225 computer analyses of, 241, 242f-243f frequency distribution in, 223f, 225 infant and childhood, 223-224 neonatal, as ultradian rhythm, 222-223, 223f occipital sharp transients in, 224-225, 224f sleep spindles in, 223f, 224 spike discharge in, 224f, 225 of uncertain significance, 225 vertex waves in, 224 sleep-activation procedures in, 222 in specific neurologic situations, 237-240 spike discharges in neurologic conditions associated with, 236-237 temporal or centroparietal, 236 in Sturge-Weber syndrome, 783 in Sydenham’s chorea, 1807 in thalamic tumors, 1700 theta and delta slowing in, 219-220, 220f time constants in, 205 training in, 203-204 in traumatic brain injury, 1420, 1431-1432 in tuberous sclerosis complex, 778 in urea cycle disorders, 608 in uremic encephalopathy, 2237-2238, 2242-2243 utility of, 203 video monitoring with, 240-241, 263 in viral infections, 1601 waking patterns in, 218-219, 219f-220f Electrographic seizure, 1094 Electrolyte(s) abnormalities of, 2324-2327 in bacterial meningitis, 1582 in malaria, 1660 Electromyography, 1852-1853 anal sphincter, 2167 in brachial plexus injury, 341 in dermatomyositis, 2077 in facioscapulohumeral muscular dystrophy, 2000 in gait evaluation, 72

Electromyography continued in Lambert-Eaton myasthenic syndrome, 1956 single-fiber, 1853 in Lambert-Eaton myasthenic syndrome, 1956 in myasthenia gravis, 1948f, 1949, 1949f in spinal cord injury, 1537, 1547 in spinal cord tumor, 1731 in spinal muscular atrophy, 1866 in stiff person syndrome, 2105 Electron transfer flavoprotein deficiency, 724 Electron transfer flavoprotein-coenzyme Q deficiency, 724 Electronic mail, 2399-2400 communicating with patients via, 2405-2406 confidentiality of, 2399-2400 Electronic textbooks, 2401-2404 Electronystagmography, 126-128 clinical applications of, 127b gain in, 128 phase in, 128 technical aspects of, 127b Electrophoresis, of CSF, 161 Electroretinography, 245-246, 246f B wave in, 245, 246f C wave in, 245 A wave in, 245, 246f Electrospray ionization, in congenital glycosylation disorders, 647 Eletriptan, for migraine, 1193t Elimination, of drugs, 1110-1111 children’s physiology and, 1117-1118, 1117t Elimination half-life, 1110-1111 E-mail, 2399-2400 communicating with patients via, 2405-2406 confidentiality of, 2399-2400 Embolism cerebral, cardiac surgery and, 2209, 2209f pulmonary. See Pulmonary embolism Embryonal carcinoma, 1704 tumor markers and survival in, 1704t Embryonal tumors, survival rates with, 1690t Emerin, 1845, 1969, 1970f diseases associated with, 1842t, 1845 in Emery-Dreifuss muscular dystrophy, 1996-1997 Emery-Dreifuss muscular dystrophy, 1969, 1995-1997 cardiac involvement in, 2224 clinical features of, 1996f, 1997, 1997f management of, 1997 molecular biology of, 1995-1996 EMIT drug screen, 2175 EMLA (eutectic mixture of topical anesthetics, prilocaine, and lidocaine), 2377 Emotional concerns, in dying, 2383 Emotional reciprocity, in autistic disorder, 906b, 907 Emotional syncope, 2132 Empty triangle sign, 1783f Empyema, diffusion-weighted imaging of, 187 ems gene family, 438 EMX2 gene, and schizencephaly, 424 Encephalitis. See also specific types and causative agents and chorea, 1279 CSF analysis in, 1575t diffusion-weighted imaging in, 187 EEG findings in, 238-239 and focal seizures, 1048-1049 viral, 1597, 1597b Encephalitis lethargica, 1292 Encephalitozoon, 1654 Encephalitozoon cuniculi, 1654 Encephalocele(s), 376-378 clinical characteristics of, 377-378 definition of, 376 Volume 1: pages 1–1180

Encephalocele(s) continued etiology of, 377 imaging of, 377, 378f incidence of, 376 location of, 377 management of, 378 versus meningoceles, 376 versus nasal glioma, 378 occipital, 378f, 391 pathogenesis of, 364, 366 prenatal diagnosis of, 378 sincipital, 377 syndromes associated with, 377, 377t Encephalofacial angiomatosis. See Sturge-Weber syndrome Encephalomyelitis, acute disseminated (ADEM), 90, 1351-1352, 1596 clinical features of, 1352 magnetic resonance imaging in, 176, 179f, 1352, 1352f pathology of, 1352 perfusion MRI in, 190 treatment of, 1352 Encephalopathy. See also specific types and causes acute, in juvenile idiopathic arthritis, 1803-1804 brain tumor and, 1726-1727, 1727f chronic with multiorgan involvement, 345, 346t without multiorgan involvement, 345, 346t CSF analysis in, 1575t diffuse, 823t EEG studies of, 237 early myoclonic, 260, 260t, 266-268, 1070t epileptic, 1055 age-dependent syndromes of, 268 cognitive and behavioral outcome of, 1173-1174 early infantile, 260, 260t, 266, 268-269 subacute neonatal, 345, 346t, 351-352, 356-360 hypertensive susceptibility-weighted imaging in, 191, 193f in systemic lupus erythematosus, 1810-1811 hypoxic-ischemic. See also Hypoxic-ischemic injury in infants and older children, 1471-1506 in newborns, 279-292, 297-306 metabolic, 345-362, 567 myoclonic, 73 neonatal, syndrome of, 492 occipital-parietal, 2239-2240 subacute epileptic, 345, 346t in term newborns, 47, 48t vision loss with, 86 Enchondroma, in Maffucci’s syndrome, 786, 786f Encoches pointes frontales, 217 Encopresis, 2168 Endocarditis, infective, 2220-2221 neurologic manifestations of, 2220-2221, 2220f-2221f Endocrine disorder(s), 2113-2125. See also specific disorders anatomy and physiology in, 2113-2114 of appetite regulation and energy balance, 2122-2123 of glucocorticoid production, 2118-2120 of pubertal development, 2114-2118 of statural growth, 2120-2121 of thyroid function, 2121-2122 of water balance, 2123-2125 Endodermal sinus tumor, 1704 tumor markers and survival in, 1704t End-of-life care, 2379-2385

Volume 2: pages 1181–2408

Index Endolabyrinthitis, purulent, 98, 105-106, 108-109, 114 Endolymphatic duct, 98, 98f Endomysium, 1838f, 1839 Endonucleases, restriction, 521-522 Endosulfan poisoning, 2183 Endothelin-1 gene (ET1), in craniofacial development, 438 Endotoxin(s) in hepatorenal syndrome, 2259 in hypoxic-ischemic injury, 302 in periventricular leukomalacia, 288 Endplate acetylcholinesterase deficiency, 1960 Endplate potential, 1941, 1942f End-point nystagmus, 125 Energy balance/metabolism, 2122-2123, 2122f cardiac involvement in, 2223 disorders of, 2122-2123 leukoencephalopathies, 1345, 1346t Enjoyment, in autistic disorder, 906b, 907 Enoxaparin for deep vein thrombosis, 2363 pediatric protocol for, 1777, 1777b Entacapone, for Parkinson’s disease, 1293 Entamoeba histolytica, 1646-1649. See also Amebiasis, cerebral Enteric infections, 2290-2292 Enteroviruses, 1610-1611 clinical features of, 1610-1611 diagnosis of, 1611 neuroimaging in, 1611, 1611f outcome of, 1603t, 1611 treatment of, 1611 Enthesitis-related arthritis, 1806 Entorhinal cortex, 137f, 991-992, 993f, 997-998 Enuresis nocturnal, 2157 in boys versus girls, 2162 definition of, 2162 risoria (daytime giggle), 2162 Environmental toxins, 2181-2186 Enzyme enhancement therapy, for lysosomal storage diseases, 664 Enzyme replacement therapy (ERT) for acid maltase deficiency, 628, 630, 2028 for Fabry’s disease, 670 for Gaucher’s disease, 673 for lysosomal storage diseases, 663-664, 663t for Maroteaux-Lamy syndrome, 690 for mucopolysaccharidoses, 685-688 Eosinophilic myositis, 2080 Ependymoblastoma(s), 1725 Ependymoma(s), 1714-1716 age at diagnosis, 1693, 1714 anaplastic incidence of, 1719t survival rates with, 1690t chemotherapy for, 1715-1716 classification of, 1691 clinical characteristics of, 1714 cytogenetics of, 1714 diagnosis of, 1715 gross appearance of, 1714 incidence of, 1687, 1692-1693, 1719t in infants and very young children, 1725, 1729 infratentorial, 1714 management of, 1715-1716 molecular markers of, 1714 in neurofibromatosis type 2, 777 neuroimaging of, 1715 prognostic factors in, 1716 radiation therapy for, 1698, 1715 spinal cord, 1730, 1731f, 1732-1734, 1733f supratentorial, 1714 surgery for, 1715

Ependymoma(s) continued survival rates with, 1690t thalamic, 1700 Ephedrine for micturition disorders, 2165t for neurocardiogenic syncope, 1211b for orthostatic hypotension, 2142 Eph-like receptor tyrosine kinases, in hindbrain patterning, 380-381, 381f Epidermal growth factor receptor, in cancer, 1747 Epidermal nevus syndrome, 786 classification of, 786, 787t clinical features of, 771t, 786, 787t genetics of, 787t Epidermoid tumor, spinal, 1540 Epidural abscess cranial, 1589, 1589f diffusion-weighted imaging of, 187 spinal, 1539, 1589 Epidural hematoma, 1402f, 1403, 1413-1414 clinical presentation of, 337, 1414 computed tomography of, 337, 337f, 1413, 1414f in fall injuries, 1459-1460 in inflicted neurotrauma, 1455-1456 morbidity and mortality in, 1414 in perinatal trauma, 337-338, 1460 outcome of, 338 surgical evacuation of, 337 spinal, 1539 Epidural space, 1402 Epigenetic(s) in autism, 920 definition of, 920 Epigenetic modification, 513 Epilepsia partialis continua, 1047, 1094 Epilepsy, 981-988, 991-1005. See also specific seizure types age-dependent encephalopathy syndromes of, 268 arachnoid cysts and, 435 attention deficit with, 1172, 1177 with autism, 917, 1056-1057 autosomal dominant in infancy, 1009-1010 nocturnal frontal lobe, 1013, 1045-1046, 1045t partial, with auditory features, 1013, 1045, 1045t behavioral aspects of, 987, 1055, 1171-1177 benign, with occipital paroxysms, 235 benign childhood, with centrotemporal spikes, 1014, 1044-1045 in celiac disease, 2289 cellular electrophysiology of, 991-1002 cellular hallmarks in, 991 cerebral palsy and, 495 classification of, 981-983, 982t-983t, 983b, 1009, 1019, 1037, 1038b-1039b, 1042, 1044 five axes system of, 981 cognitive symptoms in, 1055-1061, 1171-1177 conduct disorders with, 1173 continuous or prolonged seizures in, 1091-1102. See also Status epilepticus costs of, 1153 cryptogenic, 981, 982t, 1046-1047 cumulative risk of developing, 1151 delinquency with, 1173 differential diagnosis of, 984, 984b discipline for children with, 1177 EEG studies of, 231-236, 984, 991, 996f clinical seizure association of, 231-232 electrodecremental response in, 233 focal patterns in, 234-235 Volume 1: pages 1–1180

Volume 2: pages 1181–2408

xxxiii

Epilepsy continued focal periodic discharges in, 236-237, 237f generalized patterns in, 233-234 generalized periodic discharges in, 234 hyperventilatory response in, 220-221 hypsarrhythmia in, 233-234 interictal background in, 232, 260 multiple independent spike foci in, 236, 236f occipital spikes in, 235 outcome prediction in, 232-233 photic stimulation in, 233, 1019-1020, 1020f repeat, 231 rolandic spikes in, 234-235, 235f, 1014 secondary bilateral synchrony in, 234 sharp-wave and slow-wave complex in, 233 sleep-activation procedures in, 222 slowing of activity in, 210, 231 spike or sharp-wave discharges in, 207-208, 231 spike-and-wave patterns in, 232f, 233 subclinical patterns in, 232 synchronizing mechanisms in, 996f, 997-998, 998f temporal spikes and sharp waves in, 235-236, 235f family, community, and cultural perceptions of, 1174 febrile seizures and, 1082-1083, 1083t, 1086 focal (partial), 1037-1052 functional MRI in, 193-194, 241 generalized, 1019-1033 genetics of, 1009-1014, 1010f glial mechanisms in, 998-999 hearing loss with, 103 historical background of, 1152-1153 hyperactivity with, 1172 idiopathic, 982t-983t, 1009-1011, 1049-1050 CSF protein content in, 162t evaluation of, 1049-1050 treatment of, 1050 idiopathic partial, 235-236 impulsivity with, 1172 incidence of, 983-984, 983f, 1151 intractability of, 986-987 ion channels in, 992-994, 994t, 1001-1002 learning disabilities with, 856, 1057, 1060t, 1171-1172 limbic, 1046 localization-related, 981, 982t, 1046-1047, 1153-1155 management of, 1049-1050 long-term outcome of, 1052 magnetoencephalography in, 195, 241 with mental retardation, 1171, 1172t mental retardation and, 812b, 813, 815 metabolic factors in, 208 mimics of, 984, 984b mixed generalized-focal, 1047-1048 management of, 1050 multidisciplinary issues in, 1052 with multifocal seizures, 1047-1048 myoclonic, 1063, 1065t, 1070-1074 natural history of, 985-988 neonatal, 257, 259-260, 259b, 265-269 catastrophic syndromes of, 266 early infantile encephalopathy, 260, 260t, 266, 268-269 early myoclonic encephalopathy, 260, 260t, 266-268 therapy for, 269-271 neonatal stroke and, 333 versus neurocardiogenic syncope, 1210 neuronal firing in, 996-997, 996f neuronal synchrony/hypersynchrony in, 991, 996f, 997-998, 998f

xxxiv

Index

Epilepsy continued neurophysiology of, 991-1005 occupational planning and adjustment in, 1177 pathophysiology of, 991, 992t peer relationships in, 1177 positron emission tomography in, 196 post-neonatal, neonatal seizures and, 273, 273t post-traumatic, 1434-1435 EEG findings in, 238 prevention of, 1427-1428, 1435 prevalence of, 1151 primary microcephaly and, 403-404 probably symptomatic, 1046-1047 prognosis of, 1151 proton MR spectroscopy in, 182-183 psychiatric disorders in, 1172-1173 psychosocial outcome of, 987-988 recurrence, after first seizure, 985 remission in, 985-986, 986t with Rett’s syndrome, 917 schizencephaly and, 384 school issues in, 1171-1172, 1177 seizure type in, 981-983, 982t-983t, 983b, 991, 992f sleep and, 274, 1174, 1234 “smooth sailing,” 985 social adjustment of adults with, 1174 social aspects of, 1171, 1174-1177 social isolation in, 1177 Sturge-Weber syndrome and, 782-784 susceptibility, in immature brain, 1000-1002, 1000t symptomatic, 981, 982t, 1009, 1046 management of, 1049-1050 synaptic physiology in, 995-997 syndromes of, 981-983, 982t-983t, 1009 teasing of children with, 1177 temporal lobe, familial mesial, 1013-1014 treatment of ketogenic diet for, 1033, 1131-1146 pharmacologic, 1002-1004, 1105-1126. See also Antiepileptic agents attentional effects of, 1174-1175 behavioral effects of, 1174-1177 cessation of, 986 cognitive effects of, 1174-1177 initiation of, 985 mood effects of, 1174-1175 surgical, 1151-1164. See also Epilepsy surgery tuberous sclerosis complex and, 777-778 vestibular dysfunction with, 132 vision loss with, 86-87 Epilepsy surgery, 1151-1164 cognitive function after, 1152 cost of, 1151 early intervention with, factors favoring, 1154-1155 future trends in, 1164 goals of, 1164 historical background of, 1152-1153 indications for, 1153-1155 multidisciplinary team for, 1155 outcome studies of, 1151-1152 preoperative evaluation for, 1155-1163 concept of congruence in, 1155-1156 EEG in, 1156 functional mapping in, 1162-1163, 1162f magnetoencephalography in, 1161-1162 MR spectroscopy in, 1161 MRI in, 1154, 1154f, 1156-1157, 1157f-1158f PET in, 1160-1161, 1160f physical examination in, 1156 seizure semiology in, 1156

Epilepsy surgery continued SPECT in, 1157-1160, 1159f techniques and technologies in, 1156-1163 research issues in, 1164 types of, 1163-1164 Epileptic encephalopathy, 1055 early infantile, 266, 268-269 versus early myoclonic encephalopathy, 260, 260t, 268-269 EEG findings in, 268 etiology of, 268 incidence of, 268 prognosis in, 268 seizure type in, 268 therapy for, 268 subacute neonatal, 345, 346t, 351-352, 356-360 Epileptiform disorders with cognitive symptoms, 1055-1061 age of onset of first symptoms, 1057-1058 classification of, 1055-1058, 1060t clinical characteristics of, 1055-1058 etiology of, 1058-1059 natural history of, 1057-1058 pathophysiology of, 1058-1059 treatment of, 1059-1060, 1060t Epileptogenic focus, preoperative localization of, 1155-1163 Epimysium, 1838f, 1839 Epinephrine for acid maltase deficiency, 629-630 in autonomic assessment, 2138f for cardiac arrest, 1497-1498 deficiency of, L-ADD defects and, 359-360, 360f in topical analgesia, 2377 Episodic ataxia, 1262 associated with nystagmus, 1215 with myokymia, 1262 type 1, 1247t, 1255t, 1262, 2101t, 2103 type 2, 1247t, 1255t, 1262 type 3, 1255t, 1262 type 4, 1255t, 1262 Episodic ataxia associated with nystagmus, 1215 Episodic hypertension, in dialysis patients, 2244 Epithalamus, 383 Epstein-Barr virus (EBV), 1609-1610 and acute cerebellar ataxia, 1246-1247, 1296, 1609 clinical features of, 1609 diagnosis of, 1602, 1602t, 1609-1610 and Guillain-Barré syndrome, 1609, 1893, 1927, 1927t neuroimaging in, 1601, 1609f, 1610 neurologic sequelae of, 1609f, 1610 outcome of, 1602t, 1609-1610 in renal transplant patients, 2250 treatment of, 1609-1610 Equilibrium reactions, evaluation of, 126 Equine encephalitis, EEG findings in, 238-239 Erb’s palsy, 39, 340-341, 1890-1892, 1892f Ergotamine, for cluster headache, 1199 Erythema nodosum, in coccidioidomycosis, 1633 Erythermalgia, 1826 Erythrocyte(s). See Red blood cell(s) Erythromelalgia, 1826 Erythromycin for cyclical vomiting syndrome, 1217 drug interactions of, 2196 hepatotoxicity of, 2294 for nonepileptic paroxysmal disorders, 1213t for Sydenham’s chorea, 1808 Erythropoietin for orthostatic hypotension, 2143 for spinal cord injury, 1543 Eschar, in scrub typhus, 1643f, 1644 Volume 1: pages 1–1180

Escherichia coli, 2291 in hemolytic-uremic syndrome, 2255-2256, 2258 in meningitis, 1580t, 1581 in myositis, 2082 Escitalopram, 948 adverse effects of, 951-952 dosage of, 948t, 950 initiation and titration of, 950 pharmacokinetics of, 948t, 949 preparations of, 948t Esmolol, for neurocardiogenic syncope, 1211b Esotropia, 21-22, 80, 80f, 81 Essential myoclonus, 1293-1294 Essential tremor, 1290-1291 Etanercept, for juvenile idiopathic arthritis, 1805-1806 Ethacrynic acid and hearing loss, 110 and vertigo, 133 Ethambutol neuropathy induced by, 1909 for tuberculous meningitis, 1586 Ethamsylate, for intraventricular hemorrhage prevention, 323t, 324-325 Ethanol. See Alcohol Ethchlorvynol fetal/neonatal effects of, 2196 intoxication from, 2188 Ethic(s), 2387-2397 AMA code of, 2391-2392 bioethics, 2387 care-based, 2390-2391 character, 2390 clinical, 2387 of euthanasia, 2395-2396 gender differences in, 2390 medical, 2387 neuroethics, 2387, 2396 of perfection, 2396 of personhood, 2394-2395 problems in, 2394-2396 research, 2394 theoretical approach to, 2387-2391 Ethical responsibilities, 2391-2394 of neurologist, 2393-2394 of pediatrician, 2392-2393 of physician, 2391-2392 Ethosuximide for absence seizures, 999-1000, 1023t, 1028-1029 adverse effects of, 1123 bioavailability of, 1106t blood level of, 1051t dosage of, 1051t, 1108t elimination of, 1108t formulations of, 1106t for Landau-Kleffner syndrome, 1059 lupus syndrome induced by, 1811-1812, 2265 mechanism of action, 1119t metabolism of, 1108t optimal range of, 1117t pharmacokinetics of, 1106t, 1108t practical guide to, 1051t preparations of, 1051t protein binding of, 1108t in renal failure, action and effects of, 2267 routes of administration, 1106t volume of distribution, 1108t Ethotoin, 1106t Ethyl alcohol, for motor blockade, 2367 Ethylenediamine tetra-acidic acid, for lead poisoning, 2184 Etomidate for sedation, 2378 in traumatic brain injury, 1422

Volume 2: pages 1181–2408

Index Etoposide for cerebellar astrocytoma, 1714 for ependymoma, 1716, 1729 for primitive neuroectodermal tumors, 1729 teratogenicity of, 2198 Euthanasia ethics of, 2395-2396 passive versus active, 2395 Event-related potentials, 247 in ADHD, 875 Evoked potential(s), 241-247. See also specific types auditory, 242-244, 244f in brain death, 1562 in brain tumors, 1696, 1696f in Canavan’s disease, 1362 after cardiac arrest, 1493-1495, 1494f in coma, 1392 event-related, 247 in hepatic encephalopathy, 2295 in hypoxic-ischemic injury, 283 in multiple sclerosis, 1348-1349 somatosensory, 246, 247f in spinal cord injury, 339, 1537, 1547 in traumatic brain injury, 1432-1433 visual, 244-245, 245f Examination, neurologic. See Neurologic examination Exanthem subitum, 1610 Excitation-contraction coupling, 1848-1850, 1849f Excitatory postsynaptic potential, 207 Excitatory synaptic transmission, 995-996 in immature brain, and seizure susceptibility, 1001 Excitotoxicity in developing brain, 1404 in hypoxic-ischemic injury, 300-301, 300f, 1474-1475, 1502 reduction of, 1502 in spinal cord injury, 1531 in stroke, 1763 in traumatic brain injury, 1405-1406 Executive function in ADHD, 871, 873f in autistic disorder, 911 definition of, 892 in Tourette syndrome, 892 Exencephaly, 377, 379 Exercise bioenergetic substrate utilization in, 2023-2025 for cerebral palsy, 2359-2360, 2359f for Duchenne muscular dystrophy, 1984 glycolysis/glycogenolysis in, 2026-2027 for migraine, 1192 Exercise testing in autonomic assessment, 2135-2136, 2137f forearm ischemic, 2026-2027 isometric handgrip, 2027 in McArdle’s disease, 634, 634f in mitochondrial disease, 2053 Exercise-induced delayed onset myotonia, 2093 Exertion-induced dyskinesia, paroxysmal, 1297-1298 Exon(s), 512, 512f Exon skipping, in Duchenne muscular dystrophy, 1971-1972 Exophoria, 21 Exotropia, 21, 80, 80f, 81 Experience-dependent plasticity, 1404 Experimental allergic neuritis, 1925-1926, 1926f Expressive fluency disorders, 846b, 846t, 848-849, 848f Expressive language, 907t Expressive language disorders, 846b, 849 in autistic disorders, 907

Expressive One Word Picture Vocabulary Test-Revised (EOWPVT), 805 EXT1/EXT2, in hereditary multiple exostosis, 650t, 654 Extensor spasms, 2365 Extinction, 25 Extra-axial fluid collection, in meningitis, 1579, 1579f, 1583 Extracorporeal membrane oxygenation, 2225-2226 contraindications to, 2225 indications for, 2225 mechanisms of neurologic injury in, 2225 neurologic complications of, 2225-2226 Extradural. See Epidural Extraocular muscles, 20-22, 21f, 21t Extrapyramidal cerebral palsy, 498-499 Extrapyramidal disorders, 1271 in poisoning/intoxication, 2177, 2179b Extrapyramidal gait, 73-74 Extratemporal cortical resection, for epilepsy, 1151, 1153, 1163 Extremely low birth weight, 53 Eye abnormalities, in mental retardation/developmental delay, 812b Eye closure, and EEG, 218, 219f-220f Eye contact, in autistic disorder, 906 Eye movements. See also Nystagmus abnormal, 1246 in intraventricular hemorrhage, 320, 320t in neonatal seizures, 258, 258t in vestibular dysfunction, 125-128 assessment of, 80, 80f in infant, 39 in newborn (term), 51-52 in older child, 20-22 in preterm infant, 60 in comatose patient, 1387-1388 in traumatic brain injury, 1409 Eye of the tiger sign, 175, 1285, 1285f Eye pointing, 1316 Eyebrows, interrupted, in Apert’s syndrome, 448 Eyelid abnormalities, 88

F Fabrazyme (agalsidase β), for Fabry’s disease, 670 Fabry’s disease, 669-670, 1774 clinical features of, 669-670, 669f diagnosis of, 670 epidemiology of, 669 genetics of, 661 missed diagnosis of, 661 treatment of, 663, 663t, 670 vision loss with, 88 Face recognition, in autism, 922 Facial defect(s). See also specific types midline, with holoprosencephaly, 397 as predictor of brain defects, 397 Facial development, 437-438 Facial hemiatrophy (Parry-Romberg syndrome), 771t, 785f, 787 Facial nerve (CN VII) anatomy of, 1887, 1888f assessment of in infant, 39 in newborn (term), 52 in older child, 23-24 in smell and taste disorders, 138 impairment or palsy of, 23-24, 23f, 339, 1887-1890 bilateral, 1889 central, 1887 clinical features of, 1887-1889 Volume 1: pages 1–1180

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xxxv

Facial nerve continued differential diagnosis of, 1889, 1890t influenza vaccine and, 2348 laboratory findings in, 1889 lesion localization in, 1887, 1889t in meningeal leukemia, 1735-1736 in Möbius syndrome, 23f, 1870, 1870f, 1889 MRI findings in, 1889 prognosis of, 1889-1890 recurrent, 1890 treatment of, 1889-1890 taste innervation by, 135f, 136, 136f Facial weakness, 1890t Facioscapulohumeral muscular dystrophy, 1969, 1997-2000 clinical features of, 1998-2000, 1998f-1999f diagnostic criteria for, 1998 laboratory findings in, 2000 molecular genetics of, 1997-1998 prevalence of, 1997 treatment of, 2000 Factor H, in hemolytic-uremic syndrome, 2256 Factor V Leiden mutation and intraventricular hemorrhage, 312-313, 312t and neonatal stroke, 329-330 Factor VIIIc, in neonatal stroke, 332 Fahr’s disease, 1286-1287 MRI findings in, 1286-1287, 1287f Failure to thrive, ketogenic diet and, 1143-1144 Fainting lark, 2150-2151, 2151f Falls, 1458-1460 down stairs, 1459 from heights, 1459-1460, 1459f versus inflicted neurotrauma, 1458-1460 short, 1459 walker, 1460 False neurotransmitters, in hepatic encephalopathy, 2295-2296 Family history, 15-16 Family Village (on-line resource), 2405 Fanconi syndrome, renal, 2262-2264 laboratory findings in, 2262 in nephropathic cystinosis, 2263-2264 primary familial, 2262 secondary, 2262-2263, 2262t Fanconi’s anemia clinical features of, 560t genetics of, 560t Fanconi’s pancytopenia, 450 Fansidar (sulfadoxine-pyrimethamine), for malaria, 1659 Farber’s disease, 677 cellular findings in, 677, 677f clinical features of, 677, 677f diagnosis of, 677 treatment of, 677 vision loss with, 88t Farnesyl transferase inhibitors for neurofibromatosis type 1, 274 for tumors treatment, 1746 Farsightedness, 87 Fascicle, muscle, 1838f, 1839 Fasciculation, in uremic encephalopathy, 2237 Fast-channel congenital myasthenic syndrome, 1961-1962 Fastigial nuclei, 1241, 1242f lesions of, 1246 Fasting, therapeutic use of, 1131-1132. See also Ketogenic diet Fasting adaptation, 2037 Fasting studies, in fatty acid oxidation defects, 2044-2045 Fast-twitch muscle fibers, 1846 Fat pad distribution, in mental retardation/developmental delay, 814b

xxxvi

Index

Fatigue chronic syndrome of, 2181 in dopa-responsive dystonia with diurnal variation, 1215 ketogenic diet and, 1143 Fatty acid(s), 717 branched-chain, oxidation of, 738 free, 2037f, 2038 in hypoxic-ischemic injury, 1475-1476, 1475f, 1501 short-chain, in hepatic encephalopathy, 2295-2296 functions of, 2037 unsaturated, oxidation of, 738 very long chain, in adrenoleukodystrophy, 748 Fatty acid oxidation, 721, 721f, 1136-1138, 1136f-1137f, 2037f, 2038 alternative pathway for, 2038 beta, peroxisomal, 735, 736f, 737-738 D-specific pathway of, 736f, 737-738 L-specific pathway of, 736f, 737-738 single-enzyme defects of, 745-749 in Zellweger spectrum disorders, 742-743 defects of, 355-356, 717-718, 721, 2036-2048 biochemical features of, 2038-2042 carnitine concentrations in, 2039, 2040t, 2042-2044 carnitine uptake studies in, 2046 clinical features of, 2038-2042 corn starch, uncooked, for, 2047 diagnostic approaches in, 2044-2046 dicarboxylic acids in, 2043-2044 dietary therapy for, 2047 and encephalopathy, 355-356 enzymatic assays in, 2045t, 2046 fasting studies in, 2044-2045 genetics of, 2039-2041, 2040t, 2045t, 2046, 2048 historical background on, 2036-2037 and hypoglycemia, 348t hypoketotic hypoglycemia in, 2039, 2040t laboratory features of, differentiating, 2042-2044, 2043t laboratory findings in, 2039, 2040t metabolic decompensation in, 2038-2039 pathophysiology of, 354f, 355, 721, 721f patient history in, 2044 physical examination in, 2044 precipitating factors in, avoidance of, 2046-2047 presymptomatic recognition of, 2048 screening for, 2044-2046 susceptibility to, increased, in child, 2037-2038 tissue involvement in, 2039 treatment of, 730, 2046-2048 urinary organic acids in, 2044 in fasting adaptation, 2037 ketogenic diet and, 1136-1138 in muscle metabolism, 2023, 2037f normal pathway for, 2037f, 2038 Fatty acid supplementation, for phenylketonuria, 574 Fazio-Londe disease, 1869-1870 FCMD gene, and cobblestone malformation, 412t, 416f, 417 Febrile seizures, 981, 1079-1086 classification of, 1079 cognitive effects of, 1081-1082 complex, 1079-1080 counseling and education on, 1086 definition of, 1011, 1079 diagnosis of exclusion in, 1080 diagnostic guidelines for, 1080 EEG findings in, 237-238, 1080-1081 epidemiology of, 1079-1080

Febrile seizures continued generalized epilepsy with, plus (GEFS+), 1010-1012, 1019, 1084 genetics of, 1084 home management of, 1085 in-hospital management of, 1084-1085 initial evaluation of, 1080-1081 laboratory tests in, 1080 and mesial temporal sclerosis, 1083-1084 morbidity and mortality in, 1081-1082 pathophysiology of, 1081 prevention of, 1085-1086 antiepileptic agents for, 1085-1086 antipyretics for, 1085 barbiturates for, 1085 benzodiazepines for, 1085 daily medications for, 1085-1086 intermittent medications for, at time of fever, 1085 valproic acid for, 1085 prognosis of, 1079 recurrent, 1082 risk factors for, 1082, 1083t risk factors for, 1080 simple, 1079-1080 and subsequent epilepsy, 1082-1083, 1083t prevention of, 1086 termination of, 1084-1085 treatment of, 1084-1086 guidelines for, 1086 rationales for, 1084 Fecal incontinence, 2157, 2166-2168 differential diagnosis in, 2167b, 2168 laboratory tests in, 2167-2168 management of, 2168 neurologic examination in, 2167 overflow, 2166 partial, 2166 patient evaluation in, 2167-2168 patient history in, 2167 true, 2166 Fecal soiling, 2166 Feeding center, 2122 Feeding problems, in autism, 916 Felbamate absorption of, 1113 adverse effects of, 1032-1033, 1123 for atonic seizures, 1023t behavioral and cognitive effects of, 1175 bioavailability of, 1106t blood level of, 1051t dosage of, 1051t, 1108t, 1113 drug interactions of, 2195-2196 elimination of, 1108t, 1113 formulations of, 1106t hypersensitivity to, 1125, 1125t for juvenile myoclonic epilepsy, 1073 for Lennox-Gastaut syndrome, 1032-1033 mechanism of action, 1003f, 1004, 1004f, 1119t metabolism of, 1108t optimal range of, 1117t pharmacokinetics of, 1106t, 1108t, 1113 practical guide to, 1051t preparations of, 1051t protein binding of, 1108t, 1113 routes of administration, 1106t and sleep, 1234 testing of, 1002 for tonic seizures, 1023t volume of distribution, 1108t, 1113 Felbatol. See Felbamate Femoral nerve, 28t Fenfluramine, for autism, 925 Fentanyl adverse effects of, 2214, 2377 Volume 1: pages 1–1180

Fentanyl continued dosage of, 2376t for intracranial hypertension, 1422, 1583 for pain, 2377 pharmacokinetics of, 2377 transmucosal, 2377 Festination, 74 Fetal alcohol effects, 2197 Fetal alcohol syndrome, 402, 2197 Fetal distress, and intraventricular hemorrhage, 311 Fetal tissue transplant, for spinal cord injury, 1542 FG syndrome, 385t Fiber type disproportion myopathy, 2018 Fiberoptic sensor, for monitoring intracranial pressure, 1423 Fibrillin-related craniosynostosis, 450-451 Fibrin, in thromboembolism, 1762 Fibrinolytic therapy, for hydrocephalus, 321, 431 Fibroblast growth factors (FGFs) in hypoxic-ischemic injury, 1504-1505 for spinal cord injury, 1542 Fibroblast growth factor 14-spinocerebellar ataxia, 1255t, 1261-1262 Fibroblast growth factor receptors (FGFRs) in achondroplasia, 459-460 in craniofacial development, 438 in craniosynostosis, 443, 443f, 447-449, 447t Fibroma(s), in tuberous sclerosis complex, 779, 779f Fibrosis, in Duchenne muscular dystrophy, 1976 Fibrous dysplasia of bone, 457-458 clinical features of, 458 complications of, 458 cystic, 457 diagnosis of, 458 with McCune-Albright syndrome, 457-459 monostotic, 457-458 pagetoid, 457 polyostotic, 457-458 radiographic classifications of, 457 sclerotic, 457 treatment of, 458 Fifth day fits, 266 Filopodia, 1532 Finger extensors, testing of, 34t Finger flexors, testing of, 34t Fingerprint body myopathy, 2019 First Signs program, 928 Fish, mercury contamination in, 2184 Fistula sign, 128 FK-506. See Tacrolimus FKRP gene, 412t, 416f, 654, 1842t FLACC pain scale, 2374, 2375t Flagellate infections, 1647t, 1661 “Flail limb” sign, 341 Flare response, 2140 Flat hearing loss, 104, 112, 112f Flavin adenine dinucleotide, 2308 Flavin mononucleotide, 2308 Flaviviruses, 1595b, 1613-1616 outcome of, 1603t tick-borne, 1613, 1615-1616 Flavor, 136-137 definition of, 137 perception of ontogeny of, 144-147 retronasal, 145-146 Flavoxate, for micturition disorders, 2165t Fleas, as disease vector, 1599 Flexor spasms, 2365 Flexor toe sign, 19 Flies, as disease vector, 1599 FLNA gene, and periventricular nodular heterotopia, 412t, 419f, 420

Volume 2: pages 1181–2408

Index Flocculonodular lobe, 380, 1241, 1242f Floppy, use of term, 65 Floppy infants, 1862-1863. See also Spinal muscular atrophies Flow cytometry, in brain tumor assessment, 1691 Flucloxacillin, for bacterial meningitis, 1581 Fluconazole for candidiasis, 1638 for coccidioidomycosis, 1634 for cryptococcosis, 1633 for granulomatous amebic encephalitis, 1651-1653 for North American blastomycosis, 1634 Fluctuating myotonia, 2091 Flucytosine, for granulomatous amebic encephalitis, 1653 Fludarabine toxicity, 2193 Fludrocortisone for neurocardiogenic syncope, 1211b for orthostatic hypotension, 2141-2142 for vasovagal syncope, 2150 Fluency, 907t in reading, 864-867 Fluency disorders, 846b, 846t, 848-849, 848f Fluid abnormalities, 2324-2327 Fluid management in acute renal failure, 2234-2235 in bacterial meningitis, 1582 in intracranial hypertension, 1520 in stroke, 1779 Fluid resuscitation in hypoxic-ischemic injury, 1500 in malaria, 1660 in traumatic brain injury, 1420-1422 Fluid-attenuated inversion recovery imaging (FLAIR), 1156, 1157f-1158f in acute intermittent porphyria, 2293 Flumazenil for benzodiazepine toxicity, 2181, 2188, 2378 for hepatic encephalopathy, 2297 Flumazenil positron emission tomography, 1161 Flunarizine for alternating hemiplegia of childhood, 1190, 1288 for migraine prevention, 1194t, 1195 Fluorescence in situ hybridization (FISH), 520f, 520-521, 544, 544f, 548f, 561 in brain tumor assessment, 1691 Fluorocytosine for candidiasis, 1638 for granulomatous amebic encephalitis, 1651 Fluorodeoxyglucose (FDG) positron emission tomography, 1160-1161, 1160f Fluoroquinolone, for bacterial meningitis, 1581 Fluoxetine, 948-953 for ADHD, 879t adverse effects of, 951-952, 2189 for autism, 924, 927t clinical applications of, 948-949 dosage of, 948t, 950 initiation and titration of, 950 labeled and off-labeled use of, 938t for narcolepsy, 1232 for neurocardiogenic syncope, 1211b for obsessive-compulsive disorder, 897 pharmacokinetics of, 948t, 949 preparations of, 948t for slow-channel congenital myasthenic syndrome, 1961 Fluphenazine, for tic disorders, 896 Flupirtine, for neuronal ceroid lipofuscinosis, 1328, 1332, 1336, 1338 Flurbiprofen, for orthostatic hypotension, 2143 Fluvoxamine, 948-953 for ADHD, 879t

Fluvoxamine continued adverse effects of, 951-952 for autism, 924 clinical applications of, 948-949 dosage of, 948t, 950 initiation and titration of, 950 labeled and off-labeled use of, 938t for obsessive-compulsive disorder, 897 pharmacokinetics of, 948t, 949 preparations of, 948t FM system, for hearing impaired, 116-117 FMR1 gene, 559-560, 808-809 fMRI. See Functional magnetic resonance imaging (fMRI) Focal conditions, 5-6 Focal cortical dysplasia with abnormal but non-neoplastic cells, 410 without abnormal cell types, 425 with balloon cells, 403t, 410 without balloon cells, 425 epilepsy surgery for, 1153 Focal dystonia, 1276, 1280 Focal nodular myositis, 2080 Focal seizures, 984b, 991, 992f, 1009, 1019, 1037-1052 auras in, 1020-1021 autosomal dominant, with auditory features, 1013, 1045, 1045t behavioral arrest in, 1039-1040, 1041f benign of childhood, 1044-1045 with occipital spikes, 1045 brain tumors and, 1048, 1695 classification of, 1037, 1038b-1039b, 1042, 1044 clonic, 1040, 1041f neonatal, 258, 258t-259t, 260, 266-267 complex, 1037, 1038b, 1042-1044 with complex inheritances, 1014 congenital and prenatal factors in, 1048 cortical malformations and, 1048 EEG findings in, 1037-1042, 1038b, 1040f-1041f epilepsy syndromes with, 1044-1047 etiology of, 1048-1049 familial, with variable foci, 1014, 1045t, 1046 febrile, 1083 genetics of, 1013-1014, 1044-1045, 1045t long-term outcome of, 1052 management of, 1049-1052, 1051t Mendelian, 1013 migrating, of infancy, 1048 mixed with generalized seizures, 1047-1048, 1050 multidisciplinary issues in, 1052 postnatal infectious diseases and, 1048-1049 recognition of, 1037-1042, 1039b refractory, 1052 secondarily generalized, 1044 seizure semiology indicating, 1021b simple, 1037, 1038b, 1042-1043 tonic, neonatal, 258, 258t-259t, 260, 266-267 tonic postures in, 1041 trauma and, 1049 with uncertain alteration of consciousness, 1044 version in, 1041f, 1042 Focal transmantle dysplasia, 403t, 410 Focalin, for ADHD, 878t, 881 Folate (vitamin M), 2318-2321 in biopterin disorders, 575 and cleft lip/palate, 468 deficiency of, 2319-2320 and neural tube defects, 366-367, 369-370, 377, 2319-2320 dependency disorders of, 2305t, 2320-2321 in dihydropteridine reductase deficiency, 761 Volume 1: pages 1–1180

Volume 2: pages 1181–2408

xxxvii

Folate (vitamin M) continued in galactosemia, 620 in Kearns-Sayre syndrome, 730 metabolism of, 2318-2319 in methionine synthase deficiency, 583-584 for methylmalonic acidemia, 588 physiologic functions of, 2318 recommended daily requirement for, 2319 in pregnancy, 2319 for toxoplasmosis, 1656 Folate antagonists, teratogenicity of, 2197t Folic acid. See Folate (vitamin M) Folinic acid-responsive syndrome, 358 Follicle-stimulating hormone, in puberty normal, 2114 precocious, 2115 Fontan procedure, and stroke, 1767, 2217-2218, 2217f Fontanels, 437-438 bulging, in hypoxic-ischemic injury, 280 closure of, 437-438, 438t examination of, 38, 49-50 intracranial pressure monitoring from, 1516 Food ingestion, and orthostatic hypotension, 2135, 2135f Foot, segmental innervation of, 32t Foot dystonia, 1215, 1280 Foot plate, 379, 379f Footballer’s migraine, 1190-1191, 1199 Footling presentation, and birth trauma, 334 Forbes’ disease. See Debrancher deficiency Forced normalization, 1173 Forceps delivery, and birth trauma, 334-335, 339 Forearm, segmental innervation of, 30t Forearm ischemic exercise test, 2026-2027 Forebrain, 379 patterning of, 382-383 Forme fruste, 1316 Förster sign, in atonic cerebral palsy, 499 Foscarnet, 1603 toxicity of, 2192 Fosmidomycin, for malaria, 1659 Fosphenytoin absorption of, 1113 bioavailability of, 1106t formulations of, 1106t loading dose of, 1109t in malaria, 1660 in meningitis, 1582 for neonatal seizures, 270 in hypoxic-ischemic injury, 291 pharmacokinetics of, 1106t, 1113 routes of administration, 1106t, 1119 for status epilepticus, 1098t, 1099-1100 in traumatic brain injury, 1427 14q terminal deletion, 556t Fractured somatotopy, 1242 Fragile sites, 545 Fragile X syndrome, 559-561, 808-809 autism in, 918 clinical features of, 560-561, 808-809 diagnosis of, 559 genetics of, 559-560, 559t, 808-809 incidence of, 559 management of, 561 psychiatric disorders in, treatment of, 815 Fragile X-associated tremor/ataxia syndrome (FXTAS), 560, 808 Frameshift mutations, 531 Fraser’s syndrome, 464t Frataxin, in Friedreich’s ataxia, 1250, 1903 Freckling, axillary, in neurofibromatosis type 1, 772f, 773 Free fatty acids, 2037f, 2038 in hypoxic-ischemic injury, 1475-1476, 1475f, 1501

xxxviii

Index

Free fatty acids continued short-chain, in hepatic encephalopathy, 2295-2296 Free radicals in amyotrophic lateral sclerosis, 1871 in hypoxic-ischemic injury, 301-302, 302f, 1477-1478, 1477f, 1503 Free-flow curve, in urodynamic studies, 2164 Freeman, John, 2397 Frenzel glasses, 125 Frequency, 99-100 Frequency distribution, in EEG sleep patterns, 223f, 225 Friedreich’s ataxia, 1248-1251, 1902-1903 age of onset, 1248t cardiac involvement in, 2224 clinical manifestations of, 1248-1250, 1249f, 1902 diagnostic criteria for, 1249-1250, 1902-1903 genetics of, 1248t, 1250, 1903 hearing loss with, 105t, 1248-1249 neuroimaging in, 1249 pathology of, 1250 prevalence of, 1248 race/ethnicity and, 1248 treatment of, 1250-1251 type 2, 1248t, 1251 vertigo with, 132 vision loss with, 88t Frogleg position, 58, 58f, 66 Froin’s syndrome, 161, 1731 Frontal sharp transients, in EEG, 217 Frontal-subcortical circuits, in Tourette syndrome, 893-894, 893f Frovatriptan, for migraine, 1193t Fructose intolerance, 355 hereditary, 621 biochemistry of, 621 clinical characteristics of, 621 diagnosis of, 621 differential diagnosis of, 621 laboratory tests in, 621 management of, 621 Fructose metabolism, abnormalities of, 621 Fructose-1,6-diphosphatase deficiency, 621 Fructose-1-phosphate aldolase B deficiency, 621 Fryns’ syndrome, 464t α-Fucosidase deficiency, 692 Fucosidosis, 692 clinical features of, 692 diagnosis of, 692 early-onset, 692 later-onset, 692 MRI findings in, 692 treatment of, 692 FUCT1 gene, in congenital glycosylation disorder, 650t Fukutin, 650t, 654, 1969, 1970f diseases associated with, 1842t, 1988t Fukutin-related protein deficiency in congenital muscular dystrophies, 2002 in limb-girdle muscular dystrophy, 1988t, 1993-1994 Fukuyama’s congenital muscular dystrophy (FCMD), 417-418, 1989t, 2003 clinical features of, 417, 650t, 654, 2003 genetic testing for, 417-418 genetics of, 650t, 654, 2003 imaging in, 416f, 2003 management of, 418 Fumarase deficiency, 725, 2056 Fumarylacetoacetate hydrolase deficiency, 575-576, 575f Functional Independence Measure, 1394-1396

Functional magnetic resonance imaging (fMRI), 167, 191-194 in ADHD, 875 advantages of, 195 in autistic disorder, 911 of brain tumors, 193-194 in dyslexia, 857-863, 862f of compensatory systems, 858 of computation and component systems, 858-859, 859f identification and localization in, 857-858, 858f plasticity in, 859-861, 860f with EEG studies, 241 in epilepsy, 193-194, 241 of hydrocephalus, 430 preoperative, 193-194 for epilepsy surgery, 1162-1163, 1162f in spinal cord injury, 1537 Fundoplication, for gastroesophageal reflux, 2287 Fundus flavimaculatus, 88-89 Fungal disease, 1631-1640 CNS syndromes in, 1632t diagnosis of, 1632t geographic distribution of, 1632t in immunocompromised hosts, 1631, 1636-1640 management of, 1632t and myopathy, 2082-2083 in normal hosts, 1631-1636 risk factors for, 1632t Furosemide and CSF formation, 155 and hearing loss, 110 for hydrocephalus, 321, 430-431 and hyponatremia, 2264 for intracranial hypertension, 1522, 1583, 2299 Fusiform face area in autism, 922 in dyslexia, 861 Fusimotor system, 65-66, 1850

G G bands, 516 G6PC gene, 625 Gabapentin, 963 absorption of, 1113 adverse effects of, 959t, 963, 1123-1124, 1176 as antiepileptic agent, 1051t behavioral and cognitive effects of, 1176 for idiopathic epilepsy, 1050 mechanism of action, 1003-1004, 1003f, 1119t in porphyria, 2293 testing of, 1002 in traumatic brain injury, 1435 baseline assessments for, 959t bioavailability of, 1106t, 1113 blood level of, 1051t for chronic daily headache prevention, 1197 clinical applications of, 963 clinical management of, 963 dosage of, 963, 1051t, 1108t elimination of, 1108t, 1113 exacerbation of myoclonic seizures by, 1031, 1074t formulations of, 1106t labeled and off-labeled use of, 937, 938t metabolism of, 1108t for migraine prevention, 1193t monitoring of, 959t, 963 as mood stabilizer, 937, 959t, 963 optimal range of, 1117t Volume 1: pages 1–1180

Gabapentin continued for pain, 2378 in spinal cord injury, 2358 pharmacokinetics of, 1106t, 1108t, 1113 pharmacology of, 963 practical guide to, 1051t preparations of, 959t, 1051t protein binding of, 1108t in renal failure, action and effects of, 2267-2268 for restless legs disorder, 1233 routes of administration, 1106t for stiff person syndrome, 2106 for tic disorders, 896 for tremor, 1291 volume of distribution, 1108t, 1113 Gabitril. See Tiagabine GABRD gene, in generalized epilepsy with febrile seizures plus, 1012 GABRG2 gene, in generalized epilepsy, 1011-1012 Gadolinium-enhanced MRI, 174, 178, 189 Gag reflex, 24, 52 Gait, 69-75 antalgic (painful), 74-75 in ataxia, 1295-1296 center of gravity in, 71 cerebellar, 72-73 in cerebral palsy, prognosis for, 500, 501f conversion reaction, 75 development of, 69-70 disorders of, 69-75 acquired, 70 in aspartylglycosaminuria, 693 congenital, 69 differential diagnosis of, 72-75 evaluation of, 71-72 idiopathic, 70 dyskinetic, 73-74 evaluation of electromyography in, 72 indications for, 70 in infant, 44 kinematic data in, 72 in older child, 27, 33-35, 71-72 in vestibular dysfunction, 125b, 126 extrapyramidal, 73-74 in Friedreich’s ataxia, 1248-1249, 1249f hip weakness, 74 muscle involvement in, 71, 71f phases of, 70-71, 70f physiologic considerations in, 70-71 scissoring, 72 spastic hemiplegic, 72, 496 spastic paraplegic, 72 steppage, 74 waddling, 67, 74 in spinal muscular atrophy type III, 1864 Gait apraxia, 74 Galactokinase deficiency, 620 biochemistry of, 620 clinical characteristics of, 620 and congenital cataracts, 82 incidence of, 620 management of, 620 Galactorrhea, 2118 Galactose metabolism, 617 abnormalities of, 617-620 Galactose tolerance testing, 619 Galactose-1-phosphate uridyltransferase deficiency, 617-620 biochemistry of, 617-618, 618t clinical characteristics of, 618-619 laboratory tests in, 619 management of, 619-620 pathology of, 617

Volume 2: pages 1181–2408

Index Galactosemia, 617-620 and congenital cataracts, 82, 618-620 laboratory tests for, 619 management of, 619-620 MRI findings in, 619 phenotypes of, biochemistry criteria for, 617, 618t prenatal diagnosis of, 619 Galactosialidosis, 659, 694 clinical features of, 694 diagnosis of, 694 genetics of, 694 treatment of, 694 β-Galactosidase C deficiency, 677-680 α-Galactosidase deficiency, 669-670 β-Galactosidase deficiency, 665-667, 689, 694 Galactosylceramide lipidosis. See Krabbe’s disease Galant reflex, 43t Galea, 1402, 1402f Galen, 153 vein of, 38, 394-395 Gallamine, and malignant hyperthermia, 2195 Galutamol, for hyperkalemia, 2235 Gamma efferent system, 1850-1851 Gamma loop (motor) system, 65-66, 65f-66f Gamma-aminobutyric acid (GABA) in CSF, analysis of, 163 in epilepsy, 208, 1001 in absence seizures, 1027f, 1028 as therapeutic target, 1002-1004, 1003f-1004f, 1119 in hepatic encephalopathy, 2295-2296 inhibitory role of, 995, 1001 in ketogenesis, 1136-1138, 1137f ketogenic diet and, 1136-1139 in pyridoxine dependency disorder, 357, 357f in SSADH defect, 357f, 360-361 in status epilepticus, 1092-1093 in Tourette syndrome, 894, 895f in uremic encephalopathy, 2236 Gamma-aminobutyric acid receptor(s) in epilepsy, 995, 1011-1012 as therapeutic target, 1002-1004, 1003f-1004f GABAA, 995 GABAB, 995 in status epilepticus, 1092-1093 Gamma-hydroxybutyrate abuse/poisoning, 2186 for myoclonus dystonia, 1283 Ganciclovir, 1603 for cytomegalovirus, 1607 toxicity of, 2192 for tumor therapy, 1749 Ganglioglioma MRI of, 1154f resection of, 1154 Ganglion of Scarpa, 99 Ganglioneuroma(s), thalamic, 1700 Ganglioside(s), 665 GM1 in Guillain-Barré syndrome, 1926 in spinal cord injury, 1541-1542 Gangliosidoses, 665-669 GM1, 665-667 clinical features of, 666, 666f early infantile, 666 genetics of, 665-666 juvenile or late-onset, 666 laboratory findings in, 666 late infantile, 666 treatment of, 667 GM2, 667-669, 1072t adult-onset, 668 α, 667. See also Tay-Sachs disease

continued B1 variant of, 667 β, 667. See also Sandhoff’s disease childhood-onset, 668 classic infantile, 667-668 EEG findings in, 240 late-onset, 668 pathologic studies of, 668 prenatal diagnosis of, 669 treatment of, 669 vision loss with, 88t Gantrisin. See Sulfisoxazole Gap 0 (G0) phase, of cell cycle, 513 Gap 1 (G1) phase, of cell cycle, 513 Gap junctions, 998 Gasping syndrome, 2185 Gastric irritation, antiepileptic agents and, 1123 Gastric lavage for acetaminophen toxicity, 2190 in lindane poisoning, 2184 Gastrocnemius muscle, in gait, 71f Gastrocnemius reflex, 19t Gastroesophageal reflux, 2286-2287 clinical features of, 2286 diagnosis of, 2286 ketogenic diet and, 1143 management of, 2286-2287 Gastroesophageal reflux disease (GERD), 2286 Gastrointestinal disorder(s) in autism, 916 autonomic, 2137-2138, 2286-2288 episodic, 2285-2292 malabsorption, 2288-2290 neurologic complications of, 2285-2293 Gastrointestinal system, CNS reciprocal relationship with, 2285 Gaucher’s disease, 659, 670-673, 1072t, 1073-1074 diagnosis of, 672 genetics of, 672-673 laboratory findings in, 672 missed diagnosis of, 661 MRI findings in, 673 neurologic involvement in, 671-672, 672f prenatal testing for, 672 treatment of, 663-664, 663t, 673 type 1, 670-671, 671f type 2, 671-672 type 3, 671, 673 vision loss with, 88t G-banding, 520 GBE1 gene, in brancher enzyme deficiency, 632-633 Gbx2, in neural tube organization, 382 GDI1 gene, in mental retardation, 809, 809t Gefitinib, 1745 Gel electrophoresis, 523 Gelsolin, 2260t, 2261 Gene(s) coding region of, 511-512 definition of, 507, 511 in human genome, 518 regulatory region of, 512 structure and organization of, 511-512, 512f Gene mutations, 529-530 Gene Tests (on-line resource), 2404 Gene therapy for aspartylglycosaminuria, 693 for Duchenne muscular dystrophy, 1983-1984 ethical issues in, 2396 for Hunter’s syndrome, 688 for lysosomal storage diseases, 664 Generalized anoxic seizures, 1210 Generalized conditions, 5-6 Generalized dystonia, 1280 GM2

Volume 1: pages 1–1180

Volume 2: pages 1181–2408

xxxix

Generalized epilepsy, 981, 982t, 991, 1009. See also Generalized seizures classic, 1010-1011 with febrile seizures plus (GEFS+), 1010-1012, 1019, 1084 genetics of, 1010-1013 idiopathic, 1010-1011 Generalized seizures, 984b, 991, 992f, 1019-1033 absence, 984b, 1023-1029 atypical, 1024-1025, 1024t automatisms in, 1024 calcium channel blockers for, 999-1000 childhood, 1025 classification of, 1024, 1024t clinical features of, 1023-1025 differential diagnosis of, 1025, 1025t disorders mimicking, 984b EEG findings in, 1024t, 1026, 1026f-1027f etiology of, 1025-1026 juvenile, 1025, 1029 pathophysiology of, 999-1000, 999f, 1026-1028, 1027f prognosis of, 1029 treatment of, 999-1000, 1023t, 1028-1029 typical, 1024-1025, 1024t atonic, 1030-1031 clinical features of, 1030 EEG findings in, 1031 etiology of, 1030 prognosis of, 1030 treatment of, 1023t clonic, 1029 clinical features of, 1029 EEG findings in, 1029 etiology of, 1029 prognosis of, 1029 epidemiology of, 1019 febrile, 1083 mixed with focal seizures, 1047-1048, 1050 tonic, 1029-1030 clinical features of, 1029 EEG findings in, 1030, 1030f etiology of, 1030 in Lennox-Gastaut syndrome, 1029, 1031 neonatal, 258, 258t-259t, 274 prognosis of, 1030 treatment of, 1023t tonic-clonic, 1019-1023 clinical features of, 1019-1020 clonic phase of, 1019, 1021 differential diagnosis of, 1020 EEG findings in, 1021 etiology of, 1021 initial evaluation of, 1021 in Lennox-Gastaut syndrome, 1031 neuroimaging in, 1021 photic stimulation of, 1019-1020, 1020f postictal phase of, 1019, 1021 primary versus secondary, 1020, 1020t prodrome for, 1019 tonic phase of, 1019, 1021 treatment of, 1021-1023, 1023t tonic-clonic alone (GTCA), 1010 Generalized status epilepticus, 1093-1094, 1093b GeneralPediatrics.com, 2404 Genetic(s), 507-537 definition of, 507 Internet resources on, 507t medical, principles of, 532-537 and medicine, 537 Genetic anticipation, 1256 Genetic bottleneck, 680 Genetic code, 510, 511t Genetic counseling, 536-537 in autism, 920 in hearing loss, 107-108

xl

Index

Genetic counseling continued in hemimegalencephaly, 410 in holoprosencephaly, 398 in inborn errors of metabolism, 569-570 legal considerations in, 536 in lysosomal storage diseases, 664 in megalencephaly, 408-409 in microcephaly, 405-406 in phenylketonuria, 572 in polymicrogyria, 425 in recurrent miscarriage, 548 relevance to pediatric neurology, 537 responsibility to relatives in, 537 in schizencephaly, 425 standard of care in, 536 Genetic disorders. See also specific disorders history of, 15-16 Genetic risk, 536t, 537 Genitalia, assessment of, in gestational age estimation, 53t, 57t Genome, 537, 542 definition of, 507 human, organization of, 516-520 mitochondrial, 516-519, 715-716, 716t, 2051-2052, 2051f nuclear, 516-518 Genome mutations, 529 Genomic imprinting, 513, 534, 547, 920 disorders of, 557-558, 558t Genomic microarray, 807 Genomic signaling defects, 727-728 Genotype, 532 Genotyping, 523-524 Gentamicin for bacterial meningitis, 1580t for Duchenne muscular dystrophy, 1983 Genu recurvatum, 67 in spinal muscular atrophy type III, 1864 Geodon. See Ziprasidone Germ cell tumor(s) classification of, 1704 distribution of, 1704 incidence of, 1703-1704, 1719t management of, 1705 mixed, 1704 tumor markers and survival in, 1704t Germinal matrix, 309-310 cell genesis in, 309-310 involution by term, 309 vessel immaturity in, 310 Germinal matrix hemorrhage, 309, 310t, 315. See also Intraventricular hemorrhage timing of, 310, 311t ultrasound of, 316, 316f Germinoma(s), 1704 management of, 1705 pineal region, 1704 suprasellar, 1704 survival rate in, 1704t, 1705 tumor markers in, 1704t Gerstmann’s syndrome clinical features of, 822t cortical localization of, 822t Gerstmann-Sträussler-Scheinker syndrome, 1598 Gert, Bernard, 2388 Gestational age and EEG studies, 210, 211f-214f estimation, in preterm infant, 53-54, 53b, 53t, 54f-56f and intraventricular hemorrhage, 310-311, 311t, 321 Gestational information, in neurologic history, 3 Geste antagoniste, 1280 GFAP gene, in Alexander’s disease, 1360 Ghrelin, 2122f, 2123 Giant aneurysms, 1793

Giant axonal neuropathy, 1903-1904 clinical features of, 1903-1904, 1903f genetics of, 1903 nerve biopsy in, 1903, 1904f Giant cell arteritis, 1804t, 1824-1825 Giant cell astrocytoma(s), 1708 management of, 1708 in region of foramen of Monro, 1708, 1708f with tuberous sclerosis, 1708, 1708f Gigantism, 2121 Giggle enuresis, 2162 Gilles de la Tourette syndrome. See Tourette syndrome Gillespie’s syndrome, 389t Gingival hyperplasia, antiepileptic agents and, 1022, 1123-1124 Glasgow Coma Scale, 1382-1383, 1382t, 1408, 1408t, 1460, 1493, 2355 Glasgow Coma Scale-Modified for Children, 1382t, 1383 Glasgow Outcome Scale, 1393-1395 Glatiramer acetate, for multiple sclerosis, 1349-1350 Glaucoma congenital, 83 in mental retardation/developmental delay, 812b in neurofibromatosis type 1, 774, 774f in Sturge-Weber syndrome, 783-784 Gleevec (imatinib), 1745 GLI2 gene, and holoprosencephaly, 396 Glial cells activity, in EEG, 207 in epileptogenesis, 998-999 proliferation of, 398-400 abnormal, syndromes with, 403t malformations of, 400-410, 402t with abnormal cell types, 409-410 with normal cell types, 400-409 radial, 399 Glial fibrillary acidic protein, 1688 Glioblastoma(s), 1718-1722 age at diagnosis, 1693 classification of, 1691 diffusion-weighted imaging of, 187 genetics of, 1748 management of, 1720-1722 perfusion MRI of, 190 spinal cord, 1733f survival rates with, 1689t, 1718 Glioblastoma multiforme, 1712, 1727f Glioma(s) age at diagnosis, 1693 brainstem, 1717 evoked potentials with, 1696f malignant, 1718-1722 in infants and very young children, 1729 not otherwise specified incidence of, 1719t survival rates with, 1690t mixed, survival rates with, 1690t in neurofibromatosis type 1, 774, 774f, 776, 1702 optic, 1702-1703 in infants and very young children, 1725 perfusion MRI of, 190 supratentorial, 1718 thalamic, 1700f Global cognitive impairment with epileptiform EEG, 1057, 1060t Globoid cell leukodystrophy, 677-680. See also Krabbe’s disease Globo-Luysian group, in athetoid cerebral palsy, 499 Globus pallidus, 1272-1274, 1273f in ADHD, 874-875 Volume 1: pages 1–1180

Globus pallidus continued in dystonia, 1289 in kernicterus, 1284 in movement disorders, 1274, 1275f in pantothenate kinase-associated neurodegeneration, 1285, 1285f Glossopharyngeal nerve (CN IX) assessment of in newborn (term), 52 in older child, 24 in smell and taste disorders, 138 taste innervation by, 135f, 136, 136f GLS1 gene, in congenital glycosylation disorder, 650t Glucagon, for McArdle’s disease, 2031 Glucocerebrosidase deficiency, 670-673 Glucocorticoid(s) for hypoxic-ischemic injury, 1505 production of, disorders of, 2118-2120 Gluconeogenesis, defects of and encephalopathy, 354-355, 354f and hypoglycemia, 348, 348t Glucose in CSF, 160-161 in developing brain, 1404 in exercise, 2023-2024 for hyperkalemia, 2235, 2327 for hyperkalemic periodic paralysis, 2096 in hypoxic-ischemic injury, 290-291, 299-300, 1499 in impaired consciousness/coma, 1390 increased consumption, in illness, 348, 348t in inflicted neurotrauma, 1461 in intraventricular hemorrhage, 320, 320t in metabolic encephalopathies, 345-349 metabolism, disorders of, 346-349. See also Hyperglycemia; Hypoglycemia in muscle metabolism, 1851-1852 permissive effect of, 1136 in sports concussion, 1416, 1416f in traumatic brain injury, 1406 in uremic encephalopathy, 2235-2236 Glucose phosphate isomerase, 636-637 Glucose transporter defects, 359 clinical features of, 350t-351t, 359 MRI findings in, 352t treatment of, 359 Glucose-6-phosphatase deficiency, 624-626 biochemistry of, 625 clinical manifestations of, 622t, 625 enzyme defect in, 622t glycogen structure in, 622t laboratory tests in, 625-626 management of, 626 pathology of, 624-625 type I non-a, 625 type Ia (primary), 625 α-Glucosidase deficiency, 626-628, 698-699, 2028 Glucosylsphingosine, in Gaucher’s disease, 671-672 β-Glucuronidase deficiency, 690 Glutamate excitatory role of, 995-996, 1092 in hypoxic-ischemic injury, 297f, 300-301, 300f, 1474-1475, 1502 metabolism of, 300, 300f neonatal seizures and, 271-272 in spinal cord injury, 1531 in status epilepticus, 1092-1093 in stroke, 1763 in Tourette syndrome, 894, 895f in traumatic brain injury, 1405-1406 in umami taste, 142 Glutamate formiminotransferase deficiency, 2321

Volume 2: pages 1181–2408

Index Glutamate receptors, 995-996 metabotropic, 995-996 NMDA, 995 non-NMDA, 995 in status epilepticus, 1092-1093 Glutamine for Duchenne muscular dystrophy, 1983 in hepatic encephalopathy, 2295 in proton MR spectroscopy, 184f toxicity of, 609-610 Glutaric aciduria, 361, 493, 2042 clinical features of, 350t-351t, 361 MRI findings in, 352t, 361 riboflavin in, 595, 2308-2309 treatment of, 361 type 1, 593-595, 2308-2309 clinical manifestations of, 594 laboratory tests in, 594-595 MRI findings in, 594, 594f treatment of, 595 type 2, 594, 724, 2309 Glutaryl-CoA dehydrogenase deficiency, 593-595 Glutaryl-CoA oxidase deficiency, 751 Glutathione peroxidase, in hypoxic-ischemic injury, 302, 302f Glutathione synthetase deficiency, 595 Gluten intolerance, 2288-2289 Glutethimide intoxication, 2188 Gluteus maximus muscle in gait, 71f testing of, 34t Gluteus medius muscle, testing of, 34t Gluteus minimus muscle, testing of, 34t Glycans, 645. See also Glycosylation; Glycosylation disorders biosynthesis of, 645-647 nomenclatures for, 645 O-mannose, 645, 653, 653f xylose-based, 645 Glycerol, for intracranial pressure increase, 1520, 1660 Glyceryl trioleate, for adrenoleukodystrophy, 749 Glycine in CSF, 163 elevated levels of. See also Glycine encephalopathy in ketotic hyperglycinemia, 587 for isovaleric acidemia, 589 in uremic encephalopathy, 2236 Glycine cleavage, 580, 580f, 767 defects of, 356-357, 356f, 580-582, 767 clinical features of, 350t-351t, 356-357, 767 management of, 357 MRI findings in, 352t Glycine encephalopathy, 580-582, 767 atypical, 581 diagnosis of, 581, 767 EEG findings in, 239f, 240, 580, 767 genetics of, 581 neuroimaging in, 580-581 pathologic findings in, 581 transient variants of, 581 treatment of, 581-582, 767 Glycogen in exercise, 2023-2026 in lysosomal storage diseases, 660t metabolism of, 622-624, 623f-624f, 2025-2026, 2025f Glycogen branching enzyme, deficiency of, 631-633. See also Brancher enzyme deficiency Glycogen storage diseases, 621-637 biochemistry of, 621 cardiac involvement in, 2223-2224

Glycogen storage diseases continued clinical manifestations of, 621, 622t enzyme defects on, 622, 622t glycogen structure in, 622, 622t type I (glucose-6-phosphatase deficiency), 622t, 624-626 type II (Pompé’s disease), 621, 622t, 626-628, 698-699, 2027-2028 type III (debrancher deficiency), 622t, 630-631, 2031-2032 type IV (brancher enzyme deficiency), 622t, 631-633, 1369-1370, 2035-2036 type V (McArdle’s disease), 622t, 633-635, 1850, 2029-2031 type VI (Hers’ disease), 622t, 635 type VII (Tarui’s disease), 622t, 635-636 type VIII (phosphorylase kinase deficiency), 622t, 636, 2028-2029 Glycogen synthetase deficiency clinical manifestations of, 622t enzyme defect in, 622t glycogen structure in, 622t Glycogenolysis defects, 2025-2026, 2026t and encephalopathy, 354-355, 354f idiopathic generalized, 626-628. See also Acid maltase deficiency, infantile and myopathy, 2025-2036 Glycopeptides, in lysosomal storage diseases, 660t Glycoprotein(s), 691 Glycoproteinoses, 691-695 Glycopyrrolate for myasthenia gravis, 1951 for sialorrhea, 2362 Glycosaminoglycans, 654, 683 in amyloidosis, 2261 function of, 654 in lysosomal storage diseases, 659, 660t, 683, 684f synthesis of, defects in, 654-655 Glycosylation cell biology in, 647 enzymes in, 647 N-linked, 645-647, 646f, 648f O-linked, 645 types of, definition of, 645-647 Glycosylation disorders, 645-655 congenital, 361, 647-653 CDG-Ia, 649, 650t CDG-Ib, 649-651, 650t CDG-Ic, 650t, 651 CDG-Id, 650t, 651 CDG-Ie, 650t, 651 CDG-If, 650t, 651 CDG-Ig, 650t, 651 CDG-Ih, 650t, 651 CDG-Ii, 650t, 651 CDG-Ij, 650t, 651 CDG-Ik, 650t, 651-652 CDG-Il, 650t, 652 CDG-IIa, 650t, 652 CDG-IIb, 650t, 652 CDG-IIc, 650t, 652 CDG-IId, 650t, 652 CDG-IIe, 650t, 652 CDG-IIf, 650t, 652 clinical features of, 350t-351t, 361, 389t, 649 defects or types in, 645 diagnosis of, 647-649 group I, 361, 645, 647 group II, 361, 645, 647 MRI findings in, 352t, 361 nomenclature for, 647 prenatal testing for, 649 specific types of, 649-653, 650t testing for, indications for, 652-653 Volume 1: pages 1–1180

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Glycosylation disorders continued transferrin isoforms in, 647-649 muscular dystrophies, 653-654 biochemical and genetic tests in, 654 functional defects in, 653-654 overview of, 653 GM1 gangliosidosis, 665-667 clinical features of, 666, 666f early infantile, 666 genetics of, 665-666 juvenile or late-onset, 666 laboratory findings in, 666 late infantile, 666 treatment of, 667 GM2 gangliosidosis, 667-669 adult-onset, 668 α, 667. See also Tay-Sachs disease B1 variant of, 667 β, 667. See also Sandhoff’s disease childhood-onset, 668 classic infantile, 667-668 EEG findings in, 240 late-onset, 668 pathologic studies of, 668 prenatal diagnosis of, 669 treatment of, 669 Gnathostoma spinigerum, 1668. See also Gnathostomiasis Gnathostomiasis, 1668 classification of, 1647t clinical characteristics of, 1647t, 1668 diagnosis of, 1647t, 1668 epidemiology of, 1668 geographic distribution of, 1647t, 1668 laboratory tests in, 1668 management of, 1647t, 1668 microbiology of, 1668 mode of infection, 1647t, 1668 pathology of, 1647t, 1668 risk factors for, 1647t Goldenhar syndrome, 108t Goldenhar-Gorlin syndrome, clinical features of, 377t Goldmann perimeter test, 79-80 Golgi apparatus, glycosylation in, 645-647, 648f Golgi tendon organs, 65-66, 65f, 67f, 1851 Golgi type II cells, 1241 Gonadal function, radiation therapy and, 1743 Gonadotropin deficiency, 2116-2117 Gonadotropin-releasing hormone, in puberty normal, 2114-2115 precocious, 2115-2116 Goodman’s syndrome, 451 Goosecoid, 438 Gottren’s sign, 2076 Gowers’ maneuver, 27, 29f, 44 in Duchenne muscular dystrophy, 1976-1978, 1977f GPR56 gene and cobblestone malformation, 417 and polymicrogyria, 423, 425 GRACILE, 726 Gradient-recalled echo, in MRI, 173-174 Graft-versus-host disease, 2249-2250, 2298 Gram stain, of CSF, 160 Gram-negative meningitis, 1581 Grand mal seizures, 1019. See also Tonic-clonic seizures Granule cells, 992, 993f, 997-998, 998f, 1241, 1243f Granulomatous amebic encephalitis Acanthamoeba, 1650-1652 classification of, 1647t clinical characteristics of, 1647t, 1651 diagnosis of, 1647t, 1651 epidemiology of, 1650-1651

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Index

Granulomatous amebic encephalitis continued geographic distribution of, 1647t laboratory tests in, 1651 management of, 1647t, 1651 microbiology of, 1650-1651 mode of infection, 1646, 1647t, 1650-1651 pathology of, 1647t, 1650-1651 risk factors for, 1647t Balamuthia mandrillaris, 1652-1653 classification of, 1647t clinical characteristics of, 1647t, 1652-1653 diagnosis of, 1647t, 1652-1653 epidemiology of, 1652 geographic distribution of, 1647t, 1652 laboratory tests in, 1652-1653 magnetic resonance imaging in, 1652, 1653f management of, 1647t, 1653 microbiology of, 1652, 1652f mode of infection, 1646, 1647t, 1652 pathology of, 1647t, 1652 risk factors for, 1647t Granulomatous angiitis, 1821-1824 Granulomatous vasculitis, 1804t Graphesthesia, 26 Grasp reflex, 39-40, 43, 43t, 50, 60 in brachial plexus injury, 340-341 Gratification phenomena, 1219-1220, 1299 Gray matter degenerative diseases of, 1315-1338 volume of, and intraventricular hemorrhage, 312 Gray matter heterotopia, in developmental disorders, 840t Gray Oral Reading Test, 864-865 Gray sleeve, in African trypanosomiasis, 1663 Great arteries, transposition of, 2219f Greig syndrome, genetics of, 443f Grieving, 2383-2384 Gross motor function, screening of, in older child, 17 Gross Motor Function Classification System (GMFCS), 496, 500 “Growing skull fracture,” 336-337, 1418, 1436 Growth serotonin reuptake inhibitors and, 952 statural, disorders of, 2120-2121 stimulant therapy and, 880, 937, 942 Growth deficiency, proportionate, with severe microcephaly, 400-401, 405 Growth factor(s) in brain tumors, 1691 in hypoxic-ischemic injury, 1479, 1504-1505 in oncogenesis, 1748 in spinal cord injury, 1532, 1542 Growth hormone, 2120 deficiency of, 2120-2121 congenital, 2120 evaluation of, 2120 radiation therapy and, 1741-1742, 1742f treatment of, 2121 excess of, 2121 Growth hormone therapy, 461, 2120 GRP56 gene, and polymicrogyria, 412t GT repeats, 519 Guanfacine, 944-945 for ADHD, 880t, 882, 944-945 adverse effects of, 945 clinical applications of, 944 clinical management of, 944-945 drug interactions of, 945 labeled and off-labeled use of, 938t pharmacology of, 944 for tic disorders, 896, 1298 Guanidine, in uremic encephalopathy, 2236

Guanidine hydrochloride, for Lambert-Eaton myasthenic syndrome, 1957 Guanidinosuccinic acid, in uremic encephalopathy, 2236 Guanine, 508, 508f Guanine triphosphate cyclohydrolase deficiency, 350t, 360, 360f Guanosine triphosphate, in oncogenesis, 1748 Guanosine triphosphate cyclohydrolase (GTPCH) deficiency, 574-575, 761, 1282-1283 Guillain-Barré syndrome, 1893-1894, 1919-1931 antecedent events in, 1926-1927 autonomic dysfunction in, 1921-1922, 2149 Campylobacter jejuni and, 1927, 1927t, 2291 clinical features of, 1893, 1919-1923, 1921t clinical variants of, 1922t, 1923-1924 with CNS manifestations, 1922t, 1924 critical care management in, 1929 CSF analysis in, 1925 diagnostic criteria for, 1919, 1920b differential diagnosis of, 1924, 1924b duration of hospitalization in, 1921 duration of symptoms in, 1921 electrophysiologic features of, 1601, 1893, 1920b, 1925 epidemiology of, 1893, 1919 geographic distribution of, 1919 grading scale for, 1921, 1921t hepatitis and, 2293 incidence of, 1893, 1919 laboratory findings in, 1920b, 1924-1925 magnetic resonance imaging in, 1925 management of, 1603, 1893-1894, 1927-1929, 1929t Miller Fisher variant of, 1921, 1922t, 1923 pain in, 1922-1923 pathogenesis of, 1925 pathologic findings in, 1892f, 1893, 1925-1927, 1926f prognosis of, 1893, 1929-1931 sequelae of events in, 1926 triphasic model of, 1919-1921 vaccines and, 1910, 1927, 2347 viral causes of, 1597, 1598b, 1606-1607, 1609, 1893, 1927, 1927t Guillain-Barré Syndrome Study Group, 1921, 1929 Gustation, 135-144. See also Taste Gustatory sweating, 2137, 2139f Guthrie bacterial inhibition assay, for phenylketonuria, 570-571 Gyrate atrophy, 2311

H H band, 1839, 1839f, 1849, 1849f Habit reversal training, for tic disorders, 895 Haddad’s syndrome, 2287 Haemophilus influenzae meningitis, 1571-1573, 1581-1582 after cochlear implants, 1574 neurologic sequelae of, 1577 prevention of, 1584 prognosis of, 1583 recurrent, 1585 treatment of, 1581 vaccines against, 1584 Haemophilus influenzae type B vaccine, 2350 Hair abnormalities antiepileptic agents and, 1124 in developmental disorders, 835t in giant axonal neuropathy, 1903, 1903f Volume 1: pages 1–1180

Hair abnormalities continued in Menkes’ disease, 1321-1322 in mental retardation/developmental delay, 813b in spinal cord tumor, 1732, 1732f Hair cells, auditory, 98, 99f, 101 Hair-grooming syncope, 1212 Haldol. See Haloperidol Half-life of drugs, 1110-1111 Hallervorden-Spatz syndrome, 88t, 1284-1285 Hallucinations definition of, 1378 hypnagogic, 1235 with simple partial seizures, 1042-1043 structured, 1043 Hallucinogen abuse/toxicity, 2186 Halofantrine, for malaria, 1659 Haloperidol, 966-967 adverse effects of, 965t, 966, 2189 anticholinergic effect of, 965t for autism, 923-925, 927t, 966 clinical applications of, 966 dosage of, 965t, 966 drug interactions of, 967 extrapyramidal effect of, 965t fetal/neonatal effects of, 2196 labeled and off-labeled use of, 938t for nonepileptic paroxysmal disorders, 1213t, 1214, 1297 pharmacology of, 966 potency of, 965t preparations of, 965t in renal failure, action and effects of, 2268 for schizophrenia, 966 sedative effect of, 965t for Sydenham’s chorea, 1808 for tic disorders, 896, 966 Halothane contraindicated in Duchenne muscular dystrophy, 1986 hepatotoxicity of, 2294 and malignant hyperthermia, 2195 Halothane-caffeine contracture test, 2195 Hamartin, 781 Hamartoma(s), 1693 hepatic, 2301 hypothalamic, 1701 and precocious puberty, 2115-2116, 2115f in tuberous sclerosis complex, 779-780 Hamstring muscle in gait, 71f testing of, 34t Hamstring reflex, 19t Hand(s), segmental innervation of, 32t Hand dystonia, 1280 Hand patting, in cerebellar assessment, 19 Handheld Computing Center, 2406 Hand-over-hand pointing, 907 Hanging injury, 1488-1489 Hangman’s fracture, 1529, 1535 Hansen’s disease (leprosy), 1590-1591 Haploid number, 514, 516 Harlequin eye sign, in coronal synostosis, 445, 446f Harley-Rand-Ritter (HRR) test, 79 Hartmannella, 1653 Hartnup’s disease, 73, 584-585, 2310 clinical manifestations of, 585 incidence of, 584 laboratory tests in, 585 pathophysiology of, 585 treatment of, 585, 1247t Hawkinsinuria, 576 Head asymmetry, in hydrocephalus, 428-429 development of, 437-438

Volume 2: pages 1181–2408

Index Head continued examination of infant, 38, 48-50 preterm infant, 54f-55f, 58-62, 61f-62f Head and neck surgery, and taste disorders, 143 Head banging, 1219 Head circumference, 38, 48-50, 49f in autistic disorder, 915 brain tumors and, 1725, 1726f in developmental disorders, 830t-831t in hydrocephalus, 427-428 of infant, 38, 48-50, 49f with intracranial pressure increase, 1517 in macrocephaly, 400 in megalencephaly, 408 in mental retardation, 811 in microcephaly, 400 in post-hemorrhagic hydrocephalus, 321-322 of preterm infants, 61-62, 61f-62f in spina bifida, 372 Head growth in preterm infants, 61-62, 61f-62f in Rett’s syndrome, 1315 Head lag, in preterm infants, 54f-55f, 58 Head nodding, 1300 Head rolling, 1219 Head thrust sign, 124 Head tilt, in cerebellar tumor, 19 Head trauma. See also Traumatic brain injury and coma, prognosis in, 1395-1396 computed tomography in, 173, 176f and confusional migraine, 1190-1191 CSF protein content in, 162t diffusion-weighted imaging in, 187 EEG studies in, 238 and focal seizures, 1049 and headache, 1199-1200 inflicted, 1411-1412, 1445-1464 labyrinthine concussion in, 131 magnetic resonance imaging of, 174-175 proton MR spectroscopy in, 181-182 susceptibility-weighted imaging in, 191 unintentional or accidental, 1445 and vegetative state, 1379 Headache(s), 1183-1201 acute, 1184-1185 acute generalized, 1184t acute localized, 1184t acute recurrent, 1184-1185, 1184t analgesic overuse and, 1193, 1197 with arterial dissection, 1769 in boys versus girls, 1183 in brain abscess, 2219-2220 with brain tumor, 1200-1201, 1694, 1695f, 1720 brain tumor and, 1200-1201 in cardiac patients, 2219-2220 chronic daily, 1193, 1196-1198 analgesic agents for, 1197 definition of, 1193 lifestyle changes for, 1196 nonpharmacologic measures for, 1197-1198 outcome of, 1198 prevalence of, 1193 preventive therapy for, 1196-1197, 1196t and quality of life, 1193 secondary causes of, 1193, 1196 chronic nonprogressive, 1184-1185, 1184t chronic progressive, 1184-1185, 1184t classification of, 1183-1185, 1183b-1184b cluster, 1199 with cyclical vomiting, 1184, 1186b, 1191 diagnostic criteria for, 1185-1187, 1185b dialysis-associated, 2245 EEG studies of, 238, 1186 epidemiology of, 1183 evaluation of child with, 1185-1187

Headache(s) continued AAN practice parameter for, 1187-1188, 1200-1201 ancillary studies in, 1187 key questions in, 1186b neuroimaging in, 1187-1188, 1200-1201 with generalized tonic-clonic seizures, 1021 in hypertensive encephalopathy, 2239 with increased intracranial pressure, 1516-1517 lumbar puncture and, 158-159, 1574 management of, 1191-1197, 2378-2379 medicolegal, 1193, 1196 migraine. See Migraine(s) mixed, 1185 new daily persistent, 1193 pain in, 2378-2379 periodic syndromes of, 1184, 1184b, 1191 post-traumatic, 1199-1200, 1436 prevalence of, 1183, 1183t primary, 1183-1184, 1183b, 1187-1191, 1193, 1196-1199 secondary, 1183-1184, 1183b, 1199-1201 with sinovenous thrombosis, 1784 in Sturge-Weber syndrome, 783 syndromes causing, 1184t with systemic lupus erythematosus, 1810 temporal patterns of, 1184, 1184f in Tourette syndrome, 892 Head-shaking nystagmus, 124 Hearing aids, 104, 116-117 Hearing loss, 97-119 in achondroplasia, 460 acquired, 109-110, 109t age at onset, 104-106 amplification for, 104, 116-117 anomalies/malformations causing, 106, 108, 108t assessment of, 110-115 acoustic immittance testing in, 113-114 auditory nerve, 24, 39, 52, 108 behavioral audiometry in, 112-113, 112f113f behavioral tests in, 112-113 central auditory tests in, 113 cortical auditory event-related potentials in, 114 dichotic testing in, 113 electrophysiologic, 113-114 evoked responses/potentials in, 101-102, 102f, 111, 114, 244 imaging in, 114 otoacoustic emissions in, 101, 101f, 111, 114 screening tests in, 112 types of tests in, 112-114 auditory-evoked potentials in, 244 in autistic disorder, 244, 915-916 in cerebral palsy, 495 classification of, 102-106 clinical evaluation of, 110-115 clinical features of, 102-106 cochlear implants for, 104, 117 conductive, 102-103 causes of, 102-103, 103b in developmental disorders, 836t pathology of, 106 tests of, 100 consequences of, 97 cortical, 103 course of, 106 cytomegalovirus and, 109, 115, 1606-1607 developmental and mental status with, 111 in developmental disorders, 836t-837t drug-induced, 109t, 110, 2192-2193 education for children with, 117-118 etiology of, 106-110 Volume 1: pages 1–1180

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Hearing loss continued extracorporeal membrane oxygenation and, 2226 flat, 104 genetic, 105t, 106-108, 115 genetic counseling in, 107-108 high-risk registry for, 111, 111b hyperbilirubinemia and, 109t, 110 infectious causes of, 109, 109t kernicterus and, 1284 laboratory tests for, 110-115 management of, 116-118 meningitis and, 105-106, 109, 114, 1577 in mental retardation/developmental delay, 813b mild, 103-104, 104t moderate, 104, 104t, 112, 113f neoplasms and, 109t, 110 neural, 103 in osteogenesis imperfecta, 105t, 463 otolaryngologic evaluation in, 110-111 outcome of, 118-119 parent counseling in, 107 pathology of, 106 patient and family histories in, 110 perilingual, 104-105 physical evaluation in, 110-111 in Pompé’s disease, 699 postlingual, 104-105 prelingual, 97, 104-105 prevalence of, 97 prevocational, 104-105 profound, 104, 104t, 112, 113f psychologic evaluation in, 115-116 reconstructive surgery for, 117 retrocochlear, 103 rubella virus and, 109, 115, 1613 sensorineural, 103 causes of, 103, 103b in developmental disorders, 836t-837t fibrous dysplasia and, 458 pathology of, 106 static versus progressive, 106 severe, 104, 104t, 112, 113f severity of, 103-104, 104t shape of audiometric threshold in, 104, 112-113, 112f-113f sloping, 104, 112-113, 113f traumatic, 109t, 110 unknown causes of, 106-107 in uremic neuropathy, 2248 urine and blood tests in, 115 U-shaped, 104 vestibular dysfunction with, 103, 111-112, 124-125, 128-130 vision testing in, 111 Heart. See also Cardiac entries in hypoxic-ischemic injury, 281, 281t Heart disease acquired, 2225-2226 congenital cerebrovascular risks in, 1767, 2210-2211, 2216-2219 epidemiology of, 2207 headache in, 2219 and hearing loss, 115 hearing loss in, 115 and learning disabilities, 855-856 management of, 2207 neurological complications of infectious and parainfectious, 2220-2223 non–surgery-related, 2220-2227 in surgical management, 2207-2220 rheumatic, 2225-2226 Heart failure, in Duchenne muscular dystrophy, 1978-1979, 1985

xliv

Index

Heart rate, in sudden infant death syndrome, 1484-1485 Heat sensation, in uremic neuropathy, 2248 Heat shock protein(s), in hypoxic-ischemic injury, 1478-1479, 1501 Heat shock protein 32, 60, 70, 727, 1479, 1501 Heavy metal neuropathy, 1910-1911 Heavy metal poisoning, 826t, 2184-2185 Heel reflex, 43t Heel-to-ear maneuver, in preterm infants, 54f-55f, 58, 59f Heights, falls from, 1459-1460, 1459f Helical computed tomography, 170 Helicase, 508 Helicobacter pylori infection, 2138 Helicotrema, 97, 98f Heliotrope rash, in dermatomyositis, 2076, 2076f Heller’s syndrome, 909 HELLP syndrome, 724 Helminth infections, 1646, 1664-1674. See also specific infections Hemangioblastoma posterior fossa, 786, 1709 in von Hippel-Lindau syndrome, 784-785, 785f Hemangiomas, in Klippel-Trenaunay-Weber syndrome, 788 Hemangiomatosis-overgrowth syndromes, 408 Hematocrit, in cardiac surgery, 2209 Hematologic disorders in hypoxic-ischemic injury, 281, 281t and sinovenous thrombosis, 1785 and stroke, 1769 Hematoma(s) epidural, 337, 1402f, 1403, 1413-1414 clinical presentation of, 337, 1414 computed tomography of, 337, 337f, 1413, 1414f in fall injuries, 1459-1460 in inflicted neurotrauma, 1455-1456 morbidity and mortality in, 1414 in perinatal trauma, 337-338, 1460 outcome of, 338 surgical evacuation of, 337 spinal, 1539 lumbar puncture and, 158 scalp, 1418 subdural, 1402f, 1403, 1413 acute, 1413, 1453-1454 arachnoid cysts and, 435 chronic, 1413, 1435-1436, 1448, 1455 clinical presentation of, 337, 1413 computed tomography of, 173, 337, 1413, 1413f, 1447f, 1453f-1456f in dialysis patients, 2246 in fall injuries, 1459, 1459f and focal seizures, 1049 incidence of, 337 in inflicted neurotrauma, 1447f, 1448, 1453-1455, 1453f-1456f magnetic resonance imaging of, 337, 1435 management of, 337-339, 1413, 1435-1436 mechanisms of, 1453 in osteogenesis imperfecta, 1460 in perinatal trauma, 337-338, 1460 incidence of, 337 laboratory evaluation of, 337 outcome of, 338-339 risk factors for, 337 spinal, 1539 subacute, 1413, 1435-1436, 1448, 1455 subgaleal, 334-336, 1402f benign, 336 blood loss in, estimation of, 336

Hematoma(s) continued versus cephalohematoma, 335-336 clinical presentation of, 336 computed tomography of, 336, 336f incidence of, 336 in inflicted neurotrauma, 1452, 1452f laboratory evaluation of, 336 massive management of, 336 mortality in, 338 outcome of, 338 skull fracture with, 336, 336f subdural hematoma with, 337 Hemianopsia homonymous, 39 in Sturge-Weber syndrome, 783 Hemiballism, 1280 pathophysiology of, 1274-1275 in uremic encephalopathy, 2237 Hemicraniectomy, in stroke, 1779-1780 Hemicranium continuum, 1195 Hemidystonia, 1280 Hemifacial microsomia, 108t Hemimegalencephaly, 403t, 409-410 bilateral, 406f clinical characteristics of, 409 in developmental disorders, 841t epilepsy surgery for, 1153, 1163 genetic counseling in, 410 genetics of, 410 hypomelanosis of Ito with, 403t, 409 Klippel-Trenaunay syndrome with, 403t, 409 linear nevus sebaceus syndrome with, 403t, 409 neuroimaging in, 196, 406f, 409-410 neuromelanosis with, 403t, 409 partial, 406f pathogenesis of, 409 Proteus syndrome with, 403t, 409 severe, 406f syndromes with, 409-410 Hemiparesis alternating, of childhood, 1184, 1190, 1288 in arterial ischemic stroke, 1765, 1765f, 1781 neonatal stroke and, 333 in Parry-Romberg syndrome, 787 periventricular hemorrhagic infarction and, 287 in Sturge-Weber syndrome, 783 in Sydenham’s chorea, 1806-1807 Hemiplegia alternating, of childhood, 1184, 1190, 1288 congenital, periventricular hemorrhagic infarction and, 287 neonatal stroke and, 332-334 spastic, 496-497, 500 Hemiplegic migraine, 1189-1190 familial, 1189-1190 sporadic, 1190 Hemisphere(s), 1241, 1242f embryology of, 383, 398-400, 399f Hemispherectomy, for epilepsy, 1153, 1163 Hemi-syndrome, 1190 Hemizygous allele, 532 Hemodialysis. See Dialysis Hemolytic-uremic syndrome, 2254-2258 classic infantile, 2254-2255, 2254t classification of, 2254-2255, 2254t clinical features of, 2254, 2257, 2257t D+ or D–, 2254t, 2255-2257 endocrine, 2254t, 2255 familial, 2254-2255, 2254t, 2256 immunologic, 2254t, 2255-2257 onset of, 2254 pathology of, 2255 postinfectious, 2254-2256, 2254t Volume 1: pages 1–1180

Hemolytic-uremic syndrome continued secondary, 2254t, 2255 sporadic, 2255-2257 tacrolimus-associated, 2257 versus thrombotic thrombocytopenic purpura, 2252-2253, 2257t treatment of, 2257-2258 Hemorrhage. See specific types and anatomic sites Hemorrhagic disease of newborn, 2318 Hemorrhagic stroke, 1759, 1788-1795 aneurysms and, 1794-1795 versus arterial ischemic stroke, 1788 disorders causing, 1788b general features of, 1788-1789 intracranial hemorrhage and, 1788-1790 outcome of, 1788 subarachnoid hemorrhage and, 1788-1790 traumatic intracranial hemorrhage and, 1790 vascular disorders underlying, 1790-1795 vascular malformations and, 1790-1794 Hennebert sign, 128 Henoch-Schönlein purpura, 1821 laboratory findings in, 1818t, 1821 management of, 1821 neurologic manifestations of, 1818t, 1821 Heparan sulfate, 654, 683, 685 degradation defect of, 688-689 Heparin adverse effects of, 1776 for deep vein thrombosis, 1776, 2363 low-molecular-weight, 1776-1777, 1777b, 1787, 2218, 2363 mechanism of action, 1776 pediatric protocol for, 1776, 1776b postoperative, in cardiac patients, 2218 for sinovenous thrombosis, 1787 for stroke, 332, 1775-1776 Hepatic disease/dysfunction in Alpers’ disease, 1326-1328 cognitive effects of, 2297-2298 in galactosemia, 620 in glucose-6-phosphatase deficiency, 625 in hypoxic-ischemic injury, 281, 281t and neonatal hypoglycemia, 348, 348t neurologic complications of, 2293-2301 in phosphorylase kinase deficiency, 636 in urea cycle disorders, 608, 611-612 Hepatic encephalopathy, 2294-2298 classification of, 2294 clinical features of, 2294-2295 cognitive effects of, 2297-2298 electrophysiologic studies of, 2295 etiology of, 2294 grading of, 2294 laboratory tests in, 2295 minimal, 2297 neuroimaging in, 2295 neurologic examination in, 2294 neuropathology of, 2295 pathophysiology of, 2295-2296 precipitating factors in, 2294 prognosis of, 2297 treatment of, 2296-2297 Hepatic failure, 2294-2298. See also Hepatic encephalopathy fulminant, 2297 in hepatorenal syndrome, 2258-2259 Hepatic phosphorylase deficiency, 622t, 636 Hepatic transplantation for brancher enzyme deficiency, 633 for hepatorenal syndrome, 2259 for hyperoxaluria, 751 neurologic complications of, 2298 for urea cycle disorders, 611-612 for Wilson’s disease, 2300

Volume 2: pages 1181–2408

Index Hepatic tumors, 2301 Hepatitis, 2293-2294 fulminant, 2294 and hepatorenal syndrome, 2258 Hepatitis A virus, 2293 Hepatitis B vaccine, 2350 Hepatitis B virus, 2293 Hepatitis C virus, 2293-2294 neurologic manifestations of, 2285, 2293-2294 in renal transplant patients, 2250-2251 Hepatobiliary disease, neurologic complications of, 2293-2301 Hepatocellular carcinoma, 2301 Hepatolenticular degeneration, 2299-2300. See also Wilson’s disease Hepatomegaly, in developmental disorders, 832t Hepatophosphorylase deficiency, 635 biochemistry of, 635 clinical manifestations of, 622t, 635 enzyme defect in, 622t genetics of, 635 glycogen structure in, 622t management of, 635 Hepatorenal syndrome, 2258-2259 clinical features of, 2259 pathophysiology of, 2258-2259 treatment of, 2259 type 1, 2258-2259 type 2, 2258 Hepatorenal tyrosinemia, 575-576 clinical manifestations of, 576 clinical spectrum of, 575 disease status in target organs, 576 incidence of, 575 laboratory tests in, 576 management of, 576 neurologic crises in, 576 pathophysiology of, 575-576, 575f Hepatosplenomegaly, in mental retardation/developmental delay, 813b Hepatotoxic drugs, 2301 Herbal medicine, and neurotransmitter deficiency, 766-767 Hereditary Hearing Loss Homepage, 107 Hereditary motor and sensory neuropathy, 1897-1901. See also Charcot-MarieTooth disease with focally folded myelin, 1898 of neuronal type with onset in early childhood, 1899 Hereditary multiple exostosis, 650t, 654 Hereditary neuralgic amyotrophy, 1892 Hereditary sensory and autonomic neuropathy, 1901-1902, 2144 type I, 1901 type II, 1901 type III, 143, 1901 type IV, 1901-1902 type V, 1902 Heredity chromosomal basis of, 513, 516 molecular basis of, 507-513 Heredopathia atactica polyneuritiformis. See Refsum’s disease Heregulin, 1844 Hermansky-Pudlak syndrome, 85 Herniation, definition of, 1410 subfalcine, 1410 Herniation syndromes, 1388-1390, 1403, 1403f, 1410 brain tumors and, 1694 central, 1389, 1410, 1518 cingulate, 1403f, 1518-1519 infratentorial, 1389-1390 intracranial pressure increase and, 1518-1519, 1518f

Herniation syndromes continued lumbar puncture and, 1574 rostral-caudal deterioration in, 1388 tonsillar, 453, 1403f, 1410, 1518, 1694 transtentorial, 1518 central, 1410 downward, 1389 lateral, 1410 in malaria, 1658 uncal, 1388 Heroin, 2186, 2196 Herpes simplex virus, 1604-1606 clinical features of, 1604-1605 congenital, 364, 1604, 1604f diagnosis of, 1602, 1602t, 1605 diffusion-weighted imaging in, 187 EEG findings in, 238-239, 1601, 1605 epidemiology of, 1600 in leukemia, 1738 neonatal, 1604 neuroimaging in, 1601, 1604f, 1605, 1605f in older children and adolescents, 1604 outcome of, 1603t, 1605-1606 and pseudobulbar palsy, 1605f, 1606 relapsed or persistent, 1606 in renal transplant patients, 2250 treatment of, 1605-1606 type 1, 1604 transmission of, 1599-1600, 1604 type 2, 1604 Herpesviruses, 1595b, 1604-1610. See also specific types Hers’ disease, 635 biochemistry of, 635 clinical manifestations of, 622t, 635 enzyme defect in, 622t genetics of, 635 glycogen structure in, 622t management of, 635 Hertz (Hz), 99-100 Heterochromatin, 516, 542 Heteromorphisms, 545, 545t Heterophorias, 21 Heterotopic ossification, 2363-2365 clinical findings in, 2363-2364 incidence of, 2363 manipulation in, benefits versus risks of, 2365 pathophysiology of, 2364 radiographic features of, 2364, 2364f treatment of, 2365 Heterotropias, 21-22 Heterozygosity, loss of, 1747 Heterozygous alleles, 532 Hexosaminidase A deficiency, 1865 Hiatal hernia, with gastroesophageal reflux, 2286 High-fiber diet, for defecation disorders, 2168 Highly active antiretroviral therapy (HAART), 1622 Hindbrain, 379, 380f patterning of, 380-381, 381f-382f Hip(s) dislocation, in muscle overreactivity, 2369 infant, evaluation of, 40 segmental innervation of, 31t Hip abductors, testing of, 34t Hip girdle strength, 72 in Duchenne muscular dystrophy, 1976-1978 Hip weakness gait, 74 Hippocampal sclerosis, diffusion-weighted imaging in, 187 Hippocampus, 991-992, 993f in epilepsy abnormal neuronal firing in, 996-997, 996f neuroimaging of, 1157 synchronizing mechanisms in, 996f, 997-998, 998f Volume 1: pages 1–1180

Volume 2: pages 1181–2408

xlv

Hippocampus continued in hypoxic-ischemic injury, 1472-1473 hypoxic-ischemic injury to, 285-287 magnetic resonance imaging of, 282, 286 in meningitis, 1578-1579 neonatal seizure effects on, 272 dormant interneuron hypothesis of, 272 sprouting hypothesis of, 272 synaptic transmission in, 995-996 excitatory, 995-996 inhibitory, 995 Hippocrates, 153, 1657 Hippocratic Oath, 2391 Hirschsprung’s disease, 2152, 2287 conditions associated with, 2287 diagnosis of, 2287 genetics of, 2287 incidence of, 2287 pathogenesis of, 2287 Hirsutism, in developmental disorders, 835t Hiskey-Nebraska Test of Learning Aptitude, 116 Histamine receptor type 1 antagonists. See Antihistamine(s) Histamine receptor type 2 antagonists, for gastroesophageal reflux, 2286-2287 L-histidase deficiency, 585 Histidinemia, 585 clinical manifestations of, 585 laboratory tests in, 585 pathophysiology of, 585 treatment of, 585 Histone(s), 516, 541 Histoplasma capsulatum, 1635. See also Histoplasmosis Histoplasma duboisii, 1635 Histoplasmosis, 1635-1636 clinical characteristics of, 1635-1636 CNS syndromes in, 1632t diagnosis of, 1632t, 1635-1636 epidemiology of, 1635 geographic distribution of, 1632t, 1635 laboratory tests in, 1635-1636 management of, 1632t, 1636 microbiology of, 1635 myositis in, 2083 pathology of, 1635 in renal transplant patients, 2250 risk factors for, 1632t History family, 15-16 neurologic, 3-16 HIV. See Human immunodeficiency virus infection Hoffman reflex, 19 Hoffmann, Johann, 1862 Holmes-Adie pupil, 2132, 2152 Holocarboxylase synthase deficiency, 591, 730 clinical manifestations of, 591 diagnosis of, 591 etiology of, 591 laboratory tests in, 591 treatment of, 591 Holoprosencephaly, 379, 395-398 alobar, 395f, 396-397 clinical characteristics of, 397, 464t description of, 395-396 in developmental disorders, 841t endocrinologic effects of, 397-398 environmental causes of, 396-397 genetic causes of, 396-397, 443f, 464t genetic counseling in, 398 incidence of, 395 lobar, 395f, 396-397 magnetic resonance imaging of, 395f, 398 management of, 397-398

xlvi

Index

Holoprosencephaly continued middle interhemispheric variant, 395f, 396-397 nonsyndromic, 396 outcome in, 397 pathologic features of, 395-396 prenatal diagnosis of, 398 radiologic features of, 395-396, 395f semilobar, 395f, 396 subtypes of, 395f, 396 in trisomy 13, 550 Homeobox genes, 383 in craniofacial development, 437-438 Homepage, 2400 Homocysteine, 582 elevated levels of, 582-584 measurement of, 1774 and stroke, 329-330, 332, 1773-1774, 2320 Homocystinuria(s), 582-584, 582f, 2320 betaine for, 582f, 583 in cystathionine β-synthase deficiency, 582-583, 582f incidence of, 582 in methionine synthase deficiency, 583-584 in methylene tetrahydrofolate reductase deficiency, 584 pathophysiology of, 582, 582f Homologous chromosomes, 516 Homologs, 516 Homovanillic acid, CSF analysis for, 163 Homozygous alleles, 532 Horizontal suspension response, 43t, 50, 67 Horner’s sign, 341 Horner’s syndrome, 20, 20f, 22, 51f, 52, 88, 341, 2140, 2152 in Parry-Romberg syndrome, 787 with simple partial seizures, 1043 Hornova-Dlurosova syndrome, 2260t Hospice, 2379, 2382-2383 Hot tub drowning, 1485 HOTV test, of visual acuity, 78, 79f Hounsfield units, 170 Howland, John, 1131 Hox genes in craniofacial development, 437-438 in hindbrain patterning, 380-381, 381f Hoyeraal-Hreidarsson syndrome, 389t HSAS syndrome, 427-428, 433 Human Genome Project, 507, 507t, 518-520, 537, 542 Human herpesviruses types 6, 7, and 8, 1602t, 1610 Human immunodeficiency virus infection, 1620-1622 clinical features of, 1621 and congenital anomalies, 364 diagnosis of, 1602, 1602t, 1621-1622 EEG findings in, 239, 1622 epidemiology of, 1600, 1621 myositis in, 2081 neuroimaging in, 1622, 1622f opportunistic infections in, 1621-1622 cryptococcosis, 1631-1633 cytomegalovirus, 1606, 1622 granulomatous amebic encephalitis, 1650-1651 toxoplasmosis, 1656 outcome of, 1603t, 1622 and stroke, 1767 transmission of, 1621 treatment of, 1622 Human leukocyte antigen(s) in celiac disease, 2289 in multiple sclerosis, 1349 Human T-cell lymphotropic virus type I, 1603t, 1620, 1622-1623

Hunter-McAlpine syndrome, 451 clinical features of, 442t, 451 genetics of, 442t, 451 Hunter’s syndrome, 688 attenuated form of, 688 clinical features of, 688, 688f diagnosis of, 688 genetics of, 661 hearing loss with, 105t, 107, 115 severe form of, 688, 688f treatment of, 663, 663t, 688 vision loss with, 88t Huntington’s disease, 1277 clinical presentation of, 1277 genetics of, 1277 juvenile, 1288 magnetic resonance imaging in, 175 prognosis of, 1277 treatment of, 1277 tremor in, 1291 Hurler syndrome, 686-688 clinical features of, 686, 686f complications of, 686-687 genetics of, 687 MRI findings in, 686 skull radiography in, 686 treatment of, 687-688 vision loss with, 88, 88t Hurler-Scheie syndrome, 686-688 clinical features of, 687 treatment of, 663, 663t, 687-688 Hurst, E. Weston, 1352 HUS. See Hemolytic-uremic syndrome Hutchinson’s teeth, 1587 Hutchinson’s triad, 1587 Hyaline bodies, 1517 Hyaline body myopathy, 2019 Hydatid disease, 1668. See also Echinococcosis Hydralazine for hypertension, 2241 lupus syndrome induced by, 1811 Hydrocarbon-based solvents, intoxication/ poisoning from, 2186-2187 Hydrocephalus, 48, 62, 425-433 with achondroplasia, 460-461 acute, 427 age and, 430 with aqueductal stenosis, 427-428, 429f, 433 arachnoid cysts and, 435-436 with basilar impression, 461 with brain tumors, 1728 with Chiari II malformation, 375-376 with choroid plexus tumors, 428 classification of, 426-427 clinical characteristics of, 427-430 communicating, 427 in meningeal leukemia, 1735 computed tomography of, 429, 430f with craniosynostosis, 444, 453 with Crouzon’s disease, 448 with cryptococcosis, 1632-1633 with Dandy-Walker malformation, 391, 393 differential diagnosis of, 427, 428b diuretics for, 321, 430-431 with encephalocele, 378 etiology of, 407b fibrinolytic therapy for, 321, 431 with giant cell astrocytoma, 1708 with glycine encephalopathy, 581 with holoprosencephaly, 397-398 with intracranial hypertension, 1521, 1583 lumbar puncture for, 321, 431 magnetic resonance imaging of, 178, 183f, 429-430, 429f management of, 430-432 Volume 1: pages 1–1180

Hydrocephalus continued with meningitis, 1578, 1578f, 1583, 1585-1586 with myelomeningocele, 369, 372 with neurocutaneous melanosis, 787-788 neuroimaging of, 429-430 noncommunicating, 427 nonprogressive, 427 with osteopetrosis, 456-457 pathologic findings in, 427 pathophysiology of, 426, 426f post-hemorrhagic, 309, 315, 321-322, 430 diagnostic criteria for, 321 magnetic resonance imaging of, 322, 322f treatment of, 321 ultrasound of, 322, 322f post-traumatic, 1434 in preterm infant, 430 prognosis in, 432-433 shunting for, 430-432 complications of, 431-432 failure rate of, 431 with toxoplasmosis, 1656, 1656f ventriculomegaly and, 432 and vision loss, 86 X-linked, 427-428 Hydrocephalus ex vacuo, 430 Hydrocodone, for pain, 2377 Hydrocortisone, for intraventricular hemorrhage prevention, 323-324 Hydrogen peroxide, in peroxisomes, 737 Hydromorphone abuse/poisoning, 2186 dosage of, 2376t fetal/neonatal effects of, 2196 for pain, 2377 Hydromyelia, 1862 Hydroxocobalamin, 2311. See also Cobalamin (vitamin B12) 3-Hydroxy-3-methyl-glutaric aciduria, 353-354, 353t Hydroxychloroquine for mixed connective tissue disease, 1817 for Sjögren’s syndrome, 1818 teratogenicity of, 2182t Hydroxyindoleacetic acid (5-HIAA), CSF analysis for, 163 3-Hydroxyisobutyric aciduria, 595-596 5-Hydroxytryptamine, for vasovagal syncope, 2150 5-Hydroxytryptophan, for sepiapterin reductase deficiency, 763 Hydroxyzine hydrochloride, fetal/neonatal effects of, 2196 Hygroma(s) definition of, 1455 in inflicted neurotrauma, 1455 subdural, arachnoid cysts and, 435 Hyoscine, for neurocardiogenic syncope, 1211b Hyoscyamine sulfate, for myasthenia gravis, 1951 Hyperactivity in ADHD, 871, 872b in autism, treatment of, 925 in epilepsy, 1172 Hyperacusis in autistic disorder, 915-916 in developmental disorders, 836t in mental retardation/developmental delay, 813b Hyperammonemia in argininosuccinicacidemia, 606-607 in carbamyl phosphate synthetase I deficiency, 605 in citrullinemia, 606 crises in, management of, 612 differential diagnosis of, 609f, 610-611

Volume 2: pages 1181–2408

Index Hyperammonemia continued in impaired consciousness/coma, 356, 608, 611-613, 1390 in N-acetylglutamate synthase deficiency, 604 in ornithine transcarbamylase deficiency, 605 toxic effects of, 609-610 transient, of newborn, 356 treatment of, 611-612 in urea cycle disorders, 603-613, 718 Hyperammonemic coma, 356, 608, 611-613 Hyperargininemia, 607 Hyperbaric oxygen therapy for hypoxic-ischemic injury, 1505 for phycomycosis, 1640 for spinal cord injury, 1542-1543 Hyperbilirubinemia in cephalohematoma, 338 and cerebral palsy, 494 in CSF, 159 and hearing loss, 109t, 110 in kernicterus, 1284, 2300-2301 in subgaleal hematoma, 336, 338 Hypercalcemia, 2328 Hypercarbia, ventilation and, 290 Hyperchloremia, 2326 Hyperekplexia, 766, 1217-1218, 1302 as channelopathy, 1220 clinical presentation of, 1218 genetics of, 1214t, 1218 neurophysiologic studies of, 1218 prognosis of, 1218 term, derivation of, 1217 treatment of, 1213t, 1218 Hyperemia, in traumatic brain injury, 1406, 1411, 1431 Hyperexcitability cortical, in migraine, 1187 neuronal, in epilepsy, 991, 996-997, 996f peripheral nerve, acquired generalized, 2103-2104 clinical features of, 2101t, 2103 genetics of, 2101t pathophysiology of, 2105 treatment of, 2101t, 2105 Hyperextensibility, 65 Hyperextension, in spinal cord injury, 1528, 1530 Hyperfractionated radiation, 1698, 1718 Hyperglycemia in CSF, 160-161 in hypoxic-ischemic injury, 290-291, 299-300, 1499 in intraventricular hemorrhage, 320, 320t nonketotic, 767. See also Glycine encephalopathy Hyperglycinemia ketotic, 587 nonketotic. See Glycine encephalopathy Hyperglycolysis, in traumatic brain injury, 1406 Hyperhidrosis, 2131-2132 essential (primary), 2152 treatment of, 2152 Hyperhomocysteinemia, 582-584 measurement of, 1774 and stroke, 329-330, 332, 1773-1774, 2320 Hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), 596 Hyperinsulinemia, hypoglycemia in, 348-349, 348t Hyperkalemia, 2327 in acute renal failure, 2235 clinical features of, 2235, 2327 definition of, 2327 distal renal tubular acidosis with, 2265 management of, 2235, 2327 pathophysiology of, 2235 Hyperkalemic periodic paralysis, 2094-2096 clinical features of, 2094t, 2095

Hyperkalemic periodic paralysis continued genetics of, 2094t, 2095 laboratory tests in, 2096 with myotonia, 2094t paramyotonia congenita with, 2094t, 2097 pathophysiology of, 2095-2096 treatment of, 2094t, 2096 Hyperkinetic disorders, 1271 postoperative, in cardiac surgery, 2213-2215 treatment of, 1290 Hypermagnesemia, 2328-2329 causes of, 2328-2329, 2329b clinical manifestations of, 2328 treatment of, 2329 Hypermethioninemia, 582f Hypernatremia, 2325-2326 causes of, 2325, 2325t definition of, 2325 neonatal, 350-351 causes of, 350-351, 350t and encephalopathy, 350-351 management of, 351 neurologic manifestations of, 350 neurologic manifestations of, 2325-2326 treatment of, 2326 Hyperopia, 87 pseudopapilledema with, 90 Hyperornithinemia-hyperammonemiahomocitrullinuria syndrome, 603, 604t, 607 Hyperosmia, 146 Hyperosmolar therapy, for increased intracranial pressure, 1520-1521 in hepatic encephalopathy, 2297 in hypoxic-ischemic injury, 1499 in malaria, 1660 in meningitis, 1582-1583 in Reye’s syndrome, 2299 in traumatic brain injury, 1422-1423 Hyperostosis, 435b, 455-459 Hyperoxaluria, type I, 743t, 750-751 Hyperparathyroidism, in renal failure, 2235, 2244, 2249 Hyperphenylalaninemia, 360, 360f, 570 in biopterin disorders, 574-575 in neurotransmitter deficiencies, 759-761, 760f, 760t nonphenylketonuria, 570 phenylketonuria, 360, 570-574 Hyperpigmentation, in developmental disorders, 833t Hyperpipecolic acidemia, 743t Hyperpolarization-activated cation channel in absence seizures, 999-1000, 999f in febrile seizures, 1081 Hyperpolarizing conductances, 994 Hyperprolactinemia, 2118 Hyperreflexia, 18 Hyperreflexic bladder, 2164 Hypersensitivity angiitis, 1821 Hypersomnia idiopathic, 1233 definition of, 1233 subtypes of, 1233 periodic (Kleine-Levin syndrome), 1233 Hypertelorism, in craniosynostosis, 453 Hypertension autonomic dysfunction and, 2131-2132 in autonomic dysreflexia, 2361-2362 episodic, in dialysis patients, 2244 in hypoxic-ischemic injury, 290 malignant, 2238-2242. See also Hypertensive encephalopathy supine, 2142 Hypertensive encephalopathy, 2238-2242 autoregulation in, 2240 Volume 1: pages 1–1180

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xlvii

Hypertensive encephalopathy continued clinical features of, 2239-2241 differential diagnosis of, 2241 drug-induced, 2239 EEG findings in, 2241 etiology of, 2238-2239 management of, 2241-2242, 2241t neuroimaging in, 2239-2240 pathophysiology of, 2240 risk factors for, 2239 subacute progressive, 2242 susceptibility-weighted imaging in, 191, 193f in systemic lupus erythematosus, 1810-1811 Hypertext, 2400 Hypertext markup language (HTML), 2400 Hypertext transfer protocol (http), 2400 Hyperthermia malignant, 2195 in status epilepticus, 1100 teratogenicity of, 2197t Hyperthyroidism central, 2122 and chorea, 1279 Hypertonia, in hyperekplexia, 1218 Hypertonic saline, for increased intracranial pressure, 1423, 1520-1521 Hypertrichosis, in developmental disorders, 835t Hypertropia, 80 Hyperventilation, therapeutic, for increased intracranial pressure, 1422, 1425, 1499, 1520, 2299 Hyperventilation syncope, 1212 Hyperventilation syndrome, 1219 Hyperventilatory response, in EEG, 220-221, 220f, 1026 Hypnagogic hallucinations, 1235 Hypnagogic hypersynchrony, 221 Hypnic myoclonus, 1293 Hypoalbuminemia, in ataxia-oculomotor apraxia 1, 1253 Hypocalcemia, 2327-2328 causes of, 2327, 2327b clinical features of, 2328 neonatal, 2327-2328 in rickets, 2315 Hypocarbia, ventilation and, 290 Hypochloremia, 2326 Hypocretin deficiency, in narcolepsy, 1232 Hypogeusia, 143 Hypoglossal nerve (CN XII) assessment of in newborn (term), 52 in older child, 24-25 palsy of, 339 Hypoglycemia in CSF, 160-161 definition of, 346-348 with galactosemia, 618 with glucose-6-phosphatase deficiency, 625-626 hypoketotic, 2039, 2040t in inborn errors of metabolism, 568 ketone bodies in, 348t, 718 in malaria, 1658, 1660 neonatal, 346-349 causes of, 348, 348t clinical signs and symptoms of, 348 coma in, 348 EEG findings in, 348 and encephalopathy, 346-349, 348t evaluation algorithm for, 349, 349f in hyperinsulinemia, 348-349, 348t in hypoxic-ischemic injury, 290 in inborn errors of metabolism, 348, 348t in maladaptation to extrauterine life, 348, 348t management of, 348-349 in salicylate poisoning, 2190

xlviii

Index

Hypoglycemia continued in ataxia-telangiectasia, 1252 hypogonadotropic, 2116-2118 CNS lesions and, 2117, 2117f evaluation of, 2117 functional, 2117 isolated congenital, 2116 management of, 2117-2118 with multiple hypothalamic/pituitary hormone deficiencies, 2116-2117 Hypokalemia, 2326-2327 causes of, 2326, 2326t clinical manifestations of, 2326-2327 definition of, 2326 in enteric infections, 2290 in renal Fanconi syndrome, 2263 treatment of, 2327 Hypokalemic periodic paralysis, 2094, 2095t, 2097-2098 clinical features of, 2095t, 2097 genetics of, 2095t, 2097 laboratory tests in, 2098 pathophysiology of, 2097-2098 treatment of, 2095t, 2098 Hypoketotic hypoglycemia, 2039, 2040t Hypokinesia, in parkinsonism, 1291 Hypokinetic disorders, 1271 Hypomagnesemia, 2328 causes of, 2328, 2328b clinical manifestations of, 2328 Hypomelanosis of Ito, 789 clinical features of, 771t, 789 genetics of, 789 with hemimegalencephaly, 403t, 409 histologic features of, 789 MRI findings in, 789 Hypomyelinating disorders, 1354-1360 classification of, 1345, 1345t Hypomyelinating neuropathies, 1899-1900 Hyponatremia, 2324-2325 in acute renal failure, 2234-2235 causes of, 2324, 2325t drug-induced, 2264-2265 in enteric infections, 2290 management of, 2234-2235, 2325 in maple syrup urine disease, 580 in meningitis, 1576 neonatal, 349-350 acute severe, 350 causes of, 349, 350t clinical effects of, 349 and encephalopathy, 349-350 management of, 350 subacute or chronic, 350 Hypoparathyroidism, and Fahr’s disease, 1286 Hypoperfusion, in traumatic brain injury, 1406, 1423 Hypopigmentation in developmental disorders, 833t in incontinentia pigmenti achromians, 789 in Menkes’ disease, 1322 in neurofibromatosis type 1, 772-773 in tuberous sclerosis complex, 779, 779f Hyporeflexia, 18-19 versus hypotonia, 65 Hyposmia, 146 Hypotension in hypoxic-ischemic injury, 290 iatrogenic, 2241 in inflicted neurotrauma, 1447-1448 orthostatic, 2131-2133, 2133f in cardiovascular disorders, 2135-2137 definition of, 2132-2133 disability in, 2140 drug action in, 2140t, 2141 factors influencing, 2133, 2133t

Hypotension continued food ingestion and, 2135, 2135f management of, 2140-2143, 2140t neurogenic, 2140, 2142 non-neurogenic causes of, 2135, 2136t in pandysautonomia, 2144 in spinal cord lesion, 2147, 2147f stimuli in daily life, 2133, 2134f-2135f symptoms of, 2133t transient, 2151-2152 water ingestion for, 2141, 2141f in periventricular leukomalacia, 288 in spinal cord injury, 1538 Hypothalamic disorders, 2113-2125 of appetite regulation and energy balance, 2122-2123 of glucocorticoid production, 2118-2120 of pubertal development, 2114-2118 of statural growth, 2120-2121 of water balance, 2123-2125 Hypothalamic obesity, 2122-2123 Hypothalamic syndrome, in leukemia, 1736-1737 Hypothalamic tumors, 1700-1702 diencephalic syndrome with, 1701, 1701f endocrinopathies with, 1700-1701 management of, 1701-1702 precocious puberty with, 1701, 1701f, 2115-2116, 2115f survival rates with, 1702 Hypothalamus anatomy and physiology of, 2113-2114, 2114f embryology of, 383, 2113-2114 in sleep regulation, 1225 in temperature regulation, 1225 Hypothermia for circulatory arrest, 2207 for neuroprotection efficacy of, variables in, 304 in hypoxic-ischemic injury, 291, 304-305, 1500 in intracranial hypertension, 1521 intra-ischemic, 304 post-ischemic, 304 in spinal cord injury, 1538 in stroke, 1763, 1779 in traumatic brain injury, 1425 Hypothyroidism central, 2121-2122 muscular tone in, 69 radiation therapy and, 1743 Hypotonia, 65-69, 1244, 1276 in Alpers’ disease, 1326 in autistic disorder, 915 benign congenital, 1871 central, 69, 1871 in cerebellar disease, 19 clinical laboratory studies in, 69 conditions associated with, 68t, 69 in congenital myopathies, 2015 definition of, 65 diagnosis of, 68-69 in Down syndrome, 552 evaluation of, 66-68 examination for, 66-67 in active state, 67 in passive state, 67 floppy, as description of, 65 in genetic metabolic encephalopathies, 350t holoprosencephaly and, 397 with hyperextensibility, 65 hypoglycemia and, 348 versus hyporeflexia, 65 in infant, 66-67 with infantile acid maltase deficiency, 627, 627f Volume 1: pages 1–1180

Hypotonia continued intractable epilepsy, autism, and developmental delay (HEADD syndrome), 917 in kernicterus, 1284 in Lesch-Nyhan disease, 1285-1286 neuroimaging in, 69 in older child, 67 patient history in, 66 polychlorinated biphenyls in breast milk in, 2196 in preterm infant, 57-59, 58f, 66 in spinal muscular atrophy, 1862-1868 in Sydenham’s chorea, 1806-1807 Hypotonic cerebral palsy, 499 Hypoventilation chronic obstructive, 1227 congenital central alveolar, 1231 Hypoventilation syndrome, central, 1231 Hypovolemia, in malaria, 1660 Hypoxia in autonomic disorders, 2138-2140 in malaria, 1657 Hypoxia-inducible factor-1, preconditioning and, 305 Hypoxic-ischemic injury albumin for, 1505 anti-inflammatory therapy for, 1505 brain energy failure in, 1471-1473, 1473f calcium-mediated, 297f, 1473-1475, 1474f, 1502-1503 in cardiac arrest, 1471, 1472b, 1472t biochemical markers after, 1495 clinical outcome in, 1480-1482, 1481t prediction of, laboratory tests for, 1492-1497 delayed posthypoxic injury after, 1492 EEG findings after, 1493 epidemiology of, 1471 etiology of, 1471, 1472b, 1472t evoked potentials after, 1493-1495, 1494f magnetic resonance spectroscopy after, 1495-1497, 1496f-1497f major disorders causing, 1482-1491 mechanisms of injury, 1471-1479 morbidity and mortality in, 1480-1482, 1481t neuroimaging after, 1495-1497 neurologic complications after, 1492 neurologic examination after, 1492-1493 post-ischemic seizures after, 1492 resuscitation for, metabolism and cerebral blood flow after, 1479-1480 treatment for, 1497-1505 in cardiac surgery, 2208-2209, 2208b, 2211-2212 cardiovascular support in, 1499-1500 cell death/apoptosis in, 303f, 304, 1472-1473, 1473b, 1479, 1501-1502 cerebral blood flow in, 297, 299, 1504 after resuscitation, 1479-1480 chelating agents in, 301-302, 1504 computed tomography of, 282, 284, 284f, 286, 286f diffusion-weighted imaging of, 184-185, 282-283 EEG findings in, 238, 283 endogenous defenses in, modulation of, 1501 excitotoxicity in, 300-301, 300f, 1474-1475, 1502 genetic damage and regulation in, 1478-1479 glucocorticoids for, 1505 heat shock proteins in, 1478-1479, 1501 hyperbaric oxygen therapy for, 1505 hypothermia for, 291, 304-305, 1500 in infants and older children, 1471-1506 clinical outcome in, 1480-1482, 1481t

Volume 2: pages 1181–2408

Index Hypoxic-ischemic injury continued epidemiology of, 1471 etiology of, 1471, 1472b, 1472t hospital care in, 1498-1501 prehospital care in, 1497-1498 treatment of, 1497-1505 inflammation in, 302-304, 1479, 1505 in inflicted neurotrauma, 1447 intracellular enzymes in, activation of, 1475 intracranial pressure in, 280, 1498-1499 kernicterus in, 286, 1284 lipid peroxidation in, 1503-1504 magnesium sulfate for, 291, 301 magnetic resonance imaging of, 281-283 metabolism in, 299-300, 1471-1473, 1473f homeostasis of, restoration of, 290, 1499 rate of, reduction of, 1500-1501 after resuscitation, 1479-1480 neurologic morbidity in, 1506 neuronal necrosis in, 303f, 304, 1472-1473 neuroprotection in, 291, 301, 304-306 endogenous mechanisms of, 305-306 strategies for, 291 neurotrophic factors in, 305 in newborns, 279-292 animal models of, 298-299 large animal, 298 small animal, 299 biochemical studies in, 283 cellular and molecular mechanisms in, 300-304 central, 285-287 clinical features of, 286-287 computed tomography of, 286, 286f diagnosis of, 286 long-term sequelae of, 286 magnetic resonance imaging of, 282, 286, 286f pathogenesis of, 285-286 ultrasound of, 286, 286f cerebral edema in, 280, 291 and cerebral palsy, 279, 286, 292, 492-494 cerebral perfusion in, maintenance of, 290 classification of, 280, 280t clinical correlations of, 283-289 cortical or subcortical, 284 clinical features of, 284 computed tomography of, 284, 284f diagnosis of, 284 magnetic resonance imaging of, 284 pathogenesis of, 284 diagnosis of, 265, 279-283 electrodiagnostic techniques in, 283 evoked potentials in, 283 future directions in study of, 306 history in, 279 insult causing, 279 acute, near-total (profound), 284t, 285-286 acute, total, 279, 285 antepartum, 279 combined profound and prolonged, partial, 284t intrapartum, 279 postnatal, 279 prolonged, partial, 279, 284t severity, onset, and duration of, 279 type of, and outcome, 279, 284, 284t management of, 290-291 mild, 280, 280t moderate, 280, 280t neuroimaging in, 281-283 neurologic examination for, 279-280 neuropathologic patterns of, 283-289 organs other than brain affected in, 281, 281t

Hypoxic-ischemic injury continued parasagittal, 280, 285 clinical features of, 285 diagnosis of, 285 magnetic resonance imaging of, 282, 285, 285f pathogenesis of, 285 periventricular hemorrhagic infarction in, 287, 287t, 288f periventricular leukomalacia in, 287-288, 287t preconditioning and, 305 prevention of, 290 prognosis in, 291-292 seizures in, 280, 284, 286, 290-291 severe, 280, 280t stem cells and neurogenesis in, 305-306, 306f supportive care in, 290-291 susceptibility and vulnerability to, 298 ventilation in, maintenance of, 290 nitric oxide in, 283, 297f, 302, 1476-1477, 1477f, 1504 “no reflow” concept in, 1480 in nonaccidental trauma, 1489 oxidative stress in, 297f, 301-302, 302f, 1477-1478, 1477f, 1503 pathophysiology of, 297-306, 297f, 1471-1480 positron emission tomography of, 283 in preterm infants, 280, 287-289, 287t protein synthesis in, 1504-1505 proton MR spectroscopy of, 182, 185f, 282, 300 single-photon emission tomography of, 283 in stroke, 1762-1763 in term newborn, 284-287, 284t ultrasound of, 169, 281-282 and vegetative state, 1379 Hypsarrhythmia, in EEG, 233-234, 234f, 1065-1066, 1066f-1067f

I I band, 1839, 1841, 1849, 1849f Ibuprofen dosage of, 2376t for migraine, 1193t, 1195 overuse of, and headache, 1195 for pain, 2377 for post-traumatic headache, 1199 for tension headache, 1198 I-cell disease, 696-697, 696f, 697, 697f Ichthyosis, in Sjögren-Larsson syndrome, 1366-1367 Ideational apraxia, 822t Idebenone, for Friedreich’s ataxia, 1250 Ideomotor apraxia, 822t Idiogenic osmoles, 1523 Idiopathic generalized glycogenolysis, 626-628 Idiopathic intracranial hypertension, 1200, 1522-1523 clinical presentation of, 1522 diagnosis of, 1200 differential diagnosis of, 1522, 1522b incidence of, 1200 papilledema with, 89-90, 1522, 1522f pathogenesis of, 1200 treatment of, 1522-1523 Iduronate-2-sulfatase deficiency, 688 α-L-iduronidase deficiency, 686-688 Ifosfamide for ependymoma, 1716 toxicity of, 2193 Volume 1: pages 1–1180

Volume 2: pages 1181–2408

xlix

Iliopsoas muscle in gait, 71f testing of, 34t Illusions, definition of, 1378 Imaging, 167-196. See also specific modalities Imatinib, 1745 Imipramine, 945t for ADHD, 878t, 946 clinical applications of, 946 dosage of, 945t, 947 for glycine encephalopathy, 582 labeled and off-labeled use of, 938t for micturition disorders, 2165, 2165t pharmacokinetics of, 945t pharmacology of, 946 preparations of, 945t for school refusal, 946 for separation anxiety, 946 toxicity of, 2189 Immediate early genes, in hypoxic-ischemic injury, 1478-1479, 1504 Immediate echolalia, 908 Immediate post-traumatic seizure, 1415 Immobilization, of spinal cord injury, 1540, 1543-1544 Immune response, in spinal cord injury, 1531-1532 Immune-mediated demyelinating disorders, 1345-1354 Immune-mediated leukoencephalopathy, 1345, 1346t Immune-mediated neuropathies, 1893-1894, 1919-1934, 1920t, 1933t Immunization. See also specific vaccines and autism, 923, 2185, 2350-2351 controversy over, 2345 and disease eradication, 2345 and Guillain-Barré syndrome, 1910, 1927, 2347 and multiple sclerosis, 2347 neurologic complications of, 2345-2351 causality in, assessment of, 2345-2346 compensation program for, 2346, 2347t and polyneuropathy, 1910 recommended schedule of, 2345, 2345t types of vaccines in, 2346-2350, 2346b Immunoglobulin(s) in ataxia-telangiectasia, 1252 for autism, 925-926 in CSF, 161-163 intravenous. See Intravenous immunoglobulin Immunoglobulin G in CSF, 162-163 in multiple sclerosis, 1347-1348 in myasthenia gravis, 1941-1942 in systemic lupus erythematosus, 1812 Immunologic tests, of CSF, 160, 162-163, 162f Immunosuppressive therapy in stroke, 1779 for systemic lupus erythematosus, 1815 toxicity of, 2191-2192, 2298 Impact forces, in inflicted neurotrauma, 1447 Impact seizure, 1415 Imprinting, 513, 534, 547, 920 disorders of, 557-558, 558t Impulsivity in ADHD, 871, 872b in epilepsy, 1172 Imuran. See Azathioprine Inactivated polio vaccine (IPV), 2346 enhanced potency trivalent, 2349 Inattention, in ADHD, 871, 872b Inborn errors of metabolism, 345, 351-362, 567-596. See also specific types and autism, 916 cardiac dysfunction in, 2223 classification of, 345, 346t, 351 clinical features of, 350t-351t

l

Index

Inborn errors of metabolism continued cognitive and motor regression in, 826t-827t genetic counseling in, 569-570 glycosylation, 361, 647-662 hypoglycemia in, 346-349, 348t incidence of, 567 inheritance of, 569-570 laboratory analysis of, 568, 811 lysosomal, 659-703 MRI findings in, 352, 352t neonatal seizures with, 265 physical findings in, 567-568 signs and symptoms of, 567 treatment of, 568-569 urea cycle, 603-613 vision loss with, 87 Inbreeding, coefficient of, 533 Incontinence fecal, 2157, 2166-2168 differential diagnosis in, 2167b, 2168 laboratory tests in, 2167-2168 management of, 2168 neurologic examination in, 2167 overflow, 2166 partial, 2166 patient evaluation in, 2167-2168 patient history in, 2167 true, 2166 urinary, 2157 differential diagnosis in, 2164, 2167b functional classification of, 2162-2163, 2162f management of, 2164-2165 overflow, 2163 patient evaluation in, 2162-2164 stress, 2163 Incontinentia pigmenti, 788-789 clinical features of, 771t, 788-789 first stage of, 789 genetics of, 788 neurologic abnormalities in, 789 second stage of, 789 third stage of, 789 Incontinentia pigmenti achromians, 789 clinical features of, 771t, 789 genetics of, 789 with hemimegalencephaly, 403t, 409 histologic features of, 789 MRI findings in, 789 Indeterminate sleep segments, 222 Indomethacin for heterotopic ossification, 2365 for intraventricular hemorrhage prevention, 323t, 324-325, 324f for orthostatic hypotension, 2143 for paroxysmal hemicrania, 1199 Inertial forces, in inflicted neurotrauma, 1447 Infant(s). See also specific disorders cranial nerve evaluation in, 39, 47 cranial vault evaluation in, 38, 48-50, 49f development of, 37t electroencephalographic patterns in, 218-222 encephalopathy in, scoring and features of, 47, 48t grasping skills/reflex of, 39-40, 40f, 43, 43t head of, evaluation of, 38 hearing loss in, screening for, 112 motor evaluation in, 39-40, 42, 42t muscle testing in, 39-41, 42f, 44-45 neurologic examination of, 37-45 approach to, 37-38 caregiver involvement in, 37-38 general considerations in, 45 stage 1 of, 38-41 stage 2 of, 41-44 stage 3 of, 44 stage 4 of, 44-45

Infant(s) continued at term (birth), 47-52 nystagmus in, 39, 52, 81-82, 92 observation of, 37-38 pharmacokinetics in, 1118 preterm. See Preterm infant(s) reflex evaluation in deep tendon, 40, 45 developmental, 42-44, 43t elicitation for, 43t sensory evaluation in, 40-41, 41f, 45 speech evaluation in, 45 vision assessment in, 77-78 vision loss in, 81-87 behavioral manifestations of, 82 clinical manifestations of, 81-82 with cortical visual impairment, 85-87 diagnostic evaluation of, 87 differential diagnosis of, 82 with epilepsy, 86 with structural anomalies, 82-85 with structural cerebral anomalies, 86-87 Infant Development Inventory, 804t Infant Face Scale, 1460 Infantile bilateral striatal necrosis, 1286 Infantile myositis, 2080 Infantile neuroaxonal dystrophy, 1904-1905 clinical features of, 1904 muscle biopsy in, 1904-1905 nerve biopsy in, 1904, 1904f Infantile olivopontocerebellar atrophy, 394 Infantile onset spinal muscular atrophy, 1863-1864 Infantile pattern of neurogenic atrophy, 1867 Infantile polymyoclonia, 1294 Infantile Refsum’s disease (IRD), 740-744 clinical and pathologic features of, 741-742 genetics of, 740t, 742 laboratory diagnosis of, 742-744, 743t prenatal diagnosis of, 744 treatment of, 744 Infantile spasms, 1066-1070 ACTH therapy for, 1067-1070, 1068b clinical features of, 1066-1067 clinical laboratory tests in, 1067-1068 CMV infection and, 1606 cognitive and behavioral outcome of, 1173 cryptogenic, 1066 diagnosis of, 1066 EEG findings in, 1065-1067, 1066f-1067f idiopathic, 1066 mechanistic theories for, 1069 MRI findings in, 1069 natural history of, 1068 pathophysiology of, 1069-1070 surgery for, 1068 symptomatic, 1066 treatment of, 1068-1069, 1075 vigabatrin for, 1069 Infantile-onset spinocerebellar ataxia, 1254 Infarct(s), bland, 1759 Infarction cerebral in arterial ischemic stroke, 1762-1765. See also Arterial ischemic stroke computed tomography of, 171, 171f, 174f, 1765 diffusion-weighted imaging of, 187, 189 EEG studies of, 228 extracorporeal membrane oxygenation and, 2225-2226 large-vessel, 1763-1764, 1764f magnetic resonance angiography of, 188f, 189 magnetic resonance imaging of, 175, 177, 1764f-1766f in meningitis, 1583 periventricular hemorrhagic, 287 Volume 1: pages 1–1180

Infarction continued clinical features of, 287 diagnosis of, 287 pathogenesis of, 287 ultrasound of, 287, 288f recognition of, 1765 in sinovenous thrombosis, 1783-1784, 1783f-1784f small-vessel, 1763-1765, 1765f-1766f watershed, 1764 in spinal cord injury, 1531 Infective endocarditis, 2220-2221 neurologic manifestations of, 2220-2221, 2220f-2221f Inferior cerebral peduncle, 1242-1243, 1242f Inferior gluteal nerve, 29t Inferior oblique muscle, 20-21, 21f, 21t Inferior rectus muscle, 20-21, 21f, 21t Inflammation in bacterial meningitis, 1572, 1575, 1579 in Duchenne muscular dystrophy, 1975 in hypoxic-ischemic injury, 302-304, 1479, 1505 in intraventricular hemorrhage, 311, 313 in malaria, 1657 in periventricular leukomalacia, 288 in spinal cord injury, 1531-1532 in viral infections, 1596 Inflammatory bowel disease, 2290 epidemiology of, 2290 in glucose-6-phosphatase deficiency, 626 incidence of, 2290 MRI findings in, 2290 neurologic manifestations of, 1805t, 1806, 2285, 2290 Inflammatory myopathies, 2075-2083, 2075b congenital, 2080 idiopathic, 2075-2080, 2075b infectious, 2075, 2075b, 2080-2083 Inflammatory neuropathies, 1893-1894, 1919-1934, 1920t, 1933t Inflicted childhood neurotrauma, 1411-1412, 1445-1464. See also Child abuse Infliximab, for juvenile idiopathic arthritis, 1805-1806 Influenza myositis, 2081 clinical features of, 2081 laboratory features of, 2081 pathogenesis of, 2081 treatment of, 2081 Influenza virus, 1617 and Reye’s syndrome, 2298 Influenza virus vaccine, 2346-2348 inactivated, 2346 live-attenuated, 2346 neurologic complications of, 2347-2348 Infrafusal muscle fibers, 65-66, 66f Infraspinatus muscle, testing of, 34t Infratentorial herniation syndromes, 1389-1390 Inheritance autosomal dominant, 532-533, 533f autosomal recessive, 532-533, 533f complex, 535 mendelian, 532, 533f mitochondrial, 535, 715-717, 716f, 716t, 717f, 2014-2017 multifactorial, 535 patterns of, 532-535 polygenic (oligogenic), 535 pseudoautosomal, 533 pseudodominant, 533 X-linked, 532-534, 533f, 534t Sherman paradox in, 559 Inhibitory postsynaptic potential, 207 Inhibitory synaptic transmission, 995 in immature brain, and seizure susceptibility, 1001

Volume 2: pages 1181–2408

Index Innate immunity, in spinal cord injury, 15311532 Inner mitochondrial membrane, lipid milieu of, defects in, 728 Inosine pranobex, 1603 for subacute sclerosing panencephalitis, 1618 Input terminal one/two, in EEG, 204 Insect repellent poisoning, 2183 Insecticide poisoning, 2182-2183 Insertion, chromosomal, 529-530 Insulin in appetite/energy regulation, 2122-2123 for hyperkalemia, 2235, 2327 for hyperkalemic periodic paralysis, 2096 in hypoxic-ischemic injury, 1505 Insulin growth-factor binding proteins (IGFBPs), in megalencephaly, 408 Insulin receptors, in myotonic dystrophy type 1, 2087 Integrin α7 mutations, in congenital muscular dystrophy, 1989t, 2002 Intelligence. See also Mental retardation concept of, 800-801 Duchenne muscular dystrophy and, 1979 in dyslexia, 865 epilepsy and, 1171, 1172t hearing loss and, 116 hydrocephalus and, 433 intraventricular hemorrhage and, 323 testing of, 801-805, 802t-805t Intelligence quotient (IQ) in mental retardation, 799 qualitative description of, 805t Intensity, of sound, 99-100 Intention tremor, 1244-1246 Intercostal muscles, testing of, 34t Interferon(s) INFα in Aicardi-Goutieres syndrome, 1354 nephrotoxicity of, 2265 for subacute sclerosing panencephalitis, 1618 INFβ, for multiple sclerosis, 1349-1350 INFγ, for osteopetrosis, 457 toxicity of, 2194 Interferon regulatory factor-6 gene (IRF6), in cleft lip/palate, 467, 467t Intergenomic signaling defects, 727-728, 2059 Interictal background, in EEG, 232, 260 Interleukin(s) IL-1β, in hypoxic-ischemic injury, 302 IL-6, in hypoxic-ischemic injury, 302 toxicity of, 2194 Intermediate filaments, 1845 Intermediate hemisphere disease, 1246 Intermediate zone, 398 Intermittent self-catheterization, for micturition disorders, 2165 Internal granular layer, 1241, 1243f International 10-20 System, of EEG electrodes, 204 International Child Neurology Association website, 2401 International Classification of Sleep Disorders, 1225-1226, 1226t International Headache Society, 1183-1185, 1183b-1186b International League Against Epilepsy, 257, 260, 265-266, 981-983, 982t-983t, 1037, 1038b, 1042 International Medical Society of Paraplegia (IMSOP), 1533, 1533b, 1534f, 1546-1547 International Panel on Multiple Sclerosis Diagnosis, 1347

Internet definition/description of, 2399 future of, 2407 potential usefulness of, 2399-2405 problems with, 2405 resources on for child neurologists, 2399-2407, 2402t-2404t for patient education, 2405 on poisoning, 2198-2199 Internet Explorer, 2400 Internet Handbook on Neurology, 2405 Internuclear ophthalmoplegia, 22 Interossei muscle, testing of, 34t Interposed nuclei, 1241, 1242f lesions of, 1246 Interrupted eyebrows, in Apert’s syndrome, 448 Interstitial 2q23 deletion, 556t Interstitial 15q21 deletion, 556t Interstitial deletion, chromosomal, 529t Intestinal intussusception, 2288 Intestinal pseudo-obstruction, 2287-2288 causes of, 2287-2288, 2288b clinical features of, 2288 evaluation of, 2288 Intestine(s), in hypoxic-ischemic injury, 281, 281t Intoxication, 2173. See also Poisoning; specific agents Intra-arterial delivery, of drugs, 1746 Intracerebral hemorrhage, 338, 1788-1789 clinical presentation of, 338, 1789 computed tomography of, 338, 338f mechanism of injury, 338 pathophysiology of, 1789 risk factors for, 338, 1789 Intracranial hemorrhage in dialysis patients, 2246 extracorporeal membrane oxygenation and, 2225-2226 in hemorrhagic stroke, 1788-1790 magnetic resonance imaging of, 1420, 1420t outcome of, 339, 1789 perinatal trauma and, 334 traumatic, 1790 vitamin K deficiency and, 332, 2318 Intracranial hypertension. See also Intracranial pressure, increased benign, iron deficiency and, 2322 with dural sinus thrombosis, 1522, 1522f idiopathic, 89-90, 1200, 1522-1523 secondary, differential diagnosis of, 1522, 1522b Intracranial injuries, perinatal, 337-339 Intracranial pressure, 1402 B waves of, 1515 C waves of, 1515 and cerebral perfusion, 1514-1516 global, 1513 increased, 1513-1524 acute, management of, 1520-1521 in acute renal failure, 2234-2235 algorithm for evaluation of, 1519f, 1524 barbiturates for, 1422, 1426, 1521 brain tumors and, 1694 cerebellar astrocytoma and, 1712-1713 cerebrospinal fluid drainage for, 1424-1425 clinical manifestations of, 1516-1519 corticosteroids for, 1521 cranial enlargement with, 1517 in craniosynostosis, 453-454, 1523-1524 Cushing response with, 1518 decreased sensorium with, 1517 diplopia with, 1517 etiology of, 1514b fluid management in, 1520 Volume 1: pages 1–1180

Volume 2: pages 1181–2408

li

Intracranial pressure continued headache with, 1516-1517 in hepatic encephalopathy, 2294, 2297 herniation syndromes with, 1518-1519 hydrocephalus with, 1521 hyperosmolar therapy for, 1422-1423, 1499, 1520-1521 hyperventilation for, 1422, 1425, 1499, 1520 hypothermia for, 1521 in hypoxic-ischemic injury, 280, 1498-1499 idiopathic, 89-90, 1200, 1522-1523 in impaired consciousness/coma, 1391, 1393 lumbar puncture in, 1200, 1519-1520 in malaria, 1658, 1660 in meningitis, 1576-1577, 1582-1583 in mucopolysaccharidosis I, 686-687 neck positioning in, 1520 in neonatal stroke, 332 neuromuscular blockade for, 1422 papilledema with, 89-90, 89f, 1517, 1517f pathophysiology of, 1513-1515, 1514f-1515f personality change with, 1517 in post-hemorrhagic hydrocephalus, 321-322 pulmonary edema, acute, with, 1518 respiratory management in, 1520 in Reye’s syndrome, 2298-2299 Scandinavian protocol for, 1583 sedation for, 1422, 1520 seizures with, 1521 in sinovenous thrombosis, 1784 spinal cord tumors and, 1731-1732 in stroke, 1779-1780 surgical management of, 1425-1426 in traumatic brain injury, 1422-1427 first-tier management of, 1421f, 1422-1425 and outcome, 1430 and retinal hemorrhage, 1451-1452 second-tier management of, 1425-1427, 1425f treatment algorithm for, 1428 treatment for, 1391, 1393, 1520-1521, 1582-1583 upward gaze impairment with, 1517 vision loss with, 86, 92 low (hypotension), lumbar puncture and, 158-159, 158f monitoring of, 1423-1424, 1498-1499, 1515-1516, 1521, 1582 from anterior fontanel, 1516 complications of, 1424 indications for, 1424 methods and equipment for, 1423-1424, 1515-1516 rationale for, 1515 utility of, 1516 normative values for, 1424, 1513 A (plateau) waves of, 1515 Intrafusal fibers, 1850 Intramuscular administration adverse reactions to, 2194-2195 of antiepileptics, 1119 Intranasal administration, of antiepileptics, 1119-1120 Intranets, 2400 Intraparenchymal echodensities, 315, 317 magnetic resonance imaging of, 317, 318f, 320t versus periventricular leukomalacia, 318-319, 320t ultrasound of, 317, 317f, 320t

lii

Index

Intraparenchymal hemorrhage, 309, 310t, 315 with neonatal stroke, 332, 334 ultrasound of, 168, 168f, 316, 316f vitamin K deficiency and, 332 Intrauterine growth restriction and cerebral palsy, 493 and neonatal stroke, 330 Intravenous administration, of antiepileptics, 1119 Intravenous immunoglobulin for acute cerebellar ataxia, 1247 for acute disseminated encephalomyelitis, 1352 for chronic inflammatory demyelinating polyneuropathy, 1894, 1932 for critical illness polyneuropathy, 1911 for dermatomyositis, 2079 for Guillain-Barré syndrome, 1894, 1927-1929, 1928t for inflammatory myopathies, 2078t for juvenile idiopathic arthritis, 1806 for Kawasaki disease, 1821 for Lambert-Eaton myasthenic syndrome, 1957-1958 for Landau-Kleffner syndrome, 1059-1060 for myasthenia gravis, 1955 for polymyositis, 2080 for Sydenham’s chorea, 1279 Intraventricular hemorrhage, 309-325, 1788 anatomic factors permissive of, 309-310 animal model of, 313, 313f-314f birth weight and, 310-311, 311t, 321 blood-filling with distention (grade 3), 309, 311t, 316 without distention (grade 2), 309, 310t, 316 cerebral blood flow studies of, 311-312, 311b and cerebral palsy, 315, 320-323, 494 clinical findings in, 320 clinical manifestations of, 320, 320t cognitive effects of, 323 corticosteroid prophylaxis against, 311, 311t, 323-324, 323t CSF analysis in, 320 delivery mode and, 311, 324 distribution of, 314-315 early-onset, 311 EEG studies of, 227f, 228 environmental factors in, assessment of, 310 ethamsylate prophylaxis against, 323t, 324-325 genetic studies of, 312-313, 312t germinal matrix (grade 1), 309, 311t, 315-316, 316f gestational age and, 310-311, 311t, 321 grading of, 309, 310t, 316 and hydrocephalus, 309, 315, 321-322, 430 in hypoxic-ischemic injury, 281-282, 287 incidence of, 312, 312t indomethacin prophylaxis against, 323t, 324-325, 324f intraparenchymal echodensities in, 315, 317, 317f-318f magnetic resonance imaging of, 281-282, 317, 318f-319f mass of clot in, 315, 315f mortality in, 309 neonatal care and, 324 with neonatal stroke, 332, 334 and neurodevelopmental disability, 309, 310f, 320-321 neuroimaging of, 316-320. See also specific imaging modalities neuropathology of, 314--316 outcomes in, 320-323 with parenchymal involvement (grade 4), 309, 310t, 315-316, 316f pathophysiologic model of, 314f

Intraventricular hemorrhage continued pathophysiology of, 309-314 and periventricular leukomalacia, 315-316, 318-319 porencephaly in, 317, 317f-318f in preterm infant, 309-325 prevention of, 323-325 pharmacologic, 323-325, 323t, 324f risk factors for, 310t, 311-313 sites of origin, 314 timing of, 310, 311t ultrasound of, 168-170, 168f, 281, 309, 311, 315-317, 316f-318f and ventriculomegaly, 315-316, 319 Introns, 510, 512, 541-542 splicing of, 512, 512f Intussusception, intestinal, 2288 Inversion, genetic, 526f, 528, 529t, 546 Inversion recovery, in MRI, 173-174 Inverted duplicated 15, 555t Inverted duplication, chromosomal, 529t Inverted insertion, chromosomal, 529 Iodine 131-labeled metaiodobenzylguanidine scans, 196 Iodine deficiency, 2323 epidemiology of, 2323 and mental retardation, 808, 2323 Ion balance disorders, 345 Ion channel(s), 992-994 depolarizing conductances in, 994 disorders of (channelopathies), 267 in paroxysmal disorders, 1220 with periodic paralysis, 2094-2105, 2094t-2095t of skeletal muscle, 2085-2105 hyperpolarizing conductances in, 994 in immature brain, and seizure susceptibility, 1001-1002 ligand-gated, 992-993 in normal and epileptic firing, 994t in paroxysmal disorders, 1220 voltage-gated, 992-994, 994t Ionic flux, in traumatic brain injury, 1405-1406 Ionizing radiation teratogenicity of, 2197t and tumor risk, 1693 Iophendylate toxicity, 2194 IOSCA age of onset, 1248t genetics of, 1248t IQ. See Intelligence; Intelligence quotient (IQ) Iris absence or hypoplasia of (aniridia), 83-84 anomalies of, 88 Iron in ADHD, 877 in hypoxic-ischemic injury, 301-302, 302f neuronal brain accumulation of, 1284-1285 physiologic functions of, 2321 Iron chelation for hypoxic-ischemic injury, 301-302, 1504 for malaria, 1659 for spinal cord injury, 1543 Iron deficiency, 2321-2322 and benign intracranial hypertension, 2322 and breath-holding spells, 1205-1206, 2322 cognitive effects of, 2321 epidemiology of, 2321 neurologic effects of, 2322 and restless legs syndrome, 1233 and sinovenous thrombosis, 1783f, 1785 and stroke, 1766, 1769, 2322 Iron therapy for breath-holding spells, 1206 effects of, 2322 for restless legs disorder, 1233 Volume 1: pages 1–1180

Irressa (gefitinib), 1745 ISABEL, 2405 Ischemia hypoxic. See Hypoxic-ischemic injury perfusion MRI in, 189-191 in traumatic brain injury, 1423 Ishihara color plates, 79 Isobutyryl-CoA dehydrogenase deficiency, 595 Isochores, 516 Isochromosome(s), 529 Isochromosome 17q, in medulloblastoma, 1709 Isoelectric focusing, in congenital glycosylation disorders, 647 Isoflurane, and malignant hyperthermia, 2195 Isolated angiitis of central nervous system (IACNS), 1771-1772 Isolated lissencephaly sequence (ILS), 411f, 413-417, 413f Isoleucine in maple syrup urine disease, 352-353, 579 in organic acidopathies, 353-354, 353t Isometric handgrip exercise, 2027 Isoniazid hepatotoxicity of, 2294 lupus syndrome induced by, 1811 neuropathy induced by, 1909 toxicity of, pharmacogenetics of, 2195 for tuberculous meningitis, 1586 Isopropyl alcohol poisoning, 2185 Isotretinoin (Accutane), teratogenicity of, 364, 2198 Isotropic diffusion, 184 Isovaleric acidemia, 353-354, 353t, 588-589 clinical manifestations of, 588-589 laboratory tests in, 589 pathophysiology of, 586f, 588 treatment of, 589 Isovaleryl-CoA dehydrogenase deficiency, 586f, 588 Itraconazole for Chagas’ disease, 1662 for coccidioidomycosis, 1634 for granulomatous amebic encephalitis, 1651 for histoplasmosis, 1636 for South American blastomycosis, 1635 Ivermectin, for gnathostomiasis, 1668 Ixodes pacificus, 2181

J Jackson-Weiss syndrome, 448 clinical features of, 442t, 448 genetics of, 442t, 443, 443f, 447t, 448 Jactatio capitis, 1219 James, William, 1377 Japanese encephalitis, 1598, 1613-1614 clinical features of, 1613-1614 diagnosis of, 1614 epidemiology of, 1613 neuroimaging in, 1601 outcome of, 1603t, 1614 treatment of, 1614 vaccine against, 1614 Jaundice galactosemia and, 618 in Niemann-Pick disease, 675 Jaw reflex, 19t, 22-23 in preterm infant, 56-57, 58t JC virus, 1596, 1598 Jefferson fracture, 1529f, 1530, 1535 Jendrassik maneuver, 19 Jerash type distal hereditary motor neuropathy, 1868t Jerk nystagmus, 22

Volume 2: pages 1181–2408

Index Jervell and Lange-Nielsen syndrome, 105t, 107, 115 Jimsonweed seed poisoning, 2143-2144 Jitter, in electromyography, 1853 Jitteriness, 1299-1300 Joint Committee on Infant Hearing, 111, 111b, 113 Joubert’s syndrome, 390-391 clinical features of, 377t, 389t etiology of, 391 management of, 391 molar tooth sign in, 390-391, 391f sleep in, 1234 type III, 385t variants of, 391t Journal websites, 2401, 2402t-2403t Jugular vein, 1782 Justice, 2389 Juvenile absence epilepsy, 1025, 1029 evaluation and diagnosis of, 1072 treatment of, 1072-1073 Juvenile idiopathic arthritis, 1803-1806, 1804t acute encephalopathy with or without seizures in, 1803-1804 counseling in, 1806 management of, 1805-1806 mood disturbances in, 1805 myelopathy in, 1805 myositis in, 1805 neuropathies in, 1804-1805 neuropathologic abnormalities in, 1805 polyarticular, neurologic manifestations of, 1805 systemic, neurologic manifestations of, 1803-1805, 1805t uveitis with, 88, 1803 Juvenile myoclonic epilepsy, 1019, 1025, 1071-1073 EEG findings in, 1071f, 1072 treatment of, 1075 Juvenile rheumatoid arthritis, uveitis with, 88

K Kabuki syndrome, 464t Kainate receptors, 995 Kallmann’s syndrome, 2116 clinical features of, 464t genetics of, 464t, 556t olfactory dysfunction in, 146 Kant, Immanuel, 2387-2388 Kaposi sarcoma, 1610 in renal transplant patients, 2251 Karyotype, 520, 520f, 545, 545f, 561 in mental retardation, 812 Kaufman Assessment Battery for Children (K-ABC), 805 Kawasaki disease, 1820-1821 laboratory findings in, 1818t neurologic manifestations of, 1818t, 1820 treatment of, 1820-1821 Kayser-Fleischer rings, in Wilson’s disease, 1291, 2299-2300 KCNQ2/KCNQ3 gene, in neonatal seizures, 1009 Kearns-Sayre syndrome, 2053-2054 cardiac involvement in, 2223 clinical features of, 728, 2053-2054 diagnostic criteria for, 2053 hearing loss with, 105t, 107 magnetic resonance imaging in, 175 mitochondrial DNA defects in, 728 MRI findings in, 719f, 720 treatment of, 730 vision loss with, 88t, 89, 91

Kempe, John, 1445 Kennedy’s disease, 1868 Keppra. See Levetiracetam Keratan sulfate, 654, 683, 689 Keratitis amebic, 1651 in syphilis, 1587 Keratoconus, 88 Kernicterus, 103, 109t, 110, 494, 1284, 2196, 2300-2301 in hypoxic-ischemic injury, 286, 1284 laboratory findings in, 2301 management of, 2301 neuropathology of, 2301 Kernig’s sign, 1386, 1573, 1596-1597 Kernohan notch phenomenon, 1388 Ketamine, 2377 for glycine encephalopathy, 582 in traumatic brain injury, 1422 Ketoacidosis, in impaired consciousness/coma, 1390 3-Ketoacyl-CoA thiolase, in fatty acid oxidation, 737-738, 2037f, 2038 2-Keto-adipic acid defect, 361 Ketoconazole for Chagas’ disease, 1662 for granulomatous amebic encephalitis, 1651-1652 for South American blastomycosis, 1635 Ketogenesis, 1136-1138, 1136f-1137f Ketogenic diet, 161, 1131-1146 advantages of, 1144-1145 candidates for, selection of, 1139-1141 clinical studies of, evidence from, 1138-1139 complications of, 1142-1144, 1143b contraindications to, 1140, 1141b cost of, 1145 disadvantages of, 1145 EEG studies in, 1140-1141 efficacy of, 1131-1135, 1131t-1134t for epilepsy, 1033, 1131-1146 experimental studies of, evidence from, 1139 and fatty acid oxidation, 1136-1138 for glucose transporter defects, 359 history of, 1131-1132 hospitalization for, 1141-1142, 1141b indications for, 1139-1140, 1140b, 1140f adverse events during, 1142, 1143b initiation of, 1141-1142, 1141b laboratory abnormalities with, 1144 maintenance of, 1141-1142, 1142b adverse events during, 1142-1143, 1143b mechanism of action, 1135-1139 for myoclonic seizures, 1075 prehospital evaluation for, 1141 for pyruvate dehydrogenase defects, 355, 730 for Rett’s syndrome, 1321 in twenty-first century, 1145-1146 α-Ketoglutarate, in hepatic encephalopathy, 2295-2296 α-Ketoglutarate dehydrogenase deficiency, 725, 2056 Ketone(s), in hypoxic-ischemic injury, 299-300 Ketone body(ies), 717-718 disorders of, 2042 hypoglycemia with, 348t, 718 ketogenic diet and, 1131-1146 oxidation of, 1136-1138 Ketonemia, ketogenic diet and, 1136-1138 β-Ketothiolase deficiency, 592 clinical manifestations of, 592 diagnosis of, 592 treatment of, 592 Ketotic hyperglycinemia(s), 587 Ki-67, 1691 Kidney(s), 2233-2268. See also Renal entries Volume 1: pages 1–1180

Volume 2: pages 1181–2408

liii

Kinetic perimetry, 79 Kinsbourne’s syndrome, 1294 Kjer’s optic atrophy, 90-91 Klebsiella meningitis, 1580t, 1581 Kleeblattschädel, 444 Kleine-Levin syndrome, 1233 Klinefelter’s syndrome, 554-555 clinical features of, 554-555, 555f cytogenetics of, 554, 555f management of, 555 reading difficulties in, 855, 866 Klippel-Feil syndrome, 454-455 cardinal feature of, 454 classic triad of, 455 classification of, 455 clinical characteristics of, 455 genetics of, 454 management of, 455 Klippel-Trenaunay-Weber syndrome, 788 clinical features of, 771t, 788 genetics of, 788 with hemimegalencephaly, 403t, 409 management of, 788 Klumpke’s paralysis, 341, 1891 Knobloch syndrome, 377, 377t Koenen tumors, in tuberous sclerosis complex, 779, 779f Krabbe’s disease, 677-680, 1907-1908 cellular findings in, 677-678, 678f clinical features of, 1907-1908 diagnosis of, 679 early infantile, 678-679, 678f genetics of, 679 incidence of, 678 late infantile or juvenile, 678-680 magnetic resonance imaging in, 176, 678-679 muscular tone in, 69, 678, 678f pathologic studies of, 679 saposin A in, 680 treatment of, 679 Krebs cycle defects, 721, 725, 2056 Kufs’ disease, 702-703, 1072t, 1073, 1328, 1329t Kuru, 1598 Kuskokwim disease, 1873 Kwashiorkor, 2302 Kyphoscoliosis with diastematomyelia, 1860 in Duchenne muscular dystrophy, 1978 tumor surgery and, 1734, 1735f

L L1 cell adhesion molecule disorders, 427-428 La Crosse encephalitis, 1616 clinical features of, 1616 diagnosis of, 1616 EEG findings in, 1601, 1616 epidemiology of, 1599f, 1600 outcome of, 1603t, 1616 treatment of, 1616 Labetalol, for hypertension, 2241 Labyrinth(s), 97-98, 98f, 123 Labyrinthine concussion, 131 Labyrinthitis, 128-129 Laceration(s) cerebral, 1402f, 1403, 1414 scalp, 1418 spinal, 1530 Lacrimation in autonomic dysfunction, 2140, 2152 in Bell’s palsy, 1887-1889 β-Lactam antibiotics, toxicity of, 2191

liv

Index

Lactate in CSF, 163 in hypoxic-ischemic injury, 282-283, 299-300 in McArdle’s disease, 633, 633f in muscle metabolism, 1851-1852 in proton MR spectroscopy, 179-180, 191, 282 Lactate dehydrogenase, 1852 Lactate dehydrogenase deficiency, 637, 2035 biochemistry of, 2035 clinical features of, 2035 genetics of, 2035 laboratory data in, 2035 Lactate-to-creatinine ratio, in hypoxic-ischemic injury, 283 Lactic acidosis, 717-718 and autism, 917-918 differential diagnosis of, 2060 and encephalopathy, 354-355, 354f in malaria, 1658 in maple syrup urine disease, 577-579 in status epilepticus, 1093 thiamine therapy for, 2308 Lactulose, for hepatic encephalopathy, 2296 Lacunar skull, 459 Lafora body disease, 1072t, 1073 Lambda waves, in EEG, 220 Lambdoid synostosis, 445 versus plagiocephaly, 441t Lambdoidal suture, 436, 436f, 437t Lambert-Eaton myasthenic syndrome, 1848, 1941, 1956-1958 antibody testing in, 1956-1957 clinical features of, 1956 electrophysiologic findings in, 1956 laboratory tests in, 1956-1957 repetitive stimulation in, 1956, 1957f treatment of, 1957-1958 Lamictal. See Lamotrigine Lamin(s), 1845, 1969, 1970f Lamin A/C, 1845 diseases associated with, 1842t, 1845 in Emery-Dreifuss muscular dystrophy, 1996 Laminin, 1843 Laminin-α2. See Merosin Lamotrigine, 962-963 absorption of, 1113 adverse effects of, 959t, 963, 1075, 1123-1124, 2264 as antiepileptic agent, 1051t for absence seizures, 1023t, 1029 for atonic seizures, 1023t behavioral and cognitive effects of, 1175-1176 for generalized seizures, 1023t for juvenile myoclonic epilepsy, 1073 for Lennox-Gastaut syndrome, 1033, 1075 mechanism of action, 1003, 1003f, 1119t in mentally retarded patients, 815 for myoclonic seizures, 1075 neonatal use of, 271 testing of, 1002 for tonic seizures, 1023t in traumatic brain injury, 1435 for autism, 925 baseline assessments for, 959t, 963 bioavailability of, 1106t, 1113 blood level of, 1051t clinical applications of, 962 clinical management of, 963 dosage of, 963, 1051t, 1108t drug interactions of, 963 elimination of, 1108t, 1113 exacerbation of myoclonic seizures by, 1031, 1074t formulations of, 1106t

Lamotrigine continued hypersensitivity to, 1125, 1125t labeled and off-labeled use of, 938t metabolism of, 1108t, 1113 monitoring of, 959t, 963 as mood stabilizer, 959t, 962-963 nephrotoxicity of, 2264 for neuronal ceroid lipofuscinosis, 703, 1332 optimal range of, 1117t pharmacokinetics of, 1106t, 1108t, 1113 pharmacology of, 962 and porphyria, 2293 practical guide to, 1051t preparations of, 959t, 1051t protein binding of, 1108t in renal failure, action and effects of, 2267 for Rett’s syndrome, 1321 routes of administration, 1106t, 1120t and sleep, 1234 volume of distribution, 1108t, 1113 Landau reflex, 43t, 44 Landau-Kleffner syndrome, 917, 1047, 1055-1061 arachnoid cysts in, 435 definition of, 1056 EEG in, 1047, 1055-1056, 1058 sleep-activation procedures in, 222 etiology of, 1058-1059 language impairment in, 1055-1056, 1058-1059, 1059t magnetoencephalography in, 195 natural history of, 1057-1058 neuroimaging in, 1058 pathophysiology of, 1058-1059 treatment of, 1059-1060, 1059t Langer-Giedion syndrome, genetics of, 556t Language development cerebral palsy and, 495 cleft lip/palate and, 468 craniosynostosis and, 454 disorders of, 845-851 age for diagnosis, 845 articulation, 846b, 848-849, 848f in Asperger’s disorder, 909 in autistic disorder, 907-908, 913b classification of, 845, 846b comprehensive-expressive, 847t conditions associated with, 847b differential diagnosis of, 845, 847b discrepancy criteria for, 845 etiology of, 845-848 evaluation of, 850-851, 851b expressive, 845, 846b, 849 expressive fluency, 846b, 848-849, 848f genetics of, 847-848 higher-order, 846b, 849-850 incidence of, 846 outcome of, 850 production-expressive, 846t-847t receptive, 845, 846b, 849 risk factors for, 845-846 signs of, 845, 847b subtypes of, 847t treatment of, 851 galactosemia and, 619 hearing loss and, 97, 104-106, 115-116 normal milestones in, 845, 846b terminology in, 846b testing of, 805, 811, 845 variability in, 845, 846f Language impairment, in epileptiform disorders, 1055-1056, 1059t Lanugo, in gestational age estimation, 57t Lapdap (chlorproguanil-dapsone), for malaria, 1659 Volume 1: pages 1–1180

Large, neutral amino acids, for phenylketonuria, 574 LARGE gene, 654 LARGE gene, and cobblestone malformation, 412t Large-vessel infarction, 1763-1764, 1764f Larva migrans, 1664 in baylisascariasis, 1666 cutaneous, in gnathostomiasis, 1668 Larynx examination of, 24 fracture, in strangulation injury, 1489 Lateral geniculate nucleus, visual processing in, 77 Lateral rectus muscle, 20-22, 21f, 21t Lateral transtentorial herniation, 1410 Latex agglutination test, in cryptococcosis, 1632 Latex allergy, in spina bifida, 373 Latissimus dorsi muscle, testing of, 34t Laughter-induced syncope, 2150 Lazaroids, for hypoxic-ischemic injury, 15031504 Lead encephalopathy, acute, 2184 Lead exposure in ADHD, 877 in autistic disorder, 916 chronic, 2184 in neuropathy, 1910 in reading disorders, 855 teratogenicity of, 2197t via breast milk, 2197 Lead poisoning, 1910, 2183-2184 definition of, 2183 treatment of, 2183-2184 Leak conductance, in potassium channels, 994 Learning disabilities. See also Dyslexia with ADHD, 876 with epilepsy/epileptiform disorders, 856, 1057, 1060t, 1171-1172 with neurofibromatosis type 1, 774 with Tourette syndrome, 891-892 Leber’s congenital amaurosis, 85 cerebellar vermis hypoplasia in, 389t, 391 clinical features of, 389t electroretinography in, 85, 85f Leber’s hereditary optic neuropathy, 91, 728-729, 2055 Leg(s) in gait evaluation, 71-72 infant, evaluation of, 40 length of, discrepancies in, 71-72 muscle testing in, 27, 40 segmental innervation of, 26f, 31t-32t Leg recoil, in preterm infants, 54f-55f Legionella myositis, 2082 Leiden database, 1973 Leigh’s syndrome genetics of, 725, 2055 histopathology of, 719-720, 719f protein importation defects in, 727 proton MR spectroscopy in, 182 respiratory chain defects in, 725-727, 2058 sleep in, 1234 Leiter Performance Scale-Revised, 116, 803t Lennox-Gastaut syndrome, 268, 1031-1033 clinical features of, 1031-1032 cognitive and behavioral outcome of, 11731174 EEG studies of, 233, 1031, 1031f, 1055 etiology of, 1031-1032, 1032t ketogenic diet for, 1138 lissencephaly and, 415-417 seizures in, 1019, 1029, 1031-1033 treatment of, 815, 1032-1033, 1075, 1164 Lenticulostriate branches, arterial, 1760-1762 Leprosy, 1590-1591

Volume 2: pages 1181–2408

Index Leptin, 2122-2123 deficiency of, 2123 Leptomeningeal angioma, in Sturge-Weber syndrome, 782-783 Leptomeningeal cyst, 336-337, 1402f, 1418, 1436 Leptomeningeal melanoma, in neurocutaneous melanosis, 787-788 Leptospirosis (Leptospira), 1588 Leptotene, 514 Lesch-Nyhan disease, 1285-1286 LET (lidocaine, epinephrine, and tetracaine), 2377 Leucine, 511 in maple syrup urine disease, 352-353, 579-580 in organic acidopathies, 353-354, 353t Leukemia(s), 1735 aspergillosis in, 1738, 1738f chemotherapy-associated myelopathy in, 1737 dural sinus thrombosis in, 1736 hypothalamic syndrome in, 1736-1737 infection in, 1738 long-term effects of therapy for, 1738-1745 cognitive, 1739-1741, 1740f endocrine, 1741-1743 leukoencephalopathy, 1743-1744, 1743f meningeal, 1735-1736 neurologic complications of, 1735-1738 new therapeutic approaches for, 1745-1747 seizures in, 1737 spinal cord compression in, 1738 stroke in, 1736, 1736f Leukocoria, 80-81, 80f Leukocytes. See White blood cells Leukocytoclastic vasculitis, 1804t, 1821 Leukodystrophy, 823t, 1345. See also specific types cognitive and motor regression in, 827t in developmental disorders, 840t terminology in, 1345 Leukoencephalitis, acute hemorrhagic, 1352-1354 Leukoencephalopathy, 1345 etiologic classification of, 1345, 1346t leukemia therapy and, 1743-1744, 1743f neuroimaging of, 1743, 1743f pathologic classification of, 1345, 1345t posterior reversible, 2175, 2239-2240 with vanishing white matter, 767, 1364-1366 vision loss with, 86 Leukoma, 82-83, 82f Leukomalacia, sulfite oxidase/molybdenum cofactor deficiency and, 358 Levator ani muscle, 2166 Levator palpebra superioris, 20 Levetiracetam for absence seizures, 1023t absorption of, 1113 adverse effects of, 1123, 1176 for autism, 925, 927t behavioral and cognitive effects of, 1176 bioavailability of, 1106t, 1113 blood level of, 1051t dosage of, 1051t, 1108t elimination of, 1108t, 1114 formulations of, 1106t for generalized seizures, 1023t mechanism of action, 994, 1004, 1004f, 1119t metabolism of, 1108t for migraine prevention, 1193t, 1195 for myoclonus, 1295 for neuronal ceroid lipofuscinosis, 1333 for nonepileptic paroxysmal disorders, 1297 optimal range of, 1117t pharmacokinetics of, 1106t, 1108t, 1113-1114

Levetiracetam continued practical guide to, 1051t preparations of, 1051t protein binding of, 1108t, 1113 in renal failure, action and effects of, 2267 routes of administration, 1106t testing of, 1002 for tic disorders, 896 in traumatic brain injury, 1435 volume of distribution, 1108t, 1113 Levine-Critchley syndrome. See Neuroacanthocytosis Levodopa adverse effects of, 1288 for L-amino acid decarboxylase deficiency, 763 CSF analysis for, 163 dosage of, 1288 for dystonia, 1213t, 1215, 1283, 1288 for hyperkinetic disorders, 1290 for hyperphenylalaninemia, 360 for Lesch-Nyhan disease, 1286 for nonepileptic paroxysmal disorders, 1213t, 1214-1215, 1298 for parkinsonism, 1293 for Parkinson’s disease, 1292 pharmacokinetics of, 1288 for Rett’s syndrome, 1321 for Segawa’s disease, 762 for sepiapterin reductase deficiency, 763 for tyrosine hydroxylase deficiency, 764-765 Levodopa-carbidopa, 1288 Levorphanol, abuse/poisoning, 2186 Lexapro. See Escitalopram Lexical syntactic syndrome, 850 LGI1 gene, in autosomal dominant epilepsy, 1013 Lhermitte-Duclos disease, 394 Lhermitte’s sign, 1739 Lidocaine for analgesia, 2377 for neonatal seizures, 271 Lidoflazine, for hypoxic-ischemic injury, 1503 Ligand-gated ion channels, 992-993 Lightning injuries, 1489-1490 Lignoceroyl coenzyme A ligase, in fatty acid oxidation, 736f, 737 Limb hypertrophy, unilateral, in KlippelTrenaunay-Weber syndrome, 788 Limb-girdle muscular dystrophies, 1987-1995 autosomal dominant, 1987 autosomal recessive, 1987 calpain in, 1840 classification of, 1987-1988, 1988t genetics of, 1987 pathophysiology of, 1988-1989 type 1A (myotilinopathy), 1988t, 1994-1995 diagnosis of, 1994 pathophysiology of, 1994 type 1C (caveolinopathy), 1988t, 1989 type 2A (calpainopathy), 1988t, 1990-1991 clinical manifestations of, 1990 diagnosis of, 1990-1991 molecular pathogenesis of, 1990-1991 muscle pathology in, 1990-1991 type 2B (dysferlinopathy), 1988t, 1991-1992 clinical presentation of, 1991 diagnosis of, 1991-1992 molecular pathogenesis of, 1991 type 2C (γ-sarcoglycanopathy), 1988t, 1992-1993 type 2D (α-sarcoglycanopathy), 1988t, 1992-1993 type 2E (β-sarcoglycanopathy), 1988t, 1992-1993 Volume 1: pages 1–1180

Volume 2: pages 1181–2408

lv

Limb-girdle muscular dystrophies continued type 2F (δ-sarcoglycanopathy), 1988t, 1992-1993 type 2G (telethonin), 1988t, 1995 type 2I (fukutin-related protein gene deficiency), 1988t, 1993-1994 clinical manifestations of, 1993-1994 diagnosis of, 1994 management of, 1994 molecular pathogenesis of, 1993 type 2J (titin), 1988t, 1995 Limbic epilepsies, 1046 Limbic system embryology of, 383 in febrile seizures, 1081 Limb-kinetic apraxia, 822t Limit dextrinosis, 630-631. See also Debrancher deficiency Lincoln, Abraham, 1258 Lindane poisoning, 2183 Linear forces, and traumatic brain injury, 1402-1403, 2355 Linear nevus sebaceus syndrome, with hemimegalencephaly, 403t, 409 Linear skull fracture, 1417, 1417f Lip(s) cleft. See Cleft lip/palate embryology of, 466 Lip reading, 118 Lipid(s) in exercise, 2023 of inner mitochondrial membrane, defects of, 728, 2060 in leukoencephalopathies, 1345, 1346t in lysosomal storage diseases, 660t in muscle metabolism, 1851-1852 in Niemann-Pick disease, 674-675 in spinal cord injury, 1532 Lipid peroxidation, in hypoxic-ischemic injury, 1503-1504 Lipogranulomatosis, 677. See also Farber’s disease Lipoic acid, for pyruvate dehydrogenase deficiency, 730 Lipoma(s), in occult spinal dysraphism, 367-368, 368f Lipoprotein(a), elevated levels of, and neonatal stroke, 329-330, 332 α-Lipoprotein deficiency, 1907 biochemistry of, 1907 clinical characteristics of, 1907 management of, 1907 Liposomes, for drug delivery, 1746 Liquid chromatography, 523 in congenital glycosylation disorders, 647 in muscular dystrophy, 1980 LIS genes, 412, 412t, 413f, 414-415 Lisch nodules, in neurofibromatosis type 1, 774 Lissencephaly, 410-417 antenatal diagnosis of, 415 with cerebellar hypoplasia, 389t, 413-414, 413f, 464t and cerebral palsy, 493 classic four-layered, 411, 413 clinical characteristics of, 412-413 cobblestone complex, 389t, 416f, 417 in developmental disorders, 840t epidemiology of, 400 genetic testing for, 415 genetics of, 411f, 412, 412t, 413f isolated sequence, 411f, 413-417, 413f management of, 415-417 versus microcephaly, 402-403 with microcephaly, 403t, 405 MRI findings in, 411f, 413f outcome of, 417 pathogenesis of, 365

lvi

Index

Lissencephaly continued syndromes of, 413-415 type 2, 417 types of, 411-412, 411f, 413f X-linked, with abnormal genitalia (XLAG), 411f, 412-417 Listeria monocytogenes, 1571, 1581, 1738, 2250, 2298 LITAF gene, in neuropathy, 1897 Lithium, 958-960 adverse effects of, 959t, 960, 2189-2190, 2265 baseline assessments for, 958, 959t for bipolar affective disorder, 958-960 clinical applications of, 958 clinical management of, 958-960 for cluster headache, 1199 contraindications to, 958 dosage of, 958 drug interactions of, 960 immediate-release, 958, 959t labeled and off-labeled use of, 938t monitoring of, 959-960, 959t nephrotoxicity of, 2265 pharmacology of, 958 preparations of, 959t in renal failure, action and effects of, 2268 sustained-release, 958, 959t Lithium intoxication, 2189 Live-attenuated influenza vaccine (LAIV), 2346 Live-attenuated virus vaccines, 2348-2349 Liver. See also Hepatic entries ketogenesis in, 1136, 1137f Loading dose, 1109 Lobar holoprosencephaly, 395f, 396-397 Localization-related epilepsies, 981, 982t, 1046-1047 management of, 1049-1050 surgery for, 1153-1155 Locke, John, on mental retardation, 800 Locked-in syndrome, 1381, 1381f Locus ceruleus, in migraine, 1187 Log-kill hypothesis, 1696 Long (q) arm, of chromosome, 516, 541, 543f Long thoracic nerve, 28t Long-chain 2-enoyl-CoA hydratase (LCEH) deficiency, 724 Long-chain 3-ketoacyl-CoA thiolase (LCKT) deficiency, 724 Long-chain acyl-CoA dehydrogenase deficiency, 724-725, 2024-2025, 2048 Long-chain acyl-coenzyme A ligase, in fatty acid oxidation, 736f, 737 Long-chain L-3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, 724, 2041 Longitudinal cord syndrome, 2215 Looking, three ways of, 2391 Loop diuretics, and CSF formation, 155 Lorazepam, 956t bioavailability of, 1106t for cyclical vomiting syndrome, 1217, 2286 dosage of, 956t drug interactions of, 956t for febrile seizures, 1084-1085 formulations of, 1106t half-life of, 956t in malaria, 1660 in meningitis, 1582 for neonatal seizures, 269t, 270 in hypoxic-ischemic injury, 291 for nonepileptic paroxysmal disorders, 1213t pharmacokinetics of, 1106t, 1111-1112 preparations of, 956t routes of administration, 1106t, 1120, 1120t

Lorazepam continued for status epilepticus, 1098t, 1099-1100 in systemic lupus erythematosus, 1814 Loss of heterozygosity, 1747 Lou Gehrig’s disease. See Amyotrophic lateral sclerosis Louis-Bar syndrome, 1251. See also Ataxia-telangiectasia Lovenex, 1777 Low birth weight, 53 and neurodevelopmental disability, 309 Low copy repeats (LCRs), 518, 525-527, 525f Lower motor neurons (LMNs), 68-69 in developmental disorders, 842t in muscular tone pathology, 66-69, 68t Lowe’s syndrome, 2054 Low-molecular-weight heparin for deep vein thrombosis, 2363 pediatric protocol for, 1777, 1777b postoperative, in cardiac patients, 2218 for sinovenous thrombosis, 1787 for stroke, 332, 342, 1776-1777 Lowry-MacLean syndrome, 451, 464t LSD, 2187 LSU (Louisiana State University) reciprocating gait orthosis, 2358, 2358f Lucid interval, in inflicted neurotrauma, 1463 Luft’s disease, 725, 2059 Lumbar lordosis, in spinal muscular atrophy, 1864, 1867f Lumbar plexus, 28t Lumbar puncture, 153 in brain abscess, 1575t, 1588 complications of, 158-159 contraindications and cautions in, 156, 1575 in febrile seizures, 1080 and headache, 158-159 herniation after, 156 history of, 153 for hydrocephalus, 321, 431 for idiopathic intracranial hypertension, 1522-1523 in impaired consciousness/coma, 1390 in increased intracranial pressure, 1200, 1519-1520 indications for, 156 and intracranial hypotension, 158-159, 158f in meningeal leukemia, 1735 in meningitis, 156, 160-161, 162t, 1574-1575 needles for, 157, 157f normal pressures in, 157 patient positioning for, 156-157, 156f procedure for, 156-158 Queckenstedt test in, 157 for sinovenous thrombosis, 1787 slow flow in, methods for increasing, 157 in spinal cord injury, 1537 in spinal cord tumor, 1731 in subarachnoid hemorrhage, 338 in traumatic brain injury, 1420 tube collection in, 157-158 Lumbar spine, 1527, 1528f Lumboperitoneal shunting, for sinovenous thrombosis, 1787 Lumbosacral spinal cord injury, 1528 Lung(s), in hypoxic-ischemic injury, 281, 281t Lung cancer, small-cell, in Lambert-Eaton myasthenic syndrome, 1956 Lupus drug-induced, 1811-1812, 2265 systemic. See Systemic lupus erythematosus Lupus aseptic meningitis, 1811 Luteinizing hormone, in puberty normal, 2114 precocious, 2115 Luvox. See Fluvoxamine Volume 1: pages 1–1180

Lyme disease, 1587-1588, 1808 arthritis in, 1808 clinical characteristics of, 1587, 1805t, 1808 diagnosis of, 1587-1588 peripheral neuropathy in, 1933 treatment of, 1588 vertigo in, 132 Lymphocytic choriomeningitis virus, 1620 clinical features of, 1620 congenital, 1620, 1620f diagnosis of, 1602t, 1620 neuroimaging in, 1620, 1620f outcome of, 1603t, 1620 Lymphoma(s) incidence of, 1719t in renal transplant patients, 2251 spinal cord, 1732 survival rates with, 1690t Lysergic acid diethylamide, 2187 Lysosomal acid ceramidase deficiency, 677 Lysosomal acid lipase deficiency, 683 Lysosomal storage diseases, 659-703 cardiac involvement in, 2224 classification of, 659, 660t-661t clinical manifestations of, 662t cognitive and motor regression in, 826t diagnosis of, 663t general concepts in, 659-664 genetic counseling in, 664 genetics of, 661 mechanical factors in, 661 as orphan disorders, 661 prevalence of, 661 screening for, 661-662 treatment of, 663-664, 663t underlying causes of, 659, 661t Lysyl oxidase, in Menkes’ disease, 1324

M M band, 1839-1840, 1839f MabCampath (alemtuzumab), for multiple sclerosis, 1350 Machado-Joseph disease, 1255t, 1257, 1286 Macrocephaly with arachnoid cyst, 433 in autistic disorder, 915 in Dandy-Walker syndrome, 391-392 definition of, 400 in developmental disorders, 830t etiology of, 407b in inflicted neurotrauma, 1449 with intracranial pressure increase, 1517 in Klippel-Trenaunay-Weber syndrome, 788 in mental retardation, 811 in neurofibromatosis type 1, 774 Macrocephaly-CMTC syndrome, 403t Macroorchidism, in developmental disorders, 843t Macrophage(s) in Guillain-Barré syndrome, 1925-1926 in multiple sclerosis, 1346-1347, 1349 in spinal cord injury, 1532 Macrophage activation syndrome, 1803 Macroprolactinoma, 2118 Macropsia, in Alice in Wonderland syndrome, 1189 Macrosomia, and birth trauma, 334 Macular cherry-red spot in developmental disorders, 838t in galactosialidosis, 694 in GM1 gangliosidosis, 666 in mental retardation/developmental delay, 812b in Niemann-Pick disease, 674 in poisoning, 2175 in Tay-Sachs disease, 667, 667f

Volume 2: pages 1181–2408

Index Macular corneal dystropy, 655 Maffucci’s syndrome, 785-786 clinical features of, 771t, 786 genetics of, 786 management of, 786 neurologic complications of, 786 Magnesium abnormal concentrations of, 2328-2329 CSF concentration versus plasma, 154t in renal Fanconi syndrome, 2263 in uremic encephalopathy, 2236 Magnesium pemoline. See Pemoline Magnesium sulfate fetal/neonatal effects of, 2195 in hypoxic-ischemic injury, 291, 301, 1502 Magnetic resonance angiography (MRA), 174, 177 in brain tumors, 1696, 1696f in primary angiitis, 1823, 1823f in stroke, 188f, 189, 331, 1774 in subarachnoid hemorrhage, 1790 Magnetic resonance imaging, 167, 173-178 in acute disseminated encephalomyelitis, 176, 179f, 1352, 1352f in acute intermittent porphyria, 2293 in adrenomyeloneuropathy, 746-747, 747f advantages of, 173 in Aicardi-Goutieres syndrome, 1353f, 1354 in Alexander’s disease, 1357, 1358f-1359f in Alpers’ disease, 1327 of arachnoid cyst, 433-434, 434f of arteriovenous malformation, 1790, 1791f of astrocytoma, 1720 in autism, 921-922 in autonomic dysfunction, 2140 in Balamuthia amebic encephalitis, 1652, 1653f in Bell’s palsy, 1889 of brachial plexus injury, 341 of brain abscess, 174, 177f, 1588, 2222, 2222f in brain death, 1561 of brain myelination, 174, 282 of brain tumors, 172f, 176-177, 180f-181f, 1695, 1695f in infants and very young children, 1727 of brainstem tumors, 176, 180f, 1717, 1717f in Canavan’s disease, 176, 593, 593f, 1361f, 1362 of cavernous malformations, 1792f, 1793 of cerebellar astrocytoma, 1713 in cerebral autosomal dominant arteriopathy subcortical infarcts and leukoencephalopathy, 1369 of cerebral hemorrhage, 177-178, 181f of cerebral infarction, 175, 177, 1764f-1766f in cerebral palsy, 495, 495f in cerebrotendinous xanthomatosis, 1367 in cerebrovascular disease, 174f, 177, 178f of Chiari I malformation, 388, 388f of cobblestone malformations, 416f contraindications to, 173 of cortical malformations, 1157, 1158f of craniopharyngioma, 1706, 1706f of craniosynostosis, 444 in cytomegalovirus, 1606 in developmental disorders, 840t-841t in diabetes insipidus, 2125 of diastematomyelia, 373, 373f, 1860, 1861f of diffuse axonal injury, 1411, 1411f diffusion-weighted, 184-189. See also Diffusion-weighted imaging in enteroviruses, 1611f of ependymoma, 1715 of epidural abscess, 1589, 1589f in Epstein-Barr virus, 1609f, 1610 in Fahr’s disease, 1286-1287, 1287f

Magnetic resonance imaging continued fluid-attenuated inversion recovery in, 1156, 1157f-1158f four-coil, phased-surface-array, 176 functional, 167, 191-194 in ADHD, 875 advantages of, 195 in autistic disorder, 911 of brain tumors, 193-194 in dyslexia, 857-863, 858f-860f, 862f with EEG studies, 241 in epilepsy, 193-194, 241 of hydrocephalus, 430 preoperative, 193-194, 1162-1163, 1162f in spinal cord injury, 1537 gadolinium-enhanced, 174, 178, 189 in galactosemia, 619 in Gaucher’s disease, 673 in global development delay, 807 in glutaric aciduria, 352t, 361, 594, 594f gradient-recalled echo in, 173-174 in Guillain-Barré syndrome, 1925 in hearing loss, 114 of hemimegalencephaly, 406f in hepatic encephalopathy, 2295 in herpes simplex virus, 1605 in HIV, 1622 of holoprosencephaly, 395f, 398 of hydrocephalus, 178, 183f, 429-430, 429f in hypertensive encephalopathy, 2239-2240 of hypoxic-ischemic injury, 281-283 cortical or subcortical, 284 parasagittal, 282, 285, 285f in impaired consciousness/coma, 1390, 1397 indications for, 167 in infantile neuroaxonal dystrophy, 1904 in infantile spasms, 1069 in inflammatory bowel disease, 2290 of intracranial hemorrhage, 1420, 1420t of intraparenchymal echodensities, 317, 318f, 320t of intraventricular hemorrhage, 317, 318f-319f inversion recovery in, 173-174 in Krabbe’s disease, 176, 678-679 in Landau-Kleffner syndrome, 1058 of leukoencephalopathy, 1743, 1743f of lissencephaly, 411f, 413f in localization-related epilepsy, 1154, 1154f in lumbar puncture, 157-158, 158f in maple syrup urine disease, 577, 578f in measles virus, 1617, 1618f of medulloblastoma, 1710, 1710f in megalencephaly, 408-409 of megalencephaly, 406f in megaloencephalic leukoencephalopathy with subcortical cysts, 1363f, 1364 of meningioma, 1708f in meningitis bacterial, 1575-1576, 1576f tuberculous, 1585-1586, 1586f of meningocele, 368, 368f in mental retardation, 807 in mesial temporal sclerosis, 176, 180f, 1046, 1157 in metabolic encephalopathies, 346, 352, 352t in metachromatic leukodystrophy, 681-682 in microcephaly, 404, 404f of midline abnormalities, 178, 182f of migrational anomalies, 175, 177f in mitochondrial encephalomalacia, 719-720, 719f in multiple sclerosis, 1347, 1348f of muscle, 1853 in near-drowning, 1487 in neurocutaneous melanosis, 788 in neurofibromatosis type 2, 777 Volume 1: pages 1–1180

Volume 2: pages 1181–2408

lvii

Magnetic resonance imaging continued in neuronal ceroid lipofuscinosis, 1329t-1330t infantile, 1329t, 1335 juvenile, 1329t, 1335 juvenile-like variant, CLN9-deficient, 1330t, 1337 late infantile, classic, 1329t, 1332 in neuronal heterotopias, 419f in occult spinal dysraphism, 367-368, 368f of oligodendroglioma, 1724, 1724f of optic pathway tumor, 1702-1703, 1702f-1703f in pantothenate kinase-associated neurodegeneration, 1285, 1285f in Pelizaeus-Merzbacher disease, 1355f, 1356 perfusion, 189-191 of brain tumors, 189-190, 1696 in perinatal trauma, 335 of periventricular leukomalacia, 282, 289, 289f, 318-319, 320t in phenylketonuria, 352t, 570, 573 of pineal region tumors, 178, 182f, 1704, 1705f in poisoning, 2175 of polymicrogyria, 421f, 422 in Pompé’s disease, 698 of porencephaly, 317, 319f of post-hemorrhagic hydrocephalus, 322, 322f prenatal, 167 preoperative, for epilepsy surgery, 1154, 1154f, 1156-1157, 1157f-1158f of primitive neuroectodermal tumor, 1723 quantitative volumetric analysis in, 1156 in Schilder’s disease, 1351, 1351f of schizencephaly, 421f, 422 sensitivity and specificity of, 282 of septum pellucidum anomalies, 384f, 385 signal intensity in, 173 of sinovenous thrombosis, 1782f, 1786 in Sjögren-Larsson syndrome, 1367 in smell and taste disorders, 138 spin echo in, 173-174 in spina bifida, 194f, 370, 371f spinal, 194f, 195, 195f of spinal cord injury, 339, 1535-1537, 1536f, 1547 of spinal cord tumor, 1731, 1731f in stroke, 330, 330f, 331, 1774 in Sturge-Weber syndrome, 783 in subacute sclerosing panencephalitis, 1618, 1618f of subcortical band heterotopia, 411f of subdural hematoma, 337, 1435 susceptibility-weighted, 191 in Sydenham’s chorea, 1807-1808 of syringomyelia, 1861-1862 in systemic lupus erythematosus, 1812-1814, 1813f T1-weighted, 173-174, 177f, 180f-181f, 183f, 282 T2-weighted, 173-174, 178f-180f, 182f, 282 of teratoma, 1704, 1705f of transverse myelitis, 1875f, 1876 of traumatic brain injury, 1420, 1420t, 1431, 1432f inflicted (child abuse), 1462-1463 in tuberous sclerosis complex, 780f, 781 in uremic encephalopathy, 2238 in vanishing white matter disease and childhood ataxia with hypomyelination, 1364-1366, 1365f in varicella-zoster virus, 1608 of vein of Galen malformation, 1792f in viral infections, 1601-1602 in Whipple’s disease, 2292 in white matter disease, 176, 178f in X-linked adrenoleukodystrophy, 746, 747f, 749

lviii

Index

Magnetic resonance spectroscopy, 167, 178-184 advantages of, 195 in brain abscess, 1588 of brain tumors, 183-184, 186f, 1696 after cardiac arrest, 1495-1497, 1496f-1497f chemical shift in, 178, 184f in coma, 1396-1397 functional, 191 in hepatic encephalopathy, 2295 in Krabbe’s disease, 679 phosphorous, 178-179 in brain death, 1561-1562 preoperative, for epilepsy surgery, 1161 proton (1H), 178-184 in Alpers’ disease, 1327 in brain death, 1561-1562 diseases studied with, 180-184 in epilepsy, 182-183 in hypoxic-ischemic injury, 182, 185f, 282, 300 in near-drowning, 1487 spectral metabolites in, 179-180, 184f of traumatic brain injury, 1431, 1432f in vegetative state, 1380 Magnetic resonance venography in sinovenous thrombosis, 189f, 1783f, 1786 of stroke, 189, 189f, 330-331 Magnetic source imaging, 194-195, 241 Magnetoencephalography (MEG), 194-195, 241 in dyslexia, 195, 861 preoperative, for epilepsy surgery, 1161-1162 Magnocellular theory, of dyslexia, 856 Maintenance of wakefulness test, 1228 Majewski’s syndrome, 405 Major tranquilizers, 964. See also Dopamine receptor antagonist(s) Malabsorption syndromes, 2288-2290 Malaria, 1656-1660 cerebral, definition of, 1659 classification of, 1647t clinical characteristics of, 1647t, 1658-1659 diagnosis of, 1647t, 1658-1659 EEG findings in, 1659 epidemiology of, 1656-1658 geographic distribution of, 1647t, 1657 historical perspective on, 1657 laboratory tests in, 1658-1659 management of, 1647t, 1657, 1659-1660 maternal antibodies against, 1658 microbiology of, 1656-1658 mode of infection, 1647t, 1656-1657 neurologic sequelae of, 1658 pathology of, 1647t, 1656-1658, 1658f prophylaxis against, 1659 risk factors for, 1647t vaccines against, research for, 1660 Malignant hypertension, 2238-2242. See also Hypertensive encephalopathy Malignant hyperthermia, 2195 Malnutrition, 2301-2304 anatomic and biochemical effects of, 2302-2304 behavioral and cognitive effects of, 2304 epidemiology of, 2301-2302 incidence of, 2301-2302 neuropathologic features of, 2302-2303, 2303b protein-calorie, 2304 protein-energy, 2302-2304 recovery from, 2303-2304, 2303b in renal disease, 2244 treatment of, 2304 WHO definition of, 2302 Malta syndrome, 391 Manganese, teratogenicity of, 2198 Manganese superoxide dismutase, in spinal cord injury, 1543

Mannitol for dialysis disequilibrium, 2246 for increased intracranial pressure, 1520-1521 in diabetic ketoacidosis, 1523 in hepatic encephalopathy, 2297 in hypoxic-ischemic injury, 1499 in malaria, 1660 in meningitis, 1582-1583 in Reye’s syndrome, 2299 in traumatic brain injury, 1422-1423 Mannose-6-phosphate receptor pathway, 659 Mannosidase deficiency, 691-692 Mannosidosis, 691-692 α, 691-692 clinical features of, 691 genetics of, 691 infantile (type I), 691 milder form of (type II), 691 treatment of, 692 β, 691-692 clinical features of, 690 genetics of, 690-691 Manometry anal, 2167 esophageal, 2286 Maple syrup urine disease (MSUD), 73, 352-353, 576-580 classic, 576-577 clinical features of, 350t-351t, 352, 576-579 diagnosis of, 353 dihydrolipoyl dehydrogenase-deficient, 577-579 EEG findings in, 352-353, 577 genetics of, 576, 579 intermediate, 577 intermittent, 577 laboratory tests in, 579 management of, 353, 579-580 MRI findings in, 352, 352t, 577, 578f neuroimaging in, 577, 578f pathophysiology of, 352, 353f thiamine-responsive, 577, 579 Marasmus, 2302 Marcus Gunn syndrome, 20, 88 Marden-Walker syndrome, 464t Marfanoid craniosynostosis syndrome. See Shprintzen-Goldberg syndrome Marginal zone, 398-399 Marijuana, 2186-2187 Marker chromosomes, 546-547 Maroteaux-Lamy syndrome, 690 clinical features of, 690 treatment of, 663, 663t, 690 MASA syndrome, 427-428 Mass spectrometry, in congenital glycosylation disorders, 647 MASS1 gene, in epilepsy, 1013 Masseter muscle, 22 Masturbation, 1219-1220, 1301 Matchstick heads, poisoning from, 2185-2186 Maternal inheritance, 16, 535, 715-717, 2050-2053 Maternal serum screening, 549 Maximal electroshock test, of antiepileptic agents, 1002 Mazabraud’s syndrome, 457 McArdle’s disease, 633-635, 1850, 2029-2031 biochemistry of, 633, 633f, 2030 clinical manifestations of, 622t, 633-634, 2029 diagnosis of, 1853 enzyme defect in, 622t genetics of, 634, 2029-2031 glycogen structure in, 622t ischemic exercise testing in, 634, 634f laboratory tests in, 634, 2029 management of, 634-635, 2031 Volume 1: pages 1–1180

McArdle’s disease continued muscle biopsy in, 2029-2030 pathology of, 633 pathophysiology of, 2030 McCune-Albright syndrome, 458-459, 2121 versus Albright’s hereditary osteodystrophy, 458-459 clinical features of, 458 endocrine manifestations of, 458 fibrous dysplasia in, 457-459 McDonald criteria, for multiple sclerosis, 1347 McLeod’s cardiomyopathy, 1995 MCPH1 gene, and cortical malformations, 402t, 405 M-current potassium channel, 994 ME2 gene, in generalized epilepsy, 1011 Meadow’s syndrome, 1212 Meadow’s syndrome (Munchausen by proxy), 1212, 1386, 2173-2174 Mean sleep latency, 1228 Measles inclusion-body encephalitis, 1617 Measles vaccine, 2348 neurologic complications of, 2348 Measles virus, 1617-1618 clinical features of, 1617 diagnosis of, 1617-1618 EEG findings in, 238-239, 1617 epidemiology of, 1617 and hearing loss, 109 neuroimaging in, 1617, 1618f outcome of, 1603t, 1618 transmission of, 1617 treatment of, 1618 Measles-mumps-rubella (MMR) vaccine, 2348-2349 and autism risk, 923, 2350 Mebendazole, for trichinosis, 1667, 2082 Mechanical ventilation, in spinal cord injury, 1544 Meckel-Gruber syndrome, 377, 377t, 550 Meckel’s syndrome, clinical features of, 389t Meclizine, for nonepileptic paroxysmal disorders, 1213t MECP2 gene in mental retardation, 809, 809r mutations, in males, 1319 in Rett’s syndrome, 910-911, 1315, 1318-1321 MECP2 protein, 1319-1320 Medial longitudinal fasciculus, 22 Medial rectus muscle, 20-21, 21f, 21t Median cleft face syndrome, clinical features of, 377t Median nerve, 28t stimulation, for somatosensory-evoked potential, 246, 247f Medical College of Virginia protocol, for status epilepticus, 1098t, 1099 Medical ethics, 2387 Medicolegal headache, 1195-1196 Medicolegal issues, in inflicted neurotrauma, 1463-1464 Mediterranean fever, familial, 2261 Mediterranean myoclonus, 1254 Medium-chain acyl-CoA dehydrogenase deficiency, 724, 2041 Medium-chain triglyceride (MCT) diet, 1135, 1138 Medium-chain triglyceride oil, for fatty acid oxidation defects, 2047 MEDLINE, 2404 Medulloblastoma(s), 1709-1712 age at diagnosis, 1693 biologic markers in, 1709 chemotherapy for, 1711 clinical characteristics of, 1710 Collins’ rule in, 1709

Volume 2: pages 1181–2408

Index Medulloblastoma(s) continued cytologic studies of, 1710, 1710f gross appearance of, 1709, 1710f histology of, 1709-1710 incidence of, 1687, 1692-1693, 1719t in infants and very young children, 1725, 1726f, 1728-1729 magnetic resonance imaging of, 1710, 1710f management of, 1710-1712 versus primitive neuroectodermal tumors, 1709, 1723 prognostic factors in, 1711 radiation therapy for, 1698, 1711 endocrine effects of, 1741-1742, 1742f recurrence of, 1711 risk factors for, 1693 surgery for, 1697, 1710 survival rates with, 1690t, 1709 terminology for, 1709 Medulloepithelioma(s), 1725 Mees’ lines in arsenic poisoning, 2185 in thallium poisoning, 2185 Mefloquine, for malaria, 1659 Mega cisterna magna, 392-393, 393f Mega-corpus callosum, megalencephaly with, 403t, 408 Megalencephaly, 406-409 anatomic, 406-408 asymptomatic (benign) familial, diagnostic criteria for, 409b in autistic disorder, 915 classification of, 406 clinical characteristics of, 408 definition of, 406 etiology of, 407b genetic counseling in, 408-409 genetics of, 408-409 isolated, 403t magnetic resonance imaging of, 406f with mega-corpus callosum, 403t metabolic, 406-407 MRI findings in, 408-409 outcome of, 408 pathogenesis of, 408 primary, 408 syndromes with, 403t, 408 Megalencephaly-mega-corpus callosumpolymicrogyria (MCCP) syndrome, 408 Megalencephaly-polymicrogyria-polydactylyhydrocephalus, 403t, 406f Megaloblastic anemia, 2312-2313, 2319 Megaloencephalic leukoencephalopathy magnetic resonance imaging in, 1363f, 1364 with subcortical cysts, 1363f, 1364 Meiosis, 513-514, 515f Meiosis 1, 514 Meiosis 2, 514 Melanocortin receptors, in appetite regulation, 2123 α-Melanocyte-stimulating hormone, in appetite regulation, 2123 Melanocytic nevi, in neurocutaneous melanosis, 787-788 Melanoma leptomeningeal, in neurocutaneous melanosis, 787-788 in renal transplant patients, 2251 Melarsoprol, for African trypanosomiasis, 1664 Melatonin for delayed sleep phase syndrome, 1234 in sleep physiology, 1225 Melkersson-Rosenthal syndrome, 143, 1889-1890

Membrane cofactor protein-1, in hypoxicischemic injury, 302 Membranocranium, 436. See also Cranial vault Membranous labyrinth, 97, 98f, 123 Memory loss, in traumatic brain injury, 2356 Menarche, 2114 Mendelian inheritance, 532, 533f Meniere’s disease, 98, 129-130 Meningeal leukemia, 1735-1736 cranial nerve involvement in, 1735-1736 CSF analysis in, 1735 Meningeal tumors, incidence of, 1719t Meningioma(s), 1708 management of, 1708 in neurofibromatosis type 2, 776f, 777 neuroimaging of, 1708, 1708f as secondary malignancy, 1744, 1744f spinal cord, 1732 Meningismus, 1573 Meningitis acute bacterial, 1571-1584 antibiotics for, 1579-1582, 1580t arthritis in, 1573 blood-brain barrier disruption in, 1576 brain edema in, 1576 brain imaging in, 1575-1576, 1576f causative agents of, 1580t, 1581-1582 cerebral blood flow changes in, 1577 cerebral infarction in, 1583 chemoprophylaxis against, 1584 clinical features of, 1573-1574, 1573t after cochlear implants, 1574 complications of, 1576-1579 corticosteroids for, 1581-1582 cranial nerve damage in, 1577 dehydration in, 1576 diagnosis of, 1573-1576 differential diagnosis of, 1573 disseminated intravascular coagulation in, 1578-1579, 1582 electrolytes in, 1582 epidemiology of, 1571-1572 extra-axial fluid collections in, 1579, 1579f, 1583 fluid balance in, 1582 hydrocephalus in, 1578, 1578f, 1583 hyponatremia in, 1576 immunoprophylaxis against, 1584 inappropriate secretion of antidiuretic hormone in, 1576, 1582 initial presentation of, 1573 in institutional settings, 1571 intracranial hypertension in, 1576-1577, 1582-1583 laboratory tests in, 1574-1575 in leukemia, 1738 modes of presentation, 1573 mortality in, 1583 in neonates, 1571, 1573, 1583 neurologic findings in, 1573 neurologic sequelae after, 1576t, 15771578, 1578f neuronal damage in, 1577-1578 in older infants, 1571 pathogenesis of, 1572 pathology of, 1579 pathophysiologic changes in, 1576-1577 predisposing factors to, 1572 prevention of, 1584 prognosis of, 1583-1584, 1583t recurrent, 1585 regional variations in, 1571 in school-age children, 1571 seasonal fluctuations in, 1572 seizures in, 1577, 1582 septic shock in, 1578-1579, 1582 Volume 1: pages 1–1180

Volume 2: pages 1181–2408

lix

Meningitis continued seriously ill patients with, approach to, 1582 shunt infections, 1573-1574 stroke with, 1767 subdural effusion in, 1583 systemic manifestations of, 1573 treatment of, 1579-1583 aseptic, 1596-1597, 1597b CSF analysis in, 162t, 1575t enterovirus, 1610-1611 epidemiology of, 1598, 1599f herpes simplex, 1604-1605 lupus, 1811 in polyarteritis nodosa, 1820 Candida, 1631, 1638, 1639f and cerebral palsy, 494 chronic, 1585-1588 coccidioidal, 1634 CSF diagnosis in, 156, 160-161, 1574-1575, 1575t protein content in, 161, 162t EEG findings in, 239 and febrile seizures, 1080 and hearing loss, 105-106, 109, 114, 1577 in leptospirosis, 1588 in Lyme disease, 1587-1588 occult spinal anomalies and, 368 in syphilis, 1586-1587 tuberculous, 1585-1586 clinical features of, 1585 CSF protein content in, 162t diagnosis of, 1585-1586 epidemiology of, 1585 neuroimaging in, 1585-1586, 1586f pathogenesis of, 1585 treatment of, 1586 Meningocele, 368 definition of, 368 with diastematomyelia, 1861 versus encephalocele, 376 magnetic resonance imaging of, 194f MRI findings of, 368, 368f Meningomyelocele, with diastematomyelia, 1861 Menkes, John, 1321 Menkes’ disease, 358-359, 766, 1321-1326 animal models of, 1325 biochemistry of, 1322-1324 classic, 1321-1322 clinical features of, 350t-351t, 358, 766, 1321-1322 diagnosis of, 1322 future directions in, 1325-1326 genetics of, 1321, 1323 history of, 1321 laboratory findings in, 1322 magnetic resonance imaging in, 175 mild, 1321-1322 MRI findings in, 352t occipital horn syndrome, 1321-1326 pathogenesis of, 1325 pathology of, 1325 brain, 1325 connective tissue, 1325 kidney, 1325 prenatal diagnosis of, 1322 treatment of, 358-359, 1325 versus Wilson’s disease, 1324t Mental retardation, 799-817. See also specific syndromes in Apert’s syndrome, 448 best interest model in, 801 causes of, 800, 807-810, 808t perinatal, 800, 807, 808t postnatal, 800, 807, 808t prenatal, 800, 807, 808t

lx

Index

Mental retardation continued in cerebral palsy, 491, 495 classification of, 807, 808t with cleft lip/palate, 468 cognitive impairment in, pharmacologic treatment of, 274 comorbid conditions with, management of, 815-816 consultation and follow-up in, 814-815 in Danon’s disease, 699-700 definition of, 799-800 diagnosis of, 801-807 economic costs of, 800 epidemiology of, 799-800 epilepsy with, 1171, 1172t eye abnormalities in, 812b in fetal alcohol syndrome, 2197 in fragile X syndrome, 560-561 genetic causes of, 808-809 genetic testing in, 812 genomic microarray technology in, 807 hair abnormalities in, 813b hearing abnormalities in, 813b history and ethics of, 800-801 imaging in, advances in, 807, 812-813 intraventricular hemorrhage and, 323 iodine deficiency and, 808, 2323 laboratory testing in, 811-814 in Lennox-Gastaut syndrome, 1031 lissencephaly and, 412 maternal factors in, 800 megalencephaly and, 408 in Menkes’ disease, 1321 versus mental illness, 800 metabolic acidosis in, 813b microcephaly and, 400 mild, 799-800 moderate, 799-800 morbidity and mortality in, 275 in mucopolysaccharidoses, 685 nonsyndromic autosomal, 809 operational parameters for, 799 outcome and prognosis in, 274-275 patient evaluation in, 810-815 patient history in, 810-811 in phenylketonuria, 570-571 physical examination in, 811, 812b-814b polymicrogyria and, 422 proteomic analysis in, 807 psychiatric disorders in, 815 in Rett’s syndrome, 1315 risk factors for, 810, 810b schizencephaly and, 422 seizures in, 812b, 813, 815 severe, 799-800 in Sjögren-Larsson syndrome, 1366-1367 skin abnormalities in, 813b sleep disorders in, 274 in spastic hemiplegia, 496 in Sturge-Weber syndrome, 783 subtelomeric probe testing in, 805-807 testing for, 801-805, 802t-805t in tuberous sclerosis complex, 778 vomiting in, 813b X-linked, 464t, 808-809, 809t Mental state, in traumatic brain injury, 1408 Meperidine abuse/poisoning, 2186 as analgesia, 2377 in renal failure, encephalopathy induced by, 2266 Mercaptans, in hepatic encephalopathy, 2295-2296 Mercury in breast milk, 2197 teratogenicity of, 2197t

Mercury continued in vaccines, and autism, 923, 2185, 2350-2351 Mercury poisoning, 1911, 2184 inorganic, 2184 organic, 2184 Mercy killing, 2395-2396 Meroanencephaly, 378 Meropenem, for bacterial meningitis, 1581 Merosin, 1841f, 1843-1845, 1969, 1970f deficiency of, 1369 in congenital muscular dystrophy, 1989t, 2001-2002 diseases associated with, 1842t, 1845 Meryon, Edward, 1969-1970 Mesencephalon, 379, 380f, 381-382, 382f Mesial temporal lobe epilepsy, familial, 1013-1014 Mesial temporal sclerosis, 1046 diffusion-weighted imaging in, 187 EEG findings in, 1046 febrile seizures and, 1083-1084 magnetic resonance imaging in, 176, 180f, 1046, 1157 Mesoderm, 436-437, 1837, 1838f Messenger RNA, 507, 510-511 splicing of, 512-513, 512f Metabolic disorder(s). See also Metabolic encephalopathies; specific disorders cardiac dysfunction in, 2223-2224 heritable (genetic), 345, 346t, 351-362, 567-596. See also Inborn errors of metabolism versus inflicted neurotrauma, 1460 leukoencephalopathies, 1345, 1346t mitochondrial, 717-718, 2049-2050, 2050f myopathy in, 350t, 2023-2061 nephron and neurological dysfunction in, 2261-2262 neuropathy in, 1905-1909 proton MR spectroscopy in, 182 and stroke, 1773-1774 Metabolic encephalopathies, 345-362, 567 acute fulminant, 345, 346t, 351-356 chronic with multiorgan involvement, 345, 346t, 351, 361-362 without multiorgan involvement, 345, 346t evaluation algorithm for, 347f general patient approach in, 345-346 genetic, 345, 346t, 351-362, 567-596. See also Inborn errors of metabolism clinical features of, 350t-351t MRI findings in, 352, 352t glucose disturbances in, 346-349 laboratory studies in, 345, 347t neuroimaging in, 346 neurologic signs and symptoms of, 345, 346t sodium balance disturbances in, 349-351 subacute epileptic, 345, 346t, 351, 356-360 Metabolism of drugs, 1110-1111 children’s physiology and, 1117-1118, 1117t Metacentric chromosomes, 516 Metachromatic leukodystrophy, 680-682, 1908 clinical features of, 680f, 681 diagnosis of, 681-682 genetic bottleneck and, 680 genetics of, 681, 1908 incidence of, 680 late infantile-onset, 680f, 681, 1908 MRI findings in, 681-682 nerve biopsy in, 1908, 1908f progression of, 681 sulfatide concentration in, 680, 680f treatment of, 682, 1908 vision loss with, 88t Metadate CD, for ADHD, 878t, 881 Volume 1: pages 1–1180

Metadate ER, for ADHD, 881 Metaiodobenzylguanidine scans, 196, 2136 Metal neuropathy, 1910-1911 Metal poisoning, 826t, 2183-2185 Metamorphopsia, in Alice in Wonderland syndrome, 1189 Metaphase, 513-514, 514f-515f Metaproterenol, for hyperkalemic periodic paralysis, 2096 Metencephalon, 379, 380f Methadone dosage of, 2376t fetal/neonatal effects of, 2196 Methaqualone intoxication, 2188 Methemoglobin, in CSF, 159 Methionine, 511 Methionine adenosyltransferase deficiency, 582f Methionine synthase deficiency, 582f, 583-584 clinical manifestations of, 583 laboratory tests in, 583 pathophysiology of, 583 treatment of, 583-584 Methohexital, for sedation, 2378 Methotrexate for chronic inflammatory demyelinating polyneuropathy, 1932-1933 cognitive effects of, 1740-1741 for dermatomyositis, 2078-2079 for ependymoma, 1716 for inflammatory myopathies, 2078t for juvenile idiopathic arthritis, 1805-1806 and leukoencephalopathy, 1743-1744, 1743f, 2193 for mixed connective tissue disease, 1817 and myelopathy, 1737 for primitive neuroectodermal tumors, 1723 for sarcoidosis, 1824 for scleroderma, 1816 and seizures, 1737 teratogenicity of, 2182t toxicity of, 2192 Methsuximide, 1106t Methyl mercury, and cerebral palsy, 493 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 729 α-Methylacyl coenzyme racemase defect, 750 2-Methylbutyryl-CoA dehydrogenase deficiency, 596 Methylcobalamin, 2311. See also Cobalamin (vitamin B12) Methyl-CpG-binding protein-2 (MECP2) defect clinical features of, 350t-351t MRI findings in, 352t 3-Methylcrotonyl-CoA carboxylase (MCC) deficiency, 586f, 589, 723 clinical manifestations of, 589 diagnosis of, 589 treatment of, 589 α-Methyldopa, hepatotoxicity of, 2294 Methylene tetrahydrofolate reductase deficiency, 584, 2320-2321 clinical manifestations of, 584 laboratory tests in, 584 pathophysiology of, 584 and sinovenous thrombosis, 1785 and stroke, 1766 treatment of, 584 Methylene tetrahydrofolate reductase gene (MTHFR) and cleft lip/palate, 467, 467t and neonatal stroke, 332 and neural tube defects, 367 3,4-Methylenedioxymethamphetamine, 2187 3-Methylglutaconic aciduria, 591-592 type I, 591-592 type II, 592

Volume 2: pages 1181–2408

Index 3-Methylglutaconic aciduria continued type III, 592 type IV, 592 3-Methylglutaconyl-CoA hydratase deficiency, primary, 591-592 Methylin, for ADHD, 878t Methylmalonic acidemia, 350t-352t, 353-354, 353t, 587-588, 727 clinical manifestations of, 588 laboratory tests in, 588 pathophysiology of, 586f, 587 treatment of, 588 Methylmalonyl-CoA mutase deficiency, 727 Methylmercury, teratogenicity of, 2198 Methylphenidate for ADHD, 877-881, 878t, 939t, 941, 943 comorbid with tic disorders, 897 for autism/Asperger’s disorder, 925, 927t with clonidine, 944 dosage of, 880-881, 939t, 941 drug interactions of, 943 extended release, 939t immediate release, 939t labeled and off-labeled use of, 938t for mentally retarded patients, 815 for neurocardiogenic syncope, 1211b pharmacology of, 880-881, 939t sustained release, 939t and Tourette syndrome, 2190 toxicity of, 2190 Methylprednisolone for juvenile idiopathic arthritis, 1806 for multiple sclerosis, 1349 for spinal cord injury, 1532, 1541 for varicella-zoster virus, 1609 for viral infections, 1603 Methysergide, for cluster headache, 1199 Metoclopramide for cyclical vomiting syndrome, 2286 for orthostatic hypotension, 2143 Metopic suture, 436, 436f, 437t Metopic synostosis, 445-446 Metoprolol for migraine prevention, 1194t for neurocardiogenic syncope, 1211b Metrizamide toxicity, 2194 Metronidazole for amebiasis, 1649 for brain abscess, 1589 for methylmalonic acidemia, 588 Metropolitan Atlanta Developmental Disabilities Study, 799 Mevalonate kinase deficiency, 596 Mevalonic aciduria, 596 Mexiletine adverse effects of, 2092-2093 for myotonia congenita, 2092-2093 for myotonic dystrophy type 1, 2088 for myotonic dystrophy type 2, 2090 for pain, 2378 for paramyotonia congenita, 2097 MGAT2 gene, in congenital glycosylation disorder, 650t, 652 MIB-1, 1691 Mice asphyxia models, 299 Miconazole, for primary amebic meningoencephalitis, 1650 Microbrain, radial, 404-405 Microcephalia vera, 400 Microcephalic osteodysplastic primordial dwarfism, 403t, 405 Microcephaly, 48, 400-406 Amish lethal, 402t-403t antenatal diagnosis of, 405 borderline, 400 classification of, 401-405

Microcephaly continued clinical characteristics of, 400-401 congenital, with normal cell types, 400 definition of, 400 in developmental disorders, 830t-831t etiology of, 401-402, 401b familial, 402 genetic counseling in, 405-406 in genetic metabolic encephalopathies, 350t genetics of, 402t, 405 laboratory studies in, 402 versus lissencephaly, 402-403 with lissencephaly, 403t, 405 in mental retardation, 811 mild, 400-402 with other malformations, 400-401 pathogenesis of, 365, 400 with periventricular nodular heterotopia, 403t, 405 with polymicrogyria, 403t, 405, 422, 423t in pontocerebellar hypoplasia type 2, 394 primary, 400, 402t, 403-405 with moderate phenotype, 403, 403t MRI findings in, 404, 404f with severe phenotype, 403-404, 403t radiologic features of, 402-403, 404f with schizencephaly, 422 severe, 400, 402-403, 403t, 404f with cortical malformation, 405 with neurologic phenotype, 402 with proportionate growth deficiency, 400-401, 405 with simplified gyral pattern, 402-403 syndromic subtypes of, 403t Microdeletion syndromes, 544, 555-557, 556t Microdialysis, in coma, 1393 Microdysgenesis, 425 Microencephaly, 400 Microform, 396 Microglia, in hypoxic-ischemic injury, 303-304 Microgyria, in spastic diplegia, 498 Microlissencephaly, 405 group A, 403t group B, 403t Micronutrient(s). See also specific types deficiencies of, disorders associated with, 2321-2324 Micropsia, in Alice in Wonderland syndrome, 1189 MicroRNA, 510 Microsatellites, of DNA, 518 Microscopic polyangiitis, 1820 Microsporidiosis, 1646, 1647t, 1653-1654 classification of, 1647t clinical characteristics of, 1647t, 1654 diagnosis of, 1647t, 1654 epidemiology of, 1653-1654 geographic distribution of, 1647t laboratory tests in, 1654 management of, 1647t, 1654 microbiology of, 1653-1654 mode of infection, 1647t, 1653-1654 pathology of, 1647t, 1653-1654 risk factors for, 1647t Microtia, 108t Micturition anatomy and physiology of, 2157 disorders of, 2157-2165 autonomic, 2138 classification of, 2162f differential diagnosis of, 2164, 2168b laboratory tests in, 2163-2164 management of, 2164-2165 neurologic examination in, 2163 pathophysiology of, 2159-2162 patient evaluation in, 2162-2164 patient history in, 2162-2163 Volume 1: pages 1–1180

Volume 2: pages 1181–2408

lxi

Micturition continued radiographic evaluation of, 2164 sites of dysfunction, 2162f in spinal cord injury, 2162-2163, 2163t, 2358 regulation of autonomic, 2157 neural, 2158-2159, 2158f-2161f syncope induced by, 2150 Micturition reflex, 2159 Midazolam adverse effects of, 2214 intranasal, 1120 for neonatal seizures, 270-271 in hypoxic-ischemic injury, 291 for sedation, 2378 for status epilepticus, 1098t, 1099-1100 Midbrain, 379, 380f, 382f patterning of, 381-382 Middle cerebellar peduncle, 1242f, 1243 Middle cerebral artery, 1760-1762, 1761f Middle cranial fossa, arachnoid cyst of, 434 Middle interhemispheric variant, of holoprosencephaly, 395f, 396-397 Midface hypoplasia syndromes in craniosynostosis, 453 hearing loss with, 108t Midline cerebellar disease, 1246 Midline defects, 47 magnetic resonance imaging of, 178, 182f Midline facial defects, with holoprosencephaly, 397 Midline shift, 1410 Midline tumors, 1699-1707 Midodrine for neurocardiogenic syncope, 1211b for orthostatic hypotension, 2142-2143 Miglustat, for Gaucher’s disease, 673 Migraine(s), 1183, 1187-1191 abdominal, 1191, 2285-2286 diagnostic criteria for, 1186b acute treatment of, 1194t-1195t, 1195 aggravation by activities, 1187 analgesic overuse and, 1195 with aura, 1183-1184, 1184b, 1187-1189, 1188t without aura, 1184b-1185b, 1188 basilar artery, 131-132, 1189, 1189t chronic (transformed), 1193 classification of, 1183-1184, 1183b clinical manifestations of, 1188-1189 complementary and alternative treatments for, 1192-1195, 1192b confusional, 1190-1191 with cyclical vomiting, 1184, 1186b, 1191 cyclical vomiting syndrome and, 1217 diagnostic criteria for, 1185, 1186b dietary therapy for, 1192-1195, 1192b EEG studies of, 238 epidemiology of, 1183 footballer’s, 1190-1191, 1199 hemiplegic, 1189-1190 familial, 1189-1190 sporadic, 1190 management of, 1191-1195, 2378-2379 AAN practice parameter for, 1192 ophthalmoplegic, 1184, 1198-1199 pain in, 2378-2379 paroxysmal torticollis with, 131, 1191, 1301 pathophysiology of, 1187-1188, 1187f post-traumatic, 1199-1200, 1415, 1436 preventive or prophylactic treatment of, 1193t-1194t, 1195 prodromal features of, 1188 retinal, 1189 sensitization in, 1187-1188 and stroke, 1773 in Tourette syndrome, 892

lxii

Index

Migraine(s) continued vertigo with, 131-132 vision loss with, 92 Migrating partial seizures of infancy, 1048 Migrational anomalies. See also specific anomalies magnetic resonance imaging of, 175, 177f positron emission tomography of, 196 Mild traumatic brain injury, 1414-1415 with brief loss of consciousness, in children older than 2 years, 1428-1429 in children younger than 2 years, 1429 general management of, 1428-1430 without loss of consciousness, in children older than 2 years, 1428 Milk restriction, in galactosemia, 619-620 Milkmaid’s grip, 2225 Mill, John Stuart, 2387-2388 Miller Fisher syndrome, 1921, 1922t, 1923 Miller-Dieker syndrome, 413-414, 413f, 493 genetic testing for, 415 genetics of, 556t management of, 415-417 outcome of, 417 Miltefosine, for Chagas’ disease, 1662 Minamata disease, 2184 Mineralocorticoid(s) in hepatorenal syndrome, 2259 for neurocardiogenic syncope, 1211, 1211b Miniature endplate potential, 1941 minibrain gene, 552 Minicolumns, in autism, 922 Minimal brain damage syndrome, 871 Minimal brain dysfunction, 871 Minimal seizures, neonatal, 258 Minimally conscious state, 1380-1381 definition of, 1380 diagnostic criteria for, 1380b traumatic brain injury and, 1433 Minisatellites, of DNA, 518-519 Minocycline, for leprosy, 1591 Miosis, in poisoning/intoxication, 2177t Mirapex (pramipexole), for restless legs syndrome, 1233 Mirtazapine, 955 for ADHD, 879t adverse effects of, 955 clinical applications of, 955 clinical management of, 955 dosage of, 953t, 955 drug interactions of, 955 labeled and off-labeled use of, 938t pharmacodynamics of, 953t pharmacokinetics of, 953t pharmacology of, 955 preparations of, 953t Miscarriage, recurrent, chromosomal abnormalities and, 548 Misoprostol, for hepatorenal syndrome, 2259 Missense mutations, 530-531 Mitochondria, 715 function of, 717 Mitochondrial ATP synthase deficiency, 726-727 Mitochondrial diseases, 715-730, 2048-2060 acquired, 729-730 autism with, 917-918 classification of, 720-722, 720b biochemical, 2049-2050, 2050f, 2052t genetic, 2050-2053, 2052t clinical considerations in, 2049 clinical features of, 722-730 cognitive and motor regression in, 826t drug-induced, 729-730 encephalomyopathies in, 2048-2060. See also Mitochondrial encephalomyopathies hearing loss with, 107

Mitochondrial diseases continued histopathology of, 718-720, 719f historical perspective on, 2048-2049 inheritance patterns of, 716-717 inherited, 722-729 laboratory findings in, 730 magnetic resonance imaging in, 175 metabolic, 717-718, 2049-2050, 2050f mitochondrial DNA-associated, 728-729 morphologic considerations in, 2049 nuclear DNA-associated, 722-728, 2055-2056 pathologic patterns in, 718-719 physiologic considerations in, 2053 protein-coding gene defects in, 2055 proton MR spectroscopy in, 182 ragged red fibers in, 715, 718 treatment of, 730, 1247t vision loss with, 91 white matter abnormalities in, 1368f, 1369 Mitochondrial DNA, 519, 715-717, 716f, 716t, 2050-2053 defects of, 728-729 point mutations of, 728-729, 2054 affecting protein-coding L genes, 728-729 affecting synthetic genes, 729 sporadic large-scale rearrangements of, 728 Mitochondrial DNA depletion syndrome, 727-728 Mitochondrial DNA polymerase γ, in Alpers’ disease, 1327 Mitochondrial encephalomyopathies, 2048-2060 Mitochondrial encephalopathy with lactic acidosis and stroke-like syndrome (MELAS), 91, 715, 1774, 2054-2055 clinical features of, 2054 histopathology of, 719-720, 719f, 2055 point mutations in, 729 treatment of, 2055 Mitochondrial fission defects, 728 Mitochondrial fusion defects, 728 Mitochondrial genome, 516-519, 715-717, 716t, 2051-2052, 2051f Mitochondrial inheritance, 16, 535, 715-716, 716f, 716t, 717f, 2050-2053 Mitochondrial motility defects, 728, 2060 Mitochondrial neurogastrointestinal encephalomyopathy syndrome, 727 Mitochondrial ornithine carrier deficiency, 603 Mitochondrial trifunctional protein (MTP) deficiency, 350t-351t, 355-356, 724, 2039, 2048 Mitosis, 513-514, 514f Mitoxantrone, for multiple sclerosis, 1350 Mixed cerebral palsy, 500 Mixed connective tissue disease, 1817 laboratory findings in, 1809t neurologic manifestations of, 1809t, 1817 treatment of, 1817 Mixed germ cell tumor, 1704 Mixed glioma, survival rates with, 1690t Mixed salts of L- and D-amphetamine for ADHD, 878t, 880-881, 939t, 941 dosage of, 939t, 941 labeled and off-labeled use of, 938t pharmacology of, 939t Mixed syncope, 2149, 2150f Mixoploids, 549 MK-801, for hypoxic-ischemic injury, 1502 Möbius syndrome, 52, 1869-1870, 1889 clinical features of, 23f, 1870, 1870f cranial nerve involvement in, 23f, 1870, 1870f, 1889 differential diagnosis of, 1870 genetic forms of, 1870t type 1, 1870, 1870t type 2, 1870, 1870t type 3, 1870, 1870t Volume 1: pages 1–1180

Modafinil for delayed sleep phase syndrome, 1234 for narcolepsy, 1232 Modified Checklist for Autism in Toddlers (M-CHAT), 913 Moebius syndrome, 108t, 465t Mohr-Tranebjaerg syndrome, 727 Molar tooth malformation, cerebellar vermis hypoplasia with, 390-391 Molecular genetics definition of, 521 technology of, 521-522 Molecular layer, cerebellar, 1241 Mollaret’s meningitis, 1604 Molybdenum cofactor deficiency, 358, 358f, 582f, 584 clinical features of, 350t-351t, 358 diagnosis of, 358 management of, 358 MRI findings in, 352t Mondini malformation, 108t Monoamine(s), in CSF, 163 Monoamine oxidase(s) deficiency of, 765-766 MAO A, 765 deficiency of, 765-766 MAO B, 765 deficiency of, 765-766 Monoamine oxidase inhibitor(s) for ADHD, 878t-879t for L-amino acid decarboxylase deficiency, 763 drug interactions of, 948, 957 for sepiapterin reductase deficiency, 763 Monoclonal antibodies, 1745-1746 Mononeuritis multiplex, 1804, 1811, 1820, 1822, 1933 Mononeuropathies, postoperative, 2215 Mononucleosis, 1609 Monosaccharides, in lysosomal storage diseases, 660t Monosialogangliosides, for neuroprotection, in hypoxic-ischemic injury, 291 Monosodium glutamate, and shuddering attacks, 1219 Monosomy, 525, 529t, 546 Monosomy 1p36, 556t Monosomy 21, 525 Monosomy X, 525 Monroe-Kellie doctrine, 1513 Mood, antiepileptic agents and, 1174-1175 Mood disorder(s) in Duchenne muscular dystrophy, 1986 with epilepsy, 1173 in juvenile idiopathic arthritis, 1805 with mental retardation, 815 pharmacologic therapy for, 945-955, 957-964 in Segawa’s disease, 762 in systemic lupus erythematosus, 1810 in traumatic brain injury, 2356 Mood stabilizers, 957-964 adverse effects of, 959t baseline assessments for, 959t classification of, 958 monitoring of, 959t preparations of, 959t Morality, 2387. See also Ethic(s) common, 2387-2389 Moro reflex, 42, 42f, 42t, 48t, 50, 60, 123 in brachial plexus injury, 340 Morphine abuse/poisoning, 2186 dosage of, 2376t fetal/neonatal effects of, 2196 for Krabbe’s disease, 679

Volume 2: pages 1181–2408

Index Morphine continued for pain, 2377 pharmacokinetics of, 2377 in traumatic brain injury, 1422 Morquio’s syndrome, 689 clinical features of, 689 genetics of, 689 treatment of, 689 type A, 689 type B, 665, 689 Mosaic (Internet browser), 2400 Mosaicism, 524, 535, 546 Mosquitoes, as disease vector, 1599, 1657 Mossy fibers, 992, 993f, 997-998, 998f, 1241, 1243f, 1244 Motor and sensory axonal neuropathy, acute (AMSAN), 1922t, 1923 Motor and sensory neuropathy, hereditary, 1897-1901. See also Charcot-MarieTooth disease with focally folded myelin, 1898 of neuronal type with onset in early childhood, 1899 Motor (Broca’s) aphasia, 822t Motor automatisms, 258, 258t-259t, 260, 274 Motor axonal neuropathy, acute (AMAN), 1922t, 1923 Motor circuit, in Tourette syndrome, 893f, 894 Motor evoked potentials, in coma, 1392 Motor function. See also specific disorders evaluation of gross, in older child, 17 in infant, 39-40, 42 in newborn (term), 47, 50-51 performance tools for, 42, 42t testing of, 805 Motor neurons, 1859 cranial, diseases of, 1859-1879. See also specific diseases regulation of, 1850 Motor point block, 2367 Motor regression, 821-824 causes of, 825t-827t inherited metabolic, 826t-827t diagnosis of, 826t-843t based on signs and symptoms, 828t Motor rhythmias, 1299 Motor tics, 887, 1298 Motor unit, 1846-1847, 1850 recruitment of, 1850 Motor unit potentials, 1852-1853 Movement disorder(s), 1271-1303. See also specific disorders basal ganglia in, 1272-1274, 1273f-1274f model of, 1274, 1275f pathophysiology of, 1274-1275 in cerebral palsy, 500, 501f, 1275 childhood versus adult, 1271-1272 approach to, 1271 characteristic features of, 1271-1272 classification of, 1271, 1272t, 1276 definition of, 1271 diagnosis of, 1272, 1272t EEG findings in, 236 etiology of, 1275-1276 extrapyramidal, 1271 gait abnormalities in, 73-74 in genetic metabolic encephalopathies, 350t hyperkinetic, 1271 hypokinetic, 1271 magnetic resonance imaging of, 175 postoperative, in cardiac surgery, 2213-2215 pyramidal, 1271 during sleep EEG findings in, 240

Movement disorder(s) continued restless legs syndrome, 892, 1233, 1302 tardive, 1301-1302 transient developmental, 1299 treatment of, approach to, 1276 in uremic neuropathy, 2248 Mowat-Wilson syndrome, 465t Moyamoya disease, 1049, 1739 angiographic findings in, 1773, 1773f versus moyamoya syndrome, 1772-1773 and stroke risk, 1769, 1772-1773, 1795, 2218-2219 treatment of, 1773 MPDU1 gene, in congenital glycosylation disorder, 650t, 651 MPI gene, in congenital glycosylation disorder, 649-651, 650t MPTP, and parkinsonism, 1292-1293 MPZ gene, in neuropathy, 1897 MRI. See Magnetic resonance imaging MRS. See Magnetic resonance spectroscopy MSX gene in cleft lip/palate, 467, 467t craniosynostosis, 443, 450 Msx-1 gene, in craniofacial development, 438 Msx-2 gene, in craniofacial development, 438 mtDNA. See Mitochondrial DNA Mu rhythm, in EEG, 219 Muckle-Wells syndrome, 2261 Mucolipidoses, 695-698 type I, 695-696 clinical features of, 695-696 diagnosis of, 696 early infantile, 695 genetics of, 696 late infantile and juvenile, 695-696 type II, 650t, 696-697 clinical features of, 696, 696f-697f diagnosis of, 697 prenatal testing for, 697 treatment of, 697 type III, 650t, 696-697 clinical features of, 696 diagnosis of, 696 prenatal testing for, 697 treatment of, 697 type IV, 697-698 clinical features of, 697 diagnosis of, 697-698 genetics of, 697-698 neuroimaging in, 697 Mucopolysaccharides, in lysosomal storage diseases, 659, 660t Mucopolysaccharidoses, 683-691 arachnoid cysts in, 435 classification of, 683-684 clinical features of, 684-685 coarsening of facial features in, 684 genetics of, 685 glycosaminoglycan degradation in, 683, 684f hearing loss with, 107 incidence of, 683 MPS I, 686-688, 686f. See also Hurler syndrome; Hurler-Scheie syndrome MPS II, 688. See also Hunter’s syndrome MPS III, 688-689. See also Sanfilippo syndrome MPS IV, 689. See also Morquio’s syndrome MPS VI, 690. See also Maroteaux-Lamy syndrome MPS VII, 690. See also Sly’s syndrome MPS IX, 663t, 691 ophthalmic complications of, 685 skeletal changes in, 684, 685f treatment of, 685-686 vision loss with, 88, 88t Volume 1: pages 1–1180

Volume 2: pages 1181–2408

lxiii

Mucor, 1632t. See also Mucormycosis Mucormycosis, 1638 CNS syndromes in, 1632t diagnosis of, 1632t geographic distribution of, 1632t in leukemia, 1738 management of, 1632t risk factors for, 1632t Muenke’s syndrome, 449 clinical features of, 442t, 449 genetics of, 442t, 447, 447t, 449, 452f Mulberry molars, 1587 Mulibrey nanism, 751 Multifactorial inheritance, 535 Multifocal dystonia, 1280 Multifocal seizures, 1037, 1047-1048 management of, 1050 Multifunctional enzymes, in fatty acid oxidation, 736f, 737 Multilayer fibers, 1241 Multilobar resections, for epilepsy, 1153 Multi-mini-core-disease, 2016 classical form of, 2016 clinical features of, 2016 genetics of, 2016 ophthalmoplegic form of, 2016 pathology of, 2016 protein accumulation in, 2016, 2016t Multimodal treatment of ADHD (MTA), 942 Multiple acyl-CoA dehydrogenase deficiency, 724-725, 2042 Multiple carboxylase deficiencies, 589-592, 723, 1247t Multiple enzyme deficiencies, in lysosomal storage diseases, 660t Multiple hereditary exostosis, 650t, 654 Multiple organ failure, and polyneuropathy, 1911 Multiple sclerosis, 1346-1350 clinical characteristics of, 1347 clinical studies of, 1347-1349 CSF analysis in, 162-163, 1347-1348 diagnostic criteria for, 1347 epidemiology of, 1346 etiology of, 1346-1347 evoked potentials in, 1348-1349 genetics of, 1349 immunopathogenic hypothesis of, 1346-1347 incidence of, 1346 juvenile onset, 1346 laboratory findings in, 1347-1348 McDonald criteria for, 1347 MRI findings in, 1347, 1348f optic neuritis in, 90 pathology of, 1349 Poser criteria for, 1347 primary progressive, 1347 prognosis of, 1347 progressive-relapsing, 1347 relapsing-remitting, 1347 secondary progressive, 1347 subclassification of, 1347 treatment of, 1349-1350 in acute exacerbations, 1349 approved disease-modifying therapies in, 1349-1350 investigational therapies in, 1350 true childhood onset, 1346 vaccines and, 2347 vertigo in, 132 vision loss in, 1347 white matter plaque in, 1349 Multiple sleep latency test, 1227-1228 in narcolepsy, 1232 Multiple subpial transection, 1163-1164

lxiv

Index

Multiple sulfatase deficiency, 682-683 clinical features of, 682 diagnosis of, 683 genetics of, 682 Saudi Arabian variant of, 683 Multiple synostosis, 446-447 Multiple system atrophy (MSA), catecholamines in, 2138f Mumps vaccine, 1618, 2348 neurologic complications of, 2348 Mumps virus, 1618-1619 clinical features of, 1618 diagnosis of, 1618-1619 EEG findings in, 238-239 epidemiology of, 1618 and hearing loss, 109 outcome of, 1618-1619 treatment of, 1618-1619 Munchausen syndrome by proxy, 1212, 1386, 2173-2174 Muscle(s), 1837-1854 anatomy and structure of, 1839-1845 biochemistry of, 1846, 1852 clinical laboratory tests of, 1852-1854 contraction of, 1845-1846, 1848-1850, 1849f energy for, 1851-1852 gamma efferent system in, 1850-1851 motor unit system in, 1850 neural control of, 1850-1851 proteins in, 1839-1840, 1840f embryology and development of, 1837-1839, 1838f function of, 1846-1850 histochemistry of, 1846, 1847t, 1853, 1854f imaging of, 1853 metabolism of, 1851-1852 molecular genetics of, 1853-1854 morphology of, 1838f, 1839 plasticity of, 1838-1839 Muscle biopsy, 69, 1853 in Becker muscular dystrophy, 1987 in brancher enzyme deficiency, 2036 in congenital myopathies, 2015 in cysticercosis, 2082 in dermatomyositis, 2077, 2077f in Duchenne muscular dystrophy, 1980-1981, 1981f in myoadenylate deaminase deficiency, 2061 in myophosphorylase deficiency, 2029-2030 in phosphofructokinase deficiency, 2032-2033 in phosphoglycerate kinase deficiency, 2034 in phosphoglycerate mutase deficiency, 2034 in polymyositis, 2080, 2080f in spinal muscular atrophy, 1866f, 1867 in trichinosis, 2081, 2081f in uremic myopathy, 2249 Muscle bulk, 27-33 Muscle fiber(s), 1838f, 1845-1846 biochemical features of, 1846 characteristic features of, 1846t embryology and development of, 1837-1838 fast-twitch, 1846 histochemical reactions of, 1846, 1847t hybrid, 1840 innervation of, 1846-1847 morphology of, 1839 myosin chains in, 1840 pure, 1840 sarcotubular system of, 1841, 1841f size disproportion in, causes of, 2018, 2018t slow-twitch, 1846 type I, 1837, 1840, 1846, 1846t type II, 1840, 1846 type IIa, 1837, 1840, 1846, 1846t type IIb, 1837, 1840, 1846, 1846t type IIc, 1837

Muscle necrosis, in Duchenne muscular dystrophy, 1973-1974 Muscle overreactivity, 2365-2369. See also Spasms; Spasticity botulinum toxin for, 2367-2368 intrathecal baclofen for, 2368-2369 nerve and motor point blocks for, 2367 occupational therapy for, 2366 oral medications for, 2366-2367, 2368t orthopedic surgery for, 2369 physical therapy for, 2366 selective dorsal rhizotomy for, 2368 treatment goals in, hierarchy of, 2366 treatment planning in, 2365-2366, 2366f Muscle power, 26-27 Muscle regeneration, in Duchenne muscular dystrophy, 1976 Muscle relaxants, in spinal cord injury, 1544 Muscle spindles, 65-66, 65f-66f, 1850, 1851f Muscle stretch reflexes. See Deep tendon reflexes Muscle testing, 34t, 1852-1854 in comatose patient, 1386-1387 in infant, 39-41, 42f, 44-45 in myasthenia gravis, 1944 in newborn (term), 50-51 in older child, 26-33 patient positioning for, 26-27, 29f scoring system for, 26 in traumatic brain injury, 1409 Muscle tone, 33, 65-75. See also Hypertonia; Hypotonia anatomy and physiology of, 65-66, 65f-67f definition of, 65 evaluation of, 66-68 patient history in, 66 examination of, 66-67 in active state, 67 in passive state, 67 in infant, 41, 42f, 66-67 in newborn (term), 50, 67 in older child, 67 pathology of, 65-66 clinical laboratory studies in, 69 conditions associated with, 68t, 69 diagnosis of, 68-69 neuroimaging in, 69 phasic, 65 postural, 65 in preterm infant, 57-61, 58f-59f, 66-67 Muscle twitch, 1845 Muscle twitching in hypertensive encephalopathy, 2239 in uremic encephalopathy, 2237 Muscleblind deficiency, 2087-2088 Muscle-eye-brain disease, 83-84, 86, 417-418, 1989t, 2003 antenatal diagnosis of, 418 clinical features of, 417, 650t, 654, 2003 functional defects in, 653-654 genetic testing for, 417-418 genetics of, 650t, 2003 management of, 418 MRI findings in, 416f Muscle-specific receptor tyrosine kinase (MuSK), in myasthenia gravis, 1941 antibodies against, testing for, 1950 Muscular dystrophies, 1969-2004 Becker, 531, 1969, 1986-1987 cardiac involvement in, 1979, 1987, 2224 clinical features of, 1987, 1987f genetic counseling in, 1985-1986 genetic testing for, 1980 genetics of, 1986 laboratory findings in, 1986-1987 management of, 1981, 1987 Volume 1: pages 1–1180

Muscular dystrophies continued muscle biopsy in, 1987 neuropsychiatric involvement in, 1979 classification of, 1969, 1971t congenital, 2000-2004 diagnosis of, 2000-2001 with early rigid spine, 1989t, 2002 fukutin-related protein deficiency in, 2002 Fukuyama’s, 416f, 417-418, 650t, 654, 1989t, 2003 incidence of, 2001 integrin α7 deficiency in, 1989t, 2002 merosin-negative, 1989t, 2001 merosin-positive, 1989t, 2002 muscle biopsy in, 2000, 2000f nonsyndromic (classic), 1989t, 2001-2002 syndromic, 1989t, 2003-2004 Ullrich’s, 1989t, 2002-2003 Duchenne, 1969-1986 calcium in, 1974-1975 abnormal permeability to, 1974-1975 intracellular, chronic increase in, 1974-1975 cardiac involvement in, 1978-1979, 1985, 2224 clinical characteristics of, 1976-1980, 1977f-1978f contractures in, 1978, 1984-1985 diagnosis of, 1980-1981 drug precautions in, 1986 electron microscopy in, 1981, 1981f emotional and behavioral abnormalities in, 1986 exercise in, 1984 exon skipping in, 1971-1972 female carriers of, 1979-1980, 1985-1986 fibrosis and muscle regeneration in, 1976 gastrointestinal involvement in, 1979 gene therapy for, 1983-1984 genetic counseling in, 1985-1986 genetic testing in, 1980 genetics of, 531, 535, 1970-1972 genotype/phenotype correlation in, 1972-1973 Gowers’ maneuver in, 1976-1978, 1977f hip girdle strength in, 1976-1978 historical perspective on, 1969-1970 immunologic response in, 1975 incidence of, 1972 laboratory tests in, 1980 management of, 1981-1986 manifesting carriers of, 1979-1980 mechanical membrane fragility in, 1974 molecular pathogenesis of, 1970-1972 multidisciplinary approach in, 1981 muscle biopsy in, 1980-1981, 1981f muscle hypertrophy in, 1976, 1978f muscle necrosis in, 1973-1974 neuropsychiatric involvement in, 1979 obesity in, 1983 orthotic devices in, 1984-1985, 1985f pathophysiology of, 1973-1976 pharmacologic treatment of, 1982-1984 primary and secondary events in, 1973-1974 pulmonary involvement in, 1978, 1984 reading frame hypothesis of, 1970-1972 rehabilitation in, 1984-1985 respiratory care in, 1984 scoliosis in, 1978, 1985 signaling functions in, 1975-1976 therapeutic window in, 1976 utrophin in, 1844 vascular theory of, 1976 Emery-Dreifuss, 1969, 1995-1997 cardiac involvement in, 2224 clinical features of, 1996f, 1997, 1997f

Volume 2: pages 1181–2408

Index Muscular dystrophies continued management of, 1997 molecular biology of, 1995-1996 facioscapulohumeral, 1969, 1997-2000 clinical features of, 1998-2000, 1998f-1999f diagnostic criteria for, 1998 laboratory findings in, 2000 molecular genetics of, 1997-1998 prevalence of, 1997 treatment of, 2000 genetics of, 531, 535, 1969 glycosylation-based, 653-654 biochemical and genetic tests in, 654 clinical features of, 412t, 416f functional defects in, 653-654 overview of, 653 limb girdle, calpain in, 1840 limb-girdle, 1969, 1987-1995 autosomal dominant, 1987 autosomal recessive, 1987 calpain in, 1840 classification of, 1987-1988, 1988t genetics of, 1987 pathophysiology of, 1988-1989 type 1A (myotilinopathy), 1988t, 1994-1995 diagnosis of, 1994 pathophysiology of, 1994 type 1C (caveolinopathy), 1988t, 1989 type 2A (calpainopathy), 1988t, 1990-1991 clinical manifestations of, 1990 diagnosis of, 1990-1991 molecular pathogenesis of, 1990-1991 muscle pathology in, 1990-1991 type 2B (dysferlinopathy), 1988t, 1991-1992 clinical presentation of, 1991 diagnosis of, 1991-1992 molecular pathogenesis of, 1991 type 2C (γ-sarcoglycanopathy), 1988t, 1992-1993 type 2D (α-sarcoglycanopathy), 1988t, 1992-1993 type 2E (β-sarcoglycanopathy), 1988t, 1992-1993 type 2F (δ-sarcoglycanopathy), 1988t, 1992-1993 type 2G (telethonin), 1988t, 1995 type 2I (fukutin-related protein gene deficiency), 1988t, 1993-1994 clinical manifestations of, 1993-1994 diagnosis of, 1994 management of, 1994 molecular pathogenesis of, 1993 type 2J (titin), 1988t, 1995 oculopharyngeal, 1969, 2000 phenotypes of, 1969 severe childhood autosomal recessive, 1992 X-linked syndromes, 1995 Musculocutaneous nerve, 28t Mutagens, 529 Mutation(s), 529-531 classes of, 529-530 definition of, 529 frameshift, 531 full, premutations and risk of, 559, 559t gene, 530 and gene function, 530-531 genome and chromosomal, 530 missense, 531 nonsense (chain termination), 531 rate of, 530 transcriptional control, 531 Mutation detection methods, 522-523 Mutation scanning, 523

Myalgia, in polyarteritis nodosa, 1820 Myasthenia, familial infantile, 1958, 1960 Myasthenia gravis, 1941-1956 acetylcholinesterase inhibitors for, 1951 activities of daily living scale in, 1944-1945, 1945t antibody testing in, 1949-1950 azathioprine for, 1953-1954 categories, in childhood, 1943-1944 clinical and laboratory tests in, 1945-1950 clinical classification of, 1943, 1943b clinical features of, 1942-1943 conditions associated with, 1944 corticosteroids for, 1952-1953 cyclophosphamide for, 1954 cyclosporine for, 1954 drugs contraindicated in, 1955-1956, 1955b edrophonium (tensilon) test in, 1946-1947 electrophysiologic testing in, 1947-1949 epidemiology of, 1942 intravenous immunoglobulin for, 1955 juvenile, 1943-1944, 1944f treatment of, 1951-1956 mortality rates in, 1943 mycophenolate mofetil for, 1954 natural history of, 1943 neonatal transient, 1943-1944 treatment of, 1951 neurologic examination in, 1944-1945 plasmapheresis for, 1955 prevalence of, 1942 ptosis in, 1942-1944, 1944f, 1946 quantitative grade scale in, 1944-1945, 1945t repetitive stimulation in, 1946f, 1947-1949, 1947f ryanodine receptors in, 1841 single-fiber electromyography in, 1948f, 1949, 1949f with systemic lupus erythematosus, 1811 thymectomy for, 1951-1952 treatment of, 1950-1956 Myasthenia Gravis Foundation of America, 1943, 1943b Myasthenic syndromes, congenital, 1958-1962 classification of, 1958, 1958b clinical features of, 1958 electrophysiologic features of, 1958-1959, 1959t fast-channel, 1961-1962 laboratory tests in, 1958-1959, 1959t Lambert-Eaton myasthenic syndrome-like, 1960 localization of defect in, 1961t postsynaptic defects in, 1960, 1961t presynaptic defects in, 1959-1960, 1961t prevalence of, 1958 slow-channel, 1961t sodium-channel, 1962 synaptic defects in, 1960, 1961t synaptic vesicle paucity in, 1960 Mycobacterium leprae, 1590 Mycobacterium tuberculosis, 1585-1586, 1589 Mycophenolate mofetil for dermatomyositis, 2079 for multiple sclerosis, 1350 for myasthenia gravis, 1954 for systemic lupus erythematosus, 1815 Mycoplasma, and Guillain-Barré syndrome, 1927, 1927t Mycoplasma pneumoniae, 1590 Mycotic aneurysms, cerebral, 2221 Mydriacyl (tropicamide), toxicity of, 2191 Mydriasis, in poisoning/intoxication, 2177t Mydriatic agent toxicity, 2191 Myelencephalon, 379, 380f Volume 1: pages 1–1180

Volume 2: pages 1181–2408

lxv

Myelin in spinal cord injury, 1532 in uremic encephalopathy, 2236 Myelin and lymphocyte protein (MAL), 682 Myelin basic protein deficiency, 1360 Myelination diffusion-weighted imaging of, 187 disorders of, 1345-1360. See also specific disorders magnetic resonance imaging of, 174, 282 malnutrition and, 2303 Myelinoclastic diffuse sclerosis (Schilder’s disease), 1350-1351 Myelitis, transverse associated with immune-mediated process, infection, or both, 1875-1876 magnetic resonance imaging of, 1875f, 1876 Myelodysplasia, ultrasound in, 170 Myelomeningocele, 369-373 antenatal diagnosis of, 370 associated problems with, 372 bladder and bowel dysfunction with, 372 central nervous system complications of, 372 Chiari II malformation with, 369-372, 375 clinical characteristics of, 369 counseling in, 373 hydrocephalus with, 369 location and extent of, 369 magnetic resonance imaging of, 194f, 370, 371f management of, 370-372 in newborn period, 371-372 during pregnancy, 370-371 with membrane coverage, 369, 369f with myeloschisis, 369, 369f orthopedic problems with, 372 outcome in, 372-373 prevalence of, 369 prevention of, 369-370 ultrasound of, 370 Myelopathy chemotherapy-associated, 1737 human T-cell lymphotropic virus type Iassociated, 1622-1623 in juvenile idiopathic arthritis, 1805 radiation, 1739 in systemic lupus erythematosus, 1811 viral, 1597, 1598b Myeloschisis, myelomeningocele with, 369, 369f Myf-5, 1837 Myoadenylate deaminase deficiency, 2060-2061 biochemistry of, 2061 clinical manifestations of, 2060 genetics of, 2061 laboratory tests in, 2061 pathology of, 2061 Myoblasts, 1837, 1838f Myobloc, 2367. See also Botulinum toxin Myoclonic absences, epilepsy with, 1025, 1074 Myoclonic encephalopathy early, 260, 260t, 266-268, 1070t of infancy, 1294 syndrome of, 73 Myoclonic epilepsy, 1063, 1065t, 1070-1074 benign, of infancy, 1065t of children and adolescents, 1071-1073 juvenile, 1019, 1025, 1071-1073 EEG findings in, 1071f, 1072 treatment of, 1075 progressive, 1072t, 1072-1073 age of onset, 1248t genetics of, 1248t Ramsay-Hunt syndrome, 109, 1254, 1295, 1608-1609 severe, of infancy, 1012-1013, 1070-1071, 1065t symptomatic, of infancy, 1070-1071

lxvi

Index

Myoclonic epilepsy with ragged red fibers (MERRF), 91, 175, 715, 1072t, 1073, 2054 clinical features of, 729, 2054 point mutations in, 729, 2054 Myoclonic seizures, 1063-1075 antiepileptic agents exacerbating, 1074-1075, 1074t associated with other entities, 1074 classification of, 1063, 1065t delayed postanoxic, 1492 disorders mimicking, 984b familial, EEG findings in, 240 infantile, 1065-1070, 1065t juvenile, 1019, 1025 in Lennox-Gastaut syndrome, 1031 neonatal, 258, 258t-259t, 260, 267-268, 1063-1065, 1065t evaluation and treatment of, 1064-1065 treatment of, 1023t, 1074-1075 Myoclonic status epilepticus, 1093b, 1094 Myoclonic-astatic epilepsy, 1011, 1030, 1070t Myoclonus, 1063-1075, 1272t, 1293-1295 action, 1293 benign, 1293 of early infancy, 1217, 1299 classification of, 1293, 1294t definitions of, 1063, 1293 developmental, 1293 diagnosis of, 1063 drug-induced, 2177, 2179b, 2197 EEG findings in, 1063 epileptic, 1063, 1064f essential, 1293-1294 etiology of, 1276, 1294t in hypertensive encephalopathy, 2239 hypnic, 1293 nonepileptic, 1063, 1064f, 1293-1295 differential diagnosis of, 1063, 1064b physiologic, 1293, 1294t postanoxic, 1295 reflex, 1293 sleep, 1293 benign neonatal, 1299 spectrum of, 1063, 1064f in subacute sclerosing panencephalitis, 1617 symptomatic, 1294, 1294t versus tics, 1064t treatment of, 1295 versus tremor, 1290, 1293 uremic, 2236-2237 Myoclonus dystonia, 1283 MyoD, 1837 Myofibrils, 1837 Myofilaments, 1837 Myoglobinuria, 2025 heritable causes of, 2024b, 2025 laboratory findings in, 2025 type I exertional, 2025 type II toxic, 2025 Myoinositol, in proton MR spectroscopy, 179180, 184f Myokymia, episodic ataxia with, 1262 Myopathy(ies). See also specific types in celiac disease, 2289 congenital, 2015-2019, 2018t in developmental disorders, 842t inflammatory, 2075-2083, 2075b congenital, 2080 idiopathic, 2075-2080, 2075b infectious, 2075, 2075b, 2080-2083 metabolic, 350t, 2023-2061 mitochondrial, 2048-2060 in poisoning/intoxication, 2177, 2178b postoperative, in cardiac surgery, 2215-2216 uremic, 2249

Myophosphorylase deficiency, 633-635, 20292031 biochemistry of, 633, 633f, 2030 clinical manifestations of, 622t, 633-634, 2029 enzyme defect in, 622t genetics of, 634, 2029-2031 glycogen structure in, 622t ischemic exercise testing in, 634, 634f laboratory tests in, 634, 2029 management of, 634-635, 2031 muscle biopsy in, 2029-2030 pathology of, 633 pathophysiology of, 2030 Myopia, 87 Myosin, 1839-1840, 1840f in muscle contraction, 1848-1850, 1849f Myosin-related myopathy, 2019 Myositis in juvenile idiopathic arthritis, 1805 in mixed connective tissue disease, 1817 in systemic lupus erythematosus, 1811 Myotatic reflex, 33 Myotilin deficiency, in limb-girdle muscular dystrophy, 1988t, 1994-1995 diseases associated with, 1842t, 1994 Myotonia congenita, 2090-2093 autosomal dominant (of Thomsen), 2090-2093, 2090t autosomal recessive (of Becker), 2090-2093, 2090t clinical features of, 2090-2091, 2090t genetics of, 2090t, 2091 laboratory tests in, 2091-2092 pathophysiology of, 2091 treatment of, 2090t, 2092-2093 Myotonia fluctuans, 2093-2094 clinical features of, 2093, 2093t genetics of, 2093-2094, 2093t laboratory tests in, 2094 pathophysiology of, 2094 treatment of, 2093t, 2094 Myotonia levior, 2091 Myotonic chondrodystrophy, 2098-2099, 2102 clinical features of, 2098, 2102 diagnosis of, 2098 genetics of, 2102 laboratory findings in, 2098-2099 pathophysiology of, 2102 treatment of, 2099, 2102 type 1A (classic), 2098 type 1B, 2098 type 2, 2098 Myotonic disorders, 2085-2105, 2085b. See also specific disorders chloride-channel, 2085b, 2087, 2090-2093, 2090t sodium-channel, 2085b, 2086f, 2093-2094, 2093t-2094t Myotonic dystrophies, 2085-2090 cardiac involvement in, 2224 type 1 (of Steinert), 2085-2089 age of onset, 2086-2087, 2086t childhood-onset, 2087 classification of, 2085-2086 clinical features of, 2086-2087, 2086f, 2086t congenital, 2086-2087 genetics of, 2086t, 2087 laboratory tests in, 2088 pathophysiology of, 2087-2088 provocative stimuli in, 2086t subclassification of, 2086-2087 treatment of, 2086t, 2088-2089, 2088f type 2, 2089-2090 Volume 1: pages 1–1180

Myotonic dystrophies continued age of onset, 2086t classification of, 2085-2086 clinical features of, 2086t, 2089 genetics of, 2086t, 2089 laboratory tests in, 2090 pathophysiology of, 2089-2090 provocative stimuli in, 2086t treatment of, 2086t, 2090 Myotonic-like disorders, 2101-2105, 2101t Myotube, 1837, 1838f Myotubular myopathy, 2017-2018 clinical features of, 2017 genetics of, 2018, 2018t pathology of, 2017-2018 Myotubularin, diseases associated with, 1842t Mysoline. See Primidone Myxedema, CSF protein content in, 162t

N N-acetyl-aspartate in Canavan’s disease, 1362, 1364 in proton MR spectroscopy, 179-180, 184f in hypoxic-ischemic injury, 282 N-acetylcysteine, for acetaminophen toxicity, 2190 α-N-acetylgalactosaminidase deficiency, 694-695 N-acetylglucosamine-1-phosphotransferase (NAGPT) defects, 696 N-acetylglutamate synthase deficiency of, 603-605 treatment of, 604-605, 604t, 612 in urea cycle, 603, 604f N-acyl-L-aspartate amidohydrolase deficiency, 592-593 Nadolol, for neurocardiogenic syncope, 1211b Naegleria fowleri, 1646, 1649, 1649f-1650f. See also Primary amebic meningoencephalitis Nafcillin, for bacterial meningitis, 1580t, 1581 Naloxone for opioid toxicity, 2181, 2186 for spinal cord injury, 1541 Naltrexone for autism, 924-925, 927t for Lesch-Nyhan disease, 1286 for Rett’s syndrome, 1321 Naproxen sodium for chronic daily headache, 1196t, 1197 dosage of, 2376t for juvenile idiopathic arthritis, 1805 for migraine, 1193t-1194t for occipital neuralgia, 1199 for pain, 2377 for post-traumatic headache, 1199 for tension headache, 1198 Naratriptan, for migraine, 1193t Narcolepsy, 1231-1232 age of onset, 1231, 1231f genetics of, 1231-1232 hypocretin deficiency in, 1232 incidence of, 1231 management of, 1232 multiple sleep latency test in, 1232 polysomnography in, 1232 prevalence of, 1231 secondary, 1231 Narcotic poisoning, 2185-2186 Nasal glioma versus encephalocele, 378 Natalizumab, for multiple sclerosis, 1350 National Association of Social Workers, 2361 National Center for Birth Defects and Developmental Disabilities, 928

Volume 2: pages 1181–2408

Index National Dissemination Center for Children with Disabilities, 928 National Institute of Child Health and Human Development, 928 National Institute of Child Health and Human Development Cooperative Epidemiological Study of Sudden Infant Death Syndrome Risk Factors, 1483 National Institute of Mental Health, 928 National Institute on Deafness and Other Communication Disorders (NIDCD), 137, 138t National Institutes of Health, 928 National Library of Medicine, 2404 National Multiple Sclerosis Society, 1349 National Organ Transplant Act (1987), 1565 National Reading Panel, 866 Natural law, 2388-2389 Navajo Indians, metachromatic leukodystrophy in, 680 N-butyldeoxygalactonojirimycin, for GM1 gangliosidosis, 667 Near-drowning, 1485-1488 cold-water, 1486 definition of, 1485 epidemiology of, 1485-1486 morbidity and mortality in, 1485 pathophysiology of, 1486 prevention of, 1488 prognosis in, 1486-1488 proton MR spectroscopy in, 182, 185f warm-water, clinical outcome of, 1482, 1487 Near-infrared spectroscopy, in coma, 1393 Near-light dissociation, 2152 Nearsightedness, 87 Nebulin, 1840 Neck positioning, in intracranial hypertension, 1520 Neck-tongue syndrome, 1199 Necrosis muscle, in Duchenne muscular dystrophy, 1973-1974 neuronal in hypoxic-ischemic injury, 303f, 304, 1472-1473 in traumatic brain injury, 1407 in spinal cord injury, 1531, 1531f Necrotizing sarcoid granulomatosis, 1823-1824 Necrotizing vasculitis, 1804t, 1818-1821 Nefazodone, for ADHD, 879t Negative myoclonus, in renal failure, 2237 Neisseria meningitidis meningitis, 1573 neurologic sequelae of, 1577, 1578f prevention of, 1584 prognosis of, 1583 recurrent, 1585 sepsis in, 1578-1579 treatment of, 1581 Nelson-Denny Reading Test, 866 Nemaline myopathy, 2016-2017 clinical features of, 2016 genetics of, 2017, 2018t management of, 2017 pathology of, 2017 Nematode infections, 1646, 1664-1668. See also specific infections classification of, 1647t clinical characteristics of, 1647t diagnosis of, 1647t geographic distribution of, 1647t management of, 1647t mode of infection, 1647t pathology of, 1647t risk factors for, 1647t Neocerebellum, 1243

Neomycin for hepatic encephalopathy, 2296-2297 for methylmalonic acidemia, 588 Neonatal adrenoleukodystrophy (NALD), 361, 740-744 clinical and pathologic features of, 741-742 genetics of, 740t, 742 laboratory diagnosis of, 742-744, 743t prenatal diagnosis of, 744 treatment of, 744 Neonatal Infant Pain Scale (NIPS), 2374, 2375t Neonatal onset multisystem inflammatory disease (NOMID), 1806 Neonatal seizures, 257-274 acute reactive, 257 adverse effects in developing brain, 271-272 anarchic, 258 animal models of, 272 antiepileptic agents for, 269-271 adjuvant, for acute cases, 270-271 adverse effects of, 271 chronic therapy with, 271 decision to initiate, 269-270 first-line, 269t, 270 initial, in acute cases, 270 second-line, 269t, 270-271 uncoupling with, 270 approach to, 257 autosomal dominant, 1009-1010 benign convulsions, 266 benign familial, 266-267, 1009-1010, 1045t and brain growth retardation, 272 and brain pathway alterations, 272 classification of, 230, 257-260 clinical, 258, 258t by pathophysiology, 258t, 259-260, 259b syndromic, 260 by temporal relation to electric seizure activity, 259 clinical characterization of, 257-260, 258t clinical manifestations of, 265-269 clinical only, 259, 1094 complex purposeless movements, 258t concerns in, 257 controversies over, 257, 1094 in cranial birth injuries, 335 and direct neuronal injury, 271-272 EEG studies of, 228-230, 228f-229f, 260-265, 274 alpha activity in, 263, 264f computer analysis of, 264-265 in depressed brain, 263, 264f electrical activity in, 261f-262f, 262-263, 263f frequency, morphology, and voltage in, 261f, 262-263, 262f interictal background in, 260 interictal focal abnormalities in, 261-262 migration pattern in, 263, 263f video monitoring with, 263 electrical-only, 259 electroclinical, 259, 1094 electrographic, 1094 epileptic, 259-260, 259b, 265-269 catastrophic syndromes of, 266 early infantile encephalopathy, 260, 260t, 266, 268-269 early myoclonic encephalopathy, 260, 260t, 266-268 etiology of, 265-269, 265b focal clonic, 258, 258t-259t, 260, 266-267 focal tonic, 258, 258t-259t, 260, 266-267 generalized tonic, 258, 258t-259t, 274 in genetic metabolic encephalopathies, 350t and hippocampal development, 272 in hypoglycemia, 348 in hyponatremia, 349-350 Volume 1: pages 1–1180

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lxvii

Neonatal seizures continued in hypoxic-ischemic injury, 280, 284, 286, 290-291 incidence of, 230, 257 in intracranial hemorrhage, 338 in intraventricular hemorrhage, 309, 321 management of, goals of, 273 minimal, 258 morbidity and mortality in, 230 motor automatisms, 258, 258t-259t, 260, 274 myoclonic, 258, 258t-259t, 260, 267-268, 1063-1065, 1065t of non-epileptic origin, 259-260, 259b occurrence of, 257 ocular signs in, 258, 258t oral-buccal-lingual movements, 258, 258t, 260, 1094 outcome measures of, 273, 273t paroxysmal changes in, 258 prognosis in, 230, 271-274 clinical considerations in, 273-274, 273t multivariant analyses of, 274 by neurologic disorder, 273, 274t by seizure type, 273-274 progression movements, 258, 258t, 260 versus reflex phenomena, 259, 259t versus seizures in older children, 258 spasms, 258t-259t, 260 in spina bifida, 372 in stroke, 334 subtle, 258-259, 1094 symptomatic, 257, 265 therapy for, 269-271 etiology-specific, 269, 269t initial considerations in, 269 two-hit hypothesis of, 272 Neonate(s). See also specific disorders cranial nerve examination in, 47, 51-52 cranial vault evaluation in, 48-50, 49f EEG patterns in, 210-218 abnormal, 225-236, 226f-227f, 227t analysis of, guidelines for, 225 burst-suppression (paroxysmal), 226, 226f, 267-268, 283 continuity/discontinuity in, 212f-214f, 215-218 focal abnormalities in, 227f, 228, 261-262 focal periodic, 230-231, 230f frontal sharp transients in, 217 gestational age and, 210, 211f-214f gestational age of 28 to 31 weeks, 212f-214f, 215-216 gestational age of 32 to 34 weeks, 214f, 216-217 gestational age of 34 to 37 weeks, 217 gestational age of 38 to 42 weeks, 214f, 217-218 gestational age younger than 28 weeks, 211f, 213f, 215 invariant, 226, 227f isoelectric, 226, 226f lateralized abnormalities in, 228, 228f multifocal, sharp wave, 226, 226f, 261-262, 261f-262f normalization in, 225 ontogeny of features in, 213-215 prognosis assessment in, 225-228, 226f-227f, 227t reactivity to stimulation in, 216-217 regional changes in, 210, 213f-214f in seizures, 228-230, 228f-229f, 260-265, 261f-264f sleep patterns in, 214f, 217-218, 222-223, 223f spikes and sharp waves in, 231, 261-262, 261f-262f

lxviii

Index

Neonate(s) continued sulcal-gyral development and, 210, 211f-212f synchrony/asynchrony in, 211f, 213f-214f, 215-218, 226f encephalopathy in, 47, 48t motor function evaluation in, 50-51 neurologic examination of, 47-52 observation of, 47-48 preterm. See Preterm infant(s) reflex evaluation in, 50-51 scoring systems for, 47, 48t Neopterin in CSF, 163 in dopa-responsive dystonia, 1283 Neoral. See Cyclosporine Neospora caninum, 1656 Nephrocalcinosis, 2263 Nephron dysfunction, in metabolic disorders, 2261-2262 Nephropathic cystinosis, 701, 2263-2264 genetics of, 2263 laboratory findings in, 2263 neurologic manifestations of, 2263-2264 treatment of, 2263 Nephrosis, congenital, 2242-2244 Finnish type of, 2242-2243 Nephrotoxic drugs, 2264-2265, 2264t NEPSY, 804t Nerve agents, 2183-2184 Nerve block, 2367 Nerve conduction velocity, 246 in brachial plexus injury, 341 in Charcot-Marie-Tooth disease, 1898, 1900-1901 in chronic inflammatory demyelinating polyneuropathy, 1930t, 1932 in congenital myasthenic syndromes, 1958 in diabetic neuropathy, 1905 in Guillain-Barré syndrome, 1601, 1893, 1920b, 1925 in muscular tone disorders, 69 in preterm infants, 54 in spinal muscular atrophy, 1866 Nerve growth factor in hypoxic-ischemic injury, 1479, 1504-1505 in Rett’s syndrome, 1318 in spinal cord injury, 1532 Nestin, 1845 Netscape, 2400 Neu-Laxova syndrome, 465t Neural crest, 437-438, 2129 migration of, 437-438 disorders of, 365 Neural crest plasticity and independent gene regulation model, 437 Neural fold, 365, 365f Neural hearing loss, 103 Neural plate, 365, 365f, 379 Neural tube axes of, 364 cell differentiation in, 366 closure of, 364-366, 364t, 365f, 379, 379f defects of, 365-383. See also specific defects antenatal diagnosis of, 370 associated problems with, 372 counseling in, 373 epidemiology of, 366-367 etiology of, 366-367 evaluation for, 47 family history and, 366 folate deficiency and, 366-367, 369-370, 377, 2319-2320 imaging of, 370 management of, 370-372 outcome of, 372-373

Neural tube continued pathogenesis of, 364, 366 prevention of, 369-370 risk factors for, 366t teratogens and, 366 development of, 364-366, 364t, 365f organization of, 379-383, 379f-382f Neurally mediated syncope, 1210 α-Neuraminidase deficiency, 693-694 Neuroacanthocytosis, 1278, 1287-1288 age of onset, 1287 clinical features of, 1287 diagnosis of, 1287 histologic findings in, 1287, 1287f treatment of, 1287-1288 Neuroblastoma(s) in infants and very young children, 1725 versus myoclonic encephalopathy, 1294 myoclonus with, 73 spinal cord, 1732 Neurocardiogenic syncope, 1210-1212 clinical features of, 1210 versus epilepsy, 1210 pathophysiology of, 1210-1211 tilt-table testing in, 1211 treatment of, 1211-1212, 1211b Neurocranium, 436 Neurocristopathies, 2287 Neurocutaneous disorders, 771, 771t Neurocutaneous melanosis, 787-788 clinical features of, 771t, 787-788 MRI findings in, 788 prognosis in, 788 Neurocytoma(s) central, 1693, 1722, 1722f classification of, 1691 Neurodegenerative disorder(s), 821-824 associated with abnormal head size, 830t-831t associated with abnormal movements, 829t associated with hair abnormalities, 835t associated with hearing abnormalities, 836t-837t associated with hepatomegaly, 832t associated with lower motor neuron abnormalities, 842t associated with MRI abnormalities, 840t-841t associated with ophthalmologic abnormalities, 838t-839t associated with skin abnormalities, 833t-834t causes of, 825t-827t inherited metabolic, 823, 826t-827t classification of, 822, 823t diagnostic evaluation of, 823-824, 824t-843t based on signs and symptoms, 823-824, 828t epidemiology of, 821-823 frequency of, 822, 823t incidence of, 821-822 misdiagnosed as cerebral palsy, 823, 825t neurotransmitter deficiencies in, 766 pantothenate kinase-associated, 1284-1285, 1285f, 1292 Neuroepithelial tumors dysembryoplastic, 1693, 1722, 1732 survival rates with, 1690t Neuroethics, 2387, 2396 Neuroexam.com, 2404 Neurofibroma(s), 775 cutaneous, 772-773, 773f gastrointestinal, 773 in neurofibromatosis type 1, 772-773, 773f, 775-776 plexiform, 773, 773f, 776 spinal cord, 1731f, 1732 spinal cord compression by, 773, 773f Volume 1: pages 1–1180

Neurofibromatosis, 1693 arachnoid cysts in, 435 autism in, 919 classification of, 771 megalencephaly with, 408 peripheral versus central, 776 precocious puberty with, 1701, 1701f type 1, 772-776, 1693 clinical features of, 771t, 772-775, 772f-773f cognitive dysfunction in, treatment of, 274 cutaneous features of, 771t, 772-773, 772f-773f diagnostic criteria for, 772t genetic testing for, 776 genetics of, 775 intracranial tumors in, 774 learning disabilities in, 774 management of, 776 ophthalmologic features of, 774, 774f, 776, 1702, 1702f-1703f pathology of, 775 reading difficulties in, 855 screening for, 776 vascular anomalies in, 774-775 type 2, 776-777 clinical features of, 771t, 776-777 cutaneous features of, 771t diagnostic criteria for, 776t genetics of, 777 hearing loss with, 105t MRI findings in, 777 pathology of, 776-777 vestibular dysfunction with, 132, 776-777, 777f Neurogenic atrophy, infantile pattern of, 1867 Neurogenic bladder, 2163-2164, 2358 treatment of, 2164-2165, 2165t Neuroimaging, 167-196. See also specific modalities in preterm infant, 316-320 recommendations for, 319-320 Neurointensive care, EEG studies in, 241 Neuroleptic agents, 964-971 acute dystonic reactions to, 1288 for ADHD, 879t, 882, 897 atypical, 938t, 964, 968-971 adverse effects of, 968, 2189 common characteristics of, 968 dosage of, 967t monitoring of, 968 receptor activity of, 967t, 968 for autism, 923-924, 927t for DYT1 dystonia, 1282 fetal/neonatal effects of, 2196 labeled and off-labeled use of, 938t for mentally retarded patients, 815 for Sydenham’s chorea, 1279 and tardive movement disorders, 1301-1302, 2189 for tic disorders, 896, 1298 toxicity of, 2188-2189 typical, 938t, 964-968 adverse effects of, 964-966 classification of, 964 common characteristics of, 964-966 extrapyramidal side effects of, 964, 965t representative, 965t Neuroleptic malignant syndrome, 965t, 966, 2189 Neurologic examination in brain death, 1556-1557 after cardiac arrest, 1492-1493 for clinical encephalopathy, 279-280 in comatose patient, 1386-1388 in defecation disorders, 2167 in hepatic encephalopathy, 2294

Volume 2: pages 1181–2408

Index Neurologic examination continued of infant, 37-45 approach to, 37-38 caregiver involvement in, 37-38 cranial nerve evaluation in, 39 general considerations in, 45 grasping skills/reflex in, 39-40, 40f, 43, 43t head evaluation in, 38 motor evaluation in, 39-40 observation in, 37-38 preterm. See Neurologic examination, of preterm infant sensory evaluation in, 40-41, 41f speech evaluation in, 45 stage 1 of, 38-41 stage 2 of, 41-44 stage 3 of, 44 stage 4 of, 44-45 at term (birth), 47-52 in inflicted neurotrauma, 1461 in micturition disorders, 2163 in myasthenia gravis, 1944-1945 of newborn (term), 47-52 cranial nerve examination in, 47, 51-52 cranial vault evaluation in, 48-50, 49f motor function evaluation in, 50-51 observation in, 47-48 reflex evaluation in, 50-51 scoring systems for, 47, 48t after newborn period until 2 years of age. See Neurologic examination, of infant of older child, 17-35 cerebellar function in, 19 cranial nerve evaluation in, 19-25 emerging patterns of behavior in, 17, 18f gait evaluation in, 27, 33-35 gross motor function screening in, 17 observation in, 17 physical examination in, 17-33 reflex assessment in, 17-19 sensory system in, 25-26 skeletal muscle testing in, 26-33, 34t in poisoning, 2175-2178 of preterm infant, 52-62 body attitude (posture) in, 54f-55f, 57 challenges in, 52-53 cranial nerve evaluation in, 59-60 environmental interaction in, 55-56 gestational age estimation in, 53-54, 53b, 53t, 54f-55f, 56, 56f muscle tone in, 57-59, 58f-59f scoring system and techniques for, 54f-55f, 56, 57t in smell and taste disorders, 138 in spinal cord injury, 1533-1535 in traumatic brain injury, 1408-1409 in vestibular dysfunction (vertigo), 125 Neurologic history, 3-16 chief complaint in, 3-4 child’s involvement in, 4 chronologic aspects of, 4-5, 4f crucial role of, 3 Denver Developmental Screening Test in, 5f-6f, 7 differential diagnosis in, 3-4 family history in, 15-16 focal versus generalized conditions in, 5-6 general form for, 7, 8f-10f parent/caregiver involvement in, 3 past, review of, 3 patterns of onset in, 4-5, 4f progressive versus static conditions in, 7 school behavior assessment in, 7-15 by parents/caretaker, 7, 13b by school/supervisory personnel, 7-15, 14f-15f by teacher, 7, 11f-12f

NeuroLogicExam, 2404 Neurologists, child, 2360 ethical duties of, 2392-2394 Internet resources for, 2399-2407, 2402t-2404t Neuroma(s), traumatic, 1532 Neuromelanosis, with hemimegalencephaly, 403t, 409 Neuromuscular blockade in infantile botulism, 1963 in meningitis, 1582 in traumatic brain injury, 1422 Neuromuscular Disease Center at Washington University, 2401 Neuromuscular junction, 1847-1848, 1847f, 1941 anatomy of, 1941, 1942f diseases of, 1941-1963 acquired, 1941 autoimmune, 1941 electrophysiologic studies of, 1941 inherited, 1941 Neuromuscular transmission, 1847-1848, 1941, 1942f blocking in, 1947 Neuron(s) activity, in EEG, 206-207, 996-997, 996f direct injury of, neonatal seizures and, 271-272 hyperexcitability, in epilepsy, 991, 996-997, 996f in hypoxic-ischemic injury apoptotic death of, 303f, 304 necrotic death of, 303f, 304 new production of, 305-306, 306f networks of, 207 potential fields of, 207 synchrony/hypersynchrony, in epilepsy, 991, 996f, 997-998 Neuronal brain iron accumulation, 1284-1285 Neuronal ceroid lipofuscinosis, 701-703, 1072t, 1073, 1328-1338 adult-onset, 702-703, 702t, 1072t, 1073, 1328-1330, 1329t age of onset, 1328, 1329t-1330t biochemistry of, 1329t-1330t clinical features of, 702, 702t, 1328, 1329t-1330t computed tomography in, 1329t-1330t diagnosis of, 1328 EEG findings in, 239-240 epilepsy with mental retardation, 1328, 1329t, 1333-1335 biochemistry of, 1335 cell biology of, 1335 clinical description of, 1333-1334 clinical diagnostic tests in, 1334 genetics of, 1329t, 1334-1335 management and therapy for, 1335 pathology of, 1334 ethnicities affected, 1329t-1330t genetics of, 1328, 1329t-1330t history of, 1328-1330 infantile (INCL), 1328-1332, 1329t biochemistry of, 1331 cell biology of, 1331 clinical description of, 1330-1331 clinical diagnostic tests in, 1331 EEG findings in, 1331 Finnish cases of, 1330-1332 genetics of, 1329t, 1331 management and treatment of, 1332 neuroimaging in, 1329t, 1331 pathology of, 1331 pathophysiology of, 1331 intralysosomal inclusions in, 702t, 703, 703f juvenile (JNCL), 1328-1330, 1329t, 1335-1336 biochemistry of, 1336 cell biology of, 1336 Volume 1: pages 1–1180

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lxix

Neuronal ceroid lipofuscinosis continued clinical description of, 1335 clinical diagnostic tests in, 1335-1336 EEG findings in, 1335 genetics of, 1329t, 1336 management and treatment of, 1336 neuroimaging in, 1329t, 1335 pathology of, 1336 pathophysiology of, 1336 Scottish, 1328, 1331-1332 juvenile-like variant, CLN9-deficient, 1330t, 1336-1338 biochemistry of, 1337-1338 cell biology of, 1337-1338 clinical description of, 1337 clinical diagnostic tests in, 1337 EEG findings in, 1337 genetics of, 1330t, 1336-1337, 1337f management and treatment of, 1338 neuroimaging in, 1330t, 1337 pathology of, 1337, 1338f late infantile, classic (LINCL), 1328-1330, 1329t, 1332-1333 biochemistry of, 1333 clinical description of, 1332 clinical diagnostic tests in, 1332 EEG findings in, 1332 genetics of, 1329t, 1333 management and treatment of, 1333 neuroimaging in, 1329t, 1332 pathology of, 1332-1333 late infantile, Costa Rican or Portuguese variant, 1328, 1329t, 1333-1335 biochemistry of, 1335 cell biology of, 1335 clinical description of, 1333-1334 clinical diagnostic tests in, 1334 genetics of, 1329t, 1334-1335 management and therapy for, 1335 pathology of, 1334 late infantile, Finnish variant, 1328, 1329t, 1333-1335 biochemistry of, 1335 cell biology of, 1335 clinical description of, 1333-1334 clinical diagnostic tests in, 1334 genetics of, 1329t, 1334-1335 management and therapy for, 1335 pathology of, 1334 late infantile, Turkish variant, 1328, 1329t-1330t, 1333-1335 biochemistry of, 1335 cell biology of, 1335 clinical description of, 1333-1334 clinical diagnostic tests in, 1334 genetics of, 1329t-1330t, 1334-1335 management and therapy for, 1335 pathology of, 1334 MRI findings in, 1329t-1330t prenatal diagnosis of, 703 subtypes of, 701-702, 702t, 1072t, 1073, 1328, 1329t-1330t terminology in, 1328-1330 treatment of, 703, 1328 vision loss with, 88t, 89, 702 Neuronal differentiation, 364t, 365 Neuronal firing, 992-994, 993f abnormal, in epilepsy, 996-997, 996f Neuronal heterotopias, 418-420, 419f Neuronal migration, 364t, 365, 398-399 malformations of, 410-420 Neuronal proliferation, 364t, 365, 398-399 abnormal, syndromes with, 403t malformations of, 400-410, 402t with abnormal cell types, 409-410 with normal cell types, 400-409

lxx

Index

Neuronal tumor(s), survival rates with, 1690t Neuron-specific enolase in brain injury, 1461, 1495 in cardiac arrest, 1495 Neurontin. See Gabapentin Neuropathic pain, 2378 Neuropathology and Neuroanatomy on the Internet, 2401 Neuropathy acquired sensory, 1902 ataxia, and retinitis pigmentosa syndrome, 728-729 in genetic metabolic encephalopathies, 350t hereditary, 1894-1902 classification of, 1894, 1895t-1897t motor and sensory, 1897-1901 sensory and autonomic, 1901-1902, 2144 inflammatory, 1893-1894, 1919-1934, 1920t, 1933t metabolic, 1905-1909 peripheral, 1887-1911. See also Peripheral neuropathy toxic, 1909-1911 uremic, 1905, 2247-2249 Neuropeptide Y in appetite/energy regulation, 2123 as neurotransmitter, 2129 Neurophysiologic evaluation, 203-247. See also Electroencephalography (EEG) in neurointensive care, 241 training for, 203-204 Neuropraxia, in brachial plexus injury, 340 Neuroprotection, in hypoxic-ischemic injury, 291, 301, 304-306 endogenous mechanisms of, 305-306 Neuropsychiatric lupus, 1810 Neuropsychopharmacology, 937-971. See also specific drugs and disorders benefits versus risks of, 937-938 labeled and off-labeled use of, 937, 938t safety and efficacy of, 937 Neurorehabilitation, 2355-2369. See also Rehabilitation “Neurosciences on the Internet,” 2405 Neuroteratology, 364, 364t, 2196-2198, 2197t. See also specific drugs Neurotheology, 2396 Neurotmesis, in brachial plexus injury, 340 Neurotologic examination, 128 Neurotoxins, 2173. See also specific agents Neurotransmitter(s), 2129-2131 in CSF, analysis of, 163 deficiency of, 759-767 with hyperphenylalaninemia, 759-761, 760f, 760t without hyperphenylalaninemia, 760t, 761-766 patient approach in, 767 secondary, 766 undefined, 766-767 disorders of, 759-767 classification of, 759 neurologic symptoms of, 759 excess, in neurologic disorders, 767 in traumatic brain injury, 1406 Neurotrophic factor(s) in hypoxic-ischemic injury, 305 for spinal cord injury, 1542 Neurovestibular examination, 124-128 components of, 124 history in, 124-125 Neurulation, 365, 365f, 379, 379f Nevirapine, for HIV infection, 1622 Nevus in epidermal syndrome, 771t, 786, 787t in neurocutaneous melanosis, 787-788

Nevus comedonicus syndrome, 787t Nevus flammeus, in Sturge-Weber syndrome, 782 Newborns. See Neonatal entries; Neonate(s); specific disorders newsreaders (software), 2400 Niacin (vitamin B3), 2309-2310 deficiency of, 1385, 2309-2310 dependency disorders of, 2305t, 2310 dietary sources of, 2309 physiologic functions of, 2309 recommended daily requirement for, 2309 Niclosamide for cysticercosis, 2082 for diphyllobothriasis, 1668 Nicotinamide adenine dinucleotide, 2309 Nicotinamide adenine dinucleotide phosphate, 2309 Nicotinamide adenine dinucleotide phosphatecoenzyme Q reductase deficiency, 725, 2057 Nicotine, for tic disorders, 897 Nicotinic acid, 2309 Niemann-Pick disease, 673-677 early infantile, 674 late infantile, 674, 674f muscular tone in, 69 type A, 665, 673-675 clinical features of, 674 diagnosis of, 675 genetics of, 675 treatment of, 675 type B, 673-675 clinical features of, 674 diagnosis of, 675 genetics of, 675 treatment of, 675 type C, 675-677 clinical features of, 675-676 diagnosis of, 676 genetics of, 675-676 incidence of, 675 management of, 676-677 neuropathology of, 676 psychiatric disorders with, 676 sleep in, 1235 type D, 676-677 vision loss with, 88t Nifedipine for autonomic dysreflexia, 2362 for hypertension, 2241 nephrotoxicity of, 2265 for Raynaud’s phenomenon, 1816 Nifurtimox for African trypanosomiasis, 1664 for Chagas’ disease, 1662 Night terrors, 1378 Nightmares, 1235 Nijmegen’s breakage syndrome clinical features of, 560t genetics of, 560t Nimodipine for aneurysms, 1794 for hypoxic-ischemic injury, 1502-1503 for migraine prevention, 1194t for spinal cord injury, 1542 19q13 microdeletion, 556t Nipah virus, 1619 Nipple(s), assessment of, in gestational age estimation, 57t Niridazole, for schistosomiasis, 1673 Nitrazepam for early infantile epileptic encephalopathy, 268 for infantile spasms, 1068-1069 Nitric oxide functions of, 1476 in hypoxic-ischemic injury, 283, 297f, 302, 1476-1477, 1477f, 1504 Volume 1: pages 1–1180

Nitric oxide continued inhibition of, 1504 in malaria, 1659 production of, 1476 Nitric oxide synthase (NOS) BH4 and, 761 endothelial, 1476, 1476t in hypoxic-ischemic injury, 299, 1476-1477, 1477f inducible, 1476, 1476t isoforms of, 1476, 1476t neuronal, 1476, 1476t Nitrofurantoin neuropathy induced by, 1909 toxicity of, 2191 Nitroindazole, for hypoxic-ischemic injury, 1504 Nitrosoureas, resistance to, 1746-1747 Nitrous oxide abuse/toxicity of, 2186 polyneuropathy induced by, 1910 NLGN3 and NLGN4 genes, in mental retardation, 809, 809t NLGN4X gene, in autism, 920 N-linked glycosylation, 645-647, 646f, 648f N-methyl-D-aspartate (NMDA) receptor(s), 995 in hypoxic-ischemic injury, 297f, 301, 303, 1474-1477, 1477f, 1502 in inflicted neurotrauma, 1446 in nitric oxide regulation, 1476-1477, 1477f in status epilepticus, 1092-1093 in stroke, 1763 in uremic encephalopathy, 2236 N-methyl-D-aspartate (NMDA) receptor antagonists for glycine encephalopathy, 581-582 for hypoxic-ischemic injury, 1502 “No reflow” concept, in hypoxic-ischemic injury, 1480 Nocardia, 1636. See also Nocardiosis Nocardia asteroides, 1636 Nocardia brasiliensis, 1636 Nocardia farcinica, 1636 Nocardiosis, 1636 clinical characteristics of, 1636 CNS syndromes in, 1632t diagnosis of, 1632t, 1636 geographic distribution of, 1632t in leukemia, 1738 in liver transplant patients, 2298 management of, 1632t, 1636 in renal transplant patients, 2250 risk factors for, 1632t Nociception, 2373 Nociceptive pain, 2378 Nociceptors, 2373 Nocturnal enuresis, 2157 in boys versus girls, 2162 definition of, 2162 Nocturnal frontal lobe epilepsy, autosomal dominant, 1013, 1045-1046, 1045t Nocturnal myoclonus, 1293 Nocturnal paroxysmal dystonia, 1213-1214, 1235, 1297-1298 Nocturnal polysomnography, 1227, 1229f in narcolepsy, 1232 in periodic hypersomnia, 1233 in restless legs syndrome, 1233 Nocturnal polyuria, 2138 Nodus vesicae, 2157 Nogo-66 receptor, in spinal cord injury, 1532 N-omega-nitro-L-arginine, for hypoxic-ischemic injury, 1504 Nonaccidental trauma, 1411-1412, 1445-1464, 2355. See also Child abuse hypoxic-ischemic injury in, 1489 Noncoding DNA, 518, 541-542 Noncoding strand, in transcription, 511

Volume 2: pages 1181–2408

Index Nondisjunction, of chromosomes, 525, 546 Non-Hodgkin’s lymphoma, in renal transplant patients, 2251 Nonketotic hyperglycinemia. See Glycine encephalopathy Nonmaleficence, 2389 Non-rapid eye movement parasomnias, 1235 Non-rapid eye movement sleep, 1225, 1226f Nonsense mutations, 531 Nonsteroidal anti-inflammatory drugs (NSAIDs) for chronic daily headache, 1196t, 1197 dosage guidelines for, 2376t, 2377 for Henoch-Schönlein purpura, 1821 and hepatorenal syndrome, 2258-2259 for juvenile idiopathic arthritis, 1805 for migraine, 1193t-1194t for myotonic dystrophy type 2, 2090 nephrotoxicity of, 2265 for occipital neuralgia, 1199 with opioids, 2377 for pain, 2376-2377 for post-traumatic headache, 1199 in renal failure, actions and effects of, 2268 for tension headache, 1198 Nonverbal pragmatics, 907t Noradrenaline. See Norepinephrine Norepinephrine in autonomic assessment, 2136, 2138f deficiency of, L-ADD defects and, 359-360, 360f as neurotransmitter, 2129, 2131f for orthostatic hypotension, 2142 in Tourette syndrome, 894, 895f Norepinephrine-specific reuptake inhibitors, for ADHD, 878t, 881, 943-944 Norrie’s disease, 766 hearing loss with, 105t vision loss with, 84 North American blastomycosis, 1634 clinical features of, 1634 CNS syndromes in, 1632t diagnosis of, 1632t, 1634 geographic distribution of, 1632t management of, 1632t, 1634 risk factors for, 1632t Nortriptyline, 945t, 946 for ADHD, 878t, 946 dosage of, 945t, 947 labeled and off-labeled use of, 938t pharmacokinetics of, 945t pharmacology of, 946 preparations of, 945t NOTCH3 gene, in cerebral autosomal dominant arteriopathy subcortical infarcts and leukoencephalopathy, 1369 Notencephalocele, 377 Notochord, 379 Novantrone. See Mitoxantrone Nuchal rigidity, in meningitis, 1573, 1585 Nuclear bag fibers, 65 Nuclear chain fibers, 65 Nuclear DNA defects, 722-728, 2055-2056 Nuclear factor-κB in Duchenne muscular dystrophy, 1975-1976 in spinal cord injury, 1532 Nuclear genome, 516-518 Nuclear membrane-related proteins, 1845 Nucleoside/nucleotide reverse transcriptase inhibitors, for HIV infection, 1622 Nucleosome, 509f, 516, 541, 542f Nucleotide substitutions, 530 Nucleotides, 507-508 Nucleus accumbens, 1272, 1273f Nucleus emboliform, 1241, 1242f

Nucleus globose, 1241, 1242f Nucleus pulposus herniation, 1540 Nucleus reticularis thalami, in absence seizures, 1027f, 1028 Null point, in nystagmus, 92 Nutritional disorders, 2301-2304. See also Malnutrition; specific deficiencies Nylen-Barany maneuver, 125-126, 125b, 131 Nystagmus in albinism, 85 with brainstem tumors, 1717 in caloric testing, 24, 123-124 in cerebellar gait, 73 cerebral disease and, 92 clinical evaluation of, 125-126 congenital, 22, 52 versus spasmus nutans, 1218-1219, 1300 versus tumor-related nystagmus, 1702, 1726, 1726f congenital motor, 92 electronystagmography of, 126-128, 127b end-point, 125 episodic ataxia associated with, 1215 in Friedreich’s ataxia, 1248 head-shaking, 124 horizontal, 22 hypothalamic tumors and, 1701 in infant, 39, 52, 81-82, 92 causes of, 92, 92t jerk, 22 in labyrinthine concussion, 131 in Leber’s congenital amaurosis, 85 in mental retardation/developmental delay, 812b null point in, 92 in older child, 22 in optic nerve hypoplasia, 84 with optic pathway tumors, 1702 opticokinetic, 22, 52 paroxysmal positional, 125 pathologic, 125 perrotatory, 126-128, 127b physiologic, 125 in poisoning/intoxication, 2175-2177 positional, 125 seesaw, 22 spontaneous, 22 vertical, 22 in vestibular dysfunction, 123-126 as vestibular function parameter, 123 vibration-induced, 124 in vision loss, 81 visual deprivation, 92

O Obesity in Duchenne muscular dystrophy, 1983 hypothalamic, 2122-2123 monogenic, 2123 Obidoxime, for insecticide poisoning, 2183 Oblique muscles, 20-21, 21f, 21t Observation, in neurologic examination of infant, 37-38 of newborn, 47-48 of older child, 17 Obsession(s), definition of, 889 Obsessive-compulsive disorder autoimmune pathway of, 1807 with tic disorders, 888-889, 897 treatment of, 896t, 897, 945-946 Obstructive sleep apnea, 1230-1231 with craniofacial anomalies, 1227, 1230 with craniosynostosis, 454 polysomnography in, 1229f, 1230 Volume 1: pages 1–1180

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Obtundation, definition of, 1378 Obturator nerve, 28t Occipital blindness, hypertension-associated, 2239 Occipital encephalocele, 378f, 391 Occipital horn syndrome, 1321-1326 Occipital mastoid suture, 436f Occipital neuralgia, 1198-1199 Occipital spikes, in EEG, 235-236 Occipital transients, in EEG posterior, 221, 224f sharp, in sleep, 224-225, 224f Occipital-parietal encephalopathy, 2239-2240 Occipitoaxial dislocation, 1535 Occipitofrontal circumference (OFC), 38, 48-50, 49f. See also Head circumference of preterm infants, 61-62, 61f-62f Occipitotemporal reading system, 859, 859f-860f, 861 Occult spinal dysraphism, 367-368 radiologic findings in, 367-368, 368f spectrum of, 367 Occupational planning, in epilepsy, 1177 Occupational therapists, 2360 Occupational therapy, for muscle overreactivity (spasticity), 2366 Octreotide, for orthostatic hypotension, 2143 Ocular albinism, 84-85 Ocular coloboma, 83, 83f-84f Ocular dysmetria, 1246 Ocular motility. See also Eye movements assessment of, 80, 80f Oculocutaneous albinism, 84-85 Oculocutaneous tyrosinemia, 576 Oculogyric crises, postoperative, 2213 Oculomasticatory myorhythmia, 2292 Oculomotor apraxia, in ataxia-telangiectasia, 1251 Oculomotor circuit, in Tourette syndrome, 893f, 894 Oculomotor nerve (CN III), assessment of, 80 in newborn (term), 52-53 in older child, 20-22 Oculopharyngeal muscular dystrophy, 1969, 2000 Oculovestibular reflexes, 123 in comatose patient, 1387 Odontoid fracture, 1535 Odors, in developmental disorders, 814b, 843t Off-label use, of neuropsychopharmacologic agents, 937, 938t Ofloxacin, for leprosy, 1591 O-galactose N-acetylglucosamine biosynthesis, 655 Okazaki fragments, 509 OKT3 toxicity, 2191, 2252 Olanzapine, 969 adverse effects of, 968-969, 2189 for autism, 924, 927t clinical applications of, 969 clinical management of, 969 dosage of, 967t, 969 drug interactions of, 969 labeled and off-labeled use of, 938t pharmacology of, 969 receptor activity of, 967t for tic disorders, 896 Older child cerebellar function in, 19 cranial nerve examination in, 19-25 emerging patterns of behavior in, 17, 18f gait evaluation in, 27, 33-35 gross motor function screening in, 17 neurologic examination of, 17-35 observation of, 17 physical examination of, 17-33

lxxii

Index

Older child continued reflex assessment in, 17-19 sensory system evaluation in, 25-26 skeletal muscle testing in, 26-33, 34t vision assessment in, 78-79 OLDMEDLINE, 2404 Olfaction, 135-139, 144-147. See also Smell Olfactory nerve (CN I), 136 assessment of in newborn (term), 52 in older child, 19 in smell and taste disorders, 138 in poisoning/intoxication, 2177t Olfactory receptors, 136-137 Olfactory tract, 137f Olfactory tubercle, 137f Oligemia, in migraine, 1187 Oligoclonal bands, in CSF immunologic analysis, 162-163, 162f Oligodendrocyte(s), in periventricular leukomalacia, 288 Oligodendroglia, in hypoxic-ischemic injury, 298, 301, 306 Oligodendroglioma(s), 1724 anaplastic, survival rates with, 1689t classification of, 1691 clinical characteristics of, 1724 neuroimaging of, 1724, 1724f survival rates with, 1689t, 1724 thalamic, 1700 treatment of, 1724 Oligogenic inheritance, 535 Oligophrenin mutation, 809 Oligosaccharides, in lysosomal storage diseases, 660t O-linked glycosylation, 645 Olivopontocerebellar atrophy, 394, 1254. See also Spinocerebellar ataxia(s) Ollier’s disease, 786 O-mannose glycans, 645, 653, 653f Omega oxidation, 721 Omeprazole, for nonepileptic paroxysmal disorders, 1213t Oncogenes, 1747-1748 2n (haploid) number, 516 Online Mendelian Inheritance in Man (OMIM), 2401 Onuf’s nucleus, 2130 Open skull fracture, 1418 Open-lipped schizencephaly, 383, 384t, 421f, 422 OPHN1 gene, in mental retardation, 809, 809r Ophthalmoplegia external, 22 internal, 22 internuclear, 22 in multi-mini-core-disease, 2016 progressive external, 727 sporadic progressive external, with ragged-red fibers, 2054 Ophthalmoplegic migraine, 1184, 1198-1199 classification of, 1184, 1198 clinical course of, 1198 differential diagnosis of, 1198 mechanism of, 1198 Ophthalmoscopy, 81 Opiate antagonists, for autism, 924, 927t Opioid(s) abuse/toxicity of, 2186 adverse effects of, 2376-2377 dosage guidelines for, 2376t, 2377 endogenous, in pain, 2373 fetal/neonatal effects of, 2196 NSAIDs with, 2377 for pain, 2376-2377 pharmacokinetics of, 2377 withdrawal from, 2377

Opioid-induced toxidrome, 2178, 2180-2181 Opitz’s syndrome, 465t Oppenheim, Hermann, 1862-1863 Oppenheim’s amyotonia, 1863 Oppenheim’s dystonia, 1282 Oppositional defiant disorder, with mental retardation, 815 Opsoclonus-myoclonus syndrome, 1294 Optic atrophy, 90-91 Costeff’s syndrome of, 592 mitochondrial defects and, 728 Optic disc, 20, 44, 52 Optic fundi, 52 infant, assessment of, 44 Optic glioma, in neurofibromatosis type 1, 774, 774f, 776, 1702, 1702f-1703f Optic nerve (CN II) assessment of in infant, 39 in newborn (term), 52-53 in older child, 19-20 disorders of, 89-91 edema of (papilledema), 89-90, 89f in genetic metabolic encephalopathies, 350t hypoplasia of, 84, 84f, 387, 387t in increased intracranial pressure, 1517 in meningeal leukemia, 1735-1736 in poisoning/intoxication, 2177t Optic nerve drusen, 90, 90f Optic nerve sheath hemorrhage, in inflicted neurotrauma, 1452 Optic neuritis, 90, 90f Optic Neuritis Treatment Trial, 1349 Optic pathway tumors, 1702-1703 algorithm for evaluation of, 1703, 1704f in infants and very young children, 1725 magnetic resonance imaging of, 1702-1703, 1702f-1703f treatment of, 1703 Opticokinetic nystagmus, 22, 52 Optimal drug concentration, 1121-1122 Oral polio vaccine (OPV), 2346, 2349 Oral-buccal-lingual movements, 258, 258t, 260, 1094 Oralism versus sign language, 117-118 Orap. See Pimozide Orbicularis oculi muscle in facioscapulohumeral muscular dystrophy, 1998, 1998f in myasthenia gravis, 1944 Organ donation, in brain death, 1565 Organ of Corti, 97-99, 98f-99f Organ transplantation. See Transplantation Organic acidopathies, 353-354, 567, 585-596 clinical features of, 350t-351t, 354 cognitive and motor regression in, 826t diagnosis of, 353t, 354 dystonia in, 1286 leukoencephalopathies, 1345, 1346t management of, 354 MRI findings in, 352t versus urea cycle disorders, 356 Organophosphate insecticides, 2182-2183 Organophosphorus hydrolase, liposome encapsulating, 2183 Orientia tsutsugamushi, 1644. See also Scrub typhus Origin of replication, 508, 516 Ornipressin, for hepatorenal syndrome, 2259 Ornithine metabolism, 2311 Ornithine transcarbamylase deficiency of, 603, 605, 608, 718 outcome of, 612-613 treatment of, 604t, 605, 611-612 in urea cycle, 603, 604f ORNT1 gene, 607 Volume 1: pages 1–1180

Orofacial-digital syndrome type I, 385t type VI, 391 Oromandibular dystonia, 1280 Orphenadrine citrate, in spinal cord injury, 1544 Ortho-methyldopa, in CSF, 163 Orthomyxoviridae, 1595b, 1617 Orthopedic surgery, in muscle overreactivity (spasticity), 2369 Orthostatic hypotension, 2131-2133, 2133f in cardiovascular disorders, 2135-2137 definition of, 2132-2133 disability in, 2140 drug action in, 2140t, 2141 factors influencing, 2133, 2133t food ingestion and, 2135, 2135f management of, 2140-2143, 2140t neurogenic, 2140, 2142 non-neurogenic causes of, 2135, 2136t in pandysautonomia, 2144 in spinal cord lesion, 2147, 2147f stimuli in daily life, 2133, 2134f-2135f symptoms of, 2133t transient, 2151-2152 water ingestion for, 2141, 2141f Orthotic devices in cerebral palsy, 2360 in Duchenne muscular dystrophy, 1984-1985, 1985f in myotonic dystrophy type 1, 2088, 2088f in spinal cord injury, 2357-2359, 2358f Osmotic demyelination, 349, 2245-2246, 2325 Osmotic myelinolysis, diffusion-weighted imaging in, 187 Osserman classification, of myasthenia gravis, 1943 Ossicular chain, 97 Ossification, heterotopic, 2363-2365 Osteogenesis imperfecta, 462-466 with blue sclerae, 462-463 versus child abuse, 463-466, 1460 clinical features of, 462, 462t genetics of, 462t, 463 hearing loss with, 105t, 463 prenatal diagnosis of, 463 subtypes of, 462-463, 462t treatment of, 463 Osteomalacia, antiepileptic agents and, 1124 Osteopetrosis, 455-457 adult autosomal dominant, 455-456 clinical characteristics of, 456-457 clinical forms of, 455-456 differential diagnosis of, 456 genetics of, 456 infantile malignant autosomal recessive, 455-456 intermediate autosomal recessive, 455-456 management of, 457 neuroimaging in, 456 neuronopathic, 457 pathogenesis of, 456 type I, hearing loss with, 105t otd gene family, 438 Otic capsule, 97 Otic vesicle, 97 Otitis media and hearing loss, 102, 109 and labyrinthitis, 129 and taste perception, 143 Otoacoustic emissions, 101, 101f, 111, 114 Otolaryngologic evaluation, 110-111, 138 Otosclerosis, 105t Ototoxic drugs, 109t, 110, 133

Volume 2: pages 1181–2408

Index Otx2 gene in craniofacial development, 438 in neural tube organization, 382 Ouabain, and CSF formation, 155 Ova, mutations in, 530 Oval window, 97, 98f Ovario-leukodystrophy, 1366 Overactive bladder, 2162-2163 Overflow incontinence fecal, 2166 urinary, 2163 Overlap syndromes polyangiitis in, 1825 polymyositis in, 2079, 2079f Oxaloacetate deficiency of, 718 in ketogenesis, 1136 Oxandrolone, for Duchenne muscular dystrophy, 1983 Oxazepam, for nonepileptic paroxysmal disorders, 1297 Oxcarbazepine absorption of, 1114 adverse effects of, 1123-1124, 2264 behavioral and cognitive effects of, 1176 bioavailability of, 1106t blood level of, 1051t dosage of, 1051t, 1108t drug concentration of, 1122 elimination of, 1108t, 1114 formulations of, 1106t hypersensitivity to, 1125 mechanism of action, 1002-1003, 1003f metabolism of, 1108t, 1114 nephrotoxicity of, 2264 for nonepileptic paroxysmal disorders, 1213t optimal range of, 1117t pharmacokinetics of, 1106t, 1108t, 1114 practical guide to, 1051t preparations of, 1051t protein binding of, 1108t, 1114 in renal failure, action and effects of, 2267 routes of administration, 1106t testing of, 1002 in traumatic brain injury, 1435 volume of distribution, 1108t Oxidative phosphorylation defects, 354-355, 725, 2059 cardiac involvement in, 2223 Oxidative stress in amyotrophic lateral sclerosis, 1871 in hypoxic-ischemic injury, 297f, 301-302, 302f, 1477-1478, 1477f, 1503 mitochondrial damage in, 730 3-Oxoacyl coenzyme A thiolase deficiency, 750 5-Oxoprolinuria, 595 Oxybutynin, for micturition disorders, 2164, 2165t, 2358 Oxycephaly, 446-447 Oxycodone abuse/poisoning, 2186 dosage of, 2376t Oxygen delivery and use, in cardiac surgery, 2208-2209, 2208b Oxygen metabolism, in hypoxic-ischemic injury, 299 Oxygen therapy hyperbaric for hypoxic-ischemic injury, 1505 for phycomycosis, 1640 for spinal cord injury, 1542-1543 for hypoxic-ischemic injury, 290 versus room air resuscitation, 290 toxic effects in, 290 Oxygenation extracorporeal membrane, 2225-2226

Oxygenation continued contraindications to, 2225 indications for, 2225 mechanisms of neurologic injury in, 2225 neurologic complications of, 2225-2226 monitoring in comatose patients, 1392-1393 Oxyhemoglobin, in CSF, 159 Oxytocin, in autism, 920

P p (short) arm, of chromosome, 516, 541, 543f p53 tumor suppressor gene, 1747 P300 event-related potential, 247 Pacemakers, for reflex anoxic seizures, 1207 Pachygyria, 410, 411f, 413f, 416f, 840t. See also Lissencephaly Pachytene, 514 Pain behavioral responses to, 2374, 2374t biochemical responses to, 2374 in children with significant neurologic impairment, 2378 clinical assessment of, 2374, 2375t congenital insensitivity to, with anhidrosis, 2145 definition of, 2373 developmental differences in, 2373-2374 migraine or headache, 2378 neuropathic, 2378 in newborn infants, 2373-2374 nociceptive, 2378 physiologic/autonomic responses to, 2374, 2374t physiology of, 2373 self-report of, 2374 types of, 2378-2379 Pain management, 2373-2379 four-step approach in, 2376 in Guillain-Barré syndrome, 1923-1924 historical background of, 2373 in palliative care, 2383 in spinal cord injury, 2358 types of medications in, 2376-2378 Pain perception, 2373 anterior spinal artery occlusion and, 1877-1878 Painful gait, 74-75 PAK3 gene, in mental retardation, 809, 809t Palate cleft. See Cleft lip/palate embryology of, 466 examination of, 24 Paleocerebellum, 1243 Palliative care, 2379-2385 barriers to, 2385 bereavement in, 2383-2384 communication in, 2381-2382 protocol for, 2382, 2382b components of, 2380-2385 definitions of, 2380 developmental, emotional, and spiritual concerns in, 2383 environment for, 2382-2383 essential elements in approach to, 2384f follow-up conference in, 2384-2385 health-care decision making in, 2382 historical background of, 2379-2380 identifying need for, 2380 levels of, 2381 multidisciplinary team for, 2380, 2380b neurologic conditions appropriate for, 2379b support during dying in, 2383 symptom assessment and treatment in, 2383 transition in goals of, 2380-2381, 2381f Pallid breath-holding spells, 1203, 1205, 1212 Volume 1: pages 1–1180

Volume 2: pages 1181–2408

lxxiii

Pallidotomy for dyskinesia, 1290 for dystonia, 1289 Palmar grasp reflex, 39-40, 40f, 43, 43t, 60 Palmar grip reflex, 43t Palmitoyl protein thioesterase, in neuronal ceroid lipofuscinosis, 1328, 1329t-1330t, 1331 Pamidronate for fibrous dysplasia, 458 for McCune-Albright syndrome, 459 for osteogenesis imperfecta, 463 Panayiotopoulos’ syndrome, 1045 Pancreatitis, antiepileptic agents and, 1124 Pancuronium postoperative effects of, 2216 in traumatic brain injury, 1422 Pandysautonomia clinical features of, 2144 with other neurologic features, 2143-2144 prognosis of, 2144 pure, 2143-2144 Panic attacks, vertigo with, 133 Panoramic vision, 1043 Pantopaque toxicity, 2194 Pantothenate kinase-associated neurodegeneration, 1284-1285, 1292 age at presentation, 1285 atypical, 1285 clinical features of, 1285 genetics of, 1285 MRI findings in, 1285, 1285f treatment of, 1285 Papilledema, 20, 86, 89-90, 89f with brain tumors, 1694 with hydrocephalus, 429 with increased intracranial pressure, 89-90, 89f, 1517, 1517f, 1522, 1522f in malaria, 1658 with optic pathway tumor, 1702 in poisoning, 2175 with posterior fossa tumor, 73 versus pseudopapilledema, 90 with spinal cord tumor, 1731-1732 in systemic lupus erythematosus, 1811 Papilloma(s) choroid plexus, 1707-1708 and hydrocephalus, 428 management of, 1707-1708 prognostic factors in, 1707-1708 in tuberous sclerosis complex, 779 Paracentric inversion, 528, 529t, 546 Paracetamol intoxication, 2190 Parachute response, abnormal, 45f Paracoccidioides brasiliensis, 1634. See also Blastomycosis, South American Paradoxical embolic stroke, 2216f, 2217 Paradoxical normalization, 1173 Paragonimiasis, 1673-1674 clinical characteristics of, 1673-1674 diagnosis of, 1673-1674 epidemiology of, 1673 laboratory tests in, 1673-1674 management of, 1674 microbiology of, 1673 pathology of, 1673 Paragonimus westermani, 1673. See also Paragonimiasis Parainfluenza virus, 1617 Paraldehyde bioavailability of, 1106t formulations of, 1106t in malaria, 1660 for neonatal seizures, 271 pharmacokinetics of, 1106t routes of administration, 1106t, 1120t

lxxiv

Index

Parallel fibers, 1241, 1243f Paralysis, periodic, 2085b, 2094-2101. See also Periodic paralysis Paramyotonia congenita, 2096-2097 clinical features of, 2094t, 2096 genetics of, 2094t, 2096 with hyperkalemic periodic paralysis, 2097 clinical features of, 2094t genetics of, 2094t treatment of, 2094t laboratory tests in, 2096 pathophysiology of, 2096-2097 treatment of, 2094t, 2097 Paramyxoviruses, 1595b, 1617-1619 outcome of, 1603t Paraplegia spastic, 385t heat-shock protein deficiency in, 727 tropical spastic, 1622-1623 Parasagittal injury, hypoxic-ischemic, 280, 285 clinical features of, 285 diagnosis of, 285 magnetic resonance imaging of, 282, 285, 285f pathogenesis of, 285 Parasitic diseases, 1645-1674 classification of, 1646, 1647t-1648t clinical characteristics of, 1647t-1648t diagnosis of, 1646, 1647t-1648t epidemiology of, 1645-1646 geographic distribution of, 1645, 1647t-1648t management of, 1647t-1648t mode of infection, 1647t-1648t and myopathy, 2075b, 2081-2082 pathology of, 1647t-1648t risk factors for, 1647t-1648t Parasomnia(s), 1225-1226, 1226f, 1235 arousal disorders, 1226t associated with REM sleep, 1226t definition of, 1235 non-rapid eye movement, 1235 rapid eye movement, 1235 transition disorders, 1226t Parasympathetic nervous system, 2130, 2130f disorders of, 2132-2133 Parathyroid hormone (PTH), in renal failure, 2235, 2244, 2249 Parents neurologic history provided by, 3 school behavior assessment by, 7, 13b Parietotemporal posterior reading system, 859 Parkinsonism, 1272t, 1291-1293 in dopa-responsive dystonia with diurnal variation, 1215 drug-induced, 965, 965t, 1292-1293, 1292t etiology of, 1292-1293, 1292t in hepatic encephalopathy, 2294 pathophysiology of, 1274-1275 in poisoning/intoxication, 2177, 2179b postoperative, in cardiac surgery, 2213 primary, 1292 secondary, 1292-1293 treatment of, 1293 Parkinson’s disease, 1292 gait abnormalities in, 73-74 genetics of, 1292 infantile, 764-765 juvenile, 1288, 1292 mitochondrial dysfunction in, 729 treatment of, 1293 surgical, 1290 tremor in, 1290-1291 Paromomycin for amebiasis, 1649 for cysticercosis, 2082 Parosmia, 146

Parotid gland irradiation, for sialorrhea, 2362 Paroxetine, 948-953 for ADHD, 879t adverse effects of, 951-952 for autism, 924 dosage of, 948t, 951 initiation and titration of, 951 labeled and off-labeled use of, 938t pharmacokinetics of, 948t, 949-950 preparations of, 948t Paroxysmal ataxia, acetazolamide-responsive, 1213t-1214t, 1215, 1220 Paroxysmal choreoathetosis dystonic, 1213-1214, 1296-1297 genetics of, 1214t of Mount and Reback, 1213-1214, 12961297 treatment of, 1213t, 1214 kinesigenic, 1213-1214, 1213t, 1296-1297 etiology of, 1214-1215 genetics of, 1214-1215, 1214t treatment of, 1213t, 1214 nonkinesigenic, 1213-1214, 1297 Paroxysmal choreoathetosis-spasticity, 1297-1298 Paroxysmal depolarization shift, in EEG, 207-208, 996f, 997 Paroxysmal disorders epileptic. See epilepsy ion channels in, 1220 nonepileptic, 240, 1209-1220, 1209b. See also Syncope; specific disorders genetics of, 1214t treatment of, 1213t Paroxysmal dyskinesias, 1214, 1297 Paroxysmal exertion-induced dyskinesia, 1297-1298 Paroxysmal hemicrania, 1199 Paroxysmal nocturnal (hypnogenic) dystonia, 1213-1214, 1235, 1297-1298 Paroxysmal tonic upgaze, benign, 1215, 1300 treatment of, 1213t Paroxysmal torticollis, benign, 1191, 1216, 1300 Paroxysmal vertigo acute, with hearing loss, 128-130, 129t benign, 124-126, 130-131, 1191, 1213 treatment of, 1213, 1213t without hearing loss, 130-133 recurrent, without hearing loss, 129t Parry-Romberg syndrome, 787 clinical features of, 771t, 787f, 786-787 Pars compacta, 1272, 1273f Partial sacral dysgenesis, 374, 374f Partial (focal) seizures, 984b, 991, 992f, 1009, 1019, 1037-1052 auras in, 1020-1021 autosomal dominant, with auditory features, 1013, 1045, 1045t behavioral arrest in, 1039-1040, 1041f benign of childhood, 1044-1045 with occipital spikes, 1045 brain tumors and, 1048 classification of, 1037, 1038b-1039b, 1042, 1044 clonic, 1040, 1041f neonatal, 258, 258t-259t, 260, 266-267 complex, 1037, 1038b, 1042-1044 with complex inheritances, 1014 congenital and prenatal factors in, 1048 cortical malformations and, 1048 EEG findings in, 1037-1042, 1038b, 1040f-1041f epilepsy syndromes with, 1044-1047 etiology of, 1048-1049 familial, with variable foci, 1014, 1045t, 1046 febrile, 1083 Volume 1: pages 1–1180

Partial (focal) seizures continued genetics of, 1013-1014, 1044-1045, 1045t long-term outcome of, 1052 management of, 1049-1052, 1051t mendelian, 1013 migrating, of infancy, 1048 mixed with generalized seizures, 1047-1048, 1050 multidisciplinary issues in, 1052 postnatal infectious diseases and, 1048-1049 recognition of, 1037-1042, 1039b refractory, 1052 secondarily generalized, 1044 seizure semiology indicating, 1021b simple, 1037, 1038b, 1042-1043 tonic, neonatal, 258, 258t-259t, 260, 266-267 tonic postures in, 1041 trauma and, 1049 with uncertain alteration of consciousness, 1044 version in, 1041f, 1042 Partial status epilepticus, 1093-1094, 1093b Partial thromboplastin time, in neonatal stroke, 331-332, 331b Past pointing, in vestibular dysfunction, 125b, 126 Patau’s syndrome (trisomy 13), 465t, 525, 546, 550-551 clinical features of, 550, 550f cytogenetics of, 550 management of, 550-551 Patellar reflex in Duchenne muscular dystrophy, 1978 in older child, 18, 19t in preterm infant, 56-57, 58t Patent ductus arteriosus, and intraventricular hemorrhage, 324 Patent foramen ovale, and stroke, 1767 Pathologic processes, categories of, 3 Patient education, Internet resources for, 2405 Patient-controlled analgesia, 2377 PAX1 gene, in Klippel-Feil syndrome, 454 Pax-3, 1837 Pax-7, 1837 Paxil. See Paroxetine PCP, 2187 PDAs, 2406 Peabody Picture Vocabulary Test-Revised (PPVT-R), 805, 845 Pearson’s syndrome, 728 Pectoral muscle, testing of, 34t Pectoralis major reflex, in preterm infant, 56, 58t Pectus excavatum, 67 in anterior horn cell disease, 1876 in spinal muscular atrophy type I, 1864 Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS), 893, 1279, 1807 Pediatric Coma Scale, 1382-1383, 1382t Pediatric Evaluation of Disabilities Inventory (PEDI), 805, 1394-1396 Pediatric Functional Independent Measure (WeeFIM), 805 Pedigree, 532, 532f PediNeuroLogicExam, 45, 2404 Peer relationships in Asperger’s disorder, 909 in autistic disorder, 906-907 in epilepsy, 1177 Peiper-Isbert vertical suspension, 43t Pelizaeus-Merzbacher disease, 1354-1356 biochemistry of, 1356 classification of, 1354 clinical characteristics of, 1354-1355 clinical studies of, 1356 genetics of, 1356 magnetic resonance imaging in, 1355f, 1356

Volume 2: pages 1181–2408

Index Pelizaeus-Merzbacher disease continued pathology of, 1356 subclassification of, 1354-1355 type I (classic), 1354-1355 type II (connatal), 1355 type III (transitional), 1355 Pellagra, 1385, 2309-2310 Pelvic floor, 2166 Pelvic girdle myopathy, 2249 Pemoline for ADHD, 878t, 939t, 940, 943 adverse effects of, 940, 943, 2190 dosage of, 939t labeled and off-labeled use of, 938t pharmacology of, 939t toxicity of, 2190 Pendred’s syndrome, hearing loss with, 105t, 115 Penetrance, 532 Penetrating trauma, 1403 Penicillamine adverse effects of, 2300, 2311 for scleroderma, 1816 for Wilson’s disease, 1291, 2300 Penicillin(s) for actinomycosis, 1637 for bacterial meningitis, 1581 for leptospirosis, 1588 for Lyme disease, 1588 in renal failure, encephalopathy induced by, 2266 for Sydenham’s chorea, 1808 for syphilis, 1587 Pentamidine for African trypanosomiasis, 1664 for granulomatous amebic encephalitis, 1651, 1653 Pentazocine abuse/poisoning, 2186 fetal/neonatal effects of, 2196 Pentobarbital for intracranial hypertension, 1521 in renal failure, action and effects of, 2267 for sedation, 2378 for status epilepticus, 1100 Pentostatin toxicity, 2193 Pentoxifylline, in malaria, 1660 Pentylenetetrazol test, of antiepileptic agents, 1002 Peptide(s), in lysosomal storage diseases, 661t Peptide YY3-36, 2122f, 2123 Peptidylglycine monooxygenase, in Menkes’ disease, 1324 Percodan. See Oxycodone Perfection, and neuroethics, 2396 Perforator branches, arterial, 1760-1762 Perfusion magnetic resonance imaging, 189-191 of brain tumors, 189-190, 1696 of stroke, 1775 Pergolide for Parkinson’s disease, 1293 for tic disorders, 897 Pericentric inversion, 520f, 526f, 528, 529t, 546 Perilymphatic fistula, 130 Perimysium, 1838f, 1839 Perinatal asphyxia, 492 Perinatal trauma, 329, 334-341 anterior horn cell with, 1876 brachial plexus, 340-341, 1890-1892, 1892f clinical presentation of, 335-341 cranial, 336-339 outcomes in, 338-339 cranial nerve, 339 deaths from, 334 definition of, 334 delivery mode and, 334-335 epidemiology of, 334

Perinatal trauma continued extracranial, 335-336 intracranial, 337-339 laboratory testing in, 335 management, by diagnosis, 335-341 mechanical, 334 radiologic studies of, 335 risk factors for, 334-335 spinal cord, 339-340, 1527 Perineurium, 1887, 1888f Period gene, 1225, 1236 Periodic lateralized epileptiform discharges, 236-237, 237f Periodic paralysis, 2085b, 2094-2101 with cardiac arrhythmia (Andersen-Tawil syndrome), 2099-2100 clinical features of, 2095t, 2099, 2099f genetics of, 2095t, 2100 laboratory findings in, 2100 pathophysiology of, 2100 treatment of, 2095t, 2100 channelopathies with, 2094t-2095t classification of, 2094 hyperkalemic, 2094-2096 clinical features of, 2094t, 2095 genetics of, 2094t, 2095 laboratory tests in, 2096 with myotonia, 2094t clinical features of, 2094t genetics of, 2094t treatment of, 2094t paramyotonia congenita with, 2094t, 2097 clinical features of, 2094t genetics of, 2094t treatment of, 2094t pathophysiology of, 2095-2096 treatment of, 2094t, 2096 hypokalemic, 2094, 2095t, 2097-2098 clinical features of, 2095t, 2097 genetics of, 2095t, 2097 laboratory tests in, 2098 pathophysiology of, 2097-2098 treatment of, 2095t, 2098 sodium channel, 2095t thyrotoxic clinical features of, 2095t genetics of, 2095t treatment of, 2095t Peripheral nerve(s), 1887 anatomy of, 1887, 1888f disorders of. See Peripheral neuropathy evaluation of, 1887 in pain perception, 2373 stimulation, in somatosensory-evoked potential, 246 Peripheral nerve hyperexcitability, acquired generalized, 2103-2104 clinical features of, 2101t, 2103 genetics of, 2101t pathophysiology of, 2105 treatment of, 2101t, 2105 Peripheral nerve sheath tumors, in neurofibromatosis type 1, 774-776 Peripheral neuropathy, 1887-1911 acquired sensory, 1902 acute, 1887 in celiac disease, 2289 chronic, 1887 classification of, 1887 in developmental disorders, 842t diabetic, 1905, 2140 etiology of, 1919, 1920t in Henoch-Schönlein purpura, 1821 hereditary, 1894-1902 classification of, 1894, 1895t-1897t Volume 1: pages 1–1180

Volume 2: pages 1181–2408

lxxv

Peripheral neuropathy continued motor and sensory, 1897-1901 sensory and autonomic, 1901-1902, 2144 inflammatory, 1893-1894, 1919-1934, 1920t, 1933t intramuscular injections and, 2194 in juvenile idiopathic arthritis, 1804-1805 in Lyme disease, 1933 in mental retardation/developmental delay, 814b metabolic, 1905-1909 in poisoning/intoxication, 2177, 2178b in polyarteritis nodosa, 1820 postoperative, in cardiac surgery, 2215-2216 in systemic lupus erythematosus, 1811 toxic, 1909-1911 uremic, 1905, 2247-2249 Peripheral umbilical cord blood sampling (PUBS), 548-549 Perirolandic cortex, hypoxic-ischemic injury to, 285-287 magnetic resonance imaging of, 282, 286 Perisylvian abnormalities, and language disorders, 850-851 Periungual fibroma, in tuberous sclerosis complex, 779, 779f Periventricular hemorrhagic infarction, 287, 309-310, 315 clinical features of, 287 diagnosis of, 287 pathogenesis of, 287 ultrasound of, 287, 288f Periventricular laminar heterotopia, 420 Periventricular leukomalacia, 288-289, 318-319 and cerebral palsy, 315, 322 clinical features of, 289 common locations of, 288 computed tomography of, 289, 289f cysts of, 318, 319f definition of, 318 diagnosis of, 289, 318 diffusion-weighted imaging in, 187 EEG studies of, 227f, 228, 283 incidence of, 281 versus intraparenchymal echodensities, 318-319, 320t intraventricular hemorrhage and, 315-316, 318-319 long-term neuropathologic features of, 288-289 magnetic resonance imaging of, 282, 289, 289f, 318-319, 320t pathogenesis of, 288 in spastic diplegia, 498 ultrasound of, 169-170, 169f, 281, 288f, 289, 290f, 318-319, 319f, 320t vision loss with, 86, 91 Periventricular nodular heterotopia, 418-420 antenatal diagnosis of, 420 bilateral versus unilateral, 419-420 clinical characteristics of, 419 genetic testing for, 420 genetics of, 412t, 420 management of, 420 microcephaly with, 403t, 405 MRI findings in, 419f outcome of, 420 pathology of, 418-419 syndromes of, 419-420 X-linked, 419-420 Perlecan, in Schwartz-Jampel syndrome, 2098 Pernicious anemia, 1906, 2312-2313 Peroneal muscle, testing of, 34t Peroneal nerve, 29t Peroxins, 735-736

lxxvi

Index

Peroxisomal disorders, 361, 735-752 biogenesis defects, 735, 736t, 739-745 cognitive and motor regression in, 826t laboratory diagnosis of, 742-744, 743t prenatal diagnosis of, 744 therapy for, 744 classification of, 735, 736t, 739 current and future outlook in, 751-752 diagnostic evaluation of, 739f historical overview of, 735 multiple biochemical defects, 736t, 744-745 single-enzyme, 735, 736t, 739, 745-751 cognitive and motor regression in, 826t Peroxisome(s), 735 in amino acid metabolism, 738-739 assembly of, disorders of, 740, 740t in bile acid synthesis, 738 biogenesis of, 735 defects of, 735, 736t, 739-745, 826t distribution of, 735, 737 division of, 736-737 in fatty acid oxidation, 735, 736f, 737-738, 2038 import of, 735-736 metabolic function of, 737-739 number of, 735-737 in plasmalogen synthesis, 735, 738 in prostaglandin degradation, 738 size of, 735, 737 structure of, 735-737 Peroxisome proliferator-activated receptor α (PPARα), 736-737 Peroxisome targeting sequence 1 (PTS1), 735 Peroxisome targeting sequence 2 (PTS2), 735 Perphenazine, fetal/neonatal effects of, 2196 Perrotatory nystagmus, 126-128, 127b Persistent vegetative state, 1395 Personal digital assistants, 2406 Personality change with brain tumor, 1695 with increased intracranial pressure, 1517 Personhood, ethics of, 2394-2395 Pertussis vaccine acellular, 2350 whole-cell, 2348 Pervasive development disorders, 905. See also Autism/autistic disorder atypical, 905 broader phenotype in, 905, 918 childhood-onset, 905 diagnostic evaluation and screening in, 912-915, 913b-914b DSM-III classification of, 905 DSM-IV classification of, 905, 906t epidemiology of, 911-912 full syndrome present, 905 ICD-9 classification of, 905, 906t not otherwise specified, 905, 909 residual state, 905 Pervasive Developmental Disorders Screening Test, version II (PDDST-II), 913, 914b Pes cavus, in Friedreich’s ataxia, 1249 PET. See Positron emission tomography Peters’ anomaly, 83 Peters’ syndrome, 83, 88 Petit mal seizures, 1023. See also Absence seizures PEX gene defects, 740, 740t Pfeiffer’s syndrome, 448-449 clinical features of, 442t, 448-449 developmental outcomes of, 448 genetics of, 442t, 443, 443f, 447t, 448-449 type 1, 447t, 448-449 type 2, 447t, 448-449 type 3, 447t, 448-449

PFKM gene, in phosphofructokinase deficiency, 635-636 pH, in muscle metabolism, 1851 PHACE syndrome, 392, 392t Phakomatoses, 771-790. See also Neurofibromatosis; Tuberous sclerosis complex; von Hippel-Lindau syndrome clinical features of, 771t cutaneous features of, 771, 771t terminology for, 771 Phakomatosis pigmentokeratotica, 787t Phantogeusia, 143 Phantom pain, 2378 Phantosmia, 146 Pharmacodynamics. See also specific drugs definition of, 1105 in renal failure, 2265-2268 Pharmacokinetics. See also specific drugs children’s physiology and, 1117-1118, 1117t definition of, 1105 in infants and children, 1118 in neonates, 1118 in renal failure, 2265-2268 Pharynx, examination of, 24 Phasic tone, 65 Phenacetin, nephrotoxicity of, 2265 Phencyclidine, 2187 Phenelzine, for ADHD, 879t Phenobarbital acute therapy with, 270 adverse effects of, 271, 1050, 1122-1124, 1435, 2180-2181, 2265 behavioral and cognitive effects of, 1175 bioavailability of, 1106t blood level of, 1051t in breast milk, 2196-2197 chronic therapy with, 271 for cyclical vomiting syndrome, 2286 discontinuation of, 1126 dosage of, 1051t initial maintenance, 1108t loading, 1109t drug concentration of, 1122 elimination of, 1108t for febrile seizure prevention, 1085 for focal seizures, 1050 formulations of, 1106t for generalized seizures, 1022 hypersensitivity to, 1125 for intraventricular hemorrhage prevention, 324 and learning disabilities, 856 in leukemia, 1737 in malaria, 1660 mechanism of action, 1119t in meningitis, 1582 metabolism of, 1108t for neonatal seizures, 266-267, 269t, 270-271 nephrotoxicity of, 2265 for neuronal ceroid lipofuscinosis, 1333 for nonepileptic paroxysmal disorders, 1297 optimal range of, 1117t pharmacokinetics of, 1106t, 1108t pharmacology of, 270 practical guide to, 1051t preparations of, 1051t protein binding of, 1108t in renal failure, action and effects of, 2266-2267 routes of administration, 1106t, 1120t and sleep, 1234 for status epilepticus, 1099 for Sydenham’s chorea, 1808 in systemic lupus erythematosus, 1814 in uremic encephalopathy, 2238 volume of distribution, 1108t Volume 1: pages 1–1180

Phenol, for motor blockade, 2367 Phenothiazine(s) lupus syndrome induced by, 1811-1812 in renal failure, encephalopathy induced by, 2266 toxicity of, 2188-2189 Phenoxybenzamine, for micturition disorders, 2165, 2165t Phenylalanine elevated levels of, 360, 360f, 570 in biopterin disorders, 574-575 in neurotransmitter deficiencies, 759-761, 760f, 760t nonphenylketonuria, 570 in phenylketonuria, 360, 570-574 in Segawa’s disease, 762 in sepiapterin reductase deficiency, 763 Phenylalanine hydroxylase deficiency, 360, 360f, 569f, 570-574 Phenylalanine loading test, 1283 Phenylalanine lyase, for phenylketonuria, 574 Phenylalanine metabolism defects, 360, 360f, 570-575 Phenylketonuria, 360, 360f, 569f, 569-574 and autism, 918 classic, 570 classification of, 569-570 clinical manifestations of, 570-571 diagnosis of, 571 diet therapy for, 570, 572-574 genetic counseling in, 572 genetics of, 571 genotype-phenotype correlations in, 572 geographic distribution of, 571 maternal syndrome of, 571 MRI findings in, 352t, 570, 573 novel therapies for, 574 pathogenesis of, 571-572 proton MR spectroscopy in, 182 screening for, 570 teratogenicity in, 2197t treatment of, 572-574 Phenylpropanolamine, for micturition disorders, 2165t Phenytoin absorption of, 1114 adverse effects of, 271, 1022, 1122-1124, 1435, 2264-2265 pharmacogenetics of, 2195 as antiepileptic agent, 1051t acute therapy with, 270 chronic therapy with, 271 for focal seizures, 1050 for generalized seizures, 1022, 1023t for Lennox-Gastaut syndrome, 1032 in leukemia, 1737 in malaria, 1660 mechanism of action, 1002, 1003f, 1119t for neonatal seizures, 269t, 270 for status epilepticus, 1098t, 1099-1100 in systemic lupus erythematosus, 1814 testing of, procedures for, 1002 for tonic seizures, 1023t in traumatic brain injury, 1427-1428, 1435 in uremic encephalopathy, 2238 bioavailability of, 1106t-1107t, 1114 blood level of, 1051t chorea induced by, 1279-1280 for cyclical vomiting syndrome, 2286 discontinuation of, 1126 dosage of, 1022, 1051t initial maintenance, 1107t loading, 1109t drug interactions of, 1118, 2195-2196, 2218

Volume 2: pages 1181–2408

Index Phenytoin continued elimination of, 1107t exacerbation of myoclonic seizures by, 1031, 1074t for Fabry’s disease, 670 formulations of, 1106t-1107t generic formulations of, 1116 and gingival hyperplasia, 1022, 1123-1124 half-life of, 1107t, 1114-1115 hypersensitivity to, 1125 intramuscular injection of, adverse reactions to, 2195 lupus syndrome induced by, 1811-1812, 2265 metabolism of, 1107t, 1114-1115 nephrotoxicity of, 2264-2265 for neuronal ceroid lipofuscinosis, 703 for nonepileptic paroxysmal disorders, 1213t, 1214, 1297 optimal range of, 1117t and osteomalacia, 1124 for peripheral nerve hyperexcitability, 2105 pharmacokinetics of, 270, 1022, 1106t-1107t, 1114-1115 pharmacology of, 270 plasma concentration of, 1114-1115, 1115f practical guide to, 1051t preparations of, 1051t, 1114 protein binding of, 1107t, 1114 in renal failure, action and effects of, 2266-2267 routes of administration, 1106t-1107t for Schwartz-Jampel syndrome, 2099 teratogenicity of, 364 and vertigo, 133 volume of distribution, 1107t, 1114 Pheochromocytoma(s), in von Hippel-Lindau syndrome, 785-786 Philadelphia cervical collar, 1544 Phobia(s), with mental retardation, 815 Phonic tics, 887, 1298 Phonologic assessment, 864 Phonologic model, of dyslexia, 856-857, 867 Phonologic programming disorder, 848-849 Phonologic syntactic syndrome, 849 Phonology, 907t Phorias, 21 Phosphate(s) in muscle metabolism, 1851 in uremic encephalopathy, 2235-2236 Phosphodiesterase-4 inhibitors, for Rubinstein-Taybi syndrome, 274 Phosphofructokinase deficiency, 635-636, 2032-2033 biochemistry of, 635, 2033 clinical manifestations of, 622t, 635-636, 2032 enzyme defect in, 622t genetics of, 636, 2032-2033 glycogen structure in, 622t laboratory tests in, 636, 2032 muscle biopsy in, 2032-2033 pathophysiology of, 2033 treatment of, 2033 Phosphoglucomutase deficiency, 637 clinical manifestations of, 622t, 637 enzyme defect in, 622t glycogen structure in, 622t Phosphoglucose isomerase, 636-637 Phosphoglycerate kinase deficiency, 637, 2033-2034 biochemistry of, 2034 clinical features of, 2033 genetics of, 2034 laboratory tests in, 2034 muscle biopsy in, 2034 pathophysiology of, 2034

Phosphoglycerate mutase deficiency, 637, 2034-2035 biochemistry of, 2034 clinical features of, 2034 genetics of, 2035 laboratory data in, 2034 muscle biopsy in, 2034 pathophysiology of, 2035 Phosphohexose isomerase deficiency, 636-637 clinical manifestations of, 622t, 636-637 enzyme defect in, 622t glycogen structure in, 622t Phospholipases, in hypoxic-ischemic injury, 1475-1476, 1475f Phospholipids, in hypoxic-ischemic injury, 1475-1476, 1475f Phosphomannomutase II, in congenital glycosylation disorder, 649, 650t Phosphomannose isomerase, in congenital glycosylation disorder, 649-651, 650t Phosphorous magnetic resonance spectroscopy, 178-179 in brain death, 1561-1562 Phosphorylase activation, 623-624, 624f Phosphorylase deficiency. See Myophosphorylase deficiency Phosphorylase kinase deficiency, 636, 2028-2029 biochemistry of, 2029 clinical manifestations of, 622t, 2028 enzyme defect in, 622t glycogen structure in, 622t laboratory features of, 2028-2029 molecular genetics of, 2029 treatment of, 2029 Photic stimulation, in EEG, 216, 221, 221f, 233, 1019-1020, 1020f Photoelectric effect, in EEG, 221 Photomyoclonic effect, in EEG, 221 Photophobia, in mental retardation/developmental delay, 812b Photopsia, in migraine, 1189 Photosensitivity in developmental disorders, 834t in epileptiform EEG, 216, 221, 221f, 233, 1019-1020, 1020f in mental retardation/developmental delay, 813b Phototherapy for delayed sleep phase syndrome, 1234 for kernicterus, 2301 Phrenic nerve, 28t injury or palsy, postoperative, 2215 in uremic neuropathy, 2248 Phycomycosis, 1638-1640 clinical characteristics of, 1638-1639 CNS syndromes in, 1632t diagnosis of, 1632t, 1638-1639 geographic distribution of, 1632t laboratory tests in, 1638-1639 management of, 1632t, 1639-1640 rhinocerebral, 1638 risk factors for, 1632t Physical and Neurological Examination for Soft Signs (PANESS), 872 Physical examination, of older child, 17-33 Physical medicine and rehabilitation physicians, 2360 Physical therapists, 2360 Physical therapy for cerebral palsy, 2359-2360, 2359f for muscle overreactivity (spasticity), 2366 for spinal cord injury, 1544 Physician, ethical duties of, 2391-2392 Physician-assisted suicide, 2395-2396 Volume 1: pages 1–1180

Volume 2: pages 1181–2408

lxxvii

Physostigmine for anticholinergic toxicity, 2191 for antidepressant toxicity, 2189 for gamma-hydroxybutyrate toxicity, 2186 Phytanic acid deficiency, infantile, 741-742 in peroxisomal disorders, 743, 743t, 744, 1908-1909 Phytanoyl-CoA hydroxylase A deficiency, 751 Pia mater, 1402, 1402f Pial synangiosis, in moyamoya disease, 1773 Pica, in autism, 916 Picornaviruses, 1595b, 1610-1611 clinical features of, 1610-1611 diagnosis of, 1611 neuroimaging in, 1611, 1611f outcome of, 1611 treatment of, 1611 Piebaldism, hearing loss with, 105t Pierre Robin syndrome, 465t Piglet asphyxia model, 298 Pigmentation disorders. See also specific disorders in developmental disorders, 833t hearing loss with, 105t in incontinentia pigmenti, 788-789 in incontinentia pigmenti achromians, 789 in Menkes’ disease, 1322 in neurocutaneous melanosis, 787-788 in neurofibromatosis type 1, 772-773 in tuberous sclerosis complex, 779, 779f Pili torti, in Menkes’ disease, 1322 Pilocytic astrocytoma, 1718 age at diagnosis, 1693 hypothalamic, 1700 incidence of, 1687, 1719t survival rates with, 1689t, 1718 Pimozide, 967-968 adverse effects of, 968 anticholinergic effect of, 965t clinical applications of, 967 clinical management of, 967 dosage of, 965t, 967 drug interactions of, 968 extrapyramidal effect of, 965t labeled and off-labeled use of, 938t pharmacology of, 967 potency of, 965t preparations of, 965t sedative effect of, 965t for Sydenham’s chorea, 1808 for tic disorders, 896, 967 Pindolol, for orthostatic hypotension, 2143 Pineal region tumors, 1703-1705 clinical presentation of, 1704 incidence of, 1703-1704 management of, 1705 neuroimaging of, 178, 182f, 1704, 1705f tumor markers and survival in, 1704t Pineoblastoma(s), 1704 classification of, 1691 in infants and very young children, 1725, 1729 management of, 1705 Pineocytoma(s), 1704 Ping-pong skull fracture, 336, 1417 PINK1 gene, in Parkinson’s disease, 729 Pinna anatomy of, 97 physiology of, 100 Pipecolic acid oxidase, 739 L-Pipecolic acid oxidase defects, 743, 743t Piracetam for breath-holding spells, 1206 for myoclonus, 1295 Piriform cortex, 137f Pitt-Rogers-Danks syndrome, genetics of, 556t

lxxviii

Index

Pituitary adenoma, 1707, 2117, 2121 Pituitary gland anatomy and physiology of, 2113-2114, 2114f embryology of, 383, 2113-2114 Pituitary gland disorders, 2113-2125 of glucocorticoid production, 2118-2120 of pubertal development, 2114-2118 of statural growth, 2120-2121 of water balance, 2123-2125 Pituitary hormones, 2113 deficiencies of, 2116-2117 Pizotifen, for migraine prevention, 1194t Placidyl. See Ethchlorvynol Placing reflex, 44, 50 Plagiocephaly, 1523 deformational, 438-441, 445 diagnosis of, 440-441 frontal, 438-440, 441t incidence of, 438 posterior, 438-440, 441t versus synostoses, 441t treatment of, 440-441 Plain film(s) of cephalohematoma, 335, 335f in micturition disorders, 2164 spinal, 195 of spinal cord injury, 339, 340f, 1535, 1545f of spinal cord tumors, 1731, 1731f Plantar creases, in gestational age estimation, 53t, 57t Plantar sign, 19, 40, 51 Planum temporale asymmetry, and language development, 850-851 Plasma osmolality of, 154t solute concentrations in versus CSF, 153, 154t Plasma concentration, of drugs, 1105 Plasma exchange for multiple sclerosis, 1349 for thrombotic thrombocytopenic purpura, 2254 Plasmalogen synthesis, 735, 738 defects of, 743, 743t, 745, 750-751 Plasmapheresis for chronic inflammatory demyelinating polyneuropathy, 1894, 1932 for Guillain-Barré syndrome, 1893-1894, 1927-1929, 1928t for Lambert-Eaton myasthenic syndrome, 1957-1958 for myasthenia gravis, 1955 safety, in children, 1928-1929 Plasminogen activator inhibitor-1 in neonatal stroke, 332 in post-hemorrhagic hydrocephalus, 321 Plasmodium, 1656-1657. See also Malaria Plasmodium falciparum, 1656-1657 Plasmodium malariae, 1656-1657 Plasmodium vivax, 1656-1657 Plasticity and arterial ischemic stroke, 1763 in developing brain, 1404-1405 as “double-edged sword,” 1151 and dyslexia, 859-861, 860f experience-dependent, 1404 of muscle, 1838-1839 and seizure susceptibility, 1001-1002 with sensory loss, 115 and traumatic brain injury, 1404-1405, 1407 Platelet(s), in thromboembolism, 1762 Platelet-derived growth factor in Duchenne muscular dystrophy, 1976 in oncogenesis, 1748 Platinum agent toxicity, 2192-2193

Platybasia, 461-462 Plavix (clopidogrel), for stroke, 1777-1778 Play, in autistic disorder, 908 Pleconaril, for acute cerebellar ataxia, 1247 Plectin, 1845 diseases associated with, 1842t, 1845 Plexiform neuroma(s), 773, 773f, 776 Plexopathies, postoperative, 2215 PLP gene, in Pelizaeus-Merzbacher disease, 1355-1356 PMM2 gene, in congential glycosylation disorder, 649, 650t PMP22 gene, in neuropathy, 1897, 1900 Pneumococcal conjugated vaccine, 2350 Pneumonia, in spinal muscular atrophy, 1864, 1867 Point mutations, of mitochondrial DNA, 728-729, 2054 affecting protein-coding genes, 728-729 affecting synthetic genes, 729 Pointes lents diphasiques frontales, 217 Poison control centers, 2198-2199 Poisoning, 2173-2199. See also specific causative agents accidental, 2173 ataxia in, 2177-2178, 2180b autonomic dysfunction in, 2149 biologic toxin, 2181-2182 in child abuse, 2173-2174 cranial nerve involvement in, 2175-2177, 2177t drugs of abuse, 2186-2191 emergency evaluation of, 2174-2181 emergency management of, 2174-2181, 2174b environmental, 2181-2186 epidemiology of, 2173 extrapyramidal reactions in, 2177, 2179b insecticide, 2182-2183 Internet resources on, 2198-2199 most common agents in, 2173 myoclonus in, 2177, 2179b myopathies in, 2177, 2178b nerve agent, 2183-2184 neurologic examination in, 2175-2178 nonaccidental, 2173-2174 paralysis and rigidity in, 2177, 2179b peripheral neuropathy in, 2177, 2178b seizures in, 2175, 2176t-2177t sensorium changes in, 2175, 2176t-2177t in suicide, 2173 testing for, 2174-2175 toxidromes in, 2178-2181 tremors in, 2178, 2180b Polarity localization, in EEG, 204 Poliodystrophia cerebri progressiva. See Alpers’ disease Poliodystrophies, 823t cognitive and motor regression in, 827t Polio-like syndromes, 1874-1875 Poliomyelitis, 1597, 1610-1611, 1873-1874 anterior horn cells in, 1874 clinical features of, 1610-1611, 1874 laboratory tests in, 1874 management of, 1874 nonparalytic, 1873-1874 Poliomyelitis vaccine, 1596f, 1610, 2345 and Guillain-Barré syndrome, 1927 inactivated, 2346 enhanced potency trivalent, 2349 neurologic complications of, 2346, 2349 oral, 2346, 2349 Poliosis, in tuberous sclerosis complex, 779 Poliovirus receptor-like-1 gene (PVRL1), in cleft lip/palate, 467, 467t POLIP syndrome, 2287-2288 Volume 1: pages 1–1180

PolyA tail, 513 Poly-adenosine diphosphate-ribose-synthetase (PARS), 1477 Polyangiitis overlap syndrome, 1825 Polyarteritis nodosa, 1819-1820 angiography in, 1819-1820, 1819f laboratory findings in, 1818t, 1819 neurologic manifestations of, 1818t, 1819-1820 treatment of, 1820 Polychlorinated biphenyls in breast milk, 2196 teratogenicity of, 2198 Polygenic inheritance, 535 Polymerase chain reaction (PCR), 522, 522f in brain tumor assessment, 1691 in cytomegalovirus, 1606 in herpes simplex virus, 1605 in HIV, 1621-1622 in meningitis, 1575 in Menkes’ disease, 1322 in muscular dystrophy, 1980 in parasitic diseases, 1646 in rabies virus, 1619 in viral infections, 1602, 1602t Polymerase gamma gene (POLG), in Alpers’ disease, 1327 Polymers, for drug delivery, 1746 Polymicrogyria, 421-425 antenatal diagnosis of, 425 and cerebral palsy, 493 clinical characteristics of, 422 EEG findings in, 422 epidemiology of, 400 frontal, 423t bilateral, 422-423 frontoparietal, 423t bilateral, 421f, 423 genetic counseling in, 425 genetic testing for, 424-425 genetics of, 412t and language disorders, 850 lateral parieto-occipital, 423t management of, 425 megalencephaly with, 408 mesial parieto-occipital, 421f, 423t, 424 microcephaly with, 403t, 405, 422, 423t MRI findings in, 421f, 422 occipital, 424 outcome of, 425 parasagittal, 423t pathogenesis of, 365, 422 pathology of, 421-422 perisylvian, 421f, 422-424, 423t posterior-temporal, 423t syndromes of, 422-424, 423t Polyminimyoclonus, 1864 Polymorphisms, 518-519 detection of, 522-523 Polymyositis, 2079-2080 clinical features of, 2079 laboratory features of, 2079-2080 muscle biopsy in, 2080, 2080f in overlap syndromes, 2079, 2079f pathogenesis of, 2080 treatment of, 2080 Polyneuritis, CSF protein content in, 162t Polyneuritis cranialis, 1922t, 1924 Polyneuropathy acute inflammatory demyelinating. See Guillain-Barré syndrome chronic inflammatory demyelinating, 1894, 1922t, 1931-1934 clinical features of, 1894, 1931-1932 CSF analysis in, 1894, 1930t diagnostic criteria for, 1930t

Volume 2: pages 1181–2408

Index Polyneuropathy continued electrophysiologic findings in, 1894, 1930t, 1932 epidemiology of, 1931 incidence of, 1931 laboratory findings in, 1930t, 1932 in liver transplant patients, 2298 pathologic findings in, 1894, 1894f, 1932-1933, 1933f prognosis of, 1933 treatment of, 1894, 1932-1933 critical illness, 1911, 2216 familial amyloid, 2145, 2260, 2260t postoperative, in cardiac surgery, 2215-2216 Polypeptide(s), structure and function of, 510-511 Polyploidy, 546, 549-550 clinical features of, 549-550 cytogenetics of, 549 management of, 550 Polyradiculoneuropathy. See Polyneuropathy Polysomnography, 203, 1225, 1226f in breath-holding spells, 1204-1205 in mentally retarded patients, 274 nocturnal, 1227, 1229f in central sleep apnea, 1230f in narcolepsy, 1232 in obstructive sleep apnea, 1229f, 1230 in periodic hypersomnia, 1233 in restless legs syndrome, 1233 in upper airway resistance syndrome, 1230 in nocturnal enuresis, 2162 normative values for children, 1228t Polyuria, nocturnal, 2138 POMGnT1 gene, 412t, 416f, 417-418, 650t, 1842t Pompé’s disease, 621, 626-628, 698-699, 2027-2028 biochemistry of, 626-627, 2027-2028 clinical manifestations of, 622t, 627, 627f, 698, 2027 diagnosis of, 699 enzyme defect in, 622t genetics of, 628, 699, 2027-2028 glycogen structure in, 622t hearing loss with, 699 laboratory tests in, 627-628, 2027 management of, 628, 699, 2028 MRI findings in, 698 pathology of, 626, 2027 POMT1 gene, 412t, 418, 650t, 653-654, 1842t Pontocerebellar hypoplasia, 393-394 clinical course of, 394 with dyskinesia, 394 MRI findings in, 393-394 with spinal muscular atrophy, 394, 1868t type 1, 394 type 2, 394, 1288 Pope John Paul II, on euthanasia, 2395 Popeye configuration, in facioscapulohumeral muscular dystrophy, 1999 Popliteal angle, in preterm infants, 54f-55f, 58-61, 59f, 60t, 61f Porencephalic cyst, 1402f Porencephaly, 317 magnetic resonance imaging of, 317, 319f ultrasound of, 317, 318f Pork tapeworm, 1669-1670, 1669f. See also Cysticercosis Porphyria(s), 2292-2293 acute intermittent, 1905-1906, 2195, 2292 erythropoietic, 2292 hepatic, 2292 Portosystemic encephalopathy, chronic, 2294-2295 Port-wine stain, in Sturge-Weber syndrome, 782 Poser criteria, for multiple sclerosis, 1347

Position effect, in inversion, 546 Positional plagiocephaly, 438-441. See also Plagiocephaly, deformational Positive peak, 247 Positron emission tomography (PET), 167, 195-196 α-[11C]methyl-L-tryptophan (AMT), 1154, 1161 in autistic disorder, 916 in autonomic assessment, 2136-2137, 2140 in brain death, 1561 of brain tumors, 196, 1696 in dyslexia, 857 in epilepsy, 196 flumazenil, 1161 fluorodeoxyglucose (FDG), 1160-1161, 1160f of hypoxic-ischemic injury, 283 indications for, 196 in intraventricular hemorrhage, 312 in Landau-Kleffner syndrome, 1058 in localization-related epilepsy, 1154 preoperative, for epilepsy surgery, 1160-1161, 1160f in sports concussion, 1416, 1416f in Sturge-Weber syndrome, 783 in vegetative state, 1380 Postconcussive syndrome, 1415, 1436 Posterior cerebral artery, 1760-1762, 1761f Posterior circulation, 1760-1762, 1761f-1762f Posterior fontanel, 436 Posterior fossa arachnoid cyst, 433-434, 1709 Posterior fossa hemangioblastoma, 786, 1709 Posterior fossa hematoma, 1414 Posterior fossa tumors, 73, 1709-1718. See also specific types and anatomic sites Posterior laminectomy, 1546 Posterior lobe, 1241, 1242f Posterior occipital transients, 221, 224f Posterior reversible leukoencephalopathy syndrome, 2175, 2239-2240 Posterior slow waves of youth, 219-220, 220f Posterior spinal cord syndrome, 1538-1539 Posterior tibial muscle, testing of, 34t Postganglionic fibers, 2129 Postictal phase, of generalized tonic-clonic seizures, 1019, 1022 Postpolio syndrome, 1611 Postpump seizures, 2212-2213 Postsynaptic defects, in congenital myasthenic syndromes, 1960-1961, 1961t Postsynaptic potentials, 207 Post-traumatic stress disorder, after cardiac arrest, 1506 Postural hypotension. See Orthostatic hypotension Postural instability, in parkinsonism, 1291-1292 Postural reactions in comatose patient, 1388 evaluation of, 126 Postural strangulation, 1488 Postural tachycardia syndrome, 2151f, 2152 Postural tone, 65 Postural tremor, 1290 Posture of preterm infant, 54f-55f, 57 spinal cord tumor and, 1730 Potassium, 2326 abnormal concentrations of, 2326-2328. See also Hyperkalemia; Hypokalemia in cerebrospinal fluid, 154t extracellular concentration of, 2326 in traumatic brain injury, 1405-1406 in uremic encephalopathy, 2236 Potassium bromide, for epilepsy, 1152 Potassium channel(s), 994 A-current, 994 Volume 1: pages 1–1180

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lxxix

Potassium channel(s) continued in benign neonatal familial convulsions, 266-267 calcium-dependent, 994t delayed-rectifying, 994 in epilepsy, 994, 998, 1001-1002 glial cells and, 998 in immature brain, and seizure susceptibility, 1001-1002 inward-rectifying, 994 leak conductance in, 994 M-current, 994 voltage-gated, 994, 994t Potassium channel blockers, for spinal cord injury, 1542 Potassium chlorate poisoning, 2185-2186 Potassium chloride, for hypokalemic periodic paralysis, 2098 Potocki-Shaffer syndrome, genetics of, 556t Powassan virus, tick-borne, 1616 Prader-Willi syndrome, 558 autism in, 919 clinical features of, 557f diagnostic criteria for, 558t genetics of, 544f, 556t, 557-558, 557f, 558t muscular tone in, 69 Pragmatics, verbal and nonverbal, 907t Pralidoxime, for insecticide poisoning, 2183 Pramipexole for Parkinson’s disease, 1293 for restless legs syndrome, 1233 Praziquantel for cysticercosis, 1671, 2082 for echinococcosis, 1669 for paragonimiasis, 1674 for schistosomiasis, 1673 Prealbumin, in CSF, 161 Prechordal plate, 379 Precocious puberty, 2115-2116 definition of, 2115 diagnosis of, 2115-2116 hypothalamic tumors and, 1701, 1701f, 2115-2116, 2115f idiopathic, 2115 incidence of, 2115 management of, 2116 Preconditioning, and hypoxic-ischemic injury, 305 Prednisone adverse effects of, 1953, 1983, 2251 for astrocytoma, 1721 for chronic inflammatory demyelinating polyneuropathy, 1932 for dermatomyositis, 2078 for Duchenne muscular dystrophy, 1975, 1982-1983 for Lambert-Eaton myasthenic syndrome, 1957 for medulloblastoma, 1711 for myasthenia gravis, 1952-1953 for peripheral nerve hyperexcitability, 2105 for sarcoid myopathy, 2080 for stroke, 1779 for Sydenham’s chorea, 2225 for Wegener’s granulomatosis, 1822 Pre-eclampsia, and neonatal stroke, 330 Preferential looking test (PLT), 78, 78f Pregabalin absorption of, 1115 bioavailability of, 1107t, 1115 dosage of, 1108t elimination of, 1108t formulations of, 1107t mechanism of action, 1119t metabolism of, 1108t and myoclonic seizures, 1075 pharmacokinetics of, 1107t-1108t, 1115

lxxx

Index

Pregabalin continued protein binding of, 1108t routes of administration, 1107t volume of distribution, 1108t Preganglionic fibers, 2129 Pregnancy autonomic dysreflexia in, 2361 folate requirements in, 2319 Premature Infant Pain Profile (PIPP), 2374 Prematurity. See Preterm infant(s) Premutation, 559, 559t Premyoblasts, 1837, 1838f Prenatal diagnosis, 537, 548-549. See also specific disorders imaging modalities for, 167 indications for, 549, 549b ultrasound for, 167-170, 167f, 537, 549 Pre-reading assessment, 864-865 President’s Commission, brain death guidelines of, 1553, 1554b Pressure palsies, postoperative, 2215 Pressure passive blood flow, in preterm infants, 299, 310 Pressure transducer, for monitoring intracranial pressure, 1423, 1515-1516 Pressure-volume relationship, 1513, 1514f-1515f Presynaptic defects, in congenital myasthenic syndromes, 1959-1960, 1961t Presyncope, 1210 Preterm infant(s), 52-62 adverse drug reactions in, 2196-2197 ankle dorsiflexion in, 54f-55f arm recoil in, 54f-55f body attitude (posture) of, 54f-55f, 57 cerebral palsy in, 491, 493 cranial nerve evaluation in, 59-60 designation and definition of, 53 electrophysiologic assessment of, 53t, 54, 210-217 environmental interaction by, 55-56 general examination of, 53-54 gestational age of, estimation of, 53-54, 53b, 53t, 54f-55f, 56, 56f head growth patterns of, 61-62, 61f-62f head lag in, 54f-55f, 58 hearing loss in, 110 heel-to-ear maneuver for, 54f-55f, 58, 59f hypoxic-ischemic injury in, 280, 287-289, 287t intraventricular hemorrhage in, 309-325 leg recoil in, 54f-55f muscle tone of, 57-61, 58f-59f, 66-67 neurodevelopmental disability in, 309, 310f neuroimaging in, 316-320. See also specific imaging modalities recommendations for, 319-320 neurologic examination of, 52-62 challenges in, 52-53 scoring system and techniques for, 54f-55f, 56, 57t popliteal angle in, 54f-55f, 58-61, 59f, 60t, 61f prognosis for, 62 prone position of, 60, 61f reflex assessment in deep tendon, 56-57, 56f, 58t developmental, 60-61, 60t retinopathy of, 82 scarf sign in, 54f-55f, 58, 59f sleep cycle in, 222-223 square window test in, 54f-55f ventral suspension of, 54f-55f Primaquine, for malaria, 1659 Primary amebic meningoencephalitis, 1649-1650 causative agent of, 1649, 1649f-1650f classification of, 1647t

Primary amebic meningoencephalitis continued clinical characteristics of, 1647t, 1649-1650 diagnosis of, 1647t, 1649-1650, 1650f differential diagnosis of, 1650 epidemiology of, 1649 geographic distribution of, 1647t, 1649 laboratory tests in, 1649-1650 management of, 1647t, 1650 microbiology of, 1649 mode of infection, 1646, 1647t, 1649 pathology of, 1647t, 1649, 1649f risk factors for, 1647t Primary angiitis, 1771 Primary head shape syndrome, 444t Primase, 508 Primidone adverse effects of, 1122 bioavailability of, 1107t blood level of, 1051t in breast milk, 2196-2197 dosage of, 1051t, 1108t elimination of, 1108t formulations of, 1107t metabolism of, 1108t for myoclonus, 1294 for neonatal seizures, 271 optimal range of, 1117t pharmacokinetics of, 1107t-1108t practical guide to, 1051t preparations of, 1051t protein binding of, 1108t in renal failure, action and effects of, 2267 routes of administration, 1107t for tremor, 1291 volume of distribution, 1108t Primitive neuroectodermal tumor(s), 1722-1724 age at diagnosis, 1693 chemotherapy for, 1723, 1723f classification of, 1691, 1722 clinical characteristics of, 1722 diagnosis of, 1723 incidence of, 1719t, 1722 in infants and very young children, 1725, 1729 management of, 1723-1724 versus medulloblastoma, 1709, 1723 neuroimaging of, 1723, 1723f pathology of, 1722 radiation therapy for, 1698, 1723 surgery for, 1723 survival rates with, 1690t, 1723 Primitive reflexes, evaluation of, 42-44, 43t, 50 Principlism, 2389-2390 Prion disease, 1598 Prion protein, 2260t Probably symptomatic epilepsies, 1046-1047 Proband, 532, 535 Probst’s bundles, 386 Procainamide lupus syndrome induced by, 1811 for Schwartz-Jampel syndrome, 2102 Procarbazine for oligodendroglioma, 1724 for primitive neuroectodermal tumors, 1723, 1729 Proctoscopy, 2167 Prodrome for acute cerebellar ataxia, 1246 for generalized tonic-clonic seizures, 1019 for migraine, 1188 for neurocardiogenic syncope, 1210 Pro-drugs, 1746 Programmed cell death. See Apoptosis Progression movements, as neonatal seizure, 258, 258t, 260 Progressive bulbar paralysis of childhood, 1869-1870 Volume 1: pages 1–1180

Progressive conditions, 7 Progressive dialysis encephalopathy, 2242, 2246 Progressive myoclonic ataxia (Ramsay-Hunt syndrome), 109, 1254, 1295, 1608-1609 Progressive myoclonic epilepsies (PMEs), 1072t, 1073-1074 age of onset, 1248t EEG findings in, 1073, 1073b genetics of, 1248t Progressive neuronal degeneration of childhood with liver disease. See Alpers’ disease Progressive poliodystrophy. See Alpers’ disease Progressive systemic sclerosis, 1816 Prolactin disorders of, 2118 normal biochemistry and physiology of, 2118 Prolactinoma, 2118 Prometaphase, 513-514, 514f-515f Pronator muscles, testing of, 34t Pro-opiomelanocortin receptors, in appetite regulation, 2123 Propantheline for micturition disorders, 2165t for neurocardiogenic syncope, 1211b Propellant intoxication/poisoning, 2186 Prophase, 513-514, 514f-515f Propionic acidemia, 353-354, 353t, 585-587, 586f clinical manifestations of, 587 diagnosis of, 587 treatment of, 587 Propionyl-coenzyme A carboxylase (PCC), 723, 2317 deficiency of, 585-587, 586f, 2317 Propofol for sedation, 2378 for status epilepticus, 1100 in traumatic brain injury, 1422 Propoxyphene, fetal/neonatal effects of, 2196 Propranolol for ADHD, 880t for chronic daily headache prevention, 1196t, 1197 for cyclical vomiting syndrome, 1217, 2286 for migraine prevention, 1194t for myoclonus, 1294 for neurocardiogenic syncope, 1211b for nonepileptic paroxysmal disorders, 1213t for orthostatic hypotension, 2143 for shuddering attacks, 1219 for thyrotoxic periodic paralysis, 2101 for tremor, 1291 Propylene glycol, adverse reactions to, 2194 Propylthiouracil, teratogenicity of, 2197t Prosencephalon, 379-380, 380f, 382-383 absence of, 385-386 cleavage of, 382-383, 395 developmental disorders of, 383t, 395-398 formation of, 382-383 midline development in, 382-383, 382f patterning of, 382-383 Prosody, 907t Prosomeres, 382-383 Prostaglandin(s) degradation of, 738 in hepatorenal syndrome, 2259 Prostaglandin receptor(s), in hypoxic-ischemic injury, 299 Prostaglandin synthetase inhibitors, for orthostatic hypotension, 2143 Prosthetic heart valves, and emboli, 1767 Protease(s), in hypoxic-ischemic injury, 1475 Protease inhibitors, for HIV infection, 1622

Volume 2: pages 1181–2408

Index Protective protein/cathepsin A defects, 694 Protein(s). See also specific types accumulation, in core disease, 2015-2016, 2016t contractile, 1839-1840, 1840f in CSF, 160f, 160t, 161-162 as brain injury markers, 161-162 in intraventricular hemorrhage, 320 in neurologic disorders, in adults, 162t cytoskeletal, 1841-1845, 1841f, 1969, 1970f and human disease, 1842t, 1969, 1970f structure and function of, 510-511 Protein binding, of drugs, 1109-1110, 1110f children’s physiology and, 1117-1118, 1117t Protein C activated, in bacterial meningitis, 1582 deficiency of and sinovenous thrombosis, 1785 and stroke, 1767-1768 in neonatal stroke, 332 Protein disorder(s), leukoencephalopathies, 1345, 1346t Protein importation defects, 727, 2059 Protein kinase(s), in hypoxic-ischemic injury, 1475 Protein restriction, for urea cycle disorders, 612 Protein S, in neonatal stroke, 332 Protein synthesis, in hypoxic-ischemic injury, 1504-1505 Protein truncation test (PTT), 523 Protein-calorie malnutrition, 2304 Protein-coding L genes, point mutations affecting, 728-729 Protein-energy malnutrition, 2302-2304 Proteolipid protein, in Pelizaeus-Merzbacher disease, 1356 Proteomics, in mental retardation, 807 Proteus, 1589 Proteus syndrome, 787t with hemimegalencephaly, 403t, 409 with megalencephaly, 408 Prothrombin G20210A mutation and intraventricular hemorrhage, 312-313, 312t and stroke, 332, 1767 Prothrombin time, in neonatal stroke, 331-332, 331b Prothrombotic disorders and sinovenous thrombosis, 1782, 1785 and stroke, 331-332, 331b, 1767-1768, 1781 Proton MR spectroscopy, 178-184 in ADHD, 875 advantages of, 195 in Alpers’ disease, 1327 in brain death, 1561-1562 of brain tumors, 183-184, 186f after cardiac arrest, 1495-1497, 1496f-1497f in coma, 1396-1397 diseases studied with, 180-184 in epilepsy, 182-183 functional, 191 of hydrocephalus, 430 in hypoxic-ischemic injury, 182, 185f, 300 in ketogenic diet studies, 1138 in maple syrup urine disease, 577, 578f in mental retardation, 807 in near-drowning, 1487 spectral metabolites in, 179-180, 184f in vegetative state, 1380 Proton pump inhibitors, for gastroesophageal reflux, 2286-2287 Protozoal infections, 1646-1664. See also specific infections Protriptyline for cataplexy, 1232 pharmacology of, 946

Proud’s syndrome, 385t Pro-urokinase, 1778-1779 Proximal myotonic myopathy. See Myotonic dystrophies, type 2 Prozac. See Fluoxetine Pseudallescheria boydii, 1640. See also Allescheriosis Pseudo-ADHD, 874 Pseudoautosomal inheritance, 533 Pseudobulbar palsy, herpes simplex virus and, 1605f, 1606 Pseudocholinesterase deficiency, 2195 Pseudodominant inheritance, 533 Pseudoephedrine, for neurocardiogenic syncope, 1211b Pseudo-Hurler polydystrophy, 696-697 Pseudomonas aeruginosa meningitis, 1580t, 1581 Pseudopapilledema, 90 Pseudotumor cerebri. See Idiopathic intracranial hypertension Psoriatic arthritis, 1806 Psychiatric disorder(s) with epilepsy, 1172-1173 with mental retardation, 815 paradoxical/forced normalization of, 1173 Psychic symptoms, with simple partial seizures, 1043 Psychogenic dystonia, 1284 Psychogenic syncope, 1212-1213 Psychogenic tremor, 1290-1291 Psychologists, 2361 Psychopharmacology, 937-971. See also specific drugs and disorders benefits versus risks of, 937-938 labeled and off-labeled use of, 937, 938t safety and efficacy of, 937 PTCH gene, and holoprosencephaly, 396 Pterin(s), in dopa-responsive dystonia, 1283 Pterin-4α-carbinolamine dehydratase (PCD) deficiency, 574-575, 761 Pterygoid muscle, 22-23 Ptosis, 22, 88 muscular tone and, 68 in myasthenia gravis, 1942-1944, 1944f, 1946 Puberty definition of, 2114 delayed or arrested, 2116-2118 evaluation of, 2117 management of, 2117-2118 developmental disorders of, 2114-2118 normal physiology of, 2114-2115 precocious, 2115-2116 definition of, 2115 diagnosis of, 2115-2116 hypothalamic tumors and, 1701, 1701f, 2115-2116, 2115f idiopathic, 2115 incidence of, 2115 management of, 2116 PubMed, 2404, 2406 Pudendal nerve, 29t Pull test, for postural instability, 1291-1292 Pulmonary edema, intracranial pressure and, 1518 Pulmonary embolism, 2362-2363 clinical findings in, 2362-2363 heparin for, 1776 incidence of, 2362-2363 risk factors for, 2363 in spinal cord injury, 1544 treatment of, 2363 Pupil (eye) assessment of, 80-81 in comatose patient, 1387 in infants, 39 Volume 1: pages 1–1180

Volume 2: pages 1181–2408

lxxxi

Pupil (eye) continued in older child, 20 in autonomic dysfunction, 2132, 2140, 2152 in poisoning, 2175 white (leukocoria), 80-81, 80f Pure autonomic failure, 2151f catecholamines in, 2138f sympathetic skin response in, 2137, 2139f Pure cholinergic dysautonomia, 2143-2144 barium exam contraindicated in, 2143, 2143f clinical features of, 2143 differential diagnosis of, 2143-2144 sympathetic skin response in, 2137, 2139f treatment of, 2143 Pure pandysautonomia, 2143-2144 Purine bases, 507-508, 508f Purine biosynthesis defects, 359, 359f clinical features of, 350t-351t, 359 MRI findings in, 352t Purkinje cells, 1241, 1243f, 1244 Putamen, 1272, 1273f in movement disorders, 1274, 1275f Pyknolepsy, 1025 Pyogenic ventriculitis, diffusion-weighted imaging in, 187 Pyomyositis, 2082 Pyramidal disorders, 1271 Pyrazinamide, for tuberculous meningitis, 1586 Pyridostigmine for Lambert-Eaton myasthenic syndrome, 1957 for myasthenia gravis, 1951 for orthostatic hypotension, 2142 Pyridoxal, 2310 Pyridoxamine, 2310 Pyridoxine (vitamin B6), 2310-2311 for L-amino acid decarboxylase deficiency, 763 deficiency of, 2310 in dialysis patients, 2246 and encephalopathy, 357-358 dependency disorders of, 357-358, 357f, 2305t, 2310-2311 dietary sources of, 2310 for early infantile epileptic encephalopathy, 268 for hyperoxaluria, 751 intoxication, 2311 for McArdle’s disease, 2031 physiologic functions of, 2310 polyneuropathy induced by, 1909-1910 recommended daily requirement for, 2310 for tuberculous meningitis, 1586 Pyrimethamine for granulomatous amebic encephalitis, 1651-1652 for toxoplasmosis, 1656, 2082 Pyrimidine bases, 507-508, 508f Pyruvate in CSF, 163 metabolism of, 717, 721, 722f defects of, 354-355, 717-718, 721, 723-724 Pyruvate carboxylase, 2317 defects of, 354-355, 354f, 718, 723, 2056, 2317 French phenotype of, 723 histopathology of, 718 North American phenotype of, 723 Pyruvate cocarboxylase, in Alpers’ disease, 1327 Pyruvate dehydrogenase defects, 354-355, 354f, 717, 721, 723-724, 2056, 2308 clinical features of, 723-724 histopathology of, 718-719 protein importation defects and, 727 treatment of, 724, 730, 1247t

lxxxii

Index

Pyruvate kinase, 1852 6-Pyruvoyl-tetrahydrobiopterin synthase (PTPS) deficiency, 574-575, 761

Q q (long) arm, of chromosome, 516, 541, 543f Q fever, 1640, 1644 clinical characteristics of, 1641t, 1644 epidemiology of, 1641t geographic distribution of, 1641t incubation period of, 1641t laboratory tests in, 1641t management of, 1641t mode of infection/vector, 1641t, 1644 reservoir for, 1641t Q-banding, 520 Qinghao, for malaria, 1659 QT prolongation syndrome, 1204 Quadriceps muscle, testing of, 34t Quadriceps reflex, 19t Quadriparesis, asymmetric, periventricular hemorrhagic infarction and, 287 Quadriplegia neonatal stroke and, 333 spastic, 42f, 497-498, 500 Quantitative volumetric analysis, 1156 Queckenstedt test, 157 Quercetin, for spinal cord injury, 1543 Quetiapine, 970 adverse effects of, 968, 970 for autism, 924 clinical applications of, 970 clinical management of, 970 dosage of, 967t, 970 drug interactions of, 970 labeled and off-labeled use of, 938t for mentally retarded patients, 815 pharmacology of, 970 receptor activity of, 967t for tic disorders, 896 Quincke needle, 157, 157f Quinidine for malaria, 1657, 1659 for slow-channel congenital myasthenic syndrome, 1961 Quinine for babesiosis, 1661 bitter taste of, 142 for malaria, 1657, 1659 teratogenicity of, 2197t and vertigo, 133 Quinolone(s) for bacterial meningitis, 1581 for Mycoplasma pneumoniae infection, 1590

R R band(s), 516 Rabies vaccine, 2348 neurologic complications of, 2348 Rabies virus, 1619-1620 clinical features of, 1619 diagnosis of, 1602, 1602t, 1619 epidemiology of, 1598-1599, 1619 outcome of, 1603t, 1619-1620 postexposure prophylaxis against, 1619-1620 treatment of, 1619-1620 Raccoon eyes, 1408, 1461 Racemose cyst, 1670 Radial microbrain, 404-405 Radial nerve, 28t

Radiation, ionizing teratogenicity of, 2182t and tumor risk, 1693 Radiation myelopathy, 1739 Radiation necrosis, 1739 Radiation therapy for astrocytoma, 1721 for brain tumors, 1698 in infants and very young children, 1728, 1728f-1729f for brainstem tumors, 1718 for cerebellar astrocytoma, 1714 cognitive effects of, 1739-1741, 1740f for craniopharyngioma, 1706-1707 dose per fraction in, 1698 endocrine effects of, 1741-1743, 1742f for ependymoma, 1715, 1729 for heterotopic ossification, 2365 hyperfractionated, 1698, 1718 for hypothalamic tumors, 1702 and leukoencephalopathy, 1743-1744, 1743f long-term effects of, 1739-1743 recommendations for, 1744-1745 for medulloblastoma, 1698, 1711, 1729 for oligodendroglioma, 1724 for pineal region tumors, 1705 for primitive neuroectodermal tumors, 1698, 1723 and secondary malignancies, 1744, 1744f for spinal cord tumors, 1734 vasculopathy after, and stroke, 1769, 1770f volume of radiation in, 1698 Radicular cutaneous fields, 27f Radiographic contrast agents in sickle cell anemia, risks of, 2197 toxicity of, 2193 Radioisotopic bolus angiography, 1559 Radionuclide imaging, in brain death, 1559-1560, 1560f, 1563 Radiosurgery, 1698 for arteriovenous malformations, 1790-1792 Rage, episodic, in Tourette syndrome, 890-891, 897 Ragged red fibers, 715, 718 Ramsay Hunt syndrome, 109, 1254, 1295, 1608-1609 Ranitidine for gastroesophageal reflux, 2286-2287 for nonepileptic paroxysmal disorders, 1213t toxicity of, 2180 Rapid auditory processing theory, of dyslexia, 856 Rapid Automatized Naming, 845 Rapid eye movement parasomnias, 1235 Rapid eye movement (REM) sleep, 1225 and breath-holding spells, 1204-1205 infant and childhood, 223-224 neonatal, 223 parasomnias associated with, 1226t Ras, in neurofibromatosis type 1, 274, 776 Rasmussen’s syndrome, 1047, 1153 Rat asphyxia models, 299 Raves, drug abuse at, 2187 Raynaud’s phenomenon, 1816 in mixed connective tissue disease, 1817 in scleroderma, 1816 R-banding, 520 Reader(s) accuracy improved, 861-863, 862f nonimpaired, 861-863, 862f persistently poor, 861-863, 862f Reading assessment of, 864-865 compensatory systems in, 858 computation and component systems in, 858-859, 859f Volume 1: pages 1–1180

Reading continued functional MRI in, 857-863, 858f-860f, 862f identification and localization in, 857-858, 858f neural system plasticity in, 859-861, 860f occipitotemporal system for, 859, 859f-860f, 861 parietotemporal posterior system for, 859 Reading comprehension, 864-865 Reading disability with ADHD, 876 in dyslexia, 855, 856f. See also Dyslexia types of, 860f, 861-863 Reading frame hypothesis, of Duchenne muscular dystrophy, 1970-1972 Real-time, gray-scale ultrasound, 167-168 Real-time ultrasound, 167-168 Rebif (interferon-β), 1349-1350 Receptive language, 907t Receptive language disorders, 846b, 849 in autistic disorders, 907 Reciprocal translocation, 520f, 526f-527f, 528, 528f, 529t, 546 Recombinant DNA, 522 Recombinant vaccines, 2350 Recombination, 514 Rectal administration, of antiepileptics, 1119, 1120t Rectification, 994 Rectum anatomy and embryology of, 2166 nerve supply of, 2166 Rectus femoris muscle, in gait, 71f Rectus muscles, 20-21, 21f, 21t Recurrent laryngeal nerve palsy, 339 Red blood cell(s), in CSF, 159-160 in intraventricular hemorrhage, 320 Referential recordings, in EEG, 204 Reflex(es). See also specific types assessment of in infant, 40, 42-44, 43t, 45, 67 in newborn (term), 50-51, 67 in older child, 17-19 in preterm infant, 56-57, 56f, 58t, 60-61, 60t, 67 deep tendon absent, in spinal cord injury, 339 in Friedreich’s ataxia, 1249 in infant, 40, 45 in newborn (term), 50-51, 67 in older child, 17-19 in preterm infant, 56-57, 56f, 58t, 67 types and segmental levels of, 18, 19t in uremic neuropathy, 2248 developmental, evaluation of in brain death determination, 1556, 1556t in infant, 42-44, 43t, 50 in preterm infant, 60-61, 60t elicitation of, 43t hyperreactive, 18 hyporeactive, 18-19 versus neonatal seizures, 259, 259t oculovestibular, 123 primitive, evaluation of, 42-44, 43t, 50 spinal, in spinal cord injury, 339 Reflex anoxic seizures, 1203, 1206-1207, 1212 anesthesia protocol for children with, 1207 clinical features of, 1206 EEG findings in, 1206 laboratory tests in, 1207 pathophysiology of, 1206-1207 treatment of, 1207 Reflex myoclonus, 1293 Reflex sympathetic dystrophy, 2152 Reflex syncope, 1212. See also Breath-holding spells; Reflex anoxic seizures Refractive errors, 87

Volume 2: pages 1181–2408

Index “Refrigerator mother,” 918 Refsum’s disease, 1247t, 1908-1909 cardiac involvement in, 2224 classic, 751, 1908-1909 laboratory findings in, 743t, 1908-1909 hearing loss in, 105t, 107 infantile, 740-744, 1909 clinical and pathologic features of, 741-742 genetics of, 740t, 742 laboratory diagnosis of, 742-744, 743t prenatal diagnosis of, 744 treatment of, 744 vertigo in, 132 vision loss in, 88t Regionalization, 364-365 disorders of, 379-383 Rehabilitation, 2355-2369 in cerebral palsy, 2359-2360 in Duchenne muscular dystrophy, 1984-1985 in neonatal stroke, 332, 334 professional team for, 2360-2361 in spinal cord injury, 1544, 2356-2359 in traumatic brain injury, 2355-2356 Reissner’s membrane, 98, 99f Relaxation therapy for chronic daily headache, 1198 for migraine, 1192, 1192b for tic disorders, 895 RELN gene and autism, 920 and lissencephaly, 412t, 414-415 Remeron. See Mirtazapine Remifentanil for sedation, 2378 in traumatic brain injury, 1422 Renal artery stenosis, in neurofibromatosis type 1, 774-775 Renal cell carcinoma, in von Hippel-Lindau syndrome, 784 Renal cysts, in tuberous sclerosis complex, 780 Renal disorder(s), 2233-2268 affecting both kidneys and nervous system, 2252-2268 dialysis for, complications of, 2244-2249 drug-induced, 2264-2265, 2264t with hearing disorders, 115 in hypoxic-ischemic injury, 281, 281t in Menkes’ disease, 1325 secondarily affecting nervous system, 2233-2242 in systemic lupus erythematosus, 1809 Renal failure acute, 2233-2242 hyperkalemia in, 2235 hypertensive encephalopathy in, 2238-2242 hyponatremia in, 2234-2235 management of, 2233 morbidity in, 2233 neurologic compensation with, 2233-2234 uremic encephalopathy in, 2235-2238 water intoxication in, 2234-2235 in amyloidosis, 2259-2261 chronic, 2242-2249 aluminum toxicity in, 2243-2244, 2246 cognitive effects of, 2242, 2247 congenital uremic encephalopathy in, 2242-2244 dialysis complications in, 2242, 2244-2249 endocrinopathy in, 2244 malnutrition in, 2244 myopathy of, 2249 neuropathy of, 1905, 2247-2249 prevalence of, 2242 strokes in, 2244 in cystinosis, 701 dialysis for, complications of, 2244-2249

Renal failure continued drug action and effects in, 2265-2268, 2266t drug-induced encephalopathy in, 2266, 2266t in hemolytic-uremic syndrome, 2258 in hepatorenal syndrome, 2258-2259 Renal stones, ketogenic diet and, 1143 Renal transplantation complications of, 2249-2252 drug-related, 2251-2252 graft failure or rejection in, 2250 for hyperoxaluria, 751 infection in, 2250-2251 neuropathy after, 2249 stroke risk in, 2251 tumor risk in, 2251 Renal tubular acidosis, 2262-2264 distal, 2262, 2262t with hyperkalemia, 2265 proximal, 2262-2264, 2262t Renal tubular dysfunction, selective, 2262 Renin-angiotensin, in hepatorenal syndrome, 2258 Reoviruses, 1595b, 1616-1617 Reperfusion injury, 1478 in cardiac surgery, 2208-2209, 2208b, 2211-2212 in spinal cord injury, 1531 in stroke, 1763 Repetitive DNA, 518-519 Repetitive stimulation in Lambert-Eaton myasthenic syndrome, 1956, 1957f in myasthenia gravis, 1946f, 1947-1949, 1947f Replagal (agalsidase alfa), for Fabry’s disease, 670 Replication, of DNA, 508-509, 516 disorders of, 560t, 561 errors in, 530 Replication segregation, 716 Report of the National Reading Panel-Teaching Children to Read: An Evidence-based Assessment of the Scientific Research Literature on Reading and Its Implications for Reading Instruction, 866 Reproductive cell division, 513-515 Research ethics, 2394 Reserpine and parkinsonism, 1292 for tardive movement disorders, 1302 Resistive index, 1516 Respirator brain, 1553 Respiratory chain, 721, 722f complexes of, 716t, 721, 722f, 725 defects of, 354-355, 354f, 721-722, 725-727, 2049-2050, 2056-2059 cardiac involvement in, 2223 classification of, 725 clinical features of, 721-722 combined, 2058 complex I, 725, 2057 complex II, 725-726, 2057 complex III, 726, 2057-2058, 2223 complex IV, 726, 2058 complex V, 726-727, 2058 function of, 721 Respiratory disorder(s), autonomic dysfunction in, 2138-2140 Respiratory syncytial virus, 1617 Rest tremor, 1290 Restiform body, 1242-1243, 1242f Restless legs syndrome, 892, 1233, 1302 in uremic neuropathy, 2248 Restriction enzyme(s), 521-522 analysis of, 524 Restriction enzyme fragment length polymorphisms (RFLPs), 519 Volume 1: pages 1–1180

Volume 2: pages 1181–2408

lxxxiii

Reticular-activating system, 1383 Reticulum cell sarcoma, 1732 Retigabine, and potassium channels, 994 Retina anomalies of, 88-89, 89f neurologic disease associated with, 88t development of, 77 electroretinography of, 245-246, 246f in genetic metabolic encephalopathies, 350t neurometabolic dysfunction of, 89 Retinal angioma, retinal, in Wyburn-Mason syndrome, 789-790 Retinal dysplasia, 83-84 Retinal hemangioblastoma, in von HippelLindau syndrome, 784-785, 785f Retinal hemorrhage computed tomography of, 1456f dot (dot and blot), 1451t flame or splinter, 1451t in inflicted neurotrauma, 1412, 1412f, 14501452, 1450f-1451f, 1456f intraretinal, 1451f, 1451t in osteogenesis imperfecta, 1460 pathogenesis of, theories for, 1451-1452 in perinatal trauma, 1460 resolution rate for, 1451 staining for, 1450, 1450f subhyaloid, 1451t terminology for, 1450, 1451t vitreal, 1451t Retinal migraine, 1189 Retinitis, 89 Retinitis pigmentosa, 89 in developmental disorders, 839t in mental retardation/developmental delay, 812b Retinoblastoma gene, 1747-1748 Retinoblastoma/mental retardation, 556t Retinocephalic angiomatosis, 771t, 789-790 Retinocephalic vascular malformation, 790 Retinoic acid and holoprosencephaly, 396 and neural tube development, 366 Retinoids, teratogenicity of, 2182t Retinol (vitamin A), 2305-2307 deficiency of, 2306 physiologic functions of, 2305 recommended daily requirement for, 2305 teratogenicity of, 2197t, 2198, 2306-2307 toxicity of, 2306 Retinopathy of prematurity, 82 Retrocerebellar cyst, 392-393, 393f Retrocochlear hearing loss, 103 Retrocollis, paroxysmal, 131 Retropulsion, 74 Retroviruses, 1595b, 1620-1623 outcome of, 1603t in tumor therapy, 1749 Rett, Andreas, 1315 Rett’s syndrome, 909-911, 1315-1321 animal models of, 1320 atypical, 1316 cell biology in, 1319-1320 classic, 1315-1316, 1319 clinical description of, 1315-1316 clinical diagnostic tests in, 1316-1317 congenital, 1316 dementia in, 822-823 diagnostic criteria for, 909-910, 910b, 1315, 1316t early-onset stage of, 1315 EEG findings in, 240, 910, 1316-1317 epilepsy with, 917 genetics of, 910-911, 1315, 1318-1319 genotype-phenotype correlation in, 1318 hallmarks of, 1315

lxxxiv

Index

Rett’s syndrome continued history of, 1315 laboratory tests in, 1316-1317 late motor impairment in, 1315-1316 life expectancy in, 909 neuroimaging in, 1317 neurophysiologic tests in, 1317 pathogenesis of, 1320-1321 pathology of, 1317-1318 brain, 1317-1318 muscle, 1318 prevalence of, 909 pseudostationary stage of, 1316 regression stage of, 1315 sleep in, 1234-1235, 1316-1317 stabilization stage of, 1315-1316 stereotyped movement in, 910, 1219, 1315 treatment of, 1321 variants of, 1317t, 1319 Reviparin, 1777 Reyelike syndrome in juvenile idiopathic arthritis, 1804 in systemic lupus erythematosus, 1810 Reye’s syndrome, 1608, 2298-2299 clinical features of, 2298-2299 EEG findings in, 240 in juvenile idiopathic arthritis, 1804 laboratory findings in, 2299 mitochondrial dysfunction in, 729 pathology of, 2299 prognosis of, 2299 staging of, 2298-2299 treatment of, 2299 Rhabdoid tumors, 1729-1730 Rhabdomyoma, in tuberous sclerosis complex, 780 Rhabdoviridae, 1595b, 1619-1620 Rhagades, 1587 Rheologic changes, 2365 Rheumatic disorders. See also specific disorders autoantibodies in, 1804t classification of, 1804b neurologic manifestations of, 1803-1826 Rheumatic fever, acute, 1806-1808 CNS involvement in, pathology of, 1808 heart disease in, 2225-2226 Jones diagnostic criteria for, 1806, 1807b, 2225 neurologic manifestations of, 1805t, 1806-1808. See also Sydenham’s chorea treatment of, 1808 Rheumatoid arthritis, juvenile. See Juvenile idiopathic arthritis Rhinencephalon, 383 Rhizomelic chondrodysplasia punctata, 465t, 739-740, 744-745 biochemistry of, 744 clinical features of, 744, 745f genetics of, 740t, 745 laboratory diagnosis of, 743t, 745 prenatal diagnosis of, 745 treatment of, 745 Rhizopus, 1632t. See also Phycomycosis Rhizotomy, selective dorsal, 2368 Rhombencephalon, 379-381, 380f-382f Rhombencephalosynapsis, 394 Rhombic lips, 380-381 Rhombomeres, 380-381, 381f-382f, 438 Rhythmic habit patterns, 1299 Rhythmic movements, 1219-1220 Ribavirin, 1603 for La Crosse encephalitis, 1616 for measles virus, 1618 teratogenicity of, 2198 for West Nile virus, 1615

Riboflavin (vitamin B2), 2308-2309 deficiency of, 2308 dependency disorders of, 2305t, 2308-2309 recommended daily requirement for, 2308 supplementation for acyl-CoA dehydrogenase deficiency, 724-725 for fatty acid oxidation defects, 2047 for glutaric aciduria type 1, 595, 2308-2309 Ribonucleic acid. See RNA Ribonucleoprotein particles (RNPs), 510 Ribosomal RNA, 509-510 Ribosomes, 511 Ricin, for tumor, 1746 Rickets, 2315-2316 antiepileptic agents and, 1124, 2315 clinical features of, 2315 diagnosis of, 2315 epidemiology of, 2315 vitamin D-dependent type I, 2315-2316 Rickettsia aeschlimannii, 1644 Rickettsia africae, 1644 Rickettsia heilongjanghensis, 1644 Rickettsia honei, 1644 Rickettsia japonica, 1644 Rickettsia parkeri, 1644 Rickettsia prowazekii, 1643. See also Typhus, epidemic Rickettsia rickettsii, 1642. See also Rocky Mountain spotted fever Rickettsia slovaca, 1644 Rickettsia typhi, 1643. See also Typhus, murine or endemic Rickettsial diseases, 1640-1645, 1641t clinical characteristics of, 1640, 1641t epidemiology of, 1641t geographic distribution of, 1641t incubation period of, 1641t laboratory tests in, 1640, 1641t management of, 1640, 1641t mode of infection/vector, 1641t reservoir for, 1641t Rieger’s anomaly, 83 Rieger’s syndrome, 83 Rieske protein, 2057 Rifampicin hepatotoxicity of, 2294 for meningitis prophylaxis, 1584 for meningitis treatment, 1581 Rifampin for bacterial meningitis, 1580t for granulomatous amebic encephalitis, 1651-1652 for leprosy, 1591 for primary amebic meningoencephalitis, 1650 for tuberculous meningitis, 1586 Righting response, 125b, 126 Right-to-left shunt, 1762 Rigidity versus dystonia, 1281 nuchal, in meningitis, 1573, 1585 in parkinsonism, 1291-1292 in poisoning/intoxication, 2177, 2179b Riley-Day syndrome (familial dysautonomia), 143, 1901, 2132, 2144-2145 blood pressure profile in, 2144, 2145f clinical features of, 2144-2145 genetics of, 2144 management of, 2145 prognosis of, 2145 Riluzole, for spinal cord injury, 1542-1543 Ring chromosomes, 526f, 529 Rinne test, 100, 125 Ripples of prematurity, in EEG, 215 Volume 1: pages 1–1180

Risperdal. See Risperidone Risperidone, 968-969 adverse effects of, 896, 968-969, 2189 for autism, 924-925, 927t clinical applications of, 968 clinical management of, 969 dosage of, 967t, 969 drug interactions of, 969 labeled and off-labeled use of, 938t for mentally retarded patients, 815 for neuronal ceroid lipofuscinosis, 703 pharmacology of, 968-969 receptor activity of, 967t for tic disorders, 896 Ritalin. See Methylphenidate Ritonavir, 1603 Ritscher-Schinzel syndrome, 465t Rizatriptan, for migraine, 1193t RNA, 507, 509-510 malnutrition and, 2303 messenger, 507, 510-511 micro, 510 processing of, 512-513 ribosomal, 509-510 small nuclear, 510, 512 small nucleolar, 510 splicing of, 512-513, 512f mutations in, 531 structure of, 509 transfer, 510-511 RNA viruses, 1595, 1595b RNA-induced silencing complex (RISC), 510 Robert’s syndrome, 377t, 450 Robertsonian translocation, 520f, 526f, 528-529, 529t, 546 Rocky Mountain spotted fever, 1642-1643 clinical characteristics of, 1641t, 1642-1643, 1642f, 1644f diagnosis of, 1642-1643 epidemiology of, 1641t geographic distribution of, 1641t, 1642 incubation period of, 1641t, 1642 laboratory tests in, 1641t, 1642-1643 management of, 1641t, 1643 mode of infection/vector, 1641t, 1642, 1642f reservoir for, 1641t Rod cone dystrophy. See Leber’s congenital amaurosis Rolandic epilepsy benign, 1014, 1040f, 1044-1045, 1045t, 1151 EEG studies of, 234-235, 235f, 1014, 1040f familial forms of, 1014 Romberg’s sign, 17, 45, 125b, 126 in gait disorders, 71, 73, 75 Root pain, spinal cord tumor and, 1730 Rooting reflex, 50, 60 Ropinirole for Parkinson’s disease, 1293 for tic disorders, 897 Rosenthal fibers in Alexander’s disease, 1357-1360 in brain tumors, 1687 in cerebellar astrocytoma, 1712 Roseola, 1610 Ross’ syndrome, 2152 Rossolimo reflex, 43t Rostral-caudal deterioration, 1388 Rotatory vestibular test (RVT), 127b, 128 Rotavirus, 1616-1617, 2292 and neonatal seizures, 266 Rothmund-Thomson syndrome, 450 Round window, 97, 98f Rubbing alcohol poisoning, 2185 Rubella vaccine, 1612, 2348-2349 neurologic complications of, 2348-2349

Volume 2: pages 1181–2408

Index Rubella virus, 1611-1613 clinical features of, 1612-1613 congenital, 364, 1612-1613 diagnosis of, 1613 EEG findings in, 238-239 epidemiology of, 1612, 1613f and hearing loss, 109, 115, 1613 outcome of, 1603t, 1613 treatment of, 1613 Rubeola. See Measles virus Rubinstein-Taybi syndrome, 556t, 557 pharmacologic treatment of, 274 Rubral tremor, 1291 RUNX2 gene, in cleidocranial dysplasia, 459 Ryanodine receptors, 1841 in central core disease, 2015-2016 diseases associated with, 1842t in myasthenia gravis, 1841

S S phase, of cell cycle, 513 S2 region, 1840 S-100B protein in brain injury, 1461, 1495 in cardiac arrest, 1495 Saber shins, 1587 Sabin-Feldman dye test, 1656 Saccular aneurysm, 1793, 1794f Saccule, 97, 98f, 123 Sacral agenesis, 374-375 definition of, 374 neurologic findings in, 374 progressive deficits in, 374 radiologic findings of, 374-375, 374f treatment of, 374 Sacral dysgenesis, partial, 374, 374f Sacral plexus, 28t-29t S-acylated proteins, in lysosomal storage diseases, 661t Saddle nose, 1587 Saethre-Chotzen syndrome, 444, 449-450 clinical features of, 442t, 449, 465t genetics of, 442t, 443f, 449-450, 465t neurologic manifestations of, 449 Sagittal sinus, superior, 1781-1782, 1782f thrombosis of, 1782f, 1784 Sagittal suture, 436, 436f, 437t Sagittal synostosis, 444f, 445, 445f, 1523 St. Christopher’s Hospice, 2379 St. Vitus’ dance, 1278 Sakati-Nyhan syndrome, 451 Salbutamol, for hyperkalemic periodic paralysis, 2096 Salicylate(s) contraindications to, 2365 and hearing loss, 110 hepatotoxicity of, 2294 for heterotopic ossification, 2365 and Reye’s syndrome, 2298 Salicylate poisoning, 2189 Salla disease, 700-701 Salt iodization, 2323 Salty taste, 141t, 142 preferences for, early experiences and, 143 Sandhoff’s disease, 665, 667-669 clinical features of, 668 onset of, 668 vision loss with, 88t Sandifer’s syndrome, 131, 1213t, 1216 Sandimmune. See Cyclosporine Sanfilippo syndrome, 688-689 behavioral problems in, 688-689 clinical features of, 688-689, 689f

Sanfilippo syndrome continued subtypes of, 688 vision loss with, 88t, 689 Saposin(s), 659 Saposin A, 680 Saposin B deficiency, 680-681 Saposin C, 659, 672 Sappinia diploidea, 1653 Sarcoglycan complex, 1841f, 1843-1844, 1969, 1970f α, 1841f, 1842t, 1843-1844 in limb-girdle muscular dystrophy, 1988t, 1992-1993 β, 1841f, 1842t, 1843-1844 in limb-girdle muscular dystrophy, 1988t, 1992-1993 δ, 1841f, 1842t, 1843-1844 in limb-girdle muscular dystrophy, 1988t, 1992-1993 diseases associated with, 1842t, 1844, 1988-1989, 1989t γ, 1842t, 1843-1844 in limb-girdle muscular dystrophy, 1988t, 1992-1993 Sarcoid myopathy, 2080 Sarcoidosis, 1824 laboratory findings in, 1818t, 1824 neurologic manifestations of, 1818t, 1824 treatment of, 1824 Sarcolemma, 1841, 1841f Sarcoma(s), reticulum cell, 1732 Sarcomere, 1839, 1839f, 1841f in muscle contraction, 1848-1850, 1849f Sarcomeric proteins, 1839-1840 in limb-girdle muscular dystrophy, 1988-1989, 1988t, 1994-1995 Sarcoplasm, 1841 Sarcoplasmic reticulum, 1841, 1841f Sarcotubular system, 1841, 1841f Sarin, 2183 Sarnat score, 47, 48t Satellite cells, 1838 Satellite DNA, 518-519 Satiety center, 2122 Satoyoshi’s disease, 636-637 Saunders, Cecily, 2379 Scala media, 97-98, 98f Scala tympani, 97-98, 98f-99f Scala vestibuli, 97-98, 98f-99f Scales of Independent Behavior-Revised (SIB-R), 805 Scalp, 1402 Scalp injuries, 1403, 1418 from electrodes, 335 in inflicted neurotrauma, 1452 Scandinavian protocol, for intracranial hypertension, 1583 Scaphocephaly, 444f, 445, 445f, 1523 Scapular weakness, in facioscapulohumeral muscular dystrophy, 1999, 1999f Scapuloperoneal spinal muscular atrophy, 1868t, 1869 Scarf sign assessment for, 67 in preterm infants, 54f-55f, 58, 59f Scarlet fever, and hearing loss, 109 Scedosporium angiospermum, 1640. See also Allescheriosis Scheie syndrome, 686-688 clinical features of, 687 radiographic studies in, 687 treatment of, 687-688 vision loss with, 88t Schilder’s disease, 1350-1351 clinical characteristics of, 1351 clinical studies of, 1351 Volume 1: pages 1–1180

Volume 2: pages 1181–2408

lxxxv

Schilder’s disease continued MRI findings in, 1351, 1351f subclassification of, 1351 treatment of, 1351 versus X-linked adrenoleukodystrophy, 1351 Schindler-Kanzaki disease, 694-695 clinical features of, 695 diagnosis of, 695 genetics of, 695 Schinzel’s acrocallosal syndrome, 385t Schirmer’s test, 2140 Schistosoma, 1672. See also Schistosomiasis Schistosoma haematobium, 1672 Schistosoma intercalatum, 1672 Schistosoma japonicum, 1672 Schistosoma malayensis, 1672 Schistosoma mansoni, 1672 Schistosoma mekongi, 1672 Schistosomiasis, 1672-1673 clinical characteristics of, 1672-1673 diagnosis of, 1672-1673 epidemiology of, 1672 laboratory tests in, 1672-1673 management of, 1673 microbiology of, 1672 pathology of, 1672 Schizencephaly, 383-384, 421-425 antenatal diagnosis of, 425 arachnoid cysts in, 435 bilateral, 383-384, 384t, 424 and cerebral palsy, 493 clinical features of, 383, 384t, 422, 424 closed-lipped, 383, 384t, 422 EEG findings in, 422 etiology of, 424 familial, 423t, 424 genetic counseling in, 425 management of, 425 MRI findings in, 421f, 422 neuroimaging of, 384, 384f open-lipped, 383, 384t, 421f, 422 outcome of, 425 pathogenesis of, 364, 422 pathology of, 421-422 septo-optic dysplasia with, 387, 423t, 424 syndromes of, 422-424, 423t unilateral, 383-384, 384t, 424 vision loss with, 86 Schizophrenia, treatment of, 966, 969-971 School behavior assessment, 7-15 by parents/caretaker, 7, 13b by school/supervisory personnel, 7-15, 14f-15f by teacher, 7, 11f-12f School Functional Assessment, 1394 School issues in chronic daily headache, 1196 in dyslexia, 867 in epilepsy, 1171-1172, 1177 in hearing impairment, 117-118 in sleep apnea, 1230 in sleep physiology, 1225 in traumatic brain injury, 2356 in Wilson’s disease, 2299 School refusal, imipramine for, 946 Schwann cell, 775 Schwannoma(s) dermal, 777 in neurofibromatosis type 2, 776-777, 776f vestibular, 776, 776f Schwannomatosis, 776-777 classification of, 771 clinical features of, 771t, 777 genetics of, 777 management of, 777 Schwartz-Jampel syndrome, 2098-2099, 2102 clinical features of, 2098, 2102

lxxxvi

Index

Schwartz-Jampel syndrome continued diagnosis of, 2098 genetics of, 2102 laboratory findings in, 2098-2099 pathophysiology of, 2102 treatment of, 2099, 2102 type 1A (classic), 2098 type 1B, 2098 type 2, 2098 Sciatic nerve, 29t Sciatic neuropathy, intramuscular injections and, 2194-2195 Scimitar sign, in partial sacral dysgenesis, 374, 374f Scissoring gait, 72 Scleroderma, 1815-1816 laboratory findings in, 1809t, 1816 localized, 1815-1816 neurologic manifestations of, 1809t, 1816 systemic, 1815-1816 treatment of, 1816 Scleroderma/dermatomyositis syndrome, 2079, 2079f Sclerosis, 435b, 455-459 SCN1A gene in familial mesial temporal lobe epilepsy, 1014 in generalized epilepsy with febrile seizures plus, 1011-1012 in severe myoclonic epilepsy of infancy, 1012-1013, 1070 SCN1B gene, in generalized epilepsy with febrile seizures plus, 1011 SCN2A gene, in neonatal-infantile seizures, 1009-1010 Scoliosis in arthrogryposis multiplex congenita, 1873 in diastematomyelia, 1860-1861 in Duchenne muscular dystrophy, 1978, 1985 gait disorders in, 71 hypotonia in, 67 in neurofibromatosis type 1, 774 in Rett’s syndrome, 1316 in spinal cord injury, 2358 spinal cord tumors and, 1730-1731, 1731f in spinal muscular atrophy, 1867-1868 Scopolamine for neurocardiogenic syncope, 1211b for nonepileptic paroxysmal disorders, 1213t, 1214 for reflex anoxic seizures, 1207 for sialorrhea, 2362 toxicity of, 2191 Scotoma brain tumor and, 1694 migraine and, 1188 Scratch-and-smell test, 138 Screening Tool for Autism in Two-Year-Olds, 913 Scrub typhus, 1644 clinical characteristics of, 1641t, 1643f, 1644 epidemiology of, 1641t geographic distribution of, 1641t incubation period of, 1641t laboratory tests in, 1641t management of, 1641t, 1644 mode of infection/vector, 1641t, 1644 reservoir for, 1641t Scurvy, 2314 Sebaceous nevus syndrome, 787t Seckel’s syndrome, 402t-403t, 405 Secobarbital, rectal administration of, 1120t Second impact syndrome, 1417, 1417f Secondary malignancies, 1744, 1744f Secondary sexual characteristics, 2114 Second-wind phenomenon, 2026 Secretin, for autism, 926 Secure servers, 2406

Sedation conscious, 2377 deep, 2377 for EEG, 206 for intracranial hypertension, 1422, 1520, 1582 for pain management, 2377-2378 for postoperative movement disorders, 2214 procedural use of, 2377 for traumatic brain injury, 1422 Sedative(s) fetal/neonatal effects of, 2196 poisoning, 2187-2188 Sedative toxidromes, 2180-2181 Seesaw nystagmus, 22 Segal, Michael, 2405 Segawa’s disease, 761-762, 764-765, 1215, 1282. See also Dopa-responsive dystonia Segmental dystonia, 1280 Segmentation, 364-365 disorders of, 379-387 Seitelberger’s disease, 1904-1905 Seizure(s), 981-988. See also specific types and disorders absence, 1023-1029 anoxic epileptic, 1206 astrocytoma and, 1720 atonic, 1030-1031 with brain tumors, in infants and very young children, 1726 in celiac disease, 2289 clonic, 1029 continuous or prolonged, 1091-1102. See also Status epilepticus in cysticercosis, 1670-1671 dialysis-associated, 2246 drug- or toxin-induced, 2175, 2176t-2177t in encephalitis, 1597 in enteric infections, 2290-2292 extracorporeal membrane oxygenation and, 2226 febrile, 1079-1086 focal, 1037-1052 focal cortical dysplasia and, 410 generalized, 984b, 991, 992f, 1019-1033 generalized anoxic, 1210 glycine encephalopathy and, 580-582 hemimegalencephaly and, 409 in hepatic encephalopathy, 2294 holoprosencephaly and, 397-398 in hypertensive encephalopathy, 2239 immediate post-traumatic, 1415 impact, 1415 in impaired consciousness/coma, 1391 in intracranial hypertension, 1521 in juvenile idiopathic arthritis, 1803-1804 in leukemia, 1737 lissencephaly and, 412, 415-417 in malaria, 1658, 1660 in meningitis, 1577, 1582 in mental retardation/developmental delay, 812b, 813 mixed generalized-focal, 1047-1048 multifocal, 1037, 1047-1048 myoclonic, 1063-1075, 1065t neonatal, 257-274 acute reactive, 257 adverse effects in developing brain, 271-272 anarchic, 258 animal models of, 272 antiepileptic agents for, 269-271 adjuvant, for acute cases, 270-271 adverse effects of, 271 chronic therapy with, 271 decision to initiate, 269-270 first-line, 269t, 270 initial, in acute cases, 270 Volume 1: pages 1–1180

Seizure(s) continued second-line, 269t, 270-271 uncoupling with, 270 approach to, 257 autosomal dominant, 1009-1010 benign convulsions, 266 benign familial, 266-267, 1009-1010, 1045t and brain growth retardation, 272 and brain pathway alterations, 272 classification of, 230, 257-260 clinical, 258, 258t by pathophysiology, 258t, 259-260, 259b syndromic, 260 by temporal relation to electric seizure activity, 259 clinical characterization of, 257-260, 258t clinical manifestations of, 265-269 clinical only, 259, 1094 complex purposeless movements, 258t concerns in, 257 controversies over, 257, 1094 in cranial birth injuries, 335 and direct neuronal injury, 271-272 EEG studies of, 228-230, 228f-229f, 260-265, 274 alpha activity in, 263, 264f computer analysis of, 264-265 in depressed brain, 263, 264f electrical activity in, 261f-262f, 262-263, 263f frequency, morphology, and voltage in, 261f, 262-263, 262f interictal background in, 260 interictal focal abnormalities in, 261-262 migration pattern in, 263, 263f video monitoring with, 263 electrical-only, 259 electroclinical, 259, 1094 electrographic, 1094 epileptic, 259-260, 259b, 265-269 catastrophic syndromes of, 266 early infantile encephalopathy, 260, 260t, 266, 268-269 early myoclonic encephalopathy, 260, 260t, 266-268 etiology of, 265-269, 265b in genetic metabolic encephalopathies, 350t and hippocampal development, 272 in hypoglycemia, 348 in hyponatremia, 349-350 in hypoxic-ischemic injury, 280, 284, 286, 290-291 incidence of, 230, 257 in intracranial hemorrhage, 338 in intraventricular hemorrhage, 309, 321 management of, goals of, 273 minimal, 258 morbidity and mortality in, 230 motor automatisms, 258, 258t-259t, 260, 274 of non-epileptic origin, 259-260, 259b occurrence of, 257 ocular signs in, 258, 258t oral-buccal-lingual movements, 258, 258t, 260, 1094 outcome measures of, 273, 273t paroxysmal changes in, 258 prognosis in, 230, 271-274 clinical considerations in, 273-274, 273t multivariant analyses of, 274 by neurologic disorder, 273, 274t by seizure type, 273-274 progression movements, 258, 258t, 260 versus reflex phenomena, 259, 259t versus seizures in older children, 258 spasms, 258t-259t, 260 in spina bifida, 372

Volume 2: pages 1181–2408

Index Seizure(s) continued in stroke, 334 subtle, 258-259, 1094 symptomatic, 257, 265 therapy for, 269-271 etiology-specific, 269, 269t initial considerations in, 269 two-hit hypothesis of, 272 in neuronal ceroid lipofuscinosis, 703 oligodendroglioma and, 1724, 1724f partial, 984b, 991, 992f, 1019 periventricular nodular heterotopia and, 419 polymicrogyria and, 422 post-ischemic, 1492 postoperative, in cardiac surgery, 2212-2213, 2212f postpump, 2212-2213 post-traumatic, 1427-1428, 1435, 1448, 2356 psychogenic, EEG findings in, 240 reflex anoxic, 1203, 1206-1207 schizencephaly and, 384, 422 simple partial, 984b in sinovenous thrombosis, 1784 in sleep, 274 in stroke, 1765 supplementary sensorimotor, 1213-1214 susceptibility, in immature brain, 1000-1002, 1000t in systemic lupus erythematosus, 1809-1810, 1814 tonic, 1029-1030 tonic-clonic, 1021-1023 treatment of ketogenic diet for, 1033, 1131-1146 pharmacologic, 1105-1126. See also Antiepileptic agents unprovoked, 981 in uremic encephalopathy, 2237-2238 vertiginous, 132 vestibulogenic, 132 in viral infections, 1603 Selective dorsal rhizotomy, 2368 Selective serotonin reuptake inhibitors (SSRIs), 948-953 for ADHD, 879t adverse effects of, 951-952, 2179-2180, 2189 assessment for, 950 for autism, 924-925 clinical management of, 950-951 dosage of, 948t, 950-951 drug interactions of, 952-953 FDA warning on, 948-949, 952 fetal/neonatal effects of, 2196 initiation and titration of, 950-951 labeled and off-labeled use of, 938t for Lesch-Nyhan disease, 1286 for mentally retarded patients, 815 for myoclonus, 1295 for neurocardiogenic syncope, 1211, 1211b for obsessive-compulsive disorder, 897, 945 pharmacodynamics of, 949 pharmacokinetics of, 948t, 949-950 pharmacology of, 949-950 preparations of, 948t sexual side effects of, 951-952 and suicide risk, 948-949, 952 toxicity of, 2189 Selegiline for ADHD, 879t for Parkinson’s disease, 1293 for sepiapterin reductase deficiency, 763 for tyrosine hydroxylase deficiency, 764-765 Self-injurious behavior definition of, 891 in Lesch-Nyhan disease, 1286 in Tourette syndrome, 890-891

Self-stimulation, 1299 Sellar region, arachnoid cyst of, 434 Semantic(s), 907t Semantic pragmatic syndrome, 849-850 Semicircular canals, 97, 98f, 123 Semiconservative replication, 508 Semilobar holoprosencephaly, 395f, 396 Senataxin (SETX) gene, in amyotrophic lateral sclerosis, 1871 Senior-Loken syndrome, 391 Sense(s), chemical, 135-136. See also Smell; Taste Sense strand, in transcription, 511 Sensorimotor neuropathy with ataxia, 1255t, 1261 Sensorineural hearing loss, 103 causes of, 103, 103b in developmental disorders, 836t-837t fibrous dysplasia and, 458 in meningitis, 1577 in mental retardation/developmental delay, 813b pathology of, 106 static versus progressive, 106 Sensorium changes in, drug- or toxin-induced, 2175, 2176t-2177t decreased, in intracranial hypertension, 1517 Sensory and autonomic neuropathy, hereditary, 1901-1902, 2144 type I, 1901 type II, 1901 type III, 143, 1901 type IV, 1901-1902 type V, 1902 Sensory (Wernicke’s) aphasia, 822t Sensory ataxia, 73 Sensory neuropathy acquired, 1902 acute, 1922t inherited, 1902 Sensory seizures, 1042-1043 Sensory system assessment of in infant, 40-41, 41f, 45 in older child, 25-26 segmental innervations of, 25, 25f-27f Separation anxiety, imipramine for, 946 Sepiapterin reductase deficiency, 763-764 Sepsis and intraventricular hemorrhage, 311 and polyneuropathy, 1911 Septic shock, in bacterial meningitis, 1578-1579, 1582 Septo-optic dysplasia, 84, 383t, 385t, 387 clinical features of, 387, 387t genetics of, 387 imaging of, 387f management of, 387 with schizencephaly, 387, 423t, 424 Septo-optic dysplasia plus, 387 Septo-optic-hypothalamic dysplasia, 383t Septum pellucidum agenesis of, 383t, 384f, 385 anomalies of, 384-385 cavum, 384f, 385 divisions of, 384 Septum verum, 384 Serine biosynthesis defects, 356f, 359 clinical features of, 350t-351t, 359 MRI findings in, 352t, 359 Seroquel. See Quetiapine Serotonin in autism, 922-923 CSF analysis for, 163 Volume 1: pages 1–1180

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lxxxvii

Serotonin continued deficiency of, 759-767 herbal medicine and, 766-767 L-ADD defects and, 359-360, 360f, 762-763 patient approach in, 767 secondary, 766 in Rett’s syndrome, 1320 in Tourette syndrome, 894, 895f Serotonin reuptake inhibitors. See Selective serotonin reuptake inhibitors (SSRIs) Serotonin-dopamine antagonist(s), 964, 968-971 adverse effects of, 968 common characteristics of, 968 dosage of, 967t monitoring of, 968 receptor activity of, 967t, 968 Serotoninergic syndrome, 2178-2180 Serratus muscle, testing of, 34t Sertindole, adverse effects of, 2189 Sertraline, 948-953 for ADHD, 879t adverse effects of, 951-952 for autism, 924, 927t clinical applications of, 948-949 dosage of, 948t, 951 initiation and titration of, 951 labeled and off-labeled use of, 938t for narcolepsy, 1232 for neurocardiogenic syncope, 1211b for obsessive-compulsive disorder, 897 pharmacokinetics of, 948t, 950 preparations of, 948t Serum sickness, neuropathy of, 1909 Setting sun sign, in hydrocephalus, 429 Sex chromosomes, 516, 541 abnormalities of, 553-555 Sexual characteristics, secondary, 2114 Sexual precocity, 2115-2116 definition of, 2115 hypothalamic tumors and, 1701, 1701f SGM1 gene, in Klippel-Feil syndrome, 454 Shagreen patch, in tuberous sclerosis complex, 779, 779f Shaken baby syndrome, 1411-1412, 1445, 1790 computed tomography in, 176f Shaken impact syndrome, 1412, 1445 Sharp transients, in EEG occipital, during sleep, 224-225, 224f posterior, 221, 224f Shearing forces and thromboembolism, 1762 and traumatic brain injury, 1402-1403, 1457, 2355 Sheep asphyxia models, 298 Shepherd’s crook deformity, 458 Sherman paradox, 559 Shiga toxin, 2291 Shigellosis (Shigella), 2291 Shingles. See Varicella-zoster virus Shivering (shuddering) attacks, 1213t, 1219 Shock hepatorenal syndrome in, 2259 in hypoxic-ischemic injury, 1500 septic, in bacterial meningitis, 1578-1579, 1582 spinal, 1537-1538 Short (p) arm, of chromosome, 516, 541, 543f Short bowel syndromes, 2290 Short falls, 1459 Short stature, in mental retardation/developmental delay, 814b Short tandem repeats, 519 Short-chain acyl-CoA dehydrogenase deficiency, 724, 2024-2025, 2041-2042

lxxxviii

Index

Short-chain free fatty acids, in hepatic encephalopathy, 2295-2296 Shoulder, segmental innervation of, 30t Shoulder dystocia, and birth trauma, 334, 340, 1890-1891 Shprintzen-Goldberg syndrome, 443f, 450-451, 466t, 556t, 2287 cardiac involvement in, 2224 clinical features of, 442t, 450, 465t, 2224, 2225f genetics of, 442t, 450-451, 465t Shuddering attacks, 1213t, 1219, 1300 Shunt(s) in brain tumor management, 1697-1698, 1728 for hydrocephalus, 430-432 complications of, 431-432 failure rate of, 431 portosystemic, complications of, 2294-2295 for sinovenous thrombosis, 1787 Shunt infections, 432, 1572, 1574 Sialic acid storage disorders, 700-701 diagnosis of, 701 genetics of, 701 prenatal testing for, 701 treatment of, 701 Sialidase deficiency, 693-694 Sialidosis, 692-694, 1072t, 1073-1074 clinical features of, 693-694 diagnosis of, 694 treatment of, 694 type I, 693-694 type II, 693-696 vision loss with, 88t, 693 Sialorrhea, 2362 Sialuria, 700 Sickle cell disease contrast agents in, risks of, 2197 diffusion-weighted imaging in, 187 perfusion MRI in, 189 and stroke, 1766-1767, 1769 Sign language, 115-118 versus oralism, 117-118 Signed Exact English, 118 Silver-silver chloride electrodes, for EEG, 204 Simon, Theodore, 800 Simple febrile seizures, 1079-1080 Simple partial seizures, 984b, 1042-1043 classification of, 1037, 1038b, 1042 with motor signs, 1042 with psychic symptoms, 1043 with special sensory or somatosensory symptoms, 1042-1043 Simple partial status epilepticus, 1093b, 1094 SimulConsult, 2405 Sincipital encephalocele, 377 Sinemet (carbidopa-levodopa), for restless legs syndrome, 1233 Single base extension, 524 Single synostosis, 445 Single-condition amplification/internal primer sequencing, in muscular dystrophy, 1980 Single-fiber electromyography, 1853 in Lambert-Eaton myasthenic syndrome, 1956 in myasthenia gravis, 1948f, 1949, 1949f Single-nucleotide polymorphisms (SNPs), 519 Single-photon emission tomography (SPECT), 167, 195-196 in ADHD, 875 in autistic disorder, 916 of brain tumors, 196, 1696 of hypoxic-ischemic injury, 283 indications for, 195-196 in Landau-Kleffner syndrome, 1058 in neonatal seizures, 259 preoperative, for epilepsy surgery, 1157-1160, 1159f

Single-photon emission tomography (SPECT) continued radiotracers in, 195 of stroke, 1775 in systemic lupus erythematosus, 1814, 1814f Single-stranded conformational polymorphism, 523 Sinovenous circulation, 1781-1782, 1782f Sinovenous thrombosis, 1759, 1781-1788 anatomy and physiology in, 1781-1782, 1782f angiography (conventional) of, 1786 antithrombotic therapies for, 1786-1787 and cerebral palsy, 493 clinical features of, 1784 computed tomography of, 1783f-1784f, 1785-1786 infarction mechanisms in, 1783-1784, 1783f-1784f magnetic resonance imaging of, 1782f, 1786 magnetic resonance venography of, 189f, 1783f, 1786 mortality rate for, 1787 and neonatal stroke, 329-330, 330f in neonates and infants less than 1 year, 1784 non-antithrombotic therapies for, 1787 in older children, 1784 in older infants and preschool children, 1784 outcome of, 1787-1788 pathophysiology of, 1781-1784 radiographic features of, 1785-1786 recurrent, 1787 risk factors for, 493, 1785 septic versus non-septic, 1785 thromboembolic mechanisms in, 1782 treatment of, 1786-1787 ultrasound of, 1786 vascular patterns of, 1783f, 1784 Sinus(es), cerebral, 1781-1782, 1782f Sinus pericranii, 459 Sirenomelia, 375 Situational syncope, 1212, 2149-2151 SIX3 gene, and holoprosencephaly, 396, 398 Sjögren-Larsson syndrome, 1366-1367 biochemistry of, 1366 clinical features of, 1366-1367 genetics of, 1366 magnetic resonance imaging in, 1367 treatment of, 1367 Sjögren’s syndrome, 1817-1818 laboratory findings in, 1809t, 1817 neurologic manifestations of, 1809t, 1817-1818 treatment of, 1818 Skeletal muscle(s) bulk of, 27-33 channelopathies of, 2085-2105 extremity, segmental innervation of, 30t-32t innervation of, 28t-33t power of, 26-27 testing of, 34t in infant, 39-41, 42f, 44-45 in older child, 26-33 patient positioning for, 26-27, 29f scoring system for, 26 tone of, 33 trunk, segmental innervation of, 33t Skin, evaluation of in infant, 41 in newborns (term), 47 in preterm infant, 53, 57t Skin cancer, in renal transplant patients, 2251 Skin disorder(s) autonomic dysfunction in, 2140 in developmental disorders, 833t-834t Volume 1: pages 1–1180

Skin disorder(s) continued in mental retardation/developmental delay, 813b Skin response, sympathetic, 2137, 2139f Skull, 1402, 1402f congenital abnormalities of, 437-454. See also specific types classification of, 436 differential diagnosis of, 438b genetics of, 437-438, 439t-440t neurologic features of, 436 of ossification, 436, 436b, 455-466 of sutures, 436, 441-454 terminology for, 436 developing, injury to, 1404 examination of, 436 normal development and anatomy of, 436-437 softening of, conditions with, 438b Skull fracture, 1403, 1417-1418 basal, 1418 with cephalohematoma, 335-336 compound or open, 1418 computed tomography of, 173, 176f, 336, 336f, 1417, 1417f depressed, 336-337, 1417-1418 in fall injuries, 1459-1460 “growing,” 336-337, 1418, 1436 in inflicted neurotrauma, 1452-1453, 1452f late complications of, 1436-1437 linear, 336, 1417, 1417f perinatal, 335-337, 1460 ping-pong, 336, 1417 radiography of, 1418 with subdural hematoma, 337 with subgaleal hematoma, 336, 336f SLC2A1 gene, mutations of, 160-161 SLC6A3 gene, in ADHD, 876 SLC17A5 gene, 700 SLC25A15 gene, 607 SLC25A19 gene, and cortical malformations, 402t SLC35C1 gene, in congenital glycosylation disorder, 650t SLC262A gene, in chondrodysplasia, 650t Sleep disorders of. See Sleep-wake disorder(s) EEG studies of, 222-225, 1225, 1226f arousal patterns in, 225 computer analyses of, 241, 242f-243f frequency distribution in, 223f, 225 infant and childhood, 223-224 neonatal, as ultradian rhythm, 222-223, 223f in newborn, 214f, 217-218 occipital sharp transients in, 224-225, 224f patterns of uncertain significance in, 225 sleep spindles in, 223f, 224 spike discharge in, 224f, 225 vertex waves in, 224 and epilepsy, 274, 1174, 1234 in neurologically compromised children, 1234-1235 non-rapid eye movement, 1225, 1226f physiologic onset time of, 1225 physiology and ontogeny of, 1225 in Pompé’s disease, 698 rapid eye movement (REM), 1225 and breath-holding spells, 1204-1205 infant and childhood, 223-224 neonatal, 223 parasomnias associated with, 1226t in Sanfilippo syndrome, 689 in Segawa’s disease, 762 slow-wave, 1225, 1226f stage 1, 224 stage 2, 224

Volume 2: pages 1181–2408

Index Sleep apnea, 1229-1231 in achondroplasia, 460-461 central, 1230f Sleep apnea continued in Duchenne muscular dystrophy, 1984 obstructive, 1230 with craniofacial anomalies, 1227, 1230 with craniosynostosis, 454 polysomnography in, 1229f, 1230 and seizure control, 1234 and sudden infant death syndrome, 1484 Sleep deprivation, for EEG study, 222 Sleep history, 1226-1227 Sleep latency, 1228 Sleep myoclonus, 1293 benign neonatal, 1299 Sleep position and plagiocephaly, 438-441 and sudden infant death syndrome, 1483 Sleep segments, indeterminate, 222 Sleep spindles, 223f, 224 Sleep starts, 1293 Sleep-activation procedures, 222 Sleep-onset rapid eye movement period (SOREMP), 1228 Sleep-wake cycle neonatal, 222-223 in preterm infant, 55-56 vision loss and, 81 Sleep-wake disorder(s), 1225-1236 and ADHD, 874, 876-877, 942 arousal, 1226t assessment of, 1226-1229 actigraphy in, 1228-1229, 1229f maintenance of wakefulness test in, 1228 multiple sleep latency test in, 1227-1228 polysomnography in, 1227, 1228t, 1229f sleep history in, 1226-1227 sleep-related examination in, 1227 with autism, 917 breathing disturbances, 1229-1231. See also Sleep apnea circadian rhythm, 1225, 1226t, 1233-1235 classification of, 1225-1226, 1226t, 1235-1236 common childhood, 1229-1235 extrinsic, 1225, 1226t future trends in, 1235-1236 in hepatic encephalopathy, 2294 intrinsic, 1225, 1226t with mental disorders, 1226t with mental retardation, management of, 274 with migraine, 1192 movement EEG findings in, 240 restless legs syndrome, 892, 1233, 1302 with neurologic disorders, 1226t in neurologically compromised children, 1234-1235 prevalence of, 1225 with Rett’s syndrome, 1234-1235, 1316-1317 stimulant therapy and, 880, 942 with Tourette syndrome, 892 transition, 1226t Sloping hearing loss, 104, 112-113, 113f Slosson Intelligence Test (SIT), 805 Slow viral infections, 1598 Slow-channel congenital myasthenic syndrome, 1961t Slow-twitch muscle fibers, 1846 Slow-wave sleep, 1225, 1226f Sly’s syndrome, 690 clinical features of, 690 diagnosis of, 690 treatment of, 663t, 690 Small nuclear RNA, 510, 512 Small nucleolar RNA, 510

Small-cell lung cancer, in Lambert-Eaton myasthenic syndrome, 1956 Smallpox vaccine, 2345, 2349 neurologic complications of, 2349 Small-vessel infarction, 1763-1765, 1765f-1766f Smell, 135-139, 144-147 clinical disorders of, 137-139 clinical significance of, 146-147 clinics specializing in, 137, 138t conditions associated with, 139, 140b drug-induced, 144t, 147 genetic and congenital, 146-147 neurologic examination in, 138 psychophysical testing in, 138-139 in fetus, 144-145 in flavor perception, 137 in infants, 145-146 in newborns, 145 orthonasal, 136-137 perception of, ontogeny of, 144-147 retronasal, 136-137, 145-146 confusion with taste, 137 structures involved in, 137f in young children, 146 Smith-Lemli-Opitz syndrome, 361-362, 465t autism in, 919, 922-923 holoprosencephaly in, 396 Smith-Magenis syndrome clinical features of, 389t, 465t genetics of, 465t, 556t SMN genes, in spinal muscular atrophy, 1863t, 1865-1866 Smoking and cleft lip/palate, 468 and mental retardation, 800 “Smooth sailing epilepsy,” 985 Snake venom, 2181 Snellen chart, 20, 78-79, 79f Snoring, 1229-1230 Soap bubble appearance, in lacunar skull, 459 Soccer injury and concussion, 1415 and migraine, 1190-1191, 1199 Social Communication Questionnaire, 913-915 Social interaction in Asperger’s disorder, 909 in autistic disorder, 906-907, 906b in epilepsy, 987-988 epilepsy and, 1171, 1174-1177 Social isolation, in epilepsy, 1177 Social workers, 2361 Sodium abnormal concentrations of, 2324-2326. See also Hypernatremia; Hyponatremia in acute renal failure, 2234-2235 balance, disturbances of, 349-351. See also Hypernatremia; Hyponatremia in cerebrospinal fluid, 154, 154f, 154t in epilepsy, 208 functions of, 349 in metabolic encephalopathies, 346-349 regulation of, 2324 in traumatic brain injury, 1405-1406 Sodium benzoate for glycine encephalopathy, 581-582, 767 for urea cycle disorders, 611 Sodium bicarbonate, for hyperkalemia, 2327 Sodium channel(s) depolarizing conductances in, 994 in epilepsy, 992-994, 1001 generalized, with febrile seizures plus, 1011-1012 neonatal-infantile, 1009-1010 severe myoclonic, of infancy, 1012-1013, 1070 Volume 1: pages 1–1180

Volume 2: pages 1181–2408

lxxxix

Sodium channel(s) continued as therapeutic target, 1002-1004, 1003f hyperpolarizing conductances in, 994 in immature brain, and seizure susceptibility, 1001 voltage-gated, 992-994, 994t Sodium channel blockers, for spinal cord injury, 1542-1543 Sodium channel congenital myasthenic syndrome, 1962 Sodium channel myotonia(s), 2085b, 2086f, 2092f acetazolamide-responsive, 2092f, 2093-2094 clinical features of, 2093, 2093t, 2097f genetics of, 2093-2094, 2093t laboratory tests in, 2094 pathophysiology of, 2094 treatment of, 2093t, 2094 versus chloride channel myotonia, 2091-2092 with periodic paralysis, 2094t without periodic paralysis, 2093t Sodium channel periodic paralysis, 2095t Sodium nitroprusside for hypertension, 2241 in renal failure, encephalopathy induced by, 2266 Sodium oxybate, for cataplexy, 1232 Sodium phenylacetate, for urea cycle disorders, 611 Sodium phenylbutyrate, for urea cycle disorders, 611-612 Software, clinical decision-making, 2405 Solenoid, 509f, 516 Soleus muscle, in gait, 71f Soleus reflex, 19t Solvent(s) poisoning, 2185 teratogenicity of, 2197t volatile, poisoning/intoxication from, 21862187 Soman, 2183 Somatic cell division, 513-514 Somatic cell mutations, 530 Somatosensory seizures, 1042-1043 Somatosensory-evoked potentials, 246, 247f in brain death, 1562 after cardiac arrest, 1493-1495, 1494f in coma, 1392 in hepatic encephalopathy, 2295 in hypoxic-ischemic injury, 283 preoperative, for epilepsy surgery, 1162 in spinal cord injury, 339, 1537, 1547 in traumatic brain injury, 1432-1433 SOMI braces, 1544 Somnolence syndrome, 1739 Sonic hedgehog (Shh) in craniofacial development, 438 and holoprosencephaly, 396-398 in muscle development, 1837 and neural tube development, 366, 395 Sonography. See Ultrasound Sotos syndrome, 408, 427 Sound dimensions of, 99-100 localization of, 100 processing of, 99-102 Sour taste, 141t, 142 South American blastomycosis, 1634-1635 clinical characteristics of, 1635 CNS syndromes in, 1632t diagnosis of, 1632t, 1635 geographic distribution of, 1632t, 1634 laboratory tests in, 1635 management of, 1632t, 1635 risk factors for, 1632t Southern blot analysis, 523 in muscular dystrophy, 1980

xc

Index

Spasmodic dysphonia, 1280 Spasms flexor and extensor, 2365 in focal seizures, 1041 infantile, 1066-1070 ACTH therapy for, 1067-1070, 1068b clinical features of, 1066 clinical laboratory tests in, 1067-1068 CMV infection and, 1606 cognitive and behavioral outcome of, 1173 cryptogenic, 1066 diagnosis of, 1066 EEG findings in, 1065-1067, 1066f-1067f idiopathic, 1066 mechanistic theories for, 1069 MRI findings in, 1069 natural history of, 1068 pathophysiology of, 1069-1070 surgery for, 1068 symptomatic, 1066 treatment of, 1068-1069, 1075 vigabatrin for, 1069 neonatal, 258t-259t, 260 in Sandifer’s syndrome, 1216 Spasmus nutans, 1218-1219, 1300 versus tumor-related nystagmus, 1702 Spastic ataxia, hereditary, 1263 autosomal dominant, 1263 autosomal recessive, of Charlevoix-Saguenay, 1263 Spastic cerebral palsy, 496-498 sleep in, 1234 Spastic diplegia, 497-498 clinical findings in, 498 motor function prognosis in, 500 pathologic findings in, 498 in Segawa’s disease, 762 Spastic hemiplegia, 496-497 clinical findings in, 496-497 motor function prognosis in, 500 pathologic findings in, 497 Spastic hemiplegic gait, 72, 496 Spastic paraplegia, 385t ataxia, and mental retardation, 1263 heat-shock protein deficiency in, 727 tropical, 1622-1623 type 2, 1355 Spastic paraplegic gait, 72 Spastic quadriplegia, 42f, 497-498 clinical findings in, 497 motor function prognosis in, 500 pathologic findings in, 497-498 Spasticity, 1302-1303, 2365-2369 clinical elicitation of, 2365 definition of, 2365 versus dystonia, 1281 in heterotopic ossification, 2365 occupational therapy for, 2366 pain with, 2378 physical therapy for, 2366 in primary microcephaly, 403-404 in Sjögren-Larsson syndrome, 1366-1367 in spinal cord injury, 1544 in traumatic brain injury, 1434 treatment of botulinum toxin for, 2367-2368 goals for, hierarchy of, 2366 intrathecal baclofen for, 2368-2369 nerve and motor point blocks for, 2367 oral medications for, 2366-2367, 2368t orthopedic surgery for, 2369 planning for, 2365-2366, 2366f selective dorsal rhizotomy for, 2368 Spatial agnosia, 822t Specification, in brain development, 364-365 Spectral karyotyping, 561

Spectral metabolites, in proton MR spectroscopy, 179-180, 184f Spectrin, 1843 Speech arachnoid cysts and, 435 assessment of, in infant, 45 in autistic disorder, 907-908 cerebral palsy and, 495 cleft lip/palate and, 468 craniosynostosis and, 454 hearing loss and, 116-118 Speech audiometry, 113 Speech therapists, 2360-2361 Sperm, mutations in, 530 Sphingolipid(s), 659, 660t, 664-665, 664f Sphingolipidoses, 664-683, 664f SPIKES protocol, in palliative care, 2382, 2382b Spike-wave stupor, 1094 Spin echo, in MRI, 173-174 Spina bifida, 366-373 antenatal diagnosis of, 370 associated problems in, 372 bladder and bowel dysfunction in, 372 central nervous system complications of, 372 Chiari II malformation with, 369-372, 375 clinical characteristics of, 369 counseling in, 373 epidemiology of, 366-367 etiology of, 366-367 family history and, 366 hydrocephalus with, 369 magnetic resonance imaging of, 194f, 370, 371f management of, 370-372 in newborn period, 371-372 during pregnancy, 370-371 orthopedic problems in, 372 outcome in, 372-373 pathogenesis of, 364, 366 prevalence of, 369 prevention of, 369-370 risk factors for, 366t teratogens and, 366 ultrasound of, 370 Spina bifida occulta, 367-368 definition of, 367 with diastematomyelia, 1860 Spinal accessory nerve (CN XI), assessment of, in older child, 24 Spinal and bulbar muscular atrophy, 1868 Spinal artery, 1528 anterior, 1876-1877, 1877f occlusion of, 1876-1878 Spinal cord, 1528 alignment of, rule of 2s for, 1535 anatomy of, 1528 blood supply to, 1528 cervical, 1527, 1528f compression of, neurofibromas causing, 773, 773f imaging of, 194f, 195, 195f lesions of, autonomic dysfunction with, 2146f, 2147-2149, 2148f metastases to, magnetic resonance imaging of, 195, 195f neonatal, elasticity of, 339 structural defects of. See also specific defects epidemiology of, 363 etiology of, 363-364, 364t neuroimaging of, 363 pathogenesis of, 363-364 in systemic lupus erythematosus, 1811 vascular anomalies of, 1878-1879 Spinal cord compression, 1530 in leukemia, 1738 Spinal cord contusion, 1530 Volume 1: pages 1–1180

Spinal cord injury, 1527-1552, 1876, 2356-2359 age at time of, 1547 anatomical considerations in, 1527-1528, 1528f apoptosis in, 1531 autonomic dysfunction in, 2146f, 2147-2149, 2148f, 2361-2362 axial compression, 1528, 1529f, 1530 cervical, 339, 1527-1528 classification of, 1533, 1534f, 2357, 2358t clinical assessment of, 1532-1537, 2357-2358 clinical syndromes of, 1537-1540 complete, 1537-1538 defecation disorders in, 2167 drug therapy for, 1541-1542 early changes in, 1531, 1531f electrophysiologic evaluation of, 339, 1537, 1547 epidemiology of, 1527, 2356 etiology of, 1527-1528, 2356-2357 forward flexion, 1528-1530, 1529f general physical examination in, 1533 heterotopic ossification in, 2363-2364 history of, 1532-1533 hyperextension, 1528, 1530 immobilization of, 1540, 1543-1544 immunopathology of, 1531-1532 impairment scale in, 1533, 1533b, 1546 incidence of, 1527, 2356 incomplete, 1538 intraspinal extramedullary, 1530, 1532, 1539-1540 pathogenesis and pathologies of, 1532 intraspinal intramedullary, 1530-1532, 1537-1539 pathogenesis and pathologies of, 1530-1532 investigational treatments for, 1542-1543 laboratory studies in, 1535-1537 late changes in, 1532 lateral flexion, 1528, 1529f, 1530 level of, key muscles groups for determining, 2357, 2358t lower, differentiating features of, 2163t lumbar puncture in, 1537 management of, 1540-1546 long-term, 1543-1546 short-term, 1540-1543 micturition disorders in, 2162-2163, 2163t molecular mechanisms in, 1532 morbidity in, 1546 mortality in, 1527, 1546 necrosis in, 1531, 1531f neurologic examination in, 1533-1535 neuropathology of, 1530-1532 orthotic devices in, 2357-2359, 2358f pain management in, 2358 pathogenesis of, 1528-1530 pathophysiology of, 2356-2357 perinatal, 334, 339-340, 1527 diagnosis of, 339 differential diagnosis of, 339 incidence of, 339 morbidity and mortality in, 339 outcome of, 339-340 radiologic studies of, 339, 340f physical therapy in, 1544 postoperative, in cardiac surgery, 2215 prevention of, 1547 prognosis of, 1546-1547, 2357 psychologic therapy in, 1545 without radiographic abnormality (SCIWORA), 339, 1528-1529, 1535-1536

Volume 2: pages 1181–2408

Index Spinal cord injury continued radiographic evaluation of, 339, 340f, 1535-1537, 1536f, 1547 recovery in, mechanism of, 1547 rehabilitation in, 1544, 2356-2359 rotation, 1528, 1529f, 1530 supportive care in, 1540, 1544 surgical management of, 1545-1546, 1545f effectiveness of, 1546 indications for, 1546 timing of, 1546 very late changes in, 1532 wheelchairs in, 2357-2359 Spinal cord transection, 1530 Spinal cord tumors, 1687, 1730-1735 adjuvant therapy for, 1734 chemotherapy for, 1734 clinical characteristics of, 1730 complications of, 1734-1735, 1735f computed tomography of, 1731, 1731f CSF analysis in, 162t, 1731 diagnostic studies of, 1731-1732, 1731f extramedullary, 1732, 1732t hair abnormalities with, 1732, 1732f intramedullary, 1732-1733, 1732t versus syringomyelia, 1862 magnetic resonance imaging of, 1731, 1731f management of, 1733-1734 misdiagnoses in children with, 1730, 1730t pain characteristics with, 1730 plain films of, 1731, 1731f radiation therapy for, 1734 surgery for, 1733-1734 types of, 1732-1733, 1732t Spinal epidural abscess, 1539, 1589 Spinal fluid. See Cerebrospinal fluid Spinal fusion, 1545-1546 Spinal muscular atrophies, 1862-1868 autosomal recessive, 1865 chronic, 1864 classification of, 1863, 1863t clinical laboratory tests in, 1866-1867 complications of, 1867, 1867f congenital nonprogressive, of lower limbs, 1868t distal infantile, with diaphragmatic paralysis (SMARD1), 1864, 1868t genetics of, 1863t, 1865-1866 historical perspective on, 1862-1863 infantile onset, 1863-1864 intermediate, 1864 juvenile, 1864 management of, 1867-1868 mild, 1864-1866 motor function in, 1868 muscle biopsy in, 1866f, 1867 pontocerebellar hypoplasia with, 394, 1868t rare and atypical, 1868t, 1869-1870 scapuloperoneal, 1868t, 1869 type I, 1863-1864, 1863f, 1863t type II, 1863-1864, 1863t, 1864 type III, 1863-1865, 1863t X-linked infantile, with arthrogryposis, 1868t Spinal nerve(s) extremity muscles innervated by, 30t-32t motor functions of, 28t-29t trunk muscles innervated by, 33t tumors of, incidence of, 1719t Spinal pain, 1730 Spinal reflexes, in spinal cord injury, 339 Spinal shock, 1537-1538 Spindle delta bursts, 215 Spindle-like fast waves, 215 Spine bony, 1527-1528, 1528f cervical, 1527, 1528f ligaments of, 1527-1528

Spine continued lumbar, 1527, 1528f thoracic, 1527, 1528f Spinocerebellar ataxia(s), 1254-1264, 1255t, 1286 age of onset, 1255t fibroblast growth factor 14, 1255t, 1261-1262 Friedreich’s. See Friedreich’s ataxia genetics of, 1254-1255, 1255t infantile-onset, 1254 recessive, non-Friedreich’s type 1, 1253 type 1, 1255-1256, 1255t, 1286 type 2, 1255t, 1256-1257, 1286 type 3, 1255t, 1257, 1286 type 4, 1255t, 1257-1258 type 5, 1255t, 1258 type 6, 1255t, 1258 type 7, 1255t, 1258-1259 type 8, 1255t, 1259 type 10, 1255t, 1259 type 11, 1255t, 1260 type 12, 1260 type 13, 1255t, 1260 type 14, 1255t, 1260 type 15, 1255t, 1260 type 16, 1255t, 1260 type 17, 1255t, 1260-1261 type 18, 1255t, 1261 type 19, 1255t, 1261 type 20, 1255t, 1261 type 21, 1255t, 1261 type 22, 1255t, 1261 type 23, 1255t, 1261 type 25, 1255t, 1261 vision loss with, 88t X-linked, 1263-1264 Spinocerebellopathies, 823t Spinocerebellum, 1243 Spiral ganglion of Corti, 99, 99f Spiramycin, for toxoplasmosis, 1656 Spiritual concerns, in dying, 2383 Spirituality, 2391 Spirometry, in Duchenne muscular dystrophy, 1984 Splice acceptor site, 512 Splice donor site, 512 Splice junctions, 512 Spliceosomes, 512 Splicing, of RNA, 512-513, 512f mutations in, 531 Spondyloepiphyseal dysplasia, 465t Spongiform leukoencephalopathies, 1360-1364 classification of, 1345, 1345t Spongy degeneration of brain. See Canavan’s disease Spongy degeneration of gray matter. See Alpers’ disease Spongy glioneuronal dystrophy. See Alpers’ disease Sporadic progressive external ophthalmoplegia with ragged-red fibers, 2054 Sports concussion, 1415-1417 epidemiology of, 1415-1416 pathophysiology of, 1416, 1416f return to play guidelines in, 1429-1430, 1429t sequelae of, 1416-1417 symptomatology of, 1416 Sports injuries and headache, 1190-1191, 1199 spinal cord, 1527-1528, 1547, 2356-2357 traumatic brain, 1401 Sprotte needle, 157, 157f Sprouting hypothesis, 272 Squamosal suture, 436, 436f Square window technique, 54f-55f SRY gene, 532 Volume 1: pages 1–1180

Volume 2: pages 1181–2408

xci

SSRIs. See Selective serotonin reuptake inhibitors (SSRIs) St. Louis encephalitis, 1614-1615 clinical features of, 1614 diagnosis of, 1614-1615 EEG findings in, 238-239 outcome of, 1603t, 1614-1615 treatment of, 1614-1615 Stain(s) of CSF, 160 cytogenetic, 544 Stairs, falls down, 1459 Stance phase, of walking, 70, 70f Stanford-Binet Intelligence Scales, 803t, 805, 845 Stapes footplate, 97, 98f, 101 Staphylococcal infection. See also specific types brain abscess in, 1589 cerebrospinal fluid, 1572 meningitis in, 1580t, 1581 Staphylococcus aureus infection epidural abscess in, 1589 meningitis, 1580t, 1581 myositis in, 2082 shunt, 432, 1574 spinal, 1539 Staphylococcus epidermidis infection epidural abscess in, 1589 meningitis, 1581 shunt, 432 Stargardt’s disease, 88-89 Staring attacks, versus absence seizures, 1025 “Startle disease,” 766 Startle epilepsy, 1217 Startle response, in hyperekplexia, 1217-1218, 1302 Static conditions, 7 Static nuclear bag fibers, 65 Statural growth, disorders of, 2120-2121 Status epilepticus, 1091-1102 absence, 1093b, 1094 in adults versus children, 1095, 1095t age dependence in, 1095-1096, 1096f breath-holding spells and, 1206 classification of, 1093-1094, 1093b clonic, 1093b, 1094 definition of, 1093 EEG monitoring in, 1097-1098 electrical, 1057 epidemiology of, 1094-1095 etiology of, 1095-1096, 1095t febrile, 1081-1083 generalized convulsive, 1093, 1093b generalized nonconvulsive, 1093-1094, 1093b historical perspective on, 1093 incidence of, 1094-1095, 1101 laboratory testing in, 1097 management of, 1096-1100 emergency, goals of, 1096, 1096b overview of, 1096-1097 medical complications of, 1100, 1101b morbidity in, 1091, 1101-1102 mortality in, 1091, 1095t, 1101-1102 myoclonic, 1093b, 1094 neuroimaging in, 1097 partial, 1093, 1093b pathophysiology of, 1091-1092 post-ischemic, 1492 prognosis of, 1100-1102 recurrence of, 1096, 1096f, 1101 refractory, 1100-1102 sequelae of, 1101-1102 in sleep, 1174, 1234 subtle generalized convulsive, 1093 supportive care in, 1097 theophylline and, 2191

xcii

Index

Status epilepticus continued therapy for, 1096-1100 medical, 1098-1100 Medical College of Virginia protocol for, 1098t, 1099 recommended initial intravenous doses for, 1099-1100, 1099t tonic, 1093b, 1094 Stavudine toxicity, 2192 Steinfeld’s syndrome, 465t Stellate cells, 1241 Stem cell transplantation for aspartylglycosaminuria, 693 for fucosidosis, 692 for neuronal ceroid lipofuscinosis, 703 for Niemann-Pick disease, 675 for spinal cord injury, 1542 Steppage gait, 74 Stepping maneuver, 60 in preterm infants, 59, 59f Stepping test, in vestibular dysfunction, 125b, 126 Stereognosis, 25-26 Stereotactic lesionectomy, 1163 Stereotypy, 887, 1219-1220, 1272t, 1298-1299 in autistic disorder, 908, 915 clinical characteristics of, 1299 physiologic, 1299 in Rett’s syndrome, 910, 1219, 1315 treatment for, 1299 Sternocleidomastoid muscle, 24 Steroid sulfatase deficiency, 556t Steroid therapy. See also Corticosteroid(s); specific agents toxicity of, 2193 Stibophen, for schistosomiasis, 1673 Stickler’s syndrome, 443f, 465t Stiff baby syndrome, 766, 1218 Stiff person syndrome, 2105-2106 clinical features of, 2101t, 2105 genetics of, 2101t pathophysiology of, 2105 treatment of, 2101t, 2106 Still, George, on ADHD, 871 Stimulant(s), 940-943 for ADHD, 877-881, 878t, 939t, 940-943 comorbid with tic disorders, 897, 942 adverse effects of, 880, 937, 942-943, 2190 for Asperger’s disorder, 925 assessment for, 940-941 for autism, 925, 940 clinical applications of, 940 clinical management of, 940-942 dosage of, 939t, 941 “drug holidays” from, 941-942 drug interactions of, 943 and growth, 880, 937, 942 initiation and titration of, 941 labeled and off-labeled use of, 938t monitoring with, 941-942 over- and undertreatment with, 940 pharmacology of, 939t, 940 rebound effects of, 942 sexual side effects of, 941 toxicity of, 2190 “zombie” effect of, 942 Stimulant toxidrome, 2178-2179 Stimulation mapping, 1162 STK9 gene, and lissencephaly, 415 Stool-bulking agents, 2168 Stool-hardening agents, 2168 Stop codons, 511 Strabismic amblyopia, 87 Strabismus, 80, 80f, 81 in children, 87 in infant, 39, 81

Strangulation injury, 1456f, 1457, 1457f, 14881489 Strangulation syncope, 1212 Strattera. See Atomoxetine Streptococcal infection. See also specific types brain abscess in, 1589 epidural abscess in, 1589 group A beta-hemolytic, 893 and rheumatic fever, 1806 and Sydenham’s chorea, 1278-1279, 1806-1808 group B and cerebral palsy, 494 and meningitis, 1571, 1577-1578, 1581 meningitis in, 1571 pediatric neuropsychiatric disorders associated with, 893, 1279, 1807 Streptococcus pneumoniae meningitis, 1571, 1581-1582 after cochlear implants, 1574 extra-axial fluid collection in, 1579f immunoprophylaxis against, 1584 magnetic resonance imaging of, 1576f neurologic sequelae of, 1577-1578, 1578f prognosis of, 1583 recurrent, 1585 sepsis in, 1578-1579 treatment of, 1581 vaccine against, 2350 Streptokinase, 1778-1779 Streptomycin, for tuberculous meningitis, 1586 Stress incontinence, 2163 Stress management, for migraine, 1192, 1192b Stria vascularis, 97-98, 99f Striatal toe, 1280 Striate cortex, visual processing in, 77 Striated muscle antibodies, in myasthenia gravis, 1950 Striatum, 1272-1273, 1273f infantile bilateral necrosis of, 1286 in movement disorders, 1274-1275, 1275f String of beads sign, in angiography, 1774 String sign, in angiography, 1774 Stroke arterial ischemic, 1759-1795 age-dependent features of, 1765-1766 anatomy and physiology in, 1760-1762, 1760f-1761f angiography (conventional) in, 1764f, 1770f-1773f, 1774-1775 animal models of, 1763 antithrombotic therapies for, 1775-1779 arterial dissection and, 1769 arteriopathies and, 1769-1772 cell death/apoptosis in, 1762-1763 in children versus adults, 1759, 1766 clinical features of, 1765-1766 cognitive effects of, 1763 computed tomography of, 1774 definition of, 1759, 1766 Doppler studies of, 1775 epidemiology of, 1759-1760 epilepsy/seizures with, 1781 etiology of, 1766-1767, 1768b genetics of, 1766-1767 hematologic disorders and, 1769 hypothermia in, 1763, 1779 immunosuppressive therapy in, 1779 incidence of, 1759-1760 infarction mechanisms in, 1762-1763 infection and, 1767 interventional radiologic techniques in, 1780 in leukemia, 1736, 1736f magnetic resonance angiography in, 1774 magnetic resonance imaging of, 1774 metabolic vasculopathies and, 1773-1774 Volume 1: pages 1–1180

Stroke continued migraine and, 1773 mortality rate for, 1781 motor effects of, 1765f, 1781 moyamoya disease and, 1769, 1772-1773 neonatal, 329-330, 330f neuronal salvage in, 1763 neuroprotective agents in, 1779 neuroprotective care in, 1779 neurosurgical procedures for, 1779-1780 neurotoxic biochemical cascade in, 1763 non-antithrombotic therapies for, 1779-1781 outcome of, 1780t, 1781 pathophysiology of, 1760-1765 perfusion MR of, 1775 postradiation vasculopathy and, 1769, 1770f prothrombotic disorders and, 1767-1769, 1781 radiographic features of, 1774-1775 recurrent, 1781 rehabilitation in, 1780 risk factors for, 1766-1774 single-photon emission tomography of, 1775 socioeconomic impact of, 1760 specialized care in, 1780-1781 supportive care in, 1779 thromboembolic mechanisms in, 1762 transfusion therapy in, 1779 treatment of, 1775-1781 varicella-zoster virus and, 1608-1609, 1766, 1769-1770, 1771f, 1772 vascular patterns of, 1763-1765, 1764f-1766f vasculitis and, 1771-1772, 1772f arteriopathic, 1769-1772, 2218-2219 in cardiac disorders, 1767, 1776 postoperative, 2216-2219 preoperative, 2210-2211 cardioembolic, 2216f, 2217 hemorrhagic, 1759, 1788-1795 aneurysms and, 1794-1795 versus arterial ischemic stroke, 1788 disorders causing, 1788b general features of, 1788-1789 intracranial hemorrhage and, 1788-1790 outcome of, 1788 subarachnoid hemorrhage and, 1788-1790 traumatic intracranial hemorrhage and, 1790 vascular disorders underlying, 1790-1795 vascular malformations and, 1790-1794 hyperhomocysteinemia and, 329-330, 332, 1773-1774, 2320 iron deficiency and, 1766, 1769, 2322 neonatal, 329-334 central venous, 329-330, 330f and cerebral palsy, 492-493 classification of, 329-331 clinical presentation of, 331 cognitive effects of, 333 conditions associated with, 329 definition of, 329 diagnosis of, 331 epidemiology of, 329 epilepsy/seizures with, 332-333 evaluation of, 331-332, 331b incidence of, 329 magnetic resonance angiography of, 331 magnetic resonance imaging of, 330, 330f, 331 magnetic resonance venography of, 330-331 management of, 332

Volume 2: pages 1181–2408

Index Stroke

continued in acute period, 332 in chronic period, 332 mortality rate for, 329, 1759 motor effects of, 333 outcomes of, 332-334 predictors of, 333-334 prevalence of, 329 prothrombotic disorders and, 331-332, 331b recurrence of, 333 rehabilitation in, 332, 334 risk factors for, 329-331 sensory effects of, 333 vascular territory infarcted in, 333-334 neuroimaging of, 182, 184-185, 189, 191. See also specific stroke type paradoxical embolic, 2216f, 2217 perinatal, 329 and cerebral palsy, 493 in renal disease, 2244 in renal transplant patients, 2251 thromboembolic cardiogenic, 2216-2219 echocardiography of, 2217f epidemiology of, 2216 mechanisms of, 2216f, 2217 postoperative factors in, 2217-2218 prevention of, 2218 risk factors for, 2216-2217 Structural congenital defects, 363-469. See also specific defects epidemiology of, 363 etiology of, 363-364, 364t neuroimaging of, 363 pathogenesis of, 363-364 Structured hallucinations, 1043 Stupor definition of, 1378 with increased intracranial pressure, 1517 Sturge-Weber syndrome, 83, 782-784, 1049 angiomas in, 782-783, 782f, 784 calcifications in, 783, 783f classification of, 771-772, 782 clinical features of, 771t, 782-783, 782f EEG findings in, 783 epilepsy surgery for, 1153 management of, 784 neurologic manifestations of, 782-783 pathology of, 783-784, 784f positron emission tomography in, 196 radiologic findings in, 783, 783f Stuttering, 848 Subacute measles encephalitis, 1617-1618 Subacute sclerosing panencephalitis, 1617-1618, 2348 clinical features of, 1617 diagnosis of, 1617-1618 EEG findings in, 234, 239 myoclonic seizures in, 1030 neuroimaging in, 1618, 1618f outcome of, 1603t, 1618 Subarachnoid hemorrhage, 1403, 1412, 1788-1790 in aneurysm, 1793, 1794f clinical presentation of, 338, 1412, 1789 computed tomography of, 338, 338f, 1412, 1413f diagnosis of, 159-161, 338 Doppler ultrasound of, 170 extensive, differential of, 1455 in fall injuries, 1459 in hemorrhagic stroke, 1788-1790 in inflicted neurotrauma, 1455 outcome of, 1790 pathophysiology of, 1789 in perinatal trauma, 338 incidence of, 338 outcome in, 338

Subarachnoid hemorrhage continued risk factors for, 1790 spinal, 1539 Subarachnoid space, 1402, 1402f bacterial infection of, 1572, 1579 Subcortical band heterotopia(s), 410-417, 411f genetic testing for, 415 Subcortical cyst(s) leukoencephalopathy with, without megaloencephaly, 1364 megaloencephalic leukoencephalopathy with, 1363f, 1364 Subcortical injury, hypoxic-ischemic, 284 clinical features of, 284 computed tomography of, 284, 284f diagnosis of, 284 magnetic resonance imaging of, 284 pathogenesis of, 284 Subcortical nodular heterotopia, 419f, 420 Subdural catheter, for monitoring intracranial pressure, 1423 Subdural effusions in bacterial meningitis, 1583 chronic, in inflicted neurotrauma, 1454f, 1455, 1455f Subdural empyema, diffusion-weighted imaging of, 187 Subdural hematoma, 1402f, 1403, 1413 acute, 1413, 1453-1454 arachnoid cysts and, 435 chronic, 1413, 1435-1436, 1448, 1455 clinical presentation of, 337, 1413 computed tomography of, 173, 337, 1413, 1413f, 1447f, 1453f-1456f in dialysis patients, 2246 in fall injuries, 1459, 1459f and focal seizures, 1049 in inflicted neurotrauma, 1447f, 1448, 1453-1455, 1453f-1456f magnetic resonance imaging of, 337, 1435 management of, 337-339, 1413, 1435-1436 mechanisms of, 1453 in osteogenesis imperfecta, 1460 in perinatal trauma, 337-338, 1460 incidence of, 337 laboratory evaluation of, 337 outcome of, 338-339 risk factors for, 337 spinal, 1539 subacute, 1413, 1435-1436, 1448, 1455 Subdural hemorrhage, computed tomography of, 173, 173f, 176f Subdural hygroma, arachnoid cysts and, 435 Subependymal nodules, in tuberous sclerosis, 780f, 781 Subfalcine herniation, 1410 Subgaleal hematoma, 334-336, 1402f benign, 336 blood loss in, estimation of, 336 versus cephalohematoma, 335-336 clinical presentation of, 336 computed tomography of, 336, 336f incidence of, 336 in inflicted neurotrauma, 1452, 1452f laboratory evaluation of, 336 massive management of, 336 mortality in, 338 outcome of, 338 skull fracture with, 336, 336f subdural hematoma with, 337 Subgaleal space, 1402 Sublingual administration, of antiepileptics, 1120 Subluxation, in muscle overreactivity, 2369 Submersion injury. See Drowning; Near-drowning Volume 1: pages 1–1180

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xciii

Submetacentric chromosomes, 516 Subscapular nerve, 28t Subscapularis muscle, testing of, 34t Substance abuse, 2173, 2186-2191. See also specific drugs testing for, 2174-2175 Substance P, in hepatic encephalopathy, 2296 Substantia nigra, 1272-1274, 1273f in movement disorders, 1274-1275, 1275f Substrate oxidation defects, 2056 Substrate reduction therapy for Gaucher’s disease, 673 for lysosomal storage diseases, 663-664 Substrate transport defects, 722-723, 2056 Substrate utilization defects, 723-725 Subtelomeric probes, 805-807 Subtelomeric region abnormalities, 548, 548f Subthalamic nuclei, 1272-1274, 1273f in movement disorders, 1274-1275, 1275f Subtle generalized convulsive status epilepticus, 1093 Subtle seizures, neonatal, 258-259, 1094 Subtraction SPECT scan, 1159 Subungual fibroma, in tuberous sclerosis complex, 779 Subventricular zone, 398 in hypoxic-ischemic injury, 305-306, 306f Succinate dehydrogenase deficiency, 725 Succinate-coenzyme Q reductase deficiency, 725-726 infantile encephalomyopathic form of, 726 myopathic form of, 726 Succinic semialdehyde dehydrogenase (SSADH) defect, 357f, 360-361, 766 clinical features of, 350t-351t, 360 diagnosis of, 360-361 MRI findings in, 352t, 360 Succinyl-5-amino-4-imidazolecarboxamide ribosiduria (SAICA), 350t-352t, 359 Succinylcholine, adverse reactions to, 2195 Sucking reflex, 48t, 60 Sucrose analgesic properties of, 141-142 for pain, 2376 Sudden cardiac arrest, 2151 in children and adolescents, 1491-1497 Sudden infant death syndrome, 1482-1485 age at death, 1482 definition of, 1482 diagnosis of, certification of, 1482 epidemiology of, 1482-1483 incidence of, 1482 management of, 1485 pathophysiology of, 1484-1485 prediction of, 1485 risk factors for, 1483, 1483b, 1483t sleep position and, 1483 Sufentanil, in traumatic brain injury, 1422 Suffocation syncope, 1212 Suicide physician-assisted, 2395-2396 poisoning in, 2173 risk of, serotonin reuptake inhibitors and, 948-949, 952 Sulcus limitans, 379-380 Sulfadiazine for granulomatous amebic encephalitis, 1651-1653 for toxoplasmosis, 1656, 2082 Sulfadoxine-pyrimethamine, for malaria, 1659 Sulfamethoxypyridazine, for South American blastomycosis, 1635 Sulfatase deficiency, multiple, 682-683 Sulfatide(s), 680 Sulfatide lipidosis, 680-682. See also Metachromatic leukodystrophy

xciv

Index

Sulfisoxazole fetal/neonatal effects of, 2195 for primary amebic meningoencephalitis, 1650 Sulfite oxidase deficiency, 358, 582f, 584 clinical features of, 350t-351t, 358, 584 diagnosis of, 358 laboratory tests in, 584 management of, 358 MRI findings in, 352t pathophysiology of, 584 treatment of, 584 Sulfur amino acid metabolism, 582, 582f Sulpiride, for tic disorders, 896 Sulthiame, for idiopathic epilepsy, 1050 Sumatriptan for cluster headache, 1199 for cyclical vomiting syndrome, 1191, 2286 for migraine, 1193t, 1195, 2378 SUMF1 gene, 682 Summitt’s syndrome, 451 Superficial venous system, 1782, 1782f Superior cerebellar peduncle, 1242f, 1243 Superior gluteal nerve, 28t Superior oblique muscle, 20-22, 21f, 21t Superior rectus muscle, 20-22, 21f, 21t Superior sagittal sinus, 1781-1782, 1782f thrombosis of, 1782f, 1784 Supernumerary marker chromosomes (SMCs), 547 Superoxide, in hypoxic-ischemic injury, 301-302, 302f Superoxide dismutase (SOD) in amyotrophic lateral sclerosis, 1871 in hypoxic-ischemic injury, 1503 in Menkes’ disease, 1324 in spinal cord injury, 1543 Supinator muscles, testing of, 34t Supine hypertension, 2142 Supplementary sensorimotor seizures, 1213-1214 Suprachiasmatic nucleus, in sleep physiology, 1225 Supranuclear bulbar palsy, 25 Suprapubic extensor reflex, 43t Suprascapular nerve, 28t Supraspinatus muscle, testing of, 34t Supratentorial tumors, 1718-1724. See also specific types Suramin, for African trypanosomiasis, 1664 Surfactant, in lysosomal storage diseases, 665 Surveillance, Epidemiology, End Results (SEER) Registries, 1687, 1687f-1688f, 1692-1693 Susceptibility-weighted imaging, 191 of cavernous angioma, 191, 192f in hypertensive encephalopathy, 191, 193f Sutures, cranial, 436-437, 437f closure of, 436-437, 438t premature, 441-454, 1523-1524. See also Craniosynostosis congenital abnormalities of, 436 examination of, 38, 50 Sweating evaluation of, 2137 gustatory, 2137, 2138f Sweet taste, 141-142, 141t analgesic properties of, 141-142 in breast milk, 141 Sweet wormwood, for malaria, 1659 Swelling, cerebral. See Cerebral edema Swimming, and drowning/near-drowning, 1485-1488 Swing phase, of walking, 70, 70f

Sydenham’s chorea, 1278-1279, 1806-1808, 2225-2226 clinical characteristics of, 1806-1807, 2225 EEG findings in, 1807 laboratory findings in, 1807-1808, 2225-2226 radiographic features of, 1807-1808 treatment of, 1808, 2225 Sylvian fissure, arachnoid cyst of, 434 Sympathetic nervous system, 2129, 2130f disorders of, 2131-2132 Sympathetic skin response, 2137, 2139f Sympathomimetic agents, for micturition disorders, 2165 Sympathomimetic toxidromes, 2178-2179 Symptomatic epilepsies, 981, 982t localization-related, 1046 management of, 1049-1050 myoclonic, of infancy, 1071 Symptomatic infantile spasms, 1066 Synacthen test, 2140 Synaptic defects, in congenital myasthenic syndromes, 1960, 1961t Synaptic elimination, 1837 Synaptic physiology, 995-997 Synaptic potentials, in EEG, 206-207 Synaptic transmission, 995-996 excitatory, 995-996, 1001 in immature brain, and seizure susceptibility, 1001-1002 inhibitory, 995, 1001 Synaptic vesicle paucity, in congenital myasthenic syndromes, 1960 Synaptonemal complex, 514 Syncope, 1209-1213 breath-holding spells and, 1203 cardioinhibitory, 2149 in cardiovascular disorders, 2135-2136 cardiovascular-mediated, 1210 classification of, 1210 convulsive, 1212 defecation-induced, 2150 definition of, 1209 drug-induced, 1212 EEG findings in, 240 emotional, 2132 hair-grooming, 1212 hyperventilation, 1212 incidence of, 1209-1210 micturition-induced, 2150 mixed, 2149, 2150f neurally mediated, 1210, 2149-2151 neurocardiogenic, 1210-1212 clinical features of, 1210 versus epilepsy, 1210 pathophysiology of, 1210-1211 tilt-table testing in, 1211 treatment of, 1211-1212, 1211b psychogenic, 1212-1213 reflex, 1212. See also Breath-holding spells; Reflex anoxic seizures situational, 1212, 2149-2151 suffocation or strangulation, 1212 vasodepressor, 1210, 2149 vasovagal, 1210, 2132, 2149-2150 Syndrome of inappropriate secretion of antidiuretic hormone (SIADH), 2125 conditions associated with, 2125 diagnostic criteria for, 2125 in meningitis, 1576, 1582 treatment of, 2125 Synophrys in developmental disorders, 835t in mental retardation/developmental delay, 813b Synostosis. See also Craniosynostosis coronal, 441t, 445, 445f-446f, 1523 lambdoid, 441t, 445 Volume 1: pages 1–1180

Synostosis continued metopic, 445-446 multiple, 446-447 versus plagiocephaly, 441t sagittal, 444f, 445, 445f, 1523 single, 445 Syntax, 849-850, 907t Syntropin, 1841f Syphilis, 1586-1587 acquired, 1587 clinical characteristics of, 1586-1587 congenital, 1586-1587 hearing loss with, 109 diagnosis of, 1587 epidemiology of, 1586 treatment of, 1587 Syringobulbia, 1861 Syringomyelia, 1860-1862, 1861f basilar impression and, 461 Chiari I malformation and, 388-389, 1861-1862 clinical features of, 1862 congenital, 1861 versus intramedullary tumors, 1862 magnetic resonance imaging of, 1861 management of, 1862 osteopetrosis and, 456 post-traumatic, 1532, 1862 Systemic lupus erythematosus, 1808-1815 brainstem dysfunction in, 1811 cerebrovascular disease in, 1771, 1810 chorea in, 1810, 1814 classification of, revised criteria for, 1809, 1809b CNS infections in, 1811 CNS pathology in, 1815 computed tomography in, 1812-1814, 1813f cranial nerve dysfunction in, 1811 headache in, 1810 hypertensive encephalopathy in, 1810-1811 laboratory findings in, 1809t, 1812 magnetic resonance imaging in, 1812-1814, 1813f management of, 1809 meningitis in, 1811 myopathy in, 1811 neurodiagnostic testing in, 1812-1814 neurologic manifestations of, 1809-1815, 1809t treatment of, 1814-1815 neuropsychiatric symptoms in, 1810 pathogenesis of, 1812 peripheral neuropathy in, 1811 prognosis of, 1809 Reyelike syndrome in, 1810 seizures in, 1809-1810, 1814 single-photon emission computed tomography in, 1814, 1814f spinal cord dysfunction in, 1811

T T bands, 516 T cell(s) in Duchenne muscular dystrophy, 1975 in multiple sclerosis, 1346, 1349 in spinal cord injury, 1532 T tubules, 1841, 1841f in muscle contraction, 1848-1850 Tabun, 2183 TAC (tetracaine, epinephrine, and cocaine), 2377 Tachycardia, autonomic dysfunction and, 2131-2132 Tachycardia syndrome, postural, 2151f, 2152 Tacrolimus and hemolytic-uremic syndrome, 2257

Volume 2: pages 1181–2408

Index Tacrolimus continued for renal transplant patients, complications with, 2250-2252 toxicity of, 2191 and vision loss, 91-92 Tactile agnosia, 822t Taenia crassiceps, 1671 Taenia multiceps, 1671 Taenia serialis, 1671 Taenia solium, 1669-1670, 1669f. See also Cysticercosis Tafazzins, 592, 728, 1995 Takayasu’s arteritis, 1771, 1825 laboratory findings in, 1818t neurologic manifestations of, 1818t, 1825 treatment of, 1825 Talipes equinovarus, in Friedreich’s ataxia, 1249 Talipes planus, 67 Talwin. See Pentazocine Tandem gait, blindfolded, 125b, 126 Tangent screen testing, 79 Tangier disease, 1907 biochemistry of, 1907 clinical characteristics of, 1907 management of, 1907 Tapeworms, 1648t, 1668-1670, 1669f Tardive chorea, 1279, 1301-1302 Tardive dyskinesia, 1288, 1301-1302 haloperidol and, 966 neuroleptic agents and, 965t, 966, 968, 1301-1302, 2189 symptoms of, 1302 treatment of, 1302 Tardive dystonia, 1288, 1301-1302 Tardive movement disorders, 1301-1302 symptoms of, 1302 treatment of, 1302 withdrawal emergent, 1302 Tardive tourettism, 888 Target range, 1121 Tarui’s disease, 635-636 biochemistry of, 635 clinical manifestations of, 622t, 635-636 enzyme defect in, 622t genetics of, 636 glycogen structure in, 622t laboratory tests in, 636 Taste, 135-144 in Bell’s palsy, 1887-1888 bitter, 141t, 142 clinical disorders of, 137-139 clinical significance of, 143-144 clinics specializing in, 137, 138t conditions associated with, 139, 139b drug-induced, 144, 144t neurologic examination in, 138 psychophysical testing in, 138-139 confusion with retronasal smell, 137 definition of, 136 developmental changes in, 141, 141t, 143 in fetus and preterm infants, 140-141 in flavor perception, 137 in newborns, infants, and young children, 141-142 perception of, 23-24 ontogeny of, 140-144 preferences in, ontogeny of, 140-144 receptors for/innervation of, 135f, 136, 136f salty, 141t, 142 preferences for, early experiences and, 143 sour, 141t, 142 sweet, 141-142, 141t umami, 141t, 142 Taste receptor genes (TASR), 136 Taybi-Linder syndrome, 405

Tay-Sachs disease, 667-669 classic infantile, 667-668 clinical features of, 667-668, 667f epidemiology of, 667-668 genetics of, 531 late-onset, 668 macular cherry-red spot in, 667, 667f muscular tone in, 69 screening for, 667-668 vision loss with, 88t T-box transcription factor-22 gene (TBX22), in cleft lip/palate, 467, 467t Teachers, school behavior assessment by, 7, 11f-12f Teardrop fracture, spinal cord, 1528 Technetium 99m ethylene cysteinate, 195 Technetium 99m hexamethylpropyleneamine oxime, 195 Technetium blood flow study, in brain death, 1559, 1560f Tectum, beaked, in Chiari II malformation, 375, 375f Tegretol. See Carbamazepine Telangiectasia, in ataxia-telangiectasia, 1251, 1252f Telemedicine, 2406-2407 Telencephalon, 380f absence of, 385-386 regional boundaries within, 383 Teleopsia, in Alice in Wonderland syndrome, 1189 Telethonin, 1840, 1969, 1970f diseases associated with, 1842t in limb-girdle muscular dystrophy, 1988t, 1995 Television watching, and ADHD, 876 Telomeres, 516, 541, 543f Telophase, 513, 514f-515f Temozolomide for oligodendroglioma, 1724 as pro-drug, 1746 Temperature, body. See also Hyperthermia; Hypothermia in hypoxic-ischemic injury, 291, 304-305, 1500 in impaired consciousness/coma, 1391 in intracranial hypertension, 1521 regulation of, 1225 in traumatic brain injury, 1425 Temperature perception, anterior spinal artery occlusion and, 1877-1878 Temporal arteritis, 1824-1825 laboratory findings in, 1818t neurologic manifestations of, 1818t, 1824-1825 Temporal bone, 97 Temporal bone banks, 106 Temporal lobe epilepsy, familial mesial, 1013-1014 Temporal lobectomy, for epilepsy, 1163 with amygdalohippocampectomy, 1152, 1163 cost of, 1151 historical background of, 1152-1153 Temporal sawtooth waves, in EEG, 216 Temporalis muscle, 22 Temporomandibular joint dysfunction, 1199 Ten Commandments, 2388 Tendon xanthoma, in cerebrotendinous xanthomatosis, 1367 Tensilon test, in myasthenia gravis, 1946-1947 Tension headache, 1183, 1198 chronic, 1195, 1198 diagnostic criteria for, 1185, 1186b, 1198 epidemiology of, 1183 episodic, 1198 management of, 1198, 2378-2379 post-traumatic, 1199-1200 Tensor fasciae latae muscle, in gait, 71f Volume 1: pages 1–1180

Volume 2: pages 1181–2408

xcv

Tensor tympani muscle, 97 Tentorial notch, 1389 Tentorial tear/herniation, 337, 1388-1390 Teratogens, 364, 364t, 2182t, 2197-2198. See also specific agents and cerebral palsy, 493 and holoprosencephaly, 396-397 and neural tube defects, 366 Teratoid/rhabdoid tumor, atypical, 1709, 1729-1730 Teratoma(s), 1704 immature, 1704, 1704t in infants and very young children, 1725 mature, 1704, 1704t neuroimaging of, 1704, 1705f tumor markers and survival in, 1704t Teres major muscle, testing of, 34t Terlipressin, for hepatorenal syndrome, 2259 Terminal deletion, chromosomal, 529t Terodiline, for micturition disorders, 2165, 2165t Test of Language Development, 845 Test of Word Reading Efficiency (TOWRE), 865 Test of Written Spelling-4, 865 Testosterone, in puberty, 2114 Tetanus vaccine, 2350 Tetany, 1848 in hypocalcemia, 2328 in hypomagnesemia, 2328 in rickets, 2315 Tethered spinal cord, 367-368, 368f, 372 with diastematomyelia, 1860-1861 Tetrabenazine for DYT1 dystonia, 1282 for hyperkinetic disorders, 1290 for Lesch-Nyhan disease, 1286 and parkinsonism, 1292 for tardive movement disorders, 1302 Tetracaine, 2377 Tetracycline(s) for amebiasis, 1649 hepatotoxicity of, 2294 for rickettsial diseases, 1640 Tetrahydrobiopterin (BH4) in CSF, 163 deficiency/disorders of, 360, 360f, 574-575, 759-761, 767 for phenylketonuria, 574 role in central nervous system, 761 in sepiapterin reductase deficiency, 763 Tetrahydrocannabinol, 2186 Tetraplegia, autonomic dysfunction in, 2146f, 2147-2149, 2148f Tetraploidy, 525 Tetrathiomolybdate, for Wilson’s disease, 2300 Textbooks, electronic, 2401-2404 TGIF gene, and holoprosencephaly, 396, 398 Thalamic tumors, 1700-1707. See also specific types clinical presentation of, 1700 EEG findings with, 1700 neuroimaging of, 1700, 1700f Thalamocortical circuit, in absence seizures, 999-1000, 999f, 1026-1028, 1027f Thalamoputaminal group, in athetoid cerebral palsy, 499 Thalamotomy, for dystonia, 1289 Thalamus embryology of, 383 hypoxic-ischemic injury to, 285-287 clinical features of, 286-287 computed tomography of, 286, 286f diagnosis of, 286 magnetic resonance imaging of, 282, 286, 286f pathogenesis of, 285-286 ultrasound of, 286, 286f

xcvi

Index

Thalidomide and autism, 922 teratogenicity of, 2188 therapeutic uses of, 2188 toxicity of, 2188 Thallium poisoning, 1911, 2184 Thanatophoric dysplasia, 422 genetics of, 443f megalencephaly with, 408 Theophylline for reflex anoxic seizures, 1207 toxicity of, 2190 Theory of mind, in autism, 911 Therapeutic range, 1117, 1121 Thermoregulatory sweating response, 2137 Theta activity, in EEG, 997 in hypoxic-ischemic injury, 238 newborn in benign neonatal convulsions, 266 gestational age of 28 to 31 weeks, 213f-214f, 216 gestational age younger than 28 weeks, 211f, 213f, 215 slowing, in children, 219-220 Theta pointu alternant, 266 Thiabendazole for microsporidiosis, 1654 for trichinosis, 2082 Thiamine (vitamin B1), 2307-2308 deficiency of, 1384-1385, 1906, 2307-2308 in dialysis patients, 2246 dependency disorders of, 2305t, 2308 in maple syrup urine disease, 577, 579, 2308 physiologic functions of, 2307 in pyruvate dehydrogenase deficiency, 730, 2308 recommended daily requirement for, 2307 Thigh adductors of, in preterm infant, 58t, 59f injections into, adverse reactions to, 2195 segmental innervation of, 31t Thimerosal, and autism, 923, 2185, 2351 Thiolases deficiency of, 750 in fatty acid oxidation, 736f, 737-738, 2037f, 2038 in rhizomelic chondrodysplasia punctata, 745 Thiopental for intracranial hypertension, 1583 for sedation, 2378 Thioridazine, for autism, 923-924 Thiouracil, teratogenicity of, 2197t Thomsen’s disease, 622t, 637, 2090-2093, 2090t clinical features of, 2090-2091, 2090t genetics of, 2090t, 2091 laboratory tests in, 2091-2092 pathophysiology of, 2091 treatment of, 2090t, 2092-2093 Thoracic nerve(s), motor functions of, 28t Thoracic spinal cord injury, 1528 Thoracic spine, 1527, 1528f Thorazine. See Chlorpromazine Three ways of looking, 2391 Threshold effect, 715-716 Thromboembolic cardiogenic stroke, 2216-2219 echocardiography of, 2217f epidemiology of, 2216 mechanisms of, 2216f, 2217 postoperative factors in, 2217-2218 prevention of, 2218 risk factors for, 2216-2217 Thromboembolism cardiac surgery and, 2209, 2209f, 2216-2219 mechanisms of in arterial ischemic stroke, 1762 in sinovenous thrombosis, 1782, 1782f

Thrombolytic therapy, for stroke, 332, 1778-1779 Thrombophilia(s), and intraventricular hemorrhage, 313-314 Thrombotic microangiopathies, 2252-2258, 2253t. See also Hemolytic-uremic syndrome; Thrombotic thrombocytopenic purpura Thrombotic thrombocytopenic purpura, 1826, 2252-2254 ADAMTS13 defects in, 2253 chronic or recurrent, 2254 clinical features of, 2253 epidemiology of, 2253 versus hemolytic-uremic syndrome, 2252-2253, 2257t management of, 2254 pathogenesis of, 2252 prognosis of, 2253-2254 Thrombotic thrombocytopenic purpura-like thrombocytopenic microangiopathy, 2254 Thromboxane A2, in hepatorenal syndrome, 2259 Thumb adductor muscle of, testing of, 34t opponens muscle of, testing of, 34t Thymectomy, for myasthenia gravis, 1951-1952 Thymine, 508, 508f Thymoma(s), in myasthenia gravis, 1942, 1950, 1952 Thymosin, for ataxia-telangiectasia, 1253 Thymus gland, in myasthenia gravis, 1942 Thyroid disease, 2121-2122. See also Hyperthyroidism; Hypothyroidism hearing loss with, 105t, 115 radiation therapy and, 1743 Thyroid gland, normal physiology of, 2121 Thyroid-stimulating hormone, 2121 deficiency of, 2121-2122. See also Hypothyroidism excess of, 2122. See also Hyperthyroidism Thyrotoxic periodic paralyses, 2100-2101 clinical features of, 2095t, 2100 genetics of, 2095t, 2100-2101 laboratory findings in, 2101 pathophysiology of, 2100 treatment of, 2095t, 2101 Thyrotropin-releasing hormone, for spinal cord injury, 1542 Thyroxine, 2121 Tiagabine absorption of, 1115 adverse effects of, 1123 behavioral and cognitive effects of, 1176 bioavailability of, 1107t, 1115 blood level of, 1051t dosage of, 1051t, 1108t elimination of, 1108t, 1115 formulations of, 1107t mechanism of action, 1003, 1004f, 1119t metabolism of, 1108t, 1115 optimal range of, 1117t pharmacokinetics of, 1107t-1108t, 1115 practical guide to, 1051t preparations of, 1051t protein binding of, 1108t routes of administration, 1107t testing of, 1002 volume of distribution, 1108t, 1115 Tibialis anticus muscle, testing of, 34t Tibialis nerve, 29t Tic(s), 887, 1272t chronic, 888 complex, 887, 1298 definition of, 1298 versus dystonia, 1281 Volume 1: pages 1–1180

Tic(s) continued motor, 887, 1298 versus myoclonus, 1064t pathophysiology of, 1274-1275 phonic or vocal, 887, 1298 simple, 887, 1298 in Tourette syndrome, 887, 891 transient, 888 Tic disorder(s), 887-888, 1298. See also Tourette syndrome antiepileptic agents and, 1124 autoimmune pathway of, 1807 chronic, 888 classification of, 887-888, 1276 clinical course of, 887 clinical spectrum of, 887 etiology of, 1276 haloperidol for, 896, 966 misdiagnosis of, 887 nonpharmacologic therapy for, 895 pharmacologic therapy for, 896-897, 896t pimozide for, 896, 967 prevalence of, 1276 stimulant therapy and, 880, 942 surgical therapy for, 897 transient, 888, 1301 treatment of, 895-897, 1298 ziprasidone for, 896, 970 Tick toxins, 2181-2182 Tick-borne flaviviruses, 1613, 1615-1616 Ticlopidine, for stroke, 1777-1778 Tilt test in orthostatic hypotension, 2133f, 2135-2136 in syncope, 2150 Time constants, in EEG, 205 Timolol, for migraine prevention, 1194t Tinidazole, for amebiasis, 1649 Tinnitus, in neurofibromatosis type 2, 776-777 Tirilazad for hypoxic-ischemic injury, 1504 for spinal cord injury, 1541 Tissue-type plasminogen activator (t-PA), 17781779 Titin, 1840, 1969, 1970f diseases associated with, 1842t, 1970f in limb-girdle muscular dystrophy, 1988t, 1995 Titubation, 1244 with cerebellar gait, 73 Tizanidine adverse effects of, 2367, 2367t for muscle overreactivity (spasticity), 2367, 2367t for post-traumatic spasticity, 1434 in spinal cord injury, 1544 Tobacco, teratogenicity of, 2198 Tocainide for myotonia congenita, 2093 for paramyotonia congenita, 2097 Tocolytic agents, and intraventricular hemorrhage, 311, 311t Tocopherol (vitamin E), 2316-2317 in abetalipoproteinemia, 1907, 2316-2317 absorption of, 2316 deficiency of, 2316-2317 ataxia in, 1247t, 1251, 2316 for intraventricular hemorrhage prevention, 324 for neuronal ceroid lipofuscinosis, 703 physiologic functions of, 2316 recommended daily requirement for, 2316 Toe(s) dorsiflexors of, testing of, 34t extensors of, testing of, 40 flexor sign of, 19 infant, evaluation of, 40

Volume 2: pages 1181–2408

Index Toe(s) continued plantar-flexors of, testing of, 34t striatal, 1280 Toe-walking, 72 in spastic diplegia, 498 Togaviruses, 1595b, 1611-1613 outcome of, 1603t Toilet training, 2157, 2166 Token Test, 845 Tolerance, to drugs, 1117 Tolmetin sodium, for juvenile idiopathic arthritis, 1805 Tongue atrophy and fasciculation of, 24-25, 24f, 52, 67 in spinal muscular atrophy type I, 1864 innervation of, 24 taste sensation in, 23-24, 135f, 136, 136f Tonic neck reflex, 42-43, 42t, 48t, 50, 60, 126 Tonic postures, in focal seizures, 1041 Tonic seizures focal, neonatal, 258, 258t-259t, 260, 266-267 generalized, 1029-1030 clinical features of, 1029 EEG findings in, 1030, 1030f etiology of, 1030 in Lennox-Gastaut syndrome, 1029, 1031 neonatal, 258, 258t-259t, 274 prognosis of, 1030 treatment of, 1023t Tonic status epilepticus, 1093b, 1094 Tonic upgaze, benign paroxysmal, 1215, 1300 treatment of, 1213t Tonic-clonic seizures, generalized, 1019-1023 alone (GTCA), 1010 clinical features of, 1019-1020 clonic phase of, 1019, 1021 differential diagnosis of, 1020 disorders mimicking, 984b EEG findings in, 1021 etiology of, 1021 initial evaluation of, 1021 in Lennox-Gastaut syndrome, 1031 neuroimaging in, 1021 photic stimulation of, 1019-1020, 1020f postictal phase of, 1019, 1021 primary versus secondary, 1020, 1020t prodrome for, 1019 tonic phase of, 1019, 1021 treatment of, 1021-1023, 1023t Tonic-clonic status epilepticus, 1093b, 1094 Tonsillar herniation, 453, 1403f, 1410, 1518, 1694 Topagnosis, 25 Topamax. See Topiramate Topical analgesia, 2377 Topiramate, 963-964 absorption of, 1115 adverse effects of, 959t, 964, 1023, 1123-1124, 1175 as antiepileptic agent, 1051t for absence seizures, 1023t for atonic seizures, 1023t behavioral and cognitive effects of, 1175 for generalized seizures, 1023, 1023t for Lennox-Gastaut syndrome, 1033 mechanism of action, 1003f-1004f, 1119t for status epilepticus, 1100 testing of, 1002 for tonic seizures, 1023t in traumatic brain injury, 1435 baseline assessments for, 959t bioavailability of, 1107t, 1115 blood level of, 1051t for Canavan’s disease, 1363-1364 for chronic daily headache prevention, 1196t, 1197

Topiramate continued clinical management of, 964 discontinuation of, 1126 dosage of, 1023, 1051t, 1108t drug interactions of, 964 elimination of, 1108t, 1115 formulations of, 1107t and ketogenic diet, 1143 labeled and off-labeled use of, 938t metabolism of, 1108t for migraine prevention, 1193t-1194t, 1195 monitoring of, 959t, 964 as mood stabilizer, 959t, 963-964 for neuroprotection, with hypothermia, 305 optimal range of, 1117t pharmacokinetics of, 1107t-1108t, 1115 pharmacology of, 964, 1023 and potassium channels, 994 practical guide to, 1051t preparations of, 959t, 1051t protein binding of, 1108t, 1115 routes of administration, 1107t for tic disorders, 896 volume of distribution, 1108t, 1115 Topoisomerase-2, 1747 TORCH syndrome, 1598 “Tornado fits,” 1043 Torsion dystonia, gait abnormalities in, 74 Torticollis, 1280 in acute dystonic reactions, 1288 in myoclonus dystonia, 1283 paroxysmal, 131, 1191, 1216, 1300-1301 and plagiocephaly, 441, 445 in Sandifer’s syndrome, 1216 spinal cord tumor and, 1730 Tortipelvis, paroxysmal, 131 Touch sensation, assessment of, 25-26 in infant, 40-41, 41f Tourette, Georges Gilles de la, 887 Tourette syndrome, 887-898 academic difficulties in, 891-892 ADHD with, 889-890, 897 anxiety with, 890 autoimmune pathway of, 1807 bipolar affective disorder with, 890 clinical course of, 888 common problems in, 888-892 depression with, 890 diagnostic criteria for, 888 episodic rage in, 890-891, 897 executive dysfunction in, 892 genetics of, 892-893 haloperidol for, 896, 966 methylphenidate and, 2190 migraine in, 892 neuroanatomic localization in, 893-894, 893f, 895f neuroimmunology of, 893 neuropsychiatric issues in, 888-891 nonpharmacologic therapy for, 895 obsessive-compulsive behaviors in, 888-889, 897 pharmacologic therapy for, 896-897 pimozide for, 896, 967 prevalence of, 888 restless legs syndrome in, 892 self-injurious behaviors in, 890-891 sleep disorders in, 892 surgical therapy for, 897 tics in, 887 severity of, and psychopathology, 891 treatment of, 894-897 Tourette Syndrome Association, 887-888 Tourette-like disorder, 888 Toxic neuropathies, 1909-1911 Toxicologic testing, 2174-2175 Volume 1: pages 1–1180

Volume 2: pages 1181–2408

xcvii

Toxidromes, 2178-2181 Toxin(s), 2173. See also Poisoning; specific agents biologic, 2181-2182 environmental, 2181-2186 Toxocara, 1664-1665. See also Toxocariasis Toxocara canis, 1665 Toxocara cati, 1665 Toxocariasis, 1664-1665 clinical characteristics of, 1665 diagnosis of, 1665 epidemiology of, 1664-1665 laboratory tests in, 1665 management of, 1665 microbiology of, 1664-1665 pathology of, 1664-1665 Toxoplasma gondii, 1654. See also Toxoplasmosis Toxoplasmosis, 1654-1656, 2082 classification of, 1647t clinical characteristics of, 1647t, 1656, 1656f, 2082 and congenital anomalies, 364 diagnosis of, 1647t, 1656 epidemiology of, 1654-1656 genetics of, 1655 geographic distribution of, 1647t and hearing loss, 109, 115 intrauterine or congenital, 1655, 1655f, 1656, 1656f laboratory tests in, 1656, 2082 in leukemia, 1738 long-term sequelae of, 1655-1656 management of, 1647t, 1656, 2082 microbiology of, 1654-1656 mode of infection, 1647t, 1654-1655 pathology of, 1647t, 1654-1656 in renal transplant patients, 2250 risk factors for, 1647t Tracé discontinu, in EEG, 215-216 Trachipleistophora anthropophthera, 1654 Tract pain, spinal cord tumor and, 1730 Traction response, 43t, 44, 58, 67 Tractography, 187 Tranquilizers fetal/neonatal effects of, 2195 major, 964. See also Dopamine receptor antagonist(s) toxicity of, 2188-2189 Transcalvarial herniation, 1403f, 1410 Transcript, 511 Transcription, genetic, 507, 511 Transcriptional control mutations, 531 Transfer RNA, 510-511 Transferrin isoform analysis, in congenital glycosylation disorders, 647-649 Transferrin receptors, in tumors, 1746 Transforming growth factor-α gene (TGFA), in cleft lip/palate, 467, 467t Transforming growth factor-β in Duchenne muscular dystrophy, 1976 in spinal cord injury, 1532 Transforming growth factor-β1 in craniosynostosis, 442-443 in megalencephaly, 408 in post-hemorrhagic hydrocephalus, 321 Transforming growth factor-β3 gene (TGFB3), in cleft lip/palate, 467, 467t Transfusion therapy, in stroke, 1779 Transient cerebral arteriopathy, 1764f, 1771-1772 Transient global amnesia of childhood, 1190 Transient ischemic attacks, 1762 clinical features of, 1766 definition of, 1766 identification of, 1766 Transition disorders, sleep-wake, 1226t

xcviii

Index

Translation, genetic, 507, 510-511 Translocation, chromosomal, 520f, 526f-527f, 528-529, 528f, 546 Transmantle dysplasia, focal, 403t, 410 Transmantle heterotopia, 419f, 420 Transplantation hepatic, neurologic complications of, 2298 immunosuppressive therapy in, toxicity of, 2191-2192 renal complications of, 2249-2252 drug-related, 2251-2252 graft failure or rejection in, 2250 for hyperoxaluria, 751 infection in, 2250-2251 neuropathy after, 2249 stroke risk in, 2251 tumor risk in, 2251 Transposition of great arteries, 2219f Transsulfuration pathway, 582, 582f Transsynaptic degeneration, vision loss with, 91 Transtentorial herniation, 1518 central, 1410 downward, 1389 lateral, 1410 in malaria, 1658 Transthyretin, 161, 2260, 2260t Transverse myelitis associated with immune-mediated process, infection, or both, 1875-1876 magnetic resonance imaging of, 1875f, 1876 Tranylcypromine, for ADHD, 879t Trapezius muscle, 24 testing of, 34t Trapezoidocephaly, 451 Trauma. See also specific trauma and injuries and confusional migraine, 1190-1191 and focal seizures, 1049 and headache, 1199-1200 perinatal, 329, 334-341 anterior horn cell with, 1876 brachial plexus, 340-341, 1890-1892, 1892f clinical presentation of, 335-341 cranial, 336-339 outcomes in, 338-339 cranial nerve, 339 deaths from, 334 definition of, 334 delivery mode and, 334-335 epidemiology of, 334 extracranial, 335-336 versus inflicted neurotrauma, 1460 intracranial, 337-339 laboratory testing in, 335 management, by diagnosis, 335-341 mechanical, 334 radiologic studies of, 335 risk factors for, 334-335 spinal cord, 339-340, 1527 Traumatic brain injury, 1401-1437, 2355-2356 acute clinical syndromes in, 1410-1418 acute presentation of, 1407 anatomy of, 1402, 1402f angiography in, 1420 axonal disconnection in, 1406-1407 behavioral effects of, 1433-1434, 2355-2356 biomechanics of, 1402-1403 in boys versus girls, 1401 cell death in, 1407 cerebral blood flow in, 1406, 1430-1431 cerebral metabolism in, dynamic changes in, 1406 cerebral perfusion pressure in, 1424, 1430-1431 cognitive effects of, 1433-1434 coma in, prognosis of, 1395-1396

Traumatic brain injury continued computed tomography of, 1418-1420, 1419t, 1431 costs of, 1401 deaths in, 1401 delayed presentation of, 1407 to developing brain, 1404-1405 biomechanical factors in, 1404 excitatory neurotransmission in, 1404 metabolic factors in, 1404 neurovascular regulation in, 1404 ongoing cerebral maturation in, 1404-1405 diagnostic evaluation of, 1418-1420 electrodiagnostic testing in, 1420, 1431-1433 elevated intracranial pressure in, 1422-1427, 1430 barbiturates for, 1422, 1426 cerebrospinal fluid drainage for, 1424-1425 first-tier management of, 1421f, 1422-1425 hyperosmolar therapy for, 1422-1423 hyperventilation for, 1422, 1425 monitoring of, 1423-1424 neuromuscular blockade for, 1422 and retinal hemorrhage, 1451-1452 second-tier management of, 1425-1427, 1425f sedation for, 1422 surgical management of, 1425-1426 treatment algorithm for, 1428 epidemiology of, 1401-1402, 2355 epilepsy in, 1427-1428, 1434-1435 etiology of, by age, 1401, 1401f evoked potentials in, 1432-1433 examination in, 1408-1409, 1409t history of, 1407-1408 hydrocephalus in, 1434 immediate management of, 1410 incidence of, 1401, 2355 inflicted, 1411-1412, 1445-1464 acute presentation of, 1447-1448 autonomic and neuroendocrine responses in, 1461 biochemical markers in, 1461-1462 biologic factors in, 1446, 1446b versus birth trauma, 1460 cerebral contusions in, 1457-1458, 1458f cerebral injuries in, 1456-1457 chronic subdural effusions in, 1454f, 1455, 1455f clinical assessment and management of, 1460-1462 clinical features of, 1447-1449 computed tomography of, 1447, 1447f, 1453f-1456f, 1456-1457, 1462-1463 diagnosis of, 1462-1464 differential diagnosis of, 1458-1460 diffuse axonal injury in, 1457 epidural hematoma in, 1455-1456 extra-axial collections in, 1453-1456 extracranial injuries in, 1452-1453 factors associated with, 1463b versus falls, 1458-1460 general examination in, 1460-1461 historical perspective on, 1445 history of injuries in, evaluation of, 1463 incidence of, 1445 intracranial injuries in, 1453-1458 key questions in evaluation of, 1462b laboratory evaluation in, 1461-1462 lucid interval issues in, 1463 markers of, 1449b mechanical factors in, 1446, 1446b mechanisms of injury, 1446-1447 medicolegal issues in, 1463-1464 versus metabolic disorders, 1460 morbidity and mortality in, 1445 Volume 1: pages 1–1180

Traumatic brain injury continued neuroimaging in, 1447, 1447f, 1463 neurologic examination in, 1461 ocular injuries in, 1450-1452 optic nerve sheath hemorrhage in, 1452 pathology of, 1449-1458, 1450f predisposition of immature neuraxis to, 1445-1446, 1446b radiographic evaluation of, 1462 retinal and optic nerve sheath differential in, 1452 retinal hemorrhage in, 1412, 1412f, 1450-1452, 1450f-1451f sequelae of, 1448-1449 severity of, factors affecting, 1449b skull fracture in, 1452-1453, 1452f subacute or chronic presentation of, 1448 subarachnoid hemorrhage in, 1455 subdural hematoma in, 1447f, 1453-1455, 1453f-1456f subgaleal hematoma in, 1452, 1452f terminology in, 1445 timing of injuries in, 1463 late clinical syndromes in, 1433-1437 lumbar puncture in, 1420 magnetic resonance imaging of, 1420, 1420t, 1431, 1432f magnetic resonance spectroscopy of, 1431, 1432f mild, 1414-1415, 2355 with brief loss of consciousness, in children older than 2 years, 1428-1429 in children younger than 2 years, 1429 general management of, 1428-1430 without loss of consciousness, in children older than 2 years, 1428 moderate, 2355 motor impairment in, 1434 neuroimaging of, 1418-1420 neurometabolic cascade in, 1405-1407, 1405f neurotransmission in, 1406 nonaccidental, 1411-1412, 2355 computed tomography in, 1412, 1412f outcome of, 1412 pathophysiology of, 1404-1407, 2355 penetrating, 1403 plasticity in, 1404-1405, 1407 primary, 1447 prognosis and outcome of, 1430-1433, 2356 age and, 1430 clinical predictors of, 1430-1431 electrodiagnostic testing and, 1431-1433 gender and, 1430 injury characteristics and, 1430 neuroimaging and, 1431, 1432f physiologic measurements and, 1430-1431 rehabilitation in, 2355-2356 secondary, 1403 seizures and seizure prophylaxis in, 1427-1428, 1434-1435, 1448 sequelae of, 1401 severe, 2355 management of general principles for, 1420-1428 stabilization and secondary injury prevention in, 1420-1421 skull x-rays of, 1418 spasticity in, 1434 supportive care in, 1428 temperature control and hypothermia for, 1425 types of, 1403, 1403f ultrasound in, 1420 vegetative and minimally conscious state after, 1433 Trazodone, for migraine prevention, 1194t

Volume 2: pages 1181–2408

Index Treacher Collins syndrome, 105t, 107, 108t clinical features of, 465t genetics of, 443f, 465t Treatment of ADHD in Children with Tics (TACT), 942 Trematode infections, 1646, 1664, 1672-1674 Tremor(s), 1272t, 1290-1291 action, 1290 antiepileptic agents and, 1124 causes of, 1290t in cerebellar disease, 19 classification of, 1290 definition of, 1290 dystonic, 1280-1281, 1290 essential, 1290-1291 frequency of, 1290 in hepatic encephalopathy, 2294 intention, 1244-1246 medication-induced, 1290t in mental retardation/developmental delay, 814b versus myoclonus, 1290, 1293 physiologic, 1290 in poisoning/intoxication, 2178, 2180b postural, 1290 primary, 1290-1291 psychogenic, 1290-1291 rest, 1290 rubral, 1291 secondary, 1291 in shuddering attacks, 1219 task-specific, 1290 treatment of, 1291 in uremic encephalopathy, 2237 Trench fever, 1590 Treponema pallidum, 1586-1587. See also Syphilis Triceps muscle, testing of, 34t Triceps reflex in older child, 18, 19t in preterm infant, 56-57, 58t Triceps surae muscle, testing of, 34t Trichinella, 1666. See also Trichinosis Trichinella spiralis, 1666-1667 Trichinosis, 1666-1667, 2081-2082 classification of, 1647t clinical characteristics of, 1647t, 1666-1667, 2081 diagnosis of, 1647t, 1666-1667 epidemiology of, 1666 geographic distribution of, 1647t, 1666 laboratory tests in, 1666-1667, 2081 management of, 1647t, 2082 microbiology of, 1666 mode of infection, 1647t, 1666 muscle biopsy in, 2081, 2081f pathology of, 1647t, 1666 risk factors for, 1647t Trichoclasis, in Menkes’ disease, 1322 Trichoptilosis, in Menkes’ disease, 1322 Trichorrhexis nodosa, 606, 813b Trichothiodystrophy clinical features of, 560t genetics of, 560t Tricyclic antidepressants, 945-948 for ADHD, 878t-879t, 882, 946 adverse effects of, 947, 2189 risk factors for, 947 assessment for, 946-947 for autism, 924-925, 927t clinical applications of, 945-946 clinical management of, 946-947 dosage of, 945t, 947 drug interactions of, 947-948 initiation and titration of, 947 labeled and off-labeled use of, 938t

Tricyclic antidepressants continued mechanism of action, 946 nephrotoxicity of, 2265 for pain, 2378 pharmacology of, 945t, 946 in renal failure, encephalopathy induced by, 2266 representative, for children, 945t toxicity of, 2189 Trientine, for Wilson’s disease, 1291, 2300 Trifluoperazine, for autism, 923-924 Trifunctional enzyme protein deficiency, 350t-351t, 355-356, 724, 2038, 2048 Trigeminal nerve (CN V) assessment of in newborn (term), 52 in older child, 22-23 in smell and taste disorders, 138 facial sensation supplied by, 23, 23f Trigeminovascular system, in migraine, 1187-1188 Triglyceride(s), ketogenic diet and, 1144 Trigonocephaly, 445-446 Triheptanoin, for fatty acid oxidation defects, 2048 Trihexyphenidyl, 398 adverse effects of, 1289 and chorea, 1279-1280 dosage of, 1289 for dystonia, 1288-1289 for glutaric aciduria type 1, 595 for hyperkinetic disorders, 1290 for neuronal ceroid lipofuscinosis, 703 for tyrosine hydroxylase deficiency, 764 Trihydroxycholestanoic acid coenzyme A oxidase deficiency, 750 Trileptal. See Oxcarbazepine TRIM32, diseases associated with, 1842t Trimethadione lupus syndrome induced by, 1811-1812 teratogenicity of, 2197-2198 Trimethobenzamide, for cyclical vomiting syndrome, 2286 Trimethoprim-sulfamethoxazole for bacterial meningitis, 1581 for granulomatous amebic encephalitis, 1651-1652 for South American blastomycosis, 1635 Trimipramine, pharmacology of, 946 Tripelennamine toxicity, 2191 Tripeptidyl peptidase, in neuronal ceroid lipofuscinosis, 1328, 1332 Triple A disorder, 2152 Triploidy, 525, 529t, 546, 549-550 Triptan agents for migraine, 1193t, 1195 for post-traumatic headache, 1199 Trisomy, 525, 529t, 546 Trisomy 8, 525, 553, 553f Trisomy 9p, 555t Trisomy 13, 465t, 525, 546, 550-551 clinical features of, 550, 550f cytogenetics of, 550 management of, 550-551 Trisomy 16, 525 Trisomy 18, 464t, 525, 546, 549, 551 clinical features of, 551, 551f management of, 551 Trisomy 21, 525, 546, 551-553. See also Down syndrome Trisomy rescue, 547 Trochlear nerve (CN IV), assessment of, 80 in newborn (term), 52 in older child, 20-22 Tropheryma whippelii, 2292 Tropias, 21-22 Tropical spastic paraplegia, 1622-1623 Volume 1: pages 1–1180

Volume 2: pages 1181–2408

xcix

Tropicamide, toxicity of, 2191 Tropomyosin, 1840, 1840f in nemaline myopathy, 2017 Troponin, 1840, 1840f Troponin C, 1840 Troponin I, 1840 Troponin T, 1840 slow, diseases associated with, 1842t Trypanosoma brucei gambiense, 1662, 1662f. See also Trypanosomiasis, African Trypanosoma brucei rhodesiense, 1663 Trypanosoma cruzi, 1661. See also Trypanosomiasis, American Trypanosomiasis, 1661-1664 African, 1662-1664 classification of, 1647t clinical characteristics of, 1647t, 1663-1664 diagnosis of, 1647t, 1663-1664 epidemiology of, 1662-1663 geographic distribution of, 1647t, 1662-1663 laboratory tests in, 1663-1664 management of, 1647t, 1664 microbiology of, 1662-1663, 1662f mode of infection, 1647t, 1662-1663 pathology of, 1647t, 1662-1663 risk factors for, 1647t American, 1661-1662 autonomic dysfunction in, 2152 classification of, 1647t clinical characteristics of, 1647t, 1661-1662 diagnosis of, 1647t, 1661-1662 epidemiology of, 1661 geographic distribution of, 1647t, 1661 laboratory tests in, 1661-1662 management of, 1647t, 1662 mode of infection, 1647t, 1661 pathology of, 1647t risk factors for, 1647t classification of, 1647t clinical characteristics of, 1647t diagnosis of, 1647t East African, 1663 geographic distribution of, 1647t management of, 1647t mode of infection, 1647t pathology of, 1647t risk factors for, 1647t Tryptophan, 511, 2309-2310 in uremic encephalopathy, 2236 Tryptophan hydroxylase deficiency, 765 Tryptophol, in African trypanosomiasis, 1663 TSC1 and TSC2 genes, and cortical malformations, 402t Tuberculoma(s), 1709 diffusion-weighted imaging of, 187 Tuberculosis, in renal transplant patients, 2251 Tuberculous meningitis, 1585-1586 clinical features of, 1585 CSF protein content in, 162t diagnosis of, 1585-1586 epidemiology of, 1585 neuroimaging in, 1585-1586, 1586f pathogenesis of, 1585 treatment of, 1586 Tuberin, 781 Tuberous sclerosis complex, 403t, 777-782, 2301 autism in, 778, 918-919 behavioral features of, 778-779 cardiac features of, 780 classification of, 771 clinical features of, 771t, 777-780, 778f-779f cognitive features of, 778-779

c

Index

Tuberous sclerosis complex continued computed tomography in, 173, 175f, 781f, 781, 782t cutaneous features of, 771t, 778f, 779, 779f diagnostic criteria for, 778t EEG findings in, 778 epilepsy in, 777-778 epilepsy surgery for, 1154 genetics of, 402t, 781 giant cell astrocytoma with, 1708, 1708f laboratory testing in, 780-781 management of, 780t, 782, MRI findings in, 781, 781f ophthalmic features of, 780 pathology of, 781 positron emission tomography in, 196 pulmonary features of, 780 renal features of, 780 ultrasound in, 170, 780t D-Tubocurarine, and malignant hyperthermia, 2195 Tubular aggregate myopathies, 2019 Tumbling E test, 78, 79f Tumor(s), 1687-1749. See also specific types and anatomic sites Tumor necrosis factor-α in adrenoleukodystrophy, 748 in Duchenne muscular dystrophy, 1975-1976 in hypoxic-ischemic injury, 302 in intraventricular hemorrhage, 312t, 313 in juvenile idiopathic arthritis, 1805-1806 in multiple sclerosis, 1347 in spinal cord injury, 1532 Tumor suppressor genes, 1747 Turner’s syndrome, 525, 553-554 clinical features of, 554, 554f cytogenetics of, 553 management of, 554 reading difficulties in, 855 Turricephaly, 446-447 Twist-related craniosynostosis, 437, 442t, 443, 449-450 Twitch-myoclonus, 2236-2237, 2239 2n (diploid) number, 516 Two-hit hypothesis, 272 Two-point discrimination, 26 Tympanic cavity, 97 Tympanic membrane, anatomy of, 97 Tyndall’s effect, 159 Typhus, 1643-1644 epidemic, 1643-1644 clinical characteristics of, 1641t, 1644 epidemiology of, 1641t, 1643 geographic distribution of, 1641t incubation period of, 1641t laboratory tests in, 1641t management of, 1641t mode of infection/vector, 1641t, 1643 reservoir for, 1641t murine or endemic, 1643-1644 clinical characteristics of, 1641t, 1644 epidemiology of, 1641t, 1643 geographic distribution of, 1641t incubation period of, 1641t laboratory tests in, 1641t management of, 1641t mode of infection/vector, 1641t, 1643-1644 reservoir for, 1641t scrub, 1644 clinical characteristics of, 1641t, 1643f, 1644 epidemiology of, 1641t geographic distribution of, 1641t incubation period of, 1641t laboratory tests in, 1641t management of, 1641t, 1644

Typhus continued mode of infection/vector, 1641t, 1644 reservoir for, 1641t Tyrosine, for nemaline myopathy, 2017 Tyrosine hydroxylase deficiency, 764-765, 1282-1283 Tyrosine kinase(s), in oncogenesis, 1748 Tyrosinemia hepatorenal (type I), 575-576 oculocutaneous (type II), 576 transient, of newborn, 576, 2314

U Ulcerative colitis, 2290 Ullrich’s congenital muscular dystrophy, 1989t, 2002-2003 Ulnar nerve repetitive stimulation in Lambert-Eaton myasthenic syndrome, 1956, 1957f in myasthenia gravis, 1946f, 1947-1949, 1947f Ultradian rhythm, neonatal EEG sleep as, 222-223, 223f Ultrasound, 167 advantages of, 167 of aqueductal stenosis, 169f B-mode, 167 of cephalohematoma, 335 in cerebral palsy, 322 cranial, 167-170, 168f-169f, 281-282 in Dandy-Walker syndrome, 169-170, 169f of diastematomyelia, 1860 duplex Doppler, 168, 170 echogenicity in, 168, 168f-169f endovaginal, 169 genetic, 537 high-resolution, 537 of hypoxic-ischemic injury, 281-282, 286, 286f indications for, 167 intraoperative, 170 for tumor resection, 1697, 1734 of intraparenchymal echodensities, 317, 317f, 320t of intraventricular hemorrhage, 168-170, 168f, 281, 309, 311, 315-317, 316f-318f level 2, 537 limitations of, 168-169 in meningitis, 1575-1576 of microcephaly, 405 in micturition disorders, 2164 of muscle, 1853 neonatal, 168, 168f-169f of neural tube defects, 370 of periventricular hemorrhagic infarction, 287, 288f of periventricular leukomalacia, 169-170, 169f, 281, 288f, 289, 290f, 318-319, 319f, 320t of porencephaly, 317, 318f of post-hemorrhagic hydrocephalus, 322, 322f prenatal, 167-170, 167f, 537, 549 in arthrogryposis multiplex congenita, 1873 in preterm infant, recommendations for, 319-320 real-time, 167-168 gray-scale, 167-168 spinal, 195 in spinal cord injury, 339 in spinal muscular atrophy, 1866-1867 transabdominal, 169 transcranial Doppler in brain death, 1560-1561 in coma, 1393 Volume 1: pages 1–1180

Ultrasound continued of sinovenous thrombosis, 1786 of stroke, 1775 in traumatic brain injury, 1420 in tuberous sclerosis, 170, 782t Umami taste, 141t, 142 Uncal herniation, 1388, 1403f Uncertainty, zone of, 801 Uncinate fits, 1043 Unconsciousness. See also Coma; Consciousness, impairment of definition of, 1378 Uncoupling, in antiepileptic drug therapy, 270 Uniform Determination of Death Act (1980), 1554 Uniform resource locator (URL), 2400 Uniparental disomy, 534-535, 547, 558, 558t Uniparental heterodisomy, 534 Uniparental isodisomy, 534 United Nations declaration on rights of children, 2393 U. S. Public Law 94-142, 117-118 University of Miami Neurospinal Index, 1546 University of Pennsylvania Smell Identification Test, 138 Unresponsivity, cerebral, in brain death, 1556 Unsaturated fatty acids, oxidation of, 738 Unverricht-Lundborg progressive myoclonic epilepsy, 1072t, 1073, 1254 Upper airway resistance syndrome, 1230 Upper motor neurons (UMNs), 68-69 in muscular tone pathology, 66-69, 68t Upward gaze benign paroxysmal tonic, 1213t, 1215, 1300 impaired, with increased intracranial pressure, 1517 Urea bitter taste of, 142 for increased intracranial pressure, 1520 Urea cycle, 603-604, 604f, 717 disorders of, 356, 603-613, 718 alternate pathway therapy for, 604t, 611612 associated medical conditions with, 608 clinical description of, 604-607 clinical features of, 350t-351t, 356, 604-608 clinical presentations of, 608 cognitive and motor regression in, 826t diagnosis of, 356, 356f differential diagnosis of, 610-611 EEG findings in, 608 hemodialysis for, 611 histopathologic features of, 608 histopathology of, 718-719 hyperammonemic coma in, 356, 608 hyperammonemic crises in, management of, 612 liver dysfunction in, 608, 611-612 liver transplantation for, 611-612 mortality and morbidity in, 612-613 MRI findings in, 352t neuroimaging in, 608 neuropathology of, mechanism of, 609-610 versus organic acidopathies, 356 outcome of, 612-613 protein importation in, 727 protein restriction for, 612 treatment of, 604t, 611-612, 1247t inborn errors of, 603-613 Uremic amaurosis, 2237 Uremic encephalopathy acute, 2235-2238 clinical features of, 2236-2237 CSF analysis in, 2238 differential diagnosis of, 2237 EEG findings in, 2237-2238

Volume 2: pages 1181–2408

Index Uremic encephalopathy continued endocrine dysfunction in, 2235 in end-stage renal disease, 2236 laboratory tests in, 2237-2238 management of, 2238 pathology of, 2236 pathophysiology of, 2235-2236 congenital, 2242-2244 aluminum toxicity in, 2243-2244 EEG findings in, 2242-2243 endocrinopathy in, 2244 malnutrition in, 2244 neuroimaging in, 2243 stroke in, 2244 severe chronic, 2242 Uremic myoclonus, 2236 Uremic myopathy, 2249 Uremic neuropathy, 1905, 2247-2249 clinical features of, 2248 electrophysiology of, 2247-2248 in males versus females, 2247-2248 management of, 2249 onset of, 2247 pathologic features of, 2248 Uremic synaptosomal preparations, 2236 Uremic vasculopathy, 2249 Urethral sphincter, control of, 2160 Urge syndrome, 2163 Uridine, for galactosemia, 620 Uridine diphosphogalactose epimerase deficiency, 620 Urinalysis, 2163-2164 in metabolic disorders, 568 in substance abuse, 2175 Urinary bladder. See Bladder Urinary incontinence, 2157 differential diagnosis in, 2164, 2167b functional classification of, 2162-2163, 2162f management of, 2164-2165 overflow, 2163 patient evaluation in, 2162-2164 stress, 2163 Urinary tract disorders, autonomic dysfunction in, 2138 Urine culture, 2163-2164 Urine odor, in developmental disorders, 843t Urodynamic studies, 2164 Urokinase, 1778-1779 Ursodeoxycholic acid, for peroxisomal disorders, 744 USENET groups, 2400 U-shaped hearing loss, 104, 113 Usher’s syndrome, 103, 105t, 107, 111-112 Utilitarianism, 2387-2388 Utricle, 97, 98f, 123 Utrophin, 1844 Uveitis, 88 in arthritis, 88, 1803, 1806

V Vaccine(s). See also specific types additives to, 2350-2351 and autism, 923, 2185, 2350-2351 combination, 2350-2351 component, 2349-2350 controversy over, 2345 and disease eradication, 2345 and Guillain-Barré syndrome, 1910, 1927, 2347 live-attenuated, 2348-2349 and multiple sclerosis, 2347 neurologic complications of, 2345-2351 causality in, assessment of, 2345-2346 and polyneuropathy, 1910 recombinant, 2350

Vaccine(s) continued recommended schedule of, 2345, 2345t types of, 2346-2350, 2346b whole-killed, 2346-2348, 2346b Vaccine Injury Compensation Program (VICP), 2346, 2347t VACTERL association, 450 Vacuolar myopathy, 1995, 2019. See also Danon’s disease Vacuum extraction, and birth trauma, 334-335 Vagal tone in pallid breath-holding spells, 1205 in reflex anoxic seizures, 1206-1207 Vaginal delivery and birth trauma, 335 and intraventricular hemorrhage, 311, 324 Vagus nerve (CN X) assessment of in newborn (term), 52 in older child, 24 in smell and taste disorders, 138 taste innervation by, 135f, 136, 136f Valine, 510 in maple syrup urine disease, 352-353, 579 in organic acidopathies, 353-354, 353t Valley fever, 1633 Valproic acid (valproate) absorption of, 1115 adverse effects of, 271, 959t, 961, 1023, 1050, 1075, 1122-1124, 2265, 2294, 2301 and Alpers’ disease, 1326 as antiepileptic agent, 960-961, 1051t for absence seizures, 999-1000, 1023t, 1028-1029 for atonic seizures, 1023t behavioral and cognitive effects of, 1175 for benign neonatal familial convulsions, 267 for early infantile epileptic encephalopathy, 268 for febrile seizure prevention, 1085 for focal seizures, 1050 for generalized seizures, 1021-1023, 1023t for infantile spasms, 1068-1069 for juvenile myoclonic epilepsy, 1072-1073 for Lennox-Gastaut syndrome, 1032 in leukemia, 1737 mechanism of action, 1003, 1003f, 1119t for myoclonic seizures, 1023t, 1075 for status epilepticus, 1100 in systemic lupus erythematosus, 1814 for tonic seizures, 1023t in traumatic brain injury, 1435 for autism, 925, 927t baseline assessments for, 959t, 960 bioavailability of, 1107t blood level of, 1051t for chronic daily headache prevention, 1196t, 1197 clinical applications of, 960 clinical management of, 960-961 for cluster headache, 1199 contraindicated in glycine encephalopathy, 581 for cyclical vomiting syndrome, 2286 discontinuation of, 1126 dosage of, 961, 1023, 1051t initial maintenance, 1108t loading, 1109t drug concentration of, 1122 drug interactions of, 961, 1118, 2195-2196 elimination of, 1108t, 1116 formulations of, 1107t hepatotoxicity of, 2294, 2301 for hyperkinetic disorders, 1290 hypersensitivity to, 1125, 1125t for kernicterus, 1284 Volume 1: pages 1–1180

Volume 2: pages 1181–2408

ci

Valproic acid (valproate) continued labeled and off-labeled use of, 938t for Landau-Kleffner syndrome, 1059 metabolism of, 1108t, 1116 and metopic synostosis, 446 for migraine prevention, 1193t-1194t, 1195 monitoring of, 959t, 961, 1023 as mood stabilizer, 959t, 960-961 for myoclonus, 1295 for myoclonus dystonia, 1283 nephrotoxicity of, 2265 for neuronal ceroid lipofuscinosis, 703, 1332-1333 for nonepileptic paroxysmal disorders, 1213t, 1214 optimal range of, 1117t pharmacokinetics of, 1107t-1108t, 1115-1116 pharmacology of, 960, 1022-1023 practical guide to, 1051t preparations of, 959t, 1051t, 1115 protein binding of, 1108t, 1116 in renal failure, action and effects of, 2267 for Rett’s syndrome, 1321 routes of administration, 1107t, 1119, 1120t for Sydenham’s chorea, 1279, 1808, 2225 teratogenicity of, 364, 367, 1023, 2197-2198, 2320 volume of distribution, 1108t, 1116 Valsalva maneuver in autonomic assessment, 2135-2136 urinary voiding by, 2162, 2165 Van der Woude syndrome, 443f, 466t, 467 Vancomycin for bacterial meningitis, 1580t, 1581 for brain abscess, 1589 Vanishing white matter disease and childhood ataxia with hypomyelination, 1364-1366 clinical spectrum of, 1366 diagnostic criteria for, 1364-1366 genetics of, 1366 neuroimaging in, 1364-1366, 1365f Varicella-zoster vaccine, 1609, 2349 neurologic complications of, 2349 Varicella-zoster virus, 1607-1609 and acute cerebellar ataxia, 1247, 1296, 1597, 1608 diagnosis of, 1602, 1602t, 1608 intrauterine, 1608 in leukemia, 1738 neurologic manifestations of, 1607-1608 outcome of, 1608-1609 in renal transplant patients, 2250 and stroke, 1608-1609, 1766, 1769-1770, 1771f, 1772 transmission of, 1599-1600, 1608 treatment of, 1608-1609 Vascular endothelial growth factor in hypoxic-ischemic injury, 1505 for Krabbe’s disease, 679 Vascular malformations, 1790-1795 spinal cord, 1878-1879 Vascular resistance, in hypoxic-ischemic injury, 1500 Vasculitic diseases with neurologic-renal presentations, 2258-2261 primary, 1804t, 1818-1826 neurologic and laboratory findings in, 1818t pathogenesis of, 1818 Vasculitis, 1818-1826 granulomatous, 1804t leukocytoclastic, 1804t, 1821 necrotizing, 1804t, 1818-1821 and stroke, 1771-1772, 1772f

cii

Index

Vasculopathy, postradiation, and stroke, 1769, 1770f Vasoactive intestinal polypeptide, 2129 Vasodepressor syncope, 1210, 2149 Vaso-occlusive disease, magnetic resonance imaging in, 174f, 177, 178f Vasopressin, 2324 for cardiac arrest, 1498 and CSF formation, 155 in hepatorenal syndrome, 2258-2259 inappropriate secretion of, 1576, 1582, 2125 Vasovagal syncope, 1210, 2132, 2149-2150 Vastii muscle, in gait, 71f Vecuronium postoperative effects of, 2216 in traumatic brain injury, 1422 Vegetative state, 1379-1380, 1381f clinical course of, 1379 versus coma, 1378-1379 diagnostic criteria for, 1379, 1379b etiology of, 1379 health-care decision making in, 2382 incidence of, 2382 management of, 1380 neuroimaging in, 1379-1380 persistent, 1395 euthanasia in, 2395 recovery from, 1380 traumatic brain injury and, 1433 Vein of Galen, 1782, 1782f abnormalities of, 38, 394-395, 1789, 1792-1793 magnetic resonance imaging of, 1792f treatment of, 1792-1793 Velocardiofacial syndrome, 443f, 450-451, 466t, 556t, 2224, 2287 cardiac involvement in, 2224 clinical features of, 442t, 450, 465t, 2224, 2225f genetics of, 442t, 450-451, 465t Venereal Disease Research Laboratory (VDRL), 1587 Venezuelan equine encephalitis virus, 1612 Venlafaxine, 954 for ADHD, 879t, 954 adverse effects of, 954 for autism, 925, 927t clinical applications of, 954 dosage of, 953t, 954 drug interactions of, 954 labeled and off-labeled use of, 938t pharmacodynamics of, 953t pharmacokinetics of, 953t pharmacology of, 954 preparations of, 953t Venous angiomas, 1793, 1793f Venous circulation, 1781-1782, 1782f Ventilation in hypoxic-ischemic injury, maintenance of, 290 in spinal cord injury, 1544 in status epilepticus, 1097 Ventral induction, 382 Ventral pallidum, 1272, 1273f Ventral suspension, of preterm infants, 54f-55f Ventricular catheter, for monitoring intracranial pressure, 1423, 1515-1516 Ventricular cisternostomy, for pineal region tumors, 1705 Ventricular fibrillation, 1471, 1491 Ventricular puncture, 158 for post-hemorrhagic hydrocephalus, 321 Ventricular tumors, 1707-1709 Ventricular zone, 398 Ventriculocele, 376

Ventriculomegaly and cerebral palsy, 322 definition of, 319 and hydrocephalus, 432 in hypoxic-ischemic injury, 281-282 in intraventricular hemorrhage, 315-316, 319 in post-hemorrhagic hydrocephalus, 321-322 Ventriculoperitoneal shunting, 431-432 Ventriculostomy, for hydrocephalus, 431 Verapamil, for cluster headache, 1199 Verbal auditory agnosia, 849, 907, 1055 Verbal descriptive scale, for pain, 2375t Verbal dyspraxia, 849 Verbal pragmatics, 907t Vermis, 1241, 1242f Version, in focal seizures, 1041f, 1042 Vertebral artery, 1528, 1761f Vertebral artery dissection, 1769 Vertebral bodies, 1527, 1528f Vertebral-basilar artery system, 1761f Vertebrobasilar (basilar artery) migraine, 131-132, 1189, 1189t Vertex waves, in EEG sleep patterns, 224 Vertical supranuclear gaze palsy, 812b Vertical suspension response, 43t, 50, 67 Vertiginous seizures, 132, 1043 Vertigo, 123-133 acute, 124 acute paroxysmal, with hearing loss, 128-130, 129t assessment of, 124-128 caloric testing in, 24, 123-124, 127b, 128 electronystagmography in, 126-128, 127b neurologic examination in, 125 neurotologic examination in, 128 neurovestibular examination in, 125-128 nystagmus evaluation in, 125-126 postural and equilibrium reactions in, 126 rotatory test in, 126-128, 127b in basilar artery migraine, 1189 benign paroxysmal, 124-126, 130-131, 1191, 1213 treatment of, 1213, 1213t definition of, 123 diagnosis of, 128-133, 128b, 129t, 130f differential diagnosis of, 133 versus dizziness, 124 drug-induced, 133 with epilepsy, 132 management of, 128-133 in neurofibromatosis type 2, 132, 776-777 paroxysmal, without hearing loss, 130-133 positional, 124 recurrent paroxysmal, without hearing loss, 129t unremitting (chronic), 124-125, 129t without neurologic abnormalities, 133 with neurologic signs, 132-133 Very long chain fatty acids, in adrenoleukodystrophy, 748 Very low birth weight, and neurodevelopmental disability, 309 Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, 724, 2024-2025, 2041 Vestibular nerve, 123 Vestibular neuritis, 130 Vestibular schwannoma, in neurofibromatosis type 2, 776-777, 776f Vestibular system, 123-133 anatomy and physiology of, 123-124 assessment of blindfolded tandem gait in, 125b, 126 caloric testing in, 24, 123-124, 127b, 128 electronystagmography in, 126-128, 127b in infant, 44 neurologic examination in, 125 Volume 1: pages 1–1180

Vestibular system continued neurotologic examination in, 128 neurovestibular examination in, 124-128 nystagmus evaluation in, 123, 125-126 past pointing in, 125b, 126 postural and equilibrium reactions in, 126 righting response in, 125b, 126 Romberg test in, 125b, 126 rotatory test in, 126-128, 127b stepping test in, 125b, 126 dysfunction of central clinical testing of, 125, 125b signs and symptoms of, 125b diagnosis of, 128-133, 128b, 129t, 130f differential diagnosis of, 133 drug-induced, 133 with epilepsy, 132 with hearing loss, 103, 111-112, 124-125, 128-130 management of, 128-133 in neurofibromatosis type 2, 132, 776-777 peripheral clinical testing of, 125, 125b signs and symptoms of, 124, 124b in poisoning/intoxication, 2177 Vestibule (ear), 97-98, 98f Vestibulocerebellum, 1243 Vestibulogenic seizures, 132 Vibration-induced nystagmus, 124 Vici’s syndrome, clinical features of, 389t Video conferencing, 2406 Video-EEG monitoring, 240-241, 263 Vigabatrin adverse effects of, 271, 1123 bioavailability of, 1107t, 1116 dosage of, 1109t elimination of, 1109t, 1116 exacerbation of myoclonic seizures by, 1031, 1074t formulations of, 1107t for infantile spasms, 1068 mechanism of action, 1003, 1004f, 1119t in mentally retarded patients, 815 metabolism of, 1109t neonatal use of, 271 optimal range of, 1117t pharmacokinetics of, 1107t, 1109t, 1116 protein binding of, 1109t routes of administration, 1107t for stiff person syndrome, 2106 and vision loss, 86 volume of distribution, 1109t, 1116 Vimentin, 1688-1691, 1845 Vinblastine toxicity, 2192-2193 Vinca alkaloid toxicity, 2192 Vincristine for astrocytoma, 1721 and autonomic dysfunction, 2149 for ependymoma, 1715-1716, 1729 for medulloblastoma, 1711, 1729 and neuropathy, 1910, 2177 for oligodendroglioma, 1724 for optic pathway tumors, 1703 for pineal region tumors, 1705 for primitive neuroectodermal tumors, 1723, 1729 and seizures, 1737 for spinal cord tumors, 1734 toxicity of, 2192-2193 and vision loss, 91-92 Vinculin, 1843 Vineland Adaptive Behavior Scales, 804t, 805, 1395-1396 Vinorelbine toxicity, 2192-2193 Vinyl chloride, teratogenicity of, 2197t

Volume 2: pages 1181–2408

Index Viral infections, 1595-1623, 1595b. See also specific infections CSF analysis in, 1600-1601, 1600t, 1602, 1602t diagnostic evaluation of, 1600-1602 electrodiagnostic studies in, 1601 encephalitis in, 1597, 1597b epidemiology of, 1598-1600 general considerations in, 1595-1596 intrauterine, 1597-1598, 1598b meningitis in, 1596-1597, 1597b microbiologic evaluation of, 1602, 1602t mortality and morbidity in, 1603t and myopathy, 2075, 2075b, 2080-2083 neuroimaging in, 1601-1602 neurologic manifestations of, 1596-1598, 1597b-1598b outcome of, 1603t pathogenesis of, 1595-1596 perinatal, 1597-1598 slow, 1598 and stroke, 1767 supportive care in, 1603 treatment of, 1602-1603 vaccines against, 1595, 1596f Viral replication, 1595-1596 Virions, 1595 Virtue, 2390 Viscerocranium, 436 Visible Human Project, 2404 Vision color, assessment of, 79 delayed maturation of, 86-87 development of, 77 with hearing loss, assessment of, 111-112 Vision loss, 77-93 with brain tumor, 1694 cerebral, 91-92 cerebral palsy and, 495 in children, 87-91 differential diagnosis of, 87 examination for, 81 ocular anomalies causing, 88-89 patients feigning, 92 signs and symptoms of, 87 transient episodic, 92 with transsynaptic degeneration, 91 clinical features associated with, 80-81 craniosynostosis and, 454 in developmental disorders, 838t-839t drug-induced, 91-92 electroretinography in, 245-246 in fibrous dysplasia, 458 in hypertensive encephalopathy, 2239 in infants, 81-87 behavioral manifestations of, 82 clinical manifestations of, 81-82 with cortical visual impairment, 85-87 diagnostic evaluation of, 87 differential diagnosis of, 82 with epilepsy, 86 with structural anomalies, 82-85 with structural cerebral anomalies, 86-87 in inflicted neurotrauma, 1448-1449 laterality of, 80-81 in meningeal leukemia, 1735-1736 in multiple sclerosis, 1347 in osteopetrosis, 456-457 in poisoning, 2175 in polyarteritis nodosa, 1820 in systemic lupus erythematosus, 1811 temporal nature of, 80-81 visual evoked responses in, 244-245 vitamin A deficiency and, 2306 Vision perception disorders, EEG findings in, 236

Visual acuity assessment of, 77-79 in infant, 77-78 in older child, 22, 78-79 electrophysiologic test of, 78 HOTV test of, 78, 79f preferential looking test of, 78, 78f quantification of, 77-78 Snellen chart for, 20, 78-79, 79f tumbling E test of, 78, 79f Visual agnosia, 822t Visual analog scale, for pain, 2375t Visual aura, in migraine, 1188 Visual evoked potential, 78 in brain tumor, 1696 in coma, 1392 in hypoxic-ischemic injury, 283 in multiple sclerosis, 1348-1349 Visual field, assessment of, 20, 79-80 Visual seizures, 1042-1043 Visual theory, of dyslexia, 856 Visual-evoked responses, 244-245, 245f Vitamin(s). See also specific types deficiencies of in dialysis patients, 2246 disorders associated with, 2304-2321 definition of, 2304 dependency disorders, 2305t diversity of, 2304 excess of, disorders associated with, 2304-2321 Vitamin A (retinol), 2305-2307 deficiency of, 2306 physiologic functions of, 2305 recommended daily requirement for, 2305 teratogenicity of, 2182t, 2198, 2306-2307 toxicity of, 2306 Vitamin B1 (thiamine), 2307-2308 deficiency of, 1384-1385, 1906, 2307-2308 in dialysis patients, 2246 dependency disorders of, 2305t, 2308 in maple syrup urine disease, 577, 579, 2308 physiologic functions of, 2307 in pyruvate dehydrogenase deficiency, 730, 2308 recommended daily requirement for, 2307 Vitamin B2 (riboflavin), 2308-2309 deficiency of, 2308 dependency disorders of, 2305t, 2308-2309 recommended daily requirement for, 2308 supplementation for acyl-CoA dehydrogenase deficiency, 724-725 for fatty acid oxidation defects, 2047 for glutaric aciduria type 1, 595, 2308-2309 Vitamin B3 (niacin), 2309-2310 deficiency of, 1385, 2309-2310 dependency disorders of, 2305t, 2310 dietary sources of, 2309 physiologic functions of, 2309 recommended daily requirement for, 2309 Vitamin B6 (pyridoxine), 2310-2311 for L-amino acid decarboxylase deficiency, 763 deficiency of, 2310 in dialysis patients, 2246 and encephalopathy, 357-358 dependency disorders of, 357-358, 357f, 2305t, 2310-2311 dietary sources of, 2310 for early infantile epileptic encephalopathy, 268 for hyperoxaluria, 751 intoxication, 2311 for McArdle’s disease, 2031 physiologic functions of, 2310 Volume 1: pages 1–1180

Volume 2: pages 1181–2408

ciii

Vitamin B6 (pyridoxine) continued polyneuropathy induced by, 1909-1910 recommended daily requirement for, 2310 for tuberculous meningitis, 1586 Vitamin B12 (cobalamin), 2311-2313 absorption of, 2311-2312 and cognitive functioning, 2313 in cystathionine β-synthase deficiency, 582-583 deficiency of, 582f, 2312-2313 in dialysis patients, 2246 in methylmalonic acidemia, 586f, 587 neuroimaging in, 187, 2312-2313 in peripheral neuropathy, 1906, 2313 dependency disorders of, 2305t, 2313 for methionine synthase deficiency, 583 for methylmalonic acidemia, 588 recommended daily requirement for, 2312 Vitamin C (ascorbic acid), 2313-2314 absorption of, 2313-2314 deficiency of, 2314 dietary sources of, 2313 physiologic functions of, 2313 recommended daily requirement for, 2314 Vitamin D, 2314-2316 antiepileptic agents and, 1124, 2315 deficiency of, 2315 dependency disorders of, 2315-2316 intoxication, 2316 metabolism of, 2314-2315 physiologic functions of, 2314 Vitamin E (tocopherol), 2316-2317 in abetalipoproteinemia, 1907, 2316-2317 absorption of, 2316 deficiency of, 2316-2317 ataxia in, 1247t, 1251, 2316 for intraventricular hemorrhage prevention, 324 for neuronal ceroid lipofuscinosis, 703 physiologic functions of, 2316 recommended daily requirement for, 2316 Vitamin H (biotin), 2317 deficiency of, 590-591, 723, 2317 clinical manifestations of, 590, 2317 diagnosis of, 590 etiology of, 590, 2317 laboratory findings in, 590, 2317 treatment of, 590-591, 730, 2317 dependency disorders of, 2317 physiologic functions of, 2317 recommended daily requirement for, 2317 Vitamin K, 2317-2318 deficiency of, 2318 in intracranial hemorrhage, 332, 2318 dietary sources of, 2317 physiologic functions of, 2317-2318 Vitamin M. See Folate VNTR repeats, 518-519 Vocal tics, 887, 1298 Vocational planning, in epilepsy, 1177 Vogt-Spielmeyer disease, 1072t, 1073 Voiding cystourethrography, 2164 Vojta response, 43t Volatile solvent poisoning, 2186 Voltage-gated ion channels, 992-994, 994t Volume of distribution, 1109-1110 Vomiting brain tumors and, 1725-1726 cyclical, syndrome of, 1184, 1186b, 1191, 1213t, 1216-1217, 2285-2286 in mental retardation/developmental delay, 813b physiology of, 2285-2286 postconcussive, 1415 Von Frey hairs, in peripheral neuropathy, 2248

civ

Index

von Gierke’s disease. See Glucose-6phosphatase deficiency von Hippel-Lindau syndrome, 784-786 classification of, 771 clinical features of, 771t, 784-785, 785f cutaneous features of, 771t genetics of, 785 hemangioblastoma in, 784-785, 785f management of, 785 pathology of, 785, 785f Voriconazole for aspergillosis, 1638 for candidiasis, 1638 for phycomycosis, 1640

W Waardenburg syndrome, 105t, 107, 443f, 2287 Wada test, 1162 versus functional MRI, 194 Waddling gait, 67, 74, 1864 Wafers, for drug delivery, 1746 WAGR association, 556t, 557 “Waiter’s tip” position, in Erb’s palsy, 340 Wakefulness, 1225. See also Sleep-wake disorder(s) in consciousness, 1377 maintenance of, test of, 1228 Waking patterns, in EEG, 218-219, 219f-220f Walker falls, 1460 Walker-Warburg syndrome, 83, 86, 417-418, 1989t, 2003-2004 antenatal diagnosis of, 418 clinical features of, 377t, 417, 466t, 650t, 654, 2003-2004 functional defects in, 653-654 genetic testing for, 417-418 genetics of, 466t, 650t, 2004 management of, 418 MRI findings in, 416f O-mannose glycans in, 653f Walking. See also Gait in cerebral palsy, prognosis for, 500, 501f Wandering eye, 81 Warfarin, 1778 for deep vein thrombosis, 2363 drug interactions of, 2218 pediatric protocol for, 1778, 1778b for stroke, 1778 Water balance, 2123-2124 disorders of, 2123-2125, 2324-2326 ketogenic diet and, 1135-1136 and sodium levels, 349-351, 350t Water ingestion, for orthostatic hypotension, 2141, 2141f Water intoxication, 2234-2235 clinical features of, 2234 management of, 2234-2235 Watershed infarctions, 1764 Watershed zones, 1764 Weak central coherence theory, of autism, 911 Weaver-Smith syndrome, 408 Weber test, 100, 125 Websites, 2400-2404, 2402t-2404t academy and societal, 2401, 2402t journal, 2401, 2402t-2403t Wechsler Adult Intelligence Scale III (WAISIII), 805 Wechsler Intelligence Scale for Children (WISC), 802t, 805, 805t Wechsler Preschool and Primary Scale of Intelligence-Revised, 802t-803t, 805, 1396 Wedge fracture, spinal cord, 1529, 1529f, 1545f

Wee Functional Independence Measure, 1394-1396 Wegener’s granulomatosis, 1822 laboratory findings in, 1818t, 1822 neurologic manifestations of, 1818t, 1822 treatment of, 1822 Weight gain antiepileptic agents and, 1123 atypical neuroleptics and, 968 stimulants and, 942 Weight loss antiepileptic agents and, 1123 ketogenic diet and, 1143-1144 stimulants and, 942 Wellbutrin. See Bupropion Werdnig, Guido, 1862 Werdnig-Hoffmann syndrome, 1863-1864, 1863f Werner’s syndrome clinical features of, 560t genetics of, 560t Wernicke-Korsakoff syndrome, 2307 Wernicke’s aphasia, 822t Wernicke’s encephalopathy, 1384-1385 dialysis-associated, 2244 West Nile virus, 1613, 1615, 1874-1875 clinical features of, 1615, 1874 diagnosis of, 1615, 1875 epidemiology of, 1598, 1614f, 1615, 1874 intrauterine infection, 1615 outcome of, 1603t, 1615 pathologic features of, 1874-1875 treatment of, 1615 Western equine encephalitis, 1603t, 1612 West’s syndrome, 268, 1066-1070 “Wheelbarrow” maneuver, in muscle testing, 27, 45, 45f Wheelchairs, in spinal cord injury, 2357-2359 Whiplash injury, 1530 vestibular dysfunction with, 131 Whipple’s disease, 2285, 2292 Whitacre needle, 157, 157f White blood cells, in CSF, 159-160, 159t in intraventricular hemorrhage, 320 White matter cranial ultrasound of, 281 diffusion-weighted imaging of, 184, 187 disorders of, 1345-1370. See also specific disorders EEG findings in, 239 magnetic resonance imaging of, 176, 178f, 281 in mitochondrial disorders, 1368f, 1369 vanishing, 767, 1364-1366 White matter contusions, in inflicted neurotrauma, 1458, 1458f Whole-cell pertussis vaccine, 2348 Whole-killed vaccines, 2346-2348, 2346b Wide Range Achievement Test, Revised (WRAT-R), 865 Wildervanck malformation, 108t, 455 Williams’ syndrome, 466t, 556t, 2219, 2224-2225 Wilms’ tumor genitourinary abnormalities, and mental retardation (WAGR), 83 with ocular anomalies, 83-84 Wilson’s disease, 1291, 2299-2300 diagnosis of, 1291, 2299-2300 genetics of, 1291, 2299 versus Menkes’ disease, 1324t neuroimaging in, 175, 2300 neurologic manifestations of, 2299 pathology of, 2300 treatment of, 1291, 2300 tremor in, 1291 Volume 1: pages 1–1180

Wing Autistic Disorders Interview ChecklistRevised, 905 Withdrawal emergent tardive disorders, 1302 Wnt signaling family, 438 WNT2 gene, in autism, 920 Wobble position, in codon, 510-511 Wohlfart-Kugelberg-Welander syndrome, 1864 Wolf-Hirschhorn syndrome, 466t, 555t Wolfram’s disease, optic atrophy in, 91 Wolman’s disease, 683 Woodcock Reading Mastery Tests, 864 Woodcock-Johnson III, 864 Word attack reading test, 859f, 864 World Health Organization brain tumor classification of, 1691-1693, 1692t malnutrition definition of, 2302 World Wide Web, 2400-2401 Wormian bones, 437, 437t Wound botulism, 1963, 2182 Wrist extensors, testing of, 34t Wrist flexors, testing of, 34t Wrongful life claims, 536 Wryneck. See Torticollis Wyburn-Mason syndrome, 789-790 clinical features of, 771t, 789-790 management of, 790

X X chromosomes, 516, 541 fragility of, 559-561 Xanthochromia, 159-160 Xenon 133 angiography, in intraventricular hemorrhage, 311-312 Xenon computed tomography, in brain death, 1561 Xeroderma pigmentosum clinical features of, 560t genetics of, 560t XGPT1 gene, 654 X-inactivation, 513 X-linked adrenoleukodystrophy (XALD), 745-749 with Addison’s disease, 746t, 747 adolescent cerebral, 746, 746t adult cerebral, 746, 746t asymptomatic and presymptomatic, 746t, 747 biochemistry of, 746 childhood cerebral, 746, 746t, 747f classification of, 1345, 1346t clinical features of, 746 contiguous deletion syndrome of, 749 laboratory diagnosis of, 743t molecular basis of, 746 MRI findings in, 746, 747f, 749 pathogenesis of, 748 pathologic features of, 746 phenotypes of, 746, 746t versus Schilder’s disease, 1351 symptomatic heterozygotes in, 747-748 therapies of, 748-749 X-linked cardioskeletal myopathy and neutropenia (Barth’s syndrome), 592, 728, 1995, 2060 X-linked cutis laxa, 1321 X-linked dominant Charcot-Marie-Tooth disease, 1900-1901 X-linked hydrocephalus, 427-428 with stenosis of aqueduct of Sylvius, 427-428 X-linked inheritance, 532-534, 533f, 534t Sherman paradox in, 559 X-linked lissencephaly with abnormal genitalia (XLAG), 385t, 411f, 412-417 X-linked lysosomal storage diseases, 661

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Index X-linked mental retardation, 464t, 808-809, 809t X-linked metabolic disorders, 569 X-linked muscular dystrophy, late-onset. See Becker muscular dystrophy X-linked periventricular nodular heterotopia, 419-420 X-linked progressive deafness, 556t X-linked recessive Charcot-Marie-Tooth disease, 1901 X-linked spinal muscular atrophy with arthrogryposis, 1868t X-linked spinocerebellar ataxia, 1263-1264 X-linked vacuolar myopathy, 1995 X-linked vacuolar myopathy and cardiomyopathy. See Danon’s disease Xp deletion syndrome, 556t XXX aneuploidy, 555 Xylose-based glycans, 645 XYY aneuploidy, 555

Y Y chromosomes, 516, 541 Yale braces, 1544 Yale Children’s Inventory, 871 Yersinia myositis, 2082 Yohimbine, for orthostatic hypotension, 2142

Z Z disk, 1839-1840 Z lines, 1849-1850, 1849f Zarontin. See Ethosuximide Zavesca (miglustat), for Gaucher’s disease, 673 Zellweger spectrum disorders, 741-744. See also Infantile Refsum’s disease (IRD); Neonatal adrenoleukodystrophy (NALD); Zellweger’s syndrome

Zellweger’s syndrome, 361, 493, 739-744 bile acid synthesis in, 738, 743, 743t clinical features of, 741, 741f genetics of, 740, 740t laboratory diagnosis of, 742-744, 743t muscular tone in, 69 pathologic features of, 741 peroxisomes in, 735, 738-740, 740t prenatal diagnosis of, 744 treatment of, 744 vision loss with, 88t Zenapax (daclizumab), for multiple sclerosis, 1350 ZIC2 gene, and holoprosencephaly, 396, 398 Zidovudine, 1603 for HIV infection, 1622 and mitochondrial dysfunction, 729-730 myotoxicity of, 2081 Zileuton, for Sjögren-Larsson syndrome, 1367 Zinc deficiency of, 2323-2324 and neonatal seizures, 266 physiologic functions of, 2323 Zinc therapy, 2324 for Wilson’s disease, 1291, 2300 Zinc-finger transcription factor family, 438 Zinc-glucagon, for brancher enzyme deficiency, 633 Ziprasidone, 970-971 adverse effects of, 968, 970-971 clinical applications of, 970 clinical management of, 970 dosage of, 967t, 970 drug interactions of, 971 labeled and off-labeled use of, 938t pharmacology of, 970 receptor activity of, 967t for tic disorders, 896, 970 Zolmitriptan, for migraine, 1193t

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Volume 2: pages 1181–2408

Zoloft. See Sertraline “Zombie” effect, in stimulant therapy, 942 Zone electrophoresis, in congenital glycosylation disorders, 647 Zone of uncertainty, 801 Zonegran. See Zonisamide Zonisamide absorption of, 1116 adverse effects of, 1123-1124, 1176 behavioral and cognitive effects of, 1176 bioavailability of, 1107t, 1116 blood level of, 1051t dosage of, 1051t, 1109t for early infantile epileptic encephalopathy, 268 elimination of, 1109t, 1116 formulations of, 1107t for generalized seizures, 1023t for juvenile myoclonic epilepsy, 1073 and ketogenic diet, 1143 mechanism of action, 1003f, 1004, 1119t metabolism of, 1109t, 1116 for myoclonic seizures, 1023t, 1075 for myoclonus, 1295 for neuronal ceroid lipofuscinosis, 1333 optimal range of, 1117t pharmacokinetics of, 1107t, 1109t, 1116 practical guide to, 1051t preparations of, 1051t protein binding of, 1109t, 1116 in renal failure, action and effects of, 2267 routes of administration, 1107t testing of, 1002 volume of distribution, 1109t, 1116 Zyban. See Bupropion Zygomycosis, 1632t Zygotene, 514 Zyprexa. See Olanzapine

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